(12) United States Patent (10) Patent No.: US 7,915,283 B2 Wang Et Al

USOO7915283B2

(12) United States Patent (10) Patent No.: US 7,915,283 B2 Wang et al. (45) Date of Patent: *Mar. 29, 2011 (54) INDOLE, AZAINDOLE AND RELATED W W g ? 2. 4. 12: HETEROCYCLIC 4-ALKENYL PPERDINE WO WO 98.28292 7, 1998 AMIDES WO WOO2.04440 1, 2002 WO WO O2/O62423 8, 2002 (75) Inventors: Tao Wang, Farmington, CT (US); John F. Kadow, Wallingford, CT (US); OTHER PUBLICATIONS Nhel R St. Ret M. Font, et al., “Indoles and Pyridazino4,5-b]Indoles as Non (U ); ap. un Yeung, a. 1SOn, nucleoside Analog Inhibitors of HIV-1 Reverse Transcriptase.” Eur, (US). Zhongxing Zhang, Madison, CT J. Med. Chem., 30, pp.963-971, 1995. (US); Zhiwei Yin, Glastonbury, CT D.L. Romero, et al., J. Med. Chem., 36, pp. 1505-1508, 1993. (US); Zhilei Qui, Parsippany, NJ (US); S.D. Young, et al., “2-Heterocyclic indole-3-Sulfones as Inhibitors of Daniel H. Deon, Candiac (CA); Clint A. HIV-1 Reverse Transcriptase.” Bioorganic & Medicinal Chemistry James, Laprairie (CA); Edward H. Letters, 5(5), pp. 491–496, 1995. Ruediger, Greenfield Park (CA); Carol MJ . Genin, et al., “Synthesis and Bioactivity of Novel Bachand, Candiac (CA) Bis(Heteroaryl)Piperazine (BHAP) Reverse Transcriptase Inhibi s tors: Structure-Activity Relationships and Increased Metabolic Sta (73) Assignee: Bristol-Myers Squibb Company, by Nesbstituted Pyridine Analogs,” J. Med. Chem, 39, pp. Princeton, NJ (US) R. Silvestri, et al., Antiviral Chemistry & Chemotherapy, 9, pp. 139-148, 1998. (*) Notice: Subject to any disclaimer, the term of this A. Fredenhagen, et al., "Semicochiliodinol A and B: Inhibitors of patent is extended or adjusted under 35 HIV-1 Protease and EGF-RProtein Tyrosine Kinase Related to Aster U.S.C. 154(b) by 532 days. riquinones Produced by the Fungus Chrysosporium merdarium.” This patent is Subject to a terminal dis- Journal of Antibiotics, 50(5), pp. 395-401, 1997. claimer M. Kato, et al., “New 5-HT (Serotonin-3) Receptor Antagonists. IV. Synthesis and Structure-Activity Relationships of Azabicycloalkaneacetamide Derivatives.” Chem. Pharm. Bull. (21) Appl. No.: 12/015,767 43(8), pp. 1351-1357, 1995. V. Levacher, et al., "Broadening in the Scope of NADH Models by (22) Filed: Jan. 17, 2008 Using Chiral and Non-Chiral Pyrrolo 2,3-bPyridine Derivatives.” Tetrahedron, 47(3), pp. 429-440, 1991. (65) Prior Publication Data US 2008/O188481 A1 Aug. 7, 2008 * cited by examiner Related U.S. Application Data Primary Examiner — Bernard Dentz (60) Division of application No. 10/762,108, filed on Jan. (74) Attorney, Agent, or Firm — John F. Levis 21, 2004, now Pat. No. 7,348,337, which is a continuation-in-part of application No. 107425,370, (57) ABSTRACT filed on Apr. 29, 2003, now abandoned. (60) Provisional application No. 60/383,509, filed on May This invention provides compounds having drug and bio 28, 2002 affecting properties, their pharmaceutical compositions and s method of use. In particular, the invention is concerned with (51) Int. Cl. new piperidine 4-alkenyl derivatives that possess unique anti A6 IK3 L/454 (2006.01) viral activity. More particularly, the present invention relates A6 IK3 L/4545 (2006.01) to compounds useful for the treatment of HIV and AIDS. The (52) U.S. Cl...... 514/300: 514/323 COmpoundSpounds ofOf theth 1nVent1On forOr the general Formula:Formula I (58) Field of Classification Search ...... 514/300, 514/323 (I) See application file for complete search history. Zn W (56) References Cited U.S. PATENT DOCUMENTS wherein: 5,023,265 A 6/1991 Scherlocket al. Z is 5,124,327 A 6, 1992 Greenlee et al. 5,424,329 A 6, 1995 Boschelli et al. 6,469,006 B1 10/2002 Blair et al. O 6,476,034 B2 11/2002 Wang et al. 6,573,262 B2 6, 2003 Wallace et al. 7,348,337 B2 * 3/2008 Wang et al...... 514,300 Q FOREIGN PATENT DOCUMENTS EP O530907 A1 3, 1993 WO WO 93.01181 1, 1993 WO WO95/04742 2, 1995 Q is selected from the group consisting of: US 7,915,283 B2 Page 2

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18 Claims, No Drawings US 7,915,283 B2 1. 2 INDOLE, AZAINDOLE AND RELATED Ren et al: (Ref. 6-14)). Therefore, novel anti-HIV agents HETEROCYCLIC 4-ALKENYL PPERDINE exhibiting distinct resistance patterns, and favorable pharma AMIDES cokinetic as well as safety profiles are needed to provide more treatment options. CROSS REFERENCE TO RELATED Currently marketed HIV-1 drugs are dominated by either APPLICATIONS nucleoside reverse transcriptase inhibitors or peptidomimetic protease inhibitors. Non-nucleoside reverse transcriptase This is a Divisional application of U.S. application Ser. No. inhibitors (NNRTIs) have recently gained an increasingly 10 important role in the therapy of HIV infections (Pedersen & 10/762,108 filed Jan. 21, 2004, now allowed, which is a Pedersen, Ref 15). At least 30 different classes of NNRTI Continuation in Part application of U.S. Non-Provisional have been described in the literature (De Clercq Ref. 16) and application Ser. No. 10/425,370 filed Apr. 29, 2003, now several NNRTIs have been evaluated in clinical trials. Dipy abandoned, which claims the benefit of U.S. Provisional ridodiazepinone (nevirapine), benzoxazinone (efavirenz) and Application Ser. No. 60/383,509 filed May 28, 2002. 15 bis(heteroaryl)piperazine derivatives (delavirdine) have been approved for clinical use. However, the major drawback to the FIELD OF THE INVENTION development and application of NNRTIs is the propensity for rapid emergence of drug resistant strains, both in tissue cell This invention provides compounds having drug and bio culture and in treated individuals, particularly those subject to affecting properties, their pharmaceutical compositions and monotherapy. As a consequence, there is considerable inter method of use. In particular, the invention is concerned with est in the identification of NNRTIs less prone to the develop new piperidine 4-alkenyl derivatives that possess unique anti ment of resistance (Pedersen & Pedersen, Ref 15). A recent viral activity. More particularly, the present invention relates overview of non-nucleoside reverse transcriptase inhibitors: to compounds useful for the treatment of HIV and AIDS. perspectives on novel therapeutic compounds and strategies 25 for the treatment of HIV infection. has appeared (Buckheit, reference 99). A review covering both NRTI and NNRTIs has BACKGROUND ART appeared (De clercq, reference 100). An overview of the current state of the HIV drugs has been published (De clercq, HIV-1 (human immunodeficiency virus-1) infection 30 reference 101) remains a major medical problem, with an estimated 42 mil Several indole derivatives including indole-3-sulfones, lion people infected worldwide at the end of 2002. The num piperazino indoles, pyrazino indoles, and 5H-indolo 3.2-b ber of cases of HIV and AIDS (acquired immunodeficiency 1.5benzothiazepine derivatives have been reported as syndrome) has risen rapidly. In 2002, -5.0 million new infec HIV-1 reverse transciptase inhibitors (Greenlee et al. Ref. 1; tions were reported, and 3.1 million people died from AIDS. 35 Williams etal, Ref.2: Romero etal, Ref.3; Font etal, Ref. 17: Currently available drugs for the treatment of HIV include Romero et al. Ref. 18; Young et al. Ref. 19: Genin et al. Ref. nine nucleoside reverse transcriptase (RT) inhibitors or 20: Silvestri et al. Ref. 21). Indole 2-carboxamides have also approved single pill combinations (Zidovudine or AZT (or been described as inhibitors of cell adhesion and HIV infec RetrovirR), didanosine (or Videx(R), stavudine (or Zerit(R), tion (Boschellietal, U.S. Pat. No. 5,424,329, Ref. 4). 3-sub lamivudine (or 3TC or Epivir R), Zalcitabine (or DDC or 40 HividR), abacavir succinate (or ZiagenR), Tenofovir diso stituted indole natural products (Semicochliodinol A and B, proxil fumarate salt (or Viread(R), Combivir R (contains didemethylasterriquinone and isocochliodinol) were dis -3TC plus AZT), Trizivir R (contains abacavir, lamivudine, closed as inhibitors of HIV-1 protease (Fredenhagen et al. and Zidovudine); three non-nucleoside reverse transcriptase Ref.22). inhibitors: nevirapine (or Viramune(R), delavirdine (or 45 Structurally related aza-indole amide derivatives have been Rescriptor(R) and efavirenz (or SustivaR), and seven pepti disclosed previously (Kato et al. Ref.23; Levacher et al. Ref. domimetic protease inhibitors or approved formulations: 24: Dompe Spa, WO-09504742, Ref. 5(a); SmithKline Bee saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopi cham PLC, WO-0961 1929, Ref. 5(b); Schering Corp., U.S. navir, and Kaletra R (lopinavir and Ritonavir). Each of these Pat. No. 5,023,265, Ref. 5(c)). However, these structures drugs can only transiently restrain viral replication if used 50 differ from those claimed herein in that they are aza-indole alone. However, when used in combination, these drugs have mono-amide rather than unsymmetrical aza-indole piperi a profound effect on viremia and disease progression. In fact, dine 4-alenyl derivatives, and there is no mention of the use of significant reductions in death rates among AIDS patients these compounds for treating viral infections, particularly have been recently documented as a consequence of the wide HIV. Indole and azaindole piperazine containing derivatives spread application of combination therapy. However, despite 55 these impressive results, 30 to 50% of patients ultimately fail have been disclosed in three different PCT and issued U.S. combination drug therapies. Insufficient drug potency, non patent applications (Reference 93-95, 106) Those com compliance, restricted tissue penetration and drug-specific pounds describe oxo acetyl Substituted piperazine amides. limitations within certain cell types (e.g. most nucleoside None of these applications discloses piperidine alkenyl com analogs cannot be phosphorylated in resting cells) may 60 pounds such as described in this invention. The selection of account for the incomplete Suppression of sensitive viruses. the group attached to the oxoacetyl moiety is critical for the Furthermore, the high replication rate and rapid turnover of activity of the compounds and only certain groups provide HIV-1 combined with the frequent incorporation of muta compounds which exhibit useful levels of antiviral potency tions, leads to the appearance of drug-resistant variants and and drug like properties. treatment failures when Sub-optimal drug concentrations are 65 A PCT application WO 97/24350 describes Tachychin present (Larder and Kemp: Gulick; Kuritzkes; Morris-Jones antagonists some of which are similar in structure to a very etal; Schinazi etal:Vacca and Condra; Flexner, Berkhout and minor portion of the structures in this application: US 7,915,283 B2 4 11. Vacca, J. P.; Condra, J. H. Clinically effective HIV-1 Part of Clains in WO97.24350 protease inhibitors. Drug Discovery Today, 1997, 2, 261 272. H 12. Flexner, D. HIV-protease inhibitors. Drug Therapy, 1998, e A 338, 1281-1292. Z NP 13. Berkhout, B. HIV-1 evolution under pressure of protease O N inhibitors: Climbing the stairs of viral fitness. J. Biomed. Sci., 1999, 6, 298–305. 14. Ren, S.; Lien, E.J. Development of HIV protease inhibi 10 tors: A Survey. Prog. Drug Res., 1998, 51, 1-31. 15. Pedersen, O. S.; Pedersen, E. B. Non-nucleoside reverse S. Sa N transcriptase inhibitors: the NNRTI boom. Antiviral Chem. y H Chemother: 1999, 10, 285-314. optionally substituted with 1 or 2 substituents selected from 16. (a) De Clercq, E. The role of non-nucleoside reverse Halo, C1-4 alkyl, or mono, di, or trihalo methyl. 15 transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 2 substituents selected from Halo, C1-4 alkyl, or mono, di, or trihalo methyl. infection. Antiviral Research, 1998, 38, 153-179. (b) De A and B are either Clercq, E. 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Photochem. Synth. 1972, 1,92. 98. M. P. Pavia, S. J. Lobbestael, C. P. Taylor, F. M. Hersh b) Hankes, L. V.: Biochem. Prep. 1966, 11, 63. c) Synth. enson, and D. W. Miskell Meth. 22,837. 25 76. Hulton et. al. Synth. Comm. 1979, 9,789. 99. Buckheit, Robert W., Jr. Expert Opinion on Investiga 77. Pattanayak, B. K. et al. Indian J. Chem. 1978, 16, 1030. tional Drugs 2001, 10(8), 1423-1442. 78. Chemische Berichte 1902, 35, 1545. 100. Balzarini, J.; De Clercq, E. Antiretroviral Therapy 2001, 79. Chemische Berichte Ibid 1911, 44, 493. 31-62. 80. Moubarak, I., Vessiere, R. Synthesis 1980, Vol. 1, 52-53. 30 101. E. De clercq Journal of Clinical Virology, 2001, 22. 81. IndJ. Chem. 1973, 11, 1260. 73-89. 82. Roomi et al. Can J. Chem. 1970, 48, 1689. 83. Sorrel, T. N.J. Org. Chem. 1994, 59, 1589. 102. Merour, Jean-Yves; Joseph, Benoit. Curr. Org. Chem. 84. Nitz, T. J. et al. J. Org. Chem. 1994, 59,5828-5832. (2001), 5(5), 471-506. 85. Bowden, K. et al. J. Chem. Soc. 1946,953. 35 103. T. W. von Geldern et al. J. Med. Chem. 1996, 39,968. 86. Nitz, T. J. et al. J. Org. Chem. 1994, 59,5828-5832. 87. Scholkopfet al. Angew. Int. Ed. Engl. 1971, 10(5), 333. 104. M. Abdaoui et al. Tetrahedron 2000, 56, 2427. 88. (a) Behun, J. D.: Levine, R.J. Org. Chem. 1961,26,3379. 105. W.J. Spillane et al. J. Chem. Soc., Perkin Trans. 1, 1982, (b) Rossen, K. Weissman, S.A.; Sager, J.; Reamer, R. A.; 3, 677 Askin, D.; Volante, R. P.; Reider, P. J. Asymmetric Hydro 40 106. Wang, Tao; Wallace, Owen B. Zhang, Zhongxing: genation of tetrahydropyrazines: Synthesis of (S)-pipera Meanwell, Nicholas A. Kadow, John F. Yin, Zhiwei. Com zine 2-tert-butylcarboxamide, an intermediate in the position and Antiviral Activity of Substituted Azaindo preparation of the HIV protease inhibitor Indinavir. Tetra leoxoacetic piperazine Derivatives. U.S. patent application hedron Lett., 1995, 36,6419-6422. (c) Jenneskens, L. W.; Ser. No. 10/214,982 filed Aug. 7, 2002, which is a continu Mahy, J.; den Berg, E. M. M. de B.-V.; Van der Hoef, I.: 45 Lugtenburg, J. Recl. Trav: Chim. Pays-Bas 1995, 114, 97. ation-in-part application of U.S. Ser. No. 10/038,306 filed 89. Wang, T.; Zhang, Z.; Meanwell, N. A. Benzoylation of Jan. 2, 2002 (corresponding to PCT Int. Appl. (PCT/U502/ Dianions: Preparation of mono-Benzoylated Symmetric 00455), WO 02/062423 A1, filed Jan. 2, 2002, published Secondary Diamines.J. Org. Chem., 1999, 64, 7661-7662. Aug. 15, 2002. 90. (a) Adamczyk, M.; Fino, J. R. Synthesis of procainamide 50 metabolites. N-acetyl desethylprocainamide and desethyl SUMMARY OF THE INVENTION procainamide. Org. Prep. Proced. Int. 1996, 28, 470-474. (b) Wang, T.; Zhang, Z. Meanwell, N. A. Regioselective The present invention comprises compounds of Formula I, mono-Benzoylation of Unsymmetrical piperazines. J. Org. their pharmaceutical formulations, and their use in patients Chem., in press. 55 suffering from or susceptible to a virus such as HIV. The 91. Masuzawa, K. Kitagawa, M.: Uchida, H. Bull Chem. Soc. compounds of Formula I, which include nontoxic pharma Jpn. 1967, 40, 244-245. ceutically acceptable salts and/or hydrates thereof, have the 92. Furber, M.: Cooper, M. E.; Donald, D. K. Tetrahedron formula and meaning as described below. Each embodiment Lett. 1993, 34, 1351-1354. of a particular aspect of the invention depends from the pre 93. Blair, Wade S. Deshpande, Milind; Fang, Haiquan; Lin, 60 ceding embodiment unless otherwise stated. Pin-fang; Spicer, Timothy P.; Wallace, Owen B. Wang, Hui; Wang, Tao; Zhang, Zhongxing; Yeung, Kap-Sun. Preparation of antiviral indoleoxoacetyl piperazine deriva SUMMARY DESCRIPTION OF THE INVENTION tives U.S. Pat. No. 6,469,006. Preparation of antiviral indo leoxoacetyl piperazine derivatives. PCT Int. Appl. (PCT/ 65 The present invention comprises compounds of Formula I, US00/14359), WO 0076521 A1, filed May 24, 2000, orpharmaceutically acceptable salts thereof, which are effec published Dec. 21, 2000. tive antiviral agents, particularly as inhibitors of HIV. US 7,915,283 B2 10 A first embodiment of the invention are compounds of R'' and R'' are each independently H. (Cl-)alkyl or phenyl: Formula I, including pharmaceutically acceptable salts -- represents a carbon-carbon bond or does not exist; thereof, D is selected from the group consisting of hydrogen, (C) alkyl, (C1-)alkynyl. (Cl-) cycloalkyl, halogen, cyano, CONRR, SO2R, COR, COOR, tetrahydrofu (I) ryl, pyrrolidinyl, phenyl and heteroaryl; wherein said (C) alkyl, (C)alkynyl, phenyl and heteroaryl are each indepen dently optionally substituted with one to three same or wherein: different members selected from the group G: heteroaryl is 10 selected from the group consisting of furanyl, thienyl, thiaz Z is olyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiaz olyl, thiadiazolyl pyrazolyl, tetrazolyl, triazolyl pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl: A is selected from the group consisting of phenyl and het 15 eroaryl; wherein said phenyl and heteroaryl are each indepen dently optionally substituted with one to three same or dif ferent members selected from the group K; and heteroaryl is selected from the group consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl, thia Q is selected from the group consisting of: Zolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imi dazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,

1H-imidazo[4,5-cpyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyl and triazolyl; with the proviso that when m is 1 and A is benzoimidazolyl, 25 1H-imidazo[4,5-b]pyridin-2-yl or 1H-imidazo[4,5-cpyri din-2-yl, D is not —H; R. R. R'7, R. R. R. R', R’ are each independently selected from the group consisting of H and (Cl)alkyl: wherein (C)alkyl is optionally substituted with one to three 30 same or different halogen, amino, OH, CN or NO; B is selected from the group consisting of (C)alkyl, (C) cycloalkyl, C(O)NR'R'', phenyl and heteroaryl; wherein said (Cl)alkyl, phenyl and heteroaryl are independently optionally substituted with one to three same or different 35 halogens or from one to three same or different substituents selected from F: heteroaryl is selected from the group con sisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, fura nyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl, 40 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-cpyridin 2-yl, oxadiazolyl, thiadiazolyl pyrazolyl, tetrazolyl, tetrazi nyl, triazinyl and triazolyl, F is selected from the group consisting of (C)alkyl, (C) cycloalkyl cyano, phenyl, heteroaryl, heteroalicyclic, 45 hydroxy, (C)alkoxy, halogen, benzyl, - NRC(O)— (C)alkyl, - NR'R'', morpholino, nitro, S(C)alkyl, -SPh, NRS(O), R, piperazinyl, N-Me piperazinyl, —W is C(O)H, (CH2)COOR and CONR'R'': wherein said (C)alkyl, heteroaryl, or phenyl is optionally substituted 50 with one to three same or different halogens or one to three R7 Riis P methyl groups; heteroaryl is selected from the group consist R16 ing of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isox R15 21 NA azolyl, imidazolyl, oxadiazolyl, thiadiazolyl pyrazolyl, tet razolyl, triazolyl pyridinyl, pyrazinyl, pyridazinyl, and N 55 pyrimidinyl; heteroalicyclic is selected from the group con R22 sisting of aziridine, aZetidine, pyrrolidine, piperazine, N-me R19 R20 R21 thylpiperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; R", R. R. R', and Rare independently selected from the G is selected from the group consisting of (C)alkyl, (C) group consisting of hydrogen, halogen, cyano, nitro, COOR, 60 cycloalkyl cyano, trimethylsilyl phenyl, heteroaryl, het XR, and B; eroalicyclic, hydroxy, (C)alkoxy, halogen, benzyl, m is 1 or 2; NRC(O) (C)alkyl, NRR’7, C(O)NR'R'7 R is O or does not exist; morpholino, nitro, S(C)alkyl, - SPh, NRS(O) R. R7 is (CH),R': piperazinyl, N-Me piperazinyl, (CH2)COOR and n is 0-6: 65 —CONR'R'': wherein said (C1-)alkyl, heteroaryl, orphe R" is selected from the group consisting of H. (Cl-)alkyl, nyl is optionally substituted with one to three same or differ —C(O)–(C)alkyl, C(O)-phenyl and CONR'R'': ent halogens or one to three methyl groups; heteroaryl is US 7,915,283 B2 11 12 selected from the group consisting of furanyl, thienyl, thiaz Q is a member selected from groups (A) and (B) consisting of olyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiaz olyl, thiadiazolyl pyrazolyl, tetrazolyl, triazolyl pyridinyl, pyrazinyl, pyridaZinyl, and pyrimidinyl; heteroalicyclic is (A) selected from the group consisting of aziridine, aZetidine, pyrrolidine, piperazine, N-methylpiperazine, piperidine, tet rahydrofuran, tetrahydropyran, azepine and morpholine; K is selected from the group consisting of (C1-)alkyl, hydroxy, (C)alkoxy, halogen and NR'R'': wherein 10 said (Cl)alkyl is optionally substituted with one to three same or different halogens; R, R and R are selected from the group consisting of hydrogen and (Ce)alkyl; X is selected from the group consisting of NR', O and S; 15 R. R. R. R. R7, R, R, R are independently selected from the group consisting of hydrogen, (C)alkyl, (Ce)alkoxy, phenyl and heteroaryl; wherein said (C) alkyl, phenyl, and heteroaryl are independently optionally substituted with one to three same or different group J.; het eroaryl is selected from the group consisting of furanyl, thie nyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, provided R and Rare each independently hydrogen, meth oxadiazolyl, thiadiazolyl pyrazolyl, tetrazolyl, triazolyl, oxy or halogen; and pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl: 25 J is selected from the group consisting of (C)alkyl, phenyl, heteroaryl, hydroxy, (C)alkoxy, halogen, benzyl, NRC (O) (C)alkyl, NR'R'', morpholino, nitro. —S(C) (B) alkyl, -SPh, NR'S(O). R, piperazinyl, N-Me piperazi nyl, (CH2)COOR and CONRR: wherein said 30 (Ce)alkyl, heteroaryl, or phenyl is optionally substituted with one to three same or differenthalogens, amino, or methyl groups; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl pyrazolyl, tetrazolyl, 35 triazolyl pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl: and R° and Rare independently selected from the group con provided R is hydrogen, methoxy or halogen. sisting of hydrogen and (Ce)alkyl, wherein said (Cl)alkyl 40 Another preferred embodiment are compounds of formula is optionally substituted with one to three same or different I wherein: halogen, methyl, or CF groups. Q is a member selected from groups (A), (B) and (C) consist A preferred embodiment of the invention are compounds ing of of Formula I, wherein: Z is 45

(A)

R" is hydrogen; 55 -- represents a carbon-carbon bond; and R does not exist. A more preferred embodiment of the invention are com pounds of Formula I wherein: 60 R’ is hydrogen; and R. R. R'7, R. R. R. R. are each independently Hor methyl with the proviso that a maximum of one of R'-R’ is provided R is hydrogen, methoxy or halogen; methyl. 65 A more preferred embodiment are compounds of formula I wherein: R is hydrogen; US 7,915,283 B2 13 14 DETAILED DESCRIPTION OF THE INVENTION

(B) Since the compounds of the present invention may possess asymmetric centers, the present invention includes the indi vidual diastereoisomeric and enantiomeric forms of the com pounds of Formula I in addition to the mixtures thereof. DEFINITIONS

10 The term "C. alkyl as used herein and in the claims (unless specified otherwise) mean straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and the like. "Halogen refers to chlorine, bromine, iodine or fluorine. (C) 15 An “aryl group refers to an all carbon monocyclic or

fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi electron system. Examples, without limitation, of aryl groups are phenyl, napthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted the substi tuted group(s) is preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thio aryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, 25 halogen, nitro, carbonyl, O-carbamyl. N-carbamyl. provided R is hydrogen, methoxy or halogen; and C-amido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, Rand Rare hydrogen. sulfonamido, trihalomethyl, ureido, amino and —NR'R''. Another preferred embodiment of the present invention are wherein R and Rare independently selected from the group compounds of formula I wherein: consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, D is selected from the group consisting of hydrogen, (C) 30 C-carboxy, Sulfonyl, trihalomethyl, and, combined, a five- or alkyl, (C)alkynyl, (C)cycloalkyl, halogen, cyano, six-member heteroalicyclic ring. CONRR, SO2R, COR, COOR, tetrahydrofu As used herein, a "heteroaryl group refers to a monocyclic ryl, pyrrolidinyl, phenyl and heteroaryl; wherein said (C) or fused ring (i.e., rings which share an adjacent pair of atoms) alkyl, (C)alkynyl, phenyl and heteroaryl are each indepen group having in the ring(s) one or more atoms selected from dently optionally substituted with one to three same or 35 the group consisting of nitrogen, oxygen and Sulfur and, in different members selected from the group G: heteroaryl is addition, having a completely conjugated pi-electron system. (1) a five membered ring selected from the group consisting Unless otherwise indicated, the heteroaryl group may be of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isox attached at either a carbon or nitrogen atom within the het azolyl, imidazolyl, oxadiazolyl, thiadiazolyl pyrazolyl, tet eroaryl group. It should be noted that the term heteroaryl is 40 intended to encompass an N-oxide of the parent heteroaryl if razolyl, and triazolylor (2) a six membered ring selected from such an N-oxide is chemically feasible as is known in the art. the group consisting of pyridinyl, pyrazinyl, pyridazinyl and Examples, without limitation, of heteroaryl groups are furyl, pyrimidinyl; and thienyl, benzothienyl, thiazolyl, imidazolyl, oxazolyl, Oxa A is selected from the group consisting of phenyl and het diazolyl, thiadiazolyl, benzothiazolyl, triazolyl, tetrazolyl, eroaryl; wherein said phenyland heteroaryl are each indepen 45 isoxazolyl, isothiazolyl pyrrolyl pyranyl, tetrahydropyranyl. dently optionally substituted with one flourine, hydroxy, pyrazolyl pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, methyl, or amino; and heteroaryl is selected from the group purinyl, carbazolyl, benzoxazolyl, benzimidazolyl, indolyl, consisting of pyridinyl, furanyl and thienyl. isoindolyl pyrazinyl. diazinyl, pyrazine, triazinyltriazine, Another embodiment of the present invention is a method tetrazinyl, and tetrazolyl. When substituted the substituted for treating mammals infected with a virus, especially 50 group(s) is preferably one or more selected from alkyl, wherein said virus is HIV, comprising administering to said cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, mammal an antiviral effective amount of a compound of aryloxy, heteroaryloxy, heteroalicycloxy, thioalkoxy, thiohy Formula I, and one or more pharmaceutically acceptable car droxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, riers, excipients or diluents; optionally the compound of For cyano, halogen, nitro, carbonyl, O-carbamyl. N-carbamyl. mula I can be administered in combination with an antiviral 55 C-amido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, effective amount of an AIDS treatment agent selected from sulfonamido, trihalomethyl, ureido, amino, and —NR'R''. the group consisting of: (a) an AIDS antiviral agent; (b) an wherein R and Rare as defined above. anti-infective agent; (c) an immunomodulator, and (d) HIV As used herein, a "heteroalicyclic' group refers to a mono entry inhibitors. cyclic or fused ring group having in the ring(s) one or more Another embodiment of the present invention is a pharma 60 atoms selected from the group consisting of nitrogen, oxygen ceutical composition comprising an antiviral effective and sulfur. Rings are selected from those which provide stable amount of a compound of Formula I and one or more phar arrangements of bonds and are not intended to encomplish maceutically acceptable carriers, excipients, diluents and systems which would not exist. The rings may also have one optionally in combination with an antiviral effective amount or more double bonds. However, the rings do not have a of an AIDS treatment agent selected from the group consist 65 completely conjugated pi-electron system. Examples, with ing of: (a) an AIDS antiviral agent; (b) an anti-infective agent; out limitation, of heteroalicyclic groups are aZetidinyl, pip (c) an immunomodulator; and (d) HIV entry inhibitors. eridyl, piperazinyl, imidazolinyl, thiazolidinyl, 3-pyrrolidin US 7,915,283 B2 15 16 1-yl, morpholinyl, thiomorpholinyl and tetrahydropyranyl. A “thioalkoxy' group refers to both an S-alkyl and an When substituted the substituted group(s) is preferably one or —S-cycloalkyl group, as defined herein. more selected from alkyl, cycloalkyl, aryl, heteroaryl, het A “thioaryloxy' group refers to both an —S-aryl and an eroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, het —S-heteroaryl group, as defined herein. eroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thiohet A “thioheteroaryloxy' group refers to a heteroaryl-S- eroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro, group with heteroaryl as defined herein. carbonyl, thiocarbonyl, O-carbamyl. N-carbamyl, O-thiocar A “thioheteroalicycloxy' group refers to a heteroalicyclic bamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido, S— group with heteroalicyclic as defined herein. C-carboxy, O-carboxy, Sulfinyl, Sulfonyl, Sulfonamido, triha A “carbonyl group refers to a —C(=O)—R" group, lomethanesulfonamido, trihalomethanesulfonyl, silyl, gua 10 where R" is selected from the group consisting of hydrogen, nyl, guanidino, ureido, phosphonyl, amino and —NR'R''. alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl (bonded wherein R and Rare as defined above. through a ring carbon) and heteroalicyclic (bonded through a An “alkyl group refers to a saturated aliphatic hydrocar ring carbon), as each is defined herein. bon including straight chain and branched chain groups. Pref An “aldehyde group refers to a carbonyl group where R" erably, the alkyl group has 1 to 20 carbon atoms (whenever a 15 is hydrogen. numerical range; e.g., "1-20', is stated herein, it means that A “thiocarbonyl group refers to a C(=S)—R" group, the group, in this case the alkyl group may contain 1 carbon with R" as defined herein. atom, 2 carbon atoms, 3 carbon atoms, etc. up to and includ A “Keto' group refers to a —CC(=O)C group wherein ing 20 carbon atoms). More preferably, it is a medium size the carbon on either or both sides of the C=O may be alkyl, alkyl having 1 to 10 carbon atoms. Most preferably, it is a cycloalkyl, aryl or a carbon of a heteroaryl or heteroaliacyclic lower alkyl having 1 to 4 carbon atoms. The alkyl group may group. be substituted or unsubstituted. When substituted, the sub A “trihalomethanecarbonyl group refers to a ZCC stituent group(s) is preferably one or more individually (=O)—group with said Z being a halogen. selected from trihaloalkyl, cycloalkyl, aryl, heteroaryl, het A “C-carboxy' group refers to a —C(=O)C)—R" groups, eroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, het 25 with R" as defined herein. eroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thiohet An “O-carboxy” group refers to a R"C(—O)O-group, with eroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, R" as defined herein. carbonyl, thiocarbonyl, O-carbamyl. N-carbamyl, O-thiocar A “carboxylic acid' group refers to a C-carboxy group in bamyl, N-thiocarbamyl, C-amido, C-thioamido, N-amido, which R" is hydrogen. C-carboxy, O-carboxy, Sulfinyl, Sulfonyl, Sulfonamido, triha 30 A "trihalomethyl group refers to a —CZ, group wherein lomethanesulfonamido, trihalomethanesulfonyl, and com Z is a halogen group as defined herein. bined, a five- or six-member heteroalicyclic ring. A “trihalomethanesulfonyl group refers to an ZCS A “cycloalkyl group refers to an all-carbon monocyclic or (=O)- groups with Zas defined above. fused ring (i.e., rings which share and adjacent pair of carbon A “trihalomethanesulfonamido' group refers to a Z-CS atoms) group wherein one or more rings does not have a 35 (=O)NR' group with Zand R as defined herein. completely conjugated pi-electron system. Examples, with A “sulfinyl group refers to a —S(=O)—R" group, with out limitation, of cycloalkyl groups are cyclopropane, R" as defined herein and, in addition, as a bond only; i.e., cyclobutane, cyclopentane, cyclopentene, cyclohexane, —S(O)—. cyclohexadiene, cycloheptane, cycloheptatriene and ada A “sulfonyl group refers to a —S(=O).R" group with R" mantane. A cycloalkyl group may be substituted or unsubsti 40 as defined herein and, in addition as a bond only; i.e., tuted. When substituted, the substituent group(s) is preferably —S(O) -. one or more individually selected from alkyl, aryl, heteroaryl, A “S-sulfonamido' group refers to a S(=O)NR'R''. heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, het with R and Ras defined herein. eroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thiohet A “N-Sulfonamido' group refers to a R"S(=O)NR— eroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbo 45 group with R as defined herein. nyl, thiocarbonyl, O-carbamyl, N-carbamyl, A “O-carbamyl group refers to a OC(=O)NR'R'' as O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, defined herein. N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfona A “N-carbamyl group refers to a ROC(=O)NR' group, mido, trihalo-methanesulfonamido, trihalomethanesulfonyl, with R and R” as defined herein. silyl, guanyl, guanidino, ureido, phosphonyl, amino and 50 A “O-thiocarbamyl group refers to a OC(=S)NR'R'' - NR'R' with R and R' as defined above. group with R and R” as defined herein. An “alkenyl group refers to an alkyl group, as defined A “N-thiocarbamyl group refers to a ROC(=S)NR' herein, consisting of at least two carbonatoms and at least one group with R and R” as defined herein. carbon-carbon double bond. An “amino' group refers to an —NH group. An “alkynyl group refers to an alkyl group, as defined 55 A “C-amido' group refers to a C(=O)NR'R' group herein, consisting of at least two carbonatoms and at least one with R and R” as defined herein. carbon-carbon triple bond. A“C-thioamido' group refers to a —C(=S)NR'R' group, A “hydroxy' group refers to an —OH group. with R and R' as defined herein. An “alkoxy' group refers to both an —O-alkyl and an A “N-amido' group refers to a RC(=O)NR' group, —O-cycloalkyl group as defined herein. 60 with R and R' as defined herein. An “aryloxy' group refers to both an —O-aryl and an An “ureido' group refers to a NRC(=O)NR'R' group —O-heteroaryl group, as defined herein. with R and Ras defined herein and R' defined the same as A "heteroaryloxy' group refers to a heteroaryl-O group R and R. with heteroaryl as defined herein. A “guanidino' group refers to a RNC(=N)NR'R'' A "heteroalicycloxy' group refers to a heteroalicyclic-O- 65 group, with R', RandR as defined herein. group with heteroalicyclic as defined herein. A “guanyl group refers to a R'R''NC(=N)—group, with A “thiohydroxy' group refers to an —SH group. R’ and Ras defined herein. US 7,915,283 B2 17 18 A “cyano' group refers to a —CN group.

A “silyl group refers to a —Si(R"), with R" as defined ANTIVIRALS herein. A "phosphonyl group refers to a P(=O)(OR), with R as Drug Name Manufacturer Indication defined herein. O97 Hoechst Bayer HIV infection, AIDS, ARC A “hydrazino” group refers to a NRNR'R' group with (non-nucleoside R. R” and R' as defined herein. reverse transcriptase (RT) 10 inhibitor) Any two adjacent R groups may combine to form an addi Amprenivir GlaxoWellcome HIV infection, tional aryl, cycloalkyl, heteroaryl or heterocyclic ring fused to 141 W94 AIDS, ARC the ring initially bearing those R groups. GW 141 (protease inhibitor) Abacavir (1592U89) GlaxoWellcome HIV infection, It is known in the art that nitogen atoms in heteroaryl GW 1592 AIDS, ARC systems can be "participating in a heteroaryl ring double 15 (RT inhibitor) Acemannan Carrington Labs ARC bond, and this refers to the form of double bonds in the two (Irving, TX) tautomeric structures which comprise five-member ring het Acyclovir Burroughs Wellcome HIV infection, AIDS, eroaryl groups. This dictates whether nitrogens can be Sub ARC, in combination stituted as well understood by chemists in the art. The disclo with AZT AD-439 Tanox Biosystems HIV infection, AIDS, Sure and claims of the present invention are based on the ARC known general principles of chemical bonding. It is under AD-519 Tanox Biosystems HIV infection, AIDS, stood that the claims do not encompass structures known to be ARC unstable or notable to exist based on the literature. Adefovir dipivoxil Gilead Sciences HIV infection AL-721 Ethigen ARC, PGL Physiologically acceptable salts and prodrugs of com (Los Angeles, CA) HIV positive, AIDS 25 Alpha Interferon GlaxoWellcome Kaposi's sarcoma, pounds disclosed hereinare within the scope of this invention. HIV in combination The term “pharmaceutically acceptable salt as used herein wRetrovir and in the claims is intended to include nontoxic base addition Ansamycin Adria Laboratories ARC LM 427 (Dublin, OH) salts. Suitable salts include those derived from organic and Erbamont inorganic acids such as, without limitation, hydrochloric acid, 30 (Stamford, CT) hydrobromic acid, phosphoric acid, Sulfuric acid, methane Antibody which Advanced Biotherapy AIDS, ARC Neutralizes pH Concepts Sulfonic acid, acetic acid, tartaric acid, lactic acid, Sulfinic Labile alpha aberrant (Rockville, MD) acid, citric acid, maleic acid, fumaric acid, Sorbic acid, aco Interferon nitic acid, Salicylic acid, phthalic acid, and the like. The term AR.177 Aronex Pharm HIV infection, AIDS, “pharmaceutically acceptable salt as used herein is also 35 ARC Beta-fluoro-ddA Nat Cancer Institute AIDS-associated intended to include salts of acidic groups, such as a carboxy diseases late, with Such counterions as ammonium, alkali metal salts, BMS-232623 Bristol-Myers Squibb? HIV infection, particularly sodium or potassium, alkaline earth metal salts, (CGP-73547) Novartis AIDS, ARC (protease inhibitor) particularly calcium or magnesium, and salts with Suitable BMS-234.475 Bristol-Myers Squibb? HIV infection, organic bases such as lower alkylamines (methylamine, ethy 40 (CGP-61755) Novartis AIDS, ARC lamine, cyclohexylamine, and the like) or with substituted (protease inhibitor) CI-1012 Warner-Lambert HIV-1 infection lower alkylamines (e.g. hydroxyl-substituted alkylamines Cidofovir Gilead Science CMV retinitis, Such as diethanolamine, triethanolamine or tris(hydroxym herpes, papillomavirus ethyl)-aminomethane), or with bases such as piperidine or Curdlan sulfate AJI Pharma USA HIV infection morpholine. 45 Cytomegalovirus MedImmune CMV retinitis Immune globin In the method of the present invention, the term “antiviral Cytovene Syntex Sight threatening effective amount’ means the total amount of each active Ganciclovir CMV peripheral CMV component of the method that is sufficient to show a mean retinitis ingful patient benefit, i.e., healing of acute conditions char 50 Delaviridine Pharmacia-Upjohn HIV infection, acterized by inhibition of the HIV infection. When applied to AIDS, ARC (RT inhibitor) an individual active ingredient, administered alone, the term Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV refers to that ingredient alone. When applied to a combina Ind. Ltd. (Osaka, positive tion, the term refers to combined amounts of the active ingre Japan) asymptomatic dients that result in the therapeutic effect, whether adminis 55 didC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine RC tered in combination, serially or simultaneously. The terms didI Bristol-Myers Squibb V infection, AIDS, “treat, treating, treatment as used herein and in the claims Dideoxyinosine ARC; combination means preventing or ameliorating diseases associated with with AZT d4T HIV infection. DMP-450 AVID HIV infection, 60 (Camden, NJ) AIDS, ARC The present invention is also directed to combinations of (protease inhibitor) the compounds with one or more agents useful in the treat Efavirenz DuPont Merck HIV infection, ment of AIDS. For example, the compounds of this invention (DMP 266) AIDS, ARC (-)6-Chloro-4-(S)- (non-nucleoside RT may be effectively administered, whether at periods of pre cyclopropylethynyl inhibitor) exposure and/or post-exposure, in combination with effective 65 4(S)-trifluoro amounts of the AIDS antivirals, immunomodulators, antiin methyl-1,4-dihydro fectives, or vaccines, such as those in the following table. US 7,915,283 B2 19 20 -continued -continued

ANTIVIRALS ANTIVIRALS Drug Name Manufacturer indication Drug Name Manufacturer Indication 2H-31-benzoxazin Zidovudine: AZT GlaxoWellcome HIV infection, AIDS, 2-one, STOCRINE ARC, Kaposi's EL10 Elan Corp, PLC HIV infection sarcoma, in (Gainesville, GA) combination with Famciclovir Smith Kline herpes Zoster, other therapies herpes simplex 10 Tenofovir disoproxil, Gilead HIV infection, FTC Emory University HIV infection, fumarate salt (Viread (R) AIDS, AIDS, ARC (reverse transcriptase (reverse transcriptase inhibitor) inhibitor) Combivir (R) GSK HIV infection, GS 840 Gilead HIV infection, AIDS, ARC AIDS, (reverse transcriptase 15 (reverse transcriptase inhibitor) inhibitor) HBYO97 Hoechst Marion HIV infection, abacavir Succinate GSK HIV infection, Roussel AIDS, ARC (or Ziagen (R) AIDS, (non-nucleoside (reverse transcriptase reverse transcriptase inhibitor) inhibitor) Hypericin VIMRx Pharm. HIV infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC, AIDS Drug Name Manufacturer Indication Indinavir Merck HIV infection, AIDS, 25 ARC, asymptomatic IMMUNOMODULATORS HIV positive, also in combination with AS-101 Wyeth-Ayerst AIDS AZTiddIddC Bropirimine Pharmacia Upjohn Advanced AIDS ISIS 2922 ISIS Pharmaceuticals CMV retinitis Acemannan Carrington Labs, Inc. AIDS, ARC KNI-272 Nat Cancer Institute HIV-assoc. diseases 30 (Irving, TX) Lamivudine, 3TC GlaxoWellcome H V infection, CL246,738 American Cyanamid AIDS, Kaposi's AIDS, ARC Lederle Labs S8CO8. (reverse EL10 Elan Corp, PLC HIV infection transcriptase (Gainesville, GA) inhibitor); also FP-21399 Fuki ImmunoPharm Blocks HIV fusion with AZT 35 with CD4+ cells Lobucavir Bristol-Myers Squibb CMV infection Gamma Interferon Genentech ARC, in combination Nelfinavir Agouron HIV infection, w/TNF (tumor Pharmaceuticals AIDS, ARC necrosis factor) (protease inhibitor) Granulocyte Genetics Institute AIDS Nevirapine Boeheringer HIV infection, Macrophage Colony Sandoz ngleheim AIDS, ARC Stimulating Factor (RT inhibitor) 40 Granulocyte Hoechst-Roussel Novapren Novaferon Labs, Inc. HIV inhibitor Macrophage Colony Immunex (Akron, OH) Stimulating Factor Peptide T Peninsula Labs AIDS Granulocyte Schering-Plough AIDS, Octapeptide (Belmont, CA) Macrophage Colony combination Sequence Stimulating Factor WAZT Trisodium Astra Pharm. CMV retinitis, HIV 45 HIV Core Particle Rorer Seropositive HIV Phosphonoformate Products, Inc. ection, other CMV mmunostimulant ections L-2 Cetus AIDS, in combination PNU-140690 Pharmacia Upjohn V infection, interleukin-2 WAZT DS, ARC L-2 Hoffman-LaRoche AIDS, ARC, HIV, in rotease inhibitor) interleukin-2 Immunex combination waZT Probucol Vyrex V infection, AIDS 50 L-2 Chiron AIDS, increase in RBC-CD4 Sheffield Med. V infection, interleukin-2 CD4 cell counts Tech (Houston, TX) DS, ARC Ritonavir Abbott V infection, Cutter Biological Pediatric AIDS, in DS, ARC (Berkeley, CA) combination waZT rotease inhibitor) Saquinavir Hoffmann V infection, 55 Imreg AIDS, Kaposi's LaRoche DS, ARC (New Orleans, LA) sarcoma, ARC, PGL rotease inhibitor) MREG-2 Imreg AIDS, Kaposi's Stavudine: d4T Bristol-Myers Squibb V infection, AIDS, (New Orleans, LA) sarcoma, ARC, PGL Didehydrodeoxy RC muthiol Diethyl Merieux Institute AIDS, ARC Dithio Carbamate thymidine Alpha-2 Schering Plough Valaciclovir GlaxoWellcome Genital HSV & CMV 60 Kaposi's sarcoma interferol wfAZT, AIDS infections Methionine TNI Pharmaceutical AIDS, ARC Virazole Viratek, ICN asymptomatic HIV Enkephalin (Chicago, IL) Ribavirin (Costa Mesa, CA) positive, LAS, ARC MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma VX-478 Vertex V infection, AIDS, Muramyl-Tripeptide RC Granulocyte Amgen AIDS, in combination Zalcitabine Hoffmann-LaRoche V infection, AIDS, 65 Colony Stimulating WAZT RC, with AZT Factor US 7,915,283 B2 21 22 -continued HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse Drug Name Manufacturer Indication transcriptase, such as AZT, 3TC. ddC or ddI. A preferred Remune Immune Response Immunotherapeutic inhibitor of HIV protease is indinavir, which is the sulfate salt Corp. of N-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4- rCD4 Genentech AIDS, ARC (S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)- N'-(t-butyl Recombinant Soluble Human CD4 carboxamido)-piperazinyl)-pentaneamide ethanolate, and is rCD4-IgG DS, ARC synthesized according to U.S. Pat. No. 5,413,999. Indinaviris hybrids generally administered at a dosage of 800 mg three times a Recombinant Biogen DS, ARC 10 day. Other preferred protease inhibitors are nelfinavir and Soluble Human CD4 Interferon Hoffman-La Roche aposi's sarcoma ritonavir. Another preferred inhibitor of HIV protease is Alfa 2a DS, ARC, saquinavir which is administered in a dosage of 600 or 1200 combination waZT mg tid. Preferred non-nucleoside inhibitors of HIV reverse SK&F106528 Smith Kline V infection transcriptase include efavirenz. The preparation of ddC, ddI Soluble T4 15 Thymopentin Immunobiology HIV infection and AZT are also described in EPO 0.484,071. These combi Research Institute nations may have unexpected effects on limiting the spread (Annandale, NJ) and degree of infection of HIV. Preferred combinations Tumor Necrosis Genentech ARC, in combination include those with the following (1) indinavir with efavirenz, Factor; TNF wigamma Interferon ANTI-INFECTIVES and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddI and/or ddC and/or 3TC. Clindamycin with Pharmacia Upjohn PCP in particular, indinavir and AZT and 3TC; (3) stavudine and Primaquine Fluconazole Pfizer Cryptococcal 3TC and/or zidovudine; (4) zidovudine and lamivudine and meningitis, 141 W94 and 1592U89; (5) zidovudine and lamivudine. candidiasis In Such combinations the compound of the present inven Pastille Squibb Corp. Prevention of 25 tion and other active agents may be administered separately Nystatin Pastille oral candidiasis or in conjunction. In addition, the administration of one ele Ornidyl Merrell Dow PCP Eflornithine ment may be prior to, concurrent to, or Subsequent to the Pentamidine LyphoMed PCP treatment administration of other agent(s). sethionate (IM & IV) (Rosemont, IL) Trimethoprim Antibacterial 30 ABBREVIATIONS Trimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCP treatment Pentamidine Fisons Corporation PCP prophylaxis The following abbreviations, most of which are conven sethionate for tional abbreviations well known to those skilled in the art, are inhalation used throughout the description of the invention and the Spiramycin Rhone-Poulenc Cryptosporidial 35 diarrhea examples. Some of the abbreviations used are as follows: intraconazole Janssen-Pharm. Histoplasmosis; h-hour(s) RS1211 cryptococcal rt-room temperature meningitis mol-mole(s) Trimetrexate Warner-Lambert PCP Daunorubicin NeXstar, Sequus Kaposi's sarcoma mmol-millimole(s) Recombinant Human Ortho Pharm. Corp. Severe anemia 40 g gram(s) Erythropoietin assoc. with AZT mg milligram(s) therapy mL milliliter(s) Recombinant Human Serono AIDS-related TFA=Trifluoroacetic Acid Growth Hormone wasting, cachexia Megestrol Acetate Bristol-Myers Squibb Treatment of DCE=1,2-Dichloroethane anorexia assoc. 45 CHCl2=Dichloromethane WAIDS TPAP tetrapropylammonium perruthenate Testosterone Alza, SmithKline AIDS-related wasting THF=Tetrahydrofuran Total Enteral Norwich Eaton Diarrhea and Nutrition Pharmaceuticals malabsorption DEPBT-3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin related to AIDS 4(3H)-one 50 DMAP-4-dimethylaminopyridine P-EDC=Polymer supported 1-(3-dimethylaminopropyl)- Additionally, the compounds of the invention herein may 3-ethylcarbodiimide be used in combination with another class of agents for treat EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ing AIDS which are called HIV entry inhibitors. Examples of DMF=N,N-dimethylformamide such HIV entry inhibitors are discussed in DRUGS OF THE 55 Hunig's Base-N,N-Diisopropylethylamine FUTURE 1999, 24(12), pp. 1355-1362; CELL, Vol. 9, pp. mCPBA meta-Chloroperbenzoic Acid 243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, azaindole=1H-Pyrrolo-pyridine Vol. 5, No. 5, May 2000, pp. 183-194. 4-azaindole=1H-pyrrolo3.2-bipyridine It will be understood that the scope of combinations of the 5-azaindole=1H-Pyrrolo3.2-cpyridine compounds of this invention with AIDS antivirals, immuno 60 6-azaindole=1H-pyrrolo2.3-cpyridine modulators, anti-infectives, HIV entry inhibitors or vaccines 7-azaindole=1H-Pyrrolo2,3-bipyridine is not limited to the list in the above Table, but includes in PMB-4-Methoxybenzyl principle any combination with any pharmaceutical compo DDQ-2,3-Dichloro-5,6-dicyano-1,4-benzoquinone sition useful for the treatment of AIDS. OTf Trifluoromethanesulfonoxy Preferred combinations are simultaneous or alternating 65 NMM=4-Methylmorpholine treatments of with a compound of the present invention and an PIP-COPh=1-Benzoylpiperazine inhibitor of HIV protease and/or a non-nucleoside inhibitor of NaHMDS=Sodium hexamethyldisilazide US 7,915,283 B2 23 24 EDAC=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide The amide bond construction reaction could be carried out TMS-Trimethylsilyl using the preferred conditions described above, the EDC DCM=Dichloromethane conditions described below, other coupling conditions DCE=Dichloroethane described in this application, or alternatively by applying the MeOH=Methanol conditions or coupling reagents for amide bond construction THF=Tetrahydrofuran described later in this application for construction of substitu EtOAc-Ethyl Acetate ents R-Rs. Some specific nonlimiting examples are given in LDA=Lithium diisopropylamide this application. TMP-Li-2.2.6,6-tetramethylpiperidinyl lithium 10 Alternatively, the acid could be converted to a methyl ester DME-Dimethoxyethane using excess diazomethane in THF/ether. The methyl ester in DIBALH-Diisobutylaluminum hydride dry THF could be reacted with the lithium amide of interme HOBT=1-hydroxybenzotriazole diate H. W. The lithium amide of H. W. Li W is formed CBZ-Benzyloxycarbonyl by reacting intermediate 1 with lithium bistrimethylsilyla PCC-Pyridinium chlorochromate 15 mide in THF for 30 minutes in an ice water cooling bath. The synthesis procedures and anti-HIV-1 activities of Sodium or potassium amides could be formed similarly and 4-alkenyl piperidine amide containing analogs are below. utilized if additional reactivity is desired. Otheresters such as Preparation of the Compounds of the Invention: ethyl, phenyl, or pentafluorophenyl could be utilized and Scheme A would be formed using standard methodology. Scheme A1 D depicts the general coupling reaction using the BOP-Cl cou pling method while Scheme A2 depicts a specific reaction, Coupling reagent Q(CFO)-OH + 4NA st which typifies the coupling reactions used to make the com pounds of formula I or precursors to them. HN Step D 25 H-W Scheme Al D R

R6 NRIs D

21 A. 30 Q(C=O)1 N O OH R 19 R. R 23

Step D description: As shown in Scheme A, intermediate 35 BOP-CI, DIEA, CHCI H W (where W corresponds to claim 1 and H is hydrogen) Q O Step D can be coupled with the acid QC(O)C(O)OH (which can also be depicted as Z -OH) using standard amide bond or peptide bond forming coupling reagents. The combination of EDAC and triethylamine in tetrahydrofuran or BOPC1 and diisopro 40 pyl ethyl amine in chloroform have been utilized most fre quently but DEPBT, or other coupling reagents such as PyBop could be utilized. Another useful coupling condition employs HATU (L. A. Carpino et. al. J. Chem. Soc. Chem. Comm. 1994, 201-203: A. Virgilio et al. J. Am. Chem. Soc. 45 1994, 116, 11580-11581). A general procedure for using this reagent is Acid (1 eq) and H W-A or HCl salt (2 eq) in DMF are stirred at rt for between 1 h and 2 days. HATU (2 eq) was added in one portion and then DMAP (3 eq). The reaction was stirred at rt for 2 to 15 h (reaction progress monitored by 50 Scheme A2 standard methods ie TLC, LC/MS). The mixture is filtered through filter paper to collect the solid. The filtrate is concen trated and water is added. The mixture is filtered again and the r solid is washed with water. The solid is combined and washed 2N with water. Many reagents for amide bond couplings are 55 known by an organic chemist skilled in the art and nearly all of these are applicable for realizing coupled amide products. 21 As mentioned above, DEPBT (3-(diethoxyphosphoryloxy)- MeO O OH 1,2,3-benzotriazin-4(3H)-one) and N,N-diisopropylethy HCIoHN lamine, commonly known as Hunig's base, represents 60 N O BOP-CI, DIEA, CHCI another efficient method to form the amide bond (step D) and d \ Step D provide compounds of Claim I. DEPBT is either purchased le from Adrich or prepared according to the procedure of Ref. N 28, Li, H.; Jiang, X..Ye.Y.-H.; Fan, C.; Romoff. T.; Goodman, N M. Organic Lett., 1999. 1, 91-93. Typically an inert solvent 65 such as DMF or THF is used but other aprotic solvents could R be used. US 7,915,283 B2 25 26 -continued -continued CN

21 BOP-CI, DIEA -> -N CHCl H Step D

Scheme B

OH D EtN 30 Q(CFO)-CI + 21 NA THF HN Step D

H-W 35

HeBOP-CI, DIEA CHCI 21 A. Step D 40 N Q(C=O)1

45 As shown in Schemes B and C. Compounds of formula I can also be obtained from reacting the amine, H W with an acid halide QC(O)C(O)—C1 (also depicted as Z Cl) typi cally in the presence of a tertiary amine base to provide the desired compounds of the invention. Such reactions would 50 usually be started at a temperature of approximately 2°C. and allowed to warm to ambient temperature but lower tempera tures or even heating could be utilized if needed. The reaction of QC(O)C(O)—Cl (Z Cl) by reaction with the appropriate H W-A in the presence of a tertiary amine (3-10 eq) such as 55 triethylamine ordiisopropylethylamine in an anhydrous apro tic solvent such as dichloromethane, dichloroethane, diethyl ether, dioxane, THF, acetonitrile, DMF or the like attempera tures ranging from 0°C. to reflux. Most preferred are dichlo romethane, dichloroethane, or THF. The reaction can be 60 monitored by LC/MS. OH The acids QC(O)C(O)OH(Z-OH) can be converted to the acid chlorides QC(O)C(O)—Cl (Z Cl) using oxalyl chlo ride in a solvent such as benzene or thionyl chloride either 65 neator containing a catalystic amount of DMF. Temperatures between 0° C. and reflux may be utilized depending on the substrate. US 7,915,283 B2 27 -continued D Scheme C

D 21 A. Q(CFO)-X -- 21 NA - G - HN

HN Step D H-W

H-W 10

Scheme E D O 15 21 NA A. 1) D-Organometallic Hess 2) TFA oc=0.1 HN X = Cl, Br, I D

21 A. Procedures for coupling piperazine amides to oxoacetyl derivatives are described in the Blair, Wang, Wallace, or Wang HN references 93-95 and 106 respectively. The entire disclosures 25 Intermediate 1 in U.S. Pat. No. 6,469,006 granted Oct. 22, 2002; U.S. Pat. D = heteroaryl, aryl, alkyl No. 6,476,034 granted Nov. 5, 2002; U.S. patent application Organometallic = MgBr, Li, CeCI2, ZnBr Ser. No. 10/027,612 filed Dec. 19, 2001, which is a continu ation-in-part of U.S. Ser. No. 09/888,686 filed Jun. 25, 2001 As shown in Scheme E, addition of an organometallic (corresponding to PCT WO 02/04440, published Jan. 17, 30 reagent to a ketone can provide an intermediate tertiary alkox 2002); and U.S. patent application Ser. No. 10/214,982 filed ide which undergoes protonation and acid catalyzed elimina Aug. 7, 2002, which is a continuation-in-part of U.S. Ser. No. tion to form the desired double bond. A number of organo 10/038,306 filed Jan. 2, 2002 (corresponding to PCT WO metallic reagents could suffice as shown but an extra equiva 02/62423 published Aug. 15, 2002) are incorporated by ref lent (at least two total) could be needed to compensate for erence herein. The procedures used to couple indole or aza 35 deprotection of the amine nitrogen in many cases. indole oxoacetic acids to piperazine amides in these refer ences can be used analogously to form the compounds of this invention except the piperidine alkenes are used in place of Scheme F the piperazine benzamides. O General Schemes: 40 Z Scheme D describes a useful method for preparing the O N -- -> A. Her1) Base compounds described by H W where W is as defined in the 2) TFA description and claims of the invention. Typically, this meth O odology will work best when D is a group which lowers the 45 PKA of the hydrogens on the adjacent methylene moiety. For example cyano, Sulfonyl, amido and the like as specified in D the claim. A preferably could be aryl or heteroaryl moieties as described in claim 1. A could also be other groups described in claim 1. Alkoxide bases of C1 to C4alcohols can be utilized 50 21 NA but other bases such as lithium, Sodium, or potassium dialkyl HN amides or the corresponding bistrimethylsilyl amides could also be utilized.

