BR112017006476B1 - COMPOUND DERIVED FROM N-PYRIDINYL ACETAMIDE, ITS USE, PHARMACEUTICAL FORMULATION AND PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

N-PYRIDINYL ACETAMIDE DERIVATIVES AS INHIBITORS OF THE WNT SIGNALING REACTION SERIES. This invention relates to compounds. More specifically, the invention relates to compounds useful as Wnt signaling reaction series inhibitors. Specifically, porcupine inhibitors (Porcn) are contemplated by the invention. Furthermore, the invention contemplates processes for preparing the compounds and uses of the compounds. The compounds of the invention can therefore be used in the treatment of conditions mediated by the Wnt signaling reaction series, for example, treatment of cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, and leukemia; or enhancing the effectiveness of an anti-cancer treatment.

Description

[0001] This invention relates to compounds. More specifically, the invention relates to compounds useful as inhibitors of the Wnt signaling reaction series. Specifically, Porcupine (Porcn) inhibitors are contemplated by the invention. Furthermore, the invention contemplates processes for preparing the compounds and uses of the compounds.

[0002] The compounds of the invention can therefore be used in the treatment of conditions mediated by the Wnt signaling reaction series, for example, diseases mediated by secreted Wnt ligand, which can be treated by porcupine inhibition; treatment of cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, and leukemia; or enhancing the effectiveness of an anti-cancer treatment.

BACKGROUND

[0003] Wnt genes encode a large and highly conserved family of secreted growth factors. During normal development, transcription of Wnt family genes is tightly regulated, both temporally and spatially. To date, 19 Wnt proteins have been found in humans. All Wnt proteins are 38- to 43-kDa cysteine-rich glycoproteins. Wnts have a variety of roles during development, fate control, migration, proliferation, and cell death. These include body axis formation in zebrafish and xenopus, wing and eye development in Drosophila, and brain development in mice (Parr, et al. (1994) Curr. Opinion Genetics & Devel. 4:523- 528, McMahon AP, Bradley A (1990) Cell 62: 1073- 1085). In adults the role of Wnts is believed to be linked to the maintenance of tissue homeostasis with aberrant signaling implicated in a variety of cancers.

[0004] Wnt-mediated signaling occurs through the binding of Wnt ligand to frizzled proteins (Fzd), seven-transmembrane receptors. These receptors contain an N-terminal cysteine-rich domain (CRD) that serves as the Wnt-binding domain. Binding is stabilized by low-density lipoprotein receptor-related proteins 5 and 6 (Lrp5 and Lrp6) (He, et al. (2004) Dev Abril; 131(8):1663-77). Fizzled binding by Wnt is known to activate at least three different signaling reaction series including the "canonical" β-catenin reaction series, "non-canonical" planar cell polarity (PCP) and calcium reaction series. Wnt signaling is also regulated by alternative receptors, including Ror2, secreted antagonists such as WIF-1 (Hsieh, et al. (1999) Nature Apr 1; 398(6726): 431-6) and alternative Wnt receptors, such as Dickkopf (DKK) (Niehrs C (2006) Oncogene Dec 4;25(57):7469-81).

[0005] When inactive, β-Catenin is rapidly turned over by a conglomeration of several proteins known as the "destruction complex". The complex consists of Axin, adenomatous polyposis coli (APC), casein kinase (CK)-1a, and glycogen synthase kinase (GSK)-3β (Hamada, et al. (1999) Science 12;283(5408):1739-42) . In this state, β-catenin is phosphorylated to serine-threonine at the amino terminus leading to ubiquitination (Behrens, etal. (1998) Science 280: 596-599). In the canonical Wnt activation reaction series, Fzd binds to Wnt ligase a and activates cytoplasmic Dishevelled (Dvl) (Chen, et al. (2003) Science 301:1391-94). Wnt-bound Lrp5 and Lrp6 directly bind cytoplasmic Axin, inhibiting its function as a destruction complex stabilizer (Zeng, et al. (2008) Dev. 135, 367-375). These associations lead to destabilization of the destruction complex and cytosolic accumulation of β-catenin. Stabilization and accumulation of β-catenin leads to nuclear translocation, where it complexes with the T cell factor/lymphoid enhancer factor (TCF/LEF) high mobility group transcription factors and promotes transcription of target genes such as Cyclin D1, p21 and cMyc.

[0006] Oncogenic mutations in the β-catenin gene CTNNb1 exclusively affect specific serine and threonine and surrounding residues vital for APC-targeted degradation (Hart, et al. (1999) Curr. Biol. 9:207-210). This interaction is especially evident in colorectal cancer, where the majority of tumors present with APC mutations and an increased portion of the remainder express CTNNb1 mutations (Iwao, et al. (1998) Cancer Res March 1, 1998 58; 1021).

[0007] Many recent studies have investigated compounds targeting β-catenin or other proteins of the downstream Wnt reaction series. Recent research suggests that modulation of Wnt-Wnt receptor interaction at the cell surface is effective in reducing cellular oncogenicity. This has been shown in systems with tumorugenicity controlled by Wnt ligand overexpression (Liu, et al. (2013) PNAS 10; 110(50):20224-9) and where Wnt expression is controlled by activation of the Wnt reaction series. downstream (Vincan et al., Differentiation 2005; 73: 142153). Vincan et al. transfected nonfunctional Frd7 receptor into an SK-CO-1 cell strain with a homozygous APC mutation driving activation of the Wnt reaction series. These cells demonstrated modulated morphology and reduced tumor formation efficiency compared to parental cells in a xenograft model. These data suggest that ligand-mediated modulation of Wnt signaling may have a beneficial effect even in malignancies with downstream mutations.

[0008] The described invention is proposed to inhibit Wnt-mediated signaling. This includes paracrine signaling in tissues surrounding tumors and autocrine and paracrine signaling in cancer cells.

[0009] Wnt proteins undergo post-translational modification, shown in several mutation experiments to be vital for effective protein trafficking and secretion (Tang, et al. (2012) Dev. Biol 364, 32-41, Takada, R. et al (2006) Dev. Cell 11, 791-801). Palmitoylation of Wnt proteins occurs at several conserved amino acids (C77, S209) and is carried out by porcupin, an O-acetyltransferase, in the endoplasmic reticulum. Mutations in porcupine have been shown to be the cause of developmental disorders, including focal dermal hypoplasia, through impaired Wnt signaling pathway (Grzeschik, et al. (2007) Nat. Genet, 39 pp,833-835) . The dependence of Wnt ligand signaling on porcupine and the body of evidence linking Wnt chain reaction signaling to cancer has led to porcupine being identified as a potential anticancer target.

[0010] US 2014/0038922 describes compounds that inhibit the Wnt signaling reaction series and the use of these compounds in the treatment of diseases related to Wnt signaling. Similarly, WO 2012/003189 and WO 2010/101849 describe compounds and methods for modulating the Wnt signaling reaction series.

[0011] An object of the present invention provides alternative or improved Wnt signaling modulators. For example, an object of the present invention is to provide alternative or improved Wnt signaling inhibitors, optionally porcupin inhibitors.

[0012] Furthermore, it is an object of certain embodiments of this invention to provide new compounds for use in: Wnt-mediated diseases, such as diseases mediated with secreted Wnt ligand that can be treated by porcupin inhibition; treating cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, and leukemia; or enhancing the effectiveness of an anti-cancer treatment.

[0013] It is an objective of certain embodiments of this invention to provide new cancer treatments. In particular, it is an object of certain embodiments of this invention to provide compounds that have activity comparable to existing treatments, ideally they should have better activity. Certain embodiments of the invention also aim to provide improved solubility compared to prior art compounds and existing therapies. It is particularly attractive for certain compounds of the invention to provide better activity and better solubility over known compounds.

[0014] It is an objective of certain embodiments of this invention to provide compounds that exhibit reduced cytotoxicity with respect to prior art compounds and existing therapies.

[0015] Another objective of certain embodiments of this invention is to provide compounds having a convenient pharmacokinetic profile and an adequate duration of action following the dosage. Another object of certain embodiments of this invention is to provide compounds in which the metabolized fragment or fragments of the drug after absorption are GRAS (generally regarded as safe).

[0016] Certain embodiments of the present invention satisfy some or all of the above objectives.

BRIEF SUMMARY OF DESCRIPTION

[0017] According to the present invention, a compound of formula (I) is provided: wherein het1 represents a 5-membered heterocyclic ring system comprising 1, 2, or 3 heteroatoms selected from N, O, or S and being unsubstituted or substituted, and when substituted the ring system is replaced by 1, 2, or 3 groups independently selected at each occurrence of: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA2, -NRA2RB2, -CN, -SO2RA2, and C3-6 cycloalkyl; het1 is bonded to het2 and -(CR1R2)mC(O)NR3-, where het2 and -(CR1R2)mC(O)NR3- are bonded to non-adjacent atoms of het1; het2 is a 5- or 6-membered heterocyclic ring that may be unsubstituted or substituted, and when substituted, the ring is replaced by 1, 2, or 3 independently selected groups at each occurrence of: halo, C1-4 alkyl, C1-4 haloalkyl , -ORA1, -NRA1RB1, -CN, -NO2, -NRA1C(O)RB1, -C(O)NRA1RB1, -NRA1SO2RB1, -SO2NRA1RB1, -SO2RA1, -C(O)RA1, -C(O)ORA1 and C3-6 cycloalkyl; het3 is a 5- or 6-membered heterocyclic ring or a phenyl ring that may be unsubstituted or substituted, and when substituted, the ring is replaced by 1, 2 or 3 independently selected groups at each occurrence of: halo, C1-4 alkyl , C1-4 haloalkyl, -ORA1, -NRA1RB1, -CN, -NO2, -NRA1C(O)RB1, - C(O)NRA1RB1, -NRA1SO2RB1, -SO2NRA1RB1, -SO2RA1, -C(O)RA1, - C (O)ORA1 and C3-6 cycloalkyl; R1 and R2 are independently selected at each occurrence of: H, halo, C1-4 alkyl, C1-4 haloalkyl, -ORA3, -NRA3RB3 and C3-6 cycloalkyl; R3 is selected from: H, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl; R4 is independently selected at each occurrence of: halo, C1-4 alkyl, C1-4 haloalkyl, -CN, -ORA4, -NRA4RB4, -SO2RA4, C3-6 cycloalkyl and C3-6 halocycloalkyl; m is selected from, 1, 2 or 3; n is selected from 0, 1 or 2; and RA1, RB1, RA2, RB2, RA3, RB3, RA4 and RB4 are at each occurrence independently selected from: H, C1-4 alkyl, C1-4 haloalkyl.

[0018] In one embodiment, the compound according to formula (I) is a compound according to formulas (IIa) or (IIb):

[0019] Het2 can represent a 5- or 6-membered heterocycloalkyl, heterocycloalkenyl or heteroaryl ring that can be unsubstituted or substituted. Preferably, het2 may represent a 5- or 6-membered heterocycloalkenyl or heteroaryl ring which may be unsubstituted or substituted. More preferably, het2 may represent a 5- or 6-membered heteroaryl ring which may be unsubstituted or substituted.

[0020] Het2 can be represented by a 5- or 6-membered, aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted. Het2 can be represented by a 5- or 6-membered, aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted wherein the heterocyclic ring contains 1, 2 or 3 N heteroatoms, optionally without any additional heteroatoms (other than N) .

[0021] Het2 can be represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, thiazole, isothiazole, triazole, oxazole, isoxazole, dihydropyridine, tetrahydropyridine, pyran, tetra -hydropyran, dihydropyran, piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxin, dioxane, thiazine, oxatian and dithiane.

[0022] Het2 can be represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, pyran, tetrahydropyran, dihydropyran, piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxin , dioxane, thiazine, oxatian and dithiane.

[0023] Preferably, het2 can be represented by unsubstituted or substituted: pyrazole, imidazole, pyridine, pyridazine, pyrimidine, thiazole, isothiazole, triazole, isoxazole, tetrahydropyridine, tetrahydropyran and dihydropyran.

[0024] Particularly preferred, het2 can be represented by unsubstituted or substituted: pyridine, pyrazole, tetrahydropyran and dihydropyran.

[0025] Preferably, het2 can be represented by unsubstituted or substituted: pyrazole, imidazole, pyridine, tetrahydropyran, dihydropyran, piperidine, piperazine and morpholine.

[0026] Het2 can be represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyrazine, pyrimidine, pyridazine, pyran, tetrahydropyran, dihydropyran, piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxin, dioxane , thiazine, oxatian and dithiane.

[0027] Het2 can be represented by unsubstituted or substituted: pyrazole, imidazole, tetrahydropyran, dihydropyran, piperidine, piperazine and morpholine.

[0028] Het2 can be represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyran, tetrahydropyran, dihydropyran, piperazine, morpholine, thiomorpholine, oxazine, dioxin, dioxane, thiazine, oxathian and dithiane.

[0029] Het2 can be represented by unsubstituted or substituted: pyrazole, imidazole, tetrahydropyran, dihydropyran, piperazine and morpholine.

[0030] Optionally, het2 is represented by an unsubstituted or substituted pyridine.

[0031] Het2 can be unsubstituted or substituted by 1, 2 or 3 groups selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA1, -NO2, -NRA1C(O)RB1, -NRA1SO2RB1, -SO2NRA1RB1 , -SO2RA1, -C(O)RA1, -C(O)ORA1 and C3-6 cycloalkyl.

[0032] Het2 can be unsubstituted or substituted by 1, 2, or 3 groups selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA1, -NRA1RB1, -CN, -C(O)ORA1 and C3 -6 cycloalkyl. Preferably, het2 may be unsubstituted or substituted by 1, 2, or 3 groups selected from: halo, C1-4 alkyl, -ORA1, and C1-4 haloalkyl, where RA1 is H, methyl, or trifluoromethyl.

[0033] Het2 can be unsubstituted or substituted by 1, 2, or 3 groups selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA1, -NRA1RB1, -CN and C3-6 cycloalkyl. Preferably, het2 may be unsubstituted or substituted by 1, 2, or 3 groups selected from: halo, C1-4 alkyl, -ORA1, and C1-4 haloalkyl, where RA1 is H, methyl, or trifluoromethyl.

[0034] In a preferred embodiment, het2 is unsubstituted or substituted by 1 or 2 groups selected from: fluorine, chlorine, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, cyclopentyl, cyclopropyl, -NH2, -NMe2, -CN , -C(O)OtBu, -OMe and -OCF3.

[0035] In a particularly preferred embodiment, het2 is unsubstituted or substituted by 1 or 2 groups selected from: fluorine, methyl, trifluoromethyl and -CN.

[0036] In a particular preferred embodiment, het2 is unsubstituted or substituted by 1 or 2 groups selected from: fluorine, chlorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, and -OCF3.

[0037] Preferably, het2 is unsubstituted or substituted by 1 or 2 groups. More preferably, het2 is unsubstituted or substituted by 1 group.

[0038] Het2 can be unsubstituted pyridine, unsubstituted thiazole, unsubstituted triazole, unsubstituted pyrazole, unsubstituted isothiazole, unsubstituted pyrimidine, unsubstituted isoxazole, unsubstituted pyridazine, unsubstituted tetrahydropyridine, unsubstituted tetrahydropyran, unsubstituted dihydropyran, methylpyridine, dimethylpyridine, ethylpyridine, iso-propylpyridine, tert-butylpyridine, difluoromethylpyridine, trifluoromethylpyridine, fluoropyridine, chloropyridine, methoxypyridine, ethioxypyridine, aminopyridine, N-methyl-aminopyridine, N,N-dimethyl-aminopyridine, nitropyridine, cyanopyridine, cyclopropylpyridine, cyclopentylpyridine, methylthiazole, dimethylthiazole, ethylthiazole, iso-propylthiazole, tert-butylthiazole, difluoromethylthiazole, trifluoromethylthiazole, fluorothiazole, chlorothiazole, methoxythiazole, ethioxythiazole, aminothiazole, N-methyl-aminothiazole, N,N-dimethyl-aminothiazole, nitrothiazole, cyanothiazole, cyclopropyl thiazole, cyclopentylthiazole, methyltriazole, dimethyltriazole, ethyltriazole, iso-propyltriazole, tert-butyltriazole, difluoromethyltriazole, trifluoromethyltriazole, fluorotriazole, chlorotriazole, methoxytriazole, ethioxytriazole, aminotriazole, N-methyl-aminotriazole, N,N-dimethyl-aminotriazole, nitrotriazole , cyanotriazole, cyclopropyltriazole, cyclopentyltriazole, methylpyrazole, dimethylpyrazole, ethylpyrazole, iso-propylpyrazole, tert-butylpyrazole, difluoromethylpyrazole, methyl(trifluoromethyl)pyrazole, trifluoromethylpyrazole, fluoropyrazole, chloropyrazole, methoxypyrazole, ethioxypyrazole, aminopyrazole, N-methyl-aminopyrazole, N,N -dimethyl-aminopyrazole, nitropyrazole, cyanopyrazole, cyclopropylpyrazole, cyclopentylpyrazole, methylisothiazole, dimethylisothiazole, ethylisothiazole, iso-propylisothiazole, tert-butylisothiazole, difluoromethylisothiazole, trifluoromethylisothiazole, fluoroisothiazole, chloroisothiazole, methoxyisothiazole, ethioxyisothiazole, aminoisothiazole, N-methyl-aminoisothiazole, N,N -dimethyl-aminoisothiazole, nitroisothiazole, cyanoisothiazole, cyclopropylisothiazole, cyclopentylisothiazole, methylpyrimidine, dimethylpyrimidine, ethylpyrimidine, isopropylpyrimidine, tert-butylpyrimidine, difluoromethylpyrimidine, trifluoromethylpyrimidine, fluoropyrimidine, chloropyrimidine, methoxypyrimidine, ethioxypyrimidine, aminopyrimidine, N-methyl-aminopyrimidine , N,N -dimethyl-aminopyrimidine, N,N-dimethyl-amino(trifluoromethyl)pyrimidine, nitropyrimidine, cyanopyrimidine, cyclopropylpyrimidine, cyclopentylpyrimidine, methylisoxazole, dimethylisoxazole, ethylisoxazole, iso-propylisoxazole, tert-butylisoxazole, difluoromethylisoxazole, trifluoromethylisoxazole, fluoroisoxazole, chloroisoxazole, methoxyisoxazole, ethioxy isoxazole , aminoisoxazole, N-methyl-aminoisoxazole, N,N-dimethyl-aminoisoxazole, nitroisoxazole, cyanoisoxazole, cyclopropylisoxazole, cyclopentylisoxazole, methylpyridazine, dimethylpyridazine, ethylpyridazine, isopropylpyridazine, tert-butylpyridazine, difluoromethylpyridazine, trifluoromethylpyridazine, fluoropyridazine, chloropyridaz ine, methoxypyridazine, ethioxypyridazine , aminopyridazine, n-methyl-aminopyridazine, n, n-dimethyl-amyinopyridazine, nitropyridazine, cycopyridazine, cyclpilpyridazine, cyclpiridezine, methyltestra-hydropyridine, dimethyltetra-hydropyridine, ethyl-hydropyridine, iso-prophyropyridine, terc- butyltestra-hydropyridine, dipluorometile - hydropyridine, trifluoromethyltetrahydropyridine, fluorotetrahydropyridine, chlorotetrahydropyridine, methoxytetrahydropyridine, ethioxytetrahydropyridine, aminotetrahydropyridine, N-methyl-aminotetrahydropyridine, N,N-dimethyl-aminotetrahydropyridine, nitrotetrahydropyridine, cyanotetra -Hydropyridine, cyclopropiltetrahydropyridine, cyclopeltestrahydropyridine, methylterohydropirane, dimethyltetra hydropirane, ethylhydropirane, iso-propilterahidropirane, tert-bhydropirane, difluororometty-hydropirane, trifluoromethera -h Idropirano, fluorotetra-hydropion, chlorotetra-hydropion , methoxytetrahydropyran, ethioxytetrahydropyran, aminotetrahydropyran, N-methyl-aminotetrahydropyran, N,N-dimethyl-aminotetrahydropyran, nitrotetrahydropyran, cyanotetrahydropyran, cyclopropyltetrahydropyran, cyclopentyltetrahydropyran, methyldihydropyran , dimethyldihydropyran, ethyldihydropyran, iso-propyldihydropyran, tert-butyldihydropyran, difluoromethyldihydropyran, trifluoromethyldihydropyran, fluorodihydropyran, chlorodihydropyran, methoxydihydropyran, ethioxydihydropyran, aminodihydropyran, N -methyl-aminodihydropyran, N,N-dimethyl-aminodihydropyran, nitrodihydropyran, cyanodihydropyrancyclopropyldihydropyran, and cyclopentyldihydropyran.

[0039] Het2 can be unsubstituted pyridine, unsubstituted tetrahydropyran, unsubstituted dihydropyran, unsubstituted piperidine, unsubstituted piperazine and unsubstituted morpholine, methylpyridine, ethylpyridine, iso-propylpyridine, tert-butylpyridine, trifluoromethylpyridine, methoxypyridine, ethioxypyridine, aminopyridine, N-methyl-aminopyridine, N,N-dimethyl-aminopyridine, nitropyridine, cyanopyridine, methyltetrahydropyran, ethyltetrahydropyran, iso-propyltetrahydropyran, tert-butyltetrahydropyran, trifluoromethyltetrahydropyran, methoxytetrahydropyran, ethioxytetrahydropyran, aminotetrahydropyran, N-methyl-aminotetrahydropyran, N,N-dimethyl-aminotetrahydropyran, nitrotetrahydropyran, cyanotetrahydropyran, methyldihydropyran, ethyldihydropyran, iso-propyldihydropyran, tert- butyldihydropyran, trifluoromethyldihydropyran, methoxydihydropyran, ethioxydihydropyran, aminodihydropyran, N-methyl-aminodihydropyran, N,N-dimethyl-aminodihydropyran, nitrodihydropyran, cyanodihydropyran, methylpiperidine, ethylpiperidine, iso-propylpiperidine, tert-butylpiperidine, trifluoromethylpiperidine, methoxypiperidine, ethioxypiperidine, aminopiperidine, N-methyl-aminopiperidine, N,N-dimethyl-aminopiperidine, nitropiperidine, cyanopiperidine, methylpiperazine, ethylpiperazine, iso-propylpiperazine, tert-butylpiperazine, trifluoromethylpiperazine, methoxypiperazine, ethioxypiperazine, aminopiperazine, N-methyl-aminopiperazine, N,N-dimethyl-aminopiperazine, nitropiperazine, cyanopiperazine, methylmorpholine, ethylmorpholine, isopropylmorpholine, tert-butylmorpholine, trifluoromethylmorpholine, methoxymorpholine, ethioxymorpholine, aminomorpholine, N-methyl-aminomorpholine, N, N-dimethyl-aminomorpholine, nitromorpholine or cyanomorpholine.

