EA044589B1 - TROPOMYOSIN-DEPENDENT KINASE (TRK) INHIBITORS - Google Patents

Description

Field of technology to which the present invention relates

The present invention relates to tropomyosin-dependent kinase inhibitors (Trk inhibitors). The present invention also relates to pharmaceutical compositions containing Trk inhibitors. The Trk inhibitors of the present invention can be used for the treatment of osteoarthritis (OA), for the treatment of pain, for the treatment of postoperative pain, for the treatment of pain associated with OA, and for the inhibition of tropomyosin-dependent kinase A (TrkA), tropomyosin-dependent kinase B ( TrkB) and/or tropomyosin-dependent kinase C (TrkC), and to inhibit c-FMS (cellular receptor for colony stimulating factor-1 (CSF-1)).

Definitions

As used herein, the term amino means a functional group with a nitrogen atom and 1-2 hydrogen atoms. Amino can generally be used herein to describe a primary, secondary or tertiary amine, and one of ordinary skill in the art will be able to readily identify them given the context in which the term is used in this disclosure. The term amine or amino group or ammonia group means a functional group containing a nitrogen atom derived from ammonia (NH ₃ ). The amino groups are preferably primary amines, which means that the nitrogen atom is bonded to two hydrogen atoms and one substituent group including a substituted or unsubstituted alkyl or aryl group or an aliphatic or aromatic group. Amino groups may be secondary amines, which means that the nitrogen atom is bonded to one hydrogen atom and two substituent groups, including substituted or unsubstituted alkyl or aryl groups or an aliphatic or aromatic group, as defined below. Amino groups can be tertiary amines, which means that the nitrogen atom is bonded to three substituent groups, including substituted or unsubstituted alkyl or aryl groups or an aliphatic or aromatic group. Amino groups can also be quaternary ammonium compounds, which means that the designated amino 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 free amine form (i.e., as -NH ₂ for the primary amine) or in protonated form with a pharmaceutically acceptable anion (i.e., as -NH3+Y ^- for a primary amine, where Y ^- represents a pharmaceutically acceptable anion).

As used herein, the term amide group means a functional group containing a carbonyl group bonded to a nitrogen atom. Carbonyl group means a functional group containing a carbon atom connected by a double bond to an oxygen atom, represented as (C=O).

The term alkane means a saturated hydrocarbon linked by single bonds. Alkanes can be linear or branched. Cycloalkanes are saturated hydrocarbon rings connected by single bonds.

As used herein, the term (C ₁ -C ₁₀ )alkyl means a straight-chain, branched-chain, or saturated cyclic hydrocarbon consisting of substantially 110 carbon atoms and a corresponding number of hydrogen atoms. Typically, straight or branched chain groups have from one to ten carbon atoms, or more commonly from one to five carbon atoms. Exemplary (C ₁ -C ₁₀ )alkyl groups include methyl (represented as -CH ₃ ), ethyl (represented as -CH ₂ -CH ₃ ), n-propyl, isopropyl, n-butyl, isobutyl, etc. Other (C ₁ -C ₁₀ )alkyl groups will be readily apparent to one skilled in the art given the benefit of the present disclosure.

As used herein, the term (C ₂ -C ₉ )heteroalkyl means a straight-chain, branched-chain, or saturated cyclic hydrocarbon of substantially 2-10 atoms, wherein 2-9 of the atoms are carbon atoms and the remainder The atom(s) are selected from the group consisting of nitrogen, sulfur and oxygen atoms. Exemplary (C ₂ -C ₉ )heteroalkyl groups will be readily apparent to one skilled in the art in view of the benefit of the present disclosure.

As used herein, the term (C ₃ -C ₁₀ )cycloalkyl means a non-aromatic saturated hydrocarbon group forming at least one ring consisting of essentially 3-10 carbon atoms and an appropriate number of hydrogen atoms. (C ₃ -C ₁₀ )cycloalkyl groups can be monocyclic or polycyclic. The individual rings of polycyclic cycloalkyl groups may have different bonding possibilities, such as fused, bridged, spiro, etc., in addition to being attached via a covalent bond. Exemplary (C ₃ C ₁₀ )cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornanyl, bicyclo-octanyl, octahydro-pentalenyl, spiro-decanyl, cyclobutyl-substituted cyclopropyl, cyclopentyl-substituted cyclobutyl, cyclopropyl-substituted cyclohexyl, and t. d. Other (C ₃ C ₁₀ )cycloalkyl groups will be readily apparent to one skilled in the art given the benefit of the present disclosure.

- 1 044589

As used herein, the term (C ₂ -C ₉ )heterocycloalkyl means a non-aromatic group with 3-10 atoms that form at least one ring, where 2-9 of the ring atoms are carbon atoms and the remaining atom(s) ) rings are selected from the group consisting of nitrogen, sulfur and oxygen atoms. (C ₂ -C ₉ )heterocycloalkyl groups can be monocyclic or polycyclic. The individual rings of such polycyclic heterocycloalkyl groups may have different bonding possibilities, such as fused, bridged, spiro, etc., in addition to being attached via a covalent bond. Exemplary (C ₂ -C ₉ )heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1,3oxazolidin-3-yl, isothiase olidinyl, 1.3 -thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl , tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, piperisin-2-onyl, piperisin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl , imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8diazabicyclo[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 , 2azaspiro[4.4]nonanyl, 7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl, octahydro-1Nindolyl, etc. (C ₂ -C ₉ ) heterocycloalkyl group, like usually attached to the main structure through a carbon atom or a nitrogen atom. Other (C ₂ -C ₉ )heterocycloalkyl groups will be readily apparent to one skilled 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 atoms, 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 atoms that does not contain an aromatic functional group. The aliphatic group may be straight chain, branched chain, or cyclic and typically contains from about one to about 24 carbon atoms.

The term aryl group can be used interchangeably with the terms aryl, aryl ring, aromatic, aromatic group and aromatic ring. Aryl groups include carbocyclic aromatic groups, typically with six to fourteen carbon atoms in the ring.

Aryl groups also include heteroaryl groups, which typically have from five to fourteen ring atoms with one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms.

As used herein, the term (C ₆ -C ₁₄ )aryl means an aromatic functional group with 6-14 carbon atoms that form at least one ring.

As used herein, the term (C ₂ -C ₉ )heteroaryl means an aromatic functional group with 5-10 atoms that form at least one ring, where 2-9 of the ring atoms are carbon atoms and the remaining atom(s) z) the rings are selected from the group consisting of nitrogen, sulfur and oxygen atoms. (C ₂ -C ₉ )heteroaryl groups can be monocyclic or polycyclic. The individual rings of such polycyclic heteroaryl groups may have different bonding possibilities, such as fusions, etc., in addition to being attached via a covalent bond. Exemplary (C ₂ -C ₉ )heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5oxadiazolyl, 1,2,4-oxadiazolyl, 1,2 ,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl , 1,3,5triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro -quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinil, etc. ( A C ₂ -C ₉ )heteroaryl group is typically attached to the backbone via a carbon atom, however, one of ordinary skill in the art will recognize when certain other atoms, such as ring heteroatoms, may be attached to the backbone. Other (C ₂ -C ₉ )heteroaryl groups will be readily apparent to one skilled in the art given the benefit of the present disclosure.

As used herein, the term alkylamine means (C ₁ -C ₁₀ )alkyl containing a primary, secondary or tertiary amino group in place of one hydrogen atom, represented as (C ₁ -C ₁₀ )alkylamine and ((C ₁ -C ₁₀ )alkyl) ₂ -amine

The term alkyl ester means (C ₁ -C ₁₀ )alkyl containing an ester group in place of one hydrogen atom, represented as -O(O)C-(C ₁ -C ₁₀ )alkyl.

The term alkyl acid means (C ₁ -C ₁₀ )alkyl containing a carboxylic acid group in place of one hydrogen atom, represented as (C ₁ -C ₁₀ )alkyl-COOH.

The term aliphatic acid means an acid of non-aromatic hydrocarbons, represented as (C1- _C10 )alkyl-COOH and (C3- _C10 )cycloalkyl-COOH.

The term halogen means an ion of fluorine (F), chlorine (Cl), bromine (Br), iodine (I) or astatine (At).

The term methoxy means (C ₁ )αalkyl containing an oxygen atom instead of one hydrogen atom, represented as -(O)CH3.

The term polyol means an alcohol containing several hydroxyl (-OH) groups.

Substituted means the replacement of a carbon atom in alkyl, heterocyclic or aryl groups with one or more non-carbon substituents. Substituents other than carbon are selected from nitrogen, oxygen and sulfur atoms.

Unsubstituted means a group consisting of only hydrogen and carbon atoms.

A 3-10 membered ring means a closed ring; The 3-10 membered ring can 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 as C=O, can be, for example, aldehydes, ketones and other groups with an oxygen atom connected by a double bond to a carbon atom. Examples include, but are not limited to, glyoxal, methylglyoxal, dimethylglyoxal, and 3deoxyglucosone.

The term patient means an animal, including humans and other mammals, in need of treatment.

Prior Art

Not provided

Brief description of the invention

The present invention relates to a compound with the structure of formula (I):

Q ¹

or a pharmaceutically acceptable salt thereof, where n is 1 or 2;

m. equals 0, 1 or 2;

Q ¹ is (C2-C9)heteroaryl or (C2-C9)heterocycloalkyl, wherein (C2-C9)heteroaryl or (C2-C9)heterocycloalkyl is optionally substituted with one to four groups selected from (C1-C10)alkyl, (C2 -C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkyl-C(O)O-, COOH-( C1-C10)alkyl, COOH-(C3-C10)cycloalkyl, (C1-C10)alkyl-O-, -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O )CR ⁸ N-, F3C- or NC-, wherein each of R ⁷ and R ⁸ independently represents H or (C1-C ₁₀ )alkyl;

Q ² is (C6-C14)aryl or (C2-C9)heteroaryl, wherein (C6-C14)aryl or (C2-C9)heteroaryl is optionally substituted with one to four groups selected from (C1-C10)alkyl, (C2 -C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkyl-C(O)O-, COOH-( C1-Ciu)alkyl, COOH-(C3-Ci)cycloalkyl, (C1-Ciu)alkyl-O-, -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O )CR ⁸ N-, F3C- or NC-, wherein each of R ⁷ and R ⁸ independently represents H or (C1-C ₁₀ )alkyl;

X represents CH or N,

R ¹ represents H, (C1-C ₁₀ )alkyl, (C1-C ₁₀ )alkylamine or NH2;

R ² represents H, (C1-C ₁₀ )alkyl or (C1-C ₁₀ )alkyl-O-;

R ³ and R ⁴ are each independently H or (C1-C ₁₀ )alkyl;

each of R ⁵ and R ⁶ independently represents H or (C 1 -C ₁₀ )alkyl, where each (C ₂ -C ₉ )heteroaryl represents an aromatic group that consists of 5-10 atoms, which

- 3 044589 form at least one ring, where from 2 to 9 ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen;

each (C ₂ -C ₉ )heterocycloalkyl represents a non-aromatic group, which consists of

3-10 atoms that form at least one ring, where 2-9 ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen; and each (C ₂ -C ₉ )heteroalkyl is a straight, branched or cyclic saturated hydrocarbon consisting of 2-10 atoms, where 2-9 atoms are carbon and the remaining atoms are selected from the group consisting of nitrogen, sulfur and oxygen.

The present invention also relates to a compound of formula (I), where n is 1 or 2.

The present invention also relates to a compound of formula (I), where m is 0, 1 or 2.

The present invention also relates to a compound of formula (I), where n is 1 and m is 1.

The present invention also relates to a compound of formula (I) wherein Q ¹ is (C2-C9)heteroaryl or (C2-C9)heterocycloalkyl, wherein (C2-C9)heteroaryl or (C2-C9)heterocycloalkyl is optionally substituted with one to four groups selected from (C1-C10)alkyl, (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10) alkyl-C(O)O-, COOH-(C1-C10)αalkyl, COOH-(C3-C10)cycloαlkyl, (C1-C10)alkyl-O-, -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C- or NC- wherein each of R ⁷ and R ⁸ independently represents H or (C ₁ -C ₁₀ )αalkyl.

The present invention also relates to a compound of formula (I) wherein ^Q2 is (C6- _C14 )aryl or ( _C2 - _C9 )heteroaryl, wherein ( _C6 - _C14 )aryl or ( _C2 - _C9 ) heteroaryl is optionally substituted with one to four groups selected from (C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ - C ₁₄ )αryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )αalkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ ) cycloalkyl, (C ₁ -C ₁₀ )alkylO-, -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C- or NC-, where R ⁷ and R ⁸ are each independently H or (C ₁ -C ₁₀ )alkyl.

The present invention also provides a compound of formula (I) wherein X represents CH or N.

The present invention also provides a compound of formula (I) wherein R ¹ is H, NH2, (C ₁ -C ₁₀ )alkylamine or (C ₁ -C ₁₀ )alkyl.

The present invention also provides a compound of formula (I) wherein R ² is H, (C ₁ -C ₁₀ )alkyl or (C ₁ -C ₁₀ )alkyl-O-.

The present invention also provides a compound of formula (I) wherein R ³ and R ⁴ are each H or (C ₁ -C ₁₀ )alkyl.

The present invention also provides a compound of formula (I) wherein R ⁵ and R ⁶ are each H or (C ₁ -C ₁₀ )alkyl.

The present invention also relates to a compound of formula (I) with structure of formula (II):

or a pharmaceutically acceptable salt thereof.

The present invention also relates to pharmaceutical compositions containing a compound of formula (I).

The present invention also provides methods for treating osteoarthritis in a patient in need thereof, comprising administering to the patient a compound of formula (I).

The present invention also provides methods for treating pain in a patient in need thereof, comprising administering to the patient a compound of formula (I).

The present invention also provides methods for treating pain associated with osteoarthritis in a patient in need thereof, comprising administering to the patient a compound of Formula (I).

The present invention also provides methods for inhibiting tropomyosin-dependent kinase A in a patient, comprising administering to the patient a compound of formula (I).

The present invention also provides methods for inhibiting tropomyosin-dependent kinase B in a patient, comprising administering to the patient a compound of Formula (I).

The present invention also provides methods for inhibiting tropomyosin-dependent kinase C in a patient, comprising administering to the patient a compound of formula (I).

The present invention also provides methods for inhibiting c-FMS in a patient, comprising administering to the patient a compound of formula (I).

Brief description of some images of graphic materials

Not provided

Detailed Description of the Invention

The present invention relates to tropomyosin-dependent kinase inhibitors (TRK inhibitors). The present invention also relates to pharmaceutical compositions containing Trk inhibitors, and to the use of Trk inhibitors and pharmaceutical compositions containing Trk inhibitors for the treatment of a disease. In addition, the present invention relates to the use of Trk inhibitors for the treatment of inflammatory diseases, autoimmune disease, bone metabolic disorders 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-dependent kinase A (TrkA), tropomyosin-dependent kinase B (TrkB), tropomyosin-dependent kinase C ( TrkC), and to inhibit c-FMS (cellular receptor for colony-stimulating factor-1 (CSF-1)).

Tropomyosin-dependent kinases (Trk) are high-affinity receptors activated by soluble 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 growth factor and NT-4/5. TrkC is activated by NT3. Activation of Trk leads to the activation of downstream kinases that are involved in cell signaling, including cell proliferation, survival, angiogenesis, and metastasis. Trk has been implicated in a number of diseases, including OA.

The present invention also relates to inhibitors of c-FMS (cell receptor for colony stimulating factor-1 (CSF-1). C-FMS plays a role in regulating the functioning of macrophages and is believed to play a role in the development of inflammatory diseases, autoimmune disease, metabolic disorders in bone and cancer (Burns and Wilks, 2011, Informa Healthcare).

OA is a common and debilitating joint disease characterized by chronic pain and destruction of articular cartilage. Recent clinical trials have confirmed the value of NGF blocking for OA knee pain, demonstrating significant pain relief and high response rates in patients treated with intravenous infusion of NGF blocking antibodies (Lane, 2010, N Engl J Med). However, this technique may lead to an increased risk of side effects due to systemic inhibition of the NGF signaling pathway (FDA Arthritis Advisory Committee Meeting to Discuss Safety Issues Related to the Anti-Nerve Growth Factor Agents; http://www.fda.gov/AdvisoryCommittees/Calendar /ucm286556.ht m). Accordingly, new approaches have been taken to target pain in NGF-mediated OA through the development of Trk inhibitors, namely inhibitors of TrkA, a high-affinity receptor for NGF (Nicol, 2007, Molecular Interv). The Trk inhibitors of the present invention are delivered locally and thus avoid the systemic distribution observed with intravenous administration of anti-NGF antibodies. This treatment strategy provides the benefit of higher doses as well as greater safety due to the ability to preserve physiologically essential NGF signaling (ie, sensory/sympathetic nerve preservation, angiogenesis) at sites other than those of topical application.

The Trk inhibitors of the present invention are benzimidazole derivatives. Trk inhibitors are small molecules for topical administration.

Fig. 1: benzimidazole.

The present invention relates to pharmaceutical compositions containing Trk inhibitors. The present invention also provides methods for inhibiting Trk using Trk inhibitors and methods for treating disease using Trk inhibitors. The present invention also provides methods for treating OA, methods for treating pain, and methods for treating postoperative pain, and methods for treating pain associated with OA using Trk inhibitors. Trk inhibitors and pharmaceutical compositions containing Trk inhibitors can be administered through several dosage forms, including injection for local delivery. Trk inhibitors are active

- 5 044589 as a pharmaceutical ingredient in pharmaceutical compositions containing Trk inhibitors; 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):

where n is 1, 2, 3, 4 or 5;

m equals 0, 1, 2, 3 or 4;

Q ¹ represents H, halogen or (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, where (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₃ -C ₁₀ )cycloalkyl or (C ₂ -C ₉ )heterocycloalkyl is optionally substituted with one to four groups selected from (C ₁ -C1o)alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C1-C ₁₀ )alkylamine, (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C1-C1o)alkyl, COOH-(C3-C10)cycloalkyl, (C _g C10)alkyl-O-, -OH, -NH2, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F ₃ C-, NC-, (C ₃ -C ₁₀ )alkyl(O)P-, (C ₃ -C ₁₀ )alkyl-S-, (C ₃ -C ₁₀ )cycloalkyl-8-, (C ₆ -C ₁₄ )aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl-S-, (C ₂ -C ₉ )heteroaryl-8-, (C ₃ -C ₁₀ )alkyl(O)8-, (C ₃ -C ₁₀ )cycloalkyl(O)S-, (C ₆ -C ₁₄ )aryl(O)S-, (C ₂ -C ₉ )heteroalkyl(O)8-, (C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C ₉ )heteroaryl (O)S-, (C ₃ -C ₁₀ )alkyl-O ₂ 8-, (C ₃ -C ₁₀ )cycloalkyl-O ₂ 8-, (C ₆ -C ₁₄ )aryl-O ₂ 8-, (C ₂ -C ₉ )heteroalkylO28-, (C ₂ -C ₉ )heterocycloalkyl-O ₂ 8-, (C ₂ -C ₉ )heteroaryl-O ₂ 8- or R7R8NO28-, where each of R ⁷ and R ⁸ independently represents H, (C1-C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ - C ₉ )heteroaryl;

Q ² is (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₃ -C ₁₀ )cycloalkyl, or (C ₂ -C ₉ )heterocycloalkyl, where (C ₆ -C ₁₄ )aryl , (C ₂ -C ₉ )heteroaryl, (C ₃ -C ₁₀ )cycloalkyl or (C ₂ -C ₉ )heterocycloalkyl is optionally substituted with one to four groups selected from (C 1 -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C1-C ₁₀ )alkylamine, (C1- C ₁₀ )alkyl-C(O)O-, COOH-(C1-C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkyl, (C1-C ₁₀ )alkyl-O-, -OH, -NH ₂ , R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C-, NC-, (C ₃ -C ₁₀ )alkyl(O)P-, ( C ₃ -C ₁₀ )alkyl-8-, (C ₃ -C ₁₀ )cycloalkyl-8-, (C ₆ -C ₁₄ )aryl-8-, (C ₂ -C ₉ )heteroalkyl-8-, (C ₂ -C ₉ )heterocycloalkyl-8-, (C ₂ -C ₉ )heteroaryl-8-, (C ₃ -C ₁₀ )alkyl(O)8-, (C ₃ -C ₁₀ )cycloalkyl(O)8-, ( C ₆ -C ₁₄ )aryl(O)8-, (C ₂ -C ₉ )heteroalkyl(O)8-, (C ₂ -C ₉ )heterocycloalkyl(O)8-, (C ₂ -C ₉ )heteroaryl( O)8-, (C ₃ -C ₁₀ )alkyl-O ₂ 8-, (C ₃ -C ₁₀ )cycloalkyl-O ₂ 8-, (C ₆ -C ₁₄ )aryl-O ₂ 8-, (C ₂ -C ₉ )heteroalkylO28-, (C ₂ -C ₉ )heterocycloalkyl-O ₂ 8-, (C ₂ -C ₉ )heteroaryl-O ₂ 8- or R7R8NO28-, where each of R ⁷ and R ⁸ independently represents H , (C1- _C10 )alkyl, ( _C2 - _C9 )heteroalkyl, ( _C3 - _C10 )cycloalkyl, ( _C2 - _C9 )heterocycloalkyl, ( _C6 - _C14 )aryl, ( _C2 -C ₉ )heteroaryl;

X represents CH, N, halogen or ^CR9 , where ^R9 represents (C1- _C10 )alkyl, ( _C2 - _C9 )heteroalkyl, ( _C3 - _C10 )cycloalkyl, ( _C2 - _C9 ) heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C1-C ₁₀ )alkylamine, (C1-C ₁₀ )alkyl-C(O)O-, COOH-(C1-C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkyl, (C1-C ₁₀ )alkyl-O-, -OH, -NH2;

R ¹ represents H, halogen, (C1-C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C1-C ₁₀ )alkylamine or NH2;

^R2 is H, halogen, (C1- _C10 )alkyl, ( _C2 - _C9 )heteroalkyl, (C1- _C10 )alkylamine, (C1- _C10 )alkyl-O- or NH2;

^R3 and ^R4 are each independently H, (C1- _C10 )alkyl, ( _C2 - _C9 )heteroalkyl, (C1- _C10 )alkylamine, O-(C1- _C10 )alkyl or NH2, or R ³ and R ⁴ are taken together with the carbon atom to which they are attached to form a 3-10 membered ring, where the 3-10 membered ring is optionally substituted with one to four groups selected from (C1- _C10 )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C1-C ₁₀ )alkylamine , (C1-C ₁₀ )alkyl-C(O)O-, COOH-(C1-C ₁₀ )alkyl,

COOH-(C ₃ -C ₁₀ )cycloalkyl, (C1-C ₁₀ )alkyl-O-, -OH, -NH2; And

- 6 044589 each of R ⁵ and R ⁶ independently represents H, (C1- _C10 )alkyl, ( _C2 - _C9 )heteroalkyl, (C1-C1o)alkylamine, O-( _C1 - _C10 )alkyl or NH2, or R ⁵ and R ⁶ are taken together with the carbon atom to which they are attached to form a 3-10 membered ring, where the 3-10 membered ring is optionally substituted with one to four groups selected from (C ₁ -C ₁₀ ) alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C2-C ₉ )heteroaryl, (C ₁ - C ₁₀ )alkylamine, (C ₁ -C ₁₀ )αalkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl,

COOH-(C ₃ -C ₁₀ )cycloalkyl, (C ₁ -C ₁₀ )αalkyl-O-, -OH, -NH2;

or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the present invention provides a compound of formula (I) where n is 1, 2 or 3. In another embodiment, the present invention provides a compound of formula (I) where n is 1. In another embodiment, the present invention provides a compound of formula (I) where n is 2. In yet another embodiment, the present invention provides a compound of formula (I) where n is 3.

In a preferred embodiment, the present invention provides a compound of formula (I) where m is 0, 1 or 2. In another embodiment, the present invention provides a compound of formula (I) where m is 0. In another embodiment, the present invention provides a compound of formula (I), where m is 1. In yet another embodiment, the present invention provides a compound of formula (I), where m is 2.

In a preferred embodiment, the present invention relates to a compound of formula (I), where n is 1 and m is 1.

In a preferred embodiment, the present invention also provides a compound of formula (I) wherein Q ¹ is H, or (C6-C14)aryl, or (C2-C9)heteroaryl, optionally substituted with one to four groups selected from (C1- C10)alkyl, (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkylamine, (Cl-Cl0 )alkyl-C(O)O-, COOH-(C1-C10)alkyl, CoOH-(C3-C10)cycloalkyl, (C1-C10)alkyl-O-, -OH, -NH2, R ⁷ R ⁸ N- , R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C-, NC-, (C ₃ -C ₁₀ )alkyl(O)P-, (C ₃ -C ₁₀ )alkyl -S-, (C ₃ -C ₁₀ )cycloalkyl-S-, (C ₆ -C ₁₄ )aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl-S -, (C ₂ -C ₉ )heteroaryl-S-, (C ₃ -C ₁₀ )alkyl(O)S-, (C ₃ -C ₁₀ )cycloalkyl(O)S-, (C ₆ -C ₁₄ )aryl (O)S-, (C ₂ -C ₉ )heteroalkyl(O)S-, (C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C ₉ )heteroaryl(O)S-, (C ₃ -C ₁₀ )alkyl-O ₂ S-, (C ₃ -C ₁₀ )cycloalkyl-O ₂ S-, (C ₆ -C ₁₄ )aryl-O ₂ S-, (C ₂ -C ₉ )heteroalkyl-O ₂ S-, (C ₂ -C ₉ )heterocycloalkyl-O ₂ S-, (C ₂ -C ₉ )heteroaryl-O ₂ S- or R ⁷ R ⁸ NO2S-, where each of R ⁷ and R ⁸ independently represents H, (C1-C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ - C ₉ )heteroaryl.

In another embodiment, the present invention also provides a compound of formula (I) wherein Q ¹ is H.

In yet another embodiment, the present invention also provides a compound of formula (I) wherein Q ¹ is (C6-C14)αryl, optionally substituted with one to four groups selected from (C1-C10)alkyl, (C2-C9)heteroalkyl , (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkylamine, (C1-C10)αalkyl-C(O)O-, COOH-(C1-C10)alkyl, COOH-(C3C10)cycloalkyl, (C1-C10)alkyl-O-, -OH, -NH2, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C-, NC-, (C ₃ -C ₁₀ )alkyl(O)P-, (C ₃ -C ₁₀ )alkyl-S-, (C ₃ -C ₁₀ )cycloalkyl -S-, (C ₆ -C ₁₄ )aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl-S-, (C ₂ -C ₉ )heteroaryl-S -, (C ₃ -C ₁₀ )alkyl(O)S-, (C ₃ -C ₁₀ )cycloalkyl(O)S-, (C ₆ -C ₁₄ )aryl(O)S-, (C ₂ -C ₉ )heteroalkyl(O)S-, (C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C ₉ )heteroaryl(O)S-, (C ₃ -C ₁₀ )alkyl-O ₂ S-, (C ₃ -C ₁₀ )cycloalkyl-O ₂ S-, (C ₆ -C ₁₄ )aryl-O ₂ S-, (C ₂ -C ₉ )heteroalkyl-O ₂ S-, (C ₂ -C ₉ )heterocycloalkyl -O ₂ S-, (C ₂ -C ₉ )heteroaryl-O ₂ S- or R ⁷ R ⁸ NO2S-, where each of R ⁷ and R ⁸ independently represents H, (C1-C10)alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl.

In yet another embodiment, the present invention also provides a compound of formula (I) wherein Q ¹ is (C2-C9)heteroaryl, optionally substituted with one to four groups selected from (C1- _C10 )alkyl, ( _C2 -C ₉ ) heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C1-C ₁₀ )alkylamine, (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C1-C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkyl, (C1-C ₁₀ )alkyl-O-, -OH, - NH2, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F ₃ C-, NC-, (C ₃ -C ₁₀ )alkyl(O)P -, (C ₃ -C ₁₀ )alkyl-S-, (C ₃ -C ₁₀ )cycloalkyl-S-, (C ₆ -C ₁₄ )aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl-S-, (C ₂ -C ₉ )heteroaryl-S-, (C ₃ -C ₁₀ )alkyl (0) S-, (C ₃ -C ₁₀ )cycloalkyl(O)S -, (C ₆ -C ₁₄ )aryl(O)S-, (C ₂ -C ₉ )heteroalkyl(O)S-, (C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C ₉ )heteroaryl(O)S-, (C ₃ -C ₁₀ )alkyl-O ₂ S-, (C ₃ -C ₁₀ )cycloalkyl-O ₂ S-, (C ₆ -C ₁₄ )aryl-O ₂ S-, (C ₂ C ₉ )heteroalkyl-O ₂ S-, (C ₂ -C ₉ )heterocycloalkyl-O ₂ S-, (C ₂ -C ₉ )heteroaryl-O ₂ S- or R ⁷ R ⁸ NO2S-, where each from R ⁷ and R ⁸ independently represents H, (C1-C10)alkyl, ( _C2 - _C9 )heteroalkyl, ( _C3 - _C10 )cycloalkyl, ( _C2 - _C9 )heterocycloalkyl, ( _C6 -C ₁₄ )aryl, ( _C2 - _C9 )heteroaryl.

