Inhibitors of the Notch signaling pathway and their use in the treatment of cancer - Patents.com

Abstract

The present invention relates to novel inhibitors of the Notch signaling pathway and their use in the treatment and / or prevention of cancer. JPEG2022529324000207.jpg44170

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel inhibitors of the Notch signaling pathway and their use in the treatment and / or prevention of cancer. [Background technology]

[0002] Background of the Invention The Notch signaling pathway is a key component in the molecular circuitry that controls cell fate during development, cell survival, and cell proliferation (Shih IeM, Wang TL in Cancer Res 2007;67(5):1879-82). Aberrant activation of this pathway contributes to tumorigenesis. Notch family members are being identified as oncogenes in an ever-increasing number of cancers. The role of Notch in human cancers has recently been highlighted by the presence of activating mutations and amplifications of Notch genes in human cancers and the demonstration that genes / proteins in the Notch signaling pathway can serve as potential therapeutic targets. One of the primary therapeutic targets of the Notch pathway is the Notch receptor, where γ-secretase inhibitors have been shown to prevent the generation of the oncogenic (intracellular) domain of the Notch molecule and suppress Notch activity.

[0003] Although significant progress has been made in dissecting the complex mechanisms of this signaling pathway, the options available for developing novel Notch inhibitors are very limited. However, pioneering classes of Notch inhibitors are already in clinical trials for a few cancer types, including Ayala Pharma's γ-secretase inhibitor AL101 (formerly BMS 906024), Eli Lilly's LY3039478, and Springworks Therapeutics' nirogacestat. These inhibitors inhibit the Notch signaling pathway and may consequently induce growth arrest in tumor cells in which the Notch signaling pathway is overactivated.

[0004] One drawback of using γ-secretase inhibitors to block Notch signaling, as currently under investigation, is the broad range of additional targets, such as amyloid precursor protein. Due to their ability to block Notch signaling through all four receptors, γ-secretase inhibitors are known to induce goblet cell metaplasia in the intestine. Furthermore, several hematological malignancies and solid tumors harbor mutations (e.g., chromosomal translocations) in the Notch receptor, resulting in the constitutive expression of a dominant active form of NICD, independent of cleavage by the γ-secretase complex. Therefore, these tumors may not respond to γ-secretase inhibitor treatment.

[0005] WO2013 / 093885 discloses some Notch inhibitory compounds, and particularly discloses 6-(4-tert-butylphenoxy)pyridin-3-amine as a preferred compound. The measured Notch inhibition varies significantly among the disclosed compounds. Therefore, there remains a need to identify and develop additional specific and selective inhibitors of the Notch signaling pathway with improved properties useful for the treatment and / or prevention of cancer. Summary of the Invention

[0006] Summary of the Invention The present invention relates to a compound of formula (I) JPEG0007624930000001.jpg60170 [wherein X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3)alkyl, NH, N(C1-C3 alkyl), S, SO, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 4 , R 5 and R 6are each independently H, halogen, CN, C1-C6 alkoxy, C1-C6-S-alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl and C3-C 12 heterocyclyl; In the formula, R 7 is Y 1 If N, it does not exist or Y 1 When is C, H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 8 is Y 3 If N, it does not exist or Y 3 When is C, H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 9 is Y 2 is absent when N, or H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 12 is H, NH, NHC, C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12 Cycloalkyl and C3-C 12 heterocyclyl; with the proviso that the compound of formula (I) is not 6-([1,1'-biphenyl]-4-yloxy)-pyridin-3-amine, 4-([1,1'-biphenyl]-4-yloxy)-aniline, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine and 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine. or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

[0007] The present invention also provides a compound of formula (I) for use in a method for the prevention or treatment of cancer, preferably for use in a method for the prevention or treatment of Notch-dependent cancer. JPEG0007624930000002.jpg61170 [wherein X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3)alkyl, NH, N(C1-C3 alkyl), S, SO, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C; In the formula, Z is NR 10 R 11 [where R 10 and R 11are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 4 , R5 and R 6 are each independently H, halogen, CN, C1-C6 alkoxy, C1-C6-S-alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl and C3-C 12 heterocyclyl; In the formula, R 7 is Y 1 If N, it does not exist or Y 1 When is C, H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 8 is Y 3 If N, it does not exist or Y 3 When is C, H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 9 is Y 2 is absent when N, or H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 12 is H, NH, NHC, C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12 Cycloalkyl and C3-C 12 heterocyclyl] The present invention provides a compound of formula (I), a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof. The present invention also provides pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, and kits comprising a compound of formula (I), optionally together with reagents and / or instructions. The present invention also provides use of a compound of formula (I) for inhibiting the Notch signaling pathway in a cell in vitro or in vitro.

[0008] Surprisingly, the inventors of the present application have found that compounds that differ substantially in terms of chemical structure from the compounds specifically disclosed in WO2013 / 093885 exhibit unparalleled biological properties in inhibiting Notch, such as high potency against NOTCH-driven human cancers and high potency in downregulating NOTCH target genes. [Brief explanation of the drawings]

[0009] [Figure 1] Figure 1 shows the antiproliferative effects of compounds on a NOTCH-positive and NOTCH-dependent human leukemia cell line (RPMI8402). Cells were treated with compounds for 72 hours, and the effect on proliferation was quantified using Alamar Blue readout. [Figure 2]Figure 2 shows the effect of 6-([1,1'-biphenyl]-4-yloxy)-N-methylpyridin-3-amine on N1-ICD and cMYC (NOTCH target genes) in human leukemia cells. NOTCH-positive human leukemia RPMI8402 cells were treated with 1 μM 6-(4-tert-butylphenoxy)pyridin-3-amine and 6-([1,1'-biphenyl]-4-yloxy)-N-methylpyridin-3-amine for 24 hours. After treatment, total protein lysates were extracted, and protein expression was analyzed by Western blot. The data show that 6-([1,1'-biphenyl]-4-yloxy)-N-methylpyridin-3-amine has enhanced efficacy in downregulating the NOTCH pathway in human cancer cells compared to 6-(4-tert-butylphenoxy)pyridin-3-amine. [Figure 3]FIG. 3 shows the effects of 6-((4′-fluoro-[1,1′-biphenyl]-4-yl)oxy)pyridin-3-amine, 6-([1,1′-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 6-([1,1′-biphenyl]-4-yloxy)-2-methylpyridin-3-amine and N-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine on N1-ICD and cMYC (NOTCH target genes) in human leukemia cells. NOTCH-positive human leukemia RPMI8402 cells were treated with 1 μM of 6-(4-tert-butylphenoxy)pyridin-3-amine, 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, and N-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine for 24 hours. After treatment, total protein lysates were extracted, and protein expression was analyzed by Western blot. The data show that 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine and N-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine have enhanced potency in downregulating the NOTCH pathway in human cancer cells compared to 6-(4-tert-butylphenoxy)pyridin-3-amine. DETAILED DESCRIPTION OF THE INVENTION

[0010] Detailed Description of the Invention All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0011] In case of conflict, the present specification, including definitions, will control. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this specification belongs. As used herein, the following definitions are provided to facilitate understanding of the present invention.

[0012] As used herein, the term "comprise" is used generally in the sense of include / including, i.e., allowing for the presence of one or more features or components. The terms "comprise" and "comprising" also encompass the more restrictive terms "consist" and "consisting."

[0013] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0014] As used herein, the term "subject" is well-recognized in the art and refers to a mammal, including dogs, cats, rats, mice, monkeys, cows, horses, goats, sheep, pigs, camels, and most preferably humans. In some embodiments, the subject is a subject in need of treatment or a subject with a disease or disorder, such as cancer. However, in other embodiments, the subject may be a normal subject or a subject who has already undergone treatment for cancer. The term does not denote a particular age or sex. Thus, adult, pediatric, and neonatal subjects, whether male or female, are intended to be included.

[0015] As used herein, the terms "cancer," "cancer cell," "cell proliferative disease," and "cell proliferative disorder" refer to or describe a physiological condition in a mammal that is typically characterized by unregulated cell proliferation. According to the present invention, cancer preferably refers to solid tumors, such as those of the salivary gland, liver, brain, breast, prostate, colorectal, kidney, lung, sarcoma, or melanoma, and liquid tumors affecting the blood, such as leukemia. More preferably, according to the present invention, the cancer is a Notch-dependent cancer selected from the group including adenoid cystic carcinoma (ACC), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), mantle cell lymphoma, breast cancer, pancreatic cancer, prostate cancer, melanoma, brain tumor, tumor angiogenesis, liver cancer, and colorectal cancer. Even more preferably, the Notch-dependent cancer is resistant to gamma-secretase inhibitor treatment. Examples of gamma-secretase inhibitor therapy include: 1) the gamma-secretase inhibitors RO4929097 and cediranib maleate in the treatment of patients with advanced solid tumors (NCT01131234); 2) the gamma-secretase inhibitor RO4929097 in the treatment of younger patients with relapsed or refractory solid tumors, CNS tumors, lymphoma, or T-cell leukemia (NCT01088763); 3) a study of MK-0752 in combination with tamoxifen or letrozole to treat early-stage breast cancer (NCT00756717); and 4) GDC-0449 and RO4929097 in the treatment of patients with advanced or metastatic sarcoma (NCT01154452). ), 5) RO4929097 and erlotinib hydrochloride in the treatment of patients with stage IV or recurrent non-small cell lung cancer (NCT01193881); 6) bicalutamide and RO4929097 in the treatment of patients with previously treated prostate cancer (NCT01200810); 7) RO4929097 in the treatment of patients with recurrent invasive glioma (NCT01269411); 8) Notch signaling pathway inhibitors for patients with T-cell acute lymphoblastic leukemia / lymphoma (ALL) (NCT00100152); and 9) RO4929097 in the treatment of patients with metastatic colorectal cancer (NCT01116687).

[0016] The term "alkyl" as used herein refers to a saturated straight or branched chain group of carbon atoms derived from an alkane by the removal of one hydrogen atom. C1-C3 alkyl includes, for example, methyl, ethyl, n-propyl, i-propyl, and preferably unbranched C1-C3 alkyl. C1-C4 alkyl includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and tert-butyl, and preferably unbranched C1-C4 alkyl. C1-C6 alkyl includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, and n-hexyl, and preferably unbranched C1-C6 alkyl. C1-C 10 Alkyl includes, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl, preferably unbranched C-C 10 This includes alkyl. As used herein, the term "C0 alkyl" refers to a covalent bond. Thus, for example, the term "C0 alkylOC0 alkylaryl" refers to Oaryl.

[0017] The term "C0-C3 alkylOC0-C3 alkylaryl" as used herein refers to O-aryl, as defined herein, when both C0-C3 alkyl groups are C0 alkyl. The term refers to O-C3 alkylaryl when the first C0-C3 alkyl group is C0 alkyl. The term refers to C0-C3 alkylO-aryl when the second C0-C3 alkyl group is C0 alkyl. Preferably, the C0-C3 alkylOC0-C3 alkylaryl is C0-C3 alkylO-aryl, more preferably O-aryl or C1-C3 alkylO-aryl. The term "C0-C3 alkylOC0-C3 alkylheteroaryl" as used herein refers to O-heteroaryl, as defined herein, when both C0-C3 alkyl groups are C0 alkyl. The term refers to O-C3 alkylheteroaryl when the first C0-C3 alkyl group is C0 alkyl. The term refers to C0-C3 alkylO-heteroaryl when the second C0-C3 alkyl group is C0 alkyl. Preferably, the CO-C3 alkylOC0-C3 alkylheteroaryl is CO-C3 alkylOheteroaryl, more preferably Oheteroaryl or C1-C3 alkylOheteroaryl, most preferably Oheteroaryl. The aryl and heteroaryl of the CO-C3 alkylOC0-C3 alkylaryl and CO-C3 alkylOC0-C3 alkylheteroaryl can be NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 It may be substituted with a heterocyclyl, preferably with NH2.

[0018] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, where one, two, three, or four hydrogen atoms are bonded to an OR group, with the understanding that the point of attachment of the heteroalkyl group is through a carbon atom. a , C(O)OR a , N.R. b R c , C(O)NR b Rc , S(O) n R d (n is an integer from 0 to 2) and halogen, a is H, C1-C3 alkylcarbonyl, C1-C3 alkyl, or C 3-7 is cycloalkyl; R b and R c are each independently H, C1-C3 alkylcarbonyl, C1-C3 alkyl, C 3-7 cycloalkyl, or NR b R c is guanidinyl; when n is 0, R d is H, C1-C3 alkyl or C 3-7 cycloalkyl, and when n is 1 or 2, R d is C1-C3 alkyl or C 3-7 Preferably, the term "heteroalkyl" or "heteroalkanediyl" as used herein refers to an alkyl group or alkanediyl group, as defined herein, wherein one, two, three, or four hydrogen atoms are replaced with substituents independently selected from the group consisting of OH, NH, guanidinyl, and halogen; more preferably, one or two hydrogen atoms are replaced with substituents independently selected from the group consisting of OH, NH, and halogen. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2-hydroxy-1-methylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 1-hydroxy-2-methylpropyl, 3-hydroxy-1-(2-hydroxyethyl)-propyl, 2-hydroxy-1-methylpropyl, 1,1,1-trifluoroethyl, 1,1,1-trifluoromethyl, and 2,2,3,3-tetrafluoropropyl.

[0019] As used herein, "C 3-12 Cycloalkyl" and "C 3-7The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon radical, preferably a monovalent saturated monocyclic radical having 3 to 12 or 3 to 7 carbon atoms, respectively, derived from a cycloalkane by the removal of a single hydrogen atom. 3-7 "Cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. 3-12 Cycloalkyl" and "C 3-7 The term "cycloalkyl" also refers to C 1-3 This includes cycloalkyl groups containing alkyl groups. 3-7 Examples of "cycloalkyl" groups include cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, and 2-cyclopentylethyl. The cycloalkyl groups of this invention may be substituted.

[0020] The terms "aryloxy" or "Oaryl," as used interchangeably herein, refer to the group --OR, where R is aryl as defined herein, e.g., phenoxy.

[0021] The terms "C1-C6 alkoxy" or "C1-C6 alkyl," as used interchangeably herein, refer to the group -OR, where R is C1-C6 alkyl as defined herein. Examples are methoxy, ethoxy, propoxy, and butoxy.

[0022] The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings, preferably a monocyclic carbocyclic ring system. The aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane, or cyclopentene ring, or to a cyclohexane, cyclohexene, cyclopentane, or cyclopentene ring containing a carbonyl group. The aryl group of the present invention can be optionally substituted as further described below. Preferred aryl groups and optionally substituted aryl groups of the present invention are phenyl groups or substituted phenyl groups, respectively. Substituents include, for example, NH, O-C alkyl, C-C alkyl, C-C heteroalkyl, halogen, CN, C-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 It could be.

[0023] As used herein, the term "heteroaryl" refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic and 9- or 10-membered bicyclic groups, preferably substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, which have at least one heteroatom (O, S, or N) in at least one of the rings. Each ring of a heteroatom-containing heteroaryl group can contain one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic group can contain only carbon atoms and can be saturated, partially saturated, or unsaturated. A heteroaryl group must contain at least one fully aromatic ring, but the other fused ring or rings can be aromatic or non-aromatic. The heteroaryl group may be attached to any available nitrogen or carbon atom of any ring. The heteroaryl groups of this invention can be optionally substituted as further described below. Typically, the heteroaryl group and optionally substituted heteroaryl group of the present invention are each selected from the group consisting of substituted and / or unsubstituted aromatic 5- or 6-membered monocyclic groups, which have at least one heteroatom (O, S, or N) in the ring, preferably one or two heteroatoms selected from S and N, more preferably one S and one N in the ring, or one or two N in the ring. Preferred heteroaryl groups are optionally substituted heteroaryl groups selected from the group consisting of optionally substituted pyridinyl groups, optionally substituted pyrimidinyl groups, optionally substituted di- or triazine groups, optionally substituted thiazole groups, optionally substituted oxazole groups, and optionally substituted imidazole groups. Even more preferred heteroaryl groups are optionally substituted pyridinyl groups, optionally substituted pyrimidinyl groups, optionally substituted imidazole groups, or optionally substituted thiazole groups. Most preferably, optionally substituted pyridinyl groups, optionally substituted imidazole groups, or optionally substituted thiazole groups are used as heteroaryl groups in the present invention.Examples of the optionally substituted substituents include NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, and C3-C. 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 , or NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 It may be a heterocyclyl.

[0024] As used herein, the term "heterocyclyl" refers to a saturated monocyclic ring having 3 to 12, preferably 3 to 7, and more preferably 5 to 6 ring atoms, containing up to three, preferably 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, with the remaining ring atoms being carbon atoms. Examples of such saturated heterocycles include [1,3]dioxanyl, [1,3]dioxolanyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, oxazolidinyl, thiazolidinyl, azepanyl, and the like. Preferably, such heterocyclyl groups are unsubstituted.

[0025] The term "halo" or "halogen" as used herein refers to F, Cl, Br, or I, preferably F, Cl, or Br, and more preferably F.

[0026] The term "optionally substituted" or "substituted" means that the referenced group is substituted with one or more additional groups, preferably one additional group, individually and independently selected from the listed groups.

[0027] The compound 6-([1,1′-biphenyl]-4-yloxy)-pyridin-3-amine, which is excluded from the compounds of formula (I) in some aspects or embodiments of the present invention, has the following chemical structure: JPEG0007624930000003.jpg24170

[0028] The compound 4-([1,1′-biphenyl]-4-yloxy)-aniline, which is excluded from the compounds of formula (I) in some aspects or embodiments of the present invention, has the following chemical structure: JPEG0007624930000004.jpg23170

[0029] The compound 6-([1,1′-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, which is excluded from the compounds of formula (I) in some aspects or embodiments of the present invention, has the following chemical structure: JPEG0007624930000005.jpg22170

[0030] The compound 6-([1,1′-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, which is excluded from the compounds of formula (I) in some aspects or embodiments of the present invention, has the following chemical structure: JPEG0007624930000006.jpg22170

[0031] The compound 4-(4'-methoxy-biphenyl-4-yloxy)phenylamine, which is excluded from the compounds of formula (I) in some aspects or embodiments of the present invention, has the following chemical structure: JPEG0007624930000007.jpg26170

[0032] The compound 4-(4'-chloro-biphenyl-4-yloxy)phenylamine, which is excluded from the compounds of formula (I) in some aspects or embodiments of the present invention, has the following chemical structure: JPEG0007624930000008.jpg24170

[0033] The compound 4-(4'-tert-butyl-biphenyl-4-yloxy)phenylamine, which is excluded from the compounds of formula (I) in some aspects or embodiments of the present invention, has the following chemical structure: JPEG0007624930000009.jpg25170

[0034] The compound 4-(4-(thiazol-2-yl)phenoxy)aniline, which is excluded from the compounds of formula (I) in some aspects or embodiments of the present invention, has the following chemical structure: JPEG0007624930000010.jpg29170

[0035] The compound 4-(4-(1H-imidazol-2-yl)phenoxy)aniline, which is excluded from the compounds of formula (I) in some aspects or embodiments of the present invention, has the following chemical structure: JPEG0007624930000011.jpg31170

[0036] The compound 4-(4-(oxazol-2-yl)phenoxy)aniline, which is excluded from the compounds of formula (I) in some aspects or embodiments of the present invention, has the following chemical structure: JPEG0007624930000012.jpg30170

[0037] The compound 4-(4-(1H-pyrrol-1-yl)phenoxy)aniline, which is excluded from the compounds of formula (I) in some aspects or embodiments of the present invention, has the following chemical structure: JPEG0007624930000013.jpg29170

[0038] Thus, in a first aspect, the present invention provides a compound of formula (I) JPEG0007624930000014.jpg61170 [wherein X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3)alkyl, NH, N(C1-C3 alkyl), S, SO, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C; In the formula, Z is NR 10 R 11 [where R 10 and R 11are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 4 , R5 and R 6 are each independently H, halogen, CN, C1-C6 alkoxy, C1-C6-S-alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl and C3-C 12 heterocyclyl; In the formula, R 7 is Y 1 If N, it does not exist or Y 1 When is C, H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 8 is Y 3 If N, it does not exist or Y 3 When is C, H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 9 is Y 2 is absent when N, or H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 12 is H, NH, NHC, C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12 Cycloalkyl and C3-C 12 heterocyclyl; provided that the compound of formula (I) is not 6-([1,1'-biphenyl]-4-yloxy)-pyridin-3-amine, 4-([1,1'-biphenyl]-4-yloxy)-aniline, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine and 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, and preferably the compound of formula (I) is 6-([1,1'-biphenyl]-4-yloxy) -pyridin-3-amine, 4-([1,1'-biphenyl]-4-yloxy)-aniline, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 4-(4'-methoxy-biphenyl-4-yloxy)phenylamine, 4-(4'-chloro-biphenyl-4-yloxy)phenylamine, and 4-(4'-tert-butyl-biphenyl-4 more preferably, the compound of formula (I) is 6-([1,1'-biphenyl]-4-yloxy)-pyridin-3-amine, 4-([1,1'-biphenyl]-4-yloxy)-aniline, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 4-(4'-methoxy-biphenyl-4-yloxy)phenylamine. 4-(4-(4-(1H-pyrrol-1-yl)phenoxy)aniline, 4-(4-(1H-imidazol-2-yl)phenoxy)aniline, 4-(4-(oxazol-2-yl)phenoxy)aniline, and 4-(4-(1H-pyrrol-1-yl)phenoxy)aniline. or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

[0039] The Notch signaling pathway is evolutionarily conserved, and the fundamental molecular players of this pathway are ligands (Delta and Jagged), Notch receptors, and transcription factors (Shih IeM, Wang TL in Cancer Res 2007;67(5):1879-82). Notch is a transmembrane heterodimeric receptor, and four distinct members (Notch1, Notch2, Notch3, and Notch4) exist in humans and rodents. Under physiological conditions, binding of a Notch ligand to its receptor initiates Notch signaling by releasing the intracellular domain of the Notch receptor (Notch-ICD) through a cascade of proteolytic cleavages by both α-secretase (also known as tumor necrosis factor-α-converting enzyme) and γ-secretase. The released intracellular Notch-ICD then translocates into the nucleus, where it regulates gene expression, primarily by binding to the ubiquitous transcription factor CBF1, suppressor of hairless, and Lag-1 (CSL). This binding recruits transcriptional activators to the CSL complex, converting them from transcriptional repressors to activators, which then stimulate several downstream effectors.The physiological functions of Notch signaling are multifaceted, including the maintenance of stem cells, cell fate specification, and regulation of differentiation during development and tumorigenesis.

[0040] In cancer, molecular genetic alterations such as chromosomal translocations, point mutations, and chromosomal amplifications at the Notch receptor locus are known mechanisms of constitutive activation of the Notch pathway. Despite different mechanisms, these all result in increased levels of intracellular Notch-IC. The oncogenic potential of Notch was first discovered in human T-cell acute lymphoblastic leukemia (T-ALL), adenoid cystic carcinoma (ACC), breast cancer, and chronic lymphocytic leukemia (CLL). Notch1 signaling is essential for the normal development of T-cell progenitors, and constitutive activation of Notch1 signaling due to molecular genetic alterations has been associated with T-ALL. For example, interstitial deletions of the extracellular portion of human Notch1 due to chromosomal translocations are associated with approximately 1% of T-ALL cases, and activating point mutations in Notch1 are present in approximately 50% of T-ALL cases. T-cell leukemia / lymphoma formation has been observed in Notch-ICD transgenic mouse models, indicating a causal role of Notch activation in T-ALL development. In non-small cell lung cancer, chromosomal translocations have been identified in a subset of tumors, and these translocations are thought to increase Notch3 transcription in tumors. In ovarian cancer, Notch3 gene amplification has been found to occur in approximately 19% of tumors, and Notch3 overexpression has been found in more than half of serous ovarian cancers. Similarly, Notch signaling activation has been implicated in breast cancer development. In animal models, constitutively active Notch4 expression leads to breast tumors in mice, and Notch1-activating mutations contribute to the development of T-ALL. Recent studies have further demonstrated that overexpression of activated Notch1 and Notch3 in transgenic mice blocks mammary gland development and induces mouse breast tumors. Activated Notch signaling has also been implicated in lung and bone metastasis of breast cancer cells. Overexpression of Notch3 is sufficient to induce choroid plexus tumor formation in mouse models, suggesting a role for Notch3 in the development of certain types of brain tumors.

[0041] The present invention also encompasses chemical modification of the compounds of the present invention to extend their circulatory life. Non-limiting examples of methods for transiently or reversibly PEGylating drugs, including polypeptide-based drugs, are provided in U.S. Patent Nos. 4,935,465 (issued June 19, 1990) and 6,342,244 (issued January 29, 2002); and U.S. Published Application No. US2006 / 0074024. Those skilled in the art will typically find more detailed information regarding PEG-based reagents in published applications such as WO2005047366, US2005171328, and the NEKTAR PEG Reagent Catalog® 2005-2006 (Nektar Therapeutics, San Carlos, Calif.).

[0042] The present invention also relates to salts, hydrates, or solvates of the compounds of formula (I). Preferably, these salts, hydrates, and / or solvates are pharmaceutically acceptable. According to the present invention, pharmaceutically acceptable salts are prepared from acidic inorganic or organic compounds, or alkaline inorganic or organic compounds. As used herein, the phrase "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness of the free acids and free bases of the particular compound and that are not biologically or otherwise undesirable.

[0043] The present invention also relates to stereoisomers of the compound of formula (I). "Stereoisomer" or "stereoisomers" refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. When a compound of formula (I) has one or more asymmetric centers or double bonds with asymmetric substitution, it may exist in stereoisomeric forms and therefore may be produced as individual stereoisomers or as mixtures. Unless otherwise specified, the description is intended to include individual stereoisomers as well as mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0044] Those skilled in the art will know that when the compounds of the present invention contain a charged group, suitable counterions will be derived from organic or inorganic acids. Such counterions include halides (chloride, bromide, fluoride, iodide, etc.), sulfate, phosphate, acetate, succinate, citrate, lactate, maleate, fumarate, palmitate, cholate, glutamate, glutarate, tartrate, stearate, salicylate, methanesulfonate, benzenesulfonate, sorbate, picrate, benzoate, cinnamate, etc. If the polar moiety is a negatively charged group, suitable counterions will be selected from sodium, ammonium, barium, calcium, copper, iron, lithium, potassium, lead, etc.

[0045] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable salt, hydrate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0046] Thus, in a further aspect, the present invention provides a compound of formula (I) JPEG0007624930000015.jpg60170 [wherein X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3)alkyl, NH, N(C1-C3 alkyl), S, SO, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12Heterocyclyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 4 , R 5 and R 6 are each independently H, halogen, CN, C1-C6 alkoxy, C1-C6-S-alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12Cycloalkyl and C3-C 12 heterocyclyl; In the formula, R 7 is Y 1 If N, it does not exist or Y 1 When is C, H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 8 is Y 3 If N, it does not exist or Y 3 When is C, H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 9 is Y 2 is absent when N, or H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12and optionally substituted with heterocyclyl; In the formula, R 12 is H, NH, NHC, C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12 Cycloalkyl and C3-C 12 heterocyclyl] and a pharmaceutically acceptable carrier. Preferably, the compound of formula (I) contained in the pharmaceutical composition is not 4-([1,1'-biphenyl]-4-yloxy)-aniline, and more preferably is not 6-([1,1'-biphenyl]-4-yloxy)-pyridin-3-amine, 4-([1,1'-biphenyl]-4-yloxy)-aniline, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, or 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine. Even more preferably, the compound of formula (I) comprised in the pharmaceutical composition is not 6-([1,1'-biphenyl]-4-yloxy)-pyridin-3-amine, 4-([1,1'-biphenyl]-4-yloxy)-aniline, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 4-(4'-methoxy-biphenyl-4-yloxy)phenylamine, 4-(4'-chloro-biphenyl-4-yloxy)phenylamine, and 4-(4'-tert-butyl-biphenyl-4-yloxy)phenylamine. In particular, the compounds of formula (I) contained in the pharmaceutical composition are 6-([1,1'-biphenyl]-4-yloxy)-pyridin-3-amine, 4-([1,1'-biphenyl]-4-yloxy)-aniline, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 4-(4'-methoxy-biphenyl-4-yloxy)phenyl and 4-(4-(1H-pyrrol-1-yl)phenoxy)aniline.

[0047] In a further aspect, the present invention provides a compound of formula (I) for use in a method for the prevention or treatment of cancer. JPEG0007624930000016.jpg59170 [wherein X is selected from CH2, CF2, CHF, CO, CHOH, CHO(C1-C3)alkyl, NH, N(C1-C3 alkyl), S, SO, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 4 , R 5 and R 6 are each independently H, halogen, CN, C1-C6 alkoxy, C1-C6-S-alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl and C3-C 12 heterocyclyl; In the formula, R 7 is Y 1 If N, it does not exist or Y 1 When is C, H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 8 is Y 3 If N, it does not exist or Y 3 When is C, H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, and C1-C6 alkoxy; In the formula, R 9 is Y 2 is absent when N, or H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12Heterocyclyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 12 is H, NH, NHC, C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12 Cycloalkyl and C3-C 12 heterocyclyl] or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof. Preferably, the compound of formula (I) for use in a method for the prevention or treatment of cancer is not 4-([1,1'-biphenyl]-4-yloxy)-aniline, more preferably not 6-([1,1'-biphenyl]-4-yloxy)-pyridin-3-amine, 4-([1,1'-biphenyl]-4-yloxy)-aniline, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, or 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine. Even more preferably, the compound of formula (I) for use in a method for the prevention or treatment of cancer is not 6-([1,1'-biphenyl]-4-yloxy)-pyridin-3-amine, 4-([1,1'-biphenyl]-4-yloxy)-aniline, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 4-(4'-methoxy-biphenyl-4-yloxy)phenylamine, 4-(4'-chloro-biphenyl-4-yloxy)phenylamine, and 4-(4'-tert-butyl-biphenyl-4-yloxy)phenylamine. In particular, compounds of formula (I) for use in a method for the prevention or treatment of cancer include 6-([1,1'-biphenyl]-4-yloxy)-pyridin-3-amine, 4-([1,1'-biphenyl]-4-yloxy)-aniline, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 4-(4'-methoxy-biphenyl-4-yloxy)-2-methylpyridin-3-amine, 4-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, 4-(4'-methoxy-biphenyl ... and 4-(4-(1H-pyrrol-1-yl)phenoxy)aniline.