[0040] Het2 can be unsubstituted pyridine, unsubstituted thiazole, unsubstituted triazole, unsubstituted pyrazole, unsubstituted isothiazole, unsubstituted pyrimidine, unsubstituted isoxazole, unsubstituted pyridazine, unsubstituted tetrahydropyridine, unsubstituted tetrahydropyran, unsubstituted dihydropyran, methylpyridine, difluoromethylpyridine, trifluoromethylpyridine, fluoropyridine, chloropyridine, methoxypyridine, aminopyridine, N,N-dimethyl-aminopyridine, cyanopyridine, methylthiazole, methyltriazole, methylpyrazole, iso-propylpyrazole, cyclopropylpyrazole, cyclopentylpyrazole, methyl(trifluoromethyl)pyrazole, methylisothiazole, methylpyrimidine, trifluoromethylpyrimidine, chloropyrimidine, N,N-dimethyl-amino(trifluoromethyl)pyrimidine, dimethylisoxazole, methylpyridazine, chloropyridazine, tert-butyloxycarbonyl-tetrahydropyridine, dimethyltetrahydropyran, or dimethyldihydropyran. Preferably, het2 is trifluoropyridine.

[0041] Het2 can be pyridyl. Het2 can be pyridyl substituted or unsubstituted. Preferably, Het2 is substituted or unsubstituted 4-pyridyl. 4-Pyridyl refers to a pyridine group that is attached to Het1 at the four pyridine position. Position 1 of pyridine is the nitrogen atom as would be readily understood by the skilled person. For example, 4-pyridyl, which can be substituted, is:

[0042] Optionally, het2 is pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or piperidinyl substituted by 1 group selected from: -NRA1RB1, -CN and -C(O)NRA1RB1. Optionally, het2 is meta or substituted for het1.

[0043] Optionally, het2 is not pyridyl.

[0044] In one embodiment, the compound is a compound of the invention with the proviso that het2 is not pyridyl.

[0045] In one embodiment, the compound is a compound of the invention with the proviso that het2 is not pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or piperidinyl substituted for het1 with 1 group selected from: -NRA1RB1, -CN, -C(O )NRA1RB1. Optionally, het2 is not pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or piperidinyl meta or para substituted for het1 with 1 group selected from: -NRA1RB1, -CN, - C(O)NRA1RB1.

[0046] In one embodiment, het2 is a 5 or 6 membered heterocyclic ring that can be unsubstituted or substituted, and when substituted the ring is substituted by 1, 2 or 3 groups selected from: halo, C1-4 alkyl, C1 -4 haloalkyl, -ORA1, -NO2, -NRA1C(O)RB1, -NRA1SO2RB1, -SO2NRA1RB1, -SO2RA1, -C(O)RA1, -C(O)ORA1 and C3-6 cycloalkyl; as long as het2 is not pyridyl.

[0047] Het3 can be a 6-membered heterocyclic ring that is unsubstituted or substituted, and when substituted the ring is substituted by 1, 2 or 3 independently selected groups at each occurrence of: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA1, -NRA1RB1, -CN, -NO2, - NRA1C(O)RB1, -C(O)NRA1RB1, -NRA1SO2RB1, -SO2NRA1RB1, -SO2RA1, -C(O)RA1, -C(O)ORA1 and C3-6 cycloalkyl.

[0048] Het3 can be a 5- or 6-membered heterocyclic ring or a phenyl ring that are unsubstituted or substituted, and when substituted the ring is replaced by 1, 2 or 3 independently selected groups at each occurrence of: halo, C1- 4 haloalkyl, -ORA1, - NRA1RB1, -CN, -NO2, -NRA1C(O)RB1, -C(O)NRA1RB1, -NRA1SO2RB1, - SO2NRA1RB1, -SO2RA1, -C(O)RA1, -C(O) ORA1 and C3-6 cycloalkyl;

[0049] Het3 can be represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted and comprises at least one nitrogen atom, preferably, the ring is aromatic or saturated.

[0050] Het3 can be represented by a 5- or 6-membered, aromatic, saturated or unsaturated heterocyclic ring or a phenyl ring that are unsubstituted or substituted and comprises at least one nitrogen atom. The heterocyclic ring may optionally be an aromatic or saturated ring. The heterocyclic ring may optionally be an aromatic or unsaturated ring. Preferably, the heterocyclic ring is an aromatic ring.

[0051] Het3 can be represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted and comprises 2 heteroatoms, preferably the ring is aromatic or saturated. In a preferred embodiment, het3 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted and comprises 2 nitrogen atoms, preferably the ring is aromatic or saturated.

[0052] Het3 can be represented by a ring selected from unsubstituted or substituted: an aromatic, saturated or unsaturated 6-membered heterocyclic ring comprising 1 or 2 heteroatoms (optionally N atoms), preferably the ring is aromatic or saturated; a 5-membered heteroaryl ring; and a phenyl ring. Preferably Het3 is an unsubstituted or substituted, aromatic 6-membered heterocyclic ring.

[0053] Het3 can be represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine, piperazine, dioxin, dioxane, morpholine and thiomorpholine. Alternatively, het3 can be represented by a ring selected from unsubstituted or substituted: phenyl, pyrazole, pyridine, pyrimidine, pyrazine, dihydropyran, and piperazine. Optionally, het3 can be represented by a ring selected from unsubstituted or substituted: pyridine, pyrimidine, pyrazine, dihydropyran, and piperazine.

[0054] Preferably, het3 can be represented by a ring selected from pyrimidine, pyrazine, pyridazine or piperazine. Preferably, het3 may be represented by a ring selected from phenyl, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine or piperazine.

[0055] Preferably, het3 can be represented by a ring selected from pyrimidine, pyrazine or pyridazine.

[0056] Optionally, het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine and pyrazine. Particularly preferred is for het3 to be pyrazine.

[0057] Optionally, het3 is as described elsewhere herein with the proviso that het3 is not a ring selected from: alkyl-substituted pyridine, unsubstituted imidazole, alkyl-substituted imidazole, unsubstituted oxadiazole, alkyl-substituted oxazole, unsubstituted oxazole. Optionally, het3 is as described elsewhere herein with the proviso that het3 is not a ring selected from: unsubstituted oxazole, methyl piperazine or unsubstituted morpholine. Optionally, het3 is as described elsewhere herein with the proviso that het3 is not a ring selected from: alkyl-substituted pyridine, unsubstituted imidazole, alkyl-substituted imidazole, unsubstituted oxadiazole, alkyl-substituted oxazole, unsubstituted oxazole, methyl piperazine or unsubstituted morpholine.

[0058] Het3 can be unsubstituted or substituted by 1, 2 or 3 groups selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA1, -NRA1RB1, -CN, -C(O)RA1, -C (O)ORA1, -NRA1C(O)RB1, and C3-6 cycloalkyl. Het3 can be unsubstituted or substituted by 1, 2 or 3 groups selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA1, -C(O)RA1 and -C(O)ORA1, where RA1 is H, methyl, tert-butyl or trifluoromethyl. Preferably, het3 may be unsubstituted or substituted by 1, 2 or 3 groups selected from: C1-4 alkyl, -ORA1, -NRA1RB1, -CN, or -NRA1C(O)RB1, where RA1 is H, methyl, tert -butyl or trifluoromethyl (preferably methyl) and RB1 is H, methyl, tert-butyl or trifluoromethyl (preferably H or methyl).

[0059] In a particular preferred embodiment het3 is unsubstituted or substituted by 1 or 2 groups selected from: fluorine, chlorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, -OCF3, -C(O)Me, -C(O)OMe , -C(O)Et and -C(O)OtBu.

[0060] In a particular preferred embodiment, het3 is unsubstituted or substituted by 1 or 2 groups selected from: methyl, -OMe, -CN, -NMe2, or -NHC(O)Me.

[0061] Preferably, het3 is unsubstituted or substituted by 1 or 2 groups. More preferably, het3 is unsubstituted or substituted by 1 group.

[0062] In one embodiment, het2 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted (optionally where het2 is not represented by pyridine) and het3 is represented by an aromatic, saturated heterocyclic ring or 6-membered unsaturated which is unsubstituted or substituted and comprises 2 heteroatoms.

[0063] In one embodiment, het2 is represented by a 5- or 6-membered heterocycloalkenyl or heteroaryl ring that is unsubstituted or substituted (optionally wherein het2 is not represented by pyridine) and het3 is represented by a 5-membered heterocyclic ring. or 6-membered, aromatic, saturated or unsaturated comprising 1 or 2 heteroatoms or a phenyl ring that are unsubstituted or substituted.

[0064] In one embodiment, het2 is represented by a ring selected from unsubstituted or substituted: pyridine, pyrazole, imidazole, pyrazine, pyrimidine, pyridazine, pyran, tetrahydropyran, dihydropyran, piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxin, dioxane, thiazine, oxathian and dithiane (optionally pyrazole, imidazole, pyrazine, pyrimidine, pyridazine, pyran, tetrahydropyran, dihydropyran, piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxin, dioxane, thiazine, oxatian and ditian); and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine, piperazine, dioxin, dioxane, morpholine and thiomorpholine.

[0065] In one embodiment, het2 is represented by a ring selected from unsubstituted or substituted: pyridine, pyrazole, imidazole, pyrazine, pyrimidine, pyridazine, thiazole, isothiazole, triazole, oxazole, isoxazole, dihydropyridine, tetrahydropyridine, pyran, tetrahydropyran, dihydropyran, piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxin, dioxane, thiazine, oxathian and dithiane (optionally pyrazole, imidazole, pyridine, pyridazine, pyrimidine, thiazole, isothiazole, triazole, isoxazole, tetra -hydropyridine, tetrahydropyran and dihydropyran); and het3 is represented by a ring selected from unsubstituted or substituted: phenyl, pyrazole, pyridine, pyrimidine, pyrazine, dihydropyran, and piperazine.

[0066] Preferably, het2 is represented by a ring selected from unsubstituted or substituted: pyridine, pyrazole, imidazole, tetrahydropyran, dihydropyran, piperidine, piperazine and morpholine (optionally pyrazole, imidazole, tetrahydropyran, dihydropyran , piperidine, piperazine and morpholine); and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine and piperazine.

[0067] Preferably, het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyridazine, pyrimidine, thiazole, isothiazole, triazole, isoxazole, tetrahydropyridine, tetrahydropyran and dihydropyran (optionally pyridine , pyrazole, tetrahydropyran and dihydropyran); and het3 is represented by a ring selected from unsubstituted or substituted: phenyl, pyrazole, pyridine, pyrimidine, pyrazine, dihydropyran, and piperazine.

[0068] Het1 may represent a 5-membered heterocyclic ring system comprising 1, 2 or 3 (optionally 1 or 2) N or S atoms and being unsubstituted or substituted, and when substituted the ring system is substituted by 1, 2, or 3 groups independently selected at each occurrence of: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA2, -NRA2RB2, -CN, -SO2RA2, and C3-6 cycloalkyl.

[0069] Het1 may represent a 5-membered heterocyclic ring system comprising 1, 2 or 3 (optionally 1 or 2) N atoms and being unsubstituted or substituted, and when substituted the ring system is substituted by 1, 2, or 3 independently selected groups at each occurrence of: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA2, -NRA2RB2, -CN, -SO2RA2, and C3-6 cycloalkyl.

[0070] Het1 may represent a 5-membered heterocyclic ring system comprising 1, 2 or 3 (optionally 1 or 2) heteroatoms selected from N, O or S and being unsubstituted or substituted, and when substituted the ring system is substituted by 1, 2, or 3 independently selected groups at each occurrence of: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA2, -NRA2RB2, -CN, -SO2RA2, and C3-6 cycloalkyl; as long as the system 5-membered heterocyclic ring of het1 does not represent pyrrole, pyrazole, imidazole and triazole.

[0071] Het1 can represent a 5-membered heterocyclic ring system comprising 1, 2 or 3 heteroatoms (optionally 1 or 2) selected from N, O or S, wherein when the 5-membered heterocyclic ring comprises 1 or 2 atoms of N, it also comprises at least one atom selected from O or S.

[0072] In one embodiment, the compound is a compound of the invention with the proviso that het2 is not pyridyl; and het1 is represented by a 5-membered heterocyclic ring system comprising 1, 2, or 3 (optionally 1 or 2) N atoms and being unsubstituted or substituted, and when substituted the ring system is substituted by 1, 2, or 3 groups independently selected at each occurrence of: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA2, -NRA2RB2, -CN, -SO2RA2, and C3-6 cycloalkyl.

[0073] In one embodiment, the compound is a compound of the invention with the proviso that het2 is not pyridyl; and het1 may represent a 5-membered heterocyclic ring system comprising 1, 2 or 3 (optionally 1 or 2) heteroatoms selected from N, O or S and being unsubstituted or substituted, and when substituted the ring system is replaced by 1 , 2, or 3 independently selected groups at each occurrence of: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA2, -NRA2RB2, -CN, -SO2RA2, and C3-6 cycloalkyl; as long as the heterocyclic ring system of 5 members of het1 does not represent pyrrole, pyrazole, imidazole and triazole.

[0074] In one embodiment, het1 represents a 5-membered heterocyclic ring system comprising 1, 2 or 3 (optionally 1 or 2) N atoms and being unsubstituted or substituted, and when substituted the ring system is replaced by 1 , 2 or 3 groups independently selected at each occurrence of: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA2, -NRA2RB2, -CN, -SO2RA2, and C3-6 cycloalkyl; and het2 is a 5- or 6-membered heterocyclic ring that can be unsubstituted or substituted, and when substituted the ring is substituted by 1, 2 or 3 groups selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA1 , -NO2, -NRA1C(O)RB1, -NRA1SO2RB1, -SO2NRA1RB1, -SO2RA1, -C(O)RA1, -C(O)ORA1 and C3-6 cycloalkyl; as long as het2 is not pyridyl.

[0075] In one embodiment, het1 represents a 5-membered heterocyclic ring system comprising 1, 2 or 3 (optionally 1 or 2) heteroatoms selected from N, O or S and being unsubstituted or substituted, and when substituted the system ring is replaced by 1, 2, or 3 independently selected groups at each occurrence of: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA2, -NRA2RB2, -CN, -SO2RA2, and C3-6 cycloalkyl; as long as the 5-membered heterocyclic ring system of het1 does not represent pyrrole, pyrazole, imidazole and triazole; and het2 is a 5- or 6-membered heterocyclic ring that can be unsubstituted or substituted, and when substituted the ring is substituted by 1, 2 or 3 groups selected from: halo, C1-4 alkyl, C14 haloalkyl, -ORA1, - NO2, -NRA1C(O)RB1, -NRA1SO2RB1, -SO2NRA1RB1, -SO2RA1, -C(O)RA1, -C(O)ORA1 and C3-6 cycloalkyl; as long as het2 is not pyridyl.

[0076] Het1 can represent a substituted or unsubstituted: 5-membered heteroaryl group comprising 1, 2 or 3 (optionally 1 or 2) heteroatoms selected from N, O or S.

[0077] Het1 can represent a selected group of unsubstituted or substituted: pyrazole, imidazole, oxazole, thiazole, isoxazole, isothiazole, thiophene, furan, triazole, oxadiazole and thiadiazole.

[0078] Het1 can represent a selected group of unsubstituted or substituted: pyrazole, imidazole, and triazole.

[0079] Het1 can represent a selected group of unsubstituted or substituted: oxazole, thiazole, isoxazole, isothiazole, thiophene, furan, oxadiazole and thiadiazole.

[0080] Optionally, het1 represents an unsubstituted or substituted: imidazole, pyrazole or thiophene.

[0081] Het1 is bonded to het2 and -(CR1R2)mC(O)NR3- and het2 and - (CR1R2)mC(O)NR3- are bonded to non-adjacent atoms of het1. In one embodiment, het2 and -(CR1R2)mC(O)NR3- are bonded to het1 atoms and the atoms have at least one atom between them. For example, in one embodiment, het2 and -(CR1R2)mC(O)NR3- have a 1.3 ratio over het1. Het2 and -(CR1R2)mC(O)NR3- may not have a 1.2 relationship over het1.

[0082] In one embodiment, het2 and -(CR1R2)mC(O)NR3- can be substituted on het1 in ring positions selected from: 1,3; 2.4; 3.5; 1.4 and 2.5.

[0083] In one embodiment, the compound according to formula (I) is a compound according to formula (III): where X1 and X2 are selected from CR6 and N; and R5 and R6 are, at each occurrence, independently selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -ORA2, -NRA2RB2, -CN, -SO2RA2, and C3-6 cycloalkyl.

[0084] Preferably, one of X1 and X2 is CR6 and the other is N. In one embodiment, X1 is CR6 and X2 is N. Preferably, X1 is N and X2 is CR6.

[0085] In one embodiment, R5 and R6 are, in each occurrence, independently selected from: H or C1-4 alkyl (preferably methyl). Therefore, X1 can be CH or CMe and X2 is N, or X1 is N and X2 is CH or CMe. In embodiments, X1 is CH, X2 is N, and R5 is H; or X1 is CMe, X2 is N, and R5 is H; X1 is CH, X2 is N, and R5 is Me; or X1 is CMe, X2 is N, and R5 is Me; or X1 is N and X2 is CH, and R5 is H; or X1 is N and X2 is CMe, and R5 is H; or X1 is N and X2 is CH, and R5 is Me; orX1 is N and X2 is CMe, and R5 is Me.

[0086] Preferably, X1 is N and X2 is CH, and R5 is Me.

[0087] Het1 can be unsubstituted or substituted by 1, 2, or 3 groups (preferably 1 or 2) selected from: halo, C1-4 alkyl, C14 haloalkyl, -ORA2, -NRA2RB2 and -CN. Het1 can be unsubstituted or substituted by 1 or 2 groups selected from: chlorine, fluorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, -OCF3, -OH, -OMe, -OEt, -NH2, -NHMe, -NMe2 and -CN . Preferably, Het1 may be unsubstituted or substituted by 1 or 2 methyl groups.

[0088] In one embodiment, the compound according to formula (I) is a compound according to formula (IIIa): where R7 is, at each occurrence, independently selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA1, -NRA1RB1, -CN, -NO2, -NRA1C(O)RB1, -C(O)NRA1RB1 , -NRA1SO2RB1, -SO2NRA1RB1, -SO2RA1, - C(O)RA1, -C(O)ORA1 and C3-6 cycloalkyl, and o is 0, 1, 2 or 3 (optionally 0, 1 or 2, preferably 0 or 1).

[0089] In one embodiment, the compound according to formula (I) is a compound according to formula (IIIb): R7 can be independently selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA1, -NO2, -NRA1C(O)RB1, -NRA1SO2RB1, -SO2NRA1RB1, -SO2RA1, -C(O)RA1, -C (O)ORA1 and C3-6 cycloalkyl. R7 can be independently selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA1, -NRA1RB1, -CN, -C(O)ORA1 and C3-6 cycloalkyl. Preferably, R7 can be independently selected from: halo, C1-4 alkyl, -ORA1, and C1-4 haloalkyl, where RA1 is H, methyl, or trifluoromethyl. R7 can be independently selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA1, -NRA1RB1, -CN and C3-6 cycloalkyl. Preferably, R7 can be independently selected from: halo, C1-4 alkyl, -ORA1, and C1-4 haloalkyl, where RA1 is H, methyl, or trifluoromethyl.

[0090] In a preferred embodiment, R7 can be independently selected from: fluorine, chlorine, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, cyclopentyl, cyclopropyl, -NH2, -NMe2, -CN, -C(O)OtBu , -OMe and -OCF3.

[0091] In a particularly preferred embodiment, R7 can be independently selected from: fluorine, methyl, trifluoromethyl and -CN.

[0092] In a particular preferred embodiment, R7 can be independently selected from: fluorine, chlorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, and -OCF3.

[0093] In one embodiment, het1 represents a selected group of unsubstituted or substituted: pyrazole, imidazole, oxazole, thiazole, isoxazole, isothiazole, triazole, oxadiazole, and thiadiazole; het2 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted; and het3 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted and comprises 2 heteroatoms.

[0094] In one embodiment, het1 represents a selected group of unsubstituted or substituted: pyrazole, imidazole, oxazole, thiazole, isoxazole, isothiazole, triazole, oxadiazole, and thiadiazole; het2 is represented by a 5- or 6-membered heterocycloalkenyl or heteroaryl ring that is unsubstituted or substituted, (optionally wherein het2 is not represented by pyridine) and het3 is represented by a 5- or 6-membered heterocyclic ring, aromatic, saturated or unsaturated comprising 1 or 2 heteroatoms or a phenyl ring that are unsubstituted or substituted.

