TW200817417A - Compounds - Google Patents

Abstract

Bicyclic nitrogen containing compounds and their use as antibacterials.

Description

200817417 » IX. INSTRUCTIONS: 1. FIELD OF THE INVENTION The present invention relates to novel compounds, compositions comprising the same and their use as fungicides, including the treatment of tuberculosis. 5 [Prior Art] W002/08224, W002/50061, WO02/56882, W002/96907, W02003087098, WP2003010138, W02003064421, W02003064431, W02004002992, 10 W02004002490, W02004014361, W02004041210, W02004096982W02002050036, W02004058144, W02004087145, W006002047, W006014580, W006010040, W006017326, W006012396, W006017468, W006020561, WOOL/25227, W002/40474, is W002/07572, W02004035569, WP2004089947, W004024712, W004024713, WO04087647, W02005016916, W02005097781, W006010831, WO04035569, WO04089947, W006021448, WO06032466, W006038172, WO06046552, WO06134378 2 〇 and WO 06137485 disclose bactericidal activity. Kui Wei, naphthoquinone, morphine, cyclohexane, hexahydropine bite and hexahydroquinone σ well derivatives. SUMMARY OF THE INVENTION The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvent 200817417 compound or N-oxide: A-NR2-UR5 5

(1) where two of Z1, Z2, Z3 and Z4 are independently CRlc^N and the rest are independent of CRle; or Z3 and Z4 together represent S and one of Z1 and Z2 is CRle or N and the other one Independently CRle;

Rla, Rlb& Rle are independently selected from hydrogen; halo; cyano; (Cu) alkyl; (CV6) alkylthio; trifluoromethyl; trifluoromethoxy; carboxy; Alkyl or (Cw)alkoxy-substituted (Ci_6)alkyl-substituted hydroxy; alkoxy-substituted ((^_6)alkyl; hydroxy(Cw)alkyl; N optionally one or two ( Cu) an alkyl group, a fluorenyl group, a (Cu) alkyl group or a (C1_6) alkyl group substituted amino group; or an amine group wherein the amine group is optionally substituted by a (Cw) alkyl group; Or two of Rla, Rlb & Rle on the adjacent carbon atom may form an ethylenedioxy group; R2 is hydrogen or (Cw) alkyl, or may form a Y as defined below with R6; Is the base (1): 6 200817417

Base 且 and η is 1 or 2; or Α is base (ii):

Ketone or amine

10 W1, W2, and W3 are CR4R8 15 or W2 and # is CRY and represents the key between W3 and n. x is 0, CR4R8 or NR6; 8曰 two R4 are based on the definitions for Rla, Rlb&Rle and the other and R is hydrogen or one R4 and R8 are keto groups and the rest are hydrogen; r6 is hydrogen or ((^_6)alkyl; or γ with R2; R helium, halo, optionally substituted via (Ci_6) alkyl; or (Cl-6) alkyl; γ is cr4r8ch2; ch2cr4r8 (〇〇); CRV; cr4r8(c=〇); or (c=o)cr4r8; or when X is cr4r8, R8 and R7 together represent a bond; U is selected from CO and ch2 and 20 200817417 R5 is random Ring-substituted bicyclic carbocyclic or heterocyclic ring system (B):

(9) 5 containing up to four heteroatoms in each ring, at least one of which is aromatic (a) and (b) is aromatic; when X1 is part of the aromatic ring, it is C or N, when it is a non-aromatic ring Partially CR14, 1 When X2 is part of an aromatic or non-aromatic ring, it is N, NR13, Ο, S(0)x, CO or CR14, when it is part of a non-aromatic ring. Alternatively, CR14R15, X3 and X5 are independently N or C; Y1 is a linking group of 0 to 4 atoms, wherein each atom is independently selected when it is part of an aromatic or 15 non-aromatic ring. From N, NR13, Ο, S(0)x, CO and CR14, when it is part of a non-aromatic ring, it may be CR14R15, Y2 is a linking group of 2 to 6 atoms, and each atom of Y2 is a fang. A portion of a family or non-aromatic ring is independently selected from the group consisting of N, NR13, 0, S(0)x, CO, and CR14, and when it is part of a non-aromatic ring, it may be additionally CR14R15, R14 and R15 are independently selected from the group consisting of: hydrazine; (Cu) alkylthio; halo; carboxy (Cw) alkyl; ((^_4) alkyl; ((^_4) alkoxycarbonyl; (Cw) alkyl Carbonyl, (Ci_4) alkoxy (C!_4) alkyl; light base; radix (Ci stomach 4) alkyl; (Ci_4) alkoxy; nitro; Alkyl; a carboxy group; optionally a (Cw) alkyl mono- or disubstituted amino or amino group; or +' 8 200817417 R14 and R15 may together represent a keto group; each R13 is independently fluorene; Methyl; (C^)alkyl optionally substituted by hydroxy, (Cu) alkoxy, (Cu)alkylthio, halo or trifluoromethyl; (C2_4)alkenyl; (Cw)alkoxycarbonyl ((^_4)alkylcarbonyl; ((^_6)alkylsulfonyl 5 fluorenyl; aminocarbonyl wherein the amine group is optionally mono- or disubstituted by (Cm)alkyl; each X is independently 0, 1 Or 2. The present invention also provides a compound of the formula (1) which is not a compound wherein: ίο Z3 and Z4 together represent S and one of Z1 and Z2 is CRle or N and the other is independently CRle; and/or R3 Is an aminomethyl group; or a pharmaceutically acceptable salt, solvate or N-oxide thereof. The invention also provides a method of treating a bacterial infection comprising a nucleus 15 disease in a mammal, particularly a human, the method comprising An effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or N-oxide thereof, is administered to a mammal in need of such treatment. Use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or N-oxide thereof, for the manufacture of a medicament for use in the treatment of a bacterial infection comprising tuberculosis in a mammal. The invention also provides a pharmaceutical composition, It comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate or N-oxide thereof, and a pharmaceutically acceptable carrier. The invention also provides a compound of formula (IA), or a pharmaceutically acceptable thereof 200817417 Salt, solvate or N-oxide: A-NR2-UR5

(IA)

Wherein Z Z1, Z2 and Z3 are independently CRlc* N and the rest are independently CR1 ίο Z4 is CH;

Rla is hydrogen, halo, cyano or hydroxy substituted by (^^6)alkyl; Rlb is hydrogen; when Z3 is CRle, Rle is hydrogen; when Z1 or Z2 is CRle, Rle is hydrogen; 15 R2 Is hydrogen; A is base (ia):

(ia) 20 wherein: R3 is hydrogen or hydroxy and η is 1; or Α is base (ii):

10 200817417 W1, W2 and W3 are CH2; or W2 and W3 are CH2 and W1 represents the key between W3 and N. x is 〇 or CR4R8; R4 is hydrogen or hydroxy; 5 R8 is hydrogen; R7 is hydrazine; U is a ring system selected from CO and CH2, and R5 is a randomly substituted bicyclic heterocycle (B): 10

(B) containing up to four heteroatoms in each ring wherein ring (a) is aromatic and (b) is aromatic or non-aromatic; X1 is C; 15 X2 is N, Ο, S or CR14; X3 and X5 is C; Y1 is a linking group of 1 or 2 atoms, wherein each atom is independently selected from N and CR14; 20 Y2 is a linking group of 3 or 4 atoms, and each atom of Y2 is independently selected From NR13, Ο, S, CO or i) CR14, as part of the aromatic ring, or ii) CR14R15, as part of the non-aromatic ring; each R14 and R15 are independently selected from: Η or a group; and R13 is Η; or (Cw) alkyl. In a special aspect, regarding equation (IA), one or two Z1, Z2

11 200817417

And Z3 is N 5 in a particular aspect, and with respect to formula (IA), Rla is a hydrogen, a halogen group or a mercapto substituted group. *Another aspect, regarding formula (10), :虱: or methoxy. In yet another aspect, the formula (5) is a methoxy group.

R R la la In a special aspect, with regard to the formula (ΙΑ), A is the base (ia): R3

Wherein R is hydrogen or a meridine and η is b 2, a 4 inch aspect, and r5 in the formula (IV): 15 20 Ϊ1 wherein Rl4 is selected from hydrogen or a halogen group, such as chlorine; and CR^t The linker 'where each atom is independently selected from N, the prerequisite is that neither of the two atoms of Y1 is N. In terms of atoms, with respect to R5 in the formula (IA), γ2 is 4 CHt Η), where Q is selected from the group consisting of 〇, s and special ' 'About R5 in the formula (ΙΑ), Γ2 is not in a special aspect: Ζ and each Ζ2, Ζ3, and Ζ4 are independently CRlc; 12 200817417 (3) Z2 is N and each ZV, Z3&Z4 is independently CRlc; (4) Z3 is N and each z!, Z2 and Z4 are independently CRlc; (5) Z1 and Z3 are N and Z2 and Z4 are independently CRlc; (6) Z2 and Z3 are N and Z1 and Z4 are independently CRlc; (7) Z3 and Z4 are N And Z1 and Z2 are independently CRlc; (8) Z and Z4 are 8 and 2:1 and 24 are independently CRic; (9) z and z are s and ζι is CRlCa " is N ; 10) Z1 and Z2 are N and Z3 and Z4 are independently cr1c. 10 20 In a particular aspect, each Ru, Rlb and Rlc are independently or halo (Ci'4mthio, (ci. 4) alkyl, cyano, (iv), octyl or dentate; more particularly hydrogen , methoxy, methyl*, ethyl, aryl group, I, in the specific examples, only one Rla, R 虱. In a particular embodiment, Rla basin - non-halogen group such as fluorine, chlorine Or bromine and R1...in the ruthenium, in the mouse matrix embodiment, Rib is not hydrogen, such as fluoranthene. In another alternative, in other embodiments, Rla, Rlb hydrogen, especially octafluoro and Rlb In the other embodiment, 汐 is 匚 lc to form an ethylene dioxy group. And Ra and Rlc — j are in a special aspect, R 2 Is a hydrogen. And a special example of hydrogen includes hydrogen; an optionally substituted amine group; a dentate group; (Cm) alkyl) of the filament; optionally passed through the citric acid (Ci-4) thiol

13 200817417 Substituted aminocarbonyl. More particularly, the R3 group is hydrogen; CONH2; 1-hydroxy, alkyl such as CH2OH; optionally substituted hydroxy such as decyloxy; optionally substituted amine; and halo, especially fluoro. The most particular R3 group is hydrogen or a meridine. 5 In a particular aspect, when A is (ia), η is 1. In a particular aspect, R3 is at the 3- or 4-position, more particularly at the 3-position. In a more particular aspect, Α is (ia), η is 1 and R3 is at the 3-position, and more particularly the cis position relative to the NR2 group. In a particular embodiment, Α is an (ia) group wherein η is 1 ίο and R 3 is hydrogen or hydroxy. More particularly, wherein hydrazine is 3-hydroxy-hexahydropyridin-4-yl-amino group, the configuration is (3R, 4S). In a particular aspect, when A is (ii), X is CR4R8, R8 is Η and R4 is Η or OH. More particularly when R4 is OH and its opposite position is relative to R7. In another aspect, W1 is a key. In another aspect, R7 is is Η. In another aspect, W1 is a key, W2 and W3 are both CH2 and R7 is Η. In a particular aspect, wherein A is 3-meridinyl-4-ylindenyl, the configuration is (3S, 4S). In a particular aspect, when A is (ii), X is CR4R8, R8 is H, R4 is OH, W1, W2 and W3 are both CH2 and R7 is oxime, and A is 4-hydroxyl-2-pyrrolidin-3- Base base. More particularly R40H is in the opposite position relative to R7H. In a particular aspect, when A is (ii), X is 0, R7 is Η and W1, W2, and W3 are each CH2. In some embodiments, U is CH2. In certain embodiments, R5 is an aromatic heterocyclic ring (B) containing 8-11 14 200817417 ring atoms including 2-4 heteroatoms, at least one of which is N or NR13, in a particular embodiment, wherein Y2 contains 2-3 heteroatoms, one of which is S and 1-2 is N, and one N is bonded to X3. In an alternative embodiment, the heterocyclic ring (B) contains a ring (a) aromatic selected from the group consisting of benzo, pyridyl, ruthenium and pyrimidine and ring (b) non-aromatic and Y2 Containing 3-4 atoms including at least one hetero atom, Ο, S, CH2 or NR13 bonded to X5, wherein R13 is not hydrogen, and NHCO is bonded to X3 via N, or via Ο, S, CH2 or NH bond To X3. In a particular aspect, ring (a) contains an aromatic deficiency, and more particularly ring (a) is a bite, 10 吼 or bite. In some embodiments, R5 is:

15

Wherein Z is a point of attachment, Y3 is ch2 or 〇; and 20 R1G is independently selected from the group consisting of hydrogen, i group, (Cu) alkyl group and (Cw) alkoxy group. More particularly R1() is selected from the group consisting of hydrogen, chlorine, decyl and methoxy. Examples of ring (B) include optionally substituted: (a) and (b) if 1H-pyrrolo[2,3-b]-pyridin-2-yl, 1H-pyrrolo[3,2-b] -pyridine-2- 15 200817417 II, 3H m sit and [4,5-b]-port ratio _2_ base, 3H-mouth koukou sitting forest-4-keto-2-yl, • benzene And dimercapto, benzopyrene, 2,)]-thiadiazol-5-yl, benzo[1,2,5], and the like, dinonyl, benzopyrene-2, benzopyrene Salivation, benzo[b]thienyl, benzoxazole-2-yl, octenylene-4, 3,2, and imidazolium are lower than 5, 2, and imiprazole [l, 2 -a] 哺 _2 _ _2 吲 吲 吲 吲 吲 吲 吲 吲 _2 _2 _2 _2 _2 _2 哺 哺 哺 哺 哺 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ [4,5_b]4b dentate _2_yl, 喳咐_2_yl, anthracene, 喳吟咐_2•yl, naphthalene-2-yl, anthracene, 3-dione-isoindole ·2-Based, Benzimidazole_2-yl, 1仏Benzyltriazole_5_yl, 1Η-吲哚_5_yl, 3Η-benzoxazole-2-ketone_6_yl, 3Η_ Benzooxazole_2_ 1 vermiculite;,L keto group, 3Η_stupothionazole-2-keto-5-yl, 3Η-oxazolium 咁4-keto_6_ basic and [丨,2,3]0啥_啥_6_yl, benzo[1,2,5]indole-5-yl, benzo[1,4]indol-2-one-3-yl , benzothiazole _5_ group, benzothiazole _6_ group, Xinglin 3-yl, imipenem [i, 2_a] Takai well_2_ base, 吼 并 比 比 啡 啡 啡 啡[1,5_&] bite-2-yl,.峻 并 [i,5_a] bite _6_ base, 吼15 oxazo[UM1,2,4] three tillage _3_ base, pyridine and U,2_a]pyrimidin-4 ketone_2_ base, 吼^疋[l,2-a] squeezing _4_keto-3, guanidin-2-yl, π Kui lin _6_ yl, thiazolo[3,2-a]pyrimidin-5-one 7-yl, thiazolo[5,4氺]pyridine_2_yl, thieno[3,2-b]acridinyl, thiazolo[5,4_b]acridinyl, thiazolo[4,5- b] Pyridin-5-yl, [1,2,3]thiadiazolo[5,4-b]pyridine-6-yl, 20 2H-isoin-1-one-3-yl 16 200817417

Ο—is the point of attachment (a) is non-aromatic 17 200817417 (2S)-2,3_dihydro-1H-吲哚-2·yl, (2S)-2,3-dihydro-benzo[Μ] Dioxinyl, 3-(R,S)-3,4-dihydro-2-indole-benzo[1,4]thin-3-yl, 3-(R)_2,3-dihydro-[1 , 4] dioxo[2,3-7]pyridine-3-yl, 3_(S)-2,3-dihydro-[1,4]dioxo[2,3-b]pyridinium_ 3_yl, 2,3-dihydro-benzo[1,4]dioxo[2,3_b]pyridine-3-yl, 2,3-di-argon-benzo[1,4]dioxane -2-yl, 3-substituted-3H-carbazole 咁4-keto-2-yl,

- is the point of attachment) is a non-family 1,1,3_triketo-1,2,3,4_tetrahydro 1/6-benzo[1,4]thienyl-6-yl, benzo [1,3] bis-oxo-5-yl, 2,3-dihydro-benzo[1,4]dioxo-6-yl, 3-substituted-3H-benzoxazole-2-ketone _6•基,3_substituted_311_benzoxazole_2_thione_6_ group, 3_substituted_3H_benzothiazol-2-one-6-yl, 4H-benzo[1 , 4] jing-3-keto-6-yl (3-keto-3,4_dihydro-2H_benzo[L4] hydrazine), 4H_benzo[1,4] tidy tillage- 3-keto-6-yl (3-keto-3,4-dihydro-2H-benzo[1,4]thirsty_6_ soil) 4H/[1,4] slogan-3-one -7-yl, 4-keto-2,3,4,5-tetrahydro-benzo[b][l,4]thiazepine·? _, 5-keto-2,3-dihydrothiazolo[3,2-a]pyrimidine _6-yl, 1 Η_σ pyridine and 喧 _2 _2 ketone _7• yl (2_ 18 200817417 keto- 2,3_ dihydro-1H-pyrido[2,3-b][l,4]thien-7-yl), 2,3_dihydro, -1H-pyrido[2,3_b][l,4 Thiacin-7-yl, 2-keto-2,3-diar-argon-1H-pyrido[3,4-7]thin-7-yl, 2,3-dihydro-[1,4] Oxahydro[2,3-b]pyridin-6-yl, 2,3-dihydro-[1,4]dioxo-g[2,3-c]pyridin-7-yl, 2,3-di Hydrogen 5-Π,4]dioxo[2,3_b]pyridine-7-yl, 3,4-dihydro-2H-benzo[1,4]indole _6_yl, 3,4-di Hydrogen-2H-benzo[1,4]thienyl-6-yl, 3-keto-3,4-dihydro-2-indole-pyrido[3,2-b][l,4]噚耕-6 -yl, 3,4-dihydro-211-pyrido[3,2-b][l,4]thia+6-yl, 3-keto-3,4-diindole-2H-pyridinyl. Well-6-based, 3,4_diaza-1H-U Kui 11 Lin-2-broth J-7-based, 3,4_ 1〇二氲-1Η_σ奎口号口林-2-keto-7-yl , 6,7-two-氲-々Η-. Compared with saliva [l,5-a] bromo-5-one-2-yl, 1,2,3,4-tetrahydro-[1,8]naphthyridin-7-yl, 2-keto- 3,4-dimur-1 H-[ 1,8] nai,6·yl, 6_S homo--6,7_two mice_511_8_嗔_ 1,2,5-tri-gas-naphthalene-3 -yl, 2-keto-2,3-dihydro-1H-pyrido[3,4-b][l,4]indole-7-yl, 2-keto-2,3-dihydro- 1Η_pyridine[2,3-b][l,4]唠耕-7-yl, 6,7-15 -one-[1,4]^-oxohexidine-2-yl, [1 , 3] slogan sputum and [5,4-c] mouth bite-6-yl, 3,4-dihydro-211-pyrano[2,3-(:]pyridine-6-yl, 2, 3-dihydro[1,4]indolo[2,3-φ-pyridin-7-yl, 6,7-dihydro[1,4]dioxo[2,3-c] 3-yl, 6,7-dihydro[1,4]indolo[2,3-c]indole-3-yl, 6,7-dihydro-511-12 to 11 nanxi [2,3 -(;)Ta 0 well-3-yl, 5,6-dihydrobitothotho[2,3-〇] tower ^2 well-3-2 fluorenyl, 2,3-dihydrofuran [2, 3-c]pyridine-5-yl, 2-substituted 1H-pyrimido[5,4_1)][1,4]indole_7(611)-ketone, 2-substituted 5,6-dihydropyridine And [2,3-(1] pyrimidine-7(1H)-one, 7-substituted 2H-nonen-2-one, 7-substituted 2H-pyrano[2,3-b]pyridine_ 2-ketone, 2-substituted 6,7-dihydro-5H-pyrano[2,3-d] pyrimidine The 8-substituted 2H- pyrazol bite and [l, 2-a] pyrimidin-2-one, 2,3-dihydro -1-19200817417

HN

5 IX benzofuran-5-yl,

20

Is the point of attachment. In some embodiments, r13*H is in the ring (a) or when 20 200817417 is additionally in the ring (b) is a (Ci 4)alkyl group such as a decyl group or an isopropyl group. More specifically, it is said that R13 in the ring (9) is Η NR13 is bonded to X3 and (Cle4) alkyl when NR13 is bonded to χ5. In other specific embodiments, R14 and R15 are independently selected from the group consisting of hydrogen, a dentate group, a (Cl _4) alkyl group, a (Cl _4) saponin group, a fluorenyl group, and a cyano group. More specifically, R15 is hydrogen. More specifically, each R14 is selected from the group consisting of hydrogen, chlorine, fluorine, hydroxyl, methyl, decyloxy, nitro and cyano. More specifically, R14 is selected from hydrogen, fluorine or an exact group. 1〇 Most specifically R14 and R15 are each Η. Particular R5 groups include: [1,2,3]thiadiazolo[5,4-b]pyridin-6-yl 1H-pyrrolo[2,3-b]pyridin-2-yl 2.3-dihydro- [1,4]dioxo[2,3-b]pyridin-6-yl 15 2,3-dihydro-[1,4]dioxyg and [2,3_b]pyridine-7-yl 2.3- Dihydro-[1,4]dioxo and [2,3-c]-pyridin-7-yl 2.3-dihydro-benzo[1,4]dioxo-6-yl-2-keto-2 ,3-dihydro-1H-pyrido[2,3-b][l,4H cultivable-7-yl 2-keto-2,3-dihydro-1H-pyrido[2,3-b][ l,4] tidal _7-yl 2〇3,4-diargon-2H-benzo[1,4] succinyl-6-yl-3-mercapto-2-keto-2,3-dihydro -benzoxazol-6-yl-3-keto-3,4-dihydro-2H-benzo[1,4]indole-6-yl-3-keto-3,4-diindole-2H- Pyrido[3,2-b][l,4]噚耕-6_基(6_substituted 211_ mouth ratio °定弁[3,2_b][l,4]ϋ寻ϋ井-3(4H )-酉同) 21 200817417 3_keto-3,4_dihydro-2H-benzo[1,4]thiazin-6-yl (4H•benzo. [1,4] tiago-3 -keto-6-yl) 4-keto-4H-pyrido[l,2-a]pyrimidin-2-yl 6-nitro-benzo[1,3]dioxan-5-yl 5 7-fluoro _3_keto-_3,4_dihydro-2H-benzo[1,4]indole-6-yl-8-hydroxy_1-keto-1,2-dihydro-isoindole_3_ 8-hydroxyl group Porphyrin-2-ylbenzo[1,2,3]thiadiazol-5-ylbenzo[1,2,5]thiadiazol-5-yl 1 benzobenzothiazol-5-ylpyrrole [5,4-b]pyridyl-6-yl-3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]thirsty_6_yl (6• Substituted 2H-pyrido[3,2-b][l,4]thratic-3(4H)-one) 7·chloro-3-keto-3,4-dihydro-2H-pyrido[3 ,2-b][l,4]thiazine _6_yl 15 7-chloro-3-keto-3,4_dihydro-2Η-σ ratio bite [3,2-b][l,4 The current π well base (6-substituted 7-chloro-2H-bite and [3,2-b][l,4]4_-3(4H)__) 7-fluoro-3-yl-keto-3, 4-Dihydro-2H-pyrido[3,2-b][l,4]thinyl-6-yl-2-keto-2,3-dihydro-1H-pyrido[3,4-b] [l,4]Thiophen-7-yl[1,3]indolo[5,4_c]acridin-6-yl 2〇3,4_diindole-2H·pyrano[2,3-c Pyridine-6-yl 2.3-dihydro-5-cyano-1,4-benzodioxan-7-yl (7-substituted 2,3-dihydro-1,4-benzodioxime) -5-nitrile) 2.3-Dihydro[1,4]σ喧[2,3-cp ratio bit-7-yl 2,3-dihydro-1-benzofuran-5-yl 22 200817417 6.7 - Dihydro[1,4]dioxo[2,3-c]indole-3-yl• 6,7-dihydro[1,4] octa-[2,3-c]. Well-3-yl-6-dihydro-5H-indolo[2,3-c][1,3-c]-l-yl-3-yl 5,6-dihydrofuro[2,3-c]indole-3- 5-2-substituted 1H-pyrimido[5,4-b][l,4]Nasin-7(6H)-keto-2-substituted 4-chloro-111-pyrimido[5,4-b] [l,4] 畤7_6(6H)-keto 2-substituted 5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one 2_substituted 4_chloro-5 , 6-dipyridino[2,3_d]pyrimidin-7(1H)-one 2_substituted 4-mercapto-5,6-dihydroport ratio. And [2,3-d] mouth -7(1H)-ketone 1〇2_ substituted 4_曱oxy-5,6-dihydropyrido[2,3_d]pyrimidine_7(m) -keto 7-substituted 2Η_η克烯-2-酉 with 7-substituted 2Η-pyrano[2,3-b]pyridine_2_酉 with 4-chloro-6,7-dihydro-5H-吼喃[2,3-d] squeezing 2-yl 8-substituted 2H-pyrido[l,2-a]pyrimidin-2-one 15 6,7-dihydro-5H-pyrano[2 ,3-d]pyrimidin-2-yl 5-chloro-1-benzothiophen-2-yl-6-chloro-1-benzoindole-2-yl 1-benzoquinone-5-yl-1 Methyl-1Η-1,2,3-benzotriazol-6-yl 2〇imidazo[2,l_b][l,3]thiazole-6-yl 4-mercapto-3,4-diindole- 2H_1,4-Benzene and drink π well base 1-mercapto-1H-indol-2-yl 23 200817417

- is the point of attachment, especially 6-substituted 2H-pyrido[3,2-b][l,4]噚耕-3(4H)-ketone 24 200817417 2.3-Dihydro-[Μ]dioxos and [2,3-c]pyridine-7-yl[1,3] rugged and [5,4-(^ is more than -6-yl 3.4-diazo sigma 弁6_ substituted 2H_pyridine[3 ,2-b][l,4]throat·3(4Η)__ 6-substituted 7-chloro-2IHb bite [3,2-b][l,4]^_-3(4H)-_ 6.7- Dihydro[1,4]dioxo[2,3-c]indole_3_yl-6-dihydro[1,4]indolo[2,3<]嗒--3-yl 2-substituted 1H-pyrimido[5,4-b][l,4]indole-7(6H)-one 2-substituted 5,6-dihydropyridinium[2,3-d] mouth Bite -7(1H)-ketone

15 is a point of attachment. As used herein, the term "alkyl" includes both straight-chain and branched groups, such as fluorenyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. , second butyl, tert-butyl, pentyl and hexyl. The term "alkenyl" is inferred from this. '° Halogen or halogen includes fluorine, chlorine, bromine and iodine. The halogen group contains 1 to 3 halogen atoms. The above four depend on the nature of the heterocyclic group, and the compounds within the scope of the present invention contain one group and two or more tautomeric forms may occur, and all such tautomeric forms are included in the scope of the present invention. 25 200817417 Some of the compounds of the invention may be crystallized or recrystallized from solvents such as aqueous and organic solvents. In this case, a solvate can be formed. The invention includes within its scope stoichiometric solvates including hydrates and compounds which can be produced by processes such as freeze-drying which contain varying amounts of water. Further, the term "a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or N-oxide thereof" includes a compound of the formula (I), an N-oxide of the formula (I), and a formula (I) A pharmaceutically acceptable salt of the compound, a solvate of formula (I), or a pharmaceutically acceptable combination thereof. In a non-limiting example for illustrative purposes, "a compound of formula (I) or a pharmaceutically acceptable salt thereof" may comprise a pharmaceutically acceptable celery of a compound of formula (I) additionally present as a solvate. Since the compound of formula (I) is used in a pharmaceutical composition, it is readily understood that in certain embodiments, it is provided in a substantially pure form, such as at least 60% pure, more suitably at least 75% pure and In particular at least 15 85%, especially at least 98% purity (% is based on weight to weight). The impure preparation of the compounds can be used in the preparation of the more pure form for use in pharmaceutical compositions; these less pure preparations of the compound must contain at least 1%, more suitably at least 5% and more particularly from 10 to 59% (I) a compound or a pharmaceutically acceptable salt, solvate or N-oxide thereof. Specific compounds according to the invention include those mentioned in the examples and pharmaceutically acceptable salts, solvates or N-oxides thereof. The pharmaceutically acceptable salt of the above compound of the formula (1) includes an acid addition or a quaternary ammonium salt, for example, with a mineral acid such as hydrogen acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid or an organic acid such as acetic acid, fumaric acid or amber. Acid, maleic acid,

26 200817417 Salts of acid, benzoic acid, p-toluene, fluorite, naphthalene or tartaric acid. The compound of formula (1) can also be prepared as an N-oxide. The invention extends to all of these derivatives. Certain compounds of formula (I) may exist in the form of optical isomers, such as non-palphaliomers and mixtures of isomers in all ratios such as racemic mixtures. The invention includes all such forms, particularly pure isomeric forms. The different isomeric forms can be separated or dissociated from one another via conventional methods, or any given isomer can be obtained via conventional synthetic methods or by stereospecific or asymmetric synthesis. Certain compounds of formula (1) may also be present in polymorphic form and the invention includes such polymorphic forms. In another aspect of the invention, there is provided a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or N-oxide thereof, the process comprising the step of formulating a compound of formula (II) with formula (III) Compound reaction: 0 vvvRla Z, z3 meaning z2^\Rlb HA-N(R2°)r2' (Π) (ΠΙ) where: 20

R is UR5 or a group convertible thereto, and R2'*R2 or a group convertible thereto, wherein z1, z2, Z3, Z4, A, Rla, Rib, R2, U and R are as in formula (i The definition in 'and then optionally or as needed 27 200817417 to convert R2G and R2 to UR5 and R2' interchange any modifiable group, and/or to form a pharmaceutically acceptable salt, solvate or N-oxide thereof. This reaction is reductive alkylation (see, for example, Smith, MB; March, 5 JM Advanced Organic Chemistry, Wiley-Interscience 2001) using a suitable reducing agent such as sodium cyanoborohydride (in methanol/chloroform/acetic acid), Sodium triethoxy hydride borohydride or (polystyrylmethyl) triterpene cyano butterfly hydride. If the amine is present as the hydrochloride salt, an excess of sodium acetate is present in the fluff to buffer the reaction. It is also possible to use 3A molecular sieves to help form the initial imine intermediate. The compound of formula (II) may be present as a hemiacetal. Conveniently, one of R2G and R2' is an N-protecting group such as a third butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenyloxycarbonyl group or a trifluoroethane group. This can be removed by several methods well known to those skilled in the art (see, for example, "Protective Groups in Organic Synthesis, TW Greene and 15 PGM. Wuts, Wiley-Interscience, 1999"), such as conventional acid hydrolysis (e.g., trifluoro). Conversion of a free amine to NR2UR5 with a mercapto derivative R5COW by acetic acid/di-halogen methane, hydrochloric acid/dichlorodecane/indole alcohol, or potassium carbonate/methanol and by conventional methods such as decylamine or sulfonamide formation. For compounds wherein U is CO, or wherein U is ch2, alkylation with an alkyl halide r5ch2-20 halide in the presence of a base, thiolation/reduction with a mercapto derivative r5cow or with an aldehyde R5CHO Reductive alkylation under conventional conditions (see, for example, Smith, MB; March, JM Orgawzc CAem (6) 〇;, Wiley_Interscience 2001). Suitable conditions include sodium cyanoborohydride (in methanol/chloroform/acetic acid). (III) is the hydrochloride salt, then

28 200817417 Sodium acetate can be added to buffer the reaction. Sodium triethoxy borohydride is an alternative reducing agent. Alternatively, the compound of formula (III) can be replaced by the compound h-a_oh. After the coupling step with (II), a suitable oxidizing agent such as Dess-Martin 5 periodinane (1,1,1_ gin(ethoxy)oxy-1,1_diindole-1,2-benzoiodo-3-(1Η) is used. )-ketone) can oxidize a hydroxyl group to a cyclic ketone. This ketone is reacted with an amine HN(R2G)R2' via conventional reductive alkylation. Suitable reagents containing the desired R5 group are known compounds or are prepared analogously to known compounds, see for example W002/08224, 1〇W002/50061, WO02/56882, W002/96907, W02003087098, W02003010138, W02003064421, W02003064431 , W02004002992, W02004002490, W02004014361, W02004041210, W02004096982, W02002050036, W02004058144, W02004087145, 15 W02006014580, W02004/035569, W02004/089947, W02003082835, W02002026723, W006002047, W006010040, W006017326, W006012396, W006017468, W006020561, WO06132739, WO06134378, WO06137485 and EP0559285. 20 A compound of formula (II) can be prepared via the following Scheme 1:

Scheme 1 29 200817417 The compound of formula (IV) can be produced by allylation of a compound of formula (V) under conventional conditions (see, for example, Smith, Μ·Β·; March, J.M.

Wiley-Interscience 2001). The conversion of (IV) to (II) can be achieved under conventional conditions via treatment with ozone or ruthenium pentoxide and sodium perchlorate (see, for example, Smith, M.B.; March, J.M.).

Advanced Organic Chemistry, Wiley-Interscience 2001) ° Compounds of formula (IV) can be prepared via the following Scheme 2:

Scheme 2 10 15 Conversion of a compound of formula (VII) to a quaternary salt (VI) can be achieved by treatment with an allyl moth under conventional conditions (see, for example, Smith, MB; March, JM Advanced Organic Chemistry, Wiley-Interscience) 2001). Compound (IV) can then be prepared from (VI) via oxidation using K3 [Fe(CN)6] (see, for example, Baxter, RN.W.; Khoury, RG; Lehn, JM; 2〇Baum, G.; Fenske, D Chemistry-A European Journal (2000), 6(22), 4140). Compounds of formula (V) wherein Z1 is CH can be prepared via Scheme 3 below: 30 200817417

The bromine derivative (IX) can be hydrogenated using Pd/C to give (VIII). Demethylation with HBr affords compound (V). In an alternative aspect of the invention, there is provided a process for the preparation of a compound of formula (I) 10, and pharmaceutically acceptable salts, solvates and/or N-oxides thereof, the process comprising a compound of formula (ΠΑ) Reaction with a compound of formula (IIIA) or (IIIB): 15

A-NHR

(ΙΙΑ) R5COY R5CH2Y (ΠΙΑ) (ΙΠΒ) 20 where: R2' is R2 or a group convertible thereto and is a ruthenium or a ruthenium group, wherein Ζ1, Ζ2, Ζ3, Ζ4, A, Rla, Rlb, R2 , U and R5 are as defined in formula (I), and then optionally or need to convert R2' to R2, interchange any modifiable group, and/or form pharmaceutically acceptable

31 200817417 Salt, solvate or N-oxide. This reaction is a reductive alkylation, guanidation or alkylation as described above. The compound of the formula (πA) can be produced according to the above reaction via a compound of the formula (II) and (ΠΙ), wherein R2G is hydrogen. Alternatively, a compound of formula (IIA) wherein Z1 and Z3 are both nitrogen, can be prepared via Scheme 4 below:

The conversion of the compound of formula (XII) to (XI) is carried out under conventional conditions (see, for example, Smith, Μ·Β·; March, J.M. CTzew/Wr;;, 20 Wiley-Interscience 2001). Compound (X) can then be prepared from (XI) by catalytic hydrogenation under conventional conditions (see, for example, Smith, J. M. Advanced Organic Chemistry, Wiley-Interscience 2001). (X) can be converted to ethyl bromoacetate by alkylation, thermal cyclization and subsequent oxidation with manganese dioxide or oxygen under conventional conditions.

32 200817417 (IIA) Smith, MB; March, JM Advanced Organic CAe View Wiley-Interscience 2001) A compound of formula (II) wherein Z1 and Z3 are both nitrogen can be prepared via a change in Figure 4, where formula (XII) The compound is reacted with an amino acetal dimethyl acetal. Catalytic hydrogenation, selective alkylation with ethyl bromoacetate and thermal cyclization affords the dimethyl acetal of (II) which can be converted to the aldehyde (II) by treatment with trifluoroacetic acid.

The conversion of Rla' to Rla& Rla, Rlb, Rlc, R2, A and R5 can be carried out by conventional methods. For example, the Rla' a pyrooxycarbonyl group can be converted to the Rla carboxyl group via aqueous hydrolysis, which is subsequently converted to the Rla aminocarbonyl group and the cyano group via conventional methods. The Rla ii group can be added via a conventional i-reaction, such as chlorination of chloroammonium imine in acetic acid to introduce a gas group at Rlb. In a compound containing a randomly protected hydroxy group, a suitable conventional hydroxy protecting group which can be removed without destroying other parts of the molecule includes a fluorenyl group and a 15 alkyl decyl group, and the N-protecting group is removed by a conventional method. . For example, Rla, Rlb4 Rle decyloxy is converted to Rla, Rlb4 Rlc via treatment with lithium and diphenylphosphine (disclosed in Ireland et al, J. Amer. Chem. Soc., 1973, 7829) or HBr. Hydroxyl. The base is alkylated with a suitable alkyl derivative having a cleavage group such as a halide to give 20 Rla, R lb 4 Rle substituted alkoxy. The Rla halo group is converted to other Rla via conventional methods, for example using a metal-catalyzed coupling reaction, such as copper, conversion to a hydroxyl group, an alkyl mercaptan (via a mercaptan), and an amine group. For review, see Synlett (2003), 15 , 2428-2439 and Angewandte Chemie, International Edition, 2003, 42(44), 5400-5449. 33 200817417 Compounds of the formula HA-N(R20)R2', (V), (VII) and (IX) are known compounds or may be prepared analogously to known compounds, for example oxazolinones and oxazolines It can be prepared by the standard route disclosed by Τ·Α·Willison in //eieroqyc/zc Compounds, 6, 324 (1957) Ed. RCElderfield.嗒耕5 can be similar to Comprehensive Heterocyclic Chemistry,

The route disclosed in Volume 3, Ed A. J. Boulton and A. McKillop, and the naphthalene bite can be prepared via a route similar to that disclosed in Comprehensive Heterocyclic Chemistry, Volume 2, Ed A. J. Boulton and A. McKillop. 〇 4-halo derivatives such as (ι) are commercially available or can be prepared by methods known to those skilled in the art. The 4-bromo-substituent can be prepared from hydrazine- or naphthyridin-4-one by reaction with phosphorus tribromide (PBr3) in DMF. 4-Chloroxazoline is prepared from the corresponding 4嗤4-4-one by reaction with phosphonium chloride (p〇Cl3) or phosphorus pentachloride (PC15). 15 For compounds of the formula HA-N(R2G)R2', (V), (VII) and (IX), see for example W02004/035569, W02004/089947, W002/08224, W002/50061, WO02/56882, W002/96907 , W02003087098, W02003010138, W02003064421, W02003064431, W02004002992, W02004002490, 2〇W02004014361, W02004041210, W02004096982, W02002050036, W02004058144, W02004087145, W02003082835 > W02002026723 ^ W006002047 > W006014580, WO06134378 and WO06137485.

According to Figure 5, the trans-amino-indenyl group of formula (III). Bilo bites (A 34 200817417 is (ii), X is CR4R8, W1 is a bond, W2 and W3 are both CH2, R4 and R7 are H and R8 is OH) and can be separated from the double protection by preparative HPLC. Preparation of a sex intermediate (XV). The benzyloxycarbonyl protecting group is obtained by hydrogen removal (XIV) and the amine functional group is converted to trifluoroacetamide 5 (XIII). The third butoxycarbonyl (Boc) protecting group is removed by HCl to give pyrrolidine hydrochloride (III).

Boc,

Boc,

- OH

Boc, ,ΟΗ

Η2 Pd-C EtOH -NHCbz

(CF3CO)20 Et3N DMAP DCM (XV) (XIV) (XIII) '—NHCOCF3 E1 & E2 (cis)

HCIMeOH DCM

15 DMAP = diammonium pyridine bite Figure 5 Intermediate (XV) can be prepared by the general method of Figure 6: 20

35 200817417 5

(XV) Figure 6 Reagents and conditions: (a) N-hydroxybenzylamine hydrochloride, sec-aldehyde, terpene, EtOH, 80 ° C; (b) Pd(OH)2, H2 (50 psi), MeOH, room temperature; 10 (c) benzyloxycarbonyl-succinimide, Et3N, dichloromethane. In Figure 7, the aminopyridyl pyrrolidine of formula (III) (A is (ii), X is CR4R8, W1 is a bond, W2 and W3 are both CH2, and R4, R7 and R8 are both H). Commercially available Boc_protected amine-mercaptopyrrolidine is prepared and converted to trifluoroacetamide. 15

DMAP = bis-aminopyridine 20 Figure 7 Amino fluorenyl oxime of formula (III) (A is (ii), X is Ο, W1, W2 and W3 are each CH2) can be from palmitic dichloro Preparation of benzyl intermediate (XX) (W02003082835) (Figure 8), first protected with Boc-protecting group 36 200817417 Amino functional group (XIX), (di) by hydrogenation to obtain (in), with benzyl The oxycarbonyl group protects the morphine hydrochloride N-atom (allowing purification by chromatography) (XVIII) and hydrogenates to give the desired morpholin derivative (III). 5

10

(XVII!) Figure 8 15 shows a method for preparing a pyrimidine oxazolone unit (R5 (C) wherein Y3 diox, R1G = H).

0.5M NH3 in 1,4-dioxane 4M HCI in 1,4-dioxane

TfO

60 °C

MeOH 50 °C

BrCH2C02Et tBuOK ‘ EtOH

37 200817417 ο^γ° rVNHΝ;Ι 0s04, Nal04 dioxane/water

5 Scheme 9 The appropriately protected ethyl glycolate (in this example THP protected, j) is methylated using ethyl formate and a base such as NaH in THF or squam. The intermediate methylformate 2 is then directly reacted with hydrazine, where (2E)-3-phenyl-2-propenenimine-3 is obtained to give pyrimidine _4. The bite is converted to a difluoromethyl phthalate (5) which is subsequently reacted with ammonia in a suitable solvent such as 1,4-disastrol to give the amine 6. The amino alcohol 7 is then obtained by removing the THP-protecting group of 6 with an acid in decyl alcohol. Treatment of 7 with an ester of 2 and ethyl-acetate in an alcohol solvent such as absolute ethanol affords 15 bicyclic intermediate 8 directly. This conversion can be accomplished using, for example, potassium t-butoxide and the alkylating agent ethyl bromoacetate. Amine bases such as triethylamine can also be used in place of the alkoxides described herein (for similar examples see N.V. Sazonov and T.S. Safonova, Khimiya Geterotsklicheskikh Soedinenii, 1971, 1285-1288). The final aldehyde intermediate 9 is followed by oxidative dissociation from the phenylvinyl side 20 chain. One way to achieve this is to react 8 with NaI04 in a mixture of 1,4-dioxane-water with a catalytic amount of 〇s04. Other methods such as ozonolysis are also suitable to achieve the desired conversion. Pyrimidine dihydropyridyl " ketone ketone (r5(c) wherein Y3 = CH2 and R10 di C1) can be prepared according to the instructions in Figure 10. 38 200817417 5 10

0s04, Nal04 dioxane/water

03, DCM, DMS

Figure 10 15 Reaction with ethyl acrylate (11) via an anion of dimethyl malonate (10) to give the triester 12.12 and (2E)-3-phenyl-2-propenenimine (3) Reaction in the presence of a base, resulting in dihydroxypyrimidine 13. Triethylamine in EtOH can be used to carry out this conversion, but the preferred condition is the use of NaOMe in MeOH. It must be noted that under these latter conditions, 13 2 oxime esters (R = Me) were obtained and ethyl esters were obtained under the conditions of the former. Any one

The ester form, methyl or ethyl ester, can be used in other steps of the synthesis. Treatment with 13 with P0C13 gave dichloropyrimidine 14. Heating 14 in a sealed test tube in the presence of NH4OH typically results in a mixture of ingredients 15, 16 and 17, primarily 15 and 16. Subsequently, intermediate 15 can be converted to 16 via treatment with K2C03 in MeOH 39 200817417. Further, 17 can be further recovered into 15 (R-Et) after being treated with ethanol-based HCl. The preparation of aldehyde 18 is then accomplished by oxidative separation of the olefin side chains of 16 using 0s04 and NaI04 or via ozonolysis. 5 Figure 11 illustrates a convenient method for removing the chlorine substituent found in 18 to obtain dechlorination 20 (R5 (C) wherein 丫3 = 0112 and R1G two H). This can be achieved by first protecting the aldehyde group of 18 with p-toluenesulfonic acid (p-TsOH) and MeOH via the formation of a dimethyl acetal to give 19. The chlorine was then removed via hydrogenation using a Pd-C catalyst under H2 gas pressure. Treatment with an aqueous solution of an acid such as TFA and ίο water again releases the vine base to give 20.

Figure 11 15 Figure 12 illustrates. A method for preparing a homologue of a 4-position blending substituted substituent of a secant ring, such as R5 (C) wherein Y3 is a CH2 and R1G diOMe or Me. These homologs can be prepared from the intermediate 16 previously described 2〇 using a variety of well known methods. Illustrated in Figure 13 is the preparation of 4-decyloxy and 4-indolyl derivatives, but similar or other methods can be used to incorporate a variety of substituents. According to the following, 16 can be treated with NaOMe in refluxing methanol to give the oxirane-containing intermediate 21A. The thiol group can be prepared from 16 by the reaction of decylboronic acid via Pd intermediate, thus obtaining 21B. Use Example 40 200817417 If the ozone is dissociated or reacted with 〇s〇4 and NaI〇4, the olefin functional group is oxidatively dissociated and the aldehyde functional group is released again to obtain 22A and 22B.

Ph

21 A: R = OMe B: R = Me Ai R = ΟΜθ B: R = Me Figure 12 Prepare, for example, R (C) where Y3 = 0 and R10 = C1, σ σ σ σ ket It is shown in Figure 13 starting from diammonium diazomethane (23), prepared according to Peace, Carman, Wulfman, 658-661, (1971). 23 is reacted with ethylene glycol glycolate to obtain a substituted malonic acid vinegar 24 by catalytic reaction. The pyrimidine ring system was established by reacting with (2E)-3-phenyl-2-propenenimine and sodium decoxide via 24 to give 25. When the methyl ester is hydrolyzed under sodium methoxide reaction, the intermediate 25 is separated into a carboxylic acid. Treatment with 25 of p〇c丨3 followed by addition of VteOH gave the second gas-methyl ester 26. One of the exchanges of ammonia is used: and the second is achieved by treatment with ΝΗ4〇Η [Process 26, while obtaining a primary acid amine which is subsequently converted to the ethyl ester 27 using HCl and EtOH. The formation of the π-nothing well = ring can be carried out by treating, for example, κχΟ3 with 27 in the polar solution. Heating is typically required to complete the conversion to the bicyclic system 28. The sexual dissociation 2_phenyl B county side chain can achieve the transformation secret. In this case, the side chain of 28 is reacted with 0s〇4 and NaI〇4 to obtain an aldehyde 29 〇

41 200817417

P〇CI3 MeOH; 35% 2 steps 85%

r 〇 29

Nv^N 2.HCI/EtOH J 60% 2 steps 26 Ph

Nal04 dioxane/water 45% 10 Scheme 13 Additional details of the preparation of compounds of formula (I) are found in the examples. The bactericidal/antituberculosis compound according to the present invention can be formulated to be administered in humans 15 or veterinary medicine in any convenient manner, similar to other bactericidal/antituberculosis compounds. The pharmaceutical compositions of the present invention include suitable oral, topical or parenteral forms and can be used in the treatment of bacterial infections including tuberculosis in mammals including humans. The composition can be formulated for administration via any route. The form of the composition 20 may be in the form of a tablet, capsule, powder, granule, lozenge, suspension, cream or liquid preparation, for example, an oral sterile parenteral solution or suspension. The topical formulations of the present invention may be presented, for example, as ointments, creams or lotions, eye ointments and eye or ear drops, infiltrated dressings and aerosols, 42 200817417 and may contain suitable conventional additives in ointments and creams. For example, preservatives, solvents and lubricants that help the penetration of the agent. The formulation may also contain compatible conventional carriers such as cream and ointment bases and ethanol or oleyl alcohol for use in lotions. The carrier may be present from about 1% to about 5% to about 98% of the formulation. Formulations up to about 80% are more often formed. Tablets and capsules for oral administration may be in unit dosage form and may contain conventional excipients such as, for example, syrups, gum arabic, gelatin, sorbitol, tragacanth or polyvinyl Pyrrolidone; a filler such as lactose, sugar, corn starch, calcium phosphate, sorbitol or gan 10 oil; a lubricant for tablets such as magnesium stearate, talc, polyethylene glycol or shishi; a decomposing agent such as Potato starch; or an acceptable wetting agent such as sodium lauryl sulfate. Tablets can be applied according to methods well known in the art of normal pharmaceutical practice. The oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or may be present as an anhydrous product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, decyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, stearic acid gelatin or hydrogenated edible. Fats, emulsifiers such as egg fat, sorbitan monooleate or gum arabic; non-aqueous vehicles (which may contain edible oils) such as apricot 20 oil, oily S such as glycerol, propylene glycol or ethanol; preservatives such as Ethyl p-hydroxybenzoate or propyl or sorbic acid, and if desired, a traditional flavoring or staining agent. The suppository will contain a conventional suppository base such as cocoa-cream or other glycerides.

43 200817417 For parenteral administration, the fluid unit dosage form is prepared using a compound and a sterile vehicle, preferably water. The compound may be suspended or dissolved in the re-agent depending on the vehicle and concentration used. In preparing the solution, the compound can be dissolved in water for injection and sterile filtered, filled into a suitable vial 5 or crucible and sealed. Agents such as local anesthetics, preservatives and buffers are suitably dissolved in the vehicle. To enhance stability, the composition can be frozen and filled into vials and the water removed under vacuum. The anhydrous freeze-dried powder is then sealed in a vial and the water for injection is supplied in the accompanying vial and reconstituted to form a liquid. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle rather than dissolved and sterilization cannot be achieved by filtration. The compound can be sterilized by exposure to ethylene oxide prior to suspension in a sterile vehicle. A surfactant or a wetting agent is suitably included in the composition to promote uniform distribution of the compound. 15 Depending on the method of administration, the composition may contain from 0.1% by weight, preferably from 10% to 60% by weight, of active substance. When the composition contains a dosage unit, each unit will preferably contain from 50 to 1000 mg of active ingredient. Depending on the route and frequency of administration, the dosage for adult treatment will preferably range from 100 to 3000 mg per day, for example 1500 mg per day. This dose is equivalent to 1.5 to 50 mg/kg per day. A suitable dose is from 5 to 30 mg/kg per day. The compound of formula (I) may be the sole agent in the compositions of the invention or in combination with other bactericides including anti-tuberculosis compounds. If the other bactericide is a β-lactone, a β-lactonease inhibitor can also be used. 44 200817417 Compounds of formula (i) may be used in the treatment of bacterial infections caused by a variety of organic substances, including gram-negative and gram-positive organisms, such as upper and/or lower respiratory tract infections, skin and soft tissue infections, and/or urethra infection. The compounds of formula (I) can also be used to treat tuberculosis caused by Mycobacterium tuberculosis. 5 Some of the compounds of formula (I) are active against more than one organism. This can be determined by the methods described herein. The following examples illustrate the preparation of certain compounds of formula (1) and the activity of certain compounds of formula (I) against a variety of bacterial organisms including Mycobacterium tuberculosis. 10 [Embodiment] Examples and experimental generals in the examples abbreviations = PSI two pounds per square inch (1 PSI = 0.069 bar) 15 RT / rt two room temperature ES = electronic spray mass spectrometer LCMS two liquid chromatography Mass Spectrometer HPLO High Performance Liquid Chromatograph (Rt refers to residence time) Some reagents are also abbreviated herein. DCM means dichlorodecane, DMF 20 means dimercaptodecylamine, DMSO means disulfoxide, MeOH means decyl alcohol, TFA means trifluoroacetic acid, THF means tetrahydrofuran, and Pd/C means Palladium catalyst on carbon, Boc means third butoxycarbonyl, EtOH means ethanol, dppf means 1,1'-bis(diphenylphosphino)ferrocene, and EDC means N-[3-( Diammonium) propyl]ethylcarbodiimide hydrochloride, HOBt is 1-hydroxybenzene 45 200817417 and triazole. The proton nuclear magnetic resonance (GhNMR) spectrum was recorded at 400 or 250 MHz. The chemical shift was expressed as a fraction of the component (δ) shifted down from the internal standard tetramethyl decane (TMS). The abbreviations of NMR data are as follows: s = single crack peak, d = double • split peak, triple crack peak, q = four crack peak, multiple crack peak, dd = double crack peak of double crack peak, dt two triple crack peak Double crack peak, app=view, br=wide peak. J represents the NMR coupling constant measured in Hertz. CDC13 is deuterated chloroform, DMSO-d6 is hexamidine dimethyl hydrazine, and CD3OD is tetradecyl sterol. Mass spectra were obtained using electron spray (ES) free technique. All temperatures are expressed in degrees Celsius. Celite® is a filter paper additive consisting of the acid washed Shishizao earth stone and is a trademark of 1〇 Manville Corp., Denver, Colorado. MDAP or Mass directed autoprep = quality-dominated preparative HPLC (using a ZQ mass spectrometer (Waters)). The preparation of the tetravinylboroxine-pyridine complex is disclosed in Kerins, Fergal; O'Shea, Donal F.; J. Org Chem. (2002) 67(14) 4968. MP-carbonate refers to the large pore triethylammonium decyl polyphenylene ethene carbonate (Argonaut Technologies). Amberlyst® A21 is a weakly acidic giant reticulated twig containing a decylamine functional group and is a registered trademark of Rohm & Haas Co. SCX is an ion exchange column containing a strong anion exchange resin (phenylphosphoric acid) supplied by Varian, USA. Chiralpak IA, CHiralpak AS-H and Chiralcel OD are polysaccharide-based HPLC HPLC columns 2 (Chiral Technologies Inc.). The CHiralpak AS-H column contains sugar granules [(S)-a-methylbenzylamino decanoate] coated on 5 micron vermiculite. The Chiralpak IA column contains vermiculite (5 micron particle size, 21 milligrams internal x 250 mm long) fixed for the preparation of grade columns with sugar starch ginseng (3,5-dimercaptophenylamino phthalate). Chiralpak AD and AD-H columns contain coating

46 200817417 Sugar-coated starch ginseng (3,5-dimethylphenylaminoformate) used to prepare graded column of vermiculite (5 micron particle size AD-H and 10 micron particle size AD, 21 milligrams inside) Diameter x250 mm long; 20 micron particle size AD, 101 millimeters inside diameter x 250 mm long) (Chiral Technologies Inc.). The measured residence time is determined by the exact conditions of the chromatographic method. Referenced in the examples below is the sequence indicating its elution. Metal hydrides involved include lithium hydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium hydride, sodium borohydride, sodium triethoxy borohydride, (polystyryl fluorenyl) trimethylammonium cyano boron The hydride reaction is carried out in argon or its other inert gas. Skilled chemists will appreciate that the preparations made according to other general methods of preparation may include variables in routine parameters such as time, temperature, processing conditions, small changes in reagent volume, and the like. 15 Example 1 1-(2-{4-[(2,3-Dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)amino]-1_6 Hydropyridyl}ethyl)-7-(decyloxy)-2(1Η)-fluorenone hydrochloride

20 47 200817417 (a) 7-(Methoxy)porphyrin A suspension of NaH (3.3 g, 137.93 mmol) in dry DMF (160 ml) was cooled to 0 ° C and stirred under argon atmosphere. . 7-nonanol (8 g, 55.17 mmol) dissolved in anhydrous DMF (320) ml was added and the mixture was stirred under argon atmosphere for 1 hour. The mixture was then allowed to warm to rt and Mel (7.8 mL, 55.17 m. Ice water was then carefully added and the resulting mixture was extracted with EtOAc (3×500 mL). The organic layer extracted therefrom was then washed with water (4 mL) and brine (400 mL). The obtained organic layer was dried with EtOAc (EtOAc) (EtOAc) MS (ES+) m/z 160 (MH+). * (b) 7-(Methoxy)-1-(2-propion-1-yl) π π 钂 钂 将 将 7-(methoxy) 喳咁 (8·76 g, 55·09 毫Mol) and allyl hydrazine 15 (19.72 ml, 110.18 mmol) were refluxed in 95t: benzene (120 mL) for 1 hour, then allyl iodide (9.86 mL, 55.09 mmol) was added and The reaction temperature was increased to 110 °C. After an additional hour, the reaction temperature was increased to 120 C and the reaction was continued for 0.5 hours. The solvent was removed under vacuum and the resulting brown solid was washed with diethylbenzene and diethyl ether. The resulting solid was dried in vacuo to give the desired product (14.81 g, 82%). MS (ES+) m/z 201 (MH+). (c) 7-(decyloxy)-l-(2-propen-1-yl)-2(1Η)-fluorene 7-(decyloxy)-1-(2-propen-1-yl) Only drilled iodine (14.81 grams, 48 200817417 45.43 millimoles), KOH (11.20 grams, 199.89 millimoles) and K3 [Fe(CN)6] (32.78 grams, 99.95 millimoles) in ι: 1 Water: 14 2 Torr (400 ml) was stirred at room temperature under argon pressure for 1 hour. Again ^ KOH (1.1 g, 19.9 mmol) and K3 [Fe(CN)6] (3·28克, ^ 〇 5 mM) was added to the reaction and stirred under the same conditions for 5 hours. Then EtOAc (500 mL) and water (500 mL) were added. After rinsing with water, EtOAc EtOAc (EtOAc:EtOAc. ES+) m/z 216 (MH+) 〇(d) [7_(decyloxy)-2-keto-1(2H)-carboline]acetaldehyde 7-(methoxy)-1-(2) - Propen-1-yl)-2(1Η)-pyridone (2 g, 9.3 mmol) was dissolved in DCM (100 mL) and was bubbled with &lt Then pass argon gas into the reaction The excess of 03 was removed over 1 min, then the reaction was quenched with dimethyl sulphate (2.3 mL, 37.28 mmol). The reaction was allowed to warm to room temperature and stirred for 20 min. The desired compound (2.31 g). The alternative synthesis of this aldehyde is shown in Example 52(a)-(e). 20 MS (ES+) m/z 218 (MH+) (e) (2,3-dihydro[1, 4] Dioxazepine [2,3-C]. Specific bite _7_ thiol) (1-{2-[7-(decyloxy)-2-keto-1(211)-. Kui 11 1,7-(Methoxy)-2-keto-1(2H)- . quinolinyl] acetaldehyde (65 mg, 〇·3 mmol) and (2,3-dihydro[1,4]dioxo[2,3-c]. 1,1-hexahydropyridinylamino decanoic acid 1,1-dimercaptoethyl ester (synthesis see W02004/058144 example 99(h)) (105 mg, 0.3 mmol) in chloroform (3 ml) The solution in MeOH (3 mL) was stirred at room temperature for 1 hr. then mixture was treated with NaHH(OAc) 3 (190.8 mg, -9 mM) and stirred at room temperature for 0.5 s. Dihydro[1,4]dioxos[2,3-c]pyridin-7-ylindole Base) 4-hexamethylpyridylamine ruthenic acid ι,ι-dimethylethyl ester (52 mg, 0.15 mmol) and NaBH(OAc)3 (127 mg, 〇·6 house Moer) and The reaction was stirred at room temperature; 1 hour off. The solvent was then removed and the residue was purified eluting eluting elut elut MS (ES+) m/z 551 (ΜΗ+). (f) the title compound in (2,3-diar[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)(1-{2-[7-(methoxy) )-2-keto-1(2Η)-4 phenyl]]ethyl}_4_hexahydroindole sigma) 1,1-dimethylethyl phthalate (92 mg) in chloroform (1·5) To a solution of ML) was added 4 Ν HCl (1.5 mL) in 1,4-dioxane and the mixture was stirred at room temperature; More 4 Ν HC1 (0.5 mL) in 1,4 bis oxime was added and the reaction was stirred at room temperature for 5 hours to remove the solvent. The residue was dissolved in MeOH (25 mL) and then taken to pH 6 with Amberlyst Α 21 basic resin. The residue was filtered and the solvent was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj lU NMR (250MHz) 5(CDC13) 1.72 (m, 2H), 2.06 (m, 2H), 2.38 (t? 2H), 2.76 (t5 2H), 3.15 (m, 2H), 3.80 (bs, 1H), 3.90 (s, 2H), 3.95 (s, 3H), 4.28-4.35 (m, 4H), 4.50 (t, 2H), 6.51 (d, 1H), 6.82 (dd, 1H), 6.90 (s, 1H), 7.01 (d,1H), 7.45 (d,1H), 7.59 (d51H), 8.09 (s,lH) MS (ES+) xn/z 451 (MH+). by dissolving in DCM/methanol and adding One equivalent of 4M HCl / 1,4-dioxane was converted to the hydrochloride salt which was evaporated to dryness to give a yellow solid. Example 2 1-(2-{4-[(2,3-Dihydro[1,4]dioxo[2,3-c]pyridin-7-yl10-methyl)amino]-1 -6 Gas 1:1 ratio }定基}ethyl)-7-murine-2(1 Η)-π奎咐S isohydrochloride and Example 3 1-(2-{4-[(2,3-dihydro[ 1,4]dioxo[2,3-c]pyridin-7-ylmethyl)amino]-1-hexahydropyridinyl}ethyl)-5-fluoro-2(1H)-fluorenone hydrochloric acid

(a) N-(3-Fluorophenyl)-3,3-bis(decyloxy)propanamide Dissolving 3-fluoroaniline (50 g, 450 mmol) in toluene (500 ml) 51 200817417 25% NaOMe (120 ml) and (2E)-3, (methyloxy)-2-propenyl acrylate (57. 4 mL, 495 mmol) in MeOH were added. The mixture was heated to 70 ° C and stirred for 2.5 hours. The solvent was then reduced to about one-quarter of the original volume and the reaction was treated with NH4C1 to pH 7 (about 5 〇〇 5 mL). Add EtOAc to the reaction and separate the layers and use the aqueous layer

The EtOAc was extracted three times and the combined organic layers dried with EtOAc. The solvent was removed and the crude residue was purified on a silica gel eluting eluting eluting with 30- 50% EtOAc/40-60 EtOAc. The product containing fractions were concentrated to give the desired compound (40.68 g, 40%) and less pure batch 10 (6.17 g, 6%). MS (ES+) m/z 228 (ΜΗ+) 〇(b) 7-Fluoro-2(1H)-pyridone is added to the cooled h2S04 (35 mL) at a temperature between 10 and 20 °C. A 70% h2S04 solution was prepared in cold water (15 ml). The powder N-(3-fluorophenyl)-3,3-bis(decyloxy)propanamide (617 g, 27.2 mmol) was then carefully added to this solution and the vessel was placed on ice. After stirring for 1 hour, ice water (70 ml) was added. It was then diluted with water (23 ml). The mixture was stirred for a further 30 minutes. The precipitate was filtered and dried in a vacuum oven to give the desired product (3·67 g ' 83%). This material contains about 1% by weight of the isomer 5-fluoro-2(1Η)-porphyrinone. MS (ES+) m/z 164 (ΜΗ+) 〇(c) 7-fluoro-1-(2-propen-1-yl)-2(1Η)-喳唯酉同52 200817417 in 7-fluoro-2( 1H)-fluorenone (1. 53 g, 9.39 mmol) was added to a suspension of DMF in 〇 °C (0. 83 g of 60% by weight in oil: weight dispersion, 20.65 millimoles) and allowed to warm to room temperature. After 5 hours, allyl moth (1.91 mL, 20.65 mmol) was added. The reaction was stirred at room temperature for a further 25 hours and then water (1 mL) was added. The aqueous layer was then extracted with 10% MeOH (3.times.2 mL) in DCM and the combined organic layer was dried, evaporated and evaporated on EtOAc EtOAc. The desired compound (0.91 g, 48%) was obtained after purification. This material contains about 10% of the isomer 5-fluoro-1·(2-ίο 丙 ίί -1 -yl)-2( 1 Η)-σ奎17林酉同. MS (ES+) m/z 204 (ΜΗ+). (d) (7-Fluoro-2-keto-1(2H)-carboline)acetaldehyde 7-fluoro-1_(2-propan-1-yl)-2(1Η)_σ quilenolin (0·909 g, 4.48 15 mmol) in 1,4-dioxane (50 ml) and water (30 ml) in hydrazine. The solution of hydrazine was treated with sodium periodate (2.20 g, 10.30 mmol) and 〇s〇4 (4% in water, 5 ml). The reaction was allowed to warm to room temperature and stirred at room temperature for 1 hour, then 30 ml of water was added again. After 1 hour, sodium iodate (2·2 g, 10.30 mmol) was added again and added after 2 hours. Human sodium iodate (4.20 g, 19.70 20 house Moule). The reaction was then stirred at room temperature; after 0. 5 hours, it was evaporated, treated with water and extracted with DCM (EtOAc). The combined organic layers were dried and evaporated to give the desired product (m. This material contains about 1% by weight of an isomer (5-Ga-2-indolyl-1(2Η)-σ-quinacridyl). MS (ES+) m/z 206 (ΜΗ+) 〇

53 200817417 (e) (2,3-Dihydro[1,4]dioxol and [2,3-c]pyridin-7-ylindenyl){l-[2_(7-fluoro-2-one 1,1-(2H)-4-indenyl)ethyl]-4-hexahydropyranidinyl} 1,1-dimethylethyl carbamic acid (7-fluoro-2-indenyl-1) )-σ 奎1:7 林基)acetic acid* (123 mg, 0.602 5 mmol) and (2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7- (1,1-dimercaptoethyl hexahydroindole) (synthesis see W02004/058144 Example 99(h)) (210 mg, 〇·6〇2 mmol) A mixture of chloroform (5 mL) and MeOH (0.5 mL) was stirred for 2 hrs and then NaBH (OAc) 3 (383 mg, 1.806 mM). After the reaction was stirred for 5 hours, a saturated aqueous solution of NaHC 3 (1 mL) was added. The reaction was then extracted with 10% MeOH (3 x 200 mL) in DCM. The combined organic layers were dried, evaporated and the crude residue was applied to EtOAc EtOAc. The MeOH/DCM gradient elution was purified by column chromatography to afford the desired compound (240 mg, 74%). This material contains about 1% by weight of isomer (2,3-15 dihydroanthracene, 4]dioxane [2,3<]pyridyl-7-ylmethyl){1_[2-(5-fluoro- 2-keto-1(2Η)-4indolyl)ethyl]-4-hexahydropyridinyl}aminodecanoate. MS (ES+) m/z 539 (MH+). 20 (f) The title compound is in (2,3-monohydro[1,4]-oxo-[2,3_(:] mouth ratio σ--7-ylmethyl) {Η2_(7-fluoro_2_ Keto group _l(2Hp quinolyl)ethyl]_'hexahydropyridinyl} 1,1-didecyl carbamic acid amide (240 mg, 〇·446 mmol) in chloroform (5 ml) And a solution of MeOH (5 ml) was added to 丨 扣 扣 2008 2008 2008 2008 2008 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 The reaction was extracted with 10% MeOH (3×200 mL) in DCM. The combined organic layers were dried & evaporated and evaporated and evaporated. Purification by column chromatography to give 1-(2-{4-[(2,3-dihydro[1,4]-oxychroman[2,3-c] 吼-7-yl fluorenyl) Amino]-1-hexahydroσ ratio σ base} ethyl)-7-fluoro-2(1Η)-ηquinacone (178 mg, 91%). This material contains about 10% isomer 1_(2 -{4-[(2,3-Dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)amino]>1-hexahydropyridyl}ethyl) -5-Fluoro-2(1H)- morphinone. 1〇This substance is injected through multiple injections. Freed on a luna C18(2) (3 micron) column with H20 (0.1% TFA) and CH3CN (0.1% TFA) at a flow rate of 1.0 mL/min at 254 nm by UV detection via preparative HPLC The title compound of the base (2-{4-[(2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylfluorenyl)amino]-1- Hexahydropyridyl}ethyl)-7-15 ·Fluoro-2(1H)-pyridone (46 mg, 98% purity) and 1-(2-{4-[(2,3-dihydro[1] , 4]dioxaindolo[2,3-c]pyridin-7-ylindenyl)amino]-1-hexahydropyridinyl}ethyl)-5-fluoro-2(1H)-pyridone ( 4·6 mg, 98% purity). Main isomer (1_(2-{4-[(2,3-dihydro[1,4]dioxo[2,3_c] bite-7-yl) Methyl)amino]-1 -hexanitrogen σ σ determinate}ethyl)-7-gas-2( 1 H) _^ Oral 20 ketone) Data: MS (ES+) m/z 439 (MH+) Ln NMR (400MHz) 5(CDC13) 1.48-1.55 (2H, m), 1.58-2.00 (2H, m), 2.15-2.28 (2H, m), 2.51-2.71 (3H, m), 2.95-3.08 ( 2H, m), 3.70 (2H, s), 4.25·4·44 (ιη, 6H), 6.58-6.62 (1H, m), '6·82 (1H, s), 6·80-6·95 ( 1Η,m), 7.70 (1H,d,J 11Hz), 7.45-7.55 (1H,m),7·62 (1H,d,J 10Hz), 8.09 (s, lH). A small amount of isomer (l-(2-{4-[(2,3-dihydro[1,4]dioxo[2,3_c]pyridyl 55 200817417 bite- 7-ylindenyl)amino η-hexahydroindenyl}ethyl)_5_gas_2(ιη)·4π林

Ι.ο^-ι.δδ 2.01-2.11 (2H,m), 6H),6 61 (1H,d,jd, 9Hz), 7.55 (1H, m), 7.90 (1H, s), via dissolution in DCM /Methanol and the addition of an equivalent of 4M HC1/M_2 4 to convert these compounds into their body salts, which were then evaporated to dryness. Example 4 7_Fluoro-oxime 1]2,3] 嗟[[4,2_小比咬基基基) 10 Aminohexahydropyridyl}ethyl)-2(lH)-indolyl ketone Hydrochloride

(8) {l-[5_(7H_&amp;_l(1H)-n-Quinyl)ethyl M_hexahydropyridyl} U-didecylethyl amide amide (7-fluoro-2-keto- 1(2H)- porphyrinyl)acetaldehyde (594 mg, 2.89 mmol) and 4_hexahydropyridylamine decanoic acid u-didecylethyl ester (578 ff 56 1 gram, 1· a mixture of 1:1 mixture of chloroform and methanol (20 ml: 20 2 mixture with NaBH (OAc) 3 (1·83 g, 8.67 mmol) and in a mixture of 3 ml) Stir for 丨 hours at room temperature under argon pressure. Then stir at 4 ° for 1 day. More 4-hexahydropyridylamino decanoic acid, bis(nonyl) decanoic acid (297 mg, L45 mmol) was added and the reaction was stirred under the same conditions. It was then treated again with NaBH(OAc)3 (915 mg, 4.34 • hexane) and stirred at room temperature for 75 hours. Add more 1,1-dimethylethyl 4-hexafluoropyridylcarbamate (118 mg, 〇·578 mmol) and stir the reaction at room temperature for 1 Torr, then add NaBH (〇 Ac) 3 5 (366 mg, i·73 mmol) and the reaction was stirred for 25 min. The solvent was removed and the crude residue was purified on a silica gel eluting with </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (ES+) m/z 390 (MH+). 10 (b) 1-[2_(4_Aminohexahydropyridinyl)ethyl]winter-fluorene-quinone quinoneone {1 -[2-(7-fluoro-2-keto-1) )-Phenyloxy)ethyl]-4-hexamethylene fluorenyl} 1,1-dimethylethyl phthalate (1.32 g, 3.39 mmol) dissolved in chloroform (10 ml) A mixture of HCl (12 ml) was stirred at room temperature under argon 15 for 1 hour. The salt was then dissolved in MeOH and all solvent was removed. The residue was again dissolved in MeOH and stirred with amberlyst ion exchange resin until neutral. It was then filtered and the solvent removed. The crude residue was purified by chromatography eluting elut elut elut elut elut elut elut elut 20 MS (ES+) m/z 290 (MH+). (c) The title compound will be 1_[2_(4_amino-1-hexahydro. butyl) ethyl]-7-fluoro-2(1Η)-°#σ lin (100 mg, 0.364 mmol) And [1,3] thiazino[5,4-c]pyridine-6-aldehyde 57 200817417 (Synthesis see W02004058144, Example 61) (57 g, 0 364 mmol) dissolved in chloroform and methanol A 5:1 mixture (5 ml: 1 ml) was stirred at room temperature under argon pressure for 1 hour. The mixture was then treated with NaBH(OAc)3 (231 mg, 1.092 mmol) and stirred for an additional hour. The solvent was then removed and the crude residue was purified eluting elut elut elut elut elut elut elut elut elut elut MS (ES+) m/z 441 (MH+) 〇δΗ CDCI3, (400MHz) 1.68(m,2H),2.01 (s,2H),2.04(s,3H) 2 34 (t 2H) 2 74(t 3H) 10 3.15 (m, 2H), 3.92 (s, 2H), 4.43 (t, 2HX.5.48 (bs5 2H), 5.75 (s; 2H); 6.62 (d 1H) 6 96 fm 1H), 7.24 (m, 2H) ), 7·52 (m, 1H), 7.64 (d, 1H), 8·0〇(s, iH)· h ·,, by dissolving the obtained free state in MeOH, adding in 1,4-two 'Boiled 4M HCl' convert this compound to a di-HC1 salt. It is then evaporated to dryness. Example 5 6-[({1-[2-(7-Fluoro-2-keto)1(2H&gt;indolyl)ethyl]_4_hexahydropyridyl}amino)methyl]-2H-pyridine And [3,2_b][1,4]呤耕_3(4h)__ dihydrochloride

58 200817417 The title compound 使用 uses i_[2_(4_amino-1_hexapyridinyl)ethyl] hexafluoro-2(1Η)"quinolinone (1〇〇) by the general method of Shell 4(d) Mg, 0.346 mmol, and 3-keto-3,4-diindole-2Η-pyrido[3,2-b][l,4]indole-6-aldehyde (synthesis see WO2003087098, Example 31 (e)) (66 mg, 0.346 mmol), eluted eluted eluted elut elut elut elut elut elut elut %). MS (ES+) m/z 453 (ΜΗ+)〇δΗ CDC13,(400MHz) 1.76 (dd,2H),2.05 (m,6H),2·31 (t,2H),2.75 (m,2H) 2 82fbs 10 1H), 3.19 (m, 2H), 3.95 (s, 2H), 4.43 (t, 2H), 4.62 (s5 2H)? 6.62 (d, 1H) 6 95 (d 2H) 7 21 (d, 2H) , 7.53 (m,1H),7·63 (d,1H). V,), converted to a compound by dissolving the free base in DCM/nonanol and adding 4M HCl / 1,4-dioxane The dihydrochloride salt was then evaporated to dryness to give a yellow solid. Example 6 H2-{4_[(6,7-Dihydro[1,4]dioxo[2,3-c]indole_3• fluorenyl)amino]-1-hexahydropyridinyl} Ethyl)-7-fluoro-2(1H)^quinacone dihydrochloride

20 (a) 3,4,6-Trichloromethane plowing 59 200817417 This was prepared by a slightly modified method of Kasnar et al, Nucleosides &amp; Nucleotides (1994), 13(1-3), 459_79. The phosphonium phosphate (51 g) was suspended in water (250 ml), heated to reflux and bromine maleic anhydride (90.38 g) was added dropwise. The mixture was then heated under reflux for 4 hours and then cooled to room temperature. The reaction was repeated with 29 g of hydrazine phosphate, 53 g of bromomaleic anhydride and 130 ml of water. The precipitate was collected by filtration, washed with water and acetone, and dried in vacuo to give a white solid of 4-bromo-1,2-diazepinedione (13 g). 10 15 Two batches of solid were treated with phosphonium chloride (2 x 200 mL) and heated under reflux for 3.5 hours. The mixture was allowed to cool, evaporated and azeotroped with toluene. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate and extracted twice with DCM. The organic extract was dried and evaporated. The residue was re-dissolved in dichloromethane and chromatographed on silica gel (3 g) to afford white solid (1·1·5 g, 87%). (LC/MS analysis shows about 2〇_3〇% impurity, bromine-dichlorohydrazine ploughing 20 MS (+Ve ion electron spray) m/z 184/185/186 MS (+Ve jar electronics Spray) m/z 228/229/231 Chlorine. Well. 〇3) 2^(3,6-Dichloro_4_tata)oxy]ethanol known as ethyl alcohol (55 liters) in tetrahydrofuran 0T: (ice bath cooling) with gas to open), with liquid in the 丨) with sodium hydride (60% dispersion in oil 60 200817417 treatment for 40 minutes. After the addition, add bromine-containing two parts 3,4,6-three gas enthalpy (27 g) of the residue of the chloride column 0 was washed with anhydrous THF (50 ml) and the mixture was stirred at 〇 ° C for 1 hour and then at room temperature overnight. To a volume of 1/3, diluted with aqueous sodium bicarbonate and extracted with chloroform (5 χ) and ethyl acetate (3 EtOAc). The combined organic extracts were washed with water, dried over sodium sulfate and evaporated. After washing and drying in a 40 C vacuum oven overnight, a white solid (25.5 g, 83%) was obtained, containing a portion of bromo-derivative (1 〇 1 5%). MS (+ve ion electron spray) m/ z 209/211 (ΜΗ+). MS (+ve away) Electron spray) m/z 255/7 (MH+), desert-derivative. (c) 3-Chloro-6,7-dihydro[1,4]dioxo[2,3_c] 嗒 well will contain Partial bromine-derivatives of 2_[(3,6-dichloro-4-indolyl)oxy]ethanol (15.46 g, 0.0703 mol) in anhydrous i,4-dioxane (1.2 liters) The solution was treated with lithium hydride (2.3 g, 0.28 mol) and was quenched at room temperature under argon for 1 hour and then heated at 11 (rc overnight). The alkane was then quenched with ice water. The solution was evaporated to a half volume, adjusted to pH 8 with 5M EtOAc and evaporated to dryness. Water was applied and the residue was extracted with chloroform 5 times, dried (sodium sulfate) and evaporated Solid (12.4 g, about 77%) (containing about 15% bromine) · MS (+ve ion electron spray) m/z 173/5 (Cl MH+); 217/9 MH+). (d) 3_ Vinyl _6,7_dihydro!^,4]dioxane

61 200817417 3-chloro-6,7-dihydro[1,4]dioxo[2,3-c] arable (13.6 g, 0.079 mol) containing about 15% bromine The solution in oxyethane (4 liters) was degassed under argon pressure for 10 minutes, then hydrazine (triphenylphosphine) palladium (〇) (2 g), potassium carbonate (1 〇 33 g), 2 4,6-trivinylcyclotriborane pyridine complex (11.32 g) and water (55 ml). The mixture was heated at 95 ° C for 48 hours, cooled and evaporated to dryness. The mixture was treated with aqueous sodium bicarbonate and extracted with DCM (5 EtOAc). The extract was dried (sodium sulphate), evaporated, EtOAcjjjjjjjjjjjjj Also contains some impurities (1. 8 grams)]. MS (+ve ion electron spray) m/z 165 (ΜΗ+). (4) 6,7-Dihydro[1,4]dioxyg and [2,3-c]indole_3_aldehyde will be 3_vinyl_6,7-dihydro[μ]dioxo[2] , 3-c] 嗒耕(1)% g) A solution in 1,4-dioxane/water (600 ml / 18 〇 ml), cooled in an ice bath, starved with tetraoxide (4% w/v, 25 ml) and sodium periodate (43 g). The mixture was allowed to warm to room temperature and stirred for a further 7 hours, then the mixture was evaporated to dryness and azeotroped with M. To the mixture was added EtOAc, EtOAc (EtOAc m.) MS (+ve iontophoresis) m/z 167 (MH+). (1) Title compound The title compound was used according to the general method of Example 4 (d) using 1_[2 gas 4_month female-1-barium ratio. Alkyl)ethyl]_7-fluoro-2(1Η)-σ奎ulin (100 mg, 62 200817417 0.346 house Moule) and 6,7-dihydro[ι,4]dioxo[2,3 -c] 嗒耕-3-aldehyde (57

The title compound (86 mg, 66%) was obtained from EtOAc EtOAc.

3 nC(d〇^ 2m Z〇3 (§5 m 2·06 (S5 4HX 2·40 α 2HX 2*75 (m&gt; 3HX 1H) 6 97 to 1HW ί5 2H), 438 (m> 2HX 4e4? ( m? 2H)? 4-53(^ 2H)? 6·62 (d? 1HX 731 1H)^7·53 1H&gt;^7·65 ^ 1H&gt; By dissolving the free state in DCM/sterol and adding 4MHC1 / Ί Ί i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i And [2,3 cans bite _7_ ylmethyl)amino]_1_hexahydroindole °}ethyl)-7-gas-1,5-naphthoquinone-2(1H)-one hydrochloride

20 (a) 7-Fluoro-2-(decyloxy)-1,5-naphthalene 12 will be 8-isine-7-I _2_(methoxy h,5-naphthyridine (see 〇W〇2〇) 〇4〇58144, Example 53(g)) (5.040 g, 19.61 mmol) in MeOH (200 liters) with sodium bicarbonate (3·29 g, 39·22 mmol) and

63 200817417 !°〇[0°/^(2·5g) was given, and the resulting suspension was hydrogenated under 1 atmosphere of hydrogen gas for 4 hours. The mixture was suction filtered through diatomaceous earth and the mesh was washed with Me0H (50 liters). The combined filtrate and washings were concentrated to about 50 mL under reduced pressure and then treated with water (2 mL) and dcm 5 (300 mL). The aqueous layer was separated and extracted twice with DCM (300 mL). The combined organic layers were separated, dried EtOAc EtOAcjjjjjjj MS (ES+) m/z 179 (MH+). 1〇(b) 7-fluoro-1,5-naphthyridinium-2(1H)-one will be 7·fluoro-2-(decyloxy)-l,5-naphthalene bite (3.044 g, 17·101 mmol) The suspension in glacial acetic acid (50 mL) at room temperature under argon was treated with 33% HBr (50 mL) in acetic acid. After stirring at room temperature for 18 hours, the solvent was evaporated (a large amount of HBr smoke was produced). The residue was treated with acetic acid (1 mL 15 mL) and evaporated again, and then stirred with water (200 mL) and adjusted to pH 4 by adding solid sodium hydrogen carbonate. The mixture was then stirred at room temperature for 1 hour and then the solid was separated by suction filtration to give a white solid. The product was suction dried on a porous bed for 2 hours and then dried in a vacuum oven to afford a white solid 20 (2.412 g, 86%) of desired product.

MS (ES+) m/z 165 (MHV (c) 7-fluoro-1-(2-propen-1-yl)-1,5-naphthyridinone 7-fluoro-1,5-naphthalene-2 1Η)-_(2·152 g, 13.122 mmol) 64 200817417 Suspended in anhydrous DMF (40 ml) under argon pressure at 0 ° C, and the stirred suspension was added portionwise to sodium hydride (60% of 1.155 g) Weight: dispersion in oil, 2.2 equivalents. The suspension was allowed to warm to room temperature. After stirring at room temperature for 30 minutes, the mixture was treated with allyl iodide (2.67 mL, 2.2 eq.) and then After stirring for 30 minutes, water (100 ml) was added, then the mixture was evaporated, evaporated, evaporated, evaporated, evaporated (0% methanol gradient elution was purified by column chromatography to give the desired product as a pale brown solid (1.683 g, 63%). MS (ES+) m/z 205 (ΜΗ+). (d) -fluoro!keto-1,5-naphthyridin-1(2H)-yl)acetaldehyde (mercapto hemiacetal) 7-fluoro-1-(2•propen-1-yl)-1,5- Naphthyridine-2(1H)-one (1.683 g, 8·25 mmol) dissolved in i,4-dioxane (1〇〇 l) and add water (5 ml). Cool the solution to 〇 ° C and add sodium perchlorate (5.29 g, 24.75 mmol). Then add tetraoxide (9 ml of 4% aqueous solution). Stir The mixture was warmed to room temperature and then stirred at room temperature for a few hours. The mixture was treated with 100 ml of water and sodium periodate (10·58 g, 49·5 mmol) and stirred for 1 hour at ambient temperature. The mixture was evaporated to ca. <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Gray solid (1.531 g, 90%) of keto-1,5-n-pinidine-1(2Η)-yl)acetaldehyde (mainly methyl hemiacetal) MS (ES+) m/z 239 (ΜΗ+ The anastomosed proposed hemiacetal structure, 65 200817417 NMR (400 MHz, methanol-d4) also conforms to the proposed semi-shrinking structure. (8) (2,3-Dihydro[1,4]dioxo £ and [2,3 -c]pyridine_7_ylmethyl){1_[2_(7_*fluoroketo-1,5-naphthyridin-indole)-yl)ethyl]-4-hexahydropyridylguanidinomethyl 5-acid 1,1·dimethylethyl ester soil (7-fluoro-4-keto-1,5-naphthalene -1(2Η)-yl)acetaldehyde (mainly methyl hemiacetal) (441 mg) and (2,3-dihydro[1,4]dioxo[2,3_c]pyridine_7_ylindole 1, 4-hexahydroguanidinocarbamic acid 1, L dimethyl ethyl ester (synthesis see W02004/058144 Example 99 (h)) (747 mg, 2 14 mM) in chloro 10 imitation (2 () Mix the mixture of ML) and Me0ii (1 ml) for 2 hours and then add

NaBH(OAc)3 (1·36 g, 6.422 mmol). After the reaction was stirred for 5 hours, a saturated aqueous solution of NaHC? The reaction was then extracted with 20% methanol (3 x 200 mL) in DCM. The combined layers were dried, evaporated and the crude residue was purified eluting eluting elut elut 78%). MS (ES+) m/z 540 (MH+) 〇(f) title compound 20 (2,3-dihydro[1,4]-oxyhexa[2,3-c]indole-7-ylmethyl ) {i-[2-(7_Fluorphthyl-:^-naphthyridine-: ^ 基 基 卜 六 hexahydroacridinyl) amide 1,1-didecyl ethyl citrate (900 mg , a solution of chloroform (10 ml) and MeOH (10 ml), 4M EtOAc (10 mL)

66 200817417 5 After 5 hours, it was evaporated and treated with a saturated aqueous solution of NaHC. The reaction was then extracted with 10% MeOH (3 x 200 mL) in DCM. The combined organic layers were dried <RTI ID=0.0>: </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; .

MS (ES+) m/z 440 (MHV)H NMR (250MHz) 6(CDC13) 1.25-1.42 (2H5 m), 1.81-1.98 (2H, m) 2 01-2 21 (2H 2.40-2.55 (1H, m ) 5 2.62-2.74 (2H? t), 3.00-3.12 (2H, m)? 3.78 (2H, s); 4.25-4 35(m im 4.63 (2H, t), 6.81 (1H, s)? 6.84( 1H, d, J 10Hz)5 7.51 (1H, d, J 8Hz), 7.68 (1H d J ;〇h7; 7.98 (1H? d, J 8 Hz), 8.08(13⁄4 s). ,, i〇 via The resulting free base was dissolved in 1:1 DCM: MeOH and 1 eq. of 4M HCl in 1,4-dioxane was added. This compound was converted to the HCl salt and then evaporated to dryness to give a white solid (597 Mg). Example 8 1_(2_{4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridine-6-ylindolyl)amino]-1-hexahydropyridyl }Ethyl)-7-fluoro-1,5-naphthyridine-2(1H)-one hydrochloride

(a) {1-[2-(7-Fluoro-2-keto-1,5-naphthyridinyl-1(211)-yl)ethyl]pentahydropyridyl}amino decanoic acid 1,1-曱基基乙酉67 200817417 (7-Fluoro-2-keto-1,5-naphthyridin-1(211)-yl)acetaldehyde (mainly methyl-hemi-acid) (1·〇9 g , 5.29i millimolar) and 4_hexahydroacridinylcarbamic acid 1,1-didecylacetate (1·〇6 g, 5.291 mmol) in chloroform (5 mL) and MeOH (2.5 The mixture was stirred for 2 hours and then NaBH(〇Ac) 3 5 (3·37 g, 15.873 mmol) was added. The reaction was stirred for 0.5 h then aq. aq. NaHC.sub.3 (50 mL). The reaction was then extracted with 20% methanol (3 x 200 liters) in DCM. The combined organic layers were dried with EtOAc EtOAc EtOAc. 1〇MS (ES+) m/z 391 (MH+) 〇(b) 1-〇(4•Amino-1-hexapyridinyl)ethyl; naphthyridine_2(1H)-one dihydrochloride {1-[2_(7-fluoro-2-keto-1,5-naphthyridin-1(211)-yl)ethyl]I hexa 15 hydropyridyl}amino decanoic acid 1,1-didecyl Ethyl ester (1·591 g, 4.079 mmol) was added to EtOAc (15 mL) EtOAc. The reaction was stirred at room temperature for 0.5 h then evaporated to dryness crystals crystals crystals 20 MS (ES+) m/z 291 (MH+) 〇 (c) title compound l-[2-(4-amino-1-hexanitroindole)ethyl]-7-fluoro-1,5- Evaporate a mixture of 2-(1H)-one dihydrochloride (145 mg, 0.399 mmol) in chloroform (5 mL) EtOAc (EtOAc) (EtOAc (EtOAc) 1.162 millimolar) After treatment and stirring for 0. 25 hours, add 3,4-dipyridino[2,3-decapyridin-6-aldehyde (synthesis see W02004058144, example 126(e)) (59 mg, 0.363 millimolar) °The reaction was stirred for 5 hours and then added to 10

NaBH(OAc)3 (231 mg, 1.089 mmol). After the reaction was stirred for 5 hours, a saturated aqueous solution of NaHC? The reaction was then extracted with 20% methanol (3 x 200 mL) in DCM. The combined organic layers were dried with EtOAc EtOAcjjjjjjjj MS (ES+) m/z 438 (MH+) 〇 H NMR (250MHz) 8 (CDCl3) 1.39-1.58 (2H, m), 1.88-2.09 (4H, m), 2.11-2.28 (2H m)

2.50-2.72 (3H, m), 2.72-2.82 (2H, t), 2.92-3.03 (2H, m), 3.82 (2H, s), 4.21 (2H, t) 4 33 (2H t) 6.86 (1H, D3 J lOHzX 6.99(1H5 s), 7.58 (1H5 dd? J 10.5, 2Hz), 7.90 (1H, d, J 10Hz) 8 08 ? (1H, s), 8.42 (lH, dJ2.5Hz). 经由The resulting free base was dissolved in 1:1 DCM:MeOH and 1 eq. of 4M HCl in 1,4-diethanol was added and the compound was converted to HCl. then evaporated to dryness. Example 9 ^(2 ^44(3,4-Dihydro-2H-pyrano[2,3-c]pyridin-6-ylindenyl)amino]-1-hexahydropyridyl}ethyl)-7-fluoro-1, 5_naphthyridinone hydrochloride 69 200817417

1-[2-(4-Amino-1-hexa-pyridinyl)ethyl]-L-fluoro-1,5-naphthyridin-2(1Η)-one dihydrochloride (I27 mg, 0.350 Mix a mixture of chloroform (5 ml) and MeOH (0.1 mL) with triethylamine (154 μL, 1.018 mM) and stir for 25 hrs and then add 6,7-dihydro[ 1,4]dioxo[2,3-c]indole-3-aldehyde (53 mg, 0.318 mmol). After the reaction was stirred for 0.5 hours, NaBH(〇Ac)3 (202 mg, 0.954 mmol) was added. After the reaction was stirred for 0.5 hours, a saturated aqueous solution of NaHCO? The reaction was then extracted with 20% decyl alcohol (3 x 200 mL) in DCM. The combined organic layers were dried <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS (ES+) m/z 441 (MH+). 'H NMR (250MHz) 5(CDC13) 1.39-1.58 (2H, m), 1.88-2.09 (4H? m)? 2.11-2.28 (2H, m), 2.50-2.72 (3H, m), 2.72-2.82 ( 2H,t),2·92-3·03 (2H,m),3·82(2Η,s),4·21(2Η,t),4.33 (2H, 20 〇6·86 (1H,d, J 10Hz), 6.99(1H, s), 7.58 (1H, dd, J 10.5, 2Hz), 7.90 (1H, d, J 10Hz), 8.08 (lH, s), 8.42 (lH, dJ 2.5Hz). The resulting free base was dissolved in 1:1 DCMiMeOH and 1 equivalent of 4M HCl in 1,4-dioxane was added and this compound was converted to the HCl salt. The product was then evaporated to dryness. 200817417 Example 10 l_(2_ {4-[(3,4-Dioxa-2H-pyrano[2,3-c]pyridine-6-ylindenyl)amino]-1-hexahydropyridinyl}ethyl)-7-fluoro- 1,5-naphthalene-2 (1H)-keto hydrochloride

10 15 20 1-[&gt;(4-Amino-1-hexahydropyridinyl)ethyl]naphthyridine-2(1H)-one dihydrochloride (141 mg, 0.388 mmol) in chloroform ( A mixture of 5 ml) and MeOH ((U mL) was treated with triethylamine (156 μL, 113 Torr) and stirred for 25 hours, then [1,3] thiophene [5,4-c was added. Pyridine-6-acid (synthesis see W02004058144, Example 61) (59 mg, 0 353 mmol). Stir the reaction: 0.5 h after the addition of NaBH(〇Ac)3 (224 mg, 1.058 mmol). After the reaction was stirred for 5 hours, a saturated aqueous solution of NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The title compound was purified by chromatography eluting elut elut elut elut elut elut elut elut elut elut H NMR (250MHz) 5(CDC13) 1.38-1.56 (2H, m)? 1.85-2.01 (2H, m)5 2.11-2 30 (2Ή m) 2.49-2.72 (3H, m), 2.91-3.03 (23⁄4 m ), 3.84 (2H5s), 4.30-4.36 (m, 2H), 5 74 (2H s) SX 7·61 (1Hs ^ J 1〇·5ί 2 ^ 7·88 (1H^ J 1〇HZ); S.〇〇71 200817417 This compound was converted to the HCl salt by dissolving the obtained free base in 1:1 DCM:MeOH and adding 1 equivalent of 4M HCl in 1,4-dioxane. Then it was evaporated to dryness. Example 11 Η2-(4-[(2,3-:hydro[1,4]dioxo[2,3-c]ylpyridyl-7-ylindenyl)amine -1-hexahydropyridyl}ethylmethoxynaphthyridine-2(1H)-one hydrochloride

15 (8) 8-Bromo-2,7-bis(decyloxy)-1,5-naphthyridine 8-bromo-7-fluoro-2-(decyloxy)-1,5-naphthyridine (synthesis see W02004058144, Example 53(g)) (11.215 g, 43.64 mmol) was stirred in methanol (100 mL) at room temperature under argon atmosphere and a solution of sodium decoxide in decyl alcohol (94 ml of about 25% solution) , 10 equivalents). The mixture 20 was heated at 50 ° C for 1 hour. The mixture was allowed to cool to room temperature then diluted with water (500 mL) and brine (500 mL). The DCM extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated, then evaporated. 95%).

