JP2017095498A - Wnt SIGNALING INHIBITOR, COMPOSITION, AND COMPOUND AS USE THEREFOR - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an inhibitor for Wnt signaling route.SOLUTION: The present invention provides a compound represented by formula I, and a composition comprising the compound (X-Xindependently represent CRor N; Yis H or C (R); Yand Yindependently represent H, halogen or C (R); Rand Rindependently represent H, halogen, Calkyl, quinolinyl or the like; Rs independently represent H, halogen, cyano, Calkyl or the like; Rs independently represent H, halogen, cyano, Calkoxy or the like).SELECTED DRAWING: None

Description

  The present invention relates to compounds as inhibitors of the Wnt signaling pathway and compositions comprising the same. Furthermore, the present invention relates to the use of compounds and methods for inhibiting the Wnt signaling pathway.

  Wnt signaling is important for embryogenesis and homeostasis in adult animals. The Wnt pathway is generally involved in a network of proteins that regulate the following processes: 1, production and secretion of Wnt proteins; 2, binding of cellular receptors to Wnt; and 3, of biochemical responses triggered by interactions Intracellular transduction, (Mikels and Nusse, 2006; Macdonald, 2009; Moon, 2005).

  The so-called canonical Wnt pathway triggered by the binding of the Wnt protein to the cell surface co-receptor Frizzled LRP5 / 6 results in a change in the amount of β-catenin reaching the nucleus, which interacts with TCF / LEF family transcription factors. Acts to promote transcription of specific genes.

  Non-canonical Wnt pathways transmitted by different sets of intracellular proteins control several processes such as planar cell polarity in insects and gastrulation in vertebrates.

  Wnt signaling is also known for its role in regulating pluripotency and differentiation of embryonic and adult stem cells (Nusse, 2008). For example, streak formation during gastrulation was associated with localized Wnt activation in the embryoid body (ten Berge, 2008). Induction of numerous cell types such as heart cells, pancreatic β cells, dopminergic neurons and liver hepatocytes from embryonic stem cells or iPS cells is affected by Wnt modulation (Yang, 2008; D'Amour 2006; Inestrosa and Arenas 2010; Sullivan 2010). The Wnt pathway plays a particularly important role in skeletal tissue development such as bone formation and cartilage formation (Hoeppner, 2009; Chun, 2008). Wnt signaling is also associated with nerve regeneration in the adult central nervous system (Lie, 2005).

  The disease can result from altered Wnt pathway activity. For example, overactivation of the canonical Wnt pathway can cause abnormal cell growth (Reya and Clevers, 2005). In particular, 90% of colorectal cancers are initiated by the loss of inhibitors of the adenomatosis polyposis coli (APC) gene, the Wnt / β-catenin pathway (Kinzler and Vogelstein, 1996). Increased expression of Wnt protein and loss of extracellular inhibitors that normally suppress Wnt protein function can result in Wnt-dependent tumors (Polakis, 2007). On the other hand, the canonical Wnt pathway has also been shown to play a role in certain cancer progressions (Camilli and Weeraratna, 2010). More recently, Wnt signaling has also been implicated in cancer stem cells (Takahashi-Yanaga and Kahn, 2010).

  Evidence suggests that targeting Wnt-mediated signaling pathways may be therapeutically useful in a wide range of diseases (Barker and Clevers, 2006). Mutations in APC, beta-catenin or axin-1 that cause constitutive activation of the canonical Wnt pathway are important events in a variety of human cancers including colorectal cancer, melanoma, hepatocellular carcinoma, gastric cancer, ovarian cancer and others (Polakis, 2007). Blocking the Wnt pathway in various cancers using either genetic or chemical approaches has been shown to suppress abnormal cell growth (Herbst and Kolligs, 2007). Furthermore, inhibition of this pathway may directly affect cells that sustain cancer cell growth and allow metastases, and the cells are believed to be resistant to conventional chemotherapeutic agents.

  In addition to activation caused by mutations in gene products downstream of the receptor, abnormal Wnt pathway activity caused by other mechanisms has been associated with a wide range of cancers. These cancers include lung (small and non-small cells), breast, prostate, carcinoid, bladder, carcinoma (scarcinoma), esophagus, ovary, cervix, endometrium, mesothelioma, melanoma, sarcoma, osteosarcoma, fat Includes but is not limited to sarcoma, thyroid, tendonoma, chronic myelogenous leukemia (AML) and chronic myelogenous leukemia (CML). There are currently multiple examples of cancer cells that are dependent on up-regulated autocrine or paracrine Wnt signaling, and cell lines derived from osteosarcoma, breast cancer, head and neck cancer, and ovarian cancer are autocrine or paracrine Wnt signaling Has been shown to induce protection from apoptosis (Kansara, 2009; Bafico, 2004; Akiri, 2009; DeAlmeida, 2007; Chan, 2007; Chen, 2009; Rhee, 2002).

  Furthermore, abnormal Wnt pathways that have been implicated in the development of fibrosis include, but are not limited to, pulmonary fibrosis such as idiopathic pulmonary fibrosis and radiation-induced fibrosis, kidney fibrosis, and liver fibrosis (Morrisey, 2003; Hwang, 2009; Cheng, 2008).

  Other disorders associated with abnormal Wnt signaling include, but are not limited to, bone and cartilage disorders such as osteoporosis and osteoarthritis, obesity-related type II diabetes, and neural tissue diseases such as Alzheimer's disease (Hoeppner, 2009; Ouchi, 2010; Blom, 2010; Boonen, 2009). Wnt signaling also contributes to self-renewal and maintenance of HSC, and dysfunctional Wnt signaling is responsible for various disorders arising from those of HSC, such as leukemia and various other blood-related cancers (Reya, 2005).

  Thus, the identification of methods and compounds that modulate WNT-dependent cellular responses may provide a means for modulating the physiological functions and therapeutic treatment of diseases associated with abnormal pathway activity.

  The present invention generally provides compounds and pharmaceutical compositions thereof, where the compounds are used as Wnt signaling inhibitors, and the use of such compounds to inhibit the Wnt signaling pathway.

(Definition)
As used herein, “Wnt signaling pathway” or “Wnt pathway” refers to a pathway that causes a change in cellular behavior through binding of a Wnt protein to a cellular receptor. The Wnt pathway includes a variety of proteins including Frizzled, Disheveled, Axin, APC, GSK3β, β-catenin, LEF / TCF transcription factors, and molecules involved in the synthesis and secretion of Wnt proteins. Examples of proteins involved in functional WNT secretion include, but are not limited to, wntless / evenness discontinuity (Wls / Evi), porcupine (Porcn) and Vps35p. Wls / Evi is a seven-transmembrane protein that belongs to the Golgi apparatus and is required for secretion of Wg (Drosophila), MOM-2 (E. coli) and Wnt3A. This includes conserved structural motifs whose structure and function are both unknown. Porcupine (Porcn) is a member of the membrane-bound O-acyltransferase (MBOAT) family of palmitoyltransferases. The fatty acid modification of Wnt is important for these functions. Wnt is palmitoylated at one or two highly conserved sites. Thus, inhibitors of Porcn can block all functional Wnt signaling. Vps35p is a subunit of a multiprotein complex called a retromeric complex involved in intracellular protein transport. The Vps35p function in binding targets proteins such as WNT for recruitment to the vesicle.

  A “Wnt pathway inhibitor” or “Wnt signaling inhibitor” is a small organic molecule that inhibits Wnt signaling activity and typically has a molecular weight of about 800 g / mol or less.

  The term “method of inhibiting the Wnt pathway” refers to a method of inhibiting a known biochemical event associated with the production of a functional Wnt protein or a cellular response to the Wnt protein. As discussed herein, small organic molecules can inhibit Wnt responses according to this definition.

  A “Wnt protein” is a protein that binds to Frizzled and LRP5 / 6 co-receptors to activate canonical or non-canonical Wnt signaling. Specific examples of Wnt proteins are: Wnt-1 (NM005430), Wnt-2 (NM003391), Wnt-2B / Wnt-13 (NM004185), Wnt-3 (NM030753), WNT3a (NM033131), Wnt-4 (NM030761) , Wnt-5A (NM003392), Wnt-5B (NM032642), Wnt-6 (NM006522), Wnt-7A (NM004625), Wnt-7B (NM058238), Wnt-8A (NM058244), Wnt-8B (NM003393), Wnt-9A / Wnt-14) (NM003395), Wnt-9B / Wnt-15 (NM003396), Wnt-10A (NM025216), Wnt-10B (NM003394), Wnt-11 (NM004626), Wnt-16 (NM016087) including.

  A “Wnt pathway disorder” is a condition or disease state involving abnormal Wnt signaling. In one embodiment, the aberrant Wnt signaling is the level of Wnt signaling in a cell or tissue suspected of having a disease that exceeds the level of Wnt signaling in a normal cell or tissue. In one specific embodiment, the Wnt-mediated disorder comprises cancer or fibrosis.

  The term “cancer” refers to a condition in humans that is characterized by unregulated cell growth. Examples include but are not limited to carcinomas, lymphomas, blastomas and leukemias. More specific examples of cancer are lung (small and non-small cells), breast, prostate, carcinoid, bladder, stomach, pancreas, liver (hepatocytes), hepatoblastoma, colorectal, head and neck squamous cell carcinoma, Including, but not limited to, esophagus, ovary, cervix, endometrium, mesothelioma, melanoma, sarcoma, osteosarcoma, liposarcoma, thyroid, tendonoma, chronic myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) Not.

  The term “fibrosis” refers to a condition in humans that is typically characterized by unsuppressed proliferation and tissue sclerosis of fibroblasts. Specific examples include, but are not limited to, pulmonary fibrosis (idiopathic pulmonary fibrosis and radiation-induced fibrosis), kidney fibrosis, and liver fibrosis including cirrhosis.

  “Inhibition”, “treating” or “treatment” refers to reduction, therapeutic treatment and prophylactic or preventative treatment, the purpose being to reduce or prevent a targeted pathological disorder or condition It is. In one example, following administration of a Wnt signaling inhibitor, the cancer patient may experience a decrease in tumor size. “Treatment” or “treating” refers to (1) inhibiting a disease in a subject experiencing or showing a disease state or symptom, (2) experiencing a disease state or symptom of the disease To ameliorate the disease in a subject who is or is presenting and / or (3) any measurable reduction in disease in a subject or patient experiencing or presenting the condition or symptoms of the disease Including but not limited to affecting. To the extent that a Wnt pathway inhibitor can prevent growth and / or kill cancer cells, it can be cytostatic and / or cytotoxic.

