CYANOPYRROLE-PHENYL AMIDE 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 are provided for
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, or the synchronization of the estrus in livestock.
In another aspect, pharmaceutical compositions containing a PR modulator
described herein, optionally in combination with a progestin or estrogen are provided.
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 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, or synchronization of estrus in livestock are provided.
1

A progesterone receptor modulator is thereby characterized by having the
structure of formula I:

wherein:
Ri is selected from among:
H,
CN,
C(0)-C1-C6 alkyl, C(0)-C3-C8 cycloalkyl, C(0)-substituted C1-Q 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-C1-C6 alkyl, C(0)0-C3-C8 cycloalkyl, C(0)0-substituted C,-C6
alkyl, C(0)0-aryl, C(0)0-substituted aryl, C(0)0-heteroaryl, C(0)0-heterocycle,
C(0)0-CrC5 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 -Cg cycloalkyl, C(0)N-di-C3-C8
cycloalkyl, C(0)N-di CrC6 alkyl, C(0)N-di-substiruted CrC6 alkyl, C(0)NH-substituted
C1-Ce 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)N-diheteroaxyl, C(0)NH-heterocycle, C(0)N-
diheterocycle, C(0)NH-C3-C6 alkenyl, C(0)NH-C3-C6 alkynyl, C(0)NH-substiruted C3-
C6 alkenyl, C(0)NH-substiruted C3-C6 alkynyl, and
Ri is a linking group to a second structure of formula I to form a dimer of
formula I, said linking group is a C(O)- group;
R2 is selected from among H, C1-Ce alkyl, substituted C1-C6 alkyl, and C3-
C6 cycloalkyl;
2

provided that Ri and R2 both are not H,
provided that when Ri is C(O) substituted aryl, R? is not H;
provided that when Ri is H and R7 is H, R2 is not C1-C6 alkyl;
R3,R4, R5 and R are independently selected from among H, halogen, Q-
C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, 0-C1-C6 alkyl, O-C1-C6 substituted
alkyl, aryl, heteroaryl, heterocycle, substituted aryl, substituted heteroaryl, and
substituted heterocycle;
R7 is selected from among H, C1-C6 alkyl, 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 CN;
R2isHorC1-C6alkyl;
R3, R4, R5 and Re are independently selected from among H, halogen, C\-
C$ alkyl, C3-C6 cycloallcyl, O-C1-Cg alkyl, and O-Q-Ce substituted alkyl; and
R7 is H or d-C6 alkyl.
In another embodiment, the compound has the structure of formula I, wherein:
Ri is CN;
R2isH,
R3,R4, R5 and R6 are independently selected from H, halogen, C1-C6 alkyl,
and O-C1-C6 alkyl; and
R7 is H or Q-Ce alkyl.
In yet another embodiment, the compound has the structure of formula I, wherein:
Ri is C(0)-C1-C6 alkyl or C(0)-C3-C5 cycloalkyl;
R3, R4, R5 and R6 are, independently, selected from among H, halogen, C1-
C6 alkyl, and O-C1-C6 alkyl; and
R7 is H or C1-C6 alkyl.
In a further embodiment, the compound has the structure of formula I, wherein:
Ri is C(0)C1-C4 alkyl or C(O) C3-C6 cycloalkyl;
R3, R4, R5 and R6 are H; and R7 is Ci alkyl.
3

In still a further embodiment, the compound has the structure of formula I,
wherein Ri or R2 is CN.
In another embodiment, the compound is N-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]-2-furamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]-3-
methylbutanamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]-2-
methylpropanamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]propanamide;N-[4-
(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]butanamide;N-[4-(5-cyano-l-methyl-lH-
pyrrol-2-yl)phenyl]acetamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]benzamide; N-[4-(5 -cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl]cyclobutanecarboxamide;N-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl] cyclohexanecarboxamide; N- [4-(5 -cyano-1 -methyl-1 H-pyrrol-2-yl)phenyl] -2-
methylacrylamide; Ethyl [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]carbamate;
Isobutyl [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]carbamate;N,N'-bis[4-(5-cyano-l-
methyl-lH-pyrrol-2-yl)phenyl]urea; [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
methylphenyl]cyanamide; [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
ethylphenyljcyanamide; [4-(5-cyano-l -methyl-lH-pyrrol-2-yl)-2-
propylphenyl]cyanamide; [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
isopropylphenyljcyanamide; [2-chloro-4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]cyanamide; [2-fluoro-4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]cyanamide;
[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-methoxyphenyl]cyanamide; [4-(5-cyano-l-
methyl-lH-pyrrol-2-yl)-3-methoxyphenyl]cyanamide; [4-(5-cyano-l-methyl-lH-pyrrol-
2-yl)-3-methylphenyl]cyanamide;and[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]methylcyanamide.
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; racemic
and resolved enantiomerically pure R and S stereoisomers; other mixtures of the R and S
stereoisomers; and pharmaceutically acceptable salts thereof.
4

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 Cs). In another embodiment, an
alkyl group has 1 to about 6 carbon atoms (i.e., Ci, C2, C3, C4, C5 or Ce). In a furtlier
embodiment, an alkyl group has 1 to about 4 carbon atoms (i.e., Ci, C2, C3, or C4).
The term "cycloallcyl" 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, C6, C7, or Cs). In another embodiment, a cycloalkyl group has 3 to
about 6 carbon atoms (i.e., C3, C4, C5 or C ).
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 Cs). 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 C ).
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 Ce).
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 to, phenyl,
5

naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, indene, benzonaphthyl, and
fluorenyl.
The tenn "substituted aryl" refers to an aryl group which is substituted with one
or more substituents including halogen, CN, OH, NO2, 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, thiamorphoUnyl,
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
6

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 or
sulfur atoms in the backbone of the ring, the nitrogen or sulfur atoms can be oxidized.
The term "heteroaryl" also refers 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, thiazolyl, oxadiazolyl, oxatriazolyl,
oxepinyl, thiepinyl, diazepinyl, benzofuranyl, thionapfhene, indolyl, benzazolyl,
purindinyl, pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl, quinolinyl,
isoquinolinyl, benzodiazonyl, 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
7

