Method for Preparing Halogenated Amines
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of United States Provisional Application No.:
60/900,261, filed on February 7, 2007, which is incorporated herein by reference in its
entirety.
TECHNICAL FIELD
This invention relates to methods for preparing halogenated amines.
BACKGROUND
The replacement of one or more hydrogen atoms in an organic molecule with one
or more fluorine atoms can sometimes alter its chemical and biological nature, including
its stability, lipophilicity, and bioavailability. C-F bond is known to mimic a C-H bond
because of its similar bond length, and fluorinated groups are known to be isosteres of
many common substituents. Trifluoromethyl group (CF3) containing compounds are
known to have applications in the materials field, as well as in the pharmaceutical and
agrochemical industries.
SUMMARY
This invention relates generally to methods for preparing compounds containing
one or more halogenated amines (e.g., bis(trifiuoromefhylated) amines) from nitrile-
containing starting materials and intermediates. The inventors have discovered that
reacting a nitrile (i.e., C=N, also referred to as acyano group) containing organic
compound with a fluoroalkyl (RF) transfer agent (also referred to herein as a
fluoroalkylating agent) results in the conversion of the nitrile to an amine. This process is
summarized in the nonlimiting scheme below:


The shaded circle represents the organic compound, and each RF is a fluoroalkyl group
(e.g., CF3).
In one aspect, this invention features a method for preparing an organic
compound having one or more (e.g., 1, 2, 3, 4, 5, or 6, e.g., 1 or 2) substituents of formula
(A):
in which:
(i)eachof RFl and RF2 can be, independently, optionally substituted C1-C6
fluoroalkyl (e.g., C1-C4 perfluoroalkyl, e.g., CF3), e.g., optionally substituted with from 1-
2 substituents as described herein;
(ii) each of R3 and R4 can be, independently, hydrogen, Ra, -C(O)H, -C(O)Ra, -
C(O)ORa, or -SO2Ra, wherein Ra at each occurrence can be, independently, any organic
group, e.g., alkyl, cycloalkyl, aralkyl, heterocyclyl, aryl, or heteroaryl, each of which can
be optionally substituted as described herein; e.g., C1-C12 (e.g., C1-C10, C1-C6, or C1-C4)
alkyl, C3-C10 (e.g., C3-C8, C3-C6) cycloalkyl, C7-C20 (e.g., C7-C16, C7-C12, C7-C10) aralkyl,
heterocyclyl including 3-10 (e.g., 3-8, 3-6) atoms, C6-C18 (e.g., C6-C14, C6-C10, or phenyl)
aryl, or heteroaryl including 5-16 (e.g., 5-12, 5-10, or 5-6) atoms, each of which can be
optionally substituted with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents as
described herein; and
(iii) the organic compound can include as part of its structure any one or more of
the following substructures:
(i) C6-C18 aryl or heteroaryl including 5-16 atoms, each of which is optionally
substituted; e.g., C6-C18 (e.g., C6-C14, C6-C10, or phenyl) aryl or heteroaryl including 5-16
(e.g., 5-12, 5-10, or 5-6) atoms, each of which can be optionally substituted with from 1-
10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents as described herein;
(ii) C7-C20 aralkyl or heteroaralkyl including 6-20 atoms, each of which is
optionally substituted; e.g., C7-C20 (e.g., C7-C16, C7-C12, C7-C10) aralkyl or heteroaralkyl

including 6-20 (e.g., 6-14 or 6-10) atoms, each of which can be optionally substituted
with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents as described herein; or
(iii) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl including 3-10 atoms, or
heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted; e.g.,
C3-C10 (e.g., C3-C8, C3-C6) cycloalkyl, C3-C10 (e.g., C3-C8, C3-C6) cycloalkenyl,
heterocyclyl including 3-10 (e.g., 3-8, 3-6) atoms, or heterocycloalkenyl including 3-10
(e.g., 3-8,3-6) atoms, each of which can be optionally substituted with from 1-5 (e.g., t-
4, 1-3, 1-2, or 1) substituents as described herein; or
(iv) C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl, each of which is optionally
substituted; e.g., C1-C12 (e.g., C1-C10, C1-C6, or C1-C4) alkyl, C2-C12 (e.g., C2-C10, C2-C6,
or C2-C4) alkenyl or C2-C12 (e.g., C2-C10, C2-C6, or C2-C4) alkynyl, each of which can be
optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents as described
herein;
each of which (when two or more substructures are present) can be connected to
one another via one (or more) direct bonds or heteroatom-containing linker(s) (e.g., SO2),
or any combination thereof.
The method includes reacting one or more nitrile-containing organic compounds
(the terms "organic compound" and "compound" will be used interchangeably
throughout this specification) with one or more fluoroalkylating agents.
In some embodiments, the method can be used to prepare compounds having one
substituent of formula A. In these embodiments, the method can include reacting the
corresponding nitrile substituted compound with a fluoroalkylating agent. The starting
material, intermediates, and/or product can include one or more of the substructures
described herein.
In some embodiments, the method can be used to prepare compound having two
or more (e.g., 2, 3, 4, 5, or 6, e.g., 2) substituents of formula A.
In certain embodiments, when the organic compound includes two or more
substructures (e.g., an aryl ring; a heterocyclic ring; and either a heteroaryl ring or a
second aryl ring), each of the substituents of formula A can be located on the same
substructure, or each of the substituents of formula A can be distributed among two or
more of the substructures.

In certain embodiments, each of the substituents of formula A can be introduced
in the same reaction step. For example, a compound having two substituents of formula
A can be prepared by reacting a starting material having two nitrile groups with an
appropriate amount of the fluoroalkylating agent.
In certain embodiments, each of the substituents of formula A can be introduced
sequentially. See, e.g., the nonlimiting scheme below:

The open circles represent an organic compound or a substructure thereof; A1 and A2
each represent a substiruent of formula A (each of which can be the same or different);
and CN represents a nitrile group.
In another aspect, this invention features a method for preparing a compound of
formula (I-A) or a salt thereof from a compound of formula (II-A).
The structure of formula (I-A) is shown below:

in which:
a is 1,2, 3, 4, 5, or 6 (e.g., 1 or 2, e.g., 1);
R is:
(i) C6-C18 aryl or heteroaryl including 5-16 atoms, each of which is optionally
substituted; e.g., C6-C18 (e.g., C6-C14, C6-C10, or phenyl) aryl or heteroaryl including 5-16

(e.g., 5-12, 5-10, or 5-6) atoms, each of which can be optionally substituted with from 1-
10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents as described herein; or
(ii) C7-C20 aralkyl or heteroaralkyl including 6-20 atoms, each of which is
optionally substituted; e.g., C7-C20 (e.g., C7-C16, C7-C12, C7-C10) aralkyl or heteroaralkyl
including 6-20 (e.g., 6-14 or 6-10) atoms, each of which can be optionally substituted
with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents as described herein; or
(iii) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl including 3-10 atoms, or
heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted; e.g.,
C3-C10 (e.g., C3-C8, C3-C6) cycloalkyl, C3-C10 (e.g., C3-C8, C3-C6) cycloalkenyl,
heterocyclyl including 3-10 (e.g., 3-8, 3-6) atoms, or heterocycloalkenyl including 3-10
(e.g., 3-8,3-6) atoms, each of which can be optionally substituted with from 1-5 (e.g., 1-
4, 1-3, 1-2, or 1) substituents as described herein; or
(iv) C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl, each of which is optionally
substituted; e.g., C1-CI2 (e.g., C1-C10, C1-C6, or C1-C4) alkyl, which can be optionally
substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents as described herein; or C2-
C12 (e.g., C2-C10, C2-C6, or C2-C4) alkenyl or C2-C12 (e.g., C2-C10, C2-C6, or C2-C4)
alkynyl, each of which can be optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or
1) substituents as described herein;
each of RFI and RF2 is, independently, optionally substituted C1-C6 fluoroalkyl,
e.g., optionally substituted with from 1-2 substituents as described herein; and
each of R3 and R4 is, independently, hydrogen, Ra, -C(O)H, -C(O)Ra, -C(O)ORa,
or -SO2Ra, wherein Ra at each occurrence is, independently, as defined above for R.
The structure of formula (II-A) is shown below:

above for formula (I-A)).
The method includes reacting the compound of formula (II-A) with a
fluoroalkylating agent. In these embodiments, when a > 1, then the nitrile groups in
formula (II-A) and substituents of formula A in formula (I-A) can be located anywhere
along R. For example, if R is an aryl group that is substituted with, e.g., a heterocyclic
ring that itself is further substituted, e.g., with another cyclic structure, then the nitrile

groups in formula (II-A) and substituents of formula A in formula (I-A) can be present on
the base substituent (here, an aryl group) and/or any substituent thereof (e.g., the
heterocyclic ring and/or the other cyclic structure).
In a further aspect, this invention features a method for preparing a compound of
formula (I) or a salt thereof from a compound of formula (II).
The structure of formula (I) is shown below:

The structure of formula (II) is shown below:

R,RF1,RF2,R3,and R4 can be as defined above for formulas (I-A) and (II-A).
The method includes reacting the compound of formula (II) with a
fluoroalkylating agent.
In one aspect, this invention features a method for preparing a compound of
formula (I) or (I-A) or a salt thereof from a compound of formula (II) or (II-A),
respectively, in which R in formulas (I), (I-A), (II), and (II-A) can be C6-C10 aryl or
heteroaryl including 5-10 atoms, each of which is:
(a) substituted with 1 -SO2NRN1RN2 or -C(0)NRN1RN2; and
(b) optionally further substituted with from 1-5 substituents as described herein.
Each of RN1 and RN2 can be, independently of one another:
(i) hydrogen; or
(ii) C1-C12 (e.g., C1-C10, C1-C6, or C1-C4) alkyl or C1-C12 (e.g., C1-C10, C1-C6, or
C1-C4) haloalkyl; each of which is optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-
2, or 1) substituents as described herein; or

(iii) C7-C12 (e.g., C7-C10, benzyl) aralkyl; C3-C10 (e.g., C3-C8, C3-C5) cycloalkyl;
heteroaralkyl including 6-12 (e.g., 6-10) atoms; C3-C10 (e.g., C3-C8, C3-C6) cycloalkenyl;
heterocyclyl including 3-10 (e.g., 3-8, 3-6) atoms; or heterocycloalkenyl including 3-10
(e.g., 3-8, 3-6) atoms; each of which is optionally substituted with from 1-5 (e.g., 1 -4, 1-
3, 1-2, or 1) substituents as described herein; or
(iv) C2-C10 alkenyl or C2-C10 alkynyl, each of which is optionally substituted with
from 1-5 (e.g., 1-4,1-3, 1-2, or 1) substituents as described herein; or
(v) C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally
substituted with from 1-5 (e.g., 1-4,1-3, 1-2, or 1) substituents as described herein; or
(vi) -C(O)H, -C(O)Ra, -C(O)ORa, or -SO2Ra, in which Ra can be as defined
anywhere herein; or
(vii) RN1 and RN2, together with the nitrogen atom to which each is attached, form
a heterocyclyl including 3-10 (e.g., 3-8, 3-6, 5-6) atoms, which is optionally substituted
with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents as described herein. The heterocyclyl
can further include one or more (e.g., 1 or 2) heteroatoms, e.g., nitrogen or oxygen, in
addition to the nitrogen atom to which each of RN1 and RN2 is attached. When the
additional heteroatom is a nitrogen atom, this additional nitrogen atom can be attached to
a hydrogen atom or a substituent other than hydrogen as described herein.
In certain embodiments, each of RN1 and RN2 can be, independently, a substituent
other than hydrogen. In these embodiments, RN1 and RN2 can be the same substituent or
each can be a different substituent.
For example, each of RN1 and RN2 can be independently of one another
unsubstituted C1-C12 (e.g., C1-C10, C1-C6, or C1-C4) alkyl.
As another example, one of RN1 and RN2 can be selected from (ii)-(v) above, e.g.:
• C7-C12 (e.g., C7-C10, benzyl) aralkyl, which is substituted with from 1-5
(e.g., 1-4, 1-3, 1-2, or 1) substituents as described herein; or
• C3-C10 (e.g., C3-C8, C3-C6) cycloalkyl, which is substituted with from 1-5
(e.g., 1-4, 1-3, 1-2, or 1) substituents as described herein; or
• C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally
substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents as
described herein;

and the other can be -C(O)H, -C(O)Ra, or -C(O)ORa (e.g., -C(O)ORa, in which R3 is an
unsubstituted C1-C4 alkyl).
As a further example, RN1 and RN2 , together with the nitrogen atom to which each
is attached, form a heterocyclyl including 5 or 6 atoms (e.g., piperidyl (piperidino),
piperazinyl, morpholinyl (morpholino), pyrrolinyl, and pyrrolidinyl), which can be
optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents as described
herein. In certain embodiments, the heterocyclyl is unsubstituted. In other embodiments,
the heterocyclyl is substituted with other than optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted
cycloalkenyl, optionally substituted heterocycloalkenyl, or is not directly substituted with
an oxygen, sulfur or nitrogen atom. In still other embodiments, the heterocyclyl can be
substituted with from 1-5 C1-C6 alkyl groups.
In certain embodiments, R can be:

in which one of X and Y is -SO2NRN1RN2 or -C(O)NRN1RN2, and the other is hydrogen.
In these embodiments, each of RN1 and RN2 can be, independently of one another, as
defined anywhere herein.
In one aspect, this invention features a method for preparing a compound of
formula (VII) or a salt thereof from a compound of formula (VIII).
The structure of formula (VII) is shown below:


