CYANOPYRROLE-SULFONAMIDE PROGESTERONE
RECEPTOR MODULATORS AND USES THEREOF
BACKGROUND OF THE INVENTION
Progesterone receptor (PR) agonists and antagonists, also termed PR
modulators, have been described for use in contraception and a variety of other
indications.
What are needed are novel PR modulators which are useful as contraceptives.
SUMMARY OF THE INVENTION
In one aspect, PR modulators are provided.
In still another aspect, uses of the compounds described herein for
contraception, hormone replacement therapy, inducing amenorrhea, synchronizing
estrus in livestock, and the treatment and/or prevention of benign and malignant
neoplastic disease, uterine myometrial fibroids, endometriosis, benign prostatic
hypertrophy, carcinomas and adenocarcinomas of the endometrium, ovary, breast,
colon, prostate, pituitary, meningioma and other hormone-dependent tumors,
dysmenorrhea, dysfunctional uterine bleeding, cycle-related symptoms, and
symptoms of premenstrual syndrome and premenstrual dysphoric disorder are
provided.
In another aspect, pharmaceutical compositions containing the PR modulator
are provided.
In a further aspect, pharmaceutical compositions are provided which contain
the PR modulator in combination with a progestin or estrogen.
Other aspects and advantages of the present invention are described further in
the following detailed description of the preferred embodiments thereof.
DETAILED DESCRIPTION OF THE INVENTION
Compounds useful for contraception, hormone replacement therapy,
synchronizing estrus, treating dysmenorrhea, treating dysfunctional uterine bleeding,
inducing amenorrhea, treating cycle-related symptoms, or treating symptoms of
premenstrual syndrome and premenstrual dysphoric disorder are provided.
1


A progesterone receptor modulator provided herein is characterized by having
the structure of formula I:
wherein:
Ri is selected from among:
H,
CN,
S02-C1-C6 alkyl, S02-C3-C8 cycloalkyl, S02-substituted CrC6 alkyl,
S02-aryl, S02-substituted aryl, SCh-heteroaryl, S02-heterocycle, SO2-C3-C6 alkenyl,
S02-C3-C6 alkynyl, S02-C3-C6 substituted alkenyl, SO2-C3-C6 substituted alkynyl,
C(0)-CrC6 alkyl, C(0)-C3-Cs cycloalkyl, C(0)-substituted CrC6
alkyl, C(0)-aryl, C(0)-substituted aryl, C(0)-heteroaryl, C(0)-heterocycle, C(0)-C3-
C6 alkenyl, C(0)-C3-C6 alkynyl, C(0)-substituted C3-C6 alkenyl, C(0)-substituted C3-
C(, alkynyl,
C(0)0-CrC6 alkyl, C(0)0-C3-C8 cycloalkyl, C(0)0-substituted C1-C6
alkyl, C(0)0-aryl, C(0)0-substituted aryl, C(0)0-heteroaryl, C(0)0-heterocycle,
C(0)0-C3-C6 alkenyl, C(0)0-C3-C6 alkynyl, C(0)0-C3-C6 substituted alkenyl,
C(0)0-C3-C6 substituted alkynyl,
C(0)NH~CrC6 alkyl, C(0)NH-C3-C8 cycloalkyl, C(0)N-di-C3-C8
cycloalkyl, C(0)N-di-C1-C6 alkyl, C(0)N-di-substituted C1-C6 alkyl, C(0)NH-
substituted C1-C6 alkyl, C(0)NH-aryl, C(0)N-di-aryl, C(0)NH-substituted aryl,
C(0)N-di-substituted aryl, C(0)NH-heteroaryl, C(0)NH-heterocycle, C(0)N-
diheteroaryl, C(0)N-diheterocycle, C(0)NH-C3-C6 alkenyl, C(0)NH-C3-C6 alkynyl,
C(0)NH-substituted C3-C6 alkenyl, and C(0)NH-substituted C3-C6 alkynyl; or
Ri is a linking group to a second structure of formula I to form a dimer of
formula I, said linking group selected from C(O)- or S(0)2-,
2

R2is selected from among H, C1-Ce alkyl, substituted C1-C6 alkyl, C3-C6
cycloalkyl, S02-alkyl, and S02-substituted alkyl;
provided that at least one of Ri or R2 contain a group having an S02- bound to
the N or Ri is a S(0)2- linking group; or
R, and R2 are joined to form -(C(R8)a(R9)b)e-S02-(C(R8)d(R9)e)r;
Rg and Rg are, independently, H, halogen, or Ci to CQ alkyl;
a and b are, independently, 0 to 2, provided that a + b = 2;
d and e are, independently, 0 to 2, provided that a + b = 2;
c and f are, independently, 0 to 5, provided that one of c or f is greater than 0;
R3,R4, R5 and Rg are independently selected from among H, halogen, CN, C1-
Q alkyl, substituted d-C6 alkyl, -(CHmXn)zCHpX<„ C3-C6 cycloalkyl, 0-C1-C6 alkyl,
O-C1-C6 substituted alkyl, O-CCHmXzCHpXq, aryl, heteroaryl, heterocycle,
substituted aryl, substituted heteroaryl, and substituted heterocycle;
X is halogen;
m and n are, independently, 0 to 2, provided that m + n = 2;
p and q are, independently, 0 to 3, provided that p + q = 3;
z is 0 to 10;
R7 is selected from the group consisting of H, Q-C6 alkyl, C(0)0-C1-C6 alkyl,
C2 to C6 alkenyl, C2 to Ce alkynyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and
substituted C3-C6 cycloalkyl.
In one embodiment, the compound has the structure of formula I, wherein:
Ri is H, S02-C1-C6 (substituted or unsubstituted) alkyl, S02-C3-C6
cycloalkyl, S02 (substituted or unsubstituted) aryl, S02-heteroaryl or CN;
R2 is H or C1-Cg (substituted or unsubstituted) alkyl;
R3, R4, R5 and R& are independently selected from H, halogen, C1-C6
(substituted or unsubstituted) alkyl, C3-C6 cycloalkyl, and O-C1-C6 (substituted or
unsubstituted) alkyl; and
R7 is H or C1-Ce alkyl.
In another embodiment, the compound has the structure of formula I, wherein:
Ri is H, S02-CrC4 alkyl or CN;
R2 is H;
3

R3, R}5 R5 and R$ are independently selected from H, halogen, CrC6
(substituted or unsubstituted) alkyl, and O-C1-C6 (substituted or unsubstituted) alkyl;
and
R7 is H or C1-C6 alkyl.
In another embodiment, the compound has the structure of formula I, wherein:
Ri is SO2-C1-C4 alkyl;
R2isH;
R3, R4, R5 and Rs are H; and
R7 is C1-C6 alkyl.
Thus, in one embodiment, compounds of formula I, wherein Rt or R2 is a SO2-
(substituted or unsubstituted) C1-C4 alkyl are provided.
In a further embodiment, N-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]propane-l -sulfonamide; N-[4-(5-cyano-l -methyl-lH-pyrrol-2-yl)phenyl]-
N-(methylsulfonyl)methane sulfonamide; N- [4-(5-cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl]butane-1 -sulfonamide; N-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)phenyl]-
2,2,2-trifluoroethanesulfonamide; N-[4-(5-cyano-l -methyl- lH-pyrrol-2-yl)phenyl]-4-
isopropylbenzenesulfonamide; N-[4-(5-cyano-l -methyl-lH-pyrrol-2-
yl)phenyl]benzenesulfonamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]-4-
methylbenzenesulfonamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]propane-
2-sulfonamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]ethanesulfonamide;
N-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)phenyl]methanesulfonamide; N- [4-(5 -cyano-
l-methyI-lH-pyrrol-2-yI)-2-fiuorophenyl]methanesulfonamide;N-[4-(5-cyano-l-
methyl-lH-pyrrol-2-yl)-2-fluorophenyl]emanesulfonamide;N-[4-(5-cyano-l-methyl-
lH-pyrrol-2-yl)-3-fluorophenyl]ethanesulfonamide;N-[4-(5-cyano-l-methyl-lH-
pyrrol-2-yl)-3-fluorophenyl]propane-l-sulfonamide;N-[4-(5-cyano-l-methyl-lH-
pyrrol-2-yl)-3-fluorophenyl]butane-l-sulfonaim'de;N-[4-(5-cyano-l-methyl-lH-
pyrrol-2-yl)-3-fluorophenyl]propane-2-sulfonamide;N-[4-(5-cyano-l-methyl-lH-
pyrroI-2-yl)-2,5-difluorophenyl]-methane-sulfonamide; N-[4-(5-cyano-1 -methyl-1H-
pyrrol-2-yl)-2,5-difluorophenyl]ethane-sulfonamide;N-[4-(5-cyano-l-methyl-lH-
pyrrol-2-yl)-2,5-difluorophenyl]propane-1 -sulfonamide; N-[4-(5-cyano-1 -methyl-1H-
pyrroi-2-yl)-2,5-difluorophenyl]butane-l-sulfonamide;N-[4-(5-cyano-l-methyl-lH-
pyrrol-2-yl)-2,5-difluorophenyl]propane-2-sulfonamide;N-[4-(5-cyano-l-methyl-lH-
4

pyrrol-2-yl)-3 -(trifluoromethyl)phenyl]niethane-sulfoiiamide; N-[4-(5 -cyano-1 -
methyl-lH-pyrrol-2-yl)-3-(trifluorome1hyl)phenyl]ethane-sulfonaEiiide;N-[4-(5-
cyano-l-metliyl-lH-pyrrol-2-yl)-3-(trifluoromethyl)phenyl]propane-l-sulfonamide;
N-[4-(5-cyano-1 -methyl-1 H-pyirol-2-yl)-3-(trifluoromethyl)plienyl]butane-1 -
sulfonamide; N-[4-(5-cyano-l-meth.yl-lH-pyrrol-2-yl)-3-
(trifluoromeihyl)phenyl]propane-2-sulfonamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-
2-yl)-2-(trifluoromethoxy)phenyl]memane-sulfonaimde;N-[4-(5-cyano-l-methyl-lH-
pyrrol-2-yl)-2-(trifluoromethoxy)phenyl]ethane-sulfonamide;N-[4-(5-cyano-l-
methyl- lH-pyrrol-2-yl)-2-(trifluoromethoxy)phenyl]propane-l -sulfonamide; N-(4-
bromophenyl)ethanesulfonamide; Tert-butyl 2-cyano-5-{4-
{(ethylsulfonyl)amino]plienyl}-lH-pyrrole-l-carboxylate;N-[4-(5-cyano-lH-pyrrol-
2-yl)phenyl]ethanesulfonamide;N-[4-(5-cyano-l-ethyl-lH-pyrrol-2-
yl)phenyl]ethanesulfonamide; N-[4-(5-cyano-l -propyl-lH-pyrrol-2-
yl)phenyl]ethanesulfonamide;N-[4-(l-butyl-5-cyano-lH-pyrrol-2-
yl)phenyl]ethanesulfonamide;N-[4-(l-allyl-5-cyano-lH-pyrrol-2-
yl)phenyl]ethanesulfonamide;N-[4-(5-cyano-l-prop-2-yn-l-yl-lH-pyrrol-2-
yl)phenyl]ethanesulfonamide;N-{4-[5-cyano-l-(3-phenylpropyl)-lH-pyrrol-2-
yljphenyl}ethanesulfonamide;N-[3-cyano-4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]methanesulfonamide;N-[3-cyano-4-(5-cyano-l-methyHH-pyrrol-2-
yl)phenyl] ethanesulfonamide; N-[3-cyano-4-(5-cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl]propane-1 -sulfonamide; N-[2-cyano-4-(5-cyano-1 -methyl-lH-pyrrol-2-
yl)phenyl]methanesulfonamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3,5-
difluorophenyl]-methanesulfottamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-355-
difluorophenyl]ethane-sulfonamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3,5-
difluorophenyl]propane-l-sulfonamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3,5-
difluorophenyl]butane-l-sulfonamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
fiuorophenyl]methanesulfonamide, or a pharmaceutically acceptable salt, tautomer,
metabolite, or prodrug thereof are provided.
The compounds can contain one or more asymmetric centers and can thus give
rise to optical isomers and diastereomers. While shown without respect to
stereochemistry, the compounds can include optical isomers and diastereomers;
5

racemic and resolved enantiomerically pure R and S stereoisomers; other mixtures of
the R and S stereoisomers; and pharmaceutically acceptable salts thereof.
The term "alkyl" is used herein to refer to both straight- and branched-chain
saturated aliphatic hydrocarbon groups. In one embodiment, an alkyl group has 1 to
about 8 carbon atoms (i.e., Ci, C2, C3, C4, C5 C6, C7, or Cg). In another embodiment,
an alkyl group has 1 to about 6 carbon atoms (i.e., C\, C2, C3, C4, C5 or C6). In a
further embodiment, an alkyl group has 1 to about 4 carbon atoms (i.e., Ci, C2, C3, or
C4).
The term "cycloalkyl" is used herein to refer to cyclic, saturated aliphatic
hydrocarbon groups. In one embodiment, a cycloalkyl group has 3 to about 8 carbon
atoms (i.e., C3, C4, C5, Cg, C7, or Cg). In another embodiment, a cycloalkyl group has
3 to about 6 carbon atoms (i.e., C3, C4, C5 or Ce).
The term "alkenyl" is used herein to refer to both straight- and branched-chain
alkyl groups having one or more carbon-carbon double bonds. In one embodiment,
an alkenyl group contains 3 to about 8 carbon atoms (i.e., C3, C4, C5, C6, C7, or Cg).
In another embodiment, an alkenyl groups has 1 or 2 carbon-carbon double bonds and
3 to about 6 carbon atoms (i.e., C3, C4, C5 or Ce).
The term "alkynyl" group is used herein to refer to both straight- and
branched-chain alkyl groups having one or more carbon-carbon triple bonds. In one
embodiment, an alkynyl group has 3 to about 8 carbon atoms (i.e., C3, C4, C5, C6, C7,
or Cg). In another embodiment, an alkynyl group contains 1 or 2 carbon-carbon triple
bonds and 3 to about 6 carbon atoms (i.e., C3, C4, C5, or C6).
The terms "substituted alkyl", "substituted alkenyl", "substituted alkynyl", and
"substituted cycloalkyl" refer to alkyl, alkenyl, alkynyl, and cycloalkyl groups,
respectively, having one or more substituents including, without limitation, halogen,
CN, OH, NO2, amino, aryl, heterocyclic groups, aryl, alkoxy, aryloxy, alkyloxy,
alkylcarbonyl, alkylcarboxy, amino, and arylthio.
The term "aryl" as used herein refers to an aromatic, carbocyclic system, e.g.,
of about 6 to 14 carbon atoms, which can include a single ring or multiple aromatic
rings fused or linked together where at least one part of the fused or linked rings
forms the conjugated aromatic system. The aryl groups include, but are not limited
6