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.
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 "allcylamino" 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
acids, 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 trimethylammonium, mono-, di- and triethylammonium,
mono-, di- and tripropylammonium (iso and normal), ethyldimethylammonium,
benzyldimethylammonium, cyclohexylammonium, benzylammonium,
dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 1-
metliylpiperidinium, 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-
ethanolammomum, and the like. Physiologically acceptable alkali salts and alkaline earth
metal salts can include, without limitation, sodium, potassium, calcium and magnesium
salts in the form of esters, and carbamates.
8

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. In another embodiment, the prodrugs are carbamates. See, e.g., B.
Testa and J. Caldwell, "Prodrugs Revisited: The "Ad Hoc" Approach as a Complement
to Ligand Design", Med. Research Rev., 16(3):233-241, ed., John Wiley & Sons (1996).
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 described herein by the cell or patient.
Desirably, metabolites are formed in vivo.
9
The compounds are readily prepared by one of slcill 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
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). Alternate catalyst systems are described
in Hartwig et al., Journal of 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 THF,
dimethoxy ethane, 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.
Compounds 4, where Ri includes an amide, are readily accessible from 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), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC),
benzotriazol-1-yl-oxytripyrrolidmophosphonium 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 compounds 3 by reaction with a wide
variety of electrophilic reagents including chloroformates or activated carbonates.
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, carbamoyl chlorides, and
10

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, triethylarnine, 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 may be directly dissolved in an acid chloride or chloroforrnate
in the absence of solvent or base to generate compounds 4.
Compounds 5 are readily accessible from compounds 4 by reaction with a wide
variety of electrophilic reagents such as acid 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 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
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 derivative 4 may be directly dissolved in an acid
chloride, chloroforrnate in the absence of solvent or base to generate compounds 5.
11


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 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, 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, triethylamine, 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
12

and then reacted with the electrophilic reagent. Alternatively the aniline 1 may be
directly dissolved in an acid chloride 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, 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 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, potassium carbonate, are also
suitable bases for the reaction. The aniline derivative 8 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 derivative 8 may be
directly dissolved in an acid 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
tefralris(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
13

Hartwig, J. F. et al. 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, dimethoxy ethane, 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 provided are pharmaceutical compositions containing one or more
compounds described 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.
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 the
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
14

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, 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
15

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. For most large mammals, the total daily dosage is from about 1
to 100 mg, desirably from about 2 to 80 mg. Dosage forms suitable for internal use
contain 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 employed in the
preparation of pharmaceutical compositions may be 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 administration of the compounds is desirable.
The compounds may also be administered parenterally or intraperitoneally.
Solutions or suspensions of these active 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.
16

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.
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.
The PR modulator compound(s) may also be delivered via a transdermal patch.
Suitably, use of the patch is timed to the 28 day cycle. Li 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,
17

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-l,4-dihydro-2H-3,l-
benzoxazin-6-yl)-l-methyl-lH-pyrrole-2-carbonitrile are provided.
Further provided 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 may be 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 maybe 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 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 u.g to about 100 fig 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 u,g
to about 35 jug 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, progestin, or estrogen
is not administered.
Progestational agents include, but are not limited to, tanaproget, levonorgestrel,
norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone
acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest,
18

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 administration 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 2 8-day cycle.
In another regimen, a progestational agent may be coadministered 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 can include co-administration from days 1 to 21 of a
progestational agent, e.g., levonorgestrel, being administered at a daily dose equal in
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 coadministration 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
19

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 include (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 ug; a second phase of from 1 to 7 daily dosage
units, and desirably, 4 daily dosage units, as described above, 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
20

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 include 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.
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 may be proportionally increased or reduced as indicated by the
exigencies of the therapeutic situation. In 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.
21

The desirable pharmaceutical compositions from the standpoint of ease of
preparation and administration are solid compositions, particularly tablets and hard-filled
or liquid-filled capsules. Oral administration of the compounds is desirable.
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, 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: 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile
4-Bromoaniline (5.00 g, 29.0 mmol), l-methyl-5-cyano-2-pyrroleboronic acid
(5.2 g, 34.8 mmol), KF (5.55 g, 95.7 mmol), and Pd2(dba)3 (332 mg, 0.36 mmol) were
added to a 200 mL round bottom flask under nitrogen. The flask was sealed and purged
with nitrogen for 5 min. THF (72 mL) was added and the mixture was purged with
22

nitrogen for an additional 5 min. A solution of tri-f-butylphosphine (10 wt % in hexanes)
(2.15 mL, 0.73 mmol) was added via syringe and the mixture was stirred vigorously at 25
°C for 5 h. 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 by silica gel flash chromatography (20 %
acetone/hexane) afforded 5-(4-arninophenyl)-l-methyl-lH-pyrrole-2-carbonitrile (3.3 g)
as an off-white solid.
HPLC purity 100 % at 210-370 nm, 7.6 min.; 100 % at 290 nm, 7.6 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. HRMS: calcd for
C12H11N3 + H+, 198.10257; found (ESI, [M+H]+), 198.1027.
Example 2: 5-(4-amino-3-fluorophenyl)-1 -methyl-1 H-pyrrole-2-carbonitrile
4-Bromo-2-fluoroaniline (2.42 g, 12.8 mmol), l-methyl-5-cyano-2-pyrroleboronic
acid (2.3 g, 15.3 mmol), KF (2.45 g, 42.2 mmol), and Pd2(dba)3 (147 mg, 0.16 mmol)
were added to a 100 mL round bottom flask under nitrogen. The flask was sealed and
purged with nitrogen for 5 min. THF (32 mL) was added and the mixture was purged
with nitrogen for an additional 5 min. A solution of tri-f-butylphosphine (10 wt % in
hexanes) (0.95 mL, 0.32 mmol) was added via syringe and the mixture was stirred
vigorously at 25 °C for 5 h. 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 by flash chromatography (20%
acetone/hexane) afforded 5-(4-amino-3-fluorophenyl)-1 -methyl- lH-pyrrole-2-
carbonitrile (0.76 g) as an off-white solid.
HPLC purity 100 % at 210-370 nm, 8.4 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 C12H10FN3 + H+,
216.09315; found (ESI, [M+H]"), 216.0947
23