  The term “therapeutically effective amount” refers to an amount of a Wnt pathway inhibitor effective to “treat” a Wnt pathway disorder in a subject or mammal. In the case of cancer, a therapeutically effective amount of the drug reduces the number of cancer cells, reduces tumor size, inhibits cancer cell invasion to peripheral organs, inhibits tumor metastasis, constant tumor growth It can either inhibit to some extent and / or reduce some of one or more of the symptoms associated with cancer.

  Administration “in combination with” one or more further therapeutic agents includes simultaneous (simultaneous) and consecutive administration in any order. As used herein, the term “pharmaceutical combination” refers to the product obtained by mixing or combining the active ingredients, with fixed and non-fixed combinations of the active ingredients. Includes both. The term “fixed combination” means that the active ingredients, for example the compound of formula (1) and the auxiliary agent, are both administered to the patient simultaneously in the form of a single entity or dose. The term “non-fixed combination” means that the active ingredient, for example the compound of formula (1) and the auxiliary agent, both to the patient as separate entities, either simultaneously, in parallel or sequentially, with no specific time limit. To be administered, such administration is meant to provide a therapeutically effective level of the active ingredient in the patient's body. The latter also applies to cocktail therapy, eg the administration of 3 or more active ingredients.

  A “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer. Examples are gemcitabine, irinotecan, doxorubicin, 5-fluorouracil, cytosine arabinoside (“Ara-C”), cyclophosphamide, thiotepa, busulfan, cytoxin, taxol, methotrexate, cisplatin, melphalan, vinblastine And carboplatin without limitation.

式中、X₁、X₂、X₃、X₄、X₅、X₆、X₇およびX₈は、独立してCR₄またはNであり；
Y₁は、水素または-C（R₄）₃であり、それぞれのR₄は、同じか、または異なり；
Y₂およびY₃は、独立して水素、ハロゲンまたは-C（R₃）₃であり、それぞれのR₃は、同じか、または異なり；
R₁およびR₂は、水素、ハロゲン、C_1-6アルキル、キノリニル、 In one embodiment, the present invention provides a compound or physiologically acceptable salt thereof as a Wnt signaling inhibitor having the structure of Formula I:

In which X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ and X ₈ are independently CR ₄ or N;
Y ₁ is hydrogen or —C (R ₄ ) ₃ , and each R ₄ is the same or different;
Y ₂ and Y ₃ are independently hydrogen, halogen or —C (R ₃ ) ₃ , and each R ₃ is the same or different;
R ₁ and R ₂ are hydrogen, halogen, C _1-6 alkyl, quinolinyl,

、C_6-30アリール、N、OおよびSから選択される1-2個のヘテロ原子を含む3〜6員のヘテロシクロアルキルおよびN、OおよびSから選択される1-4個のヘテロ原子を含む5または6員のヘテロアリールから独立して選択され、式中キノリニル、

3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from C _6-30 aryl, N, O and S and 1-4 heteroatoms selected from N, O and S Independently selected from 5- or 6-membered heteroaryl, including quinolinyl,

、C_6-30アリール、3〜6員のヘテロシクロアルキルおよび5または6員のヘテロアリールのそれぞれは、1つまたは2つ、および同一または異なるR₄で任意に置換することができ；
それぞれのR₃は、水素、ハロゲン、シアノ、C_1-6アルキルおよびC_1-6アルコキシから独立して選択され、式中C_1-6アルキルおよびC_1-6アルコキシのそれぞれは、ハロ、アミノ、ヒドロキシル、C_1-6アルコキシまたはシアノで任意に置換することができ；
それぞれのR₄は、水素、ハロゲン、シアノ、C_1-6アルコキシ、-S（O）₂R₅、-C（O）OR₅、-C（O）R₅、-C（O）NR₆R₇、C_1-6アルキル、C_2-6アルケニルおよびC_2-6アルキニルから独立して選択され、式中それぞれのC_1-6アルコキシ、-S（O）₂R₅、-C（O）OR₅、-C（O）R₅、-C（O）NR₆R₇、C_1-6アルキル、C_2-6アルケニルおよびC_2-6アルキニルは、ハロ、アミノ、ヒドロキシル、C_1-6アルコキシまたはシアノで任意に置換することができ；および、
R₅、R₆およびR₇は、水素、C_1-6アルキル、C_2-6アルケニルおよびC_2-6アルキニルから独立して選択され、式中、C_1-6アルキル、C_2-6アルケニルおよびC_2-6アルキニルのそれぞれは、ハロ、アミノ、ヒドロキシル、C_1-6アルコキシまたはシアノで任意に置換することができる。

Each of C _6-30 aryl, 3-6 membered heterocycloalkyl and 5 or 6 membered heteroaryl can be optionally substituted with 1 or 2 and the same or different R ₄ ;
Each R ₃ is independently selected from hydrogen, halogen, cyano, C _1-6 alkyl and C _1-6 alkoxy, wherein each of C _1-6 alkyl and C _1-6 alkoxy is halo, amino Optionally substituted with hydroxyl, C _1-6 alkoxy or cyano;
Each R ₄ is hydrogen, halogen, cyano, C _1-6 alkoxy, —S (O) ₂ R ₅ , —C (O) OR ₅ , —C (O) R ₅ , —C (O) NR ₆ Independently selected from R ₇ , C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, wherein each C _1-6 alkoxy, —S (O) ₂ R ₅ , —C (O ) OR ₅ , —C (O) R ₅ , —C (O) NR ₆ R ₇ , C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are halo, amino, hydroxyl, C _1- Optionally substituted with ₆ alkoxy or cyano; and
R ₅ , R ₆ and R ₇ are independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl Each of and C _2-6 alkynyl can be optionally substituted with halo, amino, hydroxyl, C _1-6 alkoxy or cyano.

  In particular, formula (I) represents the following core structure, but is not limited. :

In formula I, the ring defined by X ₁ , X ₂ , X ₃ and X ₄ may be any of the following groups, but is not limited. :

Preferably, R ₁ and R ₂ in formula I are hydrogen, fluorine, chlorine, methyl,

、フェニル、モルホリニル、ピペラジニルおよび以下から選択される5または6員のヘテロアリールから独立して選択されてもよい。：

, Phenyl, morpholinyl, piperazinyl and 5 or 6 membered heteroaryl selected from: :

Preferably, R ₄ may be the same or different and each may be independently selected from hydrogen, chlorine, fluorine, cyano, —CH ₃ , —CHF ₂ , —CF ₃ , —OCH ₃ , —COOCH ₃ .

In one embodiment, at least one atom in Formula I is ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²³ I At least one of the corresponding isotopes selected from.

As used herein, for example, an H atom in any substituent (eg, CH ₂ ) includes all suitable isotopic variations (eg, H, ² H and ³ H).

As used herein, for example, other atoms in any substituent are ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³⁵ S, ¹⁸ F, ³⁶ Cl and / or ¹²³ I Includes all suitable isotopic variations including but not limited to.