In a preferred embodiment, the present invention also provides a compound of formula (I) wherein Q ² is (C ₆ -C ₁₄ )aryl or (C ₂ -C ₉ )heteroaryl, optionally substituted with one to four groups selected from (C1- _C10 )alkyl, ( _C2 - _C9 )heteroalkyl, ( _C3 - _C10 )cycloalkyl, ( _C2 - _C9 )heterocycloalkyl, ( _C6 - _C14 )aryl, ( _C2 - _C9 )heteroaryl, (C1-C ₁₀ )alkylamine,

- 7 044589 (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C1-C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkyl, (C ₁ -C ₁₀ )αlkul-O -, -OH, -NH2,

R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C-, NC-, (C3-C1o)alkyl(O)P-, (C ₃ - C1o)alkyl-S-, (C ₃ -C1o)cycloalkyl-S-, (C ₆ -C ₁₄ )aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl -8-, (C ₂ -C ₉ )heteroaryl-S-, (C ₃ -C ₁₀ )alkyl(O)S-, (C ₃ -C ₁₀ )cycloalkyl(O)S-, (C ₆ -C ₁₄ )aryl(O)S-, (C ₂ -C ₉ )heteroalkyl(O)S-, (C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C ₉ )heteroaryl(O)S-, (C ₃ -C ₁₀ )alkyl-O ₂ S-, (C ₃ -C ₁₀ )cycloalkyl-O ₂ S-, (C ₆ -C ₁₄ )aryl-O ₂ S-, (C ₂ -C ₉ )heteroalkyl -O ₂ S-, (C ₂ -C ₉ )heterocycloalkyl-O ₂ S-, (C ₂ -C ₉ )heteroaryl-O ₂ S- or R ⁷ R ⁸ NO2S-, where each of R ⁷ and R ⁸ is independently represents H, (C1-C10)alkyl, (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl. In another embodiment, the present invention also provides a compound of formula (I) wherein Q ² is (C6-C ₁₄ )aryl, optionally substituted with one to four groups selected from (C ₁ -C ₁₀ )alkyl, (C ₂ - C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C6-C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )alkylamine, ( C ₁ -C ₁₀ )αlkul-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl,

COOH-(C3-C1o)cycloalkyl, (C1-C1o)alkyl-O-, -OH, -NH2, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C-, NC-, (C ₃ -C ₁₀ )alkyl(O)P-, (C ₃ -C ₁₀ )alkyl-S-, (C ₃ -C ₁₀ )cycloalkyl-S-, (C ₆ -C ₁₄ )aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl-S-, (C ₂ -C ₉ )heteroaryl-S-, (C ₃ -C ₁₀ )alkyl(O)S-, (C ₃ -C ₁₀ )cycloalkyl(O)S-, (C ₆ -C ₁₄ )aryl(O)S-, (C ₂ -C ₉ )heteroalkyl(O)S- , (C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C ₉ )heteroaryl(O)S-, (C ₃ -C ₁₀ )alkyl-O ₂ S-, (C ₃ -C ₁₀ ) cycloalkyl-O ₂ S-, (C ₆ -C ₁₄ )aryl-O ₂ S-, (C ₂ -C ₉ )heteroalkyl-O ₂ S-, (C ₂ -C ₉ )heterocycloalkyl-O ₂ S-, ( C ₂ -C ₉ )heteroaryl-O ₂ S- or R ⁷ R ⁸ NO ₂ S-, where each of R ⁷ and R ⁸ independently represents H, (C1-C10)alkyl, (C2-C9)heteroalkyl, ( C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl. In yet another embodiment, the present invention also provides a compound of formula (I) wherein Q ² is (C2-C9)heteroaryl, optionally substituted with one to four groups selected from (C1- _C10 )alkyl, ( _C2 -C ₉ ) heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C6-C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )alkylamine, (C ₁ -C ₁₀ )αlkul-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl,

COOH-(C ₃ -C ₁₀ )cycloalkyl, (C ₁ -C ₁₀ )alkyl-O-, -OH, -NH2, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ ( O)CR ⁸ N-, F ₃ C-, NC-, (C ₃ -C ₁₀ )alkyl(O)P-, (C ₃ -C ₁₀ )alkyl-S-, (C ₃ -C ₁₀ )cycloalkyl- S-, (C ₆ -C ₁₄ )aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl-S-, (C ₂ -C ₉ )heteroaryl-S- , (C ₃ -C ₁₀ )alkyl(O)S-, (C ₃ -C ₁₀ )cycloalkyl(O)S-, (C ₆ -C ₁₄ )aryl(O)S-, (C ₂ -C ₉ ) heteroalkyl(O)S-, (C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C ₉ )heteroaryl(O)S-, (C ₃ -C ₁₀ )alkyl-O ₂ S-, ( C ₃ -C ₁₀ )cycloalkyl-O ₂ S-, (C ₆ -C ₁₄ )aryl-O ₂ S-, (C ₂ -C ₉ )heteroalkyl-O ₂ S-, (C ₂ -C ₉ )heterocycloalkyl- O ₂ S-, (C ₂ -C ₉ )heteroaryl-O ₂ S- or R ⁷ R ⁸ NO ₂ S-, where each of R ⁷ and R ⁸ independently represents H, (C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl.

In a preferred embodiment, the present invention also provides a compound of formula (I) wherein X is CH or N. In another embodiment, the present invention also provides a compound of formula (I) wherein X is CH. In yet another embodiment, the present invention also provides a compound of formula (I) wherein X is N.

In a preferred embodiment, the present invention also provides a compound of formula (I) wherein R ¹ is H, halogen, NH2 or (C ₁ -C ₁₀ )alkyl. In another embodiment, the present invention also provides a compound of formula (I) wherein R ¹ is H. In another embodiment, the present invention also provides a compound of formula (I) wherein R ¹ is halogen. In another embodiment, the present invention also provides a compound of formula (I) wherein R ¹ is NH2. In yet another embodiment, the present invention also provides a compound of formula (I) wherein R ¹ is (C ₁ -C ₁₀ )alkyl.

In a preferred embodiment, the present invention provides a compound of formula (I) wherein R ² is H, halogen, (C ₁ -C ₁₀ )alkyl or (C ₁ -C ₁₀ )alkul-O-. In another embodiment, the present invention provides a compound of formula (I) wherein R ² is H. In another embodiment, the present invention provides a compound of formula (I) wherein R ² is halogen. In another embodiment, the present invention provides a compound of formula (I) wherein R ² is (C1-C10)alkyl. In another embodiment, the present invention provides a compound of formula (I) wherein R ² is a (C1-C ₁₀ )alkyl-OB; in yet another embodiment, the present invention provides a compound of formula (I) wherein R ² is CH3-O - or CH3-CH2-O-.

In a preferred embodiment, the present invention provides a compound of formula (I) wherein R ³ and R ⁴ are each H.

In a preferred embodiment, the present invention provides a compound of formula (I) wherein ^R5 and ^R6 are each H.

In a preferred embodiment, the present invention relates to a compound of formula (I) with structure of formula (II):

- 8 044589

or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the present invention provides a compound of formula (II) where n is 1, 2 or 3. In another embodiment, the present invention provides a compound of formula (II) where n is 1. In another embodiment, the present invention provides a compound of formula (II) where n is 2. In yet another embodiment, the present invention provides a compound of formula (II) where n is 3.

In a preferred embodiment, the present invention provides a compound of formula (II) where m is 0, 1 or 2. In another embodiment, the present invention provides a compound of formula (II) where m is 0. In another embodiment, the present invention provides a compound of formula (II) where m is 1. In yet another embodiment, the present invention provides a compound of formula (II) where 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.

In a preferred embodiment, the present invention also provides a compound of formula (II) wherein Q ¹ is H, or (C6-C14)aryl, or (C2-C9)heteroaryl, optionally substituted with one to four groups selected from (C1- C10)alkyl, (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkylamine, (C1-C1o) )αalkyl-C(O)O-, COOH-(C1-C1o)alkyl, COOH-(C3-C1o)cycloalkyl, (C1-C1o)alkyl-O-, -OH, -NH2, R ⁷ R ⁸ N- , R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C-, NC-, (C ₃ -C ₁₀ )alkyl(O)P-, (C ₃ -C ₁₀ )αalkyl -S-, (c ₃ -C ₁₀ )cycloalkyl-S-, (C ₆ -C ₁₄ )aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl-S -, (C ₂ -C ₉ )heteroaryl-S-, (C ₃ -C ₁₀ )alkyl(O)S-, (C ₃ -C ₁₀ )cycloalkyl(O)S-, (C ₆ -C ₁₄ )aryl (O)S-, (C ₂ -C ₉ )heteroalkyl(O)S-, (C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C ₉ )heteroaryl(O)S-, (C ₃ -C10)alkyl-O ₂ S-, (C ₃ -C ₁₀ )cycloalkyl-O ₂ S-, (C ₆ -C ₁₄ )aryl-O ₂ S-, (C ₂ -C ₉ )heteroalkyl-O ₂ S-, (C ₂ -C ₉ )heterocycloalkyl-O ₂ S-, (C ₂ -C ₉ )heteroaryl-O ₂ S- or R ⁷ R ⁸ NO2S-, where each of R ⁷ and R ⁸ independently represents H , (C1-C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl. In another embodiment, the present invention also provides a compound of formula (II) wherein Q ¹ is H. In yet another embodiment, the present invention also provides a compound of formula (II) wherein Q ¹ is (C ₆ -C ₁₄ ) aryl, optionally substituted with one to four groups selected from (C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )alkylamine, (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )αalkyl , COOH-(C ₃ -C ₁₀ )cycloalkyl, (C ₁ -C ₁₀ )αalkyl-O-, -OH, -NH ₂ , R ⁷ R ⁸ N-, R ⁷ R ⁸ n(o)C-, R ⁷ (O)CR ⁸ N-, F3C-, NC-, (C3-C1o)alkyl(O)P-, (C3-C1o)αalkyl-S-, (C3-C1o)cycloalkyl-S-, (C6- C14)aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl-S-, (C ₂ -C ₉ )heteroaryl-S-, (C ₃ -C ₁₀ ) alkyl(O)S-, (C ₃ -C ₁₀ )cycloαlkyl(O)S-, (C ₆ -C ₁₄ )aryl(O)S-, (C ₂ -C ₉ )heteroαlkyl(O)S-, ( C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C ₉ )heteroaryl(O)S-, (C ₃ -C ₁₀ )alkyl-O ₂ S-, (C ₃ -C ₁₀ )cycloalkyl- O ₂ S-, (C ₆ -C ₁₄ )aryl-O ₂ S-, (C ₂ -C ₉ )heteroαalkyl-O ₂ S-, (C ₂ -C ₉ )heterocycloalkyl-O ₂ S-, (C ₂ -C ₉ )heteroaryl-O ₂ S- or R ⁷ R ⁸ NO2S-, where each of R ⁷ and R ⁸ independently represents H, (C1-C ₁₀ )αalkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C10)cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl. In yet another embodiment, the present invention also provides a compound of formula (II) wherein Q ¹ is (C2-C9)heteroaryl, optionally substituted with one to four groups selected from (C ₁ -C ₁₀ )alkyl, (C ₂ - C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )alkylamine, (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )αalkyl,

COOH-(C ₃ -C ₁₀ )cycloalkylα, (C ₁ -C ₁₀ )αalkyl-O-, -OH, -NH ₂ , R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F ₃ C-, NC-, (C ₃ -C ₁₀ )alkyl(O)P-, (C ₃ -C ₁₀ )alkyl-S-, (C ₃ -C ₁₀ )cycloalkyl -S-, (C ₆ -C ₁₄ )aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl-S-, (C ₂ -C ₉ )heteroaryl-S -, (C ₃ -C ₁₀ )alkyl(O)S-, (C ₃ -C ₁₀ )cycloalkyl(O)S-,

- 9 044589 (C6-C ₁ 4)aryl(O)S-, (C ₂ -C ₉ )heteroalkyl(O)S-, (C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C9 )heteroaryl(O)S-, (C ₃ -C ₁₀ )alkyl-O ₂ S-, (C ₃ -C ₁₀ )cycloalkyl-O ₂ S-, (C6-C ₁₄ )αrul-O ₂ S-, ( C ₂ -C9)heteroalkyl-O ₂ S-, (C ₂ -C ₉ )heterocycloalkyl-O ₂ S-, (C ₂ -C ₉ )heteroaryl-O ₂ S- or R7R8NO2S-, where each of R ⁷ and R ⁸ independently represents H, (C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl , (C ₂ -C ₉ )heteroaryl.

In a preferred embodiment, the present invention also provides a compound of formula (II) wherein Q ² is (C6-C14)aryl or (C2-C9)heteroaryl, optionally substituted with one to four groups selected from (C1-C10)alkyl, (C2-C9)heteroalkyl, (C3-C10)cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)aryl, (C2-C9)heteroaryl, (C1-C10)alkylamine, (C1-C10)alkyl-C (O)O-, COOH-(C1-C10)alkyl, CoOH-(C3-C10)cycloalkyl, (C1-C10)alkyl-O-, -OH, -NH2, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C-, NC-, (C3-C1o)alkyl(O)P-, (C3-C1o)alkyl-S-, (C3-C1o )cycloalkyl-S-, (C6-C14)aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl-S-, (C ₂ -C ₉ )heteroaryl-S -, (C ₃ -C ₁₀ )alkyl(O)S-, (C ₃ -C ₁₀ )cycloalkyl(O)S-, (C6-C ₁₄ )aryl(O)S-, (C ₂ -C ₉ ) heteroalkyl(O)S-, (C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C ₉ )heteroaryl(O)S-, (C ₃ -C ₁₀ )alkyl-O ₂ S-, ( C ₃ -C ₁₀ )cycloalkyl-O ₂ S-, (C ₆ -C ₁₄ )aryl-O ₂ S-, (C ₂ -C ₉ )heteroalkyl-O ₂ S-, (C ₂ -C ₉ )heterocycloalkyl- O ₂ S-, (C ₂ -C ₉ )heteroaryl-O ₂ S- or R ⁷ R ⁸ NO2S-, where each of R ⁷ and R ⁸ independently represents H, (C1-C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl. In another embodiment, the present invention also provides a compound of formula (II) wherein Q ² is (C6-C ₁₄ )aryl, optionally substituted with one to four groups selected from (C ₁ -C ₁₀ )alkyl, (C ₂ - C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )alkylamine, (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl,

COOH-(C3-C1o)cycloalkyl, (C1-Ciu)alkyl-O-, -OH, -NH2, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C-, NC-, (C ₃ -C ₁₀ )alkyl(O)P-, (C ₃ -C ₁₀ )alkyl-S-, (C ₃ -C ₁₀ )cycloalkyl-S-, (C6- C ₁₄ )aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl-S-, (C ₂ -C ₉ )heteroaryl-S-, (C ₃ -C ₁₀ )alkyl(O)S-, (C ₃ -C ₁₀ )cycloalkyl(O)S-, (C6-C ₁₄ )aryl(O)S-, (C ₂ -C ₉ )heteroalkyl(O)S-, ( C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C ₉ )heteroaryl(O)S-, (C ₃ -C ₁₀ )alkyl-O ₂ S-, (C ₃ -C ₁₀ )cycloalkyl- O ₂ S-, (C ₆ -C ₁₄ )aryl-O ₂ S-, (C ₂ -C ₉ )heteroalkyl-O ₂ S-, (C ₂ -C ₉ )heterocycloalkyl-O2S-, (C ₂ -C ₉ )heteroaryl-O ₂ S- or R7R8NO2S-, where each of R ⁷ and R ⁸ independently represents H, (C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ ) cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl. In yet another embodiment, the present invention also provides a compound of formula (II) wherein Q ² is (C ₂ -C ₉ )heteroaryl, optionally substituted with one to four groups selected from (C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C6-C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )alkylamine , (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl,

COOH-(C3-C1o)cycloalkyl, (C1-C1o)alkyl-O-, -OH, -NH2, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C-, NC-, (C ₃ -C ₁₀ )alkyl(O)P-, (C ₃ -C ₁₀ )alkyl-S-, (C ₃ -C ₁₀ )cycloalkyl-S-, (C6- C ₁₄ )aryl-S-, (C ₂ -C ₉ )heteroalkyl-S-, (C ₂ -C ₉ )heterocycloalkyl-S-, (C ₂ -C ₉ )heteroaryl-S-, (C ₃ -C ₁₀ )alkyl(O)S-, (C ₃ -C ₁₀ )cycloalkyl(O)S-, (C6-C ₁₄ )aryl(O)S-, (C ₂ -C ₉ )heteroalkyl(O)S-, ( C ₂ -C ₉ )heterocycloalkyl(O)S-, (C ₂ -C ₉ )heteroaryl(O)S-, (C ₃ -C ₁₀ )alkyl-O ₂ S-, (C ₃ -C ₁₀ )cycloalkyl- O ₂ S-, (C ₆ -C ₁₄ )aryl-O ₂ S-, (C ₂ -C ₉ )heteroalkyl-O ₂ S-, (C ₂ -C ₉ )heterocycloalkyl-O ₂ S-, (C ₂ -C ₉ )heteroaryl-O ₂ S- or R7R8NO2S-, where each of R ⁷ and R ⁸ independently represents H, (C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl.

In a preferred embodiment, the present invention also provides a compound of formula (II) wherein X is CH or N. In another embodiment, the present invention also provides a compound of formula (II) wherein X is CH. In yet another embodiment, the present invention also provides a compound of formula (II) wherein X is N.

In a preferred embodiment, the present invention also provides a compound of formula (II) wherein R ¹ is H, halogen, NH2 or (C1-C10)alkyl. In another embodiment, the present invention also provides a compound of formula (II) wherein R ¹ is H. In another embodiment, the present invention also provides a compound of formula (II) wherein R ¹ is halogen. In another embodiment, the present invention also provides a compound of formula (II) wherein R ¹ is NH2. In yet another embodiment, the present invention also provides a compound of formula (II) wherein R ¹ is (C ₁ -C ₁₀ )alkyl.

In a preferred embodiment, the present invention relates to a compound of formula (II) wherein R ² is H, halogen, (C1-C10)alkyl or (C1-C10)alkyl-O-. In another embodiment, the present invention provides a compound of formula (II) wherein R ² is H. In another embodiment, the present invention provides a compound of formula (II) wherein R ² is halogen. In another embodiment, the present invention provides a compound of formula (II) wherein R ² is (C1-C ₁₀ )alkyl. In another embodiment, the present invention provides a compound of formula (II) wherein R ² is (C ₁ -C ₁₀ )alkyl-O-. In yet another embodiment, the present invention relates to a connection

- 10 044589 formula (II), where R2 represents CH3-O- or CH3-CH2-O-.

In a preferred embodiment, the present invention also relates to a compound of formula (I), wherein the compound is selected from:

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin5-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridin-4yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2I morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine , (5-(2-amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine oxide,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -1H-benzo[d]imidazole,

3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, (5-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine oxide ,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4yl)propan- 2-amine,

4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)morpholine,

6-(4-cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b ]pyridine,

- 11 044589 (3)-1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidin- 2carboxylic acid,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1(piperidin-4-yl)-1R-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,2,4oxadiazole,

2-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,3,4oxadiazole,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2 ,3triazol-4-yl)propan-2-amine and

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-(piperidin-3-yl)-IH-1,2,3-triazol-1-yl) -ZH-imidazo[4,5 -

b]pyridine.

In a preferred embodiment, the present invention also relates to a pharmaceutical composition containing a compound according to formula (I). In yet another preferred embodiment, the present invention also relates to a pharmaceutical composition containing a compound according to formula (II). In another embodiment, the present invention also relates to a pharmaceutical composition containing a compound according to formula (I), wherein the compound is selected from:

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin5-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridin-4yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,

- 12 044589 (5-(2-amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine oxide,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -1H-benzo[d]imidazole,

3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, (5-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine oxide ,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4yl)propan- 2-amine,

4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)morpholine,

6-(4-cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b ]pyridine, (S)-1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidin- 2carboxylic acid,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,2,4oxadiazole,

2-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,3,4oxadiazole,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2 ,3triazol-4-yl)propan-2-amine and

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -ZH-imidazo[4,5—

b]pyridine.

In a preferred embodiment, the present invention also relates to methods

- 13 044589 treatment of inflammatory diseases, autoimmune diseases, metabolic disorders in bone tissue or cancer, involving the administration of a compound according to formula (I) to the patient. In yet another preferred embodiment, the present invention also provides methods for treating inflammatory diseases, autoimmune disease, bone metabolic disorders or cancer, comprising administering to a patient a compound of formula (II). In another embodiment, the present invention also provides methods for treating an inflammatory disease, an autoimmune disease, a bone metabolic disorder, or cancer, comprising administering to a patient a compound of formula (I), wherein the compound is selected from:

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin5-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridin-4yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine, (5-(2-amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine oxide,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -1H-benzo[d]imidazole,

3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,

- 14 044589 (5-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2- yl)dimethylphosphine oxide,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4yl)propan- 2-amine,

4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)morpholine,

6-(4-cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b ]pyridine, (S)-1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidin- 2carboxylic acid,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,2,4oxadiazole,

2-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,3,4oxadiazole,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2 ,3triazol-4-yl)propan-2-amine and

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)- 6(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -3H-imidazo[4,5b]pyridine.

In a preferred embodiment, the present invention also provides methods for treating osteoarthritis comprising administering to a patient a compound of Formula (I). In yet another preferred embodiment, the present invention also provides methods for treating osteoarthritis comprising administering to a patient a compound of formula (II). In another embodiment, the present invention also provides methods for treating osteoarthritis comprising administering to a patient a compound of formula (I), wherein the compound is selected from:

- 15 044589

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin5-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridin-4yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine, (5-(2-amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine oxide,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-b(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

1-(3-methoxy-4-((b-methoxypyridin-3-yl)methoxy)benzyl)-5(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -1H-benzo[d]imidazole,

3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, (5-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)3H-imidazo[4,5-b]pyridin-b-yl)pyridin-2-yl)dimethylphosphine oxide ,

3-(3-methoxy-4-((b-methoxypyridin-3-yl)methoxy)benzyl)-b(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,

2-(1-(3-(3-methoxy-4-((b-methoxypyridin-3yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-b-yl)piperidin-4yl)propan- 2-amine,

4-(3-(3-methoxy-4-((b-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-b-yl)morpholine, b-(4-cyclopropylpiperazine -1-yl)-3-(3-methoxy-4-((bmethoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,

3-(3-methoxy-4-((b-methoxypyridin-3-yl)methoxy)benzyl)-b(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b ]pyridine,

- 16 044589 (S)-1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidin- 2carboxylic acid,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,2,4oxadiazole,

2-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,3,4oxadiazole,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2 ,3triazol-4-yl)propan-2-amine and

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -3H-imidazo[4,5b]pyridine.

In a preferred embodiment, the present invention also provides methods for treating pain comprising administering to a patient a compound of formula (I). In one embodiment, the pain treated with the compound of formula (I) is post-operative pain. In yet another preferred embodiment, the present invention also provides methods for treating pain comprising administering to a patient a compound of formula (II). In another embodiment, the pain treated with the compound of formula (II) is post-operative pain. In another embodiment, the present invention also provides methods for treating pain and methods for treating postoperative pain comprising administering to a patient a compound of formula (I), wherein the compound is selected from:

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,

3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, (5-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine oxide ,

3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine and

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine.

In a preferred embodiment, the present invention also provides methods for treating pain associated with osteoarthritis, comprising administering to a patient a compound of formula (I). In yet another preferred embodiment, the present invention also provides methods for treating pain associated with osteoarthritis, comprising administering to a patient a compound of formula (II). In another embodiment, the present invention also provides methods for treating pain associated with osteoarthritis, comprising administering to a patient a compound of formula (I), wherein the compound is selected from:

- 17 044589

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin5-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridin-4yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine, (5-(2-amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine oxide,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-b(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

1-(3-methoxy-4-((b-methoxypyridin-3-yl)methoxy)benzyl)-5(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -1H-benzo[d]imidazole,

3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-b-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine,

- 18 044589 (5-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2- yl)dimethylphosphine oxide,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4yl)propan- 2-amine,

4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)morpholine,

6-(4-cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b ]pyridine, (S)-1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidin- 2carboxylic acid,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,2,4oxadiazole,

2-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,3,4oxadiazole,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2 ,3triazol-4-yl)propan-2-amine and

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -ZH-imidazo[4,5 -

b]pyridine.

In a preferred embodiment, the present invention also provides methods for inhibiting tropomyosin-dependent kinase A, comprising administering to a patient a compound of Formula (I). In yet another preferred embodiment, the present invention also provides methods for inhibiting tropomyosin-dependent kinase A, comprising administering to a patient a compound of Formula (II). In another embodiment, the present invention also provides methods for inhibiting tropomyosin-dependent kinase A, comprising administering to a patient a compound of formula (I), wherein the compound is selected from:

- 19 044589

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin5-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridin-4yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine, (5-(2-amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine oxide,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -1H-benzo[d]imidazole,

3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, (5-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine oxide ,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4yl)propan- 2-amine,

4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)morpholine,

6-(4-cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,

- 20 044589

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b ]pyridine, (S)-1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidin- 2carboxylic acid,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,2,4oxadiazole,

2-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,3,4oxadiazole,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2 ,3triazol-4-yl)propan-2-amine and

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)- 6(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -ZH-imidazo[4,5—

b]pyridine.

In a preferred embodiment, the present invention also provides methods for inhibiting tropomyosin-dependent kinase B, comprising administering to a patient a compound of formula (I). In yet another preferred embodiment, the present invention also provides methods for inhibiting tropomyosin-dependent kinase B, comprising administering to a patient a compound of formula (II). In another embodiment, the present invention also provides methods for inhibiting tropomyosin-dependent kinase B, comprising administering to a patient a compound of formula (I), wherein the compound is selected from:

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,

- 21 044589

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin5-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridin-4yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine, (5-(2-amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine oxide,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -1H- benzo[d]imidazole,

3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, (5-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine oxide ,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4yl)propan- 2-amine,

4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)morpholine,

6-(4-cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b ]pyridine, (S)-1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidin- 2carboxylic acid,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

- 22 044589

3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,2,4oxadiazole,

2-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,3,4oxadiazole,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2 ,3triazol-4-yl)propan-2-amine and

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -ZH-imidazo[4,5 -

b]pyridine.

In a preferred embodiment, the present invention also provides methods for inhibiting tropomyosin-dependent kinase C, comprising administering to a patient a compound of formula (I). In yet another preferred embodiment, the present invention also provides methods for inhibiting tropomyosin-dependent kinase C, comprising administering to a patient a compound of formula (II). In another embodiment, the present invention also provides methods for inhibiting tropomyosin-dependent kinase C, comprising administering to a patient a compound of formula (I), wherein the compound is selected from:

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin5-yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridin-4yl)-1H-benzo[d]imidazol-2-amine,

1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-(2morpholinoethyl)-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine, (5-(2-amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)1H-benzo[d]imidazol-5-yl)pyridin-2-yl)dimethylphosphine oxide,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

- 23 044589

1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -1H-benzo[d]imidazole,

3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, (5-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine oxide ,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)piperidin-4yl)propan- 2-amine,

4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)morpholine,

6-(4-cyclopropylpiperazin-1-yl)-3-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(2,7-diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5-b ]pyridine, (S)-1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)pyrrolidin- 2carboxylic acid,

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine,

3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,2,4oxadiazole,

2-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)-5-(piperidin-4- yl)-1,3,4oxadiazole,

2-(1-(3-(3-methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-1,2 ,3triazol-4-yl)propan-2-amine and

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl) -ZH-imidazo[4,5 -

b]pyridine.

In a preferred embodiment, the present invention also provides methods for inhibiting c-FMS comprising administering to a patient a compound of Formula (I). In yet another preferred embodiment, the present invention also provides methods for inhibiting c-FMS comprising administering to a patient a compound of formula (II). In another embodiment, the present invention also provides methods for inhibiting cFMS comprising administering to a patient a compound of Formula (I), wherein the compound is selected from:

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1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine,

3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, (5-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)3H-imidazo[4,5-b]pyridin-6-yl)pyridin-2-yl)dimethylphosphine oxide ,

3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridine and

3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-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 structures presented in Table 1 also include their pharmaceutically acceptable salts. 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, taurocholate, glycocholate, and cholate. . Most preferred pharmaceutically acceptable anions include chloride, carbonate and bicarbonate.