[0048] R 1 When is CO-C3 alkylOC0-C3 alkylaryl or CO-C3 alkylOC0-C3 alkylheteroaryl, any substitution on the aryl and heteroaryl groups is preferably in the para position. R 2 When is aryl or heteroaryl, any substitution is preferably in the ortho or meta position, provided that if the substituent is not halogen, O-C-C alkyl or methyl, and if the substituent is halogen, O-C-C alkyl or methyl, it is in the para position. R 9 When is CO-C3 alkylOC0-C3 alkylaryl or CO-C3 alkylOC0-C3 alkylheteroaryl, any substitution on the aryl and heteroaryl groups is preferably in the para position.

[0049] In one embodiment, X is selected from CH2, CF2, CHF, NH, N(C1-C3 alkyl), S, SO, and O. In a further embodiment, X is selected from CO, CHOH, CHO(C1-C3)alkyl, S, SO, and O. In a preferred embodiment, X is selected from CH2, NH, and O. In a more preferred embodiment, X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O. In an even more preferred embodiment, X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O. In certain preferred embodiments, X is selected from CH2, CO, CHOH, CHOCH3, and O. In more particular preferred embodiments, X is selected from CH2 and O. In even more particular preferred embodiments, X is O.

[0050] In one embodiment, R 1is H, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, CO-C3 alkylOC0-C3 alkylaryl, where aryl is optionally substituted with NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, preferably NH2; and CO-C3 alkylOC0-C3 alkylheteroaryl, where heteroaryl is optionally substituted with NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 In a further embodiment, R is selected from the group consisting of: 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 In a preferred embodiment, R is selected from heterocyclyl, C1-C6 alkoxy, and C1-C6 heteroalkyl. 1 is H, halogen, and C1-C4 alkyl, C0-C3 alkylOC0-C3 alkylaryl, where aryl is optionally substituted with NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, preferably NH2; and C0-C3 alkylOC0-C3 alkylheteroaryl, where heteroaryl is optionally substituted with NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 In a further preferred embodiment, R 1 is selected from H, halogen, C1-C6 alkyl, and C1-C6 heteroalkyl. 1is selected from H, C1-C6 alkyl, C0-C3 alkylOC0-C3 alkylaryl, where aryl is optionally substituted with NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, preferably optionally substituted NH2; C0-C3 alkylOC0-C3 alkylheteroaryl, where heteroaryl is optionally substituted with NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, preferably optionally substituted NH2. In an even more preferred embodiment, R 1 is H, C1-C4 alkyl, and C0-C3 alkylOC0-C3 alkylaryl, where aryl is optionally substituted with NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, preferably NH2; C0-C3 alkylOC0-C3 alkylheteroaryl, where heteroaryl is optionally substituted with NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 In an even more preferred embodiment, R 1 is selected from H, halogen, and C1-C4 alkyl. In an even more preferred embodiment, R 1 is H, methyl, CO-C3 alkylOC0-C3 alkylaryl, wherein aryl is optionally substituted with NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, preferably NH2; and CO-C3 alkylOC0-C3 alkylheteroaryl, wherein heteroaryl is optionally substituted with NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 In an even more preferred embodiment, R 1is C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is NH2, O1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 heterocyclyl, preferably optionally substituted by NH; C0-C3 alkylOC0-C3 alkylheteroaryl, wherein heteroaryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 In an even more preferred embodiment, R 1 is C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is NH2, O1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C0-C3 alkylOC0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 In an even more preferred embodiment, R 1 is selected from H and methyl.

[0051] In one embodiment, R 2is selected from aryl and heteroaryl, where aryl and heteroaryl are selected from NH, O—C alkyl, C—C alkyl, C—C heteroalkyl, halogen, CN, C—C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , and C1-C6 alkylC(O)R 12 In a further embodiment, R 2 is selected from aryl and heteroaryl, where aryl and heteroaryl are selected from NH, O—C alkyl, C—C alkyl, C—C heteroalkyl, halogen, CN, C(O)R 12 , C1-C6 alkylC(O)R 12 may be substituted with.

[0052] In a preferred embodiment, R 2 is selected from aryl and heteroaryl, where aryl and heteroaryl are selected from NH, C-C alkyl, C-C heteroalkyl, halogen, CN, C-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , and C1-C6 alkylC(O)R 12 In an even more preferred embodiment, R 2 is selected from aryl and heteroaryl, where aryl and heteroaryl are selected from NH, C-C alkyl, C-C heteroalkyl, halogen, CN, C(O)R 12 , C1-C6 alkylC(O)R 12 In an even more preferred embodiment, R 2 is selected from aryl and heteroaryl, where aryl and heteroaryl are selected from NH, C-C alkyl, C-C heteroalkyl, halogen, CN, C-C 12 Cycloalkyl, C3-C 12 In a particularly preferred embodiment, R 2is selected from aryl and heteroaryl, where aryl and heteroaryl are C-C alkyl, halogen, C-C heteroalkyl, C(O)R 12 , C1-C6 alkylC(O)R 12 In further particularly preferred embodiments, R 2 is selected from aryl and heteroaryl, where aryl and heteroaryl are optionally substituted with C1-C6 alkyl, halogen. In further particularly preferred embodiments, R 2 is selected from aryl and heteroaryl, where aryl and heteroaryl may be substituted with NH, halogen, or CN. In further particularly preferred embodiments, R 2 is selected from aryl and heteroaryl, where aryl and heteroaryl are C(O)R 12 , C1-C6 alkylC(O)R 12 In particularly preferred embodiments, R 2 is selected from aryl and heteroaryl, where aryl and heteroaryl are C-C alkyl, halogen, C-C heteroalkyl, C(O)R 12 , C1-C6 alkylC(O)R 12 In even more particularly preferred embodiments, R 2 is selected from aryl and heteroaryl, wherein aryl and heteroaryl are selected from O-C alkyl, C-C alkyl, C-C heteroalkyl, halogen, C-C alkylC(O)R 12 may be substituted with.

[0053] In even more particularly preferred embodiments, R 2 are NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C(O)R, respectively. 12 , C1-C6 alkylC(O)R 12In even more particularly preferred embodiments, R is selected from phenyl, pyridyl, imidazole and thiazole, optionally substituted with 2 are NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 In even more particularly preferred embodiments, R is selected from phenyl, thiazole, pyridyl, imidazole, and thiazole, optionally substituted with 2 are NH2, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C(O)R, respectively. 12 , C1-C6 alkylC(O)R 12 In even more particularly preferred embodiments, R is selected from phenyl, pyridyl, imidazole, and thiazole, each optionally substituted with 2 are C1-C6 alkyl, halogen, C1-C6 heteroalkyl, C(O)R 12 , C1-C6 alkylC(O)R 12 In even more particularly preferred embodiments, R is selected from phenyl, pyridyl, imidazole, and thiazole, each optionally substituted with 2 are each selected from C1-C6 alkyl, phenyl optionally substituted with halogen, pyridyl, imidazole, and thiazole. 2 are selected from phenyl, pyridyl, imidazole, and thiazole, each of which may be substituted with NH, halogen, or CN. 2 are C(O)R 12 , C1-C6 alkylC(O)R 12 In even more particularly preferred embodiments, R is selected from phenyl, pyridyl, imidazole, and thiazole, optionally substituted with 2are each C1-C6 alkyl, halogen, C1-C6 heteroalkyl, C(O)R 12 , C1-C6 alkylC(O)R 12 In even more particularly preferred embodiments, R is selected from phenyl, pyridyl, imidazole and thiazole, optionally substituted with 2 are each selected from C1-C6 alkyl, phenyl optionally substituted with halogen, pyridyl, imidazole, and thiazole. 2 are C(O)R 12 , C1-C6 alkylC(O)R 12 In a most particularly preferred embodiment, R is selected from phenyl, pyridyl, imidazole, and thiazole, optionally substituted with 2 are each O-C alkyl, C-C alkyl, C-C heteroalkyl, halogen, C-C alkylC(O)R 12 The group is selected from phenyl, pyridyl, imidazole, and thiazole, each optionally substituted with .

[0054] In a preferred embodiment, R 2 is selected from aryl and heteroaryl, where heteroaryl is an optionally substituted aromatic 5- or 6-membered monocyclic group. 2 is selected from aryl and heteroaryl, with the proviso that heteroaryl is not unsubstituted thiazole, oxazole, imidazole, and pyrrole. 2 is selected from aryl and heteroaryl, with the proviso that heteroaryl is not thiazole, oxazole, imidazole, or pyrrole.

[0055] In one embodiment, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 In a preferred embodiment, R 3is selected from H, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl. 3 is selected from H, halogen, and C1-C4 alkyl. In an even more preferred embodiment, R 3 is H.

[0056] In one embodiment, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl. 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C4 alkyl, and C1-C4 heteroalkyl. 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl. In certain preferred embodiments, R 4 , R 5 and R 6 are each independently selected from H, halogen, and methyl. In more particularly preferred embodiments, R 4 is selected from H and halogen, and / or R 5 and / or R 6 is selected from H and C1-C6 alkyl, particularly H and C1-C4 alkyl, and more particularly H and methyl.

[0057] In one embodiment, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 In a preferred embodiment, R 7 is Y 1 If is N, then it does not exist or Y 1When R is C, it is selected from H, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl. 7 is Y 1 If is N, then it does not exist or Y 1 When R is C, it is selected from H, halogen and C1-C4 alkyl, preferably H, halogen and methyl. In an even more preferred embodiment, R 7 is Y 1 If is N, then it does not exist or Y 1 When R is C, it is selected from H, halogen, and methyl. In particularly preferred embodiments, R 7 is Y 1 If is N, then it does not exist or Y 1 When R is C, it is selected from H and halogen. In more particularly preferred embodiments, R 7 does not exist.

[0058] In one embodiment, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12 In a preferred embodiment, R 8 is Y 3 If is N, then it does not exist or Y 3 When R is C, it is selected from H, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl. 8 is Y 3 If is N, then it does not exist or Y 3 When R is C, it is selected from H, halogen and C1-C4 alkyl, preferably H, halogen and methyl. In an even more preferred embodiment, R 8 is Y 3 If is N, then it does not exist or Y 3 When R is C, it is selected from H, halogen, and methyl. In particularly preferred embodiments, R 8 is Y 3 If is N, then it does not exist or Y3 When R is C, it is selected from H and halogen. In certain preferred embodiments, R 8 is H.

[0059] In one embodiment, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 In a preferred embodiment, R 9 is Y 2 If is N, then it does not exist or Y 2 When R is C, it is selected from H, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl. 9 is Y 2 If is N, then it does not exist or Y 2 When R is C, it is selected from H and C1-C4 alkyl, and preferably selected from H, halogen, and methyl. In an even more preferred embodiment, R 9 is Y 2 If is N, then it does not exist or Y 2 When R is C, it is selected from H, halogen, and methyl. In particularly preferred embodiments, R 9 is Y 2 If is N, then it does not exist or Y 2 When is C, it is selected from H and halogen, preferably H.

[0060] In one embodiment, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl, preferably selected from H, halogen, and methyl; R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12cycloalkyl, preferably selected from H, halogen, and methyl, and R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 It is selected from cycloalkyl, preferably H, halogen, and methyl.

[0061] In a preferred embodiment, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, R is selected from H and halogen; 8 is Y 3 If is N, then it does not exist or Y 3 is C, then H, and R 9 is Y 2 If is N, then it does not exist or Y 2 When is C, it is selected from H and methyl.

[0062] In one embodiment, R 10 and R 11 At least one of R is C1-C6 alkyl, preferably C1-C4 alkyl, more preferably methyl. 10 and R 11 is independently selected from H and methyl. In a more preferred embodiment, R 10 is H and R 11 is selected from H and C1-C4 alkyl. In an even more preferred embodiment, R 10 is H and R 11 is H or methyl. In a particularly preferred embodiment, R 10 is H and R 11 is C1-C6 alkyl. In particularly preferred embodiments, R 10 is H and R 11 is C1-C4 alkyl. In even more particularly preferred embodiments, R 10 is H and R 11 is methyl.

[0063] In one embodiment, R 12 is selected from NH, NHC-C alkyl, C-C alkyl, and C-C heteroalkyl. 12 is selected from NH, C-C alkyl, and C-C heteroalkyl. 12 is NH2.

[0064] In one embodiment, Y 1 is N. In a preferred embodiment, Y 1 and Y 2 are each independently selected from N and C; Y 3 is C. In a more preferred embodiment, Y 2 and Y 3 Y, provided that one of 1 is selected from N and C, and Y 2 and Y 3 is selected from N and C. In certain preferred embodiments, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C. In a more particularly preferred embodiment, Y 1 is N and R 7 does not exist.

[0065] In one embodiment, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 and wherein at least one of the substituents selected from is not H. In a further embodiment, R 1 , R 3 , R 8 , and R 9 At least one of the substituents selected from is not H.

[0066] Preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O, preferably selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 heterocyclyl, C1-C6 alkoxy; C1-C6 heteroalkyl, C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OCO-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12cycloalkyl; In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0067] Further preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O, preferably selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 heterocyclyl, C1-C6 alkoxy; C1-C6 heteroalkyl, C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OCO-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C12 cycloalkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 12 is selected from NH, NHC, C, C alkyl, and C, C heteroalkyl; 1 C0-C3 alkyl, C0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 When R is selected from the group consisting of aryl, ... 2 is selected from aryl and heteroaryl, wherein aryl and heteroaryl may be substituted with NH, halogen, CN, preferably aryl and heteroaryl are unsubstituted.

[0068] More preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O, preferably selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, C1-C6 alkoxy, and C1-C6 heteroalkyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 4 , R 5 and R 6are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0069] Even more preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O, preferably selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, C1-C6 alkoxy, and C1-C6 heteroalkyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 9 is Y 2If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 12 is selected from NH, NHC, C, C alkyl, and C, C heteroalkyl; 2 is aryl and heteroaryl [wherein aryl and heteroaryl are C1-C6 alkyl, halogen, C1-C6 heteroalkyl, C(O)R 12 , C1-C6 alkylC(O)R 12 is replaced by], R 1 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl, and is preferably H or methyl.

[0070] Even more preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O, preferably selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, C1-C6 alkoxy, and C1-C6 heteroalkyl; In the formula, R 2 are aryl and heteroaryl, wherein aryl and heteroaryl are NH, C-C alkyl, C-C heteroalkyl, halogen, CN, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0071] Even more preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O, preferably selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 heterocyclyl, C1-C6 alkoxy; C1-C6 heteroalkyl, C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OCO-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; preferably, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 heterocyclyl, C1-C6 alkoxy; C1-C6 heteroalkyl, C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OCO-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C0-C3 alkylOC0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2 is selected from aryl and heteroaryl, wherein aryl and heteroaryl may be substituted with NH, halogen, or CN; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8 is Y 3If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 When is C, it is selected from H, halogen, and C1-C4 alkyl.

[0072] Even more preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O, preferably selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is selected from H, halogen, C1-C4 alkyl, and C1-C4 heteroalkyl; In the formula, R 2 are aryl and heteroaryl, wherein aryl and heteroaryl are NH, C-C alkyl, C-C heteroalkyl, halogen, CN, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is selected from H, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C4 alkyl, and C1-C4 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, it is selected from H, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl; and In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0073] Particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O, preferably selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl, preferably independently selected from H and methyl, more preferably R 10 is H and R 11 is H or methyl; In the formula, R 1 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 2 aryl and heteroaryl [wherein aryl and heteroaryl are C1-C6 alkyl, C1-C6 heteroalkyl, halogen, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0074] Further particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O, preferably selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl, preferably independently selected from H and methyl, and preferably R 10 is H and R 11 is H or methyl; In the formula, R 1 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 2 is selected from aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with C1-C6 heteroalkyl; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0075] Further particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O, preferably selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11are each independently selected from H and C1-C6 alkyl, preferably independently selected from H and methyl, and preferably R 10 is H and R 11 is H or methyl; In the formula, R 1 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 2 is selected from aryl and heteroaryl, wherein aryl and heteroaryl may be substituted with C1-C6 alkyl and halogen; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0076] Further particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O, preferably selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl, preferably independently selected from H and methyl, and preferably R 10 is H and R 11 is H or methyl; In the formula, R 1 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 2 are aryl and heteroaryl, where aryl and heteroaryl are C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0077] Further particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O, preferably selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl, preferably independently selected from H and methyl, and preferably R 10 is H and R 11 is H or methyl; In the formula, R 1is C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is NH2, O1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 heterocyclyl, preferably optionally substituted with NH; C0-C3 alkylOC0-C3 alkylheteroaryl, wherein heteroaryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl, preferably optionally substituted with NH, wherein R 1 is preferably C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C0-C3 alkylOC0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl, preferably optionally substituted with NH; In the formula, R 2is selected from aryl and heteroaryl, wherein aryl and heteroaryl may be substituted with NH, halogen, C-C alkyl, CN, preferably halogen, C-C alkyl; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 When is C, it is selected from H, halogen, and C1-C4 alkyl.

[0078] Preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH, NH, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 heterocyclyl, C1-C6 alkoxy; C1-C6 heteroalkyl, C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OCO-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0079] Further preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH, NH, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 heterocyclyl, C1-C6 alkoxy; C1-C6 heteroalkyl, C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OCO-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 12 is selected from NH, NHC, C, C alkyl, and C, C heteroalkyl; 1 C0-C3 alkyl, C0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C612 Cycloalkyl, C3-C 12 When R is selected from the group consisting of aryl, ... 2 is selected from aryl and heteroaryl, wherein aryl and heteroaryl may be substituted with NH, halogen, CN, preferably aryl and heteroaryl are unsubstituted.

[0080] More preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH, NH, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, C1-C6 alkoxy, and C1-C6 heteroalkyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12, C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0081] Even more preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH, NH, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, C1-C6 alkoxy, and C1-C6 heteroalkyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 8 is Y 3If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 12 is selected from NH, NHC, C, C alkyl, and C, C heteroalkyl; 2 is aryl and heteroaryl [wherein aryl and heteroaryl are C1-C6 alkyl, halogen, C1-C6 heteroalkyl, C(O)R 12 , C1-C6 alkylC(O)R 12 is replaced by], R 1 is selected from H, halogen, C1-C6 alkyl and C1-C6 heteroalkyl, and is preferably H or methyl.

[0082] Even more preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH, NH, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, C1-C6 alkoxy, and C1-C6 heteroalkyl; In the formula, R 2 are aryl and heteroaryl, wherein aryl and heteroaryl are NH, C-C alkyl, C-C heteroalkyl, halogen, CN, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 12is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0083] Even more preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH, NH, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 heterocyclyl, C1-C6 alkoxy; C1-C6 heteroalkyl, C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OCO-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; preferably, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 heterocyclyl, C1-C6 alkoxy; C1-C6 heteroalkyl, C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OCO-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 cycloalkyl, C3-C12 heterocyclyl]; and C0-C3 alkylOC0-C3 alkylheteroaryl [heteroaryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2 is selected from aryl and heteroaryl, wherein aryl and heteroaryl may be substituted with NH, halogen, or CN; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 When is C, it is selected from H, halogen, and C1-C4 alkyl.

[0084] Even more preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH, NH, and O, preferably O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is selected from H, halogen, C1-C4 alkyl, and C1-C4 heteroalkyl; In the formula, R 2 are aryl and heteroaryl, wherein aryl and heteroaryl are NH, C-C alkyl, C-C heteroalkyl, halogen, CN, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is selected from H, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl; In the formula, R4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C4 alkyl, and C1-C4 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, it is selected from H, halogen, C1-C4 alkyl, and C3-C7 cycloalkyl; and In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0085] Particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH, NH, and O, preferably O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R10 and R 11 are each independently selected from H and C1-C6 alkyl, preferably independently selected from H and methyl, more preferably R 10 is H and R 11 is H or methyl; In the formula, R 1 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 2 aryl and heteroaryl [wherein aryl and heteroaryl are C1-C6 alkyl, C1-C6 heteroalkyl, halogen, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0086] Further particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates or stereoisomers are as follows: wherein X is selected from CH, NH, and O, preferably O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl, preferably independently selected from H and methyl, and preferably R 10 is H and R 11 is H or methyl; In the formula, R 1 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 2 is selected from aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with C1-C6 heteroalkyl; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0087] Further particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates or stereoisomers are as follows: wherein X is selected from CH, NH, and O, preferably O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl, preferably independently selected from H and methyl, and preferably R 10 is H and R 11 is H or methyl; In the formula, R 1 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 2is selected from aryl and heteroaryl, wherein aryl and heteroaryl may be substituted with C1-C6 alkyl and halogen; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0088] Further particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates or stereoisomers are as follows: wherein X is selected from CH, NH, and O, preferably O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl, preferably independently selected from H and methyl, and preferably R 10 is H and R 11 is H or methyl; In the formula, R 1 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 2 are aryl and heteroaryl, where aryl and heteroaryl are C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0089] Further particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates or stereoisomers are as follows: wherein X is selected from CH, NH, and O, preferably O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C, preferably Y 1 and Y 2 are each independently selected from N and C; Y 3 is C, and more preferably, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl, preferably independently selected from H and methyl, and preferably R 10 is H and R 11 is H or methyl; In the formula, R 1 is C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is NH2, O1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 heterocyclyl, preferably optionally substituted with NH; C0-C3 alkylOC0-C3 alkylheteroaryl, wherein heteroaryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl, preferably optionally substituted with NH, wherein R 1 is preferably C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C0-C3 alkylOC0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl, preferably optionally substituted with NH; In the formula, R 2 is selected from aryl and heteroaryl, wherein aryl and heteroaryl may be substituted with NH, halogen, C-C alkyl, CN, preferably halogen, C-C alkyl; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 When is C, it is selected from H, halogen, and C1-C4 alkyl.

[0090] Further particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 selected from heterocyclyl, C1-C6 alkoxy, and C1-C6 heteroalkyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C12 cycloalkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0091] More particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0092] Still more particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O; In the formula, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is H, halogen, C1-C6 alkyl, C3-C 12 Cycloalkyl, C3-C 12Heterocyclyl, C1-C6 alkoxy, C1-C6 heteroalkyl, C0-C3 alkylOC0-C3 alkylaryl [wherein aryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; C0-C3 alkyl, C0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, O-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C1-C6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are selected from the group consisting of NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C6 12 Cycloalkyl, C3-C 12 and optionally substituted with heterocyclyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are NH2, O-C1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 Heterocyclyl, C(O)R 12 , C1-C6 alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C1-C6 alkyl, and C1-C6 heteroalkyl; In the formula, R 8 is H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, H, halogen, C1-C6 alkyl, and C3-C 12 cycloalkyl; and In the formula, R 12 is selected from NH2, NHC1-C6 alkyl, C1-C6 alkyl, and C1-C6 heteroalkyl.

[0093] Still more particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is selected from H, C1-C6 alkyl, C0-C3 alkylOC0-C3 alkylaryl, wherein aryl is optionally substituted with NH2; C0-C3 alkylOC0-C3 alkylheteroaryl, wherein heteroaryl is optionally substituted with NH2; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are O-C alkyl, C-C alkyl, C-C heteroalkyl, halogen, C-C alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H; In the formula, R 4 is selected from H and halogen; In the formula, R 5 and R 6are each independently selected from H and C1-C6 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, then H; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, then H; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, then H; and In the formula, R 12 is NH2.

[0094] Still more particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O; In the formula, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is selected from H, C1-C6 alkyl, C0-C3 alkylOC0-C3 alkylaryl, wherein aryl is optionally substituted with NH2; C0-C3 alkylOC0-C3 alkylheteroaryl, wherein heteroaryl is optionally substituted with NH2; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are O-C alkyl, C-C alkyl, C-C heteroalkyl, halogen, C-C alkylC(O)R12 and optionally substituted with; In the formula, R 3 is H; In the formula, R 4 is selected from H and halogen; In the formula, R 5 and R 6 are each independently selected from H and C1-C6 alkyl; In the formula, R 8 is H; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, then H; and In the formula, R 12 is NH2.

[0095] Still more particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is selected from H and C1-C6 alkyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are O-C alkyl, C-C alkyl, C-C heteroalkyl, halogen, C-C alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H; In the formula, R 4is selected from H and halogen; In the formula, R 5 and R 6 are each independently selected from H and C1-C6 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, then H; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, then H; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, then H; and In the formula, R 12 is NH2.

[0096] Still more particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O; In the formula, Y 1 is N and R 7 does not exist, and Y 2 is selected from N and C, and Y 3 is C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is selected from H and C1-C6 alkyl; In the formula, R 2 are aryl and heteroaryl [wherein aryl and heteroaryl are O-C alkyl, C-C alkyl, C-C heteroalkyl, halogen, C-C alkylC(O)R 12 and optionally substituted with; In the formula, R 3 is H; In the formula, R 4 is selected from H and halogen; In the formula, R 5 and R 6 are each independently selected from H and C1-C6 alkyl; In the formula, R 8 is H; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 is C, then H; and In the formula, R 12 is NH2.

[0097] Still more particular preferred compounds of formula (I), their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers are as follows: wherein X is selected from CH2, CO, CHOH, CHO(C1-C3)alkyl, NH, and O; In the formula, Y 1 , Y 2 , and Y 3 are each independently selected from N and C; In the formula, Z is NR 10 R 11 [where R 10 and R 11 are each independently selected from H and C1-C6 alkyl; In the formula, R 1 is C0-C3 alkyl, OCO-C3 alkylaryl [wherein aryl is NH2, O1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12 and C0-C3 alkylOC0-C3 alkylheteroaryl [wherein heteroaryl is selected from the group consisting of NH2, OC1-C6 alkyl, C1-C6 alkyl, C1-C6 heteroalkyl, halogen, CN, C3-C 12 Cycloalkyl, C3-C 12and optionally substituted with heterocyclyl; In the formula, R 2 is selected from aryl and heteroaryl, wherein aryl and heteroaryl may be substituted with NH, halogen, C-C alkyl, CN; In the formula, R 3 is selected from H, halogen, and C1-C4 alkyl; In the formula, R 4 , R 5 and R 6 are each independently selected from H, halogen, and C1-C4 alkyl; In the formula, R 7 is Y 1 If is N, then it does not exist or Y 1 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 8 is Y 3 If is N, then it does not exist or Y 3 is C, it is selected from H, halogen, and C1-C4 alkyl; In the formula, R 9 is Y 2 If is N, then it does not exist or Y 2 When is C, it is selected from H, halogen, and C1-C4 alkyl.

[0098] Even more particular preferred compounds of formula (I) are JPEG0007624930000017.jpg249170JPEG0007624930000018.jpg255170JPEG0007624930000019.jpg149170.

[0099] Even more particular preferred compounds of formula (I) are JPEG0007624930000020.jpg242170JPEG0007624930000021.jpg246170JPEG0007624930000022.jpg153170.

[0100] Even more particular preferred compounds of formula (I) are JPEG0007624930000023.jpg228170JPEG0007624930000024.jpg250170JPEG0007624930000025.jpg192170

[0101] Even more particular preferred compounds of formula (I) are JPEG0007624930000026.jpg229170JPEG0007624930000027.jpg251170JPEG0007624930000028.jpg192170

[0102] Even more particular preferred compounds of formula (I) are JPEG0007624930000029.jpg232170JPEG0007624930000030.jpg250170JPEG0007624930000031.jpg192170.

[0103] Even more particular preferred compounds of formula (I) are JPEG0007624930000032.jpg233170JPEG0007624930000033.jpg121170.

[0104] Most particular preferred compounds of formula (I) are JPEG0007624930000034.jpg163170.

[0105] More particular preferred compounds of formula (I), pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers thereof are JPEG0007624930000035.jpg240170JPEG0007624930000036.jpg22170.

[0106] Still more particular preferred compounds of formula (I), pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers thereof are JPEG0007624930000037.jpg153170.

[0107] Further more particular preferred compounds of formula (I) for use, and pharmaceutical compositions comprising compounds of formula (I), are: JPEG0007624930000038.jpg233170JPEG0007624930000039.jpg72170.

[0108] Further more particular preferred compounds of formula (I) for use, and pharmaceutical compositions comprising compounds of formula (I), are: JPEG0007624930000040.jpg172170.

[0109] Preparation of compounds The compounds of the present invention can be prepared by the exemplary processes set forth in the following reaction schemes or by the processes described in the Examples. Exemplary reagents and procedures for these reactions are provided below. Starting materials can be purchased or readily prepared by one skilled in the art.

[0110] Scheme 1: X = NH, N(C1-C3-alkyl), S and O JPEG0007624930000041.jpg55170

[0111] The synthesis of diarylamino, diaryl ether, and diaryl thioether analogs is shown in Scheme 1: The respective amino-aryl moiety of formula (II) (X = NH, ultimately mono-alkylated) is reacted with the nitro-aryl halide precursor of formula (III) in a polar solvent at elevated temperature in the presence of a base. Preferably, the solvent is a mixture of DMSO and an alcohol such as tBuOH. An alcoholate such as tBuOK can be used as the base. The reaction temperature is between room temperature and 150°C, preferably between 60 and 110°C. The respective hydroxy- or mercapto-aryl moiety of formula (II) (X = O, S) is reacted with the nitro-aryl halide precursor of formula (III) in a polar solvent in the presence of a base. Preferred reaction conditions are carbonate as the base in DMF at room temperature. Finally, the nitro function of formula (IV) can be reduced to the respective amine of formula (V) under Béchamp conditions or via catalytic hydrogenation. Preferred Béchamp conditions are Fe powder in a mixture of EtOH, HO and AcOH under sonication. Catalytic hydrogenation can be carried out in the presence of Pd / C in a polar solvent such as alcohol. Alternatively, the target compound of formula (VIII) (Y 3 =N) can be obtained through substitution of the halogen of formula (VI) with the X-containing aryl moiety of formula (VII), ultimately in the presence of a protecting group (PG). Preferred conditions are phosphate as the base in a non-polar aromatic solvent at 100-150 °C under ferrocenyl catalysis [see Advanced Synthesis & Catalysis 353 (2011), 3403].