to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, indene,
benzonaphthyl, and fluorenyl.
The term "substituted aryl" refers to an aryl group which is substituted with
one or more substituents including halogen, CN, OH, N02, amino, alkyl, cycloalkyl,
alkenyl, alkynyl, alkoxy, aryloxy, alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino,
and arylthio, which groups can be substituted. Desirably, a substituted aryl group is
substituted with 1 to about 4 substituents.
The term "heterocycle" or "heterocyclic" as used herein can be used
interchangeably to refer to a stable, saturated or partially unsaturated 3- to 9-
membered monocyclic or multicyclic heterocyclic ring. The heterocyclic ring has in
its backbone carbon atoms and one or more heteroatoms including nitrogen, oxygen,
and sulfur atoms. In one embodiment, the heterocyclic ring 1 to about 4 heteroatoms
in the backbone of the ring. When the heterocyclic ring contains nitrogen or sulfur
atoms in the backbone of the ring, the nitrogen or,sulfur atoms can be oxidized. The
term "heterocycle" or "heterocyclic" also refers to multicyclic rings in which a
heterocyclic ring is fused to an aryl ring of about 6 to about 14 carbon atoms. The
heterocyclic ring can be attached to the aryl ring through a heteroatom or carbon atom
provided the resultant heterocyclic ring structure is chemically stable. In one
embodiment, the heterocyclic ring includes multicyclic systems having 1 to 5 rings.
A variety of heterocyclic groups are known in the art and include, without
limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing
rings, mixed heteroatom-containing rings, fused heteroatom containing rings, and
combinations thereof. Examples of heterocyclic groups include, without limitation,
tetrahydrofuranyl, piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, morpholinyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, pyranyl, pyronyl, dioxinyl, piperazinyl,
dithiolyl, oxathiolyl, dioxazolyl, oxathiazolyl, oxazinyl, oxathiazinyl, benzopyranyl,
benzoxazinyl and xanthenyl.
The term "heteroaryl" as used herein refers to a stable, aromatic 5- to 14-
membered monocyclic or multicyclic heteroatom-containing ring. The heteroaryl ring
has in its backbone carbon atoms and one or more heteroatoms including nitrogen,
oxygen, and sulfur atoms. In one embodiment, the heteroaryl ring contains 1 to about
4 heteroatoms in the backbone of the ring. When the heteroaryl ring contains nitrogen
7

or sulfur atoms in the backbone of the ring, the nitrogen or sulfur atoms can be
oxidized. The term "heteroaryl" also Tefers to multicyclic rings in which a heteroaryl
ring is fused to an aryl ring. The heteroaryl ring can be attached to the aryl ring
through a heteroatom or carbon atom provided the resultant heterocyclic ring structure
is chemically stable. In one embodiment, the heteroaryl ring includes multicyclic
systems having 1 to 5 rings.
A variety of heteroaryl groups are known in the art and include, without
limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing
rings, mixed heteroatom-containing rings, fused heteroatom containing rings, and
combinations thereof. Examples of heteroaryl groups include, without limitation,
furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazinyl, azepinyl, thienyl, dithiolyl, oxathiolyl, oxazolyl, tbiazolyl,
oxadiazolyl, oxatriazolyl, oxepinyl, thiepinyl, diazepinyl, benzofuranyl, thionapthene,
indolyl, benzazolyl, purindinyl, pyranopyrrolyl, isoindazolyl, indoxazinyl,
benzoxazolyl, quinolinyl, isoquinolinyl, benzodiazpnyl, napthylridinyl, benzothienyl,
pyridopyridinyl, acridinyl, carbazolyl, and purinyl rings.
The term "substituted heterocycle" and "substituted heteroaryl" as used herein
refers to a heterocycle or heteroaryl group having one or more substituents including
halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy,
alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio. A substituted
heterocycle or heteroaryl group may have 1, 2, 3, or 4 substituents.
The term "arylthio" as used herein refers to the S(aryl) group, where the point
of attachment is through the sulfur-atom and the aryl group can be substituted as
noted above. The term "alkoxy" as used herein refers to the O(alkyl) group, where
the point of attachment is through the oxygen-atom and the alkyl group can be
substituted as noted above. The term "aryloxy" as used herein refers to the O(aryl)
group, where the point of attachment is through the oxygen-atom and the aryl group
can be substituted as noted above.
The term "alkylcarbonyl'" as used herein refers to the C(0)(alkyl) group,
where the point of attachment is through the carbon-atom of the carbonyl moiety and
the alkyl group can be substituted as noted above.
8

The term "alkylcarboxy" as used herein refers to the C(0)0(alkyl) group,
where the point of attachment is through the carbon-atom of the carboxy moiety and
the alkyl group can be substituted as noted above.
The term "alkylamino" as used herein refers to both secondary and tertiary
amines where the point of attachment is through the nitrogen-atom and the alkyl
groups can be substituted as noted above. The alkyl groups can be the same or
different.
The term "halogen" as used herein refers to CI, Br, F, or I groups.
The compounds encompass tautomeric forms of the structures provided herein
characterized by the bioactivity of the drawn structures. Further, the compounds can
be used in the form of salts derived from pharmaceutically or physiologically
acceptable bases, alkali metals and alkaline earth metals.
Pharmaceutically acceptable salts may be formed from inorganic bases,
desirably alkali metal salts, for example, sodium, lithium, or potassium, and organic
bases, such as ammonium, mono-, di-, and trimethylammomum, mono-, di- and
triethylammonium, mono-, di- and tripropylammonium (iso and normal), ethyl-
dimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzyl-
ammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium,
piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-isopropylpyrrolidinium,
1,4-dimethylpiperazinium, 1-n-butyl piperidinium, 2-methylpiperidinium, l-ethyl-2-
methylpiperidinium, mono-, di- and triethanolammonium, ethyl diethanolammonium,
n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium, phenylmono-
ethanolammonium, and the like. Physiologically acceptable alkali salts and alkaline
earth metal salts can include, without Hmitation, sodium, potassium, calcium and
magnesium salts in the form of esters, and carbamates.
Other conventional "pro-drug" forms can also be utilized which, when
delivered in such form, convert to the active moiety in vivo. Such other compounds
can be in the form of esters, carbamates and other conventional "pro-drug" forms,
which, when administered in such form, convert to the active moiety in vivo. In one
embodiment, the prodrugs are esters. See, e.g., B. Testa and J. Caldwell, "Prodrugs
Revisited: The "Ad Hoc" Approach as a Complement to Ligand Design", Medicinal
Research Reviews, 16(3):233-241, ed., John Wiley & Sons (1996).
9

As described herein, the compounds of formula I and/or salts, prodrugs or
tautomers thereof, are delivered in regimens for contraception, therapeutic or
prophylactic purposes, as described herein.
The compounds discussed herein also encompass "metabolites" which are
unique products formed by processing the compounds by the cell or patient.
Desirably, metabolites are formed in vivo.
The compounds are readily prepared by one of skill in the art according to the
following schemes from commercially available starting materials or starting
materials which can be prepared using literature procedures. These schemes show the
preparation of representative compounds. Variations on these methods, or other
methods known in the art, can be readily utilized by one of skill in the art given the
information provided herein.

According to scheme 1, an appropriately substituted bromoaniline (1) is
converted into compound 3 under the action of a palladium catalyst and a suitable
coupling partner such as a boronic acid or tin derivative. The aniline may also be a
chloro, iodo, or sulfonate derivative. The coupling partner may be formed in situ
from the pyrrole (7) and lithium diisopropylamide and a trialkyl borate or may be the
pre-formed boronic acid (2) as described in co-owned US Patent Application
Publication No. US-2005-0272702-A1, which is hereby incorporated by reference.
The source of palladium is normally tetraJds(triphenylphosphine) palladium (0) or
another suitable source such as palladium dibenzylidene acetone in the presence of
tributylphosphine (Fu, G. C. et al. Journal of the American Chemical Society, 2000,
122, 4020). Alternate catalyst systems are described in Hartwig, et al. Journal of
10

Organic Chemistry, 2002,67,5553. A base is also required in the reaction; the
normal choices are sodium or potassium carbonate, cesium fluoride, potassium
fluoride, or potassium phosphate. The choice of solvents includes tetrahydrofuran
(THF), dimethoxyethane (DME), dioxane, ethanol, water, and toluene. Depending on
the reactivity of the coupling partners and reagents, the reaction may be conducted up
to the boiling point of the solvent, or may indeed be accelerated under microwave
irradiation, if necessary.
Compounds 4, where Ri includes an amide, are readily accessible from
compounds 3 by reaction with a wide variety of electrophilic reagents including acid
chlorides and carboxylic acids combined with an activating reagent such as
dicyclohexyl-carbodiimide (DCC), iV-(3-Dimemylaminopropyl)-A'-emylcarbodiimide
hydrochloride (EDC), benzotriazol-l-yl-oxytripyrrohdinophosphonium
hexafluorophosphate (the PyBOP® reagent); or for further examples see, e.g., R.C.
Larock, "Comprehensive Organic Transformations", Second Edition, John Wiley &
Sons (1999). Compounds 4, where Ri includes a carbamate, are readily accessible
from 3 by reaction with a wide variety of electrophilic reagents including
chloroformates or activated carbonates. Compounds 4, where Ri includes a
sulfonamide, are readily accessible from compounds 3 by reaction with a wide variety
of electrophilic reagents including sulfonyl chlorides or sulfonic acids combined with
an activating reagent. Compounds 4, where Ri includes a cyanamide, are readily
accessible from compounds 3 by reaction with electrophilic reagents such as
cyanogen bromide. Compounds 4, where Ri includes a urea, are readily accessible
from compounds 3 by reaction with a wide variety of electrophilic reagents including
phosgene (followed by reaction with an amine), carbamoyl chlorides, and isocyanates.
These reactions are conducted in a suitable solvent including methylene chloride,
THF, dimethylformamide (DMF), or pyridine in the presence of an amine base such
as pyridine, triethylamine, or diisopropylethyl amine. Metal salts including sodium
carbonate, cesium carbonate, potassium carbonate, are also suitable bases for the
reaction. The aniline 3 may also be pretreated with a strong base, including alkyl
lithium bases, potassium tertiary butoxide, sodium hexamethyldisilazide and similar
bases in an aprotic solvent such as ether or THF and then reacted with the
electrophilic reagent. Alternatively, the aniline 3 maybe directly dissolved in an acid
11

chloride, sulfonyl chloride, or chloroformate in the absence of solvent or base to
generate compounds 4.
12
Compounds 5 are readily accessible from compounds 4 by reaction with a
wide variety of electrophilic reagents such as acid chlorides, sulfonyl chlorides,
chloroformates, cyanogen bromide, isocyanates, and alkylating agents. Alkylating
agents are commonly comprised of an alkane possessing a suitable leaving group such
as a bromide, iodide, chloride, or sulfonate. Common examples of alkylating agents
are methyl iodide, benzyl bromide, propyl bromide, allyl chloride, and propargyl
bromide. The corresponding carboxylic acid or sulfonic acid derivative and a suitable
activating reagent can also be reacted with compounds 4 to give compounds 5. These
reactions are conducted in a suitable solvent including methylene chloride, THF,
DMF, or pyridine in the presence of an amine base such as pyridine, triethylamine, or
diisopropylethyl amine. Metal salts including sodium carbonate, cesium carbonate, or
potassium carbonate are also suitable bases for the reaction. The aniline derivative 4
may also be pretreated with a strong base, including an alkyl Hthiurn base, potassium
tertiary butoxide, sodium hexamethyldisilazide and similar bases in an aprotic solvent
such as ether or THF and then reacted with the electrophilic reagent. Alternatively
the aniline derivative 4 may be directly dissolved in an acid chloride, sulfonyl
chloride, or chloroformate in the absence of solvent or base to generate compounds 5.


An alternative method for the production of compounds 4 and 5 is shown in
Scheme 2. Compounds 8, where Ri includes an amide, are readily accessible from
aniline 1 by reaction with a wide variety of electrophilic reagents including acid
chlorides and carboxylic acids combined with an activating reagent. Compounds 8,
where Ri includes a carbamate, are readily accessible from aniline 1 by reaction with
a wide variety of electrophilic reagents including chloroformates or activated
carbonates. Compounds 8, where Ri includes a sulfonamide, are readily accessible
from aniline 1 by reaction with a wide variety of electrophilic reagents including
sulfonyl chlorides or sulfonic acids combined with an activating reagent such as PCI5,
POCl3, DCC, EDC, the PyBOP® reagent, or for further examples see, e.g., R.C.
Larock, "Comprehensive Organic Transformations", Second Edition, John Wiley &
Sons (1999). Compounds 8, where Ri includes a cyanamide, are readily accessible
from aniline 1 by reaction electrophilic reagents such as cyanogen bromide.
Compounds 8, where Ri includes a urea, are readily accessible from aniline 1 by
reaction with a wide variety of electrophilic reagents including phosgene, triphosgene,
diphosgene, carbonyl diimidazole, carbamoyl chlorides, and isocyanates. These
reactions are conducted in a suitable solvent including methylene chloride, THF,
DMF, or pyridine in the presence of an amine base such as pyridine, triemylarnine, or
diisopropylethyl amine. Metal salts including sodium carbonate, cesium carbonate, or
potassium carbonate are also suitable bases for the reaction. The aniline 1 may also
be pretreated with a strong base, including alkyl lithium bases, potassium tertiary
butoxide, sodium hexamethyldisilazide and similar bases in an aprotic solvent such as
ether or THF and then reacted with the electrophilic reagent. Alternatively the aniline
1 may be directly dissolved in an acid chlorides, sulfonyl chlorides, or chloroformate
in the absence of solvent or base to generate compounds 8.
Bromoaniline compounds 9 are readily accessible from substituted
bromoaniline compounds 8 by reaction with a wide variety of electrophilic reagents
such as acid chlorides, sulfonyl chlorides, chloroformates, cyanogen bromide,
isocyanates, and alkylating agents. Alkylating agents are commonly comprised of an
alkane possessing a suitable leaving group such as a bromide, iodide, chloride, or
sulfonate. Common examples of alkylating agents are methyl iodide, benzyl bromide,
propyl bromide, allyl chloride, and propargyl bromide. The corresponding carboxylic
13