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Table 1

Trk inhibitors

No. example Connection name Structure connections Etc. 3-1 1-(3-Methoxy-4-((4methoxybenzyl)oxy)benzyl)- 5-(1-methyl-1Hpyrazol-4-yl)-1Hbenzo[d]imidazol- 2-amine ) / 1-(3-Methoxy-4-((4- N X. N G 2--nh ₂ Etc. methoxybenzyl) hydroxy)benzyl)-5- /\ 3-2-1 (pyrimidin-5-yl)- 1H-benzo[d]imidazol-2-amine At/

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Etc . 3-2-2 1-(3-Methoxy-4- ((4-methoxybenzyl)oxy)benzyl)-5- (pyridin-4-yl)-1Hbenzo[d]imidazol2-amine N ^X T G /— ^nh2 O / 1-(3-Methoxy-4-((4- /% methoxybenzyl) \' T - ^NHi hydroxy)benzyl)- Etc. 5-(1- (2- 3-2-3 morpholinoethyl)-1H- \ 1 pyrazol-4-yl)-1H- benzo[d] imidazol-2-amine j N Y (5-(2-Amino-1-(3methoxy-4-((4- and l T G /— ^nh2 ν' methoxybenzyl) hydroxy)benzyl)- Etc. 3-3 1H-benzo[d] imidazol-5-yl) \/ pyridin-2-yl) \/ dimethylphosphine oxide /7\

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Etc . 3-4 1-(3-Methoxy-4- ((6-methoxypyridin3-yl)methoxy)benzyl)-5- (pyrimidin-5-yl)1H-benzo[d]imidazole 5 Etc. 3-5 3-(3-Methoxy-4( (6- methoxypyridine- 3-yl)methoxy)benzyl)-6- (1- (piperidin-4-yl)1H-pyrazol-4-yl)3H-imidazo [4,5-b]pyridine HN N__ / Etc. 3-6 1-(3-Methoxy-4( (6- methoxypyridine- 3-yl)methoxy) benzyl)-5-(4- (piperidin-3-yl)-1H1,2,3-triazol- 1-yl)-1H-benzo[d] imidazole ----' 7 -N /

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sg N Etc. 3-9 4-(1-(3-Methoxy- 4-((6- methoxypyridin-3yl)methoxy)benzyl)1H-benzo[d]imidazol-5-yl)morpholine / Η ₂ Ν^ N Etc. 3 — 10 2-(1-(1-(3-Methoxy-4- ((6-methoxypyridine-3- yl) methoxy)benzyl)-1Hbenzo[d]imidazol-5-yl) piperidin-4-yl)propan2-amine cr x> /

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(5-(2-Amino-3-(3 - methoxy- 4- ( (4- N.___ T G /— ^NHz Etc. 3- 16 methoxybenzyl)oxy) benzyl)-ZN- imidazo[4,5-b]pyridin-6-yl)pyridin- 2- 4 j/ yl)dimethylphosphine oxide 3-(3-Methoxy-4-((6- methoxypyridine-3- Etc. 3- yl)methoxy)benzyl)- 6- /\ 17 (4-methylpiperazin-1yl)-3H-imidazo[4,5- ST Ό ¹ b]pyridine η ₂ ν ^χ 2-(1-(3-(3-Methoxy-4( (6-methoxypyridine-3- and about Etc. 3- yl)methoxy)benzyl)-3N- /\ 18-1 imidazo[4,5-b]pyridin- 6-yl)piperidin-4-yl) ST ^0 \/ propan-2-amine R

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Etc. 318-4 4-(3-(3-Methoxy-4-((6methoxypyridine-3- yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridin6-yl)-1,4-diazabicyclo[3.2.2]nonane ST Ό ABOUT Etc. 3 — 18-5 3-(3-Methoxy-4- ((6methoxypyridin-3yl)methoxy)benzyl)-6- (2,7-diazaspiro[3.5] nonan-2-yl)-3Nimidazo[4,5-b]pyridine HN^ That 7

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Etc. 318-6 1-(3-(3-Methoxy-4-((6methoxypyridine-3- yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridin6-yl)piperidin-4-amine NH ₂ σ ό Etc. 3 — 18-7 (S)-1-(3-(3-methoxy-4((6-methoxypyridin-Zyl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridin6-yl)pyrrolidine-2carboxylic acid but σ ό Ρ ^;

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Etc. 3- 19 3-(3-Methoxy-4-((6methoxypyridin-3yl)methoxy)benzyl)-6- (1-(piperidin-4-yl)- 1H- pyrazol-4-yl)-3H- imidazo[4,5-b]pyridine N__ /—\ HN G\ ^nio · 3-(3-Methoxy-4-((6- HN Etc. 3- methylpyridin-3-yl) methoxy)benzyl)-6-(1- 20 (piperidin-4-yl)-1H- pyrazol-4-yl)-3H- ; ¹ imidazo[4,5-b]pyridine 3-(3-(3-Methoxy-4-((6- methoxypyridine-3- kA/ Etc. 3- yl)methoxy)benzyl)3H-imidazo[4,5-b] S 21 pyridin-6-yl)-5- ΛΑ (piperidin-4-yl)- > ¹ 1,2,4- oxadiazole \

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Etc. 3- 22 3-(1-(3-Methoxy-4-((6methoxypyridine-3- yl)methoxy)benzyl)-1Hbenzo[d]imidazol-5yl)-5-(piperidin-4yl)-1,2,4oxadiazole ie \ Etc. 3- 23 2-(3-(3-Methoxy-4-((6methoxypyridine-3- yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridin6-yl)-5-(piperidin-4yl) - 1,3,4-oxadiazole ⁿ \/··

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Etc. 3- 26 1-(3-Methoxy-4-((6- meth oxypyridin-3yl)methoxy)benzyl)-5(4-methylpiperazine-1- yl)-1H- benzo[d]imidazole-2- amine T G /— ^νη2 4 1-(2-Fluoro-5-methoxy- 4-((6-methoxypyridine- F\ Etc. 3- 3-yl)methoxy)benzyl)- 27 5-(4-methylpiperazin-1yl)-1H- O ^Z Ό ¹ benzo[d]imidazole

- 40 044589

Etc. 3- 28 3-(3-Ethoxy-4-((6- methoxypyridine-3- yl)methoxy)benzyl)- 6- (4-methylpiperazine-1- yl)-3N-imidazo[4,5- b]pyridine ^)χ 5 σ ό ) ¹ s 1-(1-(3-Methoxy-4-( (6- Etc. 3- 29 methoxypyridine-3- yl)methoxy)benzyl)-1Hbenzo[d]imidazol-5yl)-4-methylpiperazin2-one ο ¹

- 41 044589

Etc. 3- thirty 3-(3-Methoxy-4-((6- methoxypyridine-3- yl)methoxy)benzyl)-6- (5-methyl-1-azabicyclo [3.2.1]oct-6-en-7-yl)- ZH-imidazo[4,5- b]pyridine \ ¹ Etc. 3- 31 1-(3-Methoxy-4-((6- methoxypyridine-3- yl)methoxy)benzyl)- 5-(5-methyl-1- azabicyclo [3.2.1]oct-6-en-7-yl)- 1H-benzo[d]imidazole \ ¹

- 42 044589

- 43 044589

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- 46 044589

Etc. 3 - 37-3 3-(3-Methoxy-4-((6- methoxypyridine-3- yl)methoxy)benzyl)-6- (pyrimidin-5-yl)—ZN— imidazo[4,5-b] pyridine-2-amine N I 1 /— ^ΝΗ2 O /----° ^Ζ \ —η ---- Etc. 3 - 37-4 3-(3-Methoxy-4-((6methoxypyridin-3yl)methoxy)benzyl)6-(1,3,5-trimethyl-1H- pyrazol-4-yl)-3Nimidazo[4,5-b]pyridin2-amine Ν__/ / II 1 2—νη ₂ Etc. 3 - 37-5 3-(3-Methoxy-4-((6- methoxypyridine-3- yl)methoxy)benzyl)-6- (pyridin-4-yl)—ZN— imidazo[4,5-b] pyridine-2-amine ΓΊ Τ. - ^ΝΗ? Ο ⁷ Γ——Η

- 47 044589

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- 50 044589

- 51 044589

- 52 044589

- 53 044589

- 54 044589

Etc. 349-6b 3-(1-(3-Methoxy-4-((4(trifluoromethyl)benzyl) oxy)phenyl)ethyl)-6(1-methyl-1H-pyrazol4-yl)-3H-imidazo [4,5-b]pyridin-2-amine (enantiomer b) __ || | X—nh ₂ O /---° ^Ζ to F__^/ F ^Z F Etc. 350-1 2-(4-(2-Amino-3-(1- (3-methoxy-4-((4- (trifluoromethyl)benzyl) oxy)phenyl)ethyl)-3Nimidazo[4,5-b]pyridin6-yl)-1H-pyrazol-1yl)ethan-1-ol N__II | \----NH, F ^Z y

- 55 044589

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Etc. 3- 52 3-(1-(3-Methoxy-4-((6(trifluoromethyl)pyridin3-yl)methoxy)phenyl)ethyl)-6-(1-methyl-1Hpyrazol-4-yl)-3Nimidazo [4,5-b ]pyridine N__ O O ⁷ /---- F— VF Etc. 3- 53 3-(1-(3-Methoxy-4((6-(trifluoromethyl)pyridin-3-yl)methoxy) phenyl)ethyl)-6- (1-methyl-1Hpyrazol-4-yl)-3Nimidazo[4,5-b]pyridin-2-amine N.__ K. GGu— ⁿ ” O ⁷ G--F~^_/ f ^z f Etc. 3- 54 2-(4-(2-Amino-3-(1(3-methoxy-4-((6(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo [4,5-b]pyridin6-yl)-1H-pyrazol-1yl)ethan-1-ol 11 1 /— ^nh * O Ο ^λ Г--Ν F ^Z \

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3-(3-Methoxy-4-(1- 11 G'S (6-methoxypyridine-3- Etc. 358-1 yl)ethoxy)benzyl)6-(1-methyl-1Hpyrazol-5-yl)3H-imidazo[4,5- BUT'' b]pyridine formate / —$ ---ABOUT' O N 3-(3-Methoxy-4-(1- (6-methoxypyridine-3- Etc. 3 - 58-2 yl)ethoxy)benzyl)6-(6-methoxypyridin3-yl)-3H-imidazo ns< O [4,5-b]pyridine --° ^Ζ \ formate --- With 6-(2-Fluoropyridine-4- yl)-3-(3-methoxy- 4- (1-(6- Etc. 3- methoxypyridine-3- 58-3 yl)ethoxy)benzyl)- no ^x ZN-imidazo[4,5- y__ b]pyridine formate --- ——N

In one embodiment, the present invention relates to a pharmaceutical composition containing Trk inhibitors of formula (I). In another embodiment of the present invention, a pharmaceutical composition containing Trk inhibitors of formula (I) is administered in an effective amount to achieve the desired therapeutic effect. One skilled in the art will be able to determine the effective amount of a pharmaceutical composition containing Trk inhibitors of formula (I) depending on the individual and condition being treated.

In one embodiment of the present invention, Trk inhibitors and pharmaceutical compositions containing Trk inhibitors can be used to treat pain. In another embodiment of the present invention, Trk inhibitors and pharmaceutical compositions containing Trk inhibitors can be used in the treatment of pain associated with osteoarthritis. In yet another embodiment of the present invention, Trk inhibitors and pharmaceutical compositions containing Trk inhibitors can be used in the treatment of osteoarthritis.

In one embodiment of the present invention, Trk inhibitors and pharmaceutical compositions containing Trk inhibitors can be used to inhibit tropomyosin-dependent kinase. In another embodiment of the present invention, Trk inhibitors and pharmaceutical compositions containing Trk inhibitors can be used to inhibit TrkA. In another embodiment of the present invention, Trk inhibitors and pharmaceutical compositions containing Trk inhibitors can be used to inhibit TrkB. In yet another embodiment of the present invention, Trk inhibitors and pharmaceutical compositions containing Trk inhibitors can be used to inhibit TrkC.

The Trk inhibitors of the present invention can be administered alone or in a pharmaceutical composition containing a Trk inhibitor or several Trk inhibitors. Suitable pharmaceutical compositions may contain a Trk inhibitor and one or more pharmaceutically acceptable excipients. The form in which Trk inhibitors are administered, such as powder, tablet, capsule, solution, suspension or emulsion, depends in part on the route by which they are administered. Trk inhibitors can be administered, for example, orally or by injection. Suitable excipients include, but are not limited to, inorganic or organic materials such as gelatin, albumin, lactose, starch, stabilizers, solubilizers, 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.

Trk inhibitors and pharmaceutical compositions containing Trk inhibitors can be administered alone or in combination with one or more additional drugs. Additional drugs administered in combination with Trk inhibitors and pharmaceutical compositions containing Trk inhibitors of the present invention include therapeutic drugs for the treatment of pain and osteoarthritis. Additional drugs can be administered simultaneously with Trk inhibitors and pharmaceutical compositions containing Trk inhibitors. Additional drugs can also be administered sequentially with Trk inhibitors and pharmaceutical compositions containing Trk inhibitors.

The in vitro and in vivo effects of Trk inhibitors and methods for preparing preferred Trk inhibitors of the present 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 analytical reaction conditions for _IC50 determinations were in the linear region with respect to time and enzyme concentration. In a 384-well polypropylene plate, TrkA (0.4 nM, Carna 08-186) was preincubated in 100 mM Hepes-NaOH buffer, pH 7.5, containing 0.01% Triton X-100, 10 mM MgCl2, 0.1 % BSA, 1 mM DTT, 10 μM sodium orthovanadate, and 10 μM betaglycerophosphate, and 2.5% DMSO compound for 15 min at room temperature. The reaction was initiated with an equal volume of peptide substrate (Caliper Life Sciences, cat. no. 760430) and ATP in the above buffer. The final concentrations in the reaction mixture were 200 pM TrkA, 1.5 μM peptide substrate, and 55 μM ATP (ATP Km). The reaction mixture was incubated at room temperature for 180 min and the reaction was terminated using a buffer containing excess EDTA (100 mM Hepes-NaOH, pH 7.5, 0.02% Biij, 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 assay with -2250 volts up, -500 volts down, and -1.6 vacuum pressure. lb/sq. inch (psi). Using a LabChip 3000, the fluorescent signal of the fluorescein-labeled peptide substrate and the fluorescein-labeled peptide product present in each well was separated and measured. Results were expressed as percentage conversion by measuring peak heights for both substrate and product and dividing the peak height for product by the sum of the peak heights for both substrate and product. In each plate, controls with 100% inhibition (with a saturating concentration of staurosporine) and 0% inhibition (substrate with enzyme and DMSO) were used to calculate the percentage inhibition of the test compound and the Z'-factor value (Z'prime value).

In table Figure 2 shows the IC50 of TrkA for selected compounds.

Example 1-2: TrkB activity

Reagents and consumables were purchased from Sigma Aldrich, Carna Biosciences, or Caliper Life Sciences. All analytical reaction conditions for _IC50 determinations were in the linear region with respect to time and enzyme concentration. In a 384-well polypropylene plate, TrkB (0.6 nM, Carna 08-187) was preincubated in 100 mM Hepes-NaOH buffer, pH 7.5, containing 0.01% Triton X-100, 10 mM MgCl ₂ , 0, 1% BSA, 1 mM DTT, 10 µM sodium orthovanadate, and 10 µM beta

- 60 044589 glycerophosphate, and the 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, cat. no. 760430) and ATP in the above buffer. The final concentrations in the reaction mixture were 300 pM TrkB, 1.5 μM peptide substrate, and 70 μM ATP (ATP Km). The reaction mixture was incubated at room temperature for 180 min and the reaction was terminated using a buffer containing excess EDTA (100 mM Hepes-NaOH, pH 7.5, 0.02% Biij, 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 assay with -2250 volts up, -500 volts down, and -1.6 vacuum pressure. lb/sq. inch (psi). Using a LabChip 3000, the fluorescent signal of the fluorescein-labeled peptide substrate and the fluorescein-labeled peptide product present in each well was separated and measured. Results were expressed as percentage conversion by measuring peak heights for both substrate and product and dividing the peak height for product by the sum of the peak heights for both substrate and product. In each plate, controls with 100% inhibition (with a saturating concentration of staurosporine) and 0% inhibition (substrate with enzyme and DMSO) were used to calculate the percentage inhibition of the test compound and the Z'-factor value (Z'prime value).

In table Figure 2 shows the IC ₅₀ of TrkB for selected compounds.

Example 1-3: TrkC activity

Human TrkC catalytic domain [456-825(terminal) amino acids with accession number NP_002521.2] was expressed as an N-terminal GST fusion protein (69 kDa) using a baculovirus expression system. GST-TRKC was purified by glutathione-Sepharose chromatography and stored in 50 mM Tris-HCl, 150 mM NaCl, 0.05% Brij35, 1 mM DTT, 10% glycerol, pH 7.5, at -80C. Kinase activity was measured using an off-chip mobility shift assay. The enzyme was incubated with a fluorescein-labeled substrate, Srctide, in the presence of 100 μM ATP (Mg or Mn/ATP). Phosphorylated and non-phosphorylated substrates were separated and detected using a LabChip™ 3000.

In table 2 shows the IC ₅₀ of TrkC for selected compounds.

Example 1-4: c-FMS activity

Reagents and consumables were purchased from Sigma Aldrich, Carna Biosciences, or Caliper Life Sciences. All analytical reaction conditions for _IC50 determinations were in the linear region with respect to time and enzyme concentration. In a 384-well polypropylene plate, c-FMS (0.14 nM, Carna 08-155) was preincubated in 100 mM Hepes-NaOH buffer, pH 7.5, containing 0.01% Triton X-100, 10 mM MgCl ₂ , 0.1% BSA, 1 mM DTT, 10 µM sodium orthovanadate, and 10 µM beta-glycerophosphate, and 2.5% DMSO compound for 15 min at room temperature. The reaction was initiated with an equal volume of peptide substrate (Caliper Life Sciences, cat. no. 760430) and ATP in the above buffer. The final concentrations in the reaction mixture were 70 pM c-FMS, 1.5 μM peptide substrate, and 500 μM ATP (ATP Km). The reaction mixture was incubated at room temperature for 120 min and the reaction was terminated with 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 assay with -2250 volts up, -500 volts down, and -1.6 vacuum pressure. lb/sq. inch (psi). Using a LabChip 3000, the fluorescent signal of the fluorescein-labeled peptide substrate and the fluorescein-labeled peptide product present in each well was separated and measured. Results were expressed as percentage conversion by measuring peak heights for both substrate and product and dividing the peak height for product by the sum of the peak heights for both substrate and product. In each plate, controls with 100% inhibition (with a saturating concentration of staurosporine) and 0% inhibition (substrate with enzyme and DMSO) were used to calculate the percentage inhibition of the test compound and the Z'-factor value (Z'prime value).

In table Figure 2 shows the IC ₅₀ c-FMS for selected connections.

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table 2

Results of in vitro studies of the corresponding Trk inhibitors [IC ₅₀ TrkA, TrkB and c-FMS] Example No. Connection name IC ₅₀ TrkA (µM) IC ₅₀ TrkB (µM) IC ₅₀ TrkC (nM) IC ₅₀ c-FMS (µM) Etc. 3-1 1-(3-Methoxy-4-((4- methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H- pyrazol-4-yl)-1H-benzo[d]imidazol-2-amine 0.001 0.0005 -- 0.002 Etc. 3-2-1 1-(3-Methoxy-4-((4- methoxybenzyl)oxy)benzyl)-5-(pyrimidine-5- yl)-1H-benzo[d]imidazol-2-amine 0.086 0.023 -- 0.004 Etc. 3-2-2 1-(3-Methoxy-4-((4- methoxybenzyl)oxy)benzyl)-5-(pyridin-4-yl)1H-benzo[d]imidazol-2-amine 0.008 0.004 -- 0.002 Etc. 3-2-3 1-(3-Methoxy-4-((4- methoxybenzyl)oxy)benzyl)-5-(1-(2morpholinoethyl)-1H-pyrazol-4-yl)-1Hbenzo[d]imidazol-2-amine 0.003 0.001 -- 0.004 Etc. 3-3 (5-(2-Amino-1-(3-methoxy-4-((4methoxybenzyl)oxy)benzyl)-1Hbenzo[d]imidazol-5-yl)pyridin-2- 0.007 0.006 -- 0.001 yl)dimethylphosphine oxide Etc. 3-4 1-(3-Methoxy-4-((6-methoxypyridine-3- yl) methoxy)benzyl)-5-(pyrimidin-5-yl)-1Hbenzo[d]imidazole 0.836 0.252 -- 0.03 Etc. 3-5 3-(3-Methoxy-4-((6-methoxypyridine-3- yl) methoxy)benzyl)-6-(1-(piperidin-4-yl)-1Hpyrazol-4-yl)-3H-imidazo[4,5-b]pyridine 0.006 0.005 -- 0.002 Etc. 3-6 1-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)-1H- 1,2,3-triazol-1-yl)-1H-benzo[d]imidazole 0.175 0.086 -- 0.006 Etc. 3-7 2-(1-(3-Methoxy-4-((6-methoxypyridine-3- yl) methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)- 5-(piperidin-4-yl)-1,3,4-oxadiazole 0.434 0.439 -- 0.028 Etc. 3-8 1-(3-Methoxy-4-((6-methoxypyridine-3- yl) methoxy) benzyl)-5-(piperidin-4-yl)-1Hbenzo[d]imidazole 11.1 3.46 -- 0.359 Etc. 3-9 4-(1-(3-Methoxy-4-((6-methoxypyridine-3- yl) methoxy)benzyl)-1H-benzo[d]imidazol-5yl)morpholine 0.793 0.257 -- 0.027 Etc. 3-10 2-(1-(1-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-1H-benzo[d]imidazole-5- 0.652 0.574 -- 0.013

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yl)piperidin-4-yl)propan-2-amine Etc. 3-11 1-(3-Methoxy-4-((6-methoxypyridine-Zyl)methoxy)benzyl)-5-(2,7- diazaspiro[3.5]nonan-2-yl)-1Hbenzo[d]imidazole 0.135 0, 12 -- 0.012 Etc. 3-12 1-(1-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-1H-benzo[d]imidazol-5yl)piperidin-4-amine 1.03 0.637 -- 0.031 Etc. 3-13 1-(3-Methoxy-4-((6-methoxypyridine-3- yl) methoxy) benzyl)-5-(4-methylpiperazin-1-yl)- 1H-benzo[d]imidazole 1.13 0.443 -- 0.032 Etc. 3-14 1-(2-Amino-1-(3-methoxy-4-((6-methoxypyridine- 3-yl) methoxy)benzyl)-1H-benzo[d]imidazol-5yl)-4-methylpiperazin-2-one 8.98 4.37 -- 0.33 Etc. 3-15 3- (3-Methoxy-4-( (4- methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine 0.0003 0.0001 0.503 0.002 Etc. 3-16 (5-(2-Amino-3-(3-methoxy-4-((4- methoxybenzyl)oxy)benzyl)-3N-imidazo[4,5- b]pyridin-6-yl)pyridin-2- yl)dimethylphosphine oxide 0.0005 0.0002 -- 0.002 Etc. 3-17 3-(3-Methoxy-4-((6-methoxypyridine-3- yl) methoxy)benzyl)-6-(4-methylpiperazin-1-yl)- 3H-imidazo[4,5-b]pyridine 0.179 0.066 -- 0.016 Etc. 3-18-1 2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-Zyl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin6-yl)piperidin-4-yl)propan- 2-amine 0.054 0.057 -- 0.005 Etc. 3-18-2 4-(3-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin- 6-yl)morpholine 0.09 0.031 -- 0.008 Etc. 3-18-3 6-(4-Cyclopropylpiperazin-1-yl)-3-(3-methoxy- 4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridine 0.113 0.052 -- 0.016 Etc. 3-18-4 4-(3-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin6-yl)-1,4-diazabicyclo[3.2.2]nonane 0.47 0.349 -- 0.036 Etc. 3-18-5 3-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-6-(2,7- diazaspiro[3.5]nonan-2-yl)-3H-imidazo[4,5- b]pyridine 0.025 0.021 -- 0.007 Etc. 3-18-6 1-(3-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin- 0.232 0.133 -- 0.012

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Etc. 3-18-7 6-yl)piperidin-4-amine (S)-1-(3-(3-methoxy-4-((6-methoxypyridine-3- yl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin6-yl)pyrrolidine-2-carboxylic acid 0.008 0.013 -- 0.032 3-(3-Methoxy-4-((6-methoxypyridine-3- Etc. 3-19 yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1Hpyrazol-4-yl)-3H-imidazo[4,5-b]pyridine 3-(3-Methoxy-4-((6-methylpyridine-3- 0.001 0.0009 0.002 Etc. 3-20 yl)methoxy)benzyl)-6-(1-(piperidin-4-yl)-1Hpyrazol-4-yl)-3H-imidazo[4,5-b]pyridine 3-(3-(3-Methoxy-4-((6-methoxypyridine-3- 0.0009 0.0006 0.003 Etc. 3-21 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin6-yl)-5-(piperidin-4-yl)-1,2,4-oxadiazole 3-(1-(3-Methoxy-4-((6-methoxypyridine-3- 0.026 0.024 0.007 Etc. 3-22 yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)- 5-(piperidin-4-yl)-1,2,4-oxadiazole 2-(3-(3-Methoxy-4-((6-methoxypyridine-3- 0.306 0.317 0.015 Etc. 3-23 yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin6-yl)-5-(piperidin-4-yl)-1,3,4-oxadiazole 2-(1-(3-(3-Methoxy-4-((6-methoxypyridine-3- 0.051 0.057 — 0.013 Etc. 3-24 yl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin6-yl)-1H-1,2,3-triazol-4-yl)propan-2-amine 3-(3-Methoxy-4-((6-methoxypyridine-3- 0.088 0.043 0.007 Etc. 3-25 yl) methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H1,2,3-triazol-1-yl)-3H-imidazo[4,5-b]pyridine 1-(3-Methoxy-4-((6-methoxypyridine-3- 0.032 0.018 0.003 Etc. 3-26 yl) methoxy) benzyl)-5-(4-methylpiperazin-1-yl)1H-benzo[d]imidazol-2-amine 1-(2-Fluoro-5-methoxy-4-((6-methoxypyridine-3- 0.59 0.315 0.03 Etc. 3-27 yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)1H-benzo[d]imidazole 3-(3-Ethoxy-4-((6-methoxypyridine-3- 0.852 0.305 0.379 Etc. 3-28 yl) methoxy)benzyl)-6-(4-methylpiperazin-1-yl)- 3H-imidazo[4,5-b]pyridine 1-(1-(3-Methoxy-4-((6-methoxypyridine-3- 0.337 0.179 0.012 Etc. 3-29 yl) methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)- 4-methylpiperazin-2-one 3-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-6-(5-methyl-1- 6, 02 4.28 0.431 Etc. 3-30 azabicyclo[3.2.1]oct-6-en-7-yl)-3H- imidazo[4,5-b]pyridine 0.201 0.118 0.015 Etc. 3-31 1-(3-Methoxy-4-((6-methoxypyridine-3- 1.48 0.889 — 0.161

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Etc. 3-32 Etc. 3-33 Etc. 3-34 Etc. 3-35-1 Etc. 3-35-2 Etc. 3-35-3 yl)methoxy)benzyl)-5-(5-methyl-1azabicyclo[3.2.1]oct-6-en-7-yl)-1Hbenzo[d]imidazole 7-(3-(3-Methoxy-4-((6-methoxypyridin-Zyl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin6-yl)-1-azabicyclo[3.2.1]oct- 6-en-5-ol 7-(1-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)1-azabicyclo[3.2.1]oct-6-en-5-ol 3-(3-Methoxy-4-(1-(6-methoxypyridine-3- yl)propoxy)benzyl)-6-(1-methyl-1H-pyrazol-4yl)-3H-imidazo[4,5-b]pyridin-2-amine 3-(3-Methoxy-4-((6-methoxypyridine-3- yl) methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4yl)-3H-imidazo[4,5-b]pyridin-2-amine 3-(3-Methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4yl)-3H-imidazo[4,5-b]pyridine -2-amine 3-(3-Methoxy-4-((4- (trifluoromethyl)benzyl)oxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2amine 0.36 1.16 0.032 0.0006 0.0002 0.0002 0.15 0.372 0.026 0.0003 0.0002 0.0003 — 0.041 0.151 0.059 0.003 0.005 0.005 Etc. 3-35-4 3-(4-((6-Cyclopropylpyridin-3-yl)methoxy)-3methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)- 3H-imidazo[4,5-b]pyridin-2-amine 0.0002 0.0002 -- 0.003 Etc. 3-35-5 3-(3-Methoxy-4-((2-methylthiazol-4- yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridin-2-amine 0.0005 0.0002 -- 0.005 Etc. 3-36 3-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-6-phenyl-3H-imidazo[4,5- b]pyridin-2-amine 0.006 0.004 -- 0.007 Etc. 3-37-1 6-(4-Fluorophenyl)-3-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridin-2-amine 0.009 0.004 -- 0.009 Etc. 3-37-2 3-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-3- yl)-3H-imidazo[4,5-b]pyridin-2-amine 0.003 0.002 -- 0.005 Etc. 3-37-3 3-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-6-(pyrimidin-5-yl)-3Nimidazo[4,5-b]pyridin-2-amine 0.051 0.016 -- 0.011 Etc. 3-37-4 3-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-6-(1,3,5-trimethyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine 0.014 0.013 -- 0.005 Etc. 3-37-5 3-(3-Methoxy-4-((6-methoxypyridine-3- 0.002 0.0007 — 0.002

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yl)methoxy)benzyl)-6-(pyridin-4-yl)-3Nimidazo[4,5-b]pyridin-2-amine Etc. 3-37-6 3-(3-Methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzyl)-6-(pyridin-3-yl)-3Nimidazo[4,5-b]pyridin-2-amine 0.005 0.002 -- 0.006 Etc. 3-38 3-(3-Methoxy-4-((6-methoxypyridine-3- yl) methoxy)benzyl)- 6-(pyridin-2-yl)-3H- imidazo[4,5-b]pyridin-2-amine 0.004 0.002 -- 0.005 Etc. 3-39 3-(3-Methoxy-4-((4- (perfluoroethyl)benzyl)oxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2amine 0.0003 0.0006 -- 0.028 Etc. 3-40-1 3-(3-Methoxy-4-((4- (trifluoromethoxy)benzyl)oxy)benzyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-2-amine 0.0002 0.0002 -- 0.008 Etc. 3-40-2 3-(3-Methoxy-4-((4- ((trifluoromethyl)thio)benzyl)oxy)benzyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5— b]pyridin-2-amine 0.0002 0.0006 -- 0.018 Etc. 3-40-3 3-(4-((6-Isopropylpyridin-3-yl)methoxy)-3methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)- 0.0002 0.0002 -- 0.005 3H-imidazo[4,5-b]pyridin-2-amine Etc. 3-40-4 3-(3-Methoxy-4-( (4 - (2,2,2 - trifluoroethyl)benzyl)oxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2amine 0.0002 0.0003 -- 0.01 Etc. 3-40-5 3-(3-Methoxy-4-((2-(trifluoromethyl)thiazol-4yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4yl)-3H-imidazo[4,5-b]pyridine -2-amine 0.0002 0.0002 -- 0.007 Etc. 3-41 6-(Cyclohexylethynyl)-3-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridin-2-amine 0.065 0.08 -- 0.213 Etc. 3-42 4-(2-Amino-3-(3-methoxy-4-((6-methoxypyridine- 3-yl)methoxy)benzyl)-3H-imidazo[4,5— b]pyridin-6-yl)but-3-in-1-ol 0.007 0.003 -- 0.013 Etc. 3-43 3-(4-(Cyclopropyl(6-methoxypyridine-3- yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine 0.058 0.051 -- 0.794 Etc. 3-44 3-(3-Methoxy-4-((3-methoxy-5,6,7, 8- tetrahydroisoquinolin-8-yl)oxy)benzyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5— b]pyridin-2-amine 0.039 0.041 -- 0.765 Etc. 3-45 1-(1-(3-Methoxy-4-((6-methoxypyridine-3- 0.003 0.001 — 0.073

-66044589

yl)methoxy)phenyl)ethyl)-5-(1-methyl-1H-pyrazol4-yl)-1H-benzo[d]imidazol-2-amine Etc. 3-46 Etc. 3-47 Etc. 3-48-1 Etc. 3-48-2 Etc. 3-49 Etc. 3-496a 5-(4-Fluorophenyl)-1-(1-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1Hbenzo[d]imidazol-2-amine 5-(4-Fluorophenyl)-1-(1-(3-methoxy-4-((6- (trifluoromethyl)pyridine-3- yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole 1-(1-(3-Methoxy-4-((b-(trifluoromethyl)pyridin- 3-yl)methoxy)phenyl)ethyl)-5-(1-methyl-1Hpyrazol-4-yl)-1H-benzo[d]imidazole 4-(1-(1-(3-Methoxy-4-((6- (trifluoromethyl)pyridine-3- yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-5yl)but-3-in-1-ol 3-(1-(3-Methoxy-4-((4- (trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-2-amine 3-(1-(3-Methoxy-4-((4- (trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- 0.085 1.24 0.102 0.692 n. /O. 0.0003 0.037 0.427 0.014 0.127 n. /O. 0.0006 — 0.686 4.13 0.16 4, 68 n. /O. 0.019 o]pyridine-2-amine (enantiomer a) Etc. 3-496b 3- (1-(3-Methoxy-4-( (4- (trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1- methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5- b]pyridin-2-amine (enantiomer b) 0.005 0.003 -- 0.096 Etc. 3-50-1 2-(4-(2-Amino-3-(1-(3-methoxy-4-((4- (trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3Nimidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1yl)ethan-1-ol n. /O. n. /O. -- n. /O. Etc. 3-50-2 3- (1- (3-Methoxy-4-( (4- (trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine n. /O. n. /O. -- n. /O. Etc. 3-51 3-(1-(3-Methoxy-4-((6-(trifluoromethyl)pyridin- 3-yl)methoxy)phenyl)propyl)-6-(1-methyl-1Hpyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine n. /O. n. /O. -- n. /O. Etc. 3-52 3-(1-(3-Methoxy-4-((6-(trifluoromethyl)pyridin- 3-yl)methoxy)phenyl)ethyl)-6-(1-methyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine 0.007 0.001 -- 0.056 Etc. 3-53 3-(1-(3-Methoxy-4-((6-(trifluoromethyl)pyridin- 3-yl)methoxy)phenyl)ethyl)-6-(1-methyl-1H- pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine 0.0004 0.0006 -- 0.019 Etc. 3-54 2-(4-(2-Amino-3-(1-(3-methoxy-4-((6- n. /O. n. /O. — n. /O.