(VII)
in which:
each of m and n is, independently, 0, 1, 2, or 3 (e.g., 0, 1, or 2, e.g., 0 or 1),
provided that one of m and n is 1;
each of RF1, RR, RF1', and RF2' is, independently, optionally substituted C1-C6
fluoroalkyl, e.g., optionally substituted with from 1-2 substituents as described herein;
each of R3, R4, R3', and R4* is, independently, hydrogen, C1-C6 alkyl, -C(O)H, or -
C(O)ORa, wherein Ra is C7-C20 aralkyl (e.g., benzyl or fluorenyl) or C1-C6 alkyl (e.g.,
tert-butyl), each of which is optionally substituted, e.g., with from 1-3 substituents as
. described herein;
ring B is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is
optionally further substituted with from 1-5 substituents independently selected from
halo; NRfRg; hydroxyl; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) alkyl or C1-C12 (e.g.,
C1-C10, C1-C6, C1-C4, or C1-C3) haloalkyl, each of which is optionally substituted, e.g.,
with from 1-5 substituents as described herein; optionally substituted C1-C12 (e.g., C1-C10,
C1-C6, C1-C4, or C1-C3) alkoxy, e.g., with from 1-5 substituents as described herein; C1-
C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) haloalkoxy; nitro; C6-C10 aryl or heteroaryl
including 5-12 atoms, each of which is optionally substituted, e.g., with from 1-5
substituents as described herein; C6-C10 aryloxy or heteroaryloxy including 5-12 (e.g., 5-
10 or 5-6) atoms, each of which is optionally substituted, e.g., with from 1-5 substituents
as described herein; heterocyclyl including 3-10 (e.g., 3-6 or 5-6) atoms, C3-C10 (e.g., C3-
C8, C3-C6) cycloalkyl, C7-C12 aralkoxy or heteroaralkoxy including 6-1-2 atoms, each of
which is optionally substituted, e.g., with from 1-5 substituents as described herein; -
C(O)ORh; -C(O)NRfRg; or -NRiC(O)Rj;
each of Rf, Rs, and Rh, at each occurrence is, independently:
(i) hydrogen; or
(ii) C1-C12 alkyl or C1-C12 haloalkyl; each of which is optionally substituted; e.g.,
C1-C12 (e.g., C1-C10, C1-C6, or C1-C4 alkyl or C1-C12 (e.g., C1-C10, C1-C6, or C1-C4)
haloalkyl; each of which is optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1)
substituents as described herein; or

(iii) C7-C20 aralkyl; C3-C16 cycloalkyl; heteroaralkyl including 6-20 atoms; C3-
C16 cycloalkenyl; heterocyclyl including 3-16 atoms; or heterocycloalkenyl including 3-
16 atoms; each of which is optionally substituted; e.g., C7-C20 (e.g., C7-C16, C7-C12, C7-
Cl0) aralkyl; C3-C16 (e.g., C3-C10, C3-C8, C1-C6) cycloalkyl; heteroaralkyl including 6-20
(e.g., 6-14, 6-10) atoms; C3-C16 (e.g., C3-C10, C3-C8, C3-C6) cycloalkenyl; heterocyclyl
including 3-16 (e.g., 3-10, 3-8, 3-6) atoms; or heterocycloalkenyl including 3-16 (e.g., 3-
10, 3-8, 3-6) atoms; each of which is optionally substituted with from 1-10 (e.g., 1-5,1-4,
1-3, 1-2, or 1) substituents as described herein; or
(iv) C2-C20 (e.g., C2-C12, C2-C10, C2-C6, or C2-C4) alkenyl or C2-C20 (e.g., C2-C12,
C2-C10, C2-C6, or C2-C4) alkynyl; or
(v) C6-C16 aryl or heteroaryl including 5-16 atoms, each of which is optionally
substituted; e.g., C6-C16 (e.g., C6-C14, C6-C10, or phenyl) aryl or heteroaryl including 5-16
(e.g., 5-12, 5-10, or 5-6) atoms, each of which is optionally substituted with from 1-10
(e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents as described herein; or optionally
(vi) -C(O)H, -C(O)Ra, -C(O)ORa, or -SO2Ra, in which Ra can be as defined
anywhere herein;
R1 is hydrogen or unsubstituted C1-C3 alkyl;
RjisRh;ORh;orNRfRg;
W is C1-C4 alkyl; and
ring C is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is
optionally further substituted with from 1-5 substituents independently selected from
halo; C1-C12 (e.g., C1-Cl0, C1-C6, C1-C4, or C1-C3) alkyl or C1-CI2 (e.g., C1-C10, C1-C6,
C1-C4, or C1-C3) haloalkyl, each of which is optionally substituted, e.g., with from 1-5
(e.g., 1-4, 1-3, 1-2, or 1) substituents as described herein; C1-C12 (e.g., C1-C10, C1-C6, C1-
C4, or C1-C3) alkoxy; C1-C2 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) haloalkoxy; nitro; or
C6-C10 aryl or heteroaryl including 5-12 (e.g., 5-10) atoms, each of which is optionally
substituted, e.g., with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents as described herein.

The structure of formula (VIII) is shown below:

in which:
ring B is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is
optionally further substituted with from 1-5 substituents independently selected from
halo; NRfRg; hydroxyl; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) alkyl or C1-C12 (e.g.,
C1-C10, C1-C6, C1-C4, or C1-C3) haloalkyl, each of which is optionally substituted, e.g.,
with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents described herein; optionally
substituted C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) alkoxy, e.g., with from 1-5 (e.g.,
1-4, 1-3, 1-2, or 1) substituents described herein; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or
C1-C3) haloalkoxy; nitro; C6-C10 aryl or heteroaryl including 5-12 atoms, each of which is
optionally substituted, e.g., with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents described
herein; C6-C10 aryloxy or heteroaryloxy including 5-12 atoms, each of which is optionally
substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents described herein;
heterocyclyl including 3-10 (e.g., 3-6 or 5-6) atoms, C3-C10 (e.g., C3-C8, C3-C6)
cycloalkyl, C7-C12 aralkoxy or heteroaralkoxy including 6-12 atoms, each of which is
optionally substituted, e.g., with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents described
herein; -C(O)Re, wherein Re is C1-C6 alkyl; -C(O)NRfRg; or -NRiC(O)Rj; and
Rf, Rg, Rh, R', Rj, mj, n, ring C, and W can be as defined above in conjunction with
formula (VII).
The method includes reacting the compound of formula (VIII) with a
fluoroalkylating agent.

In some embodiments, the methods described herein can be used to prepare
compounds that modulate (e.g., inhibit) 11βHSDl.
In one aspect, this invention features the compounds themselves of formulas (I),
(I-A), and (VII), including any subgenus or specific compound(s) thereof, and/or
pharmaceuticaily acceptable salts thereof. In an embodiment, the compound can be
selected from the group consisting of:
2-(3-{[(2R)-4-{6-[l-amino-2,2,2-trifluoro-l-(trifluoromethyl)ethyl]pyridin-3-yl}-
2-methylpiperazin-l-yl]sulfonyl}phenyl)-1,1,1-trifluoropropan-2-ol;
2-(3- {[(2R)-4- {4-[ 1 -amino-2,2,2-trifluoro-1 -(trifluoromethyl)ethyl]-2-
(trifluoromethyl)phenyl} -2-methylpiperazin-1 -yl]sulfonyl}phenyl)-1,1,1 -trifluoropropan-
2-ol;
2-[4-({(2R)-4-[4-[l-amino-2,2,2-trifluoro-l-(trifluoromethyl)ethyl]-2-
(trifluoromethyl)phenyI]-2-methyIpiperazin-1 -yl} sulfonyl)phenyl]-1,1,1 -trifluoropropan-
2-ol;
1,1,1,3,3,3-hexafluoro-2-[4-( {(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-
methylpiperazin-1-yl} sulfonyl)phenyl]propan-2-amine; and
1,1,1,3,3,3-hexafluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-
methylpiperazin-l-yI}sulfonyl)phenyl]propan-2-amine; or pharmaceutically acceptable
salt thereof.
In another embodiment, the compound can be selected from the group consisting
of the title compounds of Examples 1-13.
In one aspect, this invention features a pharmaceutical composition, which
includes a compound of formulas (I), (I-A), or (VII), including any subgenus or specific
compound(s) thereof, or a salt (e.g., a pharmaceuticaily acceptable salt) thereof, or a
prodrug thereof (e.g., an effective amount thereof); and a pharmaceutically acceptable
adjuvant, carrier or diluent.
In another aspect, this invention features a method of preparing a pharmaceutical
composition that includes admixing a compound of formula (I), (I-A), or (VII), including
any subgenus or specific compound(s) thereof, or a salt (e.g., a pharmaceuticaily

acceptable salt) thereof, or a prodrug thereof (e.g., an effective amount thereof) with a
pharmaceutically acceptable adjuvant, carrier or diluent.
In one aspect, this invention relates to a method for treating a disease or condition
mediated by excess or uncontrolled amounts of Cortisol and/or other corticosteroids,
which includes administering to a subject in need thereof an effective amount of a
compound of formula (I), (I-A), or (VII), including any subgenus or specific
compound(s) thereof, or a salt (e.g., a pharmaceutically acceptable salt) thereof, or a
prodrug thereof.
In another aspect of the invention, this invention relates to methods for treating,
controlling, ameliorating, preventing, delaying the onset of, or reducing the risk of
developing one or more of diabetes (e.g., type 1 or type 2 diabetes), Syndrome X,
hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders,
dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL
levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis,
abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy,
hypertension, coronary heart disease, stroke, peripheral vascular disease, Cushing's
syndrome, glaucoma, osteoperosis, hyperinsulinemia, tuberculosis, psoriasis, cognitive
disorders and dementia (e.g., impairment associated with aging and of neuronal
dysfunction, e.g., Alzheimer's disease), depression, viral diseases, inflammatory
disorders, immune disorders); or promoting wound healing, which includes administering
to a subject in need thereof an effective amount of a compound of formula (I), (I-A), or
(VII), including any subgenus or specific compound(s) thereof, or a salt (e.g., a
pharmaceutically acceptable salt) thereof or a prodrug thereof.
Embodiments can include one or more of the following features.
The fluoroalkylating agent can have any one of the formulae delineated herein.
RF1 and RF2 can be the same or different. Each of RF1 and RF2 can be,
independently, optionally substituted C1-C4 perfluoroalkyl (e.g., CF3).
Each of R3 and R4 can be hydrogen.
R can be optionally substituted C6-C4 aryl (e.g., optionally substituted phenyl),
e.g., optionally substituted with from 1-5 (e.g., 1-4, 1-3,1-2, or 1) substituents as

described herein. R can be optionally substituted C7-C12 aralkyl (e.g., benzyl), e.g.,
optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents as described
herein.
m in formulas (VII) and (VIII) can be I, and n in formulas (VII) and (VIII) can be
0. In embodiments, each of RF1 and RF2 in formula (VII) can be CF3. Each of R3 and R4
in formula (VII) can be hydrogen. Ring C in formula (VII) has formula (IX):

in which two of Rc22, Rc23, Rc24, Rc25, and Rc26 can each be, independently, halo; C1-C12
(e.g., C1-C10, C1-C6, C1-C4, or C1-C3) alkyl or C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1
C3) haloalkyl, each of which is optionally substituted, e.g., with from 1-5 (e.g., 1-4,1-3,
1-2, or 1) substituents as described herein; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3)
alkoxy; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) haloalkoxy; nitro; or C6-C10 aryl or
heteroaryl including 5-12 atoms, each of which is optionally substituted, e.g., with from
1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents as described herein; and the others are
hydrogen. Rc22 can be CF3 or fluoro; and Rc24 can be fluoro, chloro, CF3, or optionally
substituted heteroaryl.

m in formulas (VII) and (VIII) can be 0, and n in formulas (VII) and (VIII) can be
1. In embodiments, each of RF1 and RF2 in formula (VII) can be CF3. Each of R3' and
R4 in formula (VII) can be hydrogen. Ring B in formula (VII) can have formula (X):

wherein one of Ra2, R33, and Ra4 is halo; NRfRg; hydroxyl; C1-C12 (e.g., C1-C10, C1-C6,
C1-C4, or C1-C3) alkyl or C1-C2 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) haloalkyl, each of
which is optionally substituted, e.g., with from 1-5 substituents as described herein;
optionally substituted C1-C12 (e.g., C1-C10, C1-C6, C1-C4, orC1-C3) alkoxy, e.g.,
optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents as described
herein; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) haloalkoxy; nitro; C6-C10 aryl or
heteroaryl including 5-12 atoms, each of which is optionally substituted, e.g., with from
1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents as described herein; C6-C10 aryloxy or
heteroaryloxy including 5-12 atoms, each of which is optionally substituted, e.g., with
from 1-5 (e.g., 1-4,1-3, 1-2, or 1) substituents as described herein; heterocyclyl including
3-10 atoms, C3-C10 (e.g., C3-C6) cycloalkyl, C7-C12 aralkoxy or heteroaralkoxy including
6-12 atoms, each of which is optionally substituted, e.g., with from 1-5 (e.g., 1-4, 1-3, 1-
2, or 1) substituents as described herein; -C(O)ORh; -C(O)NRfRg; or-NRiC(O)Rj; and
the others are hydrogen. Ra3 or Ra4 can be 1,1,1-trifluoro-2-hydroxy-2-propyl (e.g., R, S,
or R and S configuration at the carbon attached to the hydroxyl group). In some
embodiments, ring B in formula (VIII) can be substituted with -C(O)Re, wherein RC is C1-
C4 alkyl. In certain embodiments, the -C(O)Re can be present when the nitrile group is
allowed to react with the fluoroakylating agent.