[0112] Scheme 2: Scheme 2 illustrates the reductive alkylation of amino derivatives of formula (V): A preferred method involves stirring an amine of formula (V) and the respective aldehyde in a polar solvent, such as an alcohol, in the presence of a weak acid, such as acetic acid. A reducing agent, such as NaBHCN, is then added. Basic workup ultimately affords compounds of formula (IX). Alternatively, an amine of formula (V) and an aldehyde are mixed in a nonpolar solvent, such as dichloromethane, in the presence of a base, such as triethylamine. A reducing agent, such as NaBH(OAc) is then added. Aqueous workup ultimately affords compounds of formula (IX). N-methylated derivatives of formula (IX; R = H) can be obtained from compounds of formula (V) and paraformaldehyde in MeOH using MeONa as a base, followed by reduction with NaBH and aqueous workup.

[0113] Scheme 3: X = CH2, CF2, CHF, CHOH, CHOAlk, CO Scheme 3 shows the synthesis of carbon-bridged analogs (X = CH2, CF2, CHF, CHOH, CHOAlk, CO). The halogen-aryl moiety of formula (X) is decarboxylatively coupled to an aryl-acetate of formula (XI) catalyzed by a transition metal complex to give the nitro derivative of formula (XII). Preferred conditions are XPhos / Pd2(allyl)2Cl2 as catalyst in a non-polar solvent at elevated temperature. The methylene bridge (X = CH2) of formula (XII) can be oxidized to the respective di-aryl-ketone of formula (XIV). Preferred conditions are FeCl2 .The reduction of the carbonyl group of formula (XIV) gives benzyl alcohol of formula (XVII). A preferred reducing agent is sodium borohydride. Alternatively, benzyl alcohol of formula (XVII) can be obtained via cross-coupling of boronate of formula (XV) with aryl aldehyde of formula (XVI). Alkylation of compound of formula (XVII) with alkyl iodide in the presence of a strong base (e.g., NaH) in a polar aprotic solvent gives alkoxy derivative of formula (XVIII) [similar to Example 2 of US Pat. No. 5,965,740]. Mono-fluoro derivative of formula (XIX) can be obtained either by oxidative fluorination of compound of formula (XII) or by hydroxy substitution in compound of formula (XVII). Oxidative fluorination can be carried out under conditions such as Jacobsen's allen complex, iodosylbenzene, base, and tris(hydrogen fluoride) in polar solvents at elevated temperatures [J. Am. Chem. Soc. 136 (2014), 6842]. Substitution of benzylic hydroxy groups with fluoride can be achieved by activation with trichloroacetimidate and 1,8-diazabicyclo[5.4.0]undec-7-ene in dichloromethane in the presence of bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, followed by the addition of triethylamine tris(hydrogen fluoride) in a mixture of F3C-C6H5 and tetrahydrofuran at slightly elevated temperatures [Tetrahedron 71 (2015), 5932]. The keto derivatives of formula (XIV) can be converted to the difluoromethylene derivatives of formula (XX) using [bis(2-methoxyethyl)amino]-sulfur trifluoride at elevated temperatures [similar to US2015246938; Step 2, Preparation of Compound 76; page 55]. Finally, the nitro groups of compounds of formulas (XII), (XIV), and (XVII)-(XX) can be reduced to the respective amino derivatives as described in Scheme 1.

[0114] stereoisomer The compounds of the present invention can exist as stereoisomers where asymmetric or chiral centers exist. These compounds are designated with the designation "R" or "S" depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparation of a racemic mixture followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) attachment of the mixture of enantiomers to a chiral auxiliary, recrystallization or chromatographic separation of the resulting mixture of diastereomers, and liberation of the optically pure product from the auxiliary; (2) salt formation using an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on a chiral chromatographic column. Geometric isomers can also exist in the compounds of the present invention. The present invention contemplates various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbocyclic ring.

[0115] The compounds of the present invention can also exist as racemates, which are given the descriptor "rac". As used herein, the term racemate refers to an equimolar mixture of a pair of enantiomers. A racemate is usually formed when a stereocenter is generated by synthesis. As used herein, the term racemic mixture refers to a racemate. The compounds of the present invention can also exist as diastereomeric meso forms, which are given the descriptor "rel". As used herein, the term diastereomeric meso forms refers to achiral forms with pseudostereogenic C atoms, which are given the descriptor "r" or "s", respectively.

[0116] salt The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. "Pharmaceutically acceptable salts" means salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or can be prepared separately by reacting the free base function with a suitable acid.

[0117] Representative acid addition salts include, but are not limited to, trifluoroacetate (TFA), acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, and undecanoate salts. Additionally, basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides, e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, e.g., dimethyl, diethyl, dibutyl, and diamyl sulfate; long-chain halides, e.g., decyl chloride, bromide, and iodide, lauryl, myristyl, and stearyl; aryl alkyl halides, e.g., benzyl bromide and phenethyl bromide, and others. This results in water- or oil-soluble or dispersible products. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid.

[0118] Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the invention by reacting the carboxylic acid-containing moiety with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, or with ammonia or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable base addition salts include, but are not limited to, cations based on alkali metals or alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, as well as non-toxic quaternary ammonia and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0119] Solvate / hydrate It should be recognized that solvates and hydrates of compounds according to formula (I) are also within the scope of this application. Methods of solvation are generally known in the art. A further embodiment of the present invention also includes compounds that are identical to compounds of formula (I) except that one or more atoms are replaced by atoms having an atomic mass number or mass that is different from the atomic mass number or mass normally found in nature, such as 2 H(D), 3 H, 13 C. 127 I, etc. These isotopic analogs and their pharmaceutical salts and formulations are believed to be useful agents in therapy and / or diagnosis, where, for example, but not limited to, fine tuning of in vivo half-life times may lead to optimized dosing regimens.

[0120] Pharmaceutical Compositions In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) according to the present invention and a pharmaceutically acceptable diluent, excipient or carrier.

[0121] In one embodiment, the pharmaceutical composition further comprises another pharmaceutically active agent.

[0122] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) according to the present invention and a pharmaceutically acceptable diluent, excipient or carrier, wherein said compound of formula (I) is present in a therapeutically effective amount.

[0123] Formulation and Administration: In accordance with the present invention, the compounds of the present invention can be administered orally, parenterally, by inhalation, rectally, or topically (including via the skin, eyes, mucous membranes, scalp, sublingual, buccal, and intranasal routes), in single or divided doses; furthermore, the compounds provided by the present invention can be prepared for use in treating leukocyte populations ex vivo and in vitro. When the compounds of the present invention are administered, for example, orally, they can be administered as medicaments in the form of pharmaceutical compositions containing them in association with pharmaceutically acceptable diluents, excipients, or carrier substances. Accordingly, the present invention also provides pharmaceutical compositions containing the compounds of the present invention described above and one or more pharmaceutically acceptable diluents, excipients, or carriers. Pharmaceutical compositions can be prepared in conventional manner, and the finished dosage form can be solid dosage forms, such as tablets, dragees, capsules, etc., or liquid dosage forms, such as solutions, suspensions, emulsions, etc. Pharmaceutically acceptable diluents, excipients, or carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is known in the art. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) according to the present invention and at least one pharmaceutically acceptable diluent, excipient or carrier, wherein the composition is a tablet or capsule, preferably a tablet.

[0124] Dosing regimen Exemplary treatment regimens include administration once daily, twice daily, three times daily, every other day, twice weekly, or once weekly. The compositions of the present invention are typically administered multiple times. The interval between single doses can be, for example, less than one day, daily, every other day, twice weekly, or once weekly. The compositions of the present invention can be administered as continuous, uninterrupted therapy. In an exemplary treatment regimen, the compound of formula (I) according to the present invention can be administered at 0.1 to 100 mg per day.

[0125] therapeutic use The compounds according to the invention described above have prophylactic and therapeutic utility in human and veterinary diseases.

[0126] Thus, in a further aspect, the present invention provides the use of the compounds described herein and the pharmaceutical compositions described herein for prophylactic and / or therapeutic purposes. In one embodiment of the present invention, the compounds according to the invention described herein or the pharmaceutical compositions described herein may be used as medicaments, preferably for use in human medicine and / or veterinary medicine. Thus, the present invention provides the compounds according to the invention described herein or the pharmaceutical compositions described herein for use as medicaments.

[0127] In a further aspect, the present invention also provides a compound of the present invention or a pharmaceutical composition of the present invention for use in a method for preventing or treating cancer. A method for treating and / or preventing cancer is also provided, the method comprising administering a compound of the present invention or a pharmaceutical composition of the present invention to a subject in need thereof. Also provided is the use of a compound of the present invention or a pharmaceutical composition of the present invention for the manufacture of a medicament for treating and / or preventing cancer in a subject. Also provided is the use of a compound of the present invention or a pharmaceutical composition of the present invention for treating and / or preventing cancer in a subject.

[0128] The cancer to be prevented or treated is preferably a Notch-dependent cancer, more preferably a Notch-dependent cancer selected from the group consisting of adenoid cystic carcinoma (ACC), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), breast cancer, pancreatic cancer, prostate cancer, melanoma, brain tumor, tumor angiogenesis, liver cancer, and colorectal cancer. Preferably, the compounds of the present invention can also be used to treat Notch-dependent cancers that are resistant to beta-secretase inhibitor treatment. Notch signaling-dependent human tumors that are resistant to beta-secretase inhibitor treatment can be determined by the levels of NICD, Notch target genes, and the mutation status of Notch receptors and other components of the Notch pathway.

[0129] In a further aspect, the present invention provides a method for treating a disease associated with upregulated Notch signaling pathway activity, said method comprising administering a compound of the present invention or a pharmaceutical composition of the present invention to a subject in need thereof.

[0130] The daily dose of the compound of the present invention will necessarily vary depending on the host treated, specific administration route, and the severity and type of disease being treated.Therefore, the optimal dosage can be determined by the practitioner who treats any particular patient.It should be noted that the clinician or treating physician will know how and when to start, interrupt, adjust, or terminate treatment in conjunction with the response of individual patients.For any compound used in the method of the present invention, the therapeutically effective dose can be estimated initially from cell culture assays, animal models, or microdosing of human subjects.

[0131] As used herein, "treatment" refers to both therapeutic and prophylactic or preventative treatment. Subjects in need of treatment include those already suffering from a disorder such as cancer, as well as those in whom a disorder such as cancer is to be prevented. Thus, the mammal, preferably a human, treated herein may have been diagnosed with a disorder such as cancer, or may be predisposed to or susceptible to a disorder such as cancer.

[0132] As used herein, "prevention" includes prophylactic treatment. In prophylactic applications, the pharmaceutical combination of the present invention is administered to a subject suspected of developing cancer or at risk of developing cancer. In therapeutic applications, the pharmaceutical combination is administered to a subject, such as a patient already suffering from cancer, in an amount sufficient to cure or at least partially arrest the symptoms of the disease. Amounts effective for this use will depend on the severity and course of the disease, previous treatments, the subject's health status and response to the drugs, and the judgment of the treating physician.

[0133] The term "therapeutically effective amount" refers to an amount of a drug effective to treat a disease or disorder in a mammal. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of tumors or cancer cells, reduce tumor size; inhibit (i.e., slow to some extent, and preferably stop) cancer cell invasion into peripheral organs; inhibit (i.e., slow to some extent, and preferably stop) tumor metastasis; suppress tumor growth to some extent; and / or alleviate to some extent one or more symptoms associated with cancer. To the extent that a compound of the present invention can prevent the growth and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. The phrase "therapeutically effective amount" is used herein to mean an amount sufficient to prevent a clinically significant change in the growth or progression or mitotic activity of a target cell mass, cancer cell population, or other characteristic of pathology, or preferably an amount sufficient to reduce by at least about 30%, preferably at least 50%, preferably at least 70%, preferably at least 80%, preferably at least 90%.

[0134] In one embodiment, the compounds of the present invention can be used in combination (e.g., simultaneously, nearly simultaneously, or alternating) with conventional treatments for cell proliferative disorders, such as standard radiation therapy and / or standard chemotherapy. Standard radiation therapy and chemotherapy can also be combined chemoradiotherapy. Standard radiation therapy and / or chemotherapy can be administered before, simultaneously, or after the administration of a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition comprising the same.

[0135] The term "concomitant chemoradiotherapy" is used when the two treatments (chemotherapy and radiotherapy) are given simultaneously or nearly simultaneously, such as alternately or on the same day.

[0136] The term "standard radiotherapy" refers to the use of ionizing radiation as part of cancer treatment to control malignant cells. Preferably, the ionizing radiation is gamma irradiation. It is also common to combine radiotherapy with surgery, chemotherapy, hormone therapy, or a combination thereof. The most common types of cancer can usually be treated with radiotherapy. The exact treatment intent (curative, adjuvant, neoadjuvant, or palliative) will depend on the type, location, and stage of the tumor, as well as the general health of the subject in need thereof.

[0137] The term "standard chemotherapy" generally refers to the treatment of cancer using specific chemotherapeutic / chemical agents. Chemotherapeutic agents refer to pharmaceutical agents commonly used to treat cancer. Chemotherapeutic agents for treating cancer include, for example, altretamine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, idarubicin, ifosfamide, irinotecan, and ribozyme. Examples of antihistamines include fluticasone, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, oxaliplatin, pentostatin, procarbazine, streptozocin, taco, temozolomide, thioguanine / thioguanine, thiotepa, topotecan, treosulfan, vinblastine, vincristine, vindesine, or vinorelbine.

[0138] When a chemotherapeutic agent is used in combination with a compound according to the present invention, it may be used in the form of a pharmaceutical agent containing a combination of these two agents for simultaneous administration, or they may be used in the form of separate dosage forms, each containing one of the agents, and in the latter case, the individual dosage forms may be used, for example, sequentially, i.e., one dosage form containing the compound of the present invention, followed by a dosage form containing the chemotherapeutic agent (or vice versa).This embodiment of two separate dosage forms may be designed and provided in the form of a kit.

[0139] The compounds of the invention may also be used against cell proliferative disorders such as cancer, optionally in combination with conventional removal of tumor bulk, for example by segmental resection (biopsy or gross resection).

[0140] The term "removal of tumor volume" refers to any removal, ablation, or resection of tumor volume from a subject. Removal can be chemical, radiological, or surgical. Preferably, the removal is surgical removal, such as ablation or resection. Resection can be a "segmentectomy" (or segmentectomy), which can be a surgical procedure to remove part of an organ or gland from a subject. It can also be used to remove tumor and surrounding normal tissue. Debulking agents can also be used to remove tumor volume. The term "debulking agent" refers to any molecule (e.g., chemical, biological) or any external / environmental agent (e.g., gamma irradiation), or any agent that removes cancer cells (e.g., FL1, as described above) from the tumor volume. 0 and FL1 - This includes traditional surgical procedures that allow the death of tumor cells.

[0141] For suitable carriers, reference can be made to standard works which describe these, such as Chapter 25.2 of Volume 5 of "Comprehensive Medicinal Chemistry", Pergamon Press 1990, and "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete" by H.P. Fiedler, Editio Cantor, 2002. The term "pharmaceutically acceptable carrier" means a carrier or excipient that is generally safe and useful for preparing a pharmaceutical composition having an acceptable toxicity. Acceptable carriers include carriers that are acceptable for veterinary use as well as for human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier" includes both one and more than one such carrier.

[0142] Optionally, the pharmaceutical compositions of the present invention further comprise one or more additional active agents selected from the non-limiting group including chemotherapeutic agents for treating cancer, such as, for example, altretamine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, idarubicin, ifosfamide, irinotecan, romosozumab, riboflavin ... The agent may be selected from the group comprising acetaminophen, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, oxaliplatin, pentostatin, procarbazine, streptozocin, taco, temozolomide, thioguanine / thioguanine, thiotepa, topotecan, treosulfan, vinblastine, vincristine, vindesine and vinorelbine.

[0143] The compounds of the present invention, which can be used for the treatment and / or prevention of cancer, can be incorporated into various formulations and medicaments for therapeutic administration. More specifically, one or more compounds provided herein can be formulated into pharmaceutical compositions by combining with a suitable pharmaceutically acceptable carrier, and can be formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solutions, suppositories, injections, inhalants, and aerosols. Thus, administration of the compounds can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intracranial, and / or intratracheal administration. Furthermore, the compounds can be administered locally rather than systemically, in sustained-release or sustained-release formulations. The compounds can be formulated with common excipients, diluents, or carriers, compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered intramuscularly or intravenously. The compounds can be administered transdermally, formulated as sustained-release dosage forms, and the like. The compounds can be administered alone, in combination with each other, or in combination with other known compounds. Suitable formulations for use in the present invention can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company (1985) Philadelphia, PA, 17th ed.), which is incorporated herein by reference. In addition, for a brief review of methods for drug delivery, see Langer, Science (1990) 249:1527-1533, which is incorporated herein by reference.

[0144] The amount of a compound provided herein that can be combined with a carrier material to produce a single dosage form will vary depending on the disease being treated, the subject in need thereof, and the particular mode of administration. However, as a general guideline, suitable unit doses of a compound of the present invention can contain, for example, preferably, between 0.1 mg and about 1000 mg of active compound, between 1 mg and about 500 mg, and between 1 mg and about 300 mg. In another example, the unit dose is between 1 mg and about 100 mg. Such unit doses can be administered two or more times daily, for example, two, three, four, five, or six times daily, but preferably once or twice daily, such that the total dosage for a 70 kg human adult ranges from 0.001 to about 15 mg per kg of subject weight per administration. A preferred dosage is 0.01 to about 1.5 mg per kg of subject weight per administration, and such treatment can extend for weeks or months, or in some cases, years. However, it will be understood that the specific dosage level for any particular patient will depend on a variety of factors, including the activity of the specific compound used; the age, weight, general health, sex, and diet of the individual being treated; the time and route of administration; excretion rate; other previously administered medications; and, as is well understood by those skilled in the art, the severity of the particular disease being treated. Typical dosages may be 1 mg to about 100 mg tablets or 1 mg to about 300 mg tablets taken once daily or multiple times daily, or sustained-release capsules or tablets containing a proportionately greater amount of active ingredient taken once daily. The sustained-release effect may be achieved by capsule materials that dissolve at different pH values, capsules that release slowly by osmotic pressure, or any other known means of controlled release. It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those skilled in the art.

[0145] A further object of the present invention is a kit comprising a container and a package insert, wherein the container contains at least one dose of a medicament comprising a compound of formula (I) and, optionally, one or more pharmaceutically acceptable diluents, excipients, or carriers, and the package insert contains instructions for using the medicament to treat a subject with cancer. The kit may further comprise one or more doses of a chemotherapeutic agent. Optionally, the kit may also include reagents and / or instructions for use.

[0146] Generally, the kit comprises a container and a label or package insert affixed to or associated with the container. Suitable containers include, for example, bottles, vials, syringes, and the like. The container can be made of a variety of materials, such as glass or plastic. The container holds a pharmaceutical composition effective for treating a condition and may have a sterile access port (e.g., the container can be an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle). The label or package insert indicates that the composition is used for treating the condition of choice, such as cancer.

[0147] In a further object, the present invention provides the use of a compound of the present invention for inhibiting the Notch signaling pathway in a cell, in vitro or in vivo, typically a cancer cell.

[0148] In a further object, the present invention provides a method for producing a medicament for the treatment of a malaria parathyroid cancer, i) determining in cancer cells obtained from the subject's biological sample whether the cancer is Notch signaling pathway dependent; ii) treating said subject by administering a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition of the present invention based on whether the cancer is a Notch-dependent cancer. The present invention provides a method of treating a subject for a Notch-dependent cancer, comprising:

[0149] Typically, the dependency of the Notch signaling pathway in cancer cells is determined by any method known in the art. For example, the method may consist of an in vitro β-secretase complex activity assay as described herein.

[0150] The method of treatment may further comprise administering at least one conventional cancer treatment, which is administered before, simultaneously with, or after the administration of a therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention.

[0151] Conventional cancer treatment usually consists of radiation therapy and / or chemotherapy.

[0152] In a further object, the present invention provides the use of the compounds of the present invention in a method for inducing apoptosis in cells, either in vitro or in vivo, by inducing G0 / G1 cell cycle arrest.

[0153] In a further object, the present invention provides the use of the compounds of the present invention in diagnosing, prognosing, and / or monitoring Notch-dependent cancer in a subject.

[0154] Those skilled in the art will understand that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from its spirit or essential characteristics. The invention also includes all steps, features, compositions, and compounds referenced or shown in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features. The present disclosure is therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims, with all changes that come within the meaning and range of equivalents being intended to be embraced therein.

[0155] Throughout this application various references are cited, each of which is incorporated herein by reference in its entirety.

[0156] The foregoing description will be more fully understood with reference to the following examples, which, however, are illustrative of methods of practicing the invention and are not intended to limit the scope of the invention. [Example]

[0157] Chemical synthesis of compounds Abbreviation AcOH acetic acid Brine Saturated NaCl aqueous solution CV column volume DCM dichloromethane DME 1,2-dimethoxyethane DMF Dimethylformamide DMSO-d6 Deuterated dimethyl sulfoxide equiv equivalent EtOAc ethyl acetate Et2O diethyl ether EtOH ethanol Example Fe Iron h time M molar concentration MeOH Methanol MgSO4 Magnesium Sulfate min mL milliliter Mw Molecular weight NaHCO3 Sodium bicarbonate Na2SO4 Sodium Sulfate Pd / C Palladium Carbon pTSA p-toluenesulfonic acid RT room temperature tBuOH tert.-butanol tBuOK Potassium tert.-butylate TEA Triethylamine THF tetrahydrofuran TLC Thin Layer Chromatography (R f : retention factor)

[0158] The following general procedures were used to synthesize the reported compounds: General Procedure A: Aromatic Nucleophilic Substitution with Substituted Phenols (See Scheme 1) JPEG0007624930000044.jpg33170 Desired aryl alcohol in DMF (0.5M) A (1.1 equivalents) and the corresponding 4-halonitroaryl B To the 1.0 equiv. of nitrobenzene (1.0 equiv.) was added K2CO3 (1.2 equiv.). The reaction was stirred at room temperature. Upon completion (monitored by TLC using EtOAc / hexane or EtOAc / cyclohexane as eluent and stained with KMnO4), typically observed after 14 h, the reaction mixture was poured into a mixture of Et2O and saturated aqueous NaHCO3. The layers were separated and the aqueous phase was extracted twice with Et2O. The combined organic layers were washed with saturated aqueous NaHCO3, dried over Na2SO4 or MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by Combi-Flash column chromatography using EtOAc / hexane or EtOAc / cyclohexane as eluent to give the corresponding nitro compound. C obtained.

[0159] General Procedure B: Nitroaromatic Reduction (see Scheme 1) JPEG0007624930000045.jpg29170 Nitro compounds CTo (1.0 equiv.) was added Fe powder (5.0 equiv.) and EtOH / H2O / AcOH 2:2:1 (0.1 M). The reaction was sonicated until completion (monitored by TLC stained with KMnO4 using EtOAc / hexane or EtOAc / cyclohexane as eluent). The resulting brown slurry was filtered through filter paper, rinsed with EtOAc, and the organic solvent was evaporated. After EtOAc was added, a saturated aqueous solution of NaHCO3 was carefully added. The layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over MgSO4 or Na2SO4, filtered, and the solvent was evaporated. The crude product was purified by combiflash column chromatography using EtOAc / hexane or EtOAc / cyclohexane as eluent to give the corresponding title compound. D obtained.

[0160] General Procedure C: Aminoarylmethylation (see Scheme 2) JPEG0007624930000046.jpg31170 In an inert atmosphere, add freshly prepared sodium methoxide (Na 5.0 equivalents, MeOH 0.1 M) to a solution of the aminoaryl derivative. D (1.0 equiv.) was added. The reaction was stirred at room temperature (1 h). Paraformaldehyde (1.4 equiv.) was then added, followed after 16 h by NaBH4 (2.0 equiv.). The mixture was stirred until completion (monitored by TLC). MeOH was evaporated and EtOAc was added, followed by saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with brine, dried over MgSO4 or Na2SO4, filtered and evaporated under vacuum. The crude residue was purified by column chromatography using EtOAc / hexane or EtOAc / cyclohexane as eluent to give the target compound. E obtained.

[0161] Basic Procedure D: Suzuki Coupling JPEG0007624930000047.jpg33170 The desired boronic acid F (1.2 equiv.) in dioxane / H2O 4:1 (0.05-0.1 M) GTo a suspension of 1.0 equiv. of HCl and the correct base (2.0-2.5 equiv.), a palladium catalyst (10% mol) was added. The reaction mixture was stirred under reflux. After 16 h, EtOAc and H2O were added. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO4 or Na2SO4, filtered through a pad of Celite, and concentrated under reduced pressure. The residue was purified by column chromatography using EtOAc / hexane or EtOAc / cyclohexane as eluent to give the target compound. C obtained.

[0162] NOTE: This procedure is performed using the bromoaryl derivative F and as arylboronic acids / esters G This was also applied to Suzuki couplings between

[0163] Basic Procedure E: Suzuki Coupling JPEG0007624930000048.jpg33170 To a suspension of the desired boronic acid F (1.2 equiv.), the desired bromoaryl G (1.0 equiv.), and K2CO3 (2.0–2.5 equiv.) in dioxane / H2O 4:1 (0.05–0.1 M) was added tetrakis(triphenylphosphine)palladium(0) (10% mol). The reaction mixture was stirred under reflux. After 16 h, EtOAc and H2O were added. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO4 or Na2SO4, filtered through a pad of Celite, and concentrated under reduced pressure. The residue was purified by column chromatography using EtOAc / hexane or EtOAc / cyclohexane as eluent to give the target compound. C obtained.

[0164] General Procedure F: Nitroaromatic Reduction (see Scheme 1) JPEG0007624930000049.jpg35170Nitro compounds in a 3:1 mixture of acetone / H2O at room temperature CTo a solution of (1.0 equiv.) of HCl (5 equiv.) was added NH4Cl (5 equiv.). To this stirred solution, Zn (5.0 equiv.) was added portionwise. The reaction mixture was stirred for 1 h (monitored by TLC using EtOAc / hexane or EtOAc / cyclohexane as eluent and stained with KMnO4) and then concentrated under reduced pressure. The residue was suspended in EtOAc and filtered through a pad of Celite, which was washed with EtOAc. The filtrate was washed with NaHCO3 (2x), dried over MgSO4 or Na2SO4, filtered off, and the solvent was evaporated to give the corresponding title compound. D obtained.

[0165] General Procedure G: Aminoarylmethylation (see Scheme 2) JPEG0007624930000050.jpg33170Aminoaryl derivatives in DCE (0.25M) D To a solution of (1.0 equiv.) was added paraformaldehyde (1.1 equiv.) at room temperature. After stirring the mixture for 5 minutes, NaBH(OAc)3 (1.5 equiv.) was added, followed by AcOH (1 equiv.). The reaction was stirred overnight at room temperature. The reaction mixture was quenched by adding 1 M NaOH and diluted with H2O and CHCl2. The two layers were separated, and the aqueous layer was extracted with CHCl2 (2x). The combined organic layers were washed with brine, dried over MgSO4 or Na2SO4, filtered, and evaporated in vacuo. The crude residue was purified by column chromatography using EtOAc / hexane or EtOAc / cyclohexane as eluent to give the target compound. E obtained.

[0166] Example 1: 6-([1,1'-biphenyl]-4-yloxy)pyridin-3-amine JPEG0007624930000051.jpg21170Following general procedure B, 6-([1,1'-biphenyl]-4-yloxy)pyridin-3-amine was obtained in 97% yield (1.66 mmol, 434 mg) from 2-([1,1'-biphenyl]-4-yloxy)-5-nitropyridine (1.71 mmol, 500 mg). C 17 H 14NO; Mw = 262.31 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.75(dd,J=3.0,0.6Hz,1H),7.61-7.52(m,4H),7.47-7.39(m,2H),7.36-7.29(m,1H),7.17-7.06(m,3H),6.82(dd,J=8.6,0.6Hz,1H); 13 C NMR(101MHz,CDCl3) δ 156.60,155.34,140.87,138.96,136.84,134.28,128.85,128.45,127.11,127.09,127.01,120.20,112.77,77.48,77.16,76.84.

[0167] The starting material was prepared as follows: Step 1: 2-([1,1'-biphenyl]-4-yloxy)-5-nitropyridine JPEG0007624930000052.jpg22170Following general procedure A, 2-([1,1'-biphenyl]-4-yloxy)-5-nitropyridine was obtained in 99% yield (4.65 mmol, 1.36 g) from [1,1'-biphenyl]-4-ol (4.70 mmol, 800 mg) and 2-chloro-5-nitropyridine (4.70 mmol, 745 mg) without purification. C 17 H 12 N2O3; Mw = 292.29 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.08(d,J=2.8Hz,1H),8.50(dd,J=9.1,2.8Hz,1H),7.67(d,J=8.8Hz,2H),7.60(dd,J=8.3,1.2Hz,2 H),7.46(dd,J=8.2,6.8Hz,2H),7.40-7.33(m,1H),7.26-7.20(m,2H),7.08(dd,J=9.1,0.5Hz,1H).

[0168] Example 2: 6-([1,1'-biphenyl]-4-yloxy)-N-methylpyridin-3-amine JPEG0007624930000053.jpg21170Following general procedure C, 6-([1,1'-biphenyl]-4-yloxy)-N-methylpyridin-3-amine (4.61 mmol, 1.21 g) was used to obtain 6-([1,1'-biphenyl]-4-yloxy)-N-methylpyridin-3-amine in 86% yield (3.98 mmol, 1.10 g). C 18 H 16 NO; Mw = 276.34 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.69(d,J=3.0Hz,1H),7.59-7.53(m,4H),7.42(t,J=7.6Hz,2H),7.35-7.29(m,1H), 7.15-7.09(m,2H),7.05(dd,J=8.7,3.1Hz,1H),6.86(d,J=8.7Hz,1H),2.86(s,3H).