[0095] In one embodiment, het1 represents a selected group of unsubstituted or substituted: pyrazole, imidazole, oxazole, thiazole, isoxazole, isothiazole, triazole, oxadiazole, and thiadiazole; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, pyran, tetrahydropyran, dihydropyran, piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxin, dioxane, thiazine , oxatian and ditian; het2 is represented by unsubstituted or substituted pyridine; and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine, piperazine, dioxin, dioxane, morpholine and thiomorpholine.

[0096] In one embodiment, het1 represents a selected group of unsubstituted or substituted: pyrazole, imidazole, oxazole, thiazole, isoxazole, isothiazole, triazole, oxadiazole, and thiadiazole; het2 is represented by a ring selected from unsubstituted or substituted: pyridine, pyrazole, imidazole, pyrazine, pyrimidine, pyridazine, thiazole, isothiazole, triazole, oxazole, isoxazole, dihydropyridine, tetrahydropyridine, pyran, tetrahydropyran, di -hydropyran, piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxin, dioxane, thiazine, oxathian and dithiane (optionally pyrazole, imidazole, pyridine, pyridazine, pyrimidine, thiazole, isothiazole, triazole, isoxazole, tetrahydropyridine, tetrahydropyran and dihydropyran); and het3 is represented by a ring selected from unsubstituted or substituted: phenyl, pyrazole, pyridine, pyrimidine, pyrazine, dihydropyran, and piperazine.

[0097] Optionally, het1 represents a selected group of unsubstituted or substituted: pyrazole, imidazole, oxazole, thiazole, isoxazole, isothiazole, triazole, oxadiazole, and thiadiazole; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, tetrahydropyran, dihydropyran, piperidine, piperazine and morpholine; and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine and piperazine.

[0098] Optionally, het1 represents a selected group of unsubstituted or substituted: pyrazole, imidazole, oxazole, thiazole, isoxazole, isothiazole, triazole, oxadiazole, and thiadiazole; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyridazine, pyrimidine, thiazole, isothiazole, triazole, isoxazole, tetrahydropyridine, tetrahydropyran and dihydropyran (optionally pyridine, pyrazole, tetra- hydropyran and dihydropyran); and het3 is represented by a ring selected from unsubstituted or substituted: phenyl, pyrazole, pyridine, pyrimidine, pyrazine, dihydropyran, and piperazine.

[0099] In one embodiment, m is 1 or 2. In a preferred embodiment m is 1.

[00100] In one embodiment, the compound according to formula (I) is a compound according to formula (IV):

[00101] In one embodiment, the compound according to formula (I) is a compound according to formulas (IVa) or (IVb):

[00102] In one embodiment, the compound according to formula (I) is a compound according to formula (V):

[00103] In one embodiment, the compound according to formula (I) is a compound according to formulas (Va) and (Vb):

[00104] In one embodiment, the compound according to formula (I) is a compound according to formula (Vc):

[00105] In one embodiment, het1 represents an unsubstituted or substituted pyrazole or X1 is CR6 and X2 is N; het2 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted, and het3 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted and comprises 2 heteroatoms.

[00106] In one embodiment, het1 represents an unsubstituted or substituted pyrazole or X1 is CR6 and X2 is N; het2 is represented by a 5- or 6-membered heterocycloalkenyl or heteroaryl ring that is unsubstituted or substituted (optionally wherein het2 is not represented by pyridine) and het3 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted and comprises 2 heteroatoms.

[00107] In one embodiment, het1 represents an unsubstituted or substituted pyrazole or X1 is CR6 and X2 is N; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, pyran, tetrahydropyran, dihydropyran, piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxin, dioxane, thiazine , oxatian and ditian; and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine, piperazine, dioxin, dioxane, morpholine and thiomorpholine.

[00108] In one embodiment, het1 represents an unsubstituted or substituted pyrazole or X1 is CR6 and X2 is N; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyridazine, pyrimidine, thiazole, isothiazole, triazole, isoxazole, tetrahydropyridine, tetrahydropyran and dihydropyran (optionally pyridine, pyrazole, tetra- hydropyran and dihydropyran); and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine, piperazine, dioxin, dioxane, morpholine and thiomorpholine.

[00109] Optionally, het1 represents an unsubstituted or substituted pyrazole or X1 is CR6 and X2 is N; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, tetrahydropyran, dihydropyran, piperidine, piperazine and morpholine; and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine and piperazine.

[00110] Optionally, het1 represents an unsubstituted or substituted pyrazole or X1 is CR6 and X2 is N; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyridazine, pyrimidine, thiazole, isothiazole, triazole, isoxazole, tetrahydropyridine, tetrahydropyran and dihydropyran (optionally pyridine, pyrazole, tetra- hydropyran and dihydropyran); and het3 is represented by a ring selected from unsubstituted or substituted: phenyl, pyrazole, pyridine, pyrimidine, pyrazine, dihydropyran, and piperazine.

[00111] In one embodiment, het1 represents an unsubstituted or substituted imidazole or X1 is N and X2 is CR6; het2 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted, and het3 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted and comprises 2 heteroatoms.

[00112] In one embodiment, het1 represents an unsubstituted or substituted imidazole or X1 is N and X2 is CR6; het2 is represented by a 5- or 6-membered heterocycloalkenyl or heteroaryl ring that is unsubstituted or substituted (optionally wherein het2 is not represented by pyridine) and het3 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted and comprises 2 heteroatoms.

[00113] In one embodiment, het1 represents an unsubstituted or substituted imidazole or X1 is N and X2 is CR6; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, pyran, tetrahydropyran, dihydropyran, piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxin, dioxane, thiazine , oxatian and ditian; and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine, piperazine, dioxin, dioxane, morpholine and thiomorpholine.

[00114] In one embodiment, het1 represents an unsubstituted or substituted imidazole and either X1 is N and X2 is CR6; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyridazine, pyrimidine, thiazole, isothiazole, triazole, isoxazole, tetrahydropyridine, tetrahydropyran and dihydropyran (optionally pyridine, pyrazole, tetra- hydropyran and dihydropyran); and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine, piperazine, dioxin, dioxane, morpholine and thiomorpholine.

[00115] Optionally, het1 represents an unsubstituted or substituted imidazole; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, tetrahydropyran, dihydropyran, piperidine, piperazine and morpholine; and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine and piperazine.

[00116] Optionally, het1 represents an unsubstituted or substituted imidazole and either X1 is CR6 and X2 is N; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyridazine, pyrimidine, thiazole, isothiazole, triazole, isoxazole, tetrahydropyridine, tetrahydropyran and dihydropyran (optionally pyridine, pyrazole, tetra- hydropyran and dihydropyran); and het3 is represented by a ring selected from unsubstituted or substituted: phenyl, pyrazole, pyridine, pyrimidine, pyrazine, dihydropyran, and piperazine.

[00117] In one embodiment, het1 represents an unsubstituted or substituted thiophene; het2 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted, and het3 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted and comprises 2 heteroatoms.

[00118] In one embodiment, het1 represents an unsubstituted or substituted thiophene; het2 is represented by a 5- or 6-membered heterocycloalkenyl or heteroaryl ring that is unsubstituted or substituted (optionally wherein het2 is not represented by pyridine) and het3 is represented by a 6-membered aromatic, saturated or unsaturated heterocyclic ring that is unsubstituted or substituted and comprises 2 heteroatoms.

[00119] In one embodiment, het1 represents an unsubstituted or substituted thiophene; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, pyran, tetrahydropyran, dihydropyran, piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxin, dioxane, thiazine , oxatian and ditian; and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine, piperazine, dioxin, dioxane, morpholine and thiomorpholine.

[00120] In one embodiment, het1 represents an unsubstituted or substituted thiophene; represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyridazine, pyrimidine, thiazole, isothiazole, triazole, isoxazole, tetrahydropyridine, tetrahydropyran and dihydropyran (optionally pyridine, pyrazole, tetrahydropyran and dihydropyran); and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine, piperazine, dioxin, dioxane, morpholine and thiomorpholine.

[00121] Optionally, het1 represents an unsubstituted or substituted thiophene; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, tetrahydropyran, dihydropyran, piperidine, piperazine and morpholine; and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine and piperazine.

[00122] Optionally, het1 represents an unsubstituted or substituted thiophene; het2 is represented by a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyridazine, pyrimidine, thiazole, isothiazole, triazole, isoxazole, tetrahydropyridine, tetrahydropyran and dihydropyran (optionally pyridine, pyrazole, tetra- hydropyran and dihydropyran); and het3 is represented by a ring selected from unsubstituted or substituted: phenyl, pyrazole, pyridine, pyrimidine, pyrazine, dihydropyran, and piperazine.

[00123] In a preferred embodiment, het1 represents an unsubstituted or substituted: imidazole, pyrazole or thiophene; het2 is represented by an unsubstituted or substituted pyridine; and het3 is represented by a ring selected from unsubstituted or substituted: pyrimidine, and pyrazine.

[00124] R1 and R2 can be independently selected at each occurrence of: H, halo, C1-4 alkyl, C1-4 haloalkyl, -ORA3 and - NRA3RB3. R1 and R2 can be independently selected at each occurrence of: H, chlorine, fluorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, -OCF3, -OH, -OMe, -OEt, -NH2, -NHMe, and -NMe2. Preferably, R1 and R2 are H.

[00125] In one embodiment, m is 1 and R1 and R2 are H. In an alternative embodiment, m is 2 and R1 and R2 are H. In an alternative embodiment, m is 1 and R1 is Me, R2 is H.

[00126] R3 is optionally H or methyl.

[00127] R4 is optionally selected at each occurrence of: halo, C1-4 alkyl, C1-4 haloalkyl, -CN, -ORA4 and -NRA4RB4. R4 can be independently selected at each occurrence of: H, chlorine, fluorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, -OCF3, -OH, -OMe, -OEt, -NH2, -NHMe, and -NMe2.

[00128] RA1, RB1, RA2, RB2, RA3, RB3, RA4 and RB4 are in each occurrence independently selected from: H, methyl, ethyl and - OCF3.

[00129] In a preferred embodiment n is 0.

[00130] In a preferred embodiment, the compounds of the invention are selected from compounds of formulas (IIa), (IIIb), (IVa), (Va) or (Vc).

[00131] The invention also provides pharmaceutically acceptable salts of compounds of the invention. Accordingly, compounds of formula (I) and pharmaceutically acceptable salts thereof are provided.

[00132] The compound according to the invention can be selected from a group consisting of:

[00133] The compound according to the invention can also be selected from a group consisting of:

[00134] In one embodiment the compounds of the invention are not

[00135] According to another aspect, the present invention provides a compound of the present invention for use as a medicament.

[00136] According to another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[00137] In one embodiment, the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent. The additional pharmaceutically active agent may be an antitumor agent described below.

[00138] According to another aspect, a compound of the present invention is provided for use in modulating Wnt signaling. Optionally, Wnt signaling is modulated by porcupine (Porcn) inhibition. Modulation of Wnt signaling may include inhibition of paracrine signaling in tumor-involving tissues and autocrine and paracrine signaling in cancer cells.

[00139] According to another aspect, a compound of the present invention is provided for use in treating a condition that can be modulated by Porcn inhibition using a compound of the present invention. A compound of formula (I) may be for use in treating a condition treatable by Porcn inhibition.

[00140] Porcn inhibition is relevant for the treatment of many different diseases associated with increased Wnt signaling. In embodiments, the condition treatable by Porcn inhibition can be selected from: cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, and leukemia. Specific cancers, sarcomas, melanomas, skin cancers, hematological tumors, lymphoma, carcinoma and leukemia treatable by modulation of Wnt signaling or inhibition of Porcn can be selected from: esophageal squamous cell carcinoma, gastric cancer, glioblastomas, astrocytomas; retinoblastoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, Wilm's tumor, basal cell carcinoma, non-small cell lung cancer, brain tumor, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer breast, metastatic pancreatic cancer, pancreatic cancer, colorectal cancer, cervical cancer, head and neck squamous cell carcinoma, and head and neck cancer.

[00141] Porcn inhibition is also relevant for the treatment of a condition treatable by inhibition of Wnt ligand secretion selected from: skin fibrosis, idiopathic pulmonary fibrosis, renal interstitial fibrosis, hepatic fibrosis, proteinuria, renal graft rejection, osteoarthritis, Parkinson's disease, cystoid macular edema, cystoid macular edema associated with uveitis, retinopathy, diabetic retinopathy and retinopathy of prematurity.

[00142] The invention contemplates methods of treating the conditions mentioned above and contemplates compounds of the invention for use in a method of treating the conditions mentioned above.

[00143] In one aspect of the invention, a compound of the invention may be for use in treating a condition selected from: cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, and leukemia. Specific cancers, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, and leukemia that can be treated by the compound of the invention can be selected from: esophageal squamous cell carcinoma, gastric cancer, glioblastomas, astrocytomas; retinoblastoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, Wilm's tumor, basal cell carcinoma, non-small cell lung cancer, brain tumor, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer breast, metastatic pancreatic cancer, pancreatic cancer, colorectal cancer, cervical cancer, head and neck squamous cell carcinoma, and head and neck cancer.

[00144] The compound of the invention may also be for use in the treatment of a condition selected from: skin fibrosis, idiopathic pulmonary fibrosis, renal interstitial fibrosis, liver fibrosis, proteinuria, renal graft rejection, osteoarthritis, Parkinson's disease, macular edema cystoid, cystoid macular edema associated with uveitis, retinopathy, diabetic retinopathy and retinopathy of prematurity.

[00145] In one aspect of the invention, there is provided a method of treating a condition that is modulated by Wnt signaling, wherein the method comprises administering a therapeutic amount of a compound of the invention to a patient in need thereof. In one embodiment of the invention, there is provided a method of treating a condition that is modulated by Porcn.

[00146] The treatment method may be a method of treating a condition treatable by modulating Wnt or Porcn signaling. These conditions are described above in relation to conditions treatable by Porcn inhibition.

[00147] In one aspect of the invention, there is provided a method of treating a condition selected from: cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, and leukemia, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof. Specific cancers, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, and leukemia that can be treated by the treatment method can be selected from: esophageal squamous cell carcinoma, gastric cancer, glioblastomas, astrocytomas; retinoblastoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, Wilm's tumor, basal cell carcinoma, non-small cell lung cancer, brain tumor, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer breast, metastatic pancreatic cancer, pancreatic cancer, colorectal cancer, cervical cancer, head and neck squamous cell carcinoma, and head and neck cancer.

[00148] The treatment method may also be the treatment of a condition selected from: skin fibrosis, idiopathic pulmonary fibrosis, renal interstitial fibrosis, liver fibrosis, proteinuria, renal graft rejection, osteoarthritis, Parkinson's disease, cystoid macular edema, cystoid macular edema associated with uveitis, retinopathy, diabetic retinopathy and retinopathy of prematurity.

[00149] In one aspect of the invention, there is provided a use of a compound of the invention in the manufacture of a medicament for treating a condition that is modulated by Porcn. The condition can be any of the conditions mentioned above.

[00150] Aberrant Wnt signaling may be associated with a selected condition of: non-small cell lung cancer (NSCLC); chronic lymphocytic leukemia (CLL); gastric cancer; head and neck squamous cell carcinoma (HNSCC); colorectal cancer; Ovary cancer; basal cell carcinoma (BCC); breast cancer; bladder cancer; colorectal mesothelioma; prostate cancer; non-small cell lung cancer; lung cancer; osteosarcoma; Frz overexpression; have been associated with cancers such as prostate; colorectal; Ovary cancer; gastric; overexpression of Wnt signaling reaction series components, such as, disheveled; prostate cancer; breast cancer; mesothelioma; cervical; Frat-1 overexpression; pancreatic cancer; esophageal cancer; cervical cancer; breast cancer; and gastric cancer; loss of axin function (LOF); hepatocellular cancer; medulloblastoma; gastric cancer; colorectal cancer; intestinal carcinoid; Ovary cancer; lung adenocarcinoma; endometrial cancer; hepatocellular; hepatoblastoma; medulloblastoma; pancreatic cancer; thyroid cancer; prostate cancer; melanoma; pilomatricoma; Wilms tumor; pancreatoblastomas; liposarcomas; juvenile nasopharyngeal angiofibromas; desmoid; synovial sarcoma; melanoma; leukemia; multiple myeloma; brain tumors, such as gliomas, astrocytomas, meningiomas, schwannomas, pituitary tumors, primitive neuroectodermal tumors (PNET), medulloblastomas, craniopharyngioma, tumors of the pineal region, and non-cancerous neurofibromatoses;

[00151] Inhibition of Wnt signaling with the Wnt antagonists of the present invention can be therapeutic in the treatment of disorders resulting from dysfunctional hematopoietic disorders, such as leukemias and various blood-related cancers, such as acute chronic lymphoid and myeloid leukemias, syndrome myelodysplastic disease and myeloproliferative disorders. These include myeloma, lymphoma (e.g., Hodgkin's and non-Hodgkin's), non-progressive and chronic anemia, symptomatic and progressive blood cell deficiencies, polycythemia vera, primary or essential thrombocythemia, idiopathic myelofibrosis, chronic myelomonocytic leukemia (CMML), lymphomas of mantle cell, cutaneous T-cell lymphoma, and Waldenstrom macroglobinemia.

[00152] Other disorders associated with aberrant Wnt signaling include, but are not limited to, osteoporosis, osteoarthritis, polycystic kidney disease, diabetes, schizophrenia, vascular disease, heart disease, non-oncogenic proliferative diseases, and neurodegenerative diseases, such as, of Alzheimer's.

[00153] Aberrant Wnt signaling may be associated with a cancer selected from: brain; lung; colon; epidermoid; squamous cell; bladder; gastric; pancreatic; breast; head and neck; renal; kidney; liver; ovary; prostate; uterine; esophagus; testicular; gynecological; thyroid; melanoma; acute myeloid leukemia; chronic myeloid leukemia; Kapose sarcoma MCL;

[00154] Aberrant Wnt signaling may be associated with an inflammatory disease selected from: multiple sclerosis; rheumatoid arthritis; systemic lupus; inflammatory bowel disease; osteoarthritis; Alzheimer's.

DETAILED DESCRIPTION

[00155] Provided below are definitions of terms used in this application. Any term not defined here assumes the normal meaning as the skilled person would understand the term.

[00156] The term "halo" refers to one of the halogens, group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[00157] The term "C1-4 alkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Alkylene groups can also be linear or branched and can have two attachment sites to the rest of the molecule. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group can be halogen, for example, fluorine, chlorine, bromine and iodine, OH, C1-6 alkoxy.

[00158] The term "C1-4 alkoxy" refers to an alkyl group that is attached to a molecule through oxygen. This includes portions where the alkyl moiety may be linear or branched and may contain 1, 2, 3, 4, 5 or 6 carbon atoms, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec. -butyl, tert-butyl, n-pentyl and n-hexyl. Therefore, the alkoxy group can be methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy. The alkyl part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group can be halogen, for example, fluorine, chlorine, bromine and iodine, OH, C1-6 alkoxy.

[00159] The term "C1-4 haloalkyl" refers to a hydrocarbon chain substituted with at least one independently chosen halogen atom in each occurrence, for example, fluorine, chlorine, bromine and iodine. The halogen atom can be present in any position on the hydrocarbon chain. For example, C1-4haloalkyl may refer to chloromethyl, flouromethyl, trifluoromethyl, chloroethyl, e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl, e.g. 1,2,2-trichloroethyl, 2,2,2-trichloroethyl , fluoroethyl, for example, 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, for example, 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

[00160] The term "C2-6 alkenyl" refers to a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond(s) can be present as the E or Z isomer. The double bond can be at any possible position in the hydrocarbon chain. For example, "C2-6 alkenyl" can be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[00161] The term "C2-6 alkynyl" refers to a branched or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond can be at any possible position in the hydrocarbon chain. For example, "C2-6 alkynyl" can be ethynyl, propynyl, butynyl, pentynyl and hexinyl.

[00162] The term "C1-6 heteroalkyl" refers to a branched or linear hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at one end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. The C1-6 heteroalkyl can be linked to the rest of the molecule through a carbon or a heteroatom. For example, "C1-6 heteroalkyl" may be C1-6 N-alkyl, C1-6 N,N-alkyl, or C1-6 O-alkyl.

[00163] The term "carbocyclic" refers to a saturated or unsaturated carbon containing ring system. A "carbocyclic" system may be a monocyclic or a fused polycyclic ring system, e.g., bicyclic or tricyclic. A "carbocyclic" moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Carbocyclic" encompasses cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems including an aromatic moiety.

[00164] The term "heterocyclic" refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O or S. A "heterocyclic" system may contain 1, 2, 3 or 4 heteroatoms, e.g. , 1 or 2. A "heterocyclic" system may be a monocyclic or a fused polycyclic ring system, e.g., bicyclic or tricyclic. A "heterocyclic" moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Heterocyclic" encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties. For example, the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[00165] The term "C3-6 cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. For example, "C3-8 cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[00166] The term "C3-8 cycloalkenyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms that is non-aromatic. The ring may contain more than one double bond as long as the ring system is non-aromatic. For example, "C3-8 cycloalkyl" can be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[00167] The term "C3-8 hetero-cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom in the ring selected from N, O and S. For example, it can be 1, 2 or 3 heteroatoms, optionally 1 or 2. The "C3-8 heterocycloalkyl" can be linked to the rest of the molecule through any carbon atom or heteroatom. The "C3-8 heterocycloalkyl" may have one or more, for example one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the "C3-8 heterocycloalkyl" may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[00168] The term "C3-8 heterocycloalkenyl" refers to an unsaturated hydrocarbon ring system, which is non-aromatic, containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom on the ring selected from N, O and S. For example, it can be 1, 2 or 3 heteroatoms, optionally 1 or 2. The "C3-8 hetero-cycloalkenyl" can be linked to the rest of the molecule through any carbon atom or heteroatom. The "C3-8 heterocycloalkenyl" may have one or more, for example one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the "C3-8 heterocycloalkyl" may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.