acid or sulfonic acid derivative and a suitable activating reagent can also be reacted
with compounds 8 to give compounds 9. These reactions are conducted in a suitable
solvent including methylene chloride, THF, DMF, or pyridine in the presence of an
amine base such as pyridine, triethylamine, or diisopropylethyl amine. Metal salts
including sodium carbonate, cesium carbonate, or potassium carbonate are also
suitable bases for the reaction. The aniline derivative 8 may also be pretreated with a
strong base, including alkyl Uthium bases, potassium tertiary butoxide, sodium
hexamethyldisilazide and similar bases in an aprotic solvent such as ether or THF and
then reacted with the electrophilic reagent. Alternatively the aniline derivative 8 may
be directly dissolved in an acid chloride, sulfonyl chloride, or chloroformate in the
absence of solvent or base to generate compounds 9.
The substituted bromoaniline 8 or bromoaniline 9 is converted into compound
4 or compound 5 respectively, under the action of a palladium catalyst and a suitable
coupling partner such as a boronic acid or tin derivative. The aniline may also be a
chloro, iodo, or sulfonate derivative. The coupling partner may be formed in situ
from the pyrrole (7) (see, scheme 1) and lithium diisopropylamide and a trialkyl
borate or may be the pre-formed boronic acid (2). The source of palladium is
normally tetrakis(triphenylphosphine) palladium (0) or another suitable source such as
palladium dibenzylidene acetone in the presence of tributylphosphine (Fu, G. C. et al.
Journal of the American Chemical Society, 2000,122,4020, for alternate catalyst
systems see also Hartwig, J. F. etal. Journal of Organic Chemistry, 2002, 67, 5553).
A base is also required in the reaction and the normal choices are sodium or
potassium carbonate, cesium fluoride, potassium fluoride, or potassium phosphate.
The choice of solvents includes THF, dimethoxyethane, dioxane, ethanol, water, and
toluene. Depending on the reactivity of the coupling partners and reagents, the
reaction may be conducted up to the boiling point of the solvents, or may indeed be
accelerated under microwave irradiation, if necessary.
Also described are pharmaceutical compositions containing one or more
compounds discussed herein and a pharmaceutically acceptable carrier or excipient.
These compounds and compositions can be used in methods of treatment which
include administering to a mammal a pharmaceutically effective amount of one or
more compounds as described above as modulators of the progesterone receptor.
14

The compounds can be utilized in methods of contraception, hormone
replacement therapy, and the treatment and/or prevention of benign and malignant
neoplastic disease, uterine myometrial fibroids, endometriosis, benign prostatic
hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast,
colon, prostate, pituitary, meningioma and other hormone-dependent tumors,
dysmenorrhea, dysfunctional uterine bleeding, cycle-related symptoms, and
symptoms of premenstrual syndrome and premenstrual dysphoric disorder; and for
inducing amenorrhea. Additional uses of the present progesterone receptor
modulators include the synchronization of estrus in livestock.
The term "cycle-related symptoms" refers to psychological and physical
symptoms associated with a woman's menstrual cycle arising in the luteal phase of
the menstrual cycle. It has been reported that most women report experiencing cycle-
related symptoms. The symptoms generally disappear after the onset of menstruation,
and the patient is free from symptoms during the rest of the follicular phase. The
cyclical nature of the symptom variations is characteristic of cycle-related symptoms.
Cycle-related symptoms occur in about 95% of women who experience some
physical or mood changes with their menstrual cycles. Only about one-third of those
women experiences moderate to severe cycle-related symptoms. Women vary in the
number, type, severity, and pattern of symptoms before menstruation. One thing
common to all the types of cyclic-related symptoms is the decrease or elimination of
the symptoms in the two weeks after menstruation up to ovulation.
The term "cycle-related symptoms" refers to psychological symptoms (for
example, mood change, irritability, anxiety, lack of concentration, or decrease in
sexual desire) and physical symptoms (for example, dysmenorrhea, breast tenderness,
bloating, fatigue, or food cravings) associated with a woman's menstrual cycle.
Cycle-related symptoms occur after ovulation but before menses and usually
terminate at the start of the menstrual period or shortly thereafter. Cycle-related
symptoms include, but are not limited to, dysmenorrhea and moderate to severe cycle-
related symptoms.
Suitably, the PR modulators are formulated for delivery by any suitable route
including, e.g., transdermal, mucosal (intranasal, buccal, vaginal), oral, parenteral, etc,
15

by any suitable delivery device including, e.g., transdermal patches, topical creams or
gels, a vaginal ring, among others.
When the compounds are employed for the above utilities, they may be
combined with one or more pharmaceutically acceptable carriers or excipients, for
example, solvents, diluents and the like, and may be administered orally in such forms
as tablets, capsules, dispersible powders, granules, or suspensions containing, for
example, from about 0.05 to 5% of suspending agent, syrups containing, for example,
from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to
50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or
suspensions containing from about 0.05 to 5% suspending agent in an isotonic
medium. Such pharmaceutical preparations may contain, for example, from about 25
to about 90% of the active ingredient in combination with the carrier, more usually
between about 5% and 60% by weight.
The effective dosage of active ingredient employed may vary depending on
the particular compound employed, the mode of administration and the severity of the
condition being treated. In one embodiment, satisfactory results are obtained when
the compounds are administered at a daily dosage of from about 0.5 to about 500
mg/kg of animal body weight, desirably given in divided doses one to four times a
day, or in a sustained release form. In another embodiment, for most large mammals,
the total daily dosage is from about 1 to 100 mg. In another embodiment, the total
daily dosage is from about 2 to 80 mg. Dosage forms suitable for internal use
comprise from about 0.5 to 500 mg of the active compound in intimate admixture
with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may
be adjusted to provide the optimal therapeutic response. For example, several divided
doses may be administered daily or the dose may be proportionally reduced as
indicated by the exigencies of the therapeutic situation.
The compounds may be administered orally as well as by intravenous,
intramuscular, or subcutaneous routes. Solid carriers include starch, lactose,
dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid
carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible
oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active
ingredient and the particular form of administration desired. Adjuvants customarily
16

employed in the preparation of pharmaceutical compositions maybe advantageously
included, such as flavoring agents, coloring agents, preserving agents, and
antioxidants, for example, vitamin E, ascorbic acid, butylated hydroxytoluene (BHT)
and butylated hydroxyanisole (BHA).
The pharmaceutical compositions from the standpoint of ease of preparation
and administration are solid compositions, particularly tablets and hard-filled or
liquid-filled capsules. Oral adrninistration of the compounds is desirable.
The compounds may also be administered parenterally or intraperitoneally.
Solutions or suspensions of the compounds as a free base or pharmacologically
acceptable salt can be prepared in water suitably mixed with a surfactant such as
hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid,
polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of
storage and use, these preparations contain a preservative to prevent the growth of
microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous
solutions or dispersions and sterile powders for the extemporaneous preparation of
sterile injectable solutions or dispersions. In all cases, the form must be sterile and
must be fluid to the extent that easy syringe ability exits. It must be stable under
conditions of manufacture and storage and must be preserved against the
contaminating action of microorganisms such as bacterial and fungi. The carrier can
be a solvent or dispersion medium containing, for example, water, ethanol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof,
and vegetable oil.
The compounds may also be administered via a vaginal ring. Suitably, use of
the vaginal ring is timed to the 28 day cycle. In one embodiment, the ring is inserted
into the vagina, and it remains in place for 3 weeks. During the fourth week, the
vaginal ring is removed and menses occurs. The following week a new ring is inserted
to be worn another 3 weeks until it is time for the next period. In another
embodiment, the vaginal ring is inserted weekly, and is replaced for three consecutive
weeks. Then, following one week without the ring, a new ring is inserted to begin a
new regimen. In yet another embodiment, the vaginal ring is inserted for longer or
shorter periods of time.
17

For use in the vaginal ring, a PR modulator compound is formulated in a
manner similar to that described for contraceptive compounds previously described
for delivery via a vaginal ring. See, e.g., US Patent Nos. 5,972,372; 6,126,958 and
6,125,850.
In still another aspect, the PR modulator compound(s) are delivered via a
transdermal patch. Suitably, use of the patch is timed to the 28 day cycle. In one
embodiment, the patch is applied via a suitable adhesive on the skin, where it remains
in place for 1 week and is replaced weekly for a total period of three weeks. During
the fourth week, no patch is applied and menses occurs. The following week a new
patch is applied to be worn to begin a new regimen. In yet another embodiment, the
patch remains in place for longer, or shorter periods of time.
In one embodiment, the PR modulator(s) are used in cyclic regimens involving
administration of the PR modulator alone. In another embodiment, the cyclic regimen
involves administration of a PR modulator in combination with an estrogen or
progestin, or both. Particularly desirable progestins can be selected from among those
described in US Patent Nos. 6,355,648; 6,521,657; 6,436,929; 6,540,710; and
6,562,857 and US Patent Application Publication No. 2004-0006060-Al. Still other
progestins are known in the art and can be readily selected. In one embodiment,
combination regimens with the PR agonist (i.e., progestin) tanaproget 5-(4,4-
dimethyl-2-thioxo-1,4-dihydro-2H-3,1 -benzoxazin-6-yl)-1 -methyl-1 H-p yrrole-2-
carbonitrile are provided.
Further included are administration regimens carried out over 28 consecutive
days. These regimens may be continuous or may involve a terminal portion of the
cycle, e.g., 0 to 7 days, containing administration of no progestins, estrogens or anti-
progestins. See, e.g., the regimens described in US Patent Application Publication
No. US-2006-0009509-A1, which is hereby incorporated by reference.
The regimens described herein maybe utilized for contraception, or for any of
the other indications described herein. Where administration is for contraception, the
compositions may be formulated in oral dosage units.
When utilized for contraception, the PR modulators may be administered to a
female of child bearing age, alone or in combination with an estrogen. For the first 14
to 24 days of the cycle, a progestational agent is administered, desirably at a dosage
18

range equal in progestational activity to about 35 ug to about 150 ug levonorgestrel
per day, and more desirably equal in activity to about 35 ug to about 100 ug
levonorgestrel per day. A PR modulator may then be administered alone or in
combination with an estrogen for a period of 1 to 11 days to begin on any cycle day
between day 14 and 24. The PR modulator in these combinations may be
administered at a dose of from about 2 ug to about 50 ug per day and the estrogen
may be administered at a dose of from about 10 ug to about 35 ug per day. In an oral
administration, a package or kit containing 28 tablets will include a placebo tablet on
those days when the PR modulator or progestin or estrogen is not administered.
Progestational agents useful herein include, but are not limited to, tanaproget,
levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene,
norethindrone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone,
dienogest, drospirenone, nomegestrol, or (17-deacetyl)norgestimate. Among the
desirable progestins for use in the combinations are levonorgestrel, gestodene and
trimegestone.
Examples of orally administered regimens over a 28 day cycle include
administration of a progestational agent solely for the first 21 days at a daily dose
equal in progestational activity to from about 35 to about 100 ug of levonorgestrel. A
PR modulator compound can then be administered at a daily dose of from about 1 to
200 mg from day 22 to day 24, followed by no administration or adniinistration of a
placebo for days 25 to 28. It is most desirable that the daily dosages of each relevant
active ingredient be incorporated into a combined, single daily dosage unit, totaling
28 daily units per 28-day cycle.
In another regimen, a progestational agent may be co-administered for the first
21 days at a daily dose equal in progestational activity to from about 35 to about 150
ug levonorgestrel, desirably equal in activity to from about 35 to about 100 ug
levonorgestrel, with an estrogen, such as ethinyl estradiol, at a daily dose range of
from about 10 to about 35 ug. This may be followed as described above with a PR
modulator administered at a daily dose of from about 1 to 250 mg from day 22 to day
24, followed by no administration or administration of a placebo for days 25 to 28.
Still another regimen will include co-administration from days 1 to 21 of a
progestational agent, e.g., levonorgestrel, being administered at a daily dose equal in
19

progestational activity to from about 35 to about 100 ug levonorgestrel, and an
estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35
ug. This will be followed on days 22 to 24 by co-administration of a PR modulator (1
to 250 mg/day) and an estrogen, such as ethinyl estradiol, at a daily dose of from
about 10 to about 35 ug. From day 25 to day 28, this regimen may be followed by no
administration or administration of a placebo.
The compounds and compositions can be included in kits or packages of
pharmaceutical formulations designed for use in the regimens described herein.
These kits are desirably designed for daily oral administration over a 28-day cycle,
desirably for one oral administration per day, and organized so as to indicate a single
oral formulation or combination of oral formulations to be taken on each day of the
28-day cycle. Desirably, each kit will include oral tablets to be taken on each the days
specified, desirably one oral tablet will contain each of the combined daily dosages
indicated.
According to the regimens described above, one 28-day kit may contain (a) an
initial phase of from 14 to 21 daily dosage units of a progestational agent equal in
progestational activity to about 35 to about 150 ug levonorgestrel, desirably equal in
progestational activity to about 35 to about 100 ug levonorgestrel; (b) a second phase
of from 1 to 11 daily dosage units of a PR modulator compound, each daily dosage
unit containing the PR modulator compound at a daily dosage of from about 1 to 250
mg; and (c) optionally, a third phase of an orally and pharmaceutically acceptable
placebo for the remaining days of the cycle in which no PR modulator (i.e.,
antiprogestin or progestin) or estrogen is administered.
In one embodiment of this kit, the initial phase involves 21 daily dosage units
as described in the preceding passage, a second phase of 3 daily dosage units for days
22 to 24 of a PR modulator compound and an optional third phase of 4 daily units of
an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
In another embodiment, a 28-day cycle packaged regimen or kit contains, a
first phase of from 18 to 21 daily dosage units, and more desirably, 21 days, as
described in the preceding passages, and, further including, as an estrogen, ethinyl
estradiol at a daily dose range of from about 10 to about 35 \xg; a second phase of
from 1 to 7 daily dosage units, and desirably, 4 daily dosage units, as described above,
20

and an optional placebo for each of the remaining 0-9 days, or about 4 days, in the 28-
day cycle in which no progestational agent, estrogen or antiprogestin is administered.
A further 28-day packaged regimen or kit includes (a) a first phase of from 18
to 21 daily dosage units, each containing a progestational agent at a daily dose equal
in progestational activity to about 35 to about 150 ug levonorgestrel, desirably equal
in activity to from about 35 to about 100 ug levonorgestrel, and ethinyl estradiol at a
daily dose range of from about 10 to about 35 ug; (b) a second phase of from 1 to 7
daily dose units, each daily dose unit containing a PR modulator at a concentration of
from 1 to 250 mg and ethinyl estradiol at a concentration of from about 10 to about 35
ug; and (c) optionally, an orally and pharmaceutically acceptable placebo for each of
the remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen
or antiprogestin is administered.
In one embodiment, the package or kit just described includes a first phase of
21 daily dosage units; a second phase of 3 daily dosage units for days 22 to 24, each
daily dose unit containing an PR modulator at a concentration of from 2 to 200 mg
and ethinyl estradiol at a concentration of from about 10 to about 35 ug; and
optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable
placebo for each of days 25 to 28.
In each of the regimens and kits just described, it is desirable that the daily
dosage of each pharmaceutically active component of the regimen remain fixed in
each particular phase in which it is administered. It is also understood that the daily
dose units described are to be administered in the order described, with the first phase
followed in order by the second and third phases. To help facilitate compliance with
each regimen, it is also desirable that the kits contain the placebo described for the
final days of the cycle. It is further desirable that each package or kit comprise a
pharmaceutically acceptable package having indicators for each day of the 28-day
cycle, such as a labeled blister package or dial dispenser packages known in the art.
As used herein, the terms anti-progestational agents, anti-progestins and
progesterone receptor antagonists are understood to be synonymous. Similarly,
progestins, progestational agents and progesterone receptor agonists are understood to
refer to compounds of the same activity.
21