The starting materials, intermediates, and products can be S or N-oxides and/or
salts (e.g., pharmaceutically acceptable salts) thereof.
The methods can further include forming a salt (e.g., a pharmaceutically
acceptable salt) and/or admixing the compound with a pharmaceutically acceptable
adjuvant, carrier or diluent. The methods can further include the separation of
stereoisomer products or starting materials.
The listing of permissible optional substituents for a starting material (e.g., nitrile-
containing organic compound as described herein) can be different from that for a
product (e.g., organic compound containing substituents having formula (A) as described
herein). For example, the starting material can be only further substituted (i.e., in
addition to the nitrile) with moieties known to be stable or inert to a particular
fluoroalkylating agent or classes thereof (e.g., the fluoroalkylating agents described
herein). Thus, in some embodiments, the methods can further include the introduction of
substituents to a particular (specific or generic) nitrile-containing starting material or to a
particular (specific or generic) compound containing substituents having formula (A).
The methods can further include the modification (e.g., deprotections) of substituents that
may be present on a particular (specific or generic) nitrile-containing starting material or
to a particular (specific or generic) compound containing substituents having formula
(A). Such processes include, but are not limited to, those described in US 2007-0219198,
filed on February 7, 2007, which is incorporated herein by reference in its entirety.
The term "fluoroalkyl" refers to an alkyl group, in which one or more hydrogen
atoms is replaced by fluorine atom (F). In some embodiments, more than one hydrogen
atom (e.g., 2,3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, etc. hydrogen atoms) on a alkyl group can
be replaced by more than one fluorine atom (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13
fluorine atoms). The term "fluoroalkyl" also includes alkyl moieties in which all of
hydrogen atoms have been replaced by fluorine atoms (e.g., sometimes referred to as
perfluoroalkyl moieties, such as trifluoromethyl).
The term "fluoroalkylating agent" refers to:
(1) a fluoroalkyl-containing, nonionic compound, which upon interaction with (i)
a catalytic, stoichiometric, or excess amount of a neutral or charged chemical entity; (ii)

light; (iii) heat; or (iv) any combination thereof, fully or partially dissociates to produce
the corresponding fluoroalkyl carbanion or radical, or a reactive equivalent thereof; or
(2) a fluoroalkyl-containing salt or ionic complex.
The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine
or iodine. The term "carboxy" refers to the -COOH radical.
In general, and unless otherwise indicated, substituent (radical) prefix names are
derived from the parent hydride by either (i) replacing the "ane" in the parent hydride
with the suffixes "yl," "diyl," "triyl," "tetrayl," etc.; or (ii) replacing the "e" in the parent
hydride with the suffixes "yl," "diyl," "triyl," "tetrayl," etc. (here the atom(s) with the
free valence, when specified, is (are) given numbers as low as is consistent with any
established numbering of the parent hydride). Accepted contracted names, e.g.,
adamantyl, naphthyl, anthryl, phenanthryl, furyl, pyridyl, isoquinolyl, quinolyl, and
piperidyl, and trivial names, e.g., vinyl, allyl, phenyl, and thienyl are also used herein
throughout. Conventional numbering/lettering systems are also adhered to for substituent
numbering and the nomenclature of fused, bicyclic, tricyclic, polycyclic rings.
The term "alkyl" refers to a saturated hydrocarbon chain that may be a straight
chain or branched chain, containing the indicated number of carbon atoms. For example,
C1-C20 alkyl indicates that the group may have from 1 to 20 (inclusive) carbon atoms in
it. Any atom can be optionally substituted, e.g., with one or more substituents. Examples
of alkyl groups include without limitation methyl, ethyl, and tert-butyl.
The term "cycloalkyl" refers to saturated monocyclic, bicyclic, tricyclic, or other
polycyclic hydrocarbon groups. Any atom can be optionally substituted, e.g., by one or
more substituents. A ring carbon serves as the point of attachment of a cycloalkyl group
to another moiety. Cycloalkyl groups can contain fused rings. Fused rings are rings that
share a common carbon atom. Cycloalkyl moieties can include, e.g., cyclopropyl,
cyclohexyl, methylcyclohexyl (provided that the methylcyclohexyl group is attached to
another moiety via a cyclohexyl ring carbon and not the methyl group), adamantyl, and
norbornyl (bicyclo[2.2.1]heptyl).
The term "haloalkyl" refers to an alkyl group, in which at least one hydrogen
atom is replaced by halo. In some embodiments, more than one hydrogen atom (2, 3,4,

5, 6, 7, 8, 9, 10, II, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,etc. hydrogen
atoms) on a alkyl group can be replaced by more than one halogen (e.g., 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, etc. halogen atoms). In
these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g.,
fluoro) or the hydrogen atoms can be replaced by a combination of different halogens
(e.g., fluoro and chloro). The term "haloalkyl" also includes alkyl moieties in which all
hydrogens have been replaced by halo (e.g., sometimes referred to as perhaloalkyl
moieties, such as trifluoromethyl). The term "fluoroalkyl" defined above is a subset of
haloalkyl.
The term "aralkyl" refers to an alkyl moiety in which an alkyl hydrogen atom is
replaced by an aryl group. One of the carbons of the alkyl moiety serves as the point of
attachment of the aralkyl group to another moiety. Aralkyl includes groups in which
more than one hydrogen atom on an alkyl moiety has been replaced by an aryl group.
Any ring or chain atom can be optionally substituted e.g., by one or more substituents.
Examples of "aralkyl" include without limitation benzyl, 2-phenylethyl, 3-phenyIpropyl,
benzhydryl (diphenylmethyl), and trityl (triphenylmethyl) groups.
The term "heteroaralkyl" refers to an alkyl moiety in which an alkyl hydrogen
atom is replaced by a heteroaryl group. One of the carbons of the alkyl moiety serves as
the point of attachment of the aralkyl group to another moiety. Heteroaralkyl includes
groups in which more than one hydrogen atom on an alkyl moiety has been replaced by a
heteroaryl group. Any ring or chain atom can be optionally substituted e.g., by one or
more substituents. Heteroaralkyl can include, for example, 2-pyridylethyl.
The term"alkenyl" refers to a straight or branched hydrocarbon chain containing
2-20 carbon atoms and having one or more double bonds. Any atom can be optionally
substituted, e.g., by one or more substituents. Alkenyl groups can include, e.g., allyl, 1-
butenyl, 2-hexenyl and 3-octenyl groups. One of the double bond carbons can optionally
be the point of attachment of the alkenyl substituent. The term "alkynyl" refers to a
straight or branched hydrocarbon chain containing 2-20 carbon atoms and having one or
more triple bonds. Any atom can be optionally substituted, e.g., by one or more
substituents. Alkynyl groups can include, e.g., ethynyl, propargyl, and 3-hexynyl. One

of the triple bond carbons can optionally be the point of attachment of the alkynyl
substituent.
The term "alkoxy" refers to an -O-alkyl radical. The term "mercapto" refers to an
SH radical. The term "thioalkoxy" refers to an -S-alkyl radical. The terms "aryloxy" and
"heteroaryloxy" refer to an -O-aryl radical and -O-heteroaryl radical, respectively. The
term "thioaryloxy" refers to an -S-aryl radical. The terms "aralkoxy" and
"heteroaralkoxy" refer to an -O-aralkyl radical and -O-heteroaralkyl radical, respectively.
The term "cycloalkoxy" refers to an -O-cycloalkyl radical. The terms "cycloalkenyloxy"
and "heterocycloalkenyloxy" refer to an -O-cycloalkenyl radical and -O-
heterocycloalkenyl radical, respectively. The term "heterocyclyloxy" refers to an -O-
heterocyclyl radical. The terms "alkenyloxy" and "alkynyloxy" refer to -O-alkenyl and -
O-alkynyl radicals, respectively.
The term "heterocyclyl" refers to a saturated monocyclic, bicyclic, tricyclic or
other polycyclic ring system having 1-4 heteroatoms if monocyclic, 1-8 heteroatoms if
bicyclic, or 1-10 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (and
mono and dioxides thereof, e.g., N→ O", S(O), SO2) (e.g., carbon atoms and 1-4, 1-8, or
1-10 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively). The
heteroatom or ring carbon is the point of attachment of the heterocyclyl substituent to
another moiety. Any atom can be optionally substituted, e.g., by one or more
substituents. The heterocyclyl groups can contain fused rings. Fused rings are rings that
share a common carbon atom. Heterocyclyl groups can include, e.g., tetrahydrofuryl,
tetrahydropyranyl, piperidyl (piperidino), piperazinyl, morpholinyl (morpholino),
pyrrolinyl, and pyrrolidinyl.
The term "cycloalkenyl" refers to partially unsaturated monocyclic, bicyclic,
tricyclic, or other polycyclic hydrocarbon groups. A ring carbon (e.g., saturated or
unsaturated) is the point of attachment of the cycloalkenyl substituent. Any atom can be
optionally substituted e.g., by one or more substituents. The cycloalkenyl groups can
contain fused rings. Fused rings are rings that share a common carbon atom.
Cycloalkenyl moieties can include, e.g., cyclohexenyl, cyclohexadienyl, or norbornenyl.
The term "heterocycloalkenyl" refers to partially unsaturated monocyclic,
bicyclic, tricyclic, or other polycyclic hydrocarbon groups having 1-4 heteroatoms if

monocyclic, 1-8 heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, said
heteroatoms selected from O, N, or S (and mono and dioxides thereof, e.g., N→ O, S(O),
SO2) (e.g., carbon atoms and 1-4, 1-8, or 1-10 heteroatoms of N, O, or S if monocyclic,
bicyclic, or tricyclic, respectively). A ring carbon (e.g., saturated or unsaturated) or
heteroatom is the point of attachment of the heterocycloalkenyl substituent. Any atom
can be optionally substituted, e.g., by one or more substituents. The heterocycloalkenyl
groups can contain fused rings. Fused rings are rings that share a common carbon atom.
Heterocycloalkenyl groups can include, e.g., tetrahydropyridyl, and dihydropyranyl.
The term "aryl" refers to an aromatic monocyclic, bicyclic, or tricyclic
hydrocarbon ring system, wherein any ring atom can be optionally substituted, e.g., by
one or more substituents. Aryl groups can contain fused rings. Fused rings are rings that
share a common carbon atom. Aryl moieties can include, e.g., phenyl, naphthyl,
anthracenyl, and pyrenyl.
The term "heteroaryl" refers to an aromatic monocyclic, bicyclic, tricyclic, or
other polycyclic hydrocarbon groups having 1-4 heteroatoms if monocyclic, 1-8
heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, said heteroatoms selected from
O, N, or S (and mono and dioxides thereof, e.g., N→ O-, S(O), SO2) (e.g., carbon atoms
and 1-4, 1-8, or 1-10 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic,
respectively). Any atom can be optionally substituted, e.g., by one or more substituents.
Heteroaryl groups can contain fused rings. Fused rings are rings that share a common
carbon atom. Heteroaryl groups include pyridyl, thienyl, furyl (furanyl), imidazolyl,
isoquinolyl, quinolyl and pyrrolyl.
The term "oxo" refers to an oxygen atom, which forms a carbonyl (C=O) when
attached to carbon, or which forms part of a sulfinyl or sulfonyl group when attached to a
sulfur atom, or which forms part of an N-oxide when attached to a nitrogen. The term
"thioxo" refers to an oxygen atom, which forms a thiocarbonyl (C=S) when attached to
carbon.
The expression "optionally substituted" when used in conjunction with any
structure described herein (e.g., alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl,
heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, heteroaryl) means that the

referenced structure can either be unsubstituted or that any one or more (e.g., 1-10, 1,2,
3,4, or 5) hydrogen atoms (and/or halo atoms in the case of a haloalkyl) in the structure
can be replaced by a substituent (i.e., a group other that hydrogen group that is attached
to any atom of the aforementioned structures).
When R, Ra, Rf, Rg, Rh, Ri, Rj, R3, R4, R3', R4', RN1, or RN2 is an aryl or heteroaryl
group (or a group that contains an aryl or heteroaryl group, e.g., an aryloxy group or
heteroaryloxy group) that is substituted with one or more (e.g., 1-10, 1-5, 1-4, 1-3, 1-2, or
I) substituents, each of the substituents can be independently selected from (referred to
collectively as "Group A"):
(i) halo; NRfRg; nitro; azido; hydroxy; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-
C3) alkoxy or C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) thioalkoxy, each of which is
optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents independently
selected from Group C below; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) haloalkoxy;
C6-C16 (e.g., C6-C14, C6-C10, or phenyl) aryloxy, C6-C16 (e.g., C6-C14, C1-C10, or phenyl)
thioaryloxy, heteroaryloxy including 5-20 (e.g., 5-12, 5-10, or 5-6) atoms, or thioaryloxy
including 5-20 (e.g., 5-12, 5-10, or 5-6) atoms, each of which is optionally substituted
with from 1-10 (e.g., 1-5, 1-4,1-3, 1-2, or 1) Ra'; C2-C12 (e.g., C2-C10, C2-C6, or C2-C4)
alkenyloxy; C2-C12 (e.g., C2-C10, C2-C6, or C2-C4) alkynyloxy; C3-C16 (e.g., C3-C10, C3-
C8, C3-C6) cycloalkyloxy, C3-C16 (e.g., C3-C10, C3-C8, C3-C6) cycloalkenyloxy,
heterocyclyloxy including 3-16 (e.g., 3-10, 3-8,3-6) atoms, heterocycloalkenyloxy
including 3-16 (e.g., 3-10, 3-8, 3-6) atoms, C7-C20 (e.g., C7-C16, C7-C12, C7-C10) aralkoxy,
or heteroaralkoxy including 6-20 (e.g., 6-14, 6-10) atoms, each of which is optionally
substituted with from 1-5 (e.g., 1-4,1-3, 1-2, or 1) substituents independently selected
from Group B below; mercapto; cyano; -C(O)Rh, -C(O)ORh; -OC(O)Rh; -C(O)SRh; -
SC(O)Rh; -C(S)SRh; -SC(S)Rh; -C(O)NRfRg; -NRiC(O)Rj; -OC(O)NRfRg; or 2 adjacent
substituents on an aryl or heteroaryl ring (or a group that contains an aryl or heteroaryl
group) together form C1-C3 alkylenedioxy;
(ii) C1-C12 (e.g., C1-C10, C1-C6, G1-C4, or C1-C3) alkyl or C1-C12 (e.g., C1-C10, C1-
C6, C1-C4, or C1-C3) haloalkyl; each of which is optionally substituted with from 1-5
(e.g., 1-4, 1-3,1-2, or 1) substituents independently selected from Group D below; or