[00169] The term "aromatic" when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a π-conjugate system in the ring or ring system where all atoms contributing to the system of conjugate π are in the same plane.

[00170] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a π-conjugate system in a ring where all atoms contributing to the π-conjugate system are in the same plane. For example, the "aryl" can be phenyl and naphthyl. The aryl system itself can be replaced by other groups.

[00171] The term "heteroaryl" refers to an aromatic hydrocarbon ring system with at least one heteroatom in a single ring or in a fused ring system, selected from O, N and S. The ring or ring system has 4n +2 electrons in a π-conjugate system where all atoms contributing to the π-conjugate system are in the same plane. For example, the "heteroaryl" may be imidazole, thiene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

[00172] The term "alkaryl" refers to an aryl group, as defined above, attached to a C1-4 alkyl, where the C1-4 alkyl group provides linkage to the remainder of the molecule.

[00173] The term "alkyheteroaryl" refers to a heteroaryl group, as defined above, attached to a C1-4 alkyl, where the alkyl group provides linkage to the remainder of the molecule.

[00174] The term "halogen" here includes reference to F, Cl, Br and I. Halogen can be Cl. Halogen can be F.

[00175] A bond ending in a ^"r" represents that the bond is connected to another atom that is not shown in the structure. A bond terminating within a cyclic structure and not terminating in an atom of the ring structure represents that the bond can be connected to any of the atoms in the ring structure where it followed by valence.

[00176] Where a moiety is substituted, it may be replaced at any point on the moiety where chemically possible and consistent with atomic valence requirements. The moiety may be replaced by one or more substituents, for example, 1, 2, 3 or 4 substituents; Optionally, there are 1 or 2 substituents in a group. Where there are two or more substituents, the substituents may be the same or different. The substituent(s) may be selected from: OH, NHR, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(O)H, acyl, acyloxy, carboxy, sulfo , sulfamoyl, carbamoyl, cyano, azo, nitro, halo, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl or alkaryl. Where the group to be substituted is an alkyl group, the substituent may be =O. R may be selected from H, C1-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, e.g. R is H or C1 -3 alkyl. Where the moiety is substituted with two or more substituents and two of the substituents are adjacent, the adjacent substituents may form a C4-8 ring together with the atoms of the moiety on which the substituents are substituted, wherein the C4-8 ring is a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7 or 8 carbon atoms and 1, 2 or 3 heteroatoms.

[00177] Substituents are only present in positions where they are chemically possible, the person skilled in the art being able to decide (experimentally or theoretically) without undue effort which substitutions are chemically possible and which are not.

[00178] Ortho, meta and para substitution are terms well understood in the art. For the absence of doubt, "ortho" substitution is a pattern of substitution where adjacent carbons bear a substituent, whether a simple group, for example the fluorine group in the example below, or other portions of the molecule, as indicated by the bond end. in

[00179] "Meta" substitution is a substitution pattern where two substituents are on carbons, one carbon removed from each other, that is, with a single carbon atom between the substituted carbons. In other words, there is a substituent on the second atom away from the atom with another substituent. For example, the groups below are meta replaced.

[00180] The "para" substitution is a substitution pattern where two substituents are on carbons, two carbons removed from each other, that is, with two carbon atoms between the substituted carbons. In other words, there is a substituent on the third atom away from the atom with another substituent. For example, the groups below are for substituted.

[00181] Where two groups are substituted on non-adjacent atoms, it will be understood by the skilled person that the two groups are not substituted on the same atom or on two atoms that are bonded to each other. For example, the pyrazole ring shown below is shown with two substituents that are attached to non-adjacent atoms. Non-adjacent atoms have at least one atom between them.

[00182] By "acyl" is meant an organic radical derived from, for example, an organic acid by removing the hydroxyl group, for example, a radical having the formula R-C(O)-, where R can be selected from group H , C1-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl, for example, R is H or C1-3 alkyl. In one embodiment, acyl is alkyl carbonyl. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl and butyryl. One particular acyl group is acetyl.

[00183] The entire description of the invention of a compound also covers pharmaceutically acceptable salts, solvates and stereoisomers thereof. Where a compound has a stereocenter, both (R) and (S) stereoisomers are contemplated by the invention, equally mixtures of stereoisomers or a racemic mixture are covered by the present application. Where a compound of the invention has two or more stereocenters, any combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers can result in a diastereomeric mixture or a simple diastereoisomer. The compounds of the invention may be present as a single stereoisomer or may be mixtures of stereoisomers, for example, racemic mixtures and other enantiomeric mixtures, and diastereomeric mixtures. Where the mixture is a mixture of enantiomers, the enantiomeric excess may be any of those described above. Where the compound is a simple stereoisomer, the compounds may also contain other diastereoisomers or enantiomers as impurities. Consequently, a simple stereoisomer does not necessarily have an enatiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100%, however, it may have an e.e. or of. of about at least 85%

[00184] The invention contemplates pharmaceutically acceptable salts of the compounds of the invention. These may include the base or acid addition salts of the compounds. These can be base and acid addition salts of the compounds. Furthermore, the invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compound.

[00185] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the salts of acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, cansylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride/chloride, hydrobromide /bromide, iodate/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsilate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate /dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

[00186] Suitable base salts are formed from bases that form non-toxic salts. Examples include the salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc. Hemissals of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[00187] Pharmaceutically acceptable salts of compounds of formula (I) can be prepared by one or more of three methods: (i) reacting the compound of the invention with the desired acid or base; (ii) removing an acid-labile protecting group or base from a suitable precursor of the compound of the invention or by ring opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) converting one salt of the compound of the invention to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[00188] All three reactions are typically carried out in solution. The resulting salt may precipitate and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized.

[00189] The compounds of the invention can exist in both solvated and unsolvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is used when said solvent is water.

[00190] Included in the scope of the invention are complexes, such as clathrates, drug-host inclusion complexes in which, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[00191] Below all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[00192] Compounds of the invention include compounds of a formula number as defined herein, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined hereinafter and compounds of the invention isotopically labeled.

[00193] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds of the invention in which one or more atoms are replaced by atoms having the same atomic number, but a mass number or atomic mass different from the mass number or atomic mass most commonly found in nature.

[00194] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine , such as, 123I and 125I, nitrogen, such as, 13N and 15N, oxygen, such as, 15O, 17O and 18O, phosphorus, such as, 32P, and sulfur, such as, 35S.

[00195] Certain isotopically labeled compounds, for example, those incorporating a radioactive isotope, are useful in substrate and/or drug tissue distribution studies. The radioactive isotopes tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and rapid means of detection.

[00196] Replacement with heavier isotopes, such as deuterium, i.e. 2H, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, reduced dosage requirements or increased in vivo half-life, and consequently may be preferred in some circumstances.

[00197] Prior to purification, the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedure used. Enantiomers can be separated by conventional techniques known in the art. Therefore, the invention covers individual enantiomers, as well as mixtures thereof.

[00198] For some of the steps in the process of preparing the compounds of the invention, it may be necessary to protect potential reactive functions that are not desired to react, and to cleave said protecting groups accordingly. In such a case, any compatible protective radical can be used. Particular methods of protection and deprotection, such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or by P. J. Kocienski (Protecting Groups, Georg Tieme Verlag, 1994), can be used. All of the above reactions and preparations of new starting materials used in the above methods are conventional and suitable reagents and reaction conditions for their performance or preparation, as well as procedures for isolating the desired products will be well known to those skilled in the art with reference. to literature precedents and the examples and preparations cited here.

[00199] Also, the compounds of the present invention, as well as intermediates for their preparation, can be purified according to various well-known methods, such as, for example, crystallization or chromatography.

[00200] One or more compounds of the invention can be combined with one or more pharmaceutical agents, for example, antiviral agents, chemotherapeutics, anticancer agents, immune enhancers, immunosuppressants, antitumor vaccines, antiviral vaccines, cytokine therapy, or tyrosine kinase inhibitors , for the treatment of conditions modulated by Porcn inhibition, for example, cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammatory and immunological diseases.

[00201] The treatment method or compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammatory and immunological diseases as previously defined can be applied as a single therapy or be a combination therapy with an additional active agent.

[00202] The treatment method or compound for use in treating cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, leukemia, and central nervous system disorders may involve, in addition to the compound of the invention, surgery conventional radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of antitumor agents: (i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (e.g., cis-platinum, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustine, melphalan, chlorambucil, chlormethine, busulfan, temozolamide, nitrosoureas, ifosamide, melphalan, popobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, strotozocin and dacarbazine); antimetabolites (e.g., gemcitabine and antifolates such as 5-fluorouracil and tegafur-type fluoropyrimidines, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine and hydroxyurea); antibiotics (e.g., adriamycin-type anthracyclines, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example, vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); proteasome inhibitors, for example, carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (e.g., etoposide and teniposide-type epipodophyllotoxins, ansacrine, topotecan, mitoxantrone and camptothecin); bleoncin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), nabpaclitaxel, docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide; (ii) cytostatic agents, such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxifene), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., such as anastrozole, letrozole, vorazole, and exemestane) and 5α-reductase inhibitors, such as finasteride; and navelbene, CPT-ll, anastrazole, letrazol, capecitabine, reloxafme, cyclophosphamide, ifosamide, and droloxafine; (iii) anti-invasion agents, for example, dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to heparanase; (iv) developmental factor function inhibitors: for example, such inhibitors include developmental factor antibodies and developmental factor receptor antibodies, e.g., the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab , the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, e.g., epidermal developmental factor family inhibitors (e.g., EGFR family tyrosine kinase inhibitors, such as, gefitinib, erlotinib, 6-acrylamido-N-( 3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib) and antibodies to costimulatory molecules such as CTLA- 4, 4-lBB and PD-l, or antibodies to cytokines (IL-I0, TGF-beta); hepatocyte development factor family inhibitors; insulin development factor family inhibitors; modulators of cellular apoptosis protein regulators (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived development factor family, such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (e.g., inhibitors of Ras/Raf signaling, such as farnesyl transferase inhibitors, e.g., sorafenib, tipifarnib and lonafarnib), inhibitors of cell signaling through MEK and/or AKT kinases, inhibitors c-kit, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitors and cyclin-dependent kinase inhibitors, such as CDK2 and/or CDK4 inhibitors; and modulator of CCR2, CCR4 or CCR6; (v) antiangiogenic agents, such as those that inhibit the effects of vascular endothelial cell development factor, for example, the anti-vascular endothelial cell development factor antibody bevacizumab (Avastin™); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor, such as vandetanib, vatalanib, sunitinib, axitinib and Pazopanib; (vi) methods of gene therapy, including, for example, methods for replacing aberrant genes, such as aberrant p53 or aberrant BRCA1 or BRCA2; (vii) immunotherapy methods, including, for example, antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons, such as interferon α; interleukins, such as IL-2 (aldesleukin); interleukin inhibitors, e.g. IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines, such as HPV vaccines, for example, Gardasila, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100; dendritic cell-based vaccines (such as, Ad.p53 DC); and Toll-like receptor modulators, e.g., TLR-7 or TLR-9 agonists; and (viii) cytotoxic agents, for example, fludaribone (fludara), cladribine, pentostatin (NipentTM); (ix) steroids, such as corticosteroids, including glucocorticoids and mineralocorticoids, for example, aclomethasone, aclomethasone dipropionate, aldosterone, ancinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazole, deoxycortone, desonide, desoximethasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluchlorolone, flumethasone, flunisolide, fluocinolone , fluocinolone acetonide, fluocinonide, butyl fluocortin, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrobutyrate cortisone, aceponate hydrocortisone, hydrocortisone buteprate, hydrocortisone valerate, icometasone, icometasone embutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide , triamcinolone alcohol and its respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example, a combination of two or more steroids mentioned in this paragraph; (x) targeted therapies, e.g., PI3Kd inhibitors, e.g., idelalisib and perifosine; PD-1, PD-L1, PD-L2 and CTL4-A modulators, antibodies and vaccines; IDO inhibitors (such as indoximod); anti-PD-1 monoclonal antibodies (such as MK-3475 and nivolumab); anti-PDL1 monoclonal antibodies (such as MEDI-4736 and RG-7446); anti-PDL2 monoclonal antibodies; and anti-CTLA-4 antibodies (such as ipilimumab); (xi) antiviral agents, such as nucleotide reverse transcriptase inhibitors (e.g., zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, adefovir diprovoxyl, lobucavir, BCH-10652, emitricitabine, beta-L-FD4 (also called 3'-dichleoxy-5-fluoro-cytidine), (-)-beta-D-2,6-diamino-purine dioxolane, and lodenasine), non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine, delaviradine, efavirenz, PNU-142721, AG-1549, MKC-442 (1-ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)- (2,4(1H,3H)pyrimidineone), and (+)- alanolide A and B) and protease inhibitors (e.g. saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lasinavir, DMP-450, BMS-2322623, ABT-378 and AG-1549); (xii) chimeric antigen receptors, anticancer vaccines and arginase inhibitors.

[00203] The treatment method or compound for use in the treatment of inflammatory and immunological diseases may involve, in addition to the compound of the invention, additional active agents. The additional active agents may be one or more active agents used to treat the condition being treated by the compound of the invention and additional active agent. The additional active agents may include one or more of the following active agents:- (i) steroids, such as, corticosteroids, including glucocorticoids and mineralocorticoids, for example, aclomethasone, aclomethasone dipropionate, aldosterone, ancinonide, beclomethasone, beclomethasone dipropionate, betamethasone , betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazole, deoxycortone, desonide, desoximethasone, dexamethasone, dexamethasone sodium phosphate , dexamethasone isonicotinate, difluorocortolone, fluchlorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, butyl fluocortin, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, flupredniden acetate, flurandrenole na, fluticasone, propionate fluticasone, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icometasone, icometasone embutate, meprednisone, methylprednisolone, mometasone, paramethasone, mometasone furoate monohydrate, prednicarbate, prednis oil, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example, a combination of two or more steroids mentioned in this paragraph; (ii) TNF inhibitors, for example, etanercept; monoclonal antibodies (e.g., infliximab (Remicade), adalimumab (Humira), Certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g., etanorcept (Enbrel)); and 5-HT2A agonists (e.g., 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetide); (iii) anti-inflammatory drugs, for example, non-steroidal anti-inflammatory drugs; (iv) dihydrofolate reductase inhibitors/antifolates, for example, methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed and pralatrexate; and (v) immunosuppressants, e.g., cyclosporins, tacrolimus, pimecrolimus sirolimus, angiotensin II inhibitors (e.g., Valsartan, Telmisartan, Losartan, Irbesatan, Azilsartan, Olmesartan, Candesartan, Eprosartan) and ACE inhibitors, e.g., agents containing sulfhydryl (e.g., Captopril, Zofenopril), dicarboxylate-containing agents (e.g., Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Imidapril, Zofenopril, Trandolapril), phosphate-containing agents (e.g., Fosinopril), casokinins, lactokinins, and lactotripeptides.

[00204] Such combination treatment can be activated through simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention in a therapeutically effective dosage range described above and the other pharmaceutically active agent within its approved dosage range.

[00205] The compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous. In this way, compounds of the invention intended for pharmaceutical use can be administered as crystalline or amorphous products. They can be obtained, for example, as solid buffers, powders, or films by methods such as precipitation, crystallization, freeze drying, or vaporization drying, or evaporative drying. Radiofrequency or microwave drying can be used for this purpose.

[00206] For the aforementioned compounds of the invention, the dosage administered will, of course, vary according to the compound used, the mode of administration, the desired treatment and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range of 0.01 micrograms per kilogram of body weight (μg/kg) to 100 milligrams per kilogram of body weight (mg /kg).

[00207] A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on its own, but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, are in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[00208] Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition that is used to administer the compounds of the invention will preferably comprise from 0.05 to 99% by weight (percent by weight) of compounds of the invention, more preferably of 0.05 to 80% by weight of compounds of the invention, even more preferably from 0.10 to 70% by weight of compounds of the invention, and even more preferably from 0.10 to 50% by weight of compounds of the invention, all percentages by weight being based on the total composition.

[00209] Pharmaceutical compositions can be administered topically (e.g., to the skin) in the form, for example, of creams, gels, lotions, solutions, suspensions, or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.

[00210] For oral administration, the compounds of the invention can be mixed with an adjuvant or a vehicle, for example, lactose, sucrose, sorbitol, mannitol; a starch, for example potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example gelatin or polyvinylpyrrolidone; and/or a lubricant, for example magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin and the like, and then pressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talc and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[00211] For the preparation of soft gelatin capsules, the compounds of the invention can be mixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using those aforementioned tablet excipients. Also, liquid or semisolid formulations of the compound of the invention can be filled into hard gelatin capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavoring agents, sweetening agents (such as saccharin), preservative agents and/or carboxymethyl cellulose as a thickening agent or other excipients known to those skilled in the art.

[00212] For intravenous (parenteral) administration, the compounds of the invention can be administered as a sterile oily or aqueous solution.

[00213] The dose size for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the administration routine, in accordance with well-known principles of medicine.

[00214] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and comorbid medical conditions of the patient. The standard duration of treatment with compounds of the invention is expected to vary between one and seven days for more clinical indications. It may be necessary to extend the duration of treatment beyond seven days in cases of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply, including bones/joints, respiratory tract, endocardium, and dental tissues.

[00215] Throughout the description and claims of this specification, the words "comprises" and "contains" and variations thereof, mean "including, but not limited to", and they are not intended to (and do not) exclude other portions, additives , components, integers, or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification should be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[00216] Aspects, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, modality or example of the invention should be understood to be applicable to any other aspect, modality or example described herein unless incompatible with that. All of the features described in this specification (including any appended claims, summary and figures), and/or all of the steps of any method or process so described, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any preceding embodiments. The invention extends to any new, or any new combination, of the features described in this specification (including any appended claims, summary and figures), or to any new, or any new combination, of the steps of any method or process then described.

[00217] The reader's attention is directed to all papers and documents which are filed concurrently with or prior to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

EXAMPLES AND SUMMARY

[00218] Solvents, reagents and starting materials were purchased from commercial suppliers and used as received unless otherwise described. All reactions were carried out at room temperature unless otherwise stated. Compound identity and purity confirmations were performed by UV LCMS using a Waters Acquity SQ 2 Detector (ACQ-SQD2#LCA081). The diode array detector length was 254 nM and the MS was in positive and negative electrospray mode (m/z: 150-800). A 2 μL aliquot was injected onto a Guard column (0.2 μm x 2 mm filters) and UPLC column (C18, 50 x 2.1 mm, < 2 μm) in sequence maintained at 40°C. Samples were eluted at a flow rate of 0.6 mL/min with a mobile phase system composed of A (0.1% (v/v) formic acid in water) and B (0.1% (v /v) of formic acid in acetonitrile) according to the gradients outlined in Table 1 below. Retention times Tr : are reported in minutes. Table 1

[00219] NMR was also used to characterize final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with a 5 mm BBFO probe. Optionally, compound Rf values on silica thin layer chromatography (TLC) plates were measured.

[00220] Compound purification was carried out by fast column chromatography on silica or by preparative LCMS. LCMS purification was performed using a Waters 3100 mass detector in positive and negative electrospray mode (m/z: 150-800) with a Waters 2489 UV/Vis detector. Samples were eluted at a flow rate of 20 mL/min over an XBridgeTM prep C18 5 μM OBD 19 x 100 mm column with a mobile phase system composed of one (0.1% (v/v) formic acid in water) and B (0.1% (v/v) formic acid in acetonitrile) according to the gradient outlined in Table 2 below. Table 2

[00221] The chemical names in this document were generated using Elementary Structure to Name Conversion by Dotmatics Scientific Software. The starting materials were published in commercial sources or synthesized according to literature procedures.