72 200817417 MS (ES+) m/z 269/271 (MH+). (b) 2,7-bis(methoxy)-1,5-naphthyridine 8-bromo-2,7-bis(methoxy)-l,5-naphthyridine (11.21 g, 41.673 mmol) Stirred with sodium bicarbonate (7·00 g, 83.35 mmol) and 10% Pd/C (2.8 g) in MeOH (400 mL), and the obtained suspension was hydrogenated under 1 atmosphere of hydrogen. hour. The mixture was filtered through a pad of Celite, and the solid was washed with ethanol (300 mL). The filtrate was concentrated under reduced pressure. The aqueous layer was extracted with DCM (2×300 mL). The combined organic layers were separated, dried over anhydrous magnesium sulfate, filtered, and evaporated. MS (ES+) m/z 191 (MH+). 15 20 (C) 7_(decyloxy)-1,5-naphthyridin-2(1H)-one 2,7-bis(decyloxy)-i, 5-naphthalene (7.45 g, 39.210 mmol) Ears were treated with glacial acetic acid (100 mL) at room temperature under argon pressure using '33% coffee (100 mL) in acetic acid. After stirring at room temperature for 18 hours, the solvent was evaporated under reduced pressure to give a large amount of HBr. Dispense the solid residue fish water (about 250 liters) and adjust the pH to about 6 by adding solid carbonic acid. The mixture was then filtered and dried overnight (10) in a vacuum oven to give 7-(decyloxy)-1,5-acrididine jnu, &lt;RTI ID=0.0&gt; 2 (called ketone gray solid MS (ES+) m/z 177 (MH+) 〇73 200817417 (d) 7-(decyloxy) small (2-propenyl small group)-l,5-naphthyridine_2 (1H )-ketone 7-(methoxy M,5-naphthyridin-2(1H)-one (5.958 g, 33.852 mmol) suspended in anhydrous DMF (100 mL) at argon and 0 °C The stirred suspension was treated with sodium hydride (2.98 g, 60% dispersion in oil, 74.48 mmol) and stirred at room temperature for 5 hours. Then allyl iodide (6.88 ml, 74.475) was added. The mixture was stirred at room temperature for EtOAc (3 mL). EtOAc (EtOAc m. A brown colloid was obtained which was purified by chromatography eluting with EtOAc EtOAc EtOAc EtOAc (EtOAc) Compound (0.95 g, 13%) MS (ES+) m/z 217 (MH+). (e) [7-(decyloxy)-2-keto-1,5-distillate-1 (211) -yl]acetic acid (mercapto hemiacetal) 7-(decyloxy)-1-(2-propion-1-yl)-i 5-Naphthalene-2(1H)-one (5.046 g, 23.361 mmol) dissolved in 1,4-dioxane (1 mL) and water (100 mL). 12.49 g, 58.402 mmol, followed by the addition of osmium tetroxide (5 ml of a 4% aqueous solution). The mixture was stirred at room temperature for 1 hour, water (200 ml) was added and the mixture was stirred at room temperature for 1 hour. Concentrate to about 300 ml and draw with 20% MeOH/DCM (3x400 swell). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give [7-(decyloxy)- 2-keto group

74 200817417 -1,5-naphthyridin-1(2H)-yl] (mainly methyl hemiacetal) as a yellow solid (3·807 g, 75%). MS (ES+) m/z 219, 251 (ΜΗ+) (according to the proposed hemiacetal structure). (f) (2,3-Dioxa[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)(1-{2-[7-(decyloxy)-2 • 1,1-didecylethyl ketone-1,5-naphthyridin-1(2H)-yl]ethyl}-4-hexahydropyridyl)amino decanoate [7-(decyloxy) )-2-keto-1,5-naphthyridin-1(2H)-yl]acetaldehyde (mainly 1 〇methyl hemiacetal) (530 mg, 2.431 mmol) and (2,3 -Dihydro[1,4]dioxohexa[2,3-c]0 is more than 1,7-ylmethyl)4-hexahydro-sigma-1,1-didecylethyl ester of mercaptocarbamic acid ( For the synthesis, see W02004/058144 Example 99(h)) (848 mg, 2.431 mmol) in a mixture of chloroform (20 mL) and MeOH (1 mL), and stirred for 2 h, then NaBH(OAc)3 (1.546 mg, 7.293 15 Millions of ears). The reaction was stirred for 5 hours and then a saturated aqueous NaH.sub.3 solution (50 mL). The reaction was then extracted with 20% decyl alcohol (3 x 200 mL) in DCM. The combined organic layers were dried with EtOAc EtOAcjjjjjjjj 2 〇 MS (ES+) m/z 552 (MH+). (g) the title compound will be (2,3-dihydro[1,4]dioxo[2,3_c]pyridin-7-ylindenyl)(1-{2-[7-(decyloxy)- 2-keto-1,5-naphthyridinyl-i(2H)-yl]ethyl M- 75 200817417 Hexylpyridinyl)aminol 1,1-didecylethylamine (833 mg, 1.512 mmol) 4M HCl (10 ml) in 1,4-dioxane was added to a solution of chloroform (10 mL) and MeOH (1 mL). Evaporation and treatment with saturated aqueous NaHC03 (5 mL). The reaction was then extracted with 10% MeOH (3 x 200 mL) EtOAc. The combined organic layers were dried <RTI ID=0.0></RTI>jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS (ES+) m/z 452 (MH+). 10 !H NMR (250MHz) 5(CDC13) 1.35-L53 (2H, m), 1.85-2.00 (2H, m), 2.11-2.28 (2H, m), nt (2H,mX 178 (2H,S)? 3*98 (3ίΪ5 sX 4·26-4·40(^ 6H), 6.74 T9 W\ 1〇HZ), 6 82 1H? S)? 7*25 (1Hi 7,82 (1H, dj J 1〇Hz 8·108*28 (13⁄4 d) This compound was converted to 15 HCl salt by dissolving the obtained free base in 1:1 DCM:MeOH and adding 1 equivalent of 4M HCl in 1,4-dioxane. Then it was evaporated to dryness. Example 12 1-(2-{4-[(6,7-Dihydro[1,4]dioxo[2,3-c]indole-3-ylindenyl) Amino]-1-hexahydropyridyl}ethyl)-7-(decyloxy)-2(1Η)-4fluorenone dihydrochloride

20 76 200817417 (a) (1-{2-[7-(Hydroxy)_2-keto-1(2H)+linyl]ethyl}_4-hexapyridinyl)carbamic acid 1,1- Dimethyl acetoacetate [7-(decyloxy)_2_g-yl-1,5-naphthalene](2Η)-yl]acetic acid (2·31 g, 10.65 mmol) and 4-hexahydropyridyl Ethyl carbazide (3·15 g, 15.98 mmol) was stirred in a 1:1 mixture of chloroform and methanol (140 ml) at room temperature under argon. This mixture was then treated with NaBH(OAc)3 (1 〇·16 g, 47·93 mmol) and spoiled for 45 minutes. The solvent was then removed from the reaction and the crude residue was purified eluting elut elut elut elut MS (ES+) m/z 402 (MH+). (b) l-[2-(4-Amino-1-hexahydropyridinium)ethyl]-7-(decyloxy)-2(1Η)-porphyrinone 15 (1-{2-[ 7-(decyloxy)-2-keto-1(2H)-indolyl]ethyl b 4_hexahydropyridinyl)aminophosphonium 1,1-didecylethyl ester (2.25 g, 5.61 The mixture was dissolved in chloroform (20 ml) and HCl (15 mL) and stirred for 1 hour at room temperature under argon. The salt was then dissolved in MeOH and a small amount of toluene was added and the entire solvent was removed. The residue was again dissolved in 2 MeOH and sparged with amberlyst ion exchange resin until neutral. The resin was filtered and the solvent was removed. The crude residue was purified by chromatography eluting elut elut elut elut elut elut elut elut 77 200817417 (c) The title compound will be 1_[2·(4-amino-1-hexahydro- τι. ratio) ethyl](methoxy)-2(1Η)_π quinone (300 gram, 〇 99 millimolar) and 6,7_dihydrou,4]-oxygen 弁[2,3_〇]Ha sui-3-acid (164 mg, 0.99 mmol) dissolved in 5 10 15 chloroform and A 5:1 mixture of methanol (10 mL: 2 mL) was stirred at room temperature under argon for 4 days. It was then treated with NaBH(OAc)3 (634 mg, 2.97) and stirred for an additional hour. More 6,7-dihydro[丨,4]dioxo[2,3-c]indole-3-aldehyde (25 mg, 0.15 mmol) was added and the mixture was stirred at room temperature overnight. Then add more NaBH(〇Ac)3 (300 mg, 1.38 halo) and stir for 3 minutes. The solvent was then removed and the crude residue was purified eluting EtOAc EtOAc EtOAc EtOAc The fractions containing the desired product were concentrated to give the title compound (306 mg, 68%). 1H), 6.99(d,lH), 7.04(s, 1H), 7.45(d^^6·51^1Η)* MS (ES+) m/z 452 (MH+). ' via the free base obtained At Me 〇 H, 4M hydrazine in 1 '2 5 sinter was added and the compound was converted to a di-fermented salt. It is then evaporated to dryness. 20 shells 13 1-(2-{4·[(2,3-di-argon [1,4]dioxo[2,3々bbit_7-ylindenyl))] Hexahydrogen.Equivalent to methoxylidine-2(1H)-one dihydrochloride 78 200817417

5 (a) 1_(2_ propylene-1-yl)-7-(2-propenyl-i-oxy)_ι, 8-naphthyridin-2(1H)-one 1,8-naphthyridine-2,7 ( 1H,8H)-dione (8. gram, 49.4 mmol) (prepared according to Newkome, George R et al, j〇urnai 0f 〇rganic chemistry (1981), 46(5), 833-9) The suspension in DMF (2 mL) was treated with sodium hydride under an argon atmosphere (2.2 g of 6 〇% dispersion in mineral oil 1 gram, '1 g, 55 Torr) at 40° C is heated for 20 minutes. Add allyl bromide (~5 mL). After 2 hours, 4 minutes later, sodium nitride (2.2 g of a 60% dispersion in mineral oil, 13 g, % mmol) and allylic (~5 ml) were added. The mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (5 mL). The mixture was evaporated and the residue was purified eluting elut elut elut elut eluting , MS (ES+) m/z 243 (MH+) 〇 20 (b) 1-(2-propen-1-ylnaphthyridine-2,7(1H,8H)_dione 1-(2-propene-1 -based) _7-(2_ propylene small oxy)], 8 _ _ _ 2 (1 Η) _ 嗣 (440 mg, L8 millimolar) in acetic acid (1 ml) solution in acetic acid 33% clear The acidified acid (1 liter) was treated at 5 Torr. After heating for 1 hour, it was heated for 10 hours on the air. The mixture was evaporated to dryness and adjusted to pH 4 with saturated sodium bicarbonate water 79 Ο 200817417 solution (^5 mL). The mixture was extracted with ethyl acetate, dried <RTI ID=0.0></RTI> and dried. EtOAc m. , 34%)., 5 MS (ES+) m/z 203 (MH+). (c) 7-(Methoxy)-1_(2_propionium-i-yl)-1,8-naphthoquinone_ 2(11^)-one ketone propylene small group)-1,8-naphthyridine-2,7(m,8H)-dione (m mg, 〇: 61 mmol) in DMF (2 mL) After treatment with a solution of potassium 10 butyl butoxide in THF (1 M; 0·7 mL, 0.7 mmol) under argon pressure, hydrazinium (〇·〇 6 ml, 142 mg, 1 mmol) was added. . After 3 minutes, the mixture was evaporated and the residue was purified eluting eluting eluting eluting eluting 15 MS (ES+) m/z 217 (ΜΗ+) 〇(d) (2,3- 虱[1,4]dioxane[2,3-c]t7 is more than 唆7-7 thiol) 1-{2-[7-(decyloxy)-2-keto-1,8-naphthyridine-i(2H)-yl]ethyl}-4-hexahydropyridyl)carbamic acid 1,1 - Dimercaptoethyl ester 20 7-(decyloxy)-1-(2-propan-1-yl)-1,8-naphthyridinium 2(m)-one (110 克克' 0.51耄莫耳a solution in 1,4-dioxane/water (6 ml / 6 ml) with osmium tetroxide solution (4% in water, 〇·6 ml) and sodium periodate (500 mg '2.3 house Moules) )deal with. After 2 hours, more water (6 ml) was added. After a further 2 hours, add more sodium perrhenate (Ig 3 g, $50 8017417417 ears) and more water (6 ml). After a few hours, the mixture was concentrated and partitioned between brine (3 liters) and 1 〇〇/0 sterol (30 liters) in dichloromethane. The aqueous layer was extracted with 1% methanol (2 mL) in dichloromethane. The combined organic extracts were dried <RTI ID=0.0> 4] Dioxaindolo[2,3_c]pyridin-7-ylindenyl) 4-hexahydroindenylamino decanoic acid ι,ι-dimethylethyl ester (synthesis see W02004/058144 example 99(h) (160 mg, 〇·46 mmol) and sodium triethoxy borohydride (320 gram, 1.5 mmol). After 1 hour the mixture was treated with saturated aqueous sodium hydrogencarbonate solution. The organic extract was added to a silica gel column and eluted with 0-30% decyl alcohol in methylene chloride to give an oil (170 mg, 67% in two steps). MS (ES+) m/z 552 (ΜΗ+). 15 (e) The title compound will be (2,3-dihydro[1,4]dioxo[2,3-c]. than the bit-7-ylmethyl) (1-{2_[7-(A) Oxy)_2-keto-1,8-naphthyridinyl]ethyl}-4-hexahydropyridinyl)amino decanoic acid 1,1-dimethylethyl ester (160 mg, 〇·3 mmol) The solution in TFA/dichloromethane (2 mL / 2 mL) was allowed to stand at room temperature for 12 hrs. The residue was dissolved in dichloromethane / methanol (10 mL / 10 mL) and treated with &lt;RTI ID=0.0&gt;&gt; After 15 minutes, the mixture was filtered, washed with methylene chloride and decyl alcohol (twice) and then evaporated to give a free compound. 81 200817417 MS (ES+) m/z 452 (MH+) 〇δΗ CDCls, (250 MHz) 1.35-1.55 (2H5 m), 1.60-2.25 (4H, m)5 2.45-2.60 (1H o „ • 2.75 (2H, m)5 3.00-3.15 (2H, m)5 3.95-4.20 (5H, xn), 4.25-4.40 (4H, m) 4 55 Tiont ml 6.50-6.60 (2H5 m)? 6.80 (1H, s), 7.55 ( 1H? d)5 7.70 (1H, d)5 8.10 (1H;S) 〇( ^ 5 The residue was suspended in dichloromethane/nonanol (1 ml / 1 ml) and the supernatant was decanted after centrifugation. A small amount of the insoluble material was removed. The supernatant was treated with 1M aqueous hydrochloric acid (1 mL) in diethyl ether and diluted with diethyl ether. The title compound was isolated as a solid (115 mg). M]dioxaindolo[2,3-c]indolyl j-methyl)moon-female]-1-hexamethylene}ethyl)_2_g homo-group q,2_di-n-7-喳Nitrile dicarboxylate '-oxygen

15 (a) Trifluoromethyllithinic acid 7-mouth quinine forest 20 The suspension of 7_ thiopyridin (1 g, 6.9 mmol) in DCM (50 liters) Under argon pressure, use 〇 to bite 22 ml, 152 milli. The reaction mixture was then cooled to hydrazine and added to a mixture. The reaction was stirred at room temperature for 0.5 hr. Adding sodium to separate the two liquid layers. The aqueous layer was extracted twice again with DCM = the organic layer was sulphide, and after evaporation through the seam (4), the solid (1.88 g, 98%). MS (ES+) m/z 278 (ΜΗ+). (b) 7-porphyrinonitrile

5 A solution of gadolinyl citrate vinegar (1·88 g '6·8 Torr) in dmF (40 ml) was degassed with air for 10 minutes. Add cyanide (II) (〇·48 g, 4·08 mmol), ginseng (diethyl benzylacetone), two (〇) (155 mg, 2.5% millimolar) and 1,1'- Bis(diphenylphosphino)ferrocene (188 mg, 5% mmol) and the mixture was heated at 1 ° C and argon for 15 hours. 1 〇 The solvent was evaporated and the residue was dissolved in DCM and organic layer was washed with saturated sodium hydrogen carbonate. The aqueous layer was extracted with DCM (3×80 liters). The combined organic layers were dried, evaporated and evaporated eluting eluting eluting eluting eluting MS (ES+) m/z 155 (ΜΗ+). 15 (c) 7_Cyano_1_(2_propylene_1-yl). Kui 镊 镊 将 将 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 Heated for 2 hours. Then add more propyl broken (1. 2 ml, m 2 2 mol). After 2 hours, the intrafusal moth (1.2 ml, ΐ3·2 mmol) was added. The reaction was allowed to cool to room temperature over a two-day day. The solid was dried and dried with EtOAc (EtOAc) EtOAc (EtOAc) Oral MS (ES+) m/z 195 (ΜΗ+) 〇83 200817417 (d) 2-indolyl _l-(2-propan-1-yl)-l,2-diaza-7- 咐 咐• Will be cyano-1-(2-propenyl) porphyrin iodine (1.75 g, 5.4 mmol)

a mixture of potassium hydroxide (1.33 g, 23.76 mmol) and potassium ferricyanide (3.9 g, 1 L 9 mmol) in 50% 1,4-isosane/water at room temperature 5 2 hours. Water (50 mL) was then added and the organic layer was extracted with 10% EtOAc/EtOAc (EtOAc). The combined organic layers were washed with water (1 mL) then dried and evaporated. The residue was washed with EtOAc EtOAc (EtOAc) MS (ES+) m/z 211 (MH+). 10 (e) 2-keto-1-(2-ketoethyl)-l,2-dihydro-7-porphyrinonitrile 2-keto-1-(2-propen-1-yl)- A solution of 1,2-dihydro-7-indolecarbonitrile (600 mg, 2.9 mmol) in 1,4-dioxane (30 mL) and water (20 mL) 4% in water, 3 ml) and sodium periodate 15 (1.4 g, 6.67 mmol). The reaction was allowed to warm to room temperature; then 〇·6 g and 3.7 g of sodium molybdate were added. After a total of 4 hours, the solvent was evaporated and the residue was partitioned between water and 20% methanol-DCM. The liquid layer was separated and the organic layer was dried and evaporated tolujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (f) {l-[2-(7-Cyano-2-keto-1(2H)-carboline)ethyl]-4-hexahydropyridyl}amino decanoic acid 1,1-dimethyl Ethyl ethyl ester 2-keto-1-(2-ketoethyl)-1,2-diin-7-pyridinonitrile (0.60 84 200817417 g '2·8 mmol) and 4-third A solution of the butoxymethylamino hexafluorene hexamethylene sulphonate (2 gram, 2.8 mmol) in chloroform (30 ml) and MeOH (20 ml) was stirred at 60 ° C for 1 hour. The mixture was then treated with NaBH(OAc)3 (1·8 g, 8.5 mmol), stirred at room temperature for 1 hour, and more 4 - 3 - 5 -butoxyamino hexahydro hydrazine was added (340 Milligram, 1.4 millimole) and

NaBH(OAc)3 (1.2 g, 5.7 mmol) and the reaction was stirred at room temperature for one hour. The solvent was then removed and the residue was purified on EtOAc (EtOAc) elute elut elut elut elut elut elut elut elut (MH+) (g) Amino-1-hexachloropyrene. Alkyl)ethyl]-2-S-isol-1,2-diindole-7- η-uu-lin ride in {1-[2- (7-Cyano-2-keto-1(2Η)-fluorenyl)ethyl]hexahydropyridyl 15 pyridine}-carbamic acid 1,1-didecylethyl ester (1.1 g, 2·8 m To a solution of EtOAc (15 mL), EtOAc. Toluene was then added and the solution was evaporated, dissolved in MeOH and treated with Amberlyst A21. Filtration of the resin and removal of the solvent '20 The residue was purified on a silica gel eluting with 0-15% 2M ammonia in methanol-DCM to afford the desired compound ( 〇·82 g, 99 %). MS (ES+) m/z 297 (MH+). (h) Title Compound 85 200817417 5 10 15 H2-(4-Amino-1-hexahydropyridinyl)ethyl]_2-keto 2-diindole-7-indolecarbonitrile (200 mg, 0.68 mmol) Ear) and a solution of two gas [14] 'dioxo[2,3-C] column +3-acid (113 € g, 0.68 mol) in chloroform (15 ml) and methanol (1 g ml) NaBH(〇Ac)3 (432 mg, 2.04 mmol) was added at room temperature under argon atmosphere overnight. After 2 hours, DMF (1 mL) was added to the mixture. After 1 hour, add &amp; indoline, 4] dioxane and [2,3-C well _3 genera (1) 3 mg, 〇68 mmol) and DMF (1 ml) and the reaction was searched at room temperature. Mix overnight. The solvent was then removed and the residue was purified by column chromatography using 2% 2M ammonia elution in decyl alcohol-DCM to afford 70 mg of impure compound which was subjected to MDAP to give the title. The compound (15 mg) is directly di-decanoic acid]H NMR (400 MHz) 5 (CDC13) 1.81 (m, 2H), 2.15 (m, 2H), 2.59 (t 2H) 2 9-3 00 Tm 3m 3.32 (m, 2H), 4.17 (s, 2H)? 4.40-4.64(m, 10H)5 6.81(d, 1H)? 7.1〇(g 1H) 7 49 (d , 7.65 (d,1H), 7.71(d,1H) , 7.93(s,!H),8·31 (s,2H). λ · ^ (d, 1H), MS (ES+) m/z 447 (MH+). Example 15A 1_(2-{4-[( 2,3-Dihydro[1,4]dioxo[2,3_()]pyridine-7-ylindenyl)amino]-1-hexahydropyridyl}ethyl&gt;2-keto group 4 ,2-dihydro_7-4σlinonitrile nitrile hydrochloride

200817417 l-[2-(4-Amino-1-hexafluoridyl)ethyl l.2-keto-1,2-dihydro-7-indolecarbonitrile (300 mg, 1.01 mmol) And 2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, example 2 (c) or W003/087098, example (d)) (167 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 3 millimoles). The reaction was stirred at room temperature overnight. The solvent was removed and the residue was dried under vacuum. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut MS (ES+) m/z 446 (MH+). 'H NMR (400MHz) 6 (CDC13) 1.55 (m? 2H)? 1.97 (d? 2H), 2.23(t, 2H), 2.6-2.7 (m, 3H) ) 3 3.04(d,2H), 3.37 (bs,1H), 3.85 (s,2H),4·20-4·35 (m,4H),4.41 (m,2H),6.81 (d,1H)' , 6.85 (s, 1H), 7.46 (dd5 1H), 7.64 (d, 1H), 7.69 (d5 1H)? 7.80, (s, 1H), 8.10 (s, 1H). ' via dissolution in DCM/methanol One equivalent of 4M HCl / 1,4-bis! 5 decane was added and then evaporated to dryness to convert the material to the hydrochloride salt. The salt was dissolved in a small amount of decyl alcohol and added to the scales to allow the solvent to be decanted and the solid was dried in a vacuum oven at 40 °C. Example 15B 1-(2-{4-[(2,3-Dioxa[1,4]dioxo[2,3-c]pyridine-7- 20 fluorenyl)amino]-1-hexa Hydrogen pyridyl}ethyl)-2-keto-1,2-dihydro-7-indolecarbonitrile dicarboxylate purified by MDAP 1-(2-{4-[(2,3_ dihydro[1, 4] Dioxaindolo[2,3-c]pyridin-7-ylmethyl)amino]-1-hexahydropyridinyl}ethyl)-2-keto-1,2-dihydro-7 -N-carbonitrile, directly obtaining the dibasic acid salt of the title compound.

87 200817417 Example 16 1-(2-{44(6,7-Dihydro[1,4]dioxan[;2,3&lt;]嗒嗒-3-ylmethyl)amino]_1_hexahydro Pyridyl}ethyl)-7-(methoxy)-indole, 5-naphthyl-n-(1Η)-one hydrochloride

Ίο (4)(1_{2_[7-(Methoxy)-2-keto_1,5-naphthyridine-l(2H)-yl]ethyl μα Hydropyranyl) Aminocarboxylic acid 1,1-di Methyl ethyl ester [7-(decyloxy)-2-keto-1,5-naphthalene-indole (2Η)-yl]acetic acid (methyl hemiacetal) (3.807 g, 17.463 mmol) And a mixture of 1,1-dimethylethyl 4-hexahydropyridylcarbamate (3.493 g, 17.463 mmol) in chloroform (100 ml) 15 and MeOH (5 mL)

NaBH(OAc)3 (ll.llg, 52.39 millimolar). After the reaction was stirred for 5 hours, water (100 ml) and a saturated aqueous solution of NaHCO 3 (1 mL) were added. The reaction was then extracted with 20% MeOH (3 x 200 mL) in DCM. The combined organic layers were dried <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS (ES+) m/z 403 (MH+) 〇 (b) 1-[2-(4-Amino-1-hexahydropyridinyl)ethyl]-7-(methoxy)4,^-naphthyridine

ΐ S 88 200817417 -2(1H)-one dihydrochloride salt (1-{2_[7_(decyloxy)_2-ketonaphthyridine](2H)-yl]ethyl}-4-hexahydropyridine To a solution of dimethyl chloroacetate (5.453 g, 13.565 mmol) in chloroform (3 mL), 4N HCl (30 mL) After stirring for 5 hours, MeOH (30 mL) was added. The reaction was stirred for an additional 1 hour and then evaporated to give a crystallite crystallite. MS (ES+) m/z 303 (MH+). (c) the title compound 1-[2-(4-amino-1-hexahydropyridyl)ethyl]-7-(decyloxy)-1,5-naphthyridin-2(1H)-one dihydrochloride Salt (145 mg, 0.399 mmol) in chloroform (20 mL) MeOH (2 mL) 7-Dihydro[M]dioxygen and [2,3_c]indole_3_aldehyde (226 mg, 1.360 mmol). After the reaction was stirred for 0.5 hours, NaBH(OAc)3 (577 mg, 2.72 mmol) was added. After stirring at room temperature for 1 hour, more NaBH(OAc)3 (577 mg, 2.72 mmol) was added. After an additional hour, 20 more NaBH(OAc)3 (577 mg, 2.72 mmol) was added. The reaction was again disturbed for 5 hours and then saturated aqueous NaHC 3 (20 liters) was added. The reaction was then extracted with 2% MeOH (3 x 2 mL) in DCM. The combined organic layers were dried <RTI ID=0.0>

89 200817417 Free state of the compound (473 mg, 70%). MS (ES+) m/z 453 H NMR (250MHz) 8 (CDCl3) 1.45-1.62 (2H, m), 1.90-2.08 (2H m) 2 25-2 42 (2H m, 2.52-2.79 (3H, m) , 2.95-3.15 (2H5 m)? 4.01 (5H, m)&gt; 43〇.4.56(m 6H) r 6·73 (13⁄4 ^ J l〇Hz), 7.04 (1H, s), 7.35 (1H, s ), 7.85 (1H, d, J l〇Hz)? 8.28 (1H5 d J 2Hz). 5 via dissolving the resulting free base in 1:1 DCM:MeOH and adding in 1,4-dioxane 4MHC1, this compound was converted to the HCl salt. It was then evaporated to dryness. Example 17 1_(2_{4-[(6,7-Dihydro[1,4]dioxo][2,3-c]indole Plung-3- ίο 甲基 methyl)amino hexahydropyridyl}ethyl)-7-(decyloxy)-1,8-naphthyridin-2(1H)-one dihydrochloride

15 (a) (1-{2-[7-(Methoxy)_2-keto-1,8-naphthyridin-1(2H)-yl]ethyl}-4 -hexahydropyridinyl)aminopurine Acid 1, 丨-dimercaptoethyl ester 7((methoxy)_1-(2-propenyl)-, 8-naphthyridin-2(1H)-one (240 mg '1·1 mmol) 2 〇 solution in 1,4-dioxane/water (12 ml / 20 ml) with tetrazoic acid solution (4% in water, 1 ml) and sodium periodate (2.1 g '10 house Moules) )deal with. After 3 minutes, add more water (15 ml). After an additional 1 hour, the mixture was diluted with an equal mixture of brine and extracted twice with ethyl acetate. The dried extract was evaporated to give a yellow oil. Dissolve it in dichloromethane / methanol (6 ml / 0.6 ml) and use 4-60 90 200817417 hydropyridylamine ι, i-dimethyl ethyl ester (240 mg, 12 mmol) and Treatment with sodium triethoxy borohydride (626 mg, 3 mmol). After 2 hours, the mixture was treated with saturated aqueous sodium bicarbonate and dichloromethane. The organic extract was added to a silica gel column, eluted with 0-100% ethyl acetate in hexanes, and then eluted with 20% methanol in ethyl acetate to give a brown foam (320 mg, 72° /. After two steps). MS (ES+) m/z 403 (MH+) 〇(b) title compound ι〇(1(2^7-(methoxy)-indolylnaphthalenyl-1(2H)-yl]ethyl}- 4-Hexahydropyridyl) carbamic acid hydrazide, dimethyl dimethyl ester (31 〇 mg, 0.77 mmol) in TFA/dichloromethane (10 mL / 1 mL) at room temperature for 1 hour After evaporation to dryness, azeotrope with chloroform, and then triturated with diethyl ether. The residual solid was dried in vacuo for 1 hour and then dissolved in dichloromethane (methanol). Resin (2.5 mM carbolic acid salt per gram '2.7 g, 7.3 mmol) was treated. After 15 minutes, the mixture was filtered, washed with dichloromethane and methanol (twice) then evaporated to give oil. Dissolved in dichloromethane/nonanol (5 ml / 0.5 ml) with 6,7-dihydro[1,4]dioxan[2,3-c]indole-3-aldehyde (172 mg, ι · 〇 4 mM) and 20 sodium triacetate borohydride (500 mg, 2.4 mmol). Add more 6,7-dihydro[1,4]diox after i hours. g and [2,3_c] 嗒____aldehyde (85 mg, 0. 5 mmol). After a few hours, the mixture Saturated aqueous sodium bicarbonate and methylene chloride. The organic extract was dried and evaporated. The residue was added to a silica gel column, using in dichloromethane 〇_2〇%

91 200817417 (2M ammonia in decyl alcohol) was eluted to give the title compound as a free base oil (210 mg, 60% over two steps). MS (ES+) m/z 453 (MH+). δΗ CDCls, (250 MHz) 1.35-1.55 (2H5 m), 1.70-2.00 (2H, m), 2.10-2.25 (2H, m), 2.45-2·55 (1H,m), 2.65-2.75 (2H,m),3·00-3·10 (2H,m), 4.00 (2H,s),4.03 (3H,s),4·38 (2H, m) , 4.50 (3H, m), 4.60-4.70 (2H, m), 6.57 (1H, d), 6.62 (1H, d), 7.08 (1H, s), 7.60 (1H, d), 7.74 (1H, d). This was dissolved in EtOAc (EtOAc) (EtOAc) The title compound was isolated as a solid (250 mg). Example 18 6-{[(1-{2-[7-(decyloxy)-2-keto-1,5-naphthyridin-1(2H)-yl]ethyl}_4_hexanitropurine sigma Amino] fluorenyl}-2Η-ϋΙ:[: σ定弁[3,2-b][l,4]畤耕-3(4Η)-ketone hydrochloride

2〇[1-(4-Amino-1 -6-squirrel sigma)ethyl]-7-(decyloxy)-1,5-naphthyridin-2(m)-one di-salt The mixture was treated with triethylamine (194 μL, 1.40 mmol) and stirred for 0.25 hr. -keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-aldehyde (synthesis see 92 200817417 W02003087098, Example 31(e)) (71 mg, 0·40 millimoles). After stirring for an additional 0.5 hours, a saturated aqueous solution of NaHC3 (20 mL). The reaction was then extracted with 20% MeOH (3 x 200 mL) EtOAc. The combined organic layers were dried with EtOAc EtOAc EtOAcjjjjjj MS(ES+)m/z465(MH+). 'Η NMR (250MHz) 5(CDC13) 1.39-1.53 (2H, m), 1.85-1.99 (2H, m), 2.12-2.28 (2H? m)3 2.48- 2.72 (3H, m), 2.92-3.05 (2H, m), 3.81 (2Hr s), 3.98 (3H, s), 4.34-4.40 (m5 2H), 4.64 (2H, s), 6.73 (1H, d, J 10Hz), 6.93 (1H, d, J 8Hz), 7·20 (1H, d, J 8Hz), 7·23 (1H, d, J 2Hz), (7·84 (1H, d) , J 10 Hz), 8·28 (1H, d J 2·5Ηζ)· via dissolving the obtained free base in 1:1 DCM:MeOH and adding 1 equivalent of 4M HCl in 1,4-dioxane, This compound was converted to the HCl salt and then evaporated to dryness. Example 19 6_{[(1_{2-[7-fluoro-2-keto-l,5-naphthyridin-1(2H)-yl]ethyl M-hexahydropyridyl)amino]hydrazino 2H-pyrido[3,2_b][l,4]^|__3(4H)-one hydrochloride

1-[2-(4-Amino-1-hexahydropyridyl)ethyl]_7-(methoxy 93 200817417-based M, 5-naphthyridin-2(1H)-one dihydrochloride (180 mg , 496·496 mM). A mixture of chloroform (5 ml) and MeOH (0.1 mL) was treated with triethylamine (218 μL, 1.58 mmol) and stirred for 0. 25 hours. 3-keto-3,4-dihydro-2-indole-pyrido[3,2-b][l,4]indole-6-aldehyde (synthesis see 5 W02003087098, Example 31(e)) (80 mg, The reaction was stirred for 0.5 h then added NaHH (EtOAc) &lt;RTI ID=0.0&gt;&gt; Extraction of 20% MeOH (3×200 mL). The combined organic layers were dried, evaporated and evaporated eluting eluting Free-form base (187 mg, 83%) MS (ES+) m/z 453 (MH). MH NMR (250 MHz) 5 (CDC13) 1.34-1.65 (2H, m), 1.72-1.99 (2H, m ) 5 2.10-2.28 (2H m) 2.48-2.72 (3H, m), 2.89-3.03 (2H, m), 3.84 (2H, s), 4·30-4·36 (m, 2H), 4· 63 (2H s) ' ' 6·84 (1H,d,J 10Hz), 6·93 (1H,d,J 8Hz),7·19 (1H,d J 8Hz),7.55 (1H,dd,J 10 ' 2' 7·88 (1H, d, J 10Hz), 8.41 (1H, d J 2Hz). ' h 15 by dissolving the obtained free base in 1:1 DCM: Me〇H and adding 1 equivalent in 1 4M HC1 in 4-diindole, this compound was converted to the HCl salt and then evaporated to dryness. Example 20 1-(2-{4-[(2,3-Dihydro[1,4]) Oxygen and [2,3_中比唆-7_ 20 fluorenyl)amine]small hexahydro σ ratio 17 base}ethyl)-7 legacy-2(111)-啥十林g同二HCl

94 200817417 (4)(2,3-Dioxa[1,4]dioxo[2,3-c]bitone-7-ylmethyl){ΐ·[2_(7_-fluoroketoquinazinyl) Ethyl] ice hexahydroindenyl} 1,1-dimethylethyl carbazate 7-fluoro-2-keto-1(2Η)-σ querakisyl acetaldehyde (about 70% purity) , 〇63 5 g ' 2.16 耄 Mo Er) and (2,3_ dihydroanthracene, 4) oxo-and-denylmethyl) 4-hexa-pyridylamino-f-acid U-dimethylethyl ester (synthesis See W02004/058144 Example 99 〇 1)) (〇. 克, 2.16 mmol) in a solution of anhydrous decyl alcohol (1 mL) and chloroform (20 mL). Sodium triethoxysulfonate (1.37 g, 6.49 mmol) was added and the mixture was stirred for 1.5 hours. The aqueous solution of sodium bismuth carbonate was added for verification and the liquid layer was separated. The aqueous layer was extracted several times with DCM and the organic layer dried and evaporated. Chromatography on silica gel, elution with 0-20% methanol / DCM, followed by a second chromatography with 5 〇 1 〇〇〇 / 〇 ethyl acetate / hexane to give the product ( 〇 43 g, 37% ). MS (+ve ion electron spray) m/z 540 (ΜΗ+). 15 (b) The title compound will be (2,3-dihydro[1,4]-oxo-[2,3-〇] 比 -7-7-yl fluorenyl) {1-[2-(7-say) 2-keto-yl hydrazino)ethyl]_4_hexafluoroanthryl}-amino phthalic acid U-didecyl ethyl ester (〇·43 g, 〇·8〇 millimolar) in DCM 20 ( A solution of 8 mL) and MeOH (5 mL) was obtained eluted with EtOAc EtOAc EtOAc Drying underneath) 'To obtain the free base of the title compound (0.41 g, 100%) 〇95 200817417 δΗ (DMSO-d6), (250 MHz) 2·07 (2H, m), 2·38 (2H, br.d ), 3.10 (2H, m), 3·32 (3H, broad), 3.53 (2H, m), 4.25(2H, br. s)? 4.38 (2H, m), 4.44 (2H, m), 4.62 ( 2H, m), 5.30 (3H, v· Broad), 7·29 (1H, td)· 7·39 (1H, s), 7.82 (1H, dd), 7.92 (1H, dd), 8.22 ( 1H, s), 8.30 (1H, s), 9.88 (2H, broad), 10.89 (2H broad) · MS (+ve ion electrospray) m/z 440 (MH+). Dissolve the obtained free base This compound was converted to the di-HC1 salt at 1:1 DCM:MeOH and added to 4M HCl in H. It is then evaporated to dryness. Example 21 1-(2-{4-[(3,4-Dihydro-2H-pyrano[2,3-c]pyridine-6-ylindenyl)amino]-1-hexafluoridyl} Ethyl)-7-(decyloxy)-1,5-naphthyridine ίο -2(1H)-one hydrochloride

(a) the title compound 1-[2-(4-Amino-1-hexahydropyridinyl)ethyl]_7-(methoxy)-1,5-naphthyridin-2(1Η)-one dihydrochloride A mixture of salt (Π4 mg, 0.466 mmol) in chloroform (5 mL) and MeOH (0.11 mL) was taken with triethylamine (205 μL, 1.484 mM) and stirred for 0.25 hr. 4_ Dihydro-2-indole-pyrano[2,3-c]pyridine-6-aldehyde (synthesis see W02004058144, Example i26(e)) (69 mg, 0.424 mmol). After the reaction was stirred for 0.5 h, NaBH(OAc)3 (270 mg, 1.272 m. Stir the reaction for 5 hours, then add saturated NaHC03 to dissolve in water.

96 200817417 Liquid (50 ml). The reaction was then extracted with 20% MeOH (3 x 200 mL) EtOAc. The combined organic layers were dried <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 5 10 MS(ES+)m/z450(MH+). lU NMR (250MHz) 5(CDC13) 1.37-1.58 (2H5 m) 51.82-2.10 (4H, m), 2.11-2.29 (2H τηλ 2·40-2· 82 (5H,m), 3.80 (2H,m),3·78 (2H,s),3.98 (3H,s),4.19-4·23(ιη,2H),4·35-' ' 4.41(m , 2H), 6.73 (1H, d, J 10Hz), 6.97 (1H, s), 7·27 (1H, s), 7·82 (1H, d, J 10Hz), 8·〇8 (1H, s), 8·28 (1H, s). '· By dissolving the resulting free base in 1:1 DCM:MeOH and adding 1 equivalent of 4M HCl in 1,4-dioxane, This compound is converted to the HCl salt. It is then evaporated to dryness. Example 22 1-(2-{4-[(2,3-Di[[,4]dioxo[2,3]dioxo[2,3] Alkyl)amino]sodium hexahydropyridyl}ethyl) hexafluoro-2(1H)^奎十林§同二

15 Hydrochloride (8) 6_fluoro-2-keto-1(2Η)-π奎α morphyl acetaldehyde 6-fluoro-1-(2-propen-1-yl)_2(m)_喳哼口A solution of linketone (〇·86 g, 4.22 mmol) in 1,4-dioxane (50 ml) and water (1 ml) with iron tetrachloride (4% solution in water, 5.1 ml) And sodium periodate (4.14 g) and the mixture was stirred at room temperature for 3.5 hours. Two &amp; 97 via evaporation

V 200817417 was removed by burning and the residue was extracted several times with 10% decyl alcohol / DCM. The extract was dried and evaporated, and the crude product was chromatographed on silica gel eluting with 50-100% ethyl acetate/hexane to give aldehyde (54 g, 62%, which shows acid and *methyl) a mixture of hemiacetals). 5 Ms (+ve iontophoresis) m/z 207 (ΜΗ+), 221 (M.CH3+ from hemiacetal) (b) (2,3_dihydro[1,4]dioxan[2 ,3-c]pyridine-7-ylmethylfluoro-2-keto-1(2Η)-4σ morphyl)ethyl]-4-hexahydroindenyl}amino decanoic acid 10 U-di Ethyl ethyl ester will be 6-fluoro-2-keto-1(2Η)_ hydroxy-mercaptoacetic acid (〇·54 g, 2.62 mmol) and (2,3-dihydro[I,4]dioxane And [2,3_c]pyridine_7_ylindenyl)4_hexahydroindoletriamine decanoic acid 1,1-dimethylethyl ester (synthesis see W02004/058144 example 99(h)) (0.92 g, A solution of 2.62 mmol of anhydrous methanol (0.5 mL) and chloroform (10 mL) was stirred at room temperature for 1 hour. Sodium triethoxysilane borohydride (166 g, 7.87 mmol) was added and the mixture was stirred for 22.5 hours. The aqueous solution of sodium hydrogencarbonate was added for verification and the liquid layer was separated. The aqueous layer was extracted several times with DCM and the organic layer dried and evaporated. Chromatography on silica gel, elution with 〇-15% methanol/ethyl acetate, and chromatography to give the product (yield: 66 g, 47%). MS (+ve iontophoresis) m/z 540 (MH+). (c) the title compound will be (2,3-dihydro[μ]dioxo[2,3-c]pyridine-7-yl-methyl 98, 5 200817417 base) {H2-(6-gas-2-one) Base-1(2H)·4 linalyl)ethyl]I hexahydro hydrazinyl}amino phthalic acid U-dimethyl acetoacetate (0.66 g, 2 mmol) in DCM (12 mL) and A solution of decyl alcohol (8 ml) was treated with 4M hydrogen 5 10 15 20 chloro acid (12 mL) in EtOAc, EtOAc (EtOAc) Drying under vacuum at <RTI ID=0.0># </RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; A small amount (15 mg) of the dihydrochloride salt was treated with aqueous sodium bicarbonate and extracted with DCM. The free solution of a small amount of sample is obtained by immersing the extract and evaporating it. ΗΗ (CDC13), (250 MHz) 1.42 (2H5 m) 1 〇〇, ^ (2H, t), 2.95 (2H, br. d)? 3.79 (2H, s) i 32 ^ 2ΛΊ TM td^ &gt; 2 ·50 (13⁄4 m)&gt;2·63 dd),7·58 (1H,dd),8·10 (1H,s),8 3^/fj V),called,6·82 (1H,s) · 7.32 (1H, td), 7.39 (1H, by adding 1 equivalent of 々Μ HC1 in 1 4 _ # i, 4- π decane to l-(2-{4-[(2,3- Dihydrogen [1 4] Yiqi Meng, Ganzi corpse, J-lactated [2,3-c]pyridin-7-ylindenyl)amino]-1-hexapyridinyl} 7-glycol, 1 G )6-Fluoro-2(1Η)-Dakisone ketone in DCM/MeOH solution, followed by m 丨 丨 , , , , , , , , 单 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- Sorghum 1 ιλ,--虱_[14] 二气芦共答吨基基基基基]小六氡乳开开 (6)cj.开j 9Mm m , 基}ethyl)_δ-ethyl-7-fluoro ―1,5-naphthyridine-2(1H)-one monohydrochloride

99 200817417

1-[2-(4-Amino-1-hexafluoridyl)ethylnaphthyridine 10 15 -2(1Η)__(〇·117 g, 0·368 mmol) and 6,7-II Hydrogen [1,4]dioxyg and [2,3_c]indole-3-aldehyde (0.061 g, 0.368 mmol) dissolved in CHCI3 (2 mL) and MeOH (〇·2) at room temperature under argon In milliliters). NaBH(OAc)3 (0.234 g ' 1.10 t mole) was added and the reaction was disturbed at room temperature for 16 hours. It was then purified by chromatography eluting with EtOAc EtOAc (EtOAc) MS (ES+) m/z 469 (ΜΗ4). !H NMR (250MHz) 5(MeOD) 1.38 (3H, t), 1.58-1.70 (2H5 m), 2.03-2 14 (2U λ 2.35 (2H, m) , 2.76-2.87 (2H, m), 2.91-3.21 (5H, m), 4.30 (2H s), 438:4 53 ^ (1H,d),7.33 (1H,d),7.90 (1H,d), 8·44 (1H, s). W (63⁄4 m), 6.82 This compound was converted to Ηα by dissolving the obtained free spectroscopy in MeOH (1 mL) and EtOAc (3 mL) Salt. The solution is then evaporated to dryness to give the di-HC1 salt. 20 Example 24 1-(2-{4-[(2,3-Dihydro[1,4]dioxo[A][253-c; htbn 曱Amino]amino hexahydropyridyl}ethyl)-8-ethyl 1 fluoro_155_ 笑口定-2(1 H)-one dihydrochloride 100 200817417

5 (a) 8-Ethyl-7-fluoro-2-(decyloxy)_1,5_Steamed 8-Ethyl-7-fluoro-2-(decyloxy)-l,5-steamed Bite (synthesis see W02004/058144 Example 53(h)) (1.0 g, 4·90 mmol) in Et〇H ίο (50 ml) with 10% Pd/C (0.2 g) and the resulting The suspension was hydrogenated under 1 atmosphere of hydrogen pressure for 3 hours. The mixture was suction filtered through EtOAc (EtOAc) (EtOAc). The combined hydrazine and the washings were concentrated to give the title compound as a white oil (1·45 g, 103%) 〇 15 MS (ES+) m/z 207 (MH+). (b) 8-Ethyl-7-fluoro-1,5-naphthyridinium 2(1Η)-one is 8-ethyl-7-fluoro-2-(decyloxy)-1,5-naphthoquinone ( A suspension of 1.045 g, 5·7 7 mmol) in glacial acetic acid (10 mL) at rt. After stirring at room temperature for 18 hours, the solvent was evaporated under reduced pressure. More glacial acetic acid (1 mL) was added to the reaction mixture and the solvent was removed to give a yellow solid. This residue was taken up in water (about 50 ml) to produce a white precipitate from the solution. The pH was adjusted to 6-7 via the addition of solid sodium bicarbonate. Then the mixture is given at room temperature

101 200817417 After 2 hours of mixing, the solid was separated by suction filtration to give a white moist solid. The product was suction-dried on a porous layer for 2 hours, and then dried in a vacuum oven at 40 ° C for 18 hours to give the title compound as a white solid (yield: 8 g, 83%). 5 MS (ES+) m/z 193 (ΜΗ+) 〇(c) 8_ethyl-7-fluoro_2-(2-propenyl-i-oxy)_ι,5-naphthalene bite 8_ethyl- 7-Fluoro-1,5-naphthyridin-2(1H)-one (0·810 g, 4.22 mmol) was suspended in anhydrous DMF (12.5 mL) under argon pressure and 〇 ° C, then 1 〇 Sodium hydride (60.71 g of 60% by weight: dispersion in oil, 2.2 equivalents) was added portionwise. The suspension was allowed to warm to room temperature. After stirring at room temperature for 3 minutes, the mixture was treated with allyl iodide (0.858 ml, 2.2 eq.) and stirred for further 30 min then water (1 mL). The mixture was then extracted with 1% MeOH / DCM (3 x 20 mL). The combined organic extracts were dried with EtOAc EtOAc EtOAc EtOAc This residue was then applied to the 〇_1〇〇0/ in the scent of Shixia (50 g). The title compound was obtained as a brown oil (yield: <RTIgt; MS (ES+) m/z 233 (MH+) 〇 20 (d) 8-ethyl-7-fluoro-2-(2-propen-1-yloxy)-1,5-naphthalene-2 (1H)- The ketone was dissolved in xylene (8-ethyl-7-gas-2-(2-propen-1-yloxy)_ι, 5-naphthalene (0.660 g, 2.84 mmol) at room temperature under argon pressure ( 14 ml), then add hydrazine (triphenylphosphine) (0.329 g, 〇·284 mmol). The anti-102 &gt;-- 200817417 should be heated at 150 C for 30 minutes. The reaction was then allowed to cool and the precipitated solid was filtered. The filtrate was then purified on a silica gel eluting EtOAc EtOAc EtOAc EtOAc 181 grams, 27 〇 / 〇). 5 MS (ES+) m/z 233 (MH+). (e) (8-Ethyl-7-fluoro-2.keto-1,5-naphthyridinyl-(I)-yl)acetaldehyde 8-ethyl-7-fluoro-2-(2-propene _1_oxy)-i,5-naphthyridin-2(1H)-one (0.181 g, 〇781 mmol) dissolved in 込'二ίο 畤(4·〇) at room temperature under argon pressure ML) and water (3.5 ml). Sodium periodate (0.418 g, 1.95 mmol) and osmium tetroxide (0175 ml of a 4% aqueous solution) were then added sequentially. After 10 minutes, a white precipitate formed from the solution, which was re-dissolved by the addition of water (2 mL). The reaction was allowed to stand at rt. EtOAc (EtOAc) The aqueous I5 was then separated and washed with EtOAc (3×20 mL). The organic layer was combined and dried <RTI ID=0.0> (1) {1-[2-(8-Ethyl-7-fluoro-2-keto-l,5-naphthyridin-1(2H)-yl)ethyl]-4- 2〇pyridinyl)amine (8-ethyl hexamethylene-2- keto-1,5-naphthyridinyl-i(2H)-yl)acetaldehyde (0.168 g, 〇·718 mmol) And 1,1 -didecylethyl 4-hexahydropyridylamine decanoate (0·172 g, 0.860 mmol) dissolved in CHC13 (6 mL) and MeOH (0.6) at room temperature under argon pressure ML), then NaBH(OAc) 3 103 200817417 (0.497 g, 2.34 mmol) was added and then allowed to mix for 3 hours. The reaction was purified with EtOAc EtOAc EtOAc EtOAc. MS (ES+) m/z 419 (MH+). 5 (g) l-[2-(4-Amino-1-hexafluoridyl)ethyl]-8_ethyl_7_fluoroyi^Naphthalene-12--2 (1H)-酉同在{1 -[2-(8-ethyl-7-gas-2-keto-1,5-naphthalene _1(2H)-yl)ethyl]-4-hexahydropyridyl}amino decanoic acid 1, To a solution of 1-dimethyl EtOAc (EtOAc (EtOAc) (EtOAc) The residue was dissolved in 1:1 DCM and MeOH (2 mL) and treated with MP- carbonate resin until pH reached 8. The reaction was then filtered, EtOAc (EtOAc)EtOAc 15 MS (ES+) m/z 319 (ΜΗ+) 〇(h) title compound 1-[2-(4-aminopyrrolidine)ethyl]-8-ethyl-7-fluoro-1 , 5_ naphthyridine-2(1H)-one (0.056 g, 0·184 mmol) and 2,3-dihydro[1,4] 20 dioxo[2,3-c]pyridine-7- Aldehyde (synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19(d)) (0·030 g, 0.184 mmol) dissolved in CHC13 (1 mL) and MeOH at room temperature under argon pressure ( 0.1 ml). Then NaBH(OAc)3 (0.117 g, 0.552 mmol) was added and then the mixture was stirred at room temperature for 16 h. The reaction was purified by chromatography eluting with EtOAc EtOAc (EtOAc) MS (ES+) m/z 468 (MH+). • ]H NMR (250MHz) 6(MeOD) 1.38 (3H, t), 1.51-1.67 (2H5 m), 2.03-2.10 (2H? m), 2.18-2 · 27 (2H, m), 2·65-2·85 (2H, m), 3.00-3.21 (5H, m), 4.18 (2H, s), 4·30-4·41 (4Η, m), 4.55 (2H,t),6·84(1Η,d),6·99 (1H,s),7·93 (1H,d),8.13 (1H,s),8.45 (1H,s)· 5 via The resulting free base was dissolved in MeOH (1 mL) and EtOAc (EtOAc) The solution was then evaporated to dryness to give the di-HC1 salt. Οο Example 25 10_(2-{4-[(2,3-Dioxa[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)amino]-1-hexahydro Pyridyl}ethyl)_2,3_dihydro[1,4]dioxo[2,3-h]indole-9(10H)-one hydrochloride

(a) 5-zolyl-2,3-dimur-1,4-benzoquinodioxane 20 3-nitro-1,2-benzenediol (5 g, 32.26 mmol), dibromo Decane (12.13 ml, 64.52 mmol), tetra(n-butyl)ammonium bromide (1.1 g, 32.26 mmol) and K2C〇3 (13.35 g, 96·78 mmol) in refluxing toluene Stir in overnight. The reaction was then poured into water (150 mL) and EtOAc (EtOAc) The combined organic layers were washed with EtOAc EtOAc EtOAc (EtOAc) (b) 2,3-Diazin-1,4-benzoquinodioxin-5-amine 5 5-Shosyl-2,3-diaza-1,4-benzoquinonedioxane (5.4 g, 29 • 83 mmoles dissolved in ethanol (130 ml) and concentrated to HC1 (1.13 mL, 29.83 mmol), which was then hydrogenated with 10% Pd/C under atmospheric pressure of hydrogen and room temperature overnight. The catalyst was then filtered and washed with MeOH. After the solvent was removed, the crude product was purified via SCX. The product containing fraction was concentrated to give the desired product (4.6 g). MS (ES+) m/z 153 (MH+). (c) 2,3-Dihydro[1,4]dioxol and [2,3-h]indole concentrated sulfuric acid (30 ml), boric acid (2.29 g, 47.20 mmol), sulfur 15 iron (II) a mixture of heptahydrate (1·〇9 g, 3.93 mmol) and sodium 3-nitrobenzenesulfonate (9.5 g, 42.36 mmol) was cooled to 〇 and then added with glycerol (11 ml, 151.31 mmol) and 2,3-dihydro-1,4-benzodioxan-5-amine (4.6 g, 30.26 mmol) and water (3 mL). The mixture was then heated to 140 ° C and stirred for 4 hours. The reaction was cooled to room temperature then poured into ice water 20 (150 mL) and filtered. The resulting mixture was basified to pH 8 with 6N NaOH and stirred with EtOAc 30 min. The organic layer was separated and the aqueous extracted with EtOAc EtOAc. The combined organic layers were filtered through celite, washed with brine and dried with EtOAc. The solvent was removed to give the desired product (3.6 g, 65%). 106 200817417 MS (ES+) m/z 188 (MH+). (d) 10-(2-propionyl-1-yl)-2,3-dihydro[i,4]dioxo[2,3-h]porphyrin-10-indole iodine 5 2,3- Diterpene [1,4]dioxo[2,3-1ι] kou kou (3.65 g, 19.52 mmol) and allyl iron (6.52 ml, 39·04 mmol) in 1 Hey. The acetone was refluxed in acetone (50 ml). After 2.5 hours, more allyl iodide (0.65 ml, 3·9 mmol) was added to the mixture and the reaction was continued for 0.5 hour under the same conditions. The solvent was removed and the tar-like product was washed with terpene. It was dried under high vacuum overnight to give the desired product (5·91 g, 85%) 〇(e) 10-(2-propan-1-yl)-2,3-diindole[1,4] Oxazepine [2,3-h]porphyrin-9(10H)-one 15 will be 10-(2-propen-1-yl)-2,3-dioxa[1,4]dioxo[2] , 3-h] porphyrin-10-indole iodine (5.91 g, 16.65 mmol), ΚΟΗ (4.1 g, 73.26 mmol) and K3 [Fe(CN)6] (12.05 g, 36.63 mmol) Stir in a 50% aqueous solution of 1,4-dioxane for 1.5 hours at room temperature. Water (250 ml) was added and the aqueous layer was extracted with EtOAc EtOAc EtOAc EtOAc The organic layer was dried over MgS04 and solvent was removed. The crude residue was purified by EtOAc EtOAc EtOAc elut elut MS (ES 10) m/z 244 (MH+). 107 200817417 (f) (9-keto-2,3-monohydro[1,4]dioxo[2,3 oxime] acetyl), acetaldehyde • 1〇-(2-propene-1 · base) 2,3-dihydro[M]dioxol and [2,3_h]porphyrin-9(10H)-one (1.3 g, 5.35 mmol) dissolved in DCM (7 〇 5 mL) and cooled To _78 °c. The mixture was then stirred at 〇3 for 65 min then DMS (1.4 mL, EtOAc) Stir for another 20 minutes at room temperature. The solvent was removed to give the desired product (1.5 g). MS (ES+) m/z 246 (ΜΗ+). 10 (g) {1-[2-(9-keto-2,3-dihydro[M]dioxo[2,3-h] koukui-1〇(9Η)-yl)ethyl ]-4-hexahydropi-pyridyl j-amino dimethyl phthalate (9-keto-2,3-monohydro[1,4]dioxo[2,3_h]porphyrin_ 〇(9Η)_ 15 base) ethyl vine (1*5g '6.12 millimolar) and 4-hexahydroguanidinoic acid 1,1_-mercaptoethyl ester (1.84 g, 9.18 耄m) Dissolve in a 1:1 mixture of chloroform and Me〇H (50 ml: 50 ml) and stir at room temperature for 3 min. Add NaBH(OAc)3 (5.81 g, 27.54 mmol) and leave the reaction overnight. The solvent was removed and the residue was purified eluted EtOAc EtOAc EtOAc EtOAc EtOAc z 430 (MH+) 〇(h) 10-[2-(4-Amino-1-hexahydropyridinyl)ethyl]_2,3_dihydro[丨,4]dioxo 108 '( 'Ξ 200817417 芑And 2,3-h]porphyrin-10(9H)-one will be {l-[2-(9-keto-2,3-dihydro[ι,4]dioxo[2,3 -h] morphine-1Q(9H)-yl)ethyl]-4-hexapyridinium π-denyl}amino phthalic acid ι, ι- 曱 曱 乙 乙 曰 (1 g, 2.34 mmol) dissolved in Chloroform (8 ml) was added to 4M HCl (1 mL) in 1,4-dioxane. Then it was stirred at room temperature for 1 hour. The salt formed from the reaction was dissolved in MeOH and all solvent was removed. Re-dissolve the residue in ]VIeOH and stir with amberlyst ion exchange resin until neutral pH is reached. The resin is filtered and all solvent removed. The crude residue is used on silica gel with 0-20% 2M NH^MeOH/DCM The gradient elution was purified by column chromatography to give the desired product ( 425 mg, 55%). MS (ES+) m/z 330 (MH+). (1) title compound: 10-[2_(4- Amino-1-hexapyridinyl)ethyl]_2,3-dihydro[1,4]dioxo[2,3-h]porphyrin-1〇(9Η)-one (100 mg, 0.304 Millol) and 2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde (for synthesis see W02004058144, Example 2(c) or W003/087098, Example 19 ( d)) (50 mg '0.304 mmol) dissolved in a 5:1 mixture of chloroform and Me〇H (5 ml: 1 ml) and stirred at room temperature for 2.5 hours. More 2,3_2 Hydrogen [^4] dioxin[2,3-c]pyridine-7-aldehyde (10 mg, 0.031 mmol) was added to the reaction and stirred for 20 minutes. Then it was taken with NaBH(OAc)3 (20 mg, 0.092 millimolar) treated and stirred for 30 minutes. More 2,3-dihydro[1,4]dioxo and [2,3-c]acridin-7-aldehyde (1 mg, 0·) 031 millimoles) added to the reaction

109 200817417 Stir for 15 minutes. It was then treated with NaBH(OAc)3 (20 mg, 0. 092 mmol) and stirred for 15 min. The solvent was then removed and the crude residue was purified eluting eluting elut elut δΗ CDC13, (400MHz) 1.49 (m, 2H), 1.8-2.6 (m, 8H), 2.76 (m5 2H), 3.04 (d, 2H) 3 81 is 2H), 4..2-4.4 (m, 8H ), 4.71 (m, 2H)5 6.51 (d? 1H), 6.78 (d, 1H)? 6.83(s, 1H), 7.0lVd im MS (ES+) m/z 479 (MH^. via free base This compound was dissolved in MeOH and treated with ίο 4MHC1 in 1,4-diosane to convert this compound to the HCl salt. Then it was evaporated to dryness. Example 26 1〇-(2-{4-[(6,7-) Dihydro[1,4]dioxyg[2,3-c]indole-3-ylmethyl)amino]-1-hexahydropyridinyl}ethyl)-2,3-diar[1] ,4]dioxo[2,3-h]indole-9(10Η)-one hydrochloride

1〇-[2-(4_Aminopyrrolidine)ethyl]-2,3•dihydro[l54]dioxo[2,3-h]喳咁·1〇(9Η) -ketone (100 mg, 0.304 mmol) and 6,7-dihydro[1,4]dioxo[2,3-c]indole-3-aldehyde (50 mg, 〇·3〇4 mil 110 200817417 Mole) > A solution of 5:1 (5 ml: 1 ml) in MeOH and MeOH was stirred at room temperature for 7 hours. It was then treated with NaBH(〇Ac)3 (194 mg, 912·912 mmol) and left to stand overnight. Add more 6,7-diaza[1,4]dioxo[2,3-c]indole-3-aldehyde (25 mg, 〇·152 mmol) to the reaction and stir for another 20 minutes. The mixture was then treated with NaBH(OAc)3 (32 mg, EtOAc 152 m.) and stirred for 1 hour. The solvent is then removed and the crude residue is purified on silica gel eluting with 0-15% 2M NH3: MeOH / DCM eluting with column chromatography eluting with the desired product to afford the title compound. 1103⁄4 grams, 75%).

This compound was converted to the HCl salt by dissolving the free base in MeOH and treating with 4 MH. Then it was evaporated. Example 27 5-(2-{4-[(2,3_Dihydro[M]dioxo[2,3_φpyridinylmethyl)amino]-1-hexahydropyridyl) }ethyl)_6_keto- 5,6-dihydro-; 1,5-naphthyridin-3-carbonitrile

111 200817417 (a) 4-Bromo-6-(decyloxy)-l,5-naphthyridine-3-carboxylic acid oxime ester • In 4-di-6-(decyloxy)_1,5-naphthalene bite- 3-decanoic acid (see synthesis)

W02004058144, Example 53(d)) (8.28 g, 29.3 mmol) in a solution of DMF (200 mL), K2C 〇3 (5.934 g, 43 mmol) and 曱5 iodine (2.18 mL, 35 mmoles and the reaction was stirred at room temperature for 72 hours. The reaction was partitioned between EtOAc and water. The organic layer was separated and washed twice with water. The aqueous layer was extracted again with EtOAc and this EtOAc layer was separated and washed with water. The combined organic layers were dried <RTI ID=0.0> 10 MS (ES+) m/z 297/299 (MH+). (b) Ethyl 6-(decyloxy)-l,5-naphthyridine-3-carboxylate in methyl 4-bromo-6-(decyloxy)-1,5-naphthyridine-3-carboxylate (ι·67 g, 5.64 mmol) and NaHC〇3 (0.84 g, 10 mmol) in a mixture of Me〇H (20 mL) 15 and 1,4-dioxane (15 mL) 〇〇/0 pd/c (0.75 g) and the mixture was stirred at room temperature under 1 atm of hydrogen for 3 hours. The reaction mixture was then filtered through a pad of celite and washed with EtOH. The filtrate was evaporated and stirred in 50 mL EtOAc EtOAc. 20 MS (ES+) m/z 219 (MH+) 〇(c) 6-fluorenyl-5,6-diaza-1,5-nadine-3-decanoate 将6-(methoxy Mixture of methyl 1-(5-naphthyridin-3-carboxylate) (145 g, 6.65 mmol) in 30% HBr (40 mL)EtOAc.

112 200817417 Evaporated after 18 hours and dried under vacuum. The solid was washed with EtOAc (20%). MS (ES+) m/z 205 (MH+). 5 (6) &amp; Keto-5-(2-propenyl small)-5,6-diindole-1,5-naphthalene-3-carboxylic acid methyl ester 6_keto_5,6_dioxin , a solution of methyl 5-naphthyridin-3-carboxylate (1.963 g, 5.36 mmol) in DMF (32 mL) eluting with K2C03 (2.95 g, 21.3 mmol). Propyl iodine (〇535 宅升' 5.88 house Moule) treatment 'heated at 75 °C for 7 hours, then add 10 allyl iodine (0·15 ml, 〇·89 mmol) and stir the reaction 2 hour. The reaction was treated with EtOAc and washed three times with water. The combined aqueous layers were again swept with EtOAc and washed twice with water. The combined organic layers were dried <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 15 MS (ES+) m/z 245 (ΜΗ+). (e) yl-5-(2-propen-1-yl)-5,6-dihydro-1,5-naphthalene π--3-t-acid in-keto-5-(2-propene-1- Methyl-5,6-diindole-1,5-naphthyridin-3-carboxylate (0.809 g, 3.32 mmol) in 1,4-dioxane (1 mL) and water ( 2 Torr NaOH (2 ml) was added to a solution of 5 ml 20 liters and the reaction was stirred at room temperature for 2 hours. Then adjust the pH of the mixture to 2_3 with 2M HC1 and use

Extract with EtOAc three times. The combined organic layers were dried <RTI ID=0.0> MS (ES+) m/z 231 (MH+). 113 200817417 (f) 6-keto-5-(2-propen-1-yl)_5,6-dihydro-indole, naphthyridine_3_decylamine. 6-keto i (2-propene- 1-Base)_5,6-Dihydro-1,5-naphthyridine-3-carboxylic acid • (〇·689 g, 3 mmol) cooled in a suspension of DCM (20 mL) and DMF (2 drops) The mixture was treated with chloroform (〇·3〇6 mg, 3·5 mmol), and allowed to warm to room temperature and stirred at room temperature for 18 hours. The mixture was evaporated to a small volume and treated with aqueous ammonia. EtOAc (EtOAc) MS (ES+) m/z 230 (ΜΗ+). Ίο (g) 6-keto-5-(2•propen-1-yl)-5,6-dihydro-1,5-naphthalene-3-carbonitrile in 6-keto-5-(2-propene- 1_yl)-5,6-dihydro-1,5-naphthyridin-3-indoleamine (0.69 g, 3 mmol) in DCM (30 mL). Triethylamine (1.0 ml, 7.2 mmol) and trifluoromethanesulfonic anhydride (0.605 ml, 3.6 mmol) were added to the hydrazine suspension. The reaction was allowed to warm to room temperature and stirred at room temperature for 1 min. . It was treated four times in the next 6 hours with triethylamine (1 mL, 7.2 mmol) and trifluoromethylene anhydride (0.605 mL, 3.6 mmol) to drive the reaction to almost complete. The reaction mixture was treated with aq. The combined organic layers were dried <RTI ID=0.0> MS (ES+) m/z 212 (MH+) 〇(1〇6-keto-5-(2-ketoethyl)-5,6-dihydro-1,5-naphthalene-3-moon blue ( Mercapto hemiacetal 5-[2-hydroxy-2-(decyloxy)ethyl]-6-keto-5,6-dihydro-1,5-naphthyridine 114 200817417 -3- stake) ^ will 6-keto- 5-(2-propenyl)-5,6-dihydro-I,5-naphthalene. _3·nitrile (0·465 mg, 2·2 〇 mmol) at 1, 夂The solution in dioxane (22 ml) and water (4.4 ml) was cooled to 〇 ° C and used sodium periodate (1·10 g, 514 5 halo) and 0 〇 4 (4% in water, The reaction was allowed to warm to rt. EtOAc (EtOAc m. The product, the majority of which is slightly impure, is a thiol hemite (〇'·5 gram, 93%). ίο MS (ES+) m/z 214 (ΜΗ+), 246 (methyl hemiacetal oxime +) (1) {1_[2-(7-Cyano-2-keto-1,5-naphthoquinone-1(2H)-yl)ethyl]_4·hexa-pyridinyl}amino decanoic acid 1, 1-dimethylethyl ester 6-keto-5,6-dihydro-keto-5-(2-g-ylethyl)_5,6-dihydro-15-1,5-naphthyridinonitrile ( 〇·5 gram, 2.0 a mixture of 5 mM), 4 _ 3 butyloxycarbonylamine hexamethylene oxime (B. 8 gram '4.00 house Moule) and 3A molecular sieve in DCM (4.5 mL) and MeOH (4.5 mL) Stir at room temperature for 4 hours. Then the mixture was treated with NaBH(OAc)3 (0·94 g, 4.43 mmol), stirred at room temperature for 18 hours, filtered through a layer of celite, evaporated, and dissolved. Washed with 1% MeOH/DCM and sat. aq. EtOAc (aq.) Purification by column chromatography gave the desired compound (0.411 g, 50%)

115 200817417 MS (ES+) m/z 398 (MH+). (j) 5-[2-(4-Amino-hexahydropyridyl)ethyl]-6-keto-5,6-dihydro], 5-naphthyl-3-bron 5 in {1-[ 2-(7-Cyano-2-keto-1,5-naphthyridin-1(2H)-yl)ethyl]donghexahydropyridyl}amino phthalic acid U-didecylethyl ester (0.411 g, To a solution of DCM (16 mL), EtOAc (EtOAc) The reaction was evaporated, dissolved in MeOH and passed through an Amberlyst A.s. The desired product was purified by column chromatography eluting with EtOAc EtOAc EtOAc EtOAc. (ES+) m/z 298 (MH+). 15 (k) The title compound will be 5-[2-(4-amino-hexanitrox-butyryl)ethyl]-6-mercapto-5,6-dichloro-1,5-naphthyridin-3-ylcarbonitrile (44 mg, 0.148 mmol) and 2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde (for synthesis see W02004058144, Example 2(c) or W003/ 087098, Example 19(d)) (24.5 mg, 0.148 mmol) 2 〇 and 3A molecular sieves in chloroform (1 ml) and MeOH (1 ml) were heated at 65 ° C for 5 h, cooled and added NaBH (OAc) ) 3 (63 mg, 〇 · 30 mmol). The reaction was stirred at room temperature for 18 h, filtered over Celite and evaporated. The residue was treated with aq. aq. NaHC03 and a mixture of 4:1 DCM:MeOH. Mix the water layer with 4:1 DCM:Me〇H

116 200817417 The extract was extracted twice and the combined organic layers were dried, and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut elut lU NMR (400MHz) 6(CDC13) 1.35-1.58 (2H? m), 1.85-1.95 (2H? m), 2.12-2.22 (2H, m), 2.45-2.56 (1H, m), 2.62-2.68 ( 2H, t), 2·90-2·96 (2H, m), 3.80 (2H, s), 4.26-4.35 (m, 6H), 6·68 (1H, s), 7·05 (1H, d , J 10Hz), 7.94 (1H, d, J 10Hz), 8.10 (2H, s), 8.72 (1H, s). After dissolving in DCM/MeOH and adding 1M The substance is converted to the dihydrochloride salt. MS is a free base. Οο Add 1 equivalent of benzoic acid to 5-(2-{4-[(2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylfluorenyl)amine 'n-hexahydropyridinyl}ethyl)-6-indenyl-5,6-di-rham-1,5-naphthyl-3-in the solution . 15 Example 28 8-(2-{4-[(2,3_Dihydro[1,4]dioxo][2,3-c]pyridin-7-ylmethyl)amino]-1-hexahydro Pyridyl}ethyl)-7-keto-7,8-dihydro-1,8-naphthyridin-2-carbonitrile hydrochloride

(a) Dimethyl fluorescein 7-indole-yl-8-(2-propan-1 -yl)-7,8-di-rho-1,8-na

117 200817417 pyridine-2-ester in 1-(2-propenyl)-l,8-naphthyridin-2,7(111,811)-dione (1.172 g '5.80 mol) in DMF (100 ml) Here. To the solution of hydrazine, sodium hydroxide (60% dispersion in oil, 278 mg, 6.96 mmol) was added and the reaction was allowed to warm to room temperature and stirred at room temperature for 5 hours. Then, N-phenyldifluoromethaneimine (2.48 g, 6.96 mmol) was added and the reaction was stirred at room temperature for 1 hour, then water (5 liters) was added and evaporated. The residue was taken up in water (5 <RTI ID=0.0> The combined organic layers were dried <RTI ID=0.0> MS (ES+) m/z 335 (ΜΗ+) 〇(b) 7-keto-8-(2-propenyl)-7,8-dihydro-l,8-naphthyridin-2-carbonitrile in three Fluoromethyllithoic acid 7-keto-8-(2-propen-1-yl)-7,8-dihydro-1,8-naphthyridin-2-ester (697 mg, 2.087 mmol) DMF (10 ml) degassed solution was added with Zn(CN) 2 (147 mg, 1.252 mmol), Pd2 (dba) 3 (48 mg, 〇·〇 52 mmol) and ι, ι, _ double (Diphenylphosphino) ferrocene (58 mg '0.104 mmol). The reaction was then carried out at 5 Torr. After heating for 1 hour, heat at 70 ° C for 1 hour and heat at 10 (rc for 1 hour. Add more Zn(CN) 2 (147 mg, 1.252 mmol), Pd2 (dba) 3 (48 mg, 0.052) Millol) and i,r_bis(diphenylphosphino)ferrocene (58 mg, 0.104 mmol) and heat the reaction for 1 hour at 1 Torr. The reaction was then cooled and water (200 mL) The reaction was then extracted with dcM (3×200 liters). The combined organic layers were dried, evaporated and evaporated.

118 200817417 The rubber was eluted with a gradient of ethyl acetate / hexane to give the desired compound (374 mg, 85%). MS (ES+) m/z 212 (MH+). 5 (c) 7-keto-based (2-ketoethyl)-7,8-dihydro-naphthyridin-2-ylcarbonitrile 7-keto-8-(2-propen-1-yl)-7, 8-Diindole-1,8-naphthyridin-2-carbonitrile (374 mg, 1.773 mmol) was dissolved in dioxane (10 mL) and water (1 mL). Sodium periodate (948 mg, 4.433 mmol) and osmium tetroxide (0.38 ml of a 4% aqueous solution) were added in that order. The mixture was stirred at room temperature for 10 hours, water (4 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction was concentrated to ca. 50 mL and extracted with 20% MeOH / DCM (3x100). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give &lt;RTIgt;&lt;&gt;&gt;&gt; 7-keto-8-(2-ketoethyl)-7,8-dihydroyi[naphthyridin-2-carbonitrile Impure brown solid (423 mg, 112%). 15 MS (ES+) m/z 214 (MH+) 〇(d) {l-[2-(7-Cyano-2-keto-1,8-naphthalene-1(2H)-yl)ethyl] Hexahydropi pi to 17 疋 }} (2,3-one gas [1,4] dioxos [2,3-ten _7_yl fluorenyl) amide phthalic acid 1,1-didecyl Ester 20 will be 7-keto ketoethyl)-7,8-diindole-1,8-naphthyridin-2-carbonitrile (329 mg '1·545 mmol) and (2,3-dihydro[ 1,4] Dioxo and [2,3_c]a ratio. D-7-ylmethyl)4-di-dibutyloxy-green hexachloroamine ratio (synthesis see W02004/058144 Example 99(h) (539 mg '1.545 mM) mixture in chloroform (15 ml) and MeOH (1 ml) was stirred for 2 hours and then added 119 (3 200817417 into NaBH(OAc)3 (982 house gram ' 4.635 house Moer) After the reaction was stirred for 5 hours, aq. EtOAc EtOAc EtOAc (EtOAc m. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) The title compound 1〇 will be {1-[2-(7-cyano) -2-keto-1,8-naphthyridinyl-1(2H)-yl)ethyl]_4_hexafluoridyl}(2,3-dihydro[1,4]dioxan[2,3- c]pyridine-7-ylindenyl)

A solution of 1,1-dimethylethylamine citrate (600 mg, 1.100 mmol) in DCM (10 mL) in EtOAc (1 mL) (1 mL) After stirring for 5 hours, it was warmed to room temperature and then stirred at room temperature for 15 hr. The reaction was then extracted with 20% MeOH (3 x 200 mL) in DCM. The combined organic layers were dried <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS (ES+) m/z 447 (ΜΗ4). 20 !H NMR (250MHz) 6(CDC13) L22-1.41 (2H, m), 1.81-1.92 (2H, m), 2.11-2.20 (2H5 m) 2.42- 2.58 (1H, m)5 2.60-2.72 (2H51)? 2.59-3.12 (2H? m)5 3.78 (2H? m), 4.25-4.62 (4H m)

4·62 (2H, t), 6.81 (1H, s), 6.73 (1H, d, J 10Hz), 7.51 (1H, d, J 8Hz), 7.66 (1H, d, J 7.97 (lH) , d, J 8 Hz), 8.08 (1H, s)· This compound was converted into 4 NMR by adding the obtained free base in 1:1 DCM:MeOH and adding 1 equivalent of 4MHC1 in 1,4-dioxane.

120 200817417 HC1 salt. It is then evaporated to dryness. Example 29 5-(2-{4-[(6,7-Dihydro[1,4]dioxo[2,3-c]indole-3-ylmethyl)amino]-1-6 Nitrogen 11 is more than butyl}ethylmercapto-5,6-diaza-1,5-nabite 5 -3-carbonitrile

The title compound was obtained from the 5-[2-(4-amino-1 -hexanitropyranium sigma)ethyl]-6-mercapto-5,6-di-rham-1 via the general procedure of Example 27(k). , 5-nazetin-3-gues (20 mg) and 6,7-dihydro[1,4]dioxo[2,3-c]indole-3-aldehyde (11.2 mg) were prepared. The free base of the title compound (16 mg, 53%). MS (ES+) m/z 448 (MH+). NMR (400MHz) 5 (CDC13) 1.31-1.45 (2H, m), 1.85-1.95 (2H? m), 2.11-2.22 (2H, m), 2.51-2.60 ( 1H, m)5 2.65 (2H, t), 2.88-2.98 (2H, m), 4.00 (2H, s)? 4.31-4.42 (4H? m), 4.52 (2H, t), 7.04 (2H, m) , 7.92 (1H, d, J 10Hz), 8.12 (1H, s), 8.72 (1H, s). The material was converted to two by dissolving in DCM:MeOH and adding 1M Hydrochloride. MS is a free base. Example 30 5-(2-{4-[(6,7-Dihydro[1,4]dioxo][2,3-c]indole-3-ylindenyl)amino]-1 -6 Nitrogen 11 than bityl}ethyl)-6 - S synthyl-5,6-di-rho-1,5-naphthyridin-3-carbonitrile dihydrochloride

121 200817417

The title compound was obtained from 5-[2-(4-amino-1-hexanitro)ethyl]-6-mercapto-5,6-diaza-1,5- via the general procedure of Example 27 (k). Preparation of tea salt -3- wax (2 〇 mg) and 6,7-dihydro[1,4]dioxo[2,3-c]indole-3-aldehyde (13.3 mg) to give the title compound Free base (17 mg, 45%). MS (ES+) m/z 464 (MH+). lU NMR (400MHz) 5(CDC13) 1.31-1.46 (2H5 m), 1.85-L95 (2H5 m), 2.12-2.22 (2H? m), 2.49-2.51 ( 1H, m)5 2.57 (2H, t)? 2.88-2.95 (2H, m)5 3.23 (2H? t), 3.98 (2H5 s)? 4.30 (2H, t)? 4·65 (2H,t)5 7·04 (1H,d,J 10Hz), 7.34 (1H, s), 7.93 (1H, d, J lOHz), 8.13 (1H, s), 8.72 (1H, s). By dissolving in DCM: The material was converted to the dihydrochloride salt by MeOH and 1M EtOAc/EtOAc. MS is a free base. Example 31 7-Bromo-l-(2-{4-[(2,3-dioxin[1,4]dioxos[2,3-c])-pyridin-7-ylindenyl) Amino ]-1-hexahydropyridyl}ethyl)pyrido[2,3-b]pyrrolidone decanoate

122 200817417 (a) 7-Bromo-pyrido[2,3-b]pyrazine-2(1H)-one 5-bromo-2,3-pyridinediamine (465 mg, 2.473 mmol) and hydroxy A solution of the acetic acid monohydrate (284 mg, 3.09 mmol) in water (5 ml) was stirred at room temperature for 3 hr and then filtered and filtered and evaporated. The ether (20 mL) was washed and dried in vacuo to give a pale-brown solid (3. MS (ES+) m/z 226/228 (MH+) 〇(b) 7-bromopropen-1-yl)pyrido[2,3-b]pyrazine-2(1H)-one! - Pyrido[2,3-b]pyrazine-2(1H)-one (368 mg, 1.628 mmol) was suspended in anhydrous DMF (10 mL) at rt and rt. Treatment with KWO3 (741 mg, 5.372 mmol) and allyl iodide (331 μL, 3.581 mmol). Then it was stirred for 2 hours and then water (100 ml) was added. The mixture was extracted with DCM (3×200 mL). 15 DCM extracts were combined, dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The desired product was obtained as a pale brown solid (278 mg, 64%). MS (ES+) m/z 266/268 (MH+) 〇20 (c) (7_bromo-2-ketopyridinium[2,3-7]pyrazine-1(2H)-yl)acetaldehyde (hydrate) ) 7_&gt; Odor-1-(2-propenyl-1-yl)π ratio σ and [2,3-b]吼4_2(ih)-one (278 mg, 1.045 mmol) dissolved in 丨/二Simmer (five) ml) and water (10 ml). Sodium periodate (559 mg, 2.613 mmol) was added and, with 123 200817417, osmium tetroxide (0.22 ml of a 4% aqueous solution) was added. The mixture was stirred at room temperature for 1 hour, 40 ml of water was added and the mixture was stirred for an additional hour. The reaction was concentrated to ca. 50 mL and extracted with 20% MeOH / DCM @ EtOAc. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give (7-di- -2- yl pyrido[2,3-b] pyridin-i(2H)-yl An impure brown oil (423 mg, 107%) of acetaldehyde (mostly hydrated). MS (ES+) m/z 268/270 (MH+), 286/288 ( hydrate H+). 10 (6) keto-acridino[2,3-b]pyrazine-4(3H)-yl)ethyl]-4-hexahydropyridyl}(2,3-dihydro[丨,4]dioxo g and [2,3_c]pyridine_7_ylmethyl)carbamic acid 1,1-dimethylethyl ester (7-bromo-ketopyridinium [2,3-7]pyrazine-1 (2 deduction_base Acetaldehyde (a mixture of hydrate and hydrate) (299 mg, 1.116 mmol) and (2,3-15 bis[1,4]dioxo[2,3-c]pyridine-7- 4-merbutoxycarbonylamino hexahydropyridine (synthesis see W02004/058144 Example 99(h)) (389 mg ' 1.116 mmol) in chloroform (15 mL) and MeOH (1 mL) After stirring for 2 hours, NaBH(OAc)3 (709 mg, 3.48 mmol) was added. The reaction was stirred for 0.5 h then saturated aqueous NaHCO3 (20 mL) was added. The reaction was then applied to 20% in DCM. Extraction with MeOH (3.times.2 mL). The combined organic layer was dried, evaporated and evaporated eluting eluting (289 mg, 44%) MS (ES+) m/z 601/603 (MH+).

124 200817417 (e) The title compound will be {1-[2·(6-bromo-3-keto-pyrido[2,3_b]pyrazine-4(3H)-yl)ethyl]-4-hexahydropyridine 1,2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylmethyl)aminodecanoic acid 1,1-dimethylethyl ester (900 mg, To a solution of chloroform (5 ml) and MeOH (5 ml), 4 M.sub.1 (5 mL) After a few hours of evaporation, it was taken with aq. The reaction was then extracted with 2% MeOH (3 x 200 mL) in DCM. The combined organic layers were dried, evaporated and evaporated eluting elut eluting eluting eluting Mg, 81%).

