TW201124414A - Trisubstituted derivatives of 9H-beta-carboline (or 9H-pyridino[3,4-b]indole), preparation thereof and therapeutic use thereof - Google Patents

Abstract

Products of general formula (I): in which R3 represents heteroaryl of 5 or 6 ring members with 1 to 4 heteroatoms chosen from N, S or O, which is optionally substituted; R5 represents, in particular, Hal; OH; alkoxy; -Y-alkyl (Y=S, SO, SO2); -X-aryl or -X-heteroaryl (X=O, S, SO, SO2); -NH2, -NH(alkyl), -N(alkyl)2; -NH(aryl); -NH(heteroaryl); -N(alkyl)(aryl); -N(alkyl)(heteroaryl); -C(O)OH; linear -C(O)Oalkyl; -C(O)Oaryl; -C(O)Oheteroaryl; -CONH2; -CONH(alkyl), CON(alkyl)2; -CO-heterocycloalkyl; -CON(alkyl)(aryl); -CON(alkyl)(heteroaryl); linear, branched or cyclic -C1-C10 alkyl; aryl; heteroaryl; heterocycloalkyl; -C2-C6 alkenyl; -C2-C6 alkynyl; R6 represents, in particular, H; Hal; -OH; alkoxy; O-cycloalkyl; -Y-alkyl (Y=S, SO, SO2); -NH2; -NH(alkyl); -N(alkyl)2; -C(O)OH; -C(O)Oalkyl; -CONH2; -CONH(alkyl); CON(alkyl)2, linear, branched or cyclic C1-C10 alkyl optionally comprising a heteroatom; aryl; all optionally mono- or polysubstituted; and also the isomers and salts of said products of formula (I), and the therapeutic use thereof for treating cancer.

Description

201124414 VI. INSTRUCTIONS OF THE INVENTION: FIELD OF THE INVENTION The present invention relates to 9Η-β-carboline (or 9H-pyrido[3,4-b], indole) derivatives, their preparation and their therapeutic use. The present invention relates to compounds which act on protein kinases which are involved in the development of cancer. More specifically, the invention relates to compounds that act on a target known as Pim, which is involved in the development of cancer. [Prior Art]

Pim kinases (including Pim_i, pim_2, and Pim-3) constitute a unique family of serine/threonine kinases and function in cell growth, differentiation, and apoptosis. One of the mechanisms by which Pim kinase increases cancer cell survival and promotes cancer development involves the regulation of the activity of BAD, a key regulator of apoptosis. Pim agitation is highly homologous to each other and shows similar carcinogenic properties. Clinical reports highlight the importance of the role of Pim kinase in the development of human cancer. Abnormal expression of Pim kinases (especially pim_丨 and Pim-2) has been found in many malignant blood diseases. Amson et al. report excessive expression of Pim-1 in acute myeloid leukemia and acute lymphoblastic leukemia, and excessive expression of Pim-i in multiple leukemias appears to be caused by poor activation &,., Vol. 86, 8857-8861 (1989) ). Studies have demonstrated overexpression of Pim-1 in primary and metastatic lymphoma of the CNS (invasive form of non-Hodgkin's lymphoma) (Rubenstein et al., 5/oW, p. Vol. 9, No. 9, 3716-3723 (2006)) 〇Htittmann et al. also found excessive expression of Pim-2 in chronic B-cell lymphocytic leukemia, and proposed 152238.doc 201124414

Upregulation of Pim-2 may be associated with a more aggressive development of the disease 20,1774-1782 (2006)). Abnormalities in Pim-1 and Pim-2 are associated with multiple myeloma (Claudio et al., Vol. 100, No. 6, 2175-2186 (2002)). Diffuse large cell lymphoma has been identified (Pasqualucci et al, Vol. 412, 2001, pp. 341-346 (2001)) as well as standard Hodgkin lymphoma and nodular lymphocytes. Hypermutation of Pim-1 in Hodgkin's lymphoma (Liso et al., Vol. 108, No. 3, 1013-1020 (2006)). Many studies have also found that abnormal expression of Pim kinase is associated with various non-hematologic human cancers (prostate cancer, pancreatic cancer, head and neck cancer, etc.), and the presence of abnormally expressed Pim kinases is often associated with more aggressive phenotypes. For example, both Pim-1 and Pim-2 are involved in prostate cancer (Chen et al., Μσ/. 3(8) 443-451 (2005)). Valdman et al. have demonstrated that Pim-1 is up-regulated in patients with prostate cancer and in advanced intraepithelial neoplasia (precancerous lesions) (772e TVoWaie, (60) 367-371 (2004)), and Dai et al. suggest that overexpression of Pim-2 in prostate cancer is associated with more aggressive clinical features (77/^ 尸~1^<3, 65:276-2 86 (2005)). Xie et al. found a significant up-regulation of 44 kDa Pim-1 (Pim-1 L) in human prostate tumor samples, and noted that Pim-1L has anti-apoptotic effects on human prostate cancer cells in response to chemotherapeutic drugs. 25,70- 78 (2006)) °

Pim-2 is associated with peri-infiltration (PNI), which invades the nerves around the nerve during infiltration, which is commonly found in certain cancers, such as the former 152238.doc 201124414 adenocarcinoma 'pancreatic cancer, cholangiocarcinoma and head and neck cancer (Ayala et al., Cawcer inward 64, 6082-6090 (2004)). According to Li et al, Pim-3 is abnormally expressed in human and murine liver cancer and human pancreatic cancer tissues (Cancer Λα. 66 (13), 6741-6747 (2006)). Abnormal manifestations of Pim-3 were also observed in the metastatic sites of gastric adenomas and gastric cancers (Zheng et al., C. Caw. Res. Clin. Oncol., 134:481-488 (2008)). In summary, these reports Pim kinase inhibitors are useful in the treatment of cancer, particularly leukemia, lymphoma, myeloma, and various solid tumors, such as, for example, head and neck cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, and oral cancer. Since cancer has so far been a disease that is not curated by existing treatments, it is clear that there is a need to identify novel Pim kinase inhibitors that are effective in treating cancer. SUMMARY OF THE INVENTION The present invention relates to the products of the following general formula (I):

Wherein -R3 represents a heteroaryl group consisting of 5 or 6 ring members, wherein 1 to * are heteroatoms selected from n, s or oxime, which are bonded to the porphyrin unit via C or via R3iN, R3 Monosubstituted or polysubstituted as appropriate; -R5 is selected from the group consisting of: halogen; 2··〇Η; 152238.doc 201124414 3. Linear or scalloped alkoxy, wherein the alkyl moiety is monosubstituted, as the case may be Substituted or trisubstituted; 4. Linear or branched _γ-alkyl (Y==S, s〇, s〇2), optionally substituted, disubstituted or trisubstituted; 5. -X-aryl (X=〇, s, s〇, s〇2), monosubstituted, disubstituted or trisubstituted as appropriate; 6. -X-heteroaryl (X=〇, s, s〇, s〇2), Wherein the heteroaryl group is monosubstituted, disubstituted or trisubstituted as appropriate; 7. -NH2; 8. linear, branched or cyclic -NH(alkyl) and -N(hospital based) 2, wherein the The yl moiety is optionally substituted, disubstituted or trisubstituted; 9. -NH(aryl)' wherein the aryl moiety is optionally monosubstituted, disubstituted or trisubstituted; 10. -NH(heteroaryl), Wherein the heteroaryl moiety (having 5 or 6 ring members (of which 1 to 4 heteroaryl groups selected from heteroatoms of N, S or hydrazine are optionally substituted, disubstituted or trisubstituted via C or via N bonding to a nitrogen atom; 11. -N(alkyl)( An aryl group, wherein the (linear, branched or cyclic) alkyl moiety and the aryl moiety are optionally monosubstituted, disubstituted or trisubstituted; 12. -N(homo) (heteroaryl), Wherein the (linear, branched or cyclic) alkyl moiety and the heteroaryl moiety (having 5 or 6 ring members (wherein i to 4 heteroatoms selected from N, S or fluorene) a group, via c or via an N bond to a ruthenium atom), optionally substituted, disubstituted or tripled, 152238.doc 201124414 generation; 13. -C(0)〇H; 14. straight chain, branched chain or cyclic -C(〇)decylalkyl, optionally substituted, disubstituted or trisubstituted; 15·-C(0)0 aryl, optionally substituted, disubstituted or trisubstituted; 16. -C(0 a heteroaryl group (having a heteroaryl group having 5 or 6 ring members (1 to 4 of which are selected from hetero atoms of N, S or hydrazine) bonded to the oxygen via a c atom) , disubstituted or triple substituted; 17. -CONH2 ; a straight chain, a branched chain or a cyclic -CONH(alkyl) group and a CON(alkyl)2 group, wherein the alkyl moiety is optionally substituted, disubstituted or trisubstituted; 19. -CO-heteroalkyl group, Mono-, di- or tri-substituted; 20. -CON(alkyl)(aryl), the alkyl group is a straight chain, a branched chain or a cyclic group, wherein the alkyl group and the aryl moiety are optionally substituted by a single Substituted or trisubstituted; 21. -CON(alkyl)(heteroaryl)'alkyl is straight chain, branched or cyclic, and heteroaryl has 5 or 环 ring members (including 丨 to 4) a hetero atom from hydrazine, S or hydrazine, which is bonded to a nitrogen atom via c or via hydrazine, wherein the alkyl group and the heteroaryl moiety are optionally monosubstituted, disubstituted or trisubstituted; Branched or cyclic _Ci_Ci 〇 alkyl, optionally containing a hetero atom and optionally substituted, disubstituted or trisubstituted; 23. aryl, optionally substituted, disubstituted or trisubstituted, 152238.doc 5 • 9· 201124414 24. Heteroaryl, optionally substituted or polysubstituted; 2 5. Heterocyclic alkyl group, as appropriate, monosubstituted or polysubstituted; 26. -C2_C6, The mono- or poly-substituted ' 27. -C 2 -C 6 alkynyl group, optionally substituted or polysubstituted, -R6 is selected from the group consisting of: 1. oxime; 2. halogen; 3. -ΟΗ; 4. straight or branched chain Alkoxy, wherein the alkyl moiety is optionally monosubstituted, disubstituted or trisubstituted; 5. Ο-cycloalkyl, optionally substituted, disubstituted or trisubstituted; 6. straight or branched - Υ Alkyl (Y=S, SO, S02), optionally substituted, disubstituted or trisubstituted; 7. -NH2; 8. Linear, branched or cyclic -NH(alkyl) and -N(alkane Wherein the alkyl moiety is optionally substituted, disubstituted or trisubstituted; 9. -C(0)0H; 10. linear, branched or cyclic -c(o)oalkyl, a monosubstituted, disubstituted or trisubstituted; 11. -conh2; 12. straight chain, branched or cyclic -CONH(alkyl) and CON(alkyl)2, wherein the thio moiety is optionally substituted , disubstituted or trisubstituted; 13. linear, branched or cyclic C1_C 1 alkyl, optionally containing 152238.doc •10· 201124414 and optionally substituted, disubstituted or trisubstituted; .aryl 'optional Substituted, disubstituted or trisubstituted; the product of formula (I) is any possible racemic, enantiomeric or diastereomeric form 'and the product of the formula (I) and the inorganic acid And addition salts of organic acids or inorganic and organic tests. The invention relates in particular to compounds of the general formula (I): as defined above, wherein R3 and R6 are selected via the meanings indicated above, and R5 is selected from the group consisting of: 1 · halogen; 2. -OH; a straight or branched alkoxy group, wherein the alkyl moiety is optionally monosubstituted, disubstituted or trisubstituted; 4. -NH2; 5. linear, branched or cyclic _NH(alkyl) &_N (alkyl h, wherein the alkyl moiety is optionally monosubstituted, disubstituted or trisubstituted; 6· _NH(aryl)' wherein the aryl moiety is optionally substituted, disubstituted or trisubstituted; NH(heteroaryl), wherein the heteroaryl moiety (heteroaryl having 5 or 6 ring members (wherein 1 to 4 heteroatoms selected from N, S or oxime) is via C or via an N bond a nitrogen atom is optionally substituted, disubstituted or trisubstituted; 8. _N(alkyl)(aryl)' wherein the alkyl moiety (straight chain, branched chain or cyclic) and the aryl moiety are The situation is monosubstituted, disubstituted Ge = substituted; 152238.doc -11 - 201124414 9 · -N(alkyl)(heteroaryl), wherein the alkyl moiety (straight chain, branched chain or And a heteroaryl moiety (having a heteroaryl group having 5 or 6 ring members (wherein 1 to 4 heteroatoms selected from n, s or fluorene) is bonded via N or A nitrogen atom) may be monosubstituted, disubstituted or trisubstituted as appropriate; 10. -C(0)0H; 11' straight bond, branched chain or cyclic -c(o)decylalkyl group, as the case may be monosubstituted, Substituted or trisubstituted; 12. -C(0)0 aryl, optionally substituted, disubstituted or trisubstituted; 13. -C(0)0 heteroaryl (having 5 or 6 ring members (including 1 to 4 heteroaryl groups derived from a hetero atom of N, S or hydrazine, bonded to a polyoxy group via a c atom, optionally substituted, disubstituted or trisubstituted; 14. -CONH2 ; 15·linear , branched or cyclic (alkyl) and c〇N(alkyl) 2, wherein the pendant moiety is optionally substituted, disubstituted or trisubstituted; 16. -(1; 0-heteroalkyl, Mono-, di- or tri-substituted; 17. -CON (alkyl) (aryl), the alkyl group is a straight chain, a branched chain or a ring, wherein the alkyl group and the aryl moiety are optionally substituted, Take A or trisubstituted; 18. -CON (Hyper) (heteroaryl) The alkyl group is a linear 'branched chain or lacquer-like' and the heteroaryl has 5 or 6 ring members (1 to 4 of which are selected from N, S or oxime), via c or via n-bonding to a nitrogen atom, wherein the alkyl group and the heteroaryl moiety are optionally monosubstituted, 152238.doc -12- 201124414 or triple substituted; 19. linear, branched or cyclic-Ci CiQ alkyl, The case includes a hetero atom and is optionally monosubstituted, disubstituted or trisubstituted; 2〇_aryl 'optionally monosubstituted, disubstituted or trisubstituted; 21. heteroaryl, optionally substituted or polysubstituted; 22. a heterogeneous J exhibiting a thiol group, optionally substituted or substituted; 23·-CrC6 alkenyl, optionally substituted or substituted; 24·-CrC6 block, optionally substituted or substituted; The product of the formula (I) is any possible racemic, enantiomeric or diastereomeric form 'and the product of the formula (I) with inorganic and organic acids or with inorganic and organic bases Addition of salt. The present invention relates to a product of the formula (I) as defined above, wherein the substituents selected as R3 (i.e., the groups R1 a, Rib and Rlc) are independently selected from each other: 1. F ; 2. C1; 3. Br; 4. I; 5. Linear or branched _cvCi() alkyl, optionally substituted or polysubstituted by Rh, RJb, R3c; 6. -OH; 7. Linear or Branch chain - CKCVC!. Alkyl, optionally substituted or polysubstituted by R3a, R3b, R3c, 8. Linear or branched alkyl (Y=S, s〇, S〇2), as appropriate _ 152238.doc • 13- 201124414 R3a, R3b, R3C monosubstituted, disubstituted or trisubstituted; 9· 〇-(C3-C7)cycloalkyl, optionally substituted or polysubstituted by R3a, R3b, R3c; 10. -NH2 ; 11 · straight a chain, a branched chain or a cyclic _NH(alkyl) group and _N(alkyl)2, wherein the alkyl moiety is optionally monosubstituted, disubstituted or trisubstituted by R3a, R3b, R3c; the groups R3a, R3b and R3c (i.e., substituents of the groups Rla, Rib, Rlc, R2a, R2b and R2c) are independently selected from each other: 1. F; 2. C1; 3. Br; 4. I; 5. straight a chain or a branched chain -CVCh)alkyl group, optionally substituted or polysubstituted by R4a, R4b, R4c; 6. -C3-C7 ring-based, optionally substituted or substituted by R4a, R4b, R4c; -OH; 8. Linear or branched bond -O-(Ci-Cio)alkyl, optionally substituted or polysubstituted by R4a, R4b, R4c; 9. Linear or branched - Y-alkyl (Y = S, SO, S〇2), monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c, as appropriate; 10 -0-(C3-C7)cycloalkyl, optionally substituted or polysubstituted by R4a, R4b, R4c; 152238.doc -14 - 201124414 11. -Ο-aryl, optionally via R4a, R4b, R4c Monosubstituted or polysubstituted; 12. aryl, optionally substituted or polysubstituted by R4a, R4b, R4c; 13. Heteroaryl, optionally substituted or polysubstituted by R4a, R4b, R4c; Mono- or polysubstituted by R4a, R4b, R4c, as appropriate; 15. -N〇2; 16. -NH2; 17. -NH-aCVCio)alkyl or (C3-C7)cycloalkyl or heterocycloalkane Each group is optionally substituted or polysubstituted by R4a, R4b, R4c; 18. -NGCVCm)alkyl or (C3-C7)cycloalkyl)2, each group optionally via R4a, R4b, R4c Mono- or poly-substituted; 19. -NHaryl or NHheteroaryl, optionally substituted or polysubstituted by R4a, R4b, R4c; 20. -NHC(O), substituted by R4a, R4b, R4c; -NCCCVC!. Alkyl)C(O), substituted by R4a, R4b, R4c; 22. -NHS(02), substituted by R4a, R4b, R4c; 23. -NGCVC!. )alkyl)S(02), substituted by R4a, R4b, R4c; 24. -C02, substituted by R4a, R4b, R4c; 25. -CONH2 ; 26. Linear, branched or cyclic-CONH (alkyl And CON(alkyl)2, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c, as appropriate; 152238.doc -15- 201124414 27. -C(O)heterocycloalkyl, Monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c, as appropriate; 28. -S, substituted by R4a, R4b, R4c; 29. -S(02), substituted by R4a, R4b, R4c; 30. -S (O), substituted by R4a, R4b, R4c; 3 1. pendant oxy group (double bond O); 32. -C2-C6 alkenyl group, optionally substituted by R4a, R4b, R4c or polysubstituted; 33. a C2-C6 alkynyl group, optionally substituted or polysubstituted with R4a, R4b, R4c; the groups R4a, R4b and R4c (i.e., substituents of the groups R3a, R3b and R3c) are independently selected from each other : 1. F ; 2. C1 ; 3. Br ; 4. I ; 5. -CF3 ; -CHF2 ; 6. Direct or branching bond - C 1 - C 1 0 burning base, 7 . - C 3 - C 7 ί 烧 ,, 8. -OH ; 9. Direct or branched bond - Ο - ( C1 - C1 q ) alkyl; 10. Linear or branched - Y-alkyl (Y = S, so 11.o-(c3-c7)cycloalkyl; 12.-O-aryl; 152238.doc -16- 201124414 13. aryl; 14. heteroaryl; 15. heterocycloalkyl; 16. -N〇2; 17. -NH2; 18·-NH-GCj-C,. Or an alkyl or (heteroalkyl) group; 21. -NHSCOO alkyl; 22. -NCCCVC,. Alkyl)S(〇2)alkyl; 23.-C02 alkyl; 24. -CONH2 ; 25. Linear, branched or cyclic _(:〇)^11(alkyl) and CON(alkyl 2; 26. -C(O)heterocycloalkyl; 27. -S-alkyl; 28.-S(02)alkyl; 29.-S(O)alkyl; 3 0. pendant oxy ( Double bond 〇); 31. straight or branched chain _C2_C6 alkenyl; 32. straight or branched chain - C2_C6 alkynyl; racemic, enantiomeric or diastereomeric (I) product and inorganic The acid and the organic acid or the product of the formula (I) are in any possible conformational form, and the addition salts of the inorganic and organic bases. The invention relates to the general formula (I) as defined above. Product where the group 152238.doc

S 17-201124414 The substituents selected for R5 and R6 (ie, the 'groups R2a, R2b and R2c) are selected independently of each other: 1. F; 2. C1; 3. B r.; I; 5. Linear or branched _Cl_c1G alkyl, optionally substituted or polysubstituted by R3a, R3b, R3c; 6. -C3-C7 cycloalkyl, optionally substituted by R3a, R3b, R3c or more Substituent; 7. -OH; 8_linear or branched chain-〇-(Ci-C1())alkyl group is optionally substituted or polysubstituted by R3a, R3b, R3C; 9. Linear or branched chain-Y -alkyl (Y=S, SO, S02), optionally substituted by R3a, R3b, R3C, disubstituted or trisubstituted; 10·-0-(C3-C7)cycloalkyl, optionally via R3a, R3b , R 3c monosubstituted or polysubstituted; η · aryl 'optionally substituted or polysubstituted by R 3a, R 3b, R 3c; 12. aryl, optionally substituted by R 3 a, R 3b, R 3c or polysubstituted; Heteroaryl, optionally substituted or polysubstituted by R3a, R3b, R3c; 14. Heterocycloalkyl as appropriate or substituted by R3a, R3b, R3c; 152238.doc 201124414 15. -N〇2 16. -NH2; 17. -NH-UCi-Cw)alkyl or (C3-C7)cycloalkyl or heterocycloalkyl , each group is optionally substituted or polysubstituted by R3a, R3b, R3c; 18. -NGCVCm)alkyl or (C3-C7)cycloalkyl)2, each group optionally via R3a, 'R3b, R3c Monosubstituted or polysubstituted; 19. -NHaryl or NHheteroaryl, optionally substituted or polysubstituted; 20. -NHC(O), substituted by R3a, R3b, R3c; 21·-NCCC^-C ,. )alkyl)C(O), substituted by R3a, R3b, R3c; 22. -NHS(02), substituted by R3a, R3b, R3c; 23. -N((C丨-C).)alkyl)S (02), substituted by R3a, R3b, R3c; 24. -C02, substituted by R3a, R3b, R3c; 25. -CONH2; 26. Linear, branched or cyclic -CONH(alkyl) and CON(alkane Wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R3a, R3b, R3c, as appropriate; 27. -C(O)heterocycloalkyl, optionally substituted by R3a, R3b, R3c, Substituted or trisubstituted; 28. -S, substituted by R3a, R3b, R3c; 29. -S(02), substituted by R3a, R3b, R3c; 30. -S(O), substituted by R3a, R3b, R3c; 31. a pendant oxy group (double bond 0); 32. a -C2-C6 alkenyl group, optionally substituted or polysubstituted by R3a, R3b, R3c;

And s. The substituents of Rlc, R2a, R2b and R2c are selected independently of each other: 1. F; 2. C1; 3. Br; 4. I; 5. Linear or branched chain - CrCw alkyl, optionally via R4a , R4b, R4c monosubstituted or polysubstituted; 6· _C3_C7 cycloalkyl 'optionally substituted or polysubstituted by R4a 'R4b, R4c; 7. -OH; 8. Direct or branched alkyl, optionally R4a , R 4b, R 4c monosubstituted or polysubstituted; 9 · direct bond or branched chain -Y-alkyl (Y = S, SO, so2), as the case is R ^ ' R4b, R4c monosubstituted, disubstituted or trisubstituted; 10. -0-(C3-C7)cycloalkyl, optionally substituted or polysubstituted by R4a, R4b, R4c; aryl, optionally substituted by R4a, R4b, R4C or polysubstituted; 12. aryl, R4a, R4b, monosubstituted or polysubstituted, as appropriate; heteroaryl, optionally substituted or polysubstituted by R4a 'R4b 'Rk; 152238.doc 20· 201124414 14. Heterocycloalkyl, optionally via R4a, R4b , R4c monosubstituted or polysubstituted; 15. -N〇 2; 16. -NH2; 17. alkyl or (C3-C7)cycloalkyl or heterocycloalkyl), each group being mono- or polysubstituted by R4a, R4b, R4c, as appropriate; 18. -N(( Ci_Ci〇)alkyl or (C3-C7)cycloalkyl) 2 'each group is optionally substituted or polysubstituted by R4a, R4b, R4c; 19. -NH aryl or NH heteroaryl, optionally via R4a , R4b, R4c monosubstituted or polysubstituted; 20. -NHC (O), substituted by R4a, R4b, R4c; 21. -NCCCVCw) alkyl) C (O), substituted by R4a, R4b, R4c; NHS (02), replaced by R4a, R4b, R4c; 23. -NUCVC!. Alkyl)S(02), substituted by R4a, R4b, R4c; 24·-CO2, substituted by R4a, R4b, R4c; 25. -CONH2; 26. Linear, branched or cyclic-CONH (alkyl And CON(alkyl)2, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c, as appropriate; 27. -C(O)heterocycloalkyl, optionally via R4a, R4b, R4c monosubstituted, disubstituted or trisubstituted; 28. -S, substituted by R4a, R4b, R4c; 29. -S(02), substituted by R4a, R4b, R4c; 30. -S(O), via R4a, R4b ' R4c substituted; 152238.doc -21 201124414 31. Side oxy (double bond Ο); 32. -C2-C6 dilute group, optionally substituted or polysubstituted by R4a, R4b, R4c; 33. -C2_C6 alkyne And optionally substituted by R4a, R4b, R4c; the groups R4a, R4b and R4〇 (ie, the substituents of the groups R3a, R3b and R3c) are independently selected from each other: 1. F; 2. C1; 3. Br; 4. I; 5. -CF3; -CHF2; 6. Linear or branched chain-CrCiG succinyl; 7. -C3-C7 cycloalkyl; 8. -OH; . Linear or branched _〇-(Ci-Cid) 炫; 10. Linear or branched alkyl (Y=S, SO, S〇2); 11. -0-(C3_C7) An alkyl group, 12.-anthracene-aryl; 13. aryl; 14. heteroaryl; 15. heterocycloalkyl; 16. -Ν〇2; 17. -ΝΗ2; 152238.doc -22- 201124414 18. -NH-((C丨-Ci〇)alkyl or (C3-C7)cycloalkyl or heterocycloalkyl); 19. -NUCVCm)alkyl or (C3-C7)cycloalkyl)2; -NHaryl or NHheteroaryl; 21. -NHS(02)alkyl; 22. -N((Ci-Ci.)alkyl)S(〇2)院; 23. -C02 alkyl; 24 -CONH2 ; 25. straight chain, branched or cyclic -CONH(alkyl) and CON(alkyl) 2 ; 26. -C(O)heterocycloalkyl; 2 7. - S -alkyl; 28 -S(02)alkyl; 29.-S(O)alkyl; 30. pendant oxy (double bond 〇); 31. straight or branched _c2_C6 alkenyl; 32. straight or branched _ C2_C6 alkynyl; the product of the formula (I) is any possible racemic, enantiomeric and diastereomeric octagonal form A and the product of the formula (1) and inorganic and organic acids or inorganic Organically tested addition salts. The invention relates in particular to a product of the formula (I) as defined above, wherein -R3 represents from 5 or 6 ring members (of which 1 to 4 are hetero-forms selected from N, S or hydrazine) An aryl group which is bonded via C or via N bonds to the genus 7L 'R3 depending on the situation, 3, (4), Ric monosubstituted or polysubstituted; -R5 is selected from: 1 · Halogen; 152238.doc • 23· 201124414 2. -OH ; 3. Linear or branched alkoxy, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R 2a, R 2b, R 2c as appropriate; 4. Linear or branched - Y -alkyl (Y=S 'SO, S02), optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; 5. -X-aryl (X=0, S, SO, S02), depending on The case is monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c; 6. -X-heteroaryl (X=0, S, SO, S02), wherein the heteroaryl is optionally R2a, R2b, R2c Substituted, disubstituted or trisubstituted; 7. -NH2; 8. linear, branched or cyclic -NH(alkyl) and -N(alkyl)2, wherein the alkyl moiety is optionally R2a, R2b, R2c monosubstituted, disubstituted or trisubstituted; 9. -NH(aryl), wherein The aryl moiety is optionally monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c; 10. -NH(heteroaryl), wherein the heteroaryl moiety (having 5 or 6 ring members (of which 1 to 4 a heteroaryl group selected from a hetero atom of N, S or hydrazine, via a C or via a N bond to a nitrogen atom), optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; 11. -N( Alkyl)(aryl), wherein the (linear, branched or cyclic) alkyl moiety and the aryl moiety are optionally substituted, disubstituted or trisubstituted by R2a, R2b, R2c; Alkyl)(heteroaryl), wherein the (linear, branched or cyclic) alkyl moiety and the heteroaryl moiety (having 5 or 6 ring members (including 1 152238.doc -24- 201124414 to a heteroaryl group of 4 heteroatoms selected from N, S or hydrazine, via a C or via a N bond to a nitrogen atom), optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; (0)0H; 14. Linear, branched or cyclic -C(0)0 alkyl, optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; 15· -C(0)0 Base, depending on the situation via R2a, R2b, R2c Substituted, disubstituted or trisubstituted; 16_-C(0)0 heteroaryl (heteroaryl having 5 or 6 ring members, wherein 1 to 4 are heteroatoms selected from N, S or fluorene) C atom bonded to oxygen), optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; 17. -CONH2; 18. linear, branched or cyclic-CONH (alkyl) and CON (alkane) Wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c, as appropriate; 19. -CO-heterocycloalkyl, monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c -CON(alkyl)(aryl), the alkyl group being a straight chain, a branched chain or a cyclic group, wherein the alkyl group and the aryl moiety are optionally substituted, disubstituted or trisubstituted by R2a, R2b, R2c; 20. -CON(alkyl)(heteroaryl), the alkyl group is a straight chain, a branched chain or a cyclic group, and the heteroaryl group has 5 or 6 ring members (of which 1 to 4 are selected from N, S or a hetero atom of hydrazine), bonded to a nitrogen atom via C or via N, 152238.doc -25- 201124414 wherein the alkyl group and the heteroaryl moiety are monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c, as appropriate ; 21. Straight chain , branched or cyclic -C^-Cw alkyl, optionally containing a hetero atom and optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; 22. aryl, optionally via R2a, R2b, R2c Monosubstituted, disubstituted or trisubstituted; 23. Heteroaryl, optionally substituted or polysubstituted by R2a, R2b, R2c; 24. Heterocycloalkyl, optionally substituted or polysubstituted with R2a, R2b, R2c; 25. -C2-C6 alkenyl, optionally substituted or polysubstituted by R2a, R2b, R2c; 26·-C2-C6 alkynyl, optionally substituted or substituted by R2a, R2b, R2c; From: 1. Η; 2. Halogen; 3. -ΟΗ; 4. Linear or branched alkoxy, wherein the alkyl moiety is optionally substituted, disubstituted or trisubstituted by R2a, R2b, R2c; Ο-cycloalkyl, optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; 6. linear or branched - Y-alkyl (Y=S, SO, S02), optionally 152238. Doc -26- 201124414 R2a, R2b, R2c monosubstituted, disubstituted or trisubstituted; 7. -NH2; 8. linear, branched or cyclic -NH(alkyl) and -N(alkyl)2, of which The alkyl moiety is optionally R2a, R 2b, R2c monosubstituted, disubstituted or trisubstituted; 9. -C(0)0H; 10. Linear, branched or cyclic -C(0)0 alkyl, optionally substituted by R2a, R2b, R2c , disubstituted or trisubstituted; 11. -CONH2; 12. linear 'branched or cyclic-CONH(alkyl) and CON(alkyl)2, wherein the alkyl moiety is optionally R2a, R2b, R2c Substituted, disubstituted or trisubstituted; 13. straight chain, branched or cyclic -C1-C10 alkyl, optionally containing a hetero atom and optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; An aryl group, optionally substituted, disubstituted or trisubstituted with R2a, R2b, R2c; such groups Rla, Rib and Rlc (ie, substituents of the group R3) are independently selected from one another: 1. F ; 2. C1; 3. Br; 4. I; 5. Linear or branched-CVCh) alkyl, optionally substituted or substituted by R3a, R3b, 152238.doc • 21 · 201124414 R3c; OH; 7. Linear or branched _〇-(Ci-Ci〇) alkyl, optionally substituted or polysubstituted by R3a, R3b, R3C; 8. Linear or branched-γ-alkyl (Y= S, SO, S02), monosubstituted by R3a, R3b, R3c, as appropriate Disubstituted or trisubstituted; 9·〇-(C3-C7)cycloalkyl, optionally substituted or polysubstituted by R3a, R3b, R3c; 10. -NH2; 11-straight, branched or cyclic-NH (alkyl) and -N(alkyl) 2, wherein the alkyl moiety is optionally monosubstituted, disubstituted or trisubstituted by R3a, R3b, R3c; such groups R2a' R2b and R2c (ie, groups) The substituents of R5 and R6 are independently selected from each other: 1. F; 2. C1; 3. Br;