Preparation of Intermediates: 55 Standard olefination conditions such as Wittig, Horner Emmons, Petersen or Arsenic based can be used to convert the Scheme D ketone to the desired products. Some general reviews of this O methodology and directions for use are contained in the fol D 60 lowing references: Wadsworth, W. S., Jr., in “Organic Reac tions”, Dauben, W. G., Ed., Wiley, New York, 1977, 25, 73. O N ls 1) Base, THF -- A. --- McMurry, J. E. Acct. Chem. Res. 1983, 16, 405. Cushman, 2) TFA M., et al. Bioorg. Med. Chem. 2002, 10, 2807. When Z-triphenyl phosphine, butyl lithium or LDA could be used 65 to generate the phosphorus ylide in THF and then the ylide reacted with the ketone to provide the desired product. The phosphinate orphosphine oxide based reagents could be used US 7,915,283 B2 29 with similar bases or with sodium or potassium methoxide or -continued ethoxide in the corresponding alcohol solvents. X

21 A. Scheme G HN Br BOCO X = I, Br, Cl D Her HN Base HCI 10 21NA P or N Br PPh catalyst HN --- OTf

N N 15 21 A.

HN N. Metal - SnR3B(OH)2, AIR2,MgBr, and alike D SPPh. 1. O A. As shown above in Scheme H, substituted azaindoles con taining a chloride, bromide, iodide, triflate, or phosphonate N N Be Base undergo coupling reactions with a boronate (Suzuki type reactions) or a stannane to provide Substituted azaindoles. 25 Stannanes and boronates are prepared via Standard literature procedures or as described in the experimental section of this N application. The vinyl bromides, chlorides, triflates, or phos D phonates may undergo metal mediated coupling to provide 30 compounds of formula W-H. Stille or Suzuki couplings are 4 YA particularly useful. A detailed discussion of the references and best conditions for these kinds of metal mediated cou pling is described later in this application where the discus N N sion is combined with a description of how these types of O 35 reactions may also be used to funtionalize indoles and azain doles. When Aris Benzene, Starting Materials are Commercially D Available

40 21 A. Scheme I HN

Intermediate 1 45 O N N -- O

Scheme H 50 D 21 A. R D 1) X-Y, base 1) Ru, Mo catalyst He o 1) Ru, Mo catalyst 21 NA O N 2) TFA 2) TFA R Air HN N X-Y = Br-Br, I-CI, 55 O NBS, NCS, NIS Alternatively, the compounds W H could be prepared via olefin metathesis using highly active Rhodium catalysts. The methylene starting material can be prepared via simple Wittig O 60 methylenation of the precursor ketone which is prepared via literature methods. The olefin metathesis is preferably carried A. TfG) out using 1% of the imadazoylidene ruthenium benzylidene --- catalyst described in the following reference. The reaction is HN carried out starting at low temperatures (-40') or similar. 65 Starting methylene material is mixed with excess olefin (5 to 100 equivalents) and the reaction is warmed to ~40° C. Syn thesis of Symmetrical Trisubstituted Olefins by Cross Met US 7,915 283 B2 31 32 athesis. Chatterjee, Arnab K.; Sanders, Daniel P.: Grubbs, Robert H., Organic Letters, ACS ASAP. -continued Additional references are listed below which show addi tional conditions and substrates which may be used with this catalysts. Functional group diversity by ruthenium-catalyzed olefin 1. Br2. K2CO3 --- cross-metathesis. Toste, F. Dean; Chatterjee, Arnab K.; 2. aq. MaCH, MeOH Grubbs, Robert H., The Arnold and Mabel Beckman Labo ratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, 10 Pasadena, Calif., USA. Pure and Applied Chemistry (2002), 74(1), 7-10. A Versatile Precursor for the Synthesis of New Ruthenium Olefin Metathesis Catalysts. Sanford, Melanie S.: Love, Jennifer A.; Grubbs, Robert H. Arnold 15 and Mabel Beckman Laboratories for Chemical Synthesis 1.HC-dioxane Division of Chemistry and Chemical Engineering, Califor -- nia Institute of Technology, Pasadena, Calif., USA. Orga 2. BOPCI/iPrNEt/CHCI nometallics (2001), 20025), 5314-5318. Olefin metathesis with 1,1-difluoroethylene. Trnka, Tina M.: 20 Day, Michael W.; Grubbs, Robert H. Arnold and Mabef Beckman Lab. of Chemical Synthesis, California Institute of Technology, Pasadena, Calif., USA. Angewandte Che mie, International Edition (2001), 40(18), 3441-3444. D-SnBus Scheme Kshows a sequence in which a piperidone is coverted 25 (Ph3P)2PdCl2 to a monofuntionalized olefin via Wittig olefination. Bromi THF,900 C. nation and dehydrobromination provides a versatile vinyl OR, bromide intermediate. This intermediate is coupled to the QC(O)C(O)OH acid with BOPC1 to provide a compound of V formula I. This intermediate is then funtionalized using pal- 3 O ladium mediated couplings to either boronates or stannanes. Conditions for these couplings are described in this applica tion.

Scheme K 40

ACH2PPh3 He nBuLi, THF 45 Scheme L shows specific examples of general Scheme K which are some of those described in the experimental sec tion.

Scheme L.

O / PhCH2PPh3 1. Br2. K2CO3 Her Her nBuLi, THF 2. aq. NaOH, MeOH N N M M BOC BOC US 7,915,283 B2 33 34 -continued Br

1. HC-dioxane 2. BOPCI/iPrNEt/CHCI OH O BOC MeO N N Na2NN H MeO () S C j

N Br N O MeO N nBug Cy- B O

--- Nin N H MeO MeO

e N N MeO N

N O MeO O

NS N H MeO

Scheme M shows how a protected vinyl bromide can be Scheme M converted to a carboxylic acid via lithium bromide exchange Br and reaction with carbon dioxide. As described in this appli 60 cation and the incorporated ones, carboxylic acids are excel lent precursors to many heterocyles or amides. The rest of R17 1. n-BuLi, THF Scheme M shows conversion to funtionalized oxadiazoles. 2. CO Other chemistry described in this application depicts other 65 N methods for converting acids to groups of other compounds of the invention. US 7,915,283 B2

-continued -continued HOC A R18 R22 R23 5 HOC R17 EDCL, HOBt, DMF EDCL, HOBt, DMF NHNHR -e- R16 R20 NHNHR N R15 R19 BOC 10 N Ac2O or TFAA, NEt3 C R = H, CHO (R = H) R = COR, COR BOC O

A 15 O RHNHN R18 R22 R23 RHNHN R17 PPH, CCCCl3 PPh3, ClCCCl3 He iPrNEt, MeCN iPrNEt, MeCN R16 R20 2O N R15 R19 BOC R1 BOC 25 R = H, CHO X AcO or TFAA, NEt3 N \ le A (R = H) N R = COMe, COCF R18 / R22 R23 R17 1. TFA, DCM 30 RI 2. oxoacetic acid R16 R20 BOPCI, DIEA N R15 R19 X BOC Y2 1. TFA, DCM 2. oxoacetic acid BOPCI, DIEA

BOC

R = H, Me, CFs

50 Scheme N depicts a more specific example of Scheme M.

MeO O N Scheme N 55 e O N N f \ Br 60 MeO N

Hess1.n-BuLi, THF 2. CO Scheme P depicts methods for functionalizing the vinyl bro N mide to install groups D (or A). Either a modified Stille 65 coupling or a Zinc mediated coupling are depicted. Details of BOC these transformations are discussed later in the section on metal couplings. US 7,915,283 B2 37

Scheme P

D A Br A

D-SnBus R18 \ R22 R 1. n-BuLi; ZnCl2 R18 / R22 R23 -- R17 R17 23 2. I, Pd(Ph3P) R17 THF, 90° C. R16 R20 R16 R20 R16 N N R15 R19 R15 R19 BOC

Scheme Q depicts some specific examples of Scheme P.

Scheme O

2 N ( 2 Br N X-sh, 1. n-BuLi; ZnCl2 2. N I, Pd(Ph3P)4 THF, 90° C. 2 N N N BOC BOC BOC

Scheme R depicts methods for functionalizing the vinyl bro mide to install groups D (or A). Either a modified Stille coupling, Zinc mediated coupling, or a Suzuki boronic acid coupling are depicted. A method for converting the vinyl 35 bromide to vinyl idodide is shown. If the vinyl bromide fails to undergo efficient reaction, the more reactive iodide can be prepared as a better partner. Details of these transformations are discussed later in the section on metal couplings. 40

Scheme R D A Br A

R18 R22 R RZnBr R18 /Rs R23 23 -- R17 R17 Pd(Ph3P)4, THF R17 R16 R20 R16 R20 R16 N N R15 R19 R15 50 R, BOC BOC

|Pg.55 I2

D A I A D D (HO)2B R18 /Rs R23 Bus sn1 R18 R22 V R18 a R23 HerD R17 Pd(dba), R17 Pd(dba)3, R17 tri-2-furylphosphine Na2CO3 R16 R20 R16 R20 R16 N N N R15 R19 R15 R19 R15 BOO65 BOC US 7,915,283 B2

Scheme S provides specific examples of Scheme R.

Scheme S. F F MeO e N MeO

N Br 21 ZnBr F F B(OH)2 OMe se Pd(dba)3, Na2CO3 Pd(Ph3P)4, THF N BOC BOC BOC his 12 OH EtOC s H (HO)2B HN N-N OH N2 X-coil I BuSn a -e- Pd(dba)3, Pd(dba)3 s Na2CO3 tri-2-furylphosphine N N BOC BOC BOC

Scheme T shows methods for converting the vinyl bromide into more funtionalized groups D (or A). A key aldehyde intermediate is generated from the vinyl bromide and can be as used to generate heteroaryls such as the oxazole via reaction with Tosmic.

Scheme T 40

Br A HOC A

R18 R22 R R18 R45 R R 23 1.n-BuLi, THF R 23 TosMIC, K2CO3 ------7 2. DMF 7 MeOH R16 R20 R16 R20 N N Ris R19 R15 19 BOC BOC 1.n-BuLi, THF 2. ZnCl2 3. AcCl, (Ph3P)4Pd 55 S CH CHBr O A O A -(N A R18 R22 R R18 R22 6. R18 R22 23 23 R23 1. LDA, THF: TMSCI MeCSNH R17 Hs R17 He R17 2. NBS, THF EtOH R16 R20 R16 R20 R16 R20 N N N R15 R19 R15 R19 R15 R19 BOC BOC 65 BOC US 7,915,283 B2

Scheme U shows how a hydrazide (generated from the acid) Scheme V provides more specific examples of Scheme U. can be used to prepare oxadiazoles with different substitu entS. Scheme V 5 Scheme U. O O A HNHN RCOCl, Na2CO3, H2O HNHN 10 O e R18 R22 RCOCl, Na2CO3, H2O RCOH, EDCL, HOBT --- R R O 7 23 RCOH, EDCL, HOBT N R16 R20 N R15 R19 15 BOC BOC

2O HNHN -N Ph3P, Cl3CCCl3 --- R O DIEA, MeCN Ph3P, Cl3CCCl3 --- DIEA, MeCN 25 N

BOC TBS-CI imidazole - R = CH2OH TBS-C imidazole - R = CH2OH DMF R1 =- CHOTBS DMF R = CHOTBS 30 RI X N M e

BOC

Scheme W shows some other methods for installing D (or A).

Scheme W.

N /NQ Br OCH le

1. n-BuLi, THF TosMIC, KCO3 He- He 2. DMF MeOH

N N N

BOC BOC BOC

1. n-BuLi, THF 2. ZnCl2 3. AcCl, (Ph3P)4Pd US 7,915,283 B2 43 -continued Br S Me Me-K O O N 1. LDA, THF: TMSCI MeCSNH He- He 2. NBS, THF EtOH

N N

BOC BOC BOC

Scheme X shows a particular example where a functionalized 15 -continued heteroaryl or in this case aryl are coupled and then further functionalization can occur (in this case reduction of an ester to an alcohol).

Scheme X COEt 25 Br A N R18 R22 R17 R23 N 21 SnMe 30 R16 N R20 (Ph3P)2PdCl2 THF, 90° C. R15 R19 s BOC Scheme Y provides more specific examples of Scheme X.

Scheme Y

40 COEt Br LAH, THF He rn N 45 2 SnMe (Ph3P)2PdCl2 N THF, 90° C.

BOC 50

55 COEt

1. TFA, DCM Hs 21 2. BOP-CI, DIEA, CHCI O N OH S. LAH, THF 60 Q O

65 BOC US 7,915,283 B2

-continued -continued OH R2 AlCl3 N CICOCOOMe 21 5 N Step B 1. TFA, DCM CHCl2 -- Na2NN Nan 2. BOP-CI, DIEA, CHCI H MeO O OH R4 e 10 2a O N N N / \ R2 O BOC N N OMe N Step C O 15 N KOH

NK Na2NNH Me OH R4 2O 3a O O R2 O H Step D R3 He 25 DEBPT, (i-Pr).NEt / N-V DMF N 2NN H

30 R4 4a

NY. 35 i-K Me 40

Procedures for making Q(C=O), OH or Q(C— O), X (as defined in formula I of the description of the invention and in schemes A-C above) are described herein 45 and in the same references just cited for the coupling reaction Scheme 1 (Blair, Wang, Wallace, or Wang references 93-95 and 106 respectively). Additional general procedures to construct Sub- R stituted azaindole Q and Z of Formula I and intermediates useful for their synthesis are described in the following so N1 N 2^a MgBr Schemes. The following Schemes provide specific examples Step A of methodology which can be used to prepare Q or Q(CO)m- R3 21 NO OH or derivatives in which the acid has been converted to an acid halide or ester. R4 55 1b

Scheme la R2 R2 AlCl3 R3 60 CICOCOOMe N 4\ MgBr N N Step B N Step A CHCl2 21 NO THF R 2 N

R4 65 R4

US 7,915,283 B2 49 50

-continued with an aryl or heteroaryl nitro group, Such as in 1a-le, to form a five-membered nitrogen containing ring as shown. Some references for details on how to carry out the transfor mation include: Bartoli et al. a) Tetrahedron Lett. 1989, 30, 2129.b).J. Chem. Soc. Perkin Trans. 1 1991,2757.c).J. Chem. Soc. Perkin Trans. II 1991, 657. d) Synthesis (1999), 1594. e) Zhang, Zhongxing; Yang, Zhong; Meanwell, Nicholas A.; Kadow, John F.; Wang, Tao. “A General Method for the Preparation of 4- and 6-AZaindoles”. Journal of Organic 10 Chemistry 2002, 67 (7), 2345-2347 WO 0262423 Aug. 15, 2002 “Preparation and antiviral activity for HIV-1 of substi tuted azaindoleoxoacetylpiperazines’ Wang, Tao; Zhang, Zhongxing; Meanwell, Nicholas A.: Kadow, John F.; Yin, Scheme le. Zhiwei. R 15 In the preferred procedure, a solution of vinyl Magnesium bromide in THF (typically 1.0M but from 0.25 to 3.0M) is added dropwise to a solution of the nitro pyridine in THF at R3 212N. MgBr -78 under an inert atmosphere of either nitrogen or Argon. Step A After addition is completed, the reaction temperature is He R NO THF 2O allowed to warm to -20° and then is stirred for approximately 12 h before quenching with 20% aq, ammonium chloride Rs solution. The reaction is extracted with ethyl acetate and then 1e worked up in a typical manner using a drying agent such as R2 anhydrous magnesium Sulfate or Sodium sulfate. Products are AlCl3 25 generally purified using chromatography over Silica gel. Best R3 CICOCOOMe results are generally achieved using freshly prepared vinyl N Step B Magnesium bromide. In some cases, vinyl Magnesium chlo CHCl2 ride may be substituted for vinyl Magnesium bromide. In R4 N Some cases modified procedures might occasionally provide 30 enhanced yield. An inverse addition procedure can some Rs times be employed. (The nitro pyridine solution is added to 2e O the vinyl Grignard solution). Occasionally solvents such as O dimethoxy ethane or dioxane may prove useful. A procedure R2 in which the nitro compound in THF is added to a 1M solution OMe 35 of vinyl magnesium bromide in THF at -40°C. may prove R3 Step C beneficial. Following completion of the reaction by TLC the N HerKOH reaction is quenched with sat ammonium chloride aqueous solution and purified by standard methods. A reference for R4 N this alternative procedure is contained in M. C. Pirrung, M. 40 Wedel, and Y. Zhao et al. Syn Lett 2002, 143-145. Rs Substituted azaindoles may be prepared by methods 3e described in the literature or may be available from commer O cial sources. Thus there are many methods for synthesizing O intermediates 2a-2d and the specific examples are too numer R H-W-A 45 ous to even list. Methodology for the preparation of many R OH Step D -- compounds of interest is described in references of Blair, 3 N DEBPT, (i-Pr).NEt Wang, Wallace, and Wang references 93-95 and 103 respec DMF tively. A review on the synthesis of 7-azaindoles has been published (Merour et. al. reference 102). Alternative synthe R N 50 ses of aza indoles and general methods for synthesizing inter Rs mediates 2 include, but are not limited to, those described in 4e the following references (a-k below): a) Prokopov, A. A.; O Yakhontov, L. N. Khim.-Farm. Zh. 1994, 28(7), 30-51; b) O Lablache-Combier, A. Heteroaromatics. Photoinduced Elec R2 55 tron Transfer 1988, Pt. C, 134-312; c) Saify, Zafar Said. Pak. W J. Pharmacol. 1986, 202), 43-6; d) Bisagni, E. Jerusalem R3 N NA Symp. Ouantum Chem. Biochem. 1972, 4, 439-45; e) Yakh ontov, L. N. Usip. Khim. 1968, 37(7), 1258-87; f) Willette, R. N E. Advan. Heterocycl. Chem. 1968, 9, 27-105:g) Mahadevan, R4 H 60 I.; Rasmussen, M. Tetrahedron 1993, 49(33), 7337-52; h) Rs Mahadevan, I.; Rasmussen, M. J. Heterocycl. Chem. 1992, 5e 29(2), 359-67: i) Spivey, A.C.; Fekner. T.; Spey, S.E.: Adams, H. J. Org. Chem. 1999, 64(26), 9430-9443; ) Spivey, A. C.: Fekner, T.: Adams, H. Tetrahedron Lett. 1998, 39(48), 8919 Step A in Schemes 1a-1e depict the synthesis of a aza 65 8922; k) Advances in Heterocyclic Chemistry (Academic indole or indole intermediates, 2a-2e via the well known press) 1991, Vol. 52, pg. 235-236 and references therein. Other Bartoli reaction in which vinyl magnesium bromide reacts references later in this application. Starting indole interme US 7,915,283 B2 51 52 diates of formula 2e (Scheme le) are known or are readily water could be added to the alcohols. Propanols or butanols prepared according to literature procedures, such as those could also be used as solvents. Elevated temperatures up to described in Gribble, G. (Refs. 24 and 99), Bartolietal (Ref. the boiling points of the solvents may be utilized if ambient 36), reference 37, or the book by Richard A. Sundberg in temperatures do not suffice. Alternatively, the hydrolysis may reference 40. Other methods for the preparation of indole 5 be carried out in a non polar solvent such as CHCl, or THF intermediates include: the Leimgruber-Batcho Indole synthe in the presence of Triton B. Temperatures of -78°C. to the sis (reference 93); the Fisher Indole synthesis (references 94 boiling point of the solvent may be employed but -10°C. is and 95); the 2,3-rearrangement protocol developed by Gas preferred. Other conditions for ester hydrolysis are listed in sman (reference 96); the annelation of pyrroles (reference reference 41 and both this reference and many of the condi 97); tin mediated cyclizations (reference 98); and the Larock 10 tions forester hydrolysis are well known to chemists of aver palladium mediated cyclization of 2-alkynyl anilines. Many age skill in the art. other methods of indole synthesis are known and a chemist Alternative Procedures for Step B and C: with typical skill in the art can readily locate conditions for Imidazolium Chloroaluminate: preparation of indoles which can be utilized to prepare com We found that ionic liquid 1-alkyl-3-alkylimidazolium pounds of Formula I. 15 chloroaluminate is generally useful in promoting the Friedel Step B. Intermediate 3a-e can be prepared by reaction of Crafts type acylation of indoles and azaindoles. The ionic intermediates 2, with an excess of ClCOCOOMe in the pres liquid is generated by mixing 1-alkyl-3-alkylimidazolium ence of AlCls (aluminum chloride) (Sycheva et al. Ref. 26, chloride with aluminium chloride at room temperature with Sycheva, T. V.; Rubtsov, N. M.; Sheinker, Yu. N.; Yakhontov, vigorous stirring. 1:2 or 1:3 molar ratio of 1-alkyl-3-alkylimi L. N. Some further descriptions of the exact procedures to dazolium chloride to aluminium chloride is preferred. One carry out this reaction are contained ina) Zhang, Zhongxing; particular useful imidazolium chloroaluminate for the acyla Yang, Zhong; Wong, Henry; Zhu, Juliang; Meanwell, Nicho tion of azaindole with methyl or ethyl chlorooxoacetate is the las A.: Kadow, John F.; Wang, Tao. “An Effective Procedure 1-ethyl-3-methylimidazolium chloroaluminate. The reaction for the Acylation of Azaindoles at C-3.J. Org. Chem. 2002, is typically performed at ambient temperature and the azain 67(17), 6226-6227; b) Tao Wang et al. U.S. Pat. No. 6,476, 25 doleglyoxyl ester can be isolated. More conveniently, we 034 B2 “Antiviral Azaindole derivatives” published Nov. 5, found that the glyoxyl ester can be hydrolyzed in situ at 2002; c) W. Blair et al. PCT patent application WO 00/76521 ambient temperature on prolonged reaction time (typically A1 published Dec. 21, 2000; d) O. Wallace et al. PCT appli overnight) to give the corresponding glyoxyl acid (interme cation WO)2/04440A1 published Jan. 17, 2002. Some reac diates 4a-4-e) for amide formation (Scheme 2). tions of 5-cyano-6-chloro-7-azaindoles and lactam-lactim 30 tautomerism in 5-cyano-6-hydroxy-7-azaindolines. Khim. Geterotsikl. Soedin., 1987, 100-106). Typically an inert sol Scheme 2 vent such as CHCl is used but others such as THF, EtO, DCE, dioxane, benzene, or toluene may find applicability either alone or in mixtures. Other oxalate esters such as ethyl 35 - N -- or benzyl mono esters of oxalic acid could also suffice for 21NN either method shown above. More lipophilic esters ease iso H lation during aqueous extractions. Phenolic or Substituted phenolic (Such as pentafluorophenol) esters enable direct (indole or azaindole) coupling of the H W-A in Step D without activation. Lewis 40 O | G \, e acid catalysts, such as tin tetrachloride, titanium IV chloride, N N Cl and aluminum chloride are employed in Step B with alumi OR N-1 N1 N. num chloride being most preferred. Alternatively, the azain C + AlCl3 dole is treated with a Grignard reagent such as MeMgI (me O r.t. 45 thyl magnesium iodide), methyl magnesium bromide or ethyl R = Me or Et magnesium bromide and a Zinc halide, Such as ZnCl2 (Zinc O OR chloride) or zinc bromide, followed by the addition of an oxalyl chloride mono ester, such as CICOCOOMe (methyl chlorooxoacetate) or another ester as above, to afford the O N N in situ aza-indole glyoxyl ester (Shadrina et al. Ref.25). Oxalic acid 50 RX - I N Her esters such as methyl oxalate, ethyl oxalate or as above are 21 N used. Aprotic solvents such as CHCl, Et2O, benzene, tolu H ene, DCE, or the like may be used alone or in combination for 3a-3e this sequence. In addition to the oxalyl chloride mono esters, (indole or azaindole) oxalyl chloride itself may be reacted with the azaindole and 55 then further reacted with an appropriate amine. Such as O OH H W-A. Step C. Hydrolysis of the methyl ester, (intermediates 3a-3e. Schemes 1a-1e) affords a potassium salt of intermedi ates 4, which is coupled with alkenylpiperidines H W-A as 60 shown in Step D of the Schemes 1a-le. Some typical condi tions employ methanolic or ethanolic sodium hydroxide fol lowed by careful acidification with aqueous hydrochloric acid of varying molarity but 1M HCl is preferred. The acidi (indole or azaindole) fication is not utilized in many cases as described above for 65 the preferred conditions. Lithium hydroxide or potassium A representative experimental procedure is as follows: hydroxide could also be employed and varying amounts of 1-ethyl-3-methylimidazolium chloride (2 equiv.: purchased US 7,915,283 B2 53 54 from TCI; weighted under a stream of nitrogen) was stirred in -continued an oven-dried round bottom flask at r.t. under a nitrogen AlCl3 atmosphere, and added aluminium chloride (6 equiv.; anhy N N CICOCOOMe Step B drous powder packaged under argon in ampules purchased Her 21 NN CHCl2 from Aldrich preferred; weighted under a stream of nitrogen). H The mixture was vigorously stirred to form a liquid, which C was then addedazaindole (1 equiv.) and stirred until a homog 10 enous mixture resulted. The reaction mixture was added O dropwise ethyl or methyl chlorooxoacetate (2 equiv.) and O then stirred at r,t. for 16 h. After which time, the mixture was 10 cooled in an ice-water bath and the reaction quenched by OMe carefully adding excess water. The precipitates were filtered, N washed with water and dried under high vacuum to give the N Step C aZaindoleglyoxylic acid. For some examples, 3 equivalents of Na2NN KOH 1-ethyl-3-methylimidazolium chloride and chlorooxoacetate 15 H may be required. A more comprehensive reference with addi C tional examples is contained in: Yeung, Kap-Sun; Farkas, 11 Michelle E.; Qiu, Zhilei, Yang, Zhong. Friedel–Crafts acyla O H tion of indoles in acidic imidazolium chloroaluminate ionic O V W-A liquid at room temperature. Tetrahedron Letters (2002), OH Step D 43(33), 5793-5795. Her N N DEBPT, (i-Pr).NEt Related references: (1) Welton,T. Chem. Rev. 1999,99, 2071; DMF (2) Surette, J. K. D.; Green, L.; Singer, R. D. Chem. Com 25 Na2NN mun. 1996, 2753; (3) Saleh, R.Y.WO 0015594. H Step D. Was Described Above. C It should be noted that in many cases reactions are depicted 12 for only one position of an intermediate, such as the R O position, for example. It is to be understood that Such reac 30 O tions could be used at other positions, such as R-R', of the W various intermediates. Reaction conditions and methods N given in the specific examples are broadly applicable to com rN\, t N pounds with other substitution and other transformations in 35 2 N this application. Schemes 1 and 2 describe general reaction H schemes for taking appropriately substituted Q (indoles and C aZaindoles) and converting them to compounds of Formula I. While these schemes are very general, other permutations such as carrying a precursor or precursors to substituents R through R through the reaction scheme and then converting 40 Schemes 3 provide more specific examples of the transfor it to a compound of Formula I in the last step are also con mation previously described in Scheme A. Intermediates 9-13 templated methods of this invention. Nonlimiting examples are prepared by the methodologies as described for interme of Such strategies follow in Subsequent schemes. diates 1c-5c in Scheme 1c. Scheme 4 is another embodiment The amide bond construction reactions depicted in step D 45 of the transformations described in Schemes 1a-1e and 3. of Schemes 1a-1e could be carried out using the specialized Conversion of the phenol to the chloride (Step S, Scheme 4) conditions described herein or alternatively by applying the may be accomplished according to the procedures described conditions or coupling reagents for amide bond construction in Reimann, E.; Wichmann, P.; Hoefner, G.; Sci. Pharm. described in Wallace, reference 95. Some specific nonlimit 1996, 64(3), 637-646; and Katritzky, A. R. Rachwal, S.; ing examples are given in this application. 50 Smith, T. P.; Steel, P. J.; J. Heterocycl. Chem. 1995, 32(3), 979-984. Step T of Scheme 4 can be carried out as described Additional procedures for synthesizing, modifying and for Step A of Scheme 1. The bromo intermediate can then be attaching groups are contained in references 93-95 and 103 or converted into alkoxy, chloro, or fluoro intermediates as are described below. shown in Step U of Scheme 4. When step U is the conversion 55 of the bromide into alkoxy derivatives, the conversion may be carried out by reacting the bromide with an excess of, for example, Sodium methoxide or potassium methoxide in methanol with cuprous salts, such as copper I bromide, cop Scheme 3 per I iodide, and copper I cyanide. The reaction may be 60 carried out at temperatures of between ambient and 175° C. N 2n MgBr but most likely will be around 115° C. or 100° C. The reaction N - Step A - may be run in a pressure vessel or sealed tube to prevent 21 NO THF escape of Volatiles Such as methanol. Alternatively, the reac tion can be run in a solvent such as toluene or Xylene and the C 65 methanol allowed to partially escape the reaction vessel by 9 heating and then achieving reflux by adding a condenser. The preferred conditions on a typically laboratory scale utilize 3 US 7,915,283 B2 55 56 eq of sodium methoxide in methanol, CuBr as the reaction -continued catalyst (0.2 to 3 equivalents with the preferred being 1 eq or less), and a reaction temperature of 115° C. The reaction is V carried out in a sealed tube or sealed reaction vessel. The W-A copper catalyzed displacement reaction of aryl halides by 5 Step X methoxide is described in detail in H. L. Aalten et al. 1989, DEBPT, (i-Pr).NEt Tetrahedron 45(17) pp 5565 to 5578 and these conditions DMF described herein were also utilized in this application with azaindoles. The conversion of the bromide into alkoxy deriva 10

tives may also be carried out according to procedures described in. Palucki, M.; Wolfe, J. P.; Buchwald, S. L.; J. Am. Chem. Soc. 1997, 119(14), 3395-3396; Yamato, T.: Komine, M.: Nagano, Y.; Org. Prep. Proc. Int. 1997, 29(3), 300-303: Rychnovsky, S. D.; Hwang, K.J. Org. Chem. 1994, 59(18), 15 5414-5418. Conversion of the bromide to the fluoro deriva tive (Step U, Scheme 4) may be accomplished according to Antipin, I. S.; Vigalok, A.I.: Konovalov, A.I.; Zh. Org. Khim. 1991, 27(7), 1577-1577; and Uchibori, Y.: Umeno, M.; Seto, H.; Qian, Z. Yoshioka, H.; Synlett. 1992, 4, 345-346. Con- 20 version of the bromide to the chloro derivative (Step U, Scheme 5) may be accomplished according to procedures described in Gilbert, E. J.; Van Vranken, D. L.; J. Am. Chem. Soc. 1996, 118(23), 5500-5501; Mongin, F.; Mongin, O.: Scheme 5 Trecourt, F. Godard, A.; Queguiner, G., Tetrahedron Lett. 25 Br X 1996, 37(37), 6695-6698; and O'Connor, K.J.; Burrows, C. J.J. Org. Chem. 1991, 56(3), 1344-1346. Steps V, W, and X N N of Scheme 4 are carried out according to the procedures previously described for Steps B, C, and D of Scheme 1a-le. Na2 Step U Na2 POCl. respectively. The steps of Scheme 4 may be carried out in a 30 NO NO Step S different order as shown in Schemes 5 and Scheme 6. OH OH X = OR, FCI X