15 Example 32 1-(2-{4-[(2,3-Dihydro[1,4]dioxo[2,3-(:]pyridine-/7-ylindenyl)amino]] Hydrogen 11 than bite} ethyl)-5,7-difluoro-2(111)-«|^林_ dicaprate

125 200817417 &amp;) (3,5-difluorophenyl)-3,3-bis(methoxy)propanamide 3,5-difluoroaniline (5 g, 38.8 mmol), 3_ A solution of decyl decyl acrylate (4.6 ml, 42.7 mmol) and sodium methoxide solution (25% in Me 〇 H, 12 mL) in toluene (50 mL) under argon atmosphere was stirred at 7 rc for 3 h. Add more sodium methoxide solution (25 〇 / 〇 in Me0H, 6 mL) and stir the reaction overnight. Add sodium methoxide solution (25% in MeOH, 12 liters) and 3-methoxy methacrylate (5) ML, 46.4 mmoles and heat the reaction for 5 hours at 70 C. Add MeOH and reduce the volume of toluene to about 10 ml. Acidify the residue with a saturated solution of ammonium chloride, solid ammonium chloride and 5N HCl. To pH 7. The aqueous layer was taken up with ethyl acetate (2×5 mL). The combined organic layers were dried, evaporated and evaporated. The petroleum ether elution was purified by chromatography to give the desired compound (12 g, 126%). 2.64 (2 Η, d), 3,7 (6H, s), 4.78 (2H, 6.90 〇H, m)5 7.30(2H) m), (b) 5,7-difluoro-2(1H)-pyridone in The temperature is maintained at 10-20. (: A 70% H2S〇4 solution was prepared by adding cooled h2S04 (70 ml) to cold water (30 ml). The acid was then slowly added to the water while maintaining the temperature between 10-20 °C. The powder N-(3,5-monofluorophenyl)-3,3-bis(decyloxy)propionic acid amine (12 g, 49 mmol) was added to the cooled solution over 1 hour, then at 5 〇c Mix for 15 hours. Carefully add the ice-water mixture (100 ml), then add water (4 ml). Stir the mixture for 5 hours and filter the formed solids at 4 〇. 〇的真126 200817417 空Drying in the oven over the weekend. The solid was still wet, so it was dried in a dry box with p2o5 to give the desired compound (12 g, 136%). MS (ES+) m/z 182 (MH+) 〇5 ( c) 5,7-Difluoro-1-(2•propen-1-yl)_2(1H)-fluorenone 5,7-difluoro-2(1H)-fluorenone (640 mg, 3.54 m) The suspension of DMF (15 ml) in argon atmosphere and 〇 ° 用 was treated with sodium hydride (60% in mineral oil, 312 mg, 7.8 mmol) and allowed to warm to room temperature. After 0. 5 hours of warming, allyl iodide (0.72 ml, 7. 8 mM 1 )). After 5 hours, sodium hydride (60% in mineral oil, 200 mg, 5 house Mo) and propyl propyl moth (〇·35 ml, 3.8 mmol) were added. Water (15 ml) was added and the aqueous layer was extracted with EtOAc EtOAc EtOAc. 350 mg of the desired compound (45%). 15 MS (ES+) m/z 222 (MH+) 〇(d) (5,7-difluoro-2-keto-1(2Η)-4咁)) Aldehyde 5,7-difluoro-1-(2-propen-1-yl)-2(1Η)-fluorenone (1.65 g, 7.46 mmol) dissolved in a 3-necked flask in dcm (80 mL) And cooled to 20 to _78 ° C. Then it was stirred under 〇 3 for 1.5 hours, then argon was passed through the reaction to remove excess hydrazine 3, and then the reaction was quenched with DMS (2 mL, 29.84 mmol) Then, it was left to warm to room temperature and stirred overnight. The solvent was evaporated to give an impure product (2.1 g). 127 200817417 (e) {l-[2-(5,7-difluoro_2_) Keto-1(2H)-indenyl)ethyl]_4_hexahydropyridyl, sigma}mino 1,1-dimercaptoacetate (5, 7--Fluoro-2-keto-1 (211) _. Quesyl) acetic acid (2.1 g, 9.4 mmol) and heart hexahydropyridinylcarbamate U-dimethylethyl ester (2.82 g) , 5,1 耄mol) dissolved in a 1:1 mixture of chloroform and MeOH (6 mL: 6 liters) and stirred at room temperature for 1 hour. It was then treated with NaBH(〇Ac)3 (8.92 g, 42.3 mmol) and stirred for an additional hour. Add more u-dimethylethyl 4-hexahydropyridylcarbamate (47 〇, mg, 2.35 mmol) and stir the reaction under the same conditions for 2 , minutes, then use ίο NaBH(OAc)3 (1.98 g, 9.4 mmol) was treated and stirred for a further 25 min. More 1,6-hydrogen σ than 1,1 -didecylethyl carbazide (470 mg, 2·35 Torr) was added and the reaction was stirred for 20 minutes. More NaBH(OAc)3 (500 mg, 2.38 mmol) was then added to the reaction and the mixture was stirred until the temperature was disturbed. The solvent was then removed and the crude residue was purified eluting elut elut elut elut elut eluting MS (ES+) m/z 408 (MH+). (1) 1·[2-(4-Amino-1-hexahydropyridyl)ethyl]_5,7-difluoro_2(1Η&gt;喳咁20 _ will be {1-[2-(5,7-difluoro) -2-keto-1(2Η)_ porphyrinyl)ethyl]_4•hexahydroport oxime oxime ethyl phthalate 1,1-^-mercaptoethyl ester (2 g, 4.9 mmol) Dissolved in chloroform (20 ml) and added to 々Μ HC1 (20 ml) in 1,4-bis., which was stirred at room temperature for 1 hour. Then the salt was dissolved in Me〇H and 128 200817417 Remove all solvent. Re-dissolve the residue in MeOH and stir only with amberlyst ion exchange tree until neutral, filter the resin and remove the solvent. Mix the crude residue on silica gel with 0-20% 2M NH^MeOH /DCM gradient elution was purified by column chromatography to give the desired product ( 970 mg, 65%). MS (ES+) m/z 308 (MH+) 〇 (g) title compound ίο 15 20 [2-(4-Amino-1-hexahydropyridinyl)ethyl]_5,7-difluoro-2(1Η)”quinacone (150 mg, 0.49 mmol) and 2,3·dihydrogen [1,4]dioxo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, Example 2(c) or W003/087098, Example 19(d)) (80 mg, 0.49 mmol) Dissolved in chlorine It was mixed with a 5:1 mixture of MeOH (5 mL: 1 mL) and stirred at room temperature for 1 hour, then treated with NaBH(OAc)3 (310 mg, 1.47 mmol) and under the same conditions Stir the mixture for another 2 hours. Then remove the solvent from the reaction and purify the crude residue on a silica gel with a gradient of 〇2〇% 2ΜNH^MeOH/DCM. Purify by column chromatography. The title compound (20 mg, 89%) was obtained after EtOAc. m/z 457 (ΜΗ4). δΗ MeOD, (400MHz) 1.74 (m, 2H), 2.17 (d, 2H), 2.37 (m? 2H), 2.83 (t, 2H), 3.19 (mm ! η5&quot;3 *40 (m? 2HX 4,21 (dj 2HX 4*35(m^2H^ 438 ^ 4A9 ^ 2H)&gt; 6.66 (d H), 6.96-7.02 (m, 2H), 7·29 (d, 1H ), 8.05 (d, 1H), 8.13 (s, 1H), 8·28 (bs, 2H)· ' Example 33 l-(2-{4-[(6,7-Dihydro[1,4] Oxygen E and [2,3-c] ploughing each 129 200817417 methyl)amino]-1-hexanitrogen to 17-denier}ethyl)-5,7-diox-2(1 H)-u Kudzu

The title compound is 1-[2-(4-ίοamino-1-hexahydropyridyl)ethyl]-5,7-difluoro-2(1H)-oxime via the general procedure of Example 32 (g). Prepared by anthrone and 6,7-dihydro[1,4]dioxo[2,3-c]indole-3-aldehyde, the obtained product was directly dibromide (34 mg, 15%). δΗ MeOD, (400MHz) 1.75 (m, 2H), 2.19 (d, 2H), 2.45 (t, 2H), 2·90 (t, 2H), 3·19 (m, 1H), 3.25-3.4 (m , 2H), 4·36 (s, 2H), 4.45 — 4.52 (m, 4H), 4.59 (m, 2H), 6.67 (d, 1H), 7.00 (m, 1H), 7.25 (s, 1H), 7·30 (d,1H), 8.05 (d,1H),8·28 (bs,2H). i5 MS (ES+) m/z458 (MH4). Example 34 6-[({l-[2-( 7-fluoro-2-keto-1(2H)-indenyl)ethyl]anthracene hydroxypyridyl}amino) fluorenyl]-2H-pyrido[3,2-b][l,4 Thiacin-3(4H)-ketone dihydrochloride

N, /〇20 (a) 7-fluoro-2(1H)-fluorenone (and 6-fluoro-2(1H)-fluorenone) 130 200817417 4-fluoro-1,2-stupid A mixture of amine (44·9 g) and 5〇0/〇2 in a stupid with ethyl acetate (74.53 liter) in ethanol (1 liter) was heated under reflux for 3.5 hours in ice. After cooling, the obtained solid was collected and washed twice with ethanol. After drying under vacuum at 40 C, a solid (51·4 g, 88%) was obtained, which was 7-fluoro-2(1Η)-fluorenone and 6-fluoro a 2:2 mixture of -2(1Η)_porphyrinone. MS (+ve ion electron spray) m/z 165 (ΜΗ+). (b) 7-fluoro small (2-propenyl-1-yl)-2(1Η)-fluorenone will be 7-fluoro-2(1Η)-fluorenone in anhydrous DMF (250 ml) and a 1:2 mixture of 6-fluoro-2(1Η)-nonyl ketone (2 g, 0122 mol) and anhydrous potassium carbonate (50.5 g, 0.38 mol) with allyl iodide (12.3 ml, 〇· Treatment with 134 moles and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness. EtOAc m. Apply 〇4〇0/ to the silicone. The ethyl acetate-hexyl acetate elution was purified twice by chromatography. The earlier eluted fraction was found to be small (2-propenyl)-2-(ih)-4 linoleone (4.7 g) [something containing the isomer 6_fluoro- Structure (6·7 gram. MS (+ve ion electron spray) m/z 2〇5 (ΜΗ+). (c) (7-fluoro-2-keto-l(2H)-喳 喳Acetaldehyde will be 7-fluoro small (2-propen-1-yl)-2(1Η)" quetiazone (2.4 g, 11.77 mmol) in 1,4-dioxane (14 ml) The solution in water (25 ml) was treated with tetrazoic acid (4% solution in water, iv 4·5 ml) and sodium periodate (1·9 g) 131 200817417 and the mixture was stirred at room temperature for 1.5 hours. The mixture was evaporated to dryness on a silica gel and eluted on a 300 g silica gel column with 1:1 ethyl acetate-hexane and then ethyl acetate. The earlier eluted fraction was obtained (7_ Fluor-2-one = _1 (2Η)-fluorenyl) acetaldehyde, which was developed with diethyl ether/dcm 3:1 to ~2 5 product (1·56 g). The garment was passed to MS (+ve ion electron) Spray) m/z 207 (ΜΗ+). (d) {1-[2-(7-Fluoro-2-keto-l(2H)-carbolinyl)ethyl]_4_hexahydropyridyl } 1,1-dimethylethyl carbamic acid 10 (7-fluoro-2-keto 4(211)- Molecular phenyl) acetaldehyde (2·48 g, 12 mmol) and u hexahydropyridyl carbamic acid u-dimethylethyl ester (3·61 g, 18 mmol) in MeOH (10 mL) The solution in chloroform (2 mL) was stirred at room temperature overnight, sodium triacetoxyborohydride (7. 6 g, 36 mmol) was added and the mixture was stirred at room temperature overnight. Water and sodium carbonate were added. The solution was extracted with DCM (3 χ), dried (Na2SO4), evaporated and evaporated eluting with EtOAc EtOAc EtOAc EtOAc MS (+ve iontophoresis) m/z 391 (MH+). (e) 1_[2-(4-Amino-;[_hexahydropyridinyl)ethyl]_7_fluoro-2(111) _ 喳 ^ 咁 ketone 20 dihydrochloride, will be {1_[2-(7-fluoro_2-keto-1 (2Η)_, kurinlin) ethyl]_4_hexahydropyridyl, yl} A solution of U-dimercaptoethyl urate (4 g) in anhydrous Me〇H (15 I liter) and vaginal water DCM (30 ml) used in 4 1 in 1,4_二σ垸Treatment with chloric acid (3 mL) and stirring at rt for 3 h. evaporating 132 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; However, it was filtered, and washed with cold MeOH and diethyl ether to give the product (3 〇5 g1. MS (+ve ion electron spray) m/z 291 (MH+). 5 (1) The title compound is 1_[2-(4-amino+hexafluoridyl)ethyl]_7_qi-2(1H)-porphyrinone dihydrochloride (6 mg, 〇166 mmol) And 3酉Iso-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiazine_6-aldehyde (synthesis W02004058144, Example 7(d)) (32 mg A solution of 10 MeOH (3 mL), chloroform (3 mL) and triethylamine (6 mL) was stirred at room temperature for one hour and then at 70 ° C overnight. It was cooled and added with sodium tris(sulfonate hydride) (0. 106 g, 〇·5 mmol) and mixed to / sub-stirred: mix for 5 hours. Add more 3-keto-3,4-dihydrogen to bite [3,2-b][l,4]thratic-6-aldehyde (4 mg) and mix the mixture at room temperature for 3 small When I5. Sodium triethoxysilane borohydride (53 mg) was added and the mixture was stirred at room temperature for 72 hours. Water and sodium carbonate solution were added and the mixture was extracted with EtOAc (EtOAc) (EtOAc) Test. 2 〇 MS (+ve ion electron spray) m/z 469 (MH+). δΗ (CDC13)? (400 MHz) 1.40-1.53 (2H, m), 1.92 (2H, br.d), 2.20 (2H, t), 2.55 (1H, m), 2·65·2·70 (2H ,m),2·98 (2H,m), 3.49 (2H,s),3·83 (2H,s),4·30 (2H,m),6·98 (1H,d), 7·06 (1H,m), 7.12 (1H,m),7·58 (1H,d),7·86 (1H,m), 8.20 (1H,s),8·30 (1H,br.s)· Evaporated after dissolving in DCM/MeOH and adding 1M EtOAc / ether

133 200817417 To dry, convert this material to the dihydrochloride salt. MS is a free base. Example 35 1-(2-{4-[(2,3-Dioxa[1,4]dioxo[2,3-c])-pyridin-7-ylmethyl)amino]-1- Hexanitrox 0 base} ethyl)-7-gas 吼 弁 弁 [2,3-b] pyridin-2 (1Η)-ketone hydrochloride

(a) 5-Actyl-3-stone succinyl-2-sigmine octazone 2-bromo-5-fluoro-3-nitropyridine (1.176 g, 5.321 mmol) in 2 ΜΝΗ 3 (20 mL) in MeOH The solution was sealed in a heating pot and heated at 75 ° C for 6 hours and then heated at 90 ° C for 18 hours. The reaction mixture was cooled with EtOAc EtOAc m. The combined organic layers were dried and the solvent removed. The residue was purified by chromatography eluting eluting elut elut elut elut elut elut elut elut elut MS (ES+) m/z 158 (MH+). (b) 5-Fluoro-2,3-pyridyldiamine 5-Fluoro-3-nitro-2-prolinylamine (561 mg, 3.573 mmol)

134 200817417 A suspension of ethanol (100 ml) was treated with 10% Pd/c (100 mg) and the mixture was stirred at room temperature under 1 atmosphere of hydrogen for 5 hours. The reaction mixture was then filtered through a pad of celite and washed with EtOH (500 mL). The filtrate was evaporated to give the desired product as a white solid (435 <RTIgt; MS (ES+) m/z 128 (MH+) 〇(c) 7-fluoropyrido[2,3-b]pyrazine-2(1H)-one and 7-fluoropyrido[2,3-b]pyridin Plough-3(4H)-ketone 10 5-Fluoro-2,3-pyridinediamine (435 mg, 3.425 mmol) and dihydroxyacetic acid monohydrate (410 mg, 4.453 mmol) in water (30 The solution in cc) was stirred at room temperature for 18 hours. The reaction was then concentrated to ca. 5 mL and EtOAc (EtOAc:EtOAc) MS (ES+) m/z 166 (MH+). The isomer 7-fluoropyrido[2,3-b]indole-3(4H)-one was obtained as an impure brown solid by evaporation of the organic material used in the development. 20 (d) Fluorine + (1 propen-1-yl)pyrido[2,3-b]pyrrolidone 7-fluoropyrido[2,3-b]pyrazine-2(1H)-one (306) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 2.41 millimoles). Add water after stirring for 1 hour

135 200817417 (100 ml). The mixture was extracted with DCM (2×200 mL) EtOAc EtOAc The combined organic extracts were dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (177 mg, 47%). MS (ES+) m/z 206 (MH+) 〇(e) (7_Fluoro-2 ketopyrido[2,3_b]pyrylene)acetaldehyde (methyl hemite) 10 7-fluoro- Bu (2_ propylene small base) bite and [2,3_b] mouth than morphine-2 (1H)-ketone (163 mg, 0.795 mmol) dissolved in L4-dioxane (5 ml) and water (5 In milliliters). Sodium periodate (426 mg, 1.99 mmol) and osmium tetroxide (0.17 ml of a 4% aqueous solution) were added in that order. The reaction was stirred at room temperature for 2 h then taken up with water (20 mL) and extracted with 20% MeOH / DCM (3xl. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated and evaporated to afford (7-fluoro-2-ketopyridino[2,3_b]pyramine (2H&gt; yl) acetaldehyde (mostly present as fluorenyl) Hemi-acetal impure ochre oil (193 mg, 117%) MS (ES+) m/z 207 (MH+), 240 (decyl hemiacetal h+). 20 (f) (2, 3- Hydrogen [1,4]dioxaindole[2,3_c]pyroo_7_ylindenyl){1-}[2-(6-fluoro-3-keto-indenyl][2,3-1) ]Sakaguchi-4(3H)-yl)ethyl]-4-hexahydropyridinyl}amino decanoyl decanoate (7-fluoro-2-ketopyrano[2,3- b] Pyridin-1 (2H)-yl)acetaldehyde (large 136 (3 200817417 partially present as methyl hemiacetal) (193 mg, assumed to be 0.795 mmol) and (2,3_ dihydrogen [1 , 4] dioxo[2,3_c]pyridine-7-ylmethyl) 4-tert-butoxycarbonylamino hexahydropyridine (synthesis see W02004/058144 example 99(h)) (277 gram, 0.795 A mixture of chloroform (1 mL) and Me 〇H 5 (0.5 mL) was stirred at room temperature under argon for 2 hrs and then NaBH(OAc)3 (377 mg, 1.59 mmol) Stir the reaction! Add more NaBH(OAc)3 after hours (377 mg, 1.59 mmol). The reaction was stirred for 1 h then EtOAc EtOAc (EtOAc) And use the crude residue on the silicone with 0-10%

The MeOH/DCM gradient elution was purified by chromatography to afford the desired crude oil (195 mg, 45%). MS (ES+) m/z 541 (MH+). 15 (g) the title compound in (2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl){1-}[2-(6-fluoro- 3-keto group σ is more than [2, 3-1)]. ratio. Well-1,3(3H)-'yl)ethyl]-4-hexahydropyridinyl}aminocarbamic acid 1,1-didecylethyl ester (195 mg, 0.361 mmol) in chloroform (5 mL) MeOH To a solution of (5 ml), EtOAc (EtOAc)EtOAc. The reaction was then extracted with 20% MeOH (3 x 100 mL) in DCM. The combined organic layers were dried, evaporated and evaporated eluting elut eluting eluting eluting %). MS (ES+) m/z 441 (MH^.)H NMR (250MHz) 5(CDC13) 1.32-1.65 (2H, m), 1.85-2.00 (2H, m), 2.10-2.30 (2H5 m)? 51-2·72 (3H, m), 2.85-3.05 (2H, m), 3.81 (2H, s), 4.26_4.63 (m, 6H), 6.83 (1H, s), 7.62 (1H, Dd, J 9, 3 Hz), 8.10 (1H, s), 8.46 (1H, s), 8·51 (1H, d, J 2·5Ηζ). 5 By dissolving the obtained free base in 1: 1 DCM: MeOH and 1 eq. of 1M HCl in diethyl ether was added to convert the compound to HCl salt. Dihydro-5H-pyrano[2,3-c]嗒井-3-ylmethyl 1 fluorenyl)amino]-1_hexapyridinyl}ethyl)-7-fluoro-2(1H) -indolone dioxalate

(8) 4_Bromo-2_{[4-(decyloxy)phenyl]methyl}_6_({[4-(decyloxy)phenyl] fluorenyl}oxy)-3(2Η)- tartaric acid and 5-bromo-2-{[4-(methoxy)phenyl]methyl b 6-({[4-(methoxy)phenyl]methyl}oxy)_3(2Η)_嗒耕酮A solution of 4-decyloxybenzyl alcohol (6.2 mL, 50 mmol) in dry diethyl ether (EtOAc) (EtOAc) The mixture was heated under reflux for 1 hour, cooled, washed with water, dried, dried and evaporated. The 4-methoxybenzyl bromide thus formed was added to 4-bromo-I,2·diin-3,6-nonanedione (prepared as in Example 6(a)) (4 g, 21 mmol) And a mixture of potassium carbonate (8.28 mg, 60 mmol) in anhydrous DMF (60 138 200817417 ml) and stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water three times, dried over magnesium sulfate and evaporated to a small volume. Part of the solid was filtered and washed with ethyl acetate. The sputum base was dried to dryness and the residue was chromatographed eluted eluted with 20% ethyl acetate / hexane then ethyl acetate. The lower polarity of the desired product (3.233 g) was obtained, the desired product of the higher polarity was obtained, and a mixture of the two (1.351 g). Total production: 6.3 grams, 7 〇〇 / 〇. Products of lower polarity · MS (+ve ion electron spray) m/z 431 and 433 (MH+, 15%), 121 (100%). 10 Higher polarity products: MS (+ve ion electron spray) m/z 431 and 433 (MH+, 15%), 121 (100%) 〇(8)(2ε)-Η2·{[4-(methoxy) Phenyl]fluorenyl}_6_({[4_(methoxy)phenyl)indolyl}lacyl ketone-2,3-dihydro-4-tower]]butyl butyl acrylate 15 and 2£&gt;3-[Bu{[4-(methoxy)phenyl]indolyl 3-({[4-(methoxy)phenyl]indolyl)oxy)-6-ketodihydrol Tatric acid]_2_butyl acrylate argon gas into 4-bromo-2-{[4-(decyloxy)phenyl]fluorenyl}-6-({[4-(methoxy)))曱 }}oxy)-3(2Η)-tower ketone and 5-indo-2-{[4-(methoxy)phenyl]indolyl}-6-({[4-(oxime) a mixture of phenyl] fluorenyl}oxy 20 yl)-3(2Η)_ euplamide (1·35 g, 3.14 mmol) in anhydrous 1,4-dioxane (7.5 ml) 20 minutes. The solution was then bis(tris-tert-butylphosphino)palladium (32 mg, 0.0628 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (29 mg, 0.0314 mmol) , dicyclohexyldecylamine (〇·74 ml, 3.45 mmol) and n-butyl acrylate (0.543 ml, 3.78 m)

139 200817417: Dan 2) ^ 纟 argon pressure and until the next mixing 1 , then at 95. . Granted the instrument. The mixture was dispensed in a solution of acetic acid and a water towel, and the separation = = acid extraction. The combined organic solution was dried and evaporated, and the product was subjected to a lower polarity product ((2E)_H2_{[4_() by using 15/〇 acetic acid ethane/hexane and 35% acetic acid/hexane.曱oxy)phenyl]fluorenyl}-6-({[4-(decyloxy)phenyl]methyl}oxy)_3-keto-2,3_dihydro_4_ Tatricin]- 2-butyl acrylate) (838 g, 55%). 10 15 MS (+ve iontophoresis) m/z 479 (MH+, 7〇%), 121 (100%) 〇 more polar product ((2Ε)-3-[1-{[4-(甲Oxy)phenyl]methyl}_3_({|&gt;(decyloxy)phenyl]fluorenyl}oxy)_6-keto", dihydro_4_roughing]butyl butyl-2-acrylate (58〇mg, 39〇/〇) MS (+ve iontophoresis) m/z 479 (MH+, 70%), 121 (100%) 〇(c) 6,7-dihydro_211_pyran And [2,3_c]嗒耕-3(5H)-ketone

Method A (1) 3-(2-{[4-(indolyl)phenyl]indolyl}-3,6-dione-l,2,3,6-tetrahydro 20 -4-pyrene Well base) butyl propionate (2Ε)-3-[2_{[4-(decyloxy)phenyl]indolyl} winter ({[4-(decyloxy)phenyl]methyl}oxy) )-3-keto-2,3-dihydro-4-indole]butyl -2-acrylate (838 mg) in ethanol (15 ml) / 1,4-dioxane (1 ml) The solution was treated with 10% Pd/C (400 mg) and stirred at atmospheric pressure of hydrogen pressure and room temperature 140 200817417 for 2 hours. The catalyst was filtered using celite and the filtrate was evaporated and dissolved again in 1,4-dioxane, and then evaporated to dryness to give the product as a colorless oil (0.56 g, 89%). MS (+ve iontophoresis) m/z 361 (MH+, 60%), 121 5 (100%) 〇(2) 5-(3-propylpropylmethoxy)phenyl]methylhydrazine二氲-3,6_ 口荅口井二@同将3_〇{[4-(methoxy)phenyl]fluorenyl}_3,6_dioxinyl_1,2,3,6_ 0 Hydrogen hydrazine butyl acrylate (〇·56 g, 1.56 mmol) was dissolved in anhydrous THF (30 mL). The solution was treated with a 1 M solution of lithium aluminum hydride in THF (1······················ Stir in an ice bath for 30 minutes. 2 Torr of hydrochloric acid was added until pH 3 was obtained, and the mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried and evaporated. The residue was chromatographed on EtOAc (EtOAc) elute MS (+ve iontophoresis) m/z 291 (MH+, 30%), 121 (100%) 〇〇(3) 4-(3-hydroxypropyl)-i,2-dihydro_3,6 - 嗒 二 二 将 将 5-(3-hydroxypropyl decyloxy) phenyl] hydrazinium dihydro-3,6" 荅 二 diketone (2.734 g) with anisole (1 〇 ml) and TFA (100 liters) was treated at 40. (: stirring overnight. The solution was cooled, evaporated to dryness and 141 s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s The mixture was cooled and evaporated <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; m/z 171 (MH+, 100 〇/〇). (4) The title compound is 4-(3-hydroxypropyl)-12-dihydro-3,6-indole diketone oxime 48 g, 8·7 The suspension in THF (105 ml) was placed in an ultrasonic bath for 5 minutes' and then cooled in an ice bath under argon atmosphere. Triphenylphosphine (3.67 g, 14 mmol) was added sequentially. And diisopropyl azodicarboxylate (2 76 ml, 14 house Mo). After 30 minutes, The solvent was evaporated and the residue was taken in a vac. EtOAc overnight. EtOAc EtOAc EtOAc EtOAc. /DCM elution gave the product as a grey solid (1 </ br> 49 g, 79%) MS (+ ve

Method B (5) 3-(1_([4_(Methoxy)phenyl]methyl}_3,6-dione-l,2,3,6-tetrahydro-2-indole-4-indole) Butyl propionate will be (2Ε)_3-[1-{[4-(decyloxy)phenyl]indolyl}_3-({[4-(methoxy)phenyl]indolyl}oxy)-6 -keto-1,6-dihydro-4-indole]butyl -2-acrylate (580 mg) in ethanol (15 ml) / hydrazine, 'dioxane (5 ml) solution with 10% Pd/C (400 mg) was treated and stirred under atmospheric pressure of hydrogen pressure at room temperature 142 200817417 for 2 hours. When the red color is used, the catalyst is evaporated and the filtrate is evaporated and dissolved again in 1,4_2, and the sputum is evaporated to dryness, 98%). 1 43 MS (+ve iontophoresis) m/z 361 (MH+, 50%) 121 (100%) 〇h 1Z1 (6)M3-propylpropylmethoxy)phenyl]indolyl dichloride-3, 6-tower π well diketone 3_(1_{[4-(methoxy)phenyl]methyl b 3,6-dione 2 3 6 10 tetrahydrocarbyl) propionic acid butyl vinegar (0.43 g , 1.19 millimolar) dissolved in anhydrous THF (20 $ liter). The solution was brought to _3 Torr under argon pressure. For example, dilute the brain with 1 M solution of hydrogen in THF (4 mL, 14 mmol), and gradually warm to 〇. Stir and stir in an ice bath for 3 minutes. 2 m of chlorous acid was added until pH 3 was obtained, and the mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers dried and evaporated. The resulting solid was triturated with ethyl acetate. EtOAc (EtOAc m. %), 121 (100%). Zo (7) methoxy)phenyl]fluorenyl}-6,7-dihydro-2H-pyrano[2,3-c] Tatricin-3(5H)-one will be '(3-hydroxypropyl) 1-{[4_(methoxy)phenyl]indolyl 1,2-dihydro-3,6-indole dione (2.624 g, 9·1 mmol) in THF (100 mL) The suspension was placed in the ultrasonic bath for 15 minutes. Add 143 &quot;·· -3⁄4 200817417 diphenylphosphine (3·57 g '13·6亳 Moule) under argon pressure, then cool the reaction mixture to -i〇c and add azodicarboxylic acid diiso Propyl ester (2.66 ml, 13.6 mmol) was allowed to gradually warm to room temperature. After a few hours, the solvent was evaporated. Chromatography on silica gel, the by-product was removed by elution with ethyl acetate, and then eluted with 10% ethanol/ethyl acetate to give the product (2.55 g) containing a small amount of triphenylphosphine oxide. MS (+ve iontophoresis) m/z 273 (ΜΗ+, 50%), 121 (100%) 〇ίο (8) The title compound is 2-{[4-(decyloxy)phenyl]methyl b 6, dihydro 2H_ 吼 并 [2» combination. Well _3(5H)-ketone (2·75 g, ι〇·ι mmol) was treated with anisole (1 liter) and TFA (10 mL) and heated at 7 (rc for 24 hours. The solution was cold-twisted, the residue was dissolved and the residue was dissolved in 2.5% Me〇H/DCM. 15 铋 was added to the silicone column and then eluted with this solvent mixture, followed by 5%.

The product was eluted with EtOAc / EtOAc (EtOAc) MS (+ve iontophoresis) m/z 153 (MH+, 100%). (4) Dimethylmethyllithic acid 6,7-dihydro-5H-pyrano[2,3-c] tartar-3-ester 6,7-dihydro-5H-pyrano[2,3 -c] 嗒u well _3(5H)_ ketone (152 mg, 1 mmol) in DMF (2.5 ml) in argon atmosphere with ice cooling, using hydrogenated steel (60 mg in oil 6 〇% dispersion, 15 mmol) was treated and stirred for 1 hour and allowed to warm to room temperature. Add N-phenyl-bis(trifluoromethylene phthalocyanine) (505 mg, i millimolar) and continue to stir for 2 small

144 200817417 hours. The mixture was diluted with ethyl acetate, washed with aq. sodium hydrogen Chromatography, elution with 4% EtOAc / EtOAc (EtOAc:EtOAc) . (4) 3-vinyl-6,7-dihydro- 5Η·pyrano[2,3-c] plowing argon into argon trifluoromethanesulfonate 6,7-diindole-5H-pyrano[ 2,3-c] A solution of indole-3-ester (228 mg, 0.8 mmol) in 1,2-dimethoxyethane (65 mL) over 15 min. Tritium (triphenylphosphine)palladium (ruthenium) (5 Torr, 0.0475 Torr) was added and the solution was stirred under argon for 2 Torr. The mixture was then treated with potassium carbonate (U1 mg, 〇8 mmol), water (19 mL) and divinyl boroborane pyridine complex (180 mg, 0. 75 mM). After stirring at 80 ° C for 2 hours, the mixture was cooled and partitioned between dCm and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted twice with EtOAc/EtOAc. The combined organic solution was dried over sulphuric acid: EtOAc: EtOAc (EtOAc) MS (+ve iontophoresis) m/z 163 (MH+, 100%). (f) 6,7-Dihydro-5H-pyrano[2,3_c]indole_3_aldehyde will be 3_vinyl-6,7-dihydro-5H-pyrano[2,3-c ] 嗒耕(100mg 二〇·6Πmmol) in a constant burning (Μ ml) / water (11 ml) in a solution cooled in ice / water and with sodium periodate (3 〇 6 mg, 1.43 mmol 145 200817417 Ears and 4% aqueous solution of bismuth iron oxide (〇·55 ml). Warmed to room temperature with i Xiaorui Ling 1 mixture, after stirring for 4.75 hours, it will be dissolved. Add 1, 屯二The decane was evaporated and a few milliliters of DCm was added and the compound was placed in the ultrasonic cell for a short period of time. The whole mixture was applied to a silicone tube and the product was eluted with ethyl acetate to give the product (55 mg, 54%). Primary MS (+ve iontophoresis) m/z 165 (MH+, 100%). (g) title compound 10 15 amino-1 hexahydropyridyl)ethyl]_7_fluoro-2 (1 Η) - morphinone dihydrochloride (60 mg, 〇·16 ό millimolar) and 6,7_ monohydro-5 Η-pyrano[2,3-c] 嗒 _3_ aldehyde (3 〇 mg, 183·183 mmol.) The gluten solution in jMeOH (3 mL), chloroform (3 mL) and triethylamine (6 mL) was stirred at room temperature overnight. It was cooled and sodium triacetoxyborohydride (0.106 g &lt;5&gt; More 6,7-dihydro-5-indole-[2,3-c]indole-3-acid (10 mg) was added and the mixture was stirred at room temperature for 2 hr. Sodium triethoxysulfonate (53 g) was added and the mixture was stirred at room temperature for 18 h. Water and sodium carbonate solution were added and the mixture was extracted with 1% MeOH-DCM (3 χ), dried (Na2SO4), and eluted with 〇2〇% Me〇H-DCM on silica gel to give The free base of the title compound (25 mg). MS (+ve iontophoresis) m/z 439 (MH+). 2 65 Π H ^70 OR ; ^52 (2H? m)^ L92 (2H? br dX 210 (2H&gt; m)j 2·20 (2H? Γ2Η rnf ?7 Π N 2*85 ^ ^ 3M ^ d) 4*°2 ^ ^ 433 ^ ^ 4A2 (2H9 m)? 7.06 (1H3 m). 7.12 (1H5 m), 7.28 (1H? s), 7.86 (1H5 m)? 8.22 (1H, s).

146 200817417 The free base was treated with excess oxalic acid (~20 mg) in diethyl ether in chloroform / DCM and evaporated to dryness. Ethyl ether was added and the title compound (31 mg) was obtained. Example 37 4-(2-{4-[(2,3-Dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)amino]-1-hexafluorene Pyridyl}ethyl)-6-(decyloxy) oxacyclo[2,3-b]pyrazine-3(4H)-one dihydrochloride

(a) {1-[2-({[(Phenylmethyl)oxy)))amino)ethyl]_4_hexahydro-u-bityl}1,1-diyl Ethyl ester of phenylmethyl (2-bromoethyl)carbamate (12. 9 g, 50 mmol) (according to AJ Brouwer and RMJ Liskamp, European Journal of Organic Chemistry (2005), (3), Method 487-495 prepared from (2-bromoethyl) carbamic acid phenyl methyl ester and phenyl decyl chlorocarbonate), 4-6 hexahydrotolylamino decanoic acid 1,1 dimethyl ester ( 1 gram, 5 〇 millimolar), a mixture of potassium carbate (6.9 g, 50 mM), acetonitrile (1 mM) and DMF (30 mL) at 4 (TC stirring for 2.5 days. The inorganic residue was decanted and evaporated. The residue was partitioned between ethyl acetate and diluted brine. EtOAc (EtOAc) Ion-electron spray) m/z 378 (MH+).

147 200817417 (b) [1-(2-Aminoethyl)_4_hexahydropyridyl]carbamic acid ^-dimethylethyl. Ester 5 will be {1-[2_({[()) A solution of dimethyloxy]carbonyl]amino)ethyl]hexahydropyridyl} carbamic acid dimethyl ester (8.2 g, 21.8 mmol) in 5 ethanol (500 liters) via 10 % Pd/C (50 含水/〇 dispersion of water, 4.0 g) was hydrogenated overnight. The mixture was filtered, evaporated and evaporated with EtOAc EtOAc EtOAc MS (+ve ion electronic spray) m/z 244 (ΜίΙ+). 10 (c) methoxy)-3-nitro-2-pyridyl]amino}ethyl)-cardiac hexahydrophenyl butyl amide 1,1-didecylethyl amide -6-(methoxy)_3_石肖基σ ratio ι(ι·9g, 1〇mmol), [1-(2_月女基ethyl)-4-hexahydroindenyl]amino group Mixture of dimercaptoethyl phthalate (2.43 g, 10 mmol) and potassium carbonate (14 g, 1 mmol) in acetonitrile (35 15 house liters) and DMF (10 ml) at 40° C is heated for 30 minutes. The mixture was filtered, washed with acetonitrile and evaporated. The residue was dissolved in a small amount of &lt;RTI ID=0.0&gt; The organic extract was added to a silica gel column eluted with 0-100% ethyl acetate in hexane to afford a yellow solid (3.1 g, 78%). 2 〇 MS (+ve ion electron spray) m/z 396 (MH+). (d) [1-(2-{[3_Amino_6_(decyloxy)_2-pyridyl]amino sulfonylethyl)_4_hexahydroacridinyl]amino decanoic acid u-didecyl Ethyl ester^[1-(2-{[6-(methoxy)_3_nitro-2-pyridyl]amino}ethyl)_4_ 148 200817417 hexamethylene] dimethyl carbamate The ester (3.0 g, 7.6 mmol) solution in ethanol (500 liters) was hydrogenated overnight over 10% Pd/C (aqueous 50 〇 / 〇 dispersion, 1.5 gram). The mixture was dried, evaporated and combined with chloroform to give a pale oil (2·8 g, 1%). 5 MS (+ve ion electron spray) m/z 366 (ΜΗ+). (e) N_[2-({2-[4_({[(u)))) Base) 吼唆 吼唆 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 】 Amino phthalic acid U-dimercaptoacetate (2·8 g, 7.6 mmol) / hexahydrate 酉夂^^(〇·85 ml, 13 g, 7.6 mmol) The acid clock (2 g, I5·2 耄mol) in acetonitrile (40 ml) and DMF (20 ml) was applied overnight under argon pressure. The mixture was simmered and washed with acetonitrile. The residue was dissolved in a small volume of DCM (2 mL) and washed with 15 water (2 mL). The organic extract was added to a silica gel column and then eluted with 0-100% ethyl acetate in hexane to give a color oil: 38%). , · MS (+Ve ion electron spray) m / z 452 (MH +). 20 (1) ({2 [6 (methoxy))-3- keto oxime ratio bite [2,3_b] morphine _4(3h)-yl] ethyl hexahydropyridyl]amino decanoic acid 1,1 -dimethylethyl ester

He[2_({2_[4«[(i,i-didecylethyl)oxy]carbonyl}amino)-1_hexahydropyridyl]ethyl}amino)-6-(methoxy A solution of -3-pyridyl]glycine guanidine (1.2 g 2.7 mM) in toluene (4 〇 0 mL) in chloro 149 200817417 gas [lower U, 24 λ Ι. This solution was treated with manganese dioxide (2.0 g &apos; 23 moles) at room temperature. After 7 hours, the mixture was filtered and washed with warm W to give a dark oil after evaporation. The residue was chromatographed eluting with EtOAc EtOAc (EtOAc) MS (+Ve ion electron spray) m/z 404 (ΜΗ+). (g) 4-[2·(4-Amino-1-hexahydroindole), acetyl 6-(methoxy), and [2,3-b]pyrazole-3(4Η)-one (1-{2-[6-(decyloxy)_3-ketopyrido[2,3-7]pyrazine_4(3Η)_yl]ethylidene 4-hexahydropyridinyl]amino decanoic acid A solution of hydrazine-dimercaptoethyl ester (47 mg of '1.2 mmol) in DCM / trifluoroacetic acid (1 mL / 1 mL) was stirred at room temperature for 30 min then evaporated to dryness. After trituration with diethyl ether, the obtained solid was dried in vacuo. The solid was dissolved in DCM /MeHH (20 ml / 20 ml) and MP_ carbonate resin (2 g of carbonate per gram, 3 g, After about 5 hours, the mixture was filtered and washed with a small volume of DCM and MeOH. The combined filtrate was evaporated to give a yellow oil (containing small material from resin). The residue was taken up in 20% MeOH (20 mL) elute MH+) (h) The title compound bites 4-[2-(4-amino-1-hexahydropyridyl)ethyl]_6_(decyloxy)

150 200817417 and [2,3-b]pyrazine-3(4H)-one (150 mg, 0.494 mmol) and 2 3 hydrogen [M]dioxo[2,3-c]pyridine-7- Aldehyde (synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19(d)) (82 5 10 15 mg '0.496 house Moule) in anhydrous DCM (10 ml) and anhydrous Me〇H 〇 house liter) The solution in the solution was stirred at room temperature for 5 minutes. Add triethylphosphonium sulfonate (316 mg, 1.49 mmol) and stir the mixture under argon for 18 hours with saturated aqueous NaHC3 (5 mL) and 1 〇:1 DCM: Treat with MeOH (10 mL). The layers were separated and the aqueous was washed with EtOAc EtOAc. The organic extracts were combined, washed with brine, passed through a hydrophobic frit and evaporated to an orange gel. Purification by gradient elution with a gradient of 0% to 30% DCM / MeOH on a EtOAc EtOAc (EtOAc) MH+). !HNMR 6(CDC13) 1.44 (2H, m). 1.90 (2H, m), 2.18 (2H5 m), 2.58 (1H, m), 2 74 (2H 3.04 (2H? m), 3.81 (2H , s), 4.03 (3H, s), 4.27 (2H, m), 4.32 (2H, m), 4.58 (2H't J 7 ;

Hz), 6.73 ( 1H, d, J = 8.4 Hz), 6.82 (1H? s), 8.01 (1H, d5 J = 8.4 Hz), 8.09 (1H; s), 8.15 (1H, s). A solution of the base (128 mg, 0.283 mmol) in EtOAc (EtOAc) After centrifugation, the solvent was decanted and the solid was dried to give the title compound ( 154 mg). Example 38 Dihydrofuro[2,3-c]pyridine-5-ylindenyl)amino]-1-hexahydropyridyl}ethyl)_7_fluoro-2(1H)_4Df^g with dihydrochloride &amp;amp ; 200817417

5 (8) Acetic acid {5-({[4-(decyloxy)phenyl)indolyl)oxy)-4-[(tridecyl)ethynyl]-2-pyridyl}methyl ester acetic acid (5 -({[4-(Methoxy)phenyl)methyl}oxy)-4-{[(trifluoromethyl)sulfonyl]oxy-2-pyridyl} decyl ester (synthesis see W02004058144 example) 60(d)) (10g, 23mmol) dissolved in acetonitrile (400ml) and added 10 to triethylamine (65ml) and copper iodide (1) (0.44g, 2.3mmol). The mixture was degassed and placed under argon atmosphere. Trimethyldecyl acetylene (10 mL, 69 mmol) and bis(triphenylphosphine)palladium dichloride (11) (0.645 g, 0.99 mmol) The mixture was heated at 45 ° C for 18 hours. The mixture was then cooled and filtered. Chromatography on silica gel eluting with a gradient of 20-75% ethyl acetate in 40-60 ° C petroleum ether affording oil (8.4 g, 96%) MS (+ve ion electron spray) m/z 384 (MH+). 20 (b) Acetic acid {5-hydroxy-4-[(tridecyl)ethynyl]-2-pyridyl} oxime trifluoroacetic acid The salt will be {5-({[4-(methoxy)phenyl)indolyl)oxy)-4-[(tridecyl)ethynyl]-2-pyridyl} decyl acetate (8.45 g, Treated with trifluoroacetic acid (9.4 ml) and triethyl decane (3.33 ml) 152 200817417 and stirred at ambient temperature for 18 hrs in DCM (70 mL). Chromatography, elution with a gradient of 2 - 8% Me sH in Dcm to give an oil (10 g, 100%) MS (+ve ion e-spray) m/z 264 (MH+). (c) furan acetate [ 2,3-c]pyridine _5_ decyl oxime 匕 one will be acetic acid {5-hydroxy_4-[(trimethyl decyl) ethynyl]-2-pyridyl} methyl ester difluoroacetate (10 g, 22 Mol) dissolved in pyridine (200 ml) and = copper molybdenum (1) (5.2 g, 27 mmol), heated under reflux for 18 hours, and allowed to cool. Evaporate to dryness and residue Dispense between ethyl acetate and water. The mixture is removed by filtration through diatomaceous earth. The organic layer is separated from the filtrate, dried and chromatographed on silica gel in 40-60 C petroleum ether. 10-60% ethyl acetate gradient elution. Acid furo[2,3-c]pyridin-5-ylmethyl ester (1·15 g, 27%) and the less polar product [2-(trimethyldecyl)furo[2,3_c]pyridine_ Oil of 5-methyl oxime ester (1.3 g, 23%) MS (+ve ionic electron spray) m/zi 92 (MH+) &amp; MS (+ve ion electron spray) m/z 264 (MH+). (d) Furo[2,3-c]pyridin-5-ylmethanol furfuryl R,3-c]acridine-5-yl decyl acetate (115 g) in ι,4-di-alkane (30) The solution in liters and water (1 liter) was treated with 2M sodium hydroxide (12 liters) and stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated and dried and evaporated to dryness. As 153 200817417 this gives oil (0.63 g, 70%). MS (+ve ion electron spray) m/z 150 (ΜΗ+). (e) 2,3·Dihydrofuro[2,3_c]pyridin-5-yl decyl alcohol is dissolved in furo[2,3-c]pyridine-5-ylmethanol (1.29 g, 8.7 mmol) Ethanol (50 ml) was deuterated by 10% Pd/C for 18 hours at room temperature and 1 atmosphere of hydrogen. The mixture was filtered through celite and the filtrate was evaporated to dryness to give (1·31 g, 1%). MS (+ve ion electron spray) m/z 152 (ΜΗ+). (1) 2,3-Dihydrofuro[2,3-c]pyridine-5-aldehyde 2,3-dioxafuro[2,3-c]pyridine-5-ylmethanol (1.31 g, 8.7 mmol) Dissolved in DCM (100 mL), treated with manganese (IV) (6 g, 69 mmol) and heated under reflux for one hour. The oil was obtained by filtration through celite and evaporation of the filtrate to dryness (yield: 9 g, 70%). MS (+ve iontophoresis) m/z 150 (MH+). (g) the title compound is amino-1-hexahydrou-butyryl)ethyl]+fluoro-2(1Η)-fluorenone dihydrochloride (6 mg, 166 166 mmol) and 2 , 3_ Dihydrofuro[2,3-c]pyridine-5-aldehyde (30 mg, 0.20 mmol) in MeOH (3 mL), EtOAc (3 mL) and triethylamine (0·〇6 The solution in milliliters was heated under reflux with 3 Α molecular sieves overnight. It was cooled and added to sodium triethylphosphonium borohydride (〇·Π克, 〇·52 mmol) and the mixture was allowed to stand at room temperature.

154 200817417 Spoiled overnight. An aqueous solution of sodium bismuth carbonate was added and the aqueous layer was extracted several times with 1% MeOH-DCM. The organic layer was dried and evaporated. Chromatography on EtOAc (EtOAc) elute 5 MS (+ve iontophoresis) m/z 424 (MH+). δΗ(CDC13),(250 ΜΗζ) 1·49 (2H,m),1·93 (2H,br.d),2·19 (2H,t),2 59 (1H )π (2H, t)? 2.98 (2H5 br. d)5 3.22 (2H, t), 3.87 (2H, s), 4.31 (23⁄4 t), 4.61 (2H t) 7 〇8/m λ 7·13 (1H,m),7· 21 (1H, s), 7.86 (1H, dd), 8.07 (1H, s), 8.22 (1H, s) (, called, the free base in chloroform / DCM used in 1,4- 2. Treatment of 〇.4M 10 hydrochloric acid (0.6 ml) in the alkane and evaporation of the solution to dryness afforded the dihydrochloride salt. Example 39 1_(2-{4-[(2,3-dihydroindole) Methyl [2,3-(;] 吼-5-ylmethyl)amino] hexahydropyridyl}ethyl)_7U(1H)L lindane dihydrochloride 20

Η2#-Amino hexahydropyridyl)ethyl]_7_fluoro-2(1H)L-linone dihydrochloride (60 mg, 0·166 mmol) and 3 _ base-3,4- Dihydro 2 Η-pyrido[3,2_b][l,4] hexamede aldehyde (synthesis see W〇2〇〇3〇87〇98, example 31(e)) (35 mg, 〇·2〇 A solution of Me 〇H (3 mL), chloroform (3 mL) and triethylamine (6 mL) was then stirred with 3A molecular sieves overnight. This was cooled and added to sodium trihydroxyl borohydride (0.11 g, 〇. 52 mmol) and the mixture was stirred at room temperature for 155. The mixture was basified with aqueous sodium bicarbonate and the aqueous layer was extracted several times with 10% MeOH-D. The organic layer was dried and evaporated. Chromatography on silica gel eluting with EtOAc (EtOAc) 5 δΗ (CDC13), (250 ΜΗζ) 1·49 (2H, m), 1.92 (2H, br.d), 2·19 (2H, t), 2·55 (1H, m), 2·69 ( 2H,t),2.99 (2H,br·d),3·83 (2H,s),4·31 (2H,t),4.63 (2H,s),6.95 (1H,d),7·08 ( 1H, m),7·14 (1H,m),7·20 (1H,d),7.85 (1H,dd),8·22 (1H,s) MS (+ve ion electron spray)m/z 453 (MH+). The free state was treated in chloroform/DCM with 〇·4Μ 〇hydrochloric acid (0·75 ml) in 1,4-second-burning and the solution was evaporated to dryness to give the dihydrochloride example 40 Η2-{4 -[(6,7-dihydro[1,4]indolo[2,3-c]indole-3-ylindenyl)amino hexahydropyranyl}ethyl)-7-fluoro-2 (1H)-porphyrinone di 15 hydrochloride

(a) 2_[(3,6-two gas_4_嗒_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ And the solution of triethylene sulphate (9 mils) was stirred at 0 ° C (ice bath) with 2-mercaptoethanol (8 33 亳 夕 日 。 。 。. After adding the ingredients, the mixture was stirred at room temperature for 72 hours. The mixture was stirred with aqueous sodium hydrogencarbonate and DCM and the solid was taken from </ br> </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; A solid was obtained after the volume, which was washed and dried (5 g) according to the above. The total yield of solid (27.9 g, 91%) by NMR showed partial bromine-homolog (5 〇%). 5 0) 3 -Chloro-6,7-di-argon [1,4]π-thi[2,3_c]-tower 2-((3,6-dichloro-hydronium)sulfanyl]ethanol (13 g) A solution of anhydrous i,4-dioxane (25 mM) was then portionwise treated with lithium hydride (3 g) and heated at 105_11 24 for 24 hours. The reaction mixture was cooled. And quenched with ice-water. Adjust the solution to pH 10-11 with 5M hydrochloric acid and steam Water was added and the mixture was extracted 4 times with DCM, dried (MgSO4), evaporated and evaporated eluting (containing about 10% bromine species) MS (+ve ion electron spray) m/z 189/91 (MH+); 233/5 (Br 15 MH+) 〇δΗ (CDC13, 400MHz) 3·23 (2H, m), 4.67 (2H, m), 7.26 (1H, s) (major chlorine compound) (c) 3-vinyl-6,7-dihydro[1,4]indole[2, 3-c]嗒耕20 3-Chloro-6,7-dihydro[1,4]indolo[2,3-c]morphine (1.0 g) in dimethoxyethane (2 ml) The solution in the solution was degassed under argon pressure and then added with hydrazine (triphenylphosphino) (0) (135 mg), carbonate (0.695 g), trivinylcyclopentane pyridine complex (0.8 g). And water (3.7 ml). Heat the mixture overnight at 5 ° C. Add more trivinylboroxine pyridine complex (0.4 g) 157 200817417 and hydrazine (diphenylphosphino) (〇) (3〇家克) and heating for 24 hours. The mixture was cooled, treated with aqueous sodium carbonate solution, extracted 4 times with DCM, dried (sodium sulfate), evaporated It was chromatographed on a silica gel (70 g) with 0-100% ethyl acetate-hexane to give a solid (···························· Fog) m/z 181 (MH+). (d) 6,7-Dihydro[1,4]indolo[2,3-c]indole-3-aldehyde 3_vinyl-6,1 dihydro[I,4]indolethio[ 2,3_c] 嗒耕(32〇mg) In a solution of 1,4-dioxane/water (20ml/5ml), use a solution of 4% sulphuric acid (4% w/v, 2 ml) and Treatment with sodium iodate (Ig) was first cooled in an ice bath and then allowed to warm to room temperature. After 2.5 hours, the mixture was evaporated to dryness and dissolved in hexanes and chloroform. The mixture was added to the mixture and the mixture was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 〇/〇) 〇MS (+ve ion electronic spray) m/z 183 (ΜΗ+). (e) The title compound is 1-[2-(4-amino-1-hexahydropyridyl)ethyl]_7_fluoro 2〇2(1Η)-4σ clone ketone dihydrochloride (6〇 mg , ο ι% millimolar) and 酉同基_3,4_ dihydro-2H-pyrido[3,2_b][l,4]sarsin-6-aldehyde (35 mg, 〇·20 halo) A solution of MeOH (3 mL), chloroform (3 mL) and triethylamine (EtOAc) It was cooled and added to sodium triethoxy borohydride (0.11 g, 0.52 mmol) and the mixture 158 200817417 was stirred at room temperature for 7-8 hours. More triacetoxy oxime (100 mg) was added and stirring was continued overnight. Sodium triethoxy borohydride (100 mg) was added again, and after 8 hours, 50 mg and aldehyde (5 mg) were added. Stirring was continued for another night. The mixture was basified with aqueous sodium bicarbonate and the aqueous layer was extracted several times with 10% MeOH-D. The organic layer was dried and evaporated. Chromatography on EtOAc (EtOAc-EtOAc) δΗ (CDC13), (250 MHz) 1.54 (2H, m), 1·99 (2H, br.d), 2·28 (2H, t), 2·66 (1H, m), 2.72 (2H, t ), 3.05 (2H, br·d) 5 3.21 (2H, m), 4.02 (2H, s), 4·37 (2H, t), 4·67 (2H, m), 7.07 (1H, m)5 7·21 (1H,dd),7·36 (1H,s),7·85 (1H,dd),8·22 (1H,s). MS (+ve iontophoresis)m/z 457 ( MH+). The free base was treated with 0.4 M hydrochloric acid (0.25 mL) in 1,4-diosane in chloroform/DCM and evaporated to dryness to give dihydrochloride 15 Example 41 l-(2-{( 3R,4S)-4_[(2,3-Dihydro[1,4]dioxo[2,3-c]-to-bit-7-ylindenyl)amino]-3-pyridyl-1 -hexanitrogen to sigma}ethyl)-7-gas-1,5-naphthyridin-2(1H)-one hydrochloride

20 159 200817417 (a) {(3R,4S)-l-[2_(7-fluoro-2-keto-1,5-naphthoquinone-1(2H)-yl)ethyl]-3-hydroxy-4 -1,1-dimercaptoethyl ester of hexahydropyridyl}aminocarbamate (7-fluoro-2-keto-1,5-naphthyridin-1(2H)-yl)acetaldehyde oxime (200 mg, 0.8396 mmol) and [(3R,4S)-3-pyridyl-4-hexahydropyridinium 5-yl]amino decanoic acid 1,1-dimethylethyl ester (synthesis see W02004058144, Example 5(c) 'cis-(3-carbyl-4-hexahydropi-butyryl)aminocarbamic acid tert-butylacetate to palm isomer 1) (182 mg, 1 equivalent) in chloroform (1 mL) ) and Me〇H (〇5 ml) were stirred under argon atmosphere for 2 hours. Sodium triacetate hydride (534 mg, 3 eq.) was added in one portion and the mixture was stirred at room temperature for 1 hr. then quenched with saturated aqueous sodium bicarbonate (20 mL) and used in DCM. 20% by volume: volume MeOH (3 x 200 ml) was extracted. The organic extracts were combined, dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2M ammonia) eluted. The title compound (247 mg) was obtained as a white foam. MS (ES+) m/z 407 (MH+) 〇(b) l-{2-[(3R,4S)-4-amino-3-carbyl-1-hexahydropyridinium]ethyl-fluoro 20 -1,5-naphthyridine-2(1Η)-one dihydrochloride salt {(3R,4S)-l_[2-(7.fluoro-2-keto)-1,5-naphthyridin-1-(2Η&gt; Ethyl]-3-hydroxy-4-hexahydropyridinyl guanidinium decanoate, dimethyl ester 卩 4 〇 mg, 0.5905 mmol, dissolved in DCM (1 mL) and solution Treated with 4M hydrochloric acid (2 mL) in 1,4-dioxane. Observed blistering and sinking

160 200817417 Deposit formation. After 2 hours, the solvent was removed under reduced pressure and the residue was dried overnight under reduced pressure to give l-{2-[(3R,4S)-4-amino-3-hydroxy-1-hexahydropyridine. A gray solid (220 mg) of 7-fluoro-1,5-naphthyridin-2(1Η)-one dihydrochloride. 5 MS (ES+) m/z 307 (MH+) 〇(C) title compound 10 15 20 l-{2-[(3R,4S)-4-amino-3-trans-l-hexahydro- 0 ratio Mercapto]ethyl}-7_fluoro-1,5-naphthalene-2 (1H)-one dihydrochloride (1 mg, 0.2637 mmol) at 9:1 volume: volume of chloroform: MeOH (5 ml) was stirred at room temperature under argon pressure and triethylamine (129 μL, 3.5 eq.) was added. The mixture was stirred at room temperature for 10 minutes, then 2,3-dihydro[1,4]dioxyg and [2,3-indene]17 was compared to hydrazine-7-disk (synthesis see \¥02004058144, Example 2 ( (;) or W003/087098, Example 19(d)) (44 mg, 0.264 mmol) and the mixture was stirred at room temperature for 1 hour and then added in one portion with triethyloxy sulfonate (168 mg). The mixture was stirred at room temperature; the mixture was stirred over the weekend. A saturated aqueous solution of sodium bicarbonate (2 mL) was added and the organic layer was diluted with DCM to a full volume of about 20 mL. The organic layer was separated using a hydrophobic frit and The aqueous layer was extracted with EtOAc EtOAc (EtOAc). ·· 8.44 (1H,d,J 2Ηζ),8·34 (1H,s),8·11 (1H,s) 7 91 (1H d J 10Hz), 7·54 (1H, dd, J 8Hz, 2Hz ), 6.89-6.86 (2H, m), 4·53-4·44 (1H, m), 4:36-4.20 m), 4.12 (1H, s), 4·08 (2H, s), 3.32 3.28 (1H,m), 3.03-2.99 (2H,m), 2.80-2.71 (2H m) 2·39 (1H,d , J 11Hz), 2·32·2·25 (1H, m), 1.95-1.84 (2H, m)·, 'Enter MS (ES+) m/z 456 (MH+).

161 200817417 This material was converted to the hydrochloride salt by dissolving in DCM and then adding 1 eq. MS is a free base. Example 42 1-(2-{Muscle 48)_4_[(2 3_ Dioxa[1,4] Dioxo; and [2,3_(^-pyridin-7-ylindenyl)amino]_3_hydroxyl _丨_hexahydropyridyl}ethyl)_7_(methoxy

(a) {(3R,4S)_l_[2-(7-(Methoxy)-2-keto 4,^naphthalene _1(211)-yl)ethyl]-3-hydroxy-4-hexahydro [7-(Methoxy)-2-keto-1,5-naphthyridin-1(2H)-yl]acetaldehyde methyl hemiacetal (200 mg, 799·7992 mmol) and [(3R,4S)-3-hydroxy_4_hexahydro port ratio octyl] 1,1-dimercaptoethyl carbamate (synthesis Ί W02004058144, an example 5(c), cis-(3-hydroxy-4-hexahydropyridinyl)amino decanoic acid tert-butyl ester to palmate isomer 1) (173 mg, ! equivalent) in 'gas imitation (10 ml) and It was stirred under argon atmosphere for 2 hours in MeOH (0.5 mL). Sodium triethoxy borohydride (5 〇 8 mg, 3 eq.) was added in one portion and the mixture was stirred at room temperature over the weekend and then quenched with saturated aqueous sodium succinate (20 mL) and used in DCM 20% by volume: volume MeOH (3x200 liters) stroke. The organic extracts are combined, dried over anhydrous 162., η </ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ 〇_2〇% in DCM (in

Stripped with 2M ammonia in MeOH. The appropriate fractions were combined and evaporated under reduced pressure to give &lt;(3,,,,,,,,,,,,,,,,,,,,,,,, Gray beads of 4_hexahydropyridinyl}aminocarbamate ι, ι·didecylacetate (263 mg). MS (ES+) m/z 419 (MH+). (b) l-{2-[(3R,4S)-4-Amino3_yl-based succinylpyridinium]Ethyl}-7-(methoxy)-1,5-naphthyridine -2(1Η)-keto-dihydrochloride salt {(3R,4S)_l-[2-(7-(methoxy)_2-keto 4,5-naphthyridinyl)ethyl&gt; 3-hydroxyl -4-Hexidopyridinyl}amino phthalic acid u-didecyl ethyl ester (258 pg '0.6165 house Moule) dissolved in DCM (10 ml) and used in 1,4-dioxane Treatment with 4M chlorous acid (2 mL). Foaming 15 and precipitate formation were observed. After 2 hours, the solvent was removed under reduced pressure. MS (ES+) m/z 319 (MH+) 〇 20 (C) title compound: 1-{2_[(3R,4S)-4-amino-3-yl-based hexahydro-hydrogen π-decyl]ethyl} -7-(decyloxy)-indole, 5-naphthalene-2(m)-one dihydrochloride (1 mg, 0.2556 house mole) at 9:1 volume: volume of chloroform: Me〇H ( Stir at room temperature under argon pressure and add triethylamine (125 μL, 3.5 eq.). 163 ( 3 ) 200817417 The mixture was stirred at room temperature for 10 minutes, then 2,3 dioxin [匕...dioxyg and [2,3-decapyridyl-7-aldehyde (see W02004058144 for synthesis, example 2 (c) Or W003/087098 'Example 19(d)) and the mixture was stirred at room temperature for 1 hour and then added in portions with sodium triethyloxyborohydride (163 mg) in one portion. The mixture was then stirred at room temperature over the weekend. A saturated aqueous solution of sodium hydrogencarbonate (3 mL) was added and the organic layer was diluted with DCM to a volume of about 20 liters. The organic layer was separated using a hydrophobic frit and the aqueous layer was extracted with DCM (2×20 liter). The combined Dcm extracts were evaporated under reduced pressure and purified to purified crystals crystals crystals lR NMR 5 (CDC13, 400MHz) 8.71 (1H, s), 8.294 (1H, d, J 2Hz)5 8.10 (1H, s), 7.87 (1H, d, J10Hz), 7.21 (lH, d, J2Hz), 6.85 (lH, s), 6.75 (lH, d, J10Hz), 4.58-4.46 (2H, m), 4.39-4·28 (4H, m), 4.08 (1H, s), 4.02 (2H, s), 4.00 (3H, s), 3.33-3.29 (1H, m), 3·00-2·90 (2H, m), 2.83-2.70 (2H, m), 2.42 (1H5 d, J 11Hz), 2.35-2.28 MS (ES+) m/z 468 (MH+). 15 Hydrochloride. MS is a free base. Example 43 1-(2-{4-[(2,3-Dihydro[1,4]dioxo[2,3-c]pyridine-7-ylmethyl)amino]-1-hexahydropyridyl) σ定基}ethyl)_6,7-difluoro-2(1H)-. Quillazin and 20 dihydrochloride

164 200817417 (a) 6,7-Difluoro-2(1H)-fluorenone 4,5-difluoro-I,2-phenylenediamine (〇·6〇g), ie 5〇 in toluene A mixture of % dimethyl ester (〇·87 house liter) in ethanol (25 ml) was heated under reflux for 2 hours and then cooled. After refrigerated overnight, the resulting solid was collected and washed with EtOAc EtOAc (EtOAc) MS (+ve ion electron spray) m/z 183 (ΜΗ+). (^) 6,7--Fluoro-1-(2-propenyl-1-yl)-2(1Η)- 奎 咐 咐 将 将 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水 无水6,7-Difluoro-2(1H)-hydroxyquinone (10 gram, 3.13 mmol) in (10 ίο 宅升) with allyl hydrazine (〇·31 ml, 3.45 mol) The mixture was treated and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, water was added and the mixture was extracted with EtOAc (3 EtOAc). EtOAc was evaporated. Product (0·44 g, 15 63%) 〇MS (+ve ion electron spray) m/z 223 (ΜΗ+). (c) (6,7-Difluoro-2-keto-1(2H)-porphyrinyl)acetaldehyde 6,7-difluoro-1-(2-propen-1-yl)-2 ( lH)- solution of guanidinoline (0.44 20 g, 丨·98 mmol) in 1,4-dioxane (25 ml) and water (50 ml) with iron tetrachloride (4% solution in water) , 2.49 ml) and sodium periodate Π·95 g) were treated and the mixture was stirred at room temperature for 2 75 hours. The 1,4-dioxane was removed by evaporation and the aqueous residue was extracted several times with DCM / MeOH. The extract was dried and evaporated, and the residue was chromatographed on a Shixi rubber column with 165 200817417 ^ /° 11 ethyl ester / hexane to obtain a mixture of acid and corresponding sulfhydryl semi-fine (about 1:1). , 0.38 grams, 80%). MS (+Ve iontophoresis) m/z 225 (MH+), 239 (M.CH3+ from semi-acetal). 5 (d) (2,3_Dihydro[M]dioxo[2,3_c-azepine_7-ylmethyl){K〇(6,7-difluoro-2-keto-1)喳畤咁 喳畤咁 ) ) 乙基 乙基 乙基 乙基 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 Acetaldehyde/mercapto hemiacetal 1 hydrazine (about 1:1, 〇·19 g, 〇·79 mM) and (2,3_dihydro[1,4]dioxo[2] ,3-c]pyridine-7-ylmethyl)4_hexapyridinylamino decanoic acid u-monoethyl ester (synthesis see W02004/058144 example 99 (1ι)) (〇·2 g, 〇·8 A solution of anhydrous Me〇H (〇2 mL) and chloroform (5 mL) was stirred at room temperature for 1.5 hours. Sodium triethoxysilane borohydride (〇.5 15 g 2 2.37 mmol) was added and the mixture was stirred at room temperature for 7 hours. The carbon hydrazine was added to an aqueous solution of sodium hydride to alkalinize and the liquid layer was separated. The aqueous layer was extracted with dcm. The organic layer was dried and evaporated. Chromatography on EtOAc (EtOAc/EtOAc) (2,3-Dihydro[1,4]dioxo[2,3_c]pyridine-7-ylindenyl)jL[2-(6,7-difluoro-2-keto-1(2H)喳 咁 咁 ) ) 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 1- 1- 1- 1- 1-

166 200817417 A solution of DCM (5 mL) in MeOH (3 mL) was taken in 4M hydrochloric acid (5 mL) The title compound (0.256 g, 105%). A small amount (6-7 mg) of the dihydrochloride salt was treated with aqueous solution of hydrogen sulphate and extracted several times with DCM. The extract was dried and evaporated to give a small amount of freeness. 10 δΗ (CDC13), (250 MHz) 1.43 (2H, m\ 1.90 (2H, br.d) 2 1R rou x〇bLd);^;79,(2H&gt; 8)5 430 wm)»6 OH, f ): dd), 8.10 (1H, s), 8·25 (1H, s)· Example Pepper 1-(2-{4-[(6,7-Dihydro[1,4]dioxos[2] »答11井_3_ 曱 )))amino]-1-hexahydroindenyl}ethyl)_7_敦j(10)-啥十林嗣二HCl

(4) 4-[(6,7-monohydro[1,4]monooxo[2,3-c]indole_3_ylindenyl)amine 20-yl]-1 -6-mouse.比 竣 竣 竣 曱酉 曱酉 曱酉 曱酉 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- , 47 mM) and 6,7-dihydro[1,4]dioxo[2,3_c]indole (synthesis see Example 6(e)) (6.46 g, 39 mmol) in DCM (200 ml) and

167 200817417 7 Mixture of 2 (: force: liter) was stirred at room temperature for 4 hours' then added to sodium p-dimethoxy borohydride (12·4 g) in ice. After that time, the mixture was treated with aqueous sodium hydrogencarbonate solution to water. The aqueous layer was taken with DCM$ and organic layer dried and evaporated. Chromatography), eluted with 〇_1〇% Me〇H/DCM, obtained ^ t ^ 62%) 〇 seat (li.i MS (+ve ion electronic spray) m/z 385 (MH+ 10 15 (b) 4-((6,7-Dihydro[1,4]dioxo[2,3_c]嗒 _3_ylmethyl){[(ιι_ monomethyl) Oxy]carbonyl]amino)-indole_hexa-pyridyl carboxylic acid phenyl decyl ester +, sodium bicarbonate (7.34 g) was slowly added to 4_[(6,7-dihydro^,4]: oxindole and [ 2,3-c]嗒耕-3-ylindenyl)amino]_;[_ hexamidine carboxylic acid phenylmethyl ester (1 U g, 29 mmol) in Me0H (200 mL) ^ After the mixture was cooled in an ice bath, ditributyl dicarbonate (6 9 8 g, 32 mmol) was added portionwise. The mixture was stirred at room temperature for about 3 days, then filtered and evaporated. Chromatography, elution with 0-100% ethyl acetate to give the product as a white solid (11 89 g, 85%) MS (+ve ion electron spray) m/z 485 (MH+). (6,7-Dihydro[1,4]dioxan[2,3_c]嗒耕_3_ylindenyl)_4_hexahydro&quot;1,1-dimercaptoic acid The ester will be 4-((6,7-dihydro[1,4]dioxyg[2,3-c] 嗒 各 各 )) {[(11- Yue-yl) oxy] several yl} amino) _1 - hexahydro-pyrazol bite buffer acid phenyl Yue said unitary (11.89 g '25 pen Wu ear) in ethanol with pd (9〇 home L) / c

168 200817417 (aqueous paste, 2 g) hydrogenated for 21 hours. The mixture was filtered and evaporated to give a white crystallite. MS (+ve iontophoresis) m/z 351 (MH+). 5 (d) (6,7-dihydroindole, 4]dioxo[2,3-c]indole-3-ylindenyl){1-[2-(7-fluoro-2-keto) Ethyl)ethyl;|_夂 hexahydropyridyl}aminocarbamic acid 1,1 - fluorenyl hydrazide (6,7-diox[1,4]dioxo[2,3_c]嗒耕-3_基基基)_4_ hexahydropyridinyl decanoic acid 1,1-didecylethyl ester (〇·68 g, 194 mmol) and 10 (7-fluoro_2_S homo-yl_1 (2Η)-Phenanyl)acetaldehyde (synthesis see Example 34(C)) (〇.4 g, 1.94 halo) in anhydrous Me〇H (〇5 ml) and chloroform (1 mL) The solution in the mixture was stirred at room temperature for 2 hours. Triethyl ethoxylated sodium hydride (1.23 g ' 5.82 mmol) was added and the mixture was stirred for 2.5 hours. The solution was basified by the addition of aqueous sodium hydrogencarbonate solution and the layers were separated. The aqueous layer was extracted 15 times with DCM and the organic layer dried and evaporated. Chromatography on silica gel (50 g) eluting with EtOAc (EtOAc) The title compound 2〇(6,7-diaza[1,4]dioxoE and [2,3-c]indole fluorenyl) {1-[2-(7-fluoro-2-keto) 4(2^-fluorenyl)ethyl]_4_hexahydropyridyl}amino carboxylic acid 1,1-dimethylethyl ester (0.37 g, 〇·68 mmol) in DCM (7 mL) The solution in MeOH (5 mL) was obtained eluted with EtOAc EtOAc

The title compound was obtained as a pale yellow solid (0.35 g, 100%). A portion of the salt (1 mg) was taken up in water <RTI ID=0.0>(S </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; δΗ (CDC13), (250 MHz) 1.44 (2H, m), 1.91 (2H, br.d), 2·18 (2H, t), 2·54 (1H, m), 2·65 (2H, t ), 2·96 (2H, br·d), 4·00 (2H, s), 4·30 (2H, t), 4·35 (2H, m), 4.50 (2H, m), 7·03 (1H, s), 7·09 (2H, m), 7·86 (1H, dd), 8.22 (1H, s). Small impurity signals also at δ 3·90 (t), 6.66 (s) MS (+ve iontophoresis) m/z 441 (MH+). Example 44B l-(2-{4-[(6,7-Dihydro[1,4]dioxo[2,3-indolyl]indole-3-ylindenyl)amino]-1-hexa Hydrogen pyridyl}ethyl)-7-fluoro-2(1H)-porphyrinone benzoate 1-(2-{4-[(6,7-dihydro[1,4]dioxane) [2,3-c]morphin-3-ylindenyl)amino]-1-hexahydrou-yl hydrazino}ethyl)-7- Dun-2(1 Η)-σ奎吟u-linone II Hydrochloride dissolved in methanol: isopropanol: acetonitrile (0·2:0·2:1·2) with excess isopropylamine via HPLC (Chiralpak IA 5 μm, 21 χ 250 mm column, 80:20:0.1 Acetonitrile: isopropanol: isopropylamine eluted at 20 ml/min, 330 gm in 50 mg injection, 254 nm uv spec.) further purified to give the title compound as a free base (177 mg). The free base was slurried in MeOH and 1.0 equivalent of benzoic acid was added to give a complete solution. Concentration to a semi-solid, decyl-tert-butyl ester was added and concentrated again (5x), and the yellow solid was dried at 45 &lt *·, 170 200817417 δΗ (CD3OD), (400 MHz) 1·57 (2H, m), 2·05 (2H, m), 2·25 (2H, m), 2·78 (2H, m), 2·95 (1H,m),3·19 (2H,m), 4.22 (2H,s),4·45 (4H,m),4·59 (2H,m),7·20 (1H,m ), 7·26 (1H, s), 7.42 (3H, m), 7.52 (1H, m), 7.91 (1H, m), 8.00 (2H, m), 8.18 (1H, s). 5 Example 44C l-(2-{4-[(6,7-Dihydro[1,4]dioxo[2,3-c]indole_3_ylmethyl)amino]-l-six Hydropyridyl}ethyl)-7-fluoro-2(1H)-indolone fumarate method 1 10 1 equivalent of 0.5 M fumaric acid (5.9 ml) in MeOH was added to 1-(2) -{4-[(6,7·Dihydro[1,4]dioxo][2,3-c]indole-3-ylindolyl]amino]-1-hexahydropyridinyl}ethyl a solution of 7-fluoro-2(1H)-indolone (1.30 g, 2.95 mmol) in DCM, followed by evaporation to give the m. . 15 Method 2 (a) Ν-(4-fluoro-2-nitrophenyl)glycinate 2,5-difluoronitrobenzene (54·6 g, 343 mmol), glycine A mixture of oxime ester hydrochloride (47.3 g, 374 mmol) and triethylamine (114.5 mL, 818 2 mM mmol) in THF (1500 mL) was heated at 65 ° C (internal temperature) for 3 nights . Further, glutamate hydrochloride (30 g) and triethylamine (20 ml) were added and heating was continued for 2 nights. The mixture was allowed to cool, filtered and evaporated to dryness. The residue was treated with 5M EtOAc (EtOAc) (EtOAc) The product was then extracted with ethyl acetate (600 mL total), filtered and evaporated. The residue was slurried with water (1 liter), filtered and dried to give product (40 g, 51%). MS (+ve iontophoresis) m/z 229 (MH+). (b) 7-Fluoro-3,4-indan_2 (1Η)_σ奎σ σ linalone methyl hydrazine-(4-fluoro-2-nitrophenyl)glycine (4 gram, Millions) heated to 9 〇t in water (2000 ml). Sodium dithionite (243. 8 g '1401 mmol) was added portionwise. The resulting mixture was at 1 Torr. Stir for 2 hours' and then allow to cool. The solid was filtered, washed with water and dried then evaporated. The liquid was concentrated by evaporation to ~700 mL to give an additional precipitate which was filtered and dried to give an additional product (1·90 g, total yield 15.65 g, 54%). MS (+ve ion electron spray) m/z 167 (ΜΗ+). (4) 7-Fluoro-2(1H) quinacridone 7-fluoro-3,4-dihydro-2(1H)-pyridone (15.65 g, 92.88 mmol) in di-methane/ The solution in methanol (1:1, 600 mL) was stirred with argon dioxide (78.25 g) at room temperature for 1.5 hours. The mixture was passed through diatomaceous earth, washed several times with 10% decyl alcohol/dichloromethane (~ liter), and the filtrate was filtered to give the product (7·27 g). The residual filtrate solids were taken several times with dimercaptoamine at 60-70 ° C, then filtered and the extract was evaporated to give an additional product (6.66 g). The total yield was 13.93 g (91.5%). ). MS (+Ve iontophoresis) m/z 165 (MH+). 200817417 (d) 7-Fluoro-1-(2-propan-1-yl)_2(ΐΗ)-σ Kui. No. 0 Lintongtong 7-Fluoro-2 (1Η)-called ketone (3.84 g, 23 mmol), dilute propyl iodide (2.39 ml '25.5 mmol) and potassium carbonate (9 56 g, 69 3 mmoles of the mixture in monomethylamine (60 liters) was stirred at room temperature for 3 hours and then 5 shots. The residue was dissolved in dichloromethane/water and the layers were separated. The aqueous layer was taken with a chloroform (3 Torr) and the organic layer was dried and evaporated. The crude product was chromatographed on EtOAc (EtOAc) elute MS (+ve ion electron spray) m/z 205 (ΜΗ+). (e) (7-Fluoro-2-keto-i(2H)-fluorenyl)acetaldehyde 7-Fluoro-1_(2-propen-1-yl)_2(1H)_. a solution of quinolinone (7.9 g, 38·7 mmol) and sodium periodate (38.15 g, 178.3 mmol) in butanol (5 ml) and water (920 ml) Treatment with osmium tetroxide (4% solution in water, 1 mL) and the mixture was stirred at room temperature for 24 hours. It was evaporated to dryness and the residue was dissolved in water and evaporated with methylene chloride /THF. The organic extract was dried and evaporated under reduced pressure at room temperature to give aldehyde (7.82 g, 80%, LCMS, 82% purity). MS (+ve ion electron spray) m/z 207 (ΜΗ+). Oxidation can alternatively be carried out by odor decomposition in 3:1 DCM/MeOH followed by treatment with dimethyl sulfide to produce a mixture of aldehyde and hemiacetal which can be used in the next step. (f) {1_[2_(7_Fluoro-2·ketoquinolinyl)ethyl]_4_hexahydropyridinium 173 \ .«;!· * 200817417 base} carbamic acid 1,1-di Ethyl ethyl ester • (7_Fluoro 1 keto-1-(N-)-hydroxyphenanthryl) acetaldehyde (9·56 g, 46 4 mmol p and 4-hexahydropyridylamine formic acid u_ 2 A solution tray of methyl ethyl ester (ι〇·2 g, 51 mmol) in methanol (200 ml) and chloroform (400 liters) was stirred at room temperature for 2 hours at room temperature. Triethoxyboron was added. Sodium hydride (30 g, 140 mmol) was added and the mixture was stirred at room temperature for 4 hrs. A solution of sodium hexyl oxyborate (15 g) was added and the mixture was stirred overnight. The aqueous layer was separated and the aqueous layer was adjusted to pH 8 by adding 2M sodium hydroxide and then extracted 1 〇 four times with 1% methanol/dichloromethane. The organic layer was dried and evaporated. 1 kg) was chromatographed and eluted with 50-70% ethyl acetate / hexane to give the product (6·25 g). The impure material (6.7 g) was prepared from a similar preparation of 1 〇 8 g. An impure substance is re-chromatographed on tannin (600 g) as if Additional product (3.65 g) was obtained after elution. 15 MS (+ve ion-electron spray) m/z 391 (ΜΗ+). Using 1,2-di-hexane as solvent and in The temperature during the sodium borohydride reaction is kept below 5 ° C to prevent the formation of a cyclic reduction product. 20 (g) 1-[2, 4-aminohexahydropyridinyl)ethyl &gt; 7-fluoro-2 (1H)-indolone dihydrochloride will be {1-[2_(7-fluoro-2-keto-1(2H)-indenyl)ethyl]_4_hexahydropyridinyl} The solution of the female base armor 1'1_ monomethyl vinegar (8.72 g, 22.36 mmol) in decyl alcohol (90 liters) and one gas simmer (150 ml) was used at 1,4_two 174 Treatment of 4M hydrochloric acid (150 liters) in 200817417 j (added under slow flow, observed some exothermic and rapid precipitation) and stirred at room temperature for 2.5 hours. The mixture was taken up to dryness and the residue was crystallised from diethyl ether. The solid was filtered, washed with EtOAc and dried to give EtOAc (EtOAc) MS (+Ve ion electron spray) m/z 291 (ΜΗ+). Instead of HC1 in TFA in the DCM and resulting in trifluoroacetate, it can be used in the next step. (h) the title compound will be an amine hexahydropyridyl)ethyl]_7-fluoroindole-dihydrochloride (8·0 gram, 22.2 mmol), (6,7-dioxin [1, 4] Dioxo[2,3_c] 嗒3_aldehyde (4 〇 8 g, 24.45 mmol) and triethylamine (8.03 ml, 55·5 mmol) in anhydrous chloroform (25 〇ml) and anhydrous decyl alcohol (250 ml) were mixed and heated under reflux with 3 Α molecular sieve for 6-7 hours. After cooling, sodium triethoxy borohydride (18·9 g, 1 mM) was added. The mixture was stirred overnight at room temperature. Sodium triethoxysulfonate (10 g) was added again, and after 6 hours, (5 g) was added again. After stirring for 2 hours, it was basified by the addition of aqueous sodium hydrogencarbonate. The liquid layer was separated, and the aqueous layer was extracted several times with 1 〇〇/0 sterol/dichloro decane. The organic layer was dried and evaporated, and the crude product was chromatographed on silica gel (500 g) using 〇_2 〇% sterol/methylene chloride elution to obtain the free base of the product (extracted in about 1 Torr and 2% methanol in two parts of the extract, 5.98 g, 61%). TFA salt can be used instead of HCl salt. And using dimethyl acetamide / isopropanol as a solvent For chloroform/sterol, add borohydride and add another

175 200817417 Equivalent TFA. A solution of fumaric acid (1.58 g, 1 eq.) in methanol (ca. 40 mL) was added to a freedness in dichlorohydrin/ decyl alcohol (about 200 mL). The solvent was evaporated to give a fumarate-brown solid (7.41 g). 5 Dissolve less sulphate in a small amount of methanol under heating. The solution was filtered and allowed to slowly evaporate at room temperature to give a fine gray crystal. A crystallized fumarate (melting point 230-232 ° C) can also be obtained from the yeast to give crystals. Crude (6,7-dioxin[1,4]dioxo[2,3-c]indole-3-ylmethyl 1 fluorenyl) {1-[2-(7-fluoro-2-one) U-dimethylethyl ester free base (266.6 g, purity ranging from 77% to 99%) using ChiralpakAD (20 micron, 101.6) Indigo X25 mm) and chemically purified to 99.5% by preparative HPLC using 50:50:0.1 acetonitrile·sterol: isopropanol as the mobile phase. The desired stripped portion of the solution was combined and concentrated to a minimum stirred volume under high vacuum of 50-55 ° C until the product crystallised to yield a thick white thick. After cooling to ambient temperature, the product was collected and washed with methanol. After drying to 50 mils at 50-55 ° C / &lt; 5 mm Hg, a free free test of 215 · 5 g was obtained. The dissolution was started at 187.84 °C via a differential scanning card (in TA Instrument model qi〇〇2〇Differential Scanning Calorimeter. The sample was placed and weighed on the Ai plate. The plate was sealed with a manual extruder supplied by the vendor) The sample was incubated from 35 ° C to 300 ° C at 15 ° C / min. Example 44D 1-(2_{4-[(6,7-Dihydro[1,4]dioxo[2,3-c]嗒π well 176 200817417 methyl)amino]-1-hexa ^比.定基}Ethyl)-7-Gas-2(1 Η)-Bite 5ϋ林嗣. Hydrochloride will be 30 mg of 1-(2-{4_[(6,7-dihydro[1,4] Dioxol and [2,3-c] tower. Well-3-ylmethyl)amino]-1-hexamethyl ton sigma}ethyl)_7-murine 5 -2(1Η)-porphyrin The ketofumarate was slurried in 0.25 ml of decyl alcohol and 3 drops of isopropylamine and 0.25 ml of isopropanol and 1.0 ml of acetonitrile were added and the mixture was heated to 60 ° C. The sample was dissolved and cooled to 30 °C. The mixture was eluted on a Chiralpak IA column (5 micron, 21 x 250 nm) with 80:20:0.1 acetonitrile:isodecyl alcohol:isopropylamine and the main extract was concentrated to a white solid ίο (20 mg). This was dissolved in warm methanol (5 mL) and 1 equivalent of 6N HCl was added. The mixture was concentrated and dried under high vacuum <RTI ID=0.0> Example 44E 1_(2-{4-[(6,7-Dihydro[1,4]dioxo E and [2,3_c]indole-3-15 fluorenyl)amino]-1-hexazone 0定基}ethyl)-7-gas-2( 1H)-^17 loss 1:1 lindane citrate added acetone (7.0 ml) to crystalline (6,7-dihydro[1,4 Dioxindole[2,3-c]indole-3-ylindenyl){1-[2-(7-fluoro-2-keto-1(2H)-jun ϋ u 林 林 林) Base]-4-hexanitrogen to sigma base} Amino decanoic acid 1,1 -diindolyl ethyl ester free base (152.90 mg, 0.3471 mmol). The thick slurry was heated at 50 ° C for 1 hour and then cooled to room temperature. Citric acid (3.0 M solution in water, 1.0 eq.) was added to the thick slurry at room temperature. A thick slurry was obtained upon addition of the acid and combined with a second portion of acetone (3.0 mL). The thick slurry was then heated at 50 ° C for 12 hours, slowly cooled to 23 t (cooling rate was l.l ° C / min. · mm ·-· & 177 200817417 clock) and stirred at 23 ° C for 6 hours. The thick slurry was further cooled to 5 ° C (cooling. rate was 〇.l ° C / min) and stirred at 5 ° C for 12 hours. The thick slurry was filtered, washed with acetone and air dried for 15 minutes. The weight of the obtained crystalline citrate was 187.3 mg. 5 Example 44F 1_(2_{4-[(6,7-Dihydro[1,4]dioxo][2,3-c]indole_3_ylmethyl)amino]-1-hexahydropyridine Ethyl}ethyl)-7-fluoro-2(m)-porphyrinone L-tartrate Adds isopropanol (500 μl) to crystalline (6,7-dihydro[1,4] 1〇[芑,[2,3-c]嗒耕-3-ylindenyl){1-[2-(7-fluoro-2-keto-1(2H)-indenyl)ethyl] 1,4-Hexidopyridinyl}aminocarbamic acid 1,1-didecylethyl ester free base (20.40 mg, 0.0463 mmol). The thick slurry was cooled to room temperature after heating for 1 hour at TC. L-tartaric acid (1.0 M solution in methanol, 2.0 eq.) was added to the thick slurry at room temperature. The thick slurry 15 was then at 40 ° C. Heat for 5 hours, slowly cool to 23 ° C (cooling rate is (U ° C / min) and stir at 23 ° C for 5 hours. The thick slurry is further cooled to 5 ° C (cooling rate is 〇.l ° C / min And stirring at 48 ° C for 48 hours. Filtration of an aliquot (75 μL) was carried out to a sample of L-tartrate after agglomeration. 2〇Example 45 6-{[(1-{2-[6- (decyloxy)-3-ketopyrido[2,3-b]&lt;cultivated-4(3H)-yl]ethyl}-4-hexahydropyridinyl)amino]indenyl}-2« ^比啶和[3,2-b][l,4]哼耕-3(4H)ketone 178 200817417

5 10 15 20 4-[2_(4_Aminopyrrolidine)ethyl]methane (methoxy) bite and [2,3-b]吼口井-3 (4H; M with ( 50 grams, 0J648 millimolar) and 3_g homo--3,4-dihydro-2H-pyrido[3,24][1,4] hexan-6-aldehyde (synthesis see W02003087098, example 31 (e () (29.4 mg, 0.1648 mmol). A solution of anhydrous DCM (5 mL) and dry EtOAc (5 mL) was stirred at room temperature for 5 min. 〇4·7 mg, 耄·494 耄 )) and the mixture was stirred under argon atmosphere for 24 hours. The reaction was treated with saturated aqueous NaHC03 (2 mL) and 9:1 DCM:MeOH (5 mL). The aqueous layer was separated and extracted with 9:1 DCM:MeOH (10 mL) and 5:1 DCM:MeOH (2×20 mL). The organic extracts were combined, passed through a hydrophobic frit and evaporated to an orange coll. The ruthenium tube was eluted with 80:20 DCM:MeOH to give the product as a yellow solid (39.8 mg, 52%). MS (ES+) m/z 466 (MH+). !H NMR 5 (CDC13, 400 MHz) 1.49 (2H, m). 1.93 (2H, m) 2 1R λ ^ 2.77 (2H5 m), 3.10 (2H, m), 3.85 (2H, s), 4.03 (3H, s), 4 .58 (4H 1H d

Hz), 6.94 (1H? d, J 8 Hz), 7.18 (1H? d5 J 8 Hz), 8.00 (!H5 ^ Example 46A 4-(2-{4-[(6,7-Dihydro[1, 4] dioxo[2,3-c;j 嗒 曱 曱 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基Pyridin-3 (4Η)-keto dihydrochloride

179 200817417

5 4_[2_(4_Amino-1-hexahydropyridyl)ethyl]_6-(decyloxy) acridine [2,3_b]pyrazine_3(4H), (50 mg, 0.1648 m Mohr) and 6,7-dihydro[1,4]-oxo[2,3_c] talin-3_over (30.1 mg, 0.181 mmol) in anhydrous DCM (5 mL) and anhydrous MeOH ( The solution in 0.5 ml) was stirred at room temperature for 5 minutes. Sodium triacetate bromide (115 mg, ίο 〇 · 543 mmol) was added and the mixture was stirred under argon for 24 hours. 6,7-Dioxa[1,4]dioxo[2,3-c]indole-3-aldehyde (50 mg, 〇·236 mmol) was added again and the reaction was stirred for 5 hours with saturation. Treatment with aqueous NaHCO3 (2 mL) and 9:1 DCM:MeOH (5 mL). The layers were separated and the aqueous layer was extracted with 9:1 DCM:MeOH (10 mL) and 5:1 DCM:MeOH (2x20 The organic extracts were combined, passed through a hydrophobic frit and evaporated to an orange colloid. It was eluted on a 20 gram silica gel column with a gradient of 20:1 to 1 :1 DCM:MeOH to give the title compound as a free solid base of the crude solid (26·1 mg, 35%). MS(ES+)m/z454(MH+). ln NMR 5(CDC13) 1.42 (2H, m). 1.92 (2H, m), 2.19 (2H, m), 2.55 (1H, 2.75 (2H5 m), 20 3.06 (2H,m), 4.00 (2H,s),4·03 (3H,s)5 4.37 (2H,m),4·51 (2H,m),4.58 (2H,m) 6 ' (1H,d , J 8.4 Hz), 7·03 (1H, s), 8·01 (1H, d, J 8·4 Hz), 8·15 (1H, s). ' ' Free base (26·1 mg) , </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt;

180 200817417

Example 46B 4-(2-{4-[(6,7-Dihydro[1,4]dioxo][2,3-c]indole+3- 5ylmethyl)amino]-1-hexa Hydropyridyl}ethyl)-6-(methoxy)-pyrido[2,3-b]pyroxy-3(4H)·ketofumarate Add 1 equivalent of fumaric acid to 4-( 2-{4-[(6,7-Dihydro[1,4]dioxo[2,3-c]indole-3-ylmethyl)amino]]_hexapyridinyl}ethyl a solution of -6-(methoxy)-bite and [2,3-b]吼n well-3(4H)-one, followed by a strip of the title compound. 10 Example 47 1-(2-{4-[(6,7-Dihydro[1,4]dioxo[2,3_φ"_____)-amino]-1-hexahydropyridyl }Ethyl)_7_(methoxy)-2(1 Η)-Rugged Sun Dihydrochloride

15 hexahydroacridinyl)ethyl]_7_(methoxy(4) 1-[2-(4-amino-1yl)-2(1Η)-π奎唠σlinone 20 9ηυ, ^ 々N°° ratio 11 Alkyl)ethyl]-7-fluoro-2(1Η)-fluorenone dihydrochloride^ ^ ^ ^ ^ ^

181 200817417 6 drops of a solution of vaporized ammonium were added and the mixture was evaporated to dryness. The residue was extracted several times with 10% MeOH / DCM and filtered and evaporated. The residue was chromatographed on EtOAc (EtOAc) elute 5 MS (+ve ion electron spray) m/z 303 (ΜΗ+). (b) title compound

H2-(4-Amino-1-hexafluoropyridinyl)ethyl]_7_(decyloxy)-2(1Η)-fluorenone (2 mg, 〇66 mmol) And (6,7-dihydro[1,4] 0-oxohexo[2,3-c] talin-3-acid (116 mg, 0.70 mmol) in MeOH (8 mL) and chloroform (8 The solution in ML) was heated under reflux with 3A molecular sieves overnight. It was allowed to cool and sodium triethylphosphonium borohydride (0.54 g, 2.55 mmol) was added and the mixture was stirred at room temperature overnight. Aldehyde (20 mg) and ethoxylated borohydride (100 mg) were added after 7 hours. The mixture was spoiled for three days, then alkalized with aqueous sodium hydrogencarbonate and the layers separated. The aqueous layer was extracted with EtOAc EtOAc (EtOAc)EtOAc. 0 δΗ (CDCI3), (250 MHz)' 1.45 (2H, m), 1.92 (2H, br.d, part, obscured by water), 2·21 (2H, t)3 2.56 (1H, m) ,2·68 (2H,t)5 2·99 (2H,br·d),3.93 (3H,s),4·00 (2H,s), 4.35 (4H ,m),' 4·52 (2H,m), 6.88 (1H,m),6·93 (1H,dd),7.03 (1H,s),7.78 (1H,d),8·12 (1H, s)· ' MS (+ve iontophoresis) m/z 453 (MH+). Use free base in MV/DMM/MeOH in 1,4-two π

The title compound dihydrochloride was obtained after treatment with EtOAc/EtOAc (EtOAc): Example 48 1-(2]4_[(2,3-Dioxa[1,4]dioxoindole b]acridine_7_fumarate fluorenyl)amino]-1-hexahydropyridyl }Ethyl)-7-fluoro-2(111)_fluorenone

10 Amino-based hexamethylene oxime 11 butyl group) ethyl]_7_gas-2(1H)-porphyrinone dihydrochloride (6 〇 mg, 〇166 mm Moule) and (23_ 一氲[1 , 4] dioxin and [2,3-b] pyridine-7-over (synthesis see w〇2003/087098 example 20(e)) (33 mg, 0.197 mmol) in Me〇H (3 house) The solution in liters, chloroform (3 ml) and triethylamine (6 ml) was heated under reflux for 15 times with a 3 Α molecular engineer to cool and add triacetate triaconate (0·11). g, 0.52 mmol, and the mixture was stirred at room temperature for 7 hours. Add diethylstilbene sodium hydride (〇 11 g) and stir the mixture for another 5 days before adding two portions of three Hydroxyl borohydride (〇 11 g). Add hydrogen carbonate aqueous solution to verify and extract the aqueous layer several times with Me〇H-DCM. The organic layer was dried and evaporated. 0-20〇/〇

The free state of the title compound (2 mg, 27%) was obtained after eluting with MeOH-DCM. Br*d)^ 2·18 2·52 (1Η, m)5 2.66

Td),7·13 (1H,dd),7·21 (1H,d)5 7·86 (1H,dd),'8·22, (1H,1)· 183 200817417 MS (+ve iontophoresis Fog) m/z 440 (MH+). The free base was treated with 1 equivalent of 0.5 M fumaric acid (0.1 mL) in DCM and evaporated to dry. The solid was triturated with EtOAc (EtOAc) Example 49 1-(2-{4-[(6,7-Dihydro[1,4]dioxo[2,3-c]indole-3-ylmethyl)amino]-1_6氲pyridyl}ethyl)-6,7-difluoro-2(1H)-porphyrinone trifluoroacetate

(a) {1-[2-(6,7-Difluoro-2-keto-1(2H)-carboyl)ethyl]-4-hexahydropyridinyl}(6,7-dihydrol) [1,4]dioxo[2,3-indene] indole-3-ylindenyl)amino 15 1,1-didecylethyl phthalate (6,7-dihydro[1, 4] 1,1-didecylethyl phthalate (0.31 g, 0.89 mmol) of dioxindino[2,3-c]indole-3-ylindolyl-4-pyridinium pyridinium decanoate And a mixture of (6,7-difluoro-2-keto-1(2H)-indenyl)acetaldehyde/decyl hemiacetal (about 1:1, 0.2 g, 0.89 mmol) in anhydrous A solution of MeOH (0. 25 mL) EtOAc (EtOAc) Sodium triethoxy borohydride (0.57 g, 2.67 mmol) was added and the mixture was stirred for 6 h. The solution was basified by the addition of aqueous sodium hydrogencarbonate and the layers were separated. The aqueous layer was extracted several times with DCM, and the organic layer was dried and evaporated. Chromatography on silica gel eluting with EtOAc (EtOAc:EtOAc) 184 200817417 MS (+ve iontophoresis) m/z 559 (MH+). (b) the title compound will be {l-[2-(6,7-difluoro-2-keto-1(2H)-indolyl)ethyl]-4-hexahydropyridinyl} (6, 1,1-Dimethylethyl 7-dihydro[1,4]dioxo-E[2,3-c]indole-3-ylindenyl)carbamate (0.17 g, 0.305 mmol) The solution in MeOH (0.65 mL) wasEtOAc. The residue was triturated with EtOAc (EtOAc) 10 δΗ (CD3OD), (250 MHz) 2.04 (2H, m), 2.49 (2H, br.d), 3.15 (2H, t),, 3·55 (2H, m), 3.60 (1H, m), 4.02 (2H, br·d), 4.46 (4H, m), 4.59 (2H, m), 4.676 (2H51), 7·24 (1H, s). 7.69 (1H, dd), 7·83 (1H, Dd),), 8·23 (1H, s). MS (+ve ion electron spray) m/z 459 (MH+). 15 Example 50 7-Chloro-6-{[({(38,43)-1-[2-(7-fluoro-2-keto-1(2H)-indolyl)ethyl]-4-3⁄4 -3-3 -17 咯 σ 定 } } } } } } } } } } } } } } } 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3

1-{2-[(3S,4S)-3-(Aminoguanidino)-4-hydroxy-1-. Biropyridyl] B 185 200817417 base}_7_Fluoro-2 (111&gt;-quinolinone (100 mg, 〇·33 奎毛夫斗) and 7-chloro-3-indolyl _3,4-di -Μ-咕唆[3,2-b][l,in the form of phenolic aldehyde (Human Cheng W02003064421, Example 15(c)) (70 mg, 〇33 亳 Mo in A 5 10 15 alcohol (2 ml) The solution in dichloroacetic acid (4 ml) was chilled overnight at room temperature. Sodium triethoxysulfon borohydride (130 mg, 0.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. Chromatography on silica gel eluting with 0-10% methanol-DCM-1% EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) ) 2.58 - 2 67 fm 2 m 2 (ΛΛ /=11.75, 6.44Hz, 1 Η) 2.76 - 2.88 (m, 2 Η) 2.90 - 2.99 (m, 2 Η) 3 12 (dd Λ 36 Hz, 1 H) 3.31 (dt, 7=3.28, 1.64 Hz, 2 H) 3.35 (s, 3 H) 3.85.3.95 (m 2m /=6.06, 3.28 Hz5 1 H) 4.43 (ddd5 /=8.21, 6.06, 5.94 Hz5 2 H) 4.66 (s; 2 H) 6 59 d J=9 60

Hz, 1 H) 7.08 (td? J=8.46, 2.27 Hz51 H) 7.36 (s, 1 H) 7.39 (dd, 7=11 49 2 15 Hz \ R) 7.72 (dd? /=8.59, 6.32 Hz, 1 H) 7.85 - 7.91 (m, 2 H). 2.15 Hz, 1H) MS (+ve iontophoresis) m/z 502 (MH+).