[0169] Example 3: 6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine Following the general procedure B, 6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine was obtained in 93% yield (2.43 mmol, 0.64 g) from 5-nitro-2-((6-phenylpyridin-3-yl)oxy)pyridine (2.63 mmol, 0.77 g). C 16 H 13 NO; Mw = 263.30 g.mol -1 ;solid; 1 H NMR(400MHz,CDCl3) δ 8.53(d,J=2.7Hz,1H),7.96(d,J=7.3Hz,2H),7.71(dd,J=7.9,5.9Hz,2H),7.51(dd,J=8.6,2.7Hz,1H),7.4 6(t,J=7.5Hz,2H),7.39(t,J=7.3Hz,1H),7.13(dd,J=8.6,2.9Hz,1H),6.86(d,J=8.6Hz,1H),3.63(s,2H).

[0170] The starting material was prepared as follows: Step 1: 5-nitro-2-((6-phenylpyridin-3-yl)oxy)pyridine JPEG0007624930000054.jpg23170Following general procedure A, 5-nitro-2-((6-phenylpyridin-3-yl)oxy)pyridine was obtained in 93% yield (2.63 mmol, 0.77 g) from 6-phenylpyridin-3-ol (2.92 mmol, 0.51 g) and 2-chloro-5-nitropyridine (2.84 mmol, 0.45 g). C 16 H 11 N3O3; Mw = 293.28 g.mol -1 ;solid; 1 H NMR(400MHz,CDCl3) δ 9.04(d,J=2.7Hz,1H),8.59(d,J=2.6Hz,1H),8.54(dd,J=9.0,2.8Hz,1H),8.04-7.97(m,2H),7.83(d,J=8.6 Hz,1H),7.62(dd,J=8.6,2.8Hz,1H),7.52-7.47(m,2H),7.45(dd,J=4.9,3.6Hz,1H),7.16(d,J=9.0Hz,1H).

[0171] Example 4: 3-Fluoro-4-(4-(pyridin-2-yl)phenoxy)aniline JPEG0007624930000055.jpg24170Following general procedure B, 3-fluoro-4-(4-(pyridin-2-yl)phenoxy)aniline was obtained from 2-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine (4.38 mmol, 1.36 g) in 42% yield (1.8 mmol, 0.51 g). C 17 H 13 FNO; Mw = 280.30 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 8.63(d,J=5.0Hz,1H),7.90(d,J=8.5Hz,2H),7.75(s,1H),7.66(d,J=8.0Hz,1H),7.28(m,1H), 7.02-6.94(m,2H),6.90(t,J=8.8Hz,1H),6.46(dd,J=12.0,2.7Hz,1H),6.39(ddd,J=8.6,2.7,1.3Hz,1H).

[0172] The starting material was prepared as follows: Step 1: 2-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine JPEG0007624930000056.jpg24170Following general procedure A, 2-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine was obtained in 30% yield (4.38 mmol, 1.36 g) from 4-(pyridin-2-yl)phenol (14.6 mmol, 2.50 g) and 1,2-difluoro-4-nitrobenzene (14.3 mmol, 2.28 g). C 17 H 11 FN2O3; Mw = 310.28 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.71(ddd,J=4.9,1.8,0.9Hz,1H),8.12(dd,J=10.2,2.6Hz,1H),8.10-8.04(m,2H),8.01(ddd,J=9.0,2.6,1. 5Hz,1H),7.84-7.76(m,1H),7.76-7.71(m,1H),7.29(s,1H),7.23-7.16(m,2H),7.06(dd,J=9.1,7.9Hz,1H).

[0173] Example 5: 3-Fluoro-4-(4-(pyridin-3-yl)phenoxy)aniline JPEG0007624930000057.jpg25170Following general procedure B, 3-fluoro-4-(4-(pyridin-3-yl)phenoxy)aniline was obtained in 63% yield (11.1 mmol, 3.1 g) from 3-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine (17.7 mmol, 5.48 g). C 17 H 13 FNO; Mw = 280.30 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.82(d,J=2.4Hz,1H),8.57(dd,J=5.0,1.5Hz,1H),7.95(s,1H),7.52-7.47(m,2H),7.45(s,1H),7.06 -7.00(m,2H),6.97(t,J=8.7Hz,1H),6.54(dd,J=12.0,2.7Hz,1H),6.46(ddd,J=8.6,2.7,1.2Hz,1H).

[0174] The starting material was prepared as follows: Step 1: 3-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine JPEG0007624930000058.jpg26170Following general procedure A, 3-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine was obtained in 79% yield (17.7 mmol, 5.48 g) from 4-(pyridin-3-yl)phenol (22.4 mmol, 3.84 g) and 1,2-difluoro-4-nitrobenzene (22.0 mmol, 3.50 g). C 17 H 11 FN2O3; Mw = 310.28 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.88(s,1H),8.64(d,J=5.0Hz,1H),8.13(dd,J=10.2,2.7Hz,1H),8.09-7.98(m,2H), 7.69-7.61(m,2H),7.55-7.48(m,1H),7.23-7.17(m,2H),7.11(dd,J=9.0,7.8Hz,1H).

[0175] Example 6: 4-([1,1'-biphenyl]-4-yloxy)-3-fluoro-N-methylaniline JPEG0007624930000059.jpg24170Following general procedure C, 4-([1,1'-biphenyl]-4-yloxy)-3-fluoro-N-methylaniline was obtained in 77% yield (3.2 mmol, 0.93 g) from 4-([1,1'-biphenyl]-4-yloxy)-3-fluoroaniline (4.1 mmol, 1.15 g). C 19 H 16 FNO; Mw = 293.34 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.57-7.52(m,2H),7.52-7.47(m,2H),7.41(t,J=7.6Hz,2H),7.31(t,J=7.4Hz,1H),7.03-6.9 5(m,3H),6.46(dd,J=12.7,2.7Hz,1H),6.39(dd,J=8.7,1.7Hz,1H),4.04(s,1H),2.85(s,3H).

[0176] The starting material was prepared as follows: Step 1: 1-(4-bromophenoxy)-2-fluoro-4-nitrobenzene JPEG0007624930000060.jpg21170Following general procedure A, 1-(4-bromophenoxy)-2-fluoro-4-nitrobenzene (12.0 mmol, 3.73 g) was obtained in 96% yield from 4-bromophenol (12.8 mmol, 2.21 g) and 1,2-difluoro-4-nitrobenzene (12.5 mmol, 1.99 g). C 12 H7BrFNO3; Mw = 312.09 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.10(dd,J=10.2, 2.7Hz,1H),8.01(ddd,J=9.1,2.7,1.6Hz,1H),7.57-7.51 (m,2H),7.05-7.00(m,1H),7.00-6.94(m,2H).

[0177] Step 2: 4-(2-fluoro-4-nitrophenoxy)-1,1'-biphenyl Following general procedure E, a mixture of phenylboronic acid (12.1 mmol, 1.48 g), 1-(4-bromophenoxy)-2-fluoro-4-nitrobenzene (9.9 mmol, 3.10 g), KCO (21.5 mmol, 2.97 g), and Pd(PPh) (10% mol) in dioxane / HO 4:1 (0.05-0.1 M) was converted to 4-(2-fluoro-4-nitrophenoxy)-1,1'-biphenyl in 56% yield (5.6 mmol, 1.72 g). C 18 H 12 FNO3; Mw = 309.30 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.11(dd,J=10.2,2.6Hz,1H),8.01(ddd,J=9.1,2.6,1.5Hz,1H),7.67-7.62(m,2H),7.61-7.56(m, 2H),7.46(t,J=7.5Hz,2H),7.37(t,J=7.3Hz,1H),7.19-7.14(m,2H),7.06(dd,J=9.0,8.0Hz,1H).

[0178] Step 3: 4-([1,1'-biphenyl]-4-yloxy)-3-fluoroaniline JPEG0007624930000062.jpg25170Following general procedure B, 4-(2-fluoro-4-nitrophenoxy)-1,1'-biphenyl (5.5 mmol, 1.70 g) gave 4-([1,1'-biphenyl]-4-yloxy)-3-fluoroaniline in 85% yield (4.7 mmol, 1.31 g). C 18 H 14 FNO; Mw = 279.31 g mol -1 ; 1H NMR(400MHz,CDCl3) δ 7.58-7.52(m,2H),7.52-7.48(m,2H),7.41(t,J=7.6Hz,2H),7.31(t,J=7.4Hz,1 H),7.01-6.93(m,3H),6.53(dd,J=12.0,2.7Hz,1H),6.48-6.42(m,1H),3.70(br s,2H).

[0179] Example 7: 4-([1,1'-biphenyl]-4-yloxy)aniline JPEG0007624930000063.jpg21170Following general procedure B, 4-(4-nitrophenoxy)-1,1'-biphenyl (7.1 mmol, 2.08 g) gave 4-([1,1'-biphenyl]-4-yloxy)aniline in 33% yield (2.4 mmol, 0.62 g). C 18 H 15 NO; Mw = 261.32 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.57-7.53(m,2H),7.53-7.47(m,2H),7.45-7.39(m,2H),7.34-7.28(m ,1H),7.03-6.97(m,2H),6.95-6.89(m,2H),6.74-6.66(m,2H),3.61(br s,2H).

[0180] The starting material was prepared as follows: Step 1: 4-(4-nitrophenoxy)-1,1'-biphenyl JPEG0007624930000064.jpg21170Following general procedure A, 4-(4-nitrophenoxy)-1,1'-biphenyl was obtained in 61% yield (7.1 mmol, 2.08 g) from [1,1'-biphenyl]-4-ol (11.8 mmol, 2.00 g) and 4-fluoro-nitrobenzene (11.5 mmol, 1.63 g). C 18 H 13 NO3; Mw = 291.31 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 8.26-8.20(m,2H),7.69-7.63(m,2H),7.62-7.57(m,2H),7.50-7.43(m,2H),7.41-7.34(m,1H),7.19-7.14(m,2H),7.11-7.05(m,2H).

[0181] Example 8: 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine JPEG0007624930000065.jpg23170Following general procedure B, 6-([1,1'-biphenyl]-4-yloxy)-2-methyl-3-nitropyridine (5.3 mmol, 1.61 g) gave 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine in 90% yield (4.7 mmol, 1.31 g). C 18 H 16 NO; Mw = 276.34 g.mol -1 ; 1 HNMR(400MHz,CDCl3) δ 7.59-7.52(m,4H),7.42(t,J=7.6Hz,2H),7.32(ddd,J=7.4,3.9,1.2Hz,1H),7.10(d, J=8.7Hz,2H),7.02(d,J=8.4Hz,1H),6.63(d,J=8.4Hz,1H),3.49(s,2H),2.37(s,3H).

[0182] The starting material was prepared as follows: Step 1: 6-([1,1'-biphenyl]-4-yloxy)-2-methyl-3-nitropyridine JPEG0007624930000066.jpg22170Following general procedure A, 6-([1,1'-biphenyl]-4-yloxy)-2-methyl-3-nitropyridine was obtained in 89% yield (5.3 mmol, 1.63 g) from [1,1'-biphenyl]-4-ol (5.9 mmol, 1.00 g) and 6-chloro-2-methyl-3-nitropyridine (5.8 mmol, 1.00 g). C 18 H 14N2O3; Mw = 306.32 g.mol -1 ; 1 HNMR(400MHz,CDCl3) δ 8.38(d,J=8.9Hz,1H),7.63(dd,J=16.5,7.9Hz,4H),7.46(t,J=7.6Hz,2H),7.37( dd,J=8.3,6.4Hz,1H),7.24(d,J=8.7Hz,2H),6.84(d,J=8.9Hz,1H),2.78(s,3H).

[0183] Example 9: 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine JPEG0007624930000067.jpg22170Following general procedure B, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine was obtained in 74% yield (1.5 mmol, 410 mg) from 6-([1,1'-biphenyl]-4-yloxy)-4-methyl-3-nitropyridine (2.0 mmol, 600 mg). C 18 H 16 NO; Mw = 276.34 g.mol -1 ; 1 HNMR(400MHz,CDCl3) δ 7.69(s,1H),7.61-7.52(m,4H),7.42(t,J=7.6Hz,2H),7.33(dt,J=9.2,4.3Hz ,1H),7.12(d,J=8.7Hz,2H),6.72(s,1H),3.03(s,2H),2.21(d,J=0.5Hz,3H).

[0184] The starting material was prepared as follows: Step 1: 6-([1,1'-biphenyl]-4-yloxy)-4-methyl-3-nitropyridine JPEG0007624930000068.jpg21170Following general procedure A, 6-([1,1'-biphenyl]-4-yloxy)-4-methyl-3-nitropyridine was obtained in 38% yield (2.3 mmol, 0.71 g) from [1,1'-biphenyl]-4-ol (5.9 mmol, 1.00 g) and 6-chloro-4-methyl-3-nitropyridine (5.8 mmol, 1.00 g). C 18 H 14 N2O3; Mw = 306.32 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.92(s,1H),7.69-7.63(m,2H),7.63-7.57(m,2H),7.49-7.42(m,2H),7.40- 7.34(m,1H),7.25-7.20(m,2H),6.88(d,J=0.9Hz,1H),2.69(d,J=0.8Hz,3H).

[0185] Example 10: 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine JPEG0007624930000069.jpg23170 Following general procedure B, 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine was obtained in 58% yield (3.9 mmol, 1.10 g) from 2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitropyridine (6.8 mmol, 2.10 g). C 17 H 13 FNO; Mw = 280.30 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.75(d,J=3.0Hz,1H),7.51(m,4H),7.16-7.07(m,5H),6.82(d,J=8.6Hz,1H). 19 F NMR (376 MHz, chloroform-d) δ 116.54.

[0186] The starting material was prepared as follows: Step 1: 2-(4-bromophenoxy)-5-nitropyridine JPEG0007624930000070.jpg17170Following general procedure A, 2-(4-bromophenoxy)-5-nitropyridine was obtained in 89% yield (37.2 mmol, 10.97 g) from 4-bromophenol (42.8 mmol, 7.40 g) and 2-chloro-5-nitropyridine (41.6 mmol, 6.60 g). C 11 H7BrN2O3; Mw = 295.09 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.03(d,J=2.6Hz,1H),8.49(dd,J=9.0,2.8Hz,1H),7.57(d,J=8.8Hz,2H),7.06(m,3H).

[0187] Step 2: 2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitropyridine Following general procedure E, a mixture of 4-fluorophenylboronic acid (8.9 mmol, 1.25 g), 2-(4-bromophenoxy)-5-nitropyridine (7.8 mmol, 2.30 g), KCO (19.5 mmol, 2.70 g), and Pd(PPh) (10% mol) in dioxane / HO 4:1 (0.05-0.1 M) was converted to 2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-5-nitropyridine in 87% yield (6.8 mmol, 2.10 g). C 17 H 11 FN2O3; Mw = 310.28 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.07(d,J=2.7Hz,1H),8.50(dd,J=9.0,2.7Hz,1H),7.62(d,J=8.5Hz,2H),7.55(dd,J =8.5,5.4Hz,2H),7.23(d,J=8.6Hz,2H),7.14(t,J=8.6Hz,2H),7.09(d,J=9.0Hz,1H).

[0188] Example 11: 6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine JPEG0007624930000072.jpg21170Following general procedure B, 6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine was obtained in 46% yield (1.8 mmol, 0.48 g) from 5-(4-((5-nitropyridin-2-yl)oxy)phenyl)thiazole (3.8 mmol, 1.15 g). C 14 H 11 N3OS; Mw = 269.32 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.67(s,1H),7.95(s,1H),7.67(d,J=3.0Hz,1H),7.49(d,J=8.7Hz,2H),7.05(m,3H),6.76(d,J=8.6Hz,1H).

[0189] The starting material was prepared as follows: Step 1: 5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine JPEG0007624930000073.jpg24170To a suspension of 2-(4-bromophenoxy)-5-nitropyridine (20.6 mmol, 6.08 g), CH3COOK (61.1 mmol, 6.00 g), and bis(pinacolato)diboron (30.5 mmol, 7.75 g) in dioxane (0.1 M, 150 mL) was added Pd(dppf)Cl2 under an inert atmosphere. .CHCl (5% mol) was added. The red mixture was stirred at 105 °C for 16 h. The reaction mixture was filtered through a pad of Celite. Water was added to the filtrate, and the mixture was extracted with EtOAc (2x). The organic layer was washed with saturated aqueous NaHCO, brine, dried over NaSO, filtered, and concentrated. The crude product was purified by Combi-Flash column chromatography using EtOAc / cyclohexane (1%-20%) as the eluent to give 5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (15.6 mmol, 5.93 g, 76% yield). C 17 H 19 BN2O5; Mw = 342.16 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.04(d,J=2.5Hz,1H),8.47(dd,J=9.1,2.8Hz,1H),7.94-7.88(m,2H),7.20-7.13(m,2H),7.06-7.01(m,1H),1.35(s,12H).

[0190] Step 2: 5-(4-((5-nitropyridin-2-yl)oxy)phenyl)thiazole Following general procedure D, a mixture of 5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (9.2 mmol, 3.50 g), 5-bromothiazole (7.4 mmol, 1.25 g), CsCO (15.0 mmol, 4.90 g), and PdCl(PPh) (10% mol) in dioxane / HO 4:1 (0.05-0.1 M) was converted to 5-(4-((5-nitropyridin-2-yl)oxy)phenyl)thiazole in 52% yield (3.8 mmol, 1.15 g). C 14 H9N3O3S; Mw = 299.30 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 9.05(d,J=2.6Hz,1H),8.78(s,1H),8.51(dd,J=9.1,2.8Hz,1H),8.08(s,1H),7.67(d,J=8.2Hz,2H),7.23(d,J=8.4Hz,2H),7.10(d,J=9.0Hz,1H).

[0191] Example 12: 4-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)aniline JPEG0007624930000075.jpg21170Following general procedure B, 4-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)aniline was obtained in 88% yield (21.9 mmol, 6.33 g) from 2,2'-dimethyl-4-(4-nitrophenoxy)-1,1'-biphenyl (24.9 mmol, 7.96 g). C 20 H 19 NO; Mw = 289.38 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.26-7.24(m,2H),7.23-7.18(m,1H),7.10(d,J=6.8Hz,1H),7.00(d,J=8.3Hz,1H),6.96-6.91(m,2 H),6.84(d,J=2.5Hz,1H),6.77(dd,J=8.4,2.6Hz,1H),6.75-6.71(m,2H),2.07(s,3H),2.00(s,3H).

[0192] The starting material was prepared as follows: Step 1: 1-Bromo-2-methyl-4-(4-nitrophenoxy)benzene JPEG0007624930000076.jpg20170Following general procedure A, 1-bromo-2-methyl-4-(4-nitrophenoxy)benzene was obtained in 91% yield (27.1 mmol, 8.34 g) from 4-bromo-3-methyl-phenol (31.5 mmol, 6.01 g) and 4-fluoro-nitrobenzene (29.9 mmol, 4.22 g). C 13 H 10BrNO3; Mw = 308.13 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.24-8.18(m,2H),7.57(d,J=8.6Hz,1H),7.05-6.96(m,3H),6.80(dd,J=8.6,2.9Hz,1H),2.41(s,3H).

[0193] Step 2: 2,2'-dimethyl-4-(4-nitrophenoxy)-1,1'-biphenyl Following general procedure E, a mixture of o-tolylboronic acid (30.9 mmol, 4.20 g), 1-bromo-2-methyl-4-(4-nitrophenoxy)benzene (27.1 mmol, 8.34 g), KCO (55.0 mmol, 7.60 g), and Pd(PPh) (10% mol) in dioxane / HO 4:1 (0.05-0.1 M) was converted to 2,2'-dimethyl-4-(4-nitrophenoxy)-1,1'-biphenyl in 92% yield (24.9 mmol, 7.96 g). C 20 H 17 NO3; Mw = 319.36 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.26-8.21(m,2H),7.31-7.27(m,2H),7.24(d,J=4.8Hz,1H),7.14(dd,J=14.2,7.6Hz,2H),7. 11-7.04(m,2H),7.00(d,J=2.5Hz,1H),6.95(dd,J=8.2,2.2Hz,1H),2.09(s,3H),2.07(s,3H).

[0194] Example 13: 4-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-N-methylaniline JPEG0007624930000078.jpg20170Following general procedure C, 4-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-N-methylaniline was obtained in 86% yield (8.9 mmol, 2.70 g) from 4-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)aniline (10.4 mmol, 3.00 g). C 21 H 21 NO; Mw = 303.41 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.26-7.23(m,2H),7.20(ddd,J=9.0,5.8,3.7Hz,1H),7.10(d,J=6.8Hz,1H),7.04-6.95(m,3H),6.84(s,1H) ),6.77(dd,J=8.2,2.1Hz,1H),6.64(d,J=7.9Hz,2H),3.78(s,1H),2.86(s,3H),2.07(s,3H),2.00(s,3H).

[0195] Example 14: 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-N-methylpyridin-3-amine JPEG0007624930000079.jpg22170 Following general procedure C, 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-N-methylpyridin-3-amine was obtained in 78% yield (0.2 mmol, 53 mg) from 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine (0.2 mmol, 65 mg). C 20 H 20 NO; Mw = 304.39 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 7.72(d,J=3.0Hz,1H),7.26-7.24(m,2H),7.21(m,1H),7.11(d,J=6.8Hz,1H),7.08-7.02(m,2H),6.95(d, J=2.5Hz,1H),6.89(dd,J=8.2,2.6Hz,1H),6.86(d,J=8.7Hz,1H),2.87(s,3H),2.08(s,3H),2.02(s,3H).

[0196] The starting material was prepared as follows: Step 1: 2-(4-bromo-3-methylphenoxy)-5-nitropyridine JPEG0007624930000080.jpg21170Following general procedure A, 2-(4-bromo-3-methylphenoxy)-5-nitropyridine was obtained in 98% yield (6.2 mmol, 1.93 g) from 4-bromo-3-methyl-phenol (6.8 mmol, 1.28 g) and 2-chloro-5-nitropyridine (6.4 mmol, 1.01 g). C 12 H9BrN2O3; Mw = 309.12 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.04(d,J=2.7Hz,1H),8.49(dd,J=9.0,2.9Hz,1H),7.59(d,J=8.6Hz,1H),7.10-7.01(m,2H), 6.88(dd,J=8.6,2.8Hz,1H),2.42(s,3H).

[0197] Step 2: 2-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-5-nitropyridine Following general procedure E, a mixture of o-tolylboronic acid (1.9 mmol, 264 mg), 2-(4-bromo-3-methylphenoxy)-5-nitropyridine (1.3 mmol, 400 mg), KCO (2.6 mmol, 358 mg), and Pd(PPh) (10% mol) in dioxane / HO 4:1 (0.05-0.1 M) was converted to 2-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-5-nitropyridine in 95% yield (1.2 mmol, 392 mg). C 19 H 16 N2O3; Mw = 320.35 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.11(d,J=2.8Hz,1H),8.49(dd,J=9.1,2.8Hz,1H),7.35-7.31(m,1H),7.29(m,1H),7.25-7.22(m,1 H),7.18(d,J=8.2Hz,1H),7.15(dt,J=7.0,1.2Hz,1H),7.09-7.00(m,3H),2.10(s,3H),2.09(s,3H).

[0198] Step 3: 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine JPEG0007624930000082.jpg21170Following general procedure B, 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine was obtained in 37% yield (0.5 mmol, 132 mg) from 2-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-5-nitropyridine (1.2 mmol, 392 mg). C 19 H 18 NO; Mw = 290.37 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 7.79(d,J=2.8Hz,1H),7.25(s,2H),7.23-7.18(m,1H),7.12(t,J=6.2Hz,2H),7.06(d,J=8.2Hz,1H),6.96( d,J=1.9Hz,1H),6.90(dd,J=8.3,2.3Hz,1H),6.82(d,J=8.6Hz,1H),2.85(s,2H),2.08(s,3H),2.02(s,3H).

[0199] Example 15: 3-Fluoro-4-(4-(pyridin-4-yl)phenoxy)aniline JPEG0007624930000083.jpg25170Following general procedure B, 3-fluoro-4-(4-(pyridin-4-yl)phenoxy)aniline was obtained in 71% yield (211 mg, 0.752 mmol) from 4-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine (330 mg, 1.06 mmol). C 17 H 13 FNO; Mw = 280.30 g.mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 8.59(dd,J=4.5,1.6Hz,2H),7.80-7.74(m,2H),7.65(dd,J=4.5,1.6Hz,2H),7. 01-6.93(m,3H),6.51(dd,J=13.3,2.5Hz,1H),6.44-6.39(m,1H),5.39(s,2H).

[0200] The starting material was prepared as follows: Step 1: 4-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine JPEG0007624930000084.jpg25170 Following general procedure E, 4-(4-(2-fluoro-4-nitrophenoxy)phenyl)pyridine was obtained in 75% yield (300 mg, 0.967 mmol) from 1-(4-bromophenoxy)-2-fluoro-4-nitrobenzene (400 mg, 1.28 mmol; Example 6: Step 1). C 17 H11 FN2O3; Mw = 310.28 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.68(d,J=6.1Hz,2H),8.13(dd,J=10.2,2.7Hz,1H),8.04(ddd,J=9.0,2.6,1.5Hz,1H),7.70 (d,J=8.8Hz,2H),7.49(d,J=6.2Hz,2H),7.19(d,J=8.8Hz,2H),7.10(dd,J=9.0,7.9Hz,1H).

[0201] Example 16: 6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine JPEG0007624930000085.jpg21170Following general procedure B, 6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine was obtained in 21% yield (15 mg, 0.057 mmol) from 2-(4-((5-nitropyridin-2-yl)oxy)phenyl)thiazole (100 mg, 0.300 mmol). C 14 H 11 N3OS; Mw = 269.32 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.00-7.95(m,2H),7.85(d,J=3.3Hz,1H),7.77(d,J=3.0Hz,1H),7.31(d,J=3.3Hz,1H),7.16-7.11(m,3H),6.84(d,J=8.5Hz,1H).

[0202] The starting material was prepared as follows: Step 1: 2-(4-((5-nitropyridin-2-yl)oxy)phenyl)thiazole JPEG0007624930000086.jpg21170Following general procedure A, 2-(4-((5-nitropyridin-2-yl)oxy)phenyl)thiazole was obtained in 61% yield (206 mg, 0.688 mmol) from 4-(thiazol-2-yl)phenol (0.23 g, 1.30 mmol) and 2-chloro-5-nitropyridine (0.18 g, 1.10 mmol). C 14 H9N3SO3; Mw = 299.30 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.06(d,J=2.8Hz,1H),8.51(dd,J=9.0,2.8Hz,1H),8.10-8.04(m,2H),7.88(d, J=3.3Hz,1H),7.36(d,J=3.3Hz,1H),7.29-7.23(m,2H),7.10(d,J=9.0Hz,1H).

[0203] Example 17: (4'-((5-aminopyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methanol JPEG0007624930000087.jpg22170Following general procedure B, (4'-((5-nitropyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methanol (50 mg, 0.16 mmol) gave (4'-((5-aminopyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methanol in 44% yield (20 mg, 0.044 mmol). C 18 H 16 N2O2; Mw = 292.34 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.75(d,J=2.9Hz,1H),7.57(dd,J=6.5,2.1Hz,3H),7.50(d,J=7.7Hz,1H),7.42(t,J=7.6Hz,1 H),7.33(d,J=7.6Hz,1H),7.18-7.06(m,3H),6.82(d,J=8.6Hz,1H),4.76(s,2H),3.49(s,2H).

[0204] The starting material was prepared as follows: Step 1: (4'-((5-nitropyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methanol Following general procedure E, (4'-((5-nitropyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methanol was obtained in 65% yield (281 mg, 0.872 mmol) from 2-(4-bromophenoxy)-5-nitropyridine (400 mg, 1.36 mmol; Example 10: Step 1) and (3-(hydroxymethyl)phenyl)boronic acid (240 mg, 1.60 mmol). C 18 H 14 N2O4; Mw = 322.32 g.mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 9.07(dd,J=2.8,0.6Hz,1H),8.50(dd,J=9.1,2.8Hz,1H),7.71-7.65(m,2H),7.62(td,J=1.8,0.7Hz,1H),7.54(dt,J=7.6,1.6Hz,1H),7.46 (t,J=7.5Hz,1H),7.37(dt,J=7.6,1.4Hz,1H),7.26-7.22(m,2H),7.08(dd,J=9.1,0.6Hz,1H),4.79(d,J=5.9Hz,2H),1.72(t,J=5.9Hz,1H).

[0205] Example 18: 6-((3'-(aminomethyl)-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine JPEG0007624930000089.jpg211702-((4'-((5-aminopyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methyl)isoindoline-1,3-dione (51 mg, 0.121 mmol) was suspended in methanol (1 mL, 0.1 M) (low solubility at room temperature) under N2. Hydrazine hydrate (15 mg, 0.30 mmol) was added. The yellow solution was refluxed overnight. Upon reaching room temperature, a white solid precipitated. The reaction mixture was filtered, and the filtrate was concentrated. The crude residue was purified on a Biotage Isolera Four (KP-sil 25 g column, DCM / MeOH, MeOH 1-15%; 28 CV) to give 6-((3'-(aminomethyl)-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine as a pale yellow solid (20 mg, 0.07 mmol, 57%). C 18 H 17 N3O;Mw=291.35g.mol-1; 1 H NMR(400MHz,DMSO-d6) δ 7.66(d,J=1.8Hz,1H),7.65-7.61(m,2H),7.57(d,J=2.9Hz,1H),7.52(dt,J=7.7,1.5Hz,1H),7.41(t,J=7.6Hz,1H),7 .33(d,J=7.7Hz,1H),7.10(dd,J=8.6,3.0Hz,1H),7.06-7.02(m,2H),6.81(d,J=8.6Hz,1H),5.13(s,2H),3.88(s,2H).