I; straight or branched-Ci-Cio, optionally substituted or polysubstituted by R3a, R3b, R3c; • C3_C7 cycloalkyl, optionally substituted or substituted by R3a, R3b, R3c; -OH; 8. Direct bond or branched chain _〇_(Ci C...alkyl, as appropriate, 152238.doc -28· 201124414 R3b, R3c monosubstituted or polysubstituted; 9. Linear or branched -Y- Alkyl (Y=S, SO, S02), monosubstituted, disubstituted or trisubstituted by R3a, R3b, R3c, as appropriate; 10. -0-(C3-C7)cycloalkyl, optionally via R3a, R3b, R3c monosubstituted or polysubstituted; 11. -Ο-aryl, optionally substituted or polysubstituted by R3a, R3b, R3c; 12. aryl, optionally substituted or substituted by R3a, R3b, R3c; a heteroaryl group, optionally substituted or polysubstituted by R3a, R3b, R3c; 14. a heterocycloalkyl group, optionally substituted or polysubstituted by R3a, R3b, R3c; 15. -N〇2; 16. -NH2 17. -NH-((Ci-C1C))alkyl or (C3-C7)cycloalkyl or heterocycloalkyl), each group being optionally substituted or polysubstituted by R3a, R3b, R3c; -N((Ci-C10)alkyl or (C3-C7)cycloalkyl)2, each group optionally via R3a, R3b , R 3c monosubstituted or polysubstituted; 19. -NH aryl or NH heteroaryl, optionally substituted or polysubstituted; 20. -NHC (O), substituted by R3a, R3b, R3c; 21. -NCCC^ -C〗. And alkyl)C(0), substituted by R3a, R3b, R3c; 22. -NHS(02), substituted by R3a, R3b, R3c; 23. -NCCCVC,. )alkyl)S(02), substituted by R3a, R3b, R3c; 24. -C02, substituted by R3a, R3b, R3c; 152238.doc -29- 201124414 25. -CONH2 ; 26. Linear, branched or Cyclo-CONH(alkyl) and CON(alkyl)2, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R3a, R3b, R3c, as appropriate; 27. -C(O)heterocycloalkyl, Monosubstituted, disubstituted or trisubstituted by R3a, R3b, R3c, as appropriate; 28. -S, substituted by R3a, R3b, R3c; 29. -S(02), substituted by R3a, R3b, R3c; 30. -S (O), substituted by R3a, R3b, R3c; 31. pendant oxy (double bond O); 3 2. -C2-C6 alkenyl, optionally substituted or polysubstituted by R3a, R3b, R3c; a -C2-C6 alkynyl group, optionally substituted or polysubstituted by R3a, R3b, R3c; such groups R3a, R3b and R3c (ie, substituents of the groups Rla, Rib, Rlc, R2a, R2b and R2c) The lines are independently selected from each other: 1. F; 2. C1; 3. Br; 4. I; 5 · Direct or branched bond - C1 -C1 〇 基 'Substituting R4 a, R4b, R4c as appropriate Or polysubstituted; 6. -C3-C7 cycloalkyl, optionally substituted or substituted by IUa, R4b, R4c; 152238.doc -30- 201124414 7. -OH ; 8. Direct or branched _〇_(Ci_Ciq)alkyl, optionally substituted or polysubstituted by R4a, R4b, R4c; 9. Linear or branched γ-alkane Base (Y=S, s〇, s〇2), monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c, as appropriate; ιο· -ο·%-. 7) a cycloalkyl group, optionally substituted or polysubstituted by R4a, R4b, R4e; 11 _ aryl, optionally substituted or substituted by R4a, iub, R4c; 12. ^• base, optionally via R4a, R4b, R4e monosubstituted or polysubstituted; 13. Heteroaryl, optionally substituted or polysubstituted by R4a, R4b, R4c; 14. Heterocyclic alkyl group, optionally substituted or substituted by R4a, R4b, R4c; 15. -N〇2; 16. -NH2; 17. -NH-GCi-CW alkyl or (Ca-C7)cycloalkyl or heterocycloalkyl), each group optionally via R4a, R4b, R4c Substituted or polysubstituted; 18·-NGCVCw) alkyl or (C3-C7)cycloalkyl) 2, each group optionally substituted or polysubstituted by R4a, R4b, R4c; 19·-NH aryl or NH Aryl group, optionally substituted or polysubstituted by R4a, R4b, R4c; 20. -NHC(O), substituted by R4a, R4b, R4c; 21. -N((C丨-Ci.)alkyl)C( O), substituted by R4a, R4b, R4c, s 152238.doc,, 201124414 22. -NHS(02), substituted by R4a, R4b, R4c; 23. -NaCVC!. )alkyl)S(02), substituted by R4a, R4b, R4c; 24. -C〇2, substituted by R4a, R4b, R4c; 25. -CONH2 ; 26. Linear 'branched chain or cyclic-CONH( Alkyl) and CON(alkyl)2, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c, as appropriate; 27. -C(O)heterocycloalkyl, optionally via R4a, R4b, R4c monosubstituted, disubstituted or trisubstituted; 28· -S, substituted by R4a, R4b, R4c; 29. -S(02), substituted by R4a, R4b, R4c; 30. -S(O), Substituting R4a, R4b, R4c; 31. pendant oxy (double bond O); 32. -C2-C6 alkenyl., optionally substituted or polysubstituted by R4a, R4b, R4c; 33. -C2-C6 alkynyl And optionally substituted by R4a, R4b, R4c; the groups R4a, R4b and R4c (ie, the substituents of the groups R3a, R3b and R3c) are independently selected from each other: 1. F; 2. C1; 3 . Br ; 4. I ; 5. -CF3 ; -CHF2 ; 152238.doc -32- 201124414 6. Direct or branching key _Ci-C1() alkyl; 7. -(:3- (:7-cycloalkyl; 8.-OH; 9·linear or branched-CKCi-CM)alkyl; 10·straight or branched-Y-alkyl (Y=S, SO, S〇2) ; 11· -o- (c3-c7)cycloalkyl; 12.-oxime-aryl; 13. aryl; 1 4. heteroaryl; 15. heterocycloalkyl; 16. -Ν〇2; 17. -ΝΗ2; -NH-((Ci-C1()) leukoyl or (c3-C7)cycloalkyl or heterocycloalkyl); 19. -N((Ci-Ci〇)alkyl or (C3-C7) ring-burning 20.) -NHaryl or NHheteroaryl; 21. -NHS(02)alkyl; 22. -NGG-Cm)alkyl)S(〇2)alkyl; 23.-C02 alkyl 24. -CONH2; 25. straight chain, branched or cyclic -CONH(alkyl) and CON(alkyl)2; 26.-C(O)heterocycloalkyl; 27.-S.alkyl; 28. -S(02)alkyl;

S 29. -S(O)alkyl; 152238.doc -33- 201124414 3 0. pendant oxy (double bond 〇); 31. straight or branched _c2-C6 alkenyl; 32. straight chain or branch Chain_C2_C6 alkynyl; the product of the formula (I) is any possible racemic, enantiomeric or diastereomeric form 'and the product of the formula (1) with inorganic and organic acids Or addition salts with inorganic and organic tests. The invention relates in particular to the product of the formula (1) as defined above, wherein R3 represents a heteroaryl group consisting of 5 or 6 ring members, of which 1 to 4 are heteroatoms selected from N, 3 or fluorene, It is bonded to the unitary unit via N, which belongs to R3, and R3 is optionally substituted or replaced by R丨a, R丨b, R丨c as shown above, and R5 and R6 have the same as shown above. Meaning, the product of the formula (1) is in any possible racemic, enantiomeric or diastereomeric form, and the product of the formula (1) is tested with an inorganic acid and an organic acid or with an inorganic test. Addition of salt. The terms used above or below have the following meanings: _alkyl, (q-Cw)alkyl or Cl_Ci()alkyl means a straight or branched chain, saturated carbon chain having from 丨 to 1 碳 carbon. The meaning is that (1) carbon contains at least one carbon-carbon double bond: any linear or branched carbon chain. -C; 2-C6 alkynyl means at least - - 徊叾 anti-carbon bond having from 1 to 6 carbons of any straight or branched chain carbon chain. - Square means phenyl or naphthyl. - Heteroaryl means that the aromatic monocyclic ring containing at least one hetero atom (N, 〇, s), Yube or especially, is a bite, a bite, a saliva... than saliva, triazole, I52238 .doc .34 - 201124414 porphin, furan, thiazole, oxazole, isoxazole; and aromatic bicyclic systems containing at least one hetero atom (N, 0, S), especially: n, benzoxazole , azaindole, benzofuran, benzothiophene, quinoline, tetrazole. '-Heterocycloalkyl means any non-aromatic monocyclic or bicyclic (spiro or non-spirocyclic ring) containing at least one heteroatom (N, 〇, s in various possible oxidation states) with or without unsaturation. 'In particular: morpholine, piperazine, piperidine' η ratio: oxetane, epoxide, dioxane, imidazolidone, imidazolinedione, 7-oxabicyclo[2.2.1 ]Geng Shao, Azacyclobutane, Nitrogen, Hexahydrogenate [3,4-Desilo, Hexahydropilylo[2,3__嘻, hexanitrogen][3^ pyridine , hexahydro (tetra) and [2,3 external ratio, 2,7-diazaspiro[4,4]壬/ 2,6-diazaspiro[4,4] brothel, 3,6_two gas Heterospiral [4,4] sputum, 3,7: aza snail [4,4] sputum, 3,8 _ spirulina [4,4] sputum, 3,9-diaza snail

[4,4]壬, 4,6-diazaspiro[4,4]壬, 4,7-diazaspiro[ο]decane 4,8·diazaspiro[4,4 ] decane, 4,9-diazaspiro[4,4]nonane, Μ·diazaspiro[4,4] brothel, ls7•diazaspiro[4,4]壬, n snail [μ]壬垸、•二气杂螺[4,4]壬, popular 〇 〇 各 各 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Octahydro-compound [2,3 curry, human hydrogen „(4) and [2,3_d]n 咯[2,3-e]pyridine. L like 7) cycloalkyl radical means any non-form formed only by carbon atoms Aromatic rings of propylene, ring Dingxuan, ring money, ring hexagram, Cycloheptane; but, also & have unsaturation 'such as cyclopentene, cyclohexene, cycloheptin or; [2.2. 1] heptane. Also --c〗-c丨. Alkyl hydroxy means any linear or branched chain saturated carbon chain having at least one hydroxy group having 152238.doc • 35* 201124414 carbons. It means that there are at least _ a financial base (c_〇c) of any linear or branched saturated carbon chain having from ^ to 10 carbon atoms. -<^-(:10 alkylamine means at least An amine (first amine, second amine or third amine) Any linear or branched chain saturated carbon bond having up to (7) carbon atoms. In the product of formula (1) as defined above, the ruler 3 may especially be substituted as indicated above. Or „ββ, R5 and R6 have any of the values defined above, and the product of the formula (1) is in any possible racemic, enantiomeric and diastereomeric forms, and The addition salt of the product of the formula (1) with an inorganic acid and an organic acid or with an inorganic test. In particular, when a linear or branched chain CrCw alkyl or 〇_(Cl_ClQ) alkyl is optionally substituted by i When substituted or substituted, the substituent formed may be CF3, CHF2, OCF3 or -CHF2. The invention relates in particular to the product of formula (I) as defined above, wherein -R3 represents pyridinyl or pyrazolyl, R3 is optionally monosubstituted or polysubstituted by Ria, Rlb, Rlc; -R5 is selected from the group consisting of: 1. Halogen; 2. -OH; 3. Linear or branched chain oxy group where the base portion of the hospital is R2a as appropriate , R2b ' R2c monosubstituted, disubstituted or trisubstituted; 4. -NH2 ; 152238.doc • 36 · 201124414 5. -C(0)0H ; 6. Linear Branched or cyclic -C(0)O alkyl, optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; 7. -CONH2; 8. Linear, branched or cyclic -CrCw alkyl , optionally containing a hetero atom and optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; 9. aryl, optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; , optionally substituted or substituted by R 2a, R 2b, R 2c; 11. heterocycloalkyl, as the case may be mono- or polysubstituted by R 2a, R 2b, R 2 c ; 12. -C 2 -C 6 alkenyl, optionally via R 2a , R 2b, R 2c mono- or poly-substituted; 13. -C2-C6 alkynyl, optionally substituted by R2a, R2b, R2c or polysubstituted; -R6 is selected from: 1. Η; 2. Halogen; a straight or branched alkoxy group, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c, as appropriate; 5. 0-cycloalkyl, optionally via R2a, R2b, R2c Single substitution

S 152238.doc -37- 201124414 Generation or trisubstituted; 6. -NH2; 7. Linear, branched or cyclic -NH(alkyl) and -N(alkyl)2, wherein the alkyl moiety is optionally Monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c; 8. -C(0)OH; 9. Linear, branched or cyclic -C(0)0 alkyl, optionally via R2a, R2b, R2c monosubstituted, disubstituted or trisubstituted; 10. -CONH2; 11. straight chain, branched or cyclic -CONH(alkyl) and CON(alkyl)2, wherein the alkyl moiety is optionally R2a, R2b , R 2c monosubstituted, disubstituted or trisubstituted; 12. straight chain, branched or cyclic -C1-C10 alkyl, optionally containing a hetero atom and optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted The groups Rla, Rib and Rlc (i.e., the substituents of the group R3) are independently selected from each other: 1. F; 2. C1; 3. Br; 4. Linear or branched chain-CrC] . Alkyl, optionally substituted or polysubstituted by R3a, R3b, R3c; 5. -OH; 6·· Direct or branched bond-O-(Ci-Ciq)alkyl group, as appropriate, by R3a, 152238.doc - 38 - 201124414 R3b, R3c monosubstituted or polysubstituted; the groups R2a, R2b and R2C (i.e., the substituents of the groups R5 and R6) are independently selected from each other: 1. F; 2. C1; 3. Br ; 4 · linear or branched - CVCw alkyl 'optionally R1a, R3b, R3c monosubstituted or polysubstituted; 5 · _C3_C7 cycloalkyl ' optionally substituted by R3a, R3b, R3c or polysubstituted ; 6. -OH; 7 · linear or branched chain _ 〇 _ (Ci_Ci ()) alkyl, optionally substituted by R3a, R3b, R3c or poly; 8. linear or branched - Y-alkyl (y=s, SO, S02), monosubstituted, disubstituted or trisubstituted by R3a, R3b, R3c, as appropriate; 9·-〇_(C3-C7)cycloalkyl, optionally via R3a, R3b, R3c Substituted or polysubstituted; 10. -no2 ; 11. -nh2 ; 12. -NH-((C丨-C丨ο) 炫 or (c3-c7)cyclodextrin or heterocyclo)) groups Monosubstituted or polysubstituted by R3 a, R3 b, R3 c as appropriate; 13. -NRC^-Cio) fluorenyl or (C3-C7)cyclodextrin) 2, each group Monocyclic or polysubstituted by R3a, R3b, R3c; 14. -NHC(〇)' substituted by R3a, R3b, R3c; έ 152238.doc -39- 201124414 15. -NGCVCw)alkyl)C(O ), substituted by R3a, R3b, R3c; 16. -NHS (02), substituted by R3a, R3b, R3c; 17. -NCCCrC]. )alkyl)S(02), substituted by R3a, R3b, R3c; 18. -C02, substituted by R3a, R3b, R3c; 19. -CONH2 ; 20. Linear, branched or cyclic -CONH (alkyl And CON(alkyl)2, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R3a, R3b, R3c, as appropriate; 21. -C(O)heterocycloalkyl, optionally via R3a, R3b, R3c monosubstituted, disubstituted or trisubstituted; 22. -S(02) > substituted by R3a, R3b, R3c; 23. pendant oxy (double bond Ο); such groups R3a, R3b, R3c (ie The substituents of the groups Rla, Rib, Rlc, R2a, R2b and R2c are independently selected from each other: 1. F; 2. C1; 3. Br; 4. Linear or branched chain - CVCw alkyl, depending on The case is mono- or polysubstituted by R4a, R4b, R4c; 5. -C3-C7 cycloalkyl, optionally substituted or polysubstituted by R4a, R4b, R4c; 6. -OH; 7. Linear or branched ◦-(Ci-Cio) alkyl, optionally substituted or polysubstituted by R4a, R4b, R4c; 152238.doc -40- 201124414 8. Linear or branched-Y-alkyl (Y=S, SO, S02), monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c, as appropriate; 9. -NH2; 10. -NH-GCV Cm)alkyl or (c3-c7)cycloalkyl or heterocycloalkyl), each group being mono- or polysubstituted by R4a, R4b, R4c as appropriate; 11. -Ν(((^-<:10) Alkyl or (C3-C7)cycloalkyl) 2, each group being optionally mono- or polysubstituted by R4a, R4b, R4c; 12. -NHC(O), substituted by R4a, R4b, R4c; -NCCCi-C!.)alkyl)C(O), substituted by R4a, R4b, R4c; 14. -NHS(02), substituted by R4a, R4b, R4c; 15. -NCCCVCw)alkyl)S(02 , substituted by R4a, R4b, R4c; 16. -C02, substituted by R4a, R4b, R4c; 17. -CONH2; 18. Linear, branched or cyclic -CONH(alkyl) and CON(alkyl) 2, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c as appropriate; 19. -S(02), substituted by R4a, R4b, R4c; 20. pendant oxy group (double bond Ο) The groups R4a, R4b and R4c (i.e., the substituents of the groups R3a, R3b and R3c) are independently selected from each other: 1. F; 2. C1; 3. Br; 4. -CF3; CHF2; 5-152238.doc -41 - 201124414 5. Linear or branched _Cl_c1() alkyl; 6·-(:3-(:7-cycloalkyl; 7.-OH; 8_linear or branched chain· · ((:]-(:1())alkyl; 9. Linear or branched - Υ-alkyl (y = s, SO, SCh); 10 · -0-(C3-C7) cycloalkyl ; 11. -no2 ; 12. -NH2 ; 13. -NH-CCCVC,. An alkyl or (C3-C7)cycloalkyl or heterocycloalkyl); 14. -NGCVCw)alkyl or (C3-C7)cycloalkyl)2; 15. -NHS(02)alkyl; - Ν(((ν(:1())alkyl)S(02)alkyl; 17. -C〇2 院; 18. -CONH2 ; 19. Linear, branched or cyclic-CONH (alkane And /(alkyl) 2; 20. -S(02)alkyl; 21. - pendant oxy (double bond Ο); the product of equation (1) is any possible racemic, enantiomeric and a diastereoisomeric form, and an addition salt of the product of the formula (I) with an inorganic acid and an organic acid or with an inorganic base and an organic base. The subject matter of the invention is especially the formula as defined above (I) The product has the following name: -5·Bromo-6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-Ν-{4-[6-methoxy-3- (.Bis -3-yl)-9Η-β-味琳-5-yl]phenyl}- 152238.doc •42- 201124414 alkanesulfonamide-N-[2-(dimethylamino)B 4-[6-methoxy-3-(pyridin-3-yl)·9Η-β-carboline-5-yl]benzamide-indole-[3-(dimethylamino)propane 4-[6-methoxy-3-(pyridine-3-yl)-9Η-β-carboline-5-yl]benzamide-5[6-methoxy-3-(pyridine -3-yl)-9 Η-β-carboline-5-yl]benzoyl benzoate-6-methoxy-5-{4-[3-(piperidin-1-yl)propoxy]phenyl}-3-( Indole-3-yl)-9Η-β-carboline-6-methoxy-5-{4-[3-(morpholin-4-yl)propoxy]phenylpyridin-3-yl )-9Η-β-carboline• 5-[3-(4-ethyl0-oxa-1-yl)_3~methylbut-1-yn-1-yl]-6-methoxy-3- (pyridin-3-yl)-9Η-β-carboline-oxime, Ν-diethyl-2-{4-[6-methoxy-3-0-pyridin-3-yl)-9Η-β-咔-5-yl]piperazine-l-yl}ethylamine-6-fluoro-5-methoxy-3-(pyridin-3-yl)-9Η-β-carboline Ν-[2-(two Methylamino)ethyl]-4_[6-fluoro·3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide-N-[4-(l -methylpiperidinyl)]-4-[6-fluoro-3-(°-pyridin-3-yl)_9Η_β_porphyrin_-5-yl]benzamide _-(2-aminoethyl )-4-[6-fluoro-3-(.by -3-yl)-9Η-β-咔--5-yl]benzamide• 4-[6_fluoro-3-(° 唆-3-yl)_9Η-β-leaf #-5-yl]benzoic acid• N-[(l S,2S)-2-aminocyclohexyl]·4-[6-fluoro-3-(° 唆Small porphyrin-5-yl]benzamide 152238.doc -43- 201124414 _ 5-decyloxy-3-(n ratio -3-yl)-9Η-β-味淋-1\[- [2-(dimethylamino) Base]-4-[3-(° ratio bit-3-yl)-911 (味琳-5-yl]benzamide-N-[(lS,2S)-2-aminocyclohexyl]_4- [6-methoxyethoxy-3-(1-indolyl-1Η-° than 嗤-4-yl)-9Η-β-吟琳-5-yl]benzamide-6-methoxy Ethoxy-5-{4-[3-(ethylamino)propoxy]phenyl}_3_(didecyl-1Η-pyrazole-4.yl)-9Η-β-carboline-N-[( lS,2S)-2-Aminocyclohexyl]-4-[6-cyclobutyloxy-3-(didecyl-1Η-°bizozol-4-yl)-9Η-β-咔淋-5-yl Benzomethamine-6-decyloxy-5-{4-[3-(ethylamino)propoxy]phenylindolyl-1pyridazole-4-yl)-9Η-β-咔Porphyrin-5-methoxy-3-(1-methyl-1Η-0 ratio) sit-4-yl)-9Η-β-味琳-5-{4-[3-(ethylamino)propyl Oxy]phenyl}-3-(1-indolyl-1Η-»Bizozol-4-yl)-9Η-β-Β·^·. The present invention also relates to the following products of formula (I): -4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-fluorenyl-fluorenyl- Ν-(1-decylpyrrolidin-3-yl)phenylhydrazine-4_[6.methoxy-3-(pyridine·3_yl)-9Η-β-carboline-5-yl]-oxime -曱基-Ν-(1-曱-substrate-4-yl)benzoquinone-[4-(2.methoxyethyl)piperazine-! • group]{4_[6-methoxyl_ 3_(.bipyridyl_3_yl)-9Η-β-carboline-5-yl]phenyl}methanone-4-[6-methoxy-3-(pyridine-3-yl)-9Η-β- Porphyrin-5-yl]-indole-[2-mercapto-2-(pyrrolidin-1.yl)propyl]benzamide-indole-[2-(didecylamino)ethyl]-anthracene _Ethyl_4_[6_曱oxy_3_(.bipyridin-3_ 152238.doc •44- 201124414 base)-9Η-β-咔琳基] alumine-4-[6-methoxy _3-("比比_3_基)·9Η-β-咔琳-5-yl] fluorenyl-N-[(1-indolyl-2-yl)methyl] benzoate -[3-(didecylamino)pyrylene-1-yl]{4-[6-methoxy-3-(»pyridyl_3_yl)_ 9Η-β-carboline-5-yl Phenyl}fluorenone-{4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]phenyl](7-methyl-2,7 -diazaspiro[4.4]non-2-yl)anthone-anthracene-[3-(didecylamino) Base]_4-[6-decyloxy-3-(11-pyridine-3-yl)_9Η-β-咔琳-5-yl]-Ν-methylbenzoin-4-[6-methoxy 3-(pyridin-3-yl)-9Η·β-carboline-5-yl]-anthracene-[2-(p-stylamino)ethyl]clumamine-{4-[6-A Oxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]phenyl}(2_mercapto octa[beta]-5Η-0 piroxi[3,4-c]n ratio Bite-5-yl) formazan-1,3,-bipyrrolidin-1,-yl {4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5 -yl]phenyl}anthone-[(3S)-3-(didecylamino)pyrrolidin-1-yl]{4-[6-methoxy-3-(pyridine-3-yl)- 9Η-β-carboline-5-yl]phenyl}fluorenone-{4-[6-decyloxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl] Stupid base} [(3aS, 6aS)-5-methylhexahydro. More than [3,4-b]. Biloxi-1(2Η)-yl]nonanone-4-[6-decyloxy-3-(acridin-3-yl)-9Η-β-carboline-5-yl]-Ν-[2- (2-mercaptopiperidin-1-yl)ethyl]obetylcarboxamide-indole-[2-(dipropan-2-ylamino)ethyl]-4-[6-methoxy-3- (0-pyridin-3-yl)_ 9Η-β-carboline-5-yl]benzamide-indole-ethyl-4-[6-methoxy-3-(pyridin-3-yl)- 9Η-β-carboline_5-yl] 152238.doc -45· 201124414 [(1-Methyl.byrrolidin-3-yl)methyl]benzamide-5[6-methoxy- 3-(Pyridin-3-yl)-9Η-β-carboline-5-yl]-indole-[(3-indolyl-1Η-pyrazol-4-yl)indolyl]benzamide-4 [6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-indole-[2-(pyrrolidin-1-yl)propyl]benzamide- N-{[(2S)-1-ethyl. Bilpyridin-2-yl]fluorenyl}-4-[6-decyloxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide-N -[l-(Dimethylamino)propan-2-yl]-4-[6-decyloxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl] Benzomethine-Ν-(1Η-imidazol-2-ylmethyl)-4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzene Formamide-N-(l-ethylpiperidin-3-yl)-4-[6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzene Methotrexate-4-[6-decyloxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]-indole-{2-[(methylsulfonyl) Amino]ethyl}benzamide-indole-[2-(diethylamino)ethyl]-4-[6-decyloxy-3-(°-pyridin-3-yl)-9Η-咔- porphyrin-5-yl]-indole-mercaptobenzamide-4 - [ 6 - hydrazinyl-3 - (. than bite-3 -yl)-9 Η - β - 味 - · 5 -yl]-Ν-[3-(2-oxo-oxyl-pyrrolidin-1-yl)propyl]benzamide-[(3R)-3-(didecylaminopyrrolidine-1 -yl]{4-[6-decyloxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]phenylindolone-4 - [ 6 -decyloxy -3 - (. than bite-3 -yl)-9 Η - β - miso > -5 -yl]-N-[2-(l-mercaptopiperidin-4-yl)ethyl]phenylhydrazine Guanamine-4 -[6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-indole-(1Η-四152238.doc -46- 201124414 oxazol-5-ylmethyl Benzalamide 4-[6-methoxy-3_(pyridin-3-yl)-9Η·β-carboline-5-yl]-indole-[2-(1_methylpyrrolidin-2-yl) Ethyl] alumine-oxime [(2-hydroxypyridin-4-yl)methyl]-4-[6-decyloxy-3-(.by -3-yl)-9Η-β -porphyrin-5-yl]benzamine•Ν-[2·(azepane-buyl)ethyl]-4-[6-decyloxy-3-(pyridin-3-yl) -9Η-β-carboline-5-yl]benzamide-indole-[3-(dimethylamino)-2,2-dimethylpropyl]-4-[6-methoxy- 3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide-indole-[2-(ethionylamino)ethyl]-4-[6-methoxy -3-(pyridine-3-yl)_9Η_β-carboline-5-yl]benzamide-5[6-methoxy-3-(acridin-3-yl)-9Η-β-咔啉-5-yl]-Ν-(1methylazetidin-3-yl)benzamide-indole-[4-(dimethylamino)butyl]-4-[6-methoxy Base-3-(η ratio _3_yl) β-carboline-5-yl]benzamide-N-[(l-ethylpyrrolidin-2-yl)methyl]-4-[ 6-methoxy·3·(吼唆·3 yl)-9Η-β· porphyrinyl]benzamide-5[6-A Base-3-(0 is more than -3-yl)-9Η-β-°^琳-5-yl] • 2-Aminoamino)ethyl]benzamide® - 6-decyloxy-5- [4-(propan-2-yl)pyr-1-yl]-3-(°-pyridyl, 3-yl)·9Ή β • 4-[6-methoxy- 3-(ο比咬-3 -基)_9Η·β-叶淋基]_2_曱基丁3 alkyn-2-amine-4-[6-methoxy-3-(〇比 bit·3·yl)-9Η-β-叶淋-5-yl]mercapto 3 152238.doc • 47- 201124414 alkyn-2-ol-5-[3-(4-ethylpiperazin-1-yl)-3-methylbut-1-yne- 1-yl]-6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-6-indole- 5- [4-(1-indenyl)-4-yl )嗓-1 -yl]-3-(0-bite-3_yl)-9Η-β-carboline-Ν,Ν-diethyl- 2-{4-[6-methoxy-3 - ( 0 唆-3 -yl)-9 Η - β -0卡吓· - 5_基]娘°秦-1-yl}ethylamine-6-decyloxy-5-(4-methyl-1,4 -Diazepane-buyl)-3-(pyridin-3-yl)-9Η-β-carboline-2-{4-[6-methyllacyl-3-(° ratio. Ding-3-yl)-9H-β-miso ·5-yl] enough · °Q-1 _ base}ethanol-6-methoxy-5-[4-(4-methylpiperazine-b Piperidin-1-yl]-3-(pyridin-3-yl)-9Η-β-carboline-6-methoxy-5-[4-(morpholin-4-yl)piperidine-1 -yl]-3-(pyridin-3-yl)-9Η-β-°Karin-3-{4-[6-methoxy-3-(.pyridin-3-yl)-9Η-β- Porphyrin-5-yl]phenyl}propionic acid-6-methoxy-5-(4-mercaptothiophen-2-yl)-3-(pyridin-3-yl)-9Η-β-carboline- 5 - (1H - α 丨 丨 0 -6 -yl)-6 - methoxy-3 - (0 to bite -3 -yl)-9 Η - β - 味 - · {2-[6-甲Oxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]phenyl}nonanol-indole-cyclopropyl-4-[6-methoxy-3-( Pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide-6-methoxy-5-(4-indolyl-phenyl-3-yl)-3-(. 3-based)-9 H - β -吟咐· _ 3-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-indole, fluorene-di Methyl aniline 152238.doc -48- 201124414 -6-decyloxy-5-(1-indolyl-1H-indol-5-yl)-3-(pyridin-3-yl)-9Η-β-咔淋-6-methoxy-5-(1-indolyl-1Η-pyrazol-4-yl)-3-(pyridin-3-yl)_9Η-β- 咔琳-Ν-{4-[6- Oxyloxy- 3-(0-bito-3-yl)-9Η-β-叶淋-5-yl]] benzyl} acetamidine-Ν-{3-[6-methoxy- 3-(0-bite-3 -yl)-9Η-β-吟淋-5-yl]]]} decanesulfonamide-6-methoxy-5-(2-methoxyphenyl)-3·(〇 ratio π定- 3-carbaline-5-(2-ethoxypyridin-3-yl)-6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-4-({3- [6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]phenyl}amino)-4-oxobutanoic acid-Ν-[2·(two Mercaptoamino)ethyl]-3-[6-decyloxy-3-(pyridyl-3-yl)-9Η-β-carboline-5-yl]benzamide-Ν-{4 -[6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzyl}decanesulfonamide-{4-[6-methoxy-3- (e-pyridyl_3·yl)-9Η-β-carboline-5-yl]phenyl}(morpholin-4-yl)anthone-6-methoxy-5-(1-methyl-1H -d-pyrazol-5-yl)-3-(°-pyridin-3-yl)_9Η-β--indole-(2-decyloxyethyl)-4-[6-decyloxy-3-( Pyridin-3-yl)·9Η-β·porphyrin-5-yl] benzoic acid-{3-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline- 5-yl] phenyl hydrazin-4-yl) fluorenone 152238.doc -49· 201124414 _ {4-[6-曱oxy-3_(° than bite base)-9Η-β-叶淋-5 _ base] stupid }(4-Methylpiperazin-1-yl)methanone_N-{4-[6-methoxy·3·(pyridine-3-yl)-9Η-β-carboline _5·yl]benzene -2- -2-methylpropionamine-Ν-(3-indolylpropylmethoxy-3-(0-pyridin-3-yl)-9Η-β-morpholin-5-yl]benzamide Indole-6-methoxy-3,5-di(0-but-3-yl)_9Η-β-咔-Ν-{2-[6-methoxy-3-(0 ratio bite-3 -yl)-9Η-β-leaf ♦ _5_yl]phenyl}methanesulfonamide-6-decyloxy-5-(1士0°°坐-4-yl)-3-(° than bite- 3-yl)-9Η-β-imiline-6-methoxy_5-[3-(indolylsulfonyl)phenyl]-3-(w-biti-3-yl)-9Η-β- Porphyrin-6-methoxy-5-(2-decyloxy-5-yl)-3-(0-bito-3-yl)_9Η-β-η卡琳-.5-[6-曱oxy_3_(° than pyridine_3·yl)-9Η-β·porphyrin-5-yl]. Bisidine-2-amine-2-{4-[6-methoxy_3_(° ratio -3-yl)-9Η-β-ylide-5-yl]phenoxy}-oxime, Ν- Dimercaptoethylamine-6-methoxy·3-(°-pyridin-3-yl)-5-{4_[2·(indolyl-1-yl)ethoxy]benzene*}-9Η-咔- porphyrin-3-{4-[6-methoxypyridin-3-yl)-9Η-β-carboline-5-yl]phenoxy}_ Ν, Ν, 2-trimethyl propyl -iamine-6-methoxy-5-{4-[2-(morphin-4-yl)ethoxy]phenyl}-3-(»biti-3-yl)-9Η-β- Porphyrin-Ν,Ν-diethyl-2-{4-[6-methoxy-3-(pyridin-3-yl)-9Η·β-咔琳-5-yl]phenoxy}ethyl@ 152238.doc •50· 201124414 • ΗΜό-methoxy-3-decapyridin-3-yl)-9Η-β- porphyrin-5-yl]phenoxy}_ 3-(morphin-4-yl) Propane-2-ol-5-{4-[3-(morpholin-4-yl)propoxy]phenyl}-3-(° ratio pyridine·3·yl)_9Η-β-porphyrin • 5- {4-[3-(piperidin-1-yl)propoxy]phenyl}-3-(° ratio pyridine·3_yl)_9Η-β-porphyrin-Ν-ethyl-3-{4- [3-("Bistidin-3-yl)-9Η-β-carboline_5·yl]phenoxy}prop-1- 1-amine-indole-[2-(didecylamino)ethyl] -4-[3-(η-pyridin-3-yl)-9Η-β-carboline-5-yl]benzoguanamine-4-[6-decyloxy-3-(pyridin-3-yl) ·9Η-β-咔-5-yl]-indole-(pyrrolidin-3-yl)benzamide-5[6-methoxy-3-(«pyridin-3-yl)-9Η-β-carboline-5 ·]]Ν-(»Byrrolidine-2-ylindenyl)benzamide-4[6-(cyclobutyloxy)-3-(.pyridin-3-yl)-9Η- β-Porphyrin-5-yl]-indole-(pyrrolidin-2-ylindenyl)benzenef-amine-N-(2-aminocyclohexyl)-4-[6-(oxetane_ 3_yloxy)_3-(acridin-3-yl)-9Η-β-carboline-5-yl]benzamide-5[6-decyloxy-3-(1-methyl- 1Η-pyrazolyl)-9Η-β-carboline-5-yl]-indole-(pyrrolidin-2-ylmethyl)benzamide• 4-[6-(cyclopropyloxy)-3 -(1-methylzolyl) sister_0_咔淋_ 5-yl]-Ν-[2-(ethylamino)ethyl]benzamide-Ν-(2-aminocyclopentyl )-4-[6-methoxy_3_(bumethyl-1Η_pyrazole-4-yl)-9Η·β-carboline-5-yl] stupidin-N-ethyl-3-{4- [3-(l-Methyl-1H-pyrazole-4-yl)_6_(propan-2-yloxy 9Η-β-carboline-5-yl]phenoxy}propan-1-amine I52238.doc -51 - 201124414 -6_methoxy_3_(1_曱基·1Η_Μ_4·基Μ基基基)Phenyl]-9Η-β-carboline. The compound of formula (1) may contain one or more asymmetric carbon atoms. Thus 1 may exist as an enantiomer or diastereomer. Such enantiomers and diastereomers, as well as mixtures thereof, including racemic mixtures, form part of the present invention. The compound of formula (1) may comprise - or a plurality of ε/ζ stereochemical configurations for double bonds or - or a plurality of cis/trans stereochemical configurations for non-aromatic rings. These various stereoisomers, as well as mixtures thereof, form part of the present invention. The compound of formula (I) may be present or may be present in the form of an addition salt with an acid. Such addition salts form part of the invention. These salts can be prepared with pharmaceutically acceptable acids (ρ·C.

