NZ721051B2 - Tropomyosin-related kinase (trk) inhibitors - Google Patents
Tropomyosin-related kinase (trk) inhibitors Download PDFInfo
- Publication number
- NZ721051B2 NZ721051B2 NZ721051A NZ72105114A NZ721051B2 NZ 721051 B2 NZ721051 B2 NZ 721051B2 NZ 721051 A NZ721051 A NZ 721051A NZ 72105114 A NZ72105114 A NZ 72105114A NZ 721051 B2 NZ721051 B2 NZ 721051B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- methoxy
- alkyl
- benzyl
- cycloalkyl
- heteroaryl
- Prior art date
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- 108091000080 Phosphotransferase Proteins 0.000 title claims abstract description 18
- 102000020233 phosphotransferase Human genes 0.000 title claims abstract description 18
- 102000005937 Tropomyosin Human genes 0.000 title claims abstract description 16
- 108010030743 Tropomyosin Proteins 0.000 title claims abstract description 16
- 239000003112 inhibitor Substances 0.000 title abstract description 73
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- 230000007547 defect Effects 0.000 claims abstract description 10
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 307
- 125000000217 alkyl group Chemical group 0.000 claims description 209
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 170
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 160
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 137
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 135
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 115
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- 150000003839 salts Chemical class 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 18
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- ZYGSFPNXGAOSOS-UHFFFAOYSA-N COC1=CC=C(COC(C2=CC(OC)=CC=C2)N2C(N)=NC3=C2C=CC=C3C2=NN(CCN3CCOCC3)C=C2)C=C1 Chemical compound COC1=CC=C(COC(C2=CC(OC)=CC=C2)N2C(N)=NC3=C2C=CC=C3C2=NN(CCN3CCOCC3)C=C2)C=C1 ZYGSFPNXGAOSOS-UHFFFAOYSA-N 0.000 claims description 11
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- 230000001404 mediated effect Effects 0.000 claims description 5
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Classifications
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
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- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
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- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Abstract
benzo[d]imidazole and 3H-imidazo[4,5-d]pyridine derivatives as disclosed as tropomyosin-related kinase inhibitors (Trk inhibitors) useful in the treatment of disease. These Trk inhibitors can be used as pharmaceutical agents and in pharmaceutical compositions. Trk inhibitors are useful in the treatment of inflammatory diseases, autoimmune disease, defects of bone metabolism and/or cancer, and are particularly useful in the treatment of osteoarthritis (OA), pain, and pain associated with OA. Trk inhibitors are also useful for inhibiting tropomyosin-related kinase A (TrkA), tropomyosin-related kinase B (TrkB), tropomyosin-related kinase C (TrkC), and/or c-FMS (the cellular receptor for colony stimulating factor-1 (CSF-1)). atment of inflammatory diseases, autoimmune disease, defects of bone metabolism and/or cancer, and are particularly useful in the treatment of osteoarthritis (OA), pain, and pain associated with OA. Trk inhibitors are also useful for inhibiting tropomyosin-related kinase A (TrkA), tropomyosin-related kinase B (TrkB), tropomyosin-related kinase C (TrkC), and/or c-FMS (the cellular receptor for colony stimulating factor-1 (CSF-1)).
Description
TITLE OF THE INVENTION
TROPOMYOSIN-RELATED KINASE (TRK) INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
Not applicable
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
Not applicable
THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT
Not applicable
INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON COMPACT DISC
Not applicable
BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to tropomyosin-related kinase inhibitors (“Trk
inhibitors”). This invention also relates to pharmaceutical compositions comprising
Trk inhibitors and to the use of Trk inhibitors and pharmaceutical compositions
comprising Trk inhibitors to treat disease. This invention further relates to the use of
Trk inhibitors to treat inflammatory diseases, autoimmune disease, defects of bone
metabolism and cancer. The Trk inhibitors of the present invention can be used to
treat osteoarthritis (OA), to treat pain, to treat post-operative pain, to treat pain
associated with OA, and to inhibit tropomyosin-related kinase A (TrkA),
tropomyosin-related kinase B (TrkB), and/or tropomyosin-related kinase C (TrkC),
and to inhibit c-FMS (the cellular receptor for colony stimulating factor-1 (CSF-1)).
Definitions
As used herein, the term “amino” means a functional group having a nitrogen
atom and 1 to 2 hydrogen atoms. “Amino” generally may be used herein to describe a
primary, secondary, or tertiary amine, and those of skill in the art will readily be able
to ascertain the identification of which in view of the context in which this term is
17965367_1 (GHMatters) P41917NZ00
used in the present disclosure. The term “amine” or “amine group” or “ammonia
group” means a functional group containing a nitrogen atom derived from ammonia
(NH ). The amine groups are preferably primary amines, meaning the nitrogen is
bonded to two hydrogen atoms and one substituent group comprising a substituted or
unsubstituted alkyl or aryl group or an aliphatic or aromatic group. The amine groups
may be secondary amines meaning, the nitrogen is bonded to one hydrogen atom and
two substituent groups comprising a substituted or unsubstituted aklyl or aryl groups
or an aliphatic or aromatic group, as defined below. The amine groups may be
tertiary amines meaning the nitrogen is bonded to three substituent groups comprising
a substituted or unsubstituted alkyl or aryl groups or an aliphatic or aromatic group.
The amine groups may also be quaternary amines meaning the designated amine
group is bonded to a fourth group, resulting in a positively charged ammonium group.
It is understood that any or all of the amines in the present invention may be in
the free amine form (that is, as –NH2 for a primary amine) or in a protonated form
with a pharmaceutically acceptable anion (that is, as –NH Y for a primary amine,
where Y is the pharmaceutically acceptable anion).
As used herein, the term “amide group” means a functional group comprising
a carbonyl group linked to a nitrogen. A “carbonyl group” means a functional group
comprising a carbon atom double bonded to an oxygen atom, represented by (C=O).
The term “alkane” means a saturated hydrocarbon, bonded by single bonds.
Alkanes can be linear or branched. “Cycloalkanes” are saturated hydrocarbons rings
bonded by single bonds.
As used herein, the term “(C -C )alkyl” means a saturated straight chained or
1 10
branched or cyclic hydrocarbon consisting essentially of 1 to 10 carbon atoms and a
corresponding number of hydrogen atoms. Typically straight chained or branched
groups have from one to ten carbons, or more typically one to five carbons.
Exemplary (C -C )alkyl groups include methyl (represented by -CH ), ethyl
1 10 3
(represented by -CH2-CH3), n-propyl, isopropyl, n-butyl, isobutyl, etc. Other (C1-C-
)alkyl groups will be readily apparent to those of skill in the art given the benefit of
the present disclosure.
As used herein, the term “(C -C )heteroalkyl” means a saturated straight
chained or branched or cyclic hydrocarbon consisting essentially of 2 to 10 atoms,
wherein 2 to 9 of the atoms are carbon and the remaining atom(s) is selected from the
group consisting of nitrogen, sulfur, and oxygen. Exemplary (C -C )heteroalkyl
17965367_1 (GHMatters) P41917NZ00
groups will be readily apparent to those of skill in the art given the benefit of the
present disclosure.
As used herein, the term “(C -C )cycloalkyl” means a nonaromatic saturated
3 10
hydrocarbon group, forming at least one ring consisting essential of 3 to 10 carbon
atoms and a corresponding number of hydrogen atoms. (C -C )cycloalkyl groups
3 10
can be monocyclic or multicyclic. Individual rings of multicyclic cycloalkyl groups
can have different connectivities, for example, fused, bridged, spiro, etc., in addition
to covalent bond substitution. Exemplary (C -C )cycloalkyl groups include
3 10
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, bicyclo-octanyl,
octahydro-pentalenyl, spiro-decanyl, cyclopropyl substituted with cyclobutyl,
cyclobutyl substituted with cyclopentyl, cyclohexyl substituted with cyclopropyl, etc.
Other (C -C )cycloalkyl groups will be readily apparent to those of skill in the art
3 10
given the benefit of the present disclosure.
As used herein, the term “(C2-C9)heterocycloalkyl” means a nonaromatic
group having 3 to 10 atoms that form at least one ring, wherein 2 to 9 of the ring
atoms are carbon and the remaining ring atom(s) is selected from the group consisting
of nitrogen, sulfur, and oxygen. (C -C )heterocycloalkyl groups can be monocyclic or
multicyclic. Individual rings of such multicyclic heterocycloalkyl groups can have
different connectivities, for example, fused, bridged, spiro, etc., in addition to
covalent bond substitution. Exemplary (C -C )heterocycloalkyl groups include
pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,
thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl,
isoxazolidinyl, 1,3-oxazolidinyl, isothiazolidinyl, 1,3-thiazolidinyl, 1,2-
pyrazolidinyl, 1,3-pyrazolidinyl, piperidinyl, thiomorpholinyl, 1,2-
tetrahydrothiazinyl, 1,3-tetrahydrothiazinyl, tetrahydrothiadiazinyl,
morpholinyl, 1,2-tetrahydrodiazinyl, 1,3-tetrahydrodiazinyl, tetrahydroazepinyl,
piperazinyl, piperizinonyl, piperizinonyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl,
imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-
azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-
diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, octahydro-2H-
pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-
azaspiro[4.4]nonanyl, 7-oxaaza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl,
octahydro-1H-indolyl, etc. The (C -C )heterocycloalkyl group is typically attached to
the main structure via a carbon atom or a nitrogen atom. Other (C -
17965367_1 (GHMatters) P41917NZ00
C )heterocycloalkyl groups will be readily apparent to those of skill in the art given
the benefit of the present disclosure.
The term “aliphatic group” or “aliphatic” means a non-aromatic group
consisting of carbon and hydrogen, and may optionally include one or more double
and/or triple bonds. In other words, an aliphatic group is any group consisting of
carbon and hydrogen which contains no aromatic functionality. An aliphatic group
may be straight chained, branched or cyclic and typically contains between about one
and about 24 carbon atoms.
The term “aryl group” may be used interchangeably with “aryl,” “aryl ring,”
“aromatic,” “aromatic group,” and “aromatic ring.” Aryl groups include
carbocyclic aromatic groups, typically with six to fourteen ring carbon atoms. Aryl
groups also include heteroaryl groups, which typically have five to fourteen ring
atoms with one or more heteroatoms selected from nitrogen, oxygen and sulfur.
As used herein, the term “(C6-C14)aryl” means an aromatic functional group
having 6 to 14 carbon atoms that form at least one ring.
As used herein, the term “(C -C )heteroaryl” means an aromatic functional
group having 5 to 10 atoms that form at least one ring, wherein 2 to 9 of the ring
atoms are carbon and the remaining ring atom(s) is selected from the group consisting
of nitrogen, sulfur, and oxygen. (C -C )heteroaryl groups can be monocyclic or
multicyclic. Individual rings of such multicyclic heteroaryl groups can have different
connectivities, for example, fused, etc., in addition to covalent bond substitution.
Exemplary (C -C )heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl,
isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-
oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-
thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-
triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl,
pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-
tetrahydro-quinolinyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl,
benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl,
isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl,
phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinyl, etc. The (C -C )heteroaryl
group is typically attached to the main structure via a carbon atom, however, those of
skill in the art will realize when certain other atoms, for example, hetero ring atoms,
17965367_1 (GHMatters) P41917NZ00
can be attached to the main structure. Other (C -C )heteroaryl groups will be readily
apparent to those of skill in the art given the benefit of the present disclosure.
As used herein, the term “alkyl amine” means an (C -C )alkyl containing a
1 10
primary, secondary, or tertiary amine group in place of one hydrogen atom,
represented by (C -C )alkyl amine and ((C -C )alkyl) amine.
1 10 1 10 2
The term “alkyl ester” means a (C -C )alkyl containing an ester group in
1 10
place of one hydrogen atom, represented by-O(O)C-(C1-C10)alkyl.
The term “alkyl acid” means an (C -C )alkyl containing a carboxylic acid
1 10
group in place of one hydrogen atom, represented by (C -C )alkyl-COOH.
1 10
The term “aliphatic acid” means an acid of nonaromatic hydrocarbons,
represented by (C -C )alkyl-COOH and (C -C )cycloalkyl-COOH.
1 10 3 10
The term “halo” means a fluorine (F), chlorine (Cl), bromine (Br), iodine (I),
or astatine (At) ion.
The term “methoxy” means a (C1)alkyl containing an oxygen in place of one
hydrogen atom, represented by –(O)CH .
The term “polyol” means an alcohol containing multiple hydroxyl (-OH)
groups.
“S u b s t it u t e d” means the substitution of a carbon in alkyl, heterocyclic or aryl
groups with one or more non-carbon substituents. Non-carbon substituents are
selected from nitrogen, oxygen and sulfur.
“Unsubstituted” means the group is comprised of only hydrogen and carbon.
A 3 to 10 member ring means a closed ring; the 3 to 10 member ring may be
acyclic, aromatic or heterocyclic.
The term “pharmaceutically acceptable anion” means an anion that is
suitable for pharmaceutical use. Pharmaceutically acceptable anions include but are
not limited to halides, carbonate, bicarbonate, sulfate, bisulfate, hydroxide, nitrate,
persulfate, phosphate, sulfite, acetate, ascorbate, benzoate, citrate, dihydrogen citrate,
hydrogen citrate, oxalate, succinate, tartrate, taurocholate, glycocholate, and cholate.
The term “dicarbonyl" refers to an organic molecule containing two or more
adjacent carbonyl groups. Carbonyl groups, represented by C=O, can be, for
example, aldehydes, ketones, and other groups with an oxygen atom doubly bonded to
a carbon atom. Examples include but are not limited to glyoxal, methylglyoxal,
dimethyl glyoxal, and 3-deoxyglucosone.
17965367_1 (GHMatters) P41917NZ00
The term “patient” means an animal, including a human and other mammals
with a need to
Related Art
It is to be understood that, if any prior art publication is referred to herein, such
reference does not constitute an admission that the publication forms a part of the
common general knowledge in the art.
BRIEF SUMMARY OF THE INVENTION
The present disclosure relates to a compound with the structure of Formula (I):
wherein:
n is 1, 2, 3, 4 or 5;
m is 0, 1, 2, 3 or 4;
Q is H, halo or (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl,
6 14 2 9 3 10
(C -C )heterocycloalkyl,
wherein the (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or
6 14 2 9 3 10
(C -C )heterocycloalkyl is optionally substituted by one to four
groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
7 8 7 8 7 8
, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
(C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -
3 10 3 10 3 10 6
C )aryl-S-, (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-,
14 2 9 2 9
17965367_1 (GHMatters) P41917NZ00
(C -C )heteroaryl-S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-,
2 9 3 10 3 10
(C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-,
6 14 2 9
(C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-,
3 10 2 3 10 2 6 14 2
(C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-,
2 9 2 2 9 2
(C -C )heteroaryl-O S-, or R R NO S-,
2 9 2 2
wherein R and R is each independently H, (C1-C10)alkyl,
(C -C )heteroalkyl, (C -C )cycloalkyl,
2 9 3 10
(C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl;
2 9 6 14 2 9
Q is (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or (C -
6 14 2 9 3 10 2
C )heterocycloalkyl,
wherein the (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or
6 14 2 9 3 10
(C -C )heterocycloalkyl is optionally substituted by one to four
groups selected from (C1-C10)alkyl, (C2-C9)heteroalkyl,
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
7 8 7 8 7 8
, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
(C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -
3 10 3 10 3 10 6
C )aryl-S-, (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-,
14 2 9 2 9
(C2-C9)heteroaryl-S-, (C3-C10)alkyl(O)S-, (C3-C10)cycloalkyl(O)S-,
(C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-,
6 14 2 9
(C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-,
3 10 2 3 10 2 6 14 2
(C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-,
2 9 2 2 9 2
(C -C )heteroaryl-O S-, or R R NO S-,
2 9 2 2
wherein R and R is each independently H, (C -C )alkyl,
1 10
(C2-C9)heteroalkyl, (C3-C10)cycloalkyl,
(C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl;
2 9 6 14 2 9
X is CH, N, halo or CR ,
wherein R is (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
17965367_1 (GHMatters) P41917NZ00
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
, -OH, -NH ;
R is H, halo, (C -C )alkyl, (C -C )heteroalkyl, (C -C )alkylamine, or NH ;
1 10 2 9 1 10 2
R is H, halo, (C -C )alkyl, (C -C )heteroalkyl, (C -C )alkylamine, (C -
1 10 2 9 1 10 1
C )alkyl-O-, or NH ;
2
R and R are each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C1-C10)alkylamine, O-(C1-C10)alkyl, or NH2 or R and R are taken
together with the carbon to which they are attached to form a 3 to 10
member ring,
wherein the 3 to 10 member ring is optionally substituted by one to
four groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C1-C10)alkyl, COOH-(C3-C10)cycloalkyl, (C1-C10)alkyl-O-
, -OH, - NH ; and
R and R are each independently H, (C -C )alkyl, (C -C )heteroalkyl, (C -
1 10 2 9 1
C )alkylamine, O-(C -C )alkyl, or NH or R and R are taken
1 10 2
together with the carbon to which they are attached to form a 3 to 10
member ring,
wherein the 3 to 10 member ring is optionally substituted by one to
four groups selected from (C1-C10)alkyl, (C2-C9)heteroalkyl,
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
, -OH, - NH ;
or a pharmaceutically acceptable salt thereof.
In one embodiment, provided is a compound comprising the structure of
Formula (I):
17965367_1 (GHMatters) P41917NZ00
wherein:
n is 1, 2, 3, 4 or 5;
m is 0, 1, 2, 3 or 4;
Q is (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or
6 14 2 9 3 10
(C -C )heterocycloalkyl,
wherein the (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or
6 14 2 9 3 10
(C -C )heterocycloalkyl is optionally substituted by one to four
groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
7 8 7 8 7 8
, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
(C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-,
3 10 3 10 6 14
(C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-,
2 9 2 9
(C -C )heteroaryl-S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-,
2 9 3 10 3 10
(C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-,
6 14 2 9
(C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-,
3 10 2 3 10 2 6 14 2
(C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-,
2 9 2 2 9 2
(C -C )heteroaryl-O S-, or R R NO S-,
2 9 2 2
wherein R and R is each independently H, (C -C )alkyl,
1 10
(C -C )heteroalkyl, (C -C )cycloalkyl,
2 9 3 10
(C -C )heterocycloalkyl, (C -C )aryl, or (C -C )heteroaryl;
2 9 6 14 2 9
17965367_1 (GHMatters) P41917NZ00
Q is (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or (C -
6 14 2 9 3 10 2
C )heterocycloalkyl,
wherein the (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or
6 14 2 9 3 10
(C -C )heterocycloalkyl is optionally substituted by one to four
groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C2-C9)heteroaryl, (C1-C10)alkylamine, (C1-C10)alkyl-C(O)O-,
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
7 8 7 8 7 8
, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
(C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-,
3 10 3 10 6 14
(C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-,
2 9 2 9
(C -C )heteroaryl-S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-,
2 9 3 10 3 10
(C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-,
6 14 2 9
(C2-C9)heterocycloalkyl(O)S-, (C2-C9)heteroaryl(O)S-,
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-,
3 10 2 3 10 2 6 14 2
(C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-,
2 9 2 2 9 2
(C -C )heteroaryl-O S-, or R R NO S-,
2 9 2 2
wherein R and R is each independently H, (C -C )alkyl,
1 10
(C -C )heteroalkyl, (C -C )cycloalkyl,
2 9 3 10
(C -C )heterocycloalkyl, (C -C )aryl, or (C -C )heteroaryl;
2 9 6 14 2 9
X is CH or CR ,
wherein R is (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
, -OH, or -NH ;
R is H, halo, (C -C )alkyl, (C -C )heteroalkyl, (C -C )alkylamine, or NH ;
1 10 2 9 1 10 2
R is (C2-C9)heteroalkyl, (C1-C10)alkylamine, (C1-C10)alkyl-O-, or NH2;
R and R are each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )alkylamine, O-(C -C )alkyl, or NH or R and R are taken
1 10 1 10 2
together with the carbon to which they are attached to form a 3 to 10
member ring,
wherein the 3 to 10 member ring is optionally substituted by one to
four groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
17965367_1 (GHMatters) P41917NZ00
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
, -OH, or - NH ; and
R and R are each independently H, (C -C )alkyl, (C -C )heteroalkyl, (C -
1 10 2 9 1
C )alkylamine, O-(C -C )alkyl, or NH or R and R are taken
1 10 2
together with the carbon to which they are attached to form a 3 to 10
member ring,
wherein the 3 to 10 member ring is optionally substituted by one to
four groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
, -OH, or - NH2;
or a pharmaceutically acceptable salt thereof; wherein any alkyl is straight chained,
branched, or cyclic; and any heteroalkyl is straight chained, branched, or cyclic.
The present disclosure further relates to a compound of Formula (I), wherein n
is 1, 2, or 3.
The present disclosure further relates to a compound of Formula (I), wherein
m is 0, 1, or 2.
The present disclosure further relates to a compound of Formula (I), wherein n
is 1 and m is 1.
The present disclosure further relates to a compound of Formula (I), wherein
Q is H or (C -C )aryl or (C -C )heteroaryl wherein the (C -C )aryl or
6 14 2 9 6 14
(C -C )heteroaryl is optionally substituted by one to four groups selected from
(C -C )alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl, (C -C )heterocycloalkyl,
1 10 2 9 3 10 2 9
(C -C )aryl, (C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
6 14 2 9 1 10 1 10
COOH-(C1-C10)alkyl, COOH-(C3-C10)cycloalkyl, (C1-C10)alkyl-O-, -OH, -NH2,
7 8 7 8 7 8
R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, (C -C )alkyl(O)P-, (C -C )alkyl-S-,
3 3 10 3 10
(C -C )cycloalkyl-S-, (C -C )aryl-S-, (C -C )heteroalkyl-S-,
3 10 6 14 2 9
(C -C )heterocycloalkyl-S-, (C -C )heteroaryl-S-, (C -C )alkyl(O)S-,
2 9 2 9 3 10
(C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-,
3 10 6 14 2 9
(C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-, (C -C )alkyl-O S-,
2 9 2 9 3 10 2
(C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-O S-,
3 10 2 6 14 2 2 9 2
17965367_1 (GHMatters) P41917NZ00
7 8 7
(C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, wherein R
2 9 2 2 9 2 2
and R is each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl.
3 10 2 9 6 14 2 9
The present disclosure further relates to a compound of Formula (I), wherein
Q is (C -C )aryl or (C -C )heteroaryl optionally substituted by one to four groups
6 14 2 9
selected from (C -C )alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl,
1 10 2 9 3 10
(C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkylamine,
(C -C )alkyl-C(O)O-, COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl,
1 10 1 10 3 10
7 8 7 8 7 8
(C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
1 10 2 3
(C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-,
3 10 3 10 3 10 6 14
(C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-S-,
2 9 2 9 2 9
(C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-,
3 10 3 10 6 14
(C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9 2 9
(C3-C10)alkyl-O2S-, (C3-C10)cycloalkyl-O2S-, (C6-C14)aryl-O2S-,
(C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or
2 9 2 2 9 2 2 9 2
7 8 7 8
R R NO S-, wherein R and R is each independently H, (C -C )alkyl,
2 1 10
(C -C )heteroalkyl, (C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
2 9 3 10 2 9 6 14
(C -C )heteroaryl.
The present disclosure further relates to a compound of Formula (I), wherein
X is CH or N.
The present disclosure further relates to a compound of Formula (I), wherein
R is H, halo, NH , or (C -C )alkyl.
2 1 10
The present disclosure further relates to a compound of Formula (I), wherein
R is H, halo, (C -C )alkyl, or (C -C )alkyl-O-. The present invention further relates
1 10 1 10
to a compound of Formula wherein R is CH -O- or CH -CH -O-.
3 - 3 2
The present disclosure further relates to a compound of Formula (I), wherein
R and R are each H.
The present disclosure further relates to a compound of Formula (I), wherein
R and R are each H.
The present disclosure further relates to a compound of Formula (I), with the
structure of Formula (II):
17965367_1 (GHMatters) P41917NZ00
(II);
or a pharmaceutically acceptable salt thereof.
In another embodiment, there is provided a compound comprising the
structure of Formula (II):
wherein:
n is 1, 2, 3, 4 or 5;
m is 0, 1, 2, 3 or 4;
Q is (C -C )heteroaryl
wherein the (C -C )heteroaryl is optionally substituted by one to
four groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
17965367_1 (GHMatters) P41917NZ00
7 8 7 8 7 8
, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
(C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-,
3 10 3 10 6 14
(C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-,
2 9 2 9
(C -C )heteroaryl-S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-,
2 9 3 10 3 10
(C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-,
6 14 2 9
(C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9
(C3-C10)alkyl-O2S-, (C3-C10)cycloalkyl-O2S-, (C6-C14)aryl-O2S-,
(C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-,
2 9 2 2 9 2
(C -C )heteroaryl-O S-, or R R NO S-,
2 9 2 2
wherein R and R is each independently H, (C -C )alkyl,
1 10
(C -C )heteroalkyl, (C -C )cycloalkyl,
2 9 3 10
(C -C )heterocycloalkyl, (C -C )aryl, or (C -C )heteroaryl;
2 9 6 14 2 9
Q is (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or (C -
6 14 2 9 3 10 2
C9)heterocycloalkyl,
wherein the (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or
6 14 2 9 3 10
(C -C )heterocycloalkyl is optionally substituted by one to four
groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
7 8 7 8 7 8
, -OH, -NH2, R R N-, R R N(O)C-, R (O)CR N-, F3C-, NC-,
(C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-,
3 10 3 10 6 14
(C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-,
2 9 2 9
(C -C )heteroaryl-S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-,
2 9 3 10 3 10
(C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-,
6 14 2 9
(C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-,
3 10 2 3 10 2 6 14 2
(C2-C9)heteroalkyl-O2S-, (C2-C9)heterocycloalkyl-O2S-,
(C -C )heteroaryl-O S-, or R R NO S-,
2 9 2 2
wherein R and R is each independently H, (C -C )alkyl,
1 10
(C -C )heteroalkyl, (C -C )cycloalkyl,
2 9 3 10
(C -C )heterocycloalkyl, (C -C )aryl, or (C -C )heteroaryl;
2 9 6 14 2 9
X is N;
R is H or NH ; and
17965367_1 (GHMatters) P41917NZ00
R is H, halo, (C -C )alkyl, (C -C )heteroalkyl, (C -C )alkylamine, (C -
1 10 2 9 1 10 1
C )alkyl-O-, or NH ;
2
or a pharmaceutically acceptable salt thereof; wherein any alkyl is straight chained,
branched, or cyclic; and any heteroalkyl is straight chained, branched, or cyclic.
In yet another embodiment, there is provided compound having the formula:
or a pharmaceutically acceptable salt thereof.
In a further embodiment, provided is a compound selected from the group
consisting of
3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidinyl)-1H-
pyrazolyl)-3H-imidazo[4,5-b]pyridine,
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-
b]pyridinyl)pyridinyl)dimethylphosphine oxide,
3-(3-Methoxy((6-methylpyridinyl)methoxy)benzyl)(1-(piperidinyl)-1H-
pyrazolyl)-3H-imidazo[4,5-b]pyridine,
3-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-
b]pyridinyl)(piperidinyl)-1,2,4-oxadiazole,
2-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-
b]pyridinyl)(piperidinyl)-1,3,4-oxadiazole,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-
b]pyridinyl)-1H-1,2,3-triazolyl)propanamine, and
17965367_1 (GHMatters) P41917NZ00
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidinyl)-1H-
1,2,3-triazolyl)-3H-imidazo[4,5-b]pyridine.
In yet another embodiment, there is provided a compound selected from the
group consisting of
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazolyl)-1H-
benzo[d]imidazolamine
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyrimidinyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyridineyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-(2-morpholinoethyl)-1H-
pyrazolyl)-1H-benzo[d]imidazolamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-
-yl)pyridinyl)dimethylphosphine oxide,
1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidinyl)-1H-
1,2,3-triazolyl)-1H-benzo[d]imidazole,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-methylpiperazin
yl)-3H-imidazo[4,5-b]pyridine,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-
b]pyridinyl)piperidinyl)propanamine,
4-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-
b]pyridinyl)morpholine,
6-(4-Cyclopropylpiperazinyl)(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(2,7-
diazaspiro[3.5]nonanyl)-3H-imidazo[4,5-b]pyridine
(S)(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-
b]pyridinyl)pyrrolidinecarboxylic acid and
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidinyl)-1H-
pyrazolyl)-3H-imidazo[4,5-b]pyridine;
or a pharmaceutically acceptable salt thereof.
The present disclosure further relates to pharmaceutical compositions
comprising a compound of Formula (I).
17965367_1 (GHMatters) P41917NZ00
The present disclosure further relates to methods of treating inflammatory
diseases, autoimmune disease, defects of bone metabolism or cancer in a patient in
need thereof comprising administering to the patient a compound according to
Formula (I).
The present disclosure further relates to methods of treating osteoarthritis in a
patient in need thereof comprising administering to the patient a compound according
to Formula (I).
The present disclosure further relates to methods of treating pain in a patient in
need thereof comprising administering to the patient a compound according to
Formula (I).
The present disclosure further relates to methods of treating pain associated
with osteoarthritis in a patient in need thereof comprising administering to the patient
a compound according to Formula (I).
The present disclosure further relates to methods of inhibiting tropomyosin-
related kinase A in a patient comprising administering to the patient a compound
according to Formula (I).
The present disclosure further relates to methods of inhibiting tropomyosin-
related kinase B in a patient comprising administering to the patient a compound
according to Formula (I).
The present disclosure further relates to methods of inhibiting tropomyosin-
related kinase C in a patient comprising administering to the patient a compound
according to Formula (I).
The present disclosure further relates to methods of inhibiting c-FMS in a
patient comprising administering to the patient a compound according to Formula (I).
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)
Not applicable
17965367_1 (GHMatters) P41917NZ00
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to tropomyosin-related kinase inhibitors (Trk
inhibitors). This invention also relates to pharmaceutical compositions comprising
Trk inhibitors and to the use of Trk inhibitors and pharmaceutical compositions
comprising Trk inhibitors to treat disease. This invention further relates to the use of
Trk inhibitors to treat inflammatory diseases, autoimmune disease, defects of bone
metabolism and cancer. The Trk inhibitors of the present invention can be used to
treat osteoarthritis (OA), to treat pain associated with OA, and to inhibit tropomyosin-
related kinase A (TrkA), tropomyosin-related kinase B (TrkB), tropomyosin-related
kinase C (TrkC), and to inhibit c-FMS (the cellular receptor for colony stimulating
factor-1 (CSF-1)).
Tropomyosin-related kinases (Trk) are high affinity receptors activated by
solubule growth factors called neutrophins (NT). TrkA, also known as neurotrophic
tyrosine kinase receptor type 1, is activated by nerve growth factor (NGF). TrkB is
activated by brain derived growth factor and NT-4/5. TrkC is activated by NT3. The
activation of Trk leads to the activation of downstream kinases that are implicated in
cell signaling, including cell proliferation, survival, angiogenesis and metastasis. Trk
have been implicated in a number of diseases, including OA.
The invention also relates to inhibitors of c-FMS (the cellular receptor for
colony stimulating factor-1 (CSF-1). C-FMS plays a role in the regulation of
macrophage function, and is believed to play a role in inflammatory diseases,
autoimmune disease, defects of bone metabolism and cancer (Burns and Wilks, 2011,
Informa Healthcare).
OA is a prevalent and debilitating joint disease characterized by chronic pain
and destruction of articular cartilage. Recent clinical trials have confirmed a role for
blocking NGF in OA knee pain, demonstrating significant pain relief and high
responder rates in patients treated by intravenous infusion with anti-NGF blocking
antibodies (Lane, 2010, N Engl J Med). However, this modality may lead to an
increased risk for adverse events due to systemic inhibition of NGF signaling (FDA
Arthritis Advisory Committee Meeting to Discuss Safety Issues Related to the Anti-
Nerve Growth Factor Agents;
http://www.fda.gov/AdvisoryCommittees/Calendar/ucm286556.htm) Accordingly, a
novel approach toward targeting NGF-mediated OA pain has been adopted through
17965367_1 (GHMatters) P41917NZ00
the development of Trk inhibitors, specifically TrkA inhibitors, the high-affinity
receptor for NGF (Nicol, 2007, Molecular Interv). The Trk inhibitors of the present
invention are delivered locally and thereby avoid the systemic distribution observed
with intravenous anti-NGF administration. This treatment strategy provides enhanced
dosing convenience, as well greater safety by allowing for the maintenance of
physiologically necessary NGF signaling (i.e. sensory/sympathetic nerve
maintenance, angiogenesis) at non-local sites.
The Trk inhibitors of the present invention are benzimidazole derivatives. The
Trk inhibitors are small molecules for local administration.
Figure 1: Benzimidazole
This invention relates to pharmaceutical compositions comprising Trk
inhibitors. This invention also relates to methods of inhibiting Trk with Trk inhibitors
and methods of treating disease with Trk inhibitors. The invention also pertains to
methods of treating OA, methods with treating pain, and methods of treating post-
operative pain, and methods of treating pain associated with OA with Trk inhibitors.
The Trk inhibitors and the pharmaceutical compositions comprising Trk inhibitors can
be administered in multiple dosage forms, including an injection for local delivery.
The Trk inhibitors are the active pharmaceutical ingredient in pharmaceutical
compositions comprising Trk inhibitors; the Trk inhibitors can also be co-
administered and/or co-formulated with other active ingredients for the treatment of
disease, including OA and pain associated with OA.
The present invention relates to a compound with the structure of
Formula (I):
17965367_1 (GHMatters) P41917NZ00
wherein:
n is 1, 2, 3, 4 or 5;
m is 0, 1, 2, 3 or 4;
Q is H, halo or (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl,
6 14 2 9 3 10
(C -C )heterocycloalkyl,
wherein the (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or
6 14 2 9 3 10
(C -C )heterocycloalkyl is optionally substituted by one to four
groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
7 8 7 8 7 8
, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
(C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -
3 10 3 10 3 10 6
C )aryl-S-, (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-,
14 2 9 2 9
(C -C )heteroaryl-S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-,
2 9 3 10 3 10
(C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-,
6 14 2 9
(C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-,
3 10 2 3 10 2 6 14 2
(C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-,
2 9 2 2 9 2
(C -C )heteroaryl-O S-, or R R NO S-,
2 9 2 2
wherein R and R is each independently H, (C -C )alkyl,
1 10
(C -C )heteroalkyl, (C -C )cycloalkyl,
2 9 3 10
(C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl;
2 9 6 14 2 9
17965367_1 (GHMatters) P41917NZ00
Q is (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or (C -
6 14 2 9 3 10 2
C )heterocycloalkyl,
wherein the (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or
6 14 2 9 3 10
(C -C )heterocycloalkyl is optionally substituted by one to four
groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C2-C9)heteroaryl, (C1-C10)alkylamine, (C1-C10)alkyl-C(O)O-,
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
7 8 7 8 7 8
, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
(C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -
3 10 3 10 3 10 6
C )aryl-S-, (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-,
14 2 9 2 9
(C -C )heteroaryl-S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-,
2 9 3 10 3 10
(C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-,
6 14 2 9
(C2-C9)heterocycloalkyl(O)S-, (C2-C9)heteroaryl(O)S-,
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-,
3 10 2 3 10 2 6 14 2
(C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-,
2 9 2 2 9 2
(C -C )heteroaryl-O S-, or R R NO S-,
2 9 2 2
wherein R and R is each independently H, (C -C )alkyl,
1 10
(C -C )heteroalkyl, (C -C )cycloalkyl,
2 9 3 10
(C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl;
2 9 6 14 2 9
X is CH, N, halo or CR ,
wherein R is (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
, -OH, -NH ;
R is H, halo, (C -C )alkyl, (C -C )heteroalkyl, (C -C )alkylamine, or NH ;
1 10 2 9 1 10 2
R is H, halo, (C1-C10)alkyl, (C2-C9)heteroalkyl, (C1-C10)alkylamine, (C1-
C )alkyl-O-, or NH ;
2
R and R are each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )alkylamine, O-(C -C )alkyl, or NH or R and R are taken
1 10 1 10 2
together with the carbon to which they are attached to form a 3 to 10
member ring,
17965367_1 (GHMatters) P41917NZ00
wherein the 3 to 10 member ring is optionally substituted by one to
four groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
2 9 1 10 1 10
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
, -OH, - NH ; and
R and R are each independently H, (C1-C10)alkyl, (C2-C9)heteroalkyl, (C1-
C )alkylamine, O-(C -C )alkyl, or NH or R and R are taken
1 10 2
together with the carbon to which they are attached to form a 3 to 10
member ring,
wherein the 3 to 10 member ring is optionally substituted by one to
four groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
3 10 2 9 6 14
(C2-C9)heteroaryl, (C1-C10)alkylamine, (C1-C10)alkyl-C(O)O-,
COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-
1 10 3 10 1 10
, -OH, - NH ;
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the present invention relates to a compound of
Formula (I), wherein n is 1, 2, or 3. In another embodiment, the present invention
relates to a compound of Formula (I), wherein n is 1. In another embodiment, the
present invention relates to a compound of Formula (I), wherein n is 2. In yet another
embodiment, the present invention relates to a compound of Formula (I), wherein n is
In a preferred embodiment, the present invention relates to a compound of
Formula (I), wherein m is 0, 1, or 2. In another embodiment, the present invention
relates to a compound of Formula (I), wherein m is 0. In another embodiment, the
present invention relates to a compound of Formula (I), wherein m is 1. In yet
another embodiment, the present invention relates to a compound of Formula (I),
wherein m is 2.
In a preferred embodiment, the present invention relates to a compound of
Formula (I), wherein n is 1 and m is 1.
In a preferred embodiment, the present invention further relates to a compound
of Formula (I), wherein Q is H or (C -C )aryl or (C -C )heteroaryl optionally
6 14 2 9
substituted by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
17965367_1 (GHMatters) P41917NZ00
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl,
3 10 2 9 6 14 2 9
(C -C )alkylamine, (C -C )alkyl-C(O)O-, COOH-(C -C )alkyl,
1 10 1 10 1 10
7 8 7 8
COOH-(C -C )cycloalkyl, (C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-,
3 10 1 10 2
R (O)CR N-, F C-, NC-, (C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-,
3 3 10 3 10 3 10
(C -C )aryl-S-, (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-
6 14 2 9 2 9 2 9
S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-,
3 10 3 10 6 14
(C2-C9)heteroalkyl(O)S-, (C2-C9)heterocycloalkyl(O)S-, (C2-C9)heteroaryl(O)S-,
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-
3 10 2 3 10 2 6 14 2 2 9
O S-, (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, wherein
2 2 9 2 2 9 2 2
R and R is each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl. In
3 10 2 9 6 14 2 9
another embodiment, the present invention further relates to a compound of Formula
(I), wherein Q is H. In yet another embodiment, the present invention further relates
to a compound of Formula (I), wherein Q is (C6-C14)aryl optionally substituted by
one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl,
3 10 2 9 6 14 2 9
(C -C )alkylamine, (C -C )alkyl-C(O)O-, COOH-(C -C )alkyl,
1 10 1 10 1 10
7 8 7 8
COOH-(C -C )cycloalkyl, (C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-,
3 10 1 10 2
R (O)CR N-, F C-, NC-, (C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-,
3 3 10 3 10 3 10
(C -C )aryl-S-, (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-
6 14 2 9 2 9 2 9
S-, (C3-C10)alkyl(O)S-, (C3-C10)cycloalkyl(O)S-, (C6-C14)aryl(O)S-,
(C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-
3 10 2 3 10 2 6 14 2 2 9
O S-, (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, wherein
2 2 9 2 2 9 2 2
R and R is each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl. In yet
3 10 2 9 6 14 2 9
another embodiment, the present invention further relates to a compound of Formula
(I), wherein Q is (C2-C9)heteroaryl optionally substituted by one to four groups
selected from (C -C )alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl,
1 10 2 9 3 10
(C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl, (C -C )alkylamine,
2 9 6 14 2 9 1 10
(C -C )alkyl-C(O)O-, COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl,
1 10 1 10 3 10
7 8 7 8 7 8
(C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
1 10 2 3
(C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-,
3 10 3 10 3 10 6 14
(C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-S-,
2 9 2 9 2 9
17965367_1 (GHMatters) P41917NZ00
(C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-,
3 10 3 10 6 14
(C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-
3 10 2 3 10 2 6 14 2 2 9
O S-, (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, wherein
2 2 9 2 2 9 2 2
R and R is each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl.
3 10 2 9 6 14 2 9
In a preferred embodiment, the present invention further relates to a compound
of Formula (I), wherein Q is (C -C )aryl or (C -C )heteroaryl optionally substituted
6 14 2 9
by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl,
3 10 2 9 6 14 2 9
(C -C )alkylamine, (C -C )alkyl-C(O)O-, COOH-(C -C )alkyl,
1 10 1 10 1 10
7 8 7 8
COOH-(C -C )cycloalkyl, (C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-,
3 10 1 10 2
R (O)CR N-, F C-, NC-, (C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-,
3 3 10 3 10 3 10
(C6-C14)aryl-S-, (C2-C9)heteroalkyl-S-, (C2-C9)heterocycloalkyl-S-, (C2-C9)heteroaryl-
S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-,
3 10 3 10 6 14
(C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-,
3 10 2 3 10 2 6 14 2
(C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or
2 9 2 2 9 2 2 9 2
7 8 7 8
R R NO S-, wherein R and R is each independently H, (C -C )alkyl,
2 1 10
(C -C )heteroalkyl, (C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl,
2 9 3 10 2 9 6 14
(C2-C9)heteroaryl. In another embodiment, the present invention further relates to a
compound of Formula (I), wherein Q is (C -C )aryl optionally substituted by one to
6 14
four groups selected from (C -C )alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl,
1 10 2 9 3 10
(C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl, (C -C )alkylamine,
2 9 6 14 2 9 1 10
(C -C )alkyl-C(O)O-, COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl,
1 10 1 10 3 10
7 8 7 8 7 8
(C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
1 10 2 3
(C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-,
3 10 3 10 3 10 6 14
(C2-C9)heteroalkyl-S-, (C2-C9)heterocycloalkyl-S-, (C2-C9)heteroaryl-S-,
(C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-,
3 10 3 10 6 14
(C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-
3 10 2 3 10 2 6 14 2 2 9
O S-, (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, wherein
2 2 9 2 2 9 2 2
R and R is each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl. In yet
3 10 2 9 6 14 2 9
17965367_1 (GHMatters) P41917NZ00
another embodiment, the present invention further relates to a compound of Formula
(I), wherein Q is (C -C )heteroaryl optionally substituted by one to four groups
selected from (C -C )alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl,
1 10 2 9 3 10
(C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl, (C -C )alkylamine,
2 9 6 14 2 9 1 10
(C -C )alkyl-C(O)O-, COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl,
1 10 1 10 3 10
7 8 7 8 7 8
(C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
1 10 2 3
(C3-C10)alkyl(O)P-, (C3-C10)alkyl-S-, (C3-C10)cycloalkyl-S-, (C6-C14)aryl-S-,
(C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-S-,
2 9 2 9 2 9
(C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-,
3 10 3 10 6 14
(C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-
3 10 2 3 10 2 6 14 2 2 9
O S-, (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, wherein
2 2 9 2 2 9 2 2
R and R is each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl.
