(12) Patent Application Publication (10) Pub. No.: US 2008/0261947 A1 Seko Et Al

US 20080261947A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0261947 A1 Seko et al. (43) Pub. Date: Oct. 23, 2008

(54) FUSED PYRIDAZINE DERIVATIVE Publication Classification COMPOUNDS AND DRUGS CONTAINING (51) Int. Cl. THESE COMPOUNDS AS THE ACTIVE A63L/50 I (2006.01) INGREDIENT C07D 237/32 (2006.01) C07D 40/12 (2006.01) C07D 403/2 (2006.01) (75) Inventors: Takuya Seko, Osaka-shi (JP); Jun A6II 3/55 (2006.01) Takeuchi, Mishima-gun (JP); A6IP 29/00 (2006.01) Shinya Takahashi, Mishima-gun A6IP3/10 (2006.01) A6IP27/06 (2006.01) (JP); Yoshihisa Kamanaka, A6IP 25/00 (2006.01) Mishima-gun (JP); Wataru A6IP 9/00 (2006.01) Kamoshima, Mishima-gun (JP) C07D 47L/04 (2006.01) C07D 413/14 (2006.01) A 6LX 3/5.377 (2006.01) Correspondence Address: (52) U.S. Cl...... 514/210.21; 544/237; 544/119: SUGHRUE MION, PLLC 514/233.8: 514/248: 514/234.2:544/117; 2100 PENNSYLVANIA AVENUE, N.W., SUITE 544/236; 540/599; 514/217.05 8OO (57) ABSTRACT WASHINGTON, DC 20037 (US) Fused pyridazine derivatives represented by formula (I) or pharmaceutically acceptable salts thereof (wherein each sym (73) Assignee: ONO PHARMACEUTICAL CO., bol has the meaning as defined in the specification.). LTD. (I) (21) Appl. No.: 12/137,267

(22) Filed: Jun. 11, 2008

Related U.S. Application Data (62) Division of application No. 10/505,012, filed on Aug. Because of inhibiting poly(ADP-ribose)polymerase, the 18, 2004, now Pat. No. 7,402,580, filed as application compounds represented by formula (I) are useful as preven No. PCT/JP2003/001694 on Feb. 18, 2003. tives and/or remedies for various ischemic diseases (in brain, cord, heart, digestive tract, skeletal muscle, retina, etc.), inflammatory diseases (inflammatory bowel disease, mul tiple cerebrosclerosis, arthritis, etc.), neurodegenerative dis eases (extrapyramidal disorder, Alzheimer's disease, muscu lar dystrophy, lumbar spinal canal Stenosis, etc.), diabetes, (30) Foreign Application Priority Data shock, head trauma, renal failure, hyperalgesia, etc. More over, these compounds are useful as agents against retrovi Feb. 19, 2002 (JP) ...... P2002-42259 ruses (HIV etc.), sensitizers in treating cancer and immuno Jul. 9, 2002 (JP) ...... P2002-199673 Suppressants. US 2008/026 1947 A1 Oct. 23, 2008

FUSED PYRIDAZINEDERVATIVE ease (TIPS., 19, 287 (1998); Eur J. Pharmacol., 350, 1 COMPOUNDS AND DRUGS CONTAINING (1998)) and hyperalgesia (Pain, 72, 355 (1997)) in vitro, in THESE COMPOUNDS AS THE ACTIVE vivo and in PARP knockout mouse. And it is reported that INGREDIENT PARP inhibitor is useful as an antiretroviral drug such as an anti HIV drug (Biochem. Biophys. Res. Commun., 180, 504 CROSS-REFERENCE TO RELATED (1991)), a sensitizer of anticancer therapy (Radiat. Res., 126, APPLICATIONS 367 (1991); Br. J. Cancer, 72,849 (1995)) or an immunosup 0001. This is a Divisional of U.S. application Ser. No. pressant (Int. J. Immunopharmac., 17, 265 (1995)). 10/505,012 filed Aug. 18, 2004, which is a 371 of PCT Appli 0008 PARP inhibitor is useful for prevention and/or treat cation No. PCT/JP03/01694, Feb. 18, 2003, which claims ment of various diseases, for example, ischemic diseases priority from Japanese Application No. 2002-42259 filed on (cerebral infarction, myocardial infarction, reperfusion injury or postoperative injury etc.), inflammatory diseases (inflam Feb. 19, 2002 and 2002-199673 filed on Jul. 9, 2002. The matory bowel disease, multiple Sclerosis, arthritis or lung above-noted applications are incorporated herein by refer injury etc.), neurodegenerative disorders (extrapyramidal dis ence in their entirety. ease, Parkinson's disease, Alzheimer's disease, muscular TECHNICAL FIELD dystrophy or lumbar spinal canal Stenosis etc.), glaucoma, 0002 The present invention relates to fused pyridazine diabetes, diabetic complication, shock, head trauma, spinal derivative compounds. cord injury, renal failure, hyperalgesia or blood flow obstruc tion etc. And it is useful as an antiretroviral drug Such as an 0003 More particularly, the present invention relates to anti HIV drug, a sensitizer of anticancer therapy or an immu (1) pyridazine derivative compounds represented by formula nosuppressant. (I) 0009. As PARP inhibitor, for example, in the specification of WO00/44726, it is described that 2H-phthalazin-1-one derivatives represented by formula (A) (I) (A)

(wherein all symbols have the same meanings as described below), or pharmaceutically acceptable salts thereof, (2) a process for preparing thereof, and (3) an agent comprising the same as an active ingredient. BACKGROUND ART 0004 Poly(ADP-ribose)polymerase (abbreviated as (wherein R'' is PARP hereinafter), which is a nuclear enzyme activated by (i) C1-4 alkyl substituted by hydroxy or amino, or DNA strand breaks, plays a role in the transfer reaction of (ii) -A14-A24-A34, ADP-ribose moiety from nicotinamide adenine dinucleotide (0010 in which A' is NRC(O)– etc. wherein R is (abbreviated as NAD" hereinafter) to various proteins such as hydrogen or C1-4 alkyl etc., A is C1-8 alkylene etc., A' is histones, DNA-polymerases and DNA-topoisomerases, etc. (i), hydrogen, (ii) - NR'R'' or (iii) Cyc etc. wherein R is (i) hydrogen, (ii) C1-8 alkyl etc., and R'' is (i) hydro 0005) DNA strand breaks caused by Peroxynitrite gen or (ii) C1-8 alkyl etc., Cycf" is 3-10 membered mono- or (ONOO) and oxygen radicals lead to overactivation of PARP bi-heterocyclic ring containing 1-4 of nitrogen atoms, 1-2 of (PARP is activated up to 100 times when Zn finger domain of oxygen atoms and/or one sulfur atom, R’ is hydrogen or PARP binds to DNA with nicks.). It is thought that overacti halogen etc. Necessary parts were extracted from the descrip vation of PARP causes depletion of NAD", which is essential tion of groups.) have PARP inhibitory activity. for electron transport system, and consequently depletion of (0011. In the specification of DE3302021, it is described ATP leading to energy failure, ultimately resulting in cell that compounds represented by formula (B) death. (The suicide hypothesis of PARP activation: Free Radic. Biol Med., 21, 855 (1996); TIPS., 19, 287 (1998)). (B) Therefore, it is considered that PARP inhibitor is useful as O inhibitor of cell death. 0006 Since caspase-3, which is one of interleukin-1B RB converting enzyme family, specifically cleaves PARP as the t substrate (Cell., 81, 801 (1995)), it is suggested PARP is 2N associated with apoptosis. R2B 0007. It is reported that 3-aminobenzamide and nicotina H H R3B mide generally known as inhibitors of PARP are useful for 21 H 4B inhibition of cell death and improvement of diseases on vari N (CH2)R R ous models of ischemic diseases (cerebral, myocardial, intes N tinal, skeletal muscular or retinal ischemia etc.), inflamma tory diseases (arthritis, inflammatory bowel disease or O multiple Sclerosis etc.), diabetes, shock, extrapyramidal dis US 2008/026 1947 A1 Oct. 23, 2008

(wherein R' is hydrogen or C1-3 alkyl, R' is hydrogen, R' 6,7,8-tetrahydrophthalazin-1 (2H)-one (CAS Registry No. and R', taken together, are C1-4 alkylene, R. is hydrogen or 134973-24-3) are described as synthetic intermediate. methyl, nB is 0-3, R is 1-pyrrolyl. Necessary parts were DISCLOSURE OF THE INVENTION extracted from the description of groups.) have inhibitory 0019. In order to find a compound having poly(ADP-ri activity of platelet aggregation. bose)polymerase activity, the present inventors have con 0012. In the specification of WO98/31674, it is described ducted intensive studies and found, as a result, that the objects that compounds represented by formula (C) can be accomplished by the pyridazine derivative represented by formula (I), and thus the present invention has been accomplished. 0020. The present invention relates to (C) (1) a fused pyridazine derivative compound represented by formula (I)