These dosage regimens may be adjusted to provide the optimal therapeutic
response. For example, several divided doses of each component may be administered
daily or the dose maybe proportionally increased or reduced as indicated by the
exigencies of the therapeutic situation, hi the descriptions herein, reference to a daily
dosage unit may also include divided units which are administered over the course of
each day of the cycle contemplated.
The compounds and compositions can further be provided in kits and delivery
devices for a variety of other therapeutic uses as described herein including, e.g.,
hormone replacement therapy, the treatment and/or prevention of benign and
malignant neoplastic disease. Such kits contain components in addition to the
compounds, including, e.g., instructions for delivery of the compounds, diluents,
vials, syringes, packaging, among other items.
Such kits may optionally be adapted for the selected application, e.g., hormone
replacement therapy, treatment and/or prevention of uterine myometrial fibroids,
endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the
endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other
hormone-dependent tumors, dysmenorrhea, dysfunctional uterine bleeding, cycle-
related symptoms, and symptoms of premenstrual syndrome and premenstrual
dysphoric disorder; for inducing amenorrhea; or the synchronization of the estrus in
livestock.
The following examples are provided to illustrate the invention and do not
limit the scope thereof. One skilled in the art will appreciate that although specific
reagents and conditions are outlined in the following examples, modifications can be
made which are meant to be encompassed by the spirit and scope of the invention.
EXAMPLES
Example 1: A/-[4-(5-cyano-1-methyI-1 H-pyrrol-2-yl)phenyl]propane-1-
sulfonamide
The general procedure for sulfonylation of 5-(4-aminophenyl)-l-methyl-1H-
pyrrole-2-carbonitrile is as follows.
22

5-(4-Aminophenyl)-l-methyHH-pyrrole-2-carbonitrile (98 mg, 0.5 mmol)
was dissolved in dichloromethane (2 mL) and triethylamine (87 jiiL, 0.6 mmol) was
added. Propane sulfonyl chloride (62 fiL, 0.55 mmol) was added and the mixture was
stirred 16 hours. The mixture was diluted with 50% ether in ethyl acetate and washed
with water, saturated NaHCC>3, 2N HC1, brine, dried over MgSC<4, and concentrated.
Flash chromatography (0%-100% ethyl acetate in hexane) afforded iV-[4-(5-cyano-l-
methyl-lH-pyrrol-2-yl)phenyl]propane-l-sulfonamide (0.039 g).
HPLC purity 97.8 % at 210-370 nm, 8.8 min.; 97.7% at 284 nm, 8.8 min.; the
Xterra™ RP18 instrument, 3.5/z, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95
(Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd
for CisHnNaOaS + 1, 304.11142; found (ESI-FTMS, [M+H]*), 304.11165.
Example 2: N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-N-
(methylsulfonyl)methane sulfonamide
The title compound was prepared according to general procedure for
sulfonylation of 5-(4-aminophenyl)-1 -methyl-1 H-pyrrole-2-carbonitrile using
methane sulfonyl chloride (43 pL, 0.55 mmol) to provide 7V-[4-(5-cyano-l-methyl-
1 H-pyrrol-2-yl)phenyl] -N-(methylsulfonyl)methanesulfonamide (0.021 g).
HPLC purity 95.3% at 210-370 nm, 8.0 min.; 95.3% at 290 nm, 8.0 min.; the
Xterra™ RP18 instrument, 3.5, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd
for C4H15N3O4S2 + H+, 354.05767; found (ESI-FTMS, [M+H], 354.05748.
Example 3: A/-[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)phenyI]butane-1-
sulfonamide
The title compound was prepared according to general procedure for
sulfonylation of 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using butane
sulfonyl chloride (72 pL, 0.55 mmol) to provide 7V-[4-(5-cyano-l-methyl-lH-pyrrol-
2-yl)phenyl]butane-l-sulfonamide (0.026 g).
HPLC purity 98.9% at 210-370 nm, 9.3 min.; 98.9% at 284 nm, 9.3 min.; the
Xterra™ RP18 instrument, 3.5/i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95
23

(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd
for C16Hi9N302S + H+, 318.12707; found (ESI-FTMS, [M+H]4), 318.12729.
Example 4: N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-2,2,2-
trifluoroethanesulfonamide
The title compound was prepared according to general procedure for
sulfonylation of 5-(4-aminophenyl)-l-rnethyl-lH-pyrrole-2-carbonirrile using 2,2,2-
trifluoro-ethanesulfonyl chloride (55 (iL, 0.55 rnmol) to provide JV-[4-(5-cyano-l-
methyl-lH-pyrrol-2-yl)phenyl]-2,2,2-trifluoroethanesulfonarnide (0.014 g).
HPLC purity 100% at 210-370 nm, 9.0 min.; the Xterra™ RP18 instrument,
3.5/i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold4 min.
Example 5: W-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-4-
isopropylbenzenesulfonamide
The title compound was prepared according to general procedure for
sulfonylation of 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using 4-
isopropyl-benzenesulfonyl chloride (120 mg, 0.55 mmol) to provide iV-[4-(5-cyano-l-
methyl-lH-pyrrol-2-yl)phenyl]-4-isopropylbenzenesulfonamide (0.049 g).
HPLC purity 97.2% at 210-370 nm, 10.3 min.; 97.2% at 286 nm, 10.3 min.;
the Xterra™ RP18 instrument, 3.5/i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd
for C2iH21N302S + H1", 380.14272; found (ESI-FTMS, [M+H]*), 380.14319.
Example 6: N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]
benzenesulfonamide
The title compound was prepared according to general procedure for
sulfonylation of 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using
benzenesulfonyl chloride (70 /iL, 0.55 mmol) to provide 7V-[4-(5-cyano-l-methyl- 1H-
pyrrol-2-yl)phenyl]benzene sulfonamide (0.046 g).
HPLC purity 93.0% at 210-370 nm, 9.3 min.; 94.8% at 286 nm, 9.3 min.; the
Xterra™ RP18 instrument, 3.5/i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95
24

(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd
for Ci8H15N302S + H*, 338.09577; found (ESI-FTMS, [M+H]+), 338.09611.
Example 7: A/-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)phenyl]-4-
methylbenzenesulfonamide
The title compound was prepared according to general procedure for
sulfonylation of 5-(4-aminophenyl)-l -methyl-lH-pyrrole-2-carbonitrile using p-
toluenesulfonyl chloride (105 mg, 0.55 mmol) to provide JV-[4-(5-cyano-l-methyl-
lH-pyrrol-2-yl)phenyl]-4-methyl benzenesulfonamide (0.036 g).
HPLC purity 98.3% at 210-370 nm, 9.7 min.; 97.8 % at 286 rim, 9.7 min.; the
Xterra™ RP18 instrument, 3.5/x, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd
for C19H17N3O2S + H+, 352.11142; found (ESI-FTMS, [M+H]1"), 352.11183.
Example 8: A/-[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)phenyl]propane-2-
sulfonamide
5-(4-Aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile (0.27 g, 1.37 mmol)
was dissolved in isopropyl sulfonyl chloride (0.50 mL, 2.8 mmol) and heated to 70 °C
for 6 hours. The mixture was cooled and diluted with water and extracted with ethyl
acetate. The organics were combined, washed with water, brine, dried over MgS04,
and concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded
7Y-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]propane-2-sulfonamide (0.009 g).
HPLC purity 94.7% at 210-370 nm, 8.8 min; the Xterra™ RP18 instrument,
3.5, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph-3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for CisHnNsOzS + H+,
304.1114; found (ESI, [M+H]"), 304.1132.
Example 9: A/-[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)phenyl]ethanesulfonamide
5-(4-Aminophenyl)-l -methyl- lH-pyrrole-2-carbonitrile (1.3 g, 6 mmol) was
dissolved in pyridine (10 mL), ethane sulfonyl chloride (0.54 mL, 5.7 mmol) was
added, the mixture was stirred for 4 hours, and then water was added. The mixture
was diluted with ethyl acetate and washed with water, saturated CuS04,2N HCl,
25

brine, dried over MgSC>4, and concentrated. Flash chromatography (5%-50% ethyl
acetate in hexane) afforded iV-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]ethanesulfonamide (1.33 g).
HPLC purity 100% at 210-370 nm, 8.3 min.; the Xterra™ RP18 instrument,
3.5/i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for CsNsChS + If',
290.09577; found (ESI, [M+H]*), 290.0958.
Example 10: /V-[4-(5-cyano-1-methyl-1H-pyrrol-2-yI)phenyl]
methanesulfonamide
5-(4-Aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile (0.5 g, 2.3 mmol) was
dissolved in pyridine (5 mL), methane sulfonyl chloride (0.16 mL, 2.1 mmol) was
added, the mixture was stirred for 4 hours, and then water was added. The mixture
diluted with ethyl acetate and the mixture was washed with water, saturated Q1SO4,
2N HC1, brine, dried over MgSC>4, and concentrated. Flash chromatography (5%-
50% ethyl acetate in hexane) afforded 7V-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]methanesulfonamide (0.382 g).
MS (ES) m/z 276.1; HPLC purity 100% at 210-370 nm, 7.9 min.; the Xterra™
RP18 instrument, 3.5/i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon.
Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min.
Example 11: A/-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-fluorophenyl]
methanesulfonamide
5-(4-amino-3-fluorophenyl)-l-methyl-lH-pyrrole-2-carbonitrile (0.15 g, 0.70
mmol) was dissolved in pyridine (1.5 mL), methane sulfonyl chloride (0.05 mL, 0.63
mmol) was added, the mixture was stirred for 4 hours, and then water was added. The
mixture diluted with ethyl acetate and the mixture was washed with water, saturated
CUSO4, 2N HC1, brine, dried over MgSCU, and concentrated. Flash chromatography
(5%-50% ethyl acetate in hexane) afforded A-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-
2-fluorophenyl] methane sulfonamide (0.147 g).
HPLC purity 98.3% at 210-370 nm, 7.8 min.; the Xterra™ RP18 instrument,
3.5fi, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
26

Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C13H12FN3O2S + H+,
294.07070; found (ESI, [M+H]4), 294.0696.
Example 12: A/-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)-2-f!uorophenyl]
ethanesulfonamide
5-(4-amino-3-fluorophenyl)-l-methyl-lH-pyrrole-2-carbonitrile(0.31 g, 1.44
mmol) was dissolved in pyridine (3 mL), ethane sulfonyl chloride (0.12 mL, 1.3
mmol) was added, the mixture was stirred for 4 hours, and then water was added. The
mixture diluted with ethyl acetate and the mixture was washed with water, saturated
CUSO4,2N HC1, brine, dried over MgS04, and concentrated. Flash chromatography
(5%-50% ethyl acetate in hexane) affordediV-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-
2-fluorophenyl] ethane sulfonamide (0.127 g). HPLC purity 100 % at 210-370 nm,
8.3 min.; the Xterra™ RP18 instrument, 3.5/1,150 x 4.6 mm column, 1.2 mL/min.,
85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min.
HRMS: calcd for C14H14FN3O2S + H*, 308.08635; found (ESI, [M+H]", 308.0855.
27

Example 13: 5-(4-amino-2-fluorophenyl)-1-methyl-1H-pyrrole-2-carbonitriie
4-Bromo-3-fluoroaniline (0.95 g, 5.0mmol), l-mefhyl-5-cyano-2-
pyrroleboronic acid (1.35 g, 9.0 mmol), KF (0.96 g, 16.5 mmol), and Pd2(dba)3 (120
mg, 0.125 mmol) were added to a 50 mL round bottom flask under nitrogen. The
flask was sealed and purged with nitrogen for 5 minutes. THF (12.5 mL) was added
and the mixture was purged with nitrogen for an additional 5 minutes. A solution of
tri--butylphosphine (10% wt in hexanes) (0.74 mL, 0.25 mmol) was added via
syringe and the mixture was stirred vigorously at 25 °C for 16 hours. The mixture
was diluted with 250 mL of EtOAc, filtered through a plug of silica gel, washed with
200 mL of EtOAc and concentrated to give a crude brown/black semi-solid.
Purification via Isco chromatography (the Redisep® column, silica, gradient 5%-
100% ethyl acetate in hexane) afforded 5-(4-amino-2-fluorophenyl)-l -methyl- 1H-
pyrrole-2-carbonitrile as a white solid (1.05 g, 98%).
HPLC purity 100.0% at 210-370 nm, 8.4 min.; the Xterra™ RP18 instrument,
3.5/x, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 216.0.
Example 14: A/-[4~(5-cyano-1-methyl-1 H-pyrrol-2-yl)-3-fluorophenyl]
methanesulfonamide
5-(4-amino-2-fluorophenyl)-l-methyl-lH-pyrrole-2-carbonitrile (0.20 g, 0.93
mmol) was dissolved in pyridine (2.0 mL). Methanesulfonyl chloride (0.07 mL, 0.9
mmol) was added and the mixture was stirred for 16 hours, followed by the addition
of water. The mixture was diluted with ethyl acetate and then was washed with water,
saturated CUSO4,2N HC1, brine, dried over MgSC>4, and concentrated. The crude
product was purified via Isco chromatography (the Redisep® column, silica, gradient
5-50% ethyl acetate in hexane) to afford 0.18 g of Ar-[4-(5-cyano-l -methyl-lH-pyrrol-
2-yl)-3-fluorophenyl]methanesulfonamide.
HPLC purity 100.0% at 210-370 nm, 8.3 min.; the Xterra™ RP18 instrument,
3.5jU, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 293.9.
28