Wermuth; Handbook of Pharmaw, 〇, maceutlcal Salts; Wiley ed.), but other salts of acids suitable for use in, for example, purification or isolation of the compound of formula (1), also form part of the present invention. u, *』c, 坨, %, 15〇, 15n, %, 123 ΐ 24ι and these compounds (regardless of their isotopic composition) constitute the part of the present invention

The compound of formula (1) may comprise one or more isotopes of the above-mentioned atoms, especially gases D, hydrazine, nC 135. All synthetic intermediates which are not described in the literature to produce the compounds belonging to the cleavage compound also form part of the present invention. The subject matter of the present invention is also any synthetic method known to those skilled in the art to make it possible to prepare a product of formula (1) as defined above. The subject matter of the present invention is in particular a method of synthesizing one of the products of formula (1) as defined above, I52238.doc • 52- 201124414, which is described below in the general scheme. The strategy for synthesizing the tricyclic nucleus is based on two coupling reactions; first, by means of an An-type η-pyridyl and Bn-type aryl halide catalyzed by an Ib complex (Suzuki type or Stille type) The coupling reaction between the species forms a carbon-carbon bond, producing an intermediate of formula Cn. After reduction as appropriate, an intramolecular carbon-nitrogen bond is formed to produce a 9H-pyrido[3,4-b]fluorene unit (intermediate of formula Dn, see general procedure below). The reaction to the functional adjustment of the 3, 5 and 6 positions makes it possible to obtain a compound of the formula (I).

Coupling (Stiller, eucalyptus, etc.) is subsequently reduced (in the case of nitro) R^N.

Hartwig-Buchwald or copper salt X = -Μ

Br or I

A compound of formula (I), wherein R3, R5 and R6 are as defined above.

R" Two SnMe3 or -B(OH)2 or -B, ,0-

R^sN = 02N, H2N, HPivN R = Cl, OMe, OH, 〇S02CF3 or R3 R· = Η, OMe, OH, OS02CF3, Br as defined above or R5 R" = Η, as defined above Br, OH or the R6 general procedure as defined above starting from an intermediate of the formulae An, Bn, Cn and Dn as defined above, the operating conditions for obtaining the product of formula (I) as defined above are described below. For example, the process for preparing a compound of the invention having a (3'-pyridyl) unit at the 3-position consists of the following steps: in the first step, from 2-152238.doc-53-201124414 (3^pyridine) Preparation of 5-chloro-4-(trimethylstannyl)-2,3·-bipyridyl-A (Journal of the Chemical Society, Perkin transactions i 2002, (M), 1847 -1849). The synthesis for the compound having a (Γ-fluorenyl-1Ή-pyrazole-4) group at the 3-position requires preparation of 2,5-dichloro-4-(trimethylstannyl) by a similar method. Pyridinium 2 (Scheme 1).

Process 1

The Bn type synthesis intermediate is commercially available or prepared according to the following method. 2-Bromo-4-nonyloxyaniline B1 is prepared, for example, by bromination of p-aniline. N-(4-fluoro-2-iodo-3-methoxyphenyl)-2,2-dimethylpropanamide B2 and N-(2-iodo-3-indolylphenyl)-2, 2-Dimethylpropionamide B3 is obtained in two steps (protection of the streptoamine functional group followed by iodination via orthometallization) (Scheme 2).

1? PivCI, TEA CH2CI2

2? nBuLi, THF -78〇C , I,

B2: Rp = F B3 : Rp = H Scheme 2 201124414 For the introduction of a more complex alkoxy group at the 6 position, the starting product is 3-bromo-4-nitrophenol, which is alkyl (or cycloalkyl or heterocyclic) Alkylation of the alkyl) complex gives the B4 intermediate (Scheme 3).

RBr, Bu4NI

B4 Ralc= Me, Et, CH2CH2OMe, Cyclopropyl, Cyclobutyl. Flow 3 is carried out in the next step of the singularity between the von Fusheng Anxing t5n. When Bn carries a nitro group, the nitro group is reduced to an amine by a conventional method (di-stannized tin or rhodium-acetic acid). Therefore, an intermediate before the Cn-type cyclization is obtained (Scheme 4).

Pd(PPh3)4 PdCI2(dppb) Cul Dioxane or CuO, DMF, 95°C overnight 110°C, 2h

SiF^F^NsC^N, reduction of SnCI2, EtOH or Zn, AcOH

In the next step, a tricyclic unit Dn is obtained by means of an intramolecular aryl amination reaction catalyzed by a palladium complex or a copper (I) or (II) salt (Scheme 5):

Pd(OAc)2, Josiphos tBuOK, dioxane 95°C overnight or microwave 120°C for 1 hour or Cul or Cu(acac)2 (<2〇〇3, DMSO 150-170°C Process 5

Where Josiphos is a compound having the formula: 152238.doc -55- 201124414 In the case where the intermediate Dn has an alkoxy group at the 6 position (D1 _R"=_〇alkyl or 〇〇cycloalkyl and R,=H) Next, the 5-position is brominated via the action of dibromo in acetic acid (Scheme 6).

Br2l AcOH

Process 6

The Dn-type bicyclic intermediate is converted into the product of formula (1) in several steps. For the compound D3 of the present invention having a (1,-methyl-anthracene pyrazole-4,yl group) unit at the 3-position, the (Γ-fluorenyl-1Ή-pyrazole-4,-yl) unit system Introduced in the Suzuki reaction (Scheme 7).

In the case where the intermediate Dn has a decyloxy group (D5 R'=OMe) at the 5-position after cyclization, the functional group adjustment at this position consists of including a demethylation reaction and formation of a triflate. The two-step sequence of derivative D7 consists of (flow 8). 152238.doc • 56· 201124414

HCI, AcOH Microwave 1 hour 120〇C-150°C

Flow 8 r" (CF3s〇2) 2〇

The introduction of a phenyl retinoic acid unit at the 5-position by means of a three-gas scorpion vinegar D7 or a bromide oxime 2 by means of a suzuki-type coupling, followed by an interest.

The activation of the acid g-based group in the form of a cool-based nitride (the action of the sulfur-containing chlorine) or the activation of the form (the action of HATU) makes it possible to obtain the decylamine of the formula (1).

1? SOCI2 reflow or HATU DMF

2? Amine CH2CI2, 25 °C

R3b, R3c Formula (1) If R = R3 as defined above, Scheme 10 Intermediates D2 and D7 make it possible to react with eucalyptus with the appropriate chain or with another fungus (Sonogashira) or The Hartwig-Buchwald type coupling reaction obtains a compound of formula (I) in a coupling step (Scheme 11). -57- 152238.doc 201124414 pd(PPh3)4 CS2C03 Dioxane / Yong Microwave 120-130 ° C 1 hour

The subject of the invention is also a product of formula (1) as defined above and a prodrug thereof as a medicament, the product of formula (I) being any possible racemic, enantiomeric and diastereomeric An isomeric form, and a pharmaceutically acceptable addition salt of the product of the formula (1) with an inorganic acid and an organic acid or with an inorganic base and an organic base. The subject matter of the invention is especially the product of formula (I) as defined above as a drug, the name of which is as follows: -5-bromo-6-methoxy-3-(pyridin-3-yl)·9Η-β-咔啉-Ν-{4-[6-methoxy-3-("bipyridin-3-yl)-9Η-β-carboline-5-yl]phenyl}methanesulfonamide-Ν-[2 -(didecylamino)ethyl]-4-[6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]phenylguanamine-indole-[ 3-(Didecylamino)propyl]-4-[6-methoxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide- 4-[6·methoxy-3-(0-Bit-3-yl)-9Η-β-flavored>-5-yl]benzoic acid vinegar-6-methoxy-5·{4 -[3-(piperidin-1-yl)propoxy]phenyl}-3-(acridin-3-yl)-9Η-β-carboline-6-methoxy-5-{4-[ 3-(morpholin-4-yl)propoxy]phenyl}-3-(.pyridin-3-yl)-9Η-β-carboline 152238.doc -58- 201124414 _ 5·[3-( 4-ethylpiperazin-1-yl)-3-methylbut_1-yne-1-yl]_6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline _ Ν , Ν-diethyl-2-{4-[6-decyloxy-3-(0-But-3-yl)-9Η-β-咔Hao-5-yl]azizin-l-yl}B Amine-6-fluoro-5-methoxy-3-(pyridin-3-yl)_9Η-β-carboline-Ν-[2-( Methylamino)ethyl]-4-[6-fluoro-3-(pyridin-3-yl)-9Η-β-0-carboxolin-5-yl]benzamide-N-[4-(l -mercaptopiperidinyl]]-4-[6-fluoro-3-(0-pyridyl-3-yl)-9Η-β-carboline-5-yl]benzamide-5 Ν-(2-amine Benzyl)-4-[6-fluoro-3-(°-pyridyl-3-yl)-9Η_β-carboline·5-yl] 曱醯-amine-4-[6-dun-3-(pyridine- 3-yl)-9Η-β-porphyrin-5-yl]benzoic acid-N-[(lS,2S)-2.aminocyclohexyl]-4-[6-fluoro-3-(pyridylpyridinium) -3-yl)-9Η-β-carboline-5-yl]benzoguanamine-5-methoxy-3-(pyridin-3-yl)-9Η-(3-porphyrin_Ν-[2 -(didecylamino)ethyl]-4-[3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide-N-[(lS,2S)- 2-Aminocyclohexyl]-4-[6-methoxyethoxy-3-0曱'yl-1Η-pyrazol-4-yl)-9Η-β-carboline-5-yl]benzamide Amine amine-6-methoxyethoxy-5-{4-[3-(ethylamino)propoxy]phenyl-3-G.methyl-1Η-pyrazole-4-yl)- 9Η-β-carboline-:^-[(13,23)-2-aminocyclohexyl]-4-[6-cyclobutyloxy-3-(1-indolyl-1Η-pyrazole-4 -yl)-9Η-β-carboline-5-yl] alumine-6-methoxy-5-{4-[3_(ethylamino)propoxy]phenyl}-3-( 1-曱基- 152238.doc -59 · 5 201124414 1H-pyrazol-4-yl)-9Η-β-carboline-5-methoxy-3-(1-methyl_1Η-. Ratio*s-4-yl)-9Η-β-味琳-5-{4-[3-(ethylamino)propoxy]phenyl}·3_(1•indolyl-1Ηindoleazole- 4_yl)-9Η-β-carboline. The subject matter of the present invention is also a product of the formula (1) as defined above as a drug, the name of which is as follows: -4-[6-decyloxy-3-(pyridine·3·yl)·9Η_β·porphyrin_5_yl曱 ___(1-decylpyrrolidin-3-yl)benzamide-5[6-methoxy-3-(pyridine-3-yl)_9Η-β-carboline·5- Base]_Ν_曱基·Ν_(1-mercaptopiperidin-4-yl)benzamide-[4-(2-decyloxyethyl)piperazine-decyloxy_3·(0-pyridine -3_yl)-9Η-β-味琳-5-yl]phenyl}anthone-4-[6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5- Base]-Ν-[2-mercapto-2-(pyrrolidin-1-yl)propyl;|Buthammeramine•Ν-[2-(didecylamino)ethyl]_Ν_ethyl_ 4-[6·曱oxy_3_(e-pyridyl_3·yl)-9Η-β-咔琳-5-yl]benzamide-5[6-decyloxy-3-(° ratio Bite-3-yl)-9Η-β-叶琳-5-yl]-Ν-methyl-Ν-[(卜曱基拉ridin-2-yl)indolyl]benzamine-[3-(—曱Amino group) 〇辰 bit-1-yl]{4-[6-methoxy-3-(.biter than 3_yl)_ 9Η-β-carboline-5-yl]phenyl}methanone -{4-[6-Methoxy-3-(pyridine-3-yl)-9Η-β-carboline-5-yl]phenyl](7-methyl-2,7-diazaspiro[ 4.4]壬-2-yl)曱_ -Ν-[3-(two Amino) propyl]·4·[6_decyloxy-3-(.pyridin-3-yl)_9Η-β-咔-5-yl]-indole-methylbenzoguanamine 152238. Doc •60· 201124414 -4-[6-decyloxy-3-(.pyridin-3-yl)-9Η-β-carboline_5·yl]-Ν-[2-(phenylamino) Ethyl]benzamide-{4-[6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]phenyl}(2-mercapto octahydro- 5Η-pyrrolo[3,4-c]pyridin-5-yl)methanone-1,3,-bipyrrolidin-1'-yl {4-[6-decyloxy-3-(pyridine-3- ))-Η-β-morpholine-5-yl]phenyl}anthone-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]{4-[6-decyloxy -3-(pyridin-3-yl)-9Η-β-carboline-5-yl]phenyl}methanone-{4-[6-methoxy-3-(pyridin-3-yl)-9Η-咔- porphyrin-5-yl]phenyl} [(3aS,6aS)-5-fluorenylhexahydro 0-pyrazino[3,4-b]eit^-l(2H)-yl]nonanone-4 -[6·decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-N-[2-(2-mercaptopiperidin-1-yl)ethyl] Clandamine-N-[2_(dipropan-2-ylamino)ethyl]_4-[6-methoxy-3-(°-pyridin-3-yl)-9Η-β-0 Karin -5-yl]benzamide-indole-ethyl-4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-Ν-[( 1-mercaptopyridin Pyridin-3-yl)hydrazino]benzamide-4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-Ν-[(3 -mercapto-1Η-pyrazol-4-yl)indolyl]benzoin-4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl ]-Ν-[2-(pyrrolidin-1-yl)propyl]benzamide-N-{[(2S)-1-ethyllalocidin-2-yl]indolyloxy-Μ0 Bipyridine-3-yl)-9Η-β-carboline-5-yl]benzamide-N-[l-(didecylamino)propan-2-yl]-4-[6-methoxy Base-3-(° ratio -3-yl)-9Η-β-carboline-5-yl]phenyl hydrazine 152238.doc -61- 201124414 -N-(1H-imidazol-2-ylmethyl) 4-[6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide-N-(l-ethylpiperidin-3-yl) 4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide-5[6-decyloxy-3-(acridine) -3-yl)-9Η-β-carboline-5-yl]-indole-{2-[(decylsulfonyl)amino]ethyl}benzamide-Ν-[2-(2-B Amino)ethyl]-4-[6-decyloxy-3-(. Bipyridin-3-yl)-9Η-β-carboline-5-yl]-indole-methylbenzamide-4-[6-decyloxy-3-(pyridin-3-yl)-9Η- β-Porphyrin-5-yl]-indole-[3-(2-Sideoxypyrrolidin-1-yl)propyl]benzamide-[(3R)-3-(dimethylamino)吼rrolidine-1-yl]{4-[6-decyloxy-3-(acridin-3-yl)-9H-β-morpholin-5-yl]phenyl}methanone-4-[6 -decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-N-[2-(l-nonylpiperidin-4-yl)ethyl]benzamide Amine-4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-N-(1H-tetrazol-5-ylmethyl)benzamide Amine-4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-N-[2-(l-methylpyrrolidin-2-yl) Ethyl]benzamide-N-[(2-hydroxy.pyridin-4-yl)methyl]-4-[6-decyloxy-3-(.pyridin-3-yl)-9Η-咔-porphyrin-5-yl]benzamide-indole-[2-(azepane-1-yl)ethyl]-4-[6-methoxy-3-(pyridine-3- ))-9Η-β-carboline-5-yl]benzamide Ν-[3-(didecylamino)-2,2-dimercaptopropyl]-4-[6-oxime 3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide 152238.doc -62- 201124414 -N-[2-(ethylideneamino)B Base]-4-[6-A Oxy-3-(° ratio bite_3_yl)-9H_β_porphyrin-5-yl]phenylhydrazine _ 4-[6-methoxy-3-("bipyridin-3-yl) -9Η-β-carboline-5-yl]-NU-methylazetidin-3-yl)benzamine• N-[4_(didecylamino)butyl]-4-[ 6-methoxy_3-(0-pyridin-3-yl)-9H-β-carboline-5-yl]benzamide+ N-[(l-ethylpyrrolidin-2-yl)indole 4-[6-methoxy_3_(° than indol-3-yl)-9Η·β-porphyrin-5-yl]benzamide-5_[6-methoxy-3- (pyridin-3-yl)-9Η-β-carboline-5-yl]-indole-[2-(pyridine-2-ylamino)ethyl]benzamide-6-decyloxy-5- [4-(Prop-2-yl)π-piperazine-1-yl]-3-(0-bite base)_9Η_β·咔琳_ 4-[6-曱-oxy-3-(° ratio pyridine-3- )9_-β-carboline-5-yl]-2-mercaptobut-3-yn-2-amine_ 4-[6-methoxy-3-(pyridin-3-yl)·9Η-β -porphyrin-5-yl]-2-methylbuty-3_yn-2-ol_ 5-[3-(4.ethylpiperazin-1-yl)_3_methylbut-1-yne-b _6_methoxy_ 3-(pyridin-3-yl)-9Η_β-carboline_ 6-decyloxy-5-[4-(1-methylpiperidin-4-yl)-benzin比)pyridyl 3 yl)-9Η-β-carboline-oxime, Ν-diethyl-2-{4-[6-methoxy-3-(pyridin-3-yl)-9Η-β-啉-5-5]°辰° Qin-l-yl}ethylamine _ 6-decyloxy-5-(4-indolyl-1,4-diazepane-buyl)_3_(pyridyl) ·9Η-β-味淋: 152238.doc 201124414 -2-{4-[6-曱乳基-3 - (0 bite-3-yl)-9 Η - β -叶琳-5-基]派D Qin-1- 1 -yl}ethanol-6-decyloxy-5-[4-(4-mercaptopiperazin-1-yl)piperidin-1-yl]-3-(pyridin-3-yl)- 9Η-β-carboline-6-methoxy-5-[4-(morpholin-4-yl)piperidin-1-yl]-3-(pyridin-3-yl)-9Η-β-咔琳• 3-{4-[6-decyloxy-3-(acridin-3-yl)-9Η-β-carboline-5-yl]phenyl}propanoic acid-6-decyloxy-5 - ( 4-methyl D-cepan-2-yl)-3 - (° ratio - 3 -yl)-9 Η - β - 0 card scare · -5-(1Η-吲哚-6-yl)-6-曱Oxy-3-(pyridin-3-yl)-9Η-β-carboline-{2-[6-decyloxy-3-(. Bispin-3-yl)-9Η-β-carboline-5-yl]phenyl}nonanol-indole-cyclopropyl-4-[6-decyloxy-3-(pyridin-3-yl)- 9Η-β-carboline-5-yl]benzamide-6-methoxy-5-(4-methyl°cephen-3-yl)-3 - (° ratio bit-3-yl)- 9 Η -β - 0 Carlin-3-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-indole, fluorenyl-dimercaptoaniline-6 -Methoxy-5-(1-methyl-1Η-indol-5-yl)-3-(pyridin-3-yl)-9Η-β--6-methoxy-5-(1-A Base-1 Η-pyrazol-4-yl)-3-(pyridin-3-yl)-9Η-β-. Carlin-Ν-{4-[6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzyl}acetamid-Ν-{3-[6 -decyloxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]benzyl}decanesulfonamide-6-methoxy-5-(2-oxime Phenyl)-3-(pyridin-3-yl)-9Η-β-carboline 152238.doc -64- 201124414 -5-(2-ethoxy η than 唆3-yl)-6-methoxy Base-3-(° vs. 唆-3-yl)-9Η-β-叶淋_ 4-({3-[6-methoxy-3-(° than -3-yl)-9Η-β-啼-5-yl]phenyl}amino)-4-oxobutanoic acid _ Ν-[2-(didecylamino)ethyl]-3-[6-decyloxy-3-( .Bistidin-3-yl)-9Η-β_carboline-5-yl]benzamide-Ν-{4-[6-decyloxy-3-(D-Bit·3·yl)-9Η -β-叶你-5-yl]mercapto}methanesulfonamide {4-[6-methoxy-3-(0-bite_3-yl)_9Η-β-味淋-5-yl] } ( 吗 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 (2-methoxyethyl)-4-[6-methoxy-3-(° ratio _3-yl)-9Η-β-calloline-5-yl]benzamide _ {3- [6-decyloxy-3-(0-bit _3-yl)-9Η-β-leaf ##*-5-yl]benzine}(吗琳_4-基)曱-ketone-{4-[ 6-methoxy -3-(0-bite base)-9Η-β-叶琳-5-yl]phenyl](4-mercaptopiperazin-1-yl)anthone-anthracene-{4-[6-decyloxy -3-(0-pyridin-3-yl)_9Η-β-咔琳_5-yl]phenyl}-2-mercaptopropanamine-indole-(3-methoxypropyl)-4-[ 6.Methoxy-3-(0-pyridyl-3-yl)-9Η-β-carboline-5-yl]benzamide 6 6-decyloxy-3,5-di(pyridine-3- Base)_9Η-β_porphyrin•Ν-{2-[6-decyloxy-3-(pyridin-3-yl)_9Η_β_叶淋_5·yl]phenyl}decanesulfonamide 152238. Doc -65· 201124414 -6-methoxy_5_(1H-pyrazol-4-yl)-3-(pyridin-3-yl)-9Η-β-carboline-6-methoxy-5-[ 3-(decylsulfonyl)phenyl]_3_(pyridin-3-yl)-9Η-β-carboline-6-methoxy-5-(2-decyloxypyrimidin-5(yl)_3_( Pyridine-3-yl)-9Η-β-carboline-5-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]pyridin-2-amine- 2-{4-[6-decyloxy-3-(tacral-3-yl)-9Η-β-carboline-5-yl]phenoxy}-indole, indole-dimercaptoethylamine-6 - oxime-3-(. Bipyridin-3-yl)-5-{4-[2-(indolyl-1·yl)ethoxy]phenyl}-9114-carboline-3-{4-[6·methoxy- 3-(.by pyridine_3_yl)_9Η-β-. Carboxolin-5-yl]phenoxy}-indole, indole, 2-trimethylpropan-1-amine-6-methoxy-5-{4-[2-(morpholin-4-yl) Oxy]phenyl}-3-(.pyridin-3-yl)-9Η-β-carboline-oxime, Ν-diethyl-2-{4-[6-methoxy-3-(pyridine -3-yl)-9Η-β_ porphyrin-5-yl]phenoxy}ethylamine-1-{4-[6-decyloxy-3·indolyl-3-yl)-9Η-β- Porphyrin-5-yl]phenoxybu 3-(morpholin-4-yl)propan-2-ol-5-{4-[3-(morpholin-4-yl)propoxy]phenyl} _3_bubidin-3·yl)-9Η-β-味琳-5-{4-[3-(0-bit-1-yl)propoxy]phenyl}-3-(° than bite- 3-yl)-9Η-β-味琳-Ν-ethyl-3-{4-[3-(pyridin-3-yl)-9Η-β-carboline-5-yl] phenyloxy} propyl 1-amine-indole-[2-(dimethylamino)ethyl]-4-[3-(pyridin-3-yl)-9Η-β-imi-_5_yl]benzamide+ 4- [6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-indole-(pyridinium-3-yl)benzamide 152238.doc •66· 201124414 _ 4-[6-decyloxy-3-(pyridin-3-yl)_9H_p_porphyrin·5-yl]-N-(indolyl-2-methyl)benzamide-5 [6-(cyclobutyloxy)-3-(β ratio _3-yl)-9Η-β-°^ 冬 基 ]]pyrrolidin-2-ylmethyl)benzamide-N- (2- Cyclohexyl)-4-[6-(oxacyclobutane _3_yloxy to butyl-3-yl)-9Η-β-味琳-5-yl]benzene T-trending amine-4-[6 - 曱oxy-3-(1-methyl-lH-° than sal _4_yl)-9 Η-β-leaf 基 Ν Ν · (° 比洛 bit -2-ylmethyl) benzoic amine -4-[6-(cyclopropyloxy)-3-(1-methyl-1Η-« ratio) sit-4-yl)-9Η-β-咔淋-5-yl][2·(B Amino)ethyl]benzamine-indole-(2-aminocyclopentyl)-4-[6-decyloxy-3-(l-decyl-1Η-pyrazole-4-yl) -9Η-β-e Carlin-5-yl]benzene nitrite-N-ethyl-3-{4·[3-(1-methyl-1H-pyrazol-4-yl)-6-( Prop-2-yloxy)-911-0-°Kalazine-5-yl] phenyloxy}propan-1-amine-6-methoxy-3-(1-methyl-lH-n-pyrazole 4-yl)-5-[4-(«> benzo-3-ylmethoxy)phenyl]-9Η-β-carboline. The subject matter of the invention is also a pharmaceutical composition comprising a compound of the invention as an active ingredient and at least one pharmaceutically compatible excipient. The subject matter of the invention is also a pharmaceutical composition of the invention for use in the treatment of cancer. Thus, according to another aspect thereof, the present invention relates to a pharmaceutical composition comprising a compound of the present invention as an active ingredient, wherein the pharmaceutical composition contains an effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt of the compound. And at least one pharmaceutically acceptable excipient. 152238.doc •67· 201124414 These excipients are selected from the usual excipients known to those skilled in the art depending on the pharmaceutical form and the mode of administration desired. In the pharmaceutical composition for use in the present invention, subcutaneous, intramuscular or intravenous administration, the above formula (1) (4) or its salt may be in unit dosage form i and I known as an excipient. The mixture is administered to animals and humans for the treatment of the above conditions or diseases. Suitable unit dosage forms include oral forms such as lozenges, soft or hard gelatin capsules, powders, granules and solutions or suspensions; and sublingual, buccal, subcutaneous, intramuscular or intravenous administration. These drugs can be used as a treatment! In particular, it is used to treat cancers that are sensitive to dysregulation of pim kinase. A Pim kinase inhibitor that is the subject of the present invention is useful for treating cancer. Since cancer is still a disease that is not currently curable by existing therapies, it is clear that there is a need to identify a novel Pim kinase inhibitor that is effective in treating cancer. According to another aspect, the invention is also directed to a method of treating the above-described condition, acicular form comprising administering to a patient an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. The following examples describe the preparation of certain compounds in accordance with the present invention. These are limiting, and are merely illustrative of the invention. The exemplified compound numbers can be found in the numbers given in the tables below to illustrate the chemical structure and physical properties of some of the compounds of the present invention. It may be noted that the compound of formula Dn may be a synthetic intermediate for obtaining a product of formula (1) or may have constituted a product of formula (I) by applying the methods described above or below or known to those skilled in the art. Other commonly used methods obtain 152238.doc -68- 201124414 other products of formula (i), all of which form part of the invention. In particular, the subject matter of the present invention is also an intermediate for the synthesis of the product of formula (I) as described in the above scheme as a novel industrial product. The subject matter of the present invention is therefore a synthetic intermediate of the formula An as defined in the general scheme above and defined below as a novel industrial product:

Wherein 〇- -M = -SnMe3 or -B(OH)2 or R = Cl, OMe, OH, 0S02CF3 or R3 as defined above, the subject matter of the invention is therefore especially useful as a novel industrial product for the synthesis as described above Intermediate of the product of formula Bn as described herein and defined below:

Where X = Br or I

F^N = 02N, H2N, HPivN R· = H, OMe, OH, 0S02CF3, Br, or R5 R·· = H, Br, OH as defined above or R6 as defined above An intermediate for the synthesis of a product of the formula Cn as described in the above scheme and defined below, especially as a novel industrial product:

Wherein F^F^N = 02N, H2N, HPivN R = Cl, OMe, OH, 0S02CF3 or R3 R_ = H, OMe, OH, OS02CF3, Br as defined above, or R5 R" as defined above H, Br, OH or R6 as defined above The subject matter of the invention is therefore an intermediate, in particular as a novel industrial product, for the synthesis of the product of the formula Dn as described in the above scheme and defined below:

Dn where R = Cl, OMe, OH, 0S02CF3 or R3 R_ = H, OMe, OH, 0S02CF3, Br as defined above, or R5 R.. = H, Br, OH as defined above or as above Definition R6-69-152238.doc 201124414 [Embodiment] Overview: ► Abbreviation: 1H NMR: Proton Nuclear Magnetic Resonance DAD: Wavelength Scanning Detector DCM: Dichloromethane DME: 1,2-Dimethoxyethane DMF : dimethylformamide DMSO: diterpene ELSD: light scattering detector HATU · hexafluorophosphate 0-(7-azabenzotriazol-1-yl)-Ν, Ν, Ν·, Ν·-Four 曱锞 HPLC, UPLC: High Performance Liquid Chromatography LC: Liquid Chromatography LDA: Diisopropyl guanamine lithium 1 ^ butyl] \4?: 2,2,6,6-tetradecyl Lithium piperidine MS: mass spectrometry TFA · · trifluoroacetic acid THF : tetrahydrofuran

Tr: residence time ► All reactions were carried out using an anhydrous solvent in the Acros Organics AcroSeal range. The solvent used for extraction and chromatography is from SDS. The reaction carried out under microwave was carried out using a Biotage or CEM device. The tannin extract was purified using a commercially available ruthenium dioxide cartridge. Preparative HPLC purification system utilization 152238.doc •70· 201124414

The Macherey-Nagel column (Nucleodur C18 phase) or other phase (Chiralcel 00_1 or 0)-^1 or AS-H, Chiralpak, Kromasil Cis) is carried out with a suitable dissolving agent. ► LC-MS-DAD-ELSD analysis: 2 possible experimental conditions: ❶LC-MS-DAD-ELSD analysis: MS=Waters ZQ; electrospray mode +/-; mass range m/z=100-1200; LC= Agilent HP 1100; column LC=X Bridge 18 C Waters 3·〇χ50 mm-2.5 μηι.; LC oven = 60 ° C; flow rate = 1.1 ml/min β eliminator: Α = water + 0.1 % formic acid, Β = Acetonitrile with the following gradient: Time %A %B 0.0 95 5 5.0 0 100 5.5 0 100 6.5 95 5 7.0 95 5 ❷LC-MS-DAD-ELSD analysis: MS = Platform II Waters Micromass; electrospray +/-; Range m/z = 100-l 100; LC Alliance 2695 Waters; Column X Terra 18C Waters 4.6 mm x 75 mm-2.5 μηι ; LC oven = 60 ° C; Flow rate = : 1.0 ml/min o Dissolving agent: A = water + 0.1% citric acid, B = acetonitrile with the following gradient: Time %A %B 0 95 5 6.0 5 95 8.0 5 95 9.0 95 5 13.0 95 5 152238.doc -71- 201124414 ► UPLC-MS-DAD-ELSD Analysis : 2 possible experimental conditions: ❶ UPLC-MS-DAD-ELSD analysis: MS = Quattro Premier XE Waters; electrospray +/-; mass range m / z = 100-l 100; UPLC Waters; column Acquity UPLC B eH C18 2.1 mmx50 mm-1.7 μιη; UPLC oven = 70 ° C; flow rate = 0.7 ml / min. Eluent: A = water + 0.1% formic acid, B = acetonitrile + 0.1% citric acid with the following gradient: Time %A %B 0 95 5 5 0 100 5.5 95 5 6.0 95 5 ❷UPLC-MS-DAD-ELSD Analysis: MS = SQD Waters; electrospray + / ·; mass range m / z = 100-1 100; UPLC Waters; column Acquity UPLC Beh C18 2.1 mm >< 50 mm -1.7 μιη; UPLC oven = 70 ° C; Rate = 1 ml/min o Dissolving agent: 八 = water + 0. 1% citric acid, B = acetonitrile + 0·1% citric acid with the following gradient: time %A %B 0 95 5 0.8 50 50 1.2 0 100 1.85 0 100 1.95 95 5 2.00 95 5 About detection: 152238.doc -72- 201124414 DAD Wavelength consideration λ=210-400 nm ELSD : Sedere Sedex 85 ; Spray temperature = 35 ° C; Spray pressure = 3.7 bar ❸ UPLC -MS-DAD-ELSD analysis (4 minutes): MS = SQD Waters; electrospray +/-; mass range m/z = 100-1100; UPLC Waters; column Acquity UPLC Beh .C1 8 2· 1 mmx50 mm- 1.7 μιη; UPLC oven = 70 ° C; flow rate = 1 ml / min. Eluent: A = water + 0.1% formic acid, B = acetonitrile + 0.1% citric acid, with the following gradient: time %A %B 0 95 5 1.60 50 50 3.20 0 100 3.85 0 100 3.95 95 5 4.00 95 5 About detection : DAD wavelength considers λ=210·400 nm ELSD : Sedere Sedex 85 ; spray temperature = 35 ° C; spray pressure = 3.7 bar NB : depending on the structure analyzed, the dilution solvent is: dimethyl sulfoxide; decyl alcohol; Acetonitrile; dichloromethane. ►Basic preparative HPLC Method 1 was injected into 2 ml of DMSO. Preparative HPLC: Macherey-Nagel 100x21 mm reverse phase C18 Nucleodur 152238.doc -73- 201124414 1 0 μ column; Eluent: acetonitrile and water containing 10 mM ammonium bicarbonate, pH 9-10 with aqueous ammonia solution . 10% acetonitrile stage: 2 minutes, gradient to 95% acetonitrile over 23 minutes followed by an 8 minute 95% acetonitrile stage. Flow rate 20 ml/min. Collected according to UV absorption: 254 nm. Method 2 was injected into 5 ml of DMSO. Preparative HPLC: Macherey-Nagel 250x40 mm reverse phase C18 Nucleodur Gravity 10 μ column 0 Dissolving agent: acetonitrile and water containing 10 mM ammonium bicarbonate, pH 9-10 with aqueous ammonia solution. 10% acetonitrile stage: 3 minutes, gradient to 95% acetonitrile over 37 minutes followed by an 8 minute 95% acetonitrile stage. The flow rate is 70 ml/min. Collected according to UV absorption: 254 nm. ► Acidic preparative HPLC Method 3 was injected into 2 ml of DMSO. Preparative HPLC: Macherey-Nagel 10〇χ21 mm reverse phase C18 Nucleodur 10 μ column. Dissolving agent: acetonitrile containing 0.07% TF hydrazine and water containing 0.07% TFA. 10% acetonitrile stage: 2 minutes, gradient to 95% acetonitrile over 23 minutes followed by an 8 minute 95% acetonitrile stage. Flow rate 20 ml/min. Collected according to UV absorption: 254 nm. 152238.doc -74- 201124414 Method 4 was injected into 5 ml of DMSO. Preparative HPLC: Macherey-Nagel 250 x 40 mm reverse phase C18 Nucleodur 10 μ column. Dissolving agent: acetonitrile containing 0.07% TF hydrazine and water containing 0.07% TFA. 10% acetonitrile stage: 3 minutes, gradient to 95% acetonitrile over 37 minutes followed by an 8 minute 95% acetonitrile stage. The flow rate is 7 〇 ml/min. According to UV absorption, · 254 nm ° 3 times 5 m 1 injection is required. EXAMPLES Example 1: Synthesis of 5·indol-6-decyloxy-3-(pyridin-3-yl)-9Η-β-咔 步骤 Step 1: Synthesis of 5-gas-2,3,-linked "Bite