(I) O

(R') - Z E se A (0021 wherein R is (wherein R' is C1-4 alkoxyetc., R is C1-8 alkoxyetc., R. (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) and R' is hydrogen or RandR', taken together, are bond, hydroxy, (5) halogen atom, (6) nitro, (7) NR'R'', (8) C2-8 R is hydrogen etc. Necessary parts were extracted from the acyl, (9) C1-8 alkoxy substituted by phenyl or (10) C2-8 acyl description of groups.) have phosphodiesterase inhibitory substituted by NRR, activity. (0022 R and Rare each independently 0013. In Journal of Medicinal Chemistry., 44(16), 251 1 (1) a hydrogen atom or (2) C1-8 alkyl, 2522 and 2523-2535 (2001), it is described that 4-(3-chloro 0023 X and Y are each independently 4-methoxyphenyl)-4a,5,8,8a-tetrahydrophthalazin-1 (2H)- (1) C, (2) CH or (3) N, one (CAS Registry No. 244077-36-9) and 4-(3,4- 0024 is dimethoxyphenyl)-5,6,7,8-tetrahydrophthalazin-1 (2H)-one (1) a single bond or (2) a double bond, (CAS Registry No. 358368-98-6) have phosphodiesterase inhibitory activity. 0014. In Tetrahedron., 39(20), 3419-27 (1983), 4-phenyl x1 6,7,8,8a-tetrahydropyrrolo 1,2-d1.2.4 triazin-1 (2H)-one (CAS Registry No. 893 11-30-8) is described as synthetic YS intermediate. 0015. In Synthesis., 240-242 (1995), 4-phenyl-5,6,7,8-tet (1) partially or fully saturated C3-10 mono-carbocyclic aryl rahydrophthalazin-1 (2H)-one (CAS Registry No. 154810 or (2) partially or fully saturated 3-10 membered mono-het 22-7), 4-(4-methylphenyl)-5,6,7,8-tetrahydrophthalazin-1 ero aryl containing 1 to 4 hetero atom(s) selected from oxy (2H)-one (CAS Registry No. 154810-23-8), 4-(4- gen, nitrogen and Sulfur atoms, fluorophenyl)-5,6,7,8-tetrahydrophthalazin-1 (2H)-one 0025 A is (1) A', (2) A, (3) A, (4) A or (5) A, (CAS Registry No. 154810-24-9), 4-(4-chlorophenyl)-5,6,7, 0026 A' is 8-tetrahydrophthalazin-1 (2H)-one (CAS Registry No. 154810-25-0), and 4-(4-bromophenyl)-5,6,7,8-tetrahydro phthalazin-1 (2H)-one (CAS Registry No. 154810-26-1) are described as synthetic intermediate. 0016. In Bioorganic and Medicinal Chemistry., 6,349-454 es (1998), 7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo 1.2- (R)-- -HD-D-D, d1,2,4-triazin-1 (2H)-one (CAS Registry No. 206126-90-1) N and 4-phenyl-8,8a-dihydro1.3thiazolo 3,4-d1.2.4 tri azin-1 (2H)-one (CAS Registry No. 206126-96-7) are 0027 A is -E-E-E-E, described as synthetic intermediate. 0028 A is 0017. In Journal of Medicinal Chemistry., 43(12), 2310 2323 (2000), 4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydro phthalazin-1 (2H)-one (CAS Registry No. 212142-89-7) is described as synthetic intermediate. 0018. In the specification of FR2647676, 4-t-butoxycar bonylmethyl-5,6,7,8-tetrahydrophthalazin-1 (2H)-one (CAS Registry No. 134972-12-6) and 4-ethoxycarbonylmethyl-5, US 2008/026 1947 A1 Oct. 23, 2008

0029 A' is 0042 E' is C1-4 alkylene, 0043 E is (1) - C(O)NR , (2) - NRC(O) , (3) NR , (4) —C(O)C)— or (5) —S , 21 0044 R is + (R'). (1) a hydrogen atom, (2) C1-8 alkyl or (3) C1-8 alkyl substi S tuted by phenyl, 0045 E is 0030 A is (1) a bond or (2) C1-8 alkylene, 0046 E is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) Cyc5, (5)NR'R'', (6) OR27, (7) SR-7, (8) COOR27, (9) C1-8 alkyl substituted by two of OR’, (10) C1-8 alkyl substituted by 1 (R), to 3 halogen atom(s), (11) cyano or (12) C2-8 acyl, 0047 R’ is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) Cyc5 or (6) C1-8 alkyl substituted by Cyc5 0031. D is or OR2, (1) - NRC(O) , (2) NRC(S) , (3) NRSO, , (4) 0.048 R2 is CH. NR , (5) –CH-O-, (6) - OC(O) , (7) (1) a hydrogenatom, (2)C1-8 alkyl, (3)C1-8alkoxycarbonyl, CH NRC(O) , (8) - NRC(O)NR7 (9) - NRC (4) phenyl or (5) C1-8 alkyl substituted by phenyl, (O)O (10) - NRC(S)NR7 (11) - NR or (12) 0049 R7 is NRC(—NR7) , (1) a hydrogen atom, (2) C1-8 alkyl, (3) Cyc5 or (4) C1-8 0032 R and R7 are each independently alkyl substituted by Cyc5, (1) a hydrogen atom, (2) C1-8 alkyl, (3) phenyl or (4) C1-8 0050 R is alkyl substituted by phenyl, (1) a hydrogen atom or (2) C1-8 alkyl, 0033 D2 is 0051 G' is C1-8 alkylene, (1)C1-8 alkylene, (2) C2-8alkenylene, (3) Cyc2, (4)–(C1-4 0.052 Cyc1 is alkylene)-O-(C1-4 alkylene)-, (5) —(C1-4 alkylene)-S (1) partially or fully saturated C3-10 mono- or bi-carbocyclic (C1-4 alkylene)-, (6)–(C1-4 alkylene)-NR (C1-4 alky aryl, or (2) partially or fully saturated 3-10 membered mono lene)-, (7)-(Cyc2)-(C1-8 alkylene)-, (8) —(C1-8 alkylene)- or bi-hetero aryl containing 1 to 4 hetero atom(s) selected (Cyc2)- or (9) —(C1-4 alkylene)-(Cyc2)-(C1-4 alkylene)- from oxygen, nitrogen and Sulfur atoms, 0034 R is 0053 G? is (1) a hydrogenatom, (2) C1-8 alkyl, (3) C1-8alkoxycarbonyl, (1) a hydrogenatom, (2)C1-8 alkyl, (3)C1-8alkoxycarbonyl, (4) phenyl or (5) C1-8 alkyl substituted by phenyl, (4) C2-8 acyl, (5) Cyc6, (6) C1-8 alkyl or C2-8 alkenyl sub 0035 Dis stituted by 1 to 2 substituent(s) selected from Cyc6, hydroxy (1) a hydrogen atom, (2) - NR'R'', (3) Cyc3, (4) —OR'', and C1-8 alkoxy, (7) C1-8 alkoxycarbonyl substituted by (5) COOR, (6) CONR'R'', (7) cyano, (8) a halogen atom, Cyc6, (8) C(O)-Cyc6, (9) nitro, (10) NR'R'', (11) C1-8 (9) C(—CR')NR'R'7 or (10) NRC(—NR) alkoxy or (12) C1-8 alkyl substituted by NR'R'', NR20R2, 0054) R' and Rare each dependently 0036 Rand Rare each independently (1) a hydrogen atom or (2) C1-8 alkyl, R is (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) C2-8 alkynyl, (5) Cyc3, (6) C1-8 alkoxy, (7) C2-8 alkenyloxy, hydroxy, (5) nitro, (6) NR'R'', (7) C1-8 alkyl substituted by (8) C2-8 alkynyloxy or (9) C1-8 alkyl substituted by Cyc3, NR'R'', (8) NHSO,OH, (9) amidino, (10) cyano, (11) a C1-8 alkoxy, C1-8 alkylthio, cyano, hydroxy or 1 to 3 halogen halogen atom, (12) Cyc8 or (13)C1-8 alkyl substituted by atom(s), Cyc8, 0037) R' and R'' are each independently 0055 Rand Rare each independently (1) a hydrogen atom, (2) C1-8 alkyl, (3) C2-8 alkenyl, (4) (1) a hydrogen atom or (2) C1-8 alkyl, C2-8 alkynyl, (5) C1-8 alkoxycarbonyl, (6) C2-8 acyl, (7) 0056 Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 are each C3-8 cycloalkyl, (8) C1-8 alkoxycarbonyl substituted by independently Cyc4 or 1 to 3 halogen atom(s), or (9) C1-8 alkyl substituted (1) partially or fully saturated C3-10 mono- or bi-carbocyclic by C1-8 alkoxy, aryl, or (2) partially or fully saturated 3-10 membered mono 0038 R'' and R'' are each independently or bi-hetero aryl containing 1 to 4 hetero atom(s) selected (1) a hydrogen atom or (2) C1-8 alkyl, from oxygen, nitrogen and Sulfur atoms, 0039) R', R', R'7, R', R, R and R are each inde 0057 Cyc7 is pendently (1) partially or fully saturated C3-10 mono- or bi-carbocyclic (1) a hydrogenatom, (2) C1-8 alkyl, (3) C1-8alkoxycarbonyl, aryl, or (2) partially or fully saturated 3-10 membered mono (4) phenyl or (5) C1-8 alkyl substituted by phenyl, or bi-hetero aryl containing 1 to 4 hetero atom(s) selected 0040 R is from oxygen, nitrogen and Sulfur atoms, with proviso that (1) a hydrogen atom, (2) C1-8 alkyl, (3) C1-8 alkoxy, (4) Cyc7 is not benzene, hydroxy, (5) halogenatom, (6) nitro or (7) NR'R'', 0058 Cyc2, Cyc3, Cyc4, Cyc5, Cyc6 and Cyc8 are 0041) R' and Rare each independently optionally substituted by 1 to 3 substituent(s) selected from (1) a hydrogen atom or (2) C1-8 alkyl, (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C1-8 alkoxy, (4) halogen US 2008/026 1947 A1 Oct. 23, 2008 atom, (5) trihalomethyl, (6) trihalomethoxy, (7) C1-8 alkoxy 0069 (7) 4-(4-chlorophenyl)-5,6,7,8-tetrahydro carbonyl, (8) oxo, (9) C1-8 alkyl substituted by C1-8 alkoxy phthalazin-1 (2H)-one, or phenyl, (10) hydroxy and (11)NR'R'': (0070 (8) 4-(4-bromophenyl)-5,6,7,8-tetrahydro m and n are each independently 1 or 2, phthalazin-1 (2H)-one, 0059 wherein 0071 (9) 7-hydroxy-4-phenyl-6,7,8,8a-tetrahydropyrrolo 1,2-d1.2.4 triazin-1 (2H)-one, (i) when A is A" or A, then 0072 (10) 4-phenyl-8,8a-dihydro1.3thiazolo 3,4-d1, 2.4 triazin-1 (2H)-one, 0073 (11) 4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydro x1 phthalazin-1 (2H)-one, 0074 (12) 4-t-butoxycarbonylmethyl-5,6,7,8-tetrahydro YS phthalazin-1 (2H)-one, (0075 (13) 4-ethoxycarbonylmethyl-5,6,7,8-tetrahydro is not phthalazin-1 (2H)-one, or 0076 a pharmaceutically acceptable salt thereof, (2) a process for preparing thereof, and (3) an agent comprising the same as an active ingredient. 0077. In the specification, C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl or isomeric groups thereof.