(iii) C7-C20 (e.g., C7-C16, C71-C12, C7-C10) aralkyl; C3-C16 (e.g., C3-C10, C3-C8, C3-
C6) cycloalkyl; heteroaralkyl including 6-20 (e.g., 6-14, 6-l0)atoms; C3-C16 (e.g., C3-C10,
C3-Cg, C3-C6) cycloalkenyl; heterocyclyl including 3-16 (e.g., 3-10, 3-8, 3-6) atoms; or
heterocycloalkenyl including 3-16 (e.g., 3-10, 3-8, 3-6) atoms; each of which is
optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents independently
selected from Group B below; or
(iv) C2-C20 (e.g., C2-C12, C2-C10, C2-C6, or C2-C4) alkenyl or C2-C20 (e.g., C2-C12,
C2-C10 C2-C6, or C2-C4) alkynyl; or
(v) C6-C16 (e.g., C6-C14, C6-C10, or phenyl) aryl or heteroaryl including 5-16 (e.g.,
5-12, 5-10, or 5-6) atoms, each of which is optionally substituted with from 1-10 (e.g., 1-
5, 1-4, 1-3,1-2,orl)Ra'.
Ra at each occurrence is, independently, C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-
C3) alkyl, C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) haloalkyl, C2-C12 (e.g., C2-C10,
C2-C6, or C2-C4) alkenyl; C2-C12 (e.g., C2-C10, C2-C6, or C2-C4) alkynyl; C3-C16 (e.g., C3-
C10, C3-C8, C3-C6) cycloalkyl; C3-C16 (e.g., C3-C10, C3-C8, C3-C6) cycloalkenyl,
heterocyclyl including 3-16 (e.g., 3-10,3-8, 3-6) atoms, heterocycloalkenyl including 3-
16 (e.g., 3-10,3-8, 3-6) atoms; C7-C20 (e.g., C7-Cl6, C7-C12, C7-C10) aralkyl; C6-C16 (e.g.,
C6-C14, C6-C10, or phenyl) aryl; heteroaryl including 5-16 (e.g., 5-12, 5-10, or 5-6) atoms;
halo; NRfRg; nitro; azido, hydroxy; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) alkoxy;
C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) thioalkoxy; C1-C12 (e.g., C1-C10, C1-C6, C1-
C4, or C1-C3) haloalkoxy; C6-C16 (e.g., C6-C14, C6-C10, or phenyl) aryloxy, C6-C16 (e.g.,
C6-C14, C6-C10, or phenyl) thioaryloxy; heteroaryloxy including 5-20 (e.g., 5-12, 5-10, or
5-6) atoms; thioaryloxy including 5-20 (e.g., 5-12, 5-10, or 5-6) atoms; C2-C12 (e.g., C2-
C10, C2-C6, or C2-C4) alkenyloxy; C2-C12 (e.g., C2-C10, C2-C6, or C2-C4) alkynyloxy; C3-
C16 (e.g., C3-C10, C3-C8, C3-C6) cycloalkyloxy; C3-C16 (e.g., C3-C10, C3-C8, C3-C6)
cycloalkenyloxy; heterocyclyloxy including 3-16 (e.g., 3-10, 3-8, 3-6) atoms;
heterocycloalkenyloxy including 3-16 (e.g., 3-10, 3-8, 3-6) atoms; C7-C20 (e.g., C7-C16,
C7-Cl2, C7-C10) aralkoxy; heteroaralkoxy including 6-20 (e.g., 6-14, 6-10) atoms;
mercapto; cyano; -C(O)Rh, -C(O)ORh; -OC(O)Rh; -C(O)SRh; -SC(O)Rh; -C(S)SRh; -
SC(S)Rh; -C(O)NRfRg; -NRiC(O)Rj; -OC(O)NRfRg; or 2 adjacent substituents on an aryl

or hetcroaryl ring (or a group that contains an aryl or heteroaryl group) together form C1-
C3 alkylenedioxy.
When R, Ra, Rf, R8, Rh, Ri, Rj, R3, R4, R3', R4', RN1, or RN2 is an aralkyl,
cycloalkyl; heteroaralkyl, cycloalkenyl, heterocyclyl, or heterocycloalkenyl group (or a
group that contains an aryl or heteroaryl group, e.g., a cycloalkyloxy, cycloalkenyloxy;
heterocyclyloxy, heterocycloalkenyloxy, aralkoxy; or heteroaralkoxy) that is substituted
with one or more (e.g., 1-10, 1-5, 1-4, 1-3, 1-2, or 1) substituents, each of the substituents
can be independently selected from (referred to collectively as "Group B"):
(i) halo; NRfRg; nitro; azido; hydroxy; oxo, thioxo, =NRk, C1-C12 (e.g., C1-C10,
C1-C6, C1-C4, or C1-C3) alkoxy or C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3)
thioalkoxy, each of which is optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1)
substituents independently selected from Group C below; C1-C12 (e.g., C1-C10, C1-C6, C1-
C4, or C1-C3) haloalkoxy; C6-C16 (e.g., C6-C14, C6-C10, or phenyl) aryloxy, C6-C16 (e.g.,
C6-C14, C6-C10, or phenyl) thioaryloxy, heteroaryloxy including 5-20 (e.g., 5-12, 5-10, or
5-6) atoms, or thioaryloxy including 5-20 (e.g., 5-12, 5-10, or 5-6) atoms, each of which
is optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents
independently selected from Group A above; C2-C12 (e.g., C2-C10, C2-C6, or C2-C4)
alkenyloxy; C2-C12 (e.g., C2-C10, C2-C6, or C2-C4) alkynyloxy; C3-C16 (e.g., C3-C10, C3-
C8, C3-C6) cycloalkyloxy, C3-C16 (e.g., C3-C10, C3-C8, C3-C6) cycloalkenyloxy,
heterocyclyloxy including 3-16 (e.g., 3-10, 3-8, 3-6) atoms, heterocycloalkenyloxy
including 3-16 (e.g., 3-10, 3-8, 3-6) atoms, C7-C20 (e.g., C7-C16, C7-C12, C7-C10) aralkoxy,
or heteroaralkoxy including 6-20 (e.g., 6-14, 6-10) atoms, each of which is optionally
substituted with 1-5 (e.g., 1-4,1-3, 1-2, or 1) Rb'; mercapto; cyano; -C(O)Rh, -C(O)ORh; -
OC(O)Rh; -C(O)SRh; -SC(O)Rh; -C(S)SRh; -SC(S)Rh; -C(O)NRfRg; -NRiC(O)R.j; -
OC(O)NRfRg; or
(ii) C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) alkyl or C1-C12 (e.g., C1-C10, C1-
C6, C1-C4, or C1-C3) haloalkyl; each of which is optionally substituted with from 1-5
(e.g., 1-4, 1-3,1-2, or 1) substituents independently selected from Group D below; or
(iii) C7-C20 (e.g., C7-C16, C7-C12, C7-C10) aralkyl; C3-C16 (e.g., C3-C10, C3-C8, C3-
C6) cycloalkyl; heteroaralkyl including 6-20 (e.g., 6-14,6-10) atoms; C3-C16 (e.g., C3-C10,

C3-C8, C3-C6) cycloalkenyl; heterocyclyl including 3-16 (e.g., 3-10, 3-8, 3-6) atoms; or
heterocycloalkenyl including 3-16 (e.g., 3-10, 3-8, 3-6) atoms; each of which is
optionally substituted with from 1-10 (e.g., 1-5, 1-4, 1-3, 1-2, or 1) Rb'; or
(iv) C2-C20 (e.g., C2-C12, C2-C10, C2-C6, or C2-C4) alkenyl or C2-C20 (e.g., C2-C12,
C2-C10, C2-C6, or C2-C4) alkynyl; or
(v) C6-C16 (e.g., C6-C14, C6-C10, or phenyl) aryl or heteroaryl including 5-16 (e.g.,
5-12, 5-10, or 5-6) atoms, each of which is optionally substituted with from 1-5 (e.g., 1-4,
1-3, 1-2, or 1) substituents independently selected from Group A above.
Rb at each occurrence is, independently, C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-
C3) alkyl or C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) haloalkyl, each of which is
optionally substituted with from 1-5 (e.g., 1-4,1-3, 1-2, or 1) substituents independently
selected from Group D below; C2-C!2 (e.g., C2-C10, C2-C6, or C2-C4) alkenyl; C2-C12
(e.g., C2-C10, C2-C6, or C2-C4) alkynyl; C3-C16 (e.g., C3-C10, C3-Cg, C3-C6) cycloalkyl; C3-
C16 (e.g., C3-C10, C3-C8, C3-C6) cycloalkenyl, heterocyclyl including 3-16 (e.g., 3-10, 3-8,
3-6) atoms, heterocycloalkenyl including 3-16 (e.g., 3-10, 3-8, 3-6) atoms; C7-C20 (e.g.,
C7-C16, C7-C12, C7-C10) aralkyl; C6-C16 (e.g., C6-C14, C6-C10, or phenyl) aryl; heteroaryl
including 5-16 (e.g., 5-12, 5-10, or 5-6) atoms; halo; NRfR8; nitro; azido, hydroxy; oxo,
thioxo, =NRk, C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) alkoxy; C1-C12 (e.g., C1-C10,
C1-C6, C1-C4, or C1-C3) thioalkoxy; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3)
haloalkoxy; C6-C16 (e.g., C6-C14, C6-C10, or phenyl) aryloxy, C6-C16(e.g., C6-C14, C6-C10,
or phenyl) thioaryloxy; heteroaryloxy including 5-20 (e.g., 5-12, 5-10, or 5-6) atoms;
thioaryloxy including 5-20 (e.g., 5-12, 5-10, or 5-6) atoms; C2-C12 (e.g., C2-C10, C2-C6, or
C2-C4) alkenyloxy; C2-C12 (e.g., C2-C10, C2-C6, or C2-C4) alkynyloxy; C3-C16 (e.g., C3-
C10, C3-C8, C3-C6) cycloalkyloxy; C3-C16 (e.g., C3-C10, C3-C8, C3-C6) cycloalkenyloxy;
heterocyclyloxy including 3-16 (e.g., 3-10, 3-8, 3-6) atoms; heterocycloalkenyloxy
including 3-16 (e.g., 3-10, 3-8, 3-6) atoms; C7-C20 (e.g., C7-C16, C7-C12, C7-C10) aralkoxy;
heteroaralkoxy including 6-20 (e.g., 6-14, 6-10) atoms; mercapto; cyano; -C(O)Rh , -
C(O)ORh; -OC(O)Rh; -C(O)SRh; -SC(O)Rh; -C(S)SRh; -SC(S)Rh; -C(O)NRfRg; -
NRiC(O)Rj; or -OC(O)NRfRg.

When R, Ra, Rf, Rg, Rh, Ri, Rj, R3, R4, R3', R4', RN1, or RN2 is an alkoxy or
thioalkoxy group that is substituted with one or more (e.g., 1-10, 1-5, 1-4, 1-3, 1-2, or 1)
substituents, each of the substituents can be independently selected from (referred to
collectively as "Group C"): NRfRg; nitro; azido; hydroxy; oxo, thioxo, =NRk,C1-C12
(e.g., C1-C10, C1-C6, C1-C4, or C1-C3) alkoxy or C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-
C3) thioalkoxy; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) haloalkoxy; C6-C16 (e.g., C6-
C14, C6-C10, or phenyl) aryloxy, C6-C16 (e.g., C6-C14, C6-C10, or phenyl) thioaryloxy,
heteroaryloxy including 5-20 (e.g., 5-12, 5-10, or 5-6) atoms, or thioaryloxy including 5-
20 (e.g., 5-12, 5-10, or 5-6) atoms, each of which is optionally substituted with from 1-5
(e.g., 1-4, 1-3, 1-2, or 1) substituents independently selected from Group A above; C2-C12
(e.g., C2-C10, C2-C6, or C2-C4) alkenyloxy; C2-C12 (e.g., C2-C10, C2-C6, or C2-C4)
alkynyloxy; C3-C16 (e.g., C3-C10, C3-C8, C3-C6) cycloalkyloxy, C3-C16 (e.g., C3-C10, C3-
Cg, C3-C6) cycloalkenyloxy, heterocyclyloxy including 3-16 (e.g., 3-10, 3-8, 3-6) atoms,
heterocycloalkenyloxy including 3-16 (e.g., 3-10, 3-8, 3-6) atoms, C7-C20 (e.g., C7-C16,
C7-C12, C7-C10) aralkoxy, or heteroaralkoxy including 6-20 (e.g., 6-14, 6-10) atoms, each
of which is optionally substituted; mercapto; cyano; -C(O)Rh, -OC(O)Rh; -C(O)SRh; -
SC(O)Rh; -C(S)SRh; -SC(S)Rh; -C(O)NRfRg; -NRiC(O)Rj; or -OC(O)NRfRg.
When RF1, RF2, RF1, RF2', R, Ra, Rf, R8, Rh, Ri, Rj, R3, R4, R3, R4', RN1, or RN2 is
an alky or haloalkyl group (including a fluoroalkyl group) that is substituted with one or
more (e.g., 1-10, 1-5, 1-4, 1-3, 1-2, or 1) substituents, each of the substituents can be
independently selected from (referred to collectively as "Group D"): NRfRg; nitro; azido;
hydroxy; oxo; thioxo; =NRk; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, orC1-C3) alkoxy or C1-
C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) thioalkoxy, each of which is optionally
substituted with from 1-5 (e.g., 1-4,1-3, 1-2, or 1) substituents independently selected
from Group C above; C1-C12 (e.g., C1-C10, C1-C6, C1-C4, or C1-C3) haloalkoxy; C6-C16
(e.g., C6-C14, C6-C10, or phenyl) aryloxy, C6-C16 (e.g., C6-C14, C6-C10, or phenyl)
thioaryloxy, heteroaryloxy including 5-20 (e.g., 5-12, 5-10, or 5-6) atoms, or thioaryloxy
including 5-20 (e.g., 5-12, 5-10, or 5-6) atoms, each of which is optionally substituted
with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1) substituents independently selected from Group A
above; C2-C12 (e.g., C2-C10, C2-C6, or C2-C4) alkenyloxy; C2-C12 (e.g., C2-C10, C2-C6, or

C2-C4) alkynyloxy; C3-C16 (e.g., C3-C10, C3-C8, C3-C6) cycloalkyloxy, C3-C16 (e.g., C3-
C10, C3-C8, C3-C6) cycloalkenyloxy, heterocyclyloxy including 3-16 (e.g., 3-10, 3-8, 3-6)
atoms, heterocycloalkenyloxy including 3-16 (e.g., 3-10, 3-8, 3-6) atoms, C7-C20 (e.g.,
C7-C16, C7-C12, C7-C10) aralkoxy, or heteroaralkoxy including 6-20 (e.g., 6-14, 6-10)
atoms, each of which is optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or 1)
substituents independently selected from Group A above; mercapto; cyano;; -C(O)Rh, -
C(O)ORh; -OC(O)Rh; -C(O)SRh; -SC(O)Rh; -C(S)SRh; -SC(S)Rh; -C(O)NRfRg; -
NRiC(O)Rj; or-OC(O)NRfRg.
In embodiments, Groups C and D can further include C3-C10 (e.g., C3-C6)
cycloalkyl and heterocyclyl including 3-8 (e.g., 3-6 or 5-6) atoms, each of which can be
optionally substituted with from 1-5 (e.g., 1-4, 1-3, 1-2, or I) substituents independently
selected from Group A above.
Rk can be as defined for Rf, R8, and Rh.
When R, Ra, Rf, Rg, Rh, Ri, Rj, R3, R4, R3', R4', RN1, or RN2 is an alkenyl or alkynyl
group that is substituted with one or more (e.g., 1-10,1-5, 1-4, 1-3, 1-2, or 1)
substituents, each of the substituents can be independently selected from halo or a Group
C or D substituent.
The details of one or more embodiments of the invention are set forth in the
description below. Other features and advantages of the invention are in the claims.
DETAILED DESCRIPTION
In general, the starting material can be any organic compound that is substituted
with one or more nitrile groups (see, e.g., the Summary section of the specification). In
some embodiments, starting materials (as well as intermediates and products formed in
the methods described herein) can also include compounds described generically,
subgenerically, and specifically in US 2007-0219198, filed on February 7, 2007, which is
incorporated herein by reference in its entirety. The inventors named on the present
application and on US 2007-0219198 are obligated to assign to the same assignee.
Starting materials (as well as intermediates and products formed in the methods described
herein) can also include one or more structural features described in US 2007-0219198.