In preferred embodiments, examples of compounds of the present invention include, but are not limited to:
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((5- (2-methylpyridin-4-yl) pyridin-2-yl) methyl) -7-phenylquinazolin-4-amine;
N- (4-morpholinobenzyl) -7-phenylquinazolin-4-amine;
N-((6-morpholinopyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((6- (2-methylmorpholino) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((6- (4-methylpiperazin-1-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
4- (5-(((7-phenylquinazolin-4-yl) amino) methyl) pyridin-2-yl) thiomorpholine 1,1-dioxide;
N-((6- (6-methylpyridin-3-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((6- (5-methylpyridin-3-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
7-phenyl-N-((6- (pyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7-phenyl-N-((6- (pyridin-3-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7-phenyl-N-((6- (pyridin-2-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7-phenyl-N-((6- (pyridazin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7-phenyl-N-((6- (pyrazin-2-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7-phenyl-N-((6- (pyrimidin-5-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
N-((6- (2-fluoropyridin-4-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((6- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((5- (6-methylpyridin-3-yl) pyridin-2-yl) methyl) -7-phenylquinazolin-4-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -7-phenylquinazolin-4-amine;
N- (4- (2-fluoropyridin-4-yl) benzyl) -7-phenylquinazolin-4-amine;
N-benzyl-7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4-methylbenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4-methoxybenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4-fluorobenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4-chlorobenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4-bromobenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4- (trifluoromethyl) benzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
4-((7- (2-methylpyridin-4-yl) quinazolin-4-ylamino) methyl) benzonitrile;
N- (4-morpholinobenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4-phenylbenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (3-fluoro-4-phenylbenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4- (3-fluorophenyl) benzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
7- (3-Fluorophenyl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (3-chlorophenyl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7-m-tolylquinazolin-4-amine;
3- (4-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methylamino) quinazolin-7-yl) benzonitrile;
4- (4-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methylamino) quinazolin-7-yl) benzonitrile;
7- (2-methylpyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (6-methylpyridin-3-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (5-methylpyridin-3-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (pyridin-2-yl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (pyridin-3-yl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (pyridin-4-yl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (pyridazin-4-yl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (pyrazin-2-yl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (pyrimidin-5-yl) quinazolin-4-amine;
7- (2-fluoropyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (2- (trifluoromethyl) pyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (2-methoxypyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (3-methylpyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7-morpholinoquinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (piperidin-1-yl) quinazolin-4-amine;
7- (4-methylpiperazin-1-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
1- (4- (4-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methylamino) quinazolin-7-yl) piperazin-1-yl) ethanone;
4- (4-(((2'-methyl- [2,4'-bipyridin] -5-yl) methyl) amino) quinazolin-7-yl) thiomorpholine 1,1-dioxide;
7- (1,2,3,6-tetrahydropyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (1,2,3,6-tetrahydropyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
1- (4- (4-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methylamino) quinazolin-7-yl) piperidin-1-yl) ethanone;
N-((2′-methyl- [2,4′-bipyridin] -5-yl) methyl) -7- (4- (methylsulfonyl) piperazin-1-yl) quinazolin-4-amine;
7- (1-methyl-1H-pyrazol-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (isoxazol-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (thiazol-2-yl) quinazolin-4-amine;
N- (3-methyl-4- (2-methylpyridin-4-yl) benzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (3-fluoro-4- (2-methylpyridin-4-yl) benzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -7- (pyrazin-2-yl) quinazolin-4-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -7- (2-fluoropyridin-4-yl) quinazolin-4-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -7-morpholinoquinazolin-4-amine;
2- (3-Fluorophenyl) -N- (4- (2-methylpyridin-4-yl) benzyl) pyrido [3,4-b] pyrazin-5-amine;
2- (3-fluorophenyl) -N-((2′-methyl- [2,4′-bipyridin] -5-yl) methyl) pyrido [3,4-b] pyrazin-5-amine;
2- (3-fluorophenyl) -N- (3-methyl-4- (2-methylpyridin-4-yl) benzyl) pyrido [3,4-b] pyrazin-5-amine;
N- (3-fluoro-4- (2-methylpyridin-4-yl) benzyl) -2- (3-fluorophenyl) pyrido [3,4-b] pyrazin-5-amine;
2- (2-methylpyridin-4-yl) -N- (4- (2-methylpyridin-4-yl) benzyl) pyrido [3,4-b] pyrazin-5-amine;
N-((2'-methyl- [2,4'-bipyridin] -5-yl) methyl) -2- (2-methylpyridin-4-yl) pyrido [3,4-b] pyrazin-5-amine ;
N- (3-methyl-4- (2-methylpyridin-4-yl) benzyl) -2- (2-methylpyridin-4-yl) pyrido [3,4-b] pyrazin-5-amine;
N- (3-fluoro-4- (2-methylpyridin-4-yl) benzyl) -2- (2-methylpyridin-4-yl) pyrido [3,4-b] pyrazin-5-amine;
N-((2 ′, 3-dimethyl- [2,4′-bipyridin] -5-yl) methyl) -6- (pyrazin-2-yl) -2,7-naphthyridin-1-amine;
6- (2-methylmorpholino) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
(S) -6- (2-Methylmorpholino) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
(R) -6- (2-methylmorpholino) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
1- (4- (8-((4- (2-methylpyridin-4-yl) benzyl) amino) -2,7-naphthyridin-3-yl) piperazin-1-yl) ethanone;
6- (1H-imidazol-1-yl) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
6- (4-Methyl-1H-imidazol-1-yl) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -6- (1H-tetrazol-5-yl) -2,7-naphthyridin-1-amine;
6- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
6- (1-methyl-1H-pyrazol-3-yl) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -6- (thiazol-5-yl) -2,7-naphthyridin-1-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -6- (oxazol-5-yl) -2,7-naphthyridin-1-amine;
N-((2 ′, 3-dimethyl- [2,4′-bipyridin] -5-yl) methyl) -6- (5-methylpyridin-3-yl) -2,7-naphthyridin-1-amine;
N-((2 ′, 3-dimethyl- [2,4′-bipyridin] -5-yl) methyl) -6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-amine;
N-((3-Fluoro-2'-methyl- [2,4'-bipyridin] -5-yl) methyl) -6- (2-methylpyridin-4-yl) -2,7-naphthyridine-1- Amines;
N-((2 ′, 3-dimethyl- [2,4′-bipyridin] -5-yl) methyl) -6- (5-fluoropyridin-3-yl) -2,7-naphthyridin-1-amine;
N- (3-methyl-4- (2-methylpyridin-4-yl) benzyl) -6- (pyrazin-2-yl) -2,7-naphthyridin-1-amine;
N- (3-fluoro-4- (2-methylpyridin-4-yl) benzyl) -6- (pyrazin-2-yl) -2,7-naphthyridin-1-amine;
Methyl-4- (8-((4- (2-methylpyridin-4-yl) benzyl) amino) -2,7-naphthyridin-3-yl) piperazine-1-carboxylate;
4- (8-((4- (2-methylpyridin-4-yl) benzyl) amino) -2,7-naphthyridin-3-yl) piperazin-2-one;
2- (4- (8-((4- (2-methylpyridin-4-yl) benzyl) amino) -2,7-naphthyridin-3-yl) piperazin-1-yl) acetonitrile;
2-methyl-4- (4-(((6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-yl) amino) methyl) phenyl) pyridine 1-oxide;
6- (2-chloropyridin-4-yl) -N-((2 ′, 3-dimethyl- [2,4′-bipyridin] -5-yl) methyl) -2,7-naphthyridin-1-amine;
6- (2-chloropyridin-4-yl) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
2'-methyl-4-(((6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-yl) amino) methyl) -2H- [1,4'-bipyridine] -2 -on;
2- (2-methylpyridin-4-yl) -5-(((6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-yl) amino) methyl) benzonitrile;
N- (3-methoxy-4- (2-methylpyridin-4-yl) benzyl) -6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-amine;
N-((3-Chloro-2'-methyl- [2,4'-bipyridin] -5-yl) methyl) -6- (2-methylpyridin-4-yl) -2,7-naphthyridine-1- Amines;
N- (4- (2- (difluoromethyl) pyridin-4-yl) benzyl) -6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-amine;
Or a physiologically acceptable salt thereof.

  In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the invention and usually comprising at least one acceptable carrier or diluent, said compound being free or pharmaceutically acceptable Salt form. Such compositions may be oral compositions, injectable compositions or suppositories. The composition may also be made in a conventional manner by the method of mixing, granulating, or coating.

  In an embodiment of the invention, the composition is an oral composition, which may be a tablet or a gelatin capsule. Preferably, the oral composition comprises the compound for tablets a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants such as silica, talc (C) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; and, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; Optionally, d) disintegrants such as starch, agar, alginic acid or its sodium salts or effervescent mixtures; and / or e) additives such as absorbents, colorants, flavors and sweeteners. Including.

  In another embodiment of the invention, the composition is an injectable composition and may be an aqueous isotonic solution or suspension.

  In yet another embodiment of the invention, the composition is a suppository and may be prepared from a fat emulsion or suspension.

  Preferably, the composition is sterilized and / or includes an adjuvant. Such adjuvants can be preservatives, stabilizers, wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure, buffers and / or any combination thereof.

  Alternatively or in addition, the composition further comprises other therapeutically beneficial substances for different applications such as solubilizers, stabilizers, tonicity enhancing agents, buffers and / or preservatives. Also good.

  In an embodiment of the invention, the composition may be a formulation suitable for transdermal application. Such formulations comprise an effective amount of the compound of the invention and a carrier. Preferably, the carrier may contain an absorbable pharmacologically acceptable solvent to assist passage through the skin of the host. A transdermal device containing the formulation may also be used. The transdermal device includes a backing member, optionally a reservoir containing the compound with a carrier, optionally a controlled rate barrier for delivering the compound to the host's skin at a predetermined rate, controlled over an extended period of time. It may be in the form of a bandage and means for securing the device to the skin. Otherwise, matrix transdermal formulations may also be used.

  In other embodiments of the invention, the composition may be a formulation suitable for topical application such as the skin and eyes, and may be an aqueous solution, ointment, cream or gel well known in the art.

  In another aspect, the present invention provides a method of inhibiting Wnt secretion from a cell by contacting the cell with an effective amount of the compound or physiologically acceptable salt thereof or the pharmaceutical composition described above. To do.

  In another aspect, the present invention provides a method of inhibiting Wnt signaling in a cell with an effective amount of the above compound or physiologically acceptable salt thereof or the above pharmaceutical composition. In one embodiment, the cells are contained within a mammal and the amount administered is a therapeutically effective amount. In other embodiments, inhibition of Wnt signaling further results in inhibition of cell proliferation. In a further embodiment, the cell is a cancer cell. In yet other embodiments, the cell is a fibrogenic cell.

  Cell proliferation is measured by using methods known to those skilled in the art. For example, a convenient assay for measuring cell proliferation is the CellTiter-Glo ™ assay commercially available from Promega (Madison, Wis.). The assay procedure involves adding CellTiter-Glo® reagent to cells cultured in a multi-well dish. The luminescent signal measured by a luminometer or imaging device is proportional to the amount of ATP present, which is directly proportional to the number of viable cells present in the culture. In addition, cell proliferation may also be measured using colony formation assays known in the art.

  The present invention also provides a method for treating cancer or fibrosis associated with the Wnt signaling pathway with an effective amount of the compound. One skilled in the art will be able to easily determine whether a cancer is related to the Wnt pathway by analyzing cancer cells using one of several techniques known in the art. . For example, immunity and nucleic acid detection methods can be used to examine cancer cells for abnormalities in the level of proteins or mRNAs involved in Wnt signaling.

  Cancer or fibrosis associated with the Wnt pathway includes those in which the activity of one or more components of the Wnt signaling pathway is upregulated from a basal level. In one embodiment, inhibiting the Wnt pathway can include inhibiting Wnt secretion. As another example, inhibiting the Wnt pathway can include inhibiting downstream components of cell surface receptors. In other embodiments, inhibition of Wnt secretion can include inhibiting the activity of any protein associated with secretion of functional WNT.

  Furthermore, the present invention provides a method for treating a Wnt pathway disorder in a subject suffering from a disorder by administering to the subject a therapeutically effective amount of a Wnt inhibitor. In one embodiment, the disorder is an abnormality, eg, a cell proliferative disorder associated with increased Wnt signaling activity. In other embodiments, the disorder is caused by an increase in the amount of Wnt protein. In still other embodiments, the cell proliferative disorder is cancer, lung (small and non-small cells), breast, prostate, carcinoid, bladder, stomach, pancreas, liver (hepatocytes), hepatoblastoma, Colorectal, head and neck squamous cell carcinoma, esophagus, ovary, cervix, endometrium, mesothelioma, melanoma, sarcoma, osteosarcoma, liposarcoma, thyroid, tendonoma, chronic myelogenous leukemia (AML) and chronic bone marrow Including but not limited to sex leukemia (CML). In yet other embodiments, the cell proliferative disorder is fibrosis, including idiopathic pulmonary fibrosis and pulmonary fibrosis, such as radiation-induced fibrosis, liver fibrosis, including renal fibrosis and cirrhosis. It is not limited. In yet other embodiments, the disorder is osteoarthritis, Parkinson's disease, retinopathy, macular degeneration.

  For therapeutic use, the compounds of the present invention can be administered alone in a therapeutically effective amount via any acceptable method known in the art. As used herein, a therapeutically effective amount may vary widely depending on the severity of the disease, the age and associated health of the subject, the potency of the compound used and other factors. In general, satisfactory results are shown to be obtained systemically at daily dosages of about 0.03 to 2.5 mg / kg of subject body weight. In one embodiment, the daily dose indicated for a larger mammal as a human is in the range of about 0.5 mg to about 100 mg. Preferably, the compound is administered in divided doses up to 4 times per day or in delayed form. In other embodiments, suitable unit dosage forms for oral administration contain approximately 1-100 mg of active ingredient.

  Alternatively, the compounds of the present invention may be administered in a therapeutically effective amount as an active ingredient in combination with one or more therapeutic agents, such as a pharmaceutical combination. There will be a synergistic effect when the compounds of the invention are used with chemotherapeutic agents known in the art. The dosage of the co-administered compound can vary depending on the type of auxiliary drug used, the particular drug used, the condition being treated, and the like.

  The compounds of the invention or compositions thereof may be administered by any conventional route. In one embodiment, it is administered enterally, such as orally, and in the form of a tablet or capsule. In other embodiments, it is administered parenterally and in the form of injections or suspensions. In still other embodiments, it is administered topically and in the form of a lotion, gel, ointment or cream, or in the form of a nasal or suppository.

