AU2011320651A1 - HIV integrase inhibitors - Google Patents

Abstract

Tricyclic compounds of Formula I are inhibitors of HIV integrase and inhibitors of HIV replication: (I), wherein R

Description

WO 2012/058173 PCT/US20111/057557 TITLE OF THE INVENTION HIV INTEGRASE INHIBITORS FIELD OF THE INVENTION 5 The present invention is directed to certain imidazolo [5,1 -a] naphthyridine compounds and pharmaceutically acceptable salts thereof These compounds are inhibitors of the HIV integrase enzyme. The present invention is also directed to the use of the compounds and their salts in the prophylaxis or treatment of infection by HIV and in the prophylaxis, treatment, or delay in the onset or progression of AIDS. 10 BACKGROUND OF THE INVENTION A retrovirus designated human immunodeficiency virus (HIV), particularly the strains known as HIV type-1 (HIV-1) virus and type-2 (HIV-2) virus, is the etiological agent of the complex disease that includes progressive destruction of the immune system 15 (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the insertion by virally-encoded integrase of +proviral DNA into the host cell genome, a required step in HIV replication in human T lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three 20 steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes. 25 Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)]. All three enzymes have been shown to 30 be essential for the replication of HIV. It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz and protease inhibitors such as indinavir and nelfinavir. The compounds of this invention are inhibitors 35 of HIV integrase and inhibitors of HIV replication. The inhibition of integrase in vitro and HIV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro in HIV infected cells.

WO 2012/058173 PCT/US2011/057557 2 The following references are of interest as background: US 7598264 B2 discloses certain hydroxy polyhydro-2,6-naphthyridine dione compounds that are HIV integrase inhibitors. US 2009/0054399 Al discloses tricyclic analogs of hydroxy polyhydro-2,6 5 naphthyridine dione compounds which are HIV integrase inhibitors. US 7211572 B2 discloses certain nitrogen-containing fused ring compounds and their use as HIV integrase inhibitors. WO 2006/107478 A2 discloses a crystalline sodium salt of 6-(3-chloro-4 fluorobenzyl)-4-hydroxy-2-isopropyl-N,N-dimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6 10 naphthyridine- 1 -carboxamide, which is an HIV integrase inhibitor. WO 2008/048538 Al discloses certain hexahydro-diazocinonaphthyridine trione compounds which are HIV integrase inhibitors. WO 2009/154870 Al discloses hydroxy substituted polyhydropyridazinopyridodiazocine trione compounds and hydroxy substituted 15 polyhydropyrimidopyridodiazocine trione compounds which are HIV integrase inhibitors. SUMMARY OF THE INVENTION The present invention is directed to certain certain imidazolo[5, 1 a]naphthyridine compounds. These compounds (including hydrates and solvates thereof), 20 optionally in the form of pharmaceutically acceptable salts, are useful in the inhibition of retroviral integrases and for the prophylaxis or treatment of infections or other adverse diseases or conditions caused by retroviruses. The compounds of the present invention are, for example, useful in: (a) the inhibition of HIV integrase (e.g., HIV- 1 or HIV-2) and SIV, (b) the prophylaxis or treatment of infection by HIV or SIV, and (c) the prophylaxis, 25 treatment, and delay in the onset or progression of AIDS and/or ARC. As another example, the compounds are useful in: (a) the inhibition of XMRV, (b) the prophylaxis or treatment of infection by XMRV and (c) the prophylaxis, treatment or delay in the onset or progression of diseases or conditions caused by XMRV infection such as prostate cancer or chronic fatigue syndrome. In still another example, the compounds are useful in: (a) the 30 inhibition of HTLV (e.g., type 1, type 2 or type 3), (b) the prophylaxis or treatment of infection by HTLV and (c) the prophylaxis, treatment or delay in the onset or progression of diseases or conditions caused by HTLV such as T-cell leukemia or T-cell lymphoma. In the foregoing uses, the compounds can be used per se but are typically employed with one or more other ingredients in pharmaceutical compositions and optionally in combination with 35 other antiretroviral agents, anti-infectives, immunomodulators, antibiotics or vaccines. More particularly, the present invention includes compounds of Formula I and pharmaceutically acceptable salts thereof: WO 2012/058173 PCT/US2011/057557 3

R

3 A 0 R RIA R 2 B R3B N

R

2 A X N R R1B N N R RCO OH (), or a phannaceutically acceptable salt thereof, wherein: RIA and RIB are each independently: 5 (1) H, (2) C1-6 alkyl, (3) OH, (4) 0-C1 -6 alkyl, (5) C1-6 haloalkyl, 10 (6) O-Cl-6 haloalkyl, (7) halogen, (8) CN, (9) N(RA)RB, (10) C(O)N(RA)RB, 15 (11) C(O)RA, (12) C(O)ORA, (13) SRA, (14) S(O)RA, (15) SO 2 RA, 20 (16) N(RA)SO 2 RB, (17) N(RA)SO 2 N(RA)RB, (18) N(RA)C(O)RB, or (19) N(RA)C(O)C(O)N(RA)RB; or alternatively R1A and RIB are respectively located on adjacent carbons in the phenyl ring 25 and together form methylenedioxy or ethylenedioxy; RIC is: (1) H, (2) C1-6 alkyl, (3) 0-C1-6 alkyl, 30 (4) C1-6 haloalkyl, (5) 0-C1-6 haloalkyl, or WO 2012/058173 PCT/US2011/057557 4 (6) halogen; R2A and R2B are each independently: (1) H, (2) C1-8 alkyl, 5 (3) C1-8 haloalkyl, or (4) C1 -8 alkyl substituted with OH, C(O)N(RA)RB, C(O)RA, CO 2 RA, or

C(O)-N(RA)-C

2 -8 alkylene-ORB; or alternatively R2A and R 21 B together form oxo; R3A and R3B are each independently: 10 (1) H, (2) fluoro, (3) C1-8 alkyl, optionally substituted with OH, 0-C1-8 alkyl, O-C1-g haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, C(O)-N(RA)-C 2 -8 alkylene -ORB, SRA, S(O)RA, SO2RA, SO 2 N(RA)RB, N(RA)C(O)RB, 15 N(RA)CO 2 RB, N(RA)SO2RB, N(RA)SO 2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB; (4) Cl-8 haloalkyl, or (5) OH, 0-C 1-8 alkyl, 0-C 1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, C(O)-N(RA)-C 2 -8 alkylene -ORB, SRA, S(O)RA, 20 SO 2 RA, S0 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO 2 RB, N(RA)SO 2 RB, N(RA)S0 2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB; alternatively R3A and R3B together form oxo;

R

4 , R 5 and R 6 are defined as set forth in Part A, Part B or Part C below: (A) R 4 is: 25 (1) H, (2) C1-8 alkyl, (3) C1-8 haloalkyl, (4) C1-8 alkyl substituted with OH, 0-C1-8 alkyl, O-C}-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, C(O)-HetP, CO 2 RA, 30 C(O)-N(RA)-C2-8 alkylene-ORB, SRA, S(O)RA, SO 2 RA, S0 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO 2 RB, N(RA)SO 2 RB, N(RA)SO2N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB, (5) CycA, (6) C1-8 alkyl substituted with CycA, 35 (7) C1-g alkyl substituted with AryA, (8) C 1-8 alkyl substituted with HetA, (9) C1-8 alkyl substituted with HetP; WO 2012/058173 PCT/US2011/057557 5 (10) C-8 hydroxyalkyl substituted with C1-8 haloalkyl or CycA; or (11) Het A

R

5 and R 6 are each independently: 5 (1) H, (2) C1-g alkyl, (3) C1-8 haloalkyl, or (4) Ci-8 alkyl substituted with OH, 0-C1-8 alkyl, 0-C 1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, C(O)-N(RA)-C2-8 10 alkylene-ORB, SRA, S(O)RA, S0 2 RA, S0 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)S0 2 RB,

N(RA)SO

2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB, (5) CycB, (6) AryB, 15 (7) HetB, (8) C1 - alkyl substituted with CycB, (9) C 1-8 alkyl substituted with AryB, (10) C1-8 alkyl substituted with HetB, or (11) C1 -8 alkyl substituted with HetQ; 20 or (B) R 4 and R 5 together with the atoms to which they are attached form a 4- to 8 membered fused azacycloalkyl ring which is optionally substituted with from 1 to 4 substituents each of which is independently: (1) Cl-s alkyl, 25 (2) C1 -8 haloalkyl, or (3) C 1-8 alkyl substituted with OH, 0-C 1-8 alkyl, 0-C1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, C(O)-N(RA)-C2-8 alkylene-ORB, SRA, S(O)RA, SO 2 RA, SO 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)SO 2 RB, 30 N(RA)SO 2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB, (4) CycB, (5) AryB, (6) HetB, (7) Cl-8 alkyl substituted with CycB, 35 (8) Ci-8 alkyl substituted with AryB, (9) Ci-g alkyl substituted with HetB, or (10) C1-8 alkyl substituted with HetQ; WO 2012/058173 PCT/US2011/057557 6

R

6 is: (1) H, (2) C1-8 alkyl, 5 (3) CI-8 haloalkyl, or (4) C-8 alkyl substituted with OH, O-Cl-8 alkyl, O-C1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, C(O)-N(RA)-C2-8 alkylene-ORB, SRA, S(O)RA, SO 2 RA, SO 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO 2 RB, N(RA)SO 2 RB, 10 N(RA)SO 2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB, (5) CycB, (6) AryB, (7) HetB, (8) CI -8 alkyl substituted with CycB, 15 (9) CI -8 alkyl substituted with AryB, (10) CI- g alkyl substituted with HetB, or (11) C-8 alkyl substituted with HetQ; or (C) R4 is: 20 (1) H, (2) C1-8 alkyl, (3) C1-8 haloalkyl, or (4) C 1-8 alkyl substituted with OH, O-C 1-8 alkyl, 0-C 1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, -C(O)HetA, 25 C(O)N(RA)HetP, -C(O)N(RA)HetP, C(O)-N(RA)-C2-8 alkylene-ORB, SRA, S(O)RA, SO2RA, S02N(RA)RB, N(RA)C(O)RB, N(RA)CO 2 RB, N(RA)SO 2 RB,

N(RA)SO

2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB, (5) CycA, 30 (6) Ci1-8 alkyl substituted with CycA, (7) C1-8 alkyl substituted with AryA, (8) CL-8 alkyl substituted with HetA, or (9) Ci-8 alkyl substituted with HetP; 35 R 5 and R 6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 4- to 8-membered cycloalkyl, which can be optionally fused to a benzene ring or a 5 or 6-membered heteroaryl ring, WO 2012/058173 PCT/US2011/057557 7 (ii) a 6- to 10-membered fused or bridged bicycloalkyl, or (iii) a 5- to 8 membered heterocyclylalkyl in which the ring heteroatom is selected from N, 0 and S where the S is optionally oxidized to S(O) or S(O)2; wherein the spirocyclic ring is optionally substituted on a ring carbon with oxo and is 5 optionally substituted with from I to 4 substituents each of which is independently: (1) C1-8 alkyl, (2) C1 -8 haloalkyl, or (3) C1 -g alkyl substituted with OH, O-C1-8 alkyl, 0-C 1-8 haloalkyl, CN, 10 N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, C(O)-N(RA)-C2-8 alkylene-ORB, SRA, S(O)RA, SO 2 RA, SO2N(RA)RB, N(RA)C(O)RB, N(RA)CO 2 RB, N(RA)SO 2 RB,

N(RA)SO

2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB, (4) CycB, 15 (5) AryB, (6) HetB, (7) CI-8 alkyl substituted with CycB, (8) Ci-8 alkyl substituted with AryB, (9) C -8 alkyl substituted with HetB, or 20 (10) CI-8 alkyl substituted with HetQ; AryA is an aryl which is optionally substituted with from 1 to 5 substituents, wherein: (A) each of the substituents is independently: (1) Cl1-6 alkyl, 25 (2) C1-6 alkyl substituted with OH, O-C1-6 alkyl, 0-C 1-6 haloalkyl, CN, NO2, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA,

SO

2 RA, SO 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO 2 RB,

N(RA)SO

2 RB, N(RA)SO 2 N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB, 30 (3) O-C1-6 alkyl, (4) C1-6 haloalkyl, (5) O-C1-6 haloalkyl, (6) OH, (7) halogen, 35 (8) CN, (9) N02, (10) N(RA)RB, WO 2012/058173 PCT/US2011/057557 8 (11) C(O)N(RA)RB, (12) C(O)RA, (13) C(O)-C1-6 haloalkyl, (14) C(O)ORA, 5 (15) OC(O)N(RA)RB, (16) SRA, (17) S(O)RA, (18)

SO

2 RA, (19) SO 2 N(RA)RB, 10 (20) N(RA)SO 2 RB, (21) N(RA)SO 2 N(RA)RB, (22) N(RA)C(O)RB, (23) N(RA)C(O)N(RA)RB, (24) N(RA)C(O)C(O)N(RA)RB, or 15 (25) N(RA)CO2RB; or (B) when there are two or more substituents on the aryl, two of the substituents are respectively located on adjacent carbons on the aryl ring and together form methylenedioxy or ethylenedioxy, and other substituents, if any, are each independently one of groups (1) to (25) as set forth in (A) above; 20 each AryB independently has the same definition as AryA; CycA is a 3- to 8-membered monocyclic or bicyclic cycloalkyl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, OH, C1-6 alkyl, 0-C1-6 alkyl, C1-6 alkyl substituted with -OH, 0-C1-6 alkyl, C1-6 25 haloalkyl, or 0-C1 -6 haloalkyl; each CycB independently has the same definition as CycA; HetA is a heteroaryl which is optionally substituted with from 1 to 5 substituents, each of which is independently: (1) C 1-6 alkyl, 30 (2) C1-6 alkyl substituted with OH, 0-C1-6 alkyl, 0-C1-6 haloalkyl, CN, N02, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, SRA, S(O)RA, SO 2 RA,