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(trifluoromethyl)pyridine-3- yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5- b]pyridin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol Etc. 3-55 4-(2-Amino-3-(1-(3-methoxy-4-((6- (trifluoromethyl)pyridine-3- yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5- b]pyridin-6-yl)but-3-in-1-ol 0.001 0.001 -- 0.137 Etc. 3-56 4- (3- (4- ( (6-(Difluoromethyl)pyridine-3- yl)methoxy)-3-methoxybenzyl)-3H-imidazo[4,5- b]pyridin-6-yl)but-3-in-1-ol 0.017 0.004 -- 0.025 Etc. 3-57 3-(3-Methoxy-4-(1-(6-methoxypyridine-3- yl)ethoxy)benzyl)-6-(1-methyl-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridine formate 0.035 0.013 -- 0.058 Etc. 3-58-1 3-(3-Methoxy-4-(1-(6-methoxypyridine-3- yl)ethoxy)benzyl)-6-(1-methyl-1H-pyrazol-5- yl)-3H-imidazo[4,5-b]pyridine formate 0.449 0.219 -- 0.082 Etc. 3-58-2 3-(3-Methoxy-4-(1-(6-methoxypyridine-3- yl) ethoxy)benzyl)-6-(6-methoxypyridin-3-yl)3H-imidazo[4,5-b]pyridine formate 0.16 0.061 -- 0.103 Etc. 3-58-3 6-(2-Fluoropyridin-4-yl)-3-(3-methoxy-4-(1-(6methoxypyridin-3-yl)ethoxy)benzyl)-3H- imidazo[4,5-b]pyridine formate 0.215 0.068 -- 0.102

But. means not detected

-- means not tested

Example 2: in vivo studies

Example 2-1: Effect of Trk inhibitors on peptidoglycan polysaccharide-reactivated knee arthritis

Male Lewis rats were acclimated to the testing laboratory conditions for 7 days. The rats were housed 5 per cage in polycarbonate shoebox-style cages with wire lids, wood shaving bedding, and hanging food and water bottles.

On day -21, male Lewis rats were randomized into treatment groups based on body weight. 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 with an IV injection of PGPS into the tail. Animals were dosed intra-articularly with vehicle, triamcinolone and test compound on day -7. Treatment groups are presented in table. 3 below.

Table 3

Treatment groups with PGPS knee arthritis

Group Treatment Dose 1 Carrier (Lack of reactivation) Not applicable 2 Carrier Not applicable 3 Triamcinolone 0.06 mg 4 3-(3-Methoxy-4-((4- methoxybenzyl)oxy)benzyl)-b-(1-methyl-1Hpyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2amine 1 mg

Rats were weighed at inclusion and on days 0, 4, 14, and 18. Knee thickness was measured using a caliper at the inclusion stage and on days 0, 2, 4, 14, 16 and 18. Gait analysis was performed on days 0–4 and 14–18, with video recordings of selected animals on days 3 and 17. Gait analysis was performed by applying ink to the ventral surface of the foot and recording the mass transferred during movement on the paper.

Animals were removed from the experiment on day 18. The right knees were removed, excess tissue was trimmed, and collected in 10% neutral buffered formalin. After two days in formalin buffer and three days in 10% formic acid, a decalcification agent, the knees were cut into two approximately equal

- 68 044589 halves in the frontal plane, and were embedded in paraffin and stained using

T.Blue. Subsequently, histological studies were performed regarding bone resorption, inflammation, pannus and cartilage damage.

Body weight, gait defect, and caliper measurements were analyzed using one-way analysis of variance (1-way ANOVA) with Dunnett's multiple comparison post hoc test. Gait scores were analyzed using the Kruskal-Wallis test (nonparametric ANOVA) with Dunn's multiple comparison post hoc test. Histopathology scores were analyzed using the Kruskal-Wallis test (nonparametric ANOVA) with Dunn's multiple comparison post hoc test.

Animals in the vehicle control group achieved an average body weight of approximately 96 grams during the study, which was significantly reduced compared to the non-reactivation control group. No significant differences were observed when any treatment groups were compared. After the second reactivation, several animals developed systematic PGPS inflammation, which affected the ankle joints and compromised pain measurements. Gait scores and gait defect scores for the vehicle control group peaked on the second day after the first reactivation and on the first day after the second reactivation, and were significantly higher compared to the nonreactivation control group at all time points except two time points. before reactivation (days 0 and 14). The first reactivation reached a higher maximum but fell more sharply. The pattern completely changed for the caliper knee measurements, with a much higher peak and a sharper drop after the second reactivation. Histopathological sections showed marked to severe inflammation with pannus and mild to mild cartilage damage and minimal to moderate bone resorption. All parameters were significantly increased compared with the nonreactivation control group, which had the least lesions, with the exception of bone resorption, which ranged from minimal to marked.

Animals treated with 0.06 mg triamcinolone had significantly reduced gait scores and gait defects throughout the first reactivation (days 1–4) and on days 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%). Caliper knee measurements were significantly reduced on days 2, 4, 16, and 18, and before the first reactivation on day 0, with corresponding 53-106% reductions in AUC. In histopathological sections, significant reductions of 61–88% were observed in all parameters, with a significant 74% reduction in total scores.

Animals treated with 1 mg 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1Hpyrazol-4-yl)-3H-imidazo[4,5-b]pyridine -2-amine were characterized by significant decreases in gait scores and gait defects throughout the first reactivation. Scores were significantly reduced throughout the second reactivation, and reductions in the defect were significant on days 15, 17, and 18. AUC values for first (92–93%) and second (85–86%) reactivations were significantly reduced for both scores and defect, and the summed AUC was significantly lower for defect (84%). Caliper knee measurements were significantly reduced on day 14 (immediately before the second reactivation). AUC values, as a rule, did not change with treatment. In histopathological sections, significant reductions of 49–94% were observed in all parameters, with a significant 70% reduction in sum scores.

Example 2-2: Effect of Trk Inhibitors on Sodium Moniodoacetate-Induced Osteoarthritis

Male Wistar rats were acclimated to the conditions of the testing laboratory for 5 days. Rats were individually housed in microisolator polycarbonate shoebox cages with corn cob bedding and water bottles. Food of known composition in the form of dry granules and nutritional components were available ad libitum.

Animals were randomized by treatment using an online random number generator. Each treatment group was assigned a number, entered into a random number generator, recorded, and then broadcast back to the corresponding treatment. All injections were given in the left leg unless the treatment was indicated as contralateral, in which case the injection was given in the right leg. At the time of injections with treatments, both legs of all animals were shaved to conceal information for the test performer.

The rats were weighed the day before injection of sodium monoiodoacetate (MIA), an agent used to induce osteoarthritis in animals. On the day of injection, rats from groups 2–8 received a subcutaneous (SC) dose of buprenorphine at least one hour before induction. All groups received induction of anesthesia. Untreated animals were then allowed to return to normal. All other animals received an MIA injection. In MIA-treated animals, the hindlimb was flexed and an injection of MIA (25 μl) was injected into the intraarticular space using a 27-gauge 1/2-inch needle. Standard postoperative management was carried out (twice a day for 48 hours).

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Group 1 2 3 Treatment Unprocessed MIA/LRS* MIA/3-(3-methoxy-4-((4- methoxybenzyl)oxy)benzyl)-6- (1-methyl-1H-pyrazol-4-yl)-3Nimidazo[4,5-b]pyridin-2-amine (100 mcg), same side Animals/ Group 8 8 8 Animals / Moment time 8 8 8 4 MIA/3-(3-methoxy-4-((4- methoxybenzyl)oxy)benzyl)-6- (1-methyl-1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-2-amine (100 mcg), on the opposite side 8 8 5 MIA/3-(3-methoxy-4-((4methoxybenzyl)oxy)benzyl)-6- (1-methyl-1H-pyrazol-4-yl)-3Nimidazo[4,5-b]pyridin-2-amine (30 mcg), same side 8 8 6 MIA/3-(3-methoxy-4-((4- methoxybenzyl)oxy)benzyl)-6- (1-methyl-1H-pyrazol-4-yl)-3Nimidazo[4,5-b]pyridin-2-amine (30 µg), on the opposite side 8 8 7 MIA/3-(3-methoxy-4-((4- methoxybenzyl)oxy)benzyl)-6(1-methyl-1H-pyrazol-4-yl)-3Nimidazo[4,5-b]pyridin-2-amine (10 µg), on the same side 8 8 8 MIA/3-(3-methoxy-4-((4- methoxybenzyl)oxy)benzyl)-6- (1-methyl-1H-pyrazol-4-yl)-3Nimidazo[4,5-b]pyridin-2-amine (10 mcg), on the opposite side 8 8

*Lactated Ringer's solution: control/placebo injection.

On day 8, the test article was administered as described above. Weight bearing was assessed on days -1, 7, 14, 21, 28, and 35 post-induction. A weight bearing scale was used using a plexiglass chamber to estimate the amount of weight distributed to each hindlimb. Animals were acclimated to the chamber conditions for at least 5 min before testing, and weight distribution was recorded 5 times.

No adverse effects on body weight were observed as a result of the treatment. MIA/LRS was significantly worse than M1A/3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl- 70 044589

1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, on the same side, 100 μg and 30 μg on day 35 (p < 0.05).

3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5b]pyridin-2-amine, 100 and 30 mcg injections on the same side were effective for four weeks after injection. 3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4yl)-3H-imidazo[4,5-b]pyridin-2-amine, 10 mcg, on the same side, effectiveness was visible 2-4 weeks after administration. 3 -(3 -Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)3H-imidazo[4,5-b]pyridin-2-amine , 100 mcg, on the same side, did not show systemic pain relief at any time point during the study (1-4 weeks), whereas administration of 3-(3-methoxy-4((4-methoxybenzyl)oxy)benzyl)- 6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine, 30 μg, on the opposite side, resulted in effectiveness only at the 3 week time point. and the introduction of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3Himidazo[4,5-b]pyridin-2- amine, 10 μg, on the contralateral side, resulted in efficacy at 3 and 4 weeks after administration.

Animals were removed from the experiment on day 36. Both kneecaps were collected from each animal; the skin was removed from the joint and the patella was removed, leaving the same amount of infrapatellar fat pad intact around the joint. The patella was placed in an appropriate container with rolled gauze to secure the patella in the container and then placed in 4% paraformaldehyde. The samples were subjected to histological examination.

Knee histopathology showed no adverse changes associated with 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H -imidazo[4,5b]pyridin-2-amine.

Example 3: synthesis of Trk inhibitors

Example 3-1: Synthesis of 1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)1H-benzo[d]imidazol- 2-amine

Example 3-1-1: Preparation of 3-methoxy-4-((4-methoxybenzyl)oxy)benzonitrile

To a stirred solution of 4-hydroxy-3-methoxybenzonitrile (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 temperature and stirred. After 1 hour, the mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated to provide 4.56 g (>100%) of 3-methoxy-4-((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-((4-methoxybenzyl)oxy)phenyl)methanamine

To a stirred solution of crude 3-methoxy-4-((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 mild exothermic effect). The resulting mixture was allowed to stir at room temperature. After 1 h, the reaction mixture was cooled to 0°C with the slow addition of water (930 μl) (gas evolution). The mixture was then treated with 1 N. sodium hydroxide solution (930 µl) and additional water (2.8 ml). The resulting mixture was stirred for 15 minutes and then filtered through celite using ethyl acetate. The filtrate was dried over magnesium sulfate, filtered and concentrated to give 3.90 g (86% for 2 steps) 3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)methanamine as an off-white solid.

Example 3-1-3: Preparation of 4-bromo-K-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline

To a stirred solution of 3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)methanamine (4.48 g, 16.39 mmol) in acetonitrile (75 ml) was added 4-bromo-1-fluoro-2-nitrobenzene ( 3.43 g, 15.61 mmol) and diisopropylethylamine (2.52 g, 19.51 mmol). The resulting bright yellow solution was heated to reflux temperature. After 16 hours, the orange mixture was allowed to cool to room temperature and diluted with water. The mixture was extracted with dichloromethane (2x150 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 7.71 g (99%) 4bromo-K-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline as an orange semi-solid substances.

Example 3-1-4: Preparation of 4-bromo-K ¹ -(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2diamine

To a stirred suspension of 4-bromo-K-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2nitroaniline (7.71 g, 16.30 mmol) in tetrahydrofuran (100 ml), ethanol (25 ml ) and water (25 ml), ammonium chloride (0.44 g, 8.15 mmol) and iron powder (9.10 g, 163 mmol) were added. The mixture was heated to reflux temperature. After 5 hours, the reaction mixture was allowed to cool to room temperature and filtered through celite using ethanol. The filtrate was concentrated and the residue was partitioned between dichloromethane and water. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated to give 6.73 g (95%) 4-bromo-K1-(3-methoxy-4-((4methoxybenzyl)oxy)benzyl)benzene-1,2-diamine as a brown solid.

Example 3-1-5: Preparation of 5-bromo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H- 71 044589 benzo[d]imidazol-2-amine

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-K ¹ -(3-methoxy-4-((4-methoxybenzyl )oxy)benzyl)benzene-1,2-diamine (3.40 g, 7.67 mmol) in methanol (75 ml), acetonitrile (75 ml) and dichloromethane (25 ml). The diamine solution was added over 45 minutes. 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 1 N. sodium hydroxide solution, dried over magnesium sulfate, filtered and concentrated to give 2.46 g of an orange-brown solid. Trituration of the crude material with diethyl ether gave 1.54 g of 5-bromo-1-(3-methoxy-4((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine as an off-white solid matter.

Example 3-1-6: Preparation of 1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4yl)-1H-benzo[d]imidazol- 2-amine

To a stirred suspension of 5-bromo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1Hbenzo[d]imidazol-2-amine (0.28 g, 0.59 mmol) in 1. 4-dioxane (8 ml) and water (6 ml) was added 1-methyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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(P) acetate (0.007 g, 0.029 mmol). The reaction mixture was heated to 125°C in a microwave reactor. After 15 minutes, 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 give 0.33 g of a light green solid. Purification by chromatography (Combi-Flash, 12 g SiO ₂ , gold column, eluent: 1-5% 2 M ammonia in methanol/dichloromethane) gave 0.13 g (48%) of product as an off-white solid: 1H 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-1-(3-methoxy-4-((4methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine

The following compounds were prepared using the procedure described in Example 3-1 using the appropriate boronic acid/boronate ester coupling partner.

Example 3-2-1: 1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1Hbenzo[d]imidazol-2-amine ^1H 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 (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) 4 68.

Example 3-2-2: 1 -(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyridin-4-yl)-1Hbenzo[d]imidazol-2-amine ^1H NMR ( 400 MHz, DMSO-d ₆ ) 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-((4-methoxybenzyl)oxy)benzyl)-5-(1 -(2-morpholinoethyl)-1H-pyrazol4-yl)-1H-benzo[ d]imidazol-2-amine ^1H 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-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1Hbenzo[d]imidazol-5 -yl)pyridin-2 -yl) dimethylphosphine oxide

Example 3-3-1: Preparation of 4-iodo-K-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline

To a stirred solution of 3-methoxy-4-((4-methoxybenzyl)oxy)phenyl)methanamine (5.02 g, 18.37 mmol) in acetonitrile (75 ml) was added 1-fluoro-4-iodo-2-nitrobenzene ( 4.67 g, 17.49 mmol) and diisopropylethylamine (2.83 g, 21.86 mmol). The resulting bright yellow solution was heated to reflux temperature. After 17 hours, the orange mixture was allowed to cool to room temperature and diluted with water. The mixture was extracted with dichloromethane (3x100 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 9.49 g (>100%) 4iodo-K-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline as orange semi-solid substance.

Example 3-3-2: Preparation of 4-iodo-K ¹ -(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2diamine

To a stirred solution of 4-iodo-K-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline (9.10 g, 17.49 mmol) in tetrahydrofuran (50 ml), ethanol ( 50 ml) and water (10 ml) were added ammonium chloride (7.48 g, 139.9 mmol) and iron (II) sulfate heptahydrate (14.59 g, 52.47 mmol). Bright orange sus

- 72 044589 pension was treated with zinc (3.43 g, 52.47 mmol). The mixture was gradually heated to reflux temperature. After 3.5 hours, the color of the reaction mixture changed from orange to olive green. At this stage, the reaction mixture was allowed to cool to room temperature. The mixture was filtered through celite and the precipitate after filtration was washed with methanol. The filtrate was concentrated, the residue was suspended in water. The aqueous mixture was extracted with chloroform (x3). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 8.32 g (97%) 4-iodo-Na(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine in the form of a reddish solid.

Example 3-3-3: Preparation of 5-iodo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1Hbenzo[d]imidazol-2-amine

To a stirred suspension of 4-iodo-K ¹ -(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2diamine (8.32 g, 16.97 mmol) in dichloromethane (100 ml) and methanol (50 ml), a solution of cyanogen bromide (5.0 M in acetonitrile, 17.0 ml, 85.00 mmol) was added. 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 minutes, a precipitate formed. The solids were separated by filtration, washed with water and dried to give 4.42 g (51%) 5-iodo-1-(3-methoxy-4-((4methoxybenzyl)oxy)benzyl)-N-benzo[d]imidazole -2-amine as a tan solid.

Example 3-3-4: Preparation of 5-(6-chloropyridin-3-yl)-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)1 H-benzo[d]imidazole-2- amine

To a stirred suspension of 5-iodo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1Hbenzo[d]imidazol-2-amine (0.40 g, 0.78 mmol) in 1. (6chloropyridin-3-yl)boronic acid (0.14 g, 0.89 mmol), potassium phosphate (0.58 g, 2.72 mmol), tricyclohexylphosphine was added to 4-dioxane (10 ml) and water (4 ml). (0.044 g, 0.16 mmol) and palladium(P) acetate (0.017 g, 0.078 mmol). The reaction mixture was heated to 125°C in a microwave reactor. After 15 minutes, the reaction mixture was diluted with water. The mixture was extracted with chloroform (x3). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 0.43 g of a brown solid. Chromatographic purification (Combi-Flash, 24 g SiO ₂ , gold column, eluent: 5-10% methanoladichloromethane) gave 0.23 g (58%) 5-(6-chloropyridin-3-yl)-1-(3 -methoxy-4-((4-methoxybenzyl)oxy)benzyl)1H-benzo[d]imidazol-2-amine as a light yellow solid.

Example 3-3-5: preparation of (5-(2-amino-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1Hbenzo[d]imidazol-5 -yl)pyridin-2 - yl)dimethylphosphine oxide

To a stirred suspension of 5-(6-chloropyridin-3-yl)-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)1H-benzo[d]imidazol-2-amine (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(P) 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 shares of dimethylphosphine oxide (0.029 g, 0.37 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.035 g, 0.060 mmol) and palladium(P) acetate (0.007 g, 0.030 mmol) were added. The reaction mixture was subjected to a second heating cycle in a microwave reactor (45 min, 150°C). After the second heating cycle, the reaction mixture was diluted with water and extracted with chloroform (x3). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 0.24 g of a bright yellow solid. Chromatographic purification (Combi-Flash, 12 g SiO ₂ , gold column, eluent: 5-10% methanol/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 0.052 g (32%) of product as a yellow solid : ¹ H NMR (400 MHz, DMSO-d6) δ ¹ 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(pyrimidin-5-yl)1H-benzo[d]imidazole

Example 3-4-1: Preparation of tert-butyl-3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzylcarbamate

To a stirred solution of tert-butyl-4-hydroxy-3-methoxybenzylcarbamate (22.44 g, 88.59 mmol) in acetonitrile (250 ml) was added potassium carbonate (30.61 g, 221.5 mmol) and 5-(chloromethyl )-2methoxypyridine hydrochloride (18.33 g, 94.46 mmol). The resulting mixture was heated to reflux temperature and stirred. After 23 hours, the light green suspension was allowed to cool to room temperature and was diluted with water (600 ml), resulting in the formation of a precipitate. Solids were separated by filtration and washed with water. The wet 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 give 31.92 g (96%) tert-butyl-3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzylcarbamate as an off-white solid .

Example 3-4-2: Preparation of (3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine

- 73 044589

To a stirred solution of tert-butyl-3-methoxy-4-((6-methoxypyridin-3yl)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 hours, the reaction mixture was concentrated to dryness and the residue was dissolved in water (250 ml). The acidic solution was extracted with diethyl ether (2x125 ml; organic phases were discarded). The aqueous phase was then made basic using concentrated ammonium hydroxide. The main aqueous phase was then extracted with dichloromethane (2x200 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 21.46 g (92%) of (3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine as an off-white solid .

Example 3-4-3: Preparation of 4-iodo-K-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-2nitroaniline

To a stirred solution of (3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (5.00 g, 18.23 mmol) in acetonitrile (75 ml) was added 1-fluoro-4-iodo -2-nitrobenzene (4.55 g, 17.04 mmol) and diisopropylethylamine (3.30 g, 25.56 mmol). The yellow solution was heated to reflux temperature and stirred. After 4 hours, the orange-brown mixture was allowed to cool to room temperature and diluted with water (150 ml). The resulting bright orange precipitate was separated by filtration and washed with water. The wet 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 give 7.10 g (80%) of 4-iodo-K-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-2-nitroaniline in as a bright orange solid.

Example 3-4-4: Preparation of 4-iodo-K1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)benzene1,2-diamine

To a stirred solution of 4-iodo-K-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-2nitroaniline (7.10 g, 13.62 mmol) in tetrahydrofuran (100 ml), Ammonium chloride (5.83 g, 109.0 mmol) and iron(II) sulfate heptahydrate (13.25 g, 47.67 mmol) were added to methanol (50 ml) and water (10 ml). The bright orange suspension was treated with zinc (3.12 g, 47.67 mmol). The mixture was gradually heated to reflux temperature. After 20 min, the color of the reaction mixture changed from orange to olive green. At this stage, the reaction mixture was allowed to cool to room temperature. The mixture was filtered through celite and the precipitate after filtration 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 obtain 6.49 g of 4-iodo-K ¹ -(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)benzene-1,2-diamine in as a reddish solid.

Example 3-4-5: Preparation of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazole

Triethyl orthoformate (4.45 ^g , 30.03 mmol) and p-toluenesulfonic acid monohydrate (0.075 g, 0.39 mmol). As the resulting mixture was heated to reflux temperature, the solids gradually dissolved to form an orange solution. After 45 minutes, 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 solids were separated by filtration. The wet solids were dissolved in ethyl acetate (250 ml) and the solution was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 5.99 g (91%) 5-iodo-1-(3-methoxy-4-(( 6-methoxypyridin-3yl)methoxy)benzyl)-1H-benzo[d]imidazole as a tan solid.

Example 3-4-6: Preparation of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(pyrimidin5 -yl)-1H-benzo[d]imidazole

To a suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-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-1,3,2dioxaborolan-2-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, 0.037 mmol). The reaction mixture was heated to 125°C in a microwave reactor. After 15 minutes, 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 give 0.45 g of a light green solid. Purification chromatography (Combi-Flash, 12 g SiO ₂ , gold column, eluent: 1-5% methanoladichloromethane) gave 0.14 g (40%) of product as an off-white solid: 1H NMR (400 MHz, DMSOd6 ) 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4yl)-1H-pyrazol-4-yl)- 3H-imidazo[4,5-b]pyridine

- 74 044589

-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-( 1 -(piperidin-4-yl)-1 H-pyrazol-4yl)-3H-imidazo[4, 5-b]pyridine was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-1H-benzo[d]imidazole and tert-butyl-4-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazol-1-yl)piperidin-1-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 group under acidic conditions: ¹ H NMR (500 MHz, CDCI3) δ 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-(piperidin-3yl)-1H-1,2,3-triazole -1 -yl)-1 N-benzo[d]imidazole

To a suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.32 g, 0.63 mmol) in dimethyl sulfoxide (4 ml) and water (1 ml) were added 3-ethynylpiperidine hydrochloride (0.11 g, 0.75 mmol), sodium azide (0.051 g, 0.79 mmol), sodium salt of L-ascorbic acid (0.025 g, 0 .13 mmol), trans-N,N ¹ -dimethylcyclohexane-1,2-diamine (0.023 mg, 0.158 mmol), potassium carbonate (0.13 g, 0.95 mmol) and copper(1) iodide (0.024 g, 0.13 mmol). The resulting blue mixture was allowed to stir at room temperature. After 16 h, the yellow mixture was diluted with 5 N ammonium hydroxide and extracted with chloroform (2x30 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 0.53 g of a yellow oil. Chromatographic purification (Combi-Flash, 24 g SiO2, gold column, eluent: 110% methanol/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 0.15 g (45%) of product as a white foamy solid : ^1H NMR (400 MHz, DMSO-d6) 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazol-5-yl)-5-(piperidin-4 -yl)-1,3,4-oxadiazole

Example 3-7-1: Preparation of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazole-5-carbonitrile

To a stirred solution of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[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 hours the mixture was allowed to cool to room temperature and it was concentrated. The residue was purified by silica gel chromatography (eluent: 2% methanoladichloromethane) to give 0.70 g (87%) 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[ d]imidazole-5-carbonitrile as a yellow solid.

Example 3-7-2: Preparation of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazole-5-carboxylic acid

To a solution of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5carbonitrile (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 temperature and stirred. After 48 hours, the reaction mixture was allowed to cool to room temperature and was extracted with 10% methanol in dichloromethane. The extracts were washed with saline, dried and concentrated. The residue was purified by preparative HPLC to give 0.50 g (68%) 1-(3methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carboxylic acid as a light yellow solid.

Example 3-7-3: Preparation of tert-butyl-4-(2-(1-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-1H-benzo[d]imidazol-5- carbonyl)hydrazinecarbonyl)piperidine-1-carboxylate

To a solution of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5carboxylic acid (0.30 g, 0.72 mmol) in dichloromethane was added tert-butyl-4(hydrazinecarbonyl)piperidine-1-carboxylate (0.24 g, 0.98 mmol), 1-[bis(dimethylamino)methylene]-1H1,2,3-triazolo[4,5-b]pyridinium -3-oxide 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 hours, the mixture was concentrated and the residue was purified by silica gel chromatography (eluent: 2% methanoladichloromethane) to give 0.30 g (65%) tert-butyl-4-(2-(1-(3-methoxy-4-( (6methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carbonyl)hydrazinecarbonyl)piperidine 1-carboxylate as a yellow solid.

Example 3-7-4: preparation of tert-butyl-4-(5-(1-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-1 H-benzo[d]imidazole-5 -yl)-1,3,4-oxadiazol-2-yl)piperidin-1-carboxylate

To the stirred mixture of tert-butyl-4-(2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)1H-benzo[d]imidazole-5-carbonyl)hydrazinecarbonyl) piperidine-1-carboxylate (0.18 g, 0.28 mmol) in

- 75 044589

Triethylamine ₍ 0.42 g, 4.20 mmol). The resulting mixture was heated to 120°C and stirred. After 16 hours, the mixture was extracted with dichloromethane. The extracts were washed with saline, dried and concentrated. The residue was purified by silica gel chromatography (eluent: 1% methanoladichloromethane) to give 0.14 g (70%) tert-butyl-4-(5-(1-(3-methoxy-4-((6-methoxypyridin-3yl) )methoxy)benzyl)-1 H-benzo[d]imidazol-5-yl)-1,3,4-oxadiazol-2-yl)piperidin-1-carboxylate as a yellow solid.

Example 3-7-5: Preparation of 2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazol-5-yl)-5-(piperidine -4-yl)-1,3,4-oxadiazole

To a solution of tert-butyl-4-(5-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazol-5-yl)-1,3 ,4-oxadiazol-2-yl)piperidin-1-carboxylate (0.090 mg, 0.14 mmol) in dichloromethane (10 ml) at -20° C. was added trifluoroacetic acid (1.0 ml). The resulting mixture was stirred at -20°C. After 1 hour the mixture was concentrated. The residue was purified by preparative HPLC to give 0.010 g (14%) of product as a yellow solid: 1H NMR (500 MHz, CDCl ₃ ) 8.43 (s, 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(piperidin-4-yl)1H-benzo[d]imidazole

Example 3-8-1: Preparation of tert-butyl-4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)1H-benzo[d]imidazol-5-yl) -5,6-dihydropyridine-1(2H)-carboxylate

To a stirred solution of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazole (0.801 g, 1.60 mmol) in 1,4- dioxane (10 ml) and 2 M sodium carbonate solution (3.2 ml), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin- 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 hours, the reaction mixture was allowed to cool to room temperature and filtered. The filtrate was diluted with water (30 ml) and extracted with dichloromethane (3x50 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 (eluent: 5% methanoladichloromethane) to give 0.79 mg (89%) tert-butyl-4-(1-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy) benzyl)-1H-benzo[d]imidazol-5-yl)-5,6-dihydropyridine-1(2H)carboxylate as a light yellow solid.