58.8 g of cesium carbonate, 10 mi of water and 76 g of lanthanum (triphenylphosphine) palladium were added to 19.6 g of 2,5-dichloropyridine and 28.5 g of 3-(4,4,5,5-tetramethyl-1, 3,2-Dioxaboron-2-yl)pyridine in 350 ml of dioxane. After stirring under reflux (at a temperature of 91 ° C) for 8 hours and returning to a temperature of about 2 Torr, the medium was poured into 400 ml of water and 100 ml of a saturated solution of potassium hydrogencarbonate. The aqueous phase was extracted three times with 5 mL of ethyl acetate and then the combined organic phases were concentrated to dryness under reduced pressure. The residue was dissolved in decyl alcohol and subsequently deposited on 70 g of SCX sulphur dioxide (Varian B 〇 讥 讥 scx cartridge) adjusted with methanol. Filtration was carried out using a solution of 300 N ammonia in methanol, and 8.32 g of orange yellow was obtained. After washing three times with 300 ml of decyl alcohol, 2 n was used. The solution was concentrated to dryness under reduced pressure, 152 238. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (d), which will be used as it is in the next step - LC-MS-DAD-ELSD: Tr (min) = 2.28; [M+H]+ : m/z 191 Step 2: Synthesis of 5-chloro-4- (three-child) Base tin base)_2,3, 〇 〇 唆ai

3 〇 ml of butyllithium was slowly added to a solution of 5 g of diisopropylamine in 25 ml of tetrahydrofuran cooled to a temperature of -74 ° C while maintaining the temperature between _74 χ: and -70 °C. Then add 8 3 g 5_gas_2,3, and join the sputum of the Zheng Zheng &amp; Funan. After mixing for 2 hours and 3 minutes, a solution of 9 97 g of chloro(trimethyl)stannane in 40 ml of tetrahydrofuran was poured while maintaining the temperature between -74 Torr and -71 °C. After stirring at this temperature for a few hours, 1 〇〇 of mi water was poured while the mixture was returned to a temperature of about 2 Torr. The medium was then poured into 2 ml of water and 100 ml of a saturated aqueous solution of potassium hydrogencarbonate. The aqueous phase was extracted twice with 3 EtOAc (EtOAc)EtOAc. The residue was deposited on 7 μg of SCX cerium oxide (70 g Varian Bond Elut SCX cartridge) in 30 ml of methanol' and the filter cartridge was rinsed with 25 〇ml of water and 250 ml of sterol ammonia solution (2 N) Dissolution. The dissolved fraction was concentrated to dryness under reduced pressure. The residue was then combined to 10 g of cerium oxide (Merck 4 〇 _ 63 μ) and purified by column chromatography (eluent: heptane / ethyl acetate, gradient 100/0 to 50/50). And obtained 11.89 g of orange-yellow oil in the form of 5_ chaotic _4-(trimethyl stilbene)-2,3'-linked ratio bite. LC-MS-DAD-ELSD: Tr (min) = 4.29; [M+H]+: m/z 355; 1H NMR (400 MHz, DMSO-66). ppm: 0.45 (s, 9 H) 7.52 (dd 152238.doc -76 · 201124414 J=7.6, 5.1 Hz, 1 H) 7.94 (d, J=1.0 Hz, 1 H) 8.40 (dt, J=7.9, 2.1 Hz, 1 H) 8.63 (s, 1 H) 8.64-8.66 (m, l H) 9.22 (d, J=2.4 Hz, 1 H) Step 3: Synthesis of 2-bromo-4-nonyloxyaniline B1

39 g of tetrabutylammonium tribromide was added to a solution of 10 g of 4 methoxyaniline in a mixture of 32 〇 ml of dioxane and 160 ml of sterol. After stirring at the temperature of (10)^ for 1 hour, the medium was poured into a solution of 5 M thiosulfate brine. The aqueous phase was extracted twice with EtOAc and EtOAc EtOAc m. The residue was purified twice using a sulphuric acid column (solvent: heptane/ethyl acetate, gradient 9/1 to 5/5) to give 6 g of 2-bromo-4-decyloxy as a brown liquid. aniline. UPLC-MS-DAD-ELSD: Tr (min)=0.56 ; [M+H]+ : m/z 202 Step 4: Synthesis of 2-(5-chloro-2,3'-linked&quot; -4-oxyloxyaniline Cl

5.49 g 2-bromo-4.methoxyaniline, 8 g 5-chloro-4-(trimethylstannyl)-2,3'-bipyridine, 862 mg iodine in 85 ml of dioxane The steel and 6.8 g fluorinated planer were introduced into the reactor of the microwave oven. After microwave irradiation at a temperature of 100 ° C for 1 hour, the medium was filtered through diatomaceous earth, the insoluble matter was washed with ethyl acetate, and water and 10 ml of ethyl acetate were added to the filtrate. 152238.doc -77· 201124414 The aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure, using a oxidizer column (solvent: After purifying the residue by heptane / ethyl acetate (EtOAc /EtOAc /EtOAc /EtOAc /EtOAc Oxyaniline UPLC-MS-DAD-ELSD: Tr (min) = 0.59 ; [M+H]+ : m/z 312 Step 5: Synthesis of 6-methoxy-3_(pyridin-3-ylamine Lin D1

Unloading 122 mg of copper and 1.3 g of carbonic acid to 1 g of 2-(5-chloro-2,3'-linked. than biti-4-yl)-4-decyloxyaniline in 15.5 ml of dimethyl In the solution in the amine. After stirring overnight at a temperature of about 160 ° C under argon, the medium was cooled and then poured into 100 ml of a 14% aqueous ammonia solution, and 丨〇〇m ethyl acetate was added. After the mixture was filtered through Clarcel, the aqueous phase was extracted again with 10 EtOAc. The combined organic phases were washed with a 14% aqueous ammonia solution and then concentrated to dryness under reduced pressure. After purifying the residue by ruthenium dioxide column chromatography (solvent: dichloromethane/methanol gradient: 100/0 to 95/5), 445 mg of 6-decyloxy-3- ° than bite-3-yl)-9Η-β-咔琳. </ RTI> <RTIgt; ;1£1,1/=2.4 and 8.8 1^,111); 7.47 to 7.56 (111,2^1); 7.90 ((1, •7=2.4Hz, lH); 8.51 (td, 1/=1.9) &amp;8.1Hz, lH); 8.56 (dd, 152238.doc -78- 201124414 l/=1.9&amp;4.6Hz, lH); 8.85(s,iH);8.97(s,lH);9.37(d, • 7=1.9 Hz, 1 H); 11.52 (width s, 1 η) Step 6: Synthesis of 5-bromo-6-decyloxy_3_(pyridine·3·yl)_9Η_β_carboline (Example 1)

288 mg of 6-decyloxy-3-(pyridine-3-yl)·9Η_β_carboline was dissolved in a mixture of 20 ml of acetic acid and 30 ml of tetrahydrofuran. Subsequently, 12 ml of tetrahydropyrazine solution (0.65 ml) was added to 60 ml of tetrahydroanthraquinone). After stirring at a temperature of about 20 ° C for 3 hours and 30 minutes, the medium was concentrated under reduced pressure. The residue was dissolved in a mixture of 25 ml of ethyl acetate and 20 ml of 10% aqueous ammonia. The organic phase was washed twice with 20 ml of 10% aqueous ammonia solution and the combined aqueous phases were re-extracted with 6 ml of ethyl acetate. The organics were combined and concentrated to dryness under reduced pressure. After purifying the residue by ruthenium dioxide column chromatography (solvent: dioxane/nonanol, gradient 100/0 to 90/10), 255 mg of a beige solid in the form of 5-di-6-methoxy -3--3-(. 唆-3-yl. UPLC-MS-DAD-ELSD: Tr (min)=3.01 ; [M+H] + : m/z 354 ; [MH]-: m/z 352 1H NMR (400 MHz, DMSO-56) ppm: 3.94 (s, 3 H); 7.49 (d, •7=8·8 Hz, 1 H); 7.52 (dd, J=4.9 and 7-8 Hz, 1 H 7.65 (d, •/=8.8 1^, 111); 8.46 (1 (1, 1/=1.7 and 7.8 1^, 111); 8.58 ((1, •7=1.7&amp;4.9Hz, lH); 9.04 (s, lH); 9.07 (s, lH); 9.31 (d, / = 1.7 Hz, 1 H); 11.88 (width s, 1 H) 152238.doc • 79- 201124414 Example 2: Synthesis of N -{4-[6-Methoxy-3-(pyridin-3-yl)-9H-p-porphyrin-5-yl]phenyl}methanesulfonamide

In a microwave oven reactor, 62.9 mg of Ν-[4-(4,4,5,5·tetradecyl-1,3,2-dioxaboran-2-yl)phenyl] under argon Methane sulfonamide, 46 mg carbonic acid planer, 8 mg hydrazine (triphenylphosphine) palladium and 0.2 ml water were added to 25 mg 5-bromo-6-methoxy-3-(° ratio -3-yl)-9Η -β - Wei Lin in a solution of 0.9 1111 two ° smoldering. After microwave irradiation for 1 hour at a temperature of 130 ° C, the medium was poured into 1 〇 ml of water, and then the aqueous phase was extracted twice with 20 ml of ethyl acetate. The combined organic phases were dried <RTI ID=0.0> After purification by ruthenium dioxide column chromatography (solvent: dichlorohydrazine/decyl alcohol, gradient 100/0 to 94/6), 22 mg of N-{4-[6-methoxy-3- (. than the bite-3-yl)-9Η-β-味琳·5-yl]phenyl}-burning amine. </ RTI> <RTIgt; (s, 3 H); 3.77 (s, 3 H); 7.27 (d, J = 0.9 Hz, 1 H); 7.41 (dd, J = 4.8 and 7.9 Hz, H); 7.44 to 7_49 (m, 5 H 7.62 (d, "/=8.8 Hz, 1 H); 8.03 (td, •7=1.9 and 7.9 Hz, 1 H); 8.49 (dd, J=i.5 and 4.8 Hz, 1 H); 8.88 (width d, "7=1.9 Hz, 1 H); 8.97 (d,7=0 9 Hz,! H); 9 96 (width m, i 152238.doc -80- 201124414 H); 11.68 (width s, 1 Η) Example 3: Synthesis of N-[2-(dimethylamino)ethyl]_4_[6·decyloxy_3_(pyridin-3-yl)-9Η-β-flavor-5-yl Benzoyl

In a microwave oven reactor, 111 mg of Ν-[2-(dimethylamino)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2 under argon - Dioxaborom-2-yl)benzamine, 190 mg cesium carbonate ' 13.5 mg hydrazine (triphenylphosphine) palladium and 0.3 ml water were added to 50 mg 5 · bromo-6-decyloxy-3- ( Pyridin-3-yl)-9Η-β-carboline in 1.2 ml of dioxane. After microwave irradiation at 130 ° C for 1 hour, the medium was poured into 10 ml of water and then the aqueous phase was extracted twice with 20 ml of ethyl acetate. The combined organic phases were dried with anhydrous magnesium sulfate, filtered and evaporatedEtOAc Chromatography by ruthenium dioxide column (solvent: dioxane / methanol, gradient 96/4 to 90/10, and dichloromethane / methanol / 28-30% aqueous ammonia solution, gradient 90/10/0.5 to 85/15/0.5) After purification, 29 mg of N-[2-(dimethylamino)ethyl]-4-[6-decyloxy-3-(»pyridin-3- Base)-9Η-β-carboline-5-yl]benzamide. </ RTI> <RTIgt; s, 6 H); 2.48 (t, J = 6.7 Hz, 2 H); 3.45 (m, 2 H); 3-77 (s, 3 H); 7.19 (d, 7 = 1.1 Hz, 1 H); 7.39 (ddd, *7=0.7 and 4.8 and 7.9 Hz, 1 H); 7.50 (d, 152238.doc -81 - 201124414 7=9.0 Hz, 1 H); 7.59 (d, y=8.6 Hz, 2 H) ; 7.66 (d ^ 1 H), 7.97 to 8.02 (m, 1 jj); 8.08 (d, «7=8.6 Hz 2 port, ' ' z H); 8.48 rdd ·/= port and 4.8 Hz, i H) 8 52 J=5 8 Hz to (dd,

', 8.79 Γ 官 HJ=1.7 Hz, 1 H); 8.98 (dj J=1A Hz, 1 H); n.73 , Example 4: Synthesis of N-[3-(dimethylamino)propyl bromide Μmethoxy 1 H) pyridine-3-yl)-9H_P- porphyrin-5-yl]benzamide A 3 (ratio

The product was obtained by the same procedure as the procedure used in Example 3, γ 曰 from a mixture of 1 ml-° smoldering and 〇25 ml of water, 46 ms $ s J-cyclo-6-methoxy-3-(° Bipyridin-3-yl)-91^0-porphyrin hydrobromide (1:2), 93 mg N-[3-(dimethylamino)propyl]-4-(4,4,5, 5-tetramethyl-1,3,2-dihydrocha-gas, indole-2-yl)benzamide, 152 mg of carbonic acid planing and 8 mg of cerium (triphenylphosphine). Microwave irradiation at a temperature of 120 C for 30 minutes and chromatographic column chromatography (solvent: dichloromethane / methanol, gradient 95/5 to 9 〇 / 1 Torr, then dichloromethane / methanol / 28 - After purification of 30% aqueous ammonia, 85/15/0.5), 14 mg of N-[3-(dimethylamino)propyl]-4-[6.methoxy-3- 0 is 唉-3-yl)-9Η-β-咔啭-5-yl]benzamide. UPLC-MS-DAD-ELSD: Tr (min) = 0.39 [M+H] + : m/z 480 ; base peak: m/z 218 [MH]-: m/z 478 152238.doc -82- 201124414 1H NMR (400 MHz, DMSO-56) ppm: 1.73 (m, 2 H); 2.17 (s 6 H); 2.32 (t, 7 = 7.0 Hz, 2 H); 3.37 (m, 2 H); 3.77 (s , 3 H); 7.18 (d, /=1.0 Hz, 1 H); 7.38 (dd, J=4.8 &amp; 8'lHz, lH)· 7.50 (d, /=9.0 Hz, 1 H); 7.59 (d ,·7=8.5 Hz, 2 H); 7.65 (d J=9.0 Hz, 1 H); 8.01 (td, *7=2.0 and 8.1 Hz, 1 H); 8.07 (d J=8.5 Hz, 2 H) ; 8.47 (dd, *7=1.6 and 4.8 Hz, 1 H); 8.66 (width t */=5.5 Hz, 1 H); 8.79 (width d, "7=1.6 Hz, 1 H); 8.98 (d, */=1 〇

Hz, 1 H); 11_72 (width s, 1 H) Example 5: Synthesis of 4-[6-methoxy-3-(acridin-3-yl)-9Η_β_porphyrin_5_yl benzoic acid ester

The product was prepared by the same procedure as used in Example 3, but from a mixture of 1·6 ml of dioxane and 0.2 ml of water, 73 mg of 5-bromo-6-methoxy-3-(pyridine-3) -yl)-9Η-β-porphyrin hydrobromide (1:2), m mg 4_ (4,4,5,5-tetramethyl-1,3,2-dioxaborate-2-yl) Methyl benzoate, 184 mg cesium carbonate and 13 mg bismuth (triphenylphosphine) palladium were initially "microwave irradiated at a temperature of 12 ° C for 30 minutes and chromatographed by a sulphur dioxide column (solubilizer: two After purification of methyl chloride / decyl alcohol, gradient 95/5 to 90/10), 45 mg of 4-[6-methoxy-3-(.sup.-3 -yl)-9?-? Weilin-5-yl]methyl benzoate. UPLC-MS-DAD-ELSD: Tr (min)=0.7〇; [M+H] + : m/z 410 ; 152238.doc •83 - 201124414 [MH]-: m/z 408 1H NMR (400 MHz, DMSO-66). ppm: 3.77 (s, 3 H); 3.96 (s, 3 H); 7.22 (d, *7=1.0 Hz, 1 H); 7.40 (ddd, "/=1.0 and 4.8 and 8.0 Hz , 1 H); 7.51 (d, /= 9.0 Hz, 1 H); 7.68 (m, 3 H); 8.04 (ddd, l/=1.8 & 2.0 &amp; 8.0 Hz, lH); 8.21 (d, &gt ;/=8_6Hz, 2H); 8.48 (dd, J=1.6 and 4.8 Hz, 1 H); 8.76 (width d, J=2.〇Hz, 1 H); 8.99 (d, J=lO Hz, 1 H 11.76 (s, 1 H) Example 6: Synthesis of 6-methoxy-5-{4-[3-(piperidin-1-yl)propoxy]phenyl b-3-(»bipyridine-3 -yl)-9Η-β-porphyrin

The product was prepared by the same procedure as used in Example 3, but from &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&& 3-yl)_9Η-β-carboline, 156 mg 1-{3-[4-(4,4,5,5-tetramethyl-1'3,2-dioxaboromid-2-yl)benzene Starting with oxy]propyl}piperidine, 244 mg cesium carbonate and 21 mg hydrazine (triphenylphosphine) palladium. After microwave irradiation for 30 knives at 12 ° C &gt; C 2 temperature and purification by cesium dioxide column chromatography (eluent: dichlorohydrazine / sterol gradient 100/0 to 85/15), 65 mg yellow was obtained. Solid form of 6-methoxy-5_{4_[3·(派咬小基)propyloxy]phenyl b 3·bbi bite winter base)-9Η-β·味. UPLC MS DAD-ELSD: Tr (min) = 〇.5〇; [m+H] + : m/z 493 ; 152238.doc -84- 201124414 [M+2H]2+: m/z 247 (base peak [M_H]_: m/z 491 1H NMR (400 MHz, DMS〇- §6) ppm: 1.35 to 1.42 (m, 2 H); 1.46 to 1.54 (m, 4 H); 1.96 (qd, / =6.6 and 6.8 Hz, 2 H); 2.28 to 2.41 (m, 4 H); 2.46 (t, j=jΛ Hz, 2 H); 3.76 (s, 3 H); 4.15 (t, 7=6.4 Hz, 2 H); 7.18 (d, J = 8.8 Hz, 2 H); 7.31 (%s, 1 H); 7.37 to 7.43 (m, 3 H); 7.45 (d, "/= 9.0 Hz, 1 H); 7.59 (d, •==9.0 Hz, 1 H); 8.06 (ddd, “/=1.7 and 2.0 and 8.3 Hz, 1 H); 8.49 (dd,·7=1.7 and 4·6 Hz, 1 H); 8.85 (width d, *7 = 1.7 Hz, 1 H); 8.96 (d, J = 1.0 Hz, 1 H); 11.65 (width s, ih) Example 7: Synthesis of 6-methoxy-5·{4- [3-(morpholin-4-yl)propoxy]phenyl b-3-(pyridin-3-yl)-9H_p-porphyrin

The product was prepared by the same procedure as used in Example 3, but from 6 ml of a mixture of 1.2 ml of dioxan and 0.3 ml of water, 5 bromo-6 methoxy-3-(pyridine-3- Base)-9Η-β·porphyrin, i18 mg 4 gas 3_[4_(4,4 5 5_tetramethyl-1,3,2-dioxaboromid-2-yl)phenoxy]propyl} Morpholine, 18 〇 § 铯 铯 and 15 mg 二 (diphenylphosphine) were initiated. Microwave irradiation at a temperature of 12 Torr for 30 minutes and purification by silica gel column chromatography (esolvent: digastron/methanol, gradient 100/0 to 90/10) gave 61 mg of a yellow solid. Form 6-decyloxy-5-{4-[3-(morpholin-4-yl)propoxy]phenyl}_3_(π-pyridyl·3_yl)-9Η-β-flavor. 5 152238.doc -85· 201124414 UPLC-MS-DAD-ELSD: Tr (min) = 0.44 ; [M+H] + : m/z 495 ; [M+2H]2 + : m/z 248 (base peak )[MH]-: m/z 493 1H NMR (400 MHz, DMSO-56). ppm: 1.98 (m, 2 H); 2.41 (m, 4 H); 2.47 to 2.52 (m partially masked, 2 H) ; 3.59 (m, 4 H); 3.76 (s, 3 H); 4.17 (t, /=6.4 Hz, 2 H); 7.18 (d, 7=8.7 Hz, 2 H); 7.30 (width s, 1 H ); 7.36 to 7.43 (m, 3 H); 7.45 (d, /=9.0 Hz, 1 H); 7.59 (d, ·7=9·0 Hz, 1 H); 8.07 (td, J=1.9 and 7.9) Hz, 1 H); 8.49 (dd, "7=1.5 and 4.6 Hz, 1 H); 8.84 (width d, *7 = 1.5 Hz, 1 H); 8.96 (d, J = 0.7 Hz, 1 H); 11.64 (s, 1 H) Example 8: Synthesis of 5-[3-(4-ethylpiperazine·i•yl)_3·indolyl 4•yne 4 _ kib 6_ 曱oxy-3-(0 Than -3- base)-9Η-β-imiline

53 mg 5-> odor-6-meroxy_3_(pyridine-3-yl)_9Ηρ咔琳, 41 mg 1-ethyl-4-(2-methylbut-3-yne-2-yl) A suspension of piperazine, 5 mg of copper iodide and 14 mg of bis(triphenylphosphine)dichloropalladium in 1 such as triethylamine was introduced into a microwave drying reactor. After the reactor was blown with nitrogen, it was 丨2〇. The medium was placed under microwave irradiation for 3 minutes at a temperature of 〇. 14 mg of bis(diphosphine) dipalladium in 2 ml of dimercaptoguanamine was added and the resulting mixture was again placed under light shot for 3 minutes. Add 41 post 1-ethyl-4-(2-methylbut-3-ynyl)pyrazine twice and at the temperature of 2 152238.doc -86. 201124414 radiation for 30 minutes and 1 hour After 30 minutes, the medium was filtered through EtOAc (EtOAc)EtOAc. After purifying the residue by ruthenium dioxide column chromatography (solvent: dichlorohydrazine/methanol, gradient 100/0 to 95/05), 50-[3-(4-) Ethyl buck. Qin-1-yl)_3-mercapto-1-n-1-yl]-6-methoxy-3-(. than -3-yl)-9H-β-weilin. UPLC-MS-DAD-ELSD: Tr (min)=2.34 i [M+H] + : m/z 454 \ [MH]-: m/z 452 1H NMR (400 MHz, DMSO-36) ppm: 0.88 to 1·〇8 (m,3 H); 1.58 (s,6 H) 2.19 to 2.80 (m partially obscured, 10 H); 3.92 (s,3 H); 7.40 (d, J=8.8 Hz, lH); 7.52 (dd, l/= 4.8 & 8.0 Hz, lH); 7.62 (d, /= 8.8 Hz, 1 H); 8.38 (ddd, «7=1.8 and 2.0 and 8.0 Hz, 1 H); 8.58 (width d, J = 4.8 Hz, 1 H); 8.88 (width s, 1 H); 9.04 (d, /=1.0 Hz, 1 H); 9.23 (width s, 1 H); 11.73 (width s, 1 H) Example 9: Synthesis of N,N-diethyl-2-{4-[6-methoxy-3-(pyridin-3-yl)-9H-p-carboline-5-yl]piperazine-l- Ethylamine

Under argon, it will be 14 mg (1E,4E)-1,5-diphenylpentan 1,4-dien-3-one-palladium (3:2) in 0.5 ml of hexaoxan. 28 mg hydrazine, hydrazine-binaphthyl-2,2'-diylbis(diphenylphosphino) was introduced into a microwave oven reactor and was given at a temperature of about 152238.doc • 87 - 201124414 degrees at around 20 °C. After 5 minutes, '53 mg of 5-bromo-6-methoxy-3-(pyridin-3-yl)·9Η·poporphyrin added to 5 ml of dioxane, 36 mg of sodium tributoxide and 139 mg of N'N-diethyl-2-(piperazinyl)ethylamine. After microwave irradiation for 1 hour at a temperature of 14 Torr:, the reaction mixture was placed under irradiation for 2 hours at the same temperature. Addition of μ mg -diphenylpenta-1,4-diene-3-p-palladium (3:2) and 56 mg of bis(diphenyl) 2,2,2-diyl bis(diphenyl) under argon A mixture of phosphatidane in 0.6 ml of dioxane. After microwave irradiation for 5 hours at a temperature of 14 ° C, the medium was poured into 1 ml of water and extracted three times with ethyl acetate. The combined organic phases were dried with anhydrous magnesium sulfate, filtered and evaporated After purification by preparative HpLC, 15 mg of N,N-diethyl-2-{4_[6-methoxy-3-(pyridin-3-yl)_9Η-β- as a yellow lyophilized material was obtained. Porphyrin_5_yl]piperazine_丨_yl}ethylamine. </ RTI> <RTIgt; t, J=7 3 Hz 6 11); 3.00 to 4.50 (width "1,12 11"; 3.25 (4,1/=7.3112,411); 3.91 (s, 3 H); 7.44 (d, 7=8.8 Hz, 1 H); 7.49 (d, J=8.8 Hz, 1 H); 7.65 (dd, *7=4.9 and 7.8 Hz, 1 H); 8.58 (width d, J = 7.8 Hz, 1 H); 8.67 (dd, J = 1.2 and 4.9 Hz, 1 H); 8.85 (width s, ih); 9.04 (s, 1 H); 9.32 (width d, J = 1.2 Hz, 1 H); 11.76 (width s, i H) Example 10: Synthesis of 6-fluoro-5-methoxy·3·(π 比 bit·3·yl)_9Η·ρ_吟琳 Step 1: Synthesis of 4-fluoro-3-methoxyantamine 152238. Doc -88- 201124414

14 g, 5 g of 1-fluoro-2-foxy-4-nitrostene and 2 ml of ml of hydrogen furan were added to a mixture of 40 ml of water and 40 ml of ethanol. A solution of 5 7 g of ammonium chloride in 18 ml of water was added dropwise. After stirring the mixture for 1 hour and 10 minutes at a temperature of 5 (rc), the mixture was filtered through celite and washed with dichloromethane, and then the aqueous phase was extracted twice with 100 ml of dichloromethane. The phase was washed twice with 50 ml of water, dried over anhydrous magnesium sulfate, and then concentrated and evaporated to dryness under reduced pressure to afford 4.32 g of 4- fluoro-3-indoleoxylamine as a brown solid. LC-MS-DAD-ELSD : Tr (min) = 0.68; [M+H] + : m/z 142 Step 2: Synthesis of N-(4-fluoro-3-methoxyphenyl)-2,2-dimethylpropanamide

10.9 g of 2,2-dimercaptopropene gas was added to a solution of 12.8 g of 4-gas-3-decyloxyaniline in 340 ml of dichloromethane with stirring. 12.6 ml of triethylamine was added dropwise at a temperature of 〇 °c. After returning to a temperature of about 2 Torr and mixing at this temperature for 1 hour and 45 minutes, the solution was poured into 1 〇〇 of mi water. The aqueous phase was extracted twice with 50 ml of a methane, and the combined organic phases were dried over anhydrous magnesium sulfate. 19 g of a pink solid liter of N-(4-fluoro-3-methoxyphenyl)·2,2-dimercaptopropylamine was obtained. UPLC-MS-DAD-ELSD: Tr (min) = 0.82; [M+H] + : m/z 226 ; [MH]-: m/z 224 152238.doc 5 -89- 201124414 Step 3: Synthesis of N- (4-fluoro_2_hard_3_methoxyphenyl)_2,2-dimethylpropanamide B2

Add 69 ml of butyl lithium (1 6 M hexane solution) and 6 〇 ml of tetrahydrofuran to 10 g at a temperature of 〇 ° C. (___________methoxyphenyl 2 dimethyl The solution of acrylamide in 65 ml of tetrahydrofuran. After stirring for 4 hours at a temperature of &£&gt;c, the mixture was cooled to a temperature of _7 〇&lt;t and slowly added to 14 g of iodine in 25 ml of tetrahydrofuran. After stirring at a temperature of _78 art, and returning to a temperature of about 20 C, the medium was poured into 25 ml of an aqueous solution of ammonium chloride, and the aqueous phase was extracted three times with 100 ml of ethyl acetate. The combined organic phases were washed successively with 200 ml of aq. sodium sulphate aqueous sodium sulfate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure to dryness. The residue was purified by oxidizing stone chromatography (solvent: dioxane) to obtain 128 g of iodo-3-methoxyphenyl)2,2-dimethylpropanamine in the form of an orange crystal. LC-MS-DAD-ELSD: Tr (min) = 4.31; [M+H]+: m/z 352; base: m/z 225; [M-Η]-: m/z 350 Step 4: Synthesis Ν_[2-(5·gas_2,3,_bipyridyl_4·yl)_4-fluoro·3_methoxyphenyl]-2,2·dimethylpropanol 匸2

152238.doc -90- 201124414 1.21 g of 5-chloro-4-(trimethylstannyl)-2,3,-bipyridine, 1-7 g of cesium fluoride and 434 mg of copper iodide under argon Add to 4 g of N-(4-fluoro-2-A-3-indene basic)-2,2-dimercaptopropylamine in 40 ml of degassed dimercaptoamine. 8 〇〇 mg of bis(triphenylphosphine) di-palladium was added under a rat atmosphere with stirring. After stirring at 100 ° C for 1 hour and 30 minutes, 3.22 g of 5-chloro-4-(tridecylstannyl)-2,3'- previously dissolved in 40 ml of dimethylformamide was added. Bipyridyl' and the reaction was allowed to proceed at a temperature of i ° ° C for 45 minutes. After cooling, the medium was poured into 150 ml of water and 100 ml of ethyl acetate, and then the aqueous phase was extracted twice with 100 ml of ethyl acetate, and then the combined organic phases were washed with saturated aqueous sodium sulfate, anhydrous sulfuric acid The magnesium was dried, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (solvent: 4/6 methane / ethyl acetate) to afford 2.46 g of white crystals of N-[2-(5- gas-2,3 --Dipyridin-4-yl)-4-fluoro-3-methoxyphenyl]-2,2-dimercaptopropionamide. UPLC-MS-DAD-ELSD: Tr (min) = 0.80; [M+H] + : m/z 414 ; [MH]-: m/z 412 Step 5. Synthesis of 6-^-5-methoxy- 3- (βΛ^-3 -yl)_9Η-β - Wei Lin (Example 10)

A total of 94 mg of palladium acetate and 267 mg of (R)-(-)-l-[(S)-2-(dicyclohexylphosphino)ferrocene group under argon in several microwave oven reactors ] Ethyl di-t-butylphosphine was introduced into 16 ml of degassed dioxane. After removing 152238, doc -91 - 201124414 gas with argon and stirring the mixture in a water bath for 4 minutes, add 2 49 g gas 5_ gas-2,3'-bipyridyl 4-yl)_4-fluoro-3-anthracene A mixture of 2,2,2-dimercaptopropionamide and 1.15 g of sodium tributoxide in 46 ml of dioxane. After microwave irradiation for 1 hour at a temperature of 120 ° C, the contents of the plurality of reactors were combined to add 50 ml of sterol and 150 ml of ethyl acetate. The organic phase was washed with aq. EtOAc / EtOAc. After purifying the residue by ruthenium dioxide column chromatography (esolvent: dichloromethane/sterol' gradient 100/0 to 95/5), 1.2 g of 6-fluoro-5-methoxy in the form of yellow crystals was obtained. Base - 3- (D is more than -3-yl)-9Η-β-η lyon. </ RTI> <RTIgt; d, J = 2.9 Hz, 3 H); 7.28 (dd, J = 3.2 and 8·8 Hz, 1 H); 7.45 to 7.55 (m, 2 H); 8.48 ((1(1(1,1/1) 1.8 and 2.0 and 7.9 1^,11^); 8.54 to 8.62〇, 2 11); 9.03 (d, *7=0.7 Hz, 1 H); 9.33 (width d, /=1.8 Hz, 1 H); 11.81 (width s, 1 H) Example 11: Synthesis of N-[2-(dimethylamino)ethyl]·4_[6·fluoro_3_(pyridine_3·yl)-9Η·β-porphyrin-5 -yl]benzamide oxime step 1: synthesis of 6-gas-3-(e ratio -3-yl)-9Η-ρ_ 味-5-ol (D6 R3=3'-pyridyl, R&quot;= F)

D6 (R3 = 3_-pyridyl, R&quot; = f) 615 mg of 6-fluoro-5·decyloxy_3-(pyridine-3- 152238.doc -92- 201124414 base) at a temperature of 150 ° C The bath of -9 Η-β-carboline (Example 10) in a mixture of 15 ml of acetic acid and 3 ml of concentrated hydrochloric acid was placed under microwave irradiation for 8 hours.丨·5 m丨 concentrated hydrochloric acid was added to the medium, and after 2 hours and then at 15 Torr. The medium was concentrated under microwave irradiation for 1 hour and 30 minutes. The medium was concentrated to dryness several times with deuterium under reduced pressure. The residue was dissolved in a riddle and the solid was rotary filtered and dried and dried under vacuum. 613 mg of 6-fluoro-3-(pyridin-3-yl)-9Η-β-flavor-5-ol was obtained as a green solid. </ RTI> </ RTI> <RTIgt; 7.46 to 7.56 (m,1 H); 7.86 to 8.06 (m,1 H); 8.76 to 8.89 (m, 2 H); 9.02 (m,1 H); 9.10 〇, 1 H); 9.47 (m,1 H); 10.91 (width m, 1 H); 12.12 (width m, 1 H) Step 2: Synthesis of trifluoromethanesulfonic acid 6_fluoro_3_(pyridine·3_*)_9Η_ρ_porphyrin_ 5-based vinegar D7R3=3'-efc bite base, r&quot;=jt)

Add 0.09 ml of trifluorosulfonate anhydride to 50 mg of 6-fluorodine-3-yl)-911-0-weilin-5-ol under argon at a temperature of 0 ° C in a 1.5 ml 11 bite In the solution. After stirring for 4 hours and 15 minutes, the medium was poured into 50 ml of water' and then the aqueous phase was extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 50 mL of saturated aqueous sodium chloride, dried over magnesium sulfate and filtered and evaporated. After purification of the residue in preparative HPLC in acid 152238.doc -93 - 201124414, a 22.5 mg yellow lyophilized material of 6-fluoro-3-(pyridin-3-yl) -9-Η-β-porphyrin-5-yl ester, which was used as it is in the next step. </ RTI> <RTIgt; Ethyl]-4-[6-fluoro·3·(pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide (Example 11)

One chlorine added (11) (1:1) and 0.225 ml 1.5 Μ carbonic acid aqueous solution to 46 mg two, said Acacia acid 6-gas _3-(u ratio bite_3_base)-9Η-β-flavor Lin-5-based vinegar D7 and 53.8 1^&gt;^-[2-(dimethylamino)ethyl]_4_(4,4,5,5-tetradecyl-1,3,2-oxo The shed _2_ base) is in the solution of 1 mi two broth. After microwave irradiation for 30 minutes at a temperature of 140 C, the medium was poured into 5 Torr of water and then extracted three times with 25 ml of ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium sulfate, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. After purifying the residue by basic preparative HPLC, 33 mg of lyophilized material iN[2•(dimethylamino)ethyl]·4-[6-fluoro-3-(pyridin-3-yl) was obtained. ) _9 Η · β · porphyrin _ 5 _ phenyl hydrazine. UPLC-MS-DAD-ELSD: Tr (min)=0.45 ; [M+H] + : m/z 454 ; 152238.doc -94- 201124414 [M+2H]2+: m/z 227.5 (base peak) ;[μ·Η]_: m/z 452 1H NMR (400 MHz, DMSO- 66) ppm: 2.26 (s, 6 H); 2.53 (m partially masked, 2 H); 3.42 to 3.50 (m, 2 H 7.39 to 7.45 (m, 2 H); 7.58 ((1 (1, /= 9.0 and 9.8 out, 111); 7.69 to 7.77 (111, 3 11); 8.06 (td, ·7=1·7 and 8.3 Hz, 1 H); 8.13 (d, /=8.5 Hz, 2 H); 8·17 (s, 1 H); 8.51 (dd, J=1.7 and 4·6 Hz, 1 H); 8.59 (width t, J = 5.6 Hz, 1 H); 8.84 (width d, J = 1.7 Hz, 1 H); 9.07 (d, J = l. 〇 Hz, 1 H); 12.03 (width s, 1 H) Example 12 : Synthesis of N-[4-(l-methylpiperidinyl)]-4-[6-fluoro-3-(pyridin-3-yl)-9H-p-porphyrin-5-yl]benzamide Step 1: Synthesis of N-[4-(l-fluorenyl), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroin-2-yl) Benzylamine

521 mg 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)benzamide

Jun, 200 mg 4-amino-1-methylbirthine, 603 mg TOTU and 7 mL DMF were introduced into a 25 ml round bottom flask. Then triethylamine (1 23 ml) was added dropwise and the mixture was then mixed. 6 hours. The reaction was quenched by the addition of 5 〇 mi steaming water and the aqueous phase was extracted with 3 X 25 ml of ethyl acetate. After the combined organic phases were washed with 5 liters of water, the phases were dried over magnesium sulfate and evaporated under reduced pressure. Thus, 301 mg of Ν-[4-(1·methyl 唆 唆)]_4·(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzene was obtained. The amine was taken and used in the next step without further purification.