SO

2 N(RA)RB, N(RA)C(O)RB, N(RA)CO 2 RB, N(RA)SO2RB,

N(RA)SO

2 N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB, 35 (3) 0-C1-6 alkyl, (4) C1-6 haloalkyl, (5) 0-C 1-6 haloalkyl, WO 2012/058173 PCT/US2011/057557 9 (6) OH, (7) halogen, (8) CN, (9) N02, 5 (10) N(RA)RB, (11) C(0)N(RA)RB, (12) C(O)RA, (13) C(O)-C1 -6 haloalkyl, (14) C(O)ORA, 10 (15) OC(O)N(RA)RB, (16) SRA, (17) S(0)RA, (18) SO 2 RA, (19) SO 2 N(RA)RB, 15 (20) N(RA)SO 2 RB, (21) N(RA)SO 2 N(RA)RB, (22) N(RA)C(O)RB, (23) N(RA)C(O)N(RA)RB, (24) N(RA)C(O)C(O)N(RA)RB, or 20 (25) N(RA)CO 2 RB; each HetB independently has the same definition as HetA; HetP is (i) a 4- to 7-membered, saturated or mono-unsaturated heterocyclic ring containing at least one carbon atom and from I to 4 heteroatoms independently selected from N, 0 and S, where each S is optionally oxidized to S(O) or S(0)2 or (ii) a 6- to 10 25 membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, 0 and S, where each S is optionally oxidized to S(O) or S(0)2; and wherein the saturated or mono unsaturated heterocyclic or heterobicyclic ring is optionally substituted with a total of from I to 4 substituents, each of which is independently halogen, C1-6 alkyl, C1-6 30 haloalkyl, 0-C1-6 alkyl, 0-C 1-6 haloalkyl, oxo, C(O)N(RA)RB, C(O)C(O)N(RA)RB, C(O)RA, CO 2 RA, SRA, S(O)RA, SO 2 RA, or SO 2 N(RA)RB; each HetQ independently has the same definition as HetP; each RA is independently H, C1-6 alkyl or C1-6 haloalkyl; each RB is independently H, C1-6 alkyl or C1-6 haloalkyl; 35 each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic; and WO 2012/058173 PCT/US2011/057557 10 each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from I to 4 heteroatoms independently selected from N, 0 and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, 0 and S, 5 wherein either one or both of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(O)2. The present invention also includes pharmaceutical compositions containing a compound of Formula I or a pharmaceutically acceptable salt thereof. The present 10 invention further includes methods involving compounds of Formula I for the treatment of AIDS, the delay in the onset or progression of AIDS, the prophylaxis of AIDS,'the prophylaxis of infection by HIV, and the treatment of infection by HIV. Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and 15 appended claims. DETAILED DESCRIPTION OF THE INVENTION The present invention includes compounds of Formula I above (including hydrates and solvates thereof), and pharmaceutically acceptable salts thereof These 20 compounds are effective inhibitors of wild-type HIV integrase (e.g., HIV-1) and may be effective inhibitors of mutant strains of HIV integrase. A first embodiment of the present invention (alternatively referred to herein as "Embodiment El I") is a compound of Formula I (alternatively and more simply referred to as "Compound I"), or a pharmaceutically acceptable salt thereof, wherein: 25 AryA is phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently: (1) C 1-6 alkyl, (2) 0-C 1-6 alkyl, (3) Cl-6 haloalkyl, 30 (4) O-CI-6 haloalkyl, (5) OH, (6) halogen, (7) CN, (8) N(RA)RB, 35 (9) C(O)N(RA)RB, (10) S(O)RA, (1) SO2RA, WO 2012/058173 PCT/US2011/057557 11 (12) N(RA)SO2RB, (13) N(RA)SO 2 N(RA)RB, (14) N(RA)C(O)RB, or (15) N(RA)C(0)C(0)N(RA)RB; and 5 each AryB independently has the same definition as AryA; CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently OH, C1 -6 alkyl, 0-C1 -6 alkyl, or C1 -6 alkyl -substituted with O-C1 -6 alkyl; each CycB independently has the same definition as CycA; 10 HetA is a 5- or 6-membered. heteroaromatic ring containing a total of from I to 3 heteroatoms independently selected from N, S and 0, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently C1-4 alkyl, OH, O-C1-4 alkyl, halogen, CN, C(O)N(RA)RB, C(O)RA, C(O)ORA, or SO 2 RA; 15 each HetB independently has the same definition as HetA; HetP is a 5- or 6-membered saturated heterocyclic ring containing a total of from 1 to 2 heteroatoms selected from I to 2 N atoms, zero to 1 0 atom, and zero to I S atom, wherein the S atom is optionally S(0) or S02, wherein the saturated heterocyclic ring is optionally substituted with from I to 3 substituents each of which is 20 independently C1 -4 alkyl, oxo, C(O)N(RA)RB, C(O)RA, CO2RA, or SO 2 RA; and each HetQ independently has the same definition as HetP; and all other variables are as originally defined (i.e., as defined in the Summary of the Invention). A second embodiment of the present invention (Embodiment E2) is a 25 compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: RIA and RIB are each independently: (1) H, (2) C1-6 alkyl, (3) OH1, 30 (4) 0-C1-6 alkyl, (5) C1-6 haloalkyl, (6) 0-C 1-6 haloalkyl, (7) halogen, (8) CN, 35 (9) N(RA)RB, (10) C(O)N(RA)RB, (11) C(O)RA, WO 2012/058173 PCT/US2011/057557 12 (12) C(O)ORA, (13) SRA, (14) S(O)RA, (15) SO 2 RA; or 5 or alternatively R1A and RIB are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy; R1C is: (1) H, (2) C1 -6 alkyl, 10 (3) 0-C1-6 alkyl, (4) C 1-6 haloalkyl, (5) 0-C1 -6 haloalkyl, or (6) halogen; and all other variables are as originally defined or as defined in Embodiment El. 15 A third embodiment of the present invention (Embodiment E3) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: RIA and RIB are each independently: (1) H, (2) C1-4 alkyl, 20 (3) OH, (4) O-C 1-4 alkyl, (5) CF3, (6) OCF3, (7) Cl, 25 (8) Br, (9) F, (10) CN, (11) NH2, (12) N(H)-C1-4 alkyl, 30 (13) N(C1-4 alkyl)2, (14) C(Q)NH2, (15) C(O)N(H)-C1-3 alkyl, (16) C(0)N(C 1-3 alkyl)2, (17) CH(O), 35 (18) C(O)-C1-4 alkyl, (19) CO2H, (20) C02-C1-4 alkyl, WO 2012/058173 PCT/US2011/057557 13 (21) SO2H, or (22) SO2-C1-4 alkyl; RIC is: (1) H, 5 (2) C1-4 alkyl, (3) O-C 1-4 alkyl, (4) CF3, (5) OCF3, (6) Cl, 10 (7) Br, or (8) F; and all other variables are as originally defined or as defined in Embodiment El. A fourth embodiment of the present invention (Embodiment E4) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: 15 R1 A and R 1 B are each independently: (1) H, (2) CH3, (3) CH2CH3 (4) OH, 20 (5) OCH3, (6) CF3, (7) OCF3, (8) Cl, (9) Br, 25 (10) F, (11) CN, (12) NH2, (13) N(H)CH3, (14) N(CH3)2, 30 (15) C(O)NH2, (16) C(O)N(H)CH3, (17) C(O)N(CH3)2, (18) CH(0), (19) C(O)CH3, 35 (20) CO2H, (21) CO2CH3, (22) S02H, or WO 2012/058173 PCT/US2011/057557 14 (23) SO2CH3; RIC is: (1) H, (2) CH3, 5 (3) OCH3, (4) CF3, (5) OCF3, (6) Cl, (7) Br, or 10 (8) F; and all other variables are as originally defined or as defined in Embodiment El. A fifth embodiment of the present invention (Embodiment E5) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: RIA and R 1 1 B are each independently: 15 (1) H, (2) CH3, (3) Cl, (4) Br, or (5) F; 20 RIC is: (1) H, (2) CH3, (3) Cl, (4) Br, or 25 (5) F; and provided that at least one of R1A, RIB and R1C is other than H; and all other variables are as originally defined or as defined in Embodiment El. A sixth embodiment of the present invention (Embodiment E6) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RIA is F in 30 the para position of the benzyl moiety; R 1 B is H, Cl, or Br in the ortho or meta position of the benzyl moiety; R1C is H; and all other variables are as originally defined or as defined in Embodiment El. A seventh embodiment of the present invention (Embodiment E7) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2A and 35 R3A are each independently H, fluoro, or C1-6 alkyl; R2B is H; R3Bis H; and all other variables are as originally defined or as defined in any one of the foregoing embodiments.

WO 2012/058173 PCT/US2011/057557 15 An eighth embodiment of the present invention (Embodiment E8) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2A, R2B, R3A, and R3B are each H; and all other variables are as originally defined or as defined in any one of the foregoing embodiments. 5 A ninth embodiment of the present invention (Embodiment E9) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 and R6 are defined as set forth in Part A, Part B or Part C below: (A) R 4 is: (1) H, 10 (2) Cl-8 alkyl, (3) Cj -6 haloalkyl, (4) C1-6 alkyl substituted with O-C1-6 alkyl, C(O)N(RA)RB, C(O)RA, CO 2 RA, SRA, S(0)RA, SO 2 RA, or S0 2 N(RA)RB, (5) CycA, or 15 (6) C1 -6 alkyl substituted with CycA, one of R 5 and R6 is H or C1 -6 alkyl, and the other of R 5 and R 6 is: (1) H, (2) C1-8 alkyl, (3) C1-6 haloalkyl, 20 (4) C 1-6 alkyl substituted with O-C1 -6 alkyl, C(O)N(RA)RB, C(O)RA, CO 2 RA, S(O)RA, SO 2 RA, or SO 2 N(RA)RB, (5) CycB, or (6) C1-6 alkyl substituted with CycB; or 25 (B) R 4 and R 5 together with the atoms to which they are attached form a 5- to 7 membered fused azacycloalkyl ring which is optionally substituted with from 1 to 3 substituents each of which is independently: (1) C 1-6 alkyl, (2) C 1-6 haloalkyl, or 30 (3) C1-6 alkyl substituted with OH, 0-C1-6 alkyl, 0-C1-6 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, SRA, S(O)RA, or SO 2 RA, (4) CycB, or (5) C 1-6 alkyl substituted with CycB; 35 R6 is: (1) H, (2) C1-8 alkyl, WO 2012/058173 PCT/US2011/057557 16 (3) Cl -6 haloalkyl, or (4) C1-6 alkyl substituted with OH, O-C1-6 alkyl, O-C1-6 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, SRA, S(O)RA, SO 2 RA, or S02N(RA)RB; 5 or (C) R4 is as defined in Part A; R5 and R 6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl, or (iii) a 5- to 7-membered 10 heterocyclylalkyl in which the ring atom is selected from N, 0 and S, where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted on a ring carbon with oxo and is optionally substituted with from I to 3 substituents each of which is independently: (1) C 1-6 alkyl, 15 (2) Cl-6 haloalkyl, or (3) C1-6 alkyl substituted with OH, 0-C 1-6 alkyl, 0-C 1-6 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, SRA, S(O)RA, SO 2 RA, or S0 2 N(RA)RB, (4) CycB, or 20 (5) C1-6 alkyl substituted with CycB; and all other variables are as originally defined or as defined in any one of the foregoing embodiments. In an aspect of this embodiment, CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently OH, C1 -6 alkyl, 0-C1 -6 alkyl, or C 1-6 alkyl substituted with 0-C 1-6 alkyl; and each CycB 25 independently has the same definition as CycA. A tenth embodiment of the present invention (Embodiment E10) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 and R6 are defined as set forth in Part A, Part B or Part C below: (A) R 4 is: 30 (1) H, (2) C 1-4 alkyl, (3) C1-4 fluoroalkyl, (4) C1-4 alkyl substituted with 0-C 1-4 alkyl, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, 35 C(O)O-C1-4 alkyl, S-C1-4 alkyl, or S02-C1-4 alkyl, (5) CycA, or (6) CH2-CycA; WO 2012/058173 PCT/US2011/057557 17 one of R 5 and R 6 is H or CI-4 alkyl, and the other of R5 and R 6 is: (1) H, (2) C-8 alkyl, (3) C1-4 fluoroalkyl, 5 (4) C1 -6 alkyl substituted with 0-C 1-6 alkyl, (5) CycB, or (6) CH2-CycB; or (B) R 4 and R 5 together with the atoms to which they are attached form a 5- or 10 6-membered fused azacycloalkyl ring which is optionally substituted with from I to 3 substituents each of which is independently: (1) C1-4 alkyl, (2) C 1-4 fluoroalkyl, or (3) C1-4 alkyl substituted with 0-C 1-4 alkyl; 15 R 6 is (1) H, or (2) C1-4 alkyl; or (C) R 4 is as defined in Part A: 20 R 5 and R 6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl which is optionally substituted on a ring carbon with oxo, or (iii) a 5- or 6-membered heterocyclylalkyl in which the ring atom is selected from N, 0 and S, where the S is optionally oxidized 25 to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently: (1) C1-4 alkyl, (2) C 1-4 fluoroalkyl, or (3) C1-4 alkyl substituted with 0-C1-4 alkyl; 30 and all other variables are as originally defined or as defined in any one of the foregoing embodiments. In an aspect of this embodiment, CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently Cl-4 alkyl, 0-C1-4 alkyl, or C1-4 alkyl substituted with 0-C1-4 alkyl; and CycB independently has the same definition as CycA. 35 An eleventh embodiment of the present invention (Embodiment El 1) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4, R 5 and R6 are defined as set forth in Part A, Part B or Part C below: WO 2012/058173 PCT/US2011/057557 18 (A) R4 is: (1) H, (2) C 1-4 alkyl, (3) CF3, 5 (4) CH2CF3, (5) (CH2)1-3-T, wherein T is C(O)NH2, C(O)NH(CH3), C(O)N(CH3)2, CO2H, C(O)OCH3, or S02CH3, (6) (CH2)2-3-U, wherein U is OCH3 or SCH3, (7) CycA, or 10 (8) CH2-CycA; one of R 5 and R 6 is H or C1-4 alkyl, and the other of R 5 and R6 is: (1) H, (2) Cl-8 alkyl, (3) CF3, 15 (4) CH2CF3, (5) CycB, or (6) CH2-CycB; or (B) R 4 and R 5 together with the atoms to which they are attached form a 5- or 6 20 membered fused azacycloalkyl ring which is optionally substituted with from I to 3 substituents each of which is independently: (1) C1-4 alkyl, (2) CF3, (3) CH2CF3, 25 (3) C1-4 alkyl substituted with 0-C1-4 alkyl;

R

6 is (1) H, or (2) C1-4 alkyl; or 30 (C) R 4 is as defined in Part A:

R

5 and R 6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl which is optionally substituted on a ring carbon with oxo, or (iii) a 5- or 6-membered heterocyclylalkyl in which 35 the ring atom is selected from N, 0 and S, where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently: WO 2012/058173 PCT/US2011/057557 19 (1) C 1-4 alkyl, (2) CF3, or (3) CH2CF3; and all other variables are as originally defined or as defined in any one of the foregoing 5 embodiments. In an aspect of this embodiment, CycA is a 3- to 6-membered cycloalkyl; and CycB is a 3- to 6-membered cycloalkyl. A twelfth embodiment of the present invention (Embodiment E12) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 and R6 are defined as set forth in Part A, Part B or Part C below: 10 (A) R 4 is: (1) H, (2) CH3, (3) CH2CH3, (4) CH2CH2CH3, 15 (5) CH(CH3)2, (6) CH2CH(CH3)2, (7) CH2CF3, (8) CH2C(O)OH, (9) CH2C(O)OCH3, 20 (10) CH2C(O)OCH2CH3, (11) CH2CH20CH3, (12) CH2CH2SCH3, (13) CycA, or (14) CH2-CycA; 25 R 5 is: (1) H, (2) CH3, (3) CH2CH3, (4) CH2CH2CH3, 30 (5) CH(CH3)2, (6) C(CH3)3, (7) CH(CH2CH3)2, (8) CH(CH3)CH2CH3, or (9) C(CH2CH3)3, 35 (10) CH2CF3, or (11) CycB;

R

6 is H, CH3, or CH2CH3; WO 2012/058173 PCT/US2011/057557 20 or (B) R4 and R5 together with the atoms to which they are attached form a 5- or 6 membered fused azacycloalkyl ring which is: *-Np

*-N

* or * ; wherein the azacycloalkyl ring is optionally 5 substituted with I or 2 substituents each of which is independently methyl or ethyl; and each asterisk (*) denotes the point of attachment to the rest of the compound;

R

6 is (1) H, 10 (2) CH3, or (3) CH2CH3; or (C) R 4 is as defined in Part A:

R

5 and R 6 together with the carbon atom to which they are both attached 15 form a spirocyclic ring which is: *X *> OS or , ; wherein the spirocyclic ring is optionally substituted with I or 2 methyl groups; and each asterisk (*) denotes the point of attachment to the rest of the compound; 20 and all other variables are as originally defined or as defined in any one of the foregoing embodiments. In an aspect of this embodiment, CycA is cyclopropyl; and CycB is cyclopropyl, cyclobutyl, or cyclopentyl. A thirteenth embodiment of the present invention (Embodiment E13) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R4, R5 and 25 R 6 are as defined in Embodiment E12, except that in part B of the definition of R4, R 5 and

R

6 :

R

4 and R 5 together with the atoms to which they are attached form a fused azacycloalkyl ring which is: WO 2012/058173 PCT/US2011/057557 21 *-N *-N *-N CH *- *-N

OH

3 * CH 3 *

CH

3 ,or *-N * H 3 C CH 3 H3;and

R

6 is (1) H, (2) CH3, or (3) CH2CH3; and 5 in part C of the definition of R 4 , R 5 and R 6 :

R

4 is (1) H, (2) CH3, (3) CH2CH3, (4) CH2CH2CH3, (5) CH(CH3)2, (6) CH2CH(CH3)2, (7) CH2C(O)OH, (8) cyclopropyl, or (9) CH2-cyclopropyl; and