  In other embodiments, the invention also provides: a) a first agent that is a compound of the invention as disclosed herein, in a free form or in a pharmaceutically acceptable salt form, and b) at least A pharmaceutical combination, preferably a kit, is provided comprising one auxiliary agent. In addition, the kit may include instructions for its administration.

  The combinations of the present invention may be used in vitro or in vivo. Preferably, the desired therapeutic benefit of administration is by contacting a cell, tissue or organism with a single composition or pharmacological formulation comprising a compound of the invention and one or more agents, or May be achieved by contacting the cell with two or more different compositions or formulations comprising one agent and the other comprising the other. The combined agents may be administered separately at the same time or within a period of time. Preferably, separate administration can produce the desired therapeutic benefit. The compound may precede other drugs, be concurrent with other drugs, and / or after an interval ranging from minutes to weeks. One skilled in the art would normally be able to guarantee the time interval between each delivery, and the separately administered drugs will still have a convenient combined effect on the cells, tissues or organisms. Will be able to. In one embodiment, it is contemplated that contacting a cell, tissue or organism in substantially 2, 1, 4 or more ways substantially simultaneously with the candidate substance, ie, less than about 1 minute. In other embodiments, one or more agents may be administered between about 1 minute and 14 days.

  In other embodiments, the present specification provides the use of the present compound or a physiologically acceptable salt thereof or the present pharmaceutical composition for the manufacture of a medicament for treating a disorder mediated by the Wnt pathway as described above. To do.

  In another aspect, the specification provides a method for preparing a compound of the invention or a salt or derivative thereof.

  In one embodiment, a compound having formula (I) may be prepared according to any one of the synthetic methodologies described in the examples below. In the reactions described, reactive functional groups such as hydroxy, amino, imino, thio or carboxy groups are protected to avoid their unwanted involvement in the reaction if they are desired in the final product. It may be. Conventional protecting groups may be used in accordance with standard practice (see, eg, T. W. Greene and P. G. M. Wuts in “Protective Groups in Organic Chemistry”, John Wiley and Sons, 1991). Suitable leaving groups for use in the described synthetic methodology include halogen leaving groups and other conventional leaving groups known in the art. Preferably the leaving group is chloro or bromo.

  In other embodiments, the compounds of the invention or salts thereof may also be obtained in the form of hydrates, or these crystals may be obtained, for example, as a solvent used for crystallization (present as a solvate) May be included. The salt is usually free by treatment with a suitable basic agent, preferably with an alkali metal carbonate, alkali metal bicarbonate or alkali metal hydroxide, more preferably with potassium carbonate or sodium hydroxide. Can be converted to a compound. The compounds of the invention in base addition salt formation may be converted to the corresponding free acids by treatment with a suitable acid such as hydrochloric acid. In view of the close relationship between the free form of the new compound and those in the form of these salts, including those salts that can be used as intermediates, for example in the purification or identification of the new compounds It is understood that any reference to a free compound suitably refers to the corresponding salt.

  Salts of the present compounds with salt forming groups may be prepared in a manner known in the art. Thus, acid addition salts of compounds of formula (I) can be obtained by treatment with an acid or with a suitable anion exchange reagent. Pharmaceutically acceptable salts of the compounds of this invention may be formed as acid addition salts from compounds of formula (I) having a basic nitrogen atom with an organic or inorganic acid.

  Preferably, suitable inorganic acids include but are not limited to halogen acids such as hydrochloric acid, sulfuric acid or phosphoric acid.

  Preferably, suitable organic acids are carboxylic acids, phosphoric acids, sulfonic acids or sulfamic acids such as acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelin. Acids, suberic acid, azelaic acid, amino acids such as malic acid, tartaric acid, citric acid, glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4 Aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1 , 5-Naphthalene-disulfonic acid, 2-, 3- or 4-methyl Including other organic protonic acids such as benzene sulfonic acid, methyl sulfate, ethyl sulfate, dodecyl sulfonic acid, N cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid or ascorbic acid, It is not limited.

  Alternatively, pharmaceutically unacceptable salts such as picrates or perchlorates for isolation or purification can be used. If there is no therapeutic use, only pharmaceutically acceptable salts or free compounds are used and can be applied in the form of pharmaceutical preparations.

  In yet another embodiment, the unoxidized form of the compound of the invention is prepared from the N-oxide of the compound of the invention by treatment with a reducing agent in a suitable inert organic solvent at 0-80 ° C. May be. Preferably, the reducing agent is sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide or the like. Preferably, the converted organic solvent is acetonitrile, ethanol, aqueous dioxane or the like.

  In still other embodiments, prodrug derivatives of the compounds of the invention may be prepared by methods known in the art (for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters , Vol. 4, p. 1985). In a preferred embodiment, a suitable prodrug is a non-derivatized compound of the invention with a suitable carbamylating agent such as 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate or the like. It may be prepared by reacting.

  In yet other embodiments, protected derivatives of the compounds of the invention may be made by means known in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, “Protecting Groups in Organic Chemistry”, 3rd edition, John Wiley and Sons, Inc., 1999.

  In yet other embodiments, the compounds of the invention may be prepared as their individual stereoisomers. The method comprises reacting a racemic mixture of compounds with an optically active degrading agent to form a paired diastereoisomeric compound, separating the diastereomers, and recovering the optically pure enantiomer. Including. Separation of enantiomers may be performed by using covalent diastereomeric derivatives of the compounds of the invention or by using separable complexes such as crystalline diastereomeric salts. Diastereomers have different physical properties as indicated by melting point, boiling point, solubility, reactivity, etc., and can be easily separated by taking advantage of these differences. Diastereomers may be separated by preparative crystallization, chromatography, or by separation / resolution techniques based on solubility differences. The optically pure enantiomer is then recovered with the separating agent by any practical means that cannot result in racemization. A more detailed description of techniques applicable to the separation of compound stereoisomers from these racemic mixtures can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., Can be found in 1981.

In conclusion, the compounds of the present invention can be made by the methods described in the Examples;
Optionally, pharmaceutically acceptable salts may be converted from the compounds of the invention;
Optionally, pharmaceutically acceptable N-oxides may be converted from the unoxidized form of the compounds of the invention;
Optionally, individual isomers of the compounds of the invention are separated from the mixture of isomers; and
Optionally, pharmaceutically acceptable prodrug derivatives may be converted from non-derivatized compounds of the invention.

  Unless the production of starting materials is specifically stated, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the examples below. One skilled in the art can appreciate that the above transformations are only representative of methods for the preparation of the compounds of the present invention, and that other well-known methods are used as well.

Detailed Description of Preferred Embodiments
The invention is further illustrated, but not limited, by the following and examples describing the preparation of the compounds of the invention.

  Example 1: N- (4- (2-methylpyridin-4-yl) benzyl) -6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-amine (Compound No. 1)

  Process 1:

  2-Cyanoacetamide (50 g, 601.8 mmol) and ethyl acetoacetate (75 mL, 601.8 mmol) were dissolved in MeOH. KOH (37.0 g, 1.1 eq) was dissolved in MeOH and added dropwise to the mixture to give some white solid. The mixture was heated to reflection in an oil bath for 8 hours and then cooled to RT. The solid was filtered and then re-decomposed in warm water and then filtered again. 6N HCl was added to the filtration to neutralize to pH <7. A white solid precipitated again and was filtered. The solid was further washed with MeOH, water and MeOH, then dried by vacuum to give the final product 3-ethynyl-4-methylpyridine-2,6-diol (yield ˜41%).

  Process 2:

3-Ethynyl-4-methylpyridine-2,6-diol (28.0 g, 195.2 mmol) was dissolved in POCl ₃ (60.0 mL). The reaction mixture was sealed in a pressure tube and heated to 180 ° C. for 6 hours. After the reaction was cooled to room temperature, excess POCl ₃ was removed under vacuum. Crushed ice was slowly added to the mixture to produce a solid. The solid was filtered and dried under vacuum to give the final product 2,6-dichloro-4-methylpyridine-3-carbonitrile (yield ˜92%) without further purification.

  Process 3:

  2,6-Dichloro-4-methylpyridine-3-carbonitrile (20.0 g, 107.5 mmol) in 200 mL isopropyl alcohol was added to N, N-dimethylformamide dimethyl acetal (12.82 g, 107.5 mmol). The reaction was stirred at 65 ° C. for 18 hours. After cooling the reaction to RT, the precipitate was collected by filtration, washed with 50 mL isopropyl alcohol, air dried and the product 2,6-dichloro-4-((E)-) without further purification. 2- (Dimethylamino) vinyl) pyridine-3-carbonitrile (yield ~ 26%).

  Process 4:

2,6-Dichloro-4-((E) -2- (dimethylamino) vinyl) pyridine-3-carbonitrile (4.0 g, 16.6 mmol) was added along with 20 ml concentrated HCl in a sealed tube. The reaction is stirred for 18 hours at 45 ° C. After cooling the reaction to RT room temperature, ice water was added to the solution to produce a heavy yellow slurry. The precipitate was collected by filtration, washed with cold water, ether and ethyl acetate and dried under vacuum to give a pale yellow solid 6,8-dichloro-2,7-naphthyridin-1 (2H) -one (Yield ~ 80%). MS m / z 215.0 (M + 1). ¹ HNMR (300 MHz, DMSO-d6): δ11.75 (s, 1H), 7.76 (s, 1H), 7.50 (t, J = 6.6Hz, 1H), 6.52 (d, J = 6.6Hz, 1H) .

  Process 5:

  6,8-Dichloro-2,7-naphthyridin-1 (2H) -one (3.0 g, 13.96 mmol) was dissolved in iPrOH (120 mL) to form a suspension. The solution was cooled to 0 ° C. in an ice bath and then hydrazine solution (5.6 g, 80%, 10 eq) was added dropwise. The mixture was stirred for 15 minutes at RT and then heated in an oil bath at 55 ° C. overnight. After the reaction mixture was cooled to RT, it was filtered to give a solid directly, and then the solid was washed with 70 mL MeOH and dried by vacuum. The product 6-chloro-8-hydrazinyl-2,7-naphthyridin-1 (2H) -one (yield ˜98%) was used directly in the next step reaction without further purification.

  Process 6:

6-Chloro-8-hydrazinyl-2,7-naphthyridin-1 (2H) -one (1.50 g, 7.12 mmol) was dissolved in MeCN (90 mL) to form something like a suspension. 1N NaOH (17.80 mL, 2.5 eq) was added, followed by the same amount of water (107.80 mL) to the mixture. The reaction mixture was heated at 50 ° C. and stirred until a clear solution was obtained. The solution was again cooled to 0 ° C. and NaOCl (11.05 g, 12% solution, 2.5 eq) was added dropwise and then the reaction was stirred overnight at RT. After the reaction was performed, the solution was cooled to 0 ° C. and then added to 1N HCl to neutralize (pH˜6). The precipitate was collected and the filtrate was extracted with 100 ml × 2 EA. The organic layers were combined, dried over Na ₂ SO ₄ and evaporated to give additional crude product. The combined solid material 6-chloro-2,7-naphthyridin-1 (2H) -one (yield ˜93%) was used in the next reaction without further purification. MS m / z 181.1 (M + 1).