Example 3-8-2: Preparation of tert-butyl 4-(1-(4-hydroxy-3-methoxybenzyl)-1H-benzo[d]imidazol-5yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl-4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)1H-benzo[d]imidazol-5-yl)-5,6- Dihydropyridine-1(2H)-carboxylate (0.56 g, 1.00 mmol) in methanol (15 ml) was added with ammonium formate (0.63 g, 10 mmol) and palladium on carbon (0.30 g). The reaction mixture was heated to 60°C in an H ₂ atmosphere. After 16 hours, the reaction mixture was allowed to cool to room temperature and filtered through celite. The filtrate was concentrated. The residue was purified by silica gel chromatography (eluent: 5% methanoladichloromethane) to give 0.42 g (96%) tert-butyl-4-(1-(4-hydroxy-3-methoxybenzyl)-1H-benzo[d]imidazole-5 -yl)piperidine-1-carboxylate as a light yellow solid.

Example 3-8-3: Preparation of tert-butyl-4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)1H-benzo[d]imidazol-5-yl) piperidine-1-carboxylate

To a stirred solution of tert-butyl 4-(1-(4-hydroxy-3-methoxybenzyl)-1H-benzo[d]imidazol-5yl)piperidine-1-carboxylate (0.51 g, 1.16 mmol) in K Potassium carbonate (0.32 g, 2.32 mmol) was added to K-dimethylformamide (5 ml). The mixture was treated with a solution of 5-(chloromethyl)-2-methoxypyridine (219 mg, 1.39 mmol) in K,K-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 (3x30 ml). The combined organic layers were washed with brine (3x10 ml), dried over sodium sulfate, filtered and concentrated to give 0.53 g (82%) tert-butyl-4-(1-(3-methoxy-4-((6-methoxypyridine -3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5yl)piperidine-1-carboxylate as a light yellow solid.

Example 3-8-4: Preparation of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(piperidin4-yl)-1H-benzo[d]imidazole

To a stirred and cooled (5°C) solution of tert-butyl-4-(1-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl )piperidine-1-carboxylate (0.28 g, 0.51 mmol) in dichloromethane (1 ml), trifluoroacetic acid (1 ml) was added. The resulting mixture was allowed to warm to room temperature and stirred. After 2 hours, the mixture was treated with 1 N. sodium hydroxide solution to achieve pH 10 and extracted with dichloromethane (3x10

- 76 044589 ml). The combined organic layers were washed with brine (3x10 ml), dried over sodium sulfate, concentrated. The residue was purified by preparative HPLC to give 0.018 g (8%) product as a white solid: 1H NMR (500 MHz, MeOD-d ₄ ) 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazol-5-yl)morpholine

To a suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.32 g, 0.64 mmol) in dimethyl sulfoxide (4 ml) 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 (x3). The combined organic phases were washed with water (x2), brine, dried over magnesium sulfate, filtered and concentrated. Chromatographic purification (CombiFlash, 40 g SiO ₂ column, eluent: 1-5% methanol/dichloromethane) gave 0.076 g (26%) of product as an off-white solid: 1H NMR (400 MHz, CDCl ₃ ) 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), 6.786.67 (m, 3H), 5 .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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazol-5-yl)piperidin-4- yl)propan-2-amine

Example 3-10-1: Preparation of 2-(piperidin-4-yl)propan-2-amine 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 hours, the mixture was allowed to cool to room temperature and was treated with tert-butyl 4-cyanopiperidine-1-carboxylate (2.25 g, 10.70 mmol). The mixture was cooled to -20° C. as a 1.5 M solution of methyllithium lithium bromide complex (21.4 mL, 32.10 mmol) was added. After 1 hour at -20°C, the mixture was quenched with a saturated ammonium chloride solution and diluted with ethyl acetate. The two-phase mixture was filtered to remove undissolved solid material and the filtrate layers 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 acid resin in methanol (1.1 eq/ml, 20 ml added). After 2 hours at room temperature, the mixture was filtered. The filter cake was washed with methanol, followed by ammonia in methanol (3 M to 6 M). The filtrate was concentrated to obtain a waxy solid (containing both the free diamine and the carbamate-protected monoamine). This crude mixture was dissolved in methanol and treated with hydrogen chloride (2.0 M in diethyl ether). The mixture was allowed to stir at room temperature.

After 20 hours the mixture was concentrated. The residue was suspended in toluene and re-concentrated to give 0.96 g (42%) of 2-(piperidin-4-yl)propan-2-amine dihydrochloride as a white solid.

Example 3-10-2: Preparation of 2-(1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazol-5-yl)piperidin- 4-yl)propan-2-amine

To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazole (0.15 g, 0.30 mmol) in dimethyl sulfoxide ( 5 ml) 2-(piperidin-4yl)propan-2-amine 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, additional L-proline (0.007 g, 0.057 mmol) was added and heating continued. After an additional 5 hours, the reaction mixture was allowed to cool to room temperature and 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. An oil was obtained by chromatographic purification (Biotage, 10 g SiO2 column, eluent: 10% methanol/dichloromethane to 3 M ammonia in methanol/dichloromethane). The oil was dissolved in aqueous acetonitrile and lyophilized to give 0.070 g (45%) of the product as a tan solid: 1H NMR (400 MHz, CDCl ₃ ) 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(2,7diazaspiro[3.5]nonan-2-yl)-1H-benzo [d]imidazole

Example 3-11-1: preparation of tert-butyl-2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)- 77 044589

1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazole (0.61 g, 1.22 mmol) in dimethyl sulfoxide ( 4 ml) added tert-butyl-2,7diazaspiro[3.5]nonane-7-carboxylate (0.30 g, 1.34 mmol), copper(1) iodide (0.02 8 g, 0.15 mmol), carbonate potassium (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 temperature and was diluted with 3 N ammonium hydroxide solution (20 ml). The mixture was extracted with dichloromethane, resulting in a thick emulsion. The emulsion 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 SiO ₂ column, eluent: 1-5% methanol/dichloromethane) gave 0.53 g (72%) tert-butyl-2-(1-(3-methoxy-4-(( 6methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7carboxylate.

Example 3-11-2: Preparation of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(2,7diazaspiro[3.5]nonan-2-yl)-1H -benzo[d]imidazole

To a stirred solution of tert-butyl-2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)1H-benzo[d]imidazol-5-yl)-2,7- diazaspiro[3.5]nonane-7-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 hour, the mixture was concentrated and the residue was partitioned between 3 M ammonium hydroxide 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. Purification chromatography (Combi-Flash, 40 g SiO2, gold column, eluent: 1-15% methanol/dichloromethane) gave 0.28 g (64%) of product as a solid: 1H NMR (400 MHz, CDC13) 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 (br, 1H), 1.821.74 (m, 4H) ppm; (M+1)=500.

Example 3-12: Synthesis of 1-(1 -(3 -methoxy-4-((6-methoxypyridin-3 -yl)methoxy)benzyl)-1 H-benzo[d]imidazol5-yl)piperidin-4-amine

Example 3-12-1: Preparation of tert-butyl-(1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazol-5-yl) piperidin-4-yl)car bamata

To a suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.48 g, 0.96 mmol) in dimethyl sulfoxide (4 ml) added tert-butyl-piperidin-4-ylcarbamate (0.22 g, 1.05 mmol), copper(1) iodide (0.022 g, 0.11 mmol), potassium carbonate (0.32 g, 2 .32 mmol) and L-proline (0.026 g, 0.23 mmol). The light yellow reaction mixture was heated to 120°C. After 16 hours, additional portions of tert-butyl-piperidin-4-ylcarbamate (0.048 g, 0.47 mmol), copper(1) 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 hours. After a total of 20 hours, the reaction mixture was allowed to cool to room temperature and diluted with 3N ammonium hydroxide solution (25 ml). The mixture was extracted with dichloromethane (x3). The combined organic phases were washed with water (x2), brine, dried over magnesium sulfate, filtered and concentrated. Chromatographic purification (CombiFlash, 40 g SiO2, column, eluent: 1-10% methanol/dichloromethane) gave 0.33 g (60%) tert-butyl-(1-(1-(3-methoxy-4-( (6methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)carbamate in the form of a solid with impurities.

Example 3-12-2: Preparation of 1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazol-5-yl)piperidin-4-amine

To a stirred solution of tert-butyl-(1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)1H-benzo[d]imidazol-5-yl)piperidin-4- yl)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 was partitioned between 3 M ammonium hydroxide 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. Purification chromatography (Combi-Flash, 40 g SiO ₂ , gold column, eluent: 1-15% methanol/dichloromethane) gave 0.19 g (62%) of product as a solid: 1H NMR (400 MHz, CDCI3) 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 ( ush, 2H), 1.62-1.50 (m, 2H) ppm; (M+1)=474.

Example 3-13: Synthesis of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-methylpiperazin-1yl)-1H-benzo[d]imidazole

To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H

- 78 044589 benzo[d]imidazole (0.25 g, 0.50 mmol) in dimethyl sulfoxide (5 ml), 1-methylpiperazine (0.28 g, 1.50 mmol), copper(1) iodide (0.029 g, 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 hour, the reaction mixture was allowed to cool to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified by preparative HPLC to give 0.045 g (19%) of product as a white solid: 1H NMR (500 MHz, CDC13) 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-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)1H-benzo[d]imidazol-5-yl)-4 -methylpiperazin-2-one

Example 3-14-1: Preparation of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)1 H-benzo[d]imidazol-2-amine

To a stirred suspension of 4-iodo-N ¹ -(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)benzene1,2-diamine (3.82 g, 7.77 mmol) in dichloromethane ( 40 ml) and methanol (20 ml), a solution of cyanogen bromide (5.0 M in acetonitrile, 7.8 ml, 38.87 mmol) was added. The resulting brown reaction mixture was allowed to stir at room temperature. After 18 hours, 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 give 5.26 g of a brown semi-solid. Chromatographic purification (Combi-Flash, 80 g SiO ₂ column, eluent: 5-10% methanol/dichloromethane) gave 2.78 g (69%) 5-iodo-1-(3-methoxy-4-((6 -methoxypyridin-3-yl)methoxy)benzyl)1H-benzo[d]imidazol-2-amine as a brown solid.

Example 3-14-2: Preparation of 1-(2-amino-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)1H-benzo[d]imidazol-5-yl) -4-methylpiperazin-2-one

To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazol-2-amine (0.25 g, 0.48 mmol ) in 1,4-dioxane (8 ml) added 4-methylpiperazin-2-one (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) and tribasic potassium phosphate (0.32 g, 1.52 mmol). The mixture was heated to 145°C in a microwave reactor. After 3 hours the mixture was allowed to cool to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified by silica gel chromatography (eluent: 2-5% methanol/dichloromethane) followed by preparative HPLC to give 0.030 g (12%) of product as a white solid: 1H NMR (500 MHz, CDC13) 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-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)3H-imidazo[4,5-b ]pyridine-2-amine

Example 3-15-1: Preparation of 5-bromo-N-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3-nitropyridin2-amine

To a stirred solution of 3-methoxy-4-(4-methoxybenzyloxy)phenyl)methanamine (2.00 g, 7.32 mmol) and 5-bromo-2-chloro-3-nitropyridine (1.66 g, 6.97 mmol ) in acetonitrile (50 ml) was added N,Ndiisopropylethylamine (1.13 g, 8.71 mmol). The resulting mixture was heated to reflux temperature 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 give 3.34 g (>100%) 5-bromo-M-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3-nitropyridin-2-amine as a yellow-brown solid.

Example 3-15-2: Preparation of 5-bromo-M ² -(3-methoxy-4-(4-methoxybenzyloxy)benzyl)pyridine-2,3diamine

Sodium hydrogen sulfite was added to a stirred solution of 5-bromo-N-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3nitropyridin-2-amine in tetrahydrofuran (40 ml), ethanol (40 ml) and water (40 ml). (6.09 g, 34.99 mmol). The resulting mixture was heated to reflux temperature 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 with dichloromethane three times. The combined organic phases were washed with brine, dried (magnesium sulfate), filtered and concentrated to give 3.10 g of a tan solid. Chromatographic purification (Combi-Flash 40 g SiO ₂ , gold column, 1-2.5% methanol/dichloromethane) gave 1.28 g (51%) 5-bromo-N ² -(3-methoxy-4-( 4-methoxybenzyloxy)benzyl)pyridine-2,3-diamine as a yellow solid.

Example 3-15-3: Preparation of 6-bromo-3-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3H-imidazo[4,5b]pyridin-2-amine

- 79 044589

To a stirred solution of 5-bromo-N ² -(3-methoxy-4-(4-methoxybenzyloxy)benzyl)pyridine-2,3diamine (0.850 g, 1.91 mmol) in dichloromethane (30 ml) and methanol (30 ml) cyanogen bromide (5.0 M in acetonitrile, 573 μL, 2.87 mmol) was added. The resulting solution was allowed to stir at room temperature. After 24 h, a second aliquot of cyanogen bromide solution (600 μl) was added and stirring continued. After 48 h, a third aliquot of cyanogen bromide solution (600 μl) was added and stirring continued. Overall, after 72 hours, the reaction mixture was concentrated and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide, dried over magnesium sulfate, filtered and concentrated to give 1.17 g of a brown solid. Chromatographic purification (Combi-Flash, 40 g SiO ₂ , gold column, 1-10% methanol/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 0.28 g (32%) 6-bromo-3( 3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine as a brown solid.

Example 3-15-4: Preparation of 3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol4-yl)-3H-imidazo[4,5- b]pyridine-2-amine

To a stirred solution of 6-bromo-3-(3-methoxy-4-(4-methoxybenzyloxy)benzyl)-3H-imidazo[4,5b]pyridin-2-amine (0.25 g, 0.53 mmol) in 1 ,4-dioxane (10 ml) and water (4 ml) was added 1-methyl-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.14 g, 0.66 mmol), tribasic potassium phosphate (0.39 g, 1.84 mmol), tricyclohexylphosphine (0.015 g, 0.052 mmol), palladium(P) acetate (0.005 g, 0.026 mmol). The reaction mixture was heated to 125°C 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 give 0.36 g of a greenish-brown solid. Chromatographic purification (Combi-Flash, 12 g SiO2, gold column, 1-10% methanol/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 0.10 g (41%) of product as a light green solid substances: 1H NMR (400 MHz, DMSO-d ₆ ) 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-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5b]pyridin-6-yl)pyridin- 2-yl)dimethylphosphine oxidane oxide

Example 3-16-1: Preparation of 5-iodo-K-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3-nitropyridin2-amine

To a stirred solution of 3-methoxy-4-(4-methoxybenzyloxy)phenyl)methanamine (3.80 g, 13.92 mmol) and 2-chloro-5-iodo-3-nitropyridine (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 temperature and allowed to stir. After 16 hours, the brown reaction mixture was allowed to cool to room temperature and was diluted with water. The mixture was extracted with chloroform (x3). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 6.88 g (>100%) 5-iodo-K-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3-nitropyridine- 2 amines as a yellow-brown solid.

Example 3-16-2: Preparation of 5-iodo-K ² -(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyridine-2,3diamine

To a stirred suspension of 5-iodo-K-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3nitropyridin-2-amine (6.72 g, 13.25 mmol) in tetrahydrofuran (75 ml), Ammonium chloride (5.68 g, 106.0 mmol) and iron(II) sulfate heptahydrate (11.05 g, 39.76 mmol) were added to methanol (25 ml) and water (25 ml). The yellow mixture was treated with zinc (2.60 g, 39.76 mmol) and the resulting dark mixture was heated to reflux. After 3 hours, the reaction mixture was allowed to cool to room temperature and filtered through celite using 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 give 6.67 g (>00%) 5-iodo-K ² -(3-methoxy-4((4-methoxybenzyl)oxy)benzyl) pyridine-2,3-diamine as a brown solid.

Example 3-16-3: Preparation of 6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5b]pyridin-2-amine

To a stirred suspension of 5-iodo-K ² -(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyridine-2,3diamine (6.33 g, 13.25 mmol) in dichloromethane (100 ml) and methanol (50 ml) was added a solution of cyanogen bromide (5.0 M in acetonitrile, 13.3 ml, 66.27 mmol). The resulting dark brown reaction mixture was allowed to stir at room temperature. After 68 hours, the now black reaction mixture was treated with 1 N. 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 give 6.43 g of a brown oil. Purification chromatography (Combi-Flash, 120 g SiO ₂ column, eluent: 1-5% methanol/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 2.40 g of black oil. A second chromatographic purification (Combi-Flash, 80 g SiO2, column, eluent: 1-5% methanol/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 0.98 g (14%) 6 -iodo-3-(3methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine as a gray solid.

Example 3-16-4: Preparation of 6-(6-chloropyridin-3-yl)-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)3H-imidazo[4,5-b]pyridine -2-amine

To a stirred suspension of 6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5b]pyridin-2-amine (0.34 g, 0.66 mol ) in 1,4-dioxane (10 ml) and water (4 ml) added (6-chloropyridin-3yl)boronic acid (0.12 g, 0.76 mmol), tribasic potassium phosphate (0.49 g, 2. 33 mmol), tricyclohexylphosphine (0.037 g, 0.13 mmol) and palladium(P) 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 (x3). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 0.44 g of a brown solid. Chromatographic purification (Combi-Flash, 24 g SiO ₂ , gold column, eluent: 5-10% methanol/dichloromethane) gave 0.20 g (60%) 6-(6-chloropyridin-3-yl)-3- (3-methoxy-4-((4methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine as a tan solid.

Example 3-16-5: Preparation of (5-(2-amino-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3Nimidazo[4,5-b]pyridin-6-yl) pyridin-2-yl)dimethylphosphine oxide

To a stirred suspension of 6-(6-chloropyridin-3-yl)-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)3H-imidazo[4,5-b]pyridin-2-amine ( 0.17 g, 0.34 mmol) in 1,4-dioxane (12 ml), dimethylphosphine oxide (0.053 g, 0.69 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.079 g, 0.14 mmol), palladium(P) 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 hour, the reaction mixture was allowed to cool to room temperature. The mixture was diluted with water and extracted with chloroform (x2). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 0.27 g of a yellow solid. Purification chromatography (Combi-Flash, 12 g SiO2 column, eluent: 5-10% methanol/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 0.078 g (42%) of product as a tan solid: 1H NMR (400 MHz, DMSO-d ₆ ) 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1yl)-3H-imidazo[4,5-b] pyridine

Example 3-17-1: Preparation of 5-iodo-K-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3nitropyridin-2-amine

To a stirred solution of (3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (9.11 g, 33.21 mmol) in acetonitrile (150 ml) was added 2-chloro-5-iodo -3-nitropyridine (9.90 g, 34.81 mmol) and N,N-diisopropylethylamine (6.44 g, 49.81 mmol). The yellow solution was heated to reflux temperature and stirred. After 3 hours, the red-brown mixture was cooled to 0° C., resulting in the formation of a precipitate. The precipitate was separated by filtration and washed with acetonitrile (50 ml) and water (200 ml). The wet 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 give 14.67 g (85%) 5-iodo-K-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-3-nitropyridine- 2-amine as a yellow-brown solid.

Example 3-17-2: Preparation of 5-iodo-K ² -(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)pyridine2,3-diamine

To a stirred suspension of 5-iodo-K-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3nitropyridin-2-amine (14.67 g, 28.09 mmol) in acetic acid (130 ml) iron powder (10.98 g, 196.6 mmol) was added. The bright yellow mixture was heated to ~85°C. After 15 minutes of heating, the reaction mixture became a gray-brown suspension and was allowed to cool to room temperature. The mixture was diluted with ethyl acetate (400 ml) and the thick mixture was filtered through celite with additional ethyl acetate (100 ml). The filtrate was washed with water (2 x 150 ml) and 5 N ammonium hydroxide solution (4 x 125 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated to give 11.67 g (84%) of 5-iodo-K ² -(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)pyridin-2, 3-diamine as a tan solid.

Example 3-17-3: Preparation of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridine

To a stirred suspension of 5-iodo-K ² -(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)pyridine2,3-diamine (11.67 g, 23.70 mmol) in ethanol ( 175 ml) triethyl orthoformate (8.90 g, 60.05 mmol) and p-toluenesulfonic acid monohydrate (0.23 g, 1.19 mmol) were added. As the mixture was heated to reflux temperature, the solids dissolved to produce a brown solution. After 30 minutes, the reaction mixture was cooled to 0°C, which resulted in the formation of a precipitate. The solids were separated by filtration, washed with a little cold ethanol and dried to give 10.34 g (87%) 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)- 3H-imidazo[4,5-b]pyridine as an off-white solid.

Example 3-17-4: preparation of 3-(3-methoxy-4-((6-methoxypyridin-3-yl) methoxy)benzyl)-6-(4methylpiperazin-1 -yl)-3 H-imidazo [4,5 -b]pyridine

To a stirred suspension of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Himidazo[4,5-b]pyridine (1.40 g, 2.79 mmol ) in dimethyl sulfoxide (15 ml), 1-methylpiperazine (0.44 g, 4.40 mmol), copper(T) 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/N2 (x3) and then heated to 120°C. As the mixture was heated, it turned a dark blue/black color. After 19 hours, the brown mixture was allowed to cool to room temperature and diluted with 5N ammonium hydroxide solution (100 ml). The mixture was extracted with dichloromethane (3x50 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 1.78 g of a brown oil. Chromatographic purification (Combi-Flash, 40 g SiO ₂ , gold column, eluent: 1-10% methanol/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 0.60 g (45%) of the product as a tan-colored solid: 1H NMR (400 MHz, CDCl ₃ ) 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-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine

The following compounds from 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Himidazo[4,5-b]pyridine were prepared using the procedure described in Example 3- 17-4 by using the appropriate amine coupling partner.

Example 3-18-1: 2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5b]pyridin-6-yl )piperidin-4-yl)propan-2-amine ^1H NMR (400 MHz, CDCl3): 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), 1.261.24 (m, 1H), 1.06 (s, 6H) ppm; (M+1) 517.

Example 3-18-2: 4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5b]pyridin-6-yl)morpholine

1H NMR (400 MHz, CDCI3) 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-Cyclopropylpiperazin-1 -yl)-3 -(3 -methoxy-4-((6-methoxypyridin-3 yl)methoxy)benzyl)-3H-imidazo[4,5- b]pyridine

1H NMR (400 MHz, DMSO-d ₆ ) 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5b]pyridin-6-yl)-1 ,4-diazabicyclo[3.2.2]nonane

1H 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.

Example 3-18-5: 3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan2-yl)-3H-imidazo [4,5-b]pyridine

The synthesis is a two-step process involving coupling followed by deprotection of the carbamate, which is described for Example 3-11.

1H NMR (400 MHz, CDC13) 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5b]pyridin-6-yl)piperidin- 4-amine

The synthesis is a two-step process involving coupling followed by deprotection of the carbamate, which is described for Example 3-12.

1H NMR (400 MHz, CDCI3) 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,

- 82 044589

3H), 2.42 (br, 2H), 2.01-1.94 (m, 2H), 1.66-1.51 (m, 2H) ppm; (M+1) 475.

Example 3-18-7: (S)-1-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5b]pyridin-6- yl)pyrrolidine-2-carboxylic acid ^1H NMR (500 MHz, CD3OD) δ 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4yl)-1H-pyrazol-4-yl)- 3H-imidazo[4,5-b]pyridine

Example 3-19-1: Preparation of tert-butyl-4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-3H-imidazo[4,5-b] pyridin-6-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylate

To a stirred suspension of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Himidazo[4,5-b]pyridine (0.20 g, 0.40 mmol ) in K,K-dimethylformamide (8 ml) and water (2 ml) was added tert-butyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazol-1-yl)piperidin-1carboxylate (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 hour, the reaction mixture was allowed to cool to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified by silica gel chromatography (eluent: 5% methanol/dichloromethane) to give 0.15 g (60%) tert-butyl-4-(4-(3-(3-methoxy-4-((6 -methoxypyridin-3yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidin-1-carboxylate as a yellow solid.

Example 3-19-2: Preparation of 3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1(piperidin-4-yl)-1H-pyrazol-4- yl)-3H-imidazo[4,5-b]pyridine

To a stirred solution of tert-butyl-4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl )-1H-pyrazol-1-yl)piperidin-1-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 1 M potassium carbonate solution (20 ml) and extracted with dichloromethane (3x10 ml). The combined organic phases were washed with brine (3x20 ml), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give 0.065 g (52%) of product as a white solid: 1H NMR (500 MHz, CDCl ₃ ) 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-4-((6-methylpyridin-3-yl)methoxy)benzyl)-6-(1-(piperidin-4yl)-1H-pyrazol-4-yl)- 3H-imidazo[4,5-b]pyridine

Example 3-20-1: Preparation of tert-butyl-3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzylcarbamate

To a stirred solution of tert-butyl-4-hydroxy-3-methoxybenzylcarbamate (21.02 g, 82.99 mmol) in acetonitrile (250 ml) was added potassium carbonate (30.61 g, 221.5 mmol) and 5-(chloromethyl )-2methylpyridine hydrochloride (16.25 g, 91.29 mmol). The resulting mixture was heated to reflux temperature. After 63 h, the brown suspension was allowed to cool to room temperature and diluted with water (1000 ml). The mixture was extracted with dichloromethane (3x250 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 31.59 g (>100%) tert-butyl-3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzylcarbamate as a brown oil.

Example 3-20-2: Preparation of (3-methoxy-4-((6-methylpyridin-3-yl)methoxy)phenyl)methanamine

Trifluoroacetic acid (50 mL, 649.0 mmol). The resulting brown solution was allowed to stir at room temperature. After 2 hours, the reaction mixture was concentrated to dryness and the residue was dissolved in water (250 ml). The acidic solution was extracted with diethyl ether (2x125 ml; organic phases were discarded). The aqueous phase was then made basic using concentrated ammonium hydroxide. The main aqueous phase was then extracted with dichloromethane (3x100 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 19.22 g (90%) of (3-methoxy4-((6-methylpyridin-3-yl)methoxy)phenyl)methanamine as a brown solid.

Example 3-20-3: Preparation of 5-iodo-K-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3nitropyridin-2-amine

To a stirred solution of (3-methoxy-4-((6-methylpyridin-3-yl)methoxy)phenyl)methanamine (7.30 g, 28.26 mmol) in acetonitrile (200 ml) was added 2-chloro-5-iodine -3-nitropyridine (8.44 g, 29.67 mmol) and K,K-diisopropylethylamine (5.48 g, 42.39 mmol). The brown mixture was heated to reflux temperature

- 83 044589 phlegm. After 5 hours, the brown mixture was allowed to cool to room temperature and diluted with water (600 ml). The resulting precipitate was separated by filtration and washed with water (200 ml). The wet solids were dissolved in ethyl acetate (300 ml) and this solution was washed with water (100 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated to give 13.57 g (95%) of 5-iodo-M-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3nitropyridine- 2-amine as a bright yellow solid.

Example 3-20-4: Preparation of 5-iodo-M ² -(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)pyridine2,3-diamine

To a stirred suspension of 5-iodo-N-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3nitropyridin-2-amine (13.57 g, 26.80 mmol) in acetic acid (100 ml) iron powder (8.10 g, 145.0 mmol) was added. The bright yellow suspension was gradually heated to 90°C. After 30 minutes of heating, the dark brown reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (400 ml). The mixture was filtered through celite with additional ethyl acetate (100 ml). The filtrate was then washed with water (2x150 ml) and 1 N. sodium hydroxide solution (2x200 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated to give 6.97 g (55%) 5-iodo-N ² -(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)pyridin- 2,3-diamine as a brown solid.

Example 3-20-5: Preparation of 6-iodo-3-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridine

To a stirred suspension of 5-iodo-N2-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)pyridine2,3-diamine (6.98 g, 14.65 mmol) in ethanol (100 ml) triethyl orthoformate (3.56 g, 24.02 mmol) and p-toluenesulfonic acid monohydrate (0.050 g, 0.26 mmol) were added. As the resulting mixture was heated to reflux temperature, the solids gradually dissolved to produce a brown solution. After 90 minutes, the reaction mixture was allowed to cool to room temperature and the mixture was concentrated to give 7.91 g of a brown oil. Purification chromatography (Combi-Flash, 220 g SiO ₂ , gold column, eluent: 1-5% methanol/dichloromethane) gave 5.22 g (73%) 6-iodo-3-(3-methoxy-4-( (6-methylpyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5b]pyridine as a tan solid.

A portion of this material was used to prepare the compound of Example 3-20 using the procedure specified for the synthesis of Example 3-19: 1H NMR (500 MHz, CDC13) 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5b]pyridin-6-yl)-5- (piperidin-4-yl)-1,2,4-oxadiazole

Example 3-21-1: Preparation of 3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridine-6-carbonitrile

To a stirred solution of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridine (1.00 g, 1.99 mmol ) in N,N-dimethylformamide (15 ml) was added copper(1) cyanide (0.53 g, 6.00 mmol). The mixture was heated to 150°C. After 5 hours the mixture was allowed to cool to room temperature and it was concentrated. The residue was purified by silica gel chromatography (eluent: 2% methanol/dichloromethane) to give 0.53 g (66%) 3-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-3H- imidazo[4,5-b]pyridine-6-carbonitrile as a yellow solid.

Example 3-21-2: preparation of N'-hydroxy-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6- carboximidamide

To a stirred solution of 3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridine-6-carbonitrile (0.53 g, 1.32 mmol ) a solution of hydroxylamine (50% weight in water, 0.1 ml) was added in ethanol. The mixture was heated to 100°C. After 1 hour, the mixture was concentrated to give 0.66 g (>100%) N'-hydroxy-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4 ,5b]pyridine-6-carboximidamide as a white solid.