Example 15: A/-[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)-3-f!uorophenyl]
ethanesulfonamide
This compound was prepared according to the procedure described in
Example 14 using ethane sulfonyl chloride (85 piL, 0.9 mmol) to provide N-[4-(5-
cyano-l-methyl-lH-pyrrol-2-yl)-3-fluorophenyl]ethanesulfonamide (0.135 g).
HPLC purity 100.0% at 210-370 nm, 9.7 min.; the Xterra™ RP18 instrument,
3.5ju, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C4H14FN3O2S +
H"1", 308.08635; found (ESI, [M+H]+), 308.0867.
Example 16: N-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)-3-fIuorophenyl]propane-
1-sulfonamide
The sulfonamide was prepared according to the procedure described in
Example 14 using propane sulfonyl chloride (50 \£L, 0.45 mmol) to provide JV-[4-(5-
cyano-1 -methyl-1 H-pyrrol-2-yl)-3-fluorophenyl]propane-1 -sulfonamide (96 mg).
HPLC purity 99.2% at 210-370 nm, 9.3 min.; the Xterra™ RP18 instrument,
3.5/i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 321.9.
Example 17: A/-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fiuorophenyl]butane-1-
sulfonamide
The sulfonamide was prepared according to the procedure described in
Example 14 using butane sulfonyl chloride (58 /JL, 0.45 mmol) to provide Ar-[4-(5-
cyano-1 -methyl-1 H-pyrrol-2-yl)-3-fluorophenyl]butane-l -sulfonamide (60 mg).
HPLC purity 97.7% at 210-370 nm, 9.8 min.; the Xterra™ RP18 instrument,
3.5/i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 335.9.
Example 18: N-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)-3-fluorophenyl]propane-
2-sulfonamide
5-(4-amino-2-fluorophenyl)-l-methyl-lH-pyrrole-2-carbonitrile (200 mg, 0.93
mmol) was dissolved in isopropyl sulfonyl chloride (0.50 mL, 2.8 mmol), pyridine
29

(0.2 mL) was added and the mixture was heated to 100 °C for 6 hours. The mixture
was then cooled and diluted with water and extracted with ethyl acetate. The organics
were combined, washed with water, brine, dried over MgSOzt, and concentrated.
Flash chromatography (0%-100% ethyl acetate in hexane) afforded JV"-[4-(5-cyano-l-
methyl-lH-pyrrol-2-yl)-3-fluorophenyl]propane-2-sulfonarnide (58 mg).
HPLC purity 92.5% at 210-370 nm, 9.2 min.; the Xterra™ RP18 instrument,
3.5/x, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 321.9.
Example 19: 5-(4-amino-2,5-difluorophenyl)-1 -methyl-1 H-pyrrole-2-carbonitrile
4-Bromo-2,5-difluoroaniUne (0.1 g, 4.85 mmol), l-methyl-5-cyano-2-pyrrole-
boronic acid (1.3 g, 8.7 mmol), KF (0.93 g, 16 mmol), and Pd2(dba)3 (117 mg, 0.12
mmol) were added to a 50 mL round bottom flask under nitrogen. The flask was
sealed and purged with nitrogen for 5 minutes. THF (12.1 mL) was added and the
mixture was purged with nitrogen for an additional 5 minutes. A solution of tri-t-
butylphosphine (10% wt in hexanes) (0.72 mL, 0.24 mmol) was added via syringe and
the mixture was stirred vigorously at 25 °C for 16 hours. The mixture was diluted
with 250 mL of EtOAc, filtered through a plug of silica gel, washed with 200 mL of
EtOAc and concentrated to give a crude brown/black semi-solid. Purification via Isco
chromatography (the Redisep® column, silica, gradient 5-100% ethyl acetate in
hexane) afforded 5-(4-amino-2,5-difluorophenyl)-1 -methyl-1 H-pyrrole-2-carbonitrile
as a white solid (0.87 g, 77%).
HPLC purity 100.0% at 210-370 nm, 8.9 min.; the Xterra™ RP18 instrument,
3.5/-1, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 234.0.
Example 20: A/-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)-2,5-difluorophenyl]-
methane-sulfonamide
5-(4-armo-2,5-difluoropheaiyl)-l-memyl-lH-pyirole-2-carbonitrile(0.15 g,
0.64 mmol) was dissolved in pyridine (2.0 mL). Methanesulfonyl chloride (46 /xL,
0.6 mmol) was added and the mixture was stirred for 16 hours, followed by the
addition of water. The mixture was diluted with ethyl acetate, washed with water,
30

saturated CUSCM,2N HC1, brine, dried over MgS04, and concentrated. The crude
product was purified via Isco chromatography (the Redisep® column, silica, gradient
5-50% ethyl acetate in hexane) to afford 0.142 g of 7V-[4-(5-cyano-l-methyl-lH-
pyrrol-2-yl)-2,5-difluorophenyl]-methane-sulfonamide.
HPLC purity 99.0% at 210-370 nm, 8.3 min.; the Xterra™ RP18 instrument,
3.5/i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 311.8.
Example 21: A/-[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)-2,5-difluorophenyl]
ethane-sulfonamide
The sulfonamide was prepared according to procedure described in Example
20 using ethane sulfonyl chloride (56 fiL, 0.6 mmol) to provide iV-[4-(5-cyano-l-
methyHH-pyrrol-2-yl)-2,5-difluorophenyl]ethane-sulfonamide (46 mg).
HPLC purity 100.0% at 210-370 nm, 8.7 min.; the Xterra™ RP18 instrument,
3.5jit, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 323.9.
Example 22: A/-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-
difluorophenyl]propane-1-sulfonamide
The sulfonamide was prepared according to the procedure described in
Example 20 using propane sulfonyl chloride (67 /xL, 0.6 mmol) to provide 7V-[4-(5-
cyano-1 -methyl-1 H-pyrrol-2-yl)-2,5-difluorophenyl]propane-1 -sulfonamide (41 mg).
FfPLC purity 100.0% at 210-370 nm, 9.2 min.; the Xterra™ RP18 instrument,
3.5/1,150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 339.9.
Example 23: A/-[4-(5-cyano-1-methyl-1H-pyrroI-2-yl)-2,5-
difluorophenyl]butane-1-sulfonamide
The sulfonamide was prepared according to the procedure of Example 20
using butane sulfonyl chloride (77 jiiL, 0.6 mmol) to provide 7V-[4-(5-cyano-l-methyl~
lH-pyrrol-2-yl)-2,5-difluorophenyl]butane-l-sulfonamide (28 mg).
31

HPLC purity 84.8% at 210-370 nm, 9.7 min.; the Xterra™ RP18 instrument,
3.5/x, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 353.9.
Example 24: W-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-
difIuorophenyl]propane-2-sulfonamide
5-(4-amino-2,5-difiuorophenyl)-l-methyl-lH-pyrrole-2-carbonitrile (150 mg,
0.64 mmol) was dissolved in isopropyl sulfonyl chloride (1.0 mL, 9.0 mmol), pyridine
(0.2 mL) was added and the mixture was heated to 100 °C for 6 hours. The mixture
was then cooled, diluted with water and extracted with ethyl acetate. The organics
were combined, washed with water, brine, dried over MgS04, and concentrated.
Flash chromatography (0%-100% ethyl acetate in hexane) afforded JV-[4-(5-cyano-l-
methyl-lH-pyrrol-2-yl)-2,5-difluorophenyl]propane-2-sulfonamide(26mg).
HPLC purity 97.6% at 210-370 nm, 9.1 min.; the Xterra™ RP18 instrument,
3.5/i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 339.9.
Example 25: 5-[4-amino-2-(trifluoromethyl)phenyl]-1-methyl-1 H-pyrrole-2-
carbonitrile
4-Bromo-3-trifluoromethylaniline (1.77 g, 7.4 mmol), l-methyl-5-cyano-2-
pyrrole-boronic acid (2.0 g, 13.3 mmol), KF (1.42 g, 24.4 mmol), and Pd2(dba)3 (179
mg, 0.185 mmol) were added to a 50 mL round bottom flask under nitrogen. The
flask was sealed and purged with nitrogen for 5 minutes. THF (18.5 mL) was added
and the mixture was purged with nitrogen for an additional 5 minutes. A solution of
tri--butylphosphine (10% wt in hexanes) (1.1 mL, 0.37 mmol) was added via syringe
and the mixture was stirred vigorously at 25 °C for 16 hours. The mixture was diluted
with 250 mL of EtOAc, filtered through a plug of silica gel, washed through with 200
mL of EtOAc and concentrated to give a crude brown/black semi-solid. Purification
via Isco chromatography (the Redisep® column, silica, gradient 5-100% ethyl acetate
in hexane) afforded 5-[4-amino-2-(trifluoromethyl)phenyl]-l-methyl-lH-pyrrole-2-
carbonitrile as a white solid (1.8 g, 92%).
32

HPLC purity 100.0% at 210-370 nm, 9.1 min.; the Xterra™ RP18 instrument,
3.5/ii, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 266.1.
Example 26: A/-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-
(trifluoromethyl)phenyl]methane-sulfonamide
5-[4-ammo-2-(trifluoromemyl)phenyl]-l-methyl-lH-pyrrole-2-carbonitrile
(0.34 g, 1.3 mmol) was dissolved in CH2CI2 (5 mL) and pyridine (0.2 mL).
Methanesulfonyl chloride (90 /xL, 1.2 mmol) was added and the mixture was stirred
for 16 hours followed by the addition of water. The mixture, was then diluted with
ethyl acetate, the mixture was washed with water, 2N HC1, brine, dried over MgS04,
and concentrated. The crude product was purified via Isco chromatography (the
Redisep® column, silica, gradient 5-50% ethyl acetate in hexane) to afford 0.29 g of
A'-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-(trifluoromethyl)phenyl]-
methanesulfonamide.
HPLC purity 98.2% at 210-370 nm, 9.0 min.; the Xten-a™ RP18 instrument,
3.5/x, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 341.8.
Example 27: A/-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-
(trifluoromethyl)phenyl]ethane-sulfonamide
The sulfonamide was prepared according to the procedure of Example 26
using ethane sulfonyl chloride (113 juL, 1.2 mmol) to provide 7Y-[4-(5-cyano-l-
methyl- lH-pyrrol-2-yl)-3 -(trifluoromethyl)phenyl]ethane-sulfonamide (140 mg).
HPLC purity 100.0% at 210-370 nm, 9.3 min.; the Xterra™ RP18 instrument,
3.5jU, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 355.8.
Example 28: A/-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-
(trifluoromethyl)phenyl]propane-1 -sulfonamide
33

The sulfonamide was prepared according to the procedure of Example 26
using propyl sulfonyl chloride (134 [iL, 1.2 mmol) to provide iV-[4-(5-cyano-l-
methyl-1 H-pyrrol-2-yl)-3 -(trifluoromethyl)phenyl]propane-1 -sulfonamide (46 mg).
HPLC purity 99.6% at 210-370 nm, 9.7 min.; the Xterra™ RP18 instrument,
3.5pt, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 371.8.
Example 29: A/-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-
(trifluoromethyl)phenyl]butane-1 -sulfonamide
The sulfonamide was prepared according to the procedure of Example 26
using butyl sulfonyl chloride (163 /*L, 1.2 mmol) to provide A/-[4-(5-cyano-l-methyl-
1 H-pyrrol-2-yl)-3 -(trifluoromethyl)phenyl]butane-1 -sulfonamide (340 mg).
HPLC purity 99.0% at 210-370 nm, 10.1 min.; the Xterra™ RP18 instrument,
3.5/x, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold4 min. MS (ES) m/z 385.9.
Example 30: A/-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-
(trifluoromethy!)phenyl]propane-2-sulfonamide
5-[4-anmio-2-(trifluoromemyl)phenyl]-l-memyl-lH-pyrrole-2-carbonitrile
(0.33 g, 1.25 mmol) was dissolved in isopropyl sulfonyl chloride (1.0 mL, 9.0 mmol),
pyridine (0.5 mL) was added, and the mixture was heated to 100 °C for 6 hours. The
mixture was cooled and diluted with water and extracted with ethyl acetate. The
organics were combined, washed with water, brine, dried over MgSCU, and
concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded AT-
[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-(trifluoromethyl)phenyl]-propane-2-
sulfonamide (50 mg).
HPLC purity 95.4% at 210-370 nm, 9.6 min.; the Xterra™ RP18 instrument,
3.5jx, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 371.9.
Example 31: 5-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-1-methyl-1H-pyrrole-
2-carbonitrile
34

