WO2014175832A1

WO2014175832A1 - Wnt pathway modulators

Info

Publication number: WO2014175832A1
Application number: PCT/SG2014/000183
Authority: WO
Inventors: Athisayamani Jeyaraj DURAISWAMY; Jenefer ALAM
Original assignee: Agency For Science, Technology And Research
Priority date: 2013-04-26
Filing date: 2014-04-25
Publication date: 2014-10-30
Also published as: GB201307564D0; GB2513403A

Abstract

The invention provides a compound of structure Ar1-Ar2-X-C(R1R2)-C(=O)-N(R3)-Ar3-Ar4 for modulating WNT activity. In this structure, Ar1, Ar2, Ar3 and Ar4 are, independently, optionally substituted aryl or heteroaryl groups; R1 and R3 are, independently, H or optionally substituted alkyl groups; R2 is H or an optionally substituted alkyl group or an alkylene group which, together with the carbon atom to which it is attached and X, forms a non-aromatic ring or an alkylene group which, together with the carbon atom to which it is attached and X and two adjacent atoms of Ar2, forms a non-aromatic ring; X is O, CR4R5, N or NR4, wherein if X is N, it is bonded to R2; R4 is H, optionally substituted alkyl or an alkylene chain, optionally containing a heteroatom and/or a carbonyl group, which, together with the C or N to which it is attached and two adjacent atoms of Ar2, forms a non-aromatic ring; R5 is H, NH2 or an optionally substituted alkyl group.

Description

WNT PATHWAY MODULATORS

Field

[0001] The invention relates to WNT pathway modulators, processes for making them and methods for using them.

Background

[0002] Wnt proteins are secreted glycoproteins acting as growth factors that regulate various cellular functions, including proliferation, differentiation, death, migration, and polarity, by activating multiple intracellular signaling cascades, including the β-catenin-dependent and - independent pathways. There are 19 Wnt members that have been found in humans and mice, and they exhibit unique expression patterns and distinct functions during development. In humans and mice, the 10 members of the Frizzled (Fz) family comprise a series of seven-pass transmembrane receptors that have been identified as Wnt receptors. In addition to Fz proteins, single-pass transmembrane proteins, such as low-density lipoprotein receptor-related protein 5 (LRP5), LRP6, receptor tyrosine kinase (RTK)-like orphan receptor l(Rorl), Ror2, and receptorlike tyrosine kinase (Ryk), have been shown to function as co-receptors for Wnt signaling.

Therefore, it has been assumed traditionally that the binding of different Wnts to their specific receptors selectively triggers different outcomes via distinct intracellular pathways.

[0003] In the absence of Wnt signaling, β-catenin is bound and phosphorylated by a "destruction complex" containing the adenomatous polyposis coli (APC) and Axin proteins, as well as glycogen synthase kinase 3 (GSK.3) and casein kinase I (CKI). Phosphorylated β-catenin is bound by the F box protein Slimb/p-TrCP and polyubiquitinated, leading to proteosomal degradation. In addition, the complex acts to prevent nuclear localization of b-catenin. Upon Wnt binding to Frizzled (Fz) and low-density lipoprotein-related proteins 5 and 6 (LRP5/6), GSK3, Axin, and other destruction complex components are recruited to the receptor complex. The function of the destruction complex is inhibited, and unphosphorylated β-catenin accumulates in the cytoplasm and eventually translocates to the nucleus. There, it associates with TCF proteins, converting TCF from a repressor into an activator of Wnt-responsive gene transcription. [0004] Deregulation of components of Wnt/p-catenin signaling is implicated in a wide spectrum of diseases including degenerative diseases, metabolic diseases, and a number of cancers such as cervical, colon, breast, bladder, head and neck, gastric, lung, ovarian, prostate, thyroid, non- small-cell lung, as well as chronic lymphocytic leukemia, mesothelioma, melanoma, pancreas adenocarcinoma, basal cell carcinoma, osteosarcoma, hepatocellular carcinoma, Wilm's tumor and medulloblastoma.

[0005] Wnt signaling plays a role both during development, and within stem cell niches in adults. This is best established in skin, hematopoietic stem cells, mammary gland and in intestinal proliferation. For example, high level expression of DKK1, an inhibitor of Wnt signaling, blocks normal stem cell proliferation in mouse intestine, suggesting there is an essential role for Wnt signaling in maintenance of stem cells in the digestive tract. The role of Wnt in self renewal and expansion of stem cells has also been demonstrated for embryonic and neural stem cells, suggesting that Wnt signaling may be a general requirement of stem cell maintenance. Inhibition of Wnt signaling, e.g., by overexpression of axin or an extracellular Wnt-binding protein, sFRP, reduces hematopoietic stem cell (HSC) growth in vitro and the ability to reconstitute HSCs in vivo. Notably, while overexpression of activated β-catenin can expand HSC populations in culture for extended periods, two groups have reported that β-catenin is not required for HSC survival and serial transplantation, supporting the proposal that there is more to Wnt signaling than stabilization of β-catenin in stem cell survival. Diverse Wnts can regulate stem cell proliferation: Wnts 1, 5a, and 10b are able to stimulate expansion of HSC populations and Wnt5a acts synergistically with stem cell factor (SCF) to expand and promote self renewal of HSCs. The demonstration of a role for Wnt5a in HSC self renewal and its ability to synergize with stem cell factor is particularly interesting because Wnt5a often acts in a β-catenin independent manner. While Wnt signaling is critical for stem cell maintenance, it may act via signaling pathways distinct from or in parallel to the β-catenin pathway.

[0006] The Wnt/^-catenin signaling pathway is essential to embryonic development and organ morphogenesis, and dysregulation of this pathway in adults has been linked to fibroblast biology and fibrosis. It has been demonstrated that Wnt/^-catenin signaling plays a role in severe fibrotic diseases, such as pulmonary fibrosis, liver fibrosis, skin fibrosis and renal fibrosis. [0007] Dysregulation of Wnt/p-catenin signaling contributes also to the development of diabetic retinopathy by inducing retinal inflammation, vascular leakage, and neovascularization.

[0008] The binding of Wnt proteins to plasma membrane receptors on mesenchymal cells induces the differentiation of these cells into the osteoblast lineage and thereby supports bone formation. Wnts are also key signaling proteins in joint remodeling processes. Active Wnt signaling contributes to osteophyte formation and might have an essential role in the anabolic pattern of joint remodeling that is observed in ankylosing spondylitis and osteoarthritis. In contrast, blockage of Wnt signaling facilitates bone erosion and contributes to catabolic joint remodeling, a process that is observed in rheumatoid arthritis.

[0009] There is therefore a need for compounds that modulate and/or inhibit the WNT pathway so as to treat diseases associated with WNT activity.

Summary of Invention

[00010] In a first aspect of the invention there is provided a compound of structure I for modulating WNT activity:

Ar¹-Ar²-X-C(R¹R²)-C(=0)-N( ³)-Ar³-Ar⁴

00

wherein:

Ar¹, Ar², Ar³ and Ar⁴ are, independently, optionally substituted aryl or heteroaryl groups;

R and R^J are, independently, H or optionally substituted alkyl groups;

R² is H or an optionally substituted alkyl group or an alkylene group which, together with the carbon atom to which it is attached and X, forms a non-aromatic ring or an alkylene group which, together with the carbon atom to which it is attached and X and two adjacent atoms of Ar², forms a non-aromatic ring; X is O, CR⁴R⁵, CH₂0, N or NR⁴, wherein if X is N, it is bonded to R²;

R⁴ is H, optionally substituted alkyl or an alkylene chain, optionally containing a heteroatom and/or a carbonyl group, which, together with the C or N to which it is attached and two adjacent atoms of Ar , forms a non-aromatic ring; and

R⁵ is H, NH₂ or an optionally substituted alkyl group.

[00011 ] The following options may be used in conjunction with the first aspect, either individually or in any suitable combination.

[00012] R¹ and R³ may both be H.

[00013] X may be O, NH or CH₂.

[00014] R² may be H or it may be methyl. In some embodiments X is a nitrogen atom and R² is (CH )₃ and is attached to said nitrogen atom so as to form a 5-membered ring.

[00015] Ar¹ may be a 5-membered heterocyclic ring or it may be a pyridyl ring. It may contain 1 or 2 ring nitrogen atoms. In some embodiments Ar¹ has no ring atoms that are not N or C.

[00016] Ar² may be a 6-membered ring. Ar¹ and X may be in a 1,4-relationship on Ar², or may be in a 1 ,3 -relationship or a 1 ,2-relationship thereon. Ar may be a phenyl or may be pyridyl.

[00017] Ar³ may be a 6-membered ring. Ar⁴ and the nitrogen atom attached to Ar³ may be in a 1 ,4-relationship on Ar . Ar may be a phenyl ring or may contain 1 or 2 ring nitrogen atoms.

[00018] Ar⁴ may be a 6-membered ring. Ar⁴ may be a phenyl ring or may contain 1 or 2 ring nitrogen atoms. [00019] In some embodiments, X=0 and R , R and R are all H. In other embodiments X=NH, R¹ and R³ are H and R² is CH₃.

[00020] The compound may be any of the compounds from Examples 1 to 139 provided herein (not including intermediates described in the syntheses). The compound may be a racemate. It may be a single optical isomer. In the event that diastereomers are possible, it may be a single diastereomer or it may be a mixture of diastereomers. It may be any one of the following compounds:





10

11











[00025] At each asymmetric centre in the molecule independently, the stereochemistry may be S or may be R.

[00026] The compound may have a IC₅₀ against HEK293-STF3A cells of less than about 5μηι, or less than about Ιμιη, or less than about Ο.ΐμπι, or less than about 0.01 μπι.

[00027] In an embodiment of this aspect there is provided a compound of structure (I):

Ar^]-Ar²-X-C(HR²)-C(=0)-N(H)-Ar³-Ar⁴

(I)

wherein:

Ar¹ is a 5-membered heterocyclic ring having either two or three heteroatoms independently selected from O and N provided that at least one is N;

Ar² is either a phenyl ring which is substituted in the 1 and 4 positions by Ar¹ and X, or a pyridine ring in which Ar¹ is in the 2 position and X is in the 5 position of said ring;

Ar³ and Ar⁴ are, independently, optionally substituted aryl or heteroaryl groups;

R² is H or methyl or -(CH )₃- which, together with the carbon atom to which it is attached and X, forms a pyrrolidine ring, wherein if R is -(CH₂)₃-, X is N; and

X is O, N or NH, wherein if X is N, it is bonded to R².

[00028] In this embodiment, Ar¹ may be unsubstituted or may have a single substituent, e.g. methyl, ethyl, isopropyl, phenyl, trifluoromethyl, morpholino or dimethylamino.

[00029] Specific examples of Ar include:

[00030] In a further.embodiment, there is provided a compound of structure (la):

(la)

wherein:

A is CH or N;

1 is selected from the following groups:

Ar .3 a„„ndj A_r4 are, independently, optionally substituted aryl or heteroaryl groups.

[00031] In a further embodiment, there is provided a compound of structure (lb):

(lb)

wherein:

A is CH or ;

X is O or NH;

R² is H or Me;

Ar¹ is selected from the following groups:

Ar and Ar are, independently, optionally substituted aryl or heteroaryl groups.

[00032] The invention as described in the first aspect also encompasses all enantiomers and diastereomers of the compounds as well as salts of the compounds. The salt may be a pharmaceutically or veterinarially acceptable salt, for example a hydrochloride salt. Suitable salts include those listed in P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zurich:Wiley-VCH VHCA, 2002.

[00033] In a second aspect of the invention there is provided a process for making a compound of structure I as described in the first aspect. There is also provided a compound when made by the process of the second aspect. This process may comprise coupling a compound of structure II wi

(Π) (III)

1 2 3 L 2 4

wherein R , R , R , X, Ar , Ar , Ar and Ar are as defined in the first aspect. [00034] Alternatively the process may comprise coupling a compound of structure IV with a compound of structure V

Ar'-Ar²-X-H Hal- ^^² (=0)Ν^³)-Ατ³-Ατ⁴

(IV) (V) wherein Hal is a halogen, e.g. CI, Br or I and R¹, R², R³, X, Ar¹, Ar², Ar³ and Ar⁴ are as defined in the first aspect.

[00035] It will be understood that other coupling reactions may lead to the compounds of the first aspect, e.g. coupling an Ar¹ derivative with an Ar²-X-C(R¹R²)-C(=0)-N(R³)-Ar³-Ar⁴ derivative. These various coupling reactions will be readily apparent to a skilled person. In certain instances one or more functional groups may be protected during the coupling reaction. In this case, a subsequent reaction may be required in order to deprotect the protected functional group to generate the desired product.

[00036] In a third aspect of the invention there is provided a pharmaceutical composition comprising the compound of the first aspect, or a compound made by the process of the second aspect, and one or more pharmaceutically acceptable carriers, diluents and/or adjuvants.

[00037] In a fourth aspect of the invention there is provided use of a compound according to the first aspect, or of a compound made by the process of the second aspect, for the manufacture of a medicament for the treatment of a condition characterised by excessive WNT activity.

[00038] The condition may be a cancer, e.g. any one of cervical, colon, breast, bladder, head and neck, gastric, lung, ovarian, prostate, thyroid, non-small-cell lung, as well as chronic lymphocytic leukemia, mesothelioma, melanoma, pancreas adenocarcinoma, basal cell carcinoma, osteosarcoma, hepatocellular carcinoma, Wilm's tumor or medulloblastoma. The condition may be a severe fibrotic disease, such as pulmonary fibrosis, liver fibrosis, skin fibrosis or renal fibrosis. It may be a degenerative disease. It may be a metabolic disease such as diabetic retinopathy.

[00039] In a fifth aspect of the invention there is provided a compound according to the first aspect, or a compound made by the process of the second aspect, for use in therapy.

[00040] In a sixth aspect of the invention there is provided a method of treating a condition characterised by excessive WNT activity, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the first aspect, or of a compound made by the process of the second aspect, or of a composition according to the third aspect. The disease or condition may be selected from the group consisting of cancer, fibrosis, stem cell and diabetic retinopathy. The cancer may be a cancer characterised by high WNT activity.

[00041] The condition may be a cancer, e.g. cervical, colon, breast, bladder, head and neck, gastric, lung, ovarian, prostate, thyroid, non-small-cell lung, as well as chronic

lymphocytic leukemia, mesothelioma, melanoma, pancreas adenocarcinoma, basal cell carcinoma, osteosarcoma, hepatocellular carcinoma, Wilm's tumor or medulloblastoma.The condition may be a severe fibrotic diseases, such as pulmonary fibrosis, liver fibrosis, skin fibrosis or renal fibrosis. It may be a degenerative disease. It may be a metabolic disease such as diabetic retinopathy.

[00042] The subject may be a human subject or may be a non-human subject, e.g. a mammalian non-human subject or a non-human non-mammal.

Brief Description of Drawings

[00043] Fig. 1 shows a scheme of Wnts and signalling pathways. [00044] Fig. 2 shows results of efficacy testing on compound 129. [00045] Fig. 3 shows results of efficacy testing on compound 136. Description of Embodiments

[00046] The invention relates to the preparation and the use of new compounds that modulate Wnt activity, to pharmaceutical compositions containing these compounds, to methods of using the compounds, either as a single agent or in combination, for treating diseases and conditions associated with Wnt pathway activity i.e. cancer, fibrosis, stem cell and diabetic retinopathy. Thus the invention relates to a class of compounds that act as inhibitors of the Wnt pathway and to pharmaceutical compositions comprising these compounds and to their use for the preparation of a medicament for the prophylaxis and treatment of diseases having a dysfunction linked to Wnt signaling pathway where Wnt plays a role in proliferation of cancer via multiple mechanisms, including a key role in stem cells maintenance. Suitable cancers that may be treated include, but are not limited, to cervical, colon, breast, bladder, head and neck, gastric, lung, ovarian, prostate, thyroid, non-small-cell lung, as well as chronic lymphocytic leukemia, mesothelioma, melanoma, pancreas adenocarcinoma, basal cell carcinoma,

osteosarcoma, hepatocellular carcinoma, Wilm's tumor and medulloblastoma. The compounds may be used in the treatment other diseases with high Wnt expression such as fibrosis (including skin, idiopathic pulmonary, liver, renal interstitial, myocardial, infarct and liver) and diabetic retinopathy.

[00047] Figure 1 illustrates diverse Wnts, Wnt receptors and downstream pathways which all contribute to the role of Wnt. These pathways all play a role in development, stem cell maintenance, cancer and metastasis.

[00048] The compounds of the present invention are defined by structure (I):

Ar'-A^-X-QR^-C ^-N R^-Ar^Ar⁴

(I)

[00049] In the definition of the various components of this structure, the following apply:

[00050] Aryl (aromatic): this refers to homoaryl (i.e. carbocyclic) groups. They may be monocyclic (i.e. phenyl) or may be fused ring structures, optionally a 2 or 3 fused ring structures (e,g. naphthyl, anthracyl etc.). [00051] Heteroaryl (heteroaromatic): this refers to aromatic structures comprising at least one ring heteroatom. These structures may have 1, 2 or 3 heteroatoms per ring. Each heteroatom may, independently, be nitrogen, oxygen or sulfur, or may be some other heteroatom. In many embodiments, the heteroatom or at least one of the heteroatoms, is nitrogen. Heteroaryl groups may comprise 5 membered rings or 6 membered rings. In some instances a heteroaryl group may be a fused ring structure, e.g. with 2 or 3 fused rings, at least one of which is heterocyclic. In some instances a heteroaryl group may comprise one or more fused aryl (i.e. homoaryl) rings. Examples of heteroaryl groups are pyridyl, oxazolyl, indolyl, imidazolyl, thiazolyl, pyrazolyl, pyridazinyl, furyl, thiophenyl, pyrazinyl, pyrimidinyl etc. In the case of imidazolyl and pyrazolyl groups, these may be attached through one of the nitrogen atoms or through a carbon atom. In the latter case, one of the nitrogen atoms may be substituted with an alkyl, aryl or heteroaryl group or some other group, or may bear a hydrogen atom.

[00052] For aryl or heteroaryl groups which have two substituents, the substituents may be in any suitable relationship, i.e. for 5 membered rings they may be in a 1,2 or 1,3 relationship and for 6 membered rings they may be in a 1,2, 1 ,3 or 1,4 relationship, provided (for heteroaryl rings) that such substitution is possible. Similarly if aryl or heteroaryl rings have more than 2 substituents, they may be in any suitable relationship. For example 3 substituents on a phenyl ring maybe in a 1,2,3, 1,2,4, 1,3,5 or 1,3,5 relationship.

[00053] Alkyl: these groups may have from 1 to about 20 carbon atoms, or 1 to 16, 1 to 12, 1 to 8 or 1 to 6, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. They may be linear, branched or cyclic or may comprise two or more of these forms, provided that branched or cyclic alkyl groups have at least 3 carbon atoms. They may be optionally substituted. The term should be taken to encompass unsaturated equivalents of these groups (i.e. alkenyl and alkynyl groups). Examples include methyl, ethyl, propyl, butyl, cyclopropyl, cyclohexyl, cyclohexylmethyl, propenyl etc. Alkyl groups are bonded to one atom.

[00054] Alkylene: these may have from 1 to about 20 carbon atoms, or 1 to 16, 1 to 12, 1 to 8 or 1 to 6, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. They may be linear, branched or cyclic or may comprise two or more of these forms, provided that branched or cyclic alkylene groups have at least 3 carbon atoms. They may be optionally substituted. The term should be taken to encompass unsaturated equivalents of these groups. Examples include -(C¾) -, -CH=CH- -(CH₂)2- -(CH₂)₃- etc. Alkylene groups may be bonded to two atoms, or to the same atom through two bonds, each to a different atom in the alkylene group or to the same atom in the alkylene group. In some cases the alkylene group may be bonded through terminal atoms, i.e. may be α,ω-alkylene groups.

[00055] Optionally substituted: this indicates that there may or may not be substituents other than those specifically indicated. For example structure (I) contains a moiety -Ar³-Ar⁴, in which Ar is optionally substituted. This should be taken to indicate that Ar has at least substituent Ar⁴ and may have other non-hydrogen substituents or may have no other non- hydrogen substituents. Possible substituents include alkyl groups, aryl groups and heteroaryl groups, as defined elsewhere herein and each of which may be optionally substituted. Other suitable substituents include hydroxy, alkoxy (i.e. -O-alkyl), aryloxy (i.e. -O-aryl), perhaloalkyl (e.g. trifluoromethyl), perhaloalkoxy (e.g. trifluoroalkoxy), halo (e.g. fluoro, chloro or bromo), ester (either -0-C(=0)R or -C(=0)-OR, where R is alkyl or aryl), amide (either -NR'-C(=0)R or -C(=0)-NRR', where R and R' are H, alkyl or aryl or, in the latter case, where R and R', together with the nitrogen atom to which they are attached, form an aliphatic ring for example an azetidine or aziridine ring), amine (i.e. NRR', where R and R' are H, alkyl or aryl or, together with the nitrogen atom to which they are attached, form an aliphatic ring for example an azetidine or aziridine ring), morpholino, etc.

[00056] It will be recognised that many of the compounds within the scope of the present invention may be present as different optical isomers and/or diastereomers. In such cases, the present invention contemplates all of the various alternatives with respect to asymmetric centres, either as pure substances or as mixtures of optical isomers and/or diastereomers. In particular, where optical isomers are possible, the invention encompasses (+), (-) and racemic forms. The degree of optical purity of (+) and (-) forms may be greater than about 50%, or greater than about 60, 70, 80, 90, 95 or 99%.

[00057] The compounds of the invention are amides. In certain embodiments, X is N and R² is (CH₂)₃, so that the -X-C(R^!R²)- of the molecule represents a pyrrolidine ring. 2

[00058] In many embodiments Ar is a 6 membered ring. It may be fused with a second ring, optionally also 6-membered. It may be homoaromatic or it may be heteroaromatic. In some such embodiments, Ar³ is also a 6-membered ring. In many examples, Ar¹ is a 5 membered ring however in other examples it is a 6 membered ring. In many examples Ar⁴ is a 5 membered ring.

[00059] In summary, options contemplated by the invention are set out below. The code used is as follows:

5: 5 membered ring; 6: 6 membered ring; o: homoaromatic; e: heteroaromatic. For each option the combination is in the order Ar¹ Ar²Ar³ Ar⁴. Thus, for example 5e6o6o6o represents a compound in which Ar¹ is a 5 membered heteroaromatic ring and Ar², Ar³ and Ar⁴ are all 6 membered homoaromatic rings. The contemplated options include:

5e5e5e5e, 5e5e5e6e, 5e5e5e6o, 5e5e6e5e, 5e5e6e6e, 5e5e6e6o, 5e5e6o5e, 5e5e6o6e, 5e5e6o6o, 5e6e5e5e, 5e6e5e6e, 5e6e5e6o, 5e6e6e5e, 5e6e6e6e, 5e6e6e6o, 5e6e6o5e, 5e6e6o6e, 5e6e6o6o, 5e6o5e5e, 5e6o5e6e, 5e6o5e6o, 5o6e6e5e, 5e6o6e6e, 5e6o6e6o, 5e6o6o5e, 5e6o6o6e,

5e6o6o6o, 6e5e5e5e, 6e5e5e6e, 6e5e5e6o, 6e5e6e5e, 6e5e6e6e, 6e5e6e6o, 6e5e6o5e, 6e5e6o6e, 6e5e6o6o, 6e6e5e5e, 6e6e5e6e, 6e6e5e6o, 6e6e6e5e, 6e6e6e6e, 6e6e6e6o, 6e6e6o5e, 6e6e6o6e, 6e6e6o6o, 6e6o5e5e, 6e6o5e6e, 6e6o5e6o, 6e6e6e5e, 6e6o6e6e, 6e6o6e6o, 6e6o6o5e, 6e6o6o6e, 6e6o6o6o, 6o5e5e5e, 6o5e5e6e, 6o5e5e6o, 6o5e6e5e, 6o5e6e6e, 6o5e6e6o, 6o5e6o5e,

6o5e6o6e, 6o5e6o6o, 6o6e5e5e, 6o6e5e6e, 6o6e5e6o, 6o6e6e5e, 6o6e6e6e, 6o6e6e6o,

6o6e6o5e, 6o6e6o6e, 6o6e6o6o, 6o6o5e5e, 6o6o5e6e, 6o6o5e6o, 6o6e6e5e, 6o6o6e6e,

6o6o6e6o, 6o6o6o5e, 6o6o6o6e, 60606060.

[00060] In some embodiments Ar has no more than 1 heteroatom. In others it has no

2

more than 1 nitrogen atom. In some embodiments Ar is a 6-membered ring (either

homoaromatic or heteroaromatic). In other embodiments, when -X-C(R R )- is -CH₂-CH₂-, Ar is not a pyrazole ring linked to Ar² through a nitrogen atom in Ar¹. In some embodiments, Ar¹ has no more than 3 nitrogen atoms. Any two or more of these embodiments may be combined. Thus, for example in some embodiments, Ar² is a 6-membered ring (either homoaromatic or heteroaromatic), Ar 1 has no more than 3 nitrogen atoms, and, when -X-C(R 1 R2 )- is -CH₂-CH₂-, Ar¹ is not a pyrazole ring linked to Ar² through a nitrogen atom in Ar¹. [00061] In some embodiments Ar is a l-methylpyrazole-5-yl group. Ar may be a 1- methylpyrazole-5-yl group, X may be N or NH and Ar may be a pyridine ring having the 1 - methylpyrazole-5-yl group in the 2 position and the N or NH in the 5-position.