In a preferred embodiment, the present invention further relates to a compound
of Formula (I), wherein X is CH or N. In another embodiment, the present invention
further relates to a compound of Formula (I), wherein X is CH. In yet another
embodiment the present invention further relates to a compound of Formula (I),
wherein X is N.
In a preferred embodiment, the present invention further relates to a compound
of Formula (I), wherein R is H, halo, NH2, or (C1-C10)alkyl. In another embodiment,
the present invention further relates to a compound of Formula (I), wherein R is H.
In another embodiment, the present invention further relates to a compound of
Formula (I), wherein R is halo. In another embodiment, the present invention further
relates to a compound of Formula (I), wherein R is NH . In yet another embodiment,
the present invention further relates to a compound of Formula (I), wherein R is (C -
C )alkyl.
In a preferred embodiment, the present invention relates to a compound of
Formula (I), wherein R is H, halo, (C -C )alkyl, or (C -C )alkyl-O-. In another
1 10 1 10
embodiment, the present invention relates to a compound of Formula (I), wherein R
is H. In another embodiment, the present invention relates to a compound of Formula
(I), wherein R is halo. In another embodiment, the present invention relates to a
compound of Formula (I), wherein R is (C -C )alkyl. In another embodiment, the
1 10
present invention relates to a compound of Formula (I), wherein R is (C -C )alkyl-
1 10
17965367_1 (GHMatters) P41917NZ00
O-. In yet another embodiment, the present invention relates to a compound of
Formula (I), wherein R is CH -O- or CH -CH -O-.
3 - 3 2
In a preferred embodiment, the present invention relates to a compound of
Formula (I), wherein R and R are each H.
In a preferred embodiment, the present invention relates to a compound of
Formula (I), wherein R and R are each H.
In a preferred embodiment, present invention relates to a compound of
Formula (I), with the structure of Formula (II):
(II);
or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the present invention relates to a compound of
Formula (II), wherein n is 1, 2, or 3. In another embodiment, the present invention
relates to a compound of Formula (II), wherein n is 1. In another embodiment, the
present invention relates to a compound of Formula (II), wherein n is 2. In yet
another embodiment, the present invention relates to a compound of Formula (II),
wherein n is 3.
In a preferred embodiment, the present invention relates to a compound of
Formula (II), wherein m is 0, 1, or 2. In another embodiment, the present invention
relates to a compound of Formula (II), wherein m is 0. In another embodiment, the
present invention relates to a compound of Formula (II), wherein m is 1. In yet
another embodiment, the present invention relates to a compound of Formula (II),
wherein m is 2.
In a preferred embodiment, the present invention relates to a compound of
Formula (II), wherein n is 1 and m is 1.
17965367_1 (GHMatters) P41917NZ00
In a preferred embodiment, the present invention further relates to a compound
of Formula (II), wherein Q is H or (C -C )aryl or (C -C )heteroaryl optionally
6 14 2 9
substituted by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl,
3 10 2 9 6 14 2 9
(C -C )alkylamine, (C -C )alkyl-C(O)O-, COOH-(C -C )alkyl,
1 10 1 10 1 10
7 8 7 8
COOH-(C -C )cycloalkyl, (C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-,
3 10 1 10 2
R (O)CR N-, F3C-, NC-, (C3-C10)alkyl(O)P-, (C3-C10)alkyl-S-, (C3-C10)cycloalkyl-S-,
(C -C )aryl-S-, (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-
6 14 2 9 2 9 2 9
S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-,
3 10 3 10 6 14
(C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-
3 10 2 3 10 2 6 14 2 2 9
O S-, (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, wherein
2 2 9 2 2 9 2 2
R and R is each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl. In
another embodiment, the present invention further relates to a compound of Formula
(II), wherein Q is H. In yet another embodiment, the present invention further relates
to a compound of Formula (II), wherein Q is (C -C )aryl optionally substituted by
6 14
one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl,
3 10 2 9 6 14 2 9
(C -C )alkylamine, (C -C )alkyl-C(O)O-, COOH-(C -C )alkyl,
1 10 1 10 1 10
7 8 7 8
COOH-(C3-C10)cycloalkyl, (C1-C10)alkyl-O-, -OH, -NH2, R R N-, R R N(O)C-,
R (O)CR N-, F C-, NC-, (C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-,
3 3 10 3 10 3 10
(C -C )aryl-S-, (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-
6 14 2 9 2 9 2 9
S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-,
3 10 3 10 6 14
(C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-
3 10 2 3 10 2 6 14 2 2 9
O S-, (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, wherein
2 2 9 2 2 9 2 2
R and R is each independently H, (C1-C10)alkyl, (C2-C9)heteroalkyl,
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl. In yet
3 10 2 9 6 14 2 9
another embodiment, the present invention further relates to a compound of Formula
(II), wherein Q is (C -C )heteroaryl optionally substituted by one to four groups
selected from (C -C )alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl,
1 10 2 9 3 10
(C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl, (C -C )alkylamine,
2 9 6 14 2 9 1 10
(C -C )alkyl-C(O)O-, COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl,
1 10 1 10 3 10
17965367_1 (GHMatters) P41917NZ00
7 8 7 8 7 8
(C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
1 10 2 3
(C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-,
3 10 3 10 3 10 6 14
(C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-S-,
2 9 2 9 2 9
(C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-,
3 10 3 10 6 14
(C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-
3 10 2 3 10 2 6 14 2 2 9
O2S-, (C2-C9)heterocycloalkyl-O2S-, (C2-C9)heteroaryl-O2S-, or R R NO2S-, wherein
R and R is each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl.
3 10 2 9 6 14 2 9
In a preferred embodiment, the present invention further relates to a compound
of Formula (II), wherein Q is (C -C )aryl or (C -C )heteroaryl optionally substituted
6 14 2 9
by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl,
3 10 2 9 6 14 2 9
(C1-C10)alkylamine, (C1-C10)alkyl-C(O)O-, COOH-(C1-C10)alkyl,
7 8 7 8
COOH-(C -C )cycloalkyl, (C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-,
3 10 1 10 2
R (O)CR N-, F C-, NC-, (C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-,
3 3 10 3 10 3 10
(C -C )aryl-S-, (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-
6 14 2 9 2 9 2 9
S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-,
3 10 3 10 6 14
(C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9 2 9
(C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-
3 10 2 3 10 2 6 14 2 2 9
O2S-, (C2-C9)heterocycloalkyl-O2S-, (C2-C9)heteroaryl-O2S-, or R R NO2S-, wherein
R and R is each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl. In
3 10 2 9 6 14 2 9
another embodiment, the present invention further relates to a compound of Formula
(II), wherein Q is (C -C )aryl optionally substituted by one to four groups selected
6 14
from (C -C )alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl, (C -C )heterocycloalkyl,
1 10 2 9 3 10 2 9
(C -C )aryl, (C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-,
6 14 2 9 1 10 1 10
COOH-(C1-C10)alkyl, COOH-(C3-C10)cycloalkyl, (C1-C10)alkyl-O-, -OH, -NH2,
7 8 7 8 7 8
R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, (C -C )alkyl(O)P-, (C -C )alkyl-S-,
3 3 10 3 10
(C -C )cycloalkyl-S-, (C -C )aryl-S-, (C -C )heteroalkyl-S-,
3 10 6 14 2 9
(C -C )heterocycloalkyl-S-, (C -C )heteroaryl-S-, (C -C )alkyl(O)S-,
2 9 2 9 3 10
(C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-,
3 10 6 14 2 9
(C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-, (C -C )alkyl-O S-,
2 9 2 9 3 10 2
(C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-O S-,
3 10 2 6 14 2 2 9 2
17965367_1 (GHMatters) P41917NZ00
7 8 7
(C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, wherein R
2 9 2 2 9 2 2
and R is each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl. In yet
3 10 2 9 6 14 2 9
another embodiment, the present invention further relates to a compound of Formula
(II), wherein Q is (C -C )heteroaryl optionally substituted by one to four groups
selected from (C -C )alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl,
1 10 2 9 3 10
(C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkylamine,
(C -C )alkyl-C(O)O-, COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl,
1 10 1 10 3 10
7 8 7 8 7 8
(C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-,
1 10 2 3
(C -C )alkyl(O)P-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-,
3 10 3 10 3 10 6 14
(C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-S-,
2 9 2 9 2 9
(C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-,
3 10 3 10 6 14
(C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-,
2 9 2 9 2 9
(C3-C10)alkyl-O2S-, (C3-C10)cycloalkyl-O2S-, (C6-C14)aryl-O2S-, (C2-C9)heteroalkyl-
O S-, (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, wherein
2 2 9 2 2 9 2 2
R and R is each independently H, (C -C )alkyl, (C -C )heteroalkyl,
1 10 2 9
(C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl.
3 10 2 9 6 14 2 9
In a preferred embodiment, the present invention further relates to a compound
of Formula (II), wherein X is CH or N. In another embodiment, the present invention
further relates to a compound of Formula (II), wherein X is CH. In yet another
embodiment the present invention further relates to a compound of Formula (II),
wherein X is N.
In a preferred embodiment, the present invention further relates to a compound
of Formula (II), wherein R is H, halo, NH , or (C -C )alkyl. In another
2 1 10
embodiment, the present invention further relates to a compound of Formula (II),
wherein R is H. In another embodiment, the present invention further relates to a
compound of Formula (II), wherein R is halo. In another embodiment, the present
invention further relates to a compound of Formula (II), wherein R is NH2. In yet
another embodiment, the present invention further relates to a compound of Formula
(II), wherein R is (C -C )alkyl.
1 10
In a preferred embodiment, the present invention relates to a compound of
Formula (II), wherein R is H, halo, (C -C )alkyl, or (C -C )alkyl-O-. In another
1 10 1 10
embodiment, the present invention relates to a compound of Formula (II), wherein R
is H. In another embodiment, the present invention relates to a compound of Formula
17965367_1 (GHMatters) P41917NZ00
(II), wherein R is halo. In another embodiment, the present invention relates to a
compound of Formula (II), wherein R is (C -C )alkyl. In another embodiment, the
1 10
present invention relates to a compound of Formula (II), wherein R is (C -C )alkyl-
1 10
O-. In yet another embodiment, the present invention relates to a compound of
Formula (II), wherein R is CH -O- or CH -CH -O-.
3 - 3 2
In a preferred embodiment, the present invention further relates to a compound
of Formula (I), wherein the compound is selected from:
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-1H-benzo[d]imidazolamine
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyrimidinyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyridineyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-(2-morpholinoethyl)-
1H-pyrazolyl)-1H-benzo[d]imidazolamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-1H-
benzo[d]imidazolyl)pyridinyl)dimethylphosphine oxide,
3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-1H-benzo[d]imidazole,
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyridinyl)dimethylphosphine oxide,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-
methylpiperazinyl)-3H-imidazo[4,5-b]pyridine,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)piperidinyl)propanamine,
4-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)morpholine,
6-(4-Cyclopropylpiperazinyl)(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(2,7-
17965367_1 (GHMatters) P41917NZ00
diazaspiro[3.5]nonanyl)-3H-imidazo[4,5-b]pyridine
(S)(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyrrolidinecarboxylic acid,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine
3-(3-Methoxy((6-methylpyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
3-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,2,4-oxadiazole,
2-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,3,4-oxadiazole,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)-1H-1,2,3-triazolyl)propanamine, and
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-3H-imidazo[4,5-b]pyridine.
In a preferred embodiment, the present invention further relates to a
pharmaceutical composition comprising a compound according to Formula (I). In yet
another preferred embodiment, the present invention further relates to a
pharmaceutical composition comprising a compound according to Formula (II). In
another embodiment, the present invention further relates to a pharmaceutical
composition comprising a compound according to Formula (I) wherein the compound
is selected from:
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-1H-benzo[d]imidazolamine
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyrimidinyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyridineyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-(2-morpholinoethyl)-
1H-pyrazolyl)-1H-benzo[d]imidazolamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-1H-
benzo[d]imidazolyl)pyridinyl)dimethylphosphine oxide,
3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
17965367_1 (GHMatters) P41917NZ00
1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-1H-benzo[d]imidazole,
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyridinyl)dimethylphosphine oxide,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-
methylpiperazinyl)-3H-imidazo[4,5-b]pyridine,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)piperidinyl)propanamine,
4-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)morpholine,
6-(4-Cyclopropylpiperazinyl)(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(2,7-
diazaspiro[3.5]nonanyl)-3H-imidazo[4,5-b]pyridine
(S)(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyrrolidinecarboxylic acid,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine
3-(3-Methoxy((6-methylpyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
3-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,2,4-oxadiazole,
2-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,3,4-oxadiazole,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)-1H-1,2,3-triazolyl)propanamine, and
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-3H-imidazo[4,5-b]pyridine.
In a preferred embodiment, the present invention further relates to methods of
treating inflammatory diseases, autoimmune disease, defects of bone metabolism or
cancer comprising administering to the patient a compound according to Formula (I).
In yet another preferred embodiment, the present invention further relates to methods
17965367_1 (GHMatters) P41917NZ00
of treating inflammatory diseases, autoimmune disease, defects of bone metabolism or
cancer comprising administering to the patient a compound according to Formula (II).
In another embodiment, the present invention further relates to methods of treating
inflammatory diseases, autoimmune disease, defects of bone metabolism or cancer
comprising administering to the patient a compound according to Formula (I) wherein
the compound is selected from:
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-1H-benzo[d]imidazolamine
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyrimidinyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyridineyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-(2-morpholinoethyl)-
1H-pyrazolyl)-1H-benzo[d]imidazolamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-1H-
benzo[d]imidazolyl)pyridinyl)dimethylphosphine oxide,
3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-1H-benzo[d]imidazole,
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyridinyl)dimethylphosphine oxide,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-
methylpiperazinyl)-3H-imidazo[4,5-b]pyridine,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)piperidinyl)propanamine,
4-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)morpholine,
6-(4-Cyclopropylpiperazinyl)(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(2,7-
diazaspiro[3.5]nonanyl)-3H-imidazo[4,5-b]pyridine
17965367_1 (GHMatters) P41917NZ00
(S)(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyrrolidinecarboxylic acid,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine
3-(3-Methoxy((6-methylpyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
3-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,2,4-oxadiazole,
2-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,3,4-oxadiazole,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)-1H-1,2,3-triazolyl)propanamine, and
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-3H-imidazo[4,5-b]pyridine.
In a preferred embodiment, the present invention further relates to methods of
treating osteoarthritis comprising administering to the patient a compound according
to Formula (I). In yet another preferred embodiment, the present invention further
relates to methods of treating osteoarthritis comprising administering to the patient a
compound according to Formula (II). In another embodiment, the present invention
further relates to methods of treating osteoarthritis comprising administering to the
patient a compound according to Formula (I) wherein the compound is selected from:
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-1H-benzo[d]imidazolamine
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyrimidinyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyridineyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-(2-morpholinoethyl)-
1H-pyrazolyl)-1H-benzo[d]imidazolamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-1H-
benzo[d]imidazolyl)pyridinyl)dimethylphosphine oxide,
3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
17965367_1 (GHMatters) P41917NZ00
yl)-1H-1,2,3-triazolyl)-1H-benzo[d]imidazole,
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyridinyl)dimethylphosphine oxide,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-
methylpiperazinyl)-3H-imidazo[4,5-b]pyridine,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)piperidinyl)propanamine,
4-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)morpholine,
6-(4-Cyclopropylpiperazinyl)(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(2,7-
diazaspiro[3.5]nonanyl)-3H-imidazo[4,5-b]pyridine
(S)(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyrrolidinecarboxylic acid,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine
3-(3-Methoxy((6-methylpyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
3-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,2,4-oxadiazole,
2-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,3,4-oxadiazole,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)-1H-1,2,3-triazolyl)propanamine, and
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-3H-imidazo[4,5-b]pyridine.
In a preferred embodiment, the present invention further relates to methods of
treating pain comprising administering to the patient a compound according to
Formula (I). In an embodiment, the pain treated by the compound according to
Formula (I) is post-operative pain. In yet another preferred embodiment, the present
invention further relates to methods of treating pain comprising administering to the
17965367_1 (GHMatters) P41917NZ00
patient a compound according to Formula (II). In another embodiment, the pain
treated by the compound according to Formula (II) is post-operative pain. In another
embodiment, the present invention further relates to methods of treating pain and
methods of treating post-operative pain comprising administering to the patient a
compound according to Formula (I) wherein the compound is selected from:
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-1H-benzo[d]imidazolamine,
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyridinyl)dimethylphosphine oxide,
3-(3-Methoxy((6-methylpyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine, and
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine.
In a preferred embodiment, the present invention further relates to methods of
treating pain associated with osteoarthritis comprising administering to the patient a
compound according to Formula (I). In yet another preferred embodiment, the
present invention further relates to methods of treating pain associated with
osteoarthritis comprising administering to the patient a compound according to
Formula (II). In another embodiment, the present invention further relates to methods
of treating pain associated with osteoarthritis comprising administering to the patient
a compound according to Formula (I) wherein the compound is selected from:
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-1H-benzo[d]imidazolamine
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyrimidinyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyridineyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-(2-morpholinoethyl)-
1H-pyrazolyl)-1H-benzo[d]imidazolamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-1H-
benzo[d]imidazolyl)pyridinyl)dimethylphosphine oxide,
3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
17965367_1 (GHMatters) P41917NZ00
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-1H-benzo[d]imidazole,
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyridinyl)dimethylphosphine oxide,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-
methylpiperazinyl)-3H-imidazo[4,5-b]pyridine,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)piperidinyl)propanamine,
4-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)morpholine,
6-(4-Cyclopropylpiperazinyl)(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(2,7-
diazaspiro[3.5]nonanyl)-3H-imidazo[4,5-b]pyridine
(S)(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyrrolidinecarboxylic acid,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine
3-(3-Methoxy((6-methylpyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
3-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,2,4-oxadiazole,
2-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,3,4-oxadiazole,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)-1H-1,2,3-triazolyl)propanamine, and
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-3H-imidazo[4,5-b]pyridine.
In a preferred embodiment, the present invention further relates to methods of
inhibiting tropomyosin-related kinase A comprising administering to the patient a
compound according to Formula (I). In yet another preferred embodiment, the
17965367_1 (GHMatters) P41917NZ00
present invention further relates to methods of inhibiting tropomyosin-related kinase
A comprising administering to the patient a compound according to Formula (II). In
another embodiment, the present invention further relates to methods of inhibiting
tropomyosin-related kinase A comprising administering to the patient a compound
according to Formula (I) wherein the compound is selected from:
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-1H-benzo[d]imidazolamine
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyrimidinyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyridineyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-(2-morpholinoethyl)-
1H-pyrazolyl)-1H-benzo[d]imidazolamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-1H-
benzo[d]imidazolyl)pyridinyl)dimethylphosphine oxide,
3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-1H-benzo[d]imidazole,
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyridinyl)dimethylphosphine oxide,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-
methylpiperazinyl)-3H-imidazo[4,5-b]pyridine,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)piperidinyl)propanamine,
4-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)morpholine,
6-(4-Cyclopropylpiperazinyl)(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(2,7-
diazaspiro[3.5]nonanyl)-3H-imidazo[4,5-b]pyridine
(S)(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
17965367_1 (GHMatters) P41917NZ00
imidazo[4,5-b]pyridinyl)pyrrolidinecarboxylic acid,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine
3-(3-Methoxy((6-methylpyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
3-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,2,4-oxadiazole,
2-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,3,4-oxadiazole,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)-1H-1,2,3-triazolyl)propanamine, and
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-3H-imidazo[4,5-b]pyridine.
In a preferred embodiment, the present invention further relates to methods of
inhibiting tropomyosin-related kinase B comprising administering to the patient a
compound according to Formula (I). In yet another preferred embodiment, the
present invention further relates to methods of inhibiting tropomyosin-related kinase
B comprising administering to the patient a compound according to Formula (II). In
another embodiment, the present invention further relates to methods of inhibiting
tropomyosin-related kinase B comprising administering to the patient a compound
according to Formula (I) wherein the compound is selected from:
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-1H-benzo[d]imidazolamine
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyrimidinyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyridineyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-(2-morpholinoethyl)-
1H-pyrazolyl)-1H-benzo[d]imidazolamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-1H-
benzo[d]imidazolyl)pyridinyl)dimethylphosphine oxide,
3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
17965367_1 (GHMatters) P41917NZ00
yl)-1H-1,2,3-triazolyl)-1H-benzo[d]imidazole,
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyridinyl)dimethylphosphine oxide,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-
methylpiperazinyl)-3H-imidazo[4,5-b]pyridine,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)piperidinyl)propanamine,
4-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)morpholine,
6-(4-Cyclopropylpiperazinyl)(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(2,7-
diazaspiro[3.5]nonanyl)-3H-imidazo[4,5-b]pyridine
(S)(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyrrolidinecarboxylic acid,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine
3-(3-Methoxy((6-methylpyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
3-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,2,4-oxadiazole,
2-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,3,4-oxadiazole,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)-1H-1,2,3-triazolyl)propanamine, and
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-3H-imidazo[4,5-b]pyridine.
In a preferred embodiment, the present invention further relates to methods of
inhibiting tropomyosin-related kinase C comprising administering to the patient a
compound according to Formula (I). In yet another preferred embodiment, the
present invention further relates to methods of inhibiting tropomyosin-related kinase
C comprising administering to the patient a compound according to Formula (II). In
17965367_1 (GHMatters) P41917NZ00
another embodiment, the present invention further relates to methods of inhibiting
tropomyosin-related kinase C comprising administering to the patient a compound
according to Formula (I) wherein the compound is selected from:
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-1H-benzo[d]imidazolamine
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyrimidinyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyridineyl)-1H-
benzo[d]imidazolamine,
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-(2-morpholinoethyl)-
1H-pyrazolyl)-1H-benzo[d]imidazolamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-1H-
benzo[d]imidazolyl)pyridinyl)dimethylphosphine oxide,
3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-1H-benzo[d]imidazole,
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyridinyl)dimethylphosphine oxide,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-
methylpiperazinyl)-3H-imidazo[4,5-b]pyridine,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)piperidinyl)propanamine,
4-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)morpholine,
6-(4-Cyclopropylpiperazinyl)(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(2,7-
diazaspiro[3.5]nonanyl)-3H-imidazo[4,5-b]pyridine
(S)(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyrrolidinecarboxylic acid,
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
17965367_1 (GHMatters) P41917NZ00
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine
3-(3-Methoxy((6-methylpyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine,
3-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,2,4-oxadiazole,
2-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)(piperidinyl)-1,3,4-oxadiazole,
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)-1H-1,2,3-triazolyl)propanamine, and
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin
yl)-1H-1,2,3-triazolyl)-3H-imidazo[4,5-b]pyridine.
In a preferred embodiment, the present invention further relates to methods of
inhibiting c-FMS comprising administering to the patient a compound according to
Formula (I). In yet another preferred embodiment, the present invention further
relates to methods of inhibiting c-FMS comprising administering to the patient a
compound according to Formula (II). In another embodiment, the present invention
further relates to methods of inhibiting c-FMS comprising administering to the patient
a compound according to Formula (I) wherein the compound is selected from:
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-1H-benzo[d]imidazolamine,
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine,
(5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)pyridinyl)dimethylphosphine oxide,
3-(3-Methoxy((6-methylpyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine, and
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin
yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine.
Non-limiting examples of suitable Trk inhibitors according to Formula (I) are
presented in Table 1. It is understood that any the structures presented in Table 1 also
include pharmaceutically acceptable salts thereof. Preferred pharmaceutically
acceptable anions include but are not limited to halides, carbonate, bicarbonate,
sulfate, bisulfate, hydroxide, nitrate, persulfate, phosphate, sulfite, acetate, ascorbate,
benzoate, citrate, dihydrogen citrate, hydrogen citrate, oxalate, succinate, tartrate,
17965367_1 (GHMatters) P41917NZ00
taurocholate, glycocholate, and cholate. Most preferred pharmaceutically acceptable
anions include chloride, carbonate, and bicarbonate.
Table 1: Trk Inhibitors
Example
Compound Name Compound Structure
1-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)(1-
Ex. 3-1
methyl-1H-pyrazolyl)-1H-
benzo[d]imidazolamine
1-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)
Ex. 31
(pyrimidinyl)-1H-
benzo[d]imidazolamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
1-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)
Ex. 32
(pyridineyl)-1H-
benzo[d]imidazolamine
1-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)(1-
Ex. 33 (2-morpholinoethyl)-1H-pyrazol-
4-yl)-1H-benzo[d]imidazol
amine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
(5-(2-Amino(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-1H-
Ex. 3-3
benzo[d]imidazolyl)pyridin
yl)dimethylphosphine oxide
1-(3-Methoxy((6-
methoxypyridin
Ex. 3-4
yl)methoxy)benzyl)(pyrimidin-
-yl)-1H-benzo[d]imidazole
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(3-methoxy((6-
methoxypyridin
Ex. 3-5 yl)methoxy)benzyl)(1-
(piperidinyl)-1H-pyrazolyl)-
3H-imidazo[4,5-b]pyridine
1-(3-Methoxy((6-
methoxypyridin
Ex. 3-6 yl)methoxy)benzyl)(4-
(piperidinyl)-1H-1,2,3-triazol-
1-yl)-1H-benzo[d]imidazole
2-(1-(3-Methoxy((6-
methoxypyridin
Ex. 3-7 yl)methoxy)benzyl)-1H-
benzo[d]imidazolyl)
(piperidinyl)-1,3,4-oxadiazole
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
1-(3-Methoxy((6-
methoxypyridin
Ex. 3-8
yl)methoxy)benzyl)(piperidin-
4-yl)-1H-benzo[d]imidazole
4-(1-(3-Methoxy((6-
methoxypyridin
Ex. 3-9
yl)methoxy)benzyl)-1H-
benzo[d]imidazolyl)morpholine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
2-(1-(1-(3-Methoxy((6-
methoxypyridin
Ex. 3-10 yl)methoxy)benzyl)-1H-
benzo[d]imidazolyl)piperidin-
4-yl)propanamine
1-(3-methoxy((6-
methoxypyridin
Ex. 3-11 yl)methoxy)benzyl)(2,7-
diazaspiro[3.5]nonanyl)-1H-
benzo[d]imidazole
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
1-(1-(3-Methoxy((6-
methoxypyridin
Ex. 3-12 yl)methoxy)benzyl)-1H-
benzo[d]imidazolyl)piperidin-
4-amine
1-(3-Methoxy((6-
methoxypyridin
Ex. 3-13 yl)methoxy)benzyl)(4-
methylpiperazinyl)-1H-
benzo[d]imidazole
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
1-(2-Amino(3-methoxy((6-
methoxypyridin
Ex. 3-14 yl)methoxy)benzyl)-1H-
benzo[d]imidazolyl)
methylpiperazinone
3-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)(1-
Ex. 3-15
methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
(5-(2-Amino(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-3H-
Ex. 3-16 imidazo[4,5-b]pyridin
yl)pyridinyl)dimethylphosphine
oxide
3-(3-Methoxy((6-
methoxypyridin
Ex. 3-17 yl)methoxy)benzyl)(4-
methylpiperazinyl)-3H-
imidazo[4,5-b]pyridine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
2-(1-(3-(3-Methoxy((6-
methoxypyridin
Ex. 31 yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridin
yl)piperidinyl)propanamine
4-(3-(3-Methoxy((6-
methoxypyridin
Ex. 32 yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridin
yl)morpholine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
6-(4-Cyclopropylpiperazinyl)-
3-(3-methoxy((6-
Ex. 33 methoxypyridin
yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridine
4-(3-(3-Methoxy((6-
methoxypyridin
Ex. 34 yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)-1,4-
diazabicyclo[3.2.2]nonane
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(3-Methoxy((6-
methoxypyridin
Ex. 35 yl)methoxy)benzyl)(2,7-
diazaspiro[3.5]nonanyl)-3H-
imidazo[4,5-b]pyridine
1-(3-(3-Methoxy((6-
methoxypyridin
Ex. 36 yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridin
yl)piperidinamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
(S)(3-(3-Methoxy((6-
methoxypyridin
Ex. 37 yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridin
yl)pyrrolidinecarboxylic acid
3-(3-Methoxy((6-
methoxypyridin
Ex. 3-19 yl)methoxy)benzyl)(1-
(piperidinyl)-1H-pyrazolyl)-
3H-imidazo[4,5-b]pyridine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(3-Methoxy((6-
methylpyridin
Ex. 3-20 yl)methoxy)benzyl)(1-
(piperidinyl)-1H-pyrazolyl)-
3H-imidazo[4,5-b]pyridine
3-(3-(3-Methoxy((6-
methoxypyridin
Ex. 3-21 yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)
(piperidinyl)-1,2,4-oxadiazole
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(1-(3-Methoxy((6-
methoxypyridin
Ex. 3-22 yl)methoxy)benzyl)-1H-
benzo[d]imidazolyl)
(piperidinyl)-1,2,4-oxadiazole
2-(3-(3-Methoxy((6-
methoxypyridin
Ex. 3-23 yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)
(piperidinyl)-1,3,4-oxadiazole
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
2-(1-(3-(3-Methoxy((6-
methoxypyridin
Ex. 3-24 yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)-1H-
1,2,3-triazolyl)propanamine
3-(3-Methoxy((6-
methoxypyridin
Ex. 3-25 yl)methoxy)benzyl)(4-
(piperidinyl)-1H-1,2,3-triazol-
1-yl)-3H-imidazo[4,5-b]pyridine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
1-(3-methoxy((6-
methoxypyridin
Ex. 3-26 yl)methoxy)benzyl)(4-
methylpiperazinyl)-1H-
benzo[d]imidazolamine
1-(2-fluoromethoxy((6-
methoxypyridin
Ex. 3-27 yl)methoxy)benzyl)(4-
methylpiperazinyl)-1H-
benzo[d]imidazole
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(3-Ethoxy((6-
methoxypyridin
Ex. 3-28 yl)methoxy)benzyl)(4-
methylpiperazinyl)-3H-
imidazo[4,5-b]pyridine
1-(1-(3-Methoxy((6-
methoxypyridin
Ex. 3-29 yl)methoxy)benzyl)-1H-
benzo[d]imidazolyl)
methylpiperazinone
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(3-Methoxy((6-
methoxypyridin
Ex. 3-30 yl)methoxy)benzyl)(5-methyl-
1-azabicyclo[3.2.1]octenyl)-
3H-imidazo[4,5-b]pyridine
1-(3-methoxy((6-
methoxypyridin
Ex. 3-31 yl)methoxy)benzyl)(5-methyl-
1-azabicyclo[3.2.1]octenyl)-
1H-benzo[d]imidazole
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
7-(3-(3-methoxy((6-
methoxypyridin
Ex. 3-32 yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)
azabicyclo[3.2.1]octenol
7-(1-(3-Methoxy((6-
methoxypyridin
Ex. 3-33 yl)methoxy)benzyl)-1H-
benzo[d]imidazolyl)
azabicyclo[3.2.1]octenol
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(3-methoxy(1-(6-
methoxypyridin
Ex.3-34
yl)propoxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-
methoxypyridin
Ex. 31 yl)methoxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(3-methoxy((6-
(trifluoromethyl)pyridin
Ex. 32
yl)methoxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
3-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)be
Ex. 33 nzyl)(1-methyl-1H-pyrazol-
4-yl)-3H-imidazo[4,5-
b]pyridinamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(4-((6-cyclopropylpyridin
yl)methoxy)
Ex. 34 methoxybenzyl)(1-methyl-
1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
3-(3-methoxy((2-
methylthiazol
Ex. 35
yl)methoxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-
methoxypyridin
Ex. 3-36 yl)methoxy)benzyl)phenyl-
3H-imidazo[4,5-b]pyridin
amine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
6-(4-fluorophenyl)(3-
methoxy((6-
Ex. 31 methoxypyridin
yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-
methoxypyridin
Ex. 32 yl)methoxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-
methoxypyridin
Ex. 33 yl)methoxy)benzyl)
(pyrimidinyl)-3H-
imidazo[4,5-b]pyridinamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(3-methoxy((6-
methoxypyridin
Ex. 34 yl)methoxy)benzyl)(1,3,5-
trimethyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-
methoxypyridin
Ex. 35 yl)methoxy)benzyl)(pyridin-
4-yl)-3H-imidazo[4,5-
b]pyridinamine
3-(3-methoxy((6-
methoxypyridin
Ex. 36
yl)methoxy)benzyl)(pyridin-
3-yl)-3H-imidazo[4,5-
b]pyridinamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(3-methoxy((6-
methoxypyridin
Ex. 3-38 yl)methoxy)benzyl)(pyridin-
2-yl)-3H-imidazo[4,5-
b]pyridinamine
3-(3-methoxy((4-
(perfluoroethyl)benzyl)oxy)ben
Ex. 3-39
zyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridin-
2-amine
3-(3-methoxy((4-
(trifluoromethoxy)benzyl)oxy)
Ex. 31 benzyl)(1-methyl-1H-
pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(3-methoxy((4-
((trifluoromethyl)thio)benzyl)o
Ex. 32 xy)benzyl)(1-methyl-1H-
pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine
3-(4-((6-isopropylpyridin
yl)methoxy)
Ex. 33
methoxybenzyl)(1-methyl-
1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(3-methoxy((4-(2,2,2-
trifluoroethyl)benzyl)oxy)benz
Ex. 34 yl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridin-
2-amine
3-(3-methoxy((2-
(trifluoromethyl)thiazol
Ex. 35
yl)methoxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
6-(cyclohexylethynyl)(3-
methoxy((6-
Ex. 3-41 methoxypyridin
yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
4-(2-amino(3-methoxy
((6-methoxypyridin
Ex. 3-42 yl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)but-
3-ynol
3-(4-(cyclopropyl(6-
methoxypyridin
yl)methoxy)
Ex. 3-43
methoxybenzyl)(1-methyl-
1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
3-(3-methoxy((3-methoxy-
,6,7,8-tetrahydroisoquinolin-
Ex. 3-44
8-yl)oxy)benzyl)(1-methyl-
1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
1-(1-(3-methoxy((6-
methoxypyridin
Ex. 3-45
yl)methoxy)phenyl)ethyl)(1-
methyl-1H-pyrazolyl)-1H-
benzo[d]imidazolamine
-(4-fluorophenyl)(1-(3-
methoxy((6-
Ex. 3-46 methoxypyridin
yl)methoxy)phenyl)ethyl)-1H-
benzo[d]imidazolamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
-(4-fluorophenyl)(1-(3-
methoxy((6-
Ex. 3-47 (trifluoromethyl)pyridin
yl)methoxy)phenyl)ethyl)-1H-
benzo[d]imidazole
1-(1-(3-methoxy((6-
(trifluoromethyl)pyridin
Ex. 31
yl)methoxy)phenyl)ethyl)(1-
methyl-1H-pyrazolyl)-1H-
benzo[d]imidazole
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
4-(1-(1-(3-methoxy((6-
(trifluoromethyl)pyridin
Ex. 32
yl)methoxy)phenyl)ethyl)-1H-
benzo[d]imidazolyl)but
ynol
3-(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)ph
Ex. 3-49 enyl)ethyl)(1-methyl-1H-
pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)ph
enyl)ethyl)(1-methyl-1H-
Ex. 36a
pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine (enantiomer
3-(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)ph
enyl)ethyl)(1-methyl-1H-
Ex. 36b
pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine (enantiomer
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
2-(4-(2-Amino(1-(3-
methoxy((4-
(trifluoromethyl)benzyl)oxy)ph
Ex. 31
enyl)ethyl)-3H-imidazo[4,5-
b]pyridinyl)-1H-pyrazol
yl)ethanol
3-(1-(3-Methoxy((4-
(trifluoromethyl)benzyl)oxy)ph
Ex. 32 enyl)ethyl)(1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridin-
2-amine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(1-(3-methoxy((6-
(trifluoromethyl)pyridin
yl)methoxy)phenyl)propyl)
Ex. 3-51
(1-methyl-1H-pyrazolyl)-
3H-imidazo[4,5-b]pyridin
amine
3-(1-(3-methoxy((6-
(trifluoromethyl)pyridin
Ex. 3-52 yl)methoxy)phenyl)ethyl)(1-
methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridine
3-(1-(3-methoxy((6-
(trifluoromethyl)pyridin
Ex. 3-53 yl)methoxy)phenyl)ethyl)(1-
methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
2-(4-(2-amino(1-(3-
methoxy((6-
(trifluoromethyl)pyridin
Ex. 3-54
yl)methoxy)phenyl)ethyl)-3H-
imidazo[4,5-b]pyridinyl)-
1H-pyrazolyl)ethanol
4-(2-amino(1-(3-methoxy
((6-(trifluoromethyl)pyridin
Ex. 3-55 yl)methoxy)phenyl)ethyl)-3H-
imidazo[4,5-b]pyridinyl)but-
3-ynol
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
4-(3-(4-((6-
(difluoromethyl)pyridin
yl)methoxy)
Ex. 3-56
methoxybenzyl)-3H-
imidazo[4,5-b]pyridinyl)but-
3-ynol
3-(3-methoxy(1-(6-
methoxypyridin
Ex. 3-57
yl)ethoxy)benzyl)(1-methyl-
1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridine formate
3-(3-methoxy(1-(6-
methoxypyridin
Ex. 31 yl)ethoxy)benzyl)(1-methyl-
1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridine formate
17965367_1 (GHMatters) P41917NZ00
Example
Compound Name Compound Structure
3-(3-methoxy(1-(6-
methoxypyridin
Ex. 32 yl)ethoxy)benzyl)(6-
methoxypyridinyl)-3H-
imidazo[4,5-b]pyridine formate
6-(2-fluoropyridinyl)(3-
methoxy(1-(6-
Ex. 33
methoxypyridin
yl)ethoxy)benzyl)-3H-
imidazo[4,5-b]pyridine formate
In one embodiment, the invention relates to a pharmaceutical composition
comprising Trk inhibitors of Formula (I). In another embodiment of the invention,
the pharmaceutical composition comprising Trk inhibitors of Formula (I) are
administered in an effective amount to achieve the desired therapeutic effect. The
skilled artisan will be able to determine the effective amount of the pharmaceutical
composition comprising Trk inhibitors of Formula (I) depending on the individual and
the condition being treated.
In one embodiment of the invention, the Trk inhibitors and pharmaceutical
compositions comprising Trk inhibitors can be for use in treating pain. In another
17965367_1 (GHMatters) P41917NZ00
embodiment of the invention, the Trk inhibitors and pharmaceutical compositions
comprising Trk inhibitors can be for use in treating pain associated with osteoarthritis.
In yet another embodiment of the invention, the Trk inhibitors and pharmaceutical
compositions comprising Trk inhibitors can be for use in treating osteoarthritis.
In one embodiment of the invention, the Trk inhibitors and pharmaceutical
compositions comprising Trk inhibitors can be for use in inhibiting tropomyosin-
related kinase. In another embodiment of the invention, the Trk inhibitors and
pharmaceutical compositions comprising Trk inhibitors can be for use in inhibiting
TrkA. In another embodiment of the invention, the Trk inhibitors and pharmaceutical
compositions comprising Trk inhibitors can be for use in inhibiting TrkB In yet
another embodiment of the invention, the Trk inhibitors and pharmaceutical
compositions comprising Trk inhibitors can be for use in inhibiting TrkC
The Trk inhibitors of the present invention may be administered alone or in a
pharmaceutical composition comprising a Trk inhibitor or multiple Trk inhibitors.
Suitable pharmaceutical compositions may comprise a Trk inhibitor and one or more
pharmaceutically acceptable excipients. The form in which the Trk inhibitors are
administered, for example, powder, tablet, capsule, solution, suspension or emulsion,
depends in part on the route by which it is administered. The Trk inhibitors can be
administered, for example, orally or by injection. Suitable excipients include, but are
not limited to, are inorganic or organic materials such as gelatin, albumin, lactose,
starch, stabilizers, melting agents, emulsifying agents, salts and buffers. Suitable
pharmaceutically acceptable excipients for intra-articular formulations such as
solutions or suspensions include, but are not limited to, commercially available inert
gels or liquids.
The Trk inhibitors and pharmaceutical compositions comprising Trk inhibitors
can be administered alone or in combination with one or more additional drugs.
Additional drugs administered in combination with the Trk inhibitors and
pharmaceutical compositions comprising Trk inhibitors of the present invention
include therapies for the treatment of pain and osteoarthritis. The additional drugs
may be administered concomitantly with the Trk inhibitors and pharmaceutical
compositions comprising Trk inhibitors. The additional drugs may also be
administered in series with the Trk inhibitors and pharmaceutical compositions
comprising Trk inhibitors.
17965367_1 (GHMatters) P41917NZ00
In vitro and in vivo effects of Trk inhibitors and methods of preparing the
preferred Trk inhibitors of the invention are described in the Examples.