S 152238.doc -95- 201124414 Step 2: Synthesis of N-[4-(l-methylpiperidinyl)]-4-[6-fluoro-3-(»pyridin-3-yl)-9Η-Ρ -porphyrin-5-yl]benzamide (Example 12)

Add 7.1 mg of [ι,ι·_bis(diphenylphosphino)ferrocene] dipalladium (11) (1:1) and 0.389 ml of 1.5 hydrazine carbonate aqueous solution to the chloroform 80 mg trifluoromethanesulfonic acid 6-fluoro-3-(pyridin-3-yl)-9Η-β-carboline-5-yl ester D7 and 111.6 mg Ν-[4-(1-methylpiperidinyl) ] 4-(4,4,5,5-tetramethyl-1,3,2-dioxos-2-yl)benzamide in 2 ml of a solution of dioxane. After microwave irradiation for 30 minutes at a temperature of 140 ° C, the medium was poured into 50 ml of water and then extracted three times with 25 ml of ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated. After purifying the residue by basic preparative HPLC, 97 mg of the lyophilized material was obtained as _[4_(1_mercaptopiperidinyl)- 4-[6-fluoro-3-(pyridinium- 3-yl)-9Η-β-carboline-5-yl]benzamide. UPLC-MS-DAD-ELSD: Tr (min) = 0.47 ; [M+H] + : m/z 480 ; [M +2H]2+: m/z 240 (base peak); m/z 478 Example 13: N-(2.Aminoethyl)_4_[6_Fluor_3 decabiidine_3_yl)_9Η_β_咔啉-5-yl]benzamideamine 1 : Ν·[2-(Tertidinoxycarbonylamino)ethyl]_4_(4,4,5,5•tetradecyl _ 1,3,2 -Bromide-flavored 2-based)benzamide 152238.doc •96· 201124414

500 mg 4·(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) benzoic acid, 387 mg Ν-(2-aminoethyl)amine T-butyl formate, 694 mg TOTU and 7 ml DMF were introduced into a 25 ml round bottom flask. Triethylamine (1.41 ml) was then added dropwise and the mixture was then spoiled for 6 hours. The reaction was quenched by the addition of 50 ml of steaming water and the aqueous phase was extracted with 3 x 25 ml of ethyl acetate. After washing the combined organic phases with 50 ml of brine, EtOAc m. Thus 623 mg of Ν-[2·(t-butoxycarbonylamino)ethyl]-4-(4,4,5,5-tetradecyl-1,3,2-dioxaborazole-2- Phenylamine was used in the next step without further purification. Step 2: Synthesis of Ν-(2-aminoethyl)-4-[6-1-3-(&quot;Bite-3-yl)-9Η-β-carboline-5-yl]benzamide (Example 13)

Add 7 mg of bis(diphenylphosphino)ferrocene dichloride mixed with dioxane to (11) (1:1) and 0.266 ml of 1_5 Μ carbonate aqueous solution to 70 mg of difluoroantimony The acid is more than -3-yl)-9Η-β-. Karin-5-based from D7 and 130 mg Ν_[2-(t-butoxycarbonylamino)ethyl]_4_(4,4 5 5_tetradecyl-1,3,2-dioxaborazole -2·yl)benzamide in a solution of 1.75 ml of dioxane. After microwave irradiation for 30 minutes at a temperature of 140 ° C, the medium was poured into 50 ml of water and then extracted three times with 25 ml of ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography, and 89 mg of N-[2-(t-butoxycarbonylamino)ethyl b 4_[6_fluoro_3_(11 bite-3-yl)-9Η-β was obtained. - Porphyrin-5-yl] benzoate. The latter compound was dissolved in 3 ml of sterol' and then a 2 m 4 guanidine hydrochloride solution was added. After 1 hour and 30 minutes, the medium was neutralized with an aqueous sodium hydrogencarbonate solution, and then extracted with EtOAc EtOAc. The combined organic phases were dried with anhydrous magnesium sulfate, filtered and evaporated After purifying the residue by basic preparative HPLC, 20 mg of N-(2-aminoethyl)-4-[6-fluoro-3-(pyridin-3-yl)-9Η-β-咔- 5-yl]benzamide. </ RTI> <RTIgt; Pyridin-3-yl)-9H-p-porphyrin-5-yl]benzoic acid

19.6 mg of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (11) (1:1) and 1.072 ml of 1·5 Μ aqueous solution of cesium carbonate mixed with dichlorosilane Add to 281 mg of trifluoromethanesulfonic acid 6-fluoro-3-(pyridin-3-yl)-9Η-β-carboline-5-yl ester D7 and 210 mg 4·(4,4,5,5-four A solution of decyl-1,3,2-dioxaboron-2-yl)benzoate in 7 ml of dioxane. After microwave irradiation at 120 ° C for 1 hour, the medium was poured into 5 ml of water and then extracted three times with 50 ml of acetic acid 152238.doc -98 - 201124414 vinegar. The combined organic phases were washed with a saturated aqueous solution of sodium sulfate, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (solvent: (: 1 / 2 (: 12/1^ 011: 100/0 to 90/10)), and 214 mg of 4-[6-fluoro-3-(pyridine- 3-yl)-9Ρί-β-carboline-5-yl] methyl benzoate. This compound was dissolved in 6 ml of THF and 4 ml of methanol, and then aqueous lithium hydroxide monohydrate (210 mg K3 ml water) was added. After 3 hours, 20 ml of distilled water was added and the pH of the medium was returned to 4 by the addition of aqueous hydrochloric acid. The precipitate was filtered off, washed with distilled water, dried by rotary filtration, and then in vacuo in the presence of potassium hydroxide at 5 It was dried underneath, thus obtaining 166 mg of 4-[6-fluoro-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzoic acid. UPLC-MS-DAD-ELSD: Tr (min) = 0.66; [M+H] + : m/z 384 ; [MH]-: m/z 382 Example 15. N-[(lS,2S)-2-Aminocyclohexyl]_4_[6- Gas-3 ten bite _3·yl)_9H-P-porphyrin-5-yl]benzamide

A mixture of 80 mg of 4-[6-fluoro-3-(0-But-3-yl)-9Η-β-weilin-5-yl]benzoic acid and 1.6 ml of sulfurous chlorine was refluxed for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& Brewing chlorine. Suspending this compound

S 152238.doc -99- 201124414 In 1 ml of dichloromethane, this suspension is then added to a solution of 238 mg (lS,2S)-(+)-diaminocyclohexane in 1 ml of dichloromethane in. This mixture was stirred at ambient temperature for 20 hours, then 1 ml of decyl alcohol and 250 mg of cerium oxide were added, and then the reaction mixture was concentrated to dryness under reduced pressure. The product was purified by silica gel chromatography (solvent: CH2C12/NH3 2 N (in MeOH): 100/0 to 9/9). Thus, 48 11^1^-[(18,23)-2-aminocyclohexyl]-4-[3-fluoro-6-(&quot;bipyridin-3-yl)-9Η-β-carboline- 5-yl]benzamide. UPLC-MS-DAD-ELSD: Tr (min) = 0.47; [M+H] + : m/z 480 ; [M+2H]2+: m/z 240 (base peak); [MH]-: m /z 478 Example 16: Synthesis of 5-methoxy-3-(pyridin-3-yl)-9H-p-flavor Step 1: Synthesis of N-(3-decyloxyphenyl)-2,2-di Methyl propyl amide

8.6 g of sodium carbonate was added to a solution of 1 〇 g of 3-methoxyaniline in 23 〇 ml of methylene chloride. 10 m丨2,2_dimethylpropane chloride was added dropwise. After stirring the suspension for about 6 hours at a temperature of about 20 C, an additional 8 mg of sodium carbonate and 1 ml of 2,2-dimethylpropane were added. After stirring for 6 hours at a temperature of about 汕, 800 mg of sodium carbonate and 1 ml of 2,2 dimethylpropionamidine were added. After stirring for 16 hours, the medium was poured into 2 〇〇 ml of water and then extracted three times with 1 〇〇 ml of ethyl acetate, and the combined organic phases were dried over anhydrous magnesium sulfate.

152238.doc •100- 201124414 In the next step. LC-MS-DAD-ELSD: Tr (min) = 3.61; [M+H] + : m/z 208 Step 2: Synthesis of N-(2-iodo-3-methoxyphenyl)-2,2- Dimethyl propylamine B3

The product can be prepared as described in Step 3 of Example 10, but from a solution of 1 〇g n-(3-decyloxy)-2,2-dimethylpropanamide in 45 ml of tetrahydropurine. Start with a solution of 75.3 ml butyl clock (1.6 Μ 炫 炫 solution) and is·3 g 峨 in 25 ml of tetrahydroanthracene. After purification by ruthenium dioxide column chromatography (solvent: methylene chloride), 12.3 g of N-(2-hard-3-methoxyphenyl)·2.2-difluorenyl in the form of a red oil was obtained. Acrylate. UPLC-MS-DAD-ELSD: Tr (min) = 0.99; [M+H] + : m/z 334 ; [MH]-: m/z 332 Step 3: Synthesis of N-[2-(5_气- 2,3'-bipyridyl_4_yl)_3•methoxyphenyl]_2.2-dimercaptopropanamide C3

The product can be prepared as described in Step 4 of Example 10 but in a microwave oven.

g cesium fluoride and 400 mg bismuth steel start. Add under nitrogen and under stirring 152238.doc -101· 201124414

At 30 minutes and by chromatography on a silica dioxide column (dissolving agent: 5/5 di-methane/

Step 4: Synthesis of 2-(5-gas-2,3,-bipyridyl)-3-methoxyaniline C4

2.15 g contains 50% Ν-[2-(5·gas-2,3·-biapite-4-yl)-3-methoxybenzyl]-2,2-·-mercaptopropylamine The mixture was refluxed in a solution of 24 ml of water and 7 ml of a solution of 4 Μ hydrochloric acid. After adding 2 ml of 4 ml of 4 Μ hydrochloric acid to one of the caesium sulphate, add 5 ml once and reflux for 13 hours, pour the medium into 100 ml of a saturated aqueous solution of sodium hydrogencarbonate and then extract with 10 〇 ml of ethyl acetate. three times. The combined organic phases were dried over anhydrous MgSO4, filtered and evaporated. After purifying the residue by ruthenium dioxide column chromatography (solvent: 4/6 dichloromethane / ethyl acetate), 621 mg of 2-(5-gas-2,3·- 0 is more than -4-yl)-3-methoxyaniline. UPLC-MS-DAD-ELSD: Tr (min)=0.64; [M+H] + : m/z 312 Step 5 · Synthesis of 5-methoxy-3-(°lfc--3-yl)-9Η- --flavor (example 16)

实例 Example 16 152238.doc -102- 201124414 In a microwave oven reactor, 620 mg of 2-(5-chloro-2,3'-linked. butyl-4-yl)-3-methoxyaniline, 114 Mg copper iodide and 827 mg carbonic acid were introduced into 19 ml of dimethyl hydrazine. After microwave irradiation twice at a temperature of 160 ° C for 5 hours and 3 minutes, the medium was poured into a mixture of 50 ml of 10% ammonium aqueous solution and 50 ml of acetic acid. The aqueous phase was extracted twice with 50 ml of EtOAc EtOAc. After purifying the residue by ruthenium dioxide column chromatography (solvent: di-methane, 95/5 dichloromethane/methanol, followed by 90/10 dioxane/methanol), 170 mg of milky white solid was obtained. 5_Methoxy-3-(pyridin-3-yl)-9Η·β-carboline. LC-MS-DAD-ELSD: Tr (min) = 2.64; [M+H] +: m/z 276; [M-Η]-: m/z 274 1H NMR (400 MHz, DMSO-56) ppm: 4.09 (s, 3 H); 6.81 (d, */=8.1^12,111); 7.20 ((1,&gt;/=8.11^,111); 7.47 to 7.55 (111,2 ^); 8.46〇 ( 1, /= 2.0 and 8.0 1^, 11^); 8.55 to 8.59 (111, 2 11); 8.98 (d, "/=1.2 Hz, 1 H); 9.31 (width d, J = 2.0 Hz, 1 H 11.75 (width m, 1 H) Example 17: N-[2-(dimethylamino)ethyl]-4_[3-(pyridyl)-9H-p-miso·_5-yl]benzene Invitrogen Step 1: Synthesis of 3-(pyridin-3-yl)·9Η-β-carboline-5-ol (D6 R3=3'-pyridyl 'R”=H)

152238.doc •103- 201124414 l7〇mg 5-methoxy-3-(pyridin-3-yl)-9H-β-carboline (Example 10) in 4.2 ml of acetic acid with 0.85 at a temperature of 150 °C The solution in a mixture of ml of concentrated hydrochloric acid was placed under microwave irradiation for 6 hours. 400 μL of concentrated hydrochloric acid was added to the medium, and the medium was placed under microwave irradiation at 150 ° C for 7 hours. The reaction medium was concentrated to dryness with toluene several times under reduced pressure. The residue was dissolved in B. and the solid was filtered and dried and dried in a vacuum bell jar. 134 mg of 3-(pyridin-3-yl)-9Η-β-carboline-5-ol was obtained as a red solid. UPLC-MS-DAD-ELSD: Tr (min) = 0.55; [M+H] + : m/z 262 Step 2: Synthesis of 3-(pyridin-3-yl)-9H-h porphyrin trifluoromethanesulfonate -5-yl ester (D7 R3=3,-pyridyl, R"=H)

0.26 ml of trifluorodecanesulfonic anhydride was added to 134 mg of 3-(pyridin-3-yl)-9Η·β-carboline-5-ol and 12 mg of DMAP at 4 ° C under argon. In a solution of m bupidine. After 4 hours, 1 〇〇 μΐ trifluoromethane was added to the acid anhydride. This medium was poured into 50 ml of water, and then the aqueous phase was extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with aq. After purification of the residue in an acidic medium by preparative HPLC, 77 mg of yellow trifluoromethanesulfonic acid in the form of a lyophilized material, 3-(D-pyridyl_3_yl)_9Η-β-咔--5-yl The ester was used as it is in the next step. LC-MS-DAD-ELSD: Tr (min) = 3.47; [M+H] + : m/z 394 ; 152238.doc • 104 - 201124414 [MH]-: m/z 392 Step 3: Synthesis of N-[ 2-(Dimethylamino)ethyl]-4-[3_(n ratio bite_3_yl)·9H-P-porphyrin-5-yl]phenyl hydrazide (example π)

'1 1 gas handle (11) (1:1) and 〇·3〇4 ml 1.5 Μ carbonate aqueous solution added to 77 mg trifluoromethanesulfonate 3-(pyridin-3-yl)-9Η-β-咔Porphyrin-5-based vinegar D7 (R3=3·-» than bite, R&quot;=H) and 77 mg Ν-[2·(didecylamino)ethyl]-4-(4,4,5 , 5-tetramethyl-1,3,2-dioxaboran-2-yl)benzamide in a solution of 1 ί 8 ml of diche. After microwave irradiation at a temperature of 120 ° C for 30 minutes, the medium was poured into 50 ml of water and then extracted three times with 25 ml of ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered and evaporated. After purifying the residue by preparative preparative HPLC, 55 mg of [2-(dimethylamino)ethyl]-4-[3-(^b)-3-yl) -9Η-β-carboline-5-yl]benzamide. LC-MS-DAD-ELSD: Tr (min) = 2.27; [m+H] +: m/z 436; [MH]-: m/z 434 Example 18: N-[(lS,2S)-2· Aminocyclohexyl]·4_[6-methoxyethoxy.3_(1-methyl-1Η-°bizozol-4-yl)-9Η-β-咔琳-5-yl]benzamide s 152238.doc •105- 201124414 Step 1: Synthesis of 2,5-dichloro-4-trimethylstannylpyridine A2

A solution of 10.45 ml (74.32 mmol) of diisopropylamine in 1000 ml of tetrahydrofuran was stirred at -78 °C under argon. 28.6 ml (74.32 mmol) of butyllithium (2.5 M) in hexane was slowly added while maintaining the temperature below -70 °C. After stirring at -78 ° C for 30 minutes, 10 g (67.5 7 mmol) of 2,5-dialdehyde was added over 25 minutes. Than the solution of 200 ml tetrahydrogen sigma. After stirring at -78 ° C for 1 hour and 30 minutes, 17.5 g (87.84 mmol) of trimethyltin chloride and 100 ml of tetrahydrogen were added dropwise. Fu. The reaction mixture was stirred at ambient temperature for 14 hours and then hydrolyzed with 400 ml of a saturated solution of ammonium chloride and 350 ml of water. The suspension was extracted three times with 500 ml of ethyl acetate. The organic solution was separated by sedimentation, dried over magnesium sulfate and then concentrated to dryness using a rotary evaporator to yield 27 g of a crude oil, which was chromatographed with cerium dioxide (200 g) (solvent: cyclohexane / acetic acid Ethyl ester = 97.5 / 2.5, purified by volume. 12.46 g (59%) of the material was obtained as a white powder. LC-MS-DAD-ELSD: Tr (min) = 5.09; [M+H] + : m/z 309 (corresponding to the isotope profile of the tin derivative) Step 2: Synthesis of 2-bromo-4-(methoxy Ethoxy)-1-nitrobenzene (B4, Ralc=CH2CH2OMe)

152238.doc •106- 201124414 8 g of 3-bromo-4-nitrophenol, 5.07 g of potassium carbonate and 6 77 g of tetrabutyl iodide were introduced into a dry 250 ml one-necked flask under argon. Then, ι 6 〇 ml of anhydrous DMF and 5.17 ml of 2-bromoethyl methyl ether were introduced, and then the mixture was heated at 100 ° C for 1 hour with stirring. The reaction medium was concentrated under reduced pressure, and the residue was dissolved in water and ethyl acetate. After phase separation, the organic phase was dried over magnesium sulfate and filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (400 g EtOAc EtOAc: EtOAc: EtOAc) Thus, 9.1 g of 2-bromo-4-(methoxyethoxy)-indole_nitrobenzene was obtained. UPLC-MS-DAD-ELSD: Tr (min) = 0.99 Step 3: Synthesis of 2-(2,5-dichloropyridin-4-yl)-4.methoxyethoxy nitrobenzene

Introducing 9,1 g of 2-bromo-4-(decyloxyethoxy)_!_nitrobenzene B4 in a 500 ml three-necked flask equipped with a water-cooled condenser (dry and under argon) Ralc=CH2CH2OMe), 995 mg of dichloro[1,4-bis(diphenylphosphino)butane]palladium and 4·7 g of copper oxide (π) and dissolved in 2 ml of anhydrous DMF. The mixture was placed under an argon atmosphere and then heated at 100 ° C with stirring. After 5 minutes, a solution of 15.36 g of 2,5-dioxa-4-tridecylstannylpyridine A2 in 60 ml of anhydrous DMF was added, and then at 11 Torr. (The mixture was heated for two hours. After cooling, the reaction medium was filtered through celite, and the solid was washed with ethyl acetate several times, and then the filtrate was concentrated under reduced pressure. 矽 I52238.doc • 107- 201124414 The product was purified (400 g SiO 2 ; eliminator: heptane / Et EtOAc: 3/1). 6.2 g of 2-(2,5-dipyridin-4-yl)-3- methoxy ethoxy ··1 - decyl benzene. UPLC-MS-DAD-ELSD: Tr (min)=1.10 ; [M+H] + : m/z 343 and 345 (corresponding to the isotope profile of a chlorine compound) Step 4: Synthesis 2-(2,5-Dichloropyridine-4-yl)·4-methoxyethoxyaniline

In a 500 ml round bottom flask, 7 3 g 2 (2,5-dichloropyridin-4-yl)_3_methoxyethoxy-1-nitrobenzene was dissolved in 2 mL of acetic acid. Subsequently, 19.4 g of zinc powder was gradually introduced (the exotherm was controlled by cooling the round bottom flask with ice). The medium was then stirred at ambient temperature for 3 minutes. The reaction medium was filtered through celite, and the solid was washed several times with ethyl acetate, and then the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and then washed with a 28 〇/〇 aqueous ammonia solution until the pH was constant at 8-9. The organic phase was dried over magnesium sulfate, filtered and evaporated. The product was subsequently purified by oxime chromatography (34 〇 g si 〇 2, solvant: heptane / EtOAc: EtOAc). Thus 3 g 2 (2,5 dipyridin-4-yl)-4-methoxyethoxyaniline was obtained. UPLC-MS-DAD-ELSD: Tr (min)=〇.91 ; [M+H] + : m/z 313^ 3 1 5 (corresponding to the isotope profile of the digas compound) Step 5: Synthesis of 3-chloro- 6-methoxyethoxy_9H_p_porphyrin 152238.doc -108· 201124414

Introducing 3 g of 2-(2,5-diox-4-butoxy-4-yl)-4-methoxyethoxyaniline, 2.65 g of carbonic acid and 2.5 g of copper (II) propionate into 250 ml The crucible in a three-necked flask was then added with 100 ml of DMSO and the mixture was heated at 150 ° C for 1 hour. After cooling, the reaction medium was poured into a mixture of 800 ml of an aqueous ammonium chloride solution and ethyl acetate under vigorous stirring. The aqueous phase was extracted again, and the combined organic phases were washed sequentially with a 4% aqueous solution of water & brine. The organic phase was dried over magnesium sulfate, filtered and evaporated. The product was subsequently purified by silica gel chromatography (2 〇〇 g si02, solvating agent: Gengyuan/EtO Ac: 3/2). Thus, 2.2 g of 3-chloro-6-methoxyethoxyethoxy-9Η-β-carboline was obtained. UPLC-MS-DAD-ELSD: Tr (min) = 0.80; [M+H] + : m/z 277 ; [MH]-: m/z 275 Step 5: Synthesis of 3-(1-mercapto-1H- Pyrazole-4·yl)-6-methoxyethoxy-9H-P-porphyrin

1·1 g of 3-chloro-6-methoxyethoxy_9Η-β·porphyrin, 145 mg [1, Γ·bis-(diphenylphosphino)ferrocene]dichloropalladium (11 ), 1.24 g ι_methyl-4-(4,4,5,5-tetradecyl-indole, 3,2-diboron benzo-2-yl)-lH-pyrazole, 8 ml 1.5 Μcarbonic acid The aqueous chain solution and 23 ml of 1,4-dioxane were placed in a 35 ml microwave reactor. The tube was sealed and then subjected to microwave irradiation for 2 hours at 15 ° C. Add 152238.doc • 109- 201124414 plus 145 mg [1,1,-bis(diphenylphosphino)ferrocene]dichloropalladium ( II) and 413 mg of 1-methyl-4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)-lH-pyrazole, and then The tube was subjected to microwave irradiation for 1 hour at 150 °C. If the reaction is still incomplete (monitored by UPLC/MS), this can be repeated again. The reaction mixture was diluted with 1 50 ml of ethyl acetate and washed with 150 ml of water. After separation by sedimentation, the aqueous phase was extracted with ethyl acetate (100 ml), and then the organic phase was combined, dried over magnesium sulfate, filtered and then concentrated in vacuo. The residue was purified by column chromatography (150 g EtOAc, eluting solvent: CH2Cl2 / MeOH 100/0 to 95/5). This gave 2.3 g of 3-(1-indolyl-1H-pyrazol-4-yl)-6-methoxyethoxyethoxy-9Η-β-carboline as a solid. UPLC-MS-DAD-ELSD: Tr (min) = 0.51; [M+H] + : m/z 323 ; [MH]-: m/z 321 Step 6: Synthesis of 5-bromo-3-(1-methyl base-iH-n ratio-4-yl)_6-methoxyethoxy-9Η-β-carboline will be 2.3 g

2.3 g of 3-(1-methyl- oxime-pyrazole-4-yl)6-methoxyethoxy-9H porphyrin was dissolved in 500 ml of acetic acid. Add bromine acetic acid solution dropwise (〇 73ι porphyrin dissolved in 5〇〇

152238.doc -110- 201124414 To dry. 2.8 g of 5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-6-methoxyethoxy-9Η-β-carboline are obtained, which can be used without further purification In the next step. UPLC-MS-DAD-ELSD (4 minutes): Tr (min) = i ; [μ + η] + : m/z 401 and 403 Step 7: Synthesis of 4-丨6_曱oxyethoxy-3_( 1_mercapto-1H_pyrazole_4_yl)_ 9H-p-porphyrin-5-yl]benzoic acid

In the tube of the microwave device, 1.0 g of 5-oxa-3-(1-methyl-1H-0 is 嗤-4-yl)-6-methoxyethoxyethoxy-9Η-β- miso, 1.96 g 4-(4,4,5,5-tetradecyl-1,3,2-dioxaborin-2-yl)benzoic acid methyl ester, 288 mg bismuth (triphenylphosphine) palladium and 4.06 g of carbonic acid Dissolved in 20 ml of dioxane and 5 ml of water. After 1 hour of microwave rotation at a temperature of 130 ° C, the medium was poured into 5 μl of water and then extracted three times with 50 ml of ethyl acetate. The combined organic phases were dried <RTI ID=0.0> The residue was purified by silica gel chromatography (solvent: CH2Cl2 / MeOH: 100/0 to 96/4) and 270 mg of 4-[6-methoxyethoxy-3-(1-methyl-1H) -. Ratio. Sodium-4-yl)-9Η-β-^ You-5-yl]methyl benzoate. This compound was dissolved in 29 ml of THF and 10 ml of decyl alcohol' and then aqueous lithium hydroxide monohydrate solution (5 〇〇 mg in 20 ml of water) was added. After two hours, the pH of the medium was returned to 4 by the addition of aqueous hydrochloric acid, and then the medium was extracted with 4×50 ml of ethyl acetate/THF (8/2). 152238.doc -111 · 201124414 The organic phases were combined, dried over magnesium sulfate, filtered and then concentrated in vacuo. Thus, 288 mg of 4-[6-methoxyethoxy-3-(1-indolyl-1H-pyrazol-4-yl)-9Η-β-carboline-5-yl]benzoic acid was obtained. UPLC-MS-DAD-ELSD: Tr (min) = 0.56; [M+H] + : m/z 443 ; [MH]-: m/z 44 i Step 8: Synthesis of N-[(lS,2S)- 2-Aminocyclohexyl]-4_[6-decyloxyethoxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-p-indole-5-yl]benzamide Indoleamine (Example 18)

100 mg of 4-[6-decyloxyethoxy-3-(1-methyl-1H-pyrazol-4-yl)-9Η-β-carboline-5-yl]benzoic acid with 1.8 ml The mixture of sulphur sulphur was refluxed for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; - Weilin-5-yl] benzamidine chloride. This compound was suspended in 2.5 ml of dichloromethane, and this suspension was added to a solution of 25 7 11(18,28)-(+)-diaminocyclohexane in 2.51111 dioxane. The mixture was stirred at ambient temperature for 2 hours, and then 1 ml of methanol and 450 mg of cerium oxide were added. The reaction mixture was concentrated to dryness under reduced pressure. The product was purified by silica gel chromatography (solvent: CH2C12/NH3 2 N (in MeOH): 100/0 to 9/9). Thus, 65 mg of N-[(lS,2S)-2-aminocyclohexyl]·4-[6-decyloxyethoxy]3-(diphenyl- 152238.doc-112-201124414 1H-pyrazole- 4-yl)-9Η-β-morpholin-5-yl]phenyl hydrazine. LC-MS-DAD-ELSD: Tr (min) = 2.41; [M+H] +: m/z 539; [MH]-: m/z 537 Example 19: Synthesis of 6-methoxyethoxy _5_ {4_[3_(ethylamino)propoxy]phenyl}-3-(1-methyl-1Η-» than 嗤-4-yl)_9Η-β·咔琳 Step 1: Synthesis 1-{3 -[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy]propyl}ethylamine

1.2 g of 2-[4-(3-bromopropoxy)phenyl]-4,4,5,5-tetradecyl-1,3,2-dioxabort in a tube of a microwave device 4.7 g of carbonic acid planer was suspended in 11 mi of THF. Then 4.5 ml of 2 Μethylamine in THF was added. The tube was subjected to microwave irradiation for 1 hour at 150 °C. The reaction medium was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic phase was washed with water. The organic phase was dried&apos; filtered and then concentrated to dryness under reduced pressure. Obtaining 2 g of a smear-like oil of 1·{3·[4-(4,4,5,5-tetramethyldiboron-2-yl)-p-oxy]propyl}ethylamine Further purification can be used in the next step. Step 2: Synthesis of 6-methoxyethoxy_5_{4-[3-(ethylamino)propoxy]phenyl}-3-(1-indolyl·1Η-pyrazole-4·yl )-9Η-β-carboline (Example 19)

Example 19 152238.doc • 113· 201124414 The product was prepared by the same procedure as used in Example 6, but from 110 mg of 5-bromo-3-(1-methyl-1H-pyrazol-4-yl)- 6-methoxyethoxy 9 Η-β-carboline (Step 6 of Example 18), 252 mg 1-{3-[4-(4,4,5,5-tetramethyl·1,3, 2 - Oxygen-enriched-2-yl)phenoxy]propyl}ethylamine, in mi. 32 mg of hydrazine (triphenylphosphine) palladium and 0.36 ml of a 1.5% aqueous solution of cesium carbonate were started in the alkane. Microwave irradiation at a temperature of 150 ° C for 45 minutes and after purification by a dioxide column chromatography [esolvent: di-methane/NH 3 2 Μ (in decyl alcohol), gradient 100/0 to 80/20] , 4 mg of 6-methoxyethoxy_5-{4-[3-(ethylamino)propoxy]phenyl}_3-(1-methyl-1H-. -Base)-9H-β-味琳. UPLC-MS-DAD-ELSD: Tr (min) = 0.46; [M+H] + : m/z 500 ; [MH]-: m/z 498 Example 20: Synthesis of N-[(lS,2S)-2 -Aminocyclohexyl]-4-[6-cyclobutyloxy-3-(1-methyl-1Η-° than 咏-4-yl)-9Η-β-味琳-5-yl]Benzene Indoleamine Step 1. Synthesis of 2-, odor-4-(cyclobutyloxy)-1-reylbenzene (Β4, Ralc=cyclobutyl)

5 g of 3-bromo-4-nitrophenol, 6.33 g of potassium carbonate and 4.23 g of tetrabutyl iodide were introduced into 250 ml of a single-necked flask which was dried under argon. Subsequently, 100 ml of anhydrous DMF and 3.24 ml of bromocyclobutane were introduced, and then the mixture was heated at 100 ° C for 1 hour while mixing. 3.24 ml of bromocyclobutane was introduced. After cooling, the reaction medium was concentrated under reduced pressure and the residue was dissolved in a mixture of water and ethyl acetate 152238.doc - 114 · 201124414 and vigorously stirred. After phase separation, the organic phase was dried with magnesium sulfate, filtered and evaporated. The crude product was purified by silica gel chromatography (solvent: CH2C12 / heptane: 1/4). Thus 4.6 g of 2-bromo-4·(cyclobutyloxyoctylbenzene) was obtained. UPLC-MS-DAD-ELSD: Tr (min)=1.15 Step 2: Synthesis of 2-(2,5-dichloropyridine-4 -yl)-4-cyclobutyloxy-1-nitrobenzene