[00062] The compounds of the invention are commonly made by coupling a compound of structure II with a compound of structure III

so as to form an amide bond. Suitable conditions for this reaction are well known to those skilled in the art. Commonly a coupling agent, for example HATU (l-[bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-6]pyridinium 3-oxide hexafiuorophosphate), BOP ((benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafiuorophosphate), DCC (Ν,Ν'- dicyclohexylcarbodiimide), DIPC (Ν,Ν'-diisopropylcarbodiimide), HO At (3- hydroxytriazolo[4,5-Z>]pyridine) or similar will be used. Typically the reaction will be conducted under an inert atmosphere, e.g. nitrogen, argon, helium etc. The reaction may be conducted in any suitable solvent, commonly a dipolar aprotic solvent such as N-methyl morpholine, dioxane, THF, acetone, DMSO, DMF etc.

[00063] The synthesis of reagents II and III will depend on the details of the structure of these compounds. For example reagent II may be made by coupling a suitable Ar¹ -containing compound With a. suitable Ar²-X- C(R¹R²)-C(=0)-OA reagent (where -OA is a removable protecting group such as alkoxy). Coupling between aromatic/heteroaromatic groups may be conducted by well known methods such as a copper (I) catalysed coupling. Similarly reagent III may be made by coupling a suitable Ar -containing reagent with a suitable HN(R³)-Ar³- containing reagent (optionally protected to prevent unwanted reaction of the amine function) by a similar aryl and/or heteroaryl coupling reaction, followed if necessary by deprotection of the amine function.

[00064] Another route to making the compounds of the invention involves coupling a compound of structure IV with a compound of structure V

ΑΛΑ Χ-Η Hal-C(R¹R²)-C(=0)N(R³)- Ar³-Ar⁴

(IV) (V) [00065] The skilled person will readily appreciate how to conduct such coupling reactions. For example if X is OH, the reaction may be accomplished under mild conditions in the presence of a mild base such as carbonate. Synthesis of reagents IV and V may be accomplished by commonly known methods. For example HN(R³)-Ar³-Ar⁴ may be converted to reagent V by reaction with an appropriate haloacetyl halide. This may be a base catalysed reaction, e.g. using a tertiary amine catalyst such as triethylamine.

[00066] In some instances pyridine rings in reagents may be protected as their N-oxide and subsequently deprotected using a suitable reducing agent, e.g. iron powder in acetic acid.

[00067] In certain cases the coupling reactions such as described above may not be the final step ifi th@ synthesis. Thus the coupling may be effected before coupling Ar¹ to Ar², or before coupling Ar⁴ to Ar³. Suitable aryl-aryl coupling reactions that may be used to couple Ar¹ to Ar², or Ar⁴ to Ar³ (either before or after other coupling reactions used in the synthesis) include reaction of aryl halides (commonly bromides or iodides) with nitrogen heterocycles such as imidazole. This coupling may be catalysted by Cu(I) and base. Other suitable coupling reactions include reaction of palladium catalysed coupling of boronates or alkyl tin derivatives.

[00068] An alternative way to define certain of the compounds of the present invention is set out below. It should be noted that in this definition, X and R to R₇ are not necessarily the same as for the earlier definition although the general definitions of "alkyl", "aryl" etc. do apply.

X = O, N, C

Y = C, N

Ri = substituted and unsubstituted 5 membered or 6 membered heterocycles including, but not limited to:

where R = H, alkyl, aryl, amine, amide

R-2, R3 ⁼ (independently) alkyl, alkoxy, amine, carboxylic acid, carboxylic amide or fused bicycle

R₄ = alkyl or fused ring with aromatic ring at R₃

R₅ = smaller alkyl, cyclic amino acid fused with R4 or R5 is fused with R₇

R₆ = biaryl, biaryl with heteroatom(s) or 5 membered and 6 membered heterocycles including, but not limited to:

R₇ = F, O, C0₂H, CONHalkyl or CONHaryl, CONdialkyl or cyclic amide

[00069] As discussed earlier, the compounds of the present invention may be used in therapy. They may be used for manufacture of medicaments for use in therapy.

[00070] The compounds of the present invention may be administered as compositions either therapeutically or preventively. In a therapeutic application, compositions are

administered to a patient already suffering from a disease, in an amount sufficient to cure or at least partially arrest the disease and its complications. The composition should provide a quantity of the compound or agent sufficient to effectively treat the patient.

[00071 ] The therapeutically effective dose level for any particular patient will depend upon a variety of factors including: the disorder being treated and the severity of the disorder; activity of the compound or agent employed; the composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of sequestration of the agent or compound; the duration of the treatment; drugs used in combination or coincidental with the treatment, together with other related factors well known in medicine.

[00072] One skilled in the art would be able, by routine experimentation, to determine an effective, non-toxicamount of agent or compound which would be required to treat applicable diseases.

[00073] Generally, an effective dosage is expected to be in the range of about 0.000 lmg to about lOOOmg per kg body weight per 24 hours; typically, about O.OOlmg to about 750mg per kg body weight per 24 hours; about O.Olmg to about 500mg per kg body weight per 24 hours; about O.lmg to about 500mg per kg body weight per 24 hours; about O.lmg to about 250mg per kg body weight per 24 hours; about 1.Omg to about 250mg per kg body weight per 24 hours. More typically, an effective dose range is expected to be in the range about 1.Omg to about 200mg per kg body weight per 24 hours; about 1.Omg to about 1 OOmg per kg body weight per 24 hours; about 1.Omg to about 50mg per kg body weight per 24 hours; about 1.Omg to about 25mg per kg body weight per 24 hours; about 5. Omg to about 50mg per kg body weight per 24 hours; about 5. Omg to about 20mg per kg body weight per 24 hours; about 5. Omg to about 15mg per kg body weight per 24 hours.

[00074] Typically, in therapeutic applications, the treatment would be for the duration of the disease state.

[00075] Further, it will be apparent to one of ordinary skill in the art that the optimal quantity and spacing of individual dosages will be determined by the nature and extent of the disease state being treated, the form, route and site of administration, and the nature of the particular individual being treated. Also, such optimum conditions can be determined by conventional techniques.

[00076] It will also be apparent to one of ordinary skill in the art that the optimal course of treatment, such as, the number of doses of the composition given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests. [00077] In general, suitable compositions may be prepared according to methods which are known to those of ordinary skill in the art and accordingly may include a pharmaceutically acceptable carrier, diluent and/or adjuvant.

[00078] These compositions can be administered by standard routes. In general, the compositions may be administered by the parenteral (e.g., intravenous, intraspinal, subcutaneous or intramuscular), or oral, or by direct injection to the affected site.

[00079] The carriers, diluents and adjuvants must be "acceptable" in terms of being compatible with the other ingredients of the composition, and not deleterious to the recipient thereof.

[00080] Examples of pharmaceutically acceptable carriers or diluents are demineralised or distilled water; saline solution; vegetable based oils such as peanut oil, saffiower oil, olive oil, cottonseed oil, maize oil, sesame oils such as peanut oil, saffiower oil, olive oil, cottonseed oil, maize oil, sesame oil, arachis oil or coconut oil; silicone oils, including polysiloxanes, such as methyl polysiloxane, phenyl polysiloxane and methylphenyl polysolpoxane; volatile silicones; mineral oils such as liquid paraffin, soft paraffin or squalane; cellulose derivatives such as methyl cellulose, ethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose or hydroxypropylmethylcellulose; lower alkanols, for example ethanol or iso-propanol; lower aralkanols; lower polyalkylene glycols or lower alkylene glycols, for example polyethylene glycol, polypropylene glycol, ethylene glycol, propylene glycol, 1,3 -butyl ene glycol or glycerin; fatty acid esters such as isopropyl palmitate, isopropyl myristate or ethyl oleate;

polyvinylpyrridone; agar; carrageenan; gum tragacanth or gum acacia, and petroleum jelly.

Typically, the carrier or carriers will form from 10% to 99.9% by weight of the compositions.

[00081] The compositions of the invention may be in a form suitable for administration by injection, in the form of a formulation suitable for oral ingestion (such as capsules, tablets, caplets, elixirs, for example), in an aerosol form suitable for administration by inhalation, such as by intranasal inhalation or oral inhalation, in a form suitable for parenteral administration, that is, subcutaneous, intramuscular or intravenous injection. [00082] For administration as an injectable solution or suspension, non-toxic parenterally acceptable diluents or carriers can include, Ringer's solution, isotonic saline, phosphate buffered saline, ethanol and 1,2 propylene glycol.

[00083] Some examples of suitable carriers, diluents, excipients and adjuvants for oral use include peanut oil, liquid paraffin, sodium carboxymethylcellulose, methylcellulose, sodium alginate, gum acacia, gum tragacanth, dextrose, sucrose, sorbitol, mannitol, gelatine and lecithin. In addition these oral formulations may contain suitable flavouring and colourings agents. When used in capsule form the capsules may be coated with compounds such as glyceryl monostearate or glyceryl distearate which delay disintegration.

[00084] Adjuvants typically include emollients, emulsifiers, thickening agents, preservatives, bactericides and buffering agents.

[00085] Solid forms for oral administration may contain binders acceptable in human and veterinary pharmaceutical practice, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents. Suitable binders include gum acacia, gelatine, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include corn starch, methylcellulose,

polyvinylpyrrolidone, guar gum, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha- tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.

Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

[00086] Liquid forms for oral administration may contain, in addition to the above agents, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.

[00087] Suspensions for oral administration may further comprise dispersing agents and/or suspending agents. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, poly-vinyl-pyrrolidone, sodium alginate or acetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like.

[00088] The emulsions for oral administration may further comprise one or more emulsifying agents. Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as guar gum, gum acacia or gum tragacanth.

[00089] Methods for preparing parenterally administrable compositions are apparent to those skilled in the art, and are described in more detail in, for example, Remington's

Pharmaceutical Science, 15th ed., Mack Publishing Company, Easton, Pa., hereby incorporated by reference herein.

[00090] The composition may incorporate any suitable surfactant such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.

[00091] The compositions may also be administered in the form of liposomes. Liposomes are generally derived from phospholipids or other lipid substances, and are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used. The compositions in liposome form may contain stabilisers, preservatives, excipients and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art, and in relation to this specific reference is made to: Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq., the contents of which is incorporated herein by reference.

[00092] The oral formulation may be formulated with pharmacologically acceptable ingredients to make a tablet or capsule etc with an enteric coating. Methods for such

formulations are well known to those skilled in the art (see e.g., Remington: The Science and Practice of Pharmacy, 19 ed. (1995) Mack Publishing Company, Easton, Pa.; herein

incorporated by reference). The enteric coating may be an enteric coating which enhances delivery of the composition or active(s) drugs to specific regions of the gastrointestinal tract for enhanced bioavailability, such as are described in United States of America Patent Application Publication No. 20040162263 entitled "Pharmaceutical formulations targeting specific regions of the gastrointesinal tract" to Sands et al and published 19 August 2004.

Examples

[00093] The following examples provide compounds according to the present invention together with a number of general synthetic schemes for preparing the compounds. Each synthetic scheme has been illustrated with a specific example, and the examples following that may be made by the same general process. The person skilled in the art will readily appreciate the variations required to the illustrated example of each synthetic scheme in order to prepare other related coKBpoiinds. With reference to the following examples, reference in this

specification to a compound number will refer to the product described in, or finally produced by, the example of the same number. Thus, for example, Compound 2 is

ed in Example 2 and Compound 94 is

produced in Example 94. It should be noted that Compound

35 is the compound finally produced in Example 35 in which X=0, however all three

compounds (i.e. in which X= H, O or CH₂) are contemplated in the invention).

[00094] Example 1 : N-(biphenyl-4-yl)-2-(4-(2-methyl-lH-imidazol-l- yl)phenoxy)acetamide

X = Cl .or Br

General Procedure 1 :

[00095] To biphenyl-4-amine (500 mg, 2.95 mmol) in anhydrous DCM (15 ml) at 0°C was added triethylamine (495 μΐ, 3.54 mmol) and 2-chloroacetyl chloride (282 μΐ, 1.418 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and. stirred for 2h, then it was diluted with H₂0 (30 mL) and extracted with DCM (3x15 mL). The combined organic layer was dried over Na₂S0₄ and was concentrated under reduced pressure. The crude product N-(biphenyl-4-yl)-2-bromoacetamide (600 mg, brown solid) was used without further purification. 1H NMR (400 MHz, OMSO-d₆) δ 10.38 (s, 1H), 7.70-7.63 (m, 6H), 7.46-7.42 (m, 2H), 7.35-7.31 (m, IH), 4.27 (s, 2H).

[00096] To a solution of N-(biphenyl-4-yl)-2-bromoacetamide (92 mg, 0.316 mmol) and 4-(2-methyl-lH-imidazol-l-yl)phenol (55 mg, 0.316 mmol) in DMF (2 ml) was added K₂C0₃ (153 mg, 1.105 mmol). The solution was heated at 70°C for 16 h, then it was diluted with H₂0 (25 mL) and extracted with EtOAc (3x25 mL). The combined organic layer was dried over Na₂S0₄ and was concentrated under reduced pressure. The crude residue was purified by preparative HPLC (CI 8, eluent ACN, water, formic acid 0.1%) to afford N-(biphenyl-4-yl)-2-(4- (2-methyl-lH-imidazol-l-yl)phenoxy)acetamide (17 mg, 14%, HPLC 96%) as white solid. 1H NMR (400 MHz, DMSO-<¾) δ 10.23 (s, 1H), 7.76-7.74 (m, 2H), 7.66-7.64 (m, 4H), 7.46-7.31 (m, 5H), 7.20 (d, J=1.6Hz, 1H), 7.15-7.13 (m, 2H), 6.87 (d, J=1.6Hz, 1H), 4.80 (s, 2H), 2.24 (s, 3H); ¹³C NMR (400 MHz, DMSO-i₆) δ 166.28, 157.19, 143.64, 139.52, 137.73, 135.31, 131.05, 128.80, 127.00, 126.87, 126.84, 126.51, 126.18, 120.93, 119.95, 115.30, 67.27, 13.31; MS (ESI) m/z 384 [C₂₄H_2]N₃0₂ + H]⁺. .

[00097] In some cases NaH is used as a base (instead of K₂C0₃) under an inert gas, e.g. nitrogen. 2-bromoacetyl chloride may be used instead of 2-chloroacetyl chloride.

[00098] Example 2 : 2-(4-( 1 H-pyrazol- 1 -yl)phenoxy)-N-(biphenyl-4-yl)acetamide

73mg, 61%, HPLC 98%, light brown solid. 1H NMR (400 MHz, DMSO-i _d) δ 10.20 (s, IH), 8.38 (d, J=2.4Hz, IH), 7.78-7.64 (m, 9H), 7.44 (t, J=7.2Hz, 2H), 7.33 (t, J=7.6Hz, IH), 7.14 (t, J=9.2Hz, 2H), 6.50 (t, J=2.0Hz, IH), 4.77 (s, 2H) ; ¹³C NMR (400 MHz, DMSO- ) δ 166.45, 156.09, 140.41, 139.61, 137.79, 135.39, 134.00, 128.87, 127.48, 127.06, 126.90, 126.26, 120.08, 119.92, 115.47, 107.38, 67.51; MS (ESI) m/z 370 [C₂₃H₁₉N₃0₂ + H]⁺.

[00099] Example 3: 2-(2-(lH-imidazol-l-yl)phenoxy)-N-(biphenyl-4-yl)acetamide

29 mg, 19%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-c¾ δ 10.13 (s, 1H), 8.10 (s, 1H), 7.70-7.61 (m, 7H), 7.48-7.33 (m, 5H), 7.23-7.21 (m, 1H), 7.14-7.08 (m, 2H), 4.86 (s, 2H) ; ¹³C NMR (400 MHz, DMSO-c¾ δ 166.09, 150.52, 139.55, 137.70, 135.38, 128.87, 128.67, 128.33, 127.08, 126.99, 126.30, 126.25, 125.43, 121.75, 120.49, 119.76, 113.85, 67.46; MS (ESI) m/z 370 [C₂₃H₁₉N₃0₂ + H]⁺.

[000100] Example 4 : 2-(3 -( 1 H-imidazol- 1 -yl)phenoxy)-N-(biphenyl-4-yl)acetamide

112 mg, 49%, HPLC 99%, white solid. Ή NMR (400 MHz, DMSO-<¾ δ 10.20 (s, 1H), 8.28 (s, 1H), 7.78-7.72 (m, 3H), 7.65 (d, J= 8.8 Hz, 4H), 7.48-7.42 (m, 3H), 7.37-7.26 (m, 3H), 7.11 (s, 1H), 7.03-6.99 (m, 1H), 4.83 (s, 2H); ¹³C NMR (400 MHz, DMSO-i¾: 166.28,

158.88,139.60, 137.96, 137.78, 135.57, 135.40, 130.80, 129.86, 128.89, 127.09, 126.93, 126.27, 120.06, 118.01, 112.96, 112.91, 109.18, 67.35; MS (ESI) m/z 370 [C₂₃H₁₉N₃0₂ + H]⁺. oxy)-N-(biphenyl-4-yl)acetamide

36 mg, 34%, HPLC 98%, off-white solid. 1H NMR (400 MHz, DMSO-c¾) δ 10.22 (s, IH), 9.02 (s, 2H), 7.77-7.72 (m, 2H), 7.67-7.61 (m, 6H), 7.47-7.41 (m, 2H), 7.36-7.30 (m, IH), 7.21-7.16 (m, 2H), 4.82 (s, 2H); MS (ESI) m/z 371 [C₂₂H₁₈N₄0₂ + H]⁺.

[000101] Example6: 2-(4-(l H-imidazol- 1 -yl)benzyloxy)-N-(biphenyl-4-yl)acetamide

6.8 mg, 6%, HPLC 97%, white solid. 1H NMR (400 MHz, DMSO-< ₆) δ 9.91 (s, IH), 8.26 (s, IH), 7.78-7.72 (m, 3H), 7.69-7.60 (m, 6H), 7.59-7.54 (m, 2H), 7.47-7.41 (m, 2H), 7.36-7.30 (m, IH), 7.11 (s, IH), 4.68 (s, 2H), 4.15 (s, 2H); MS (ESI) m/z 384 [C₂₄H₂iN₃0₂ + H]⁺.

[000102] Example 7: 2-(4-(lH-benzo[d]imidazol-l-yl)phenoxy)-N-(biphenyl-4-

yl)acetamide

23 mg, 19%, HPLC 98%, white solid. 1H NMR (400 MHz, DMSO-<¾) ^ 10.21 (s, IH), 8.46 (s, IH), 7.79-7.73 (m, 3H), 7.69-7.59 (m, 6H), 7.55-7.51 (m, IH), 7.48-7.41 (m, 2H), 7.36-7.23 (m, 5H), 4.84 (s, 2H); MS (ESI) m/z 420 [C₂₇H₂₁N₃0₂ + H]⁺.

[000103] Example 8: 2-(4-(lH-pyrrol-l -yl)phenoxy)-N-(biphenyl-4-yl)acetamide

49mg, 65%, HPLC 97%, beige solid. Ή NMR (400 MHz, DMSO-_¾ δ 10.20 (s, IH), 7.76-7.74 (m, 2H), 7.66-7.64 (m, 4H), 7.52-7.42 (m, 4H), 7.35-7.31 (m, IH), 7.25 (t, J=2.0 Hz, 2H), 7.1 1- 7.08 (m, 2H), 6.22 (t, J=2.0 Hz, 2H), 4.75 (s, 2H); ¹³C NMR (400 MHz, DMSO-< ) δ 166.53, 155.45, 139.59, 137.80, 135.36, 134.14, 128.87, 127.06, 126.90, 126.25, 120.84, 120.04, 119.06, 115.62, 109.93, 67.48; MS (ESI) m/z 369 [C₂₄H₂₀N₂O₂ + H]⁺.

[000104] Example 9: N-(biphenyl-4-yl)-2-(4-(l -methyl- lH-pyrrol-3-yl)phenoxy)acetamide

32mg, 28%, HPLC 96%, off-white solid. 1H NMR (400 MHz, DMSO-i¾ δ 10.20 (s, IH), 7.76- 7.74 (m, 2H), 7.66-7.64 (m, 4H), 7.46-7.31 (m, 5H), 7.06-7.04 (m, 2H), 6.78 (t, J=2.0Hz, IH), 6.07-6.01 (m, 2H), 4.75 (s, 2H), 3.60 (s, 3H) ; ¹³C NMR (400 MHz, DMSO- ₆) δ 166.60, 156.66, 139.60, 137.83, 135.35, 133.10, 129.30, 128.87, 127.06, 126.90, 126.25, 123.55, 120.03, 114.71, 107.76, 107:13, 67.24, 34.69 ; MS (ESI) m/z 383 [C₂₅H₂₂N₂0₂ + H]⁺.

[000105] Example 10: N-(biphenyl-4-yl)-2-(4-(pyridin-3-yl)phenoxy)acetamide

8mg, 16%, HPLC 97%, off-white solid. ^ιΉ NMR (400 MHz, DMSO-<¾ δ 10.16 (s, IH), 8.85 (d, J= 2.0Hz, IH), 8.51 (d, J= 4.4Hz, IH), 8.02 (d, J= 8.0Hz, IH), 7.76-7.63 (m, 8H), 7.44 (t, J= 7.2Hz, 3H), 7.33 (t, J= 7.2Hz, IH), 7.15 (d, J= 8.8Hz, 2H), 4.79 (s, 2H) ; MS (ESI) m/z 381

[C₂₅H₂₀N₂O₂ + H]⁺.

[000106] Example 11 : N-(biphenyl-4-yl)-2-(4-(4,5-dimethyl- 1 H-imidazol- 1 - yl)phenoxy)acetamide

32 mg, 30%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-¾) δ 10.23 (s, IH), 7.76-7.74 (m, 2H), 7.66-7.64 (m, 4H), 7.56 (s,lH), 7.44 (t, J=7.6 Hz, 5H), 7.35-7.31 (m, 3H), 7.14-7.12 (m, 2H), 4.80 (s, 2H), 2.09 (s, 3H), 2.03 (s, 3H); ¹³C NMR (400 MHz, DMSO-d₆) δ 166.20, 162.93, 157.11, 139.42, 137.62, 135.21, 135.06, 132.96, 129.92, 128.69, 126.89, 126.74, 126.44, 126.08, 122.20, 119.85, 115.23, 67.17, 12.50, 8.56; MS (ESI) m/z 398 [C₂₅H₂₃N₃0₂ + H]⁺.

[000107] Example 12: 2-(4-(lH-pyrazol-3-yl)phenoxy)-N-(biphenyl-4-yl)acetamide

31 mg, 24%, HPLC 98%, off-white solid. 1H NMR (400 MHz, DMSO- ) δ 10.42 (s, IH), 9.44 (s, IH), 7.76 (d, J=2.4 Hz, IH), 7.71-7.58 (m, 8H), 7.44 (t, J=7.6 Hz, 2H), 7.32 (t, J=7.6 Hz, IH), 6.78-6.76 (m, 2H), 6.59 (d, J=2.4 Hz, IH), 5.04 (s, 2H); ¹³C NMR (400 MHz, DMSO-< ₆) δ 165.54, 156.87, 150.67, 139.50, 137.99, 135.17, 133.07, 128.79, 126.97, 126.94, 126.33, 126.16, 124.39, 119.48, 115.25, 101.75, 54.55; MS (ESI) m/z 370 [C₂₃H₁₉N₃0₂ + H]⁺.

[000108] Example 13: N-(biphenyl-4-yl)-2-(4-(2-ethyl-lH-imidazol-l- yl)phenoxy)acetamide

43 mg, 81%, HPLC 95%, beige solid. ^lH NMR (400 MHz, DMSO-c¾ δ 10.23 (s, IH), 7.76-7.64 (m, 6H), 7.46-7.31 (m, 5H), 7.18-7.12 (m, 3H), 6.89 (s, IH), 4.80 (s, 2H), 2.58-2.49 (m, 2H), 1.1 1 (t, J=7.6Hz, 3H); MS (ESI) m/z 398 [C₂₅H₂3N₃0₂ + H]⁺.

Example 14: N-(biphenyl-4-yl)-2-(4-(2-phenyl-lH-imidazol-l-

41 mg, 73%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-<¾ δ 10.20 (s, IH), 7.75-7.73 (m, 2H), 7.66-7.64 (m, 4H), 7.44-7.41 (m, 3H), 7.33-7.25 (m, 8H), 7.15-7.08 (m, 3H), 4.78 (s, 2H); ¹³C NMR (400 MHz, DMSO- ) δ 166,26, 157.41, 145.70, 139.59, 137.79, 135.39, 131.63, 130.47, 128.88, 128.43, 128.16, 128.09, 128.03, 127.29, 127.08, 126.91, 126.26, 123.95, 120.03, 115.44, 67.34; MS (ESI) m/z 446 [C₂₉H₂₃N₃0₂ + H]⁺.

[000110] Example 15 : N-(biphenyl-4-yl)-2-(4-(2-isopropyl- 1 H-imidazol- 1 - yl)phenoxy)acetamide

7 mg, 6%, HPLC 98%, white solid. 1H NMR (400 MHz, DMSO-_¾) δ 10.25 (bs, 1H), 7.78-7.72 (m, 2H), 7.69-7.61 (m, 4H), 7.48-7.41 (m, 2H), 7.38-7.30 (m, 3H), 7.18-7.10 (m, 3H), 6.89 (d, J = 1.2Hz, 1H), 4.81 (s, 2H), 2.95-2.80 (m, 1H), 1.19 (d, J= 6.8Hz, 6H); MS (ESI) m/z 412

[C₂₆H₂₅N₃0₂ + H]⁺.