Add 1 equivalent of benzoic acid to 7-chloro-6-{[({(3s,4S) small [2-(7-fluoro-2-keto-1(2Η)-α quinacridyl)ethyl] a solution of -4-transmethyl-3_pyrrolidinyl}methyl)amino]indolyl}_2Η-pyrido[3,2_b][l,4H till-3(4Η)-one in MeOH, followed by Evaporation gave the title compound as the benzoate. Example 51A H2-{4_[(2,3-Dihydro[1,4]dioxo][2,3-c]pyridin-7-ylindenyl)amino:hi-hexahydropyridyl}ethyl )-7-(decyloxy)pyrido[2,3_b]pyrazine-2(1H)-one hydrochloride 186 '' ^ 200817417

(4) 7_(decyloxy) small (2-propenyl + yl) acridine [2,3_b]t well_2 (1h), 7_gas-1_(2-propene small base compared to pyridine [2,3_b Pyridin-2 (1h)__ (196 4»g '〇·956 house Moer) in y[eOH (5 ml) solution with 曱1 〇 〇 ( (25% w/v in MeOH, 1.03 ml, 4.780 mmoles) was treated and stirred at room temperature for 1 hour. More 7-fluoro-1_(2-propen-1-yl)pyridino[2,3-b]pyrazine-2 was used for the reaction. (1H)-ketone (657 mg, 3.204 mmol) was repeated in MeOH (15 mL) and sodium succinate (25% w/v in MeOH, 3.45 mL, 16.02 mmol). The mixture was combined and taken up with EtOAc EtOAc (EtOAc)EtOAc. The product was purified by column chromatography eluting EtOAc EtOAc (EtOAc) b) [7-(decyloxy)-2-ketoacridino[2,3-b]pyrazine-1(2H)-yl]acetaldehyde ( Base hemiacetal) 7-(methoxy)-1-(2-propen-1-yl)pyridinium, 乂187 200817417 [2,3-b]. Ratio α well_2(iH)-ketone (846 mg, 3·9 〇〇 millimolar) dissolved in μ· a 'burn (20 liters) and water (10 ml). Force 11 into the sodium molybdenum (2 〇 9 g, 9.75 . The mixture was stirred for 4 hours at room temperature and then extracted with 2% MeOH/DCM (3×200 5 mL). Dry over magnesium sulfate, filter and evaporate under reduced pressure to give [7_(decyloxy)-2- ketopyrido[2,3-b]pyrazine-1(2H)-yl]acetaldehyde (mostly present Methyl hemiacetal impure brown solid (969 mg, 113% &gt; MS (ES+) m/z 220 (MH+), 252 (methyl hemiacetal h+). 10 (c) (2,3 - monohydro[1,4]oxyxo[2,3_c] 吼-7-ylindenyl)(1-{2-[6-(methoxy)-3- keto 吼π定[ 2,3-b]. Ratio. Well _4(311)-yl] Ethyl}-4-hexahydropyridyl)amino decanoic acid 1,; 1 dimethyl hydrazine Yl)-2-ketopyrido[2,3-b]indole-1 (2H)-yl]ethyl 15 aldehyde Sulfhydryl semi-shrinking) (969 mg, 3.510 mmol) and monooxo[2,3-c]bitone-7-ylindenyl) 4-hexahydroguanidinoyl decanoic acid Acetate (synthesis see WO2004/058144 Example 99(h)) (1 22 g '3.510 mmol) in a mixture of gas (40 liters) for 1 hour, then add NaBH(OAc)3 (377 mg, 1.59 millimoles). After the reaction was stirred for 20 hours, a saturated aqueous solution of NaHC 3 (1 mL) was added. The reaction was then extracted with 10% MeOH (3 x EtOAc) in DCM. The combined organic layers were dried <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> <RTIgt; 188 '( Ξ 200817417 MS (ES+) m/z 553 (MH+). (d) The title compound is in (2,3-dihydro[1,4]dioxo[2,3-c]acridine_7 -ylmethyl)(1-{2-[6-(methoxy)-3-keto.pyrido[2,3-b]pyrrol-4(3H)-yl]ethyl}-4 - hexahydropyridyl) guanidinium ruthenate, iota-dimethylethyl ester (1·4〇8 g, 2·5510 mmol) in chloroform (2 mL) and MeOH (5 mL) 4M HCl (10 ml) in 1,4-dioxane was added and the reaction was stirred at EtOAc EtOAc EtOAc. Extraction of 20% MeOH (3×1 mL). EtOAc. 266 mg, 23%) MS (ES+) m/z 453 (MH^.)H NMR (250MHz) 5 (CDC13) 1.32-1.52 (2H, m), 1.82-1.98 (2H, m), 2.09-2.25 (2H, m)

2·42-2·2·61 (1H, m), 2.61-2.72 (2H, t), 2·85·3·01 (2H, m), 3.78 (2H, s), 4·00 (3H, s),, 4·26-4·34(ιη,6H),6·81 (1H,s),7·21 (1H,d5 J 2·5Ηζ),8·10 (1H,s),8· 34 (1H, s), 8·51 (1H d, J 2.5Hz)·, by dissolving the obtained free base in 1:1 DCM:MeOH and adding 1 equivalent of 4M in 1,4-dioxane HC1 converts this material into an HCl salt. It is then evaporated to dryness. Example 51B 1-(2_{4-[(2,3-Dihydro[1,4]dioxo[2,3_c]pyridine·7-ylmethyl)amino]-1-hexahydropyridinyl} Ethyl)_7_(decyloxy)pyrido[2,3-b]pyrazine-2(1H)-one dicarboxylate purified by MDAP 1-(2-{4-[(2,3-dihydro) [1,4]dioxanthene

189 200817417 [2,3-c]pyridin-7-ylmercapto)amino]-1-hexahydropyridinyl}ethyl)-7_(decyloxy) than bite and ^-ink-out-of-print- The title compound is obtained after the ketone. Example 52 6-({[(3R,4R)·4-hydroxy small {2_[7-(methoxy)-2-keto-1(2H)")) } · · ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) )

(a) (2Ε)-3-(ethoxy)-2-propenyl chloride Cooled to hydrazine in grass mash (40 mL, 0.453 mmol). In a solution of N2t15, ethyl vinyl ether (29 mL, 0.302 mol) was added via the addition funnel while maintaining the internal temperature at a rate of 〇 °C. After the addition was complete, the reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was heated at 90 &lt;0&gt;C for 90 minutes and then heated at 12 (TC) for one hour. The product was isolated as a yellow oil, which was obtained by vacuum evaporation to give 22 g (54%). 2 〇1H NMR (400 MHz, CHLOROFORM-i /) δ ppm 1.37 (t, J7.07 Hz 3 H) 4 04 (q *77 07

Hz, 2 H) 5.48 (d, J 12.13 Hz, 1 H) 7.77 (d9 J 12.13 Hz5 1 H). ' * (b) (2E)-3-(ethoxy)-N-[3-(曱Add pyridine (15. 8 ml, oxy)phenyl]-2-propenylamine in m-anisidine (1·8 mL, 0.163 mol) in DCM (400 mL). 〇196 Mo 190 200817417 ear), (2E)-3-(ethoxy)-2-propenyl chloride (22 g, 0.163 mol) was added to this reaction mixture via an addition funnel. After warming to ambient temperature, the reaction was stirred for 18 h then diluted with EtOAc EtOAc. The crude product was washed sequentially with saturated aqueous NaHC03 (2×400 mL), brine (1×250 mL) and 0.25 MHCI (1×250 mL). The organic layer was dried with EtOAc EtOAc EtOAc m. MS (ES+) m/z 222 (MH+). 1〇(c) 7-(decyloxy)-2(1Η)-porphyrinone (2E)-3-(ethoxy)-N-[3-(methoxy)phenyl]-2- Propylene amine (25 g '〇·113 mol) was dissolved in concentrated H2S04 and stirred for 1 hour. The reaction mixture was poured into ice and filtered. The crude product was washed with EtOAcqqqqm 15 MS (ES+) m/z 175.6 (ΜΗ+). 1Η NMR (400 MHz, DMSO 〇 δ ppm 3·80 (s, 3 Η), 6.30 (d, J = 9.35 Ηζ, 1 Η) 6·77 - 6.83 (m, 2 Η) 7·55 (d, 〇Γ=8·34 Hz, 1 Η) 7·81 (d, J=9.35 Hz, 1 Η) 11·63 (s,1 Η). (d) 7-(decyloxy)-indole_(2-propenyl)_2(1Η)_fluorenone

7-(Methoxy)-2(1Η)-πquinactone (5 g, 〇〇29 mol) was applied in dmF 2 〇 (7 liters). Add 0H to the solution of 0 and underarm (60% in oil, 2,5 g, 0.063 m), stir for 1 min, warm to ambient temperature and mix for 30 minutes. Allyl iodide (3.13 liters, 0.034 moles) was added to the reaction mixture and stirred overnight. The reaction was quenched with water (2 ml) / quenched. Column chromatography (gradient_5% Me〇H in DCM) 191. MS (ES+) m/z 215.8 (ΜΗ+). (4) [7-(Methoxy)_2-keto-1(2H)-.奎 基 ] acetaldehyde 5 in 7-(decyloxy)-1 _(2_propionyl-1-yl)-2( 1H)-° 奎ϋ林酉同 (4 14 g, 0.019 mol) 1,4_ Diterpenoid (80 ml) and water (40 ml) were added sodium molybdate (9.5 g, 0.044 mol) and osmium tetroxide (10 ml, 4% aqueous solution) in a stirred solution of ν2. ) and stir overnight. The reaction was concentrated and partitioned between 20% MeOH / DCM (EtOAc) The organic layer 10 was dried over magnesium sulfate, filtered and concentrated. The title compound was obtained as a green solid (71%). MS (ES+) m/z 217·8 (MH+). (f) {[(3S,4R)-4-Hydroxy-3_pyrrolidinyl]methyl}aminocarbamic acid phenylmethyl hydrazine 15 (3R, 4R) winter warping base [({[(phenyl) Thio)oxy]alkyl}amino) fluorenyl]-1-pyrrolidinecarboxylic acid ι,ι_didecylethyl ester (synthesis see WO2006002047, preparation 24(c) (±)-cis-3-hydroxyl -4-[({[(phenylmethyl)oxy))}amino)indolyl]-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester E2 isomer) (2 g, To a stirred solution of DCM (50 mL) was added trifluoroacetic acid (5 mL) and stirred for 2 hr. The reaction mixture was concentrated and placed under high vacuum for 3 h. The TFA salt was dissolved in 1 mL of 10:1 CHCl3:MeOH and MP-carbonate resin (8 g; 22.8 mmol) was added and stirred overnight. The reaction mixture was filtered and evaporated to give crystal crystal crystal crystal crystal crystal

192 200817417 MS (ES+) m/z 251·3 (MH+). (g) [((3R,4R)-4 propyl group is small {2_[7_(decyloxy)-2-keto)](2H)_U quinolinyl]ethyl b-3-pyrrolidyl)methyl Phenylmethyl carbamate will be {[(3S,4H)-4•hydroxy-3-pyrrolidinyl]methyl}amino phenyl decanoate (3 〇〇 mg, U0 mmol) and [7_(decyloxy)_2-keto-1(2H)- porphyrinyl]acetaldehyde (26 mg, 丨12 mmol) in anhydrous DCM (5 mL) and anhydrous MeOH (1 mL) Mix with the solid sodium carbonate of the tip of the spoon. The reaction mixture was stirred under a nitrogen atmosphere for a few hours, then sodium triethylphosphonium bromide (762 mg, 3.6 mmol) was added and stirred overnight. The reaction mixture was condensed and subjected to column chromatography (90:1 〇: i DCM:Me?H:NH??H? 452.3 (MH+) 〇(h) l]2-[(3R,4R)-3_(aminomethyl)_4_pyridylpyrrolidyl]ethyl}-7-(methoxy)-2( 1Η)-唉π林酉同在[((3R,4R)_4_ per base small d7_(methoxy)butanyl-1(2H)_4咐yl]ethyl}_h ratio slightly thiol) 2% pd(〇H) 2/c was added to a solution of amino phthalic acid phenyl hydrazine vinegar (337 gram, 0.746 Torr), degassed and allowed to stand at 1% atmospheric pressure for 18 hours. The mixture was filtered through EtOAc (EtOAc) elute elut elut elut elut elut elut elut (3R,4R)-3-(Aminoguanidino)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-(methoxy)-2(1Η)-fluorenone (118 mg, 0.372 Millol) and '3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]thratic-6-aldehyde (synthesis see 5 W02004058144, Example 7 (d )) (77 mg, 0.398 mmol) in anhydrous DCM (5 mL) and anhydrous MeOH (1 m The mixture was mixed with 1 scoop of solid sodium carbonate. The reaction mixture was stirred under a nitrogen atmosphere for 18 hours, then sodium triacetoxyborohydride (241 mg, 1.09 mmol) was added and stirred for 1 hour. Concentration and column chromatography (90:10:1 EtOAc: EtOAc: EtOAc: EtOAc) 1H NMR (400 MHz, CD3OD) δ ppm 3.45-3.56 (m,3 Η) 3·74 (s,4 Η) 4·00 (s,5 Η) 4·24 (dd,/5.68, 2.15 Ηζ ,1 Η) 4.39 (s,3 Η) 4.66 (s,1 Η) 4.73 - 4.82 (m,3 Η) 6.58 (d,J9.35 Ηζ? 1 Η) 7.01 (dd, 78.59? 2.02 Ηζ? 1 Η ) 7.08 (d, J 1.77 Hz, 1 Η) 7.16 (d? /7.83 Ηζ5 1 Η) 7.69 (d, J8.59 Ηζ, 1 Η) 7·84 (d, J7.83 Ηζ, 1 Η) 7· 92 (d, /= 9.35 Ηζ, 1 Η). 15 Dihydrochloride salt was prepared by adding 149 μl of 4NHC1/1,4-dioxane to a solution of a free base. Example 53 6-({[((3R,4R)-4-hydroxy-1-{2-[7-(decyloxy)-2-oneyl-1(2H)-indenyl]ethyl}-) 3-pyrrolidino)indenyl]amino}indenyl)-2H-pyrido[3,2-b][l,4]indole-3(4H)-one dihydrochloride 20 200817417 {2-[(3R,4R)-3-(Aminoguanidino)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-(methoxy)-2(1Η)-pyridone ( 111 mg, 0.350 mmol, and 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-aldehyde (synthesis see • W02003087098, example 31(e)) (68 mg, 0.385 mmol) was mixed with 1 scoop of solid sodium carbonate in 5 mL of DCM (5 mL) and anhydrous MeOH (1 mL). The reaction mixture was stirred under a nitrogen atmosphere for 18 hr and then sodium triacetoxyborohydride (233 mg, 1.05 m. The reaction mixture was concentrated and purified with EtOAc EtOAcjjjjjjjj MS (ES+) m/z 496.5 (MH+). 1H NMR (400 MHz, CD3OD) δ ppm 3.49 (dd5 J 10.99, 1.64 Hz, 3 H) 3.69 - 3.81 (m5 4 H) 3.96 - 4.02 (m? 4 H 4.23 (dd? J5.56, 2.02 Hz, 1 H) 4.34 (s, 3 H) 4.66 (s, 1 H) 4.71 (s? 2 H) 4.73 - 4.82 (m, 3 H) 6.59 (d? 78.84 Hz, 1 H) 7.00 (d, 78.59 Hz, 1 H) 7.07 (s, 1 H) 7.14 (d, /8.08 Hz3 1 H) 7.39 ((1,/8.08 Hz, 1 H) 7.68 (d, J8. 59 Hz, 1 H) 7.90 (d? J9.60 Hz, 1 H). 15 Dihydrochloride is prepared by adding 102 μl of 4NHC1/1,4-dioxane to the free-form solution. Example 54 6-({[((3R,4R)-4-hydroxy-1-{2-[7-(decyloxy)-2-keto-1,5-naphthyridin-1(2H)_) Ethyl 4-ethylpyridinyl)indenyl]amino}曱2〇yl)-2H-pyrido[3,2-b][l,4]indole-3(4H)-ketofuma Acid salt

195 200817417 (a) [((3R,4R)-4_)-yl-l_{2_[7-(methoxy)_2 keto-1,5-naphthyl-1,3-(2Η)-yl]ethyl} -3-pyrrole thiol] phenyl phenyl phthalate in [7-(methoxy)-2-keto-1,5-naphthyridin-1(2Η)-yl]acetaldehyde ( Add hydrazino hemiacetal) (0.500 g, 2·29 mmol) to a solution of 1:1 (MeOH/CHCl3) (40 mM 5 liters) of {[(3S,4R)-4-hydroxypyrrolidine_ 3-methyl]methyl}amino phenyl carbamate (0.658 g, 2.29 mmol) and triethylamine (0·351 mL, 2.52 mmol). The resulting solution was stirred at ambient temperature for 1 hour. Na(OAc)3BH (1.46 g, 6.87 mmol) was added and the solution was further stirred at room temperature for 18 hours. The reaction mixture was concentrated on EtOAc (EtOAc) elute elute . MS (ES+) m/z 453 (MH+). (b) l-{2-[(3R,4R)-3-(Aminomethyl)-4-hydroxypyrrolidinyl]ethyl 15yl}-7-(decyloxy)-1,5-naphthalene Oral-2(1H)-one in [((3R,4R): 4-hydroxy-1-{2-[7-(decyloxy)-2-S-yl-1,5-naphthyridine-1 (2H)-yl]ethylidene 3-pyrrolidinyl)hydrazino]phenyl phenyl carbamate (0·76 g, 1.68 mmol) in Me〇H (1 () mL) 10% Pd/C (0.20 g) was added and the resulting solution was exposed to 20 on a parr shaker for 1 hour at 20 PSI of H2. No reaction was observed. The solution was then exposed to a 5 psi h2 on a Parr shaker. The solution was filtered through celite and concentrated under reduced pressure (0.408 g, EtOAc). MS (ES+) m/z 319·2 (MH+). 196 200817417 (C) The title compound is 1-{2-[(3R,4R)_3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}_7_(methoxy)-1, 5-naphthyridin-2(1H)-one (〇·140 g, 〇·44 mmol) Add 3-keto- 3,4 in a solution of 1:1 (MeOH/CH 2 Cl 2 ) (25 mL) -5 Diterpene-2H-pyrido[3,2-b][l,4]indole-6-aldehyde (synthesis see WO2003087098, Example 31(e)) (0.078 g, 0.44 mmol) and sodium sulfate (0.100 g) and the resulting solution was stirred at ambient temperature for 18 h. Na(OAc)3BH (0·28 g ' 1.32 mmol) was added and the solution was stirred at room temperature for additional 2 hours. The reaction mixture was concentrated on silica gel and chromatographed [0-00% CHC13 / (90:10:1) CHCl3 / MeOH / NH4OH] to give a colorless oil. This material was further purified by EtOAc (EtOAc:EtOAc) The free state was obtained by treating the carbonate resin supported with excess polymer in MeOH for 3 hours. 15 1H NMR (400 MHz5 CD3OD) δ ppm 2.70 - 2.79 (m5 1 Η) 3.04 - 3.12 (m, 3 Η) 3.14 - 3.24 (m,3 Η) 3·26 (d, J=5.05 Hz, 1 Η) 3.37 (s,5 Η) 4.02 - 4.07 (m,3 Η) 4.27 (d,J=2.27 Hz, 2 H) 4.46 - 4.57 (m, 2 H) 4.60 - 4.68 (m, 1 H) 4.70 (d, J=1.26 Hz, 2 H) 6.63 (d5 7=9.60 Hz, 1 H) 6.68 (s5 3 H) 7.09 (d, J=8.08 Hz51 H) 7.37 (d, J=8.08 Hz, 1 H) 7.46 (d , 7=2.27 Hz, 1 H) 7.87 (d5 7=9.60 Hz, 1 H) 8.31 (d5 J=227 Hz, 1 H). Fumarate is treated with 1 equivalent of fumaric acid in MeOH 20 6-({[(3R,4R)-4- peryl_1-{2_[7-(decyloxy)-2. keto-1,5-naphthalene-1(2H)-yl]) Kip 3-pyrrolidinyl)indolyl]amino}indenyl)-2H-pyrido[3,2-b][l,4]Nastil-3(4H)-one is formed as a gray solid ( 0.026 grams, 10%). 197 200817417 Example 55 6-({[(3R,4R)_4-hydroxyl small {2_[7-(methoxy)-oxanyl-1,5-naphthalene-1(2H)-yl]ethyl} _3-pyrrole σ-decyl)methyl]amino}methyl)-2Η_pyrido[3,2_b][l,4]thratic-3(4Η)-keto fumarate

10 15 20 in 1_{2-[(3,411)_3-(aminomethyl)-4-yl-1-yl]ethyl}-7-(decyloxy)-1, 5-naphthoquinone-2(1Η)-酉同(〇·140g, 〇·44mmol) Add 3-indole _3 to a solution of 1:1 (MeOH/CH2Cl2) (25ml). 4_ Dihydro-2H-pyrido[3,2-b][l,4]thratic-6-aldehyde (synthesis see W02004058144, Example 7(d)) (0.085 g, 0·44 mmol) and sulfuric acid Sodium (0.100 g) and the resulting solution was stirred at ambient temperature for 18 h. Na(OAc)3BH (0.28 g, 1.32 mmol) was added and the solution was stirred at room temperature for further 2 hr. The reaction mixture was concentrated on silica gel and chromatographed [0-00% CHC13 / (90:10:1) CHCl3 / MeOH / NH4OH] to give a colorless oil. This material was further purified by HPLC (CH3CN/H20 w 1% TFA) to afford the title compound of trifluoroacetate (0.090 g). The carbonate resin, supported with an excess of polymer, was treated in MeOH for 3 hours, then the silica gel was filtered and the solution was concentrated to give a free base. LCMS: m/z 497 (M+H)+.; TM 7·90 (dj J=9·2 1H&gt;»7·45^7·8 1H), 7.22 (dd, J 9.2 Hz, 1H), 7.10 (s, lH), 6.81 (d, J = 7·8 Hz 1H) 3 95 (d J = 14 4 Hz 1H), 3.85 (s, 3H), 3·77 (d, J = 14.3 Hz, 1H) , 3.59 (m 1H) 3 31, L· 3 Bu, 1H), 2.10 (m, 1H)? 2.07 (m, 1H), 2.04 (m, 1H), 1.94 (m5 1H), 1.46 (m, 1H) 198 200817417 Fumarate is treated by treatment with 6 equivalents of fumaric acid 6-({[(3R,4R)-4-), benzyl-1 - {2-[7-(methoxy)-2-酉同基-1,5-nathenium-1 (2H)-yl]ethyl}-3-pyrrolidinyl)indolyl]amino}mercapto)-2H-pyrido[3,2-b][ l, 4] thiot-3 (4H)-one formed to give a gray solid (0.035 5 g, 13%) 〇 Example 56 l-(2-{(3S,4R)-4-[(2,3- Dihydro[1,4]dioxanyl[2,3-c]. 咬-7-ylindenyl)amino]-3-yl-1-hexayl-to-bityl}ethyl)- 7-Fluoro-1,5-naphthyridine-2(1H)-one hydrochloride 10

15 (a) {(3S,4R)_l-[2-(7-Fluoro-2-keto-1,5-naphthyridin-1(2H)-yl)ethyl]-3-pyridyl-4- Six rat sigma determinate} 1,1 - dimethyl hydrazine carboxylic acid (7-fluoro-2-keto-1,5-naphthyridin-1(2Η)-yl)acetaldehyde decyl hemiacetal (200 mg, 0.8396 mmol) and [(3S,4R)-3-hydroxy-4-hexahydropyridine 20-yl]amino decanoic acid 1,1-didecylethyl ester (synthesis see W02004058144, Example 5 ( c), cis-(3-hydroxy-4-hexahydropyridyl)carbamic acid tert-butyl ester to palmate isomer 2) (182 mg, 1 eq.) in chloroform (10 ml) and MeOH (0.5 ml) Stir under argon pressure: mix for 2 hours. Sodium triethoxy hydride borohydride (534 mg, 3 eq.) was added in one portion and the mixture was stirred at room temperature for a week.

199 200817417 Finally, it was quenched by the addition of saturated aqueous sodium bicarbonate (2 mL). Separate the organic layer with a hydrophobic glass-coupler and use a DCM (2x20)

Pen liter) extraction,. The organic extracts were combined in a stomach, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a crude product which was purified on a silica gel eluted by column 5 column chromatography using 0-20% in DCM Stripped with 2M ammonia in MeOH. The appropriate fractions were combined and evaporated under reduced pressure to give &lt;(3S, &lt;RTI ID=0.0&gt;&gt; _Hydroxy-4-hexahydropyridyl}amino dimethyl phthalate (31 〇 mg) of brown blister. ίο MS (ES+) m/z 407 (MH+). (b) l-{2- [(3S,4R)-4-amino-3-hydroxy-1-hexahydropyridyl]ethyl b 7-fluoro-1,5-naphthoquinone-2(1H)-one dihydrochloride will {( 3S,4R)-l-[2-(7-fluoro_2-keto-1,5-naphthyl-1(2H)-yl)ethyl15-yl]dongsylhexahydropyridinyl}aminocarbamic acid 1 , 1-Dimercaptoethyl ester (31 mg, 0.7627 mmol) was dissolved in DCM (1 mL). To the bubbling and the formation of the precipitate. After 2 hours, the solvent was removed under reduced pressure and the residue was dried under reduced pressure overnight to give l-{2-[(3S,4R)-4-amino-3 - hydroxy-1-2 〇 /, ^ ϋ疋 ϋ疋 ] ] ] ] ] ] 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 MS (ES+) m/z 307 (ΜΗ+). (c) title compound Ο 200 200817417 l l-{2_[(3S,4R)-4-amino-3-carbyl-1-6吼σ定基]B-yl b 7_fluoro], 5-naphthyridine-2(1Η)-_dihydrochloride (247 mg, 0.6513 mmol) at 9:1 volume: volume chloroform: MeOH (1.0 ml Stir at room temperature under argon pressure and add triethylamine (318 μl, 3.5 equivalents). Mix mixture 5 at room temperature for 1 minute, then add (2,3-dihydro[1,4] Oxidyl [2,3-c]pyridine-7-aldehyde (1〇8 mg, synthesized see w〇2〇04058144, Example 2(c) or W003/087098, Example 19(d)) and the mixture is in the chamber After stirring for 2 hours, the mixture was treated with sodium triethyl sulfonium borohydride (414 mg) in one portion. The mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium hydrogencarbonate (5 ml) was added and the organic layer was applied. The DCM was diluted to a total volume of about 1 mL. The organic layer was separated and dried with DCM (250 mL). White beads (130 mg) of the free state of the compound.

15 NMR δ (400ΜΗζ? CDC13): 8.44 (1H? d, J 2Hz), 8.34 (1H, s), 8.11 (1H, s)5 7.91 (1H, d, J 10Hz), 7.54 (1H, dd, J 8Hz, 2Hz), 6.89-6.86 (2H, m), 4.53-4.44 (1H, m), 4·36-4·2〇ϋ m), 4·12 (1H, s), 4·08 (2H, s),3·32·3·28 (1H,m),3.03-2.99 (2H,m),2.80-2.71 (2H m) ' &quot; 2.39 (1H, d, J 11Hz), 2.32-2.25 (1H , m), 1.95-1.84 (2H, m). ' ' MS (ES+) m/z 456 (MH+). This material was converted by dissolving in DCM and adding 1 equivalent of 1M HC1/ether and evaporating 2 〇 to dryness. Hydrochloride. MS is a free base. Example 57 1〇-(2-{4-[(2,3-Dihydro[1,4]dioxo[2,3-indene]吼唆7-ylindenyl)amino]-1 -hexahydro-sigma ratio sigma}ethyl)-6-fluoro-2,3-dihydro[1,4]dioxo[2,3-h]indole-9(10H)-one hydrochloride 201 200817417

5 (a) 5-Fluoro-3-nitro-1,2-benzenediol with boric acid (20.45 g, 330.7 mmol) and hydrogen peroxide (35%, 36.8 ml) in tetrahydrofuran (150 ml) The solution was treated with concentrated sulfuric acid (15 mL) and the mixture was applied at room temperature for 30 min. Add 1-(5-fluoro-2-yl-3-ylidenephenyl)ethanone (15 g, 75.4 mmol) in tetrahydrofuran (45 mL) and heat the reaction at 7 5 C 4 8 hours. The reaction mixture was cooled to room temperature, diluted with H~~~~ The combined organic layers were dried with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH , 50%), the desired product and a 5:1 mixture of 1-(5-fluoro-2-hydroxy-3-methyl-schottylphenyl)ethanone (4 g) and recovering 1-(5-fluoro-2-carbyl) 3-nitrophenyl)ethanone (1.5 g). ^NMR (250MHz) 6(DMSO) 6.91-6.97(m, 1H), 7.17-7.22 (m, 1H), l〇5 (bs? 2H). 20 (b) 7-gas-5-nitro-2 , 3_2 _1,4-benzoquinone dioxol 5-fluorobutyryl-1,2-benzenediol (6.55 g, 37.9 mmol), anhydrous potassium carbonate (21 g, 151.6 mmol) a mixture of 1,2-dibromomethane (8.2 ml) in DMF (70 ml) at 8 (TC and argon pressure for 5 min 202 200817417. The reaction was allowed to cool to room temperature and water (200 mL) was added. The aqueous layer was extracted with EtOAc EtOAc (EtOAc (EtOAc) (EtOAc). ) 4.38 (m5 4H), 6.88 (m? 1H), 7.25 (m 1H). 5 (c) 7-Fluoro-2,3-dihydro-1,4-benzodioxime-5-amine 7 -Fluoro-5-nitro-2,3-dihydro-1,4-benzodioxan (6e96 g, 35 mmol) and 5% Pd/C (4 g) in MeOH (500 mL) The atmospheric pressure of the gas is stored at room temperature and stirred overnight. The catalyst is filtered and the solvent is removed by 10, the residue is dissolved in MeOH (100 mL), and more 5% Pd/C (paste, 3 g) is added. ) and the mixture in hydrogen (4 Stir at room temperature overnight in the presence of 5 psi). The catalyst was filtered and the solvent was removed. The residue was taken up in Dcm (20 mL), and the solid was filtered and the compound in DCM was filled with silica gel (pre-wet with petroleum ether) The desired compound (3 g, 51%) was obtained by eluting with 10% _50 〇 / 〇 〇 〇 : : : 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 〇(d) 6-Fluoro-2,3-dihydro[1,4]dioxo[2,3_h]porphyrin 20 Concentrated sulfuric acid (25 ml), boric acid (2.22 g, 35·6 m Mohr), iron (II) sulfate heptahydrate (831 mg, 2.99 mmol) and 3-nitrososulfonic acid sodium salt (7.25 g '32.2 mmol) in a flask cooled in an ice bath Add glycerol (8.4 ml, 23 亳 Mo) and 7|2,3_ dihydro] ▲ stupid and dioxin-5-amine (3.9 g, 23 亳 Mo), then add water ( 25. The reaction was heated at 14 ° C for 3 hours and then cooled to room temperature. Mixture 203 200817417 to ice-water (100 ml) and filtered. Filtered and liquidated with 6N sodium hydroxide (13 mL) After pH 8 and ethyl acetate (300 ml) were disturbed. The mixture was then filtered through celite and the layers separated. The water was extracted with ethyl acetate (3×300 ml), and the combined organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated to give the crude product in ethyl acetate. The compound was then dissolved in a green solid (2.78 g, 60%). &quot; MS (ES+) m/z 206 (ΜΗ+). 10 (8) 6-Fluoro-1 〇_(2·propenyl small group)_2,3-dihydrofl,4] [2,3-h]. Quinoline _10_锵 iodine

?, fluorine-2,3: dihydro[M]dioxygen and [2,3 zhongkui 7 13.6 house Moer) and propyl propyl hydrazine (2.5 ml true 15 20 ml) and argon (four) Ah, heating, then in the pure 5 A 25 so that f should be cooled to the chamber pan, the solvent is decanted «solid in the _ ^ ^ dry after the instrument to get the desired product (4 grams, 8 , MS (ES +) m/z 246 (MH+) 〇(f) 7-fluoro_1〇-(2·propene small group, 丞)_2,3-diblue π 41 - 4 [2,3-h]喳咁-9(10H )-ketone'------------------- 6] (7 g, 2 i. 4 mmol) at room temperature / 1,4-dioxane in water (100 ml), stir in the buttercup, then at 45. 〇Overnight 204 200817417 Into water (100 ml) and the aqueous layer was extracted with 15% MeOH / DCM. The organic layer was dried over MgS 4 and the solvent was removed. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut 5 MS (ES+) m/z 261 (MH+). (g) (7-fluoro-9-keto-2,3-dihydro[1,4]dioxo[2,3_h]4 oxo-10(9H)-yl)acetaldehyde 7-fluoro- 10-(2-propen-1-yl)-2,3-dihydro[1,4]dioxanium [2,3-h]indole-9(10H)-one (0·62 g, 2·4 mM) dissolved in DCM (20 mL) and cooled to -78 °C. The mixture was then stirred under 〇3 bubble for 25 min then DMS (0.79 mL, 5·5 mmol) was then taken and warmed to room temperature. Stir at room temperature: mix for 30 minutes. The solvent was removed to give the desired product (0.75 g, &gt; 100%). 15 MS (ES+) m/z 264 (ΜΗ+). (h) (2,3-Dihydro[1,4]dioxyg and [2,3_c]pyridyl-7-ylmethyl){l-[2_(7-fluoro·9·ketodihydro[ Μ] Dioxo[2,3_h]喳咁-1〇(9Η)-yl)ethyl]_4_hexahydro. 1,1-didecylethyl ester 20 (fluoro)-amino-2,3-dihydro[1,4]dioxo[2,3_h]喳Porphyrin-10(9H)-yl)acetaldehyde (375 mg, 1.4 mmol) and (2,3-dihydro[1,4]dioxo and P,3-c]pyridine-7-yl Mercapto) 1,1-dihydropyridylamino decanoic acid 1,1-didecylethyl ester (synthesis see W02004/058144 Example 99(h)) (489 mg, 1.4 mmol) in chloroform (1 (1 ml) The solution in MeOH (2 205 200817417 ml) was stirred at room temperature for 0.5 h. The mixture was then treated with NaBH(OAc)3 (Biezke' 2.8 mmol) and stirred at room temperature for one day. The granules were removed and the residue was partitioned between saturated aqueous sodium bicarbonate solution and 10% Me0H/DCM. The layers were separated and the aqueous layer was extracted with 1 EtOAc / EtOAc (EtOAc) The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was subjected to column chromatography on silica gel eluting with 0-20% MeOH-DMeOH to give the desired compound. MS (ES+) m/z 597 (MH+). 10 (1) The title compound is in (2,3-dioxin[1,4]dioxyg and [2,3-c]. than beer-7-ylmethyl) {1-[2-(7-icon-9) - Keto-2,3-dihydro[1,4]dioxo[2,3-11]11-quinone-11--10(911)-yl)ethyl]-4-hexanitrogen. Add 4M HCl (6 ml) in 1,4-15 dioxane to a solution of 1,1·» dimethyl acetate (330 mg) in chloroform (6 ml). The reaction was stirred at room temperature for 30 minutes. Toluene (10 mL) was added and the solution was evaporated, dissolved in MeOH and treated with Amberlyst A21. The resin was filtered and the solvent was removed; the residue was purified by chromatography eluting eluting elut elut ). δΗ CD3OD, (250MHz) 1.57 (m, 2H), 2.04 (d, 2H), 2.30 (9), 2H), 2.81 (m, 3H) 3·15 (d, 2H), 3.96 (s, 2H), 4.30- 4.41 (m, 8H), 4.73 (m, 2H), 6.51 (4 1H), 6.67 (d, 1H), 6.99 (s, 1H), 7.93 (d, 1H), 8.06 (s, 1H). MS (ES+) m/z 497 (MH+). via 1 eq.

206 200817417 4MHC1 treatment in alkane to convert this compound to the HCl salt. It was then evaporated to dryness to give a grey solid. LCMS is a free base. • Example 58 7-[({1-[2-(7-fluoro_2-keto-1(2H)-喳崎咁)ethyl]]5 5 氲pyridyl}amino)methyl]- 1Η-pyrido[2,3-b][l,4]thorbicin-2(3H)· 酉 畜 畜 马

10 1-[2-(4-Amino-1-hexa-pyridinyl)ethyl]-7-fluoro-2 (lHp-ku 0-oxanone dihydrochloride (60 mg, 0.166 mmol) And 2-酉同基_2,3-Dihydro_1Η-ϋ ratio bite [2,3-b][l,4]u 塞σ井-7_搭(Synthesis see 2〇〇4/〇58144 Example 48(e)) (85% purity, 44 mg, 0.197 mmol) 15 solution in Me 〇H (3 mL), chloroform (3 mL) and triethylamine (6 mL) Heated overnight with 3 Α molecular sieves, allowed to cool and added sodium triethoxy borohydride (〇·11 g, 0·52 mmol), and the mixture was stirred at room temperature overnight. Sodium borohydride (O ii gram) and the mixture was stirred for another 4 days, then two portions of triethoxy borohydride 20 (0.11 g and 0.22 g) were added. The solution was basified with aqueous sodium bicarbonate and water. The layers were extracted several times with 10% MeOH-EtOAc (EtOAc)EtOAc.口207 200817417 δΗ (CDC13), (250 MHz) 1·40 (2H, m), 1·90 (2H, br.d), 2·18 (2H, t), 2· 52 (1H,m), 2.68 (2H,t), 2.98 (2H,br·d),3·57 (2H,s),3.80 (2H,s),4·31 (2H,t),7.07 ( 2H,m),7·15 (1H, d),7·87 (1H,dd),8.13 (1H,d),8·23 (1H,s). MS (+ve ion electron spray) m/ The free base in DCM was taken up in EtOAc EtOAc (EtOAc (EtOAc)EtOAc. 7-Fluoro-1_indole (4_{[(7-keto-1,5,6,7-tetrahydro-1,8-naphthyridin-2-yl)methyl]aminopi- 1-hexahydropyridine Ethyl)ethyl;j_2(1H)-fluorenone fumarate

Amino-1-hexahydropyridyl)ethyl]-7-fluoro-2(1H)-croxazone dihydrochloride (6 mg, 166 gram mmol) and 7-keto-1 ,5,6,7-tetrahydro-1,8-naphthyridin-2-al (for synthesis see w〇2003/087098 Example 307(f)) (35 mg, 〇·197 mmol) in MeOH (3 ml) The solution in chloroform (3 liters) and diethylamine (6 liters in 〇·〇) was heated under reflux with 3A molecular sieves overnight. Chloroform (2 ml) and MeOH (2 ml) were added, and the mixture was evaporated and evaporated, and evaporated. Sodium triethoxy borohydride (0.11 g) was added and the mixture was stirred overnight. Add sodium bicarbonate water to dissolve 208. &lt; 1 ) 200817417 Liquid test and extract the aqueous layer several times with 10% MeOH-DCM. The organic layer was dried and evaporated. Chromatography on silica gel eluting with EtOAc (EtOAc:EtOAc) 2 十3,) '^^/巧抱) I % (2H,m), 1.95 presumed 2H,m,mostly obscured by water), (1H 7 07 nu {}^ ml 2M (4H? mX 2*97 ( 4H? m)? 3*84 (23⁄4 431 (23⁄4 ^ 6·94 (JH; d), 7.07 (1H? td)5 7.14 (1H? dd)5 7.43 (1H, d)? 7.86 (1H? dd) , 8.03 (1H, br. s), 8.22 MS (+ve iontophoresis) m/z 451 (MH+). 10 The free state in DCM is tested with 〇·5Μ fumaric acid (〇·〇7 ml) , i, though, treated and evaporated to dryness. The solid was triturated with diethyl ether, dissolved in EtOAc, evaporated and dried to give the fumarate. Example 60 6-chloro-4-(2-{4-[( 2,3-Di-argon [1,4]dioxo[2,3-c]pyridin-7-ylmethyl)amino]-1-hexahydropyridinyl}ethyl)-; 1,2, 4_benzotriene-3(411)-one 1-oxide hydrochloride

(a) N-(5-Chloro-2-nitrophenyl)urea was added to a solution of triphosgene (3.613 g, 12.175 mmol) in toluene (15 ml) with cyclosylcholine anilide (2· ι, 12175 mmol; solution in toluene (15 mL) over 0.5 hours, then the reaction was taken at 8 Torr. 〇 209 200817417 Heated for 24 hours. The reaction was then cooled and carefully poured into an aqueous solution of nh3. The mixture was stirred for 1 h, filtered, washed with EtOAc EtOAcjjjjjjjj 5 (b) 6-Chloro_1,2,4-benzotris-3(4H)-one 1-oxide N-(5-chloro-2-stone-cholylphenyl)urea (1.558 g, 7.230 m A suspension of aqueous NaOH (4.34 g NaOH in 15 mL water) was heated under reflux for 0.5 h then cooled and treated with water (1 mL). The ίο mixture was then heated again under reflux and the hot mixture was filtered through a Buchner funnel. The filtrate was then acidified with cone. EtOAc (EtOAc) (EtOAc) MS (ES+) m/z 198/200 (MH+). 15 (c) 6-Chloro-4_(2-propion-1-yl)-l,2,4-benzotris-_3(4H)-one 1_oxide 6-gas-1,2,4- Benzotris-3 (4H)__ 1_oxide (7 〇〇 mg, 3.544 mmol) was suspended in anhydrous dmf (2 〇 20 liters) under argon pressure and room temperature, and the stirred suspension was stirred. Treated with Κπ〇3 (1.614 g, 11 695 mmol) and allyl iodide (〇·43 ml, 4.607 mmol). After stirring at room temperature for 2 hours, allyl iodide (0·86 ml, 9 214 mmol) was added again, and the reaction was heated at 60 C for 1 hour, and then water (1 (10) ml) was added. The mixture was extracted with DCM (3×200 mL). The combined organic extracts were dried over anhydrous MgSO.sub.sub.sub.sub.sub.sssssssssssssssssssssssssssssss Gradient elution 'to give the desired product as a pale solid, (472 mg, 56%). 5 MS (ES+) m/z 238/240 (MH+)〇(8)(6-chloro-1-oxo_3•keto-1,2,4-benzotrim-4(3H)-yl)B The aldehyde dissolves 6-chloro-4-(2-propen-1-yl)-1,2,4-benzotrid-3(4H)-one 1-oxide (104 mg, 0.438 mmol) In 1,4-dioxane (4 ml) 10 and water (2 ml). Sodium periodate (234 mg, 1.096 mmol) was added followed by osmium tetroxide (0.09 mL of a 4% aqueous solution). The mixture was stirred at room temperature for 6 hours then extracted with 20% MeOH / DCM (3. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give (6-chloro-1-oxy-3- keto-1,2,4-benzotrisin 3H)-yl) acetaldehyde as an impure yellow oil (89 mg, 85%). MS (ES+) m/z 240/242 (MH+). (e) {1-[2-(6-gasooxy-3-keto-l-yl, 2,4-benzotriindole-4(311)-yl)ethyl&gt; 4-hexapyridinyl} (2,3-Dihydro[1,4]dioxogen; and [2,3-c]pyridine-7-2hydrazinyl)aminodecanoic acid 1,1-didecylethyl ester (6) -Chlorooxy-3-keto-1,2,4-benzotrim-4(3H)-yl)acetaldehyde (89 mg, 0.372 mmol) and (2,3-dihydro[1 , 4] Dioxane H: and [2,3-c]pyridin-7-ylmethyl) 4-hexahydropyridylamino decanoic acid 1,1-didecylethyl ester (synthesis see WO2004/058144 Example 99 (h)) (117 mg, 0.334 mmol)

211 200817417 A mixture of chloroform (5 ml) and MeOH (0.5 mL) was stirred for 2 hr then NaBH(OAc)3 (212 mg, 1. After the reaction was stirred for 1 hour, a saturated aqueous solution of NaHC? The reaction was then extracted with 10% MeOH (3 x 200 mL) in DCM. The combined organic layers were dried, evaporated and purified EtOAc EtOAcjjjjjj ). MS (ES+) m/z 573/574 (MH+). 1〇(f) the title compound will be {1-[2-(6-chloro-1-oxy-3-S-iso-1,2,4-benzotriyl)ethyl]-4_hexahydro 12 1,1-dimercaptoethyl ester (81 mg, 2,3-dihydro[1,4]dioxo[2 3 -pyridin-7-ylindenyl)carbamic acid To a solution of chloroform (1 ml) in MeOH (1 mL), EtOAc (EtOAc) Treated with saturated aqueous NaHCI3 (50 mL). After the reaction, the reaction was carried out with 20% MeOH (3×100 liters) in DCM. The combined organic layers were dried, evaporated, and the crude residue was purified on &lt;&gt; A -20% MeOH/DCM gradient elution afforded the title title: </ RTI> <RTIgt; MS (ES+) m/z 473/475 (MH+). lU NMR (250MHz) 5(CDC13) 1.38^1.51 (2H? m), 1.85-1.99 (2H, m), 2.12^2 26 Qw 2.52-2.82 (3H, m), 2.92-3.02 (2H, m), 3·81 (2H, s), 4.27-4.38 (m, 6H), 6.81 (ih ^ ; m), (1H, d, J 10Hz), 7·58 (1H, s), 8·08 (1H, s),8·27 (1H,d,J 10·5Ηζ)· '),7·28 212 ,. 200817417 MS (+ve ion electrons are used in congratulations) m/z 451 (MH+). , Fen Dan: The free base of the kiln is dissolved in 1:1 DCM: MeOH and added to the 4M HCl in 1 1,4-dioxane, which is converted into the HCl salt. It is then evaporated to dryness. 5 Example 61 6-({[((3S,4S)-4-hydroxydecyloxy)_2-keto-1(2H)" quinacyl]ethyl b 3)-pyridinyl)methyl] Amino}methyl)_2H"pyridinium[3,2-b][l,4] thiaphin-3(4H)-one dihydrochloride

(a) {[(3R,4S)_4-Pyridyl-3-indolyl] phenyl]amino phenyl decanoate in (3S,4S)-3-carboxy_4-[({[ (Phenylfluorenyl)oxy]alkyl}amino) 15 methyl]-1-pyrrolidinecarboxylic acid 1,1-didecylethyl ester (synthesis see WO2006002407 Preparation 24(c), (±)-cis -3-hydroxy ice [({[(phenylmethyl)oxy)] lysyl}amino) fluorenyl]-lu than slightly σ deterministic acid 1,1-dimethylethyl E1 construct () 1 g of ' 2.85 mmoles) was added to a solution of DCM (50 liters) of triturated acetic acid (50 ml) and stirred for 2 hours. The reaction mixture was concentrated and placed under high vacuum for 3 hours. The TFA salt was dissolved in DCM (5 mL) and hydrazine-carbonate resin (4 g; 11.4 m. The reaction mixture was filtered and evaporated to give crystal crystal crystal crystal crystal MS (ES+) m/z 251.3 (ΜΗ+).

213 200817417 (b) [((3S,4S)-4-Phenyl-1·{2-[7-(methoxy)-2-keto)(2Η)-π奎口林基]ethyl} -3-pyrrole yl) methyl] carbamic acid phenyl hydrazine is intended to be {[(3R,4S)-4_transyl-3" 咬 各 曱 曱 } } } } } } } } } } 甲Ester (84 mg, 3.35 mmol) and [7_(decyloxy)-2-keto-5 4(211)-fluorenyl] acetaldehyde (663 mg, 3.05 mmol) in helmet water dcm (10 ml) and anhydrous MeOH (2 ml) were mixed with a spoonful of solid sodium carbonate. The reaction mixture was stirred under a nitrogen atmosphere for a few hours, then sodium triethyl sulfonium hydride (2.03 g, 9.12 mmol) was added and stirred overnight. The reaction mixture was concentrated and purified with EtOAc EtOAc m. MS (ES+) m/z 452.8 (MH+). (c) l-{2-[(3S,4S)-3-(Aminomethyl)_4•transylpyridinyl]ethyl}-7-(decyloxy)-2(1Η)-喳唯酉同15 in [((3S,4S)I)+(2-17-(methoxy)_2-keto-1(2Η)-4咐yl]ethyl b3) Add 2% pd(〇H) 2/c to a solution of methyl]amino phenyl formate (1 g, 2.21 moles), degas and place for 2 hours at 1 atmosphere C of H2. The reaction mixture was filtered with EtOAc EtOAc (EtOAc) (EtOAc) -[(3S,4S)-3-(Aminomethyl) glacial viaylpyrazine sigma]ethyl 214 200817417 yl}-7-(decyloxy)-2(m)-pyridone (146 mg , 0.460 mmol, and 3-keto-3,4-dihydro-2H-pyrido[3,2_b][l,4]thin-6-aldehyde (for synthesis see 'WQ2004058144, Example 7(d) (98 mg, 0.506 mmol) was mixed with 1 scoop of a solid solid sodium carbonate in anhydrous DCM (5 mL) and anhydrous MeOH (1 mL). The reaction mixture was stirred under nitrogen for 18 hours and then Add sodium triethoxy borohydride (306 mg, 1.38 mmol) The mixture was stirred for 1 h. The title compound was obtained from mjjjjjjlili (ES+) m/z 496.4 (ΜΗ+). 1Η NMR (400 MHz, CD3OD) δ ppm 3.43 - 3.55 (m, 3 H) 3.58 (s, 2 H) 3.68 (s, 3 H) 3.73 (s, 3 H) 4.00 (s5 4 H) 4.38 (s, 2 H) 4.65 (s5 1 H) 4.76 (t5 J5.94 Hz, 3 H) 6.59 (d5 J9.35 Hz, 1 H) 7.02 (dd5 J8.59, 2.02 Hz, 1 H) 7.07 (s, 1 H) 7.16 (d, J7.83 Hz, 1 H) 7.70 (d5 J8.59 Hz, 1 H) 7.85 (d? J7.83 Hz, 1 H) 7.92 ( d, J9.35 Hz, 1 H). The dihydrochloride salt was prepared by adding 92 μl of 4N HC1/1,4-dioxane to the free-form solution. 15 Example 62 7-Chloro- 6-({[((3S,4S)) 4-hydroxy-1-{2-[7-(decyloxy)-2. keto-1(2H)-indolyl]ethyl}-3-pyrrole Acryl)indolyl]amino}indenyl)-2H-pyrido[3,2-b][ 1,4]indole-3(4H)-one dihydrochloride

1-{2-[(3S,4S)-3-(Aminomercapto)-4-hydroxy-1-tonyridinyl]ethyl}-7-(methoxy)-2(1Η)- Porphyrinone (68 mg, 0.214 mmol) and 7-215 200817417 chloro-3-keto-3,4-dihydro-2H-pyrido[3,2_b][l,4]噚耕-6- Aldehyde (synthesis see W02003064421, Example 15(c)) (50 mg, 0.236 mmol), mixed with 1 scoop of sharp, solid sodium carbonate in anhydrous DCM (5 mL) and anhydrous MeOH (1 mL). The reaction mixture was stirred under a nitrogen atmosphere for 18 hrs, and then sodium triethyl bromo hydride hydride (143 mg, 0.643 mmol) was added and stirred for 1 hour. The reaction mixture was concentrated and purified with EtOAc EtOAcjjjjjjjj MS (ES+) m/z 514 (MH+). 1H NMR (400 MHz, CD3OD) δ ppm 3.40 (dd, J 12.63, 6.06 Hz, 2 H) 3.57 (dd5 J 12.38, 10 6.57 Hz, 2 H) 3.68 ( S5 1 H) 3.75 (t5 J5.43 Hz, 3 H) 4.00 (s5 4 H) 4.47 (s? 2 H) 4.68 (s? 1 H) 4.73 - 4.82 (m, 5 H) 6.61 (d3 J9.35 Hz? 1 H) 7.01 (dd, /8.72, 1.89 Hz, 1 H) 7.08 (d, J 1.52 Hz, 1 H) 7.54 (s, 1 H) 7.69 (d, 78.84 Hz, 1 H) 7.91 (d, /9.35 Hz, 1 H). The dihydrochloride salt was prepared by adding 93 μl of 4N HC1/1,4-dioxane to the free-form solution. 15 Example 63 3_{[({(3S,4S)_l-[2_(7-fluoro-2-keto-1(2H)-carbolinyl)ethyl]-4-hydroxy-3-pyrrolidinyl} Methyl)amino]mercapto}-5H-indoligic and [3,4-b][l,4]thorbic-6(7H&gt; ketone

1-{2-[(3S,4S)-3-(Aminoguanidino)-4-hydroxy-1-pyrrolidinyl]ethyl 216 200817417 base}-7-(decyloxy)-2(1Η) - anthrone (100 mg, on-moleketone-6,7-dihydro-5H-indole and [3,4-b] [M] thioglycolaldehyde (Human see W02004058144, Example 58) A solution of 65 mg, 0.33 mmol, in methanol (2 mL), DCM (4 mL) was stirred overnight at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction was evaporated and purified eluting eluted eluting eluting eluting eluting Gray powder. 10 1H NMR (400 MHz, CD3OD) δ ppm 2.39 - 2.50 (m, 1 Η) 2.68 - 2.80 (m? 3 Η) 2.86 -2.99 (m, 4 Η) 3.13 (dd, J= 10.5, 5.6 Hz, 1 H) 3.49 (dd? 7=14.1, 7.1 Hz, 2 H) 3.73 - 3.81 (m, 2 H) 4.35 - 4.49 (m, 3 H) 6.60 (d? 7=9.49 Hz, 1 H) 7.07-7.10 (m, 2 H) 7.43 (d, J=11.9

Hz, 1 H) 7.76 (dd, *7-8.6, 6.3 Hz, 1 H) 7.89 (d, /=9.5 Hz, 1 H) MS (+ve ion electrospray) m/z 485 (M+H)+. Example 64 l-[2-((3S,4S)-3-{[(2,3-Dihydro[1,4]dioxo[15,3-c]pyridin-7-ylfluorenyl) Amino]methyl}-4-hydroxy small u-pyridyl)ethylfluoro-2(1H)-indolone dihydrochloride

1-{2-[(38,48)-3-(Aminoguanidino)-4-trans-yl-1-fluorenyl]ethyl}-7fluoro-2(1H)"quinacone (60 Mg, 〇·2 mmol) and 2,3-dihydro[1,4] 217 200817417 5 10 Dioxo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, Example 2 (c Or W003/087098, Example 19(d)) (32 mg, 〇·2 mmol). A solution in methanol (1 mL), DCM (3 mL) Diethylene ethoxylated sodium nitrite (85 house grams & 0.4 house moles) was added and the mixture was stirred at room temperature for 1 hour. The reaction was evaporated and chromatographed on silica gel eluting with 0-10% methanol-DCM-1% NKUOH. The oil was treated with 1 M EtOAc in EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ) 2 62 2.70 (m, 2 H) 2.76 - 2·86 (m, 2 H) 2.96 (dd, J=9.09, 7.83 Hz, 1 H) 3.14 (dd, 36 5.56 Hz, 1 H) 3.33 (dt, /=3.28, 1.64 Hz, 1 H) 3.73 - 3.81 (m, 2 H) 4.31 (dd, 〇5 9 7〇Hz, 2 H) 4.35 - 4.46 (m, 5 H) 6.61 (d? J=9.35 Hz 1 H) 6.97 (s, 1 H) 7.10 (td jJg L Hz, 1 H) 7.42 (dd, &gt;11.37, 2.27 Hz, 1 H) 7.75 (dd, J=8.59, 6.32 Hz, 1 H) 7 90 (d Aolc Hz, 1 Η) 7·92 (s, 1 H) 8.00 (s, 1 H)· 1 5 ^935 MS (+ve iontophoresis) m/z 455 (MH+). Example 65 3-[({1-[2_〇Fluoro-2-keto-1(2H)-hydroxyl-4-yl)ethyl]- 4 hexahydroacridinyl}amino)methyl]_5H_嗒耕和[3,44][1,4]thia__6(7-indanone fumarate

1-[2-(4-Amino-1-hexahydropyridinyl)ethyl]-7-gas-2(1Η)-4 rosinone dihydrochloride (90 mg, 〇·25 mmol) And 6_keto-6,7-dihydro-5H-tower σ well[3,4-b] [1,4] 喧耕-3-disk (see synthesis

218 200817417 W02004058144, Example 58(d)) (48 mg, 〇·25 mmol) at

A solution of MeOH (5 mL), chloroform (5 mL) and triethylamine (m. It was allowed to cool and sodium triacetoxyborohydride (0.166 g, 0.78 mmol) was added and the mixture was stirred at room temperature for 8 hr. Sodium triethoxy borohydride (0.166 g) was added again and the stirrer was placed. Aqueous sodium bicarbonate solution was added and the aqueous layer was extracted several times with 1 MeOH-D. The organic layer was dried and evaporated. Chromatography on EtOAc, EtOAc (EtOAc) elute 10 6H (CDClsX (250 MHz) 1.41 (2H? m), 1.90 (2H, br.d), 2.18 (23⁄4 t), 2 57 rm (2H, t), 2.97 (2H, br. d), 3.65 ( (2H, s) , 7·20 (1H, MS (+ve iontophores) m/z 470 (MH+). The free base in chloroform was treated with 1 equivalent of 〇5M fumaric acid in MeOH and evaporated to dryness. The fumarate salt was obtained. Example 66 l-(2-{(3S,4R)_4-[(2,3-Dihydro[1,4]dioxo[2,3-c]acridine-7_ Alkyl)amino]_3_hydroxy+hexahydro}yl}ethyl)-7-methoxyl-1,5-naphthyridinone hydrochloride 1 20

219 200817417 (8)((3S,4R)-3-Hydroxy-1 {2-[7-(methoxy)_2-keto-1,5-naphthyridinyl]ethylhexahydropyridinyl) amide I, 〗 〖Dimethylethyl ester [7-(methoxy)-2-keto-1,5-naphthyridin-1(2H)-yl)acetaldehyde methyl hem (200 mg) and [ (3R,4S)_3_hydroxy_4_hexafluoropyridyl]1,1-dimethylethylamine decanoate (synthesis see WO2004058144, Example 5(c), cis-(3-carbyl-4- The hexahydropyridyl) carbamic acid tert-butyl ester was stirred in chloroform (10 ml) and MeOH (0.5 mL) under argon for 2 hr. Sodium triethoxysulfonate hydride (534 mg) was added in one portion and the mixture was stirred at room temperature overnight and then quenched by addition of saturated aqueous NaHCO? The organic layer was separated using a hydrophobic frit and the aqueous layer was extracted with DCM (2×20 mL). The organic extracts were combined, dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2 cm of ammonia) eluted. The title compound (226 mg) was obtained from m. MS (ES+) m/z 419 (MH+). (b) l-{2-[(3S,4R)_4_Amino_3_hydroxy+hexahydropyridyl]ethyl}-7-(decyloxy)-1,5-naphthalene-2 (lH) )-g and the dihydrochloride salt ((3S,4R)-3-carbyl-1{2-[7-(decyloxy)_2, phenylnaphthyridin-1(2H)-yl]ethyl}_4 - hexahydropyridyl)amino decyl decanoate (223 g) dissolved in DCM (2 mL) and treated with 4M hydrochloric acid (2 mL) in hexane. . Foaming and sedimentation were observed. After a period of 2 hours, the solvent was evaporated and evaporated, mjjjjjjjjjjjj MS (ES+) m/z 319 (MH+). 5 (C) the title compound l-{2-[(3S,4R)-4-amino-3-hydroxy hexahydropyridyl]ethyl}-7-(decyloxy&gt;1,5-naphthyridine -2(1H)-one dihydrochloride (2 〇 9 mg) was stirred in a 9:1 volume: volume of chloroform: MeOH (5 mL) at room temperature under argon and triethylamine (250 dl) The mixture was stirred at room temperature for 1 〇 for 1 ,, then 2,3 bis[I,4]dioxo[2,3-c]pyridine-7-aldehyde was added (synthesis see W02004058144, example 2(c) or W003/087098, Example 19(d)) (44 mg, 0.264 mmol) and the mixture was stirred at room temperature for 4 hours, then sodium triethyloxyborohydride (360 mg) was added in one portion. The mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium sulphate 15 (2 mL) was added and the organic layer was diluted with DCM to a volume of about 50 cc. The organic layer was separated and water was used. The layers were extracted with DCM (2×10 mL).

NMR δ (400MHz, CDC13): 8·71 (1H, s), 8.29 (1H, d, J 2Hz), 8.10 (1H, s), 7·87 (1H, d, J 2〇10Hz), 7.21 ( 1H, d5 J 2Hz), 6.85 (1H, s), 6.75 (1H, d, J 10Hz), 4.58-4.46 (2H, m)5 4.39- 4·28 (4H, m), 4.08 (1H, s) , 4.02 (2H, s), 4.00 (3H, s), 3.33 - 3.29 (1H, m), 3·00-2·90 (2H, m), 2.83-2.70 (2H, m), 2·42 ( 1H,d,J 11Hz),2·35-2·28 (1H,m),1.92-1.81 (2H,m)· MS (ES+) m/z 468 (MH+). By dissolving in DCM and adding 1 equivalent The im HC1/ether was evaporated to dryness and the material was converted to the hydrochloride salt. MS is a free base.

221 200817417 Example 67 H2_((3S,4S)-3-{[(2,3-Dihydro[1,4]dioxo[2,3-c]acridin-7-ylfluorenyl)amine ] 曱基卜 4-hydroxy-i-α-pyridyl)ethyl]-7-(methoxy)-1,5-naphthyridin-2(1Η)-one fumarate

(8) [((3S,4S)_4_hydroxy-1_{2-[7-(methoxy)-2-keto-1,5-naphthyridin-1(2H)-yl]ethyl}_3_pyrrolidinyl) Methyl]aminophenyl phthalate in 17-(methoxy)·2-keto-1,5-naphthyridin-1(2H)-yl]acetaldehyde (mercapto-semi- 1 acetal) (0·654 g, 3.0 mmol) Add {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]decyl}amine in 1:1 (MeOH/CHCl3) (50 mL) Phenyl decyl decanoate (0.750 g, 3.00 mmol) and Na2S04 (0.100 g) and the resulting solution was stirred at ambient temperature for 18 h. Na(OAc)3BH (1·91 g, 9·0 mmol) was added and the solution was stirred for additional 2 hours. The reaction mixture was concentrated on a silica gel and chromatographed on a silica gel column [0-100% CHC13 / (90:10:1) CHCl3 / MeOH / NH4OH] to give a colorless oil (0.897 g, 66%) 〇MS (ES+) m/z 453 (MH+). 20 (b) l-{2-[(3S,4S)-3-(Aminomercapto)-4-hydroxyl 17-pyridinyl]ethyl}-7-(decyloxy)-1,5 -naphthalene bite_2(111)-ketone in [((3S,4S)-4-hydroxy small {2-[7-(indolyl)-l-naphthyridin-1(2H)-yl] Ethyl 3-pyridolidinyl) indenyl] phenyl decyl decanoate (0.90 g, 1.99 mmol) was added to a solution of MeOH (30 mM). 222 200817417 10% Pd/C ( 0. 20 g) and the resulting solution was exposed to a Pr shaker at 50 PSI Kb. The solution was filtered through celite and concentrated under reduced pressure to give the product (0.571 g, 90%). m/z 319 (MH+) 〇(c) the title compound in l-{2-[(3S,4S)-3-(aminomercapto)-4-hydroxypyrrolidinyl]ethyl}-7- (Methoxy)-1,5-naphthalene-2(111)-yan 1 (〇.114 g, 〇.358 mmol) was added to a solution of 1:1 (MeOH/CH 2 Cl 2 ) (25 mL) 2,3-Dihydrofuran [1,4]dioxo[2,3-c]pyridine-7-aldehyde (for synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19(d)) (0.059 g, 0.358 mmol) and sodium sulfate (0.100 g) and the resulting solution was stirred at ambient temperature for 18 h. Na(OAc)3BH (0.228 g, 1.07 mmol) was added and the mixture was stirred at room temperature for further 2 hr. The reaction mixture was concentrated on a silica gel and EtOAc (EtOAc: EtOAc (EtOAc) The title compound of the fumarate was formed by treatment with 1 equivalent of fumaric acid to give a gray solid (0.048 g, 23%). LCMS: m/z 468 (M+H)+· 1H NMR (400 MHz, CD3OD) δ ppm 2.64 - 2·73 (m,1 Η) 3·04 - 3·14 (m,6 Η) 3·24 ( Ddd, 2〇/=18.44, 12.51, 5.94 Ηζ3 2 Η) 3.33 (dt, 7=3.28, 1.64 Hz, 2 Η) 4.05 (s, 3 Η) 4.19 (s, 2 Η) ? 4.31 - 4.36 (πι, 2 Η) 4.36 - 4.41 (m, 2 Η) 4.51 - 4.62 (m? 3 Η) 6.64 - 6.68 (m5 3 Η) 6 98 (s 1 Η) 7.47 (d, 7=2.27 Hz, 1 Η) 7.84 ( D5 J=9.60 Hz, 1 Η) 7.93 (s, 1 Η) 8.30 (d5 J-2 27 Hz 1 H). ,·' Example 68 6-({[((3S,4S)-4-) 1-{2-[7-(decyloxy)_2-keto-1,5-naphthyridin-1(2H)-yl]ethyl}-3-pyrrolidinyl)indolyl]amino}A -2H-Acridine[3,2-b][l,4]咩耕_3(4H)-ketofumarate 223 200817417

5 in 1 -{2-[(3S,4S)-3-(aminoindenyl)-4-yl-1-pyrylene]ethyl}-7-(methoxy)-1,5• Naphthyridine-2(1Η)-one (0.114 g, 0.358 mmol) was added to a solution of 1:1 (MeOH/CH2Cl2) (25 mL). And [3,2-b][l,4]啐耕_6_aldehyde (synthesis see W02003087098, example 31(e)) (0.064 g, 0.358 mmol) and sodium sulphate 10 (0.10 g) and The resulting solution was stirred at ambient temperature for 18 hours. Na(OAc)3BH (0.228 g, 1.07 mmol) was added and the solution was stirred at room temperature for further 2 hr. The reaction mixture was concentrated on silica gel and chromatographed [0-00% CHC13 / (90:10:1) CHCl3 / MeOH / NH4OH] to give a colorless oil. The title compound of the fumarate was formed by treatment with 1 eq. of EtOAc (yield: EtOAc) LCMS: m/z 481 (M+H)+. 1H NMR (400 MHz5 CD3OD) δ ppm 2.68 - 2.78 (m, 1 H) 2.96 - 3.06 (m5 3 H) 3.06 -3.16 (m, 3 H) 3.23 ( Dd, 7=12.51, 5.18 Hz, 1 H) 3.33 (dt, J=3.28? 1.64 Hz5 3 H) 4.01 - 4.07 (m, 3 H) 4.26 (d, /=1.77 Hz, 2 H) 4.45 - 4.57 ( m, 2 H) 4.59 - 4.67 (m, 1 H) 4.69 (d, /=1.26 Hz5 2 H) 6.62 (d, 7=9.60 Hz? 1 H) 6.66 (s5 2 H) 7.09 (d, /=8.08 Hz, 1 H) 7.36 (d? /=8.08 Hz? 1 H) 7.46 (d, /=2.27 Hz, 1 H) 7.86 (d, 7=9.60 Hz, 1 H) 8.29 (d5 /=2.27 Hz, 1 Example 69 6-({[((3S,4S)-4-hydroxy-1·{2-[7-(decyloxy)-2-keto-1,5-naphthyridin-1(2H)-yl) Ethyl}-3-pyrrolidinyl)methyl]amino}indenyl)-2H-pyrido[3,2-b][l,4]thratic-3(4H)-one fumarate 224 200817417

5 in l-{2-[(3S,4S)_3-(aminomethyl) ice vial-1_ mouth ratio bite base] ethyl}-7-(methoxy)-1,5- Naphthalene aceton-2 (111)-ketone (〇.114 g, 358.358 mmol) was added to a solution of 1:1 (MeOH/CH 2 Cl 2 ) (25 mL), 3-keto-3,4-dihydro- 2IHb唆[3,2-1)][1,4]喧12 well-6-disc (synthesis see W〇2〇〇4〇58144, example 71(d)) (0.070 g, 0.358 mmol) Sodium sulfoxide (0.100 g) was added and the resulting solution was stirred at ambient temperature for 18 h. Na(OAc)3BH (0.228 g, 1.07 mmol) was added and the solution was stirred at room temperature again for 2 hours. The reaction mixture was concentrated on celite and chromatographed on a hexane column [0-100% CHC13 / (90:10:1) CHCl3 / MeOH / NH4OH] The fumarate was formed by treatment with 1 equivalent of fumaric acid to give the title compound as a pale solid (0.053 g, 24 〇 / 。). LCMS: m/z 497 (M+H)+. 1H NMR (400 MHz, CD3OD) δ ppm 2.70 - 2·79 (m,1 Η) 2·96 - 3.07 (m,3 Η) 3 07 - 3.17 ( m, 3 Η) 3.24 (dd, 7=12.63, 5.05 Hz, 1 H) 3.33 (dt5 7=3.28,1.64 Hz, 3 H) 3 37 (m 1 H) 3.51 - 3.59 (m,2 H) 4.01 - 4.07 (m,3 H) 4.27 - 4.35 (m,2 Η) 4·45 - 4·57 (m,2 H), 4.58 - 4.69 (m,1 H) 6.59 (d, /=9.60 Hz, 1 H 6.66 (s,2 H) 7.12 (d, J=7.83 Hz i H) 7 46 (d5 J=2.02 Hz, 1 H) 7.80 (d, J=7.83 Hz, 1 H) 7.87 (d, /=9.60 Hz, 1 H) 8.30 (d J=2 53 Hz 1H). 5 20 Example 70 H2-((3S,4S)-3-{[(6,7-Dihydro[1,4]dioxo[ 2,3&gt;_c] Tetyl fluorenyl)amino] fluorenyl}-4-yl group-based small u 嘻σ-based) ethyl]-7-(decyloxy)-1,5-naphthalene-bit-2 1 Η)-keto fumarate

225 200817417

X〇r. , 5 in l-{2-[(3S,4S)-3-(aminomercaptopurine*.hydroxypyrrolidinyl)ethyl}-7-(methoxy)_1,5-naphthyridine-2 (1Η )-ketone (〇·114 g, Ο·3% mmol) In a solution of 1··1 (MeOH/CH 2 Cl 2 ) (25 ml), 6,7-dihydro[M]dioxane [2] , 3-c] indole-3-aldehyde (0.060 g, 0.358 mmol) and sodium sulfate (0.100 g) and the resulting solution was stirred at ambient temperature for 10 hours. Add Na(OAc)3BH (0.228 g, 1·〇7 mmol) and the solution was stirred at room temperature for another 2 hours. The reaction mixture was concentrated on Shiqi gum and chromatographed on a Shixi rubber column [0-100% CHC13/ (90:10:1) CHCl3/MeOH/NH4OH] gave a colorless oil. LCMS: m/z 469 (Μ+Η)+·1Η NMR (400 MHz, CD3OD) δ ppm 2·41 (d, J=7.83 Ηζ,1 Η) 2 ·61 (t, J=8.72 Ηζ, 1 Η) 15 2·66 - 2·74 (m, 2 Η) 2·81 - 2·90 (m, 3 Η) 2·92 - 2·98 (m, 1 Η) 3·13 (dd'5 〇1〇36 5' 56 Hz 1 Η) 3.96 (d, J=2.53 Ηζ, 2 Η) 4·06 (s,3 Η) 4·38 (td,&gt; 6.00, 3·16 Ηζ,1 Η) 4 43 '· 4 52 (m' 4 Η) 4·54 - 4·61 (m,2 Η) 6.74 (d,/=9·60 Ηζ,1 Η) 7 ·24 (s, 1 Η) 7·52 (d,&gt;2·27 Hz 1 Η) ' 7.92 (d, /=9.60 Hz, 1 Η) 8.30 (d, 7=2.27 Hz, 1 Η). 5 ; Fumarate is used Formation of 1 equivalent of fumaric acid gave the title compound as a grey solid (0.018g, 8%). 20 Example 71 7-chloro-6-({[(3S,4S)-4-hydroxy_1-{ 2_[7_(decyloxy)_2-keto-1,5-naphthyridin-1(2H)-yl]ethyl}-3-pyrrole) fluorenyl]amino}methyl)-2H-pyridine And [3,2-b][l,4]噚耕_3(4H)1 with fumarate

226 200817417

In l-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl 10yl}-7-(methoxy)_1,5-naphthyridine _2(1H)-one (0.114 g, 358 · 358 mmol) in a solution of 1:1 (MeOH/CH 2 Cl 2 ) (25 mL), 7-chloro-3,4-dihydro-2-indole-pyridyl Bite and [3,2_b][l,4]Saki--6-vine (synthesis see W02003064421, Example 15(c)) (〇.076 g, 〇·358 mM) and sodium citrate (0.100 g) The resulting solution was stirred at ambient temperature for 18 hours and then Na(OAc)3BH (0.228 i &lt;&apos;&gt; The reaction mixture was concentrated on a celite gel, and a colorless oil was obtained from the column of J. s. The fumarate was formed by treatment with 1 equivalent of fumaric acid to give the title compound as a grey solid (yield: 78 g, 34%). LCMS: m/z 515 (M+H) +. 1H NMR (400 MHz, DMSO J6) δ ppm 2·23 - 2·34 r... 2.80 (m, 2H) 2.85 (dd, J = 1.75, 7.20 Hz ,lH)2.90(;^)2.63-2.71(m,2H)2·71- 5.81 Hz,1 H) 3.81 - 3·91 (m,3 H) 3.98 (s,4 H) 4 20"1 H) 3·〇8 (dd,J=iai1, 4.41 (m, 2 H) 4.68 (s, 3 H) 6.56 (s? 3 H) 6.64 (d? j^9 ^ ^H) 431' H) 7.56 (s , 1 H) 7.85 (d, 7=9.85 Hz5 1 H) 8.28 (d ^53 ^ ^ (d, J==2*2? Hz? 1 20 Example 72 6_({[(3S) small my methoxy Base)_2_g-isokisidine-1(2H)-yl]ethyl}-3-(10) "decyl"methyl]amino}indenyl)_2Η_σ ratio bite [3,2-b][l,4; K 耕-3(4Η)-ketone 227 200817417

5 (a) [((3S)-l-{2-[7-(Methoxy)-2-keto-1,5-naphthoquinone-1(2H)-yl]ethyl b-3-pyrrolidine Phenylmethyl carbazate in [7-(methoxy)-2-keto-1,5-naphthyridin-1(2H)-yl]acetaldehyde (methyl hemiacetal) (0.500 g, 2.29 mmol) in a solution of 1:4 (MeOH/CHCl3) (4 mL), [(3R)-3_pyrrolidinyl-indenyl]aminophenyl phthalate The ester (synthesis see WO2006002047 Preparation 23(b)) (0.536 g, 2.29 mmol) and triethylamine (0.351 mL, 2.52 mmol) and the resulting solution was stirred at ambient temperature for 1 hour. Na(OAc)3BH (1·46 g, 6.87 mmol) was added and the solution was stirred for additional 18 hours. The reaction mixture was concentrated on EtOAc (EtOAc:EtOAc:EtOAc:EtOAc MS (ES+) m/z 437 (MH+)〇(b) l-{2-[(3S)-3-(aminomercapto)_1-σ ratio thiol base] ethyl b 7-(decyloxy) -1,5-naphthyridine-2(1Η)-one 2〇 in [((3S)-4-hydroxy-1-{2-[7-(decyloxy)-2-keto-1,5 -naphthyl]ethylpyrrolidino)indolyl]amino decanoic acid phenylmethyl hydrazine (0.33 g, 0.761 mmol) in MeOH (30 mL) was added with a catalyst 10% Pd /C (0.20 g) and the resulting solution was exposed to 50 PSI of H2 on a Parr shaker. Filter the solution through the Celite® pad and

228 200817417

Concentration under reduced pressure gave a colourless oil (0.100 g, 43%). MS (ES+) m/z 303 (MHV (c) title compound in 1_{2_[(3S)_3_(aminomethyl) hydrazinyl]ethyl}_7_(methoxy)-1,5- Naphthyridine-2(1Η)-one (0.050 g, 0.165 mmol) on w

-2H-pyrido[3,2-b][l,4]indole-6-aldehyde (synthesis see W〇2〇03087098, example 31(e)) (0.029 g, 〇165 mmol) and Sodium thiosulfate (0.05 g) and the resulting solution was stirred at ambient temperature for 18 h. Na(OAc)3BH (0.105 g, 0.496 mmol) was added and the solution was stirred at room temperature for further 2 hr. The reaction mixture was concentrated on silica gel and chromatographed on a silica gel column [0-100% CHC13/(90:10:1) CHCl3/MeOH/NH4OH] to give a colorless oil. The oil was purified via hplc (ch3cn/h2o) to afford white solid (0.0065 g, 9%). LCMS: m/z 465 (M+H) +. 1H NMR (400 MHz, CD3OD) δ ppm 1.53 (dd5 /=13.01, 6.19 Hz, 1 H) 2.02 - 2.12 (m, 1 H) 2.40 - 2.52 (m5 2 H) 2.63 (d, ^=7.07 Hz, 2 H) 2.72 - 2.81 (m, 3 H) 2.82 - 2.86 (m, 1 H) | 2·87 - 2.95 (m,1 H) 3.74 _ 3.82 (m, 2 H) 4.05 (s,3 H) 4.49 (t5 &gt;7.45 Hz, 2 H) 4.65 (s,2 H) 6.76 (d, /=9.85 Hz, 1 H) 6.98 (d, /=8.08 Hz? 1 H) 7.28 (d, J=8.08 Hz, 1 H) 7.50 (d5 7=2.27 Hz, 1 H) 7.93 (d, J=9.60 Hz, 1 H) 8.30 (d, J=2.53 Hz, 1 H). Example 73 6-({[(3S,4S)-4_hydroxyl small {2_[7-(methoxy)-2)keto-1(2H)_ hydroxyquinolinyl]ethyl}-3比 啶 基 曱 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; 229 229 229 229 229 229 229 229 229 229 229 229 229 229 229 229 229 229 229 229 229 229 229 229 229

5 l-{2-[(3S,4S)-3-(Aminothiol) ice viapyrrolidyl]ethyl}-7-(methoxy)-2(1Η)-4olinone (116 mg, 〇·365亳 and 3-keto-3,4-dihydro-[3,2_1)][1,4]. Wait. Well _6-acid: (People see W02003087098, Example 31(e)) (72 mg, 〇·4〇2 mM in dilute water DCM (5 ml) and anhydrous MeOH (1 ml) with a spoon tip Solid = 10 sodium carbonate was mixed. The reaction mixture was stirred under nitrogen pressure for 18 hours, then added to triethyloxyhydride (243 mg, ι·m mmol) and the mixture was shaken 1]. The reaction mixture was concentrated. Purification by column chromatography (9 EtOAc EtOAc: EtOAc: EtOAc: EtOAc) MH+). 1H NMR (400 MHz, CD3OD) δ ppm 2.72 (d, /5.05 Hz, 1 H) 2.99 (d, J 17.68 Hz 3 m 3·06 · 3.14 (m,1 H) 3.14 - 3.20 (m, 1 H) 3.22 - 3.30 (m,1 Η) 3·33 (s,4 H) 3 38 is' 1 m 3.96 (s, 3 H) 4.23 - 4.33 (m, 2 H) 4.41 - 4.51 (m, l H) 4.55 (s, 1 H) 4.63 - 4.73 (m 3 K 6.34 (d? J9.35 Hz, 1 H) 6.96 - 7.05 (m, 2 H) 7.11 (d5 J7.83 Hz, 1 H) 7.39 ( d J7 33 Uy 1 H) 7.65 (d, J8.59 Hz, 1 H) 7.80 (d5 J9.35 Hz, 1 H). 5 The title compound hydrochloride is via 43 μl (1 equivalent) of 4N 20 HC1/154-.1111 loss Zhang Yuan added to Prepared by free-form solution. Example 74 ^[2-((3148)-3^(2,3-Dihydro[Μ]dioxo[2,3-tetradecyl-7-ylmethyl) Amino] hydrazino 4-hydroxy small σ ratio ^ each base) ethyl]-7-(decyloxy)-2(1Η)-ϋ 嘴 纲 盐 hydrochloride

23〇 200817417

5 1-{2-[(3s,4S)-3-(Aminoguanidino)·4-yl-1-pyridinyl]ethyl}-7-(methoxy)-2(1Η) ”Pupinone (94 mg, 0.296 mmol) and 2,3·dioxa[1,4]dioxyg[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144' example 2 (c Or W003/087098, Example 19(d)) (54 mg, 0. 326 mmol) in anhydrous DCM (5 mL) and anhydrous MeOH (1 mL). After the reaction mixture was stirred under a nitrogen atmosphere for 18 hr, sodium <RTI ID=0.0></RTI> </RTI> <RTIgt; The reaction mixture was concentrated and purified with EtOAc EtOAcjjjjjjjjj 15 MS (ES+) m/z 467.5 (ΜΗ+). 1Η NMR (400 MHz, CD3OD) δ ppm 2.62 - 2.72 (m, 1 H) 2.87 (dd, J9.60, 7.58 Hz 1 H) 2.94 - 3.00 ( m, 3 H) 3.02 - 3.06 (m, 2 H) 3.23 (d, J5.56 Hz5 2 H) 3.33 (dt, J3.28, 1.64 Hz 1 H) 3.94 - 4.00 (m, 3 H) 4.19 (s , 2 H) 4.31 - 4.41 (m? 5 H) 4.50 - 4.60 (m? 3 H) 6.37 (d J 9.35 Hz, 1 H) 6.94 - 7.03 (m, 3 H) 7.60 (d? /8.84 Hz, 1 H) 7.75 (d, J9.35 Hz, 1 H) 7 92 (s, 1 H). The title compound hydrochloride is obtained by passing 33 μl (1 eq.) of 4N 2 〇HC1/1,4-dioxin. The alkane is added to a solution of the free base to prepare. Example 75 l-[2-((3S,4S)-3-{[(6,7-Dihydro[1,4]dioxo[2,3-c]indole-3-ylmethyl) Amino]methylhydroxy_1_pyrrolidinyl)ethyl]_7-(decyloxy)-2(1Η)-indolone ketone hydrochloride 231 200817417

5 10 15 l-{2-[(3S,4S)_3_(Aminoguanidino)_4-hydroxypyrrolidyl]ethyl}-7-(methoxy)-2(1Η)-pyridone (118 mg, 0.372 mmol) and 6,7-dihydro[1,4]dioxo[2,3-c]indole+3-aldehyde (68 mg, 〇·4〇9 mmol) It was mixed with solid sodium carbonate of i scoop in anhydrous DCM (5 mL) and anhydrous MeOH (1 mL). After the reaction mixture was allowed to stand at atmospheric pressure for 18 hours, triethyl-bromo-sodium hydride (247 mg, 112 mmol) was added and stirred for 1 hour. The reaction mixture was concentrated and purified with EtOAc EtOAcjHHHHHH MS (ES+) m/z 468.3 (MH+). 1H NMR (400 MHz, CD3OD) δ ppm 2.65 (d5 J5.05 Hz, 1 H) 3.07 (s 1 H) 3 12 3 20 (m, 3 H) 3.20 - 3.29 (m, 4 H) 3.97 (s, 3 H) 4.31 (d? J2.02 Hz5 2 H) 4.48 fd J4 04 0 H) 4.53 (s, 1 H) 4.59 (s, 5 H) 6.40 (d , 79.35 Hz, 1 H) 6.96 - 7.06 (m 2 H) 7 21 r, 1 m2 7.62 (d? 78.59 Hz, 1 H) 7.78 (d, J935 Hz, 1 H). , 〆叫 U (s, 1 H) The title compound hydrochloride was prepared by adding 33 [mu]L (equivalent equivalent) of 4N HCI/I,4-di 4 to a free solution. 20 Example 76 6-{[({(3S,4S)-l-[2-(7-fluoro-2-keto-oxime(2Η)-σ 嘴)) ethyl]-4-hydroxy-3 -pyrrolidinyl}mercapto)amino]mercapto 2H_pyrido[3,2氺][1,4]thratic-3(411)-one hydrochloride

232 200817417

1-{2-[(3S,4S)-3-(Aminomethyl)-4-hydroxy-1^pyrrolidinyl]ethyl 7-fluoro-2(1H)-indolyl ketone (100 Mg, 0.33 mmol, and 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4] thiaphin-6-aldehyde (synthesis see ίο W02004058144, Example 7 (d)) (64 mg, 0. 33 mmol) in EtOAc (2 mL). Sodium triethoxysulfonate (13 g, 0.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was evaporated and chromatographed on silica gel eluting with 0-10% methanol-DCM-1% EtOAc. The oil was treated with EtOAc (EtOAc) (EtOAc) 1H NMR (400 MHz, CD3OD) δ ppm 2.37 - 2.46 (m, 1 Η) 2.59 (t5 J=8.72 Hz, 1 H) 2.63 -2.71 (m,2 Η) 2·77 - 2.89 (m,2 H) 2.93 - 3.00 (m,1 H) 3.15 (dd5 J=10.48, 5·43 Hz, 1 H) 3.33 (dt9 7=3.28, 1.64 Hz, 3 H) 3.52 (s, 2 H) 3.77 - 3.85 (m, 2 H) 4.37 (td, J=5.94, 3.28 Hz, 1 H) 4.42 - 4.48 (m, 2 H) 6.62 (d, /=9.60 Hz, 1 H) 7.03 (d5 7=7.83 Hz, 1 H) 7.10 (td, /=8.46, 2.27 Hz? 1 H) 7.42 (dd? 7=11.62, 2.27 Hz, 1 H) 7.69 (d? /=7.58 Hz5 1 H) 7.75 (dd? J=8.72, 6.19 Hz, 1 H) 7.90 (d, /=9.35 Hz, 1 H). 20 MS (+ve iontophoresis) m/z 484 (MH+). Add 1 equivalent of benzoic acid to 6-{[({(3S,4S)-l-[2-(7-fluoro-2-keto-1(2H)-indolyl)ethyl]-4- a solution of hydroxy-3-pyrrolidinyl}mercapto)amino]indenyl}-2沁pyrido[3,2-b][l,4]thien-3(4H)-one, followed by evaporation Benzoate. 233 200817417 Example 77 6_{[({(3S,4S)-l-[2_(7_Fluoro-2-keto-1(2Η)-σ 奎 林 linyl) ethyl]-4-hydroxy-3-pyrrole Pyridyl}methyl)amino]methyl}_2Η-pyrido[3,2-b][l,4]indole-3(4Η)-keto disodium salt

10 (a) 1-{2-[(3S,4S)-3-(Aminomethyl)-4-alkyl-1-ylidene]ethyl}-7-fluoro-2(1H)- Porphyrins According to Examples 78(a)-(b), 7-fluoro-2-keto-1(2H)-喳π-linyl)acetaldehyde (0.205 g, 1 mmol) and {[(3R, Preparation of 4S)-4-hydroxy-3-pyrrolidinyl]methyl-15-yl}amino phenyl carbamate. (b) 6-{[({(3S,4S)_H2-(7-fluoro-2-keto-1(2H)-4)phenyl)ethyl] hydroxyhydroxy-3-hydrazinyl}methyl) Amino] sulfhydryl}_2 pyridine. And [3,2-b][l,4]^_-3(4H)-_ 20 will be 1-{2_[(3S,4S)-3_(amino thiol group M_ via base small π 嘻口定美]Ethyl}_7_Fluoro-2(1H)-indoleketone (1〇〇mg, 〇·33mmolole/,) Long 1酉同基-3,4-Dihydro-2Η- Pyrido[3,2-b][l,4] morphine _6-jun (W02003087098, Example 3l(e)) (60 gram, 〇·33 〇 〇 见 醇 ( (2 house liter), The solution in DCM (4 ml) was stirred at room temperature overnight 234 200817417 into diethyl bis &amp;&amp; oxy saponin (0·13 g '0·6 halo) and the mixture was stirred at room temperature The reaction was evaporated and the title compound (73 mg) was obtained eluted eluted eluted eluted eluted eluted eluted eluted Hydrochloride 1H NMR (400 MHz, CD3OD) δ ppm 2.36 - 2.46 (m, 1 Η) 2.58 (t, J=8.84 Hz 1 H) 2 62 2.71 (m, 2 H) 2.78 - 2.84 (m, 1 H) 2.85 - 2.88 (m, 1 H) 2.98 (dd, J=9.〇95 7.83 Hz 1 m 3.15 (dd, /=10.36, 5.56 Hz, 1 H) 3.33 (dt, /=3.28, 1.64 Hz, 3 H) 3.73 - 3.81 (m 2 m 4 36 (td5 /=6.06, 3.28 Hz, 1 H) 4.42 - 4.47 (m, 2 H) 4.64 (s, 2 H) 6.62 (d3 7=9.60 Hz 1 H) 6 98 (d, /=8.08 Hz, 1 H) 7.10 (td, 7=8.46, 2.27 Hz, 1 H) 7.27 (d, /=8.08 Hz, 1 H 7.42 (dd Jl 1.49, 2·15 Hz, 1 H) 7.75 (dd, cA=8.59, 6·32 Hz, 1 H) 7.90 (d, *Λ=9·60 Hz 1 H) MS (+ve ion) Electrospray) m/z 468 (MH+). Example 78 6_{[({(3R,4R)-l-[2_(7-fluoro-2-keto-1(2H)_, quinolate) 4-hydroxy-3-pyrrolidinyl}indenyl)amino]methyl b 2H-pyridyl[3,2-b][l,4]Salt-3(4H)-keto disodium Acid salt

(a) ({(3R,4R) small [2-(7-fluoro-2-keto-1(2H)" quinolyl)ethyl]_4_ylamino-3-pyrrolidinyl}methyl) Phenylmethyl phthalate ketone 7-fluoro-2-keto-1(211)-412 linyl): (〇·2〇5 g, 1 mmol) and {[(3S,4R) -4-hydroxy-3-pyrrolidinyl]decyl}amino phenyl hydrazine 235 200817417 (Synthesis see Example 52(f) or W02006002047 Preparation 24(d)(±){[cis+hydroxy-3- Pyrrolidinyl]hydrazino}amino phthalic acid phenyl phthalate E2 genus ' • substance) (0·25 g '1 mmol) in decyl alcohol (1 ml) and chloroform (3 ml solution at room temperature After stirring overnight, sodium triethoxysulfonate (1), 6 5 g, 3 mmoles was added and the mixture was stirred at room temperature for 2 hours. The mixture was extracted with DCM (3×), dried (Na.sub.2.sub.4), evaporated, and eluted on silica gel, eluting with 0-10% decyl alcohol-DCM-1% ΝΗβΗ to give the product foam (〇3 g) . MS (+ve iontophoresis) m/z 440 (MH+). 10 (b) l-{2-[(3R,4R)_3_(Aminomethyl)-4-hydroxypyrrolidinyl]ethyl}-7-fluoro({(3R,4R)-l-[ 2-(7-Fluoro-2-keto-1(2H)-indenyl)ethyl]brylidene-3-pyrrolidyl}indenyl)aminophenyl decanoate (0·3) A solution of anhydrous decyl alcohol (15 mL) was treated with 10% Pd/C (0.08 g) and shaken at 15 psi and room temperature for 2 hours. The Pd catalyst was filtered through Celite®. The filtrate was evaporated to dryness to give oil (0.2 g). MS (+ </ RTI> ion ion spray) m/z 305 (MH+). 20 (C) the title compound will be 1_{2-[(3,4&amp;)-3-(aminomercapto)-4-yl-1-yl-1-yl]ethyl}-7-fluoro-2 (1H)-fluorenone (90 mg, 0.3 mmol) and 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]哼耕-6- A solution of the aldehyde (synthesis see W02003087098, Example 31(e)) (53 mg, 0.3 mmol) in decyl alcohol 236 200817417 (2 mL), DCM (4 mL) Sodium triethoxysulfonate (0.127 g, 0.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was evaporated and chromatographed on silica gel eluting with EtOAc EtOAc EtOAc EtOAc The oil was treated with 1M EtOAc (EtOAc m. 1H NMR (400 MHz, CD3OD) δ ppm 2.38 - 2.46 (m, 1 Η) 2.58 (t, J=8 84 Hz 1 m ? 2.71 (m, 2 H) 2.79 - 2.84 (m51 H) 2.86 - 2.91 (m9 1 H) 2.98 (dd5 /=8 97 7 96 Hz 1 m ^ 3.15 (dd? &gt;10.48, 5.43 Hz, 1 H) 3.33 (dt, /=3.28, 1.64 Hz, 5 H 3.78 ^ 4.36 (td, J =6.065 3.28 Hz, 1 H) 4.43.4.48 (m, 2 H) 4.65 (s9 2 H) 6 62 (d /4 35 H; 1 m 6.98 (d5 7=8.08 Hz, 1 H) 7.11 (td5 /= 8.46, 2.27 Hz5 1 H) 7.27 ^ (dd, 7=11.49, 2.15 Hz, 1 H) 7.76 (dd, J=8.59, 6.32 Hz, 1 H) 7 9; H) 10 MS (+ve ion electronic spray) m/z 468 (MH+). Example 79 6-{[({(3R,4R)-l-[2-(7•fluoroketol_1(2H&gt; porphyrinyl)ethyl]-4-hydroxy- 3-pyrrolidyl}indenyl)amino]indenyl}_2H_pyrido[3,2-1?][1,4]thratic-3(411)-one dihydrochloride

1-{2-[(3R,4R)-3-(Aminoguanidino)-4-yl-1-pyryllyl]ethyl}_7_fluoro-2(1^1)_. Quinone (9 〇 mg, 〇·3 mmol) and keto _3,4_ dihydro-2H-pyrido[3,2_b][l,4]thiatinoic acid (for synthesis see 237 200817417 W02004058H4, Example 7(8)) (60 mg, EtOAc (3 mL)). Sodium triethoxy borohydride (0.127 g, 〇·6 mmol) was added and the mixture was stirred for 1 hour. The reaction was evaporated and chromatographed on silica gel eluting with EtOAc &lt;RTI ID=0.0&gt;0&gt; The title compound (4 mg) of the dihydrochloride salt was obtained after workup of 1M EtOAc in EtOAc. 1H NMR (400 MHz, CD3OD) δ ppm 3.37 (none, 21 Η) 238 - 2 47 1 m 2 SQ rt 10 /=8.84 Hz, 1 H) 2.63 - 2.71 (m, 2 H) 2.77 - 2.87 (m, 2 H) 2.88 - 2.91 (m ! m 2 〇7 /-9.09, 7.83 Hz, 1 H) 3.15 (dd, /=10.36, 5.56 Hz, 1 H) 3.33 (dt5 /=3 28 1 64 Hz 3 m' 3.52 (s, 2 H) 3.77 - 3.85 (m, 2 H) 4.34 - 4.40 (m, 1 H) 4.42 - 4.49 (m 2 H) 6 62 rd /=9.35 Hz, 1 H) 7.03 (d, /= 7.83 Hz, 1 H) 7.10 (td, 7=8.46, 2.27 Hz; 42 fdd

SfH: -^1H) 7-69 (d^=783 H^^ MS (+ve ion electron spray) m/z 484 (MH+). Example 80 6-{[({(3S,4S)-l- [2-(7-Fluoro-2·keto-l55_naphthalene _1(2H)_15-yl)ethyl]-carbyl pyrrolidinyl}methyl)amino]indenyl}-2H-pyridine [3,2-1?][1,4]哼耕-3(411)__hydrochloride

F 20 (a) ({(38,4δ)-1_[2-(7-fluoro_2-keto),5-naphthyridin-1(2H)-yl)ethyl]-4-hydroxy-3- Phenylpyridyl}methyl)aminophenyl decanoate phenyl decyl {{(3S,4R)-4-pyridylpyridinyl]hydrazino) amide (1·17 g, 4.560) Millol) and (7-fluoro-2-keto-yl-naphthyridin-1(2H)-yl)acetaldehyde (mercapto hemiacetal) (855 mg, 417 mmol) in 238 200817417 water DCM (5 ml) and anhydrous MeOH (1 ml) were mixed with a spoon of solid sodium carbonate. After the reaction mixture was stirred under a nitrogen atmosphere for 1 hour, sodium triethyl sulfonium hydride (2.76 g, 12.44 mmol) was added and the mixture was stirred overnight. • The reaction mixture was concentrated and purified by column chromatography (EtOAc: EtOAc) MS (ES+) m/z 442·4 (MH+) 〇(b) l-{2-[(3S,4S)-3-(aminoindenyl)-4-yl-1-yl-sigma sigma Ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one 10 in ({(3S,4S)-l-[2-(7-fluoro-2-keto_1,5_) Add 1〇 to a solution of phenyl phthalate-1 (2H)-yl)ethyl]-4-hydroxy-3-pyrrolidinyl}methyl)amino phenyl decanoate (17 g, 3.85 mmol) % Pd/C, degassed and placed under H2 at 1 atmosphere for 18 hours. The reaction mixture was filtered with EtOAc EtOAcjjjjjjj 15 MS (ES+) m/z 307.3 (ΜΗ+). (c) The title compound will be 1-{2-[(3S,4S)-3-(aminomercapto)-4-hydroxypyrrolidinyl]ethyl}-7-fluoro-1,5-naphthyridine- 2(1H)-ketone (108 mg, 0·353 mmol) and 3-2 ketone group _3,4_dihydro 2 Η-pyrido[3,2-b][l,4:K tillage- 6-aldehyde (synthesis see W02003087098, Example 31(e)) (69 mg, 0.388 mmol) was combined with 1 scoop of solid sodium carbonate in anhydrous DCM (5 mL) and anhydrous MeOH (1 mL). After the reaction mixture was stirred under a nitrogen atmosphere for 18 hrs, sodium triacetoxyborohydride (235 mg, 1.06 m.m. The reaction mixture was concentrated and purified EtOAcjjjjjjjjjj MS (ES+) m/z 470.5 (MH+). 1H NMR (400 MHz, CD3OD) δ ppm 2·69 (d, "76.06 Hz, 1 Η) 2·84 (d, /7.07 Hz, 1 Η) 2.88 - 2.95 (m, 2 H) 2.99 - 3.09 (m5 1 H) 3.12 (dd, 79.60, 4.80 Hz, 1 H) 3.19 - 3.29 (m, 1 H) 3.68 (s? 2 H) 4.24 - 4.31 (m, 2 H) 4.32 - 4.42 (m? 1 H) 4.47 - 4.55 (m? 1 H) 4.57 - 4.68 : (m, 1 H) 4.71 (d, 71.77 Hz, 2 H) 6.72 (d? J9.85 Hz, 1 H) 7.11 (d, / 7.83 Hz, 1 H) 7.39 (d «78.08 Hz, 1 H) 7.89 - 8·00 (m, 2 H) 8.52 (d, /2.02 Hz, 1 H). ' The acid salt was prepared by the addition of 43 microliters (1 equivalent) of 4N HCl / 1,4-dioxane to a free base. Example 81 6-{[({(38,48)-1-[2-(7-Fluoro-2-keto-1,5-naphthyridinyl)(211)-yl)ethyl M-carbyl-3 -吼吼唆基}methyl)amino]methylpyridin[3,2-7][1,4]thratic-3(411)-ketone hydrochloride