Step 1:
4-Bromoaniline (0.86 g, 5.0 mmol) was dissolved in CH2C12 (15 mL), pyridine
(0.5 mL) was added, and 3-chloropropanesulfonyl chloride (0.6 mL, 5.0 mmol) was
added. The mixture was stirred for 4 hours, diluted with ethyl acetate, and then
washed with water, 2N HC1, brine, dried over MgS04, and concentrated. The crude
product was purified via Isco chromatography (the Redisep® column, silica, gradient
5-60% ethyl acetate in hexane) to afford 1.2 g (77%) #-(4-bromophenyl)-3-
chloropropane-1 -sulfonamide.
HPLC purity 98.4% at 210-370 nm, 9.3 min.; the Xterra™ RP18 instrument,
3.5/u, 150 x 4.6 mm column, 1.2 mL/rnin., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 311.6.
Step 2:
7V-(4-Bromophenyl)-3-chloropropane~l-sulfonarnide (1.0 g, 3.2 mmol) was
dissolved in DMF, CS2CO3 (1.56 g, 4.8 mmol) was added, and the mixture was stirred
for 3 hours. The mixture was then diluted with ether, washed with water, 2N HC1,
brine, dried over MgS04, and concentrated. The crude product was purified via Isco
chromatography (the Redisep® column, silica, gradient 5-60% ethyl acetate in
hexane) to afford 0.65 g (74%) 2-(4-bromophenyl)isothiazolidine 1,1-dioxide.
HPLC purity 100.0% at 210-370 nm, 7.9 min.; the Xterra™ RP18 instrument,
3.5/x, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 275.7.
Step 3:
2-(4-Bromophenyl)isothiazolidine 1,1-dioxide (0.56 g, 2.0 mmol), l-methyl-5-
cyano-2-pyrroleboronic acid (0.36 g, 2.4 mmol), KF (0.38 g, 6.6 mmol), and
Pd2(dba)3 (48 mg, 0.05 mmol) were added to a 50 mL round bottom flask under
nitrogen. The flask was sealed and purged with nitrogen for 5 minutes. THF (5 mL)
was added and the mixture was purged with nitrogen. A solution of td-t-
butylphosphine (10% wt in hexanes) (0.3 mL, 0.1 mmol) was added via syringe and
the mixture was stirred vigorously at 25 °C for 16 hours. The mixture was diluted
with EtOAc, filtered through a plug of silica gel, washed with 200 mL of EtOAc and
35

concentrated to give a crude brown/black semi-solid. Purification via Isco
chromatography (the Redisep® column, silica, gradient 5%-100% ethyl acetate in
hexane) afforded 5-[4~( 1,1 -dioxidoisothiazolidin-2-yl)phenyl]-1 -methyl-1 H-pyrrole-
2-carbonitrile as a white solid (54 mg).
HPLC purity 100.0% at 210-370 nm, 8.3 min.; the Xterra™ RP18 instrument,
3.5//1,150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 301.8.
Example 32: 5-[4-amino-3-(trifluoromethoxy)phenyl]-1-methyl-1 H-pyrrole-2-
carbonitrile
4-Bromo-2-(trifluoromethoxy)aniline (1.3 g, 5.0 mmol), 5-cyano-l-methyl-
lH-pyrrol-2-yl boronic acid (0.9 g, 6.0 mmol), potassium fluoride (0.96 g, 16.5
mmol), and tris(dibenzylideneacetone)dipalladium (0.12 g, 0.12 mmol) were placed in
an oven dried flask under nitrogen and THF (12.5 mL) was added. Tri-t-
butylphosphine (10 wt% in hexane) (0.356 mL, 0.24 mol) was added and the reaction
was stirred for 16 hours. The reaction mixture was filtered through silica, rinsed with
ethyl acetate, and concentrated. The crude product was pre-adsorbed onto the
Celite™ reagent and purified via Isco chromatography (the Redisep® column, silica,
gradient 5-30% ethyl acetate in hexane) to afford 1.0 g (71%) of 5-[4-amino-3-
(trifluoromethoxy)phenyl]-1 -methyl-1 H-pyrrole-2-carbonitrile.
HPLC purity 98.2% at 210-370 nm, 9.6 min.; the Xterra™ RP18 instrument,
3.5/i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
PH=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 281.
Example 33: A/-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-
(trifluoromethoxy)phenyl]methane-sulfonamide
Methanesulfonyl chloride (0.05 mL, 0.65 mmol) was added dropwise to a
solution of 5-[4-amino-3-(trifluoromethoxy)phenyl]-l -methyl-lH-pyrrole-2-
carbonitrile (0.16 g, 0.56 mmol) in dry pyridine (2.0 mL). The solution was heated to
50 °C overnight. The solution was cooled to room temperature and pre-adsorbed onto
the Celite™ reagent. The crude product was purified via Isco chromatography (the
Redisep® column, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.1 g
36

(50%)ofiV-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
(trifluoromethoxy)phenyl]methanesulfonamide.
HPLC purity 90.1% at 210-370 nm, 9.0 min.; the Xterra™ RP18 instrument,
3.5/J, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Amnion. Form. Buff.
PH=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 359.
Example 34: A/-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-
(trifluoromethoxy)phenyl]ethane-sulfonamide
Using the procedure of Example 33, 7V-[4-(5-cyano-l -methyl- lH-pyrrol-2-yl)-
2-(trifluoro-methoxy)phenyl]ethanesulfonamide was prepared using ethanesulfonyl
chloride and 5-[4-amino-3-(trifluoromethoxy)phenyl]-l-methyl-lH-pyrrole-2-
carbonitrile.
HPLC purity 92.5% at 210-370 nm, 9.4 min. the Xterra™ RP18 instrument,
3.5jit, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
PH=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 2,13.
Example 35: N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-
(trifluoromethoxy)phenyl]propane-1-sulfonamide
Using the procedure of Example 33, JV-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-
2-(trifluoro-methoxy)phenyl]propane-l-sulfonamide was prepared from
propanesulfonyl chloride and 5-[4-amino-3-(trifluoromethoxy)phenyl]-l-methyl-lH-
pyrrole-2-carbonitrile.
HPLC purity 94.5% at 210-370 nm, 9.8 min.; the Xterra™ RP18 instrument,
3.5/i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammon. Form. Buff.
PH=3.5/ACN+MeOH) for 10 min., hold 4 min. MS (ES) m/z 387.
Example 36: A/-(4-bromophenyl)ethanesulfonamide
A mixture of ethanesulfonyl chloride (2.1 mL, 22 mmoi), and 4-bromoaniline
(3.44 g, 20 mmoi) in pyridine (35 mL) was stirred at room temperature for 2 hours.
The reaction mixture was acidified with IN HC1 solution and extracted with ether.
The combined organic layers were dried over magnesium sulfate, and concentrated.
The solid was triturated with hexane to afford the title compound (4.85 g, 92%).
37

HPLC purity component = 100% at 210-370 nm; RT = 8.2 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5jti, 150 x 4.6 mm, 1.2 mL/min.
Example 37: Terf-butyl 2-{4-[(ethylsulfonyl)amino]phenyl}-1H-pyrrole-1-
carboxylate
A mixture of N-(4-bromophenyl)ethanesulfonamide (1.88 g, 7.2 mmol), N-
methylpyrrole-2-carbonitrile-5-boronic acid (2.11 g, 10 mmol),
tetraMs(triphenylphosphine) palladium(O) (0.42 g, 0.36 mmol), and sodium carbonate
(3.2 g, 30 mmol in 60 mL of water) in dimethoxyethane (200 mL) was heated to
reflux for 4 hours. The mixture was cooled and partitioned between saturated
ammonium chloride and ethyl acetate. The combined organic layers were dried over
magnesium sulfate, and concentrated. The residue was purified by silica gel Flash
Chromatography (hexane/ethyl acetate; 7:3) to afford the title compound (2.4 g, 97%).
HPLC purity component = 95.8% at 210-370 nm; RT = 9.8 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5/x, 150 x 4.6 mm, 1.2 mL/min.
Example 38: Terf-butyl 2-cyano-5-{4-{(ethylsulfonyl)amino]phenyl}-1 H-pyrrole-
1-carboxylate
ferButyl2-{4-[(emylsulfonyl)amino]phenyl}-lH-pyrrole-l-carboxylate(3.0
g, 8.58 mmol) was dissolved in tetrahydrofuran (85 mL) and cooled to -78°C,
followed by the slow addition of chlorosulfonyl isocyanate. After tert-Butyl 2- {4-
[(ethylsulfonyl)amino]phenyl}-lH-pyrrole-l-carboxylate was consumed, dimethyl
formamide (6.86 mL) was added and the solution allowed to warm to room
temperature. After 2 hours, the mixture was cooled and partitioned between water
and diethyl ether. The combined organic layers were dried over magnesium sulfate,
and concentrated. The residue was purified by silica gel flash chromatography
(hexane/ethyl acetate; 7:3) to afford the title compound (1.84 g, 57%). The title
compound was used immediately in the next step.
38

Example 39: N-[4-(5-cyano-1 H-pyrrol-2-yl)phenyl]ethanesulfonamide
re7-r-butyl-2-cyano-5-{4-{(etliylsulfonyl)ainino]phenyl}-lH-pyrrole-l-
carboxylate (2.3g, 6.1 mmol) was dissolved in dimethylacetaraide (60 mL) and heated
to 170 °C for 30 minutes. The mixture was cooled and partitioned between water and
ethyl acetate. The organic layers were dried over magnesium sulfate, and
concentrated. The residue was purified by silica gel Flash Chromatography
(hexane/ethyl acetate; 1:1) to afford the title compound (1.51 g, 90%).
HPLC purity component = 100% at 210-370 nm; RT = 8.9 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5/i, 150 x 4.6 mm, 1.2 rnL/min. FfRMS: calcd for C13H13N3O2S +
H+, 275.3312; found (ESI-FTMS, [M+H]1+), 276.075.
Example 40; A/-[4-(5-cyano-1-ethyl-1 H-pyrrol-2-yl)phenyl]ethanesulfonamide
Ar-[4-(5-cyano-lH-pyrrol-2-yl)phenyl]ethanesulfonamide (0.160 g, 0.58
mmol) was dissolved in tetrahydrofuran (10 mL). Potassium tert-butoxide (1.25 mL
of a 1 M solution, 1.25 mmol) was dropwise added and the mixture stirred 15
minutes. Ethyl iodide (0.046 mL, 0.58 mmol) was dropwise added, followed by
dimethyl formamide (5 mL) and the mixture stirred for 4 hours. The mixture was
then partitioned between saturated ammonium chloride and ethyl acetate. The
combined organic layers were dried over magnesium sulfate, and concentrated. The
residue was purified by silica gel Flash Chromatography (hexane/ethyl acetate; 7:3) to
afford the title compound (0.020g, 11%).
HPLC purity component = 100% at 210-370 nm; RT = 8.9 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5/1,150 x 4.6 mm, 1.2 mL/min. HRMS: calcd for C15H17N3O2S +
FT", 303.10415; found (ESI-FTMS, [M+H]1"), 304.1109.
Example 41: A/-[4-(5-cyano-1-propyl-1 H-pyrrol-2-yl)phenyl]ethanesulfonamide
j\r-[4-(5-cyano-lH-pyrrol-2-yl)phenyl]ethanesurfonamide (0.150 g, 0.54
mmol) was alkylated according to the procedure of Example 40 using potassium tert-
butoxide (1.08 mL of a 1 M solution, 1.08 mmol) and propyl iodide (0.056 mL, 0.50
mmol) to afford the title compound (0.10 g, 6.2%).
39

HPLC purity component = 100% at 210-370 nm; RT = 9.3 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5/i, 150 x 4.6 mm, 1.2 mL/min. HRMS: calcd for C16H19N3O2S +
if, 317.1198; found (ESI-FTMS, [M+H]1+), 318.1274.
Example 42: A/-[4-(1-butyl-5-cyano-1 H-pyrrol-2-yl)phenyl]ethanesulfonamide
N-[4-(5-cyano-lH-pyrrol-2-yl)phenyl]emanesulfonamide (0.150 g, 0.54
mmol) was alkylated according to the procedure of Example 40 using potassium tert-
butoxide (1.08 mL of a lM solution, 1.08 mmol) and butyl iodide (0.066 mL, 0.50
mmol) to afford the title compound (0.10 g, 6%).
HPLC purity component = 100% at 210-370 nm; RT = 9.8 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5JLI, 150 x 4.6 mm, 1.2 mL/min. HRMS: calcd for Ci7H2lN302S +
FT", 331.1354; found (ESI-FTMS, [M+H]1+), 332.1437.
Example 43: A/-[4-(1-allyl-5-cyano-1 H-pyrrol-2-yl)phenyl]ethanesulfonamide
N-[4-(5-cyano-lH-pyrrol-2-yl)phenyl]ethanesulfonamide (0.150 g, 0.54
mmol) was alkylated according to the procedure of Example 40 using potassium tert-
butoxide (1.08mL of a lM solution, 1.08 mmol) and allyl bromide (0.041 mL, 0.50
mmol) to afford the title compound (0.10 g, 6.3%).
HPLC purity component = 100% at 210-370 nm; RT = 9.0 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5/i, 150 x 4.6 mm, 1.2 mL/min. HRMS: calcd for Ci6H17N302S +
H\ 316.11142; found (ESI, [M+Hf), 316.1126.
Example 44: A/-[4-(5-cyano-1-prop-2-yn-1-yl-1H-pyrrol-2-
yl)phenyl]ethanesulfonamide
N-[4-(5-cyano-lH-pyrrol-2-yl)phenyl]ethanesulfonamide (0.150 g, 0.54
mmol) was alkylated according to the procedure of Example 40 using potassium tert-
butoxide (1.08 mL of a 1M solution, 1.08 mmol) and propargyl bromide (80% in
toluene, 0.055 mL, 0.50 mmol) to afford the title compound (0.10 g, 6.3%).
40

