TW201247629A - Wnt pathway antagonists - Google Patents

Abstract

The present invention relates to novel compounds of formula (I) as herein described and pharmaceutical compositions thereof. The compounds of formula (I) have inhibitory effect on the Wnt pathway and are therefore useful in the preparation of a medicament, in particular for the treatment of cancer.

Description

201247629 VI. Description of the Invention: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel compounds having an inhibitory effect on Wnt pathways and their medical use. [Prior Art]

The Wnt gene family encodes a large class of secreted proteins associated with the Inti/Wntl 1 pro-oncogene and the Drosophila wingless (Wg), a Drosophila Wntl homolog (Cadigan et al. (1997), Genes & Development 11:3286-3305). Wnt is expressed in a variety of tissues and organs and is required for developmental processes, including Drosophila sectioning; C. elegans endothelial development; and establishment of mammalian limb polarity, neural ridge differentiation, kidney morphogenesis, sex determination, And brain development (Parr et al. (1994), Curr. Opinion Genetics & Devel. 4: 523-528). The Wnt pathway is a major regulator of animal development, including both during embryogenesis and mature organs (Eastman et al. (1999) Curr Opin Cell Biol 11: 233-240; Peifer et al. (2000) 'Science 287; 1606- 1609). In the process of embryonic development and adult body constant, the Wnt pathway participates in diverse biological processes accompanied by diverse diversity within the genome to become the Wnt allele (〇rth〇l〇gue) (a total of 19 Wnts are recognized in humans). To be able to activate at least three intracellular signaling pathways (Moon et al. 2002; Nelson and Nusse, 2004; Seto and Bellen, 2004) 'The path of calcium media and the plane polar path (Stmtt, 2003; Veeman et al. 2003; KuM, 2004), and the standard Wnt_(3_catenin 101111810 3 201247629 pathway. In the standard Wnt pathway, 'Wnt ligand binds to its Frizzled receptor, a family of Frizzled receptors has Reports frizzled protein ("Fz") seven transmembrane domain receptors (Bhanot et al. (1996), Nature 382: 225-230). Thus Wnt pathway activates cytoplasmic protein Dishevelled (Dvl- in humans and mice) 1, 2 and 3) (Boutros et al. (1999)

Mech Dev 83:27-37) and phosphorylated LRP5/6. This produces a signal that prevents phosphorylation and degradation of alizarin/p_catenin, which in turn leads to an increase in cytosolic β-catenin (Perrimon (1994), Cell 76: 781-784). ). This β-catenin is translocated to the nucleus where β-catenin binds to the TCF (T cell factor) transcription factor (also known as lymphoid potentiating gene binding factor-1 (LEF1)) and is used as TCF/LEF-induced transcription. The co-activator (Bienz et al. (2000), Cell 103: 311-320; Polakix et al. (2000))' and ultimately resulted in increased gene expression of the Wnt target gene. In the absence of Wnt, the cytoplasmic β-catenin protein is constantly degraded by the action of the Axin complex, which is composed of the scaffold protein worm. Glue, tumor suppressor factor adenomatous polyp E. coli gene product (Apc), casein kinase 1 (CK1), and glycogen synthase kinase 3 (GSK3). CK1 and GSK3 sequentially phosphorylate the amino terminal region of β-catenin, resulting in the recognition of β-linked protein by β-Trcp ', a ubiquitin ligase subunit, followed by β-linked Ubiquitination and proteolysis (only 6 et al., 2004; ^ this continuous elimination of ρ-catenin, preventing the binding of cyclin to the nucleus, whereby the Wnt-labeled stem gene binds DNA-bound sputum cytokines/ Lactate 101111810 4 201247629 Barred Strengthening Gene Factor (TCF/LEF) Family Protein Inhibition. A growing number of studies suggest how to trigger Wnt-associated disorders that are not only responsible for beta-linkage degradation, but also for adenomatous polyps Initiation of gene product (APC) or artichoke protein mutations (eg, colorectal cancer), but also by other machines. Superactive mutants at the LRP5 co-receptor level and high bone density family autosomal dominant syndrome Related (Boyden et al, N Engl J Med. 2002; 346(20): 1513-21). Autocrine Wnt signaling mediated by specific Wnt ligands is actually linked to lung cancer (Akiri et al., Oncogene 2009 28 ( 21): 2163- 72), breast cancer (Schlange et al, Breast Cancer Res. 2007; 9(5): R63 and Matsuda et al, Breast Cancer Res. 2009; 11(3): R32) and pancreatic cancer (Nawroth et al., PLoS One. 20〇7 Apr 25; 2(4): e392) and other tumors, and also linked to the dissemination of malignant melanoma cells (O'Connell et al, J Biol Chem. 2009 Aug 20., E. Pre-Electronics). Wnt signaling forms a class of paracrine factors that affect the growth of multiple myeloma cells (Derksen et al, PNAS. 2004; 101(16): 6122-7). The process of tumor metastasis is a symptom of most malignant tumors. Additional interventional regions representing Wnt inhibitors (Nguyen et al, Cell, 2009; 138(1): 51-62) or tumor recurrence in patients with glioblastoma (Sakarlassen et al, PNAS 2006, 103 (44) 16466), Different pathways here seem to control primary and recurrent tumors. In addition, there is strong evidence that the Wnt pathway is involved in cancer, such as gastric cancer (TanigUChi et al.

Oncogene. 2005 Nov 24;24(53):7946-52), medulloblastoma 101111810 5 201247629 (Vibhakar et al, Neuro Oncol. 2007 Apr;9(2): 135-44), glioblastoma (Pu Et al, Cancer Gene Ther. 2009 (4): 351-61), hepatocellular carcinoma (Colnot et al, Proc Natl Acad Sci US A. 2004 Dec 7; 101 (49): 17216-2), basal cell carcinoma ( Yang et al, Nat Genet. 2008 Sep; 40(9): 1130-5), leukemia (Staal, Blood, 109, 12, 5073-5074, 2007; Tickenbrock et al, Int. J. Oncol) 33, 1215- 1221, 2008 ; Zhao, Cancer Cell, 12, 528-541, 2007) 'Wilm-type tumors (Rivera et al., Science, 315, 642-645, 2007 and Major et al., Science, 316, 1043-1046, 2007) And familial adenomatous polyps (Kinzler et al, Science 253, 661-665, 1991 and Nishisho et al, Science 253, 665-669, 1991). There is also evidence that inhibition of the Wnt pathway is beneficial for patients with pulmonary fibrosis and renal fibrosis (K0nigshoff Et al., PLoS One 3(5): e2142, 2008 and Henderson et al, PNAS, 107 (32), 14309-14314, 2010; Pulkkinen K. et al., Organogenesis 2008, 55-59; Brack et al. ,Science 2007, 317(5839),807-10), and Wnt inhibition can be used to treat diseases or conditions involving myelin damage such as ischemic neurological damage and multiple sclerosis (Casaccia P. Nat. Neurosci. 2011, 14, 945-947; Fancy, SPJ et al., Nat. Neurosci. 2011, 14, 1009-1016; Fancy, SPJ et al., Genes Dev. 2009, 23, 1571-1585). In a specific example, the following formula I is proposed. 101111810 6 201247629

Y—Q (Ο where, as valence and stability permit: any hydrogen atom with a broken bond may be replaced by a fluorine atom; Χι is CR2 or N; X2 is CR3 or N; -Y-Q is

Secrets 4 ring-based base, alkyl sulfhydryl, oxyalkyl sulfhydryl, wherein any dioxyalkyl, alkylaminomethyl, oxyalkylamine, a fluorenyl group can be passed through the side The gas acyl or heterogeneous is substituted by 1, 2 or 3 selected from the group consisting of a fluorenyl group; the group listed below is substituted: c 0 linear group 101111810 201247629 branch or ring wire, oxygen Silk, silk, silk B-based, oxyalkylamine, oxysiloxy, neoyloxy, (tetra), cyano' or

CrC6 aryl or heteroaryl is optionally substituted with a tooth atom, C _C3 alkyl, C1_C3 oxyalkyl; RAH; F; C1; Br; 0H; CN; linear branched or cyclic (tetra)alkyl, alkenyl , alkynyl, oxymethylene, oxyalkenyl, oxyalkynyl, azinyl, azaynyl, alkyloxy, oxy, neoyloxy, dioxymethyloxy, oxynitridyloxy, The nitrogen alkyloxy group, the di-silylamine group, the oxysilyl group, the nitrogen-based amine group are optionally substituted with one or more of (3); the heart is an arylmethylamino group or a heteroarylmethylamine. Or a C5_C6 arylmethyloxy or hetero 6 arylmethyloxy group, wherein the aryl or heteroaryl moiety is optionally attached via one or more CrC3 filaments, CA filament groups, (tetra) or CN group substitution; R2 is Η or C1; R3 is Η, C1 or F; R4 is Η or C1;

Rs is CpC: 3 linear, branched or cyclic alkyl;

Rx is Η; linear, branched or cyclic Ci_C3 yard; η can be zero, 1, 2 or 3; when η = 2 or above, Ry is independently F; linear, branched or cyclic

CrC3 alkyl; or Ry and its carbon atom--side oxygen; X3 is N, 或 or S; tautomers, optical isomers and pharmaceutically acceptable salts; 101111810 201247629 but with the following exception

101111810 9 201247629

In a specific example, a compound of the following formula (I-bis) is proposed

(1-bis) where, as valence and stability permits: Any carbon atom bonded to a carbon may be replaced by a fluorine atom; 101111810 10 201247629 Χι is CR, X2 is CR3 or N; -Y-Q is

~^\XQ : ~i>~Q : -ιν〇f 卩 is a heart ^6 linear branch or cyclic alkyl group, alkylmercapto group, oxo group, dioxyalkyl group, alkylaminocarbamyl group An oxyalkylaminocarbamyl group, wherein any one of the fluorenylene groups may be substituted with a pendant oxy group; the Cs-Ck) aryl or heteroaryl group is optionally selected from 1, 2 or 3 selected from the group consisting of Substituted group substitution: Cr (: 6 linear branched or cyclic β alkyl, oxyalkyl, alkylamino, alkylamino fluorenyl, oxyalkylamine, oxy-alkyloxy, a nitroalkyloxy group, a _ atom, a cyano group, or a C5_C6 aryl group or a heteroaryl group is optionally substituted with a halogen atom, a CrC3 alkyl group, or a CrC3 oxyalkyl group; R^H; F; Cl; Br; OH; Linear, branched or cyclic C alkyl, alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl, rimene, azynylene, alkyloxy, alkenyloxy, oxyalkyl Oxygen, dioxyalkyloxyl 101111810 11 201247629 base, oxynitrideoxy, nitrogen ^ ^ ^ ^ rolling base, dialkylamino group, oxyalkylamine group, nitrogen alkyl amine group selectively -A® ,, u, one or more F4CN substitutions; c5-c6 square base Arylmethyl^^^ oxime or C5_c6 aryl decyloxy or heteroaryl fluorenyloxy, where aryl or heteroaryl moiety can be selectively subjected to one or a plurality of C丨-c3 alkyl groups, cc 3 alkoxy groups, halogen atoms or CN groups;

Xv2 ^ i f R3 is Η, Cl or F; R4 is Η or Cl; R5 is a linear, branched or cyclic alkyl group of Crc3;

Rx is Η; linear, branched or cyclic Cl_c3 alkyl; η can be zero, 1 '2 or 3; when η = 2 or more, Ry is each independently f; linear, branched or cyclic CrC3 alkyl; Or % together with the carbon atom to which it is attached form a pendant oxy group; tautomers, optical isomers and pharmaceutically acceptable salts thereof. In one embodiment, Q is a CrQ linear branch or a cyclic alkyl group, an alkylcarbenyl group, an oxyalkyl group, a dioxyalkyl group, an alkylamino fluorenyl group, or an oxyalkylamino fluorenyl group, wherein Any of the fluorenylene groups may be substituted with a pendant oxy group; the C5_C6 aryl or heteroaryl group is optionally substituted with 2 or 3 groups selected from the group consisting of Ci_c6 linear branches or cyclic alkyl groups. , oxyalkyl, alkylamino, alkylaminocarboxamyl, oxyalkylamino, oxyalkyloxy, nitroalkyloxy, dentate, cyano, or eve:6 aryl or hetero The aryl group is optionally substituted with a halogen atom, c]_C3 alkyl, c^_c^101111810 12 201247629 oxyalkyl; and Xj, X2, X3, Y, Rl, R2, R3, ft 4, R_5, Rx, η, Ry are as defined in the above formula (I) or (I-bis). In another embodiment, Q is a CrC6 linear branch or a cyclic alkyl group, an alkyl fluorenyl group, an oxyalkyl group, a dioxyalkyl group, an alkylamino group, an oxyalkylamino group, or an oxoalkyl group. Any one of the fluorenylene groups may be substituted with a pendant oxy group; [1,2,4] oxadiazolyl, [1,3,4]oxadiazolyl, benzimidazolyl, benzothiazolyl, benzo Thienyl, stupid and oxazolyl, imidazolyl, 2H-carbazolyl, isoxazolyl, carbazolyl, phenyl, n-cyanoyl, t-butyl, tamarind, beta fluorene, feeding Indole [l,2-a]e is optionally substituted with 1, 2 or 3 groups selected from the group consisting of: a bite, a butyl group, a pyrimidinyl group, a quinolyl group, or a thiazolyl group: CrC6 linear branch or cyclic alkyl group, oxyalkyl group, alkylamino group, alkylaminocarboxamyl group, oxyalkylamino group, oxyalkyloxy group, nitroalkyloxy group, halogen atom, cyano group, Or [1,3,4] oxadiazolyl, phenyl, furyl or pyridyl is optionally substituted with _ atom, CrC3 alkyl, oxyalkyl; and Χι, Χ2, Χ3, Υ, Ri, R2 And R3, R4, r5, Rx, n, and Ry are as defined in the above formula (I) or (I_bis). In another embodiment, Q is a CrC6 linear branch or a cyclic alkyl group, an alkyl fluorenyl group, an oxyalkyl group, a dioxyalkyl group, an alkylaminomethyl fluorenyl group, an oxyalkylaminomethyl fluorenyl group, Any of the fluorenylene groups may be substituted with a pendant oxy group; hydrazine, 2, 4] oxadiazolyl, benzothiazole 101111810 13 201247629 base, benzo-oxazolyl, isoxazolyl, phenyl, pyrene The base, β-pyrazolyl, hydrazine, fluorenyl, pyridyl, pyrimidinyl, quinolyl, or thiazolyl is optionally substituted with 1, 2 or 3 groups selected from the following list :CrCA^ branched or cyclic alkyl, oxyalkyl, alkylamino, alkylaminocarboxamyl, oxyalkylamino, oxyalkyloxy, nitroalkyloxy, halogen atom, cyanide a group or a [i,3,4] oxadiazolyl group optionally substituted with a tooth atom, a Ci_c3 alkyl group, an alkyl group; and Χι, X2, X3, Y, a heart, r2, r3, r4, r5, Rx , n, the office is as defined in the previous formula (I) or (I-bis). In another embodiment, Q is a CrC6 linear branch or a cyclic alkyl group, a decyl fluorenyl group, an oxyalkyl group, a dioxyalkyl group, an alkylaminomethyl fluorenyl group, an oxyalkylaminomethyl fluorenyl group, Any one of the methylene groups may be substituted with a pendant oxy group; 2-benzothiazolyl '2-oxazolyl, 2-pyridyl, 2-pyridyl, 2-pyrimidinyl, 2-thiazolyl, 3- Isosazolyl, 3-0-saltyl, 3-tower, 3-nl:bn, 4-n-saltyl, 4-thalanoyl, 4-pyridyl, 4-pyrimidinyl, 4- Thiazolyl, 5-[1,2,4]oxadiazolyl, 5-[1,3,4]thiadiazolyl, 5-benzimidazolyl, 5-benzothienyl, 5-benzopyridinium Azolyl, 5- 0 m ° sit-on, 5-isosyl, 5-° ratio, sit-up, 5-cylamyl, 5-cylinyl, 6-benzothiazolyl, 8-quinolyl 4-2Η-carbazolyl, phenyl or 3-imidazo[l,2-a]pyridine, each group optionally having 1, 2 or 3 groups selected from the following list Substituted: (^-<:6 linear branched or cyclic alkyl, oxyalkyl, alkylamino, alkylamino fluorenyl, oxyalkylamino, oxyalkyloxy, nitrogen 101111810 14 201247629 Alkoxy group, halogen atom, cyanide Or [1,3,4]β diazolyl is optionally substituted with a halogen atom, a CrC3 alkyl group, a CrC3 oxyalkyl group; and X!, X2, X3, Y, R2, R3, r4, r5 , Rx, η, the system is as defined in the above formula (I) or (I-bis). In another specific example, Q is a CrC6 linear branch or a cyclic alkyl group, an alkyl fluorenyl group, an oxyalkyl group, Dioxyalkyl, alkylamino fluorenyl, oxyalkylamino fluorenyl, wherein any one fluorenylene group may be substituted with a pendant oxy group; 2-benzothiazolyl, 2-pyridyl, 2 - pyridyl, 2-pyrimidinyl, 2-thiazolyl, 3-isosazolyl, 3-pyrazolyl, 3-indolyl, butyl, 4-n-pyrazolyl, 4-indenyl, 4-pyridyl, 4-11 dimethyl, 4-«. thiol, 5-[1,2,4> oxadiazolyl, 5-benzoxazolyl, 5-isoxazolyl, 5 - carbazolyl, 5-pyrimidinyl, 5-quinolinyl, or phenyl is optionally substituted with 1, 2 or 3 groups selected from the group consisting of CrC6 linear branches or cyclic alkyl groups , oxyalkyl, alkylamino, alkylaminocarboxamyl, oxyalkylamino, oxyalkyloxy, nitroalkyloxy, functional atom, cyano, or H4] oxadiazolyl Sex Substituted by _ atom, Crc3 alkyl, Crc3 oxyalkyl; and Χΐ, χ2, χ3, Y, R, R2, R3, R4, R5, Rx, n, Ry are as in the above formula (1) or (I-bis In another specific example, XACR2; R2 is Η; Χ2 is CR3, 101111810 15 201247629 -YQ is

Q is 1 to 3 (^-(:3 alkyl-substituted pyrazolyl, wherein - or a plurality of carbon-bonded hydrogen atoms may be substituted by a fluorine atom; R4 is Η; and R!, R3 and Rs It is as defined in the above formula (1) or (I_bis). In another specific example, a compound selected from the following compounds is proposed:

CHa 101111810 16 201247629

In another specific embodiment, 乂1 is 0112; R2 is Η; Χ2 is CR3; -QY is ']-q. Q is 11荅; base is linear branch or cyclic CrC6 oxyalkyl, oxyalkenyl, An oxyalkynyl group, an alkyloxy group, an oxyalkyloxy group, a nitroalkyloxy group; R4 is Η; and R3, R5 and Rx are as defined in the above formula (1) or (I-bis). 101111810 17 201247629 In another embodiment, a compound selected from the group consisting of:

In another specific example, 乂1 is 0112; R2 is Η; Χ2 is CR3, and -Q-Y is 〇

Q is 4-° ratio α, R! is a linear, branched or cyclic CrC6 alkyloxy group, alkenyloxy group, oxyalkyloxy group, dioxyalkyloxy group, oxyalkylamine group, optionally It is replaced by F or CN; 101111810 18 201247629 R4 is Η; and R5 is as defined in the above formula (I) or (I-bis). In another embodiment, a compound selected from the group consisting of:

201247629

In another embodiment, X!gCR2; R2 is Η; X is CR3, h is a linear, branched or cyclic crc6 alkyloxy or oxyalkyloxy group; R3 is F; R4 is Η; and X3 , YQ, R5, Rx, η and Ry are as defined in the above formula (1) or (I_bis).

101111810 20 201247629

H3c

101111810 21 201247629

H3C—N, N, CH3 In another specific example, a compound of the formula (I-ter) is proposed as follows:

(1-ter) where, as valence and stability permit: any carbon atom bonded to carbon may be replaced by a fluorine atom; Χι is CR2, R»2 is Η, X is CR3, Q is CrC3 linear, branched or A cyclic alkyl fluorenyl group; 1^ is 011, a linear branched or cyclic CrC6 alkyl group, an alkenyl group, an alkynyl group, an oxyalkyl group 101111810 22 201247629 a base 'oxyxyloxy group, an oxy 9 amino group; R4 is a fluorene R3 is Η, ci or F; R5 is CK: 3 linear, branched or cyclic alkyl; η can be zero, 1, 2 or 3; 2 or more 'Ry are each independently F; linear, branched or ring. The 丨C3 alkyl group or the carbon atom to which it is attached forms a pendant oxy group; , A', a structure, an optical isomer, and a pharmaceutically acceptable surface. ; /, in the system 'the compound falls within the above formula (I-ter),

Rl is a linear branch or a cyclic crc6 alkyl group. In another specific example, connecting φ

C'Cvo^, 故出—A compound selected from the list below:

H, C

101111810 23 201247629 In another embodiment, 乂1 is 0112; R2 is Η; 111 is (:1-(:3 linear branch or cyclic alkyloxy; Χ2 is CR3, R3 is Η; ; R4 is Η ; -QY is 〇

^—NF^—QQ is a C5-C1() aryl or heteroaryl group optionally substituted with 1, 2 or 3 groups selected from the group consisting of: (^-0:6 linear branches or Cyclic alkyl, oxyalkyl, alkylamino, alkylaminoindenyl, oxyalkylamino, oxyalkyloxy, nitroalkyloxy, halogen, cyano, or C5-C6 The aryl or heteroaryl group is optionally substituted with a halogen atom, a C1-C3 alkyl group, a C1-C3 oxyalkyl group, and R5, Rx, η are as defined in the above formula (I) or (I-bis). In another embodiment, a compound selected from the group consisting of:

101111810 24 201247629

101111810 25 5 201247629

101111810 26 201247629

101111810 27 201247629 ο

In another specific example, Χι is CR2; R2 is Η; Χ2 is CR3; R4 is Η; R5 is sulfhydryl and X3, YQ, Ri, R3, R4, Rx, n, and Ry are as in the above formula (1) or ( I-bis). In another embodiment, 乂1 is ;; X2 is CR3; R4 is Η and X3, YQ, 28 101111810 201247629, R2, R3, 尺5, Rx,, A 糸 as in the previous formula (1) or (I_bis) Righteousness. In another specific example, X^N; χ A 2 horse CR3; R4 is Η; -Y-Q is ^1L-nrx~q;

Ri definition («Λ — and X3, Ri, R2, R3, R4, Rs, p

Kx, n and Ry are as defined in the above formula (I) or (I-bis). In another specific example, X^N; 2 horses. 1 ; R4 is Η ; -Y-Q is

-Q and X3, Ri, R2, R3, R4, Rs, redemption

Kx, n and Ry are as defined in the above formula (1) or (I-bis). In any of the specific examples, preferred compound A is a compound wherein Y is a thiol group. All specific examples can be combined. [Embodiment] (Compound Synthesis) The compound of the present invention can be obtained from the general reaction chart 13 depending on the dish 胄' of the compound. The compound of formula la can be prepared according to Method A reported in Reaction Scheme 1. 101111810 29 201247629 Ο

Where -Y-Q is

Q

X2 is CR3 and Ri, R4, R5, Rx, Ry, χι, χ3, Q and n are defined as formula (I). Methyl 4-aminomercapto-cyclohexanecarboxylate is reacted with an appropriate thio-fluoro-benzene or an appropriately substituted nitro-pyridine to obtain a compound of the formula 1, which can be reduced to the formula 2 using standard reaction procedures. Aniline. Substituted nitro-fluoro-benzenes and nitrobromopyridines are either commercially available or have been described as described in the literature or can be synthesized using standard procedures. Methyl 4-aminomethylcyclohexanecarboxylate can be synthesized from the corresponding acid analogously to the method reported by the intermediate of Formula 6 (for example, see w〇〇7〇64273). 2 The compound of the formula 3 is obtained by cyclization with CDI (1 H. sylvestre) or triphosgene (Wu (trimethyl) carbonate). The compound can be converted to the corresponding _ 4, and the appropriate coupling agent is _coupled to the compound 5 compound. Burning Γ will get l""8 compound. Further, the compound of the formula 3 can be deuterated to give a hydrolysis of 4 to 4 (7) 7, and 7 is coupled with an amine in the presence of a suitable couple of 101111810 201247629 to obtain a compound 8. Alternatively, the compound of formula 8 can be obtained starting from amine 9, which is reacted with an appropriate nitro-fluoro-benzene or substituted bromo-nitropyridine to give the intermediate 1 oxime. Amine 9 can be synthesized starting from 4-aminomercapto-cyclohexane decanoic acid according to standard reaction procedures. The nitro compound 10 can be reduced to the corresponding diphenylamine 11 using standard reduction conditions, and then reacted with triphosgene or CDI to give a compound of the formula 12. The intermediate product 12 is then burned to the compound 8 in the presence of a base using a suitable alkylating agent.