0092. In the specification, halogen means chlorine, bro Zole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, mine, fluorine or iodine. azepine, diazepine, furan, pyran, oxepine, thiophene, thiaine, 0093. In the specification, partially or fully saturated thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, C3-10 mono-carbocyclic aryl represented by oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine, benzofuran, isobenzofuran, x1 benzothiophene, isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, YS phthalazine, pteridine, naphthyridine, quinoxaline, quinaZo line, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole is cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc. cycloheptane, cyclooctane, cyclononane, cyclodecane, 0096. Also, partially or fully saturated 3-10 membered cyclopropene, cyclobutene, cyclopentene, cyclohexene, mono- or bi-hetero aryl containing 1-4 hetero atoms selected cycloheptene, cyclooctene, cyclononene, cyclodecene, from oxygen, nitrogen or Sulfur atom, means aziridine, aze cyclohexadiene, cycloheptadiene, cyclooctadiene etc. tidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, 0094. In the specification, partially or fully saturated 3-10 triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, membered mono-hetero aryl containing 1 to 4 hetero atom(s) pyrazolidine, dihydropyridine, tetrahydropyridine, piperi selected from oxygen, nitrogen and Sulfur atoms represented dine, dihydropyrazine, tetrahydropyrazine, piperazine, dihy by dropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropy ridazine, dihydroazepine, tetrahydroazepine, perhy x1 droazepine, dihydrodiazepine, tetrahydrodiazepine, perhy drodiazepine, oxirane, OXetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydroox YS epine, tetrahydrooxepine, perhydrooxepine, thirane, thiet ane, dihydrothiophene, tetrahydrothiophene, dihydrothiaine means aziridine, aZetidine, pyrroline, pyrrolidine, imidazo (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), line, imidazolidine, triazoline, triazolidine, tetrazoline, tetra dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihy Zolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahy drooxazole, tetrahydrooxazole (oxazolidine), dihydroisox dropyridine, piperidine, dihydropyrazine, azole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahy tetrahydrothiazole (thiazolidine), dihydroisothiazole, tet dropyrimidine, perhydropyrimidine, dihydropyridazine, tet rahydroisothiazole (isothiazolidine), dihydrofurazan, tet rahydropyridazine, perhydropyridazine, dihydroazepine, tet rahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole rahydroazepine, perhydroazepine, dihydrodiazepine, (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihy tetrahydrodiazepine, perhydrodiazepine, oxirane, oxetane, drooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tet dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropy rahydrooxazepine, perhydrooxazepine, dihydrooxadiaz ran, dihydrooxepine, tetrahydrooxepine, perhydrooxepine, epine, tetrahydrooxadiazepine, perhydrooxadiazepine, thirane, thietane, dihydrothiophene, tetrahydrothiophene, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tet dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tet rahydrothiopyran), dihydrothiepine, tetrahydrothiepine, per rahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, hydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazoli perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadi dine), dihydroisoxazole, tetrahydroisoxazole azepine, perhydrothiadiazepine, morpholine, thiomorpho (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazo line, oxathiane, indoline, isoindoline, dihydrobenzofuran, lidine), dihydroisothiazole, tetrahydroisothiazole (isothiazo perhydrobenzofuran, dihydroisobenzofuran, perhy lidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiaz droisobenzofuran, dihydrobenzothiophene, perhydroben ole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, Zothiophene, dihydroisobenzothiophene, perhydroisoben tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiaz Zothiophene, dihydroindazole, perhydroindazole, dihydro ine, dihydrooxazepine, tetrahydrooxazepine, perhydroox quinoline, tetrahydroquinoline, perhydroquinoline, dihy azepine, dihydrooxadiazepine, tetrahydrooxadiazepine, per droisoquinoline, tetrahydro isoquinoline, perhydroisoquino hydrooxadiazepine, dihydrothiadiazole, line, dihydrophthalazine, tetrahydrophthalazine, perhydro tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tet phthalazine, dihydronaphthyridine, tetrahydronaphthyridine, rahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroqui dihydrothiazepine, tetrahydrothiazepine, perhydrothiaz noxaline, perhydroquinoxaline, dihydroquinazoline, tetrahy epine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhy droquinazoline, perhydroquinazoline, dihydrocinnoline, tet drothiadiazepine, morpholine, thiomorpholine, Oxathiane, rahydro cinnoline, perhydrocinnoline, benzoxathiane, dioxolane, dioxane, dithiolane, dithiane etc. dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomor 0095. In the specification, among partially or fully satu pholine, dihydrobenzoxazole, perhydrobenzoxazole, dihy rated 3-10 membered mono- or bi-hetero aryl containing 1 to drobenzothiazole, perhydrobenzothiazole, dihydrobenzimi 4 hetero atoms selected from oxygen, nitrogen or Sulfur atom dazole, perhydrobenzimidazole, dioxolane, dioxane, represented by Cyc1, Cyc2, Cyc3, Cyc4, Cyc5, Cyc6, Cyc7 dithiolane, dithiane, dioxaindan, benzodioxane, chroman, and Cyc8, 3-10 membered mono- or bi-hetero aryl containing benzodithiolane, benzodithiane etc. 1 to 4 hetero atoms selected from oxygen, nitrogen or Sulfur (0097. The above hetero ring includes N-oxide which is the atom means, for example, pyrrole, imidazole, triazole, tetra compound where nitrogen is oxidized. US 2008/026 1947 A1 Oct. 23, 2008