HPLC purity component = 99% at 210-370 nm; RT = 8.5 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5ju, 150 x 4.6 mm, 1.2 mL/min. HRMS: calcd for C16H15N3O2S +
H+, 313.0885; found (ESI-FTMS, [M+H]1+), 314.0971.
Example 45: A/-{4-[5-cyano-1-(3-phenylpropyl)-1H-pyrrol-2-
yl]phenyl}ethanesulfonamide
N-[4-(5-cyano-lH-pyrrol-2-yl)phenyl]ethanesulfonamide (0.150 g, 0.54
mmol) was alkylated according to the procedure of Example 40 using potassium tert-
butoxide (1.08 mL of a 1 M solution, 1.08 mmol) and l-Iodo-3-phenylpropane (0.093
mL, 0.60 mmol) to afford the title compound (0.020 g, 10%).
HPLC purity component = 100% at 210-370 nm; RT = 10.4 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5fi, 150 x 4.6 mm, 1.2 mL/min. HRMS: calcd for C22H23N3O2S +
H+, 393.1511; found (ESI-FTMS, [M+H]1+), 394.1566.
Example 46: 5-amino-2-chlorobenzonitriie
A mixture of 2-chloro-5-nitrobenzonitrile (10 g, 54.8 mmol) and stannous
chloride dihydrate (56 g, 248.6 mmol) in isopropyl alcohol (125 mL) and
concentrated hydrochloric acid solution (62.5 mL) was heated to reflux for 1 hour.
The mixture was then cooled and neutralized with sodium hydroxide solution (2N).
The aqueous layer was extracted with methylene chloride. The combined organic
layers were dried over magnesium sulfate and concentrated to afford the title
compound (8 g, 96%).
HPLC purity component = 100% at 210-370 nm; RT = 7.2 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5/x, 150 x 4.6 mm, 1.2 mL/min.
Example 47: 5-(4-amino-2-cyanophenyl)-1 -methyl-1 H-pyirole-2-carbonitrile
A mixture of 5-amino-2-chlorobenzonitrile (1.3 g, 8.58 mmol),
tris(dibenzylideneacetone)dipalladium (0.192 g, 0.209 mmol), N-methyl-5-
cyanopyrroleboronic acid (2.55 g, 17.16 mmol), and potassium fluoride (1.81g, 31.25
41

mmol) in tetrahydrofuran (20 mL) was stirred under nitrogen. Tri-teil-
butylphosphine (10% solution in hexane, 1.23 mL, 0.414 mmol) was added to the
mixture and allowed to stir 3 hours at 50 °C until the starting bromide was consumed.
The mixture was then diluted with 1/1 hexane/tetrahydrofuran and filtered through a
plug of silica gel. The solvent was evaporated and the residue was purified by silica
gel column chromatography (hexane/ethylacetate, 90/10 to 50/50) to afford, the title
compound (1.77 g, 92%).
HPLC purity component = 98% at 210-370 ran; RT = 7.8 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5JLI, 150 x 4.6 mm, 1.2 mL/min.
Example 48: A/-[3-cyano-4-(5-cyano-1-methyl-1H-pyrrol-2-
yl)phenyl]methanesulfonamide
A mixture of methanesulfonyl chloride (0.074 mL, 1 mmol) and 5-(4-amino-2-
cyanophenyl)-l-methyl-lH-pyrrole-2-carbonitrile (0.166 g, 0.75 mmol) in pyridine (1
mL) was heated to 50 °C for 4 hours. The reaction mixture was acidified with IN
HC1 solution and extracted with ethyl acetate. The combined organic layers were
dried over magnesium sulfate and concentrated. The residue was purified by silica
gel column chromatography (hexane/ethylacetate, 90/10 to 60/40) to afford the title
compound (0.059 g, 33%).
HPLC purity component = 98.1% at 210-370 nm; RT = 9.1 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. the Xterra™
RP18 instrument, 3.5/1,150 x 4.6 mm, 1.2 mL/min. HRMS: calcd for C14H12N4O2S +
Ff, 300.341; found (ESI-FTMS, [M+H]1+), 301.0744.
Example 49: N-[3-cyano-4-(5-cyano-1-methyl-1H-pyrrol-2-
yl)phenyl]ethanesulfonamide
This compound was prepared according to the procedure of Example 48 using
ethanesulfonyl chloride (0.094 mL, 1 mmol) to afford the title compound (0.079 g,
42%).
HPLC purity component = 95.9% at 210-370 nm; RT = 9.6 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
42

RP18 instrument, 3.5ft, 150 x 4.6 mm, 1.2 mL/min. HRMS: calcd for C15H14N4O2S +
H*, 314.3679; found (ESI-FTMS, [M+H]1+), 315.0908.
Example 50: A/-[3-cyano-4-(5-cyano-1-methyl-1 H-pyrroI-2-yl)phenyl]propane-
1 -sulfonamide
This compound was prepared according to the procedure described in
Example 48 using propanesulfonyl chloride (0.115 mL, 1 mmol) to afford the title
compound (0.100 g, 50%). HPLC purity component = 96.6% at 210-370 nm; RT =
10.3 min.; 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold
4 min the Xterra™ RP18 instrument, 3.5(i, 150 x 4.6 mm, 1.2 mL/min. HRMS: calcd
for Ci6Hi6N402S +H+, 328.3948; found (ESI-FTMS, [M+H]l+), 329.1069.
Example 51: W-[2-cyano-4-(5-cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl]methanesulfonamide
This compound was prepared according to the procedure of Example 48 using
methane-sulfonyl chloride (0.044 mL, 0.6 mmol) and 5-(4-amino-3-cyanophenyl)-l-
methyl-lH-pyrrole-2-carbonitrile (0.100 g, 0.45 mmol) to afford the title compound
(O.lOOg, 50%).
HPLC purity component = 96.6% at 210-370 nm; RT = 10.3 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5/A, 150 x 4.6 mm, 1.2 mL/min. HRMS: calcd for CiIiQjS +
tf", 300.0681; found (ESI-FTMS, [M+H]1+), 301.10763.
Example 52: 5-(4-amino-2,6-difluorophenyl)-1 -methyl-1 H-pyrrole-2-carbonitrile
A mixture of 4-bromo-3,5-difiuoroaniline (0.782 g, 3.78 mmol),
tris(dibenzyhdene-acetone)dipalladium (0.096 g, 0.105 mmol),N-methyl-5-
cyanopyrroleboronic acid (1.12g, 7.46 mmol), and potassium fluoride (0.789 g, 13.6
mmol) in THF (10 mL) was stirred under nitrogen. Tri-fert-butylphosphine (10%
solution in hexane, 0.621 mL, 0.210 mmol) was added to the mixture and allowed to
stir until the starting bromide was consumed. The mixture was then diluted with 1/1
hexane/tetrahydrofuran, filtered through a plug of silica gel, the solvent evaporated
43

and the residue purified by silica gel column chromatography (hexane/ethylacetate,
70/30) to afford the title compound (1.77 g, 92%).
HPLC purity component = 100% at 210-370 nm; RT = 8.8 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5/i, 150 x 4.6 mm, 1.2 mL/min. HRMS: calcd for C12H9F2N3 +
H*, 233.0764; found (ESI-FTMS, [M+H]1+), 234.0433.
Example 53: A/-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)-3,5-difluorophenyl]-
methanesulfonamide
A mixture of methanesulfonyl chloride (0.046 mL, 0.66 mmol) and 5-(4-
amino-2,6-difiuorophenyl)-l-methyl-lH-pyrrole-2-carbonitrile (0.100 g, 0.429 mmol)
in pyridine (1.5 mL) was heated to 50° C for 4 hours. The reaction mixture was
acidified with IN HC1 solution and extracted with ethyl acetate. The combined
organic layers were dried over magnesium sulfate, and concentrated. The residue was
purified by silica gel column chromatography (dichloromethane/acetone, 97/3) to
afford the title compound (0.060 g, 45%).
HPLC purity component = 100% at 210-370 nm; RT = 8.7 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5ju, 150 x 4.6 mm, 1.2 mL/min.
Example 54: A/-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)-3,5-
difluorophenyljethane-sulfonamide
This compound was prepared according to the procedure of Example 53 using
ethanesulfonyl chloride (0.062 mL, 0.66 mmol). The residue was purified by silica
gel column chromatography (dichloromethane/acetone, 98/2) to afford the title
compound (0.050 g, 35%).
HPLC purity component = 100% at 210-370 nm; RT = 9.1 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5fi, 150 x 4.6 mm, 1.2 mL/min.
Example 55: N-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)-3,5-
difluorophenyl]propane-1-sulfonamide
44

This compound was prepared according to the procedure of Example 53 using
propanesulfonyl chloride (0.076 mL, 0.66 mmol). The residue was purified by silica
gel column chromatography (dichlorornethane/acetone, 99/1) to afford the title
compound (0.025 g, 17%).
HPLC purity component = 99.4% at 210-370 ran; RT = 9.6 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5fi, 150 x 4.6 mm, 1.2 mL/rnin.
Example 56: /V-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3,5-
difluorophenyl]butane-1-sulfonamide
This compound was prepared according to the procedure of Example 53 using
butanesulfonyl chloride (0.084 mL, 0.66 mmol). The residue was purified by silica
gel column chromatography (dichloromethane/acetone, 99/1) to afford the title
compound (0.025g, 16%).
HPLC purity component = 100% at 210-370 ran; RT = 10 min.; 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min the Xterra™
RP18 instrument, 3.5/i, 150 x 4.6 mm, 1.2 mL/min.
EXAMPLE 57: PHARMACOLOGY
An assay was performed to identify compounds having progesterone receptor
modulator activity. This assay identifies progestins or antiprogestins by determining a
compound's effect on alkaline phosphatase activity in T47D cells.
A. REAGENTS:
Culture medium: DMEM:F12 (1:1) (GIBCO, BRL) supplemented with
5% (v/v) charcoal stripped fetal bovine serum (not heat-inactivated), 100 U/mL
penicillin, 100 \ig/mL streptomycin, and 2 mM the GlutaMax™ reagent (GIBCO,
BRL).
Alkaline phosphatase assay buffer:
I. 0.1M Tris-HCl, pH 9.8, containing 0.2% the Triton™ X-100
reagent
II. 0.1M Tris-HCl, pH 9.8, containing 4 mM p-nitrophenyl
phosphate (Sigma).
45

B. CELL CULTURE AND TREATMENT:
Frozen T47D cells are thawed in a 37 °C water bath and diluted to
280,000 cells/mL in culture medium. To each well in a 96-well plate (Falcon, Becton
Dickinson Labware), 180 \xL of diluted cell suspension is added.
Twenty /iL of reference or test compounds diluted in the culture
medium is then added to each well. When testing for progestin antagonist activity,
reference antiprogestins or test compounds are added in the presence of 1 nM
progesterone. The cells are incubated at 37 °C in a 5% C02/humidified atmosphere for
24 hours.
For high throughput screening, one concentration of each compound
will be tested at 0.3 jtig/mL. Based on an average molecular weight of 300 g/mol for
the compounds in the library, the concentration is approximately 1 pM. Subsequently,
active compounds will be tested in dose response assays to determine EC50 and IC50.
C. ALKALINE PHOSPHATASE ENZYME ASSAY:
At the end of treatment, the medium is removed from the plate. Fifty
fiL of assay buffer I is added to each well. The plates are shaken in a titer plate shaker
for 15 min. Then 150 JUL of assay buffer II is added to each well. Optical density
measurements are taken at 5 minute intervals for 30 minutes at a test wavelength of
405 nM.
D. ANALYSIS OF RESULTS:
Analysis of dose-response data. For reference and test compounds, a
dose response curve is generated for dose (x-axis) vs. the rate of enzyme reaction
(slope) (y-axis). Square root-transformed data are used for analysis of variance and
nonlinear dose response curve fitting for both agonist and antagonist modes. Huber
weighting is used to down-weight the effects of outliers. ECsoor ICso values are
calculated from the retransformed values. JMP software (SAS Institute, Inc.) is used
for both one-way analysis of variance and non-linear dose response analysis in both
single dose and dose response studies.
E. REFERENCE COMPOUNDS:
Progesterone and trimegestone are reference progestins and RU486 is
the reference antdprogestin. All reference compounds are run in full dose response
curves and the ECsoand IC50 values are calculated.
46

Example
# Compound Name IC5o
(nM) Active
Dose
(nM) Inhibition
(%)
1 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]propane-l -sulfonamide 9.8
2 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]-N-
(methylsulfonyl)methanesulfonamide -300
3 N-[4-(5-cyano-1 -methyl- lH-pyrrol-2-
yl)phenyl]butane-1 -sulfonamide -300
4 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]-2,2,2-trifluoroemanesulfonamide 58.4
5 N-[4-(5-cyano-1 -methyl- lH-pyrrol-2-
yl)phenyl]-4-isopropylbenzenesulfonamide -3000
6 N-[4-(5-cyano-1 -methyl- lH-pyrrol-2-
yl)phenyl]benzenesulfonamide -30
7 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyll -4-memylbenzenesulfonamide -3000
8 N-[4-(5-cyano-l -methyl- lH-pyrrol-2-
yl)phenyl]propane-2-sulfonamide 1.5
9 N-[4-(5-cyano-1 -methyl- lH-pyrrol-2-
yl)phenyl]ethanesulfonamide 10
10 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]methanesulfonamide 8.2
11 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
fluorophenyl]methanesulfonamide 28.9
12 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
fluorophenyl]ethanesulfonamide 29.9
14 A-[4-(5-cyano-1 -methyl- lH-pyrrol-2-yl)-3 -
fluorophenyl]methanesulfonamide 18.3 10000
15 JV-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
fluorophenyl] ethanesulfonamide 3.8 10000
16 A[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
fluorophenyl]propane-1 -sulfonamide 3.5
17 N-[4-(5-cyano-l-memyl-lH-pyrrol-2-yl)-3-
fiuorophenyl]butane-l-sulfonamide 6.6
18 A-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
fluorophenyl]propane-2-sulfonamide 9.3 10000
20 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-
2,5-difluorophenyl]-methane-sulfonamide 39.8 10000
21 A/-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-
2,5-difluorophenyI]e±ane-sulfonamide 22.1
23 --(S-cyano-1 -methyl-1 H-pyrrol-2-yl)-
2,5-difluorophenyl]butane-1 -sulfonamide 266.6
24 7-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-
2,5-difluorophenyl]propane-2-sulfonamide 230.8
26 //-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
(trifluoromethyl)phenyl]methane-
sulfonamide 13.4
47

Example
# Compound Name ic50
(nM) Active
Dose
(nM) Inhibition
(%)
27 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
(trifltaoromethyl)phenyl]ethane-sulfonamide 10.2
28 AT-[4-(5-cyano-l-methyl-lH-pyirol-2-yl)-3-
(trifluoromethyl)phenyl]propane-l-
sulfonamide 9.4
29 AT-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
(trifluoromethyl)phenyl]butane-l-
sulfonamide 53.7
30 A44-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
(trifluoromethyl)phenyl]propane-2-
sulfonamide 25.2
31 5-[4-{l, 1 -dioxidoisothiazolidin-2-
yl)phenyl]-l-methyl-lH-pyrrole-2-
carbonitrile 179.5
33 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
(trifluoromethoxy)phenyl]methane-
sulfonamide 32.2
34 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
(trifluoromethoxy)phenyl]ethane-
sulfonamide 35.8
35 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
(trifluoromethoxy)phenyl]propane-1 -
sulfonamide 40.7
39 N-[4-(5-cyano-lH-pyrrol-2-
yl)phenyl]ethanesulfonamide 68.6
40 A/-[4-(5~cyano-l -ethyl-lH-pyrrol-2-
yl)phenyl]ethanesulfonamide 84.1
41 JV-[4-(5-cyano-l -propyl- lH-pyrrol-2-
y l)pheny I] ethanesulfonamide 721.4
42 N-[4-(l-butyl-5-cyano-lH-pyrrol-2-
yl)phenyl]ethanesulfonamide 545.6
43 W-[4-(l-allyl-5-cyano-lH-pyrrol-2-
yl)phenyl]ethanesulfonamide 600.1
44 W-[4-(5-cyano-l-prop-2-yn-l-yl-lH-pyrrol-
2-yl)phenyl] ethanesulfonamide 796.5
45 N-{4-[5-cyano-l-(3-phenylpropyl)-lH-
pyrrol-2-yl]phenyl} ethanesulfonamide 3000 15
48 ./V-[3-cyano-4-(5-cyano-1 -methyl- 1H-
pyrrol-2-yl)plienyl]methanesulfonamide 198.4
49 N-[3-cyano-4-(5-cyano-1 -methyl-lH-
pyrrol-2-yl)phenyl]ethanesulfonamide 123.8
50 N-[3-cyano-4-(5-cyano-l-methyl-lH-
pyrrol-2-yl)phenyl]propane-l-sulfonamide 86.8
51 N-[2-cyano-4-(5-cyano-l-methyl-lH-
pyrrol-2-yl)phenyl]methanesulfonamide 3000 50
53 N-l--cyano-1 -methyl-1 H-pyrrol-2-yl)-
3,5-difluoroplienyl]-methanesulfonamide 16
54 A44-(5-cyano-l-metb.yl-lH-pyrrol-2-yl)-
3,5-difluorophenyl]ethane-sulfonamide 19
48