In some embodiments, the nitrile can be attached to an optionally substituted C6-
C10 aryl (e.g., phenyl). In other embodiments, the nitrile can be attached to an optionally
substituted C7-C12 aralkyl, e.g., benzyl.
In some embodiments, the starting material can include a substituent having a
formula -C(O)Re, wherein Re is C1-C6 alkyl (e.g., Re can be CH3). In other embodiments,
substituent selection for the starting materials can be made on the basis of whether a
particular substituent is known to be stable or inert to a particular fluoroalkylating agent
or classes thereof (e.g., the fluoroalkylating agents described herein). Thus, in some
embodiments, the starting material can be only further substituted (i.e., in addition to the
nitrile) with moieties known to be stable or inert to a particular fluoroalkylating agent or
classes thereof (e.g., the fluoroalkylating agents described herein).
The methods described herein also extend to the use'of starting materials and
intermediates having masked nitrile groups or other substituents, which can provide a
nitrile group (or its equivalent) in situ (e.g., in situ in the presence of the fluoroalkylating
agent).
In some embodiments, the fluoroalkylating agent can be a perfluoroalkylating
agent (e.g., a trifluoromethylating agent).
In some embodiments, the fluoroalkylating agent can be a nucleophilic
fluoroalkylating agent (e.g., a fluoroalkylating agent that can undergo 1,2 addition to an
enolizable or non-enolizable carbonyl compound).
In some embodiments, the fluoroalkylating agent can be a silicon-based reagent,
e.g., a compound having formula (III):

in which:
RF can be C1-C6 fluoroalkyl; and
each of Rb, Rc, and Rd can be, independently, C1-C12 alkyl or C2-C12 alkenyl, each
of which is optionally substituted.

In embodiments, each of Rb, Rc, and Rd can be, independently, C1-C4 alkyl (e.g.,
CH3 or CH2CH3). In other embodiments, one of Rb, Rc, and Rd is C2-C4 alkenyl (e.g.,
CH=CH2), and the other two are each, independently, C1-C4 alkyl (e.g., CH3 or CH2CH3).
In embodiments, RF can be C1-C4 perfluoroalkyl (e.g., CF3).
An exemplary fluoroalkylating agent of formula (III) is CF3Si(CH3)3, sometimes
referred to as Ruppert's reagent or the Ruppert-Prakash reagent. Methods for the
synthesis and use of Ruppert's reagent are described in, e.g., Prakash, G. K. S.;
Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393; Prakash, G. K. S.;
Yudin, A. K. Chem. Rev. 1997, 97, 757; and Prakash, G. K. S.; Hu, J.; Olah, G. A., J.
Org. Chem. 2003, 68, 4457, incorporated herein by reference thereto.
Other fluoroalkylating agent of formula (III) include, without limitation,
triethyltrifluoromethylsilane, CF3Si(CH2CH3)3, see, e.g., US Patent 5,008,425; and
vinyl(trifluoromethyl)dimethylsilane, which is commercially available, e.g., from the
following vendors: ABCR GmbH & CO. (Ryan Scientific in the US), Oakwood Products,
Inc. (US), and Gelest, Inc. (US).
In some embodiments, about 2 equivalents (or a relatively small excess thereof)
of the fluoroalkylating agent of formula (III) is used per nitrile functional group.
Typically, a moiety having a relatively strong affinity for silicon (e.g., a fluoride
ion source or oxygen nucleophile) is present during the reaction between the nitrile-
containing compound and the compound of formula (III). In certain embodiments, about
1 equivalent of fluoride ion is used per equivalent of nitrile-containing compound.
In some embodiments, the fluoroalkylating agent can be a fluoroalkyl-containing
salt or ionic complex, e.g., an ionic complex formed upon interaction of a fluoroalkyl
halide (e.g., a fluoroalkyl iodide) and a reducing agent. For example, trifluoromethyl
iodide (CF3I) can be used as a nucleophilic trifluoromethylating agent under the
activation of electron-donating tetrakis-(dimethylamino)ethylene (TDAE). See, e.g., Ait-
Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W. Jr. Org. Lett. 2001, 3, 4271. As a
further example, see J. Org. Chem. 2006, 71, 3564, which describes the use of other
fluoroalkyl iodides to introduce other perfluoroalkyl groups (RF), such as C2F5 or /1-C4F9,
by using RFI and TDAE.

In these embodiments, the methods can further include reacting a compound
having formula (IV): RF-X, wherein RF is C1-C6 fluoroalkyl; and X is halo; with a
reducing agent (e.g., TDAE). In embodiments, X can be iodo. In embodiments, RF is
CF3, CF2CF3,or(CF2)3CF3.
Jn some embodiments, the fluoroalkylating agent can be a hemiaminal that is
formed between fiuoral (CF3CHO) and a cyclic amine. For example, the fluoroalkylating
agent can be compound having formula (V):

in which RF can be C1-C6 fluoroalkyl; and ring A is optionally substituted morpholinyl or
piperazinyl.
In embodiments, RF can be CF3. See, e.g., Billard, T. B.; Langlois, B. R. Org.
Lett. 2000, 2, 2101; Billard, T.; Langlois, B. R.; Blond, G. Eur. J. Org. Chem. 2001,
1467; Billard, T.; Langlois, B. R. J. Org. Chem. 2002, 67, 997; and Langlois, B. R.;
Billard, T. Synthesis 2003, 185.
In these embodiments, a base is typically present during the reacting of the
compound of the nitrile-containing compound and the compound of formula (V). By
way of example, the base can be a metal salt (e.g., K+) of a C1-C6 alkoxide (e.g., tert-
butoxide).
In some embodiments, the fluoroalkylating agent can be a compound having
formula (VI): Ar-S(O)x-RF; in which Ar can be optionally substituted phenyl; x can be 0,
1 or 2 (e.g., 1 or 2); and RF is C1-C6 fluoroalkyl.
In embodiments, RF can be CF3. In embodiments, x can be 2. See, e.g., US
Patent 7,087,789 and Prakash, G. K. S.; Hu, J.; Olah, G. K.J. Org. Chem. 2003, 68,
4457.

In these embodiments, a base is typically present during the reacting of the
compound of the nitrile-containing compound and the compound of formula (VI). By
way of example, the base can be a metal salt (e.g., K+) of a C1-C6 alkoxide (e.g., tert-
butoxide).
In some embodiments, the fluoroalkylating agent can be fluoroform (CF3H).
Methods for the synthesis, deprotonation, and trifluoromethylation of fluoroform are
described in, e.g., Webster J. L.; Lerou, J. J. U.S. Pat. No. 5,446,218, 1995; Shono, T.;
Ishifume, M.; Okada, T.; Kashimura, S. J. Org. Chem. 1991, 56, 2; Barhdadi, R.;
Troupel, M; Perichon, J. Chem. Comm. 1998, 1251; Folleas, B.; Marek, I.; Normant, J.-
R; Saint-Jalmes, L. Tetrahedron Lett. 1998, 39, 2973; Folleas, B.; Marek, I.; Normant, J.-
F.; Saint-Jalmes, L. Tetrahedron 2000,56,275; Russell, J.; Roques, N. Tetrahedron
1998, 54. 13771; Large, S.; Roques, N.; Langlois, B. R J. Org. Chem. 2000, 65, 8848;
Roques, N.; Russell, J.; Langlois, B.; Saint-Jalmes, L.; Large, S. PCT Int. Appl. 1998,
WO 9822435; and Roques, N.; Mispelaere, C. Tetrahedron Lett. 1999, 40, 6411.
Other fluoroalkylating agents include trifluoromethylcopper reagents; sodium
trifluoroacetate used in conjunction with copper halide catalysts, see, e.g., Tet. Lett. 2005,
46, 3161); trifluoroacetic and trifluoromethanesulfinic acid derivatives;
trifluoroacetamides, trifluoroacetophenone and adducts thereof, and
trifluoromethanesulfmamides. See, e.g.,Angew. Chem. Int. Ed. 2003, 42, 3133; Synlett.
2004, 2119; and Chem. Eur. J. 2005,11, 939; Langlois, B. R.; Billard, T. Synthesis 2003,
185; Jablonski, L.; Joubert, J.; Billard, T.; Langlois, B. R. Synlett 2003, 230; Inschauspe,
D.; Sortais, J.-P.; Billard, T.; Langlois, B. R. Synlett 2003, 233; and Jablonski, L.; Billard,
T.; Langlois, B. R. Tetrahedron Lett. 2003, 44, 1055; and Synlett 2002, 646.
In some embodiments, the fluoroalkylating agent can be agent that can used to
introduce a difluoromethyl group (-CF2H).
In certain embodiments, the fluoroalkylating agent can be difluoromethyl phenyl
sulfone (PhSO2CF2H). See, e.g., Eur. J. Org. Chem. 2005, 2218; Org. Lett. 2004, 6,
4315; US Patent 7,087,789; and Angew. Chem. Int. Ed. 2005, 44, 5882.

In certain embodiments, the fluoroalkylating agent can be TMS-CF2SO2Ph. See,
e.g., Jet. Lett. 2005, 46, 8273.
In certain embodiments, the fiuoroalkylating agent can be TMS-CF2H, TMS-
CF2SePh, TMSCF2TMS, or TMS-SiCF2SPh. See, e.g., Yudin, A. K.; Prakash, G. K. S.;
Deffieux, D.; Bradley, M.; Bau, R.; Olah, G. A. J. Am. Chew. Soc. 1997, 119, 1572 1581.
In some embodiments, the method can further include other protecting group
and/or functional group manipulation steps. Additionally, the various synthetic steps
may be performed in an alternate sequence or order to give the desired compounds.
Synthetic chemistry transformations and protecting group methodologies (protection and
deprotection) useful in synthesizing the compounds described herein are known in the art
and include, for example, those such as described in R. Larock, Comprehensive Organic
Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective
Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M.
Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994);
and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and
Sons (1995), and subsequent editions thereof.
In some embodiments, starting materials and reagents can be synthesized according
to methods described herein and/or conventional, organic chemical synthesis methods from
commercially available starting materials and reagents. As can be appreciated by the
skilled artisan, further methods of synthesizing such compounds will be evident to those
of ordinary skill in the art.
The reaction products and intermediates described herein can be separated from a
reaction mixture and further purified by a method such as column chromatography, high-
pressure liquid chromatography, or recrystallization.
The starting materials, intermediates, and products of the methods described
herein may contain two or more asymmetric centers and thus occur as racemates and
racemic mixtures, single enantiomers, individual diastereomers and diastereomeric
mixtures. All such isomeric forms of these compounds are expressly included in the
present invention. The compounds of this invention may also contain linkages (e.g.,
carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation

is restricted about that particular linkage, e.g. restriction resulting from the presence of a
ring or double bond. Accordingly, all cis/trans and E/Z isomers and rotational isomers
are expressly included in the present invention. The compounds of this invention may
also be represented in multiple tautomeric forms, in such instances, the invention
expressly includes all tautomeric forms of the compounds described herein, even though
only a single tautomeric form may be represented. All such isomeric forms of such
compounds are expressly included in the present invention. All crystal forms of the
compounds described herein are expressly included in the present invention.
The compounds of this invention include the compounds themselves, as well as
their salts and their S or N-oxides, if applicable. A salt, for example, can be formed
between an anion and a positively charged substituent (e.g., amino) on a compound
described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate,
phosphate, citrate, methanesulfonate, tri fluoroacetate, and acetate. Likewise, a salt can
also be formed between a cation and a negatively charged substituent (e.g., carboxylate)
on a compound described herein. Suitable cations include sodium ion, potassium ion,
magnesium ion, calcium ion, and an ammonium cation such as tetramethylamrnonium
ion.
Pharmaceutically acceptable salts of the compounds of this invention include
those derived from pharmaceutically acceptable inorganic and organic acids and bases.
Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-
hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-
naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-
phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate,
tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in
themselves pharmaceutically acceptable, may be employed in the preparation of salts
useful as intermediates in obtaining the compounds of the invention and their
pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases
include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium

and N-(alkyl)4+ salts. This invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or
dispersible products may be obtained by such quaternization. Salt forms of the
compounds of any of the formulae herein can be amino acid salts of carboxy groups (e.g.
L-arginine, -lysine, -histidine salts).
The invention will be further described in the following examples. It should be
understood that these examples are for illustrative purposes only and are not to be
construed as limiting this invention in any manner.
EXAMPLES
Example 1
2,2,2-Trifluoro-1-r3-(piperidine-l-sulfonyl)-phenyl]-l-trifluoromethyl-ethylamine
Scheme 1