Examples
Example 1: In vitro Studies
Example 1- 1: TrkA Activity
Reagents and consumables were purchased from Sigma Aldrich, Carna
Biosciences, or Caliper Life Sciences. All assay reaction conditions for IC
determinations were within the linear range with respect to time and enzyme
concentration. In a 384 well polypropylene plate, TrkA (0.4 nM, Carna 08-186) was
pre-incubated in a 100 mM Hepes-NaOH pH 7.5 buffer containing 0.01% Triton X-
100, 10 mM MgCl , 0.1% BSA, 1 mM DTT, 10 μM sodium orthovanadate and 10
μM beta-glycerophosphate and compound with a concentration of 2.5 % DMSO for
minutes at room temperature. The reaction was initiated with an equal volume of
peptide substrate (Caliper Life Sciences catalog no. 760430) and ATP in the
aforementioned buffer. The final concentrations in the reaction were 200 pM TrkA,
1.5 μM peptide substrate and 55 μM ATP (ATP Km). The reaction was incubated at
room temperature for 180 minutes and terminated with a buffer containing excess
EDTA (100 mM Hepes-NaOH pH 7.5, 0.02% Brij, 0.1% CR-3, 0.36% DMSO and
100 mM EDTA). The plate was run for one cycle on a LabChip 3000 (Caliper Life
Sciences, Hopkinton, MA) in an off-chip mobility shift type assay with an upstream
voltage of – 2250 volts, a downstream voltage of -500 volts and a vacuum pressure of
-1.6 psi. The LabChip 3000 separates and measures the fluorescent signal of
fluorescein labeled peptide substrate and fluorescein labeled peptide product present
in each well. Results are expressed as percent conversion by measuring peak height
for both the substrate and product and dividing the product peak height by the sum of
peak heights for both substrate and product. On every plate 100 % inhibition (with a
saturating concentration of staurosporine) and 0 % inhibition (substrate with enzyme
and DMSO) controls were used to calculate percent inhibition of tested compounds
and a Z`prime value.
Table 2 displays the TrkA IC for selected compounds.
Example 1- 2: TrkB Activity
Reagents and consumables were purchased from Sigma Aldrich, Carna
Biosciences, or Caliper Life Sciences. All assay reaction conditions for IC
17965367_1 (GHMatters) P41917NZ00
determinations were within the linear range with respect to time and enzyme
concentration. In a 384 well polypropylene plate, TrkB (0.6 nM, Carna 08-187) was
pre-incubated in a 100 mM Hepes-NaOH pH 7.5 buffer containing 0.01% Triton X-
100, 10 mM MgCl , 0.1% BSA, 1 mM DTT, 10 uM sodium orthovanadate and 10 μM
beta-glycerophosphate and compound with a concentration of 2.5 % DMSO for 15
minutes at room temperature. The reaction was initiated with an equal volume of
peptide substrate (Caliper Life Sciences catalog no. 760430) and ATP in the
aforementioned buffer. The final concentrations in the reaction were 300 pM TrkB,
1.5 μM peptide substrate and 70 μM ATP (ATP Km). The reaction was incubated at
room temperature for 180 minutes and terminated with a buffer containing excess
EDTA (100 mM Hepes-NaOH pH 7.5, 0.02% Brij, 0.1% CR-3, 0.36% DMSO and
100 mM EDTA). The plate was run for one cycle on a LabChip 3000 (Caliper Life
Sciences, Hopkinton, MA) in an off-chip mobility shift type assay with an upstream
voltage of – 2250 volts, a downstream voltage of -500 volts and a vacuum pressure of
-1.6 psi. The LabChip 3000 separates and measures the fluorescent signal of
fluorescein labeled peptide substrate and fluorescein labeled peptide product present
in each well. Results are expressed as percent conversion by measuring peak height
for both the substrate and product and dividing the product peak height by the sum of
peak heights for both substrate and product. On every plate 100 % inhibition (with a
saturating concentration of staurosporine) and 0 % inhibition (substrate with enzyme
and DMSO) controls were used to calculate percent inhibition of tested compounds
and a Z`prime value.
Table 2 displays the TrkB IC for selected compounds.
Example 1- 3: TrkC Activity
Human TrkC, catalytic domain [456-825(end) amino acids of accession
number NP_002521.2] was expressed as N-terminal GST-fusion protein (69 kDa)
using baculovirus expression system. GST-TRKC was purified by using glutathione
sepharose chromatography and stored in 50 mM Tris-HCl, 150 mM NaCl, 0.05%
Brij35, 1 mM DTT, 10% glycerol, pH7.5 at -80C. The kinase activity was measured
by off-chip mobility shift assay. The enzyme was incubated with fluorecence-labeled
substrate, Srctide, in the presence of 100 uM of ATP (Mg/or Mn)/ATP). The
phosphorylated and unphosphorylated substrates were separated and detected by
LabChip™3000.
Table 2 displays the TrkC IC for selected compounds.
17965367_1 (GHMatters) P41917NZ00
Example 1- 4: c-FMS Activity
Reagents and consumables were purchased from Sigma Aldrich, Carna
Biosciences, or Caliper Life Sciences. All assay reaction conditions for IC
determinations were within the linear range with respect to time and enzyme
concentration. In a 384 well polypropylene plate, c-FMS (0.14 nM, Carna 08-155)
was pre-incubated in a 100 mM Hepes-NaOH pH 7.5 buffer containing 0.01% Triton
X-100, 10 mM MgCl2, 0.1% BSA, 1 mM DTT, 10 uM sodium orthovanadate and 10
μM beta-glycerophosphate and compound with a concentration of 2.5 % DMSO for
minutes at room temperature. The reaction was initiated with an equal volume of
peptide substrate (Caliper Life Sciences catalog no. 760430) and ATP in the
aforementioned buffer. The final concentrations in the reaction were 70 pM c-FMS,
1.5 μM peptide substrate and 500 μM ATP (ATP Km). The reaction was incubated at
room temperature for 120 minutes and terminated with a buffer containing excess
EDTA (100 mM Hepes-NaOH pH 7.5, 0.02% Brij, 0.1% CR-3, 0.36% DMSO and
100 mM EDTA). The plate was run for one cycle on a LabChip 3000 (Caliper Life
Sciences, Hopkinton, MA) in an off-chip mobility shift type assay with an upstream
voltage of – 2250 volts, a downstream voltage of -500 volts and a vacuum pressure of
-1.6 psi. The LabChip 3000 separates and measures the fluorescent signal of
fluorescein labeled peptide substrate and fluorescein labeled peptide product present
in each well. Results are expressed as percent conversion by measuring peak height
for both the substrate and product and dividing the product peak height by the sum of
peak heights for both substrate and product. On every plate 100 % inhibition (with a
saturating concentration of staurosporine) and 0 % inhibition (substrate with enzyme
and DMSO) controls were used to calculate percent inhibition of tested compounds
and a Z`prime value.
Table 2 displays the c-FMS IC for selected compounds.
Table 2: In vitro Results of Representative Trk Inhibitors
[TrkA, TrkB and c-FMS IC ]
Example IC TrkA IC TrkB IC TrkC IC c-FMS
50 50 50 50
No. Compound Name ( μM) ( μM) (nM) ( μM)
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)-
Ex. 3-1 5-(1-methyl-1H-pyrazolyl)-1H- 0.001 0.0005 -- 0.002
benzo[d]imidazolamine
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)-
Ex. 31 0.086 0.023 -- 0.004
-(pyrimidinyl)-1H-benzo[d]imidazolamine
Ex. 32 0.008 0.004 -- 0.002
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)-
17965367_1 (GHMatters) P41917NZ00
Example IC TrkA IC TrkB IC TrkC IC c-FMS
50 50 50 50
No. Compound Name ( μM) ( μM) (nM) ( μM)
-(pyridineyl)-1H-benzo[d]imidazolamine
1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)-
Ex. 33 5-(1-(2-morpholinoethyl)-1H-pyrazolyl)-1H- 0.003 0.001 -- 0.004
benzo[d]imidazolamine
(5-(2-Amino(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-1H-
Ex. 3-3 0.007 0.006 -- 0.001
benzo[d]imidazolyl)pyridin
yl)dimethylphosphine oxide
1-(3-Methoxy((6-methoxypyridin
Ex. 3-4 yl)methoxy)benzyl)(pyrimidinyl)-1H- 0.836 0.252 -- 0.03
benzo[d]imidazole
3-(3-methoxy((6-methoxypyridin
Ex. 3-5 yl)methoxy)benzyl)(1-(piperidinyl)-1H- 0.006 0.005 -- 0.002
pyrazolyl)-3H-imidazo[4,5-b]pyridine
1-(3-Methoxy((6-methoxypyridin
Ex. 3-6 yl)methoxy)benzyl)(4-(piperidinyl)-1H- 0.175 0.086 -- 0.006
1,2,3-triazolyl)-1H-benzo[d]imidazol
2-(1-(3-Methoxy((6-methoxypyridin
Ex. 3-7 yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)- 0.434 0.439 -- 0.028
-(piperidinyl)-1,3,4-oxadiazole
1-(3-Methoxy((6-methoxypyridin
Ex. 3-8 yl)methoxy)benzyl)(piperidinyl)-1H- 11.1 3.46 -- 0.359
benzo[d]imidazole
4-(1-(3-Methoxy((6-methoxypyridin
Ex. 3-9 yl)methoxy)benzyl)-1H-benzo[d]imidazol 0.793 0.257 -- 0.027
yl)morpholine
2-(1-(1-(3-Methoxy((6-methoxypyridin
Ex. 3-10 yl)methoxy)benzyl)-1H-benzo[d]imidazol 0.652 0.574 -- 0.013
yl)piperidinyl)propanamine
1-(3-methoxy((6-methoxypyridin
Ex. 3-11 yl)methoxy)benzyl)(2,7-diazaspiro[3.5]nonan- 0.135 0.12 -- 0.012
2-yl)-1H-benzo[d]imidazole
1-(1-(3-Methoxy((6-methoxypyridin
Ex. 3-12 yl)methoxy)benzyl)-1H-benzo[d]imidazol 1.03 0.637 -- 0.031
yl)piperidinamine
1-(3-Methoxy((6-methoxypyridin
Ex. 3-13 yl)methoxy)benzyl)(4-methylpiperazinyl)- 1.13 0.443 -- 0.032
1H-benzo[d]imidazole
1-(2-Amino(3-methoxy((6-methoxypyridin-
Ex. 3-14 3-yl)methoxy)benzyl)-1H-benzo[d]imidazol 8.98 4.37 -- 0.33
yl)methylpiperazinone
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)-
Ex. 3-15 6-(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5- 0.0003 0.0001 0.503 0.002
b]pyridinamine
(5-(2-Amino(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-
Ex. 3-16 0.0005 0.0002 -- 0.002
b]pyridinyl)pyridinyl)dimethylphosphine
oxide
3-(3-Methoxy((6-methoxypyridin
Ex. 3-17 yl)methoxy)benzyl)(4-methylpiperazinyl)- 0.179 0.066 -- 0.016
3H-imidazo[4,5-b]pyridine
17965367_1 (GHMatters) P41917NZ00
Example IC TrkA IC TrkB IC TrkC IC c-FMS
50 50 50 50
No. Compound Name ( μM) ( μM) (nM) ( μM)
2-(1-(3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin
Ex. 31 0.054 0.057 -- 0.005
yl)piperidinyl)propanamine
4-(3-(3-Methoxy((6-methoxypyridin
Ex. 32 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin 0.09 0.031 -- 0.008
yl)morpholine
6-(4-Cyclopropylpiperazinyl)(3-methoxy
Ex. 33 ((6-methoxypyridinyl)methoxy)benzyl)-3H- 0.113 0.052 -- 0.016
imidazo[4,5-b]pyridine
4-(3-(3-Methoxy((6-methoxypyridin
Ex. 34 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin 0.47 0.349 -- 0.036
yl)-1,4-diazabicyclo[3.2.2]nonane
3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(2,7-diazaspiro[3.5]nonan-
Ex. 35 0.025 0.021 -- 0.007
2-yl)-3H-imidazo[4,5-b]pyridine
1-(3-(3-Methoxy((6-methoxypyridin
Ex. 36 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin 0.232 0.133 -- 0.012
yl)piperidinamine
(S)(3-(3-Methoxy((6-methoxypyridin
Ex. 37 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin 0.008 0.013 -- 0.032
yl)pyrrolidinecarboxylic acid
3-(3-Methoxy((6-methoxypyridin
Ex. 3-19 yl)methoxy)benzyl)(1-(piperidinyl)-1H- 0.001 0.0009 -- 0.002
pyrazolyl)-3H-imidazo[4,5-b]pyridine
3-(3-Methoxy((6-methylpyridin
yl)methoxy)benzyl)(1-(piperidinyl)-1H-
Ex. 3-20 0.0009 0.0006 -- 0.003
pyrazolyl)-3H-imidazo[4,5-b]pyridine
3-(3-(3-Methoxy((6-methoxypyridin
Ex. 3-21 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin 0.026 0.024 -- 0.007
yl)(piperidinyl)-1,2,4-oxadiazole
3-(1-(3-Methoxy((6-methoxypyridin
Ex. 3-22 yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)- 0.306 0.317 -- 0.015
-(piperidinyl)-1,2,4-oxadiazole
2-(3-(3-Methoxy((6-methoxypyridin
Ex. 3-23 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin 0.051 0.057 -- 0.013
yl)(piperidinyl)-1,3,4-oxadiazole
2-(1-(3-(3-Methoxy((6-methoxypyridin
Ex. 3-24 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin 0.088 0.043 -- 0.007
yl)-1H-1,2,3-triazolyl)propanamine
3-(3-Methoxy((6-methoxypyridin
Ex. 3-25 yl)methoxy)benzyl)(4-(piperidinyl)-1H- 0.032 0.018 -- 0.003
1,2,3-triazolyl)-3H-imidazo[4,5-b]pyridine
1-(3-methoxy((6-methoxypyridin
Ex. 3-26 yl)methoxy)benzyl)(4-methylpiperazinyl)- 0.59 0.315 -- 0.03
1H-benzo[d]imidazolamine
1-(2-fluoromethoxy((6-methoxypyridin
yl)methoxy)benzyl)(4-methylpiperazinyl)-
Ex. 3-27 0.852 0.305 -- 0.379
1H-benzo[d]imidazole
3-(3-Ethoxy((6-methoxypyridin
Ex. 3-28 yl)methoxy)benzyl)(4-methylpiperazinyl)- 0.337 0.179 -- 0.012
3H-imidazo[4,5-b]pyridine
17965367_1 (GHMatters) P41917NZ00
Example IC TrkA IC TrkB IC TrkC IC c-FMS
50 50 50 50
No. Compound Name ( μM) ( μM) (nM) ( μM)
1-(1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)-
Ex. 3-29 6.02 4.28 -- 0.431
4-methylpiperazinone
3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(5-methyl
Ex. 3-30 0.201 0.118 -- 0.015
azabicyclo[3.2.1]octenyl)-3H-imidazo[4,5-
b]pyridine
1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)(5-methyl
Ex. 3-31 1.48 0.889 -- 0.161
azabicyclo[3.2.1]octenyl)-1H-
benzo[d]imidazole
7-(3-(3-methoxy((6-methoxypyridin
Ex. 3-32 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin 0.36 0.15 -- 0.041
yl)azabicyclo[3.2.1]octenol
7-(1-(3-Methoxy((6-methoxypyridin
Ex. 3-33 yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)- 1.16 0.372 -- 0.151
1-azabicyclo[3.2.1]octenol
3-(3-methoxy(1-(6-methoxypyridin
Ex.3-34 yl)propoxy)benzyl)(1-methyl-1H-pyrazol 0.032 0.026 -- 0.059
yl)-3H-imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-methoxypyridin
Ex. 31 yl)methoxy)benzyl)(1-methyl-1H-pyrazol 0.0006 0.0003 -- 0.003
yl)-3H-imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-(trifluoromethyl)pyridin
Ex. 32 yl)methoxy)benzyl)(1-methyl-1H-pyrazol 0.0002 0.0002 -- 0.005
yl)-3H-imidazo[4,5-b]pyridinamine
3-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)benzyl)(1-methyl-
Ex. 33 0.0002 0.0003 -- 0.005
1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin
amine
3-(4-((6-cyclopropylpyridinyl)methoxy)
Ex. 34 methoxybenzyl)(1-methyl-1H-pyrazolyl)- 0.0002 0.0002 -- 0.003
3H-imidazo[4,5-b]pyridinamine
3-(3-methoxy((2-methylthiazol
Ex. 35 yl)methoxy)benzyl)(1-methyl-1H-pyrazol 0.0005 0.0002 0.005
yl)-3H-imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-methoxypyridin
Ex. 3-36 yl)methoxy)benzyl)phenyl-3H-imidazo[4,5- 0.006 0.004 -- 0.007
b]pyridinamine
6-(4-fluorophenyl)(3-methoxy((6-
Ex. 31 methoxypyridinyl)methoxy)benzyl)-3H- 0.009 0.004 -- 0.009
imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-methoxypyridin
Ex. 32 yl)methoxy)benzyl)(1-methyl-1H-pyrazol 0.003 0.002 0.005
yl)-3H-imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-methoxypyridin
Ex. 33 yl)methoxy)benzyl)(pyrimidinyl)-3H- 0.051 0.016 -- 0.011
imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-methoxypyridin
Ex. 34 yl)methoxy)benzyl)(1,3,5-trimethyl-1H- 0.014 0.013 -- 0.005
pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-methoxypyridin
Ex. 35 yl)methoxy)benzyl)(pyridinyl)-3H- 0.002 0.0007 -- 0.002
imidazo[4,5-b]pyridinamine
17965367_1 (GHMatters) P41917NZ00
Example IC TrkA IC TrkB IC TrkC IC c-FMS
50 50 50 50
No. Compound Name ( μM) ( μM) (nM) ( μM)
3-(3-methoxy((6-methoxypyridin
Ex. 36 yl)methoxy)benzyl)(pyridinyl)-3H- 0.005 0.002 -- 0.006
imidazo[4,5-b]pyridinamine
3-(3-methoxy((6-methoxypyridin
Ex. 3-38 yl)methoxy)benzyl)(pyridinyl)-3H- 0.004 0.002 -- 0.005
imidazo[4,5-b]pyridinamine
3-(3-methoxy((4-
(perfluoroethyl)benzyl)oxy)benzyl)(1-methyl-
Ex. 3-39 0.0003 0.0006 -- 0.028
1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin
amine
3-(3-methoxy((4-
(trifluoromethoxy)benzyl)oxy)benzyl)(1-
Ex. 31 0.0002 0.0002 0.008
methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine
3-(3-methoxy((4-
((trifluoromethyl)thio)benzyl)oxy)benzyl)(1-
Ex. 32 0.0002 0.0006 0.018
methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine
3-(4-((6-isopropylpyridinyl)methoxy)
Ex. 33 methoxybenzyl)(1-methyl-1H-pyrazolyl)- 0.0002 0.0002 -- 0.005
3H-imidazo[4,5-b]pyridinamine
3-(3-methoxy((4-(2,2,2-
trifluoroethyl)benzyl)oxy)benzyl)(1-methyl-
Ex. 34 0.0002 0.0003 -- 0.01
1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin
amine
3-(3-methoxy((2-(trifluoromethyl)thiazol
Ex. 35 yl)methoxy)benzyl)(1-methyl-1H-pyrazol 0.0002 0.0002 -- 0.007
yl)-3H-imidazo[4,5-b]pyridinamine
6-(cyclohexylethynyl)(3-methoxy((6-
Ex. 3-41 methoxypyridinyl)methoxy)benzyl)-3H- 0.065 0.08 0.213
imidazo[4,5-b]pyridinamine
4-(2-amino(3-methoxy((6-methoxypyridin-
Ex. 3-42 3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin- 0.007 0.003 -- 0.013
6-yl)butynol
3-(4-(cyclopropyl(6-methoxypyridin
Ex. 3-43 yl)methoxy)methoxybenzyl)(1-methyl-1H- 0.058 0.051 -- 0.794
pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
3-(3-methoxy((3-methoxy-5,6,7,8-
tetrahydroisoquinolinyl)oxy)benzyl)(1-
Ex. 3-44 0.039 0.041 -- 0.765
methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine
1-(1-(3-methoxy((6-methoxypyridin
Ex. 3-45 yl)methoxy)phenyl)ethyl)(1-methyl-1H- 0.003 0.001 -- 0.073
pyrazolyl)-1H-benzo[d]imidazolamine
-(4-fluorophenyl)(1-(3-methoxy((6-
Ex. 3-46 methoxypyridinyl)methoxy)phenyl)ethyl)-1H- 0.085 0.037 -- 0.686
benzo[d]imidazolamine
-(4-fluorophenyl)(1-(3-methoxy((6-
Ex. 3-47 (trifluoromethyl)pyridin 1.24 0.427 -- 4.13
yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole
1-(1-(3-methoxy((6-(trifluoromethyl)pyridin-
Ex. 31 3-yl)methoxy)phenyl)ethyl)(1-methyl-1H- 0.102 0.014 -- 0.16
pyrazolyl)-1H-benzo[d]imidazole
4-(1-(1-(3-methoxy((6-
(trifluoromethyl)pyridin
Ex. 32 0.692 0.127 -- 4.68
yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-
-yl)butynol
17965367_1 (GHMatters) P41917NZ00
Example IC TrkA IC TrkB IC TrkC IC c-FMS
50 50 50 50
No. Compound Name ( μM) ( μM) (nM) ( μM)
3-(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)(1-
Ex. 3-49 n/d n/d -- n/d
methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine
3-(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)(1-
Ex. 36a 0.0003 0.0006 -- 0.019
methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine (enantiomer a)
3-(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)(1-
Ex. 36b 0.005 0.003 -- 0.096
methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine (enantiomer b)
2-(4-(2-Amino(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-
Ex. 31 n/d n/d -- n/d
imidazo[4,5-b]pyridinyl)-1H-pyrazol
yl)ethanol
3-(1-(3-Methoxy((4-
Ex. 32 (trifluoromethyl)benzyl)oxy)phenyl)ethyl)(1H- n/d n/d -- n/d
pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
3-(1-(3-methoxy((6-(trifluoromethyl)pyridin-
Ex. 3-51 3-yl)methoxy)phenyl)propyl)(1-methyl-1H- n/d n/d -- n/d
pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
3-(1-(3-methoxy((6-(trifluoromethyl)pyridin-
Ex. 3-52 3-yl)methoxy)phenyl)ethyl)(1-methyl-1H- 0.007 0.001 -- 0.056
pyrazolyl)-3H-imidazo[4,5-b]pyridine
3-(1-(3-methoxy((6-(trifluoromethyl)pyridin-
Ex. 3-53 3-yl)methoxy)phenyl)ethyl)(1-methyl-1H- 0.0004 0.0006 -- 0.019
pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
2-(4-(2-amino(1-(3-methoxy((6-
(trifluoromethyl)pyridin
Ex. 3-54 n/d n/d -- n/d
yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-
b]pyridinyl)-1H-pyrazolyl)ethanol
4-(2-amino(1-(3-methoxy((6-
(trifluoromethyl)pyridin
Ex. 3-55 0.001 0.001 -- 0.137
yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-
b]pyridinyl)butynol
4-(3-(4-((6-(difluoromethyl)pyridin
Ex. 3-56 yl)methoxy)methoxybenzyl)-3H-imidazo[4,5- 0.017 0.004 -- 0.025
b]pyridinyl)butynol
3-(3-methoxy(1-(6-methoxypyridin
Ex. 3-57 yl)ethoxy)benzyl)(1-methyl-1H-pyrazolyl)- 0.035 0.013 -- 0.058
3H-imidazo[4,5-b]pyridine formate
3-(3-methoxy(1-(6-methoxypyridin
Ex. 31 yl)ethoxy)benzyl)(1-methyl-1H-pyrazolyl)- 0.449 0.219 0.082
3H-imidazo[4,5-b]pyridine formate
3-(3-methoxy(1-(6-methoxypyridin
Ex. 32 yl)ethoxy)benzyl)(6-methoxypyridinyl)-3H- 0.16 0.061 -- 0.103
imidazo[4,5-b]pyridine formate
6-(2-fluoropyridinyl)(3-methoxy(1-(6-
Ex. 33 methoxypyridinyl)ethoxy)benzyl)-3H- 0.215 0.068 -- 0.102
imidazo[4,5-b]pyridine formate
n/d indicates none detected
-- indicates not tested
Example 2: In vivo Studies
17965367_1 (GHMatters) P41917NZ00
Example 2- 1: Effect of Trk Inhibitors on Reactivated Peptidoglycan-
Polysaccharide Knee Arthritis
Male Lewis rats were acclimated to the testing facility for 7 days. The rats
were housed in 5 per cage in shoe-box polycarbonate cages with wire tops, wood chip
bedding and suspended food and water bottles.
On day -21, the male Lewis rats were randomized into treatment groups by
body weight. The rats were anesthetized and injected with peptidoglycan-
polysaccharide (PGPS) into the right knee to induce PGPS arthritis. Arthritis was
reactivated on days 0 and 14 by an IV tail injection of PGPS. The animals were dosed
intra-articularly with vehicle, triamcinolone and test compound on day -7. The
treatment groups are presented in Table 3 below.
Table 3: PGPS Knee Arthritis Treatment Groups
Group Treatment Dose
Vehicle
1 N/A
(No reactivation)
2 Vehicle N/A
3 Triamcinolone 0.06 mg
3-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)(1-
4 1 mg
methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
The rats were weighed at baseline on days 0, 4, 14 and 18. Knee thickness
was measured by caliper at baseline and on days 0, 2, 4, 14, 16 and 18. Gait analysis
occurred on days 0-4 and 14-18, with video recording of selected animals on days 3
and 17. Gait analysis was performed by applying ink to the ventral surface of the foot
and documenting weight bearing during movement across paper.
The animals were terminated at day 18. Right knees were removed, trimmed
of extraneous tissue, and collected into 10% neutral buffered formalin. After two
days in the formalin buffer and three days in 10% formic acid decalcifier, the knees
were cut into two approximately equal halves in the frontal plane and processed for
paraffin embedding and stained with T.Blue. Histological examinations were
subsequently performed for bone resorption, inflammation, pannus and cartilage
damage.
Body weights, gait deficiency and caliper measurements were analyzed using
a one-way analysis of variance (1-way ANOVA) with Dunnett’s multiple comparison
post-test. Gait scores were analyzed using a Kruskal-Wallis test (non-parametric
17965367_1 (GHMatters) P41917NZ00
ANOVA) with Dunn’s multiple comparison post-test. Histopathology scores were
analyzed using a Kruskal-Wallis test (non-parametric ANOVA) with Dunn’s multiple
comparison post-test.
Vehicle control animals gained an average of approximately 96 grams of body
weight over the course of the study, which was a significant reduction from the non-
reactivated controls. There were no significant differences compared to any of the
treatment groups. Following the second reactivation, several animals developed
systemic PGPS inflammation that affected the ankles and compromised the pain
measurement. Gait scores and deficiency for the vehicle controls peaked two days
after the first reactivation and one day after the second reactivation, and were
significantly increased over the non-reactivated controls at all time points except for
the two pre-reactivation time points (days 0 and 14). The first reactivation peaked
higher, but dropped off more sharply. The pattern was reversed for knee caliper
measurements, with a much higher peak and sharper drop-off after the second
reactivation. Histopathology sections had marked to severe inflammation with
minimal to mild pannus and cartilage damage and minimal to moderate bone
resorption. All parameters were significantly increased over the non-reactivated
controls, which had minimal lesions, except for bone resorption, which ranged from
minimal to marked.
Animals treated with 0.06 mg of Triamcinolone had significantly reduced gait
scores and deficiency throughout the first reactivation (days 1-4) and on day 15, 17,
and 18 of the second reactivation. AUC values were also significantly reduced,
whether each reactivation was calculated separately (74-99%) or summed (88-92%).
Knee caliper measurements were significantly reduced on days 2, 4, 16, and 18, as
well as prior to the first reactivation on day 0, with corresponding 53-106% reductions
in the AUC. Histopathology sections had significant 61-88% reductions in all
parameters, with a significant 74% reduction in summed scores.
Animals treated with 1 mg of 3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)
(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine had significant reductions
in gait scores and deficiency throughout the first reactivation. Scores were
significantly reduced throughout the second reactivation, and reductions in deficiency
were significant on days 15, 17, and 18. AUC values for the first (92-93%) and
second (85-86%) reactivations were significantly reduced for both scores and
deficiency, and the summed AUC was significantly reduced for deficiency (84%).
17965367_1 (GHMatters) P41917NZ00
Knee caliper measurements were significantly reduced on day 14 (just prior to the
second reactivation). AUC values were generally unaffected by treatment.
Histopathology sections had significant 49-94% reductions in all parameters, with a
significant 70% reduction in summed scores.
Example 2- 2: Effect of Trk Inhibitors on Monosodium Iodoacetate Induced
Osteoarthritis
Male Wistar rats were acclimated to the testing facility for 5 days. The rats
were individually housed in micro-isolator shoe-box polycarbonate cages with cob
bedding and water bottles. Dry pelleted food of known composition and nutritional
components was provided ad libitum
Animals were randomized by treatment type using an online random number
generator. Each treatment group was assigned a number, entered into the random
number generator, recorded then translated back to the associated treatment. All
injections were given in the left leg unless the treatment indicated “Contralateral” in
which case the injection was given in the right leg. Both legs were shaved on all
animals at the time of the treatment injections to blind the test administrator.
The rats were weighed the day prior to injection with monosodium iodoacetate
(MIA), the agent used to induce osteoarthritis in the animals. The day of injection,
rats from groups 2-8 received a subcutaneous (SC) dose of buprenorphine at least one
hour prior to induction. Anesthesia induction was achieved for all groups. Naïve
animals were then placed in recovery. All other animals received an injection of
MIA. In animals receiving MIA, the hind leg was flexed and an injection of MIA (25
µL) was injected into the intra-articular space using a 27 gauge ½ inch needle.
Standard postoperative care was performed (twice daily for 48 hours).
Animals / Animals /
Group Treatment Group Time Point
1 Naïve 8 8
2 MIA / LRS* 8 8
MIA / 3-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-
3 8 8
imidazo[4,5-b]pyridinamine (100
µg) Ipsilateral
MIA / 3-(3-Methoxy((4-
4 8 8
methoxybenzyl)oxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-
17965367_1 (GHMatters) P41917NZ00
imidazo[4,5-b]pyridinamine (100
µg) Contralateral
MIA / 3-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H- 8 8
imidazo[4,5-b]pyridinamine (30
µg) Ipsilateral
MIA / 3-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-
6 8 8
imidazo[4,5-b]pyridinamine (30
µg) Contralateral
MIA / 3-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-
7 8 8
imidazo[4,5-b]pyridinamine (10
µg) Ipsilateral
MIA / 3-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-
8 8 8
imidazo[4,5-b]pyridinamine (10
µg) Contralateral
* Lactated Ringer’s Solution: injection control/placebo.
On Day 8 the test article was administered as described above. On Days -1, 7,
14, 21, 28, and 35 post-induction, weight bearing was assessed. A weight bearing
scale was utilized using a plexiglass chamber to assess the amount of weight
distributed in each hind limb. The animals were acclimated to the chamber for at least
minutes prior to testing and the weight distribution was recorded 5 times.
No adverse observations were found in body weight results due to treatment.
MIA/LRS was significantly worse than MIA/3-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine Ipsilateral 100 μg and 30 μg at day 35 (p<0.05).
3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine 100 and 30 μg Ispilateral injections were
effective throughout the four weeks following administration. The 3-(3-methoxy
((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine 10 μg Ipsilateral efficacy was observed at 2 through 4 weeks
following administration. 3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine 100 μg Contralateral did
not show systemic pain relief at any timepoint throughout the study (1-4 weeks),
17965367_1 (GHMatters) P41917NZ00
whereas 3-(3-methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine 30 μg Contralateral administration resulted in
efficacy at only the 3 week timepoint and 3-(3-methoxy((4-
methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine 10 μg Contralateral administration resulted in efficacy at 3 and 4
weeks following administration.
The animals were terminated at day 36. Both stifles were collected from each
animal; the skin was removed from the joint and the patella was removed while
leaving as much of the fat pad intact with the joint. The stifle was placed in the
appropriate cassette with rolled gauze to secure the stifle in the cassette and then
placed into 4 % Paraformaldehyde. These samples were examined histologically.
Histopathology revealed no adverse changes attributable to 3-(3-methoxy
((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine in the knee joint.
Example 3: Synthesis of Trk Inhibitors
Example 3- 1: Synthesis of 1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-
methyl-1H-pyrazolyl)-1H-benzo[d]imidazolamine
Example 3- 1- 1: Preparation of 3-Methoxy((4-
methoxybenzyl)oxy)benzonitrile
To a stirred solution of 4-hydroxymethoxybenzonitrile (2.43 g, 16.29 mmol) in
acetonitrile (75 mL) was added cesium carbonate (6.68 g, 20.50 mmol) and p-
methoxybenzyl chloride (2.81 g, 17.92 mmol). The reaction mixture was heated to
reflux and stirred. After 1 h, the mixture was allowed to cool to room temperature
and was filtered. The filtrate was concentrated to provide 4.56 g (>100 %) 3-
methoxy((4-methoxybenzyl)oxy)benzonitrile as an off-white solid. The crude
material was used without purification in the next reaction.
Example 3- 1- 2: Preparation of (3-Methoxy((4-
methoxybenzyl)oxy)phenyl)methanamine
To a stirred solution of crude 3-methoxy((4-
methoxybenzyl)oxy)benzonitrile (4.39 g, 16.29 mmol) in tetrahydrofuran (50 mL)
was added lithium aluminum hydride (0.93 g, 24.44 mmol Caution: gas evolution and
moderate exotherm). The resulting mixture was allowed to stir at room temperature.
After 1 h, the reaction mixture was cooled to 0 °C while water (930 L) was added
17965367_1 (GHMatters) P41917NZ00
slowly (gas evolution). The mixture was then treated with 1N sodium hydroxide
solution (930 L) and additional water (2.8 mL). The mixture was allowed to stir for
min, and then it was filtered through Celite with the aid of ethyl acetate. The
filtrate was dried over magenisum sulfate, filtered, and concentrated to provide 3.90 g
(86% for 2 steps) of 3-methoxy((4-methoxybenzyl)oxy)phenyl)methanamine as an
off-white solid.
Example 3- 1- 3: Preparation of 4-bromo-N-(3-methoxy((4-
methoxybenzyl)oxy)benzyl)nitroaniline
To a stirred solution of 3-methoxy((4-methoxybenzyl)oxy)phenyl)methanamine
(4.48 g, 16.39 mmol) in acetonitrile (75 mL) was added 4-bromofluoro
nitrobenzene (3.43 g, 15.61 mmol) and diisopropylethylamine (2.52 g, 19.51 mmol).
The resulting bright yellow solution was heated to reflux. After 16 h, the orange
mixture was allowed to cool to room temperature and was diluted with water. The
mixture was extracted with dichloromethane (2 x 150 mL). The combined organic
phases were dried over magnesium sulfate, filtered, and concentrated to provide 7.71
g (99%) of 4-bromo-N-(3-methoxy((4-methoxybenzyl)oxy)benzyl)nitroaniline
as an orange semi-solid.
Example 3- 1- 4: Preparation of 4-bromo-N -(3-methoxy((4-
methoxybenzyl)oxy)benzyl)benzene-1,2-diamine
To a stirred suspension of 4-bromo-N-(3-methoxy((4-methoxybenzyl)oxy)benzyl)-
2-nitroaniline (7.71 g, 16.30 mmol) in tetrahydrofuran (100 mL), ethanol (25 mL),
and water (25 mL) was added ammonium chloride (0.44 g, 8.15 mmol) and iron
powder (9.10 g, 163 mmol). The mixture was heated to reflux. After 5 h, the reaction
mixture was allowed to cool to room temperature and was filtered through Celite with
the aid of ethanol. The filtrate was concentrated, and the residue partitioned between
dichloromethane and water. The organic phase was separated, dried over magnesium
sulfate, filtered, and concentrated to provide 6.73 g (95%) of 4-bromo-N -(3-
methoxy((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine as a brown solid.
Example 3- 1- 5: Preparation of 5-bromo(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazolamine
To a stirred solution of cyanogen bromide (5.0 M in acetonitrile, 5.0 mL, 25.0 mmol)
in water (75 mL) was added a solution of 4-bromo-N -(3-methoxy((4-
methoxybenzyl)oxy)benzyl)benzene-1,2-diamine (3.40 g, 7.67 mmol) in methanol (75
17965367_1 (GHMatters) P41917NZ00
mL), acetonitrile (75 mL), and dichloromethane (25 mL). The addition of the diamine
solution was conducted over 45 min. The resulting brown solution was allowed to stir
at room temperature. After 16 h, the reaction mixture was concentrated, and the
residue was dissolved in dichloromethane. The solution was washed with 1N sodium
hydroxide solution, dried over magnesium sulfate, filtered, and concentrated to
provide 2.46 g of an orange-brown solid. Trituration of the crude material with
diethyl ether afforded 1.54 g of 5-bromo(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazolamine as an off-white solid.
Example 3- 1- 6: Preparation of 1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)-
5-(1-methyl-1H-pyrazolyl)-1H-benzo[d]imidazolamine
To a stirred suspension of 5-bromo(3-methoxy((4-methoxybenzyl)oxy)benzyl)-
1H-benzo[d]imidazolamine (0.28 g, 0.59 mmol) in 1,4-dioxane (8 mL) and water
(6 mL) was added 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole (0.15 g, 0.73 mmol), potassium phosphate (0.44 g, 2.06 mmol),
tricyclohexylphosphine (0.016 g, 0.059 mmol), and palladium(II)acetate (0.007 g,
0.029 mmol). The reaction mixture was heated to 125 °C in a microwave reactor.
After 15 min, the reaction mixture was diluted with water. The mixture was extracted
with ethyl acetate (x3), and the combined organic phases were washed with brine,
dried over magnesium sulfate, filtered, and concentrated to provide 0.33 g of a light
green solid. Chromatographic purification (Combi-Flash, 12 g SiO gold column, 1-
% 2 M ammonia in methanol/dichloromethane elute) afforded 0.13 g (48%) of the
product as an off-white solid: H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.71 (s,
1H), 7.34 – 7.24 (m, 3H), 7.05 – 6.87 (m, 6H), 6.65 – 6.60 (m, 1H), 6.50 (s, 2H), 5.11
(s, 2H), 4.90 (s, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 3.69 (s, 3H) ppm; (M+1) 470.
Example 3- 2: Synthesis of Additional Compounds from 5-bromo(3-methoxy-
4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazolamine
The following compounds were prepared using the procedure described in
Example 3- 1 by employing the appropriate boronic acid/boronate ester coupling
partner:
Example 3- 2- 1: 1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyrimidin-
-yl)-1H-benzo[d]imidazolamine
H NMR (400 MHz, DMSO-d6) δ 9.09 – 9.07 (m, 3H), 7.57 – 7.54 (m, 1H), 7.34 –
7.30 (m, 2H), 7.28 – 7.20 (m, 2H), 7.01 (d, J = 1.9 Hz, 1H), 6.98 – 6.89 (m, 3H), 6.71
17965367_1 (GHMatters) P41917NZ00
(br s, 2H), 6.66 (dd, J = 8.3, 1.9 Hz, 1H), 5.20 (s, 2H), 4.93 (s, 2H), 3.74 (s, 3H), 3.72
(s, 3H) ppm; (M+1) 468.
Example 3- 2- 2: 1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyridine
yl)-1H-benzo[d]imidazolamine
H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 4.6, 1.5 Hz, 2H), 7.66 (dd, J = 4.6,
1.6 Hz, 2H), 7.56 (d, J = 1.4 Hz, 1H), 7.36 – 7.27 (m, 3H), 7.21 (d, J = 8.2 Hz, 1H),
7.01 (d, J = 1.8 Hz, 1H), 6.98 – 6.88 (m, 3H), 6.72 – 6.64 (m, 3H), 5.20 (s, 2H), 4.93
(s, 2H), 3.74 (s, 3H), 3.72 (s, 3H) ppm; (M+1) 467.
Example 3- 2- 3: 1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-(2-
morpholinoethyl)-1H-pyrazolyl)-1H-benzo[d]imidazolamine
H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.74 (s, 1H), 7.36 – 7.27 (m, 3H),
7.07 – 7.01 (m, 2H), 6.98 (d, J = 1.9 Hz, 1H), 6.96 – 6.89 (m, 3H), 6.65 (dd, J = 8.3,
1.9 Hz, 1H), 6.54 (br s, 2H), 5.14 (s, 2H), 4.92 (s, 2H), 4.20 (t, J = 6.6 Hz, 2H), 3.74
(s, 3H), 3.71 (s, 3H), 3.59 – 3.50 (m, 4H), 2.72 (t, J = 6.6 Hz, 2H), 2.44 – 2.36 (m,
4H) ppm; (M+1) 569.
Example 3- 3: Synthesis of (5-(2-Amino(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazolyl)pyridin
yl)dimethylphosphine oxide
Example 3- 3- 1: Preparation of 4-iodo-N-(3-methoxy((4-
methoxybenzyl)oxy)benzyl)nitroaniline
To a stirred solution of 3-methoxy((4-methoxybenzyl)oxy)phenyl)methanamine
(5.02 g, 18.37 mmol) in acetonitrile (75 mL) was added 1-fluoroiodo
nitrobenzene (4.67 g, 17.49 mmol) and diisopropylethylamine (2.83 g, 21.86 mmol).
The resulting bright yellow solution was heated to reflux. After 17 h, the orange
mixture was allowed to cool to room temperature and was diluted with water. The
mixture was extracted with dichloromethane (3 x 100 mL). The combined organic
phases were dried over magnesium sulfate, filtered, and concentrated to provide 9.49
g (>100 %) of 4-iodo-N-(3-methoxy((4-methoxybenzyl)oxy)benzyl)nitroaniline
as an orange semi-solid.
Example 3- 3- 2: Preparation of 4-iodo-N -(3-methoxy((4-
methoxybenzyl)oxy)benzyl)benzene-1,2-diamine
To a stirred solution of 4-iodo-N-(3-methoxy((4-methoxybenzyl)oxy)benzyl)
nitroaniline (9.10 g, 17.49 mmol) in tetrahydrofuran (50 mL), ethanol (50 mL), and
water (10 mL) was added ammonium chloride (7.48 g, 139.9 mmol) and iron (II)
17965367_1 (GHMatters) P41917NZ00
sulfate heptahydrate (14.59 g, 52.47 mmol). The bright orange suspension was
treated with zinc (3.43 g, 52.47 mmol). The mixture was gradually warmed to reflux.