Example
# Compound Name ICS0
(Nm) Active
Dose
(nM) Inhibition
{%)
55 K-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-
3,5-difluorophenyl]propane-l-sulfonamide 6.2
56 A4-(5-cyano-l-methyl-lH-pyrrol-2-yI)-
3,5-difluorophenyl]butane- I-sulfonamide 8.6
In the table provided above, the IC50 values show the relative progesterone
receptor antagonist activity in this assay. Lower numbers are indicative of higher
potency, i.e., greater PR antagonist activity. The assay has a standard deviation of
about ± 6. Further, compounds 45 and 51 gave 15 and 50% inhibition, respectively,
at an active dose of 3000 nM.
All publications cited in this specification are incorporated herein by reference
herein. While the invention has been described with reference to a particularly
preferred embodiment, it will be appreciated that modifications can be made without
departing from the spirit of the invention. Such modifications are intended to fall
within the scope of the appended claims.
49

CLAIMS:
1. A compound having the structure of formula I, or a pharmaceutically
acceptable salt thereof:

wherein:
Ri is selected from the group consisting of:
H,
CN,
SO2-C1-C6 alkyl, SO2-C3 -C8 cycloalkyl, S02-substituted C1-C6 alkyl,
S02-aryl, S02-substituted aryl, S02-heteroaryl, SCVheterocycle, SO2-C3-C6 alkenyl,
S02-C3-C6 alkynyl, S02-C3-C6 substituted alkenyl, S02-C3-C6 substituted alkynyl,
C(0)-C1-C6 alkyl, C(0)-C3-C8 cycloalkyl, C(0)-substituted C1-C6
alkyl, C(0)-aryl, C(0)-substituted aryl, C(0)-heteroaryl, C(0)-heterocycle, C(0)-C3-
C6 alkenyl, C(0)-C3-C6 alkynyl, C(0)-substituted C3-C6 alkenyl, C(0)-substituted C3-
C6 alkynyl,
C(0)0-CrC6 alkyl, C(0)0-C3-C8 cycloalkyl, C(0)0-substituted Q-Ce
alkyl, C(0)0-aryl, C(0)0-substituted aryl, C(0)0-heteroaryl, C(0)0-heterocycle,
C(0)0-C3-C6 alkenyl, C(0)0-C3-C6 alkynyl, C(0)0-C3-C6 substituted alkenyl,
C(0)0-C3-C6 substituted alkynyl,
C(0)NH-C1-C6 alkyl, C(0)NH-C3-C8 cycloalkyl, C(0)N-di-C3-C8
cycloalkyl, C(0)N-di-d-C6 alkyl, C(0)N-di-substituted CrC6 alkyl, C(0)NH-
substituted CrC6 alkyl, C(0)NH-aryl, C(0)N-di-aryl, C(0)NH-substituted aryl,
C(0)N-diaryl, C(0)NH-heteroaryl, C(0)NH-heterocycle, C(0)N-diheteroaryl,
C(0)N-diheterocycle, C(0)NH-C3-C6 alkenyl, C(0)NH-C3-C6 alkynyl, C(0)NH-
substituted C3-C6 alkenyl, and C(0)NH-substituted C3-C6 alkynyl; or
50

Ri is a linking group to a second structure of formula I to form a dimer
of formula I, said linking group selected from the group consisting of C(O)- and
S(0)r;
R2 is selected from the group consisting of H, C1-C6 alkyl, substituted C1-C6
alkyl, C3-C6 cycloalkyl, S02-alkyl, and S02-substituted alkyl;
provided that at least one of Ri or R2 contain a group having an SO2- bound to
the N or Ri is a S(0)2- linking group; or
Ri and R2 are joined to form -(C(R8)a(R9)b)c-S02-(C(R8)d(R9)e)r;
Rs and R9 are, independently, H, halogen, or C\ to C6 alkyl;
a and b are, independently, 0 to 2, provided that a + b = 2;
d and e are, independently, 0 to 2, provided that a + b = 2;
c and fare, independently, 0 to 5, provided that one of c or f is greater than 0;
R3,R4, R5 and R$ are independently selected from the group consisting of H,
halogen, CN, CrC6 alkyl, substituted Q-Ce alkyl, -(CHmXn)zCHpXq, C3-C6
cycloalkyl, 0-CrC6 alkyl, 0-C1-C6 substituted alkyl, 0-(CHmXn)zCHpXq, aryl,
heteroaryl, heterocycle, substituted aryl, substituted heteroaryl, substituted
heterocycle;
X is halogen;
m and n are, independently, 0 to 2, provided that m + n = 2;
p and q are, independently, 0 to 3, provided that p + q = 3; and
z is 0 to 10;
R7 is selected from the group consisting of H, C1-C6 alkyl, C(0)0-C1-C6 alkyl,
C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, and
substituted C3-C6 cycloalkyl.
2. The compound according to claim 1, wherein:
Ri is selected from the group consisting of S02-C1-C6 alkyl, S02-C3-Cg
cycloalkyl, S02-substituted C1-C6 alkyl, S02-aryl, S02-substituted aryl, S02-
heteroaryl, CN, S02-C3-C6 alkenyl, S02-C3-C6 alkynyl, S02-C3-C6 substituted
alkenyl, and S02-C3-C6 substituted alkynyl;
R2isHorC1-C6alkyl;
51

R.3, R4, R5 and R are independently selected from the group consisting of H,
halogen, C1-Cs alkyl, C3-C6 cycloalkyl, O-C1-C6 alkyl, and O-C1-C6 substituted alkyl;
and
R7 is H or C1-C6 alkyl.
3. The compound according to claim 1, wherein:
Ri is selected from the group consisting of SO2-C1-C4 alkyl, SO2-C3-C5
cycloalkyl, and CN;
R2isH;
R3, R4, R5 and Rg are independently selected from the group consisting of H,
halogen, C1-C6 alkyl, O-C1-Ce alkyl, -(CHmXn)2CHpXq, and O-CCELXnCHpXq; and
R7 is H or C1-C6 alkyl.
4. The compound according to claim 1, wherein:
Ri is SO2-C1-C4 alkyl;
R2isH;
each of R3, R4, R5 and R6 is H or F; and
R7 is CrC6 alkyl.
5. The compound according to claim 1, wherein:
Ri is SO2-C3-C5 cycloalkyl;
R2isH;
R3, R4, R5 and R6 are, independently, H or F; and
R7 is Ci alkyl.
6. The compound according to claim 1, wherein:
Ri is S02-C3-C6 alkyl;
R2isH;
R3, R4, R5 and R6 are, independently, H or F; and
R7 is Ci alkyl.
7. The compound according to claim 1, wherein:
52

Ri is selected from the group consisting of S02-substituted C2-C6 alkyl,
wherein the alkyl is substituted with one or more halogen, and CF3.
8. The compound according to claim 1, wherein:
Ri is a C(O) linking group to a second structure of formula (I) to form a dimer
thereof.
9. The compound according to claim 1,7, or 8, wherein R2 is selected
from the group consisting of H and SO2-C1-C4 alkyl.
10. The compound according to claim 1, 7, 8, or 9, wherein R3 is selected
from the group consisting of H, C1-C3 alkyl, a halogen selected from the group
consisting of F and CI, and O-C1-C3 alkyl.
11. The compound according to claim 1, 7, 8, 9, or 10, wherein R4 is
selected from the group consisting of H and O-C1-C3 alkyl.
12. The compound according to claim 1,7, 8,9,10, or 11, wherein R5 is
selected from the group consisting of H, C1-C3 alkyl, a halogen selected from the
group consisting of F and CI, and O-C1-C3 alkyl.
13. The compound according to claim 1, 7, 8, 9,10,11, or 12, wherein R6
is selected from the group consisting of H and halogen, wherein the halogen is F.
14. The compound according to any one of claims 1 to 4 and 7 to 13,
wherein R7 is Q alkyl.
15. The compound according to claiml, wherein the compound is selected
from the group consisting of:
7V-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]propane-l-
sulfonamide;
53

JV-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)phenyl] -N-
(methylsulfonyl)methane sulfonamide;
iV-[4-(5-cyano-1 -methyl- lH-pyrrol-2-yl)phenyl]butane-1 -sulfonamide;
7V-[4-(5-cyano-1 -methyl-lH-pyrrol-2-yl)phenyl]-2,2,2-
trifluoroethanesulfonamide;
i\r-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]-4-
isopropylbenzenesulfonamide;
JV-[4-(5-cyano-1 -methyl-lH-pyrrol-2-yl)phenyl]benzenesulfonamide;
A[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]-4-
methylbenzenesulfonamide;
AT-[4-(5-cyano-l-memyl-lH-pym>l-2-yl)phenyl]propane-2-
sulfonamide;
7[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]ethanesulfonamide;
N-[4-(5 -cyano-1 -methyl-1 H-pyrrol-2-yl)phenyl]methanesulfonamide
JV-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
fluorophenyljmethanesulfonamide;
7V-[4-(5-cyano-l-methyl-lH-pyiTol-2-yl)-2-
fluorophenyl] ethanesulfonamide;
JV-[4-(5-cyano-1 -methyl- lH-pyrroi-2-yI)-3-
fluorophenyl]ethanesulfonamide;
iV-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-fluorophenyl]propane-l-
sulfonamide;
JV-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-fluorophenyl]butane-l-
sulfonamide;
iV-[4-(5-cyano-1 -methyl- lH-pyrrol-2-yl)-3-fluorophenyl]propane-2-
sulfonamide;
--(S-cyano-l-methyl-lH-pyrrol-y-difluorophenylJ-methane-
sulfonamide;
Ar-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2,5-difluorophenyl]ethane-
sulfonamide;
Ar-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2,5-difluorophenyl]propane-
1-sulfonamide;
54

//-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2,5-difluorophenyl]butane-l-
sulfonamide;
A-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2,5-difluorophenyl]propane-
2-sulfonamide;
iV-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
(trifluoromethyl)phenyl]methane-sulfonamide;
[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
(trifluoromethyl)phenyl]ethane-sulfonamide;
N-[4-(5-cyano-l-methyl-ffl-pyrrol-2-yl)~3-
(trifluoromethyi)phenyl]propane-1 -sulfonamide;
iV-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
(trifluoromethyl)phenyl]butane-1 -sulfonamide;
N-[4-(5 -cyano-1 -methyl- lH-pyrrol-2~yl)-3-
(trifiuoromethyl)phenyl]propane-2-sulfonamide;
N-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)-2-
(trifluoromethoxy)phenyl]m.ethane-sulfonamide;
A-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
(trifluoromethoxy)phenyl]ethane-sulfonamide;
N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
(trifluoromethoxy)phenyl]propane-1 -sulfonamide;
iV-(4-bromophenyl)ethanesulfonamide;
Terr-butyl 2-cyano-5- {4- {(ethylsulfonyl)amino]phenyl} - lH-pyrrole-1 -
carboxylate;
iV-[4-(5-cyano-lH-pyrrol-2-yl)phenyl]ethanesulfonamide;
N-[4-(5-cymo-l -ethyl-1 H-pyrrol-2-yl)phenyl]ethanesulfonamide;
Ar-[4-(5-cyano-l-propyl-lH-pyrrol-2-yl)phenyl]ethanesulfonamide;
Ar-[4-(l-butyl-5-cyano-lH-pyrrol-2-yl)phenyl]ethanesulfonamide;
iV-[4-(l-allyl-5-cyano-lH-pyrrol-2-yl)phenyl]ethanesulfonamide;
JV-[4-(5-cyano-1 -prop-2-yn-1 -yl-1 H-pyrrol-2-
yl)phenyl]ethanesulfonamide;
N- {4-[5-cyano-1 -(3-phenylpropyl)- lH-pyrrol-2-
yljphenyl} ethanesulfonamide;
55

iV-[3-cyano-4-(5-cyano-l-memyl-lH-pyrrol-2-
yl)phenyl]methanesulfonamide;
N- [3-cyano-4-(5-cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl] ethanesulfonamide;
iV-[3-cyano-4-(5-cyano-l-methyHH-pyrrol-2-yl)phenyl]propane-l-
sulfonamide;
N- [2-cyano-4-(5 -cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl]methanesulfonamide;
--(S-cyano-l-methyl-lH-pyrrol-y-S-difluorophenyl]-
methanesulfonamide;
AL[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3,5-difluorophenyl]ethane-
sulfonamide;
N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3,5-difluorophenyl]propane-
1-sulfonamide;
iV-[4-(5-cyano-1 -methyl- lH-pyrrol-2-yl)-3,5-difluorophenyl]butane-1 -
sulfonamide; and
JV-[4-(5-cyano-1 -methyl- lH-pyrrol-2-yl)-3-
fluorophenyl]methanesulfonamide.
16. A pharmaceutical composition comprising a compound according to
any of claims 1 to 15 and a pharmaceutically acceptable carrier.
17. The pharmaceutical composition according to claim 16, wherein said
composition is an oral dosage unit.
18. The pharmaceutical composition according to claim 16, wherein said
composition is a solid oral dosage unit.
19. The pharmaceutical composition according to any of claims 16 to 18,
wherein said composition further comprises an estrogen.
56

20. The pharmaceutical composition according to any of claims 16 to 18,
wherein said composition further comprises a progestin.
57

Progesterone receptor modulators of formula (I), or a pharmaceutically acceptable salt thereof, Formula (I); wherein R1, R2, R3, R4, R5, R6 and R7 are as defined herein, are useful for contraception and hormone replacement therapy are described. Also provided are products containing these compounds.