Step A. To a mixture of 3-cyano-benzenesulfonyl chloride (170 mg, 0.84 mmol,
1A) and triethylamine (0.24 mL, 1.69 mmol) in 2 mL dichloromethane at 0 °C was added
piperidine (124 µL, 1.26 mmol). The reaction mixture was stirred at 25 °C for 16 h and
concentrated to give a yellow oily residue. Flush column chromatography of the residue
(silica gel, hexane : ethyl acetate =1:3) provided compound 3-(piperidine-l-sulfonyl)-
benzonitrile (189 mg, 90%) as a white solid.
1H NMR (400 MHz, CDCl3): δ 1.42 -1.52 (m, 2 H), 1.62 - 1.72 (m, 4 H), 2.99 -
3.08 (m, 4 H), 7.71 (dd, J = 7.83, 7.83 Hz, 1 H), 7.89 (d, J = 7.83 Hz, 1 H), 8.00 (d, J =
7.83 Hz, 1 H), 8.07 (s, 1 H).
Step B. To a mixture of 3-(piperidine-l-sulfonyl)-benzonitrile (80 mg, 0.32
mmol) and (trifluoromethyl)trimethylsilane (0.14 mL, 0.96 mmol) in 3 mL dry THF at 0
°C under nitrogen was added tetrabutylammonium fluoride (176 mg, 0.67 mmol) in 1 mL
dry THF. The reaction mixture was stirred at 0 °C for 2 h and concentrated to give a
yellow oily residue. Flush column chromatography of the residue (silica gel, hexane :

ethyl acetate = 6:1) afforded 2,2,2-trifiuoro-1 -[3-(piperidine-1 -sulfonyl)-phenyl]-1 -
trifluoromethyl-ethyiamine 1B (55 mg, 55%) as a colorless oil and starting material 1A
(28 mg, 0.112mmol,35%).
1H NMR (400 MHz, CDCl3): δ 1.37 - 1.50 (m, 2 H), 1.56 -1.70 (m, 4 H), 2.24 (s,
2 H), 2.92 - 3.09 (m, 4 H), 7.63 (dd,7= 8.08, 8.08 Hz, 1 H), 7.87 (d, J = 8.08 Hz, 1 H),
8.01 (d, J= 8.08 Hz, 1 H), 8.20 (s, 1 H).
Example 2
2,2,2-Trifluoro-l-r4-(piperidine-1-sulfonyl)-phenvn-1-trifluoromethyl-ethylamine
Scheme 2

Step A. . 4-(Piperidine-l-sulfonyl)-benzonitrile was prepared according to a
procedure similar to that described in Example 1, Step A. 4-Cyano-benzenesulfonyl
chloride (170 mg, 0.84 mmol) was converted to the desired product (200 mg, 95%) as a
white solid.
1H NMR (400 MHz, CDCl3): δ 1.42 - 1.50 (m, 2 H), 1.61 -1.70 (m, 4 H), 3.00 -
3.07 (m, 4 H), 7.83 (d, J= 8.84 Hz, 2 H), 7.87 (d, J = 8.84 Hz, 2 H).
Step B. The title compound of Example 2 was prepared according to a procedure
similar to that described in Example 1, Step B. 4-(Piperidine-I-sulfonyl)-benzonitriIe
(0.12 g, 0.48 mmol) was converted to the desired product (93.0 mg, 50%) as a colorless
oil.
1HNMR (400 MHz, CDCl3): δ 1.40 - 1.50 (m, 2 H), 1.62 -1.71 (m, 4 H), 2.23 (s,
2 H), 2.99 - 3.09 (m, 4 H), 7.82 (d,J= 8.84 Hz, 2 H), 7.97 (d, J =8.84 Hz, 2 H).
Example 3
2,2,2-Trifluoro-l-[3-(pyrrolidine-l-sulfonyl)-phenvl)-l-trifluoromethyl-ethyiamine
Scheme 3


Step A. 3-(Pyrrolidine-l -sulfonyl)-benzonitrile was prepared according to a
procedure similar to that described in Example 1, Step A. 3-Cyano-benzenesulfonyl
chloride (200 mg, 1.00 mmol) was converted to the desired product (217 mg, 92%) as a
white solid.
1H NMR (400 MHz, CDC13): δ 1.79 - 1.85 (m, 4 H), 3.24 - 3.32 (m, 4 H), 7.69
(dd, J= 7.83, 7.83 Hz, 1 H), 7.87 (d, J= 7.83 Hz, 1 H), 8.07 (d, J= 7.83 Hz, 1 H), 8.13
(s, 1 H).
Step B. The title compound of Example 3 was prepared according to a procedure
similar to that described in Example 1, Step B. 3-(Pyrrolidine-l-sulfonyl)-benzonitrile
3A (76 mg, 0.32 mmol) was converted to the desired product (35.0 mg, 30%) as a
colorless oil.
1H NMR (400 MHz, CDC13): δ 1.73 -1.80 (m, 4 H), 2.23 (s, 2 H), 3.22 - 3.29 (m,
4 H), 7.64 (dd, J = 7.83, 7.83 Hz, 1 H), 7.94 (d, J = 7.83 Hz, 1 H), 8.02 (d, J = 7.83 Hz, 1
H), 8.28 (s, 1 H).
Example 4
3-(1-Amino-2,2,2-trifluoro-l-trifluoromethvl-ethyl)-N,N-diethvl-benzenesulfonamide
Scheme 4

Step A. 3-Cyano-N, N-diethyl-benzenesulfonamide was prepared according to a
procedure similar to that described in Example 1, Step A. 3-Cyano-benzenesulfonyl
chloride (220 mg, 1.09 mmol) was converted to the desired product (250 mg, 96%) as a
white solid.

1H NMR (400 MHz, CDCl3): δ 1.82 (t, J= 6.82 Hz, 6 H), 3.28 (q, J= 6.82 Hz, 4
H), 7.68 (dd, J= 7.83, 7.83 Hz, 1 H), 7.87 (d, J = 7.83 Hz, 1 H), 8.06 (d, J= 7.83 Hz, 1
H), 8.13 (s, 1 H).
Step B. The title compound of Example 4 was prepared according to a procedure
similar to that described in Example 1, Step B. 3-Cyano-N,N-diethyl-
benzenesulfonamide 4A (98 mg, 0.41 mmol) was converted to the desired product (65.0
mg, 42%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.11 (t, J= 7.07 Hz, 6 H), 2.24 (s, 2 H), 3.26 (q, J
= 7.07 Hz, 4 H), 7.60 (dd, J= 7.83, 7.83 Hz, 1 H), 7.92 (d, J = 7.83 Hz, 1 H), 7.97 (d, J =
7.83 Hz, 1 H), 8.26 (s, 1 H).
Example 5
3-(l-Amino-2,2,2-trifluoro-l-trifluoromethvl-ethyl)-N-(tert-butoxvcarbonvl)-N-
cvclohexyl-benzenesulfonamide
Scheme 5

Step A. 3-Cyano-N-(tert-butoxycarbonyl)-N-cyclohexyl-benzenesulfonarnide.
To a mixture of 3-cyano-benzenesulfonyl chloride (210 mg, 1.04 mmol) and (0.29
mL, 2.08 mmol) in 2 mL dichloromethane at 0 °C was added cyclohexylamine (180 µL,
1.56 mmol). The reaction mixture was stirred at 25 °C for 16 h and washed with water
and brine. The organic layer was concentrated under rotary vacuum to give a yellow oily
residue, which was then dried under high vacuum for 16 h to afford a yellow solid. To
this yellow solid was added di-tert-butyl dicarbonate (330 mg, 1.52 mmol), 4-
(dimethylamino)-pyridine (20 mg, 0.16 mmol), and 3 mL dry acetonitrile. The reaction
mixture was stirred at 25 °C for 16 h and concentrated to give a yellow oily residue.
Flush column chromatography of the residue (silica gel, hexane : ethyl acetate = 5:1)
provided 3-cyano-N-(tert-butoxycarbonyl)-N-cyclohexyl-benzenesulfonamide 5A (300
mg, 79%) as a white solid.

1H NMR (400 MHz, CDCl3): δ 1.09 - 1.24 (m, 2 H), 1.29 - 1.47 (m, 2 H), 1.38 (s,
9 H), 1.78 - 1.92 (m, 4 H), 2.10 - 2.24 (m, 2 H), 4.25 - 4.37 (m, 1 H), 7.66 (dd, J= 7.83,
7.83 Hz, 1 H), 7.87 (d, J =7.83 Hz, 1 H), 8.13 (d, J =7.83 Hz, lH),8.19(s, I H).
Step B. The title compound of Example 5 was prepared according to a procedure
similar to that described in Example 1, Step B. 3-Cyano-iV-(tert-butoxycarbonyl)-N-
cyclohexyl-benzenesulfonamide 5A (150 mg, 0.41 mmol) was converted to the desired
product (71.0 mg, 34%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.30 (s, 9 H), 1.59 -1.70 (m, 2 H), 1.79- 1.90 (m,
4 H), 2.13 - 2.22 (m, 4 H), 2.22 (s, 2 H), 4.26 - 4.38 (m, 1 H), 7.61 (dd, J = 7.83, 7.83 Hz,
1 H), 8.00 (d, J= 7.83 Hz, 1 H), 8.04 (d, J = 7.83 Hz, 1 H), 8.30 - 8.34 (s, 1 H).
Example 6
3-(l-Amino-2,2,2-trifluoro-l-trifluoromethyl-ethyl)-N-benzyl-N-(tert-butoxvcarbonyl)-
benzenesulfonamide
Scheme 6

Step A. N-Benzyl-N-tert-butoxycarbonyl)-3-cyano-benzenesulfonamide.
The title compound was prepared according to a procedure similar to that
described in Example 5, Step A. 3-Cyano-benzenesulfonyl chloride (245 mg, 1.20
mmol) was converted to the desired product (388.7 mg, 87%) as a white solid.
1H NMR (400 MHz, CDCl3): δ 1.38 (s, 9 H), 5.06 (s, 2 H), 7.37-7.38 (m, 5 H),
7.52 (dd, J= 7.58, 7.58 Hz, 1 H), 7.74 (s, 1 H), 7.80 (d, J= 7.58 Hz, 1 H), 7.85 (d, J =
7.58 Hz, 1 H).
Step B. The title compound of Example 6 was prepared according to a procedure
similar to that described in Example 1, Step B. N-Bcnzyl-N-(tert-butoxycarbonyl)-3-
cyano-benzenesulfonamide 6A (165 mg, 0.44 mmol) was converted to the desired product
(112.0 mg, 50%) as a colorless oil.

1H NMR (400 MHz, CDCl3): δ 1.29 (s, 9 H), 2.02 (s, 2 H), 5.07 (s, 2 H), 7.28 -
7.43 (m, 5 H), 7.52 (dd, J = 8.34, 7.83 Hz, 1 H), 7.85 (d, J = 7.83 Hz, 1 H), 7.95 (d, J =
8.34 Hz, 1H), 8.04-8.10 (s, 1 H).
Example 7
[3-(1-Amino-2,2,2-trifluoro-l-trifluoromethyl-ethyl)-phenyl]-piperidin-l-yl-methanone
Scheme 7

Step A. 3-(Piperidine-l-carbonyl)-benzonitrile.
The title compound was prepared according to a procedure similar to that
described in Example 1, Step A. 3-Cyano-bertzoyl chloride (150 mg, 0.91 mmol) was
converted to the desired product (186.7 mg, 97%) as a mixture of two isomers in a 1 : 1
ratio. White solid.
1H NMR (400 MHz, CDCl3): δ 1.50 - 1.59 (m, 2 H), 1.64 - 1.75 (m, 4 H), 3.26 -
3.36 (m, 2 H), 3.65 - 3.76 (m, 2 H), 7.54 (dd, J = 7.83, 7.83 Hz, 1 H), 7.63 (d, J = 7.83
Hz, 1 H), 7.68 (s, 1 H), 7.70 (d, J= 7.83 Hz, 1 H).
Step B. The title compound of Example 7 was prepared according to a procedure
similar to that described in Example 1, Step B. 3-(Piperidine-l-carbonyl)-benzonitrile 7A
(110 mg, 0.51 mmol) was converted to the desired product (80.0 mg, 44%) as a mixture
of two isomers in a 1:1 ratio. White solid.
1H NMR (400 MHz, CDCl3): 8 1.48 - 1.57 (m, 2 H), 1.63 - 1.74 (m, 4 H), 2.20 (s,
2 H), 3.23 - 3.36 (m, 2 H), 3.64 - 3.79 (m, 2 H), 7.46 - 7.54 (m, 2 H), 7.78 - 7.84 (m, 2
H).

Example 8
3-(1-Amino-2,2,2-trifluoro-1-trifluoromethyl-ethyl)-N-(tert-butoxycarbonyl)-N-(4-
methoxy-pheny)-benzenesulfonamide
Scheme 8

Step A. 3-Cyano-N-(tert-butoxycarbonyl)-N-(4-methoxy-phenyl)-
benzenesulfonamide.
The title compound was prepared according to a procedure similar to that
described in Example 5, Step A. 3-Cyano-benzenesulfonyl chloride (250 mg, 1.24
mmol) was converted to the desired product (408.9 mg, 85%) as a white solid.
1H NMR (400 MHz, CDCl3): δ 1.53 (s, 9 H), 3.85 (s, 3 H), 6.94 (d, J= 8.84 Hz, 2
H), 7.12 (d, J = 8.84 Hz, 2 H), 7.71 (dd, J = 8.34, 8.34 Hz, 1 H), 7.93 (d, J= 8.34 Hz, 1
H), 8.22 (d, J= 8.34 Hz, 1 H), 8.29 (s, 1 H).
Step B. The title compound of Example 8 was prepared according to a procedure
similar to that described in Example 1, Step B. 3-Cyano-N-(tert-butoxycarbonyl)-N-(4-
methoxy-phenyl)-benzenesulfonamide 8A (225 mg, 0.58 mmol) was converted to the
desired product (120.0 mg, 39%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.32 (s, 9 H), 2.23 (s, 2 H), 3.84 (s, 3 H), 6.93 (d, J
= 8.84 Hz, 2 H), 7.12 (d, J = 8.84 Hz, 2 H), 7.66 (dd, J = 8.08, 8.08 Hz, 1 H), 8.07 (d, J =
8.08 Hz, 1 H), 8.13 (d, J= 8.08 Hz, 1 H), 8.41 (s, 1 H).
Example 9
[4-(l-Amino-2,2,2-trifluoro-l-trifluoromethvl-ethyl)-phenyl]-piperidin-l-yl-methanone
Scheme 9

Step A. 4-(Piperidine-l-carbonyl)-benzonitrile.