35 N Scheme 4 2n MgBr Br Br N -> 21 NO Step T N N 40 C 2 POCl. 2 4 NMB X NO Step S NO Step T N AlCl3, CICOCOOMe CHCI C C N 2 45 N 21 N MeMgBr, ZnCl2 H CICOCOOMe

Br X Step V AlCl3, N N Step U N N CICOCOOMeCHCl2 50 N 2 N N 2 N MeMgBr,O Step W. ZnCl2 KOH C C Step V X = OR, F, Cl 55

H. A V / 60 W Step X -- DEBPT, (i-Pr).NEt Step W DMF KOH

65 US 7,915,283 B2

-continued Scheme 7 Step A 5 R 2n MgBr o -- X. THF NO

1a-1e 10 Step B AlCl3 CICOCOOMe NY CHCl2 N H 15

2a-2e Br Br O O N POCl. N 4 NMB 2O OMe He- Hess Step S Step T N 2 p N 2 p N Step C NO NO R- to - N OH C 25 H

Br 3a-3e AlCl3, CICOCOOMe O N N CHCl2 O MeMgBr, ZnCl2 30 Nn 2 N CICOCOOMe OK or Step V Rx. N HN - A C N - W - DEBPT, (i-Pr).NEt N DMF 35 H

4-a-4e O 1) Step U O He- 40 2) Step W KOH W N N A. Rx. 45 N O B O 5a-5e r R = R2-R4 for azaindoles or R2-Rs for indoles OH H A 50 Rx n N N Nw 1 N N N = Q (most generic definition unless specified except for DEBPT, (i-Pr).NEt el-N/ caveats N 21 N DMF H H R6 is nothing C R2 is not depicted (in the interest of convenience) but is considered hydrogen. Other 55 R2 groups would work similarly in these transformations within reactivity limits of a X = OR, F, Cl chemist skilled in the art. R7 is Hydrogen

Scheme 7 depicts a shorthand method for representing the 60 reactions in Scheme 1a-le and generic Q. It is understood, for the purposes of Scheme 7 and further Schemes, that 1b is used to synthesize 2b-5b. 1c provides 2c-5c and 1d provides 2d-5d etc. The Substituents R represent for azaindoles R-R and for indoles R-Rs. In formulas in following schemes, one of 65 the substituents may be depicted but it is understood that each 5a formula can represent the appropriate generic azaindoles or indole in order to keep the application Succinct. US 7,915,283 B2 59 -continued Scheme 8 O R2 COOMe COOMe WQ R N N A n N N1 N N RX R1 || R N R 2 N R 2 N H 18a and 18b R4 R4 10 n = 1 or 2 R = R2-R4 for azaindoles or R2-Rs for indoles 2 R COOMe COOMe R R 2 N N 3 N N 15 R R Na2 2 Scheme 1() N R1 N1 N R2 R4 MgBr

Hs An alternative method for carrying out the sequence out THF, -40° C. lined in steps B-D (shown in Scheme 9) involves treating an NO aZaindole, Such as 16, obtained by procedures described in Br the literature or from commercial sources, with MeMgI and 25 6a ZnCl, followed by the addition of CICOCOCl (oxalyl chlo R2 = F, OMe ride) in either THF or EtO to afford a mixture of a glyoxyl R2 chloride azaindole, 17a, and an acyl chloride azaindole, 17b. The resulting mixture of glyoxyl chloride azaindole and acyl 30 N EtOCCOCI chloride azaindole is then coupled with H W-A under basic --- conditions to afford the products of step D as a mixture of CH2Cl2, AlCl3 N compounds, 18a and 18b, where either one or two carbonyl H groups link the azaindole and group W. Separation via chro matographic methods which are well known in the art pro Br 35 vides the pure 18a and 18b. This sequence is summarized in 7a. Scheme 9, below. R2 O OEt Scheme 9 NaOH, EtOH 40 He O then HCI N RX N He1) MeMg.I H 2) ZnCl2 Br N 3) CICOCOOCI s 8a. 45 16 R2 O

O OH O 50 Cl O N H RX- N -- OrrBr N H 55 9a NMM, EDAC, DMF 17a H-W-A -- HOBt R2 O O Y A C W 60 H A RX N a W Y O N pyridine H N H Br 65 17b 10a US 7,915,283 B2 61 62 Scheme 10 shows the preparation of an indole intermediate tioner of the art can make this distinction when not specifi 7a, acylation of 7a with ethyl oxalyl chloride to provide cally delineated. Many methods are intended to be applicable intermediate 8a, followed by ester hydrolysis to provide inter to all the series, particularly functional group installations or mediate 9a, and amide formation to provide intermediate 10a. interconversions. For example, a general strategy for provid Alternatively, the acylation of an indole intermediate. Such ing further functionality of this invention is to position or as 7a', could be carried out directly with oxalyl chloride install a halide Such as bromo, chloro, or iodo, aldehyde, followed by base mediated coupling with H W-A to provide cyano, or a carboxy group on the azaindole and then to con an intermediate of Formula 10a' as shown in Scheme 5. Vert that functionality to the desired compounds. In particular, conversion to Substituted heteroaryl, aryl, and amide groups 10 on the ring are of particular interest. Scheme 5 General routes for functionalizing azaindole rings are R2 shown in Schemes 7A, 8 and 9. As depicted in Scheme 7A, the azaindole, 17, can be oxidized to the corresponding N-oxide R3 derivative, 18, by using mCPBA (meta-Chloroperbenzoic N CCOCOC 15 --- Acid) in acetone or DMF (eq. 1, Harada et al. Ref. 29 and RI THF Antonini etal, Ref. 34). The N-oxide, 18, can be converted to R4 NH a variety of substituted azaindole derivatives by using well R5 documented reagents such as phosphorus oxychloride (POCl) (eq. 2, Schneller et al. Ref. 30), tetramethylammo 7a. nium fluoride (MeNF) (eq. 3), Grignard reagents RMgX (R-alkyl oraryl, X-Cl, Br or I) (eq. 4, Shiotani et al. Ref.31), trimethylsilyl cyanide (TMSCN) (eq. 5, Minakata et al. Ref. R2 O 32) or AcO (eq. 6, Klemm et al. Ref. 33). Under such con 25 ditions, a chlorine (in 19), fluorine (in 20), nitrile (in 22), alkyl R3 C (in 21), aromatic (in 21) or hydroxyl group (in 24) can be i-PrNEt, DMF He introduced to the pyridine ring. Nitration of azaindole N-ox O R. R.17 ides results in introduction of a nitro group to azaindole ring, R4 N RI R15 R18 as shown in Scheme 8 (eq. 7, Antonini etal, Ref.34). The nitro 5 H D 30 R group can Subsequently be displaced by a variety of nucleo HN philic agents, such as OR, NR'R' or SR, in a well established R22 A chemical fashion (eq. 8, Regnouf De Vains et al. Ref. 35(a), Miura et al. Ref.35(b), Profft etal, Ref.35(c)). The resulting R19 R20 R23 N-oxides, 26, are readily reduced to the corresponding aza 35 indole, 27, using phosphorus trichloride (PC1) (eq. 9, Anto

nini et al. Ref 0.34 and Nesi et al. Ref. 36). Similarly, nitro substituted N-oxide, 25, can be reduced to the azaindole, 28, using phosphorus trichloride (eq. 10). The nitro group of R2 O compound 28 can be reduced to either a hydroxylamine (NHOH), as in 29, (eq. 11, Walseretal, Ref.37(a) and Barker R3 et al. Ref. 37(b)) or an amino (NH) group, as in 30, (eq. 12, Nesi et al. Ref. 36 and Ayyangar et al. Ref. 38) by carefully selecting different reducing conditions. R4 N RI H 45 R5 Scheme 7A eq. 1 10a O

Other methods for introduction of an aldehyde group to 50 form intermediates of formula 1 1 include transition metal RX G) WS. mCPBA catalyzed carbonylation reactions of suitable bromo, trifluo N R romethane Sulfonates(y1), or Stannanes(y1) indoles. Alterna H tive the aldehydes can be introduced by reacting indolyl 55 anions or indolyl Grignard reagents with formaldehyde and 17 then oxidizing with MnO, or TPAP/NMO or other suitable oxidants to provide intermediate 11. Some specific examples of general methods for preparing O functionalized azaindoles or indoles or for interconverting 60 functionality on aza indoles or indoles which will be useful W. for preparing the compounds of this invention are shown in RX NA the following sections for illustrative purposes. It should be N R understood that this invention covers substituted 4, 5, 6, and 7 O- H aZaindoles and also indoles that the methodology shown 65 below may be applicable to all of the above series while other 18 shown below will be specific to one or more. A typical prac US 7,915,283 B2 63 64 -continued -continued

O y POCl3 NC–G) N N 22 18 10

ci-O 15 RX- GD N

25 N

18 30

RX N 45

HNO TFA 55 N

TMSCN 2 RX -3- ON PhCOC N N N 65 18 25 US 7,915,283 B2

-continued -continued eq. 8 O O RX RX W. 17 in W. RXH in-O NA ON N NA - - N R RXNa H O N R X = O, N, S 29 25 10 eq. 12 O O RX RX 17 in W. Na2S 7 in W 15 n He RX N NA ON A. MeOHIHO N R N R H O- H 28 26 eq.9 O O RX RX 17 in W. PCl W. n He HN 7 NA RX N A. EtOAc 25 N R X = O, N, S N R O- H H

26 30

30 O The alkylation of the nitrogen atom at position 1 of the RX azaindole derivatives can be achieved using NaHas the base, 17 in W. DMF as the solvent and an alkyl halide or sulfonate as alky RX NA lating agent, according to a procedure described in the litera 35 N R ture (Mahadevan et al. Ref39) (Scheme 9). H

27 eq. 10 Scheme 9 O 40 RX O 7 in W. PCl n Hess in W. NaH, DMF ON N A. EtOAc X. n He N R 45 R GO A. RX O- H N R H 25 17

O 50 O RX 7 in W. ON NA W. N R RX O NA H 55 R. 28 R eq. 11 O 31 RX 60 H.P-C ON 17 Wn - T - In the general routes for Substituting the azaindole ring N R described above, each process can be applied repeatedly and H combinations of these processes is permissible in order to 65 provide azaindoles incorporating multiple substituents. The 28 application of such processes provides additional compounds of Formula I. US 7,915,283 B2 67 -continued Scheme 10A N NO R-R, it N N CH 2 N N H

N THF 2 NO 1N CH 32 R3-Rs i 2 THF NO NMe2 =\ NO as above N H2, Pd/C --- NMe2 N 21 NO H2/Raneyor Ni 15 =\ N as above 33 R-Rs it -- NH2 21 NO N N rN\, R2 Rs-i N 21 N 2NN H H 34 25 The amino indole, 34, can now be converted to compounds The synthesis of 4-aminoaZaindoles which are useful pre of Formula I via, for example, diazotization of the amino cursors for 4, 5, and/or 7-substituted azaindoles is shown in group, and then conversion of the diazonium salt to the fluo Scheme 10A above. ride, chloride or alkoxy group. See the discussion of Such The synthesis of 3,5-dinitro-4-methylpyridine, 32, is 30 conversions in the descriptions for Schemes 17 and 18. The described in the following two references by Achremowiczet. conversion of the amino moiety into desired functionality al.: Achremowicz, Lucjan. Pr: Nauk. Inst. Chem. Org. Fiz. could then be followed by installation of the oxoacetopip Politech. Wroclaw. 1982, 23, 3-128; Achremowicz, Lucian. eridinealkene moiety by the standard methodology described Synthesis 1975, 10,653-4. In the first step of Scheme 10A, the above. 5 or 7-substitution of the azaindole can arise from reaction with dimethylformamide dimethyl acetal in an inert 35 N-oxide formation at position 6 and Subsequent conversion to Solvent or neat under conditions for forming Batcho-Le the chloro via conditions such as POCl in chloroform, acetic imgruberprecursors provides the cyclization precursor, 33, as anhydride followed by POCl in DMF, or alternatively TsCl shown. Although the step is anticipated to work as shown, the in DMF. Literature references for these and other conditions are provided in some of the later Schemes in this application. pyridine may be oxidized to the N-oxide prior to the reaction 40 using a peracid such as MCPBA or a more potent oxidant like The synthesis of 4-bromo-7-hydroxy or protected hydroxy meta-trifluoromethyl or meta nitro peroxybenzoic acids. In 4-azaindole is described below as this is a useful precursor for the second step of Scheme 10A, reduction of the nitro group 4 and/or 7 substituted 6-aza indoles. using for example hydrogenation over Pd/C catalyst in a The synthesis of 5-bromo-2-hydroxy-4-methyl-3-nitro solvent such as MeOH, EtOH, or EtOAc provides the 45 pyridine, 35, may be carried out as described in the following cyclized product, 34. Alternatively the reduction may be car reference: Betageri, R.; Beaulieu, P. L.; Llinas-Brunet, M: ried out using tin dichloride and HCl, hydrogenation over Ferland, J. M.: Cardozo, M.; Moss, N.; Patel, U.; Proudfoot, Raney nickel or other catalysts, or by using other methods for J. R. PCT Int. Appl. WO9931066, 1999. Intermediate 36 is nitro reduction Such as described elsewhere in this applica prepared from 35 according to the method as described for tion. A general method for preparing indoles and azaindoles 50 Step 1 of Scheme 10A. PG is an optional hydroxy protecting of the invention utilize the Leim-Gruber Batcho-reation group such as triallylsilyl, methyl, benzyl or the like. Inter sequence as shown in the scheme below: mediate 37 is then prepared from 36 by the selective reduction of the nitro group in the presence of bromide and Subsequent cyclization as described in the second step of Scheme 10A. 1N CH3 55 Fe(OH) in DMF with catalytic tetrabutylammonium bro R-R-i N THF mide can also be utilized for the reduction of the nitro group. The bromide may then be converted to alkoy using the con 2 NO2 DMF dimethoxy acetal ditions employed in step U of scheme 4. The compounds are NMe2 then converted to compounds of Formula I as above. The =\ 60 protecting group on the C-7 position may be removed with N H2, Pd/C TMSI, hydrogenation orin the case of allyl standard palla R-R-i N — - dium deprotection conditions in order to generate the free C-7 21 H2/Raney Ni hydroxy compound which can also be depicted as its pyridone NO Or Or H2 platinum 65 tautomer. As described earlier POBr3 or POC13 can be used to or Fei HCI convert the hydroxy intermediate to the C-7 bromo or chloro intermediate respectively. US 7,915,283 B2 69 70 -continued Scheme 11 Br

N CH3 THF N 21 NO

OH 10

Br NMe2 =\ N H2, Pd/C He Step F N or pd (O) 21 NO H2/Raney Ni He RSnR3 OPG O

36 Br

rN\, N 2 N H

OPG 30 37

Step E Scheme 14 depicts the nitration of an azaindole, 41, (R—H). Numerous conditions for nitration of the azaindole 35 may be effective and have been described in the literature. Step F NOs in nitromethane followed by aqueous sodium bisulfite As shown above in Scheme 15, Step F, substituted azain according to the method of Bakke, J. M.; Ranes, E.; Synthesis doles containing a chloride, bromide, iodide, triflate, orphos 1997, 3, 281-283 could be utilized. Nitric acid in acetic may phonate undergo coupling reactions with a boronate (Suzuki also be employed as described in Kimura, H.; Yotsuya, S.; 40 type reactions) or a stannane (Stille type coupling) to provide Yuki, S.; Sugi, H.; Shigehara, I.; Haga, T.; Chem. Pharm. Bull Substituted indoles or azaindoles. This type of coupling as 1995, 43(10), 1696-1700. Sulfuric acid followed by nitric mentioned previously can also be used to functionalize vinyl acid may be employed as in Ruefenacht, K. Kristinsson, H., halides, triflates or phosphonates to add groups D or A or Mattern, G.; Hely Chim Acta 1976, 59, 1593. Coombes, R. G.; precursors. Stannanes and boronates are prepared via stan 45 dard literature procedures or as described in the experimental Russell, L. W.; J. Chem. Soc., Perkin Trans. 1 1974, 1751 section of this application. The Substituted indoles, azain describes the use of a Titatanium based reagent system for doles, or alkenes may undergo metal mediated coupling to nitration. Other conditions for the nitration of the azaindole provide compounds of Formula I wherein R is aryl, het can be found in the following references: eroaryl, or heteroalicyclic for example. The indoles or azain Lever, O. W. J.; Werblood, H. M.; Russell, R. K. Synth. 50 dole intermediates, (halogens, triflates, phosphonates) may Comm. 1993, 23(9), 1315-1320; Wozniak, M.: Van Der undergo Stille-type coupling with heteroarylstannanes as Plas, H. C.J. Heterocycl Chem. 1978, 15,731. shown in Scheme 15 or with the corresponding vinyl reagents as described in earlier Schemes. Conditions for this reaction

are well known in the art and the following are three example 55 references a) Farina, V.; Roth, G. P. Recent advances in the Stille reaction; Adv. Met.-Org. Chem. 1996, 5, 1-53.b) Farina, V. Krishnamurthy, V.; Scott, W. J. The Stille reaction; Org. React. (N.Y.) 1997, 50, 1-652. and c) Stille, J. K. Angew: Chem. Int. Ed. Engl. 1986, 25, 508-524. Other references for 60 general coupling conditions are also in the reference by Rich ard C. Larock Comprehensive Organic Transformations 2nd Step E Ed. 1999, John Wiley and Sons New York. All of these refer ences provide numerous conditions at the disposal of those skilled in the art in addition to the specific examples provided 65 in Scheme 15 and in the specific embodiments. It can be well 41 recognized that an indole Stannane could also couple to a heterocyclic or aryl halide or triflate to construct compounds US 7,915,283 B2 71 72

of Formula I. Suzuki coupling (Norio Miyaura and Akiro -continued Suzuki Chem. Rev. 1995,95.2457) between a triflate, bromo, or chloro azaindole intermediate and a suitable boronate 1. MeOCCOCl, AlCl could also be employed and some specific examples are con DCM-MeNO He tained in this application. Palladium catalyzed couplings of 5 2. 1 MK2CO3, MeOH Stannanes and boronates between halo azaindole or indole intermediates or vinylhalides or vinyl triflates or similar vinyl substrate are also feasible and have been utilized extensively for this invention. Preferred procedures for coupling of a chloro or bromo azaindole or vinyl halide and a stannane 10 employ dioxane, Stoichiometric oran excess of the tin reagent (up to 5 equivalents), 0.1 to 1 eq of tetrakis triphenyl phos phine Palladium (O) in dioxane heated for 5 to 15 hat 110 to 120°. Other solvents such as DMF, THF, toluene, or benzene could be employed. Another useful procedure for coupling a 15 halo indole or azaindole with a suitable tributyl heteroaryl or other Stannane employs usually a slight excess (1.1 eqs) but up to several equivalents of the Stannane, 0.1 eqS CuI, 0.1 equivalents of tetrakis triphenyl phosphine palladium (O) all of which is usually dissolved in dry DMF (approximately 5 mmol of halide per 25 mL of DMF but this concentration can be reduced for sluggish reactions or increased if solubility is Alternatively, the Stille type coupling between a stannane an issue). The reaction is usually heated at an elevated tem (~1.1 eqs) and a vinyl, heteroaryl, or aryl halide may proceed perature of about 90° C. and the reaction is usually run in a 25 better using (0.05 to 0.1 eq) bvPd2(dba) as catalyst and sealed reaction vessel or sealed tube. When the reaction is tri-2-furylphosphine (-0.25 eq) as the added ligand. The reac completed it is usually allowed to cool, filtered through meth tion is usually heated in THF or dioxane at a temperature anesulfonic acid SCX cartridges with MeOH to remove triph between 70 and 90° C. Preferred procedures for Suzuki cou enyl phosphine oxide, and then purified by standard crystal pling of a chloroazaindole and a boronate employ 1:1 DMF lization or chromatographic methods. Examples of the utility 30 water as solvent, 2 equivalents of potassium carbonate as base Stoichiometric or an excess of the boron reagent (up to 5 of these conditions are shown in Scheme Z below. equivalents), 0.1 to 1 eq of Palladium (0) tetrakis triphenyl phosphine heated for 5 to 15 h at 110 to 120°. Less water is occasionally employed. Another useful condition for cou Scheme Z. 35 pling a heteroaryl or aryl boronic acid to a stoichiometric R2 amount of vinyl halide or triflate utilizes DME as solvent (-0.33 mmol halide per 3 mL DME), ~4 eq of 2M sodium e 1. SnBus carbonate, and 0.05 eq Pd2 dba3 heated in a sealed tube or R4 sealed vessel at 90° C. for ~16 h. Reaction times vary with N h \ (Ph3P)4Pd, CuI 40 substrate. Another useful method for coupling involves use of N DMF coupling an aryl, heteroaryl, or vinyl Zinc bromide or chloride N R4 = heteroaryl coupled with a vinyl, aryl, or heteroaryl halide using tetrakis Br triphenyl phosphine palladium (O) heated in THF. Detailed R2 example procedures for preparing the Zinc reagents from 1. MeOCCOCl, AlCl 45 halides via lithium bromide exchange and then transmetala e DCM-MeNO tion and reaction conditions are contained in the experimental N h \ He2.1M K2CO3, MeOH section. If standard conditions fail new specialized catalysts N and conditions can be employed. Discussions on details, con N H ditions, and alternatives for carrying out the metal mediated R4 50 couplings described above can also be found in the book R2 O OH “Organometallics in Organic Synthesis: A Manual: 2002, 2" Ed. M. Schlosser editor, John Wiley and Sons, West Sussex, e England, ISBN 047198416 7. O Some references (and the references therein) describing NsN \ catalysts which are useful for coupling with aryl and het N eroaryl chlorides are: H Littke, A. F.; Dai, C. Fu, G. C. J. Am. Chem. Soc. 2000, R4 122(17), 4020-4028; N SnBus MeO n Varma, R. S.; Naicker, K. P. Tetrahedron Lett. 1999, 40(3), 60 439-442; Wallow, T.I.: e- 2 Novak, B. M.J. Org. Chem. 1994, 59(17), 5034-7: Buchwald, -N- S.: Old, D. W.; N h (Ph3P)4Pd, CuI Wolfe, J. P.; Palucki, M.: Kamikawa, K. Chieffi, A.; Sadighi, N DMF J. P.; Singer, R. A.; N H 65 Ahman, J PCT Int. Appl. WO 0002887 2000; Wolfe, J. P.; B Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38(23), 3415: Wolfe, J. P. Singer, R. A.; Yang, B. H.; US 7,915,283 B2 73 Buchwald, S. L. J. Am. Chem. Soc. 1999, 121(41), 9550 -continued 9561; Wolfe, J. P.: Aromatic N-E O Aromatic Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38(16), 2413 Ringp/ Rin77 X 2416: Bracher, F.; RSri RSri E Hildebrand, D.: Liebigs Ann. Chem. 1992, 12, 1315-1319; E = Electrophile = R-halide, RCOCl, ROCOCl, R'R''NCOCl, RSOCl, R'NCO, RNSO, RNCNR" and Bracher, F.; Solvent = CH2Cl2, THF, Ether, DMF R = Me, Bu Hildebrand, D.; Liebigs Ann. Chem. 1993, 8, 837-839. Base = NaH, Buli, LDA, K2CO3, EtN, DBU, Alternatively, the boronate or Stannane may be formed on DMAP, NaHMDS the azaindole via methods known in the art and the coupling 10 performed in the reverse manner with aryl or heteroarylbased Boronate reagents are prepared as described in reference halogens or triflates. 71. Reaction of lithium or Grignard reagents with trialkyl Known boronate or stannane agents could be either pur borates generates boronates. Alternatively, Palladium cata chased from commercial resources or prepared following 15 lyzed couplings of alkoxy diboron or alkyl diboron reagents disclosed documents. Additional examples for the prepara with aryl or heteroaryl halides can provide boron reagents for tion of tin reagents or boronate reagents are contained in the use in Suzuki type couplings. Some example conditions for experimental section, and references 93-95 and 106. coupling a halide with (MeO)BB(OMe)2 utilize PdCl2 Novel Stannane agents could be prepared from one of the (dppf), KOAc, DMSO, at 80° C. until reaction is complete following routes. when followed by TLC or HPLC analysis. Related examples are provided in the following experi Scheme Tin-O1 mental section.

B RSnCl Methods for direct addition of aryl or heteroaryl organo 8Se. - H - Ring Aromatic-SnBus 25 Ring Aromatic-H Solvent metallic reagents to alpha chloro nitrogen containing hetero Base = LDA, TMP-Li, n-Buli, S-Buli, t-Buli cyles or the N-oxides of nitrogen containing heterocycles are Solvent = THF, ether, DME R= Me, Bu known and applicable to the azaindoles. Some examples are Shiotani et. Al. J. Heterocyclic Chem. 1997, 34(3),901-907; 30 Fourmigue et al. J. Org. Chem. 1991, 56(16), 4858-4864.

Scheme Tin-O2 Scheme 12 Base RSnCl Br, C1, OMe, or F Ring Aromatic Br, I He -- Solvent 35 Ring Aromatic SnBus N -- Base = n-BuLi, S-BuLi, t-Buli Solvent = THF, ether, DME N R= Me, Bu 2 N H 40 Cor Br R4 = Cl, Br, I Scheme Tin-O3. 1 R3SnLi HNRzRy Cu" (2 eq.) Ring Aromatic F, Cl, Br, I - - Ring Aromatic SnBus Solvent 45 (3.3-3.0 eq.) K2CO3 (2 eq.) 145° C. Solvent = THF, ether, DME O R= Me, Bu 2 copper bronze and KOH Br, C1, OMe, or F

50 Scheme Tin-O4 NrN an H Ring Aromatic-Cl, Br, I, OT? inSolvent St.- Pd(0) R4 55 Ring Aromatic SnBus R4 = NRzRy where Solvent = Dioxane, Toluene R4 is heteroaryl or amino R= Me, Bu as defined by the invention 3 60 1N Scheme Tin-05 R-R N -- 2 N Aromatic NH or Aromatic Base H Her Solvent Cor Br Ringp/ si- XH Electrophiles 65 R3 Sl R3 Sl US 7,915,283 B2 76 -continued -continued HNRzRy Cu" (2 eq.) MeO (3.3-3.0 eq.) K2CO3 (2 eq.) 145° C. e- \ O S 5 2 copper bronze and KOH N / \ HeN f N Cu, KOH N C H R- R3 1NN 2 N 10 H MeO R4 e 1. MeOCCOCl, AICl R4 = NRZRy where He R4 is heteroaryl or amino 15 N f \ 2. K2CO3, MeOH as defined by the invention N COCOWA H N -- R-R - N 2 N H Cor Br MeO O OH 1

25 HNRzRy Cu" (2 eq.) (3.3-3.0 eq.) K2CO3 (2 1459 C. Ns ( \ 2 copper bronze and KOH 30 COCOWA R- R3 1NN an H As shown in Schemes 12 and 13, a mixture of halo-indole 35 or halo-azaindole intermediate, 1-2 equivalents of copper R4 powder, with 1 equivalent preferred for the 4-F,6-azaindole R4 = NRzRy where series and 2 equivalents for the 4-methoxy,6-azaindole series; R4 is heteroaryl or amino 1-2 equivalents of potassium carbonate, with 1 equivalent as defined by the invention preferred for the 4-F,6-azaindole series and 2 equivalents for 40 the 4-methoxy,6-azaindole series; and a 2-30 equivalents of the corresponding heterocyclic reagent, with 10 equivalents preferred; was heated at 135-160° C. for 4 to 9 hours, with 5 Scheme 13 hours at 160° C. preferred for the 4-F,6-azaindole series and 7 hours at 135° C. preferred for the 4-methoxy,6-azaindole Rs? 45 series. The reaction mixture was cooled to room temperature N f \ He and filtered through filter paper. The filtrate was diluted with N Cu, KOH methanol and purified either by preparative HPLC or silica gel. In many cases no chromatography is necessary, the prod Cl, Br, I, or OTf N 50 uct can be obtained by crystallization with methanol. e RX Alternatively, the installation of amines or N linked het is N f 1. MeOCCOCl, AICl eroaryls may be carried out by heating 1 to 40 equivalents of N \ He2. K2CO3, MeOH the appropriate amine and an equivalent of the appropriate N aza indole chloride, bromide or iodide with copper bronze R4 55 (from 0.1 to 10 equivalents (preferably about 2 equivalents) O OH and from 1 to 10 equivalents of finely pulverized potassium hydroxide (preferably about 2 equivalents). Temperatures of 120° to 200 may be employed with 140-160° generally preferred. For Volatile starting materials a sealed reactor may 60 be employed. The reaction is most commonly used when the halogen being displaced is at the 7-position of a 6-aza or 4-azaindole but the method can work in the 5-aZaseries or when the halogen is at a different position (4-7 position pos (RH is a heteroarylor amine with free N-H) sible). As shown above the reaction can be employed on R = R2-R4 for azaindoles 65 azaindoles unsubstituted at position 3 or intermediates which or R3-Rs for indoles contain the dicarbonyl or the intact dicarbonyl piperidine alkene. US 7,915,283 B2 77 78 34(5), 1031 provide methods for preparing indoles with sub stituents at the 7-position. The Fukuda references provide methods for functionalizing the C-7 position of indoles by either protecting the indole nitrogen with 2,2-diethyl pro panoyl group and then deprotonating the 7-position with sec/ 1) sec Buli --- Buliin TMEDA to give an anion. This anion may be quenched 2) DMF with DMF, formaldehyde, or carbon dioxide to give the alde hyde, benzyl alcohol, or carboxylic acid respectively and the protecting group removed with aqueoust butoxide. Similar 10 transformations can be achieved by converting indoles to

indoline, lithiation at C-7 and then reoxidation to the indole such as described in the Iwao reference above. The oxidation level of any of these products may be adjusted by methods 15 well known in the art as the interconversion of alcohol, alde hyde, and acid groups has been well studied. It is also well understood that a cyano group can be readily converted to an aldehyde. A reducing agent such as DIBALH in hexane Such as used in Weyerstahl, P.; Schlicht, V.: Liebigs Ann/Recl. 1997, 1, 175-177 or alternatively catecholalane in THF such as used in Cha, J.S.: Chang, S.W.; Kwon, O.O.; Kim, J. M.: Synlett. 1996, 2, 165-166 will readily achieve this conversion to provide intermediates such as 44 (Scheme 16). Methods for synthesizing the nitriles are shown later in this application. It 25 is also well understood that a protected alcohol, aldehyde, or acid group could be present in the starting azaindole and carried through the synthetic steps to a compound of Formula I in a protected form until they can be converted into the desired substituent at R through R. For example, a benzyl 30 alcohol can be protected as a benzyl ether or silyl ether or other alcohol protecting group: an aldehyde may be carried as an acetal, and an acid may be protected as an ester or ortho ester until deprotection is desired and carried out by literature 35 methods.