After 3.5 h, the color of the reaction mixture had turned from orange to olive-green.
At this point the recation mixture was allowed to cool to room temperature. The
mixture was filtered through Celite, and the filtercake was washed with methanol.
The filtrate concentrated, the residue was suspended in water. The aqueous mixture
was extracted with chloroform (x 3). The combined organic phases were dried over
magnesium sulfate, filtered, and concentrated to afford 8.32 g (97 %) of 4-iodo-N -(3-
methoxy((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine as a tan solid.
Example 3- 3- 3: Preparation of 5-iodo(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazolamine
To a stirred suspension of 4-iodo-N -(3-methoxy((4-
methoxybenzyl)oxy)benzyl)benzene-1,2-diamine (8.32 g, 16.97 mmol) in
dichloromethane (100 mL) and methanol (50 mL) was added cyanogen bromide
solution (5.0 M in acetonitrile, 17.0 mL, 85.00 mmol). The resulting brown reaction
mixture was allowed to stir at room temperature. After 16 h, the mixture was treated
with 1 N sodium hydroxide solution (250 mL) and was allowed to stir at room
temperature. After 15 min, a precipitate formed. The solids were isolated by
filtration, washed with water, and dried to afford 4.42 g (51%) of 5-iodo(3-
methoxy((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazolamine as a tan
solid.
Example 3- 3- 4: Preparation of 5-(6-chloropyridinyl)(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazolamine
To a stirred suspension of 5-iodo(3-methoxy((4-methoxybenzyl)oxy)benzyl)-
1H-benzo[d]imidazolamine (0.40 g, 0.78 mmol) in 1,4-dioxane (10 mL) and water
(4 mL) was added (6-chloropyridinyl)boronic acid (0.14 g, 0.89 mmol), potassium
phosphate (0.58 g, 2.72 mmol), tricyclohexylphosphine (0.044 g, 0.16 mmol), and
palladium(II)acetate (0.017 g, 0.078 mmol). The reaction mixture was heated to 125
°C in a microwave reactor. After 15 min, the reaction mixture was diluted with water.
The mixture was extracted with chloroform (x 3). The combined organic phases were
dried over magnesium sulfate, filtered, and concentrated to provide 0.43 g of a brown
solid. Chromatographic purification (Combi-Flash, 24 g SiO gold column, 5-10%
methanol/dichloromethane elute) afforded 0.23 g (58%) of 5-(6-chloropyridinyl)
17965367_1 (GHMatters) P41917NZ00
(3-methoxy((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazolamine as a
light yellow solid.
Example 3- 3- 5: Preparation of (5-(2-Amino(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazolyl)pyridin
yl)dimethylphosphine oxide
To a stirred suspension of 5-(6-chloropyridinyl)(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazolamine (0.15 g, 0.30 mmol) in
1,4-dioxane (4 mL) was added dimethylphosphine oxide (0.029 g, 0.37 mmol), 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene (0.035 g, 0.060 mmol), palladium(II)
acetate (0.007 g, 0.030 mmol), and cesium carbonate (0.20 g, 0.60 mmol). The
reaction mixture was heated to 150 °C in a microwave reactor. After 45 min,
additional portions of dimethylphophine oxide (0.029 g, 0.37 mmol), 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene (0.035 g, 0.060 mmol), and
palladium(II) acetate (0.007 g, 0.030 mmol) were added. The reaction mixture was
subjected to a second round of heating in the microwave reactor (45 min, 150 °C).
After the second heating cycle, the reaction mixture was diluted with water and was
extracted with chloroform (x 3). The combined organic phases were dried over
magnesium sulfate, filtered, and concentrated to provide 0.24 g of a bright yellow
solid. Chromatographic purification (Combi-Flash, 12 g SiO2 gold column, 5-10%
2M ammonia in methanol/dichloromethane elute) afforded 0.052 g (32%) of the
product as a yellow solid: H NMR (400 MHz, DMSO-d6) δ H NMR (400 MHz,
DMSO) δ 9.03 (d, J = 1.9 Hz, 1H), 8.22 – 8.14 (m, 1H), 7.95 (dd, J = 8.2, 4.9 Hz,
1H), 7.52 (s, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.28 – 7.19 (m, 2H), 7.02 (d, J = 1.9 Hz,
1H), 6.96 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.71 – 6.64 (m, 3H), 5.20 (s,
2H), 4.93 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 1.68 (d, J = 13.5 Hz, 6H) ppm; (M+1) =
543.
Example 3- 4: Synthesis of 1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(pyrimidinyl)-1H-benzo[d]imidazole
Example 3- 4- 1: Preparation of tert-butyl 3-methoxy((6-methoxypyridin
yl)methoxy)benzylcarbamate
To a stirred solution of tert-butyl 4-hydroxymethoxybenzylcarbamate (22.44 g,
88.59 mmol) in acetonitrile (250 mL) was added potassium carbonate (30.61 g, 221.5
mmol) and 5-(chloromethyl)methoxypyridine hydrochloride (18.33 g, 94.46
mmol). The resulting mixture was heated to reflux and stirred. After 23 h, the light
17965367_1 (GHMatters) P41917NZ00
green suspension was allowed to cool to room temperature and was diluted with water
(600 mL), resulting in the formation of a precipitate. The solids were isolated by
filtration and washed with water. The moist solids were dissolved in dichloromethane
(300 mL), and a small amount of water separated and was removed. The organic
phase was dried over magnesium sulfate, filtered, and concentrated to provide 31.92 g
(96%) of tert-butyl 3-methoxy((6-methoxypyridinyl)methoxy)benzylcarbamate
as an off-white solid.
Example 3- 4- 2: Preparation of (3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)methanamine
To a stirred solution of tert-butyl 3-methoxy((6-methoxypyridin
yl)methoxy)benzylcarbamate (31.92 g, 85.25 mmol) in dichloromethane (100 mL)
was added trifluoroacetic acid (75 mL, 973.5 mmol). The resulting yellow solution
was allowed to stir at room temperature. After 2 h, the reaction mixture was
concentrated to dryness, and the residue was dissolved in water (250 mL). The acidic
solution was extracted with diethyl ether (2 x 125 mL; organic phases discarded).
The aqueous phase was then made basic with concentrated ammonium hydroxide.
The basic aqueous phase was then extracted with dichloromethane (2 x 200 mL). The
combined organic phases were dried over magnesium sulfate, filtered, and
concentrated to provide 21.46 g (92%) of (3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)methanamine as an off-white solid.
Example 3- 4- 3: Preparation of 4-iodo-N-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)nitroaniline
To a stirred solution of (3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)methanamine (5.00 g, 18.23 mmol) in acetonitrile (75 mL) was
added 1-fluoroiodonitrobenzene (4.55 g, 17.04 mmol) and
diisopropylethylamine (3.30 g, 25.56 mmol). The yellow solution was heated to
reflux and stirred. After 4 h, the orange-brown mixture was allowed to cool to room
temperature and was diltued with water (150 mL). The resulting bright orange
precipitate was isolated by filtration and washed with water. The moist solids were
dissolved in dichloromethane, and a small amount of water separated and was
removed. The organic phase was dried over magnesium suflate, filtered, and
concentrated to provide 7.10 g (80%) of 4-iodo-N-(3-methoxy((6-methoxypyridin-
3-yl)methoxy)benzyl)nitroaniline as a bright orange solid.
17965367_1 (GHMatters) P41917NZ00
Example 3- 4- 4: Preparation of 4-iodo-N -(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)benzene-1,2-diamine
To a stirred solution of 4-iodo-N-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)nitroaniline (7.10 g, 13.62 mmol) in tetrahydrofuran (100 mL),
methanol (50 mL), and water (10 mL) was added ammonium chloride (5.83 g, 109.0
mmol) and iron (II) sulfate heptahydrate (13.25 g, 47.67 mmol). The bright orange
suspension was treated with zinc (3.12 g, 47.67 mmol). The mixture was gradually
warmed to reflux. After 20 min, the color of the reaction mixture had turned from
orange to olie-green. At this point the recation mixture was allowed to cool to room
temperature. The mixture was filtered through Celite, and the filtercake was washed
with chloroform. The filtrate was then washed with 5N ammonium hydroxide
solution (75 mL). The organic phase was dried over magnesium sulfate, filtered, and
concentrated to provide 6.49 g of 4-iodo-N -(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)benzene-1,2-diamine as a tan solid.
Example 3- 4- 5: Preparation of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazole
To a stirred suspension of 4-iodo-N -(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)benzene-1,2-diamine in ethanol (100 mL) was added triethyl
orthoformate (4.45 g, 30.03 mmol) and p-toluenesulfonic acid monohydrate (0.075 g,
0.39 mmol). As the resulting mixture was warmed to reflux, the solids gradually
dissolved to provide an orange solution. After 45 min, the reaction mixture was
allowed to cool to room temperature, resulting in the formation of a precipitate.
Water (250 mL) was added to the mixture, and the solids were isolated by filtration.
The moist solids were dissolved in ethyl acetate (250 mL), and this solution was
washed with brine, dried over magnesium sulfate, fitlered, and concentrated to
provide 5.99 g (91%) of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazole as a tan solid.
Example 3- 4- 6: Preparation of 1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(pyrimidinyl)-1H-benzo[d]imidazole
To a suspension of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.37 g, 0.74 mmol) in 1,4-dioxane (10
mL) and water (4 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan
yl)pyrimidine (0.19 g, 0.93 mmol), potassium phosphate (0.55 g, 2.60 mmol),
tricyclohexylphosphine (0.021 g, 0.074 mmol), and palladium(II)acetate (0.008 g,
17965367_1 (GHMatters) P41917NZ00
0.037 mmol). The reaction mixture was heated to 125 °C in a microwave reactor.
After 15 min, the reaction mixture was diluted with water. The mixture was extracted
with chloroform (x3), and the combined organic phases were dried over magnesium
sulfate, filtered, and concentrated to provide 0.45 g of a light green solid.
Chromatographic purification (Combi-Flash, 12 g SiO gold column, 1-5%
methanol/dichloromethane elute) afforded 0.14 g (40%) of the product as an off-white
solid: H NMR (400 MHz, DMSO-d6) δ 9.17 – 9.14 (m, 3H), 8.50 (s, 1H), 8.20 (d, J
= 2.5, 1H), 8.12 (d, J = 1.7, 1H), 7.77 – 7.70 (m, 2H), 7.65 (dd, J = 8.4, 1.7 Hz, 1H),
7.12 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.87 – 6.80 (m, 2H), 5.45 (s, 2H),
4.97 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H) ppm; (M+1) = 454.
Example 3- 5: Synthesis of 3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)-
6-(1-(piperidinyl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine
3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidinyl)-1H-pyrazol-
4-yl)-3H-imidazo[4,5-b]pyridine was prepared from 5-iodo(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazole and tert-butyl 4-(4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazolyl)piperidine
carboxylate according to the procedure described in Example 3- 4- 6 for the synthesis
of Example 3- 4. The final product was obtained after removal of the carbamate
protecting under acidic conditions: H NMR (500 MHz, CDCl ) 8.20 (d, J = 2.0 Hz,
1H), 7.93 (s, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.68 (dd, J = 8.5, 2.0 Hz,
1H), 7.41 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.76
(d, J = 8.5 Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H), 5.29 (s, 2H), 5.04 (s, 2H), 4.29-4.25 (m,
1H), 3.95 (s, 3H), 3.79 (s, 3H), 3.29-3.27 (m, 2H), 2.83-2.78 (m, 2H), 2.23-2.21 (m,
2H), 1.99-1.85 (m, 2H) ppm; (M+1) = 525.
Example 3- 6: Synthesis of 1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(4-(piperidinyl)-1H-1,2,3-triazolyl)-1H-
benzo[d]imidazole
To a suspension of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.32 g, 0.63 mmol) in dimethyl sulfoxide
(4 mL) and water (1 mL) was added 3-ethynylpiperidine hydrochloride (0.11 g, 0.75
mmol), sodium azide (0.051g, 0.79 mmol), L-ascorbic acid sodium salt (0.025 g, 0.13
mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.023 mg, 0.158 mmol),
potassium carbonate (0.13 g, 0.95 mmol), and copper(I) iodide (0.024 g, 0.13 mmol).
The resulting blue mixture was allowed to stir at room temperature. After 16 h, the
17965367_1 (GHMatters) P41917NZ00
yellow mixture was diluted with 5N ammonium hydroxide solution and extracted
with chloroform (2 x 30 mL). The combined organic phases were dried over
magnesium sulfate, filtered, and concentrated to provide 0.53 g of a yellow oil.
Chromatographic purification (Combi-Flash, 24 g SiO gold column, 1-10% 2M
ammonia in methanol/dichloromethane elute) afforded 0.15 g (45%) of the product as
a white foamy solid: H NMR (400 MHz, DMSO-d ) δ 8.61 – 8.53 (m, 2H), 8.20 (d, J
= 2.4 Hz, 1H), 8.11 (d, J = 1.9 Hz, 1H), 7.79 – 7.71 (m, 3H), 7.12 (d, J = 1.9 Hz, 1H),
7.03 (d, J = 8.2 Hz, 1H), 6.89 – 6.80 (m, 2H), 5.46 (s, 2H), 4.97 (s, 2H), 3.84 (s, 3H),
3.73 (s, 3H), 3.25 – 3.16 (m, 1H), 3.01 – 2.91 (m, 1H), 2.90 – 2.80 (m, 1H), 2.68 –
2.51 (m, 2H), 2.12 – 2.03 (m, 1H), 1.72 – 1.44 (m, 3H) ppm; (M+1) = 526.
Example 3- 7: Synthesis of 2-(1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)(piperidinyl)-1,3,4-
oxadiazole
Example 3- 7- 1: Preparation of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolecarbonitrile
To a stirred solution of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazole (1.00 g, 1.99 mmol) in N,N-
dimethylformamide (20 mL) was added zinc(II) cyanide (0.64 g, 3.52 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.46 g, 0.40 mmol) and potassium
carbonate (0.63 g, 4.54 mmol). The mixture was heated to 150 C. After 4 h, the
mixture was allowed to cool to room temperature and was concentrated. The residue
was purified by silica gel chromatography (2% methanol/dichloromethane elute) to
give 0.70 g (87%) of 1-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)-1H-
benzo[d]imidazolecarbonitrile as a yellow solid.
Example 3- 7- 2: Preparation of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolecarboxylic acid
To a solution of 1-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)-1H-
benzo[d]imidazolecarbonitrile (0.70 g, 1.75 mmol) in 1,4-dioxane (10 mL) was
added 50% sodium hydroxide solution (20 mL). The resulting mixture was heated to
reflux and stirred. After 48 h, the reaction mixture was allowed to cool to room
temperature and was extracted with 10% methanol in dichloromethane. The extracts
were washed with brine, dried and concentrated. The residue was purified by Prep-
HPLC to afford 0.50 g (68%) of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolecarboxylic acid as a light yellow solid.
17965367_1 (GHMatters) P41917NZ00
Example 3- 7- 3: Preparation of tert-butyl 4-(2-(1-(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazole
carbonyl)hydrazinecarbonyl)piperidinecarboxylate
To a solution of 1-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)-1H-
benzo[d]imidazolecarboxylic acid (0.30 g, 0.72 mmol) in dichloromethane was
added tert-butyl 4-(hydrazinecarbonyl)piperidinecarboxylate (0.24 g, 0.98 mmol),
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid
hexafluorophosphate (0.34 g, 0.89 mmol), diisopropylamine (0.19 g, 1.47 mmol).
The resulting mixture was allowed to stir at room temperature. After 16 h, the mixture
was concentracted and the residue was purified by silica gel chromatography (2%
methanol/dichloromethane elute) to afford 0.30 g (65%) tert-butyl 4-(2-(1-(3-
methoxy((6-methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazole
carbonyl)hydrazinecarbonyl)piperidinecarboxylate as a yellow solid.
Example 3- 7- 4: Preparation of tert-butyl 4-(5-(1-(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazolyl)-1,3,4-
oxadiazolyl)piperidinecarboxylate
To a stirred mixture of tert-butyl 4-(2-(1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolecarbonyl)hydrazinecarbonyl)piperidine-
1-carboxylate (0.18 g, 0.28 mmol) in 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane
2,4,6-trioxide (T P) (2.70 g, 8.49 mmol) was added triethylamine (0.42 g, 4.20
mmol). The resulting mixture was heated 120 C and stirred. After 16 h, the mixture
was extracted with dichloromethane. The extracts were washed with brine, dried and
concentrated. The residue was purified by silica gel chromatography (1%
methanol/dichloromethane elute) to afford 0.14 g (70%) of tert-butyl 4-(5-(1-(3-
methoxy((6-methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazolyl)-
1,3,4-oxadiazolyl)piperidinecarboxylate as a yellow solid.
Example 3- 7- 5: Preparation of 2-(1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)(piperidinyl)-1,3,4-oxadiazol
To a -20 °C solution of tert-butyl 4-(5-(1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)-1,3,4-oxadiazolyl)piperidine
carboxylate (0.090 mg, 0.14 mmol) in dichloromethane (10 mL) was added
trifluoroacetic acid (1.0 mL). The resulting mixture was stirred at -20 C. After 1 h,
the mixture was concentrated. The residue was purified by Prep-HPLC to afford
0.010 g (14%) of the product as a yellow solid: H NMR (500 MHz, CDCl ) 8.43 (s,
17965367_1 (GHMatters) P41917NZ00
1H), 8.19 (d, J = 1.0 Hz, 1H), 8.02-8.01 (m, 2H), 7.67 (dd, J = 8.5, 2.0 Hz, 1H), 7.42
(d, J = 8.5 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.76 – 6.72 (m, 3H), 5.32 (s, 2H), 5.03
(s, 2H), 3.93 (s, 3H), 3.78 (s, 3H), 3.31 – 3.29 (m, 2H), 3.23 – 3.21 (m, 1H), 2.92 –
2.88 (m, 2H), 2.23 – 2.21 (m, 2H), 2.02 – 1.98 (m, 2H) ppm; (M+1) = 527.
Example 3- 8: Synthesis of 1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(piperidinyl)-1H-benzo[d]imidazole
Example 3- 8- 1: Preparation of tert-butyl 4-(1-(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazolyl)-5,6-
dihydropyridine-1(2H)-carboxylate
To a stirred solution of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.801 g, 1.60 mmol) in 1,4-dioxane (10
mL) and 2 M sodium carbonate solution (3.2 mL) was added 4-(4, 4, 5, 5-tetramethyl-
1, 3, 2-dioxaborolanyl)-5, 6-dihydropyridine-1(2H)-carboxylate (0.65 mg, 2.10
mmol). The mixture was treated with [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.12 mg, 0.16 mmol) and
heated to 100 C . After 16 h, the reaction mixture was allowed to cool to room
temperature and filtered. The filtrate was diluted with water (30 mL) and extracted
with dichloromethane (3 x 50 mL). The combined organic layers were washed with
brine (30 mL x 2), dried over sodium sulfate, and concentrated. The residue was
purified by silica gel chromatography (5% methanol/dichloromethane elute) to afford
0.79 mg (89%) of tert-butyl 4-(1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)-5,6-dihydropyridine-1(2H)-
carboxylate as a light yellow solid.
Example 3- 8- 2: Preparation of tert-butyl 4-(1-(4-hydroxymethoxybenzyl)-
1H-benzo[d]imidazolyl)piperidinecarboxylate
To a stirred solution of tert-butyl 4-(1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)-5,6-dihydropyridine-1(2H)-
carboxylate (0.56 g, 1.00 mmol) in methanol (15 mL) was added ammonium formate
(0.63 g, 10 mmol) and palladium on carbon (0.30 g). The reaction mixture was
heated to 60 C under H . After 16 h, the reaction mixture was allowed to cool to
room temperature and was filtered through Celite. The filtrate was concentrated. The
residue was purified by silica gel chromatography (5% methanol/dichloromethane
elute) to afford 0.42 g (96%) of tert-butyl 4-(1-(4-hydroxymethoxybenzyl)-1H-
benzo[d]imidazolyl)piperidinecarboxylate as a light yellow solid.
17965367_1 (GHMatters) P41917NZ00
Example 3- 8- 3: Preparation of tert-butyl 4-(1-(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazolyl)piperidine
carboxylate
To a stirred solution of tert-butyl 4-(1-(4-hydroxymethoxybenzyl)-1H-
benzo[d]imidazolyl)piperidinecarboxylate (0.51 g, 1.16 mmol) in N,N-
dimethylformamide (5 mL) was added potassium carbonate (0.32 g, 2.32 mmol). The
mixture was treated with a solution of 5-(chloromethyl)methoxypyridine (219 mg,
1.39 mmol) in N,N-dimethylformamide (2 mL) added dropwise. The mixture was
stirred at room temperature. After 16 h, the mixture was diluted with saturated
ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 x 30 mL).
The combined organic layers were washed with brine (3 x 10 mL), dried over sodium
sulfate, filtered and concentrated to afford 0.53 g (82%) of tert-butyl 4-(1-(3-
methoxy((6-methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazol
yl)piperidinecarboxylate as a light yellow solid.
Example 3- 8- 4: Preparation of 1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(piperidinyl)-1H-benzo[d]imidazole
To a stirred and cooled (5 °C) solution of tert-butyl 4-(1-(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazolyl)piperidine
carboxylate (0.28 g, 0.51 mmol) in dichloromethane (1 mL) was added trifluoroacetic
acid (1 mL). The resulting mixture was allowed to warm room temperature and stir.
After 2 h, the mixture was treated with 1 N sodium hydroxide solution to achieve a
pH ~ 10 and was extracted with dichloromethane (3 x 10 mL). The combined organic
layers were washed with brine (3 x 10 mL), dried over sodium sulfate, concentrated.
The residue was purified by prep-HPLC to afford 0.018 g (8%) of the product as a
white solid: H NMR (500 MHz, MeOD-d ) 8.25 (s, 1H), 8.16 (d, J = 2.5 Hz, 1H),
7.76 (dd, J = 8.5, 2.5 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.20 (dd, J = 8.5,
1.0 Hz, 1H), 7.00 - 6.97 (m, 2H), 6.82-6.79 (m, 2H), 5.41 (s, 2H), 5.01 (s, 2H), 3.91
(s, 3H), 3.79 (s, 3H), 3.24 - 3.21(m, 2H), 2.86 - 2.81 (m, 3H), 1.93-1.90 (m, 2H), 1.78
- 1.75 (m, 2H) ppm; (M+1) = 459.
Example 3- 9: Synthesis of 4-(1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)morpholine
To a suspension of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.32 g, 0.64 mmol) in dimethyl sulfoxide
17965367_1 (GHMatters) P41917NZ00
(4 mL) was added morpholine (0.067 g, 0.77 mmol), copper(I) iodide (0.015 g, 0.076
mmol), potassium carbonate (0.22 g, 1.54 mmol), and L-proline (0.018 g, 0.15 mmol).
The light yellow reaction mixture was heated to 120 °C. After 16 h, the reaction
mixture was allowed to cool to room temperature and was diluted with 3 N
ammonium hydroxide solution (20 mL). The mixture was extracted with
dichloromethane (x 3). The combined organic phases were washed with water (x 2),
brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic
purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute)
afforded 0.076 g (26%) of the product as an off-white solid: H NMR (400 MHz,
CDCl ) δ 8.18 (d, J = 1.9 Hz, 1H), 7.85 (s, 1H), 7.66 (dd, J = 8.5, 2.5 Hz, 1H), 7.35 -
7.13 (m, 2H), 6.98 (dd, J = 8.8, 2.2 Hz, 1H), 6.90 - 6.82 (m, 1H), 6.78 - 6.67 (m, 3H),
.23 (s, 2H), 5.02 (s, 2H), 3.93 (s, 3H), 3.95 – 3.85 (m, 4H), 3.76 (s, 3H), 3.18 – 3.12
(m, 4H) ppm; (M+1) = 461.
Example 3- 10: Synthesis of 2-(1-(1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)piperidinyl)propanamine
Example 3- 10- 1: Preparation of 2-(piperidinyl)propanamine
dihydrochloride
A stirred suspension of cesium(III) chloride (5.27 g, 21.40 mmol) in tetrahydrofuran
(50 mL) was heated to 60 °C. After 2 h, the mixture was allowed to cool to room
temperature and was treated with tert-butyl 4-cyanopiperidinecarboxylate (2.25 g,
.70 mmol). The mixture was cooled to -20 °C while a 1.5 M solution of
methyllithium·lithium bromide complex (21.4 mL, 32.10 mmol) was added. After 1 h
at -20 °C, the mixture was quenched with saturated ammonium chloride solution and
diluted with ethyl acetate. The biphasic mixture was filtered to remove the
undissolved solid material, and the layers of the filtrate were separated. The organic
phase was washed with brine, dried over magnesium sulfate, filtered, and
concentrated. The residue was treated with Dowex 50-WX8-200 acidic resin in
methanol (1.1 eq/mL, 20 mL added). After 2 h at room temperature, the mixture was
filtered. The filtercake was washed with methanol followed by ammonia in methanol
(3 M to 6 M). The filtrate was concentrated to provide a waxy solid (containing both
the free diamine and the carbamate-protected monoamine). This crude mixture was
dissolved in methanol and was treated with hydrogen chloride (2.0 M in diethyl
ether). The mixture was allowed to stir at room temperature. After 20 h, the mixture
17965367_1 (GHMatters) P41917NZ00
was concentrated. The residue was suspended in toluene and reconcentrated to afford
0.96 g (42%) of 2-(piperidinyl)propanamine dihydrochloride as a white solid.
Example 3- 10- 2: Preparation of 2-(1-(1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)piperidinyl)propanamine
To a stirred suspension of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.15 g, 0.30 mmol) in dimethyl sulfoxide
(5 mL) was added 2-(piperidinyl)propanamine dihydrochloride (0.19 g, 0.90
mmol), copper(I) iodide (0.005 g, 0.030 mmol), potassium carbonate (0.25 g, 1.80
mmol), and L-proline (0.007 g, 0.057 mmol). The light yellow reaction mixture was
heated to 100 °C. After 24 h, an additional portion of L-proline (0.007 g, 0.057
mmol) was added and heating continued. After an additional 5 h, the reaction mixture
was allowed to cool to room temperature and was diluted with ammonium hydroxide
solution and ethyl acetate. The organic phase was separated and washed with
saturated sodium bicarbonate solution (x 2), brine, dried over magnesium sulfate,
filtered, and concentrated. Chromatographic purification (Biotage, 10 g SiO2 column,
% methanol/dichloromethane to 3 M ammonia in methanol/dichloromethane elute)
provided an oil. The oil was dissolved in aqueous acetonitrile and lyophilized to
afford 0.070 g (45%) of the product as tan solid: H NMR (400 MHz, CDCl ) 8.20 (s,
1H), 7.85 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.03
(d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.77 – 6.72 (m, 2H), 6.71 (s, 1H), 5.23
(s, 2H), 5.03 (s, 2H), 3.94 (s, 3H), 3.77 (s, 3H), 3.72 – 3.68 (m, 2H), 2.67 (t, J = 12.0
Hz, 2H), 1.89 (dd, J = 12.0, 4.0 Hz, 2H), 1.53 – 1.50 (m, 2H), 1.35 – 1.25 (m, 1H),
1.15 (s, 6H) ppm; (M+1) = 516.
Example 3- 11: Synthesis of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)(2,7-diazaspiro[3.5]nonanyl)-1H-benzo[d]imidazole
Example 3- 11- 1: Preparation of tert-butyl 2-(1-(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazolyl)-2,7-
diazaspiro[3.5]nonanecarboxylate
To a stirred suspension of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.61 g, 1.22 mmol) in dimethyl sulfoxide
(4 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonanecarboxylate (0.30 g, 1.34
mmol), copper(I) iodide (0.028 g, 0.15 mmol), potassium carbonate (0.41 g, 2.94
mmol), and L-proline (0.034 g, 0.29 mmol). The light yellow reaction mixture was
heated to 120 °C. After 16 h, the reaction mixture was allowed to cool to room
17965367_1 (GHMatters) P41917NZ00
temperature and was diluted with 3 N ammonium hydroxide solution (20 mL). The
mixture was extracted with dichloromethane, resulting in a thick emulsion. The
elmusion was filtered through Celite to remove any insoluble material. The organic
phase was washed with water, brine, dried over magnesium sulfate, filtered, and
concentrated. Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5%
methanol/dichloromethane elute) afforded 0.53 g (72%) of tert-butyl 2-(1-(3-
methoxy((6-methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazolyl)-
2,7-diazaspiro[3.5]nonanecarboxylate.
Example 3- 11- 2: Preparation of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)(2,7-diazaspiro[3.5]nonanyl)-1H-benzo[d]imidazole
To a stirred solution of tert-butyl 2-(1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)-2,7-diazaspiro[3.5]nonane
carboxylate (0.53 g, 0.88 mmol) in dichloromethane (10 mL) was added
trifluoroacetic acid (5.0 mL. 64.90 mmol). The reaction mixture was allowed to stir at
room temperature. After 1 h, the mixture was concentrated, and the residue
partitioned between 3 M ammonium hydroxide solution and dichloromethane. The
phases were separated, and the aqueous phase was extracted with dichloromethane.
The combined organic phases were washed with brine, dried over magnesium sulfate,
filtered, and concentrated. Chromatographic purification (Combi-Flash, 40 g SiO
gold column, 1-15% methanol/dichloromethane elute) afforded 0.28 g (64%) of the
product as a solid: H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 2.1 Hz, 1H), 7.80 (s,
1H), 7.65 (dd, J = 8.5, 2.4 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.88 - 6.79 (m, 2H), 6.78
- 6.65 (m, 3H), 6.47 (dd, J = 8.6, 2.1 Hz, 1H), 5.18 (s, 2H), 5.00 (s, 2H), 3.92 (s, 3H),
3.75 (s, 3H), 3.61 (s, 4H), 2.86 - 2.78 (m, 4H), 2.54 (b, 1H), 1.82 - 1.74 (m, 4H) ppm;
(M+1) = 500.
Example 3- 12: Synthesis of 1-(1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)piperidinamine
Example 3- 12- 1: Preparation of tert-butyl (1-(1-(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazolyl)piperidin
yl)carbamate
To a suspension of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.48 g, 0.96 mmol) in dimethyl sulfoxide
(4 mL) was added tert-butyl piperidinylcarbamate (0.22 g, 1.05 mmol), copper(I)
iodide (0.022 g, 0.11 mmol), potassium carbonate (0.32 g, 2.32 mmol), and L-proline
17965367_1 (GHMatters) P41917NZ00
(0.026 g, 0.23 mmol). The light yellow reaction mixture was heated to 120 °C. After
16 h, additional portions tert-butyl piperidinylcarbamate (0.048 g, 0.47 mmol),
copper(I) iodide (0.018 g, 0.095 mmol), and L-proline (0.022 g, 0.19 mmol) were
added. Heating was continued for an additional 4 h. After a total of 20 h, the reaction
mixture was allowed to cool to room temperature and was diluted with 3 N
ammonium hydroxide solution (25 mL). The mixture was extracted with
dichloromethane (x 3). The combined organic phases were washed with water (x 2),
brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic
purification (CombiFlash, 40 g SiO2 column, 1-10% methanol/dichloromethane elute)
afforded 0.33 g (60%) of tert-butyl (1-(1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)piperidinyl)carbamate as an impure
solid.
Example 3- 12- 2: Preparation of 1-(1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)piperidinamine
To a stirred solution of tert-butyl (1-(1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)piperidinyl)carbamate (0.33 g, 0.58
mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5.0 mL. 64.90
mmol). The reaction mixture was allowed to stir at room temperature. After 2 h, the
mixture was concentrated, and the residue partitioned between 3 M ammonium
hydroxide solution and dichloromethane. The phases were separated, and the aqueous
phase was extracted with dichloromethane. The combined organic phases were
washed with brine, dried over magnesium sulfate, filtered, and concentrated.
Chromatographic purification (Combi-Flash, 40 g SiO gold column, 1-15%
methanol/dichloromethane elute) afforded 0.19 g (62%) of the product as a solid: H
NMR (400 MHz, CDCl ) δ 8.18 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.65 (dd, J = 8.5,
2.4 Hz, 1H), 7.36 - 7.26 (m, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.01 (dd, J = 8.8, 2.2 Hz,
1H), 6.89 - 6.82 (m, 1H), 6.78 - 6.67 (m, 3H), 5.21 (s, 2H), 5.01 (s, 2H), 3.93 (s, 3H),
3.76 (s, 3H), 3.60 – 3.52 (m, 2H), 2.85 - 2.72 (m, 3H), 1.98 - 1.90 (m, 2H), 1.80 (b,
2H), 1.62 - 1.50 (m, 2H) ppm; (M+1) = 474.
Example 3- 13: Synthesis of 1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(4-methylpiperazinyl)-1H-benzo[d]imidazole
To a stirred suspension of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.25 g, 0.50 mmol) in dimethyl sulfoxide
(5 mL) was added 1-methylpiperazine (0.28 g, 1.50 mmol), copper(I) iodide (0.029 g,
17965367_1 (GHMatters) P41917NZ00
0.15 mmol), sodium carbonate (0.32 g, 2.60 mmol), and L-proline (0.035 g, 0.30
mmol). The mixture was heated to 90 °C in a microwave reactor. After 1 h, the
reaction mixture was allowed to cool to room temperature and was filtered through
Celite. The filtrate was concentrated, and the residue purified via prep-HPLC to
afford 0.045 g (19%) of the product as a white solid: H NMR (500 MHz, CDCl )
8.20 (d, J = 2.5 Hz, 1H), 7.87 (s, 1H), 7.68 (dd, J = 8.5, 2.0 Hz, 1H), 7.36 (d, J = 1.0
Hz, 1H), 7. 18 (d, J = 9.0 Hz, 1H), 7.02 (dd, J = 9.0, 2.0 Hz, 1H), 6.88 (d, J = 8.5 Hz,
1H), 6.77 (d, J = 8.5 Hz, 1H), 6.73-6.72 (m, 2H), 5.25 (s, 2H), 5.04 (s, 2H), 3.95 (s,
3H), 3.78 (s, 3H), 3.24 – 3.18 (m, 4H), 2.67 – 2.62 (m, 4H), 2.39 (s, 3H) ppm; (M+1)
= 474.
Example 3- 14: Synthesis of 1-(2-Amino(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)methylpiperazinone
Example 3- 14- 1: Preparation of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolamine
To a stirred suspension of 4-iodo-N -(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)benzene-1,2-diamine (3.82 g, 7.77 mmol) in dichloromethane (40
mL) and methanol (20 mL) was added cyanogen bromide solution (5.0 M in
acetonitrile, 7.8 mL, 38.87 mmol). The resulting brown reaction mixture was allowed
to stir at room temperature. After 18 h, the mixture was treated with 1N sodium
hydroxide solution (50 mL) and allowed to stir. After 30 min, the phases were
separated, and the aqueous phase was extracted with chloroform. The combined
organic phases were dried over magnesium sulfate, filtered, and concentrated to
provide 5.26 g of a brown semi solid. Chromatographic purification (Combi-Flash,
80 g SiO2 column, 5-10% methanol/dichloromethane elute) afforded 2.78 g (69%) of
5-iodo(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)-1H-
benzo[d]imidazolamine as a brown solid.
Example 3- 14- 2: Preparation of 1-(2-Amino(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazolyl)
methylpiperazinone
To a stirred suspension of 5-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolamine (0.25 g, 0.48 mmol) in 1,4-
dioxane (8 mL) was added 4-methylpiperazinone (0.11 g, 0.96 mmol), CuI (0.036
mg, 0.19 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.044 g, 0.38 mmol),
17965367_1 (GHMatters) P41917NZ00
and tribasic potassium phosphate (0.32 g, 1.52 mmol). The mixture was heated to
145 C in a microwave reactor. After 3 h, the mixture was allowed to cool to room
temperature and was filtrated through Celite. The filtrate was concentrated, and the
residue was purified by silica gel chromatography (2-5% methanol/dichloromethane
elute) followed by prep-HPLC to afford 0.030 g (12%) of the product as a white solid:
H NMR (500 MHz, CDCl ) 8.17 (s, 1H), 7.66 (dd, J = 8.0, 2.0 Hz, 1H), 7.25 (s,
1H), 7.01 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.76
– 6.74 (m, 2H), 6.64 (d, J = 7.5 Hz, 1H), 4.99 (s, 2H), 4.89 (br s, 2H), 4.81 (s, 2H),
3.94 (s, 3H), 3.79 (s, 3H), 3.72 (t, J = 5.0 Hz, 2H), 3.30 (s, 2H), 2.82 (t, J = 5.0 Hz,
2H), 2.44 (s, 3H) ppm; (M+1) = 503.
Example 3- 15: Synthesis of 3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)
(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
Example 3- 15- 1: Preparation of 5-bromo-N-(3-methoxy(4-
methoxybenzyloxy)benzyl)nitropyridinamine
To a stirred solution of 3-methoxy(4-methoxybenzyloxy)phenyl)methanamine
(2.00 g, 7.32 mmol) and 5-bromochloronitropyridine (1.66 g, 6.97 mmol) in
acetonitrile (50 mL) was added N,N-diisopropylethylamine (1.13 g, 8.71 mmol). The
resulting mixture was heated to reflux and allowed to stir. After 64 h, the reaction
mixture was allowed to cool to room temperature and was diluted with water. The
mixture was extracted twice with dichloromethane. The combined organic phases
were dried over magnesium sulfate, filtered, and concentrated to provide 3.34 g (>
100%) of 5-bromo-N-(3-methoxy(4-methoxybenzyloxy)benzyl)nitropyridin
amine as a yellow-brown solid.
Example 3- 15- 2: Preparation of 5-bromo-N -(3-methoxy(4-
methoxybenzyloxy)benzyl)pyridine-2,3-diamine
To a stirred solution of 5-bromo-N-(3-methoxy(4-methoxybenzyloxy)benzyl)
nitropyridinamine in tetrahydrofuran (40 mL), ethanol (40 mL), and water (40 mL)
was added sodium hydrosulfite (6.09 g, 34.99 mmol). The resulting mixture was
heated to reflux and allowed to stir. After 4 h, the reaction mixture was allowed to
cool to room temperature and was diluted with water. The yellow mixture was
extracted three times with dichloromethane. The combined organic phases were
washed with brine, dried (magnesium sulfate), filtered, and concentrated to provide
3.10 g of a yellow-brown solid. Chromatographic purification (Combi-Flash 40 g
17965367_1 (GHMatters) P41917NZ00
SiO gold column, 1-2.5% methanol/dichloromethane) afforded 1.28 g (51%) of 5-
bromo-N -(3-methoxy(4-methoxybenzyloxy)benzyl)pyridine-2,3-diamine as a
yellow solid .
Example 3- 15- 3: Preparation of 6-bromo(3-methoxy(4-
methoxybenzyloxy)benzyl)-3H-imidazo[4,5-b]pyridinamine
To a stirred solution of 5-bromo-N -(3-methoxy(4-
methoxybenzyloxy)benzyl)pyridine-2,3-diamine (0.850 g, 1.91 mmol) in
dichloromethane (30 mL) and methanol (30 mL) was added cyanogen bromide (5.0 M
in acetontitrile, 573 L, 2.87 mmol). The resulting solution was allowed to stir at
room temperature. After 24 h, a second aliquot of cyanogen bromide solution was
added (600 L) and stirring continued. After 48 h, a third aliquot of cyanogen
bromide solution (600 L) was added and stirring continued. After a total of 72 h, the
reaction mixture was concentrated, and the residue was dissolved in dichloromethane.
The solution was washed with 1N sodium hydroxide solution, dried over magnesium
sulfate, filtered, and concentrated to provide 1.17 g of a brown solid.
Chromatographic purification (Combi-Flash, 40 g SiO gold column, 1-10% 2M
ammonia in methanol/dichloromethane) afforded 0.28 g (32%) of 6-bromo(3-
methoxy(4-methoxybenzyloxy)benzyl)-3H-imidazo[4,5-b]pyridinamine as a
brown solid.
Example 3- 15- 4: Preparation of 3-(3-Methoxy((4-
methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine
To a stirred solution of 6-bromo(3-methoxy(4-methoxybenzyloxy)benzyl)-3H-
imidazo[4,5-b]pyridinamine (0.25 g, 0.53 mmol) in 1,4-dioxane (10 mL) and water
(4 mL) was added 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole (0.14 g, 0.66 mmol), potassium phosphate tribasic (0.39 g, 1.84 mmol),
tricyclohexylphosphine (0.015 g, 0.052 mmol), palladium(II) acetate (0.005 g, 0.026
mmol). The reaction mixture heated to 125 ºC in a microwave reactor. After 15 min,
the reaction mixture was allowed to cool to room temperature and was diluted with
water. The mixture was extracted twice with ethyl acetate. The combined organic
phases were washed with brine, dried over magnesium sulfate, filtered, and
concentrated to provide 0.36 g of a greenish brown solid. Chromatographic
purification (Combi-Flash, 12 g SiO gold column, 1-10% 2M ammonia in
17965367_1 (GHMatters) P41917NZ00
methanol/dichloromethane) afforded 0.10 g (41%) of the product as a light green
solid: H NMR (400 MHz, DMSO-d6) δ 8.12 – 8.08 (m, 2H), 7.83 (d, J = 0.6 Hz,
1H), 7.58 (d, J = 1.9 Hz, 1H), 7.32 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 1.9 Hz, 1H), 6.96
– 6.85 (m, 5H), 6.72 (dd, J = 8.3, 1.9 Hz, 1H), 5.18 (s, 2H), 4.92 (s, 2H), 3.85 (s, 3H),
3.74 (s, 3H), 3.70 (s, 3H) ppm, (M+1) = 471.