[000111] Examp -(biphenyl-4-yl)-2-(4-(l-methyl-lH-pyrazol-5-

100 mg, 91%, HPLC 96%, white solid. 1H NMR (400 MHz, DMSC ^) δ 10.24 (bs, 1H), 7.78- 7.73 (m, 2H), 7.68-7.62 (m, 4H), 7.52-7.41 (m, 5H), 7.37-7.30 (m, 1H), 7.15-7.10 (m, 2H), 6.33 (d, J= 1.6Hz, 1H), 4.80 (s, 2H), 3.83 (s, 3H); ¹³C NMR (400 MHz, DMSO-J₆): 166.39, 157.83, 142.32, 139.58, 137.80, 137.71, 135.34, 129.75, 128.84, 127.04, 126.88, 126.23, 123.22, 120.00, 114.93, 105.36, 67.17, 37.33; MS (ESI) m/z 384 [C₂₄H₂₁N₃0₂ + H]⁺. [000112] Example 17: 2-(4-(lH-imidazol-5-yl)phenoxy)-N-(biphenyl-4-yl)acetamide

8 mg, 8%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-i¾ δ 10.17 (bs, 1H), 7.78-7.72 (m, 2H), 7.72-7.67 (m, 2H), 7.67-7.62 (m, 6H), 7.48-7.41 (m, 3H), 7.36-7.30 (m, 1H), 7.05-6.98 (m, 2H), 4.72 (s, 2H); MS (ESI) m/z 370 [C₂₃H₁₉N₃0₂ + H]⁺.

[000113] Example 18: N-(biphenyl-4-yl)-2-(4-(l-methyl-lH-imidazol-5- yl)phenoxy)acetamide

83 mg, 76%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-c¾ δ 10.22 (bs, 1H), 7.79- 7.72 (m, 2H), 7.69-7.61 (m, 5H), 7.49-7.41 (m, 4H), 7.37-7.30 (m, 1H), 7.13-7.06 (m, 2H), 6.99- 6.94 (m, 1H), 4.78 (s, 2H), 3.64 (s, 3H); ¹³C NMR (400 MHz, DMSO-<¾: 6 166.50, 157.35, 139.60, 139.22, 137.82, 135.35, 132.27, 129.26, 128.87, 127.06, 126.91, 126.88, 126.25, 122.83, 120.01, 114.98, 67.19, 32.15; MS (ESI) m/z 384 [C₂₄H₂₁N₃0₂ + H]⁺.

[000114] Example 19: N-(biphenyl-4-yl)-2-(3-fluoro-4-(lH-imidazol-l- yl)phenoxy)acetamide

80 mg, 72%, HPLC 98%, white solid. 1H NMR (400 MHz, DMSO-c¾ δ 10.23 (bs, 1H), 7.94 (s, 1H), 7.78-7.70 (m, 2H), 7.70-7.61 (m, 4H), 7.61-7.53 (m, 1H), 7.50-7.40 (m, 3H), 7.37-7.30 (m, 1H), 7.24-7.17 (m, 1H), 7.10 (s, 1H), 7.04-6.97 (m, 1H), 4.85 (s, 2H); ¹³C NMR (400 MHz, DMSO-i¾: δ 165.95, 158.21, 158.11 , 156.30, 153.83, 139.58, 137.75, 137.44, 135.41, 128.96, 128.88, 127.09, 126.94, 126.76, 126.26, 120.43, 119.99, 1 18.60, 118.48, 1 1 1.47, 103.84, 103.60, 67.49; MS (ESI) m/z 388 [C₂₃H₁₈FN₃0₂ + H]⁺. -(biphenyl-4-yl)-2-(3-methyl-4-(oxazol-5-yl)phenoxy)acetamide

102 mg, 92%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-J^) ^ 10.19 (bs, 1H), 8.42 (s, 1H),.7.78-7.71 (m, 2H), 7.69-7.57 (m, 5H), 7.48-7.41 (m, 2H), 7.38-7.29 (m, 2H), 7.05-7.00 (m, 1H), 7.00-6.95 (m, 1H), 4.78 (s, 2H), 2.42 (s, 3H); ¹³C NMR (400 MHz,

δ 166.32, 157.81, 151.02, 149.71, 139.58, 137.77, 136.53, 135.35, 128.83, 128.29, 127.03, 126.87, 126.22, 123.05, 120.14, 120.02, 117.30, 1 12.47, 67.09, 21.32; MS (ESI) m/z 385 [C₂₄H₂₀N₂O₃ +

H]⁺.

[000116] Example 21 : 2-(4-( 1 H-imidazol- 1 -yl)-2-methoxyphenoxy)-N-(biphenyl-4- yl)acetamide

29 mg, 26%, HPLC 97%, white solid. 1H NMR (400 MHz, MeOH-<¾) <S 8.09 (s, IH), 7.74-7.69 (m, 2H), 7.65-7.58 (m, 4H), 7.56-7.53 (m, IH), 7.46-7.39 (m, 2H), 7.34-7.29 (m, IH), 7.26 (d, J = 2.4Hz, IH), 7.23-7.19 (m, IH), 7.15-7.09 (m, 2H), 4.74 (s, 2H), 4.01 (s, 3H); MS (ESI) m/z 400 [C₂₄H₂₁N₃O₃ + H]⁺.

Example 22: 2-(4-(l H-imidazol- 1 -yl)-3-methylphenoxy)-N-(biphenyl-4-

40 mg, 37%, HPLC 96%, white solid. ^!H NMR (400 MHz, MeOH-^) δ 7.40 (s, IH), 7.74-7.69 (m, 2H), 7.64-7.58 (m, 4H), 7.45-7.39 (m, 2H), 7.34-7.29 (m, IH), 7.28-7.22 (m, 2H), 7.16-7.09 (m, 2H), 7.05-7.00 (m, IH), 4.76 (s, 2H), 2.16 (s, 3H); MS (ESI) m/z 384 [C₂₄H₂iN₃0₂ + H]⁺.

[000118] Example 23: N-(biphenyl-4-yl)-2-(4-(oxazol-5-yl)phenoxy)acetamide

71 mg, 66%, HPLC 99%, off- white solid. 1H NMR (400 MHz, DMSO-^) δ 10.20 (s, IH), 8.38 (s, IH), 7.77-7.72 (m, 2H), 7.72-7.67 (m, 2H), 7.67-7.62 (m, 4H), 7.55 (s, IH), 7.48-7.41 (m, 2H), 7.36-7.30 (m, 1H), 7.16-7.10 (m, 2H), 4.79 (s, 2H); MS (ESI) m/z 371 [C₂₃H_lgN₂0₃ +

H]⁺.

[000119] Example 24: 2-(4-(l H-imidazol- l-yl)-2-methylphenoxy)-N-(biphenyl-4- yl)acetamide

23 mg, 21%, HPLC 98%, white solid. 1H NMR (400 MHz, MeOH-^) δ 8.01 (s, IH), 7.72-7.66 (m, 2H), 7.63-7.57 (m, 4H), 7.49-7.45 (m, IH), 7.44-7.37 (m, 3H), 7.37-7.27 (m, 2H), 7.10 (s, IH), 7.08-7.02 (m, IH), 4.82 (s, 2H), 2.42 (s, 3H); MS (ESI) m/z 384 [C₂₄H₂₁N₃0₂ + H]⁺.

[000120] Example 25: N-(biphenyl-4-yl)-2-(4-(thiazol-5-yl)phenoxy)acetamide

71 mg, 66%, HPLC 99%, off- white solid. 1H NMR (400 MHz, DMSO-<¾ δ 10.23 (bs, IH), 9.02 (s, IH), 8.20 (s, IH), 7.78-7.70 (m, 2H), 7.70-7.60 (m, 6H), 7.49-7.40 (m, 2H), 7.38-7.30 (m, IH), 7.10 (d, J = 8.8 Hz, 2H), 4.79 (s, 2H); MS (ESI) m/z 387 [C₂₃Hi₈N₂0₂ + H]⁺.

[000121] Example 26: N-(biphenyl-4-yl)-2-(4-(4-methyl-l H-imidazol- 1- yl)phenoxy)acetamide

23 mg, 11%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-cfe) δ 10.20 (s, 1H), 8.00 (d, J=1.2Hz, 1H), 7.76-7.74 (m, 2H), 7.66-7.64 (m, 4H), 7.55-7.51 (m, 2H), 7.45 (t, J=7.6Hz, 2H), 7.34 (t, J=7.6Hz, 2H), 7.14-7.12 (m, 2H), 4.78 (s, 2H), 2.15 (s, 3H); MS (ESI) m/z 384

[C₂₄H₂iN₃0₂ + H]⁺.

Example 27: 2-(4-(lH-imidazol-l -yl)-3-methoxyphenoxy)-N-(biphenyl-4-

30 mg, LC-MS 99%. 1H NMR (400 MHz, CDC1₃) δ (ppm): 8.24 (br. s, 1H), 7.71-7.57 (m, 7H), 7.45 (t, J= 8.0 Hz, 2H), 7.36 (t, J= 8.0 Hz, 1H), 7.15 (t, J= 12.0 Hz, 2H), 6.72 (d, J= 4.0 Hz, IH), 6.64-6.62 (dd, J= 4.0, J= 4.0 Hz, 1H), 4.68 (s, 2H), 3.87 (s, 3H); MS (ESI) m/z 400 [M+l].

[000123] Example 28: 2-(4-(lH-imidazol-l-yl)-3-(trifluoromethyl)phenoxy)-N-(biphenyl- 4-yl)acetamide

50 mg, LC-MS 99%. 1H NMR (400 MHz, CDC1₃) δ (ppm): 8.20 (s, IH), 7.70-7,58 (m, 7H), 7.47-7.33 (m, 5H), 7.26 (s, IH), 7.08 (s, IH), 4.68 (s, 2H); MS (ESI) m/z 438 [M+l ].

[000124] Example 29: 2-(5-(lH-imidazol-l-yl)pyridin-2-yloxy)-N-(biphenyl-4- yl)acetamide

30 mg, 6%, LC-MS 99%, off-white solid. 1H NMR (400 MHz, DMSO- ₆) δ (ppm): 10.5 (s, IH), 9.1 (bs, IH), 8.3 (s, IH), 7.90-7.87 (m, 2H), 7.70-7.63 (m, 7H), 7.44 (t, J= 8.0 Hz, 2H), 7.33 (t, J = 8.0 Hz, IH), 6.66 (d, J = 12.0 Hz, IH), 4.8 (s, 2H); MS (ESI) m/z 371.05 [C₂₂H₁₈N₄0₂ +H] ⁺.

[000125] Example 30: 2-(4-(lH-imidazol-l-yl)-3-(trifluoromethoxy)phenoxy)-N- (biphenyl-4-yl)acetamide

60 mg, LC-MS 99%. 1H NMR (400 MHz, CDC1₃) δ (ppm): 8.20 (s, 1Η),7.70-7.68 (m, 3H), 7.63- 7.58 (m, 4H),7.46-7.41 (m, 3H), 7.36 (d, J= 8.0 Hz, IH), 7.22 (bs, IH), 7.14-7.13 (bs, 2H), 7.06 (dd, J= 4.0 Hz, IH), 4.70 (s, 2H); MS (ESI) m/z 453 [M+l].

[000126] Example 31 : 2-(4-(lH-imidazol-l-yl)-2-(trifluoromethoxy)phenoxy)-N- (biphenyl-4-yl)acetamide

40 mg, LC-MS 99%. 1H NMR (400 MHz, CDC1₃) δ (ppm): 8.41 (bs, IH), 7.81 (s, IH), 7 7.58 (m, 6H), 7.47-7.43 (t, J= 8.0 Hz, 2H),7.38-7.35 (m, 3H), 7.24 (bs, 2H), 7.17 (d, J = IH), 4.73 (s, 2H); MS (ESI) m/z 453 [M+l].

[000127] Example 32: N-(biphenyl-4-yl)-2-(4-(pyridin-4-yl)phenoxy)acetamide

100 mg, 45%, LC-MS 98%. 1H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.27 (s, IH), 8.59 (d, J = 5.7 Hz, 2H), 7.82 (d, J= 8.8 Hz, 2H), 7.75 (d, J= 8.8 Hz, 2H), 7.7-7.6 (m, 6H), 7.45 (t, J= 7.9 Hz, 2H), 7.34 (t, J= 7.5 Hz, IH), 7.15 (d, J= 8.8 Hz, 2H), 4.82 (s, 2H); MS (ESI) m/z 381.20 [C₂₅H₂₀N₂O₂+ H]⁺.

[000128] Example 33 : N-(biphenyl-4-yl)-2-(4-(oxazol-4-yl)phenoxy)acetamide

150 mg, 33%, LC-MS 98 %. 1H NMR (400 MHz, DMSO- d₆) δ (ppm): 10.21 (s, IH), 8.52 (s, IH), 8.42 (s, IH), 7.75 (d, J= 8.4 Hz, 4H), 7.65 (d, J- 8.8 Hz, 4H), 7.45 (t, J= 7.6 Hz, 2H), 7.34 (d, J= 7.2 Hz, IH), 7.09 (d, J= 8.8 Hz, 2H), 4.76 (s, 2H); MS (ESI) m/z 371 [M+l].

[000129] Example 34: N-(biphenyl-4-yl)-2-(7-(oxazol-5-yl)-3-oxo-2H- benzo[b] [ 1 ,4]oxazin-4(3H)-yl)acetamide

28 mg, 56%, HPLC 96%, white solid. Ή NMR (400 MHz,

δ 10.46 (bs, IH), 8.41 . (s, IH), 7.71-7.61 (m, 7H), 7.48-7.38 (m, 4H), 7.36-7.29 (m, IH), 7.23-7.17 (m, IH), 4.85-4.75 (m, 4H); MS (ESI) m/z 426 [C₂₅H₁₉N₃0₄ + H]⁺.

[000130] Example 35 : 2-(4-( 1 H-imidazol- 1 -yl)phenoxy)-N-(biphenyl-4-yl)propanamide

General procedure 2:

[000131] To a solution of 4-(l H-imidazol- l-yl)phenol (300 mg, 1.873 mmol) and ethyl 2- bromopropanoate (243μ1, 1.873mmol) in DMF (4 ml) was added K₂C0₃ (906 mg, 6.555 mmol). The solution was heated at 70°C for 16 h, then it was diluted with H₂0 (25 mL) and extracted with EtOAc (3x25 mL). The combined organic layer was dried over Na₂S0₄ and was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, eluent Hexane/EtOAc 50:50) to afford ethyl 2-(4-(l H-imidazol- 1- yl)phenoxy)propanoate as a yellow oil (325 mg). 1H NMR (400 MHz, CDCI₃) δ 7.74 (s, IH), 7.29-7.26 (m, 2H), 7.18-7.17 (m, 2H), 6.97-6.95 (m, 2H), 4.76 (q, J= 6.8Hz, IH), 4.23 (q, J= 7.2Hz, 2H), 1.644 (d, J= 6.8Hz, 3H), 1.26 (t, J= 7.2Hz, 3H).

[000132] Methyl ethyl 2-(4-(lH-imidazol-l-yl)phenoxy)propanoate obtained from the above reaction (163 mg, 0.625 mmol) was added to a solution of LiOH (30 mg, 1.250 mmol) in THF (1 mL) and H₂0 (1 mL) and stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure and the residue was acidifed to pH 1 using 1M HC1. It was then concentrated and the residue dried at 50°C under vacuum to yield 2-(4-(lH-imidazol-l- yl)phenoxy)propanoic acid. The crude product (140 mg) was used without further purification.

[000133] To a solution of 2-(4-(lH-imidazol-l-yl)phenoxy)propanoic acid (140 mg, 0.603 mmol) in DMF (3 mL) was added HATU (344 mg, 0.905 mmol) and N-methyl morpholine (265 μΐ, 2.412 mmol). The reaction mixture was stirred at room temperature under inert atmosphere for 1 h, followed by the addition of biphenyl-4-amine (102 mg, 0.603 mmol). The reaction mixture was left to stir for 16 h, then it was diluted with H₂0 (25 mL) and extracted with EtOAc (3x25 mL). The combined organic layer was dried over Na₂S0₄ and was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, eluent Hexane/EtOAc 30:70) to afford 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(biphenyl-4- yl)propanamide (146 mg, 63%, HPLC 99%) as a white solid. 1H NMR (400 MHz, DMSO-i ₆) δ 10.19 (s, IH), 8.09 (s, IH), 7.74-7.71 (m, 2H), 7.63-7.54 (m, 7H), 7.43 (t, J= 7.6Hz, 2H), 7.32 (t, J= 7.6Hz, IH), 7.11 (d, J= 8.8Hz, 2H), 7.05 (s, IH), 4.96 (q, J= 6.8Hz, IH), 1.59 (d, J= 6.4Hz, 3H) ; ¹³C NMR (400 MHz, DMSO- ₆) δ 169.82, 155.97, 139.59, 137.84, 135.51, 135.45, 130.86, 129.53, 128.87, 127.07, 126.87, 126.25, 122.05, 120.07, 118.26, 1 16.18, 74.17, 18.56; MS (ESI) m/z 384 [C₂₄H₂iN₃0₂ + H]⁺.

[000134] In some cases when X = NH, NH was protected as its NBoc derivative in order to achieve good amide coupling.

[000135] Example 36: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(biphenyl-2-yl)acetamide

80 mg, 47%, HPLC 99%, white solid. Ή NMR (400 MHz, DMSO-- ) δ 9.22 (s, IH), 8.14 (s, IH), 7.88 (d, J=8.0 Hz, IH), 7.65 (s, IH), 7.55-7.27 (m, 10H), 7.08 (s, IH), 6.91 (d, J=8.8 Hz, 2H), 4.61 (s, 2H); ¹³C NMR (400 MHz, DMSO-<¼) S 166.33, 155.90, 138.12, 135.49, 134.88, 134.00, 130.99, 130.19, 129.59, 128.86, 128.71, 128.04, 127.57, 125.54, 124.00, 121.86, 1 18.24, 115.59, 67.22; MS (ESI) m/z 370 [C₂₃Hi₉N₃0₂ + H]⁺.

[000136] Example 37 : 2-(4-( 1 H-imidazol- 1 -yl)phenoxy)-N-(4-(pyridin-4- yl)phenyl) acetamide

110 mg, 69%, HPLC 99%, off-white solid. 1H NMR (400 MHz, DMSO-^) δ 10.32 (s, IH), 8.60 (d, J=6.0 Hz, 2H), 8.13 (s, IH), 7.81 (s, 4H), 7.70-7.57 (m, 5H), 7.15 (d, J=9.2 Hz, 2H), 7.07 (s, IH), 4.80 (s, 2H); ¹³C NMR (400 MHz, DMSO- ) δ 166.63, 156.52, 150.16, 146.28, 139.43, 135.51, 132.01, 130.87, 129.55, 127.23, 121.96, 120.63, 120.00, 118.28, 1 15.73, 67.38; MS (ESI) m/z 371 [C₂₂H₁₈N₄0₂ + H]⁺.

[000137] Example 38: 4-(2-(4-(l H-imidazol- l-yl)phenoxy)acetamido)benzamide

16mg, 13%, HPLC 98%, brown solid. 1H NMR (400 MHz, DMSO-< ) δ 10.34 (s, IH), 8.13 (s, IH), 7.85 (d, J=8.8 Hz, 3H), 7.71 (d, J=8.8 Hz, 2H), 7.64 (s, IH), 7.57 (d, J=8.8 Hz, 2H), 7.24 (br s, IH), 7.13 (d, J-8.8 Hz, 2H), 7.07 (s, IH), 4.79 (s, 2H); MS (ESI) m/z 337 [Ci₈H₁₆N₄0₃ + H]⁺.

[000138] Example 39: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(biphenyl-4-yl)-N- methylacetamide

14mg, 10%, HPLC 98%, light brown solid. 1H NMR (400 MHz, CDC ) δ 7.71-7.31 (m, 1 IH), 7.25-7.16 (m, 3H), 6.90 (br s, 2H), 4.53 (s, 2H), 3.36 (s, 3H); MS (ESI) m/z 384 [C₂₄H₂iN₃0₂ + H]⁺.

[000139] Example 40: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(4-(pyridin-3- yl)phenyl)acetamide

81 mg, 60%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-i¾ δ 10.21 (s, IH), 8.88 (d, J=2.0 Hz, IH), 8.54-8.52 (m, IH), 8.11-8.03 (m, 2H), 7.79-7.56 (m, 7H), 7.47-7.44 (m, IH), 7.15 (d, J=8.8 Hz, 2H), 7.07 (s, IH), 4.79 (s, 2H); ¹³C NMR (400 MHz, DMSC ¾) δ 167.00, 157.09, 148.59, 147.80, 138.93, 136.02, 135.51, 134.07, 132.72, 131.42, 130.05, 127.65, 124.27, 122.50, 120.69, 118.78, 116.30, 68.02; MS (ESI) m/z 371 [C₂₂Hi₈N₄0₂ + H]⁺. [000140] Example 41 : 3-(4-(lH-imidazol-l-yl)phenyl)-N-(biphenyl-4-yl)propanamide

85 mg, 34%, HPLC 98%, off-white solid. 1H NMR (400 MHz, DMSO-i¾ δ 10.02 (s, IH), 8.20 (s, IH), 7.70-7.55 (m, 9H), 7.45-7.39 (m, 4H)), 7.31 (t, J= 7.6 Hz, IH), 7.08 (s, IH), 2.98 (t, J= 7.6Hz, 2H), 2.68 (t, J= 7.6Hz, 2H); ¹³C NMR (400 MHz, DMSO-c¾) δ 170.21, 139.90, 139.64, 138.57, 135.33, 134.96, 134.65, 129.64, 129.52, 128.77, 126.86, 126.78, 126.1 1, 120.23, 1 19.34, 117.89, 37.66, 30.03; MS (ESI) m/z 368 [C₂₄H₂iN₃0 + H]⁺.

Example 42: 2-(4-(lH-imidazol-l-yl)phenylamino)-N-(5-phenylpyridin-

15 mg, 8%, HPLC 96%, off-white solid. 1H NMR (400 MHz, DMSO-<¾ δ 10.59 (s, IH), 8.64 (d, J=2.0 Hz, IH), 8.17-8.15 (m, IH), 8.10-8.07 (m, IH), 7.97 (s, IH), 7.70-7.68 (m, 2H), 7.50- 7.45 (m, 3H), 7.40-7.31 (m, 3H), 7.00 (s, IH), 6.73 (d, J=8.8 Hz, 2H), 6.25 (d, J=8.4 Hz, IH), 4.31-4.23 (m, IH), 1.44 (d, J=6.8 Hz, 3H); MS (ESI) m/z 384 [C₂₃H_2IN₅0 + H]⁺.

[000142] Example 43: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(4-(thiazol-2- yl)phenyl)acetamide

75 mg, 54%, HPLC 98%, yellow solid. 1H NMR (400 MHz, DMSO- ) δ 10.35 (s, 1H), 8.13 (s, IH), 7.94-7.93 (m, 2H), 7.89-7.88 (m, IH), 7.80-7.78 (m, 2H), 7.73 (m, IH), 7.64 (t, J- 1.2Hz, IH), 7.59-7.57 (m, 2H), 7.15-7.13 (m, 2H), 7.07 (s, IH), 4.80 (s, 2H) ; MS (ESI) m/z 377

[C₂₀H₁₆N₄O₂S + H]⁺.

[000143] Example 44: 2-(4-(lH-imidazol-l -yl)phenoxy)-N-(biphenyl-3-yl)acetamide

15 mg, 18%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO- /₆) δ 8.05 (s, IH), 7.91 (s, IH), 7.64-7.58 (m, 3H), 7.55-7.48 (m, 3H), 7.47-7.38 (m, 5H), 7.37-7.31 (m, IH), 7.25-7.19 (m, 2H), 7.13 (s, IH), 4.77 (s, 2H); MS (ESI) m/z 370 [C₂₃H₁₉N₃0₂ + H]⁺.

[000144] Example 45: 2-(4-(lH-imidazol-l -yl)phenoxy)-N-(2'-methoxybiphenyl-4- yl)acetamide

23 mg, 18%, HPLC 98%, beige solid. 1H NMR (400 MHz, DMSO-<¾ δ 10.16 (s, IH), 8.13 (s, IH), 7.68-7.64 (m, 3H), 7.59-7.57 (m, 2H), 7.45-7.42 (m,2H), 7.34-7.26 (m, 2H), 7.15-6.99 (m, 5H), 4.78 (s, 2H), 3.76 (s, 3H); ¹³C NMR (400 MHz, DMSO-d₆) δ 166.34, 156.57, 156.11, 137.08, 135.52, 133.52, 130.86, 130.15, 129.55, 129.52, 129.33, 128.60, 121.98, 120.75, 1 19.28, 118.29, 115.74, 111.76, 67.44, 55.47; MS (ESI) m/z 400 [C₂₄H₂₁N₃0₃ + H]⁺.

[000145] Example 46 : 2-(4-( 1 H-imidazol- 1 -yl)phenoxy)-N-(3 '-methoxybiphenyl-4- yl)acetamide

11 mg, 7%, HPLC 98%, beige solid. 1H NMR (400 MHz, DMSO- ) δ 10.20 (s, IH), 8.13 (s, IH), 7.75-7.57 (m, 7H), 7.35 (t, J=7.6 Hz, IH), 7.22-7.13 (m, 4H), 7.07 (s, IH), 6.90 (d, J=6.4 Hz, IH), 4.78 (s, 2H), 3.81 (s, 3H); MS (ESI) m/z 400 [C₂₄H₂₁N₃0₃ + H]⁺.