0098. In the specification, partially or fully saturated hetero aryl containing 1 to 2 hetero atom(s) selected from C3-10 mono- or bi-carbocyclic aryl represented by Cyc1. oxygen, nitrogen and Sulfur atom. Moreover, partially or fully Cyc2, Cyc3, Cyc4, Cyc5, Cyc6, Cyc7 and Cyc8 is cyclopro saturated C3-7 mono-carbocyclic aryl, or partially or fully pane, cyclobutane, cyclopentane, cyclohexane, cyclohep saturated 3-7 membered mono-hetero aryl is preferably fol tane, cyclooctane, cyclononane, cyclodecane, cyclopropene, lowing compounds; cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, aZulene, perhydroaZulene, perhydropentalene, indene, perhydroindene, indan, naphthalene, teterahy dronaphthalene or perhydronaphthalene etc. 0099. Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl, alkylene and alkoxy group includes straight or branched ones. In addition, isomers on double bond, ring, fused ring (E-, Z-. cis-, trans-isomer), isomers generated from asymmetric car bon atom(s) (R—, S , Cl-, 3-isomer, enantiomer, diastere omer), optically active isomers (D-, L-, d-, 1-isomer), polar 0107 Partially or fully saturated 3-7 membered mono compounds generated by chromatographic separation (more hetero aryl containing 1 to 2 hetero atom(s) selected from polar compound, less polar compound), equilibrium com oxygen, nitrogen and Sulfur atoms is preferably following pounds, mixtures thereofat Voluntary ratios and racemic mix compounds; tures are also included in the present invention. 0100. According to the present invention, unless other wise indicated and as is apparent for those skilled in the art, symbol ...' indicates that it is bound to the opposite side of the sheet (namely C-configuration), symbol 1 indicates that it is bound to the front side of the sheet (namely B-configu us N1 N,N1 21N ration), symbol rindicates that it is Cl-, 3- or a mixture thereof, and symbol 1ndicates that it is a mixture of c-con figuration and B-configuration. OC 0101 The compound of the present invention can be con Verted into a pharmaceutically acceptable salt by known Ot methods. 0102 The pharmaceutically acceptable salt is preferably water-soluble. DC 0103) The pharmaceutically acceptable salt means, for C N example, salts of alkali metals (potassium, Sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, /1 etc.), ammonium salts (tetramethylammonium, tetrabutylam N S monium, etc.), salts of organic amines (triethylamine, methy CCN, Nu-N N, lamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanola 1n 1 mine, tris(hydroxymethyl)methylamine, lysine, arginine, N N-methyl-D-glucamine, etc.), acid-addition salts (inorganic C N, (OCN. acid salts (hydrochloride, hydrobromate, hydroiodate, sul fate, phosphate, nitrate, etc.), organic acid salts (acetate, tri I0108. In the specification, A is preferably A' A' or A. fluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, 0109. In the specification, D' is preferably NRC(O) , benzoate, citrate, methanesulfonate, ethanesulfonate, benze NRC(S)-, - NRSO, or -CH NR , and more nesulfonate, toluenesulfonate, isethionate, glucuronate, glu preferably NRC(O)-. conate, etc.), etc. I0110. In the specification, D is preferably C1-8 alkylene, 0104 Furthermore, solvates or solvates of the above alkai C2-8 alkenylene. —(C1-4 alkylene)-O (C1-4 alkylene)- (earth) metals, ammonium, organic amines and acid-addition —(C1-4 alkylene)-S (C1-4 alkylene)- —(C1-4 alkylene)- salts of the compound of the present invention are included in NR (C1-4 alkylene)- or —(C1-8 alkylene)-(Cyc2)-, and the pharmaceutically acceptable salt of the present invention. more preferably C1-8 alkylene. 0105. The solvate is preferably nontoxic and water 0111. In the specification, D is preferably NR'R' or soluble. Appropriate Solvate means, for example, Solvates Cyc3. Such as water, an alcohol Solvent (ethanol etc.), etc. I0112. In the specification, E' is preferably C1-4 alkylene. 0106. In the specification, I0113. In the specification, E° is preferably C(O) NR NRC(O) , NR or S I0114. In the specification, E is preferably bond or C1-8 alkylene. x1 (0.115. In the specification, E is preferably Cyc5 or NR25R26. YS 0116. In the specification, Cyc1 is preferably partially or fully saturated 3-10 membered mono-hetero aryl containing 1 is preferably partially or fully saturated C3-7 mono-carbocy to 2 hetero atom(s) selected from oxygen, nitrogen and Sulfur clic aryl, or partially or fully saturated 3-7 membered mono atOm. US 2008/026 1947 A1 Oct. 23, 2008

I0117. In the specification, when A is A or A', at least one of X and Y is preferably N. 0118. In the specification, when A is A or A, (I-B-1)

x1 (R)-H YS 2 N is preferably El-E2-E3-E. (wherein all symbols have the same meanings as described above.), compounds represented by formula (I-B-2) (I-B-2) O

s H N H N HN S (wherein all symbols have the same meanings as described s s N or above.), compounds represented by formula (I-C-1)

S ~- (I-C-1) N N. 0119) Among the compounds of the present invention rep resented by formula (I), preferred compounds are compounds represented by formula (I-A-1)

(I-A-1) (wherein all symbols have the same meanings as described above.), and compounds represented by formula (I-C-2) (R') - || NH| 2 N (I-C-2) 21 (R)-- --D-D2-D NN (wherein all symbols have the same meanings as described above.), compounds represented by formula (I-A-2)

(I-A-2) (wherein all symbols have the same meanings as described above.). I0120 Concrete compounds of the present invention include compounds shown in Tables 1 to 90, compounds described in Examples, and pharmaceutically acceptable salts thereof. I0121. In each Table, Me represents methyl group, Et rep resents ethyl group, Pr represents propyl group, i-Pr repre sents isopropyl group, Bu represents butyl group, c-Pr repre sents cyclopropyl group, c-Bu represents cyclobutyl group, c-Pen represents cyclopentyl group, c-Hex represents cyclo hexyl group, Ph represents phenyl group, Bn represents ben (wherein all symbols have the same meanings as described Zyl group, and other symbols have the same meanings as above.), compounds represented by formula (I-B-1) described above. US 2008/026 1947 A1 Oct. 23, 2008

TABLE 1. TABLE 1-continued

(I-A-1-1) (I-A-1-1)

No No -D2-D

27 N

MeSn-> Me Nie Š.

28 Me

N-1N1\ 2 Me 9 H

N-- 2 N1N1 N e 10 NH Me

N-- 30 Me H 11 ~s. 12 H 13 Me Me 14 15 16 17 TABLE 2 18 19 (I-A-1-1) 2O O 21 NuNu-1CH 2N 22 N-1N1\

O 23 N-N-N-1" S. H 24 N1\1\ No -D2-D 25 CH x-N-N- e Me Me Me 26

32 N-1N1 N N CH2 H US 2008/026 1947 A1 Oct. 23, 2008

TABLE 2-continued TABLE 2-continued (I-A-1-1) O (I-A-1-1)

33 No

45 34

y NH

35 46 O 36 47 37 Cr 38 48

49 40

NH 41

51 43 . 52 44 . US 2008/026 1947 A1 Oct. 23, 2008 10

TABLE 2-continued TABLE 3

I-A-1-1 (I-A-1-1) O ( ) O

2N 2

O O ls ls N D2-D3 N D2-D3 H No -D2-D No -D2-D 61 OMe 53

OMe N-1N-N N-1N1N 62 N-1N1N N

N1N1 a N OMe OMe 63

N 55 Me Me O- OMe 64 OMe

Me Me MeSan-> Me O

56 65 OMe N OMe Me Me xn- N Me Me 57 66 N N1N1 N Me Me OMe

58 N-1N1S N 67

N1N1 N

59 68 N-1N1S N

N1N1 N OMe 21 69

60 N-1N1N N OMe US 2008/026 1947 A1 Oct. 23, 2008 11

TABLE 3-continued TABLE 3-continued

(I-A-1-1) (I-A-1-1) O

No No 70

71 - or 81

72 N-N-1-

OMe

73 82

2 74 r 83 N-N-- 75 84

OMe 76 rol 85 77 - or 86 78 N-1N1 asO. 79 87 N-N-1 nsO

US 2008/026 1947 A1 Oct. 23, 2008 13

TABLE 5 TABLE 5-continued (I-A-1-2) O (I-A-1-2) O

NH 2N" - l O N D2-D l D2-D H H CI Cl

No D2-D3 No -D2-D3

31 42 Me l Me N-1 Snu1 ~s. xn- n-N H Me Me Me 32 43 N-1 Snu1a N-1N1 n N CH2 H NY. Me

33 Me N-1 n1n NH

NH 34 46

35 O NH2 47 NH2

36 48

38 NH2

39 r2

51 40 N-1N1 O) 41 52 ro US 2008/026 1947 A1 Oct. 23, 2008 14

TABLE 5-continued TABLE 6 (I-A-1-2) (I-A-1-2) O O NH NH 2N 2N

O O ls ls N D2-D3 N D2-D3 H C C No -D2-D3

No -D2-D 61 OMe

53 N1N1 N

OMe 62 N-1N1\ N1N1 N N

OMe S4

N-1N1 n N 63 OMe N

Me Me 55 OMe 64 OMe

N Me x-rMe Me Me

65 OMe 56 N OMe Me Me xn- N Me Me 57 66 N N N-1N1 Me Me OMe 58 N-1S-1\ 67

N-1N1 N

59 68 N-1N1S N

N1N1 N OMe 2 69

60 N-1N1\ N OMe US 2008/026 1947 A1 Oct. 23, 2008 15

TABLE 6-continued TABLE 6-continued (I-A-1-2) O (I-A-1-2)

C C No No 70

71 - or 81 N-N-1 ns

72 OMe 82 N-N-1N 73 O 83 N-N-1a 74 Nul

OMe 75 -ro 85

76 -or 86

77 rol OMe

87 78 r 21 88 79 n-n-r N O US 2008/026 1947 A1 Oct. 23, 2008 16

TABLE 7 TABLE 7-continued (I-A-1-3) (I-A-1-3) O

2N es.O H CF CF

No No -D2-D3

27 N Me Š. Me Me

28 Me

N-1N1\ 2 Me 9 H

e N-- 2 N-1N1 N

10 NH Me N-- 30 Me H

11 12 H MeSX-r-s. Me 13 14 15 16 17 TABLE 8 18 19 (I-A-1-3) 2O O 21 NuNN-6CH 2N 22 N-n-n-n 23 N-N-N-1CH N l D2-D3 H 24 CF CH No -D2-D3 25 CH xn- n-n e 26 Me Me Me