L_{2-[(3S,4S)-3-(Aminomethyl) glacial-1-pyrrolidinyl]ethyl}-7-fluorohydrofuran-2(1H)-S with (130 mg, 0.423 mmoler) and 20 keto_3,4_diindole-2H-pyrido[3,2-b][l,4]thratic-6-aldehyde (synthesis see W020〇4〇58144, Example 7 (d)) (90 mg, 0.465 mmol) was mixed with 1 scoop of solid sodium carbonate in anhydrous DCM (5 mL) and anhydrous MeOH (1 mL). After the reaction mixture was stirred under a nitrogen atmosphere for 18 hr, diethyl ether &lt;RTI ID=0.0&gt;&gt;&gt; The reaction mixture was concentrated and purified EtOAcjjjjjjjjj MS (ES+) m/z 485·5 (MH+). 1H NMR (400 MHz, CD3OD) δ ppm 2·61 - 2·70 (m,1 Η) 2·72 - 2.82 (m,3 Η) 2· 84 -5 2·89 (m,2 Η) 2·94 - 3.06 (m,2 Η) 3·17 - 3·26 (m,1 Η) 3·57 (s,2 Η) 3·68 (s , 2 Η) 4.29 (d, 79.85 Hz, 2 Η) 4.36 (ddd, J 14.65, 5.81, 5.56 Hz, 1 Η) 4.51 (ddd, 77.52, 4.04, 3.85 Hz, 1 H) 4.54-4.65 (m, 1 H) 6.68 (d, 79.85 Hz, 1 H) 7.11 - 7.17 (m, 1 H) 7.80 - 7.86 (m, 1 H) 7.91-7.98 (m, 2 Η) 8·52 (d,/2.27 Hz, 1 H). The title compound hydrochloride was prepared via the addition of 49 [mu]l (1 eq.) of 4N EtOAc / 1,4- ss. 〇Example 82 7-Chloro_6_{[({(38,48)-1-|&gt;(7-fluoro-2-keto-1,5-naphthyridin-1(2H)-yl)ethyl] 4-hydroxy-3-pyrrolidinyl}methyl)amino]methyl}-211_pyrido[3,2-b][l,4]indole_3(4H)-one hydrochloride

1-{2-[(3S,4S)-3-(Aminomercapto)-4-hydroxy-1-indolyl]ethyl}-7-fluoro-1,5-naphthyridine-2 ( 1H)-ketone (118 mg, 0.386 mmol) and 7-2 chloro-3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4] morphine -6-aldehyde (synthesis see W02003064421, Example 15(c)) (90 mg, 0.425 mmol) was mixed with 1 scoop of solid sodium carbonate in anhydrous DCM (5 mL) and anhydrous MeOH (1 mL). After the reaction mixture was stirred under a nitrogen atmosphere for 18 hr, sodium <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; The reaction mixture was concentrated and purified with EtOAc EtOAcjjjjjjj MS (ES+) m/z 503.3 (ΜΗ+). 1Η NMR (400 MHz, CD3OD) δ ppm 2.69 - 2.78 (m, 3 H) 2.86 (dd? J 10.74, 6.19 Hz? 1 H) 5 2.91-3.00 (m51 H) 3.01-3.12 (m, 2 H) 3.23 (dd, J9.22? 3.66 Hz, 1 H) 3.68 (s, 2 H) 4.29- 4.39 (m, 3 H) 4.56 (td, J6.63 , 2.40 Hz, 1 H) 4.64 (ddd, J 14.78, 8.72, 6.32 Hz, 1 H) 4.71-4.75 (m? 2 H) 6.63 (d5 /9.60 Hz, 1 H) 7.54 (s, 1 H) 7.87 ( d, 79.60 Hz, 1 H) 7.95 (dd, /=10.48, 2.15 Hz, 1 H) 8.51 (d, J2.27 Hz, 1 H). The title compound hydrochloride is added via 41 μl (1 eq.) Prepared by a solution of 4N HC1/1,4-dioxane to a free base. 10 Example 83 l-[2-((3S,4S)-3-{[(2,3-Dihydro[1,4]dioxo[2,3-c]pyridin-7-ylfluorenyl) Amino]mercapto}-4-hydroxy-1-pyrrolidinyl)ethyl]-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride

1-{2-[(3S,4S)-3-(Aminomethyl&gt;4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-1,5-naphthyridine-2 (1Η )-ketone (110 mg, 0.359 mmol) and 2,3-dihydro[indene]dioxo[2,3-c]pyridine-7-aldehyde (synthesis see 2〇W〇2〇〇4〇) 58144, Example 2(c) or W003/087098, Example 19(d)) (65 mg, 0.395 mmol) in anhydrous DCM (5 mL) and anhydrous MeOH (1 mL) with 1 sp. After the reaction mixture was stirred under a nitrogen atmosphere for 18 hrs, sodium triethyloxy borohydride (239 mg, 1.00 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction 242 200817417 mixture was concentrated. Purification by column chromatography (90:10:1 DCM:MeOH:HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 400 MHz, CD3OD) δ ppm 2.54 (d, J5.81 Hz, 1 H) 2.78 (dd? J9.47, 7.20 Hz, 1 H) 2.82 - 2.91 (m5 5 H) 3.09 (d3 75.56 Hz, 2 H) 3.33 (dt5 /=3.28, 1.64 Hz, 1 H) 4.03 -4.12 (m, 2 H) 4.33 (dd, J5.31, 2.53 Hz, 2 H) 4.37 - 4.41 (m5 2 H) 4.44 - 4.51 (m, 3 H) 6.78 (d, J9.60 Hz, 1 H) 6 .97 (s,1 H) 7.87-7.92 (m,2 Η) 7·96 (dd5 J 10.61,2.02 Hz,1 H) 8.51 (d, 72.27 Hz, 1 H). The title compound hydrochloride is added Prepared by 25 μl (1 equivalent) of 4N HC1/1,4-dioxane to a free base. ίο Example 84 1-(2_{4-[(2,3-Dihydro[1,4] Dioxo[2,3_c]pyridin-7-ylindenyl)amino]-1-hexanitrogen 11 σ σ}ethyl)-5-fluoro(decyloxy)-2(m)-喳咁Ketobenzoate and Example 85 1-(2_{4-[(2,3-Dihydro[1,4]dioxo[2,3-supridyl-7- 15 fluorenyl)amino] -1-hexahydro-17-sigma-based}ethyl)-7-fluoro-5-(decyloxy)-2(m)-indolone benzoate

(8) 7-Fluoro-5-(decyloxy)-1-(2-propen-1-yl)-2(1Η)-fluorenone and 5-fluoro243 200817417 -7-(decyloxy)-1-( 2-propen-1-yl)-2(m)-porphyrinone (1:1 mixture) 5,7-difluoro-1_(2-propen-1-yl)-2(lH)-fluorenone (350 mg, 1.58 famol) dissolved in anhydrous MeOH (7 mL). Methanol was added slowly (85 mg '1·58 mmol) and the reaction was heated under reflux for 5 nights under argon. More sodium methoxide (42.5 mg, 0.79 mmol) was added and more sodium methoxide (63.8 mg, 1.18 mmol) was added over 3 hours. After the reaction was stirred at reflux overnight, additional sodium methoxide (85 mg, 1.58 m.m.). The MeOH was removed and the residue was partitioned between water and ethyl acetate. The organic layer was dried (sodium sulfate) and evaporated to give a creamy oil. Mixture of isomers (62%). MS (ES+) m/z 222 (MH+). 15 03) [7-Gapent-5-(decyloxy)-2-keto__(2Η)-σ奎σ林基]acetic acid and [5-fluoro-7-(decyloxy)-2-one Base-1 (2Η)-. Quinolyl] Ethylene (1:1 mixture) 7-like-5-(methoxy)-1-(2-propenyl-1-yl)_2(115)-44 ketone and fluoro-7-(曱Oxy)-1-(2-propenyl small)_2(ΐΗ)-σ奎咐酉同 (1:1 mixture) (240 mg, 1.03 mmol) DCM dissolved in a 3-necked flask (8 2 liters) and cooled to _78 °C. It was then spoiled under 03 for 2 minutes and then quenched with DMS (0. 29 mL, 4.12 mmol). Then place to allow to warm to room temperature. Evaporation of the solvent gave an impure product (3〇4 mg)· MS (ES+) m/z 236 (ΜΗ+)〇244 200817417 (c) (2,3-Dihydro[1,4]dioxan[ 2,3_c]pyridine-7-ylmethyl)(1_{2_[5_fluoro-7-(methoxy)-2-keto-1(2H)-indenyl]ethyl hexahydropyridyl ) 1 dimethyl dimethyl carbamate and (2,3-dihydro] dioxo [2,3-c] mouth bite 1 yl methyl) (1_{2_[7_Fluor_5_(methoxy) )) _ keto 5 - 1 (2H)- fluorenyl] ethyl b 4-hexahydropyridyl) carbamic acid 1, dimethyl dimethyl ester (1:1 mixture) [7_Fluorine_ 5_(methoxy)_2_gisoyl_1(2Hpquinuclyl)acetaldehyde and [5_fluoro-7-(decyloxy)-2-keto-1(2H)-indolyl]acetaldehyde (1 :1 mixture) (3〇4 house grams, 1.29 house moles) and (2,3_dihydro[μ]dioxo[2,3_c]acridine_7_1〇ylindenyl)4_hexahydrogen 1,1-dimethylethyl acridineamine decanoate (synthesis see W02004/058144 Example 99(h)) (848 mg, 2.413 mmol) (450 mg ' 1.29 faint) dissolved in A 5:1 mixture of chloroform and MeOH (25 liters, 5 liters) and spoiled for 1 hour at room temperature under nitrogen pressure. Use NaBH(OAc)3 (820 mg, 3.87 m) The ear was treated and stirred for an additional 1 hour. The solvent was removed and the crude material was chromatographed on silica gel eluting with a gradient of 0-10% MeOH / DCM. The fractions containing the desired product were concentrated (300 mg, 41 %) MS (ES+) m/z 569 (MH+) 〇2〇(d) title compound (2,3-dihydro[1,4]dioxo[2,3-c]pyridine_7_ (曱-based) (1-{2_[5-fluoro·7-(decyloxy)-2-keto-1(2H)-indenyl]ethyl b-tetrahydropyridyl) amide U-dimercaptoethyl ester and (2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylmethyl)(1-{2-[7-fluoro- 5-(methoxy)_2-ketone 245 200817417 yl-1(2H)+linyl]ethyl}_4_hexahydroindenyl) carbamic acid hydrazine · vinegar (1:1 mixture) (30() (Mg, 〇.53 mmol) dissolved in chloroform (5 liters) sub-added to 4 Μ Ηα solution in 1,4-dioxane (1 ml of the reaction was stirred at room temperature under argon pressure for an hour! The formed solid was dissolved in 5 Me〇H and the solvent was removed. The solid was again dissolved in MeOH and

The Amberlyst tree only looks at the towel pH. The title of the title compound was obtained from EtOAc (EtOAc): MS (ES+) m/z 469 (MH+) 〇 ι〇 This material was isolated by preparative HPLC using a single injection

Chiralpak AS-H column, eluted with MeOH (0.1% isopropylamine) at a flow rate of 20.0 ml/min, and detected at 254 nm to give the title compound 1-(2-{4-[(2,3- Dihydro[1,4]dioxo[2,3-c]pyridin-7-ylmethyl)amino]pyrohydropyridinyl}ethyl)-5-fluoro-7-(methoxy) -2(1Η)-喳 ketone 15 (39 mg, &gt;99.8% purity) and 1-(2-{4-[(2,3-dihydro[1,4]dioxo[2,3] -c]pyridine-7-ylmercapto)amino]-1_hexahydropyridyl}ethyl)-7-fluoro-5-(methoxy)-2(1Η)-fluorenone (32 mg, &gt ; 99.8% purity) free state test. 1-(2-{4-[(2,3-Dihydro[1,4]dioxo[2,3-decyridin-7-ylmethyl) 20-amino]-1-hexahydroindole Ratio }}ethyl)-5-fluoro-7-(decyloxy)-2(1 Η)-σ 奎嘴_ NMR (400ΜΗζ) δ( CD3OD) 1·65 (1H,m),2·10 (2Η,d),2·25 (2Η,t),2.73 (2Η,t), 2·98 (1H,m),3·19 (2H,d),3·96 (3H,s),4 ·1 (2H, s), 4·33 (2H, m), 4·39 (2H, m), 4.49 (2H, t), 6.54 (1H, d), 6·78 (1H, m), 6 ·90 (1H, s), 7.00 (1H, s), 7·39 (2H, m), 7.46 (1H, m), 7.99 (3H, m), 8.11 (lH, s)· 1-(2- {4-[(2,3-Dihydro[1,4]dioxo[2,3-(:]pyridin-7-ylmethyl))

246 200817417 Amino] hexahydropyridyl}ethyl)-7-fluoro-5-(decyloxy)-2(1Η)-fluorenone]H NMR (400ΜΗζ) δ( CD3OD) 1.65 (2H, m ), 2.10 (2H, d), 2.24 (2H, t), 2.72 (2H, t), 2.99 (1H, m), 3.18 (2H, d), 3·99 (3H, s), 4.11 (2H, s),4·33 (2H,m), 4·39 (2H, m),4·44 (2H,m),6·55 (1H,d),6.75 (1H,m)5 7.00 (2H, m), 7.40 (2H, m), 7.46 (1H, m) 5 7·99 (2H, . m), 8.12 (1H, s), 8.20 (1H, d). 5 via 1 equivalent of stupid These compounds were converted to the title compound monophenylphosphonate by citric acid treatment. Example 86 5-Chloro-3-(2-{4-[(2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylmethyl)amino] -1-hexahydro-external b. Stationary}ethyl)-i,3-benzopyrene η 10 -2(3Η)-one dihydrochloride

CI

15 (4) 5-Chloro-3-(2-propan-1-yl)-1,3-benzoquinone 17-spin-2(3Η)-酉 will be 5-chloro-1,3-benzothiazole-2 ( 3Η)-ketone (1.85 g, 1 mmol) dissolved in DMF (50 mL) and treated with potassium sulphate (1.66 g, 12 mmol) and allyl moth (1.1 mL, 12 mmol). Then at 1〇〇. 〇 Heat for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water (EtOAc (EtOAc) &lt The organic layer was washed with saturated brine, separated and dried. Chromatography on silica gel eluting with a gradient of EtOAc EtOAc (EtOAc) MS (ES+) m/z 226 and 228 (ΜΗ+, 1〇〇 and 3〇%, respectively). 247 200817417 (b) (5-Chloro-2-keto-i,3-benzothiazol-3(2H)-yl)acetaldehyde will be 5-chloro&quot;·3_(2-propen-1-yl)- 1,3-Benzothiazol-2(3H)-one (〇·43 ^ 'h9 mmol) was dissolved in 1,4-dioxane (20 mL) and water (22 liters) was added. Sodium periodate (〇·94 g, 4·4 mmol) and 5,々% osmium tetroxide (2.1 ml) in water were added in sequence and stirred at room temperature for 3 minutes to form a large precipitate. Things. Water (2 ml) and sodium periodate (1.9 g, 8.9 mol) were added sequentially and the mixture was stirred at room temperature for 18 h. The mixture was vacuumed/shrinked to at least volume and partitioned between water (5 mL) and DCM (2χ5 mL). The organic layer was separated and dried. Chromatography on silica gel eluting with EtOAc (EtOAc:EtOAc: MS (ES+) m/z 226 and 228 (Μ_Η, 1〇〇 and 35%, respectively). (c) the title compound 15 (5-chloro-2-keto-1,3-benzothiazol-3(2H)-yl)acetaldehyde (0·10 g '〇·44 mmol) and (2) ,3-di-argon [l,4]:^g and [2,3_c]pyridine-7-ylmethyl)4_hexahydropyridylaminocarboxylic acid 1,1-dimethylethyl ester (0.154 g, 〇· 44 mmol (synthesis see W02004/058144 Example 99(h)) dissolved in chloroform (10 ml) and MeOH (1.5 ml) with acetic acid (8 drops) and (poly 20 styrylmethyl) Treatment with methyl cyanoquinone (Novabiochem) (4.1 mmol/g, 0.87 g) and the mixture was stirred at room temperature for 60 hours. The reaction was filtered and evaporated to dryness. Chromatography on silica gel, eluting with a gradient of 0-12% MeOH / DCM to afford &lt;RTI ID=0.0&gt; Ethyl]-4-hexahydropyridyl}(2,3-dihydro[1,4]dioxo 248 200817417 芑[2,3-c]pyridin-7-ylindenyl) decanoic acid 1 , 1-Dimercaptoethyl ester oil (0.25 g, 1 〇〇〇 /.). MS (ES+) m/z 561 and 563 (ΜΗ+). This was dissolved in DCM (10 mL). The residue was partitioned between 1% aqueous carbonate (30 mL) in water and 10% MeOH (3 x 30 mL) in DCM. The organic layer was dried, filtered and evaporated to dryness. Chromatography on silica gel eluting with EtOAc (EtOAc:EtOAc:EtOAc NMR δ(CDCls) 1.29-1.45 (2H5 m)51.73 (2H&gt; s)51.80-1.93 (2H, m)? 2.05^ 18 Γ2Η 10 m), 2.42-2·55 (1H,m),2·66 ( 2H,t,J 6·5 Hz),2·85-2·96 (2H,m),3·75 (2H s) 3 99 βΗ' t ακΤ4'22-4'35 (4H, m), 6 , 82 (m, s), 7·07'7·13 (2Hs mX 733 (1^d&gt; MS (ES+) m/z 461 and 463 (MH+, 3〇 and 1〇%, respectively).

This material was &gt; glutathioned in MeOH and treated with an excess of hcI in ethyl acetate. The title compound dihydrochloride was obtained as a white solid. Example 87 1-(2-{4-[(2,3-Dihydro[1,4]dioxo[2,3_c;jpyridine-7-ylmethyl)amino]-1-hexahydro) ϋ定基}Ethyl)-6-fluoro-[ι,3]喧σ sita[5,4-b]pyridine-2(1H)-one dihydrochloride

(a) 2-Ga-5-gas-3-stone Schottky. ratio. 249 200817417 The title compound is a general method from Sugimoto ei fl/, Tetrahedron Letters (1999), 40, 7477-7478 from 5-fluoro-3-nitro-2(1H)-pyridinone (1·〇克Prepared with 6.3 mmoles to give (0.7 g, 62%) of brown oil which crystallised after standing. 5 lK NMR 6 (CDC13) 7.99-8.05 (1H, 8.55 (1H, d, J 2.8Hz). (b) 6-Fluoro[1,3]thiazolo[5,4_b]pyridine-2(1H)-one 2-Chloro-5-fluoro-3-nitropyridine (0.7 g, 3.9 mmol) was suspended in THF (20 mL) and water (EtOAc······· (〇·63 g) treatment. The mixture was placed in a Bergoff pressure chamber and pressurized to 1500 kPa (15 bar) with carbon monoxide and then heated at 90 ° C for 18 hours. The reaction was cooled and ventilated to remove excess carbon monoxide, and the solution was suspended/suspended. The solution was evaporated to dryness <RTI ID=0.0>~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The title compound (〇. 〇 5 g, 7.4%). -1_(2_propan-1-yl)[1,3]喧. Sit and [5,4-1&gt;]11 to 11 to 2(111)-keto 0 to 6-fluoro[1,3] Thiazolo[5,4-b]pyridine-2(1H)-one (0.045 g, 0.31 mmol) dissolved in DMF (3 mL) with potassium carbonate (0.043 g, 0.31 mmol) The iodine (3 ml, 0.33 mmol) was treated and then heated at 100 ° C for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. Saline F should be washed, isolated 250 200817417 and dried. Chromatography on silica gel eluting with 10-50% ethyl acetate / 40-60 petroleum ether to give the title compound (0.046 g, 73%). MS (ES+) m/z 211 (MH+,1〇〇%) 〇(4)(6-fluoro-2-keto[1,3]thiazino[5,4-b]acridine-2(1H) -Based on a 6-fluoro-1-(2-propen-1-yl)[ι,3]thiazolo[5,4-b]pyridine-2(1H)-one (0.046 g, 0·22) Molol) dissolved in DCM (8 mL) and MeOH (1 mL) and the solution was cooled to -7 (TC). The gas mixture of the ozone containing gas in the oxygen was bubbled through the solution for 20 minutes to give a pale green solution. After argon gas bubbles were passed through the solution for 5 minutes, dimercaptosulfur (64 ml, 0.87 mmol) was added. The mixture was allowed to warm to room temperature and then evaporated to dryness. MS (ES+) m/z 245 (MeOH acetal oxime +, 100%). (e) the title compound (6-fluoro-2-keto[1,3]thiazolo[5,4-b]pyridine-2(1H)-yl)acetaldehyde (0.046 g, 〇·22 mmol) and (2,3-Dihydro[1,4]dioxo[2,3-c]pyridyl-7-ylindenyl)4-hexahydropyridylamine decanoic acid ι,ι_二曱基乙Ester (0.069 g '〇·2 mmol) (synthesis see W02004/058144 Example 99(h)) Dissolved in chloroform (5 ml) and MeOH (1 ml) with acetic acid (1 () drops) and (B) The compound was treated with Novabiochem (4.1 moles/g, 〇·39 g) and the mixture was stirred at room temperature for 60 hours. The reaction was filtered and evaporated to dryness to give (2, <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 2-keto[1,3]thiazole

251 200817417 [5,4-b] meal base) ethyl]_4_hexahydroindenyl}amino group. thiol was dissolved in dcm (3 ml) and extracted with trifluoro acid U pen) at room temperature treatment 4 After an hour, evaporate to dryness. The residue was dissolved in MeOH and stirred with a polymer fixed on a carbonate resin = filtered and evaporated. Chromatography on Shixia gel, eluting with 0-12% of 2]\/[Ammonia/〇〇]^1 in 1⁄2 011 to give the title compound as a free base (〇·〇5 g , 51%). 4 NMR δ( CDC13) 1.29-1.45 (2H,m), 1.73 (2H,s),1.80-1.93 (2H,m),2.05—2.18 (2H, m), 2.42-2·55 (1H,m) ,2·66 (2H,t,J 6·5 Hz), 2·80-2·92 (2H,m)5 3·75 (2H,s),3·99 (2H,t, J 6·5Ηζ ), 4·22~4·35 (4H, m), 6.80 (1H, s), 7·16 (1H, dd, J 2.5 and 9 Hz), 8.10 (1H, s), 8.18 (1H, dd5J land 2.5 Hz). MS (ES+) m/z 446 (MH+5 100%). 10 This material was dissolved in MeOH and treated with an excess of 4M HCl in EtOAc. The title compound dihydrochloride was obtained as a gray solid. 15 Example 88 6_{[({(3S)-H2-(7-fluoro-2-keto-hydroxyquinolinyl)ethyl]-3-pyrrolidinyl}methyl)amino]methylpyrene [3,2-b][l,4]畤耕-3(4H)-ketone

252 200817417 (8) (7-Fluoro-2-keto-1(211)-17 quinoxalinyl)acetic acid 7-fluorosuccinyl (2-propion-1-yl)-2(indole)-4 4-linthone ( 5·〇克, 0.025 mmol) was cooled to -70 ° C in a solution of 3:1 CH 2 Cl 2 : MeOH (500 mL). Dimethyl sulphide (19 ml, 0. 25 mmol) was added and the reaction was stirred at -7 EtOAc for 90 min then warmed to room temperature overnight. The solvent was evaporated under reduced pressure to give a viscous orange oil. Purification by column chromatography (p/. to 1% hexanes:EtOAcEtOAc) MS (ES) m/z 206 [M+H]+. Ίο (b) ({(3S)-l-[2_(7-fluoro-2-keto-1(2H)) quinacyl)ethyl]_3_pyrrolidinyl}methyl)carbamic acid phenyl Methyl ester in (7-fluoro-2-keto-1(2H)-carboline)acetaldehyde (1.17 g, 5.71 mmol) and [(3R)-3-4b-decylmethyl]amine Phenyl formate vinegar (can be similar to the 3R isomer of 23(b) prepared in WO2006002047, prepared from (R)-3-(aminomethyl MN-Boc-bite) (1.34 g, 5.71 mmol) 8 eq. of Na 2 SO 4 (6.5 g, 46 mmol) was added in a solution of 1:1 CH 2 Cl 2 : MeOH (80 mL) and the reaction was stirred at ambient temperature for 18 hr. The sodium oxyborate (3.63 g, 17.0 mmol) was treated and stirred for a further 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous NaHC? The organic layer was dried over EtOAc (EtOAc) (EtOAc:EtOAc: 253 200817417 MS (ES) m/z 424 [M+H]+ (c) M2-[(3S)-3-(Aminomethyl)-1-pyrrolidinyl]ethyl gas • -2 (1H )-Phenolinone 5 in ({(33) small [2_(7-fluoro_2-keto-1(2H)) quinacyl)ethyl]pyrrolidyl}methyl)amino phthalic acid benzene Base oxime ester (820 mg, 1.94 mmol) 5% Pd/C (200 mg, 5% by weight aqueous) was added to a solution of MeOH (30 mL). The mixture was saponified at 15 psi for 2.5 hours via Celite ® The pad is filtered and concentrated to give a clear oil which is darkened and solidified (555 mg, 99%). MS (ES) m/z 290 [M+H]+ (d) 6 -{[({(3S)-l_[2_(7_ fluoro_2-keto-l(2H)_u ku π linyl)ethyl]j• phenanthridyl}methyl)amino] fluorenyl }_2Η-pyridine and 15 [3,2-b][l,4]H3(4H)__ in 1_{2_[(3S)_3_(aminomercapto) 吼 吼 】 】 】 -2(1H)-pyridone (87 mg, 〇·3〇 mmol) and 3-keto- 3,4-dihydro-2H-indole[3,2_b][l,4]畤Add argon-6-aldehyde (synthesis see W02003087098 'Example 31(e)) (54 mg, 0.302 mmol) to Na 2 S〇4 (355 mg, 2.50 mmol) and react at ambient temperature Spoiled for 18 hours. The intermediate imine was treated with triacetic acid side gasification (160 mg, 0.75 mmol) and stirred for a further 16 hours. The solvent was removed under reduced pressure, and the residue was partitioned between dichloromethane and aqueous sodium carbonate, and the organic layer was dried (NajO4). Column chromatography on tannin

The title compound was obtained as an amorphous solid (6-9 mg, 51%). ' 1H NMR (400Mz, CDC13) δ 7.65 (d, J = 9.5 Hz, lH), 7.56-7.53 (m, 1H), 7.21 (d, J = 8·1 Hz, 1H), 7.16 (dd, J = 9·6Ηζ, J = 2·2 Hz, 1H), 6.99-6.95 (m, lH), 6.92, (d, J = 8·1 Hz, 1H), 6.71 (d, J = 9.5 Hz) , 4.65 (s, 2H), 4·46·4·37 (m, 2H), 3·83 (s, 2H), 2.95 (apparent t, lH), 2.80 (t, J = 7.63 Hz, 2H), 2.73 (t, J = 6.91 Hz, 2H), 2.67 (d, J = 6.92 Hz, lH), 2.58-2.54 (m, 1H), 2.48-2.07 (m·1H), 2.07-2.00 (m, lH) , 1.58-1.28 (m,1H)· MS(ES) 7tz/z452[M+H]+. Example 89 6-({[(2S)-4-{2-[7_(methoxy)-2) -keto-1,5-naphthyridin-1(2H)-yl]ethyl}-2-ifu π-linyl)methyl]amino}indenyl)-2H-pyrido[3,2_b][ l,4] tige-3(4H)-ketone hydrochloride

(4) Racemic 2-{[(2R,S)|(phenylindenyl)-2-morpholine]indenyl}_1沁isosaki-1,3(2H)_dione in 4- Benzyl-2-(chloromethyl)fosfolon (2 g, 8.86 mmol) in a solution of DMF (10 ml) with potassium sulfoxide (1·96 g, 10.6 mmol) ) and the mixture is at 165. (The mixture was heated for 4 hours. After cooling, the reaction mixture was poured into water (20 ml) and the product was extracted to CHC13 (3 EtOAc), and the combined organic layers were washed with a small amount of water, brine and dried (Na2S04). Evaporation gave a pale brown solid which was used directly in the next step. 255 200817417 LC/MS (ES) m/e 337 (M+H)+. - · _. One (b) racemic {[(2R, S)-4-(phenylmethyl)-2-moffinyl]methyl}amine will be crude 2-{[(2R,S)_4_(phenylmethyl)_2_? Base 5 iso-α 哚 13(211)-dione (~8·8 houser) was suspended in absolute ethanol (15 ml) and treated with hydrazine monohydrate (0.75 ml, 15.4 mmol). To reflux, the reaction solution turned yellow and homogeneous, then the white solid precipitated. After 2 hours, the reaction was cooled to room temperature, diluted with CHCI3 and filtered and evaporated. CHC13, washed with a small amount of water, brine and dried (Na2sjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs (c) Racemic {[(2R,S)-4-(phenylindolyl)-2-moffinyl]methyl}amine 15 1,1-dimethylethyl decanoate in crude {[(2R) ,S)-4-(phenylindenyl)_2_isfosyl]fluorenyl}amine (169 g, 8.2 mmol) in DCM (15 ml) in 〇 ° C solution was added dicarbonate Tributyl ester (L88 g, 8.6 mmol). The cooling bath was removed and the reaction was stirred at room temperature: 2 hours. The solvent was removed in vacuo and the obtained oil was purified on a 2 ' system with CHCl3_MeOH_NH4 The title compound was obtained as a white solid (1.94 g, 71% over 3 steps): lc/MS (ES) m/e 307 (M+H) + (d) {[ (2S)-4-(phenylindenyl)-2-iuf-fusin]indolyl}amino phthalic acid 1,1_2 256 200817417 methyl acetamidine and {[(2R)-4-(benzene Methyl chloroforminyl]methyl carbamic acid 1,1:didecylethyl ester {{(2R,S)-4-(phenylmethyl)-on-fosyl)methylamine 1,1-Methyl ethane carboxylic acid (10 g) was passed through a preparative HPLC (chiraicei 5 0D 77 mm x 240 mm column, 95:5 hexane: ethanol, 280 cc / min flow L owed Injection 〇·5g, uv@254nm) dissociation, got {[(2S)-4-(Benzylmethyl)-2-ifufu]]]]]]]]]]]]]]]]]]] :4 194 minutes, [a]D_14 6〇) of colorless oil and {[(2R)_4_(phenylmethyl)_2_ifufuyl] fluorenyl}amine 曱1 〇1, 一-methyl A colorless oil of ethyl ester (4.99 g, &gt; 98% ee, retention time = 3.477 min, [a] D = +14.6). (e) [(2R)-2-Isofosylhydrazino]didecylaminocarbamate at {[(2S)-4-(phenylindenyl)-2-morpholine]]yl }Aminoguanidine 15 丨,1·dimethylethyl ester (屯9 g, 16 mmol) was added 10% Pd/C (1.5 g) in ethanol (160 mL). The suspension was hydrogenated at 50 psi using a Parr Shaker apparatus for 8 hours. The reaction was filtered through a pad of Celite® and the pad was washed several times with methanol. The filtrate was concentrated to give EtOAc m. The absolute stereochemistry of the title compound was determined by vibrating circular dichroism. (1) [((2S)_4_{2-[7_(decyloxy)-2-keto-1,5-naphthyridin-1(2H)-yl]ethyl}_2_morpholinyl)indenyl] Amino ruthenic acid ι, ΐ-dimercaptoethyl ester 257 200817417

The resulting solution is scrambled at the soil temperature for 1 $ /

J 〇田丞丞T base] carbamic acid 1,1_2 2,29 halo) and Na2S04 (0.100 g) and will be scrambled for 18 hours. Na(OAc)3BH LC/MS was added: m/z 419 (MH+) </RTI> (1.46 g, 6.78 moles) and the mixture was stirred for a further 2 hours. The reaction mixture was concentrated on EtOAc and EtOAc (EtOAc) EtOAc (EtOAc) (g) l-{2-[(2S)-2-(Aminomethyl)_4_morpholinyl]ethyl b 7-(methoxy)-1,5-naphthyridin-2(1H)- Ketone in [((2S)_4_{2-[7-(methoxy)_2-keto-naphthyridine-1 (2H); | ethyl}-2- oxalinyl) methyl] carbamic acid - Dimercaptoethyl ester (〇·46 15 g, 丨·10耄莫) was added to the solution of CH2Cl2 (1 mL) in HC4 (1·1 〇 ml, 4·). 4 〇 mmol) and the resulting solution was stirred at ambient temperature for 16 hours. Concentrated under reduced pressure, and the free base was obtained after treatment with an excess of phthalic acid carbonate to give a yellow oil (3·3 g, 85 %) 〇2〇LC/MS: m/z 319 (ΜΗ+). (h) The title compound is in l-{2-[(2S)-2_(aminoindolyl)_4_fofofyl]ethyl 7-(Methoxy)-1,5-naphthyridinium-2(1H)-one (0.100 g, 0314 mmol) was added to a solution of 1:1 258 200817417 (MeOH/CH 2 Cl 2 ) (25 mL) 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,.4]thiaphene (synthesis see W02004058144, Example 7(d)) (0.061 g, 0.314 mmol) And sodium sulfate (0.100 g) and the resulting solution was stirred at ambient temperature for 18 hours. 5 Add Na(OAc)3BH ( 0.200 g, 942·942 mmoles) and the solution was stirred for a further 2 hours. The reaction mixture was concentrated on silica gel and chromatographed on a silica gel column [0-100% CHC13/(90:10:1) CHCl3/MeOH </RTI> </ RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; +Η)+. 1Η NMR (400 MHz, CD3OD) δ ppm 1.26 (t, J=7.07 Ηζ, 1 Η) 1.98 - 2.04 (m, 2 Η) 2.28 (td, 1.37, 3·28 Hz, 1 Η) 2·61 - 2·72 (m, 4 Η) 2.92 (dd, "7=18.82, 11.24 Hz, 2 Η) 3.52 (s 2 Η) 3·58 - 3.69 (m, 2 Η) 3·75 - 3 ·83 (m,2 Η) 3·83 - 3·91 (m,1 Η) 4·04 (s5 3 'Η) 4·12 (q ' /=7.16 Hz, 1 Η) 4.50 (t, /= 7.20 Hz, 2 Η) 6.75 (d5 J-9.60 Hz, 1 H) 7.01 (d5 J=7.83 Hz 1 H) 7.50 (d, /=2.27 Hz, 1 H) 7.68 (d, /-7.83 Hz51 H) 7.92 (d, 7=9.85 Hz? 1 H) 8.29 (d 7=2.27 Hz, 1 H). ' 15 Example 90 7i-6-({[((2S)-4-{2-[7_(methoxy) _2·keto-_,5-naphthyridin-1(2H)-yl]ethyl}_2_morpholineyl)methyl]amino}methyl)_2H_pyridox[3,2-b ][l,4]噚耕-3(4H)-ketone hydrochloride

In l-{2-[(2S)-2-(aminomethylmorphine)ethyl}_7-(methoxy)-1,5-hydropyridine-2(m)-one (0·100)克,0.314 mmol; in a solution of 1:1 (MeOH/CH 2 Cl 2 ) (25 mL), 3-keto- 3,4_di-gas 259 200817417 -2H_pyridine[3,2-b][ M] Well -6-aldehyde (synthesis see - W02003064421, Example 15 (c)) (0.067 g, 0.314 mmol) and sodium sulfate (〇·1 g) and the resulting solution was stirred at ambient temperature 18 Add Na(OAc)3BH (0.200 g '〇·942 mmol) and stir the solution for another 2 hours. Concentrate the reaction mixture on Shishijiao and chromatograph on Shishi rubber column [0- 100% CHC13 / (90:10:1) CHCl3 / MeOH / EtOAc (EtOAc: EtOAc)克,54%) LCMS: m/z 515 (M+H)+. 1H NMR (400 MHz, CD3OD) δ ppm 2.02 (t, /=10.61 Hz, 1 H) 2.28 (td, /=11.37, 3.28 10 Hz, 1 H) 2.64 - 2.74 (m, 4 H) 2.88 - 2.98 (m5 2 H) 3.62 (td, /=11.37, 2.27 Hz, 1 H) 3.67 (td, /=4.99, 2.65 Hz, 1 H ) 3.84 - 3.92 (m5 3 H) 4.04 (s, 3 H) 4.43 - 4.53 (m, 2 H) 4.67 (s, 2 H) 6.74 (d, /=9.60 Hz, 1 H) 7.35 (s? 1 H) 7.48 (d, 7=2.27 Hz, 1 H) 7.90 (d , /=9.60 Hz, 1 H) 8.27 (d, J = 2.27 Hz, 1H). Example 91 l-[2-((2S)-2-{[(2,3_Dihydro[1,4]) Oxazepine [2,3-c]pyridinium 15 yl-7-ylindenyl)amino]methylmorpholine)ethyl]-7-(decyloxy)-1,5-naphthyridine-2 (1Η)-ketone

In l-{2-[(2S)-2-(aminomercapto)-4_morpholine]ethyl}-7-(methoxy)-1,5-naphthyridin-2(1H)- Ketone (0·100 g, 〇·314 mmol) in a solution of I:1 (MeOH/CH 2 Cl 2 ) (25 mA) was added 2,3-dihydro t1,4]dioxane [2,3_c Pyridine_7-aldehyde (synthesis see W02004/058144, example 2(c) 260 200817417 or W003/087098, example 19(d)) (0.052 g, 〇·314 亳mol) and sulphuric acid (0.100 g) And the resulting solution was stirred at ambient temperature for 18 hours. Na(OAc)3BH (0.200 g '0.942 mmol) was added and the solution was further stirred for 2 hours. The reaction mixture was concentrated on EtOAc (EtOAc)EtOAc. LCMS: m/z 468 (M+H)+. 1H NMR (400 MHz, CD3OD) δ ppm 1·98 - 2.06 (m,1 Η) 2.28 (td, /=11 31 3 16 Η Η) 2.61 - 2.72 (m, 4 Η) 2.92 (dd, /=17.68, 11.12 Hz, 2 H) 3.58 - 3.67 (rn'l H) 3 70 ^ (m, 2 H) 3.89 (ddd5 /=9.98, 1.52, 1.39 Hz, 1 H) 4.05 (s5 3 H) 4.30 - 4.40 (m 4 HU s /=7.07, 1.52 Hz, 2 H) 6.75 (d, J=9.60 Hz, 1 H) 6.96 (s,1 H) 7 52 id J =2 27, and ϋ1 (10) 10 7.93 (d5 J=9.85 Hz5 1 H) 8.01 (s, 1 H) 8.30 (d5 J=2.53 Hz, 1 H) · ) Example 92 7i_6-({[((3S)) -l-{2-[7-(oximeoxy)_2_gisoyl-i,5_英咬-1(2H)-yl]ethyl}_3-hexahydropyridinyl)indolyl]amino group ··吼吼[3,2-b][l,4]唠耕-3(4H)-ketone

20 (a) (3S)_3_[({[(Phenylmethyl)oxy)carbonyl}amino)methyl]-i_hexaqi acridinecarboxylic acid U-dimethylethyl ester (3S) -3-(Aminoguanidino)-1_hexahydropyridinium carboxylic acid 1, 丨_dimethylethylhydrazine (2.0 g, 9.33 mmol) in DCM (12 liters) in hydrazine. Diethylamine (1.7 ml, 12.1 mmol) was added to the hydrazine solution and then hydrazine-(oxygen oxy-oxygen) was added.

261 200817417 base) amber imine (2. 56 g, 1 〇 3 mmol). After a few minutes the cooling bath was removed and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with ethyl acetate and washed with water (2×), 1NH.sub.1, saturated aqueous NaH.sub.3, brine, &lt;RTI ID=0.0&gt;&gt; The product was purified on celite eluting with ethyl acetate-DEtOAc to afford &lt;RTI ID=0.0&gt;&gt;&gt; LC/MS (ES) m/e 349 (M+H)+. (b) [(3R)-3-Hexapyridylfluorenyl]amino phenyl decanoate 1 〇(3S)-3-[({[(phenylphenyl))oxy]carbonyl}amine Base 曱 H H H 氲吼 叛 叛 叛 1, 1, _ dimethyl dimethyl ester (~ 9.3 mM) dissolved in DCM (25 liters) and used in 1,4-two π burning 4M HC1 (24 ml, 96 mmol) treatment. The reaction was stirred at room temperature for 3 hours at which time LC/MS showed that all starting material had consumed. The reaction was concentrated in vacuo to give a viscous gel. This material was dissolved in water and extracted with ethyl acetate. The aqueous layer was separated and solid NaWO3 was added to bring the pH to ~1 〇. The product was then extracted to CH.sub.3 (3.sub.3) and the combined organic layer was dried (Na.sub.2) and concentrated to give the desired product as an orange oil (2. 3 g, 100% over 2 steps). LC/MS (ES) m/e 249 (Μ+Η)+ 〇20 (c) [((3S)-l-{2-[7-(曱-oxy)-2-keto-1,5_ Naphthyridine-1(2Η)-yl]ethyl}-3-hexapyridinyl)indenyl]amino decanoic acid phenyl decyl ester in [7-(methoxy)-2-keto-1,5 -Naphthyridine-1(2Η)-yl]acetaldehyde (mercapto hemiacetal) (0.250 g, 1.15 mmol) in a solution of 1:1 (MeOH/CHCl3) (25 m 262 200817417 L) [(3R)-3-Hexhydropyridylmethyl]amino phenyl carboxylate (0.100 g) was added and the resulting solution was stirred at ambient temperature for 18 h. Na(OAc)3BH (0.57 g, 2.7 mmol) was added and the solution was stirred for a further 2 hr. The reaction mixture was concentrated on EtOAc (EtOAc m.) LC/MS: m/z 451 (M+H) + (d) l-{2-[(3S)_2(aminoalkyl) hexamethylenepyridinyl]ethyl b 7-(methoxy)- 1,5-naphthyridine-2(1Η)-one 10 in (methoxy keto-1,5-naphthyridin-1(2H)-yl]ethyl}-3-hexahydropyridyl) fluorenyl] Add 〇〇/0 pd/c (0·20 g) to a solution of phenyl carbazate (〇·2 g, 0.44 mmol) in MeOH (30 mL) and dissolve the solution at 50 PSI Parr The shaker is turned on. The solution was filtered through EtOAc (EtOAc)EtOAc. (e) the title compound in l-{2-[(3S)-2-(aminomethyl)-1-hexachloropyridinium]ethyl 20-yl}-7-(decyloxy)-1,5-naphthalene Pyridine-2(m)-one (0.149 g, 0.472 mmol) was added to a solution of 1:1 (MeOH/CH.sub.2Cl.sub.2) (25 mL). 2H-pyrido[3,2-b][l,4] oxan-6-aldehyde (synthesis see W02003064421, example I5(c)) (0.100 g, 0.472 mmol) and sodium sulphate (0.100 g) The resulting solution was stirred at ambient temperature for 18 hours.

263 200817417 Na(OAc)3BH (0.300 g '1·42 halo) was added and the solution was stirred for additional 2 hours. The reaction mixture was concentrated on silica gel and chromatographed on a silica gel column [0-100% CHC13 / (90:10:1) CHCl3 / MeOH / ΝΗ40 Η] to give a colorless oil which was further purified by HPLC (CH3CN/H2 〇) The title compound was obtained as a white powder (0.041 g, 17%). LCMS: m/z 513 (Μ+Η)+· 1Η NMR (400 MHz, CD3〇D) δ ppm 1·04 (t, J=6.95 Hz, 1 Η) 1·57 · 1.68 (m,1 Η) 1 73 1.78 (m5 /=10.01, 3.46, 3.46, 3.28 Hz, 1 H) 1.80 - L91 (m&gt; 3 H) 2.12 - 2 23 fm (d? 7=6.06 Hz5 2 H) 2.65 - 2.76 (m, 2 H) 2.97 (s? 1 H) 3.10 - 3.16 (m 1 H) 3 85 3 〇Vr 2 H) 4.05 (s, 3 H) 4.48 - 4.56 (m, 2 H) 4.69 (s? 2 H) 6.79 ( d? J=9.60 Hz 1 H) 7 41 f 1 m 7.54 (d, /=2.27 Hz, 1 H) 7.93 (d? J=9.60 Hz, 1 H) 8.30 (d5 J=2.27 Hz 1 H) ...) Example 93 7_Chloro-6_{[({(3S)-l_[2-(7-fluoro_2-ketolinyl)ethyl]-3-hexahydro)}methyl)amino]indenyl] [3,2-b][l,4]哼耕-3(4H)-one dihydrochloride

(a) M2_[(3S)-3-(aminomercapto)sodium hexahydropyridinyl]ethyl b 7-gas 20 -2(111)^ quinolone (7·fluoro: keto_1 ( 2H) mercapto) acetaldehyde (〇·25g, 1亳mol) and [(3R)-3-hexahydropurine σ-decyl fluorenyl]amino phthalic acid phenyl hydrazine g (〇·275 g, 1 A solution of methanol (1 ml) and DCM (3 ml) was stirred at room temperature overnight and triethyl ethoxy hydride sodium hydride (〇·424 g, 2 亳m) was added 264 200817417 and The mixture was stirred at room temperature for 2 hours. The mixture was extracted with dcm, dried (sodium sulphate), evaporated and chromatographed on silica gel eluting with 〇 〇 〇 曱 - - - - CM -1 -1 -1 , , , , , , , , , , , , , ( ). The foam (0.2 g) was treated with (〇 (10) g) in dry methanol (15 mL) and shaken at 15 psi and room temperature for 2 hours. The Pd catalyst was removed via cdite@filter. The filtrate was evaporated to dryness to give an oil (18 g). MS (+ve ion electron spray) m/z 3〇4 (m+h)+. (b) 7-Chloro-6-{[({(3S)-l-[2-(7•fluoro-2-keto)-1(2H)-indenyl)ethyl 10 15 20 yl]-3_ Hexahydropyridyl}methyl)amino]methyl}_2Η_pyridyl[3,2-7][1,4]_cultivation_3(411)-one will lP-[(3S)-3-(amine Methyl)hexahydropyridyl]ethyl}_7_fluoro-2(1H)-fluorenone (90 mg, 〇·3 mmol) and 7-chloro-3-yl-keto-3, dihydrogen -2Η-pyrido[3,2_b][M]噚__heart aldehyde (synthesis see W02003064421, Example 15(4)) (64 mg, 〇3 mmol) in decyl alcohol (2 liters), DCM (4 mL) The solution in the solution was stirred at room temperature overnight. Sodium diethyl sulfoxyborohydride (〇·127 g, 0.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was evaporated and chromatographed on silica gel eluting with EtOAc &lt;RTI ID=0.0&gt;&gt; The title compound (14 mg) of the di-hydrochloride salt was obtained after the title compound (1 mg).

NMR (400 MHz, CD3OD) δ ppm ΐ·〇7 (s,1 H) ! 59 ] 69 ( 1H 1.83 - 1.94 (m, 2 H) 2.15 - 2.23 (m, 1 H) 2.56 - 2.61 (m* 2 H) 2 1 11 r , ^ 2 H) 1 H) 3.13 - 3.20 (m51 H) 3.90 (s5 2 H) 4.49 (td /=14 21 7 7 f ; ^ H) Z9? ^

Hz, 1 H) 7.11 (td, 7=8.46, 2.27 Hz, 1 H) 7.38 - V.50 (m 2 H) 7^5 H) 7.91 (d, J=9.60 Hz, lH) 1,H) 7 ·75 (dd, /=8.72, 6.19 Hz, 1

265 200817417 MS (+ve iontophoresis) m/z 500 (M+H)+. • Example 94 5-(2_{4-[(2,3-Dihydro[1,4]dioxo][2,3-c]pyridin-7-ylindenyl)amino]-1-hexa Hydropyridyl}ethyl)-3-(methoxy)tonidine 5 [2,3-b]pyrrol-6(5H)-one hydrochloride

(a) 6-Gas-3-stone Schottky-2-17 is an ice-cold solution of 2,6-dichloro-3-nitropyridine (55.65 g, 288 mmol) in EtOH (500 mL). Sodium carbonate (76.32 g, 720 mmol 15 ears) was added followed by aqueous ammonia (35%, 21 mL). The reaction was then allowed to warm to room temperature, stirred at room temperature for 1 hour, then at 50 ° C for 1 hour and then at 90 ° C for 1 hour. 20 ml of ammonia water was added again and heating was continued at 90 ° C for 1 hour. 50 ml of ammonia water was added again and heating was continued at 90 ° C for 1 hour. The reaction was allowed to warm to EtOAc (EtOAc m. lU NMR (250MHz) 6(CDC13) 6.94 (2H, d? J = 8.5Hz)? 8.38 (2H, d3 J = 8.5Hz). (b) 6-({[4-(methoxy)phenyl] Mercapto}oxy)-3-nitro-2-acridinium

266 200817417 4_Methoxybenzyl alcohol (4·8 g, 34 7 Zhen (100 ml) of sodium (0.S g, 34 7 m; to toluene, x. ^. Mao Meier) After most of the sodium is dissolved, add 6 greedy 3, benzyl 2_(tetra)amine (5 g, 28 at 12 (TC heating for 4 hours. Still iron has #私私寸戌肝汉应.^ ^ ^ ^ ^, 仞..., There is a starting material to be retained, and in another flask, the anion of 4-methoxyl-n-alcohol is used (using G.6 g of sodium and 4 g of 4_f-oxyl alcohol in toluene in toluene) and at room temperature. Add to the reaction. Then add the human water (10) mM at room temperature _ 5 hours and reduce the volume to 200 ml. Then add diethyl ether and extract the aqueous layer (3 x 500 liters). The combined organic layer is dried (MgS 〇 4 The residue was purified by chromatography eluting with EtOAc EtOAc EtOAc

Sl 531 (2K 51 614 (1Hj dX 6 94 ^ m), 7.44 15 (c) 6_({[4_(decyloxy)phenyl]indolyl}oxy)_2,3-pyridinediamine in 6·( {[4_(Methoxy)phenyl]methyl}oxy) determinate j pyridinamine (4.8 g ' 17.53⁄4 ul) and gram (11 g, 175 mmol) in methanol (200 mL) Acetic acid (5 ml) was added dropwise to the suspension at room temperature. After 0.5 h, the reaction was filtered thru Celite and solvent evaporated. Res. The layers were separated and dried with EtOAc EtOAc (EtOAc) (ES+) m/z 246 (MH+).

267 200817417 (d) N-[2-Amino-6-({[4-(methoxy)phenyl]indolyl)oxy)-3-acridinyl] 5 ethyl glycinate in 6- ({[4-(decyloxy)phenyl]decyl}oxy)-2,3-pyridinediamine (3·9 g, 15.9 mmol) in DMF (200 mL) under argon atmosphere Potassium carbonate (4.8 g, 35 mmol) was added at room temperature followed by ethyl bromoacetate (1·77 mL, 15.9 mmol). The reaction was stirred at room temperature for 2.5 hours, 1 〇 then solvent was removed and the residue was dried under high vacuum for one hour. The residue was chromatographed on silica gel eluting eluting elut elut MS (ES+) m/z 332 (ΜΗ+). 15 (e) 6-({[4-(Methoxy)phenyl)indolyl}oxy)acridino[2,3-b]4b^-3(4H)-_ will be N-[2- Amino-6-({[4-(decyloxy)phenyl)indolyl}oxy)-3-ylation butyl]glycolic acid ethyl ester (5 g, 15.1 mmol) dissolved in toluene (5 〇〇 ml) and heated under reflux for 2.5 days, the reaction was allowed to cool to room temperature and 20 mM (2. 4 g, 27.5 mmol) was added. After stirring at room temperature for 5 hours, 0.8 g of an emulsification was added and the reaction was stirred at room temperature overnight. The reaction was filtered through celite and washed with a large amount of 20% methanol/DCM. The solvent was removed and the solid was purified eluting elut elut elut elut 'H NMR(250MHz) 5(DMSO) 3.75 (3H, s), 5.35 (2H, s), 6.77(1H d) 6 93 (2H3 m)? 7.50 (2H,m),8·03 (1H,s ), 8.08 (1H, d), 12·9 (1H, bs). ' ' 268 200817417 (f) Difluorodecylsulfonic acid 6-({[4-(decyloxy)phenyl)methyloxime Pyridyl[2,3_b.]pyridinium 3-indole 6-({[4-(indolyl)phenyl]methyl}oxy)acridino[2,3-b]pyrrole Well _3 (4 Η) __ (1 gram, 3.5 mM) in DMF (100 mL) in argon 麈 I solution was cooled to 〇 并 and sodium hydride (6 〇 % in mineral oil, 180 gram , 4.2 millimoles). After the reaction was stirred at room temperature for 5 hours, Ν-phenyl-bis(trifluoromethylsulfonimide) (^-trifluoro-indole phenyl [(trifluoromethyl) fluorenyl] fluorenyl group was added. Continued guanamine) (154 g, 4.2 mM). The reaction was stirred at room temperature for 1 hour then water was added and the solvent was evaporated at <RTIgt; The residue was taken up in water and extracted with DCM. The combined organic layers were dried, evaporated and purified eluting elut elut 'HNMRC^OMHz) 5(CDC13) 3.83 (3H, s), 5.58 (2H, s), 6.94(2H, m), 7.31 (1H, d), 7 46 (2H,m),8·33 (1H ,d),8·Ή (1H,s)· ' 15 (g) 3-bromo-6-({[4-(decyloxy)phenyl)methyl}oxy)π-pyridyl[2,3 -b] Pyridine-trifluoromethanesulfonic acid 6-({[4-(decyloxy)phenyl)indolyl)oxy)[2,3-b]pyroxy-3-ester (1.39 g, 3.35 mmol) was dissolved in anhydrous benzene (1 mL) under argon pressure and tetrabutylammonium bromide (2.16 g, 6/? mM) was added. The reaction was heated at 85 °C for 4 hours, 8 g of tetrabutylammonium bromide was added and the reaction was heated at 90 °C for 6 hours, 0.54 g of bromide was added and the reaction was heated for 3 hours. The reaction was cooled to rt. EtOAc was evaporated. The liquid layer 269 200817417 was separated and the aqueous layer was extracted with diethyl ether (2×300 mL). The combined organic layers were washed with EtOAc EtOAc m. 4 NMR (250 ΜΗζ) δ (CDC13) 3·83 (3H, s), 5·56 (2H, 5 s), 6.94 (2Η, m), 7·27 (1Η, at the solvent peak), 7.45 (2Η, m), 8.57 (1Η, d), 8.79 (1Η, s). (h) 3-(decyloxy)-6-( {[4-(decyloxy)phenyl]indolyl}oxy)rr is π and :|:2,3-b]pyridine 10 will 3 -Bromo-6-({[4-(methoxy)phenyl]indolyl}oxy)acridino[2,3-b]pyrazine (1.19 g, 3.44 mmol) suspended in sterol and Sodium methoxide solution (25% in methanol, 1.1 mL) was added at room temperature under argon. After 20 minutes, all solids were dissolved in the solution and the reaction was stirred at room temperature over 1520. The solvent was removed and the residue was partitioned between water (25 mL) and

Between MeOH/DCM (200 ml). (2x100 house liter) stroke. The combined organic layers were dried, subjected to column chromatography and eluted with DCM to afford (59%)

The aqueous layer was evaporated with 1 EtOAc / EtOAc / EtOAc (EtOAc) And [2,3 sec. +6 (5 ♦ 、, ear) solution in B (丨〇〇 )), then 270 200817417 added ammonium nitrate garnish (IV) dissolved in water (50 ml) (i· 〇 9 grams, 2 millimoles). The reaction was stirred at room temperature for Q. 5 h then added 20% MeOH / DCM and water. The layers were separated and the aqueous layer was extracted twice with 20% MeOH / DCM. The combined organic layers were dried with EtOAc EtOAcjjjjjjj

MS (ES+) m/z 178 (MHV (l) 3-(methoxy)-5-(2-propenyl) acridine [2,3_b]pyrazine_6(5H)-one 3 (Methoxy)-p-pyridyl[2,3_b]indanyl-6(5H)-one (0.3 g, 1.7 10 houser) was suspended in DMF (10 ml) at room temperature under argon pressure and then It was treated with potassium carbonate (0.47 g, 3.4 mmol) and allyl iodide (019 ml, 2.04 mmol). The reaction was completed after 1 hour at room temperature. Water (5 mL) was added sequentially. And 10% MeOH/DCM (100 mL). The layers were separated and the aqueous layer was extracted twice with EtOAc / EtOAc (EtOAc) Evaporation and chromatography of the crude product on silica gel eluting with 0-5% methanol-DCM to afford 176 mg of pure product and </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> MS (ES+) m/z 218 (MH+ 20 (m) [3_(decyloxy)-6-ketopyrido[2,3-b]pyrazine-5(6H)-yl]ethyl hydrazine methoxy)-5-(2 -propen-1-yl)pyrazine and [2,3-b]pyr 4-6(5Η)-one (176 mg, 〇·81 mmol) dissolved in 1,4-dioxene at room temperature Sodium peroxygenate (433) in alkane (1 ml) and water (5 ml) 271 200817417 mg, 3.09 mmol) and a 4% solution of iron oxide in water (〇17 mmol-L). After the reaction was stirred at room temperature for 3 hours, 1,4-dioxane was evaporated and the aqueous layer was extracted with 20% MeOH / DCM (3. The combined 5 coats were dried (Mg S 〇 4) and then benzene was added and the solvent was evaporated to give 1 <RTIgt; 197 (3H,SX 5,24 (2H,SX 6*83 (1H,dX 7 93 md)y (n) (2,3-dihydro[1,4]dioxan[2,3-c]吡2·[3-(decyloxy)-6-ketopyrano[2,3-b]pyrazine-5(6H)-yl] ethyl b [1,3-dihydropyridinyl]amino decanoic acid 1,1-dimethylethyl ester will be [3_(methoxy)-6--yl. The ratio is determined by [2,3-b]吼σ well-5 (6H)-yl]acetaldehyde (185 mg, 0.84 mmol) and (2,3-dihydro[1,4]dioxan[2,3-(^ is more than -7-ylmethyl) 4-Hexane 11 to 1,7-ylaminocarbamic acid 1,1-dimethyl 15 ethyl ester (synthesis see W02004/058144 Example 99(h)) (238 mg, 0.84 mmol) in chloroform (10 ml) The suspension in methanol (1.5 ml) was stirred at room temperature under argon atmosphere for 1 hour and then sodium triethyloxy borohydride (515 mg, 2.52 mmol) was added. The reaction was stirred at room temperature overnight. Add a saturated aqueous solution of sodium hydrogencarbonate (1 ml) and extract the aqueous layer with 1 〇 0 / 2 MeOH / DCM (3 x 50 mL). The combined organic layer was dried (MgSCU), filtered and evaporated Pipe column chromatography, eluted with 0-10% sterol-DCM To 252 mg of the title compound (60%) 〇MS (ES+) m/z 553 (MH+). 272 200817417 (Ο) title compound (2,L dihydro[1,4]dioxo[2,3- c] acridine-7-ylmethyl) (M2-indole (methoxy) ketopyridino[2,3-b]pyrazine 6H)-yl]ethyldihexahydropyridinyl) 1,1-Dimethylethyl citrate (250 mg, 〇·45 mmol) was dissolved in chloroform (5 mL) and treated with 4 Ν HCl (5 liters) in 1,4-dioxane. The reaction was completed after 1 hour. Toluene was added and the W+ solution was removed. The residue was dissolved in Me〇fj and treated with Amberlyst® A21 resin until the pH was basic. The resin was filtered to remove the methanol.

The residue was subjected to column chromatography on silica gel eluting with EtOAc EtOAc EtOAc (EtOAc) 2Η5^ΠΗ 140 m L88 (2H? dX 2*01 m bsX 2ΛΊ m nu ^ ^ 7I5 n*L〇SH,m 5 3*03 (2Hj 3·78 (23⁄4 4·07 (3H&gt; s), 4, 30 (4H&gt; 111)5 4*58

Ls^'m/z 45; (^)(1H,SX 7·83 (1H^d)&gt; 8·09 (1Hs SX 8·10 (1H5 S)· via dissolving in dichlorodecane/sterol Add 1 equivalent of 4M HC1/1,4-dioxane, then evaporate to dryness and convert the material to the hydrochloride salt. The residue is dissolved in a small amount of decyl alcohol and diethyl ether is added to precipitate, the solvent is decanted and solid Drying in a vacuum via a P2q5 dehumidifying agent. 20 Example 95 5-(2-{4-[(6,7-Dihydro[ι,4]dioxoS[2,3-c] taphthylmethyl) Amino]-1-hexahydropyranidyl}ethyl)-3-(decyloxy) hydrazino and [2,3_b]pyrazine-6(5Η)1 with fumarate 273 200817417

10 15 20 (8) (6,7-Dihydro[1,4]dioxo[2,3_c]indanyl-3-ylindenyl)(1_{2-[3-(methoxy)-6-keto) D(iv) and [2,3 ternary 5 (called yl)ethyl}-4-hexahydropyridyl) carbamic acid ethyl methacrylate "will be called methoxy"-6-keto aceto[2, 3_b]=Final (5 (called base) acetamidine (耄克, assuming 191 mg of aldehyde art and [2,3-physin-3 ylmethyl) 4 hexahydroindole. Deuterated aminomethyl ethane vinegar A suspension of (305 mg) in chloroform (1 ml) and methanol (15 liters) was added with triethyl decyloxy hydride (553 gram) at room temperature under argon. The reaction was allowed to stand at room temperature overnight. A saturated aqueous solution of sodium sulphate (20 liters) was added and the aqueous layer was extracted with 1% MeOH / DCM (3 EtOAc). The residue was chromatographed on silica gel eluting with EtOAc EtOAc EtOAc The title compound will be (6,7-dihydro[1,4]dioxyg[2,3_c]indole_3ylindenyl)(1-{2-[3-(decyloxy)-6-one Pyridyl[2,3_b]pyrazine_5(6H)_yl] 274 2008 17417

Ethyl}-4-hexapyridinyl)amino decanoic acid 1,1-dimethylethyl ester (358 mg, 0.65 mmol) was dissolved in DCM (5 mL) and then trifluoroacetic acid (5 m. ). After 1 hour all the solvent was removed and the residue was dissolved in MeOH - and treated with Amberlyst A21 resin to pH. The resin was filtered, 5 MeOH was removed and the residue was applied to EtOAc EtOAc EtOAc EtOAc EtOAc ). 1K (2H, m)? 3.99 (2H, s), 4.07 (3H, s), 4.37 (2H, m), 4.50-4.60 (4H, m), 6·75 (1H, d), 7.04 (13⁄4 s), 7·83 (1H , d), 8.11 (1H, s)· MS (ES-f) m/z 454 (MH+). This material was converted by dissolving in decyl alcohol and adding 1 equivalent of 0.5 M fumaric acid solution, then evaporating to dryness. Rich in horse salt. Example 96 1-(2-{4-[(2,3-Dihydro[1,4]dioxo[2,3-c]pyridine-indolyl)amino]-1-hexapyridine }ethyl)-7-fluoro-1,5-naphthyridine-2(1Η)-one 5-oxide hydrochloride

20 (a) 7-Fluoro-1,5-naphthyridin-2(1Η)-one 5-oxide 275 200817417 7-Fluoro-1,5-naphthalene bite-2(111)_嗣 (1.280 g, 7.798) Millol) and -m-p-peroxybenzoic acid (2.123 g, ca. 1.2-equivalent, based on a ratio of 111% to 75%) were stirred in refluxing chloroform (6 mL) overnight. mCPBA (0.420 g) was again added and the mixture was stirred under reflux for 6 hours. 5 The mixture was diluted with DCM to a total volume of about 1 mL and filtered by suction. The collected solid was washed with DCM (2×20 mL) and air dried to give 7-fluoro-1,5-naphthyridin-2(1H)-one 5-oxide as a brown solid (1.045 g, containing about 12%) Starting material). MS (ES+) m/z 281 (MH+) 〇ίο (b) 7-fluoro-1-(2-propen-1-yl)-l,5-naphthyridinone 5-oxide will be crude 7-fluoro-1 , 5-naphthalene-2(1H)-one 5-oxide (0.995 g, 5.524 mmol) and potassium carbonate in anhydrous DMF (20 ml) under argon pressure and added allyl iodide ( 1.5 ml, about 3 equivalents). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between DCM (100 ml) and water (100 ml). The organic layer was separated using a hydrophobic frit and the aqueous layer was extracted with DCM (2. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporatedEtOAc. It was subjected to column chromatography on silica gel and eluted with 0-10% decyl alcohol in 20 DCM. The appropriate fractions were combined and evaporated <RTI ID=0.0> Brown amorphous solid · MS (ES+) m/z 221 (ΜΗ+). 276 200817417 (C) (7-Fluoro-5-oxy-2-keto-1,5-naphthyridine qpH)-yl)acetaldehyde (methylhalf aldehyde).· '7-Fluoro-1 -(2-propenyl-1-yl)_丨55_naphthyridine-2(1H)__ 5•oxide (340 g, 1.544 mmol) stirred in hydrazine, 4_dioxane (16 ml) Water (8 ml) was added, followed by sodium periodate (990 mg, 2.3 equivalents) and iron oxide (1 ml of a 4% aqueous solution). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure (water bath temperature 3 (rc) to a volume of about 1 </ </ RTI> </ RTI> </ RTI> </ RTI> and the residue was extracted with 20 〇 / 〇 methanol (vol.: volume, 3 x 50 ml) in DCM. The extract was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give (7-fluoro-5-oxy-2-keto-1,5-naphthyridin-1 (2H)-yl) Brown foam (327 gram) of aldehyde (mostly methyl hemiacetal). LCMS showed the main peak of aldehyde hydrate (32%) and mercapto hemiacetal (64%). MS (ES+) m/z 241 (MH acid hydrate), m/z 255 (MH+methyl-half-15 acetal (d) {1_[2-(7-fluoro-5-oxy-2-keto-1,5-naphthyridinyl) Ethyl]-4-hexafluoridyl} 1,1 -didecylethyl carbazate (7-fluoro-5-oxy-2-keto-oxime, 5-naphthyridine_1 ( 2Η)_) acetaldehyde (mercapto 20 hemiacetal) (327 gram, I286 millimolar) and 4-hexafluoropyridylamino decanoic acid 1, L. dimethyl ethyl ester (283 mg, ι · ι equivalent) After stirring the mixture in chloroform· sterol (9:1 vol.·vol) for 2 hours, NaBii(〇Ac)3 (481 gram 2 mil) was added. The reaction was turbulent for 5 hours. After adding Saturated aqueous solution of NaHc(R) (5 mL). The mixture was diluted with DCM (8 mL) and the organic layer was partitioned with EtOAc </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The aqueous layer was washed with DCM (2 x 50 liters). The extract was dried, evaporated and purified eluted eluted elut elut elut elut elut elut elut elut elut MS (ES+) m/z 407 (MH+) 〇(e) l-[2-(4-Amino-1-hexahydropyridinyl)ethyl]naphthyridine-2(ih)_one 5-oxide Dihydrochloride salt will be {1_[2_(7_fluoro-5-oxy-2-keto-i,5-naphthyridin-i(2H)-yl)ethylhexahydrocarbazide}amino decanoic acid Dissolved in DCM (3 ml) and added 4MHC1 (0.830 ml, about 4 equivalents) in 14-dioxane. Add 10 ml 1) (:^ The solid was dispersed, followed by the addition of 830 mL of 4M HCU in hexanes, hexanes, and the mixture was stood at room temperature for 3 hrs. Mg) MS (ES+) m/z 307 (ΜΗ+). (f The title compound is 1-[2_(4-amino-1_hexahydropyridyl)ethyl&gt;7-fluoro 4,5-naphthyridin-2(1H)-one 5-oxide dihydrochloride ( 100 mg, 264·264 mmoles were stirred in chloroform (2 ml) and methanol (0·1 mL) and triethylamine (13 mL). After stirring at room temperature for 10 minutes, 3,4-dihydro-2-indole-pyrano[2,3-c]pyridine-6-aldehyde (synthesis see W02004058144, example 126(e)) (44 gram '1 equivalent) was added. After the mixture was stirred at room temperature for additional 3 hours, triethyl 278 200817417 sodium oxahydride borohydride (168 mg, 3 eq.) was added. After a further 3 hours, a saturated aqueous solution of sodium hydrogencarbonate (1 mL) was added and the organic layer was diluted with DCM to give a total volume of about 50 ml. The organic layer was separated using a hydrophobic frit and the aqueous layer was extracted with DCM (2. The combined DCM extracts were evaporated EtOAc m m m m m m m MS (ES+) m/z 456 (MH.sup.) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS is a free test. 10 Example 97 7-Fluoro-1_(2-{4-[([1,3]pyrazino[5,4-c]pyridin-6-ylindenyl)amino]-1-hexahydropyridinyl} Ethyl)-1,5-naphthyridine-2(1H)-one 5-oxide hydrochloride

1-[2-(4-Amino-1-hexafluoridyl)ethyl]naphthyridine-2(1H)-one 5-oxide dihydrochloride (91 mg) at 9:1 volume·· Volume atmosphere: Stir in methanol (3 ml) and add triethylamine (〇 117 mL). After stirring at room temperature for 5 minutes, add [1,3] thiazolo[5,4-c]pyridoxal (synthesis see W02004〇58144 'Example 61) (40 mg, 丨 equivalent) and mix the mixture at room 279 200817417 After stirring for another 3 hours, triethyl ethoxylated sodium hydride (152 mg, 3 eq.) was added. After an additional 1 hour, a saturated aqueous solution of sodium canonium carbonate (g) was added) and the organic layer was diluted to a total volume of about 20 ml. The organic layer was separated using aq. EtOAc (EtOAc).

MS (ES+) m/z 458 (MHV: EtOAc: EtOAc: EtOAc (EtOAc) From (7-fluoroketo-l(2H)-. quinacyl)acetic acid, [(3R)-3-indolyl) methyl phenyl carbamate (may be similar to W〇2〇〇) 6〇〇2〇47 Preparation 23(b) Preparation) and the specific aldehyde were produced by the general method of Example 72. Example Test Formal Structure Aldehyde 98 Free State Test HN S 3-keto-3,4-dihydrogen -2H-pyrido-MS (ES+) m/z [3,2-7][1,4]thin-6-aldehyde (for synthesis see 468 (MH+) CQ FXXJ° 'W02004058144, Example 7(d)) 280 200817417 99 free state test MS (ES+).m/z 486 _+) Va HN 〇ft NH b FW° 7-chloro-3-indolyl-3,4-dinitrogen 2Η-σ ratio σ determinate [3, 2-b][l,4] tigeol-6-aldehyde _ (synthesis see W02003064421, example 15 (c)) 100 free state test 2,3-diox[1,4]dioxo[2,3 - ten ratio MS (ES+) m/z pyridine-7- aldehyde (synthesis see 439 (MH+) \ NH W02004058144, example 2 (c) or Q FO〇r° W003/087098, example 19(d)) 101 free state Alkali Q 6,7- Yun [1,4] dioxyno and [2,3 -c] despair MS (ES +) m / z p farming 3-aldehyde 440 (MH +) NH b FO〇r °

281 200817417 Table 2: Example 102_112 was made from a specific starting material via the general method of Example 50. ... _ Example number test for the structure of the starting material 102 monofumarate MS (ES+) m/z 481 (MH+) rcC former XIX, [7-(methoxy)-2-benyl-1,5-naphthalene Pyridin-1(2H)-yl]acetaldehyde (mercapto hemiacetal) {[(3S,4R)-4-hydroxy-3-hydroxypyridyl]methyl}aminobenzoic acid phenyl decyl 3- Mercapto-3,4-·-^-2Η-σΛ and [3,2-b][l,4]哼耕-6-aldehyde (synthesis see W02003087098, example 31(e)) 103 free-form base MS ( ES+) m/z 497/499 (MH+) 〇^γ° a-VN HN^ H&amp; °XXr°^ [7-(methoxy)-2- sgyl-1,5-naphthyridine-1 (2H )-yl]acetaldehyde (mercapto hemiacetal) phenyl-3-azabicyclo[3.1.0]hex-6-ylcarbamic acid phenylmethyl ester (synthesis see preparation 1 below) 7-presentation- 3-S-iso-3,4-diaza-2H-pyrido[3,2-7][1,4]indole-6-aldehyde (synthesis see W02003064421, example 15(6))

282 200817417 104 Free-form base MS (ES+) m/z 463 (MH+) o^f° όίΝΗ JN w [7-(decyloxy)-2-keto-1,5-naphthyridin-1(2H)- Acetaldehyde (methyl hemiacetal) phenyl-3-azabicyclo[3.1.0]hexyl-6-ylcarbamic acid phenyl decyl ester (synthesis see preparation 1 below) 3 -mercapto-3, 4-Dinitro-2H-. Ratio σ and P,2-b][l,4]畤耕-6-aldehyde (for synthesis see W02003087098, Example 31(e)) 105 free-form base MS (ES+) m/z 450 (MH+) r?. Let HN^ Ηη\Η; ΓΗ曱oxy)-2-keto-1,5-naphthyridin-1(2H)-yl]acetaldehyde (methyl hemiacetal) hang-3-azabicyclo[ 3.1.0] hexyl-6-ylamino decanoic acid phenylmethyl hydrazine (synthesis see preparation 1 below) 2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7 - aldehyde (synthesis see W02004058144, example 2 (c) or W003/087098, example 19 (6)) 106 free state test MS (ES+) m/z 469 (MH+) (7-gas-2-mercapto-1,5-tea唆-1(2H)-yl)acetaldehyde (methyl hemiacetal) [(2R)-2-morpholine-methyl] 1,1-didecylethyl 3-ketoamine -3,4-Dihydro-2H-pyrido[3,2-b][l,4]Salt-6-aldehyde (synthesis see WO2003087098, Example 31 (seven))

283 200817417 107 Free state test MS (ES+) m/z 485 (MH+) rQ (7-murine-2-mercapto-1,5-steamed sigma-1 (2Η)-yl) acetaldehyde (methyl half-shrinkage) Aldehyde) phenyl-3-azabicyclo[3.1.0]hexyl-6-ylcarbamic acid phenylmethyl ester (synthesis see preparation 1 below) 3-mercapto-3,4-dichloro-2Η_σΛ^ and [ 3,2-b][l,4] tigeol-6-aldehyde (synthesis see W02004058144, example 7(d)) 108 mono-HC1 MS (ES+) m/z 503/505 (MH+) (7-gas- 2_mercapto-1,5-evaporated-1(2H)-yl)acetaldehyde (methylheptaic acid) 3-azabicyclo[3.1.0]hex-6-ylaminocarbamate甲基酉 (Synthesis see Preparation 1 below) 7-Chloro-3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-aldehyde ( For the synthesis see WO2003064421, Example 15(c)) 109 mono-HC1 MS (ES+) m/z 466 (MH+) HO^XX) [7-(decyloxy)-2-keto-1,5-naphthyridine- 1(2H)-yl]acetaldehyde (mercapto hemiacetal) [(3R,4S)-3-hydroxy-4-hexahydropyridyl]carbamic acid 1,1-dimethylethyl ester (synthesis see W02004058144 , Example 5(c) 'Ch-(3-predyl-4-hexaazinopyridine) carbamic acid tert-butyl ester to palm isomer 1)

Vm- 284 200817417 - - 3,4-Dihydro-2H-pyrano[2,3-decapine-6-acid (synthesis see W02004058144, example 126(e)) 110 mono-HC1 MS (ES+) m /z 481 (MH+) h〇^〇c:t° 0XD〇r0^ ΓΜmethoxy)-2-keto-1,5-naphthyridin-1(2H)-yl]acetaldehyde (methyl half-condensation Aldehyde) [(3R,4S)-3-hydroxy-4-hexahydropyridinyl]amino phthalic acid U-dimethylethyl ester (synthesis see W02004058144, Example 5(c), cis-(3-hydroxy-4) - hexahydropyridyl) carbamic acid tert-butyl ester to palm isomer 1) 3-mercapto-3,4-^-^ -2H- utb and [3,2-b][l,4]噚Plough-6-aldehyde (synthesis see W02003087098, example 31(e)) 111 single_HC1 MS (ES+) m/z 454 (MH+) °wf (7-gas-2-mercapto-1,5-tea bite- 1(2H)-yl)acetaldehyde (methyl hemiacetal) [(3R,4S)-3-hydroxy-4-hexahydropyridinyl]amino decanoic acid 1,1-dimethylethyl ester W02004058144, Example 5(c), cis-(3-hydroxy-4-hexahydropyridyl)amino decanoic acid tert-butyl ester to palm isomer 1) 3,4-dihydro-2H-pyrano[ 2,3 -c] ton of 唆-6-acid (synthesis see W02004058144, example 126(e)) 285 200817417 112 single-HC1 MS (ES+) m/z 469 (MH+)

(7-fluoro-2-keto-1,5-naphthoquinone-1(2H)-yl)acetaldehyde (methyl sulfhydryl) '[(3R,4S)-3-hydroxyindole hexahydropyridinyl] U. dimethyl urethane (synthesis see W02004058144, Example 5 (c), cis-(3-trans--4- hexahydropyridyl) carbamic acid tert-butyl ester to palm isomer 1) 3 - Sun-based-3,4-dinitro-2H-indole. And [3,2-b][l,4]. Well-6_ aldehyde (synthesis see W02003087098, example 31(e)) Preparation 1 Hang-3-azabicyclo[3.1.0]hex-6-yl Synthesis of Phenylmethylcarbamate Benzyl-3-azabicyclo[3.1.0]hex-6-ylaminophosphonic acid phenylmethyl ester is known from 5 hanging-6-[bis (phenyl Amidino)-3-azabicyclo[3·1·0]hex-3-desoleic 1,1-dimethylethyl ester (for synthesis see De Meijere·A·; Williams, C. M. Kourdioukov, Α,; Sviridov, S, V·; Chaplinski, V·; Kordes, M,; Savchenko, Α, Ι·; Stratmann, C,; Noltemeyer, Μ· Chemistry-A European Journal (2002), 8( 16), 3789_3801) is synthesized by ίο from the following three steps. (1) Hydrogenation with Pd2(OH)2 catalyst to obtain 1,1-didecylethyl -6-amino-3-azabicyclo[3·1·0]hex-3-carboxylate, (2) Protection of -6-amino-3-azabicyclo[3.1·0]hex-3-carboxy 286 with benzyl chloroformate 200817417 Acid i,i-didecylethyl ester monoamine Hanging _6_({[(phenylfluorenyl))yl)amino)_3_nitro-heterobicyclo[·3·1·〇]hexa-3carboxylic acid dimethylethyl ester, and subsequently (3 Removal of the protective -6_({[(phenylfluorenyl)oxy)carbonylamino)-3-azabicyclo[3·1·〇]hex-3-carboxylic acid 1,1_ by HC1/DCM Di-decylethyl ester gave the title compound. Table 3 - Example 113-118 is from [6-(decyloxy)-3-yl-pyrido[2,3-b]pyrylene-4(3Η)-yl Acetaldehyde (synthesis see Example 126 (e) below) and the specific starting materials were made via the general procedure of Example 50. Example No. of Test Form Structure Starting Material 113 Di-HC1 MS (ES+) m/z 516/ 518 (MH+), xX:r. 's--- {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}aminobenzoic acid phenylmethyl ester 7-chloro-3-one -3,4-Dihydro-2H-pyrido[3,2-b][l,4]indole aldehyde (synthesis see W02003064421, Example 15(c)) 114 II-HC1 {[(3R,4S)-4-hydroxy-3-pyrrolidinyl] MS HO y-N \〇methyl}amino phenyl hydrazide 1 (ES+) N /〇3-keto-3,4 - dihydro-2H-acridine m/z 482 P,2-b][l,4] Jinteng-6-aldehyde (synthesis see (MH+) W02003087098, example 31(e))

287 200817417 115 Di-HC1 MS (ES+) m/z 498 (MH+) {[(3R,4S)-4_Hydroxy-3-pyrrolidinyl]methyl}aminobenzoic acid phenylmethyl ester 3-keto- 3,4-Dihydro-2H-pyrido[3,2-b][l,4]thiatinoaldehyde (Synthesis see W02004058144, Example 7(6)) 116 II-HC1 MS (ES+) m/z 469 (MH+) ^°XXX {[(3 R,4S)-4_Hydroxypyrrolidinyl]methyl}aminocarbamic acid phenylmethyl ester 2,3-dihydro[1,4]dioxo[2,3- c] Pyridin-7-aldehyde (synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19(d)) 117 Di-HC1 MS (ES+) m/z 480 (MH+) cr«Xc:r xc: (r [(3R)-3-Hexahydropyridylmethyl]amino) phenylmethyl ester 3- _ yl-3,4_ dihydro-2 Η-σΛ σ定和[3,2-b][l, 4] 畤耕-6-aldehyde (synthesis see W02003087098, example 31(e)) 118 II-HC1 MS (ES+) m/z 514/516 _+) crw° ,xc:(r [(3R)-3· Benzyl hexahydropyridylmethyl]amino decanoate 7-chloro-3-keto-3,4-dihydro-21^ ratio °[3,2-7][1,4]畤4 -6 雀(Synthesis see W02003064421, Example 15(6)) I--^ 288 200817417 Example 116A 4-[2_((3S,4S)-3_{[(2,3_二氲[1,4] Dioxindane[ 2,3-c] 口比唆-7-基甲) Amino] methyl old Ji Bu 4-yl small scales bite-yl) ethyl] · 6_ (methyloxy) "and instigate than [2,3_b] _3 roar coffee _) _ -one dihydrochloride

10 (4) [((3S,4S)_4-hydroxy small (2-[cardo(methoxy)-3-ketoacridine)

Ob] mouth ratio 4_4(3H)-yl]ethyl b 3 吼嘻 定 定 ) 甲基 甲基 甲基 甲基 甲基 甲基 将 将 将 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 _4 (called base) acetaldehyde (0.348 g including partial hemiacetal) (Synthesis see Example 126 (Printed and 15 {[(3R, 4S)) hydroxypyrrolidinyl]methyl}amino decanoic acid phenyl A solution of the ester (〇·395 g) (prepared as in Example 61 (a)) in decyl alcohol (2 mL) and EtOAc (6 mL) was stirred overnight at room temperature. · 671 g) and the mixture was stirred at room temperature for a few hours. The mixture was extracted with dcm (3x), dried (sodium sulfate), evaporated, and chromatographed on silica gel, using 1 〇% 20 sterol-chloroform-1 The product was obtained after elution with EtOAc (m.). 200817417 (b) 4.{2-[(38548).3.( ^ ^ Ψ ^ ^ &amp; ^ ^ ^ 3 ^ • 基} Winter (曱乳基唆唆[2,3中比畔部H) ,

[((3S,4S)|经基+{2|(methoxy oxime and base bite [='3 巧比井4(3H&gt; base: ethylbu 3_pyrrolidinyl)methyl] A solution of benzoic acid benzene 5 1曱® (1·0, 2·2 halo) in methanol was treated with 1% pd/C (〇·44 g) and shaken at 15 psi and room temperature for 2 hours. It will be filtered through Ceth^eO, filtered, and liquid swelled. The residue is dissolved again in dCm liter) and decyl alcohol (5 ml), using oxidized violent (IV) (561 mg, 6.6 lm) 'Processing' and stirring at room temperature for 2 hours. The solid was filtered and concentrated to give a product (0.6 g, 85%). LCMS: m/z 320 (ΜΗ+) 〇(c) {2-[(38,48)-3-(Aminomethyl)-4_hydroxy-1-.pyrrolidinyl]ethyl 15 yl 6-(methoxy)pyrido[2,3-b Pyridin-3 (4H)-ketone (70 mg, 0.22 mmol) and 2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde (see Synthesis) W02004058144, Example 2(c) or W003/087098, Example 19(d)) (36 mg, 0.22 mmol) in MeOH (1 mL) and DCM (5 mL) Sodium triethoxy borohydride (0·093 2〇 The mixture was stirred at room temperature for 1 hour. The solvent was evaporated and chromatographed on silica gel eluting with 0-20% methanol-DCM-2% ΝΗ40 。 to give an oil. 1H NMR (400 MHz, METHANOL-^) δ ppm 2.30 - 2.41 (m, 1 H) 2.55 (t, 7=8.97 Hz, 1 H) 2.60 - 2.68 (m, 2 H) 2.83 - 2.93 (m, 2 H) 2.95 - 3.02 (m, 2 H) 3.19 (dd, /=10.61, 5.56 290 1 200817417 3;7U 3·8〇(m,2 H) 4·08 (S,3 H) 4·29 4·40 (m,5 H) 4·57 -4·65 (m,2 Η) 6·81 -6·86 (m,1 Η) 6·95 (s,1 Η) 8·00 (s51 Η) 8.06 - 8·1〇 (m, 2 Η) LCMS: ι η / 469 469 ( ΜΗ + ). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -[2-((3S,4S)-3-{[(2,3-Dioxa[1,4]dioxo[2,3-c]pyridin-7-ylindenyl))] }}_4_hydroxypyrrolidinyl)ethyl]_6-(decyloxy)-acridino[2,3_b]pyridin-3(4H)-one benzoate stearate is via free state It was prepared by dissolving in Me〇H and adding jade 10 as a stupid formic acid. The solvent is evaporated and the benzoate is recovered. Table 4: Examples 119-120 are from 5,7-difluoro-2-keto-1(2H)-mercaptoacetaldehyde (from (2-amino-3,5-difluorophenyl)amine Prepared via the general methods of Examples 34(a)-(c)) and the specific starting materials. The formal structure of the example numbering was prepared via the general method 15 of Example 43 (dHe);----n starting material 119 Mono-fumarate MS (ES+) m/z 458 (MH+). Evaluation of F (2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylmethyl)4_hexahydro. ratio. Alkylamine decanoic acid 1 L- , ▲ , ... 丨 曱 乙酯 ethyl ester (synthesis see W02004/058144 Example 99 (10) 291 200817417 120 mono-fumarate 〇ς 〇 〇 fly (6,7-dihydro[1,4 Dioxindane MS (ES+) Ί Oc]17 σ 曱 曱 base) 4-hex m/z 459 氢 Hydropyridylaminocarbamic acid 1,1·di(MH+) Methyl acetamidine Example 121 4- (2-{4_[(2,3-Dioxa[1,4]dioxo[2,3_c]pyridin-7-ylmethyl)amino]-1_hexahydroindenyl}ethyl)_6_ (methoxy)β1,2,4-benzotrim-3(411)-ketohydrochloride 5

10 (a) 6-(decyloxy)-4_(2-propenyl-1-yl)-ι, 2,4-benzotrim well _3(4Η)-one in 6·chloro-4-(2• Propylene-1-yl)-1,2,4_benzotrim _3(4Η)-ketone 1-oxide (preparation see Example 60(c)) (420 g, L77 mmol) at Me〇 A solution of H (10 ml) was added to a sodium decoxide solution (25% w/v, 8. 84 15 mmol, I·9 ml) and then the reaction was stirred at room temperature for 2 hours. Treated with water (100 mL) and extracted with DCM (2×100 mL). The combined organic layers were dried with EtOAc EtOAc m. Foam (205 mg, 53%). 20 MS (ES+) m/z 218 (MH+).