Example 3- 16: Synthesis of (5-(2-Amino(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)pyridin
yl)dimethylphosphine oxide
Example 3- 16- 1: Preparation of 5-iodo-N-(3-methoxy((4-
methoxybenzyl)oxy)benzyl)nitropyridinamine
To a stirred solution of 3-methoxy(4-methoxybenzyloxy)phenyl)methanamine
(3.80 g, 13.92 mmol) and 2-chloroiodonitropyridine (3.77 g, 13.25 mmol) in
acetonitrile (50 mL) was added potassium carbonate (2.29 g, 16.57 mmol). The
resulting bright yellow mixture was heated to reflux and allowed to stir. After 16 h,
the brown reaction mixture was allowed to cool to room temperature and was diluted
with water. The mixture was extracted with chloroform (x 3). The combined organic
phases were dried over magnesium sulfate, filtered, and concentrated to provide 6.88
g (> 100%) of 5-iodo-N-(3-methoxy((4-methoxybenzyl)oxy)benzyl)
nitropyridinamine as a yellow-brown solid.
Example 3- 16- 2: Preparation of 5-iodo-N -(3-methoxy((4-
methoxybenzyl)oxy)benzyl)pyridine-2,3-diamine
To a stirred suspension of 5-iodo-N-(3-methoxy((4-methoxybenzyl)oxy)benzyl)
nitropyridinamine (6.72 g, 13.25 mmol) in tetrahydrofuran (75 mL), methanol (25
mL), and water (25 ml) was added ammonium chloride (5.68 g, 106.0 mmol) and
iron(II) sulfate heptahydrate (11.05 g, 39.76 mmol). The yellow mixture was treated
with zinc (2.60 g, 39.76 mmol), and the resulting dark mixture was heated to reflux.
After 3 h, the reaction mixture was allowed to cool to room temperature and was
filtered through Celite with the aid of methanol. The filtrate was concentrated, and
the residue was dissolved in chloroform. The solution was washed with water,
filtered through Celite, dried over magnesium sulfate, filtered, and concentrated to
provide 6.67 g (> 100%) of 5-iodo-N -(3-methoxy((4-
methoxybenzyl)oxy)benzyl)pyridine-2,3-diamine as a brown solid.
17965367_1 (GHMatters) P41917NZ00
Example 3- 16- 3: Preparation of 6-iodo(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridinamine
To a stirred suspension of 5-iodo-N -(3-methoxy((4-
methoxybenzyl)oxy)benzyl)pyridine-2,3-diamine (6.33 g, 13.25 mmol) in
dichloromethane (100 mL) and methanol (50 mL) was added cyanogen bromide
solution (5.0M in acetonitrile, 13.3 mL, 66.27 mmol). The resulting dark brown
reaction mixture was allowed to stir at room temperature. After 68 h, the now black
reaction mixture was treated with 1N sodium hydroxide solution (75 mL) and stirred
at room temperature. After 30 min, the mixture was diluted with water, and the
phases were separated. The organic phase was dried over magnesium sulfate, filtered,
and concentrated to provide 6.43 g of a brown oil. Chromatographic purification
(Combi-Flash, 120 g SiO2 column, 1-5% 2M ammonia in methanol/dichloromethane
elute) provided 2.40 g of a black oil. A second chromatographic purification (Combi-
Flash, 80 g SiO2 column, 1-5% 2M ammonia in methanol/dichloromethane elute)
afforded 0.98 g (14%) of 6-iodo(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinamine as a gray solid.
Example 3- 16- 4: Preparation of 6-(6-chloropyridinyl)(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridinamine
To a stirred suspension of 6-iodo(3-methoxy((4-methoxybenzyl)oxy)benzyl)-
3H-imidazo[4,5-b]pyridinamine (0.34 g, 0.66 mol) in 1,4-dioxane (10 mL) and
water (4 mL) was added (6-chloropyridinyl)boronic acid (0.12 g, 0.76 mmol),
potassium phosphate tribasic (0.49 g, 2.33 mmol), tricyclohexylphosphine (0.037 g,
0.13 mmol), and palladium(II) acetate (0.015 g, 0.066 mmol). The reaction mixture
was heated to 125 °C in a microwave reactor. After 30 min, the reaction mixture was
diluted with water. The mixture was extracted with chloroform (x 3). The combined
organic phases were dried over magnesium sulfate, filtered, and concentrated to
provide 0.44 g of a brown solid. Chromatographic purification (Combi-Flash, 24 g
SiO2 gold column, 5-10% methanol/dichloromethane elute) afforded 0.20 g (60%) of
6-(6-chloropyridinyl)(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinamine as a tan solid.
Example 3- 16- 5: Preparation of (5-(2-Amino(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)pyridin
yl)dimethylphosphine oxide
17965367_1 (GHMatters) P41917NZ00
To a stirred suspension of 6-(6-chloropyridinyl)(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridinamine (0.17 g, 0.34 mmol)
in 1,4-dioxane (12 mL) was added dimethylphosphine oxide (0.053 g, 0.69 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.079 g, 0.14 mmol),
palladium(II) acetate (0.015 g, 0.069 mmol), and cesium carbonate (0.22 g, 0.69
mmol). The reaction mixture was heated to 150 °C in a microwave reactor. After 1 h,
the reaction mixture was allowed to cool to room temperature. The mixture was
diluted with water and extracted with chloroform (x 2). The combined organic phases
were dried over magnesium sulfate, filtered, and concentrated to provide 0.27 g of a
yellow solid. Chromatographic purification (Combi-Flash, 12 g SiO2 column, 5-10%
2M ammonia in methanol/dichloromethane elute) afforded 0.078 g (42%) of the
product as a tan solid: H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 1.8 Hz, 1H),
8.32 – 8.21 (m, 2H), 7.99 (dd, J = 7.9, 5.1 Hz, 1H), 7.82 (d, J = 1.8 Hz, 1H), 7.32 (d, J
= 8.6 Hz, 2H), 7.11 (d, J = 1.7 Hz, 1H), 7.05 (s, 2H), 6.98 – 6.87 (m, 3H), 6.72 (dd, J
= 8.2, 1.7 Hz, 1H), 5.24 (s, 2H), 4.93 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 1.69 (d, J =
13.5 Hz, 6H) ppm; (M+1) = 544.
Example 3- 17: Synthesis of 3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(4-methylpiperazinyl)-3H-imidazo[4,5-b]pyridine
Example 3- 17- 1: Preparation of 5-iodo-N-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)nitropyridinamine
To a stirred solution of (3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)methanamine (9.11 g, 33.21 mmol) in acetonitrile (150 mL) was
added 2-chloroiodonitropyridine (9.90 g, 34.81 mmol) and N,N-
diisopropylethylamine (6.44 g, 49.81 mmol). The yellow solution was heated to
reflux and stirred. After 3 h, the red-brown mixture was cooled to 0 °C resulting in
the formation of a precipitate. The precipitate was isolated by filtration and washed
with acetonitrile (50 mL) and water (200 mL). The moist solids were dissolved in
dichloromethane, and a small amount of water separated and was removed. The
organic phase was dried over magnesium sulfate, filtered, and concentrated to provide
14.67 g (85%) of 5-iodo-N-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)-
3-nitropyridinamine as a yellow-brown solid.
Example 3- 17- 2: Preparation of 5-iodo-N -(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)pyridine-2,3-diamine
17965367_1 (GHMatters) P41917NZ00
To a stirred suspension of 5-iodo-N-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)nitropyridinamine (14.67 g, 28.09 mmol) in acetic acid (130
mL) was added iron powder (10.98 g, 196.6 mmol). The bright yellow mixture was
warmed to ~85 °C. After 15 min of heating, the reaction mixture became a gray-
brown suspension and waas allowed to cool to room temperature. The mixture was
diluted with ethyl acetate (400 mL), and the thick mixture was filtered through Celite
with the aid of additional ethyl acetate (100 mL). The filtrate was washed with water
(2 x 150 mL) and 5N ammonium hydroxide solution (4 x 125 mL). The organic
phase was dried over magnesium sulfate, filtered, and concentrated to provide 11.67 g
(84%) of 5-iodo-N -(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)pyridine-
2,3-diamine as a tan solid.
Example 3- 17- 3: Preparation of 6-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine
To a stirred suspension of 5-iodo-N -(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)pyridine-2,3-diamine (11.67 g, 23.70 mmol) in ethanol (175 mL)
was added triethyl orthoformate (8.90 g, 60.05 mmol) and p-toluenesulfonic acid
monohydrate (0.23 g, 1.19 mmol). As the mixture was warmed to reflux, the solids
dissolved to provide a brown solution. After 30 min, the reaction mixture was cooled
to 0 °C, resulting in the formation of a precipitate. The solids were isolated by
filtration, washed with a small amount of cold ethanol, and dried to provide 10.34 g
(87%) of 6-iodo(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-
imidazo[4,5-b]pyridine as an off-white solid.
Example 3- 17- 4: Preparation of 3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(4-methylpiperazinyl)-3H-imidazo[4,5-b]pyridine
To a stirred suspension of 6-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (1.40 g, 2.79 mmol) in
dimethylsulfoxide (15 mL) was added 1-methylpiperazine (0.44 g, 4.40 mmol),
copper(I) iodide (0.16 g, 0.84 mmol), L-proline (0.19 g, 1.67 mmol), and potassium
carbonate (0.96 g, 6.97 mmol). The mixture was degassed under vacuum/backfilled
with N2 (x 3), and then it was heated to 120 °C. As the mixture warmed, it became
dark blue/black in color. After 19 h, the brown mixture was allowed to cool to room
temperature and was diluted with 5N ammonium hydroxide solution (100 mL). The
mixture was extracted with dichloromethane (3 x 50 mL). The combined organic
phases were dried over magnesium sulfate, filtered, and concentrated to provide 1.78
17965367_1 (GHMatters) P41917NZ00
g of a brown oil. Chromatographic purification (Combi-Flash, 40 g SiO2 gold
column, 1-10% 2M ammonia in methanol/dichloromethane elute) afforded 0.60 g
(45%) of the product as a tan solid: H NMR (400 MHz, CDCl ) δ 8.26 (d, J = 2.4 Hz,
1H), 8.18 (d, J = 2.4 Hz, 1H), 7.92 (s, 1H), 7.69 – 7.61 (m, 2H), 6.91 – 6.84 (m, 2H),
6.80 (dd, J = 8.2, 2.0 Hz, 1H), 6.74 (dd, J = 8.5 Hz, 1H), 5.34 (s, 2H), 5.02 (s, 2H),
3.93 (s, 3H), 3.80 (s, 3H), 3.25 – 3.18 (m, 4H), 2.68 – 2.61 (m, 4H), 2.38 (s, 3H) ppm;
(M+1) = 475.
Example 3- 18: Synthesis of Additional Compounds from 6-iodo(3-methoxy-
4-((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine
The following compounds 6-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine using the procedure described in
Example 3- 17- 4 by employing the appropriate amine coupling partner:
Example 3- 18- 1: 2-(1-(3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)piperidinyl)propan
amine
H NMR (400 MHz, CDCl ): 8.20 (s, 1H), 8.11 (s, 1H), 7.85 (s, 1H), 7.58 – 7.56 (m, 2H), 6.81 ( d, J =
8.0 Hz, 1H), 6.78 (s, 1H), 6.74 (dd, J = 8.0, 4.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.27 (s, 2H), 4.95 (s,
2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.62 – 3.57 (m, 2H), 2.65 (t, J = 12.0 Hz, 2H), 1.83 (dd, J = 12.0, 4.0
Hz, 2H), 1.52 – 1.48 (m, 2H), 1.26 – 1.24 (m, 1H), 1.06 (s, 6H) ppm; (M+1) 517.
Example 3- 18- 2: 4-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-
3H-imidazo[4,5-b]pyridinyl)morpholine
H NMR (400 MHz, CDCl ) δ 8.24 (d, J = 2.5 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.95 (s, 1H), 7.70 -
7.59 (m, 2H), 6.92 - 6.71 (m, 4H), 5.35 (s, 2H), 5.02 (s, 2H), 3.95 - 3.88 (m, 7H), 3.80 (s, 3H), 3.21 -
3.13 (m, 4H) ppm; (M+1) 462.
Example 3- 18- 3: 6-(4-Cyclopropylpiperazinyl)(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine
H NMR (400 MHz, DMSO-d ) δ 8.43 (s, 1H), 8.24 – 8.18 (m, 2H), 7.73 (dd, J = 8.4, 2.5 Hz, 1H),
7.58 (d, J = 2.5 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.85 – 6.78 (m, 2H), 5.34
(s, 2H), 4.96 (s, 2H), 3.84 (s, 3H), 3.72 (s, 3H), 3.13 – 3.05 (m, 4H), 2.75 – 2.67 (m, 4H), 1.70 – 1.63
(m, 1H), 0.48 – 0.41 (m, 2H), 0.37 – 0.30 (m, 2H) ppm; (M+1) 501
Example 3- 18- 4: 4-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-
3H-imidazo[4,5-b]pyridinyl)-1,4-diazabicyclo[3.2.2]nonane
H NMR (400 MHz, CDCl ) δ 8.18 (d, J = 2.6, 1H), 8.14 (d, J = 2.6 Hz, 1H), 7.89 (s, 1H), 7.66 (dd, J =
8.5, 2.5 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 6.92 – 6.83 (m, 2H), 6.81 (d, J = 8.2, 2.0 Hz, 1H), 6.74 (d, J
= 8.5 Hz, 1H), 5.32 (s, 2H), 5.02 (s, 2H), 3.93 (s, 3H), 3.80 (s, 3H), 3.54 – 3.46 (m, 2H), 3.24 – 2.99
(m, 7H), 2.21 – 2.09 (m, 2H), 1.81 – 1.69 (m, 2H) ppm; (M+1) 501.
17965367_1 (GHMatters) P41917NZ00
Example 3- 18- 5: 3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)
(2,7-diazaspiro[3.5]nonanyl)-3H-imidazo[4,5-b]pyridine
Synthesis is a two-step process including coupling followed by carbamate
deprotection as described for Example 3- 11.
H NMR (400 MHz, CDCl ) δ 8.21 - 8.16 (m, 1H), 7.93 - 7.88 (m, 1H), 7.79 - 7.73 (m, 1H), 7.70 - 7.62
(m, 1H), 7.14 - 7.09 (m, 1H), 6.91 - 6.71 (m, 4H), 5.32 (s, 2H), 5.02 (s, 2H), 3.93 (s, 3H), 3.80 (s, 3H),
3.72 - 3.67 (m, 4H), 3.10 (b, 1H) 2.90 (s, 4H), 1.90 - 1.84 (m, 4H) ppm; (M+1) 501.
Example 3- 18- 6: 1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-
3H-imidazo[4,5-b]pyridinyl)piperidinamine
Synthesis is a two-step process including coupling followed by carbamate
deprotection as described for Example 3- 12.
H NMR (400 MHz, CDCl ) δ 8.26 (d, J = 2.5 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 7.93 (s, 1H), 7.70 -
7.60 (m, 2H), 6.93 - 6.71 (m, 4H), 5.34 (s, 2H), 5.01 (s, 2H), 3.92 (s, 3H), 3.80 (s, 3H), 3.59 - 3.51 (m,
2H), 2.88 - 2.77 (m, 3H), 2.42 (b, 2H), 2.01 - 1.94 (m, 2H), 1.66 - 1.51 (m, 2H) ppm; (M+1) 475.
Example 3- 18- 7: (S)(3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)pyrrolidinecarboxylic acid
H NMR (500 MHz, CD OD) 8.31 – 8.19 (m, 1H), 8.17 – 8.13 (m, 1H), 7.87 (br s, 1H), 7.64 (dd, J =
8.5, 2.5 Hz, 1H), 7.22 – 7.11 (m, 1H), 7.04 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H),
6.79 (d, J = 8.5 Hz, 1H), 5.38 (s, 2H), 4.98 (s, 2H), 4.22 – 4.12 (m, 1H), 3.90 (s, 3H), 3.78 (s, 3H), 3.68
– 3.58 (m, 1H), 3.42 – 3.39 (m, 1H), 2.37-2.08 (m, 4H) ppm; (M+1) 490.
Example 3- 19: Synthesis of 3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(1-(piperidinyl)-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridine
Example 3- 19- 1: Preparation of tert-butyl 4-(4-(3-(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)-1H-
pyrazolyl)piperidinecarboxylate
To a stirred suspension of 6-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (0.20 g, 0.40 mmol) in N,N-
dimethylformamide (8 mL) and water (2 mL) was added tert-butyl 4-(4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazolyl)piperidinecarboxylate (0.15
g, 0.40 mmol), potassium carbonate (0.22 g, 1.59 mmol), and
tetrakis(triphenylphosphino)palladium(0) (0.021 g, 0.018 mmol). The mixture was
heated to 100 °C. After 1 h, the reaction mixture was allowed to cool to room
temperature and was filtered through Celite. The filtrate was concentrated, and the
residue purified via silica gel chromatography (5% methanol/dichloromethane elute)
17965367_1 (GHMatters) P41917NZ00
to provide 0.15 g (60%) of tert-butyl 4-(4-(3-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)-1H-pyrazolyl)piperidine
carboxylate as a yellow solid.
Example 3- 19- 2: Preparation of 3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(1-(piperidinyl)-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridine
To a stirred solution of tert-butyl 4-(4-(3-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)-1H-pyrazolyl)piperidine
carboxylate (0.15 g, 0.24 mmol) in dichloromethane (10 mL) was added
trifluoroacetic acid (0.5 mL). The resulting mixture was stirred at room temperature.
After 1 h, the reaction mixture was concentrated, and the residue was diluted with 1M
potassium carbonate solution (20 mL) and extracted with dichloromethane (3 x 10
mL). The combined organic phases were washed with brine (3 x 20 mL), dried over
sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to
afford 0.065 g (52%) of the product as a white solid: H NMR (500 MHz, CDCl )
8.59 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.67
(d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H),
6.75 (d, J = 8.5 Hz, 1H), 5.40 (s, 2H), 5.03 (s, 2H), 4.30 (m, 1H), 3.94 (s, 3H), 3.82 (s,
3H), 3.31 – 3.28 (m, 2H), 2.84 – 2.80 (m, 2H), 2.24 – 2.22 (m, 2H), 2.04 – 1.97 (m,
2H) ppm; (M+1) = 526.
Example 3- 20: Synthesis of 3-(3-Methoxy((6-methylpyridin
yl)methoxy)benzyl)(1-(piperidinyl)-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridine
Example 3- 20- 1: Preparation of tert-butyl 3-methoxy((6-methylpyridin
yl)methoxy)benzylcarbamate
To a stirred solution of tert-butyl 4-hydroxymethoxybenzylcarbamate (21.02 g,
82.99 mmol) in acetonitrile (250 mL) was added potassium carbonate (30.61 g, 221.5
mmol) and 5-(chloromethyl)methylpyridine hydrochloride (16.25 g, 91.29 mmol).
The resulting mixture was heated to reflux. After 63 h, the brown suspension was
allowed to cool to room temperature and was diluted with water (1000 mL). The
mixture was extracted with dichloromethane (3 x 250 mL). The combined organic
phases were dried over magnesium sulfate, filtered, and concentrated to provide 31.59
17965367_1 (GHMatters) P41917NZ00
g (>100%) of tert-butyl 3-methoxy((6-methylpyridin
yl)methoxy)benzylcarbamate as a brown oil.
Example 3- 20- 2: Preparation of (3-methoxy((6-methylpyridin
yl)methoxy)phenyl)methanamine
To a stirred solution of tert-butyl 3-methoxy((6-methylpyridin
yl)methoxy)benzylcarbamate (29.74 g, 82.97 mmol) in dichloromethane (100 mL)
was added trifluoroacetic acid (50 mL, 649.0 mmol). The resulting brown solution
was allowed to stir at room temperature. After 2 h, the reaction mixture was
concentrated to dryness, and the residue was dissolved in water (250 mL). The acidic
solution was extracted with diethyl ether (2 x 125 mL; organic phases discarded).
The aqueous phase was then made basic with concentrated ammonium hydroxide.
The basic aqueous phase was then extracted with dichloromethane (3 x 100 mL). The
combined organic phases were dried over magnesium sulfate, filtered, and
concentrated to provide 19.22 g (90%) of (3-methoxy((6-methylpyridin
yl)methoxy)phenyl)methanamine as brown solid.
Example 3- 20- 3: Preparation of 5-iodo-N-(3-methoxy((6-methylpyridin
yl)methoxy)benzyl)nitropyridinamine
To a stirred solution of (3-methoxy((6-methylpyridin
yl)methoxy)phenyl)methanamine (7.30 g, 28.26 mmol) in acetonitrile (200 mL) was
added 2-chloroiodonitropyridine (8.44 g, 29.67 mmol) and N,N-
diisopropylethylamine (5.48 g, 42.39 mmol). The brown mixture was heated to
reflux. After 5 h, the brown mixture was allowed to cool to room temperature and
was diluted with water (600 mL). The resulting precipitate was isolated by filtration
and washed with water (200 mL). The moist solids were dissolved in ethyl acetate
(300 mL), and this solution was washed with water (100 mL). The organic phase was
dried over magnesium suflate, filtered, and concentrated to provide 13.57 g (95%) of
-iodo-N-(3-methoxy((6-methylpyridinyl)methoxy)benzyl)nitropyridin
amine as a bright yellow solid.
Example 3- 20- 4: Preparation of 5-iodo-N2-(3-methoxy((6-methylpyridin
yl)methoxy)benzyl)pyridine-2,3-diamine
To a stirred suspension of 5-iodo-N-(3-methoxy((6-methylpyridin
yl)methoxy)benzyl)nitropyridinamine (13.57 g, 26.80 mmol) in acetic acid (100
mL) was added iron powder (8.10 g, 145.0 mmol). The bright yellow suspension was
gradually warmed to 90 °C. After 30 min of heating, the dark brown reaction mixture
17965367_1 (GHMatters) P41917NZ00
was allowed to cool to room temperature and was diluted with ethyl acetate (400 mL).
The mixture was filtered through Celite with the aid of additional ethyl acetate (100
mL). The filtrate was then washed with water (2 x 150 mL) and 1N sodium
hydroxide solution (2 x 200 mL). The organic phase was dried over magnesium
sulfate, filtered, and concentrated to provide 6.97 g (55%) of 5-iodo-N2-(3-methoxy-
4-((6-methylpyridinyl)methoxy)benzyl)pyridine-2,3-diamine as a brown solid.
Example 3- 20- 5: Preparation of 6-iodo(3-methoxy((6-methylpyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine
To a stirred suspension of 5-iodo-N2-(3-methoxy((6-methylpyridin
yl)methoxy)benzyl)pyridine-2,3-diamine (6.98 g, 14.65 mmol) in ethanol (100 mL)
was added triethyl orthoformate (3.56 g, 24.02 mmol) and p-toluenesulfonic acid
monohydrate (0.050 g, 0.26 mmol). As the resulting mixture was warmed to reflux,
the solids gradually dissolved to provide a brown solution. After 90 min, the reaction
mixture was allowed to cool to room temperature, and the mixture was concentrated
to provide 7.91 g of a brown oil. Chromatographic purification (Combi-Flash, 220 g
SiO2 gold column, 1-5% methanol/dichloromethane elute) afforded 5.22 g (73%) of
6-iodo(3-methoxy((6-methylpyridinyl)methoxy)benzyl)-3H-imidazo[4,5-
b]pyridine as a tan solid.
A portion of this material was used to prepare Example 3- 20 using the procedure
outlined for the synthesis of Example 3- 19: H NMR (500 MHz, CDCl ) 8.58 (d, J
= 1.5 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.00 (s, 1H), 7.83 (s,
1H), 7.74 (s, 1H), 7.66 (dd, J = 8.0, 2.0 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.92 (d, J =
1.0 Hz, 1H), 6.86 – 6.83 (m, 2H), 5.39 (s, 2H), 5.08 (s, 2H), 4.31 – 4.26 (m, 1H), 3.81
(s, 3H), 3.29 – 3.26 (m, 2H), 2.82 – 2.77 (m, 2H), 2.55 (s, 3H), 2.23 – 2.22 (m, 2H),
2.01 – 1.92 (m, 2H) ppm; (M+1) = 510.
Example 3- 21: Synthesis of 3-(3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)(piperidinyl)-1,2,4-
oxadiazole
Example 3- 21- 1: Preparation of 3-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinecarbonitrile
To a stirred solution of 6-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (1.00 g, 1.99 mmol) in N,N-
dimethylformamide (15 mL) was added copper(I) cyanide (0.53 g, 6.00 mmol). The
17965367_1 (GHMatters) P41917NZ00
mixture was heated to 150 C. After 5 h, the mixture was allowed to cool to room
temperature and was concentrated. The residue was purified by silica gel
chromatography (2% methanol/dichloromethane elute) to give 0.53 g (66%) of 3-(3-
methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine
carbonitrile as a yellow solid.
Example 3- 21- 2: Preparation of N'-hydroxy(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine
carboximidamide
To a stirred solution of 3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)-
3H-imidazo[4,5-b]pyridinecarbonitrile (0.53 g, 1.32 mmol) in ethanol was added
hydroxylamine solution (50% weight in water, 0.1 mL). The mixture was heated to
100 °C. After 1 h, the mixture was concentrated to provide 0.66 g (> 100%) of N'-
hydroxy(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-
b]pyridinecarboximidamide as a white solid.
Example 3- 21- 3: Preparation of tert-butyl 4-(3-(3-(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)-1,2,4-
oxadiazolyl)piperidinecarboxylate
To a stirred solution of N'-hydroxy(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinecarboximidamide (0.38 g, 0.75
mmol) in N,N-dimethylformamide (10 mL) was added 1-(tert-
butoxycarbonyl)piperidinecarboxylic acid (0.21 g, 0.92 mmol), 1-
[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid
hexafluorophosphate (0.35 g, 0.92 mmol) and N,N-diisopropylethylamine (0.19 g,
1.50 mmol). The reaction mixture was stirred at room temperature. After 1 h, the
mixture was diluted with ethyl acetate and brine. The organic phase was separated,
dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved
in 1,4-dioxane (20 mL) and heated to 85 °C. After 16 h, the reaction mixture was
allowed to cool to room temperature and was concentrated. The crude product was
purified by silica gel chromatography (2% methanol/dichloromethane elute) to
provide 0.14 g (25%) of tert-butyl 4-(3-(3-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)-1,2,4-oxadiazolyl)piperidine-
1-carboxylate as a yellow solid.
17965367_1 (GHMatters) P41917NZ00
Example 3- 21- 4: Preparation of 3-(3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)(piperidinyl)-1,2,4-
oxadiazole
To a stirred solution of tert-butyl 4-(3-(3-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)-1,2,4-oxadiazolyl)piperidine-
1-carboxylate (0.14 g, 0.22 mmol) in dichloromethane (20 mL) was added
trifluoroacetic acid (0.20 g, 1.79 mmol). The reaction mixture was allowed to stir at
room temperature. After 1 h, the mixture was diluted with cold saturated sodium
carbonate solution. The phases were separated, and the aqueous phase extracted with
dichloromethane. The combined organic phases were washed with brine, dried over
magnesium sulfate, filtered, and concentrated. The residue was purified by Prep-
HPLC to provide 0.067 g (57%) of the product as a white solid: H NMR (500 MHz,
DMSO-d ) 9.02 (d, J = 1.5 Hz, 1H), 8.75 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.21 (d, J
= 2.0 Hz, 1H), 7.75 (dd, J = 8.5, 2.0 Hz, 1H), 7.16 (d, J = 1.5 Hz, 1H), 7.03 (d, J = 8.0
Hz, 1H), 6.89 (dd, J = 8.0, 2.0 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 5.48 (s, 2H), 4.98 (s,
2H), 3.84 (s, 3H), 3.74 (s, 3H), 3.26 – 3.21 (m, 1H), 3.02 – 3.00 (m, 2H), 2.65 – 2.61
(m, 2H), 2.02 – 2.00 (m, 2H), 1.75 – 1.67 (m, 2H) ppm; (M+1) = 528.
Example 3- 22: Synthesis of 3-(1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)(piperidinyl)-1,2,4-
oxadiazole
3-(1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazol-
-yl)(piperidinyl)-1,2,4-oxadiazole was prepared from 5-iodo(3-methoxy
((6-methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazole using the procedure
outlined for Example 3- 21: H NMR (500 MHz, DMSO-d ) 8.55 (s, 1H), 8.26 (s,
1H), 8.21 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.77 – 7.73 (m, 2H), 7.12 (d, J
= 1.5 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.87 – 6.83 (m, 2H), 5.46 (s, 2H), 4.98 (s,
2H), 3.85 (s, 3H), 3.74 (s, 3H), 3.22 – 3.17 (m, 1H), 3.02 – 3.00 (m, 2H), 2.65 – 2.61
(m, 2H), 2.01 – 1.99 (m, 2H), 1.73 – 1.68 (m, 2H) ppm; (M+1) = 527.
Example 3- 23: Synthesis of 2-(3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)(piperidinyl)-1,3,4-
oxadiazole
2-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-
b]pyridinyl)(piperidinyl)-1,3,4-oxadiazole was prepared from 6-iodo(3-
17965367_1 (GHMatters) P41917NZ00
methoxy((6-methylpyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine
according to the procedure outlined for the synthesis of Example 3- 7: H NMR (500
MHz, CD OD) 9.13 (d, J = 1.5 Hz, 1H), 8.67 – 8.62 (m, 2H), 8.15 (d, J = 1.5 Hz,
1H), 7.76 (dd, J = 8.5, 2.0 Hz, 1H), 7.15 (d, J = 1.5 Hz, 1H), 7.01 – 6.95 (m, 2H), 6.80
(d, J = 9.0 Hz, 1H), 5.53 (s, 2H), 5.01 (s, 2H), 3.90 (s, 3H), 3.82 (s, 3H), 3.51 – 3.46
(m, 3H), 3.21 – 3.16 (m, 2H), 2.44 – 2.41 (m, 2H), 2.18 – 2.09 (m, 2H) ppm; (M+1) =
528.
Example 3- 24: Synthesis of 2-(1-(3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)-1H-1,2,3-triazolyl)propan-
2-amine
2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-
b]pyridinyl)-1H-1,2,3-triazolyl)propanamine was prepared from 6-iodo(3-
methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine and
2-methylbutynamine according to the procedure described for the synthesis of
Example 3- 6: H NMR (400 MHz, DMSO-d ) δ 8.92 (d, J = 2.3 Hz, 1H), 8.76 (s,
1H), 8.65 (s, 1H), 8.56 (d, J = 2.3 Hz, 1H), 8.21 (d, J = 2.5, 1H), 7.74 (dd, J = 8.5, 2.5
Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.88 (dd, J = 8.2, 2.0 Hz,
1H), 6.83 (d, J = 8.5 Hz, 1H), 5.48 (s, 2H), 4.98 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H),
1.98 (br s, 2H), 1.46 (s, 6H) ppm; (M+1) = 501.
Example 3- 25: Synthesis of 3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(4-(piperidinyl)-1H-1,2,3-triazolyl)-3H-imidazo[4,5-
b]pyridine
3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidinyl)-1H-
1,2,3-triazolyl)-3H-imidazo[4,5-b]pyridine was prepared from 6-iodo(3-
methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine
according to the procedure described for the synthesis of Example 3- 6: H NMR
(400 MHz, DMSO-d ) δ 8.91 (d, J = 2.3 Hz, 1H), 8.76 (s, 1H), 8.64 (s, 1H), 8.56 (d, J
= 2.3 Hz, 1H), 8.20 (d, J = 1.7 Hz, 1H), 7.74 (dd, J = 8.5, 2.4 Hz, 1H), 7.16 (d, J = 2.0
Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.87 (dd, J = 8.3, 2.0 Hz, 1H), 6.83 (d, J = 8.5 Hz,
1H), 5.48 (s, 2H), 4.97 (s, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 3.22 – 3.16 (m, 1H), 2.98 –
2.79 (m, 2H), 2.65 – 2.52 (m, 2H), 2.14 – 2.03 (m, 1H), 1.71 – 1.43 (m, 3H) ppm;
(M+1) = 527.
17965367_1 (GHMatters) P41917NZ00
Example 3- 26: Synthesis of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)(4-methylpiperazinyl)-1H-benzo[d]imidazolamine
1-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-methylpiperazin
yl)-1H-benzo[d]imidazolamine was prepared from 5-iodo(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazolamine and 1-
methylpiperazine according to the procedure described for the synthesis of Example
3- 13: H NMR (500 MHz, CDCl ) 8.19 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 8.5, 3.0
Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H),
6.79 – 6.75 (m, 2H), 6.72 (s, 1H), 6.67 (d, J = 8.5 Hz, 1H), 5.03 (s, 2H), 5.02 (s, 2H),
3.94 (s, 3H), 3.77 (s, 3H), 3.22 – 3.17 (m, 4H), 2.65 – 2.59 (m, 4H), 2.37 (s, 3H) ppm;
(M+1) = 489.
Example 3- 27: Synthesis of 1-(2-fluoromethoxy((6-methoxypyridin
yl)methoxy)benzyl)(4-methylpiperazinyl)-1H-benzo[d]imidazole
Example 3- 27- 1: Preparation of 5-((4-bromofluoro
methoxyphenoxy)methyl)methoxypyridine
To a stirred solution of 4-bromofluoromethoxyphenol (2.82 g, 12.25 mmol) in
N,N-dimethylformamide (50 mL) was added 5-(chloromethyl)methoxypyridine
hydrochloride (2.50 g, 12.86 mmol) and potassium carbonate (5.08 g, 36.75 mmol).
The reaction mixture was heated to 100 °C. After 2 h, the mixture was allowed to
cool to room temperature and was diluted with water. The mixture was extracted with
ethyl acetate (3 x 25 mL). The combined organic phases were washed with brine,
dried over magnesium sulfate, filtered, and concentrated. Chromatographic
purification (0-33% ethyl acetate/hexanes elute) afforded 2.76 g (66%) of 5-((4-
bromofluoromethoxyphenoxy)methyl)methoxypyridine as an oil.
Example 3- 27- 2: Preparation of 2-fluoromethoxy((6-methoxypyridin
yl)methoxy)benzonitrile
To a stirred solution of 5-((4-bromofluoromethoxyphenoxy)methyl)
methoxypyridine (4.57 g, 13.36 mmol) in N,N-dimethylformamide (50 mL) was
added copper(I) cyanide (3.59 g, 40.07 mmol). The mixture was heated to 150 °C.
After 16 h, the mixture was allowed to cool to room temperature and was diluted with
dichloromethane. The mixture was filtered through Celite. The filtrate was washed
with water and brine, dried over magnesium sulfate, filtered, and concentrated.
Chromatographic purification (Combi-Flash, 80 g SiO2 column, 1-5%
17965367_1 (GHMatters) P41917NZ00
methanol/dichloromethane elute) afforded 3.25 g (84%) of 2-fluoromethoxy((6-
methoxypyridinyl)methoxy)benzonitrile as an off-white solid.
Example 3- 27- 3: Preparation of (2-fluoromethoxy((6-methoxypyridin
yl)methoxy)phenyl)methanamine
To a 0 °C stirred solution of 2-fluoromethoxy((6-methoxypyridin
yl)methoxy)benzonitrile (3.25 g, 11.27 mmol) in tetrahydrofuran (50 mL) was added
(in three portions) lithium aluminum hydride (0.86 g, 22.55 mmol). Mild gas
evolution was noted upon each addition, and the color of the reaction mixture became
olive-green. After 1.5 h, the mixture was quenched by the slow addition of water (1.0
mL), 15% sodium hydroxide solution (1.0 mL), and water (3.0 mL). The resulting
off-white suspension was allowed to stir at 0 °C. After 15 min, the mixture was
filtered through Celite with the aid of ethyl acetate. The filtrate was concentrated to
provide 1.91 g (58%) of (2-fluoromethoxy((6-methoxypyridin
yl)methoxy)phenyl)methanamine as a crude oil.
Example 3- 27- 4: Preparation of N-(2-fluoromethoxy((6-methoxypyridin-
3-yl)methoxy)benzyl)iodonitroaniline
To a stirred solution of (2-fluoromethoxy((6-methoxypyridin
yl)methoxy)phenyl)methanamine (0.89 g, 3.04 mmol) in acetonitrile (15 mL) was
added 1-fluoroiodonitrobenzene (0.89 g, 3.35 mmol) and N,N-
diisopropylethylamine. The resulting yellow solution was heated to reflux. After 16
h, the mixture was allowed to cool to room temperature and was diluted with water.
The mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic
phases were washed with brine, dried over magnesium sulfate, filtered, and
concentrated. Chromatographic purification (Combi-Flash, 40 g SiO2 column, 0-33%
ethyl acetate/hexanes elute) afforded 0.38 g (23%) of N-(2-fluoromethoxy((6-
methoxypyridinyl)methoxy)benzyl)iodonitroaniline as a solid.
Example 3- 27- 5: Preparation of N -(2-fluoromethoxy((6-methoxypyridin-
3-yl)methoxy)benzyl)iodobenzene-1,2-diamine
To a stirred solution of N-(2-fluoromethoxy((6-methoxypyridin
yl)methoxy)benzyl)iodonitroaniline (0.38 g, 0.70 mmol) in tetrahydrofuran (10
mL), methanol (5 mL), and water (1 mL) was added ammonium chloride (0.30 g, 5.64
mmol) and iron (II) sulfate heptahydrate (0.69 g, 2.47 mmol). The bright orange
suspension was treated with zinc (0.16 g, 2.47 mmol). The mixture was gradually
warmed to reflux. After 3.5 h, the color of the reaction mixture had turned from
17965367_1 (GHMatters) P41917NZ00
orange to olive-green. At this point the reaction mixture was allowed to cool to room
temperature. The mixture was filtered through Celite, and the filtercake was washed
with chloroform (250 mL). The filtrate was washed with 5N ammonium hydroxide
solution (75 mL). The organic phase was dried over magnesium sulfate, filtered, and
concentrated to afford 0.36 g (100 %) of N -(2-fluoromethoxy((6-
methoxypyridinyl)methoxy)benzyl)iodobenzene-1,2-diamine as a tan solid.
Example 3- 27- 6: Preparation of 1-(2-fluoromethoxy((6-methoxypyridin-
3-yl)methoxy)benzyl)iodo-1H-benzo[d]imidazole
To a stirred solution of N -(2-fluoromethoxy((6-methoxypyridin
yl)methoxy)benzyl)iodobenzene-1,2-diamine (0.36 g, 0.70 mmol) in ethanol (10
mL) was added triethyl orthformate (0.31 g, 2.11 mmol) and p-toluenesulfonic acid
(0.007 g, 0.035 mmol). The reaction mixture was heated to reflux. After 30 min, the
brown solution was allowed to cool to room temperature and was concentrated. The
residue was partitioned between water and dichloromethane. The phases were
separated, and the aqueous phase extracted with dichloromethane. The combined
organic phases were washed with water and brine, dried over magnesium sulfate,
filtered, and concentrated. Chromatographic purification (Combi-Flash, 12 g SiO
column, 1-5% methanol/dichloromethane elute) afforded 0.25 g (68%) of 1-(2-fluoro-
-methoxy((6-methoxypyridinyl)methoxy)benzyl)iodo-1H-
benzo[d]imidazole as a tan solid.
Example 3- 27- 7: Preparation of 1-(2-fluoromethoxy((6-methoxypyridin-
3-yl)methoxy)benzyl)(4-methylpiperazinyl)-1H-benzo[d]imidazole
To a stirred suspension of 1-(2-fluoromethoxy((6-methoxypyridin
yl)methoxy)benzyl)iodo-1H-benzo[d]imidazole (0.20 g, 0.39 mmol) in dimethyl
sulfoxide (4 mL) was added 1-methylpiperazine (0.039 g, 0.39 mmol), copper(I)
iodide (0.009 g, 0.046 mmol), potassium carbonate (0.19 g, 1.35 mmol), and L-
proline (0.010 g, 0.092 mmol). The light yellow reaction mixture was heated to 120
°C. After 16 h, the reaction mixture was allowed to cool to room temperature and was
diluted with 3 N ammonium hydroxide solution (20 mL). The mixture was extracted
with dichloromethane. The organic phase was washed with water (2 x 15 mL), brine,
dried over magnesium sulfate, filtered, and concentrated. Chromatographic
purification (CombiFlash, 40 g SiO column, 1-5% methanol/dichloromethane elute)
provided 0.062 g of impure material. Subsequent re-purification via Prep-HPLC
afforded 0.030 g (16%) of the product as a solid: H NMR (400 MHz, CDCl ) δ 8.19
17965367_1 (GHMatters) P41917NZ00
(d, J = 2.0 Hz, 1H), 7.88 (s, 1H), 7.65 (dd, J = 8.5, 2.5 Hz, 1H) 7.33 (d, J = 2.1 Hz,
1H), 7.29 - 7.22 (m, 2H), 7.07 - 6.99 (m, 1H), 6.78 - 6.69 (m, 2H), 6.56 (d, J = 7.1 Hz,
1H), 5.30 (s, 2H), 5.00 (s, 2H), 3.94 (s, 3H), 3.69 (s, 3H), 3.25 - 3.18 (m, 4H), 2.71 -
2.59 (m, 4H), 2.39 (s, 3H) ppm; (M+1) = 492.
Example 3- 28: Synthesis of 3-(3-Ethoxy((6-methoxypyridin
yl)methoxy)benzyl)(4-methylpiperazinyl)-3H-imidazo[4,5-b]pyridine
Example 3- 28- 1: Preparation of 3-ethoxy((6-methoxypyridin
yl)methoxy)benzaldehyde
To a stirred solution of 3-ethoxyhydroxybenzaldehyde (2.75 g, 16.55 mmol) in
acetonitrile (75 mL) was added 5-(chloromethyl)methoxypyridine hydrochloride
(3.37 g, 17.38 mmol) and potassium carbonate (9.15 g, 66.20 mmol). The mixture
was heated to reflux. After 3 h, the yellow mixture was allowed to cool to room
temperature and was diluted with water (400 mL), resulting in the formation of a
precipitate. The solids were isolated by filtration and washed with water (50 mL).
The filtrate was extracted with chloroform (2 x 100 mL). The organic phases were
combined with the previously isolated solids. The resulting solution was dried over
magnesium sulfate, filtered, and concentrated to provide 3.40 g (72%) of 3-ethoxy
((6-methoxypyridinyl)methoxy)benzaldehyde as a yellow solid.