Example 3: A/-[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)phenyl]-2-furamide
The general procedure for acylation of 5-(4-aminophenyl)-l -methyl- lH-pyrrole-
2-carbonitrile is as follows.
5-(4-Aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile (98 mg, 0.5 mmol) was
dissolved in dichloromethane (2 mL) and triethylamine (87 juL, 0.6 mmol) was added.
Furan-2-carbonyl chloride (54 piL, 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 NaHC03, 2N HC1, brine, dried over MgSC>4, and passed through a plug of silica
gel. The solution was concentrated to give JV-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]-2-furamide (0.041 g).
HPLC purity 100% at 210-370 ran, 8.9 min.; 100% at 302 nm, 8.9 min.; the
Xterra™ RP18 instrument, 3.5 ft, 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
C17HBN3O2 + it, 292.10805; found (ESI, [M+H]+), 292.1072.
Example 4: A/-[4-(5-cyano-1-methyl-1 H-pyrrol-2~yl)phenyl]-3-methylbutanamide
The title compound was prepared according to the general procedure for acylation
of 5-(4-aniinophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using 3-methyl-butyryl
chloride (67 fiL, 0.55 mmol) to provide 7Y-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]-
3-methyl butanamide (0.042 g).
HPLC purity 100% at 210-370 nm, 9.4 min.; 99.6% at 290 nm, 9.4 min.; the
Xterra™ RP18 instrument, 3.5 fi, 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
C17H19N3O + H+, 282.16009; found (ESI, [M+H]*), 282.1608.
Example 5: A/-[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)phenyl]-2-methylpropanamide
The title compound was prepared according to the general procedure for acylation
of 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using isobutyryl chloride (58
24

/xL, 0.55 mmol) to provide//-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]-2-
methylpropanamide (0.026 g).
HPLC purity 100% at 210-370 ran, 8.9 min.; 100% at 290 nm, 8.9 min.; the
Xterra™ RP18 instrument, 3.5 fi, 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
CgHnNaO + H+, 268.14444; found (ESI, [M+H]4), 268.1433.
Example 6: A/-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)phenyl]propanamide
The title compound was prepared according to the general procedure for acylation
of 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using propionyl chloride (48
[AL, 0.55 mmol) to provide Ar-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]propanarnide
(0.012 g).
HPLC purity 100% at 210-370 nm, 8.4 min.; 99.7% at 290 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. HRMS: calcd for
C15Hi5N30 + H+, 254.12879; found (ESI, [M+H]+), 254.1293.
Example 7: A/-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)phenyl]butanamide
The title compound was prepared according to the general procedure for acylation
of 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using butyryl chloride (59 /xL,
0.55 mmol) to provide N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]butanamide
(0.045 g).
HPLC purity 100% at 210-370 nm, 9.0 min.; 99.9% at 272 ran, 9.0 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
Ci6Hi7N30 + H*, 268.14444; found (ESI, [M+H]+), 268.1432.
25

Example 8: /V-[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)phenyi]acetamide
The title compound was prepared according to the general procedure for acylation
of 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using acetyl chloride (39 /xL,
0.55 mmol) to provide iV-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]acetamide (0.018
g).
HPLC purity 100% at 210-370 nm, 7.8 min.; 100% at 290 nm, 7.8 min.; the
Xterra™RP18 instrument, 3.5 fi, 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
C14H13N3O + H4, 240.11314; found (ESI, [M+H]*), 240.1135.
Example 9: A/-[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)phenyl]benzamide
The title compound was prepared according to the general procedure for acylation
of 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using benzoyl chloride (64 /XL,
0.55 mmol) to provide 7Y-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]benzamide (0.035
g).
HPLC purity 97.4% at 210-370 nm, 9.6 min.; 97.2% at 298 nm, 9.6 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
C19H15N3O + H+, 302.12879; found (ESI, [M+H]4), 302.1273.
Example 10: /V-[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)phenyl]cyclobutane-
carboxamide
The title compound was prepared according to the general procedure for acylation
of 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using cyclobutane carbonyl
chloride (60 fiL, 0.55 mmol) to provide iV-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]
cyclobutane carboxamide (0.048 g).
HPLC purity 99.5% at 210-370 nm, 9.3 min.; 99.5% at 290 nm, 9.3 min.; the
Xterra™ RP18 instrument, 3.5 n, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95
26

(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for
C,7H17N30 + H*, 280.14444; found (ESI, [M+Hj4), 280.145.
Example 11: A/-[4-(5-cyano1-methyl-1 H-pyrrol-2-yl)phenyl]cyclohexane-
carboxamide
The title compound was prepared according to the general procedure for acylation
of 5-(4-aminophenyl)-l -methyl- lH-pyrrole-2-carbonitrile using cyclohexanecarbonyl
chloride (67 /xL, 0.55 mmol) to provide 7V"-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]cyclohexanecarboxamide (0.039 g).
HPLC purity 99.5% at 210-370 nm, 10.1 min.; 99.6% at 290 nm, 10.1 min.; the
Xterra™ RP18 instrument, 3.5 /*, 150 x 4.6 mm column, 1.2 mUrnin., 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for
C19H21N3O + Ff1", 308.17574; found (ESI, [M+ H]+), 308.1764.
Example 12: N-[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)phenyl]-2-methylacrylamide
The title compound was prepared according to the general procedure for acylation
of 5-(4-aminophenyl)-1 -methyl-1 H-pyrrole-2-carbonitrile using 2-methyl-acryloyl
chloride (53 p,L, 0.55 mmol) to provide 7Y-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]-
2-methylacrylamide (0.037 g).
HPLC purity 99.2% at 210-370 nm, 8.8 min.; 99.1% at 296 nm, 8.8 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. HRMS: calcd for
C,6Hi5N30 + H+, 266.12879; found (ESI, [M+H]4), 266.1295.
Example 13: Ethyl [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl] carbamate
The title compound was prepared according to the general procedure for acylation
of 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using ethyl chloroformate (53
/iL, 0.55 mmol) to provide ethyl [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]carbamate
(0.026 g).
27