32 N-1N1 N N CH2 H US 2008/026 1947 A1 Oct. 23, 2008 17

TABLE 8-continued TABLE 8-continued (I-A-1-3) (I-A-1-3) O t 2N 1.O H CF CF

No No D2-D

33 N1 N1)-Nil,

34 46

36 48 21

51 40

41 52

42 53

43 54 US 2008/026 1947 A1 Oct. 23, 2008 18

TABLE 8-continued TABLE 9 (I-A-1-3) (I-A-1-3) O O NH NH 2N 2 N

O O ls ls N D2-D3 N D2-D3 H CF CF No -D2-D

No -D2-D3 61 OMe

55 N-1N1N 62 N-1N1N NO-os N

Me Me 63 56 N

OMe Me Me Me Me

64 OMe 57 San-> N Me Me

N1N1 N 65 OMe 58 xn- O N-1N-1- Me Me

Me x-rMe N 59 OMe

N1N1 N N1N1 N OMe 68 N1N1N N 60 21

N-1N1N N OMe 69 US 2008/026 1947 A1 Oct. 23, 2008 19

TABLE 9-continued TABLE 9-continued

(I-A-1-3) (I-A-1-3) O O

CF CF No No

71 - or 81 N-N-1 ns

72 OMe

82 73 r 2 83 N-N-1N 74 r

OMe 75 rol 85

76 - or 86

77 rol OMe 87 78 r 21 88 79 N-N-- O

US 2008/026 1947 A1 Oct. 23, 2008 21

TABLE 11-continued TABLE 11-continued (I-A-1-4) O (I-A-1-4)

33 No

34 y NH

46 35 O NH2

47 36 or 37 48 21 N S 38 uC

39 NH2 40 50 r 41 2

51 42 N1N1 O) 52 N-1N1N O) 43

44 53 N-1N1NO-os US 2008/026 1947 A1 Oct. 23, 2008 22

TABLE 11-continued TABLE 12

(I-A-1-4) O (I-A-1-4) O

2N 2

N-D2-D N-D2-D H H No -D2-D3 No -D2-D 61

OMe S4 N1N1\ N1N1 N OMe O 62 N1N1S N 55

OMe OMe N 63

56 x^-r N Me Me Me Me OMe N 57 Me Me

N-1N1 N 65 OMe 58 N-1S-1N xn O Me Me

66 59 San-> N Me Me OMe

N1N1 N OMe 67

60 N-1N1N

N-1N1\ N OMe 68 N-1N1\ N US 2008/026 1947 A1 Oct. 23, 2008 23

TABLE 12-continued TABLE 12-continued (I-A-1-4) (I-A-1-4) O O

No No

69 79 - OMe 70 -or 81 71 rol OMe 82 72 r 2 83 73 N-N-1- r

84 74 N1 - OMe

85 75 -or 86 N-N-1N 76 OMe

87 77 r 2 78 88 n-n-r O US 2008/026 1947 A1 Oct. 23, 2008 24

TABLE 13 TABLE 13-continued (I-A-1-5) (I-A-1-5) O

2 N

N-D2-D H C C

No No -D2-D3

27 N Me Š. Me Me

28 Me

N-1N-1a 21 Me H 9

e N-- 2 N1N1 N-N- 10 NH Me N-- 30 Me H

11 H 12 MeX-ra-'s. Me 13 14 15 16 TABLE 1.4 17 18 (I-A-1-5) 19 O 2O

21 NuNu-6CH 2 N 22 N-1N1\

23 CH N-D2-D N-N-N-1 H C 24 No -D2-D CH 25 CH x-N- e Me Me Me 26

32 N1N1\ N CH2 H US 2008/026 1947 A1 Oct. 23, 2008 25

TABLE 14-continued TABLE 14-continued (I-A-1-5) O (I-A-1-5)

C C No No 33

y NH 34 46

35 C NH

36 Crs 48

49 38

50 39

40 51

44 US 2008/026 1947 A1 Oct. 23, 2008 26

TABLE 14-continued TABLE 1.5 (I-A-1-5) O (I-A-1-5) O

NH t 2 l 2N

ND-D N T2-T3D4-D C C No -D2-D3 No -D2-D 61 55 OMe O-os N-1 n-N MeX- Me 62 N-1N1\ N

56 OMe

OMe Me x-rMe O N

58 65

59 Me Me

N1N1 N N OMe Me Me OMe 60 67

N-1N1S N OMe US 2008/026 1947 A1 Oct. 23, 2008 27

TABLE 15-continued TABLE 15-continued (I-A-1-5) O (I-A-1-5)

C C No No 68

69 ro 79 rol OMe 70

71 -or 81 N-N-1 ns

72 OMe 82 N-N-1- 73 O 83 N-N-1 ns 74 Nul

OMe 75 - 85

76 -or 86 N-N-1 ns 77

OMe

US 2008/026 1947 A1 Oct. 23, 2008 29

TABLE 16-continued TABLE 17-continued (I-A-1-6) (I-A-1-6)

CF CF No

No -D2-D3 35

30 Me ~s. 36 H Me Me 37

TABLE 17 38 (I-A-1-6)

31 H

32 N-1N1N N CH

33 Me 45

34 CH2 46 H Me Me Me US 2008/026 1947 A1 Oct. 23, 2008 30

TABLE 17-continued TABLE 17-continued (I-A-1-6) (I-A-1-6)

No -D2-D No -D2-D

57 47 NH2 N-1N1N 48 58 ro

59 N-1S-1NOl OMe uCl NH 60 N-1N1\ OMe

21 O

51 TABLE 1.8 -O (I-A-1-6) O 52 -ro r 2 N 53 -O OMe

S4 N-1N1N N N-D2-D OMe H CF

55 No -D2-D OMe 61 OMe N

Me Me N1N1 N 56 N 62 N-1N1\ N OMe Me Me OMe US 2008/026 1947 A1 Oct. 23, 2008 31

TABLE 18-continued TABLE 18-continued (I-A-1-6) (I-A-1-6) O O

2N 2N

H H CF CF

No -D2-D No D2-D3

63 72

N N-1N-N Me Me 73 N-1N1N O 64 OMe O x-ror 74 r 65 OMe

-O 75 x -- Me Me x-r -> 66 San-> Ol Me Me N Me Me OMe N 67 N-1N1N 77 -- 68 N-1-1a 21 78 N-1'N-1a

69 79

8O O OMe 70 XroN N-N-1a 71 N-1 ns 81 N-N-1N Null OM US 2008/026 1947 A1 Oct. 23, 2008 32

TABLE 18-continued TABLE 19 (I-A-1-7) (I-A-1-6)

No CF

83 N-- 2 10 N-- 84 11 12 13 14 15 16 85 17 18 19 2O

21 86 NuN-6CH 22 CH OMe 23 87 N-N-N-1CH 24 N-1N1N NY.CH 25 N-N-N-1" 88 26 US 2008/026 1947 A1 Oct. 23, 2008 33

TABLE 19-continued TABLE 20-continued (I-A-1-7) (I-A-1-7) O O

2N 2N

H HYpp N YD2-D3

N -D2-D3 No -D2-D O 33 Me H 27 N N-N-N X-r Me Š. CH2 Me Me 34 CH N 28 Me H H 35 NullsMe 29 N-N-N N Me Me xn-Me CH2

Me 36 N-1'N1n NH2 30 Me ~s 37 N-1 O N-1N CH2 H Me xn->Me Me H Me

38 Me TABLE 20 N1 O n-n 4fn. (I-A-1-7) O 39 O N1 N1 y1)Me S. NH 2N 40 N-N-1N NH2

41 S CH N-1 n-rreH 2 NH Me YD2-D 42 Me No -D2-D S 31 H N-1N-1N 4fn.

Me x-N-N-"Me Me 43 ~.