[0206] The starting material was prepared as follows: Step 1: 2-((4'-((5-nitropyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methyl)isoindoline-1,3-dione To a 25 mL round-bottom flask was added (4'-((5-nitropyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methanol (0.117 g, 0.363 mmol), triphenylphosphine (0.115 g, 0.438 mmol), and phthalimide (0.068 g, 0.46 mmol) under N2, followed by THF (2 mL). Diisopropyl azodicarboxylate (0.075 mL, 0.39 mmol) was added dropwise at 0 °C. The yellow solution was stirred at room temperature (2 days). The mixture was concentrated and the crude material was purified on a Biotage Isolera Four (KP-sil 25 g column, cyclohexane / EtOAc, EtOAc 0-40%, 15 CV) to give 2-((4'-((5-nitropyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methyl)isoindoline-1,3-dione (158 mg, 0.350 mmol, 96%) as a yellow foam. C 26 H 17 N3O5; Mw = 451.44 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.07(dd,J=2.8,0.6Hz,1H),8.49(dd,J=9.0,2.8Hz,1H),7.87-7.84(m,2H ),7.72(dd,J=5.5,3.0Hz,2H),7.66(d,J=1.8Hz,1H),7.66-7.62(m,2H),7. 50(dt,J=7.3,1.7Hz,1H),7.47-7.43(m,1H),7.40(t,J=7.5Hz,1H),7.24- 7.20(m,2H),7.07(dd,J=9.0,0.6Hz,1H),4.92(s,2H).TLC(Cyclohexane / EtOAc 7:3) R f =0.42

[0207] Step 2: 2-((4'-((5-aminopyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methyl)isoindoline-1,3-dione JPEG0007624930000091.jpg241702-((4'-((5-Nitropyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methyl)isoindoline-1,3-dione (158 mg, 0.350 mmol) was suspended in EtOAc (3 mL) under N. Pd / C (10%, 16 mg) was added to give a black suspension, which was stirred under a H atmosphere (1 atm) overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated to give 170 mg of crude product as a yellow oil. The crude product was purified on a Biotage Isolera Four (KP-sil 25 g column, cyclohexane / EtOAc, 12-100% EtOAc, 18 CV) to give 2-((4'-((5-aminopyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)methyl)isoindoline-1,3-dione as a yellow gum (100 mg, 0.200 mmol, 67%). C 26 H 19 N3O3; Mw = 421.46 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.85(dd,J=5.4,3.1Hz,2H),7.75(dd,J=3.0,0.7Hz,1H),7.71(dd,J=5.5,3.0Hz,2H),7.63(s,1H),7.56-7.52(m, 2H),7.47(dt,J=7.0,1.8Hz,1H),7.43-7.34(m,2H),7.14-7.09(m,3H),6.81(dd,J=8.7,0.6Hz,1H),4.90(s,2H).

[0208] Example 19: 2-(4'-((5-aminopyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)acetamide JPEG0007624930000092.jpg22170 Following general procedure B, 2-(4'-((5-aminopyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)acetamide (21 mg, 0.060 mmol) was used to obtain 2-(4'-((5-nitropyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)acetamide in 89% yield (17 mg, 0.053 mmol). C 19 H 17 N3O2; Mw = 319.36 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.74(d,J=2.9Hz,1H),7.56(d,J=8.6Hz,2H),7.53-7.46(m,2H),7.42(t,J=7.6Hz,1H),7. 24(s,1H),7.17-7.06(m,3H),6.82(d,J=8.6Hz,1H),5.37(d,J=24.0Hz,2H),3.66(s,2H).

[0209] The starting material was prepared as follows: Step 1: 2-(4'-((5-nitropyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)acetonitrile Following the general procedure E, 2-(4'-((5-nitropyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)acetonitrile was obtained in 99% yield (432 mg, 1.7 mmol) from 2-(4-bromophenoxy)-5-nitropyridine (500 mg, 1.69 mmol; Example 10: Step 1) and 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (536 mg, 2.20 mmol). C 19 H 13 N3O3; Mw = 331.33 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 9.07(d,J=2.7Hz,1H),8.51(dd,J=9.1,2.8Hz,1H),7.69-7.63(m,2H),7.57(d,J=6.7Hz,2H),7.4 7(t,J=8.0Hz,1H),7.33(d,J=7.9Hz,1H),7.28-7.24(d,2H),7.10(d,J=9.0Hz,1H),3.84(s,2H).

[0210] Step 2: 2-(4'-((5-nitropyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)acetamide JPEG0007624930000094.jpg21170H2SO4 (500 μl; 9.0 mmol) was slowly added to 2-(4'-((5-nitropyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)acetonitrile (50 mg, 0.18 mmol) at 0 °C. The mixture was stirred at room temperature overnight. The solution was poured into ice water and neutralized with a 2 M aqueous solution of NaOH. A 2 M aqueous solution of HCl was then used to obtain a solution with a pH of 6. The aqueous layer was washed three times with EtOAc. The crude product was purified on a Biotage Isolera Four (KP-sil 25 g column, cyclohexane / EtOAc, 0–100% EtOAc, 18 CV) to give 2-(4′-((5-nitropyridin-2-yl)oxy)-[1,1′-biphenyl]-3-yl)acetamide as a yellow gum (30 mg, 0.100 mmol, 57%). C 19 H 15 N3O4; Mw = 349.35 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.07(d,J=2.8Hz,1H),8.51(dd,J=9.1,2.8Hz,1H),7.66(d,J=8.6Hz,2H),7.57-7.51(m,2H),7.46 (t,J=7.7Hz,1H),7.30(d,1H),7.24(d,2H),7.09(d,J=9.0Hz,1H),5.43-5.32(m,2H),3.67(s,2H)

[0211] Example 20: 6-((2-(4-aminophenoxy)-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine Following general procedure B, 5-nitro-2-((2-(4-nitrophenoxy)-[1,1'-biphenyl]-4-yl)oxy)pyridine (166 mg, 0.387 mmol) gave 6-((2-(4-nitrophenoxy)-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine in 32% yield (50 mg, 0.13 mmol). 6-((2-(4-nitrophenoxy)-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine (50 mg, 0.130 mmol) was then suspended in MeOH (1.5 mL, 0.08 M). Pd / C (10%, 6.7 mg) was added, resulting in a black suspension. The mixture was stirred under a H atmosphere (1 atm) overnight. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated. The crude product was purified on a Biotage Isolera Four (KP-sil 10 g column, cyclohexane / EtOAc, 50-100% EtOAc, 22 CV) to give 6-((2-(4-aminophenoxy)-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine as an orange solid (40 mg, 0.110 mmol, 86%). C 23 H 19 N3O2; Mw = 369.42 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.72(d,J=2.9Hz,1H),7.57(d,J=7.1Hz,2H),7.40-7.34(m,4H),7.07(dd,J= 8.6,3.0Hz,1H),6.84(d,J=8.8Hz,2H),6.80-6.74(m,2H),6.64-6.60(m,3H).

[0212] The starting material was prepared as follows: Step 1: 4-Methoxy-[1,1'-biphenyl]-2-ol To phenylboronic acid (310 mg, 2.50 mmol) in a 500 mL round-bottom flask was added 2-bromo-5-methoxyphenol (0.41 g, 2.00 mmol), potassium carbonate (0.66 g, 4.70 mmol), water (4 mL), and 2-propanol (16 mL) under N2. Next, bis(triphenylphosphine)palladium(II) chloride (140 mg, 0.20 mmol) was added, and the yellow suspension was stirred at room temperature for 20 minutes before being heated to reflux (16 h). The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. Water and EtOAc were added to the residue. The layers were separated, and the aqueous layer was washed with EtOAc (twice). All organic layers were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified on a Biotage Isolera Four (KP-sil 50 g column, hexane / EtOAc, 2-20% EtOAc, 16 CV) to give 4-methoxy-[1,1'-biphenyl]-2-ol as a brown oil (0.87 g, 84%). C 13 H 12 O2; Mw = 200.24 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.51-7.41(m,4H),7.38(d,J=7.1Hz,1H),7.19-7.12(m,1H),6.57(d,J=7.1Hz,2H),5.25(s,1H),3.83(s,3H).

[0213] Step 2: 4-Methoxy-2-(4-nitrophenoxy)-1,1'-biphenyl JPEG0007624930000097.jpg37170Following general procedure A, 4-methoxy-2-(4-nitrophenoxy)-1,1'-biphenyl was obtained in 66% yield (0.255 g, 0.794 mmol) from 4-methoxy-[1,1'-biphenyl]-2-ol (0.244 g, 1.20 mmol) and 1-fluoro-4-nitrobenzene (0.200 g, 1.40 mmol). C 19 H 15 NO4; Mw = 321.33 g.mol-1 ; 1 H NMR(400MHz,CDCl3) δ 8.11-8.05(m,2H),7.43(d,J=8.6Hz,1H),7.41-7.37(m,2H),7.29(t,J=7.4Hz,2H),7.24-7.2 0(m,1H),6.92(dd,J=8.6,2.6Hz,1H),6.90-6.85(m,2H),6.68(d,J=2.6Hz,1H),3.84(s,3H). TLC (cyclohexane / EtOAc 9:1) f =0.39

[0214] Step 3: 2-(4-nitrophenoxy)-[1,1'-biphenyl]-4-ol JPEG0007624930000098.jpg35170In a 100 mL round-bottom flask, 4-methoxy-2-(4-nitrophenoxy)-1,1'-biphenyl (255 mg, 0.794 mmol) was dissolved in CHCl (10 mL, 0.06 M) under N. The brown solution was cooled to 0 °C. A solution of BBr in CHCl (0.5 M, 2.38 mL, 1.19 mmol) was added dropwise via syringe pump over 1 h. The solution was allowed to reach room temperature and then stirred for 4 h. The mixture was quenched with water at 0 °C and then neutralized with 6 M aqueous NaOH. The layers were separated, the aqueous layer was washed with CHCl (twice), and the combined organic layers were washed with brine, dried (NaSO), filtered, and concentrated. The crude product was purified on a Biotage Isolera Four (KP-sil 25 g column, cyclohexane / EtOAc, EtOAc 0-15%, 22 CV) to give 2-(4-nitrophenoxy)-[1,1′-biphenyl]-4-ol as 139 mg of a yellow solid (51%). C 18 H 13 NO4; Mw = 307.31 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 8.12-8.06(m,2H),7.41-7.35(m,3H),7.29(t,J=7.5Hz,2H),7.25-7.22(m,1H),6 .91-6.86(m,2H),6.84(dd,J=8.4,2.5Hz,1H),6.64(d,J=2.5Hz,1H),4.94(s,1H).

[0215] Step 4: 5-nitro-2-((2-(4-nitrophenoxy)-[1,1'-biphenyl]-4-yl)oxy)pyridine Following the general procedure A, 5-nitro-2-((2-(4-nitrophenoxy)-[1,1'-biphenyl]-4-yl)oxy)pyridine was obtained in 86% yield (166 mg, 0.387 mmol) from 2-(4-nitrophenoxy)-[1,1'-biphenyl]-4-ol (139 mg, 0.452 mmol) and 2-chloro-5-nitropyridine (72 mg, 0.452 mmol). C 23 H 15 N3O6; Mw = 429.39 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.07(d,J=2.8Hz,1H),8.52(dd,J=9.0,2.8Hz,1H),8.14-8.09(m,2H),7.58(d,J=8.5Hz,1H),7.49-7.44(m,2H), 7.38-7.28(m,3H),7.19(dd,J=8.5,2.4Hz,1H),7.11(d,J=9.0Hz,1H),7.00(d,J=2.4Hz,1H),6.97-6.93(m,2H).

[0216] Example 21: 6,6'-([1,1'-biphenyl]-2,4-diylbis(oxy))bis(pyridin-3-amine) JPEG0007624930000100.jpg28170Following general procedure B, 6,6'-([1,1'-biphenyl]-2,4-diylbis(oxy))bis(pyridin-3-amine) was obtained in 13% yield (10 mg, 0.021 mmol) from 6,6'-([1,1'-biphenyl]-2,4-diylbis(oxy))bis(3-nitropyridine) (90 mg, 0.31 mmol). C 22 H 18 N4O2; Mw = 370.41 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.75(d,J=2.9Hz,1H),7.66(d,J=2.9Hz,1H),7.53-7.48(m,2H),7.38(d,J=8.5Hz,1H),7.32(t,J=7.4Hz,3H),7.0 9(dd,J=8.7,2.9Hz,1H),7.01-6.96(m,1H),6.92(dd,J=8.4,2.3Hz,1H),6.82-6.78(m,2H),6.62(d,J=8.7Hz,1H).

[0217] The starting material was prepared as follows: Step 1: 6,6'-((4-bromo-1,3-phenylene)bis(oxy))bis(3-nitropyridine) Following general procedure A, 6,6'-((4-bromo-1,3-phenylene)bis(oxy))bis(3-nitropyridine) was obtained in 97% yield (320 mg, 0.74 mmol) from 4-bromoresorcinol (150 mg, 0.78 mmol) and 2-chloro-5-nitropyridine (260 mg, 1.60 mmol). C 16 H9BrN4O6; Mw = 433.17 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.05(dd,J=2.8,0.6Hz,1H),9.02(dd,J=2.8,0.6Hz,1H),8.52(ddd,J=9.0,8.3,2.8Hz,2H),7.73(d,J=8.7Hz,1H),7.18-7.05(m,4H).

[0218] Step 2: 6,6'-([1,1'-biphenyl]-2,4-diylbis(oxy))bis(3-nitropyridine) To a 50 mL round-bottom flask was added phenylboronic acid (120 mg, 0.96 mmol), 6,6'-((4-bromo-1,3-phenylene)bis(oxy))bis(3-nitropyridine) (320 mg, 0.74 mmol), potassium carbonate (210 mg, 1.50 mmol), water (1 mL), and 2-propanol (6 mL) under N2. Bis(triphenylphosphine)palladium(II) chloride (51 mg, 0.071 mmol) was then added, and the yellow suspension was stirred at room temperature for 5 min and then heated to reflux (16 h). The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. Water and EtOAc were added to the residue. The layers were separated, and the aqueous layer was washed with EtOAc (twice). All organic layers were combined, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified on a Biotage Isolera Four (KP-sil 50 g column, cyclohexane / EtOAc, 0-25% EtOAc, 22 CV) to give 6,6'-([1,1'-biphenyl]-2,4-diylbis(oxy))bis(3-nitropyridine) as a colorless oil (90 mg, 28%). C 22 H 14 N4O6; Mw = 430.38 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.09(dd,J=2.8,0.6Hz,1H),8.92(dd,J=2.8,0.6Hz,1H),8.52(dd,J=9.0,2.8Hz,1H),8.34(dd,J=9.0,2.8Hz,1H),7.56(d,J= 8.4Hz,1H),7.45-7.40(m,2H),7.35-7.27(m,3H),7.23(dd,J=8.5,2.4Hz,1H),7.16-7.10(m,2H),6.90(dd,J=9.0,0.6Hz,1H).

[0219] Example 22: 6-((2-(2-(4-aminophenoxy)ethyl)-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine Following general procedure B, 6-((2-(2-(4-aminophenoxy)ethyl)-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine was obtained in 12% yield (5 mg, 0.012 mmol) from 5-nitro-2-((2-(2-(4-nitrophenoxy)ethyl)-[1,1'-biphenyl]-4-yl)oxy)pyridine (48 mg, 0.10 mmol). C 25 H 23 N3O2; Mw = 397.48 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.75(d,J=3.0Hz,1H),7.42-7.38(m,2H),7.37-7.31(m,3H),7.20(d,J=8.3Hz,1H),7.13-7.07(m,2H),6.96( dd,J=8.3,2.5Hz,1H),6.82(d,J=8.6Hz,1H),6.59-6.51(m,4H),3.92(t,J=7.4Hz,2H),3.01(t,J=7.4Hz,2H).

[0220] The starting material was prepared as follows: Step 1: 2-(2-bromo-5-methoxyphenyl)acetic acid JPEG0007624930000104.jpg281702 In a 50 mL round-bottom flask, 2-(3-methoxyphenyl)acetic acid (1.50 g, 9.00 mmol) was dissolved in CHCl (25 mL, 0.36 M). N-Bromosuccinimide (1.80 g, 9.90 mmol) was added portionwise at 0 °C under N. The colorless solution was stirred at room temperature for 3 h. Water was added to the mixture, and the layers were separated. The aqueous layer was washed with CHCl. ​​All organic layers were combined, washed with brine, dried (NaSO), filtered, and concentrated to give 2-(2-bromo-5-methoxyphenyl)acetic acid as an orange solid (2.22 g, 100%). C9H9BrO3; Mw = 245.07 g.mol-1 ; 1 H NMR(400MHz,CDCl3) δ 7.46(d,J=8.8Hz,1H),6.86(d,J=3.0Hz,1H),6.73(dd,J=8.8,3.0Hz,1H),3.81(s,2H),3.79(s,3H).

[0221] Step 2: 2-(2-bromo-5-methoxyphenyl)ethan-1-ol JPEG0007624930000105.jpg281702 In a 50 mL round-bottom flask, 2-(2-bromo-5-methoxyphenyl)acetic acid (2.22 g, 9.06 mmol) was dissolved in dry THF (16 mL, 0.55 M). The yellow solution was cooled to 0 °C, and a 2.4 M solution of LiAlH4 in THF (2.30 mL, 5.5 mmol) was added dropwise. The yellow solution was stirred at room temperature (2 h). The reaction mixture was quenched with 1 M NaOH (10 mL) at 0 °C. The THF was evaporated, and CHCl and water were added. The cloudy mixture was stirred for 1 h. The layers were separated, and the aqueous layer was washed with CHCl. All organic layers were combined, washed with 1M HCl, brine, dried (Na 2 SO 4 ), filtered and concentrated to give 2-(2-bromo-5-methoxyphenyl)ethan-1-ol as a pale yellow oil (1.35 g, 65%). C9H 11 BrO2; Mw = 231.09 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.43(d,J=8.8Hz,1H),6.83(d,J=3.0Hz,1H),6.67(dd,J=8.8,3.1Hz,1H),3.88(t,J=6.6Hz,2H),3.78(s,3H),2.99(t,J=6.6Hz,2H).

[0222] Step 3: 1-Bromo-4-methoxy-2-(2-(4-nitrophenoxy)ethyl)benzene JPEG0007624930000106.jpg411702 In a 5 mL round-bottom flask, 2-(2-bromo-5-methoxyphenyl)ethan-1-ol (190 mg, 0.82 mmol) was dissolved in dry DMF (3 mL, 0.3 M). NaH (60%, 42 mg, 1.00 mmol) was added portionwise to give a dark yellow suspension. The solution was stirred at room temperature (15 min), and then 1-fluoro-4-nitrobenzene (110 mg, 0.78 mmol) was added. The dark green suspension was stirred at room temperature overnight. The mixture was quenched by the addition of water, followed by the addition of EtOAc. The layers were separated. The aqueous layer was washed with EtOAc. All organic layers were combined, washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified on a Biotage Isolera Four (KP-sil 25 g column, cyclohexane / EtOAc, EtOAc 0-20%, 16 CV) to give 1-bromo-4-methoxy-2-(2-(4-nitrophenoxy)ethyl)benzene as a yellow solid (150 mg, 60%). C 15 H 14 BrNO4; Mw = 352.18 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.22-8.16(m,2H),7.45(d,J=8.8Hz,1H),6.98-6.93(m,2H),6.88(d,J=3.0Hz,1H),6.70(dd,J= 8.8,3.0Hz,1H),4.28(t,J=7.0Hz,2H),3.79(s,3H),3.23(t,J=7.0Hz,2H).TLC(Cyclohexane / EtOAc 9:1) R f =0.28

[0223] Step 4: 4-Methoxy-2-(2-(4-nitrophenoxy)ethyl)-1,1'-biphenyl JPEG0007624930000107.jpg391702To a 50 mL round-bottom flask was added phenylboronic acid (63 mg, 0.51 mmol), 1-bromo-4-methoxy-2-(2-(4-nitrophenoxy)ethyl)benzene (150 mg, 0.43 mmol), potassium carbonate (154 mg, 1.11 mmol), water (1 mL), and 2-propanol (4 mL) under N2. Next, bis(triphenylphosphine)palladium(II) chloride (39 mg, 0.054 mmol) was added, and the yellow suspension was stirred at room temperature for 5 minutes before being heated to reflux (16 h). The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. Water and EtOAc were added to the residue. The layers were separated, and the aqueous layer was washed with EtOAc (twice). All organic layers were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified on a Biotage Isolera Four (KP-sil 50 g column, cyclohexane / EtOAc, EtOAc 0-30%, 13 CV) to give 4-methoxy-2-(2-(4-nitrophenoxy)ethyl)-1,1′-biphenyl as a colorless oil (120 mg, 81%). C 21 H 19 NO4; Mw = 349.39 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.12-8.06(m,2H),7.47-7.38(m,3H),7.34-7.30(m,2H),7.19(d,J=8.4Hz,1H),6.92(d,J=2.6Hz,1H),6 .86(dd,J=8.4,2.7Hz,1H),6.70-6.64(m,2H),4.06(t,J=7.4Hz,2H),3.85(s,3H),3.09(t,J=7.4Hz,2H).

[0224] Step 5: 2-(2-(4-nitrophenoxy)ethyl)-[1,1'-biphenyl]-4-ol In a 100 mL round-bottom flask, 4-methoxy-2-(2-(4-nitrophenoxy)ethyl)-1,1'-biphenyl (115 mg, 0.329 mmol) was dissolved in CHCl (4 mL, 0.9 M) under N. The brown solution was cooled to 0 °C. A solution of BBr in CHCl (0.5 M, 1.0 mL, 0.50 mmol) was added dropwise via syringe pump over 30 minutes. The solution was allowed to reach room temperature and then stirred for 2.3 hours. The mixture was quenched with water at 0 °C and then neutralized with 6 M aqueous NaOH. The layers were separated, and the aqueous layer was re-extracted with CHCl (2 times). The combined organic layers were washed with brine, dried (NaSO), filtered, and concentrated. The crude product was purified on a Biotage Isolera Four (KP-sil 25 g column, cyclohexane / EtOAc, 5-40% EtOAc, 13 CV) to give 2-(2-(4-nitrophenoxy)ethyl)-[1,1′-biphenyl]-4-ol as a yellow oil (47 mg, 41%). C 20 H 17 NO4; Mw = 349.39 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.13-8.07(m,2H),7.47-7.38(m,3H),7.33-7.28(m,2H),7.13(d,J=8.2Hz,1H),6.86(d,J=2.7Hz,1H),6 .78(dd,J=8.3,2.7Hz,1H),6.70-6.65(m,2H),4.76(s,1H),4.05(t,J=7.4Hz,2H),3.07(t,J=7.4Hz,2H).

[0225] Step 6: 5-nitro-2-((2-(2-(4-nitrophenoxy)ethyl)-[1,1'-biphenyl]-4-yl)oxy)pyridine Following the general procedure A, 5-nitro-2-((2-(2-(4-nitrophenoxy)ethyl)-[1,1'-biphenyl]-4-yl)oxy)pyridine was obtained in 75% yield (48 mg, 0.10 mmol) from 2-(2-(4-nitrophenoxy)ethyl)-[1,1'-biphenyl]-4-ol (47 mg, 0.14 mmol) and 2-chloro-5-nitropyridine (27 mg, 0.17 mmol). C 25 H 19 N3O6; Mw = 457.44 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.08(dd,J=2.8,0.6Hz,1H),8.51(dd,J=9.0,2.8Hz,1H),8.13-8.07(m,2H),7.49-7.43(m,3H),7.40-7.32(m, 3H),7.20(d,J=2.4Hz,1H),7.15-7.08(m,2H),6.72-6.66(m,2H),4.08(t,J=7.2Hz,2H),3.14(t,J=7.2Hz,2H).

[0226] Example 23: N-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine To a freshly prepared solution of MeONa (4.4 equiv., 2.609 mmol) in MeOH (0.15 M) was added 6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine (1.0 equiv., 0.588 mmol, 155 mg; Example 3) under an inert atmosphere. The resulting suspension was stirred for 0.5 h to form a solution. Next, a suspension of paraformaldehyde (1.4 equiv., 0.824 mmol, 27 mg) in MeOH (1 ml) was poured into the previous solution, and the mixture was stirred for 14 h. NaBH (2.0 equiv., 1.165 mmol, 45 mg) was added to the reaction, and the mixture was stirred for 3 h (completion monitored by TLC). The mixture was finally diluted with HO at 0 °C. The aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was purified by Combi-Flash column chromatography using EtOAc / cyclohexane (15%-70%) as the eluent to give N-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine (0.436 mmol, 121 mg, 74% yield). C 17 H 15 NO; Mw = 277.33 g.mol -1 ;solid; 1 H NMR(400MHz,CDCl3) δ 8.52(d,J=2.7Hz,1H),7.95(d,J=7.5Hz,2H),7.71(d,J=8.6Hz,1H),7.63(d,J=3.0Hz,1H),7.51-7 .42(m,3H),7.38(t,J=7.3Hz,1H),7.05(dd,J=8.7,3.0Hz,1H),6.89(d,J=8.7Hz,1H),2.86(s,3H).

[0227] Example 24: 6-(4-(pyridin-2-yl)phenoxy)pyridin-3-amine Following general procedure B, 6-(4-(pyridin-2-yl)phenoxy)pyridin-3-amine was obtained in 67% yield (0.23 mmol, 60 mg) from 5-nitro-2-(4-(pyridin-2-yl)phenoxy)pyridine (100 mg, 0.341 mmol). C 16 H 13 NO; Mw = 263.30 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.67(dd,J=4.8,0.8Hz,1H),7.98(d,J=8.7Hz,2H),7.76-7.66(m,3H),7.23-7.17(m ,1H),7.15(d,J=8.8Hz,2H),7.12-7.06(m,1H),6.81(d,J=8.6Hz,1H),3.24(s,2H).

[0228] The starting material was prepared as follows: Step 1: 5-nitro-2-(4-(pyridin-2-yl)phenoxy)pyridine JPEG0007624930000112.jpg22170Following general procedure A, 5-nitro-2-(4-(pyridin-2-yl)phenoxy)pyridine (500 mg, 1.70 mmol) was obtained in 97% yield from 4-(pyridin-2-yl)phenol (1.75 mmol, 0.300 g) and 2-chloro-5-nitropyridine (1.75 mmol, 0.278 g). C 16 H 11 N3O3; Mw = 293.28 g.mol -1 ; 1 H NMR(300MHz,CDCl3) δ 9.11-9.05(m,1H),8.91-8.85(m,1H),8.62(d,J=4.8Hz,1H),8.52(dd,J=9.1,2.8Hz,1H),7.94-7. 85(m,1H),7.67(d,J=8.6Hz,2H),7.42-7.36(m,1H),7.29(d,J=8.6Hz,2H),7.11(d,J=9.0Hz,1H).

[0229] Example 25: 6-(4-(pyridin-3-yl)phenoxy)pyridin-3-amine Following general procedure B, 6-(4-(pyridin-3-yl)phenoxy)pyridin-3-amine was obtained in 52% yield (1.25 mmol, 330 mg) from 5-nitro-2-(4-(pyridin-3-yl)phenoxy)pyridine (710 mg, 2.42 mmol). C 16 H 13 NO; Mw = 263.30 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.85-8.81(m,1H),8.56(dd,J=4.8,1.6Hz,1H),7.84(ddd,J=7.9,2.4,1.6Hz,1H),7.74(dd,J=3.0,0.6Hz,1H),7.55(d,J=8.7Hz,2 H),7.34(ddd,J=7.9,4.8,0.9Hz,1H),7.17(d,J=8.7Hz,2H),7.11(dd,J=8.6,3.0Hz,1H),6.83(dd,J=8.6,0.7Hz,1H),3.48(s,2H).

[0230] The starting material was prepared as follows: Step 1: 5-nitro-2-(4-(pyridin-3-yl)phenoxy)pyridine Following general procedure A, 5-nitro-2-(4-(pyridin-3-yl)phenoxy)pyridine was obtained in 40% yield (270 mg, 0.92 mmol) from 4-(pyridin-3-yl)phenol (2.34 mmol, 0.400 g) and 2-chloro-5-nitropyridine (2.34 mmol, 0.370 g). C 16 H 11 N3O3; Mw = 293.28 g.mol -1 ; 1H NMR(300MHz,CDCl3) δ 9.07(dd,J=2.8,0.6Hz,1H),8.70(ddd,J=4.8,1.7,1.1Hz,1H),8.50(dd,J=9.1,2.8Hz,1H), 8.10(d,J=8.9Hz,2H),7.79-7.74(m,2H),7.28(d,J=9.0Hz,3H),7.08(dd,J=9.1,0.6Hz,1H).

[0231] Example 26: 6-(4-(pyridin-4-yl)phenoxy)pyridin-3-amine Following general procedure B, 6-(4-(pyridin-4-yl)phenoxy)pyridin-3-amine was obtained in 57% yield (0.40 mmol, 100 mg) from 5-nitro-2-(4-(pyridin-4-yl)phenoxy)pyridine (19 mg, 0.672 mmol). 16 H 13 NO; Mw = 263.30 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.64(dd,J=4.6,1.6Hz,2H),7.75(d,J=3.0Hz,1H),7.66-7.60(m,2H),7.50(dd,J=4.6,1.6Hz,2H),7.20-7.10(m,3H),6.85(d,J=8.6Hz,1H).

[0232] The starting material was prepared as follows: Step 1: 5-nitro-2-(4-(pyridin-4-yl)phenoxy)pyridine Following general procedure E, 5-nitro-2-(4-(pyridin-4-yl)phenoxy)pyridine was obtained in 95% yield (33 mg, 0.11 mmol) from 2-(4-bromophenoxy)-5-nitropyridine (50 mg, 0.17 mmol; Example 10: Step 1) and pyridin-4-ylboronic acid (25 mg, 0.20 mmol). C 16 H 11N3O3; Mw = 293.28 g.mol -1 ; 1 H NMR(300MHz,CDCl3) δ 9.06(d,J=2.7Hz,1H),8.69(d,J=6.2Hz,2H),8.62(dd,J=9.1,2.7Hz,1H),7.70(d, J=8.7Hz,2H),7.52(d,J=6.2Hz,2H),7.30(d,J=8.7Hz,2H),7.11(d,J=9.1Hz,1H).