In a 250 ml three-necked flask equipped with a water-cooled condenser (dry and under argon), introduce 4.6 g of 2-bromo-4-(cyclobutyloxy)-p-nitrobenzene B4 (Ralc=cyclobutane) Base), 511 mg of dichloro[1,4-bis(diphenylphosphino)butane]palladium and 2.42 g of copper (II) iodide and dissolved in 115 ml of anhydrous DMF. The mixture was placed under an argon atmosphere and then heated at 100 ° C with stirring. After 5 minutes, a solution of 7.88 g of 2,5-dichloro-4-trimethylstannylpyridine A2 in 35 ml of anhydrous DMF was added, and then the mixture was heated at 11 ° C for 2 hours. After cooling, the reaction medium was filtered through celite, and the solid was washed with ethyl acetate several times and then filtrated under reduced pressure, by chromatography (400 g SiO 2 ; solvant: heptane / EtOAc: 9/1) The product was purified. Thus, 3.2 g of 2-(2,5-one-milk-buty-4-yl)-3-bromobutyloxy-1-nitrobenzene was obtained. UPLC-MS-DAD-ELSD: Tr (min)=1.18 ; [M+H] + : m/z 339A 341 (corresponding to the isotope profile of the digas compound) Step 3: Synthesis of 2-(2,5-dichloro Pyridin-4-yl)-4-cyclobutylaniline

S 152238.doc •115· 201124414

&lt;!&gt; In a 250 ml round bottom flask, 32 g of 2(5,5·dichloropyridin-4-yl)_3_cyclobutyloxy-1·nitro group was dissolved in 150 ml of acetic acid. Subsequently, 8.63 g of zinc powder was gradually introduced (the exotherm was controlled by cooling the round bottom flask with an ice bath). The medium was then stirred at ambient temperature for 30 minutes. The reaction medium was filtered through celite to 'wash the solid several times with ethyl acetate' and then the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and then washed with a 28% aqueous ammonia solution until the pH was constant from 8-9. The organic phase was dried over magnesium sulfate, filtered and evaporated. The product was subsequently purified by silica gel chromatography (200 g SiO 2 , solvating agent: heptane/Et〇Ac: 4/1). Thus 1.70 g of 2-(2,5-dipyridinyl-4-yl)-4-cyclobutylaniline were obtained. LC-MS-DAD-ELSD: Tr (min)=4.54; [M+H] + : m/z 309 and 3 11 (corresponding to the isotope profile of the dichloro compound) Step 4: Synthesis of 3-chloro-6-ring Butyloxy-9H-P-porphyrin

Introducing 1.7 g of 2-(2,5-dichloro D-buty-4-yl)-4-cyclobutyloxyaniline, 1.52 g of potassium carbonate and 1.44 g of copper acrylated copper hydride (Π) into 150 ml In a round bottom flask. Then 600 ml of DMSO was added and the mixture was heated at 150 ° C. After cooling, the reaction medium was poured into a mixture of a chlorinated aqueous solution and ethyl acetate under vigorous stirring. The aqueous phase is extracted again, and then the combined organic phases are sequentially washed with 14% aqueous water solution, water and brine. The organic phase was dried over <RTI ID=0.0>: </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Thus 1 g of 3-chloro-6-cyclobutyloxy-9 Η-β-carboline was obtained. UPLC-MS-DAD-ELSD: Tr (min)=l.〇7 ; [M+H] + : 273 m/z ; [MH]-: m/z 271 Step 5: Synthesis of 3-(1-methyl -1H-pyrazol-4-yl)-6-cyclobutyloxy-9H-P- 咔

1.0 g of 3-chloro-6-cyclobutyloxy-9Η-β-β kalin, 268 mg [1,1'-bis(diphenylphosphino)ferrocene] dipalladium (ruthenium), 915 mg 1-methyl-4-(4,4,5,5-tetradecyl-1,3,2-dioxos-2-yl)-111-0 than '» sitting, 7.3 11111.5

The acid slurry aqueous solution and 2 〇 ml of l,4-dioxane were placed in a 35 mL microwave reactor. The tube was sealed and then at 15 Torr. (: subjected to microwave irradiation for 1 hour. Add 134 mg [1,1,_bis(diphenylphosphino)ferrocene] digas palladium (11) and 915 mg 1-mercapto-4-(4,4 , 5,5-tetramethyl-1,3,2-dioxaboron-2-yl)-iH-pyrazole, and then subject the tube to microwave irradiation for 1 hour at 15 (TC). If the reaction is still not This operation can be repeated once more (by UPLC/MS monitoring). The reaction mixture is diluted with 150 ml of ethyl acetate and washed with 15 mL of water. After separation by sedimentation, water is extracted with 100 ml of ethyl acetate. Phase 'and then the organic phases were combined, dried over magnesium sulfate, filtered and then concentrated in vacuo and purified by ruthenium dioxide column chromatography (15 〇g SiO 2 , solvating agent: CH 2 Cl 2 /Me 〇 H 152238.doc 5 • 117- 201124414 100/0 to 95/5) Purification of the residue. Obtained 530 mg of solid form of 3-(1-methyl-1H-pyrazol-4-yl)-6-cyclobutyloxy_9Η-β- Porphyrin. UPLC-MS-DAD-ELSD (4 min): Tr (min) = 1.31; [μ+Η] + . m/z 319 Step 6: Synthesis 5-Methyl-3-(1-methyl- 1H-® than sal-4-yl)-6-cyclobutyloxy·9H-P-carboline

53 〇 mg of 3-(1-indolyl-1H-pyrazole-4-yl)-6-cyclobutyloxy-9 Η-β· porphyrin was dissolved in 125 ml of acetic acid. A solution of bromine in acetic acid (〇 17 ml of bromine in 5 ml of acetic acid) was added dropwise. After stirring at ambient temperature for two hours, 5 ml of the same bromine/acetic acid solution was added to complete the reaction, and the mixture was allowed to mix for two hours. If the reaction is still incomplete (monitored by UPLC/MS), this can be repeated again. The reaction medium was then concentrated under reduced pressure. The residue was dissolved in a mixture of methylene chloride and water, stirred, and neutralized by aqueous sodium hydrogen carbonate. The organic phase was washed with an aqueous solution of sodium thiosulfate. The organic phase was dried and filtered and then concentrated to dryness under reduced pressure. The residue was purified by ruthenium dioxide column chromatography (70 g of SiO 2 sol solvent: CH 2 Cl 2 / MeOH 100/0 to 95/5). Obtained 242 mg of 5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-6-cyclobutyloxy-9Η-β-carboline and used for further purification without further purification In one step. UPLC-MS-DAD-ELSD (4 minutes): Tr (min) = 1.53; [Μ+Η] + . m/z 397 and 399 152238.doc -118- 201124414 Step 7: Synthesis of 4-[6-cyclobutene Benzyloxy-3-(1-methyl-1H-pyrazole-4-yl)_ 9Η-Ρ-mispeptidyl]benzoic acid

In the tube of the microwave device '〇·3 g 5-bromo-3-(1-indolyl-1Η-pyrazole-4-yl)6-cyclobutyloxy-9Η-β-咔, 594 mg 4- (4,4,5,5-tetradecyl-1,3,2-diboron-flavored 2-yl) decyl benzoate '88 mg hydrazine (triphenylphosphine) palladium and 1.23 g of carbonic acid 6 ml of dioxane and 15 mL of water. After microwave irradiation for 1 hour at a temperature of 130 ° C, the medium was poured into 5 〇 ml of water and then extracted three times with 50 ml of ethyl acetate. The combined organic phases were dried with anhydrous magnesium sulfate, filtered and evaporatedEtOAc. The residue was purified by silica gel chromatography (solvent: CH2Cl2 / MeOH: 100/0 to 95/5), and 162 mg of 4-[6-cyclobutyloxy_3_(1-methyl-1H. Iridazole 4_yl)·9Η-β-porphyrin-5-yl] decyl benzoate. This compound was dissolved in 9 mL of THF and 3 mL of methanol, and then an aqueous solution of lithium hydroxide monohydrate (in 6 mL of water) was added. After 1 hour, the pH of the medium was returned to 4 by the addition of aqueous hydrochloric acid, and the medium was extracted with 4×50 ml of ethyl acetate/THF (8/2). The organic phases were combined and dried over magnesium sulfate, filtered and then dried under vacuum. Thus, 162 mg of 4-[6-cyclobutyloxy_3_(1-methyl-1Hpyrazol-4-yl)-9Η-β-carboline-5-yl]benzoic acid was obtained. UPLC-MS-DAD-ELSD (4 minutes)·· Tr (min)=1.40 ; [Μ+Η] + : m/z 439 ; [M-HJ-: m/z 437 152238.doc -119- 201124414 8: Synthesis of N-[(lS,2S)-2-aminocyclohexyl]-4-[6-cyclobutyloxy-3-(1-indolyl-1H-.pyran-4-yl)- 9H-p-Yelup-5-yl]benzamide (Example 20)

162 mg of 4-[6-cyclobutyloxy-3-(1-indolyl-1H-pyrazol-4-yl)-9Η-β-carboline-5-yl]benzoic acid with 2.8 ml of sulfur The mixture of ruthenium chloride was refluxed for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; -5-based] Benzoquinone gas. This compound was suspended in 4 ml of dichloromethane, and this suspension was added to a solution of 412 mg of (lS,2S)-(+)-diaminocyclohexane in 4 ml of dichloromethane. The mixture was stirred at ambient temperature for 2 hours, followed by the addition of 1 mL of decyl alcohol and 600 mg of cerium oxide. The reaction mixture was concentrated to dryness under reduced pressure. The product was purified by silica gel chromatography (solvent: CH2C12/NH3 2 N (in MeOH): 100/0 to 90/10). Thus 86 mg of N-[(lS,2S)-2-aminocyclohexyl]_4_[6-cyclobutyloxy_3 (1methyl-1H-pyrazol-4-yl)-9Η-β-咔Lynn 5_yl]benzamide. UPLC-MS-DAD-ELSD: Tr (min)=〇.59 ; [m+H] + : m/z 535 ; [M+2H]2+: m/z 268 (base peak); m/z 533 Example 21 · Synthesis of 6-decyloxy·5_{4_[3·(ethylamino)propoxy]phenyl b 3·(1-methyl-1Η-° than 嗤-4·yl)·9Η- Β-吁琳152238.doc •120· 201124414 Step 1: Synthesis of 2-(2,5-dichloroindole·4-yl)-4-decyloxy-1-nitrobenzene

In a 500 mL three-necked flask equipped with a water-cooled condenser (dry and under argon), 5.44 g of 2-bromo-4-methoxy-p-nitrobenzene, 2.71 g of ruthenium (triphenylphosphine) palladium were introduced. And 893 mg of copper (I) iodide and dissolved in 70 mL of anhydrous DMF. A solution of 8.01 g of diox-4-trimethylstannylpyridine A2 in 24 mL of anhydrous DMF was added, and then the mixture was heated at 110 ° C for 1 hour. After cooling, the reaction medium was diluted with ethyl acetate and the organic phase was washed with water. The organic phase was dried over MgSO.sub.4, filtered and evaporated to give &lt;RTI ID=0.0&gt;&gt;&gt; UPLC-MS-DAD-ELSD: Tr (min)=1.50 ; [M+H] + : m/z 299 and 3 01 (corresponding to the isotope profile of the digas compound) Step 2: Synthesis of 2-(2,5- Dichloropyridin-4-yl)-4-decyloxyaniline

Dissolve 8.51 g of 2_(2,5-dipyridin-4-yl)-3-methoxy-1-nitrobenzene and 32.1 g of tin dichloride dihydrate (11) in a 250 mL round bottom flask In 45 mL of 37% hydrochloric acid. The medium was then heated to 75 t with stirring for 1 hour. After cooling, ethyl acetate and water were added, and the medium was neutralized with a 21% sodium hydroxide solution. After separation by sedimentation, the organic phase was dried over magnesium sulfate, filtered and evaporated. The product was subsequently crystallized by wet milling with dichloromethane. After filtration and rotary filtration drying, 3.97 g of 2_(2,5-dipyridinyl-4-yl)_4_曱 152238.doc-121-201124414 oxoamine was obtained. UPLC-MS-DAD-ELSD: Tr (min) = 0.83; [M+H] + : m/z 269 and 271 (corresponding to the isotope profile of a milk compound) Step 3: Synthesis of 3-chloro-6-methoxy -9H-P-porphyrin

53 8 mg of 2-(2,5-dichloropyridin-4-yl)-4-decyloxyaniline, 553 mg of potassium carbonate and 524 mg of copper(II) acetoacetate were introduced into a microwave tube. Then 20 mL of DMSO was added and the mixture was heated at 140 °C for two hours. After cooling, the reaction medium was poured into a mixture of 7% aqueous ammonia solution and ethyl acetate under vigorous stirring. This mixture was filtered through diatomaceous earth, and then the liquid was placed in a separatory funnel. The aqueous phase was extracted with additional ethyl acetate and then washed sequentially with 14% aqueous ammonia, water and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated. Thus, 25 6 mg of 3-chloro-6-nonyloxy-9Η-β-flavor was obtained. UPLC-MS-DAD-ELSD: Tr (min) = 0.85 i [M+H] + : m/z 233 Step 4: Synthesis of 3-(1-indolyl·1Η-°Λ峻-4-yl)-6 -曱oxy_9Η-β-吟琳

250 mg 3-gas-6-decyloxy, 47 mg [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 447 mg 1-methyl-4-( 4,4,5,5·tetradecyl-1,3,2-dioxos-2-yl)-1Η-° ratio, 2 ml 1.5 Μ carbonated water 152238.doc -122- 201124414 solution and 5 ml of 1,4-dioxane was placed in a microwave reactor. The tube was sealed and then subjected to microwave irradiation at 150 ° C for 1 hour. Add 12 mg [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (H) and 112 mg 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaboron-2-yl)-1 Η-pyrazole, and then the tube was subjected to microwave irradiation for 1 hour at 150 °C. The reaction mixture was diluted with 50 ml of ethyl acetate and washed with 50 ml water. After separation by sedimentation, the aqueous phase was extracted with 50 ml of ethyl acetate, and then organic phases were combined, dried over magnesium sulfate, filtered and then concentrated in vacuo. The residue was purified by ruthenium dioxide column chromatography (solvent: CH.sub.2Cl.sub.2 / MeOH 100/0 to 90/10). There was obtained 132 mg of 3-(1-methyl-1H-pyrazol-4-yl)-6-indolyl-9--pyridinium as a brown solid. UPLC-MS-DAD-ELSD: Tr (min)—0.49 * [M+H] + im/z 279 » [MH]-: m/z 277 Step 5: Synthesis of 5-ML-3-(1-methyl -1H-1* than sal-4-yl)-6-methoxy-9H-P-porphyrin

102 mg of 3-(1·methyl-1H-pyrazol-4-yl)-6-decyloxy-9Η-β- miso was dissolved in a mixture of 10 ml of acetic acid and 5 ml of tetrahydrofuran. Then, 5 ml of a bromotetrahydrofuran solution (0.51 ml in 5 〇 ml of tetrahydrofuran) was added dropwise. After stirring at ambient temperature for two hours, 2.5 mL of the same bromine in THF was added to complete the reaction. The latter operation can be repeated depending on the progress of the reaction (monitored by UPLC/MS). After 6 hours, the reaction medium was concentrated under reduced pressure. Residue 152238. doc -123- 201124414 The residue was dissolved in a mixture of di-methane and water, stirred, and neutralized by the addition of aqueous sodium hydrogencarbonate. The organic phase was washed with an aqueous solution of sodium thiosulfate. The organic phase was dried, filtered and then concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (solvent: &lt;RTI ID=0.0&gt;&gt; 88 mg of 5-bromo-3-yl(1-methyl-1H-pyran-4-yl)-6-decyloxy-9 Η-β-carboline was obtained as a green solid. UPLC-MS-DAD-ELSD: Tr (min) = 0.60; [M+H] + : m/z 357A 359 ; [MH]- 355 and 357 Step 6: Synthesis of 6-methoxy_5_{4_[3 · (Ethylamino)propoxy]phenyl} 3_(1-methyl-1H-pyrazol-4-yl)-9Η·β-carboline (Example 21)

85 mg 5-bromo-3-(1-methyl-1Η-pyrazol-4-yl)-6-methoxy-9Η-β-carboline (Step 6 of Example 18), 218 111§1- {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy]propyl}ethylamine (Example 丨9 Step 丨), 28 mg of ruthenium (triphenylphosphine) palladium and 233 mg of carbonic acid dissolved in 2.4 ml of dioxane and 〇6 ml of water. Microwave irradiation at 13 °C for 丨 hours and after purification by cerium oxide column chromatography [esolvent: di-methane/ΝΑ 2 Μ (in decyl alcohol), gradient 100/0 to 80/20] It is necessary to carry 6-methoxy-5-{4-[3-(ethylamino)propoxy]phenyl}_3_(1•曱基_152238.doc - in an acidic medium by HPLC. 124- 201124414 1Η·pyrazole_4-yl)-9Η-β·porphyrin was re-purified. The pure soluble fraction was passed through a 3 g Bond Elut SCX column and recovered by dissolving with 2 Ν ammonia methanol. The product was expected. Thus obtained 29 mg of 6-methoxy-5-{4-[3-(ethylamino)propoxy]phenyl}-3-(1-methyl-iH-indoleazole-4 -based)-9Η-β-carboline. UPLC-MS-DAD-ELSD: Tr (min)=0.49; [M+H] + : m/z 456 ; [M+2H]2+·· m/z 228 (base peak); [MH b · m/z 454 Example 22: Synthesis of 5-methoxy·3·(ι_methyl_1H-pyrazole_4_ylbu 9H_p_porphyrin Step 1: Synthesis [2-(2,5-dichloro-11-pyridyl-4-yl)_3_methoxyphenyl]_2,2-dimethylpropanamide

The product can be prepared as described in Step 4 of Example 10, but in four reactors in a microwave oven and from 7 g of N-(2_iodo·3·methoxyphenyl)_2,2·dimethyl a solution of acetamide in 75 ml of degassed dimethyl decylamine under argon, 7.84 g of 2,5-dioxa-4-(trimethylstannyl)pyridine A2, 3 2 g of fluorine Huayu and 800 mg copper iodide start. 736 mg of bis(diphenylphosphine)dichloropalladium was added under argon with stirring. The medium was heated under stirring at 13 °C for two hours at room temperature. Purification by cerium oxide column chromatography (solvent: 4/1 heptane/ethyl acetate) made it possible to obtain 3.19 g Ν[[2_(2 ,5·dichloropyridine_4•yl)_3-methoxyphenyl]-2,2-dimethylpropanamide LC-MS-DAD-ELSD: Tr (min)=3.67 Step 2: Synthesis Ν-{2-[5·Chloro-2-(ι·methyl_1H•pyrazole_4_yl)pyridine_4_yl]-3-methoxyphenyl b 2,2-dimethylpropanthene Amine I52238.doc -125· 201124414

7.3 g of N-[2-(2,5-digas.pyridyl-4-yl)_3_methoxyphenyl]_2,2-dimethylpropionamide, 916 mg [M,-double ( Diphenylphosphino)ferrocene]digas palladium (II), 4.34 g 1-methyl_4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron· 2_base)-1Η-pyrazole, 44.5 ml 1·5 Μ 酸 酸 酸 酸 solution and no mi ι, 4 _ 2 ° smoldering in a 250 mL round bottom flask. Under the mixing, it is 1 〇〇. The mixture was heated under the arm for 1 hour. The reaction mixture was diluted with 3 mL of ethyl acetate and washed with 300 mL water. After separation by sedimentation, the aqueous phase was extracted with 3 mL of ethyl acetate, and then organic phase was combined, dried over magnesium sulfate, filtered and then concentrated in vacuo. The residue was purified by silica gel column chromatography (6 </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Obtaining 6.62 g of ruthenium-{2·[5-Gas-2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl]-3-decyloxyphenyl}-2 , 2-dimethylpropanamide. UPLC-MS-DAD-ELSD: Tr (min) = 0.84 ; [M+H] + : m/z 399 ; [MH]-: m/z 397 Step 3. Synthesis 5·methoxy·3_(ι_曱基比唾_4_基)琳 (Example 22)

39.4 1118 palladium acetate and 11111^(11)_(+1_[(8)_2_(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine were introduced into the dry and under argon atmosphere 152238 .doc • 126· 201124414 round bottom flask, and then add 8 8 ml of degassed under argon

Base}-2,2-dimercaptopropionamide and 482 m ·4-yl) ° pyridine-4-yl]-3-methoxybenzene mg second sodium sulphate introduced into the microwave oven reactor m] in dioxane. The catalyst solution was added to the microwave tube via a syringe, and the tube was irradiated for a few hours at a temperature of 14 (TC). After cooling, 5 ml of methanol and 50 ml of ethyl acetate were added. The organic phase was treated with 5% sodium hydrogencarbonate. The aqueous solution was washed with MgSO4, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Obtained 5-methoxy-3-(1-methyl-1H-pyrazol-4-yl)-9Η·β-carboline in the form of 670 melon yellow crystals. UPLC-MS-DAD-ELSD: Tr (min ) = 0.53 ; [M+H] + : m/z 279 ; [MH]-: m/z 277 Example 23: 5-{4-[3-(ethylamino)propoxy]phenyl b -(^methyl_1H_pyrazol-4-yl)-9H-P-carboline Step 1: Synthesis of 3-(1-methyl-1H-&quot;Biazol-4-yl)-9Η_β-咔淋- 5-alcohol (D6 R3=3,·pyridyl, R”=H)

4.08 g of 5-methoxy-3·(1-indolyl-1H-pyrazol-4-yl)-9Η-β-carboline (Example 10) in a mixture of 61 ml of acetic acid and 49 ml of concentrated hydrochloric acid The solution was placed in an autoclave. After the autoclave was closed, the medium was heated at a temperature of 160 ° C under a pressure of 20 bar for two hours. The reaction medium 152238.doc -127- 201124414 was concentrated to dryness several times with toluene under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and aqueous sodium hydrogen carbonate. The organic phase was dried, filtered and then concentrated to dryness under reduced pressure. 3.008 g of 3-(1_indolyl-1H-pyrazole-4-yl)_9H_p_咔-lin-5-ol was obtained. UPLC-MS-DAD-ELSD: Tr (min)=0.40; [M+H] + : m/z 265 ; [MH]-: m/z 263 Step 2. Synthesis of dioxin-burning acid 3·( _曱基比唾基)_9H_p_ 味淋-5_基醋 (D7R3=3'-0 than bite base,

Add 0.145 ml of trifluoromethane anhydride to 150 mg of 3-(1-mercapto-1H-pyrazol-4yl)-9Η-β-carboline _5 under argon at a temperature of 〇 ° C Alcohol and 12 mg of DMAP in 4 ml of pyridine. After 4 hours, add 1 〇〇 μΐ three to say that the acid anhydride is. The medium was poured into 50 ml of water and the aqueous phase was extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 50 ml of a saturated aqueous solution of sodium chloride and dried over sulphuric acid, and then concentrated to dryness under reduced pressure. After purification of the residue in an acidic medium by preparative HPLC, </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Porphyrin-5-yl ester. UPLC-MS-DAD-ELSD: Tr (min) = 0.75; [M+H] + : m/z 397 ; [MH]-: m/z 395 Step 3: Synthesis 5-{4-[3-(B Amino)propoxy]phenyl}-3-(l-methyl-152238.doc • 128 · 201124414 1Η-»比唆-4-yl)-9Η-β-啼琳 (Example 23)

The product was prepared by the same procedure as used in Example 6, but from 111 mg of trifluoromethanesulfonic acid 3-(1-methyl]indole-pyrazole·44)_9Ηβ-leaf _ 5_yl ester, 256 mg 1-{3_[4-(4,4,5,5-tetradecyl-1,3,2-dioxaboron-2-yl)phenoxy]propyl}ethylamine (Step of Example 19) ), 32 肆 (triphenylphosphine) palladium and 0.36 ml 1.5 Μ aqueous cesium carbonate solution and 1.8 ^1 1,4·2 chewing start. The microwave was lightly shot at a temperature of 130 C for 1 hour and chromatographed by a dioxide dioxide column [solvent: dichloromethane / NH 3 2 Μ (in decyl alcohol), gradient 1 〇〇 / 〇 to 80 / 20] After purification, it is necessary to carry out 5_{4-[3-(ethylamino)propoxy]phenyl}_3_(1-methyl-m_. than salivyl) base in an acidic medium by HPLC. The fraction of _ 9Η-β-carboline was repurified. The pure fraction was passed through a 2 g B〇nd Elut SCX column and the expected product was recovered by dissolving with 2 N ammonia methanol. Thus, 9 mg of 5-{4-[3-(ethylamino)propoxy]phenyl}}_3·(didecyl-1H-pyrazole-4-yl)-9Η-β-carboline was obtained. UPLC-MS-DAD-ELSD: Tr (min) = 0.50; [M+H] + : m/z 426 ; [M+2H]2+: m/z 213 (base peak); [MH]-: m /z 424 Examples 24 to 26: Step 1: Synthesis of 4-[3-(l-methyl-1H-pyrazole-4-yl)-9Η-β-carboline-5-yl]benzoic acid 5 152238. Doc • 129· 201124414

4-[3-(l-Mercapto-1H-pyrazol-4-yl)-9Η-β-carboline-5-yl] benzoic acid was obtained as the product from step 2 of Example 23. The product was prepared by the same procedure as that used in Example 6, but from 630 mg of trifluoromethanesulfonic acid 3-(1.methyl-1H-pyrazol-4-yl)- -9 邛- porphyrin-5-yl. Ester, 485 melon § 4-(4,4,5,5-tetradecyl-1,3,2-dioxos-2-yl) benzoate, 45 mg and dioxane Starting with bis(diphenylphosphino)ferrocene]dichloropalladium (11) (1:1) and 2.4 ml of 1.5 hydrazine carbonate aqueous solution and 14 ml of 1,4-dioxane. After microwave irradiation for 15 minutes at a temperature of TC, it was hydrolyzed and extracted with ethyl acetate. After drying and dry extraction, the desired product was crystallized by wet milling with a mixture of heptane and ethyl acetate. 495 mg 4-[3-(1-methyl-1H-pyrazol-4-yl)-9Η-β-carboline-5-yl]benzoate oxime. UPLC-MS-DAD-ELSD: Tr (min =0.98 ; [M+H] + : m/z 383 ; (intermediate methyl ester) saponification is carried out by reacting 10 to 16 equivalents of lithium hydroxide monohydrate in a THF/nonanol/water mixture. 425 mg 4-[3-(1-methyl-1H-pyrazol-4-yl)-9Η-β-carboline-5-yl] benzoic acid. UPLC-MS-DAD-ELSD: Tr (min) = 0.79 ; [M+H] + : m/z 369 ; [MH]-: m/z 367 Step 2: N-丨2-(ethylamino)ethyl]-4-[3-(l-甲-1-[1-(l-methyl-1H. 152238.doc) • 130·201124414 °Bizozol-4·yl)-9H-p-porphyrin-5-yl]-N-[(2S)·pyrrolidin-2-ylmethyl]benzamide (Example 25); N-[(lS,2S)-2-aminocyclohexylmethyl-1Η-pyrazol-4-yl)-9Η-Ρ-porphyrin-5-yl]benzamide (Example 26)

Examples 24 through 26 were prepared using the method described in step 8 of Example ί 8 . After the formation of the intermediate thiol chloride, the product is reacted in an amount of the appropriate diamine (Ν-ethylethylenediamine or (S)-aminomercaptopyrrole&quot; in methylene chloride*. In the case where a large number of other geometric isomers exist (Examples 24 and 25), the product can be isolated by acid preparative HPLC (Method 3 or 4). Example 24: UPLC-MS-DAD-ELSD: Tr (min) 〇.59 [Μ+Η] + : 439 m/z Example 25: UPLC-MS-DAD-ELSD: Tr (min). 0.61 [M+H] + : 451 m/z Example 26: UPLC-MS-DAD-ELSD: Tr (min wide 0.68 [M+H] + : 465 m/z Example 27: 4-[6-bromo-3 -(1-mercapto-1H-pyrazole-4-ylindole-5_yl]-indole-[2-(ethylamino)ethyl]phenyl hydrazide

Example 27 5 152238.doc -131 - 201124414 In a 250 mL round bottom flask, 295 mg of N-[2-(ethylamino)ethyl]_ 4-[3-(1-methyl-1Η-° The ratio of -4-yl)-9Η-β_味淋-5-yl] stupid amine (Example 24) was dissolved in glacial acetic acid. A solution of ruthenium-bromobutadienyl imine (143 mg) in glacial acetic acid was added dropwise over 15 minutes. This mixture was mashed at ambient temperature: 3 hours' and then hydrolyzed. The aqueous phase was extracted with ethyl acetate. After drying and filtration, the reaction mixture was concentrated to dryness under reduced pressure. The product was purified by chromatography (solvent: CH2C12 / NH3 2 N (in MeOH): loo / ο to 80 / 20). Thus 327 mg 4-[6-bromo-3-(1-methyl-1H-°bizozol-4-yl)-9Η·β-carboline-5-yl]-N-[2-(ethyl Amino)ethyl]benzhydrazide UPLC-MS-DAD-ELSD: Tr (min)=0.69 [M+H] + : 517 and 519 m/z Example 28: N-[2-(ethylamino) Ethyl]-4-[6-methyl-3-(1-methyl-1H_ ° than -4-yl)-9Η-β-咔琳-5-yl]benzamide

[2-(Ethylamino)ethyl]benzamide (17 〇mg) with thioglycolic acid (59 mg) and [dichloromethane][1,1'-bis(diphenyl) Phosphyl) Ferrocene] Dichloro (11) (1:1) (36 mg), fluorinated (175 mg) and dioxane (4 mL) were introduced into a microwave tube. The mixture was irradiated at 140 ° C for 2 Torr. After hydrolysis, the aqueous phase was extracted with ethyl acetate. After drying and filtration, the reaction mixture was concentrated to dryness under reduced pressure. Separation of N-152238 by acid preparative HPLC (Method 3 or 4), doc • 132· 201124414 [2-(ethylamino)ethyl]-4-[6-methyl·3_(ι_曱基_ ΗΗ_β sits _4_base) than 9Η-β-carboline-5-yl]phenylguanamine. LC-MS-DAD-ELSD: Tr (min) = 2.42 [M+H] + : 339 m/z; [ΜΗ]-: 337 m/z Examples 29 and 30: 4-[6-(cyclobutyloxy) Benzyl-3-(1methyl-1H-pyridyl-4-yl)_9H-P-porphyrin-5-yl]-N-[2-(ethylamino)ethyl]benzimidamide Example 29); 4-[6-(cyclobutyloxy)-3-(1-indolyl·1H_0-biazole·4_yl)-911_External 咻-5-yl]-N-[(2S) -pyrrolidin-2-ylindenyl]benzamide (Example 3〇)

Examples 29 and 30 were obtained starting from the product of Step 7 of Example 2 using the method described in Step 8 of Example 18. After the formation of the intermediate sulfhydryl group, the product is reacted in dichloromethane with an excess of the appropriate diamine (Ν·ethylethylenediamine or (s)-aminomercaptopyrrolidine). The product was purified by gel chromatography (solvent: 2 N (in MeOH): 100/0 to 9 〇 /1 〇) or by acidic preparative HpLC (method 3 or 4). Another method starting from methyl 4-[6-cyclobutyloxymethyl-1Hpyrazol-4-yl)_9Η·β·porphyrin-5-yl]benzoate is also used. In this case, the appropriate diamine (2.8 mmol) was dissolved in dry toluene (8 mL), the mixture was cooled to 〇C, and then 2 Μ trimethyl aluminum benzene solution (2.6 mmol) and Butyllithium solution (27 Μ in heptane, 27 paws "). Add 4.6238.doc -133 · 201124414 and add 4-[6-cyclobutyloxy-3- (THF) dissolved in 3.6 mL of THF Methyl-1H-.Bizozol-4-yl)-9Η-β-carboline-5-yl]benzoic acid methyl ester. The mixture was stirred at ambient temperature for 2 hours and then hydrolyzed with 30 mL aqueous sodium potassium tartrate solution The aqueous phase was extracted with EtOAc. EtOAc (EtOAc) The product was purified by acidic preparative HPLC (Method 3 or 4). Example 29: UPLC-MS-DAD-ELSD: Tr (min) = 0.73 [M+H] + : 509 m/z ; MH]-: 507 m/z. Example 30: UPLC-MS-DAD-ELSD: Tr (min)=0.73 [M+H] + : 521 m/z ; [MH]-: 519 m/z Example 31 to 33 : Step 1: Synthesis of 4-[6-methoxy-3-(1-methyl·ιη_° than sal-4-yl)-9Η-β-carboline-5-yl] Formic acid

4-[6-Methoxy-3-(bumethyl-1Η-pyrazole-4-yl)_9Η-β-carboline-5-yl]benzoic acid was obtained according to the same procedure used for the procedure , which will be 170 mg 5-bromo-3-(1-methyl-1Η•pyrazole_4_yl)_6-methoxy_9Η-β-leaf#, 85 mg 4-(4,4,5,5 - tetradecyl·ι,3,2-dioxane oxime_2_yl) methyl benzoate, 38 mg hydrazine (triphenylphosphine) palladium and 212 mg carbonic acid planed in 〇45 mL water and 2 ml dioxane In the solution. Saponification was carried out by reacting 101 mg of lithium monohydrate monohydrate 152238.doc • 134- 201124414 in a THF/methanol/water mixture. Thus, 75 mg of 4-[6-decyloxy-3-(1-methyl-1H-pyrazol-4-yl)-9Η-β-carboline-5-yl]benzoic acid was obtained. UPLC-MS-DAD-ELSD: Tr (min)=0.81 [M+H] + : 399 m/z ; [MH]-: 397 m/z Step 2: Ν·[2-(ethylamino)B 4-[6-decyloxy-3-(1-methyl-1H-pyrazole-4(yl)-9H-p-porphyrin-5-yl]benzamide (Example 31); N-[(lS,2S)-2-Amino-based hexyl]-4-[6-methoxy- 3-(1-methyl-1H-® than s--4-yl)-9Η-β-咔Lin-5-yl]benzamine (Example 32); 4-[6-methoxy-3-(1-methyl-1Η-pyrazol-4-yl)·9Η-ρ·porphyrin-5 -yl]-N-[(2S)-pyrrolidin-2-ylmethyl]benzamide (Example 33)