[000146] Example 47 : 2-(4-( 1 H-imidazol- 1 -yl)phenoxy)-N-(3 '-methylbiphenyl-4- yl)acetamide

95 mg, 68%, HPLC 97%, beige solid. 1H NMR (400 MHz, DMSO- ) δ 10.19 (s, IH), 8.13 (s, IH), 7.74-7.72 (m, 2H), 7.65-7.57 (m, 5H), 7.46-7.42 (m, 2H), 7.32 (t, J=7.6 Hz, IH), 7.16-7.13 (m, 3H), 7.07 (s, IH), 4.78 (s, 2H), 2.36 (s, 3H); ¹³C NMR (400 MHz, DMSO-</₆) δ 1 6.37, 156.56, 139.55, 137.98, 137.71, 135.52, 135.50, 130.86, 129.56, 128.76, 127.72, 126.92, 126.88, 123.39, 121.97, 119.99, 118.28, 115.73, 67.41, 21.09; MS (ESI) m/z 384 [C₂₄H₂iN₃0₂ + H]⁺. Example 48: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(2'-methylbiphi

80 mg, 65%, HPLC 96%, beige solid. 1H NMR (400 MHz, DMSO- ) δ 10.20 (s, IH), 8.13 (s, IH), 7.72-7.57 (m, 5H), 7.31-7.23 (m, 5H), 7.19-7.14 (m, 3H), 7.07 (s, IH), 4.79 (s, 2H), 2.23 (s, 3H); ¹³C NMR (400 MHz, DMSO- ₆) 6 16639, 156.58, 140.83, 137.17, 136.63, 135.52, 134.69, 130.87, 130.30, 129.56, 129.45, 129.28, 127.12, 125.89, 121.99, 119.44, 118.29, 115.74, 67.45, 20.17; MS (ESI) m/z 384 [C₂₄H₂₁N₃0₂ + H]⁺.

Example 49: 2-(4-( 1 H-imidazol- 1 -yl)phenoxy)-N-(3-phenylisoxazol-5-

25 mg, 19%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO- ) δ 12.00 (br s, IH), 8.13 (s, IH), 7.86-7.84 (m, 2H), 7.64 (s, IH), 7.58-7.56 (m, 2H), 7.51-7.49 (m, 3H), 7.14-7.12 (m, 2H), 7.07 (s, IH), 6.78 (s, IH), 4.90 (s, 2H); MS (ESI) m/z 361 [C₂₀Hj₆N₄O₃ + H]⁺.

[000149] Example 50: 2-(4-(l H-imidazol- l-yl)phenoxy)-N-(4-(pyridin-2- yl)phenyl)acetamide

40 mg, 30%, HPLC 99%, off- white solid. Ή NMR (400 MHz, OMSO-d₆) δ 10.21 (s, IH), 8.64 (d, J=4.4 Hz, IH), 8.12 (s, IH), 8.10-8.04 (m, 2H), 7.94-7.89 (m, IH), 7.88-7.81 (m, IH), 7.80- 7.74 (m, 2H), 7.63 (s, IH), 7.61-7.55 (m, 2H), 7.33-7.27 (m, IH), 7.19-7.13 (m, 2H), 7.07 (s, IH), 4.80 (s, 2H); MS (ESI) m/z 371 [C₂₂H₁₉N₄0₂ + H]⁺.

Example 51 : 2-(4-(l H-imidazol- 1 -yl)phenoxy)-N-(5-phenylpyridin-

29 mg, 21%, HPLC 99%, off- white solid. 1H NMR (400 MHz, DMSO-i¾ δ 10.60 (s, IH), 8.68 (s, IH), 8.17-8.09 (m, 3H), 7.74-7.68 (m, 2H), 7.62 (s, IH), 7.60-7.53 (m, 2H), 7.52-7.45 (m, 2H), 7.43-7.36 (m, IH), 7.16-7.09 (m, 2H), 7.08 (s, IH), 4.89 (s, 2H); MS (ESI) m/z 371

[C₂₂H₁₉N₄0₂ + H]⁺.

Example 52: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(benzo[d]thiazol-2-

16 mg, 14%, HPLC 99%, off- white solid. 1H NMR (400 MHz, DMSO-i¾ δ 12.62 (s, 1H), 8.26 (s, 1H), 8.00 (d, J= 7.2Hz, IH), 7.78 (d, J= 8.0Hz, 1H), 7.72-7.67 (m, 1H), 7.63-7.55 (m, 2H), 7.49-7.42 (m, IH), 7.36-7.29 (m, IH), 7.18-7.1 1 (m, 3H), 5.00 (s, 2H); MS (ESI) m/z 351

[C₁₈H₁₄N₄0₂S + H]⁺.

[000152] Example 53 : 2-(4-( 1 H-imidazol- 1 -yl)phenoxy)-N-(isoquinolin-6-yl)acetamide

16 mg, 15%, HPLC 98%, off-white solid. 1H NMR (400 MHz, MeOH-i¾ δ 9.57 (s, IH), 9.34 (s, IH), 8.88-8.80 (m, IH), 8.50-8.42 (m, 2H), 8.34 (d, J= 6.8Hz, IH), 8.19-8.12 (m, IH), 8.02- 7.97 (m, IH), 7.78-7.68 (m, 3H), 7.38-7.30 (m, 2H), 4.95 (s, 2H); MS (ESI) m/z 345

[C₂₀H₁₆N₄O₂ + H]⁺.

Example 54: 2-(4-(l H-imidazol- l-yl)phenoxy)-N-(5-phenylpyrazin-!

14 mg, 12%, HPLC 97%, white solid. 1H NMR (400 MHz, DMSO-i¾) δ 11.05 (s, IH), 9.40- 9.34 (m, IH), 9.08-9.02 (m, IH), 8.51 (s, IH), 8.15-8.08 (m, 2H), 7.79 (s, IH), 7.67-7.59 (m, 2H), 7.57-7.42 (m, 3H), 7.29 (s, IH), 7.30-7.22 (m, 2H), 4.95 (s, 2H); MS (ESI) m/z 372

[C₂₁H₁₇N₅0₂ + H]⁺.

Example 55: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(5-phenylpyrimidin-

7 mg, 13%, HPLC 96%, white solid. 1H NMR (400 MHz, DMSO-i¾ S 10.92 (s, IH), 9.03 (s, 2H), 8.49 (bs, IH), 7.82-7.75 (m, 3H), 7.63-7.56 (m, 2H), 7.56-7.49 (m, 2H), 7.49-7.41 (m, IH), 7.2.8 (s, IH), 7.15-7.09 (m, 2H), 5.10 (s, 2H); MS (ESI) m/z 372 [C₂iH₁₇N₅0₂ + H]⁺.

Example 56: 2-(4-(lH-imidazol-l -yl)phenoxy)-N-(4'-methylbiphenyl-4-

4 mg, 36%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-<¾ δ 10.20 (s, IH), 8.14 (s, IH), 7.77-7.69 (m, 2H), 7.67-7.51 (m, 7H), 7.29-7.21 (m, 2H), 7.18-7.11 (m, 2H), 7.07 (s, IH), .78 (s, 2H), 2.33 (s, 3H); ¹³C NMR (400 MHz, DMSO-< ) δ 166.30, 156.54, 137.48, 136.70, 136.29, 135.49, 135.32, 130.84, 129.53, 129.43, 126.58, 126.05, 121.94, 120.00, 1 18.25, 1 15.72, 67.42, 20.58; MS (ESI) m/z 384 [C₂₄H₂₁N₃0₂+ H]⁺.

[000156] Example 57: 2-(4-(2-methyl-lH-imidazol-l -yl)phenylamino)-N-(5- phenylpyridin-2-yl)propanamide

8 mg, 12%, HPLC 98%, brown solid. Ή NMR (400 MHz, DMSO-- ) δ 10.61 (s, IH), 8.65-8.64 (m, IH), 8.18-8.16 (m, IH), 8.11-8.08 (m, IH), 7.70-7.68 (m, 2H), 7.48 (t, J=7.2 Hz ,2H), 7.40- 7.36 (m, IH), 7.13-7.09 (m, 3H), 6.81-6.80 (m, IH), 6.72-6.70 (m, 2H), 6.35-6.34 (d, J=7.6 Hz ,1H), 4.31-4,23 (m, IH), 2.18 (s, 3H), 1.45 (d, J=6.8 Hz ,3H) ; MS (ESI) m/z 398 [C₂₄H₂₃N₅0 + H]⁺.

[000157] Example 58: N-(5-(4-fluorophenyl)pyridin-2-yl)-2-(4-(2 -methyl- lH-imidazol-1- yl)phenylamino)propanamide

10 mg, 14%, HPLC 99%, brown solid. Ή NMR (400 MHz, DMSO-< ) δ 10.61 (s, IH), 8.63 (d, J=2.0 Hz, IH), 8.18-8.06 (m, 2H), 7.76-7.72 (m, 2H), 7.30 (t, J=8.8 Hz, 2H), 7.11 (t, J=8.8 Hz, 3H), 6.81 (d, J=0.8 Hz, IH), 6.71 (d, J=8.8 Hz, 2H), 6.34 (d, J=8.0 Hz, IH), 4.30-4.23 (m, IH), 2.18 (s, 3H), 1.44 (d, J=6.8 Hz, 3H); MS (ESI) m/z 416 [C₂₄H₂₂FN₅0 + H]⁺. [000158] Example 59: 2-(4-(lH-imidazol-l-yl)phenylamino)-N-(5-(4- fluorophenyl)pyridin-2-yl)propanamide

12 mg, 7%, HPLC 97%, beige solid. 1H NMR (400 MHz, DMSO-<¾ δ 10.59 (s, IH), 8.62 (d, J=2.4 Hz, IH), 8.16-8.14 (m, IH), 8.09-8.06 (m, IH), 7.97 (s, IH), 7.75-7.72 (m, 2H), 7.49 (s, IH), 7.33-7.28 (m, 4H), 7.00 (s, IH), 6.73 (d, J=8.8 Hz, 2H), 6.25 (d, J=8.4 Hz, IH), 4.30-4.23 (m, IH), 1.44 (d, J=6.8 Hz, 3H); MS (ESI) m/z 402 [C₂₃H₂₀FN₅O + H]⁺.

[000159] Example 60: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(4-( iophen-2- yl)phenyl)acetamide

150 mg, 70%, LC-MS 95%, off-white solid. 1H NMR (400 MHz, CDC1₃) δ (ppm): 10.22 (s, IH), 8.13 (s, IH), 7.85-7.52 (m, 7H), 7.40 (dd, J = 4.8 Hz, 2H), 7.20-7.1 1 (m, 4H), 4.78 (s, 2H); MS (ESI) m/z 376.08 [C₂₁H₁₇N₃0₂S+H]⁺.

[000160] Example 61 : 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(4-(thiazol-5- yl)phenyl)acetamide

170 mg, 52%, LC-MS 96%. 1H NMR (400 MHz, DMSO-i½) δ (ppm): 10.28 (bs, 1H), 9.05 (bs, 1H), 8.25 (s, 1H), 8.14 (bs, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.75-7.54 (m, 7H), 7.15 (d, J = 8.8 Hz, 2H), 7.08 (s, 1H) 4.79 (s, 2H); MS (ESI) m/z 377.11 [C20H16N4O2S+HJ+.

[000161] Example 62: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(6-phenylpyridazin-3- yl)acetamide

60 mg, 25%, LC-MS 95%, off-white solid. 1H NMR (400 MHz, CDC1₃) δ (ppm): 11.37 (s, 1H), 8.38 (dd, J = 9.6 Hz, 2H), 8.11 (d, J = 7.2 Hz, 3H), 7.65-7.52 (m, 6H), 7.13 (d, J = 8.8 Hz, 3H), 4.96 (s, 2H); MS (ESI) m/z 372.06 [C₂iHi₇N₅0₂ +H]⁺.

[000162] Example 63: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(4-(pyrimidin-4- yl)phenyl)acetamide

100 mg, 54%, LC-MS 90%. 1H NMR (400 MHz, DMSO-e?6) δ (ppm): 10.40 (s, IH), 9.20 (s, IH), 8.81 (d, J = 5.3 Hz, IH), 8.22 (d, J = 8.8 Hz, 2H), 8.81 (s, 1Ή), 8.04 (t, J = 2.8 Hz, IH), 7.84 (d, J = 8.3 Hz, 2H), 7.65 (s, IH), 7.58 (d, J - 7.8 Hz, 2H), 7.15 (d, J = 9.2 Hz, 2H), 7.07 (s, 2H), 4.82 (s, 2H); MS (ESI) m/z 372.12 [C21H17N502+H] +.

[000163] Example 64: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(4-(pyridazin-3- yl)phenyl)acetamide

150 mg, 80%, LC-MS 97%, off-white solid. 1H NMR (400 MHz, CDC1₃) δ (ppm): 10.36 (s, 9.17 (d, J = 4.0 Hz, IH), 8.20-8.13 (m, 4H), 7.87-7.73 (m, 3H), 7.66-7.57 (m, 3H), 7.15 (d, J 8.8 Hz, IH), 7.08 (s, 2H); MS (ESI) m/z 372.06 [C₂₁Hi₇N₅0₂ +H]⁺.

[000164] Example 65: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(3-methylbiphenyl-4- yl)acetamide

140 mg, 33%, LC-MS 98%. Ή NMR (400 MHz, DMSO-<¾) δ (ppm): 9.57 (s, IH), 8.15 (s, IH), 7.7-7.58 (dd, 4H), 7.56-7.42 (m, 5H), 7.34 (t, J= 7.5 Hz, 2H), 7.17 (d, J= 8.8 Hz, 2H), 7.08 (s, IH), 4.82 (s, 2H), 2.26 (s, 3H); MS (ESI) m/z 384.14 [C₂₄H₂iN₃0₂ + H]⁺. [000165] Example 66: 2-(4-( 1 H-imidazol- l-yl)phenoxy)-N-(4-phenylthiophen-2- yl)acetamide

4 mg, 7%, LC-MS 95%, off-white solid. ^lH NMR (400 MHz, DMSO- ₆) δ (ppm): 11.4 (s, IH), 8.1 (s, IH), 7.66-7.42 (m, 5H), 7.39 (t, J= 8.0 Hz, 2H), 7.3 (s, IH), 7.21-7.1 1 (m, 3 H), 6.90 (s, IH), 4.8 (s, 2H); MS (ESI) m/z 376.02 [C₂₁H_i7N₃0₂S + H]⁺.

[000166] Example 67: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(2-methoxybiphenyl-4- yl)acetamide

100 mg, 25%, LC-MS 99%. 1H NMR (400 MHz, DMSO-<¾) δ (ppm): 10.23 (s, IH), 8.15 (s, IH), 7.66 (s, IH), 7.59 (d, J- 8.8 Hz, 2H), 7.51 (s, IH), 7.46 (d, J= 7.4 Hz, 2H), 7.42-7.22 (m, 5H), 7.15 (d, J= 8.3 Hz, 2H), 7.08 (s, IH), 7.79 (s, 2H), 3.74 (s, 3H); MS (ESI) m/z 400.13 [C₂₄H₂₁N₃0₃ + H]⁺.

[000167] Example 68: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(4'-methoxybiphenyl-4- yl)acetamide

30 mg, 16%, HPLC 98%, off-white solid. 1H NMR (400 MHz, CDC1₃) δ (ppm): 10.19 (s, 1H), 8.14 (s, 1H), 7.71 (m, 3H), 7.59 (d, 7= 8.4 Hz, 6H), 7.14 (m, 3H), 7.0 (d, J= 8.4 Hz, 2H), 4.78 (s, 2H), 3.78 (s, 3H); MS (ESI) m/z 400.06 [C₂₄H₂₁N₃0₃ +H]⁺.

[000168] Example 69: N-(4'-fluorobiphenyl-4-yl)-2-(4-(oxazol-5- yl)phenylamino)acetamide

8 mg, 10%, LC-MS 97%), off- white solid. Ή NMR (400 MHz, CDC13) δ (ppm): 8.42 (s, 1H), 7.81 (s, 1H), 7.64-7.56 (m, 8H), 7.2 (s, 1H), 7.1 (t, J= 8.0 Hz, 2H), 6.76 (d, J= 7.8 Hz, 2H), 4.58 (s, 1H), 3.99 (d, J= 8.0 Hz, 2H); MS (ESI) m/z 388.17 [C₂₃Hi₈FN₃0₂+ H]⁺.

[000169] Example 70: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(4-phenylthiazol-2- yl)acetamide

80 mg, 25%, LC-MS 97%. IH NMR (400 MHz, DMSO-i/6) δ (ppm): 12.54 (s, IH), 8.13 (s, IH), 7.9 (d, J = 7.1 Hz, 2H), 7.65 (d, J = 1 1.4 Hz, 2H),7.65 (d, J = 8.8 Hz, 2H),7.44 (t, J = 7.7 Hz, 2H), 7.33 (t, J = 6.75 Hz, IH), 7.12 (d, J = 5.2 Hz, 2H), 7.07 (s, IH), 4.95 (s, 2H); MS (ESI) m/z 377.09 [C20H16N4Q2S+H] ⁺.

Example 71 : 2-(4-(lH-imidaz;ol-l-yl)phenoxy)-N-(6-phenylpyridin-

1 10 mg, 50%, HPLC 97%, off-white solid. 1H NMR (400 MHz, CDC1₃) δ (ppm): 10.47 (s, IH), 8.89 (s, IH), 8.20-8.15 (m, 2H), 8.06-7.95 (m, 3H), 7.66-7.58 (m, 3H), 7.50-7.98 (m, 3H), 7.17- 7.08 (m, 3H), 4.83 (bs, 2H); MS (ESI) m/z 371.17 [C₂₂H₁₈N₄0₂ +H]⁺.

[000171] Example 72: 3-(4-(2-methyl-lH-imidazol-l-yl)phenyl)-N-(5-phenylpyridin-2- yl)propanamide

9 mg, 8%, HPLC 96%, beige solid. 1H NMR (400 MHz, DMSO-< ) δ 10.62 (s, IH), 8.63 (d, J=2.4 Hz, IH), 8.20-8.17 (m, IH), 8.10-8.08 (m, IH), 7.71_r7.69 (m, 2H), 7.50-7.34 (m, 7H), 7.23 (s, IH), 6.88 (s, IH), 2.99 (t, J=7.6 Hz, 2H), 2.79 (t, J=7.6 Hz, 2H), 2.25 (s, 3H) ; MS (ESI) m/z 383 [C₂₄H₂₂N₄0 + H]⁺. [000172] Example 73: 2-(4-(l -methyl- lH-pyrazol-5-yl)phenylamino)-N-(6- phenylpyridazin-3 -yl)propanamide

70 mg, 15%, LC-MS 96%, off-white solid. 1H NMR (400 MHz, DMSO-<¾ δ (ppm): 11.35 (s, 1H), 8.40 (d, J = 9.2 Ηζ, ΙΗ), 8.24 (d, J= 9.2 Ηζ, ΙΗ), 8.09 (d, J= 8.0 Hz, 2H), 7.56-7.48 (m, 3H), 7.36 (s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 6.73 (d, J= 8.4 Hz, 2H), 6.39 (d, J= 8.0 Ηζ, ΙΗ), 6.21 (s, 1H), 4.37 (q, J = 6.8 Ηζ, ΙΗ), 3.77 (s, 3H), 1.48 (d, J= 6.8 Hz, 3H); MS (ESI) m/z 399.24 [C₂₃H₂₂N₆0+H]⁺.

[000173] The racemates may be separated by either chiral preparative HPLC or may be chirally synthesized by using the method reported for the preparation of intermediate 5.

[000174] Example 74: N-(2,3M>ipyridin-5-yl)-2-(4-(l -methyl- lH-pyrazol-5- yl)phenylamino)propanamide

65 mg, 20 %, LC-MS 96 %, off-white solid. 1H NMR (400 MHz, CDC13) δ (ppm): 9.16 (s, 1H), 8.79 (s, 1H), 8.64 (d, J= 2.2 Hz, 1H), 8.62 (s, 1H) 8.37-8.34 (dd, J = 2.4 Hz, 1H), 8.28 (d, J= 7.9 Hz, 1H), 7.75 (d, J= 8.8 Hz, 1H), 7.48 (d, J= 1.8 Hz, 1H), 7.41-7.38 (q, J= 4.8 Hz, 1H), 7.3 (d, J= 8.3 Hz, 2H), 6.77 (d, J= 8.8 Hz, 2H), 6.23 (d, J= 1.8 Hz, 1H), 4.17 (bs, 1H), 3.99 (q, J= 7.0 Hz, 1H), 3.86 (s, 3H), 1.68 (d, J - 7.1 Hz, 3H); MS (ESI) m/z 399.24 [C₂₃H₂₂N₆0 + H]⁺. [000175] Example 75: 2-(4-(l-methyl-lH-pyrazol-5-yl)phenylamino)-N-(6-(pyridin-3- yl)pyridazin-3 -yl)propanamide

12 mg, 4%, LC-MS 99%, pale yellow solid. 1H NMR (400 MHz, DMSO-d₆) δ (ppm): 1 1.43 (s, 1H), 9.26 (s, 1H), 8.69 (d, J = 4.0 Hz, 1H), 8.55-8.28 (m, 3H), 7.65-7.52 (m, 1H), 7.36 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 6.40 (d, J = 8.3 Hz, 1H), 6.21 (s, 1H), 4.45- 4.32 (m, lH), 3.78 (s, 3H), 1.48 (d, J - 7.0 Hz, 3H); MS (ESI) m/z 400.25 [C₂₂H₂₁N₇0 + H]⁺.

[000176] Example 76: N-(6-phenylpyridazin-3-yl)-2-(4-(2-(trifluoromethyl)-lH-imidazol- 1-yl) phenylamino) propanamide

56 mg, 30%, LC-MS 96%, pale yellow solid. 1H NMR (400 MHz, CDC1₃) δ (ppm): 11.39 (s, 1H), 8.40 (d, J = 9.2 Hz, 1H), 8.24 (d, J= 9.6 Hz, 1H), 8.08 (d, J= 6.6 Hz, 2H), 7.56-7.48 (m, 4H), 7.19-7.17 (m, 3H), 6.72 (d, J= 8.8 Hz, 2H), 6.58 (d, J = 7.9 Hz, 1H), 4.38 (t, J = 7.5 Hz, 1H), 1.49 (d, J= 7.1 Hz, 3H); MS (ESI) m/z 453.22 [C₂₃H₁₉F₃N₆0 + H]⁺.

[000177] Example 77: N-(6-phenylpyridazin-3-yl)^2-(4-(2-(trifluoromethyl)-lH-imidazol- 1 -yl)phenylamino)acetamide

70 mg, 10%, LC-MS 97 %, off-white solid. 1H NMR (400 MHz, DMSO-c ₆) δ (ppm): 10.16 (s, IH), 8.67 (d, J= 9.6 Hz, 1H), 8.03-7.93 (m, 3H), 7.54-7.48 (m, 3H), 7.21-7.14 (m, 3H), 7.16 (d, J= 8.8 Hz, 3H), 7.08 (s, 1H), 6.72 (d, J= 8.8 Hz, 2H), 5.1 (bs, 1H), 4.19 (d, J= 5.2 Hz, 2H); MS (ESI) m/z 439.15 [C₂₂H₁₇F₃N₆0+H]⁺.

[000178] Example 78: N-(6-(4-fluorophenyl)pyridazin-3-yl)-2-(4-(2-(trifluoromethyl)-lH- imidazol- 1 -yl)phenylamino)propanamide

50 mg, 30%, LC-MS 99%, white solid. 1H NMR (400 MHz, CDC13) δ (ppm): 1 1.39 (s, 1H), 8.40 (d, J= 9.2 Hz, 1H), 8.24 (d, J = 9.7 Hz, IH), 8.15 (q, J= 5.5 Hz, 2H), 7.55 (s, 1H), 7.38 (t, J = 8.8, 2H), 7.19-7.17 (m, 3H), 6.72 (d, J= 8.8 Hz, 2H), 6.57 (d, J= 7.5 Hz, IH), 4.38 (t, J= 7.3 Hz, IH), 1.49 (d, J= 6.6 Hz, 3H); MS (ESI) m/z 471.19 [C₂₃H₁₈F₄N₆0 + H]⁺.

[000179] Example 79: N-(6-(4-fluorophenyl)pyridazin-3-yl)-2-(4-(2-(trifluoromethyl)-lH- imidazol- 1 -yl)phenylamino)acetamide

70 mg, 70%, LC-MS 95%, off-white solid. 1H NMR (400 MHz, DMSO- d) δ (ppm): 11.30 (s, IH), 8.39 (d, J- 10.0 Hz, IH), 8.26 (d, J= 10.0 Ηζ, ΙΗ), 8.16 (t, J= 8.8 Hz, 2H), 7.56 (s, IH), 7.38 (t, J= 8.8 Hz, 2H), 7.18 (d, J= 9.2 Hz, 3H), 6.71 (d, J= 8.8 Hz, 2H), 6.59 (s, IH), 4.13 (d, J= 6.0 Hz, 2H); MS (ESI) m/z 457.18 [C₂₂.H_]6F₄N₆0 + H]⁺.

[000180] Example 80: N-(biphenyl-4-yl)-2-(4-(2-(trifluoromethyl)-lH-imidazol-l- yl)phenylamino)propanamide

27 mg, 27%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSC ¾ δ 10.19 (s, IH), 7.76- 7.68 (m, 2H), 7.67-7.59 (m, 4H), 7.56-7.51 (m, IH), 7.48-7.40 (m, 2H), 7.36-7.29 (m, IH), 7.20- 7.13 (m, 3H), 6.73-6.67 (m, 2H), 6.46 (d, J= 7.2Hz, IH), 4.20-4.05 (m, IH), 1.46 (d, J= 6.8Hz, 3H); MS (ESI) m/z 398 [C₂₅H₂iF₃N₄0 + H]⁺.

[000181] Example 81 : 2-(4-(2-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)phenylamino)- N-(5-phenylpyridin-2-yl)propanamide

16 mg, 7%, LC-MS 99%. 1H NMR (400 MHz, CDC1₃) δ (ppm): 8.99 (s, 1H), 8.49 (d, J= 2.2 Hz, 1H), 8.36 (dd, J= 1.8 Hz, 8.8 Hz, 1H), 7.96 (d, J= 8.4 Hz, 1H), 7.55 (d, J= 7.5 Hz, 2H), 7.47 (t, J= 7 Hz, 2H), 7.43 - 7.35 (m, 1H), 7.13 (d, J= 8.3 Hz, 1H), 7.07 (q, J= 2.6 Hz, 1H), 6.99 (s, 1H), 6.87 (s. 1H), 6.86 - 6.78 (m, 1H), 4.67 (s, 1H), 4.12 - 3.98 (m, 1H), 2.15 (s, 3H), 1.70 (d, J = 7 Hz, 3H); MS (ESI) m/z 464.2 [C₂₅H₂ F₃N₅0-H]⁺.

