Processes for Preparing Gonadotropin Releasing Hormone Receptor Antagonists
[0001] This application claims the benefit of provisional application U.S. Serial No.
60/580,665, filed June 17, 2004, which is hereby incorporated by reference into the subject
application in its entirety.
[0002] Throughout this application, various publications are referenced. The
disclosures of these publications in their entireties are hereby incorporated by reference into
this application in order to more fully describe the state of the art as known to those skilled
therein as of the date of the invention described and claimed herein.
[0003] This patent disclosure contains material that is subject to copyright protection.
The copyright owner has no objection to the facsimile reproduction by anyone of the patent
document or the patent disclosure, as it appears in the U.S. Patent and Trademark Office
patent file or records, but otherwise reserves any and all copyright rights whatsoever.
FIELD OF INVENTION
[0004] The present invention relates to processes for preparing Gonadotropin
Releasing Hormone ("GnRH") (also known as Leutinizing Hormone Releasing Hormone ("LHRH")) receptor antagonists.
BACKGROUND
[0005] GnRH is a decameric peptide released from the hypothalamus. In the anterior
pituitary gland, GnRH activates the GnRH receptor. Activation of the GnRH receptor triggers the release of follicle stimulating hormone (FSH) and leuteinizing hormone (LH). FSH and LH stimulate the biosynthesis and release of sex steroids in the gonads of both genders.
[0006] Typically, this is desirable, but certain sex hormone dependent pathological
conditions exist where it would be beneficial to prevent activation of the GnRH receptor. For example, inhibition of the GnRH receptor can lead to a large drop in sex steroid production, which in turn can alleviate sex hormone dependent pathological conditions such as prostate cancer, endometriosis, uterine fibroids, uterine cancer, breast cancer, ovarian cancer, testicular cancer, or primary hirsulism. Moreover, there arc other situations where it would

be beneficial to prevent activation of the GnRH receptor, such as during some points of the in vitro fertilization process, such as to prevent LH surge.
[0007] Currently marketed GnRH therapeutics are peptides that exhibit receptor
antagonism in one of two ways. The first is through GnRH receptor superagonism. The GnRH receptor, when stimulated in bursts, causes normal release of the gonadotropins, FSH and LH. Under constant stimulation, the receptor becomes desensitized and the overall effect is GnRH receptor inhibition. The superagonism process is somewhat undesirable, as inhibition via this process can take up to two weeks to arise in human patients. During this delay there is often an increase in disease symptoms due to the initial hormone stimulation phase. This phenomenon is referred to as flare.
[0008] The second method for receptor inhibition is through direct antagonism of the
GnRH receptor with peptide antagonists. This causes an immediate drop in plasma LH
levels. However, as mentioned above, current pharmaceuticals that cause blockade of the
GnRH receptor are all peptides. As such they are not orally bioavailable and must be
administered via parenteral means such as intravenous, subcutaneous or intramuscular
injection. Thus, an orally effective GnRH antagonist would be of significant benefit
[0009] Therefore, based upon the foregoing, it is clear that GnRH receptor
antagonists are useful, and development of new GnRH receptor antagonists is highly desirable. U.S. Patent Application Serial No. 60/580,640, the disclosure of which is incorporated herein as if reproduced in its entirety, teaches compounds of formula II and IV as defined herein useful as GnRH receptor antagonists.
[0010] However, it is desirable to have methods of making such compounds which
are efficient for large scale production.
SUMMARY
[0011] ' The present invention provides methods comprising reacting compounds having Formula I:

(Figure Remove)
wherein:
A is aryl or heteroaryl, each optionally substituted;
RI, Ra, RS, and Rj are, independently, H or optionally substituted alkyl; and
RS, Re, RI, Rg, Rg, RIO, RU, and Ri2, are, independently, H, alkyl, alkenyl, or alkynyl, each alkyl, alkenyl, or alkynyl being optionally substituted; with compounds having formula:
Lg-(CR13Ru)k-D wherein:
D is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl being optionally substituted;
Lg is halogen or OSO2R32, wherein R32 is alkyl; aryl, or fluoroalkyl, each optionally substituted;
k is 0,1, 2, or 3; and
Ri3 and RH are, independently at each occurrence, H or optionally substituted alkyl, in an organic solvent in the presence of base, thereby forming compounds having Formula II, or
a pharmaceutically acceptable salt thereof:



(Figure Remove)
wherein B is
[0012] The present invention further comprises methods comprising reacting
compounds having Formula III:



(Figure Remove)
wherein:
RI is H or alkyl;
Rg and RIO, are, independently, H, alkyl, alkenyl, or alkynyl, each alkyl, alkenyl, or alkynyl being optionally substituted; and
R;,, is Ci-C6 alkyl, C2-C6 alkenyl, CrCfl alkynyl, NR22R23, CR24(CF3)2, JR22, or C(=O)R22, wherein J is O or SO,,,, wherein m is 0, I, or 2;

R22 and R23 are, independently, H, Q-C? alkyl, C2-C7 alkenyl, C2-C? alkynyl, aryl, or heteroalkyl, each alkyl, alkenyl, alkynyl, aryl, or heteroalkyl being optionally substituted, alternatively, R22 and RZ3, taken together with the atoms to which they are attached, form a cyclic or heterocyclic group, e.g., of 3-8 ring members and the heteroatoms are selected from O, N and S, optionally substituted with R2o-E-R2i, wherein E is O, N, NR2|, or SO,,,,
R20 and R2i are, independently, H, C\-C$ alkyl, or heteroalkyl, alternatively, R2o and R2i, taken together with the atoms to which they are attached, form a cyclic or heterocyclic group, e.g., of 3-8 ring members and the heteroatoms are selected from O, N and S; and
R24isH,orOH; with compounds having formula:
Lfi-(CRi3Ri4).c-D wherein:
D is heterocycloalkyl or heteroaryl, each optionally substituted;
Lg is halogen or OSO2R32, wherein R32 is alkyl, aryl, or fluoroalkyl, each optionally— substituted;
kisO, 1,2, or 3; and
Rn and RH are, independently at each occurrence, H or optionally substituted alkyl, in an organic solvent in the presence of base, thereby forming compounds having Formula IV, or a pharmaceutically acceptable salt thereof: Rsi



(Figure Remove)

[0013J

The present invention further comprises compounds having Formula III:



(Figure Remove)
Wherein:
RI isHoralkyl;
Rg and RIO, are, independently, H, alkyl, alkenyl, or alkynyl, each alkyl, alkenyl, or alkynyl being optionally substituted; and
R3( is C,-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR22R23, CR24(CF3)2, JR22, or C(=O)R22, wherein J is O or SO,n, wherein m is 0, 1, or 2;
R22 and R23 are, independently, H, Ci-C? alkyl, C2-C7 alkenyl, C2-Cy alkynyl, aryl, or heteroalkyl, each alkyl, alkenyl, alkynyl, aryl, or heteroalkyl being optionally substituted, alternatively, R22 and R2j, taken together with the atoms to which they are attached, form a cyclic or heterocyclic group, e.g., of 3-8 ring members and the heteroatoms are selected from O, N and S, optionally substituted with R2o-E-R2|, wherein E is O, N, NR2|, or SOm,
R2o and R2| are, independently, H, CpCa alkyl, or heteroalkyl, alternatively, R2o and R2i, taken together with the atoms to which they are attached, form a cyclic or heterocyclic group, e.g., of 3-8 ring members and the heteroatoms are selected from O, N and S; and
R24 is H, or OH.
DETAILED DESCRIPTION
[0014] In one embodiment, the present invention comprises a method comprising
reacting a compound having Formula I:
(Figure Remove)

wherein:
A is aryl or heteroaryl, each optionally substituted;
RI, Ra, RS, and R* are, independently, H or optionally substituted alkyl; and
R5, Re, RI, Rg, R9, RIO, RH, and R]2, are, independently, H, alkyl, alkenyl, or alkynyl, each alkyl, alkenyl, or alkynyl being optionally substituted; with a compound having formula:
Lg-(CR13Ri4)k-D wherein:
D is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each alkyl, cycloalkyl, heterocycloalkvl, aryl, or heteroaryl being optionally substituted;
Lg is halogen or OSOaRja, wherein Rj2 is alkyl, aryl, or fluoroalkyl, each optionally substituted;
k is 0, 1, 2, or 3; and
Ri3 and RH are, independently at each occurrence, H or optionally substituted alkyl, in an organic solvent in the presence of base, thereby forming a compound having Formula II, or
salts thereof:



(Figure Remove)
wherein B is (CR|3Ri4)k-D.
[0015] In one embodiment, D is optionally substituted heteroaryl. In another
embodiment, D js optionally substituted C|-Cg alkyK
[0016] In one embodiment, R|, R2, Rj, and R4 are, independently, H or Cj-Cs alkyl.
[0017] In one embodiment, RS, R6, R?, Rg, Rg, RIO, Rn, and R|2, are, independently,
H, CrC4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl.

[0018]
C,-C3 alkyl.

In one embodiment, R|3 and R|4 are, independently at each occurrence, H or

[0019] In one embodiment, Lg is Br.
[0020] In one embodiment, Lg-(CRj3R|4)k-D is 6-Bromomethyl-quinoxaline.
[0021] In one embodiment, the method further comprises brominating 6-
methylquinoxaline, thereby forming Lg^CRnR^X-D. In one embodiment, brominaiion is
achieved using N-bromosuccinimide ("NBS") (e.g., 1.1. equivalents) and
azobisisobutyronitrile ("AIBN") (e.g.,2.4 mol%) of in carbon tetrachloride ("CCI4") at reflux.
[0022] In one embodiment, the method further comprises reacting 4-
methylphenylene-],2-diamine with glyoxal, thereby forming said 6-methyIquinoxaline.
[0023] In one embodiment, the base comprises potassium carbonate or N,N-
diisopropylethylamine.
[0024] In one embodiment, the solvent comprises at least one of acetone, acetonitrile
("MeCN"), dimethylsulfoxide ("DMSO"), and tetrahydrofuran ("THF").
[0025] Fn one embodiment, tlie base comprises potassium carbonate and said solvent
comprises acetone. In one embodiment, 2 equivalents of potassium carbonate are used.

[0026] In one embodiment, 1 equivalent of Lg-(CRnRu)k-D is used.
[0027] In one embodiment, the compound of formula I has formula:
(Figure Remove)
wherein:
A is optionally substituted aryl and Rg is H or C|-C4 alkyl.
[0028] In one embodiment, A is phenyl substituted with Q-Q alkyl, C2-Cs alkenyl,
C2-Q alkynyl, NR22R23, CR24(CF3)2, JR^, or C(=O)R22, wherein J is O or SOnl, wherein m is
0,1, or 2; R22 and Ra are, independently, H, Cj-C? alkyl, CrC? alkenyl, C2-Cv alkynyl, _ary_I,
'or heteroalkyl," each alkyl, aikenyl, alkynyl, aryl, or heteroalkyl being optionally substituted,
alternatively, R22 and R23, taken together with the atoms to which they are attached, form an
optionally substituted cyclic or optionally substituted heterocyclic group, e.g., of 3-8 ring
members and the heteroatoms are selected from O, N and S, optionally substituted with R2o-
E-R2i, wherein E is O, N, NR2j, or SO,,,, R20 and R2i are, independently, H, Ci-Cs alkyl, or
heteroalkyl, alternatively, R2o and R2|, taken together with the atoms to which they are
attached, form a cyclic or heterocyclic group, e.g., of 3-8 ring members and the heteroatoms
are selected from O, N and S; and R24 is H, or OH.
[0029] In one embodiment, the method further comprises reacting a compound
(Figure Remove)
, thereby forming said compound of Formula II. In one embodiment, Lg is Br. In one embodiment, the reacting is carried out in toluene-THF in the
presence of 5 mol% of Pd2(dba)3 and 10 mol% of CyMAP ligand with 3 equivalents of solid lithium hexamethyldisilazide ("LiHMDS")-
[0030] In one embodiment, the method further comprises chlorinating a compound
(Figure Remove)
with N-chlorosuccinimide ("NCS") in methanol, and
reacting the resulting N-chloride with potassium carbonate, thereby forming said compound
(Figure Remove)

having formula
[0031] In one embodiment, the method further comprises reacting a compound

o
having formula (Figure Remove)
with thionyl chloride to form an imidoyl chloride,
and reacting said imidoyl chloride with aqueous ammonia, thereby forming said compound

having formula
[0032] In one embodiment, the method further comprises reacting a compound of
(Figure Remove)
with a compound of formula

are combined
embodiment, Lg' is Br. In one embodiment,
under Schotten-Bauman conditions with NaHCO3.
[0033] In one embodiment, A is optionally substituted aryl.
[0034] In one embodiment, A is aryl substituted with Ci-Cg alkyl, C2-Cg alkenyl, €2-
C6 alkynyl, NR22R23, CR24(CF3)2, JR22, or C(=O)R22, wherein J is O or SOm, wherein m is 0,
1, or 2; R22 and R23 are, independently, H, C\-Q alkyl, C2-C? alkenyl, CrC? alkynyl, aryl, or
heteroalkyl, each alkyl, alkenyl, alkynyl, aryl, or heteroaryl being optionally substituted,
alternatively, R22 and R23, taken together with the atoms to which they are attached, form an
optionally substituted cyclic or optionally substituted heterocyclic group, e.g., of 3-8 ring
members and the heteroatoms are selected from O, N and S optionally substituted with R2o-E-
R2i, wherein E is O, N, NR2i, or SO,n, R2o and R2| are, independently, H, C|-C3 alkyl, or
heteroalkyl, alternatively, R2o and R2|, taken together with the atoms to which they are
attached, form a cyclic or heterocyclic group, e.g., of 3-8 ring members and the heteroatoms
are selected from O, N and S; and R24 is H, or OH.
[0035] In one embodiment, A is para t-butyl phenyl.
[0036] In one embodiment, the method further comprises adding 2 equivalents of
ethereal HCI to a solution of the compound having Formula n in ethanol, thereby forming a
salt.
[0037] In one embodiment, the present invention comprises a method comprising
reacting a compound having Formula III:
(Figure Remove)
wherein:
RI is H or alkyl;
Rgand R10, are, independently, H, alkyl, alkenyl, oralkynyl, each alkyl, alkenyl, or alkynyl being optionally substituted; and
R3i is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR22R23, CR24(CF3)2, JR22, or C(=O)R22, wherein J is O or SOm, wherein m is 0, 1, or 2;
R22 and R21 are, independently, H, Ci-C7 alkyl, C2-C? alkenyl, C2-C7 alkynyl, aryl, or heteroalky!, each alkyl, alkenyl, alknyl, aryl, or heteroalkyl being optionally substituted, alternatively, R22 and R23, taken together with the atoms to which they are attached, form a cyclic or heterocyclic group, e.g., of 3-8 ring members and the heteroatoms are selected from O, N and S, optionally substituted with R20-E-R2], wherein E is O, N, NRzi, or SOm,
R2o and R2i are, independently, H, CpCs alkyl, or heteroalkyl,
alternatively, RzoandRai, taken, together with the atoms to which they are attached,— form a cyclic or heterocyclic group, e.g., of 3-8 ring members and the heteroatoms are selected from O, N and S; and
R24 is H, or OH; with a compound having formula:
D is heterocycloalkyl or heteroaryl, each optionally substituted;
Lg is halogen or OSO2R32, wherein R32 is alkyl, aryl, or fluoroalkyl, each optionally substituted;
kisO, 1,2, or 3; and
Ri3 and RH are, independently at each occurrence, H or optionally substituted alkyl, in an organic solvent in the presence of base, thereby forming a compound having Formula IV, or a pharmaceutical I y acceptable salt thereof:

(Figure Remove)

IV.