292 200817417 (b) [6-(Methoxy) each_yl-l,2,4·Benzene tri-farming_4(sister)_yl]acetaldehyde-based semi-shrinking disc) 6-(decyloxy) 4-(2-propen-1-ylbenzotris- 3 (4 Η) ketone (Ρ mg, 〇·346 mmol) dissolved in Μ_dioxane (5 ml) and water 5 (2 ml) Sodium periodate (185 mg, 0.865 mmol) was added followed by osmium tetroxide (0.1 ml of a 4% aqueous solution). The mixture was stirred at room temperature for 4 hours and 1,4-dioxane was added in vacuo. Evaporation, the residual aqueous layer was extracted with EtOAc EtOAc EtOAc (EtOAc) _ ketobenzotrim-4 (3H)-yl] acetaldehyde (mostly thiol half-condensed) impure yellow oil (89 mg, Η?%) MS (ES+) m/z 220 (MH+), 252 (methyl hemiacetal H+) (c) (1_{2-[6-(decyloxy)-3-keto-l,2,4-benzotriene_4 (311 )_基]B 15 kib 'hexahydro σ ratio octyl) amide, ι, ι dimethyl ethyl ester [6-(decyloxy)-3-keto-1,2,4-benzene And three tillage _4 (311) _ base] acetaldehyde (mercapto hemiacetal) (89 m , 0.346 mmol, and 1,1-dimethylethyl 4-hexahydropyridylcarbamate (69 mg, 0.346 mmol) in chloro & (5 mL) and MeOH (0.5 mL) After the mixture was stirred for 2 hours, 20 NaBH(OAc)3 (220 克 '1 · 〇 38 mAh) was added. After the reaction was allowed to stand for an hour, a saturated aqueous solution of NaHC 3 (20 mL) was added, and then the mixture was applied to DCM. Extraction of 20% MeOH (3×100 mL). The combined organic layer was dried, evaporated and evaporated eluting 48 293 200817417 mg, 34%). MS (ES+) m/z 404. (MH+) (d) 4_[2-(4-Aminopyrohydropyridinyl)ethyl]_6-(methoxybenzene 5 and three tillage-3(4Η)-keto dihydrochloride in (1-{2_[6-(methoxy)-3-nano-1,2,4·benzotrid-4 (3Η) -ethyl]ethyl}-4-hexahydropyridyl) carbamic acid hydrazide-didecyl ethyl ester (48 mg '0.119 mmol) in chloroform (2 ml) was added at 1,4_2 4MHC1 (2 ml) in sm.. The reaction was stirred at room temperature for 1 hour, evaporated and purified with 10 ethyl acetate. The desired compound of a yellow oil which was used without further purification (42 mg, 94%). MS (ES+) m/z 304 (ΜΗ+). (e) the title compound 15 4-[&gt;(4-amino-1-hexahydropyridinyl)ethyl]-6-(methoxy)-1,2,4-benzotrid-3 ( A mixture of 4H)-keto-dihydrochloride (42 mg, 0.112 mmol) in chloroform (2 mL) and MeOH (0.1 mL) After stirring for 0.25 hours, 2,3-dihydro[indenyl]dioxo[2,3-c]pyridine-7-aldehyde was added (for synthesis see 20 W02004058144, Example 2 (C) or W003/087098, Example 19 (d )) (18 mg, 0.112 mmol). The reaction was stirred for 5 hours and then NaBH(OAc)3 (71 mg, 0.336 mmol). After the reaction was stirred for 1 hour, a saturated aqueous solution of NaHC EtOAc (1 mL) was then evaporated. The combined organic layers 294 200817417 were dried, evaporated, EtOAcjjjjjjjjjjjj . MS (ES+) m/z 453 (^^. !H NMR (400MHz) 5 (CDC13) 1.55-1.63 (2H, m), 1.99-2.02 (2H, m), 2.27-2.32 (2H, m), 2.67 -2.72 (3H,m), 3.02-3.11 (2H,m),3.87 (2H,m),4.02 (3H,s)5 4·27-4·36 (6H,m),6·86 (2H, Br s),7·00 (1H,dd,J 9,2Hz),8·09 (1H,s),8·29 (1H,d J 9Hz)· Dissolve the obtained free base in 1:1 DCM: MeOH and 1 eq. of 4 MH.sub.1 in 1,4-dioxane was added to convert the free base of the title compound to the HCl salt and then evaporated to dryness. Example 122 1-(2_{4-[(2) ,3-dihydrofuro[2,3-c]pyridinej-ylmethyl)aminol·1-hexahydropyridyl}ethyl)-7-(methoxy)-2( 1H)-porphyrin Ketone dihydrochloride

1-[2-(4-Amino-1-hexahydro-pyridylpyryl)ethyl]_7-(decyloxy)-2(1Η)-pyridone (preparation see Example 47(4)) (50 mg , 0·17 millimolar) and 2,3-dihydropyrano[2,3-c]4b bite-5-patch (preparation see Example 38(f)) (27 gram, 〇·ΐ 8 mM The solution in sterol (2 ml) and chloroform (2 ml) was heated with 3A molecular sieves under reflux overnight. The mixture was allowed to cool and diethyldimethoxy-copper hydride (018 g, 〇·85 mmol) was added, and 295 200817417 mixture was stirred at room temperature overnight. More aldehyde (3 mg) and ethoxylated ruthenium (Q·180 g) were added, and the mixture was stirred at room temperature overnight. Again 5 ίο 15 add acid (5.4 mg) and ethoxylated borohydride (36 mg and 6 mg). The mixture was stirred again overnight, then neutralized by the addition of aqueous sodium carbonate solution and the layers were separated. The aqueous layer was extracted 4 times with 1 〇 0 / 〇 methanol-dichloromethane, and the organic layer was dried and evaporated. Chromatography on silica gel eluting with 〇 2 〇% methanol-dichloromethane to give the title compound as a free base (56 mg, 76%): f) H2^aHm) 〇250 (2H&gt;1 *96 (2H, br*d, part* obscuredby water), 2.20(2H 3H s) (2H&gt;br· 3·22 (23⁄4 ^ 3·86^ ^ 3.93 (2Ha 8.0; 8.12 (1H s) ^ 〇H? ^ ^92 (1H? ^ ^2° ^ 7*78 MS (+ve iontophoresis) m/z 436 (MH+). The free base in methylene chloride is used in hydrazine, 4_dioxane. After treatment with 0.4MHC1 (0·70 ml), the dihydrochloride salt was obtained (43 mg, pyridine, 123 2-[((Η2-σ二-2-keto-1)) Bite base} silk) methyl ΗΗ "Bite bite and [5,4_b] [1, morphine ketone hydrochloride ~

20 &quot; in 4-gas-2-[({1_[2_(7_fluoro_2-keto)(2H)•喳vyl)ethylhexahydroacridinyl}amino)methyl]_1Η_σ唆 唆 [[,], 4] ketone (preparation see example 124 (j)) (67 mg, 〇 13 mmol) in a solution of methanol (, 296 200817417 liters) was added NaHC03 (40 mg), then added 10% Pd/C catalyst (30 mg). The resulting mixture was stirred at room temperature and hydrogen gas (balloon) at atmospheric pressure for 24 hours. The reaction mixture was filtered through a pad of EtOAc (EtOAc) (EtOAc) elute MS (ES+) m/z 453 (MH+). lH NMR (400MHz, CDC13) δ 1.58 (2H, m\ 1.88-2.09 (2H, m), 2.28 (2H, m), 2·60-2·72 ( 3H,m),3·17 (2H,m),3·92(2Η,s),4·41(2Η,t),4·72 (2H,' s),6.63 (1H,d,J 10Hz ), 6.97 (1H, m), 7·2 (1H, dd, J 10.5, 2Hz), 7.50 (1H, dd, J 10.5Hz 2Hz), 7.68 (1H, d, J 10Hz), 7.9 (1H, s ' i〇 The free base of the title compound was converted to the HCl salt by dissolving the free base in 1:1 DCM:MeOH and adding 1 equivalent of 4MHC1 in 1,4-dioxane. Example 124 4-Chloro-2-[({l-[2-(7-fluoro-2-keto-1(2H)-carboyl))]yl]]]hexahydro]. Amino)methyl], u-[5,4-b][l,4]畤耕-7(6Η)-one hydrochloride

(a) Didecyl {[2-(ethoxy)-2-ketoethyl]oxy}malonate in diammonium diazomalonate (4 g, 25 mmol) (according to Peace) ,

Carman, Wulfman, Synthesis, 658-661, (1971) Preparation) To a solution of j) CM 297 200817417 (10 ml) was added ethyl glycolate (1.2 ml, 12.8 mmol), followed by cesium acetate (II) Dimer (2 g, 20% Mo). The reaction mixture was stirred at room temperature for 24 hours. The resulting suspension was filtered through a pad of Celite® and the solvent was removed in vacuo. The crude residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS (ES+) m/z 235 (MH+). (b) ({4-Hydroxy-6-keto-2-[(E)-2-phenylethindene/.dihydro-5" sessile 10 yl) oxy)acetic acid in {[2-( Ethyl ethoxy)-2-ketoethyl]oxy}malonic acid diterpene (3 g, 12.8 mmol) in MeOH (10 mL) at room temperature (2E)-3-benzene Base-2-acrylic acid imide (1·87 g '12·8 mmol) (preparation see Example 3 (g)), followed by NaOMe (8.3 g, 38·4 mmol, in methanol 25% solution in 15). The resulting mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the obtained solid was used in the next step without purification. MS (ES+) m/z 288 (ΜΗ+) 〇20 (c) ({4,6-Dichloro-2-[(E)_2-phenylvinyl]-5-pyrimidyl}oxy)acetate oxime 曰夂 in crude ({4-hydroxy-6) -keto-2-[(Ε)_2_phenylvinylhydrazine, 6_di-pyrimidinyl}oxy}acetic acid (~I2·8 mmol) with p〇cl] liter, 76.9 mmol Then, n,N-dimethylaniline (1·7亳l 298 200817417 12·8 mmol) was added. The resulting mixture was placed in a sealed test tube at 12 ° C. Heating for 3 hours. Cool to Q°c and use cold methanol The solvent was removed in vacuo and the crude residue was purified eluting elut elut elut elut elut elut elut elut ES+) m/z 340 (MH+). (d) 2-({4-Amino-6·chloro-2-[(E)-2-phenylethenyl]]] Amine ίο in ({4,6-dichloro-2-[(E)-2-benzylethenyl]-5-fluorenyl)oxy) decyl acetate (1·1 g, 3.24 mmol) To a solution of 1,4-dioxane (1 mL) was added EtOAc (2 mL, 20 eq.). The mixture was then warmed at 65 ° C for 4 hr. The solvent was evaporated and the residue was purified eluting with EtOAc EtOAc EtOAc EtOAc. (Mulcan) was purified using a gradient of 0-10% MeOH in EtOAc (EtOAc: EtOAc: EtOAc: 4-chloro-2-[(E)-2-phenylvinyl]-6H-pyrimido[5,4-b] [1,4] slogan -7 (8H)- 20 ketone. (e) ({4-Amino-6-murine-2-[(E)-2-benylethyl]-5-σ-mercapto}oxy)ethyl acetate The ruthenium chloride gas bubble is passed into 2-({4_amino-6-chloro-2-[(indol)-2-benzene 299 200817417-vinyl]-5-pyrimidinyloxy)acetamide ( A solution of 0.6 g, 1.97 mmoles in ethanol (20-ml). The resulting mixture was heated at i ° ° C for 3 hours. Evaporation of the mixture under reduced pressure gave the desired product (0.55 g, 84) which was used in the next step. 5 MS (ES+) m/z 334 (MH+). (1) 4_Gas-2-[(E)_2-phenylvinyl]_6H-pyrimido[5,4-b] [1,4] slogan -7(8H)-one in ({4-amino Chloro-2_[(Ε)·2-phenylvinyl]vyryl}}oxy- 1 yl)ethyl acetate (〇·55 g, 1.65 mmol) was added to a solution of dmf (5 mL) K: 2C 〇 3 (〇·46 g '3.3 mmol) and the resulting full compound was heated at 75 ° C for 1 hour. The solvent was evaporated under reduced pressure and the~~~~~~~ The organic extracts were combined, dried over anhydrous MgS 〇 4 filtered and concentrated to give a solid. The solid of the desired product was obtained (0.47 g, 99%). MS (ES+) m/z 288 (MH+). (g) 4_Chloro-7-keto-6,7-diindole-1H-pyrimidine and [5,4_b] 2〇 in 4-present -2-[(E)-2-benzidine基]_6h_ 口密定定[5,4-b] [1,4]噚耕-7(8H)-ketone (〇·45 g, 1.16 亳mol) in μ-di-4-alkane (25 NaI〇4 (1.26 g, 4.4 mmol) and catalyst amount of Os〇4 (〇.36 ml, 4% by weight in water) were added to a solution of ML) and water (10 ml). The resulting mixture was stirred at room temperature for 5 hours. Evaporating solvent will be disabled under reduced pressure

300 200817417 Residues were extracted with 10% sterol (3 x 50 mL) in DCM. The organic extracts were combined, dried over anhydrous EtOAc (EtOAc EtOAc) Yellow solid (0·28 5 g, 84%). MS (ES+) m/z 214 (ΜΗ+)〇NMR (400MHz, CDC13) δ 5·03 (2H,s),8·9(1Η,bs),9.9 (1H,s)· { (h) { L-[1 2 3-(7-Fluoro-2-keto-1(2H)_4 phenyl)ethyl] hexahydropyridinyl} i-ylamino decanoic acid 1,1-dimethylethyl ester (7-Fluoro-2-keto-1(211)-417)-ethylidene (〇·50 g, 2.41 mmol) (synthesis see Example 88(a)) and 4-hexahydropyridyl Ammonium carbamate, dimethyl dimethyl ester (0.48 g, 2.41 mmol) was combined in 1:1 MeOH / DCM (20 mL). Excess NaJO4 was added as a desiccant and the solution was stirred at ambient 15 for 16 hours. NaBH(OAc)3 (1.53 g, 7.23 mmol) was added and the mixture was stirred for additional 2 hr. The solution was concentrated on a silica gel in vacuo and the crude residue was purified eluting with EtOAc EtOAc (EtOAc) Yellow solid (0.678 g, 72%). 20 LCMS: m/z 390·4 (MH+). 301 1 1-[2-(4-Amino-l-hexahydro. butyl) ethyl]_7-fluoro-2(1Η)-σ奎ϋ林酉同盐2 Acidate 3 in {1-[ 2-(7_Fluoroketo-1(2Η)" quinuclidyl)ethyl&gt;4_hexahydropyridine 200817417 base}amino decanoic acid 1,1-didecyl vinegar (0.67 g, 174 mmol) To the solution of DCM (10 mL) was added 4M HCl (218 mL, 8.716 Mo) in Μ-二姐 and the solution was stirred at ambient temperature for 16 hours. The solution was concentrated under reduced pressure to give the desired product as a white solid ( s 55 g, 98%). LCMS: m/z 290.0 (MH+) s (j) (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj A solution of ketohydrochloride (0.40 g, 〇·12 mmol) in DCM (5 mL) and methanol (2 mL) was added to 4-chloro-7-keto-6,7-dihydro-1H -pyrimido[5,4-b] [1,4]Sorry _2_acid (0.026 g, 0.12 mmol) followed by NaHC〇3 (0.1 g, 1.2 mmol) and anhydrous Na2SO4 as dry Agent. After the resulting mixture was stirred at room temperature for 24 hours, NaBH(OAc)3 (80 mg, 15 〇·36 mmol) was added. The reaction was stirred for 1 hour. The reaction mixture was concentrated and the~~~~~~~ The combined organic extracts were dried (M.sub.4), evaporated and purified eluted elut elut elut elut elut elut elut elut 24 mg, 40%). 2〇MS (ES+) m/z 487 (MHVH NMR (400MHz, CDC13) δ 1·58 (2H, m), 1·88-2·09 (2H, ιη), 2·28 (2H, m), 2·60·2·72 (3H,m), 3.17 (2H,m),3·92(2Η,s),4·41(2Η,t),4·72 (2H, s), 6.63 (1H , d, J 10Hz), 6.97 (1Η, m), 7.2 (1H, dd, J 10.5, 2Hz), 7.50 (1H, dd, J 10·5Ηζ, 2Hz), 7.68 (1H5 d, J10Hz). The free base of the title compound was converted to the HCl salt by dissolving the free base in 1:1 DCM:MeOH and adding 1 eq. of </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Example 125 2-{[(1-{2_[6-(methoxy)_3-ketopyrido[2,3-b]indole-4(3Η)-yl]ethylhydrazine-hexahydropyridine Amino]methyl}-5,6-dihydropyrido[2,3-d]pyrimidin-7(1Η)-_

(a) 2-[Bis(decyloxy)methyl]-4- gas-5,8-dihydropyrido[2,3_(1] venting -7(6Η)-one in 4-chloro-7 -keto-5,6,7,8-tetrahydropyrido[2,3_d]pyrimidine_2_p (preparation see example 126(k)) (1.43 g, 6.78 mmol) on Me〇 p-TsOH.H2〇 (〇·13 g, 〇·68 mmol) was added to the solution of H. The solution was heated under reflux for 2.5 hours and then cooled to ambient temperature. The desired product, which was used without further purification. LCMS: m/z 257.9 (ΜΗ+). 2 〇(b) 2-[bis(methoxy)methyl]_5,8-dihydropyrido[2, 3-d]pyrimidin-7(6H)-one in crude 2-[bis(methoxy)indenyl]_4_chloro-5,8-dipyridino[2,3_d]pyrimidine_7(6H)_ The ketone (assumed to be 6.78 mmol) was dissolved in Me〇H and 10% Pd/C (0.15 g) was added thereto. The solution was stirred under h2 pressure (balloon) 303 200817417 overnight. Pd/C was filtered and The solution was concentrated in vacuo <RTI ID=0.0>(</RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; , 72%). 5 LCMS: m/z 223.9 (MH +) ° (c) 7-keto-5,6,7,8-tetrahydropyrido[2,3-(1]pyrimidin-2-al in 2-[bis(decyloxy)indenyl]- 5,8-Dihydropyrido[2,3-d]pyrimidin-7(6H)-one (0.873 g, 3.91 mmol) was added to a solution of 1:1 H20/acetone (1 mL) 10 -TsOH-H2 〇 (0.074 g, 0.391 mmol) and the reaction was heated at 80 ° C for 3 days and then p-Ts0H.H20 (0.20 g) was added. After the starting material disappeared, the solution was concentrated in vacuo. The desired product (1.023 g). EtOAc: m/z (m/m) Acridine[2,3_b]吼耕_3(4H)-ketohydrochloride (preparation see example U6(m)) (〇.6〇〇20 g, 1.98 mmol) in 1:1 Add 7-keto-5,6,7,8-tetrahydropyrido[2,3_d]pyrimidine-2-allate to Me溶液H/DCM solution (〇35〇g, 198 mmol=^1°° 3 (〇·831g, 9.90 halo) and an excess of ΝΜ〇4. =1 Stir at room temperature overnight. Then add NaBH(0Ac)3 in the straight line. The resulting solution was further mixed for 1 hour, then the - shoulder was on the ground and the crude residue was passed through column chromatography (Shi Xi

</ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The title compound was obtained as a free base (0.396 g, 43%). 5 LCMS: m/z 465.2 (MH+). 1H NMR (400 MHz, CDC13) δ 1.42 - 1.53 (m, 2 Η) 1.90 (d, /=10.86 Hz, 2 Η) 2.18 (t, 7=10.61 Hz, 2 H) 2.52 - 2.60 (m 1 H) 2 66 -2.77 (m, 5 H) 2.93 (t, /=7.71 Hz? 2 H) 3.07 (d, /=11.62 Hz, 2 H) 3.98 (s, 2 H) 4.00 - 4.03 (m5 3 H) 4.52 - 4.62 (m, 2 H) 6.70 (d, J=SM Hz5 1 H) 7.99 (d, J=8.59 Hz 1 H) 8 12 fs 1 H) 8.34 (s3 1 H). The free base of the title compound was converted to the HCl salt by the addition of 1 equivalent of 1M HCl in diethyl ether. 10 Example 126 4-Chloro-2-{[(Κ{2-[6-(methoxy)-3-ketopyrido[2,3-b]pyrylene-4(3H)-yl]ethyl }-4-Hexidopyridinyl)amino]indolyl 5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one hydrochloride

(a) N-[2,2-bis(decyloxy)ethyl]-6-(decyloxy)-3-nitro-2-indole. Amine 20 will be 2-chloro-6-(decyloxy)-3-nitropyridine (10 g, 53 mmol), aminoacetaldehyde dimethyl acetal (5.6 g, 6.2 mL, 53 Mixture of millimolar and potassium carbonate (7.4 g, 53 mmol) in acetonitrile (1 mL) and DMF (1 mL) was heated at 40 °C for 30 min. The mixture was filtered and extracted with DCM and brine. The organic extract was added to a ruthenium tube column and then eluted with 0-100% ethyl acetate in hexane 2020 200817417 to give a yellow solid (12.4 g, -90%) 〇\MS (+ve ion e-spray) Fog) m/z: 258 (MH+). 5 (b) N2-[2,2-bis(methoxy)ethyl]-6-(methoxy)-2,3-pyridinediamine will be N-[2,2-bis(decyloxy) A solution of ethyl]-6-(decyloxy)-3-nitro-2-pyridinamine (2.5 g, 10 mmol) in furfuryl alcohol was hydrogenated at 10 psi via 10% Pd/C (0.9 g) 0.5 hours. The mixture was filtered, evaporated and evaporated with EtOAc EtOAc. Ίο MS (+ve iontophoresis) m/z: 228 (MH+). (c) N-[2-{[2,2-bis(methoxy)ethyl]amino}-6-(decyloxy)-3^pyridyl]glycolic acid ethyl ester N2-[ 2,2-bis(decyloxy)ethyl]-6-(decyloxy)-2,3-pyridinediamine 15 (2.2 g, 10 mmol), ethyl bromoacetate (1.1 mL, 1.65 g) A mixture of 10 mmoles of potassium carbonate (2.1 g, 20 mmol) in acetonitrile (50 mL) and DMF (5 mL) The mixture was filtered and evaporated. The residue was dissolved in ethyl acetate and washed with water and brine. The organic extract was concentrated and added to a silica gel column eluted with EtOAc EtOAc (EtOAc) MS (+ve iontophoresis) m/z: 314 (MH+). (d) 4-[2,2-bis(decyloxy)ethyl]-6-(decyloxy) oxacyclo[2,3-b]pyrazole-3(4H)-one 306 200817417 _〇{[2,2-bis(decyloxy)ethyl]amino}-6-(decyloxy)-3"bibbityl]glycolic acid ethyl ester (1 g, 3.2 mmol) And potassium carbonate (1.3 grams, 9.6

, millimolar) The mixture in DMF (64 ml, 〇·〇5Μ) was heated at l〇5-U 〇 °C for 2 hours. The mixture was allowed to cool to room temperature and then Μ 〇 2 ( 〇············ The reaction was filtered, concentrated and the residue dissolved in ethyl acetate and washed with water. The organic extract was concentrated and added to a silica gel column eluted with EtOAc EtOAc (EtOAc) MS (+ve ion electronic spray) m/z: 266 (ΜΗ+). 10 (e) [6_(Methoxy)oxanylpyrido[2,3_b]n than tillage_4(3H)-yl]acetaldehyde Add trifluoroacetic acid (3 ml) to water at room temperature 4-[2,2-bis(methoxy)ethyl]_6_(methoxy-polypyridyl[2,3-b]pyrazine-3(4H)-one (0.9 g) (3 ml) , 3.4 mM) and stirred for 2 hours. 15 The reaction mixture was concentrated and the residue was purified EtOAc EtOAc EtOAc EtOAc Mixture of aldehyde and hemiacetal (〇·6 g, 8〇%) MS (+ve ion electron spray) m/z: 220 (ΜΗ+). 2〇(1)丨,1,3-1,3-tricarboxylic acid 3 · Ethyl oxalic acid dimethyl ester was added to NaH (0.038. g, 0·95 m) in a solution of propyl sulfonate (2.5 g, 18.9 mmol) in anhydrous THF (20 mL). Moore, 60% in mineral oil). Stir the reaction at ambient temperature for 15 minutes. In another Ting bottle, dissolve the C-B, ie σ2 ml, 9.45 mmol.

307 200817417 THF (1 ml) and then added dropwise to a solution of dimethyl malonate for 30 minutes. The reaction was stirred at ambient temperature overnight and concentrated in vacuo. The residue was dissolved in EtOAc and washed with EtOAc EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by EtOAc EtOAc elut elut elut elut elut Ln NMR (400 MHz, CDC13) δ 1.24 (t3 y=7.〇7 Hz, 3 H) 2.20 (q, /=7.24 Hz, 2 H) 2.37 (t, /=7.33 Hz, 2 H) 3.47 (t , /=7.33 Hz, 1 H) 3.70 - 3.75 (m,6 H) 4.12 (q, /=7.24 Hz, 2 H). 10 (S) (2E)-3-Phenyl-2-propene Cinnamonitrile (25·0 g, 194 mmol) was dissolved in EtOH. The solution was cooled to 0 C and HCl gas bubbles were bubbled through the solution for 30 minutes. The solution was stirred at ambient temperature for 1 hour and then concentrated in vacuo. The residue was dissolved in EtOAc (EtOAc) (EtOAc)EtOAc. After the addition, the solution was allowed to warm to ambient temperature and stirred overnight, and the obtained NH4Cl was filtered. The solution was concentrated in vacuo and the obtained product was used without further purification (28.6 g, crude). LCMS: m/z 147·4 (MH+). 10 (h) 3-{4-hydroxy-6-keto-2-[(E)-2-phenylidenevinyl]_M_dihydro-5^-mididyl}ethyl propionate 1,1, 3-ethyltricarboxylate 3-ethyl ester 1, L. dimethyl ester (1·65 g, 711 mmol) and (2Ε)-3-phenyl-2-propenenimine (ΐ·〇4 g) , 7.11 millimoles)

308 200817417 Mix in EtOH (36 ml). Triethylamine (1·9 mL, 14.2 mmol) was added and the solution was heated under reflux for 3 hrs. The solution was cooled to room temperature and treated with NaOMe (1.0 mL, 5.33 mmol, 25-30% w/w solution) in MeOH and the solution was refluxed for 5 hours. Two additional portions of NaOMe (2 x 1.0 mL) in MeOH were added and the solution was refluxed overnight. A yellow precipitate formed subsequently and was filtered. The mother liquor was acidified to pH 2 with IN HC1 and the solution was concentrated in vacuo. The resulting material was combined with a yellow solid and used without further purification. LCMS: m/z 315.2 (MH+). 10 〇〇3-{4,6-Dichloro-2-[made]-2-phenylvinyl]-5-pyrimidinyl}propionic acid ethyl ester crude 3-{4-hydroxy-6-keto group _ 2-[(E)-2-Phenylvinyl]-1,6-dihydro-5-pyrimidinyl}propionic acid ethyl ester (7.1 mmol) dissolved in p〇Cl3 (25 mL) and N, N-dimethylaniline (0.862 g, 0.9 ml, 7.1 mmol) was slowly added to the solution slowly. The reaction was then heated under reflux for 2 hours. After cooling to ambient temperature, the resulting solution was carefully and slowly added to ice water to quench excess P0C13. The mixture was extracted with EtOAc (3×) The crude residue was purified by EtOAc EtOAc (EtOAc) elute LCMS: m/z 351.4 (MH+). (1) 4-Chloro-2-[(E)-2-phenylvinyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one 309 200817417 at 3-{4, 6-Dichloro-2-[(E)-2-phenylvinyl]-5-pyrimidinyl}propionic acid w ethyl ester (0·42 g, 1.19 mmol) in 1,4-dioxane In a solution of scent (5 ml). Add concentrated NH4 〇H (3.5 mL). The reaction was heated at 75 ° C overnight in a sealed tube. The solution was concentrated in vacuo, diluted with water andEtOAcEtOAc The organic layer was washed with brine, dried over Na 2 EtOAc and concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc) eluting LCMS: m/z 286.2 (MH+). At the same time, 3-{4-amino-6-chloro-2-[(E)-2-phenylethenyl]-5-carbenyl}propanamine (0.175 g) was obtained. 1〇 LCMS: m/z 303.3 (MH+) 〇 3_{4_月女基-6-rat-2-[(E)-2-phenylethenyl]_5-0 dense. The decylamine (0.175 g, 0·58 mmol) was dissolved in EtOH and the HC1 gas bubble was bubbled through the solution until saturation. The solution was heated under reflux for 2 hours, cooled to ambient temperature and concentrated in vacuo. The residue was taken up in water, taken to EtOAc (EtOAc)EtOAc. The organic layers were combined, dried over NajEtOAc, filtered and concentrated in vacuo to afford &lt;RTI ID=0.0&gt; A white solid of ethyl ester. LCMS: m/z 332.2 (MH+). This product was then dissolved in DMF (5 mL) and treated with K.sub.2.sub.3 (.sup.16 g, 1.16 mmol) and at 75. 〇 Heat for 20 3 minutes. The solution was allowed to cool, diluted with water and extracted with EtOAc (3 EtOAc). The organic layer was dried over Naj.sub.4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc) eluting with EtOAc (EtOAc: EtOAc:EtOAc: 310 200817417 LCMS: m/z 286.2 (MH+). (k) 4-Chloro-7-keto- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine_2-aldehyde 4-chloro-2-[(E)-2- Phenylvinyl]dihydropyridinium and [2,3_d] pyrimidine _7(6H)-one (0·18 g, 〇·64 mmol) dissolved in [4-di, alkane/water 2 · 1 bath (6 house liters) and cool to 〇c. Add NaI〇4 (0·314 g, 1.47 mmol) and the catalyst 〇s〇4 (1 mL, 4% in water) and stir the solution overnight at ambient temperature, dilute with water and use 1 〇〇 /0 MeOH /DCM (4X) extraction. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut LCMS: m/z 212.0 (MH+). (l) (1-{2-[6-(Methoxy)_3-keto acridine[2,3-b]. Specific tillage-4(3H)-yl]ethyl}-4-hexahydro [6-(Methoxy)-3-ketoxanthene [2,3-b] is pyridine-amino) decanoic acid dimethyl ester. Specific tillage-4(3H)·yl]acetaldehyde (0·250 g, ι·ΐ4 mmol) and 4-hexahydropyridylamino decanoic acid 1,1-didecylethyl ester (〇·229 g , 1.14 mmoles, mixed in a 1:1 MeOH/DCM solution. An excess of Na2SO4 was added as a drying agent and the solution was stirred at ambient temperature overnight. NaBH(OAc)3 (0.724 g, 3.42 mmol) was added and the solution was stirred for additional 2 hours. The solution was concentrated on a silica gel in vacuo and the crude residue was purified eluting with EtOAc EtOAc EtOAc EtOAc EtOAc

311 Compound of 200817417 (0.271 g, 59%). LCMS: m/z 404.6 (MH+). (m) 4-[&gt;(4-Amino-1-hexahydropyridinyl)ethyl]_6_(decyloxy)acridin-5 [2,3-b]pyrone-3(4H)-one In the 〇{2_[6_(methoxy)-3-yl-keto-u-pyridyl[2,3_noun ratio till-4(3H)-yl]ethyl}_4-hexahydropyridyl)carbamic acid 1, 1-Dimercaptoethyl ester (0.27 g '0.67 mmol) was added to a solution of DCM in HCl (1. <RTI ID=0.0></RTI> </RTI> The reaction mixture was stirred at 〇 ambient temperature for 3 hours. The reaction solution was concentrated in vacuo to give hydrazine hydrochloride. The hydrochloride salt was dissolved in 1:1 MeOH / DCM. This solution was then treated with MP stone, 树日树月曰 (1〇 equivalent·, Argonaut Technologies Inc.) and stirred for 1 hour. The resin was filtered and the solution was concentrated in vacuo to give a white solid (yield: 22 g, quantitative). Lcms: m/z 3〇4.3 (MH+). (η) the title compound in 4-[2-(4-amino-fluorenyl-hexahydropyridinyl)ethyl]-6-(methoxy)pyridine 3 and [2,3-b] is compared to the well-3 (4Η)-ketone (〇·〇64 g, 0.213 mmol) at 1:1

To a solution of MeOH/DCM was added 4 to 7-keto- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine: aldehyde (45 g, 0.213 mmol) and excess Ν0〇4. The solution was stirred at ambient temperature overnight, then NaBH(OAc)3 (35 g, s. 6% millimolar) was added. The resulting solution was stirred at 312 '(S) 200817417 for 2 hours, concentrated in vacuo to EtOAc (EtOAc) elute 1) Gradient elution to give the title compound as a free base (0.062 g, 58%). LCMS: m/z 499.6 (MH+).]H NMR (400 MHz, CDC13) δ 1.48 - 1.59 (m, 2 H) 1.96 (d, /=15.92 Hz, 2 H) 2.28 (s, 2 H) 2.58 - 2.69 (m, 1 H) 2.73 - 2.84 (m, 5 H) 3.03 - 3.15 (m5 4 H) 4.01 - 4.06 (m, 4 H) 4.54 - 4.65 (m, 2 H) 6.66 - 6.76 (m, 1 H) 7.96 - 8.05 (m5 1 H) 8.09 - 8.15 (m, 1H). A portion of the title compound was obtained by dissolving the free base in 1:1 MeOH / DCM and 1 eq. The free base (27 mg) is converted to the HCl salt. It was then evaporated to dryness (yield 25 mg). Example 127 4-mercapto-2-{[(1 - {2-[6-(decyloxy)-3-one). σ 定 [2,3-b] pyridin-4 (3Η)- Ethyl]ethyl}-4-hexahydropyridyl)amino]mercapto}-5,6-dihydropyrido[2,3-d]pyrimidin-7(1Η)-one hydrochloride

(a) 3-{4-hydroxy-6-keto-2-[(indolyl)-2-phenylvinyl]-indole, 6-diin-5-pyrimidinyl} propionate decyl ester 1,1 , 3-propanetricarboxylic acid 3-ethyl ester 1,1-didecyl ester (23·8 g, 103 mmol) and (2Ε)-3-phenyl-2-propenenimine (10.0 g, 68.4 Mix in MeOH (400 mL), work up in NaOMe (l.sub.3, 313 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The solution becomes private and the color solution is filtered. The solution was concentrated in vacuo and diluted with water to aq. The aqueous parent leg Ae was extracted. Extracting the yellow meditation of the _ shape and many differences. The combined (iv) yellow (iv) was used in the silk and was no longer purified. LCMS: m/z 301·0 (ΜΗ+). (b) 3-{4,6-Dichloro-2-[(E)-2-phenylvinyl]-5-pyrimidinyl}ethyl propionate 〇3_{4_hydroxy-6-keto-2 -[(E)-2-Phenylvinyl JI6-dihydro-5-pyrimidinyl}propionic acid methyl ester was dissolved in pock (75 ml) using N,N-didecylaniline (4.85 g, 40 mmol) The ears were treated and heated under reflux for 2 hours. After cooling to ambient temperature, the resulting solution was carefully and slowly added to ice water to quench excess POCI3. The mixture was extracted with EtOAc (2 EtOAc) &EtOAc. The crude residue was purified by EtOAc EtOAc elut elut elut elut elut LCMS: m/z 337.2 (MH+). &gt; (c) 4-Chloro-2-[(E)_2_phenylvinyl]_5,8-dihydroσ ratio bite [2,3-d],. Ding-7(6H)-one in 3-{4,6-dichloro-2-[(£)-2-phenylvinyl]-5"mididyl}propionic acid ethyl ester (3.04 g, 9.02 m Add a concentrated NH4〇H (20 ml) to a solution of 1,4-two π (1 mL). Heat the reaction in a sealed tube at 60 〇 314 200817417 for 16 hours. Concentrated, diluted with water, and extracted with EtOAc. EtOAc (EtOAc m.). 〇·· 1) Gradient elution to give a yellow solid (1·69 g) containing 4H[(E)-2-phenylvinyl]-5,8-dihydropyrido[2,3-d&gt;唆_7(6H)-g is the same as (LCMS: m/z 285·9 (MH+)) and 3-{4-amino-m[(E)_2-phenylvinyl]_5_acridinyl} Indoleamine (LCMS: m/z 317·9 (MH+)). K2C〇3 (〇.74 g, 5.3 mmol) was added to the combined product (1·69 g) dissolved in DMF (20 ml). The solution was heated at 〇 〇 〇 〇 。 。 。 。 。 。 。 。 。 。 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空 真空Obtained the desired product as a grey solid (0.92 g, 36 〇 / 〇 over 2 steps). LCMS: m/z 285·9 (MH+) 〇(d) 4-indolyl-2_[(Ε)_2-phenyl Vinyl]_5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one

4-Chloro-2-[(E)-2-phenylvinyl]_5,8-dihydropyrido[2,3-d]pyridin-7(6H)-g with (0·434 g, 2·05 mmol) dissolved in DMF (5 ml) and added to the vial of the microwave. Add MeB(OH)2 (0. 273 grams, 4. 56 millimolar), Pd(Ph3P)2Cl2 (0. 107 grams, 0. 152 millimoles) and K2C〇3 (1.05 grams, 7. 61 millimoles) and cap the vial. The reaction will be at 140. Heat in a microwave for 10 minutes. The reaction was concentrated on silica gel and purified by column chromatography eluting with EtOAc (EtOAc:EtOAc:EtOAc:EtOAc: . 431 • grams, 74%). LCMS: m/z 265. 9 (MH+) 〇5 (4) 4-mercapto-7-keto-5,6,7,8-tetrahydroindeno[2,3_(^], 唆-2-acid 4- 4-yl-2- [(E)-2-Phenylvinyl]_5,8-dipyridinium α[2,3-d] σ 密-7 (6Η)__(0·43 g' 1. 63 house Mo) dissolved in dcm (20 ml) and the solution was cooled to -78 °C. Ozone bubbles are introduced into the solution until they become dark blue. After stirring at -78 ° C for another 10 minutes, dimethyl sulfide was added in one portion (1. 〇 10 ml). The solution was allowed to warm to ambient temperature overnight. The solution was concentrated on celite and purified by column chromatography (EtOAc) eluting with DCM/DCM-MeOH-NH4OH (90············· . 178 grams, 49%). LCMS: m/z 191. 9 (MH+). 15 (f) The title compound is 4-[&gt;(4-amino-1-hexahydropyridinyl)ethyl]methane (methoxy)tI than pyridine[2,3-b]pyrazole-3 ( 4H)-keto hydrochloride (0. 097 g, 287·287 mmol) in a solution of 1:1 MeOH/DCM (16 mL), 4_mercapto-7-keto 20-5,6,7,8-tetraindole 1 bite [2,3_(1]0密12定_2_醒(〇. 〇 64 grams, 〇. 287 millimoles), NaHC〇3 (0. 12 grams, 1. 44 millimoles) and an excess of Na2s〇4. The bath was spoiled at ambient temperature for 16 hours, followed by the addition of NaBH(OAc)3 (0. 182 grams, 〇 · 861 millimoles). The resulting solution was stirred for a further 2 hours, concentrated on silica gel and the crude residue was purified by column chromatography (EtOAc).

316 200817417 A gradient of DCM/DCM-MeOH-EtOAc (EtOAc: EtOAc) LCMS: m/z 479·2 (MH+)· 1H NMR (400 MHz, CDC13) δ ppm 1.41 -1.51 (m, 2 H) 1.91 (d, 1.12 Hz, 2 H) 2.20 (t, 7 = 10.61 Hz, 2 H) 2.45 (s5 3 H) 2.49 - 2.59 (m, 1 H) 2.68 - 2.79 (m? 4 H) 2.93 (t, J=7.71 Hz, 2 H) 3.06 (d, J=11.62 Hz, 2 H ) 3.92 (s, 2 H) 4.04 (s, 3 H) 4.54 - 4.63 (m? 2 H) 6.72 (d, 7=8.59 Hz, 1 H) 8.01 (d, /=8.59 Hz? 1 H) 8.14 ( s, 1 H). The title compound 孓 free base was converted to the HCl salt by dissolving the free base in 1:1 MeOH/DClV [and adding 1 equivalent of 4M HCl in 1,4-dioxane. It is then evaporated to dryness. Example 128 4-(decyloxy)-2-{[(1-{2-[6_(decyloxy)_3-ketopyrido[2,3-b]. Ratio - Well-4(3H)- Ethyl 4-ethyl hexahydroindenyl)amino]hydrazino}-5,6-dihydropyrido[2,3-(1]pyrimidin-7(111)-one hydrochloride

Hydroquinone is pyridine|; 2,3-d] (8) 4-(methoxy)-2-[(E)-2-phenylvinyl]_5,8-dipyrimidin-7(6H)-one 20 4-Chloro-2-[(E)-2-phenylethenyl]_5,8-dihydropyrimidine-7(6H)-one (0.45 g ' 1.58 mmol) in Me〇H ( The NaOMe (Ο., gram, 174 mmol) of the wool was added to the suspension for 1 hour, and the mixture was heated under reflux for 3 hours, then added with hydrazine. :: and continuously refluxed. This step was repeated twice for 9 hours. All starting materials ^

317 200817417 After the loss (LCMS), the reaction was concentrated on silica gel and purified by column chromatography eluting with EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: The product was a grey solid (0.404 g, 91%). LCMS: m/z 282.2 (MH+). (b) 4-(decyloxy)-7-keto-5,6,7,8-tetra-argon σ ratio bite [2,3-d] sputum-2-acid 4-(decyloxy) )-2-[(E)-2-phenylethenyl]-5,8-dihydro-do[2,3-d]pyrimidin-7(6H)-one (0·40 g, 1.44 Dissolve in DCM (20 mL) and cool the solution to -78 °C and pass 〇3 bubbles into the solution until it turns dark blue. After further stirring at -78 ° C for 10 minutes, dimethyl sulfide (1·〇 ml) was added in one portion. The solution was allowed to warm to ambient temperature over 2 days. The solution was concentrated on silica gel and purified by EtOAc EtOAc (EtOAc) ). LCMS·· m/z 207.6 (MH+). (c) the title compound in 4-[2-(4-amino-1-hexahydroindole.methyl)ethyl]_6_(methoxy&gt; than biting [2,3-b] pyridin-3 ( 4Η&gt; Ketone hydrochloride (0.105 g, 〇·3〇9 mmol) was added to a solution of 1:1 MeOH/DCM (16 mL), 4-(methoxy)_7-keto 5'6,7 , 8 - 4 吼 吼 疋弁 疋弁 [2,3-d] ° -2- acid (0.074 g, 〇 309 mmol), he sinks 3 (0.13 g, 1.55 mmol) and an excess of him 28〇4. The solution was stirred for 16 hours at the temperature of the ring, followed by the addition of NaBH(OAc)3 (0.196 g, 0.927 mmol). The resulting solution was stirred for a further 2 hours and concentrated on silica gel. The crude residue was purified by column chromatography (EtOAc) eluting </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (0. Π 4g, %) ° LCMS: m/z4953 (MH+). 1H NMR (400 MHz, CDC13) δ 1.41 - 1.51 (m, 2 Η) 1.85 - 1·96 (m, 2 Η) 2· 19 (t, /=10.61 Ηζ, 2Η) 2·55 (ddd, J=14.21, 10·29, 4.04 Ηζ, 2 Η) 2·65 (t, /=7.58 Hz, 2 Η) 2.71 - 2.78 (m , 2 Η) 2.83 (t, /=7.71 Hz, 2 Η) 3.06 (d, /=11.62 Hz, 2 Η) 3.84 - 3.90 (m,2 Η) 3·98 - 4.01 (m,3 Η) 4·01 - 4.04 (m,3 Η) 4.54 - 4·62 (m, 2 Η) 6.72 (d, /=8.59 Hz, 1 Η) 8·01 (d, /=8.59 Ηζ, 1 Η) 8.14 (s,1 Η) 8.73 (s,1 Η). Dissolve the free base The free base of the title compound was converted to the HCl salt in 1:1 MeOH / DCM and 1 eq. of THF in 1,4-dioxane. Keto-based small [2-(4-{[(3-keto-3,4-dihydro-2H-pyridin[3,2-b] [1,4] 噚____)) Aminobutyr-1-pyridinyl)ethyl]-1,2-diindole-4-indonitrile dihydrochloride

(^) Trifluoromethanesulfonic acid 1-{2_[4-({[(1,1-didecylethyl)oxy)carbonyl) Amino: hexahydropyridyl]ethyl b 7_fluoro_ 2_keto-]L,2-dihydrofurfuryl ester, trifluorodecylsulfonic acid 7-fluoro-2-keto-1-(2-ketoethyl) 4,1 dihydro-4- Oxime ester (prepared as shown in Example 13(e)) (49 g, 12·5 mmol) and hexahydroindole amino decanoic acid i-methane diacetate (2.5 g, 12· 5 mM) = solution of chlorodecane (50 liters) and sterol (5 liters) with 3α molecules for 1 hour. Add sodium triacetate hydride (8 gram, 37· 6 319 200817417 Moer = stir w &amp; 5 days, then extract the mixture with sodium citrate and extract the mixture with methylene chloride. The organic layer was separated, dried and concentrated. The title compound (0.59 g, 12%) was obtained after EtOAc EtOAc (EtOAc): Cyano--fluoro as a base" (qiu- fluorenyl) ethyl]_4_hexa-pyridyl}-amino carboxylic acid 1,1-dimethylethyl acetonate in difluorodecyl sulfonic acid 1-{2矸4 - "[(1, 卜 dimethylethyl) oxy] carbonyl 1 fluorenyl) amine 6 A solution of pyridyl]ethyl}-7-fluoro-2-keto-1,2-dihydro-4-carboline ester (〇·ι7 g, 〇·32 mmol) in DMF (1 mL) Adding zinc oxide (0.036 g, 〇·3 mmol), ginseng (di-family acetonitrile) - (0.022 g, 0.024 mmol) and u, bis(diphenylphosphino) ferrocene Iron (0.056 g, 0.1 Torr) and degassed with argon. The mixture was heated for 15 hours in 卯.c. The solution was allowed to cool and then partitioned between ethyl acetate and brine. The residue was mixed with the crude material from a similar experiment on a half scale. The combined material was chromatographed on a 5 gram gel (1 gram of SPE eluted with a gradient of ethyl acetate/methanol 0-3%) to give a brown oil. It was solidified to the title compound (0.113 g, 46%). </RTI> <RTI ID=0.0></RTI> <RTIgt; Fluoro-2-keto-1,2-dihydro-4-indolenin hydrochloride will be {1_[2_(4-cyano-7-fluoro_2_indenyl-1(2H)" quinine π Linji)ethyl] ice 320 200817417 hexacridinyl}amino phthalic acid 1,1-didecyl ethyl ester (0.113 g, 〇 · 27 mmol) dissolved in 4,4, containing 4MHC1 - 2 - 2 - (2) (1) (1) titled compound in 1-[2_(4-amino-1-6) Hydropyridyl)ethyl]_7_fluoro-1-keto"2_dihydro-4-indole nitrile hydrochloride (0.062 g, 0.16 mmol) and 3__yl_3'4 dihydro-2H-pyridine [3,2-b] [1,4]哼耕-6-aldehyde (synthesis see 1〇W02003087098, Example 31(e)) (0.028 g, 0·16 mmol) in w MeOH/DCM (6 ml The solution was added with sodium acetate (〇·ΐ〇克, 12 mmol), acetic acid (0.5 ml) and 3 Α molecular sieve 1 and the mixture was stirred for 1 hour. Polymer supported cyanoborohydride (0.10 g) was added and the mixture was stirred for 18 hours then filtered and the solid was washed with dichloromethane. The 15 layers were washed with sodium carbonate solution, dried and concentrated. The product was obtained by chromatography on silica gel eluting with EtOAc (EtOAc EtOAc EtOAc EtOAc The precipitate was separated, washed with diethyl ether and dried then evaporated 20 LCMS: m/z 477 [ΜΗ+]. Free-form base NMR: δΗ (CDC13), (250 ΜΗζ) 1·55 (2H, m), 1.9 (2H, m), 2·25 (2H, m), 2.6 (3H, m), 3·05 ( 2H,m),3.85 (2H,s),4·4 (2H,t,J=7Hz),4·65 (2H,s),4·8 (2H,ν· br),6·9 (1H ,d, J=8Hz), 7.07 (1H, s), 7.15 (1H? m), 7.2 (1H, d, J=8Hz), 7.3 (1H, m), 7.9 (1H? dd, J=9? 6Hz) 321 200817417 Example 130 Bu (2-{4-[(2,3-dihydro[ι,4]dioxo[2,3_c]pyridine-7-ylindolyl)amino]-b hexahydro 11 Bipyridyl}ethyl)-7-fluoro-2-keto-1,2-diindole-4-4 quinone nitrile trifluoroacetate

(a) 7-Fluoro-1-(2-propenyl small)-2Η_3,1-Benzo-π cultivating _2,4(111)-dione in 7-fluorobenzo-industrial _2,4 (111 ) _ diketone (5. 〇 1 g, 27·7 mmol) in DMF (l 〇〇 ml) at 0 ° C was added sodium hydride (111 g, 27. 7 mmol, 60% In paraffin, it takes 15 minutes. Allyl iodine (2.6 ml, 27.7 mmol) was added and the solution was stirred for 2 hours and then poured onto water (200 mL) of ice (1 g). The precipitate was collected, washed with EtOAc EtOAc (EtOAc) LCMS: m/z 222 [ΜΗ+] 〇 ))-1,2-dihydro-3-porphyrincarboxylate

j ‘ 17·7 亳 Mo Er, 60% in the stone for 0.5 hours until the bubbling stops. 1--2li~3,l-benzoindole _2,4(1H)_ (b) 7-fluoro-4-hydroxy-2-branched 1-yl-1-(2-propenyl q-acid ethyl ester in propylene Add hydride (1,4 g, liter) to a solution of dimethyl hydride (2.84 g, liter) for 5 minutes and stir the solution for 5 times to make 7-fluoropropen-1-yl; μ2 Η 322 200817417 Diketone (3.92 g, 17.7 mmol) was added to the i solution and the solution was stirred at ambient temperature for 1 hour and then heated at 10 ° C for 18 hours. The solution was allowed to cool and concentrated. The organic layer was extracted with ethyl acetate and then extracted with ethyl acetate. The organic extracts were dried and concentrated to give the title compound as brown solid (4·63 g, 90%) LCMS: m/z 292 [ΜΗ+]. (c) 7-fluoro-4-hydroxy-1·(2-propen-1-ylpyridone) 7-fluoro-4-yl-based_2_ g with the base small (2-two Mu · &quot; base)-1,2_ dihydro ί porphyrin acid ethyl ester (4.46 g, 15.3 mmol) suspended in 2N sodium hydroxide solution (70 ml) and Heating under reflux for 4 hours. After cooling, adjust the pH to ~pjj 6 with 2N hydrochloric acid and filter the sediment of the household. After washing and vacuum drying, the title compound was obtained as a white solid (2·73 g, 810 / 〇) 〇15 LCMS: m/z 220 [ΜΗ+] 〇(d)trifluoromethanesulfonic acid 7_fluoro_2_ Keto group·Bu(2-propenyl-1-yl)_l52_dihydro-4-hydroxyl quinone 20 in 7-fluoro-4-hydroxypropyl-1-yl)-2(1H)-fluorenone 2·57 g '11.7耄莫耳) Add a tri-monthly female (1.8 liters, 12.9 house moles) to a suspension of methylene chloride (5 Torr) and cool the mixture to 〇.〇. Trifluoromethyl phthalic anhydride (2.18 liters '12 9 mM) for 15 minutes and mixed for 18 hours 'maintained at ambient temperature for 1 hour. The solution was washed with brine and saturated aqueous cesium carbonate solution, (d) The oil was concentrated to a white solid (2 ηg, 56%). LCMS: m/z 352 [MH+] 〇(4) Difluoromethyllithium ruthenium phthalate 2-keto small (2_@同基ethyl)-i,2-dihydro- 4-uquinacyl ester in trifluoromethyl Sulfonic acid 7-fluoro-2-keto 4_(2-propenyl) 4,2-diindole-4-indanyl ester (5.6 g, 16 mmol) , 4_dioxane (150 ml) and water (30 liters) were added sodium periodate (7.96 g, 37·3 mmol) and iron tetrachloride (14·3 ml) in a solution of 〇°c. 4% solution in water). The mixture was allowed to warm to ambient temperature and stirred for 5 hours. The solution was partitioned between water and dioxane and the organic layer was separated, dried and evaporated to give a crude product (6 </ RTI> </ RTI> </ RTI> </ RTI> solvent) which was used in the next step without further purification. LCMS: m/z 372 [MH++H2 〇] ° (1) difluoromethyllithic acid l-{2-[4-((2,3-dihydro[ι,4]dioxo[2, 3-c]biting _7_ylindenyl){[(U_didecylethyl)oxy]carbonyl}amino)-1-hexyl]ethyl}-7-fluoro-2 -keto-1,2-dihydroline ester 7-fluoro-2-yl-l-(2-g-isoylethyl)_ι,2-dihydro-4-indolyl ester of crude difluorononyllithic acid (5.6 g, 15.9 mmol, assuming 1% from the previous step) dissolved in THF (5 mL) and added sequentially (2,3-dihydro[丨,4]dioxo[2, 3-c]吼.1-7-ylmethyl)4-hexahydroprenylguanidinium decanoic acid 1,1-didecylethyl ester (synthesis see W02004/058144 example 99(h)) (5·60 Gram, 15.9 millimoles) and sodium sulphate (~15 grams). After 2 hours, two 324 200817417 sodium ethoxide borohydride (12.3 g, 5δ solution was stirred for 18 hours. Will, also Moh) was added for 1 hour and the solution was mixed for 18 h. Ethyl acetate was diluted and washed with carbon solution. The layer (10) Q-cutting SpE acid/SPE was washed with 2··1 ethyl acetate/hexane to the wrong acid ethyl acetate/1% methanol to give the title compound as a transparent oil (2·81 g, 26%). LCMS: m/z 687 [ΜΗ+] 〇(g) {H2♦Cyanobutyryl-2,yl-1(2Η)Linyl)ethyl]_heart hexanitrogen 1 〇吼 base} (2, 3_Dihydro t1,4]dioxo[2,3-c]indole-7-ylmethyl)amino decanoic acid 1,1-dimethylethyl ester difluorodecyl sulfonic acid 1_{ 2-[4-((2,3-Dihydro[1,4]dioxo[2,3-decene _7_ylindenyl){[(U_:decylethyl)oxy]]叛基}Amino)1- /, 虱 比 疋 ] ] ] ] ] ] 7 7 - - - ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( , 0·19 millimolar), cyanide (0.027 g, 〇·23 mmol), ginseng (dibenzylideneacetone) dipalladium (〇·〇17 g, 0.019 mmol) and, -double The bath of (a phosphino)ferrocene (0 042 g, 〇·〇 76 mmol) in DMF (3 ml) was degassed with argon and then heated at 9 ° C for 18 hours. The mixture was allowed to cool and then partitioned between ethyl acetate and brine. The organic layer was separated, dried and concentrated. Chromatography (1 gram of SPE eluted with ethyl acetate / EtOAc EtOAc) LCMS: m/z 564 [ΜΗ+] 〇(h) title compound 325 200817417 {1-[2-(4-cyano-7-fluoro-2-keto-1(2H)-indenyl) (4-hexaacridinyl) (2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylmethyl)amino decanoic acid 1,1- Dimethylethyl ester (〇·〇61 g, 〇·ΐΐ mmol) was dissolved in trifluoroacetic acid (3 liter) and allowed to mix for 15 minutes and then concentrated. The residue was dissolved in ethyl acetate and diethyl ether was added to cause a precipitate to form. The precipitate was filtered to give the titled <RTI ID=0.0>

Example 131 Η2_{4-[(2,3-dioxin[1,4]dioxyg and [2,3-decapyridyl-7-ylindenyl)amino]-1-hexahydropyranyl}B Base&gt;7-fluoro-4-indolyl ketone dihydrochloride

(a) (2,3-Dihydro[1,4]dioxog[2,3-c]pyridin-7-ylmethyl){i_[2-(7-fluoro-4-indolyl-2 -S synthyl-1(2Η)-4σ-linyl)ethyl]-4-hexahydroindenyl} 1,1-dimethylethyl phthalate in 1-trifluoromethanesulfonic acid 1-{2 -[4-((2,3-Dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl){[(1,1-dimethylethyl)oxy) (carbonyl) amine (amino) hexahydroindole is more than butyl] ethyl}-7-fluoro-2-keto-1,2-dihydro _4_ σ α a lin g (preparation see example 130 (ί)) (0·155 g, 0.23 mmol), a solution of M_二崎烧326 200817417 (2 ml) was added with decylboronic acid (〇·〇5 g, 〇·92 mmol), 肆 (triphenyl) Phosphine) palladium (0) (0·〇 51 g, 0·004 mmol) and trivalent potassium triphosphate (0.1.55 g, 0.73 house mole). After the mixture was degassed with argon, it was dried at 9 Torr. Heat for 18 hours. After cooling the mixture, the organic layer was separated in ethyl acetate and water, dried and concentrated. Chromatography (10 g of Shixi gum at 处 每 each. 乙酉), to give the title compound (0.062 g, 5%), show LCMS: m/z 553 [ΜΗ+]. (b) the title compound will be (2,3-dihydro[1,4]dioxyg and [2,3&lt;], fluorenyl) {1-[2-(7-fluoro-4-methyl-2) -keto-1(2H)-indenyl)ethyl 1,1-methylpyridyl}aminocarbamic acid 1,1-dimethylethyl ester (0.061 g, 〇^ hexahydrogen dissolved in 4M HCl containing 1,4 - 1 molar was stirred in dioxane. The solid was washed with diethyl ether and diethyl ether was evaporated. The solid was dried <RTI ID=0.0># </RTI> </RTI> <RTIgt; LCMSm/z453[MH+] δΗ (DMSOd6), (400 MHz) 2.33 (2H, m), 2.2-2.45 (2H, m), 2.49 (33⁄4 x 3·35 (3H,m),3·5 (1H , m), 3.7 (1H, m), 3·78 (2H, d, J=11Hz), 4 3 (2^ ', .15 (23⁄4 m) 4·65 (2H, t, J=7Hz), 6·55 (1H, s), 7·2 (1H, m), 7.5 (1H, s), 7.75 (iH df; ” 4.5 (2H, “), (1H, dd, J=9, 6 Hz) , 8.4 (1H, s), 10.0 (2H, br), 11.0 (1H, br) · ', 2, 12, 2), 7.9' 20 Example 132 H2-{4_[(2,3-dihydro[1 , 4] dioxo[2,3~~oxymethyl)amino]+hexahydropyridyl}ethyl)-7, gas ̄7-7 base)-2(m)-fluorenone disalt Acid salt

327 200817417

OMe (8)7_f74, sulfhydryl) small (2: propylene-baked seven base. Please (preparation see 4 fluorenyl-(tetra)-based seven (2) two olefins 旬 妒 妒 妒 ( ( (preparation see example l30 (c)) (10 g, 4·5 Add sodium nitride (0.2 ^ ear (4) qing 0 ml) to the solution of bismuth. Add a == 〇 house Moer in the resulting solution, 6 〇% in stone 10 and continue in 旳 (4) !hour, after 30 (four) '4.8 millimoles) Jiang, and β into the s..., and then stirred at ambient temperature for 18 hours. :;=?, the residue is separated between methylene chloride and water. The title compound (0.386 g, 36./(〇. LCMS: m/z 234 [MH+] 〇 15 (8)) was obtained as the title compound (0.386 g, 36%). [7-Fluoro-4_(methoxy)_2-keto-1(2Η)" quinolyl]ethyl m(methoxy)-1-(2-propenyl)-2-(1Ηρ quinolinone) (0.386 g, 1.66 mmol), sodium sulphate (〇·83 g, 3.7 mmol) and osmium tetroxide (1.7 ml, 4% in water) in water (3 ml) The solution of hydrazine, 4_2-20 decane (15 ml) was stirred for 5 hours. The mixture was separated between dichloromethane and water. After concentration, the title compound (0.364 g, 93%) was obtained. (c) (1-{2-[7-fluoro_4_(decyloxy)-2-keto-1 (2)) Kib 4

328 200817417 Hexahydropyridine bite, face I field cabin 1,

克' I·55 pens) and 4_hexahydrogen

Isoformyl-1(2H)-mercapto]acetaldehyde (0.364 吼13-decylaminocarbamic acid 1,1-dimethylethyl chloromethane (5 ml) and decyl alcohol (5 ml), triethylene hydrazine Sodium oxyborohydride (1·〇g, 5 days, then add the solution in sodium carbonate solution and stir for 5 hours. Add, —丨_ 4·7 house Moer) and stir the mixture for $ _ extract with m The mixture was separated, EtOAc (EtOAc m. LCMS: m/z 420 [MH+] 〇(d) 1_[2-(4-Aminopyrohydropyridinyl)ethyl]-7-fluoro-4-(decyloxy)-2 (lH) -uquinone will be (1-{2_[7-fluoro_4_(decyloxy)-2-keto-1(2H)-indolyl]ethyl}-4-hexahydropyridinyl)amine Didecyl thioglycolate (〇·4 g, 〇·95 mmol) was stirred in 4 M HCl in 1,4-dioxane (15 mL) for 5 hours and then cooled. The aqueous layer was extracted with ethyl acetate and sodium carbonate solution. The organic layer was dried and concentrated to an oil containing a crude product. The aqueous layer was analyzed by lc/ms. The product was shown to be mainly in the aqueous layer. The aqueous layer was concentrated and the obtained solid was washed with methanol (10%) of dichloropurin, and the material obtained after evaporation was again treated with methanol (1%) of dichloromethane. After the solution was concentrated, the title compound was obtained (yield: 114 g, 37%) 〇LCMS m/z 320[MH+]〇200817417 (e) 1 (2_{4-[(2,3-dihydro[1,4] Dioxaindolo[2,3-c]pyridin-7-ylindenyl)amino]-1-hexahydropyridinyl}ethyl)-7-fluoro_4_(decyloxy)_2 (111) Indone ketone dihydrochloride salt 1-[2-(4-Amino-1-hexahydropi-butyrate)ethyl]•Fluoride (methoxy)_2(1H) quinacone (0.057 g) , 〇·18 mmoles) and 2,3_dioxin [M] dioxo[2,3-c]pyridine-7-aldehyde synthesis see W02004058144, Example 2(c) or W003/087098, Example 19 (d)) (0.027 g, 0.16 mmol) in 10 15 20 1:1 solution of chlorohydrazine/methanol (4 ml) was stirred with 3A molecular sieves for 2 hours and then sodium triethyloxy borohydride was added ( 〇 115 g, 〇·54 mmol, and the mixture was stirred overnight. The solution was diluted with dichloromethane and washed with sodium carbonate solution. The aqueous layer was taken with dichloromethane/decyl alcohol (10 〇 / ) Was extracted and the combined organic layers were dried and concentrated. On silica gel to give the title compound as the free state test (ο · Chromatography (20 g SPE, burning / methanol 0-20 X) eluted with a gradient of dichloromethane). 】] g) was converted to the dihydrochloride salt by dissolving it in methylene chloride and adding 4NHC1 in 1,4-dioxane. Diethyl ether was added to the solution and the precipitate was collected (0.022 g, 23%). LCMS m/z 469 [ΜΗ+]. Free State Base NMR: δΗ (CDC13)5 (400 MHz) 1.55 (2H, m), 2.0 (3H, m), 2.25 (2H m) 2 6 f3H m), 3.05 (2H? m), 3.8 (2H, s)? 3.95 (33⁄4 s)? 4.35 (6H, m), 5.95 (1H, s) 6 8 flk ; 6 〇? (1H,m), 7·15(1Η,m),7·95 (1H, m),8·1 (1H,s) Λ s), 6.9 Example 133 2-({[(3S)-M2-[6-(曱-oxy)-3- keto pyridine) [2,3 -13]° than well-4(311)-yl]ethyl}-3-hexahydroindenyl)methyl]amino}methyl)-5,6-dihydro 17 is more than bite [2, 3-d]. Bite-7(1 Η)-keto dihydrochloride 330 200817417

5 (8) [((3S)_l_{2_[6-(曱-oxy)-3-酉 is the same as σ 咬[2,3-b]pyrazine_4(3Η)_yl]ethyl b3- Hexahydro-pyridinyl)methyl]amino decanoic acid, phenyl hydrazine vinegar [6-(methoxy)-3-ketopyrido[2,3-b]pyridin-4(3Η)- Ethyl acetal (synthesis see Example 126(e)) (0.30 g, 1.36 mmol) and ((3r)_3-hexapyridylmethyl]amino decanoic acid phenylmethyl ester (synthesis) See Example 92(b)) (0.337 g, 1.36 mmol) in 1:1 MeOH/DCM solution (30 liters). Add excess NaJO4 as a desiccant and stir the solution at ambient temperature for 16 h. NaBH(OAc)3 (0·86 g, 4.08 15 mmol) and the reaction was stirred for additional 2 hours. The resulting solution was condensed on a silica gel under vacuum and the crude residue was subjected to column chromatography. Chromatography, eluting with EtOAc EtOAc EtOAc EtOAc (EtOAc) 20 (b) 4-{2-[(3S)-3-(Aminomethyl)-1_hexahydro 0-butyryl]ethyl(methoxy)pyrido[2,3-b]pyrazine -3(4Η)-ketone in [((3S)-l-{2-[6_(decyloxy)) ketopyrindolo[2, 3-7]pyrazine-4(3H)-yl]ethyl}_3_hexahydropyridyl)indolyl]amino decanoic acid

331 200817417 Phenylmethyl ester (0·37 g, 〇·83 mmol) was added 10% Pd/c ( 〇 〇 〇) in MeOH (20 mL). The solution was hydrogenated at 50 PSI for 3 hours on a Parr apparatus. The Pd/C catalyst was filtered, Mn 〇 2 (0.22 g, 2.48 Torr) was added and the solution was stirred at ambient temperature for 16 hours. The y[n〇2 was filtered and the crude material (yellow oil) was used without further purification (〇·26 g, 97% over 2 steps). LCMS: m/z 318·1 [ ΜΗ+] 〇 (C) title compound 10 15 20 in 4-{2-[(3S)-3-(aminomethyl)+hexahydropyridyl]ethyl b 6_ (decyloxy) acridine [2,3-b]pyrazine-3(4H)-one (0.072 g, 0.23 mmol) in a solution of 1:1 MeOH / DCM (2 mL) Add 7-keto-5,6,7,8-tetrahydropyridyl and [2,3_d] sputum (preparation see Example 125(c)) (〇.〇4 g, 0.23 mmol) and excess Na2S04. After the solution was stirred at ambient temperature for 16 hours, NaBH(?Ac)3 (1.68 g, 7.92 moles) was added. The resulting solution was stirred for additional 2 hours. LCMS analysis showed only 50 ° / ❻ product, so add an additional portion of 7-keto _5,6,7,8_tetrahydro hydrazine and [2,3-d]pyrimidin-2-aldehyde (〇· 4 g, 0.23 mmol, and the reaction was stirred for a further 16 hours. The solution was then concentrated on a silica gel under vacuum and the crude residue was purified by column chromatography eluting with EtOAc (EtOAc) The free product of the desired product as a yellow oil (0.034 g, 32%). m/z 479.2 (MH+). 1H NMR (400 MHz, CDC13) δ 1.57 -1.69 (m5 2 Η) 1.73.1 Η) 1.95 (d3 7=8.59 Hz, 2 H) 2.18 (td, 7=10.99, 3.03 Hz, 1 H) 2.51 - 2.63 (m, 2 H) 2.67 -

332 200817417 2.75 (m, 4 Η) 2.81 - 2.92 (m, 1 Η) 2.92 - 3.01 (m, 2 Η) 3.21 - 3.32 (m, 1 Η) 3.88 - 4.00 (m, 2 Η) 4.00 - 4.05 (m ,3 Η) 4·57 - 4·68 (m,2 Η) 6·73 (d,/=8·59 Hz,1 Η) 8.00 - 8.04 (m, 1 Η) 8.23 (s,1 Η) 8 36 (s, 1 Η). The compound was converted to the di-HC1 salt by dissolving the free base in 1:1 MeOH/DCM and adding .2 equivalents of 4M HCl in 1,4-dioxane. 5 Then evaporate to dryness. Example 134 cis-7-chloro-6_{[({(3RS,5RS)-l-[2-(7-fluoro-2-keto-1(2Η)-4)-yl)ethyl&gt; 5-hydroxy-3 -hexahydropyridyl}methyl)amino]mercapto}-211-1,4·benzoxanthine-3(4H)_gand dihydrochloride 10

15 (8) cis-indole RS, 5RS)-5_|^yl-3-hexahydro-π ratio σ-destinic acid in 5-hydroxy-3-pyridinecarboxylic acid decyl ester (15 g, 1 〇 millimolar) in water ( 4 〇 ml) was added with aq. NaOH (5 ml of a 6 Ν solution, 3 〇 mmol) and 铑 (750 克, 5% by weight on alumina). The reaction was hydrogenated on a hydrazine unit at 45 psi of H2 for 36 hours. The gas was replaced with N2 and the solution was filtered through a pad of Celite® to remove the catalyst. The solution was then concentrated under reduced pressure to give the desired compound (yield: 15 g, 9%) which was used in the next reaction. MS (ES+) m/z 146 (MH+) 〇

333 200817417 (b) cis-(31^,5118)-5-hydroxyl small {[(phenylmethyl)oxy]carbonyl}·3-hexahydroindole sigma acid in cis-(3RS,5RS)- 5-Hydroxy-3-hexahydropyridinecarboxylic acid (5.2 g, 31.0 mmol) was added to benzyl chloroformate (7.0 mL, 5 〇·〇 mmol) in 0.5 N NaOH (100 mL). Stir at room temperature and N2 for 14 hours. The reaction was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The combined organic extracts were dried with EtOAc (EtOAc) MS (ES+) m/z 280 (MH+). 10 (C) cis-(3RS,5RS)-5-{[(l,l-dimethylethyldiindenyl)decyl]oxy} small {[(phenylfluorenyl)oxy]yl }-3-hexahydroindole ratio rr to betrayic acid in cis-(3RS,5RS)_5_transyl-1_{[(phenylindolyl)oxy]pyridyl 3_hexahydropyridinecarboxylic acid (0.78 g, 2.8 millimoles) Et3N 15 (2.0 ml, 15 mmol) and tributyl dimethyl decyl alkyl (1.06 g '7·molar) were added to CHC13. The reaction was stirred at N2 for 14 hours at room temperature. The reaction was diluted with 200 liters of CHCI3 and washed with a saturated aqueous solution of NaHC 〇3, aq. 0.1N EtOAc, sat. The organic layer was dried over NajO4, and the solvent was removed to give the desired compound (yield: 80 g, 73%) as a colorless oil. MS (ES+) m/z 394 (ΜΗ+) 〇((1) cis-(3118,51^)-3-{[(1,1-didecylethyl)(dimethyl)decyl]oxy }}-5-(by fluorenyl)-1-hexahydroindole phenyl phthalate 334 200817417

In cis((3RS,5RS)-5_{[(1,1-didecylethyl)(diindenyl)oxalyl]oxy}-1-{[(phenylmethyl)oxy] Addition of 1N BHrTHF in THF (6.0 mL, 6·0 mmol) in THF (20 mL) in THF (20 mL) The ear was stirred and stirred at room temperature under n2 for 6 hours. The excess was quenched by the addition of MeOH and the reaction was stirred for 2 hours. The reaction was partitioned between EtOAc (EtOAc)EtOAc. The solvent was removed and the crude residue was purified EtOAcjjjjjjjj MS (ES+) m/z 380 (MH+). (e) cis-(3RS,5RS)-3-{[(l,l-dimethylethyl)(didecyl)decyl]oxy}-5-[(1,3-dione- 1,3-Dihydro-2H-isoindol-2-yl)methyl] hexahydro-15 pyridine carboxylic acid phenylmethyl ester in cis-(3RS,5RS)-3-{[(l,l-two Methyl ethyl)(didecyl)decyl]oxy}-5-(hydroxyindenyl)-1-hexapyridinecarboxylic acid phenyl decyl ester (500 mg, 1.4 mmol) in THF (25 mL Add quinone (250 mg, 1.7 mmol), triphenylphosphine (450 mg, 1.7 mmol) and di 20 azo azodicarboxylate (300 mg, 1.7 mmol) ). The reaction was stirred at room temperature under Ν2 for 16 hours. The reaction was partitioned between EtOAc (EtOAc)EtOAc. The solvent was removed and the crude residue was purified EtOAc EtOAc elut elut elut elut elut

335 200817417 mg, 93%) yellow oil. MS (ES+) m/z 509 (MH+). (1) cis-(3RS,5RS)_3-(aminomethyldimercaptoethyl)(dimethyl) sulphate]oxy}-1-hexahydroindole phenylmethyl ester in cis- (3118,5118)-3-{[(1,1-didecylethyl)(diindenyl) oxalate]oxy}_5_[(1,3-dione-based-1,3_2 Hydrogen 2 沁 吲哚 吲哚 I 曱 曱 ] ] ] ]] Anhydrous hydrazine (〇·2 ml, 6·5 mmol) was added to EtOH (20 ml) in a carboxylic acid phenyl hydrazine s (660 mg, ΐ·3 mmol). The reaction was stirred at room temperature under nitrogen for 14 h and the reaction was filtered over Celite®. The filtrate was partitioned between EtOAc (EtOAc)EtOAc. The solvent was removed to give the desired compound (450 mg, m. 15 MS (ES+) m/z 379 (MH+). ^ (g) cis-(3RS55RS)_3-{[(1,1-dimethylethyl)(dimethyl)decyl]oxy}_5_ [({[(1,1-dimethylethyl) )oxy]carbonyl]amino)indenyl]-1-hexahydropyridinecarboxylic acid phenyl decyl ester 2〇 in cis-(3RS,5RS)-3-(aminomercapto) winter {[(1,1) -Dimethylethyl)(didecyl)decyl]oxy}-1-piperidinecarboxylic acid phenyl decyl ester (450 mg, 1.2 mmol) in Et.sub.3 (25 mL). ML, 2.4 mM) and dibutyl butyl dicarbonate (315 mg, 1.4 mmol). The reaction was stirred at rt EtOAc (EtOAc) EtOAc. The solvent was removed and the crude residue was purified EtOAcjjjjjjjjj 5 MS (ES+) m/z 479 (MH+) ° (h) cis-[((3RS,5RS)_5-{[(1,b dimethylethyl)(dimethyl)decyl]oxy] -3-hexamethylene) hydrazino] 1,1-dimethylethyl carbazate in cis-(3RS,5RS)-3-{[(l,l-didecylethyl)曱基)石石alkyl] 1〇oxy}-5- [({[(1,1-didecylethyl)oxy]carbonyl}amino)methyl]-1-hexahydropyridinecarboxylic acid Phenylmethyl ester (550 mg, 1.1 mmol) was added to EtOH (50 mL) and Pd/C (150 mg, 10%). The reaction was hydrogenated on a Parr apparatus at 40 psi of H2 for 1.5 hours. Hydrogen was replaced with N2 and the solution was filtered through a pad of Celite® to remove the catalyst and washed with additional EtOH 15 (5 mL). The filtrate was concentrated under reduced pressure to give the desired compound (390 mg, 1%). (1) cis_({(3RS,5RS)-5-{[(l,l-didecylethyl)(diindenyl)decyl]oxyb 1-[2-(7-fluoro-2-one) 1,1-dimethylethyl ester of cis-[((3RS,5RS)-5) in cis-[(3RS,5RS)-5 -{[(l,l-didecylethyl)(dimethyl)decyl]oxybu-3-hexahydropyridyl)indolyl]amino decanoate, dimethyldiethyl ester (350 mg (1.0 mmol), (7-fluoroketo-1(2H)" quinolyl)acetaldehyde was added to Me〇H [(2 ml) and CHC13 (8 ml) (see Example 2(d) for preparation) 337 200817417 (200 mg, 1.00 mmol) and the reaction was stirred at room temperature and n2 for 8 hours. Na(OAc)3BH (530 mg, 2.5 mmol) was added and the mixture was stirred at room temperature under nitrogen for 14 hr. The solvent was removed and the crude residue was purified EtOAcjjjjjjjj MS (ES+) m/z 534 (MH+). (]) cis_1-{2_[(3118,5118)-3-(aminomercapto)-5-carbyl-1-hexahydro-1^-indenyl]ethyl}-7-fluoro-2 ( 1Η)_喳咁 ketone hydrochloride 1〇 in cis-({(3RS,5RS)-5-{[(l,l-dimethylethyl)(diindenyl)decyl]oxy}-1 -[2-(7-fluoro-2-S-iso-1(2Η)-^σ-linyl)ethyl]-3-hexanitropyridinyl}indenyl)amino decanoic acid 1,1-di Hydryl ethyl ester (410 mg, 0.78 mmol) in DCM (9 mL) and MeOH (1 mL). The reaction was stirred at room temperature under nitrogen pressure for 2 hours. The reaction was concentrated under reduced pressure to give the desired compound (yield: 270 mg, 100%) MS (ES+) m/z 320 (ΜΗ+). 2〇(k) the title compound in cis_l_{2-[(3RS,5RS)-3-(aminomethyl)-5-hydroxy-1-hexahydropyridinyl]ethyl b-7-fluoro-2 ( 1H)-Indolone hydrochloride (90 mg, 〇25 mmol) in a solution of CHC13 (10 mL) and MeOH (1 mL). Hydrogen-2H-pyrido[3,2-b]4 α well aldehyde (see synthesis)

338 200817417 W02003064421, Example 15(c)) (56 mg, 0·25 mmol) and Et3N (0.2 mL, 1.5 mmol). The reaction was stirred at room temperature under N.sub.2 for 16 h then NaBH.sub.4 (12 mg, 0.32 m. After the reaction was stirred for 1 hour, the solution was removed and the crude residue was purified by chromatography on silica gel eluting with a gradient of 0-10%]\^011/0 €\4 (1%1^114011). The free base of the title compound (35 mg, 27%). MS (ES+) m/z 516, 518 (MH+). δΗ CDC13, (400MHz) 1.89-2.2 (m, 5H), 2.25-2.74(m, 4H), 2.80-3.33 (m, 3H), 4 0- 4 45

(m, 4H), 4.58 (s, 2H), 4·60-4·75 (m, 2H), 6·47 (d, 1H, /= 8.6), 7·10 (m, 1H), 7.16 ( d ·1Η J =9.6 Hz), 7.28 (s? 1H), 7.54 (dd? 1H, J=8.6, 6.2 Hz), 7.61 (d, 1H, J=9.6 Hz).,, 10 via the freedom to be obtained The title base was dissolved in 10% MeOH / DCM and 1M EtOAc (EtOAc) It is then evaporated to dryness. Example 135 6-({[((3S,4R)-4-hydroxyl]]2-[6-(decyloxy)-3-keto-pyrido[2,3_b] quinone _4(3Η) -yl]ethylidene 3_hexahydropyridinyl)indenyl]amino}methyl)-2Η" than bite [3,2-b][l,4] thioglycol _ 3(4Η)-ketone II Hydrochloride

(a) 3,6-Dihydro-1(211)_ mouth is added to the 1 liter round bottom flask equipped with a stir bar in the 1 liter round bottom flask equipped with a stir bar, 4_二崎烧339 200817417 (300 ml 1,2,3,6-tetrahydropyridine (20 g, 〇·241 mmol). To this solution was added triethylamine (0.289 mmol, 40 ml) and cooled to 〇 °C. Di-tert-butyl dicarbonate (0.265 mM, 58 g) was added portionwise to this cooled solution. The reaction mixture was concentrated to give 43 g (99%) of product. MS (ES+) m/z 127 (minus the butyl group). (8) 2-(phenylindenyl)hexahydroisoxazo[4,5-c]pyridine-5(4H)-decanoic acid ι,; ι_didecylethyl ester and 2-(phenylindenyl)hexahydroisophthalate Imidazo[5,4-c]pyrozole -6(2H)-carboxylic acid 1,1-didecylethyl ester was added to a toluene (3 ml) in a 1 liter round bottom flask equipped with a stir bar. 1,1-Dimethylethyl 3,6-dihydro-1(2H)-pyridinecarboxylate (25 g, 〇·ΐ 36 mmol) and isopropanol (100 mL). To this solution were added triethylamine (0.204 mmol, 28 mL), hydrazine-benzylhydroxylamine hydrochloride (0.204 mmol, 15 32·7 g) and sec-furaldehyde (0.682 mol, 20.5 g). ) and heated to 85 ° C. After 3 days, column chromatography gave an mixture of the isomer and (cis)-p-pallic isomer ((10% MeCN: 40% DCM: 50% hexane, 12.8 g (43%)) Yellow oil: MS (ES+) m/z 319·2 (MH+). 2〇(c) 3-(Aminomethyl)-4-predyl-l-hexanitrogen^Bitter Wei acid 1,1-II Methyl acetamidine and 4-(aminomercapto)-3-hydroxy-1-hexahydropyridinecarboxylic acid 1,1-dimethylethyl acetonate in 2-(phenylmethyl)hexahydroisoxazo[ 4,5-c]pyrazine&gt;5(4H)-remediate 1,1-dimethylethyl ester and 2-(phenylmethyl)hexahydroisoxazo[5,4-c]pyro

Add 6% Pd(OH)2/C to a mixture of -6(2H)-carboxylic acid U-dimethylethyl ester (12.8 g, 0. 04 mmol) in Et〇H 340 200817417 (100 mL) ( 2 grams). The mixture was hydrogenated at 55 psi and ambient temperature. The crude product was filtered through EtOAc (EtOAc)EtOAc.

5 MS (ES+) m/z 231.3 (MHV (d) 4-hydroxy-3-[({[(phenylmethyl)oxy)carbonyl}amino)methyl]hexahydropyridinecarboxylic acid 1,1_ Di-nonylethyl ester and 1,1-dimethylethyl 3-hydroxy-4-[({[(phenyl)))]carbonyl]amino)methyl]-1_hexahydropyridinecarboxylate 1〇 in 3-(Aminomethyl)-4-carboxy-1-hexahydroport than bite tauric acid ι,ι-dimethylethyl ester and 4-(aminomethyl)-3-hydroxy-1- Hexahydropyridyl tartrate ι,ι_didecyl ethyl ester (8.8 g '0.038 house moles) was added triethylamine (0.046 mmol, 6.4 ml) to N-benzyloxy in a mixture of methylene chloride. Carbonyloxy-pyrmineimine (〇〇35 mol, 8.8 g) and left overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (50% ethyl acetate /hexane) The product isomer mixture (11 g, 79%) is obtained. The isomer mixture is dissociated via preparative HPLC (Chiralpak AD 20u 101·6 X 250 mm column; loo./MeCN contains 0.1% different) Propylamine; 400 ml/min), 4-hydroxy-3-[({[(phenyl) 20-yloxy))]amino) fluorenyl hexahydro hydrazine, l-l-diindole Ethyl vinegar and 3-hydroxy-4-[({[(phenylphenyl)oxy)carbonyl) hydrazinyl)methyl]hexahydroport σ疋 疋 疋 1, 1, 1, 1, The structure of the isomer is confirmed by NOE (Nuclear Overhauser Effect) MS (ES+) m/z 365·5 (MH+)〇341 nr· 200817417 (e) (3S,4R)-4_yl (benzene) 1,1-dimethylethyl ester (E2) and (3R,4S)_4_hydroxyl winter [({[ (Phenylmethyl)oxy]amino}amino)indenyl] small hexahydropurine bite tarenic 1,1-dimethylethyl ester (E1) 5 will be light kesher [([[phenyl] 1,1,2-dimethylethyl ester of 1,7-amino)methyl]sodium hexahydropyridinecarboxylate via supercritical fluid chromatography (SFC) using Chiralpak AD_H 30 X 250 mm column (2 〇% isopropanol in c〇2; 70 ml/min; 30 ° C; uv 220 nm) dissociation to give E1 (first eluted isomer; 98% ee) and E2 (second Elected isomer; 1〇94% ee) The palm isomer is assumed to be (3S,4R)_4-trans-yl-3-[({[(phenyl)))oxy)carbonyl) Methyl]-1-hexahydropyridinecarboxylic acid 1,1_two Methyl ethyl ester (E2) and (3R,4S)-4-hydroxy-3-[( {[(phenylindolyl)oxy)carbonyl)amino)indenyl]-1-hexanitrogen σ The white solid of 1,1-dimercaptoethyl citrate 1). Ε2 isomer: 1H NMR (400 MHz, DMSO 〇 δ ppm 1.37 (s, 9 Η) 1·40 - ι·5 ΐ (m, 2 Η) 1.56 (d, 15 7 = 15.41 Hz, 2 H) 2.90 - 3.02 (m, 2 H) 3.06 - 3.15 (m, 1 H) 3.59 (s, 2 H) 3.80 (s, 1 H) 4 65 (s,1 H) 5.02 (s,2 H) 7.21 (t,&gt ;5.43 Hz,1 H) 7.29 - 7.40 (m,5 H)· · MS (ES+) m/z 365.5 Optical rotation: [a]d=-7.8. (sterol, 01·00, 20. 〇El Structure: 2〇1H NMR (400 MHz, DMS0-4) δ ppm 1.37 (s, 9 Η) 1.41 ^ i.5i (m&gt; l H) 1.54 (s, 2 H) 2·90 - 3.01 (m, 2 H) 3.04 - 3.14 (m,1 H) 3.57 (d, /=17.18 Hz, 1 H) 3.80 (s,1 H) 4 64 (d /=2.27 Hz,1 H) 5.02 (s,2 H) 7.21 (t, J=5.43 Hz, 1 H) 7.29 - 7·39 (m, 5 h)· MS (ES+) m/z 365.5 (MH^. ' Optical rotation: 342 200817417 [a]d=+7.5° (sterol, 01.00, 20〇C) (1) {[(3R,4R)-4-hydroxy-3-hexafluoropyridinyl]fluorenyl} phenyl decyl carboxylate 5 in (3S,4R)-4 -Carboxyl winter [({[(phenylmethyl)oxy)))amino) decylpiperidinecarboxylic acid 1,1-didecylethyl ester (E2) (500 mg, 1.37 mmol) 20 ml TFA/DCM (50%) After the reaction mixture was stirred for 1 hour, it was concentrated. The crude product was dissolved in chloroform, and treated with 500 mg of MP-carbonate resin (2·9 mmol/g) and stirred overnight. Free state of the product (370 mg, 1%) MS (ES+) m/z 265.4 (ΜΗ+) 〇(g) [((3S,4R)-4_ 经基-l-{2-[ 6_(曱oxy)-3-酉 is the same as the base bite and [2,3-b]吼. Well-4(3H)-yl]ethyl}-3-hexahydropyridinyl)methyl]amine Benzoic acid 15 phenylmethyl ester in [6-(methoxy)-3-keto oxime and [2, 3-1] 1 [1 morphine-4(311)-yl] acetaldehyde (preparation See Example 126(e)) (0.r.sup.78g, 1.27 mM). To a mixture of anhydrous DCM (10 mL) and dry MeOH (3 mL) -3-Hexahydrocarbazide] fluorenyl}phenyl phenyl carbazate 20 (〇·37 g, 1.4 μm) and a spoonful of anhydrous sodium sulfate. The reaction was disturbed overnight. The crude intermediate was treated with triethylphosphonium borohydride sodium (2·54 mmol, 0.538 g) and stirred; Column chromatography (9 〇: 1 〇: 〇.5 DCM: MeOH: EtOAc: EtOAc) ield:

343 200817417 MS (ES+) m/z 468.3 (MH+) 〇 (h) 4-{2-[(3S,4R)-3-(aminoindenyl)_4-yl-l-l-hexahydroindole. Alkyl]ethyl}-6-(decyloxy)-l,4-dipyridinium[2,3_b]pyrazine-3(2H)-one 5 in [((3S,4R)-4-) -1_{2-[6-(Methoxy)-3-oneyl-bufidine-[2,3-b]pyrazine-4(3H)-yl]ethyl}_3_hexahydropyridinyl) To a solution of EtOH, 20% Pd(OH) 2 /C (100 mg) was added to the phenyl carbazate (234 mg, 0.502 mmol). The mixture was hydrogenated overnight at 1 atmosphere of nitrogen and ambient temperature. The crude product was filtered with EtOAc EtOAc (EtOAc) MS (ES+) m/z 336 (MH+). (i) 4-{2-[(3S,4R)-3-(Aminoguanidino)-4-yl-1-1-hexahydro.咬{][(3S,4R)-3-(amine) Alkyl hydroxy hexahydropyridyl] ethyl}-6-(methoxy)_1,4-diindole. 嗖[2,3-bp than gram--3(2H)-one (170 mg, 0.508 mmol; Mn 〇 2 (156 mg, 1.52 mmol) was added to a solution of DCM:MeOH 10:1. The reaction mixture was stirred at ambient temperature and Ν2; After the product (142 mg, 2〇84%) 〇1H NMR (400 MHz, MeOD) δ ppm 1.26 «1.36 (m? 1 H) 1.68 - 1.79 (m, 2 H) 1.86 -1 〇» (m, 2 H) 2.00 - 2.11 (m, 1 H) 2.54 (d, /=7·33 Hz, 2 H) 2.75 (td, /=12.57, 5.94 Hz 2 H, 2.87 - 2.98 (m, 2 H) 3.13 (dd , J=12.88, 6.82 Hz, 1 H) 3.37 (s? 1 H) 3.90 - 3.98 (m 3.66, 3.47, 3·47 Hz, 1 H) 4.04 - 4.09 (m,3 H) 4.53 - 4.59 (m, 1 H) 4.61 - 4.68 (m '1 m ' 6.77 - 6.86 (m,1 H) 8.03 - 8.12 (m,2 H).

344 200817417 (j) Title compound 5 10 15 in 4-{2-[(3S,4R)-3-(aminomethyl)-4)-based hexamethylene hydrazide than butyl] ethyl}_6-(A Oxygen is more than [2,3-b]. It is the same as σ well-3(4H)-S (〇·〇73g, 0.22耄莫) in DCM (10ml) and MeOH (3ml) Add 3-keto-3,4-dihydro-2H to the mixture and bite (see W02004058144, Example 7(d)) (〇.〇47 g, 0.242 mmol) and sodium sulfate. After 3 days, the crude intermediate was treated with triethylphosphonium hydride (0.44 mmol, 93 mg) and stirred overnight. After column chromatography (95:5:1 DCM:MeOH:NH4OH) Obtain the product and get 24 mg

Free state base of the product (21%). The bis-HC1 salt was obtained by the addition of 4N EtOAc / EtOAc (EtOAc) 1H NMR (400 MHz, MeOD) δ ppm 1·67 - 1.78 (m, 2 Η) 1.86 -1.97 (m /=6.51 6.16 6·16, 3·16 Hz, 1 Η) 2·47 (d, J= 9.35 Hz, 1 H) 2.53 (dd, J=12.〇〇, 6 44 Hz i out 2 66 is 9 H) 2.75 (dd, “7=12.00, 6.69 Hz, 2 H) 2.81 (t, 々6.95 Hz , 2 Η) 3·37 (s 2 i 3 51 3 54, rm 2 H) 3.74 (s, 2 H) 3.89 - 3.95 (m, 1 H) 4.03 - 4.07 (m, 3 H) 4.63 (td J= 12 44 5 94 Hz 9 H) 6.81 (d, /=8.59 Hz, 1 H) 7.01 (d5 7=7.83 Hz, 1 H) 7.68 (d, ^ Hz λ H\ 〇〇7 /=8.59 Hz, 1 H ) 8.09 (s, 1 H). · Hz, 1 H) 8.07 (d, MS (ES+) m/z 512.5 (MH^. Example 136 6-({[(3S,4R)_4· 2_[6_(methoxy)_3_ steel base_吼2〇唆 and [2,3 handsome than well _4(3H)-yl]ethyl}! hexahydroindenyl) fluorenyl]amine ^ 曱Base) -2H-+ is defined as - which rushing number + form ketone diterpene acid stepping soil

345 200817417

4-{2-[(3S,4R)-3-(Aminomethyl)_4-ylamino-1-hexanol ratio 17 alkyl]ethyl}_6-(decyloxy)pyridin[2, 3-b] pyridin-3(4H)-one (prepared as described in Example 135(i); 0.072 g, 0.22 mmol) in a mixture of anhydrous DCM (10 mL) and dry MeOH (3 mL) Keto-3,4-dihydro-2Η-ϋΙλ ίο pyridine[3,2-b][l,4]Salt-6-aldehyde (synthesis see W02003087098, Example 31(e)) (0.042 g, 0.238 Millions of water and a spoonful of anhydrous sodium sulfate. The reaction was stirred at N2 for 18 hours. The crude intermediate was treated with sodium trihydrogen borohydride (0.44 mmol, 93 mg) and stirred for 2 hr. Column chromatography (95:5:1 DCM:MeOH:EtOAcHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The bis-HC1 salt was obtained by the addition of 4N EtOAc / EtOAc (EtOAc) 1H NMR (400 MHz5 MeOD) δ ppm 1.67 - 1.78 (m, 2 H) 1.91 (td5 7=6.25, 3.16 Hz, 1 H) 2.47 (d5 J=9.60 Hz, 1 H) 2.53 (dd5 /=12.00, 6.44 Hz, 1 H) 2.68 (s5 2 H) 2.75 (dd? /=12.00, 6.69 Hz, 1 Η) 2·81 (t, /=6.95 Hz, 2 H) 3.37 (s, 2 H) 3.71 (s, 2 H) 3.92 (d, J=4.29 Hz, 1 H) 20 4.03 - 4.08 (m, 3 H) 4.59 - 4.66 (m, 4 H) 6.81 (d? J=8.59 Hz, 1 H) 6.96 (d5 / =8.08 Hz 1 H) 7.26 (d, J = 7.83 Hz, 1 H) 8.06 - 8.11 (m, 2 H)· ' MS (ES+) m/z 496.5 (MH+). Example 137 4-[2-(( 3S,4R)-3-{[(2,3-Dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)amino]indolyl 4-hydroxy- 1-hexahydropyridyl)ethyl 346 200817417 yl]-6-(decyloxy)π ratio 定[2,3-b]吼口-3(4H)-one dihydrochloride

4-{2_[(3S,4R) Winter (Aminomethyl)-4-yl-1-hexafluoro-r rr-decyl] Ethyl} Winter (methoxy)pyrido[2,3-b <RTIgt;Popyl-3(4Η)-one (Synthesis see Example 135(i); 0.157 g, 0.471 mmol) in a mixture of anhydrous DCM (20 mL) and anhydrous MeOH (4 mL) Dihydro[1,4]dioxo 10 and [2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19(d)) (0.042 g, 0.471) Millol) and activated 4A molecular sieves. The reaction was stirred under N2 for 18 h. The crude intermediate was treated with sodium triethyloxyborohydride (0.942 mmol, 199 mg) and stirred for 2 hr. Column chromatography (9 〇:1 〇:〇.5 00^:]\^ 011::^114011) 15 gave the product as a yellow oil to give 24 mg (11%) of the title compound as a free base. . The bis-HC1 salt was obtained by the title compound (yield: EtOAc). 1H NMR (400 MHz, MeOD) δ ppm 2.05 - 2.16 (m, 2 H) 2.64 (d, J = 6.06 Hz, 1 H) 3.35 -3.44 (m, 5 H) 3.74 (t, J=5.94 Hz, 2 H) 3.82 (d, J=11.62 Hz, 1 H) 4.00 (d, 7=10.36 Hz, 1 H) 4.08 - 4.18 (m5 4 H) 4.22 (s, 1 H) 4.52 - 4.61 (m, 4 H) 4.63 - 4.71 (m, 3 H) 6.89 (d, 7=8.59 Hz, 1 H) 7.79 - 7.85 (m, 1 H) 8.12 - 8.21 (m, 2 H) 8.56 - 8.64 (m, 1 H). 2 〇MS (ES+) m/z 492.8 (MH+). Example 138 H2-((3S,4R)-3-{[(2,3-Dihydro[M]dioxo[2,3-c]pyridine _7-ylmercapto)amino]mercapto 4_hydroxysuccinylpyridinyl)ethyl]_7-fluoro-2(1H)-porphyrinone dihydrochloride.·· 347 200817417

5 (8)({(3S,4R)_l-[2-(7-Fluoro-2-keto)](2H)-4)-yl)ethyl]- 4-ylamino-3-hexanylpyridyl} fluorenyl) Phenyl decyl phthalate is based on {[(3R,4R)-4-carbyl-3-hexahydropyridinyl] fluorenyl) carbamic acid amide (Synthesis See Example 135(f) ; 0.72 g, 2.72 mmol; in a mixture of anhydrous DCM (10 mL) and anhydrous MeOH (2 mL), (7-ίο fluoro-2-keto Κ Η Η Η 喳 ) ) )) Example 88(a)) (0.559 g, 2.72 mmol) and activated 4A molecular sieve. The reaction was stirred at n2 for 18 hours. The crude intermediate was treated with sodium triethoxysulfon borohydride (2.72 mmol, 577 mg) and stirred for 2 hr. Column chromatography (90:10 DCM:MeOH) afforded the product as a pale yellow oil to afford 306 mg (25%) MS (ES+) m/z 454·3 (MH+). (b) l-{2-[(3S,4R)-3-(Aminoguanidino: Μ-hydroxy-1-hexahydropyridyl)ethyl}-7-fluoro-2(m)-fluorenone 20({(3S,4R)-l-[2-(7-fluoro_2-keto-1(2H)-fluorenyl)ethyl;H-hydroxy-3-hexahydropyridyl}methyl To a solution of phenyl decyl decanoate (306 mg, 675 675 mmol) in EtOH (50 mL) was added 20% Pd(OH) 2 / C (70 mg). Hydrogenation at ambient temperature for 3 hours. The crude product was filtered with EtOAc EtOAc EtOAc EtOAc EtOAc (EtOAc) 320·3 (MH.) 5 (c) H2-((3S,4R)_3-{[(2,3-Dihydro[1,4]dioxo[2,3-decapyridin-7 -ylmethyl)amino]methyl-4-hydroxy-1-hexahydropyridyl)ethyl]-7-fluoro-2(1Η)-pyridone in l-{2-[(3S,4R) -3-(Amino fluorenyl-1-ylhexahydroindole sigma) ethyl}-7-fluoro-2(1Η)_ morphinone (0·210 g, 〇·657 mmol) in anhydrous Ίο 2,3-Dihydro[M]dioxo[2,3-c]pyridine-7-aldehyde was added to a mixture of DCM (10 ml) and anhydrous MeOH (2 mL) (synthesis see W02004058144) Example 2 (c) or W003/087098, Example 19(d)) (0.109 g, 0·657 mmol) and 4 molecular sieves. The reaction was stirred under N2 for 18 hours. Sodium borohydride (m. 3 mM millimolar, I5 278 house) was treated and scrambled for 2 hours. After column chromatography (95:5:1 DCM:MeOH:NH.sub. 159 mg (52%) of the title compound was obtained as a white solid. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; NMR (400 MHz, MeOD) δ ppm 2.05.2.16 (m, 2 H) 2.59 (d5 &gt;6.32 Hz 1 m 1 99 3.30 (m, 2 H) 3.35 - 3.46 (m, 3 H) 3.57 « 3.63 (m , 3 H) 3.97 - 4.05 (m5 1 Η) ;.22T 1 m 4.49 - 4.56 (m, 5 H) 4.58 - 4.66 (m, 3 H) 6.70 (d, 7=9.35 Hz, 1 H) 7.18 (td , J=8 46 2 27 Hz? 1 H) 7.57 (dd? 7=11.125 2.02 Hz? 1 H) 7.66 (s, 1 H) 7.83 (dd/^S^ 6 19 Hz 1 HV 8.00 (d, /= 9.60 Hz, 1 H) 8.52 (s, 1 H). 5 1 MS (ES+) m/z 469.3 (MH^. 349 200817417 Example 139 6-{[({(3S,4R)-l-[2-( 7-fluoro-2-keto-1(2H)-indenyl)ethyl]-4-yl-3 - 1-0 mice given σ-yl} methyl) amino] methyl} Bian predetermined ratio σ [3,2-b] [l, 4] fathoms farming -3 (4Η) - dihydrochloride.