Reaction Figure 1: Method A

101111810 31 201247629 The compound of formula lb can be prepared according to Method B reported in Reaction Scheme 2.

RS (lb) where -Y-Q is

The center of the heart is a linear branch or a cyclic Cl_C6 alkyl group, a dilute base, a block oxynitride, an oxygen wire, a nitrogen county, a nitrogen wire, an oxy oxy group, an oxyalkyloxy group, a neoyloxy group, a silk amine group. a dialkylamino group, an oxyalkylamino group, a azoalkylamino group, the group optionally being subjected to one or more F or (3); c5-c6 arylmethylamino or heteroaryl Methylamino or c5_c6 aryl fluorenyloxy or heteroaryl fluorenyloxy wherein the aryl or heteroaryl moiety is optionally substituted with - or a plurality of Q-broken groups, CrC3 alkoxy groups, (d) Sub or (3) group substitution, and R5, Qm, Rx, Ry, as defined in formula (1). > Stinky intermediate 13 can be converted to the formula 丨4 compound by a known method known to those skilled in the art such as Buchwald and Sonogashira. The compound of formula 13 can be synthesized according to the general method A described in Scheme 1. 101111810 32 201247629

Reaction Figure 2: Method B

«5 Formula Ic compounds can be prepared according to Method C reported in Reaction Scheme 3.

Wherein -YQ is 〇(Ry)n 〉Ry)n (Ry)n >-NRx-0 (Ry)n (Ry)n and the heart is a dialkylamino group, an oxyalkylamino group or a nitrogen alkylamine And R5, Q, Ry, Rx, X3 and η are as defined in formula (I), 4-aminomethyl-cyclohexane decanoate and commercially available 2,6-dibromo-3-nitroacridine The reaction yields compound 15, which is reacted with an amine according to standard procedures to give the intermediate of formula 16. The reduction of the diphenylamine 17 is achieved using standard methods, and the diphenylamine 17 is obtained by CDI or triphosgene cyclization to give the compound 18. The intermediate product 18 101111810 33 201247629 is alkylated to 19.19 according to standard procedures to give intermediate 20 which can be coupled with an amine in the presence of a suitable coupling agent to give a compound of formula 21.

Reaction Figure 3: Method C

The compound of formula Id can be prepared according to Method D reported in Reaction Scheme 4.

Ri

Where -Y-Q is

Q

101111810 34 201247629 and Ri are optionally substituted with one or more F or CN substituted alkyloxy, oxyalkyloxy, oxycarbazolyl, azoxyoxy; 4c5_c6 arylmethyloxy Or a heteroaryl fluorenyloxy group wherein the aryl or heteroaryl moiety is optionally substituted with one or more CrC3 alkyl groups, CrC3 alkoxy groups, halogen atoms or CN* and R5, Q, Ry, Rx, χ3, and η are defined by the formula (1). 3-fluoro-4-nitro-, hydrazine-protected with a suitable protecting group (pg) such as τΉΙ>, reacted with 4-aminomercapto-cyclohexane decanoate to obtain compound 23, and then used standard Reduction of the reduction procedure to diphenylamine 24. 24 alkylation with CDI or triphosgene to obtain intermediate 25 which can be alkylated to 26.26 using standard alkylation procedures to give the corresponding carboxylic acid 27, and subsequently 0-deprotection. Compound 28' is converted to its oxime ester derivative using standard conditions. 29. The phenol of formula 29 is obtained by alkylation using a suitable alkylating agent in the presence of sodium hydroxide or potassium carbonate to obtain the intermediate of formula 30. When Rl = 〇CHF2, alkylation can be carried out using the procedures described in the references (for example, see US 5,731,477). The intermediate product 30 is then hydrolyzed to the corresponding citric acid 31 and coupled to the amine in the presence of a suitable coupling agent to provide the compound of formula 32.

Reaction Figure 4: Method D) 0111118 35 201247629

The compound of formula Ie can be prepared according to the method E reported in Scheme 5. 〇

Wherein ^ is -CH and R,, Xj, R4 and 115 are as defined in formula (I). Compounds of formula 34 can be obtained by alkylation of intermediate 33 with the appropriate bromoalkyl ketone. The intermediate product 33 can be obtained according to the method A reported in the reaction scheme 1. Reaction Figure 5: Method E 101111810 36 201247629

The compound of the formula If can be prepared according to the method F reported in the reaction scheme of Figure 6.

Where -Y-Q is (Ry) (%)〇 (^y)n (Ry)n (Ry)n

And Ri is a compound of the group II, an oxyalkylamino group, an IL-based amine group, and R5, Q, Ry, Rx, and η are as defined in the formula (I). Intermediate 36 can be initiated from 2,4-di-5-nitro-pyrimidine 35 using a second amine (NR7R8) and 4-aminomethyl-cyclohexanecarboxylate for two consecutive nucleophilic aromatic substitutions. synthesis. 36 is reduced to diphenylamine 37 using standard reduction procedures, followed by cyclization with triphosgene to obtain a compound of formula 38 which can be alkylated to 39 according to standard procedures. 39 hydrolysis to give intermediate 40, 40 may be present in the appropriate even 101111810 37 201247629 mixture Coupling with an amine affords the compound of formula 41.

Reaction Figure 6: Method F

The compounds of the formulae Ig and Ih are prepared according to the method G reported in the reaction scheme of Figure 7.

And the core is a linear branch or a cyclic CrC6 alkyl, alkenyl, alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl, azaenyl, azynyl group, the group is selectively subjected to one or 101111810 38 201247629 Substituted by F or CN; Cs-C6 aryl fluorenyl or heteroarylmethyl or C5_C6 aryl - at this point aryl or heteroaryl moiety hydrazine optionally with ~ or more c 1 _ c 3 alkyl And a crc3 alkoxy group, a halogen atom or a (3) group substitution and R5, q, r, R, η, and X3 are as defined in the formula (1). Commercially available via 42 and gas compound 42 can be synthesized according to the general method A described in Reaction Scheme 1 starting from 2 gas-6-methoxy-3-nitroso. The intermediate product 43 can be obtained by a diterpene reaction, and then a compound of the formula 44 can be obtained with an amine in the presence of a suitable coupling agent. Alternatively, the intermediate product 43 can be reacted with a dimethanol in the presence of a strong acid to obtain an intermediate 45 domain. The resulting product can be hydrolyzed to the reaction. Figure 7: Method G7 and reaction with an amine to obtain a compound of the formula 48.

101111810 39 201247629 & can be prepared according to Method H reported in Reaction Scheme 8.

R5 (ίο where ^ is (^-(:6 linear branched or cyclic alkyl, oxyalkyl, dioxyalkyl; -yl or heteroaryl optionally followed by hydrazine, 2 or 3 selected from the following The base is 圑^. (^ linear branch or ring subtractive group, oxygen wire, alkyl amine group, alkylamino group, oxygen wire, oxyalkyloxy group, nitrogen oxy group, functional atomic group Or a C5-C6 aryl or heteroaryl group optionally via a halogen atom,

Cl C3 alkyl, Cl_C3 oxygen substitution and Ri, & X, 115 are as defined by formula (I). Coupling of the compound of the formula 49 with hydrazine taurate gives the dimercapto group from hydrazine 52 and then cyclization affords 53. Further, 49 is reacted with ruthenium formate for the third product to obtain an intermediate product 50, and after deprotection to 51, a compound of the formula 52 is obtained by coupling with formic acid. 52 Compounds of formula 53 are obtained by ring closure using standard reference procedures. The compound of the formula 49 can be synthesized human according to the method described in the reaction scheme of Figure 1. Reaction Figure 8: Method Η 101111810 40 201247629

The compound of formula II can be prepared according to the method i reported in the reaction scheme 9

Rs wherein (^c5-c10 aryl or heteroaryl is optionally substituted with a compound selected from the group consisting of 2, or 3 selected from the group consisting of the following: Cl_M-functional branched anthracene, oxyalkyl, alkylamine a base, an alkylaminomethyl fluorenyl group, an oxyalkylamino group, an oxyalkyleneoxy group, a nitroalkyloxy group, a halogen atom, a cyano group, or a C^C6 aryl or heteroaryl group, optionally via a halogen Atom, Cl_C3 alkyl, Cl_C3 oxyalkyl substituted and r5 are as defined in formula (1). 49 is coupled with hydrazine-methyl-hydroxyamine to obtain Weinreb decylamine intermediate 55, which is then converted to a ketone according to standard procedures known to those skilled in the art. 56. Ketone 56 is treated with a strong base in the presence of active formic acid to obtain β-diketone 57, which can be converted to π to saliva by treatment with hydrazine. The compound of formula 49 can be synthesized according to the method described.

Reaction Scheme 9: Method I 101111810 41 201247629

The compound of the formula Im can be prepared according to the method L reported in Reaction Scheme 10.

R5 (lm)

Where Y-Q

广(quot)(R,)〇1 is OH, linear branch or ring 匸^^6, azo, alkynyl, oxyalkyl, oxygen, oxyalkynyl, nitroalkenyl, nitrogen block, county An oxy group, an oxyalkyloxy group, an oxyalkyloxy group, a nitrogen-based oxy group, a dialkylamino group, an oxyalkylamino group, a azoalkylamino group, optionally subjected to one or more Substituted; c5-c6 arylalkylamino or heteroarylmethylamino or C5_C6 arylmethyloxy or heteroarylmethyloxy, in the thiol or heteroaryl moiety 101111810 42 201247629 Optionally substituted with one or more ^-alkyl, CrC3 alkoxy, halogen or CN groups, and r5, q, Rx, Ry, as defined for formula (1). Compound 59 can be obtained according to the procedure described in the Reaction Scheme. The intermediate product 6 can be obtained by a method known to those skilled in the art, such as Sonogashira or Suzuki coupling, starting from the corresponding bromine intermediate 59. Hydrolysis of 60 affords the general formula 61 compound, which is then coupled with an amine in the presence of a coupling reagent to provide compound 62. Alternatively, 59 can be converted to dihydroxyborate 63, and subjected to accepting-coupling to obtain a hydrolyzed sigma 64 to obtain a corresponding enantibody 65, which can be coupled with an amine to obtain a hydration product. Corresponding to π, after partial hydrolysis of vinegar, 'can be reacted with an amine to obtain 69. Alternatively, compound 67 can be obtained by (10) conversion to 7 〇 7 〇 water (iv) (tetra) acid 71 ′ in accordance with standard procedures to obtain 72. Reaction Figure 10: Taiben τ

101111810 43 201247629 11 Report method Μ Preparation. Compound of formula In can be based on reaction diagram

Wherein Q4; Cl_C6CVCl (^ or the base is selectively (4) 2 or 3 selected from the following table (10) generation: W6 linear branch or cyclic alkyl, oxygen-burning, county Wei, burning base The base, the neoylamino group, the oxyalkyloxy group, the nitrogen oxy group, the _ atom, the cyano group, and the Ri, ^ system are defined by the formula (I). ' ° The synthesis of the first decylamine 74 followed by dehydration to obtain the intermediate product 75 It can then be converted to the amidoxime derivative 76 by treatment with hydroxylamine. Coupling with the carboxylic acid followed by the closure of the compound to obtain the compound of the formula 77 intermediate 73 can be obtained using the method A reported in Reaction Scheme 1.

Reaction Figure 11: Method M

101111810 44 201247629 Compounds can be prepared according to the method N reported in Reaction Scheme 12.

The hydrazine gas 79 is reacted with trimethyldecyl diazonium to obtain an intermediate product 80, and the intermediate product 80 can be converted to an α-bromo ketone by treatment with hydrobromic acid 81. 81 is reacted with fluorenyl hydrazine to obtain a compound of the formula 82. Intermediate product 73 can be obtained using the method reported in Reaction Scheme 1.

Reaction Figure 12: Method N

73 79 8〇

The compound of formula Ip can be prepared according to the method P reported in Reaction Scheme 13. 〇

R5 αρ) 101111810 45 201247629 wherein Q is a C5-C10 aryl or heteroaryl group which is optionally substituted with a compound selected from the following table: linear branch or ring secret group, oxyalkyl group, burn group , fluorene methyl sulfhydryl, oxygen filament, oxyalkyloxy, oxyalkyloxy, sulfonium atom, cyano m system, as defined by formula (1). The compound was obtained by coupling with 73^14. Deprotection is carried out to obtain the inter-filament filaments 88, and then the method known to those skilled in the art, such as the B-d coupling reaction system, obtains the compound (10). The intermediate product 73 can be obtained using the method A2 reported in Reaction Scheme 1.

Reaction Figure 13 - Method P

(Analysis of small molecule inhibitors for intercepting Wnt signaling pathways.) The pharmacological activity of the compounds of the present invention was first verified in vitro by Wnt receptor assay.

Wnt-reactive luciferase (TCF-luciferase (firefly) and Wnt_independent (TA-Renilla) reporter plastid (alone or in combination) in DBTRG-05MGglocytes Tumor cell line (ATCC) stably metastasizes infection, 101111810 46 201247629 This cell line shows no mutations in the APC, the shellac and/or the β-catenin gene, according to the Wellcome Trust Sanger Institute database, and is considered to be intact Wnt path cascade. TCF-luciferase: three copies of 4x TCF reactive elements were cloned into pcDNA3.1/Zeo(+) vector (Invitrogen), the constitutive CMV promoter was deleted and inserted Wnt/β-catenin pathway activity was measured after Promega's firefly luciferase (phFL-TK). The resulting plasmids were sorted for quality control. TA-Renilla: two vectors (pCDNA3.1/ from Invitrogen) Hygro(-)) and pHRL-TK are digested with restriction enzymes Mlu 1 and BamH 1 and joined by T4- ligase to form the final composition. The full-length cDNA containing hRL (the jellyfish luciferase optimized by human code) ) has a 5' TA-min promoter and mammalian expression vector backbone pCDNA3.1/Hyg Ro(-), which ablates the constitutive CMV promoter. The composition is then ordered for quality control and used as internal control for cell number and toxicity. Cells at 20 μg/ml Zeocin and 20 μg/ml Zeocin plus 30 μg/ Methyl hygromycin (81: 〇11^丨11) was separately grown. Cells were seeded at a rate of 6,500 cells per well in a 96-well plate pretreated with poly-D-lysine. IC50 determination: after inoculation 36-hour cells were co-cultured with 8-dit dilution compound (〇6% DMSO (v/v)). Each compound was repeated three times in a single well plate. The dual-energy enzyme reporter assay system (Pr〇mega) was used. Luciferase assay was performed. After 24 hours of compound addition, the medium was removed, and 30 μl of hydrazine lysis buffer was added to each well for 3 minutes. 45 μ47 was added to each well. 201247629 liter Dual-Glo luciferase reagent (promega) and use after 1 second delay

The Mithras LB940 instrument detects luciferase for 1 second. After the firefly luciferase was quantified, 45 μl of Dual Stop & Glo reagent (promega) was added to each well, and firefly and jellyfish luciferase were detected using the same parameters as described above. The data are expressed as a percentage of firefly and jellyfish luciferase, and the values are calculated using the four-parameter 8-shaped function (乂1^^ model 205). A secondary screening using a luciferase biochemical assay can identify compounds that act directly on the enzyme (luciferase modulators and/or quenchers) rather than true inhibitors of the Wnt pathway. Glow-luciferase assay: Quantumum recombinant camphorase was diluted 1G6-fold in 1 mg/ml acetylated BSA21X cell culture lysing reagent (Pr〇mega). Then 5 μl of the compound dilution (10)_final concentration was mixed with 35 μl of diluted Quantumum recombinant luciferase in a 96-well white well plate. Two microliters of LAR1 (from Promegef photozyme assay reagent) was added to each well, and luciferase oxime was detected using a Mithras LB94G instrument. Each compound was tested at a single-site point on two different copy cell plates. #料系 indicates the percentage of negative control (DMSO). (Other assays) The drug of the compound of the present invention (IV) can be tested in a test tube for growth inhibition of tumor cell lines. Such cell lines may, for example, represent glioblastoma (such as MTRG-05MG) or colorectal cancer (e.g., then - 101111810 Ao 201247629 H C Τ 116). The different genetic background of cancer cells will help to understand which compound is acting at that level of the pathway. If the cell contains a truncated APC allele, it will affect the destruction of the living complex; if the cell contains the p-catenin gene towel function mutation increase ϋ 'prevent the β-catenin protein decomposition, resulting in the formation of downstream genes Sexual activation. Multiple assays can be used to test for growth inhibition. Such assays include so-called soft agar assays (Freedman et al, CeU 3 (1974) '355-359 and Macpherson et al, Virology 23 (1964), pp. 291-294) and thus growth inhibition is not dependent on cells. Adhesive to the plastic material in the hole for the assay. (Soft Agar Anchored Independent Irrelevant Assay Analysis) DBTRG cells were seeded in a 24-well format in the presence of a single 25 vector or compound (〇 6% DMS® (v/v)). Each well consisted of a layer of two agars: the bottom layer contained 0.6% hydrazine and the top layer contained 0.35% agar plus cells and compounds. Cells (2500 cells per well) were co-cultured with 734 dilutions on the day of inoculation, and community scores were obtained two weeks after staining with MTT solution o/n. Photographs and calculations of the population were performed using a GelCoimtTM instrument (0xf〇rd 〇ptr〇nix, UK). To determine the IC50, the data is expressed as a percentage of the control group, and the values are calculated using the XLFit version 4.2 using the four-parameter S-shaped 5 function (XLFit model 2〇5). The pharmacological activity of the compounds of the invention is tested in vivo in animal models that mimic disease. Such animal models include subcutaneous or local vaccination of cancer cells. (Formulation and administration) Ι011118Ι0 49 201247629 The compound of formula i is preferably mixed with pharmaceutically acceptable _, coffee, etc. In general, it is preferred to administer the pharmaceutical composition by oral administration, but some formulations may be administered through the parenteral, intravenous, intramuscular, gingival, buccal, subcutaneous, suppository, intranasal or other routes. Give. The skilled artisan can modify the formulation to provide a variety of formulations for a particular route of administration within the teachings of this specification without causing the present invention to be unstable or detrimental to its therapeutic activity. More specifically, the present compound has been modified to achieve a higher solubility solution in water or other vehicle by minor modifications (salt formation, esterification, etc.), which are among the skill of the industry. Inside. It is also within the skill of those skilled in the art to modify the route of administration and dosage of a particular person to manage the pharmacodynamics of the compounds of the present invention to achieve maximum beneficial effects in the patient. In certain pharmaceutical dosage forms, the prior parental forms of the compound include, in particular, brewed and ether derivatives, as well as various salt forms of the present compounds. Those skilled in the art will understand how to conveniently modify the compound into a prodrug form to assist in the delivery of the active compound to the host organism or to the stem location of the patient. A skilled artisan can also utilize the advantageous pharmacokinetic parameters of the prodrug form (when applicable) to deliver the compound to the host organism or to the target site in the patient to maximize the desired effect of the compound. The actual preparation of such dosage forms is known or known to those skilled in the art; for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition 101111810 50 201247629 1975. In general, the composition or formulation to be administered contains an amount of the active compound which is effective to modify the symptoms of the individual being treated. Although the compounds of the present invention are not known to have an optimal human dose, they are generally from about 0.05 mg/kg to about 100 mg/kg body weight. Of course, the amount of active compound administered will depend on the individual being treated and the diseased bear, the severity of the condition, the mode of administration, and the dosing schedule and the judgment of the clinician. For the purposes of the present invention, a prophylactically or prophylactically effective amount of a composition according to the invention (i.e., substantially reducing the risk of a patient entering a disease state or a condition or a conditional deterioration) is at a concentration effective to the aforementioned therapeutically effective amount. The range is usually the same as the therapeutically effective amount. In several embodiments of the invention, one or more compounds of formula (1) are administered in combination with one or more other pharmaceutically active agents. The term "combination" as used herein refers to a medicament that is administered to a body at the same time. It is to be understood that when an individual is simultaneously exposed to two (or more) agents, two or more agents are considered to be "combined". Each of the two or more agents may be administered according to different dosages; however, individual agents of different agents are not required to be administered at the same time or within the same composition. As long as two (or more) agents remain in the individual's body, they are considered to be "combined". (Examples) All reagents and solvents are commercially available. Air sensitive and moisture sensitive liquid solutions are delivered through a syringe. The reaction process is traced by thin layer chromatography (TLC) and/or liquid chromatography/mass spectrometry (HPLC-MS or UPLC-Ms) 101111810 51 201247629. TLC analysis was performed on cerium oxide (Merck 60 F254), and the dots were visualized by 254 nm ultraviolet light and potassium citrate or ninhydrin staining. The purification by column chromatography was carried out using a ruthenium dioxide ruthenium or a ruthenium dioxide (Merck 60) or using a rapid purification apparatus from Bench. The purity of the compound is above 90%. All NMR spectroscopy spectra were recorded using a Bruker Avance AV 400 system (400.13 MHz for 1 inch) equipped with BBI probes. (Analytical method) Method a Analytical HPLC-MS using Gemini NH C18 3.0 μm 2,00 X 50 mm column using Waters Micromass ZQ (ES ionization) and