[00222] The compounds of the invention can be synthesized by analogy with the following reaction routines: General Scheme 1

[00223] The steps in General Scheme 1 shown above can be performed in the order shown above or in a different order. For example, as the skilled person would appreciate, Suzuki coupling can be performed after coupling with Biaryl alpha-chloroacetamide, etc. Protection groups can be present or absent as needed. For example, a nitrogen atom can be protected or unprotected. Intermediate 1: 4-iodo-1-trityl-imidazole

[00224] 4-Iodoimidazole (5.38 g, 27.72 mmols) was dissolved in THF (86 mL). Trityl chloride, (8.5 g, 30.49 mmols) and triethylamine (7.73 mL, 55.44 mmols) were added and the reaction was heated to 70°C. After 3 h, TLC showed that the reaction had been completed. Therefore, the reaction mixture was allowed to cool to 45°C and filtered to remove the suspended white solid. The filtrate was concentrated, redissolved in DCM (300 mL) and washed with 5 wt% aqueous sodium thiosulfate solution (300 mL), which was again extracted with DCM (150 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated to yield the crude product. The white solid was taken up in EtOAc (300 ml) and heated at reflux for 30 minutes. The mixture was cooled and the solid was obtained by vacuum filtration. The white solid was dried in the vacuum oven for 3 hours providing 4-iodo-1-trityl-imidazole (6.721 g, 15.40 mmols, 55.57% yield). MS Method 2: Tr: 2.08 min, ES+ m/z 459 [M+Na]+1H NMR (400 MHz, DMSO) δ/ppm: 7.35-7.40 (m, 10H), 7.06-7.11 (m, 7H).Intermediate 2: (1-Tritylimidazol-4-yl)boronic acid

[00225] To a suspension of 4-iodo-1-trityl-imidazole (3.00 g, 6.88 mmols) in THF (55 mL) at 0°C was slowly added isopropylmagnesium chloride (8.6 mL, 17 .19 mmols), the clear solution was then allowed to stir for 10 minutes. Trimethyl borate (3.83 mL, 34.38 mmol) was added portion by portion and the reaction mixture was allowed to stir for 10 minutes at 0°C before being allowed to reach room temperature and stirring for a further 10 minutes. 1 M HCl (30 mL) was then added and the reaction was stirred for 10 minutes. The reaction was quenched by slowly pouring it into a saturated solution of NaHCO3 solution (100 mL) which was then extracted with EtOAc (3 x 50 mL). The combined organic phases were then dried over Na2SO4 and concentrated in vacuo to provide the crude product (1-tritylimidazol-4-yl)boronic acid (2.53 g, 7.15 mmols, 103.92% yield) as a off-white solid.MS Method 2: Tr: 1.47 min, ES+ m/z 355 [M+H]+1H NMR (400 MHz, DMSO) δ / ppm: 7.20-7.45 (m, 10H), 6.95-7.10 (m, 7H). Intermediate 3: 4-(1-trityl-1H-imidazol-4-yl)-2-(trifluoromethyl)pyridine

[00226] 4-Iodo-2-(trifluoromethyl)pyridine (0.03 mL, 3.27 mmols), (1-trithylimidazol-4-yl)boronic acid (1.01 g, 2.98 mmols), carbonate potassium (822.53 mg, 5.95 mmols) were added to a microwave flask with 1,4-dioxane (12 mL) and water (4 mL) (all reagents were divided equally between two microwave flasks) , and the flask was flooded with nitrogen for 10 minutes. [1,1-Bis(diphenylphosphine)ferrocene]palladium(II) chloride dichloromethane complex (121.50 mg, 0.15 mmol) was added, then the flask was flooded again with nitrogen for another 5 minutes. The reaction was heated under microwave irradiation at 100°C for one hour. The product was observed, however, starting material also remained. The reaction was heated to 100°C for another hour thermally, but the reaction did not progress further. The reaction was concentrated and then partitioned between water and EtOAc. The organic layer was washed with water and brine, the organic layer was then dried over sodium sulfate, filtered and concentrated. Flash column chromatography (SiO2, 0-50% EtOAc in heptane) provided 4-(1-trityl-1H-imidazol-4-yl)-2-(trifluoromethyl)pyridine (512 mg, 1.12 mmol, 37. 7% production).MS Method 2: Tr : 2.16 min, ES+ m/z 456 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 8.64-8.68 (d, J = 7.9 Hz, 1H), 8.00 (s, 1H), 7.79-7.81 (d, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7, 38-7.42 (m, 10H), 7.18-7.28 (m, 6H). Biaryl alpha-chloroacetamide: Synthesis A - Step 1 Intermediate 4: 5-pyrimidin-5-ylpyridin-2-amine

[00227] A microwave flask with stir bar was charged with pinacol ester of 2-aminopyridine-5-boronic acid (0.95 g, 4.3 mmols), 5-bromopyrimidine (600 mg, 3.77 mmols) , sodium carbonate (1.20 g, 11.32 mmols), toluene (5 mL), water (5 mL), ethanol (5 mL) and degassed for 10 minutes. Tetracis(triphenylphosphine)palladium(0) (436 mg, 0.38 mmol) was then added and the sealed vial was then irradiated at 100°C for one hour. Analysis showed completion, so the reaction mixture was concentrated to dryness, then the residue was suspended in DCM and 1 M aqueous HCl was then added. The phases were separated and the aqueous phase was basified with 10% aqueous NaOH to pH-12. The aqueous layer was again extracted with EtOAc several times, dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with diethyl ether and then filtered yielding 5-pyrimidin-5-ylpyridin-2-amine (355 mg, 1.65 mmol, 43.702% yield) as a pink powder. MS Method 2: Tr: 0 .36 min, ES+ m/z 173 [M+H]+ 1H NMR (400 MHz, MeOD) δ/ppm: 9.07-9.09 (s, 1H), 9.00-9.02 (s, 2H), 8.28-8.38 (dd, J = 2.5, 0.7 Hz, 1H), 7.84-7.87 (dd, J = 8.8, 2.5 Hz, 1H) , 6.72-6.75 ((dd, J = 8.8, 0.7 Hz, 1H).

[00228] Biaryl alpha-chloroacetamide: Synthesis A - Step 2 Intermediate 5: 2-chloro-N-(5-pyrimidin-5-yl-2-pyridyl)acetamide

[00229] To a pink suspension of 5-pyrimidin-5-ylpyridin-2-amine (355 mg, 2.06 mmols), THF (1.5 mL) and N,N-diisopropylethylamine (0.72 mL, 4.12 mmols) chloroacetyl chloride (0.16 mL, 2.06 mmols) was added dropwise at room temperature. The suspension turned black and a large exotherm was provided. Analysis of the reaction after 30 minutes showed that it was completed. The reaction was diluted with methanol and then concentrated. The resulting residue was purified by flash column chromatography (12 g SiO2, 30-100% EtOAc in heptane, then 0 to 20% MeOH in EtOAc) yielding an off-white/brown solid 2-chloro-N-(5 -pyrimidin-5-yl-2-pyridyl)acetamide (194 mg, 0.78 mmol, 37.84% yield).MS Method 2: Tr: 1.10 min, ES+ m/z 249 [M+H] + 1H NMR (400 MHz, CDCl3) δ/ppm: 9.29 (s, 1H), 8.98 (s, 1H), 8.93-8.97 (bs, 1H), 8.58-8, 60 (dd, J = 2.4, 0.7 Hz, 1H), 8.39-8.42 (d, J = 8.7 Hz, 1H), 7.97-8.01 (dd, J = 8.7, 2.4Hz, 1H), 4.27 (s, 2H).Example 1: N-(5-pyrimidin-5-yl-2-pyridyl)-2-[4-[2-(trifluoromethyl) -4-pyridyl]imidazol-1-yl]acetamide

[00230] To a round-base flask were added 2-chloro-N-(5-pyrimidin-5-yl-2-pyridyl)acetamide (64 mg, 0.26 mmol), DMF (2 mL) and potassium carbonate (71.14 mg, 0.5100 mmol), to the brown suspension was added 4-(1H-imidazol-4-yl)-2-(trifluoromethyl)pyridine (60.35 mg, 0.2800 mmol) and stirred at temperature room for one hour, a small amount of product was seen, the reaction was heated to 50°C overnight. LCMS analysis showed that the reaction was complete. The reaction was partitioned between water and EtOAc. The organic layer was then washed with brine, concentrated and then dissolved in an 8:1:1 mixture of DMSO:water:MeCN (15 mg/0.75 mL) and purified by preparatory LCMS. The resulting fraction was combined, concentrated and dried overnight in the vacuum oven yielding N-(5-pyrimidin-5-yl-2-pyridyl)-2-[4-[2-(trifluoromethyl)-4-pyridyl]imidazole -1-yl]acetamide (29.9 mg, 0.07 mmol, 27.31% yield).MS Method 1: Tr: 2.85 min, ES+ m/z 426.1 [M+H]+ 1H NMR (400 MHz, DMSO) δ/ppm: 11.20 (s, 1H), 9.22 (s, 2H), 9.21 (s, 1H), 8.85-8.87 (dd, J = 2.4, 0.6 Hz, 1H), 8.69-8.71 (d, J = 5.1, 1H), 8.29-8.33 (dd, J = 8.7, 2.4 , 1H), 8.16-8.19 (m, 3H), 7.99-8.22 (dd, J = 5.1, 1.0 Hz, 1H), 7.88-7.90 (d , J = 1.0 Hz, 1H), 5.14 (s, 2H).

[00231] Biaryl to Biaryl alpha-chloroacetamide: Synthesis B - Step 1 Intermediate 6: 2-(5-nitro-2-pyridyl)pyrazine

[00232] To a microwave flask were added 2-bromo-5-nitropyridine (800 mg, 3.94 mmol), triphenylphosphine (103.37 mg, 0.39 mmol), (tributylstanyl)-pyrazine (1. 00 ml, 3.17 mmols) and toluene (8 ml), the reaction mixture was degassed with nitrogen for 10 minutes before adding palladium (II) acetate (88.48 mg, 0.39 mmol). The reaction was degassed again and then heated in the microwave for two hours at 130°C. The reaction was partitioned between water and EtOAc, the organic layer was washed several times with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was taken up in DCM and filtered to remove solids. The residue resulting from concentrated filtrate was purified by flash column chromatography (40 g SiO2, eluted with 0-70% EtOAc in heptane). Fractions 23-33 were combined and concentrated. The orange solid was then triturated with EtOH providing 2-(5-nitro-2-pyridyl)pyrazine (114 mg, 0.5639 mmol, 17.79% yield).MS Method 2: Rt: 1.38 min, ES-m/z 202.9 [MH]- 1H NMR (400 MHz, DMSO) δ/ppm: 9.61-9.63 (d, J = 1.4Hz, 1H), 9,519.56 (m, 1H ), 8.76-8.89 (m, 3H), 8.58-8.62 (dd, J = 8.8, 0.7 Hz, 1H). Biaryl alpha-chloroacetamide: Synthesis B - Step 2 Intermediate 7:6-pyrazin-2-ylpyridin-3-amine

[00233] A round-base flask was charged with 2-(5-nitro-2-pyridyl)pyrazine (114 mg, 0.56 mmol) and methanol (5.64 mL). The mixture was purged and evacuated with nitrogen, palladium, 10% by weight on wet carbon powder (60.02 mg) was added to the reaction and the system was purged and evacuated again. A balloon of hydrogen was then added and the reaction was stirred overnight at room temperature. LCMS analysis showed partial hydrogenation, the above procedure was repeated and more palladium, 10 wt% on wet carbon powder (60.02 mg) was added along with more hydrogen and stirred overnight at room temperature. LCMS analysis showed that the reaction was complete. The mixture was filtered through celite and the filtrate was loaded directly onto a methanol-enhanced SCX cartridge. The cartridge was eluted with methanol (3CV) and 1 M ammonia in methanol (3CV). The ammonia jet was then concentrated, ethanol trituration was attempted on the product, however, this did not remove the product, 6-pyrazin-2-ylpyridin-3-amine (113 mg, 0.66 mmol, 116% yield ) taken raw.MS Method 2: Tr : 0.45 min, ES+ m/z 173.2 [M+H]+ Biaryl alpha-chloroacetamide: Synthesis B - Step 3 Intermediate 8: 2-chloro-N-(6- pyrazin-2-yl-3-pyridyl)acetamide

[00234] To an orange suspension of 6-pyrazin-2-ylpyridin-3-amine (113 mg, 0.66 mmol), THF (2.19 mL) and N,N-diisopropylethylamine (0.23 mL, 1.31 mmol) chloroacetyl chloride (0.05 mL, 0.66 mmol) was added dropwise at 0°C and then allowed to reach room temperature. The suspension turned black and a large exotherm was provided. The reaction was then concentrated. The resulting residue was purified by flash column chromatography (12 g SiO2, 0-100% EtOAc then 0 to 20% MeOH in EtOAc). Fractions 23-28 were combined and concentrated to give brown solid 2-chloro-N-(6-pyrazin-2-yl-3-pyridyl)acetamide (60 mg, 0.24 mmol, 36.76% yield) .MS Method 2: Tr : 1.19 min, ES+ m/z 249.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ/ppm: 9.50-9.51 (d, J = 1 .5 Hz, 1H), 8,918.92 (m, 1H), 8.68-8.70 (dd, J = 2.6, 1.5 Hz, 1H), 8.59-8.61 (d, J = 2.6 Hz, 1H), 8.38-8.42 (m, 1H), 8.27-8.31 (dd, J = 8.7, 2.7 Hz, 1H), 4.88 (s, 2H).Example 2: N-(6-pyrazin-2-yl-3-pyridyl)-2-[4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]acetamide

[00235] To a round-based flask were added 2-chloro-N-(6-pyrazin-2-yl-3-pyridyl)acetamide (60 mg, 0.24 mmol), DMF (2 mL) and potassium carbonate (66.7 mg, 0.48 mmol), to the brown suspension was added 4-(1H-imidazol-4-yl)-2-(trifluoromethyl)pyridine (56.58 mg, 0.27 mmol) and the reaction was heated to 50°C for 3 hours. TLC analysis showed a small amount of starting material present and mainly product. The reaction was cooled and diluted with EtOAc and water. The organic layer was washed several times with water. The organic layer was then dried over sodium sulfate, filtered and concentrated. The resulting yellow residue was purified by preparatory LCMS. The resulting fractions were loaded onto a MeOH-enhanced SCX cartridge which was eluted with methanol (3CV) and then 1 M ammonia in methanol, the ammonia stream was then concentrated and analyzed, however the product was still not sufficiently clean. . The resulting solid was recrystallized from EtOH. The resulting solid was dried in a vacuum oven at 40C overnight yielding N-(6-pyrazin-2-yl-3-pyridyl)-2-[4-[2-(trifluoromethyl)-4-pyridyl]imidazole- 1-yl]acetamide (19.7 mg, 0.046 mmol, 19.19% yield).MS Method 1: Tr: 3.05 min, ES+ m/z 426.2 [M+H]+

[00236] 1H NMR (400 MHz, DMSO) δ/ppm: 108.86-10.91 (bs, 1H), 9.49-9.50 (d, J = 1.5 Hz, 1H), 8, 92-8.94 (m, 1H), 8.67-8.73 (m, 3H), 8.35-8.38 (d, J = 8.6 Hz, 1H), 8.25-8, 28 (dd, J = 8.7, 2.6 Hz, 1H), 8.16-8.19 (m, 2H), 7.99-8.02 (m, 1H), 7.89-7, 90 (d, J = 1.0 Hz, 1H), 5.11 (s, 2H). Example 3

[00237] The following compounds were prepared using Biaryl alpha-chloroacetamide A synthesis in an analogous manner, varying the arylide and/or arylboronate used. General Scheme 2

[00238] The steps in General Scheme 2 shown above can be performed in the order shown above or in a different order. For example, as the skilled person would appreciate, Suzuki coupling can be performed after coupling with Monoaryl alpha-chloroacetamide. Protection groups can be present or absent as needed. For example, a nitrogen atom can be protected or unprotected. Intermediate 9: 4-(1H-pyrazol-4-yl)-2-(trifluoromethyl)pyridine

[00239] A microwave flask was charged with 1,4-dioxane (10 ml) and water (3 ml) which were degassed with nitrogen for ~10 minutes. To this were added 4-iodo-2-(trifluoromethyl)pyridine (500 mg, 1.83 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- tert-butyl 1H-pyrazol-1-carboxylate (808 mg, 2.75 mmols) and potassium carbonate (506 mg, 3.66 mmols) followed by [1,1'-bis(diphenylphosphine) chloride dichloromethane complex )ferrocene]palladium (II) (149 mg, 0.1800 mmol). The vessel was then sealed, flooded with nitrogen and irradiated for 1 hour at 110°C. LC-MS after this time showed conversion to deprotected product and no starting material remaining, so the reaction was set up.

[00240] The reaction mixture was concentrated to dryness, then taken up in MeOH. This was loaded onto a 5 g SCX cartridge and washed through ~10 CV of MeOH. The product was then eluted with 1 M ammonia in MeOH (~5 CV). The ammonia wash was then concentrated to dryness, but did not produce the desired product. The MeOH washes were then concentrated to dryness and the remaining residue was triturated with chloroform. The resulting suspension was sonicated and then filtered, washing with a little chloroform, yielding 4-(1H-pyrazol-4-yl)-2-(trifluoromethyl)pyridine (384 mg, 1.80 mmol, 98.35% production) as a beige solid.MS Method 2: Tr : 1.30 min, ES+ m/z 214.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ/ppm: 8.66 (s, 1H ), 8.34-8.38 (m, 2H), 8.08 (s, 1H), 7.89-7.92 (m, 1H).Example 4: N-(5-pyrazin-2-yl -2-pyridyl)-2-[4-[2-(trifluoromethyl)-4-pyridyl]pyrazol-1-yl]acetamide

[00241] A vial was charged with 2-chloro-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (50 mg, 0.20 mmol), 4-(1H-pyrazol-4-yl)- 2-(trifluoromethyl)pyridine (64 mg, 0.30 mmol) and potassium carbonate (55 mg, 0.40 mmol) which were suspended in DMF (1 mL). The vessel was then sealed, flooded with nitrogen, and allowed to stir at room temperature overnight. LC-MS after this time showed complete consumption of starting material and a new peak corresponding to the desired product. The reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was then extracted with EtOAc (x2). The organics were then combined, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness, providing an off-white solid. Purification by flash column chromatography was performed, (12 g SiO2, eluting with 50-100% EtOAc in heptane). The product-containing fractions were combined and concentrated to dryness, providing a white solid. LC-MS showed desired product, the solid was also purified by preparative LCMS, the fractions combined and concentrated to dryness and also dried in the vacuum oven overnight, yielding N-(5-pyrazin-2-yl-2-pyridyl )-2-[4-[2-(trifluoromethyl)-4-pyridyl]pyrazol-1-yl]acetamide (10 mg, 0.024 mmol, 11.69% yield) as a white solid.MS Method 1: Tr: 3.27 min, ES+ m/z 426.2 [M+H]+ 1H NMR (400 MHz, DMSO) δ/ppm: 11.16-11.22 (bs, 1H), 9.31-9.33 (d, J = 1.4Hz, 1H), 9.14-9.16 (d, J = 2.4Hz, 1H), 8.64-8.74 (m, 4H), 8,548.58 (dd, J = 8.6, 2.4Hz, 1H), 8.31 (s, 1H), 8.17-8.21 (d, J = 8.7Hz, 1H), 8.14 (s, 1H) , 7.92-7.95 (d, J = 5.2 Hz, 1H), 5.24 (s, 2H). Example 5: N-(5-Pyrazin-2-yl-2-pyridyl)-2 -[4-[2-(methyl)-4-pyridyl]pyrazol-1-yl]acetamide was prepared in an analogous manner.

[00242] MS Method 1: Tr: 2.09 min, ES+ m/z 372.2 [M+H]+ 1H NMR (400 MHz, DMSO) δ/ppm: 9.31-9.33 (d, J = 1.5 Hz, 1H), 9,139.15 (dd, J = .2.5, 1.7 Hz, 1H), 8.72-8.74 (m, 1H), 8.64-8.65 (d, J = 2.5Hz, 1H), 8.54-8.57 (dd, J-8.7, 2.4Hz, 1H), 8.42-8.43 (d, J = 0, 7 Hz, 1H), 8.37-8.39 (d, J = 5.2 Hz, 1H), 8.17-8.2 (d, J = 8.7 Hz, 1H), 8.10- 8.11 (d, J = 0.7 Hz, 1H), 7.47-7.51 (bs, 1H), 7.38-7.41 (dd, J = 5.1, 1.2 Hz, 1H), 5.25 (s, 2H). 2.5 (s, 3H).Example 6

[00243] The following compounds were prepared using General Scheme 2 by varying the substitution on the pyrazole boronate ester and the aryl halide. The biaryl alpha-chloroacetamide A synthesis method was used to prepare the coupling partner during the final step in an analogous manner, varying the aryl alide and/or aryl/vinylboronate used. Monoaryl alpha-chloroacetamide: Synthesis A - Step 1 Intermediate 10: tert-butyl 4-(6-nitro-3-pyridyl)piperazine-1-carboxylate

[00244] A microwave flask was charged with 5-chloro-2-nitropyridine (1 g, 6.31 mmols), 1-boc-piperazine (1.29 g, 6.94 mmols) and potassium carbonate (3 .3 mL, 18.92 mmols), which were suspended in DMSO (15 mL). The resulting mixture was irradiated for one hour at 100°C. After this time, the mixture solidified. LC-MS showed that the reaction had not gone to completion. The solid mixture was then transferred to a flask along with DMSO (5 ml) and heated to 110°C, at which point the solid mixture melted. This was allowed to warm overnight, after which LC-MS showed product formation and no starting material. The reaction was allowed to cool. The reaction mixture was then added to water and extracted with EtOAc (x3). The organics were then combined, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness, providing an orange solid. Purification by flash column chromatography was then performed (40 g SiO2, eluting with 0-50% EtOAc in heptane). The product-containing fractions were combined and concentrated to dryness, yielding tert-butyl 4-(6-nitro-3-pyridyl)piperazine-1-carboxylate (1.24 g, 4.02 mmols, 63.81% yield ) as a bright orange/yellow solid. MS Method 2: Tr : 1.61min, ES+ m/z 309.1 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 8.10-8.13 (d, J = 9.1Hz , 1H), 8,068.07 (d, J = 3.0 Hz, 1H), 7.12-7.16 (dd, J = 9.2, 3.0 Hz, 1H), 3.55-3, 59 (m, 4H), 3.36-3.41 (m, 4H), 1.42 (s, 9H). Monoaryl alpha-chloroacetamide: Synthesis A - Step 2 Intermediate 11: 4 (6 aminopyridin-3-yl )tert-butyl piperazine-1-carboxylate

[00245] A vial was charged with tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (1 g, 4 mmols) which was dissolved in methanol (100 ml). The resulting solution was then degassed by evacuation and the vessel again charged with nitrogen (repeated twice). Palladium, 10% by weight on carbon powder, dry (42 mg, 0.40 mmol) was then added in one portion and the system closed and evacuated again, again charging with hydrogen (repeated twice). This was allowed to stir at room temperature. After 4 hours, LC-MS showed that the reaction was essentially complete, so the system was evacuated and recharged with nitrogen (repeated twice), the solution filtered through celite and the filtrate concentrated to dryness, yielding a brown oily solid. tert-Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (800 mg, 3.63 mmols, 90.88% yield).MS Method 2: Tr: 1.22 min, ES+ m /z 279.2 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 7.70-7.71 (d, J = 3.1Hz, 1H), 7.087.11 (d, J = 8.0Hz, 1H), 6.40-6.43 (dd, J = 8.0, 3.1Hz, 1H), 4.11-4.15 (bs, 2H), 3.50-3, 54 (m, 4H), 2.86-2.89 (m, 4H), 1.42 (s, 9H).Monoaryl alpha-chloroacetamide: Synthesis A - Step 3 Intermediate 12: 4-[6-[(2 tert-butyl-chloroacetyl)amino]-3-pyridyl]piperazine-1-carboxylate