In the preparation of 1-{2-[(3S,4R)-3-(aminomethyl)-4-hydroxy-1-hexahydropyridinyl]ethyl 7-fluoro-2(1H)-indolone (preparation See Example 138(b); 0.066 g, 10 0.207 mmol) of 3-keto-3,4-dihydro-2H-pyridine in a mixture of anhydrous DCM (10 mL) and dry MeOH (2 mL) [3,2-b][l,4]噚耕-6-aldehyde (synthesis see WO2003087098, Example 31(e)) (0.037 g, 0.207 mmol) and 4 molecular sieves. The reaction was stirred under N2 for 18 hours. The crude intermediate was treated with sodium triethoxysulfonate (0.414 mmol, 15 mg, 88 mg) and stirred for 2h. Column chromatography (95 on 1 DCM: MeOH: EtOAc) afforded the product as a pale yellow oil to afford 24 mg (24%) of the title compound. The bis-HC1 salt was obtained by the addition of 4HCI / 1,4-diosane (0.025 ml 2〇1H NMR (400 MHz, MeOD) δ ppm 1.77 (d, J=7.58 Hz, 1 H) 1.82 (s, 1 H) 2.29 (d, 7=3.03 Hz, 2 H) 2.74 (s3 1 H) 2.88 (d, 7=6.57 Hz, 4 H) 2.98 (s, 1 H) 3.11 - 3.20 (m, 2 H) 3·93 - 4.02 (m,1 Η) 4·44 (s5 1 H) 4.60 - 4.69 ( m,1 H) 4.72 (s,3 H) 6.66 (d, "7=9.35 Hz, 1 H) 7.10 - 7.16 (m5 3 H) 7.39 - 7.47 (m, 3 H) 7.78 (dd5 7=8.59, 6.32 Hz, 1 H) 7.93 (s, 1 H). MS (ES+) m/z 482.1 (MH+). Example 140 l-[2-((3R,4S)-3-{[(2,3-dihydro) [1,4]dioxane 350 200817417 -hexahydropyridyl)ethyl [2,3-φ than 唆-7-ylindenyl)amino]methyl}_4_yl group <yl-Il_2(ih )-cardinone dihydrochloride

(8) {[(3S,4S)-4·Phenyl_3_hexahydrobenzyl]methyl}aminocarbamic acid phenylmethyl ester at 3 (3R:4S)_4_yl group_3_[({[(benzene) Methyl)oxy]arginylamino) 10 methyl b-hexahydropyridinecarboxylic acid u-didecylethyl ester (synthesis see Example 135(e)) (l gram '2.74 耄 Moel) One milliliter (50%) was added to the flask. The reaction mixture was stirred for a few hours and then concentrated. The crude product was made detectable by the addition of 6N NaOH and was taken to 10% MeOH / DCM (250 liters). The organic portion was dried over anhydrous sodium sulfate, filtered andEtOAc MS (ES+) m/z 265·4 (MH+). (b) ({(3R,4S)-H2-(7-fluoro_2-keto-1(2H)-indolyl)ethyl]-4-hydroxy-3-hexahydropyridinyl}methyl) Amino phenyl phthalate 20 in {[(3S, 4S)-4-hydroxy! Benzyl hydrazinyl]methyl}amino phenyl decanoate (0.607 g, 2.29 mmol) was added to a mixture of anhydrous DCM (20 mL) and anhydrous MeOH (4 m). Ketopropyl-1(2H)-carbolyl)acetaldehyde (prepared as described in Example 88(a)) (0·471 g, 2.29 mmol) and activated 4 Å molecular sieve. The reaction was stirred under Ν2 for an hour. The crude intermediate 351 200817417 was treated with sodium triethoxysulfonate (4.48 mmol, 971 mg) and stirred for 2 hours. Column chromatography (95:5:0.5 DCM: MeOH:EtOAc) afforded 525 mg (50%) of product. MS (ES+) m/z 454·3 (MH+). 5 (c) l-{2-[(3R,4S)-3-(Aminomercapto)-4-hydroxysuccinylpyridinyl]ethyl}-7-fluoro-2(111)-11 quinone. Lin Shutong ({(3R,4S)-1-|&gt;(7_fluoro-2-keto-1(2H)-indenyl)ethyl]-4-hydroxy-3-hexapuridinyl} Add methyl 20% methyl phenyl carbamate (525 mg, 10 1.16 mmol) to a solution of EtOH (100 mL)

Pd(OH) 2 / C (100 mg). The mixture was hydrogenated at atmospheric pressure of hydrogen at ambient temperature for 2 hours. The crude product was filtered with EtOAc EtOAc EtOAc (EtOAc) (d) the title compound is 1-{2-[(3,48)-3-(aminomethyl)-4_carboxy-1_hexamethylene]ethyl}-7-fluoro-2 ( 1H) _ 奎 口 林 酮 〇 〇 (〇 〇 〇 〇 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Dioxo[2,3_c]pyridine-7-aldehyde (for synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19(d)) (0.054 g, 0.326 mmol) and 4 molecular sieves. The reaction was spoiled under N2 for 18 hours. The crude intermediate was treated with sodium triethoxy borohydride (0.326 亳 Mo 352 200817417

Gray solid. 3 m (Ss 2 H) 2·59 1 H&gt; 3 60 (s&gt; 3 H) 3.69 (s, 2 H)

7=8.46, 2.27 Hz, 1 H) 7.52 - 7 J=9.60 Hz, 1 H) 8.46 (s? 1 H). MS (ES+) m/z 469.3 (MH+). 10 Example 141A 6_{[({( 311,43)-1-[2-(7-fluoro-2-keto-1(2H&gt;indolyl)ethyl]-4-hydroxy-3-hexahydropyridyl}methyl)amino]- }}_2H_pyridine[3,2-1?][1,4]Sakiguchi-3(411)-ketodihydrochloride

In l_{2-[(3R,4S)-3-(aminomethyl)-4-transyl hexamethylpyridyl]ethyl}-7-fluoro-2(111)-. Quaternone-3 (4) - Dihydrogen JH-pyridyl[3,2-b][l,4]indole-6-aldehyde (0.059 g, 0.332 mmol) and 4 molecular sieves. The reaction was stirred at % for 18 hours. The crude intermediate was treated with triethylphosphonium hydride (0.332 mmol, 70 mg) and stirred for 2 hr. Column chromatography (90:10:1〇〇\/1:]\^〇11::^114〇11) gave the product nipple 353 &lt; S') 200817417 color oil, obtained 87 mg (54 %) of the free base of the title compound. The bis-HC1 salt was prepared by the addition of _4N EtOAc / EtOAc (EtOAc: EtOAc) 1Η NMR (400 MHz, MeOD) δ ppm 2.〇9 (s&gt;! H) 2 16 (s? j H) 2 6〇(s?! H) 3.19 (s, 1 H) 3.34 (s,10 H ) 3.60 (s,2 H) 3.97 (s,1 H) 4.20 (s,ih) 4.35 (s,2 H) 4.73 (s,2 H) 4.80 (s,1 H) 6.76 (d, /=9.35 Hz , 1 H) 7.12 - 7.21 (m5 2 H) 7.40 (d, J=8.08 Hz, 1 H) 7.59 (dd, J=11.37, 2.02 Hz, 1 H) 7.83 (dd, /=8.72, 6.19 Hz, 1 H) 8.01 (d, 7=9.60 Hz, 1 H). MS (ES+) m/z 482.2 (MH^. Example 141B 6-{[({(3R,4S)-l_[2-(7_Fluor_ 2-keto-1(2H)-carbolinyl)ethyl]-4-hydroxy-3-hexahydropyridyl}methyl)amino]methyl b 2H-pyridine and ίο [3,2_b][l , 4]H3(4H), trifluoroacetate i_{2_[(3R,4S) winter (aminomercapto)-4-hydroxy-1-hexahydropyridyl]ethyl}_7-fluoride outlined in Example 141A -2(1H)-porphyrinone (preparation see Example 140(c)) and 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4] The product of the 6-aldehyde reaction was purified by HPLC, eluting with acetonitrile &lt;~TFA, and then the solvent was evaporated to give the title trifluoroacetate. Table 5: Examples ι 42 253, 255-256 and 259- 281 is used by the method outlined in Example 121(c)-(e) The central unit of the third butoxycarbonyl protection or the central unit for the protection of benzyloxycarbonyl 20 via the method outlined in Example 61 (bHd) is prepared from a specific starting material. 354 200817417 Example No. Test Form Structure Starting Material (Preparation See the example mentioned) 142 II-HC1 MS (ES+) m/z 465 (MH+) r^XCT0' °Χ;Ϊ&gt;&quot; via 2-{[(1-{2-[6-(methoxy) Benzyl-3-one oxazino[2,3-b]indole-4(3H)-yl]ethyl}-4-hexahydropyridyl)amino]methyl}-5,6-di Rat 1:7 vs. sigma [2,3-b]pyrimidin-7(1Η)-one (Example 125(d)) was treated with 2 equivalents of HCl to prepare 143 mono-HC1 MS (ES+) m/z 452 ( MH+) r^&gt;〇〇ir. FW° (7-fluoro-2-keto-1,5-naphthyridin-1(2Η)-yl)acetaldehyde (methyl hemiacetal) (Example 7(d)) 4-Hexidopyridylamine 1,1-dimethylethyl formate 7-keto-5,6,7,8-tetrahydrofuran and [2,3-d]pyrimidin-2-aldehyde (Example 125(c)) 144 mono-HC1 MS (ES+) m/z 481 (MH+) ro〇n〇!r xcr [6-(decyloxy)-3-ketopyridino[2,3-b] ton tillage-4(3H) -yl]acetaldehyde (Example 126(e)) {[(3R,4S)-4-hydroxy-3-hydroxypyridyl]methyl}aminobenzoic acid phenylmethyl ester 7-indole-5, 6,7,8-tetrahydrol port ratio [2,3-d]pyrimidin-2-aldehyde (Example 125(c)) 145 _HC1 MS (ES+) m/z 467 (MH+) r&lt;xr °y; W° (7-fluoro-2-keto-1(2H)-indenyl)acetaldehyde (Example 88(8)) {[(3R,4S)-4-hydroxy-3-portyrrolidinyl] Methyl}aminophenyl carbamate 7-indenyl-5,6,7,8-tetrahydro port ratio 355 200817417 and [2,3-d]pyrimidin-2-ylaldehyde (example 125 (c )) 146 mono-HC1MS (ES+) m/z 468 (MH+) w (7-fluoro-2-keto-1,5-naphthyridin-1(2H)-yl)acetaldehyde (methyl hemides) (Example 7(d)) {[(3R,4S)-4-Hydroxy-3-pyrrolidinyl]methyl}aminocarboxylic acid phenylmethyl ester 7-fluorenyl-5,6,7,8-tetra Rat 1:7 than the mouth and [2,3-d] Pyrimidine-2-aldehyde (Example 125(c)) 147 Mono-HC1 MS (ES+) m/z 486 (MH+) w° ^ (7-fluoro-2-keto-1,5-naphthyridin-1 (2H) )-yl)acetic acid (methyl hemiacetal) (Example 7(6)) {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}amino phenyl decanoate 4-chloro-7 -keto-5,6,7,8-tetrahydrogen 唆 卩 - - as 喷 - - - (Example 126(k)) 148 II-HC1MS (ES+) m/z 515/517 (MH+ Rce words\:iy, α [6-(methoxy) keto-acridino[2,3-b]indole-4(3H)-yl]acetaldehyde (example 126(e)) {[ (3R,4S)-4-hydroxy-3-hydroxypyridinyl]fluorenyl}phenylcarbamic acid phenylmethyl ester 4-rat-7-i homologous-5,6,7,8-four mouse mouth ratio唆[2,3-(1], 唆-2-acid (example 126(k)) 149 mono-HC1 MS (ES+) m/z 501/503 (MH+) FO〇r° c, (7-fluorine -2-keto-1(2H)-carbolyl)acetaldehyde (Example 88(8)) {[(3R,4S)-4-hydroxy-3-hydroxypyridyl]indenyl}amino phenyl hydrazide Ester 356 200817417 4-Q-7-mercapto-5,6,7,8-tetrachloropyrido[2,3-d]pyrimidin-2-aldehyde (Example 126(k)) 150 II_HC1 MS (ES+ m/z 502/503 (MH+) &quot;C〇r. c, (7-fluoro-2-keto-1,5-naphthyridin-1(2H)-yl)acetaldehyde (methylheptaic acid) (Example 7(d)) {[(3R,4S)- 4-hydroxy-3-hydroxypyridyl]methyl}aminobenzoic acid phenylmethyl ester 4-gas-7-@同基-5,6,7,8-tetrazolopyridin[2,3-d Pyrimidine-2-aldehyde (Example 126(k)) 151 mono-HC1 MS (ES+) m/z 465 (MH+) 0 \ (7-fluoro-2-keto-1(2H)-indenyl) Aldehyde (Example 88(8)) 4-hexahydroexo b dimethylamino carbamic acid 1,1-dimethylethyl ester 4-methyl-7-keto-5,6,7,8-tetrapyridinium[2, 3-d]pyrimidine-2-aldehyde (Example 127(e)) 152 bis-HC1 MS (ES+) m/z 511 (MH+). . , [6-(methylidyl)-3-mercaptopurine [2,3-b] ton-4(3H)-yl]acetaldehyde (Example 126(e)) {[(3R,4S) -4-hydroxy-3-pyrrolidinyl]hydrazino}phenyl phenyl carbazate 4-(methoxy)-7-keto-5,6,7,8-tetrahydropyridin[2 , 3-d]pyrimidine-2-aldehyde (Example 128(b)) 153 Mono-HC1 MS (ES+) m/z 481 (MH+) ηΛ u. (7-Mexium-2-flavored)-based-1(2Η)-ϋ奎口林基)acetaldehyde (Example 88(8)) 4-hexahydroindoletriamine decanoic acid 1,1-didecylethyl ester 4 -(methoxy)-7-ketoyl 357 200817417 -5,6,7,8-tetrahydroindeno[2,3-d]pyrimidin-2-aldehyde (Example 128(b)) - 154 Single - HC1 MS (ES+) m/z 467 (MH+) W° ° via 2-[({l-[2-(7-fluoro-2-keto-1(2H)-carboyl)ethyl) ]-4-hexaazin-11-based}amino)methyl]-4-(methoxy)-5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one (example) 153) It was prepared by treatment with 33% ΗΒι in AcOH. 155 mono-fumarate MS (ES+) m/z 470 (MH+) rOr^:] Xx}/ /〇[7-say-4-(methoxy)-2-keto-1(2H)- Porphyrinyl]acetaldehyde (Example 132(b)) 4-hexahydropyridylamino decanoic acid 1,1-dimethylethyl 6,7-dihydro[1,4]dioxo[2, 3-c] 嗒 各 aldehyde 156 bis-HC1MS (ES+) m/z 455 (MH+) FxxJj° N OH Trifluoromethanesulfonic acid 1-{2-[4-((2,3·dihydro[ 1,4]dioxo[2,3-decapyridin-7-ylfluorenyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)piperidine] Ethyl 7-fluoro-2-keto-1,2-dihydro-4-porphyrin (Example 130(f)) is deuterated to give (2,3-dihydro[1,4]dioxane And [2,3-c]pyridin-7-ylmethyl){1-[2-(7-fluoro-4-hydroxy-2-keto-1(2H)-indolyl)ethyl]-4 - Hexazapine. The 1,1-didecylethyl decanoate was subsequently protected by 4MHC1/1,4-dioxane. 358 200817417 157 free-form base MS (ES+) m/z482 (MH+) Ηχτα^/FO〇r° (7-fluoro-2·keto-1(2H)-fluorenyl) acetaldehyde (Example 88(a) Cis-[((3RS,5RS)-5-{[(U-Didecylethyl)(dimethyl)decyl]oxy}-3-hexahydropyridinyl)methyl]carbamic acid 1 , 1-dimercaptoethyl 3-keto-3,4-dihydro-2H-pyrido P,2-b][l,4]indole-6-aldehyde (synthesis see W02003087098, example 31 (e )) 158 free-form base MS (ES+) m/z 498 (MH+) H0XT«xc!t° (7-fluoro-2-keto-1(2H)-fluorenyl) acetaldehyde (example 88(8)) cis- [((3RS,5RS)-5-{[(l,l-dimethylethyl)(dimethyl)decyl]oxy}-3-hexahydropyridyl)methyl]carbamic acid U- Dimethyl ethyl ester 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]thratic-6-aldehyde (synthesis see W02004058144, example 7(d)) 159 Di-HC1 MS (ES+) m/z 469 (MH+) Ηχτ〇ο〇W° (7-fluoro-2-keto-1(2H)-carboline)acetic acid (Example 88(a)) cis- [((3RS,5RS)-5-{[(l,l-dimethylethyl)(dimethyl)hydrazino]oxy}-3-hexahydroindole.]]))]]]]]] 1,1-dimethylethyl 2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde See W02004058144, Example 359 200817417 2(c) or W003/087098, Example 19(6)) 160 A and B di-HC1 (A) and benzoate (B) MS (ES+) m/z 482 (MH+) H /? HN 〇VW〇XX/[6-(decyloxy)-3-03⁄4 base^ bite and [2,3-b]吼耕-4(3H)-yl]acetaldehyde (Example 126(e)) [ (3R,4S) 1,1-dimethylethyl hydroxy-4-hexahydropyridinyl]carbamate (W02004058144, Example 5(c), 川页-(3-Pyridyl-hexanitropyridinium 4-yl)-amino decanoic acid tert-butyl ester to palm isomer 1) 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]4 Plough-6-aldehyde (synthesis see W02003087098, example 31(e)) 161 single_compromised MS (ES+) m/z 443 (MH+) A w NN (7-fluoro-2-ketopyridino[2,3- b] 咐耕-1(2H)-yl)acetaldehyde (mercapto hemiacetal) (Example 35(e)) 4-hexahydroindolyl decanoic acid 1,1-dimethylethyl ester [1 , 3] indolo[5,4-c]acridin-6-aldehyde (synthesis see W02004058144, example 61) 162 single_HC1 MS (ES+) m/z 455 (MH+) \Nxr NN [7-(A Oxy)-2-ketopyrido[2,3-b]indole-1(2H)-yl]acetaldehyde (mercapto hemiacetal) (Example 51A(b)) 4-Hexidopyridylamine 1,1-dimethylethyl sulfonate [1,3] Thio[5,4-·pyridinyl 360 200817417 -6-acid (synthesis see W02004058144, Example 61) 163 Di-HC1 MS (ES+) m/z 465 (MH+) via l-[2-(4-amine Small hexahydroacridinyl)ethyl]-7-fluoro-2(1H)-oxazinone dihydrochloride (Example 44C(g)) was treated with a solution of NaOMe in MeOH and then 3- steel -3-3?4---nitro-2Η-ϋ ratio α弁[3,2-b][l,4]噚耕-6-aldehyde (synthesis see W02003087098, example 31(e)) reductive alkyl Chemical. 164 A and B mono-HC1 (A) and mono-fumarate (B) MS (ES+) m/z 451 (MH+) xw X〇r. , [7-(decyloxy)-2-ketoacyl[2,3-b]indole-1(2H)-yl]acetaldehyde (methyl hemiacetal) (Example 51A(b)) 1,1-Dimethylethyl 4-hexahydropyridylcarbamate 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-aldehyde (Synthesis see W02004058144, Example 126 ( e)) 165 di-HC1 MS (ES+) m/z 481 (MH+) w, via 1-[2-(4-amino-1-hexahydropyridyl)ethyl]-7-fluoro-2 ( 1Η)-4: σΙσlinone dihydrochloride (Example 44C(g)) was treated with a solution of NaOMe in MeOH and then 3-keto-3,4-dihydro-2H-pyridine[3,2 -b][l,4]Thioin-6-aldehyde (synthesis see W02004058144, Example 7(d)) Reductive alkylation.

361 200817417 166 Di-HC1 MS (ES+) m/z 469 (MH+) XO&quot; (7-fluoro-2-keto-1(2H)-indenyl) acetaldehyde (Example 34(c)) · [ (3R,4S)-3-hydroxy-4-hexahydropyridinyl]amino decanoic acid 1,1-dimethylethyl ester (W02004058144, Example 5(c), cis-(3· borrowing: yl-hexaquinone) Pyridyl-4-yl)-carbamic acid tert-butyl ester to palm isomer 1) 3-keto-3,4-dihydro-2H-pyrido P,2-b][l,4;K tillage -6-aldehyde (synthesis see W02003087098, example 31(e)) 167 mono-fumarate MS (ES+) m/z 469 (MH+) HN N-^ , ^ °ti:r [6-(methoxy --3-ketopyrido[2,3-b]indole-4(3H)-yl]acetaldehyde (Example 126(e)) [(3R,4S)-3-hydroxy-4-hexahydropyridine 1,1-dimethylethyl amide amide (W02004058144, Example 5(c), cis-(3-carbo-hexahydropyridin-4-yl)-carbamic acid tert-butyl ester Pair of palmomers 1) 2,3-Dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, Example 2 (c) or W003/087098, examples 19(d)) 168A and B di-HC1 (A) and free base (B) MS (ES+) m/z (7-fluoro-2-keto-1(2H)-fluorenyl) acetaldehyde (Example 34(C)) [(3R,4S)-3-hydroxy-4-hexa-36 2 200817417 2(c) or W003/087098, Example 19(6)) 171 - bis-HC1 MS (ES+) m/z 452 (MH+) XO0, via 1-[2-(4-aminopyrrolidine) Ethyl]-7-fluoro-2(1H)-4 oxalicone dihydrochloride (Example 44C(g)) was treated with NaOMe in MeOH and then 2,3-dihydro[1] , 4] dioxo and [2,3-c] ratio. D--7-acid (synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19 (d)) Reductive alkylation 172 mono-HC1 MS (ES+) m/z 467 (MH+) [6-( Methoxy)-3-keto 11 is more than a bite [2,3-b]indole-4(3H)-yl]acetaldehyde (Example 126(e)) [(3R,4S)-3-hydroxy- 1,1-Dimercaptoethyl ester of 4-hexahydropyridyl]amino decanoate (W02004058144, Example 5(c), cis-(3-amino-hexahydron-pyridin-4-yl)-amino group Tributyl acrylate for palmate isomer 1) 3,4-dihydro-2H-pyrano[2,3-c]pyridine aldehyde (synthesis see W02004058144, example 126(e)) 173 mono-HC1 MS (ES+) m/z 470 (MH+) ^oa&gt; XX?. 0 [7-(Methoxy)-5-oxy-2-keto-1,5-naphthyridin-1(2H)-yl]acetaldehyde, similar to (7-fluoro-5-oxy-2 -keto-1,5-naphthyridin-1(2H)-yl]acetaldehyde (mercapto hemiacetal) (Example 96(c)) from 7-(decyloxy)-1,5-naphthyridine- 2(1H)-ketone

364 200817417 - - (Example 11(c)) 4_Hexidopyridylaminocarbamic acid 1,1-dimethylethyl [1,3]indolo[5,4-c]acridin-6-aldehyde (W02004058144, Example 61) 174 Single-HC1 MS (ES+) m/z 497 _+) rxx;r ,; 0~[7-(Methoxy)-5-lacto-2-ylidene-1,5-naphthyridin-1(2H)-yl]acetaldehyde, similar to (7-fluoro-5-oxyl- 2-keto-1,5-naphthyridin-1(2H)-yl]acetaldehyde (methyl hemiacetal) (Example 96(c)) from 7-(methoxy)-1,5-naphthyridine -2(1Η)-ketone (Example 11(c)) 4-hexahydroindole-l-ylaminocarbamate 1,1-didecylethyl ester 3-tanning-3,4-di-mo-211-perpenopyridine And [3,2-b][l,4]thorbic-6-aldehyde (W02004058144, Example 7(6)) 175 II-HC1 MS (ES+) m/z 470 (MH+) HN NN σΗ w [6-(曱氧Benzyl-3-ketopyrido[2,3-b]indole-4(3H)-yl]acetaldehyde (Example 126(e)) [(3R,4S)-3-hydroxy-4-hexaquinone Pyridyl]urethane U-dimethylethyl ester (W02004058144, Example 5(c), cis-(3-carbyl-hexamethylpyridin-4-yl)-carbamic acid tert-butyl ester Isomer 1) 6,7-Dihydro[1,4]dioxo[2,3-c]indole-3-acid (Synthesis see Example 6(e)) 365 200817417 176 Single-HC1 MS ( ES+) m/z 467 (MH+) cXr&gt;, 〇H [7-(methoxy)-2-keto-1(2H)-indenyl]acetaldehyde (Example 1(d)) -[( 3R,4S)-3-hydroxy-4-hexahydropyridinyl]urethane U-didecyl ethyl ester (W02004058144, Example 5(c), cis-(3-hydroxy-hexafluoropyridyl) Pyridine-4-yl)-carbamic acid tert-butyl ester to palm isomer 1) 2,3-dihydro[1,4]dioxo[2,3-(^]0 to 0--7 - (Synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19(6)) 177 Mono-HC1 MS (ES+) m/z 443 (MH+) °xyx. (7-fluoro-3-ketopyridine) 2,3-b;h than tillage-4(3H)-yl]acetaldehyde (from 7-fluoropyrido[2,3-b] tonnes of tillage-3 (4H&gt; ketone, (from Example 35(c) Byproducts)) By way of an overview of Example 35(d)-(e) 4-Dihydropyridylaminocarbamic acid 1,1-dimethylethyl ester [1,3], thiazepine [5,4-c Pyridine-6-aldehyde (W02004058144, Example 61) 178 Di-HC1 MS (ES+) m/z 456 (MH+), OH χα 7-Ga-2-indole-1(2H)- porphyrinyl] Aldehyde (Example 34(C)) [(3R,4S)-3-Hydroxy-4-hexahydropyridinyl]amino decanoic acid 1,1-didecylethyl ester (W02004058144, Example 366 200817417 - - 5 (c ), Chuan Page - (3-carbyl • hexaazinopyridinyl), tert-butyl carbazate, palmo isomer 1) 2,3-dihydro[1,4]dioxan[ 2,3-c]pyridine-7-aldehyde (for synthesis see W02004058144, Example 2(c) or W003/087098, Example 19(6)) 179 Mono-HC1 MS (ES+) m/z 469 (MH+) rQ-OQQ °XX7° 0H [3-(Methoxy)-6-keto oxime and [2,3-b; h than tillage-5(6H)-yl] acetaldehyde (Example 126(e)) [(3R, 4S Tris-hydroxy-4-hexahydropyridyl]amino decanoic acid 1,1-dimethylethyl ester (W02004058144, Example 5(c), cis-(3-amino-hexahydropyranyl) )-T-butyl carbamic acid to palm isomer 1) 2,3-Dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19(6)) 180 mono-HC1 MS (ES+) m/z 457 (MH+) ^900 r1 FX〇r (3,7-difluoro-2-keto-1(2H)- Mercapto[]acetaldehyde (from 3-fluoroaniline sequentially reacted with n-BuLi and 2-fluoro-3-(methoxy)-2-propionate B to give (2Z)-2-fluoro -N-(3-Phenylphenyl)-3-(methoxy)-2-propenylamine. It was subsequently treated with 70% H2SO4 to give 3,7-difluoro-2(1H)-fluorenone. This is followed by sequential treatment with sodium hydride and allylic 367 200817417 iodine to give 3,7-dioxa-1 -(2-propion-1-yl)-2(1Η)-fluorenone, followed by Os 〇4/NaI04 treatment. (1,3-Dihydro[1,4]dioxo[2,3-c]pyridin-7-ylmethyl)4-hexa-pyridylaminocarbamic acid 1,1-dimethylethyl ester ( For the synthesis see WO2004/058144 Example 99(10) Method coupling similar to Example 7 (eHf) 181 Mono-HC1 MS (ES+) m/z 466 (MH+) o~ [7-(methyllacyl)-5-lact-2- Steel-based-1,5-naphthyridin-1(2H)-yl]acetaldehyde, similar to (7-fluoro-5-oxo-2-keto-1,5-naphthyridin-1(2H)-yl Acetaldehyde (methyl hemiacetal) (Example 96(c)) from 7-(methoxy)-1,5-nathene-2(111)-oxime (Example 11(c)) 4-Six Hydrogen pyridylamine decanoic acid 1,1-dimethylethyl 2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, Example 2 (c) or WO03/087098, Example 19(6)) 182 Mono-HC1 MS (ES+) m/z 479 (MH+) plus: r. w, 1-[2-(4-amino-1-hexamethyl) ]-7-(methoxy)-1,5-tea sigma-2(1H)-S homodihydrochloride (Example 16(b)) 3 - fluorenyl-3,4-diaza- 2Η- 口 啶 并 [3,2 七][1,4]畤耕-6-carboxylic acid (W02004058144, -!tf***i 368 200817417 - - Example 65) with HATU (0-(7-nitrogen) Heterobenzotriazol-1-yl)-N,N,N',N,-tetramethyl-indole-hexafluorocartrate And triethylamine coupling 183 free state test MS (ES+) m/z 511 (MH+) °w [7-gas-8-(1-3⁄4yl-1-methylethyl)-2-keto-1, 5-naphthyridine-2(1H)-yl]acetaldehyde (from Pd(OAc)2, dppf and carbon monoxide gas (at atmospheric pressure) 8-bromo-7-fluoro-2-(methoxy)- L,5-^^ (W02004058144, Example 53(g)) is carbonylated to give 3-fluoro-6-(decyloxy)-1,5-naphthalene. Methyl 4-carboxylic acid. Treatment with magnesium bromide affords 2-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-2-propanol. Treatment with HBr affords 7-fluoro- 8-(1-Controll-1-mercaptoethyl)-1,5-naphthyridin-2(1H)-one and subsequent addition of allyl hydrazine and K2C03 with Pd(PPh3)4 in diphenylbenzene Heating gave 7-fluoro-8-(1-hydroxy benzhydrylethyl)-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one. It is converted to the desired intermediate by the action of 0s04 and Nal〇4. 4- hexahydropyridylamino decanoic acid 1,1-didecyl ethyl ester 3-keto-3,4-dihydro-2H-pyridyl 369 200817417 - * ' pyridine [3,2 VII] [1, 4] 畤耕-6-aldehyde (synthesis see W02003087098) Example 31(e)) 184 Tri-HC1 MS (ES+) m/z 483 (MH+) fT〇/° 4^0;] 4-Amino-1, 4-Six squid 11-dicarboxylic acid 1-(1,1-dimethylethyl) 4-decyl ester (commercially available) with 2,3-diindole [1,4]dioxo[ 2,3-c]pyridine-7. aldehyde (synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19 (d)) gives 4-[(2,3-dihydro[1,4] Dioxaindolo[2,3-c]pyridin-7-yl)methyl]amino]-1,4-hexanitroindole ratio 11-dicarboxylic acid 1-(1,1-dimethylethyl ester) 4-methyl ester. After removal of the protection with TFA, 4-[(2,3-dihydro[1,4]dioxo][2,3-c]pyridin-7-yl)methyl]amine ]-4·hexahydropyridyl phthalate, followed by 4-[(2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-yl)methyl]amine Base&gt;4-hexahydroindole methyl ester with [6-(methoxy)-3-ketoindole 定[2,3-b]咕耕-4(3Η)-yl]acetaldehyde Reductive alkylation of (Example 126(e)) gives 4-[(2,3-dihydro[1,4]dioxo[2,3-c] ratio唆_7_yl) fluorenyl]amino]-1-{2-[6-(methoxy)-3- keto 咐 定 并 [2,3-b] ton till 4 (3 Η)-based ] B?μ· 370 200817417 base}-4-hexahydropyridinecarboxylate methyl ester. The ester unit is reduced with NaBH4 to give the product. 185 A and B di-HC1 (A) and benzoate (B) MS ( ES+) m/z 469 (MH+) W. (7-fluoro-2-keto-1(2H)-indenyl)acetaldehyde (Example 88(8)) 4-[(2,3-dihydro[1,4 Dioxaindolo[2,3-c]pyridin-7-yl)methyl]amino]-4- hexafluoroantimonate (Example 184) Coupling 186 free base by the procedure outlined in Example 184 MS (ES+) m/z 458 (MH+) °t!7F [7-(fluoro)-2-keto-1,5-naphthyridin-1(2H)-yl]acetaldehyde (methyl hemiacetal) (Example 7(d)) [(cis)-3-Axo-4-hexahydro-b-blocking]Phenyl decyl carbamate (p. palmomer 1 W02003064421, Example 6(b)) 2,3 -Dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19(d)) 187 mono-phenylhydrazine Acid salt MS (ES+) m/z 470 (MH+) [3-(methoxy)-6-keto acridine [2,3-b] ton of -5-(6H)-yl] acetaldehyde (example) 94(m)) [(3R,4S)-3-hydroxyindole hexahydropyridyl]amine 1,1-dimethylethyl acid (W02004058144, Example 5(c), cis-(3-hydroxy-4-hexahydropyridyl) amino decanoic acid tert-butyl ester to palm isomer 1) 371 200817417 6,7-dioxa[1,4]dioxo[2,3-c]indole-3-aldehyde (Example 6(e)) 188 mono-HC1 MS (ES+) m/z 435 (MH+) 1 W (7-methyl-2-ketopyridino[2,3-bp ratio tillage-1(2H)-yl]-ethylidene (from 6-amino-5-succinyl-picoquinone at 10 Hydrogenation in the presence of %Pd/C syrup gives 5-methyl-2,3-pyridinediamine which is subsequently reacted with dihydroxyacetic acid monohydrate to give 7-mercaptopyridine [2,3-b] -2(1H)-one. Alkylation with allyl iodide in DMF using potassium carbonate as the test and the resulting 7-methyl-1-(2-propen-1-yl)pyrido[2,3-b] -2(1H)-ketone dissociated in the presence of ozone to give the product) 4_hexahydroindolyl decanoic acid 1,1-dimethylethyl ester 3,4-dihydro-2H-pyrano[^ . -(^ than biting ^-acid ^ synthesis see W02004058144, example 126 (e)) 189 mono-HC1 MS (ES+) m/z 437 (MH+) W (7-mercapto-2-ketopyridino[2, 3 7] Xiang Geng-1 (2H)-yl]acetaldehyde (Example 188) 4-hexahydropyridylamine decanoic acid 1,1-dimethylethyl 2,3-dihydro[1,4] Dioxo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19(6)), / -if*», Ο 372 200817417 190 Single-HC1 MS (ES+) m/z 482 (MH+) l-{2-[(3R,4S)-4-Amino-3-3⁄4yl-1-hexazone^~17]-ethyl}-7- -1,5-catechol-2(1H)-one dihydrochloride (Example 41(b)) was treated with sodium ethoxide to form 1-{2-[(3R,4S)-4-amino-3. Alkyl-1-hexanitrogen to 11-amino]-7-(ethoxy)-1,5-naphthyridin-2(m).one, which is subsequently outlined by way of example &lt;c) , 3-Dihydro[1,4]dioxo[2,3-c]acridin-7-acid (synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19(d)) Reducibility Alkylation. 191 mono-HC1 MS (ES+) m/z 484 (MH+) H〇1 0 w l-{2-[(3R,4S)-4-amino-3-ylyl-1-pyrazole 1:1 Ratio σ determinate] ethyl}-7-gas-1,5-catechol-2(1Η)-one dihydrochloride (Example 41(b)) is treated with sodium thioantate to form l-{2-[ (3R, 4S)-4-amino-3-carbyl-1-hexanitrogen 17 ratio. Alkyl]ethyl}-7-(methylthio)-1,5-naphthyridin-2(1H)-one, which is subsequently outlined by Example 4(c) with 2,3-dihydro[1,4] Dioxyindolo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19 (d)) Reductive alkylation. 192 Tri-HC1 MS (ES+) m/z (7-fluoro-2-keto-1(2H)-indenyl) acetaldehyde

373 200817417 437 (MH+) Square V» (Example 34(c)) 4-[(2,3-Dihydro[1,4]dioxo[2,3-c]pyridin-7-yl)methyl Methylamino]-4-hexahydropyridinecarboxylate (Example 184) Coupling 193 mono-fumarate MS (ES+) m/z 457 (MH+) xaF i (7-fluoro-) 2-keto-1(2H)-indolyl)acetaldehyde (Example 34(c)) [(3R,4S)-3-hydroxy-4-hexapyridinyl]carbamic acid 1,1-di Methyl ethyl ester (synthesis see W02004058144, Example 5(c) 'cis-(3-3⁄4 -4- hexaazinopyridyl) amino decanoic acid tert-butyl ester to palm isomer 1) 6J-dihydro[ 1,4] dioxin and [2,3-c] ΰ -3- -3- disk (Cheng 6 (e)) 194 single-HC1 MS (ES+) m/z 441 (MH+) XaF (7-fluorine 3-ketopyrido[2,3-7]-cultivated-4(3Η)-yl]acetaldehyde (from the method outlined in Example 35(d)-(e) was obtained from 7-gas 11 唆[2 , 3-b] ton of cultivable-3(4H)-ketone (by-product from Example 35(c))) 1,1-dimethylethyl 2,3-dihydroethyl hexahydropyridylcarbamate [1,4]dioxo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, example 2 (c) or W003/087098, example 19 (6)) 195 free state test ((7-fluoro-2) -keto-1,5-naphthyridine 374 200 817417 MS (ES+) m/z 458 (MH+) xcr. -1(2H)-yl)acetaldehyde (methyl hemiacetal) (Example 7(d)) [(cis)-3-fluoro-4-hexa Phenylpyridyl]phenylcarbamic acid phenylmethyl ester (p-isomer 1 W02003064421, Example 6(b)) 2,3-dihydro[1,4]dioxo[2,3-c]pyridine- 7-aldehyde (synthesis see W02004058144, example 2 (c) or W003/087098, example 19(6)) 196 mono-trifluoroacetate MS (ES+) m/z 459 (MH+) w N_N ((7-fluorobutanyl- 1,5-naphthyridine-1(2H)-yl)acetaldehyde (methyl hemiacetal) (Example 7(d)) [(cis)_3_gas_4-six squirrel base] benzoic acid benzene Methyl ester (p-isomer 1 W02003064421, Example 6(b)) 6,7-dihydro[1,4]dioxo[2,3-c]indole aldehyde (Example 6(e) 197 free state test MS (ES+) m/z 459 (MH+) rdqX] fXj〇t° ((7-fluoro-2-keto-1,5-naphthyridin-1(2H)-yl)acetaldehyde ( Methyl hemiacetal) (Example 7(d)) [(cis)-3-fluoro-4-hexahydropyridyl]amino decanoic acid phenyl oxime (E2 isomer can be similar to Example 6 ( The method of b) is obtained from [(川页)-3-fluoro-4-mercaptohexanitropyridinyl]aminoglycolate carbazate ethyl ester to palmomer 2 (W02003064421, example 375 200817417 - - 6 (a)) 6, 7-Dihydro[1,4]dioxo[2,3-&lt;3]^σ well-3-disk (Cheng 6(e)) 198 A and B II-HC1 (A) and benzoquinone Acid salt (B) MS (ES+) m/z 467 (MH+) 0^X0 [6-(decyloxy)-3-ketopyrido[2,3-b]indole-4(3H)-yl Acetaldehyde (Example 126(e)) [(3R)-3_Hexahydropyridylfluorenyl]phenyl phenyl carbamate 2,3-dihydro[1,4]dioxan[2,3 -c]pyridine-7-aldehyde (synthesis see W02004058144, example 2(c) or W003/087098, example 19(6)) 199A and B di-HC1 (A) and benzoate (B) MS (ES+) m/z 468 (MH+) C^XO ^°xxy° [6-(methoxyi)-3-amine ratio. And [2,3-b] ton of cultivable-4(3H)-yl] acetaldehyde (Example 126(e)) [(3R)-3-hexahydropyridyl fluorenyl] phenyl formate 6,7-Dihydro[1,4]dioxo[2,3-c]indole-3-aldehyde (Example 6(e)) 200A and B di-HC1 (A) and benzoate (9) MS (ES+) m/z 468 (MH+) Kf° , iX: r. [6-(Methoxy)-3-ketoacridino[2,3-7]indole-4(3H)-yl]acetaldehyde (Example 126(e)) [(3R)-3-pyrrolidine Phenylmethylamine phenyl phthalate (W02006002047 Preparation 23(b)) 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4] -6-aldehyde (W02003087098, Example 31(e)) 201 free base [6-(methoxy) keto acridine 376 200817417 MS (ES+) m/z 500/502 (MH+) H /9 and [ 2,3-b] morphine-4(3H)-yl]acetaldehyde (Example 126(e)) [(3R)-3-pyrrolidinylfluorenyl] phenyl methyl carbamate (W02006002047 Preparation 23 ( b)) 7-Chloro-3-branched 1-yl-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-aldehyde (W02003064421, Example 15(c) 202 di-HC1 MS (ES+) m/z 482 (MH+) [6-(decyloxy)-3-ketopyrido[2,3-b]indole-4(3H)-yl] acetaldehyde (Example 126(e)). [(3R)-3-Pyrrolidinylmethyl] phenyl carbamate (W02006002047 Preparation 23(b)) 3-keto-3,4-dihydro-2H- Pyrido[3,2-b][l,4]thratic-6-aldehyde (W02004058144, Example 7(d)) 203 free state test MS (ES+) m/z 482 (MH+) ?&quot;Ύ° άΝΗ HN-^ 乂ΧΧΓ [6-(Methoxy)-3-keto oxime][2,3-7]咕耕-4(3H)-yl] Acetaldehyde (Example 126(e)) {[(3R,4S)-4-Hydroxy-3-pyrrolidinyl]methyl}aminocarbamic acid phenyl hydrazone 3-keto-3,4-dihydro- 2H-pyrido[3,2-b][l,4]indole-6-aldehyde (W02003087098, Example 31(8)) 204 Di-HC1 MS (ES+) m/z (7-fluoro-2-keto-1 , 5-naphthyridin-1(2H)-yl)acetaldehyde (mercapto-half 377 200817417 453 (MH+) acetal) (Example 7(d)) [(3R)-3-pyrrolidinylmethyl]amine Phenyl decyl phthalate (W02006002047 Preparation 23(b)) 3-keto-3,4-dihydro-2H-pyrido[3,2-7][1,4]indole-6-aldehyde (W02003087098, Example 31(e)) 205 Di-HC1 MS w^° [7-(Methoxy)-2-keto (ES+) m/z /ν^Γ&gt; un J \ A&gt;-O -1,8- Naphthyridine-1(2H)-yl]acetaldehyde 481 (MH+) /0Oc7° (from 7-(methoxy)-1-(2-propen-1-yl)-1,8-naphthalene according to Example 17(8) Pyridin-2(1H)-one treated with OSO4/N3IO4) {[(3R,4S)-4-Hydroxy-3-pyrrolidinyl]methyl}carbamic acid phenylmethyl ester 3-keto-3,4 - dihydro-2H-pyridoindole, 2-7][1,4]indole-6-aldehyde (W02003087098, Example 31(e)) 206 free base 0 (7-fluoro-2-keto-1) 2H)-喳咁MS (ES+) HNK group) acetaldehyde (Example 88(8)) m/z H [(3R)-3- Rhyrylmethyl] 486/488 (phenylmethyl carbazide _+) N w° (W02006002047 Preparation 23(b)) 7-Chloro-3-keto-3,4-diindole-2H- Pyrido[3,2-b][l,4]indole-6-aldehyde (W02003064421, Example 15(c)) 207 Di-HC1 MS (7-fluoro-2-ketoporphyrin 378 200817417 (ES+) m/z 469 (MH+) H / w group) acetaldehyde (Example 88(a)) [(3R)pyrrolidinylmethyl] phenyl decyl carbamate (W02006002047 Preparation 23(b)) 6-ketone Base-6,7-dihydro-5H-indole and [3,4-b][l,4]titer-3-aldehyde (W02003087098, example 312(6)) 208 di-HC1 MS (ES+) m/z 469 (MH+) w (7-fluoro-2-keto-1(2H)-carbolyl)acetaldehyde (Example 34(c)) {[(3R,4S)-4-hydroxy-3-pyrrolidinyl) Methyl}phenyl phenylcarbamate 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-aldehyde (W02003087098, Example 31 (e)) 209 Di-HC1 MS (ES+) m/z 482 (MH+) Η P HO, plant g W-^ Q [6-(曱oxy)-3-酉 is the same as the mouth and mouth [2] , 3-b] ton of cultivable-4(3H)-yl] acetaldehyde (example 126(e)) {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]fluorenyl} carbamic acid phenyl Methyl 2-keto-2,3-dioxin-1H-pyrido[3,4-b][l,4]畤耕-7- (W02004002992, Example 22(1)) 210 free-form base MS (ES+) m/z 468 (MH+) 3-ketopyrido[2,3-b;h than tillage-4(3H)acetaldehyde (from 2 mice) -3- stone Xiaoji ^ ratio. It is treated with (8) aminoacetaldehyde dimethyl acetal and potassium carbonate to form 379 200817417 4! Leaf A7 αχ N-[2,2-bis(decyloxy)ethyl]-3-stone Schottyl-2-fluorene 17 fixed amine. (b) Reduction of N-[2,2-bis(decyloxy)ethyl]-3-indolyl-2-guanidine amine by catalytic hydrogenation to give N2_[2,2-bis(decyloxy)B Base]-3-stone Schottylamine. (c) N2-[2,2-bis(methoxy)ethyl]-3-indolyl-2-4 (: sigma-amine is alkylated with ethyl bromoacetate or potassium carbonate to give hydrazine-( 2-{[2,2-bis(methoxy)ethyl]aminopyr-3-pyridyl)glycine ethyl ester. (6) Treatment of N-(2-{[2,2) with potassium carbonate at 110 °C - ethyl bis(methoxy)ethyl]amino}-3-pyridyl)glycine, followed by oxidation with manganese dioxide). {[(3R, 4S)-4-hydroxy-3-. Phenyryl]methyl}aminobenzoic acid phenylmethyl 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]thratic-6-aldehyde ( W02004058144, Example 7(d)) 211 free-form base MS (ES+) m/z 498 (MH+) s^fu άΝΗ ΗΝ-^ HO J [6-(methoxy)-3-keto-based bite and P, 3-b] cultivative-4(3H)-yl]acetaldehyde (example 126(e)) {[(3R,4R)-4-hydroxy-3-pyrrolidinyl]methyl}amino decanoic acid phenyl Methyl ester (see Example 215) 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]thin-6-aldehyde (W02004058144, real

380 200817417 Example 7(d)) 212 Ηα MS (ES+) m/z 481 (MH+) ,^ w° [7-(Methoxy)-2-keto-1(2H)-fluorenyl Acetaldehyde (Preparation C) {[(3R,4S)-4-Hydroxy-3-pyrrolidinyl]methyl}aminocarboxylic acid phenylmethyl ester 3·keto-3,4-dihydro-2H-pyridine And [3,2-b][l,4H tillage-6-aldehyde (W02003087098, example 31(e)) 213 free state test MS (ES+) m/z 498 (MH+) plant B nJ f [6-(a Oxy)-3-ketopyrido[2,3-b]indole-4(3H)-yl]acetaldehyde (Example 126(e)) [(3R)-3-pyrrolidinylmethyl]amine Phenylmethyl carbamate (may be prepared similar to W02006002047 Preparation 23(b)) 2,3-Dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, Example 2(c) or W003/087098, Example 19(d)) 214 Free State MS (ES+) m/z 468 (MH+) °y^s HN p P NH ibw (7-fluoro-2-keto- 1(2H)-indenyl)acetaldehyde (Example 88(8)) [(3S)-3-pyrrolidinylmethyl]aminomethyl phthalate (W02006002047 Preparation 23(b)) 3-keto-3 , 4_diindole-2H-pyrido[3,2-b][l,4]thin-6-aldehyde (W02004058144, Example 7(d)) 215 free base (7-fluoro-2-keto) -1(2H)-喳咁381 200817417 MS (ES+) m /z484 (MH+) ry° crH ; HN—* y yl)acetic acid (Example 88(a)) {[(3R,4R)-glycol-3-pyrrolidinyl]methyl}aminocarbamic acid phenylacetate ( Conversion via Mitsunobu alcohol and subsequent acid removal protection from (3S,4S)-3-hydroxy-4-[({[(phenylmethyl)oxy)carbonyl}amino)methyl]-1-pyrrolidinecarboxylate 1,1_Dimethylethyl acid (W02006002047 Preparation 24(c) E1) 3-indolopyrido[3,2-b][l,4]thin-6-aldehyde (W02004058144, Example 7(6)) 216 Di-HC1 MS (ES+) m/z 452 (MH+) 07. 3-keto-based bite and [2,3-b]pyrazine-4(3H)acetaldehyde (Example 210) {[(3R, 4S)-4-hydroxy-3-pyrrolidinyl]methyl}aminobenzoic acid phenylmethyl ester 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l, 4] 哼耕-6-aldehyde (W02003087098, Example 31(e)) 217 free state MS (ES+) m/z 482 (MH+) fY 6r Hljl" y [6-(decyloxy)-3-keto咐^定[2,3七]咕耕-4(3H)-yl]acetaldehyde (Example 126(e)) {[(3R,4R)-4-hydroxy-3-pyrrolidinyl]fluorenyl} Phenyl decyl carbamate (see Example 215) 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-aldehyde (W02003087098, 382 200817417 Example 31(e)) 218 Single-H C1 MS [7-(Methoxy)-2-keto (ES+) m/z -1(2H)-indenyl]acetaldehyde 497 (MH+) HO, plant N fly w° (Preparation C) { [(3R,4S)-4-Hydroxy-3-pyrrolidinyl]methyl}aminobenzoic acid phenylmethyl ester 3 -mercapto-3,4-diaza-2H-cyclopyridyl P,2-b ][l,4]Tiogulin-6-aldehyde (W02004058144, Example 7(d)) 219 Di-HC1 MS [7-(Methoxy)-2-keto (ES+) m/z HO, Plant/' 'O'·. -1,8-naphthyridine-1(2H)-yl]acetaldehyde 468 (MH+) /0xXr° -rV0 (7-(decyloxy)-1-(2-propene) treated with 0s04/NaI04 according to Example 17(8) -1-yl)-1,8-naphthyridin-2(1H)-one to give intermediate aldehyde) {[(3R,4S)-4-hydroxy-3-hydroxypyridyl]methyl}amine Phenylmethyl formate 2,3-dihydro[1,4]dioxane and synthesized see W02004058144, Example 2 (c) or W003/087098, Example 19 (d)) 220A free base [6-(methoxy ))-3-keto oxime and B (A) and mono HfjjJ and [2,3-b] 吼耕-4(3H)-yl]-HC1 (B) HOvV acetaldehyde (Example 126(e)) MS (ES+) {[(3R,4S)-4.hydroxy-3-pyrrole m/z 469 pyridine]] hydrazinyl} carbamic acid benzene (MH+) °xxr methyl ester 2,3-dihydro[1, 4] Dioxaindolo[2,3-c]pyridine-7-aldehyde (for synthesis see 383 200817417 W02004058144, Example 2 (c) or W003/087098, Example 19(6)) 221 Free State Test MS (ES+) m/z 468 (MH+) rr° φτ HN—* y wF (7-fluoro-2-keto-1(2H)-fluorenyl) acetaldehyde (Example 88(a)) {[(3S,4S)-4-hydroxyl -3-Pyrrolidinyl]hydrazino}amino phenyl carboxamide (transformed via Mitsunobu alcohol and subsequently acid removed, derived from (3R, 4R)-3-hydroxyl - 1,1-dimethylethyl 4-(({[(phenyl)methyl)oxy)carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (W02006002047 Preparation 24(c) E2) 3 -酉同基-3,4-&gt;•Wind^-211-mouthpyridin[3,2-b][l,4]畤耕-6-aldehyde (W02003087098, Example 31(e)) 222 II -HC1 MS (ES+) m/z 468 (MH+) w (7-fluoro-2-keto-1,5-naphthyridin-1(2H)-yl)acetaldehyde (methylheptaic acid) (Example 7(6) {[(3R,4S)-4-hydroxy-3-hydroxypyridyl]methyl}aminobenzoic acid phenyl decyl 3-keto-3,4-dihydro-2H-benzo[1, 4] 畤耕-6-aldehyde (W02002056882, Example 5(b)) 223A and B bis-trifluoroacetate (A) and di-HC1 (B) MS (ES+) m/z 456 (7-fluoro-2 -keto-1(2H)-indolyl)acetaldehyde (Example 34(c)) {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]decyl}aminobenzoic acid benzene t tfr · 384 200817417 The minimum inhibitory concentration (MIC) is determined as the lowest concentration at which a compound inhibits visible growth. A mirror reader was used to help determine the MIC endpoint. Each of the listed examples is tested in at least one of the salt forms of the examples according to the identification of the present application. Unless otherwise stated, the examples listed have a MICS of 2 μg/ml against at least one of the above listed microorganisms, except for Examples 156, 274 and 303, with a MIC of 28 μg/ml and Example 183 against at least one of the above listed microorganisms MIC = 16 μg/ml, And Example 272 showed no activity against the above listed microorganisms at S16 micrograms/ml. For at least one of the above microorganisms, there is at least one example of MICS 2 μg/ml.

Tanner, A, C. and WU, CC 1992. Adaptation of sensitive broth micro dilution technique to antimicrobial susceptibility testing of Mycoplasma gallisepticum. Avian Diseases^ 36, 74-717. Mycobacterium tuberculosis H37Rv inhibition sputum method for measuring minimal inhibition of each test compound Concentration (MIC) was performed on a 96-well flat-bottom polystyrene microtiter plate. Ten times the drug dilution was performed in pure DMSO starting at a concentration of 400 micromoles. Five microliters of these solutions were added to 95 microliters of Middlebrook 7H9 medium (A-line of the culture dish, column M0). Using Isoniazid as a positive control, starting from 160 μg/ml, prepare 8 double-diluted Esplanade and add 5 μl of this control series to 95 μl of Middlebrook 7H9 (Difco Catalogue Ref 271310) + ADC medium (Becton Dickinson Catalogue Ref. 211887) (11 歹 ij, line AH). Five microliters of pure DMSO was added to 12 columns (growth and blank control). 444 200817417 - · · · 2,3-Dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde (for synthesis see W02004058144, Example 2(c) or W003/087098, Example 19(6) 227 di-HC1 MS (ES+) m/z 470 (MH+) HO, plant NN [6-(methoxy)-3-ketopyridin[2,3-b;h than tillage-4(3H) -yl]acetaldehyde (example 126(e)) {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}aminocarbamic acid phenylmethyl ester 6,7-dihydro[1,4 Dioxo[2,3-c]indole-3-aldehyde (Example 6(e)) 228 Di-HC1 MS (ES+) m/z 469 (MH+) [6-(Methoxy)-3 -Ketyl acridine [2,3-b; h than morphine-4(3H)-yl] acetaldehyde (Example 126(e)) {[(3R,4S)-4-hydroxy-3-pyrrolidinyl) Methyl}phenyl phenyl carbazate 2,3-dihydro[1,4]dioxane (WO02056882, Example 40(e)) 229 II-HC1 MS (ES+) m/z 454 _+) [6-(Methoxy) ketopropyl acridine [2,3-b] morphine 4(3Η)_yl] acetaldehyde (Example 126(e)) [(3R)-3-pyrrolidinyl Thiol] phenyl carbazate (may be prepared similar to W02006002047 Preparation 23(b)) 6,7-dioxa[1,4]dioxo[2,3-c]indole-3-aldehyde (Example 6(e))

386 200817417 230 Di-trifluoroacetate MS (ES+) m/z 499 (MH+) Hv^iT^sl〇xx:r [6-(Methoxy)-3-ketoacridino[2,3- b] 吼耕-4(3H)-yl]acetaldehyde (Example 126(e)) {[(3R,4S)-4-Hydroxy-3-pyrrolidinyl]methyl}carbamic acid phenyl decyl ester 6 - copper base _6, 7-two mice - 51 ^ -. Answer ploughing [3,4-b] [1,4] tigeline-3-aldehyde (W02004058144, Example 58(6)) 231 Di-trifluoroacetate MS (ES+) m/z 478 (MH+) Taste [6-( Methoxy)-3-ketoacridino[2,3-b;h cultivating-4(3H)-yl]acetaldehyde (Example 126(e)) {[(3R,4S)-4-hydroxyl 3-portpyrrolidyl]methyl}aminobenzoic acid phenyl decyl 3-keto-3,4-diaza _6_ kou gu glin disk (WO2006132739, example 2(b)) 232 single-HC1 MS (ES+) m/z 451 (MH+) [7-(Methoxy)-2-ketopyrido[2,3-b]indole-1(2H)-yl]acetaldehyde Aldehyde) (Example 51A(b)) [(3R)-3-pyrrolidinylfluorenyl] 1,1-dimethylethylamine decanoic acid 3,4-dihydro-2H-pyran (W02004058144, Example 126(e)) 233 free-form base MS (ES+) m/z 455 (7-fluoro-2-keto-1(2Η)-fluorenyl)acetic acid (Example 88(a)) {[(3R, 4R)-4-hydroxy-3-pyrrole

387 200817417 - (MH+) (9° HN-JVNX〇rF pyridine)methyl}amino phenyl carbamate (see Example 215) 2,3-Dihydro[1,4]dioxan[2, 3-c]u than 唆-7-disk (synthesis see W02004058144, example 2(c) or W003/087098, example 19(d)) 234 single-HC1 MS (ES+) m/z 455 (MH+) ί ca 3 -keto-indolo[2,3-b]indole-4(3H)acetaldehyde (Example 210) {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}aminocarboxylic acid Phenylmethyl 2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde (for synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19 (d )) 235 Mono-HC1 MS (ES+) m/z 451 (MH+) /0W° O [7-(Methoxy)-2-ketopyrido[2,3-b]咕耕-1(2H) -yl]acetaldehyde (methyl hemiacetal) (Example 51A(b)) [(3S)-3-pyrrolidinylfluorenyl] 1,1-dimethylethyl carbamic acid 3,4-dihydrogen -2H-pyrano[2,3-c]^--6-acid (W02004058144, Example 126(e)) 236 Di-trifluoroacetate MS (ES+) m/z 479 (MH+) ^C〇 r. [6-(Methoxy)-3-ketoacridazino[2,3-b] ton till-4(3H)-yl]acetaldehyde (Example 126(e)) {[(3R,4S) ) 4-hydroxy-3-pyrrolidinyl]methyl}aminobenzoic acid benzene

388 200817417 methyl ester 2-keto-2H-(pyrano[2,3-b]pyridine-7-aldehyde (preparation E) 237 free state test MS (ES+) m/z 482 (MH+) 〔:r^ Cc:ri Γ&quot;1 [6-(Methoxy)-3-ketoacridine P,3-b]indole-4(3H)-yl]acetaldehyde (Example 126(e)) [(2R ) 2 - oxasulfonyl-fluorenyl] 1,1-dimethylethyl carbamate 3-copper _3,4_ di-n-pyridin[3,2_b][l,4]崎耕-6- Aldehyde (W02003087098, Example 31(e)) 238 free base MS (ES+) m/z 468 (MH+) [:roi:rw° (7-fluoro-2-keto-1(2H)-fluorenyl) Acetaldehyde (Example 88(a)) [(2R)-2-Morfolinyl-indenyl] 1,1-dimethylethyl carbazate 3-keto-3,4-diindole-2H- Pyrido[3,2-b][l,4]indole-6-aldehyde (W02003087098, Example 31(e)) 239 free base MS (ES+) m/z 502/504 (MH+) [:rc〇 y'(7-Fluoro-2-keto-1(2H)-indenyl)acetaldehyde (Example 88(8)) [(2R)-2-morpholine-indenyl] carbamic acid 1,1-di Methyl ethyl ester 7-chloro-3-keto-3,4-dihydro-2H-pyrido[3,2-b][1,4]indole-6-aldehyde (W02003064421, Example 15(c) 240A, B and C free state (A), mono(7-fluoro-2-keto-1(2H)-fluorenyl) acetaldehyde (Example 88(8)) 389 200817417 -HCL(B) and benzoate (C) MS (ES+) m/z 484 (MH+) c:r«xc:r [(2R)-2-morpholineyl-methyl]aminopurine Acid 1,1-dimethylethyl hydrazine - _ 3 - fluorenyl _3,4-dichloro 2 Η - σ pyridine [3,2-b] [l, 4] thioglycol-6-aldehyde (W02004058144 , Example 7(6)) 241 free-form base MS (ES+) m/z 496 (MH+) [7-(decyloxy)-2-S-yl-1(2H)-indenyl]acetaldehyde (Example 1 (6)) [ (2R)-2-Isofosyl-methyl] 1,1-dimethylethyl phthalic acid 3-mercapto-3,4_diaza-2Η-σΛ pyridine P,2-b][ l,4]thiophene-6-aldehyde (W02004058144, Example 7(d)) 242 free state test MS (ES+) m/z 480 (MH+) XaJ [7-(methoxy)-2-keto-1 (2Η)-4咁yl]acetaldehyde (Example 1(6)) [(2R)-2-Isofosyl-methyl] 1,1-dimethylethyl carbamic acid 3-indenyl-3,4 - bis-pyridinium [3,2-7][1,4] 噚耕-6-aldehyde (W02003087098, Example 31(e)) 243 free-form base MS (ES+) m/z 484 _+) (7-fluorine 2-keto-1(2H)-indenyl)acetaldehyde (Example 88(8)) [(2S)-2-Isofosyl-methyl] 1,1-didecylethyl amide -keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]thiat-6-390 200817417 (W02004058144, Example 7(6)) 244 Single-HC1 MS (ES+) m/z 469 (MH+) c:r«x〇1 °XXX 3,4-Dihydro-2H-pyrano[2,3-ο]^ σ定-6-acid (W02004058144, Example 126(e)) [(2R)-2-Isofosyl-methyl] 1,1-didecylethyl phthalate 2,3-dihydro[ 1,4]dioxo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144, example 2(c) or W003/087098, example 19(d)) 245 single_110:1 MS (ES+ m/z 455 (MH+) fly r〇X]: w° (7-fluoro-2-keto-1(2H)-fluorenyl) acetaldehyde (Example 88(8)) [(2R)-2-? Mercapto-fluorenyl] 1,1-dimethylethylamine 1,2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7-aldehyde (synthesis see W02004058144) , Example 2 (c) or W003/087098, Example 19(d)) 246 Mono-HC1 MS (ES+) m/z 456 (MH+) [:r〇〇〇w° (7-fluoro-2-keto- 1(2H)-indenyl)acetic acid (Example 88(a)) [(2R)-2-Isofosyl-fluorenyl] 1,1-dimethylethyl amide, 6,7-di Hydrogen [1,4]dioxan and 6(e)) 247 mono-HC1 MS (ES+) m/z (7-fluoro-2-keto-1,5-naphthyridin-1(2H)-yl) E disk (methyl half r... 391 200817417 456 (MH+) FWQaXc:) shrink) (Example 7 (d)) [ (2R>2-nofolinyl-methyl] 1,1-dimethylethyl carbamic acid 2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7 - aldehyde (for synthesis see W02004058144, Example 2 (c) or W003/087098, Example 19(d)) 248 Di-HC1 MS (ES+) m/z 496 (MH+) W. Small 4-[(2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylfluorenyl)amino] via EDC, HOBt and methylamine {[(1,1-Dimethylethyl)oxy]carbonyl}-4-hexahydropyridinecarboxylic acid (W02004058144 Example 87(c)) was converted to 4-[(2,3-dioxin[1,4] Dioxaindolo[2,3-c]pyridin-7-ylmethyl)amino]-4-[(decylamino)carbonyl]-1-hexahydropyrrolidine dimercaptoethyl ester. This is then treated with an acid to give 4-[(2,3-dioxin[1,4]dioxo[2,3-c]pyridin-7-ylmethyl)amino]-N-methyl -4- six winds ^ than guanamine. This was reductively alkylated with (7-fluoro-2-keto-1(2Η)-4indolyl)acetaldehyde (Example 88(a)) to give the product. 249 free state test MS (ES+) m/z 482 (MH+) °xxr 3,4-dihydro-2H-pyrano[2,3-(:]. than 唆-6-acid (W02004058144, example 126 ( e)) 392 200817417 {[(3S,4S)-4-Hydroxy-3-pyrrolidinyl]methyl}carbamic acid phenylmethyl ester (see Example 221) 3-keto-3+dihydro-2H- Pyrido[3527][1,4]indole-6-aldehyde (W02003087098, Example 31(e)) 250 mono-HC1 MS (ES+) m/z 434 (MH+) w° , , N 1-[2 -(4-Amino-1-hexa-indole 1?-decyl)ethyl]-7-(decyloxy)-1,5-naphthyridin-2(1H)-one dihydrochloride (Example 16 (b) )) [1,2,4]triazolo[l,5-a]pyridine-6-aldehyde (from 6-bromo[1,2,4]triazolo[l,5-a]pyridine (Edmondson) , SD et al? Journal of Medicinal Chemistry (2006), 49(12), 3614-3627) via standard vinylation followed by dissociation with osmium tetroxide/sodium periodate) Coupling 251 using the method outlined in Example 16(c) mono-HC1 MS (ES+) m/z 466 (MH+) j (7-fluoro-2-keto-1,5-naphthyridin-1(2H)-yl)acetaldehyde (decyl hemyl hexanoic acid) (example) 7(d) 8-Azabicyclo[3.2.1]oct-3-ylamino decanoic acid -1,1-dimercaptoethyl S (from -8-(phenylmethyl)- 8-Azabicyclo[3.2.1]oct-3-amine ( According to Riley et al, J. Heterocyclic Chem., (19), 1982, 485), it is reacted with bis(1,1-dimercaptoacetate) to give [8-(phenyl 393 200817417 methyl)- 8-Azabicyclo[3.2.1]oct-3-yl]carbamic acid conjugated-1,1-dimethylethyl ester. [8-(Phenylmethyl)-8 with Pd(OH)2 -Azabicyclo[3.2.1]oct-3-yl]amino decanoic acid dimethyl phthalate oxime to give the product) 2,3-dihydro[1,4]dioxo[2, 3-c]u than 唆-7-disk (synthesis see W02004058144, example 2(c) or W003/087098, example 19(d)) 252 II-HC1 MS (ES+) m/z 479 (MH+) h^h NN [7-(Methoxy)-2-ketopyrido[2,3-b;h than tillage-1(2H)-yl]acetaldehyde (mercapto hemiacetal) (Example 51A(b)) 8-Azabicyclo[3.2.1]oct-3-ylaminocarbamic acid pendant 1,1-dimethylethyl ester (Example 251) 2,3-Dihydro[1,4]dioxo[ 2,3-c]pyridine-7-aldehyde (for synthesis see W02004058144, Example 2(c) or W003/087098, Example 19(d)) 253 Di-HC1 MS (ES+) m/z 526 (MH+) °tx: X° cis-4-{2-[(3RS,5SR) each (amino fluorenyl)-5-(methoxy) hexacridinyl]ethyl b 6-(methoxy)pyridin[ 2,3-b]咕耕-3(4H)-ketone ( Preparation B) The above intermediate was chromatographed according to the method outlined in Example 134(k) using 3-indole-3,4-diaza-2H- 394 2008 2008 200817417 and [3,2-b][l,4] Thiophosphor-6-aldehyde (W02004058144, Example 7(d)) Reductive alkylation 255 Di-HC1 MS (ES+) m/z 498 (MH+) HXr〇XV. FW° was dissociated by a 1 inch pair of chiralpak AS-H (5 micron) column with 90:10:0.1 acetonitrile:methanol:isopropylamine as the mobile phase via a semi-preparative grade of palmitic HPLC Example 158. The first eluted isomer 256 di-HC1 MS (ES+) m/z 498 (MH+) FW° using 1 inch to chiralpak AS-H (5 micron) column with 90:10:0.1 acetonitrile:methanol : Isopropylamine was used as the mobile phase to dissociate Example 158 via a semi-preparative grade of palmitic HPLC. The second eluted isomer 259 mono-HC1 MS (ES+) m/z 481 (MH+) Hr^Ts> 夕:丄[7-(methoxyiyl)-2-keto^ [2,3-b]咐耕-1(2H)-yl] acetaldehyde (mercapto hemiacetal) (Example 51A(b)) 8-Azabicyclo[3.2.1]oct-3-ylamine 1,1-Dimethylethyl phthalate (Example 251) [1,3] hydrazino[5,4-c]acridin-6-acid (synthesis see W02004058144, Example 61) 260 II- HC1 MS (ES+) m/z 467 (MH+) O^QO^°TXr° [7-(decyloxy)-2-keto-1,8-naphthyridin-1(2H)-yl]acetaldehyde According to Example 17(8), 7-(methoxy)-1-(2-propenyl small)-1,8-naphthyridin-2(1H)-one was treated with Os〇4/NaI〇4) 395 200817417 - - [(3R)-3-Hexahydropyridinylmethyl]carbamic acid phenyl decyl 6,6-dihydro[1,4]dioxo[2,3-c]indole-3-aldehyde ( Example 6(e)) 261 Di-HC1 MS (ES+) m/z 498 (MH+) °w° [7·(Methoxy)-2-ketopyridine[2,3-b] 1(2H)_yl] acetaldehyde (mercapto hemiacetal) (Example 51A(b)) {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamic acid phenyl hydrazine Ester 3 - fluorenyl-3,4-diaza-2H-cyclopyrido[3,2-b][l,4]thratic-6-aldehyde (W02004058144, Example 7(4)) 26 2 free state test MS (ES+) m/z 502/504 (MH+) Q c, 〇^C:J [6-(decyloxy)-3-ketopyridino[2,3-b] 4(3H)-yl]acetaldehyde (Example 126(e)) {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamic acid phenylmethyl ester 4-chloro-6, 7-Dihydro[1,4]dioxo[2,3-d]pyrimidin-2-al (see Preparation A below) 263 Mono-HC1 MS (ES+) m/z 471 (MH+) HO丫N^ ^〇' 丨^ °χατ NN [7-(Methoxy)-2-ketoacridino[2,3-b]indole-1(2H)-yl]acetaldehyde (methyl hemiacetal) (Example 51A(b)) [(3R,4S)-3-Hydroxy-4-hexapyridine)]1,1-didecylethyl carbamate (W02004058144, Example 5(c), cis-(3) -hydroxy-4-hexahydro

396 200817417 Pyridyl) carbamic acid tert-butyl ester to palm isomer 1) [1,3] quinoxa[5,4-c]pyridine-6-aldehyde (synthesis see W02004058144, example 61) 264 single- HC1 MS (ES+) m/z 467 (MH+) [7-(decyloxy)-2-ketopyrido[2,3-b]indole-1(2H)-yl]acetaldehyde (methyl half) Acetal) (Example 51A(b)) [(3R,4S)-3-Hydroxy-4-hexamidinepyridinyl]carbamic acid 1,1-didecylethyl ester (W02004058144, Example 5(c), cis -(3-hydroxy-4-hexahydropyridinyl)amino decanoic acid tert-butyl ester to palm isomer 1) 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6 - aldehyde (W02004058144, example 126(e)) 265 mono-HC1 MS (ES+) m/z 470 (MH+) 丫) ^nX-oh w (7-fluoro-2-keto-1,5-naphthyridine- 1(2H)-yl)acetaldehyde (mercapto-hemi-acid) (Example 7(d)) and [(2S)-4,4-bis(ethoxy)-2-hexahydropyridyl]methanol (from 10% Pd/C hydrogenation of {(2S)-4,4-bis(ethoxy)-l-[(lR)-phenylethyl]-2-hexahydropyridyl}methanol 4 in EtOH using NaBH ( Reductive alkylation of OAc)3 in 1,2-dichloroethane gives 1-{2-[(2S)-4,4-bis(ethoxy 397 200817417 L丄nw)-2-(3⁄4 Methyl)-1-hexapyridinyl]ethyl}-7-fluoro-1,5-naphthalene Pyridin-2(1H)-one. Removal of protection with _ 2M HClfmF and the resulting product with 1-(2,3-dihydro[1,4] using NaBH(OAc)3 in 1,2-dichloroethane. Reductive amination of dioxo[2,3-c]-pyridin-7-yl)methylamine 2 followed by hydrazine (2%-14% in DCM (2M NH3 elution in methanol) )) Chromatographic separation followed by the reverse isomer to obtain the product, and the anti-isomer is first eluted. 1 · Prepared by the method of JF Lau et al., Tet. 58(2) 7339-7344 (2002). Using 2,3-dihydro[1,4]dioxo[2,3-c]acridin-7-yl-methanol using diphenylphosphonium azide (synthesis see WO2004002490, Example 6(b)) It is converted to 7-(azidoindenyl)-2,3-dihydro[1,4]dioxo[2,3-c]pyridine and then hydrogenated with Pd/C/H2. 266 single- HC1 MS (ES+) m/z 470 (MH+) WF See Example 265, cis isomer second elution 267 Single-HC1 MS (ES+) m/z 464 (MH+) ~ 〇 XX^«-〇 J [7-(decyloxy&gt;2-keto-1,8-naphthyridin-1(2H)-yl]acetaldehyde (from 7-(methoxy)-1-(2- according to Example 17(8)) Propylene-1- 398 200817417 - - - yl)-l,8-naphthyridine-2(1H)-one treated with Os〇4/NaI〇4) 7-keto-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-aldehyde (Example 125(c)) 268 Mono-HC1 MS (ES+) m/z 485 (MH+ y-N 〉OH 'NN [7-(methoxy)-2-ketoacridino[2,3-b]indole-1(2H)_yl] acetaldehyde (methyl hemiacetal) (Example 51A(b)) {[(3S,4S)-4_Hydroxy-3-hexahydropyridinyl]methyl}aminocarbamic acid phenylmethyl ester [1,3]indolo[5,4-cK pyridine -6-disc (synthesis see W02004058144, example 61) 269 di-trifluoroacetate MS (ES+) m/z 464 (MH+) V 〇〇H&gt; XxyF 7- gas-2-mercapto-1(2H)-喳崎咁基]Acetaldehyde (Example 3 you)) 8- {[(曱-oxy)indolyl]oxy}-1-indolyl-1,2-di-rho--3-iso-linic acid (W02004058144 Example 57 (e)) After coupling, the methoxy-methyl ester was deprotected with 4 MHC 1 / 1,4-dioxane and purified by HPLC to give the desired product. 270 mono-HC1 MS (ES+) m/z 470 (MH+) A w (7·fluoro-2-keto-1,5-naphthyridin-1(2H)-yl)acetaldehyde (methyl hemi-acid) (Example 7(d)) with [(2R)-4,4-bis(ethoxy)-2-hexahydropyridinyl] decyl alcohol (from 10% Pd/C in EtOH hydrogen 399 200817417) {(2R -4,4-bis(ethoxy)-l-[(lR)-phenylethyl]-2-hexahydropyridyl}methanol 4 using NaBH(OAc)3 in 1,2-dichloroethane After reductive alkylation, 1-{2-[(2S)-4,4-bis(ethoxy)-2-(hydroxymethyl)-1-hexahydropyridinyl]ethyl}-7- Fluoro-1,5-naphthyridin-2(1Η)-one. Removal of protection with 2MHC1:THF and using NaBH(OAc)3 in 1,2-dichloroethane to give the product with 1-(2,3) - Reductive amination of dimur [1,4]dioxo E and [2,3-cK pyridin-7-yl)decylamine 2 followed by ruthenium (3% to 15% in DCM (in methanol The 2MNH3 elution in the)) chromatographic separation of the anti-isomers to obtain the product, the anti-isomer is first eluted. 1. By: JF Lauet al., Tet. 58 (2) 7339-7344 (2002 Preparation of the method 2. Using 2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylmethanol using diphenylphosphonium azide (synthesis see WO2004002490, example 6(b)) is converted to 7-(azidoindenyl)-2,3-dihydro[1,4]dioxo[2,3-c]pyridine and subsequently hydrogenated with Pd/C/H2 Preparation: 2008 20081717 271 Single-HC1 MS (ES+) m/z 470 (ΜΗ&quot;), human 〆0H w See example 270, cis isomer second elution to 272 II-HC1 MS (ES+) m/z 478 (NfflT) HO /~N /〇W° [6-(Methoxy)-3-keto oxime and [2,3-7] 吼耕-4(3H)-yl] acetaldehyde (example) L26(e)) {[(3R,4S)-4-hydroxy-3-hydroxypyridyl]fluorenyl}amino phenyl carboxylate 2-keto-2H-pyrido[l,2-a 17-Styrosine-8-acid was obtained from (a) 4-({[1,1-didecylethyl)(diphenyl)decyl]oxy group treated with 25% NaOCH3 in MeOH.曱-[4-({[(1,1-Dimercaptoethyl)(diphenyl)decyl]oxy}}}-pyridylamine-2-pyridylamine Methyl)-2-1:1 to 17-based]-3,3-bis(decyloxy)propanamide (b) heated in HOAc Ν-[4-({[(1,1-dimethyl) Ethyl)(diphenyl)decyl]oxy}methyl)-2-. ratio. Benzyl]-3,3-bis(decyloxy)propanamide gives 8-({[(1,1-didecylethyl)(diphenyl)decyl]oxy}methyl)-2H - acridine [l,2-a]pyrimidin-2-one (c) treatment of 8-({[(1,1-didecylethyl)(diphenyl)) alkoxy]oxyl with TBAF }曱基)_2H-Acridine [l,2-aj Mouth-2-one, followed by oxidative oxidation with oxidative to give the desired thiophene).

401 200817417 273 Mono-fumarate MS (ES+) m/z 465 (ΜΗ&quot;) F 0 1-[2-(4-Amino-1-hexanitrogen)ethyl]_7-gas 2-mercapto-1,2-dihydro-4-σ quinone nitrile hydrochloride (Example 129(c)) 6,7-dihydro[1,4]dioxan[2,3-c 17荅11 Well-3-Acid (Example 6(e)) Coupling 274 by the method outlined in Example 4(c) bis-HC1 MS (ES+) m/z 462 (ΜΗ&quot;) [6-(methoxy) -3-keto group ratio bite and P,3-b]咐耕-4(3H)-yl] acetaldehyde (example 126(e)) 4-hexahydropyridylamino decanoic acid 1,1-dimethyl Ethyl 2-keto-2H-pyrido[l,2-a]pyrimidine-8-aldehyde (see Example 272) 275 free base MS (ES+) m/z 462 (MJH〇J〇c〇0τϊ7 [ 6-(decyloxy)-3-ketopyrido[2,3-b]indole-4(3H)-yl]acetaldehyde (Example 126(e)) 4_Hexidopyridylamine decanoic acid 1,1-Dimercaptoethyl 6,7-dihydro-5H-pyrano[2,3_d]pyrimidine Winter Solvent (Preparation D) 276 Free State Base MS (ES+) m/z 435 (ΜΗ&quot;) Λ o^jCo 1 [7-(Methoxy)-2-keto-1,5-naphthyridin-1(2H)-yl]acetaldehyde (mercapto hemiacetal) (Example 11(e)) 4- 1,1-didecylethyl hexahydrocarbamate, 2,3·di-nitrile-1-benzoquinone-5- (Commercial supply) 402 200817417 277 Mono-trifluoroacetate MS (ES+) m/z 470 (ΜΗ') HK〇X] /0 丫W〇; 丨[6-(methoxy)-3-keto Pyrido[2,3-b]indole-4(3H)-yl]acetaldehyde (Example 126(e)) {[(3R,4S)-4-hydroxy-3-hydroxypyridinyl]methyl }Phenyl decyl carbamate 6,7-dihydro[1,4]dioxo[2,3-d]pyrimidin-2-aldehyde (W0200401436 intermediate 8) 278A 278B mono-HC1 benzoic acid Salt MS (ES+) m/z 452 (MET) 丫0 7-fluoro-2-keto-1(2H)-carbolyl]acetaldehyde (Example 34(c)) 4-Hexidopyridylamino 1,1-dimethylethyl formate 7-keto-5,6,7,8-tetrahydroindole and [2,3-d]pyrimidin-2-aldehyde (Example 125(c)) 279 -HC1 MS (ES+) m/z 454 (ΜΗΓ) HfV丫0γ A, N^-〇^ ! /ατχχ. [6-(Methoxy) ketopropyl acridine [2,3-b]indole-4(3H)-yl]acetaldehyde (Example 126(e)) 4-Hexidopyridylaminocarboxylic acid 1 ,1-dimethylethyl 6,7-dihydro[1,4]dioxo[2,3-&lt;1]^ sigma-2-acid (W02004014361, intermediate 8) 280 II-HC1 MS (ES+) m/z 441 (MFt) /N, /0, aXC; S|J^ W° 7-fluoro-2-keto-1(2Η)-fluorenyl]acetaldehyde (Example 34 ( c)) 1,1-dimethylethyl 4-hexahydropyridylcarbamate 6,7-dihydro[1,4]dioxo[2,3-d]pyrimidin-2-aldehyde (W02004014361 , Intermediate 8) 403 200817417 281 II_HC1 MS (ES+) m/z 468 (Mlf)

[6_(Methoxy), 3-ketopyl group is more than [2,3_b]. Ratio of +4(3H)-yl]acetaldehyde (Example 126(e)) {[(3R,4S)-4-Phenyl-3-.比 各 ] ] ] 甲基 甲基 甲基 甲基 甲基 甲基 甲基 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 2 6 制备 制备 制备 制备 制备 制备,7-Dihydro[1,4]dioxo[2,3_d] sneeze_2_

Cl (a) 1,1,3·propanetricarboxylic acid 3-ethyl ester 1,1-didecyl ester 10 15 in dimethyl malonate (2.5 g, 18.9 mmol) in anhydrous THF (20 mL) was added NaH (0.038 g, 〇·95 mmol, 60% in mineral oil). The reaction was stirred at ambient temperature for 15 minutes. In a separate flask, ethyl acrylate was dissolved in dry THF (1 mL) and then added dropwise to a solution of dimethanolate for 30 minutes. The reaction was concentrated at ambient temperature for 16 hours. The residue was dissolved in Et EtOAc (ethyl acetate) and washed with saturated NH4CI solution and brine. The organic layer was dried over Na2s EtOAc, filtered and evaporated. The crude residue was purified by EtOAc EtOAc EtOAc (EtOAc: ]H NMR (400 MHz, CDC13) δ 1.24 (t, J=7.07 Hz, 3H) 2.20 (q9 /=7.24 Hz, 2H) 2.37 (t, ^=7.33 Hz, 2H) 3.47 (t3 &gt;=7.33Hz , 1 H&gt;3.70-3.75 (m? 6H) 4.12 (q? &gt;7.24Hz5 2H). 404 200817417 (b) (2E)-3-Phenyl-2-propanimide cinnamonitrile (25.0 g '194 mmol' dissolved in Et〇H (ethanol) (2 mL). The solution was cooled to Ot and the HC1 gas bubble was bubbled through the solution for 3 minutes. The solution was stirred at ambient temperature for 16 hours after vacuum Concentrate. Dissolve the residue in EtOAc (100 mL). The temperature was stirred overnight and the obtained N^Cl was filtered. The solution was concentrated in vacuo and the obtained product was used without further purification (28·6 g, crude). 10 LCMS: m/z 147·4 (ΜΗ+ ) 〇(4)3_{4_hydroxy-6-keto_2_[(Ε)-2_phenylvinyl]-1,6-dihydro-5-pyrimidinyl}ethyl propionate will be 1,1,3- 3-ethyl glycerol tricarboxylate 1,1·didecyl ester (ι·65 g, 7·11亳15 mol) and (2Ε)-3-phenyl-2-propenenimine (ΐ·〇4 g, 7.11 mmol). Mix in EtOH (36 mL). Add triethylamine (1·········· No change. The solution was allowed to cool to room temperature and treated with NaOMe (1·〇 ml ' 5.33 mmol, 25-30% w/w solution) in MeOH and the solution was refluxed for 20 hours for 3 hours. NaOMe in MeOH (2×1························································································ Consolidation and use without further purification. LCMS: m/z 315·2 (MH+). 405 200817417 I (d) 3-{4,6-dichloro-2-[(E)-2-phenylethene] -5-pyrimidinyl}ethyl propionate will be crude 3-{4-hydroxy-6-keto-2·[(Ε)-2-phenylvinyldipyridinium dihydro, -5-pyrimidinyl} Ethyl acetate was dissolved in POCI3 (25 mL) and hydrazine, hydrazine-bis- phenylamine (〇·9 mL, 7.1 mmol) was slowly added to the solution, and then the reverse 5 was heated under reflux for 2 hours. After cooling to ambient temperature, the resulting solution was carefully and slowly added to ice water to quench excess p〇Cl3. The mixture was extracted with EtOAc (3.sub.4). The crude residue was purified by EtOAc EtOAc EtOAc (EtOAc)

LCMS: m/z 351.4 (MHV (e) 3-{4,6-diox-2-[(E)-2-phenylethene; μ5_pyrimidinyl}_丨_propanol in 3-{4 ,6-Dichloro-2-[(E)-2-phenylvinyl]_5-pyrimidinylpropionic acid 15 ethyl ester (0·35 g, 丨.04 mmol) in THF (10 mL) A solution of lithium aluminum hydride in THF (2.0 mL, 2 〇 mmol) was added to the solution of _78 。. The reaction was stirred under a nitrogen atmosphere for 1 hour and then allowed to warm. The reaction was quenched by EtOAc (3 mL). After concentrating in vacuo, EtOAc (m.)

406 200817417 (f) 4_Chloro-2-[(E)-2-phenylvinyl]_6,7-dihydro-5H-pyrano[2,3,dj 4 0 intimate, in Μ4,6 · Dichloro-2-[(Ε)-2·phenylvinyl]-5-pyrimidinyl}-septaol (275 mg, 0·89 mmol) was added to DMF (4 mL) with k2c〇5 ( 0. 50 grams, 3. 6 millimoles). The suspension was warmed to 60 ° C and allowed to stir at nitrogen 3 for 16 hours. The reaction was allowed to cool to rt. The water was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. The crude residue was purified by EtOAc EtOAc (EtOAc) , LCMS: m/z 272.9 (ΜΗ+). (g) 4_gas-6,7-one rat_511_° than 弁 弁 [2,3-(1]^3 密密-2-搭15 4_氯-2-[(Ε)·2_ Phenylvinyl]-6,7-dihydro-5H-pyridox[2,3-d]pyrimidine (〇·21 g, 〇·79 mmol) dissolved in iota, 4_dioxane/water 2:1 solution (6 ml) and cooled to (TC. Add NaI〇4 (〇·5 g, 2 4 mmol) and catalyst 〇s〇4 (0.25 ml, 4% aqueous solution) and solution Stir at ambient temperature for 2 hours. The reaction solution was diluted with water (1 mL) and extracted with 20 Et0Ac (4×). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. Purification by chromatography (EtOAc) eluting with EtOAc EtOAc (EtOAc: EtOAc (EtOAc: EtOAc) 5SR)-3-(Aminoalkyl)-5-(decyloxy)-1-hexanitroindole.]]]}}}-(decyloxy) oxime.

(8) cis-(3RS,5SR)-3-[(l,3-diketo-1,3_dihydro-2H-isoindole-2-yl) fluorenyl]-5-pyridyl-1-hexanitro Ι: σ deterministic acid phenyl decyl ester 10 in cis-(3RS,5SR)-3-{[(l,l-didecylethyl)(didecyl)decyl]oxy}-5_[( 1,3-diketosyl-1,3_diindole-2H-isoindole-2-yl)hydrazino] hexahydropyridine phenyl decyl ester (preparation see Example 134(e)) (0.92 g) A solution of tetrabutylammonium fluoride in THF in 1N (4 mL, 4.0 mmol) was then. The reaction was stirred under nitrogen pressure 15 and allowed to warm to room temperature over 2 h. The reaction was partitioned between EtOAc and saturated aqueous NH4CI. The organic layer was separated and washed with EtOAc EtOAc EtOAc. The crude residue was purified by EtOAc EtOAc EtOAc elut elut elut elut MS (ES+) m/z 395·1 (MH+). (b) cis-(3RS,5SR)-3-[(1,3-diketo-1,3-dihydro-2Η-isoindol-2-yl)methyl&gt; 5-(decyloxy) )-1-pyropyridinecarboxylic acid phenylmethyl ester 408 200817417 in cis-(3RS,5SR)-3-[(l,3-dione-1,3-1,3-dihydro-2H-iso-inducing hydrazine- 2-yl) fluorenyl]-5-yl-l-hexahydro-n-halogenated tartrate ( 380 gram, gram, 〇 · 96 mM) added methyl hydrazine in 5 ml of CHfl 2 ( 1 ml, 16.1 mmol, and AgW (1.15 g, 5.00 m). The reaction was filtered through a pad of EtOAc (EtOAc)EtOAc. The crude residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut MS (ES+) m/z 409.3 (MH+). 10 (4) cis-2-{[(3RS,5SR)_5-(decyloxy)-3-hexahydropyridinyl]indenyl}_1Η-heteropurine-1,3(2Η)-dione in cis- (3RS,5SR)-3_[(1,3-dione-l-l-dihydro-dihydro-2-indole-iso-indolyl) fluorenyl]-5-(decyloxy)-1-hexahydro Add pd/C (50 mg, 10%) to EtOH (20 mL). The reaction was hydrogenated at 45 psi for 3 hours on a Parr apparatus. The catalyst was removed by replacing the hydrogen with N2 and the solution was filtered through Celite® layer and washed again with EtOH (5 mL). The filtrate was concentrated under reduced pressure to give the desired compound (125 mg, 90% MS (ES+) m/z 274.9 (MH+). (d) 2_[((3RS,5SR)_5_(曱-oxy)_ΐ-{2·[6-(decyloxy)_3-keto-yl. The ratio is 2[3,3_b]pyridine-4 (3Η )-yl]ethylbu-3-hexahydropyridinyl)indenyl]_1Hj

409 200817417 吲哚-1,3(2H)-dione^ in cis-2-{[(3RS,5SR)_5_(decyloxy)-3-hexahydropyridyl]fluorenyl-yl}-1^isoindole哚-1,3(2H)-dione (125 mg, 0.43 mmol)

[6-(decyloxy)-3-keto-5pyrido[2,3-b]pyrazine-4(3H)-yl]acetaldehyde was added to MeOH (1 mL) and CHC13 (5 mL). See Example 126(e)) (100 mg, 0.50 mmol) and the reaction was stirred at room temperature under n2 for 4 h. Na(OAc)BH (210 mg, 1.0 mmol) was added and the mixture was stirred at room temperature under nitrogen for a further 14 hr. The reaction was partitioned between EtOAc EtOAc (EtOAc)EtOAc. The solvent was removed and the crude residue was purified eluting EtOAc EtOAc EtOAc EtOAc MS (ES+) m/z 478·2 (MH+). (4) cis_4_{2-[(3RS,5SR)-3-(aminomercapto)-5-(decyloxy)succinylpyridinyl]ethyl}-6-(decyloxy)pyridinium[ 2,3-b]pyrazine-3(4Η)1 is in the same 2-[((3RS,5SR)_5_(decyloxy)_1_{2-[6_(decyloxy)-butanone) 2,3-b]. Tillage-4(3H)-yl]ethyl}-3-hexahydropyridyl)indole 20-based HH-isoindole-1,3(2H)-dione (110 mg, 0.23 millimoles)

Anhydrous hydrazine (5 ml, 15.0 mmol) was added to EtOH (5 mL). The reaction was warmed to 40 ° C and stirred under nitrogen pressure for 24 hours. The reaction was filtered through EtOAc (EtOAc) (EtOAc) The aqueous layer was extracted with EtOAc (2×25 mL). The solvent was removed to give the desired compound (62 g, 77%) as a brown solid which was used without purification. MS (ES+) m/z 348.0 (MH+). Preparation of C··[7-(Methoxy)-2-keto-1(2H)-carbolyl]acetaldehyde (a) 7-(Methoxy)-2(1Η)-fluorenone And 6 gas methoxy bisulphonone 4-(decyloxy)_1,2-phenylenediamine (1 gram, 72.5 mmol) and ethyl glyoxylate (50% in toluene, A mixture of 丨5·2 ml, 74·2 mmoles in ethanol (4 mL) was heated under reflux for 2 hours, then cooled and refrigerated overnight. The solid was filtered, washed with ice-cold ethanol and dried to give a mixture of 7-(decyloxy)-2(1Η)-fluorenone and 6-(methoxyxanthone (about 1:1 ratio, 9 • 99 g). The liquid was concentrated and cooled in ice to give another mixed isomer (approximately 2:1 ratio) which was collected and washed and dried (1·11 g) as before. (b) 7_(decyloxy)-2-(2-propen-1-yloxy) ♦ spray (〇-allyl^ and 6-(methoxy)-2-(2-propene-1) - gas base slogan π lin (〇 _ propyl 2) 7-(decyloxy)-2(1Η)-pyridone and 6_(decyloxy)-2(1Η)-4 linolenic acid Mixture (1 U g, 63.1 mmol) with propyl iodide (6.25 mL, 69·9 mmol) and potassium carbonate (26.2 g, 189.8 mmol) in dimercaptoamine (200 mL) Stir at room temperature for 2.5 hours, then evaporate. The residue, &lt;RTI ID=0.0&gt;&gt;&quot;&quot;&quot;&quot;&quot; 411 200817417 Chromatography on Shixia, elution with ()·_%(d)/petroleum ether, firstly obtained 〇·propyl propyl isomer 1 (1.18 g, 9%), The second is (tetra) propyl isomer 2 (1.99 g, 15%), and finally two oxime-allyl isomers 7·(methoxy)-2-(2•propan-1-oloxy a mixture of 4 lin and 6_(decyloxy)_ 2_(2-propoxyoxy)porphyrin (9.18 g, 67%). (c) 7-(decyloxy)-1-(2• Propylene 4_yl)_2(111)_Osaki Ketone Ketone-allyl isomer 1 (1·18 g, 5·45 mmol) under reflux with hydrazine (diphenylphosphine) palladium ( 0) (120 mg) was heated in toluene (25 liters) for 3 hours. The solvent was evaporated and the residue was purified eluted eluted eluted - propylene-yl)-2(1Η)-fluorenone (1 gram, 87%). (d) The title compound is 7-(methoxy)-1-(2-propen-1-yl) )-2(1Η)-porphyrinone (Ig3 g, 4.75 house Moule) and sodium chlorate (4.68 g, 21.8 mmol) in 2-butanol (20 liters) and water The mixture in (40 liters) was treated with iron tetraoxide (4% solution in water, 1.1 ml) and the mixture was stirred for 3.75 hours. The butanol was evaporated and the residue was diluted with water and with dichloromethane. The extract is burned and then extracted with chlorohydrazine/THF. The extract was dried and evaporated, and the residue was purified eluted eluted eluted eluting eluting eluting z 219 (ΜΗ+), 237 ([Μ+Η20]Η+), 233 (MCH3+), 251 ([M+MeOH]H+). 412 200817417 Preparation D: 6,7-dihydro-5H-pyrano[2,3-d]pyrimidine_2_路

(Dian 5-(3-hydroxypropyl)-2-[()-2-phenylvinyl]-4(111)-pyrimidinone in δ-valerolactone (2.0 g, 20 mmol) in anhydrous ether (2 ml) was added ethyl formate (1.6 ml, 21 mmol) and sodium hydride (1 g of 60% by weight in oil: weight dispersion, 25 mmol). Stirring was carried out for 45 minutes under nitrogen pressure. A solution of (2 Ε)-3-phenyl-2-propenenimine (2.92 g, 20 mmol) in EtOH (25 mL) was added and then the mixture was warmed to The mixture was stirred at 70 ° C for 4 hours. The reaction was cooled to rt. EtOAc (EtOAc &lt; And the crude residue was purified by column chromatography on Shishi gum using 〇-ΐ〇〇/0

The MeOH/DCM gradient was eluted. The product-containing extract was concentrated to give the desired compound (2.3 g, 45%). MS (ES+) m/z 257 (ΜΗ+). 20 (b) 2_[(E)-2-Phenylvinyl H,7-dihydro-5H-pyrano[2,3-d]pyrimidine in 5-(3-hydroxypropyl)_2-[(e _2-Phenylvinyl]_4(1H)-pyrimidinone (1.0 g '4.0 mmol) was added to triphenylphosphine (16 g '6.0 mmol) and azodicarboxylate in thF (20 mL). Diethyl acid (1 gram, 6 〇 millimolar). The reaction was allowed to stir at room temperature under nitrogen pressure for 14 hours. The reaction was partitioned between EtOAc EtOAc (EtOAc) (EtOAc) The combined organic extracts were dried with EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 5 compounds (0.81 g, 84%). MS (ES+) m/z 239 (MH+). (c) 6,7-Dihydro-5H-^ and 2_[(Ε)-2·phenylvinyl]_6,7-dihydro-5H-pyrano[2,3-d].唆 (〇·5 g, 2.1 mmol) was dissolved in DCM (20 mL) and 〇3 was bubbled at -78 °C for 15 min. The excess hydrazine 3 was then removed by passing nitrogen through for 10 minutes and then quenched with dimercaptosulfur _ (2·〇 ml '32.2 house Moule). The reaction was allowed to warm to rt and stirred for additional 14 h. The entire solvent was then removed to give the desired compound (28 g, 80%) which was used without further purification. MS (ES+) m/z 165 (ΜΗ+). Preparation E: 2-keto-2H-pyrano[2,3-b]pyridine-7-aldehyde (8)3-(ylmethyl)-6-mercapto-2(1H)4 pyridine _6_Mercaptopyridine-3-carboxylic acid (2 g, 13 mmol) was dissolved in dry THF (80 mL) and the solution was cooled to -7 °C. Then add UAIH4 (32 ml, 32 mmol) for 20 minutes. The reaction mixture was allowed to warm to room temperature at 70. Heat for 1 hour. After cooling to 〇 ° C, AO (2 mL), i〇〇/0 NaOH (4 mL) and finally 414 200817417 were added to the reaction mixture.