Waters PDA 2996 was performed with a Waters 2795 separation module. Temperature: 40 ° C. Ultraviolet light was detected at 215 nm and 254 nm. ESI+ is detected in the 80-1000 m/z range. Gradient: 0·1°/〇 formic acid/water and 0,1% formic acid/acetonitrile with a gradient of 95/5 to 5/95 at a flow rate of 1.0 ml/min over a period of 10 minutes. Method b Analytical HPLC-MS was carried out using a Gemini NH C18 3.0 micron 2.00 X 50 mm column using a Waters 2795 separation module equipped with Waters Micromass ZQ (ES ionization) and Waters PDA 2996. Temperature: 40 ° C 0 UV light was detected at 215 nm and 254 nm. ESI+ is detected in the 80-1000 m/z range. Gradient: 0.1% citric acid/water and 0.1% citric acid/acetonitrile with a gradient of 95/5 to 5/95 at a flow rate of 1.0 ml/min over a 5 minute period. 101111810 52 201247629 Method c Analytical HPLC-MS was performed using an X_BΓidge C18 3.5 micron 2.10 x 503⁄4 meter column using a Waters 2795 separation module equipped with Waters Micromass ZQ (ES ionization) and Waters PDA 2996. Temperature: 40 ° C. Ultraviolet light was detected at 215 nm and 254 nm. ESI+ is detected in the 80-1000 m/z range. Gradient: 0.1% ammonia/water and acetonitrile with a gradient of 85/15 to 95/5 at a flow rate of 0.8 ml/min for 1 min. Method d Analysis 11?1^-1^ using 乂-6]^(^6(:18 3.5 micron 2.10 parent 50 mm column, using Waters 2795 equipped with Waters Micromass ZQ (ES ionization) and Waters PDA 2996 Separation module. Temperature: 40 ° C. UV detection at 215 nm and 254 nm. ESI + detection in the range of 80-1000 m / z. Gradient: 0.1% ammonia / water and acetonitrile with a gradient of 85 / 15 to 95 /5 flow rate of 0.8 ml/min for 5 minutes. Method e Analyze UPLC-MS using column BEH C18 1.7 μm, 2.1x5.00, using Acquity Waters UPLC equipped with Waters SQD (ES ionization) and Waters Acquity PDA detector Temperature: 40 ° C. UV detection at 215 nm and 254 nm. ESI + detection is in the range of 80-1000 m / z. Gradient 0.1% ammonia / water and acetonitrile with a gradient of 85 / 15 to 5 / 95 Flow rate: 0.8 ml/min for 3 minutes. Method f 101111810 53 201247629 Analysis UPLC-MS uses column BEH C18 1.7 μm, 2.1x5.00, using Waters SQD (ES ionization) and Waters Acquity PDA detector Acquity Waters UPLC. Temperature: 40 ° C. UV detection at 215 nm and 254 nm. ESI+ The measurement range is in the range of 80-1000 m/z. Gradient 0.1% formic acid/water and 0.1% citric acid/acetonitrile have a gradient of 95/5 to 5/95. Flow rate: 0.6 ml/min for 3 minutes. (Preparative HPLC method) Method a Preparative HPLC was performed using a Gemini NX C18 5 micron, 100 X 21.2, using a Waters 2525 pump equipped with a binary gradient module and a Waters 2767 system coupled to Waters Micromass ZQ25 (ES) or Waters 2487 DAD. 0.1% citric acid/water and 0.1% citric acid/methanol flow rate: 40 ml/min. Method b Preparative HPLC using X-Bridge C18 5 micron, 19x 150, using a binary gradient module Waters 2525 pump And a Waters 2767 system connected to Waters Micromass ZQ25 (ES) or Waters 2487 DAD. Gradient 0.1% ammonia/water and sterol flow rate: 17 ml/min. Method c Preparative HPLC using X-Bridge C18 5 micron, 19x150 Performed using a Waters 2525 pump equipped with a binary gradient module and a Waters 2767 system consuming to Waters MS3〇〇SQ or Waters 2487 DAD. Ladder 101111810 54 201247629 Degree 0.1% formic acid/water and 0.1% formic acid/methanol flow rate: 17 ml/min. Example 1 (Method A2): trans-4-(5-gas-6-methoxy-3-indolyloxy-2,3-dihydro-benzimidazolyl-1ylmethyl) Cyclohexane decanoic acid pyridyl decyl 1,4-difluoro-2-methoxy-5-nitro-benzoquinone F K2C03, Mel fAAn〇2 ~TTmT ρΛΛν〇2 ' Potassium carbonate (4.77 g , 34.49 millimolar) and catalytic amount of 1,4,7,10,13,16-hexacyclooctadecane were added to 2,5-difluoro-4-nitro at room temperature, (3.02 g, 17.25 Milliol) in a stirred solution of 2-butanone (8 mL). After 3 minutes, methyl iodide (2.25 ml, 36.22 mmol) and the reaction mixture were added at 4 Torr. 〇 Add heat to the weekend. The reaction mixture was concentrated under reduced pressure. Add acetic acid (5 liters) and water (50 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3 <<2> The organic layer was collected, washed with EtOAc EtOAcjjjjjjjjjj 07115?2>103'§10 value [189.12] measured value: no mass reaction, lamp = 1.32, (method f) 'HNMR (DMSO) δ: 3.97 (3Η, s), 7.47-7.52 (1H, m) , 8.13-B.18 (1H, m). Trans-4_[(4-fluoro-5-methoxy-2-nitro-phenylamino)-indenyl]-cyclohexane decanoate 101111810 55 201247629

ο F

Οο2

KgC〇3, DMF

Potassium carbonate (10.02 g, 72, 51 mmol) was added to i,4-difluoro-2-methoxy-5-nitro-benzene (2.77 g, 14.50 mmol) in DMF (15 mL) Stirred in the valley solution. After 30 minutes, trans-4-aminomercapto-cyclohexanecarboxylic acid methyl ester (3.00 g, 14.50 mmol) and the reaction mixture k.sub. The reaction mixture was concentrated under reduced pressure. The organic phase was separated and the aqueous phase was taken in DCM (3×20 mL). The organic layer was washed with EtOAc EtOAc EtOAcjjjjjjjjjjj 'HNMR (DMSO) δ: 1.02-1.11 (2Η, m), 1.29-1.39 (2H, m), 1.61-1.70 (1H, m), 1.80-1.84 (2H, m), 1.89-1.94 (2H, m ), 2.22-2.30 (1H, m), 3.25-3.28 (2H, m), 3.57 (3H, s), 3.96 (3H, s), 6.46-6.48 (1H, m), 7.83-7.86 (1H, m ), 8.46-8.49 (1H, m). (:161121?=〇5, calculated value [340,35], measured value []^+11+]341,11丁= 1.71 (method f) 〇反-4 -[(2-Amino-4-fluoro-5-decyloxy-phenylamino)-indolyl]-cyclohexyl decanoate

Pd/C 10%, EtOH 55〇C J 4£>

_4-[(4-Fluoro-5-decyloxy-2-nitro-phenylamino)-indolyl]-cyclohexane oxime 101111810 56 201247629 decyl phthalate (4.79 g, 14.09 mmol) Suspended in 5 ml of ethanol, combined with pd/c 10% (0.50 g) and transferred into the Eyeia reactor. The mixture was placed at 55 ° C under 4 bar of hydrogen pressure for 4 hours and then filtered through cellulose. The cellulose was washed with ethanol (300 ml). The organic solution was concentrated under reduced pressure to give 4. <RTIgt; HNMR (DMSO) δ: _ pick (2H, m), 丨25 福 (2H, m), 58心58 (1H, m), 1.88-1.91 (4H, m), 2.22-2.29 (1H, m), 2.80-2.83 (2H, m), 3.57 (3H, • s), 3.67 (3H, s), 4.18-4.21 (iH, m), 4.39 (2H, bp), 6.13-6.15 (1H m) 6.36-6.40 (1H, m). '反·4_(5_Fluoryl_6_decyloxy_2_sideoxy·2,3·diaza-benzopyranoylmethyl)-methyl cyclohexanecarboxylate t phosgene, tea °y-vn temperature f1^n&gt;=0 triphosgene (4.10 g, 13.81 mmol) is added in several portions to the reverse-4-[(2-amino-based fluorofluoromethoxy) cooled to hydrazine Methyl-phenylamino)-methyl]-cyclohexanecarboxylic acid methyl ester (4.28 g ' 13.81 mmol) and TEA 〇 92 ml, ΐ 3 8 ι mmol. 耳) in THF (10 ml) . The reaction mixture was allowed to stand at room temperature and allowed to stand overnight. Water (50 ml) was slowly added to the reaction mixture, and then the THF was removed under reduced pressure. The precipitate formed was washed with water (dm) and dried to give 4.51 g of the title compound (yield 97%). 101111810 57 201247629 'HNMR (DMSO) δ: 1.01-1.10 (2H, m), 1.19-1.29 (2H, m), 1.60-1.63 (2H, m), 1.70-1.78 (1H, m), 1.85-1.88 ( 2H, m), 2.20-2.27 (1H, m), 3.55 (3H, s), 3.58-3.60 (2H, m), 3.81 (3H, s), 6.84-6.87 (1H, m), 7.00-7.02 ( 1H, m), 10.70 (1H, s)

C17H21FN204 'calculated value [336 37], measured value [M+h+] 337, RT = 1.24 (method f). Trans-4-(5-fluoro-6-decyloxy_3_fluorenyl-2-ylidene-2,3-dihydro-moutmidimidazole-1-ylindenyl)-cyclohexanone formate Purpose

Indole iodine (1.11 ml, 17.86 mmol) was added to trans-4-(5-fluoro-6-decyloxy-2-oxo-2,3-dihydro-benzimidazole-丨-yl group Methyl)-cyclohexanecarboxylate (1.50 g, 4.46 mmol) in a stirred solution of potassium carbonate (EtOAc, EtOAc, EtOAc) The reaction mixture was heated overnight and then concentrated under reduced pressure. MDCM (5 mL) and water (5 mL) were added to the crude product. The organic layer was separated and washed with DCM (3 EtOAc). The organic layer was collected, washed with brine (lilulu The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) 'HNMR (DMSO) δ: l.oi-l.ll (2Η, m), 1.18-1.28 (2H, m), 1.60-1.63 (2H, m), 1.70-1,79 (1H, m), 1.84 -1.88 (2H, m), 2.20-2.26 (1H, m)) 3.25 (3H, s), 3.55 (3H, s), 3.63-3.65 (2H, m), 3.83 (3H, s), 7.07-7.09 (1H, m), 7.16-7.18 (lH,m). 58 101111810 201247629

Cl8H23FN2〇4 'calculated value [35〇 outside], measured value [M+H+] 35 卜 RT = 1.39 (method f) 〇trans-4-(5-gas-6-decyloxy-3-methyl_2 _Sideoxy·2,3-dihydro-benzoimidazol-1-ylindenyl)-cyclohexane citric acid

LiOH (0.13 g, 5.30 mmol) was added to the inverse _4_(5_fluoro-6 methoxycarbonyl-2-oxo-2,3·dihydro-benzo-di-m-methane) Methylcyclohexanecarboxylate (1.24 g, 3.53 mmol) in a stirred solution of THF (10 mL) and water (3 mL). The reaction was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was diluted with water (10 ml) and used] [1 (::1). The residue was adjusted to only 3. The obtained solid was filtered, washed with water (3×l·ml) and dried to give 1 g of the title compound ( Quantitative yield) iHNMR (DMSO) δ: l'0 (M.〇9 (2H m), i 16] 25 (2H, m), [59 cut

(2H, m), 1.69-1.78 (1H, m), 1.84-1.87 (2H, m), 3_26 (3H, s), 3.63-3.65 (2H m), 3.83 (3H, s), 7.07-7.09 ( 1H, m), 7.16-7.19 (1H, m), 12.00 (1H, bp)., C17H21FN204 mass (calculated value) [336.37] 'Measured value [M+ ore 337, RT = 1.15 (method f). ························(5-fluoro-6-methoxy-3-indolyloxy 2,3-dihydro-benzimidazol-1-ylindenyl)-cyclohexane decanoic acid pyridine·4_ Baseline 101111810 59 201247629

Trans-4-(5-fluoro-6-decyloxy-3-indolyl-2-sideoxy-2,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexane decanoic acid ( 11 mg, 0 33 mmol, TEA (7) microliters, (iv) millimolar), HATU (149 mg, G, 39 mmol) and guanidine = amine (37 mg, 〇.39 mmol) A mixture of the feet (2 ml) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue, which was taken up in hexanes, was washed with water (5 mL) and then washed with Na0H i (5 mL). The organic layer was concentrated under reduced pressure and the crude product was purified using hexanes to afford the title compound (yield 68%). HNMR (DMSO) δ: 1.02-1.13 (2 Η, m), 1.29-1.39 Qr ou, m) , 1.65-1.68 (2Ht m), 1.76-1.85 (3H, m), 2.26-2.33 (1H, m), 3.26 (3H ^ ,,

s), 3.67-3.69 (2H m), 3.84 (3H, s), 7.11-7.13 (1H, m), 7.17-7.19 (1H, m), 7 c0 ^ ’

Λ M2-7.54 (2H 8.36-8.37 (2H, m), 10.19 (1H, s). 'C22H2 pass 403 mass (calculated value) [412.47]; measured value [m book 413, RT = 0.95 (method f) Example 2 (Method A3): 5-decyloxy_丨·methyl^[anti·4_(4_^_2-ylmethyl)-cyclohexylmethylhydrazine, 3_dihydro. Stupid and savory _ 2-keto-2,fluoro-4-indolyl-1-nitro-benzoquinone

F Ν〇2 K2C03, Mel 2-butanone

ρ n〇2 potassium carbonate (35.2g, 255mmol) added to 3d, 4, nitro, please 101111810 60 201247629 grams, 127.30 millimoles) in 2-butanone (60 ml) at room temperature Stir in the solution. After 30 minutes, methyl iodide (8.72 liters, 140.00 mmol) was added and the reaction mixture was heated at 40 °C for 22 hours. The mixture was concentrated under reduced pressure. Ethyl acetate (400 ml) and water (600 ml) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×100 mL). The organic layer was collected, washed with brine (150 ml), dried over sodium sulfate and evaporated. The resulting solution was dissolved in DCM (300 mL) and washed with EtOAc 1 N (200 mL). The DCM solution was concentrated under reduced pressure to give the title compound (yield: 83%). lHNMR (CDC13) δ: 3.90 (s, 3H), 6.71-6.78 (2H, m), 8.07-8.12 (m, 1H). trans-4-[(5-methoxy-2-schyl-phenyl) Amino)-mercapto]-cyclohexanyl decanoate

Potassium carbonate (43.64 g, 315.80 mmol) was added to a stirred solution of 2-fluoro-4-methoxysuccinyl-benzene (18.00 g '105.26 mmol) in DMF (60 mL) . After 30 minutes, trans-4-aminomethyl-cyclohexanoic acid hydrazine hydrochloride (21.79 g, % mmol) was added and the reaction mixture was heated at 50 ° C for 22 hours. The reaction mixture was filtered and washed with DCM (5x 50 mL). The organic solution was concentrated to give 33.89 g (yield). 101111810 61 201247629 lHNMR (DMS0) δ: 100-1.10 (2H, m), 1.27-1.38 (2H, m), 1.59-1.69 (1H, m), 1.79-1.83 (2H, 1.90.1.93 (2h, m) , 2.22-2.29 (1H, m), 3.20-3.23 (2H, m), 3.56 (3H, s), 3.84 (3H, s), 6.26-6.31 (2H, m), 7.99-8.01 (1H, m) , 8.38-8.41 (lH,m). C16H22N2〇5 mass (calculated value) [322 36]; measured value [M+H+]= 323, RT=1.73 (method f). inverse-4-[(5-曱) Oxy-2-amino-phenylamino)-methyl]-cyclohexyl decanoate

Ο1

Trans-4-[(5-decyloxy-2-nitro-phenylamino)-indenyl]-cyclohexane decanoic acid vinegar (33.90 g '105.28 亳mol) dissolved in 35 liters of ethanol Mix pd/C 10 〇/〇 (1.80 g) and transfer to the Ecociave reactor. The reaction mixture was placed under stirring at 5 bar of hydrogen pressure overnight and then filtered through a pad of cellulose. The cellulose was washed with EtOAc (EtOAc) (EtOAc) 'HNMR (DMSO) δ: 0.92-1.03 (2Η, m), 1.23-1.34 (2H, m), 1.48-1.57 (1H, m), 1.85-1.92 (4H, m), 2.21-2.28 (1H, m ), 2.1 (2H, d, J = 6.0 Hz), 3.56 (3H, s), 3.57 (3H, s), 4.05 (2H, bp), 4.44 (1H, d, J = 6.0 Hz), 5.93-5.95 (2H, m), 6.40-6.43 (1H, m). trans-4-(6-decyloxy-2-oxo-2,3-dihydro-benzimidazol-1-ylmethyl)_ Ethyl cyclohexanecarboxylate 62 101111810 201247629

Cm (38.13 g '235.10 mmol) was added under nitrogen to anti-4 methoxy-2-amino-phenylamino)-indenyl]-cyclohexanecarboxylic acid methyl vinegar (27 46 g, 94.04 Milligram) in a stirred solution of ethyl acetate (300 ml). The reaction mixture was allowed to stand overnight and then water (500 mL) was added. The sink and precipitate were formed and filtered, washed with ethyl acetate (3×30 mL) and discarded. The organic mash is collected into the mother liquor. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (3*100 mL). The organic layer was washed with EtOAc EtOAc (EtOAc) The dark brown solid was washed with diethyl ether (3×100 mL). 'HNMR (DMSO) δ: 0.99-1.09 (2Η, m), 1.17-1.28 (2H, m), 1.59-1.63 (2H, m), 1.67-1.77 (1H, m), 1.84-1.88 (2H, m ), 2.18-2.26 (1H, m), 3.54 (3H, s), 3.6 (2H, d, J = 7.2 Hz), 3.71 (3H, s), 6.52 (1H, dd, J = 8.4 and 2.4 Hz) , 6.73 (1H, d, J = 2.4 Hz), 6.82 (1H, d, J = 8.4 Hz), 10.56 (1H, s). C17H22N204 mass (calculated value) [318.38]; measured value [M+H+] = 319, RT = 1.25 (method f). Reverse-4_(6-methoxy-2-oneoxy-2,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexanecarboxylic acid 101111810 63 201247629 ρ Ο

LfOH THF-H20

OH trans-4-(6-decyloxy-2-p-oxy-2,3-dihydro-benzoimidazol-1-ylindenyl)-methyl cyclohexane decanoate (985 mg, 3.10 mmol) The ear was dissolved in THF (6 mL), then a solution of lithium hydroxide (221 mg, 9.2 mmol) in water (3 ml) and the mixture was stirred overnight at room temperature. 5 ml of water was added, THF was removed under reduced pressure and HCl was added to pH 4 with a white precipitate. The precipitate was filtered, washed with EtOAc EtOAcjjjjjjj toMR (DMS0) δ: 0.98-1.08 (2Η, m), 1.14-1.24 (2H, m), 1.59-1.62 (2H, m), 1.68-1.76 (1H, m), 1.82-1.86 (2H, m) , 3.26 (3H, s), 3.61 (2H, d, J= 7'2 Hz), 3.73 (3H, s), 6.61 (1H, dd, J= 2.0 and 8.4 Hz), 6·80 (1H, d , J = 2.0 Hz), 6.99 (1H, d, J- 8.4 Hz), 11.97 (1H, bs). 6-decyloxy-1-[trans-4-(4-»密咬-2-yl-派.丼-1-曱醢基)_cyclohexyl fluorenyl]-1,3-dihydro-benzo σ米哇_2_酉同

TEA (55 μL, 〇 _39 mmol), HATU (150 mg, 0.39 mmol) and 2-Nanthen-1-yl-pyrimidine (65 mg, 〇39 mmol) added to the counter ( 6_ 曱 -2- 侧 侧 侧 -2 -2 -2 -2 -2 -2 -2 -2 V V V _1 _1 ( ( ( ( ( 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 ML) solution. The mixture was heated at 35 101111810 64 201247629 °C for 4 hours. The solution was washed with 0.4 Μ sodium carbonate (2 mL), ammonium sulfate (2 mL) and then water (2 mL). The organic layer was concentrated under reduced pressure and purified mjjjjjjd 'HNMR (CDC13) 6: 1.13-1.24 (2H, m), 1.52-1.62 (2H, m), 1.79-1.88 (4H, m), 1.91-1.99 (1H, tn), 2.45-2.53 (1H, m ), 3.55-3.56 (2H, m), 3.67-3.72 (4H, m), 3.79-3.85 (7H, m), 6.53-6.57 (2H, m), 6.61-6.64 (IH, ni), 6.96-6.98 OH, m), 8.32-8.33 (2H, m), 9.01 (1H, s). C24H30N6O3 mass (calculated value) [450.55]; measured value [M+H+Bu 451 ' RT = 1.14 (method f). 5-methoxy-1-methyl winter [trans-4-(4-♦定·2_基-旅啡+曱)-cyclohexyl fluorenyl]-1,3-dihydro-benzopyrimidine Alpha-ketone

A solution of milligrams, milligrams, 0.15 millimoles in DMF (5 ml) was stirred for 6 hours and then concentrated under reduced pressure. DCM (2 mmol was added to the crude product. The organic layer was separated and then purified under reduced pressure on a ruthenium dioxide column (ethyl acetate dihydrobenzimidazol-2-one (68 solution). The crude product was obtained (yield: 86%). EtOAc (EtOAc: EtOAc: EtOAc) U3-1.22 (2H) m), ,3^ 6l ^ (4H, m), 1.89-1.97 (1H, m), 2.44-2.51 (lH, m)i 3.39 (3H, s) ^ 5: , m) , 3.65-3,9 (2H, m), 3,0-3,2 (2H, m), 3.78.3,5 m); ' ; ^ m), 6·57·6·58 (1H,(8) , 6.64-6.67 (1H, m), 6.85.6 87 m) &gt; 8.32.8.33 C25H32N6〇3 mass (calculated value, for acid); measured value [M+H+] = 465, RT=1.27 (method f) . ▲' Example 3 (Method A4): 3•[反·4·(4_乙酿基__小曱基基基基基)-5-漠-1-曱-1,3-dihydro, Sit and [4,5 handsome than bite _2, anti-4·[(6-moly-3-nitro ♦ _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Speaking of -1 - base) - 嗣

Carbonate (0.677 g '4.90 mmol) was added to 2, Bu 2 filled 3 Nitrate, gram, 4.90 mmoles) and Η 邻 邻 胺 胺 胺 胺 : : : : : : : : : -Based--ethanone (1.31 g, 4.90 mmol) in a mixture of toluene (14 mL). The resulting mixture was stirred at 6 ° C for 5 hours. The mixture was washed with water (10 mL) and EtOAc. The combined organic layers were dehydrated with sodium sulfate and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) 'HNMR (CDC13) δ: 1.07-1.17 (2Η, m), 1.59-1.84 (5H, m), 1.92-1.96 (2H, m), 2.12 (3H, s), 2.42-2.50 (1H, m), 3.43-3.55 (6H, m), 3.60-3.65 (4H, m), 6.76 (1H, d, J= 8.4 Hz), 8.21 (1H, d, J= 8.4 Hz), 8.39-8.41 (1H, m) 101111810 66 201247629 1-(Reverse-4-{4-[(3-Amino-6-bromo-°-Bist-2-ylamino)-indenyl]cyclohexanyl]} Piper- 1-yl)-ethanone

1-(trans-4-{4-[(6-amino-3-triki-indot-2-ylamino)-methyl]cyclohexanyl}-piped-1-yl)- A solution of ethyl ketone (1.0 g, 2.14 mmol) in THF (20 mL) was added to a mixture of &lt;RTI ID=0.0&gt; The reaction mixture was hydrogenated at 5 bar for 5 hours at room temperature and hydrogenated at 45 ° C for 4 hours. Since the observation was not completely converted, the reaction mixture was filtered through a cellulose mat and 100 mg pt/C 5% was added. The mixture was then maintained at room temperature with stirring at 5 bar of hydrogen overnight. The mixture was filtered through a pad of cellulose and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc (EtOAc). 438/440, RT = 1·14 (Method 〇. 3-[反·4_(4-Ethylmercaptocyclohexylmethyl]_5· Desert], Dihydro-Mimi-[4,5-b&gt Bis-but-2-one