HPLC purity 100% at 210-370 nm, 9.3 min.; 100% at 288 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. HRMS: calcd for
Ci5Hi5N302 + H+, 270.12370; found (ESI-FTMS, [M+H]+), 270.12391.
Example 14: Isobutyl [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyI]carbamate
The title compound was prepared according to the general procedure for acylation
of 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using isobutyl chloroformate
(72 /xL, 0.55 mmol) to provide isobutyl [4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]carbamate (0.046 g).
HPLC purity 100% at 210-370 nm, 10.2 min.; 100% at 286 nm, 10.2 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
C17H19N3O2 + H+, 298.15500; found (ESI, [M+H]*), 298.1550.
Example 15: A/,A/'-bis[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)phenyl]urea
The title compound was prepared according to the general procedure for acylation
of 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-carbonitrile using ethyl chloroformate (53
JUL, 0.55 mmol) to provide A/,7 '-bis[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]urea
(0.006 g).
HPLC purity 100% at 210-370 nm, 10.5 min.; 100% at 304 nm, 10.5 min.; the
Xterra™ RP18 instrument, 3.5 ji, 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'
C25H20N6O + H\ 421.17713; found (ESI-FTMS, [M+Hf), 421.1775.
Example 16: [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl] cyanamide
A solution of l-methylpyrrole-2-carbonitrile (50.0g, 0.471 mol) and triisopropyl
borate (119.5 mL, 0.518 mol, 1.1 eq.) in THF (600 mL) was stirred and cooled to 0 °C.
LDA (2M in heptane/THF/ethylbenzene, 306 mL, 0.613 mol, 1.3 eq.) was added in a
28

stream, over about 15 minutes. The temperature of the reaction rose to 24 °C, and then
began to subside to 7 °C. The cooling bath was removed and the mixture was stirred for
one hour until no starting material (l-methylpyrrole-2-carbonitrile) was detected by thin
layer chromatography (TLC, 1/5: EtOAc/hexane). The reaction mixture was poured
gradually into HC1 (4N, 542 mL) cooled with ice bath. The ice bath was removed, and
the mixture stirred at room temperature for one hour. The organic phase was separated,
and the water phase extracted with EtOAc (2 x 300 mL). The combined organic phases
was dried over MgSCU, and concentrated on a rotary evaporator at or below 30 °C. The
crude product (66 g) was mixed with EtOAc (100 mL), cooled with ice-water bath and
basified with cold NaOH (2 N, 500 mL) solution. The cooling bath was removed and the
mixture was stirred efficiently until most solids had dissolved. The EtOAc phase was
then separated, and the aqueous layer extracted with ether (200 mL). The light colored
aqueous phase was cooled to 7 °C and acidified with HC1 (6N, 180 mL) to pH 2-3. A
light pink solid was collected by filtration, washed with water (2 x 30 mL), dried by
suction for an hour then in a vacuum oven at ambient temperature for 17 h to give 41.6 g
(59 %) of the N-methylpyrrole-2-carbonitrile-5-boronic acid.
A mixture of cyanogen bromide (5.0 g, 47 mmol), and 4-bromoaniline (17.8 g,
103.4 mmol) in diethylether (150 mL) was stirred for 3 days under nitrogen atmosphere.
The reaction was filtered, and the filtrate was concentrated in vacuo at room temperature
to give 4-bromophenylcyanamide (8.5 g, 92 %) as an off white solid.
4-bromophenylcyanamide (0.651 g, 3.34 mmol),
tris(dibenzylideneacetone)dipalladium (76 mg, 0.078 mmol), N-methyl-5-
cyanopyrroleboronic acid (1.1 g, 7.3 mmol), and potassium fluoride (0.776 g, 13.2 mmol)
were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous
flow of nitrogen and THF (10 mL) was added. *ri-rer£-butylphosphine (10 wt % in
hexane) (0.486 mL, 0.078 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/ethylacetate, filtered through a plug of silica gel, the solvent was evaporated and
29

the residue was flash chromatography using 5/1,4/1, then 3/2 Hexane/Ethylacetate to
give (0.250 g, 33 %) of the title compound.
HPLC purity 100% at 210-370 nm, 10 min.; 100% at 290 nm, 10.1 min.; the
Xterra™ RP18 instrument, 3.5 /i, 150 x 4.6 mm column, 1.2 mL/min., 85/15-5/95
(Ammon. found (ESI, [M+H]+), 223.0973 HRMS: calcd for Ci3Hi0N4 + H+, 223.09782;
found (ESI, [M+H]4), 223.0973.
Example 17: [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-methylphenyl] cyanamide
A mixture of cyanogen bromide (5.0 g, 47 mmol) and 4-bromo-2-methylaniline
(Aldrich Chemical Company) (19.15 g, 103.4 mmol) in diethylether (150 mL) was stirred
for 3 days under nitrogen atmosphere. The reaction was filtered, and the filtrate was
concentrated in vacuo at room temperature to give 4-bromophenylcyanamide (8.5 g, 92
%) as an off white solid. HRMS: calcd for C8H7BrN2, 209.97926; found (EI, M4),
209.9788.
(4-bromo-2-methylphenyl)cyanamide (0.698 g, 3.34 mmol),
tris(dibenzylideneacetone)dipalladium (76 mg, 0.083 mmol), N-methyl-5-
cyanopyrroleboronic acid (1.1 g, 7.3 mmol), and potassium fluoride (0.776 g, 13.2 mmol)
were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous
flow of nitrogen and THF (10 mL) was added with stirring. Then tri-ter butylphoshine
(10 wt % in hexane) (0.486 mL, 0.083 mmol) was added to the mixture and allowed to
stir 3 hours. The mixture was then diluted with 1/1 hexane/ethylacetate and filtered
through a plug of silica gel, the reaction was concentrated and the residue was flash
chromatographed using 4/1 Hexane/THF to give (0.062 g, 7 %) of the title compound.
HPLC purity 100% at 210-370 nm, 10 min.; 99.8% at 290 nm, 10.1 min.; the
Xterra™ RP18 instrument, 3.5 fi, 150 x 4.6 mm column, 1.2 niL/min., 85/15-5/95
(Ammon. Form.Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min HRMS: calcd
forC14Hi2N4 + H4, 237.11347; found (ESI-FTMS, [M+H]4), 237.1126
30