32 N-1N1N N CH2 44 H US 2008/026 1947 A1 Oct. 23, 2008 34

TABLE 20-continued TABLE 20-continued (I-A-1-7) (I-A-1-7) O O

2 2N

H N H YD2-D3 Nn D2-D3 No -D2-D No -D2-D 45 y NH 56 N 46 OMe Me Me

NH 2 57 47 ors N-1S-N 58 N-1N1 a N 48 C 59 49

N1N1 N OMe NH 60 N-1N1N OMe 50 n N N

51 O) TABLE 21 N-1N1 N (I-A-1-7) 52 N-1N1N N O

53 2 N OMe N-1 nu-N

No -D2-D

55 61 OMe OMe US 2008/026 1947 A1 Oct. 23, 2008 35

TABLE 21-continued TABLE 21-continued (I-A-1-7) (I-A-1-7) O O

2N 2N

YD2-D3

No D2-D3 No D2-D3 62 N-1N1\ 71 N-rNull

63 72

Me Me

66 76 N-1'N-1a

67 77

68 ro 78 N-N-1 ns

70 US 2008/026 1947 A1 Oct. 23, 2008 36

TABLE 21-continued TABLE 22 (I-A-1-8) (I-A-1-7)

No No

81 N-1'N-1a

OMe

82 9

N-- 2 21 r 10

83 NH N--H 2

11 N-N-> 12 13 14 15 84 16 17 OMe 18 rol 19 2O 85 21 NuNN-6CH - or 22

86 CH

23 CH

rol OMe N-N-N-1 24 87 CH r 2 25 N-N-N-1" 88 N-1N-1a 26 Null US 2008/026 1947 A1 Oct. 23, 2008 37

TABLE 22-continued TABLE 23-continued (I-A-1-8) (I-A-1-8) O O

2N 2N

YD2-D3 YD2-D3

C C

No -D2-D3 No -D2-D3

27 N 33 Me Nie Š. H Me Me N-1N-N CH2 28 Me 34 CH

H e Me Me Me

29 H 35 Me N1N1 N Me H N-N-Me xn- NullsCH Me Me 30 Me 36 O 2 N1 n1n NH2

Me TABLE 23 38 Me (I-A-1-8) O O N-1 N-1SN 2 Me H

NH 39 O 2 N N1'N1\1\Me n CH 40 N1 S N1)-Nil,

41 S CH Y D4-D2 3 N1 n1n N 2 C Me

No -D2-D 42 Me 31 NH Me N-1N-1NS 4N

Me xn-Me n-NMe 43 S H N-1 N-1N N 32 N-1N1N CH2 Me S. N US 2008/026 1947 A1 Oct. 23, 2008 38

TABLE 23-continued TABLE 23-continued

I-A-1-8 O ( ) (I-A-1-8) O NH NH 2N 2 N

YD2-D3 YD2-D3 C C No -D2-D3 No -D2-D 45 53

NH OMe 46 N1N1 N

NH2 N-1N1 a N OMe 47 Cr NH2 55 48 xn

49 N OMe Me Me

57 NH2

N-1 n-N 59 52 Nu-1Nu-N ro OMe US 2008/026 1947 A1 Oct. 23, 2008 39

TABLE 23-continued TABLE 24-continued

(I-A-1-8) (I-A-1-8) O O

2 N 2 N

YD2-D3 YD2-D C C No -D2-D3 No -D2-D 65 OMe

60 N1N1 a N OMe

TABLE 24 (I-A-1-8) O 67

2 N 68

YD2-D 69 C

No -D2-D

61 OMe 70 N-1N1 N

62 N-1N1N N 71

OMe

63 72 N

64 xn-r OMe 73 US 2008/026 1947 A1 Oct. 23, 2008 40

TABLE 24-continued TABLE 24-continued (I-A-1-8) (I-A-1-8) O

YD2-D3

No No -D2-D3 74 84

N-1 - OMe

Me Me

75 85 -or 76 N-N-1a 86 N-1 Snu1\

Ol OMe 77 87 N-1 Snu1a ro N 78 N-N-1N O 88 N-N-1N N

79 N

TABLE 25 (I-A-1-9) O

81 2N

82 YD2-D CF

83 No -D2-D3 1 Me 2 Pr 3 Bu US 2008/026 1947 A1 Oct. 23, 2008 41

TABLE 25-continued TABLE 25-continued (I-A-1-9) O (I-A-1-9) O

YD2-D3 CF CF No No -D2-D3

28 Me

N-1N1S 2 Me H

N-- 2 N-1N1 N e 10 NH N-- Me H 30 Me 11 12 13 H 14 MeX-ra-'s. Me 15 16 17 18 19 TABLE 26 2O (I-A-1-9) 21 NuN-1CH O 22 N1N1\ 2N 23 N-N-N-1CH 24 YD2-D3 CF 25 No -D2-D

e 26 x^-N-N- Me Me Me

32 N-1N1N N CH2 27 H Me US 2008/026 1947 A1 Oct. 23, 2008 42

TABLE 26-continued TABLE 26-continued (I-A-1-9) (I-A-1-9) O

CF CF3

No No D3 33 45 y NH 34 46

35 O NH2 or NH 36 37 uC

38 uCl NH

50 n 39 N r 2 40 51

41 N-1N1 N

52 N-1N1S 42 O) 53 OMe

43 N-1N1 N

54 N1N1\ N 44 O-os US 2008/026 1947 A1 Oct. 23, 2008 43

TABLE 26-continued TABLE 27

I-A-1-9 O (I-A-1-9) O ( )

NH t 2 l 2N

H Nin D2-D3 YD2-D CF CF No -D2-D No -D2-D 61 55 OMe

56 OMe

63 x-r OMe Me Me N OMe 57

64 OMe

Nu-1Nu-N Me xn-rMe 58 65

N-1N1 a N OMe xn- N Me Me 59 66 N Me Me N1N1 N OMe OMe 67

60 N-1N1 N OMe N-1N1\ N 68 N1N1 a N US 2008/026 1947 A1 Oct. 23, 2008 44

TABLE 27-continued TABLE 27-continued

I-A-1-9 O (I-A-1-9) O ( )

2N 2N

H HYpp N YD2-D CF CF No D2-D3 No -D2-D O O x- 79 Y-ro.

N-1'N-1a OMe 2 N

Nul 81 rol 72 OMe N-1N-NO 82 r 73 N-1N1\ OO 83 N-N-1N 74 Nul x-O 84 N-N-1N Me Me O-os.

75 85 N-1 Snu1a N r Me Me lr 76 N-19 n1n 86 N-1SN-1a N

OMe 77 N-19 - 87 r 21

US 2008/026 1947 A1 Oct. 23, 2008 46

TABLE 29 TABLE 29-continued

(I-A-2-1) (I-A-2-1)

N N

No No 42 31

43 32

34 46

36 48

51 40

41 52 US 2008/026 1947 A1 Oct. 23, 2008 47

TABLE 29-continued TABLE 30 (I-A-2-1) (I-A-2-1) O O NNE

2 r2N N N O O ls ls N D2-D3 N D2-D3 No -D2-D

No -D2-D3 61 OMe 53 N-1a-N OMe

N-1N-N 62 N-1N1N N

S4 OMe N-1N1N N 63 OMe N

55 Me Me OMe N 64

Me Me Me Me

56 65 OMe N OMe Me Me xn- N 57 Me Me

66 N N1N1 N Me Me OMe

58 N-1N1N N 67

N-1N1 N

59 68 N-1N1 N N

N-1N1 N OMe 2 69

60 N-1N1N N OMe US 2008/026 1947 A1 Oct. 23, 2008 48

TABLE 30-continued TABLE 30-continued

(I-A-2-1) (I-A-2-1)

N N

No No 70

71 - or 81 N-1'N-1a

72 OMe 82 N-1'N-1 ns 73 O 83 N-1'N-1a 74 Null

84 N1 - OMe

75 85

76 - or 86 N-N-1N

77 OMe 87 N-N-1 ns 78 O 88 N-1N-1 ns 79 Null US 2008/026 1947 A1 Oct. 23, 2008 49

TABLE 31 TABLE 31-continued (I-A-2-2) (I-A-2-2) O

N N 2 N H l N D2-D H C

No No D2 D.

27 N Me Š. Me Me

28 Me

N-1N1a 21 Me H 9

e N-- 2 N1N1 N-N- 10 NH Me N-- 30 Me H

11 H 12 MeX-ra-'s. Me 13 14 15 16 TABLE 32 17 18 (I-A-2-2) 19 O 2O

21 N NuNN-6CH N 2 H 22 N-1N1S

23 l N D2-D N-N-N-1" H C 24 No D D N1\11N CH 25 CH xn- n-n e Me Me Me 26 32 N1N1N N CH2 US 2008/026 1947 A1 Oct. 23, 2008 50