(trans-4-{4-[(3-amino-6-bromo-pyridyl-2-ylamino)-indenyl]cyclohexanemethyl 101111810 67 201247629 mercaptophenanyl)-acetone (0.740 Gram, 1.69 mmol, in THF (15 mL) EtOAc (EtOAc) Plant to ^ S time divided into several parts to add three phosgene (165 mg '〇56 毫, 77 ^ show +) 0 let f character reach room temperature and then add 丨 equivalent three phosgene (165 ° Gan, pen see, 0.56 mm ear). The mixture was heated at 60 ° C until the starting material was completely converted. The mixture was allowed to reach room temperature and water (5 ml) was added. The &amp; </ RTI> was removed under reduced pressure and dissolved in DCM (20 mL). The solution was taken up in EtOAc (EtOAc m.). C20H26BrN5O3 mass (calculated) [464.37]; found [m+h+] = 464/466, RT = 1.04 (method f). 3-[trans-4-(4-ethyl-bristyl-° bottom 0 well-1-indenyl)-cyclohexene mesquite T-storm]-5-bromo_ι· decyl·1,3-dihydrogen -imidazo[4,5-b]pyridin-2-one

Br

&gt;=〇

Q 0

Mel, KjC〇3, DMF 0 t Potassium carbonate (0.46 g, L99 mmol) was added to the anti-_3_[4_(4·乙乙义听耕-1-甲醯基)-cyclohexyl fluorenyl l·5 a solution of -bromo-1,3-dihydro-imidazolium y5-7]n-pyridin-2-one (0.71 g, 〗 </ RTI> 53 mmol) in DMF (1 liter). After (7), methyl iodide (0.12 ml, 1.99 mmol) was added and the mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure of DCM (1 mL) and water (5 mL). The organic layer was separated and concentrated under reduced pressure. The crude product was purified by column chromatography ( gradient:EtOAc: MeOH, 95:5) to afford 0.61 g of the title compound (yield: 83%). 'HNMR^DCB) δ: 1.10-1.20 (2Η, m), 1.50-1.59 (2H, m), 1.74-1.82 (4H, m), 1.96-2.06 (1H, m), 2.12 (3H, s), 2.39-2.47 (1H, m), 3.42-3.52 (7H, m), 3.59-3.62 (4H, m), 3.81 (2H, d, J= 7.2 Hz), 7.03 (1H, d, J= 8.0 Hz) , 7.17 (lH, d, J = 8.0 Hz). C21H28BrN503 mass (calculated value) [478.39]; measured value [M+H+] = 478/480, RT = 1.14 (method f). Example 4 (Method B): 3-[trans-4-(4-ethylindolyl-piperidinyl 4-indenyl)-cyclohexylmethyl]-5·((Ε)-3-decyloxy -propenyl)_1_mercapto-1,3-dihydro-imidazo[4,5-1)]° than ketone-2-keto 3-[trans-4-(4-ethinyl-piperazine- 1-indenyl)-cyclohexylfluorenyl]nonyloxy-propenyl) benzhydryl-1,3-dihydroimidazo[4,5-b]«pyridinyl-2-anthracene

3-[trans-4-(4-ethylindolyl-piperidin+indenyl)-cyclohexylfluorenyl]_5υ·decyl-1,3-dihydro-imidazo[4,5-b]pyridine- 2-ketone (70 mg, 〇15 mmol), ((E)-3-decyloxy-propenyl)-(4,4,5,5-tetradecyl-[1,3] East _2_ base)-butter (87 mg, 0.44 mmol), acid clock (109 mg, 〇51 mmol) / gluten in a mixture of benzene and water (2 〇: i '2.1 ml) Then, tricyclohexylphosphine (4.0 mg, 〇. 〇 1 mmol) and 1 &gt; (1 (0 8 (3 mg, 〇〇 1 mmol). The resulting mixture was at 90. (: The cells were irradiated for 10 minutes in a microwave apparatus. Water 101111810 69 201247629 (2 ml) was added to separate the layers and the aqueous phase was washed with additional DCM (2 mL). The organic phase was collected, dried over sodium sulfate, filtered and evaporated to remove solvent. Purification of the oxidized gel column (AcOEt/MeOH 9:1) and purification by preparative HPLC (Method b) afforded 18 mg of the title compound (yield 21%). 丨HNMR (CDC13) δ: 1.11-1.20 (2H,m),1.50-1.60 (2H,m),1.74-1.77 (2H, m), 1.81-1.85 (2H, m), 1.99-2.07 (1H, m), 2.12 (3H, s), 2.41 -2.48 (1H, m), 3.41-3.51 (10H, m), 3.58-3.62 (4H, m), 3.85 (2H, d, J= 7.2 Hz), 4.14.4 16 (2H, m), 6.62-6.79 (2H, m ), 6.94 (1H, d, J = 8.0 Hz), 7.07 (1H, d, J = 8.0 Hz) C25H35N5〇4 mass (calculated value) [469.59]; measured value [m+h+] = 470,RT = 1.11 (Method f). Example 5 (Method C): trans-4-{5-[(2-didecylamino-ethyl)-methyl-amino]-1 -indolyl-2-oxo 1,2-dihydro-imidazo[4,5-b]pyridine-3-ylindenyl}-cyclohexanolate ruthenium sulphate-β-glycolide anti-4_[(6_漠-3·硝Ketidyl-2-ylamino-mercaptocyclohexylcarboxylate

Potassium carbonate (2.27 g '16.4 mmol) and anti-fouling face long-term methyl 4-methylcyclohexane decanoate (1.70 g, 8.2 mmol) added to 22 %, from q ^ , △ /Smelly-3-nitropyrazole, 7.45 mmoles) in a solution of a mixture of 4 toluene (20 ml). The reaction mixture was heated at 6 (TC overnight, water (15_, organic phase separated, dehydrated with sodium sulfate, reduced to _1 residue H (tetra) gel 101111810 70 201247629 column (cyclohexane / DCM3: 2) Purification afforded 1.45 g of the title compound as a pale crystalline solid (yield 52%). 'HNMR (CDC13) δ: 1.03-U3 (2 Η, m), 1.41-1.51 (2H, m), l.62-i .72 (1HS m), 1.89-1.94 (2H, m), 2.02-2.06 (2H, m), 2.24-2.31 (1H, m), 3.51 (2H) t &gt; 6.0 Hz), 3.66 (3H, s ), 6.76 (1H, d, &gt; 8.4 Hz), 8.2 (1H, d, *7=8.4 Hz), 8 38' (lH, brs)

RT C14H18BrN304 mass (calculated) [372 22]; no mass reaction, = 1.88 (method f). ° ratio. D-trans-4-({6-[(2-dimethylamino)ethyl)-indolyl-amino]_3_des-2-ylamino}-methyl)-cyclohexane Decree

NO, Ο

0

Q NO, N, N, N'-trimethylidene ethyl diamine (2 ml) was added to the anti- 4 carefully 3 nitro-pyridin-2-ylamino)-methyl]-cyclohexanecarboxylic acid The ester (35 mg, 1 42 mmol) and the mixture were stirred at 6 (TC for 2 hours. The obtained solution was concentrated under reduced pressure and the crude product was taken from a ruthenium dioxide column (ethyl acetate / ammonia 2 〇 N in methanol) 9 Purification afforded 340 mg of the title compound (yield: 92%). [HNMR (CDClj) δ: 0.99-1.09 (2 Η, m)5 1.38-1.48 (2H, m), 1.67 (1H, bS), 1.88-1.92 ( 2H, m), 2.00-2.04 (2H, m), 2.22-2.31 (7H, m), 2.52-2.56 (2H, t, J= 6.4 Hz), 3.15 (3H, s), 3.42 (2H, t, J= 6.4 Hz), 3.66 (3H, s), 3.76 (2H, bs), 5.92 (IH, d, J=9.6 Hz), 8.16 (1H, d, J= 9.6 Hz), 8.88 (NH, brs) .

Cl9H3lN5〇4 ’ calculated value [393 ], found [M+H+] 394, RT = 1.09 (method f). 101111810 71 201247629 Trans-4-{5-[(2-Didecylamino)ethyl)-indolyl-amino] oxime oxime, 〖-dihydro-isoxazo[4,5-b] Pyridin-3-ylindenyl}-cyclohexane decanoic acid vinegar

Trans-4-({6-[(2-didecylamino-ethyl)-indolyl-aminonitroacridin-2-ylamino}-indenyl)-cyclohexane decanoate (34 mg, 〇86 mmol) was reduced using an Eyela apparatus at 6 (TC) in Pd/C (3 mM 1% w/w) in THF (15 mL). The reaction mixture was observed to be filtered, and the reaction mixture was filtered through a pad of EtOAc (EtOAc) (EtOAc (EtOAc) The THF was removed by evaporation and EtOAc (EtOAc) (EtOAc (EtOAc) A% hydrazine and ethyl acetate were purified as an eluent by column chromatography. 145 mg of the title compound was isolated (yield: 43%). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> ^+] 390,11丁 = 0.85 (method f). Reverse 4-{5-[(2-dimethylamino-ethyl)-methyl-amino]]丨_methyl_2_ side Oxy-1,2-dihydro-imidazo[4,5-b]pyridin-3-ylmethylcyclohexanecarboxylic acid Ester 101111810 72 201247629

-ethylmethyl-amino]-2 in trans-4-{5-[(2-didecylamino]-1,2-dihydro-imidazo[4,5-b]pyridine-3-yl Addition of potassium carbonate (67 g, 48 mmol) and sulfhydryl group Iodine (25 μl, 〇 4ι mmol). The mixture was allowed to stand overnight at room temperature (iv). Evaporation and removal under reduced pressure and residue: DCM (6 mL). Water (4 ml) was added and the organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography using cerium oxide _NH 2 carbazide and D C M/M e Ο Η 9:1 as the eluent. The title compound contained 60% of the true N-indolyl fourth salt. 〇211133 milk thistle 3' calculated value [403.53]; measured value|^1+1^+] 404,11丁 = 0.84 (method f). Trans-4-{5-[(2-dimethylamino-ethyl)-indenylamino]]ι-indenyl-2-ylidene-1,2-one-mouse _0 m α [4,5-b]nit. D--3-ylmethyl}-cyclohexanic acid

Lithium hydroxide (11.1 mg '0.46 ml) was added to water (1 ml) to trans-4-{5-[(2-monodecylamino-ethyl)-indolyl-amino]_1_methyl_ 2_Sideoxy 101111810 73 201247629 -1,2-Dihydro-imidazo[4,5-b]pyridin-3-ylfyl}-cyclohexane decanoate (170 mg, 0.42 mmol) In THF (4 ml) / trough. The solution was stirred overnight at room temperature. The solution was concentrated under reduced pressure and the residue was applied to the next step. 126 mg of white solid was obtained (yield 99 ° / 〇). C20H30N503U mass (calculated value for acid) [389.5 〇]; measured value [M+H+] = 390. RT = 0.70 (method f). Trans-4-{5-[(2-Didecylamino)ethyl)indolyl-amino]-1-methyl-2-oxo-I,2-dihydrocarbazino[4 ,5-7]pyridin-3-ylmethylbucyclohexanepyridinium pyridine-4-ylamine

Trans-4-{5-[(2-Dimethylamino-ethyl)-indenyl-amino]·ΐ_曱yloxy-1,2-diphos-flavored[4,5 -1)]1|Bit-3-ylindenyl}-cyclohexanic acid (58 mg, 0.15 mmol), hydrazine (18 mg, 0.18 mmol), HATU (68.4 mg, 0.18 mmol) The mixture was stirred at room temperature for 4 hours at 4 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified eluting with EtOAc EtOAc EtOAc EtOAc. 33 mg of the title compound were obtained (yield 49%). 101Π1810 74 201247629 'HNMR (CDC13) δ: 1.11-1.21 (2H 1 λο , cm), i.49·1. (2H, (6), 1.85-1.89 (2H, m), 1.97-2.08 (3H, ra) , 2.21-2.29 (1H m,, ... ' m), 2.35 (6H, s), 2.54 (2H, t, J=

7.2 Hz), 3.01 (3H, s), 3.36 (3H, s), 3.70 (2H t f- 7 , TJ~ 7.2 by), 3.77 (2H, d, J = 7.2 Hz), 6.14 (1H, d, J= 8.8 Hz), 7.04 (1H, d, J= χ 〇„ x , 5 8-8 Hz), 7.48 (2HS d, J= 5.2 Hz), 7.63 (1H, bs)3 8.46 (2H, d, J = 5.2 Hz). 》 C2脳N702 mass (calculated value) [465 6.]; measured value [m+h+] = 466. RT=0.69 (method f) Example 6 (method D): anti-adjacent-(4) Methoxy 4-yloxy)methyl-2_ oxo-2,3-dihydrobenzophenanyl succinylmethyl]-cyclohexanic acid hydrazine bismuth _4_ carbamide 2-(3 ·Fluoro-4-nitrophenoxy)tetrahydropyran

In a 500 ml four-necked round bottom bottle, 3,4·2 gas-2H_ mouth whistle (196 g, 2164 mmol) and PTSA (1. G g, 5.4 mmol) were dissolved in anhydrous two + mountain ( 17 〇 ml) and then cooled to 1 GC. While maintaining the temperature below the order, a solution of 3_gas-4-nitrophenol (17.0 g, 108.2 mmol) in anhydrous hydrazine (8 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with a saturated aqueous solution of sodium carbonate (300 mL). The organic layer was washed with a saturated aqueous solution of sodium carbonate (2. 5 mL) and then washed with brine (2. The DCM solution was dried over sodium sulfate, filtered and then evaporated and evaporated. Solid and mtbe (7 mL) 101111810 75 201247629 Wet-milling and filtration afforded 14.5 g of the title compound as a pale yellow crystalline solid. The mother liquor was evaporated under reduced pressure to give a dark oil (yield: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> using a PE/EtOAc 9/1 mixture as an eluent. This batch was added to the previous batch to give 17-5 g (72.6 mmol, yield 67%) of title compound as pale yellow crystalline solid. TLC: (EDP / EtOAc 9 Π) Rf = 0.54 (UV). Trans-4-{[2-nitro-5-(tetrahydro-2H-piperidin-2-yloxy)phenylamino]methyl)cyclohexanecarboxylic acid methyl ester

2-(3-Fluoro-4.nitrophenoxy)tetrahydro-2jj_pyran (16.3 g, 67.6 mmol) in a 500 ml four-neck round bottom flask was dissolved in anhydrous DMF (150 mL) and then added Potassium carbonate (18.72 g, 135.2 mmol). Simultaneously in a 250 ml two-headed round bottom bottle, trans-4_(aminomercapto)cyclohexane decanoic acid methyl ester hydrochloride (HQ g, 67.6 mmol) was dissolved in anhydrous DMF (100 mL) and then TEA was added. (9.4 ml, 67.6 mmol). After a few minutes the suspension was filtered under argon and the filtrate was added to a first flask. The suspension was stirred overnight at 50 Torr. The reaction mixture was quenched with water (300 mL) thenEtOAc. The collected organic solution was washed with EtOAc (EtOAc m. . This solid was used in the next step 101111810 76 201247629 without further purification. Trans-4-{[2. Amino-5-cyclohexanecarboxylic acid methyl ester (homogen-2Η-oxy-2-indolyl)phenylamino]methyl)

Weng A η ^ round bottom thief inside anti-ice {[2, JI JI (four argon _2 Η · Niang ° South _2 _ base ^ native amine] f Α 环 烧 甲酸 甲酸 25 25 25 25 · · · 25 25 64 64 · millimolar) core in ethanol (6 liters pen), then completely dissolved by heating, then add Pd / c (I · 4 grams 12.83⁄4 mol) and hydrazine monohydrate 0 9 ml (10) 8 millimol ear). The system was refluxed for 5 hours. The reaction mixture was allowed to reach room temperature, filtered over a pad of Celite, and evaporated. The residue was taken up in DCM (5 mL) and washed with water (2.times.500 mL), 5% citric acid (2x500 mL) and then brine (2x500 mL). The organic solution was dried over sodium sulfate, filtered and evaporatedEtOAc. TLC: (Cy / EtOAc 2/8) R 〇. 68 (uv). Anti-4-[2-Sideoxy-6-(tetrahydrobine~-N-2-yloxy)-2,3-dihydrobenzimidazol-1-ylmethyl]-cyclohexanecarboxylic acid decyl ester

101111810 77 201247629 CDI (11.7 g, 72.1 mmol) added to the reverse 4 {[2-amino-5-(tetrahydro-2H-pyran-2-yloxy)benzene in a soaked four-necked round bottom bottle A solution of methylamino]methyl)cyclohexanecarboxylate (13.1 g, 36.1 mmol) in dry THF (5 mL). The reaction mixture was stirred at room temperature. The solvent was evaporated under reduced pressure and the residue was purified eluted eluted eluted eluted eluted eluted The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to yield 14.5 g (yield) of crude product intermediate compound as brown solid. This intermediate was used in the next step without further purification. Trans-4-[3-mercapto-2-oxo-6-(tetrahydro-2-indole-piperidin-2-yloxy)-2,3-dihydrobenzimidazole-1 ylmethyl] _cyclohexane decanoate

虱 纳 (6.5 g '162.0 mmol) was added to a 1-liter four-necked round bottom bottle of trans-4-[2·o-oxy-6-(tetrahydro-2-indole-pyran-2-yloxy) Anhydrous DMF solution of _2,3-dihydrobenzimidazol-1-ylindenyl]-cyclohexane decanoate (2 ΐ·〇克, 54. 〇 mmol) (300 mL). The mixture was stirred at room temperature for a few hours and then decane (10.1 mL, 162.0 mmol). The mixture was stirred at room temperature for 18 h then quenched with water (500 mL). The organic layer was washed with water (2×500 mL) and brine (2×··········· This oil was purified by flash lysing using a mixture of EtOAc/EtOAc EtOAc (EtOAc) EtOAc (EtOAc) TLC: (Cy / EtOAc 3/7) R yield 0.41 (Uv). Trans-4-(6-hydroxy-3-indolyl-2-oxo-2,3-dihydro-bromoimidazolylhydrazyl)cyclohexane decanoic acid

A solution of LiOH*H2(R) (4.1 g, 97.5 mmol) in water (75 mL) was added to the anti-4-[3-mercapto-2-oxo-[6] of a 500 mL one-necked round bottom bottle. Tetrahydro-2Η-amyl-2-yloxy)-2,3-dihydrobenzimidylmethyl]-cyclohexyl decanoate (13.1 g, 32.5 mmol) of THF (150 ML) solution. The mixture was refluxed for 2 hours. The THF was evaporated under reduced pressure and hydrochloric acid (6 N, 150 mL). The solid was isolated by filtration, dissolved again in THF (300 mL) and EtOAc (2 <RTIgt; The mixture was refluxed overnight. The THF was evaporated under reduced pressure and the residue was triturated with EtOAc (EtOAc) and then filtered. 7.6 g (yield 77%) of the title compound was isolated as a light gray solid. 'H NMR (DMSO) δ: 1.1 (m&gt;2H); 1.2 (m, 2H); 1.7 (m, 3H); 1-9 (m, 2H); 2.1 (m, 1H); 3.5 (s, 3H) ), 3.6 (dds 2H), 6.5 (dd, 1H), 6.6 (d, 1H), 6.9 (d, 1H), 9.1 (bs, 1H), 12.0 (bs, 1H). anti-4-(6- Hydroxy-3-mercapto-2-oxo-2,3·dihydro-benzoimidazol-1-ylmethyl)cyclohexane decanoate 101111810 79 201247629

Trans-4-(6-carbyl-3-indolyl-2-oxo-2,3-dihydro- benzopyridinyl)cyclohexanecarboxylic acid (5 mg, L64 mmol) The ear was dissolved in methanol (5 ml) containing sulfuric acid (5 ml). The solution was refluxed for 2 hours. The solvent was removed by evaporation and the residue was washed with diethyl ether and filtered. 470 mg of the title compound were obtained (yield: 89%). C17H22N204 mass (calculated value) [318.38]; measured value [m+H+] = 3 J9 RT = 1.09 (method f). Anti-4-[6-(4-decyloxybenzyloxy)-3-methyl_2_sideoxy-2,3-dihydro-benzimidazole-1-ylindenyl]-cyclohexyl Alkanoic acid

At 0C, bismuth (13 mg, 0.35 mmol) was added in several portions to trans-4-(6-carbyl-3-methyl-2-oxo-2,3-dihydro-benzo) Taste of small base ^ base) Cyclohexanolate 曱 曱 § _ mg, 〇 · 31 millimoles) in listening (4 ml) of the two liquid. The mixture was stirred at room temperature for a few hours, then was added methyl _4^-yl-benzene (0.054 mL, EtOAc, 38 m. Water (5 ml) and solution were extracted with DCM (5 mL). The organic layer was washed with a pad of EtOAc (yield: EtOAc) (yield: EtOAc, EtOAc) The crude product was purified by using a hexahydrate/acetic acid ethyl acetate 1:1 as an eluent. 85 mg of the title compound were obtained (yield 62%).匸25113 (^205 mass (calculated value) [438.53]; measured value []^1+11+]= 439 ' RT= 1.66 (method ί). anti-4-[6-(4-methoxy-benzyl Benzyl)-3-mercapto-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl]-cyclohexane decanoic acid A α

ο

LIOH ο. ρ

ΟΗ thf/h2o oxidized chain (11 mg, 0.49 mmol) was added to the inverse 4_[6-(4-decyloxy-benzyloxy)-3-indolyl-2-yloxy-2,3· Dihydro-p- and imidazolium hydrazinyl hydrazide carboxylate (85 mg, 0.19 mmol) dissolved in THF: H 2 hydrazine (5 mL each), and the resulting suspension After stirring for 16 hours, THF was evaporated under reduced pressure, EtOAc (EtOAc m. C24H28N2〇5 mass (calculated value) [like 5〇]; measured value [M+H+]= 425, RT=1.44 (method f). inverse ·4·[6-(4-decyloxyoxy) -3-mercapto-2-yloxy-2,3-dihydro-benzomethane]•cyclohexene carboxylic acid hydrazine hydrazide 101111810 81 201247629

Trans-4-[6-(4-decyloxy-benzyloxy)_3_indolyl_2_sideoxy-2,3_dihydro_

Benzimidazol-1-ylindenyl]-cyclohexane decanoic acid (45 mg, 0.11 mmol), TEA (33 μL, 0.21 mmol), HATU (49 mg '0.13 mmol) and pyridine 4-Methylamine (12 mg '0.13 mmol) was stirred in DMF (5 mL) Water (5 ml) and mixture was extracted with DCM (2×5 mL). The organic layer was collected, dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative EtOAc (EtOAc) 'HNMR (MeOD) δ: 0.96· 1.41 (2H, m), 1·25-1·39 (2H, ηι >, 1, 59-1 87 (5H, m), 2.26-2.36 (1H, m), 3.26 (3H, s), 3.60-3.64 (2H, m), 3.72 (3H s) 6.71-6.76 (1H, m), 6.92 (1H, d, J=8.4 Hz), 6.93 (1H, brs), 6.99 (1H, d, J=8 2 Hz), 7.37 (2H, d, J=8.4 Hz), 7.53 (2H, d, J=1.2 Hz), 8.21 (1H, brs) 8.37 (2H brs), 10.2 ( 1H, brs). C29H32N404 mass (calculated) [500.60]; found [M+H+] = 501, RT = 1.28 (method f). Example 7 (Method E): 5-decyloxy-1-indole Base-3-{reverse_4_[3·sideoxy-4-(2-o-oxy-butyl)-ninnium. well-1-indenyl]-cyclohexylfluorenyl di-n-benzimidazole- 2-keto 5-methoxy-1-indolyl-3-[trans-4-(3-olyoxy-linphine-1·methyl)-cyclohexylmethyl]-1,3-two wind -Benzene glutinous rice ** sitting -2- ah 101111810 82 201247629