[000182] Example 82: N-(2,3'-bipyridin-5-yl)-2-(6-(l -methyl-lH-pyrazol-5-yl)pyridin-3- ylamino)propanamide

60 mg, 18%, LC-MS 96%. 1H NMR(400 MHz, CDC1₃) S (ppm): 10.52 (s, 1H), 9.21 (d, J = 1.8 Hz, 1H), 8.90 (d, J = 2.2 Hz, ΊΗ), 8.59 (dd, J - 1.3 Hz, 4.8 Hz, 1H), 8.37 (dt, J = 1.7, 8.0 Hz, 1H), 8.22 (dd, J = 2.6, 8.6 Hz, 1H), 8.11 (d, J = 2.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, lH), 7.55-7.45 (m, 2H), 7.37 (d, J = 1.7 Hz, 1H), 7.04 (dd. J = 2.6, 8.30 Hz, 1H), 6.60 (d, J = 7.5 Hz, 1H), 6.50 (d, J = 1.8 Hz, 1H), 4.22 (t, J = 7.0 Hz, 1H), 4.03 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H); MS (EST) m/z 400.25 [C₂₂H₂₁N₇0 + H]⁺.

[000183] The racemates may be separated by either chiral preparaive HPLC or may be synthesized by using method reported for the preparation of intermediate 5. [000184] Example 83: N-(2,3^,-bipyridin-5-yl)-2-(6-(l-methyl-lH-pyrazol-5-yl)pyridin-3- ylamino)acetamide

30 mg, 10%, LC-MS 98%, off.white solid. Ή NMR (400 MHz, DMSO- ) δ (ppm): 10.5 (s, IH), 9.23 (s, IH), 8.90 (s, IH), 8.59 (d, J= 4.8 Hz, IH), 8.39 (d, J= 9.6 Hz, IH), 8.20 (d, J = 8.8 Hz, IH), 8.12-8.04 (m, 2H), 7.52-7.48 (m, 2H), 7.38 (s, IH), 7.05 (d, J - 8.4 Hz, IH), 6.30 (t, J = 5.6 Hz, IH), 6.51 (s, IH), 4.07 (d, J = 6.0 Hz, 2H), 4.05 (s, 3H); MS (ESI) m/z 386.1 [C₂₁H_!9N₇0 +H]⁺.

[000185] Example 84: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(biphenyl-4-yl)acetamide

26 mg, 31%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-d₆) δ 10.21 (s, IH), 8.13 (s, IH), 7.77-7.72 (m, 2H), 7.68-7.61 (m, 5H), 7.61-7.55 (m, 2H), 7.48-7.41 (m, 2H), 7.36-7.30 (m, IH), 7.18-7.12 (m, 2H), 7.08 (s, IH), 4.79 (s, 2H); MS (ESI) m/z 370 [¾₃Η₁₉Ν₃0₂ + H]⁺.

[000186] Example 85: 2-(4-(l -methyl- lH-pyrazol-5-yl)-3-(morpholine-4- carbonyl)phenylamino)-N^(5-phenylpyridin-2-yl)propanamide

1H NMR (400 MHz, CDC1₃) δ (ppm): 9.05 (m, 1H). 8.40 (s, 1H), 8.36 (t, J= 8.0 Hz, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.54 (d, J= 7.2 Hz, 2H), 7.45-7.37 (m, 4H), 7.19 (d, J= 8.4 Hz, 1H), 6.77- 6.66 (m, 2H), 6.20 (s, 1H), 4.33-4.28 (m, 1H), 3.98-3.75 (m, 1H), 3.75 (s, 3H), 3.63-3.41 (m, 5H), 3.12-2.8 (m, 3H), 1.67 (d, J = 8.0 Hz, 3H); MS (ESI) m/z 511.30 [M+l].

[000187] Example 86: 2-(l-methyl-lH-pyrazol-5-yl)-5-(l-oxo-l-(5-phenylpyridin-2- ylamino)propan-2-ylamino)benzamide

100 mg, 77%, LC-MS 99%. 1H NMR (400 MHz, DMSO- d₆) δ (ppm): 10.70 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.17-8.11 (m, 2H), 7.70 (d, J= 7.6 Hz, 2H), 7.50-7.41 (m, 4H), 7.32 (d, J= 2.0 Hz, 1H), 7.15 (s, 1H), 7.07 (d, J= 8.4 Hz, 1H), 6.79-6.41 (m, 2H), 6.50 (d, J = 8.0 Hz, 1H), 6.09 (s, 1H), 4.70-4.30 (m, 1H), 3.60 (s, 1H), 1.45 (d, J = 6.4 Hz, 3H); MS (ESI) m/z 441 [M+l ].

[000188] Example 87: 2-(4-(l -methyl- lH-pyrazol-5-yl)-2-(morpholine-4- carbonyl)phenylamino)-N-(5-phenylpyridin-2-yl)propanamide

15 mg, 24%, LC-MS 96%. 1H NMR (400 MHz, DMSO- ₆) δ (ppm): 9.04 (s, 1H), 8.47 (d, J= 3.2 Hz, 1H), 8.36 (d, J= 8.3 Hz, 1H), 7.93 (dd, J= 2.7, 8.8 Hz, 1H), 7.54-7.52 (m, 2H), 7.48- 7.44 (m, 3H), 7.40-7.30 (m, 3H), 7.18 (d, J= 8.8 Hz, 1H), 6.77 (d, J= 8.8 Hz, 1H), 6.20 (s, 1H), 5.93 (d, J= 3.1 Hz, 1H), 4.02-4.00 (m, 1H), 3.64-3.70 (m, 1H), 1.68 (d, J= 7.0 Hz, 3H); MS (ESI) m/z 511.24 [C₂₉H₃₀N₆O₃+H]⁺.

[000189] Example 88: 2-(7-(l-methyl-lH-p razol-5-yl)-3-oxo-2H-benzo[b][l,4]oxazin- 4(3H)-yl)-N-(5-phenylpyridin-2-yl)propanamide

15 mg, 22%, LC-MS 99%, pale yellow solid. 1H NMR (400 MHz, DMSO-i¾) δ (ppm): 10.97 (s, 1H), 8.66 (d, J= 2.2 Hz, 1H), 7.71 (d, J= 7.1 Hz, 1H), 7.50-7.38 (m, 5H), 7.24 (d, J= 2.2 Hz, 1H), 6.74 (d, J= 8.8 Hz, 1H), 6.26 (d, J = 2.2 Hz, 1H), 5.67 (d, J= 8.4 Hz, 1H), 4.40-4.37 (m, 1H), 3.80 (s, 3H), 3.00 (bs, 6H), 1.46 (d, J= 7.1 Hz, 3H); MS (ESI) m/z 469.44

[000190] Example 89: N-(biphenyl-4-yl)-6-(l H-imidazol- 1-yl)- 1,2,3 ,4-tetrahydroquinoline- 2-carboxamide

43 mg, 44%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-i¾ δ 9.96 (s, IH), 7.98 (bs, IH), 7.78-7.72 (m, 2H), 7.70-7.60 (m, 4H), 7.51 (bs, IH), 7.48-7.40 (m, 2H), 7.36-7.30 (m, IH), 7.18-7.10 (m, 2H), 7.04 (bs, IH), 6.71 (d, J= 8.0 Hz, IH), 6.29 (d, J = 2.8 Hz, IH), 4.15-4.05 (m, IH), 2.85-2.60 (m, 2H), 2.15-1.95 (m, 2H); MS (ESI) m/z 395 [C₂₅H₂₂N₄0 + H]⁺.

[000191] Example 90: (R)-N-(2,3'-bipyridin-5-yl)-6-(l-methyl-lH-pyrazol-5-yl)-l,2,3,4- tetrahydroquinoline-2-carboxamide

HPLC 98%, [a]_D +11.0°. 1H NMR (400 MHz, DMSO-dtf) δ (ppm): 10.28 (s, IH), 9.23 (d, J = 1.8 Hz, IH), 8.94 (d, J = 2.7 Hz, IH), 8.60-8.41 (m, IH), 8.41-8.38 (m, IH), 8.25-8.23 (dd, J = 2.6 Hz, J = 2.2 Hz, IH), 8.06-8.04 (d, J = 8.3 Hz, IH), 7.51-7.48 (m, IH), 7.37 (d, J = 1.8 Hz, IH), 7.10-7.07 (m, IH), 7.04 (s, IH), 6.72-6.70 (d, J = 7.9 Hz, IH), 6.41 (d, J = 2.7 Hz, IH), 6.20 (d, J = 1.7 Hz, IH), 4.14 (s, IH), 3.80 (s, 3H), 2.80-2.67 (m, 2H), 2.12-2.04 (m, 2H); MS (ESI) m/z 411.2 [C24H22N60]+.

[000192] Example 91 : (S)-N-(2,3'-bipyridin-5-yl)-6-(l-methyl-lH-pyrazol-5-yl)-l,2,3,4- tetrahydroquinoline-2-carboxamide

HPLC 97%, [<x]b -10.06°. 1H NMR(400 MHz, DMSO- 6) δ (ppm): 10.28 (s, IH), 9.23 (d, J = 1.8 Hz, IH), 8.94 (d, J = 2.7 Hz, IH), 8.60-8.41 (m, IH), 8.41-8.38 (m, IH), 8.25-8.23 (dd, J = 2.6 Hz, J = 2.2 Hz, IH), 8.06-8.04 (d, J - 8.3 Hz, IH), 7.51-7.48 (m, IH), 7.37 (d, J - 1.8 Hz, IH), 7.10-7.07 (m, IH), 7.04 (s, IH), 6.72-6.70 (d, J = 7.9 Hz, IH), 6.41 (d, J = 2.7 Hz, IH), 6.20 (d, J = 1.7 Hz, IH), 4.14 (s, IH), 3.80 (s, 3H), 2.80-2.67 (m, 2H), 2.12-2.04 (m, 2H); MS (ESI) m/z 411.2 [C24H22N60J+.

[000193] Example 92: (R)-2-(6-(l-methyl-lH-pyrazol-5-yl)pyridin-3-ylamino)-N-(6- phenylpyridazin-3 -yl)propanamide

70% , LC-MS 98%, chiral HPLC 98%, [<x]_D +122.51°.¹H NMR(400 MHz, CDC13) δ (ppm): 11.47 (s, IH ), 8.39 (d, J = 9.2 Hz, IH), 8.24 (d, J = 9.2 Hz, IH), 8.13 (d, J = 2.7 Hz, IH), 8.09 (d, J = 8.3 Hz, 2H), 7.61-7.46 (m, 2H), 7.37 (d, J = 1.7 Hz, IH), 7.06 (dd, J = 2.6 Hz, 8.8 Hz, IH), 6.64 (d, J = 8.4 Hz, IH), 6.50 (d, J = 1.8 Hz, IH), 4.49-4.40 (m, IH), 4.03 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H); MS (ESI) m/z 400.2 [C22H21N70+HJ+.

[000194] Example 93: (S)-2-(6-(l-methyl-lH-pyrazol-5-yl)pyridin-3-ylamino)-N-(6- phenylpyridazin-3 -yl)propanamide

70%, LC-MS 98%, chiral HPLC 99%, [a]_D -102.52°. Ή NMR(400 MHz, CDC13) δ (ppm): 11.47 (s, IH ), 8.39 (d, J = 9.2 Hz, IH), 8.24 (d, J = 9.2 Hz, IH), 8.13 (d, J = 2.7 Hz, IH), 8.09 (d, J = . 8.3 Hz, 2H), 7.61-7.46 (m, 2H), 7.37 (d, J = 1.7 Hz, IH), 7.06 (dd, J = 2.6 Hz, 8.8 Hz, IH), 6.64 (d, J = 8.4 Hz, IH), 6.50 (d, J - 1.8 Hz, IH), 4.49-4.40 (m, IH), 4.03 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H); MS (ESI) m/z 400.2 [C22H21N70+H]+.

[000195] Example 94: (S)-l-(4-(l -methyl- lH-pyrazol-5-yl)phenyl)-N-(5-phenylpyridin-2- yl)pyrrolidine-2-carboxamide

General procedure 3:

[000196] To a solution of (S)-l-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)pyrrolidine-2- carboxylic acid (244 mg, 0.900 mmol) in DMF (2 mL) was added HATU (513 mg, 1.349 mmol) and N-methyl morpholine (396 μΐ, 3.597 mmol). The reaction mixture was stirred at room temperature under inert atmosphere for 1 h, followed by the addition of 2-amino-5- phenylpyridine 1-oxide (168 mg, 0.900 mmol). The reaction mixture was left to stir for 16 h, then it was diluted with H₂0 (25 mL) and extracted with EtOAc (3x25 mL). The combined organic layer was dried over Na₂S0₄ and was concentrated under reduced pressure. The crude residue was purified by preparative HPLC (CI 8, eluent ACN, water, formic acid 0.1%) to afford (S)-2-( 1 -(4-( 1 -methyl- 1 H-pyrazol-5-yl)phenyl)pyrrolidine-2-carboxamido)-5-phenylpyridine 1 - oxide (84 mg, 21%, HPLC 98%) as beige solid. 1H NMR (400 MHz, CDCI3.) δ 10.81 (s, 1H), 8.57 (d, J=8.4 Hz, 1H), 8.44 (s, 1H), 7.58-7.43 (m, 7H), 7.33-7.28 (m, 2H), 6.78 (d, J=8.8 Hz, 2H), 6.23 (s, 1H), 4.30-4.27 (m, 1H), 4.00-3.95 (m, 1H),_.3.88 (s, 3H), 3.45-3.39 (m, 1H), 2.52- 2.35 (m, 2H), 2.26-2.17 (m, 2H); MS (ESI) m/z 440 [C₂₆H₂₅N₅0₂ + H]⁺.

[000197] Iron dust (12mg, 0.215 mmol) was added to a solution of (S)-2-(l-(4-(l-methyl- lH-pyrazol-5-yl)phenyl)pyrrolidine-2-carboxamido)-5-phenylpyridine 1-oxide (63 mg, 0.143 mmol) in acetic acid (1.5 mL). The reaction mixture was heated at 100°C for 2 h, then it was diluted with H₂0 and basified to pH 8 using saturated NaHC0₃ solution. It was then extracted with EtOAc (3x15 mL) and the combined organic layer was dried over Na₂S0₄ and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (CI 8, eluent ACN, water, formic acid 0.1 %) to afford (S)-l-(4-(l -methyl- lH-pyrazol-5-yl)phenyl)-N-(5- phenylpyridin-2-yl)pynOlidine-2-carboxamide (31 mg, 51%, HPLC 97%) as off-white solid. 1H NMR (400 MHz, CDCl_a) δ 8.88 (s, 1H), 8.45-8.40 (m, 2H), 7.95-7.92 (m, 1H), 7.54-7.52 (m, 2H), 7.47-7.43 (m, 3H), 7.39-7.35 (m, 1H), 7.32-7.30 (m, 2H), 6.76 (d, J= 8.8 Hz, 2H), 6.22 (s, 1H), 4.20-4.17 (m, 1H), 3.83 (s, 4H), 3.38-3.31 (m, 1H), 2.44-2.38 (m, 2H), 2.16-2.1 1 (m, 2H); MS (ESI) m/z 424 [C₂₆H₂₅N₅0 + H]⁺.

[000198] Example 95: 2-(6-(l-methyl-lH-pyrazol-5-yl)pyridin-3-ylamino)-N-(5- phenylpyridin-2 -yl)propanamide

108 mg, 30%, HPLC 98%, beige solid.1H NMR (400 MHz, DMSO-<¾) δ 10.74 (s, IH), 8.65 (d, J=2.0 Hz, IH), 8.17-8.08 (m, 3H), 7.70-7.68 (m, 2H), 7.51-7.46 (m, 3H), 7.40-7.36 (m, 2H), 7.06-7.03 (m, IH), 6.56 (d, J=8.4 Hz, IH), 6.50 (d, J=2.0 Hz, IH), 4.40-4.33 (m, IH), 4.03 (s, 3H), 1.47 (d, J=6.8 Hz, 3H) ; MS (ESI) m/z 399 [C₂₃H₂₂N₆0 + H]⁺.

[000199] Example 96: 6-(l -methyl- lH-pyrazol-5-yl)-N-(5-phenylpyridin-2-yl)- 1,2,3, 4- tetrahydroquinoline-2-carboxamide

24 mg, 54%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-<¾ δ 10.27 (s, IH), 8.65 (d, J= 2.4 Hz, IH), 8.23-8.16 (m, IH), 8.16-8.08 (m, IH), 7.76-7,67 (m, 2H), 7.52-7.42 (m, 2H), 7.42-7.33 (m, 2H), 7.11-7.05 (m, IH), 7.03 (s, IH), 6.72 (d, J= 8.0 Hz, IH), 6.47 (d, J= 2.8 Hz, IH), 6.20 (d, J= 2.0 Hz, IH), 4.25-4.15 (m, IH), 3.80 (s, 3H), 2.80-2.70 (m, IH), 2.70-2.65 (m, IH), 2.20-2.10 (m, IH), 2.00-1.90 (m, IH); MS (ESI) m/z 410 [C₂₅H₂₃N₅0 + H]⁺.

[000200] Racemate was separated by chiral column chromatography (Isomer 1 : chiral HPLC 99%, [a]_D+20.87° (chloroform) and isomer-2: Chiral HPLC 99%, [a]_D -12.14°

(chloroform).

[000201] Example 97: 2-(4-(2-cyclopropyl-lH-imidazol-l-yl)phenylamino)-N-(5- phenylpyridin-2 -yl)propanamide

5 mg, 78%, HPLC 98%, white solid. Ή NMR (400 MHz, MeOE-d₄) S 8.53 (d, J= 2.4Hz, IH), 8.28-8.23 (m, IH), 8.10-8.03 (m, IH), 7.66-7.59 (m, 2H), 7.50-7.41 (m, 2H), 7.40-7.35 (m, IH), 7.26-7.20 (m, 2H), 7.03 (s, IH), 6.86 (s, IH), 6.85-6.78 (m, 2H), 4.15-4.05 (m, IH), 1.80-1.70 (m, IH), 1.60 (d, J - 7.2Hz, 3H), 0.95-0.82 (m, 4H); MS (ESI) m/z 424 [C₂₆H₂₅N₅0 + H]⁺.

[000202] Example 98: (S)-2-(4-( 1 -methyl- lH-pyrazol-5-yl)phenylamino)-N-(5- phenylpyridin-2 -yl)propanamide

32 mg, 22%, HPLC 96%, white solid. 1H NMR (400 MHz, DMSO-i¾ δ 10.58 (s, IH), 8.64 (d, J=2.4 Hz, IH), 8.18-8.16 (m, IH), 8.11-8.08 (m, IH), 7.70-7.68 (m, 2H), 7.48 (t, J=7.2 Hz, 2H), 7.40-7.36 (m, 2H), 7.26-7.23 (m, 2H), 6.73-6.71 (m, 2H), 6.32 (d, J=8.0 Hz, IH), 6.20 (d, J=2.0 Hz, IH), 4.31-4.24 (m, IH), 3.77 (s, 3H), 1.45 (d, J=6.8 Hz, 3H) ; MS (ESI) m/z 398 [C₂₄H₂₃N₅0 + H]⁺.

[000203] Example 99: (R)-2-(4-(l-methyl-lH-pyrazol-5-yl)phenylamino)-N-(5- phenylpyridin-2-yl)propanamide

10 mg, 18%, HPLC 97%, off-white solid. 1H NMR (400 MHz, DMSO-i¾ δ 10.58 (s, IH), 8.64 (d, J=2.0 Hz, IH), 8.18-8.16 (m, IH), 8.1 1-8.08 (m, IH), 7.70-7.68 (m, 2H), 7.48 (t, J=7.2 Hz, 2H), 7.40-7.36 (m, 2H), 7.26-7.23 (m, 2H), 6.73-6.71 (m, 2H), 6.32 (d, J=8.0 Hz, IH), 6.20 (d, J=2.0 Hz, IH), 4.31-4.24 (m, IH), 3.77 (s, 3H), 1.45 (d, J=7.2Hz, 3H) ; MS (ESI) m/z 398

[000204] Example 100: 2-((4-(l -methyl- lH-pyrazol-5-yl)phenyl)(2- morpholinoethyl)amino)-N-(5-phenylpyridin-2-yl)propanamide

6 mg, 9%, HPLC 96%, white solid. 1H NMR (400 MHz, DMSO-i¾ 6 10.92 (s, IH), 8.59 (d, J=2.4 Hz, IH), 8.22-8.20 (m, IH), 8.13-8.10 (m, IH), 7.69-7.68 (m, 2H), 7.47 (t, J=7.2 Hz, 2H), 7.40-7.32 (m, 4H), 6.81 (d, J=8.8 Hz, 2H), 6.23 (d, J=1.6 Hz, IH), 4.59 (q, J=6.8 Hz, 1H), 3.79 (s, 3H), 3.73-3.58 (m, 7H), 2.72-2.54 (m, 5H), 1.45 (d, J=7.2Hz, 3H) ; MS (ESI) m/z 51 ί

[C₃₀H₃₄N₆O₂ + H]⁺.

[000205] Example 101 : N-(5-phenylpyridin-2-yl)-2-(4-(2-(trifluoromethyl)-lH-imidazol-l- yl) phenylamino) propanamide

65 mg, 47%, LC-MS 96%, off-white solid. 1H NMR (400 MHz, CDC13) δ (ppm): 10.71 (s, IH), 8.66 (d, J= 2.2 Hz, IH), 8.19-8.09 (m, 2H), 7.71 (d, J= 7.0, 2H), 7.55 (d, J= 0.9, IH), 7.48 (t, J= 7.5 Hz, 2H), 7.39 (t, J= 7.5 Hz, IH), 7.19-7.16 (m, 3H), 6.71 (d, J= 8.8 Hz, 2H), 6.54 (d, J= 7.9 Hz, IH), 4.30 (t, J= 7.5 Hz, IH), 1.45 (d, J= 7.0 Hz, 3H); MS (ESI) m/z 452.13

[C₂₄H₂₀F₃N₅O + H]⁺.

[000206] Example 102: N-(5-phenylpyridin-2-yl)-2-(6-(2-(trifluoromethyl)-lH-imidazol-l- yl)pyridin-3 -ylamino)propanamide

34 mg, 23%, LC-MS 96%. IH NMR (400 MHz, DMSO-i 6) δ (ppm): 10.86 (s, IH), 8.67 (d, J = 2.2 Hz, IH), 8.18-8.09 (m, 2H), 7.96 (d, J - 3 Hz, IH), 7.71 (d, J = 6.6 Hz, 3H), 7.48 (t, J = 8 Hz, 2H), 7.45-7.35 (m, 2H), 7.21 (s, 2H), 7.14 (dd, J = 3, 8.7 Hz, IH), 6.82 (d, J = 7.9 Hz, IH), 4.38 (t, J = 7 Hz, IH), 1.47 (d, J = 7 Hz, 3H); MS (ESI) m/z 453.16 [C23H19F3N60+H]+.

[000207] Example 103: 2-(4-(2-morpholino-lH-imidazol-l-yl)phenylamino)-N-(5- phenylpyridin-2-yl)propanamide

15 mg, 20%, LC-MS 99%, off-white solid. 1H NMR (400 MHz, DMSO- ₆) δ (ppm): 9.13 (s, 1H), 8.46 (s, 1H), 8.38 (d, J = 8.4 Ηζ, ΙΗ), 7.95 (d, J= 8.8 Hz, 2H), 7.54 (d, J- 7.6 Hz, 2H), 7.46 (t, J= 7.2 Hz, 2H) ,7.40-7.32 (m, 3H), 6.79 (d, J= 14 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 4.15 (s, 1H), 3.96 (q, J= 7.2 Hz, 1H), 3.65 (t, J = 4.4 Hz, 4H), 3.0 (t, J = 5.2 Hz, 4H), 1.67 (d, J = 6.8 Hz, 3H); MS (ESI) m/z 469.21 [C₂₇H₂₈N₆0₂+H]⁺.

[000208] Example 104: 2 3-morpholino-4-(2-(trifluoromethyl)-lH-imidazol-l - yl)phenylamino)-N-(5-phenylpyridin-2-yl)propanamide

50 mg, 47%, LC-MS 95%. 1H NMR (400 MHz, DMSO- 6) δ (ppm): 10.75 (b r s, 1 H), 8.65 (d, J= 1.7 Hz, 1H), 8.18-8.09 (m, 2 H), 7.71-7.69 (d, , J= 7.4 Hz, 2 H), 7.53-7.37 (m, , 4 H), 7.21 (s, 1 H), 7.07-7.05 (d, J= 8.4 Hz lH),6.49-6.47(d, , J= 7.9 Hz,3 H), 4.31 (,m 1 H), 3.43-3.34 (m, 4 H), 2.67-2.62 (m, 2 H), 2.42-2.33 (m,2 H),1.44-1.42(d, , J= 6.6 Hz,3H). MS (ESI) m/z 537.21 [C28H27F3N602]⁺.

Example 105: 2-(4-(l-methyl-lH-pyrazol-5-yl)phenoxy)-N-(5-phenylpyridin-

93 mg, 24%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-i¾ 6 10.85 (s, IH), 8.62 (s, IH), 8.157-8.100 (m, 2H), 7.71-7.70 (m, 2H), 7.50-7.37 (m, 6H), 7.06-7.04 (m, 2H), 6.31 (s, IH), 5.15 (q, J= 6.8 Hz, IH), 3.80 (s, 3H), 1.59 (d, J= 6.4 Hz, 3H); MS (ESI) m/z 399

[C₂₄H₂₂N₄0₂ + H]⁺.