[00246] A vial was charged with tert-butyl 4-(6-amino-3-pyridyl)piperazine-1-carboxylate (360 mg, 1.29 mmol) and potassium carbonate (357.5 mg, 2.59 mmols) that were suspended in 1,4-dioxane (5 mL). Once the organic components dissolved, the vessel was placed under a nitrogen atmosphere and chloroacetyl chloride (0.15 mL, 1.94 mmol) was added to the stirring solution at room temperature. This was left to stir overnight. LC-MS, after this time, showed conversion to the desired product and a peak that corresponded to the starting material but appeared at a slightly lower retention time. Another equivalent of acid chloride was added and the reaction allowed to stir at room temperature for another hour. Methanol was added to the reaction mixture to quench any excess acid chloride and the resulting mixture was concentrated to dryness. The residue was then partitioned between water and EtOAc. The layers were then separated and the organics were washed with water, then brine, dried over sodium sulfate, filtered and concentrated to dryness, providing a dark purple solid. Further purification by flash column chromatography was performed (25 g SiO2, eluting with 50-60% EtOAc in heptane). The collected fractions were combined and concentrated to dryness, yielding tert-butyl 4-[6-[(2-chloroacetyl)amino]-3-pyridyl]piperazine-1-carboxylate (265 mg, 0.75 mmol, 57. 74% production) as a pink/purple solid.MS Method 2: Tr: 1.57 min, ES+ m/z 355.9 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 8, 61 (s, 1H) 7.97-8.02 (d, J = 9.0 Hz, 1H), 7.90-7.92 (d, J = 2.6 Hz, 1H), 7.20- 7.25 (dd, J = 9.0, 2.5 Hz, 1H), 4.15 (s, 2H), 3.51-3.55 (m, 4H), 3.04-3.07 ( m, 4H), 1.42 (s, 9H). Example 7: 4-[6-[[2-[4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]acetyl]amino] tert-butyl -3-pyridyl]piperazine-1-carboxylate

[00247] A vial was charged with tert-butyl 4-[6-[(2-chloroacetyl)amino]-3-pyridyl]piperazine-1-carboxylate (40 mg, 0.11 mmol) and potassium carbonate (31 .16 mg, 0.23 mmol) which were taken up in DMF (1 mL). The solution was stirred and 4-(1H-imidazol-4-yl)-2-(trifluoromethyl)pyridine (36.04 mg, 0.17 mmol) was then added. The vial was then sealed, flooded with nitrogen, and allowed to shake at room temperature over the weekend. LC-MS, after this time, showed conversion to the desired product and some starting material remaining (the excess), so the reaction was prepared. The reaction mixture was diluted with water and extracted with EtOAc (x2). The organics were then combined, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness, providing a slightly purple residue. This was loaded dry onto silica gel and purified by flash column chromatography, (12 g SiO2, eluting with 50-100% EtOAc in heptane). The fractions were combined and concentrated to dryness, providing a white solid. Further purification by preparative LCMS yielded 4-[6-[[2-[4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]acetyl]amino]-3-pyridyl]piperazine-1- tert-butyl carboxylate (18 mg, 0.034 mmol, 29.74% yield) as a white solid. MS Method 1: Tr: 3.73 min, ES+ m/z 532.2 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 8.68-8.71 (d, J = 5, 1Hz 1H) 8.01-8.09 (m, 2H), 7.81-7.95 (m, 2H), 7.69 (s, 1H), 7.58 (s, 1H), 7.27 -7.29 (m, 1H), 4.85 (s, 2H), 3.53-3.64 (m, 4H), 3.08-3.14 (m, 4H), 1.47 (s , 9H). Example 8

[00248] The following compounds were prepared using monoaryl alpha-chloroacetamide A synthesis in an analogous manner, varying the non-aromatic group, or the aryl-substituted pyrazole or imidazole (from General Scheme 1 or 2) accordingly: General Scheme 3 Intermediate 13: 2-[(4-iodo-5-methyl-imidazol-1-yl)methoxy]ethyltrimethylsilane

[00249] To a stirred solution of 4-iodo-5-methyl-1H-imidazole (5 g, 24 mmols) in THF (100 ml) cooled to 0°C was added sodium hydride (60% dispersed in mineral oil) (1.06 g, 26 mmol), the resulting suspension was stirred for one hour at this temperature. 2-(Trimethylsilyl)ethoxymethyl chloride (4.25 mL, 24 mmols) was added slowly and the solution was allowed to warm to room temperature overnight. More sodium hydride (60% dispersed in mineral oil) (0.5 eq) was added and the solution was stirred for 1.5 hours. A small amount of water was added before the solution was concentrated in vacuo. Water and DCM were added and the solution divided. The aqueous layer was washed with more DCM (x2) before the combined organics were passed through a phase separator and concentrated to dryness in vacuum to give a dark yellow oil. The residue was dissolved in DCM and purified by flash column chromatography (80 g SiO2, 0-50% EtOAc in heptane). TLC still showed both regioisomers together in all fractions, so the fractions were concentrated to dryness in vacuum to give 2-[(4-iodo-5-methyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(5-iodo-4-methyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane in a ratio of 1 : 0.6 in favor of the title product (5.59 g, 17 mmol, 69% production) as a yellow oil. MS Method 2: Tr : 1.44 min, ES+ m/z 339.1 [M+H]+ and 1.84 min, ES+ m/z 339.1 [M+H]+ 1H NMR (400 MHz, CDCl3 ) δ/ppm: 7.73 (s, 1H, minor), 7.49 (s, 1H, major), 5.22 (s, 2H, both regioisomers), 3.40-3.50 (m, 2H, both regioisomers), 2.27 (s, 3H, major), 2.26 (s, 3H, minor), 0.85-0.93 (m, 2H, both regioisomers), 0.03 ( s, 9H, both regioisomers). Intermediate 14 trimethyl-[2-[[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]methoxy]ethyl]silane

[00250] A stirred solution of 2-[(5-iodo-4-methyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane (1 g, 2.96 mmols) and [2-(trifluoromethyl)- 4-pyridyl]boronic acid (847 mg, 4.43 mmols) in monoglyme (18 mL) was degassed and charged again with N2 (x3). To this was added potassium phosphate (tribasic) (1.88 g, 8.87 mmol) in water (9 mL) followed by tricyclohexylphosphine (166 mg, 0.59 mmol) and tris(dibenzylideneacetone)dipalladium (0) (271 mg, 0.30 mmol) before the resulting solution was degassed and recharged with N2 (x3), then heated to 90°C and stirred at this temperature overnight. The solution was allowed to cool to room temperature. The mixture was filtered through a celite pad before being concentrated to dryness in vacuum to provide the crude as a thick brown oil. The residue was dissolved in the minimum amount of DCM and purified by flash column chromatography (80 g SiO2, 0-100% EtOAc in heptane). Similar fractions were identified, combined, and concentrated to dryness in vacuum to provide trimethyl-[2-[[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]methoxy]ethyl]silane (478 mg, 1.34 mmol, 45% yield) as a single regioisomer and yellow oil that solidified upon standing. MS Method 2: Tr: 1.90 min, ES+ m/z 358.2 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 8.70-8.72 (d, J = 5, 1Hz, 1H) 8.05 (s, 1H), 7.76, 7.80 (dd, J = 5.1, 2.6 Hz 1H), 7.61 (s, 1H), 5.29 (s , 2H), 3.50-3.57 (m, 2H), 2.27 (s, 3H, major), 2.55 (s, 3H), 0.90-0.96 (m, 2H), 0.00 (s, 9H). Intermediate 15: 4-(5-methyl-1H-imidazol-4-yl)-2-(trifluoromethyl)pyridine

[00251] To a stirred solution of trimethyl-[2-[[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]methoxy]ethyl]silane (1.57g, 4, 4 mmols) in DCM (25 mL) trifluoroacetic acid (16 mL, 209 mmols) was added and the resulting solution stirred at room temperature overnight. The solution was concentrated to dryness in vacuum before being dissolved in MeOH and loaded onto a MeOH-enhanced 10 g SCX cartridge, washing with MeOH and eluting with 1 M NH3 solution. The ammonia MeOH solution was concentrated to drying under vacuum to provide 4-(5-methyl-1H-imidazol-4-yl)-2-(trifluoromethyl)pyridine (950 mg, 4.18 mmols, 94% yield) as a pale yellow powder.

[00252] MS Method 2: Tr: 1.07 min, ES+ m/z 228.1 [M+H]+ 1H NMR (400 MHz, MeOD) δ/ppm: 8.67-8.68 (d, J = 5.2 Hz, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 2.57 (s, 3H). Intermediate 16: 2-fluoro-4-(5-methyl-1H-imidazol-4-yl)pyridine 2-Fluoro-4-(5-methyl-1H-imidazol-4-yl)pyridine was prepared in an analogous manner.MS Method 2: Rt: 0.72 min, ES+ m/z 178.0 [M+H] + 1H NMR (400 MHz, MeOD) δ/ppm: 8.18-8.20 (d, J = 5.2 Hz, 1H), 7.73 (s, 1H), 7.56-7.60 ( dt, J = 1.7, 5.6 Hz, 1H), 7.29 (s, 1H), 2.54 (s, 3H). Intermediate 17: 2-[5-methyl-4-[2-( trifluoromethyl)-4-pyridyl]imidazol-1-yl]acetate

[00253] Under N2, to a stirred solution of 4-(5-methyl-1H-imidazol-4-yl)-2-(trifluoromethyl)pyridine (950 mg, 4.18 mmols) in MeCN (30 ml) was added potassium carbonate (1.73 g, 12.6 mmols) and ethyl bromoacetate (0.56 ml, 5.02 mmols) before the resulting solution was heated to 80°C and stirred at this temperature for one hour. The solution was allowed to cool to room temperature and stirred overnight. The solution was filtered with the solid being washed with MeCN before the filtrate was concentrated to dryness in vacuo to provide the crude as a dark yellow crystalline solid. The residue was dissolved in DCM and purified by flash column chromatography (40 g SiO2, 40-100% EtOAc in heptane). Appropriate fractions were identified, combined, and concentrated to dryness in vacuum to provide ethyl 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]acetate (1.12 g , 3.57 mmols, 85% yield) as a pale yellow crystalline solid.MS Method 2: Tr: 1.50 min, ES+ m/z 314.1 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm:8.72-8.34 (d, J = 4.8Hz, 1H), 8.06 (s, 1H), 7.79-7.80 (d, J = 4.8Hz, 1H) , 7.58 (s, 1H), 4.71 (s, 2H), 4.29-4.34 (q, J = 7.1Hz, 2H), 2.36 (s, 3H) 1.32- 1.36 (t, J = 7.1Hz, 3H). Intermediate 18: tert-butyl 2-[4-(2-fluoro-4-pyridyl)-5-methyl-imidazol-1-yl]acetate

[00254] A vial was charged with 2-fluoro-4-(5-methyl-1H-imidazol-4-yl)pyridine (100 mg, 0.56 mmol) and cesium carbonate (276 mg, 0.85 mmol) which were suspended in acetone (2.5 mL). Tert-Butyl 2-Bromoacetate (0.09 mL, 0.62 mmol) was then added and the reaction heated to 50°C for one hour, then cooled to room temperature. The reaction mixture was then diluted with more acetone and passed through a phase separator. The filter cake was washed with acetone and the resulting filtrate then concentrated to dryness, yielding tert-butyl 2-[4-(2-fluoro-4-pyridyl)-5-methyl-imidazol-1-yl]acetate ( 160 mg, 0.55 mmol, 97% yield) as a yellow solid.

[00255] MS Method 2: Tr: 1.41 min, ES+ m/z 292.1 [M+H]+ Intermediate 19: 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl acid ]imidazol- 1-yl]acetic acid

[00256] To a stirred solution of ethyl 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]acetate (1.12 g, 3.57 mmols) in ethanol (27 mL) lithium hydroxide (231 mg, 9.64 mmols) in water (2.7 mL) was added before the resulting solution was stirred at room temperature overnight. LCMS indicated complete conversion to product. The solution was concentrated to dryness in vacuo to provide lithium 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]acetate (1.04 g, 3.57 mmols , 99% production) as an off-white powder. The material was used as it was in the next stage. MS Method 2: Tr: 1.09 min, ES+ m/z 286.1 [M+H]+ 1H NMR (400 MHz, DMSO) δ/ppm: 8.65-8.67 (d, J = 5, 2 Hz, 1H), 8.05 (s, 1H), 7.86-7.89 (d, J = 5.2 Hz, 1H), 7.60 (s, 1H), 4.19 (s, 2H), 2.36 (s, 3H). Intermediate 20: 2-[4-(2-fluoro-4-pyridyl)-5-methyl-imidazol-1-yl]acetic acid

[00257] A vial was charged with tert-butyl 2-[4-(2-fluoro-4-pyridyl)-5-methyl-imidazol-1-yl]acetate (160 mg, 0.55 mmol) which was seized in hydrogen chloride (4 M in dioxane) (3 mL, 12 mmols). The reaction mixture was then allowed to stir overnight at room temperature. A precipitate formed after this time. The reaction was concentrated to dryness, yielding 2-[4-(2-fluoro-4-pyridyl)-5-methyl-imidazol-1-yl]acetic acid (150 mg, 0.6377 mmol, 116.12% production) as a yellow solid that became darker after resting in air.MS Method 2: Tr : 0.67 min, ES+ m/z 236.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ /ppm: 9.17 (s, 1H), 8.42-8.44 (d, J = 5.2 Hz, 1H), 7.56-7.58 (dt, J = 1.7, 5, 2 Hz, 1H), 7.36 (s, 1H), 5.24 (s, 2H), 2.52 (s, 3H). Intermediate 21: 5-pyrazin-2-ylpyridin-2-amine

[00258] 5-Pyrazin-2-ylpyridin-2-amine was prepared in a manner analogous to that described for intermediate 4 in Biaryl alpha-chloroacetamide: Synthesis A - Step 1. MS Method 2: Tr: 0.42 min, ES+ m /z 173.1 [M+H]+ 1H NMR (400 MHz, DMSO) δ/ppm: 9.11-9.22 (d, J = 1.6 Hz, 1H), 8,728.73 (dd, J = 0.4, 1.6 Hz, 1H), 8.59-8.60 (dd, J = 1.6, 2.4 Hz, 1H), 8.458.61 (d, J = 2.4 Hz, 1H), 8.10-8.13 (dd, J = 2.4, 8.4 Hz, 1H), 6.55-6.57 (dd, J = 0.8, 8.8 Hz, 1H) , 6.41-6.44 (bs, 2H).Example 9: 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]-N-(5-pyrazin -2-yl-2-pyridyl)acetamide

[00259] To a stirred solution of lithium 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]acetate (1.04 g, 3.57 mmols) and 5 -pyrazin-2-ylpyridin-2-amine (738 mg, 4.29 mmols) in THF (35 mL) were added N,N-diisopropylethylamine (1.56 mL, 8.93 mmols) and propylphosphonic anhydride (6 .38 mL, 10.7 mmols) and the resulting solution heated to 70°C. The reaction was monitored by LCMS and after 2 hours more propylphosphonic anhydride (2.13 mL, 3.57 mmols) and N,N-diisopropylethylamine (0.6 mL) were added. The solution was allowed to cool to room temperature and stirred over the weekend. The solution was diluted with water and EtOAc and divided. The aqueous was washed with EtOAc (x2) before the combined organics were washed with brine. The product precipitated and was isolated by filtration and loaded onto a MeOH-enhanced 10 g SCX cartridge, washing with MeOH and eluting with 1 M NH3 MeOH solution. The ammonia methanol solution was concentrated to dryness in vacuum to provide an off-white solid which was then dried in a vacuum oven for two hours. The organics were separated from the filtrate, dried (sodium sulfate), filtered, and concentrated to dryness in vacuum to provide a light brown foam containing product of ~95% purity. This was dissolved in DCM and purified by flash column chromatography (25 g SiO2, 70-100% EtOAc in heptane, then 0-5% MeOH/EtOAc). The appropriate fractions were combined and concentrated to dryness in vacuo to provide an off-white solid. The solids were combined to provide 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide ( 1.22 g, 2.77 mmols, 78% yield) as an off-white solid. MS Method 2: Tr: 1.45 min, ES+ m/z 440.1 [M+H]+ 1H NMR (400 MHz, DMSO) δ/ppm: 11.27 (bs, 1H), 9.32-9 .33 (d, J = 1.6 Hz, 1H), 8.70-8.75 (m, 2H), 8.64-8.65 (d, J = 2.4 Hz, 1H), 8, 54-8.58 (dd, J = 2.4, 8.8 Hz, 1H), 8.17-8.19 (d, J = 9.2 Hz, 1H), 8.09 (s, 1H) , 7,927.94 (d, J = 4.4 Hz, 1H), 7.85 (s, 1H), 5.12 (s, 2H), 2.45 (s, 3H).

[00260] The compound of Example 9 can also be prepared by the procedure outlined in General Scheme 1. Example 10: 2-[4-(2-fluoro-4-pyridyl)-5-methyl-imidazol-1-yl]-N -(5-pyrazin-2-yl-2-pyridyl)acetamide

[00261] A vial was charged with 2-[4-(2-fluoro-4-pyridyl)-5-methyl-imidazol-1-yl]acetic acid (125 mg, 0.53 mmol) and 5-pyrazin-2 -ylpyridin-2-amine (110 mg, 0.64 mmol) which were taken up in dry THF (2.5 mL). N,N-diisopropylethylamine (0.46 mL, 2.66 mmols) was then added, followed by propylphosphonic anhydride (0.63 mL, 1.06 mmol). The resulting mixture was then heated at reflux for two hours, then allowed to cool to room temperature. The reaction mixture was concentrated to dryness, providing a brown oil. This was then loaded dry onto silica gel and purified by flash chromatography (12 g SiO2, eluting with 0-10% MeOH in EtOAc). The fractions containing the desired compound were combined and concentrated to dryness, providing an off-white solid. This was then loaded dry onto celite and also purified by reverse phase chromatography (12g C-18 column, eluting with 5-40% MeCN in water + 0.1% formic acid additive). Fractions containing desired compound were combined and concentrated to dryness, yielding 2-[4-(2-fluoro-4-pyridyl)-5-methyl-imidazol-1-yl]-N-(5-pyrazin-2-yl -2- pyridyl)acetamide (86 mg, 0.22 mmol, 41% yield) as a white solid.MS Method 2: Tr: 1.20 min, ES+ m/z 390.1 [M+H]+ 1H NMR (400 MHz, DMSO) δ/ppm: 11.26 (bs, 1H), 9.32-9.33 (d, J =1.4 Hz, 1H), 9.14-9.15 (d, J = 1.8 Hz 1H) 8.72-8.74 (m, 1H), 8.64-8.65 (d, J = 2.5 Hz, 1H), 8.54-8.57 (dd , J = 2.4, 8.8 Hz), 8.17-8.21 (m, 2H), 7.81 (s, 1H), 7.61-7.63 (m, 1H), 7, 32 (m, 1H), 5.09 (s, 2H), 2.42 (s, 3H). Example 11

[00262] The following compounds were prepared by analogy with examples 9 and 10 following general routine 3, varying the substitution on imidazole iodine and aryl boronate ester. The biaryl alpha-chloroacetamide A synthesis method was used to prepare the coupling partner for the final step, varying the aryl alide and/or arylboronate used. General Scheme 4

[00263] Aryl pyrazol starting materials were prepared according to the method described previously as illustrated in General scheme 2, varying the substitution on the pyrazole boronate ester and the aryl halide. The biaryl alpha-chloroacetamide A synthesis method was used to prepare the coupling partner for the final step, varying the aryl alide and/or aryl boronate used. Intermediate 22: 2-[4-(2-cyclopentylpyrazol-3-yl)- 3,5-dimethyl-pyrazol-1-yl]acetate

[00264] Ethyl bromoacetate (0.02 mL, 0.17 mmol), 4-(2-cyclopentylpyrazol-3-yl)-3,5-dimethyl-1H-pyrazole (35.7 mg, 0.16 mmol) and cesium carbonate (95.3 mg, 0.47 mmol) were added to acetone (4 mL) forming a suspension. The flask was then heated to reflux and allowed to stir overnight. The precipitate was filtered, the filtrate was evaporated to dryness. The residue was dissolved in EtOAc and dried over sodium sulfate. The solvent was evaporated, yielding ethyl 2-[4-(2-cyclopentylpyrazol-3-yl)-3,5-dimethyl-pyrazol-1-yl]acetate (51.2 mg, 0.16 mmol, 100% production) as a yellow oil. The product was used without any further purification. MS Method 2: Tr: 1.71 min, ES+ m/z 317.0 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 7.43 (s, 1H), 7.73 (s , 1H), 6.25 (s, 1H), 4.81 (s, 2H), 4.65-4.67 (m, 1H), 4.21-4.25 (q, J = 6.9 Hz, 2H), 2.39 (s, 3H), 2.36 (s, 3H), 2.04-2.18 (m, 4H), 1.85-1.91 (m, 2H), 1 .66-1.71 (m, 2H), 1.21-1.24 (t, J = 6.9 Hz, 3H). Intermediate 23: 2-[4-(2-cyclopentylpyrazol-3-yl)- 3,5-dimethyl-pyrazol-1-yl]acetic acid