Example 3- 28- 2: Preparation of 3-ethoxy((6-methoxypyridin
yl)methoxy)benzaldehyde oxime
To a stirred solution of 3-ethoxy((6-methoxypyridinyl)methoxy)benzaldehyde
(3.40 g, 11.83 mmol) in methanol (50 mL), pyridine (1.5 mL), and water (5 mL) was
added hydroxylamine hydrochloride (1.23 g, 17.75 mmol). The reaction mixture was
heated to reflux. After 2 h, the colorless solution was allowed to cool to room
temperature and was concentrated. The residue was suspended in water (50 mL) and
filtered. The solids were washed with water and then dissolved in ethyl acetate (150
mL). The solution was dried over magnesium sulfate, filtered, and concentrated to
provide 3.05 g (85%) of 3-ethoxy((6-methoxypyridinyl)methoxy)benzaldehyde
oxime as an off-white solid.
Example 3- 28- 3: Preparation of (3-ethoxy((6-methoxypyridin
yl)methoxy)phenyl)methanamine
To a stirred solution of 3-ethoxy((6-methoxypyridinyl)methoxy)benzaldehyde
oxime (3.05 g, 10.09 mmol) in acetic acid (25 mL) was added zinc (3.30 g, 50.44
mmol). The resulting mixture was heated to 65 °C. After 2 h, the gray suspension
17965367_1 (GHMatters) P41917NZ00
was allowed to cool to room temperature and was diluted with ethyl acetate (150 mL).
The mixture waas filtered through Celite with the aid of additional ethyl acetate (50
mL). The filtrate was diluted with water (50 mL) and made basic by the addition of
concentrated ammonium hydroxide solution (~ 30 mL). The phases were separated,
and the aqueous phase was extracted with ethyl acetate (50 mL). The combined
organic phases were dried over magnesium sulfate, filtered, and concentrated to
provide 2.75 g (95%) of (3-ethoxy((6-methoxypyridin
yl)methoxy)phenyl)methanamine as a yellow oil.
Example 3- 28- 4: Preparation of N-(3-ethoxy((6-methoxypyridin
yl)methoxy)benzyl)iodonitropyridinamine
To a stirred solution of (3-ethoxy((6-methoxypyridin
yl)methoxy)phenyl)methanamine (2.75 g, 9.54 mmol) in acetonitrile (50 mL) was
added 2-chloroiodonitropyridine (2.85 g, 10.01 mmol) and N,N-
diisopropylethylamine (1.85 g, 14.31 mmol). The resulting yellow mixture was
heated to reflux. After 3 h, the red-brown solution was allowed to cool to room
temperature, resulting in the formation of a precipitate. The solids were isolated by
filtration and washed with water (200 mL). The moist solids were dissolved in
dichloromethane (100 mL), and a small amount of water separated and was removed.
The solution was dried over magnesium sulfate, filtered, and concentrated to provide
4.34 g (85%) of N-(3-ethoxy((6-methoxypyridinyl)methoxy)benzyl)iodo
nitropyridinamine as an orange solid.
Example 3- 28- 5: Preparation of N -(3-ethoxy((6-methoxypyridin
yl)methoxy)benzyl)iodopyridine-2,3-diamine
To a stirred suspension of N-(3-ethoxy((6-methoxypyridinyl)methoxy)benzyl)-
5-iodonitropyridinamine (4.34 g, 8.09 mmol) in acetic acid (25 mL) was added
iron powder (2.26 g, 40.46 mmol). The reaction mixture was heated to 90 °C. After
min, the reaction mixture became a gray-brown suspension. The mixture was
allowed to cool to room temperature and was diluted with ethyl acetate (200 mL).
The mixture was filtered through Celite with the aid of additional ethyl acetate (50
mL). The filtrate was washed with water (2 x 50 mL) and then with 1N sodium
hydroxide solution (3 x 50 mL). The organic phase was dried over magnesium
sulfate, filtered, and concentrated to provide 3.99 g (97%) of N -(3-ethoxy((6-
methoxypyridinyl)methoxy)benzyl)iodopyridine-2,3-diamine as a tan solid.
17965367_1 (GHMatters) P41917NZ00
Example 3- 28- 6: Preparation of 3-(3-ethoxy((6-methoxypyridin
yl)methoxy)benzyl)iodo-3H-imidazo[4,5-b]pyridine
To a stirred suspension of N -(3-ethoxy((6-methoxypyridinyl)methoxy)benzyl)-
-iodopyridine-2,3-diamine (3.99 g, 7.88 mmol) in ethanol (50 mL) was added
triethyl orthoformate (2.67 g, 18.02 mmol) and p-toluenesulfonic acid monohydrate
(0.075 g, 0.39 mmol). As the mixture was heated to reflux, a brown solution was
obtained. After 30 min, the mixture was allowed to cool to room temperature,
resulting in the formation of a precipitate. The solids were isolated by filtration,
washed with ethanol, and dried to provide 2.50 g (61%) of 3-(3-ethoxy((6-
methoxypyridinyl)methoxy)benzyl)iodo-3H-imidazo[4,5-b]pyridine as a tan
solid.
Example 3- 28- 7: Preparation of 3-(3-Ethoxy((6-methoxypyridin
yl)methoxy)benzyl)(4-methylpiperazinyl)-3H-imidazo[4,5-b]pyridine
To a stirred suspension of 3-(3-ethoxy((6-methoxypyridinyl)methoxy)benzyl)-
6-iodo-3H-imidazo[4,5-b]pyridine (0.37 g, 0.71 mmol) in dimethylsulfoxide was
added 1-methylpiperazine (0.086 g, 0.85 mmol), copper(I) iodide (0.033 g, 0.18
mmol), L-proline (0.041 g, 0.35 mmol), and potassium carbonate (0.24 g, 1.77 mmol).
The mixture was degasssed under vacuum/backfilled with N (x 3) and then heated to
120 °C. After 16 h, the dark brown mixture was allowed to cool to room temperature
and was diluted with 5N ammonium hydroxide solution (50 mL). The mixture was
extracted with dichloromethane (3 x 50 mL). The combined organic phases were
dried over magnesium sulfate, filtered, and concentrated to provide 0.36 g of a brown
oil. Chromatographic purification (Combi-Flash, 12 g SiO gold column, 5-10% 2M
ammonia in methanol/dichloromethane elute) afforded 0.14 g (41%) of the product as
an orange solid: H NMR (400 MHz, DMSO-d ) δ 8.43 (s, 1H), 8.22 – 8.19 (m, 2H),
7.73 (dd, J = 8.5, 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.99
(d, J = 8.2 Hz, 1H), 6.86 – 6.76 (m, 2H), 5.33 (s, 2H), 4.97 (s, 2H), 3.97 (q, J = 6.9
Hz, 2H), 3.84 (s, 3H), 3.17 – 3.08 (m, 4H), 2.53 – 2.45 (m, 4H), 2.23 (s, 3H), 1.28 (t,
J = 6.9 Hz, 3H); (M+1) = 489.
Example 3- 29: Synthesis of 1-(1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)methylpiperazinone
1-(1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazol-
-yl)methylpiperazinone was prepared from 5-iodo(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazole (Step 5, Example 6)
17965367_1 (GHMatters) P41917NZ00
and 4-methylpiperazinone using the procedure outlined for Example 3- 14: H
NMR (500 MHz, CDCl ) 8.21 (d, J = 2.0 Hz, 1H), 7.97 (s, 1H), 7.70 – 7.68 (m,
2H), 7.34 (d, J = 8.5 Hz, 1H), 7.22 (dd, J = 8.5, 1.5 Hz, 1H), 6.90 – 6.89 (m, 1H), 6.78
– 6.74 (m, 3H), 5.29 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.79 (t, J = 5.5
Hz, 2H), 3.35 (s, 2H), 2.86 (t, J = 5.5 Hz, 2H), 2.46 (s, 3H) ppm; (M+1) = 488.
Example 3- 30: Synthesis of 3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(5-methylazabicyclo[3.2.1]octenyl)-3H-
imidazo[4,5-b]pyridine
Example 3- 30- 1: Preparation of tert-butyl 3-ethynylmethylpiperidine
carboxylate
To a stirred solution of tert-butyl 3-formylmethylpiperidinecarboxylate (2.10 g,
9.25 mmol) in methanol (40 mL) was added potassium carbonate (2.76 g, 20.00
mmol). The mixture was treated with dimethyl 1-diazooxopropylphosphonate
(2.11 g, 11.00 mmol), and the resulting mixture was allowed to stir at room
temperature. After 2 h, the mixture was concentrated, diluted with water, and
extracted with ethyl acetate. The organic phase was washed with brine, dried over
magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel
chromatography (6% ethyl acetate/petroleum ether elute) to afford 1.50 g (73%) of
tert-butyl 3-ethynylmethylpiperidinecarboxylate as a pale yellow oil.
Example 3- 30- 2: Preparation of 3-ethynylmethylpiperidine hydrochloride
To a stirred solution of tert-butyl 3-ethynylmethylpiperidinecarboxylate (0.50 g,
2.24 mmol) in dichloromethane (10 mL) was added a solution of hydrogen chloride in
1,4-dioxane (3.0M, 5.0 mL, 15.00 mmol). The resulting solution was allowed to stir at
room temperature. After 2 h, the mixture was concentrated to provide 0.34 g (95%) of
3-ethynylmethylpiperidine hydrochloride (340 mg, 95%) as a white solid.
Example 3- 30- 3: Preparation of 3-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)(5-methylazabicyclo[3.2.1]octenyl)-3H-
imidazo[4,5-b]pyridine
To a stirred suspension of 6-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (Step 3, Example 19, 0.20 g, 0.40
mmol) in tetrahydrofuran (3.0 mL) was added 3-ethynylmethylpiperidine
hydrochloride (0.13 g, 1.00 mmol), bis(triphenylphosphine)palladium(II) chloride
(0.055 g, 0.078 mmol), copper(I) iodide (0.030 g, 0.16 mmol), and piperidine (0.17 g,
17965367_1 (GHMatters) P41917NZ00
2.00 mmol). The mixture was heated to 60 C in a microwave reactor. After 30 min,
the mixture was allowed to cool to room temperature and was filtered through Celite.
The filtrate was concentrated, and the residue was purified by Prep-HPLC to afford
0.020 g (10%) of the product as a yellow solid: H NMR (500 MHz, CDCl3) 8.77
(d, J = 2.0 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.01 (s, 1H),
7.68 (dd, J = 8.0, 2.0 Hz, 1H), 6.94 – 6.76 (m, 4H), 6.02 (s, 1H), 5.40 (s, 2H), 5.04 (s,
2H), 3.95 (s, 3H), 3.82 (s, 3H), 3.22 (d, J = 8.5 Hz, 1H), 2.94 – 2.86 (m, 2H), 2.80 (d,
J = 9.5 Hz, 1H), 1.91 – 1.85 (m, 1H), 1.60 – 1.46 (m, 3H), 1.16 (s, 3H) ppm; (M+1) =
498.
Example 3- 31: Synthesis of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)(5-methylazabicyclo[3.2.1]octenyl)-1H-
benzo[d]imidazole
1-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(5-methyl
azabicyclo[3.2.1]octenyl)-1H-benzo[d]imidazole was prepared from 5-iodo
(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazole and
3-ethynylmethylpiperidine hydrochloride using the procedure outlined for the
synthesis of Example 3- 30: H NMR (500 MHz, CDCl ) 8.22 – 8.21 (m, 1H), 8.09
(s, 1H), 7.93 (s, 1H), 7.69 (dd, J = 8.5, 2.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.28 –
7.26 (m, 1H, partially obscurred by CHCl ), 6.89 (d, J = 8.5 Hz, 1H), 6.77 (d, J = 8.5
Hz, 1H), 6.75 – 6.73 (m, 2H), 5.93 (s, 1H), 5.28 (s, 2H), 5.04 (s, 2H), 3.95 (s, 3H),
3.80 (s, 3H), 3.21 (dd, J = 9.5, 1.5 Hz, 1H), 2.92 – 2.90 (m, 2H), 2.79 (d, J = 10.0 Hz,
1H), 1.87 – 1.83 (m, 1H), 1.57-1.43 (m, 3H), 1.14 (s, 3H) ppm; (M+1) = 497.
Example 3- 32: Synthesis of 7-(3-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)azabicyclo[3.2.1]octen-
5-ol
Example 3- 32- 1: Preparation of 3-ethynylpiperidinol hydrochloride
3-Ethynylpiperidinol hydrochloride was prepared from tert-butyl 3-ethynyl
hydroxypiperidinecarboxylate and hydrogen chloride using the procedure outlined
in Example 3- 30.
Example 3- 32- 2: Preparation of 7-(3-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)azabicyclo[3.2.1]octen-
-ol
17965367_1 (GHMatters) P41917NZ00
7-(3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-
b]pyridinyl)azabicyclo[3.2.1]octenol was prepared from 6-iodo(3-
methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine and
3-ethynylpiperidinol hydrochloride using the procedure outlined for the synthesis
of Example 3- 30: H NMR (500 MHz, CDCl ) 8.76 (d, J = 2.0 Hz, 1H), 8.29 (d, J
= 1.5 Hz, 1H), 8.20 (d, J = 2.7 Hz, 1H), 8.04 (s, 1H), 7.68 (dd, J = 8.5, 2.7 Hz, 1H),
6.93 (d, J = 2.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.85 (dd, J = 8.0, 1.5 Hz, 1H), 6.77
(d, J = 8.5 Hz, 1H), 6.19 (s, 1H), 5.41 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.83 (s, 3H),
3.43 – 3.41 (m, 1H), 2.94 – 2.91 (m, 1H), 2.85 – 2.81 (m, 2H), 1.91 – 1.84 (m, 2H),
1.74 – 1.71 (m, 2H) ppm; (M+1) = 500.
Example 3- 33: Synthesis of 7-(1-(3-Methoxy((6-methoxypyridin
yl)methoxy)benzyl)-1H-benzo[d]imidazolyl)azabicyclo[3.2.1]octenol
7-(1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazol-
-yl)azabicyclo[3.2.1]octenol was prepared from 5-iodo(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-1H-benzo[d]imidazole and 3-ethynylpiperidin-
3-ol hydrochloride using the procedure outlined for the synthesis of Example 3- 30:
H NMR (500 MHz, CDCl ) 8.21 (d, J = 2.5 Hz, 1H), 8.09 (s, 1H), 7.95 (s, 1H),
7.69 (dd, J = 8.5, 2.5 Hz, 1H), 7.59 (dd, J = 8.5, 1.0 Hz, 1H), 7.29 – 7.26 (m, 1H,
partially obscurred by CHCl ), 6.89 (d, J = 9.0 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 6.75
– 6.73 (m, 2H), 6.09 (s, 1H), 5.29 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 3.41
– 3.39 (m, 1H), 2.92 – 2.83 (m, 3H), 1.89 – 1.81 (m, 3H), 1.71 – 1.67 (m, 1H) ppm;
(M+1) = 499.
Example 3- 34: Synthesis of 3-(3-methoxy(1-(6-methoxypyridin
yl)propoxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin
amine
Example 3- 34- 1: Preparation of ethyl N-({5-iodo[({3-methoxy[(4-
methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin
yl}carbamothioyl)carbamate
To a stirred solution of 5-iodo-N -(3-methoxy((4-
methoxybenzyl)oxy)benzyl)pyridine-2,3-diamine (Example 3- 16- 2) (2.00 g, 4.07
mmol) and triethylamine (1.30 g, 1.8 mL, 12.85 mmol) in tetrahydrofuran (20 mL)
was added O-ethyl carbonisothiocyanatidate (1.07 g, 8.20 mmol). The reaction
mixture was allowed to stir at room temperature. After 3 h, the mixture was filtered,
17965367_1 (GHMatters) P41917NZ00
and the filtrate was concentrated to provide 2.30 g of ethyl N-({5-iodo[({3-
methoxy[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin
yl}carbamothioyl)carbamate as a yellow oil.
Example 3- 34- 2: Preparation of ethyl (6-iodo(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)carbamate
To a stirred solution of ethyl N-({5-iodo[({3-methoxy[(4-
methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin
yl}carbamothioyl)carbamate (2.30 g, 3.69 mmol) and triethylamine (1.30 g, 1.8 mL,
12.85 mmol) in tetrahydrofuran (20 mL) was added benzenesulfonyl chloride (0.93 g,
5.27 mmol). The resulting mixture was allowed to stir at room temperature. After 12
h, a precipitate had formed. The mixture was filtered, and the filtercake was washed
with water (2 x 10 mL) and methanol (10 mL). The solids were dried to provide 1.50
g (69%) of ethyl (6-iodo(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H-
imidazo[4,5-b]pyridinyl)carbamate as a brown solid.
Example 3- 34- 3: Preparation of ethyl (3-(3-methoxy((4-
methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinyl)carbamate
To a stirred solution of ethyl (6-iodo(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)carbamate (11.80 g,
20.05 mmol) and 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole (5.00 g, 24.03 mmol) in N,N-dimethylformamide (100 mL) and 2M aqueous
sodium carbonate solution (10 mL) was added (1,1'-
bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.87 g, 1.19 mmol). The
resulting mixture was heated to 80 ºC under a nitrogen atmosphere. After 4 h, the
mixture was allowed to cool to room temperature and was filtered through Celite.
The filtrate was diluted with water (150 mL) and extracted with ethyl acetate (3 x 200
mL). The combined organic phases were washed with water (300 mL) and brine (2 x
300 mL), dried over sodium sulfate, filtered, and concentrated. Chromatographic
purification (silica gel, 5% methanol in dichloromethane elute) afforded 2.50 g (23%)
of ethyl (3-(3-methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinyl)carbamate as a gray solid.
Example 3- 34- 4: Preparation of ethyl (3-(4-hydroxymethoxybenzyl)(1-
methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinyl)carbamate
17965367_1 (GHMatters) P41917NZ00
To a stirred solution of ethyl (3-(3-methoxy((4-methoxybenzyl)oxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinyl)carbamate (2.50 g, 4.61
mmol) in dichloromethane (100 mL) at 0 ºC was added trifluoroacetic acid (4.47 g,
3.0 mL, 39.18 mmol). The resulting mixture was allowed to stir at 0 ºC. After 2 h,
the mixture was treated with 2M potassium carbonate solution to adjust the pH to ~ 9.
The basic mixture was extracted with 1:1 methanol/dichloromethane solution (2 x 50
mL). The combined organic phases were washed with brine (2 x 50 mL), dried over
sodium sulfate, filtered, and concentrated to provide 1.80 g (93%) of ethyl (3-(4-
hydroxymethoxybenzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin-
2-yl)carbamate as a white solid.
Example 3- 34- 5: Preparation of 5-(1-chloropropyl)methoxypyridine
To a stirred solution of 1-(6-methoxypyridinyl)propanol (1.67 g, 9.99 mmol) in
dichloromethane (30 mL) at 0 ºC was added thionyl chloride (2.46 g, 1.5 mL, 20.68
mmol). The cooling bath was removed, and the mixture was allowed to warm to
room temperature. After 1 h, the reaction was quenched by the addition of saturated
aqueous sodium bicarbonate solution. The phases were separated, and the organic
phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and
concentrated to provide 1.50 g (81%) of 5-(1-chloropropyl)methoxypyridine as a
yellow oil.
Example 3- 34- 6: Preparation of 3-(3-methoxy(1-(6-methoxypyridin
yl)propoxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin
amine
To a stirred solution of ethyl (3-(4-hydroxymethoxybenzyl)(1-methyl-1H-
pyrazolyl)-3H-imidazo[4,5-b]pyridinyl)carbamate (0.300 g, 0.710 mmol) in
tetrahydrofuran (20 mL) was added 5M aqueous sodium hydroxide solution (0.72 mL,
3.60 mmol). The resulting mixture was allowed to stir at room temperature. After 2
h, the mixture was concentrated, and the residue was dissolved in N,N-
dimethylformamide (10 mL). The solution was treated with 5-(1-chloropropyl)
methoxypyridine (0.263 g, 1.42 mmol), and the resulting mixture was heated to 80 ºC.
After 3 h, the mixture was allowed to cool to room temperature and was diluted with
water (20 mL). The mixture was extracted with ethyl acetate (3 x 40 mL). The
combined organic phases were dried over sodium sulfate, filtered, and concentrated to
provide 0.26 g of a brown solid. The crude solid was dissolved in ethylene glycol (6
mL) and water (2 mL). The solution was treated with potassium hydroxide (0.13 g,
17965367_1 (GHMatters) P41917NZ00
2.32 mmol) and heated to 100 ºC. After 12 h, the mixture was allowed to cool to
room temperature and was filtered through Celite. The filtrate was concentrated, and
the residue was purified by prep-HPLC to afford 0.070 g (30%) of the product as a
white solid: H NMR (500 MHz, DMSO-d ) 8.10 – 8.07 (m, 3H), 7.83 (s, 1H), 7.66
– 7.64(m, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.04 (d, J = 1.5 Hz, 1H), 6.86 (s, 2H), 6.77 –
6.74 (m, 2H), 6.58 – 6.57 (m, 1H), 5.15 – 5.12 (m, 3H), 3.85 (s, 3H), 3.79 (s, 3H),
3.72 (s, 3H), 1.95 – 1.90 (m, 1H), 1.78 – 1.74 (m, 1H), 0.85 (t, . J = 7.5 Hz, 3H) ppm;
(M+1) = 500.
Example 3- 35: Synthesis of additional compounds from ethyl (3-(4-hydroxy
methoxybenzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin
yl)carbamate
The following compounds were prepared from ethyl (3-(4-hydroxy
methoxybenzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin
yl)carbamate using the procedure described in Example 36 by employing the
appropriate alkylating agent:
Example 3- 35- 1: 3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)
(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
H NMR (500 MHz, DMSO-d ) 8.21 (d, J = 2.5 Hz, 1H), 8.12 – 8.11 (m, 2H), 7.85
(s, 1H), 7.74 (dd, J = 8.5, 2.0 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.10 (d, J = 1.5 Hz,
1H), 6.98 (d, J = 8.5 Hz, 1H), 6.89 (s, 2H), 6.83 (d, J = 8.5 Hz, 1H), 6.74 (dd, J = 8.0,
1.5 Hz, 1H), 5.19 (s, 2H), 4.96 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.71 (s, 3H) ppm;
(M+1) = 472.
Example 3- 35- 2: 3-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin
amine
H NMR (400 MHz, DMSO-d ) 8.81 (s, 1H), 8.11- 8.09 (m, 3H), 7.93 (d, J = 8.0
Hz, 1H), 7.85 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 7.00 – 6.98
(m, 1H), 6.91 (s, 2H), 6.75 – 6.72 (m, 1H), 5.21 – 5.20 (m, 4H), 3.86 (s, 3H), 3.74 (s,
3H) ppm; (M+1) = 510.
Example 3- 35- 3: 3-(3-methoxy((4-(trifluoromethyl)benzyl)oxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine (RA09651030)
17965367_1 (GHMatters) P41917NZ00
H NMR (500 MHz, MeOD-d ) 8.17 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.68 – 7.61
(m, 5H), 7.00 (d, J = 1.5 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.75 – 6.74 (m, 1H), 5.29
(s, 2H), 5.15 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H) ppm; (M+1) = 509.
Example 3- 35- 4: 3-(4-((6-cyclopropylpyridinyl)methoxy)methoxybenzyl)-
6-(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine (RA09677155)
H NMR (500 MHz, DMSO-d ) 8.42 (d, J = 1.5 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H),
8.10 (s, 1H), 7.85 (s, 1H), 7.66 (dd, J = 8.0, 2.5 Hz, 1H), 7.59 (d, J = 2.5 Hz, 1H),
7.28 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 6.89 (s,
2H), 6.73 (dd, J = 8.0, 1.0 Hz, 1H), 5.19 (s, 2H), 4.98 (s, 2H), 3.86 (s, 3H), 3.71 (s,
3H), 2.10 – 2.07 (m, 1H), 0.95 – 0.89 (m, 4H) ppm; (M+1) = 482.
Example 3- 35- 5: 3-(3-methoxy((2-methylthiazolyl)methoxy)benzyl)(1-
methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
H NMR (500 MHz, DMSO-d ) 8.11-8.10 (m, 2H), 7.85 (s, 1H), 7.59 (d, J = 1.5
Hz, 1H), 7.48 (s, 1H), 7.11 (d, J = 1.5 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.90 (s, 2H),
6.74- 6.72 (m, 1H), 5.19 (s, 2H), 5.01 (s, 2H), 3.86 (s, 3H), 3.72 (s, 3H) 2.64 (s, 3H)
ppm; (M+1) = 462.
Example 3- 36: Synthesis of 3-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)phenyl-3H-imidazo[4,5-b]pyridinamine
Example 3- 36- 1: Preparation of ethyl (3-(4-hydroxymethoxybenzyl)iodo-
3H-imidazo[4,5-b]pyridinyl)carbamate
To a stirred solution of ethyl (6-iodo(3-methoxy((4-
methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)carbamate (Example 3-
34- 2) (2.40 g, 4.08 mmol) in dichloromethane (50 mL) at 0 ºC was added
trifluoroacetic acid (4.47 g, 3.0 mL, 39.18 mmol). The resulting mixture was allowed
to stir at 0 ºC. After 2 h, the mixture was treated with 2M potassium carbonate
solution to adjust the pH to ~ 9. The basic mixture was extracted with 1:1
methanol/dichloromethane solution (3 x 50 mL). The combined organic phases were
washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to
provide 1.30 g (70%) of ethyl (3-(4-hydroxymethoxybenzyl)iodo-3H-
imidazo[4,5-b]pyridinyl)carbamate as a light yellow solid.
Example 3- 36- 2: Preparation of ethyl (6-iodo(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)carbamate
17965367_1 (GHMatters) P41917NZ00
To a stirred solution of ethyl (3-(4-hydroxymethoxybenzyl)iodo-3H-
imidazo[4,5-b]pyridinyl)carbamate ( ) (1.30 g , 2.78 mmol) and 5M aqueous
sodium hydroxide solution (0.8 mL, 4.00 mmol) in N,N-dimethylformamide (10 mL)
and tetrahydrofuran (10 mL) was added 5-(chloromethyl)methoxypyridine (0.567
g, 3.60 mmol). The resulting mixture was allowed to stir at room temperature. After
2 h, the mixture was diluted with brine (40 mL) and extracted with ethyl acetate (3 x
40 mL). The combined organic phases were dried over sodium sulfate, filtered, and
concentrated to provide 1.10 g (71%) of ethyl (6-iodo(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)carbamate as a
white solid.
Example 3- 36- 3: Preparation of ethyl (3-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)phenyl-3H-imidazo[4,5-b]pyridinyl)carbamate
To a stirred solution of ethyl (6-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)carbamate (0.300 g, 0.51 mmol),
phenylboronic acid (0.093 g, 0.76 mmol), and sodium carbonate (0.108 g, 1.20 mmol)
in 1,4-dioxane (8 mL) and water (3 mL) was added (1,1'-
bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.080 g, 0.11 mmol). The
mixture was heated to 60 ºC under a nitrogen atmosphere. After 4 h, the reaction
mixture was allowed to cool to room temperature and was filtered through Celite.
The filtrate was diluted with water (40 mL) and extracted with ethyl acetate (3 x 20
mL). The combined organic phases were washed with brine (2 x 20 mL), dried over
sodium sulfate, filtered, and concentrated. Chromatographic purification of the
residue (silica gel, 2% methanol in dichloromethane elute) afforded 0.100 g (40%) of
ethyl (3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)phenyl-3H-
imidazo[4,5-b]pyridinyl)carbamate as a white solid.
Example 3- 36- 4: Preparation of 3-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)phenyl-3H-imidazo[4,5-b]pyridinamine
To a stirred solution of ethyl (3-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)phenyl-3H-imidazo[4,5-b]pyridinyl)carbamate (0.090 g,
0.17 mmol) in ethylene glycol (10 mL) and water (10 mL) was added potassium
hydroxide (1.00 g, 17.82 mmol). The mixture was heated to 100 ºC. After 48 h, the
mixture was allowed to cool to room temperature and was diluted with water (30 mL).
The mixture was extracted with dichloromethane (3 x 10 mL). The combined organic
phases were dried over sodium sulfate, filtered, and concentrated. The residue was
17965367_1 (GHMatters) P41917NZ00
purified by prep-HPLC to afford 0.027 g (34%) of the product as a yellow solid: H
NMR (500 MHz, CDCl ) 8.36 (s, 1H), 8.21 (s, 1H), 7.87 (s, 1H),7.70 – 7.68 (m,
3H), 7.50 (s, 2H), 7.40 (s, 1H), 6.90 – 6.77 (m, 4H), 5.31 (s, 2H), 5.05 (s, 2H), 4.77 (s,
2H), 3.95 (s, 3H), 3.81 (s, 3H) ppm; (M+1) = 468.
Example 3- 37: Synthesis of additional compounds from ethyl (6-iodo(3-
methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-
2-yl)carbamate
The following compounds were prepared from ethyl (6-iodo(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)carbamate
using a modification of the procedure described in Example 3- 36- 3 by employing
the appropriate boronic acid/boronate ester coupling partner. For these compounds,
the reactions were conducted under microwave irradiation (140 ºC for 1.5 h). Under
these conditions, both the Suzuki coupling and hydrolysis of the carbamate were
accomplished in one step:
Example 3- 37- 1: 6-(4-fluorophenyl)(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinamine
H NMR (500 MHz, DMSO-d ) 8.21 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 1.5 Hz, 1H),
7.75 - 7.69 (m, 3H), 7.66 (d, J = 2.0 Hz, 1H), 7.30 – 7.26 (m, 2H), 7.12 (d, J = 2.0 Hz,
1H), 7.00-6.98 (m, 3H), 6.83 (d, J = 8.5 Hz, 1H), 6.73 (dd, J = 8.0 Hz & 1.5 Hz, 1H),
5.23 (s, 2H), 4.96 (s, 2H), 3.84 (s, 3H), 3.72 (s, 3H) ppm; (M+1) = 486.
Example 3- 37- 2: 3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)
(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine (RA09936946)
H NMR (500 MHz, CDCl ) 8.55 (d, J = 1.5 Hz, 1H), 8.18 (d, J = 2.5 Hz, 1H), 8.03
(d, J = 2.0 Hz, 1H), 7.66 (dd, J = 6.5, 2.0 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 6.87 (d, J
= 8.0 Hz, 1H), 6.83 – 6.81 (m, 1H), 6.77 (dd, J = 6.5, 2.0 Hz, 1H), 6.75 (d, J = 8.0 Hz,
1H), 6.55 (d, J= 2.5 Hz, 1H), 5.26 (s, 2H), 5.03 (s, 2H), 4.74 (br s, 2H), 3.98 (s, 3H),
3.93 (s, 3H), 3.77 (s, 3H) ppm; (M+1) = 472.
Example 3- 37- 3: 3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)
(pyrimidinyl)-3H-imidazo[4,5-b]pyridinamine (RA09943893)
H NMR (500 MHz, DMSO-d ) 9.17 – 9.15 (m, 3H), 8.29 (d, J = 2.0 Hz, 1H), 8.20
(d, J = 2.0 Hz, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.74 (dd, J = 8.5, 2.5 Hz, 1H), 7.12 (d, J
= 1.5 Hz, 1H), 7.08 (s, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.74 –
6.72 (m, 1H), 5.25 (s, 2H), 4.97 (s, 2H), 3.84 (s, 3H), 3.72 (s, 3H) ppm; (M+1) = 470.
17965367_1 (GHMatters) P41917NZ00
Example 3- 37- 4: 3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)
(1,3,5-trimethyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
H NMR (500 MHz, CDCl ) 8.21 (d, J = 2.5 Hz, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.69
(dd, J = 6.5, 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 6.92 – 6.88 (m, 2H), 6.81 (dd, J =
6.0, 2.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.29 (s, 2H), 5.06 (s, 2H), 4.77 (br s, 2H),
3.95 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H) ppm; (M+1) = 500.
Example 3- 37- 5: 3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)
(pyridinyl)-3H-imidazo[4,5-b]pyridinamine
H NMR (500 MHz, DMSO-d ) 8.60 – 8.59 (m, 2H), 8.33 (d, J = 1.5 Hz, 1H), 8.20
(d, J = 2.0 Hz, 1H), 7.83 (d, J = 1.5 Hz, 1H), 7.75 – 7.73 (m, 3H), 7.12 (d, J = 2.0 Hz,
1H), 7.06 (s, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.73 (dd, J = 8.5,
1.5 Hz, 1H), 5.24 (s, 2H), 4.96 (s, 2H), 3.84 (s, 3H), 3.71 (s, 3H) ppm; (M+1) = 469.
Example 3- 37- 6: 3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)
(pyridinyl)-3H-imidazo[4,5-b]pyridinamine
H NMR (500 MHz, DMSO-d ) 8.90 (d, J = 2.0 Hz, 1H), 8.55 – 8.54 (m, 1H), 8.21
– 8.20 (m, 2H), 8.09 (d, J = 2.0 Hz, 1H), 7.75 – 7.72 (m, 2H), 7.47 – 7.42 (m, 1H),
7.11 (d, J = 1.5 Hz, 1H), 7.03 – 6.98 (m, 3H), 6.82 (d, J = 8.5 Hz, 1H), 6.74 – 6.72
(m, 1H), 5.24 (s, 2H), 4.96 (s, 2H), 3.83 (s, 3H), 3.71 (s, 3H); (M+1) = 469.
Example 3- 38: Synthesis of 3-(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)(pyridinyl)-3H-imidazo[4,5-b]pyridinamine
To a stirred solution of ethyl (6-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)carbamate (0.250 g, 0.42 mmol),
2-(tributylstannyl)pyridine (0.235 g, 0.63 mmol), copper(I) iodide (0.040 g, 0.21
mmol) and triethylamine (0.130 g, 1.26 mmol) in N,N-dimethylformamide (5 mL)
was added bis(triphenylphosphine)palladium(II) dichloride (0.018 g, 0.042 mmol).
The mixture was irradiated in a microwave reactor at 140 ºC. After 1.5 h, the mixture
was allowed to cool to room temperature and was filtered through Celite. The filtrate
was concentrated. The residue was purified by prep-HPLC to afford 0.025 g (13%)
of the product as a white solid: H NMR (500 MHz, DMSO-d ) 8.64 (d, J = 4.0 Hz,
1H), 8.62 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.97
(d, J = 7.5 Hz, 1H), 7.84 – 7.76 (m, 1H),7.74 – 7.72 (m, 1H), 7.32 – 7.29 (m, 1H),
7.12 (d, J = 6.0 Hz, 1H), 7.00 – 6.77 (m, 3H), 6.82 (d, J = 8.5 Hz, 1H), 6.83 – 6.74
(m, 1H), 5.24 (s, 2H), 4.96 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H) ppm; (M+1) = 469.
17965367_1 (GHMatters) P41917NZ00
Example 3- 39: Synthesis of 3-(3-methoxy((4-
(perfluoroethyl)benzyl)oxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
Example 3- 39- 1: Preparation of 4-(perfluoroethyl)benzyl 4-
methylbenzenesulfonate
To a stirred solution of (4-(perfluoroethyl)phenyl)methanol (0.60 g, 2.65 mmol) and
triethylamine (0.53 g, 5.30 mmol) in dichloromethane (30 mL) was added p-
toluenesulfonyl chloride (1.00 g, 5.30 mmol). The resulting mixture was allowed to
stir at room temperature. After 2 h, the mixture was concentrated. Chromatographic
purification of the residue (silica gel, 10% ethyl acetate in petroleum ether elute)
afforded 0.400 g (40%) of 4-(perfluoroethyl)benzyl 4-methylbenzenesulfonate as a
yellow oil.
Example 3- 39- 2: Preparation of ethyl (6-iodo(3-methoxy((4-
(perfluoroethyl)benzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)carbamate
To a stirred solution of ethyl (3-(4-hydroxymethoxybenzyl)iodo-3H-
imidazo[4,5-b]pyridinyl)carbamate (Example 31) (0.24 g, 0.52 mmol) in
tetrahydrofuran (20 mL) was added 5M aqueous sodium hydroxide solution (0.2 mLs,
1.00 mmol). The resulting mixture was allowed to stir at room temperature. After 2
h, the mixture was concentrated, and the residue was dissolved in N,N-
dimethylformamide (10 mL). The mixture was treated with 4-(perfluoroethyl)benzyl
4-methylbenzenesulfonate (0.40 g, 1.04 mmol), and the mixture was warmed to 80 ºC.
After 3 h, the mixture was allowed to cool to room temperature and was diluted with
water (20 mL). The mixture was extracted with ethyl acetate (3x 40 mL), and the
combined organic phases were dried over sodium sulfate, filtered, and concentrated to
provide 0.090 g of ethyl (6-iodo(3-methoxy((4-
(perfluoroethyl)benzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)carbamate as a
brown solid.
Example 3- 39- 3: Preparation of 3-(3-methoxy((4-
(perfluoroethyl)benzyl)oxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
To a stirred solution of ethyl (6-iodo(3-methoxy((4-
(perfluoroethyl)benzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)carbamate (0.090
g, 0.13 mmol) and 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-
pyrazole (0.054 g, 0.26 mmol) in N,N-dimethylformamide (3 mL) and 2M aqueous
17965367_1 (GHMatters) P41917NZ00
sodium carbonate solution (150 L) was added (1,1'-
bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.050 g, 0.06 mmol). The
resulting mixture was heated to 80 ºC under a nitrogen atmosphere. After 4 h, the
mixture was allowed to cool to room temperature and was filtered through Celite.
The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20
mL). The combined organic phases were dried over sodium sulfate, filtered, and
concentrated. The residue was purified by prep-HPLC to afford 0.010 g (14%) of the
product as a white solid: H NMR (400 MHz, DMSO-d ) 8.10 (s, 2H), 7.84 (s, 1H),
7.72 – 7.70 (m, 2H), 7.66 – 7.64 (m, 2H), 7.58 (d, J = 1.6 Hz, 1H), 7.12 (d, J = 1.6
Hz, 1H), 6.95 – 6.89 (m, s3H), 6.72 (d, J = 6.8 Hz, 1H), 5.19 (s, 2H), 5.15 (s, 2H),
3.85 (s, 3H), 3.73 (s, 3H) ppm; (M+1) = 559.
Example 3- 40: Synthesis of additional compounds from ethyl (3-(4-hydroxy
methoxybenzyl)iodo-3H-imidazo[4,5-b]pyridinyl)carbamate
The following compounds were prepared from ethyl (3-(4-hydroxy
methoxybenzyl)iodo-3H-imidazo[4,5-b]pyridinyl)carbamate using the
procedures described in Example 3- 39- 2 and Example 3- 39- 3 by employing the
appropriate alkylating agent:
Example 3- 40- 1: 3-(3-methoxy((4-(trifluoromethoxy)benzyl)oxy)benzyl)
(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine (RA10502607)
H NMR (500 MHz, DMSO-d ) 8.11 (s, 2H), 7.85 (s, 1H), 7.58 (d, J = 2.5 Hz, 1H),
7.54 - 7.53 (m, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.12 (s, 1H),6.94 (d, J = 8.0 Hz, 1H),
6.91 – 6.89 (m, 2H), 6.72 (d, J = 7.5 Hz, 1H), 5.19 (s, 2H), 5.05 (s, 2H), 3.86 (s, 3H),
3.73 (s, 3H) ppm; (M+1) = 525.
Example 3- 40- 2: 3-(3-methoxy((4-((trifluoromethyl)thio)benzyl)oxy)benzyl)-
6-(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
H NMR (400 MHz, CDCl ) δ 8.26 (d, J = 1.6 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J = 1.6
Hz, 1H), 7.67 - 7.64 (m, 3H), 7.49 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 1.6 Hz, 1H), 6.83 –
6.78 (m, 2H), 5.27 (s, 2H), 5.15 (s, 2H), 3.98 (s, 3H), 3.82 (s, 3H) ppm (note: NH
portons not observed); (M+1) = 541.
Example 3- 40- 3: 3-(4-((6-isopropylpyridinyl)methoxy)methoxybenzyl)
(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
H NMR (400 MHz, CDCl ) δ 8.58 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H), 7.78
(s, 1H), 7.72 – 7.70 (m, 2H), 7.64 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.89 – 6.84 (m,
17965367_1 (GHMatters) P41917NZ00
2H), 6.79 (dd, J = 6.4, 1.6 Hz, 1H), 5.27 (s, 2H), 5.09 (m, 4H), 3.98 (s, 3H), 3.80 (s,
3H), 3.10 – 3.06 (m, 1H), 1.32 (d, J = 6.8 Hz, 6H) ppm; (M+1) = 484.
Example 3- 40- 4: 3-(3-methoxy((4-(2,2,2-trifluoroethyl)benzyl)oxy)benzyl)
(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
H NMR (400 MHz, DMSO-d ) 8.96 (s, 2H), 8.48 (s, 1H), 8.26 (s, 1H), 7.97 (s,
1H), 7.86 (s, 1H), 7.42 – 7.40 (m, 2H), 7.36 – 7.34 (m, 2H), 7.18 (s, 1H), 6.98 – 6.96
(m, 1H), 6.83 – 6.81 (m, 1H), 5.30 (s, 2H), 5.04 (s, 2H), 3.88 (s, 3H), 3.75 (s, 3H),
3.66 (q, J= 9.6 Hz, 2H) ppm; (M+1) = 523.
Example 3- 40- 5: 3-(3-methoxy((2-(trifluoromethyl)thiazol
yl)methoxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin
amine
H NMR (400 MHz, DMSO-d ) δ 8.16 (s, 1H), 8.11 (s, 2H), 7.85 (s, 1H), 7.59 (s,
1H), 7.13 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.92 (s, 2H), 6.75 (d, J = 8.4 Hz, 1H), 5.20
– 5.18 (m, 4H), 3.86 (s, 3H), 3.72 (s, 3H) ppm; (M+1) = 516.
Example 3- 41: Synthesis of 6-(cyclohexylethynyl)(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinamine
Example 3- 41- 1: Preparation of 6-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinamine
To a stirred solution of ethyl (6-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)carbamate (Example 3- 36- 2)
(0.42 g, 0.71 mmol) in ethylene glycol (6 mL) and water (1 mL) was added potassium
hydroxide (0.197 g, 3.51 mmol). The resulting mixture was heated to 100 ºC. After
12 h, the mixture was allowed to cool to room temperature and was diluted with brine
(40 mL). The mixture was extracted with ethyl acetate (3 x 40 mL). The combined
organic phases were dried over sodium sulfate, filtered, and concentrated.