In one embodiment, D is optionally substituted heteroaryl.
In one embodiment, RI is H or CpCs alkyl.
In one embodiment, R9 and RIO, are, independently, H, Ci-C4 alkyl, C2-C4
C4 alkynyl.
In one embodiment, RB and RH are, independently at each occurrence, H or
[0038]
[0039]
[0040]
alkenyl, or
[0041]
C,-C3 alkyl.
[0042] In one embodiment, Lg is Br.
[0043] In one embodiment, Lg-(CR)3R]4)k-D is 6-Bromomethyl-quinoxaline.
[0044] In one embodiment, the method further comprises brominating 6-
methylquinoxaline, thereby forming Lg-(CRi3Ri«)k-D. In one embodiment, bromination is
achieved using 1.1 equivalents of N-bromosuccinimide ("NBS") and 2.4 mol% of
azobisisobutyronitrile ("AIBN") in carbon tetrachloride ("CCI4") at reflux.
[0045] In one embodiment, the method further comprises reacting 4-
methylphenylene-],2-diamine with glyoxal, thereby forming said 6-methylquinoxaline.
[0046] In one embodiment, the base is potassium carbonate or N,N-
diisopropylethylamine.
[0047] In one embodiment, the solvent includes at least one of acetone, acetonitrile
("MeCN"), dimethylsulfoxide ("DMSO"), and tetrahydrofuran ("THF").
[0048] In one embodiment, the base includes potassium carbonate and said solvent
includes acetone.
[0049] In one embodiment, 2 equivalents of potassium carbonate are used.
(0050] In one embodiment, 1 equivalent of Lu-(CRi3R|4)k-I3 is used.

[0051] In one embodiment, the method further comprises reacting a compound
(Figure Remove)
thereby forming said compound of Formula HI. In one
embodiment, Lg is Br. In one embodiment, said reacting is carried out in toluene-THF in the
presence of 5 mol% of Pda(dba)3 and 10 mol% of CyMAP ligand with 3 equivalents of solid
lithium hexamethyldisilazide ("LiHMDS").
[0052] In one embodiment, the method further comprises chlorinating a compound
(Figure Remove)
methanol, and reacting the resulting N-chloride with potassium carbonate, thereby forming
(Figure Remove)
said compound having formula
[0053] In one embodiment, the method further comprises reacting a compound
(Figure Remove)

having formula with thionyl chloride to form an imidoyl
chloride, and reacting said imidoyl chloride with aqueous ammonia, thereby forming said
(Figure Remove)

compound having formula
[0054] In one embodiment, the method further comprises reacting a compound of
(Figure Remove)
are combined under Schotten-Bauman conditions with .
In one embodiment, RSI is t-butyl.
[0057] In one embodiment, the method further comprises adding 2 equivalents of
ethereal HCI to a solution of the compound having Formula IV in ethanol, thereby forming a salt.
[0058] In one embodiment, the present invention comprises a compound having
Formula III:

(Figure Remove)
RI is H or alkyl;
jig and RIO, are, independently, H, alkyl, alkenyl, or alkynyI7each alkyl, alkenyl, or alkynyl being optionally substituted; and
R3, is C|-Q alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR22R23, CR24(CF3)2, JR22, or C(=O)R22, wherein J is O or SOm, wherein m is 0, 1, or 2;
R22 and R23 are, independently, H, Q-C? alkyl, C2-C7 alkenyl, Ca-C? alkynyl, aryl, or heteroalkyl, each alkyl, alkenyl, alkynyl, aryl, or heteroalkyl being optionally substituted, alternatively, R22 and R23, taken together with the atoms to which they are attached, form a cyclic or heterocyclic group, e.g., of 3-8 ring members and the heteroatoms are selected from O, N and S, optionally substituted with R20-E-R2I, wherein E is O, N, NR2), or SOm,
R2o and R2| are, independently, H, Cj-C3 alkyl, or heteroalkyl,
alternatively, R2o and R2t, taken together with the atoms to which they are attached, form a cyclic or heterocyclic group, e.g., of 3-8 ring members and the heteroatoms are selected from O, N and S; and
R24 is H, or OH.
[0059] In one embodiment, Rg is H or CH3.
[0060] In one embodiment, R3[ is Q-Q alkyl.
[0061] In one embodiment, R3) is t-butyl.
DEFINITIONS
[0062] All recitations of a group, such as alkyJ, are understood for the purposes of this
specification to encompass both substituted and unsubstituted forms.
[0063] The term "alkyl", as used herein, whether used alone or as part of another
group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight and branched chains containing from 1 to 12 carbon atoms, or in some instances, from I to 6 carbon atoms, unless explicitly specified otherwise. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are encompassed by the term "alkyl." C|-Ce alkyl includes straight and branched chain aliphatic groups having from I to 6 carbons. Specifically included within the definition of "alkyl" are those aliphatic hydrocarbon chains that are optionally substituted. In one embodiment, an alkyl is substituted with one or more of the following groups: -V-halogen, -V-Na, -V-NO2, -V-CN, -V-OR', -V-SR', -V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CC^R', -V-NR'CO2R', -V-NR'COR', -V-NR'CONR', -V-CON(R')2, -C(OH)(CF3)2> -CH(CF3)2, or -C(CF3)3, wherein each R' is independently hydrogen or unsubstituted (Q-CeJ-alkyl; and wherein each V is independently a bond or (Ci-CeJ-alkyl.
[0064] Likewise, the term "heteroalkyl" as used herein refers to an alkyl group (e.g.,
of 2-1 carbon atoms) in which 1-3 carbon atoms within the carbon backbone are independently replaced by O, S or N heteroatoms. For example, methoxy, ethoxy, methylthio, ethylthio, methylamine, ethylamine, dimethylamine, diethylamine, methoxy methyl, ethoxymethyl, aminomethyl, and hydroxymethyl are encompassed by the term "heteroalkyl." In one embodiment, a heteroalkyl is substituted with one or more of the following groups: -V-halogen, -V-N3. -V-NO2, -V-CN, -V-OR1, -V-SR', -V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CO2R', -V-NR'CO2R', -V-NR'COR', -V-NR'CONR', -V-CON(R')2, -C(OH)(CF3)2, -CH(CF3)2, or -C(CF3)3, wherein each R' is independently hydrogen or unsubstituted (CrCgJ-alkyl; and wherein each V is independently a bond or (Cr C6)-alkyl.
[0065] The carbon number as used in the definitions herein refers to carbon backbone
and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
[0066] The term "alkenyl", as used herein, whether used alone or as part of another
group, refers to a substituted or unsubsliluted hydrocarbon chain and includes, but is not limited to, straight and branched chains having 2 to 8 carbon atoms and containing at least one double bond. In one embodiment, the alkenyl moiety has I or 2 double bonds. Such alkenyl moieties may exist in the E or Z conformations and (he compounds of this invention
include both conformations. C2-Ce alkenyl includes a 2 to 6 carbon straight or branched chain having at least one carbon-carbon double bond. Specifically included within the definition of "alkenyl" are those aliphatic hydrocarbon chains that are optionally substituted. In one embodiment, a heteroatom, such as O, S or N, attached to an alkenyl is not attached to a carbon atom that is bonded to a double bond. In one embodiment, an alkenyl is substituted with one or more of the following groups: -V-halogen, -V-N3, -V-NO2, -V-CN, -V-OR', -V-SR', -V-S02R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CO2R', -V-NR'CO2R', -V-NR'COR', -V-NR'CONR', -V-CON(R')2> -C(OH)(CF3)2, -CH(CF3)2, or -C(CF3)3l wherein each R' is independently hydrogen or unsubstituted (Ci-Ce)-alkyl;.and wherein each V is independently a bond or (Ci-Cfi)-alkyl.
[0067] The term "alkynyl" refers to a hydrocarbon moiety containing at least one
carbon-carbon triple bond. CrQ alkynyl includes a 2 to 6 carbon straight or branched chain having at least one carbon-carbon triple bond. In one embodiment, an alkynyl is substituted with one or more of the following groups: -V-halogen, -VrN3,^V-NO2, -V-CN, -V-OR', -V— SR', -V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CO2R', -V-NR'CO2R', -V-NR'COR', -V-NR'CONR', -V-CON(R')2, -C(OH)(CF3)2, -CH(CF3)2, or -C(CF3)3, wherein each R' is independently hydrogen or unsubstituted (Q-CeJ-alkyl; and wherein each V is independently a bond or (Ci-C6)-alkyl.
[0068] The term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic, fused,
bridged, or spiro monovalent saturated hydrocarbon moiety, wherein the carbon atoms are located inside or outside of the ring system, e.g., of 3 - 15 carbon atoms. Any suitable ring position of the cycloalkyl moiety may be covalently linked to the defined chemical structure. Examples of cycloalkyl moieties include, but are not limited to, chemical groups such as cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, cycloheptyl, norbornyl, adamantyl, spiro[4.5]decanyl, and homologs, isomers, and the like. C3-C6 cycloalkyl includes monocyclic, saturated rings of 3 to 6 carbons. In one embodiment, a cycloalkyl is substituted with one or more of the following groups: -V-H, -V-halogen, -V-N3, -V-NO2, -V-CN, -V-OR', -V-SR', -V-SO2R\ -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CO2R', -V-NR'CO2R', -V-NR'COR', -V-NR'CONR', -V-CON(R')2, -C(OH)(CF3)2, -CH(CF3)2, or -C(CF3)3, wherein each R' is independently hydrogen or unsubstituted (d-C^O-alkyl; and wherein each V is independently a bond or (C|-C(,)-alkyl.
|0069| "Heteroaryl" refers to a 5 to 6 membcred aromatic hetcrocyclic ring which
contains irom 1 to 4 hetcroaloms selected from the croup consisting of oxygen, nitrogen, and
sulfur atoms in the ring and may be fused with a carbocyclic or heterocyclic ring at any possible position (e.g. of 5-8 ring atoms, the fused heterocyclic ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms in the ring). In one embodiment, a heteroaryl is substituted with one or more of the following groups: -V-H, -V-halogen, -V-N3, -V-NO2, -V-CN, -V-OR', -V-SR', -V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CO2R', -V-NR'CO2R', -V-NR'COR', -V-NR'CONR', -V-CON(R')2, -C(OH)(CF3)2, -CH(CF3)2, or -C(CF3)3, wherein each R1 is independently hydrogen or unsubstituted (C|-C6)-alkyl; and wherein each V is independently a bond or (C|-C6)-alkyl.
[0070] "Heterocycloalkyl" refers to a 5 to 7-membered saturated ring containing
carbon atoms and from 1 to 1 heteroatoms selected from N, O, and S. In one embodiment, a
heterocycloalkyl is substituted with one or more of the following: =O, -V-H, -V-halogen,
_V-N3, -V-N02, -V-CN, -V-OR', -V-SR', -V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR',
-V-CO2R', -V-NR'COR, -y-NR'COR'^-yrNRICONR'^V-CONCR'Oz, -C(OH)(CF3)2r
-CH(CF3)2, or -C(CF3)3, wherein each R' is independently hydrogen or unsubstituted (Q-Ce)-
alkyl; and wherein each V is independently a bond or (Ci-Ce)-alkyl.
[0071] The term " aryl" as used herein as a group or part of a group refers to an
aromatic carbocyclic ring , e.g., of from 6 to 14 carbon atoms such as phenyl, which may be
optionally substituted. "Phenyl", as used herein, whether used alone or as part of another
group, refers to a substituted or unsubstituted phenyl group. In one embodiment, an aryl
group such as phenyl is substituted with one or more of the following: -V-H, -V-halogen, -V-
N3, -V-NO2, -V-CN, -V-OR', -V-SR', -V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-
CO2R', -V-NR'COzR', -V-NR'COR', -V-NR'CONR', -V-CON(R')2, -C(OH)(CF3)2, -
CH(CF3)2, or -C(CF3)3, wherein each R' is independently hydrogen or unsubstituted (Q-Ce)-
alkyl; and wherein each V is independently a bond or(C]-C6)-alkyl. Additional substituents
on aryl are illustrated above in connection with A when phenyl in paragraph [0028].
[0072] An optionally substituted moiety may be substituted with one or more
substituents, examples of which are as illustrated herein. In one embodiment, an "optionally substituted" moiety is substituted with one or more of the following groups: =O, -VH, -V-halogen, -V-N3, -V-NO2, -V-CN, -V-OR', -V-SR', -V-S02R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CO2R', -V-NR'CO2R', -V-NR'COR', -V-NR'CONR', -V-CON(R')2, -C(OH)(CF3)2, -CH(CF;,)?, or -C(CF3)3, wherein each R' is independently hydrogen or unsubstidited (C|-Cr,)-alkyl or phenyl; and wherein each V is independently a bond or (Q-
[0073] When such moieties are substituted, for example, they may typically be mono-
, di-, tri- or persubstituted. Examples for a halogen substituent include 1-bromo vinyl, 1-
fluoro vinyl, 1,2-difluoro vinyl, 2,2-difluorovinyl, 1,2,2-trifluorovinyl, 1,2-dibromo ethane,
1,2 difluoro ethane, 1 -fluoro-2-bromo ethane, CFaCFs, CFjCFzCFs, and the like.
[0074] The term halogen includes bromine, chlorine, fluorine, and iodine.
[0075] For the sake of simplicity, connection points ("-") are not depicted. When an
atom or compound is described to define a variable, it is understood that it is intended to
replace the variable in a manner to satisfy the valency of the atom or compound. For
example, if "X*" was C(R*)=C(R*), both carbon atoms form a part of the ring in order to
satisfy their respective valences. Likewise, when divalent substituents are presented, it is
understood that they are not limited to the order listed, for example, as used in this
specification "OCH2" encompasses CHzO and OCH2-
[0076] As used herein, a compound of the present invention also includes a
pharmaceutically; acceptabje salt of a compound of the present inventiom-The term
"pharmaceutical ly acceptable salt" as used herein refers to a salt of an acid and a basic nitrogen atom of a compound of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, napthalenesulfonate, propionate, succinate, fumarate, maleate, malonate, mandelate, malate, phthalate, and pamoate. The term "pharmaceutically acceptable salt" as used herein also refers to a salt of a compound of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base. Exemplary bases include, but are not limited to, hydroxide of alkali metals including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamincs, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; dicthylaminc; tricthylamine; mono-, bis-, or tris-(2-OH-(C|-C6)-alkylamine), such as N,N-diniethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; moqiholine; (hioinoipholine; piperidinc; pyrrol idine; and arnino acids such as arginine, ly.sine, and the like. The term "pharmaceutically acceptable salt" also includes a hydrate of a compound of (he present invention.