[000210] Example 106: 2-(3-fluoro-4-(l -methyl- lH-pyrazol-5-yl)phenylamino)-N-(5- phenylpyridm-2-yl)propanamide

41 mg, 39%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-<¾ δ 10.72 (s, IH), 8.66 (d, J= 2.0 Hz, IH), 8.20-8.12 (m, IH), 8.12-8.05 (m, IH), 7.72-7.65 (m, 2H), 7.52-7.42 (m, 2H), 7.42-7.33 (m, 2H), 7.20-7.12 (m, IH), 6.67 (d, J= 8.0 Hz, IH), 6.60-6.50 (m, 2H), 6.21 (d, J = 2.0 Hz, IH), 4.40-4.30 (m, IH), 3.66 (s, 3H), 1.45 (d, J= 6.8 Hz, 3H); MS (ESI) m/z 416

[C₂₄H₂₂FN₅0 + H]⁺.

[000211] Example 107: 2-(2-fluoro-4-(l-methyl-lH-pyrazol-5-yl)phenylamino)-N-(5- phenylpyridin-2-yl)propanamide

187 mg, 30%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-<¾ δ 10.68 (s, IH), 8.65 (d, J= 2.4 Hz, IH), 8.20-8.12 (m, IH), 8.12-8.05 (m, IH), 7.72-7.65 (m, 2H), 7.52-7.42 (m, 2H), 7.42-7.33 (m, 2H), 7.32-7.25 (m, IH), 7.15 (d, J = 8.0 Hz, IH), 6.76 (t, J = 8.4 Hz, IH), 6.29 (d, J= 1.6 Hz, 1H), 5.95 (d, J= 7.6 Hz, IH), 4.40-4.30 (m, 1H), 3.80 (s, 3H), 1.51 (d, J= 6.8 Hz, 3H); MS (ESI) m/z 416 [C₂₄H₂₂FN₅0 + H]⁺.

[000212] Example 108: 2-(2-methyl-3-oxo-7-(2-(trifluoromethyl)-lH-imidazol-l-yl)-2H- benzo[b][l,4]oxazin-4(3H)-yl)-N-(5-phenylpyridin-2-yl)propanamide

120 mg, 42%, LC-MS 97 %„ off-white solid. 1H NMR (400 MHz, DMSO- ¾ δ (ppm): 10.76 (s, IH), 8.62 (d, J= 8.3 Hz, IH), 8.12 (d, J= 9.7 Hz, 2H), 7.70-7.68 (m, 3H), 7.50-7.34 (m, 4H), 7.27-7.17 (m, 3H), 5.51 (d, J= 7.0 Hz, 3H), 5.44 (d, J= 7.1 Hz, 3H), 4.87 (t, J= 7.0 Hz, IH), 1.56-1.46 (m, 6H); MS (ESI) m/z 520.2 [C₂₇H₂₂F₃N₅0₃+H]⁺.

[000213] Example 109: 2-(3-oxo-7-(2-(trifluoromethyl)-lH-imidazol-l-yl)-2H- benzo[b] [ 1 ,4]oxazin-4(3H)-yl)-N-(5-phenylpyridin-2-yl)propanamide

95 mg, 42%, LC-MS 95%, off-white solid. Ή NMR (400 MHz, DMSO- ₆) δ (ppm): 10.76 (s, 1H), 8.62 (s, 1H), 8.12 (s, 2H), 7.72-7.67 (m, 3H), 7.50-7.39 (m, 3H), 7.25-7.17 (m, 4H), 5.51- 5.50 (m, 1H), 4.79 (s, 2H), 1.56 (d, J= 7.1 Hz, 3H); MS (ESI) m/z 508.3 [C₂₆H₂oF₃N₅0₃ + H]⁺.

[000214] Example 110: (S)-2-(6-(l -methyl- lH-pyrazol-5-yl)-4-(morpholine-4- carbonyl)pyridin-3-ylamino)-N-(5-phenylpyridin-2-yl)propanamide

LC-MS 95%, [ct]_D +70.03°. Ή NMR (400 MHz, DMSO-< ₆) δ (ppm): 10.91 (s, 1H), 8.68 (d, J= 2.2 Hz, 1H), 8.17-8.10 (m, 3H), 7.72-7.70 (d, J = 7.5 Hz, 2H), 7.50-7.40 (m, 3H), 7.40-7.37 (m, 2H), 6.64-6.63 (d, J= 2.2 Hz, 1H), 5.92 (d, J= 7.5 Hz, 1H), 4.54- 4.50 (t, J= 7.5 Hz, 1H), 4.09 (s, 3H), 3.67 (m, 6H), 3.89-3.27 (m, 2H), 1.52-1.50 (d, J= 6.6 Hz, 3H); MS (ESI) m/z 511 .23 [C₂₈H₂₉N₇0₃]⁺.

[000215] Example 11 1 : (S)-N-(3, 3'-bipyridin-6-yl)-2-(6-(l -methyl- lH-pyrazol-5- yl)pyridin-3 -ylamino)propanamide

36% , LC-MS 98%, chiral HPLC 98%, [a]_D -72.58°. 1H NMR (400 MHz, DMSO-<¾) δ (ppm): 10.86 (s, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.74 (s, 1H), 8.58 (d, J = 6.0 Hz, 1H), 8.19 (s, 2H), 8.14- 8.11 (m, 2H), 7.52-7.48 (m, 2H), 7.37 (s, 1H), 7.05 (dd, J = 11.2 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.50 (s, 1H), 4.38 (t, J = 7.2 Hz, 1H), 4.03 (s, 1H), 1.46 (d, J = 6.8 Hz, 3H); MS (ESI) m/z 400.47 [C22H21N70+H]+.

Example 112: 2-((4-(lH-imidazol-l-yl)phenyl)(isopropyl)amino)-N-(biphenyl-4-

General procedure 4:

[000217] To 4-bromo-N-isopropylaniline hydrobromide (150 mg, 0.509 mmol) and K₂C0₃ (211 mg, 1.53 mmol) in DMF (1.02 mL) was added methyl bromoacetate (96 μΐ, 1.02 mmol). The mixture was stirred at 100°C under inert atmosphere for 48 h, then it was diluted with H₂0 (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was dried over Na₂S0₄ and was concentrated under reduced pressure to afford methyl 2-((4- bromophenyl)(isopropyl)amino)acetate (140mg, 94%); MS (ESI) m/z 288 [C₁₂H₁₆BrNQ₂ + H]⁺. [000218] Methyl 2-((4-bromophenyl)(isopropyl)amino)acetate (0.500 mmol) and LiOH (40 mg, 1.00 mmol) in water (1.25 mL) and CH₃OH (1.25 mL) was stirred for 2 h at room

temperature. CH₃OH was removed from the reaction and the aqueous layer was acidified with cone HC1 until pH~l . The mixture was concentrated under reduced pressure to afford 2-((4- bromophenyl)(isopropyl)amino)acetic acid; MS (ESI) m/∑ 21 [CnH₁₄BrN0₂ + H]⁺.

[000219] To a solution of 2-((4-bromophenyl)(isopropyl)amino)acetic acid (0.500 mmol) in DMF (2.50 mL) were added HATU (285 mg, 1.50 mmol), DIPEA (0.435 mL, 2.50 mmol) and 4- aminobiphenyl (85 mg, 0.500 mmol), The reaction mixture was stirred at room temperature under inert atmosphere for 18 h, then it was diluted with H₂0 (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was dried over Na₂S0₄ and was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel_, eluent cyclohexane/EtO Ac 70:30 to afford N-(biphenyl-4-yl)-2-((4- bromophenyl)(isopropyl)amino)acetamide (54 mg, 26%); MS (ESI) w/z 425 [C₂₃H₂₃BrN₂0 + H]⁺.

[000220] N-(biphenyl-4-yl)-2-((4-bromophenyl)(isopropyl)amino)acetamide (50 mg, 0.1 18 mmol), imidazole (16 mg, 0.236 mmol), Cul (2.2 mg, 0.012 mmol), L-proline (27 mg, 0.236 mmol), Cs₂C0₃ (77 mg, 0.236 mmol) in DMSO (1.20 mL) was stirred for 48 h at 100°C. The reaction mixture was diluted with H₂0 (20 mL) and extracted with EtOAc (3 ^χ 30 mL). The combined organic layer was dried over Na₂S0₄ and was concentrated under reduced pressure. The residue was purified by preparative HPLC (CI 8, eluent ACN, water, formic acid 0.1%) to afford 2-((4-(lH-imidazol-l-yl)phenyl)(isopropyl)amino)-N-(biphenyl-4-yl)acetamide (13 mg, 26%, HPLC 99%) as a white solid. 1H NMR (400 MHz, DMSO-c¾ δ 10.01 (s, 1H), 8.14 (s, 1H), 7.76-7.69 (m, 2H), 7.67-7.60 (m, 4H), 7.58 (s, 1H), 7.48-7.38 (m, 4H), 7.36-7.29 (m, 1H), 7.10 (s, 1H), 6.86-6.78 (m, 2H), 4.30-4.15 (m, 1H), 4.03 (s, 2H), 1.21 (d, J= 6.4Hz, 6H); MS (ESI) m/z 411 [C₂₆H₂₆N₄0 + H]⁺.

Example 1 13: 2-((4-(lH-imidazol-l-yl)phenyl)(methyl)amino)-N-(biphenyl-4-

30 mg, 31%, HPLC 99%, off- white solid. 1H NMR (400 MHz, DMSO-i¾ δ 10.13 (s, IH), 8.02 (bs, IH), 7.73-7.67 (m, 2H), 7.67-7.59 (m, 4H), 7.55 (s, IH), 7.48-7.38 (m, 4H), 7.35-7.29 (m, IH), 7.04 (s, IH), 6.83-6.76 (m, 2H), 4.23 (s, 2H), 3.10 (s, 3H); MS (ESI) m/z 383 [C₂₄H₂₂N₄0 +

H]⁺.

[000222] Example 114: (S)-l-(4-(lH-imidazol-l-yl)phenyl)-N-(biphenyl-4-yl)pyrrolidine- 2-carboxamide

43 mg, 29 %, HPLC 98%, brown solid. 1H NMR (400 MHz, CDCl_a) δ 8.28 (s, IH), 7.75 (br s, IH), 7.59-7.53 (m, 6H), 7.41 (t, J=7.2 Hz, 2H), 7.34-7.25 (m, 3H), 7.25-7.18 (m, 2H), 6.79 (d, J=9.2 Hz, 2H), 4.15-4.12 (m, IH), 3.84-3.80 (m, IH), 3.37-3.30 (m, IH), 2.44-2.39 (m, 2H), 2.16-2.08 (m, 2H) ; ^I3C NMR (400 MHz, CDC1₃) δ 171.60, 146.96, 140.41, 137.71 , 136.42, 128.81, 127.66, 127.23, 126.87, 123.41 , 120.27, 114.12, 65.41, 50.35, 31.70, 24.36; MS (ESI) m/z 409 [C₂₆H₂₄N₄0+ H]⁺.

[000223] Example 115: (R)-l-(4-(lH-imidazol-l-yl)phenyl)-N-(biphenyl-4-yl)pyrrolidine- 2-carboxamide

59mg, 41%, HPLC 97%, brown solid. 1H NMR (400 MHz, CDCl_a) δ 8.28 (s, IH), 7.76 (br s, IH), 7.59-7.53 (m, 6H), 7.41 (t, J=7.2 Hz, 2H), 7.34-7.25 (m, 3H), 7.25-7.20 (m, 2H), 6.79 (d, J=8.8 Hz, 2H), 4.15-4.12 (m, IH), 3.84-3.80 (m, IH), 3.37-3.30 (m, IH), 2.44-2.39 (m, 2H), 2.16-2.08 (m, 2H) ; ¹³C NMR (400 MHz, CDC1₃) 6 171.59, 146.95, 140.39, 137.69, 136.40, 128.79, 127.64, 127.22, 126.85, 123.44, 120.26, 114.14, 65.39, 50.34, 31.68, 24.35; MS (ESI) m/z 409 [C₂₆H₂₄N₄0+ H]⁺.

[000224] Example 1 16: (S)-l-(4-(2-methyl-lH-imidazol-l-yl)phenyl)-N-(5-phenylpyridin- 2-yl)pyrrolidine-2-carboxamide

8 mg, 4%, HPLC 97%, grey solid. 1H NMR (400 MHz, CDCl_a) δ 8.86 (s, IH), 8.45 (d, J=1.6 Hz, IH), 8.42-8.40 (m, IH), 7.96-7.93 (m, IH), 7,54-7.52 (m, 2H), 7.47-7.44 (m, 2H), 7.40-7.36 (m, IH), 7.18-7.16 (m, 2H), 6.99-6.93 (m, 2H), 6.76-6.74 (m, 2H), 4.19-4.16 (m, IH), 3.87-3.83 (m, IH), 3.38-3.31 (m, IH), 2.43-2.39 (m, 2H), 2.31 (s, 3H), 2.17-2.14 (m, 2H); MS (ESI) m/z 424 [C₂₆H₂₅N₅0 + H]⁺.

[000225] Example 117: 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(biphenyl-4-yl)-2- methylpropanamide

4-Iodophenol (lg, 4.55 mmol), sodium hydroxide (909 mg, 22.7 mmol) was refluxed in acetone (5.5 ml, 75 mmol) for 30 min. CHC1₃ (0.73 ml, 1.87 mmol) was then added and the resulting mixture was refluxed for 4 h. Upon reaction completion, the mixture was concentrated under reduced pressure, acidified with cone HC1 and the solids obtained were filtered, washed with water to afford 2-(4-iodophenoxy)-2-methylpropanoic acid (918mg, 66%); MS (ESI) m/z 307 [C₁₀H„IO₃ + H]⁺.

[000226] To a solution of 2-(4-iodophenoxy)-2-methylpropanoic acid (500 mg, 1.63 mmol) in DMF (3.3 mL) were added HATU (932 mg, 4.90 mmol), DIPEA (0.854 mL, 4.90 mmol) and 4-aminobiphenyl (290 mg, 1.72 mmol), The reaction mixture was stirred at room temperature under inert atmosphere for 18 h, then it was diluted with H₂0 (20 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layer was dried over Na₂S0₄ and was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel_; eluent cyclohexane/EtOAc 90:10) to afford N-(biphenyl-4-yl)-2-(4-iodophenoxy)-2- methylpropanamide (556 mg, 75%); MS (ESI) m/z 459 [C₂₂H₂₀rNO₂ + H]⁺.

[000227] N-(biphenyl-4-yl)-2-(4-iodophenoxy)-2-methylpropanamide ( 100 mg, 0.219 mmol), imidazole (76.1 mg, 0.438 mmol), Cul (4.2 mg, 0.0219 mmol), L-proline (50.4 mg, 0.438 mmol), Cs₂C0₃ (143 mg, 0.438 mmol) in DMSO (0.44 mL) was stirred for 18 h at 100°C. The reaction mixture was diluted with H₂0 (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was dried over Na₂S0₄ and was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel_, eluent CH₂C1₂/CH₃0H 97:3) to afford 2-(4-(lH-imidazol-l-yl)phenoxy)-N-(biphenyl-4-yl)-2-methylpropanamide (20 mg, 23%, HPLC 99%) as an off- white solid. Ή NMR (400 MHz, DMSO-_¾ δ 10.15 (s, 1H), 8.13 (s, 1H), 7.83-7.78 (m, 2H), 7.66-7.60 (m, 5H), 7.60-7.53 (m, 2H), 7.47-7.41 (m, 2H), 7.36-7.30 (m, 1H), 7.09-7.03 (m, 3H), 1.59 (s, 6H); MS (ESI) m/z 398 [C₂₅H₂₃N₃0₂ + H]⁺.

[000228] Example 118: 2-(4-(lH-imidazol-l-yl)naphthalen-l-yloxy)-N-(biphenyl-4- yl)acetamide

2 mg, 1.6%, HPLC 98%, white solid. Ή NMR (400 MHz, DMSO-i¾ δ 10.38 (bs, 1H), 8.47 (d, J= 2.0Hz, 1H), 7.91 (s, 1H), 7.79-7.72 (m, 2H), 7.70-7.61 (m, 6H), 7.54 (d, J= 8.0Hz, 1H), 7.50 (s, 1H), 7.48-7.41 (m, 2H), 7.41-7.30 (m, 2H), 7.12 (s, 1H), 7.05 (d, J= 8.0Hz, 1H), 5.05 (s, 2H); MS (ESI) m/z 420 [C₂₇H₂iN₃0₂ + H]⁺.

[000229] Example 1 19: (S)-l-(4-(l -methyl- 1 H-pyrazol-5-yl)phenyl)-N-(6-(pyridin-3- yl)pyridazin-3-yl)pyrrolidine-2-carboxamide

R = OTf or Br

General procedure 5:

[000230] l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (53 mg, 0.256 mmol), (S)- 1 -(4-bromophenyl)-N-(6-(pyridin-3-yl)pyridazin-3-yl)pyrrolidine-2- carboxamide (90 mg, 0.213 mmol), Pd(dppf)₂CH₂Cl₂ (17 mg, 0.021 mmol) and Na₂C0₃ (45 mg, 0.426 mmol) was dissolved in dioxane (3 mL) and water (1 mL). The reaction mixture was heated at reflux for 16 h, then it was diluted with H₂0 (25 mL) and extracted with EtOAc (3x25 mL). The combined organic layer was filtered over celite, dried over Na₂S0₄ and was

concentrated under reduced pressure. The crude residue was purified by preparative HPLC (CI 8, eluent ACN, water, formic acid 0.1%) to afford (S)-l-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)-N- (6-(pyridin-3-yl)pyridazin-3-yl)pyrrolidine-2-carboxamide (22 mg, 24%, AUC HPLC 96%) as white solid. 1H NMR (400 MHz, CDCl_a) δ 9.39 (s, IH), 9.18 (d, J= 2.0 Hz, IH), 8.72-8.68 (m, 2H), 8.37-8.35 (m, IH), 7.93 (d, J= 9.6 Hz, IH ), 7.47-7.43 (m, 2H), 7.32 (d, J= 8.8 Hz, 2H), 6.77 (d, J= 8.8 Hz, 2H), 6.22 (d, J= 2.0 Hz, IH), 4.25-4.22 (m, IH), 3.93-3.88 (m, 4H), 3.41-3.35 (m, IH), 2.48-2.41 (m, 2H), 2.19-2.12 (m, 2H); MS (ESI) m/z 426 [C₂₄H₂₃N₇0 + H]⁺.

[000231] Example 120: (S)-N-(biphenyl-4-yl)-l-(4-(l-methyl-lH-pyrazol-5- yl)phenyl)pyrrolidine-2-carboxamide

19mg, 12%, HPLC 99%, beige solid. 1H NMR (400 MHz, CDCl_a) δ 8.33 (s, IH), 7.62-7.56 (m, 6H), 7.51 (d, J=1.6 Hz, IH), 7.46-7.42 (m, 2H), 7.37-7.34 (m, 3H), 6.83-6.81 (m, 2H), 6.26 (s, IH), 4.21-4.18 (m, IH), 3.90-3.83 (m, 4H), 3.41-3.34 (m, IH), 2.45-2.39 (m, 2H), 2.19-2.10 (m, 2H); MS (ESI) m/z 423 [C₂₇H₂₆N₄0 + H]⁺.

[000232] Example 121 : (S)- l-(4-(l -methyl- lH-pyrazol-5-yl)phenyl)-N-(6-phenylpyridazin- 3 -yl)pyrrolidine-2-carboxamide

13 mg, 13%, HPLC 99%, brown solid. 1H NMR (400 MHz, DMSO- ) δ 11.38 (s, IH), 8.38- 8.36 (m, IH), 8.24-8.22 (m, IH), 8.10-8.08 (m, 2H), 7.56-7.50 (m, 3H), 7.37-7.32 (m, 3H), 6.65- 6.63 (m, 2H), 6.22 (d, J=1.6 Hz, IH), 4.59-4.57 (m, IH), 3.78 (s, 3H), 3.66-3.61 (m, IH), 3.42- 3.36 (m, IH), 2.43-2.32 (m, IH), 2.18-2.06 (m, 3H) ; MS (ESI) m/z 425 [C₂₅H₂₄N₆0 + H]⁺. [000233] Example 122: (S)-N-(6-(4-fluorophenyl)pyridazin-3-yl)-l-(4-(l -methyl- 1H- pyrazol-5-yl)phenyl)pyrrolidine-2-carboxamide

13 mg, 13%, HPLC 99%, yellow solid. 1H NMR (400 MHz, DM80-<¾ δ 1 1.39 (s, IH), 8.37- 8.35 (m, IH), 8.25-8.22 (m, IH), 8.17-8.13 (m, 2H), 7.39-7.32 (m, 5H), 6.64 (d, J=8.8 Hz, 2H), 6.22 (d, J=2.0 Hz, IH), 4.59-4.56 (m, IH), 3.78 (s, 3H), 3.66-3.61 (m, IH), 3.42-3.36 (m, IH), 2.49-2.32 (m, IH), 2.17-2.12 (m, 3H) ; MS (ESI) w/z 443 [C₂₅H₂₃FN₆0 + H]⁺.

[000234] Example 123: (S)-N-(5-(4-fluorophenyl)pyridin-2-yl)-l-(4-(l -methyl- lH-pyrazol- 5-yl)phenyl)pyrrolidine-2-carboxamide

10 mg, 10%, HPLC 95%, yellow solid. 1H NMR (400 MHz, DMSO-i¾ 6 10.69 (s, IH), 8.64 (d, J=2,0 Hz, IH), 8.15-8.09 (m, 2H), 7.77-7.73 (m, 2H), 7.37-7.28 (m, 5H), 6.63 (d, J=8.8 Hz, 2H), 6.22 (d, J=2.0 Hz, IH), 4.52-4.50 (m, IH), 3.78 (s, 3H), 3.66-3.62 (m, IH), 3.40-3.35 (m, IH), 2.38-2.32 (m, IH), 2.11-2.02 (m, 3H) ; MS (ESI) m/z 442 [C₂₆H₂₄FN₅0 + H]⁺.

[000235] Example 124: 2-(4-(l -methyl- lH-pyrazol-5-yl)phenylamino)-N-(5- phenylpyridin-2-yl)propanamide

15%, LC-MS 99%, off-white solid. 1H NMR (400 MHz, DMSO- ₆) δ (ppm): 10.66 (s, IH), 8.65 (s, IH), 8.18 (d, J= 8.4 Hz„ IH), 7.68 (d, J= 8.0 Hz, 2H), 7.48 (t, J= 8.0 Hz, 2H), 7.40-7.36 (m, 2H), 7.23 (d, J = 8.0 Hz, 2H) ,6.72 (d, J = 8.0 Hz, 2H), 6.37 (d, J= 8.0 Hz, IH), 6.21 (s, IH), 4.29 (q, J= 8.0 Ηζ, ΙΗ), 3.77 (s, 3H), 1.43 (d, J= 5.5 Hz, 3H); MS (ESI) m/z 385.08

[C₂₄H₂₃N₅0+H]⁺.

[000236] Example 125: (S)-l-(4-(l -methyl- lH-pyrazol-5-yl)phenyl)-N-(6-phenylpyridin-3- yl)pyrrolidine-2-carboxamide

80mg, 53%, HPLC 96%, off-white solid. 1H NMR (400 MHz, CDCl_a) δ 8.58 (d, J=2.8 Hz, IH), 8.40 (s, IH), 8.30-8.27 (m, IH), 7.96 (d, J-7.2 Hz, 2H), 7.73 (d, J=8.4 Hz, IH), 7.51-7.36 (m, 6H), 6.83 (d, J=8.8 Hz, 2H), 6.26 (d, J=1.6 Hz, IH), 4.23-4.20 (m, IH), 3.89-3.87 (m, 4H), 3.39- 3.36 (m, IH), 2.47-2.41 (m, 2H), 2.22-2.09 (m, 2H); MS (ESI) m/z 424 [C₂6H2₅N₅0 + H]⁺.

[000237] Example 126: (S)-N-(2,3'-bipyridin-5-yl)-l-(4-(l-methyl-lH-pyrazol-5- yl)phenyl)pyrrolidine-2-carboxamide

28 mg, 26%, HPLC 99%, off- white solid. Ή NMR (400 MHz, DMSO-t¼) δ 10.43 (s, IH), 9.21 (d, J= 1.6 Hz, 1H), 8.90 (d, J= 2.0 Hz, IH), 8.61-8.57 (m, IH), 8.41-8.34 (m, IH), 8.23-8.17 (m, IH), 8.03 (d, J= 8.4 Hz, IH), 7.51-7.45 (m, IH), 7.40-7.30 (m, 3H), 6.64 (d, J= 8.8 Hz, 2H), 6.23 (d, J= 1.6 Hz, IH), 4.40-4.30 (m, IH), 3.79 (s, 3H), 3.70-3.60 (m, IH), 3.40-3.30 (m, IH), 2.40-2.30 (m, IH), 2.15-2.00 (m, 3H); MS (ESI) m/z 425 [C₂₅H₂₄N₆0 + H]⁺.

[000238] Example 127: (S)-N-(3,3'-bipyridin-6-yl)-l-(4-(l-methyl-lH-pyrazol-5- yl)phenyl)pyrrolidine-2-carboxamide

26 mg, 8%, HPLC 99%, white solid. 1H NMR (400 MHz, DMSO-d₆): δ 10.46 (s, IH), 8.93 (d, J = 1.6 Hz, IH), 8.73 (d, J- 1.6 Hz, IH), 8.61-8.57 (m, IH), 8.21-8.15 (m, 2H), 8.15-8.10 (m, IH), 7.52-7.45 (m, IH), 7.40-7.30 (m, 3H), 6.63 (d, J= 8.8 Hz, 2H), 6.22 (d, J= 1.6 Hz, IH), 4.55-4.50 (m, IH), 3.79 (s, 3H), 3.70-3.60 (m, IH), 3.45-3.35 (m, IH), 2.40-2.30 (m, IH), 2.15- 1.95 (m, 3H); MS (ESI) m/z 425 [C₂₅H₂₄N₆0 + H]⁺.