  Step 7:

6-Chloro-2,7-naphthyridin-1 (2H) -one (400 mg, 2.2 mmol) was added to POCl ₃ (20.0 mL) in a pressure tube. The reaction mixture was heated to 160 ° C. for 4 hours to obtain a clear solution. The solution was cooled to room temperature, poured into DCM, and slowly crushed ice was added. Saturated NaHCO ₃ was added to the mixture to neutralize the HCl formed in the reaction. Vacuum was applied to remove DCM, and the remaining aqueous solution was extracted with 100 ml × 2 EA. The combined organic layers were washed once with brine, dried over Na ₂ SO ₄ and then evaporated under vacuum to give solid 1,6-dichloro-2,7-naphthyridine (yield ˜73%). Obtained and used in the next step reaction without further purification. MS m / z 199.0 (M + 1).

  Process 8:

(4-Bromophenyl) methanamine (1.00 g, 5.37 mmol) and 2-methylpyridin-4-yl-4-boronic acid (883.30 mg, 6.45 mmol) were dissolved in BuOH (10.0 mL) and water (2.0 mL). . K ₃ PO ₄ (2.28 g, 10.75 mmol), Pd ₂ (dba) ₃ (120.20 mg, 0.27 mmol) and S-phos (220.70 mg, 0.54 mmol) were added under N ₂ . The reaction mixture was sealed in a pressure tube and heated to 125 ° C. for 1 hour. After cooling the reaction to RT, the mixture was poured into water and extracted with 100 ml × 3 EA. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under vacuum to give the crude product. The solid was purified by silicone gel column with a 10% MeOH in DCM (including to 2n NH _3), pure (4- (2-methylpyridin-4-yl) phenyl) methanamine (89% yield) Obtained. MS m / z 199.1 (M + 1).

  Step 9:

  Dissolve 1,6-dichloro-2,7-naphthyridine (160 mg, 0.80 mmol) and (4- (2-methylpyridin-4-yl) phenyl) methanamine (239.10 mg, 1.21 mmol) in BuOH (5.0 mL). And heated to 115 ° C. overnight. After the reaction was cooled to RT, the organic solvent was removed under vacuum. The crude product was purified by silicone gel flash chromatography with EA / hexane (1: 1) and solid N- (4- (2-methylpyridin-4-yl) benzyl) -6-chloro-2,7-naphthyridine 1-amine (yield ˜90%) was obtained. MS m / z 361.1 (M + 1).

  Step 10:

N- (4- (2-methylpyridin-4-yl) benzyl) -6-chloro-2,7-naphthyridin-1-amine (50.00 mg, 0.14 mmol) and 2-methylpyridin-4-yl-4- Boronic acid (56.90 mg, 0.42 mmol) was dissolved in BuOH (3.0 mL) and water (0.6 mL). K ₃ PO ₄ (88.20 mg, 0.028 mmol), Pd ₂ (dba) ₃ (6.20 mg, 0.014 mmol) and S-phos (11.40 mg, 0.011 mmol) were added to the mixture under N ₂ . The reaction was sealed in a pressure tube and heated to 105 ° C. overnight. After cooling the reaction to RT, the mixture was poured into water and extracted three times with EA. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The crude product was further purified by prep-TLC with 5% MeOH in DCM to give the final product N- (4- (2-methylpyridin-4-yl) benzyl) -6- (2-methylpyridine-4- Yl) -2,7-naphthyridin-1-amine (yield ˜70%). . MS m / z 418.2 (M + 1) 1 HNMR (300 MHz, CDCl 3): δ2.46 (s, 3H), 2.63 (s, 3H), 4.94 (d, J = 5.10 Hz, 2H), 5.94 (br, 1H), 6.97 (d, J = 5.70 Hz, 1H), 7.31 (d, J = 4.20 Hz, 1H), 7.36 (s, 1H), 7.54 (d, J = 8.10 Hz, 2H), 7.63 (d, J = 8.40 Hz, 2H), 7.90 (s, 1H), 8.19 (d, J = 6.00 Hz, 1H), 8.22 (s, 1H), 8.51 (m, 2H), 9.08 (s, 1H) , 9.30 (s, 1H).

  Example 2: N- (3-methyl-4- (2-methylpyridin-4-yl) benzyl) -6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-amine (compound Number 2)

  Process 1:

6-chloro-2,7-naphthyridin-1 (2H) -one (200 mg, 1.10 mmol) and 2-methylpyridin-4-yl-4-boronic acid (227.60 mg, 1.66 mmol) with BuOH (5.0 mL) and Dissolved in water (1.0 mL). K ₃ PO ₄ (705.20 g, 3.32 mmol), Pd ₂ (dba) ₃ (49.60 mg, 0.22 mmol) and S-phos (91.00 mg, 0.11 mmol) were added under N ₂ . The reaction mixture was heated to 130 ° C. for 1 hour in a pressure tube. After cooling the reaction to RT, the mixture was poured into water and extracted three times with EA. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under vacuum to give the crude. The crude product was purified by column with 5% MeOH in DCM to give the final compound 6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1 (2H) -one (yield ~ 61%) Got. MS m / z 238.1 (M + 1).

  Process 2:

6- (2-Methylpyridin-4-yl) -2,7-naphthyridin-1 (2H) -one (150 mg, 0.63 mmol) is dissolved in POCl ₃ (15.0 mL) and sealed in a pressure tube. Heated to 160 ° C for hours. After cooling the reaction to RT, excess POCl ₃ was removed under vacuum. Crushed ice was added slowly to the mixture, then added to NaHCO ₃ to neutralize to pH˜7.5. The solution was extracted three times by EA and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The crude was purified by column with EA / hexane (1: 1) to give compound 1-chloro-6- (2-methylpyridin-4-yl) -2,7-naphthyridine (yield ˜55%). MS m / z 256.1 (M + 1).

  Process 3:

1-chloro-6- (2-methylpyridin-4-yl) -2,7-naphthyridine (10.00 mg, 0.039 mmol) and (3-methyl-4- (2-methylpyridin-4-yl) phenyl) methanamine (10.00 mg, 0.047 mmol) was dissolved in toluene (1.0 mL). KO ^t Bu (8.80 mg, 0.078 mmol), Pd (OAc) ₂ (0.90 mg, 0.0039 mmol) and BINAP (4.90 mg, 0.0078 mmol) were added to the mixture under N ₂ . The reaction was heated to 100 ° C. overnight. After cooling the reaction to RT, the mixture was poured into water and extracted three times with EA. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and then concentrated under vacuum. The crude product was purified by prep-TLC with EA / hexane (4: 1) and N- (3-methyl-4- (2-methylpyridin-4-yl) benzyl) -6- (2-methylpyridine-4 -Yl) -2,7-naphthyridin-1-amine (8.8 mg, yield -52%) was obtained. 1H NMR (300 MHz, CDCl3): δ2.31 (s, 3H), 2.63 (s, 3H), 2.70 (s, 3H), 4.91 (d, J = 5.10 Hz, 2H), 5.88 (br, 1H) , 7.00 (d, J = 5.40 Hz, 1H), 7.08 (d, J = 5.10 Hz, 1H), 7.12 (s, 1H), 7.22 (d, J = 7.50 Hz, 1H), 7.36 (m, 2H) , 7.77 (d, J = 4.50 Hz, 1H), 7.88 (s, 1H), 7.98 (s, 1H), 8.24 (d, J = 6.00 Hz, 1H), 8.53 (d, J = 4.80 Hz, 1H) , 8.64 (d, J = 5.40 Hz, 1H), 9.31 (s, 1H). MS m / z 432.2 (M + 1).

  Example 3: 6- (3-Fluorophenyl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) isoquinolin-1-amine (Compound No. 3)

  Process 1:

6-Bromoisoquinoline (1.80 g, 8.66 mmol) was dissolved in DCM (40 mL) and after cooling the reaction to 0 ° C., m-CPBA (2.30 g, 1.3 eq, 77% max) was slowly added in small portions. The reaction was warmed to RT and became a white suspension. At 4 hours, 100 ml of DCM was added to the solution and washed with saturated Na ₂ CO ₃ solution, water and brine. The separated organic layer was dried over Na ₂ SO ₄ , removed under vacuum and the yellow solid N-oxide 6-bromoisoquinoline was obtained without further purification (1.82 g, yield˜93%).

  Process 2:

N-oxide 6-bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 mL) and POCl ₃ (1.12 ml, 1.5 eq) was added dropwise at RT. The reaction was heated to 45 ° C. for 2 hours. After the reaction was cooled to RT, DCM and excess POCl ₃ were removed under vacuum. The crude was redissolved in 100 ml DCM and washed with saturated Na ₂ CO ₃ , water and brine. The separated organic layer was dried over Na ₂ SO ₄ and concentrated to give a brown solid. The crude was purified by flash column using 2% MeOH in DCM to give 6-bromo-1-chloroisoquinoline (1.27 g, ˜65% yield) as a pale yellow solid. MS m / z 242.0 (M + 1).

  Process 3:

Dissolve (6-chloropyridin-3-yl) methanamine (300 mg, 2.1 mmol) and 2-methylpyridin-4-ylboronic acid (345 mg, 2.52 mmol) in a pressure tube with n-butanol (10 mL) and water (2 mL) did. K ₃ PO ₄ (893 mg, 4.2 mmol), Pd ₂ (dba) ₃ (96.3 mg, 0.105 mmol) and S-phos (86.4 mg, 0.21 mmol) were added under nitrogen protection. The reaction was heated to 125 ° C. for 30 minutes and then cooled to room temperature. The solution was poured into water and extracted three times with EA. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The crude was further purified by flash chromatography with 10% MeOH in DCM (including to 2n NH _3), pure (6- (2-methylpyridin-4-yl) pyridin-3-yl) methanamine ( 0.19 g, yield ~ 45%) was obtained. MS m / z 200.1 (M + 1).

  Process 4:

  6-Bromo-1-chloroisoquinoline (100 mg, 0.41 mmol) and (6- (2-methylpyridin-4-yl) pyridin-3-yl) methanamine (165 mg, 0.82 mmol) were added in 0.5 ml in a sealed tube. In n-BuOH. The reaction was heated to 160 ° C. for 6 hours and cooled to RT. The crude was purified by flash chromatography using 8% MeOH in DCM (containing ~ 2N NH3) to give pure 6-bromo-N-((6- (2-methylpyridin-4-yl) pyridine- 3-yl) methyl) isoquinolin-1-amine (116 mg, ˜70%) was obtained. MS m / z 405.2 (M + 1).