TABLE 32-continued TABLE 32-continued

(I-A-2-2) (I-A-2-2) O O t N 2N N 2 N H l O H -- H C C No D2 D. No D2 D. 33

y NH 34 46

35 NH

36 48 37

49 38

50 39

40 51

44 US 2008/026 1947 A1 Oct. 23, 2008 51

TABLE 32-continued TABLE 33 (I-A-2-2) (I-A-2-2) O O

N N N 2 N 2 H H l OS N D2-D H H C C No D2 D. No D D 61 55 OMe N-1N1N

62 N1N1N N

OMe 56 63

Me Me xn- OMe

57 64 OMe N Me Me

N-1a-N 65 OMe 58 xn- O Me Me

N-1S-1\ 66 N Me Me OM 59 67

N1N1 N 68 N-1N1 N N N-1N1N OMe

60 69

N-1N1 a N OMe

Me Me US 2008/026 1947 A1 Oct. 23, 2008 52

TABLE 33-continued TABLE 33-continued (I-A-2-2) (I-A-2-2) O O

N" N 2 N 2N H H

O O

N ls D4-D2-T3 N ls D2-D C C No D2 D. No D2 D. 70 xn-r 8O N1 O N-1)a OMe Me Me 21

71 N-1N 81 N-1'N-1N

72 OMe N---r 82 N-1 O N-1N 73 N-1N1N r 2 N- O 83 N1 O N-1SN 74 r Null San-i- " --ro.

75 MeXro Me O 85 N1 S - or

76 N-1'N-1a N 86 N1 S N-1SN 77 N-1'nu-1N O) OMe

78 N-19 n1n N 87 r 21 79 N-1'N-1a O-os. 88 N-n-rNull US 2008/026 1947 A1 Oct. 23, 2008 53

TABLE 34 TABLE 34-continued (I-A-2-3) (I-A-2-3) O

N N 2 N H l N D2-D H CF CF

No No D D

27 N Me Š. Me Me

28 Me

N-1S-1a 2 Me 9 H

e N-- 2 N1N1 N 10 NH Me N-- 30 Me H

11 x-r H~s. 12 Me Me 13 14 15 16 17 TABLE 35 18 (I-A-2-3) 19 O 2O

21 CH

NuNu1 N N 2 22 H CH 23 l N D2-D N-N-N-1CH H 24 CF N11 CH No D D

25 N-1N1 Nue" xn- n-n e Me Me Me 26 CH2 32 N-1N1N N US 2008/026 1947 A1 Oct. 23, 2008 54

TABLE 35-continued TABLE 35-continued (I-A-2-3) (I-A-2-3) O

N N 2 N H l N D2-D N H CF CF

No D2 D. No D D 44 33 N1 N1)-Nil, 45 Y\, 34 46 O 35 NH2 47 ors 36 48 Y 37

38 49 ul NH2

50 n N 39 2

51 40

41 52 N-1N1N N

42 53 OMe N-1N1 N 54 N-1N1S 43 NO-os US 2008/026 1947 A1 Oct. 23, 2008 55

TABLE 35-continued TABLE 36 (I-A-2-3) (I-A-2-3) O O

N N N 2 N 2 H H l --O N D2-D H H CF CF No D D No D D 61 55 OMe N-1N1N

62 N-1N1N N

OMe 56 63

N Me Me xn- OMe

57 64 OMe N Me Me

N-1N1N 65 OMe 58 O N-1N1\ Me Me 66 N Me Me OMe 59 67

N1N1 N 68 N-1N1N N-1S-1N OMe N

N1N1\ N OMe

Me Me US 2008/026 1947 A1 Oct. 23, 2008 56

TABLE 36-continued TABLE 36-continued

(I-A-2-3) (I-A-2-3) O O

NH NH N 2N N 2N H H O O ls ls N D2-D N D2-D H H CF CF No D2 D. No D D 78 N-N-1 ns

21 - OMe

71 ro 8O N-1'N-1a N r

N-1Nu-N N-N-1 ns

OMe 73 n-n-r

N-l 82 r 2 74 O N-N-1- x- Nul

76 N-ry 85 - or

86 S 77 N-N-1N N-1N-1a l) OMe US 2008/026 1947 A1 Oct. 23, 2008 57

TABLE 36-continued TABLE 37-continued (I-A-2-3) O (I-A-2-4) t 2 N N N isO H CF No D D No D D 14 —(CH2). NHMe 87 15 —(CH2). NHMe 16 17 -(CH2) NMe2 2 18 —(CH2) NMe2 r 19 Pr 2O —CH2—NH-c-Bu 88 n-n-r 21 N O NuNN-6CH 22 N-1N1N

TABLE 37 23 N-N-N-1CH 24 N1N1N

N 25 CH 26 Nue"

No 27

9 N-- 29 10 NH N-- 30 H

11 12 Me Me 13 US 2008/026 1947 A1 Oct. 23, 2008 58

TABLE 38 TABLE 38-continued (I-A-2-4) (I-A-2-4) O O

N" N N 2 N 2 H H

N-D2-D N - D2-D- Ty3

No D2 D. No D2 D.

31 H 42 Me N N Me xn- N-N- N-1 S N-1N 2 Me Me Me Me H 32 CH2 43 N-1 nu1 a N-1N1N N NMe ŠsCH Me 44 33 Me N1,N1)- H N-1Nu-N CH 45 NH 34 CH2 N

Me Me Me

35 Me NH 2

N 47 xn- NullsCH2 NH Me Me 36 N-1 O N-1SN, 48 4NN

37 O CH N

N-1 n-reH 2 49 Me

50 NN 39 N-1'n-1\O NN, 2 51 40 N-N-1- -O

41 N-n-reCH2Me 52 ro US 2008/026 1947 A1 Oct. 23, 2008 59

TABLE 38-continued TABLE 39 (I-A-2-4) (I-A-2-4) O O NH " 2 N 2N N H

N-D2-D N-D2-D No D D No D2 D. 61 OMe

53 N-1N1N

N-1N-NO-os. 62 N-1N1\ N

S4 OMe 63

N OMe 55

OMe 64 OMe N xn-r

65 OMe 56 N OMe Me Me xn- N Me Me 57 66 N N-1N1 N Me Me OMe

58 N-1N1 N N 67

N1N1 N

59 68 N-1N1N N

N1N1 N OMe 2 69

60 N-1N1N N OMe US 2008/026 1947 A1 Oct. 23, 2008 60

TABLE 39-continued TABLE 39-continued

(I-A-2-4) (I-A-2-4) O O " 1, H 1'NeN

N-D4-D-T2.- T3 N-D2-D H No D D No D2 D.

8O O OMe 70 Me x-rMe N-N-1a 2 71 N-1a Null 81 rol 72 OMe

N-1N-N 82 N-1'N-1a 73 N-1S-1N O C 83 N-N-- Sar-e- 84 N-1N-1 ns 75 x-r O 85 N-1 Snu1 r 76 N-ry 86 N-1 Snu1a 77 N-N-1a Ol O) OMe 87 N-1SN-1a ro O21 79 88 N-1 n-1\ r

US 2008/026 1947 A1 Oct. 23, 2008 62

TABLE 41-continued TABLE 41-continued (I-A-2-5) O (I-A-2-5)

2N" N N

N-D-D: H CI Cl No D2 D. No D D 33 Me H 45 N1N1 N CH2 Y\ 34 CH2 x-rrN 46 Me Me Me

35 Me O NH2 H 47 xn- NullsCH NH Me Me Cr 36 N-1'N-1 n NH2 48 N 37 C

49 38

NH2

50 39 r 2 40 51 41 N-1N1 O)

52 42 N-1N1N O)

53 43 N-N-1a OMe Nie Š. N-1N1 O

44 54 N-1 N1)-Nil, N-1N1N O)- OMe US 2008/026 1947 A1 Oct. 23, 2008

TABLE 41-continued TABLE 42 (I-A-2-5) (I-A-2-5) O O

NH t 2N N 2 N N H

N D2 D3 N - D4-DT2.- T3 C C No D2 D.

No D2 D. 61 OMe

55 N-1N-N

NO- OMe 62 N-1N1N

Me xn-Me N OMe

56 63

N OMe Me Me N

57 Me Me

64 OMe N-1N1 N San-> N Me Me

58 65 N-1N1 a N OMe

xn- N 59 Me Me

MeSan-> Me N

N-1N1 N OMe OMe 67

60 N-1N1 N N-1N1 a OMe 68 N N-1N1n N US 2008/026 1947 A1 Oct. 23, 2008 64

TABLE 42-continued TABLE 42-continued (I-A-2-5) (I-A-2-5) O

N N 2 N H

N-D2-D H Cl

No D2 D. 69 ro 79 70 - OMe

71 - or 81 N-1'N-1a 72 OMe

73 r 2 83 74 N-N-r O

OMe 75 -ro 85 76 -or 86 N-1N1 as 77

OMe US 2008/026 1947 A1 Oct. 23, 2008 65

TABLE 42-continued TABLE 43-continued (I-A-2-5) (I-A-2-6)

N N

H H C CF

No D2 D. No D D 87 13 14 15 2 16 r 17 18 88 19 N-N-1- 2O N-l 21 NuNu1CH 22 TABLE 43 N-1N1\ (I-A-2-6) 23 N-N-N-1 CH 24 N Y1sn 25 CH

No 27

9 29

N-- NH 2

10 NH N-- 30 H

11 12 US 2008/026 1947 A1 Oct. 23, 2008 66

TABLE 44 TABLE 44-continued (I-A-2-6) (I-A-2-6) O O NH t 2N N 2N N H

N - TY2-TY3D4-D N-D-DH CF CF

No D2 D. No D D 31 H 42 Me N Me xn- N- N N-1 S n1n N 2 Me Me Me Me H

43 32 N-1N1 n CH N1 S n1n N S N Me n CH Me 44 33 Me N-N-1N, H N---> CH 45 NH 34 CH2