[000239] Example 128: (R)-l-(4-(l-methyl-lH-pyrazol-5-yl) phenyl)-N-(5-phenylpyridin- 2-yl) pyrrolidine-2-carboxamide

200 mg 47%, LC-MS 98%, [a]_D +200°. 1H NMR(400 MHz, DMSO-d₆) δ (ppm): 10.73 (s, 1H), 8.66 (s, IH), 8.16-8.09 (m, 2H), 7.70 (d, J = 7.4 Hz, 2H),7.48 (t, J = 7.5 Hz, 2H), 7.40-7.32 (m, 4H), 6.63 (d, J = 8.3 Hz, 2H), 6.22 (s, IH), 4.52 (d, J = 8.3 Hz, IH), 3.7 (s, 3H), 3.63 (m, 4H), 3.36 (t, J = 8.3 Hz, IH), 2.35 (t, J = 7.0 Hz, IH), 2.11 (d, J = 7.5 Hz, 3H); MS (ESI) m/z 424.24 [C₂₆H₂₅N₅0+H]⁺.

[000240] Example 129: (S)-N-(2,3'-bipyridin-5-yl)-2-(6-(l-methyHH-pyrazol-5- yl)pyridin-3-ylamino)propanamide

[000242] 600 mg, 23 %, chiral HPLC 97%, [a]_D -107.2°, c = 0.5% (1 :1 CH₃OH:CHCl₃), an off-white solid. 1H NMR(400 MHz, DMSO-c¾ δ (ppm): 10.50 (s, IH), 9.21 (s, IH), 8.90 (d, J = 2.2 Hz, IH), 8.59 (d, J = 3.9 Hz, IH), 8.37 (d, J = 7.8 Hz, IH), 8.23-8.20 (dd, J = 2.6, 8.7 Hz, IH), 8.12 (d, J = 2.6 Hz, IH), 8.02 (d, J = 8.7 Hz, IH), 7.51-7.47 (m, 2H), 7.37 (d, J = 1.7 Hz, IH), 7.05-7.02 (dd, J = 2.7, 8.8 Hz, IH), 6.56 (d, J = 7.5 Hz, IH), 6.50 (d, J = 1.8 Hz, IH), 4.22 (t, J = 7.0 Hz, IH), 4.03 (s, 3H), 1.49 (d, J = 6.6 Hz, 3H); MS (ESI) m/z 400.25 [C₂₂H₂₁N₇0+H]⁺. Example 130: 3-(4-(l -methyl- 1 H-pyrazol-5-yl)phenyl)-N-(5-phenylpyridin

48 mg, 31%, HPLC 99%, brown solid. Ή NMR (400 MHz, CDCl_a) δ 8.47 (d, J=2.0 Hz, IH), 8.28 (d, J=8.8 Hz, IH), 7.93-7.90 (m, 2H), 7.56-7.54 (m, 2H), 7.50-7.44 (m, 3H), 7.39-7.32 (m, 5H), 6.27 (s, IH), 3.87 (s, 3H), 3.13 (t, J=7.6 Hz, 2H), 2.77 (t, J=8.0 Hz, 2H); MS (ESI) m/z 383 [C₂₄H₂₂N₄0 + H]⁺,

[000244] Example 131 : l-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)-N-(5-phenylpyridin-2- yl)piperidine-2-carboxamide

34 mg, 11%, HPLC 95%, white solid. 1H NMR (400 MHz, CDC1₃) δ 9.03 (s, IH), 8.49-8.48 (m, IH), 8.37-8.34 (m, IH), 7.95-7.92 (m, IH), 7.57-7.55 (m, 2H), 7.50-7.46 (m, 3H), 7.41-7.35 (m, 3H), 7.12-7.10 (m, 2H), 6.27 (s, 1H), 4.36 (t, J= 4.8 Hz, IH), 3.89 (s, 3H), 3.58-3.53 (m, IH), 3.46-3.41 (m, IH), 2.33-2.31 (m, IH), 2.02-1.98 (m, 1H), -1.79-1.73 (m, 4H); MS (ESI) m/z 438

[000245] Example 132: 2-(4-(l-methyl-lH-pyrazol-5-yl)-2- (mo holinomethyl)phenylamino)-N-(5-phenylpyridin-2-yl) ropanamide

\

16 mg, 33%, HPLC 99%, off- white solid. 1H NMR (400 MHz, OMSO-d₆) δ 10.74 (s, IH), 8.66 (d, J= 2.4 Hz, IH), 8.20-8.11 (m, IH), 8.11-8.05 (m, IH), 7.72-7.65 (m, 2H), 7.51-7.45 (m, 2H), 7.42-7.35 (m, 2H), 7.30-7.20 (m, 2H), 7.20-7.15 (m, IH), 6.62 (d, J= 8.4 Hz, 2H), 6.22 (d, J= 1.6 Hz, IH), 4.50-4.30 (m, IH), 3.78 (s, 3H), 3.70-3.60 (m, 5H), 3.60-3.50 (m, IH), 2.50-2.30 (m, 4H), 1.49 (d, J= 6.8 Hz, 3H); MS (ESI) m/z 497 [C₂₉H₃₂N₆0₂ + H]⁺.

[000246] Example 133: (S)-l-(6-(l-methyl-lH-pyrazol-5-yl)pyridin-3-yl)-N-(5- phenylpyridin-2-yl)pyrrolidine-2-carboxamide

23%, HPLC 98%, [a]_D -227.06°. IH NMR (400 MHz, CDC13) δ (ppm): 8.79 (s, IH), 8.44 (d, J = 1.3 Hz, IH), 8.40 (d, J = 8.3 Hz, IH), 8.20 (d, J = 3.1 Hz, IH), 7.95 (dd, J = 2.2, 8.8 Hz, IH), 7.54-7.37 (m, 7H), 7.03 (dd, J = 3.1, 8.8 Hz, IH), 6.44 (d, J = 1.8 Hz, IH), 4.21 (t, J = 6.5 Hz, IH), 4.16 (s, 3H), 3.92-3.88 (m, IH), 3.39-3.37 (m, IH), 2.45-2.42 (m, 2H), 2.19-2.13 (m, 2H); MS (ESI) m/z 425.47 [C25H24N60+HJ+.

[000247] Example 134: (S)-N-(3,3'-bipyridin-6-yl)-l-(6-(l-methyl-lH-pyrazol-5- yl)pyridin-3-yl)pyrrolidine-2-carboxamide

24%, HPLC 99 %, [<x]_D -228.19 °. H NMR (400 MHz, DMSO-dtf) δ (ppm): 10.94 (s, IH), 8.95 (s, IH), 8.75 (d, J = 0.9 Hz, IH), 8.59 (d, J = 4.0 Hz, IH), 8.20-8.13 (m, 3H), 8.02 (d, J = 2.6 Hz, IH), 7.58 (d, J = 8.8 Hz, IH), 7.52-7.50 (m, IH), 7.38 (d, J - 1.7 Hz, IH), 6.99 (dd, J = 2.6, 8.8 Hz, IH), 6.53 (d, J - 1.8 Hz, IH), 4.62 (d, J = 7.4 Hz, IH), 4.05 (s, 3H), 3.67-3.63 (m, IH), 3.47- 3.41 (m, IH), 2.39-2.32 (m, IH), 2.14-2.04 (m, 3H); MS (ESI) m/z 426.2 [C24H23N70+HJ+.

[000248] Example 135: (S)-l-(6-(l-methyl-lH-pyrazol-5-yl)pyridin-3-yl)-N-(6-(pyridin-3- yl)pyridazin-3-yl)pyrrolidine-2-carboxamide

25%, HPLC 99 %.^lH NMR (400 MHz, CDC13) δ (ppm): 9.35 (s, IH), 9.19 (d, J = 1.8 Hz, IH), 8.72-8.68 (m, 2H), 8.37 (d, J = 8.4 Hz, IH), 8.21 (d, J = 3.0 Hz, IH), 7.95 (d, J = 3.0 Hz, IH), 7.48-7.44 (m, 3H), 7.05 (dd, J = 2.7, 8.4 Hz, IH), 6.44 (d, J = 1.8 Hz, IH), 4.28 (dd, J = 3.1, 8.8 Hz, IH), 4.15 (s, 3H), 3.95 (t, J = 6.8 Hz, IH), 3.44-3.38 (m, IH), 2.51-2.42 (m, 2H), 2.22- 2.15 (m, 2H); MS (ESI) m/z 427.21 [C24H22N80+HJ+.

[000249] Example 136: (S)-N-(2,3'-bipyridin-5-yl)-l-(6-(l-methyl-lH-pyrazol-5- yl)pyridin-3-yl)pyrrolidine-2-carboxamide

41%, LC-MS 98%, chiral HPLC 99%, [a]_D -203° , white solid. 1H NMR (400 MHz, CDC1₃) δ (ppm): 9.15 (s, IH), 8.63-8.61 (m, 2H), 8.32-8.24 (m, 4H), 7.74 (d, J= 8.8 Hz, IH), 7.50-7.47 (m, 2H), 7.40-7.37 (m, IH), 7.06 (dd, J= 3.1, 8.8 Hz, IH), 6.46 (d, J= 1.8 Hz, 1H), 4.22 (t, J= 6.2 Hz, IH), 4.17 (s, 3H), 3.92 (t, J= 7.25 Hz, IH), 3.44-3.37 (m, IH), 2.49-2.43 (m, H), 2.20- 2.12 (m, IH); MS (ESI) m/z 426.2 [C₂₄H₂₃N₇0+H]⁺.

[000250] Example 137: (2S,4S)-4-fluoro-l-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)-N-(5- phenylpyridin-2-yl)pyrrolidine-2-carboxamide

1H NMR (400 MHz, CDC1₃) δ (ppm): 8.97 (s, IH), 8.46 (s, IH), 8.41 (d, J= 8.4 Hz, IH), 7.94 (dd, J= 2.2, 8.4 Hz, IH), 7.54-7.33 (m, 9H), 6.78 (d, J= 8.8 Hz, 2H), 6.22 (s, IH), 5.54 (m, 0.5H), 5.37 (m, 0.5H), 4.32 (d, J= 9.9 Hz, IH), 4.16-4.06 (m, IH), 3.86 (s, 3H), 3.68-3.60 (m, IH), 3.52-3.47 (m, IH), 2.79-2.71 (m, IH), 2.60-2.56 (m, IH); MS (ESI) m/z 442.16

[C₂₆H₂₄FN₅0+H]⁺.

[000251] Example 138: 2-(4-(oxazol-5-yl)phenylamino)-N-(5-phenylpyridin-2- yl)propanamide

[000252] General procedure 6:

[000253] To a stirred solution of 2-(4-bromophenylamino)-N-(5-phenylpyridin-2- yl)propanamide (200 mg, 1.0 eq) in dioxane (5 mL) was added 5-(tributylstannyl)-2- (triisopropylsilyl)oxazole (377 mg, 1.3 eq) and Pd(PPh₃)₄ (34 mg, 0.06 eq) and the reaction mixture was heated at 100 °C for 16 h. After completion, filtered and concentrated under reduced pressure, poured in to ice cold water and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with water and brine solution, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure and purified by column chromatography (silica gel, eluent EtOAc/hexane 30:70) to afford 150 mg (55%, LC-MS 67%) of N-(5-phenylpyridin-2-yl)- 2-(4^(2-(triisopropylsilyl) oxazol-5-yl) phenylamino) propanamide as a pale yellow solid.

[000254] To a stirred solution of N-(5-phenylpyridin-2-yl)-2-(4-(2-(triisopropylsilyl) oxazol-5-yl) phenylamino) propanamide (150 mg, 1.0 eq) in anhydrous THF (5 mL) was added 1 M TBAF solution (0.41 mL, 1.5 eq) stirred at rt for 4 h. The was concentrated under reduced pressure suspended in water and extracted with EtOAc (3 10 mL). Purification by column chromatography (silica gel, eluent EtOAc/hexane 50:50) to afford 100 mg crude of crude product which was again purified by preparative HPLC to afford 45 mg of 2-(4-(oxazol-5-yl) phenylamino)-N-(5-phenylpyridin-2-yl)propanamide (40%, LC-MS 99%) as an off-white solid. 1H NMR (400 MHz, DMSO-c/₆) 6 (ppm): 10.66 (s, 1H), 8.65 (s, 1H), 8.27 (s, 1H), 8.1 (dd, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 7.49-7.34 (m, 6H), 6.71 (d, J = 8.0 Hz, 2H) , 6.43 (d, J = 8.0 Hz, 1H), 4.30 (q, 1H), 1.45 (d, J = 8.0 Hz, 3H); MS (ESI) m/z 385.08 [C₂₃H₂₀N₄O₂+H]⁺.

[000255] Example 139: 3-(4-(oxazol-5-yl)phenylamino)-l-(6-phenylpyridazin-3-yl)butan- 2-one

30 mg, 20%, LC-MS 99%, off-white solid. Ή NMR (400 MHz, DMSO-c 6) δ (ppm): 11.37 (s, 1H), 8.38 (d, J = 9.2 Hz, 1H), 8.27-8.22 (m, 2H), 8.08 (d, J = 6.8 Hz, 2H), 7.57-7.43 (m, 5H), 7.34 (s, 1H), 6.72 (d, J = 8.8 Hz, 2H), 6.45 (d, J = 8.4 Hz, 1H), 4.38 (t, J = 8.8 Hz, - 1H), 1.47 (d, J = 6.4 Hz, 3H); MS (ESI) m/z 386.2 [C₂₂Hi₉N₅0₂+H]⁺.

Key intermediate synthesis:

[000256] Intermediate 1: 2-(4-(2-methyl-lH-imidazol-l-yl)phenylamino)-N-(5- phenylpyridin-2-yl)propanamide

1 ) Cul, Cs₂C0₃

R = CH3, Et, Ph, CF3, Cyclopropyl, Isopropyl

R1 = H, CH3, isopropyl 2-methyl-lH-imidazole (603 mg, 7.349 mmol), ethyl 2-(4-bromophenylamino)propanoate (1 g, 3.675 mmol), Cul (70 mg, 0.367 mmol), L-proline (846 mg, 7.349 mmol), and Cs₂C0₃ (2.39 g, 7.349 mmol) was dissolved in DMSO (10 mL). The reaction mixture was heated at 90°C for 16 h, then it was diluted with water (100 mL) and extracted with EtOAc (30 mL x .3). The combined organic extracts were concentratrated and the residue purified by column chromatography (silica gel, eluent EtOAc/Hexane 70:30) to afford ethyl 2-(4-(2 -methyl- lH-imidazol-1- yl)phenylamino)propanoate as yellow oil (417 mg, 37%). 1H NMR (400 MHz, DMSO-i¾ δ 7.11-7.09 (m, 3H), 6.82 (s, 1H), 6.62 (d, J=6.8 Hz, 2H), 6.30 (d, J=8.0Hz, 1H), 4.13-4.06 (m, 3H), 2.18 (s, 3H), 1.39 (d, J=6.8 Hz, 3H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z 21 A [Ci₅H₁₉N₃0₂ + H]⁺.

[000257] To ethyl 2-(4-(2-methyl-lH-imidazol-l-yl)phenylamino)propanoate (490 mg, 1.793 mmol) in H₂0 (1 mL) and THF (1 mL) was added lithium hydroxide (86 mg, 3.585 mmol). The reaction mixture was stirred at room temperature for 1 h, and was then acidified using 1M HC1 solution. Solvent was then evaporated in vacuon to afford 2-(4-(2 -methyl- 1H- imidazol-l-yl)phenylamino)propanoic acid (360 mg, off-white solid) and it was used further without purification. 1H NMR (400 MHz, DMSO-< ) δ 7.65 (s, 1H), 7.58 (s, 1H), 7.25 (d, J=9.2 Hz, 2H), 6.69 (d, J=8.8 Hz, 2H), 6.47 (br s, 1H), 4.06-4.02 (m, 1H), 2.43 (s, 3H), 1.40 (d, J=6.8 Hz, 3H); MS (ESI) m/z 246 [C₁₃H₁ N₃0₂ + H]⁺.

[000258] Intermediate 2: 6-(l-methyl-lH-pyrazol-5-yl)-l,2,3,4-tetrahydroquinoline-2- carboxylic acid

The suspension of 1 -methyl- lH-pyrazole-5-boronic acid pinacol ester 1(277 mg, 1.33 mmol), methyl 6-bromo-l,2,3,4-tetrahydro-2-quinolinecarboxylate 2 (300 mg, 1.1 1 mmol), Pd(PPh₃)₄ (128 mg, 0.111 mmol), Cs₂C0₃ (1.09 g, 3.33 mmol) in dioxane: water (4:1, 5.5 ml) was irradiated in the microwave reactor at 110°C for 40 min. The mixture was concentrated under reduced pressure, diluted with water (20 mL) and extracted with EtOAc/CH₂Cl₂ (3 x 30 mL). The combined organic layer was dried over Na₂S0₄ and was concentrated under reduced pressure.This residue was dissolved in CH₂C1₂, passed through a pad of celite and the filtrate was collected and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel₍ eluent cyclohexane/EtOAc 30:70 to afford methyl 6-(l -methyl- 1 H- pyrazol-5-yl)-l,2,3,4-tetrahydroquinoline-2-carboxylate 3 (46 mg, 15%) as a white solid; MS (ESI) m/z 272 [Ci₅H₁₇N₃0₂ + H]⁺.

[000259] Methyl 6-(l -methyl- lH-pyrazol-5-yl)-l, 2,3, 4-tetrahydroquinoline-2-carboxylate 3 (46 mg, 0.170 mmol) and LiOH (8 mg, 0.339 mmol) in water (0.90 mL) and CH₃OH (0.90 mL) was stirred for 1 h at room temperature. CH₃OH was removed from the reaction and the aqueous layer was acidified with cone HC1 until pH~l . The mixture was concentrated under reduced pressure to afford 6-(l-methyl-lH-pyrazol-5-yl)-l,2,3,4-tetrahydroquinoline-2-carboxylic acid 4; MS (ESI) m/z 258 [Ci₄H₁₅N₃0₂ + H]⁺.

[000260] Intermediate 3: -(4-(2-methyl-lH-imidazol-l-yl)-3- (trifluoromethyl)phenylamino)propanoic acid

To a well stirred solution of the l-fluoro-4-nitro-2-(trifluoromethyl)benzene (2 g, 1.0 eq) in DMF (50 mL) was added Cs₂C0₃ (2.64 g, 2 eq), 2-methyl imidazole (1.1 g, 1.4eq) and stirred at rt for 3 h. The reaction mixture was poured into ice-water and the compound was extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with ice-water, brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to afford 2-methyl- 1 -(4- nitro-2-(trifluoromethyl)phenyl)-lH-imidazole (1.5 g, 58%, LC-MS 93%) as a pale brown viscous liquid. [000261 ] To a stirred solution of 2-methyl- 1 -(4-nitro-2-(trifluoromethyl)phenyl)- 1 H- imidazole (1.5 g, 1 eq) in MeOH (30 mL) was added 10% Pd/C (300 mg) and hydrogenated under H₂ (60 psi). The reaction mixture was stirred at rt for 12 h. The reaction mixture was filtered through celite pad and washed with MeOH. Filtrate was concentrated under reduced pressure to afford 4-(2-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)aniline (1.2 g, 90%, LC-MS 96%) as a pale brown solid.

[000262] To a stirred solution of 4-(2-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)aniline (500 mg, 1 eq) in EtOH-cyclohexane (1 : 1, 10 mL) was added pyruvic acid (0.6 mL, 4 eq), Pd/C (100 mg), Na₂S0₄ (350 mg, 1.2 eq). The reaction mixture was hydrogenated under H₂ (balloon pressure) at rt for 16 h. The reaction mixture was filtered through celite bed and washed with EtOH and the filtrate was concentrated. The crude compound was purified by preparative HPLC to afford 2-(4-(2-methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)phenylamino)propanoic acid (150 mg, 23%, LC-MS 99%) as a white solid.

[000263] Intermediate 4: 3-(4-(l-methyl-lH-pyrazol-5-yl)phenyl)-N-(5-phenylpyridin-2- yl)propanamide

To a solution of 3-(4-bromophenyl)propanoic acid (200 mg, 0.873 mmol) in DMF (2 mL) was added HATU (498 mg, 1.310 mmol) and N-methyl morpholine (384 μΐ, 3.492 mmol). The reaction mixture was stirred at room temperature under inert atmosphere for 30 min, followed by the addition of 5-phenylpyridin-2-amine (163 mg, 0.960 mmol). The reaction mixture was left to stir for 16 h, then it was diluted with H 0 (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layer was dried over Na₂S0₄ and was concentrated under reduced pressure. The crude residue was washed with methanol and dried in vacuum oven at 50°C overnight to afford a white solid (158 mg, 48%). 1H NMR (400 MHz, DMSO-i¾ δ 10.58 (s, 1H), 8.62 (d, J-2.0 Hz, 1H), 8.17-8.15 (m, 1H), 8.09-8.06 (m, 1H), 7.71-7.68 (m, 2H), 7.49-7.46 (m, 4H), 7.40-7.36 (m, 1H), 7.24-7.22 (m, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H).

[000264] Intermediate 5: 3-(4-(2-methyl-lH-imidazol-l-yl)phenyl)propanoic acid

2-Methyl-lH-imidazole (608 mg, 7.404 mmol), methyl 3-(4-bromophenyl)propanoate (900 mg, 3.702 mmol), Cul (70 mg, 0.370 mmol), L-proline (852 mg, 7.404 mmol), and Cs₂C0₃ (2.42 g, 7.404 mmol) was dissolved in DMSO (10 mL). The reaction mixture was heated at 90°C for 16 h, then it was diluted with water (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic extracts were concentratrated and the residue purified by column chromatography (silica gel, eluent Hexane/EtOAc 30:70) to afford methyl 3-(4-(2-methyl-lH-imidazol-l- yl)phenyl)propanoate as yellow oil (309 mg, 34%). 1H NMR (400 MHz, CDCl_a) δ 7.31-7.29 (m, 2H), 7.21-7.19 (m, 2H), 7.01 (d, J=l .6 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 3.69 (s, 3H), 3.02 (t, J=7.6 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 2.34 (s, 3H).

[000265] Methyl 3 -(4-(2-methyl-lH-imidazol-l-yl)phenyl)propanoate (308 mg, 1.261 mmol) was added to a solution of LiOH (61 mg, 2.522 mmol) in THF (1 mL) and H 0 (1 mL) and stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure and the residue was acidifed to pH 1 using 1M HC1. It was then concentrated and the residue dried at 50°C under vacuum to afford 3 -(4-(2 -methyl- lH-imidazol-l-yl)phenyl)propanoic acid. The crude product (400 mg) was used without further purification. 1H NMR (400 MHz, DMSO- d ) 6 12.20 (br s, 1H), 7.63 (d, J=1.6 Hz, 1H) 7.46-7.44 (m, 5H), 2.91 (t, J=7.6 Hz, 2H), 2.60 (t, J-7.6 Hz, 2H), 2.43 (s, 3H) ; MS (ESI) m/z 231 [C₁₃Hi₄N₂0₂ + H]⁺. [000266] Intermediate 5: (S)-N-(3,3'-bipyridin-6-yl)-2-(4-(l-methyl-lH-pyrazol-5- yl)phenylamino)propanamide

To a stirred solution of 1 ,4-dibromobenzene (10 g, 1 eq) in anhydrous DMF (10 mL) was added L-alanine (3.8 g, 1 eq), K₂C0₃ (8.85 g, 1.5 eq) and Cul (406 mg, 0.05 eq) under argon. The reaction mixture was stirred at 140 °C for 3 h. After completion, ice water and ethyl acetate were added to the reaction mixture and filtered through celite pad and washed with water. The separated aqueous layer was acidified using IN HC1 and extracted with ethyl acetate. The combined organic layer was washed with ice water, brine, dried and concentrated to afford (S)-2- (4-bromophenylamino) propanoic acid (5 g, 48%, LC-MS 56%) as a yellow solid. 1H NMR (400 MHz, DMSO-J6) δ (ppm): 12.52 (bs, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.50 (d, J - 8.8 Hz, 2H), 3.91 (q, J = 6.4 Hz, 1H), 1.36 (d, J = 7.2 Hz, 3H); MS (ESI) m/z 244 [C9H10BrNO2+H]+.

[000267] To a well stirred solution of (S)-2-(4-bromophenylamino) propanoic acid (2.6 g, 10.69 mmol) in dioxane-water (4:1, 100 mL) were added ₃P0₄ (8.3 g, 32.07 mmol), 1-methyl- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (3.3 g, 16.04 mmol) and

Pd(dppf)Cl₂ (436 mg, 5 mol%) under Ar and the reaction mixture was heated at 100 °C for 16 h. The reaction mixture was evaporated under reduced pressure and the residue was poured into ice-water and the compound was extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with ice water, brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to give a solid which was purified by column chromatography (silica gel, eluent EtOAc hexane 40:60) to afford (S)-2-(4-(l -methyl- lH-pyrazol-5-yl) phenylamino) propanoic acid (1.7 g, 48%, LC-MS 91%) as a yellow solid.

[000268] ((S)-l-(4-Bromophenyl)pyrrolidine-2-carboxylic acid

37% , LC-MS 85%. IH NMR (400 MHz, OMSO-d ) 6 (ppm): 12.65 (b, IH), 7.29 (d, J = 9.2 Hz, 2H), 6.42 (d, J = 8.8 Hz, 2H), 4.15-4.13 (m, IH), 3.40-3.35 (m, IH), 3.29-3.23 (m, IH), 2.31-2.21 (m, IH), 2.07-1.94 (m, 3H); MS (ESI) m/z 271.9 [Cl lH12BrN02+H]+.