[0233] Example 27: 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-N-methylpyridin-3-amine JPEG0007624930000117.jpg23170 Following general procedure C, 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-N-methylpyridin-3-amine was obtained in 73% yield (0.221 mmol, 85 mg) from 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine (0.303 mmol, 65 mg; Example 10). C 18 H 15 FNO; Mw = 294.33 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.68(d,J=3.0Hz,1H),7.53-7.47(m,4H),7.14-7.08(m,4H),7.05(dd,J=8.7,3.0Hz,1H),6.86(d,J=8.7Hz,1H),2.86(s,3H).

[0234] Example 28: 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-2-methylpyridin-3-amine JPEG0007624930000118.jpg23170 Following general procedure B, 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-2-methyl-3-nitropyridine (1.54 mmol, 500 mg) gave 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-2-methylpyridin-3-amine in 72% yield (1.11 mmol, 330 mg). C 18 H 15 FNO; Mw = 294.33 g.mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 7.71-7.63(m,2H),7.63-7.56(m,2H),7.32-7.22(m,2H),7.08(d,J=8.3Hz ,1H),7.02-6.96(m,2H),6.67(d,J=8.3Hz,1H),4.90(s,2H),2.18(s,3H).

[0235] The starting material was prepared as follows: Step 1: 6-(4-bromophenoxy)-2-methyl-3-nitropyridine Following general procedure A, 6-chloro-2-methyl-3-nitropyridine (29 mmol, 5.00 g) and 4-bromophenol (32 mmol, 5.50 g) gave 6-(4-bromophenoxy)-2-methyl-3-nitropyridine in 93% yield (26.9 mmol, 8.31 g). C 12 H9BrN2O3; Mw = 309.12 g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.38(d,J=8.9Hz,1H),7.72-7.42(m,2H),7.15-6.99(m,2H),6.84(d,J=8.9Hz,1H),2.73(s,3H).

[0236] Step 2: 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-2-methyl-3-nitropyridine Following general procedure E, a mixture of (4-fluorophenyl)boronic acid (4.85 mmol, 679 mg), 6-(4-bromophenoxy)-2-methyl-3-nitropyridine (3.23 mmol, 1.00 g), KCO (8.09 mmol, 1.12 g), and Pd(PPh) (0.162 mmol, 187 mg, 5% mol) in a 4:1 mixture of dioxane / HO (0.1 M) was converted to 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-2-methyl-3-nitropyridine in 90% yield (2.94 mmol, 900 mg). C 18 H 13 FN2O3; Mw = 324.31 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.38(d,J=8.9Hz,1H),7.62-7.58(m,2H),7.58-7.53(m,2H),7.25-7.21(m,2H),7.19-7.11(m,2H),6.84(dd,J=8.9,0.7Hz,1H),2.77(s,3H).

[0237] Example 29: 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methylpyridin-3-amine JPEG0007624930000121.jpg22170 Following general procedure B, 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methylpyridin-3-amine was obtained in 86% yield (476 mmol, 0.140 g) from 2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methyl-5-nitropyridine (555 mmol, 0.180 g). C 18 H 15 FNO; Mw = 294.33 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.69(s,1H),7.54-7.46(m,4H),7.14-7.06(m,4H),6.72(s,1H),2.20(s,3H),2.07(s,2H).

[0238] The starting material was prepared as follows: Step 1: 2-(4-bromophenoxy)-4-methyl-5-nitropyridine JPEG0007624930000122.jpg19170Following general procedure A, 2-(4-bromophenoxy)-4-methyl-5-nitropyridine was obtained in 40% yield (11 mmol, 3.50 g) from 4-bromophenol (31.9 mmol, 5.51 g) and 2-chloro-4-methyl-5-nitropyridine (29 mmol, 5.00 g). C 12 H9BrN2O3; Mw = 309.12 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.86(s,1H),7.55(d,J=8.9Hz,2H), 7.04(d,J=8.9Hz,2H),6.86(d,J=1.0Hz,1H),2.68(app d,J=1.0Hz,3H).

[0239] Step 2: 2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methyl-5-nitropyridine JPEG0007624930000123.jpg23170Following general procedure E, 2-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methyl-5-nitropyridine was obtained in 82% yield (1.13 mmol, 0.30 g) from 2-(4-bromophenoxy)-4-methyl-5-nitropyridine (1.13 mmol, 0.350 mg) and (4-fluorophenyl)boronic acid (1.70 mmol, 0.238 mg). C 18 H 13 FN2O3; Mw = 324.31 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.91(s,1H),7.63-7.58(m,2H),7.57-7.52(m,2H),7.23-7.19(m,2H),7.17-7.11(m,2H),6.89(d,J=0.9Hz,1H),2.69(s,3H).

[0240] Example 30: 2-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine Following the general procedure B, 2-methyl-3-nitro-6-((6-phenylpyridin-3-yl)oxy)pyridine (1.22 mmol, 374 mg) gave 2-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine in 89% yield (1.08 mmol, 300 mg). C 17 H 15 NO; Mw = 277.33 g.mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 8.40(d,J=2.5Hz,1H),8.15-7.98(m,2H),7.94(d,J=8.7Hz,1H),7.55-7.45(m,3H),7.4 4-7.37(m,1H),7.10(d,J=8.4Hz,1H),6.75(d,J=8.4Hz,1H),4.93(s,2H),2.17(s,3H).

[0241] The starting material was prepared as follows: Step 1: 6-Phenylpyridin-3-ol Following general procedure D, a mixture of phenylboronic acid (11.49 mmol, 1.40 g), 6-bromopyridin-3-ol (5.75 mmol, 1.00 g), NaCO (11.49 mmol, 1.22 g), and Pd(PPh) (0.287 mmol, 332 mg) in a 3:1 mixture of DME / HO (0.32 M) was converted to 6-phenylpyridin-3-ol in 61% yield (3.50 mmol, 600 mg). C 11 HNO; Mw = 171.20 g mol -1 ; 1H NMR(400MHz,DMSO-d6) δ 9.19(s,1H),7.40-7.34(m,1H),7.15-7.09(m,2H),6.95(dd,J=8.6,0.7H z,1H),6.65-6.57(m,2H),6.54-6.49(m,1H),6.40(dd,J=8.6,2.9Hz,1H).

[0242] Step 2: 2-methyl-3-nitro-6-((6-phenylpyridin-3-yl)oxy)pyridine Following general procedure A, 2-methyl-3-nitro-6-((6-phenylpyridin-3-yl)oxy)pyridine was obtained in 95% yield (1.22 mmol, 374 mg) from 6-chloro-2-methyl-3-nitropyridine (1.27 mmol, 220 mg). C 17 H 13 N3O3; Mw = 307.31 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.60(dd,J=2.8,0.7Hz,1H),8.42(d,J=8.9Hz,1H),8.09-7.93(m,2H),7.82(dd,J=8.7,0.7 Hz,1H),7.62(dd,J=8.7,2.8Hz,1H),7.56-7.40(m,3H),6.96(d,J=8.9Hz,1H),2.73(s,3H).

[0243] Example 31: 4-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine Following the general procedure B, 4-methyl-5-nitro-2-((6-phenylpyridin-3-yl)oxy)pyridine (0.39 mmol, 120 mg) gave 4-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine in 78% yield (0.30 mmol, 84 mg). C 17 H 15 NO; Mw = 277.33 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 8.51(dd,J=2.8,0.7Hz,1H),7.98-7.90(m,2H),7.71(dd,J=8.6,0.7Hz,1H),7.64(s ,1H),7.50-7.42(m,3H),7.41-7.35(m,1H),6.77(s,1H),3.49(s,2H),2.22(s,3H).

[0244] The starting material was prepared as follows: Step 1: 4-methyl-5-nitro-2-((6-phenylpyridin-3-yl)oxy)pyridine JPEG0007624930000126.jpg21170Following general procedure A, 4-methyl-5-nitro-2-((6-phenylpyridin-3-yl)oxy)pyridine was obtained in 76% yield (0.664 mmol, 204 mg) from 6-phenylpyridin-3-ol (0.956 mmol, 164 mg) and 2-chloro-4-methyl-5-nitropyridine (0.869 mmol, 150 mg). C 17 H 13 N3O3; Mw = 307.31 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.87(s,1H),8.57(d,J=2.7Hz,1H),8.02-7.97(m,2H),7.82(d,J=8.6Hz,1H ),7.60(dd,J=8.6,2.7Hz,1H),7.52-7.39(m,3H),6.97(s,1H),2.71(s,3H).

[0245] Example 32: 2-methyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine JPEG0007624930000127.jpg21170 Following general procedure B, 2-methyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine was obtained in 64% yield (0.42 mmol, 120 mg) from 5-(4-((6-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole (0.66 mmol, 206 mg). C 15 H13 N3OS; Mw = 283.35 g.mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 9.04(d,J=0.7Hz,1H),8.22(d,J=0.7Hz,1H),7.63(d,J=8.8Hz,2H),7.08(d,J=8. 3Hz,1H),6.99(d,J=8.7Hz,2H),6.68(d,J=8.4Hz,1H),4.92(s,2H),2.17(s,3H).

[0246] The starting material was prepared as follows: Step 1: 5-(4-((6-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole Following general procedure D, a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (4.89 mmol, 1.03 g), 6-(4-bromophenoxy)-2-methyl-3-nitropyridine (3.26 mmol, 1.01 g; Example 28, Step 1), NaCO (8.15 mmol, 864 mg), and Pd(PPh) (0.163 mmol, 188 mg, 5% mol) in a 4:1 mixture of dioxane / HO (0.06 M) was converted to 5-(4-((6-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole in 20% yield (0.67 mmol, 209 mg). C 15 H 11 N3O3S; Mw = 313.33 g.mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 9.10(app d,J=0.7Hz,1H),8.52(d,J=8.9Hz,1H),8.33(s,1H),7.91-7.71(m,2H),7.40-7.21(m,2H),7.11(d,J=8.9Hz,1H),2.60(s,3H).

[0247] Example 33: 4-methyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine JPEG0007624930000129.jpg21170Following general procedure B, 4-methyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine was obtained in 33% yield (0.424 mmol, 0.120 g) from 5-(4-((4-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole (1.02 mmol, 0.320 g). C 15 H 13 N3OS; Mw = 283.35 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.72(s,1H),8.00(s,1H),7.67(s,1H),7.54(d,J=8.7Hz,2H),7.09(d,J=8.7Hz,2H),6.73(s,1H),2.21(s,3H),2.04(s,2H).

[0248] The starting material was prepared as follows: Step 1: 5-(4-((4-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole Following general procedure E, 5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)thiazole (3.78 mmol, 0.799 mg) and 2-(4-bromophenoxy)-4-methyl-5-nitropyridine (2.52 mmol, 0.780 g; Example 29, Step 1) gave 5-(4-((4-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole in 40% yield (1.02 mmol, 0.320 g). C 15 H 11 N3O3S; Mw = 313.33 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.89(s,1H),8.78(s,1H),8.07(s,1H),7.65(d,J=8.7Hz,2H),7.21(d,J=8.7Hz,2H),6.90(s,1H),2.69(s,3H).

[0249] Example 34: N-methyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine Following general procedure C, N-methyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine (0.30 mmol, 80 mg; Example 11) was obtained in 59% yield (0.18 mmol, 50 mg). C 15 H 13 N3OS; Mw = 283.35 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.72(s,1H),8.00(s,1H),7.67(d,J=3.0Hz,1H),7.57-7.51(m,2H),7.13-7 .07(m,2H),7.05(dd,J=8.7,3.1Hz,1H),6.86(d,J=8.7Hz,1H),2.86(s,3H).

[0250] Example 35: 2-methyl-6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine JPEG0007624930000132.jpg21170Following general procedure B, 2-methyl-6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine was obtained in 68% yield (0.434 mmol, 123 mg) from 2-(4-((6-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole (0.638 mmol, 200 mg). C 15 H 13 N3OS; Mw = 283.35 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.85(d,J=8.8Hz,2H),7.76(d,J=3.3Hz,1H),7.22(d,J=3.3Hz,1H),7.01( d,J=8.8Hz,2H),6.97(d,J=8.4Hz,1H),6.59(d,J=8.4Hz,1H),2.30(s,3H).

[0251] The starting material was prepared as follows: Step 1: 2-(4-((6-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole JPEG0007624930000133.jpg21170Following general procedure A, 2-(4-((6-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole was obtained in 51% yield (1.44 mmol, 0.450 g) from 4-(2-thiazolyl)phenol (2.82 mmol, 500 mg) and 6-chloro-2-methyl-3-nitropyridine (3.10 mmol, 536 mg). C 15 H 11 N3O3S; Mw = 313.33 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.39(d,J=8.9Hz,1H),8.04(d,J=8.5Hz,2H),7.88(s,1H),7.36(s,1H),7.25(d,J=8.2Hz,2H),6.87(d,J=8.9Hz,1H),2.74(s,3H).

[0252] Example 36: 4-methyl-6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine JPEG0007624930000134.jpg21170Following general procedure F, 4-methyl-6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine was obtained in 94% yield (1.16 mmol, 330 mg) from 2-(4-((4-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole (1.24 mmol, 390 mg). C 15 H 13 N3OS; Mw = 283.35 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.95-7.90(m,2H),7.83(d,J=3.3Hz,1H),7.69(s,1H),7.28(d,J=3.3Hz,1H),7.12-7.07(m,2H),6.73(s,1H),2.21(s,3H).

[0253] The starting material was prepared as follows: Step 1: 2-(4-((4-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole JPEG0007624930000135.jpg21170Following general procedure A, 2-(4-((4-methyl-5-nitropyridin-2-yl)oxy)phenyl)thiazole was obtained in 72% yield (1.24 mmol, 390 mg) from 4-(thiazol-2-yl)phenol (1.91 mmol, 339 mg) and 2-chloro-4-methyl-5-nitropyridine (1.74 mmol, 300 mg). C 15 H 11 N3O3S; Mw = 313.33 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.89(s,1H),8.09-7.99(m,2H),7.87(d,J=3.3Hz,1H),7.34(d,J=3.3Hz,1H),7.25-7.20(m,2H),6.90-6.87(m,1H),2.68(s 3H).

[0254] Example 37: 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-2-methylpyridin-3-amine JPEG0007624930000136.jpg22170Following general procedure B, 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-2-methyl-3-nitropyridine (0.75 mmol, 250 mg) gave 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-2-methylpyridin-3-amine in 80% yield (0.60 mmol, 183 mg). C 20 H 20 NO; Mw = 304.39 g.mol -1 ; 1H NMR(400MHz,methanol-d4) δ 7.29-7.16(m,4H),7.06-7.03(m,1H),7.01(d,J=8.3Hz,1H),6.88(d,J=2.6Hz,1H),6.80( dd,J=8.3,2.6Hz,1H),6.63(dd,J=8.5,0.7Hz,1H),2.33(s,3H),2.05(s,3H),1.99(s,3H).

[0255] The starting material was prepared as follows: Step 1: 6-(4-bromo-3-methylphenoxy)-2-methyl-3-nitropyridine JPEG0007624930000137.jpg20170Following general procedure A, 6-(4-bromo-3-methylphenoxy)-2-methyl-3-nitropyridine was obtained in 94% yield (5.46 mmol, 1.76 g) from 6-chloro-2-methyl-3-nitropyridine (5.79 mmol, 1.00 g) and 4-bromo-3-methylphenol (6.37 mmol, 1.19 g). C 13 H 11 BrN2O3; Mw = 323.15 g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.36(d,J=8.9Hz,1H),7.56(d,J=8.6Hz,1H),7.05(d,J=2.6Hz,1H),6.88(dd,J=8.6,2.6Hz,1H),6.80(d,J=8.9Hz,1H),2.74(s,3H),2.42(s,3H).

[0256] Step 2: 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-2-methyl-3-nitropyridine Following general procedure D, a mixture of o-tolylboronic acid (3.71 mmol, 505 mg), 6-(4-bromo-3-methylphenoxy)-2-methyl-3-nitropyridine (2.48 mmol, 800 mg), NaCO (4.95 mmol, 525 mg), and Pd(PPh) (0.124 mmol, 143 mg, 5% mol) in a 3:1 mixture of DME / HO (0.43 M) was converted to 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-2-methyl-3-nitropyridine in 90% yield (2.24 mmol, 750 mg). C 20 H 18 N2O3; Mw = 334.38 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.38(d,J=8.9Hz,1H),7.33-7.21(m,3H),7.19-7.09(m,2H),7.07(d,J=2.5Hz,1H),7.0 2(dd,J=8.2,2.5Hz,1H),6.81(d,J=8.9Hz,1H),2.81(s,3H),2.10(s,3H),2.08(s,3H).

[0257] Example 38: N-methyl-6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine Following general procedure C, N-methyl-6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine (0.371 mmol, 100 mg; Example 16) was obtained in 86% yield (0.32 mmol, 90 mg). C 15 H 13 N3OS; Mw = 283.35 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 7.96-7.90(m,2H),7.83(d,J=3.3Hz,1H),7.68(dd,J=3.1,0.6Hz,1H),7.28(d,J=3.3Hz,1H ),7.13-7.07(m,2H),7.03(dd,J=8.7,3.1Hz,1H),6.86(dd,J=8.7,0.6Hz,1H),2.87(s,3H).

[0258] Example 39: 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-N,4-dimethylpyridin-3-amine JPEG0007624930000140.jpg23170 Following general procedure C, 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-4-methylpyridin-3-amine (0.34 mmol, 100 mg; Example 29) gave 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-N,4-dimethylpyridin-3-amine in 45% yield (0.15 mmol, 0.047 g). C 19 H 17 FNO; Mw = 308.35 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.55(s,1H),7.45-7.35(m,4H),7.10(t,J=8.3Hz,4H),6.73(s,1H),3.36(s,1H),2.91(s,3H),2.17(s,3H).

[0259] Example 40: 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-N,2-dimethylpyridin-3-amine JPEG0007624930000141.jpg22170 Following general procedure C, 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-2-methylpyridin-3-amine (0.27 mmol, 80 mg; Example 28) gave 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)-N,2-dimethylpyridin-3-amine in 72% yield (0.19 mmol, 0.060 g). C19 H 17 FNO; Mw = 308.35 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.55-7.45(m,4H),7.19-7.00(m,5H),6.74(d,J=8.6Hz,1H),2.92(s,3H),2.42(s,3H),1.65-1.48(bs,1H).

[0260] Example 41: N,4-dimethyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine Following general procedure C, 4-methyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine (0.18 mmol, 0.050 g; Example 33) gave N,4-dimethyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine in 51% yield (0.091 mmol, 0.027 g). C 16 H 15 N3OS; Mw = 297.38 g.mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 9.03(d,J=0.7Hz,1H),8.22(d,J=0.7Hz,1H),7.63(d,J=8.7Hz,2H),7.00-6.95(m,3 H),6.79(d,J=8.5Hz,1H),5.20(q,J=5.0Hz,1H),2.73(d,J=4.9Hz,3H),2.21(s,3H).

[0261] Example 42: N,2-dimethyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine JPEG0007624930000143.jpg21170 Following general procedure C, 2-methyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine (0.18 mmol, 50 mg; Example 32) gave N,2-dimethyl-6-(4-(thiazol-5-yl)phenoxy)pyridin-3-amine in 55% yield (0.098 mmol, 29 mg). C16 H 15 N3OS; Mw = 297.38 g mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 9.03(d,J=0.7Hz,1H),8.22(d,J=0.7Hz,1H),7.78-7.50(m,2H),7.05-6.90(m,3H) ,6.79(d,J=8.5Hz,1H),5.20(q,J=5.0Hz,1H),2.73(d,J=4.9Hz,3H),2.21(s,3H).

[0262] Example 43: 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-N,2-dimethylpyridin-3-amine JPEG0007624930000144.jpg22170 Following general procedure C, 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-N,2-dimethylpyridin-3-amine (0.26 mmol, 80 mg; Example 37) gave 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-N,2-dimethylpyridin-3-amine in 82% yield (0.22 mmol, 69 mg). C 21 H 22 N2O; Mw = 318.42 g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.26-7.18(m,3H),7.10(d,J=6.8Hz,1H),7.03(dd,J=8.4,3.3Hz,2H),6.92(d,J=2.5Hz,1H),6.85(dd,J=8.3 ,2.5Hz,1H),6.74(d,J=8.5Hz,1H),2.91(s,3H),2.40(s,3H),2.07(s,3H),2.01(s,3H),1.70-1.48(bs,1H).

[0263] Example 44: N,2-dimethyl-6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine Following general procedure C, 2-methyl-6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine (0.434 mmol, 0.123 g; Example 35) gave N,2-dimethyl-6-(4-(thiazol-2-yl)phenoxy)pyridin-3-amine in 93% yield (0.404 mmol, 0.120 g). C 16 H 15 N3OS; Mw = 297.38 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.89(d,J=8.9Hz,2H),7.80(d,J=8.9Hz,2H),7.25(d,J=3.3Hz,1H),7.04(d,J=8. 9Hz,2H),6.94(d,J=8.5Hz,1H),6.74(d,J=8.5Hz,1H),2.88(s,3H),2.32(s,3H).

[0264] Example 45: N,2-dimethyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine Following general procedure C, 2-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine (0.29 mmol, 80 mg; Example 30) gave N,2-dimethyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine in 80% yield (0.23 mmol, 67 mg). C 18 H 17 N3O; Mw = 291.35 g mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 8.40(d,J=2.8Hz,1H),8.03(app d,J=8.2,2H),7.93(d,J=8.7Hz,1H),7.51-7.44(m,3H),7.43-7.37(m,1H),6.98(d,J=8.2 Hz,1H),6.86(d,J=8.4Hz,1H),5.21(q,J=5.0Hz,1H),2.73(d,J=4.9Hz,3H),2.20(s,3H).

[0265] Example 46: 6-(4-(6-methoxypyridin-3-yl)phenoxy)-4-methylpyridin-3-amine Following the general procedure B, 6-(4-(6-methoxypyridin-3-yl)phenoxy)-4-methylpyridin-3-amine was obtained in 55% yield (0.490 mmol, 165 mg) from 2-(4-(6-methoxypyridin-3-yl)phenoxy)-4-methyl-5-nitropyridine (0.892 mmol, 0.300 g). C 18 H 17 N3O2; Mw = 307.35 g.mol -1 ;δ 1 H NMR(400MHz,CDCl3) δ 8.21(d,J=5.4Hz,1H),7.71(s,1H),7.62(d,J=8.8Hz,2H),7.16(d,J=8.8Hz,2H),7. 12(dd,J=5.4,1.5Hz,1H),6.97-6.94(m,3H),6.77(s,1H),4.01(s,3H),2.24(s,3H).

[0266] The starting material was prepared as follows: Step 1: 2-(4-(6-methoxypyridin-3-yl)phenoxy)-4-methyl-5-nitropyridine Following general procedure E, 2-(4-(6-methoxypyridin-3-yl)phenoxy)-4-methyl-5-nitropyridine was obtained in 55% yield (0.892 mmol, 0.300 g) from 2-(4-bromophenoxy)-4-methyl-5-nitropyridine (1.62 mmol, 0.500 g; Example 29, Step 1) and (6-methoxypyridin-3-yl)boronic acid (1.95 mmol, 0.298 g). C 18 H 15 N3O4; Mw = 337.33 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 8.91(s,1H),8.40(d,J=2.1Hz,1H),7.79(dd,J=8.6,2.6Hz,1H),7.59(d,J=8.7Hz,2 H),7.23(d,J=8.6Hz,2H),6.90(s,1H),6.86-6.81(m,1H),3.99(s,3H),2.69(s,3H).

[0267] Example 47: 6-(4-(2-methoxypyridin-4-yl)phenoxy)-4-methylpyridin-3-amine Following the general procedure B, 6-(4-(2-methoxypyridin-4-yl)phenoxy)-4-methylpyridin-3-amine was obtained in 20% yield (0.091 mmol, 28 mg) from 2-(4-(2-methoxypyridin-4-yl)phenoxy)-4-methyl-5-nitropyridine (0.446 mmol, 0.150 g). C 18 H 17 N3O2; Mw = 307.35 g.mol -1 ;δ 1 H NMR(400MHz,CDCl3) δ 8.38(d,J=2.0Hz,1H),7.78(dd,J=8.6,2.6Hz,1H),7.70(s,1H),7.53-7.48(m,2H),7.1 7-7.12(m,2H),6.85-6.80(m,1H),6.75(s,1H),4.00(s,3H),2.23(m,3H),1.61(s,2H).

[0268] The starting material was prepared as follows: Step 1: 2-(4-(2-methoxypyridin-4-yl)phenoxy)-4-methyl-5-nitropyridine Following general procedure E, 2-(4-(2-methoxypyridin-4-yl)phenoxy)-4-methyl-5-nitropyridine was obtained in 28% yield (0.446 mmol, 0.150 g) from 2-(4-bromophenoxy)-4-methyl-5-nitropyridine (1.62 mmol, 0.500 g; Example 29, Step 1) and (2-methoxypyridin-4-yl)boronic acid (1.95 mmol, 0.298 g). C 18 H 15 N3O4; Mw = 337.33 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.91(s,1H),8.40(dd,J=2.6,0.7Hz,1H),7.79(dd,J=8.6,2.6Hz,1H),7.61-7.55(m,2H),7.25-7. 20(m,2H),6.90(d,J=1.0Hz,1H),6.83(dd,J=8.6,0.7Hz,1H),3.99(s,3H),2.69(d,J=0.8Hz,3H).

[0269] Example 48: 6-(4-(1H-imidazol-4-yl)phenoxy)-4-methylpyridin-3-amine JPEG0007624930000148.jpg17170 Following general procedure B, 6-(4-(1H-imidazol-4-yl)phenoxy)-4-methylpyridin-3-amine was obtained in 61% yield (86 μmol, 23 mg) from 2-(4-(1H-imidazol-4-yl)phenoxy)-4-methyl-5-nitropyridine (0.10 mmol, 0.040 g). C 15 H 14 N4O;Mw 266.30; 1 H NMR(400MHz,methanol-d4) δ 7.72(d,J=1.2Hz,1H),7.71-7.64(m,2H),7.62(s,1H),7.37(d,J=1.2Hz,1H),7.02-6.92(m,2H),6.77-6.64(m,1H),3.35(s,1H),2.20(s,3H).

[0270] The starting material was prepared as follows: Step 1: 4-Bromo-1-trityl-1H-imidazole To a solution of 4-bromo-1H-imidazole (10.00 mmol, 2.00 g) in CHCl (20 mL) was added TEA (40.00 mmol, 4.00 g, 6.0 mL), and the mixture was cooled to 0 °C. To this was added a solution of trityl-Cl (10.00 mol, 4.00 g) in 20 mL of CHCl, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with 1 M HCl and extracted with CHCl (3x). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give 4-bromo-1-trityl-1H-imidazole (4.40 g), which was used without further purification. C 22 H 17 BrN 2;Mw= 389.30g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.39-7.30(m,10H),7.16-7.08(m,6H),6.80(d,J=1.6Hz,1H).

[0271] Step 2: 4-methyl-5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine Following general procedure E, 2-(4-bromophenoxy)-4-methyl-5-nitropyridine (3.23 mmol, 1.0 g; Example 29, Step 1) and bis(pinacolato)diborane (4.79 mmol, 1.22 g) gave 4-methyl-5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine in 95% yield (3.09 mmol, 1.10 g). C 18 H 21 BN2O5; Mw = 356.19 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 8.88(s,1H),7.90(d,J=8.5Hz,2H),7.14(d,J=8.5Hz,2H),6.82(s,1H),2.66(s,3H),1.35(s,12H).

[0272] Step 3: 4-methyl-5-nitro-2-(4-(1-trityl-1H-imidazol-4-yl)phenoxy)pyridine Following the general procedure E, 4-methyl-5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (0.3 mmol, 0.1 g) and 4-bromo-1-trityl-1H-imidazole (0.4 mmol, 0.2 g) gave 4-methyl-5-nitro-2-(4-(1-trityl-1H-imidazol-4-yl)phenoxy)pyridine in 51% yield (0.15 mmol, 81 mg). C 34 H 26 N4O3;Mw=538.61; 1 H NMR(400MHz,CDCl3) δ 8.89(s,1H),7.82-7.76(m,2H),7.53-7.48(m,1H),7.45-7.27(m,9H),7.24- 7.18(m,6H),7.13-7.07(m,3H),6.80(d,J=1.0Hz,1H),2.65(d,J=0.8Hz,3H).

[0273] Step 4: 2-(4-(1H-imidazol-4-yl)phenoxy)-4-methyl-5-nitropyridine To a solution of 4-methyl-5-nitro-2-(4-(1-trityl-1H-imidazol-4-yl)phenoxy)pyridine (0.15 mmol, 0.081 g) in DCM (10 mL) was added HCl in dioxane (0.19 mL, 4 mol, 0.75 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness, and the residue was suspended in a saturated solution of NaHCO and extracted with CHCl (3×). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. This was purified on a Biotage, 25 g silica column using DCM and MeOH as eluents to give 2-(4-(1H-imidazol-4-yl)phenoxy)-4-methyl-5-nitropyridine (0.1 mmol, 0.04 g). C 15 H 12 N4O 3;Mw= 296.29; 1 H NMR(400MHz,CDCl3) δ 8.91(s,1H),7.82(d,J=8.4Hz,2H),7.73(s,1H),7.34(d,J=1.1Hz,1H),7.23-7.09(m,2H),6.90-6.79(m,1H),2.67(d,J=0.8Hz,3H).