R

5 and R 6 together with the carbon atom to which they are both attached form a 10 spirocyclic ring which is: O XD * >0 0

H

3 S

H

3

CH

3 * * OCH 3 ***

OH

3 , or A fourteenth embodiment of the present invention (Embodiment E14) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RA and RB 15 are each independently H or C1.4 alkyl; and all other variables are as originally defined or as defined in any of the preceding embodiments. A fifteenth embodiment of the present invention (Embodiment E15) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RA and RB are each independently H or C1 -3 alkyl; and all other variables are as originally defined or 20 as defined in any of the preceding embodiments. A sixteenth embodiment of the present invention (Embodiment E16) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein RA and RB are each independently H or CH3; and all other variables are as originally defined or as defined in any of the preceding embodiments. 25 A seventeenth embodiment of the present invention (Embodiment E17) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure: WO 2012/058173 PCT/US2011/057557 22 An eighteenth embodiment of the present invention (Embodiment E18) is a 5 compound of Formula I, or an individual enantiomer or diastereomer thereof, which is selected from Examples 1-177, as set forth in the Examples below. An nineeenth embodiment of the present invention (Embodiment E19) is a compound of Formula I, or an individual enantiomer or diastereomer thereof, which is selected from the group consisting of: 10 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9', I 0'-dihydro-2'H spiro[bicyclo[2.2.1]heptane-2,3'-imidazo[5,1-a] [2,6]naphthyridine]-l',5',7'(8'H)-trione; 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2,3-dimethyl-2,3,9, 10 tetrahydroimidazo[5,1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-3-cyclobutyl-6-hydroxy-2-(2-methoxyethyl)-3 15 methyl-2,3,9,1 0-tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione; 3-(3-chloro-4-fluorobenzyl)-5-hydroxy-8,8-dimethyl-2,3,8,9,10,11 hexahydro-7aH-pyrido[2',I':2,3]imidazo[5,1-a][2,6]naphthyridine-4,6,13(1H)-trione; 3-(3-chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3,7a,8,9,10 hexahydropyrrolo[2', 1':2,3]imidazo[5,1-a] [2,6]naphthyridine-4,6,12(1H)-trione; 20 3-(3-chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3,8,9,10,11 -hexahydro 7aH-pyrido[2', 1 ':2,3]imidazo[5,1-a] [2,6]naphthyridine-4,6,13(1H)-trione; -3-(3-chloro-4-fluorobenzyl)-7a-ethyl-5-hydroxy-2,3,8,9,10,11-hexahydro 7aH-pyrido[2', 1':2,3]imidazo[5,1-a] [2,6]naphthyridine-4,6,13(1H)-trione; 8-(4-fluorobenzyl)-6-hydroxy-2-methyl-3-(1-methylethyl)-2,3,9, 10 25 tetrahydroimidazo[5, 1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 8'-(2-bromo-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9', 1 0'-dihydro-2'H spiro[cyclopentane- 1,3'-imidazo[5, 1-a] [2,6]naphthyridine]- 1',5',7'(8'H)-trione; 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-3-(1 -methylethyl)-2,3,9,10 tetrahydroimidazo[5, 1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 30 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2,3,3-trimethyl-2,3,9, 10 tetrahydroimidazo[5, 1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-(2-methoxyethyl)-3-( 1 methylethyl)-2,3,9,1 0-tetrahydroimidazo[5,1 -a][2,6]naphthyridine- 1,5,7(8H)-trione; 3-tert-butyl-8-(3 -chloro-4-fluorobenzyl)-6-hydroxy-2-methy-2,3,9,10 35 tetrahydroimidazo [5,1-a] [2,6]naphthyridine- 1,5,7(8H)-trione; 3-(3-chloro-4-fluorobenzyl)-5-hydroxy-2,3,8,9,10,1 1-hexahydro-7aH pyrido[2',1':2,3]imidazo[5,1-a][2,6]naphthyridine-4,6,13(1H)-trione; 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-(2-methoxyethyl)-3-methyl 2,3,9,10-tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione; 40 8-(3-chloro-4-fluorobenzyl)-2,3-dicyclopropyl-6-hydroxy-2,3,9,10 tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione; 3-tert-butyl-8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-2,3,9,10 tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(SH)-trione; WO 2012/058173 PCT/US2011/057557 23 8-(3-chloro-4-fluorobenzyl)-3-ethyl-6-hydroxy-2-methyl-2,3,9,10 tetrahydroimidazo[5,1-a] f2,6]naphthyridine- 1,5,7(8H)-trione; 3-tert-butyl-8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2,3,9,10 tetrahydroimidazo[5, 1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 5 8-(3-chloro-4-fluorobenzyl)-3-(1,1 -diethylpropyl)-6-hydroxy-2,3,9, 10 tetrahydroinidazo[5,1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9', 1 0'-dihydro-2'H spiro[cyclobutane- 1,3'-imidazo[5,1-a] [2,6]naphthyridine] -1 ',5',7'(8'H)-trione; 8-(3-chloro-4-fluorobenzyl)-3-ethyl-6-hydroxy-3-methyl-2,3,9, 10 10 tetrahydroimidazo[5,1-a] [2,6]naphthyridine- 1,5,7(8H)-trione; 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9', 1 0'-dihydro-2'H spiro[cyclopentane-1,3'-imidazo[5,1-a] [2,6]naphthyridine]-1 ',5',7'(8'H)-trione; 8-(3-chloro-4-fluorobenzyl)-3-cyclobutyl-6-hydroxy-2,3,9, 10 tetrahydroimidazo[5, 1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 15 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9',10'-dihydro-2'H spiro[cyclohexane- 1,3'-imidazo[5,1-a] [2,6]naphthyridine]-1 ',5',7'(8'H)-trione; 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9',10'-dihydro-2'H spiro[cycloheptane-1,3'-imidazo[5,1-a] [2,6]naphthyridine]- 1',5',7'(8'H)-trione; 8-(3-chloro-4-fluorobenzyl)-3-cyclobutyl-6-hydroxy-2,3-dimethyl-2,3,9,10 20 tetrahydroimidazo[5,1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-3-ethyl-6-hydroxy-2,3-dimethyl-2,3,9,10 tetrahydroimidazo[5,1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2,3-dimethyl-3-propyl-2,3,9,10 tetrahydroimidazo[5,1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 25 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-4',5',9,10-tetrahydro-2H spiro[imidazo[5,1-a] [2,6]naphthyridine-3,3'-thiophene]-1,5,7(8H)-trione; 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2',3-dimethyl-9',10'-dihydro-2'H spiro[cyclopentane-1,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(8'H)-trione; 8-(3-chloro-4-fluorobenzyl)-2-ethyl-6-hydroxy-3-methyl-2,3,9,10 30 tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione; 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2',4-dimethyl-9', I 0'-dihydro-2'H spiro[cyclohexane-1,3'-imidazo[5,1-a] [2,6]naphthyridine]-1',5',7'(8'H)-trione; ethyl [8-(3-chloro-4-fluorobenzyl)-6-hydroxy-3-methyl-1,5,7-trioxo 1,5,7,8,9,1 0-hexahydroimidazo[5,1-a] [2,6]naphthyridin-2(3H)-yl]acetate 35 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-3a',4'6',6a',9,10-hexahydro 1'H,2H-spiro[imidazo[5, 1-a] [2,6]naphthyridine-3,2'-pentalene]- 1,5,5',7(3'H,8H)-tetrone 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-3-(1-methylpropyl) 2,3,9,1 0-tetrahydroimidazo[5,1-a] [2,6]naphthyridine- 1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-3-(1-ethylpropyl)-6-hydroxy-2-methyl-2,3,9, 10 40 tetrahydroimidazo[5,1-a] [2,6]naphthyridine- 1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-3-cyclopentyl-6-hydroxy-2-methyl-2,3,9, 10 tetrahydroimidazo[5, 1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(2-methylpropyl) 2,3,9,1 0-tetrahydroimidazo[5,1-a] [2,6]naphthyridine- 1,5,7(8H)-trione; 45 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-3-methyl-3-(2,2,2-trifluoroethyl) 2,3,9,1 0-tetrahydroimidazo[5,1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 8'-(3-chloro-4-fluorobenzyl)-2'-ethyl-6'-hydroxy-9', I 0'-dihydro-2'H spiro[cyclopentane-1,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(8'H)-trione; WO 2012/058173 PCT/US2011/057557 24 8'-(3 -chloro-4-fluorobenzyl)-6'-hydroxy-9', 1 0'-dihydro-2'H spiro[cyclopentane-1,3'-imidazo[5,1-a] [2,6]naphthyridine]- 1 ',5',7'(8'H)-trione; 3-tert-butyl-8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-(2-methylpropyl) 2,3,9,1 0-tetrahydroimidazo [5,1-a] [2,6]naphthyridine- 1,5,7(8H)-trione; 5 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2',3,3-trimethyl-9', 10'-dihydro-2'H spiro [cyclohexane- 1,3'-imidazo [5,1-a] [2,6]naphthyridine] -1 ,5',7'(8'H)-trione; methyl [8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-1,5,7-trioxo 1,5,7,8,9,1 0-hexahydroimidazo[5,1-a] [2,6]naphthyridin-2(3H)-yl]acetate 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-(2-methylpropyl)-9',10'-dihydro 10 2'H-spiro[cyclopentane- 1,3'-imidazo[5, 1-a] [2,6]naphthyridine]- 1',5',7'(8'H)-trione; 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2-methyl-9',1 0'-dihydro-2'H spiro[cyclopentane-1,3'-imidazo[5,1-a][2,6]naphthyridine)-1',5',7'(8'H)-trione; 3-tert-butyl-8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-[2 (methylsulfanyl)ethyl]-2,3,9,1 0-tetrahydroimidazo[5,1-a] [2,6]naphthyridine-1,5,7(8H) 15 trione; 8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[2 (methylsulfanyl)ethyl]-2,3,9,1 0-tetrahydroimidazo[5,1-a] [2,6]naphthyridine- 1,5,7(8H) trione; 8-(3-chloro-4-fluorobenzyl)-3-cyclobutyl-2-(cyclopropylmethyl)-6-hydroxy 20 3-methyl-2,3,9,1 0-tetrahydroimidazo[5,1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 8'-(3-chloro-4-fluorobenzyl)-2'-cyclopropyl-6'-hydroxy-9', 1 0'-dihydro-2'H spiro [cyclopentane- 1,3'-imidazo [5,1-a] [2,6]naphthyridine] -1',5',7'(8'H)-trione; [8'-(3 -chloro-4-fluorobenzyl)-6'-hydroxy- 1',5',7'-trioxo- 1',5',7',8',9', 10' hexahydro-2'H-spiro [cyclopentane- 1,3'-imidazo [5,1-a] [2,6]naphthyridin] -2'-yl] acetic acid 25 8'-(3-chloro-4-fluorobenzyl)-2'-(cyclopropylmethyl)-6'-hydroxy-9',10' dihydro-2'H-spiro[cyclopentane-1,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(8'H)-trione; and pharmaceutically acceptable salts thereof. A twentieth embodiment of the present invention (Embodiment E20) is a 30 compound of Formula I, or an individual enantiomer or diastereomer thereof, which is selected from Examples 12, 14, 15, 17, 19, 26-29 or 150, as set forth in the Examples below. In one embodiment, for the compounds of formula (I), variables RIA, R' 3 , 35 Ric, R 2 A, R 2 B, R 3 A, R', R 4 , R' and Ri are selected independently of each other. A first class of compounds of the present invention (alternatively referred to herein as Class C1) includes compounds of Formula II: O ,R4 R3A N RIA 2 A N R 6 LN Q R1c R O OH (11) WO 2012/058173 PCT/US2011/057557 25 and pharmaceutically acceptable salts thereof, wherein: RIA, RIB and R 1 C are as defined in Embodiment E2; R2A and R3A are each independently H, fluoro, or C1-6 alkyl;

R

4 , R 5 and R 6 are as defined in Embodiment E9; 5 CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently OH, C1 -6 alkyl, 0-C1 -6 alkyl, or C1 -6 alkyl substituted with 0-C 1-6 alkyl; each CycB independently has the same definition as CycA; each RA is independently H or C1-6 alkyl; and 10 each RB is independently H or C1-6 alkyl. A first sub-class of the first class (alternatively referred to herein as "Sub class Cl-SI ") includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein R2A and R3A are each independently H, fluoro, or CH3; and all other variables are as originally defined in Class C1. 15 A second sub-class of the first class (Sub-class C 1-S2) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein each RA is independently H or C1-4 alkyl; each RB is independently H or C1-6 alkyl; and all other variables are as originally defined in Class C1 or as defined in Sub-class Cl-SI. A third sub-class of the first class (Sub-class C1-S3) includes compounds of 20 Formula II and pharmaceutically acceptable salts thereof, wherein each RA is independently H or CH3; each RB is independently H or CH3; and all other variables are as originally defined in Class C1 or as defined in Sub-class Cl-SI. A second class of compounds of the present invention (Class C2) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein: 25 RiA, R1B and R 1 C are as defined in Embodiment E3; R2A and R3A are both H;

R

4 , R 5 and R 6 are as defined in Embodiment E10; CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from I to 3 substituents each of which is independently C1-4 alkyl, 0-C 1-4 alkyl, or C1-4 alkyl 30 substituted with 0-C1-4 alkyl; and CycB independently has the same definition as CycA; each RA is independently H or C1-6 alkyl; and each RB is independently H or C1-6 alkyl. A first sub-class of the second class (Sub-class C2-S1) includes compounds 35 of Formula I and pharmaceutically acceptable salts thereof, wherein each RA is independently H or C-4 alkyl; each RB is independently H or C1-6 alkyl; and all other variables are as originally defined in Class C2.

WO 2012/058173 PCT/US2011/057557 26 A second sub-class of the second class (Sub-class C2-S2) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein each RA is independently H or CH3; each RB is independently H or CH3; and all other variables are as originally defined in Class C2. 5 A third class of compounds of the present invention (Class C3) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein: RIA, RIB and RIC are as defined in Embodiment E4; R2A and R3A are both H;

R

4 , R 5 and R 6 are as defined in Embodiment E11; 10 CycA is a 3- to 6-membered cycloalkyl; and CycB is a 3- to 6-membered cycloalkyl. A fourth class of compounds of the present invention (Class C4) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein: RIA, R IB and RIC are as defined in Embodiment E5; 15 R2A and R3A are both H;

R

4 , R 5 and R 6 are as defined in Embodiment E12; CycA is cyclopropyl; and CycB is independently cyclopropyl, cyclobutyl, or cyclopentyl. A first sub-class of the fourth class (Sub-class C4-S 1) includes compounds of 20 Formula I and pharmaceutically acceptable salts thereof, wherein RIA is F in the para position of the benzyl moiety; RIB is H, Cl, or Br in the ortho or meta position of the benzyl moiety; and RiC is H; and all other variables are as originally defined in Class C4. A second sub-class of the fourth class (Sub-class C4-S2) includes compounds of Formula II and pharmaceutically acceptable salts thereof, wherein all of the variables are 25 as originally defined in Class C4, except that in part B of the definition of R 4 , R 5 and R 6 :

R

4 and R 5 together with the atoms to which they are attached form a fused azacycloalkyl ring which is: N* N *-N *NP *-N CH

*-P

* * * H 3 , * CH 3 * CH 3 , or *-N * H 3

COH

3 30 H3C and

R

6 is (1) H, (2) CH3, or (3) CH2CH3; WO 2012/058173 PCT/US2011/057557 27 and in part C of the definition of R 4 , R 5 and R 6 :

R

4 is (1) H, (2) CH3, (3) CH2CH3, (4) CH2CH2CH3, (5) CH(CH3)2, (6) CH2CH(CH3)2, (7) CH2C(O)OH, (8) cyclopropyl, or (9) CH2-cyclopropyl; and 5 R 5 and R 6 together with the carbon atom to which they are both attached form a spirocyclic ring which is: 0 X* *>* * O

H

3 O

H

3 C CH 3 * * OH 3 ***

OH

3 or A second sub-class of the fourth class (Sub-class C4-S3) includes compounds 10 of Formula II and pharmaceutically acceptable salts thereof, wherein R1A is F in the para position of the benzyl moiety; RIB is H, Cl, or Br in the ortho or meta position of the benzyl moiety; and R 1 C is H; and all other variables are as defined in Sub-class C4-S2. LA LB In one embodiment, for the compounds of formula (II), variables RA, R 15 Rc, R 2 A, R 3 A R, R 5 and R 6 are selected independently of each other. O

R

4 N R1A R5 RiB>~ N R 6 R1B N N0R 0 OH (III) 20 and pharmaceutically acceptable salts thereof, wherein: RIA is halo; R 1 is H or halo; R4 is H, 3 to 8-membered cycloalkyl or C1.salkyl, wherein said 3 to 8 25 membered cycloalkyl group can be optionally substituted with -OH and wherein said C_ 8alkyl group is substituted with -N(C1- 6 alkyl)-SO 2 -(Cj- 6 alkyl), -O-(C 1 6 alkyl) or 3 to 8 membered cycloalkyl, wherein said 3 to 8-membered cycloalkyl substituent can be optionally substituted with -OH; WO 2012/058173 PCT/US2011/057557 28 R' is H; and

R

6 is cycloalkyl, or R 5 and R6, together with the common carbon atom to which they are attached, combine to form a spirocyclic ring which is: (i) a 4 to 8-membered cycloalkyl group or (ii) a 6 to 10-membered fused or bridged bicycloalkyl group, wherein 5 said spirocyclic rings (i) and (ii) can be optionally substituted with a -O-(C.