TEA (350 μl, 2.52 mmol), HATU (574 亳, i i · 51 mmol) and Piper-2-one (151 mg, 丨.51 mmol) added to the anti-sludge 6 Xenon-3-oxo-2-yloxy-2,3-dihydro-benzomidine. A solution of -1-ylmethyl)-cyclohexanic acid (400 mg, 1.26 mmol) in DMF (5 m). The reaction was stirred at room temperature for 2 hours. Water (5 ml) and the mixture were extracted with PC1V1 (3 mL). The organic layer was collected, dried over sodium sulfate and concentrated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: iHNMR (DMSO) δ: 1.02-1.31 (4H, m), 1.59-1.78 (5H, m&gt;, 2·5Κ2'56 (1H, m), 3.07-3.20 (2H, m), 3.26 (3H, s) , 3.52-3.56 , n), ^59 '3.63 m), 3.73 (3H, s), 3.85 (Π-Ι, bs), 4.04 (1H, bs), 6.61 (lH, dd, J . and M Hz) , 6.79 (1H, d, J= 2.4 Hz), 7.00 (iH, d, J= 8.4 Hz), 8.01-8 °5 〇H,m)&gt; 'C2lH28N4〇4 mass (calculated value) [4〇〇 .48]; measured value [M+h+]== 401, RT= 1.00 (method f). 5-decyloxy-1-methyl-3-.[trans-4-[3-olyl-4-(indolyloxy-butyl)-p-l-mercapto]-cyclohexyl Methyl}_丨,3_二氢-黎和咪°坐坐-2-鲷0. 0

^=0

NaH, DMF Ο

wide

0 under 5-nitro-1 -methoxy-1-methyl-3-[trans-'(3-side gas group, piperene ^ 101111810 83 201247629 fluorenyl)-cyclohexyl fluorenyl]-1,3- Dihydro-p-imidazole-2-one (32 g, 0.80 mmol) was dissolved in dry DMF (4 mL). 〇 Add gasification' (37 mg, 0.96 mmol). The resulting mixture was stirred at room temperature for a few hours and then added to a solution of hexanes (6 ml, W mmol), and the mixture was given for an hour. Water (4 ml) and a mixture of EtOAc (3 mL, EtOAc) 〇%). &amp; C25H34N405 mass (calculated value) [470.57]; measured value [m+°h+b 47b RT=1.13 (method d) Example 8 (method F): trans-4: {2-[(2-methoxy) _Ethyl)-Methylaminomethyl-8-sideoxy-7,8-dihydrogen-butenyl-methyl}}cyclohexyl H 0 to 0--4-bristamine anti-4- ({2-[(2-Methoxy-ethyl)-indenylamino)·5_nitro·♦ Dingylaminopurinyl)-cyclohexanecarboxylic acid methyl ester

CI

^Γρεα, thf

2,4·Dichloro-5·Accord (547 mg, 2 82 mmol) was dissolved in thf (16 mL) and the resulting solution was cooled. A solution of 4_aminomercaptocyclohexylcarbamate formic acid (483 mg ' 2.82 mmol) and mpEA (() 75 mL, 4.24 mmol) in THF was added dropwise. The solution was at _耽_丨 hours. The reaction mixture was allowed to reach room temperature and then DIPEA (EtOAc &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&& The mixture was stirred for 16 hours. The solution was concentrated under reduced pressure and the crude material was trit. The solid was filtered and dried to give crystals crystals crystals 'HNMR (CDC13) δ: 1.05 (2Η, dd 7=12.8 and 9.0 Hz), 1.43 (2H, dd, 7=12.8 and 9.0 Hz), 1.56 (3H, s), 1.61-1.74 (1H, m), 1.84-1.93 (2H, m) 1.99-2.07 (2H, m) 2.20-2.28 (2H m), 3.24 (2I-I, s), 3.34-3.47 (3H, m), 3.58-3.68 (2H, m) , 3.66 (2H, m), 3.81 (2H, t), 3.81 (2H, t, 7=10.8 and 4 Hz), 8.97 (1H, s) C17H27N505 mass (calculated value) [381.44;| ; measured value [M +H+ Bu 382, RT = 1.68 (method f). Trans-4-{2-[(2-decyloxy-ethyl)-indolyl-amino]_8• pendant oxy-7,8-dihydro- -9-yl fluorenyl} Methyl decanoate

Trans-4-({2-[(2-methoxy-ethyl)-fluorenyl-amino]-5-nitro-pyrimidin-4-ylaminomethyl)-cyclohexanecarboxylic acid decyl ester (502 Mg, 1.31 mmol, dissolved in decyl alcohol (5 mL), and the mixture was concentrated and reconstituted using a h_cuBE unit equipped with a pd/c cassette (flow rate of 14 liters 'filled with hydrogen). Millions) and solution cooling to generation. 0.38 亳mol) and the reaction was stirred at room temperature overnight to add triphosgene (117 mg, added water, the organic solution was dissolved in anhydrous DCM (1 mL) in hexanes. Miao Kuan, n. V., A ________ 101111810 85 201247629 and concentrated under reduced pressure. The crude product was purified eluted with EtOAc (EtOAc (EtOAc) Yield 30%). lHNMR (CDC13) δ: 1.12 (2H, dd «7=12.0, 9.1 Hz), 1.41 (2H, dd, J=12.〇, 9.1), 1.82 (2H, d, /=12 Hz), 1.91-1.99 (1H, m), 2.01 (2H, d, J=12 Hz), 2.27 (1H, ddt, 1H, "M2 and 6.8 Hz) 3.20 (3H, s), 3.39 (3H, s ), 3.62 (2H, t, *7=6 Hz&gt;, 3.66 (3H, s), 3.72 (2H, d J=7.2 Hz), 3.81 (2H, t), 7.92 (1H, s) C18H27N504 mass (calculation Value, for acid) [377.45]; found [M+H+] = 378 RT = 0.96 (Method f) trans-4-{2-[(2-decyloxy-ethyl)-indenyl-amino] Methyl-7-mercapto-8-tertiary-7,8-dihydro-indol-9-ylindenyl}-cyclohexanecarboxylate

Trans-4-{2-[(2-decyloxy-ethyl)indolylamino]-8-sideoxy-7,8-dihydro-indol-9-ylindenyl}-cyclohexyl The decyl decanoate (μ6 mg '0.38 mmol) was dissolved in dry DMF (15 mL) under nitrogen. Barium carbonate (189 mg '0.58 mmol) was added and the mixture was stirred at room temperature for 3 minutes. Dimethyl sulphate (0.036 ml, 〇·38 mmol) was added and the reaction was stirred for 4 hours. Water and DCM were added, EtOAc m m m m m m 101111810 86 201247629 1HNMR (CDC13) δ: 1.08 (2H, dd /=12.0 and 9.2 Hz), 1·36 (2H, dd, *7=12.0 and 9.2 Hz), 1.62 (IH, s), 1.78 (2H, d, /=12.0 Hz), 1.85-1.96 (1H,m), 1.92 (2H, d, /=12.0 Hz), 2.20-2.26 (1H, m,) 3.81 (3H, s), 3.35 (3H, s ), 3.37 (3H, s) 3.60 (2H, m), 3.62 (3H, s), 3.69 (2H, d /=7.2 Hz), 3.75-3.80 (2H, m), 7.79 (1H, s) C19H29N504 (calculated) [391.47]; found [M+H+] = 392, RT = 1.04 (method f) trans-4-{2-[(2-hydranyl-ethyl)-indenyl-amino] -7-fluorenyl-8-tertiaryoxy-7,8-dihydro-fluoren-9-ylfluorenyl}-cyclohexane lithium niobate

Trans-4-{2-[(2-曱-milyl-ethyl)-indolyl-amino]-7-indolyl-8-yloxydihydro-indol-9-ylindenyl}-cyclohexyl Ethyl decanoate (136 mg, 0.34 mmol) was dissolved in THF/H20 (6 mL, 1:1, v/v). LiOH (9 mg, 0.41 mmol). Stir overnight. The solvent and lithium salt were removed under reduced pressure and used without further purification. The title compound was obtained as a white solid (yield: 99%). C18H27N504 mass (calculated for acid) [377.45]; found [M+H+] = 378. RT = 0.82 (method f) trans-4-{2-[(2-decyloxy-ethyl)-indolyl-amino]-7-mercapto-8-sideoxy 101111810 87 201247629 -7,8 -dihydro-indolyl fluorenyl}-cyclohexane decanoic acid pyridin-4-yl decylamine

Trans-4-{2-[(2-decyloxy-ethyl)-indolylamino]-7-indolyl-8-yloxy-7,8-dihydro-indoleyl fluorenyl} Lithium cyclohexane ruthenate (126 mg '〇.33 mmol) was dissolved in DMF (1 mL) then TEA (0.054 mL, 0.39 mmol) and HATU (150 mg, 0.39 mmol). The solution was stirred for 30 minutes, then 4-aminopyridine (36 mg, 〇. 39 mmol) was added and the resulting solution was stirred over the weekend. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in methanol and eluted with hydrazine alcohol by cerium oxide-NH2. The solution was concentrated and the residue was purified mjjjlilili 1H NMR (DMSO) δ: 1.03 (2H, dd J = 10.8 and 6.0 Hz), 1.32 (2H dd household 10.8 and 6.0 Hz), 1.63-1.71 (2H, m), 1.76-1.87 (3H, m), 2.23 2.35 (1H m)' 3.23-3.25 (5H, s), 3.46-3.60 (10H, m), 3.66-3.77 (2H, m), 7.52 (2H H * Hz), 7.69 (1H, s), 8.35 ( 2H, dd). 〇C23H31N703 mass (calculated value) [453.55]; measured value [M+h+] = 454_6, RT = 0.72 (method f) Example 9 (method Gl): trans-4-(1-mercapto -2,5-di-side oxy 4,2,4,5•tetrahydro-isoxazo[4,5-b]«pyridin-3-ylmethyl)-cyclohexane decanoic acid 嗒 · 4 · 醯 醯 反 -4- ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 101 101 101 101 101 101 101 101 101 101 101 101 101 101 101 101 101 3-mercapto-based)-cyclohexanic acid

Trans-4-(5-decyloxy-1-methyl_2_sideoxy-1,&gt;dihydro-imidazo[4,5-b]. butyl-3-ylindenyl)-ring a suspension of citric acid (0.500 g, I.57 mmol) and sodium hydride (7 〇 4 mg, 4.7 mM millimolar) in acetonitrile (1 mL) in a pressurized tube at 8 ° C Heat was then added to trimethyl decane (1.02 g, 9.40 mmol) and the mixture was stirred at 100 °C for 2 hours. The solvent was removed under reduced pressure. The title compound was obtained as a reddish brown solid (yield: 95%). C15H19N304 mass (calculated value) [305.34]; found [M+h+] = 306, RT = 0.80 (method f) trans-4-(1-mercapto-2,5-di- oxy-1,2, 4,5-tetrahydro-imidazo[4,5-1)]'» than -3--3-methyl)-cyclohexane-formic acid tartar-4-yl decylamine

Trans-4-(1-mercapto-one-oxy-1,2,4,5-tetrazole-mouth m. Sit and [4,5-b] mouth bite-3-ylindenyl)-cyclohexyl Burning citric acid (1 mg, 〇33 mmol) dissolved in DMF (1 ml) then TEA (91 μl, 0.39 mmol), HATU 101111810 89 201247629 (149 mg '〇·39 mmol) And 4-amino-based arable (37.4 mg, 0.39 mmol) and mixed delta at room temperature overnight. The reaction mixture was concentrated under reduced EtOAcqqqqqqlilililililililililililililili 'HNMR (CD30D) δ: 1.13-1-23 (2Η, m), 1.44-1.54 (2H, m), 1.78-1.81 (» X .94 2.05 (3H, rn), 2.35-2.44 (1H, m) , 3.39 (3H, s), 3.76 (2H, d, 1=7'2 HZ), 6 39 〇H&gt;d&gt;1=8 0 7.36 (11-1, d, J=8.0 I-Iz), g .05-8.08 (III, m), 8.93-8.95 (1H, m), 9.23-9.24 (1H, m). C19H22N603 mass (calculated value) [382.43]; measured value [M+H+ Bu 383. RT = 0.76 (Method f) Example 10 (Method G): trans-4-[5-(3-decyloxybenzyloxy)-indole-methyl-2-oxooxy-1,2-dihydro-imidazole And [4,5_b]pyridine·3_ylmethyl]-cyclohexane decanoic acid 0 bite &gt; 4-yl decylamine trans-4-(1-methyl-2,5-di- oxy-u , 4,5, hydrogen-isoxazol [4,5 secondary ratio. D--3-ylmethyl)·cyclohexene carboxylic acid decyl ester

Trans-4-(1-mercapto-2,5-di-tertiary oxo diterpene tetrahydrogen + sit and ^but bit -3-yl fluorenyl)-cyclohexanic acid (75 〇 mg ' 2 % 毫Mohr) was suspended in i 25 M HC1 in decyl alcohol solution (15 ml) and in 5 generations _3 hours. The solvent was removed to give 780 mg of the title compound (yield: 99%). 101111810 90 201247629 HNMR (CDC13) δ: 1.HM.20 (2H,m),13(M 4〇(2h,(6),^ 72 ι π (2H, m), 1.87-1.98 (3H, m), 2.19 -2.26 (1H, m), 3.40 (3H&gt; ^ 3 'g ' ' 3.80-3.82 (2H, m), 6.53 (1H, m), 7.36-7.38 (1H, m). ' ' C16H21N304 mass (calculated value ) [319.36]; measured value [m+h+] = 320. RT=1.03 (method f) anti_4·[5_(3·methoxyloxy)oxymethyl^-oxyl imidazo[4 ,5-b]pyridin-3-ylindenyl]-cyclohexanecapric acid methyl ester

In the anti-4 ♦ methyl 2,5 · two-side oxo 2 from four gas _ miso and [4, called t-dipyl thiol) - cyclohexanyl citrate ( cool ((10) mg, 〇 3 i millimolar) in a suspension of 2 butanone (2 ml), adding potassium carbonate (87 g, 〇63 mmol) and 3-oxo bromide (189 mg, 0.94 mmol) , and the mixture in the thief «mix overnight. The solvent was concentrated under reduced EtOAc. The organic phase is dehydrated and concentrated with sodium sulfate. The crude product was purified by ruthenium dioxide column using cyclohexane/ethyl acetate 2:1 elution. Obtained 120 mg of the title compound (yield: 88%). HNMR (CDC13) δ: 0.92-1.03 (2 Η, m), 1.23-1.33 (2H, m), 1.65-1.69 (2H, m), 1.77-1.89 (3H , m), 2.11-2.20 (1H, m), 3.32 (3H, s), 3.58 (3H, s), 3.68-3.69 (2H, m), 3.74 (3H, s), 5.26 (2H, s), 6.43-6.45 (1H, m), 6.75-6.78 (1H, m), 6.92-6.96 (2H, m), 7.05-7.07 (1H, m), 7.19-7.23 (1H, m). C24H29N305 mass (calculated value )[439·52]; measured value [M+H+Bu 440, RT=1.72 (method f) 101111810 91 201247629 anti-o-(3-methoxyoxyloxy)methylidene·2_sideoxy# Diazo _ imipenone [4,5 secondary ratio. Lithium-3-ylmethyl]-cyclohexylformate

Ortho-(3_methoxyoxy)oxymethyl-2,oxy#diazepine_Saliva[4,5-zhongling-3·ylmethyl]•cyclohexanic acid formate 20 mg , 〇·27 mmol) dissolved in Qing (2 ml). Add a solution of KOH. 2 mg, 0.30 mmol (m) in water (1 ml) and solution col overnight. The solution was concentrated under reduced pressure to give the title compound (126 m. C23H26N305U. Quality [outside...^ Bei nose value] [425.49]; measured value [M+H+] 426. RT = 1_50 (method f). Ortho-(3.methoxy-yloxy)+methyl_2_sideoxyn. Meter. Sit and [4,5 sec. _3_ylmethyl]·cyclohexylcarboxylic acid terminal 4 yl amide

Reverse o-oxyl) small? Base_2·Sideoxy·u•Dinitrogen·Sit and [4,5 sec-bite-3·ylmethyl]•cyclohexanic acid (1) mg, (iv) millimolar) dissolved in DMF (1 ml) ). Add TEA (〇〇32 ml, (four) millimolar), HATU (123 mg, 〇·32 mmol) and 4_amine carbamide 5 mg 0.32 mmol). . The mixture was concentrated under reduced pressure of 101111810 92 201247629. The crude product was dissolved in DCM (3 mL) and the solution was washed with sodium carbonate (2 liters &apos; 0.4 M). The organic phase was separated and dehydrated by sodium sulfate filtration and concentration. The residue was purified on a ruthenium dioxide column using EtOAc (10) (95:05). 1H NMR (DMSO) δ: 0.95-1.09 (2H, m), 1.25-1.38 (2H, m), 1.59-1.71 (2H, m), 1.71-1.86 (3H, m)5 2.21-2.33 (1H, m) , 3.29(3H, s)5 3.64 (2H, d, J=7.4 Hz), 3.72 (3H, s), 6.53 (1H, d, J=8.4 Hz), 6.84 (1H,dd,J=8,4 And l_〇Hz), 6.98 (2H, s), 7.27 (1H, t, 7.6 Hz), 7.54 (2H, d, ^=8.4 Hz), 7.54 (2H, d, 7=6.4 Hz), 8.36 ( 2H, d, J=6.4 Hz), 8.35 (2H, d, J=6.4 Hz), 10.71 (1H, brs). C28H31N504 mass (calculated value) [501 59]; measured value [M+H+ Bu 502 ' RT = 1.21 (Method f) Example 11 (Method H2): 5-decyloxy-1·indolyl-3_{trans-4-[5-(1·indolyl-3-difluoroindolyl-1H-pyridyl) Azyl)-[1,3,4]oxadiazolyl]-cyclohexylmethyl}-1,3-dihydro-benzimidazole-2-ketone-N--4-(6-decyloxy曱-Mercapto-2-yloxy-2,3-dihydro-benzoimidazole-1-ylindenyl)-cyclohexanecarboxylate

OH

N-butyl carboxylic acid. HATU.DMF.TEA i 2) HCI. EtjO. DCWI trans-4-(6-decyloxy-3-methyl_2-sideoxy-2,3-dihydro-benzene And imidazole-1_ylindenyl) hexanoic acid (6GG mg '1.9 millimolar), HATU (86〇 mg, 2.3 millimolar), TEA (〇.31 ml, 23 mmol) and tillage The third brew of citric acid (H0 mg '0.83 mmol) was dissolved in DMF (2 mL) and the mixture was stirred at room temperature for 10 hours at room 101111810 93 201247629. The solvent was removed under reduced pressure and the crude product was washed with methanol to afford 610 mg of the intermediate. The solid was dissolved in kDCM (1 mL) and 2 HCl was added to diethyl ether. Allow the solution to stir over the weekend. The precipitate was filtered and washed with diethyl ether (3×5 mL). (460 mg, yield 72%). *HNMR (DMSO) δ: 1.00-1.10 (2H) m), , .26-1.36 (2H, m)s 1.62-1.66 (2H, m), 1.72-1.75 (3H, m)? 2.18-2.25 (1H , m), 3.27 (3Hj s)&gt; 3.64 (2H, d, &gt;8.0HZ)), 3.74 (3H, s), 6.63 (1H, dd, #8.0 and 1.6 Hz), 6 83 (1H,d , wind 6 Hz), 7.01 (d, 1H, "7=8.0 Hz), 10.29, (2H, bs), 10.88 (m, s) 0; 171124 〇 3 € (calculated value) [332.41]; measured Value|^+only+]= 333,RT=0.88 (method f) 1-mercapto-3-dimethyl fluorenyl-1H-B is more than 嗤-4-decanoic acid n,-[anti_4_(6_曱Oxy-3-mercapto-2-yloxy-2,3-dihydro-benzopyroxym i-yl)-cyclohexanyl]-醯肼

Anti-Ν'_4-(6-decyloxy_3_indolyl-2-ylidene-2,3-dihydro-benzoimidazol-1-ylindenyl)-cyclohexane decanoate 180 mg, 〇49 mmol, HATU (223 mg '0.59 mmol)' ΤΕΑ (0·15 ml, ι.08 mmol) and 3 _(trifluoromethyl mg, 〇, 59 mmol) ) Dissolve in a ring (2 ml) and mix at room temperature overnight. The solvent was removed under reduced pressure and the title crystal crystal crystal crystal crystal crystal 101111810 94 201247629 'HNMR (DMSO) δ: 1.00-1.10 (2H, m), 1.27-1.37 (2H, m), 1.63-1.66 (2H, m), 1.73-1.76 (3H, m), 2.13-2.20 ( 1H, m), 3.27 (3H, s), 3.64 (2H, d, JN8.0 Hz), 3.74 (3H, s), 3,95 (3H, s), 6_62 (1H, dd, «/=8.0 And 1,6 Hz), 6,85 (1H, d, ^=1.6 Hz), 7.01 (1H, d, &gt; 8.0 Hz) 8.32 (1H, s), 9.77 (1H, bs), 10.06 (1H, Bs). 匸221125?3 Can 04 mass (calculated value) [5〇8.5〇]; measured value []^+11+]= 509, RT=1.17 (method f) 5-methoxy-1-indenyl -3-·[trans-4-[5-(l-methyl_3_trifluoroindolyl-1H.pyrazol-4-yl)-[1,3,4]oxadiazol-2-yl] -cyclohexyl sulfhydryl, 3_dihydrobenzimidazole

2-keto-1-indolyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ν'-[trans-4-(6-decyloxy-3-mercapto-2-yloxy- 2,3-Dihydro-benzoimidazolylhydrazyl)-cyclohexaneindolyl]-indole (154 mg, 0.30 mmol), DMAP (185 mg, 0,97 mmol) Rhubarb xenon (92.5 mg, 0.49 mmol) was mixed in a microwave tube and irradiated at 14 °t for 15 minutes. The crude product was dissolved in mDCM (1 mL) and washed with 1 N argon (n. The organic layer was collected, concentrated under reduced pressure, and the crude product was purified by reversed phase chromatography using H.sub.2:CH3CN as an eluent with a gradient of from 05:95 to 95:05 and using hydrazine 1% formic acid as a crystal phase modifier. The title compound was isolated as a powder (43 g, yield 29%). 101111810 95 201247629 'HNMR (DMSO) 6: 1.21 (2H, dd, 12.4 and 3.6 Hz), 11.48 (2H, dd, 12.4 and 3.6 Hz), 1·72 (2H, d, /=12.6 Hz), 1.78- 1,87 (1H,m), 2.01 (2H,d, /=12.6 Hz), 2.88-2.98 (1H, m), 3.27 (3H} s), 3.68 (2H, d, /=7.4 Hz)), 3.75 (3H, s), 3.998 C3H, s), 6·63 (1H, dd, J=8.2 and 2.4 Hz), 6 85 (1H, d, 4 Hz), 7.02 (1H, d, J=8.2 Hz) 8.69 (1H, s). C23H25F: 3N6〇3 Mass (calculated value) [49〇49]; measured value [m+jj+卜491, RT=1.46 (method f) Example 12 (method HI): 3 -{trans-4-[5-(1·t-butyl _5_indolyl 2ίί-pyrazol-3-yl)-[1,3,4&gt; et aloxazol-2-yl]-cyclo己基曱基卜5_曱oxy·didecyl-1,3-dihydro-benzoxanthene-2-@同一1-third-butyl-5-mercapto-1Η-pyrazole-3-decanoic acid Ν'·[trans-4-(6-decyloxy-3-mercapto-2-oxo-2,3-dihydro-benzimidazole _ 丨-yl fluorenyl)-cyclohexaneyl fluorenyl ]-醯肼