[0274] Example 49: 6-(4-(2H-tetrazol-5-yl)phenoxy)-4-methylpyridin-3-amine In a flask, 2-(4-(2H-tetrazol-5-yl)phenoxy)-4-methyl-5-nitropyridine (0.14 mmol, 42 mg) was dissolved in EtOH (1.4 mL, 0.10 mol) and flushed with nitrogen. Pd / C (0.014 mmol, 15 mg) was added, a hydrogen balloon was attached, and the mixture was evacuated / backfilled (3x). The mixture was then left stirring for 5 h. Upon complete conversion, the mixture was evacuated / backfilled (3x) with nitrogen, filtered through a syringe filter, and concentrated under reduced pressure. The crude material was purified on a Biotage C18 column (25 g, 5-95% MeOH / HO+0.1% HCOOH) to give 6-(4-(2H-tetrazol-5-yl)phenoxy)-4-methylpyridin-3-amine (0.097 mmol, 26 mg) in 69% yield as a pale yellow solid. C 13 H 12 NO; Mw = 268.28 g mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 7.99(d,J=8.8Hz,2H),7.58(s,1H),7.12(d,J=8.7Hz,2H),6.79(s,1H),2.12(s,3H).

[0275] The starting material was prepared as follows: Step 1: 4-(2H-tetrazol-5-yl)phenol JPEG0007624930000154.jpg18170 Teflon coated magnetic stir bar and Findenser TMA 100 mL round-bottom flask equipped with a condenser was charged with 4-hydroxybenzonitrile (8.39 mmol, 1.00 g), sodium azide (25.2 mmol, 1.64 g), triethylamine hydrochloride (25.2 mmol, 3.47 g), and toluene (42.0 mL, 0.20 M). The reaction mixture was heated at 100 °C overnight with vigorous stirring. It was then cooled to ambient temperature, poured into a separatory funnel, and extracted with HO (3x). The combined aqueous phases were treated dropwise with HCl (conc.) to precipitate the product. The precipitate was collected by vacuum filtration and dried under vacuum to give 4-(2H-tetrazol-5-yl)phenol as an off-white solid in 88% yield (7.40 mmol, 1.19 g). C7H6N4O; Mw = 162.15 g mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 10.16(s,1H),7.86(d,J=8.7Hz,2H),6.95(d,J=8.7Hz,2H).

[0276] Step 2: 2-(4-(2H-tetrazol-5-yl)phenoxy)-4-methyl-5-nitropyridine A 100 mL round-bottom flask was charged with 4-(2H-tetrazol-5-yl)phenol (0.62 mmol, 100 mg), 2-chloro-4-methyl-5-nitropyridine (1.85 mmol, 319 mg), and anhydrous K2CO3 (1.85 mmol, 256 mg). DMF (2.1 mL, 0.30 mol) was added, and the resulting brown suspension was heated to 60 °C overnight. Upon complete conversion by TLC, the reaction mixture was cooled to room temperature, concentrated to a minimum amount of solvent, and loaded directly onto a Biotage C18 column (30 g cartridge, 5–95% MeOH / HO+0.1% HCOOH) to give 2-(4-(2H-tetrazol-5-yl)phenoxy)-4-methyl-5-nitropyridine (0.15 mmol, 45 mg) in 24% yield. C 13 H 10 N6O3; Mw = 298.26 g mol -1 ; 1H NMR(400MHz,DMSO-d6) δ 8.87(s,1H),8.22-7.99(m,2H),7.52-7.36(m,2H),7.30(s,1H),2.63(s,3H).

[0277] Example 50: 6-(4-(1H-pyrazol-4-yl)phenoxy)-4-methylpyridin-3-amine JPEG0007624930000156.jpg18170 To a solution of 4-methyl-6-(4-(1-trityl-1H-pyrazol-4-yl)phenoxy)pyridin-3-amine (0.08 mmol, 0.04 g) in DCM (0.4 mL) was added a 4 M solution of HCl in dioxane (0.2 mL, 0.8 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with H2O and the two layers were separated. The aqueous layer was washed with DCM. The aqueous layer was basified with a saturated aqueous solution of NaHCO3 to pH = 8. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. 6-(4-(1H-pyrazol-4-yl)phenoxy)-4-methylpyridin-3-amine was obtained as a light green solid in 90% yield (0.072 mmol, 19 mg). C 15 H 14 NO; Mw = 266.30 g mol -1 ; 1 H NMR(400MHz,methanol-d4) δ 7.91(s,2H),7.61(s,1H),7.58-7.52(m,2H),7.00-6.92(m,2H),6.72-6.67(m,1H),2.20(app d,J=0.8Hz,3H).

[0278] The starting material was prepared as follows: Step 1: 4-Bromo-1-trityl-1H-pyrazole JPEG0007624930000157.jpg201704-Bromo-1H-pyrazole (3.40 mmol, 500 mg) was dissolved in DMF (4.00 mL, 0.85 mol), placed under N2, and cooled to 0 °C. To this solution was added tBuOK (4.08 mmol, 458 mg, 1.20 equiv) and trityl-Cl (3.74 mmol, 1.04 g, 1.10 equiv), and the mixture was left stirring at room temperature overnight. The reaction mixture was diluted with HO, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography using cyclohexane:EtOAc as eluent to afford 4-bromo-1-trityl-1H-pyrazole (2.638 mmol, 1.027 g) as a white solid in 77% yield. C 22 H 17 BrN2; Mw = 389.30 g mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 7.76(d,J=0.7Hz,1H),7.51(d,J=0.7Hz,1H),7.43-7.31(m,9H),7.11-6.99(m,6H).

[0279] Step 2: 4-methyl-5-nitro-2-(4-(1-trityl-1H-pyrazol-4-yl)phenoxy)pyridine JPEG0007624930000158.jpg19170 According to general procedure D, 4-methyl-5-nitro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (0.85 mmol, 302 mg; Example 48, Step 2), 4-bromo-1-trimethyl ... A mixture of 4-methyl-1H-pyrazole (0.77 mmol, 300 mg), K2CO3 (1.54 mmol, 213 mg), and Pd(PPh3)4 (0.08 mmol, 89 mg, 10% mol) was converted to 4-methyl-5-nitro-2-(4-(1-trityl-1H-pyrazol-4-yl)phenoxy)pyridine (0.41 mmol, 223 mg) in 54% yield. C 34 H 26 N4O3; Mw = 538.61 g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.87(s,1H),7.93(d,J=0.8Hz,1H),7.60(d,J=0.9Hz,1H),7.52-7.46(m,2H),7.40-7 .27(m,9H),7.22-7.16(m,6H),7.13-7.07(m,2H),6.82(d,J=1.0Hz,1H),2.66(s,3H).

[0280] Step 3: 4-methyl-6-(4-(1-trityl-1H-pyrazol-4-yl)phenoxy)pyridin-3-amine JPEG0007624930000159.jpg24170 Following general procedure B, 4-methyl-6-(4-(1-trityl-1H-pyrazol-4-yl)phenoxy)pyridin-3-amine (0.08 mmol, 0.04 g) was prepared from 4-methyl-5-nitro-2-(4-(1-trityl-1H-pyrazol-4-yl)phenoxy)pyridine (0.20 mmol, 0.10 g) in 42% yield. C 34 H 28 NO; Mw = 508.61 g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.89(d,J=0.8Hz,1H),7.64(s,1H),7.55(d,J=0.8Hz,1H),7.41-7.37(m,2H),7.40-7.27(m, 9H),7.22-7.17(m,6H),7.01(d,J=8.7Hz,2H),6.65(t,J=0.7Hz,1H),3.42(s,2H),2.18(app d,J=0.8Hz,3H).

[0281] Example 51: 6,6'-((4'-fluoro-[1,1'-biphenyl]-2,4-diyl)bis(oxy))bis(pyridin-3-amine) Following general procedure B, 6,6'-((4'-fluoro-[1,1'-biphenyl]-2,4-diyl)bis(oxy))bis(pyridin-3-amine) (0.05 mmol, 0.02 g) was prepared from 6,6'-((4'-fluoro-[1,1'-biphenyl]-2,4-diyl)bis(oxy))bis(3-nitropyridine) (0.156 mmol, 0.070 g) in 32% yield after purification. C 22 H 17 FN4O2; Mw = 388.39 g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.73(dd,J=3.1,0.7Hz,1H),7.64(dd,J=3.0,0.7Hz,1H),7.49-7.44(m,2H),7.34(d,J=8.5Hz,1H),7.08(dd,J=8.6,3. 0Hz,1H),7.03-6.95(m,3H),6.91(dd,J=8.6,2.4Hz,1H),6.81-6.77(m,2H),6.61(dd,J=8.6,0.7Hz,1H),3.53(s,4H). 19 F NMR(377MHz,CDCl3) δ -115.99.

[0282] The starting material was prepared as follows: Step 1: 4'-Fluoro-2-methoxy-[1,1'-biphenyl]-4-ol Following general procedure D, a mixture of 4-bromo-3-methoxyphenol (9.9 mmol, 2.0 g), (4-fluorophenyl)boronic acid (11 mmol, 1.5 g), KCO (20 mmol, 2.7 g), and Pd(PPh)Cl (0.985 mmol, 0.691 g) in a 3:1 mixture of 2-propanol / HO (0.1 M) was converted to 4'-fluoro-2-methoxy-[1,1'-biphenyl]-4-ol (5.45 mmol, 1.19 g) in 55% yield. C 13 H 11 FO2; Mw = 218.22 g.mol -1;1H NMR(400MHz,CDCl3) δ 7.48-7.40(m,2H),7.14(d,J=8.2Hz,1H),7.10-7.01(m,2H),6.51(d,J=2.4Hz,1H),6.47(dd,J=8.2,2.4Hz,1H),3.79(s,3H).

[0283] Step 2: 4'-Fluoro-[1,1'-biphenyl]-2,4-diol JPEG0007624930000162.jpg211704'-Fluoro-2-methoxy-[1,1'-biphenyl]-4-ol (916 μmol, 200 mg) was dissolved in DCM (9.16 mL, 0.1 M), placed under N2, and cooled to -78 °C. BBr3 (1.83 mmol, 1.83 mL, 1 M in DCM) was added dropwise. After 30 min at that temperature, the mixture was allowed to slowly reach room temperature overnight. Although a small amount of starting material was still observed, the reaction mixture was quenched by the slow addition of water. The aqueous layer was neutralized / basified with 15% NaOH and extracted with DCM (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography using EtOAc:cyclohexane to give 4'-fluoro-[1,1'-biphenyl]-2,4-diol (0.74 mmol, 152 mg) in 81% yield as a white solid. C 12 H9FO2; Mw = 204.20 g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.48-7.33(m,2H),7.18-7.07(m,2H),7.09-7.05(m,1H),6.65-6.35(m,2H),5.07(s,1H),4.81(s,1H).

[0284] Step 3: 6,6'-((4'-fluoro-[1,1'-biphenyl]-2,4-diyl)bis(oxy))bis(3-nitropyridine) Following general procedure A, 6,6'-((4'-fluoro-[1,1'-biphenyl]-2,4-diyl)bis(oxy))bis(3-nitropyridine) was obtained in 63% yield (0.44 mmol, 195 mg) from 4'-fluoro-[1,1'-biphenyl]-2,4-diol (0.69 mmol, 140 mg) and 2-chloro-5-nitropyridine (1.51 mmol, 239 mg). C 22 H 13 FN4O6; Mw = 448.37 g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 9.09(dd,J=2.8,0.6Hz,1H),8.93(dd,J=2.8,0.6Hz,1H),8.52(dd,J=9.0,2.8Hz,1H),8.37(dd,J=9.0,2.8Hz,1H),7.53(d,J=8.5Hz,1H),7.44 -7.36(m,2H),7.23(dd,J=8.4,2.4Hz,1H),7.13(dd,J=9.1,0.6Hz,1H),7.10(d,J=2.3Hz,1H),7.04-6.98(m,2H),6.91(dd,J=9.0,0.6Hz,1H).

[0285] Example 52: 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-4-methylpyridin-3-amine JPEG0007624930000164.jpg22170 Following general procedure B, 6-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-4-methylpyridin-3-amine was obtained in 61% yield (0.31 mmol, 94 mg) from 2-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-4-methyl-5-nitropyridine (0.508 mmol, 170 mg). C 20 H 20 NO; Mw = 304.39 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 7.71(s,1H),7.25-7.23(m,2H),7.23-7.18(m,1H),7.13-7.09(m,1H),7.05(d,J=8.3Hz,1H),6.94(d, J=2.6Hz,1H),6.88(dd,J=8.3,2.5Hz,1H),6.73-6.71(m,1H),2.21(s,3H),2.08(s,3H),2.02(s,3H).

[0286] The starting material was prepared as follows: Step 1: 2,2'-dimethyl-[1,1'-biphenyl]-4-ol JPEG0007624930000165.jpg24170Following general procedure D, 2,2'-dimethyl-[1,1'-biphenyl]-4-ol was obtained in 85% yield (4.54 mmol, 0.900 g) from 4-bromo-3-methylphenol (5.3 mmol, 1.0 g) and o-tolylboronic acid (6.95 mmol, 0.944 g). C 14 H 14 O; Mw = 198.26 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.28-7.18(m,3H),7.11-7.07(m,1H),6.97(d,J=8.2Hz,1H),6.77(d,J=2.4Hz,1H),6.71(dd,J=8.2,2.6Hz,1H),5.21(app d,1H),2.06(s,3H),2.01(s,3H).

[0287] Step 2: 2-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-4-methyl-5-nitropyridine Following general procedure A, 2-((2,2'-dimethyl-[1,1'-biphenyl]-4-yl)oxy)-4-methyl-5-nitropyridine was obtained in 61% yield (0.526 mmol, 176 mg) from 2-chloro-4-methyl-5-nitropyridine (0.869 mmol, 150 mg) and 2,2'-dimethyl-[1,1'-biphenyl]-4-ol (0.956 mmol, 190 mg). C 20 H 18 N2O3; Mw = 334.37 g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.30-7.27(m,3H),7.25-7.21(m,1H),7.19-7.13(m,2H),7.05(d,J=2.5Hz,1H), 7.00(dd,J=8.2,2.4Hz,1H),6.86(s,1H),2.69(s,3H),2.10(s,3H),2.08(s,3H).

[0288] Example 53: 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-2-methylpyridin-3-amine JPEG0007624930000167.jpg25170 Following general procedure B, 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-2-methylpyridin-3-amine was obtained in 89% yield (2.80 mmol, 732 mg) from 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-2-methyl-3-nitropyridine (2.80 mmol, 910 mg). C 17 H 14 FNO; Mw = 295.31 g mol -1 ; 1H NMR(400MHz,CDCl3) δ 8.49(dd,J=2.8,0.7Hz,1H),7.98-7.88(m,2H),7.64(dd,J=8.4,0.7Hz,1H),7.45(dd,J=8.7,2.8Hz, 1H),7.19-7.08(m,2H),7.04(d,J=8.4Hz,1H),6.68(dd,J=8.4,0.7Hz,1H),3.50(s,2H),2.33(s,3H).

[0289] The starting material was prepared as follows: Step 1: 2-Bromo-5-(methoxymethoxy)pyridine JPEG0007624930000168.jpg16170 To a solution of 6-bromopyridin-3-ol (29 mmol, 5.0 g) in dry DMF (29 mL) at 0 °C under N was added NaH (29 mmol, 1.1 g, 60% wt) in small portions. The mixture was stirred at 0 °C for 1 h. Methyl chloromethyl ether (29 mmol, 2.3 g, 2.2 mL) was then added slowly. The mixture was stirred at 0 °C for 1 h and then allowed to warm to room temperature over the weekend. The reaction mixture was cooled to 0 °C and saturated NaHCO solution was added. The mixture was allowed to warm to room temperature and diluted with H O. The mixture was extracted with AcOEt (3x). The combined organic layers were washed with H O (3x) and brine. The mixture was dried over MgSO, filtered, and concentrated under reduced pressure. The product, 2-bromo-5-(methoxymethoxy)pyridine (29 mmol, 6.3 g) was isolated as a colorless oil in quantitative yield. C7H8BrNO2; Mw = 218.05 g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.15(dd,J=3.1,0.6Hz,1H),7.35(dd,J=8.7,0.6Hz,1H),7.27-7.20(m,1H),5.15(s,2H),3.46(s,3H).

[0290] Step 2: 2-(4-fluorophenyl)-5-(methoxymethoxy)pyridine Following general procedure D, a mixture of (4-fluorophenyl)boronic acid (32.0 mmol, 4.4 g), 2-bromo-5-(methoxymethoxy)pyridine (29.0 mmol, 6.3 g), KCO (58.0 mmol, 8.0 g), and Pd(PPh)Cl (2.9 mmol, 2.0 g) in a 4:1 mixture of 2-propanol / HO (0.1 M) was converted to 2-(4-fluorophenyl)-5-(methoxymethoxy)pyridine in 56% yield (16.20 mmol, 3.79 g). C 13 H 12 FNO2; Mw = 233.24 g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.46(dd,J=2.9,0.7Hz,1H),7.97-7.83(m,2H),7.60(dd,J=8.7,0.7Hz,1H),7.4 3(dd,J=8.7,2.9Hz,1H),7.13(dd,J=8.9,8.5Hz,2H),5.23(s,2H),3.51(s,3H).

[0291] Step 3: 6-(4-fluorophenyl)pyridin-3-ol To a solution of 2-(4-fluorophenyl)-5-(methoxymethoxy)pyridine (16.20 mmol, 3.79 g) in dioxane (20 mL) was added 4 M HCl (146 mmol, 36.6 mL) in dioxane at room temperature. The mixture was heated at 80 °C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in HO and extracted with DCM (3x). The aqueous layer was neutralized to pH = 6-7 with solid NaCO. The precipitated white solid was filtered off, washed with hexane, and dried under vacuum for 2 h to give 6-(4-fluorophenyl)pyridin-3-ol (15.0 mmol, 2.83 g) in 92% yield. C 11 H8FNO; Mw = 189.19 g mol -1 ; 1H NMR(400MHz,DMSO-d6) δ 10.04(s,1H),8.20(dd,J=2.9,0.7Hz,1H),8.09-7.93(m,2H),7.78(dd,J=8.7,0.7Hz,1H),7.33-7.15(m,3H).

[0292] Step 4: 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-2-methyl-3-nitropyridine JPEG0007624930000171.jpg24170Following general procedure A, 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-2-methyl-3-nitropyridine was obtained in 100% yield (3.00 mmol, 900 mg) from 6-(4-fluorophenyl)pyridin-3-ol (3.00 mmol, 600 mg) and 6-chloro-2-methyl-3-nitropyridine (3.00 mmol, 500 mg). C 17 H 12 FN3O3; Mw = 325.29 g mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.58(dd,J=2.7,0.7Hz,1H),8.42(d,J=8.9Hz,1H),8.03-7.96(m,2H),7.76(dd,J=8.7,0.7Hz, 1H),7.60(dd,J=8.7,2.7Hz,1H),7.20-7.14(m,2H),6.96(dd,J=8.9,0.7Hz,1H),2.72(s,3H).

[0293] Example 54: 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-N,2-dimethylpyridin-3-amine Following general procedure C, 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-2-methylpyridin-3-amine (1.155 mmol, 0.341 g) and paraformaldehyde (1.617 mmol, 1.40 equiv.) gave 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-N,2-dimethylpyridin-3-amine in 70% yield (0.810 mmol, 0.250 g) after purification. C 18 H 16 FN3O;MW=309.34g mol-1; 1 H NMR(400MHz,DMSO-d6) δ 8.38(d,J=2.7Hz,1H),8.08(dd,J=8.9,5.6Hz,2H),7.93(d,J=8.7Hz,1H),7.46(dd,J=8.7,2.9Hz,1H),7.30(t,J=8 .9Hz,2H),6.98(d,J=8.5Hz,1H),6.86(d,J=8.5Hz,1H),5.21(q,J=5.0Hz,1H),2.73(d,J=5.0Hz,3H),2.20(s,3H).

[0294] Example 55: 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-4-methylpyridin-3-amine JPEG0007624930000173.jpg24170 Following general procedure B, 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-4-methylpyridin-3-amine was obtained in 96% yield (2.58 mmol, 763 mg) from 2-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-4-methyl-5-nitropyridine (2.70 mmol, 900 mg). C 17 H 14 FNO; Mw = 295.31 g mol -1 ; 1H NMR(400MHz,CDCl3) δ 8.48(dd,J=2.8,0.6Hz,1H),7.95-7.89(m,2H),7.66(dd,J=8.1,0.6Hz,1H),7.64(s,1H),7.47(dd,J=8.7,2.8Hz,1H),7.19(app t,J=8.7Hz,2H),6.77(s,1H),3.48(s,2H),2.22(s,3H).

[0295] The starting material was prepared as follows: Step 1: 2-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-4-methyl-5-nitropyridine JPEG0007624930000174.jpg25170 Following general procedure A, 2-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-4-methyl-5-nitropyridine was obtained in 90% yield (2.70 mmol, 900 mg) from 6-(4-fluorophenyl)pyridin-3-ol (3.00 mmol, 600 mg; Example 53, Step 3) and 2-chloro-4-methyl-5-nitropyridine (5.00 mmol, 800 mg). C 17 H 12 FN3O3; Mw = 325.29 g mol -1 ;H NMR(400MHz,CDCl3) δ 8.86(s,1H),8.55(dd,J=2.8,0.6Hz,1H),8.01-7.95(m,2H),7.76(dd,J=8.7,0.6Hz,1H),7.60(dd,J=8.6,2.8Hz,1H),7.17(app t,J=8.8Hz,2H),6.97(s,1H),2.72(s,3H).

[0296] Example 56: 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-N,4-dimethylpyridin-3-amine Following the general procedure C, 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-4-methylpyridin-3-amine (1.14 mmol, 0.337 g) and paraformaldehyde (1.60 mmol, 1.40 equiv.) gave 6-((6-(4-fluorophenyl)pyridin-3-yl)oxy)-N,4-dimethylpyridin-3-amine in 69% yield (0.786 mmol, 0.243 g) after purification. C 18 H 16 FN3O;MW=309.34g mol-1; 1 H NMR(400MHz,DMSO-d6) δ 8.41(d,J=2.8Hz,1H),8.11-8.03(m,2H),7.94(d,J=8.7Hz,1H),7.52(dd,J=8.7,2.8Hz,1H) ,7.36-7.24(m,3H),6.87(s,1H),5.14(q,J=4.9Hz,1H),2.74(d,J=4.9Hz,3H),2.15(s,3H).

[0297] Example 57: (4-aminophenyl)(4'-fluoro-[1,1'-biphenyl]-4-yl)methanol JPEG0007624930000176.jpg27170 Following general procedure F, (4'-fluoro-[1,1'-biphenyl]-4-yl)(4-nitrophenyl)methanol (1.52 mmol, 0.500 g) was purified to afford (4-aminophenyl)(4'-fluoro-[1,1'-biphenyl]-4-yl)methanol in 98% yield (1.55 mmol, 0.445 g). C 19 H 16 FNO; Mw = 293.33 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.56-7.48(m,4H),7.47-7.41(m,2H),7.22-7.15(m,2H),7.13-7.07(m,2H),6.71-6.60(m,2H),5.80(s,1H).

[0298] The starting material was prepared as follows: Step 1: (4'-Fluoro-[1,1'-biphenyl]-4-yl)boronic acid To a solution of 4-bromo-4'-fluoro-1,1'-biphenyl (1.99 mmol, 0.500 g) in dry THF (19.9 ml) was added dropwise tert-butyllithium (2.390 mmol, 1.4 ml) at -78 °C under an inert atmosphere. The reaction mixture was stirred at -78 °C for 20 minutes, after which trimethyl borate (1.99 mmol, 0.222 ml) was added dropwise. After stirring for 1 hour, the reaction mixture was brought to room temperature, quenched with 1 N HCl, and stirred for 30 minutes. The reaction mixture was concentrated in vacuo, and the observed precipitate was filtered off and air-dried to give (4'-fluoro-[1,1'-biphenyl]-4-yl)boronic acid (1.852 mmol, 0.400 g) as a white powder in 93% yield. The NMR spectrum was identical to that previously reported (Neya et al., WO2003022842).

[0299] Step 2: (4'-fluoro-[1,1'-biphenyl]-4-yl)(4-nitrophenyl)methanol To a solution of chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.093 mmol, 0.046 g) in dry dioxane (12.3 ml) at room temperature under an inert atmosphere was added potassium hydroxide (1.852 mmol, 1.234 ml), and the mixture was stirred for 3 minutes. To this solution was added (4'-fluoro-[1,1'-biphenyl]-4-yl)boronic acid (1.852 mmol, 0.400 g), followed by 4-nitrobenzaldehyde (3.760 mmol, 0.560 g). The mixture was stirred at room temperature for 14 hours and then quenched by the addition of brine. The mixture was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage KP-Sil 50 g, hexane / EtOAc, 0-20%) to give (4'-fluoro-[1,1'-biphenyl]-4-yl)(4-nitrophenyl)methanol (1.46 mmol, 0.473 g) in 79% yield as a white solid. C 19 H 14 FNO3; Mw = 323.32 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.25-8.16(m,2H),7.65-7.59(m,2H),7.56-7.48(m,4H),7.44-7.39(m,2H),7.17-7.06(m,2H),5.97(s,1H),2.41(s,1H). 19 F NMR(377MHz,CDCl3) δ -115.19.

[0300] Example 58: 4-((4'-fluoro-[1,1'-biphenyl]-4-yl)(methoxy)methyl)aniline JPEG0007624930000179.jpg32170 Following general procedure F, 4-fluoro-4'-(methoxy(4-nitrophenyl)methyl)-1,1'-biphenyl (1.78 mmol, 0.600 g) gave 4-((4'-fluoro-[1,1'-biphenyl]-4-yl)(methoxy)methyl)-aniline in 78% yield (1.30 mmol, 0.400 g) after purification. C 20 H 18 FNO; Mw = 307.37 g.mol -1 ; 1 H NMR(300MHz,Chloroform-d) δ 7.59-7.44(m,4H),7.45-7.33(m,2H),7.22-7.00(m,4H),6.76-6.55(m,2H),5.19(s,1H),3.38(s,3H).

[0301] The starting material was prepared as follows: Step 1: 4-fluoro-4'-(methoxy(4-nitrophenyl)methyl)-1,1'-biphenyl To a solution of (4'-fluoro-[1,1'-biphenyl]-4-yl)(4-nitrophenyl)methanol (0.464 mmol, 0.15 g; Example 57, Step 2) in acetone (4.64 ml) was added CsCO (1.392 mmol, 0.453 g), followed by iodomethane (0.696 mmol, 0.044 ml). The reaction mixture was refluxed in a sealed tube at 60 °C for 4 h. The cooled reaction mixture was loaded directly onto silica, and the residue was purified by flash chromatography (Biotage KP-Sil 25 g, hexane / EtOAc, 0-20%) to give 4-fluoro-4'-(methoxy(4-nitrophenyl)methyl)-1,1'-biphenyl (0.406 mmol, 0.137 g) in 88% yield. C 20 H 16 FNO3; Mw = 337.34 g.mol -1 ; 1H NMR(400MHz,CDCl3) δ 8.22-8.17(m,2H),7.61-7.48(m,6H),7.41-7.36(m,2H),7.15-7.07(m,2H),5.36(s,1H),3.43(s,3H).

[0302] Example 59: 4-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)aniline JPEG0007624930000181.jpg24170Following general procedure F, 4-fluoro-4'-(fluoro(4-nitrophenyl)methyl)-1,1'-biphenyl (0.92 mmol, 0.300 g) gave 4-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)aniline in 60% yield (1.30 mmol, 0.154 g) after purification. C 19 H 16 FN; Mw = 277.34 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.56-7.50(m,2H),7.49-7.44(m,2H),7.27-7.24(m,2H),7.16-7.09(m,2H),7.06-7.01(m,2H),6.71-6.66(m,2H),3.94(s,2H).

[0303] The starting material was prepared as follows: Step 1: 4-fluoro-4'-(fluoro(4-nitrophenyl)methyl)-1,1'-biphenyl To a solution of (4'-fluoro-[1,1'-biphenyl]-4-yl)(4-nitrophenyl)methanol (1.54 mmol, 0.500 g; Example 57, Step 2) in dry DCM (7.73 ml) was added diethylaminosulfur trifluoride (1.85 mmol, 0.245 ml) dropwise at -78 °C under an inert atmosphere. The reaction mixture was stirred at the same temperature for 2 hours and then allowed to reach room temperature. The reaction was then quenched using saturated NaHCO3 solution. The two layers were separated, and the aqueous layer was extracted with DCM (2x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-fluoro-4'-(fluoro(4-nitrophenyl)methyl)-1,1'-biphenyl (1.38 mmol, 0.450 g) in 89% yield as a yellow solid. C 19 H 13 F2NO2; Mw = 325.31 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.29-8.22(m,2H),7.59-7.49(m,6H),7.42-7.36(m,2H),7.17-7.09(m,2H),6.58(d,J=47.0Hz,1H).

[0304] Example 60: (4-aminophenyl)(4'-fluoro-[1,1'-biphenyl]-4-yl)methanone hydrochloride To a solution of tert-butyl (4-(4'-fluoro-[1,1'-biphenyl]-4-carbonyl)phenyl)carbamate (0.51 mmol, 0.200 g) in DCM (10 ml) was added 3 ml of 4 M HCl in dioxane. This was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, and the residue was suspended in EtO, sonicated for 10 minutes, and filtered off. The residue was washed with EtO and then air-dried to give (4-aminophenyl)(4'-fluoro-[1,1'-biphenyl]-4-yl)methanone hydrochloride in 58% yield (0.29 mmol, 0.098 g). C 19 H 14 FNO .HCl; Mw = 291.33 g.mol -1 ; 1 H NMR(400MHz,DMSO-d6) δ 9.33(s),7.90-7.74(m,8H),7.72-7.65(m,2H),7.41-7.30(m,2H).