Example 18: [4-(5-cyano-1-methyl~1 H-pyrrol-2-yl)-2-ethylphenyl]cyanamide
A mixture of cyanogen bromide (5.0 g, 47 mmol) and 4-bromo-2-ethylaniline
(20.6 g, 103 mmol) in diethylether (150 mL) was stirred for 3 days under nitrogen
atmosphere. The amine hydrobromide was filtered off, and the filtrate was concentrated
in vacuo at room temperature and triturated with hexane to give 4-
bromophenylcyanamide (2.3g, 10 %) as an off white solid. HRMS: calcd for CciHgBrNa
+ H+, 225.00218; found (ESI-FTMS, [M+HJ*), 225.00277.
4-bromo-2-ethylphenylcyanamide (0.125g, 0.5 mmol), tris(dibenzylideneacetone)
dipalladium (11.6mg, 0.0126 mmol), N-methyl-5-cyanopyrroleboronic acid (0.150 g, 1
mmol), and potassium carbonate (0.276 g, 2 mmol) were placed in a 40 mL vial fitted
with a septa. The vial was then filled with a continuous flow of nitrogen and THF (2 mL)
was added. Tri-tert-butylphosphine (10 wt % in hexane) (0.0486 mL, 0.0252 mmol) was
added to the mixture and allowed to stirred until the starting bromide was consumed. The
mixture was then diluted with 1/1 hexane/ethylacetate and filtered through a plug of silica
gel, the solvent was evaporated and the residue was flash chromatographed using 4/1
Hexane/THF to give (0.030 g, 24%) the title compound.
HPLC purity 100% at 210-370 nm, 10 min.; 99.4% at 290 nm, 10.1 min.; the
Xterra™ RP18 instrument, 3.5 fi, 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. HRMS: calcd for
C15H14N4 + H4", 251.12912; found (ESI-FTMS, [M+H]1+), 251.12953.
Example 19: [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-propylphenyl] cyanamide
A mixture of cyanogen bromide (1.89 g, 17.9 mmol), and 2-n-propylaniline (3.87
g, 28.65 mmol) in ether (50 mL) was stirred for 2.5 hours under nitrogen atmosphere.
The mixture was poured into water and extracted with diethylether. The solvent was
dried over magnesium sulfate and concentrated in vacuo at room temperature to give 2-
propylphenylcyanamide (1.2 g, 26 %) as an off white solid.
(2-propylphenyl)cyanamide (0.550 g, 3.43 rnmol), sodium acetate (0.278 g, 3.4
mmol), and catalytic acetic acid were combined in dichloromethane (25 mL). Bromine
31

(0.17 mL, 3.43 mmol) was added dropwise and allowed to stir 2.5 hours. The mixture
was then poured into brine and extracted with diethylether. The solvent was dried over
magnesium sulfate and evaporated in vacuo. The solid was triturated with 9/1
Hexane/acetone, filtered, and dried to give 4-bromo2-propylphenylcyanamide (0.200g,
24%) an off white solid. HRMS: calcd for CioHnBrN2 + H4", 239.01783; found (ESI-
FTMS, [M+H]4), 239.01782.
4-bromopropylphenylcyanamide (0.125 g, 5 mmol) tris(dibenzylideneacetone)
dipalladium (11.6 mg, 0.0126 rnmol), N-methyl-5-cyanopyrroleboronic acid (0.150 g, 1
mmol), and potassium carbonate (0.276 g, 2 mmol) were placed in a 40 mL vial fitted
with a septa. The vial was then filled with a continuous flow of nitrogen and THF (2 mL)
was added with stirring. Tri-teri-butylphosphine (0.0486 mL, 0.0252 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/ethylacetate and filtered through a plug of silica gel,
solvent was evaporated and the residue was flash chromatographed using 4/1
Hexane/THF to give (0.025 g, 18%) of [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
propylphenyljcyanamide.
HPLC purity 100% at 210-370 nm, 10 min.; 99% at 290 nm, 10.1 min.; the
Xterra™ RP18 instrument, 3.5 n, 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
Ci6H16N4 + H+, 265.14477; found (ESI-FTMS, [M+H]14), 265.14535.
Example 20: [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-isopropylphenyl] cyanamide
A mixture of cyanogen bromide (1.89 g, 17.9 mmol) and 2-isopropylaniline
(3.875 g, 28.65 mmol) in diethylether (25 mL) was stirred for 2.5 hours under nitrogen
atmosphere. The aniline hydrobromide was filtered, the diethylether evaporated, and the
residue flash chromatographed using 4/1 Hexane/acetone to give (1.85 g, 64%) the title
compound. HRMS: calcd for Ci0HnBrN2 + H4, 183.08927; found (ESI-FTMS, [M+Na]),
183.08928.
32

(2-isopropylphenyl) cyanamide (0.550 g, 3.43 mmol) and catalytic acetic acid
were combined in dichloromethane (20 mL). Bromine (0.17 mL, 3.43 mmol) was added
dropwise and allowed to stir 2.5 hours. The mixture was then poured into brine and
extracted with diethylether. The solvent was dried over magnesium sulfate and
evaporated in vacuo. The residue flash chromatographed using 9/1, then 4/1
Hexane/acetone to give (0.380 g, 47%) as an off white solid. HRMS: calcd for
CioHiiBrN2 + H*, 239.01783; found (ESI-FTMS, [M+H]14), 239.01844.
4-bromo-2-isopropylphenylcyanamide (0.132 g, 0.5 mmol) tris
(dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-
cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol)
were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous
flow of nitrogen and THF (2 mL) was added with stirring. Then tri-ter/-butylphosphine
(0.0486 mL, 0.0252 mmol) was added to the mixture and allowed to stir until starting
bromide was consumed. The mixture was then diluted with 1/1 hexane/ethylacetate and
filtered through a plug of silica gel, solvent evaporated and the residue was flash
chromatographed using 4/1 Hexane/THF to give (0.025 g, 18%) [4-(5-cyano-l-methyl-
lH-pyrrol-2-yl)-2-isopropylphenyl] cyanamide.
HPLC purity 100% at 210-370 nm, 10 min.; 99.6% at 290 nm, 10.1 min.; the
Xterra™ RP18 instrument, 3.5 fi, 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
C16H16N4 + it, 265.14477; found (ESI, [M+H]*), 265.1467
Example 21: [2-chloro-4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl] cyanamide
A mixture of cyanogen bromide (1.87 g, 15 mmol), and 2-chloroaniline (3.14 mL,
30 mmol) in ether (15 mL) was stirred for 2 days under nitrogen atmosphere. The
reaction was filtered, the filtrate evaporated, and the residue flash chromatographed using
95/5 Hexane/acetone to give (0.430 g, 18 %) of the title compound.
(2-chlorophenyl) cyanamide (0.400 g, 2.6 mmol), sodium acetate (0.250 g, 3
mmol) and catalytic acetic acid were combined in dichloromethane (25 mL). Bromine
33