The title compound was prepared according to a procedure similar to that
described in Example 1, Step A. 4-Cyano-benzoyl chloride (100 mg, 0.60 mmol) was
converted to the desired product (110 mg, 85%) as a mixture of two isomers in a 1 : 1
ratio. White solid.
1H NMR (400 MHz, CDCl3): δ 1.49 - 1.56 (m, 2 H), 1.66 - 1.75 (m, 4 H), 3.24 -
3.34 (m, 2 H), 3.67 - 3.76 (m, 2 H), 7.49 (d,J= 8.59 Hz, 2 H), 7.71 (d, J = 8.59 Hz, 2 H).
Step B. The title compound of Example 9 was prepared according to a procedure
similar to that described in Example 1, Step B. 4-(Piperidine-l-carbonyI)-benzonitrile 9A
(110 mg, 0.51 mmol) was converted to the desired product (79.0 mg, 44%) as a mixture
of two isomers in a 1:1 ratio. White solid.
1H NMR (400 MHz, CDCl3): δ 1.49 - 1.57 (m, 2 H), 1.62 - 1.74 (m, 4 H), 2.20 (s,
2 H), 3.26 - 3.40 (m, 2 H), 3.68 - 3.77 (m, 2 H), 7.47 (d, J= 8.84 Hz, 2 H), 7.81 (d, J =
8.84 Hz, 2 H).
Example 10
4-(l-Amino-2,2,2-trifluoro-l-trifluoromethvl-ethyl)-N-(tert-butoxvcarbonyl)-N-(4-
methoxy-phenyl)-benzenesulfonamide
Scheme 10

Step A. 4-Cyano-N-(tert-butoxycarbonyl)-N-(4-methoxy-phenyI)-
benzenesulfonamide.
The title compound was prepared according to a procedure similar to that
described in Example 5, Step A. 4-Cyano-benzenesulfonyl chloride (125 mg, 0.622
mmol) was converted to the desired product (212.4 mg, 88%) as a white solid.
1H NMR (400 MHz, CDCl3): δ 1.34 (s, 9 H), 3.85 (s, 3 H), 6.94 (d, J = 8.84 Hz, 2
H), 7.12 (d, J= 8.84 Hz, 2 H), 7.85 (d, J= 8.84 Hz, 2 H), 8.11 (d, J= 8.84 Hz, 2 H).
Step B. The title compound of Example 10 was prepared according to a
procedure similar to that described in Example 1, Step B. 4-Cyano-N-(tert-

butoxycarbonyl)-N-(4-methoxy-phenyl)-benzenesulfonamidc 10A (363 mg, 0.935 mmol)
was converted to the desired product (250.0 mg, 51%) as a white solid.
1H NMR (400 MHz, CDCl3): δ 1.32 (s, 9 H), 2.23 (s, 2 H), 3.84 (s, 3 H), 6.95 (d, J
= 8.84 Hz, 2 H), 7.18 (d, J= 9.09 Hz, 2 H), 7.99 (d, J= 8.84 Hz, 2 H), 8.07 (d, J= 9.09
Hz, 2 H).
Example 11
3-(l-Amino-2,2,2-trifluoro-l-trifluoromethyl-ethyl)-N,N-diethyl-benzamide
Scheme 11

Step A. 3-Cyano-N,N-diethyl-benzamide.
The title compound was prepared according to a procedure similar to that
described in Example 1 A. 3-Cyano-benzoyl chloride (190 mg, 1.15 mmol) was
converted to the desired product (230 mg, 99%) as a mixture of two isomers in a 1 : 1
ratio. White solid.
1HNMR(400MHz,CDCl3): δ 1.10- 1.19 (m, 3 H), 1.22 - 1.31 (m, 3 H), 3.20-
3.28 (m, 2 H), 3.53 - 3.60 (m, 2 H), 7.53 (dd, J= 7.83, 7.83 Hz, 1 H), 7.62 (d, J = 7.83
Hz, 1 H), 7.67 (s, 1 H), 7.70 (d, J= 7.83 Hz, 1 H).
Step B. The title compound of Example 11 was prepared according to a
procedure similar to that described in Example 1, Step B. 3-Cyano-N,N-diethyl-
benzamide 11A (230 mg, 1.13 mmol) was converted to the desired product (231.0 mg,
60%) as a mixture of two isomers in a 1:1 ratio. White solid.
1HNMR(400MHz,CDCl3): δ 1.09 -1.14 (m, 3 H), 1.23 - 1.28 (m, 3 H), 2.22 (s,
2 H), 3.16 - 3.24 (m, 2 H), 3.52 - 3.59 (m, 2 H), 7.47 - 7.50 (m, 2 H), 7.79 - 7.82 (m, 2
H).

Example 12
4-(l-Amino-2,2,2-trifluoro-l-(rifluoromethyl-ethvl)-N,N-diethyl-benzamide
Scheme 12

Step A. 4-Cyano-N,N-diethyl-benzamide.
The title compound was prepared according to a procedure similar to that
described in Example 1, Step A. 4-Cyano-benzoyl chloride (200 mg, 1.21 mmol) was
converted to the desired product (220 mg, 90%) as a mixture of two isomers in a 1 : 1
ratio. White solid.
1H NMR (400 MHz, CDCl3): δ 1.13 (t, J= 6.32 Hz, 3 H), 1.26 (t, J= 6.32 Hz, 3
H), 3.18 - 3.25 (m, 2 H), 3.52 - 3.60 (m, 2 H), 7.48 (d, J= 8.59 Hz, 2 H), 7.71 (d, J = 8.59
Hz, 2 H).
Step B. The title compound of Example 12 was prepared according to a
procedure similar to that described in Example 1, Step B. 4-Cyano-N,N-diethyl-
benzamide 12A (220 mg, 1.09 mmol) was converted to the desired product (141.0 mg,
38%) as a mixture of two isomers in a 1:1 ratio. White solid.
1HNMR(400MHz, CDCl3): δ 1.13 (t, J= 6.50 Hz, 3 H), 1.26 (t,.J=6.50Hz, 3
H), 2.20 (s, 2 H), 3.25 (q, J= 6.50 Hz, 2 H), 3.56 (q, J= 6.50 Hz, 2 H), 7.45 (d, J= 8.34
Hz, 2 H), 7.81 (d, J= 8.34 Hz, 2 H).
Example 13
4-(l-Amino-2,2,2-trifluoro-l-trifluoromethyl-ethyl)-N,N-diethvl-benzenesulfonamide
Scheme 13

Step A. 4-Cyano-N, N-diethyl-benzenesulfonarnide.

The title compound was prepared according to a procedure similar to that
described in Example 1, Step A. 4-Cyano-benzenesulfonyl chloride (240 mg, 1.19
mmol) was converted to the desired product (281 mg, 99%) as a white solid.
1H NMR (400 MHz, CDCl3): δ 1.15 (t, J = 7.07 Hz, 6 H), 3.28 (q, J= 7.07 Hz, 4
H), 7.80 (d, J= 8.84 Hz, 2 H), 7.93 (d, J = 8.84 Hz, 2 H).
Step B. The title compound of Example 13 was prepared according to a
procedure similar to that described in Example 1, Step B. 4-Cyano-N,N-diethyl-
benzenesulfonamide 13A (300 mg, 1.26 mmol) was converted to the desired product
(123.0 mg, 26%) as a colorless oil. Note that the final product was isolated via HPLC
under neutral conditions.
1H NMR (400 MHz, CDCl3): 8 1.14 (t, J = 7.07 Hz, 6 H), 2.27 (s, 2 H), 3.27 (q, J
= 7.07 Hz, 4 H), 7.87 (d, J= 8.84 Hz, 2 H), 7.94 (d, J = 8.84 Hz, 2 H).
Example 14
2-(3-{[(2R)-4-{6-[1-amino-2,2,2-trifluoro-1-(trifluoromethy)ethyl]pyridin-3-yl}-2-
methylpiperazin- 1-vl]sulfonyl} phenyl)-1,1,1 -trifluoropropan-2-ol
Scheme 14

Step 1 A: A mixture of (R)-2-methyl-piperazine (1.0 g, 9.98 mmol), 5-bromo 2-
cyanopyridine (1.66 g, 9.08 mmol), tris(dibenzylidineacetone)dipalldium (O) (83.15 mg,
0.0908 mmol), rac-2,2'-bis(diphenylphosphino)-l,l'-binaphtyl (169.37 mg, 0.272 mmol)
and sodium tert-butoxide (1.09 g, 11.35 mmol) were charged to a microwave vial.
Toluene (10.0 mL) was introduced under nitrogen atmosphere and the reaction mixture
was irradiated at 110°C for 35 minutes. Reaction was complete as determined by TLC.
Reaction mixtures was diluted with dichloromethane, washed with water, saturated brine
then dried over Na2SO4 and concentrated. The crude product was purified via flash
column chromatography to yield 5-[(3R)-3-methylpiperazin-l-yl]pyridine-2-carbonitriIe
as brown color oil (1.15 g, 39.1% yield).

Step 1B: To a stirred solution of 5-[(3R)-3-methylpiperazin-l-yl]pyridine-2-
carbonitrile (250 mg, 1.24 mmol) and 3-acetylbenzenesulfonyl chloride (270.3 mg, 1.24
mmol) in anhydrous dichloromethane (4 mL) was added diisopropylethylamine (0.43
mL, 2.48 mmol). The mixture was stirred at room temperature for over night. Reaction
was complete as determined by TLC. The reaction mixture was purified via flash column
chromatography to yield 5-{(3R)-4-[(3-acetyIphenyl)sulfonyl]-3-methylpiperazin-l-
yl}pyridine-2-carbonitrile in 80.3% yield (383 mg) as a light yellow solid.
Step 1C: To a 50 mL flask containing 5-{(3R)-4-[(3-acetylphenyl)sulfonyl]-3-
methylpiperazin-l-yl}pyridine-2-carbonitrile (383 mg, 0.996 mmol) and 6.0 mL of 0.5 M
TMS-CF3, was added 0.996 mL of 1.0 M tetrabutylammonium fluoride in THF at 0°C.
After stirring for 2h, the solution was diluted with saturated NaHCO3, extracted (2 x
CH2Cl2), washed with brine and dried over Na2SO4, and concentrated under reduced
pressure. Purification by flash column chromatography to yield 2-(3- {[(2R)-4- {6-[ 1 -
amino-2,2,2-trifluoro-1 -(trifluoromethyl)ethyl]pyridin-3-yl} -2-methylpiperazin-1 -
yl]sulfonyl}phenyl)-l,l,l-trifluoropropan-2-ol as a light yellow solid.
HRMS: calcd for C22H23F9N4O3S + H+, 595.14199; found (ESI-FTMS,
[M+H]1+), 595.14231.
Example 15
2-(3-{[(2R)-4-{4-[1-amino-2,2,2-trifluoro-l-(trifluoromethvnethyl]-2-
ftrifluoromethyl)phenyl} -2-methylpiperazin- 1-yl]sulfonyl} phenyl)-1.1.1 -trifluoropropan-
2-ol
Scheme 15

The title compound of Example 15 was prepared according to a procedure similar
to that described in Example 14. HRMS: calcd for C24H23F12N3O3S + H+, 662.13412;
found (ESI-FTMS, [M+H]1+), 662.13513.

Example 16
2-[4-({(2R)-4-[4-n-amino-2,2,2-trifluoro-1-(trifluoromethyl)cthyl]-2-
(trifluoromethyl)phenyl]-2-methylpiperazin-l-yl}sulfonyl)phenyl]-1,1,1-trifluoropropan-
2-ol

The title compound was prepared according to a procedure similar to that
described in Example 14. HRMS: calcd for C24H23F12N3O3S + H+, 662.13412; found
(ESI-FTMS, [M+H]1+), 662.13495.
Example 17
1.1,1.3,3,3-hexafluoro-2-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-
methvlpiperazin-l-yl}sulfonyl)phenyl]propan-2-arnine
Scheme 17

The title compound was prepared according to a similar procedure for Example
14. In step 1B, 4-cyanobenzenesulfonyl chloride was used as starting material to make
intermediate. HRMS: calcd for C21H19F10N3O2S + H+, 568.11110; found (ESI-FTMS,
[M+H]1+), 568.11129.
Example 18
1.1.1,3,3,3-hexafluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-
methylpiperazin-1 -yl} sulfonyl)phenyl]propan-2-amine


The title compound was prepared according to a similar procedure for Example
14. In step 1B, 3-cyanobenzenesulfonyl chloride was used as starting material to make
intermediate, for C21H19F10N3O2S + H+, 568.11110; found (ESI-FTMS, [M+H]1+),
568.11142.
Example 19
Biological Testing
Compounds described herein can be tested in a cell-based assay using a stable
CHO cell line expressing human 11b-HSDl. Cells are plated at 20,000 cells/well in 96
well plates and incubated overnight (12-16 hrs) at 37°C/5% CO2. Cells are treated with
different concentration of compound in 90 microliter serum-free media and incubated for
30 minutes at 37°C/5%CO2. 10ul of 5 micromolar cortisone (final concentration 500nM)
is then added to the cells and the plate is incubated at 37°C/5%CO2 for 120minutes. 15
microliter of media is withdrawn and amount of Cortisol in the media is measured using
the DiscoverX HitHunter Cortisol Assay (DiscoverX corp, CA).
To determine the potency of compounds against mouse 1 lb-HSDl, a stable CHO
cell line expressing mouse 1 lb-HSDl is used. Cells are plated at 20,000 cells/well in 96
well plates and incubated overnight (12-16 hrs) at 37°C/5% CO2. Cells are treated with
different concentration of compound in 90 microliter serum-free media and incubated for
30 minutes at 37°C/5%CO2. To determine the potency of the compound against mouse
11-bHSDl in the presence of serum, 90 microliter media containing 10% delipidized
human serum is used instead of serum free media. lOul of 5 micromolar cortisone (final
concentration 500nM) is then added to the cells and the plate is incubated at
37°C/5%CO2 for 120minutes. 15 microliter of media is withdrawn and amount of
Cortisol in the media is measured using the DiscoverX HitHunter Cortisol Assay
(DiscoverX corp, CA).