The preparation of a key aldehyde intermediate, 43, using a procedure adapted from the method of Gilmore et. Al. Synlett 1992, 79-80 is shown in Scheme 16 above. The alde hyde substituent is shown only at the R position for the sake of clarity, and should not be considered as a limitation of the methodology. The bromide or iodide intermediate is con Verted into an aldehyde intermediate, 43, by metal-halogen Step 1 exchange and Subsequent reaction with dimethylformamide H-Pol-C or in an appropriate aprotic solvent. Typical bases used include, Na2S, MeOH-HO but are not limited to, alkyl lithium bases such as n-butyl lithium, sec butyl lithium or tert butyl lithium or a metal such as lithium metal. A preferred aprotic solventis THF. Typically the transmetallation is initiated at -78°C. The reaction may be allowed to warm to allow the transmetalation to go to completion depending on the reactivity of the bromide inter mediate. The reaction is then recooled to -78°C. and allowed to react with dimethylformamide. (allowing the reaction to 55 warm may be required to enable complete reaction) to pro vide an aldehyde which is elaborated to compounds of For mula I. Other methods for introduction of an aldehyde group to form intermediates of formula 43 include transition metal catalyzed carbonylation reactions of suitable bromo, trifluo 60 romethane Sulfonyl, or stannyl azaindoles. Alternative the aldehydes can be introduced by reacting indolyl anions or indolyl Grignard reagents with formaldehyde and then oxi dizing with MnO, or TPAP/NMO or other suitable oxidants to provide intermediate 43. 65 The methodology described in T. Fukuda et al. Tetrahe 46 dron 1999, 55,9151 and M. Iwao et. Al. Heterocycles 1992, US 7,915,283 B2 79 80 -continued The amino group of the azaindole, 46, can also be con verted to a bromide via diazotization and displacement by bromide as described in Raveglia, L. F.; Giardina, G. A.; Grugni, M.; Rigolio, R.; Farina, C.; J. Heterocycl. Chem. 1997, 34(2), 557-559: Talik, T.: Talik, Z.; Ban-Oganowska, H.; Synthesis 1974, 293; and Abramovitch, R. A.; Saha, M.: Can. J. Chem. 1966, 44, 1765.

10 Scheme 18 47 1) Conversion of amino group N to halide, hydroxy or n protected hydroxy Step G Step 1 of Scheme 17 shows the reduction of a nitro 2) coupling to aryls or heteroaryls group on 45 to the amino group of 46. Although shown on 15 2 via halide or triflate (from hydroxy) N or conversion to cyano (nitrile), position 4 of the azaindole, the chemistry is applicable to or acid, then to compounds of NH2 Formula I other nitro isomers. The procedure described in Ciurla, H.; 3) installation of oxopiperazine acetic Puszko, A.; Khim Geterotsikl Soedin 1996, 10, 1366-1371 acid as described. uses hydrazine Raney-Nickel for the reduction of the nitro Steps 2 and 3 may be reversed as group to the amine. Robinson, R. P.; Donahue O. K. M.; Son, appropriate P.S.; Wagy, S. D.J. Heterocycl. Chem. 1996,33(2), 287-293

describes the use of hydrogenation and Raney Nickel for the reduction of the nitro group to the amine. Similar conditions are described by Nicolai, E.; Claude, S.; Teulon, J. M.; J. Heterocycl. Chem. 1994, 31(1), 73-75 for the same transfor 25 mation. The following two references describe some trimeth ylsilyl sulfur or chloride based reagents which may be used for the reduction of a nitro group to an amine. Hwu, J. R.; Wong, F. F.; Shiao, M. J.J. Org. Chem. 1992, 57(19), 5254 30 5255; Shiao, M.J.; Lai, L.L.: Ku, W. S.; Lin, P.Y.; Hwu, J. R.: J. Org. Chem. 1993, 58(17), 4742-4744. Step 2 of Scheme 17 describes general methods for con version of amino groups on azaindoles or indoles into other functionality. Scheme 18 also depicts transformations of an 35 The preparation of 4-amino 4-azaindole and 7-methyl-4- amino azaindole into various intermediates and compounds azaindole is described by Mahadevan, I.; Rasmussen, M. J. of Formula I. Heterocycl. Chem. 1992, 29(2), 359-67. The amino group of The amino group at any position of the azaindole, such as the 4-amino 4-azaindole can be converted to halogens, 46 (Scheme 17), may be converted to a hydroxy group using hydroxy, protected hydroxy, triflate, as described above in sodium nitrite, sulfuric acid, and water via the method of 40 Schemes 17-18 for the 4-amino compounds or by other meth Klemm, L. H.; Zell, R.; J. Heterocycl. Chem. 1968, 5, 773. ods known in the art. Protection of the indole nitrogen of the Bradsher, C. K. Brown, F. C.; Porter, H. K. J. Am. Chem. 7-methyl-4-azaindole via acetylation or other strategy fol Soc. 1954, 76,2357 describes how the hydroxy group may be lowed by oxidation of the 7-methyl group with potassium alkylated under standard or Mitsonobu conditions to form 45 permanganate or chromic acid provides the 7-acid/4-N-OX ethers. The amino group may be converted directly into a ide. Reduction of the N-oxide, as described below, provides methoxy group by diazotization (sodium nitrite and acid) and an intermediate from which to install various substituents at trapping with methanol. position R. Alternatively the parent 4-azaindole which was The amino group of an azaindole, Such as 46, can be con prepared as described in Mahadevan, I., Rasmussen, M. J. verted to fluoro via the method of Sanchez using HPF, 50 Heterocycl. Chem. 1992, 29(2), 359-67 could be derivatized NaNO, and water by the method described in Sanchez, J. P.; at nitrogen to provide the 1-(2,2-diethylbutanoyl)azaindole Gogliotti, R. D.J. Heterocycl. Chem. 1993,30(4), 855-859. which could then be lithiated using TMEDA/sec Bulli as Other methods useful for the conversion of the amino group to described in T. Fukuda et. Al. Tetrahedron 1999, 55,9151 fluoro are described in Rocca, P.; Marsais, F. Godard, A.; 9162; followed by conversion of the lithio species to the Queguiner, G.; Tetrahedron Lett. 1993, 34(18), 2937-2940 55 7-carboxylic acid or 7-halogen as described. Hydrolysis of and Sanchez, J. P.; Rogowski, J. W.; J. Heterocycl. Chem. the N-amide using aqueous tert-butoxide in THF regenerates 1987, 24, 215. the free NH indole which can now be converted to compounds The amino group of the azaindole, 46, can also be con of Formula I. The chemistry used to functionalize position 7 verted to a chloride via diazotization and chloride displace can also be applied to the 5 and 6 indole series. ment as described in Ciurla, H., Puszko, A.; Khim Geterotsikl 60 Scheme 19 shows the preparation of a 7-chloro-4-azain Soedin 1996, 10, 1366-1371 or the methods in Raveglia, L. F.; dole, 50, which can be converted to compounds of Formula I Giardina, G. A.; Grugni, M.: Rigolio, R.; Farina, C.; J. Het by the chemistry previously described, especially the palla erocycl. Chem. 1997, 34(2), 557-559 or the methods in Mat dium catalyzed tin and boron based coupling methodology sumoto, J. I. Miyamoto, T.; Minamida, A.; Mishimura, Y.: described above. The chloro nitro indole, 49, is commercially Egawa, H.; Mishimura, H.; J. Med. Chem. 1984, 27(3), 292; 65 available or can be prepared from 48 according to the method or as in Lee, T. C.; Salemnick, G.; J. Org. Chem. 1975, 24, of Delarge, J.; Lapiere, C. L. Pharm. Acta Helv. 1975, 50(6), 3608. 188-91. US 7,915,283 B2 81 82 -continued Scheme 19 R2 N N R Steps N --- n Formula I SOCl. 2 N compounds He 2 NO R. Rs OH 48 10 The following references describe the synthesis of 7-halo or 7 carboxylic acid, or 7-amido derivatives of 5-azaindoline s 2n MgBr which can be used to construct compounds of Formula I. He Bychikhina, N. N.; Azimov, V. A.; Yakhontov, L. N. Khim. 21 NO THF Geterotsikd. Soedin. 1983, 1,58–62: Bychikhina, N. N.; Azi 15 mov, V.A.; Yakhontov, L.N. Khim. Geterotsikd. Soedin. 1982, C 3,356-60; Azimov, V. A.; Bychikhina, N. N.; Yakhontov, L. 49 N. Khim. Geterotsikd. Soedin. 1981, 12, 1648-53: Spivey, A. N C.; Fekner, T.: Spey, S. E.; Adams, H. J. Org. Chem. 1999, N-\ 64(26), 9430-9443; Spivey, A. C.; Fekner, T.: Adams, H. He- Formula I Tetrahedron Lett. 1998, 39(48), 8919-8922. The methods 2 N He compounds described in Spivey et al. (preceding two references) for the H preparation of 1-methyl-7-bromo-4-azaindoline can be used C to prepare the 1-benzyl-7-bromo-4-azaindoline, 54, shown 50 25 below in Scheme 21. This can be utilized in Stille or Suzuki couplings to provide 55, which is deprotected and dehydro genated to provide 56. Other useful azaindole intermediates, Scheme 20, below, shows another synthetic route to sub such as the cyano derivatives, 57 and 58, and the aldehyde stituted 4-aza indoles. The 3-aminopyrrole, 51, was reacted to derivatives, 59 and 60, can then be further elaborated to provide the pyrrolopyridinone, 52, which was then reduced to 30 compounds of Formula I. give the hydroxy azaindole, 53. The pyrrolo2,3-bipyridines described were prepared according to the method of Britten, A. Z. Griffiths, G. W. G. Chem. Ind. (London) 1973, 6,278. Scheme 21 The hydroxy azaindole, 53, can then be converted to the N Tin or triflate then further reacted to provide compounds of Formula 35 Suzuki coupling I. He 2 N BZ

Scheme 20 Br 40 O O 54

HN N 1) Hydrogenation N R OEt n 2) Pd n N He 45 dehydrogenation / \ HeR3 2 N 2 N BZ H R4 R4 Rs R. 55 56 51 50 H R2 N N Reduction N cyanation R Hs He 21 N R3 BZ 55 O Rs Br 52 54

N 1) Hydrogenation N R N 60 n 2) Pd n N N R 1) triflation He -- dehydrogenation 2) Cyanide displacement 2 N 2 N R 21 or coupling BZ H (H R5 CN CN 65 57 58 US 7,915,283 B2 84 -continued The preparation of azaindole oxoacetyl or oxo piperidines N 1 eq Alkyl lithium N then either another with carboxylic acids can be carried out from nitrile, alde equivalent or Li metal hyde, or anion precursors via hydrolysis, oxidation, or trap He ping with CO respectively. As shown in the Scheme 22, Step 2 N 1, or the scheme below step a 12 one method for forming the BZ nitrile intermediate, 62, is by cyanide displacement of a halide Br in the aza-indole ring. The cyanide reagent used can be 54 Sodium cyanide, or more preferably copper or Zinc cyanide. N 1) Hydrogenation N The reactions may be carried out in numerous solvents which n 2) Pd n N 10 are well known in the art. For example DMF is used in the Hedehydrogenation case of copper cyanide. Additional procedures useful for car 2 N 21 N BZ H rying out step 1 of Scheme 24 are Yamaguchi, S.:Yoshida, M.: CHO CHO Miyajima, I.: Araki, T.; Hirai, Y.; J. Heterocycl. Chem. 1995, 15 32(5), 1517-1519 which describes methods for copper cya 59 60 nide;Yutilov, Y.M., Svertilova, I.A.; Khim Geterotsikl Soedin 1994, 8, 1071-1075 which utilizes potassium cyanide; and Alternatively the 7-functionalized 5-azaindole derivatives Prager, R. H.; Tsopelas, C.; Heisler, T.; Aust. J. Chem. 1991, may be obtained by functionalization using the methodolo 44 (2), 277-285 which utilizes copper cyanide in the presence gies of T. Fukuda et al. Tetrahedron 1999, 55,9151 and M. of MeCS(O)F. The chloride or more preferably abromide on Iwao et. Al. Heterocycles 1992, 34(5), 103 described above the azaindole may be displaced by Sodium cyanide in dioxane for the 4 or 6 azaindoles. The 4 or 6 positions of the 5 aza via the method described in Synlett. 1998, 3, 243-244. Alter indoles can be functionalized by using the azaindole N-oxide. natively, Nickel dibromide, Zinc, and triphenyl phosphine in The conversion of indoles to indolines is well known in the can be used to activate aromatic and heteroaryl chlorides to art and can be carried out as shown or by the methods 25 displacement via potassium cyanide in THF or other suitable described in Somei, M.; Saida, Y.; Funamoto, T.; Ohta, T. Chem. Pharm. Bull. 1987, 35.(8), 3146-54; M. Iwao et. Al. solvent by the methods described in Eur. Pat. Appl. , 831083, Heterocycles 1992, 34(5), 1031; and Akagi, M.: Ozaki, K. 1998. Heterocycles 1987, 26(1), 61-4. The conversion of the cyano intermediate, 62, to the car 30 boxylic acid intermediate, 63, is depicted in step 2, Scheme

22 or in step a 12, Scheme 23. Many methods for the conver sion of nitrites to acids are well known in the art and may be employed. Suitable conditions for step 2 of Scheme 22 or the conversion of intermediate 65 to intermediate 66 below 35 employ potassium hydroxide, water, and an aqueous alcohol Such as ethanol. Typically the reaction must be heated at refluxing temperatures for one to 100 h. Other procedures for hydrolysis include those described in: Shiotani, S.; Taniguchi, K. J. Heterocycl. Chem. 1997, 40 34(2), 493-499; Boogaard, A. T.; Pandit, U. K.: Koomen, G.-J.; Tetrahedron 1994,50(8), 2551-2560; Rivalle, C.: Bisa gni, E.: Heterocycles 1994, 38(2), 391-397: Macor, J. E.; Post, R.; Ryan, K.J. Heterocycl. Chem. 1992, 29(6), 1465 45 1467. The acid intermediate, 66 (Scheme 23), may then be esteri fied using conditions well known in the art. For example, reaction of the acid with diazomethane in an inert solvent such as ether, dioxane, or THF would give the methyl ester. 50 Intermediate 67 may then be converted to intermediate 68 according to the procedure described in Scheme 2. Interme diate 68 may then be hydrolyzed to provide intermediate 69.

55 Scheme 23 R R3 60 21 Step a 11 --- N N R

Br R6 65 7, 64 US 7,915,283 B2 86 -continued tional group preparations 2" ed. New York: Wiley-VCH, R 1999. One preferred method is the use of silver nitrate or silver oxide in a solvent such as aqueous or anhydrous metha R3 21 Step a 12 nol at a temperature of ~25° C. or as high as reflux. The --- reaction is typically carried out for one to 48 hand is typically N monitored by TLC or LC/MS until complete conversion of N R product to starting material has occurred. Alternatively, KmnO or CrO/HSO could be utilized. CN R6

16, 65 10

R2 Step a13 15 -- Step a33 N N R

R6 70 HO O 17, 66 R2 O Y A R2 25 R3 W

N1 O R3 21 N R Step a 4 N step as N R 30 R6 HO O

R6 69 RO O Scheme 25 gives a specific example of the oxidation of an 35 aldehyde intermediate, 70a, to provide the carboxylic acid intermediate, 69a.

Scheme 25 40 F O Y A

21 W HerAgNO3 MeOH, H2O N O RT-100° C. 45 S. N H CHO 70a

F O w1.

55 N1 O N N H 20, 69 HO O 60 69a As shown in Scheme 24, step a13 another preparation of the indoleoxoacetylalkenylpiperidine 7-carboxylic acids, 69. Alternatively, intermediate 69 can be prepared by the is carried out by oxidation of the corresponding 7-carboxal nitrile method of synthesis carried out in an alternative order dehyde, 70. Numerous oxidants are suitable for the conver as shown in Scheme 26. The nitrile hydrolyis step can be sion of aldehyde to acid and many of these are described in 65 delayed and the nitrile carried through the synthesis to pro standard organic chemistry texts such as: Larock, Richard C. vide a nitrile which can behydrolyzed to provide the free acid, Comprehensive organic transformations: a guide to func 69, as above. US 7,915,283 B2 87 88 -continued Scheme 26

N Step a3 N R Her

CN R6 10 65

R2 O 15

R3 21 C Step H The direct conversion of nitrites, such as 72, to amides, such as 73, shown in Scheme 27, Step H, can be N O step a4 carried out using the conditions as described in Shiotani, S.; N R 20 Taniguchi, K.J. Heterocycl. Chem. 1996, 33(4), 1051-1056 (describes the use of aqueous sulfuric acid); Memoli, K. A.; CN R6 Tetrahedron Lett. 1996, 37(21), 3617-3618: Adolfsson, H.; 71 Waernmark, K.; Moberg, C.; J. Org. Chem. 1994, 59(8), 2004-2009; and El Hadri, A.; Leclerc. G.; J. Heterocycl. Chem. 1993,30(3), 631-635. 25 Step I for NH2 R2 O Shiotani, S.; Taniguchi, K. J. Heterocycl. Chem. 1997, Y A 34(2), 493-499; Boogaard, A. T.; Pandit, U. K.: Koomen, R3 21 W G.-J.; Tetrahedron 1994,50(8), 2551-2560; Rivalle, C.: Bisa Stepal 2 30 gni, E.: Heterocycles 1994, 38(2), 391-397: Macor, J. E.; N O He N R Post, R.; Ryan, K.J. Heterocycl. Chem. 1992, 29(6), 1465 1467. CN R6 Step J 72

Step al6 Her

Step H 60 The following scheme (28A) shows an example for the preparation of 4-fluoro-7 substituted azaindoles from a known starting materials. References for the Bartoli indole 65 synthesis were mentioned earlier. The conditions for trans formation to the nitrites, acids, aldeheydes, heterocycles and amides have also been described in this application. US 7,915,283 B2 89 90

Scheme 28A Either:

1) vinyl magnesium bromide N N (Bartoli) He Na2NN NO H C C Prepared as in U.S. Pat. No. 5,811,432 Or: F 1) Vinylmagnesium chloride 1) Nitro reduction, N 2) toluene, 110 deg C. (SnCl2, HCl or alternatives) D Her2) SOCI2, Na2- N NO Ns S. C C no Prepared as in U.S. Pat. No. 5,811,432 Tetrahedron Letters 1986, 27,837.

F 1) methyl oxalylchloride, AICI3 N N (up to 5 eqs) 2) KOH hydrolysis 3) Piperazine N 21 N or methylpiperazine coupling as above H C Boron or tin mediated couplings cyano diplacement (Suzuki, Stille) (CuCN or KCN or NaCN

Hydrolysis DIBAL. (reduction) C-7 Heterocycles C-7Amides -ie- C-7Acid C-7 Aldehyde / C-7 Heterocycles US 7,915,283 B2 92 ences 41-53 but this list is not limiting. Some carboxylic acid to amine coupling reagents which are applicable are EDC, Diisopropylcarbodiimide or other carbodiimides, PyBop (benzotriazolyloxytris(dimethylamino) phosphonium hexafluorophosphate), 2-(1H-benzotriazole-1-yl)-1,1,3,3- tetramethyl uronium hexafluorophosphate (HBTU). A par ticularly useful method for azaindole 7-carboxylic acid to J amide reactions is the use of carbonyl imidazole as the cou Step a 17 pling reagent as described in reference 53. The temperature of 10 this reaction may be lower than in the cited reference, from 80° C. (or possibly lower) to 150° C. or higher. A more specific application is depicted in Scheme 30.

15 Scheme 3 () R2 O Y A R3 N W 1,1' carbonyldimidazole RNH2, THF, reflux N 21 R O

R6 HO O 25 74 R2 O A 1. R3 N W

N O 30 21 R Step a 18 Her R6 R-N O H 75 35

The following four general methods provide a more detailed description for the preparation of indolecarboamides and these methods were employed for the synthesis of com pounds of Formula I. Method 1: To a mixture of an acid intermediate, Such as 75. (1 equiv), an appropriate amine (4 equiv.) and DMAP 0.1 tp 1 eq dis solved CHCl (1 mL) was added EDC (1 eq). The resulting mixture should be shaken at rt for ~12 h, and then evaporated in vacuo. The residue was dissolved in MeCH, and subjected to preparative reverse phase HPLC purification. Method 2: To a mixture of an appropriate amine (4 equiv.) and HOBT 50 (16 mg, 0.12 mmol) in THF (0.5 mL) should be added an acid intermediate, such as 74, and NMM ~1 eq followed by EDC. Steps aé, a 17, and a18 encompasses reactions and condi The reaction mixture was shaken at rt for 12 h. The volatiles tions for 1', 2' and 3° amide bond formation as shown in were evaporated in vacuo; and the residue dissolved in MeOH Schemes 28 and 29 which provide compounds such as those and subjected to preparative reverse phase HPLC purifica of Formula 73. 55 tion. The reaction conditions for the formation of amide bonds Method 3: encompass any reagents that generate a reactive intermediate To a mixture of an acid intermediate. Such as 74, amine (4 for activation of the carboxylic acid to amide formation, for equiv.) and DEPBT (prepared according to Li, H.; Jiang, X. example (but not limited to), acyl halide, from carbodiimide, Ye.Y.; Fan, C.; Todd, R.; Goodman, M. Organic Letters 1999, acyl iminium salt, symmetrical anhydrides, mixed anhy 60 1,91; in DMF was added TEA. The resulting mixture should drides (including phosphonic/phosphinic mixed anhydrides), be shaken at rt for 12 h; and then diluted with MeOH and active esters (including silyl ester, methyl ester and thioester), purified by preparative reverse phase HPLC. acyl carbonate, acyl azide, acyl Sulfonate and acyloxy Method 4: N-phosphonium salt. The reaction of the indole carboxylic A mixture of an acid intermediate, such as 74, and of acids with amines to form amides may be mediated by stan 65 1,1-carbonyldiimidazole in anhydrous THF was heated to dard amide bond forming conditions described in the art. reflux under nitrogen. After 2.5 h, amine was added and Some examples for amide bond formation are listed in refer heating continued. After an additional period of 3-20 hat US 7,915,283 B2 93 94 reflux, the reaction mixture was cooled and concentrated in locate literature preparations of known amines or procedures vacuo. The residue was purified by chromatography on silica to synthesize new amines. These procedures are then carried gel to provide a compound of Formula I. out by one with typical skill in the art to provide the com In addition, the carboxylic acid may be converted to an acid pounds of Formula I for use as antiviral agents. chloride using reagents such as thionyl chloride (neator in an 5 inert Solvent) or oxalyl chloride in a solvent such as benzene, As shown below in Scheme 32, step a13, suitable substi toluene, THF, or CHC1. The amides may alternatively, be tuted azaindoles, such as the bromoazaindole intermediate, formed by reaction of the acid chloride with an excess of 76, may undergo metal mediated couplings with aryl groups, ammonia, primary, or secondary amine in an inert Solvent heterocycles, or vinyl Stannanes to provide compounds of such as benzene, toluene, THF, or CHCl2 or with stoichio 10 Formula I wherein Rs is aryl, heteroaryl, or heteroalicyclic for metric amounts of amines in the presence of a tertiary amine example. The bromoazaindole intermediates, 76 (or azain Such as triethylamine or a base such as pyridine or 2.6-luti dole triflates or iodides) may undergo Stille-type coupling dine. Alternatively, the acid chloride may be reacted with an with heteroarylstannanes as shown in Scheme 32, step a13. amine under basic conditions (Usually sodium or potassium Conditions for this reaction are well known in the art and hydroxide) in Solvent mixtures containing water and possibly 15 references 68-70 as well as reference 52 provide numerous a miscible co solvent such as dioxane or THF. Scheme 25B conditions in addition to the specific examples provided in depicts a typical preparation of an acid chloride and deriva Scheme 14 and in the specific embodiments. It can be well tization to an amide of Formula I. Additionally, the carboxylic recognized that an indole Stannane could also couple to a acid may be converted to an esterpreferably a methyl or ethyl heterocyclic or aryl halide or triflate to construct compounds ester and then reacted with an amine. The ester may beformed of Formula I. Suzuki coupling (reference 71) between the by reaction with diazomethane or alternatively trimethylsilyl bromo intermediate, 76, and a suitable boronate could also be diazomethane using standard conditions which are well employed and some specific examples are contained in this known in the art. References and procedures for using these or application. other ester forming reactions can be found in reference 52 or 54. 25 Additional references for the formation of amides from acids are: Norman, M. H.; Navas, F. III: Thompson, J. B.: Scheme 32 Rigdon, G. C.; J. Med Chem. 1996, 39(24), 4692-4703; R2 O Hong, F.; Pang, Y.-P.; Cusack, B.: Richelson, E.; J. Chem. R w1. A Soc., Perkin Trans 1 1997, 14,2083-2088: Langry, K.C.; Org. 30 3 21 Step a13 Prep. Proc. Int. 1994, 26(4), 429-438: Romero, D. L.; Morge, R. A.; Biles, C.: Berrios-Pena, N.; May, P. D.; Palmer, J. R.: N O Johnson, P. D.; Smith, H. W.; Busso, M.; Tan, C.-K.; Voor Sa R man, R. L.; Reusser. F.; Althaus, I. W.; Downey, K. M.; et al.: Br R6 J. Med. Chem. 1994, 37(7), 999-1014; Bhattacharjee, A.; 35 Mukhopadhyay, R.; Bhattachariya, A.; Indian J. Chem., Sect 76 B 1994, 33(7), 679-682. It is well known in the art that heterocycles may be pre pared from an aldehyde, carboxylic acid, carboxylic acid R2 O ester, carboxylic acid amide, carboxylic acid halide, or cyano 40 A moiety or attached to another carbon substituted by a bromide or other leaving group such as a triflate, mesylate, chloride, ne W1 iodide, orphosphonate. The methods for preparing Such inter N O mediates from intermediates typified by the carboxylic acid N R intermediate, 69, bromo intermediate, 76, or aldehyde inter 45 mediate, 70 described above are known by a typical chemist Rs R6 practitioner. The methods or types of heterocycles which may be constructed are described in the chemical literature. Some representative references for finding such heterocycles and I their construction are included in reference 55 through 67 but 50 should in no way be construed as limiting. However, exami nation of these references shows that many versatile methods are available for synthesizing diversely substituted hetero cycles and it is apparent to one skilled in the art that these can be applied to prepare compounds of Formula I.Chemists well 55 versed in the art can now easily, quickly, and routinely find Scheme 33 numerous reactions for preparing heterocycles, amides, X O oximes or other substituents from the above mentioned start Y A Het-SnBus N W dioxane, 120° C. ing materials by searching for reactions or preparations using --- a conventional electronic database Such as Scifinder (Ameri 60 O can Chemical Society), Crossfire (Beilstein), Theilheimer, or N O Het-B(OH)2 21 N Pd(PPh)4, K2CO3 Reaccs (MDS). The reaction conditions identified by such a H DMF, Water search can then be employed using the Substrates described in Br this application to produce all of the compounds envisioned X = F, OMe and covered by this invention. In the case of amides, com 65 mercially available amines can be used in the synthesis. Alter natively, the above mentioned search programs can be used to US 7,915,283 B2 95 96 -continued reactions. The trityl could be replaced with an alternate pro X O tecting group Such as a monomethoxy trity1, CBZ., benzyl, or appropriate silyl group if desired. Reference 73 demonstrates N the preparation of oxazoles containing a triflouoromethyl 5 moiety and the conditions described therein demonstrates the N 2 N O synthesis of oxazoles with fluorinated methyl groups H appended to them. Het The aldehyde could also be reacted with a metal or Grig 10 nard (alkyl, aryl, or heteroaryl) to generate secondary alco hols. These would be efficacious or could be oxidized to the As shown in Scheme 34, step a14, aldehyde intermediates, ketone with TPAP or MnO, or PCC for example to provide 70, may be used to generate numerous compounds of For ketones of Formula I which could be utilized for treatment or mula I. The aldehyde group may be a precursor for any of the reacted with metal reagents to give tertiary alcohols or alter substituents R through Rs but the transormation for Rs is 15 natively converted to oximes by reaction with hydroxylamine depicted above for simplicity. The aldehyde intermediate 70, hydrochlorides in ethanolic solvents. Alternatively the alde may be reacted to become incorporated into a ring as hyde could be converted to benzyl amines via reductive ami nation. An example of oxazole formation via a Tosmic reagent is shown below in Scheme 35. The same reaction Scheme 34 2O would work with aldehydes at other positions and also in the R2 O 5 and 6 aza indole series. A 1 R3 21 W Step al4

K2CO3, MeOH R6 He TOSMIC O H 70

described in the claims or be converted into an acyclic group. The aldehyde, 70, may be reacted with a Tosmic based reagent to generate oxazoles (references 42 and 43 for 45 example). The aldehyde, 70, may be reacted with a Tosmic 78 reagent and than an amine to give imidazoles as in reference 72 or the aldehyde intermediate, 70, may be reacted with hydroxylamine to give an oxime which is a compound of Formula I as described below. Oxidation of the oxime with 50 NBS, t-butyl hypochlorite, or the other known reagents would Scheme 36 shows in step a15, a cyano intermediate. Such as provide the N-oxide which react with alkynes or 3 alkoxy 62, which could be directly converted to compounds of For vinyl esters to give isoxazoles of varying Substitution. Reac mula I via heterocycle formation or reaction with organome tion of the aldehyde intermediate 70, with the known reagent, tallic reagents. 77 (reference 70) shown below under basic conditions would 55 provide 4-aminotrityl oxazoles.