(0.130 mL, 2.5 mmol) was added dropwise and allowed to stir 1 hour. The mixture was
then poured into brine and extracted with diethylether. The organic layer was dried over
magnesium sulfate and evaporated in vacuo. The residue was flash chromatographed
using 85/15 to give (0.220 g, 37%) an off white solid.
4-bromo-2-chlorophenylcyanamide (0.114 g, 0.5 mmol), tris
(dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-
cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol)
were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous
flow of nitrogen and THF (2 mL) was added with stirring. Tri-te butylphosphine (10
wt % in hexane) (0.0486 mL, 0.0252 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/ethylacetate, filtered through a plug of silica gel, the solvent evaporated and the
residue was flash chromatographed using 4/1 Hexane/THF to give [2-chloro-4-(5-cyano-
1-methyl-lH-pyrrol-2-yl)phenyl] cyanamide) (0.015 g, 12 %).
HPLC purity 100% at 210-370 ran, 10 min.; 99% at 290 nm, 10.1 min.; the
Xterra™RP18 instrument, 3.5 p, 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
C13H9CIN4 + IT", 257.05885; found (ESI-FTMS, [M+H]14), 257.05911.
Example 22: [2-fluoro-4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)phenyl]cyanamide
A mixture of cyanogen bromide (1.87 g, 15 mmol) and 2-fiuoroaniline (2.88 mL,
30 mmol) in ether (15 mL) was stirred for 2 days under nitrogen. The reaction was
filtered, the filtrate evaporated, and the residue flash chromatographed on silica gel using
95/5 Hexane/acetone to give the title compound (1 g, 25 %).
(2-fluorophenyl) cyanamide (0.900 g, 6.6 mmol), sodium acetate (0.572 g, 7
mmol) and catalytic acetic acid were combined in dichloromethane (50 mL). Bromine
(0.324 mL, 6.3 mmol) was added dropwise and allowed to stir 1 hour. The mixture was
then poured into brine and extracted with diethylether. The solvent was dried over
magnesium sulfate and evaporated in vacuo. The residue flash chromatographed using
34

85/15 to give (0.513 g, 36%) an off white solid. HRMS: calcd for CvttjBrFNa,
213.95419; found (EI, M4), 213.9533
4-bromo-2-fluorophenylcyanamide (0.106 g, 0.5 mmol),
tris(dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-
cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol)
were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous
flow of nitrogen and THF (2 mL) was added with stirring. Tri-tert-butylphosphine (10
wt % in hexane) (0.0486 mL, 0.0252 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/ethylacetate, filtered through a plug of silica gel, the solvent evaporated and the
residue was flash chromatographed on silica gel using 4/1 Hexane/THF to give [2-fluoro-
4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]cyanamide (0.015 g, 12 %).
HPLC purity 100% at 210-370 ran, 10 min.; 99.6% at 290 nm, 10.1 min.; the
Xterra™ RP18 instrument, 3.5 /i, 150 x 4.6 mm column, 1.2 rnL/min., 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min HRMS: calcd for
C3H9FN4 + H+, 241.08840; found (ESI-FTMS, [M+H]1+), 241.08852.
Example 23: [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-methoxyphenyl] cyanamide
(2-methoxyphenyl) aniline (2.42 g, 12 mmol) and catalytic acetic acid were
combined in dichloromethane (20 mL). Bromine (0.17 mL, 3.43 mmol) was added
dropwise and the reaction allowed to stir for 2.5 hours. The mixture was then poured into
brine and extracted with diethylether. The organic layer was dried over magnesium
sulfate, evaporated in vacuo, and used without further purification.
A mixture of cyanogen bromide (0.550 g, 5.19 mmol), and (4-bromo-2-
methoxyphenyl) aniline (2.42 g, 12 mmol) in ether (5 mL) was stirred for 3 days under
nitrogen atmosphere. The reaction was filtered, the filtrate evaporated, and the residue
flash chromatographed on silica gel using 9/1 Hexane/acetone as eluant to give (0.350 g,
30 %) of the title compound.
35

(4-bromo-2-methoxyphenyl) cyanamide (0.113 g, 0.5 mmol)
tris(dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-
cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol)
were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous
flow of nitrogen and THF (2 mL) was added with stirring. Tri-ter -butylphosphine
(0.0486 mL, 0.0252 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/ethylacetate,
filtered through a plug of silica gel, solvent evaporated and the residue was flash
chromatographed using 4/1 Hexane/THF to give [4-(5-cyano-l -methyl- lH-pyrrol-2-yl)-
2-methoxyphenyl]cyanamide (0.020 g, 16 %).
HPLC purity 98.9 % at 210-370 nm, 10 min.; 99% at 290 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
(Amnion. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min HRMS: calcd for
Ci4H12N40 + H*, 253.10839; found (ESI-FTMS, [M+H]1+), 253.10866.
Example 24: [4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)-3-methoxyphenyl]cyanamide
A mixture of cyanogen bromide (0.550 g, 5.19 mmol) and 4-bromo-3-
methoxyaniline (Lancaster Synthesis Inc., P.O. Box 1000, Windham, NH 03087-9977)
(2.2 g, 11 mmol) in ether/TFTJF (6 mL) was stirred for 3 days under nitrogen atmosphere.
The reaction was filtered, the filtrate evaporated, and the residue flash chromatographed
on silica gel using 9/1 Hexane/acetone to give (4-bromo-3-methoxyphenyl)cyanamide
(0.300 g, 12%). HRMS: calcd for 2 C8H7BrN20 + H+' 452.95562; found (ESI-FT/MS,
[2M+H]14), 452.9556.
4-bromo-3-methoxyphenyl)cyanamide (0.113 g, 0.5 mmol) tris
(dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-
cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol)
were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous
flow of nitrogen and TFfF (2 mL) was added with stirring. Tri-tert-butylphosphine (10
wt % in hexane) (0.0486 mL, 0.0252 mmol) was added to the mixture and allowed to stir
36