  Process 5:

6-bromo-N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) isoquinolin-1-amine (20 mg, 0.05 mmol), 3-fluorophenylboronic acid (10.5 mg, 0.075 mmol), Na ₂ CO ₃ (21 mg, 0.2 mmol) and tetrakis (triphenylphosphine) palladium (5.8 mg, 0.005 mmol) were added in a pressure tube. Dioxane / water (3: 1, 2 ml) was added to the tube and heated to 125 ° C. for 10 minutes. After cooling the reaction to RT, the solution was diluted with 50 ml water and extracted three times with EA. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under vacuum. The crude was further purified by flash chromatography with 10% MeOH (containing ~ 2N NH3) in DCM to give pure 6- (3-fluorophenyl) -N-((6- (2-methylpyridine-4- Yl) pyridin-3-yl) methyl) isoquinolin-1-amine (15.8 mg, ˜75%) was obtained. 1H NMR (400 MHz, CDCl3): δ2.71 (s, 3H), 5.00 (d, J = 5.6Hz, 2H), 7.32-7.38 (m, 2H), 7.59-7.65 (m, 1H), 7.75- 7.83 (m, 3H), 8.10 (d, J = 8.4Hz, 1H), 8.21 (d, J = 8.8Hz, 1H), 8.27-8.31 (m, 2H), 8.39 (s, 2H), 8.72 (d , J = 8.8Hz, 1H), 8.79 (d, J = 6.0Hz, 1H), 8.91 (d, J = 1.6Hz, 1H), 10.02 (s, 1H) .MS m / z 421.2 (M + 1) .

  Example 4: N- (4- (2-methylpyridin-4-yl) benzyl) -2- (2-methylpyridin-4-yl) -1,6-naphthyridin-5-amine (Compound No. 4)

  Process 1:

1,6-Naphthyridin-5 (6H) -one (2.9 g, 19.84 mmol) was dissolved in POCl ₃ (40 mL) and heated to 100 ° C. for 24 hours. After cooling the reaction to room temperature, excess POCl ₃ was removed under vacuum. A small amount of crushed ice in saturated Na ₂ CO ₃ solution was added slowly, resulting in many bubbles and solids. The solid was filtered and the solution was extracted 3 times with EA. The combined organic layers were dried over Na ₂ SO ₄ and concentrated under vacuum. The combined solids were further dried under vacuum to give 5-chloro-1,6-naphthyridine without further purification (2.6 g, yield ˜80%). MS m / z 165.1 (M + 1).

  Process 2:

5-Chloro-1,6-naphthyridine (1.5 g, 9.11 mmol) is dissolved in DCM (45 mL), cooled by an ice bath, and m-CPBA (3.7 g, 2 eq, 77% max) is slowly added in small amounts. Added. The reaction was warmed to RT and continued for 3 hours. An additional 100 ml of DCM was added to the solution and washed with saturated Na ₂ CO ₃ solution, water and brine. The organic layer was dried over Na ₂ SO ₄ , concentrated under vacuum and N-oxide 5-chloro-1,6-naphthyridine as a yellow solid without further purification (1.25 g, yield˜76%) Got.

  Process 3:

N-oxide 5-chloro-1,6-naphthyridine (1.2 g, 6.64 mmol) is dissolved in dry DCM (30 mL), Et3N (1.85 mL, 13.29 mmol) is added, followed by POCl in 5 ml dry DCM. ₃ (0.93 ml, 9.97 mmol) was added dropwise. The reaction was heated to 48 ° C. for 2 hours. An additional 100 ml of DCM was added to the solution and washed with saturated Na ₂ CO ₃ solution, water and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated under vacuum to give a yellow solid. The crude was further purified by a silicon column using EA / hexane (1: 4) to give a white solid 2,5-dichloro-1,6-naphthyridine (0.6 g, yield ˜45%). MS m / z 199.0 (M + 1).

  Process 4:

2,5-dichloro-1,6-naphthyridine (200 mg, 1.0 mmol), 2-methylpyridin-4-yl-4-boronic acid (137 mg, 1.0 mmol), Na ₂ CO ₃ (424 mg, 4.0 mmol) and tetrakis (Triphenylphosphine) palladium (116 mg, 0.1 mmol) was added to the flask and 16 ml of dioxane and 4 ml of water were further added. The reaction was stirred very well and heated to 90 ° C. for 4 hours. After cooling the reaction to RT, the solution was diluted with 100 ml water and extracted three times with EA. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude was further purified by flash chromatography with EA / hexane (1: 1) to give solid 5-chloro-2- (2-methylpyridin-4-yl) -1,6-naphthyridine (143 mg, yield ~ 56). %). MS m / z 256.1 (M + 1).

  Process 5:

5-Chloro-2- (2-methylpyridin-4-yl) -1,6-naphthyridine (20.00 mg, 0.078 mmol) and (4- (2-methylpyridin-4-yl) phenyl) methanamine (25 mg, 0.118 mmol) was dissolved in toluene (2.0 mL). KO ^t Bu (13.2 mg, 0.118 mmol), Pd (OAc) ₂ (2.7 mg, 0.012 mmol) and BINAP (15.0 mg, 0.024 mmol) were added to the mixture under N ₂ . The reaction was heated to 100 ° C. overnight. After cooling the reaction to RT, the mixture was poured into water and extracted three times with EA. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and then concentrated under vacuum. The crude product was purified by prep-TLC with 8% MeOH in DCM by N- (4- (2-methylpyridin-4-yl) benzyl) -2- (2-methylpyridin-4-yl) -1,6- Purified to naphthyridine-5-amine (31 mg, ˜61% yield). ¹ H NMR (400 MHz, DMSO-d6): δ9.12 (d, J = 8.8Hz, 1H), 8.77-8.83 (m, 2H), 8.49 (d, J = 8.4Hz, 1H), 8.40 (s , 1H), 8.31 (d, J = 6.4Hz, 1H), 8.21 (s, 1H), 8.11 (d, J = 5.6Hz, 1H), 8.06 (d, J = 6.4Hz, 1H), 7.99 (d , J = 8.4Hz, 2H), 7.65 (d, J = 8.4Hz, 2H), 7.23 (d, J = 6.4Hz, 1H), 5.76 (s, 1H), 4.93 (d, J = 5.6Hz, 2H ), 2.72 (s, 6H). MS m / z 432.2 (M + 1).

  Example 5: N- (4- (2-methylpyridin-4-yl) benzyl) -2-phenylpyrido [4,3-b] pyrazin-5-amine (Compound No. 5)

  Process 1:

  To 20 ml ethanol was added phenylglyoxal monohydrate (940 mg, 6.99 mmol) and 2-chloro-3,4-diaminopyridine (1000 mg, 6.99 mmol). The mixture was refluxed overnight. After cooling the reaction, the crude precipitated product was filtered, washed with 15 ml ethanol, dried under vacuum and 5-chloro-2-phenylpyrido [3,4-b] pyrazine was obtained without further purification. Obtained (1.28 g, yield ~ 76%). MS m / z 241.0 (M + 1); 1H NMR (300 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.64 (d, J = 6.0Hz, 1H), 8.38-8.43 (m, 2H) , 8.07 (d, J = 6.0Hz, 1H), 7.64-7.68 (m, 3H).

  Process 2:

N- (4- (2-methylpyridin-4-yl) benzyl) -2-phenylpyrido [3,4-b] pyrazin-5-amine (50 mg, 0.21 mmol) and (4- (2-methylpyridin-4 -Il) phenyl) methanamine (42 mg, 0.21 mmol) was dissolved in toluene (4.0 mL). KO ^t Bu (24 mg, 0.21 mmol), Pd (OAc) ₂ (4.5 mg, 0.021 mmol) and BINAP (26.4 mg, 0.042 mmol) were added to the mixture under N ₂ . The reaction was heated to 100 ° C. overnight. After cooling the reaction to RT, the mixture was poured into water and extracted three times with EA. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and then concentrated under vacuum. The crude product was purified by flash chromatography using 7% MeOH in DCM to give N- (4- (2-methylpyridin-4-yl) benzyl) -2-phenylpyrido [4,3-b] pyrazine- 5-Amine (61 mg, yield 72%) was obtained. MS m / z = 404.2 (M + 1); ¹ H NMR (400MHz, DMSO-d6) δ 9.53 (s, 1H), 8.77 (d, J = 6.4Hz, 1H), 8.35-8.39 (m, 2H) , 8.21 (s, 1H), 8.11 (d, J = 6.0Hz, 1H), 8.07 (d, J = 6.4Hz, 1H), 7.96 (d, J = 8.4Hz, 2H), 7.60-7.65 (m, 5H), 7.14 (d, J = 6.0Hz, 1H), 5.76 (s, 1H), 4.90 (d, J = 6.4Hz, 2H), 2.71 (s, 3H).

  One skilled in the art can clearly understand and know that other compounds can be prepared by the same strategy as Examples 1-5.

  Compound table:

  Example 6: Wnt pathway reporter gene assay

  Materials and Methods: NIH3T3 mouse fibroblasts (American Type Culture Collection, Manassas, VA) were transfected with a plasmid containing the luciferase gene driven by 5 copies of the TCF element. Fresh cells selected with 1 μg / mL Zeocin (Gibco / Invitrogen, Carlsbad, Calif.), Dulbecco's modified Eagle supplemented with 10% FBS (Invitrogen), 50 units / mL penicillin and 50 μg / mL streptomycin (Invitrogen) The cells were cultured in a medium (Invitrogen, Carlsbad (CA)) at 37 ° C. in an air atmosphere with 5% CO 2. Suspension HEK293 cells (ATCC) were transfected with a plasmid containing the full-length human Wnt-3a cDNA sequence driven by the CMV promoter, and stable cells were cultured in FreeStyle293 medium (Invitrogen) supplemented with 100 μg / mL G418. Selected.

  NIH3T3 TCF-Luc cells and 293WNT3a cells were co-cultured in 96-well plates in DMEM medium supplemented with 0.5% FBS. After 16 hours, firefly luciferase activity is measured with a Steady-Glo ™ luciferase assay system (Promega). Cells were treated with different concentrations of the compounds of the invention during co-culture. IC50 was defined as the concentration at which the compound decreased the emission intensity by 50%. To normalize cell volume and viability, the CellTiter Glo assay is then performed in duplicate plates.

All compounds shown in the patent have an IC ₅₀ <5 μM in the Wnt pathway reporter gene assay. Optional examples are listed in the table below.

  Example 7: Mechanistic study of Wnt pathway inhibitors

  Compounds that inhibited TCF reporter gene activity induced by Wnt-3a cells co-cultured in the primary assay were followed up in a mechanistic study to identify the site of action of the compound. Two different activators were evaluated, one with purified recombinant Wnt-3a protein (StemRD Inc, Burlingame, CA) and the other with the GSK-3b inhibitor 6-bromoindigo red-3′-oxime ( StemRD Inc, Burlingame, CA).