Example 3-21-3: preparation of tert-butyl-4-(3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b ]pyridin-6-yl)-1,2,4-oxadiazol-5-yl)piperidin-1-carboxylate

To a stirred solution of N'-hydroxy-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridine-6-carboximidamide (0.38 g, 0.75 mmol) in Ν,N-dimethylformamide (10 ml) was added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.21 g, 0.92 mmol), 1[bis(dimethylamino)methylene ]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide 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 hour, the mixture was diluted with ethyl acetate and saline. 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 hours, the reaction mixture was allowed to cool to room temperature and concentrated. The crude product was purified by chromatography on

- 84 044589 silica gel (eluent: 2% methanol/dichloromethane) to obtain 0.14 g (25%) tert-butyl-4-(3-(3-(3methoxy-4-((6-methoxypyridin-3-yl) methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1,2,4-oxadiazol5-yl)piperidin-1-carboxylate as a yellow solid.

Example 3-21-4: preparation of 3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridin-6-yl)- 5-(piperidin-4-yl)-1,2,4-oxadiazole

To a stirred solution of tert-butyl-4-(3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-6- yl)-1,2,4-oxadiazol-5-yl)piperidin-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 hour, the mixture was diluted with cold saturated sodium carbonate solution. 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. The residue was purified by preparative HPLC to give 0.067 g (57%) of product as a white solid: 1H NMR (500 MHz, DMSO- _d6 ) δ 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-4-((6-methoxypyridin-3 -yl)methoxy)benzyl)-1 H-benzo[d]imidazol5-yl)-5-(piperidin- 4-yl)-1,2,4-oxadiazole

3-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5-(piperidin4-yl)-1, 2,4-oxadiazole was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazole using the procedure specified for Example 3-21 : 1H NMR (500 MHz, DMSO-d ₆ ) δ 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5b]pyridin-6-yl)-5 - (piperidin-4-yl)-1,3,4-oxadiazole

2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5(piperidin-4- yl)-1,3,4-oxadiazole was prepared from 6-iodo-3-(3-methoxy-4-((6-methylpyridin-3yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine according to the procedure specified for the synthesis in example 3-7: 1H NMR (500 MHz, CD3OD) 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridin-6-yl) -1H-1,2,3-triazol-4-yl)propan-2-amine

2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)1H-1, 2,3-triazol-4-yl)propan-2-amine was prepared from 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-3H-imidazo[4,5 -b]pyridine and 2-methylbut-3-yn-2-amine according to the procedure described for the synthesis of example 3-6: 1H NMR (400 MHz, DMSO-d ₆ ) 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3yl)-1H-1,2,3-triazole -1-yl)-3H-imidazo[4,5-b]pyridine

-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol1-yl)-3H -Imidazo[4,5-b]pyridine was prepared from 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine according to the procedure described for the synthesis of example 3-6: 1H NMR (400 MHz, DMSO-d ₆ ) 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.

Example 3-26: Synthesis of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4methylpiperazin-1-yl)-1H-benzo[d]imidazol-2- amine

-(3-Methoxy-4-((6-methoxypyridin-3 -yl)methoxy)benzyl)-5-(4-methylpiperazin-1 -yl)-1 Nbenzo[d]imidazol-2-amine was prepared from 5-iodo -1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)1H-benzo[d]imidazol-2-amine and 1-methylpiperazine according to the procedure described for the synthesis of example 3-13 : 1H NMR (500 MHz, CDC13) 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.

- 85 044589

Example 3-27: Synthesis of 1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4methylpiperazin-1 -yl)-1 H-benzo[d ]imidazole

Example 3-27-1: Preparation of 5-((4-bromo-5-fluoro-2-methoxyphenoxy)methyl)-2-methoxypyridine

5-(chloromethyl)-2-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 hours, the mixture was allowed to cool to room temperature and was diluted with water. The mixture was extracted with ethyl acetate (3x25 ml). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by chromatography (eluent: 033% ethyl acetate/hexanes) provided 2.76 g (66%) of 5-((4-bromo-5-fluoro-2-methoxyphenoxy)methyl)-2methoxypyridine as an oil.

Example 3-27-2: Preparation of 2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzonitrile

Copper cyanide ( T) (3.59 g, 40.07 mmol). The mixture was heated to 150°C. After 16 hours 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. Purification chromatography (Combi-Flash, 80 g SiO ₂ column, eluent: 1-5% methanol/dichloromethane) gave 3.25 g (84%) of 2-fluoro-5methoxy-4-((6-methoxypyridine-3- yl)methoxy)benzonitrile as an off-white solid.

Example 3-27-3: Preparation of (2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine

To a stirred solution of 2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzonitrile (3.25 g, 11.27 mmol) in tetrahydrofuran (50 ml) at 0°C was added ( three parts) lithium aluminum hydride (0.86 g, 22.55 mmol). We noticed a slight evolution of gas with each addition and the color of the reaction mixture turned olive green. After 1.5 h, the mixtures were quenched by slowly adding water (1.0 mL), 15% sodium hydroxide solution (1.0 mL), and water (3.0 mL). The resulting off-white suspension was stirred at 0°C. After 15 minutes the mixture was filtered through celite using ethyl acetate. The filtrate was concentrated to give 1.91 g (58%) of (2-fluoro-5-methoxy-4-((6methoxypyridin-3-yl)methoxy)phenyl)methanamine as a crude oil.

Example 3-27-4: Preparation of N-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodo2-nitroaniline

To a stirred solution of (2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (0.89 g, 3.04 mmol) in acetonitrile (15 ml), 1-fluoro -4-iodo-2-nitrobenzene (0.89 g, 3.35 mmol) and N,N-diisopropylethylamine. The resulting yellow solution was heated to reflux temperature. After 16 hours, the mixture was allowed to cool to room temperature and was diluted with water. The mixture was extracted with ethyl acetate (3x25 ml). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Chromatographic purification (Combi-Flash, 40 g SiO ₂ column, eluent: 0-33% ethyl acetate/hexanes) gave 0.38 g (23%) N-(2-fluoro-5-methoxy-4-((6 -methoxypyridin-3-yl)methoxy)benzyl)-4-iodo-2-nitroaniline in the form of a solid.

Example 3-27-5: Preparation of N ¹ -(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4iodobenzene-1,2-diamine

To a stirred solution of N-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4iodo-2-nitroaniline (0.38 g, 0.70 mmol) in tetrahydrofuran ( 10 ml), methanol (5 ml) and water (1 ml), ammonium chloride (0.30 g, 5.64 mmol) and iron (II) sulfate heptahydrate (0.69 g, 2.47 mmol) were added. The bright orange suspension was treated with zinc (0.16 g, 2.47 mmol). The mixture was gradually heated to reflux temperature. After 3.5 hours, the color of the reaction mixture changed from orange to olive green. At this stage, the reaction mixture was allowed to cool to room temperature. The mixture was filtered through celite and the filter cake was washed with chloroform (250 ml). The filtrate was washed with 5 N ammonium hydroxide solution (75 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated to give 0.36 g (100%) N ¹ -(2-fluoro-5-methoxy-4-((6methoxypyridin-3-yl)methoxy)benzyl)-4-iodobenzene -1,2-diamine as a tan solid.

Example 3-27-6: Preparation of 1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo1 H-benzo[d]imidazole

To a stirred solution of N ¹ -(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4iodobenzene-1,2-diamine (0.36 g, 0.70 mmol) in ethanol (10 ml), triethyl orthoformate (0.31 g, 2.11 mmol) and p-toluenesulfonic acid (0.007 g, 0.035 mmol) were added. The reaction mixture was heated to reflux temperature. After 30 minutes, the brown solution was allowed to cool to room temperature and concentrated. The residue was partitioned between water and dichloromethane. The phases were separated and the aqueous phase was 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 ₂ column, eluent: 1-5% methanol/dichloromethane) gave 0.25 g (68%) 1-(2-fluoro-5-methoxy-4 -((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-Nbenzo[d]imidazole as a tan solid.

Example 3-27-7: Preparation of 1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4methylpiperazin-1 -yl)-1 H-benzo [d]imidazole

To a stirred suspension of 1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5iodo-1H-benzo[d]imidazole (0.20 g, 0.39 mmol ) in dimethyl sulfoxide (4 ml) was added 1methylpiperazine (0.039 g, 0.39 mmol), copper(T) 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 diluted with 3 N. ammonium hydroxide solution (20 ml). The mixture was extracted with dichloromethane. The organic phase was washed with water (2x15 ml), brine, dried over magnesium sulfate, filtered and concentrated. Chromatographic purification (CombiFlash, 40 g SiO ₂ column, eluent: 1-5% methanol/dichloromethane) yielded 0.062 g of impurity material. Subsequent re-purification by preparative HPLC gave 0.030 g (16%) of product as a solid: 1H NMR (400 MHz, CDCl ₃ ) δ 8.19 (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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin1-yl)-3H-imidazo[4,5-b] pyridine

Example 3-28-1: Preparation of 3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde

To a stirred solution of 3-ethoxy-4-hydroxybenzaldehyde (2.75 g, 16.55 mmol) in acetonitrile (75 ml) was added 5-(chloromethyl)-2-methoxypyridine hydrochloride (3.37 g, 17.38 mmol) and potassium carbonate (9.15 g, 66.20 mmol). The mixture was heated to reflux temperature. After 3 hours, the yellow mixture was allowed to cool to room temperature and was diluted with water (400 ml), resulting in the formation of a precipitate. Solids were separated by filtration and washed with water (50 ml). The filtrate was extracted with chloroform (2x100 ml). The organic phases were combined with the previously separated solids. The resulting solution was dried over magnesium sulfate, filtered and concentrated to give 3.40 g (72%) of 3-ethoxy-4-((6-methoxypyridin-3yl)methoxy)benzaldehyde as a yellow solid.

Example 3-28-2: Preparation of 3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde oxime

To a stirred solution of 3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde (3.40 g, 11.83 mmol) in methanol (50 ml), pyridine (1.5 ml) and water ( 5 ml) hydroxylamine hydrochloride (1.23 g, 17.75 mmol) was added. The reaction mixture was heated to reflux temperature. After 2 hours, the colorless solution was allowed to cool to room temperature and 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-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde oxime as an off-white solid.

Example 3-28-3: Preparation of (3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine

To a stirred solution of 3-ethoxy-4-((6-methoxypyridin-3-yl)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 hours, the gray suspension was allowed to cool to room temperature and was diluted with ethyl acetate (150 ml). The mixture was filtered through celite by adding additional ethyl acetate (50 ml). The filtrate was diluted with water (50 ml) and made basic by adding 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 give 2.75 g (95%) of (3-ethoxy-4-((6-methoxypyridin-3yl)methoxy)phenyl)methanamine as a yellow oil.

Example 3-28-4: Preparation of K-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-3nitropyridin-2-amine

To a stirred solution of (3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (2.75 g, 9.54 mmol) in acetonitrile (50 ml) was added 2-chloro-5-iodine -3-nitropyridine (2.85 g, 10.01 mmol) and K,K-diisopropylethylamine (1.85 g, 14.31 mmol). The resulting yellow mixture was heated to reflux temperature. After 3 hours, the red-brown solution was allowed to cool to room temperature, resulting in the formation of a precipitate. Solids were separated by filtration and washed with water (200 ml). The wet 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 give 4.34 g (85%)

K-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-3-nitropyridin-2-amine as an orange solid.

Example 3-28-5: preparation of K ² -(3-ethoxy-4-((6-methoxypyridin-3-yl) methoxy)benzyl)-5- 87 044589 iodopyridin-2,3-diamine

To a stirred suspension of N(3-ethoxy-4-((6-methoxypyridin-3-yl) methoxy)benzyl)-5-iodo-3nitropyridin-2-amine (4.34 g, 8.09 mmol) in acetic acid ( 25 ml) iron powder (2.26 g, 40.46 mmol) was added. The reaction mixture was heated to 90°C. After 15 min. the reaction mixture became a gray-brown suspension. The mixture was allowed to cool to room temperature and diluted with ethyl acetate (200 ml). The mixture was filtered through celite with additional ethyl acetate (50 ml). The filtrate was washed with water (2x50 ml) and then 1 N. sodium hydroxide solution (3x50 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated to give 3.99 g (97%) N ² -(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodopyridin-2 ,3-diamine as a tan solid.

Example 3-28-6: Preparation of 3-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-iodo-3Nimidazo[4,5-b]pyridine

To a stirred suspension of N ² -(3-ethoxy-4-((6-methoxypyridin-3-yl) methoxy)benzyl)-5iodopyridin-2, 3-diamine (3.99 g, 7.88 mmol) in ethanol (50 ml) triethyl orthoformate (2.67 g, 18.02 mmol) and p-toluenesulfonic acid monohydrate (0.075 g, 0.39 mmol) were added. Once the mixture was heated to reflux temperature, a brown solution was obtained. After 30 minutes the mixture was allowed to cool to room temperature, resulting in the formation of a precipitate. The solids were separated by filtration, washed with ethanol and dried to give 2.50 g (61%) 3(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-iodo-3H- imidazo[4,5-b]pyridine as a tan solid.

Example 3-28-7: preparation of 3-(3-ethoxy-4-((6-methoxypyridin-3-yl) methoxy)benzyl)-6-(4methylpiperazin-1 -yl)-3 H-imidazo [4,5 -b]pyridine

To a stirred suspension of 3-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-iodo-3Himidazo[4,5-b]pyridine (0.37 g, 0.71 mmol ) in dimethyl sulfoxide, 1-methylpiperazine (0.086 g, 0.85 mmol), copper(T) 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 degassed under vacuum/N ₂ (x3) and then heated to 120°C. After 16 hours, the dark brown mixture was allowed to cool to room temperature and diluted with 5N ammonium hydroxide solution (50 ml). The mixture was extracted with dichloromethane (3x50 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 0.36 g of a brown oil. Purification chromatography (Combi-Flash, 12 g SiO ₂ , gold column, eluent: 5-10% methanol/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 0.14 g (41%) of product as orange solid: 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.228.19 (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 (sq., 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1Hbenzo[d]imidazol-5-yl)-4-methylpiperazin-2- she

1-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-4methylpiperazin-2-one was prepared from 5-iodo -1 -(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1 Hbenzo[d]imidazole (step 5, example 6) and 4-methylpiperazin-2-one using the procedure, as indicated for example 3-14: ¹ 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(5-methyl-1azabicyclo[3.2.1]oct-6-ene-7 -yl)-3H-imidazo[4,5-b]pyridine

Example 3-30-1: Preparation of tert-butyl-3-ethynyl-3-methylpiperidine-1-carboxylate

Potassium carbonate (2.76 g, 20.00 mmol) was added to a stirred solution of tert-butyl-3-formyl-3-methylpiperidine-1-carboxylate (2.10 g, 9.25 mmol) in methanol (40 mL). The mixture was treated with dimethyl 1-diazo-2-oxopropylphosphonate (2.11 g, 11.00 mmol) and the resulting mixture was allowed to stir at room temperature. After 2 h, the mixtures were 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 (eluent: 6% ethyl acetate/petroleum ether) to give 1.50 g (73%) tert-butyl 3-ethynyl3-methylpiperidine-1-carboxylate as a pale yellow oil.

Example 3-30-2: Preparation of 3-ethynyl-3-methylpiperidine hydrochloride

To a stirred solution of tert-butyl-3-ethynyl-3-methylpiperidine-1-carboxylate (0.50 g, 2.24 mmol) in dichloromethane (10 ml) was added a solution of hydrogen chloride in 1,4-dioxane (3.0 M , 5.0 ml, 15.00 mmol). The resulting solution was allowed to stir at room temperature. After 2 hours, the mixtures were concentrated to give 0.34 g (95%) of 3-ethynyl-3-methylpiperidine hydrochloride (340 mg, 95%) as a white solid.

- 88 044589

Example 3-30-3: Preparation of 3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(5-methyl-1azabicyclo[3.2.1]oct-6-ene -7-yl)-3H-imidazo[4,5-b]pyridine

To the stirred suspension of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridine (step 3, example 19, 0.20 g, 0.40 mmol) in tetrahydrofuran (3.0 ml) added 3-ethynyl-3-methylpiperidine hydrochloride (0.13 g, 1.00 mmol), bis(triphenylphosphine) palladium(P) chloride (0.055 g, 0.078 mmol), copper(T) iodide (0.030 g, 0.16 mmol) and piperidine (0.17 g, 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 filtered through celite. The filtrate was concentrated and the residue was purified by preparative HPLC to give 0.020 g (10%) of product as a yellow solid: 1H NMR (500 MHz, CDCI3) 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(5-methyl-1azabicyclo[3.2.1]oct-6-ene-7 -yl)-1H-benzo[d]imidazole

1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(5-methyl-1-azabicyclo[3.2.1]oct-6-en7-yl)-1H- Benzo[d]imidazole was prepared from 5-iodo-1 -(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)1H-benzo[d]imidazole and 3-ethynyl-3-methylpiperidine hydrochloride using the procedure specified for the synthesis of Example 3-30: ¹ H NMR (500 MHz, CDC13) 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 hidden SnCl ₃ ), 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5b]pyridin-6-yl)-1- azabicyclo[3.2.1]oct-6-en-5-ol

Example 3-32-1: Preparation of 3-ethynylpiperidin-3-ol hydrochloride

3-Ethynylpiperidin-3-ol hydrochloride was prepared from tert-butyl-3-ethynyl-3-hydroxypiperidin-1-carboxylate and hydrogen chloride using the procedure specified in Example 3-30.

Example 3-32-2: Preparation of 7-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridin-6-yl)- 1-azabiclo[3.2.1]oct-6-en-5-ol

7-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1azabicyclo[3.2.1] oct-6-en-5-ol was prepared from 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridine and 3-ethynylpiperidin-3-ol hydrochloride using the procedure specified for the synthesis of Example 3-30: 1H NMR (500 MHz, CDCl ₃ ) 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol5-yl)-1-azabicyclo[3.2. 1]oct-6-en-5-ol

7-(1-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1 H-benzo[d]imidazol-5-yl)-1 azabicyclo[3.2.1]oct- 6-en-5-ol was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-1H-benzo[d]imidazole and 3-ethynylpiperidin-3-ol hydrochloride using the procedure specified for the synthesis of Example 3-30: 1H NMR (500 MHz, CDCl ₃ ) 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 hidden CHCl ₃ ), 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-4-(1-(6-methoxypyridin-3-yl)propoxy)benzyl)-6-(1-methyl-1Hpyrazol-4-yl)-3H-imidazo[ 4,5-b]pyridin-2-amine

Example 3-34-1: Preparation of ethyl-K-({5-iodo-2-[({3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin-3-yl}carbamothioyl )carbamate

To a stirred solution of 5-iodo-K ² -(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyridine-2,3diamine (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), O-ethylcarbonisothiocyanatidate (1.07 g, 8.20 mmol) was added. The reaction mixture was allowed to stir at room temperature. After 3 hours, the mixture was filtered and the filtrate was concentrated to obtain 2.30 g of ethyl-K-({5-iodo-2-[({3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]pyridine3 -yl }carbamothioyl)carbamate as a yellow oil.

Example 3-34-2: preparation of ethyl (6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5b]pyridin-2-yl)carbamate

To a stirred solution of ethyl-K-({5-iodo-2-[({3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin-3-yl}carbamothioyl)carbamate (2, 30 g, 3.69 mmol) and triethylamine (1.30 g, 1.8 ml,

- 89 044589

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 hours, a precipitate formed. The mixture was filtered and the precipitate after filtration was washed with water (2x10 ml) and methanol (10 ml). The solids were dried to provide 1.50 g (69%) ethyl-(6-iodo-3-(3-methoxy-4((4-methoxybenzyl)oxy)benzyl)-3H-imidazo[4,5-b]pyridine -2-yl)carbamate as a brown solid.

Example 3-34-3: Preparation of ethyl-(3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1Hpyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridin-2-yl)carbamate

To a stirred solution of ethyl (6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3Himidazo[4,5-b]pyridin-2-yl)carbamate (11.80 g , 20.05 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole (5.00 g, 24.03 mmol) in To,K-dimethylformamide (100 ml) and 2 M aqueous sodium carbonate (10 ml) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium(P) dichloride (0.87 g, 1.19 mmol). The resulting mixture was heated to 80°C under a nitrogen atmosphere. After 4 hours the mixture was allowed to cool to room temperature and filtered through celite. The filtrate was diluted with water (150 ml) and extracted with ethyl acetate (3x200 ml). The combined organic phases were washed with water (300 ml) and brine (2x300 ml), dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, eluent: 5% methanol in dichloromethane) gave 2.50 g (23%) ethyl-(3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-( 1-Methyl-1Hpyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a gray solid.

Example 3-34-4: Preparation of ethyl-(3-(4-hydroxy-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3Nimidazo[4,5-b]pyridin-2 -yl)carbamate

To a stirred solution of ethyl-(3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1Hpyrazol-4-yl)-3H-imidazo[4,5-b] pyridin-2-yl)carbamate (2.50 g, 4.61 mmol) in dichloromethane (100 ml) was added trifluoroacetic acid (4.47 g, 3.0 ml, 39.18 mmol) at 0°C. The resulting mixture was allowed to stir at 0°C. After 2 h, the mixtures were treated with 2 M potassium carbonate solution to adjust the pH to ~9. The main mixture was extracted with a 1:1 methanol/dichloromethane solution (2x50 ml). The combined organic phases were washed with brine (2x50 ml), dried over sodium sulfate, filtered and concentrated to give 1.80 g (93%) ethyl-(3-(4-hydroxy-3methoxybenzyl)-6-(1-methyl-1H -pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a white solid.

Example 3-34-5: Preparation of 5-(1-chloropropyl)-2-methoxypyridine

To a stirred solution of 1-(6-methoxypyridin-3-yl)propan-1-ol (1.67 g, 9.99 mmol) in dichloromethane (30 ml) at 0°C 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 hour, the reaction was quenched by adding saturated aqueous sodium bicarbonate. The phases were separated and the organic phase was washed with brine (20 ml), dried over sodium sulfate, filtered and concentrated to give 1.50 g (81%) 5-(1-chloropropyl)-2-methoxypyridine as a yellow oil.

Example 3-34-6: Preparation of 3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)propoxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3 N-imidazo[4,5-b]pyridin-2-amine

To a stirred solution of ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.300 g, 0.710 mmol) in tetrahydrofuran (20 ml) was added a 5 M aqueous solution of sodium hydroxide (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 K,K-dimethylformamide (10 ml). The solution was treated with 5-(1-chloropropyl)-2methoxypyridine (0.263 g, 1.42 mmol) and the resulting mixture was heated to 80°C. After 3 h, the mixture was allowed to cool to room temperature and diluted with water (20 ml). The mixture was extracted with ethyl acetate (3x40 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated to give 0.2-6 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, 2.32 mmol) and heated to 100°C. After 12 hours the mixture was allowed to cool to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified by preparative HPLC to give 0.070 g (30%) product as a white solid: 1H NMR (500 MHz, DMSO- _d6 ) δ 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-3-methoxybenzyl)-6-(1methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin- 2-yl)carbamate

The following compounds were prepared from ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-(1-methyl-1H-pyrazol4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate using the procedure described in Example 3-34-6, using an appropriate alkylating agent:

Example 3-35-1: 3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazole- 90 044589

4-yl)-3H-imidazo[4,5-b]pyridin-2-amine ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 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-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)benzyl)-6-(1-methyl-1Hpyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-2-amine ^1H NMR (400 MHz, DMSO-d6) δ 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-((4-(trifluoromethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4yl)-3H-imidazo[4 ,5-b]pyridin-2-amine (RA09651030) ¹ H NMR (500 MHz, MeOD-d ₄ ) δ 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-cyclopropylpyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1-methyl-1Hpyrazol-4-yl)-3H-imidazo[4, 5-b]pyridin-2-amine (RA09677155) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 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-4-((2-methylthiazol-4-yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-4yl)-3H-imidazo[4 ,5-b]pyridin-2-amine ^1H NMR (500 MHz, DMSO-d6) δ 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-phenyl-3Nimidazo[4,5-b]pyridin-2-amine

Example 3-36-1: Preparation of ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin2-yl)carbamate

To a stirred solution of ethyl (6-iodo-3-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-3Himidazo[4,5-b]pyridin-2-yl)carbamate (Example 3-34 -2) (2.40 g, 4.08 mmol) in dichloromethane (50 ml) at 0°C was added trifluoroacetic acid (4.47 g, 3.0 ml, 39.18 mmol). The resulting mixture was allowed to stir at 0°C. After 2 h, the mixtures were treated with a 2 M potassium carbonate solution to adjust the pH to ~9. The main mixture was extracted with a 1:1 solution of methanol/dichloromethane (3x50 ml). The combined organic phases were washed with brine (50 ml), dried over sodium sulfate, filtered and concentrated to give 1.30 g (70%) ethyl (3-(4-hydroxy-3-methoxybenzyl)-6iodo-3H-imidazo[ 4,5-b]pyridin-2-yl)carbamate as a light yellow solid.

Example 3-36-2: preparation of ethyl-(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin- 2-yl)carbamate

To a stirred solution of ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5-b]pyridin-2yl)carbamate ( ) (1.30 g, 2.78 mmol) and a 5 M aqueous solution of sodium hydroxide (0.8 ml, 4.00 mmol) in N,Ndimethylformamide (10 ml) and tetrahydrofuran (10 ml) was added 5-(chloromethyl)-2-methoxypyridine (0.567 g, 3.60 mmol ). The resulting mixture was allowed to stir at room temperature. After 2 h, the mixtures were diluted with saline (40 ml) and extracted with ethyl acetate (3x40 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated to give 1.10 g (71%) ethyl-(6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)- 3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a white solid.

Example 3-36-3: preparation of ethyl-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6phenyl-3H-imidazo[4,5-b]pyridin-2 -yl)carbamate

To a stirred solution of ethyl (6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-2-yl)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) were added (1,1'bis(diphenylphosphino)ferrocene)palladium(11) dichloride (0.080 g, 0.11 mmol). The mixture was heated to 60°C in a nitrogen atmosphere. After 4 hours, the reaction mixture was allowed to cool to room temperature and filtered through celite. The filtrate was diluted with water (40 ml) and extracted with ethyl acetate (3x20 ml). The combined organic phases were washed with brine (2x20 ml), dried over sodium sulfate, filtered and concentrated. Purification of the residue by chromatography (silica gel, eluate: 2% methanol in dichloromethane) gave 0.100 g (40%) ethyl-(3-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-6- phenyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a white solid.

Example 3-36-4: preparation of 3-(3-methoxy-4-((6-methoxypyridin-3-yl) methoxy)benzyl)-6-phenyl-3H- 91 044589 imidazo[4,5-b]pyridin- 2-amine

To a stirred solution of ethyl (3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6phenyl-3H-imidazo[4,5-b]pyridin-2-yl)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°C. After 48 h, the mixture was allowed to cool to room temperature and diluted with water (30 ml). The mixture was extracted with dichloromethane (3x10 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give 0.027 g (34%) of product as a yellow solid: 1H NMR (500 MHz, CDCl ₃ ) δ 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-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin- 2-yl)carbamate

The following compounds were prepared from ethyl (6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate by modifying the procedure described in Example 3-36-3 by using an appropriate boronic acid/boronate ester coupling partner. For these compounds, reactions were carried out under microwave conditions (140°C for 1.5 h). Under these conditions, both the Suzuki coupling reaction and carbamate hydrolysis were performed in one step.

Example 3-37-1: 6-(4-fluorophenyl)-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridin-2 -amine ¹ H NMR (500 MHz, DMSO-d6) δ 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1-methyl-1H-pyrazol-3yl)-3H-imidazo [4,5-b]pyridin-2-amine (RA09936946)

1H NMR (500 MHz, CDCl ₃ ) δ 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(pyrimidin-5-yl)-3Nimidazo[4,5-b]pyridine -2-amine (RA09943893)

1H NMR (500 MHz, DMSO-d6) δ 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.

Example 3-37-4: 3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1,3,5-trimethyl-1Hpyrazol-4-yl)-3H -imidazo[4,5-b]pyridin-2-amine

1H NMR (500 MHz, CDCl ₃ ) δ 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 (ush .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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(pyridin-4-yl)-3Nimidazo[4,5-b]pyridine -2-amine

1H NMR (500 MHz, DMSO-d ₆ ) δ 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(pyridin-3-yl)-3Nimidazo[4,5-b]pyridine -2-amine

1H NMR (500 MHz, DMSO-d ₆ ) δ 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-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(pyridin-2-yl)3H-imidazo[4,5-b]pyridine -2-amine

To a stirred solution of ethyl (6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-2-yl)carbamate (0.250 g, 0.42 mmol), 2-(tributylstannyl)pyridine (0.235 g, 0.63 mmol), copper(T) iodide (0.040 g, 0.21 mmol) and triethylamine (0.130 g, 1.26 mmol ) in N,Ndimethylformamide (5 ml) was added bis(triphenylphosphine)palladium(P) dichloride (0.018 g, 0.042 mmol). The mixture was irradiated in a microwave reactor at 140°C. After 1.5 hours the mixture was allowed to cool to room temperature and filtered through celite. The filtrate was concentrated. The residue was purified by preparative HPLC to give 0.025 g (13%) of product as a white solid: 1H NMR (500 MHz, DMSO-d ₆ ) δ 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

- 92 044589 (s, 3H), 3.70 (s, 3H) ppm; (M+1)=469.

Example 3-39: Synthesis of 3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol4-yl)-3H-imidazo[4,5 -b]pyridin-2-amine

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 hours the mixture was concentrated. Purification of the residue by chromatography (silica gel, eluent: 10% ethyl acetate in petroleum ether) gave 0.400 g (40%) of 4-(perfluoroethyl)benzyl-4methylbenzenesulfonate as a yellow oil.