[00265] Ethyl 2-[4-(2-Cyclopentylpyrazol-3-yl)-3,5-dimethyl-pyrazol-1-yl]acetate (51.2 mg, 0.16 mmol) was dissolved in ethanol (3 mL), lithium hydroxide (10.46 mg, 0.44 mmol) in water (0.30 mL) was added and the reaction was stirred at room temperature for one hour. The mixture was acidified using a 1 M HCl solution. The solvent was evaporated. The residue was taken up in EtOAc and washed with brine. The organic phase was separated and dried over Na2SO4. Evaporation of the solvent provided 2-[4-(2-cyclopentylpyrazol-3-yl)-3,5-dimethyl-pyrazol-1-yl]acetic acid (40.4 mg, 0.14 mmol, 87% yield) as a yellow oil that crystallized upon standing.MS Method 2: Tr: 1.66 min, ES+ m/z 308.1 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 7.46 ( s, 1H), 6.24 (s, 1H), 4.81 (s, 2H), 4.66-4.69 (m, 1H), 3.50-4.20 (bs, 1H), 2 .39 (s, 3H), 2.37 (s, 3H), 2.13-2.21 (m, 2H), 2.00-2.10 (m, 2H), 1.89-1. 99 (m, 2H), 1.66-1.71 (m, 2H). Example 12: 2-[4-(2-cyclopentylpyrazol-3-yl)-3,5-dimethyl-pyrazol-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide

[00266] A stirred solution of 2-[4-(2-cyclopentylpyrazol-3-yl)-3,5-dimethyl-pyrazol-1-yl]acetic acid (40.4 mg, 0.14 mmol), 5- pyrazin-2-ylpyridin-2-amine (24.13 mg, 0.1400 mmol), propylphosphonic anhydride (0.13 mL, 0.2100 mmol) and N,N-diisopropylethylamine (0.06 mL, 0. 35 mmol) in THF (5 mL) was heated at reflux overnight. LCMS indicated complete conversion to product. THF was removed in vacuo, then EtOAc and water were added to the mixture and the layers separated. The organic layer was washed with water, then brine, dried, then concentrated in vacuo to give a yellow gum, which was purified by LC (50-100% EtOAc in heptane) to give 2-[4-(2 -cyclopentylpyrazol-3-yl)-3,5-dimethyl-pyrazol-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (5.9 mg, 0.01 mmol, 10% production).MS Method 2: Tr: 1.62 min, ES+ m/z 433.3 [M+H]+ 1H NMR (400 MHz, DMSO) δ/ppm: 11.03 (s, 1H), 9 .31-9.33 (d, J = 1.4 Hz, 1H), 9.13-9.14 (d, J = 1.8 Hz, 1H), 8.71-8.75 (m, 1H ), 8.62-8.43 (d, J = 1Hz, 1H), 8.53-8.57 (dd, J = 2.4, 8.7 Hz, 1H), 8.17-8.20 (d, J = 8.7 Hz, 1H), 7.75-7.78 (d, J = 2.24 Hz, 1H), 6.28-6.29 (d, J = 2.4 Hz, 1H), 5.06 (s, 2H), 4.66-4.75 (q, J = 6.7 Hz, 1H), 2.38 (s, 3H), 2.24 (s, 3H), 1.91-2.13 (m, 4H), 1.77-1.83 (m, 2H), 1.62-1.69 (m, 2H). Example 13

[00267] Other examples were prepared following General Scheme 4 by varying the substitution on the pyrazole boronate ester and the aryl halide. The biaryl alpha-chloroacetamide A synthesis method was used to prepare the coupling partner for the final step, varying the aryl alide and/or arylboronate used. General Scheme 5 Intermediate 24: 4-iodo-3,5-dimethyl-1-tetrahydropyran-2-yl-pyrazole

[00268] To a solution of 3,5-dimethyl-4-iodo-1H-pyrazole (1.69 g, 7.61 mmols) in DCM (25 mL) was added 3,4-dihydro-2H-pyran (1.04 mL, 11.4 mmols) and pyridinium p-toluenesulfonate (383 mg, 1.52 mmol). The reaction was stirred at 40°C overnight and then for 4 days at room temperature. The mixture was diluted with DCM (50 ml), washed with saturated aqueous NaHCO3 (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (40 g SiO2, 0-30% EtOAc in heptane) to provide 4-iodo-3,5-dimethyl-1-tetrahydropyran-2-yl-pyrazole (2, 36 g, 7.7 mmols, 101.19% yield) as a white solid.

[00269] MS Method 2: Tr: 1.78 min, ES+ m/z 307.0 [M+H]+

[00270] 1H NMR (400 MHz, CDCl3) δ/ppm: 5.23-5.26 (d, J = 10.4 Hz, 1H), 4.05-4.08 (m, 1H), 3, 62-3.69 (m, 1H), 2.39-2.49 (m, 1H), 2.35 (s, 3H), 2.25 (s, 3H), 2.09-2.14 ( m, 1H). 1.88-1.94 (m, 1H), 1.64-1.79 (m, 3H). Intermediate 25: 4-(3,6-dihydro-2H-pyran-4-yl)-3 ,5-dimethyl-1-tetrahydropyran-2-yl-pyrazole

[00271] A vial was charged with 4-iodo-3,5-dimethyl-1-tetrahydropyran-2-yl-pyrazole (1.3 g, 4.25 mmols), cesium carbonate (4.15 g, 12.7 mmols) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (1.78 g, 8.49 mmols) which were seized in DMF (18.7 mL). The resulting solution was then degassed by evacuation and charged again with nitrogen (repeated twice).

[00272] [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (347 mg, 0.42 mmol) was then added, the system evacuated and charged with nitrogen once more , then the reaction mixture heated to 80°C for 4 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3, then brine, dried over sodium sulfate, filtered and concentrated to dryness, yielding a thick brown oil. This was purified by column chromatography (80 g SiO2, eluting with 2060% EtOAc in heptane). The product-containing fractions were combined and concentrated to dryness, yielding 4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-1-tetrahydropyran-2-yl-pyrazole (200 mg, 0.76 mmol, 18% yield) as a yellow oil.MS Method 2: Tr: 1.46 min, ES+ m/z 263.5 [M+H]+ 1H NMR (400 MHz, CDCl3 ) δ/ppm: 5.51-5.58 (m, 1H), 5.15-5.19 (dd, J = 2.4, 10.4 Hz, 1H), 4.26-4.30 ( q, J = 2.7 Hz, 2H), 4.04-4.10 (m, 1H), 3.85-3.90 (t, J = 5.4 Hz, 2H), 3.60-3 .68 (dt, J = 2.4, 11.6 Hz, 1H), 2.42- 2.54 (m, 1H), 2.26-2.31 (m, 2H), 2.24 (s , 3H), 2.20 (s, 3H), 2.05-2.12 (m, 1H), 1.89-1.94 (m, 1H), 1.62-1.76 (m, 2H ), 1.25-1.29 (m, 1H). Intermediate 26: 3,5-dimethyl-1-tetrahydropyran-2-yl-4-tetrahydropyran-4-yl-pyrazole

[00273] To a round base flask was added 4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-1-tetrahydropyran-2-yl-pyrazole (100 mg, 0.38 mmol) and methanol (5 mL). The solution was purged and evacuated with nitrogen several times before adding palladium, 10 wt % on wet carbon powder (81 mg, 0.08 mmol) after which the system was again purged and evacuated several times. The reaction vessel was then charged with hydrogen and shaken vigorously overnight. The mixture was filtered through a celite pad, washed with MeOH and dried, yielding 3,5-dimethyl-1-tetrahydropyran-2-yl-4-tetrahydropyran-4-yl-pyrazole (90 mg, 0. 34 mmol, 90% production) as a colorless oil.MS Method 2: Tr: 1.41 min, ES+ m/z 265.0 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 5 .15-5.19 (dd, J = 2.4, 10.4 Hz, 1H), 4.03-4.11 (m, 3H), 3.60-3.68 (dt, J = 2, 4, 12.5 Hz, 1H), 3.44-3.52 (dt, J = 2.0, 12.5 Hz, 2H), 2.61-2.68 (tt, J = 4.0, 12.5 Hz, 1H), 2.44-2.55 (m, 1H), 2.29 (s, 3H), 2.28 (s, 3H), 2.05-2.12 (m, 1H ), 1.89-2.03 (m, 3H), 1.52-1.79 (m, 5H). Intermediate 27: 4-(3,6-dihydro-2H-pyran-4-yl) -3,5-dimethyl-1H-pyrazole

[00274] To a round base flask was added 4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-1-tetrahydropyran-2-yl-pyrazole (505 mg, 1.92 mmol) and 4 M hydrogen chloride in dioxane (4.81 mL, 19.3 mmols) was added dropwise. The reaction was stirred at room temperature over the weekend. The pH was adjusted to basic by addition of saturated NaHCO3. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated, yielding a yellow oil. The resulting residue was loaded onto a methanol-enhanced SCX cartridge and eluted with methanol (3 CV) and 1 M ammonia in methanol (3 CV). The ammonia stream was then concentrated providing 4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-1H-pyrazole (280 mg, 1.57 mmol, 82% production) as a colorless oil.MS Method 2: Tr: 0.96 min, ES+ m/z 179.0 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 5.55-5.62 (m, 1H), 4.27-4.31 (q, J = 2.7 Hz, 2H), 3.87-3.92 (t, J = 5.4 Hz, 2H), 2.30- 2.36 (m, 2H), 2.52 (s, 6H). Intermediate 28: 4-tetrahydropyran-4-yl-1H-pyrazole

[00275] 1-Tetrahydropyran-2-yl-4-tetrahydropyran-4-yl-pyrazole (120 mg, 0.51 mmol) was dissolved in 1,4-dioxane (2 mL) and 4 M HCl in dioxane (1.27 mL, 5.09 mmols) was added dropwise. The reaction was stirred at room temperature overnight. The pH was adjusted to basic by addition of saturated NaHCO3. The organic layer was extracted with EtOAc, separated, washed with brine, dried over sodium sulfate and evaporated, yielding 4-tetrahydropyran-4-yl-1H-pyrazole (72.8 mg, 0.47 mmol, 94% production) as a white solid that was used without further purification.MS Method 2: Tr: 0.88 min, ES+ m/z 181.0 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm : 4.04-4.12 (m, 2H), 3.46-3.56 (m, 2H), 2.63-2.72 (tt, J = 3.8, 12.5 Hz, 1H) , 2.29 (s, 6H), 1.90-2.01 (m, 2H), 1.51-1.63 (m, 3H). Intermediate 29: acid 2-[4-(3,6- dihydro-2H-pyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]acetic acid

[00276] Following the step two procedure described for alkylation and hydrolysis of intermediate 23 in General Scheme 4, acid 2-[4-(3,6-dihydro-2H-pyran-4-yl)-3,5- dimethyl-pyrazol-1-yl]acetic acid was prepared. MS Method 2: Tr: 1.06 min, ES+ m/z 237.0 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 5.57-5.63 (m, 1H), 4 .77 (s, 2H), 4.274.30 (m, 2H), 3.86-3.92 (m, 2H), 2.90-3.50 (bs, 1H), 2.26-2.33 (m, 2H), 2.22 (s, 3H), 2.20 (s, 3H). Intermediate 30: 2-[4-(3,6-dihydro-2H-pyran-4-yl)- Ethyl 3,5-dimethyl-pyrazol-1-yl]propanoate

[00277] A vial was charged with 4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-1H-pyrazole (150 mg, 0.84 mmol), 2-bromopropionate of ethyl (0.16 mL, 1.26 mmol) and potassium carbonate (345 mg, 2.52 mmols) which were suspended in MeCN (5 mL). The flask was then heated to reflux and allowed to stir overnight. After this time, a TLC analysis showed SM left, so ethyl 2-bromopropionate (0.16 mL, 1.26 mmol) was added again and the reaction was stirred for a further 24 hours. The precipitated solid was filtered and washed with EtOAc. The filtrate was evaporated to dryness, yielding a yellow oil which was purified by flash column chromatography (12 g, SiO2, 20-100% EtOAc in heptane). Ethyl 2-[4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]propanoate was isolated as a colorless oil (31 mg, 0. 11 mmol, 13% production).1H NMR (400 MHz, CDCl3) δ/ppm: 5.50-5.58 (m, 1H), 4.84-4.88 (q, J = 7.1Hz, 1H), 4.15-4.30 (m, 4H), 3.86-3.92 (m, 2H), 2.29-2.34 (m, 2H), 2.20 (s, 3H) , 2.27 (s, 3H), 1.81-1.82 (d, J = 7.1Hz, 3H), 1.19-1.25 (q, J = 6.2Hz, 3H). Intermediate 31: 2-[4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]propanoic acid

[00278] Ethyl 2-[4-(3,6-Dihydro-2H-pyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]propanoate (31.2 mg, 0.11 mmol) was dissolved in ethanol (5 mL), lithium hydroxide (6.71 mg, 0.28 mmol) in water (0.20 mL) was added and the reaction was stirred at room temperature for 16 h. Evaporation of the solvent provided 2-[4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]propanoic acid. MS Method 2: Tr: 1, 51min, ES+ m/z 251.1 [M+H]+ Intermediate 32: 2-[4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazol-1 acid -yl]acetic

[00279] Following steps i-iv in General Scheme 5, 2-[4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazol-1-yl]acetic acid was prepared starting from 4-iodo-1H-pyrazole and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester.

[00280] MS Method 2: Tr: 1.66 min, ES+ m/z 308.1 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 7.63 (s, 1H), 7, 43 (s, 1H), 5.84-5.95 (bs, 1H), 5.04 (s, 2H), 3.98-4.04 (m, 2H), 3.55-3.63 ( t, J = 6.0 Hz, 2H), 2.34-2.40 (m, 2H), 1.43-1.54 (m, 9H) Example 14: 2-[4-(3.6- dihydro-2H-pyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide

[00281] A stirred solution of 2-[4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]acetic acid (108 mg, 0. 46 mmol), 5-pyrazin-2-ylpyridin-2-amine (103 mg, 0.60 mmol), propylphosphonic anhydride (0.55 mL, 0.92 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) in THF (5 mL) was heated to reflux and stirred for two hours. The THF was removed in vacuum to give a yellow gum, which was purified by flash column chromatography (12 g SiO2, 50-100% EtOAc in heptane) to give 2-[4-(3,6-dihydro -2H-pyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (45 mg, 0.12 mmol, 25% production) as a colorless solid.MS Method 2: Tr: 1.34 min, ES+ m/z 391.2 [M+H]+ 1H NMR (400 MHz, DMSO) δ/ppm: 11.05 (s, 1H), 9.30-9.34 (d, J = 1.4 Hz, 1H), 9.12-9.14 (d, J = 1.9 Hz, 1H), 8.72-8.74 (m, 1H), 8.63-8.65 (d, J = 2.4 Hz, 1H), 8.53-8.57 (dd, J = 2.4, 8.7 Hz, 1H), 8.16-8.20 (d, J = 8.8 Hz, 1H), 5.57 (s, 1H), 5.00 (s, 2H), 4.17-4.21 (m, 2H) , 3.77-3.82 (t, J = 5.6 Hz, 2H), 2.24-2.39 (m, 2H), 2.18 (s, 3H), 2.09 (s, 3H ).Example 15: 2-[4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]-N-(5-pyrazin-2- yl-2-pyridyl)propanamide

[00282] A stirred solution of lithium 2-[4-(3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]propanoate (29 mg, 0 .11 mmol), 5-pyrazin-2-ylpyridin-2-amine (19 mg, 0.11 mmol), propylphosphonic anhydride (0.13 mL, 0.22 mmol) and N,N-diisopropylethylamine (0. 05 mL, 0.28 mmol) in THF (5 mL) was heated to reflux and stirred for 24 h. After this time, LC-MS showed no conversion to the desired product, so propylphosphonic anhydride (0.26 mL, 0.44 mmol), N,N-diisopropylethylamine (0.1 mL, 0.56 mmol) and 5-Pyrazin-2-ylpyridin-2-amine (19 mg, 0.1100 mmol) was added. The reaction was stirred for an additional 24 h. The THF was removed in vacuum to give a yellow gum, which was purified by flash column chromatography (4 g SiO2, 50-100% EtOAc in heptane), followed by preparative reversed-phase HPLC giving 2-[4-( 3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)propanamide as a white solid (10.3 mg, 0.03 mmol, 22% production). MS Method 1: Tr: 3.28 min, ES+ m/z 405.3 [M+H]+ 1H NMR (400 MHz, DMSO) δ/ppm: 10.77 (s, 1H), 9.29-9 .32 (d, J = 1.4 Hz, 1H), 9.09-9.11 (d, J = 1.9 Hz, 1H), 8.71-8.75 (m, 1H), 8. 62-8.65 (d, J = 2.4 Hz, 1H), 8.53-8.57 (dd, J = 2.4, 8.7 Hz, 1H), 8.19-8.24 ( d, J = 8.8 Hz, 1H), 5.57 (s, 1H), 5.16-5.23 (q, J = 7 Hz 1H), 4.17-4.21 (m, 2H) , 3.76-3.8 (t, J = 5.9 Hz, 2H), 2.22-2.37 (m, 2H), 2.21 (s, 3H), 2.12 (s, 3H ), 1.63-1.67 (d, J = 7 Hz, 3H). Example 16: 4-[1-[2-oxo-2-[(5-pyrazin-2-yl-2-pyridyl)amino]ethyl]pyrazol-4-yl]-3,6-dihydro-2H- tert-butyl pyridine-1-carboxylate

[00283] Intermediate 32 was subjected to coupling according to step v) of General Scheme 5 to form 4-[1-[2-oxo-2-[(5-pyrazin-2-yl-2-pyridyl)amino]ethyl tert-butyl]pyrazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate.MS Method 1: Tr: 3.68 min, ES+ m/z 462.3 [M+H ]+ 1H NMR (400 MHz, DMSO) δ/ppm: 11.06 (s, 1H), 9.31-9.32 (d, J = 1.3 Hz, 1H), 9.11-9.14 (d, J = 2.2 Hz, 1H), 8.71-8.74 (m, 1H), 8.63-8.65 (d, J = 2.5 Hz, 1H), 8.52- 8.57 (1H, dd, J = 2.4, 8.8 Hz, 1H), 8.15-8.21 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H) , 7.66 (s, 1H), 5,945.99 (bs, 1H), 5.11 (s, 2H), 3.92-3.98 (bs, 2H), 3.49-3.54 (t , J = 5.6 Hz, 2H), 2.30-2.37 (m,2H), 1.42 (s, 9H).Example 17

[00284] In a similar way, the following examples were also prepared. Example 18: 2-[3,5-dimethyl-4-(1,2,3,6-tetrahydropyridin-4-yl)pyrazol-1-yl]-N-(5-pyrazin-2-yl-2 -pyridyl)acetamide

[00285] 4-[3,5-dimethyl-1-[2-oxo-2-[(5-pyrazin-2-yl-2-pyridyl)amino]ethyl]pyrazol-4-yl]-3,6- tert-butyl dihydro-2H-pyridine-1-carboxylate (37.2 mg, 0.08 mmol) was dissolved in DCM (5 mL) and trifluoroacetic acid (0.58 mL, 7.6 mmols) was added dropwise. The reaction was stirred at room temperature for one hour. The mixture was washed with saturated NaHCO3 and brine.