6 alkyl) group. In one embodiment, for the compounds of formula (III), R A is F and RB is H or Cl. In one embodiment, for the compounds of fonnula (III), R4 is H, cyclopropyl, 10 -CH 2

CH

2

N(CH

3

)SO

2

CH

3 , -CH 2

CH

2

OCH

3 or: OH In one embodiment, for the compounds of formula (III), R' is H and R 6 is cyclopropyl. In another embodiment, for the compounds of fonnula (III), R' is H and R4 15 and R are each cyclopropyl. In one embodiment, for the compounds of formula (III), R5 and R, together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:

H

3 CO or 20 1-tin In another embodiment, for the compounds of formula (III), R5 and R, together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure: 25 In one embodiment, for the compounds of formula (III), RiA is F and RB is H or Cl; R4 is cyclopropyl or -CH 2

CH

2

N(CH

3

)SO

2

CH

3 ; R 5 is H; and R6 is cyclopropyl. In another embodiment, for the compounds of formula (III), RiA is F and RB 30 is H or Cl; R is H, -CH 2

CH

2

N(CH

3

)SO

2

CH

3 , -CH 2

CH

2

OCH

3 or: WO 2012/058173 PCT/US2011/057557 29 OH ; and R5 and RW, together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure:

H

3 CO /b or 5 In another embodiment, for the compounds of formula (III), RIA is F and R1B is H or Cl; R4 is H, -CH 2

CH

2

N(CH

3 )SO2CH 3 , -CH 2

CH

2 0CH 3 or: OH ; and R5 and RW, together with the common carbon atom to which they are attached, combine to 10 form a spirocyclic group having the structure: 15 In one embodiment, for the compounds of formula (III), variables RIA, R 1 ( J, R4, R5 and R 6 are selected independently of each other. Another embodiment of the present invention is 20 a compound of Formula I, or a pharmaceutically acceptable salt thereof, as originally defined or as defined in any of the foregoing embodiments, sub-embodiments, aspects, classes, or sub-classes, wherein the compound or its salt is in a substantially pure forn. As used herein "substantially pure" means suitably at least about 60 wt.%, typically at least about 70 wt.%, preferably at least about 80 wt.%, more preferably at least about 90 wt.% 25 (e.g., from about 90 wt.% to about 99 wt.%), even more preferably at least about 95 wt.% (e.g., from about 95 wt.% to about 99 wt.%, or from about 98 wt.% to 100 wt.%), and most preferably at least about 99 wt.% (e.g., 100 wt.%) of a product containing a compound of Formula I or its salt (e.g., the product isolated from a reaction mixture affording the compound or salt) consists of the compound or salt. The level of purity of the compounds 30 and salts can be determined using a standard method of analysis such as thin layer WO 2012/058173 PCT/US2011/057557 30 chromatography, gel electrophoresis, high performance liquid chromatography, and/or mass spectrometry. If more than one method of analysis is employed and the methods provide experimentally significant differences in the level of purity determined, then the method providing the highest purity level governs. A compound or salt of 100% purity is one which 5 is free of detectable impurities as determined by a standard method of analysis. With respect to a compound of the invention which has one or more asymmetric centers and can occur as mixtures of stereoisomers, a substantially pure compound can be either a substantially pure mixture of the stereoisomers or a substantially pure individual diastereomer or enantiomer. 10 The present invention also includes prodrugs of the compounds of Formula I. The term "prodrug" refers to a derivative of a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is converted in vivo into Compound 1. Prodrugs of compounds of Formula I can exhibit enhanced solubility, absorption, and/or lipophilicity compared to the compounds per se, thereby resulting in increased bioavailability and 15 efficacy. The in vivo conversion of the prodrug can be the result of an enzyme-catalyzed chemical reaction, a metabolic chemical reaction, and/or a spontaneous chemical reaction (e.g., solvolysis). When the compound contains, for example, a hydroxy group, the prodrug can be a derivative of the hydroxy group such as an ester (-OC(O)R), a carbonate ester ( OC(O)OR), a phosphate ester (-0-P(=O)(OH)2), or an ether (-OR). Other examples include 20 the following: When the compound of Formula I contains a carboxylic acid group, the prodrug can be an ester or an amide, and when the compound of Formula I contains a primary amino group or another suitable nitrogen that can be derivatized, the prodrug can be an amide, carbamate, urea, imine, or a Mannich base. One or more functional groups in Compound I can be derivatized to provide a prodrug thereof. Conventional procedures for 25 the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, edited by H. Bundgaard, Elsevier, 1985; J. J. Hale et al., J Med. Chem. 2000, vol. 43, pp.1 2 3 4 -1 2 4 1; C. S. Larsen and J. Ostergaard, "Design and application of prodrugs" in: Textbook of Drug Design and Discovery, 3P edition, edited by C. S. Larsen, 2002, pp. 410-458; and Beaumont et al., Current Drug Metabolism 2003, vol. 4, pp. 461 30 458; the disclosures of each of which are incorporated herein by reference in their entireties. Other embodiments of the present invention include the following: (a) A pharmaceutical composition comprising an effective amount of a compound of Formula I as defined above, or a prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 35 (b) A pharmaceutical composition which comprises the product prepared by combining (e.g., mixing) an effective amount of a compound of Formula I as defined WO 2012/058173 PCT/US2011/057557 31 above, or a prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (c) The pharmaceutical composition of (a) or (b), further comprising an effective amount of an anti-HIV agent selected from the group consisting of HIV antiviral 5 agents, immunomodulators, and anti-infective agents. (d) The pharmaceutical composition of (c), wherein the anti-HIV agent is an antiviral selected from the group consisting of HIV protease inhibitors, HIV reverse transcriptase inhibitors (nucleoside or non-nucleoside), HIV integrase inhibitors, HV fusion inhibitors, and HIV entry inhibitors. 10 (e) A combination which is (i) a compound of Formula I as defined above, or a prodrug or pharmaceutically acceptable salt thereof, and (ii) an anti-HIV agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti infective agents; wherein Compound I and the anti-HIV agent are each employed in an amount that renders the combination effective for inhibition of HIV integrase, for treatment 15 or prophylaxis of infection by HIV, or for treatment, prophylaxis of, or delay in the onset or progression of AIDS. (f) The combination of (e), wherein the anti-HIV agent is an antiviral selected from the group consisting of HIV protease inhibitors, HIV reverse transcriptase inhibitors (nucleoside or non-nucleoside), HIV integrase inhibitors, HIV fusion inhibitors, 20 and HIV entry inhibitors. (g) A method for the inhibition of HIV integrase in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof. (h) A method for the prophylaxis or treatment of infection by HIV (e.g., 25 HIV-1) in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof. (i) The method of (h), wherein the compound of Formula I is administered in combination with an effective amount of at least one other HIV antiviral 30 selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, non nucleoside HIV reverse transcriptase inhibitors, nucleoside HV reverse transcriptase inhibitors, HIV fusion inhibitors, and HIV entry inhibitors. (j) A method for the prophylaxis, treatment or delay in the onset or progression of AIDS in a subject in need thereof which comprises administering to the 35 subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof.

WO 2012/058173 PCT/US2011/057557 32 (k) The method of (j), wherein the compound is administered in combination with an effective amount of at least one other HIV antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, HIV fusion 5 inhibitors, and HIV entry inhibitors. (1) A method for the inhibition of HIV integrase in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f). (m) A method for the prophylaxis or treatment of infection by HIV (e.g., 10 HTV- 1) in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f). (n) A method for the prophylaxis, treatment, or delay in the onset or progression of AIDS in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f). 15 (o) A method for the inhibition of XMRV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier. 20 (p) A method for the prophylaxis or treatment of infection by XMRV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier. 25 (q) A method for the prophylaxis, treatment or delay in the onset or progression of a disease or condition caused by XMRV infection (e.g., prostate cancer or chronic fatigue syndrome) in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally 30 administered as a component in a composition further comprising a pharmaceutically acceptable carrier. (r) A method for the inhibition of HTLV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound 35 or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier.

WO 2012/058173 PCT/US2011/057557 33 (s) A method for the prophylaxis or treatment of infection by HTLV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a 5 composition further comprising a pharmaceutically acceptable carrier. (t) A method for the prophylaxis, treatment or delay in the onset or progression of a disease or condition caused by HTLV infection (e.g., T-cell leukemia or T cell lymphoma) in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I or a prodrug or pharmaceutically acceptable 10 salt thereof, wherein the compound or its prodrug or salt is optionally administered as a component in a composition further comprising a pharmaceutically acceptable carrier. The present invention also includes a compound of Formula I, or a prodrug or pharmaceutically acceptable salt thereof, (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation of a medicament for: (a) therapy (e.g., of the human body), 15 (b) medicine, (c) inhibition of HIV integrase, (d) treatment or prophylaxis of infection by HIV, (e) treatment, prophylaxis of, or delay in the onset or progression of AIDS, (f) inhibition of XMRV, (g) treatment or prophylaxis of infection by XMRV, (h) treatment or prophylaxis or delay in the onset or progression of a disease or condition caused by XMRV infection, (i) inhibition of HTLV, () treatment or prophylaxis of infection by HTLV, (k) 20 treatment or prophylaxis or delay in the onset or progression of a disease or condition caused by HTLV infection. In these uses, the compounds of the present invention can optionally be employed in combination with one or more anti-HIV agents selected from HIV antiviral agents, anti-infective agents, and immunomodulators. Additional embodiments of the invention include the pharmaceutical 25 compositions, combinations and methods set forth in (a)-(t) above and the uses (i)(a)-(k) through (iii)(a)-(k) set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, sub embodiments, aspects, features, classes, or sub-classes described above. In all of these embodiments etc., the compound may optionally be used in the form of a prodrug or 30 pharmaceutically acceptable salt. Additional embodiments of the present invention include each of the pharmaceutical compositions, combinations, methods and uses set forth in the preceding paragraphs, wherein the compound of the present invention or a salt or prodrug thereof employed therein is substantially pure. With respect to a pharmaceutical composition 35 comprising a compound of Formula I or its prodrug or salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that the term "substantially pure" is in reference to a compound of Formula I or its prodrug or salt per se.

WO 2012/058173 PCT/US2011/057557 34 Still additional embodiments of the present invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(n) above and the uses (i)(a)-(e) through (iii)(a)-(e) set forth above, wherein the HIV of interest is HIV-1. Thus, for example, in the pharmaceutical composition (d), the compound of Formula I is 5 employed in an amount effective against HIV-I and the anti-HIV agent is an HIV-I antiviral selected from the group consisting of HIV-l protease inhibitors, HIV-I reverse transcriptase inhibitors, HIV-I integrase inhibitors, HIV-I fusion inhibitors and HIV-I entry inhibitors. As used herein, the term "alkyl" refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the 10 specified range. Thus, for example, "C1-6 alkyl" (or "C1-C6 alkyl") refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso- propyl, ethyl and methyl. As another example, "C 1-4 alkyl" refers to n-, iso-, sec- and t-butyl, n and isopropyl, ethyl and methyl. The term "cycloalkyl" refers to any monocyclic or bicyclic ring of an alkane 15 having a number of carbon atoms in the specified range. Thus, for example, "C3-8 cycloalkyl" (or "C3-C8 cycloalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "azacycloalkyl" refers to a cycloalkyl group as defined above in which one of the ring carbons has been replaced with a ring nitrogen. Thus, for example, 20 the term "a 4- to 8-membered fused azacycloalkyl" refers to the following groups: *N *.NP *-P -N q **-- * * ,or wherein the asterisks (*) denote the ring atoms that are attached to the rest of the compound, providing thereby a fused ring system. The term "heterocycloalkyl" refers to a cycloalkyl group as defined above in 25 which one of the ring carbons has been replaced with a ring heteroatom which is N, 0 or S. Thus, for example, the term "a spirocyclic ring which is a 5- to 8-membered heterocyclylalkyl" refers to the following groups: WO 2012/058173 PCT/US2011/057557 35 * L * L*LLL L * LL L * L L LL wherein L is the heteroatom and the asterisks (*) denote the points of attachment to the rest 5 of the compound providing thereby a spirocycle. The term "alkylene" refers to any divalent linear or branched chain aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, "-C2-8 alkylene-" refers to any of the C2 to Cg linear or branched alkylenes. A class of alkylenes of interest with respect to the invention is -(CH2)2-4-, and sub-classes of 10 particular interest include -CH2CH2- and -CH2CH2CH2-. The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo). The term "haloalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, Cl, Br and/or J). 15 Thus, for example, "C1-6 haloalkyl" (or "Cl-C6 haloalkyl") refers to a CI to C6 linear or branched alkyl group as defined above with one or more halogen substituents. The term "fluoroalkyl" has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2)0-4CF3 (i.e., trifluoromethyl, 2,2,2 trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.). A fluoroalkyl of particular interest is CF3. 20 The term "C(O)" refers to carbonyl. The terms "S(O)2" and "S02" each refer to sulfonyl. The term "S(0)" refers to sufinyl. An asterisk ("*") as the end of an open bond in a chemical group denotes the point of attachment of the group to the rest of the compound. The term "aryl" refers to (i) phenyl, (ii) a 9- or 1 0-membered bicyclic, fused 25 carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic. Suitable aryls include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl, indanyl, acenaphthenyl and fluorenyl. A class of aryls suitable for use in the present invention is phenyl, naphthyl, and indenyl. Another class of suitable aryls is phenyl and naphthyl. A 30 particularly suitable aryl is phenyl.