H2 〇 (2 ml). The reaction mixture was stirred at room temperature for 1 hour. Add Na2S〇4 (6 g), stir the mixture for additional 30 min, filter and rinse with MeOH. The filtrate was concentrated to dryness to give the desired product (2 g, 100%). LCMS (ES+) m/z 140 (MH+). 5 (b) 6-Methyl-2-mercapto-1,2-diaza-3-indenate 3-(hydroxyindenyl)-6-mercapto-2 (1H&gt;pyridone (2.0 g, 13 mmoles dissolved in CH2CI2 (80 mL), THF (80 mL) and MeOH (5 mL), EtOAc (3·7 g, 43 mmol). The reaction mixture was heated at 57 ° C for 18 hours. The reaction was filtered through Celite® pad and concentrated to give a solid (1·8 g, 90%). LCMS (ES+) m/z 138 (MH+). (c) 7·methyl-2H_pyran[ 2,3-b]pyridin-2-one in 6-fluorenyl-2-keto-1,2-dihydro-3-acridinal (318 mg, 2·3亳15 mol) in Ac2〇 ( Et3N (1 ml) was added to 3 ml). The reaction was heated at 120 ° C for 18 hours. The reaction was concentrated and the obtained material was dissolved.

MeOH was placed on silica gel and evaporated. Purification by column chromatography (EtOAc) eluting with EtOAc/EtOAc (EtOAc) LCMS (ES+) m/z 162 20 (MH+) 〇(d) The title compound in 7-methyl-2H-pyrano[2,3-b]pyridine-2__ (160 mg, 0.98 mmol) in a microwave oven A solution of 1,4-dioxane (12 ml) in a reaction vial of 415 200817417 was added with Se〇2 (328 mg, 3.00 mmol). Cap the reaction bottle and will

The mixture was heated in a microwave oven at 160 ° C for 90 minutes. The reaction was filtered through DCM, diluted &lt The resulting material was dissolved in MeOH and placed on silica gel and evaporated. Purified by column chromatography (purine) using a DCM/Me EtOAc gradient (0-10% MeOH) to give the desired product as a creamy solid (12 mg, 40%) cLCMS (ES+) m/z 176 (MH+). Preparation F: 7-keto-6,7-17-1-pyrimido[5,4_1}][1,4]indole-2-aldehyde 10 (8)2_[(Ε)_2·phenylvinyl]_5-(four Hydrogen-2H_pyran-2-yloxy)-4(1Η)- 0 ketamine slowly added NaH (0.38 g, 9.5 mmol, 60% paraffin oil) to (tetrahydro-2H-pyran) Ethyl 2-oxy)acetate (prepared by treatment of ethyl hydroxyacetate with 3,4-dihydro-2H-pyran and TsOH) (i·g, 5.3 mmol) and 15 anhydrous ethyl decanoate (3.9 g, 53 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature for 15 minutes and then heated at 65 °C for 45 minutes. The reaction mixture was concentrated to dryness to give a creamy solid. A solid was added to a solution of (2E)-3-phenyl-2-propanimide (〇·78 g, 5.3 mmol) in MeOH/EtOAc (20 mL / 20 mL). C 2 〇 was heated for 4 hours. The resulting material was poured into EtOAc (3 g) (EtOAc) Purification by column chromatography (EtOAc) eluting with EtOAc EtOAc (EtOAc) LCMS (ES+) m/z 299 (MH+).

416 200817417 (b) Trifluoromethyl-supply acid 2_[(8)_2_Stupyl-ethyl 4-glycolyl]-4-pyrimidinyl ester. In 2_[(6)phenylvinyl ]_5-(tetrahydro-2-indole-2-pyran-2-yloxy)_4(10) "Carmelin (2.04 g ' 6.84 mol) in pyridine (1.22 liters, 15.05) in dcm (25 ml) 5 suspension Millimeter). After cooling to _7 passages, slowly add trifluoromethyl phthalic anhydride (ι 38 ml '8.2 mM) via dropwise addition. The reaction is at _78. (: 1 G minutes, then, after The cold material was changed to an ice water bath and the mixture was again subjected to _G.5 hours. The reaction mixture was poured into water and the aqueous layer was extracted with DCM. The organic layer was washed with water, 10 NaHC 3 saturated aqueous solution and brine. Drying over Na2SO4, EtOAc (EtOAc) m. Base]-5_(tetrahydro-2-indole-π-pyranyloxy)-4-0 occluded amine to crude difluoro fluorenyl sulphate 2-[(E)-2-indolyl] (tetrazo-2H) -pyran-2-oxy)-4-0 pyridine vinegar (6.8 mmol) with ammonia in 丨, 4- 哼 哼 (136 24 20 I the reaction solution 0.5M L) at a pressure of 60 ° C. The reaction was concentrated in vacuo, the residue was dissolved in water and ^ thousand and,

Wash with NaHC〇3 saturated aqueous solution and brine. The organic layer was dried over Na 2 EtOAc, filtered and concentrated. The crude residue was purified by EtOAc EtOAc (EtOAc) elute 417 200817417 LCMS (ES+) m/z 298.0 (MH+). , (d) 4_Amino-2-[(E)_2_phenylvinyl]_5"Methylene alcohol hydrochloride salt 2_[(E)-2-phenylvinyl]_5-(tetrahydro- 2H-Pyr-2-yloxy)-4_5 pyrimidinamine (1.28 g, 4.3 mmol) was suspended in Me〇H (25 mL) and heated in a 50 ° C oil bath until completely dissolved. !, '4 Μ HC1 (0.11 ml, 〇·43 mmol) in the two sigma, and the reaction was heated at 50. 〇 heating for 1.5 hours. At this point, LCMS showed a little progress, so add again! Raise 4MHC1/1,4-bisaki and heat for 3 hours. Cooling the reaction to room temperature results in the formation of a white precipitate. The solvent is removed in vacuo and the resulting brown solid is dried under high vacuum overnight. 1 〇 8 g (loo%, HC1 salt). This material was used without further purification. LCMS (ES+) m/z 214.0 (MH+) 〇15 (e) [(6)-2-phenylvinyl]-1H- Bite and [5,4-b] [1,4]呤耕-7(6H)-one in 4-amino-2-[(E)-2-phenylethenyl]nonanol hydrochloride Potassium (250 mg, 1.0 mmol) in a suspension of absolute ethanol (5 mL) at room temperature with potassium butoxide (224 mg, 2.0 mmol) After stirring for 5 minutes, 20% bromoacetic acid ethyl ester (EtOAc········································· And a small amount of water. The layers were separated and the aqueous layer was extracted with EtOAc EtOAc EtOAc EtOAc (EtOAc) 106 mg (42%). 'LCMS (ES+) m/z 254.0 (MH+). (f) title compound 5 in 2-[(E)-2-phenyletheneHH-pyrimido[5,4-b [l,4] Addition of NaI04 to a suspension of 1,4·dioxane (12 ml) and water (3 ml) in a solution of 7(6Η)·ketone (106 mg, 〇·418 mmol) (357 mg, 1.67 mmol) and 0s04 (〇·1 ml, 4% by weight in water) and the reaction mixture was stirred at room temperature. After 2 hours, 3 ml of ίο 1,4-dioxane was added again. 180 mg of NaI04. After a total of 7.5 hours, the reaction was capped and stored in a freezer over the weekend. After warming to room temperature, additional 0s04 (0.1 liters, 4% by weight in water) was added and the reaction was carried out. Stirring for 4 hours. The solvent was evaporated to give a white solid, and dissolved in DCM and water. The aqueous layer was extracted with 10% MeOH-CHCl3 (6X). The combined 15 ml extracts were dried <RTI ID=0.0></RTI> to <RTI ID=0.0> LCMS (ES+) m/z 1800 (MH+). Preparation of G: 7-keto- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2-aldehyde 2〇(a) sodium α-methylpyridylglutarate Prepared from diethyl glutarate and ethyl formate in the presence of sodium metal in diethyl ether according to the literature method (J. Bigs, P. Skyes, /. C/zewz'ca/ (1959), 1849-55) . A solid (28 g, 45%) was obtained. LCMS (ES+)

m/z 238 (MHV 419 200817417 (b) 3-{4-Hydroxy-2-[(E)-2-phenylvinyl]-5-pyrimidinyl}propionic acid ethyl ester α-methyl glutaric acid Diethylene glycol sodium salt (1 g, 4.2 mmol) and (2Ε)-3_phenyl-2-propanimide imine prepared in Shell 126 (g) (〇·6ΐ克, 4.2, Mo The mixture was combined with EtOAc (EtOAc) (EtOAc) , 56%). The mother liquor containing additional product is not separated. LCMS (ES+) m/z 299

(ΜΗ V (c) 3-{4-chloro-2-[(Ε)-2-phenylvinyl]_5-pyrimidinyl}ethyl propionate 3-{4_hydroxy_2_[(Ε)_2 -Phenylvinyl]_5_σ-midridinyl}ethyl propionate (11.6 g, 38·9 mmol) was heated in P(R)Cl3 (3 mL) at 12 (rc) for 4 hours. The solvent was removed in vacuo. The crude residue was purified by EtOAc EtOAc (EtOAc) elute ES+) m/z 317 (MH+) 〇(4)2 [(E)-2-propenylvinyl]_5,8-dihydro σ ratio bite [2,3_d] 唆-7 (1H), at room temperature Add 3_{N-chlorophenylvinyl]-pyrimidinyl}ethyl propionate (6.6 g, 2〇·83 耄mol) to a 320 ml sealed flask and ammonia in MeOH (5.9 ml, 417) Millules, 7 Μ solution). The flask was sealed and the reaction was heated at 110 for 7 hours. After 3 hours, the solid was allowed to stand. Then the reaction was stirred at room temperature overnight, then heated again for $420 200817417 hours. The Buchner funnel was filtered and the resulting solid was washed with ethanol and dried to give a solid (2 g, 36.3% &gt; LC MS (ES+)

m/z 252 (MHV 5 (e) 7-keto-5,6,7,8-tetrahydropyrazole and [2,3_feeding bite_2-added in a round bottom flask in DMF (10 2-[(E)-2-Phenylvinyl]-5,8-dihydroindole 定 并 [2,3_d] pain tr -7 (1H in soaring) and sterol (1 〇 ml) )-ketone (600 mg, 2.39 mmol). Ozone bubbles were bubbled through the solution at room temperature for 20 minutes and excess ozone was stripped with a stream of nitrogen to remove 1 。. House liter, 23.9 faints) and the reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the obtained solid was dissolved in 2% MeOH-DCM.

Leached with MeOH-DCM. The extracted fractions were obtained to give the title compound (4 g, 95% yield). 15 LCMS (ES+) m/z 177 (MH+).

Example 254 (+/-)1_(2_{3-(Aminomethyl)_4_[(2,3-diaza π,4]dioxo[2,3-φ ratio -7-ylmethyl Amino] hexahydroindole phantom ethyl-2(1Η)-pyridone ketone isomer 1 trihydrochloride

F 421 200817417 (4) Racemic 4-hydroxy-indole _ (stupyl thiol) _3_ hexahydropyridine carboxylic acid ethyl ester (instead of the mixture) in 4-keto-1-(phenyl fluorenyl) hexa Ethyl hydropyridine carboxylic acid hydrochloride (56.2 g, 190 mmol) was added to a solution of decyl alcohol (methanol) (31.8 mL, 230 mmol) and the mixture was stirred at room temperature. minute. Sodium borohydride (24.0 g, 630 mmol) was added portionwise with ice-cooling, and the mixture was stirred at room temperature for 4.5 hr. A 5N HCl solution (200 mL) was added and the mixture was evaporated. The aqueous residue was basified with aqueous sodium bicarbonate and extracted several times with a mixture of 9:1 di-methane: methanol. The extract was dried and evaporated to give a product (44.3 g, &lt MS (+ve ion electron spray) m/z 264 (Mh+). % (b) Racemic 4-hydroxy-1-(phenylmethyl)-3-hexahydropyridinecarboxylic acid in 4-hydroxyl-(phenylphenylsulfonium hexafluoropyridinecarboxylate (3 g) 21.4 NaOH (126 ml) was added to a solution of THF/water (800 ml / 80 ml). The reaction mixture was stirred at room temperature for 5 hours, and then 5N hydrogen acid solution was used. The pH was adjusted to 7. The concentrate was reduced by at least volume. The residue was extracted with 10% methanol/dichloromethane and the solid was filtered and extracted with 10% methanol/dichloromethane. The volume of the aqueous layer was separated from the extract, which was evaporated to the liver and the residue was extracted as above. The whole organic extract was evaporated to give the product (25·8 g, 96%). MS (+Ve ion-electron spray m/z 236 (MH+) 422 200817417 (C) Racemic 4-hydroxyl-(phenylphenyl)-3-hexahydropyridinium in 4-hydroxy-1-(phenylindenyl) _3_ hexahydropyridinecarboxylic acid (12 g) and triethylamine (3.53 ml, 25.5 mmol) in a solution of N,N-dimethyl decylamine (6 mM), 1-hydroxy-7 -azabenzotriazole (3.48 g, 25.6 mmol) and N-[3-(diamido)propyl ]-N,-ethylcarbodiimide hydrochloride (8.54 g, 56.2 mmol). After stirring for 5-10 minutes, ammonium bicarbonate (15.3 g, 204 mmol) was added. The organic layer was dried and evaporated. The residue was chromatographed on silica gel eluting with 1 - 2 〇% decyl alcohol / chlorohydrin to give the desired compound (4.15 g, 35%). Product (1·02 g) MS (+ve ion electron mist) m/z 235 (ΜΗ' 80%), 257 (1%). (d) Racemic aminomethyl (phenyl) a suspension of 4-hydroxyl-(phenylmethyl)_3_hexahydropyridiniumamine (5.62 g, 23 9 mmol) in THF (65 mL). The mixture was treated dropwise with a borane-indole sulfide complex (2 Μ solution in THF, 26.4 mL, 52.8 mmol). After stirring at room temperature for 5 hours, the reaction mixture was heated at 80 ° C for 1.5 hours. Add sterol (16 ml) and The mixture was heated for 5 hours. The mixture was evaporated and the residue was chromatographed on silica gel eluting with 1 〇 -3 〇% (2 Μ 曱 曱 曱 / / / , , , , , , , , 2.6 2.6 2.6 MS (+ve ion electron spray) m/z 221 (ΜΗ+).

423 200817417 (e) Racemic {[4-hydroxy-1-(phenylindenyl)_3_hexahydropyridinyl] 1,1-dimethylethyl phthalate 3-(amino fluorenyl) )-1-(phenylmethylhexahydro). It is dissolved in dichlorodecane (1 〇〇 ml) and then dicarbonate 5 2-3 in comparison with hexanol (2·67 g, 12.1 house Moule). A solution of butyl ester (2·67 g, H2 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 4 hr. The product was obtained by eluting with 〇2〇%(2]^1 ammonia/sterol)/dichloromethane (3·12 g, 81 °/〇) MS (+ve ion electron spray) m/z 321 ( ΜΗ+), 265 (removal of C4H8). 10 (f) Racemic {[4-hydroxy-3-hexahydropyridinyl]methyl} carbamic acid-monomethyl hydrazine Small (phenylindolyl)-(3-hexahydropyridinyl)hydrazino}amine ruthenate, dimethyl dimethyl ester (3·7 g, 11.5 mM millimolar) in methanol (70 ml) In the 15th, the gluten solution was stirred overnight with 20% palladium hydroxide/carbon (moist, 〇·7 g) at room temperature under a hydrogen pressure. Filtration through diatomaceous earth, evaporation of methanol to give the desired product ( 2·65 g, 100%) MS (+ve iontophoresis) m/z 231 (ΜΗ+). 2〇(g) racemic ({1_[2_(7-gas_2-keto-) 1(2H)+ 咁))ethyl]-4-hydroxy-3-hexahydropyridyl}methyl)carbamic acid u-dimethylethyl ester will be racemic {[4-amino-3) -hexahydropyridyl]fluorenyl}amino decanoic acid 1, bisdidecyl ethyl ester (2.65 g, 11.56 mmol) and 7-fluoro-2-keto-1 (2H)-fluorenyl) A mixture of acetaldehyde (see Example 34(c) for the synthesis) (2 39 g, ι 6 424 200817417 MeOH) in dichloromethane (75 mL) and methanol (3·8 mL) Add sodium triethoxysilane borohydride (7·39 g, 34 67 耄mol) and continue to stir for 4 hours. Add the aqueous solution of hydrogen hydride to verify the liquid layer and separate the water layer. The mixture was extracted twice with decyl alcohol/dichloromethane and the organic layer was dried and evaporated. EtOAc EtOAc EtOAc EtOAc MS (+ve ion electron spray)^/ζ 421 (ΜΗ+). (h) Racemic ({1-[2-(7-fluoro-2-keto-1(2H)_喳) Ethyl]ethyl]_4_ 1 fluorenyl-3-hexahydropyridinyl} 1,1-dimethylethyl guanidino phthalate in racemic ({1-[2-(7-fluoro-2-keto-1(2H)-4 yl)ethyl)&gt; 4-ylamino-3-hexahydroacridinyl}hydrazino)amino phthalic acid u-dimercaptoethyl (2.0 g, 4.76 mmol) in anhydrous dichloromethane (12 mL) Dess-Martin periodinane was added in portions (丨丄 参 ( (醯 醯 丨 ;;; ^ dihydro 15 -1, 2 · benzoiodonium _3_(1] 9 [),, 3.03 g, 7.12 Millions) lasted 5 minutes. After the mixture was stirred for 1 hour, a 1% aqueous solution of sodium sulfite (7 liters) and an aqueous solution of sodium hydrogencarbonate (6 liters) were added and stirring was continued for 5 hours. The liquid layer was separated and the aqueous layer was extracted twice with dichloromethane. The organic extract was dried and evaporated. EtOAc mjjjjjjj MS (憎 ion electronic spray) m/z 441 (MNa+), 459

([M+H20]NaV (1) outside / 旋旋ί±({4_[(2,3_ dihydro[ι,4] dioxin and [2,3_cp ratio bite_7_ base 425 s 200817417 = base) Amino]-l-[2-(7-fluoro-2-keto-1(2H)-indolyl)ethyl]-3_hexahydropyridinyl}indenyl) carbamic acid hydrazine, ^ two Mercaptoethyl ester isomers 丨 and 2 will be racemic ({1-[2-(7-fluoro-2-keto-i(2H)-fluorenyl)ethyl]-4-keto) -3-3-hexahydropyridyl} fluorenyl) guanidinium carbamate, bisdidecyl ethyl ester 5 (1·35 g, 3·23 mmol) and (2,3-dihydro[1,4] Oxygen and [2,3刈pyridylmethyl)amino]amine (〇·54 g, 3·23 mmol, from 2,3-diindole [1,4]-oxy-S and [2,3 -c]pyridine-7-ylmethanol (synthesis see WO2004002490, example 6(b)) with diphenylphosphonium azide and hydrazine, 8-diazabicyclo[5.4〇]undec-7- The alkene is prepared in toluene at room temperature, then at room temperature, followed by hydrogenation of the resulting azide via a 5% Pd/C paste in 2:1 1 ethanol/acetic acid. Mix the mixture in (30 ml) and methanol (3 ml) with 3 molecular sieves: mix for 1 hour. Add triethoxymethoxypenicillin (2·〇5 g, 9.69 mmol) And continue to stir at room temperature. After 6 hours, add more borohydride (〇·20g), add more amine (0·20g) and borohydride (〇.8〇15g) after overnight. After stirring for another 6 hours, an aqueous solution of sodium hydrogencarbonate was added and the layers were separated. The aqueous layer was extracted twice with 10% methanol/dichloromethane and the organic extracts were dried and evaporated. , eluted with 0-20% decyl alcohol / dioxane, the main product (isomer 1,1·12 g, 61%) was obtained first, followed by the minor product (isomer 2,0·10 g) , 5% good purity and purity of 〇·ΐ7g poor 20) MS (+ve ion electron spray) m/z 569 (ΜΗ+). (j) The title compound will be racemic ({4-[( 2,3-Dihydro[1,4]dioxo[2,3-c]pyridine-7-

426 200817417 hydrazinyl)amino]&gt;1-[2-(7-fluoro-2-keto-1(2H)-44-phenyl)ethyl]-3-hexahydropyridinyl}hydrazino)carbamic acid 1,1-dimethylethyl ester isomer 1 (0.55 g, 0·〇9 mmol) was used dropwise in 1, in dichloromethane (2 ml) and methanol (1 ml). The mixture was treated with EtOAc (2 mL). MS (+ve ion electron spray) m/z 469 (ΜΗ+). Example 257 (+/-) 1-(2_{3-(Aminoguanidino)-4_[(2,3-dihydro[1,4]dioxo 10 oxime[2,3-c]pyridine- 7-ylmethyl)amino]-1-hexahydropyridylhydrazineethyl&gt;7-fluoro-2(1H)-nonanthone isomer 2 trihydrochloride

15 20 will be racemic ({Heart [(2,3_ dihydro[1,4] bismuth [Hep than pyridylmethyl)amino]-[2-(7-fluoro-2- Keto group · 1 (2 Η) + Nodyl) ethyl] 冬定基} fluorenyl) carbamic acid ... dimethyl ethoxylated isomer 2 (about = purity 'G.05 g' 0.09 mmol) Dichloromethane (2 ml) and _hydrochloric acid (2 ml) used in the dropwise addition of dimethyl hydrate were not allowed to stand at room temperature for 2.5 hours and then evaporated. The residue was treated with hydrazine and extracted several times with 1% methanol/dichloromethane. Will be sent. Chromatography on Shishi gum, using 〇3 〇% (in methanol, if eluted, to give the free compound of the title compound (29)

427 ·(S 200817417 MS (+ve iontophoresis) m/z 469 (MH+). The free base of the title compound was used in dichloromethane in 4M hydrogen acid in 丨, 4_二吟院. • 46 ml) was treated and the solvent was evaporated to give trihydrochloride (42 mg). </RTI> </RTI> 258. <RTI ID=0.0># </ </ </ 4] Dioxaindolo[2,3-c]acridine-7-ylindenyl)amino]mercaptohexahydropyridyl)ethylfluoro-2(1H)-porphyrinone trihydrochloride

(a) 1-[2-(3-{[(2,3-Dihydro[1,4]dioxo[2,3-c]pyridine-7-ylmethyl)amino]methyl} -4·hydroxy-1-hexahydropyridinyl)ethyl]_7_gas-2(1H)-isophilic thyrosine oxime 1^, about 77% pure oxindole[2,3-c]pyridin Bite -7-aldehyde (which will be racemic ({1-[2-(7-fluoro-2-keto)(2Η&gt; 唆林)yl)-4-keto-3-hexahydro Pyridyl} indenyl) guanidinium carbamate, bis-decylethyl ester (preparation see Example 254(h)) (1.3 g, 3.14 mmol) in dichloromethane (3 〇 liter) at room temperature Treated with trifluoroacetic acid (12 ml) for 15 hours. The solvent was removed, triturated with diethyl ether and treated with Mp_ carbonate resin in 10 〇 / decyl alcohol / dichloro decane to remove 1-{2-[ 3-(Aminomercapto)-4-hydroxyhexahydroport butyl]ethyl}-7U(lH)_ valenolin (1·31 g, degree). This material is 2,3- Dihydro[1,4]di 428 200817417 Obvious W02004058144, Example 2(c) or W003/087098, Example 19(d)) (0.52 g, 3.14 mmol) and 3A molecular sieve in 1:1 chloroform/methanol ( In 80 ml), heat under reflux overnight, then add sodium triethoxysulfonate (3.28 g, 15 mmol) and The mixture was stirred at room temperature for 8 hours. It was basified with aqueous sodium bicarbonate solution, extracted with 1 〇〇/0 decyl alcohol/dichloromethane and chromatographed on silica gel, washed with 0-20% decyl alcohol / methane. Raise and then elute with 〇20% (2Μ ammonia/nonanol)/dichloropurine to obtain the product (〇·57 g, 37〇/〇) MS (+ve ion electron spray) m/z 470 ( ΜΗ+). (8) (2,3_Dihydro[1,4]dioxo[2,3_c]pyridin-7-ylindenyl){1_[2-(7-fluoro-2-keto-1 (2H) 奎 十 林 ))) ethyl]_4_keto-3-hexahydropyridyl} fluorenyl) 1,1-dimethylethyl carbazate 1-[2_(3-{[( 2,3_Dihydro[1,4]dioxo[2,3-cK-pyridin-7-ylmethyl)amino]indenyl}-4-yl-l-hexahydro-sigma ratio) Ethyl]-7-fluoro-2(lH)_4ti morphone (〇·54 g, ι·ΐ 5 mmol) and di-tert-butyl di-butyrate (0·27 g, 1.2 mmol) It was stirred at room temperature overnight in dichloromethane (2 mL). The mixture was washed with an aqueous solution of sodium hydrogencarbonate, the solvent was removed, and the residue was chromatographed on the saponin and eluted with 〇-1〇〇/0 sterol/dichloropyrene to obtain (2,3-dihydrogen). [1,4] Dioxo[2,3_decapyridyl_7_ylindazyl-helium-fluoro-2-keto-1-(2Η) "Quitalin" ethyl hydrazine- Ketosyl_3_hexahydropyridyl}methyl) Isomer of 1,1-dimethylethylamine decanoate (total 527 g, 80 〇/〇). This material is combined with Dess-Martin Transiodane (1,1,1_g ((ethoxy)oxy)_ι, ι_dihydro-1,2-benzidino_3-(ih)_S, 0.59 g, 1.39 mmol) Stir in dichlorohydrin (25 ml) at room temperature for 2·25 hours. Treat the mixture with sodium sulfite, ./* Ρ·ν 429 ' ^ 200817417 aqueous solution and sodium bicarbonate solution (15 liters each) 〇·5 The liquid layer was separated, the aqueous layer was extracted with dichloromethane, and the organic extract was evaporated to give a residue, which was chromatographed on silica gel and washed with 0-10 〇 / sterol / dichloro decane. And then eluted again with 0-10% decyl alcohol / ethyl acetate to give the product (0.23 g, 44%) MS (+ve ion electron spray) m/z 568 (Μ +) (c) ({4-Amino small [2_(7-fluoro-2-keto-1(211)-hydroxyquinolinyl)ethyl]-3-hexahydroacridinyl} fluorenyl (1,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)amino decanoic acid 1,1-dimethylethyl ester (2,3 -Dihydro[1,4]dioxo[2,3-c]pyridine-7-ylindenyl){1-[2-(7-fluoro-2-keto-i(2H)-喳崎Mercapto)ethyl&gt;4-keto-3-hexahydropyridinyl}decyl)amino decanoic acid-didecylethyl ester (0.23 g, 〇·41 mmol) and ammonium acetate (0.31 The mixture was stirred for 4 hours in 1:1 dichloromethane (1 mL). Stirring was continued for two nights, after the first night, the shed hydride was added again (as mentioned above) and added again after 7 hours. It was alkalized with sodium bicarbonate and extracted with 1 〇〇/0 sterol/dichlorodecane. The organic extract was evaporated and chromatographed on silica gel eluting with EtOAc EtOAc EtOAc EtOAc (EtOAc) Spray) m/z 569 (ΜΗ+). (d) The title compound will be ({4-amino-1_[2_(7_fluoro-2-) Group _1 (2Η) -σ Kyu Han aminopterin-yl) acetate

430 200817417 yl]-3-hexahydroacridinyl}indenyl) (2,3-dihydro[1,4]dioxo[2,3-c]pyridinyl-7-ylmethyl)amine 1,1-Dimethylethyl carbamic acid (0·10 g, 0·21 mmol) was treated with trifluoroacetic acid in dichloromethane by the method outlined in part (a). After treating with MP-carbonate resin and removing the solvent, the crude material was chromatographed on 5 矽 gel and eluted with 0-20% (2M ammonia/nonanol)/dichlorodecane to obtain the product free grievance. Two washed compounds. This was further purified by automated HPLC equipped with a mass-directed fraction (monitor Mw 468). After evaporating the eluate, the residue was treated with 4M hydrochloric acid and methanol in excess of 1,4-dioxane. The solvent was evaporated to give the titled trihydrochloride 10 (30 mg). MS (+ve iontophoresis) m/z 469 (MH+). Table 6: Examples 282-307 were prepared from the specific starting materials via the methods outlined in Examples 121 (c)-(e). Example number test for the structure of the starting material (preparation see the examples mentioned) 282 free-form base MS (ES+) m/z 403 (MIT) Φ φ° (2-keto-1,5-naphthyridine-1 ( 2Η)_))acetic acid (from 1,5-naphthalene-2 (111)-_ (see J. Chem. Soc., 212-214, 1956)*, which was first treated with sodium hydride and then with ally After the treatment with keel, 1-(2-propenyl-1-yl)-5-naphthalene-2(1H)-indole is obtained, which is subsequently treated with OsCVNalO4 to give the title compound. 431 200817417 4- hexahydroindole 1,1-dimethylethyl formate 1-benzoquinone-2-acid (commercial supply) 283 free-form alkali MS (ES+) m/z 420 (ΜΗΓ) 么~〇rN^〇(7-gas 2-mercapto-1(2H)-indenyl)acetaldehyde (Example 2(d)) 4-Hexidopyridylaminocarbamate 1,1-dimethylethyl ester 1-benzofuran-2 - aldehyde 284 free-form base MS (ES+) m/z 432 (ΜΗ&quot;) 夂~〇rN^°丨1-[2-(4-amino-1-hexa-nitrogen-butyryl)ethyl]-7 -(Methoxy)-2(1Η)-fluorenone, commercially available according to the description of Example 12(ab)**, 1_benzoquinone-2-acid commercial supply) 285 free-form base MS (ES+ m/z 433 (MH^ Λ ; 丨j [7-(methoxy)-2-) Benzyl-I,5-naphthyridin-1(2H)-yl]acetaldehyde (mercapto hemiacetal) (Example 11(e)) 4-hexa.1,1-dimethyl group of 17-based carboxylic acid Ethyl 1-benzoquinone-2-carboxylic acid (commercially available) 286 free-form base MS (ES+) m/z 449 (MFt) Λ ryH^〇V^N 〜Nj u0 1-[2-(4- Amino-1-hexafluorobutanyl)ethyl]-7-(methoxy)-2(1Η)-fluorenone, 1,3-benzoyl according to Example 12 (a-b)** Thiazole-2-aldehyde (commercial supply) 432 s* 200817417 287 free-form base MS (ES+) m/z 437 (μηΤ) 夂~〇rN-» (7-fluoro-2-keto-1(2H)- Acetyl) acetaldehyde (Example 2 (6)) 4- hexahydro guanidinocarbamic acid 1,1-dimethylethyl ester 1,3-benzothiazole-2- aldehyde (commercial supply) 288 free test MS (ES+) m/z 402 (ΜΗ4) a^〇rN^〇: (2-keto-1(2Η)-4 phenyl) acetaldehyde (commercially available from 2(1Η)-4^林The ketone is reacted with sodium hydride and then reacted with ethyl iodoacetate to give (2-keto-1(2H&gt; 4 fluorenyl)acetate. This is followed by reduction with sodium borohydride to give 1-(2-hydroxyethyl)-2(1 fluorene)-carboline, which is obtained from the titled compound. 1,1-Didecylethyl carbamic acid 1-benzofuran-2-acid (commercially available) 289 Free-form base MS (ES+) m/z 452 (ΜΗ&quot;) a^a^; (2- Ketopropyl-1(2Η)-4-mentyl)acetaldehyde (obtained as described in Example 288) 4-Hexidopyridylaminocarbamic acid 1,1-dimethylethyl ester 5- fluoro-1-phenylindole Pheno-2-acid (see Bioorganic &amp; Medicinal Chemistry, 12(9), 2251-2273; 2004) 433 200817417 290 Free-form base MS (ES+) m/z 453 (ΜΗΓ) 广1 ςα° 1 (2- Mercapto-1,5-tealt-1(2H)-yl)acetaldehyde (from 1,3-pentazinidine-2(1H)-one (obtained as described in Example 282) 4-hexahydropyridyl 1,1-dimethylethyl phthalic acid 6-chloro-1-benzophenan-2- acid (commercially available) 291 free-form base MS (ES+) m/z 414 (ΜΗΤ) ~αΝ^ ° (2-keto-1,5-naphthyridin-1(2H)-yl)acetaldehyde (from 1,5-naphthyridin-2(1H)-one (obtained as described in Example 282) 4- Six Hydrogen pyridylcarbamic acid 1,1-dimethyl Ester 2-hydroxyl. Lin 292 free state test MS (ES+) m/z 404 (ΜΗΓ) (2-keto-1(2Η)-4 fluorenyl) acetaldehyde (obtained according to the description of Example 288) 4- Six rat σ ratio σ定定胺1,1-didecylethyl 2,3-diaza-1-benzoquinone-5-aldehyde (commercial supply) 293 free-form base MS (ES+) m/ z 422 (MH^) (7-fluoro-2-indolyl)-1(2Η)-indenyl)acetaldehyde (Example 2(8)) 4_6 gas 吼17-based carboxylic acid 1,1-dimethyl乙酉2,3-Diazin-1-benzoquinone-5-aldehyde (commercial supply)

434 200817417 294 Free State Base MS (ES+) m/z 419 (ΜΗΓ) ca° (2-keto-1,5-naphthyridin-1(2H)-yl)acetaldehyde (from 1,5-naphthyridine) -2(1H)-ketone (obtained according to the description of Example 282) 4-hexahydropyridylaminocarbamic acid 1,1-dimethylethylhydrazine 1-benzothiophene-5-aldehyde (commercial supply) 295 free state Base MS (ES+) m/z 418 (μηΓ) QN~〇rN (2-keto-1(2H)-fluorenyl) acetaldehyde (obtained according to the description of Example 288) 4-hexazone 1717-decylamine 1,1-dimethylethyl benzoate 1-phenylporphin-5-acid (commercial supply) 296 free-form base MS (ES+) m/z 436 (MET) PA (7-fluoro-2-one -1(2H)-indenyl)acetaldehyde (Example 2(d)) 4-Hexidopyridylaminocarbamate 1,1-dimethylethyl ester 1-benzothiophene-5-aldehyde (commercial Supply) 297 free state test MS (ES+) m/z 448 (ΜΗ&quot;) 1-[2-(4-Amino-1-hexachlorobutidinyl)ethyl]_7-(decyloxy)- 2(1Η)-fluorenone, commercially available according to the example 12(ab)**, 1-benzophenone-5-acid^ commercial supply) 298 free-form base MS (ES+) m/z 449 ( MH^) N "~C^ [7-(decyloxy)-2-keto-I,5-naphthyridin-1(2H)_yl]B (Mercapto hemiacetal) (Example 11(e)) 435 200817417 4-Dihydropyridylaminocarbamic acid 1,1-didecylethyl ester 1-benzothiophene-5-aldehyde (commercial supply) 299 Free MS (ES+) m/z 421 (ΜΗΓ): (2-keto-1,5-naphthyridin-1(2H)-yl)acetaldehyde (from 1,5-naphthyridin-2) 1H)-ketone (obtained according to the description of Example 282) 4- hexahydropyridylaminocarbamic acid 1,1-didecylethyl 2,3-dihydro-1,4-benzodioxan-6-aldehyde (Commercial supply) 300 free-form alkali MS (ES+) m/z 451 (ΜΗΓ) 八&quot;J〇C0] [7-(methoxy)-2-yl-1,5-naphthyridine-1 (2H _ base] acetaldehyde (methyl hemiacetal) (Example 11 (e)) 4-hexahydropyridylamino decanoic acid 1,1-dimethylethyl 2,3-dihydro-1,4- Benzodioxan-6-aldehyde (commercial supply) 301 free-form base MS (ES+) m/z 435 (MPT) 夂~σ shoulder (7-fluoro-2-keto-1(2H)-喳呤Mercapto) acetaldehyde (Example 2(d)) 4-Hexpyridylaminocarbamic acid 1,1-didecylethyl ester 1-methyl-1H-1,2,3-benzotriazole-6- Aldehydes (see WO 2004007491 A1) 302 free-form base MS (ES+) m/z 447 (ΜΗΤ) cT fVN, 1-[2-(4-amino-1-hexafluoropyridyl)ethyl]-7- (曱Base)-2(1Η)-fluorenone, according to the description of Example 12(ab)**, 436 200817417 1-mercapto-1Η_1,2,3-benzotriazole-6-aldehyde (commercial supply) 303 free state base MS (ES+) m/z 409 (MKT) ίΤ^ι Κι μ Κι (2-keto-1,5-naphthyridin-1(2Η)-yl)acetaldehyde (from 1,5- Tea 11 -2 (111)-oxime (obtained according to the description of Example 282) 4-hexamethyl hydrazide 17-decylaminocarbamic acid 1,1-didecylethyl ester imidazo[2,lb][l,3]thiazole -6-aldehyde (commercial supply) 304 free-form base MS (ES+) m/z 464 (ΜΗΓ) gossip jCx. [7-(decyloxy)-2-yl-1,5-naphthyridinyl-1(2H)-yl]acetaldehyde (methyl hemiacetal) (Example 11(e)) 4-hexahydro 1,1-dimercaptoethyl pyridylaminocarbazide 4-mercapto-3,4-dihydro-211-1,4-benzoindole-7-aldehyde (commercial supply) 305 free state test MS (ES+) m/z 461 (ΜΗΓ) 1- [2-(4-Amino-1-hexa-pyrene ratio σ-decyl)ethyl]-7-(decyloxy)-2(1Η)_pyridone 2- mercapto-1,2,3,4-tetrazir-7-furfural was obtained according to the example l2(ab)** (see WO 2006137485 Α1 ρ·225, papr [0489] 295) 306 Free state test MS (ES+) m/z 462 (ΜΗΤ) [7-(methoxy)-2-keto-1,5-naphthyridine_1(2H)-yl]acetaldehyde (mercapto hemiacetal) (Example 11(e)) 437 C 3 200817417 4- Six mouse 比1,17-dimethylethyl carbazide 1,1-dimethylethyl 2-mercapto-1,2,3,4-tetras-7-喳Porphyrin (commercial supply) 307 free state test MS (ES+) m/z 416 A〇(2-mercapto-1,5-Qinbit-1(2Η)-yl)acetaldehyde (from 1,5- Naphthyridine-2(1Η)-one (obtained as described in Example 282) 4-hexahydropyridylamino decanoic acid 1,1-dimethylethyl ester 1-mercapto-1 fluorene-indole-2-aldehyde ( Commercial supply) * 1,5-naphthalene -2(1H)-one can also be obtained by dehalogenation of 8-bromo-2-(decyloxy)-1,5-naphthyridine by treatment with 10% H2Pd/C in EtOH followed by hydrolysis with 6NHC1 The title compound is obtained in 76% yield. ** This compound can also be obtained from sodium hydride and then [1-(2-ethylethyl)-4-hexahydropyridinyl]amino phthalic acid U-didecyl Ethyl ester treatment of 7-(decyloxy)anthracene (Example 1 (8)). This amino chloroethyl phthalate was obtained by using 5 NaBH(OAc)3 as a reducing agent in a single step to give chloroethane and 4-hexahydroindole. Obtained by reductive amination of 1,1-dimethylethyl phthalate decanoate. Table 7: Unless otherwise stated, Examples 308-317 were used by the method outlined in Examples 121 (c)-(e) The central unit of the tributoxycarbonyl protection and the central unit for the protection of the benzyloxycarbonyl group by the method outlined in Example 61 (b)-(d) were prepared from a specific starting material. 438 200817417 The formal structure of the example numbering test Starting material (preparation see the examples mentioned) 308 Trifluoroacetate MS (ES+) m/z 483 (ΜΗ&quot;) 1 [3_(Methoxy)-6-ketopyrido[2,3-b]吼Plow-5(6H)-yl]acetaldehyde (Example 94(m)) {[(3R,4R)-4-hydroxy-3-6 Phenylmethylidene]methyl}aminocarbamate (Example 135(f)) 2,3-Dihydro[1,4]dioxan[2,3-division bit-7-acid (W02004058144, Example 2(c) or W003/087098, Example 19(6)) 309 Trifluoroacetate MS (ES+) m/z 450 (MHO, r〇«XO: [6-(methoxy)-3-ketoacridine [2,3-b] ton of cultivable-4(3H)-yl]acetaldehyde (Example 126(e)) 4-hexahydroindoletriamine decanoic acid 1,1-dimethylethyl ester 5,6, 7,8-tetrahydro-2-purine aldehyde (from the condensation of copper hexoxide with methyl decanoate in the presence of sodium decoxide to give (2E)-2-(hydroxymethylene)cyclohexanone sodium salt. Condensation of (2E)-2-(hydroxymethylene)cyclohexanone sodium salt with (2E)-3-phenyl-2-propionimide in ethanol at 80 ° C to give 2-[(E) -2-Phenylvinyl]-5,6,7,8-tetrahydro. Kui saliva 0 forest. Ozone decomposition of 2-[(E)-2-phenylethylene 439 200817417 base]-5,6,7,8-tetrahydroanthracene sulphate gives 5,6,7,8·tetrahydro-2-hydroxyl Tannic acid). 310 Trifluoroacetate MS (ES+) m/z 452 (ΜΗΓ) :] [7-(Methoxy)-2-yl-1(2H)-indenyl]acetaldehyde (Example 1(d) 4-Dihydropyridylamino decanoic acid 1,1-dimethylethyl hydrazine is 6,7-dihydro[1,4]dioxo[2,3-c]. Bite-2-acid (W02004014361, intermediate 8) 311 II-HC1MS (ES+) m/z 466 (ΜΗΓ) W [6-(methyllacyl)-3-fluorenyl σ-pyridyl and P,3-b吼耕-4(3Η)-yl]acetaldehyde (Example 126(e)) {[(3R,4S)-4-Hydroxy-3-pyrrolidinyl]methyl}carbamic acid phenylmethyl ester 5, 6,7,8-tetrahydro, 2-port quinine sitting linal (Example 309) 312 Di-trifluoroacetate MS (ES+) m/z 467 (MFt) r-〇~v^^ [6- (Methoxy)-3-keto-p-pyridyl[2,3-b]indole. Well-4(3H)-yl]acetaldehyde (Example 126(e)) 4-Hexidopyridylaminocarbamic acid 1,1-dimethylethylhydrazine 7-keto-6,7-dihydro-1H_ Pyrimido[5,4-7][1,4]indole-2-aldehyde (Preparation F) 312 Di-HC1 salt MS (ES+) m/z 454 (Mtf) 7-Ga-2-indole-1 2H)-indenyl]acetaldehyde (Example 34(c)) 4-Hexidopyridylaminocarbamate 1,1-dimethylethylhydrazine 7-keto-6,7-dihydro-1H-pyrimidine 440 200817417 pyridine[5,4-b][l,4]哼耕-2-aldehyde (Preparation F) 313 II-HC1 MS (ES+) m/z 483 (ΜΗΓ) Λ' &quot;XX7° [6- (Methoxy)-3-ketopyrido[2,3-b] ton _4(3H)-yl] acetaldehyde (Example 126(e)) {[(3R,4S)-4-hydroxy_ 3_pyrrolidinyl]methyl}amino phenyl benzoate 7-_yl-6,7-dihydro-indole-mouth pyridine [5,4-7][1,4] sulphonic-2-aldehyde (Preparation F) 315 mono-HC1 salt MS (ES+) m/z 454 (MPf) X; I7F 7-fluoro-2-keto-1(2Η)-fluorenyl]acetaldehyde (Example 34(6)) [( 3R,4S) 1,1-dimethylethyl hydroxy-4-hexahydropyridyl]amino decanoate (W02004058144, Example 5(c), cis-(3-lightyl-4-hexahydropyridyl) ) tert-butyl carbamic acid to palm isomer 1) 7-keto-5,6,7,8-tetrahydro-perpyridinium [ 2,3-d]pyrimidine-2-aldehyde (Example 125(c)) 316 Di-HC1 MS (ES+) m/z 483 (MKT) hvt work.丨,^ j [6-(Methoxy)-3-ketopyrido[2,3-7]indole-4(3H)-yl]acetaldehyde (Example 126(4)) {[(3R,4S)-4 -Hydroxy-3-pyrrolidinyl]methyl}amino phenyl carbazate 6-indoleyl-6,7-dimur cultivating [3,4-b][l,4]. Well-3_ aldehyde (similar to 6-keto-6,7-dihydro-5H-indole

441 200817417 [3,4-b][l,4]tit-3-aldehyde (WO 2004/058144 Example 58(d)) but with methyl glycolate instead of methyl thioglycolate 317 II-HC1MS (ES+ m/z 467 (MHT) 〇yW〇U7 — i [6-(decyloxy)-3-ketopyridino[2,3-7] ton-4(3H)-yl]acetaldehyde (Example 126) (e) 4-Dihydropyridylaminocarbamate 1,1-dimethylethyl 6-keto-6,7-dihydro-5H-indole and [3,4-b][l,4啐耕-3-aldehyde (Example 316) Bioactive antimicrobial activity test: 5 10 Using the method recommended by Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, "Methods for Dilution Susceptibility Tests for Bacteria that Grow Aerobically" Whole cell antimicrobial activity was determined by microdilution of microbial liquid medium. The compounds were tested in sequential two-fold dilutions ranging from 0.016 to 16 meg/ml. The compounds were evaluated against Gram-positive microorganisms selected from the group consisting of Staphylococcus aureus, Streptococcus mutans, Streptococcus pyogenes, Streptococcus faecalis, and Streptococcus faecium. This evening also evaluated the compound against Gram-negative microorganisms, selected from the group consisting of B. catarrhalis, E. catarrhalis, Escherichia coli, Pseudomonas aeruginosa, Legionella faecalis, Chlamydia pneumoniae, Enterobacter cloacae , puerperal cognac, Klebsiella pneumoniae, malt-like maltese cells g and pneumonia 442 15 200817417 protoplasts. • Testing Legionella pneumoniae isolates using an improved CLSI method for microdilution of microbial liquid media. For this test, the compounds were tested in sequential two-fold dilutions in the range of 〇3 to 32/concentration. The inoculum of each test isolate was prepared in buffered leaven 5 parent microbial liquid medium and adjusted to a density equivalent to 0.5 McFarland standard. After inoculation, the microtiter plate was incubated at 37 ° C for 72 hours. For the Chlamydia pneumoniae isolate, the stock solution was thawed and diluted in CCM (Chlamydia Culture Media) to obtain an inoculum containing ~; [x 104 inclusion bodies 1 〇 forming unit / ml GFUs / ml). A 100 microliter aliquot of the inoculum was added to all wells of a microtiter plate containing Hep-2 (human epithelial (pharyngeal) cell line) cells to confluent growth. The microtiter plate was centrifuged at 1 〇〇g for 1 hour and then incubated at 35 C for 1 hour in 5% C 〇2. Ten microliters of the diluted test compound prepared in a 2-fold dilution sequence in CCM/cycloheximide was then added to the microtiter plate. After 72 hours of incubation in 5% CO 2 at 35 ° C, the microtiter plates were stained with mouse monoclonal fluorescently coupled antibodies (Kallestad Cat· #532 Roche Biomedical Products) according to the manufacturer's recommendations. After staining, the IFUs produced an apple green color, and the stained Hep-2 cells were visually observed via a red counter under loo magnification observation. MIC 20 is defined as the lowest concentration of a compound when no IFUs are seen. P. pneumoniae MICs were determined using the method described by Tanner and Wu [1992]. This method has been modified to allow for the pre-determination of the approximate titration of challenge inoculum and the test target is set at 1〇4 cfu/liter, with a tolerance of 1〇3–1〇5 cfu/ml. 443 200817417 The inoculum was normalized to approximately 1×10 07 cfu/ml and diluted 1/100 in Middlebrook 7H9+ ADC medium and 0.025% Tween 80 (Sigma P4780) to obtain the final inoculum of H37Rv species (ATCC25618). One hundred microliters of this inoculum was added to the entire plate except for the G-12 and H-12 tanks (blank control group 5). All the plates were placed in a sealed box to prevent the surrounding grooves from drying and incubated at 37 ° C for 6 days without shaking. The resazurin solution was prepared by dissolving a piece of Azurol (Resazurin Tablets for Milk Testing; Ref 330884Y VWR International Ltd) in 30 ml of sterile PBS (phosphate buffered saline). Add 25 μl of this solution to each tank. Fluorescence measured after 48 hours (Spectramax M5

Molecular Devices, 530 nm excitation, 590 nm radiation to determine the MIC value. Results of the Mycobacterium tuberculosis H37Rv inhibition test method 15 Examples 2, 4-13, 15A, 16-23, 25-28, 31, 34-39, 41, 43, 45, 46A, 49, 51B, 53, 56, 57, 64, 65, 73, 74, 77, 78, 80, 83, 86-89, 9 94-97, 100, 101, 106, 107, 109, 110, 114, 116, 119-122, 129, 131, 134-136, 138-141A, 144, 147-149, 158, 159, 162, 164A, 165, 170A, 171, 20 173, 177, 179, 180, 182, 188-190, 193-194, 205, 209 , 211, 212, 217-219, 225, 226, 228, 232, 237, 244, 251, 254, 257, 258, 265, 266, 270, 271, 273, 274, 276, 278 and 282-307 in tuberculosis Bacillus H37Rv inhibition test in the test. Example 2, 4·13, 15A, 16-21, 27, 34, 37-39, 45, 46A, 51B, 445 200817417 53, 57, 65, 73, 74, 77, 80, 88, 89, 94, 95 , 106, 107, 109, 110, 114, 116, 120, 122, 129, m, 134-136, 138, 139, 144, 147-149, 158, 162, 164A, 165, 170A, 171, 173, 179 , 180 , 182 , 190 , 193 &gt; 205 , 209 , 211 , 5 212 , 217-219 , 225 , 226 , 228 , 237 , 244 , 273 , 276 , 278 , 282-290 , 292-298 , 300 , 302 , 304-306 shows that the MIC value is 4.0 μg/ml or lower. Examples 4-6, 10_13, 15A, 16, 18, 19, 21, 27, 34, 39, 45, 46A, 65, 73, 77, 80, 88, 89, f 94, 95, 106, 107, 109, 110, 114, 116, 122, 129, 135, ί 136, 139, 144, 147-149, 162, 164A, 165, 170A, 171, 173, 179, 182, 190, 205, 209, 2U, 212, 217 -219, 228, 237, 244, 273, 276, 278, 283-286, 290, 292-298, 300, 304-306 showed a MIC value of 1.7 μg/ml or less.

446

Claims (1)

200817417 X. Patent Application Range: 1. The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or N-oxide thereof: θ A-NR^——UR5 (I) where two of Zl, Z2, f, and f are independently CR1, N and the rest of the sites are CR e; or z3 and z4 together represent that one of Saziz2 is cr1, n and the other independently Is CRlc; '15 20 and then independently selected from hydrogen; South base; (C丨-6) sulfur-burning group; trifluoromethyl group; trifluoromethane pit, : by = hindered carpet base, (C〗 6) Alkoxy-substituted (Ci_6) calcined hydrazine is optionally substituted by one or two I groups, a formazan 1 or an alkylcarbonyl group or a (CK6)alkylsulfonyl group - 1 1 s κ Zuo Li, / Zhiji; or amine base! Wherein the base is optionally passed (R in the C1 year base atom, 'Rib and the substituent in R1C' or in the dicentral dioxy group; one of them may form a stretching R squirrel or a (Cl _4) alkyl group, Or with R6, the shape is defined as Y 447 200817417 A is the base (1)·· R3 A 5 (ia) Wherein: R3 is based on the amine group of Rla, Rlb and Rlc and n is 1 or 2; the definition is either _ group or A is a group (ϋ): ten CH2 N (ϋ) 15 20 w1, w2 and w3 Is cr4r8 or W2 and W3 are CRV and wl X is 0, cr4R^nr6; and the bond between n. One R4 is based on Rla, Rib &amp; lc and 1 hydrogen or screaming and another R is hydrogen or (Cw) alkyl; or together with R2 forms γ; R疋 hydrogen; i group; Ck) a substituted hydroxy group; or a (Cl-6) fluorenyl group; Y is CR4R8CH2; CH2CR4R8; (〇0); CR4R8; cr4r8(c=〇); or (O0)CR4R8; or when X is CR4R8, R8 And r7 together represent a key; 448 200817417 U is a ring system (B) selected from the group consisting of CO and ch2x R5 which are optionally substituted bicyclic carbocycles or heterocycles: Containing up to four heteroatoms in each ring, at least one of which is aromatic (a) and (b) is aromatic; when X1 is part of the aromatic ring, it is C or N, when it is a non-aromatic ring The fraction is CR14. When X2 is part of an aromatic or non-aromatic ring, it is N, NR13, 0, S(0)x, CO or CR14. When it is part of a non-aromatic ring, it may be CR14R15, X3 and X5 are independently N or C; 15 Y1 is a linking group of up to 4 atoms, wherein each atom is independently selected from N, NR13 when it is part of an aromatic or non-aromatic ring. 0, S(0)x, CO and CR14, when it is part of a non-aromatic ring, it may be CR14R15, Y2 is a linking group of 2 to 6 atoms, and each atom of Y2 is aromatic or non-aromatic. A portion of the ring is independently selected from N, NR13, 0, S(0)x, 2〇CO, and CR14. When it is part of a non-aromatic ring, it may be CR14R15, and each R14 and R15 are independent. Selected from: H; (Cw) alkylthio; halo; thiol (Ci_4) alkyl, (Ci stomach 4) alkyl, (Ci_4) calcined base; (Ci_4) alkyl group, (Ci_4 Alkoxy (Ci_4) alkyl; Zhaoji; base (C!_4) alkyl; (Cl_4) alkoxy; nitro; cyano Carboxy; optionally substituted with (C^)alkyl mono- or di-449 200817417 substituted amino or aminocarbonyl, or R1 and R15 together represent a keto group; • each Rl3 is independently H; trifluoromethyl (Cm) alkane 5 group, (c2-4) alkenyl group, (Cl·4) alkane optionally substituted by a hydroxyl group, a (Cu) alkoxy group, a (Cu) alkylthio group, a dentate group or a trifluoromethyl group Oxycarbonyl; (Cw) alkylcarbonyl; ((^_6) alkylsulfonyl; aminocarbonyl wherein the amine group is optionally mono- or disubstituted by (Cw) alkyl; each X is independently hydrazine, 1 or 2. The compound according to claim 3, wherein each Rla, ruler 1{) and 1〇R1° are independently hydrogen, methoxy, methyl, ethyl, cyano or dentate. 3. A compound according to claim 2, wherein Rla is methoxy, cyano, fluoro, chloro or bromo and Rlb&amp; R1. Yes. 4. A compound according to any of the preceding claims, wherein r1 is hydrogen. 5. A compound according to any of the preceding claims, wherein 卩 is ^ only. 15 6. A compound according to any of the preceding claims, wherein: 1 Zj is N and each Z], 2; 3 and Z4 are independently CRlc; Z1 and Z2 are N and Z1 and Z4 are independently CRlc; Z4 is S together and Z1 and Z4 are independently; 23 and Z4 are S together and Z1 is CRle and Z4 is N; 2〇Z and Z1 are N and Z2 and Z4 are independently CRle. 7. A compound according to item 6 of the scope of the patent application, wherein R5 is a 6-substituted 2H "by bite [3, 2_b] [1, 4] ten wells · 3 (4 Η), k · 450 1 , 2&quot;&quot;Dihydro-[1,4]dioxo[2,3_c]acridine_7_yl 2 [1,3]indolo[5,4-indolyl]pyridin-6-yl 200817417 3,4 - dihydrogen-pyrano[2Χϋ is more than 6-substituted 2Η-pyridyl[3,2_^&gt;][1,4]thratic-3(411)-keto•6·substituted 7_chlorine _2沁pyrido[3,2-b][l,4K cultivative-3(4Η)-keto 6,7-dihydro[indene]dioxo[2,3-c]indole-3-yl 5 6,7-Dihydro[1,4]indole[2,3_c]indole-3-yl 2_substituted 1H-pyrimido[5,4_b][l,4;K 耕-7(6H __ 2_Substituted 5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one. 8. A compound according to claim 6 or 7 wherein A is (ia) Wherein η is 1 and R 3 is hydrogen or hydroxy or A is 3-hydroxypyrrolidin-4-ylmethyl 10 - or 4-hydroxyhexahydropyridin-3-ylmethyl. 9 · According to claims 1 to 5 A compound according to any one of the preceding claims, wherein R5 is: Wherein: Y3 is ch2 or 0; and R10 is independently selected from the group consisting of hydrogen, halo, (Cw) alkyl and (Ci.1) alkoxy. The compound according to any one of claims 1 to 5, wherein 5 is selected from the group consisting of: ^ 451 1 , 2-dihydroanthracene, 4] dioxin and [2,3-c] 3-yl 2 6,2-dihydro[1,4]indole[2,3_c]indole base 200817417 2-substituted 1H_pyrimidine[5,4-1)][1,4] -7(6H)__ 2-substituted 5,6-dipyrido[2,3-d]pyrimidin-7(1H)-one. 11. The compound according to claim 9 or claim 1, wherein: each of Z1, z2, Z3 and Z4 is independently CRlc; 5 &amp; is N and each Z2, Z3 and Z4 are independently CRlc; Z2 is N And each z1, Z3 and Z4 are independently CRlc; Z3 is N and each z1, Z2 and Z4 are independently CRle; Z1 and Z3 are N and Z2 and Z4 are independently CRlc; Z2 and Z3 are N and Z1 and Z4 Independently CRlc; 10 Z3 and Z4 are N and Z1 and Z2 are independently CRlc; Z3 and Z4 are S and Z1 and Z4 are independently CRlc; Z3 and Z4 are S and Z1 is CRle and Z4 is N ; Z1 and Z2 are N and Z3 and Z4 are independently CRlc. 12. The compound according to any one of claims 9 to 11, wherein A 15 is an (ia) group wherein η is 1 and R 3 is hydrogen or hydroxy or A is 3-hydroxy oxime-4-yl fluorenyl Or 4-pyridyl hexammine bite _3_ylmethyl. The compound according to any one of claims 1 to 5, wherein A is 4-hydroxyhexahydropyridin-3-ylmethyl. 14. A compound according to claim 13 wherein R5 is selected from the group consisting of: 20 6-substituted 2H-pyrido[3,2-1)][1,4]呤耕·3(4H)-one 2.3 - Dihydro-[M]dioxo E and [2,3-c]acridin-7-yl[1,3] rugged [5,4-〇]吼17-dec-6-yl-3.4-dihydrogen Pyrano[2,3_c]pyridyl-6-yl-6-substituted 2H-pyrido[3,2氺][1,4]thratic-3(411)-ketone 452 200817417 6- substituted 7_ Chloro-2Η·pyrido[3,2-b][l,4;K tillage·3(4Η)-keto-6-dihydroanthracene, 4]dioxo[2,3-c]indole-3 -yl 6.7-dihydroanthracene, 4Η thia[2,3-c]indole-3-yl 2-substituted 1H.pyrimido[5,4-b][l,4]呤耕_7(6H ) ketone 5 2-substituted 5,6-dihydropyrido[2,3-d]pyrimidin-7(1H)-one. 15. The compound according to claim 13 or 14, wherein: each of Z1, Z2, Z3 and Z4 is independently CRlc; Z1 is N and each Z2, Z3 and Z4 are independently CRlc; Z2 is N and each Z1 Z3 and Z4 are independently CRlc; ίο Z3 is N and each Z1, Z2 and Z4 are independently CRlc; Z1 and Z3 are N and Z2 and Z4 are independently CRlc; Z2 and Z3 are N and Z1 and Z4 are independently Is CRlc; Z3 and Z4 are N and Z1 and Z2 are independently CRle; Z3 and Z4 are S and Z1 and Z4 are independently CRlc; 15 Z3 and Z4 are S and Z1 is CRle and Z4 is N; Z1 and Z2 are N and Z3 and Z4 are independently CRlc. , 16. A compound selected from the group consisting of: 1-(2_{4-[(2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7-ylfluorenyl) Amino]-1-hexafluoropyridyl}ethyl)-7-(methoxy)-2(1Η)-fluorenone; 20 1-(2-{4-[(2,3-dihydro) [1,4]dioxaindolo[2,3-〇] mouth ratio σ -7-yl fluorenyl)amino]-1-hexahydropyridinyl}ethyl)·7-fluoro-2(1Η) -fluorenone; 1_(2-{4_[(2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)amino]-1-hexa氲pyridyl}ethyl)-5-fluoro-2(1H)-porphyrinone; 7-fluoro-small (2-{4-[([1,3] oxo[5,4-c]pyridine- 6-ylmercapto)amino]-1· •««Η 453 200817417 hexahydropyridyl}ethyl)-2(1Η)-indoxone; 6-[({1-[2-(7-fluoro) -2-keto-1(2H)-indenyl)ethyl]-4-hexahydropyrrolyl}amino)indolyl]-2H-pyrido[3,2-b][l,4]噚耕·3(4Η)-ketone; 1-(2-{4-[(6,7-dihydro[1,4]dioxo[2,3-c] 嗒-3-yl fluorenyl) Amino group &gt;1-hexahydropyridyl}ethyl)-7-fluoro-2(1H)-fluorenone; 1-(2-{4_[(2,3-dihydro[1,4]- Oxygen and [2,3-(;] bite-7-ylindenyl)amino]_1_hexahydropyridyl}ethyl)·7-fluoro-1,5-naphthyridin-2(1H)- ketone U(2-{4_[(3,4-Dihydro-2H-pyrano[2,3_c]pyridin-6-ylmethyl)amino]-1_hexahydropyridyl}ethyl)-7- Fluorin-1,5-naphthyridin-2(1H)-one; 1-(2-{4-[(3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-yl) Methyl)amino]-1_hexahydropyridyl}ethyl)-7-fluoro-l,5-naphthyridin-2(1H)-one; 1-(2-{4-[(3,4_ 2 Hydrogen-2H-σ ratio mer to [2,3-c]. BIT-6-ylmethyl)amino]-1-hexahydropyridinyl}ethyl)-7-fluoro-l,5-naphthyridine -2(1H)-one; Κ2-{4·[(2,3-dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)amino]-1 -hexahydropyridyl}ethyl)-7-(decyloxy)-i,5-naphthyridin-2(1H)-one; 1-(2_{4-[(6,7-dihydro[1, 4] Dioxo[2,3-indene]indole-3-ylmethyl)amino]-1-hexahydropyridyl}ethyl)-7-(decyloxy)·2(1Η)- Porphyrin; 1-(2-{4-[(2,3-dihydro[1,4]dioxo][2,3-c]pyridin-7-ylindenyl)amino]&gt;Hexafluoropyridyl}ethyl)-7-(decyloxy)-i,8-naphthyridin-2(1H)-one; U(2-{4-[(6,7-dihydro[1,4] Dioxo[2,3_c]indole-3-ylmethyl)amino]-1-hexafluoroanthryl}ethyl)-2-keto-1,2-dihydro-7-11奎σlinonitrile; Κ(2-{4-[(2,3-di-argon[1,4]dioxo[ ; 2,3-c]pyridin-7-ylmethyl)amino]-1-hexahydropyridinyl}ethyl)-2-keto-l,2-dihydro-7-indoleonitrile; (2_{4-[(6,7-Dihydro[1,4]dioxo[2,3-c]indol-3-ylmethyl)amine 454 200817417]]-1-hexahydropyridyl }Ethyl K7-(methoxy)-l,5-naphthyridin-2(1Η)-one; 1-(2-{4_[(6,7-dihydro[M]dioxo] and [2, 3_c]嗒耕-3-ylindenyl)amino>&gt;1-hexahydropyridyl}ethyl)-7-(decyloxy)-1,8-naphthyridin-2(1H)-one; 6- {[(1-{2-[7-(曱-oxy)-2)keto-l,5-naphthyridin-1(2H)-yl]ethyl}-4-hexahydropyridyl)amino]曱基}-2H-pyrido[,3,2-b][l,4]畤耕-3(4H)-one; 6-{[(1-{2-[7-fluoro-2-keto) -1,5-naphthyl stilbene-ι(2Η)-yl]ethyl}-4-hexahydroacridinyl)amino]hydrazino 2H_pyrido[3,2-b][1,4] Slogan _ -3(4H)_ ketone; 1_(2_{4-[(2,3·Dihydro[1,4]dioxo[2,3_c]pyridine-7-ylindenyl)amino]- 1-hexahydropyridyl}ethyl)-7·fluoro-2(1H)_purine ketone; l-(2-{4-[(3,4-dihydro-2H-σ than mercapto[2] , 3-c] 吼_6_ hydrazinyl)amino]-1-hexahydropyridinyl}ethyl)-7-(methoxy)-l,5-naphthyridin-2(1H)-one; -(2·{4-[(2,3_two [1,4]dioxyg and [2,3-c]cyclopyridin-7-ylindenyl)amino]-1-hexahydropyridyl}ethyl)_6_fluoro-2(1H)-喳Porphyrin; 1_(2]4-[(6,7-dihydro-[1,4]dioxo[2,3-c]indole_3_ylindenyl)amino]-1- Hexahydropyridyl}ethyl)·8-ethyl-7-fluoro-1,5-naphthyridin-2(1H)-one; 1_(2-{4_[(2,3-dihydro[1,4] Dioxygen and [2,3-c]pyridin-7-ylindenyl)amino-H-hexafluoropyridyl}ethyl)_8-ethyl-7-fluoro-1,5-naphthyridin-2-( 1H)-keto; 10-(2-{4-[(2,3-dihydro[1,4]dioxoindenyl]pyridin-7-ylindenyl)amino]-1-hexahydropyridine }}ethyl)·2,3-dihydro[1,4]dioxo[2,3-h] oxime-9(10H)-one; 10_(2-{4-[(6,7) -Dihydro[1,4]dioxo[2,3-c]indole_3-ylindenyl]-female]-1-hexamethylene}ethyl)-2,3-di Hydrogen [1,4]dioxo[2,3-h] 455 200817417 口奎口林_9(1011)-ketone; 5_(2-{4-[(2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7-yl) Amidino)amino]-1-hexazonebite}ethyl)-6-mercapto-5,6-diaza-1,5_steamed-3-monthly; 8-(2-{4_ [(2,3_Dihydro[1,4]dioxo[2,3-c]acridin-7-ylmethyl)amino]-1-hexanitrogen 17-bite}ethyl)- 7-S synthyl-7,8-diaza-1,8-evaporated-2-wax; 5_(2-{4-[(6,7-dihydro[1,4]dioxo[2, 3_c]嗒耕_3_ylmercapto)amino]-1-hexahydropyridyl}ethyl)·6-keto-5,6-dihydro-1,5-naphthyridin-3-carbonitrile; - (2_{4-[(6,7-dioxin[1,4]dioxo[2,3-〇] 口 -3-ylmercapto)amino]-1-hexahydroindole 11定基}Ethyl)-6-keto-5,6-dihydro-1,5-tea bite-3-month f; 7-moly-1-(2-{4_[(2,3-dihydro[ 1,4] dioxin and [2,3-〇] 吼-7-ylmercapto)amino]-1-hexahydropyridyl}ethyl)pyridine[2,3-b]pyridyl Plowing-2(1H)-one; Bu (2_{4-[(2,3_Dihydro[1,4]dioxo][2,3-c]pyridin-7-ylindenyl)amino] 1-hexahydropyridyl}ethyl)-5,7-difluoro-2(1H)-fluorenone; 1-(2-{4_[(6,7-dihydro[1,4]dioxo)艺和[2,3_c]嗒耕_3_基曱基) Amino]-1- Hydropyridyl}ethyl)_5,7-difluoro-2(1Η)_喳4 ketone; 6-[({1-[2_(7·fluoro-2-keto-1)(2H)_4 g. Ethyl]ethyl]|hexahydro port ratio σ定基}amino) fluorenyl]-2H-吼σ定[3,2_b][l,4]喧井井_3(4H)-酉同; 2-{4_[(2,3-Dihydro[1,4]dioxan|; 2,3-c] mouth bite-7-ylmercapto)amino]-1-hexahydropyrene than bite }ethyl}-7-fluoroindole and [2,3-b]indole-2(1H)-one; 1-(2-{4-[(6,7-dihydro-5H-pyran) And [2,3_c] 嗒 各 各 甲基 甲基 甲基 } } } } } } } } } } } } } } } } } } } 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- -{4-[(2,3-Dihydro[1,4]monooxindole|^2,3-(;]吼唆-7-ylindenyl)amine 456 200817417 base]-1-hexahydroindole Bite base} ethyl)-6-(decyloxy) nick and [2,3-b]4b well _3(4Η)-one; • dihydrofuro[2,3-c]pyridine-5 -indolyl)amino]·1-hexahydropyridyl}ethyl)-7-fluoro-2(1Η)-indolone; 5 1-(2-{4-[(2,3_2) Hydrofuro[2,3-c]pyridin-5-ylindenyl)amino]-1_hexaquinone 吼 定}}ethyl)-7-gas-2(111)-° quinone. No. 同@同; 1-(2_{4-[(6,7-Di-argon [1,4] 嗔[[2,3-c] 口井-3_ ylmethyl)amino]-1- Six gas } base} ethyl)-7-gas-2 (1 Η)-啥π morphine; 1_(2-{(3 feet, 48) winter[(2,3_二氲[1,4 Dioxymangan [2,3-micropyridin-7-yl 10 fluorenyl)amino]-3-hydroxy hexahydropyridyl}ethyl)-7-fluoro-1,5-naphthyridine&quot; 2(1H)·, 1-(2-{(311,48)-4-[(2,3_Dihydro[1,4]dioxo]; and [2,3-(;]° ratio bite -7-ylmercapto)amino]-3-hydroxy-1-hexahydropyridyl}ethyl)-7-(decyloxy)-1,5-naphthyridin-2(1H)-one; 15 1 -(2-{4-[(2,3-dioxin[1,4]monooxo[2,3-〇]吼 bit-7-ylindenyl)amino]-1-hexafluorene Alkyl}ethyl)-6,7-difluoro-2(1Η)_σ奎口号. Linthone; 6-{[(1_{2-[6-(methoxy)-3-ketoacridino[ 2,3-b]pyrazine_4(3Η)-yl]ethyl b-tetrahydropyridyl)amino]indenyl}-2Η-pyrido[3,2-b][l,4] Till-3 (4H) ketone; 20 4-(2-{4-[(6,7-dihydro[1,4]dioxo][2,3-c]indole-3_ylindenyl) Amino]-1-hexahydropyridinyl}ethyl)-6-(methoxy)-pyrido[2,3-b]pyrazine-3(4H)-one; 1 -(2 - {4- [(6,7 - ^1 nitrogen) [1,4]·monooxane [2,3-c] 荅 井 well-3-ylmercapto)amino]-1-hexahydropyridinyl}ethyl)-7-(methoxy) -2(1Η&gt;fluorenone; 457 200817417 l-(2_{4-[(2,3-Dihydro[1,4]dioxo[2,3-b]pyridin-7-ylmethyl) Amino group &gt; 1-hexahydropyridyl}ethyl K7·fluoro·2(1Η)-fluorenone; . 1-(2-{4-[(6,7-dihydro[1,4]] Dioxo[2,3-c]indole_3_ylmercapto)amino]-1-hexahydropyridyl}ethyl)·6,7-difluoro-2(1H)-porphyrin Ketone; 5 7_ chloro-6-{[({(3S,4S)-l-[2_(7_fluoro-2-keto)-1(2H)-indolyl)ethyl&gt; 4-hydroxy-3-pyrrole Acryl}mercapto)amino]mercapto}-2H-pyrido[3,2-b][l,4]indole-3(4H)-one; 1-(2-{4_[(2, 3. Dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)amino]-1-hexahydropyridinyl}ethyl)-7-(decyloxy) Pyrido[2,3-b]pyrazine ίο -2(1H)-酉; 6-({[(3R,4R)-4-)yl-1_{2_[7-(曱oxy)_2_S Homo-l-(2H)-hydroxyl- linyl]ethyl} -3-benzoxyl s-yl) fluorenyl]amino}indenyl)·2Η-11 唆[3,2-b][l , 4] timol-3·4Η) ketone; 6-({[(3R,4R)_4-starting-1-(2-[7-(methoxy)-2) _ keto-1,5_ tea bite 15-1(2H)-yl]ethylidene-3-pyrrolidinyl)methyl]amino}methyl)-2H-pyrido[3,2-b][l , 4] Saki--3(4H)-ketone; % 6-({[(3R,4R)_4-)-yl-1-{2_[7_(decyloxy)-2-keto-1,5-naphthalene Bite-1(2H)-yl]ethyl}-3-oxazolidinyl)indolyl]amino}mercapto)-2H_pyrido[3,2-b][l,4] 3(4H)-_ Fumarate; 20 6-({[(3R,4R)-4_hydroxy_1-{2-[7·(decyloxy)-2-keto-1,5 -naphthoquinone-1(2H)-yl]ethyl}-3-pyrrolidinyl)indolyl]amino}mercapto)-2H-pyridyl[3,2-b;l[l,4]thiazide Plough-3(4H)-ketone; l-(2_{(3S,4R)-4-[(2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7- Alkyl)amino]-3-hydroxy-1-hexahydropyridinyl}ethyl)-7-fluoro-1,5-naphthalene 458 200817417 -2(1H)·ketone; 10-(2-{4 -[(2,3-Dihydro[1,4]dioxoindol c]pyridin-7-ylmethyl). Amino]-1-hexahydro 12-bityl}ethyl)-6-fluoro -2,3-dihydro[1,4]dioxo[2,3-h]porphyrin-9(10H)-one; 5 7-[({ 1·[2-(7•fluoro-2) -keto-1(2Η)-ϋϋ崎咐)ethyl]-4-hexahydropurine σ-based}amino)indenyl]-1Η-pyrido[2,3-b][l,4] Sulphur tillage -2(3Η)-ketone; 7-|1-1-[2·(4-{[(7· keto·1,5,6,7·tetradecyl-1,8-naphthalene-2) )methyl]amino}-1-hexanitropurine. Alkyl)ethyl]-2(111)-17 Kui 17; 6-chloro-4-(2-{4_[(2,3_di-argon[1,4]dioxo[2,3] -c]4b -7-ylmethyl 10 yl)amino>&gt;1-hexahydropyridinyl}ethyl)-1,2,4·benzotrim-3(4H)-one 1-oxide; 6-({[((3S,4S)-4-hydroxy_1-{2-[7-(decyloxy)-2-keto-1(2H)-indenyl]ethyl}-3- Pyrrrolidinyl)indolyl]amino}indenyl)-2H-pyrido[3,2-b][l,4]thorbic-3(4H)-one; 15 7-chloro-6-({[ ((3S,4S)-4-hydroxyl small {2-[7-(decyloxy)-2- keto-1(2H)-indenyl]ethyl}-3-pyrrolidinyl)indolyl]amine }}methyl)-2H-i acridine [3,2-7][1,4]畤耕-3(411)-ketone; 3][({(3S,4S)-1_[2_(7- Fluor-2-(keto)-1(2H)-indolyl)ethyl]-4-hydroxy-3-pyrrolidinyl}methyl)amino]indenyl}_5H-嗒耕和[3,4_b][l , 4] 2〇 tidal-6(7H)-one; l-[2_((3S,4S)-3_{[(2,3_dihydro[1,4]dioxo[2,3- c] acridine-7-ylmercapto)amino]mercapto}-4-hydroxy-1-pyrrolidinyl)ethyl]-7-fluoro-2(111)- 4 fluorenone; 3-[({ 1-[2-(7-fluoro_2·_ 奎17 σ linyl)ethyl]_4_hexahydroport ratio bite 459 200817417 }}amino)methyl]-5H-嗒And [3,4-b][l,4]thorbic-6(7H),; l-(2-{(3S,4R)_4-[(2,3_di-argon[1,4]dioxo芑[2,3_c]pyridine-7-yl. fluorenyl)amino]-3-hydroxy-1-hexahydropyridinyl}ethyl)-7-(decyloxy) 4,5-naphthyridine-2 ( 1H)-keto; 5 H2-((3S,4S)_3_{[(2,3-dihydro[1,4]dioxo][2,3-c]pyridine-7-ylindenyl) ]methyl}-4-hydroxy-1-pyridinyl)ethyl]-7-(methoxy)-1,5-naphthyridin-2(1H)-one; 6-({[((3S) , 4S)-4-transmethoxy-1_{2-[7-(decyloxy)_2-keto-1,5-naphthalene-1(2H)-yl]ethyl}tungyryryl)indolyl] Amino}indenyl)-2H-pylotry ίο and [3,2-b][l,4]啐耕-3(4H)-_ Fumarate; 6- ({[(3S,4S)) _4-hydroxyl small {2_[7-(decyloxy)-2-keto-1,5-naphthalene _ 1 (2H)-yl]ethyl}_3-pyrrolidinyl)indolyl]amino}曱Base)_2H_pyridox[3,2_b][l,4]thorbic-3(4H)-one; l-[2-((3S,4S)-3-{[(6,7-dihydrol) [1,4]dioxo[2,3-c]indole-3-yl 15 methyl)amino]methyl}-4-hydroxy-1-pyrrolidinyl)ethyl]-7-( Methoxy)-1,5·naphthyridin-2(1H)-one; 7-chloro-6_({[(3S,4S)-4-)-based small {2-[7-(decyloxy) -2·keto-1,5-naphthyridine_ 1(211)-yl]ethyl}_3.pyrrolidinyl)indolyl]amino}indenyl)_2H_pyrido[3,2-b][l,4]indole-3(4H)-one ; 2〇6-({[((3S)-l-{2-[7-(曱oxy)_2-keto-1,5-naphthyridin-1(2H)-yl]ethyl}-3 _ 吼 吼 啶 曱 曱 ] ] ] ] ] ] ] ] -3 ( ( ( ( ( ( ( ( ( ( ( ( ( 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 (曱oxy)_2_ fluorenyl-1(2H)-indenyl]ethyl}-3-pyrrolidinyl)methyl]amino}indenyl)_2H_pyridine 460 200817417 [3,2-b] [l,4]_ tillage_3(411)-ketone; 1-[2-((38,48)_3_{[(2,3_dihydro[1,4]&lt;1&apos; 3_c] 比 口 -7 -7 -7 曱 ) ) ) ) ) ) ) ) ) ) ) -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 -7 5 H2-((3S,4S)_3-{[(6,7-Dihydro[1,4]dioxo[2,3_c]indol-3-ylindolyl)amino]indolyl}- 4-hydroxy-1-pyrrolidinyl)ethyl]-7-(decyloxy)-2(lH)-uquinone; 6-{[({(3S,4S)-l_[2_(7- Fluor-2-one 1(2H)-carbino)ethyl]-4-hydroxy-3-pyrrolidinyl}mercapto)amino]fluorenyl}·2Η-pyrido[3,2-b ] [ 1,4] 1〇 耕 -3 -3(4H)-one; 6-{[({(3S,4S) small [2-(7-fluoro_2-keto-1(2H)-) Ethyl)ethyl]·4·hydroxy-3-pyrrolidinyl}indenyl)amino]indenyl}-2Η-pyrido[3,2-b][l,4] 啐耕-3(4H) -ketone; 6-{[({(3R,4R)_l-[2-(7-fluoro-2-keto-1(2H)).咐 )))ethyl H-15 hydroxy-3-pyrrolidinyl}methyl)amino] hydrazino 2H_pyrido[3,2-b][l,4] slogan tillage-3(4H)_ Ketone; 6-{[({(3R,4R)-l-[2_(7-fluoro-2-keto-1(2H)-indolyl)ethyl]-4-hydroxy-3-pyrrolidinyl } mercapto)amino]methyl}-2H-pyrido[3,2-b][l,4] thioglycol-3(4H)-one; 2〇6-{[({(3S,4S) -l-[2-(7-murine-2-S-iso-1,5-teabit-1(2H)-yl)ethyl]-4-hydroxy-3-inertyryl}indenyl)amine曱]曱}}H-pyrido[3,2-b][l,4]咩耕·3(4Η)_ ketone; 6-{[({(3S,4S)-l-[2-( 7- m _ group-1,5·naphthyridine-1(2Η)·yl)ethyl]-4-hydroxy-3-pyrrolidinyl}methyl)amino]methyl}-2Η-pyridyl 461 200817417 [3,2-b][l,4]thorbic-3(4H)-one; 7-chloro-6-{[({(3S,4S)-l_[2-(7-fluoro-2-one) Base_1,5·naphthyridine_1(211)-yl) • ethyl]_4_hydroxy-3-pyrrolidinyl}methyl)amino]methyl b 2Η-pyrido[3,2-b] [l,4]啐耕-3(4Η)-ketone; 5 1-[2_((38,48)_3-{[(2,3-dihydro[1,4]dioxos[2,3 -(:]biting _7-ylindolyl)amino]methyl}-4-yl-1-ylidene)ethyl]-7-fluoro-1,5-naphthoquinone 2 (1Η) -嗣, 1-(2-{ 4-[(2,3-Dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)amino]-1-hexahydropyridyl}ethyl)-5 • Fluorin-7-(decyloxy)-2(1Η)-pyridone; 10 Dihydro[1,4]dioxo[2,3_c]pyridin-7-ylmethyl)amino] 1-hexahydropyridyl}ethyl)-7-fluoro-5-(decyloxy)-2(1Η)-pyridone; 5-chloro-3-(2-{4-[(2,3) -Dihydro[1,4]dioxo[2,3-c].Bit-7-ylmethyl)amino]-1-hexahydropyridyl}ethyl)-1,3-benzo Thiazole-2(3H)-one; 1_(2-{4_[(2,3-dihydro[1,4]dioxo[2,3-(:]. than bit-7-yl) Amine 15 yl]-1-hexahydro 17-bite}ethyl)-6-fluoro-[1,3]indolo[5,4-b]indolyl-2(1H)-one; 6- {[({(3S)-l-[2-(7-fluoro_2-keto-1(2Η)·4 fluorenyl)ethyl]-3-pyrrolidinyl} fluorenyl)amino] fluorenyl }_2Η-口比啶和[3,2-b][l,4]崎耕-3(4Η)_ 酉同; 2〇6-({((2S)-4-{2_[7-(曱oxy)-2-keto-1,5-naphthyridin-1(2Η)-yl]ethyl b-2-oxafosyl)methyl]amino}mercapto)-2Η-pyridyl[3 ,2-bHM] tibia _3(4H)-one; 7' chloro-6-({[(2S)-4-{2-[7-(曱oxy)_2-keto-1,5 -naphthyridinyl]ethyl}-2-morpholine) Amino}indenyl)-2H-pyridinium 462 200817417 [3,2-b][l,4] cultivating _3(4H)-one; l-[2-((2S)-2-{ [(2,3-Dihydro[l,4]dioxo[2,3-c]pyridin-7-ylindole-yl)amino]indenyl}-4-morpholineyl)ethyl] -7-(decyloxy)-1,5-naphthyridine-2(1Η)·one; 5 7_chloro-6-({[(3S)_l-{2-[7-(methoxy)) -2_keto-1,5-naphthyridine-1(2Η)-yl]ethyl}-3-hexahydropyridyl)indolyl]amino}methyl)-2Η-pyrido[3,2- b][l,4]哼耕·3(4Η)_ ketone; 7-chloro-6-{[({(3S)-l-[2-(7-fluoro-2-keto-1)(2Η) _Mercapto)ethyl]-3-hexahydroacridinyl}indenyl)amino]indenyl}-2Η-pyrido[3,2-b][l,4]唠10 -3(4H )-ketone; 5-(2-{4-[(2,3-dihydro[1,4]dioxo[2,3-c]pyridine-7-ylmethyl)amino]-1- Hexahydropyridyl}ethyl)-3-(decyloxy)pyrido-R,3-b]pyrazine 6(5H)-酉; 5-(2-{4·[(6,7-dihydro) [1,4]dioxo[2,3_c]indol-3-ylmercapto)amine 15yl]-1-hexahydropyridyl}ethyl)-3-(decyloxy)pyridin[2 ,3-b]pyrazine_6(5H)_ ketone; * 1-(2_{4-[(2,3-dihydro[1,4]dioxo[2,3-c]pyridine_7 _ylmercapto)amino]-1-hexa定基}ethyl)-7-gas-1,5-tea bite-2(1 H)-嗣5-oxide; 2〇7-fluoro-1-(2_{4-[([1,3]畤Thio[5,4-c]cyclopyridin-6-ylmercapto)amino]-1-hexahydropyridinyl}ethyl)-1,5-naphthyridin-2(1H)-one 5-oxide 4-(2-{4-[(2,3-Dihydro[M]dioxo[2,3-c]pyridin-7-ylindenyl)amino]-1-hexahydropyridyl) }ethyl)-6-(methoxy)-1,2,4-benzotriazine-3(4H)·one; 463 200817417 1- (2-{4·[(2,3-dihydrofuran) And [2,3-c]pyridin-5-ylmethyl)amino]-1-, hexahydropyridyl}ethyl)-7-(methoxy)-2(1Η)-fluorenone; ▲ 2-[({1-[2-(7-fluoro-2-keto-1(2H)-indolyl)ethyl]-4-hexahydropyridine} Amino)methylHH-pyrimidine[ 5,4-b][l,4K tillage_7(6H)-one; 5 4_chloro-24(042-(7-fluoro-2-keto-1(2Η)-fluorenyl)ethyl] -4-hexahydropyridine}amino)indolyl]_1Η-pyrimido[5,4-b][l,4;K cultivating -7(6Η)__ ; 2- {[(1-{2-[6 -(decyloxy)-3-ketopyrido[2,3-b]pyrazine_4(3Η)-yl]ethyl}-4-hexahydropyridyl)amino]methyl}_5,6 _Dihydropyrido[2,3-d]pyrimidin-7(1H)-one; 10 4_ chloro·2-{[(1-{2·[6·(曱oxy)-3-顚J group The ratio of [2,3-b] is better than that of the well-4(3H)-yl]ethyl}-4-hexahydropyridyl)amino]methyl}-5,6-dihydropyridyl[ 2,3-d]pyrimidin-7(1H)-one; 4_mercapto-2-{[(1-{2-[6-(decyloxy)-3-keto) bite [2,3 -1)]Sakaguchi-4(3H)-yl]ethyl}·4_hexahydro 17-bite base)amino]mercapto}_5,6·dihydrou than bite 15 and [2,3- d]pyrimidin-7(1Η)-one; 4-(decyloxy)-2-{[(1-{2·[6-(methoxy)-3-keto) bite [2,3- b] 吼4_3(3H)-yl]ethylhexahydropyridyl)amino]methyl}_5, dihydropyrido-R,3-d]pyrimidin-7(1H)-one; 7-fluoro -2- _ _l-[2-(4-{[(3- g)-based 3,4_ dihydro-2H-吼 bite and 20 [3,2-b][l,4]今乌井-6-yl)methyl]amino}-1_hexahydroindenyl)ethyl]-1,2-diaza-4_啥u lin, 1-(2-{4-[(2, 3-Dihydro[1,4]dioxo[2,3-indole]. Well_3-mercapto)amino]-1-hexahydroindenyl}ethyl)-7-fluoro-2-keto-1,2-dihydro-4-4indene nitrile; 1-(2_ {4-[(2,3-Dihydro[1,4]dioxo[2,3-indene] Titrate-3-ylindenyl)amine 464 200817417 yl]-1-hexahydropyridyl} Ethyl)-7-fluoro-4-methyl-2(1H)-fluorenone; • 1-(2-{4_[(2,3-dihydro[1,4]dioxan[2, 3-c] indole-3-ylindenyl)amine.]]-1-hexahydropyridyl}ethyl)·7-fluoro-4-(decyloxy)-2(1Η)-fluorenone; 2-({[(3S)-l-{2-[6_(曱oxy)_3_ keto acridine[2,3-b]pyrazine 5 -4(3H)-yl]ethyl b 3 -hexahydropyridyl)indolyl]amino}methyl)-5,6-dihydroindeno[2,3-(1]0 crypt-7-(1H)-one; cis-7-chloro- 6-{[({(3RS,5RS)-l-[2-(7fluoro-2-keto-1(2H)-carbinyl)ethyl]-5-trans-yl-3-6-nitrogen 11 ratio Ole base] benzyl]amino]methyl}-2H-1,4-benzoindole-3(4H)-one; ίο 6-({[(3S,4R)-4-hydroxy-1_{ 2-[6-(decyloxy)-3-ketopyridino[2,3-bp ratio till-4(3H)-yl]ethyl}-3-hexaarridinyl)methyl]amino} Methyl)-2H-pyrido[3,2_b][1,4]thratic-3(4H)-one; 6-({[(3S,4R)-4-hydroxy-1-{2-[ 6-(methoxy)·3- Pyrido[2,3-b]indole-4(3Η)-yl]ethyl}-3-hexamethylpyridyl)indolyl]amino}曱15yl)-2Η_吼吼[ 3,2-b] [1,4]噚耕-3(4Η)_one; 4-[2-((3S,4R)-3-{[(2,3_Dihydro[1,4]) Oxazepine [2,3-c] 比pyridin-7·ylmercapto)amino]mercapto}-4-hydroxy-1-indolyl)ethyl]-6-(methoxy)- Pyrido[2,3_b]pyrazine-3(4H)-one; H2_((3S,4R)-3-{[(2,3-dihydro[1,4]dioxo[2,3- c] acridine-7-2 fluorenyl)amino]mercapto}-4-yl-1-^ than 嘻σ-decyl)ethyl]-7-gas-2(1Η)-fluorenone; 6-{[({(3S,4R)_l-[2_(7-fluoro-2-keto-1(2Η)-indolyl)ethyl]-4-hydroxy-3-hexahydropyridyl}曱Amino]merino}-2Η-pyrido[3,2-b][1,4]啐耕·3(4Η)_ ketone; 465 200817417 l-[2-((3R,4S)-3 -{[(2,3-diaza[1,4]dioxo[2,3-cK pyridine-7-ylmethyl)amino]methyl}-4-yl--1-17-Bilo Ethyl)ethyl]-7-fluoro_2(1H)_Koukoulin Reward I; 6-{[({(311,48)-1-[2-(7-fluoro-2-keto) 1(2«〇-fluorenyl)ethyl]-4-hydroxy-3-hexahydropyridinyl}indenyl)amino]indenyl}_2H-pyrido[3,2-b] [1,4]啐耕-3(4H)- Ketone; (+/-) 1-(2-{3·(Aminomethyl)·4·[(2,3-diaro[1,4]dioxyg[2,3-c]pyridine- 7-ylmercapto)amino]-1-hexahydropyridinyl}ethyl)-7-fluoro-2(1H)-indolerone isomer 1; (+/-)1-(2-{ 3-(Aminomethyl)-4-[(2,3-dihydro[1,4]dioxoE and [2,3-c] acridine-7-ylmethyl)amino]-1- Hexahydropyridyl}ethyl)-7-fluoro-2(1H)-indolone isomer 2; racemic 1-[2-(4-amino-3-{[(2,3-) Dihydro[1,4]dioxo[2,3-c]acridin-7-ylindenyl)amino]hydrazinyl hydrazine-hexahydropyridyl}ethyl)_7_Fluorophenoline 咐A ketone; or a free state of any of the compounds of Tables 1 to 7; or a pharmaceutically acceptable salt of any of the above compounds. 17· 1-(2-{4-[(6,7-Dihydro[1,4]dioxohexa[2,3_c]acridin-7-ylindenyl)amine 1·1 -hexahydropyridine And ethyl or pharmaceutically acceptable salts thereof. 18· 1_(2_{4-[(6,7-Dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)amino-M-hexahydroindole)} Ethyl)-7-fluoro-2(1Η)-ϋ奎畤琳 ketone dihydrochloride; 1 (2-{4_[(6,7-dihydro[1,4]dioxo[2,3] -c]4bσ定冬基曱)aminoguanidine-hexahydropyridyl}ethyl)-7-fluoro-2(m)-porphyrinone benzoate; 466 200817417 l-(2-{4 -[(6,7-Dihydro[1,4]dioxoS and [2,3_c]pyridin-7-ylmethyl)amine•yl]-1-hexahydro 17-bityl}ethyl)-7 -Fluoro-2(1Η)-4σ fluorenone fumarate; ^ 1-(2-{4-[(6,7-Dihydro[1,4]oxyxan[2,3-c] Oral ratio 唆-7_ylmethyl)amino]-1-hexahydropyridinyl}ethyl)-7-fluoro-2(1H)-porphyrinone hydrochloride; 5 1-(2-{4_ [(6,7-Dihydro[1,4]dioxo-g[2,3-c]pyridin-7-ylmethyl)amino]-l-hexanitrogen-7-to-bityl}ethyl)- 7-1 -2(1 H)-啥今咐g with lemon: a salt; or 1-(2-{4-[(6,7-dihydro[1,4]dioxo[2, 3_小比淀-7-ylmethyl)amino]-1-hexahydroindenyl}ethyl)-7-fluoro-2(1 Η)-σ Kui. Lin Ketone L-tartaric acid 10 salt. 19·4_[2_((3S,4S)-3-{[(2,3-Dihydro[1,4]dioxo[2,3-c]). _7·yl fluorenyl) Amino]mercapto}-4_transamino-1_indolyl)ethyl]-6-(decyloxy) σ-pyridyl[2,3_b]pyrazole-3(4Η)-one or A pharmaceutically acceptable salt. 20.4-[2_((38,48)_3_{[(2,3-Dihydro[1,4]dioxo[6,3-.].Bist-7-yl 15 fluorenyl)amino] Mercapto}_4·hydroxypyrrolidinyl)ethyl]-6-(methoxy)-p-pyridyl[2,3_b]pyrazine-3(4H)-one dihydrochloride; or 4-[2 -((3S,4S)-3-{[(2,3-Dihydro[1,4]dioxo[2,3-c]pyridin-7-ylindenyl)amino]indolyl}- 4-hydroxy-1-pyrrolidinyl)ethyl]_6-(decyloxy)pyridyl[2,3-b]. Than the well-3(4H)-ketobenzoate. 20 21. A method of treating a bacterial infection in a mammal, the method comprising administering an effective amount of a compound according to claim 1 of the patent application to a mammal in need of such treatment. 22. Use of a compound according to claim 1 of the patent application for the treatment of a bacterial infection in a mammal. 467 200817417 23. A pharmaceutical composition comprising a compound according to item 1 of the scope of the patent application and a pharmaceutically acceptable carrier. 468 200817417 VII. Designation of representative representatives: (1) The representative representative of the case is: (No). (2) A brief description of the symbol of the representative figure: None 8. If there is a chemical formula in this case, please disclose the chemical formula A-NR2—UR5, 1a 〇 丫Z, z3\z2 (I) which can best display the characteristics of the invention.