Trans-4-(6-decyloxy-3-indolyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylindenyl)cyclohexane decanoic acid (190 mg, 1.5 mM) Moer), HATU (580 mg, Mohr) 'TEA (0.73 ml, 1.5 mmol) and 1·T-butyl-ih-pyrazole-3-decanoate (250 mg '1.3 mmol) The ear was dissolved in DMF (7 mL) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the crude material was dissolved in methanol (1 mL). The title compound was purified by reverse phase chromatography using water: acetonitrile as an eluent with a gradient of from &lt;RTI ID=0.0&gt;&gt; Separation mark? The compound was a pale yellow solid (242 mg, yield 38%). 1HNMR (DMSO) S: 1.00-U0 (2Η, m), [π] 37 (2Η, ,, 157167 (11H, m), 1.73-1.76 (3H, m), 2.13-2.20 (1H, m), 2 42 (3H, s), 3 27 (3H, s), 3.64 (2H, d, 7=8.0 Hz)), 3.74 (3H, s), 6.43 (iHj s)&gt; 6.62 (1H, d, J= 8.0 Hz)! 6.85 (1H, d, 7=0.6 Hz), 7.01 (1H, d, ^=8.0 Hz) 9.57 (1H, s), 9.65 (lH&gt; s) , C26H36N6〇4 mass (calculated value)Η %.6. ; measured value [m+h+] = 497, RT = 1.32 (method f) 3-{trans-4-[5-(1_tri-butyl-5-methyl)_[i,3 4] No. 0 diazol-2-yl]-cyclohexylmethyl}-5-methoxy_丨_曱yl·Li dihydrogen_stupid. Sodium-2-one

1-second-butyl-5-mercapto-1H-0 than argon-3-indole Ν'-[trans·4·(6-decyloxy-3-mercapto-2-yloxy-2 ,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexanecarbazyl]-oxime (240 mg, 0.48 mmol), DMAP (296 mg, 2.42 mmol), toluene Neodymium chloride (230 mg, 1.21 mmol) was mixed in a microwave tube and irradiated twice at 140 ° C for 15 minutes. The crude product was dissolved in dcm (1 mL) and washed with 1 N sodium hydroxide (10 mL) and then washed with 1 n hydrochloric acid (10 mL). The organic layer was collected, concentrated and purified by reverse phase chromatography using water acetonitrile as an eluent with a gradient of from 05:95 to 95:05 and 0.1% decanoic acid as a crystal modifier. The title compound was isolated as a powder (47 mg, yield 20%). 101111810 97 201247629 'HNMR (DMSO) δ: U5-1.26 (2H, m), 1.40-1.51 (2H, m), 1.59 (9^ s), 1.70-1.73 (2H, m), 1.82-1.88 (1H, m), 2.06-2.09 (2H, m), 2.88-2.96 (1H m) 3.28 (3H, s), 3.68 (2H, d, J=8.0 Hz), 3.75 (3H, s), 6.62-6.64 (2H , m), 6.85-6.86 (1H, m), 7.00-7.03 (1H, m). C26H34N603 mass (calculated) [478.60]; found [M+H+] = 479, RT = 3.68 (method c). Example 13 (Method I): 5-methoxy-1-methyl-3-[trans-4-(5-pyridine-4-yl-2H-*»pyrim-3-yl)-cyclohexylfluorenyl ]-1,3-Dihydro-benzo-salt sal -2- keto-trans-4-(6-decyloxy-3-mercapto-2-yloxy-2,3-dihydro- benzopyrene _ι_基曱基)cyclohexane decanoic acid methoxy-methyl-decylamine

Trans-4-(6-decyloxy-3-mercapto-2-oxo-2,3-dihydro-benzoxazole·indolylmethyl)cyclohexane decanoic acid (1.5 g, 4.72 Mol) dissolved in DMF (1 mL). Add HATU (2.15 g, 5.66 mmol), TEA (1.57 ml, 11.32 mmol) and N,0-dimercaptoamine hydrochloride (552 mg, 5.67 mmol) and mixture at room temperature Stir overnight. The solvent was removed under reduced pressure and the residue was crystallised eluted eluted eluted eluted eluted eluting The organic phase is dehydrated with sodium sulfate, filtered and the solvent removed. The title compound was purified by reverse phase chromatography using water: acetonitrile as eluent with gradients 〇5: 95 to 95:05 and 0.1% of formic acid as crystal modifier. The title compound was isolated as a powder (1.40 g, yield 82%). 101111810 98 201247629 'HNMR (DMSO) δ: 1.02-1.12 (2H, m), 1.19-1.29 (2H, m), 1.60-1.79 (5H, m), 2.55-2-62 (1H, m), 3.03 ( 3H, s), 3.26 (3H, s), 3.62-3.63 (5H, m), 3.73 (3H, s), 6.61 (1H, dd, J=8.〇 and 3.0 Hz), 6 82 (1H,d , /=3·〇hz), 6.99 (1H, d, 7=8.0 Hz) C19H27N304 mass (calculated value) [361.44]; measured value [M+H+] = 362 ' RT= 1.24 (method f) anti-acetamidine --cyclohexyl fluorenyl)-5-methoxy-1-methyl-1,3-dihydro _ benzo flavor

The methyl clock (2.8 ml of ι_6 in diethyl ether) was at _78. Add to trans-4-(6-methoxy-3-indolyl-2-oxo-2,3-dihydro-benzoimidazolylmethyl)-hexane & formic acid A solution of oxy-methyl-decylamine (1.15 g, 3.2 mmol) in dry THF (6 liters). After % minutes, it was recorded at room temperature and removed under reduced pressure. The crude product was dissolved in EtOAc (EtOAc)EtOAc. The crude product was purified by a ruthenium dioxide column using 88:12 to EtOAc: 1 hexanes. The title compound was isolated as a white solid (860 mg, yield: 85%) 〇101111810 1 99 201247629 lHNMR (DMSO) 6: 0.99-1.15 (4H, ι , 1.62-1.73 (3H, m), 1.80-1.83 (2H, m ), 2.05 (3H, s), 2.23-2-30 (1H, m), 3.26 (3H, s) 3 63 (2h dj 8 〇h 3.73 (3H, s), 6.61 (1H, dd, J=8.0 And 3.0 6 Ro ' d' J 8_0 Hz), (1H, d, /= 8.0 Hz). h (1H, d, J=3.0 Hz), 7.00 c臓4N203 mass (calculated value) [316.4G]; measured Value [福+] = 317, RT = 1.30 (method f) 1-[trans-4-(6-decyloxy-3.methyl-2-yloxyj 3 dihydro-benzimidazole-1-曱 )))-cyclohexyl]-3-π than 0-1,4-yl-internal"3

Cm (10) mg, ο·95 mmol) was added to the secret acid (ιΐ7 mg, 〇.95 mmol) in the anhydrous coffee (H). Mix the mixture for hours until completely dissolved. Draw ds (i〇4 ml, m millimolar) in a separate round bottom bottle and add it to the 耽 反 反 反 反 4 4 4 _ _ _ _ _ ) ) ) 笨 笨 笨 笨 笨 笨 笨 笨A solution of 2-ketone _ mg, 〇·95 mmoles in anhydrous THF (2 mL). The mixture was allowed to react for 3 minutes. Finally, the CDI-activated secret acid solution and the obtained mixture are added at room temperature·16 hours. Water is added, THF is added under reduced pressure, and DCM is added. The organic phase is separated, and the sulfur-dehydration solution is evaporated to remove the solvent. . The residue was purified by a second addition of cyclohexane/ethyl acetate (gradient 88 · 12 to 0. 100) and then using 1:1 acetic acid/methanol as the eluent. The title compound was isolated as oil (10) mg, yield 59%). 101111810 100 201247629 C24H27N3O4 mass (calculated value) [421.50]; measured value [M+H+] = 422, RT = 1.47 (method f). 5-decyloxy-1-indolyl-3-[trans-4-(5-pyridin-4-yl-2H-pyrazol-3-yl)-cyclohexylfluorenyl]-1,3-dihydro- Benzimidazol-2-one

Hydrazine monohydrate (0.017 ml, 0.35 mmol) was added to 1-[trans-4-(6-methoxy-3-indolyl-2-yloxy-2,3-dihydro-benzimidazole) A stirred solution of -1-ylindenyl)-cyclohexyl]-3-pyridin-4-yl-propane-1,3-dione (120 mg, 0.29 mmol) in ethanol (2 mL). The resulting mixture was allowed to stir at 70 ° C for 16 hours. The solvent was removed by evaporation and the residue was purified mjjjjjjjjjj The solvent was removed under reduced pressure and the residue was crystallised eluted eluted eluting The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The title compound was isolated as a powder (yield: 58 mg, yield: 48%). lHNMR (DMSO) δ: 0.98-1.13 (2Η, m), 1.23-1.30 (2H, m), 1.56-1.66 (2H, m), 1.67-1.81 (1H, m), 1.82-1.90 (2H, m) , 2.16-2-27 (1H, m), 3.28 (3H, s), 3·64-3·72 (2H,m), 3.74 (3H,s), 6.62 (1H, dd, J=8.4 and 2.0 Hz),6_84 (1H, d, J=2.0 Hz), 6.98 (1H, d, 7=8.4 Hz) C24H27N502 mass (calculated value) [417.52]; measured value [M+H+] = 418, RT=1.00 ( Method f) Example 14 (Method LI): 3-[trans-4-(4-ethylindolylpiperidine-1-yl)-101111810 101 201247629 cyclohexylfluorenyl]·5·ethyl bromide曱基])• Dihydro _ stupid and taste. Sit _2_嗣 ( (6 / odor 3-mercapto-2-oxooxy 2,3-di-argon-benzimidazole _ 丨 曱 曱 ))-cyclohexane decanoic acid

Methyl hard (1.1 liters, 17 32 mils) was added dropwise to the anti-o-di- 2_ side oxy 2,3-monohydro-benzo- _α-small methyl group) 7 grams of '13.32 millimoles) in a suspension of carbonated (3.99 grams, 17.32 millimoles) in DMF (10 ml). The reaction mixture was stirred at room temperature for 2 hours. The crude product was dissolved in dcm (2q mL) and water (2 (4) mL). The organic layer was separated, dried over sodium sulfate and concentrated to afford 5 g. HNMR (CDC13) 5: 1.05-1.16 (2Η, m), 1.33-1.44 (2H, m), 1.77-1.89 (3H, m), 1.97-2.02 (2H, m), 2.21-2.29 (1H, m) , 3.39 (3H, s), 3.64 (3H, s), 3.67 (2H, d, J= 8 Hz), 6.83 (1H, d, J= 8.0 Hz), 7.08 (1H, d, J= 2.0 Hz) , 7.20 (1H, dd, J=8.0 and 2.0 Hz). Trans-4-(3-methyl-2-oxo-6-tridecylsulfonylethynyl) 2,3-dihydrobenzoyl Ββ坐-1-ylindenyl)-cyclohexanyl decanoate

TEA (20 ml) 'ethynyl trimethyl decane (0.335 g, 3.41 mmol 101111810 102 201247629 ears), CuI (9) mg, 0.26 mmol (0 mol) added to the o- 1 (1) 2 84 mg 'imidazolyl group A A rolling base-2,3-dihydro-benzene people this soil has been burned formic acid® (1. 〇克 ' 2.62 亳 耳 于 loot: 糌 R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R毫』: The substance is concentrated in the process, adding acetic acid

• The hydrazine and the organic solution are dehydrated with water, and the crude product is filtered by oxidizing = ethyl phthalocyanine 1.1 柞h. The rolling s column is made of cyclohexane/B•-曰·1. Age purification. Obtained G. solid (yield 80 〇 / 〇).嗖 嗖 σ σ, HNMR (CDC.3) 5: 1.04.1, 3 (2H, m), , 3l.Ul OH, m), 1.94.1.98 (2H> m)&gt;, 2〇.2 26 (1H&gt; 3 ^ &gt; 1-74-1.87 Γ;;7·6Η&quot; anti-o-ethyl group ·3.Μ_2_sideoxy.2,3_dihydrogen 钵i•ylmethyl)· Ring hexane

\ Hydroxide | £ (15G mg, 6.28 millimoles) added to the anti-_4_(3•methyl·2_sideoxy-6-trimethyl succinyl ethynyl 2,3_dihydrobenzo flavor唾 ] • • ) • 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 835 The reaction was heated at 6 Torr for 16 hours. The reaction was concentrated under reduced pressure and the aqueous solution was acidified to 6 with 6 n hydrochloric acid to afford a dark brown IS. (4) mg of the title compound was obtained (yield 97%). 101111810 103 201247629 匸181^2(^203 quality (calculated value) [312.37]; measured value [1^+11+]= 313,RT= 1.24 (method f) 3-[trans-4-(4-ethyl Base-α bottom σ well, 1-mercapto)-cyclohexylmethyl]ethynyl-1·indolyl-1,3-dihydro-benzoimidazol-2-one

Trans-4·(6-ethynyl-3-indolyl-2-oxo-2,3-dihydro-benzopyroxy)-cyclohexanecarboxylic acid (60 mg' 0.19 m Mol) dissolved in dmf (2 ml) and then added TEA (0.032 ml, 0.23 mmol), HATU (73 mg, 0.19 mmol) and 1-ethylhydrazine (0.26 ml, 〇·23 mmol) The solution was stirred for 16 hours and then concentrated under reduced pressure. The crude product was purified using EtOAc/MeOH EtOAc (EtOAc) The title compound was obtained as a white solid (yield 25%). 'HNMR (CDC13) δ: 1.10-1.20 (2Η, m), 1.49-1.59 (2H, tn), 1.75., 85 (4H, m), 1.87-1.97 (1H, m), 2.12 (3H, s) , 2.41-2.47 (1H, m), 3.06 (1H, s) 3.40-3.50 (7H, m) 3.58-3.62 (4H, m), 3.72 (2H, d), J= 8.0 Hz), 6.91 (1H, d 8.0 Hz), 7.09 (1H, d, J= 1.6 Hz), 7.26-7.29 (1H, m). C24H30N4O3 mass (calculated value) [422.53]; measured value [M+H+]= 423,RT= 1.15 ( Method f) Example 15 (Method L2): 3-[Reverse-4-(4-ethylindolylpiperidinylmethyl)-cyclohexylmethyl]-5-(2.nonyloxy-ethyl Amino)-1-methyl-indole, 3-dihydro-bromoimidazol-2-one 101111810 104 201247629 trans-4-[3-mercapto-2-epoxy-6-(4,4,5 ,5-tetramethyl-[1,3,2]dioxaboron-2-yl)-2,3-dihydro-benzimidazole-i-ylmethyl]-cyclohexane decanoic acid. Methyl ester

CH3C02K. Pd{dppf)CI2

Trans-4-(6-bromo-3-indolyl-2-oxo-2,3-dihydro-benzopyran-1-ylmethyl)-cyclohexanecarboxylic acid decyl ester (1.0 g, 2.62 Millol), 贰 (pinacolato) diboron (0.733 g, 2.89 mmol), pd(dppf)Cl2 (0.214 g, 0-26 mmol), potassium acetate (0.90 g, 9.2 亳) Mix together, then add diterpene (10 ml). The mixture was allowed to mix for 9 hours at TC (addition of ethyl acetate (15 mL) and water (1)). The organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by dioxin/g madness using cyclohexane/ethyl acetate 4··1 as an eluent system. Obtained the title character gram (quantitative yield) C23H33BN2〇5 mass (calculated value) [428·34] 429, RT=1.74 (method f)

Trans-4·[6-(2-decyloxy-ethylamino)·3_methyl-oxy 3 benzoim-β-yl-1-ylmethyl]-cyclohexanyl decanoate

Trans-4-[3-methyl-2-oxo-6-(4,4,5,5-tetra 101111810 105 201247629 -2-yl)-2,3-dihydro-benzimidazole_ι_ Base ]] _ cyclohexane decanoate (1) 8 g ' 1.87 mmol), copper acetate (〇, 51 g, 2.8 mmol), TEA (〇 52 ml '3.74 mmol) and 2-曱Oxyethylamine (0 65 mL, 7 47 mmol) was stirred in DCM (10 mL) over EtOAc. Add water (1 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. &lt;RTI ID=0.0&gt;&gt;&gt; 150 mg of the title compound were obtained (yield 21%). (3H, m), 1.93-1.97 (2H, m), 2.17-2.25 (1H, m), 3.25 (2H, t, J= 10.4 Hz), 3,32 (3H, s), 3.37 (3H, s ), 3.59-3.63 (7H, m), 6.28 (1H, d, 2.0 Hz), 6.37 (lH) dd 8.4 and 2.0 Hz), 6,75 (1H, d, J= 8.4 Hz)· ' ' 4-[6-(2-Methoxy-ethylamino)_3_methyl_2_sideoxy-2,3-dihydro-benzoimidazol-1-ylindenyl]-cyclohexane曱acid

In the trans-4-[6-(2-decyloxy-ethylamino)_3 oxalyl-2-yloxy-2, Hong 2'HNMR (CDC13) δ: 1.02-1.12 (2Η, m), 1.28-1.39 (2H, m), 1.75-1.85 methyl hydrogen-benzoimidazol-1-ylmethyl]-cyclohexanecarboxylate (1 mg, 〇27 mmol) in THF (2 mL) Into the solution, add hydrazine (19 mg, hydrazine, 8 Torr) to water (1 mL). The mixture was stirred for 3 hours and then concentrated under reduced pressure. 1 N Hydrochloric acid (2 mL) was added and the solution was extracted with DCM (2×10 mL). The organic layer was collected and concentrated to give the title compound (yield: 67%) ???101111810 106 201247629 C19H27N304 mass (calculated value) [361.44]; measured value [m+h+]== 361, RT=0.88 (method f) 3-[Reverse-4-(4-ethyl-aryl-Nangyan-1-yl)-cyclohexylmethyl]methoxy-ethylamino)-1-indolyl-1,3- Diazo-benzoquinone

Nxx&gt;=. •0

Ο

J. TEA

DMF

W&gt;=〇Q O'trans-4-[6-(2-decyloxy-ethylamino)-3-indolyl-2-ylidene-2,3-dihydro-benzimidazole-1 - 曱 曱 ] • 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 65 125 And 1-ethylhydrazoline (28 mg, 〇 22 mmol). The solution was stirred overnight and then concentrated under reduced pressure. The crude product was firstly purified by a preparative HPLC on a silica gel column (Ac0Et/Me0H9: 1) (method: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; )&gt; $〇(5H, m), 2.05 (3H, s), 2,2-2,0 (1H, m), 3,2 (2H&gt; , J== ? 2 ^ 3;9 ^88 334 (3H, s), 3.36-3.43 (4HS m), 3.52-3.62 (8H, m), 3i9〇(m&gt;bs; 6 25 H § * piece 2·〇HZ), 6.35 (1H, dd, 2.0 and 8.4 Hz), 6 is (ih, &amp; ''C25H37N504 mass (calculated value) [47Ug]; measured 峨472, RT = 0.75 (method f) Example 16 (method L3): 3_[reverse transmission Methyl hydrazide) _ % hexylmethyl] _5 de · i • methyl and cup 2, trans-4-(tetra) _3_ fluorenyl 2 _ wei group 2, 3 _ dihydro benzophenidazole Base 101111810 107 201247629 base)-cyclohexane decanoate

Trans-4-[3-methyl-2-oxo-6-(4,4,5,5-tetrafyl-7,3,2]disamidronium-2-yl)_2,3-dihydro - Stupid and glutinous rice seven U f base] - Cyclohexane methyl formate (8 g, L87 mmol) dissolved in THF (10 ml). Hydrogen peroxide (〇 5 ml) and acetic acid (〇. 1 ml) were added and the mixture was stirred at room temperature over the weekend. The mixture was condensed under reduced pressure and then water (10 mL) and DCM (1 mL). The organic layer was separated, dried over sodium sulfate and concentrated. The residue was purified by a cerium oxide column using cyclohexane/ethyl acetate 3··7 as an eluent system. 300 mg of the title compound were obtained (yield 51%). lHNMR (CDCI3) δ: 1.05-1.15 (2Η, m), 1.32-1.42 (2Η, m), 1.77.1.88 (3H, m), 1.97-2.01 (2H, m), 2.21-2.29 (1H, m) , 3.38 (3H, s), 3.65 (3H, s), 3.66 (2H, d, J = 7.2 Hz), 6.54-6.55 (1H, m), 6.56-6.59 (1H, m), 6.78-6.80 (1H , m). &lt;:171122 committed 04 mass (calculated value) [318.38]; measured value 1 &gt; 1 + 11 +] = 319, RT = l. 〇 9 (method f) trans-4- (6-hydroxy- 3-mercapto-2·p-oxy-2,3-dihydro-benzoimidazol-1-ylmethyl)-cyclohexanecarboxylic acid

Lithium hydroxide (19 mg, 0.80 mmol) was added to water (1 mL) to anti 101111810 108 201247629 -4-(6-hydroxy-3-indolyl-2-oxo-2,3-dihydro- Benzimidazolylcarbamate oxime cyclohexane decanoate (85 mg, 0.27 mmol) in THF (2 liters). The mixture was stirred for 3 hours and then concentrated under reduced pressure. Add 丨N-hydrochloric acid (2 ml) and EtOAc (m.qqqqqqqqqqqqq Method f) 3-[Reverse-4-(4-ethylindolyl-piperidin-1-carboxyl)-cyclohexyldecyl]-5hydroxy-1-indolyl-1,3-dihydro-benzo ϋ米α sitting -2-_

Trans-4-(6-carbyl-3-indolyl-2-oxo-2,3-dihydro-benzopyrimidinyl)-cyclohexane decanoic acid (55 mg, 0.18) Mol) dissolved in DMF (2 ml), then added TEA (30 μl, 0.22 mmol) 'HATU (82 mg, 0.22 mmol) and 1-ethylhydrazine-piped (28 mg, 0.22 m) Moore). The solution was stirred overnight at room temperature. The solution was stirred overnight and then concentrated under reduced pressure. The crude product was purified by EtOAc EtOAc (EtOAc) &quot;HNMR (CDCh) δ: 1.11-1.20 (2Η, m), 1.48*1.58 (2H, m), 1.75-1.92 (5H, m), 2.13 (3H, s), 2.41-2.47 (1H, m) , 3,37 (3H, s), 3.44-3.54 (4H„ 3.61-3.69 (6H, m)5 6.55-6.56 (1H, m), 6.58-6.61 (1H, m), 6.77-6.79 (1H, m C22H30N4O4 mass (calculated value) [414.51]; measured value [M+H+] = 101111810 109 201247629 415, RT = 〇.84 (method f) Example 17 (Method B 4) · · Reverse o-ethoxy -2·Sideoxy 2,3_diamine_Benzene-salt-s-l-ylmethylcyclohexanoic acid σ than biting ice-based amine-trans-4-(6-ethoxy_3_A Base side oxy·2,3-dihydro-benzimidazole_ι_ylmethyl)-cyclohexanecarboxylic acid methyl vinegar