[0077] The term "patient", as used herein, refers to a mammal, in one embodiment, a
human.
[0078] The terms "administer", "administering", or "administration", as used herein,
refer to either directly administering a compound or composition to a patient, or
administering a prodrug derivative or analog of the compound to the patient, which will form
an equivalent amount of the active compound or substance within the patient's body.
[0079] The term "carrier", as used herein, shall encompass carriers, excipients, and
diluents.
[0080] The term "tautomer" as used herein refers to compounds produced by the
phenomenon wherein a proton of one atom of a molecule shifts to another atom. See, Jerry
March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth
Edition, John Wiley & Sons, pages 69-74 (1992).
[0081] The compounds of this invention may contain an asymmetric carbon atom and
some of the cojrnppjindj^thi^rryention rnayjco.ntain one or more asymmetric centers and
may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereo isomers and pharmaceutically acceptable salts thereof. Where a stereoisomer is provided, it may in some embodiments be provided substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of the corresponding enantiomer refers to a compound that is isolated or separated via separation techniques or prepared free of the corresponding enantiomer. "Substantially free", as used herein, means that the compound is made up of a significantly greater proportion of one stereoisomer, in one embodiment, less than about 50% of the other, in another embodiment, less than about 75%, and in yet another embodiment, less than about 90%, in one embodiment, less than about 95%, in another embodiment, less than about 98%, and in yet another embodiment, less than about 99%.
[0082] The terms "effective amount", "therapeutically effective amount" and
"effective dosage" as used herein, refer to the amount of a compound, that, when
administered to a patient, is effective to at least partially ameliorate (and, in other
embodiments, cure) a condition form which the patient is suspected to suffer.
[0083] Compounds of the present invention have been found to act as GnRH receptor
antagonists. They are therefore useful in the treatment of prostate cancer, endometriosis, uterine fibroids, uterine cancer, breast cancer, ovarian cancer, testicular cancer, primary

hirsutism, or LH surge. In addition, they are useful as oral contraceptives. The present invention thus provides pharmaceutical compositions comprising at least one compound of the present invention and one or more pharmaceutically acceptable carriers, excipients, or diluents.
[0084] Examples of such carriers are well known to those skilled in the art and are
prepared in accordance with acceptable pharmaceutical procedures, such as, for example,
those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R.
Gennaro, Mack Publishing Company, Easton, PA (1985), which is incorporated herein by
reference in its entirety. Pharmaceutically acceptable carriers are those that are compatible
with the other ingredients in the formulation and biologically acceptable.
[0085] The compounds of this invention may be administered orally or parenterally,
neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants,
solubj[izerst^uspeading agents, fillers^glidants, compression aids, binders or tablet ——-
disintegrating agents or encapsulating materials. They are formulated in conventional
manner, for example, in a manner similar to that used for known antihypertensive agents,
diuretics and (3-blocking agents. Oral formulations containing the active compounds of this
invention may comprise any conventionally used oral forms, including tablets, capsules,
buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the
carrier is a finely divided solid, which is an admixture with the finely divided active
ingredient In tablets, the active ingredient is mixed with a carrier having the necessary
compression properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets in one embodiment contain up to 99% of the active ingredient.
[0086] Capsules may contain mixtures of the active compound(s) with inert fillers
and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
[0087] Useful tablet formulations may be made by conventional compression, wet
granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrates, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfatc, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymcthyl cellulose, carboxymcthylcellulose calcium, polyvinylpyrrolidme, alginic acid, acacia gum, xanthan

gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes and ion exchange resins. Exemplary surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colliodol silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s). The oral formulation may also consist of administering the active ingredient in water or fruit juice, containing appropriate solubilizers or emulisifiers as needed.
[0088] Liquid carriers may be used in preparing solutions, suspensions, emulsions,
syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a

both or pharmaceuticaHy acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, including sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceuticaHy acceptable propellant.
[0089] Liquid pharmaceutical compositions, which are sterile solutions or
suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be in either liquid or solid form.
|0090] In one embodiment, the pharmaceutical composition is in unit dosage form,
e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged

compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets
containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it
can be the appropriate number of any such compositions in package form. Such unit dosage
form may contain from about 1 nig/kg to about 250 nig/kg, and may given in a single dose or
in two or more divided doses. Such doses may be administered in any manner useful in
directing the active compounds herein to the recipient's bloodstream, including orally, via
implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections),
rectally, vaginally, and transdermally. Such administrations may be carried out using the
present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams,
patches, suspensions, solutions, and suppositories (recta! and vaginal).
[0091] When administered for the treatment or inhibition of a particular disease state
or disorder, it is understood that the effective dosage may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being^tr^aje^^^jl^sjhejvariou_s_physical factors related to the-individual being-^ treated. In therapeutic application, compounds of the present invention are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as a "therapeutically effective amount". The dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the size, age and response pattern of the patient.
[0092] In some cases it may be desirable to administer the compounds directly to the
airways in the form of an aerosol. For administration by intranasal or intrabrochial inhalation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution.
[0093] The compounds of this invention may be administered parenterally or
intraperitoneally. Solutions or suspensions of these active compounds as a free base or
pharmaceutically acceptable salt may be prepared in water suitably mixed with a surfactant
such as hydroxyl-propylcellulose. Dispersions may also be prepared in glycerol, liquid
polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and
use, these preparations contain a preservative to inhibit the growth of microorganisms.
[0094] The pharmaceutical forms suitable for injectable use include sterile aqueous
solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to

the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
[0095] The compounds of this invention can be administered transdermally through
the use of a transdermal patch. For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
[0096] Transdermal administration may be accomplished through the use of a
transdermal patch containingjheactivecQmpound and a carrier that is inert to the active-
compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption
into the blood stream via the skin. The carrier may take any number of forms such as creams
and ointments, pastes, gels and occlusive devices. The creams and ointments may be viscous
liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised
of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active
ingredient may also be suitable. A variety of occlusive devices may be used to release the
active ingredient into the blood stream, such as a semi-permeable membrane covering a
reservoir containing the active ingredient with or without a carrier, or a matrix containing the
active ingredient. Other occlusive devices are known in the literature.
[0097] The compounds of this invention may be administered rectally or vaginally in
the form of a conventional suppository. Suppository formulations may be made from
traditional materials, including cocoa butter, with or without the addition of waxes to alter the
suppository's melting point, and glycerin. Water soluble suppository bases, such as
polyethylene glycols of various molecular weights, may also be used.
[0098] In certain embodiments, the present invention is directed to prodrugs of
compounds of the present invention. Various forms of prodrugs are known in the art, for example, as discussed in, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al. (ed.), "Design and Application of Prodrugs", Textbook of Drug Design and Development, Chapter 5, 1 13-191 (1991), Bundgaard, et al.. Journal of Drug