WO 2012/058173 PCT/US2011/057557 36 The term "heteroaryl" refers to (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, 0 and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or I 0-membered bicyclic, fused ring system which contains from 1 to 4 heteroatoms independently selected from N, 0 and S, and 5 wherein in the fused ring system any one or more of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N in a ring is optionally in the form of an oxide, and each S is optionally S(0) or S(O)2. Suitable heteroaryls include, for example, pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, quinolinyl, 10 tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, isoindolyl, benzodioxolyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, chromanyl, isochromanyl, cinnolinyl, quinazolinyl, benzothienyl, benzofuranyl, imidazo[1,2 a]pyridinyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4 ON 15 dioxinyl (i.e., 0 ), benzo-1,3-dioxolyl (i.e., A 0 ), thiazolyl, and isothiazolyl. A class of heteroaryls suitable for use in the present invention (e.g., suitable for use as HetA and/or HetB) consists of 5- and 6-membered heteroaromatic rings containing from I to 4 heteroatoms independently selected from N, 0 and S, wherein each N is optionally in the form of an oxide. Heteroaryls belonging to this class include pyridinyl, 20 pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, and oxadiazolyl. A sub-class of heteroaryls N N N suitable for use in the present invention consists of * , * rN, N N - / , and * . Another suitable class consists of 5- and 6-membered heteroaromatic rings containing a total of from 1 to 3 heteroatoms independently selected 25 from 1 to 3 N atoms, from zero to 1 0 atom, and from zero to 1 S atom. The term "saturated or mono-unsaturated heterocyclic ring" refers to (i) a 4 to 7-membered, saturated or mono-unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, 0 and S, where each S is optionally oxidized to S(O) or S(0)2 or (ii) a 6- to I 0-membered saturated or 30 mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, 0 and S, where each S is optionally oxidized to S(O) or S(0)2. Suitable saturated heterocycles include, for example, azetidinyl, pyrrolidinyl, imidazolinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, piperidinyl, piperazinyl, WO 2012/058173 PCT/US2011/057557 37 hexahydropyrimidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, thiazinanyl, azepanyl, diazepanyl, thiazepanyl and thiadiazepanyl. A class of suitable saturated or mono-unsaturated heterocyclic rings (e.g., suitable as HetP and/or HetQ) are the 4- to 7-membered rings containing at least one carbon 5 atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(0)2 (e.g., see HetZ). Another suitable class consists of 5 or 6-membered saturated heterocyclic rings containing a total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 0 atom, and zero to 1 S atom, wherein the S atom is optionally S(O) or S02. Suitable mono-unsaturated heterocyclic rings include those 10 corresponding to the saturated heterocyclic rings listed in the preceding sentence in which a single bond is replaced with a double bond (e.g., a carbon-carbon single bond is replaced with a carbon-carbon double bond). It is understood that the specific rings and ring systems suitable for use in the present invention are not limited to those listed in the preceding paragraphs. These rings 15 and ring systems are merely representative. Unless it is expressly stated to the contrary or is otherwise clear from the context, any of the various cyclic rings and ring systems described herein may be attached to the rest of the compound at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results. 20 Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heteroaromatic ring described as containing from "i to 4 heteroatoms" means the ring can contain 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a heterocyclic ring described as containing from "1 to 4 heteroatoms" is intended 25 to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, I to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, I heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms. As another example, a phenyl or naphthyl (see, e.g., the definition of AryA) described as optionally substituted with "from 1 to 5 substituents" is intended to include as aspects thereof, a phenyl or naphthyl substituted with 30 1 to 5 substituents, 2 to 5 substituents, 3 to 5 substiuents, 4 to 5 substituents, 5 substituents, 1 to 4 substituents, 2 to 4 substituents, 3 to 4 substituents, 4 substituents, I to 3 substituents, 2 to 3 substituents, 3 substituents, I to 2 substituents, 2 substituents, and 1 substituent. When any variable (e.g., RA or RB) occurs more than one time in any constituent or in Formula I or in any other formula depicting and describing compounds of 35 the present invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

WO 2012/058173 PCT/US2011/057557 38 Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring provided such ring substitution is chemically allowed and results in a stable compound. As would be recognized by one of ordinary skill in the art, certain of the 5 compounds of the present invention can exist as tautomers. All tautomeric forms of these compounds, whether isolated individually or in mixtures, are within the scope of the present invention. For example, in instances where a hydroxy (-OHl) substituent is permitted on a heteroaromatic ring and keto-enol tautomerism is possible, it is understood that the substituent might in fact be present, in whole or in part, in the keto form, as exemplified 10 here for a hydroxypyridinyl substituent: 0 OH Compounds of the present invention having a hydroxy substituent on a carbon atom of a heteroaromatic ring are understood to include compounds in which only the hydroxy is present, compounds in which only the tautomeric keto form (i.e., an oxo substitutent) is 15 present, and compounds in which the keto and enol forms are both present. A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject). The compounds of the present 20 invention are limited to stable compounds embraced by Formula I. Thus, for example, for compounds of the invention containing the group C(O)-N(RA)-C2-8 alkylene-ORB, it is understood that the N(RA) moiety and the ORB moiety are typically not attached to the same carbon atom in the C2-8 alkylene moiety. As a result of the selection of substituents and substituent patterns, certain 25 compounds of the present invention can have asymmetric centers and can occur as mixtures of stereoisomers, or as individual diastereomers, or enantiomers. All isomeric forms of these compounds, whether individually or in mixtures, are within the scope of the present invention. All solvates and hydrates of compounds of Formula I are within the scope of 30 the present invention. The atoms in a compound of Formula I may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the WO 2012/058173 PCT/US2011/057557 39 atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula . For example, different isotopic forms of hydrogen (H) include protium (1 H) and deuterium

(

2 H). Protium is the predominant hydrogen isotope found in nature. Enriching for 5 deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the 10 Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. The methods of the present invention involve the use of compounds of Formula I in the inhibition of HIV integrase (e.g., wild type HIV-l and/or mutant strains thereof), the prophylaxis or treatment of infection by human immunodeficiency virus (HIV) 15 and the prophylaxis, treatment or delay in the onset or progression of consequent pathological conditions such as AIDS. Prophylaxis of AIDS, treating AIDS, delaying the onset or progression of AIDS, or treating or prophylaxis of infection by HIV is defined as including, but not limited to, treatment of a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential 20 exposure to HIV. For example, the present invention can be employed to treat infection by HIV after suspected past exposure to HIV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery. As another example, the present invention can also be employed to prevent transmission of HIV from a pregnant female infected with HIV to her unborn child or from an HIV-infected 25 female who is nursing (i.e., breast feeding) a child to the child via administration of an effective amount of Compound I or a prodrug or pharmaceutically acceptable salt thereof. The compounds can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt which possesses the effectiveness of the parent compound and which is not biologically or 30 otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, or benzoic acid. When compounds employed in the present invention carry an acidic moiety 35 (e.g., -COOH or a phenolic group), suitable pharmaceutically acceptable salts thereof can include alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as WO 2012/058173 PCT/US2011/057557 40 quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound. The term "administration" and variants thereof (e.g., "administering" a 5 compound) in reference to a compound of Formula I mean providing the compound or a prodrug or salt of the compound to the individual in need of treatment or prophylaxis. When a compound or a prodrug or salt thereof is provided in combination with one or more other active agents (e.g., antiviral agents useful for treating or prophylaxis of HIV infection or AIDS), "administration" and its variants are each understood to include provision of the 10 compound or prodrug or salt thereof and other agents at the same time or at different times. When the agents of a combination are administered at the same time, they can be administered together in a single composition or they can be administered separately. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or 15 indirectly, from combining the specified ingredients. By "pharmaceutically acceptable" is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof. The term "subject" as used herein refers to an animal, preferably a mammal, 20 most preferably a human, who has been the object of treatment, observation or experiment. The term "effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In one embodiment, the effective amount is a "therapeutically 25 effective amount" for the alleviation of the symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactically effective amount" for prophylaxis of the symptoms of the disease or condition being prevented. The term also includes herein the amount of active compound sufficient to inhibit HIV integrase (wild type and/or mutant strains thereof) and thereby elicit the response being sought (i.e., 30 an "inhibition effective amount"). When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free form (i.e., the non-salt and non-prodrug form) of the compound. In the method of the present invention (i.e., inhibiting HIV integrase, treating or prophylaxis of HIV infection or treating, prophylaxis of, or delaying the onset or 35 progression of AIDS), the compounds of Fonnula I, optionally in the form of a salt or a prodrug, can be administered by any means that produces contact of the active agent with the agent's site of action. They can be administered by any conventional means available for WO 2012/058173 PCT/US2011/057557 41 use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The compounds of the invention can, 5 for example, be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Liquid preparations suitable for oral 10 administration (e.g., suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like. Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating 15 agents and the like. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a solubility aid. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Further description of methods suitable for use 20 in preparing pharmaceutical compositions for use in the present invention and of ingredients suitable for use in said compositions is provided in Remington's Pharmaceutical Sciences, 18 th edition, edited by A. R. Gennaro, Mack Publishing Co., 1990 and in Remington - The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, 2005. 25 The compounds of Formula I can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses. One preferred dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses. Another preferred dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses. For oral administration, the 30 compositions can be provided in the form of tablets or capsules containing 1.0 to 500 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including 35 the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of WO 2012/058173 PCT/US2011/057557 42 administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. As noted above, the present invention is also directed to use of a compound of Formula I with one or more anti-HIV agents. An "anti-HIV agent" is any agent which is 5 directly or indirectly effective in the inhibition of HIV reverse transcriptase or another enzyme required for HIV replication or infection, the treatment or prophylaxis of HIV infection, and/or the treatment, prophylaxis or delay in the onset or progression of AIDS. It is understood that an anti-HIV agent is effective in treating, preventing, or delaying the onset or progression of HIV infection or AIDS and/or diseases or conditions arising therefrom or 10 associated therewith. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of one or more anti-HIV agents selected from HIV antiviral agents, imunomodulators, antiinfectives, or vaccines useful for treating HIV infection or AIDS. Suitable HIV antivirals for use in combination with the compounds of the present invention 15 include, for example, those listed in Table A as follows: Table A Name Type abacavir, ABC, Ziagen@ nRTI abacavir +lamivudine, Epzicom@ nRTI abacavir + lamivudine + zidovudine, Trizivir@ nRTI amprenavir, Agenerase® PI atazanavir, Reyataz@ PI AZT, zidovudine, azidothymidine, Retrovir@ nRTI darunavir, Prezista@ Pi ddC, zalcitabine, dideoxycytidine, Hivid@ nRTI ddl, didanosine, dideoxyinosine, Videx® nRTI ddl (enteric coated), Videx EC@ nRTI delavirdine, DLV, Rescriptor@ nnRTI efavirenz, EFV, Sustiva@, Stocrin® nnRTI efavirenz + emtricitabine + tenofovir DF, Atripla@ nnRTI + nRTI emtricitabine, FTC, Emtriva@ nRTI emtricitabine + tenofovir DF, Truvada@ nRTI envirine, Coactinon@ nnRTI enfuvirtide, Fuzeon® FI enteric coated didanosine, Videx EC® nRTI etravirine, TMC-125 nnRTI fosamprenavir calcium, Lexiva@ PI indinavir, Crixivan@ PI lamivudine, 3TC, Epivir@ nRTI lamivudine + zidovudine, Combivir@ nRTI lopinavir P1 lopinavir + ritonavir, Kaletra@ PI WO 2012/058173 PCT/US2011/057557 43 maraviroc, Selzentry@| El nelfinavir, Viracept@ PI nevirapine, NVP, Viramune@ nnRTI raltegravir, MK-0518, Isentress® II rilpivirine, TMC-278 nnRTI ritonavir, Norvir® PI saquinavir, Invirase@, Fortovase® PI stavudine, d4T,didehydrodeoxythymidine, Zerit@ nRTI tenofovir DF (DF = disoproxil fumarate), TDF, Viread® nRTI tipranavir, Aptivus@ P1 El= entry inhibitor; FI = fusion inhibitor; InI integrase inhibitor; PI = protease inhibitor; nRTI= nucleoside reverse transcriptase inhibitor; nnRTI = non-nucleoside reverse transcriptase inhibitor. Some of the drugs listed in the table are used in a salt form; e.g., 5 abacavir sulfate, indinavir sulfate, atazanavir sulfate, nelfinavir mesylate. In one embodiment, the one or more anti-HIV agents are selected from lamivudine, abacavir, ritonavir and lopinavir. 10 In another embodiment, the compound of formula (I) is used in combination with a single anti-HIV agent which is lamivudine. In another embodiment, the compound of formula (I) is used in combination with two anti-HIV agent which are lamivudine and abacavir. In still another embodiment, the compound of formula (I) is used in 15 combination with two anti-HIV agent which are ritonavir and lopinavir. In one embodiment, the present invention provides pharmaceutical compositions comprising (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof; (ii) a pharmaceutically acceptable carrier; and (iii) one or more additional anti 20 HIV agents selected from lamivudine, abacavir, ritonavir and lopinavir, or a pharmaceutically acceptable salt thereof, wherein the amounts present of components (i) and (iii) are together effective for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in the subject in need thereof. 25 In another embodiment, the present invention provides a method for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof, which comprises administering to the subject (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (ii) one or more additional anti-HIV agents selected from lamivudine, 30 abacavir, ritonavir and lopinavir, or a pharmaceutically acceptable salt thereof, wherein the WO 2012/058173 PCT/US2011/057557 44 amounts administered of components (i) and (ii) are together effective for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in the subject in need thereof. It is understood that the scope of combinations of the compounds of this 5 invention with anti-HIV agents is not limited to the HIV antivirals listed in Table A, but includes in principle any combination with any pharmaceutical composition useful for the treatment or prophylaxis of AIDS. The HIV antiviral agents and other agents will typically be employed in these combinations in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in the Phyicians Desk 10 Reference, Thomson PDR, Thomson PDR, 57* edition (2003), the 580 edition (2004), the 5 9 th edition (2005), and the like. The dosage ranges for a compound of the invention in these combinations are the same as those set forth above. The compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this 15 invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes. 20 The compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds. For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful. antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, 25, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes. List of Abbreviations 30 ACN acetonitrile AcOH = acetic acid Alk alkyl Ar aryl Boc tert-butoxycarbonyl 35 BOP = benzotriazol- 1 -yloxytris(dimethylamino) phosphonium hexafluorophosphate br = broad d = doublet 40 DABCO = 1,4-diazabicyclo(2,2,2)octane WO 2012/058173 PCT/US2011/057557 45 DBU = 1,8-diazabicyclo[5,4.0]undec-7-ene DCE = 1,2-dichloroethane DIPEA = NN-diisopropylethylamine DMA = N,N-dimethylacetamide 5 DMF = dimethylformamide DMSO = dimethyl sulfoxide EDCI = 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride ESI = electrospray ionization 10 EtOAc = ethyl acetate EtOH = ethanol HATU = 2-(l H-7-Azabenzotriazol- l-yl)- 1,1,3,3 -tetramethyl uronium hexafluorophosphate HOAc = acetic acid 15 HOAt = l-hydroxy-7-azabenzotriazole HOBt = I-hydroxybenzotriazole HRMS = high resolution mass spectrometry IPAc = iso-propyl acetate LCMS = liquid chromatography / mass sepectrometry 20 m = multiplet mCPBA meta-chloroperoxybenzoic acid MeCN = acetonitrile MeOH= methyl alcohol MeTHF= 2-methyltetrahydrofuran 25 min minutes MS mass spectroscopy MTBE = methyl tert-butyl ether NMP = 1-methyl 2-pyrrolidinone NMR = nuclear magnetic resonance spectroscopy 30 PG = protecting group Piv = pivalate, 2,2-dimethylpropanoyl Ph = phenyl rt = room temperature s = singlet 35 SFC = supercritical fluid chromatography t = triplet TFA = trifluoroacetic acid THF = tetrahydrofuran wt% = weight percent 40 The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of 45 ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary WO 2012/058173 PCT/US2011/057557 46 ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. Scheme A depicts a method for preparing compounds of the present invention, wherein benzyl halide 1 is reacted with amide 2 in the presence of a base. The 5 corresponding tertiary amide is deprotonated and reacted with phenyl methyl sulfone to generate sulfoxide 3. The sulfoxide is then converted to the corresponding a,p-unsaturated product via a Pummerer rearrangement and sulfide oxidation to compound 4. Reaction with the anion of a protected amino ester and acid hydrolysis affords the alpha amino ester 5. Elimination of the sulfone under basic conditions affords the unsaturated ester 6. 10 Conversion of 6 to the pyridinone compound 2 can be accomplished in the presence of an ester oxalyl chloride followed by treatment with LiBr. Hydrolysis of ester 7 to the acid affords compound 8 which is then transformed to the tris-pivalate 9 using standard conditions. Compounds 8 and 9 serve as valuable intermediates which can be transformed to HV integrase inhibitors using the procedures and methods described in the following 15 schemes. Scheme A R1A RA 3BA R 2 B R3A R 3 B R2BR

R

2 A 1) NaOH, MTBE R2A ReR R1. R 5 Br HN 2) LiHMDS, PhSO 2 Me N S Ph RIC Ric 1 20 3 O 0 RIA R 3 A R 3 Ph 1) Ac 2 O, MeSO 3 H R2A * 1_EtO2C- N Ph 2) NaiO 4 , MeOH/H 2 0 N , Ph LiOt-Bu RI O 2) 2 N HCI R1A R 2 B R 3 A R 3 B CO 2 Et RiA R 2 B R3A R 3 B CO 2 Et R2A NH 2 i-Pr 2 NEt R2A R B N Ph NH1B 2 'N S' toluene, 90 *C R-N R1c | 11 Ric 200 0 0 WO 2012/058173 PCT/US2011/057557 47 RpA R2B R3A R 3 BCO 2 Et 1) EtO 2 CCOCI

R

2 ^ A NH NaOH DIPEA R THF/EtOH 2) LiBr, DABCO Ric, N 7 O OH RA 2 R 3BO 2 RA R 3A R 3

BC

0 2PiV Ri- NH Et 3 N, PivCI, THF 'V R R1c Ric OPiv 8 OH 90 OPiv Scheme B depicts a method for the conversion of bis-hydroxy carboxylic acid compound 8 to bis-methoxy carboxylic acid I utilizing a silver-catalyzed methylation and 5 base-mediated ester hydrolysis. Compound I serves as a valuable intermediate which can be transformed to HIV integrase inhibitors using the procedures and methods described in the following schemes. Scheme B 1A 2BR 3BCO 2 H RIA R 2 B R3A R3BCO 2 Me RN AN Mel, Ag 2

CO

3 R1 N AN 1> OH O~ce 10 8 0 OH 10 0 OMe RIA rR 3 A R3BCO 2 H LiOH R AN Rlc' OMe _1. 0 OMe Scheme C depicts a method for preparing compounds of the present invention, wherein carboxylic acid 11 is reacted with primary amine 12 under standard amide coupling conditions (e.g. EDCI/HOAt/base/DMF) to yield secondary amide 13. The 15 methyl ethers of product 13 can be cleaved under acidic conditions (e.g. HBr in AcOH) to afford the hydroxyl pyridinone 14. Treatment of 14 with an aldehyde or ketone 15 under acidic conditions (e.g. catalytic sulfuric acid or TFA) will afford the product aminal 16.