  The results of such mechanistic studies indicate that some of the active compounds in the present invention were not able to inhibit Wnt-3a interaction with the receptor because they did not inhibit TCF reporter gene activation by the recombinant Wnt-3a protein. It was shown to inhibit Wnt pathway activation at the previous position. Candidates for such action include, but are not limited to, wntless / evenness discontinuity (Wls / Evi), porcupine (Porcn) and Vps35p.

Example 5: Effect of Wnt pathway inhibitor on cancer cells
Compounds that inhibit Wnt secretion and intracellular signaling were expected to depend on autocrine Wnt signaling to inhibit cancer cell growth. Effect of Wnt pathway inhibitors on cell proliferation, anchorage-independent growth and resistance to apoptosis in two-dimensional culture in cell lines known to require Wnt autocrine signaling. Known Wnt-dependent cell lines in published literature: PA-1 (ovarian teratocarcinoma cancer), MDA-MB-157 (breast cancer), Saos-2 (osteosarcoma) and SNU1076 (head and neck squamous cell carcinoma) The compounds are evaluated by using standard assays. Inhibitor effects are seen in these cell lines, further confirming the expected activity for the compounds.

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（式中、X₁、X₂、X₃、X₄、X₅、X₆、X₇およびX₈は、独立してCR₄またはNであり；
Y₁は、水素または-C（R₄）₃であり、それぞれのR₄は、同じか、または異なり；
Y₂およびY₃は、独立して水素、ハロゲンまたは-C（R₃）₃であり、それぞれのR₃は、同じか、または異なり；
R₁およびR₂は、水素、ハロゲン、C_1-6アルキル、キノリニル、

、C_6-30アリール、N、OおよびSから選択される1-2個のヘテロ原子を含む3〜6員のヘテロシクロアルキルおよびN、OおよびSから選択される1-4個のヘテロ原子を含む5または6員のヘテロアリールから独立して選択され、式中キノリニル、

、C_6-30アリール、3〜6員のヘテロシクロアルキルおよび5または6員のヘテロアリールのそれぞれは、1つまたは2つおよび同じ、または異なるR₄で任意に置換することができ；
それぞれのR₃は、水素、ハロゲン、シアノ、C_1-6アルキルおよびC_1-6アルコキシから独立して選択され、式中C_1-6アルキルおよびC_1-6アルコキシのそれぞれは、ハロ、アミノ、ヒドロキシル、C_1-6アルコキシまたはシアノで任意に置換することができ；
それぞれのR₄は、水素、ハロゲン、シアノ、C_1-6アルコキシ、-S（O）₂R₅、-C（O）OR₅、-C（O）R₅、-C（O）NR₆R₇、C_1-6アルキル、C_2-6アルケニルおよびC_2-6アルキニルから独立して選択され、式中それぞれのC_1-6アルコキシ、-S（O）₂R₅、-C（O）OR₅、-C（O）R₅、-C（O）NR₆R₇、C_1-6アルキル、C_2-6アルケニルおよびC_2-6アルキニルは、ハロ、アミノ、ヒドロキシル、C_1-6アルコキシまたはシアノで任意に置換することができ；
R₅、R₆およびR₇は、水素、C_1-6アルキル、C_2-6アルケニルおよびC_2-6アルキニルから独立して選択され、式中、C_1-6アルキル、C_2-6アルケニルおよびC_2-6アルキニルのそれぞれは、ハロ、アミノ、ヒドロキシル、C_1-6アルコキシまたはシアノで任意に置換することができる。） (Appendix)
(Appendix 1)
A compound or a physiologically acceptable salt thereof as a Wnt signaling inhibitor having the structure of the following formula I:

Wherein X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ and X ₈ are independently CR ₄ or N;
Y ₁ is hydrogen or —C (R ₄ ) ₃ , and each R ₄ is the same or different;
Y ₂ and Y ₃ are independently hydrogen, halogen or —C (R ₃ ) ₃ , and each R ₃ is the same or different;
R ₁ and R ₂ are hydrogen, halogen, C _1-6 alkyl, quinolinyl,

3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from C _6-30 aryl, N, O and S and 1-4 heteroatoms selected from N, O and S Independently selected from 5- or 6-membered heteroaryl, including quinolinyl,

Each of C _6-30 aryl, 3-6 membered heterocycloalkyl and 5 or 6 membered heteroaryl can be optionally substituted with one or two and the same or different R ₄ ;
Each R ₃ is independently selected from hydrogen, halogen, cyano, C _1-6 alkyl and C _1-6 alkoxy, wherein each of C _1-6 alkyl and C _1-6 alkoxy is halo, amino Optionally substituted with hydroxyl, C _1-6 alkoxy or cyano;
Each R ₄ is hydrogen, halogen, cyano, C _1-6 alkoxy, —S (O) ₂ R ₅ , —C (O) OR ₅ , —C (O) R ₅ , —C (O) NR ₆ Independently selected from R ₇ , C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, wherein each C _1-6 alkoxy, —S (O) ₂ R ₅ , —C (O ) OR ₅ , —C (O) R ₅ , —C (O) NR ₆ R ₇ , C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are halo, amino, hydroxyl, C _1- Optionally substituted with ₆ alkoxy or cyano;
R ₅ , R ₆ and R ₇ are independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl Each of and C _2-6 alkynyl can be optionally substituted with halo, amino, hydroxyl, C _1-6 alkoxy or cyano. )

から選択される、付記1に記載の化合物。 (Appendix 2)
The core structure of formula I defined by X ₅ , X ₆ , X ₇ and X ₈ is

2. The compound according to supplement 1, wherein the compound is selected from:

から選択される、付記1または2に記載の化合物。 (Appendix 3)
The ring in formula I defined by X ₁ , X ₂ , X ₃ and X ₄ is

The compound according to appendix 1 or 2, selected from:

、フェニル、モルホリニル、ピペラジニル、および、

から選択される5または6員のヘテロアリール、から独立して選択される、付記2または3に記載の化合物。 (Appendix 4)
R ₁ and R ₂ are hydrogen, fluorine, chlorine, methyl,

, Phenyl, morpholinyl, piperazinyl, and

4. The compound according to appendix 2 or 3, which is independently selected from 5 or 6 membered heteroaryl selected from

(Appendix 5)
Each of R ₄ is independently selected from hydrogen, chlorine, fluorine, cyano, —CH ₃ , —CHF ₂ , —CF ₃ , —OCH ₃ , —COOCH ₃ , any one of appendices 2 to 4 Compound described in 1.

(Appendix 6)
At least one atom in formula I corresponds to selected from ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²³ I The compound according to any one of appendices 1 to 5, which is at least one of isotopes.