Examples 31, 32 and 33 were obtained using the method described during step 8 of Example 18. After the intermediate is formed, the product is dichlorohydrazine with an excess of the appropriate diamine ((8)-aminomethylpyrrolidine or 〇s, 2S)-(+)-diaminocyclohexane or N- Ethyl ethylenediamine) reaction. By gelatin chromatography (dissolving agent: (:112 (:12/&gt;^32&gt;1 (in)^011): 1〇〇/〇 to 9〇/1〇) or by acidic preparative HPLC ( Method 3 or 4) Purification of the product. Also used from 4-[6-methoxy-3-(1-indolyl-1H-pyrazole-4-yl)_9Η·β·porphyrin-5-yl] awkward Another method for the initiation of the acid oxime ester. In this case, the 152238.doc • 135· 201124414 is dissolved in anhydrous benzene (8 mL) and the mixture is cooled to 0 ° C. Then, a solution of 2 Μ trimethylaluminum in toluene (2.6 mmol) and a solution of n-butyl chain (2.7 Μ in 2.7 mmol) were added, followed by the addition of 4-[6-methoxyl dissolved in 3.6 mL of THF. 3-(1-methyl-1H-pyrazol-4-yl)-9Η-β-carboline-5-yl]benzoic acid oxime ester = the mixture was stirred at ambient temperature for 2 hours, and then with 30 The aqueous solution of potassium potassium tartrate was hydrolyzed. The aqueous phase was extracted with ethyl acetate. After drying and filtered, the reaction mixture was concentrated to dryness under reduced pressure by chromatography (solvent: CH2C12/NH3 2 ) 6〇11): 100/0 to 90/10) or purified by acidic preparation type 1^[(:(Method 3 or 4)) Example 31: UPLC-MS-DAD-ELSD: Tr (min) = 0.59 [M+H] + : 481 m/z ; [MH]-: 479 m/z Example 32: UPLC-MS-DAD-ELSD: Tr (min) = 0.65 [M+H] + : 495 m/z ; [MH]-: 493 m/z Example 33: UPLC-MS-DAD-ELSD: Tr (min) = 0.57 [M+H] + : 469 m/z ; [MH]-: 467 m/z Examples 34 to 68 4-[6-decyloxy group by reacting 10 to 15 equivalents of lithium hydroxide monohydrate in a THF/methanol/water mixture 3-(Pyridin-3-yl)-9Η-β-carboline-5-yl]methyl benzoate was saponified. After acidification with aqueous hydrochloric acid, 4-[6-decyloxy-3 was isolated by filtration. -(pyridin-3-yl)-9Η-β-carboline-5-yl] benzoic acid. General procedure for Examples 34 to 68: 152238.doc -136- 201124414

Prepared in 80 mL DMF containing 4-[6-decyloxy-3-(pyridin-3-yl)-9H-β_ porphyrin-5-yl]benzoic acid (2.51 g, 5.6 mmol), HATU (6.16) A solution of mmol, 1.1 eq.) and diisopropylethylamine (DIPEA, 7 mmol, 1.25 eq.). 2 mL of this solution was removed and subsequently added to 0.175 mmol (1.25 eq.) of the appropriate amine in the tube. If the appropriate amine is in the form of a hydrochloride, 1,25 equivalents of DIPEA are added to the HC1 present per molecule. The tube was closed and then the various mixtures were heated overnight at 50 °C with stirring. After cooling, 0.1 mL of TFA was added. After filtration, the expected product 45-83 present in each filtrate was purified by preparative HPLC. Analytical conditions: Waters UPLC BEH C18 2.1x50 mm; 1.7 μ, H20+0.1% FA: AcN+0.08% FA 95 : 5 (0 minutes) to 5:95 (1.1 minutes) to 5:95 (1.7 minutes) to 95 : 5 (1.8 minutes) to 95:5 (2 minutes), 0.9 ml/min, 55 〇C. Or HPLC : YMC-Pack Jshere H80 33χ2·1 ; 4 μ ; H20 + 0.0.5% TFA/CH3CN: 98/2 (1 minute) to 5/95 (5 minutes). MS: Waters LCT classic TOF-MS, 8-channel Mux, 0.15 second scan time (for quality 100-1500). MS debt test: Waters SQD Single Quadrupol, 0.5 second scan time (for mass 120-1200) The structure obtained by this method is described in Table 1. 152238.doc -137- 201124414 Table 1 Example No. Name Structure Retention Time (minutes) [Μ+Η]+ Observation 34 N-[2-(ethylamino)ethyl]-4-[6-decyloxy -3-(.bipyridin-3-yl)-9Η-β-carboline-5-yl]benzamide- 466 35 Ν-[2-(ethylideneamino)ethyl]-4-[ 6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide Ρ Ύ. 1 0.94 480.2 36 4-[6-Methoxy-3-(acridin-3-yl)-9Η-β-carboline-5-yl]-indole-[2-(1-indolylpyrrolidine- 2-yl)ethyl]benzamide 1 0.89 506.25 37 4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-Ν- [3-(2-Sideoxy.pyrrolidin-1-yl)propyl]benzimidamide? 0.99 520.22 38 Ν-[2-(dipropan-2-ylamino)ethyl]-4· [6-decyloxy-3-0-pyridin-3-yl)-9Η-β-carboline-5-yl]benzamine? 0.95 522.3 152238.doc -138- 201124414 39 4-[6-A Oxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-N-[2-(phenylamino)ethyl]benzoquinone ρ 9 1 1.1 514.22 40 N -[2-(Dimethylamino)ethyl]-N-ethyl-4-[6-nonyloxy-3-0-pyridin-3-yl)-9Η-β-carboline-5-yl ] Benzamide&amp;amine 1 0.9 494.23 41 N-[l-(Dimethylamino)propan-2-yl]-4-[6-methoxy-3-(e ratio -3-yl) )-9Η-β-porphyrin-5-yl]benzamide 1 0.88 480.21 42 Ν-[3-(Dimethylamino)propyl]-4-[6-decyloxy-3-0 ratio Pyridin-3-yl)-9Η-β-carboline-5-yl]-indole-mercaptobenzamide 1 1 0.88 494.21 43 [(3S)-3-(didecylamino)°bibromopyridine -1-yl]{4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-咔-5-yl]phenyl}methanone 1 0.85 492.2 44 N-[(l-ethylpyrrolidin-2-yl)methyl]-4-[6-decyloxy-3-0.pyridin-3 -yl)-9Η-β-carboline-5-yl] benzamidine 1 0.91 506.22

S 152238.doc •139- 201124414 45 4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-N-indenyl-N-( L-decylpyrrolidin-3-yl)benzoguanamine ^6 1 0.88 492.23 46 4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-°·^· _5-yl]-N-(1Η-tetrazol-5-ylindenyl)benzamide 〇? 0.94 477.17 47 4-[6-decyloxy-3-(&quot;pyridin-3-yl) -9Η-β-carboline-5-yl]-indole-[2-(pyridin-2-ylamino)ethyl]benzamide? 0.91 515.2 48 [(3R)-3-(didecylamine) ))pyrrolidin-1-yl]{4-[6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]phenyl fluorenone 1 0.85 492.21 49 Ν -[2-(diethylamino)ethyl]-4-[6-decyloxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]-indole- Mercaptobenzamide 1 0.91 508.24 50 N-{[(2S)-1-ethylpyrrolidin-2-yl]indolyl}-4-[6-decyloxy-3-(pyridin-3-yl) )-9Η-β-porphyrin-5-yl]benzamide 1 0.91 506.26 152238.doc •140· 201124414 51 N-(l-ethylpiperidin-3-yl)-4-[6-methoxy Base-3-(0 is more than -3-yl)_9Η-β-carboline-5-yl]benzamide pr 1 0.89 506.23 52 4-[6-decyloxy-3-(pyridine-3- Base)-9Η-β-carboline-5-yl]-indole-[2-(2-mercaptopiperidone) Acridine-1-yl)ethyl]benzamide ~9 ? 0.94 520.26 53 4-i&gt;-甲乳巷·_:Κ0叫-3-基)-9Η-β-carboline-5-yl]- Ν-[4-(pyrrolidin-1-yl)butyl]benzoquinone <Ν=^ 1 0.9 520.24 54 [4-(2-methoxyethyl)piperazine-l-yl]{4- [6-decyloxy-3-(acridin-3-yl)-9Η-β-carboline-5-yl]phenyl}methanone 1 1 0.87 522.27 55 4-[6-decyloxy-3- (pyridin-3-yl)-9Η-β-carboline-5-yl]-indole-(1-indolyl azetidin-3-yl) benzoic acid 1 0.86 464.2 56 4-[6-曱oxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-indole-[(3-methyl-1Η-pyrazol-4-yl)methyl]benzamide Amine? 0.97 489.19 5 152238.doc -141 - 201124414 57 N-(1H-imidazol-2-ylmethyl)-4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β- Porphyrin-5-yl]benzamide 9 0.87 475.18 58 {4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]phenyl}( 2-mercapto octahydro-5Η-°pyrolo[3,4-c]acridin-5-yl)methanone 0.88 518.24 59 [3-(didecylamino)piperidin-1-yl]{ 4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]phenyl}fluorenone 5 1 0.88 506.21 60 1,3'-bipyrrolidin- Γ-based {4-[6-decyloxy-3-(. Bis-pyridine-3·yl)-9Η-β-carboline-5-yl]phenyl}fluorenone 0.87 518.2 61 Ν-ethyl-4-[6-decyloxy-3-(.pyridin-3- ))-9Η-β- porphyrin-5-yl]-N-[(l-decylpyrrolidin-3-yl)indolyl]benzamide-9 2 0.92 520.24 62 {4-[6-曱 Oxygen 3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]phenyl}[3-(piperidin-1-yl)azetidin-1-yl]indole Ketone 〇ΗΝ^?^Να〇1 0.89 518.23 152238.doc •142· 201124414 63 4-[6-Methoxy-3-(pyridin-3-yl)·9Η-β-carboline-5-yl]- N-methyl-N-[(l-nonylpiperidin-2-yl)indolyl]benzamide Ν=\ 1 0.91 520.27 64 N-[(l-ethylpyrrolidin-3-yl) 曱4-[6-methoxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]-indole-methylbenzamide® 0.9 520.27 65 Ν- [3-(Dimethylamino)-2,2-dimercaptopropyl]-4-[6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5- Benzoamine I 0.91 508.25 66 1^-(1-cyclopropyl. Chent-4-yl)-4-[6-decyloxy-3-(°-precipitate-3-yl)-9Η -β-porphyrin-5-yl]benzamide 9 0.89 518.24 67 4-[6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-oxime -[2-mercapto-2-(»pyrrolidin-1-yl)propyl]benzamide Amine 1 0.92 520.25 68 4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]-indole-(2_[(fluorenylsulfonyl)amino group ]ethyl}benzamide® 0.96 516.18 Examples 69 to 100: 5 152238.doc -143 - 201124414 General Procedures

Pd(PPh3)4/DMF Cs2C03/water dioxane

0.2 mmol of 5-bromo-6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline (Example 1), 0.4 mmol of citric acid derivative (acid or vinegar) in 2 ml 1 , a solution of 4-second noise, a solution of 0.4 mmol of sulphuric acid in 0.5 ml of water and then 0.02 mmol of hydrazine (triphenylphosphine) palladium (0) in 0.5 ml of dimethylformamide under argon The solution was placed in the reactor sequentially, the tube was sealed and stirred at 10 ° C for 18 hours. After cooling, the reaction mixture was diluted with 6 ml of 1,4-dioxane, 2 ml of decyl alcohol and 0.1 ml of trifluoroacetic acid, and then 150 mg of propanethiol type grafted onto ceria at ambient temperature. The resin was treated for 4 hours. The reaction mixture was filtered and then washed twice with a 4:1 mixture of 1,4-dioxane: decyl alcohol. After evaporation under reduced pressure, the residue was dissolved in 2 ml of dimethylacetamide and 0.1 ml of trifluoroacetic acid, filtered, and then purified by preparative HPLC. Analytical conditions: Waters UPLC BEH C18 2.1x50 mm ; 1_7 μ, H20+0_l%FA: AcN+0.08°/〇FA 95 :5 (0 minutes) to 5:95 (1.1 minutes) to 5:95 (1.7 minutes) From 95:5 (1.8 minutes) to 95:5 (2 minutes), 0.9 ml/min, 55 〇C. Or HPLC: YMC-Pack Jshere H80 33x2.1; 4 μ; Η20+ 0.0.5% TFA/CH3CN: 98/2 (1 minute) to 5/95 (5 minutes). MS: Waters LCT classic TOF-MS, 8-channel Mux, 0.15 second scan time (for quality 100-1500). 152238.doc 201124414 0.5 second scan time (for mass MS detection: Waters SQD single quadrupole 120-1200) The structure obtained by this method is described in the table. Table 2 Example number name structure ----- residence time (minutes) [Μ + Η] ten observations 69 3-{4-[6-曱oxy-3-(〇比咬-3-基)-9Η -β"卡咐-5. 基] 基基}propionic acid °γ〇Η Η 1.05 424.14 70 6-methoxy-5-(6-decyloxy. than -3-yl)-3-(° More than bite-3-base)-9Η-β-flavored ο 6 secret. Η 1.05 383.13 71 6·曱oxy·3,5·2 (. than bite-3-yl)-9Η·β-°*^ly drip Q ρ secret, Η 0.9 353.13 72 Ν-{2-[6- Methoxy-3-(.by -3-yl)·9Η-β_叶惊-5-yl] stupid} methanesulfonamide Η 1.02 445.1 73 5-[6-decyloxy-3-(pyridine -3-yl)-9Η-β·porphyrin-5-yl]thiophene-2-furoic acid Η 0.99 402.08 152238.doc •145· 201124414 74 6-decyloxy-5-(4-mercaptothiophene- 2·yl)-3-(° ratio bit-3-yl)-9Η-β-porphyrinΗ 1.12 372.3 75 6-曱lacyl-3-(° ratio bit-3-yl)-5-(°3⁄4咬-5-基)-9Η~ β·味琳Ν^Ν ¥ Η 0.92 354.12 76 {2-[6-decyloxy-3-(indolyl-3-yl)-9Η-β-carboline- 5-yl]phenyl}sterol NQ CXoh H 1 382.15 77 Ν-cyclopropyl-4-[6-decyloxy-yl)-9Η-β-carboline-5-yl]phenylguanamine YO 丫NH nQ ό 、, Η 1.01 435.17 78 6-decyloxy-5-(4-mercaptothiophen-3-yl)-3-(.biter-3_yl)·9Η-β-carboline, Η 1.1 372.11 79 2-[6-Methyls-3-(0-But-3-yl)-9Η-β-porphyrin-5-yl]benzoquinone Η 1.05 377.12 80 6-Methoxy-5-( 1-mercapto-1Η-吲哚-5-yl)-3-(°pyridin-3-yl)-9Η-β-carboline Q % Η 1.11 405.17 152238.doc •146· 201124414 81 5-[6-oxime ratio -3-yl)·9Η-β-carboline-5-yl]吼 -2--2-amine νη2 Q ό Secret. Η 0.79 368.12 82 Ν-(2-decyloxyethyl)-4-[6-decyloxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]phenylhydrazine Amine 〇γΝ^ Q ό 、, Η 1 453.17 83 Ν-{4-[6-methoxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]benzyl} Acetamine V. ΝΗ Η 0.98 423.17 84 {3-[6-methoxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]phenyl}(morpholine- 4-yl)fluorenone 0 phenanthrene, oxime 1.01 465.19 85 6-decyloxy-5-(2-decyloxyphenyl)-3 decapyridin-3-yl)-9Η-β-carboline^〇〇 : Η 1.07 382.14 86 5-(2-ethoxyl. than bite ~3·yl)-6-decyloxy-3-(°~--3-yl)-9Η·β-carboline nQ. , Η 1.06 397.15 87 4-({3-[6-methoxy-3-(mouthpyridin-3-yl)-9Η-β-carboline-5-yl]phenyl]amine) Butyl acid O nrKi ^ 〇 H secret, Η 0.99 467.16 5 152238.doc -147- 201124414 88 {4-[6-methoxy-3-(° ratio -3-yl)-9Η-β-carboline -5-yl]phenyl}(4-mercaptopiperazin-1-yl)indole_k/丫Η 0.84 478.21 89 {4-[6-methoxy-3-(°-pyridyl-3-yl) -9Η-β-carboline-5-yl]phenyl}(morpholin-4-yl)anthone Ογ〇Q ό Η 1 465.19 90 6-oxime-5-[3-(mercaptosulfonyl) Phenyl]-3-(pyridin-3-yl)-9Η-β-carboline Q nf secret. Η 1.01 430.12 91 6-Methoxy-5-(1-methyl-1Η-pyrazol-5-yl)-3-(°pyridin-3-yl)-9Η-β-carboline nQ c. secret. Η 0.96 356.16 92 Ν-{3-[6-decyloxy-3-(-specific bite *3·yl)-9Η-β-°·^·stimulate *-5-yl]benzyl}decane sulfonate Indoleamine / S, NH secret. Η 1.01 459.14 93 Ν-{4-[6-methoxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]benzyl}methanesulfonamide °~s =0 ΗΝ^ Q ό 、, Η 1.01 459.15 94 6-methoxy·5-(1Η-pyrazol-4-yl)-3-(.pyridin-3-yl)-9Η-β-porphyrin ηΛ 〇_ Η 0.89 342.12 152238.doc -148- 201124414 95 6-decyloxy-5·(1-methyl·1Η-pyrazole·4_yl)_3 decyl-3-yl)-9Η-β- 〇|·琳 Q u Η 0.93 356.14 96 Ν-{3-[6-methoxy_3-(〇比咬-3-yl)-9Η·β-&lt;^·琳_5-yl]phenyl }Methanesulfonamide Q ςτ^ Hi&quot; Η 1 445.13 97 5-(1Η-吲哚-6-yl)-6·methoxy-3-(ton-3-yl)-9Η-β-啼Q άΝΗ 、, Η 3.16 391.19 98 3-[6-decyloxy-3-(&quot;Bite-3-yl)-9Η-β-吟'#-5-yl]-Ν,Ν-dimercapto Aniline Q ρτ&quot; Η 1.07 395.15 99 仏[2-(Dimethylamino)ethyl]-3-[6-decyloxy-3-(.by -3-yl)-9Η-β_ 味琳- 5-yl]benzamide η/, Q (/° 密., Η 0.89 466.22 100 Ν-(3-methoxypropyl)-4-[6-decyloxy-3-(» ratio bite -3-yl)-9Η-β-carboline_5_yl]benzamide U Η 1.02 467.2 Any of the present invention may be utilized The product of formula (1) prepares a pharmaceutical composition as defined above; such pharmaceutical compositions form part of the invention. In vitro biochemical test procedure 152238.doc • 149· 201124414 Can be confirmed by means of certain pharmacological tests Pharmacological properties of the compounds of the invention. Examples of the following pharmacological assays were carried out using the compounds of the invention.Example 1 TR-FRET assay for inhibition of Pim kinase activity, according to conventional in vitro TR-FRET (time-resolved-fluorescence resonance energy transfer) The assay measures the compounds of the invention. The TR-FRET assay is based on the acidification of specific Seri 12 residues in the Badin protein, which has been shown to be a natural receptor for Pim kinase in cells. The assay uses the following reagents:

Pim kinase - His6-tagged full-length human recombinant Pim-1, Pim-2 or Pim-3 protein (prepared according to J. Mol. Biol. (2005) 348, 183-193); Bad-His6-tagged full-length human recombination Bad protein (prepared according to J. Mol. Biol. (2005) 348, 183-193); a-His6-APC - SureLightTM allophycocyanin-conjugated mouse monoclonal antibody against His6 tag (Perkin Elmer ( PerkinElmer), AD0059H, Waltham, Massachusetts, United States; oc-P~Bad-Eu - mouse monoclonal antibody against phosphorylated Bad (Serll2) (7Ell) Cell Signaling Technology #9296B, Danvers, Massachusetts, United States, USA. The acidified Bad was routinely labeled with LanceTM Eu-W1024 reagent by Perkin Elmer. The assay is based on the PerkinElmer LanceTM technology: an Eu-labeled antibody binds to phosphorylated Seri 12 and interacts with the anti-His6 antibody by 152238.doc-150-201124414 APC labeling with a His6 tag that binds to Bad. To generate the TR-FRET signal. The TR-FRET signal was detected using a SpectraMax M5 plate reader (Molecular Devices) with the following settings: λ ε χ = 340 nm, λ ειη 1 = 6 ΐ 5 nm, Xem 2 = 665 nm. The ratio of the 665 nm camp light signal to the 615 nm fluorescent signal is used as the signal reading for ICsq (based on a 4-parameter logistic model). The assay was performed in a 384-well format; liquid handling was performed using a Beckman 3000 liquid handling station. The test compound was double-repeated at 10 concentration points; the highest compound concentration was usually 30 μΜ. The concentration of ATP is 40 μΜ. Example 2 Cell viability assays Representative compounds of the invention were also screened using a variety of human tumor cell lines representing various pathological signs for effects on cell proliferation and viability. These cell lines include: Hematology cancer model: TF-1 (acute myelogenous leukemia; AML 诊断6 at diagnosis); KG-1 (AML; erythroleukemia developed into AML); KG-la (AML; derived from Subfamily of mature KG-1); EOL-l (AML; eosinophilic leukemia); PL-21 (AML; M3); ML-2 (AML; developed into T-ALL, developed into AML M4) NHL); HL-60 (AML, M3);

Kasumi-1 (AML);

S 152238.doc -151 - 201124414 GDM-1 (AML); K-562 (CML-chronic myelogenous leukemia; acute transformation); JURL-MK1 (CML; acute transformation); DND-41 (T-ALL-T cell Acute lymphoblastic leukemia); Jurkat (T-ALL); NALM-6 (B-ALL-B cell ALL); CEM (ALL; lymphosarcoma that develops into ALL);

Jeko-l (B-NHL-B cell non-Hodgkin's lymphoma; mantle cell lymphoma derived from large cell variants in leukemia transformation); WSU-DLCL2 (B-NHL; diffuse large B-cell lymphoma) ; RL (B-NHL; diffuse undifferentiated); OCI-LylO (B-NHL);

DoHH-2 (B-NHL); RPMI-8226 (MM - multiple myeloma); JVM-2 (B-CLL-B cell chronic lymphocytic leukemia); JVM-3 (B-CLL); and KSM-12 -BM(MM) 〇 solid tumor model: HCT-116 (colon cancer); HT-29 (colon cancer); HC-15 (colon cancer); H460 (lung cancer; non-small cell lung cancer); A375 (melanoma) 816?10 (melanoma); 152238.doc -152- 201124414 MDA-A1 (breast cancer); MDA-MB231 (breast cancer); MDA-MB231adr (breast cancer); PANC-1 (pancreatic cancer); and PC-3 (prostate cancer). For measurement of viability, tumor cells were cultured in 96-well or 384-well format for 48 hours or 72 hours using a 3-fold dilution of the compound of the invention (typically a total of 9 doses, with a maximum dose of 10 μΜ or 30 μΜ). Preferably 72 hours. Cell viability was assessed by adding CellTiter-Blue® (Promega, Madison, Wisconsin, United States) for 4 hours and using a SpectraMax Genmini EM plate reader (Molecular Devices, California, USA) The city of Sunnyvale (California, United States) reads the endpoint reading. CellTiter-Blue® Cell Viability Assays Quantify the ability of cells in culture to restore resazurin to resorufin. The intensity of the glory signal is proportional to the number of viable cells. EC5G represents the concentration at which the compound reduces cell viability/amplification by 50%. Example 3 The activity of the molecule against JEKO or DND-41 cell lines was assessed by measuring the degree of acidification and total Bad content of Bad using Elisa technique. JEKO or DND-41 cells were resuspended at a concentration of 500 000 cells/ml. The cells were then diluted in RPMI-1640 medium containing 20% fetal bovine serum. Place 225 μΐ cells in the plate. The molecules were then serially diluted (8 points, diluted to 1/3, range starting at 10 mM). Subsequently, 152238.doc -153 - 201124414 Each dilution point was diluted to 1/1 于 in the medium. Subsequently, 25 μM of each concentration was added to the cells, followed by incubation at 37 ° C for 3 hours. Transfer 100 μΐ of these cells into a poly-D• lysine-treated plate. The plate was then placed at 37. (: culture for 5-10 minutes and then centrifuge at 1500 rpm for 5 minutes. Add 100 volumes of 8% fix solution (formaldehyde in solution in PBS buffer) to each well. Cover with self-adhesive membrane and cover. The plates were incubated at ambient temperature for 2 且 minutes and then stored overnight at 4 lt.t. Then 'removed the liquid and washed twice with wash buffer. Add 100 μl of quenching buffer and then at ambient temperature Incubate for 15 minutes. After washing, add 100 μM of stock buffer, then incubate at ambient temperature for hr. After washing, add 5 μμ1 to each plate to 1/25 〇 (for pBAD (Cell Signaling catalog) No. 5284)) and primary antibody diluted to 1/5 〇〇 (for Bad (MBL Cat. No. 591)). Each plate was incubated for 2 hours at ambient temperature. After washing twice, 5 〇... secondary antibody (diluted to 1/16) Add to the Pbad plate (tebu-bio reference number: FE-021), and add 5 μμΐ to HRP-conjugated IgG secondary antibody (Santa Cruz catalog number sc_ 2004, diluted to ι/ 1〇〇〇) Add to the Bad plate. Incubate at ambient temperature 1 The washing solution was washed 4 times, followed by washing three times with PBS. Finally, '1 μμ丨 of the developing solution was added, followed by incubation for 1 minute. Finally, 100 μΐ of the stock solution was added, and then read at 45°ηηι. The chemical results indicate biochemical results according to the following classifications: Class A: IC5〇 is less than ΙΟΟηΜ 152238.doc •154- 201124414 Class B: IC5〇 is between 100 nM and 1000 nM (or 1 μΜ) Category C: IC5〇 Class D between 1 μΜ and 5 μΜ: IC5Q is greater than 5 μΜ

Example No. ICsoPiml IC5〇Pim2 IC5〇Pim3 IC5〇CDK1 IC5〇PLK1 1 BDC 2 ABADD 3 AAADD 4 ABADD 5 BCBDD 6 AB 7 AB 8 AD 9 AB 10 BDCDD 11 BCBDD 12 ACB 13 ABA 15 ABA 16 CDDDD 17 ABA 18 ABADD 20 AAA 21 AAA

Example Number ICS0Piml IC5〇 Pim2 IC5〇 Pim3 IC5〇 CDK1 IC5〇 PLK1 24 A B A 25 A A A 26 A B A 27 A B A 28 A A D D 29 A A A 30 A A A

S 152238.doc -155- 201124414

31 AAA 32 AAA 33 AAA 34 AAA 35 ABB 36 ABA 37 BCB 38 ABA 39 BCB 40 ABA 41 AAA 42 ABA 43 ABA 44 ABA 45 ABA 46 BCB 47 ABA 48 ACA 49 ABA 50 ABA 51 ABA 52 ABA 53 ABA 54 BDB 55 AAA 56 AAB 57 ABA 58 ABA 59 ACA 60 ACA 61 ABA 62 BCB 63 ABA 64 ABA 152238.doc -156- 201124414

65 ABA 66 ABA 67 ABA 68 ABB 69 ACB 70 BCC 71 CDC 72 CDC 73 CDC 74 BCB 75 CDD 76 BDC 77 ACB 78 BCB 79 CDC 80 ACB 81 BDC 82 ABB 83 BCB 84 CDC 85 BDC 86 CDD 87 CDC 88 ACB 89 BCB 90 CDC 91 CDC 92 BDC 93 ABA 94 BCB 95 BDC 96 BDC 97 ACB 98 BDC 152238.doc -157- 5 201124414 99 Β DC 100 Β Β Β Cell results The cell proliferation results are expressed according to the following classification: Class A: EC5〇 or IC5 〇 less than ΙΟΟηΜ Class B: EC50 or IC50 between 100 nM and 1000 nM (or 1 μΜ) Category C: EC50 or IC50 between 1 μΜ and 5 μΜ

Example No. EOL-1-^ECso * μΜ (lymphoma) EC50 of MV4-11, μΜ (myeloma) ICS0 (DND-41) of phosphorylated BAD 2 Β Β 3 C C B 4 Β C 6 Β C B 7 Β C

Example No. Phosphorylated BAD IC50 (DND-41) 24 B 28 C 30 B 31 B 33 C 152238.doc -158·

Claims (27)