[00286] The organic layer was dried over sodium sulfate and evaporated in vacuum, providing a pale yellow solid analyzed as 2-[3,5-dimethyl-4-(1,2,3,6-tetrahydropyridin-4- yl)pyrazol-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (6 mg, 0.01 mmol, 20% yield).MS Method 1: Tr: 2.07 min , ES+ m/z 390.1 [M+H]+

[00287] 1H NMR (400 MHz, DMSO) δ/ppm: 11.05 (s, 1H), 9.31-9.34 (d, J = 1.4 Hz, 1H), 9.10-9, 14 (d, J = 1.9 Hz, 1H), 8.72-8.75 (m, 1H), 8.63-8.65 (d, J = 2.5 Hz, 1H), 8.52 -8.56 (m, 1H), 8.15-8.21 (m, 1H), 5.52 (bs, 1H), 4.99 (s, 2H), 3.37-3.40 (m , 2H), 2.91-2.97 (m, 2H), 2.15-2.22 (m, 5H), 2.08 (s, 3H). Intermediate 33: (2,6-dimethyl-3 ,6-dihydro-2H-pyran-4-yl)trifluoromethanesulfonate

[00288] To a round-base flask that had been dried in the vacuum oven overnight was added 2,6-dimethyltetrahydropyran-4-one (830 mg, 6.48 mmols) in THF (20 ml). The solution was cooled to -78°C and 1.0 M lithium bis(trimethylsilyl)amide solution in THF (9.07 mL, 9.07 mmols) was added dropwise. The solution was allowed to stir for one hour at -78°C before addition of N-phenyl bis-trifluoromethane sulfonimide (2776 mg, 7.77 mmol) in THF (5 ml). The reaction formed a cream suspension and was then allowed to rise to room temperature for 4 hours after which an orange solution formed. TLC analysis (5% EtOAc in heptane) showed no remaining 2,6 dimethyltetrahydropyranone and a new site. The reaction was diluted with EtOAc and quenched with 1 M HCl. The phases were separated and the organic layer was then washed with 1 M NaOH. The organic layer was dried over sodium sulfate, filtered and concentrated and columnated over silica. gel (0-15% EtOAc in heptane) to provide (2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl) trifluoromethanesulfonate (1.1 g, 4.13 mmols, 64 % production) as a clear liquid and a mixture of stereoisomers. 1H NMR (400 MHz, CDCl3) δ/ppm: 5.69-5.71 (m, 1H), 4.31-4.39 (m, 1H), 3.73-3.82 (m, 1H) , 2.19-2.38 (m, 2H), 1.31-1.33 (d, J = 3.6Hz, 3H), 1.29-1.31 (d, J = 4.1Hz, 3H) Intermediate 34: 4-(2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-1H-pyrazole

[00289] 2,6-Dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate) (1075 mg, 4.13 mmols) and 3,5-dimethyl-4-(4,4, Tert-butyl 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-carboxylate (1464.15 mg, 4.54 mmol) was dissolved in 1,4-dioxane (9 mL) before adding tribasic potassium phosphate (1315 mg, 6.2 mmols) in water (2 mL) and degassing by bubbling N2 through the mixture for 10 minutes. Tricyclohexylphosphine (58 mg, 0.21 mmol) and tris(dibenzylideneacetone)dipalladium (0) (95 mg, 0.10 mmol) were added, degassing continued for a further 2 minutes before thermally heating to 100°C (external pressure ) for 18 hours. The reaction was cooled and then the dioxane was removed in vacuum. The mixture was then partitioned between water and EtOAc. The organic layer was washed with water several times, then dried over sodium sulfate, filtered and concentrated. The resulting residue was then loaded onto a methanol-enhanced SCX cartridge. The column was eluted with methanol (3 CV) and 1 M ammonia in methanol (3 CV). The ammonia stream was concentrated to provide 4-(2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-1H-pyrazole (854 mg, 4.14 mmols, 100% production) as a mixture of stereoisomers.MS Method 2: Tr: 1.66 min, ES+ m/z 391.3 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 5 .46-5.48 (m, 1H), 4.35-4.43 (m, 1H), 3.76-3.85 (m, 1H), 2.25 (s, 6H), 2.05 -2.22 (m, 2H), 1.28-1.32 (m, 6H).Example 19: 2-[4-(2,6-dimethyltetrahydropyran-4-yl)-3,5-dimethyl -pyrazin-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide

[00290] Using steps 3-5 of General Scheme 5, 2-[4-(2,6-dimethyltetrahydropyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]-N-(5 -pyrazin-2-yl-2-pyridyl)acetamide was prepared.MS Method 1: Tr: 3.41 min, ES+ m/z 419.3 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm : 9.00-9.02 (d, J = 1.5Hz, 1H), 8.918.93 (m, 1H), 8.79-8.82 (bs, 1H), 8.63-8.65 (m, 1H), 8.53-8.56 (d, J = 2.5 Hz, 1H), 8.34-8.37 (m, 2H), 5.48-5.51 (m, 1H ), 4.84 (s, 2H), 4.35-4.43 (m, 1H), 3.77-3.85 (m, 1H), 2.29 (s, 3H), 2.24 ( s, 3H), 2.16-2.23 (m, 1H), 2.04-2.11 (m, 1H), 1.31-1.34 (d, J = 2.8 Hz, 3H) , 1.28-1.31 (d, J = 2.3 Hz, 3H). Intermediate 35: 2-[4-(2,6-dimethyltetrahydropyran-4-yl)-3,5-dimethyl-acid pyrazol-1-yl]acetic acid

[00291] To a round-base flask, 2-[4-(2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-3,5-dimethyl-pyrazol-1- ethyl yl]acetate (340 mg, 1.16 mmol) and methanol (2 mL). The solution was purged and evacuated with nitrogen several times before adding palladium, 10 wt% on carbon, wet (618 mg, 0.58 mmol), after which the system was again purged and evacuated several times. The reaction vessel was then charged with hydrogen and shaken vigorously overnight. The reaction was flooded with nitrogen and filtered through a celite pad and washed with methanol. Methanol was concentrated to give the reduced product, to which water (0.58 mL), ethanol (3 mL) and lithium hydroxide monohydrate (44 mg, 1.05 mmol) were added. The reaction was stirred for 30 minutes at room temperature. The ethanol was removed by vacuum concentration, the aqueous layer was then acidified to pH3 with 1 M HCl. The aqueous layer was then extracted 3 times with EtOAc. The organic layers were combined, dried over sodium sulfate, filtered and then concentrated to provide 2-[4-(2,6-dimethyltetrahydropyran-4-yl)-3,5-dimethyl-pyrazol-1-yl acid ]acetic acid (168 mg, 0.63 mmol, 60% yield) as a white solid. MS Method 2: Tr: 1.26 min, ES+ m/z 267.2 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 4.80 (s, 2H), 4.00-4 .60 (bs, 1H), 3.50-3.53 (m, 2H), 2.59-2.62 (m, 1H), 2.20 (s, 3H), 2.05 (s, 3H ), 1.39-1.60 (m, 4H), 1.23-1.26 (m, 6H). Example 20: 2-[4-(2,6-dimethyltetrahydropyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl) acetamide

[00292] A stirred solution of 2-[4-(2,6-dimethyltetrahydropyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]acetic acid (50 mg, 0.19 mmol), 5-pyrazin-2-ylpyridin-2-amine (39 mg, 0.23 mmol), propylphosphonic anhydride (0.22 mL, 0.38 mmol) and N,N-diisopropylethylamine (0.08 mL, 0. 47 mmol) in THF (2 mL) was heated to reflux and stirred overnight at 80°C. The THF was removed in vacuum to give a yellow gum which was purified by silica gel column chromatography using 0-100% EtOAc in heptane, then 0-10% MeOH in EtOAc. The fractions containing the product were combined and concentrated. The residue was columnated again (0-3% MeOH in EtOAc) and also purified by preparative LCMS. The cleaned fractions were concentrated to give 2-[4-(2,6-dimethyltetrahydropyran-4-yl)-3,5-dimethyl-pyrazol-1-yl]-N-(5-pyrazin-2-yl- 2-pyridyl)acetamide (16 mg, 0.04 mmol, 20% yield) as a white solid.MS Method 1: Tr: 3.35 min, ES+ m/z 421.3 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 9.01-9.03 (d, J = 1.6 Hz, 1H), 8.938.95 (m, 1H), 8.74-8.78 (bs, 1H ), 8.65-8.72 (m, 1H), 8.55-8.57 (d, J = 2.5 Hz, 1H), 8.36-8.39 (m, 2H), 4, 84 (s, 2H), 3.54-3.64 (m, 2H), 2.71-2.80 (dt, J = 2.1, 6.0 Hz, 1H), 2.35 (s, 3H), 2.28 (s, 3H), 1.48-1.68 (m, 4H), 1.25-1.29 (d, J = 6.2 Hz, 6H).Example 21

[00293] The following dihydropyrans were prepared in a manner analogous to example 19, tetrahydropyrans were prepared in an analogous manner to example 20. General Scheme 6

[00294] Other compounds of the invention can be prepared by analogy with the following routine: Intermediate 36: 2-(5-bromo-2-thienyl)-N-(5-chloro-2-pyridyl)acetamide

[00295] A vial was charged with 2-(5-bromo-2-thienyl)acetic acid (300 mg, 1.36 mmol) and 5-chlor-2-pyridinamine (174 mg, 1.36 mmol), which were taken up in DMF (5 mL) and N,N-diisopropylethylamine (0.47 mL, 2.71 mmols) was added. The solution was stirred and HATU (567 mg, 1.49 mmol) was added. The resulting solution was allowed to stir overnight. The reaction mixture was diluted with water and partitioned with EtOAc. Separation was difficult, so some saline was added to aid. The phases were then separated and the organic layer was washed with a 1:1 mixture of brine and water (x2). The aqueous washes were then combined and extracted once with EtOAc. The organics were then combined, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness, yielding a brown oil. Purification by flash column chromatography was performed (25 g SiO2, eluting with 0-50% EtOAc in heptane). The product-containing fractions were combined and concentrated to dryness, yielding 2-(5-bromo-2-thienyl)-N-(5-chloro-2-pyridyl)acetamide (104 mg, 0.31 mmol, 23.11 % production) as a brown crystalline solid. MS Method 2: Tr: 1.83 min, ES+ m/z 332.8 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 8.10-8.15 (m, 2H), 7 .82-7.91 (bs, 1H), 7.58-7.63 (dd, J = 9.0, 2.9 Hz, 1H), 6.90-6.92 (d, J = 3, 8 Hz, 1H), 6.71-6.73, (dt, J = 3.8, 0.9 Hz, 1H), 3.81 (s, 2H). Intermediate 37: N-(5-chloro-2-pyridyl)-2-[5-(2-methyl-4-pyridyl)-2-thienyl]acetamide

[00296] A vial was charged with 2-(5-bromo-2-thienyl)-N-(5-chloro-2-pyridyl)acetamide (100 mg, 0.30 mmol), 1,4-dioxane (2 mL ) and water (1 mL). The resulting solution was then degassed under vacuum and the system was again charged with nitrogen. This was repeated twice before adding [1,1_apos_-bis(diphenylphosphine)ferrocene]palladium(II) chloride dichloromethane complex (24 mg, 0.03 mmol). Then, the system was purged with nitrogen again and the reaction mixture heated to 85°C for one hour thermally. The reaction mixture was concentrated to dryness and the solid purified by flash column chromatography, (12 g SiO2, eluting with 20-100% EtOAc in heptane). The product-containing fractions were combined and concentrated to dryness, yielding N-(5-chloro-2-pyridyl)-2-[5-(2-methyl-4-pyridyl)-2-thienyl]acetamide (75 mg, 0.22 mmol, 72.33% production) as a yellow solid. MS Method 2: Tr: 1.27 min, ES+ m/z 344.0 [M+H]+ 1H NMR (400 MHz, CDCl3) δ/ppm: 8.39-8.43 (d, J = 5, 6 Hz, 1H), 8.12-8.16 (d, J = 9.0 Hz, 1H), 8.11-8.13 (d, J = 2.6 Hz, 1H), 7,917.95 ( bs, 1H), 7.59-7.62 (dd, J = 9.0, 2.6 Hz, 1H), 7.32-7.34 (d, J = 3.7 Hz, 1H), 7 .23-7.25 (m, 1H), 7.17-7.21 (m, 1H), 6.96-6.98 (1H, d, J = 3.7 Hz, 1H), 3.91 (s, 2H), 2.53 (s, 3H).Example 22: 2-[5-(2-methyl-4-pyridyl)-2-thienyl]-N-(5-pyrazin-2-yl-2 -pyridyl)acetamide

[00297] A vial was charged with N-(5-chloro-2-pyridyl)-2-[5-(2-methyl-4-pyridyl)-2-thienyl]acetamide (70 mg, 0.20 mmol), bis(pinacolato)diboron (56 mg, 0.22 mmol), tris(dibenzylideneacetone)dipalladium (0) (9 mg, 0.01 mmol) which were then added to the solution, the system flooded with nitrogen again and the reaction heated to 110°C for two hours. The reaction mixture was diluted with EtOAc and filtered through a fine celite pad, eluting with EtOAc. The filtrate was then concentrated to dryness, yielding 2-[5-(2-methyl-4-pyridyl)-2-thienyl]-N-[5-(4,4,5,5-tetramethyl-1,3 Raw ,2-dioxaborolan-2-yl)-2-pyridyl]acetamide (130 mg, 0.2986 mmol, 146% yield) as a red/orange oil was immediately taken over the final Suzuki reaction without purification.

[00298] Iodopyrazine (85 mg, 0.41 mmol) and sodium carbonate (87 mg, 0.83 mmol). This was taken up in toluene (1.6 ml), ethanol (0.40 ml) and water (0.40 ml). The resulting solution was then degassed through evacuation and the system was again charged with nitrogen (x3). Tetracis(triphenylphosphine)palladium(0) (31.85 mg, 0.03 mmol) was then added to the solution, the system evacuated and charged with nitrogen again, and the solution heated to 85°C for two hours. The reaction was concentrated to dryness and purified by flash column chromatography (12 g SiO2 eluting with 50-100% EtOAc with 2% triethylamine in heptane). The product-containing fractions were combined and concentrated to dryness, providing a light orange solid. The compound was also purified by preparative LCMS, which provided 2-[5-(2-methyl-4-pyridyl)-2-thienyl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (7 mg , 0.018 mmol, 6.5% yield) as an off-white solid. MS Method 2: Tr: 1.13 min, ES+ m/z 388.1 [M+H]+ 1H NMR (400 MHz, DMSO) δ/ppm: 11.09 (s, 1H), 9.31.9 .33 (d, J = 1.3Hz, 1H), 9.11-9.13 (d, J = 2.1Hz, 1H), 8.72-8.74 (m, 1H), 8,638.65 (d, J = 2.6 Hz, 1H), 8.52-8.56 (dd, J = 8.7, 2.4 Hz, 1H), 8.408.43 (d, J = 5.5 Hz, 1H), 8.22-8.26 (d, J = 9.2 Hz, 1H), 7.63-7.65 (d, J = 3.7 Hz, 1H), 7.48 (s, 1H ), 7.39-7.42, (m, 1H), 7.08-7.10 (d, J = 3.5 Hz, 1H), 4.10 (s, 2H), 2.51 (s , 3H).Example 23

[00299] The following compounds were prepared in an analogous manner using appropriately substituted thiophenes, aryl/vinyl boronates and aryl halides.

Dual-cell β-catenin reporter assay

[00300] Mouse L cells transfected to constitutively produce biologically active murine Wnt-3a, referred to as L-Wnt cells, were purchased from the American Type Culture Collection, ATCC, Manassas, VA (ATCC). These cells were cultured in DMEM supplemented with 10% FCS (Gibco/Invitrogen, Carlsbad, CA), 1% geneticin, and 1% sodium pyruvate (Sigma) at 37°C with 5% CO2. Cells were seeded in 96-well plates and treated with serial dilutions of compound diluted in 0.1% DMSO concentration. After 24 hours, cell supernatants were transferred to a 96-well plate previously seeded with WnT Leading Light® Reporter Cells, stably transfected with a luciferase gene under control of W track response elements. After an additional 24 hours, the cells are treated with One-glo luciferase assay system (Promega, Madison, WI) and the luminescent signal read by Envision. The IC50 of the compound is determined as the concentration that reduces the induced luciferase signal to 50% of the DMSO control.

[00301] Assay results for certain compounds of the invention are provided below. The table shows the IC50 value of the compound categorized as "+", "", "++" and "+++". The "+" category refers to compounds with an IC50 of >100 μM. The "++" category refers to compounds with an IC50 of 5 to 100 μM. The "+++" category refers to compounds with an IC50 <5 μM.

Specificity Immunoprecipitation

[00302] L-Wnt cells can be evaluated by treatment with alkanyl-palmitate and various concentrations of compound. After 24 hours, cell lysates can be washed in PBS (SOURCE) and collected in chilled lysis buffer (LYS BUFFER). Dynabeads (SOURCE) can be incubated with anti-wnt-3a antibody (Abcam) for 20 minutes and incubated with lysates for one hour. The beads can be isolated by magnet and the loose fraction retained. Click chemistry can be performed on samples using Click-iT® protein buffer kit (Life technologies), following the protocol provided, to conjugate biotin to alkanyl palmitate. The elutes can be separated from the samples by magnet and the resulting samples boiled for 20 minutes to dissociate the conjugates. The beads can be removed and the elutes and loose fraction can be run by polyacrylamide gel electrophoresis, transferred to a membrane and stained for biotin using streptavidin-horseradish peroxidase and for total Wnt by specific antibody.

Cell death assay

[00303] Cells in development medium (DMEM, 10% FCS) can be treated with a serial dilution of compound diluted in 0.1% DMSO for 72 hours. Viable cell number was measured by the ability to reduce resazurin to resorufin which was detected by fluorescence emission at 590 nm.

Focus formation test

[00304] Capan-2 cells can be seeded onto standard development medium 6-well plates and treated with serial dilutions of compound. The cell medium was changed every four days with fresh compound added. After ten days of development, cells can be fixed in methanol and treated with crystal violet to visualize. The area recovered by cell colonies was detected by Operetta and analyzed using Columbus software.

Claims (21)

1. Compound, characterized by the fact that it has formula (III), or a pharmaceutically acceptable salt thereof: where: X1 and X2 are selected from CR6 and N, provided that X1 and X2 are not both CR6; and het2 is a ring selected from: pyrazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, thiazole, isothiazole, triazole, oxazole, isoxazole, dihydropyridine, tetrahydropyridine, pyran, tetrahydropyran, dihydropyran, piperidine, piperazine, morpholine, thiomorpholine, oxazine, dioxin, dioxane, thiazine, oxathian and dithiane which may be unsubstituted or substituted, wherein when substituted, the ring is replaced with 1, 2 or 3 groups independently selected at each occurrence from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA1, -NRA1RB1, -CN, -C(O)ORA1 and C3-6 cycloalkyl; het3 is a ring selected from: phenyl, pyrazole, pyridine, dihydropyran, pyrimidine, pyrazine, pyridazine, piperazine, dioxin, dioxane, morpholine and thiomorpholine which can be unsubstituted or substituted and when substituted the ring is substituted with 1, 2 or 3 groups independently selected at each occurrence from: fluorine, chlorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, -OCF3, -C(O)Me, - C(O)OMe, -C(O)Et, -C (O)OtBu, -OMe, -CN, -NMe2 or -NHC(O)Me; R1 and R2 are independently selected at each occurrence from: H, chlorine, fluorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, -OCF3, -OH, -OMe, -OEt, -NH2, -NHMe and -NMe2; R3 is selected from: H and C1-4 alkyl; R4 is independently selected at each occurrence from: chlorine, fluorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, -OCF3, -OH, -OMe, -OEt, -NH2, -NHMe, -NMe2 and CN; R5 and R6 are, at each occurrence, independently selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl; m is 1; n is selected from 0 or 1; and RA1, RB1, RA4 and RB4 are, at each occurrence, independently selected from: H, methyl and ethyl. 2. Compound according to claim 1, characterized in that het2 represents a ring selected from unsubstituted or substituted: pyrazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, pyran, tetrahydropyran, dihydropyran, piperidine, piperazine, morpholine , thiomorpholine, oxazine, dioxin, dioxane, thiazine, oxatian and dithiane. 3. Compound according to claim 1 or 2, characterized in that het3 represents a ring selected from unsubstituted or substituted: pyrimidine, pyrazine, pyridazine, piperazine, dioxin, dioxane, morpholine and thiomorpholine. 4. Compound according to any one of claims 1 to 3, characterized by the fact that R3 is H or methyl. 5. Compound according to any one of claims 1 to 4, characterized by the fact that R4 is independently selected at each occurrence of: H, chlorine, fluorine, methyl, ethyl, trifluoromethyl, trifluoroethyl, -OCF3, -OH, - OMe, -OEt, -NH2, -NHMe, and -NMe2. 6. Compound according to claim 1, characterized in that the compound is selected from: 7. Compound according to any one of claims 1 to 6, characterized in that it is for use as a medicine. 8. Compound according to any one of claims 1 to 6, characterized in that it is for use in modulating Wnt signaling. 9. Compound according to any one of claims 1 to 6, characterized in that it is for use in the treatment of a condition that can be modulated by Porcn inhibition. 10. Compound for use according to claim 9, characterized by the fact that the condition treatable by Porcn inhibition can be selected from: cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, and leukemia. 11. Compound, according to claim 9 or 10, characterized by the fact that the condition is selected from: esophageal squamous cell carcinoma, gastric cancer, glioblastomas, astrocytomas; retinoblastoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, Wilm's tumor, basal cell carcinoma, non-small cell lung cancer, brain tumor, hormone-refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer breast, metastatic pancreatic cancer, pancreatic cancer, colorectal cancer, cervical cancer, head and neck squamous cell carcinoma, and head and neck cancer. 12. Compound, according to claim 9 or 10, characterized by the fact that the condition is selected from: skin fibrosis, idiopathic pulmonary fibrosis, renal interstitial fibrosis, liver fibrosis, proteinuria, renal graft rejection, osteoarthritis, liver disease. Parkinson's, cystoid macular edema, cystoid macular edema associated with uveitis, retinopathy, diabetic retinopathy and retinopathy of prematurity. 13. Compound according to any one of claims 1 to 6, characterized in that it is for use in the treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, and leukemia. 14. Compound, according to claim 13, characterized by the fact that the condition is selected from: esophageal squamous cell carcinoma, gastric cancer, glioblastomas, astrocytomas; retinoblastoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, Wilm's tumor, basal cell carcinoma, non-small cell lung cancer, brain tumor, hormone-refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer breast, metastatic pancreatic cancer, pancreatic cancer, colorectal cancer, cervical cancer, head and neck squamous cell carcinoma, and head and neck cancer. 15. Compound according to claim 13, characterized by the fact that the condition is selected from: skin fibrosis, idiopathic pulmonary fibrosis, renal interstitial fibrosis, liver fibrosis, proteinuria, renal graft rejection, osteoarthritis, Parkinson's disease , cystoid macular edema, cystoid macular edema associated with uveitis, retinopathy, diabetic retinopathy and retinopathy of prematurity. 16. Use of a compound as defined in any one of claims 1 to 6, characterized in that it is for the manufacture of a medicament for the treatment of a condition that is modulated by Porcn. 17. Use of a compound as defined in any one of claims 1 to 6, characterized in that it is for the manufacture of a medicament for the treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, tumors hematological, lymphoma, carcinoma, and leukemia. 18. Use according to claim 17, characterized in that the condition is selected from: esophageal squamous cell carcinoma, gastric cancer, glioblastomas, astrocytomas; retinoblastoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, Wilm's tumor, basal cell carcinoma, non-small cell lung cancer, brain tumor, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer breast, metastatic pancreatic cancer, pancreatic cancer, colorectal cancer, cervical cancer, head and neck squamous cell carcinoma, and head and neck cancer. 19. Use according to claim 17, characterized in that the condition is selected from: skin fibrosis, idiopathic pulmonary fibrosis, renal interstitial fibrosis, liver fibrosis, proteinuria, renal graft rejection, osteoarthritis, Parkinson's disease, cystoid macular edema, cystoid macular edema associated with uveitis, retinopathy, diabetic retinopathy and retinopathy of prematurity. 20. Pharmaceutical formulation, characterized in that it comprises a compound, as defined in any one of claims 1 to 6, and a pharmaceutically acceptable excipient. 21. Pharmaceutical composition according to claim 19, characterized in that it is a combination product comprising an additional pharmaceutically active agent.