[0305] The starting material was prepared as follows: Step 1: tert-butyl((4'-fluoro-[1,1'-biphenyl]-4-yl)(4-nitrophenyl)methoxy)dimethylsilane To a solution of (4'-fluoro-[1,1'-biphenyl]-4-yl)(4-nitrophenyl)methanol (3.09 mmol, 1.00 g; Example 57, Step 2) in DMF (31 ml) at room temperature was added imidazole (6.09 mmol, 0.421 g) and tert-butyldimethylsilyl chloride (4.02 mmol, 0.606 g), and the reaction mixture was stirred overnight. The reaction was quenched by the addition of brine and extracted with EtO (3x). The combined organic layers were washed with water (5x), and the separated organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give the crude material. This was purified by flash chromatography (Biotage KP-Sil 50 g, hexane / EtOAc, 0-20%) to give tert-butyl((4'-fluoro-[1,1'-biphenyl]-4-yl)(4-nitrophenyl)methoxy)dimethylsilane (1.37 mmol, 0.600 g) in 44% yield as a white solid. C 25 H 28 FNO3Si; Mw = 437.58 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 8.20-8.17(m,2H),7.61-7.46(m,6H),7.41-7.36(m,2H),7.15-7.06(m,2H),5.86(s,1H),0.94(app d,9H),0.04(bs,3H),0.01(bs,3H).

[0306] Step 2: 4-(((tert-butyldimethylsilyl)oxy)(4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)aniline JPEG0007624930000185.jpg26170Following general procedure F, tert-butyl((4'-fluoro-[1,1'-biphenyl]-4-yl)(4-nitrophenyl)methoxy)dimethylsilane (12.57 mmol, 5.50 g) gave 4-(((tert-butyldimethylsilyl)oxy)(4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)aniline in 99% yield (12.50 mmol, 5.10 g). C 25 H 30 FNOSi; Mw = 407.60 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.56-7.35(m,6H),7.17-7.03(m,4H),6.66-6.59(m,2H),5.70(s,1H),0.92(app d,9H),0.01(s,3H),-0.03(s,3H).

[0307] Step 3: tert-butyl (4-(((tert-butyldimethylsilyl)oxy)(4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)phenyl)carbamate To a solution of 4-(((tert-butyldimethylsilyl)oxy)(4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)aniline (14.72 mmol, 6.00 g) in DCM (75 ml) at room temperature was added DMAP (1.472 mmol, 0.18 g) and triethylamine (29.4 mmol, 4.1 ml). To this stirred solution was added a solution of Boc anhydride (10.83 mmol, 5.50 g) in DCM (20 ml). The reaction mixture was stirred at room temperature overnight. It was then washed with water and 1 N HCl. The organic layer was dried over Na2SO4, filtered, and concentrated to give tert-butyl (4-(((tert-butyldimethylsilyl)oxy)(4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)phenyl)carbamate (12.80 mmol, 6.5 g) in 87% yield. C 30 H 38 FNO3Si; Mw = 507.71 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.54-7.48(m,2H),7.48-7.27(m,8H),7.15-7.04(m,2H),5.75(d,J=2.1Hz,1H),1.41(d,J=4.9Hz,9H),0.98-0.81(m,9H),up to 0.09-0.12(m,6H).

[0308] Step 4: tert-butyl (4-((4'-fluoro-[1,1'-biphenyl]-4-yl)(hydroxy)methyl)phenyl)carbamate To a solution of tert-butyl (4-(((tert-butyldimethylsilyl)oxy)(4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)phenyl)carbamate (10.83 mmol, 5.50 g) in 24170 THF (110 mL) at room temperature under an inert atmosphere was added tetrabutylammonium fluoride (16.25 mmol, 8.12 ml). The reaction mixture was stirred at room temperature for 4 h. It was then diluted with saturated NH4Cl solution and extracted with Et2O (2x). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage KP-Sil 100 g, hexane / EtOAc, 0-80%) to give tert-butyl (4-((4'-fluoro-[1,1'-biphenyl]-4-yl)(hydroxy)methyl)phenyl)carbamate (6.40 mmol, 2.52 g) as a foam in 59% yield. C 24 H 24 FNO3; Mw = 393.45 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.54-7.46(m,4H),7.41-7.34(m,4H),7.23-7.18(m,2H),7.14-7.07(m,2H),5.87(s,1H),2.26(s,1H),1.44(s,9H).

[0309] Step 5: tert-butyl (4-(4'-fluoro-[1,1'-biphenyl]-4-carbonyl)phenyl)carbamate To a solution of tert-butyl (4-((4'-fluoro-[1,1'-biphenyl]-4-yl)(hydroxy)methyl)phenyl)carbamate (0.762 mmol, 0.300 g) in DCM (80 mL) was added MnO2 (4.57 mmol, 0.40 g), and the suspension was stirred at room temperature for 16 h. The reaction mixture was filtered through a fritted funnel, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage KP-Sil 25 g, hexane / EtOAc, 0-40%) to give tert-butyl (4-(4'-fluoro-[1,1'-biphenyl]-4-carbonyl)phenyl)carbamate (0.588 mmol, 0.230 g) as a yellow solid in 77% yield. C 24 H 22 FNO3; Mw = 391.43 g.mol -1 ; 1 H NMR(400MHz,CDCl3) δ 7.94-7.80(m,4H),7.71-7.56(m,4H),7.46-7.41(m,2H),7.21-7.13(m,2H),1.48(s,9H).

[0310] Biological properties of the compound Identification of compounds with high efficacy against NOTCH-driven human cancers To determine the anti-cancer potency of compounds, the NOTCH-positive / driven human T-cell acute lymphoblastic leukemia cell line RPMI 8402 was treated with selected compounds and the downregulation of NOTCH target genes was measured.

[0311] Materials and Methods cell culture One million human NOTCH-positive T-ALL cell lines, RPMI8402, were treated with 1 μM NOTCH-targeting compounds for 24 hours. After treatment, cells were harvested and washed with 1x PBS. Total RNA and protein lysates were extracted as described below.

[0312] RNA extraction Total RNA was extracted from cells using a TRIzol® extraction kit (Invitrogen). 6 Cells were washed with ice-cold 1x PBS and lysed with 1 ml of TRIzol® solution at room temperature for 5 minutes to dissociate nucleoprotein complexes. The lysed cells were then treated with 200 μl of chloroform, vigorously shaken for 15–30 seconds, and incubated at room temperature for 2–3 minutes. The sample was centrifuged at 14,000 rpm for 10 minutes at 4°C using an Eppendorf tabletop centrifuge. After centrifugation, the upper aqueous phase was transferred to a new Eppendorf tube. To precipitate total RNA, 500 μl of isoamyl alcohol was added to the separated aqueous phase and incubated at room temperature for 10 minutes. The sample was centrifuged at 4°C for 10 minutes to obtain an RNA pellet. The resulting RNA pellet was washed with 1 ml of ice-cold 75% ethanol and spun down at 14,000 rpm at 4°C. The RNA pellet was dried from excess ethanol and resuspended in 40 μl of DPEC water.

[0313] cDNA synthesis Total RNA extracted from cells was used to synthesize cDNA by reverse transcription, which was carried out according to one of two protocols.

[0314] The first protocol is SuperScript TM RT (Invitrogen) was used for the reverse transcription reaction. RNA concentration was measured using a NanoDrop® ND-1000 spectrophotometer (Witec AG). 500 ng of total RNA was mixed with 10 mM dNTP mix and 100 ng of random primers. The reaction mixture was incubated at 65°C for 5 minutes and quickly incubated on ice for 1 minute. After incubation on ice, 5x first-strand buffer and 0.1 M DTT were added, and the mix was incubated at 25°C for 2 minutes. 200 U of SuperScript 1000 was used to initiate the reverse transcription reaction. TM II RT was added to the reaction mix and incubated for 50 minutes at 42° C. The reaction was stopped by incubating the reaction mixture at 75° C. for 15 minutes.

[0315] In the second protocol, reverse transcription was performed using PrimeScript RT Master Mix (Takara). RNA concentration was measured using a NanoDrop® ND-1000 spectrophotometer (Witec AG). 1 μg of total RNA was mixed with 4 μL of 5X PrimeScript RT Master Mix for a total reaction volume of 20 μL. The reaction mix was incubated at 37°C for 15 minutes and then heat-inactivated at 85°C for 5 seconds.

[0316] Quantitative real-time PCR analysis QRT-PCR was performed using a 7900 HT Fast Real-Time PCR System (Applied Biosystems) or a QuantStudio 3 System (ThermoFisher). Briefly, 12.5 ng of template cDNA was used in a final volume of 10 μL in a 96- or 384-well plate format with a 0.5 M primer concentration and 1X SYBR Green dye. Melting curves and ct values ​​were analyzed using SDS software (Applied Biosystems) or QuantStudio Design and Analysis software (ThermoFisher).

[0317] Western blot analysis Cells were lysed in RIPA buffer (50 mM Tris.Cl, pH 7.5, 150 mM NaCl, 1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1% SDS) for 30 min at 4°C. Lysed cells were centrifuged and debris was removed at 14,000 rpm at 4°C. The supernatant was transferred to a new Eppendorf tube. Protein concentration was determined by Bradford assay using a spectrophotometer (Ultrospec 3000 pro).

[0318] For Western blotting, 40 μg of protein was first denatured in 1x SDS gel loading buffer (100 mM Tris.Cl, pH 6.8, 200 mM DTT, 4% SDS, 0.2% bromophenol blue, 20% glycerol) by heating at 99°C for 5 minutes. The denatured protein samples were stored on ice until loading onto an acrylamide gel. Samples were run on 8% or 10% acrylamide gels in Tris-glycine electrophoresis buffer (25 mM Tris, 250 mM glycine, 0.1% SDS). After separation on the acrylamide gel, the protein samples were transferred to a PVDF membrane (PEQ Labs, catalog number 39-3010) using transfer buffer (39 mM glycine, 48 mM Tris base, 0.037% SDS, and 20% methanol).

[0319] For immunoblotting, membranes were blocked with 5% milk and incubated with primary antibodies overnight at 4°C. The membranes were washed three times for 5 minutes with 1xTBST (1xTBS + 0.5% Tween 20) and incubated with HRP-conjugated secondary antibodies for 1 hour at room temperature. Signals were detected using Super Signal West chemiluminescent substrate (Thermo Scientific, catalog no. 34077).

[0320] Western blotting was then performed using Jess (ProteinSimple, BioTechne). Samples containing 0.8 μg of protein were denatured by heating at 95°C for 5 minutes in loading buffer containing DTT. Samples were run on a 12-230 kDa gel matrix, and the incubation times for the primary and secondary antibodies were 1 hour and 30 minutes, respectively. Data were analyzed using Compass for SW (ProteinSimple, BioTechne) software.

[0321] Alamarblue / PrestoBlue proliferation assay Alamarblue® and PrestoBlue proliferation assays were performed to measure the proliferation kinetics of Notch inhibitor-treated cells. Alamarblue® and PrestoBlue are composed of the cell-permeable substrate resazurin. In metabolically active, proliferating cells, resazurin is converted to resorufin by the inherent reducing power of viable cells, producing red fluorescence. Therefore, resorufin production serves as an indicator of the viability of a cell population.

[0322] Proliferation assays were performed by seeding 5,000 cells / well in 96-well plates. Cells were treated with DMSO or compounds for 72 hours using concentrations ranging from 0.01 to 10 μM. Each concentration was tested in quadruplicate. To determine proliferation kinetics, 10 μl of Alamarblue® or PrestoBlue (Invitrogen) was added to each well and incubated for 4 hours. Readings were performed using a Tecan F500 (Tecan) multiplate reader or a Varioskan LUX (ThermoFisher) multiplate reader.

[0323] Example 27: Compounds that show high efficacy against NOTCH-driven human cancers To determine the anti-cancer efficacy of the compounds compared to 6-(4-tert-butylphenoxy)pyridin-3-amine (described in WO 2013 / 093885), the NOTCH-positive / driven human T-cell acute lymphoblastic leukemia cell line RPMI8402 was treated with selected compounds. As shown in Figure 1 and Table 1, the compounds were: 4-([1,1'-biphenyl]-4-yloxy)aniline, 6-([1,1'-biphenyl]-4-yloxy)-N-methylpyridin-3-amine, 4-([1,1'-biphenyl]-4-yloxy)-3-fluoro-N-methylaniline, 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridine. N-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine and 6-((2-(2-(4-aminophenoxy)ethyl)-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine exhibit antiproliferative potency that is 1.05 to 9 times greater than that of 6-(4-tert-butylphenoxy)pyridin-3-amine.

[0324] JPEG0007624930000189.jpg126170 * Comparative compounds described in WO2013 / 093885 Table 1: Antiproliferative effects of compounds on NOTCH-positive human leukemia cells. Cells were treated with compounds (concentration range 0.01-10 μM) for 72 h. Antiproliferative effects were measured using the Alamar blue assay (see Materials and Methods for details). IC 50 Values ​​were calculated using Graph prism software.

[0325] Example 28: Downregulation of mRNA transcripts of NOTCH target genes To further determine the anti-NOTCH activity and potency of the compounds (compared to 6-(4-tert-butylphenoxy)pyridin-3-amine), NOTCH-positive human leukemia cell lines were treated with the compounds at a concentration of 1 μM for 24 hours. The effect on NOTCH signaling was examined by quantifying the mRNA transcript levels of NOTCH target genes by quantitative PCR. The increased potency of the newly synthesized compounds was calculated as the percentage improvement over 6-(4-tert-butylphenoxy)pyridin-3-amine activity. As shown in Table 2, the compounds exhibit enhanced potency in downregulating NOTCH target genes, such as HES1, cMYC, and DTX1.

[0326] JPEG0007624930000190.jpg255170JPEG0007624930000191.jpg182170 * Comparative compounds described in WO2013 / 093885 Table 2: Human leukemia cells RPMI8402 were treated with compounds at 1 mM concentration for 24 hours at 37°C. Total RNA was extracted, cDNA was synthesized, and RNA expression of each gene was quantified using quantitative PCR (qPCR). The activity of 6-(4-tert-butylphenoxy)pyridin-3-amine in downregulating NOTCH target genes was set to 100%, and the corresponding activity increase of various compounds was calculated using 6-(4-tert-butylphenoxy)pyridin-3-amine activity as the reference point. ND: Not determined.

[0327] Example 29: Downregulation of NOTCH target genes at the protein level To further confirm the anti-NOTCH activity and efficacy of the compounds, NOTCH-positive leukemia cell lines were treated with selected compounds at a concentration of 1 μM for 24 hours. Total protein lysates were analyzed by Western blot analysis using N1-ICD (cleaved active NOTCH1 intracellular domain), cMYC, and ACTIN-specific antibodies. As shown in Figures 2 and 3, compared to 6-(4-tert-butylphenoxy)pyridin-3-amine (described in WO2013 / 093885), 6-([1,1'-biphenyl]-4-yloxy)-N-methylpyridin-3-amine, 6-((4'-fluoro-[1,1'-biphenyl]-4-yl)oxy)pyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine and N-methyl-6-((6-phenylpyridin-3-yl)oxy)pyridin-3-amine show stronger downregulation of cMYC and N1-ICD (both direct target genes of NOTCH signaling in human leukemia cells).

[0328] Example 30: Compounds that show high efficacy against NOTCH-driven human cancers To determine the anti-cancer potency of the compounds compared to 6-(4-tert-butylphenoxy)pyridin-3-amine (described in WO2013 / 093885), the NOTCH-positive / driven human T-cell acute lymphoblastic leukemia cell line RPMI8402 was treated with selected compounds. The compounds shown in Figure 1 and Table 3 exhibit 1.5- to 24-fold greater anti-proliferative potency than 6-(4-tert-butylphenoxy)pyridin-3-amine.

[0329] JPEG0007624930000192.jpg128170 * Comparative compounds described in WO2013 / 093885 Table 3: Antiproliferative effects of compounds on NOTCH-positive human leukemia cells. Cells were treated with compounds (concentration range 0.03-100 μM) for 72 h. Antiproliferative effects were measured using the PrestoBlue assay (see Materials and Methods for details). IC50 Values ​​were calculated using Graph prism software.

[0330] Example 31: Downregulation of NOTCH target genes at the protein level To further confirm the anti-NOTCH activity and efficacy of the compounds, NOTCH-positive leukemia cell lines were treated with selected compounds at a concentration of 1 μM for 24 hours. Total protein lysates were analyzed by Jess Western blot analysis using antibodies specific for N1-ICD (cleaved active NOTCH1 intracellular domain), cMYC, and GAPDH. The compounds shown in Table 4 showed stronger downregulation of cMYC and N1-ICD (both direct target genes of NOTCH signaling in human leukemia cells) compared to 6-(4-tert-butylphenoxy)pyridin-3-amine (described in WO 2013 / 093885).

[0331] JPEG0007624930000193.jpg237170 * Comparative compounds described in WO2013 / 093885 Table 4: Human leukemia cells RPMI8402 were treated with compounds at 1 μM concentration for 24 h at 37 °C. Total protein lysates were analyzed by Jess Western blot.

[0332] Example 32: Downregulation of mRNA transcripts of NOTCH target genes To further determine the anti-NOTCH activity and potency of the compounds (compared to 6-(4-tert-butylphenoxy)pyridin-3-amine), NOTCH-positive human leukemia cell lines were treated with the compounds at a concentration of 1 μM for 24 hours. The effect on NOTCH signaling was examined by quantifying the mRNA transcript levels of NOTCH target genes by quantitative PCR. As shown in Table 5, compared to 6-(4-tert-butylphenoxy)pyridin-3-amine, the listed compounds show enhanced potency in downregulating NOTCH target genes, such as cMYC, DTX1, and HES1.

[0333] JPEG0007624930000194.jpg243170JPEG0007624930000195.jpg49170 * Comparative compounds described in WO2013 / 093885 Table 5: Human leukemia cells RPMI8402 were treated with compounds at 1 mM concentration for 24 h at 37 °C. Total RNA was extracted, cDNA was synthesized, and RNA expression of each gene was quantified using quantitative PCR (qPCR).

Claims

1. Formula (I) [In the formula, X is selected from CH 2 , CO, CHOH, CHO(C 1 -C 3 )alkyl, NH, and O; Y 1 is N, R 7 is absent, Y 2 is selected from N and C, and Y 3 is C; Z is NR 10 R 11 , where R 10 and R 11 are each independently selected from H and C 1 -C 6 alkyl; R 1 is H, halogen, C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, C 0 -C 3 alkylOC 0 -C 3 alkylaryl, where aryl is optionally substituted with NH 2 , OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halogen, CN, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl; C 0 -C 3 alkylOC 0 -C 3 alkylheteroaryl, where heteroaryl is optionally substituted with NH 2 , OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halogen, CN, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl; and C 1 -C 6 alkyl substituted with aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with NH 2 , OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halogen, CN, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl; R 2 is selected from aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with NH 2 , OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halogen, CN, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocyclyl, C(O)R 12 , C 1 -C 6 alkylC(O)R 12 ; R 3 is selected from H, halogen, C 1 -C 6 alkyl, and C 3 -C 12 cycloalkyl; R 4 , R 5 and R 6 are each independently selected from H, halogen, CN, C 1 -C 6 alkyl, and C 1 -C 6 heteroalkyl; R 8 is selected from H, halogen, C 1 -C 6 alkyl, and C 3 -C 12 cycloalkyl; R 9 is absent when Y 2 is N or is selected from H, halogen, C 1 -C 6 alkyl, and C 3 -C 12 cycloalkyl when Y 2 is C; and R 12 is selected from NH 2 , NHC 1 -C 6 alkyl, C 1 -C 6 alkyl, and C 1 -C 6 heteroalkyl; with the proviso that the compound of formula (I) is not 6-([1,1'-biphenyl]-4-yloxy)-pyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 6-[4-(6-methoxy-3-pyridinyl)phenoxy]-3-pyridinamine and 6-[(5'-fluoro-2'-methoxy-([1,1'-biphenyl]-4-yl)oxy]-3-pyridinamine]. or a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

2. X is CH ２ , CO, CHOH, CHO (C １ -C ３ ) selected from alkyl, NH, and O; Y １ is N and R ７ does not exist, and Y ２ is selected from N and C; Y ３ is C; Z is NR １０ R １１ [Here, R １０ and R １１ are each independently H and C １ -C ６ alkyl; R １ But, H, C １ -C ６ Alkyl, C ０ -C ３ Alkyl OC ０ -C ３ Alkylaryl, where aryl is NH ２ may be substituted with]; C ０ -C ３ Alkyl OC ０ -C ３ alkylheteroaryl, where heteroaryl is NH ２ and optionally substituted with; R ２ aryl and heteroaryl, wherein aryl and heteroaryl are each independently selected from the group consisting of OC １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, halogen, C １ -C ６ Alkyl C(O)R １２ and optionally substituted with; R ３ is H; R ４ is selected from H and halogen; R ５ and R ６ each independently represents H and C １ -C ６ alkyl; R ８ is H; R ９ But Y ２ is not present or Y ２ is H when is C; and R １２ NH ２ That is, 2. A compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

3. X is CH ２ , NH, and O; Y 1 is N, R 7 is absent, Y 2 is selected from N and C, and Y 3 is C; Z is NR １０ R １１ [Here, R １０ and R １１ are each independently H and C １ -C ６ alkyl; R １ H, halogen, C １ -C ６ Alkyl, C ３ -C １２ Cycloalkyl, C ３ -C １２ Heterocyclyl, C １ -C ６ Alkoxy, C １ -C ６ Heteroalkyl, C ０ -C ３ Alkyl OC ０ -C ３ Alkylaryl, where aryl is NH ２ , O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, halogen, CN, C ３ -C １２ Cycloalkyl, C ３ -C １２ and optionally substituted with heterocyclyl; ０ -C ３ Alkyl OC ０ -C ３ alkylheteroaryl, where heteroaryl is NH ２ , O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, halogen, CN, C ３ -C １２ Cycloalkyl, C ３ -C １２ and C substituted with aryl or heteroaryl. １ -C ６ alkyl, wherein aryl and heteroaryl are each independently NH ２ , O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, halogen, CN, C ３ -C １２ Cycloalkyl, C ３ -C １２ and optionally substituted with heterocyclyl; R ２ is aryl and heteroaryl, wherein aryl and heteroaryl are each independently selected from the group consisting of NH ２ , O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, halogen, CN, C ３ -C １２ Cycloalkyl, C ３ -C １２ Heterocyclyl, C(O)R １２ , C １ -C ６ Alkyl C(O)R １２ and optionally substituted with; R ３ H, halogen, C １ -C ６ Alkyl, and C ３ -C １２ cycloalkyl; R ４ , R ５ and R ６ are each independently H, halogen, CN, C １ -C ６ Alkyl, and C １ -C ６ heteroalkyl; R ８ H, halogen, C １ -C ６ Alkyl, and C ３ -C １２ cycloalkyl; R ９ But Y ２ is not present or Y ２ When is C, H, halogen, C １ -C ６ Alkyl, and C ３ -C １２ cycloalkyl; and R １２ But NH ２ , N.H.C. １ -C ６ Alkyl, C １ -C ６ Alkyl, and C １ -C ６ heteroalkyl, 2. A compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

4. X is CH ２ , CO, CHOH, CHO(C １ -C ３ ) selected from alkyl, NH, and O; Y 1 is N, R 7 is absent, Y 2 is selected from N and C, and Y 3 is C; Z is NR １０ R １１ [Here, R １０ and R １１ are each independently H and C １ -C ６ alkyl; R １ H, halogen, C １ -C ６ Alkyl, C ３ -C １２ Cycloalkyl, C ３ -C １２ Heterocyclyl, C １ -C ６ Alkoxy, and C １ -C ６ heteroalkyl; R ２ is aryl and heteroaryl, wherein aryl and heteroaryl are each independently selected from the group consisting of NH ２ , O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, halogen, CN, C ３ -C １２ Cycloalkyl, C ３ -C １２ Heterocyclyl, C(O)R １２ , C １ -C ６ Alkyl C(O)R １２ and optionally substituted with; R ３ H, halogen, C １ -C ６ Alkyl, and C ３ -C １２ cycloalkyl; R ４ , R ５ and R ６ are each independently H, halogen, CN, C １ -C ６ Alkyl, and C １ -C ６ heteroalkyl; R ８ H, halogen, C １ -C ６ Alkyl, and C ３ -C １２ cycloalkyl; R ９ But Y ２ is not present or Y ２ When is C, H, halogen, C １ -C ６ Alkyl, and C ３ -C １２ cycloalkyl; and R １２ But NH ２ , N.H.C. １ -C ６ Alkyl, C １ -C ６ Alkyl, and C １ -C ６ heteroalkyl, 2. A compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

5. X is CH ２ , NH, and O; Y 1 is N, R 7 is absent, Y 2 is selected from N and C, and Y 3 is C; Z is NR １０ R １１ [Here, R １０ and R １１ are each independently H and C １ -C ６ alkyl; R １ H, halogen, C １ -C ６ Alkyl, C ３ -C １２ Cycloalkyl, C ３ -C １２ Heterocyclyl, C １ -C ６ Alkoxy, and C １ -C ６ heteroalkyl; R ２ is aryl and heteroaryl, wherein aryl and heteroaryl are each independently selected from the group consisting of NH ２ , O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, halogen, CN, C ３ -C １２ Cycloalkyl, C ３ -C １２ Heterocyclyl, C(O)R １２ , C １ -C ６ Alkyl C(O)R １２ and optionally substituted with; R ３ H, halogen, C １ -C ６ Alkyl, and C ３ -C １２ cycloalkyl; R ４ , R ５ and R ６ are each independently H, halogen, CN, C １ -C ６ Alkyl, and C １ -C ６ heteroalkyl; R ８ H, halogen, C １ -C ６ Alkyl, and C ３ -C １２ cycloalkyl; R ９ But Y ２ is not present or Y ２ When is C, H, halogen, C １ -C ６ Alkyl, and C ３ -C １２ cycloalkyl; and R １２ But NH ２ , N.H.C. １ -C ６ Alkyl, C １ -C ６ Alkyl, and C １ -C ６ heteroalkyl, 2. A compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

6. X is CH ２ , CO, CHOH, CHO (C １ -C ３ ) selected from alkyl, NH, and O; Y １ is N and R ７ does not exist, and Y ２ is selected from N and C; Y ３ is C; Z is NR １０ R １１ [Here, R １０ and R １１ are each independently H and C １ -C ６ alkyl; R １ But H and C １ -C ６ alkyl; R ２ aryl and heteroaryl, wherein aryl and heteroaryl are each independently selected from the group consisting of OC １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, halogen, C １ -C ６ Alkyl C(O)R １２ and optionally substituted with; R ３ is H; R ４ is selected from H and halogen; R ５ and R ６ each independently represents H and C １ -C ６ alkyl; R ８ is H; R ９ But Y ２ is not present or Y ２ is H when is C; and R １２ NH ２ That is, 2. A compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

7. X is CH ２ , CO, CHOH, CHO (C １ -C ３ ) selected from alkyl, NH, and O; Y 1 is N, R 7 is absent, Y 2 is selected from N and C, and Y 3 is C; Z is NR １０ R １１ [Here, R １０ and R １１ are each independently H and C １ -C ６ alkyl; R １ But, C ０ -C ３ Alkyl OC ０ -C ３ Alkylaryl, where aryl is NH ２ , O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, halogen, CN, C ３ -C １２ Cycloalkyl, C ３ -C １２ and C ０ -C ３ Alkyl OC ０ -C ３ alkylheteroaryl, where heteroaryl is NH ２ , O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, halogen, CN, C ３ -C １２ Cycloalkyl, C ３ -C １２ and optionally substituted with heterocyclyl; R ２ is aryl and heteroaryl, wherein aryl and heteroaryl are each independently selected from the group consisting of NH ２ , halogen, C １ -C ６ alkyl, optionally substituted with CN; R ３ H, halogen, and C １ -C ４ alkyl; R ４ , R ５ and R ６ are each independently H, a halogen, or C １ -C ４ alkyl; R ８ H, halogen, and C １ -C ４ alkyl; R ９ But Y ２ is not present or Y ２ When is C, H, halogen, and C １ -C ４ selected from alkyl, 2. A compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

8. R １ H, halogen, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, C ０ -C ３ Alkyl OC ０ -C ３ Alkylaryl, where aryl is NH ２ , C １ -C ６ Alkyl, C １ -C ６ may be substituted with heteroalkyl, halogen, CN; and C ０ -C ３ Alkyl OC ０ -C ３ alkylheteroaryl, where heteroaryl is NH ２ , O.C. １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Heteroalkyl, halogen, CN, C ３ -C １２ Cycloalkyl, C ３ -C １２ 4. The compound of formula (I) according to claim 1 or 3, wherein the compound is selected from the group consisting of:

9. R ２ is selected from aryl and heteroaryl, where aryl is an optionally substituted phenyl group, where any substitutions on the phenyl group are in the meta or para position, the compound of formula (I), its pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer according to any one of claims 1 to 8.

10. R ２ is selected from aryl and heteroaryl, where heteroaryl is an optionally substituted aromatic 5- or 6-membered monocyclic group, or a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, according to any one of claims 1 to 8.

11. The compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, selected from the group consisting of:

12. The compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, selected from the group consisting of:

13. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 12, 6-([1,1'-biphenyl]-4-yloxy)-pyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 6-[4-(6-methoxy-3-pyridinyl)phenoxy]-3-pyridinamine, 6-[(5'-fluoro-2'-methoxy-([1,1'-biphenyl]-4-yl)oxy]-3-pyridinamine, a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof; and a pharma- ceutically acceptable carrier.

14. A medicine for preventing or treating cancer, comprising the compound of formula (I) according to any one of claims 1 to 12, 6-([1,1'-biphenyl]-4-yloxy)-pyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-2-methylpyridin-3-amine, 6-([1,1'-biphenyl]-4-yloxy)-4-methylpyridin-3-amine, 6-[4-(6-methoxy-3-pyridinyl)phenoxy]-3-pyridinamine, 6-[(5'-fluoro-2'-methoxy-([1,1'-biphenyl]-4-yl)oxy]-3-pyridinamine, or a pharma- ceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

15. The pharmaceutical composition of claim 14, wherein the cancer is a Notch-dependent cancer.

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