WO 2012/058173 PCT/US2011/057557 48 Scheme C R 1A R 2 A Rs 3 CO 2 H R 4 NH R1A R 3 2 R38 C(O)NHR 4 R1~~i ~ A 2A - acid SNR2 > 12 R R2 RG N OMe R OMe j1 0 OMe 13 0 OMe 2 B R 3 A R 3 6

C(O)NHR

4

R

3 A R 3 B N R K R2 RRR 1A R 2B / 3 R5 2A R 5

R

6 2 1 B r R2 / N H f R2/ N Re R - - R N N acid i N O RC0 RIGC 140 OH 16 0 OH Scheme D provides a preparative sequence similar to that of Scheme C, 5 except that an acetal or ketal (or hemi-acetal or -ketal) 17 is used in place of the aldehyde or ketone for the condensation reaction of the final Step in the presence of a protic acid. Scheme D R OMA R 8

C(O)NHR

4 IA 2 B RA R 3 B CO)H R 4 NRAR3A B r R1B . N NH O 5tiK N N- R ON R 10 OMe 11 0 OMe 13 0 OMe R3A R4 C)NRRO OR 0 R 10 IAR A 3 B WA R 2

R

5

XR

6 > R1 R2 157 RAN ANH 17 RA AN R 6 RI0 protic acid N > oN 14 0 OH 16 0 OH 10 R =alkyl, e.g. Me, Et Scheme E is a variation of Schemes C and D, wherein compounds of the invention can be prepared ftrm activated mixed anhydride 9, which is reacted with primary amine 12 to yield secondary amide compound 18. Conversion of 18 to the desired product 16 can be conducted using either the procedure of Scheme C or Scheme D. 15 WO 2012/058173 PCT/US2011/057557 49 Scheme E RIA R 2 8 R3A R3B CO 2 Piv R IA R2B R 3 A R3B C(O)NHR 4 SN R 4

NH

2 N NH Ric OPiv RNc'O Q 0 OPiv 18 O OH R4 0 RO OR IA p2RpA R3B N RA R 2 B R 5 R 5 r 6 o R 6 R2^ N R 8 R ') N acid RIc' 0 R = alkyl, e.g. Me, Et 16 0 OH Scheme F depicts another route to the desired compounds, wherein mixed anhydride 9, or a related carboxylic acid derivative, can be reacted with a source of 5 ammonia (e.g. NH 3 (gas) or NH40H) to afford the primary amide 19, which can be deprotonated to 20 and then alkylated with an electrophile to afford the product 16. Scheme F O RiA R 2 8 R3A Rae CO 2 Piv RIA R2 R3A R3B C(O)NH RK Re R1 N NH 4 0H NH H RR IBfI _ RAN K' N N< - R 8 ' N H 2 S0 4 R'C OPiv RIC 0 0 O OPiv 19 0 OH O o R4 R3A R 3 B NH RA R 3 B N

X

5

X-R

4 R ~ N R RIL R N R 6 RiR6 R N NaH R N N R1c 0 R1c O 12 0 OH 16 0 OH 10 X = Leaving group such as 1, Br, OMs Scheme G presents yet another procedure for preparing compounds of the invention, wherein a specific imidazolonaphthyridine trione 16a (where RiA = -OMe) is treated with a strong acid (e.g. HBr in AcOH) in order to cleave the benzyl group and afford 20. Compound 20 is dissolved in a suitable organic solvent (e.g. DMSO or DMF) is 15 deprotonated by treatment with a strong base (e.g. KO-t-Bu) and then alkylated with benzyl halide 14 to provide desired product 16, which can be isolated and purified using WO 2012/058173 PCT/US2011/057557 50 conventional techniques such as silica gel chromatography or reverse-phase preparative HPLC. Scheme G O ,4 0 ,F4 0 oR RIA R3A R 3 N RR3

R

3 N 5 R2A N R 6 R2A N R 6 RB N t HBr in AcOH (48%) H N R c O 80 *C, 16 h 20 O Liga O OH 24 O OH 5 RiA =-OMe R1AR R1B y R RR3A R N x R 2~RR R RRc 21 R1R- - N R 6 N N strong base Ric 0 16 0 OH X = Leaving group, e.g. Br, CI, OMs Scheme H outlines a further procedure to prepare compounds of the present invention where an R4 alkyl alcohol 21 is converted to a leaving group (e.g. OMs, Cl, Br) and this compound (2) is displaced with a nucleophile (e.g. an amine, sulfonamide, 10 succinimide) under basic conditions to afford a further R4 functionalized compound 23. In the case R7 or R8 are hydrogen, this amine compound 23 can also be further functionalized to a compound such as a sulfonamide or amide using standard conditions. Scheme H WO 2012/058173 PCT/US2011/057557 51 R 4 C OH

R

4 C X

R

4 D R 4 A

R

4 D R 4 A 0 R4B 0 ) 4B R3A R33 N RR R3B N R IA R 2 B R 5 R1A R2B RB R R N R 6

R

1 R N R 6 N t NN R N 21 OH 22 0 OH X Leaving group (Br, CI, OMs) R7, 4,N-RS

R

4 D R 4 A 0 n R 4 B RLN R 8 DA R 2 BRA R 3 B N 5 H R2A / N R 6 base R N N 23 0 OH Scheme I describes a procedure for preparation of compounds of the present invention where a compound such as 24 (R is a protecting group, e.g. R = Me) is converted 5 to a secondary amide 25. This transformation can be accomplished in the presence of a suitable oxidant (e.g. oxygen), base (e.g. NaH, KOt-Bu) and solvent (e.g. DMF, DMSO). The secondary amide is treated with a benzylic halide (or other suitable leaving group) in the presence of a base (e.g. KOt-Bu) to afford 26. Compound 26 can be transformed to inhibitors of the present invention using chemistry outlined in these general methods or 10 specific examples. Scheme I O 0 3A38O RA 2B3A R 3 B OH oR R OH R1A Re oxidantR2 R2A N base

R

2 A N R- N N solvent HN N OR R~c OR 24 OR 0 OR RIA R18"Dl3A0R 3 OH X RIA R 2 B RiI (>, N base K>RN N solvent R 1 OR 26 0 OR WO 2012/058173 PCT/US2011/057557 52 Scheme J presents a further method to prepare compounds of the present invention. A compound 16 is treated under oxidative conditions (oxygen, KOt-Bu, DMSO), affording alcohol compound 27. 5 Scheme J

~~

5 02 (gas) N R OH N 5 KOt-Bu R N N R RicO DMSO Ric O O OH 0 OH 16G 27 Scheme K depicts a method for the preparation of compounds of the invention wherein a secondary amide 27 is reacted with R 4 -X (e.g. an aryl or heteroaryl 10 halide or cyclopropyl boronic acid) in the presence of a base (e.g. Cs 2

CO

3 , NaH) and/or a metal catalyst (e.g. Pd or Cu) to afford the compound 16, which can be isolated and purified using conventional techniques such as silica gel chromatography or reverse-phase preparative HPLC. 15 Scheme K o 0 I R3A R3B N H 4 R3 R3B N R1A R R 5 X-R RIA R 2 B RR5 R2A / Re R2 N R 6 R18 RiG 1c N 0 metal catalyst 1 N N R (e.g .Pd or Cu) R~c 0 OH 0 OH 27 16 Scheme L outlines a method for the preparation of compounds of general structure 28. An electron-deficient alkene 29 is treated with 27 under suitable conditions 20 (e.g. Cul, NMP, heat) to afford the derivatives compound 28. Scheme L R~c

R

40 EWG

R

4 D R 4 A O - R4A/ EWG O R4. 1A R 2 A R 3 B NHR R RiA\ R R 2 3B RS RN N R R29 RN < N R6 N N.N N Rc 0 Rlc-Ik 0 O OH 0 OH 27 28 WO 2012/058173 PCT/US2011/057557 53 In the methods for preparing compounds of the present invention set forth in the foregoing schemes, functional groups in various moieties and substituents (in addition to those already explicitly noted in the foregoing schemes) may be sensitive or reactive under 5 the reaction conditions employed and/or in the presence of the reagents employed. Such sensitivity/reactivity can interfere with the progress of the desired reaction to reduce the yield of the desired product, or possibly even preclude its formation. Accordingly, it may be necessary or desirable to protect sensitive or reactive groups on any of the molecules concerned. Protection can be achieved by means of conventional protecting groups, such as 10 those described in Protective Groups in Organic Chemist, ed. J.F.W. McOmie, Plenum Press, 1973 and in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3 rd edition, 1999, and 2 nd edition, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art. Alternatively the interfering group can be introduced into the molecule subsequent to the reaction Step of 15 concern. The following examples serve only to illustrate the invention and its practice. The examples are not to be construed as limitations on the scope or spirit of the invention, In these examples, all temperatures are degrees Celsius unless otherwise noted, and "room temperature" refers to a temperature in a range of from about 20'C to about 25 0 C. Mass 20 spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI). IH NMR spectra were recorded on Varian or Bruker instruments at 400-500 MHz. Compounds described herein were synthesized as a racemic mixture unless otherwise stated in the experimental procedures. 25 Preparation of Key Intermediates EXAMPLE INT-A 6-(3-Chloro-4-fluorobenzyl)-3,4-bis[(2,2-dimethylpropanoyl)oxy]-5-oxo-5,6,7,8-tetrahydro 2,6-naphthyridine-1-carboxylic 2,2-dimethylpropanoic anhydride (Intermediate A) 30 Step 1: 1-(3-Chloro-4-fluorobenzyl)-3-(phenylsulfinyl)piperidin-2-one F + 1) NaOH, PTC, MTBE F x Br HN 'z P Ci Br HN 2) LIHMDS, PhSO 2 Me Ci / To a 2000 L glass-lined reactor, under the protection of nitrogen, MTBE (633 kg) and valerolactam (34.9 kg, 350 mol) were charged by vacuum. After initiating stirring, a WO 2012/058173 PCT/US2011/057557 54 33% aqueous solution of tetrabutylammonium hydrogen sulfate (8.35 kg) was added. The mixture was cooled to 20-30 *C and then a 50% aqueous solution of sodium hydroxide (270 kg) was added to the mixture at a rate of 10-15 L/minute at this temperature. After the addition, the mixture was maintained at the same temperature for 30 minutes followed by 5 the addition of 3-chloro-4-fluoro-benzylbromide (62.9 kg, 280 mol) at a rate of 2-3 kg/minute at 20-30 'C. After 5-10 h, water (283 kg) was added to the reaction mixture at a rate of 30-40 kg/minute at 20-30 *C to quench the reaction. The mixture was stirred for 30 minutes and then the water phase was separated out. The organic phase was washed with 25% aqueous brine solution (226 kg), and the organic phase was dried with anhydrous 10 sodium sulfate (30 kg) under stirring. The dried mixture was filtered by nutsche filter and the filter cake was rinsed with MTBE (50 kg). The combined filtrate was concentrated under reduced pressure (T < 35 'C, PS -0.08 MPa) until the mixture volume remained at about 3 50-500 L. Petroleum ether was added (138.4 kg) to the mixture and concentrated continuously. After the mixture volume remained at about 350-500 L, another 138 Kg of 15 petroleum ether was added to the mixture and then concentrated. The mixture was cooled to 0-5 *C, stirred for 2-3 h, and then filtered. The filter cake was dried by rotary conical dryer below 35 *C to afford 67.7 kg of 1-(3-chloro-4-fluorobenzyl)piperidin-2-one (99% yield). To a 1500 L low temperature reactor, THF (117.5 kg) and hexamethyl disilylamine (73.5 kg, 455 mol) were charged. The mixture was cooled down to -30 to -20 20 'C. To the solution was added n-BuLi (130.6 kg, 455 mol) at a rate of 50-60 kg/h at -30 to 20 *C. After the addition, the reaction mixture was maintained at the same temperature for 30 minutes. Under the protection of nitrogen, to another 1500 L low temperature reactor, THF (222.5 kg) was charged, followed by the benzyl lactam from the above Step (50 kg, 207 mol). The mixture was cooled to -30 to -20 'C and then the THF solution of LiHMDS 25 which was prepared in advance was added at the rate of 100~150 L/h at -30 to -20 C. The reaction mixture was maintained at this temperature for 6 h until the reaction was complete as monitored by HPLC analysis. Methyl phenyl sulfone (45.7 kg, 228 mmol) was added into the reaction mixture at a rate of 5-10 kg/h at -30 to -20 C. After the addition, the reaction mixture was maintained at this temperature for 1 h until HPLC analysis revealed 30 complete consumption of the sulfone starting material. Under the protection of nitrogen, 4 N aqueous HCl solution was added to quench the reaction at a temperature of -5 to 5 *C. Ethyl acetate (424 kg) was added into the mixture and the water phase was separated out (repeated 2x). The combined organic phases were washed twice with water (170 kg) and 25% brine (2 x 204 kg), dried for 8 h with anhydrous sodium sulfate (50 kg) and filtered by nutsche 35 filter. The filter cake was rinsed with ethyl acetate (50 kg) for 30 minutes, and then combined with the filtrate. The filtrate was concentrated under reduced pressure (T S 30 *C, P < -0.08 MPa) until a volume of about 300~350 L of the mixture remained. MTBE (340 WO 2012/058173 PCT/US2011/057557 55 kg) was added into the concentrated liquor and then concentration was continued until 150-200 L volume of the mixture remained. Petroleum ether (73 kg) was added into the concentrated liquors under stirring, and then the mixture was cooled to 0 *C to induce crystallization. The crystallized mixture was filtered by nutsche filter under the protection of 5 nitrogen. The filter cake was rinsed with the mixed solvent of MTBE (20 kg) and petroleum ether (24 kg) to afford the desired product as a white solid. Step 2: 1-(3-Chloro-4-fluorobenzyl)-3-(phenylsulfinyl)-5,6-dihydropyridin-2(1H) one F 1) Ac 2 0, MeSO 3 H F CN TP 2) Na1O 4 , MeOH/H 2 0 CN 10 0 0 Under the protection of nitrogen, to a clean and dry 1000 L glass-lined reactor, was charged acetonitrile (340 kg), followed by 1-(3-chloro-4-fluorobenzyl)-3 (phenylsulfinyl)piperidin-2-one (70 kg, 190 mol). Under stirring, acetic anhydride (39.1 kg, 380 mol) was added to the mixture at the rate of 10 kg/minute, and then methanesulfonic 15 acid (9.2 kg, 100 mol) was added at the rate of 1 kg/minute at 18 to 28 *C. After the addition, the mixture was stirred at this temperature for 10-15 h until complete as determined by HPLC analysis. The mixture was then concentrated under reduced pressure (T < 30 *C, P K -0.08 MPa). Under the protection of nitrogen, deoxygenated ethyl acetate (315 kg) was added, the mixture was washed with 5% brine (3 x 315 kg) and then water 20 phase was separated out. The organic phase was concentrated under reduced pressure (T S 30 OC, P : -0.08 MPa) after which deoxygenated methanol (486 kg), deoxygenated purified water (124.6 kg) and sodium periodate (102.2 kg, 480 mol) were added to the mixture and the mixture stirred at 18 to 28 'C for 26 h. The mixture was filtered by nutsche filtration and the filter cake was rinsed with dichloromethane (2 x 133 kg), and then the filtrates were 25 combined. The filtrate was diluted with water (700 kg) and then extracted with dichloromethane (2 x 455 kg). The combined organic layers were washed with 15% brine (378 kg), dried with anhydrous sodium sulfate (21 kg) and filtered by nutsche filtration. The filter cake was rinsed with dichloromethane (2 x 35 kg) and the mother liquors were concentrated under reduced pressure (T < 30 *C, P < -0.08 MPa) until the remaining mixture 30 volume was about 200-250 L. Isopropyl alcohol (138 kg) was added and the mixture was concentrated continuously. After the remaining mixture volume was about 200-250 L, a mixture of isopropyl alcohol (35 kg) and petroleum ether (30 kg) was added, and then the mixture was concentrated for the third time. After the concentration was completed, petroleum ether (168 kg) was added. Then mixture was cooled to -5 to 0 'C to induce WO 2012/058173 PCT/US2011/057557 56 crystallization. The mixture was filtered by centrifuge and the filter cake was dried to afford the title product (59.4 kg, 85% yield). Step 3: Ethyl amino[l -(3-chloro-4-fluorobenzyl)-2-oxo-3-(phenylsulfinyl)piperidin 5 4-yl]acetate F 1Ph 0 OEt I N Ph EtO 2 C tN Ph