HO

Etl· K2C〇3 2-丁醐

Ethyl moth (36.5 μl, 0.45 mmol) was added to trans-4-(6-carbyl-3-methyl-2-oxo-2,3-dihydro-benzimidazole small methyl ) _ cyclohexanecarboxylic acid decyl ester (120 mg '0.38 mmol) and carbonic acid unloading (1 〇 4 mg, 〇75 mmol) in a suspension of 2-butanone (2 ml) and mixture at 5 Hey. Stir it overnight. Ethyl 2 μl of Ο.% millimolar was added again and the mixture was heated for a few hours. The reaction mixture was concentrated under reduced pressure. The organic solution was concentrated to give the title compound (yield: 92%). HNMR (CDOI3) 5* 1.06-1 16 ow ι λ λα 6 (2Ηί m)i ^32'1·44 (5Η, m), 1.78-1.98, m), 1.96-2.01 (2Η, m), 2.21- 2.29 (1H, m), 3.38 (3H, s), 3.64 (3H s) 3 67 (2H, d, J= 7.2 Hz), 4.01 (2H, q, J= 7.2 Hz), 6.57 (1H, d, J= 2 4 ^ ; 6; _ dd, J= 8.4 and 2.4 Hz), 6.84 (1H, d, J= 8.4 Hz). 'Anti-winter (6-ethoxy-3-indolyl-2-side oxygen) Base-2,3·dihydro-benzopyranyl-ylmercapto)-cyclohexanecapric acid 101111810 110 201247629

In the form of trans-4-(6-ethoxy-3-indolyl-2-oxo-2,3-dihydro-benzimidazole-bupyridyl)-cyclohexyl carboxylic acid (121 mg, A solution of a hydrazone clock (25 mg, 丨.05 mmol) in hydrazine (ml) was added to a solution of EtOAc (2 mL). The mixture was stirred for 4 hours. The mixture was extracted with EtOAc (3 mL). The organic solution was dried over sodium sulfate, filtered and evaporated. C18H24N204 mass (calculated value) [332.40]; found [m+h+] = 333 RT = 1.26 (method f) trans-4-(6-ethoxy-2-oxooxy-2,3-dihydro- Benzo- σ m. sit _1_ylmethylcyclohexanecarboxylic acid pyridin-4-yl decylamine

Trans-4-(6-ethoxy-3-indolyl-2-oxo-2,3-dihydro-benzimidazolyl-yl-methyl)-cyclohexanecarboxylic acid (55 mg, 0.18 m Moer), tea (30 μl, 〇 22 mM), HATU (82 mg, 0.22 mmol) and. The mixture was stirred at room temperature for 4 hours at room temperature for a mixture of <RTI ID=0.0># </RTI> </RTI> <RTIgt; The solution was concentrated under reduced pressure and the crude material was purified eluted from EtOAc EtOAc EtOAc. The title compound was dissolved in EtOAc (3 mL). -HNMR (MeOD) δ: Um.21 (2H, m)&gt; K44 (3H, t, 6.8 Hz)&gt; L5〇. 1.61 (2H, m), 1.85-2.03 (5H, m)s 2.23-2.29 (1H, m), 3.39 (3H s) 3 71 (2H d 7, Hz), 4.05 (2H, q, ^ 6, Hz)s 6,9 (1Hj dj J= 2 4 Hz)} ;(iHj dd&gt ;*j: 2.4 and 8.4 Hz),6·86 (1H, d, J= 8 4 Hz), 7·46·7 48 (2h, pyr 7 8.46-8.47 (2H, m). C21H24N403 mass (calculated value [4〇8.5G]; measured value = 409, RT = 1.11 (method f) Example 18 (method M): 5-decyloxy_3 gas decyloxy-phenyl)-[1,2, 4]»号-Sal-3-yl]-cyclohexylindolylmethyl quinone diazoloimidazole-2-one trans-4-(6-methoxy-3-methyl-2- oxo _ 2,3·Dihydro··Benzimide Sodium_ι_ylmercapto)-cyclohexane decanoate

Trans-4-(6-methoxy-3-methyl-2-yloxy-2,3-dihydro-benzoimidazolylhydrazyl)-cyclohexanic acid (5.0 g '15 7 mmol) A suspension of &lt;NMM (2 mL, 15 7 mmol) in THF (7 mL) was cooled to EtOAc. Hey. Add methacrylic acid isopropenyl ester (1 Μ 曱 ,, 15 7 ml) and the mixture was stirred at 〇c for 3〇101111810 112 201247629 minutes, then add ammonium hydroxide solution (25% in water) and any mixture to reach 6 temperate Stir for another 2 hours. Ethyl acetate and a precipitate were added, filtered, washed with ethyl acetate and dried to give 4.9 g of the title compound as a white solid (yield 98%) HNMR (CDC13) δ: 1.01-1.12 (2H, m)? 1.30-1.41 (2H m) 1 75 (3H, m), 1·88-1·91 (2H, m), 2.01-2.09 (1H, m), 3-32 (3H, s), '3.625~(H5 J- 8.0 Hz ), 3.76 (3H, s), 5.22-5.35 (2H, m), 6.49 (1H, d, J = 4.0 Hz) 6 dd, J = 8.0 Hz, J = 4.0 Hz), 6.79 (1H, d, J = 8.0 Hz). (1ϊί, C17H23N303 mass (calculated value) [317.39]; measured value [m+h+] &lt; 318, RT=1.02 (method f) trans-4-(6-decyloxy-3-methyl Benzyl-2-oxo-2,3-dihydro-benzimidazole-丨-ylindenyl)·cyclohexanecarbonitrile

Trans-4-(6-methoxy-3-indolyl-2-oxo-2,3-dihydro-benzimidazole-indole-yl)-cyclohexanecarboxylic acid decylamine (4 g, 12.6 mM) and TEA (11.4 ml, 82 mmol) in DCM (80 mL) was cooled to dryness. TFAA (2.2 mL, 15.7 mmol) was added slowly and the mixture was stirred for 2 hours. Room temperature. The organic phase was washed with water (2 x 80 mL) and a saturated solution of sodium carbonate (2 EtOAc). The organic phase was dried over sodium sulfate and evaporated under reduced pressure to remove solvent. The crude product was dissolved in EtOAc (30 mL) and water (35 mL) 101111810 113 201247629 Yield The mixture was placed in an ice bath to give 2.4 g of the title compound as a grey solid (64%). lHNMR (CDC13) δ: 1.07-1.17 (2Η, m), 1.48-1.59 (2H, , 〇1 m), 2.11-2.14 (2H, m), 2.36- 2.43 (1H. m), 3.39 (3H, s ), 3.68 (23⁄4 d , 3.83 (3H, s), 6.53-6, 54 (1H, m), 6.64-6.67 (1H, m), 6.85-6.87 (1H Hz)s N-hydroxy-trans-4- (6-decyloxy-3-indolyl-2-ylidene-23-), ~ gas-stupidimidazole-1-ylindenyl)-cyclohexane

Hydroxylamine (50% by weight solution in water, 〇·21 ml), force, main trans-4-(6-methoxy-3-indol-2-yloxy-2,3-dihydro- A solution of benzopyrene, sulphonyl-J-hexane carbonitrile (5 〇 0 mg, 1.67 mmol) in ethanol (10 mL). : Liquid back to _2^. 隔_夜' and then 1.5 equivalents of the amine and the reaction mixture were refluxed overnight to obtain a complete conversion. The solvent was evaporated under reduced pressure to give 554 mg (yield). C17H24N403 mass (calculated value) [332.41]; measured value [M+H+] = 333, RT = 0.83 (method f) 5-decyloxy-3-{reverse_4·[5-(4-decyloxy) Phenyl)_[ι,2,4]soxadiazole-3_yl]-cyclohexylmethyl}indenyl-dihydro-benzimidazole_2-one 101111810 114 201247629

Λχ EDC chlorate, HOBt, ΤΈΑ, ° 〇 ΤΕΑ (0·116 ml '0.83 mmol), ΗΟΒΤ (63 mg, 0.47 mmol) and EDC gas hydride (9 〇 mg ' 0.47 毫Mole) added to N. hydroxy-trans-4-(6-decyloxy_3_indolyl 2_sideoxy-2,3_dihydro-benzimidazole _ 丨-yl fluorenyl)- It is already late (120 mg, 0.36 mmol) in Erqi. In the recovered solution of the mountain (15 ml), the resulting mixture was allowed to stand overnight at room temperature and then refluxed overnight. The solvent was evaporated under reduced pressure and DCM (EtOAc) The organic solution was washed with water (1 mL). The organic phase is separated, dehydrated with sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLe (Method b) to afford 50 mg of the title compound (yield: 3%). HNMR (DMSO) δ: 1.15-1.25 (2Η, m), 1.39-1.49 (2H, m), 1.69-1.73 (2H, m), 1.80-1.89 1H, m), 1.99-2.03 (2H, m), 2.72-2.80 (1H, m), 3.27 (3H, s), 3.68 (2H, d, J=8.0 Hz), 3.74 (3H, s), 3,83 (3H, s), 6.62 (1H, dd, J= 8.0 Hz, J= 2.4 Hz), 6.85 (1H, d, slice .4 and 2.4 Hz), 7.0 (1H, d, “7=8.0 Hz), 7.10-7.13 (2H, m), 7.97-8.00 (2H, m). C25H28N4〇4 mass (calculated value) [448 a]; measured value [M+H+] = 449, RT = 1_73 (method f). Example 19 (Method N): N-{4-[trans-4-(6.nonyloxy-3-indolyl-2-oxo-2,3-dihydro-benzimidazole-1.yl)曱))cyclohexyl]_1Η•imidazole_2_yl}_ acetamidine 3-[trans-4-(2-bromo-ethenyl)-cyclohexylfluorenyl]·5_fluorenyl fluorenyl _丨,3_ 101111810 115 201247629 Two dressing - benzo miso-2-

3&gt;HBr48% in water, two 〇, etc.

1) Grass cockroach, DMF, DQ1 2) Trimethyl decyl diazane, THF, CH3CN

Grasshopper (0.38 ml, 4.53 mmol) and DMF (〇〇3 mL) were added to trans-4-(6-methoxy-3-indolyl-2-oxo-2,3-dihydrogen) a stirred solution of benzoimidazole hydrazinyl decanoate (1.2 g, 3.77 mmol) in anhydrous DCM (30 mL). The resulting solution was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The crude product was dissolved in THF/CH3CN (8 mL, 1:1 v/v) and the solution was cooled to 0 °C. Trimethyl sulfonyl diazonium hydride (20 M in diethyl ether, 5.7 mL, 11.34 mmol) was added dropwise and the mixture was allowed to warm to warm and stirred for 3 h. The solvent was removed under reduced pressure. Add two. number. Mountain (7 ml) to crude product and then slowly add hydrogen bromide (48% in water). The mixture was stirred at room temperature for 1 hour. Ice water and the mixture were added and extracted with DCM (5 χ 1 mL). The organic layer was collected, dried over sodium sulfate, filtered and concentrated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: 'HNMR (DMSO) δ: l.〇〇.i.2i (4H, m), 1.62-1.65 (2H,m), 1.68-1.78 · (1H, m), 1.83-1.86 (2H, m), 2.49 -2.58 (1H, m), 3.26 (3H, s), 3.63 (2H, d, J= 8.0 Hz), 3.73 (3H, s), 4,44 (2H, s), 6.62 (1H, dd, · 7=8·0 and 2.4 Hz), 6.81 (1H, d, J=2A Hz), 7.00 (2H, d, J-8.0 Hz).

Cl8H23BrN2〇3 mass (calculated value) [395 3〇]; measured value [M+H+ Bu 395/397, RT= 1.46 (Method f) 101111810 116 201247629 N-{4-[Reverse-4-(6-曱Oxygen曱 曱 _2 _2 _2 _2 _2 _2 办 办 办 办 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' '

3- [Reverse-4-(2-bromo-ethenyl)-cyclohexylfluorenyl]·5_methoxy oxime 1 3 dihydro-benzobenzene·2·_(25〇 mg, 〇.63 Millol) was added to N 胍 (192 mg, L9 mmol) in DMF 〇〇 ml). The resulting mixture was allowed to ride at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with EtOAc (EtOAc)EtOAc. lHNMR (DMSO) δ: 1.06-1.23 (4H, m), 1.62-1.658 (2H, m), 1.72-1.80 (1H, m), 1.89-1.92 (2H, m), 1.98 (3H, s), 2.25 -2.34 (1H, m), 3.27 (3H, s), 3.65 (2H, d, J= 8.0 Hz), 3.74 (3H, s), 6_35 (1H, brs), 6.62 (1H, dd, &gt; 8.0 And 2.4 Hz), 6.83 (1H, d, J=2A Hz), 7.00 (2H, d, &gt; 8.0 Hz), 10.83-11.15 (2H, m). C21H27N503 mass (calculated value) [397.48]; measured value [M+H+] = 398, RT = 0.94 (Method f) Example 20 (Method P): 5-decyloxy-1-indolyl-3-[trans-4-(4-pyrimidin-5-yl- Piper-1-ylidene)-cyclohexyldecyl]-1,3-dihydro-benzoimidazol-2-one 4-[trans-4-(6-methoxy-3-indolyl-2 - sideoxy·2,3-dihydro-benzimidazole 101111810 117 201247629 -1-ylmethyl)-cyclohexaneindolyl]-piperidin-1-decanoic acid third butyl vinegar 0

0

Q

CDI, CHSCN ' y CDI (993 mg, 6.12 mmol) was added to the anti-winter (6·decyloxy_3_methyl-2-oxo-2,3-dihydro-benzone. Small base f-based) _ cyclohexanic acid (Ig 5 g, 4.71 mmol) in acetonitrile (1 ml). The mixture was smashed for 1 hour and then added with tert-butyl-1-nital acid.酉 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 965 The organic solution was dehydrated with sulfuric acid steel by gasification (saturated solution '2x5 ml), and 2.28 g of the title compound (yield 99%) was obtained in consideration of concentration. 〇C26H38N405; mass calculated value [injury called: measured Value [_]+ = 487.4 m/z; RT = 1.48 (method f) 5-methoxy-1-methyl-3-[trans-tetradecylcarbazyl)cyclohexylmethyl]-1 , 3-dihydro-benzo-flavored π-sodium-2-one oxime.

&gt;〇 &lt;&gt;

TFA Ο boc

0CM

Si &gt;=0

Ο ο Trifluoroacetic acid (8 ml) was added to 4_[anti-o-methoxy-3-methyl-2'-oxy-2,3-dihydro-benzo-saltyl-methyl)·cyclohexane A solution of tert-butyl benzoate (2.29 g, 4.70 mmol) in DCM (20 mL) was obtained. 101111810 118 201247629 The solution was stirred at room temperature overnight and then the reaction mixture was concentrated under reduced pressure. DCM (10 mL) was added to the crude product and the organic solution was washed with EtOAc (EtOAc). The organic layer was concentrated to give h82 g of the title compound as white foam (yield). C21H30N4O3; mass (calculated) [386.50]; found [m+H]+ = 387.2 m/z, RT = 0.89 min (method f). 5-decyloxy-1-indolyl-3-[trans-4-(4-pyrimidin-5-yl-piperidinyl)-cyclohexylfluorenyl]-1,3-dihydro-benzene And σ米嗤_2_ ketone

Toluene (2 ml) was added to a mixture of Pd(〇ac)2 (6.0 mg, 0.03 mol) and BINAP (16 mg, 〇.〇3 mmol). The resulting mixture was transferred to a carbonated crop (252 mg '0.78 mmol), anti-4_(6-methoxy-3-indenyl-2-oxo-2,3-dihydro-benzimidazole_ι _ 曱 )) _ cyclohexane phthalic acid piperidinyl ester (100 mg, 0.26 mmol) and 5-bromopyrimidine (53 mg, 〇 · 34 mmol) in a vial. The resulting mixture was at 9 Torr. (: stirring and heating for 6 hours. Water (3 ml) was added, the organic phase was separated, and the aqueous layer was evaporated and evaporated. Purification by ruthenium dioxide column gave 55 mg of the title compound (yield 46%) 〇101111810 119 201247629 'η NMR (CDC13) δ: 1.11-1.22 (2Η, m), 1.50-1.60 (2Η, m), 1.77- 1.97 (5H, m), 2.43-2.50 (1H, s), 3.23 (4H, bs), 3.39 (3H, s), 3.65-3.72 (4H, m), 3.79 (2H, bs), 3.83 (3H, s), 6.57 (1H, d, J = 2.4 Hz), 6.66 (1H, dd, J = 8.4 and 2.4 HZ), 6.86 (1H, d, J = 8.4 Hz), 8.38 (2H, s), 8.75 ( 1H, s). C25H32N603; mass calculated value [464.57]; measured value [M+H]+ = 465 m/z; RT=1.12 min (method f) Examples 21 to 18 listed in the table are based on The method of column 3 was fabricated and characterized by NMR (data not shown) and HPLCMS (blocks 4, 5, 6, 7 and 8) 101111810 120 201247629 10111185121 to Example QO y ° °i5 Structural General Method 432 1 Expected value MW 1.36 1.46 Residence time 433 ON Measured value MW (M+1) 00 I—» o Pure Analytical method 201247629 101111-0 122 to Example ° ^丫ζ, U Μ ° 〇ζ^ Structural general method Ο 474 Expected value MW II 1.45 1.38 Residence time οο Measured value MW (M+1) Η-» 纯度 Purity&gt; -b Analysis method 201247629 51111810 123 Example 〇^~\ Q_z ° °fj Structural general method i § LT\ s Expected value MW 1.33 1 Residence time Os LA 8 Measured value MW (M+1) v〇Is) h—» o Purity a&gt; Analytical method 201247629 101111810 124 to Example ίΎχ 0-0 ω ” General method 00 Expected value MW U) t—» 1.17 Residence time 399 〇 Measured value MW (M+1) t—» o Η-» o Purity *-h Analysis Method 201247629 U) On the example, ' P 0=f /=z2 oH VP 0=Λ /=\ 0-0 .义ο y Structural General Method 00 Expected Value MW 1.28 t—^ 1 0.96 Residence Time to g vo U) v〇 Measured Value MW (M+1) )-4 o VO Η—^ o Purity Analysis Method 201247629 U) cyi Implementation Example 〇 y \ Q n -n P °=&lt; _/=\ % 〇Ή , , P °=\ /=\ i~\^f «? ^'Z^yjT S 〇H β. °&gt;0 1 Structural general method d to H—» 00 00 § Expected value MW 1 1.37 1.24 t—* 139 1 Residence time 6 K) v〇409 to measured value MW (M+1) VO Os VO 〇\ j Purity *-b &gt;-h Analysis Method 201247629 U) oo υο Example J TI 〇M , P r\ r\J ^J〇r\ 〇y\ ιΛ_^ζ ο 〇-〇〆Structure General Method [ 1 412 U) 1 Expected value MW 1 1.18 1.04 1_ 1.27 Residence time Hk U) U) U\ Measured value MW (M+1) VO Lh )Q \D 〇\ Analysis method 201247629 U) Example Q ύ ^ π °9. 〇ο Q ryzx i) ί Q 〇一ZV^Z,- je ¥ .义o^N1 , ώ &lt;a 结 冓 General Method 1 472 412 Expected Value MW 1.27 1.42 1.21 Residence Time &lt;Χ 1 U) OJ Measured Value MW (M+1) ν〇o Purity&gt;-b ►- +&gt; Analysis method 201247629 6 fe Example 1 &quot;Π_ Ο -z TL ο ^ ώ 〇ο sY, c/γ 〇·°^° Structure fc General method 1 to Expected value MW Η-^ U) Η-» ~ 1 1.33 ί 1 1.48 Residence time _1 g 00 4^ &lt;Χ υο Measured value MW (M+1) Η—» Ο ο Purity analysis method 201247629 Example % CV2n^Z, ° °i5 Η3Ί fly, N- 〇h3c Ί LN I. Structural general method 1 1 Η-» Expected value MW i 1.37 1 1 1.22 Residence time \U\ o 00 to measured value MW (M+1) h—» o VO Purity•&quot;b Analysis method 201247629 101111810 131 Example Q rr2x c? Q °Φ ° 0iz) Structural general method to oo Expected value MW 1.25 1 1.44 Residence time_1 I—* U&gt; v〇 Measured value MW (M+1) 00 \〇 Purity analysis Method 201247629

201247629 Οι Examples Η Η .汾Ά Vi 广,,] Structure ο 气 ο 通用 通用 § δ Expectation MW 1.42 Residence time to LT Measured value MW (M+1) 纯度 Purity &gt;-h Analysis method 201247629 Example ο . ύ O ΖγΖ, - JlQ Structural General Method Expected Value MW 1.37 1 1.31 1 Residence Time 1 __1 Ul 4^ Measured Value MW (Μ+1) H-» 〇^3 Purity*-h Analytical Method 201247629 101111810 One 35 ON 3 EXAMPLES 2 - 2s^Z, - Q rrzv^z, ° 〇zf3 General formula for the structure 474 1 Expected value MW 1.36 1.47 Residence time 469 Measured value MW (M+1) On Purity&gt;-b Analysis method 201247629 101111810 136 U \ 00 3 Example CK 0· ^ V 0 CHg q~Q crzv^z, - 〇FT k 9. Ο γ·l force b ΓΤζγΖ,: c*? II i.. o°^° General method H -* U) § Expected value MW 4.56 1.49 1 1.45 1 Residence time 414 429 Measured value MW (M+1) oo Purity »-b &gt;-+) Analytical method 201247629 101111810 137 〇\ g Example 0-0 π o ° cM 〇=P 0-0 ϋ| II i oz oz General method U) H-1 U\ Expected value MW _i 1.31 1.31 1 1.22 Residence time 1 H-* G\ U\ Measured value MW (M+1) Hk o ——Ο 纯度 Purity analysis method 201247629 101111810 138