Me x-rr,Me Me 46

35 Me NH2

N 47 xn- NullsCH2 NH Me Me

36 N-1'N-1a 48

37 O CH

N-1 n-re 2 49 Me

38 Me O ~1. 39 N1 O Y1,1\s r 21 51 40 N-1N1)- -O

41 n-n-re"Me 52 -ro US 2008/026 1947 A1 Oct. 23, 2008 67

TABLE 44-continued TABLE 45 (I-A-2-6) (I-A-2-6) O O NH " 2 N 2N N H

N-D2-D N-D2-D H H CF CF No D D No D2 D. 61 OMe

53 N-1N-N -O OMe 62 N1N1N N OMe S4 N-1N1N N O-os 63 N

55 Me Me OMe N 64 OMe

56 N 65 OMe OMe Me Me

57 Me Me

N-1N1 N 66 San- N Me Me

58 N-1N1N N OMe 67

N-1N1 N 59 68 N-1N1N N N1N1 N OMe 2

60 N-1N1N OMe 69 N US 2008/026 1947 A1 Oct. 23, 2008 68

TABLE 45-continued TABLE 45-continued (I-A-2-6) (I-A-2-6) O O " H H

N-D-D N-D2-D CF CF

2 3 - - - No D D

70 x-r 8O O OMe X-r)2 ro 71 N-1N Null 81 N-1'N-1NO 72 r OMe N-1N1 Nu 82 N-1'N-1N N 73 N-n-r O Nul 83 N-1'N-1 ns

75 XroO 85 -or 76 N-ry

77 -- rol OMe 87 78 N1 O N-1SN r 2 79 N-N-1N 88 N-N-1- O O-os. O US 2008/026 1947 A1 Oct. 23, 2008 69

TABLE 46 TABLE 46-continued

(I-A-2-7) (I-A-2-7) O

N N 2 N H

YD2-D3 No No -D2-D

27 N Me Š. Me Me

28 Me

9 N-1N1a 2 Me H

N-- 2 29 M e 10 NH N1N1 N N-- Me H 30 Me 11 12 13 x-r H ~s. 14 Me Me 15 16 17 18 19 TABLE 47 2O (I-A-2-7) O 21 NuN-6CH

22 N N 2 N-n-n-n H 23 N-N-N-1CH YD2-D3 24 CH No -D2-D 25 CH xn- N-N- e Me Me Me 26

32 N-1N1N N CH H US 2008/026 1947 A1 Oct. 23, 2008 70

TABLE 47-continued TABLE 47-continued (I-A-2-7) (I-A-2-7) O

2 N N N

YD2-D

No D2-D3 No

33 Me 45 H N-1N1 N CH2 46 34 CH x-rr,H Me Me Me 47 35 Me NNulls Me Me 48

36 N-1'N-1a NH

37 N-1'N-1a N CH2 49 H Me

38 Me 50 N-1'N-1a N 21 Me H

39 Nu-'nu-1a N 51 Me Š.

40 N1 SN-1N NH 52 41 N-1 nu1a CH H Me 53

42 Me

N-1 n-1N 2 Me 54 H

43 N-1 S n1n N Me Š. 55 OMe 44 N-1 n-1\ NH2 US 2008/026 1947 A1 Oct. 23, 2008 71

TABLE 47-continued TABLE 48-continued (I-A-2-7) (I-A-2-7) O

2 N N N

No No -D2-D 62

56 N OMe

63 57

64 58 N1N1\ N

59 65

N-1N1N OMe

60 N-1N1N N OMe 66

TABLE 48 67 (I-A-2-7)

68 N-1S-1N N 21

xn- N Me Me 61 OMe 70 x-r Me Me 2 US 2008/026 1947 A1 Oct. 23, 2008 72

TABLE 48-continued TABLE 48-continued (I-A-2-7) (I-A-2-7)

N N

71 No

rol OMe

73 82 r 2 74 83 N-N-- O

75 84 -ro OMe 76 85

77 -or 86 N-N-1 ns 78 OMe

87 79 r 21 88 N-1N-1 ns Nul

US 2008/026 1947 A1 Oct. 23, 2008 74

TABLE 50-continued TABLE 50-continued (I-A-2-8) (I-A-2-8) O

2 N" N N

YD2D;

Cl Cl

No D2-D No D3 33 45

NH 34 46

35 O NH

47 or NH 36 48 21 37 N

49 38 ul NH2

50 39 r 2 40 51

41 N1N1 O) 52 N-1N1N O) 42

53 OMe

43 --O 54 OMe 44 rol US 2008/026 1947 A1 Oct. 23, 2008

TABLE 50-continued TABLE 51

(I-A-2-8) O (I-A-2-8) O NH t N 2N N 2 N H

H HYpp N YD2-D3

C C No -D2-D3 No -D2-D 61 OMe 55

N-1N1 N OMe xn- O- 62 N-1N1N N Me Me OMe

56 63

OMe Me Me Me Me

64 OMe 57 San-> N Me Me

65 OMe N-1N1 N N

58 Me xnMe N-1N1 a 66 N x-r N Me Me OMe

N-1N1 N

N-1N1 N OMe 68 N-1N1N N 60 2

N-1N1\1\-OMN US 2008/026 1947 A1 Oct. 23, 2008 76

TABLE 51-continued TABLE 51-continued

(I-A-2-8) (I-A-2-8) O O

2N N 2 " N H

H HYppi N YD2-D3

C C

No -D2-D3 No -D2-D3

70 78 N-1 O n1n N x-r N Me Me 21 79 71 - OMe Null 8O ro OMe 72

uC rol OMe 73 N-1S-1N O 82 N-1'N-1 nsO 74 O 83 N-1'N-1NO N Null

75 OMe

85 N-1 n-1\ OMe 76 N-N-1N \\ N-Snu1

77 -- Ol OMe

US 2008/026 1947 A1 Oct. 23, 2008 78

TABLE 52-continued TABLE 53-continued (I-A-2-9) (I-A-2-9) O O

NH 2N N N N 2 H

H YD2-D3 N D2-D3 CF CF No -D2-D

No -D2-D 35 Me N 30 Me xn- NullsCH2 ~s Me Me xn-r 21 Me 36 N-1'N-1N M e Me NH2 37 O CH

TABLE 53 Me

(I-A-2-9) 38 Me O N-N-1a 21 Me NH H l 39 N-1'N-1a NH 2 NY.Me CH 40 N-1 Snu1a H NH2 N D2-D3 41 S CH CF N-1 n-reH Me 2 3 No -D4-D 42 Me

31 Me S

Me Me Me 43 S N-1 N1 y1) 32 N-1N1N N CH2 Me Š H Me 44 N1 N1)-Nil, 33 Me N-1N-NNulls CH 45 YA 34 CH 46 x-rrH Me Me Me NH2 US 2008/026 1947 A1 Oct. 23, 2008 79

TABLE 53-continued TABLE 53-continued (I-A-2-9) (I-A-2-9) O

N N 2 H N

YD2-D3 CF

No -D2-D No -D2-D

57 47 NH2 N-1N1N 58 N-1S-1N 48 21 N N 59

N1N1 N OMe 49 -O. NH2 60 N-1N1S OMe 50 r n N N 51 -O TABLE 54 (I-A-2-9) 52 -ro 53 N -O OMe

S4 N-1N1\ N OMe

55 No -D2-D OMe N 61 OMe

Me Me

56 N 62 N-1N1N N OMe Me Me OMe US 2008/026 1947 A1 Oct. 23, 2008 80

TABLE 54-continued TABLE 54-continued (I-A-2-9)

N N

N 73

64 OMe San- C 74

65 OMe

-O 75 66

76 Xrol OMe 67 77

68 N-1N1\ N 78

70 Xro 71 N-1 ns 81

US 2008/026 1947 A1 Oct. 23, 2008 84

TABLE 56-continued TABLE 57-continued (I-B-1-2) (I-B-1-3)

No No

71 72 73 74 75 76 77 78 11 79 12 13 14 15 16 17 18 19 81 2O 21 22

23 82 -NH -O)

24 83

27 (I-B-1-3)

29 —(CH2) - - OH 30 —(CH2) - - OMe 31 —(CH2) - —NH2 32 —(CH2) - - NHMe No 33 —(CH2) - NHEt 34 —(CH2) - NHPir - OH 35 —(CH2) - - NH-i-Pr - OMe 36 —(CH2) - —NMe2

US 2008/026 1947 A1 Oct. 23, 2008 90

TABLE 61-continued TABLE 61-continued

(I-B-1-7) (I-B-1-7)

2N Me El l r NE3. O No No -E- 13 32 —(CH2)2— o ci-( )– NH2 14

17 18 19 2O NO 21 22 23 24 25 26

30 23

31 24 -XOX US 2008/026 1947 A1 Oct. 23, 2008 91

TABLE 62-continued TABLE 62-continued (I-B-1-8)

No No

25 54

26 55

27 56

28 57 58 59 60 61 29 62 30 63 31 32 65 33 66 34 67 35 68 36 69 37 70 38 71 39 72 40 73 41 74 42 75 43 76 77 45 78 46 47 79 48 49 50

51 80

81 52

53 82 US 2008/026 1947 A1 Oct. 23, 2008 92

TABLE 62-continued TABLE 63-continued (I-B-1-8) O (I-B-1-9)

2 N

E3-E4

No -E- -E No 83 -(CH2)— 15 -N - (CH) OMe

84 —(CH2)— / \ 16 -N O —CH2— -(CH) NH2

17 TABLE 63 18 (I-B-1-9) 19 2O 21 22 23 24 25 26

27 N O

29 1

1 1

31 13

32 14