77 60 Step a15 --

Removal of the trityl group would provide 4-amino 65 oxazoles which could be substituted by acylation, reductive alkylation or alkylation reactions or heterocycle forming US 7,915,283 B2 97 98 -continued -continued

TMS-CHN MeOHAPH Her then HOAc

Scheme 37 shows a method for acylation of a cyanoindole intermediate of formula 65 with oxalyl chloride which would give acid chloride, 79, which could then be coupled with the 15 appropriate amine in the presence of base to provide 80.

CCOCOC -- 25

30 Tetrazole alkylation with alkylhalides would be carried out prior to azaindole acylation as shown in Scheme 39. Interme

He diate 65 could be converted to tetrazole, 83, which could be alkylated to provide 84. Intermediate 84 could then be acy lated and hydrolyzed to provide 85 which could be subjected 35 to amide formation conditions to provide 86. The group appended to the tetrazole may be quite diverse and still exhibit impressive potency.

O 40 W

R. 45 R6 8O R NHCl, NaN DMF The nitrile intermediate, 80, could be converted to the 50 tetrazole of formula 81, which could then be alkylated with trimethylsilyldiazomethane to give the compound of formula 82 (Scheme 38).

55 R R3 N NHCl, NaNa, DMF R- X, K2CO3 60 2 R HeCHCN

R6 N N N W / 65 N-NH US 7,915,283 B2 99 100 -continued -continued

R R3 N CCOCOC CCOC He Nn 2 CHCl2 Toluene R then H'THF 1N R6 W / 10 N-N V R 84 15

TMS-CHN MeOHAPH Her

EDAC, H-W-A He NMM, DMAP, DMF

Nab N OMe 89

A 7-cyanoindole, such as 80, could be efficiently converted to the imidate ester under conventional Pinner conditions using 1,4-dioxane as the solvent. The imidate ester can be reacted with nitrogen, oxygen and Sulfur nucleophiles to pro vide C7-substituted indoles, for example: imidazolines, ben 86 Zimidazoles, aZabenzimidazoles, oxazolines, oxadiazoles, 45 thiazolines, triazoles, pyrimidines and amidines etc. For Scheme 40 shows that an oxadiazole such as, 88, may be example the imidate may be reacted with acetyl hydrazide prepared by the addition of hydroxylamine to the nitrile, 80, with heating in a nonparticipating solvent Such as dioxane, followed by ring closure of intermediate 87 with phosgene. THF, or benzene for example. (aqueous base or aqueous base Alkylation of oxadiazole, 88, with trimethylsilyldiaz 50 in an alcoholic solvent may need to be added to effect final omethane would give the compound of formula 89. dehydrative cyclization in some cases) to form a methyl tri azine. Other hydrazines can be used. Triazines can also be installed via coupling of Stannyl triazines with 4, 5, 6, or 7-bromo or chloroazaindoles. The examples give an example 55 of the formation of many of these heterocycles.

Scheme 40 REFERENCES R2 O A (1) Das, B. P: Boykin, D. W.J.Med. Chem. 1977, 20, 531. R3 N w 1 60 (2) Czamy, A.; Wilson, W. D.; Boykin, D.W. J. Heterocyclic HNOHHCl, EtOH Chem. 1996, 33, 1393. N O He (3) Francesconi, I.; Wilson, W. D.; Tanious, F. A.: Hall, J. E.; 2 R Bender, B.C.: Tidwell, R. R.; McCurdy, D.; Boykin, D.W. CN R6 J. Med. Chem. 1999, 42, 2260. 65 Scheme 41 shows addition of either hydroxylamine or 80 hydroxylamine acetic acid to aldehyde intermediate 90 may give oximes of Formula 91. US 7,915,283 B2

-continued O 1 A W 5 R'NH-NH HNOHHCI, EtOH R3, R2 ly -- Hip- O O O N R HNOCH2COHHCl, EtOH R6 90 10 \

15 O - A W

R3, R2 ly O 2O N R 91 N 1.Ne5 R6 An acid may be a precursor for substituents R through Rs R when it occupies the corresponding position such as Rs as ' shown in Scheme 42.

30 O A 1. W R3, R2 ly NH-OH 35 O O N R R3, R2 ly R6 HOOC \ 40 R

O 45 W - A

N R 50 l 6

or and 55 O O A - A w1. W R3, R2 R3, R2 ly O 60 ly O O R O R \ R6 Nin \ R6

65 R US 7,915,283 B2 103 104 man, B.; Despuy, M. E.; Rapoport, H.; J. Am. Chem. Soc. Scheme 42 1965, 87, 3530 will provide the dimethylamino compound R2 O shown. A Step B" shows displacement with potassium cyanide ne W1 would provide the cyano derivative according to the method Step a 16 described in Miyashita, K.: Kondoh, K. Tsuchiya, K. Miy N O N R abe, H.: Imanishi, T: Chem. Pharm. Bull 1997, 45(5), 932 935 or in Kawase, M.: Sinhababu, A. K. Borchardt, R. T.; R6 10 Chem. Pharm. Bull. 1990, 38(11), 2939-2946. The same HO O transformation could also be carried out using TMSCN and a 69 tetrabutylammonium flouride source as in Iwao, M.; Motoi, R2 O O.; Tetrahedron Lett. 1995, 36(33), 5929-5932. Sodium cya R3 21 W - A nide could also be utilized. 15

N O N R Scheme 43

Rs R6

An acid intermediate, such as 69, may be used as a versatile precursor to generate numerous Substituted compounds. The acid could be converted to hydrazonyl bromide and then a pyrazole via reference 74. One method for general hetero cycle synthesis would be to convert the acid to an alpha bromo ketone (ref 75) by conversion to the acid chloride using stan dard methods, reaction with diazomethane, and finally reac tion with HBr. The alpha bromo ketone could be used to prepare many different compounds of Formula I as it can be converted to many heterocycles or other compounds of For mula I. Alpha amino ketones can be prepared by displacement of the bromide with amines. Alternatively, the alpha bromo ketone could be used to prepare heterocycles not available directly from the aldeheyde or acid. For example, using the conditions of Hulton in reference 76 to react with the alpha bromo ketone would provide oxazoles. Reaction of the alpha bromoketone with urea via the methods of reference 77 would provide 2-amino oxazoles. The alphabromoketone could also be used to generatefurans using beta keto esters (ref78-80) or other methods, pyrroles (from beta dicarbonyls as in ref 81 or by Hantsch methods (ref 82) thiazoles, isoxazoles and imi dazoles (ref 83) example using literature procedures. Cou pling of the aforementioned acid chloride with N-methyl-O- methyl hydroxylamine would provide a “Weinreb Amide' which could be used to react with alkyl lithiums or Grignard reagents to generate ketones. Reaction of the Weinreb anion with a dianion of a hydroxylamine would generate isoxazoles (ref84). Reaction with an acetylenic lithium or other carban ion would generate alkynyl indole ketones. Reaction of this alkynyl intermediate with diazomethane or other diazo com pounds would give pyrazoles (ref 85). Reaction with azide or hydroxylamine would give heterocycles after elimination of water. Nitrile oxides would react with the alkynyl ketone to give isoxazoles (ref 86). Reaction of the initial acid to provide an acid chloride using for example oxalyl chloride or thionyl chloride or triphenyl phosphine/carbon tetrachloride pro vides a useful intermediate as noted above. Reaction of the acid chloride with an alpha ester Substituted isocyanide and 60 base would give 2-substituted oxazoles (ref 87). These could be converted to amines, alcohols, or halides using standard reductions or Hoffman/Curtius type rearrangements. Scheme 43 describes alternate chemistry for installing the oxoacetyl alkenylpiperidine moiety onto the 3 position of the 65 azaindoles. StepA" in Scheme 43 depicts reaction with form aldehyde and dimethylamine using the conditions in Fryd US 7,915,283 B2 105 106 -continued -continued

Step C" of Scheme 43 depicts hydrolysis of the nitrile with sodium hydroxide and methanol would provide the acid via the methods described in Iwao, M.; Motoi, O.; Tetrahedron Lett. 1995, 36(33), 5929-5932 for example. Other basic 15 hydrolysis conditions using either NaOH or KOH as described in Thesing, J.; etal.: Chem. Ber: 1955, 88, 1295 and Geissman, T. A.; Armen, A.; J. Am. Chem. Soc. 1952, 74, 3916. The use of a nitrilase enzyme to achieve the same transformation is described by Klempier N. de Raadt A, Griengl H, Heinisch G, J. Heterocycl. Chem., 1992 29, 93, and may be applicable. Step D" of Scheme 43 depicts an alpha hydroxylation which may be accomplished by methods as described in Hanessian, S.; Wang, W.; Gai, Y.; Tetrahedron Lett. 1996, 25 37(42), 7477-7480; Robinson, R.A.: Clark, J.S.: Holmes, A. B. J. Am. Chem. Soc. 1993, 115(22), 10400-10401 (KN (TMS) and then camphorsulfonyloxaziridine or another oxaziridine; and Davis, F. A.; Reddy, R. T.; Reddy, R. E.; J. 30 Scheme 44 depicts the preparation of Formula I com Org. Chem. 1992, 57(24), 6387-6389. pounds by coupling HWCO)A to the acid as described in Step E" of Scheme 43 shows methods for the oxidation of Step F" of Scheme 43, followed by hydroxylation as in Step the alpha hydroxy ester to the ketone which may be accom D" of Scheme 43 and oxidation as described in Step E" of plished according to the methods described in Mohand, S.A.: Scheme 43. Levina, A.; Muzart, J.; Synth. Comm. 1995, 25 (14). 2051 35 2059. A preferred method for step E" is that of Ma, Z.; Bobbitt, J. M.; J. Org. Chem. 1991, 56(21), 6110-6114 which utilizes 4-(NH Ac)-TEMPO in a solvent such as CHCl in the presence of para toluenesulfonic acid. The method described in Corson, B. B.; Dodge, R. A.; Harris, S.A.: Hazen, R. K.: Org. Synth. 1941, I, 241 for the oxidation of the alpha hydroxy ester to the ketone uses KmnO as oxidant. Other methods for the oxidation of the alpha hydroxy ester to the ketone include those described in Hunaeus: Zincke; Ber: Dtsch Chem. Ges. 1877, 10, 1489: Acree; Am. Chem. 1913, 50, 391; and Claisen: Ber: Dtsch. Chem. Ges. 1877, 10,846. Step F" of Scheme 43 depicts the coupling reactions which may be carried out as described previously in the application and by a preferred method which is described in Li, H.; Jiang, X.; Ye. Y.-H.; Fan, C.; Romoff. T.; Goodman, M. Organic Lett., 1999. 1, 91-93 and employs 3-(Diethoxyphosphory ne O loxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT); a new cou N - - pling reagent with remarkable resistance to racemization. NS Ri 55 H Rs

Scheme 44 A

I --

65 US 7,915,283 B2 107 108 plished according to procedures described in Norman, M. H.; -continued Navas, F. III: Thompson, J. B. Rigdon, G.C.; J. Med. Chem. 1996, 39(24), 4692-4703: Hong, F.; Pang, Y.-P.; Cusack, B.: Richelson, E.J. Chem. Soc., Perkin Trans 1 1997, 14, 2083 2088; Langry, K. C.; Org. Prep. Proced. Int. 1994, 26(4), 429-438: Romero, D. L.; Morge, R. A.; Biles, C.; Berrios Pena, N.; May, P. D.; Palmer, J. R.; Johnson, P. D.; Smith, H. W.; Busso, M.; Tan, C.-K.; Voorman, R. L.; Reusser, F.; Althaus, I. W.; Downey, K. M.; et al.; J. Med. Chem. 1994, 10 37(7), 999-1014 and Bhattacharjee, A.; Mukhopadhyay, R.; Bhattachariya, A.; Indian J. Chem. Sect B 1994, 33 (7), 679 682.

15 Scheme 46 R R3 N BOCO -e- N 2 t R4 Rs R 25 R3 Step A N 1. BuLi -- 2). CICOCOOMe N 21 N1 BOC 3) H 30 4) (RICO)2O CONRR R4 Rs R2 O Scheme 45 depicts a method for the preparation which could be used to obtain amido compounds of Formula I. Step G' represents ester hydrolysis followed by amide formation 35 (Step H' as described in Step F" of Scheme 43). Step I of N 21 Scheme 45 depicts the preparation of the N-oxide which could be accomplished according to the procedures in Suzuki, R4 H.; Iwata, C.; Sakurai, K., Tokumoto, K. Takahashi, H., Hanada, M.; Yokoyama, Y.; Murakami.Y.; Tetrahedron 1997, 40 53(5), 1593-1606; Suzuki, H.; Yokoyama, Y.; Miyagi, C.: Murakami, Y.: Chem. Pharm. Bull. 1991, 39(8), 2170-2172: and Ohmato, T.: Koike, K., Sakamoto,Y.; Chem. Pharm. Bull. 1981,29,390. Cyanation of the N-oxide is shown in Step J' of Scheme 45 which may be accomplished according to Suzuki, 45 H.; Iwata, C.; Sakurai, K., Tokumoto, K. Takahashi, H., Hanada, M.; Yokoyama, Y.; Murakami.Y.; Tetrahedron 1997, 53(5), 1593-1606 and Suzuki, H.; Yokoyama, Y.: Miyagi, C.: Murakami, Y.: Chem. Pharm. Bull. 1991, 39(8), 2170-2172. Scheme 46 shows a method which could be used for the Hydrolysis of the nitrile to the acid is depicted in Step K' of 50 synthesis of an azaindole acetic acid derivative. Protection of Scheme 45 according to procedures such as Shiotani, S.; the amine group could be effected by treatment with di-tert Tanigucchi, K. J. Heterocycl. Chem. 1996, 33(4), 1051 butyldicarbonate to introduce the t-Butoxycarbonyl (BOC) 1056; Memoli, K. A.; Tetrahedron Lett. 1996, 37(21), 3617 group. Introduction of the oxalate moiety may then be accom 3618: Adolfsson, H.; Waernmark, K.; Moberg, C.; J. Org. plished as shown in Step A of Scheme 46 according to the Chem. 1994, 59(8), 2004-2009; and El Hadri, A.; Leclerc. G.; 55 procedures described in Hewawasam, P.; Meanwell, N. A.; J. Heterocycl. Chem. 1993, 30(3), 631-635. Step L of Tetrahedron Lett. 1994, 35(40), 7303-7306 (using t-Buli, or Scheme 45 depicts a method which could be utilized for the s-buli, THF); or Stanetty, P: Koller, H.; Mihovilovic, M.; J. preparation of amido compounds of Formula I from the cyano Org. Chem. 1992, 57(25), 6833-6837 (using t-Buli). The derivative which may be accomplished according to proce intermediate thus formed could then be cyclized to form the dures described in Shiotani, S.; Taniguchi, K. J. Heterocycl. 60 azaindole as shown in Step B of Scheme 46 according to the Chem. 1997, 34(2), 493-499; Boogaard, A.T.: Pandit, U. K.: procedures described in Fuerstner, A.; Ernst, A.; Krause, H.; Koomen, G.-J.; Tetrahedron 1994,50(8), 2551-2560; Rivalle, Ptock, A.; Tetrahedron 1996, 52(21), 7329-7344 (using. C.: Bisagni, E.: Heterocycles 1994, 38(2), 391-397; and TiCl3, Zn, DME); or Fuerstner, A.; Hupperts, A.; J. Am. Macor, J. E.; Post, R.; Ryan, K. J. Heterocycl. Chem. 1992, Chem. Soc. 1995, 117(16), 4468-4475 (using Zn, excess 29(6), 1465-1467. Step M' of Scheme 45 shows a method 65 Tms-Cl, TiCl3 (cat.), MeCN). which could be used for the preparation of amido compounds Scheme 49 provides another route to azaindole intermedi of Formula I from the acid derivative which may be accom ates which could then be further elaborated to provide com US 7,915,283 B2 109 110 pounds of Formula I. Such as the amido derivatives shown. -continued Steps G". and H" of Scheme 49 may be carried out according to the procedures described in Takahashi, K.; Shibasaki, K. Ogura, K.: Iida, H.; Chem. Lett. 1983, 859; and Itoh, N.; Chem. Pharm. Bull. 1962, 10, 55. Elaboration of the interme- 5 diate to the amido compound of Formula I could be accom plished as previously described for Steps I-M" of Scheme 45.

10 (ONR,R, Scheme 50 shows the preparation of azaindole oxalic acid Scheme 49 derivatives. The starting materials in Scheme 50 may be pre Scheme 49 pared according to Tetrahedron Lett. 1995, 36, 2389-2392. CN Steps A, B, C, and D' of Scheme 50 may be carried out OMe 15 according to procedures described in Jones, R. A.; Pastor, J.; Siro, J.; Voro, T. N.; Tetrahedron 1997, 53(2), 479-486; and W. Singh, S. K.; Dekhane, M.: Le Hyaric, M.; Potier, P.; Dodd, R. NA H.; Heterocycles 1997, 44(1),379-391. Step E' of Scheme 50 1 KNIMDs could be carried out according to the procedures described in G" o Suzuki, H.; Iwata, C.; Sakurai, K., Tokumoto, K.; Takahashi, H.; Hanada, M.; Yokoyama, Y.; Murakami, Y.; Tetrahedron 1997, 53(5), 1593-1606; Suzuki, H.; Yokoyama, Y.: Miyagi, C.; Murakami, Y.: Chem. Pharm. Bull. 1991, 39(8), 2170 2172; Hagen, T. J.; Narayanan, K. Names, J.; Cook, J. M.; J. Org. Chem. 1989, 54, 2170; Murakami, Y.; Yokoyama, Y.: 25 Watanabe, T: Aoki, C.; et al.: Heterocycles 1987,26,875; and Hagen, T. J.; Cook, J. M.; Tetrahedron Lett. 1988, 29(20), 2421. Step F" of Scheme 50 shows the conversion of the phenol to a fluoro, chloro or bromo derivative. Conversion of mCPBA the phenol to the fluoro derivative could be carried out accord --> so ing to procedures described in Christe, K.O. Pavlath, A. E.; Cup. J. Org. Chem. 1965, 30, 3170; Murakami, Y.: Aoyama, Y.: H Nakanishi, S.; Chem. Lett. 1976, 857: Christe, K.O.; Pavlath, A. E.; J. Org. Chem. 1965, 30, 4104; and Christe, K. O.: Pavlath, A. E.J. Org. Chem. 1966,31,559. Conversion of the phenol to the chloro derivative could be carried out according 35 to procedures described in Wright, S.W.; Org. Prep. Proc. Int. 1997, 29(1), 128-131; Hartmann, H.; Schulze, M.: Guenther, R. Dyes Pigm 1991, 16(2), 119-136; Bay, E.; Bak, D. A.: Timony, P. E.; Leone-Bay, A.; J. Org. Chem. 1990, 55,3415; Hoffmann, H., et al.: Chem. Ber: 1962, 95,523; and Vanalan, J. A.; Reynolds, G. A.; J. Org. Chem. 1963. 28, 1022. Con 40 version of the phenol to the bromo derivative may be carried out according to procedures described in Katritzky, A. R. Li, J.; Stevens, C. V.; Ager, D. J.; Org. Prep. Proc. Int. 1994, 26(4), 439-444; Judice, J. K.; Keipert, S.J.; Cram, D. J.; J. Chem. Soc., Chem. Commun. 1993, 17, 1323-1325; Schaef 45 fer, J. P.; Higgins, J.J. Org. Chem. 1967, 32, 1607; Wiley, G. A.: Hershkowitz, R. L.; Rein, R. M.; Chung, B.C.; J. Am. Chem. Soc. 1964, 86,964; and Tayaka, H.; Akutagawa, S.; Noyori, R.; Org. Syn. 1988, 67, 20.

Scheme 5 () O O O O R3 OR R3 OR W \ O NH2 W \ O R4 - Step A -- N N R ep N R Rs R4 k RO OR Step C Step B' OR

NH US 7,915,283 B2 111 112

-continued

Step E"

25 Scheme 51 describes methods for the preparation of aza indole acetic acid derivatives by the same methods employed for the preparation of azaindole oxalic acid derivatives as shown and described in Scheme 50 above. The starting mate rial employed in Scheme 51 could be prepared according to J. 30 Org. Chem. 1999, 64, 7788-7801. Steps A", B", C", D", and E" of Scheme 51 could be carried out in the same fashion as previously described for Steps A, B, C, D', and E' of Scheme 50.

Scheme 51 O O O O R3 OR OMe R OR OMe 3

R4 / \ N li - N W \ R Stepep A N R O Rs R4 Rs

RO OR Step C Step B"R3 OR

NH2

O RO O OMe RO OH OMe R R3 OR W \ 3 21 N NS N N R R4 Rs R4 Rs Step D" Step E" s Fit US 7,915,283 B2 113 114

-continued

Scheme Z below shows that alkynes may be installed to Scheme ZAProvides a More Specific Example of Scheme Z. form substituent D via a metal mediated coupling to the vinyl halide, or triflate. Usually excess alkyne (2.5 eqs are used but Stoichiometric amounts or greater excesses may also be 15 employed). Preferred conditions utilize about 0.05 to 0.1 eq palladium catalyst (PdCl2(PhCN)2 and about double the equivalents of Cul relative to catalyst (0.1 to 0.2 eqs). The reaction is heated for several hours at a temperature of about SCHEME ZA 60° C. in an amine such as piperidine. Alternatives for run ning this reaction include using Castro-Stephens conditions in which a primary amine such as for example butylamine, is Br used with CuI, a Palladium (O) catalyst such as tetrakis triph enylphosphine palladium (O) in an inert solvent such as THF or dioxane. 25 PdCl2(PhCN)2/Cul -- O N piperidine MeO trifurylphosphine E R 30 O SCHEMEZ N N N 2 N Br H OMe

PdCl2(PhCN)2/Cul N piperidine 40 R O trifurylphosphine E R O N R-H N N 2NN 45 H

N O MeO

21 N OMe

Scheme ZB below shows an example of how the alkyne used to construct D may be functionalized by first deproto nation with a suitable base such as LDA in THF at low temperature and then reaction with a suitable electrophile. Carbon dioxide is in the example shown below to provide an 65 acid but alkyl halides, alkyl cyanoformates, or isocyantes could be used to provide alkyl substitution, esters, or amides respectively. US 7,915,283 B2 115 116 Scheme ZC Shows a General Scheme for Synthesizing C SCHEME ZB Linked Triazoles of the Compound of Formula I.

Scheme ZC w - A He1) LDATHF/-78° C. 2) CO2 10 O

RX O PS N HCl (gas), MeOH O C. - - - - - 10 min 15 2 N 7O C. - - - - - 1 hr

25 1. NaOH, MeOH: 3 hrs then 1NHCI He 2. BOC-NH-NH2, DEPBT, DIPEA, DMF, O/N

Scheme ZB1 Shows a Specific Example of Scheme ZB.

SCHEME ZB1 Ho1.4M HCl (in dioxane) S 40 2. HN ls R 150 C., 20 min.

45 OMe Hs1) LDATHF/-78° C. 2) CO f N N le N 50 MeO H HOC

60 Scheme ZD depicts a more narrow version of Scheme ZC which is meant to provide an example but not be limiting. In N both Schemes ZD and ZC., R depicts substituents as described MeO 65 by the claims of the invention which a chemist of normal skill could be used in the reaction sequence. Simple alkyls and the like would for example work well. US 7,915,283 B2

Scheme ZE RX N 1. 10N NaOH (10 equiv.) 5 EtOH, 115 C., 3 h 2. then HCI --- N HCl (gas), MeOH NC H -- O C. ------10 min RX 7O C. - - - - - 1 hr 10 N 1) BocNHNH2, DEPBT iPr2NEt, DMF, r.t.

Her2) 4N HCl, 1,4-dioxane, r.t.

HO NH 15 O S RXN ls 2. HN R 150 C., 1 h -- 2O HN N H 1. NaOH, MeOH: 3 hrs A No then 1NHCI HN O He O 2. BOC-NH-NH2, DEPBT, RN N DIPEA, DMF, O/N 10 equiv, AlCl3 N 25 1:5 MeNO2, CH2C2 N 2NN Her.t. 2h H No O 30

OEt 35 NaOH, MeOH ---

He1. 4M HCl (in dioxane) S ls 40 2. HN R 150 C., 20 min.

R depicts substitution as described by the claims of the invention.

55 Scheme ZF Provides a More Specific Example of Scheme ZE for Illustration.

60 OMe

R / \ 1. 10N NaOH (10 equiv.) N EtOH, 115 C., 3 h 2. then HCI Scheme ZE Depicts a Method for Preparing C-Trizole Sub- 6s stituted Indoles and Azaindoles which can then be Coupled to NC N HWA Using the Standard Methodology. US 7,915,283 B2 119 120 -continued CIC(O)NR'R''. In some cases it may be advantageous to OMe use no added base and just a solvent such as dichloromethane, 1,2-dichloroethane, chloroform, THF, dioxane, pyridine or 1) BocNHNH2, DEPBT DMF. In other cases an alkylamine base such as triethylamine iPr2NEt, DMF, r.t. or diisopropyl ethylamine in a solvent such as dichlo 2) 4N HCl, 1,4-dioxane, r.t. He romethane, 1,2-dichloroethane, chloroform, THF, or dioxane may provide the best reaction. In some cases adding DMAP HO NH to the above reactions could prove beneficial. In other cases, O deprotonation of the indole NH with sodium hydride, potas OMe S sium hydride, or lithium bistrimethylsily acetamide in THF, 10 dioxane, or DMF may be needed before adding the desired / \ 2. . reagent for generating R. 150 C., 1 h EXPERIMENTAL --- HN N 15 Chemistry M H HN O All Liquid Chromatography (LC) data were recorded on a OMe Shimadzu LC-10AS liquid chromatograph using a SPD 10AV UV-Vis detector with Mass Spectrometry (MS) data / \ 10 equiv, AlCl3 N 1:5 MeNO2, CH2C2 determined using a Micromass Platform for LC in electro r.t. 2h spray mode. He LC/MS Method (i.e. Compound Identification)

25 Column A: YMCODS-AS73.0 x 50 mm column Column B: PHX-LUNA C18, 4.6x30mm Column Column C: XTERRA ms C18 4.6x30mm column Column D: YMCODS-AC18 4.6x30mm column Column E: YMCODS-AC18 4.6x33mm column OEt Column F: YMC C18 S54.6 x 50 mm column 30 Column G: XTERRA C18 S73.0 x 50 mm column Column H: YMC C18 SS 4.6x33mm column NaOH, MeOH Her Column I: YMCODS-AC18 S73.0 x 50 mm column Column J: XTERRA C-18 SS 4.6 x 50 mm column Column K: YMCODS-AC18 4.6x33mm column Column L: Xterra MS C185uM 4.6x30mm column 35 Column M: XTERRA MS C-187 u 4.6 x 50 mm column Gradient: 100% Solvent A0% Solvent B to 0%. Solvent A 100% Solvent B Gradient time: 2 minutes Hold time 1 minute Flow rate: 5 ml/min Detector Wavelength: 220 nm. Solvent A: 10% MeOH/90% HO/0.1% Trifluoroacetic Acid Solwent B: 10% HO/90% MeOH/0.1% Trifluoroacetic Acid Compounds purified by preparative HPLC were diluted in methanol (1.2 ml) and purified using the following methods on a Shimadzu LC-10A automated preparative HPLC sys tem. Preparative HPLC Method (i.e. Compound Purification) Purification Method Initial gradient (40% B, 60% A) ramp 50 to final gradient (100% B, 0% A) over 20 minutes, hold for 3 Compounds of formula I where R6 is O are prepared from minutes (100% B, 0% A) the compounds I where R6 is nothing by stirring them with from 1 to 30 equivalents of a peroxyacetic acid Such as meta chloroperoxybenzoic acid, trifluoroacetyl peroxybenzoic Solvent A: 10% MeOH/90% HO/0.1% Trifluoroacetic Acid acid, fluoroacetic peroxybenzoic acid, or meta nitro peroxy 55 Solvent B: 10% HO/90% MeOH/0.1% Trifluoroacetic Acid benzoic acid in an inert solvent Such as ethyl acetate, dichlo Column: YMC C18 SS 20 x 100 mm column romethane, 1,2-dichloroethane, chloroform, THF, or diox Detector Wavelength: 220 nm. ane. Temperatures usually are ambient but for sensitive sub strates lower temperatures may be used and in Some cases slightly elevated temperatures, up to 50° may be needed to 60 General and Example Procedures Excerpted from improve reaction rate. Peroxy acetic acid generated in situ Analogous Oxoacetyl Piperazineamide Applications from acetic acid and hydrogen peroxide may also find use. Compounds in which R" are not H may be prepared from The procedures described references 93-95 and 106 are compounds or intermediates where R is H via standard meth applicable example procedures for synthesizing the com odology well known to organic chemists ie alkylation with 65 pounds of formula I in this application and the intermediates alkyl halides, acylation with acid chlorides or anhydrides, used for their synthesis. The following guidelines are illus reaction with alkyl chloroformates or with isocyanates or trative but not limiting. US 7,915,283 B2 121 The general Bartoli (vinyl Magnesium bromide) methods -continued for preparing functionalized indoles or azaindoles described in the applications can be utilized for preparing new indoles DEPBT, Hunig's base or azaindoles from the appropriate nitro aromatics or het -e- eroaromatics for this application. For example, in PCT/US02/ DMF, rt 00455, the general procedure for preparing intermediate 2a (7-chloro-6-azaindole) from 2-chloro-3-nitro pyridine can be considered a general procedure illustrating conditions which O can be used to prepare azaindoles for this application. This O should be obvious since the same class of intermediates are 10 needed for both inventions. Similarly, the general procedure from the same application to prepare intermediate 3a, Methyl (7-chloro-6azaindol-3-yl) oxoacetate, provides experimental Na2 details for carrying our Step B of (Schemes 1-5 in this appli 15 cation). Similarly, the general procedure from the same appli C cation to prepare intermediate 4a (Potassium(7-chloro-6aza can be used as a procedure for indol-3-yl) oxoacetate, provides an example of the general method for hydrolying oxoacteicesters (Step C of Schemes 1-5). General procedures for carrying out the same steps in the indole series are provided in references 93 and 95. An example Bartoli reaction preparation of a functionalized indole is given in the preparation of intermediate 1 of PCT/ US01/20300 where the preparation of 4-fluoro-7-bromo-aza indole is described from 2-fluoro-5-bromonitrobenzene. Sub DEPBT, Hunig's base sequent procedures for the preparation of intermediates 2 and He 3 describe procedures for adding the alkyl oxoacetate and then for ester hydrolysis to provide the carboxylate salt and then the carboxylic acid after acidification. Thus the chemis try described in the incorporated previous applications for preparing azaindole and indole intermediates is obviously applicable since the desired compounds are the same. Procedures for carrying out the coupling of the indole or aZaindole oxoacetic acids to piperazine amides are described 35 in the references 93-95 and 106. These can also be used as procedures for preparing the piperidine alkenes of this inven tion by taking the experimental procedures and Substituting a piperazine alkene in place of the piperazine amide. This is Preparation of intermediate 4 from PCT/US01/20300 40 possible because both groups have a free amine with rela O tively similar activity and since the other portions of both the O piperazine benzamide and the alkenyl piperidine are rela tively unreactive to many conditions, they can be installed OH similarly. For example, the preparation of intermediate 4 of PCT/US01/20300 and the preparation of intermediate 5a of 45 N PCT/US02/00455 describe couplings of a piperazine benza N mide or methyl piperazine benzamide to an indole or azain H dole oxoacetic acid or carboxylate salt respectively. (The acid or salt can be used interchangeably). These same procedures 50 can be used directly for the preparation of the compounds of EDC-HCl, Hydroxybenzotriazole this invention by substituting the desired piperidine alkene for Hess N-Methyl morpholine the piperazine amides utilized in earlier applications. DMF, rt