until the starting bromide was consumed. The mixture was then diluted with 1/1
hexane/ethylacetate, filtered through a plug of silica gel, solvent evaporated and the
residue was flash chromatographed on silica gel using 4/1 Hexane/THF to give [4-(5-
cyano-l-methyl-lH-pyrrol-2-yl)-3-methoxyphenyl]cyanamide (0.020 g, 16%).
HPLC purity 97.8% at 210-370 nm, 10 min.; 98.3% at 290 nm, 10.1 min.; the
Xterra™ RP18 instrument, 3.5 fL, 150 x 4.6 mm column, 1.2 rnL/min., 85/15-5/95
(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min HRMS: calcd for
C4H12N4O + H+, 253.10839; found (ESI-FTMS, [M+H]"1"), 253.1087.
Example 25: [4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-methylphenyl] cyanamide
A mixture of cyanogen bromide (0.550 g, 5.19 mmol), and (4-bromo-3-
methylaniline (2.04 g, 11 mmol) (Aldrich Chemical Company) in diethyl ether/THF (8
mL) was stirred for 3 days under nitrogen. The reaction was filtered, the filtrate
evaporated, and the residue flash chromatographed on silica gel using 9/1
Hexane/acetone to give (4-bromo-3~methylphenyl)cyanamide (0.289 g, 13 %). HRMS:
calcd for 2 C8H7BrN2 + H+, 420.96579; found (ESI-FT/MS, [2M+H]*), 420.966.
(4-bromo-3-methylphenyl)cyanamide (0.104 g, 0.5 mmol) tris
(dibenzylideneacetone) dipalladium (11.6 mg, 0.0126 mmol), N-methyl-5-
cyanopyrroleboronic acid (0.150 g, 1 mmol), and potassium carbonate (0.276 g, 2 mmol)
were placed in a 40 mL vial fitted with a septa. The vial was then filled with a continuous
flow of nitrogen and THF (2 mL) was added with stirring. Tri-te butylphosphine (10
wt % in hexane) (0.0486 mL, 0.0252 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/ethylacetate, filtered through a plug of silica gel, the solvent evaporated and the
residue was flash chromatographed on silica gel using 4/1 Hexane/THF to give [4-(5-
cyano-l-methyl-lH-pyrrol-2-yl)-3-methylphenyl]cyanamide (0.015 g, 13 %).
HPLC purity 99.2% at 210-370 nm, 10 min.; 99.2% at 290 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
37

(Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min., hold 4 min HRMS: calcd for
C14H12N4 + if, 237.11347; found (ESI-FTMS, [M+H]+), 237.11358.
Example 26: [4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)phenyl]methylcyanamide
Methylphenylaniline (6 mL, 55 mmol) was dissolved in acetonitrile, the mixture
cooled to - 20 ° C, and N-bromosuccinimide (9.76 g, 55 mmol) was added. The stirred
mixture was allowed to warm to room temperature. After 3 hours, the solvent was
removed in vacuo, the residue dissolved in ethylacetate and washed with water, the
organic layer was then dried over magnesium sulfate and evaporated in vacuo to afford
(4-bromophenyl)methylamline (11.3 g) which was used without further purification.
A mixture of cyanogen bromide (3.18 g, 30 mmol), and (4-bromophenyl) methyl
aniline (11.25 g, 61 mmol) in ether (50 mL) was stirred for 3 days under nitrogen. The
mixture was filtered, the filtrate evaporated, and the residue flash chromatographed on
silica gel using 9/1 Hexane/acetone to give (4-bromophenyl)methylcyanamide (2 g, 16
%).
(4-bromophenyl)methyl cyanamide (0.100 g, 0.47 mmol)
tetxakis(triphenylphosphine)palladium(0) (0.050 g, 0.043 mmol), N-methyl-5-
cyanopyrroleboronic acid (0.150 g, 1 mmol), potassium carbonate (0.345 g, 2.5 mmol)
and dimethoxyethylether/water 3:1 were placed in a microwave reaction vial fitted with a
septa. The vial was then filled with a continuous flow of nitrogen. Using microwave
assisted conditions, the mixture was heated to 100°C for 15 minutes. The mixture was
poured into water, extracted with ethyl acetate, the ethylacetate dried over magnesium
sulfate, and evaporated in vacuo. The residue was flash chromatographed using 9/1
Hexane/ethylacetate to give [4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]methylcyanamide (0.030 g, 27 %). HPLC purity 100% at 210-370 ran, 10 min.;
the Xterra™ RP18 instrument, 3.5 fi, 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
C14H12N4 + Ff*", 237.11347; found (ESI, [M+H]*), 237.1127.
38

Example # Compound Name T47D CeU Alkaline
Phosphate Assay IC50
(nM)
1 5-(4-aminophenyl)-l-methyl-lH-pyrrole-2-
carbonitrile 108.9
2 5-(4-amino-3-fluorophenyl)-l-methyl-lH-
pyrrole-2-carbonitrile 65.4
3 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]-2-fur amide 126.4
4 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl] -3-methylbutanamide 304.3
5 N-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl]-2-methylpropanamide 168
6 N-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl]propanamide 76.7
7 N-[4-(5-cyano-1 -methyl- lH-pyrrol-2-
yl)phenyl]butanamide 78.8
8 N-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl] acetamide -300
9 N-[4-(5-cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl]benzamide 90.5
10 N-[4-(5-cyano-1 -methyl- lH-pyrrol-2-
yl)phenyl]cyclobutanecarboxamide 83.9
11 N-[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl] cyclohexanecarboxamide 325
12 N-[4-(5-cyano-1 -methyl-lH-pyrrol-2-
yl)phenyl]-2-methylacrylamide 97.2
13 ethyl [4-(5-cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl]carbamate 265.7
14 isobutyl [4-(5 -cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl]carbamate 378
15 N,N'-bis[4-(5-cyano-l-methyl-lH-pyrrol-2-
yl)phenyl]urea 642.1
16 [4-(5 -cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl]cyanamide 54.1
17 [4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)-2-
methylphenyl]cyanamide 67.1
18 [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
ethylphenyl] cyanamide -300
19 [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
propylphenyl]cyanamide <300
39