Chromatographic purification of the residue (silica gel, 3% methanol in
dichloromethane elute) afforded 0.206 g (56%) of 6-iodo(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinamine as a yellow
solid.
Example 3- 41- 2: Preparation of 6-(cyclohexylethynyl)(3-methoxy((6-
methoxypyridinyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinamine
To a stirred suspension of 6-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinamine (0.14 g, 0.27 mmol),
17965367_1 (GHMatters) P41917NZ00
ethylnylcyclohexane (0.044 g, 0.41 mmol) in piperidine (3 mL) was added
bis(triphenylphosphine)palladium(II) dichloride (0.038 g, 0.054 mmol) and copper(I)
iodide (0.021 g, 0.11 mmol). The mixture was irradiated in a microwave reactor at 60
ºC. After 30 min, the reaction mixture was allowed to cool to room temperature and
was filtered through Celite. The filtrate was concentrated, and the residue was
purified by prep-HPLC to provide 0.032 g (23%) of the product as a white solid: H
NMR (500 MHz, DMSO-d ) 8.20 (s, 1H), 7.91 (s, 1H), 7.74 (dd, J = 8.5, 1.5 Hz,
1H), 7.42 – 7.32 (m, 1H), 7.07 – 6.97 (m, 4H), 6.83 (d, J = 8.5 Hz, 1H), 6.71 (d, J =
7.5 Hz, 1H), 5.20 (s, 2H), 4.96 (s, 2H), 3.84 (s, 3H), 3.69 (s, 3H), 2.65 – 2.58 (m, 1H),
1.88 – 1.78 (m, 2H), 1.75 – 1.62 (m, 2H), 1.50 – 1.46 (m, 3H), 1.35 – 1.32 (m, 3H)
ppm; (M+1) = 498.
Example 3- 42: Synthesis of 4-(2-amino(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinyl)butynol
This compound was prepared from 6-iodo(3-methoxy((6-methoxypyridin
yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridinamine and butynol using the
procedure described in Example 3- 41- 2: H NMR (500 MHz, DMSO-d ) 8.21 (s,
1H), 7.93 (s, 1H), 7.74 (dd, J = 8.5, 2.0 Hz, 1H), 7.41 (s, 1H), 7.08 – 6.97 (m, 4H),
6.83 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 5.20 (s, 2H), 4.96 (s, 2H), 4.91 (t, J
= 5.5 Hz, 1H), 3.84 (s, 3H), 3.69 (s, 3H), 3.61 – 3.57 (m, 2H), 2.56 (t, J = 6.5 Hz, 2H)
ppm; (M+1) = 460.
Example 3- 43: Synthesis of 3-(4-(cyclopropyl(6-methoxypyridinyl)methoxy)-
3-methoxybenzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin
amine
Example 3- 43- 1: Preparation of cyclopropyl(6-methoxypyridinyl)methanol
To a stirred -78 ºC solution of 5-bromomethoxypyridine (3.70 g, 19.79 mmol) in
tetrahydrofuran (10 mL) was added 2.6 M n-butyllithium solution in hexane (8.4 mL,
21.84 mmol). The mixture was allowed to stir at -78 ºC for 30 min, and then
cyclopropanecarboxaldehye (1.70 g, 23.74 mmol) was added in one portion. The
cooling bath was removed, and the mixture was allowed to warm to room
temperature. After 2 h, the mixture was quenched by the addition of saturated
aqueous ammonium chloride solution (100 mL). The resulting mixture was extracted
with ethyl acetate (3 x 100 mL). The combined organic phases were dried over
sodium sulfate, filtered, and concentrated. Chromatographic purification of the
17965367_1 (GHMatters) P41917NZ00
residue (silica gel, 20% ethyl acetate in petroleum ether elute) afforded 2.90 g (80%)
of cyclopropyl(6-methoxypyridinyl)methanol as a yellow oil.
Example 3- 43- 2: Preparation of 4-(cyclopropyl(6-methoxypyridin
yl)methoxy)methoxybenzonitrile
To a stirred 0 ºC solution of cyclopropyl(6-methoxypyridinyl)methanol (3.80 g,
21.20 mmol), 4-hydroxymethoxybenzonitrile (1.60 g, 10.73 mmol), and
triphenylphosphine (5.60 g, 21.35 mmol) in tetrahydrofuran (10 mL) was added
diethyl azodicarboxylate (3.70 g, 21.25 mmol) dropwise. The resulting mixture was
allowed to warm to room temperature. After 2 h, the mixture was concentrated.
Chromatographic purification of the residue (silica gel, 10% ethyl acetate in
petroleum ether elute) afforded 2.70 g (80%) of 4-(cyclopropyl(6-methoxypyridin
yl)methoxy)methoxybenzonitrile as a light yellow oil.
Example 3- 43- 3: Preparation of (4-(cyclopropyl(6-methoxypyridin
yl)methoxy)methoxyphenyl)methanamine
To a stirred 0 ºC solution of 4-(cyclopropyl(6-methoxypyridinyl)methoxy)
methoxybenzonitrile (2.50 g, 8.06 mmol) in ethanol (20 mL) was added cobalt(II)
chloride hexahydrate (2.20 g, 9.25 mmol) in small portions. The resulting mixture
was allowed to stir at 0 ºC. After 30 min, the mixture was treated with sodium
borohydride (1.80 g, 47.58 mmol) added in small portions. The mixture was allowed
to warm to room temperature. After 30 min, the mixture was filterd through Celite,
and the filtercake was washed with ethanol (20 mL). The filtrate was concentrated to
provide 2.50 g (99%) of (4-(cyclopropyl(6-methoxypyridinyl)methoxy)
methoxyphenyl)methanamine as a colorless oil.
Example 3- 43- 4: Preparation of N-(4-(cyclopropyl(6-methoxypyridin
yl)methoxy)methoxybenzyl)iodonitropyridinamine
To a stirred solution of (4-(cyclopropyl(6-methoxypyridinyl)methoxy)
methoxyphenyl)methanamine (2.50 g, 7.95 mmol) and potassium carbonate (1.41 g,
.20 mmol) in acetonitrile (10 mL) was added 2-chloroiodonitropyridine (2.90
g, 10.20 mmol). The resulting mixture was heated to 80 ºC. After 2 h, the mixture
was filtered, and the filtrate was concentrated. Chromatographic purification of the
residue (silica gel, 20% ethyl acetate in petroleum ether elute) afforded 2.60 g (58%)
of N-(4-(cyclopropyl(6-methoxypyridinyl)methoxy)methoxybenzyl)iodo
nitropyridinamine as a yellow oil.
17965367_1 (GHMatters) P41917NZ00
Example 3- 43- 5: Preparation of N-(4-(cyclopropyl(6-methoxypyridin
yl)methoxy)methoxybenzyl)(1-methyl-1H-pyrazolyl)nitropyridin
amine
To a stirred solution of N-(4-(cyclopropyl(6-methoxypyridinyl)methoxy)
methoxybenzyl)iodonitropyridinamine (2.20 g, 3.91 mmol), 1-methyl
(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole (0.896 g, 4.30 mmol), and
potassium carbonate (1.10 g, 7.95 mmol) in toluene (10 mL) and water (1 mL) was
added (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.143 g, 0.20
mmol). The resulting mixture was heated to 100 ºC and stirred under a nitrogen
atmosphere. After 16 h, the mixture was allowed to cool to room temperature and
was diluted with water (15 mL). The mixture was extracted with ethyl acetate (2 x 60
mL). The combined organic phases were dried over sodium sulfate, filtered, and
concentrated. Chromatographic purification of the residue (silica gel, 33% ethyl
acetate in petroleum ether elute) afforded 1.10 g (55%) of N-(4-(cyclopropyl(6-
methoxypyridinyl)methoxy)methoxybenzyl)(1-methyl-1H-pyrazolyl)
nitropyridinamine as a light brown solid.
Example 3- 43- 6: Preparation of N -(4-(cyclopropyl(6-methoxypyridin
yl)methoxy)methoxybenzyl)(1-methyl-1H-pyrazolyl)pyridine-2,3-
diamine
To a stirred solution of N-(4-(cyclopropyl(6-methoxypyridinyl)methoxy)
methoxybenzyl)(1-methyl-1H-pyrazolyl)nitropyridinamine (1.10 g, 2.13
mmol) and ammonium chloride (0.564 g, 10.54 mmol) in ethanol (8 mL) and water (2
mL) was added iron powder (0.596 g, 10.67 mmol). The mixture was heated to 80 ºC.
After 2 h, the mixture was allowed to cool to room temperature and was filtered
through Celite. The filtrate was concentrated. Chromatographic purification of the
residue (neutral alumina, 2% methanol in dichloromethane elute) afforded 0.984 g
(95%) of N -(4-(cyclopropyl(6-methoxypyridinyl)methoxy)methoxybenzyl)
(1-methyl-1H-pyrazolyl)pyridine-2,3-diamine as a brown solid.
Example 3- 43- 7: Preparation of ethyl (3-(4-(cyclopropyl(6-methoxypyridin
yl)methoxy)methoxybenzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinyl)carbamate
To a stirred solution of N -(4-(cyclopropyl(6-methoxypyridinyl)methoxy)
methoxybenzyl)(1-methyl-1H-pyrazolyl)pyridine-2,3-diamine (0.55 g, 1.13
mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.799 g, 7.90 mmol). The
17965367_1 (GHMatters) P41917NZ00
resulting mixture was allowed to stir at room temperature. After 15 min, the mixture
was treated with ethyl carbonisothiocyanatidate (0.444 g, 3.39 mmol), and the
resulting mixture was allowed to stir at room temperature. After 30 min, the mixture
was filtered, and the filtrate was concentrated. The residue was dissolved in
tetrahydrofuran (5 mL) and was treated with triethylamine (0.799 g, 7.90 mmol) and
benzenesulfonyl chloride (0.259 g, 1.43 mmol). The resulting mixture was allowed to
stir at room temperature. After 16 h, the mixture was concentrated. Chromatographic
purification of the residue (neutral alumina, 50% ethyl acetate in petroleum ether
elute) afforded 0.45 g (68%) of ethyl (3-(4-(cyclopropyl(6-methoxypyridin
yl)methoxy)methoxybenzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinyl)carbamate as a brown oil.
Example 3- 43- 8: Preparation of 3-(4-(cyclopropyl(6-methoxypyridin
yl)methoxy)methoxybenzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine
To a stirred solution of ethyl (3-(4-(cyclopropyl(6-methoxypyridinyl)methoxy)
methoxybenzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridin
yl)carbamate (0.44 g, 0.75 mmol) in n-butanol (4 mL) and water (4 mL) was added
potassium hydroxide (0.42 g, 7.49 mmol). The mixture was heated to 130 ºC. After
16 h, the mixture was allowed to cool to room temperature and was diluted with water
(15 mL). The mixture was extracted with ethyl acetate (2 x 60 mL). The combined
organic phases were dried over sodium sulfate, filtered, and concentrated. The
resiude was purified via prep-HPLC to provide 0.058 g (15%) of the product as a
white solid: H NMR (500 MHz, CDCl ) δ 8.24 (d, J = 1.5 Hz, 1H), 8.09 (d, J = 3.0
Hz, 1H), 7.78 (s, 1H), 7.70 – 7.68 (m, 2H), 7.64 (s, 1H), 6.78 – 6.23 (m, 4H), 5.21 (s,
2H), 4.85 (s, 2H), 4.50 (d, J = 8.5 Hz, 1H), 3.98 (s, 3H), 3.93 (s, 3H), 3.79 (s, 3H),
1.45 – 1.40 (m, 1H), 0.75 – 0.70 (m, 1H), 0.61 – 0.50 (m, 2H), 0.38 – 0.34 (m, 1H)
ppm; (M+1) = 512.
Example 3- 44: Synthesis of 3-(3-methoxy((3-methoxy-5,6,7,8-
tetrahydroisoquinolinyl)oxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
Example 3- 44- 1: Preparation of 3-methoxy-5,6,7,8-tetrahydroisoquinolinol
To a stirred 0ºC solution of 3-methoxy-6,7-dihydroisoquinolin-8(5H)-one (1.90 g,
.72 mmol) in methanol (30 mL) was added sodium borohydride (1.10 g, 29.08
mmol) in small portions. The resulting mixture was allowed to warm to room
17965367_1 (GHMatters) P41917NZ00
temperature. After 2 h, the mixture was quenched with water (20 mL) and was
extracted with ethyl acetate (3 x 100 mL). The combined organic phases were dried
over sodium sulfate, filtered, and concentrated. Chromatographic purification of the
residue (silica gel, 50% ethyl acetate in petroleum ether elute) afforded 1.60 g (85%)
of 3-methoxy-5,6,7,8-tetrahydroisoquinolinol as a light yellow solid.
Example 3- 44- 2: Preparation of 3-(3-methoxy((3-methoxy-5,6,7,8-
tetrahydroisoquinolinyl)oxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
This compound was prepared from 3-methoxy-5,6,7,8-tetrahydroisoquinolinol
using the procedures outlined in Example 3- 43- 2 through Example 3- 43- 8: H
NMR (400 MHz, CDCl ) δ 8.25 (d, J = 1.6 Hz, 1H), 8.12 (s, 1H), 7.77 (s, 1H), 7.70
(d, J = 2.0 Hz, 1H), 7.63 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 1.6 Hz, 1H),
6.79 (dd, J = 8.4, 1.6 Hz, 1H), 6.50 (s, 1H), 5.27 – 5.24 (m, 3H), 5.03 (s, 2H), 3.97 (s,
3H), 3.89 (s, 3H), 3.76 (s, 3H), 2.87 – 2.81 (m, 1H), 2.72 – 2.65 (m, 1H), 2.19 – 1.73
(m, 4H) ppm; (M+1) = 512
Example 3- 45: Synthesis of 1-(1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethyl)(1-methyl-1H-pyrazolyl)-1H-benzo[d]imidazol
amine
Example 3- 45- 1: Preparation of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethanone
To a stirred suspension of 1-(4-hydroxymethoxyphenyl)ethanone (3.96 g, 23.82
mmol) and potassium carbonate (13.17 g, 95.29 mmol) in acetonitrile (75 mL) was
added 5-(chloromethyl)methoxypyridine hydrochloride (4.85 g, 25.01 mmol).
After 2 h, the mixture was diluted with water (150 mL) and extracted with
dichloromethane (3 x 100 mL). The combined organic phases were dried over
magnesium sulfate, filtered, and concentrated to provide a yellow oil. Trituration of
the crude material with hexanes afforded 5.48 g (85%) of 1-(3-methoxy((6-
methoxypyridinyl)methoxy)phenyl)ethanone as a white solid.
Example 3- 45- 2: Preparation of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethanone oxime
To a stirred suspension of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethanone (5.48 g, 19.07 mmol) and potassium carbonate (10.54
g, 76.29 mmol) in methanol (100 mL) and water (10 mL) was added hydroxylamine
sulfate (4.70 g, 28.61 mmol). The resulting mixture was heated to reflux. After 64 h,
17965367_1 (GHMatters) P41917NZ00
the mixture was allowed to cool to room temperature and was diluted with water (250
mL). The resulting suspension was filtered, and the filtercake was washed with water
(50 mL) and dried to provide 5.55 g (96%) of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethanone oxime as a white solid.
Example 3- 45- 3: Preparation of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethanamine
To a stirred solution of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethanone oxime (5.55 g, 18.36 mmol) in acetic acid (40 mL)
was added zinc dust (6.00 g, 91.79 mmol). The resulting mixture was heated to 65 ºC.
After 1 h, the mixture was allowed to cool to room temperature and was filtered
through Celite. The filtercake was washed with methanol (100 mL). The filtrate was
concentrated, and the residue dissolved in 5N ammonium hydroxide solution (75 mL).
The mixture was extracted with chloroform (2 x 50 mL). The combined organic
phases were dried over magneisum sulfate, filtered, and concentrated to provide 4.56
g (86%) of 1-(3-methoxy((6-methoxypyridinyl)methoxy)phenyl)ethanamine
as a yellow oil.
Example 3- 45- 4: Preparation of 4-iodo-N-(1-(3-methoxy((6-methoxypyridin-
3-yl)methoxy)phenyl)ethyl)nitroaniline
To a stirred solution of 1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethanamine (1.93 g, 6.68 mmol) and potassium carbonate (3.70
g, 26.75 mmol) in acetonitrile (75 mL) was added 1-fluoroiodonitrobenzene
(2.14 g, 8.02 mmol). The mixture was heated to reflux. After 16 h, the orange
mixture was allowed to cool to room temperature and was diluted with water (150
mL). The mixture was extracted with dichloromethane (3 x 75 mL), and the
combined organic phases were dried over magnesium sulfate, filtered, and
concentrated to provide 3.82 g of an orange solid. Trituration of the crude material
with hexanes afforded 3.17 g (89%) of 4-iodo-N-(1-(3-methoxy((6-
methoxypyridinyl)methoxy)phenyl)ethyl)nitroaniline as a bright ornage solid.
Example 3- 45- 5: Preparation of 4-iodo-N1-(1-(3-methoxy((6-
methoxypyridinyl)methoxy)phenyl)ethyl)benzene-1,2-diamine
To a stirred suspension of 4-iodo-N-(1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethyl)nitroaniline (3.17 g, 5.92 mmol) and ammonium chloride
(2.53 g, 47.37 mmol) in tetrahydrofuran (50 mL)/methanol (20 mL)/water (10 mL)
was added iron(II) sulfate heptahydrate (5.76 g, 20.73 mmol) and zinc dust (1.35 g,
17965367_1 (GHMatters) P41917NZ00
.73 mmol). The resulting mixture was heated to reflux. After 1 h, the mixture was
allowed to cool to room temperature and was filtered through Celite. The filtercake
was washed with methanol (50 mL). The filtrate was concentrated, and the residue
was diluted with 3N ammonium hydroxide solution (100 mL). The basic mixture was
extracted with chloroform (3 x 50 mL), and the combined organic phases were dried
over magnesium sulfate, filtered, and concentrated to provide 2.02 g (68%) of 4-iodo-
N -(1-(3-methoxy((6-methoxypyridinyl)methoxy)phenyl)ethyl)benzene-1,2-
diamine as a brown solid.
Example 3- 45- 6: Preparation of 5-iodo(1-(3-methoxy((6-methoxypyridin-
3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazolamine
To a stirred solution of 4-iodo-N -(1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethyl)benzene-1,2-diamine (2.02 g, 4.00 mmol) in
dichloromethane (20 mL)/methanol (10 mL) was added cyanogen bromide solution
(5.0M in acetonitrile, 4.0 mL, 20.00 mmol). The resulting dark brown solution was
allowed to stir at room temperature. After 17 h, the mixture was diluted with 1N
sodium hydroxide solution (20 mL), and the basic mixture was allowed to stir. After
min, the phases were separated, and the aqueous phase was extracted with
chloroform (30 mL). The combined organic phases were dried over magnesium
sulfate, filtered, and concentrated to provide 3.36 g of a brown oil. Chromatographic
purification of the residue (CombiFlash, 120 g SiO gold column, 1-5% methanol in
dichloromethane elute) provided a brown semi-solid. Trituration of this material with
1:1 diethyl ether/dichloromethane afforded 0.801 g (38 %) of 5-iodo(1-(3-
methoxy((6-methoxypyridinyl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol
amine as a tan solid.
Example 3- 45- 7: Preparation of 1-(1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethyl)(1-methyl-1H-pyrazolyl)-1H-benzo[d]imidazol
amine
To stirred mixture of 5-iodo(1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazolamine (0.267 g, 0.50 mmol), 1-
methyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1H-pyrazole (0.138 g, 0.63
mmol), tricyclohexylphosphine (0.014 g, 0.050 mmol), potassium phosphate tribasic
(0.381 g, 1.76 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was added
palladium(II) acetate (0.005 g, 0.025 mmol). The mixture was heated to 125 ºC in a
microwave reactor. After 30 min, additional portions of catalyst (0.005 g) and ligand
17965367_1 (GHMatters) P41917NZ00
(0.014 g) were added, and the mixture was reheated in a microwave reactor to 150 ºC.
After 60 min of reaction time, the crude mixture was transferred to a 20 mL
microwave reaction vial and was treated with an additional portions of boronate ester
(0.050 g) , catalyst (0.005 g), and ligand (0.014 g). The mixture was diluted with
additional 1,4-dioxane (8 mL) and water (4 mL). The mixture was heated to 150 ºC
in a microwave reactor. After a total of 105 min, the reaction was complete. The
mixture was diluted with water (30 mL) and extracted with dichloromethane (3 x 25
mL). The combined organic phases were dried over magnesium sulfate, filtered, and
concentrated to provide 419 mgs of a brown oil. Chromatographic purification
(CombiFlash, 12 g SiO gold column, 1-5% 2M ammonia in
methanol/dichloromethane elute) provided 109 mgs of an impure tan solid. A second
chromatographic purification (CombiFlash, 12 g SiO gold column, 1-5% 2M
ammonia in methanol/dichloromethane elute) afforded 0.063 g (26 %) of the product
as as a yellow solid: H NMR (400 MHz, CDCl3) δ 8.22 – 8.16 (m, 1H), 7.75 (d, J =
0.8 Hz, 1H), 7.68 (dd, J = 8.5, 2.4 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.53 (d, J = 1.5
Hz, 1H), 7.20 – 7.16 (m, 1H), 7.11 – 7.06 (m, 1H), 6.96 – 6.87 (m, 2H), 6.80 – 6.73
(m, 2H), 5.55 (q, J = 7.1 Hz, 1H), 5.05 (s, 2H), 4.33 (br s, 2H), 3.95 (s, 3H), 3.94 (s,
3H), 3.76 (s, 3H), 1.87 (d, J = 7.1 Hz, 3H) ppm; (M+1) = 485.
Example 3- 46: Synthesis of 5-(4-fluorophenyl)(1-(3-methoxy((6-
methoxypyridinyl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazolamine
To a stirred solution of 5-iodo(1-(3-methoxy((6-methoxypyridin
yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazolamine (Example 36) (0.195 g,
0.37 mmol), 4-fluorophenylboronic acid (0.064 g, 0.46 mmol), and potassium
phosphate tribasic (0.413 g, 1.91 mmol) in tetrahydrofuran (5 mL)/water (4 mL) was
added 2 generation XPhos precatalyst (0.015 g, 0.018 mmol). The yellow solution
was degassed under vacuum/backfilled with nitrogen (x 3). The mixture was heated
to 60 ºC. After 90 min, the mixture was treated with an additional portion of boronic
acid (0.030 g) and precatalyst (0.014 g), and the temperature was increased to 75 °C.
After a total reaction time of 150 min, the brown mixture was allowed to cool to room
temperature and was diluted with water (30 mL). The mixture was extracted with
dichloromethane (3 x 25 mL). The combined organic phases were dried over
magnesium sulfate, filtered, and concentrated to provide 0.282 g of a brown oil.
Chromatographic purification (CombiFlash, 12 g SiO gold column, 1-5% 2M
ammonia in methanol/dichloromethane elute) afforded 0.142 g (78%) of the product
17965367_1 (GHMatters) P41917NZ00
as a yellow solid: H NMR (400 MHz, CDCl ) δ 8.20 (dd, J = 2.4, 0.8 Hz, 1H), 7.68
(dd, J = 8.4, 2.5 Hz, 1H), 7.62 – 7.52 (m, 3H), 7.23 (dd, J = 8.4, 1.7 Hz, 1H), 7.17 –
7.06 (m, 3H), 6.96 – 6.88 (m, 2H), 6.81 – 6.79 (m, 1H), 6.78 – 6.74 (m, 1H), 5.58 (q,
J = 7.0 Hz, 1H), 5.05 (s, 2H), 4.49 (s, 2H), 3.93 (s, 3H), 3.76 (s, 3H), 1.88 (d, J = 7.0
Hz, 3H) ppm; (M+1) = 499.
Example 3- 47: Synthesis of 5-(4-fluorophenyl)(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole
Example 3- 47- 1: Preparation of 5-iodo(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole
To stirred solution of 4-iodo-N1-(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)ethyl)benzene-1,2-diamine [prepared from 5-(chloromethyl)
(trifluoromethyl)pyridine using the procedures described in Example 31 through
Example 35] (1.04 g, 1.91 mmol) in ethanol (30 mL) was added triethyl
orthoformate (1.0 mL, 5.89 mmol) and p-toluenesulfonic acid monohydrate (0.025 g,
0.13 mmol). The yellow solution was heated to reflux. After 30 min, the mixture was
allowed to cool to room temperature and was concentrated to provide a yellow oil.
Chromatographic purification (CombiFlash, 24 g SiO gold column, 1-5%
methanol/dichloromethane elute) afforded 0.803 g (76%) of 5-iodo(1-(3-methoxy-
4-((6-(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole as
a yellow solid.
Example 3- 47- 2Preparation of 5-(4-fluorophenyl)(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole
To a stirred solution of 5-iodo(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole (0.248 g, 0.45 mmol), (4-
fluorophenyl)boronic acid (0.088 g, 0.63 mmol), and potassium phosphate tribasic
(0.485 g, 2.24 mmol) in tetrahydrofuran (7 mL)/water (5 mL) was added 2
generation XPhos precatalyst (0.024 g, 0.031 mmol). The yellow solution was
degassed under vacuum/backfilled with nitrogen (x 3). The mixture was heated to 75
ºC. After 45 min, the brown reaction mixture was allowed to cool to room
temperature and was diluted with water (30 mL). The mixture was extracted with
dichloromethane (2 x 25 mL). The combined organic phases were dried over
magnesium sulfate, filtered, and concentrated to provide 0.271 g of a brown oil.
Chromatographic purification (CombiFlash, 12 g SiO gold column, 1-5%
methanol/dichloromethane elute) afforded 0.200 g (86 %) of the product as an off-
17965367_1 (GHMatters) P41917NZ00
white solid: H NMR (400 MHz, CDCl ) δ 8.78 (d, J = 2.0 Hz, 1H), 8.08 (s, 1H), 7.99
– 7.94 (m, 2H), 7.70 (dd, J = 8.1, 0.8 Hz, 1H), 7.61 – 7.52 (m, 2H), 7.40 (dd, J = 8.4,
1.7 Hz, 1H), 7.27 – 7.23 (m, 1H), 7.16 – 7.09 (m, 2H), 6.88 – 6.84 (m, 1H), 6.80 –
6.76 (m, 1H), 6.75 – 6.73 (m, 1H), 5.60 (q, J = 7.0 Hz, 1H), 5.20 (s, 2H), 3.80 (s, 3H),
2.01 (d, J = 7.0 Hz, 3H) ppm; (M+1) = 522.
Example 3- 48: Synthesis of additional compounds from 5-iodo(1-(3-methoxy-
4-((6-(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole
The following compound was prepared from 5-iodo(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole using the
procedure described in Example 3- 47- 2 by employing the appropriate boronate ester
coupling partner.
Example 3- 48- 1: 1-(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)ethyl)(1-methyl-1H-pyrazolyl)-1H-benzo[d]imidazole
H NMR (400 MHz, CDCl3) δ 8.82 – 8.75 (m, 1H), 8.04 (s, 1H), 7.99 – 7.93 (m, 1H),
7.89 (dd, J = 1.7, 0.7 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 7.72 – 7.68 (m, 1H), 7.64 –
7.57 (m, 1H), 7.34 (dd, J = 8.4, 1.6 Hz, 1H), 7.18 (dd, J = 8.4, 0.7 Hz, 1H), 6.85 (d, J
= 8.2 Hz, 1H), 6.80 – 6.70 (m, 2H), 5.57 (q, J = 7.0 Hz, 1H), 5.20 (s, 2H), 3.95 (s,
3H), 3.79 (s, 3H), 1.99 (d, J = 7.0 Hz, 3H) ppm; (M+1) = 508.
Example 3- 48- 2: 4-(1-(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazolyl)butynol
To a stirred mixture of 5-iodo(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole (0.210 g, 0.38 mmol), 3-butynol
(0.041 g, 0.57 mmol), copper(I) iodide (0.019 g, 0.10 mmol) in piperidine (4 mL) was
added bis(triphenylphosphine)palladium(II) chloride (0.037 g, 0.053 mmol). The
mixture heated to 100 ºC in a microwave reactor. After 30 min, the reaction mixture
was allowed to cool to room temperature and was diluted with 5N ammonium
hydroxide solution (30 mL). The mixture was extracted with dichloromethane (3 x 25
mL). The combined organic phases were dried over magnesium sulfate, filtered, and
concentrated to provide 0.386 g of a brown solid. Chromatographic purification
(CombiFlash, 12 g SiO gold column, 1-5% methanol/dichloromethane elute)
afforded 0.157 g (84%) of the product as a light yellow solid: H NMR (400 MHz,
CDCl ) δ 8.78 (d, J = 2.1 Hz, 1H), 8.04 (s, 1H), 8.00 – 7.93 (m, 1H), 7.90 – 7.84 (m,
1H), 7.72 – 7.68 (m, 1H), 7.28 – 7.23 (m, 1H), 7.13 – 7.08 (m, 1H), 6.87 – 6.82 (m,
17965367_1 (GHMatters) P41917NZ00
1H), 6.76 – 6.64 (m, 2H), 5.55 (q, J = 7.0 Hz, 1H), 5.19 (s, 2H), 3.83 (t, J = 6.2 Hz,
2H), 3.77 (s, 3H), 2.71 (t, J = 6.2 Hz, 2H), 2.00 – 1.92 (m, 4H) ppm; (M+1) = 496.
Example 3- 49: Synthesis of 3-(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)(1-methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
Example 3- 49- 1: Preparation of 5-iodo-N-(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)nitropyridinamine
To a stirred solution of 1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethanamine [prepared from 1-(chloromethyl)
(trifluoromethyl)benzene using the procedures described in Example 31 through
Example 33] (2.52 g, 7.75 mmol) and N,N-diisopropylethylamine (2.7 mL, 15.18
mmol) in acetonitrile (30 mL) was added 2-chloroiodonitropyridine (2.39 g,
8.13 mmol), The orange solution was heated to reflux. After 15 h, the brown
reaction mixture was allowed to cool to room temperature and was diluted with water
(60 mL). As the mixture was stirred, a yellow precipitate formed. The solids were
isolated by filtration and washed with water (50 mL), and dried to provide 4.19 g
(94%) of 5-iodo-N-(1-(3-methoxy((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)
nitropyridinamine as a yellow solid.
Example 3- 49- 2: Preparation of 5-iodo-N -(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)pyridine-2,3-diamine
To a stirred mixture of 5-iodo-N-(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)nitropyridinamine (4.19 g, 7.31
mmol), and ammonium chloride (3.14 g, 58.47 mmol) in tetrahydrofuran (40
mL)/methanol (40 mL)/water (20 mL) was added iron(II) sulfate heptahydrate (7.18
g, 25.58 mmol) and zinc dust (1.69 g, 25.58 mmol). The yellow mixture was heated
to 60 ºC. As the mixture warmed, an olive green color developed. After 5 min, the
warm reaction mixture was filtered through Celite with the aid of ethyl acetate (100
mL). The filtrate was diluted with 5N ammonium hydroxide solution (30 mL), and
the phases were separated. The aqueous phase was extracted with ethyl acetate (2 x
50 mL). The combined organic phases were dried over magnesium sulfate, filtered,
and concentrated to provide 3.72 g of a brown oil. Chromatographic purification
(CombiFlash, 120 g SiO gold column, 30-60% ethyl acetate/heptane elute) afforded
2.39 g (60%) of 5-iodo-N -(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)pyridine-2,3-diamine as an off-white solid.
17965367_1 (GHMatters) P41917NZ00
Example 3- 49- 3: Preparation of ethyl (6-iodo(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin
yl)carbamate
To stirred solution of 5-iodo-N -(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)pyridine-2,3-diamine (2.39 g, 4.40 mmol)
and triethylamine (0.92 ml, 6.60 mmol) in tetrahydrofuran (30 mL) was added with
ethoxycarbonyl isothiocyanate (0.64 ml, 5.28 mmol). After 3 h, the mixture was
diluted with brine (100 mL) and extracted with ethyl acetate (3 x 50 mL). The
combined organic phases were dried over magnesium sulfate, filtered, and
concentrated to provide 3.16 g of a brown foamy solid. The crude solid was dissolved
in tetrahydrofuran (30 mL) and was treated with triethylamine (1.53 mL, 11.01 mmol)
and benzenesulfonyl chloride (1.42 mL, 11.01 mmol). The yellow mixture was
allowed to stir at room temperature. After 63 h, the mixture was diluted with water
(100 mL) and allowed to stir at room temperature. After 2 h, the reaction mixture was
extracted with dichloromethane (3 x 50 mL). The combined organic phases were
washed with saturated potassium carbonate solution (50 mL), dried over magnesium
sulfate, filtered, and concentrated to provide 3.62 g of a brown oil. Chromatographic
purification (CombiFlash, 80 g SiO gold column, 10-30% ethyl acetate/heptane
elute) provided a tan solid. Trituration of this material with diethyl ether (50 mL)
afforded 1.30 g (46%) of ethyl (6-iodo(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridinyl)carbamate
as a white solid.
Example 3- 49- 4: Preparation of 6-iodo(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridinamine
To a stirred solution of ethyl (6-iodo(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridinyl)carbamate
(1.30 g, 2.03 mmol) in ethanol (8 mL)/water (6 mL) was added potassium phosphate
tribasic (1.76 g, 8.12 mmol). The mixture was heated to 160 °C in a microwave
reactor. After 1 h, the reaction mixture was diluted with water (100 mL), resulting in
a precipitate. The solids were isolated by filtration, washed with water (25 mL), and
dried to provide 1.02 g (88%) of 6-iodo(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridinamine as a
white solid.
17965367_1 (GHMatters) P41917NZ00
Example 3- 49- 5: Preparation of 3-(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)(1-methyl-1H-pyrazolyl)-3H-
imidazo[4,5-b]pyridinamine
To a stirred mixture of 6-iodo(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridinamine (0.253
g, 0.45 mmol), 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-pyrazole
(0.158 g, 0.76 mmol), potassium phsophate tribasic (0.495 g, 2.29 mmol) in
tetrahydrofuran (5 mL)/water (4 mL) was added 2 generation XPhos precatalyst
(0.032 g, 0.041 mmol). The yellow solution was degassed under vacuum/backfilled
with nitrogen (x 3). The mixture heated to 75 ºC. After 4 h, the mixture was allowed
to cool to room temperature and was diluted with water (40 mL). The mixture was
extracted with ethyl acetate (3 x 25 mL). The combined organic phases were dried
over magnesium sulfate, filtered, and concentrated to provide 0.320 g of a brown oil.
Chromatographic purification (CombiFlash, 12 g SiO2 gold column, 1-5% 2M
ammonia in methanol/dichloromethane elute) afforded 0.178 g (77%) of the product
as a tan solid: H NMR (400 MHz, CDCl ) δ 8.25 (d, J = 1.9 Hz, 1H), 7.77 (d, J = 0.8
Hz, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.66 – 7.62 (m, 3H), 7.57 – 7.53 (m, 2H), 6.96 –
6.92 (m, 1H), 6.89 – 6.84 (m, 2H), 6.11 (q, J = 7.1 Hz, 1H), 5.21 (s, 2H), 4.46 (br s,
2H), 3.98 (s, 3H), 3.80 (s, 3H), 1.87 (d, J = 7.1 Hz, 3H) ppm; (M+1) = 523.
Example 3- 49- 6 a and Example 3- 49- 6 b: Chiral separation of 3-(1-(3-
methoxy((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)(1-methyl-1H-
pyrazolyl)-3H-imidazo[4,5-b]pyridinamine
The racemic 3-(1-(3-methoxy((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)(1-
methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridinamine was subjected to chiral
separation using SFC (21 x 250 mm AS column, 25% methanol/0.5% diethylamine,
flow rate 50 g/min) to provide the two enantiomers. The absolute configuration has
not been assigned.
17965367_1 (GHMatters) P41917NZ00
Figure 2: Example 3- 49- 6a Figure 3: Example 3- 49- 6b
Example 3- 50: Synthesis of additional compounds from 6-iodo(1-(3-methoxy-
4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin
amine
The following compounds were prepared from 6-iodo(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridinamine using
the procedure described in Example 3- 49- 5 by employing the appropriate boronate
ester coupling partner.
Example 3- 50- 1: 2-(4-(2-Amino(1-(3-methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridinyl)-1H-
pyrazolyl)ethanol (RA10074277)
H NMR (400 MHz, CDCl ) δ 8.23 (d, J = 1.9 Hz, 1H), 7.80 (d, J = 0.8 Hz, 1H), 7.71
(d, J = 0.8 Hz, 1H), 7.68 – 7.61 (m, 3H), 7.58 – 7.53 (m, 2H), 6.96 – 6.92 (m, 1H),
6.89 – 6.84 (m, 2H), 6.11 (q, J = 7.1 Hz, 1H), 5.20 (s, 2H), 4.44 (br s, 2H), 4.35 –
4.27 (m, 2H), 4.11 – 4.02 (m, 2H), 3.80 (s, 3H), 1.87 (d, J = 7.1 Hz, 3H), 1.68 (s, 1H)
ppm; (M+1) = 553.
Example 3- 50- 2: 3-(1-(3-Methoxy((4-
(trifluoromethyl)benzyl)oxy)phenyl)ethyl)(1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine (RA10161874)
H NMR (400 MHz, DMSO-d ) δ 12.90 (s, 1H), 8.17 (d, J = 2.0 Hz, 2H), 7.96 – 7.88
(m, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.67 – 7.59 (m, 3H), 7.23 (d, J = 1.3 Hz, 1H), 7.07
17965367_1 (GHMatters) P41917NZ00
– 6.92 (m, 4H), 5.66 (q, J = 7.0 Hz, 1H), 5.16 (s, 2H), 3.74 (s, 3H), 2.04 (d, J = 7.0
Hz, 3H) ppm; (M+1) = 509.
Example 3- 51: Synthesis of 3-(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)propyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine
Example 3- 51- 1: Preparation of 3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)benzonitrile
To a stirred solution of (6-(trifluoromethyl)pyridinyl)methanol (2.70 g, 15.25
mmol) in dimethylsulfoxide (25 mL) was added 60% sodium hydride dispersion
(0.639 g, 15.98 mmol; gas evolution and mild exotherm noted upon addition). After
min, the dark brown reaction mxiture was treated with 4-fluoro
methoxybenzonitrile (2.24 g, 14.52 mmol) and allowed to stir. 45 min after the
addition, the orange-brown mixture was diluted with water (150 mL) and extracted
with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine
(50 mL), dried over magnesium sulfate, filtered, and concentrated to provide 4.50 g of
an orange solid. Chromatographic purification (CombiFlash, 120 g SiO gold
column, 10-25% ethyl acetate/heptane elute) afforded 1.93 g (43%) of 3-methoxy
((6-(trifluoromethyl)pyridinyl)methoxy)benzonitrile as an off-white solid.
Example 3- 51- 2: Preparation of 1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)propanone
To a stirred 0 ºC solution of 3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)benzonitrile (1.69 g, 5.48 mmol) in tetrahydrofuran (15 mL) was added
ethylmagnesium bromide solution (1.0 M in tetrahydrofuran, 7.0 mL, 7.00 mmol)
followed by copper(I) iodide (0.010 g, 0.055 mmol). The resulting red-brown mixture
was allowed to warm to room temperature and stir. After 16 h, the mixture was
treated with 1N hydrochloric acid solution (25 mL) and allowed to stir. After 30 min,
the mixture was adjusted pH ~ 7 with saturated potassium carbonate solution (20 mL)
and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were
dried over magnesium sulfate, filtered, and concentrated to provide 1.86 g of a brown
oil. Chromatographic purification (CombiFlash, 40 g SiO column, 25-50% ethyl
acetate/heptane elute) afforded 1.44 g (77%) 1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)propanone as an off-white solid.
Example 3- 51- 3: Preparation of 5-iodo-N-(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)propyl)nitropyridinamine
17965367_1 (GHMatters) P41917NZ00
This compound was prepared from 1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)propanone using the procedures described in Example 3- 45- 2
through Example 3- 45- 4.
Example 3- 51- 4: Preparation of 5-iodo-N -(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)propyl)pyridine-2,3-diamine
To a stirred suspension of 5-iodo-N-(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)propyl)nitropyridinamine (1.25 g, 2.12 mmol) in acetic acid
(20 mL) was added iron (0.714 g, 12.77 mmol). The yellow mixture was heated to
125 ºC. As the mixture was heated, the yellow color faded and a gray suspension
formed. After 10 min, the mixture was allowed to cool to room temperature and was
diluted with ethyl acetate (75 mL). The suspension was filtered through Celite with
the aid of ethyl acetate (50 mL). The filtrate was washed with water (2 x 30 mL) and
then with concentrated ammonium hydroxide (2 x 30 mL). The organic phase was
dried over magnesium sulfate, filtered, and concentrated to provide 1.20 g (>100%) of
5-iodo-N -(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)propyl)pyridine-2,3-diamine as a brown oil.
Example 3- 51- 5: Preparation of 3-(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)propyl)(1-methyl-1H-pyrazol-
4-yl)-3H-imidazo[4,5-b]pyridinamine
This compound was prepared from 5-iodo-N -(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)propyl)pyridine-2,3-diamine using the
procedures described in Example 3- 49- 3 through Example 3- 49- 5: H NMR (400
MHz, CDCl ) δ 8.79 (s, 1H), 8.25 (d, J = 1.7 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.81 –
7.59 (m, 4H), 7.01 – 6.84 (m, 3H), 5.80 – 5.70 (m, 1H), 5.21 (s, 2H), 4.68 (br s, 2H),
3.98 (s, 3H), 3.79 (s, 3H), 2.58 – 2.35 (m, 2H), 0.97 – 0.86 (m, 3H) ppm; (M+1) =
538.