A number of embodiments of the invention have been described. Nevertheless, it
will be understood that various modifications may be made without departing from the
spirit and scope of the invention. Accordingly, other embodiments are within claims.

WHAT IS CLAIMED IS:
1. A method for preparing an organic compound or a salt thereof having one
or more substituents of formula (A):
wherein:
(i) each of RF1 and RF2 is, independently, optionally substituted C1-C6 fluoroalkyl;
(ii) each of R3 and R4 is, independently, hydrogen, Ra, -C(O)H, -C(O)Ra, -
C(O)ORa, or -SO2Ra, wherein Ra at each occurrence is, independently, any organic group,
selected from alkyl, cycloalkyl, aralkyl, heterocyclyl, aryl, or heteroaryl, each of which is
optionally substituted; and
(iii) the organic compound comprises as part of its structure any one or more of
the following substructures:
(i) C6-C18 aryl or heteroaryl including 5-16 atoms, each of which is optionally
substituted; or
(ii) C7-C20 aralkyl or heteroaralkyl including 6-20 atoms, each of which is
optionally substituted; or
(iii) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl including 3-10 atoms, or
heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted; or
(iv) C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl, each of which is optionally
substituted;
each of which, when two or more substructures are present, is connected to one
another by a direct bond or a hcteroatom-containing linker;
the method comprising reacting a nitrile-containing organic compound with a
fluoroalkylating agent.

2. The method of claim 1, wherein RF1 and RF2 are the same.
3. The method of claim 1, wherein each of RF1 and RF2 is, independently,
optionally substituted C1-C4 perfluoroalkyl.
4. The method of claim 1, wherein each of RF1 and RF2 is CF3.
5. The method of claim 1, wherein each of R3 and R4 is hydrogen.
6. The method of claim 1, wherein the organic compound having one or
more substituents of formula (A) is a compound of formula (I) or a salt thereof:

wherein:
R is:
(i) C6-C18 aryl or heteroaryl including 5-16 atoms, each of which is optionally
substituted;
(ii) C7-C20 aralkyl or heteroaralkyl including 6-20 atoms, each of which is
optionally substituted; or
(iii) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl including 3-10 atoms, or
heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted; or
(iv) C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl, each of which is optionally
substituted;
each of RF1 and RF2 is, independently, optionally substituted C1-C6 fluoroalkyl;
and

each of R3 and R4 is, independently, hydrogen, Ra, -C(O)H, -C(O)Ra, -C(O)ORa,
or -SO2Ra, wherein Ra at each occurrence is, independently, as defined above for R;
and the nitrile-containing organic compound is a compound of formula (II):

wherein R is as defined above.
7. The method of claim 6, wherein R is optionally substituted C6-C10 aryl.
8. The method of claim 6, wherein R is optionally substituted phenyl.
9. The method of claim 6, wherein R is optionally substituted C7-C12 aralkyl.
10. The method of claim 6, wherein R is optionally substituted benzyl.
11. The method of claim I, wherein the fluoroalkylating agent is a
perfluoroalkylating agent.
12. The method of claim 1, wherein the fluoroalkylating agent is a
trifiuoromethylating agent.
13. The method of claim 1, wherein the fluoroalkylating agent is a compound
having formula (III):

wherein:
RF is C1-C6 fluoroalkyl; and

each of Rb, Rc, and Rd is, independently, C1-C12 alkyl or C1-C12 alkenyl, each of
which is optionally substituted.
14. The method of claim 13, wherein a fluoride ion is present during the
reacting of the compound of formula (II) and the compound of formula (III).
15. The method of claim 13, wherein each of R , Rc, and R is, independently,
C1-C4, alkyl.
16. The method of claim 13, wherein each of Rb, Rc, and Rd is -CH3.
17. The method of claim 13, wherein each of Rb, Rc, and Rd is -CH2CH3.
18. The method of claim 13, wherein one of Rb, Rc, and Rd is C2-C4 alkenyl,
and the other two are each, independently, C1-C4 alkyl.
19. The method of claim 13, wherein one of Rb, Rc, and Rd is -CH=CH2, and
the other two are each -CH3.

20. The method of claim 1, wherein the fluoroalkylating agent is a
fluoroalkyl-containing salt or ionic complex.
21. The method of claim 20, wherein the method further comprises reacting a
compound having formula (IV):
RF-X
wherein RF is C1-C6 fluoroalkyl; and X is halo;
with a reducing agent.
22. The method of claim 21, wherein the reducing agent is
tetrakis(dirnethylamino)ethylene (TDAE).
23. The method of claim 21, wherein X is iodo.
24. The method of claim 21, wherein RF is CF3, CF2CF3, or (CF2)3CF3.
25. The method of claim 1, wherein the fluoroalkylating agent is a compound
having formula (V):

wherein:
RF is C1-C6 fluoroalkyl; and
ring A is optionally substituted morpholinyl or piperazinyl.
26. The method of claim 25, wherein a base is present during the reacting of
the compound of formula (II) and the compound of formula (V).

27. The method of claim 26, wherein the base is a metal salt of a C1-C6
alkoxide.
28. The method of claim 25, wherein RF is CF3.
29. The method of claim 1, wherein the fluoroalkylating agent is a compound
having formula (VI): Ar-S(O)x-RF;
wherein:
Ar is optionally substituted phenyl;
x is 1 or 2; and
RF isC1-C6fluoroalkyl.
30. The method of claim 29, wherein a base is present during the reacting of
the compound of formula (II) and the compound of formula (VI).
31. The method of claim 30, wherein the base is a metal salt of a C1-C6
alkoxide.
32. The method of claim 29, wherein RF is CF3.
33. The method of claim 29, wherein x is 2.
34. The method of claim 1, wherein the fluoroalkylating agent is CF3H.
35. The method of claim 1, wherein the compound of formula (II) further
comprises a substituent having a formula -C(O)Re, wherein Re is C1-C6 alkyl.
36. The method of claim 35, wherein Re is CH3.

37. A method for preparing a compound of formula (VII) or a salt thereof:

wherein:
each of m and n is, independently, 0 or 1, provided that one of m and n is 1;
each of RF1, RF2, RF1 , and RF2 is, independently, optionally substituted C1-C6
fluoroalkyl;
each of R3, R4, R3', and R4' is, independently, hydrogen, C1-C6 alkyl, -C(O)H, or -
C(O)ORa, wherein Ra is C7-C20 aralkyl or C1-C6 alkyl, each of which is optionally
substituted;
ring B is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is
optionally further substituted with from 1-5 substituents independently selected from
halo; NRfRE; hydroxyl; C1-C12 alkyl or C1-C12 haloalkyl, each of which is optionally
substituted; optionally substituted C1-C12 alkoxy; C1-C12 haloalkoxy; nitro; C6-C10 aryl or
heteroaryl including 5-12 atoms, each of which is optionally substituted; C6-C10 aryloxy
or heteroaryloxy including 5-12 atoms, each of which is optionally substituted;
heterocyclyl including 3-10 atoms, C3-C10 cycloalkyl, C7-C12 aralkoxy or heteroaralkoxy
including 6-12 atoms, each of which is optionally substituted; -C(O)ORh; -C(O)NRfRg; or
-NRiC(O)Rj;

each of Rf, Rg, and Rh , at each occurrence is, independently:
(i) hydrogen; or
(ii) C1-C12 alkyl or C1-C12 haloalkyl; each of which is optionally substituted; or
(iii) C7-C20 aralkyl; C3-C16 cycloalkyl; heteroaralkyl including 6-20 atoms; C3-C16
cycloalkenyl; heterocyclyl including 3-16 atoms; or heterocycloalkenyl including 3-16
atoms; each of which is optionally substituted; or
(iv) C2-C20 alkenyl or C2-C20 alkynyl; or
(v) C6-C16 aryl or heteroaryl including 5-16 atoms, each of which is optionally
substituted;
Rj is Rh;ORh;or NRfRg;
W is C1-C4 alkyl; and
ring C is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is
optionally further substituted with from 1-5 substituents independently selected from
halo; C1-C12 alkyl or C1-C12 haloalkyl, each of which is optionally substituted; C1-C12
alkoxy; C1-C12 haloalkoxy; nitro; or C6-C10 aryl or heteroaryl including 5-12 atoms, each
of which is optionally substituted;
from a compound of formula (VIII):


wherein:
ring B is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is
optionally further substituted with from 1-5 substituents independently selected from
halo; NRfRg; hydroxyl; C1-C12 alkyl or C1-C12 haloalkyl, each of which is optionally
substituted; optionally substituted C1-C12 alkoxy; C1-C12 haloalkoxy; nitro; C6-C10 aryl or
heteroaryl including 5-12 atoms, each of which is optionally substituted; C6-C10 aryloxy
or heteroaryloxy including 5-12 atoms, each of which is optionally substituted;
heterocyclyl including 3-10 atoms, C3-C10 cycloalkyl, C7-C12 aralkoxy or heteroaralkoxy
including 6-12 atoms, each of which is optionally substituted; -C(O)Re, wherein Re is C1-
C6 alkyl; -C(O)NRfRg; or -NRiC(O)Rj; and
m, n, ring C1 and W are as defined above in conjunction with formula (VII);
the method comprising reacting the compound of formula (VIII) with a
fluoroalkylating agent.
38. The method of claim 37, wherein m in formulas (VII) and (VIII) is 1, and
n in formulas (VII) and (VIII) is 0.
39. The method of claim 38, wherein each of RF1 and RF2 in formula (VII) is
CF3.
40. The method of claim 38, wherein each of R3 and R4 in formula (VII) is
hydrogen.

41. The method of claim 38, wherein ring C in formula (VII) has formula
(IX):

wherein two of Rc22, Rc23, Rc24, Rc25, and Rc26 are each, independently, halo; C1-
C12 alkyl or C1-C12 haloalkyl, each of which is optionally substituted; C1-C12 alkoxy; C1-
C12 haloalkoxy; nitro; or C6-C10 aryl or heteroaryl including 5-12 atoms, each of which is
optionally substituted; and the others are hydrogen.
42. The method of claim 41, wherein Rc22 is CF3 or fluoro; and Rc24 is fluoro,
chloro, CF3, or optionally substituted heteroaryl.
43. The method of claim 37, wherein m in formulas (VII) and (VIII) is 0, and
n in formulas (VII) and (VIII) is 1.
44. The method of claim 43, wherein each of RF1 and RF2 in formula (VII) is
CF3.
45. The method of claim 43, wherein each of R3 and R4 in formula (VII) is
hydrogen.

46. The method of claim 43, wherein ring B in formula (VII) has formula (X):

wherein one of Ra2, Ra3, and Ra4 is halo; NRfRg; hydroxyl; C1-C12 alkyl or C1-C12
haloalkyl, each of which is optionally substituted; optionally substituted C1-C12 alkoxy;
C1-C12 haloalkoxy; nitro; C6-C10 aryl or heteroaryl including 5-12 atoms, each of which is
optionally substituted; C6-C10 aryloxy or heteroaryloxy including 5-12 atoms, each of
which is optionally substituted; heterocyclyl including 3-10 atoms, C3-C10 cycloalkyl, C7-
C12 aralkoxy or heteroaralkoxy including 6-12 atoms, each of which is optionally
substituted; -C(O)ORh; -C(O)NRfRg; or-NRfC(O)Rj; and the others are hydrogen.
4-7. The method of claim 46, wherein Ra3 or Ra4 is l,l,l-trifluoro-2-hydroxy-
2-propyl.
48. The method of claim 43, wherein ring B in formula (VIII) is substituted
with -C(O)Re, wherein Re is C1-C4 alkyl.

49. The method of claim 37, wherein the fluoroalkylating agent is a compound
having formula (III):

wherein:
RF is C1-C6 fluoroalkyl; and
each of Rb, Rc, and Rd is, independently, C1-C12 alkyl or C2-C12 alkenyl, each of
which is optionally substituted.
50. The method of claim 49, wherein a fluoride ion is present during the
reacting of the formula (VII) and the compound of formula (III).
.51. The method of claim 49, wherein each of Rb, Rc, and Rd is, independently,
C1-C4 alkyl.
52. The method of claim 49, wherein each of Rb, Rc, and Rd is -CH3.
53. The method of claim 49, wherein each of Rb,Rc, and Rd is -CH2CH3.
54. The method of claim 49, wherein one of Rb, Rc, and Rd is C2-C4 alkenyl,
and the other two are each, independently, C1-C4 alkyl.
55. The method of claim 49, wherein one of Rb, Rc, and Rd is -CH=CH2, and
the other two are each -CH3.
56. A compound selected from the group consisting of:
2-(3- {[(2R)-4- {6-[ 1 -amino-2,2,2-trifluoro-1 -(trifluoromethyl)ethyl]pyridin-3-yl} -
2-methylpiperazin-l-yl]sulfonyl}phenyl)-l,l,l-trifluoropropan-2-ol;

2-(3-{[(2R)-4-{4-[l-amino-2,2,2-trifluoro-l-(trifluoromethyl)ethyl]-2-
(trifluoromethyl)phenyl} -2-methylpiperazin-1 -yl]sulfonyl} phenyl)-1,1,1 -trifluoropropan-
2-ol;
2-[4-({(2R)-4-[4-[l-amino-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-2-
(trifluoromethyl)phenyl]-2-methylpiperazin-l-yl}sulfonyl)phenyl]-1,1,1-trifloropropan-
2-ol;
1,1,1,3,3,3-hexafluoro-2-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-
methyIpiperazin-l-yl}sulfonyl)phenyl]propan-2-amine; and
1,1,1,3,3,3-hexafluoro-2-[3-( {(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-
methylpiperazin-l-yl}sulfonyl)phenyl]propan-2-amine; or a pharmaceutically acceptable
salt thereof.
57. A compound selected from the group consisting of the title compounds of
Examples 1-13, or a pharmaceutically acceptable salt thereof.

This invention relates to methods for preparing halogenated amines.