Example # Compound Name T47D Cell Alkaline
Phosphate Assay IC50
(nM)
20 [4-(5-cyaao-1 -methyl- lH-pyrrol-2-yl)-2-
isopropylphenyl]cyanamide <300
21 [2-chloro-4-(5-cyano-l-methyl-lH-pyrrol-
2-yl)phenyl]cyanamide 897
22 [4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)-2-
fluorophenyl]cyanamide 669.9
23 [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-
methoxyphenyljcyanamide <300
24 [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
methoxyphenyl]cyanamide 83.9
25 [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-
methylphenyl] cyanamide 55
26 [4-(5-cyano-1 -methyl-1 H-pyrrol-2-
yl)phenyl]methylcyanamide 88.2
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.
40

What is Claimed Is:
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,
C(0)-C1-C6 alkyl, C(0)-C3-C8 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-C6
alkynyl,
C(0)0-C!-C6 alkyl, C(0)0-C3-C8 cycloalkyl, C(0)0-substituted CrC6
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 C1-C6 alkyl, C(0)N-di-substituted CrC6 alkyl, C(0)NH-
substituted d-C6 alkyl, C(0)NH-aryl, C(0)N-di-aryl, C(0)NH-substiruted aryl, C(0)N-
di-substituted aryl, C(0)NH-heteroaryl, C(0)N-di-heteroaryl, C(0)NH-heterocycle,
C(0)N-di-heterocycle, 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-Q alkynyl; or
Ri is a linking group to a second structure of formula I to form a dimer of formula
I, said linking group is a C(O)- group.
41

R.2 is selected from the group consisting of H, C1-C6 alkyl, substituted Q-C6 alkyl,
and C3-C6 cycloalkyl;
provided that both Ri and R2 are not H;
provided that where Ri is C(O) substituted aryl, R2 is not H;
provided that when Ri is H and R7 is H, R2 is not C1-C6 alkyl;
R3, R4, R5 and Re are independently selected from the group consisting of H,
halogen, C1-C6 alkyl, substituted Q-C alkyl, C3-C6 cycloalkyl, 0-Q-C6 alkyl, O-C1-C6
substituted alkyl, aryl, heteroaryl, heterocycle, substituted aryl, substituted heteroaryl,
and substituted heterocycle; and
R7 is selected from the group consisting of H, C1-C6 alkyl, substituted C1-C6 alkyl,
C3-C6 cycloalkyl, and substituted C3-C6 cycloalkyl.
2. The compound according to claim 1, wherein:
Ri is CN;
R2isHorC1-C6alkyl;
R3, R4, R5 and R$ are, independently, selected from the group consisting of H,
halogen, C1-C6 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 CN;
R2isH;
R3,R4, R5 and Rg are, independently, selected from the group consisting of H,
halogen, C1-C6 alkyl, and O-C1-C6 alkyl; and
R7isHorC1-C6alkyl.
4. The compound according to claim 1, wherein:
Ri is C(0)CrC6 alkyl, C(0)-C3-C5 cycloalkyl or C(O);
42

R.3, Rt, R5 and Re are, independently, selected from the group consisting H,
halogen, Q-Ce allcyl, and 0-C1-C6 alkyl; and
R7 is H or CrC6 alkyl.
5. The compound according to claim 4, wherein:
Ri is C(0)C1-C4 alkyl or C(0)-C3-C6 cycloalkyl;
R3, R4, R5 and R$ are H; and
R7 is Ci alkyl.
6. The compound according to claim 1, wherein Ri is selected from the
group consisting of CO(NH2), CN, C(0)-heteroaryl, wherein the heteroaryl is a furan,
C(0)aryl, wherein the aryl is a phenyl ring, and C(0)0-C1-C3 alkyl.
7. 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.
8. The compound according to claim 1, 6, 7, or 8, 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.
9. The compound according to claim 1, 6, 7, 8, or 9, wherein R4 is selected
from the group consisting of H and O-C1-C3 alkyl.
10. The compound according to claim 1, 6, 7, 8,9, or 10, 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.
11. The compound according to claim 1, 6, 7, 8, 9, 10, or 11, wherein R6 is
selected from the group consisting of H and halogen, wherein the halogen is F.
43

12. The compound according to claim 1, wherein R7 is Ci alkyl.
13. The compound according to claiml, wherein the compound is selected
from the group consisting of:
N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]-2-fliramide;
N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]-3-methylbutanamide;
N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]-2-methylpropanamide;
N-[4-(5-cyano-l -methyl- lH-pyrrol-2-yl)phenyl]propanarnide;
N- [4-(5 -cyano-1 -methyl-1 H-pyrrol-2-yl)phenyl]butanamide;
N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]acetamide;
N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]benzamide;
N-[4-(5-cyano-l -methyl-1 H-pyrrol-2-yl)phenyl]cyclobutanecarboxamide;
N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]cyclohexanecarboxamide;
N-[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]-2-methylacrylamide;
Ethyl [4-(5-cyano-1 -methyl-1 H-pyrrol-2-yl)phenyl]carbamate;
Isobutyl [4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]carbamate;
N,N'-bis[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]urea;
[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-methylphenyl]cyanamide;
[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-ethylphenyl]cyanamide;
[4-(5-cyano-1 -methyl- lH-pyrrol-2-yl)-2-propylphenyl]cyanamide;
[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-isopropylphenyl]cyanamide;
[2-chloro-4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]cyanamide;
[2-fluoro-4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]cyanamide;
[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-2-methoxyphenyl]cyanamide;
[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-methoxyphenyl]cyanamide;
[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)-3-methylphenyl]cyanamide; and
[4-(5-cyano-l-methyl-lH-pyrrol-2-yl)phenyl]methylcyanamide.
44

14. A pharmaceutical composition comprising a compound according to any
of claims 1 to 13 and a pharmaceutically acceptable carrier.
15. The pharmaceutical composition according to claim 14, wherein said
composition is an oral dosage unit.
16. The pharmaceutical composition according to claim 14, wherein said
composition is a solid oral dosage unit.
17. The pharmaceutical composition according to any of claims 14 to 16,
wherein said composition further comprises an estrogen.
18. The pharmaceutical composition according to any of claims 14 to 16,
wherein said composition further comprises a progestin.
45

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. These compounds are useful for contraception and hormone replacement therapy. Also provided are products containing these compounds.