Delivery reviews, 8:1-38 (1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.
(1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American
Chemical Society (1975), each of which is incorporated by reference in its entirety.
[0099] It is understood that the dosage, regimen and mode of administration of these
compounds can vary according to the malady and the individual being treated and, in some embodiments, is subject to the judgment of the medical practitioner involved. In one embodiment, the administration of one or more of the compounds herein begins at a low dose and is increased until the desired effects are achieved.
[0100] The compounds of the invention can be prepared using a variety of methods
starting from commercially available compounds, known compounds, or compounds prepared by known methods. General synthetic routes to many of the compounds of the invention are included in the following schemes. It is understood by those skilled in the art that protection and deprotecrion steps not shown in the Schemes may-be required for these synthe^e^^dJ[iayh^_grder.pjLstep_Sjna.yJh.CLchanged.to accommodate functionality in the—-target molecules.
Method of Making
[0101] Scheme 1 provides an overview of a method of making compounds of the
Formula II. The individual steps labeled in Scheme 1 are described below.
(Figure Remove)
[0102] Amide C is prepared from 4-r-butylbenzoyI chloride and 2-bromoaniIine
under Schotten-Bauman conditions in THF-water mixture with NaHCCh as a base. The yield of the isolated and recrystallized amide is above 90%, and no optimization is required. Step 2. Formation of benzamidine.


(Figure Remove)
[0103] Benzamidine E is prepared by adaptation of the literature procedures
(Artmonova, T. V.; Zhivich, A. V.; Dubinskii, M. Yu.; Koldobskii, G. I. Synthesis 1996, 72, 1428. Katritzky, A. R.; Tarraga, T.A. Heterocydes 1982,18,21). Amide C is converted to imidoyl chloride D by treatment with thionyl chloride at reflux. Reaction of D with aqueous ^ammonia gives the desired amidine-E with the- total"yieldTof^70^85%"r;=~~^^; ^"^ Step 3. Preparation of 4-bromobenzimidazole

(Figure Remove)
[0104] Amidine E is chlorinated with NCS in methanol at room temperature.
Resulting N-chloride F is treated with potassium carbonate which causes the ring closure to benzimidazole G. The reaction gives consistent yields on any scale from less than a gram to almost 300 g. On the largest scale, however, an unexpected exotherm was observed when, after addition of potassium carbonate, the reaction mixture was being heated to effect the ring closure. The exotherm went unnoticed in smaller scale runs. Another safety point came to our attention after the large scale run. According to the Bretherick's, the combination of NCS and methanol may not be entirely safe. If safety is a concern, acetonitrile may be used instead of methanol with no deleterious effects on yield and purity.
(Figure Remove)
[0105] The coupling between 4-bromobenzimidazole G and N-Boc-piperazine is
carried out in toIuene-THF mixture in the presence of 5 mol% of Pd2(dba)3 and 10 mol% of CyMAP with 3 eq. of solid LiHMDS as the base. LiHMDS is dispensed in a plastic bag under nitrogen blanket, while the rest of the reagents are loaded in open air. The reaction is complete in about 1 hrat 50°Cand gives a mixture of products consisting of 80% of N-Boc-piperazinobenzimidazole I.
[0106] The mixture is enriched in I when it is isolated as a solid after aqueous workup
(90% purity). This mixture is taken directly into the Boc-removal step. The deprotection is carried out with HCI in THF-water mixed solvent. The reagent and solvent ratios allow the deprotected product to crystallize out of the reaction mixture as an HCI salt J which is separated by filtration. The crystals came out further enriched in the desired product J (97% purity). The HCI salt J is purified by treatment of its warm aqueous solution with activated carbon. From the filtered solution, the free base is precipitated with I M NaOH solution and extracted with EtOAc. Final solid K is isolated in 42% yield (based on the amount of bromobenzimidazole) and is 98% pure. Step 5. Preparation of 6-methylquinoxaline
(Figure Remove)
[0107] 6-MethyIquinoxaline M is prepared from 4-methylphenylene-l,2-diamine L
and glyoxal. According to the literature precedents, glyoxal in this reaction could be used as either 40% aq. solution or a crystalline bisulfite adduct, both are commercially available. It was our finding that the bisulfite adduct gave a much cleaner reaction and higher yield of the product. The reaction is carried out in water at 60 °C, the product M is isolated by extraction with ether and purified by distillation. Step 6. Bnomination of 6-methylquinoxaIine

(Figure Remove)



[0108]

Several different combinations of the solvent (DCE, PhCI, PhH, CCI4), radical

initiator (Bz2O2, AIBN), temperature (45-85 CC) and time (1-24 hr) have been screened to
determine the optimal set of conditions for radical bromination. The best result in terms of the mono- to bis-bromide ratios and isolated yield and purity of the mono-brominated product is observed with 1.1 eq. of NBS, 2.4 mol% of AIBN in CC14 at reflux for 1.5 hr. The pure mono-bromide crystallizes out of the reaction mixture and is separated by filtration. 6-Bromomethylquinoxaline decomposes fairly rapidly when stored in a vial at room temperature and has to be prepared at least within several days before use in the subsequent step. Step 7. Alkylation of 4-piperazinobenzimidazole

(Figure Remove)
[0109]
Alkylation is carried out with 1 .0 eq of the bromide N and 2 eq of

base in acetone at room temp, over 22 hr. The product is isolated by filtration, purified by niuliiple washes with water and dried in a vacuum desiccator over Step 8. Formation of the salt form
(Figure Remove)
[0110] Dihydrochloride salt prepared was found to be the best of a series of possible
formulations as judged by its crystallinity, solubility, stability, etc. The salt is prepared by
adding 2 eq of ethereal HC1 to a solution of the free base in ethanol. The salt is isolated by
filtration.
[0111] One of skill in the art will recognize that the above Scheme and Steps can be
adapted to produce the other compounds andjpharrnaceutically acceptable.salts of compounds
according to the present invention.
EXAMPLES EXAMPLE 1
[0112] LCMS analysis was done on an open access Agilent chromatograph with UV
and mass detectors, 5 cm CIS column, 5 min gradient of 95% water to 95% MeCN. HPLC analysis was done on a Waters liquid chromatograph, 15 cm CIS column, 20 min runs with a 10 min gradient from 95% water to 95% MeCN (0.05% TFA) and 1 mL/min flow.
W-(2-bromophenyI)-4-/£rf-butylbenzamide

(Figure Remove)
[0113] 2-Bromoaniline (98%, Oakwood 005347, 214 g, 1.25 mol), NaHCO3 (270 g,
3.2 mol)^THF(500 mL) and~water(500 mL)~wefeplaced into a5^LGround-bottom flask equipped with an overhead stirrer, thermometer and a 500-mL addition funnel. Solution of t-butyl benzoyl chloride (>98%, Fluka 19660, 250 mL, 1.37 mol) in 250 mL of THF was placed into the addition funnel and was added slowly (in 25 min) to the stirred mixture of reagents in the flask. (No external heating or cooling was administered, slight exotherm was observed raising the temperature inside the flask to 35 °C).
[0114] After the addition was complete, the reaction mixture was left stirring
overnight (14 hr). LCMS analysis after that showed complete conversion to the amide (product peak @ 4.30 min, MH* 332Br; by-product peak @ 4.74 min 2M+Na* 699 corresponds to te/Y-butylbenzoyl anhydride).
[0115] The liquid from the reaction flask was decanted off the precipitate into a sep.
funnel, the aq. layer was separated and extracted with ether (2 x 150 mL). Inorganic salts left in the reaction flasks were washed with ether (2 x 100 mL). Combined organic solutions were further diluted with 200 mL of ether, washed with 50 mL of water, 100 mLof aq. 1 M HC1, 50 mL of aq. K^CCh and 50 mL of brine. The resulting solution was dried with MgSC>4 and filtered through a cotton plug. The solvents were removed in vacuum, the oily residue solidified slowly into a white cake.
[0116] The cake was dissolved in approximately 100 mL of hot heptane, allowed to
cool to r.t. and seeded with a couple of crystals of the amide. The product crystallized from the solution as white needles. The mixture was kept in a freezer for 14 hr. The crystals were
quickly filtered through a paper filter, washed with cold petroleum ether and dried in air. Yield 384 g (93%) as colorless needles.
A'-(2-bromophenyl)-4-/4 to give 70 g (0.147 mol) of the desired product as a white amorphous solid. Purity 98% (HPLC at 254 nm).
2-(4-tert-butylphenyl)-4-{[4-(6-quinoxaIyl)methyI]piperazin-l-yl}benzimidazole dihydrochloride dihydrate