55 Preparation of intermediate 5a from PCT/US02/00455 O O

OK 60 N N -- N 2 N H C 65 can be used as a procedure for US 7,915,283 B2 123 124 -continued -continued O O

OH N WN y Na2NNH y O 10 DEPBT, Hunig's base His

F 15 can be used as a procedure for

Once attached via a similar amide bond, both the pipera Zine benzamides and the piperidinyl alkene moieties are rela tively inert and thus reaction conditions used for functional 30 izing indoles or azaindoles in the presence of piperazine benzamides are useful for carrying out the same transforma tions in the presence of the piperidine alkenes. Thus the methods and transformations described in references 93-95 and 106 including the experimental procedures which 35 describe methods to functionalize the indole or azaindole moiety in the piperazine amide series are generally applicable for construction and functionalization of the piperidine alk enes of this invention. These same applications describe gen 40 eral methods and specific preparations for obtaining Stannane and boronic acid reagents used for synthesizing the com pounds of formula I. or even as a procedure for Group-B(OH)2 -- 45 Preparation of Example 1 from PCT/US02/00455 Typical Boronpalladium coupling procedure

Pd(Ph3)4, KCO3 --- DMF, H2O, rt

55 C O

60 Pd(Ph3)4, KCO3 - but to - Group

B(OH)2 65 functionalized indole or azaindole where R is as described for Scheme 7 US 7,915,283 B2 125 126 -continued Preparation of Example 39 from PCT/US02/00455 An example of the typical Stannane/palladium coupling procedure O O 5 OMe W N N N A -- a 7 N 21 N 10 H where R is as described for Scheme 7 C SnBus

2 Pd(Ph3)4 15 Preparation of Example 20 from PCT/US01/20300 N f --Dioxane, 110 deg C. An example to show how functionalization procedures of oxoacetyl piperazine benzamides can be used to carry out 20 similar transformations in the corresponding piperidine alk CS

NaN, NHCI He DMF, 85 deg C. can be used as a procedure for then cool, HCl

Pol(Ph3)4 Hess Dioxane, 110 deg C.

NaN, NHCI He DMF, 85 deg C. or even as a procedure for then cool, HCl

Group-SnBus -- 55

60 Pd(Ph3)4 He Dioxane, 110 deg C.

65 functionalized indole or azaindole US 7,915,283 B2 128 -continued -continued or even as a procedure for CN O O ---1) NaHMDS, THF 2) TFA RX CN XsN N R19 NaN, NHCI R DMF, 85 deg C. %-4NN 20 then cool, HCl 10 21 NC H HN

functionalized indole or azaindole H-W-a

15 NaHMDS (3 ml, 1M in THF) was added to a solution of 1-tert-butoxycarbonyl-4-piperidone (500 mg) and benzyl cyanide (352 mg) in dry THF (10 ml) at room temperature. The reaction mixture was kept stirring for 12 hours before being quenched with MeOH (2 ml). After solvents were removed under vacuum, the residue was charged with 5 ml of TFA and the resulted mixture was HNN stirred for 12 hours. Then, TFA was removed under vacuum N and the residue was partitioned between saturated NaHCO where R is as described for Scheme 7 (20 ml) and EtOAc (10 ml). The aqueous solution was 25 extracted with EtOAc (2x10 ml). The combined organic layer was filtered and concentrated to afford a crude product of intermediate H W-a, which was used in the further reactions without any purification. General Procedures and Preparation of Selected Method I-B: Preparation of Intermediates with the Following Examples 30 Sub-Structure

A. General Procedure for the Preparation of D 4-Substituted Piperidines 35 21 NA Method I-A: Preparation of intermediates with the following sub-structure HN D = phenyl or heteroaryl group A = as defined for compounds of Formula I CN 40 Method Example 2

45 Preparation of Intermediate H W-b

Method Example 1 50 1) Ph.MgBr, THF He 2) TFA Preparation of Intermediate H W-a oHCI (Where H is hydrogen, W corresponds to claim 1 and a is an 55 identifier for the intermediates)

60 O N N --

65 US 7,915,283 B2 129 130 PhMgI (3 ml, 3M in THF) was added to a solution of After solvents were removed under vacuum, the residue 4-bnenzoylpiperidine hydrochloride (200mg) in dry THF (10 was charged with 5 ml of TFA and the resulted mixture was ml) at room temperature. The reaction mixture was kept stir stirred for 12 hours. Then, TFA was removed under vacuum ring for 12 hours before being quenched with MeOH (2 ml). and the residue was partitioned between saturated NaHCO After solvents were removed under vacuum, the residue (20 ml) and EtOAc (10 ml). The aqueous solution was was charged with 5 ml of TFA and the resulted mixture was extracted with EtOAc (2x10 ml). The combined organic layer stirred for 12 hours. Then, TFA was removed under vacuum was filtered and concentrated to afford a crude product of H W-c, which was used in the further reactions without any and the residue was partitioned between saturated NaHCO purification. (20 ml) and EtOAc (10 ml). The aqueous solution was 10 extracted with EtOAc (2x10 ml). The combined organic layer was filtered and concentrated to afford a crude product of H W-b, which was used in the further reactions without any Method I-D: Preparation of Intermediates with the Following purification. Sub-Structure 15

Method I-C: Preparation of Intermediates with the Following Sub-Structure HN D = Cl, Br, I D A = as defined for compounds of Formula I

21 NA 25 HN D = F, Cl, Br Method Example 4 A = as defined for compounds of Formula I 30 Preparation of Intermediate H W-d

Method Example 3 1) Br, DMAP, CH2Cl2 35 Preparation of Intermediate H W-c 2) TFA s 3) EtN, THF, 110° C. O

40 Br

Bromine (0.21 ml) and DMAP (535 mg) was added to a 50 Solution of 1-tert-butoxycarbonyl-4-piperidone (1 g) in dry C 1) NaHMDS, THF --ee CHCl (50 ml) at room temperature. The reaction mixture 2) TFA was kept stirring for 12 hours before being added with MeOH C (2 ml). 55 After solvents were removed under vacuum, the residue 21 was charged with 20 ml TFA and the resulted mixture was stirred for 12 hours. Then, TFA was removed under vacuum HN and the residue was partitioned between saturated NaHCO (50 ml) and EtOAc (20 ml). The aqueous solution was H-W-c 60 extracted with EtOAc (2x20 ml). The combined organic layer was filtered and concentrated to afford a residue. The residue was then dissolved in a mixed solution of THF NaHMDS (0.84 ml, 1M in THF) was added to a solution of (20 ml) and triethylamine (5 ml) in a sealed tube. The mixture 1-tert-butoxycarbonyl-4-piperidone (139 mg) and Diphenyl was heated up to 110°C. for 12 hours. After cooling down, the (C-chlorobenzyl)phosphonate (250mg) in dry THF (10 ml) at 65 solvents were removed to afford a crude product of H W-d, room temperature. The reaction mixture was kept stirring for which was used in the further reactions without any purifica 12 hours before being quenched with MeOH (2 ml). tion. US 7,915,283 B2 131 132 Method I-E: Preparation of Intermediates with the Following Method Example 6 Sub-Structure Via McMurry Reactions Preparation of Intermediate H W-k D 21 NA

HN 10 N- -- Method Example 5 15 1) Grubb's Catalysts Preparation of Intermediate H W-003 He CHCl2, 40° C. 2) TFA

O N --

25 O

O The Grubb’s catalyst was added into a solution of N-Boc TiCl3,1-131 Li 21 4-methylenepiperidine (100 mg) and 1-fluoro-2-vinylben DME 30 Zene (123 mg) in methylene chloride (10 ml). After the reac HN tion was heated at 40° c. for 10 hours, TFA (2 ml) was subjected to the solution at room temperature and the result ing mixture was kept stirring for another 10 hours. Solvents Titanium trichloride (5 g) and DME (60 ml) were added to was removed under vacuum to give a residue, which could be flask (250 ml) which was filled with nitrogen. Lithium (0.72 35 purified using Shimadzu automated preparative HPLC Sys g) was etched to brilliance in methanol, quickly washed in tem. petroleum ether, and cut into Small pieces directly into the Method I-G: Preparation of Intermediates with the Following stirred suspension. The mixture was refluxed for three hours. Sub-Structure The black slurry was then cooled to room temperature, and 40 N-Boc-piperidin-4-one (755 mg) and acetophenone (455 mg) dissolved in DME (20 ml) were subjected to it. And the resulting mixture was refluxed for 16 hours.

Saturated NaCO, solution (30 ml) and water (20 ml) were 45 added into the reaction mixture after it cooled down to room temperature. Insolubles were filtered away. Organic and aqueous layers were separated. The aqueous layer was then extracted with methylene chloride (3x50 ml) and combined organic layer was washed with brine, dried over MgSO. 50 Removal of solvents provided a residue, which was purified by silica gel column chromatography to afford the desired Method Example product H W-003 (410 mg).

55 Preparation of Intermediate H W-X Method I-F: Preparation of Intermediates with the Following Sub-Structure Via Metathesis

BocO Her EtN, THF step a 65 N US 7,915,283 B2 133 134 -continued and N.N.N,N'-tetramethylethylenediamine (55.3 ml) in THF (1000 ml) dropwise at -78°C. over two hours and Mel (43 O O ml) was added four hours later at this temperature. After the Sec-BuLi, MeI reaction was warmed up to room temperature over 12 hours, THF it was quenched with water (300 ml). The aqueous layer was extracted with ether (3x500 ml) and the combined organic layer was dried over MgSO and concentrated to provided a residue which was purified by silica gel column chromatog raphy to provide the desired compound (42 g). O1. O 10 Step c TFA (132 ml) was added to the product (27 g) obtained in step b at 0°C., followed by an addition of water (3 ml). The 15 reaction mixture was then heated to reflux for 2.5 hours. After I W O Solvents were removed under vacuum, the residue was dis O O solved in EtOAc (30 ml) and ether (60 ml). The suspension TFA BocO, NaHCO He was left in a freezer for tow hours. And the final filtration gave step c H2O, CHCI 2-methyl-4-piperidone (16.5 g). N N step d H H Step d A mixture of 2-methyl-4-piperidone (16.3 g). NaHCO (9.5 g) and di-tert-butyl dicarbonate (17.4 g) in water (50 ml) O CN and CHCl (125 ml) was stirred at room temperature for six 25 hours. 40 ml of water was then added and phases were sepa KOH rated. The aqueous layer was extracted with CHCl (4x30 ml) -- He and the combined organic layer was dried over MgSO and MeOH concentrated to provided a residue which was purified by silica gel column chromatography to provide the N-Boc-2- 1. step e 30 methyl-4-piperidone (13.3 g). O uk Stepe Benzyl cyanide (2.75 g) and N-Boc-2-methyl-4-piperi 35 done (5 g) were added into a solution of KOH (3.52 g) in MeOH (23 ml) and the mixture was stirred at 65° C. for 4.5 hours. Then, solvents were removed under vacuum to provide a residue which was dissolved in EtOAc (200 ml). The CN CN organic solution was washed with water and concentrated to 40 gave another residue which was purified by silica gel column TFA chromatography to afforded desired products (5.5 g). Hessstepf Stepf N N 45 To a stirred solution of the product (5.5 g) obtained in step 1. H e in methylene chloride (40 ml) was added TFA (17.6 ml) and O O the resulting mixture was left stirring at room temperature for two hours before solvents were removed under vacuum. The residue was partitioned between EtOAc (50 ml) and water (50 50 ml). After pH was adjusted to 10, the aqueous layer was extracted by EtOAc (3x30 ml). The Organic layers were Step a combined, washed with water and brine, dried over MgSO A solution of di-tert-butyl dicarbonate (80 g) in THF (200 and concentrated to provided the desired product (2.7 g), ml) was added dropwise into a solution of 1,4-dioxa-8-aza which was carried onto the next step with purification. spiro4.5 decane (50 g) and triethylamine (66.8 ml) in THF 55 (500 ml) over one hour. After the reaction was then stirred at room temperature for three hours, solvents were removed Method I-H: Preparation of Intermediates with the Following under vacuum. The residue was dissolved in EtOAc (600 ml) Sub-Structure and the resulting organic solution was washed Subsequently with water (300 ml), 5% NaHCO, (300 ml) and brine (300 60 ml). The organic layer was then dried over MgSO and con centrated to provide crude product (93 g) which was carried to step b without purification.

Step b 65 sec-Butyl lithium (1.3M in cyclohexane, 168 ml) was added into a solution of the crude product obtained in step a US 7,915,283 B2 135 136 Method Example 8 Step c The residue obtained in step b was dissolved in TFA (2 ml) Preparation of Intermediate H W-y at room temperature and the resulting mixture was kept stir ring for 12 hours. The following concentration under vacuum afforded a residue which was used in further reactions with out purification. O Method Example 9 Preparation of Intermediate H W-Z r NaHMDS 10 N -- PPh3'Br - I - step a O

NaHMDS -- r CN THF step a

O C C -s-s N CHCl2 25 step b

O C

30 - --s-s - - CH2Cl2 step b

35 N C

TFA N C 1. 1s step c CN O O 40

TFA N C 45 -s-s step c N H 50 CN Step a NaHMDS (1M in THF, 6.4 ml) was added into a solution of 1-benzyl-3-methyl-4-piperidone (1 g) and benzyl triph enylphosphonium brimide (2.56 g) in THF at room tempera ture and the reaction was heated to reflux for 12 hours. After 55 the mixture cooled to room temperature, water (50 ml) and N EtOAc (50 ml) were added. Organic and aqueous layers were then separated and aqueous solution was extracted with Step a EtOAc (3x50 ml). Organic layers were combined, dried over NaHMDS (1M in THF, 6.4 ml) was added into a solution of MgSO and concentrated to provided a residue which was 60 1-benzyl-3-methyl-4-piperidone (1 g) and benzyl cyanide carried onto the next step with purification. (0.68 ml) in and the reaction was stirred at room temperature Step b for 12 hours. After the mixture cooled to room temperature, The residue (200 mg) obtained from the previous step was water (50 ml) and EtOAc (50 ml) were added. Organic and dissovled in a solution of 1-chloroethylchloroformate (1 ml) aqueous layers were then separated and aqueous solution was in methylene chloride (20 ml), and the reaction was refluxed 65 extracted with EtOAc (3x50 ml). Organic layers were com for 12 hours. Removal of solvents under vacuum provided a bined, dried over MgSO and concentrated to provided a residue. residue which was carried onto the next step with purification. US 7,915,283 B2 137 138 Step b -continued The residue (200 mg) obtained from the previous step was dissovled in a solution of 1-chloroethylchloroformate (1 ml) O in methylene chloride (20 ml), and the reaction was refluxed S N for 12 hours. Removal of solvents under vacuum provided a 5 residue.

TFA Step c 10 N The residue obtained in step b was dissolved in TFA (2 ml) 1. step c at room temperature and the resulting mixture was kept stir ring for 12 hours. The following concentration under vacuum afforded a residue which was used in further reactions with 15 out purification.

O Method I-I: Preparation of Intermediates with the Following S Sub-Structure N

25 N H SOR

Step a 30 A solution of LDA (2M in THF, 13.8 ml) in THF (20 ml) was added dropwise to a solution of benzyl methyl sulfone Method Example 10 (4.27 g) in THF (25 ml) at -30°C. The reaction mixture was stirred at -30°C. for one hour before N-Boc-4-piperidone (5 Preparation of Intermediate H W-004 35 g) in THF (20 ml) was added dropwise. After one and a half hour, the reaction was quenched with 1N HCl (28 ml). The solution was extracted with ether (3x100 ml). The combined organic layer was washed with brine, dried over MgSO, O concentrated to provide a residue which was used in step b 40 without purification.

LDA Step b N -- Yso, - MsCl (8 ml) was added to an ice-cooled solution of the 1. step a 45 residue obtained in step a and triethylamine (20 ml) in meth O O ylene chloride (150 ml) over 15 minutes. The reaction was then heated to reflux for three hours. After solvents were removed under vacuum, saturated NaHCO3 solution (150 ml) was added and aqueous layer was extracted with EtOAc 50 (3x100 ml). The combined organic layer was washed with brine, dried over MgSO concentrated to provide a residue which was purified by Silica gel column chromatography to afforded the desired product (3.1 g). O 55 S N Step c OH The product obtained in step b (2 g) was dissolved in TFA (10 ml) and the mixture was heated to reflux for one hour. 60 MsCl, EtN After solvents were removed under vacuum, saturated He NaHCO3 solution was added to adjust pH to 8. The aqueous N CHCl2 layer was extracted with ether (3x50 ml). After pH of water step b Solution was adjust to 10, the aqueous layer was further extracted with methylene chloride (3x50 ml). The combine 65 organic layer was washed with brine, dried over MgSO, concentrated to provide a residue (1.4 g) which was used in further reactions without purification. US 7,915,283 B2 139 140

Compd. Method MS (M+H)" MS (M + H) Observ. And Number Structure Used Calcd. Retention Time

I-A 199.12 199.15 Rf = 0.88 min (column C)

CONC

2SO.16 250.27 Rf = 1.35 min (column C)

208.09 208.19 Rf = 1.34 min (column C)

2S2.04 252.15 Rf = 1.31 min (column C)

COB r

I-A 2OO.12 200.11 HNHN NN Rf = 0.41 min (column L) NC

I-A 239.13 239.11 Rf = 0.60 min (column L) N

NC N US 7,915,283 B2 141 142 -continued

R16

Compd. Method MS (M + H) MS (M + H) Observ. And Number Structure Used Calcd. Retention Time

I-A 231.15 231.15 (LDA Rf = 0.71 min (column L) HN e used as base)

I-C 19O.12 190.13 Rf = 0.80 min (column L)

I-C or I-F 188.14 188.18 Rf = 1.18 min (column L)

I-F 192.12 192.17 Rf = 1.03 min (column L)

I-F 208.09 2O8.13 Rf = 1.18 min (column L) US 7,915,283 B2 144 -continued

R R16

R19

Compd. Method MS (M+H)" MS (M + H) Observ. And Number Structure Used Calcd. Retention Time

HN I-C or I-F 188.14 18816 Rf = 1.17 min (column L)

I-A 277.03 277.06 Rf = 1.01 min (column L)

NC B

I-A 233.08 233.10 Rf = 0.97 min (column L)

NC C

I-A 217.11 217.14 Rf = 0.76 min (column L)

217.11 217.14 Rf = 0.89 min (column L)

I-A 242.13 242.16 Rf = 0.51 min (column L)

NH2 US 7,915,283 B2 145 146 -continued

R 15 R16

R19

Compd. Method MS (M+H)" MS (M + H) Observ. And Number Structure Used Calcd. Retention Time

I-A 251.08 251.07 Rf = 0.93 min (column L)

NC CoC I-A 235.10 235.11 Rf = 0.71 min (column L)

NC C, OF HN F I-A 235.10 235.11 Rf = 0.91 min (column L) N F

21413 21416 Rf = 0.50 min (column L)

NC HN

HN I-A 2OO.12 2002O 2N Rf = 0.38 min (column L)

213.14 213.24 Rf = 0.83 min (column M)

and

Y-CN US 7,915,283 B2 147 148 -continued

R16 R17 R19 D

Compd. Method MS (M + H) MS (M + H) Observ. And Number Structure Used Calcd. Retention Time

18812 Rf = 1.15 min (column L)

213.14 Rf = 0.97 min (column L) H-W-Z 'O I-H 213.14

H-W-001 LIN I-A 255.10 255.09 Rf = 1.13 min (column L)

H-W-OO2 HN I-A 205.08 2OS.12 Rf = 0.74 min (column L)

S NC

18838 Rf = 1.53 min (column G) H-W-OO3 CO I-E 188.14

HN I-I 2S2.11 252.2O H-W-004 Rf = 0.53 min (column M)

MeOS

*The compound was prepared by removing the tBoc protecting group from commercially available N-BOC-4-PH ENYLMETHYL ENE PIPERDINE which can be purchased from Arch Corporation, New Brunswick, NJ. Alternatively the preparation of either the free base or ydrochloride salt has been described in the patent literature: Free base: Fujita, Kazushi; Murata, Shinobu; Kawakami, Hajime. 1999, JP 11001481 A2 Hydrochloride salt: Kato, Kaneyoshi; Terauchi, Jun; Suzuki, Nobuhiro; Takekawa, Shiro. PCT Int, Appl. (2001), WO 0125228A1. US 7,915,283 B2 149 150 B. General Procedure for the Preparation of the Final and the residue was purified using Shimadzu automated pre Products with the Following Sub-Structure parative HPLC System to give compound I-a (6.3 mg). Method F-B: Preparation of Structures in claim I from Acid Y Example 2 A N Preparation of Compound I-b O 10 O D OMe Method F-A: Preparation of Structures in claim I from Acyl OH Chloride N --

Example 1 15 2 Preparation of Compound I-a N N HN O THF N HeEtN, EDAC Cl CN N O O OMe N 25 THF N N N HeEtN N N N CN NC O 30 O I-b Intermediate H W-a (235 mg, crude), 7-azaindole-3-gly N oxylic acid (200mg, Wang etal, U.S. Pat. No. 6,476,034 (WO 35 01/62255) reference 94) and EDAC (280 mg) was dissolved N N in a mixed solution of THF (10 ml) and triethylamine (1 ml). H After the reaction was stirred for 11 hours, solvents were NC removed under vacuum and the residue was purified using Intermediate H W-a (160 mg, crude) and indole-3-gly Shimadzu automated preparative HPLC System to give com oxylyl chloride (100mg) was dissolved in a mixed solution of 40 pound I-b (2.9 mg). THF (10 ml) and triethylamine (1 ml). After the reaction was Characterization of the Final Compounds of Formula I with stirred for 11 hours, solvents were removed under vacuum the Following Formula:

MS (M+H)" MS Observ. And Compl. Method (M+H) Retention Time Number Structure Used Calcd. and NMR

Ia O F-A 370.16 370.33 min Example 1 O Rf = 1.63 min (column C) N

US 7,915,283 B2 153 154 -continued

Q R19

MS (M+H)" MS Observ. And Compd. Method (M+H)" Retention Time Number Structure Used Calcd. and NMR

Ie O 440.14 440.10 Example 5 Rf = 1.82 min OMe (column L) N

C OMe

If O F-A 431.44 431.09 Example 6 (PrNEt Rf = 2.53 min used, (column G N Start 9% B = Gradient Time = 20, 3 min Gradient Flow Rate = Time = 4 ml/min) 8 min, Flow Rate = 40 ml/min, column Xterra MS C-18 SuM30 x 100 mm)

Ig O 484.09 483.98 Example 7 Rf = 1.83 min OMe (column L) N

N B OMe

Ih O 420.19 420.17 Example 8 Rf = 1.74 min OMe (column G) N H NMR (500 MHz, CDOD) 88.18 (ss, 1H), 7.24 (m, 6H), 4.12 (s.3H), N 3.77-2.14 (m, 8H), 1.98 (ss, OMe 3H)

US 7,915,283 B2

-continued O R O i Rig

R17 Q R19 D

A MS (M+H)" MS Observ. And Compd. Method (M+H) Retention Time Number Structure Used Calcd. and NMR

Ix O F-B 471.18 471.48 Example 23 O Rf = 1.18 min OMe (column C) N N N Na2NN N-CN H OMe N2 NH

Iy O F-B 435.12 435.13 Example 24 O Rf = 1.54 min OMe (column L) N N N N 21 NN N H C NC

40 General Procedures for the Preparation of Pyrazoles Methyl ketone (1 eq.) was added into a solution of 3-Substituted pyrazoles can be prepared via the following dimethoxy-DMF (5-10 eq.) in DMF and the resulting mixture rOutes: Route P-A was heated to 110-115° C. for 12 hours. Solvents were then H 45 removed under vacuum to provide a residue. N N Hexane M The above residue was mixed with hydrazine (5-10 eq.) in He- N 1150 C. A ethanol and the reaction was kept in refluxing for 12 hours. 10 hours l TMS Removal of Solvents in vacco gave a residue, which was R carried onto further reactions without purification. R 50 Alkyne (1 eq.) was dissolved in a 2M solution of diaz omethane (5-10 eq.) in hexane and resulting mixture was heated to 110-115° C. for 12 hours. After reaction was quenched with MeOH, removal of solvents provided a resi due which was used in the next step without any purification. 55 Route P-C Route P-B O OMe DMF 1150 C. He R --- 10 hours 60 - - . NHNH2 O --- H THF N NHNH2 M --EtOH || M N --- 65 US 7,915,283 B2 163 164 -continued TABLE XX-continued H N Y Preparation of Pyrazoles M HPLCR, H R N (column). NiO-2HO N Method MS (M+H)" O He N THF M Compound" Structure Used or (M+ Na)" eN 10 NH R Pyrazole-005 H 0.48 min N (column L) R Y M 15 Hydrazine (10-20 eq.) was added into a solution of alk enone or alkenal (1 eq.) in THF and the resulting mixture was heated to 110-115° C. for 12 hours. After the mixture cooled down to room temperature, an excess of NiO2-2H2O (5-10 eq.) was then added into the reaction mixture and the reaction Pyrazole-006 0.63 min was stirred at room temperature for another 12 hours. N (column L) N Insoluble materials were then filtered away and concentration / under vacuum provided a residue that was used in the further reactions without purification. 25 TABLE XX Preparation of Pyrazoles Pyrazole-007 H 0.21 min N HPLCR, (cloumin G) (column). 30 Method MS (M + H)" /N Compound" Structure Used or (M+ Na)" Pyrazole-001 P-A 0.35 min (column L) HO 35 Pyrazole-008 H 0.81 min N (column L). MS (M+H)": N Calcd 197.13 M Found 197.18 Pyrazole-002 P-A (0.59 min 40 (column L)

O 45 t C O Pyrazole-003 P-A 1.07 min (column L.), 50

Calcd 139.12 Pyrazole-009 H Found 139.18 N N N M 55

Pyrazole-010 H 0.34 min N Pyrazole-004 P-A, P-B, 0.53 min 60 (column L) Y P-C (column L) M M OH 65 . US 7,915,283 B2 165 166 TABLE XX-continued TABLE XX-continued

Preparation of Pyrazoles Preparation of Pyrazoles HPLCR, HPLCR, (column). (column). Method MS (M+H)" Method MS (M+H)" Compound" Structure Used or (M+ Na)" Compound" Structure Used or (M+ Na)" 10 Pyrazole-O16 0.31 min (column L). Pyrazole-011 H P-A 0.47 min N MS (M+H)": N (column L.), M Calcd 141.10 N MS (M+H)": Found 141.17 M Calcd 155.08 Found 155.06 15

O O OH \ Pyrazole-017 P-A 0.27 min (column L). MS (M + Na)": Pyrazole-012 0.38 min N Calcd 149.07 25 M (column G) Found 149.13

M HO

C O 30 ( Pyrazole-018 0.22 min (column L) MN Pyrazole-013 35 /

40 HO

Pyrazole-019 0.61 min (column L). MS (M + Na)": Calcd 175.08 Pyrazole-014 45 X Found 175.14

50 Pyrazole-020 0.79 min (column L). MS (M + Na)": X Calcd 189.10 Found 189.17

55 Pyrazole-015 0.26 min HO (column L.), MS (M + Na)": Calcd 149.07 Pyrazole-021 O.S9 Found 149.11 (column L). 60 MS (M+H)": X Calcd 141.10 Found 141.18