NH

2 xN N0~ CI II LiOt-BuN 0 0 2) 2 N HC O Ph To a 100 L flask was added THF (40 L), followed by the unsaturated sulfoxide (5.0 kg, 13.7 mol) and the commercially available ethyl 2 (diphenylmethyleneamino)acetate (4.0 kg, 15.1 mol). The batch was stirred at room 10 temperature to dissolve the solids and then cooled to 0 *C in an ice/water bath. Lithium tert butoxide (1.4 L, 1 M in THF) was then added drop-wise, maintaining the temperature below 15 *C. The batch was stirred at 0 'C for 1 h until full conversion is evidenced by HPLC analysis. To the cooled batch was added 2M aqueous HCl solution (35 L) at a rate that allows the batch to warm gradually to room temperature (15 minutes). The hazy yellow 15 solution was then stirred at room temperature for 30-45 minutes. The solution was charged to a 200 L extractor, and MTBE (25 L) was added. Layers were separated, and the organic layer was extracted with 2 M aqueous HCI solution (5 L). The combined aqueous layers were washed with MTBE (2 x 25 L) to remove residual benzophenone. The acidic aqueous layer was recharged to a 100 L flask, along with IPAc (25 L) and the batch was cooled to 0 20 'C. Aqueous 5M NaOH solution (~25 L) was added drop-wise, keeping the temperature below 5 'C, until the pH was 8.5. Layers were then separated, and the aqueous layer was re extracted with IPAc (8 L). Step 4: Ethyl (2Z)-amino[ 1 -(3-chloro-4-fluorobenzyl)-2-oxopiperidin-4 25 ylidenejethanoate 0 OEt 0 OEt

FNH

2 i-Pr 2 NEt F NH S NN toluene, 90 C N 0 Ph 0 To a 100 L flask was added the sulfoxide from the previous Step (6.4 kg, 13.7 mol) as a solution in IPAc. The batch was solvent switched to toluene then adjusted to WO 2012/058173 PCT/US2011/057557 57 a total volume of 65 L (KF = 200 ppm). Hunig's base (2.4 L, 13.8 mol) was added, along with a water-cooled condenser and the slurry was heated to 90 *C. After 30 minutes at 90 'C, the batch was assayed for conversion and then cooled slightly. Batch concentration commenced at -70 'C and the volume was reduced to 18 L, upon which a slurry formed. 5 Once the appropriate volume is reached, IPAc (2 L) was added in a single addition, and the slurry was slowly cooled to room temperature, and stirred until the supernatant concentration was below 16 mg/mL. The slurry was filtered, rinsed with 5:1 heptane:IPAc (12 L), and dried overnight on the filter pot with vacuum and nitrogen sweep to give a fluffy white solid (3.0 Kg, 65% isolated yield). 10 Step 5: Ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8 hexahydro-2,6-naphthyridine- 1 -carboxylate 0 OEt

CO

2 Et F 1) EtO 2 CCOCI F

NH

2 DIPEA N C1N 2) LiBrDABCO C1 N NHo 0 0 OH JIn a 100 L flask was charged the starting imine (3.50 kg, 8.80 mol) and THF 15 (45 L). The batch was cooled to 0 *C and DIPEA was added (1.70 L, 1.4 mol). To the resulting solution was added drop-wise the monoethyl oxalyl chloride (1.2 L, 9.24 mol) at such a rate that the temperature is maintained below 3.5 *C (45 minutes to I h). After stirring the reaction mixture for 30 minutes below 3.5 *C, the reaction was monitored for completion by HPLC analysis. To the batch was added directly, as a solid, LiBr (3.06 kg, 20 35.2 mol) followed by DABCO (1.97 kg, 17.6 mol). The batch was allowed to warm to room temperature and stirred overnight (16 h) at room temperature. The reaction mixture was quenched with 2 M aqueous HCl solution (35 L) and stirred at room temperature for 30 minutes. Approximately half to three quarters of the total THF was then removed under reduced pressure, and the resulting slurry was diluted to the original quench volume with 25 water. The approximate amount of THF removed was 36-38 L. The slurry was stirred at room temperature for 30 minutes and filtered. The wet cake was washed with water (2 x 12 L) and then with MTBE (3 x 12 L) and dried under vacuum/N 2 sweep until dry, affording the title product. 30 Step 6: 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6 naphthyridine- 1 -carboxylic acid WO 2012/058173 PCT/US2011/057557 58

CO

2 Et

CO

2 H F> /NH NqOH, F- NH N THF/EtOH N CIDOO C1 O 0 OH 0 OH A 100 L flask was charged with the ester from the previous Step (3.08 kg, 7.80 mol) and 37 L of a 1:1 mixture of EtOH/THF. To the resulting slurry was added 9.4 L of a 5 M aqueous NaOH solution and the batch was warmed to 50-53 *C for 45 minutes. The 5 slurry was then diluted with 10 L of water (-3.33 L/Kg) and stirred for an additional 1 h at 50-53 *C. Upon completion of the hydrolysis, the batch was cooled to 15 "C and acidified with 6 L of concentrated HCl and stirred at room temperature for 12 h until the reaction was complete as monitored by HPLC analysis. The slurry was then filtered, washed with water (3 x 12 L) and dried under vacuum/N 2 sweep at 35 *C until dry to give the title acid as a 10 colorless solid. Step 7: 6-(3-Chloro-4-fluorobenzyl)-3,4-bis[(2,2-dimethylpropanoyl)oxy)-5-oxo 5,6,7,8-tetrahydro-2,6-naphthyridine- 1 -carboxylic 2,2-dimethylpropanoic anhydride 0 OPiv C0 2 H FN / NH Et 3 N, PivCI, THF F N c N N ' cIN N 'N Oi 0 OH 0 OPiv 15 Intermediate A A 100 mL flask was charged with 15 mL of THF (KF < 300 ppm) and the acid (2.73 mmol, 1.0 g). Triethylamine (1.90 mL, 13.65 mmol) was then added under nitrogen at 20 'C. The slurry was cooled to 10 *C and trimethylacetyl chloride (1.18 mL, 9.56 mmol) added. The slurry was then stirred at 20 *C for 5 h until HPLC analysis revealed 20 complete conversion. The slurry was filtered (to remove Et 3 N/HCl salt) and the solid washed with 5 mL of dry THF. The solid was discarded and the filtrate then solvent switch under reduced pressure to heptane with a final volume of 15 mL. The resultant slurry was stirred at 20 0 C for 1 h, filtered, washed with one bed of heptane and dried in oven at 40 *C with a nitrogen stream for 12 h to give Intermediate A. MS (+ESI) m/z = 619. 25 EXAMPLE INT-B 6-(3-Chloro-4-fluorobenzyl)-3,4-dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1 carboxylic acid (Intermediate B) WO 2012/058173 PCT/US2011/057557 59 Step 1: Methyl 6-(3-chloro-4-fluorobenzyl)-3,4-dimethoxy-5-oxo-5,6,7,8-tetrahydro 2,6-naphthyridine- 1 -carboxylate 0 OH 0 OMe F N N Mel, Ag 2

CO

3 F N ci N ~ H N OMe 0 OH 0 OMe 5 A round bottom flask equipped with a mechanical stirrer was charged with 6 (3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1 carboxylic acid from Example INT-A, Step 6 (180 g, 491 mmol) and DCE (1.8 L, 0.2 M). Silver carbonate (4 equiv) was added, followed by the addition of methyl iodide (8 equiv). The mixture was stirred at room temperature for 20 h. The mixture was then heated between 10 35-39 *C for 6 days which resulted in >99% conversion to the fully tris-methylated product. The solids were filtered on Solka Floc and rinsed with MeOH. The filtrate was concentrated to dryness to yield a yellow solid. The product was triturated from MeOH. The residue was suspended in MeOH (1 L, 5 mL/g) and stirred at room temperature for 20 minutes. The mixture was cooled to 0 "C and stirred for I h. The solid was filtered on a Buchner funnel 15 and rinsed with cold MeOH (300 mL, 1 x 1.5 mL/g). The solid was dried on a sintered glass funnel for 2 h to afford the title product. Step 2: 6-(3-Chloro-4-fluorobenzyl)-3,4-dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6 naphthyridine-1-carboxylic acid O OMe 0 OH F XN UOH F 7N x N OMe C N OMe O OMe 0 OMe 20 Intermediate B A round bottom flask equipped with a mechanical stirrer was charged with methyl ester (132 g, 324 mmol) from Step 1 and 1:1 THF/MeOH (1.2 L total, 0.27 M). Aqueous lithium hydroxide (2 M, 2 equiv) was added and the reaction was heated to 40 'C for 15 minutes (>99% conversion to the acid). The solution was cooled to 0 *C and 25 acidified to pH = 2 using 6 M aqueous HCL. The product was extracted with CH 2 C1 2 (3 x 10 mL/g), dried over MgSO 4 , filtered and concentrated. The product was triturated from MTBE. The residue was suspended in MTBE (1 L, 6 mL/g)/hexanes (1 L, 6 mL/g) and WO 2012/058173 PCT/US2011/057557 60 stirred at room temperature for 90 minutes. The mixture was filtered on a Buchner funnel and rinsed with hexanes (1 x 1.5 mL/g). The solid was dried on a sintered glass funnel for 2 h to afford the title compound. MS (+ESI) m/z = 395. 5 EXAMPLE INT-C 6'-Hydroxy-2'-methyl-9',10'-dihydro-1'H-spiro[cyclopentane-1,3'-imidazo(5, 1 a](2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione (Intermediate C) Step 1: 4-Methoxy-6-(4-methoxybenzyl)-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6 10 naphthyridine- 1 -carboxylic acid 0 OEt 0 OH MeO / N TFAA PhMe, 100C M NH N N N urea H 2 0 2 then LiOH N O 0 OMe CH 2 Cl 2 0 OMe W012005/087768 Example 20, step 2 Ethyl 4-methoxy-6-(4-methoxybenzyl)-5-oxo-5,6,7,8,-tetrahydro-2,6 naphthyridine-1-carboxylate (14.0 g, 38.1 mmol, described in WO/2005/087768, Example 20, Step 2, page 117) and urea-hydrogen peroxide complex (7.5 g, 80 mmol, 2.1 equiv) were 15 dissolved in CH 2 C1 2 (200 mL) and cooled to 0 *C. To the solution was added trifluoroacetic anhydride (10.8 mL, 76 mmol, 2 equiv) slowly over 20-30 minutes. The reaction mixture was stirred at 0 *C for 30 minutes and allowed to warm to room temperature overnight. The reaction mixture was cooled to 0 'C and neutralized to pH = 7 with aqueous K 2 HP0 4 solution. Solid sodium bisulfite was added to quench the remaining oxidant and the mixture 20 was poured into a separatory funnel containing water (200 mL) and extracted with CH 2 Cl 2 (3 x 100 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. The unpurified material from the previous Step was dissolved in 200 mL of toluene and acetic anhydride (33 mL, 348 mmol, 7.2 equiv) was added. The reaction flask was fitted with a reflux condenser and the mixture was 25 heated to 120 'C in an oil bath for 16 h. The cooled reaction mixture was concentrated under reduced pressure. This material was dissolved in ethanol (180 mL) and LiOH.H 2 0 (7.0 g, 292 mmol, 6.9 equiv) was added together with 32 ml of water. The reaction mixture was stirred at room temperature for 2 h, after which LCMS analysis reveals complete conversion of starting material. The ethanol solvent was removed under reduced pressure 30 and the crude reaction mixture was diluted with IM aqueous HCl solution to afford a yellow suspension. The mixture was filtered through filter paper on a Hirsch funnel (under WO 2012/058173 PCT/US2011/057557 61 Hirsch ftunnel (under vacuum) and the yellow solid was washed with diethyl ether, and dried on the vacuum pump overnight to afford a white solid. Step 2: 4-Methoxy-6-(4-methoxybenzyl)-N-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro 5 2,6-naphthyridine- I -carboxamide 0 OH 0 H M MeO HATU (2.5 equiv) MeG M N N MeNH 2 HCI (5 equiv) M EtN(i-Pr)2 (5 equiv) N N 0 OMe DMF, 23 *C, 16 h 0 OMe A three-necked, round-bottom flask fitted with a N 2 inlet, magnetic stir bar and addition funnel was charged with the carboxylic acid from the previous Step (11.9 g, 33.2 mmol) and DMF (120 mL). The solution was cooled to 4 0 C and then HATU (31.6 g, 10 83 mmnol, 2.5 equiv) was added followed by methylamine hydrochloride (11.2 g, 166 mmol, 5 equiv) and DIPEA (46.4 mL, 266 mmol, 8 equiv). The reaction mixture was stirred for 16 h at room temperature. The clear solution was cooled to 0 "C and diluted with water (150 mL) and acidified with 2M HCI aqueous solution. The resulting solution was extracted with