(Figure Remove)

Removal of trace Pd
[0134] To the suspension of the free base (103 g, 0.216 mol) in EtOAc (1.6 L) was
added a solution of L-cysteine (Aldrich, 2.8 g, 23 mmol) in 400 mL of water. The resulting mixture was heated at 50 °C while being stirred rapidly with an overhead stirrer. The mixture became clear when the temperature reached 32 °C. After 3 hr of stirring at 50 °C, the mixture was allowed to cool to rt. The layers were separated, the aq. layer was extracted with EtOAc (2 x 50 mL). Combined organic solutions were washed with water, brine, dried over Na2S04 and concentrated in vacuum. The residue was triturated with heptane, filtered and dried in a vacuum desiccator to give 102 g (99% recovery) of the product as an off-white solid. Preparation of the salt
[0135] The free base (110 g, 0.231 mol) was mixed with anhydrous ethanol (0.880 L)
and the slurry was heated to 60°C at which point of the solid dissolved. The resulting clear
light-yellow solution was allowed to cool to 40 °C, then 2 M solution of HC1 in ether
(Aldrich, 234 mL, 0.468 mol, 2.03 eq) was added slowly while the solution was being stirred.
The resulting mixture remained clear. The stirring was stopped, and the mixture was left
overnight at rt. Thick precipitate formed was filtered, washed with 0.6 L of ether and dried in
a vacuum oven at 58 °C for 24 hr. Yield of the salt was 105 g (83%).
[0136] Various modifications of the invention, in addition to those described herein,
will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

CLAIMS
(Figure Remove)
or a pharmaceutically acceptable salt thereof, wherein B is (CR,3Ri4)k-D,
D is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl being optionally substituted;
kisO, 1,2, or 3;
Ri3 and R^ are, independently at each occurrence, H or optionally substituted alkyl,
A is aryl or heteroaryl, each optionally substituted;
R], R2, Rj, and R4 are, independently, H or optionally substituted alkyl; and R5, R<5, R7, Rg, Rg, R]o, RII, and Rn, are, independently, H, alkyl, alkenyl, or alkynyl, each alkyl, alkenyl, or alkynyl being optionally substituted; which comprises reacting a compound having Formula I:

R
(Figure Remove)

wherein A and RpR]2 are as defined above; with a compound having formula:
wherein D,k and Ri3 and RH are as defined above, and Lg is halogen or OSOaRaa, wherein R32 is alkyi, aryl, or fluoroalkyl, each optionally substituted; in an organic solvent in the presence of a base; and if desired converting the compound of formula II to a pharmaceutically acceptable salt.
2. The method of claim 1, wherein RI, R2, RS, and R4 are, independently, H or Q-Cs alkyl.
3. The method of claim 1 or claim 2, wherein RS, Re, R?, Rg, RS, RIO, RII and Ria, are,
independently, H, Q-C4 alkyl, alkenyl or alkynyl.
4. The method of claim 1 wherein RI, R2, Ra, R4, RS, Re, R?, Rg, RIO, RII and R|2 are H and
R9isHorC|-G,alkyl.
5. The method of claim I, wherein the compound of formula I has the formula:
(Figure Remove)

wherein A is optionally substituted aryl and Rg is H or C|-C4 alkyl.
6. The method of claim 5 in which the compound of Formula I is prepared by a process comprising reacting a compound having formula

(Figure Remove)

with a compound having formula

(Figure Remove)
wherein Lg and Rg are as defined in claim 5 and Boc is tertiary butyloxycarbonyl and removing the Boc protecting group.
7. The method of claim 6, wherein Lg is Br or triflate.
8. The method of claim 6 or claim 7, wherein the reaction of the compounds of formula V
and VI is carried out in toluene-THF in the presence of Pd2(dba).i and CyMAP ligand with solid lithium hexamethyldisilazide.
9. The method of any one of claims 6 to 8, in which the compound of
formula
(Figure Remove)

is prepared by a process comprising chlorinating a compound having formula
(Figure Remove)

with N-chlorosuccinimide in methanol, and reacting the resulting N-chloride with potassium carbonate.
10. The method of claim 9 in which the compound having formula

(Figure Remove)

is prepared by a process comprising reacting a compound having formula

(Figure Remove)


with thionyl chloride to form an imidoyl chloride, and reacting said imidoyl chloride with aqueous ammonia.
I I. The method of claim 10, in which the compound having formula
(Figure Remove)


is prepared by a process comprising reacting a compound of formula

(Figure Remove)


withji compound of formula^
(Figure Remove)
wherein Lg' is a halogen.
12. The method of claim 11, wherein Lg' is Br.
13. The method of claim 11 or 12, wherein the reaction of the compounds of formula

(Figure Remove)

14. The method of any one of claims 1 to 1 3, wherein RIS and RM are, independently at
each occurrence, H or Q-Cs alkyl.
15. The method of any one of claims 1 to 14, wherein A is optionally substituted aryl.
1 6. The method of claim 15, wherein A is aryl, e.g., phenyl, substituted with Q-Cg alkyl, C2-C6 aTkeny], C2-C6 alkynyl, NR22R23, CR24(CF3)2, JR&, or C(=O)R22l wherein J is O or SOm, wherein m is 0, 1 , or 2;
R22 and Ry are, independently, H, C|-C7 alkyl, C2-C7 alkenyl, Ca-C? alkynyl, aryl, or heteroalkyl, each alkyl, alkenyl, alkynyl, aryl, or heteroalkyl being optionally substituted,
alternatively, R22 and R23, taken together with the atoms to which they are attached, form an optionally substituted cyclic or optionally substituted heterocyclic group optionally substituted with R2o-E-R2i, wherein E is O, N, NRai, or SOm,
R2o and R2j are, independently, H, Ci-Ca alkyl, or heteroalkyl,
alternatively, R2oand R2i, taken together with the atoms to which they are attached, form a cyclic or heterocyclic group; and
R24 is H, or OH.
17. The method of any one of claims I to 15, wherein A is para t-butyl phenyl.
I 8. The method of any one of claims I to 17, wherein D is optionally substituted heteroaryl.
19. The method of any one of claims 1 to 17, wherein D is optionally substituted C|-Cg alkyl.
20. The method of any one of claims 1 to 17, wherein D is (quinoxalin-6-yl)methyl.
21. The method of any one of claims 1 to 20, wherein Lg is Br.
22. The method of any one of claims I to 17, wherein Lg-(CRi3Ri4)k-D is 6-bromomethyI-
quinoxaline.
23. The method of claim 22, in which the 6-bromomethyl-quinoxaline is prepared by a
process comprising brominating 6-methylquinoxaline.
24. The method of claim 22, wherein the bromination is achieved using N-bromosuccinimide
and azobisisobutyronitrile in carbon tetrachloride at reflux.
25. The method of claim 23 or claim 24, in which the 6-methylquinoxaline is prepared by a
process comprising reacting 4-methylphenylene-i,2-diamine with glyoxal.
26. The method of any one of claims 1 to 25, wherein the solvent comprises at least one of
acetone, acetonitrile, dimethylsulfoxide, and tetrahydrofuran
27. The method of any one of claims 1 to 26, wherein said base comprises potassium
carbonate or N,N-diisopropyIethylamine.
28. The method of any one of claims I to 27, wherein said base comprises potassium
carbonate and said solvent includes acetone.
29. The method of claim 27 or 28, wherein 2 equivalents of potassium carbonate are used.
30. The method of any one of claims 1 to 29, wherein 1 equivalent of LB-(CR|3Ri4)k-D is
used.
31. A method for preparing a compound of Formula IV:

(Figure Remove)


or a pharmaceutically acceptable salt thereof
wherein -
RI is H or alky);
Rg and RIO, are, independently, H, alkyl, alkeny], oralkynyl, each alkyl, alkenyl, or alkynyl being optionally substituted; and
R3i is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR22R23, CR24(CF3)2, JR22, or C(=O)R22, wherein J is 0 or SOm, wherein m is 0, 1, or 2;
R22 and R23 are, independently, H, CrC7 alkyl, C^-Ci alkenyl, C2-C? alkynyl, aryl, or heteroalkyl, each alkyl, alkenyl, alkynyl, aryl, or heteroalkyl being optionally substituted,
alternatively, R22 and R23, taken together with the atoms to which they are attached, form a cyclic or heterocyclic group optionally substituted with R20-E-R2|, wherein E is O, N, NR2,,orSOm,
R2o and R2| are, independently, H, C|-C3 alkyl, or heteroalkyl,
alternatively, R2o and R2], taken together with the atoms to which they are attached, form a cyclic or heterocyclic group; and
R24 is H, or OH;
D is heterocycloalkyl or heteroaryl, each optionally substituted;
Lg is halogen or OSO2R32, wherein R32 is alkyl, aryl. or fluoroalkyl, each optionally subs tiiu led;
k isO, 1,2, or 3; and
RU and RH arc, independently at each occunence, H or optionally substituted alkyl, which comprises reacting a compound having Formrla III:

(Figure Remove)


III
with a compound having formula:
Lg-(CR13Ri4)k-D wherein Lg, Rn, RU, k and D are as defined above, in an organic solvent in the presence of
base; and if desired converting the compound of formula TV to a pharmaceutically acceptable salt.
32. The method of claim 31 wherein D is optionally substituted heteroaryl.
33. The method of claim 31 or claim 32 wherein R| is H orQ-Cs alkyl.
34. The method of any one of claims 31 to 33 wherein Rg and RJQ, are, independently, H, C\-
d alkyl, alkenyl, or alkynyl.
35. The method of any one of claims 31 to 34 wherein Rn and Rf4 are, independently at each
occurrence, H orQ-Cs alkyl.
36. The method of any one of claims 31 to 35 wherein Lg-(CRnRi4)k-D is 6-bromomethyl-
quirioxalmc.
37. The method of any one of claims 31 to 35, wherein Lg is Br.
}8. The method of claim 36 in which ihc 6-bromomethyl-c|iiinoxaline is prepared by a process which comprises brotmnating 6-metliyk|iiiiioxa!me.

39. The method of claim 38 wherein the bromination is achieved using N-bromosuccinimide
and azobisisobutyronitrile in carbon tetrachloride at reflux.
40. The method of claim 38 or claim 39 in which 6-methylquinoxaline is prepared by a
process which comprises reacting4-methylphenylene-l,2-diamine with glyoxal.
41. The method of any one of claims 31 to 40 wherein said base includes potassium
carbonate and N,N-diisopropylethylamine.
42. The method of any one of claims 31 to 41 wherein the solvent includes at least one of
acetone, acetonitrile, dimethylsulfoxide, and tetrahydrofuran.
43. The method of any one of claims 31 to 41 wherein said base includes potassium carbonate
and said solvent includes acetone.
44. The method of any one of claims 41 to 43 wherein 2 equivalents of potassium carbonate
are used.
45. The method of any one of claims 31 to 43 wherein 1 equivalent of Lg-(CR|3Ri4)k-D is
used.
46. The method of any one of claims 31 to 45, in which the compound of Formula III is
prepared by a process which comprises reacting a compound having formula
(Figure Remove)

with a compound having formula

and deprotccting.
47. The method of claim 46, wherein L,, is Br.

48. The method of claim 46 or claim 47, wherein the reaction is carried out in toluene-THF
in the presence of Pd2(dba)3 and CyMAP ligand with solid lithium hexamethyldisilazide.
49. The method of any one of claims 46 to 48 in which the compound having formula

(Figure Remove)

is prepared by a process which comprises chlorinating a compound having formula

(Figure Remove)

with N-chlorosuccinimide in methanol, and reacting the resulting N-chloride with potassium carbonate.

50. The method of claim 49, in which said compound having formula
(Figure Remove)

is prepared by a process which comprises reacting a compound having formula

(Figure Remove)


/ith thionyl chloride to fonn an imidoyl chloride, and reacting said imidoyl chloride with queous ammonia.
51. The method of claim 50 in which said compound having formula

(Figure Remove)

is prepared by a process which comprises reacting a compound of formula
(Figure Remove)

with a compound of formula

(Figure Remove)

wherein Lg' is a halogen.
52. The method of claim 51, wherein

(Figure Remove)
arc combined under Scholten-Bauman conditions with NailCOj.

53. The method of claim 51 or claim 52 wherein Lg' is Br.
54. The method of any one of claims 31 to 53 wherein R}\ is t-butyl.
55. The method of any one of claims 1 to 30 in which the compound of formula II is
converted to a salt by a process comprising adding 2 equivalents of ethereal HCI to a solution of the compound having Formula II in ethanol.
56. The method of any one of claims 31 to 54 in which the compound of formula IV is
converted to a salt by a process comprising adding 2 equivalents of ethereal HCI to a solution of the compound having Formula IV in ethanol.
57. A compound having Formula III:
(Figure Remove)

wherein:
R, is H or alky!;
Ry and RIO, are, independently, H, alkyl, alkenyl, or alkynyl, each alkyl, alkcnyl, or alkynyl being optionally substituted; and

RM is CrQ alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR22R23, CR24(CF3)2, JR22, gr C(=O)R22, wherein J is O or SOm, wherein m is 0, 1, or 2;
R22 and R23 are, independently, H, Ci-C? alkyl, C2-Cv alkenyl, C2-C7 alkynyl, aryl, or heteroalkyl, each alkyl, alkenyl, alkynyl, aryl, or heteroaryl being optionally substituted,
alternatively, R22 and R23, taken together with the atoms to which they are attached, form a cyclic or heterocyclic group optionally substituted with R20-E-R2i, wherein E is O, N, NR21,orSOm,
R2o and R2| are, independently, H, CrC3 alkyl, or heteroalkyl,
alternatively, R2o and R2i, taken together with the atoms to which they are attached, form a cyclic or heterocyclic group; and
R24 is H, or OH.
58. The compound of claim 57 wherein Rg is H or CH3.
59. The compound of claim 57 or claim 58 wherein R3j is Cj-Cg alkyl.
60. The compound of claim 59 wherein R3| is t-butyl.
£j-The invention substantially such as herein described