HO HO 65 US 7,915,283 B2 167 168 TABLE XX-continued TABLE XX-continued Preparation of Pyrazoles Preparation of Pyrazoles HPLCR, HPLCR, (column). (column). Method MS (M + H)" Method MS (M + H)* Compound" Structure Used or (M+ Na)" Compound" Structure Used or (M+ Na)" Pyrazole-027 H P-A 0.36 min Pyrazole-022 P-A 0.22 min N (column G). 10 N MS (M+H)": (column L) M Calcd 171.08 Found 171.13

15 (O Pyrazole-023 H P-A 0.34 min N (column L.), Pyrazole-028 P-A 0.93 min MS (M + Na)": (column G) MN Calcd 193.10 Found 193.14 M

OH 25 OH O Pyrazole-024 H P-A 1.05 min \ N (column L.), 30 MS (M+H)": MN Calcd 228.08 Found 228.14 sOH O Pyrazole-029 P-A 0.29 min N 35 (column G). Y MS (M+H)": M Calcd 155.08 O Found 155.14

Pyrazole-025 H P-A 1.43 min N (column G). Y MS (M+H)": OH A Calcd 247.11 45 Found 247.18 General Procedure to Cross-Link N-Nitrogen of N-Contain ing Heterocycles (e.g., Triazole, Pyrazole and Imidazole, etc) O with AZaindole or Indole Halides 50 Method G-A: for N-Containing Heterocycles with Melting Points Lower than or Equal to 160° C. Indole or azaindole halide (30 mg, 1 eq.), triazole or pyra zole or imidazole (3-20 eq.), Cu (0.1-1 eq.) and KCO (2-5 /N eq.) were combined in a sealed tube which was degassed O 55 before sealed. The mixture was heated to 160° C. for 4-16 O hours. After cooling down to room temperature, the mixture Pyrazole-026 H P-A (0.25 min was added with MeOH (14 ml) and dichloromethane (7 ml). N (column G) After filteration, the filtrare was concentrated to give a residue which was purified using a Shimadzu automated preparative MN 60 HPLC System to provide the desired compound. Method G-B: for N-Containing Heterocycles with Melting Points Lower or Higher than or Equal to 160° C. Substituted pyrazole, imidazole or triazole (>3 eq.) was CN 65 mixed with an excess of HMDS (> or = 10 eq) or TMS-Cl (> or = 10 eq.). After the resulting mixture was heated up to 140° C. for 4-16 hours, HMDS or TMS-C1 was removed in US 7,915,283 B2 169 170 vacco and the residue was combined with indole or azaindole General Procedures to Cross-Link Tin or Boronic Agents halide, under the condition described in Method G-A to pro with Azaindole or Indole Halides (WO-02/062423 Published vide desired products. on Aug. 15, 2003) All the tin or boronic agents described in WO-02/062423 Example 25 and its continuing-in-part applications are applicable in con Preparation of Product I-N-001 structing Formula I defined in this application. Coupling with Tin Agents: To a sealed tube, indole or azaindole halide (20 mg, 1 eq.), 10 O Stannyl agent (1-2 eq.) and Pd(Ph-P) (0.1-1 eq.) were com O bined in 1.5 ml of dioxane. The reaction was heated at 110 OMe 170° C. for 4-16 hours (it required much shorter time when N reaction was run in a microwave reactor. After the mixture n Cu cooled down to room temperature, it was poured into 5 ml of N N Y -> 15 Nae-NN NN/ K2CO3 water. The solution was extracted with EtOAc (4x5 ml). The H 160° C. combined extract was concentrated in vacuo to give a residue C NC which was purified using a Shimadzu automated preparative O HPLC System to give the desire compound. O OMe 2O N Example 26 N N Preparation of Example I-C-001 Na2NN N H 25 NC N N KN f. OMe o, if 30 N Compound Iy 100 mg), triazole (470 mg), Cu (28 mg.) and N N -- KCO (60 mg) were combined in a sealed tube which was N N degassed before sealed. The mixture was heated to 160° C. for 21 N 6 hours. After cooling down to room temperature, the mixture NC was added with MeOH (30 ml) and dichloromethane (20 ml). C After filteration, the filtrare was concentrated to give a residue which was purified using a Shimadzu automated preparative HPLC System to provide the desired compound I-N-001 (18 SnBus mg). 40 n Pd(PPh3)4 N --> Dioxane N a- 150° C. Characterization of the Final Compounds of Formula I:

MS (M+H)" MS Observ. And Compd. Method (M+H) Retention Time Number Structure Used Calcd. and NMR

I-N-OO1 O G-A 468.18 468.41 O Rf = 1.74 min OMe (column G) N H NMR (500 MHz, N N CDOD) 8 9.35 (s, Nn 2 N 1H), 8.30 N (m, 2H), 7.83 (d, NN NC 1H, N J = 8.00 Hz), \ / 7.42 (m, N SH), 4.03 (s, 3H), 3.95-2.56 US 7,915,283 B2 171 172 -continued -continued B(OH)2

He Dioxane 150° C. Microwave

To a sealed tube, compoundly 41 mg), tri-butyltin pyrazine (55 mg) and Pd(Ph-P) (0.3 eq.) were combined in 3 ml of 15 dioxane. The reaction was heated at 150° C. for 5 hours. After the mixture cooled down to room temperature, it was poured OMe into 5 ml of water. The solution was extracted with EtOAc (4x5 mL). The combined extract was concentrated in vacuo to N give a residue which was purified using a Shimadzu auto- 20 N mated preparative HPLC System to give the desire compound I-C-001 (6 mg). Coupling with Boronic Acids NC To a sealed tube, indole or azaindole halide (20 mg, 1 eq.), boronic acid (1-5 eq.), Pd(Ph-P) (0.1-1 eq.) and KCO (2-5 eq.) were combined in 1.5 ml of DMF or dioxane with or without 1.5 ml of water. The reaction was heated at 110-170° C. for 4-16 hours (it required much shorter time when reac SO tion was run in a microwave reactor). After the mixture cooled down to room temperature, it was poured into 20 ml of water. The solution was extracted with EtOAc (4x20 ml). The com- 30 bined extract was concentrated to give a residue which was purified using a Shimadzu automated preparative HPLC Sys tem to give the desired product. To a sealed tube, compound Iy (30 mg), 4-methylsulfo Example 32 35 nylphenylboronic acid (42 mg) and Pd(Ph-P) (0.3 eq.) were Preparation of Example I-C-007 combined in 3 ml of dioxane. The reaction was heated at 150° C. in a microwave reactor for 20 minutes. After the mixture O cooled down to room temperature, it was poured into 20 ml of O OMe water. The solution was extracted with EtOAc (4x20 ml). The N combined extract was concentrated to give a residue which 40 was purified using a Shimadzu automated preparative HPLC rN\, System to give the desired product I-C-007 (5 mg). Na2NN N H NC C Characterization of the Final Compounds of Formula I:

MS (M+H)" MS Observ. And Compd. (M+H) Retention Time Number Calcd. and NMR

I-C-001 479.18 479.21 Example 26 Rf = 1.56 min (column G) H NMR (500 MHz, CDC1) 89.80 (d. 1H, J = 6.5 Hz), 8.58 (m, 2H), 8.20 (d. 1H, J = 8.5 Hz), 8.13 (d. 1H, J = 8.5 Hz), 7.30 (m, 5H), 4.11 (s, 3H), 3.96– 2.60 (m, 8H)

US 7,915,283 B2 175 176 -continued MS (M+H)" MS Observ. And Compd. (M+H) Retention Time Number Structure Calcd. and NMR

I-C-OO6 494-19 494.46 Example 31 Rf = 1.29 min (column C)

I-C-007 O 555.17 555.21 Example 32 Rf = 1.34 min (column C) N N

I-C-008 O 556.17 556.18 Example 33 Rf = 0.99 min (column G) N Na N

I-C-009 O 556.17 556.50 Example 34 Rf = 1.27 min (column C) N

NC US 7,915,283 B2

-continued MS (M+H)" MS Observ. And Compd. (M+H) Retention Time Number Structure Calcd. and NMR

I-C-O10 O 493-19 493.53 Example 35 O Rf = 1.29 min OMe (column C) N N N N 2 N N NC

I-C-O11 534.12 S34.57 Example 36 Rf = 1.31 min (column C)

I-C-O12 O 52020 S2O.33 Example 37 O Rf=520.33 min OMe (column L)

NC US 7,915,283 B2

-continued

MS (M+H)" MS Observ. And Compd. (M+H) Retention Time Number Structure Calcd. and NMR

I-C-O13 O 574.25 574.30 Example 38 O Rf = 1.41 min OMe (column L) N N N N 2NN N H NC

O N )

I-C-O14 O S88.26 S88.38 Example 39 O Rf = 1.46 min OMe (column L) N N N N 21 NN N H NC

O N

I-C-O15 O S63.23 S63.31 Example 40 O Rf = 1.53 min OMe (column L) N N N N 2NN N H NC

O O US 7,915,283 B2 182 -continued

MS (M+H)" MS Observ. And Compd. (M+H) Retention Time Number Structure Calcd. and NMR

I-C-O16 O 535.2O 535.58 Example 41 Rf = 1.42 min OMe (column C) N

I-C-O17 O S49.21 S49.27 Example 42 Rf = 1.51 min OMe (column L) N

I-C-O18 O S21.18 S21.51 Example 43 Rf = 1.36 min OMe (column C) N

OH US 7,915,283 B2 184 -continued MS (M+H)" MS Observ. And Compd. (M+H) Retention Time Number Structure Calcd. and NMR

I-C-O19 S21.18 S21-22 Example 44 Rf = 1.34 min (column L)

I-C-O2O 549.21 549.48 Example 45 Rf = 1.74 min (column C)

I-C-021 O SO2.19 SO2.2O Example 46 O Rf = 1.37 min OMe (column L) N N N N 21 N N H NC

General Procedure for Hydrolysis of CN to Amide Nitrile derivative (40 mg) was dissolved in 0.1 ml of con 60 centrated HSO and reaction was heated to 40-100° C. for 1-12 hours. After the mixture was cooled down to room temperature, it was diluted with water (10 ml) and methanol (10 ml). Saturated solution of NaHCO was added to adjust pH to 5. Then, Solvents was removed under vacuum to give a 65 residue which was purified using a Shimadzu automated pre parative HPLC System to provide the desired compound. US 7,915,283 B2 185 186 Example 47 -continued O O OMe Preparation of Example I-A-001 5 N N

N 2 N H 10 OMe HN O O OMe O Compound Ic (40 mg) was dissolved in 0.1 ml of concen N trated HSO and reaction was heated to 60° C. for three H2SO4 15 hours. After the mixture was cooled down to room tempera N N 60° C. ture, it was diluted with water (10 ml) and methanol (10 ml). N Saturated solution of NaHCO was added to adjust pH to 5. 2NN Then, solvents was removed under vacuum to give a residue H NC which was purified using a Shimadzu automated preparative OMe o HPLC System to provide the desired compound I-A-001 (1.2 mg). Characterization of the Final Compounds of Formula I:

MS (M+H)" MS Observ. And Compl. (M+H) Retention Time Number Structure Calcd. and NMR

I-A-001 O 449.18 44952 Example 47 O Rf = 1.31 min OMe (column C) N rN\, N 21 N Y. H OMe O NH2

I-A-002 O 453.13 453.14 Example 48 O Rf = 1.32 min OMe (column G) N rN\, N 21 N N H C O NH2

I-A-003 497.19 497.23 Example 49 Rf = 1.39 min (column G) US 7,915,283 B2 187 188 Synthesis of Additional Vinylpiperidine Intermediates Example 48a

Preparation of Preparation of 1-4-(1-Bromo-1-phenyl-methylene)- 4-(1-Phenyl-methylene)-piperidine-1-carboxylic piperidin-1-yl)-2-(4,7-dimethoxy-6-azaindol-3-yl)- Acid Tert-Butyl Ester ethane-1,2-dione

Br / 10

N M BOC N O 15 MeO To a Suspension of benzyltriphenylphosphonium chloride O (2.24 g, 5.76 mmol) was added n-BuLi (2.3M in hexanes, 3.0 N mL, 6.9 mmol) at 0°C. The mixture was allowed to stir for 30 N min, after which time it had become a deep red solution. To N 21 N this was added N-Boc-4-piperidone (0.748 g. 6.05 mmol) and H the solution was stirred at room temperature for 48 hours. The MeO reaction was quenched with NHCl and extracted with EtOAc (x2). The combined organic layers were washed, (H2O, brine) A solution of 4-(1-bromo-1-phenyl-methylene)-piperi and dried (NaSO) and evaporated. The residue was purified dine-1-carboxylic acid tert-butyl ester in 4NHC1-dioxane (10 by flash chromatography (SiO/hexane-EtOAc, 4:1) to afford 25 mL) was stirred at room temperature for 2 h. The volatiles the product (1.41 g, 90%) as a colourless liquid which solidi were then removed in vacuo and the residue was dissolved in fied on standing: CHCl (15 mL). To this solution was added 4,7-dimethoxy 6-azaindol-3-yl-oxoacetic acid (0.906 g, 3.37 mmol) and Hnmr (400 MHz, CDC1) & 7.33-729, (m, 2H), 7.17-7.21 Hünig's base (2.40 mL, 13.8 mmol). After 5 min, BOPCl (m,3H), 6.35 (s, 1H), 3.50 (t, J=5.8 Hz, 2H), 3.39 (t, J=5.5 Hz, 30 (0.950 g, 3.73 mmol) was added as a solid and the mixture 2H), 2.45 (t, J=5.5 Hz, 2H), 2.32 (app t, J=5.3, 5.6 Hz, 2H), was allowed to stir at room temperature for 48 hours. The 1.47 (s, 9H). reaction mixture was then adsorbed directly onto silica gel and purified by flash chromatography (SiO/EtOAc) to give Preparation of 4-(1-Bromo-1-phenyl-methylene)- the title compound (1.101 g, 71%) as a yellow solid: piperidine-1-carboxylic Acid Tert-Butyl Ester 35 'Hnmr (400 MHz, CDC1) & 12.98 (d. J=14.2 Hz, 1H), 8.13 (dd, J=12.4, 3.0 Hz, 1H), 7.46-7.28 (m, 6H), 3.97 (d. J=6.6 Br Hz, 3H), 3.82 (s, 3H), 3.71 (m, 1H), 3.54 (m. 1H), 3.45 (m, 1H), 3.27 (m. 1H), 2.71 (m, 1H), 2.56 (m, 1H), 2.34 (m. 1H), / 2.20 (m. 1H) 40 LCMS m/e 484, 486 (M+H)"..

N Example 49a M BOC Preparation of 1-4-(1-Phenyl-1-(thiazol-2-yl)-meth 45 ylene)-piperidin-1-yl)-2-(4.7-dimethoxy-6-azaindol To a solution of 4-(1-phenyl-methylene)-piperidine-1-car 3-yl)-ethane-1,2-dione boxylic acid tert-butyl ester (30.0g, 0.11 mol) in CHCl (300 mL) containing KCO (22.5g, 0.16 mol) was added a solu tion of Br (5.9 mL, 0.16 mol) in CHCl (50 mL) at 0°C. over 1 h. The mixture was allowed to stir for 1 hat room tempera 50 K ture and then it was diluted with water, the layers were sepa rated and the aqueous phase extracted with CHC1. The | combined organic layers were washed (HO, brine), dried (NaSO) and evaporated. The residue was dissolved in 55 MeOH (300 mL) and a solution of NaOH (75 g, 1.88 mol) in H2O (250 mL) was slowly added, followed by another 100 mL of MeOH to maintain homogeneity. The mixture was MeO heated at 40°C. for 4 hours and then most of the MeOH was N removed in vacuo and the mixture was extracted with EtOAc 60 (x3). The combined organic layers were washed, (H.O. N brine), dried (NaSO) and evaporated. The residue was puri Na2NN fied by flash chromatography (SiO/hexane-EtOAc, 4:1) to H afford the product (36.2g, 94%) as a yellow-orange solid: MeO Hnmr (400 MHz, CDC1) & 7.39-7.27 (m, 5H), 3.56 (app 65 t, J=5.9, 5.5 Hz, 2H), 3.36 (t, J=5.9 Hz, 2H), 2.66 (t, J=5.9 Hz, A mixture of 1-4-(1-bromo-1-phenyl-methylene)-piperi 2H), 2.26 (t, J=5.9 Hz, 2H), 1.49 (s.9H). din-1-yl)-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-di US 7,915,283 B2 189 190 one (0.032 g, 0.066 mmol), 2-(tri-n-butylstannyl)thiazole Preparation of 4-(1-Phenylmethylene-1-carboxylic (0.025 g, 0.066 mmol) and bistriphenylphosphinepalladium acid)-piperidine-1-carboxylic Acid Tert-Butyl Ester dichloride (0.001 g, 1 mol %) in THF (4 mL) was heated at 90°C. in a sealed tube under Arfor 15 h. The cooled mixture was then diluted with EtOAc, washed (1 M KF, brine), dried 5 (NaSO) and evaporated to give a clear yellow oil. Purifica HOC tion by preparative HPLC afforded the product (0.011 g, 34%) as a white solid: Hnmr (400 MHz, CDC1) 89.38 (d. J=11.6 Hz, 1H), 7.98 10 (dd, J=3.5, 4.5 Hz, 1H), 7.84 (d, J-3.0 Hz, 0.5H), 7.76 (d. J=3.1 Hz, 0.5H), 7.44-7.19 (m, 7H), 4.02 (d. J=4.6 Hz, 3H), 3.92 (s, 3H), 3.87 (app t, 1H), 3.73 (app t. 1H), 3.60 (app t, BOC 1H), 3.47 (app t, 1H), 3.12 (app t, 1H), 3.03 (app t, 1H), 2.41 (app t, 1H), 2.32 (app t, 1H). 15 To a solution of 4-(1-bromo-1-phenyl-methylene)-piperi LCMS: m/e 489 (M+H)". dine-1-carboxylic acid tert-butyl ester (6.85g. 19.4 mmol) in 50 mL of dry THF was added n-BuLi (1.8M in hexanes, 13.0 mL, 23.4 mmol) at -78° C. under Ar. The mixture was allowed to stir for 20 min, after which time CO gas (previ ously dried by passing through a CaCl drying tube) was Example 50 bubbled through the solution for 30 minutes and then a large excess of solid CO, was added. The mixture was allowed to Preparation of 1-4-(1-Phenyl-1-(pyridin-2-yl)-meth warm to room temperature over 12 hand then it was quenched ylene)-piperidin-1-yl)-2-(4.7-dimethoxy-6-azaindol 25 with Saturated aqueous NHCl and the aqueous phase was 3-yl)-ethane-1,2-dione washed with EtOAc. The pH of the aqueous phase was adjusted to about 2 with 10% HCl and then it was extracted with EtOAc (x3) and the combined organic phases were washed (HO, brine), dried (NaSO) and evaporated. The 30 er residue was purified by flash chromatography (SiO/hexane EtOAc, 4:1) to afford the product (2.49 g, 40%) as a colorless N | liquid which solidified on standing: N 'Hnmr (400 MHz, CDC1,) & 10.54, (brs, 1H), 7.38-7.34 | 35 (m,3H), 7.18-7.15 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 3.40-3.37 (m. 2H), 2.88 (t, J=5.8 Hz, 2H), 2.18 (m, 2H), 1.45 (s, 9H). LCMS: m/e316 (M-H). N O MeO 40 Preparation of 4-(1-Phenylmethylene-1-carboxylhy O drazide)-piperidine-1-carboxylic Acid Tert-Butyl 21 ) Ester N N 45 MeO

To a solution of 1-4-(1-bromo-1-phenyl-methylene)-pip eridin-1-yl)-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2- 50 dione (0.030 g, 0.062 mmole), pyridine-3-boronic acid (0.011 g, 0.093 mmol) in 4 mL of DME was added 2M sodium carbonate (0.12 mL, 0.24 mmol) and EtOH (1 mL) and the resulting mixture was degassed with a stream of Ar BOC bubbles for 10 min. To this mixture was added Pd(dppf)Cl. 55 (0.003 g, 5 mol%) and the reaction mixture was heated with A mixture of 4-(1-phenylmethylene-1-carboxylic acid)- stirring at 90° C. for 18 h. The cooled mixture was then piperidine-1-carboxylic acid tert-butyl ester (0.153 g, 0.481 filtered (C-18 cartridge and 0.45 um filter), the residue was mmol), EDCI (0.113 g, 0.590 mmol), and HOBt (g, 0.602 washed with MeOH and the filtrate was evaporated. Purifica mmol) in DMF (3 mL) was stirred for 30 min at room tem tion of the residual material by preparative HPLC afforded the 60 perature and hydrazine hydrate (1.0 mL) was added. Stirring title compound (0.011 g, 37%) as a light gray solid: was continued for 12 hand then the mixture was poured into Hnmr (400 MHz, CDC1) & 9.38 (s, 1H), 8.50-8.40 (m, water and extracted with EtOAc (x3). The combined organic 2H), 8.00 (d. J=3.0 Hz, 1H), 7.46-7.18 (m, 6H), 7.12-7.06 (m, layers were washed, (HOx5, brine) and dried (Na2SO). The 2H), 4.03 (s, 3H), 3.93 (s.3H), 3.77 (q, J=5.1, 5.5 Hz, 2H), 65 solvent was removed in vacuo and the residue was purified by 3.49 (m, 2H), 2.50 (m, 2H), 2.43 (m, 2H). preparative HPLC to give a colorless oil (147 mg, 92%): LCMS: m/e 483 (M+H)". LCMS: m/e330 (M-H). US 7,915,283 B2 191 192 Preparation of 4-(1-Phenylmethylene-1-(N-formyl) Preparation of 4-1-Phenylmethylene-1-(1,3,4-oxa carboxylhydrazide)-piperidine-1-carboxylic Acid diazol-2-yl)piperidine-1-carboxylic Acid Tert-Butyl Tert-Butyl Ester Ester

/7No \ le OHCHNHN 10

N 15 BOC BOC Method A: To a suspension of 4-(1-phenylmethylene-1-(N'- Prepared as per the previous example to give the title com formyl)carboxylhydrazide)-piperidine-1-carboxylic acid pound (52% yield) as a colourless foam: tert-butyl ester (0.106 g., 0.294 mmol) in CHCN (2 mL) was Hnmr (400 MHz, CDOD) & 10.09 (s, 1H), 9.95 (s, 1H), added iPr-NEt (0.30 mL, 1.7 mmol) and PPhs (0.137 g., 0.523 8.06 (s, 1H), 741-7.35 (m, 2H), 7.32-7.25 (m, 3H), 3.46 (br mmol), followed after 5 min by hexachloroethane (0.162 g, 0.685 mmol). The mixture was stirred at room temperature m,2H), 3.32(brm,2H), 2.50 (m, 2H), 2.16 (dd, J–5.3, 6.1 Hz, for 4 h and then the solvent was removed in vacuo and the 2H), 1.41 (s, 9H). 25 residue was partitioned with EtOAc-HO. The organic phase LCMS: m/e 358 (M-H). was separated and the aqueous phase was re-extracted with EtOAc. The combined organic phases were washed (H2O, brine), dried (NaSO) and evaporated. The residue was puri fied by preparative HPLC to give the title compound (0.050g, 30 50%) as a colorless solid: 'HNMR (400 MHz, CDC1) & 8.28 (s, 1H), 7.41-7.36 (m, 3H), 7.18-7.16 (m, 2H), 3.59 (dd, J=5.6, 5.8 Hz, 2H), 3.43 (dd, J=5.5, 5.9 Hz, 2H), 2.91 (dd, J=6.1, 5.5 Hz, 2H), 2.31 (dd. J=5.8, 5.5 Hz, 2H), 1.45 (s, 9H). 35 LCMS: m/e342 (M+H)". Preparation of 4-1-Phenylmethylene-1-(5-methyl-1, 3,4-oxadiazol-2-yl)piperidine-1-carboxylic Acid Tert-Butyl Ester 40 Preparation of 4-(1-Phenylmethylene-1-(N-acetyl) carboxylhydrazide)-piperidine-1-carboxylic Acid Tert-Butyl Ester

ACHNHN 50 N

BOC

55 Method B: To a solution of 4-(1-phenylmethylene-1-car BOC boxylhydrazide)-piperidine-1-carboxylic acid tert-butyl ester (0.056 g., 0.169 mmol) and iPr-NEt (0.20 mL, 1.16 mmol) in CHCN (1 mL) was added acetic anhydride (0.02 Prepared as per the previous example to give the title com mL, 0.212 mmol) and the mixture was allowed to stir at room pound (45% yield) as a colourless oil: 60 temperature for 1 h. To this mixture was then added PPh (0.182g, 0.694 mmol), followed by hexachloroethane (0.093 Hnmr (400 MHz, CDC1) & 8.19-8.12 (m, 1H, br), 7.40 g, 0.394 mmol). The mixture was allowed to stir for 12 hand 7.21 (m, 5H), 3.93 (s, 1H, br) 3.54 (dd, J=5.3, 5.6 Hz, 2H), then it was worked up and purified as in Method A above to 3.39 (dd, J=5.3, 6.1 Hz, 2H), 2.81 (dd, J=5.3, 6.1 Hz, 1H), give the title compound (0.040 g. 64%) as a colorless solid: 2.17 (dd, J–5.3, 6.1 Hz, 1H), 2.08 s, 1H), 2.02, 2.01 (s, 3H), 65 'Hnmr (400 MHz, CDC1) & 7.44-7.34 (m, 3H), 7.39-7.23 1.45, 1.44 (s, 9H). (m. 2H), 3.56 (m,3H), 3.40 (m, 3H), 2.85 (brm, 2H), 2.33 (s, LCMS: m/e 372 (M-H). 3H), 2.20 (m, 2H). US 7,915,283 B2 193 194 Preparation of 4-1-Phenylmethylene-1-(5-trifluo General Method: A solution of 4-1-phenylmethylene-1-(1, romethyl-1,3,4-oxadiazol-2-yl)piperidine-1-car 3,4-oxadiazol-2-yl)piperidine-1-carboxylic acid tert-butyl boxylic Acid Tert-Butyl Ester ester (0.050g, 0.148 mmol) in dry CHCl (1 mL) was treated FC with TFA (0.25 mL). After stirring the mixture for 1 h, the Solvent was evaporated in vacuo and the residue was dis solved in CHC1. To this mixture was added 4,7-dimethoxy 6-azaindol-3-yloxoacetic acid (0.044 g., 0.163 mmol), iPrNEt (0.10 mL, 0.57 mmol) and then BOPC1 (0.049 g, 0.193 mmol). The mixture was allowed to stir at room tem 10 perature for 6 hand then the solvent was removed in vacuo. The residue was partitioned with EtOAc-HO, the organic phase was separated and the aqueous phase was re-extracted N with EtOAc (2x). The combined organic layers were washed BOC 15 (HO, brine), dried (NaSO) and evaporated. The residue Prepared according to method B to give the title compound was purified by preparative HPLC to give the title compound (77% yield) as a colourless solid: (0.015g, 21%) as a colorless solid: Hnmr (400 MHz, CDC1) & 742-7.37 (m, 3H), 7.18-7.16 Hnmr (400 MHz, CDC1) & 9.96 (brs, 1H), 8.32, 8.28 (s, (m. 2H), 3.61 (t, J=5.8 Hz, 2H), 3.45 (t, J=5.8 Hz, 2H), 2.92 1H), 7.96, 7.93 (s, 1H), 7.45-7.32 (m, 4H), 7.21-7.14 (m, 2H), (dd, J=6.1, 5.5 Hz, 2H), 2.33 (t, J=5.8 Hz, 2H), 9.42 (s, 9H). 3.99, 3.98 (s, 3H), 3.93-3.90 (m, 1H), 3.90 (s, 3H), 3.74 (t, Preparation of 4-1-Phenylmethylene-1-(5-ethyl-1,3, J=5.8 Hz, 1H), 3.64 (dd, J=5.2, 5.9 Hz, 1H), 3.47 (dd, J=5.3, 4-oxadiazol-2-yl)piperidine-1-carboxylic Acid Tert 5.8 Hz, 1H), 3.09 (t, J=5.9 Hz, 1H), 3.02 (dd, J=5.6, 5.8 Hz, Butyl Ester 1H), 2.50 (dd, J=6.1, 5.8 Hz, 2H), 2.41 (dd, J=5.9, 5.5 Hz, 2H). 25 LCMS: m/e 474 (M+H)".

30 Compounds in Examples 52-68 were prepared by an analo gous procedure to that of Example 51.

N 35 BOC Example 52 Prepared according to method B and purified by flash chro matography (SiO/EtOAc-hexane, 1:1) to give the title com Preparation of 1-4-(1-Phenyl-1-(5-methyl-1,3,4- pound (68% yield) as a colourless solid: 40 oxadiazol-2-yl)-methylene)-piperidin-1-yl)-2-(4.7- Hnmr (400 MHz, CDC1) & 743-7.36 (m, 3H), 7.21-7.19 dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione (m. 2H), 3.61 (t, J=5.8 Hz, 2H), 3.46 (t, J=5.8 Hz, 2H), 2.88 (dd, J=5.6, 6.0 Hz, 2H) 2.81 (q, J=7.6 Hz, 2H), 2.33 (dd. J=5.5, 6.1 Hz, 2H), 1.49 (s.9H), 1.33 (t, J=7.6 Hz, 3H). LCMS: m/e 370 (M+H)". 45 Example 51 Preparation of 1-4-(1-Phenyl-1-(1,3,4-oxadiazol-2- yl)-methylene)-piperidin-1-yl)-2-(4,7-dimethoxy-6- aZaindol-3-yl)-ethane-1,2-dione 50

55 MeO O

MeO Q | N \ O 60 N le N H ?y- O MeO N N H 65 repared as a colourless solid (33% yield): Hnmr (400 MHz, CDC1) & 10.5 (brs, 1H), 7.94, 7.91 (s, 1H), 7.40-7.30 (m, 4H), 720-7.13 (m, 2H), 3.96, 3.95 (s.3H),