[000269] (R)-l-(4-Bromophenyl) pyrrolidine-2-carboxylic acid

70% , LC-MS 77%. 1H NMR (400 MHz, DMSO-c/6) δ (ppm): 12.65 (bs, IH), 7.29 (d, J = 8.8, 2H), 6.47 (d, J = 9.2 Hz, 2H), 4.15 (dd, J = 2, 8.4 Hz, IH), 3.40-3.30 (m, IH), 3.29-3.18 (m, IH), 2.50-2.18 (m, IH), 2.10-1.94 (m, 4H); MS (ESI) m/z 271.9 [Cl lH12BrN02+H]+.

[000270] Intermediate 6:

To a solution of 2-(benzyloxy)-5-bromopyridine (2.0 g, 7.60 mmol) in 25 mL of DMF was added Cul (290 mg, 1.52 mmol), ₂C0₃ (2.1 g, 15.21 mmol) and L-prolinemethyl ester hydrochloride (1.5 g, 9.12 mmol) at rt under argon. The reaction mixture was heated at 140 °C for 16 h. TLC indicated presence of some SM and formation of a polar spot. The reaction mixture was cooled to rt, poured in to ice cold water (500 mL) and extracted with EtOAc (2 x 100 mL) to remove staring material. The aqueous layer was acidified with sat. KHS0₄ solution and then extracted with EtOAc (2 x 250 mL). The combined organic layer was washed with water, brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to afford 1.7 g of (S)-l-(6-(benzyloxy)pyridin-3-yl)pyrrolidine-2-carboxylic acid (45%, LC-MS 84%).

[000271] To a solution of (S)-l-(6-(benzyloxy)pyridin-3-yl)pyrrolidine-2-carboxylic acid (3.0 g, 3.36 mmol) in DMF (50 mL) was added DIPEA (5.4 mL, 30.20 mmol), HATU (7.65 g, 20.13 mmol) and 2,3'-bipyridin-5-amine (1.89 g, 11.07 mmol) and the reaction mixture was stirred at rt for 16 h. TLC indicated complete consumption of SM and formation of a new less polar spot. The reaction mixture was poured into ice water (150 mL) and stirred for 30 min. The precipitated solids were filtered and washed with water and dried to give crude product. The crude product was purified by column chromatography (silica gel, eluent MeOH: CHC1₃ 2:98) to afford (S)-N-(2,3'-bipyridin-5-yl)-l-(6-(¾enzyloxy)pyridin-3-yl)pyrrolidine-2-carboxamide (1.6 g, 35%, LC-MS 95%) as an off-white solid.

[000272] To a solution of ((S)-N-(2,3'-bipyridin-5-yl)-l-(6-(benzyloxy)pyridin-3- yl)pyrrolidine-2-carboxamide (600 mg, 3.55 mmol) in C¾C1₂ (25 mL) cooled to -78 °C, was added BBr₃ (11 mL, 1M in DCM, 7.09 mmol). The reaction mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was washed with diethyl ether and dried to afforded 2.5 g of (S)-N-(2,3^,-bipyridin-5-yl)-

1- (6-hydroxypyridin-3-yl)pyrrolidine-2-carboxamide HBr salt.

[000273] To a solution of (S)-N-(2,3'-bipyridin-5-yl)-l-(6-hydroxypyridin-3-yl)pyrrolidine-

2- carboxamide HBr salt from above (2.5 g, 6.92 mmol) in 10 mL of pyridine and 25 mL of DCM was cooled to 0 °C, then added triflicanhydride (2.35 mL, 13.85 mmol) at 0 °C to rt for 16 h. TLC indicated absence of SM and formation of a less polar spot. The reaction mixture was poured in to sat. NaHC0₃ solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with water, brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (silica gel, elueht MeOH: CHC1₃2:98) to afford 1.4 g of (S)-5-(2-(2,3 - bipyridin-5-ylcarbamoyl)pyrrolidin-l-yl)pyridin-2-yl trifluoromethanesulfonate. The material was used in the next step without further purification.

[000274] Intermediate 7: 2-(l-methyl-lH-pyrazol-5-yl)-5-(l-oxo-l-(5-phenylpyridin-2- ylamino)propan-2-ylamino)benzoic acid

Step-1: methyl 2-(l-methyl-lH-pyrazol-5-yl)-5-nitrobenzoate

[000275] To a stirred solution of methyl 2-bromo-5-nitrobenzoate (10 g, 38.46 mmol) was treated l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (6.2 g, 46.15 mmol) using ₃P0₄ (16.3 g, 76.92 mmol), Pd(PPh₃)₄ (2.2 g, 1.92 mmol) in 300 mL of 1,4 dioxane and water (9:1) at rt to 100 °C. TLC after 16 h indicated absence of starting material and a new polar spot was seen. After completion, the reaction mass was filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, eluent EtOAc and petroleum ether 30:70%) to methyl 2-(l -methyl- lH-pyrazol-5=yl)-5- nitrobenzoate (5 g, 50%, LC-MS 99%).

Step-2: methyl 5-amino-2-(l-methyl-lH-pyrazol-5-yl)benzoate

[000276] To a stirred solution of methyl 2-(l -methyl- lH-pyrazol-5-yl)-5-nitrobenzoate (5 g, 1 eq) was reduced with H₂ (60 psi) using Pd/C (1 g, 1.2 eq) in 250 mL of ethanol at rt. TLC after 16 h indicated absence of starting material and a new polar spot was seen. After

completion, the reaction mass was filtered and washed with ethanol 30 (mL) and concentrated under reduced pressure. The crude residue was purified by column chromatography (neutral alumina, eluent EtOAc and petroleum ether 30:70%) to afford methyl 5-amino-2-(l -methyl- 1H- pyrazol-5-yl)benzoate (2.8 g, 63.6%, LC-MS 91%).

Step-3: 2-(3-(methoxycarbonyl)-4-(l-methyl-lH-pyrazol-5-yl)phenylamino)propanoic acid

[000277] To a stirred solution of methyl 5-amino-2-(l-methyl-lH-pyrazol-5-yl)benzoate (2.5 g, 1 eq) in EtOH (100 mL) was added pyruvic acid (0.87 mL, 1.2 eq), Pd/C (500 mg), Na₂S0₄ (2.3 g, 1.5 eq). The reaction mixture was hydrogenated under H₂ (balloon) at rt for 6 h. After completion, the reaction mass was filtered through celite bed and washed with EtOH and the filtrate was concentrated to afford 2-(3-(methoxycarbonyl)-4-(l-methyl-lH-pyrazol-5- yl)phenylamino)propanoic acid (3 g, 93.7%, LC-MS 74%).

Step-4: 2-(2-(3-(methoxycarbonyl)-4-(l-methyl-lH-pyrazol-5-yl)phenylamino)propanamido)-5- phenylpyridine 1-oxide

[000278] To a stirred solution of 2-(3-(methoxycarbonyl)-4-(l -methyl- lH-pyrazol-5- yl)phenylamino)propanoic acid (3.0 g, 1 eq) in 30 mL of DMF was added 2-amino-5- phenylpyridine 1-oxide (2.2 g, 1.2 eq ), HATU (5.6 g, 1.5 eq ) and DIPEA ( 2.8 g, 3 eq) and the reaction mixture was stirred at rt. TLC after 16 h indicated absence of starting material and a new non polar spot was seen. After completion, the reaction mass was poured into water (1 x 100 mL) and extracted with EtOAc (1 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent MeOH/DCM 3:97) to afford 2-(2-(3-(methoxycarbonyl)-4-(l-methyl-lH-pyrazol-5-yl)phenylamino)propanamido)-5- phenylpyridine 1 -oxide (2.4 g, 52.1%, LC-MS 87%).

Step-5: methyl 2-(l-methyl-lH-pyrazol-5-yl)-5-(l-oxo-l-(5-phenylpyridin-2-ylamino)propan-2- ylamino)benzoate

[000279] A solution of 2-(2-(3-(methoxycarbonyl)-4-(l -methyl- lH-pyrazol-5- yl)phenylamino)propanamido)-5-phenylpyridine 1-oxide (1.9 g, 1 eq) in 50 mL of ethanol was stirred with Pd/C (1.9 g) and HCOONH₄ (5.7 g) at 100 °C under H₂ (balloon) at rt. TLC after 1 h indicated absence of starting material and a new non polar spot was seen. After completion, the reaction mass was filtered on celite bed and washed with ethanol and filtrate was concentrated. The crude residue was purified by column chromatography (neutral alumina, eluent EtOAc and petroleum ether 20:80) to afford methyl 2-(l-methyl-lH-pyrazol-5-yl)-5-(l -oxo-l-(5- phenylpyridin-2-ylamino)propan-2-ylamino)benzoate (1 g, 55.5%, LC-MS 98.8%). 1H NMR (400 MHz, DMSO- d₆) δ (ppm): 9.07 (s, 1H), 8.48 (d, J= 2.0 Hz, lH), 8.38 (d, J= 8.0 Hz, 1H), 7.95-7.93 (dd, J= 2.4 Hz, J= 2.0 Hz, 1H), 7.55-7.44 (m, 5H), 7.40-7.73 (m, 1H), 7.31-7.37 (m, 1H), 7.17 (d, J= 8.0 Hz, 1H), 6.83-6.82 (dd, J= 2.8 Hz, J= 2.8 Hz, 1H), 4.33 (d, J= 3.2 Hz, 1H), 4.04 (m, 1H), 3.68 (s, 3H), 3.61 (s, 3H), 1.68 (d, J= 6.8 Hz, 3H); MS (ESI) m/z 456 [M+l].

Step-6: 2-(l -methyl- lH-pyrazol-5-yl)-5-(l-oxo-l-(5-phenylpyridin-2-ylamino)propan-2- ylamino)benzoic acid

[000280] To a stirred solution of methyl 2-(l-methyl-lH-pyrazol-5-yl)-5-(l-oxo-l-(5- phenylpyridin-2-ylamino)propan-2-ylamino)benzoate (200 mg, 1 eq) in 6 mL of THF-H₂0, was added Li OH (75 mg, 4 eq) and the reaction mixture was stirred at rt. TLC after 16 h indicated absence of starting material and a new polar spot was seen. After completion, the reaction mass was concentrated and adjusted to pH 2 with IN HC1 and extracted with EtOAc (2 x 20 mL), dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to afford to 70 mg of material which was further purified by preparative HPLC to afford 2-( 1 -methyl- 1 H- pyrazol-5-yl)-5-(l-oxo-l-(5-phenylpyridin-2-ylamino)propan-2-ylamino)benzoic acid (30 mg, 36.8%, LC-MS 99.0%). 1H NMR (400 MHz, DMSO- d₆) δ (ppm): 12.67 (s, 1H), 10.73 (s, 1H), 8.65 (d, J= 2.4 Hz, 1H), 8.32 (s, 1H), 8.16-8.09 (m, 2H) 7.70 (d, J= 7.6 Hz, 2H), 7.49 (t, J= 7.6 Hz, 2H), 7.40-7.32 (m, 2H), 7.18 (d, J= 1.6 Hz, 1H), 7.08 (d, J= 8.0 Hz, 1H), 6.82 (dd, J= 2.4 Hz, , J= 2.4 Hz , 1H), 6.58 (d, J= 8.0 Hz, 1H), 6.04 (d, J= 1.6 Hz, 1H), 4.35 (t, J= 7.2 Hz, 1H), 3.50 (s, 3H), 1.45 (d, J= 7.2 Hz, 3H); MS (ESI) m/z 442 [M+l].

[000281]

were synthesized by using the above method.

[000282] Intermediate 7: 2-(2-methyl-3-oxo-7-(2-(trifluoromethyl)-lH-imidazol-l-yl)-2H-

To a solution of 2-amino-5-(2-(trifluorom ethyl)- lH-imidazol-l-yl)phenol (600 mg, 4.12 mmol) in 50 mL of DCM was added 2-chloropropanoyl chloride (0.36 mL, 3.07 mmol) at 0 °C to rt for 2 h. TLC indicated presence of some SM and formation of a new less polar spot. The reaction mixture was poured into 250 mL of petroleum ether and stirred for 30 min. The precipitated solids were filtered and dried to afford to afford 2-chloro-N-(2-hydroxy-4-(2-(trifluoromethyl)- 1 H-imidazol- 1 -yl)phenyl)propanamide (620 mg, 92%, LC-MS 77%).

[000283] To a solution of 2-chloro-N-(2-hydroxy-4-(2-(trifluoromethyl)- 1 H-imidazol- 1 - yl)phenyl)propanamide (620 mg, 1.86 mmol) in 50 mL of EtOAc was added ₂C0₃ (771 mg, 5.58 mmol) and stirred at rt for 16 h. TLC indicated absence of SM and a new polar spot. The reaction mixture was poured into water (250 mL) and extracted with EtOAc (2 x 100 mL). The . combined organics were washed with water, brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to afford 2-m ethyl-7-(2-(trifluoromethyl)-l H-imidazol- 1- yl)-2H-benzo[b][l,4]oxazin-3(4H)-one (1.0 g, 94%, LC-MS 87%)..

[000284] To a solution of 2-methyl-7-(2-(trifluoromethyl)-l H-imidazol- 1 -yl)-2H- benzo[b][l,4]oxazin-3(4H)-one (500 mg, 1.68 mmol) in acetone (25 mL) were added KOH (141 mg, 2.52 mmol) and ethyl 2-bromopropanoate (305 mg, 1.68 mmol) at rt. The reaction mixture was heated at reflux for 4 h. TLC indicated absence of SM and formation of a less polar spot. The reaction mixture was cooled to rt, poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organics were washed with water, brine, dried over anhydrous Na₂S0₄, filtered and concentrated to give crude product. The crude compound was purified by column chromatography (silica gel, eluent EtOAc/hexane 20:80) to afford ethyl 2-(2-methyl-3- oxo-7-(2-(trifluorom ethyl)- 1 H-imidazol- 1 -yl)-2H-benzo[b] [ 1 ,4]oxazin-4(3H)-yl)propanoate (500 mg, 75%, LC-MS 92%).

[000285] To a stirred solution of ethyl 2-(2-methyl-3-oxo-7-(2-(trifluoromethyl)- 1H- imidazol-l-yl)-2H-benzo[b][l,4]oxazin-4(3H)-yl)propanoate 6 (500 mg, 1.0 eq) in 30 mL of MeOH-THF-H₂0 was added LiOH (106 mg, 2.0 eq) at rt and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated, the aqueous layer was extracted with ethyl acetate to remove impurities. The aqueous layer was acidified with sat. KHS0 and extracted with EtOAc (2 x 100 mL). The combined organics were washed with water, brine, dried over anhydrous Na₂S0₄, filtered and concentrated under reduced pressure to afford 2-(2-methyl-3- oxo-7-(2-(trifluoromethyl)- 1 H-imidazol- 1 -yl)-2H-benzo[b] [ 1 ,4]oxazin-4(3H)-yl)propanoic acid (300 mg, 65%, LC-MS. Application example 1

Materials and Methods:

Cell lines and culture conditions:

[000286] HEK293-STF cell line was modified from Human embryonic kidney cell line HEK293 transfected with the STF reporter. HEK293-STF3A cell line was further modified from HEK293-STF cell line to express Wnt3A. This cell line was used to identify compounds that regulate either early or late signaling components of the Wnt pathway. L-Wnt3A (ATCC, #CRL- 2647) cell line was used for providing Wnt3 A conditioned media. The three cell lines were grown in DMEM with 10% FBS incubated in 37°C with 5% C02.

Cell viability assay:

[000287] 5000 cells in 75 μΐ culture media were seeded in each well of black 96 well plates (Greiner #655090) and incubated overnight at 37°C. 25 μΐ of serially diluted compound was added to the cells giving final concentration of 50 μΜ to 1.5 nM. After 1 day of treatment, 100 μΐ of CellTiter-Glo® Luminescent Cell Viability Assay reagent (#G7571, Promega) was added to each well and incubated for 10 minutes at room temperature. Luminescence was measured using Tecan Safire2® microplate reader.

STF3A assay:

[000288] 2x10⁴ HEK293-STF3A cells in 75 μΐ culture media were seeded in each well of white 96 well plates (Greiner #655098) and incubated overnight at 37°C. 25 μΐ serially diluted compound was added to the cells to give final concentration of 50 μΜ to 1.5 nM. After 1 day of treatment, 100 μΐ οί Steady-Glo® Luciferase Assay reagent (#E2520, Promega) was added to each well and incubated for 10 minutes at room temperature. Luminescence was measured using Tecan Safire2® plate reader.

STF/WNT3A conditioned medium (STF/WNT3A CM) assay: [000289] L-Wnt3 A cells were cultured in three T- 175 flasks at 3 x 104 cells/ml in 30 ml culture medium per flask. After 4 days of incubation, the Wnt3 A conditioned media were harvested and then centrifuged at 2000 rpm for 10 minutes to remove the debris. The Wnt3A conditioned media were stored at -20 °C if not used immediately.

[000290] 2x104 HEK293-STF cells in 25 μΐ culture media were added in each well of white 96 well plates (Greiner #655098).25 μΐ serially diluted compound was added to the cells. After 4 hours of incubation, 100 μΐ Wnt-3A conditioned medium was added to the cells. The final concentration of compound ranged from 33 μΜ to 1 nM. After incubation for 1 day at 37°C, 100 μΐ of Steady-Glo® Luciferase Assay reagent (#E2520, Promega) was added to each well and incubated for 10 minutes at room temperature. Luminescence was measured using Tecan Safire2® microplate reader.

Results:

STF3a IC50uM STF3a IC50uM

Example 1 <0.1 Example 36 >5

Example 2 >5 Example 37 <5

Example 3 >5 Example 38 >5

Example 4 >5 Example 39 <5

Example 5 < 1 Example 40 <0.1

Example 6 >5 Example 41 <0.1

Example 7 <5 Example 42 <0.1

Example 8 >5 Example 43 >5

Example 9 >5 Example 44 >5

ExamplelO < 5 Example 45 <5

Example 11 < 1 Example 46 < 1

Example 12 >5 Example 47 < 1

Example 13 <0.1 Example 48 <5

Example 14 <0.1 Example 49 <0.1

Example 15 <0.1 Example 50 <1

Example 16 <0.1 Example 51 <0.1 Example 17 >5 Example 52 >5

Example 18 < 1 Example 53 >5

Example 19 <0.1 Example 54 < 1

Example 20 <0.1 Example 55 >5

Example 21 <0.1 Example 56 >5

Example 22 <0.1 Example 57 <0.1

Example 23 <0.1 Example 58 <0.1

Example 24 <0.1 Example 59 <5

Example 25 >5 Example 60 <0.1

Example 26 >5 Example 61 <1

Example 27 <0.1 Example 62 <0.1

Example 28 <0.1 Example 63 < 1

Example 29 >5 Example 64 < 1

Example 30 <0.1 Example 65 >5

Example 31 <0.1 Example 66 < 1

Example 32 <0.1 Example 67 < 1

Example 33 >5 Example 68 >5

Example 34 < 0.1 Example 69 >5

Example 35 <0.1 Example 70 < 1

STF3a STF3a IC50 IC50 uM uM

Example 71 <0.1 Example 106 <0.1

Example 72 <0.1 Example 107 <0.1

Example 73 <0.1 Example 108 <0.1

Example 74 <0.1 Example 109 <0.1

Example 75 <0.1 Example 110 <0.1

Example 76 <0.1 Example 111 <0.1

Example 77 <0.1 Example 112 >5

Example 78 < 1 Example 113 < 0.1

Example 79 <0.1 Example 114 <0.1

Example 80 <0.1 Example 115 >5 Example 81 <0.1 Example 116 <0.1

Example 82 <0.1 Example 117 >5

Example 83 <0.1 Example 118 <0.1

Example 84 <0.1 Example 119 <0.1

Example 85 < 1 Example 120 <0.1

Example 86 <5 Example 121 < 0.1

Example 87 <0.1 Example 122 <0.1

Example 88 <0.1 Example 123 < 1

Example 89 < 1 Example 124 <0.1

Example 90 < 1 Example 125 <0.1

Example 91 < 1 Example 126 <0.1

Example 92 < 5 Example 127 <0.1

Example 93 <0.1 Example 128 >5

Example 94 <0.1 Example 129 <0.1

Example 95 <0.1 Example 130 <0.1

Example 96 < 0.1 Example 131 <5

Example 97 <0.1 Example 132 <0.1

Example 98 <0.1 Example 133 <0.1

Example 99 <1 Example 134 <0.1

Example 100 < 0.1 Example 135 <0.1

Example 101 <0.1 Example 136 <0.1

Example 102 <0.1 Example 137 <0.1

Example 103 <0.1 Example 138 <0.1

Example 104 <0.1 Example 139 <0.1

Example 105 <0.1

In some embodiments of the invention, those compounds in the above tables listed as having Κ 50>5μηι are explicitly excluded. In other embodiments, those compounds in the above tables listed as having IC50 >5 μπι or as having IC50 >1 μπι are explicitly excluded. In yet other embodiments, those compounds in the above tables listed as having IC50>5 μπι or as having IC50<5 μπι or as having IC50 >1 μιη are explicitly excluded. In yet further embodiments, all of the compounds listed in the above tables are excluded with the exception of those listed as having IC50O.1 μπι. Efficacy: MMTV-WNT1 Tumor Model

[0002911 To test the in vivo efficacy of Compounds 129 and 136 to prevent the growth of Wnt driven tumors, fragments from two independent MMTV-WNT1 tumors were orthotopically transplanted into female nude mice. The mice were treated with either vehicle or Compound 129 or Compound 136 at 30 mg/kg once daily for 21 days. Tumor volumes were measured on alternate days. Treatment with Compound 129 and 136 decreased tumor growth in all the treated mice. A significant decrease in tumor weights collected at sacrifice was also observed. Results are shown in Figs. 2 and 3.

Claims

1. A compound of structure I for modulating WNT activity:

Ar¹-Ar²-X-C(R¹R²)-C(=0)-N(R³)-Ar³-Ar⁴

CD

wherein:

Ar¹, Ar², Ar³ and Ar⁴ are, independently, optionally substituted aryl or heteroaryl groups; R¹ and R³ are, independently, H or optionally substituted alkyl groups;

R is H or an optionally substituted alkyl group or an alkylene group which, together with the carbon atom to which it is attached and X, forms a non-aromatic ring or an alkylene group which, together with the carbon atom to which it is attached and X and two adjacent atoms of Ar², forms a non-aromatic ring;

X is O, CR⁴R⁵, CH₂0, N or NR⁴, wherein if X is N, it is bonded to R²;

R⁴ is H, optionally substituted alkyl or an alkylene chain, optionally containing a heteroatom and/or a carbonyl group, which, together with the C or N to which it is attached and two adjacent atoms of Ar^", forms a non-aromatic ring; and

R⁵ is H, NH₂ or an optionally substituted alkyl group;

2. The compound of claim 1 wherein R¹ and R³ are both H.

3. The compound of claim 1 or claim 2 wherein X is O, NH or CH₂

4. The compound of any one of claims 1 to 3 wherein R² is H or methyl or X is a nitrogen atom and R is (CH₂)₃ and is attached to said nitrogen atom so as to form a 5-membered ring.

5. The compound of any one of claims 1 to 4 wherein Ar¹ is a 5-membered heterocyclic ring containing 1 or 2 ring nitrogen atoms.

6. The compound of any one of claims 1 to 5 wherein Ar² is a 6-membered ring.

7. The compound of claim 6 wherein Ar¹ and X are in a 1 ,4-relationship on Ar².

8. The compound of claim 6 or claim 7 wherein Ar is a phenyl or pyridyl.

9. The compound of any one of claims 1 to 8 wherein Ar³ is a 6-membered ring.

10. The compound of claim 9 wherein Ar⁴ and the nitrogen atom attached to Ar³ are in a 1 ,4- relationship on Ar^>.

11. The compound of claim 9 or claim 10 wherein Ar³ is a phenyl ring or contains 1 or 2 ring nitrogen atoms.

12. The compound of any one of claims 1 to 11 wherein Ar⁴ is a 6-membered ring.

13. The compound of claim 1 wherein Ar⁴ is a phenyl ring or contains 1 or 2 ring nitrogen atoms.

14. The compound of any one of claims 1 to 13 which is one of the following compounds:

123

124

125

126

127

128

129

150

131

132

15. The compound of any one of claims 1 to 14 having a IC₅0 against HEK293-STF3A cells of less than about 5 μηι.

16. The compound of any one of claims 1 to 14 having a IC50 against HEK293-STF3A cells of less than about Ι πι.

17. The compound of any one of claims 1 to 14 having a IC₅₀ against HEK293-STF3A cells of less than about 0.1 μιη.

18. A process for making a compound of structure I as described in claim 1 , said process comprising either:

coupling a compound of structure II with a compound of structure III

Ar¹-Ar²-X-C(R¹R²)-C(=0)-OH HN(R³)-Ar³-Ar⁴

(II) (III)

or

coupling a compound of structure IV with a compound of structure V

(IV) (V)

or coupling an Ar¹ derivative with an Ar²-X-C(R¹R²)-C(^:=0)-N(R³)-Ar³-Ar⁴ derivative wherein R¹, R², R³, X, Ar¹, Ar², Ar³ and Ar⁴ are as defined in claim 1 and Hal is a halogen.

19. A pharmaceutical composition comprising the compound of any one of claims 1 to 17 and one or more pharmaceutically acceptable carriers, diluents and/or adjuvants.

20. Use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for the treatment of a condition characterised by excessive WNT activity.

21. The use of claim 20 wherein the condition is a cancer or a fibrotic disease or a degenerative disease.

22. A compound according to any one of claims 1 to 17 for use in therapy.

23. A method of treating a condition characterised by excessive WNT activity, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 17 or of a composition according to claim 19.

24. The method of claim 23 wherein the condition is a cancer or a fibrotic disease or stem cell or diabetic retinopathy or a degenerative disease.

25. Use of a compound according to any one of claims 1 to 17 for treating a condition characterised by excessive WNT activity.

26. Use of a compound according to any one of claims 1 to 17 for modulating WNT activity.

27. A compound according to any one of claims 1 to 17 when used for modulating WNT activity.