Example 3- 52: Synthesis of 3-(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)ethyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridine
Example 3- 52- 1: Preparation of 6-iodo(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridine
To a stirred solution of 5-iodo-N -(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)ethyl)pyridine-2,3-diamine [prepared from 5-(chloromethyl)
(trifluoromethyl)pyridine using the procedures described in Example 31 through
17965367_1 (GHMatters) P41917NZ00
Example 35] (0.710 g, 1.30 mmol) in ethanol (30 mL) was added triethyl
orthoformate (1.0 mL, 5.89 mmol). The yellow solution was treated with p-
toluenesulfonic acid monohydrate (0.025 g, 0.13 mmol) and heated to reflux. After
min, the mixture was allowed to cool to room temperature and was concentrated.
The residue was partitioned between ethyl acetate (50 mL) and saturated potassium
carbonate solution (50 mL). The phases were separted, and the organic phase was
dried over magnesium sulfate, filtered, and concentrated to provide 0.739 g (>100%)
of 6-iodo(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridine as an orange solid.
Example 3- 52- 2: Preparation of 3-(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridine
This compound was prepared from 6-iodo(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridine
using the procedure described in Example 3- 49- 5: H NMR (400 MHz, CDCl ) δ
8.78 (s, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.15 – 7.93 (m, 3H), 7.79 (s, 1H), 7.74 – 7.62
(m, 2H), 6.97 – 6.83 (m, 3H), 5.99 (q, J = 7.1 Hz, 1H), 5.20 (s, 2H), 3.98 (s, 3H), 3.83
(s, 3H), 2.00 (d, J = 7.1 Hz, 3H) ppm; (M+1) = 509.
Example 3- 53: Synthesis of 3-(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)ethyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-
b]pyridinamine
Example 3- 53- 1: Preparation of ethyl (6-iodo(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-
2-yl)carbamate
To a stirred solution of 5-iodo-N -(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)ethyl)pyridine-2,3-diamine [prepared from 5-(chloromethyl)
(trifluoromethyl)pyridine using the procedures described in Example 31 through
Example 35] (1.66 g, 3.05 mmol) and triethylamine (0.64 mL, 4.57 mmol) in
tetrahydrofuran (30 mL) was added ethoxycarbonyl isothiocyanate (0.44 mL, 3.66
mmol). After 30 min, the mixture was diluted with brine (100 mL) and extracted with
ethyl acetate (3 x 50 mL). The combined organic phases were dried over magnesium
sulfate, filtered, and concentrated to provide 2.18 g as a brown foamy solid. The
crude material was dissolved in tetrahydrofuran (30 mL) and triethylamine (1.05 mL,
7.53 mmol). The light yellow solution was treated with benzenesulfonyl chloride
17965367_1 (GHMatters) P41917NZ00
(0.97 mL, 7.51 mmol) and allowed to stir at room temperature. After 17 h, the
mixture was diluted with water (100 mL) and allowed to stir at room temperature.
After 15 min, the reaction mixture was extracted with dichloromethane (3 x 50 mL).
The combined organic phases were washed with saturated potassium carbonate
solution (50 mL), dried over magnesium sulfate, filtered, and concentrated to provide
2.77 g of a brown oil. Chromatographic purification (CombiFlash, 40 g SiO gold
column, 20-40% ethyl acetate/heptane elute) afforded 1.53 g (79%) of ethyl (6-iodo-
3-(1-(3-methoxy((6-(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-3H-
imidazo[4,5-b]pyridinyl)carbamate as a tan solid.
Example 3- 53- 2: Preparation of 6-iodo(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-
2-amine
To a stirred solution of ethyl (6-iodo(1-(3-methoxy((6-(trifluoromethyl)pyridin-
3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridinyl)carbamate (1.53 g, 2.39
mmol), in ethanol (10 mL)/water (4 mL) was added potassium phosphate tribasic
(2.07 g, 9.54 mmol). The mixture was irradiated in a microwave reactor at 150 ºC.
After 1 h, the mixture was subjected to an additional round of microwave heating
(160 °C, 30 min). After a total of 90 min, the mixture was diluted with water (100
mL) and extracted with dichloromethane (2 x 50 mL). The combined organic phases
were dried over magnesium sulfate, filtered, and concentrated to provide 1.31 g (97%)
of 6-iodo(1-(3-methoxy((6-(trifluoromethyl)pyridin
yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridinamine as an orange foamy
solid.
Example 3- 53- 3: Preparation of 3-(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)(1-methyl-1H-pyrazol
yl)-3H-imidazo[4,5-b]pyridinamine
This compound was prepared from 6-iodo(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin
amine using the procedure described in Example 3- 49- 5: H NMR (400 MHz,
CDCl ) δ 8.84 – 8.76 (m, 1H), 8.25 (d, J = 1.9 Hz, 1H), 8.04 – 7.95 (m, 1H), 7.77 (d,
J = 0.8 Hz, 1H), 7.74 – 7.66 (m, 2H), 7.63 (d, J = 0.8 Hz, 1H), 6.99 – 6.94 (m, 1H),
6.94 – 6.86 (m, 2H), 6.12 (q, J = 7.1 Hz, 1H), 5.23 (s, 2H), 4.37 (s, 2H), 3.98 (s, 3H),
3.79 (s, 3H), 1.89 (d, J = 7.1 Hz, 3H) ppm; (M+1) = 524.
17965367_1 (GHMatters) P41917NZ00
Example 3- 54: Synthesis of 2-(4-(2-amino(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-
6-yl)-1H-pyrazolyl)ethanol
This compound was prepared from 6-iodo(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin
amine using the procedure described in Example 3- 49- 5 by employing the
appropriate boronate ester coupling partner: H NMR (400 MHz, CDCl3) δ 8.84 –
8.76 (m, 1H), 8.23 (d, J = 1.9 Hz, 1H), 8.03 – 7.95 (m, 1H), 7.80 (d, J = 0.8 Hz, 1H),
7.73 – 7.70 (m, 2H), 7.66 (d, J = 1.9 Hz, 1H), 7.01 – 6.85 (m, 3H), 6.11 (q, J = 7.1
Hz, 1H), 5.23 (s, 2H), 4.47 (s, 2H), 4.35 – 4.26 (m, 2H), 4.10 – 4.03 (m, 2H), 3.79 (s,
3H), 1.88 (d, J = 7.1 Hz, 3H), 1.70 (br s, 1H) ppm; (M+1) = 554.
Example 3- 55: Synthesis of 4-(2-amino(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-
6-yl)butynol
This compound was prepared from 6-iodo(1-(3-methoxy((6-
(trifluoromethyl)pyridinyl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin
amine using the procedure described in Example 3- 48- 2: H NMR (400 MHz,
CDCl ) δ 8.80 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.04 – 7.95 (m, 1H), 7.72
(dd, J = 8.1, 0.8 Hz, 1H), 7.64 (d, J = 1.7 Hz, 1H), 6.98 – 6.88 (m, 2H), 6.84 (d, J =
2.0 Hz, 1H), 6.10 (q, J = 7.1 Hz, 1H), 5.22 (s, 2H), 4.44 (br s, 2H), 3.85 (t, J = 6.2 Hz,
2H), 3.79 (s, 3H), 2.74 (t, J = 6.2 Hz, 2H), 2.01 (br s, 1H), 1.86 (d, J = 7.1 Hz, 3H)
ppm; (M+1) = 512.
Example 3- 56: Synthesis of 4-(3-(4-((6-(difluoromethyl)pyridinyl)methoxy)
methoxybenzyl)-3H-imidazo[4,5-b]pyridinyl)butynol
Example 3- 56- 1: Preparation of tert-butyl (4-((6-(difluoromethyl)pyridin
yl)methoxy)methoxybenzyl)carbamate
To a stirred solution of tert-butyl 4-hydroxymethoxybenzylcarbamate (4.70 g,
18.56 mmol) and potassium carbonate (7.64 g, 55.28 mmol) in acetonitrile (50 mL)
was added 5-(chloromethyl)(difluoromethyl)pyridine hydrochloride (4.58 g, 21.40
mmol). The mixture was heated to reflux. After 3 h, the off-white suspension was
allowed to cool to room temperature and was diluted with water (200 mL). The
mixture was extracted with dichloromethane (3 x 75 mL). The combined organic
phases were dried over magnesium sulfate, filtered, and concentrated to provide 7.74
17965367_1 (GHMatters) P41917NZ00
g (> 100%) of tert-butyl 4-((6-(difluoromethyl)pyridinyl)methoxy)
methoxybenzylcarbamate as a waxy yellow solid.
Example 3- 56- 2: Preparation of (4-((6-(difluoromethyl)pyridinyl)methoxy)-
3-methoxyphenyl)methanamine
To a stirred solution of tert-butyl 4-((6-(difluoromethyl)pyridinyl)methoxy)
methoxybenzylcarbamate (7.32 g, 18.56 mmol) in dichloromethane (30 ml) was
added trifluoroacetic acid (15 mL, 194.70 mmol). After 2 h, the reaction mxiture was
concentrated, and the residue was dissolved in water (75 mL). The acidic solution
was extracted with diethyl ether (50 mL). The aqueous phase was retained and made
basic with concentrated ammonium hydroxide solution (50 mL). The basic aqueous
phase was extracted with dichloromethane (2 x 100 mL). The combined organic
phases were dried over magnesium sulfate, filtered, and concentrated to provide 4.54
g (83%) of (4-((6-(difluoromethyl)pyridinyl)methoxy)
methoxyphenyl)methanamine as a yellow solid.
Example 3- 56- 3: Preparation of 3-(4-((6-(difluoromethyl)pyridin
yl)methoxy)methoxybenzyl)iodo-3H-imidazo[4,5-b]pyridine
To a stirred solution of N -(4-((6-(difluoromethyl)pyridinyl)methoxy)
methoxybenzyl)iodopyridine-2,3-diamine [prepared from (4-((6-
(difluoromethyl)pyridinyl)methoxy)methoxyphenyl)methanamine using the
procedures described in Example 3- 45- 4 and Example 3- 45- 5] (3.10 g, 6.05
mmol) in ethanol (50 mL) was added triethyl orthoformate (3.0 mL, 18.02 mmol).
The mixture was treated with p-toluenesulfonic acid monohydrate (50 mg, 262.86
µmol) and was heated to reflux. After 45 min, the mixture was allowed to cool to
room temperature, resulting in the formation of a precipitate. The mixture was
concentrated, and the residue dissolved in chloroform (150 mL). The solution was
washed with saturated potassium carbonate solution, dried over magnesium sulfate,
filtered, and concentrated to provide 3.15 g (99%) of 3-(4-((6-
(difluoromethyl)pyridinyl)methoxy)methoxybenzyl)iodo-3H-imidazo[4,5-
b]pyridine as a brown solid.
Example 3- 56- 4: Preparation of 4-(3-(4-((6-(difluoromethyl)pyridin
yl)methoxy)methoxybenzyl)-3H-imidazo[4,5-b]pyridinyl)butynol
This compound was prepared from 3-(4-((6-(difluoromethyl)pyridinyl)methoxy)
methoxybenzyl)iodo-3H-imidazo[4,5-b]pyridine using the procedure described in
Example 3- 48- 2: H NMR (400 MHz, CDCl ) δ 8.71 – 8.69 (m, 1H), 8.48 (d, J =
17965367_1 (GHMatters) P41917NZ00
1.7 Hz, 1H), 8.10 (d, J = 1.7 Hz, 1H), 8.02 (s, 1H), 7.92 (dd, J = 8.1, 2.1 Hz, 1H),
7.65 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.87 – 6.80 (m, 2H), 6.64 (t, J =
55.4 Hz, 1H), 5.38 (s, 2H), 5.17 (s, 2H), 3.87 (t, J = 6.3 Hz, 2H), 3.82 (s, 3H), 2.75 (t,
J = 6.3 Hz, 2H), 2.11 (br s, 1H) ppm; (M+1) = 465.
Example 3- 57: Synthesis of 3-(3-methoxy(1-(6-methoxypyridin
yl)ethoxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine
formate
Example 3- 57- 1: Preparation of 4-(((5-iodonitropyridinyl)amino)methyl)-
2-methoxyphenol
To a stirred suspension of 4-hydroxymethoxybenzylamine hydrochlirde (1.32 g,
6.82 mmol) and 2-chloroiodonitropyridine (2.00 g, 6.82 mmol) in acetonitrile
(20 mL) was added N, N-disopropylethylamine (5.96 ml, 34.10 mmol) The
suspension was stirred and heated to 100 ºC. After 1 h, the mixture was allowed to
cool to room temperature, and 2N aqueous potassium hydroxide solution (0.68 mL)
was added. The mixture was concentrated to provide 4-(((5-iodonitropyridin
yl)amino)methyl)methoxyphenol as an impure solid.
Example 3- 57- 2: Preparation of 4-((6-iodo-3H-imidazo[4,5-b]pyridin
yl)methyl)methoxyphenol
This compound was prepared in two steps from 4-(((5-iodonitropyridin
yl)amino)methyl)methoxyphenol using the procedures described in Example 3-
49- 2 and Example 3- 52- 2.
Example 3- 57- 3: Preparation of 6-iodo(3-methoxy(1-(6-methoxypyridin-
3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine
To a stirred mixture of 4-((6-iodo-3H-imidazo[4,5-b]pyridinyl)methyl)
methoxyphenol (1.32g, 3.46 mmol) and potassium carbonate (1.30 g, 9.41 mmol) in
ccetonitrile (25 mL) was added 5-(1-chloroethyl)methoxypyridine (0.72 g, 4.20
mmol). The mixture was heated at 100 °C. After 6.5 h, an additional quantity 5-(1-
chloroethyl)methoxypyridine (0.300 g, 1.75 mmol) was added, and heating was
continued. After 22 h, the mixture was allowed to cool to room temperature
and was partitioned between water and 1:5 ethyl acetate/diethyl ether. The phases
were separated, and the aqueous phase was extracted with diethyl ether. The
combined organic phases were washed with water, dried over magnesium sulfate,
filtered, and concentrated. Chromatographic purification (40 g SiO column, 0-10 %
0.01 M ammonia in methanol/dichlormethane elute) afforded 0.88 g (49%) of 6-iodo-
17965367_1 (GHMatters) P41917NZ00
3-(3-methoxy(1-(6-methoxypyridinyl)ethoxy)benzyl)-3H-imidazo[4,5-
b]pyridine as an impure solid.
Example 3- 57- 4: Preparation of 3-(3-methoxy(1-(6-methoxypyridin
yl)ethoxy)benzyl)(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine
formate
To a stirred suspension of 6-iodo(3-methoxy(1-(6-methoxypyridin
yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine (0.200 g, 0.39 mmol), potassium
phosphate tribasic (0.164 g, 0.77 mmol),1-methyl(4,4,5,5-tetramethyl-1,3,2-
dioxaborolanyl)-1H-pyrazole (0.100 g, 0.48 mmol) and tricyclohexylphosphine
(0.008 g, 0.028 mmol) in 1,4-dioxane (3 mL)/water (1.5 mL) was added
tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.013 mmol). The mixture was
degassed by bubbling nitrogen through the mixture for 2 min, and then the mixture
was irradiated in a microwave reactor at 120 ºC. After 30 min, the mixture was
allowed to cool to room temperature and was filtered through Celite. The filtrate was
subjected to direct purification (50 g C18 column, water/acetonitrile/0.1% formic acid
elute) to provide an impure material. A second purification under the same conditions
afforded 0.051 g (26%) of the product as a white solid: H NMR (400 MHz, CD OD)
δ 8.62 (d, J = 1.9 Hz, 1H), 8.37 (s, 1H), 8.20 - 8.13 (m, 1H), 8.05 (dd, J = 7.6, 1.6 Hz,
2H), 7.90 (d, J = 0.8 Hz, 1H), 7.71 (dd, J = 8.6, 2.5 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H),
6.83 - 6.69 (m, 3H), 5.42 (s, 2H), 5.37 (q, J = 6.4 Hz, 1H), 3.95 (s, 3H), 3.84 (s, 3H),
3.80 (s, 3H), 1.58 (d, J = 6.4 Hz, 3H) ppm; (M+1) = 471.
Example 3- 58: Synthesis of additional compounds from 6-iodo(3-methoxy
(1-(6-methoxypyridinyl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine
The following compounds were prepared from 6-iodo(3-methoxy(1-(6-
methoxypyridinyl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine using the procedure
described in Example 3- 57- 4 by employing the appropriate boronic acid/boronate
ester coupling partner.
Example 3- 58- 1: 3-(3-methoxy(1-(6-methoxypyridinyl)ethoxy)benzyl)
(1-methyl-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine formate (RA09683914A)
H NMR (400 MHz, CDCl ) δ 8.49 (d, J = 1.9 Hz, 1H), 8.17 - 8.03 (m, 3H), 7.64 (dd,
J = 8.6, 2.5 Hz, 1H), 7.57 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 1.5 Hz, 1H), 6.78 - 6.65 (m,
3H), 6.39 (d, J = 1.9 Hz, 1H), 5.39 (s, 2H), 5.29 (q, J = 6.4 Hz, 1H), 3.92 (s, 3H), 3.90
(s, 3H), 3.83 (s, 3H), 3.49 (s, 1H), 1.66 (d, J = 6.4 Hz, 3H) ppm; (M+1) = 471.
17965367_1 (GHMatters) P41917NZ00
Example 3- 58- 2: 3-(3-methoxy(1-(6-methoxypyridinyl)ethoxy)benzyl)
(6-methoxypyridinyl)-3H-imidazo[4,5-b]pyridine formate (RA09683951A)
H NMR (400 MHz, CDCl ) δ 8.59 (d, J = 2.0 Hz, 1H), 8.42 (dd, J = 2.6, 0.8 Hz, 1H),
8.18 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 8.03 (s, 1H), 7.82 (dd, J = 8.6, 2.6
Hz, 1H), 7.63 (dd, J = 8.6, 2.5 Hz, 1H), 6.89 (d, J = 0.9 Hz, 2H), 6.75 - 6.66 (m, 3H),
.38 (s, 2H), 5.29 (q, J = 6.4 Hz, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 3.82 (s, 3H), 1.66 (d,
J = 6.5 Hz, 3H) ppm; (M+1) = 498.
Example 3- 58- 3: 6-(2-fluoropyridinyl)(3-methoxy(1-(6-
methoxypyridinyl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine formate
(RA09683967A)
H NMR (400 MHz, CDCl ) δ 8.70 (d, J = 2.0 Hz, 1H), 8.35 - 8.29 (m, 2H), 8.10 (d, J
= 2.8 Hz, 2H), 7.64 (dd, J = 8.6, 2.5 Hz, 1H), 7.46 (dt, J = 5.3, 1.7 Hz, 1H), 7.19 (t, J
= 1.6 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H), 6.75 - 6.72 (m, 2H), 6.71 (dd, J = 8.6, 0.7 Hz,
1H), 5.39 (s, 2H), 5.29 (q, J = 6.4 Hz, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 1.66 (d, J = 6.4
Hz, 3H) ppm; (M+1) = 486.
17965367_1 (GHMatters) P41917NZ00
Claims (53)
1. A compound comprising the structure of Formula (II): 5 wherein: n is 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; Q is (C -C )heteroaryl wherein the (C -C )heteroaryl is optionally substituted by one to 10 four groups selected from (C -C )alkyl, (C -C )heteroalkyl, 1 10 2 9 (C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, 3 10 2 9 6 14 (C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-, 2 9 1 10 1 10 COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O- 1 10 3 10 1 10 7 8 7 8 7 8 , -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, 15 (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-, 3 10 3 10 6 14 (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, 2 9 2 9 (C -C )heteroaryl-S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, 2 9 3 10 3 10 (C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-, 6 14 2 9 (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-, 2 9 2 9 20 (C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, 3 10 2 3 10 2 6 14 2 (C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-, 2 9 2 2 9 2 (C -C )heteroaryl-O S-, or R R NO S-, 2 9 2 2 17965367_1 (GHMatters) P41917NZ00 wherein R and R is each independently H, (C -C )alkyl, 1 10 (C -C )heteroalkyl, (C -C )cycloalkyl, 2 9 3 10 (C -C )heterocycloalkyl, (C -C )aryl or (C -C )heteroaryl; 2 9 6 14 2 9 Q is (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or (C - 6 14 2 9 3 10 2 5 C )heterocycloalkyl, wherein the (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or 6 14 2 9 3 10 (C2-C9)heterocycloalkyl is optionally substituted by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl, 1 10 2 9 (C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, 3 10 2 9 6 14 10 (C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-, 2 9 1 10 1 10 COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O- 1 10 3 10 1 10 7 8 7 8 7 8 , -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-, 3 10 3 10 6 14 (C2-C9)heteroalkyl-S-, (C2-C9)heterocycloalkyl-S-, 15 (C -C )heteroaryl-S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, 2 9 3 10 3 10 (C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-, 6 14 2 9 (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-, 2 9 2 9 (C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, 3 10 2 3 10 2 6 14 2 (C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-, 2 9 2 2 9 2 20 (C -C )heteroaryl-O S-, or R R NO S-, 2 9 2 2 wherein R and R is each independently H, (C1-C10)alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl, 2 9 3 10 (C -C )heterocycloalkyl, (C -C )aryl or (C -C )heteroaryl; 2 9 6 14 2 9 X is N; 25 R is H or NH ; and R is H, halo, (C -C )alkyl, (C -C )heteroalkyl, (C -C )alkylamine, (C - 1 10 2 9 1 10 1 C )alkyl-O-, or NH ; 10 2 or a pharmaceutically acceptable salt thereof; wherein any alkyl is straight chained, branched, or cyclic; and any heteroalkyl is straight chained, branched, or cyclic.
2. The compound according to claim 1, wherein n is 1, 2 or 3.
3. The compound according to claim 2, wherein n is 1. 17965367_1 (GHMatters) P41917NZ00
4. The compound according to claim 2, wherein n is 2.
5. The compound according to claim 2, wherein n is 3. 5
6. The compound according to claim 1, wherein m is 0, 1, or 2.
7. The compound according to claim 6, wherein m is 0.
8. The compound according to claim 6, wherein m is 1.
9. The compound according to claim 6, wherein m is 2.
10. The compound according to claim 1, wherein n is 1 and m is 1. 15
11. The compound according to claim 1, wherein Q is (C -C )aryl or (C - 6 14 2 C )heteroaryl, wherein the (C -C )aryl or (C -C )heteroaryl is optionally substituted 6 14 2 9 by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl, 1 10 2 9 (C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, 3 10 2 9 6 14 20 (C2-C9)heteroaryl, (C1-C10)alkylamine, (C1-C10)alkyl-C(O)O-, COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-, - 1 10 3 10 1 10 7 8 7 8 7 8 OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-, 3 10 3 10 6 14 (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, (C -C )heteroaryl- 2 9 2 9 2 9 25 S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-, 3 10 3 10 6 14 (C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, 2 9 2 9 (C2-C9)heteroaryl(O)S-, (C3-C10)alkyl-O2S-, (C3-C10)cycloalkyl-O2S-, (C -C )aryl-O S-, (C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl- 6 14 2 2 9 2 2 9 O S-, (C -C )heteroaryl-O S-, or R R NO S-, 2 2 9 2 2 17965367_1 (GHMatters) P41917NZ00 wherein R and R is each independently H, (C -C )alkyl, 1 10 (C -C )heteroalkyl, (C -C )cycloalkyl, (C -C )heterocycloalkyl, 2 9 3 10 2 9 (C -C )aryl or (C -C )heteroaryl. 6 14 2 9 5
12. The compound according to claim 10, wherein Q is (C -C )aryl optionally 6 14 substituted by one to four groups selected from (C -C )alkyl, 1 10 (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-, 2 9 1 10 1 10 COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-, -OH, - 1 10 3 10 1 10 7 8 7 8 7 8 10 NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, (C -C )alkyl-S-, 2 3 3 10 (C -C )cycloalkyl-S-, (C -C )aryl-S-, (C -C )heteroalkyl-S-, 3 10 6 14 2 9 (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-S-, (C -C )alkyl(O)S-, 2 9 2 9 3 10 (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-, 3 10 6 14 2 9 (C2-C9)heterocycloalkyl(O)S-, (C2-C9)heteroaryl(O)S-, (C3-C10)alkyl-O2S-, 15 (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-O S-, 3 10 2 6 14 2 2 9 2 (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, 2 9 2 2 9 2 2 wherein R and R is each independently H, (C -C )alkyl, 1 10 (C -C )heteroalkyl, (C -C )cycloalkyl, (C -C )heterocycloalkyl, 2 9 3 10 2 9 (C -C )aryl or (C -C )heteroaryl. 6 14 2 9
13. The compound according to claim 1, wherein R is H.
14. The compound according to claim 1, wherein R is NH . 25
15. The compound according to claim 12, wherein R is H, halo, (C -C )alkyl, or 1 10 (C -C )alkyl-O-. 1 10
16. The compound according to claim 15, wherein R is H. 30
17. The compound according to claim 15, wherein R is halo.
18. The compound according to claim 15, wherein R is (C -C )alkyl. 1 10
19. The compound according to claim 15, wherein R is (C -C )alkyl-O-. 1 10 17965367_1 (GHMatters) P41917NZ00
20. The compound according to claim 19, wherein R is CH -O- or CH -CH -O-. 3 3 2
21. The compound according to claim 1, wherein X is N and R is CH -O-.
22. The compound according to claim 21, wherein Q is methylpyrazole; and Q is methoxybenzene. 10
23. The compound according to claim 21, wherein Q is 2-(dimethyl(methylene)phosphoranyl)pyridine; and Q is methoxybenzene.
24. The compound according to claim 21, wherein 15 Q is 4-(1H-pyrazolyl)piperidine; and Q is methoxybenzene.
25. The compound according to claim 21, wherein Q is 4-(1H-pyrazolyl)piperidine; and 20 Q is methylpyridine.
26. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 17965367_1 (GHMatters) P41917NZ00
27. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.
28. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 10
29. A compound selected from the group consisting of 3-(3-methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine, 3-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol yl)-3H-imidazo[4,5-b]pyridinamine, 18075902_1 (GHMatters) P41917NZ00 (5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-3H- imidazo[4,5-b]pyridinyl)pyridinyl)dimethylphosphine oxide, 3-(3-Methoxy((6-methylpyridinyl)methoxy)benzyl)(1-(piperidin yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine, 5 3-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridinyl)(piperidinyl)-1,2,4-oxadiazole, 2-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridinyl)(piperidinyl)-1,3,4-oxadiazole, 2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H- 10 imidazo[4,5-b]pyridinyl)-1H-1,2,3-triazolyl)propanamine, and 3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin yl)-1H-1,2,3-triazolyl)-3H-imidazo[4,5-b]pyridine.
30. A compound of claim 29 having the formula: 15 ; or a pharmaceutically acceptable salt thereof. 18075902_1 (GHMatters) P41917NZ00
31. A compound comprising the structure of Formula (I): wherein: 5 n is 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; Q is (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or 6 14 2 9 3 10 (C -C )heterocycloalkyl, wherein the (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or 6 14 2 9 3 10 10 (C -C )heterocycloalkyl is optionally substituted by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl, 1 10 2 9 (C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, 3 10 2 9 6 14 (C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-, 2 9 1 10 1 10 COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O- 1 10 3 10 1 10 7 8 7 8 7 8 15 , -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-, 3 10 3 10 6 14 (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, 2 9 2 9 (C -C )heteroaryl-S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, 2 9 3 10 3 10 (C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-, 6 14 2 9 20 (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-, 2 9 2 9 (C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, 3 10 2 3 10 2 6 14 2 (C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-, 2 9 2 2 9 2 (C -C )heteroaryl-O S-, or R R NO S-, 2 9 2 2 17965367_1 (GHMatters) P41917NZ00 wherein R and R is each independently H, (C -C )alkyl, 1 10 (C -C )heteroalkyl, (C -C )cycloalkyl, 2 9 3 10 (C -C )heterocycloalkyl, (C -C )aryl or (C -C )heteroaryl; 2 9 6 14 2 9 Q is (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or (C - 6 14 2 9 3 10 2 5 C )heterocycloalkyl, wherein the (C -C )aryl, (C -C )heteroaryl, (C -C )cycloalkyl, or 6 14 2 9 3 10 (C2-C9)heterocycloalkyl is optionally substituted by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl, 1 10 2 9 (C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, 3 10 2 9 6 14 10 (C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-, 2 9 1 10 1 10 COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O- 1 10 3 10 1 10 7 8 7 8 7 8 , -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-, 3 10 3 10 6 14 (C2-C9)heteroalkyl-S-, (C2-C9)heterocycloalkyl-S-, 15 (C -C )heteroaryl-S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, 2 9 3 10 3 10 (C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-, 6 14 2 9 (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-, 2 9 2 9 (C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, 3 10 2 3 10 2 6 14 2 (C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl-O S-, 2 9 2 2 9 2 20 (C -C )heteroaryl-O S-, or R R NO S-, 2 9 2 2 wherein R and R is each independently H, (C1-C10)alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl, 2 9 3 10 (C -C )heterocycloalkyl, (C -C )aryl or (C -C )heteroaryl; 2 9 6 14 2 9 X is CH or CR , 25 wherein R is (C -C )alkyl, (C -C )heteroalkyl, 1 10 2 9 (C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, 3 10 2 9 6 14 (C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-, 2 9 1 10 1 10 COOH-(C1-C10)alkyl, COOH-(C3-C10)cycloalkyl, (C1-C10)alkyl-O- , -OH, or -NH ; 30 R is H, halo, (C -C )alkyl, (C -C )heteroalkyl, (C -C )alkylamine, or NH ; 1 10 2 9 1 10 2 R is (C -C )heteroalkyl, (C -C )alkylamine, (C -C )alkyl-O-, or NH ; 2 9 1 10 1 10 2 R and R are each independently H, (C -C )alkyl, (C -C )heteroalkyl, 1 10 2 9 (C -C )alkylamine, O-(C -C )alkyl, or NH or R and R are taken 1 10 1 10 2 17965367_1 (GHMatters) P41917NZ00 together with the carbon to which they are attached to form a 3 to 10 member ring, wherein the 3 to 10 member ring is optionally substituted by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl, 1 10 2 9 5 (C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, 3 10 2 9 6 14 (C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-, 2 9 1 10 1 10 COOH-(C1-C10)alkyl, COOH-(C3-C10)cycloalkyl, (C1-C10)alkyl-O- , -OH, or - NH ; and R and R are each independently H, (C -C )alkyl, (C -C )heteroalkyl, (C - 1 10 2 9 1 10 C )alkylamine, O-(C -C )alkyl, or NH or R and R are taken 10 1 10 2 together with the carbon to which they are attached to form a 3 to 10 member ring, wherein the 3 to 10 member ring is optionally substituted by one to four groups selected from (C1-C10)alkyl, (C2-C9)heteroalkyl, 15 (C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, 3 10 2 9 6 14 (C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-, 2 9 1 10 1 10 COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O- 1 10 3 10 1 10 , -OH, or - NH ; or a pharmaceutically acceptable salt thereof; wherein any alkyl is straight chained, 20 branched, or cyclic; and any heteroalkyl is straight chained, branched, or cyclic.
32. The compound according to claim 31, wherein n is 1, 2 or 3.
33. The compound according to claim 31 or 32, wherein m is 0, 1, or 2.
34. The compound according to any one of claims 31 to 33, wherein n is 1 and m is 1.
35. The compound according to any one of claims 31 to 34, wherein Q is (C - 30 C )aryl or (C -C )heteroaryl, 14 2 9 wherein the (C -C )aryl or (C -C )heteroaryl is optionally substituted 6 14 2 9 by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl, 1 10 2 9 (C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, 3 10 2 9 6 14 (C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-, 2 9 1 10 1 10 17965367_1 (GHMatters) P41917NZ00 COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-, - 1 10 3 10 1 10 7 8 7 8 7 8 OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-, 3 10 3 10 6 14 (C -C )heteroalkyl-S-, (C -C )heterocycloalkyl-S-, (C -C )heteroaryl- 2 9 2 9 2 9 5 S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-, 3 10 3 10 6 14 (C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, 2 9 2 9 (C2-C9)heteroaryl(O)S-, (C3-C10)alkyl-O2S-, (C3-C10)cycloalkyl-O2S-, (C -C )aryl-O S-, (C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl- 6 14 2 2 9 2 2 9 O S-, (C -C )heteroaryl-O S-, or R R NO S-, 2 2 9 2 2 10 wherein R and R is each independently H, (C -C )alkyl, 1 10 (C -C )heteroalkyl, (C -C )cycloalkyl, (C -C )heterocycloalkyl, 2 9 3 10 2 9 (C -C )aryl or (C -C )heteroaryl. 6 14 2 9
36. The compound according to any one of claims 31 to 34, wherein Q is (C6- 15 C )aryl optionally substituted by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl, 1 10 2 9 3 10 (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl, (C -C )alkylamine, 2 9 6 14 2 9 1 10 (C -C )alkyl-C(O)O-, COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, 1 10 1 10 3 10 7 8 7 8 7 8 (C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, 1 10 2 3 20 (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-, (C -C )heteroalkyl-S- 3 10 3 10 6 14 2 9 , (C2-C9)heterocycloalkyl-S-, (C2-C9)heteroaryl-S-, (C3-C10)alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-, 3 10 6 14 2 9 (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-, (C -C )alkyl-O S-, 2 9 2 9 3 10 2 (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-O S-, 3 10 2 6 14 2 2 9 2 25 (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, 2 9 2 2 9 2 2 wherein R and R is each independently H, (C -C )alkyl, 1 10 (C -C )heteroalkyl, (C -C )cycloalkyl, (C -C )heterocycloalkyl, 2 9 3 10 2 9 (C6-C14)aryl or (C2-C9)heteroaryl. 30
37. The compound according to any one of claims 31 to 34, wherein Q is (C - C )heteroaryl optionally substituted by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl, 1 10 2 9 3 10 (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl, (C -C )alkylamine, 2 9 6 14 2 9 1 10 (C -C )alkyl-C(O)O-, COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, 1 10 1 10 3 10 17965367_1 (GHMatters) P41917NZ00 7 8 7 8 7 8 (C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, 1 10 2 3 (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-, (C -C )heteroalkyl-S- 3 10 3 10 6 14 2 9 , (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-S-, (C -C )alkyl(O)S-, 2 9 2 9 3 10 (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-, 3 10 6 14 2 9 5 (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-, (C -C )alkyl-O S-, 2 9 2 9 3 10 2 (C -C )cycloalkyl-O S-, (C -C )aryl-O S-, (C -C )heteroalkyl-O S-, 3 10 2 6 14 2 2 9 2 (C2-C9)heterocycloalkyl-O2S-, (C2-C9)heteroaryl-O2S-, or R R NO2S-, wherein R and R is each independently H, (C -C )alkyl, 1 10 (C -C )heteroalkyl, (C -C )cycloalkyl, (C -C )heterocycloalkyl, 2 9 3 10 2 9 10 (C -C )aryl or (C -C )heteroaryl. 6 14 2 9
38. The compound according to any one of claims 31 to 37, wherein Q is (C - C )aryl or (C -C )heteroaryl, 14 2 9 wherein the (C6-C14)aryl or (C2-C9)heteroaryl is optionally substituted 15 by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl, 1 10 2 9 (C -C )cycloalkyl, (C -C )heterocycloalkyl, (C -C )aryl, 3 10 2 9 6 14 (C -C )heteroaryl, (C -C )alkylamine, (C -C )alkyl-C(O)O-, 2 9 1 10 1 10 COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, (C -C )alkyl-O-, - 1 10 3 10 1 10 7 8 7 8 7 8 OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, 20 (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-, 3 10 3 10 6 14 (C2-C9)heteroalkyl-S-, (C2-C9)heterocycloalkyl-S-, (C2-C9)heteroaryl- S-, (C -C )alkyl(O)S-, (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-, 3 10 3 10 6 14 (C -C )heteroalkyl(O)S-, (C -C )heterocycloalkyl(O)S-, 2 9 2 9 (C -C )heteroaryl(O)S-, (C -C )alkyl-O S-, (C -C )cycloalkyl-O S-, 2 9 3 10 2 3 10 2 25 (C -C )aryl-O S-, (C -C )heteroalkyl-O S-, (C -C )heterocycloalkyl- 6 14 2 2 9 2 2 9 O S-, (C -C )heteroaryl-O S-, or R R NO S-, 2 2 9 2 2 wherein R and R is each independently H, (C -C )alkyl, 1 10 (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C -C )aryl or (C -C )heteroaryl. 6 14 2 9
39. The compound according to any one of claims 31 to 37, wherein Q is (C - C )aryl optionally substituted by one to four groups selected from (C -C )alkyl, (C -C )heteroalkyl, (C -C )cycloalkyl, 1 10 2 9 3 10 (C -C )heterocycloalkyl, (C -C )aryl, (C -C )heteroaryl, (C -C )alkylamine, 2 9 6 14 2 9 1 10 17965367_1 (GHMatters) P41917NZ00 (C -C )alkyl-C(O)O-, COOH-(C -C )alkyl, COOH-(C -C )cycloalkyl, 1 10 1 10 3 10 7 8 7 8 7 8 (C -C )alkyl-O-, -OH, -NH , R R N-, R R N(O)C-, R (O)CR N-, F C-, NC-, 1 10 2 3 (C -C )alkyl-S-, (C -C )cycloalkyl-S-, (C -C )aryl-S-, (C -C )heteroalkyl-S- 3 10 3 10 6 14 2 9 , (C -C )heterocycloalkyl-S-, (C -C )heteroaryl-S-, (C -C )alkyl(O)S-, 2 9 2 9 3 10 5 (C -C )cycloalkyl(O)S-, (C -C )aryl(O)S-, (C -C )heteroalkyl(O)S-, 3 10 6 14 2 9 (C -C )heterocycloalkyl(O)S-, (C -C )heteroaryl(O)S-, (C -C )alkyl-O S-, 2 9 2 9 3 10 2 (C3-C10)cycloalkyl-O2S-, (C6-C14)aryl-O2S-, (C2-C9)heteroalkyl-O2S-, (C -C )heterocycloalkyl-O S-, (C -C )heteroaryl-O S-, or R R NO S-, 2 9 2 2 9 2 2 wherein R and R is each independently H, (C -C )alkyl, 1 10 10 (C -C )heteroalkyl, (C -C )cycloalkyl, (C -C )heterocycloalkyl, 2 9 3 10 2 9 (C -C )aryl or (C -C )heteroaryl. 6 14 2 9
40. The compound according to any one of claims 31 to 39, wherein X is CH. 15
41. The compound according to any one of claims 31 to 40, wherein R is NH .
42. The compound according to any one of claims 31 to 41, wherein R is (C - C )alkyl-O-. 20
43. The compound according to any one of claims 31 to 42, wherein R is CH -O- or CH3-CH2-O-.
44. The compound according to claim 31, wherein the compound is: 17965367_1 (GHMatters) P41917NZ00 or a pharmaceutically acceptable salt thereof.
45. A compound selected from the group consisting of 5 1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-methyl-1H-pyrazol yl)-1H-benzo[d]imidazolamine 1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyrimidinyl)-1H- benzo[d]imidazolamine, 1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(pyridineyl)-1H- 10 benzo[d]imidazolamine, 1-(3-Methoxy((4-methoxybenzyl)oxy)benzyl)(1-(2-morpholinoethyl)- 1H-pyrazolyl)-1H-benzo[d]imidazolamine, (5-(2-Amino(3-methoxy((4-methoxybenzyl)oxy)benzyl)-1H- benzo[d]imidazolyl)pyridinyl)dimethylphosphine oxide, 15 1-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4-(piperidin yl)-1H-1,2,3-triazolyl)-1H-benzo[d]imidazole, 3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(4- methylpiperazinyl)-3H-imidazo[4,5-b]pyridine, 2-(1-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H- 20 imidazo[4,5-b]pyridinyl)piperidinyl)propanamine, 4-(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridinyl)morpholine, 6-(4-Cyclopropylpiperazinyl)(3-methoxy((6-methoxypyridin 17965367_1 (GHMatters) P41917NZ00 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine, 3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(2,7- diazaspiro[3.5]nonanyl)-3H-imidazo[4,5-b]pyridine (S)(3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)-3H- 5 imidazo[4,5-b]pyridinyl)pyrrolidinecarboxylic acid and 3-(3-Methoxy((6-methoxypyridinyl)methoxy)benzyl)(1-(piperidin yl)-1H-pyrazolyl)-3H-imidazo[4,5-b]pyridine; or a pharmaceutically acceptable salt thereof. 10
46. A pharmaceutical composition comprising a compound according to any one of claims 1 to 45.
47. The pharmaceutical composition according to claim 46, wherein the compound is: 15 ; or a pharmaceutically acceptable salt thereof.
48. Use of a compound according to any one of claims 1 to 45 in the manufacture of a medicament for treating inflammatory diseases, autoimmune disease, 20 defects of bone metabolism or cancer in a patient in need thereof, wherein treatment is mediated through tropomyosin-related kinase inhibition. 17965367_1 (GHMatters) P41917NZ00
49. Use of a compound according to any one of claims 1 to 45 in the manufacture of a medicament for treating osteoarthritis in a patient in need thereof, wherein treatment is mediated through tropomyosin-related kinase inhibition. 5
50. Use of a compound according to any one of claims 1 to 45 in the manufacture of a medicament for treating pain in a patient in need thereof, wherein treatment is mediated through tropomyosin-related kinase inhibition.
51. The use of claim 50, wherein the pain is post-operative pain.
52. Use of a compound according to any one of claims 1 to 45 in the manufacture of a medicament for treating pain associated with osteoarthritis in a patient in need thereof, wherein treatment is mediated through tropomyosin-related kinase inhibition.
53. The use according to any one of claims 48 to 52, wherein the compound is: or a pharmaceutically acceptable salt thereof. 17965367_1 (GHMatters) P41917NZ00
Applications Claiming Priority (5)
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US201361914128P | 2013-12-10 | 2013-12-10 | |
US61/914,128 | 2013-12-10 | ||
US201462040750P | 2014-08-22 | 2014-08-22 | |
US62/040,750 | 2014-08-22 | ||
PCT/US2014/069469 WO2015089139A1 (en) | 2013-12-10 | 2014-12-10 | Tropomyosin-related kinase (trk) inhibitors |
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NZ721051B2 true NZ721051B2 (en) | 2022-02-01 |
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