201124414 VII. Patent application scope: 1. A product of general formula (I): R3 represents a heteroaryl group consisting of 5 or 6 ring members (1 to 4 of which are selected from heteroatoms of n, S or 0). This heteroaryl group is bonded to the porphyrin via C or via N which belongs to R3. The unit 'R3 is optionally substituted or polysubstituted; R5 is selected from the group consisting of: 1 · halogen; 2. -OH; 3_linear or branched alkoxy, wherein the alkyl moiety is optionally monosubstituted, disubstituted or trisubstituted; 4. linear or branched _γ•alkyl (Y=s, S〇, s〇2), as the case may be monosubstituted, disubstituted or trisubstituted; 5 · aryl (X = 0, s, SO, S 〇 2), optionally substituted by a single, two or three; 6. _X-heteroaryl (X=〇, s, SO, S02), wherein the heteroaryl is optionally substituted, disubstituted or trisubstituted; 7. -NH2; 8. a straight bond, a branched chain or a cyclic -NH(alkyl) group and -N(alkyl h, wherein the alkyl moiety is optionally substituted, disubstituted or trisubstituted 152238.doc 201124414 generation ; 9. NH(aryl), wherein the aryl moiety is optionally monosubstituted, disubstituted or trisubstituted; 1〇·ΝΗ(heteroaryl), wherein the heteroaryl moiety (having 5 or 6 ring members) (wherein to 4 to 4 heteroatoms selected from ruthenium, 3 or ruthenium), via C or via a hydrazone bond to the nitrogen atom) as appropriate: monosubstituted, disubstituted or triple substituted; (aryl), wherein the (linear, branched or cycloalkyl moiety and the aryl moiety are optionally substituted by one or three substituents; 12. - oxime (alkyl) (heteroaryl) The (linear 'branched bond or morphologically) alkyl moiety and the heteroaryl moiety (having 5 or 6 cyclized: (with 丨 to 4 heteroatoms selected from Ν, 8 or 〇) a mono-, mono- or tri-substituted group, optionally via C or via a nitrogen atom; 13. -C(0)0H; 14. a straight chain, a branched chain or a cyclic (10)) (10) group, Substituted, disubstituted or trisubstituted as appropriate; 15_-C(0)0 aryl, monosubstituted or disubstituted, as appropriate; PT2, 16·C(0)0 heteroaryl (having 5 or 6 Ring member (which has a heteroaryl group selected from a hetero atom of N, S or hydrazine is bonded to the hydrazine via a 4-substituent, optionally substituted by a single substitution, a disubstituted or:;; &quot;&quot;' 152238.doc -2 - 201124414 17· -CONH2 ; IS. a straight chain, a branched chain or a cyclic -CONH(alkyl) group and c〇N(alkyl) 2, wherein the alkyl moiety is optionally substituted, disubstituted or trisubstituted; 19. -CO-heterocycloalkyl, monosubstituted, disubstituted or trisubstituted. 20. -CON(alkyl)(aryl)&apos;alkyl is straight-chain, branched or cyclic&apos; wherein the alkyl group and the aryl moiety are optionally substituted, disubstituted or trisubstituted; 21. -CON (alkyl) (heteroaryl), the alkyl group is a straight chain, the branch bond bites a ring' and the heteroaryl has 5 or 6 ring members (of which 1 to 4 are selected from N, S or a hetero atom), which is bonded to the nitrogen atom via c or via N' wherein the alkyl group and the heteroaryl moiety are optionally monosubstituted, disubstituted or trisubstituted; 22. a direct bond, a bond or a ring a ketone group, optionally containing a hetero atom and optionally substituted, disubstituted or trisubstituted; 2 3. aryl, optionally substituted, disubstituted or trisubstituted; 24. heteroaryl, as the case may be Substituted or substituted; 2 5 · heterocycloalkyl, optionally substituted or substituted; 26·-Cz-C6 alkenyl group, optionally substituted or substituted; 27. A CrC6 alkynyl group, optionally substituted or polysubstituted; R6 is selected from the group consisting of: 1. oxime; 2·halogen; 3--OH; 152238.doc 201124414 4. Linear or branched alkoxy group, wherein The alkyl moiety is optionally mono-, di- or tri-substituted; 5 · fluorene-cyclyl 'optionally monosubstituted, disubstituted or trisubstituted; 6 · straight or branched - Y-alkyl (Y =s, so, so2), as the case may be monosubstituted, disubstituted or trisubstituted; 7· -nh2 ; 8 · straight chain, branched chain or cyclic - fluorene (alkyl) and - fluorene (alkyl) 2, Wherein the alkyl moiety is optionally substituted, disubstituted or trisubstituted; 9·-C(〇)〇H; 10. linear, branched or cyclic/(1)...alkyl, as the case may be monosubstituted, Substituted or trisubstituted; 11. -conh2; 12. straight chain, branched or cyclic c〇NH(alkyl) and CON(alkyl) 2 ' wherein the alkyl moiety is optionally substituted, disubstituted or tri Substituted; 13. Linear, branched or cyclic Cl-C10 alkyl, optionally containing a hetero atom and optionally substituted, disubstituted or trisubstituted; 14 · aryl, optionally substituted, taken Substituted or trisubstituted; the product of the formula (I) is in any possible racemic, enantiomeric and diastereomeric form 'and the product of the formula (1) with an inorganic acid and an organic acid or An addition salt formed by an inorganic base and an organic base. 2. The product of the formula (1) as defined by the kiss formula is selected as 152238.doc 201124414 The substituents ', ie the groups Rla, Rib and Rlc, are independently selected from each other: 1. F ; 2. C1 ; 3. Br ; 4. I ; 5. Straight bond or branch chain - CrC,. Alkyl, optionally substituted or polysubstituted by R3a, R3b, R3c; 6. -OH; 7_ straight or branched alkyl, optionally substituted or polysubstituted by R3a, R3b, R3C; Or branched alkyl (Y=S, s〇, s〇2) 'monosubstituted, disubstituted or trisubstituted by R3a, R_3b, R3c, as appropriate; 9·0-(C3-C7)cycloalkyl, as appropriate Monosubstituted or polysubstituted by R3a, R3b, R3c; 10. -NH2; 11. Linear, branched or cyclic -NH(alkyl) and _N(alkyl)2, wherein the alkyl moiety is monosubstituted, disubstituted or trivalent via R3a, R3b, R3c, as appropriate Substituents; the substituents R3a, R3b and R3c, that is, the substituents of the groups Ria, Rib, Rlc, R2a, R2b and R2c, are independently selected from each other: 1. F; 2. C1; 3. B r ; 152238.doc 201124414 5. Linear or branched _Cl_Cu)alkyl 'optionally substituted or polysubstituted by R4a, R4b, R4c; 6. -Cs-C7 cycloalkyl, optionally via R4a, R4b, R4c Monosubstituted or polysubstituted; 7. -OH ; 8. Direct or branched _〇-((^1-匸1〇) 院基's mono- or polysubstituted by R4 a, R4b, R4c as appropriate; Linear or branched -Y-alkyl (Y=s, SO, S〇2), optionally substituted by R4a, R4b, R4c, monosubstituted or trisubstituted; 10. -0-(C3-C7) Alkyl, optionally substituted or polysubstituted by R4a, R4b, R4c; 1 1. -0-aryl, optionally substituted or polysubstituted by R4a, R4b, R4c; 12. aryl, optionally via R4a, R4b, R4c monosubstituted or polysubstituted; 13. Heteroaryl, optionally via R4a, R4b, R4c Monosubstituted or substituted; I4.heterocycloalkyl, monosubstituted or polysubstituted by R4a, R4b, R4C, as appropriate; 15. -N〇2; 16. -NH2; 17. NH-((Ci-C1())alkyl or (c3_c7)cycloalkyl or heterocyclo)) groups are optionally substituted by R4a, IMb, R4c or more 152238.doc 201124414 generation; 18. -NGCVCio)alkyl or (C3-C7)cycloalkyl)2, each group being optionally substituted or polysubstituted by R4a, R4b, R4c; 19. -NHaryl or NHheteroaryl, optionally substituted or polysubstituted by R4a, R4b, R4c; 20. -NHC(O), substituted by R4a, R4b, R4c; 21. -N((C丨-C1())alkyl)C(O), substituted by R4a, R4b, R4c; 22. -NHS (02), substituted by R4a, R4b, R4c; 23. -NGCi-Ci. )alkyl)S(02), substituted by R4a, R4b, R4c; 24·-C02, substituted by R4a, R4b, R4c; 25. -CONH2; 26. straight-chain, branched or cyclic-CONH(alkyl) and CON(alkyl)2, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c, as appropriate 27. -C(O)heterocycloalkyl, monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c, as appropriate; 28. -S, substituted by R4a, R4b, R4c; 29. -S(02) Substituted by R4a, R4b, R4c; 30. -S(O), substituted by R4a, R4b, R4c; 31. pendant oxy (double bond O); 32. -C2-C6 alkenyl, optionally via R4a, R4b, R4c monosubstituted or polysubstituted; 33. -C2-C6 alkynyl, optionally substituted or polysubstituted by R4a, R4b, R4c; 5 152238.doc 201124414 These groups R4a, R4b and R4c, also gp The substituents of the groups R3a, R3b and R3c are independently selected from each other. 1. F; 2. C1; 3. Br; 4. I; 5. -CF3; -CHF2; . Straight bond or branch bond - Ci-C1 () alkyl; 7. -C3-C7 cycloalkyl; 8. -OH; 9. Linear or branched-0-((:!-(:〗 〇) Alkyl; 10_straight bond or branch bond-Y-alkyl group (Y=S, SO, S〇2); 11. -0-(C3-C7) cycloalkyl; 12. -Ο-aryl; 13 . Aryl; 14. heteroaryl; 15. heterocycloalkyl; 16. -Ν〇2; 17. -ΝΗ2; 18_-NH-GCVCw)alkyl or (C3-C7)cycloalkyl or heterocycloalkyl ); 19. -NUCVCw) alkyl or (C3-C7)cycloalkyl) 2; 20. -NH aryl or NH heteroaryl; 21. -NHS(02)alkyl; 22_-N((Ci_Ci〇)alkyl)S(〇2)alkyl; 152238.doc 201124414 23.C02 alkyl; 24. -CONH2; 25. straight chain, branched or cyclic -CONH(alkyl) and CON(alkyl)2; 26. -C(O)heterocycloalkyl; 27_-S-alkyl; -S(02)alkyl; 29.-S(O)alkyl; 30. pendant oxy (double bond 〇); 31. straight or branched chain - C2-C6 alkenyl; 32. straight or branched _c2-C6 alkynyl; the product of the formula (1) is in any possible racemic, enantiomeric and diastereomeric form, and the product of the formula (1) with an inorganic acid and an organic acid or An addition salt formed by an inorganic base and an organic base. The product of the formula (1) as defined in claim 1, wherein the substituents of the groups 5 and R6 are optionally selected, that is, the groups R2a, (4) and R2c' are independently selected from each other: F; 2. C1; 3. Br; 4. I; 5·linear or branched chain &lt;vCi oxime, optionally substituted by ❿(8), R3c, or substituted; 6·-c3-c:7 The alkyl group is optionally substituted by R3a, monosubstituted or 152238.doc S 201124414; 7. -OH; 8. linear or branched chain -CHCVCn)alkyl, optionally substituted or substituted by R3a, R3b, R3c 9. Linear or branched alkyl (Y=S, SO, S〇2), optionally substituted by R3 a, R3 b, R3 c, disubstituted or trisubstituted; 10. -0-(C3- C7) cycloalkyl, optionally substituted or polysubstituted by R3a, R3b, R3e; 11. -Ο-aryl 'optionally substituted or polysubstituted by R3a, R3b, R3c; 12. aryl, optionally R3a, R3b, R3c monosubstituted or polysubstituted; 13. Heteroaryl 'monosubstituted or polysubstituted by R3 a, R3 b, R3 c; 14. heterocycloalkyl, optionally via R3a, R3b, R3c Substituted or substituted; 15. -N〇2 16. -NH2; 17. -NH-CCCVCio)alkyl or (C3-C7)cycloalkyl or heterocycloalkyl), each group being optionally substituted or polysubstituted by R3a, R3b, R3c; -N((Ci-C丨〇)alkyl or (CVC7)cycloalkyl)2, each group being mono- or polysubstituted by R3a, R3b, R3c, as appropriate; 19-NH-aryl or NH-heteroaryl , as the case may be single substitution or more take 152238.doc -10 · 201124414 generation; 20 · -NHC (O), replaced by R3a, R3b, R3c; 21 · -NGCVChO alkyl) C (O), via R3a, R3b , R3c substituted; 22. -NHS (02), substituted by R3a, R3b, R3c; 23. -NGCi-Cw)alkyl)S(02), substituted by R3a, R3b, R3c; 24. -C02, substituted by R3a, R3b, R3c; 25. -CONH2; 26. a straight chain, a branched chain or a cyclic -CONH(alkyl) group and a CON(alkyl)2 group, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R3a, R3b, R3c, as the case may be. 27. -C(O)heterocycloalkyl, monosubstituted, disubstituted or trisubstituted by R3a, R3b, R3c, as appropriate; 28. -S, substituted by R3a, R3b, R3c; 29· -S(02) Substituted by R3a, R3b, R3c; 30. -S(O), substituted by R3a, R3b, R3c; 31. pendant oxy (double bond O); 32. -C2-C6 alkenyl, optionally via R3a, R3b, R3c monosubstituted or polysubstituted; 3 3. -C2-C6 alkynyl, optionally substituted or polysubstituted by R3a, R3b, R3c; such radicals R3a, R3b and R3c, ie, such radicals Rla The substituents of Rib, Rlc, R2a, R2b and R2c are independently selected from each other: 1. F; 2. C1; 152238.doc -11 - 201124414 3. Br; 4. I; 5. Linear or branched Alkenyl, optionally substituted or polysubstituted by R4a, R4b, R4C; 6_-C3-C7% alkyl optionally or monosubstituted by R4a, R4b, ruthenium; 7. -OH; 8. Linear Or branched alkyl, optionally substituted or substituted by R4a, R4b, R4c 9. Linear or branched - γ-alkyl (y = s, SO, S02), optionally substituted by R4a, R4b, R4c, disubstituted or trisubstituted; 10 · -0-(C3-C7 a cycloalkyl group, optionally substituted or polysubstituted by R4a, R4b, R4c; 11. Ο-aryl 'optionally substituted or polysubstituted by R4a, R4b, IUC; 12. aryl 'as appropriate via R4a, R4b, R4c monosubstituted or polysubstituted; 13. Heteroaryl 'optionally substituted or polysubstituted by R4a, R4b, R4c; 1 4·heterocyclic alkyl group's mono- or polysubstituted by R4a, lUb, R4c as appropriate ; -N〇2 ; 16. -NH2 ; 17. -NH-((Ci-C10)alkyl or (CVC7)cycloalkyl or heterocycloalkyl), 152238.doc •12· 201124414 Monosubstituted or polysubstituted by R4a, R4b, R4c, as appropriate; 18. -((^-(:10)alkyl or (C3-C7)cycloalkyl)2, each group optionally via R4a, R4b , R 4c monosubstituted or polysubstituted; 19. -NH aryl or NH heteroaryl, optionally substituted by R 4a, R 4b, R 4c or polysubstituted; 20. -NHC (O), substituted by R4a, R4b, R4c; 21'-NGCVCjo)alkyl)C(O), substituted by R4a, R4b, R4c; 22. -NHS(02), via R4a , R4b, R4c replaced; 23. -NCCCrC!. "alkyl"S(02), substituted by R4a, R4b, R4c; 24. -C〇2, substituted by R4a, R4b, R4c; 25. -CONH2; 26. straight-chain, branched or cyclic-CONH(alkyl) and CON(alkyl)2, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c, as appropriate 27. -C(O)heterocycloalkyl, monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c, as appropriate; 28. -S, substituted by R4a, R4b, R4c; 29. -S(02) Substituted by R4a, R4b, R4c; 30. -S(O), substituted by R4a, R4b, R4c; 31. pendant oxy (double bond O); 32. -C2-C6 alkenyl, optionally via R4a, R4b, R4c monosubstituted or polysubstituted; 33. -C2-C6 alkynyl, optionally substituted by R4a, R4b, R4c or by 152238.doc -13-201124414; these groups R4a, R4b and R4c, The substituents of the groups R3a, R3b and R3c are independently selected from each other: 1. F; 2. C1; 3. Br; 4. I; 5. -CF3; CHF2; 6·linear or branched-Ci-Cn alkyl; 7. -C3-C7 cycloalkyl; 8. -OH; 9_ straight or branched bond-〇-(Ci-C1()) 10. Linear or branched-Y-alkyl (Y=S, s〇, so2); 11· o-(c3-c7)cycloalkyl; 12.-Ο-aryl; Group; 14. heteroaryl; 1 5. burning heterocyclyl group; 16. -Ν〇2: 17. -ΝΗ2; 18. -NH-UCVC ,. An alkyl or (C3-C7)cycloalkyl or heterocycloalkyl); 19. -]^((〇1-(1110)Huan 1 or (匸3-〇7)cycloalkyl) 2; 20_ -NH aryl or NH heteroaryl; 21. -NHS(02)alkyl; 152238.doc •14- 201124414 22·-NGCVCio)alkyl)S(02)alkyl; 23.-C02 alkyl; 24 -CONH2; 25, straight chain, branched or cyclic _c〇NH (Hyun) and CON (alkyl) 2; 26·-C(O)heterocycloalkyl; 27. -S-hospital 28. -S(02)alkyl; 29. -S(〇)alkyl; 30. pendant oxy (double bond 〇); 31. straight or branched _C2_C6 alkenyl; 32. straight chain or branch Chain Crt alkynyl; the product of the formula (I) is in any possible racemic, enantiomeric and diastereomeric forms, and the product of the formula (1) with inorganic and organic acids or An addition salt formed with an inorganic base and an organic base. 4. The product of formula (1) as defined in any one of the preceding claims, wherein R3 represents a heteroaryl group (5 or 6 ring members (wherein 1 to 4 are heteroatoms selected from n, s or oxime)) R3 is optionally monosubstituted or polysubstituted by Rla, Rlb, Rlc via C or via N bonding to R3, and R5 is optionally selected from: 1 · halogen; 2. -OH; 3. linear or Branched alkoxy, wherein the alkyl moiety is optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted, as the case may be _ 152238.doc -15- 201124414; 4. linear or branched - Y-alkyl (Y =S, SO, S02), monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c, as appropriate; 5. -X-aryl (X=0, S, SO, S〇2), optionally via R2a , R 2b, R 2 c monosubstituted, disubstituted or trisubstituted; 6. -X-heteroaryl (X = 0, S, SO, S02), wherein the heteroaryl is optionally substituted by R2a, R2b, R2c, Substituted or trisubstituted; 7. -NH2; 8. Linear, branched or cyclic -NH(alkyl) and -N(alkyl)2, wherein the alkyl moiety is monosubstituted by R2a, R2b, R2c, as appropriate , disubstituted or trisubstituted; 9. -NH(aryl), Wherein the aryl moiety is optionally monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c; 10. -NH(heteroaryl), wherein the heteroaryl moiety (having 5 or 6 ring members (1 of which a heteroaryl group of up to 4 heteroatoms selected from N, S or hydrazine, via a C or via a N bond to a nitrogen atom), optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; N(alkyl)(aryl), wherein the (linear, branched or cyclic) alkyl moiety and the aryl moiety are optionally substituted, disubstituted or trisubstituted by R2a, R2b, R2c; N(alkyl)(heteroaryl), wherein the (linear, branched or cyclic) alkyl moiety and the heteroaryl moiety (having 5 or 6 ring members (of which 1 to 4 are selected from N , a hetero atom of S or a hetero atom of Ο, 152238.doc -16 - 201124414, via a C or via a N bond to a nitrogen atom), optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; -C(0)0H ; 14. Linear, branched or cyclic ·(:(0)0 alkyl, optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; 15· -C(0 )0 aryl, as appropriate R2a, R2b, R2c monosubstituted, disubstituted or trisubstituted; 16·C(0)0 heteroaryl (having 5 or 6 ring members (of which 1 to 4 are heteroatoms selected from N, S or fluorene) a heteroaryl group bonded to oxygen via a C atom, optionally substituted, disubstituted or trisubstituted by R2a, R2b, R2c; 17. -CONH2; 18. straight chain, branched chain or cyclic-CONH ( Alkyl) and CON(alkyl)2, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c, as appropriate; 19. -CO-heterocycloalkyl, via R2a, R2b, R2c Substituted, disubstituted or trisubstituted; -CON(alkyl)(aryl), the alkyl group being a straight chain, a branched chain or a cyclic group, wherein the alkyl group and the aryl moiety are optionally substituted by R2a, R2b, R2c, as the case may be. , disubstituted or trisubstituted; 20. -CON(alkyl)(heteroaryl), alkyl is straight chain, branched or cyclic and heteroaryl has 5 or 6 ring members (1 to 4 of which) a hetero atom selected from N, S or hydrazine), bonded to the nitrogen atom via C or via N, wherein the alkyl group and the heteroaryl moiety are monosubstituted by 152238.doc -17- 201124414 R2a, R2b, R2c, as appropriate Second substitution Or a trisubstituted; 21. a straight chain, a branched chain or a cyclic -CrCw alkyl group, optionally containing a hetero atom and optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; 22. aryl, optionally R2a, R2b, R2c monosubstituted, disubstituted or trisubstituted; 23. Heteroaryl, optionally substituted or polysubstituted by R2a, R2b, R2c; 24. Heterocycloalkyl, optionally via R2a, R2b, R2c Substituted or polysubstituted; 25. -C2-C6 alkenyl, optionally substituted or polysubstituted by R2a, R2b, R2c; 26. -C2-C6 alkynyl, optionally substituted or substituted by R2a 'R2b, R2c R6 is selected from the group consisting of: 1. hydrazine; 2. halogen; 3. - hydrazine; 4. a linear or branched alkoxy group, wherein the alkyl moiety is monosubstituted or disubstituted by R2a, R2b, R2c, or Trisubstituted; 5. Ο-cycloalkyl, optionally substituted by R2a, R2b, R2c, disubstituted or trisubstituted; 6. straight or branched - Y-alkyl (Y = S, SO, S02), Monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c, as appropriate; 152238.doc -18- 201124414 7. -NH2; 8. Linear, branched or cyclic -NH(alkyl) and -N(alkane Base) 2, Wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c, as appropriate; 9. -C(0)0H; 10. linear, branched or cyclic -c(o)oalkyl, Monosubstituted, disubstituted or trisubstituted by R2a, R2b, R2c, as appropriate; 11. -CONH2; 12. straight chain, branched or cyclic -CONH(alkyl) and CON(alkyl)2, wherein the alkyl group Partially substituted, disubstituted or trisubstituted by R2a, R2b, R2c; 13·linear, branched or cyclic-C1-C10 alkyl, optionally containing heteroatoms and optionally by R2a, R2b, R2c Substituted, disubstituted or trisubstituted; 14. aryl' optionally substituted, disubstituted or trisubstituted with R2a, R2b, R2c; such radicals Rla'Rlb and Rlc, ie substituents of such radicals R3 , independently from each other, are selected from: 1. F; 2. C1; 3. Br; 4. I; 5 · straight or branched chain - C i -C ! 〇院 based, depending on the situation via R3 a, R3b, R3c Monosubstituted or polysubstituted; S 152238.doc • 19· 201124414 6. -OH ; 7. Straight or branched chain ◦•(Crew alkyl, optionally substituted or substituted by R3a, R3b, R3c; Straight chain or branch _γ·alkyl (Y=S, s〇, s〇2), as the case may be monosubstituted, disubstituted or trisubstituted by R3a, R3b, R3C; 9· 〇-(C3-C7)cycloalkyl, as the case may be R3a, R3b, R3c monosubstituted or polysubstituted; 10. -nh2; 11. linear, branched or cyclic _NH(alkyl) and -N(alkyl)2, wherein the β 玄R3a, R_3b, R3c are monosubstituted, disubstituted or trisubstituted; the radicals R2a, R2b and R2c, ie the substituents of the radicals R5 and R6, are independently selected from one another: 1. F; C1; 3. Br; 4. I; 5. Linear or branched _Cl_c1() alkyl, optionally substituted or polysubstituted by R3a, R3b, R3c; 6. -C3-C7 cycloalkyl, as appropriate Monosubstituted or polysubstituted by R3a, R3b, R3c; 7. -OH; 8. Linear or branched chain 〇_((^-(:ι). Hyun·base, monosubstituted or polysubstituted by R3a' R3b, R3c, as appropriate; 152238.doc • 20 - 201124414 9. Linear or branched chain Υ·alkyl (Y=S, SO, S〇2), Monosubstituted, disubstituted or trisubstituted by R3a 'R3b, R3c, as appropriate; ίο. -o-(c3-c7)cycloalkyl, optionally substituted or substituted by R3a, R3b, R3c; 11.. -0 -Aryl' optionally substituted or polysubstituted by R3a, R3b, R3c; 12. aryl 'optionally, Rjb, RJc monosubstituted or polysubstituted; 13. Heteroaryl' optionally via R3 a, R3 b , R 3 c monosubstituted or polysubstituted; 14. Heterocyclyl, optionally substituted or substituted by RJ a, RJb, R3c; 15. -N〇2 ; -NH2 ; H -NH-aC^-Cio) Ordinary or (CVC?) cycloalkyl or heterocyclic), each group optionally substituted or substituted by R3a, R3b, R3c; 1 8. -N((Ci-C10) alkyl or (C3) -C7)cycloalkyl)2, each group optionally substituted or polysubstituted by R3a, R3b, R3c; 19-NHaryl or NH heteroaryl, optionally substituted or substituted; 2〇· -NHC(O), substituted by R3a, R3b, R3C; 21, -NGCkCw)alkyl)C(0), via R3a R3b, R3C substituted; 152238.doc 201124414 22. -NHS (02), is substituted with R3a, R3b, R3c; 23 · -NCCCVC !. )alkyl)S(02), substituted by R3a, R3b, R3c; 24. -C02 &gt; substituted by R3a, R3b, R3c; 25. -CONH2 ; 26. Linear, branched or cyclic-CONH (alkane) And CON(alkyl) 2, wherein the alkyl moiety is monosubstituted, disubstituted or trisubstituted by R3a, R3b, R3c, as appropriate; 27. -C(O)heterocycloalkyl, optionally via R3a, R3b , R3c monosubstituted, disubstituted or trisubstituted; 28. -S, substituted by R3a, R3b, R3c; 29. -S(02), substituted by R3a, R3b, R3c; 30. -S(O), via R3a , R3b, R3c substituted; 31. pendant oxy (double bond O); 32. -C2-C6 alkenyl, optionally substituted by R3a, R3b, R3c or polysubstituted; 33. -C2-C6 alkynyl, as Wherein R3a, R3b, R3c are mono- or polysubstituted; the substituents R3a, R3b and R3c, that is, the substituents of the groups Rla, Rib, Rlc, R2a, R2b and R2c, are independently selected from each other. : 1. F ; 2. C1 ; 3. Br ; 152238.doc -22- 201124414 4. I ; 5. Linear or branched _Ci_c1G alkyl, optionally substituted or substituted by R4a, R4b, R4c; 6. -C3-C7 cycloalkyl, monosubstituted by R4a, R4b, R4c as appropriate Or polysubstituted; 7. -OH; 8. linear or branched oycrdo)alkyl 'optionally substituted or polysubstituted by R4a, R4b, R4C; 9·linear or branched-Y-alkyl (Y =S, SO, S02), monosubstituted, disubstituted or trisubstituted by R4a, R4b, IUC, as appropriate; -0-(C3-C7)cycloalkyl, optionally substituted or substituted by R4a, R4b, R4C 11. -0-aryl, optionally substituted or polysubstituted by R4a, R4b, R_4c; 12 aryl, optionally substituted or substituted by R4a, R4b, R4c; 13. Heteroaryl, as appropriate Monosubstituted or polysubstituted by R4a, R4b, IUe; 14. Heterocycloalkyl, optionally substituted or polysubstituted by R4a, R4b, R4c; 15·~N〇2; 16 ...NH2 ; 17· alkyl or C3-c7)cycloalkyl or heterocycloalkyl), each group optionally substituted by R4a, R4b, lUc or 152238.doc S • 23- 201124414; 18. -NGC^-Cm)alkyl or (C3-C7)cycloalkyl)2, each group being optionally substituted or polysubstituted by R4a, R4b, R4c; 19. -NH aryl or NH heteroaryl, optionally substituted by R4a, R4b, R4c Or multiple substitutions; 20. -NHC(O), via R4a, R4 b, R4c substituted; 21. -NCCCVCn)alkyl)C(O), substituted by R4a, R4b, R4c; 22. -NHS(02), substituted by R4a, R4b, R4c; 23. -NCCC^-Cw) Alkyl)S(02), substituted by R4a, R4b, R4c; 24. -C02, substituted by R4a, R4b, R4c; 25. -CONH2; 26·linear, branched or cyclic-CONH(alkyl) And CON(alkyl) 2, wherein the alkyl moiety is optionally monosubstituted, disubstituted or trisubstituted by R4a, R4b, R4c; 27. -C(O)heterocycloalkyl, optionally via R4a, R4b, R4c Monosubstituted, disubstituted or trisubstituted; 28. -S, substituted by R4a, R4b, R4c; 29. -S(02), substituted by R4a, R4b, R4c; 30. -S(O), via R4a, R4b , R4c substituted; 3 1. pendant oxy group (double bond O); 32. -C2-C6 alkenyl group, optionally substituted or substituted by R4a, R4b, R4c; -24- 152238.doc 201124414 33. -CVC6 alkynyl, optionally substituted by R^a, R4c; 5 such groups R4a, R4b and R4c, ie the substituents of the groups R3a, R3b and R3c are independent of each other The ground is selected from: 1. F; 2. C1; 3. Br; 4. I; 5. -CF3; -CHF2; 6. Linear or branched C^-Cm alkyl; 7·-C3-C7 naphthenic 8. 8-OH; 9. Linear or branched sulfhydryl; 10. Linear or branched - Y-alkyl (Y=s, SO, SOJ; 11·-〇-(c3-c7) naphthenic a group; an aryl group; a heteroaryl group; a hexacyclic group; (C3_C7) cycloalkyl or heterocycloalkyl); H-NiXCi-Ci. Alkyl or (C3-C7)cycloalkyl)2; 152238.doc •25- 201124414 20. -NH aryl or NH heteroaryl; 21. -NHS(02)alkyl; 22. -N(( Ci-Ci 〇)alkyl)S(〇2) 炫; 23. -C02 alkyl; 24. -CONH2 ; 25. Linear, branched or cyclic _C〇nh (alkyl) and CON (alkane) 2); 26·-C(O)heterocycloalkyl; 27.-S-alkyl; 28·-S(02)alkyl; 29.-S(O)alkyl; 30. Double bond 〇); 31. straight or branched chain -C2-C6 alkenyl; 32. straight or branched chain _c2-c6 alkynyl; the product of the formula (I) is any possible racemization, pair And the diastereomeric isomers, and the addition salts of the products of the formula (I) with inorganic and organic acids or with inorganic and organic bases. 5. A product of formula (1) as defined in any one of the preceding claims, the name of which is as follows: bromo-6-methoxy-3-(.by bite)_9Η_β as a lining-{4-[6-A Oxy 3-(p-pyridinyl-3-yl)_9Η_ρ-porphyrin_5-yl] stupyl} decanesulfonamide 1^-[2-(-decylamino)ethyl]-4-[6 -Methoxy_3-(«»比 bit_3-yl)-9Η-β_carboline-5-yl]benzamide 152238.doc •26- 201124414 N-[3-(dimethylamine Propyl]-4-[6-decyloxy-3-(D-pyridin-3-yl)·9Η-β-carboline-5-yl] benzoate amide 4·[6-decyloxy -3-(° than bite-3-yl)-9Η-β-leaf·leaf-5-yl]benzoic acid 66-methoxy-5-{4-[3-(旅咬 bit-1- Propyloxy]phenyl]}3·(η ratio) IIΗ-β-porphyrin 6-decyloxy-5-{4-[3-(morphin-4-yl)propoxy ]phenyl}_3-(Bite_3·yl)-9Η-β-carboline 5-[3-(4-ethyl-l-yl-l-yl)-3-indolyl-1-one-1 -yl]-6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline oxime, Ν-diethyl-2-{4-[6-曱-lacyl-3-(0比0-3-yl)-9Η-β-Miso _ _ 5-yl]piperazin-1-yl}ethylamine 6-fluoro-5-methoxy-3-(pyridin-3-yl)- 9Η-β-carboline Ν-[2-(didecylamine) Ethyl]-4-[6-fluoro-3-(&quot;bipyridin-3-yl)-9Η-β-味琳_5-yl]benzamide-Ν[4-(1·曱基Piperidinyl)]-4-[6-fluoro-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]phenylguanamine-(2-aminoethyl) -4-[6-fluoro-3-(acridin-3-yl)-9Η-β-carboline-5-yl]benzamide-5 [6-fluoro-3·(pyridin-3-yl) -9Η-β-porphyrin-5-yl]benzoic acid&gt;^-[(18,28)-2-aminocyclohexyl]-4-[6-fluoro-3-(pyridin-3-yl) -State-β-carboline-5-yl]phenylguanamine 5-methoxy-3-(acridin-3-yl)-9Η-β-carboline-[2-(didecylamino) Ethyl]-4-[3-(0-pyridin-3-yl)-9Η-β·porphyrin_ 5-yl]benzamide 152238.doc • 27- 201124414 N-[(lS,2S) 2-aminocyclohexyl]-4-[6-methoxyethoxy-3-(1-indolyl-1H-pyrazol-4-yl)-9Η-β-carboline-5-yl] Benzomethamine 6-methoxyethoxy-5-{4-[3-(ethylamino)propoxy]phenyl}-3-(1-indolyl-1Η-pyrazole-4- ))-9Η-β-carboline N-[(lS,2S)-2-aminocyclohexyl]-4-[6-cyclobutyloxy-3-(1-methyl-1Η-pyrazole- 4-yl)-9Η-β-carboline-5-yl]phenylguanamine 6-decyloxy-5-{4-[3-(ethylamino)propoxy]phenyl}-3- (1- --lH-ηBizozol-4-yl)-9Η-β-carboline 5-methoxy-3-(bumethyl-1Η-pyrazol-4-yl)-9Η-β-carboline 5-{4 -[3-(Ethylamino)propoxy]phenyl}-3-(1-indolyl-1Η-indazol-4-yl)-9Η-β-carboline. 6. A method of preparing a product of formula (I) as defined in any one of the preceding claims, characterized by the general procedure below: An Coupling R··(Stiller, eucalyptus, etc.) Subsequent reduction (in the case of nitro) Hartwig-Buchwald a compound of formula (I), wherein R3, R5 and R6 are as defined above X = Br or I -M = -SnMe3 or -B(〇H)2 or UN = 02N, H2N, HPivN R = Cl, OMe, OH ' 0S02CF3 or R3 R· = OM, OMe, OH, OS02CF3, Br or R5 R&quot; = H, Br, OH as defined above Or R6 as defined above. General Scheme 152238.doc -28- 201124414 wherein the substituents R3, R5AR6 have the meanings indicated in the preceding claims for the product of the formula (I). 7. A drug which is a product of formula (I) as defined in claims 1 to 5 and a prodrug thereof, the product of which is in any possible racemic, enantiomeric and diastereomeric An isomeric form, and a pharmaceutically acceptable addition salt of the product of the formula (1) with an inorganic acid and an organic acid or with an inorganic base and an organic base. A pharmaceutical product of the formula (1) as defined in any one of claims 1 to 4, which has the following name: 5-bromo-6-foxy-3-(pyridin-3-yl)-9Η -β-carboline Ν-{4-[6-methoxy-3-(.pyridin-3-yl)-9Η-β-carboline-5-yl]phenyl} decanesulfonamide Ν- [2-(Didecylamino)ethyl]_4-[6-decyloxy-3-(»bipyridin-3-yl)-9Η-β-carboline-5-yl]benzamide -[3-(Dimethylamino)propyl]-4-[6-methoxy-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzimidazole Amine 4-[6-methoxy-3-(pyridin-3-yl)-9Η·β-carboline-5-yl]benzoate decyl 6-decyloxy-5-{4-[3- (piperidin-1-yl)propoxy]phenyl}-3-(.pyridin-3-yl)-9Η-β-carboline 6-methoxy_5'{4-[3-( Phenyl-4-yl)propoxy]phenyl}-3-(acridin-3-yl)-9Η-β-carboline 5-[3-(4-ethyl-l-qin-1-yl)- 3-(indolyl-1-yn-1-yl)-6-indolyl-3-(e-bit _3-yl)·9Η-β- yelin Ν, Ν-diethyl-2·{ 4-[6-methoxy_3 decapyridyl_3_yl)_9Η+porphyrin-152238.doc -29- 201124414 5-yl]piperazine-l-yl}ethylamine 6-fluoro-5- Oxy-3-(pyridin-3-yl)-9Η-β-carboline Ν-[2-( Dimercaptoamino)ethyl]-4-[6-fluoro-3-(pyridin-3-yl)-9Η-β_ porphyrin-5-yl]benzamide N-[4-(l-A Piperidinyl)]-4_[6-fluoro-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide Ν-(2-aminoethyl)-4 -[6-fluoro-3-(pyridin-3-yl)-9Η-β-carboline-5-yl]benzamide-5 [6-fluoro-3-(pyridin-3-yl)-9Η- Β-porphyrin-5-yl]benzoic acid N-[(l S,2S)-2-aminocyclohexyl]-4-[6-fluoro-3-(.pyridin-3-yl)-9Η-咔- porphyrin-5-yl]benzamide 5·methoxy-3-(° ratio -3-yl)-9Η-β-味琳Ν-[2_(didecylamino)ethyl ]-4-[3-(Acridine-3-yl)-9Η-β-carboline_ 5-yl]benzamide N-[(lS,2S)-2-aminocyclohexyl]-4- [6-Methoxyethoxy-3-(1-indolyl-1Η-pyrazol-4-yl)-9Η-β-carboline-5-yl]benzoguanamine 6-methoxy ethoxy 5--5-{4-[3-(ethylamino)propoxy]phenyl}-3-(1-methyl-1Η-pyrazol-4-yl)-9Η-β-carboline N- [(lS,2S)-2-Aminocyclohexyl]-4-[6-cyclobutyloxy-3-(1-methyl-1Η-pyrazol-4-yl)-9Η-β-carboline -5-yl]phenyl hydrazine 6-methoxy-5-{4-[3-(ethylamino)propoxy]phenyl}-3-(1-indolyl-1Η-pyrazole- 4-base -9Η·β-carboline 5-methoxy-3-(didecyl-1Η-pyrazol-4-yl)-9Η-β-carboline 5-{4-[3-(ethylamino)propoxy Base]phenyl}-3·(1-methyl-1Η-°biazole-152238.doc •30- 201124414 4-base)-9Η-β-carboline and its prodrug, the product of the formula (I) Is in any racemic, enantiomeric and diastereomeric form, and the pharmaceutically acceptable form of the product of the formula (I) with inorganic and organic acids or with inorganic and organic bases. Addition salt. A pharmaceutical composition comprising as an active ingredient a product according to any one of the preceding claims, and at least one pharmaceutically compatible excipient. 10. A pharmaceutical composition according to the above claim, which is for use in the treatment of cancer. 11 · A novel industrial product which is a synthetic intermediate of the formulas An, Bn, Cn and Dn as defined in the general procedure of claim 6 and as defined below: Where -M = -SnMe3 or seven (01&quot;1) 2 or R = Cl, OMe, OH, 0S02CF3 or R3 as defined above where X = Br or I R&quot; R1R2N = 02Nl H2N, HPivN R_ = H, OMe, OH, 0S02CF3, Br, or R5 R._ = H, Br, OH as defined above or R6 as defined above Wherein RRN = 02N, H2N, HPivN R = Cl, OMe, OH, 0S02CF3 or R3 R_ = H, OMe, OH, 0S02CF3, Br as defined above, or R5 R&quot; = H, Br as defined above OH or R6 as defined above wherein R = Cl, OMe, OH, OS02CF3 or R3 R· = H, OMe, OH, OS02CF3, Br as defined above, or R5 R&quot; = H as defined above, Br, OH or R6 5 152238.doc -31 - 201124414 as defined above. IV. Designation of representative drawings: (1) The representative figure of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: 152238.doc -4-