Example 3-39-2: Preparation of ethyl-(6-iodo-3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-3Nimidazo[4,5-b]pyridine-2- yl)carbamate

To a stirred solution of ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5b]pyridin-2-yl)carbamate (example 3-36-1) (0.24 g , 0.52 mmol) in tetrahydrofuran (20 ml), a 5 M aqueous solution of sodium hydroxide (0.2 ml, 1.00 mmol) was added. 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-4methylbenzenesulfonate (0.40 g, 1.04 mmol) and the mixture was heated to 80°C. After 3 h, the mixture was allowed to cool to room temperature and diluted with water (20 ml). The mixture was extracted with ethyl acetate (3x40 ml) and the combined organic phases were dried over sodium sulfate, filtered and concentrated to give 0.090 g ethyl-(6-iodo-3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy) benzyl)3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a brown solid.

Example 3-39-3: Preparation of 3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-6-(1-methyl-1Hpyrazol-4-yl)-3H-imidazo[4 ,5-b]pyridin-2-amine

To a stirred solution of ethyl (6-iodo-3-(3-methoxy-4-((4-(perfluoroethyl)benzyl)oxy)benzyl)-3Nimidazo[4,5-b]pyridin-2-yl)carbamate (0.090 g, 0.13 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole (0.054 g, 0.26 mmol) in N ,N-dimethylformamide (3 ml) and 2 M aqueous sodium carbonate (150 μl) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium(P) dichloride (0.050 g, 0.06 mmol). The resulting mixture was heated to 80°C under a nitrogen atmosphere. After 4 hours the mixture was allowed to cool to room temperature and filtered through celite. The filtrate was diluted with water (10 ml) and extracted with ethyl acetate (3x20 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give 0.010 g (14%) of product as a white solid: 1H NMR (400 MHz, DMSO- _d5 ) δ 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-3-methoxybenzyl)-6-iodo3H-imidazo[4,5-b]pyridin-2-yl)carbamate

The following compounds were prepared from ethyl (3-(4-hydroxy-3-methoxybenzyl)-6-iodo-3H-imidazo[4,5b]pyridin-2-yl)carbamate using the procedures described in Example 3-39-2 and Example 3-39-3, by using an appropriate alkylating agent.

Example 3-40-1: 3-(3-methoxy-4-((4-(trifluoromethoxy)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4yl)-3H-imidazo[4, 5-b]pyridin-2-amine (RA10502607) ¹ H NMR (500 MHz, DMSO-d6) δ 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-((4-((trifluoromethyl)thio)benzyl)oxy)benzyl)-6-(1-methyl-1Hpyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-2-amine

1H NMR (400 MHz, CDCU) 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 ₂ protons were not observed); (M+1)=541.

Example 3 -40-3: 3-(4-((6-Isopropylpyridin-3-yl)methoxy)-3 -methoxybenzyl)-6-(1 -methyl-1Hpyrazol-4-yl)-3H-imidazo[4, 5-b]pyridin-2-amine

1H NMR (400 MHz, CDCl ₃ ) 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, 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-((4-(2,2,2-trifluoroethyl)benzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol4-yl)- 3H-imidazo[4,5-b]pyridin-2-amine

1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 2H), 8.48 (s, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.427.40 (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 (sq., J=9.6 Hz, 2H) ppm; (M+1)=523.

- 93 044589

Example 3 -40-5: 3 -(3 -Methoxy-4-((2-(trifluoromethyl)thiazol-4-yl)methoxy)benzyl)-6-(1 -methyl-1Hpyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-2-amine

1H NMR (400 MHz, DMSO-d6) 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-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2-amine

Example 3-41-1: Preparation of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridin-2-amine

To a stirred solution of ethyl (6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-2-yl)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°C. After 12 h, the mixture was allowed to cool to room temperature and diluted with saline (40 ml). The mixture was extracted with ethyl acetate (3x40 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the residue by chromatography (silica gel, eluent: 3% methanol in dichloromethane) gave 0.206 g (56%) 6-iodo-3-(3methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H -imidazo[4,5-b]pyridin-2-amine as a yellow solid.

Example 3-41-2: Preparation of b-(cyclohexylethynyl)-3-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-2- amine

To a stirred suspension of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Himidazo[4,5-b]pyridin-2-amine (0.14 g, 0.27 mmol), ethylnylcyclohexane (0.044 g, 0.41 mmol) in piperidine (3 ml), bis(triphenylphosphine) palladium(II) dichloride (0.038 g, 0.054 mmol) and copper(1) iodide (0.021 g, 0 .11 mmol). The mixture was irradiated in a microwave reactor at 60°C. After 30 minutes, the reaction mixture was allowed to cool to room temperature and filtered through celite. The filtrate was concentrated and the residue was purified by preparative HPLC to give 0.032 g (23%) product as a white solid: 1H NMR (500 MHz, DMSO- _d6 ) δ 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-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3Nimidazo[4,5-b]pyridin-6-yl )but-3-yn-1-ol

This compound was prepared from 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)3H-imidazo[4,5-b]pyridin-2-amine and but-3 -in-1-ol using the procedure described in Example 3-412: 1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.93 (s, 1H), 7.74 ( dd, J=8.5, 2.0 Hz, 1H), 7.41 (s, 1H), 7.086.97 (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-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-6-(1methyl-1H-pyrazol-4-yl)-3H-imidazo[4, 5-b]pyridin-2-amine

Example 3-43-1: Preparation of cyclopropyl(6-methoxypyridin-3-yl)methanol

A 2.6 M solution of n-butyllithium in hexane (8.4 ml, 21.84 mmol). The mixture was stirred at -78°C for 30 minutes and then cyclopropanecarboxaldehyde (1.70 g, 23.74 mmol) was added in one part. The cooling bath was removed and the mixture was allowed to warm to room temperature. After 2 h, the mixtures were quenched by adding saturated aqueous ammonium chloride (100 ml). The resulting mixture was extracted with ethyl acetate (3x100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the residue by chromatography (silica gel, eluent: 20% ethyl acetate in petroleum ether) gave 2.90 g (80%) cyclopropyl(6-methoxypyridin-3-yl)methanol as a yellow oil.

Example 3-43-2: Preparation of 4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzonitrile

To a stirred solution of cyclopropyl(6-methoxypyridin-3-yl)methanol (3.80 g, 21.20 mmol), 4hydroxy-3-methoxybenzonitrile (1.60 g, 10.73 mmol) and triphenylphosphine (5.60 g, 21.35 mmol) in tetrahydrofuran (10 ml) at 0°C, diethyl azodicarboxylate (3.70 g, 21.25 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature. After 2 hours the mixture was concentrated. Purification of the residue by chromatography (silica gel, eluent: 10% ethyl acetate in petroleum ether) gave 2.70 g (80%) of 4-(cyclopropyl(6-methoxypyridin-3yl)methoxy)-3-methoxybenzonitrile as a light yellow oil.

Example 3-43-3: Preparation of (4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine

To a stirred solution of 4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3methoxybenzonitrile (2.50 g, 8.06 mmol) in ethanol (20 ml) at 0° C.

- 94 044589 parts cobalt(II) chloride hexahydrate (2.20 g, 9.25 mmol). The resulting mixture was allowed to stir at 0°C. After 30 minutes 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 filtered through celite and the filter cake was washed with ethanol (20 ml). The filtrate was concentrated to give 2.50 g (99%) of (4-(cyclopropyl(6-methoxypyridin-3yl)methoxy)-3-methoxyphenyl)methanamine as a colorless oil.

Example 3-43-4: Preparation of N-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)5-iodo-3-nitropyridin-2-amine

To a stirred solution of (4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3methoxyphenyl)methanamine (2.50 g, 7.95 mmol) and potassium carbonate (1.41 g, 10.20 mmol) in acetonitrile (10 ml) 2-chloro-5-iodo-3-nitropyridine (2.90 g, 10.20 mmol) was added. The resulting mixture was heated to 80°C. After 2 hours, the mixture was filtered and the filtrate was concentrated. Purification of the residue by chromatography (silica gel, eluent: 20% ethyl acetate in petroleum ether) gave 2.60 g (58%) N-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)- 5-iodo-3-nitropyridine-2amine as a yellow oil.

Example 3-43-5: Preparation of N(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)5-(1-methyl-1H-pyrazol-4-yl)-3-nitropyridine -2-amine

To a stirred solution of N(4-(cyclopropyl (6-methoxypyridin-3-yl)methoxy)-3methoxybenzyl)-5-iodo-3-nitropyridin-2-amine (2.20 g, 3.91 mmol), 1-methyl -4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-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), (1,1'-bis(diphenylphosphino)ferrocene)palladium(11) dichloride (0.143 g, 0.20 mmol) was added. The resulting mixture was heated to 100°C and stirred under a nitrogen atmosphere. After 16 hours, the mixture was allowed to cool to room temperature and diluted with water (15 ml). The mixture was extracted with ethyl acetate (2x60 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the residue by chromatography (silica gel, eluent: 33% ethyl acetate in petroleum ether) gave 1.10 g (55%) Na(4-(cyclopropyl(6methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5-( 1-methyl-1H-pyrazol-4-yl)-3-nitropyridin-2-amine as a light brown solid.

Example 3-43-6: Preparation of N ² -(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)5-(1 -methyl-1 H-pyrazol-4-yl)pyridin- 2,3-diamine

To a stirred solution of N(4-(cyclopropyl (6-methoxypyridin-3-yl)methoxy)-3methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)-3-nitropyridin-2-amine (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°C. After 2 hours the mixture was allowed to cool to room temperature and filtered through celite. The filtrate was concentrated. Chromatographic purification of the residue (neutral alumina, eluent: 2% methanol in dichloromethane) gave 0.984 g (95%) N ² -(4(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5 - (1-methyl-1H-pyrazol-4-yl)pyridin2,3-diamine as a brown solid.

Example 3-43-7: Preparation of ethyl-(3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H -imidazo[4,5-b]pyridin-2-yl)carbamate

To a stirred solution of N ² -(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)-5(1-methyl-1H-pyrazol-4-yl)pyridin-2,3-diamine ( 0.55 g, 1.13 mmol) in tetrahydrofuran (5 ml) was added triethylamine (0.799 g, 7.90 mmol). The resulting mixture was allowed to stir at room temperature. After 15 minutes, 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 minutes, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (5 ml) and 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 hours, the mixtures were concentrated. Purification of the residue by chromatography (neutral alumina, eluent: 50% ethyl acetate in petroleum ether) gave 0.45 g (68%) ethyl-(3-(4(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3- methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3Nimidazo[4,5-b]pyridin-2-yl)carbamate as a brown oil.

Example 3-43-8: Preparation of 3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3-methoxybenzyl)6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo [4,5-b]pyridin-2-amine

To a stirred solution of ethyl-(3-(4-(cyclopropyl(6-methoxypyridin-3-yl)methoxy)-3methoxybenzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4, 5-b]pyridin-2-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°C. After 16 hours, the mixture was allowed to cool to room temperature and diluted with water (15 ml). The mixture was extracted with ethyl acetate (2x60 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give 0.058 g (15%) of product as a white solid: 1H NMR (500 MHz, CDC13)

- 95 044589 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-4-((3-methoxy-5,6,7,8-tetrahydroisoquinolin-8-yl)oxy)benzyl)-6(1-methyl-1H-pyrazol- 4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Example 3-44-1: Preparation of 3-methoxy-5,6,7,8-tetrahydroisoquinolin-8-ol

Sodium borohydride (1.10 g, 29.08 mmol). The resulting mixture was allowed to warm to room temperature. After 2 h, the mixtures were quenched with water (20 ml) and extracted with ethyl acetate (3x100 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the residue by chromatography (silica gel, eluent: 50% ethyl acetate in petroleum ether) provided 1.60 g (85%) of 3-methoxy-5,6,7,8-tetrahydroisoquinolin-8-ol as a light yellow solid .

Example 3-44-2: Preparation of 3-(3-methoxy-4-((3-methoxy-5,6,7,8-tetrahydroisoquinolin-8yl)oxy)benzyl)-6-(1-methyl-1H-pyrazole -4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

This compound was prepared from 3-methoxy-5,6,7,8-tetrahydroisoquinolin-8-ol using the procedures outlined in Examples 3-43-2 through Example 3-43-8: 1H NMR (400 MHz, CDCl ₃ ) 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-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-5-(1-methyl1H-pyrazol-4-yl)- 1 H-benzo[d]imidazol-2-amine

Example 3-45-1: Preparation of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one

To a stirred suspension of 1-(4-hydroxy-3-methoxyphenyl)ethan-1-one (3.96 g, 23.82 mmol) and potassium carbonate (13.17 g, 95.29 mmol) in acetonitrile (75 ml) 5-(chloromethyl)-2-methoxypyridine hydrochloride (4.85 g, 25.01 mmol) was added. After 2 h, the mixtures were diluted with water (150 ml) and extracted with dichloromethane (3x100 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give a yellow oil. Trituration of the crude material with hexanes gave 5.48 g (85%) of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one as a white solid.

Example 3-45-2: Preparation of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-onoxime

To a stirred suspension of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one (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 temperature. After 64 h, the mixture was allowed to cool to room temperature and diluted with water (250 ml). The resulting suspension was filtered and the filter cake was washed with water (50 ml) and dried to obtain 5.55 g (96%) of 1-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)phenyl)ethane- 1-Onoxime as a white solid.

Example 3-45-3: Preparation of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-amine

Zinc dust was added to a stirred solution of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethane-1one oxime (5.55 g, 18.36 mmol) in acetic acid (40 ml). (6.00 g, 91.79 mmol). The resulting mixture was heated to 65°C. After 1 hour, the mixture was allowed to cool to room temperature and filtered through celite. The precipitate after filtration was washed with methanol (100 ml). The filtrate was concentrated and the residue was dissolved in 5 N. ammonium hydroxide solution (75 ml). The mixture was extracted with chloroform (2x50 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 4.56 g (86%) of 1-(3-methoxy-4-((6-methoxypyridin3-yl)methoxy)phenyl)ethan-1-amine as yellow oils

Example 3-45-4: Preparation of 4-iodo-K-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)2-nitroaniline

To a stirred solution of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-amine (1.93 g, 6.68 mmol) and potassium carbonate (3.70 g , 26.75 mmol) in acetonitrile (75 ml) was added 1-fluoro-4iodo-2-nitrobenzene (2.14 g, 8.02 mmol). The mixture was heated to reflux temperature. After 16 hours, the orange mixture was allowed to cool to room temperature and diluted with water (150 ml). The mixture was extracted with dichloromethane (3x75 ml) and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 3.82 g of an orange solid. Trituration of the crude material with hexanes gave 3.17 g (89%) of 4-iodo-K-(1-(3-methoxy-4-((6methoxypyridin-3-yl)methoxy)phenyl)ethyl)-2-nitroaniline as bright orange solid.

Example 3-45-5: Preparation of 4-iodo-K ¹ -(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)benzene-1,2-diamine

To a stirred suspension of 4-iodo-K-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-2nitroaniline (3.17 g, 5.92 mmol) and chloride ammonium (2.53 g, 47.37 mmol) in tetrahydrofuran mixture

- 96 044589 (50 ml)/methanol (20 ml)/water (10 ml) added iron(II) sulfate heptahydrate (5.76 g, 20.73 mmol) and zinc dust (1.35 g, 20.73 mmol ). The resulting mixture was heated to reflux temperature. After 1 hour, the mixture was allowed to cool to room temperature and filtered through celite. The precipitate after filtration was washed with methanol (50 ml). The filtrate was concentrated and the residue was diluted with 3 N. ammonium hydroxide solution (100 ml). The main mixture was extracted with chloroform (3x50 ml) and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 2.02 g (68%) 4-iodo-K1-(1-(3-methoxy-4-((6- methoxypyridin-3yl)methoxy)phenyl)ethyl)benzene-1,2-diamine as a brown solid.

Example 3-45-6: Preparation of 5-iodo-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)1 H-benzo[d]imidazole-2 -amine

To a stirred solution of 4-iodo-K ¹ -(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)benzene-1,2-diamine (2.02 g, 4 .00 mmol) in a mixture of dichloromethane (20 ml)/methanol (10 ml) was added a solution of cyanogen bromide (5.0 M in acetonitrile, 4.0 ml, 20.00 mmol). The resulting dark brown solution was allowed to stir at room temperature. After 17 hours, the mixtures were diluted with 1 N. sodium hydroxide solution (20 ml) and stirring was provided for the main mixture. After 30 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 give 3.36 g of a brown oil. Purification of the residue by chromatography (CombiFlash, 120 g SiO ₂ , gold column, eluent: 1-5% methanol in dichloromethane) gave a brown semi-solid. Trituration of this material with a 1:1 mixture of diethyl ether/dichloromethane gave 0.801 g (38%) 5-iodo-1-(1-(3methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)- 1H-benzo[d]imidazol-2-amine as a tan solid.

Example 3-45-7: Preparation of 1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-5-(1methyl-1H-pyrazol-4-yl) -SH-benzo[d]imidazol-2-amine

To a stirred mixture of 5-iodo-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1Hbenzo[d]imidazol-2-amine (0.267 g, 0 .50 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazole (0.138 g, 0.63 mmol), tricyclohexylphosphine (0.014 g , 0.050 mmol), tribasic potassium phosphate (0.381 g, 1.76 mmol) in 1,4-dioxane (3 ml) and water (1 ml), palladium(II) acetate (0.005 g, 0.025 mmol) was added. The mixture was heated to 125°C in a microwave reactor. After 30 minutes, additional portions of catalyst (0.005 g) and ligand (0.014 g) were added and the mixture was reheated in the microwave reactor to 150°C. After 60 min. reaction time, the crude mixture was transferred to a 20 mL microwave-resistant reaction tube and treated with 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°C in a microwave reactor. Overall after 105 min. the reaction was completed. The mixture was diluted with water (30 ml) and extracted with dichloromethane (3x25 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 419 mg of a brown oil. Chromatographic purification (CombiFlash, 12 g SiO2, gold column, eluent: 1-5% methanol/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 109 mg of a tan solid with impurities. A second chromatographic purification (CombiFlash, 12 g SiO2, gold column, eluent: 1-5% methanol/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 0.063 g (26%) of product as a yellow solid substances: 1H NMR (400 MHz, CDCl ₃ ) 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), 7.207.16 (m, 1H ), 7.11-7.06 (m, 1H), 6.96-6.87 (m, 2H), 6.80-6.73 (m, 2H), 5.55 (sq., 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-(1-(3-methoxy-4-((6-methoxypyridin-3yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole-2 -amine

To a stirred solution of 5-iodo-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-2-amine (example 3 -45-6) (0.195 g, 0.37 mmol), 4-fluorophenylboronic acid (0.064 g, 0.46 mmol) and tribasic potassium phosphate (0.413 g, 1.91 mmol) in tetrahydrofuran (5 ml)/water (4 ml) the ^2nd generation XPhos catalyst precursor (0.015 g, 0.018 mmol) was added. The yellow solution was degassed under vacuum/nitrogen (x3). The mixture was heated to 60°C. After 90 minutes, the mixture was treated with additional boronic acid (0.030 g) and catalyst precursor (0.014 g) and the temperature was raised to 75°C. After a total reaction time of 150 min. the brown mixture was allowed to cool to room temperature and diluted with water (30 ml). The mixture was extracted with dichloromethane (3x25 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 0.282 g of a brown oil. Chromatographic purification (CombiFlash, 12 g SiO ₂ , gold column, eluent: 1-5% methanol/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 0.142 g (78%) of product as a yellow solid: 1H NMR (400 MHz, CDCl ₃ ) 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),

- 97 044589

5.58 (sq., 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-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-1H-benzo[d] imidazole

Example 3-47-1: Preparation of 5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole

To a stirred solution of 4-iodo-K1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)benzene-1,2-diamine [obtained from 5-(chloromethyl )-2-(trifluoromethyl)pyridine using the procedures described in examples from example 3-45-1 to example 3-45-5] (1.04 g, 1.91 mmol) in ethanol (30 ml) was added triethylorthoformate ( 1.0 ml, 5.89 mmol) and p-toluenesulfonic acid monohydrate (0.025 g, 0.13 mmol). The yellow solution was heated to reflux temperature. After 3 0 min. the mixture was allowed to cool to room temperature and concentrated to give a yellow oil. Chromatographic purification (CombiFlash, 24 g SiO ₂ , gold column, eluent: 1-5% methanol/dichloromethane) gave 0.803 g (76%) 5-iodo-1-(1-(3-methoxy-4-(( 6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole as a yellow solid.

Example 3-47-2: Preparation of 5-(4-fluorophenyl)-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-1H-benzo[ d]imidazole

To a stirred solution of 5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole (0.248 g, 0. 45 mmol), (4-fluorophenyl)boronic acid (0.088 g, 0.63 mmol) and tribasic potassium phosphate (0.485 g, 2.24 mmol) in a mixture of tetrahydrofuran (7 ml)/water (5 ml) XPhos catalyst precursor was added ^2nd generation (0.024 g, 0.031 mmol). The yellow solution was degassed under vacuum/nitrogen (x3). The mixture was heated to 75°C. 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 (2x25 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 0.271 g of a brown oil. Purification by chromatography (CombiFlash, 12 g SiO ₂ , gold column, eluent: 1-5% methanol/dichloromethane) gave 0.200 g (86%) of product as an off-white solid: 1H NMR (400 MHz, CDCl ₃ ) 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), 7.617.52 (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 (sq., 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-(1-(3-methoxy-4-((6(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d] imidazole

The following compounds were prepared from 5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole using the procedure described in Example 3-47-2, by using the appropriate boronate ester coupling partner.

Example 3-48-1: 1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-5-(1methyl-1H-pyrazole-4 -yl)-1 H-benzo[d]imidazole

1H NMR (400 MHz, CDCl ₃ ) 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 (sq., 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-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1Hbenzo[d]imidazole-5 - yl)but-3-in-1-ol

To a stirred mixture of 5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole (0.210 g, 0.38 mmol), 3-butyn-1-ol (0.041 g, 0.57 mmol), copper(T) iodide (0.019 g, 0.10 mmol) in piperidine (4 ml), bis(triphenylphosphine) palladium ( P) chloride (0.037 g, 0.053 mmol). The mixture was heated to 100°C in a microwave reactor. After 30 min, the reaction mixture was allowed to cool to room temperature and diluted with 5 N. ammonium hydroxide solution (30 ml). The mixture was extracted with dichloromethane (3x25 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 0.386 g of a brown solid. Chromatographic purification (CombiFlash, 12 g SiO2, gold column, eluent: 15% methanol/dichloromethane) gave 0.157 g (84%) of the product as a light yellow solid: 1H NMR (400 MHz, CDCl ₃ ) 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), 7.727 .68 (m, 1H), 7.28-7.23 (m, 1H), 7.13-7.08 (m, 1H), 6.87-6.82 (m, 1H), 6.76 -6.64 (m, 2H), 5.55 (sq., 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-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl-1Hpyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-2-amine

Example 3-49-1: preparation of 5-iodo-K-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3-98 044589 nitropyridin-2-amine

To a stirred solution of 1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethanamine [prepared from 1-(chloromethyl)-4-(trifluoromethyl)benzene using the procedures described in the examples from the example 3-45-1 from example 3-45-3] (2.52 g, 7.75 mmol) and N,N-diisopropylethylamine (2.7 ml, 15.18 mmol) in acetonitrile (30 ml) was added 2- chloro-5-iodo-3-nitropyridine (2.39 g, 8.13 mmol). The orange solution was heated to reflux temperature. After 15 h, the brown reaction mixture was allowed to cool to room temperature and was diluted with water (60 ml). As soon as the mixture was stirred, a yellow precipitate formed. The solids were separated by filtration, and washed with water (50 ml), and dried to give 4.19 g (94%) 5-iodo-K-(1-(3-methoxy-4-((4(trifluoromethyl)benzyl )oxy)phenyl)ethyl)-3-nitropyridin-2-amine as a yellow solid.

Example 3-49-2: Preparation of 5-iodo-K ² -(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)pyridine-2,3-diamine

To a stirred mixture of 5-iodo-K-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3nitropyridin-2-amine (4.19 g, 7.31 mmol ) and ammonium chloride (3.14 g, 58.47 mmol) in a mixture of 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°C. As the mixture was heated, an olive green color developed. After 5 min. the warm reaction mixture was filtered through celite using ethyl acetate (100 ml). The filtrate was diluted with 5 N. ammonium hydroxide solution (30 ml) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2x50 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 3.72 g of a brown oil. Chromatographic purification (CombiFlash, 120 g SiO ₂ , gold column, eluate: 30-60% ethyl acetate/heptane) gave 2.39 g (60%) 5-iodo-K ² -(1-(3-methoxy-4 -((4(trifluoromethyl)benzyl)oxy)phenyl)ethyl)pyridine-2,3-diamine as an off-white solid.

Example 3-49-3: Preparation of ethyl-(6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5 -b]pyridin-2-yl)carbamate

To a stirred solution of 5-iodo-K ² -(1-(3-methoxy-4-((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), ethoxycarbonyl isothiocyanate (0.64 ml, 5.28 mmol) was added. After 3 hours, the mixtures were diluted with saline (100 ml) and extracted with ethyl acetate (3x50 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 3.16 g of a brown foamy solid. The crude solid was dissolved in tetrahydrofuran (30 ml) and 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 hours, 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 (3x50 ml). The combined organic phases were washed with saturated potassium carbonate solution (50 ml), dried over magnesium sulfate, filtered and concentrated to give 3.62 g of a brown oil. Purification chromatography (CombiFlash, 80 g SiO ₂ , gold column, 10-30% ethyl acetate/heptane) gave a tan solid. Trituration of this material with diethyl ether (50 ml) gave 1.30 g (46%) ethyl (6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl) ethyl)-3H-imidazo[4,5-b]pyridin-2yl)carbamate as a white solid.

Example 3-49-4: Preparation of 6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3Nimidazo[4,5-b]pyridin- 2-amine

To a stirred solution of ethyl-(6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)3H-imidazo[4,5-b]pyridine-2 -yl) carbamate (1.30 g, 2.03 mmol), tribasic potassium phosphate (1.76 g, 8.12 mmol) was added to ethanol (8 ml)/water (6 ml). The mixture was heated to 160°C in a microwave reactor. After 1 hour, the reaction mixture was diluted with water (100 ml), resulting in a precipitate. The solids were separated by filtration, washed with water (25 ml) and dried to give 1.02 g (88%) 6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl) oxy)phenyl)ethyl)-3H-imidazo[4,5b]pyridin-2-amine in the form of a white solid.

Example 3-49-5: Preparation of 3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1methyl-1H-pyrazol-4-yl)- 3H-imidazo[4,5-b]pyridin-2-amine

To a stirred mixture of 6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3Nimidazo[4,5-b]pyridin-2-amine (0.253 g, 0.45 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole (0.158 g, 0.76 mmol), tribasic Potassium phosphate (0.495 g, 2.29 mmol) in a mixture of tetrahydrofuran (5 ml)/water (4 ml) was added to the ^2nd generation XPhos catalyst precursor (0.032 g, 0.041 mmol). The yellow solution was degassed under vacuum/nitrogen (x3). The mixture was heated to 75°C. After 4 hours, the mixture was allowed to cool to room temperature and diluted with water (40 ml). The mixture was extracted with ethyl acetate (3x25 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 0.320 g of a brown oil. Chromatographic purification (CombiFlash, 12 g SiO ₂ , gold column, eluent: 1-5% methane-99 044589 laa/dichloromethane to 2 M ammonia in methanol/dichloromethane) gave 0.178 g (77%) of the product as a tan-colored solid: ¹ H NMR (400 MHz, CDCl ₃ ) 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 (sq.,

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 3-49-6a and Example 3-49-6b: Chiral resolution of 3-(1-(3-methoxy-4-((4(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl- 1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

Racemic 3-(1 -(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazol-4yl)-3H-imidazo[4, 5-b]pyridin-2-amine was subjected to chiral resolution using SFC (21x250 mm, AS column, 25% methanol/0.5% diethylamine, flow rate 50 g/min) to obtain two enantiomers. The absolute configuration has not been defined.

Figure 2. example 3 49 6a Figure 3: example 3-49-6b

Example 3-50: Synthesis of additional compounds from 6-iodo-3-(1-(3-methoxy-4-((4(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b] pyridine-2-amine

The following compounds were prepared from 6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2- amine using the procedure described in Example 3-49-5 by using the appropriate boronate ester coupling partner.

Example 3-50-1: 2-(4-(2-amino-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3Nimidazo[4,5 -b]pyridin-6-yl)-1 H-pyrazol-1 -yl)ethan-1-ol (RA10074277) ¹ H NMR (400 MHz, CDCl ₃ ) 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), 7.687.61 (m, 3H), 7.58-7 .53 (m, 2H), 6.96-6.92 (m, 1H), 6.89-6.84 (m, 2H), 6.11 (sq., 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-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-6-(1H-pyrazol-4-yl)3H-imidazo[ 4,5-b]pyridin-2-amine (RA10161874) ¹ H NMR (400 MHz, DMSO-d ₆ ) 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), 7.07-6.92 (m, 4H), 5, bb (kv, 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-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)-6(1-methyl-1H-nirazol-4- yl)-3H-imidazo[4,5-b]pyridin-2-amine

Example 3-51-1: Preparation of 3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)benzonitrile

To a stirred solution of (6-(trifluoromethyl)pyridin-3-yl) methanol (2.70 g, 15.25 mmol) in dimethyl sulfoxide (25 ml) was added sodium hydride with a 60% dispersion (0.639 g, 15.98 mmol; at addition, gas evolution and a slight exothermic effect were observed). After 30 minutes, the dark brown reaction mixture was treated with 4-fluoro-3-methoxybenzonitrile (2.24 g, 14.52 mmol) and allowed to stir. 45 minutes after addition, the orange-brown mixture was diluted with water (150 ml) and extracted with ethyl acetate (3x50 ml). The combined organic phases were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated to give 4.50 g of an orange solid. Chromatographic purification (CombiFlash, 120 g SiO ₂ , gold column, eluent: 10-25% ethyl acetate/heptane) gave 1.93 g (43%) 3-methoxy-4-((6(trifluoromethyl)pyridine-3- yl)methoxy)benzonitrile as an off-white solid.