Si Example 0-0 o° o o : 0-0 0-0 0; θ. Structural formula fe General method 'O o J-k U) Expected value MW b; cs 1.19 Residence time 00 Η-» Private measured value MW (Μ+1) Η-» oh—ko Η-^ Ο Purity 1-h Analytical method 201247629 101111810 139 ON Example\x:c\ox ^ ι oo π rrzx Γ 0-0 Structural formula r General method 1 438 474 -1 4361 Expected value MW 1.26 1.63 Residence time 6 Ό U\ to measured value MW (M+1 ) 1-k Ο Ο vg Purity »-h Analytical method 201247629 $ Example / 〇V-° 0 Fly 0. 〇y\ 21 C^-S d Structural formula σ rr General method 472 Hk 00 〇 Expected value MW 1.04 1.24 1.21 Residence time U) 419 Measured value MW (M+1) H-» o Purity analysis method 201247629 101111810 141 to embodiment F &gt;〇°Y° ^&lt;yo-〇- 〇H 〇P 21 d Structural formula a General method § Expected value MW Η—Λ H—* Residence time Ln s § Measured value MW (M+1) 1-1 〇Η-1 〇 Purity analysis method 201247629 lollu-o 142 ON Example 〇〇ολο 0 ο b 0 Ο Ο 0 5Ύχ . Such as 〇〇ο Structural general method a 'Ο 00 _ Expected value MW 0.92 Hk Η-^ Ο Η-* Η-» 停留 Residence time 464 499 499 Measured value MW (M+1) h-k Ο Οι ►—* Ο Purity *-b ι-b Analytical method 201247629 101111COI0 143 v〇Example ch3 fb: CVG force H3C, i s&gt; ύ o 0 rzYz, · o° a Structural general method &gt;—* $ § Expected value MW 1.27 0.72 0.97 Residence time b〇6 00 £ Measured value MW (M+1) H—lo yj\ Η—» 纯度 Purity&gt;-b &gt;-b Analytical method 201247629 101111-0 144 oo Example 0-0 /'l V &lt;4 Vf 〇P % 0-0 oz 9=. o $ Q m Structural general method U) δ U\ Expected value MW 1.19 1.22 1 1.59 Residence time 464 OO Lh t Measured value MW (M+1) U) H—koh—» 〇 Purity •-b Analytical method 201247629 101111810 145 8S Example on X \_1 Ten, % oz ix 0-0 oz 〇P ° S 0-0 0-2 \=/ Structure i General method oo 3 1 1 Expected value MWi \ 1.05 1.27 1.21 1 Residence time 00 measured value MW (M+l) oo VO U) 1 Purity•-h &gt;-+) •&quot;h Analysis Method 201247629 101U1S10 146 00 oo OO Example Q Air 〇. Call Y ★CvO0 h3c l OO % Miscellaneous a General method 488 KJ\ U) Hk Expected value MW 1.66 1.25 Residence time 00 VO ^Ti U) N&gt; i Measured value MW (M+1) Hi o 纯度 Purity ih Analysis method 201247629 101111810 147 Example $ Q 0 ^-O 〇Ή ο π o \ o •n Structural formula μ *&quot;d General method § 匕Η-» Expected value MW 1.02 1.49 1.34 1 1 1 Residence time 494 Ul U) to 00 K) Measured value MW (M+1) h—^ o Η-» o 纯度 Purity·-+) Analytical method 201247629 101111-0 1400 Example b ^.丫6 ,o&quot;° ao ft O 1 Structure General Method 1—* 477 U) Expected Value MW 1.04 0.99 0.96 Residence Time K&gt; oo U&gt; Measured Value MW (M+1) η-^ o Hk o Purity&gt;-h &gt;-h Analytical Method 201247629 1SU1810 149 Example 0-0 n6 &lt;y 0*0 h 0 ,丫6 oCP Structural formula is S General method 419 Expected value MW 1.24 1.26 1.08 Residence time fo o to oo Measured value MW (M+1) Hk oo 1—ko Purity*- b Analysis method 201247629 S1111810 150 ο 1 Example b 0 2_ΖΥΖ\ &quot;°6 Λ〇JCZ 0-0 rr6 z'^\ Y oc? 0-0 JY6 死 f O c? 杂 SS General method § δ Expected value MW 1.07 1.33 1.29 Residence time U) On o 434 Measured value MW (M+1) H-* o VO G\ Purity ib Analysis method 201247629 1011=810 151 ) —k δ )—fc s Hk o H—A Example Χ 2^ ° 〇VCHa rO'々, CHj ° I Structural formula ww 1 General method G\ 〇\ 1 Expected value MW H-* U) 1.07 1.02 I Residence time 冶Os 00 &lt;ϊ Measured value MW (Μ+1) Hk ov〇 H—i Ο Purity&gt;-+) Analytical method 201247629 s H—* o Example oo hz^V\. 工z^/ X wo &gt;〇xz Structural general formula Method 422 400 Ui Expected value MW 1.23 Η-^ I-k oo Residence time 423 Η—1 σσ\ Measured value MW (M+1) h—^ o H-» o Η-» Ο Purity&gt;-+5 Analysis Method 201247629 H—» § h—ko Example 0-0, Y6 1 xZ^° 5 1 Wide CHa ch3 Structural formula _ s OB General method 1 437 452 o Expected value MW 1.33 )—a 1 1.33 _1 Residence time 438 U) I-fc measured value MW (M+1) h-^ o \〇VO purity analysis method 201247629 sml-o 154 H-* )-k to H-1 Hk H-^ H-» H-* Example 0- 0 5Y6 夂z 〇, sub i CD 0 X〇12 6 0-0 9. Structural formula S s General method 1 422 Expected value MW 1.56 1—- U&gt; 1 1 1.24 Residence time 467 1 U) Measured value MW (M+1) H—* o Η-» o Purity&gt;-h Analytical method 201247629 ί —* )—* ί-^ »—k h-^ Wk U) Example “ ί ί 6 to j s^Y2^ w 丨丨o?. Structural formula ω CO ω General method δ 6 Expected value MW 1 j 1.00 1.02 1.02 Residence time I 434 6 〇\ 6 Measured value MW (M+1) h-^ Ο U\ 纯度 Purity _1 ►-+) Analytical method 201247629 t —ι oo Η-» H-* Hk H-1 ON Example 0-0 r&quot;6 to °Λ 0-0 0&quot;1 S'2YZ-. 9. CD xz^° Structural formula S s General method 420 444 Expected value MW H—^ On 1.21 1.05 Residence time to U\ Measured value MW (M+1) v〇H-* o VO Purity analysis method 201247629 Η-^ κ&gt; h —k 1—^ Η-* Η-* Example xz ό Ζ·0 rtb Λ〇Χ2 6 ch3 Structural formula ο W w General method § 408 446 Expected value MW 1 1 1.04 1.05 ι_ 0.63 Residence time 实 Measured value MW (M +1) Η—^ Ο νο Purity&gt;-h ·&quot;+) Analytical method 201247629 1—» Η-» Η-» Example 2: , y6 Λ, ζ 〇- , γ6 γ/. 0 _y~d 0 &gt;〇ΐΖ Structural formula S α General method 1-1 § § Expected value MW Κο )—Λ 0.93 1.15 Residence time private Ul 5 ν〇Ο Measured value MW (M+1) Η-^ Ο Η- 1 Ο 'Ο 00 Purity&gt;-+) Analytical method 201247629 to Η-» Ι—ι Example 丨CHa Ρ ΖΙ r/6 Λ〇ΙΖ 6 Ο \ 〇~工结构式dd ω ω General method Ο h—ι Οο Expected value MW 1 1.07 0.68 0.91 Residence time • Η-» 472 I 实 Measured value MW (Μ+1) Ό 00 Purity ^ *-b Analysis method 201247629 H-^ Example 〇-A° 0 5. 丫, o X b SO \ 0 xz^° .6 0*0 y % Structural formula! o σ s General method o 482 434 Expected value MW 0.98 1.29 Residence time 00 U) 6 U\ Measured value MW (M+1) o VO VO 00 Purity o Analysis method 201247629

Hk H-* y Co i-* Example 0-0 x -. $ J= r% O- ? % 0*0 &quot;9 /TV 2'〇^ Structure s , General Method U) 466 iS U) Expected value MW 1.15 1.17 1 t-1 Residence time U) 00 467 1_ 424 Measured value MW (M+1) o 00 00 v〇On Purity h~K 201247629 ί—» U) Os U) U\ Η-» Example s 0° 01 rf6 ό cf , γδ D&quot; a ϋ o O General method ai δ Expected value MW 0.96 0.97 g Residence time ί: 00 454 Measured value MW (M+1) )—* o H-* o Purity »- h &gt;-b analysis method 201247629 U) οο Ui embodiment χ 2^° 6 x . R〇y', \^y F“XX&gt;. CHj •n \ 0° xz^° ό Structure ο oo General Method 1 u&gt; οο Hi 470 § Expected value MW 0.71 0.96 Residence time U) οο K) h—i Fe MW (M+1) Ό Ό Ul Purity *-b *-h Analytical method 201247629 Η-» Hk Private Hk I-* g Example Q w °o xz 6 br,6 Dx° J- p 01丫6 x^o 6 Structural formula td 2 General method 466 U) 00 Expected value MW g . 1-^ 0.71 Residence time 〇\ &lt;1 U) 00 K) Measured value MW (M+1) ) 〇VO VO Ul Purity *-b Analysis method 201247629 Hk )—* Η—* Example 0-0 Less 0 % b 0 , 丫6 ολο 6 Structural S General method Η-* Expected value MW 1 2.57 1.28 1.24 Residence time 1 1 427 1 1 ! 468 00 to measured value MW (M+1) o Ό 〇 purity o analysis method 201247629 h-* 矣Hi Example 0-0 0&quot;1 /^2 〇\ ' ^ &gt; ZO 2 ^ 〇? o, ° 0 iY6 rT &lt;?z Γ° ύ r% 〇, substructure s 3 General method 450 466 U) Expected value MW 1.29 ►—* to Ui Residence time Ch £ Measured value MW (Μ+1) ooh—» 纯度 Purity ο Analysis method 201247629 1011118 10 167 Η-* h—kh—k δ Example 0 ί 0 Χ2,. p ύ xz^° 6 Q { S2YZ\ u °0 c/Ύ 6 0*0 JY6 xz of o υ σ w S General method Read U) Hk \〇§ Expected value MW ! 0.61 0.72 0.93 1.39 1 Residence time I 494 472 1_ o 6 &lt;1 Measured value MW (M+1) 〇\ H—ko 1 Purity: _1 *-+) Analytical method 201247629 101111-0 168

Ln )—» Examples § Cj CN Λ〇 '1, %·Λ X». %N 0-0 严丫2, \ Structure E5 lH General method Ό 00 1 Expected value MW 1 h—» c 1.19 Residence time 矣o &amp; Η-» Measured value MW (M+1) VO Hk o Purity ih * -+&gt; Analysis method 201247629 U\ 00 Η-» Example rOXr〇Ον~Ό&gt; CH^ eg 〇-A°P 0 P r% IZ^° 6 Structural formula 1 〇σ 〇General method 494 Ο 4^ to Expected value MW o σ\ § 0.83 _i Residence time δ § 473 Measured value MW (M+1) Η-» oh—* o Purity ^-b *-+&gt; Analysis method 201247629 101111-0 170 σ; H—kgf— * a Example Crt, ° -Π 0-0 K( rth •n O'? K\ 〇-2n^2·^: j1 x : z6 Structural formula.^ General method ON ui Η-» U) Expected value MW 1 —* )—k 1.18 Residence time 447 g Os MW (M+1) H-* 纯度 Purity analysis method 201247629 101111810 171 t—kh—» 1 Example 1 0-0 ¢ ( J _f~〇o-7 S\ / Cr^ 0§ 〇C^ rT 5,z Structural formula 1 S δ General method 1 417 Expected value MW 1 1.15 j η-ι K) 1.16 Residence time ___ _ j f5 h—^ 矣KJ\ Η-^ 00 MW (M+1) | H—» oo Purity _1 *-+5 points Method 201 247 629

201247629 S1111810 173 δ Example zx d »Work W° $ 2X ύ ό Structure wo General method g Lh H-* U) 期望 Expected value MW 1—k 1.06 1 3.17 Residence time 〇\ 414 o Measured value MW (M+1 ) 〇Η 〇Η -» o purity &gt; -bo analysis method 201247629 ui Kk K&gt; 1 -» Example ~. Name ο \ ζχ cS 2-2 u1 o^° ή $ zx ύ Structural O General Method 1 Co U) Expected value MW 1.02 1.43 1.15 Residence time h—^ 420 Measured value MW (M+1) Η-» o VO • Purity&gt;-+) Analytical method 201247629 51111810 175 Η—* Η-* t—^ 1 Example HiC•. ~ ch3 *η 0-0 ο-ζ ^ 〇Η Or4, 〇Μ / ρ 0 1 Structural Formula X 1 General Method 457 437 I l—i ί—k 1 Expected Value MW 1.06 1.25 I 1.08 Residence Time 1 00 6 00 h —* to measured value MW (M+1) 1—» Ο Ό 00 Purity analysis method 201247629 HA 1—k Example—π 0-0 0-2 ±1′ *η 0-0 Ή cvo-P ^Χςχ: °ι0 ch3 Structural general method 1 δ to expected value MW 2.73 1.28 h—» Residence time 6 00 U) 〇 Measured value MW (M+1) Hk oo VO ^J\ Purity o 1-b Analysis method 201247629 S1111810 177 Η- * ι—» 00 Η-* Example Π 0-0. Mine, Η 〜0, 巩0 Λ^ν Ά °Χτ〇K^r°\ 0 Structural formula δ General method έ 3 1 Expected value MW 1.22 1.22 1.19 Residence time - 实 Measured value MW (M+1) Ό ΟΟ Ο ο Purity·-+) *-b Analysis Method 201247629 Η-» oo KM cc The example is called. ~. :ΟγΓΆ0〆, Ν-Ν τι 〇-〇ο-ζ ν-Ρ ^·2 ο η 0-0 VoP Structural formula S δ General method 1 1 Expected value MW 1.06 3.05 •ΰ Residence time measured value MW (M+1) \〇U) — Ο o Purity Ο o Analytical method 201247629 101111810 179 §8 h—* oo H-* 〇〇〇\ 1 Example 1 1 0-0 0&quot; 7 cM 9H3 CH3 HN N -. ~Χςζχν〇CH, 〇Structural general method 444 1 〇ON 1 Expected value MW I 1.04 1 1.57 1 1.00 Residence time 445 1 1—* i 457 Measured value MW (M+1) U) KT\ v〇OO Purity analysis method 201247629 Each of Examples 1 to 118 constitutes an individual specific example of the present invention, and the ICso value is shown to fall between 35 nM and 23 μΜ in the aforementioned notification sub-assay analysis. Examples 1 to 188 showed negligible effects in the reading of the jellyfish enzyme. In addition, the representative compounds selected were not evaluated as inhibitors of luciferase. Examples 185, 186, Ϊ53, 22, 6b 115, 72, 152, 121, 1〇6, 147, 182, 161, 68, 92, 71, 29, 14 and 1 show 32 ηΜ in soft agar assay analysis IC50 values up to 2.9 μΜ. 101111810 180

Claims (1)

201247629 VII. Patent application scope: 1. A compound of formula I, 0) where, as valence and stability permit: Any carbon atom bonded to carbon may be replaced by a fluorine atom; 乂1 is 0112 or N; X2 is CR3 or N; • YQ is (Ry) (Ry)n J- NR.-Q : J_N^ : Q is (^-(:6 linear, branched or cyclic alkyl, alkyl fluorenyl, oxyalkyl, dioxyalkyl, alkylamino fluorenyl, oxyalkylamine amide, wherein Any of the fluorenylene groups may be substituted with a pendant oxy group; a C5-C1G aryl or heteroaryl group, the selectivity 101111810 181 201247629 is substituted with 1, 2 or 3 groups selected from the group consisting of: CrC6 linear, branched Or % oxime, oxygen ox, arylamino, arylaminomethyl thiol, oxyalkylamino, oxyalkyloxy, nitroalkyloxy, dentate, cyano, or C5-C6 A aryl or heteroaryl group is selectively substituted with an i atom, (^_(: 3 county, CrC3 oxyalkyl; R^H, F; C1; Br; 〇H; CN; linear, branched or cyclic CrC6 alkyl group &amp; fast radical, oxyalkyl, oxyalkenyl, oxyalkynyl, alkynyl, alkynyl, alkyloxy, alkenyloxy, neoyloxy, di-anoyloxy, An oxyzolidineoxy group, a oxy group, a dialkylamino group, an oxo group, an alkyl group, an alkyl group, optionally substituted with - or a plurality of F or CN; (: 5-(( : 6 aryl fluorenyl or heteroaryl methyl or aryl decyloxy a heteroaryloxy group, wherein the aryl or heteroaryl moiety is optionally substituted with a methoxyl, a fluorene atom or a CN group; R2 is hydrazine or C1 ; R3 is Η, C1 or F; R4 is Η or C1; is converted to &quot;^3 linear, branched or cyclic New Zealand; Rx is H; linear, branched or cyclic Ci_C3 filament; η can be zero, 1, 2 or 3. When η = 2 or more, R _ y are each independently F; linear, branched or cyclic C "C3 alkyl; or % forms a pendant oxy group with its attached carbon atom 4; Is N, 〇 or s; 101111810 182 201247629 its tautomers, optical isomers and pharmaceutically acceptable salts; with the following exceptions: V 101111810 183 201247629 2. A compound of the formula 1 wherein the compound has the formula (I-bis): r〇Y_Q )=° Rs (I-bis) where, as valence and stability permit: the carbon atom bonded to the carbon may be replaced by a fluorine atom; 101111810 184 201247629 X2 is CR3 or N; -YQ is 0 (Ry) n 〇 &&quot; (~n eight _Q: human hair;, in Q: 卩 is 匕7-6 linear, branched or cyclic alkyl, alkyl fluorenyl, oxyalkyl, dioxyalkyl, alkylaminomethyl thiol, oxyalkylamino fluorenyl, any one of which The methyl group may be substituted with a pendant oxy group; a C5-C1() aryl or heteroaryl group, optionally substituted with 1, 2 or 3 groups selected from the group consisting of: Cl-C6 linear, branched or cyclic An alkyl group, an oxyalkyl group, an alkylamino group, an alkylaminomethyl fluorenyl group, an oxyalkyl group, an alkyloxy group, an alkyl group, a halogen atom, a cyano group, or a cs_c6 group or a heteroaryl group, optionally substituted by a halogen atom, a CrC3 alkyl group, or a crC3 oxyalkyl group; Ri is Η, F, C1; Br; 〇H; CN; linear, branched or cyclic^, a base group, a gynecological group, Alkynyl, oxyalkyl, oxyalkenyl, oxyalkynyl, nitrogen, nitrogen 101111810 185 201247629 alkynyl, alkoxy, county, oxooxy, bis(10)yloxy, oxynitridyloxy, a nitrogen-based oxy group, a di-silylamino group, an oxy-silanyl group, a azoalkylamino group, optionally substituted with - or a plurality of MCN; an arylmethylamino group or a heteroarylmethylamino group or Cvc6 arylmethyloxy or heteroaryl The methyloxy group at which the aryl or base moiety is lion-substituted by one or more CrC3 filaments, Ci-C-oxy group, (tetra) or CN group; R2 is hydrazine or C1; R3 is Η , C1 or F; R4 is Η or C1; Rs is a linear, branched or cyclic alkyl group of Cl-C3; Rx is Η; linear, branched or cyclic CrC3 alkyl; n may be zero, 1, 2 or 3; When η=2 or more, Ry is each independently ρ; linear, branched or cyclic CVC3 alkyl; or % forms a pendant oxy group with its attached carbon atom; its tautomer, optical isomer And pharmaceutically acceptable salts. 3. A compound according to claim 1 or 2, wherein the oxime is 0^6 linear, branched or cyclic, sinter, oxyalkyl, dioxyalkyl, orthoamine a fluorenyl, oxomethylthioglycan group, wherein any fluorenylene group may be substituted with a pendant oxy group; a C5_C6 filament or a heterofilament, optionally substituted with 2 or 3 groups selected from the group consisting of : linear, branched or cyclic filaments, oxygen filaments, alkyl filaments, silky methyl sulfonyl groups, oxyalkylamino groups, oxooxy groups, oxyalkyloxy groups, halogen atoms, cyano groups, or 101111810 186 201247629 a base or a heteroaryl group, optionally substituted by a halogen atom, a crC3 alkyl group, or a Ci_c oxyalkyl group; and wherein X, X2, X3, Y, ruthenium, r2, r3, r4, &amp; The scope of patent application is defined in item 1 or 2. 4. The compound of claim 1 or 2, wherein X1 is CR2; R2 is Η; cr3; -Y-Q is Q is 1 to 3 (: 1-(:3 alkyl-substituted pyrazolyl, wherein one or more carbon-bonded hydrogen atoms may be substituted with a fluorine atom; R4 is oxime; and RrRs and Rs thereof They are respectively as defined in claim 1 or 2. 5', as claimed in claim 4, the compound is selected from the following 101111810 187 201247629 101111810 188 201247629 6. The compound of claim 1 or 2, wherein 乂1 is 0112; R2 is Η; Χ2 is CR3; • Q-Y is ο Q is a β-fluorenyl group; R! is a linear, branched or cyclic CrC6 oxyalkyl group, an oxyalkenyl group, an oxyalkynyl group, an alkyloxy group, an oxyalkyloxy group, an oxynitride group, a azoalkyl group. Alkyl; R4 is hydrazine, and wherein R3, R5 and Rx are as defined in claim 1 or 2, respectively. 7. A compound as claimed in claim 6 which is selected from the group consisting of 101111810 189 201247629 8. The compound of claim 1 or 2, wherein 乂1 is (: 2; R2 is Η; X is CR3, -Q-Y is 〇 Q is a 4-π ratio σ group, R! is a linear, branched or cyclic CrC6 alkyloxy group, alkenyloxy group, oxyalkyloxy group, dioxyalkyloxy group, oxyalkylamine group, selectivity The ground system is replaced by F or CN; R4 is Η; and the R5 system thereof is as defined in claim 1 or 2, respectively. 9. A compound according to claim 8 which is selected from the group consisting of: 101111810 190 201247629 101111810 191 201247629 10. The compound of claim 1 or 2, wherein X^CR2; R2 is Η; Χ2 is CR3; I is a linear, branched or cyclic CrC6 alkyloxy or oxyalkyloxy group; R3 is F ; is Η ; and it is defined in X3, YQ, R5, item 1 or 2. 1!·If the compound of the patent application range is the same, the knowledge, η and Ry are respectively as follows: 3 Hai compound is selected from 101111810 192 201247629 201247629 R4 Rs (l-ter) where, as valence and stability permits: any carbon atom bonded to a carbon atom is substituted; Χι is CR2; R2 is Η; 乂2 is CR3; Q is crc3 linear, branched or cyclic The core is OH, linear, branched or cyclic Ci_c, base, dilute, alkynyl, oxygen 101111810 194 201247629 alkyl, oxyalkyloxy, oxyalkylamine; R4 is Η, R3 Is Η, Cl or F; Rule 5 is (: 1-〇3 linear, branched or cyclic alkyl; η can be zero, 1, 2 or 3; when η = 2 or above, Ry is independently F Linear, branched or cyclic CrC3 alkyl; or Ry together with the carbon atom to which it is attached form a pendant oxy group; tautomers, optical isomers and pharmaceutically acceptable salts thereof. The compound of Item 12, wherein R! is a linear, branched or cyclic CrC6 alkyl group. 14. A compound according to claim 12, which is selected from the group consisting of the following: 101111810 195 201247629 Compounds of class 1 or 2, of which 15. such as the scope of the patent, Chu &amp; Χ is CR2; R is Η; or cyclic alkyloxy; Ri is C1-C3 linear 乂2 is CR3, R3 is R4 is Η; -QY is ~~NRX—QQ is a C5-C10 aryl or heteroaryl group, optionally substituted with i, 2 or 3 groups selected from the group consisting of: CrC6 linear, branched or Cyclic alkyl, oxyalkyl, alkylamino, alkylaminocarboxamyl, oxyalkylamino, oxyalkyloxy, azocarbonyloxy, halogen, chaotic, or Cs- The C6 aryl or heteroaryl group is optionally substituted with a tooth atom, a CVC3 danyl group, a C1-C3 oxyalkyl group; and wherein Rs, Rx, and η are each as defined in the first or second aspect of the patent application. 16. The compound of claim 15 which is selected from the group consisting of: 101111810 196 201247629 CH, 201247629 Ch, 101111810 198 201247629 CH, 101111810 199 201247629 π·A compound of claim 1 or 2, which is used for the preparation of a medicament, in particular for the treatment of cancer, pulmonary fibrosis, renal fibrosis, ischemic nerve injury or multiple sclerosis Preparation. 18. The compound of claim 1 or 2 of the patent scope is used for the treatment of 101111810 200 201247629 from any of the following cancers: lung cancer, colorectal cancer, pancreatic cancer, breast cancer, melanoma, glioblastoma , medulloblastoma, gastric cancer, hepatocellular carcinoma, basal cell carcinoma, leukemia, Wilm-type tumor, familial adenomatous polyp. 19. A pharmaceutical composition comprising a compound of any one of claims 1 to 16 in admixture with a pharmaceutically acceptable carrier or excipient. 20. A method of treating a disease, condition, or dysfunction that benefits from inhibiting a Wnt pathway, the method comprising administering to an individual in need thereof an effective amount of a compound of any one of claims 1 to 16. . 101111810 201 201247629 IV. Designation of representative drawings: (1) The representative representative of the case is: None (2) The symbol of the symbol of the representative figure is simple: None 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 101111810 2