(Appendix 7)
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((5- (2-methylpyridin-4-yl) pyridin-2-yl) methyl) -7-phenylquinazolin-4-amine;
N- (4-morpholinobenzyl) -7-phenylquinazolin-4-amine;
N-((6-morpholinopyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((6- (2-methylmorpholino) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((6- (4-methylpiperazin-1-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
4- (5-(((7-phenylquinazolin-4-yl) amino) methyl) pyridin-2-yl) thiomorpholine 1,1-dioxide;
N-((6- (6-methylpyridin-3-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((6- (5-methylpyridin-3-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
7-phenyl-N-((6- (pyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7-phenyl-N-((6- (pyridin-3-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7-phenyl-N-((6- (pyridin-2-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7-phenyl-N-((6- (pyridazin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7-phenyl-N-((6- (pyrazin-2-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7-phenyl-N-((6- (pyrimidin-5-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
N-((6- (2-fluoropyridin-4-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((6- (4-methyl-1H-imidazol-1-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((6- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) methyl) -7-phenylquinazolin-4-amine;
N-((5- (6-methylpyridin-3-yl) pyridin-2-yl) methyl) -7-phenylquinazolin-4-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -7-phenylquinazolin-4-amine;
N- (4- (2-fluoropyridin-4-yl) benzyl) -7-phenylquinazolin-4-amine;
N-benzyl-7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4-methylbenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4-methoxybenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4-fluorobenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4-chlorobenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4-bromobenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4- (trifluoromethyl) benzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
4-((7- (2-methylpyridin-4-yl) quinazolin-4-ylamino) methyl) benzonitrile;
N- (4-morpholinobenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4-phenylbenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (3-fluoro-4-phenylbenzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4- (3-fluorophenyl) benzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
7- (3-Fluorophenyl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (3-chlorophenyl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7-m-tolylquinazolin-4-amine;
3- (4-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methylamino) quinazolin-7-yl) benzonitrile;
4- (4-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methylamino) quinazolin-7-yl) benzonitrile;
7- (2-methylpyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (6-methylpyridin-3-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (5-methylpyridin-3-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (pyridin-2-yl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (pyridin-3-yl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (pyridin-4-yl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (pyridazin-4-yl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (pyrazin-2-yl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (pyrimidin-5-yl) quinazolin-4-amine;
7- (2-fluoropyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (2- (trifluoromethyl) pyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (2-methoxypyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (3-methylpyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7-morpholinoquinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (piperidin-1-yl) quinazolin-4-amine;
7- (4-methylpiperazin-1-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
1- (4- (4-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methylamino) quinazolin-7-yl) piperazin-1-yl) ethanone;
4- (4-(((2'-methyl- [2,4'-bipyridin] -5-yl) methyl) amino) quinazolin-7-yl) thiomorpholine 1,1-dioxide;
7- (1,2,3,6-tetrahydropyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (1,2,3,6-tetrahydropyridin-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
1- (4- (4-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methylamino) quinazolin-7-yl) piperidin-1-yl) ethanone;
N-((2′-methyl- [2,4′-bipyridin] -5-yl) methyl) -7- (4- (methylsulfonyl) piperazin-1-yl) quinazolin-4-amine;
7- (1-methyl-1H-pyrazol-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
7- (isoxazol-4-yl) -N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) quinazolin-4-amine;
N-((6- (2-methylpyridin-4-yl) pyridin-3-yl) methyl) -7- (thiazol-2-yl) quinazolin-4-amine;
N- (3-methyl-4- (2-methylpyridin-4-yl) benzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (3-fluoro-4- (2-methylpyridin-4-yl) benzyl) -7- (2-methylpyridin-4-yl) quinazolin-4-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -7- (pyrazin-2-yl) quinazolin-4-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -7- (2-fluoropyridin-4-yl) quinazolin-4-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -7-morpholinoquinazolin-4-amine;
2- (3-Fluorophenyl) -N- (4- (2-methylpyridin-4-yl) benzyl) pyrido [3,4-b] pyrazin-5-amine;
2- (3-fluorophenyl) -N-((2′-methyl- [2,4′-bipyridin] -5-yl) methyl) pyrido [3,4-b] pyrazin-5-amine;
2- (3-fluorophenyl) -N- (3-methyl-4- (2-methylpyridin-4-yl) benzyl) pyrido [3,4-b] pyrazin-5-amine;
N- (3-fluoro-4- (2-methylpyridin-4-yl) benzyl) -2- (3-fluorophenyl) pyrido [3,4-b] pyrazin-5-amine;
2- (2-methylpyridin-4-yl) -N- (4- (2-methylpyridin-4-yl) benzyl) pyrido [3,4-b] pyrazin-5-amine;
N-((2'-methyl- [2,4'-bipyridin] -5-yl) methyl) -2- (2-methylpyridin-4-yl) pyrido [3,4-b] pyrazin-5-amine ;
N- (3-methyl-4- (2-methylpyridin-4-yl) benzyl) -2- (2-methylpyridin-4-yl) pyrido [3,4-b] pyrazin-5-amine;
N- (3-fluoro-4- (2-methylpyridin-4-yl) benzyl) -2- (2-methylpyridin-4-yl) pyrido [3,4-b] pyrazin-5-amine;
N-((2 ′, 3-dimethyl- [2,4′-bipyridin] -5-yl) methyl) -6- (pyrazin-2-yl) -2,7-naphthyridin-1-amine;
6- (2-methylmorpholino) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
(S) -6- (2-Methylmorpholino) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
(R) -6- (2-methylmorpholino) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
1- (4- (8-((4- (2-methylpyridin-4-yl) benzyl) amino) -2,7-naphthyridin-3-yl) piperazin-1-yl) ethanone;
6- (1H-imidazol-1-yl) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
6- (4-Methyl-1H-imidazol-1-yl) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -6- (1H-tetrazol-5-yl) -2,7-naphthyridin-1-amine;
6- (5-methyl-1,3,4-oxadiazol-2-yl) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
6- (1-methyl-1H-pyrazol-3-yl) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -6- (thiazol-5-yl) -2,7-naphthyridin-1-amine;
N- (4- (2-methylpyridin-4-yl) benzyl) -6- (oxazol-5-yl) -2,7-naphthyridin-1-amine;
N-((2 ′, 3-dimethyl- [2,4′-bipyridin] -5-yl) methyl) -6- (5-methylpyridin-3-yl) -2,7-naphthyridin-1-amine;
N-((2 ′, 3-dimethyl- [2,4′-bipyridin] -5-yl) methyl) -6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-amine;
N-((3-Fluoro-2'-methyl- [2,4'-bipyridin] -5-yl) methyl) -6- (2-methylpyridin-4-yl) -2,7-naphthyridine-1- Amines;
N-((2 ′, 3-dimethyl- [2,4′-bipyridin] -5-yl) methyl) -6- (5-fluoropyridin-3-yl) -2,7-naphthyridin-1-amine;
N- (3-methyl-4- (2-methylpyridin-4-yl) benzyl) -6- (pyrazin-2-yl) -2,7-naphthyridin-1-amine;
N- (3-fluoro-4- (2-methylpyridin-4-yl) benzyl) -6- (pyrazin-2-yl) -2,7-naphthyridin-1-amine;
Methyl 4- (8-((4- (2-methylpyridin-4-yl) benzyl) amino) -2,7-naphthyridin-3-yl) piperazine-1-carboxylate;
4- (8-((4- (2-methylpyridin-4-yl) benzyl) amino) -2,7-naphthyridin-3-yl) piperazin-2-one;
2- (4- (8-((4- (2-methylpyridin-4-yl) benzyl) amino) -2,7-naphthyridin-3-yl) piperazin-1-yl) acetonitrile;
2-methyl-4- (4-(((6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-yl) amino) methyl) phenyl) pyridine 1-oxide;
6- (2-chloropyridin-4-yl) -N-((2 ′, 3-dimethyl- [2,4′-bipyridin] -5-yl) methyl) -2,7-naphthyridin-1-amine;
6- (2-chloropyridin-4-yl) -N- (4- (2-methylpyridin-4-yl) benzyl) -2,7-naphthyridin-1-amine;
2- (2-methylpyridin-4-yl) -5-(((6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-yl) amino) methyl) benzonitrile;
N- (3-methoxy-4- (2-methylpyridin-4-yl) benzyl) -6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-amine;
N-((3-Chloro-2'-methyl- [2,4'-bipyridin] -5-yl) methyl) -6- (2-methylpyridin-4-yl) -2,7-naphthyridine-1- Amines;
2'-methyl-5-(((6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-yl) amino) methyl)-[2,4'-bipyridine] -3-carbo Nitrile;
Appendix 1 selected from N- (4- (2- (difluoromethyl) pyridin-4-yl) benzyl) -6- (2-methylpyridin-4-yl) -2,7-naphthyridin-1-amine Compound described in 1.

(Appendix 8)
A pharmaceutical composition comprising the compound according to any one of appendices 1 to 7 or a physiologically acceptable salt thereof.

(Appendix 9)
9. The pharmaceutical composition according to appendix 8, wherein the pharmaceutical composition is an oral composition, an injectable composition, or a suppository.

(Appendix 10)
The oral composition is a tablet or gelatin capsule; the injectable composition is an aqueous isotonic solution or suspension; and the suppository is prepared from a fat emulsion or suspension. 9. The pharmaceutical composition according to 9.

(Appendix 11)
At least one diluent selected from lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and glycine; a lubricant selected from silica, talc, stearic acid, its magnesium and calcium salts and polyethylene glycol; magnesium magnesium silicate A binder selected from starch glue, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone; a disintegrant selected from starch, agar, alginic acid and its sodium salts and effervescent mixtures; Item 9. The pharmaceutical composition according to appendix 8, further comprising an additive selected from a colorant, a flavor and a sweetener.

(Appendix 12)
9. The pharmaceutical composition according to appendix 8, further comprising at least one adjuvant selected from preservatives, stabilizers, wetting agents, emulsifiers, solution promoters, salts for regulating osmotic pressure and buffers.

(Appendix 13)
The pharmaceutical composition according to appendix 8 or 12, further comprising a solubilizer, a stabilizer, a tonicity enhancing agent, a buffer and a preservative.

(Appendix 14)
14. The pharmaceutical composition according to appendix 13, wherein the pharmaceutical composition is for topical application and is in the form of an aqueous solution, ointment, cream or gel.

(Appendix 15)
Contacting the cell with an effective amount of a compound according to any one of appendices 1-7 or a physiologically acceptable salt thereof or a pharmaceutical composition according to any one of appendices 8-14, A method of inhibiting Wnt secretion from cells.

(Appendix 16)
Contacting the cell with an effective amount of a compound according to any one of appendices 1-7 or a physiologically acceptable salt thereof or a pharmaceutical composition according to any one of appendix 8-14, A method of inhibiting Wnt signaling in a cell.

(Appendix 17)
A compound according to any one of appendices 1-7 or a physiologically acceptable salt thereof or any one of appendices 8-14 for the manufacture of a medicament for treating a disorder mediated by the Wnt pathway Use of the pharmaceutical composition described in 1.

(Appendix 18)
A method for treating a disorder mediated by the Wnt pathway in a subject suffering therefrom, comprising a therapeutically effective amount of a compound according to any one of appendices 1 to 7 or a physiological salt thereof Or a pharmaceutical composition according to any one of appendices 8-14, wherein the subject comprises administering to the subject.

(Appendix 19)
The use according to appendix 17 or the method according to appendix 18, wherein the disorder is cancer, fibrosis, osteoarthritis, Parkinson's disease, retinopathy, macular degeneration.

(Appendix 20)
Said cancers include lung, breast, prostate, carcinoid, bladder, stomach, pancreas, liver or hepatocytes, hepatoblastoma, colorectal, kidney and head cancer, and cervical squamous cell carcinoma, including small and non-small cells , Esophagus, ovary, cervix, endometrium, mesothelioma, melanoma, sarcoma, osteosarcoma, liposarcoma, thyroid, tendon, chronic myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) The use or method according to appendix 19.

(Appendix 21)
Appendix 19, wherein said fibrosis is selected from systemic sclerosis, skin fibrosis, idiopathic pulmonary fibrosis, kidney fibrosis, liver fibrosis, drug-induced fibrosis and radiation-induced fibrosis Use or method as described in.

(Appendix 22)
22. The method of any one of appendices 18-21, wherein the therapeutically effective amount is about 0.03 to about 2.5 mg / kg body weight at a daily dose.

(Appendix 23)
24. The method of appendix 22, wherein the therapeutically effective amount is about 0.5 mg to about 1000 mg for a human.

(Appendix 24)
The method of any one of appendices 18-23, wherein the compound is administered enterally, orally, parenterally, topically, or in nasal or suppository form.

Claims (1)

A compound or a physiologically acceptable salt thereof as a Wnt signaling inhibitor having the structure of the following formula I:

Wherein X ₁ , X ₂ , X ₃ , X ₄ , X ₅ , X ₆ , X ₇ and X ₈ are independently CR ₄ or N;
Y ₁ is hydrogen or —C (R ₄ ) ₃ , and each R ₄ is the same or different;
Y ₂ and Y ₃ are independently hydrogen, halogen or —C (R ₃ ) ₃ , and each R ₃ is the same or different;
R ₁ and R ₂ are hydrogen, halogen, C _1-6 alkyl, quinolinyl,

3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from C _6-30 aryl, N, O and S and 1-4 heteroatoms selected from N, O and S Independently selected from 5- or 6-membered heteroaryl, including quinolinyl,

Each of C _6-30 aryl, 3-6 membered heterocycloalkyl and 5 or 6 membered heteroaryl can be optionally substituted with one or two and the same or different R ₄ ;
Each R ₃ is independently selected from hydrogen, halogen, cyano, C _1-6 alkyl and C _1-6 alkoxy, wherein each of C _1-6 alkyl and C _1-6 alkoxy is halo, amino Optionally substituted with hydroxyl, C _1-6 alkoxy or cyano;
Each R ₄ is hydrogen, halogen, cyano, C _1-6 alkoxy, —S (O) ₂ R ₅ , —C (O) OR ₅ , —C (O) R ₅ , —C (O) NR ₆ Independently selected from R ₇ , C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, wherein each C _1-6 alkoxy, —S (O) ₂ R ₅ , —C (O ) OR ₅ , —C (O) R ₅ , —C (O) NR ₆ R ₇ , C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are halo, amino, hydroxyl, C _1- Optionally substituted with ₆ alkoxy or cyano;
R ₅ , R ₆ and R ₇ are independently selected from hydrogen, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl Each of and C _2-6 alkynyl can be optionally substituted with halo, amino, hydroxyl, C _1-6 alkoxy or cyano. )