Example 3-51-2: preparation of 1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propane- 100 044589

1-she

A solution of bromoethylmagnesium was added to a stirred solution of 3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)benzonitrile (1.69 g, 5.48 mmol) in tetrahydrofuran (15 ml) at 0°C (1.0 M in tetrahydrofuran, 7.0 ml, 7.00 mmol), followed by copper(T) iodide (0.010 g, 0.055 mmol). The resulting red-brown mixture was allowed to warm to room temperature and stirred. After 16 hours, the mixtures were treated with 1 N. hydrochloric acid solution (25 ml) and provided stirring. After 30 min, the mixture was adjusted to pH ~ 7 with saturated potassium carbonate solution (20 ml) and extracted with ethyl acetate (3x30 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 1.86 g of a brown oil. Chromatographic purification (CombiFlash, 40 g SiO ₂ column, eluent: 25-50% ethyl acetate/heptane) gave 1.44 g (77%) 1-(3-methoxy-4-((6-(trifluoromethyl)pyridinium- 3yl)methoxy)phenyl)propan-1-one as an off-white solid.

Example 3-51-3: Preparation of 5-iodo-K-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)propyl)-3-nitropyridin-2-amine

This compound was prepared from 1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)propan-1-one using the procedures described in Example 3-45-2 via Example 3-45 -4. Example 3-51-4: Preparation of 5-iodo-K ² -(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)propyl)pyridine-2,3-diamine

To a stirred suspension of 5-iodo-K-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)propyl)-3-nitropyridin-2-amine (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°C. As it was heated, the yellow color faded and a gray suspension formed. In 10 minutes. the mixture was allowed to cool to room temperature and diluted with ethyl acetate (75 ml). The suspension was filtered through celite using ethyl acetate (50 ml). The filtrate was washed with water (2x30 ml) and then with concentrated ammonium hydroxide solution (2x30 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated to give 1.20 g (>100%) 5-iodo-K ² -(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy )phenyl)propyl)pyridine-2,3-diamine as a brown oil.

Example 3-51-5: Preparation of 3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)propyl)-6-(1-methyl-1H-pyrazole -4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

This compound was prepared from 5-iodo-K ² -(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)propyl)pyridine-2,3-diamine using the procedures described in examples from example 3-49-3 to example 3-49-5: 1H NMR (400 MHz, CDCL3) 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-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-6-(1methyl-1H-pyrazole-4 - yl)-3 H-imidazo[4,5-b]pyridine

Example 3-52-1: Preparation of 6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5- b]pyridine

To a stirred solution of 5-iodo-K ² -(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)pyridine-2,3-diamine [obtained from 5-( 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 30 min. the mixture was allowed to cool to room temperature and concentrated. The residue was partitioned between ethyl acetate (50 ml) and saturated potassium carbonate solution (50 ml). The phases were separated and the organic phase was dried over magnesium sulfate, filtered and concentrated to give 0.739 g (>100%) 6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl )methoxy)phenyl)ethyl)-3H-imidazo[4,5b]pyridine as an orange solid.

Example 3-52-2: Preparation of 3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-6(1-methyl-1H-pyrazol- 4-yl)-3H-imidazo[4,5-b]pyridine

This compound was prepared from 6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridine at using the procedure described in example 3-49-5:

1H NMR (400 MHz, CDCl ₃ ) δ 8.78 (s, 1H), 8.55 (d, J=1.9 Hz, 1H), 8.15-7.93 (m, 3H), 7, 79 (s, 1H), 7.747.62 (m, 2H), 6.97-6.83 (m, 3H), 5.99 (kv, 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-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-6-(1methyl-1H-pyrazol-4-yl) )-3H-imidazo[4,5-b]pyridin-2-amine

Example 3-53-1: Preparation of ethyl-(6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-3H-imidazo[4 ,5-b]pyridin-2-yl)carbamate

To a stirred solution of 5-iodo-K ² -(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)pyridine-2,3-diamine [obtained from 5-( chloromethyl)-2-(trifluoromethyl)pyridine

- 101 044589 using the procedures described in examples from example 3-45-1 to example 3-45-5] (1.66 g, 3.05 mmol) and triethylamine (0.64 ml, 4.57 mmol) in tetrahydrofuran (30 ml) ethoxycarbonyl isothiocyanate (0.44 ml, 3.66 mmol) was added. After 30 min, the mixture was diluted with saline (100 ml) and extracted with ethyl acetate (3x50 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 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 (0.97 mL, 7.51 mmol) and allowed to stir at room temperature. After 17 hours, 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 (3x50 ml). The combined organic phases were washed with saturated potassium carbonate solution (50 ml), dried over magnesium sulfate, filtered and concentrated to give 2.77 g of a brown oil. Chromatographic purification (CombiFlash, 40 g SiO ₂ , gold column, eluent: 20-40% ethyl acetate/heptane) gave 1.53 g (79%) ethyl-(6-iodo-3-(1-(3-methoxy4) -((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate as a tan solid.

Example 3-53-2: Preparation of 6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4, 5-b]pyridin-2-amine

To a stirred solution of ethyl-(6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b] pyridin-2-yl)carbamate (1.53 g, 2.39 mmol) in ethanol (10 ml)/water (4 ml) was added tribasic potassium phosphate (2.07 g, 9.54 mmol). The mixture was irradiated in a microwave reactor at 150°C. After 1 h, the mixture was subjected to an additional heating cycle using microwaves (160°C, 30 min). Overall after 90 min. the mixture was diluted with water (100 ml) and extracted with dichloromethane (2x50 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 1.31 g (97%) 6-iodo-3-(1-(3-methoxy-4-((6(trifluoromethyl)pyridin-3-yl)methoxy )phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine as an orange foamy solid.

Example 3-53-3: Preparation of 3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-6-(1-methyl-1H-pyrazole -4-yl)-3H-imidazo[4,5-b]pyridin-2-amine

This compound was obtained from 6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin- 2-amine using the procedure described in Example 3-49-5: ¹ H NMR (400 MHz, CDCl3) 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 (kv, 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.

Example 3-54: Synthesis of 2-(4-(2-amino-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H- imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol

This compound was obtained from 6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin- 2-amine using the procedure described in Example 3-49-5 using the appropriate boronate ester coupling partner: 1H NMR (4 00 MHz, CDCl ₃ ) 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 (sq., 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-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4 ,5-b]pyridin-6-yl)but-3-yn-1-ol

This compound was obtained from 6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin- 2-amine using the procedure described in Example 3-48-2: 1H NMR (400 MHz, CDCU) 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 (kv, 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)pyridin-3-yl)methoxy)-3-methoxybenzyl)-3Nimidazo[4,5-b]pyridin-6-yl)but - 3-in-1-ol

Example 3-56-1: Preparation of tert-butyl-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3methoxybenzyl)carbamate

5-(Chloromethyl )-2(difluoromethyl)pyridine hydrochloride (4.58 g, 21.40 mmol). The mixture was heated to reflux temperature. After 3 hours, the off-white suspension was allowed to cool to room temperature and diluted with water (200 ml). The mixture was extracted with dichloromethane (3x75 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 7.74 g (>100%) tert-butyl 4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzylcarbamate as a waxy iron 102 044589 of that solid.

Example 3-56-2: Preparation of (4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine

Trifluoroacetic acid (15 mL, 194.70 mmol). After 2 hours, the reaction mixture 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 using concentrated ammonium hydroxide solution (50 ml). The main aqueous phase was extracted with dichloromethane (2x100 ml). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give 4.54 g (83%) of (4-((6(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxyphenyl)methanamine as a yellow solid.

Example 3-56-3: Preparation of 3-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-6-iodo3 H-imidazo[4,5-b]pyridine

To a stirred solution of N ² -(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-5iodopyridin-2,3-diamine [obtained from (4-((6-(difluoromethyl) pyridin-3-yl)methoxy)-3methoxyphenyl)methanamine (3.10 g, 6.05 mmol) in ethanol (50 ml) was added using the procedures described in Example 3-45-4 and Example 3-45-5] triethylorthoformate (3.0 ml, 18.02 mmol). The mixture was treated with p-toluenesulfonic acid monohydrate (50 mg, 262.86 µmol) and heated to reflux. After 45 minutes the mixture was allowed to cool to room temperature, resulting in the formation of a precipitate. The mixture was concentrated and the residue was dissolved in chloroform (150 ml). The solution was washed with saturated potassium carbonate solution, dried over magnesium sulfate, filtered and concentrated to give 3.15 g (99%) 3-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3methoxybenzyl)-6 -iodo-3H-imidazo[4,5-b]pyridine as a brown solid.

Example 3-56-4: Preparation of 4-(3-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-3Nimidazo[4,5-b]pyridin-6-yl )but-3-yn-1-ol

This compound was prepared from 3-(4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzyl)-6iodo-3H-imidazo[4,5-b]pyridine using the procedure described in Example 3-48-2: 1H NMR (400 MHz, CDCl ₃ ) δ 8.71-8.69 (m, 1H), 8.48 (d, J=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-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-6-(1-methyl-1Hpyrazol-4-yl)-3H-imidazo [ 4,5 -b]pyridinformate

Example 3-57-1: Preparation of 4-(((5-iodo-3-nitropyridin-2-yl)amino)methyl)-2-methoxyphenol

To a stirred suspension of 4-hydroxy-3-methoxybenzylamine hydrochloride (1.32 g, 6.82 mmol) and 2-chloro-5-iodo-3-nitropyridine (2.00 g, 6.82 mmol) in acetonitrile (20 ml ) N,Ndisopropylethylamine (5.96 mL, 34.10 mmol) was added. The suspension was stirred and heated to 100°C. After 1 hour, the mixture was allowed to cool to room temperature and 2N was added. aqueous solution of potassium hydroxide (0.68 ml). The mixture was concentrated to give 4-(((5-iodo-3-nitropyridin-2-yl)amino)methyl)-2methoxyphenol as an impurity solid.

Example 3-57-2: Preparation of 4-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-methoxyphenol

This compound was prepared in two steps from 4-(((5-iodo-3-nitropyridin-2-yl)amino)methyl)-2methoxyphenol using the procedures described in Example 3-49-2 and Example 3-52-2.

Example 3-57-3: Preparation of 6-iodo-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3Nimidazo[4,5-b]pyridine

To a stirred mixture of 4-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-methoxyphenol (1.32 g, 3.46 mmol) and potassium carbonate (1, 30 g, 9.41 mmol) in acetonitrile (25 ml) was added 5-(1-chloroethyl)-2methoxypyridine (0.72 g, 4.20 mmol). The mixture was heated at 100°C. After 6.5 hours, additional 5-(1-chloroethyl)-2-methoxypyridine (0.300 g, 1.75 mmol) was added and heating continued. After 22 hours the mixture was allowed to cool to room temperature and partitioned between water and a 1:5 mixture of 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 ₂ column, eluent: 0-10% methanol/dichloromethane to 0.01 M ammonia in methanol/dichloromethane) gave 0.88 g (49%) 6-iodo-3-(3methoxy -4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine in the form of a solid with impurities.

Example 3-57-4: Preparation of 3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-6-(1-methyl1H-pyrazol-4-yl)-3 N-imidazo[4,5-b]pyridinformate

To a stirred suspension of 6-iodo-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-3Himidazo[4,5-b]pyridine (0.200 g, 0.39 mmol ), tribasic potassium phosphate (0.164 g, 0.77 mmol), 1methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.100 g, 0.48 mmol) and tricyclohexylphosphine (0.008 g, 0.028 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.013 mmol) was added to a mixture of 1,4-dioxane (3 ml)/water (1.5 ml). The mixture was degassed by bubbling - 103 -

Claims (34)

nitrogen was passed through the mixture for 2 min and then the mixture was irradiated in a microwave reactor at 120°C. After 30 min. the mixture was allowed to cool to room temperature and filtered through celite. The filtrate was subjected to direct purification (50 g C18 column, eluent: water/acetonitrile/0.1% formic acid) to obtain impurity material. A second purification under the same conditions gave 0.051 g (26%) of product as a white solid: 1H NMR (400 MHz, CD ₃ 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 (kv, 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-(3-methoxy-4-(1-(6-methoxypyridin-3yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine The following compounds were prepared from 6-iodo-3-(3-methoxy-4-(1-(6-methoxypyridin-3yl)ethoxy)benzyl)-3H-imidazo[4,5-b]pyridine using the procedure described in the example 3-57-4 by using an appropriate boronic acid/boronate ester coupling partner. Example 3-58-1: 3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)-6-(1-methyl-1H-pyrazol5-yl)-3H-imidazo [4,5-b]pyridinformate (RA09683914A) Ή NMR (400 MHz, CDCl ₃ ) 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 (sq., 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. Example 3-58-2: 3-(3-methoxy-4-( 1 -(6-methoxypyridin-3 -yl)ethoxy)benzyl)-6-(6-methoxypyridin-3yl)-3H-imidazo[4,5 -b]pyridinformate (RA09683951A) 1H NMR (400 MHz, CDCl3) 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), 5.38 (s, 2H), 5.29 (sq., 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 3-8-3: 6-(2-fluoropyridin-4-yl)-3-(3-methoxy-4-(1-(6-methoxypyridin-3-yl)ethoxy)benzyl)3 H-imidazo [4 .5 -b]pyridinformate (RA09683967A) 1H NMR (400 MHz, CDCl3) 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 (kV, 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. CLAIM 1. A method of treating pain, comprising administering to a patient in need thereof a compound of formula (I): Q ¹ or a pharmaceutically acceptable salt thereof, where n is 1 or 2; m is 0, 1 or 2; Q ¹ represents (C ₂ -C ₉ )heteroaryl or (C ₂ -C ₉ )heterocycloalkyl, wherein (C ₂ -C ₉ )heteroaryl or (C ₂ -C ₉ )heterocycloalkyl is optionally substituted with one to four groups selected from ( C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )αalkyl, COOH-(C ₃ -C ₁₀ )cycloalkylα, (C ₁ -C ₁₀ )alkyl- O-, -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F ₃ C- or NC-, Q ² is (C ₆ -C ₁₄ )aryl or (C ₂ -C ₉ )heteroaryl, wherein (C ₆ -C ₁₄ )aryl or (C ₂ -C ₉ )heteroaryl is optionally substituted with one to four groups selected from ( C ₁ -C ₁₀ )αalkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )αalkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkylα, - 104 044589 (C ₁ -C ₁₀ )alkyl-O-, -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C- or NC -, each of R ⁷ and R ⁸ independently represents H or (C1-C ₁₀ )alkyl; X represents CH or N, R ¹ represents H, (C ₁ -C ₁₀ )alkyl, (C ₁ -C ₁₀ )alkylamine or NH2; R2 is H, (C ₁ -C ₁₀ )alkyl or (C ₁ -C ₁₀ )alkyl-O-; each of R3 and R ⁴ is independently H or (C ₁ -C ₁₀ )alkyl; each of R ⁵ and R ⁶ is independently H or (C ₁ -C ₁₀ )alkyl, where each (C ₂ -C ₉ )heteroaryl is an aromatic group that consists of 5 to 10 atoms that form at least one ring, where from 2 to 9 ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen; each (C ₂ -C ₉ )heterocycloalkyl is a non-aromatic group that consists of 3-10 atoms that form at least one ring, where 2-9 ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen , sulfur and oxygen; and each (C ₂ -C ₉ )heteroalkyl is a straight, branched or cyclic saturated hydrocarbon consisting of 2-10 atoms, where 2-9 atoms are carbon and the remaining atoms are selected from the group consisting of nitrogen, sulfur and oxygen. 2. The method according to claim 1, wherein the pain is post-operative pain. 3. The method of claim 1, wherein the pain is pain associated with osteoarthritis. 4. A method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of formula (I): or a pharmaceutically acceptable salt thereof, where n is 1 or 2; m is 0, 1 or 2; Q ¹ is (C ₂ -C ₉ )heteroaryl or (C ₂ -C ₉ )heterocycloalkyl, wherein (C2-C9)heteroaryl or (C2-C9)heterocycloalkyl is optionally substituted with one to four groups selected from (C ₁ -C ₁₀ )αlkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )αryl, (C ₂ -C ₉ )heteroaryl, ( C ₁ -C ₁₀ )αalkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkyl, (C ₁ -C ₁₀ )alkyl-O-, - OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C- or NC-, Q ² is (C ₆ -C ₁₄ )aryl or (C ₂ -C ₉ )heteroaryl, wherein (C ₆ -C ₁₄ )aryl or (C ₂ -C ₉ )heteroaryl is optionally substituted with one to four groups selected from ( C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkyl, (C1-C1o)αalkyl-O- , -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C- or NC-, each of R ⁷ and R ⁸ independently represents H or (C ₁ -C ₁₀ )alkyl; X represents CH or N, R ¹ represents H, (C ₁ -C ₁₀ )alkyl, (C ₁ -C ₁₀ )alkylamine or NH2; R ² represents H, (C ₁ -C ₁₀ )alkyl or (C ₁ -C ₁₀ )alkyl-O-; each of R ³ and R ⁴ is independently H or (C ₁ -C ₁₀ )alkyl; each of R ⁵ and R ⁶ is independently H or (C ₁ -C ₁₀ )alkyl, where each (C ₂ -C ₉ ) heteroaryl is an aromatic group that consists of 5 to 10 atoms that form at least one ring, where from 2 to 9 ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen; each (C ₂ -C ₉ )heterocycloalkyl is a non-aromatic group that consists of 3-10 atoms that form at least one ring, where 2-9 ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen , sulfur and oxygen; and each (C ₂ -C ₉ )heteroalkyl is a saturated hydrocarbon with a straight, branched or cyclic chain, consisting of 2-10 atoms, where 2-9 atoms are carbon and the remaining atoms are selected from the group consisting of nitrogen, sulfur and oxygen. 5. Method of inhibiting tropomyosin-related kinase A, tropomyosin-related kinase B or tropomyosin-related kinase C, comprising administering to a patient in need thereof a compound of formula (I): or a pharmaceutically acceptable salt thereof, where n is 1 or 2; m is 0, 1 or 2; Q ¹ represents (C ₂ -C ₉ )heteroaryl or (C ₂ -C ₉ )heterocycloalkyl, wherein (C ₂ -C ₉ )heteroaryl or (C ₂ -C ₉ )heterocycloalkyl is optionally substituted with one to four groups selected from ( C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C3-C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ ) heteroaryl, (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkyl, (Cl-Cl ₀ )αalkyl-O- , -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F ₃ C- or NC-, Q ² is (C ₆ -C ₁₄ )aryl or (C ₂ -C ₉ )heteroaryl, wherein (C ₆ -C ₁₄ )aryl or (C ₂ -C ₉ )heteroaryl is optionally substituted with one to four groups selected from ( C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkyl, (C1-C1o)alkyl-O- , -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C- or NC-, each of R ⁷ and R ⁸ independently represents H or (C ₁ -C ₁₀ )alkyl; X represents CH or N, R ¹ represents H, (C ₁ -C ₁₀ )alkyl, (C ₁ -C ₁₀ )alkylamine or NH2; R ² represents H, (C ₁ -C ₁₀ )alkyl or (C ₁ -C ₁₀ )alkyl-O-; each of R ³ and R ⁴ is independently H or (C ₁ -C ₁₀ )alkyl; each of R ⁵ and R ⁶ is independently H or (C ₁ -C ₁₀ )alkyl, where each (C ₂ -C ₉ ) heteroaryl is an aromatic group that consists of 5 to 10 atoms that form at least one ring, where from 2 to 9 ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen; each (C ₂ -C ₉ )heterocycloalkyl is a non-aromatic group that consists of 3-10 atoms that form at least one ring, where 2-9 ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen , sulfur and oxygen; and each (C ₂ -C ₉ )heteroalkyl is a straight, branched or cyclic saturated hydrocarbon consisting of 2-10 atoms, where 2-9 atoms are carbon and the remaining atoms are selected from the group consisting of nitrogen, sulfur and oxygen. 6. A method of inhibiting the cellular receptor colony-stimulating factor-1 (c-FMS), comprising administering to a patient in need thereof a compound of formula (I): - 106 044589 or a pharmaceutically acceptable salt thereof, where n is 1 or 2; m is 0, 1 or 2; Q ¹ is (C ₂ -C ₉ )heteroaryl or (C ₂ -C ₉ )heterocycloalkyl, wherein (C ₂ -C ₉ )heteroaryl or (C ₂ -C ₉ )heterocycloalkyl is optionally substituted with one to four groups selected from ( C ₁ -C ₁₀ )αalkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )αryl, (C ₂ -C9) heteroaryl, (C ₁ -C ₁₀ )αalkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkyl, (C ₁ -C ₁₀ )alkyl-O -, -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F ₃ C- or NC-, Q ² is (C ₆ -C ₁₄ )aryl or (C ₂ -C ₉ )heteroaryl, wherein (C ₆ -C ₁₄ )aryl or (C ₂ -C ₉ )heteroaryl is optionally substituted with one to four groups selected from ( C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )αalkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkyl, (C1-C10)alkyl-O- , -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C- or NC-, each of R ⁷ and R ⁸ independently represents H or (C ₁ -C ₁₀ )alkyl; X represents CH or N, R ¹ represents H, (C ₁ -C ₁₀ )alkyl, (C ₁ -C ₁₀ )alkylamine or NH2; R ² represents H, (C ₁ -C ₁₀ )alkyl or (C ₁ -C ₁₀ )alkyl-O-; each of R ³ and R ⁴ is independently H or (C ₁ -C ₁₀ )alkyl; each of R ⁵ and R ⁶ is independently H or (C ₁ -C ₁₀ )alkyl, where each (C ₂ -C ₉ ) heteroaryl is an aromatic group that consists of 5 to 10 atoms that form at least one ring, where from 2 to 9 ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen; each (C2-C9)heterocycloalkyl is a non-aromatic group that consists of 3-10 atoms that form at least one ring, where 2-9 ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen; and each (C2-C9)heteroalkyl is a straight, branched or cyclic saturated hydrocarbon of 2-10 atoms, wherein 2-9 atoms are carbon and the remaining atoms are selected from the group consisting of nitrogen, sulfur and oxygen. 7. Method according to any one of claims 1 to 6, in which n is equal to 1. 8. Method according to any one of claims 1-6, in which m is equal to 1. 9. Method according to any one of claims 1 to 6, wherein n is 1 and m is 1. 10. Method according to any one of claims 1-6, where Q ¹ represents (C2-C9)heteroaryl optionally substituted with one to four groups selected from (C1-C10)αalkyl, (C2-C9)heteroalkyl, (C3-C10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C14)αryl, (C2-C9)heteroaryl, (C1-C10)αalkyl-C(O)O-, COOH-(C1-C10)alkyl, COOH-( C3-C10)cycloalkyl, (C1-C10)alkyl-O-, -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C- or NC-, where each of R ⁷ and R ⁸ independently represents H or (C ₁ -C ₁₀ )alkyl. 11. The method according to claim 10, where Q ¹ represents (C ₂ -C ₉ )heteroaryl, optionally substituted with one to four groups selected from (C ₁ -C ₁₀ )alkyl or (C ₃ -C ₁₀ )cycloalkyl. 12. The method according to claim 10, where Q ² represents (C ₆ -C ₁₄ )aryl optionally substituted with one to four groups selected from (C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )αryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )αalkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl, COOH-(C3-C1o)cycloalkyl, (C1-C1o)alkyl-O-, -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C- , R ⁷ (O)CR ⁸ N-, F3C- or NC-, where each of R ⁷ and R ⁸ independently represents H or (C ₁ -C ₁₀ )alkyl. 13. The method according to claim 12, where Q ² represents (C ₆ -C ₁₄ )aryl, optionally substituted with one to four groups selected from (C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, ( C ₃ -C ₁₀ )cycloalkyl, (C ₁ -C ₁₀ )alkyl-O- or -OH. - 107 044589 14. Method according to any one of claims 1 to 6, where X represents N. 15. The method according to claim 13, where X represents N. 16. Method according to any one of claims 1 to 6, where R ¹ represents NH2. 17. The method according to claim 12, where R ¹ represents NH2. 18. The method according to claim 15, where R ¹ represents NH2. 19. Method according to any one of claims 1 to 6, where R ² represents (C ₁ -C ₁₀ )αalkyl-O-. 20. The method according to claim 18, where R ² represents (C ₁ -C ₁₀ )alkyl-O-. 21. The method according to claim 18, where R ² represents CH ₃ -O- or CH ₃ -CH ₂ -O-. 22. The method according to claim 12, where each of R ³ and R ⁴ represents H. 23. The method according to claim 12, where each of R ⁵ and R ⁶ represents H. 24. Method according to any one of claims 1 to 6, where the compound has the structure of formula (II): or a pharmaceutically acceptable salt thereof. 25. Method according to any one of claims 1 to 6, where the compound is or a pharmaceutically acceptable salt thereof. 26. Method according to any one of claims 1 to 6, where the compound is - 108 044589 or a pharmaceutically acceptable salt thereof. 27. The method according to any one of claims 1 to 6, where the compound is or a pharmaceutically acceptable salt thereof. 28. The method according to any one of claims 1 to 6, where the compound is - 109 044589 or a pharmaceutically acceptable salt thereof. 29. The method according to any one of claims 1 to 6, in which the compound is selected from the group consisting of: 1 -(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1Hbenzo[d]imidazol-2-amine, 1-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-5-(pyrimidin-5-yl)-1H-benzo[d]imidazol-2-amine, 1-(3-Methoxy-4 -((4-methoxybenzyl)oxy)benzyl)-5-(pyridin-4-yl)-1H-benzo[d]imidazol-2-amine, 3 -(3 -methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(1 -(piperidin-4-yl)-1 H-pyrazol-4-yl)3 H-imidazo [4,5-b]pyridine, 1 -(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-(piperidin-3-yl)- 1H-1,2,3-triazol1 -yl)- 1H-benzo[d]imidazole, 3-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5b]pyridin-2-amine, 3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3Nimidazo[4,5-b]pyridine, 2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6yl)piperidin-4-yl) propan-2-amine, 4-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6yl)morpholine, 3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl)-3Nimidazo[4,5-b] pyridine, 3 -(3 -Methoxy-4-((6-methoxypyridin-3 -yl)methoxy)benzyl)-6-( 1 -(piperidin-4-yl)-1 H-pyrazol-4yl)-3H-imidazo[4 ,5-b]pyridine, 3 -(3 -Methoxy-4-((6-methylpyridin-3 -yl)methoxy)benzyl)-6-( 1 -(piperidin-4-yl)-1 H-pyrazol-4-yl)3 H-imidazo [4,5-b]pyridine, 3-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5(piperidin-4- yl)-1,2,4-oxadiazole, 2-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-5(piperidin-4- yl)-1,3,4-oxadiazole, 2-(1-(3-(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)1H-1, 2,3-triazol-4-yl)propan-2-amine, and 3 -(3-Methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-(piperidin-3-yl)-1H-1,2,3-triazol1-yl)- 3H-imidazo[4,5-b]pyridine, or a pharmaceutically acceptable salt of the above. 30. A pharmaceutical composition containing a compound of Formula (I) and one or more pharmaceutically acceptable excipients, where formula (I) is presented as follows: - 110 044589 or a pharmaceutically acceptable salt thereof, where n is 1 or 2; m is 0, 1 or 2; Q ¹ represents (C ₂ -C ₉ )heteroaryl or (C ₂ -C ₉ )heterocycloalkyl, wherein (C ₂ -C ₉ )heteroaryl or (C ₂ -C ₉ )heterocycloalkyl is optionally substituted with one to four groups selected from ( C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkyl, (C1-C1o)alkyl-O- , -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C- or NC-, Q ² is (C ₆ -C ₁₄ )aryl or (C ₂ -C ₉ )heteroaryl, wherein (C ₆ -C ₁₄ )aryl or (C ₂ -C ₉ )heteroaryl is optionally substituted with one to four groups selected from ( C ₁ -C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C ₂ -C ₉ )heterocycloalkyl, (C ₆ -C ₁₄ )aryl, (C ₂ -C ₉ )heteroaryl, (C ₁ -C ₁₀ )alkyl-C(O)O-, COOH-(C ₁ -C ₁₀ )alkyl, COOH-(C ₃ -C ₁₀ )cycloalkyl, (C1-C1o)alkyl-O- , -OH, R ⁷ R ⁸ N-, R ⁷ R ⁸ N(O)C-, R ⁷ (O)CR ⁸ N-, F3C- or NC-, each of R ⁷ and R ⁸ independently represents H or (C ₁ -C ₁₀ )alkyl; X represents CH or N, R ¹ represents H, (C ₁ -C ₁₀ )alkyl, (C ₁ -C ₁₀ )alkylamine or NH2; R ² represents H, (C ₁ -C ₁₀ )alkyl or (C ₁ -C ₁₀ )alkyl-O-; each of R ³ and R ⁴ is independently H or (C ₁ -C ₁₀ )alkyl; each of R ⁵ and R ⁶ is independently H or (C ₁ -C ₁₀ )alkyl, where each (C ₂ -C ₉ ) heteroaryl is an aromatic group that consists of 5 to 10 atoms that form at least one ring, where from 2 to 9 ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen; each (C2-C9)heterocycloalkyl is a non-aromatic group that consists of 3-10 atoms that form at least one ring, where 2-9 ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur and oxygen; and each (C2-C9)heteroalkyl is a straight, branched or cyclic saturated hydrocarbon consisting of 2-10 atoms, where 2-9 atoms are carbon and the remaining atoms are selected from the group consisting of nitrogen, sulfur and oxygen. 31. The pharmaceutical composition according to claim 30, where Q ¹ represents (C2-C9)heteroaryl, optionally substituted with one to four groups selected from (C1-C10)alkyl or (C3-C10)cycloalkyl; and Q ² is (C6-C ₁₄ )aryl, optionally substituted with one to four groups selected from (C1-C ₁₀ )alkyl, (C ₂ -C ₉ )heteroalkyl, (C ₃ -C ₁₀ )cycloalkyl, (C1 -C ₁₀ )alkyl-O- or -OH. 32. Pharmaceutical composition according to claim 30 or 31, where X represents N. 33. Pharmaceutical composition according to claim 32, where R ¹ represents NH2 and R ² represents (C1-C ₁₀ )alkyl-O-. 34. The pharmaceutical composition according to claim 30, where the compound is - 111 044589 or a pharmaceutically acceptable salt thereof. ^gj) Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 - 112 -