CH

2 Cl 2 (2x) and the combined organic layers were washed with 1M aqueous HCl solution 15 (2 x 100 mL), dried over MgSO 4 , filtered and concentrated. MS (+ESI) m/z = 372. Step 3: 6'-Hydroxy-8-(4-methoxybenzyl)-2'-methyl-9',10'-dihydro-l'H spiro[cyclopentane-1,3'-imidazo[5,1-a] [2,6]naphthyridine]-1',5',7'(2'H,8'H) trione H0 ON, 0 Me Me N MeO N NH (10equiv) MeO N N N 0 H 2 S0 4 (3 equiv) 10 N N o 20 0 OMe dioxane, 110 *C, 64 h 0 OH A round-bottom flask fitted with a reflux condenser, a N 2 inlet and a magnetic stir bar was charged with the secondary amide from the previous Step (14.5 g, 26.9 mmol), 1,4-dioxane (300 mL), cyclopentanone (24.2 mL, 270 mmol, 10 equiv) and concentration sulfuric acid (4.32 mL, 81 mmol, 3 equiv). The reaction mixture was heated 25 to 110 'C in an oil bath for 64 h. The cooled reaction mixture was diluted with water (300 mL) and basified with IM aqueous NaOH .solution. The aqueous layer was washed with MTBE (2x), acidified with 2M aqueous HCl solution and extracted with CH 2 C1 2 (2x). The WO 2012/058173 PCT/US2011/057557 62 combined dichloromethane layers were washed with brine, dried over Na 2

SO

4 , filtered and concentrated. The yellow solid was triturated in MTBE and filtered to afford a pale yellow solid (9.2 g, 73% yield). 5 Step 4: 6'-Hydroxy-2'-methyl-9', I 0'-dihydro-1'H-spiro[cyclopentane- 1,3' imidazo[5,1-a] [2,6]naphthyridine]- 1',5',7(2'H,8'H)-trione 0 M Me N HBr in AcOH (48%) MeO N 80 *C, 16 h / N N HN O 0 0 OH 0 OH Intermediate C A round-bottom flask fitted with a nitrogen inlet, a magnetic stir bar and a reflux condenser was charged with aminal reagent from the previous Step (9.2 g, 19.6 10 mmol) and HBr (48% in acetic acid, 90 mL). The reaction mixture was heated to 80 0C for 16 h. The brown slurry was cooled to room temperature and diluted with water (100 mL). Concentration under reduced pressure afforded a dark colored oil which was purified by preparative reverse-phase column chromatography through a CI 8 -column, eluting with 5% MeCN in H20 (+0.1% TFA) to 95% MeCN in H20 (+0.1% TFA) as a gradient to provide 15 the title compound as an off-white solid. 1H NMR (500 MHz, DMSO-d) 5 8.90 (s, 1H), 3.43-3.36 (in, 2H), 3.25-3.17 (m, 2H), 2.96 (s, 3H), 2.56-2.51 (m, 2H), 2.20-2.11 (in, 2H), 1.98-1.91 (in, 2H), 1.90-1.82 (in, 2H). EXAMPLE INT-D 20 6-(3-Cbloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine 1 carboxamide (Intermediate D) 0 OPiv 0 NH 2 F A'z N NH 4 0H FAN N OPiv EtOH N / 0 OPiv 0 OH Intermediate A Intermediate D 25 A solution of Intermediate A (16.2 mmol, 10.0 g) and ammonium hydroxide (10 equiv, 28 wt %) in ethanol (65 mL, 0.25 M) was stirred at room temperature for 1 h. The reaction was acidified with concentrated HCl to pH = 2 - 3. The resulting solid was WO 2012/058173 PCT/US2011/057557 63 filtered and washed with water, then hexanes, to afford the primary amide as an off-white solid. MS (+ESI) m/z = 366. Preparation of Non-Commercial Reagents 5 2-Methoxycyclopentanone 0 0 C1 MeOH, TEA OMe To an oven-dried flask under an atmosphere of nitrogen was added 2 chlorocyclopentanone (10.0 mL, 100 mmol), anhydrous methanol (100 mL) and anhydrous 10 triethylamine (15.3 mL, 110 mmol). The reaction was stirred at room temperature for 65 h. The reaction was concentrated gently under reduced pressure and the residue was purified by coloumn chromatography through silica gel (120 g), eluting with 0-30% EtOAc in hexanes as a gradient, to afford the title compound (8.6 g, 75% yield). 'H NMR (400 MHz, CDCl 3 ) 8 3.68 (in, IH), 3.50 (s, 311), 2.35-2.15 (m, 3H), 2.09-2.00 (in, iH), 1.82-1.73 (in, 2H). [(cis)-2-Aminocyclopropyllmethanol hydrochloride t-BuO N OH TH H2N OH H HCI To a solution of tert-butyl[(cis)-2-(hydroxymethyl)cyclopropyljcarbamate 20 (1.0 g, 5.3 mmol) in THF (11 mL) was added aqueous 6 M HCI (2.0 mL, 12.3 mmol). The resulting mixture was heated to 45 *C for 3 h. The mixture was concentrated and azeotroped three times with toluene to afford the title compound (650 mg, 98% yield) as a dark oil. !H NMR (499 MHz, d 6 -DMSO) 5 8.40 (s, 3H), 3.71 (dd, J= 12.1, 5.1 Hz, 2H), 2.54 (s, IH), 1.22-1.15 (m, iH), 0.86-0.79 (in, 1H), 0.64 (dd, J= 11.0, 5.5 Hz, 1H). 25 (±)-N-(tert-Butyl)-2-oxocyclopentanecarboxamide O=C=N t-Bu O Me LIHMDS Me A dry flask was charged with cyclopentanone (0.526 ml, 5.94 mmol) and THF (30 mL) and the solution was cooled to -78 'C in a dry ice/acetone bath. Lithium 30 bis(trimethylsilyl)amide (1.0 M in THF, 6.54 ml, 6.54 mmol) was added and the reaction WO 2012/058173 PCT/US2011/057557 64 contents were stirred for 1 h at -78 'C. After this time, tert-butyl isocyanate (0.768 ml, 6.54 mmol) was added via syringe and the reaction contents were allowed to warm slowly to room temperature and stirred at this temperature for 48 h. The reaction mixture was quenched with saturated NH 4 C1 (10 mL), poured into a separatory funnel and extracted with 5 CH 2 C1 2 (2 x 50 mL), dried over Na 2

SO

4 , filtered and evaporated to afford a residue. This residue was purified via column chromatography through silica gel, eluting with 100% hexanes to 100% EtOAc as a gradient to afford the title compound (0.634 g, 58% yield). MS (+ESI) m/z = 184. 'H NMR (400 MHz, d 6 -DMSO) 6 7.51 (s, iH), 3.02 (t, J= 8.9 Hz, 1H), 2.15-2.09 (in, 4H), 1.95-1.91 (in, 1H), 1.73-1.71 (in, 1H), 1.22 (s, 9H). 10 Methyl 2-oxobicyclo[3.1.0]hexane-1-carboxylate 0 0 OMe This compound was prepared following the procedure described in J Org. Chem. 2002, 67, 6535 - 6538. 15 Methyl 2-(2-oxocyclopentyl)propanoate 0 OTMS MeO Br 0 OMe Me Me A solution of 1-(trimethylsilyloxy)cyclopentene (0.31 g, 2.00 mmol) and methyl 2-bromopropionate (0.33 ml, 3.00 mmol) in THF (10 ml) was cooled to -78 C under 20 a nitrogen atmosphere. After 15 minutes, tetrabutylammonium difluorotriphenylstaunate (1.4 g, 2.20 mmol) was added. The dry-ice/acetone bath was removed and the reaction allowed to warm to room temperature with stirring for 12 h. The reaction was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. The 25 ketone was purified by column chromatography through silica gel (24 g), eluting with 30% EtOAc in hexanes to afford the title compound (0.15 g, 44% yield). Bicyclo[4.1.0]heptan-2-one 0 0 30 WO 2012/058173 PCT/US2011/057557 65 Into a 2 L, 3-necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen was placed NaH (60 wt%, 44.0 g, 1. 10 mol, 1 10 equiv - washed four times with 500 ml of hexane). To this was added anhydrous DMS0 (1200 mL), followed by the addition of trimethyl sulfoxonium iodide (242 g, 1.10 mol, 1.10 equiv) in 5 several batches to control hydrogen evolution and exotherm. The resulting solution was stirred for 15 minutes at room temperature. To the above was added cyclohex-2-enone (96 g, 1.00 mol, 1.0 equiv) drop-wise with stirring over a 30 minute period. The resulting solution was stirred for an additional 2 h while the temperature was maintained at 50 'C. The reaction mixture was cooled to room temperature, then quenched by the addition of 1500 10 niL of H 2 0/ice. The resulting solution was poured into a 4 L separatory funnel and extracted with diethyl ether (3 x 500 mL). The organic layers were combined, washed with saturated brine (3 x 150 mL), dried over MgSO 4 and concentrated under vacuum. The residue was dissolved in MeOH (500 mL) and 2-aminoethanol (200 g, 3.00 mol, 3.0 equiv) was added. The resulting solution was stirred for 16 h at room temperature. The reaction mixture was 15 poured into a 2 L separatory funnel containing water (I L) and extracted with CH 2

C

2 (3 x 500 mL). The organic layers were combined, washed with 10% aqueous HCl solution (3 x 150 mL), dried over MgSO 4 and concentrated under vacuum. The oil was purified by distillation under reduced pressure (10 mm Hg) and the desired fractions collected at 90 "C, affording the desired bicyclo[4.1.0]heptan-2-one as colorless liquid (30 g, 26% yield). IH 20 NMR (300 MI-Iz, CDC1 3 ) 6 2.29-2.24 (m, 1H), 1.93-1.90 (m, 3H), 1.73-1.70 (m, 4H), 1.23 1.20 (m, 1H), 1.15-1.10 (in, IH). 2-(2-Methoxyethyl)cyclopentanone SMe 2 N NH r - _OMe 0 Br OMe 25 Step1: 2-Cyclopentylidene- 1,1 -dimethylhydrazine To a solution of cyclopentanone (16.8 ml, 200 mmol) in toluene (100 mL) was added dimethylhydrazine (15.3 ml, 200 mmol) and TFA (0.2 ml, 2.60 mmol). The solution was stirred at 90 *C for 12 h. The mixture was cooled to room temperature and 30 washed with water. The organic layers were combined, dried over Na 2

SO

4 , filtered and concentrated under reduced pressure affording 21.1 g of a brown liquid. Step 2: 2-(2-Methoxyethyl)cyclopentanone WO 2012/058173 PCT/US2011/057557 66 A solution of 2-cyclopentylidene-1,1-dimethylhydrazine (1.3 g, 10 mmol) in THF (20 mL) was cooled to - 30 *C in a bath. To this was added a solution of n butyllithium (6.6 mL, 11 mmol, 1.8 M in hexanes) and the mixture was stirred at -30 C for 1 h. The solution was warmed to 0 *C and I -bromo-2-methoxyethane was added (0.94 ml, 5 10 mmol). The solution was warmed to room temperature and stirred for an additional 2 h followed by the addition of potassium phosphate (2.1 g, 10 mmol), phosphorous acid (1.6 g, 20 mmol) and water (10 mL). After stirring for 14 h, the mixture was poured into a separatory funnel containing water (50 mL) and the aqueous layer was extracted with diethyl ether (2 x 50 mL). The organic layers were dried over Na 2

SO

4 , filtered and concentrated 10 under reduced pressure. The ketone was purified by column chromatography through silica gel (100 g), eluting with 25% EtOAc in hexanes to affording the title compound (0.42 g, 30% yield). (±)-(1R,6S,7R)-ethyl 2-oxobicyclo[4.1.0]heptane-7-carboxylate Br 0 Me- OEt 0 ~H I Me O H CO 2 Et 15 H Step 1: (2-Ethoxy-2-oxoethyl)dimethylsulfoniun A solution of ethyl bromoacetate (167 g, 100 mmol) and dimethyl sulfide (62 g, 100 mmol) in acetone (3 L) was stirred at 15 'C under at atmosphere of N 2 for 24 h. The 20 mixture was filtered and the solid was washed with acetone (2 x 500 mL) to afford the title compound (165 g, 72% yield). Step 2: (±)-(IR,6S,7R)-Ethyl 2-oxobicyclo[4.1.0]heptane-7-carboxylate 25 A solution of (2-ethoxy-2-oxoethyl)dimethylsulfonium (183.4 g, 80 mmol) and DBU (123 g, 80 mmol) in CHC1 3 (1.4 L) was stirred under an atmosphere of nitrogen at room temperature for 1 h. Cyclohex-2-enone (60.8 g, 63 mmol) was added and the mixture was stirred at 13 *C for 18 h. The reaction mixture was poured into a 3 L separatory funnel, washed with water (3 x 500 mE) and the organic layer was removed, dried over MgSO 4 , 30 filtered and concentrated. The mixture was purified by recrystallization from Et 2 O to afford the title compound as a white solid (40 g, 34% yield). MS (+ESI) m/z= 183. 'H NMR (300 MHz, d 6 -DMSO) < 4.12-3.32 (in, 2H), 2.53-2.49 (in, 1H), 2.26-2.17 (in, 1H), 2,08-1.85 (in, 5H), 1.66-1.56 (in, 2H), 1.22-1.17 (t, J= 7.2 Hz, 3H).

WO 2012/058173 PCT/US2011/057557 67 (iS,5R)-Bicyclo[3.1.0]hexan-2-one OH n- BuLi OH TPAP O o C-Mg - C1 TMP NMO Step 1: (S)-I -Chlorohex-5-en-2-ol 5 To an oven-dried flask under an atmosphere of nitrogen was added (S)-2 (chloromethyl)oxirane (25.0 g, 270 mmol), anhydrous THF (270 mL) and copper (I) iodide (5.15 g, 27.0 mmol). The mixture was cooled to -78 *C in a dry ice/ acetone bath. A solution of allyl magnesium chloride (2.0 M in THF, 149 mL, 298 mmol) was added over 25 minutes to the reaction. The reaction was slowly warmed to -10 C over 2 h and the cooling 10 bath was then removed. The reaction was stirred further for 3 h at room temperature. Aqueous NH 4 CI was added to quench the reaction, the reaction was poured into a separatory funnel and extracted with diethyl ether (3 x 200 mL). The combined organic layers were dried over Na 2

SO

4 , filtered through a plug of silica gel, and concentrated under reduced pressure to afford the title compound (33 g, 91% yield). 'H NMR (400 MHz, CDCl 3 ) $ 5.82 15 (ddt, J= 17.2, 10.2, 6.6 Hz, 11-1), 5.07 (dq, J= 17.2, 1.7 Hz, 1H), 5.01 (dq, J= 10.2, 1.7 Hz, IH), 3.85-3.80 (m, 1H), 3.64 (dd, J= 11.1, 3.5 Hz, 1H), 3.49 (dd, J= 11.1, 7.0 Hz, 1H), 2.27-2.15 (m, 3H), 1.67-1.61 (m, 2H). Step 2: (1S,2S,5R)-Bicyclo[3.1.0]hexan-2-ol 20 To an oven-dried flask under an atmosphere of nitrogen was added (S)-1 chlorohex-5-en-2-ol (33.0 g, 245 mmol), anhydrous MTBE (900 mL), and 2,2,6,6 tetramethylpiperidine (107 mL, 635 mmol). The solution was cooled to -78 *C in a dry ice/ acetone bath. A solution of n-butyl lithium (1.6 M in hexanes, 556 mL, 889 mmol) was 25 added over 30 minutes to the reaction. The reaction was slowly warmed to room temperature over 16 h. The reaction was re-cooled to -20 *C and methanol (50 mL) was added portion-wise. The reaction was warmed to room temperature and diluted with MTBE (300 mL). The reaction was poured into a separatory funnel and the organic layer was washed successively with 2 M aqueous HCl solution (2 x 400 mL) and then water. The 30 combined aqueous layers were back-extracted with MTBE (2 x 100 mL). The combined organic layers were dried over Na 2 S04, filtered, and concentrated under reduced pressure to afford the title compound which was used without further purification. 'H NMR (400 MHz, CDCl 3 ) 6 4.23 (d, J= 4.8 Hz, 1H), 2.00-1.88 (m, 1H), 1.68 (dd, J= 12.5, 8.1, 1H), 1.55 (dd, J= 14.5, 8.4, 1H), 1.45-1.28 (m, 3H), 0.48-0.41 (m, 111), 0.05-0.01 (m, 1H).

WO 2012/058173 PCT/US2011/057557 68 Step 3: (IS, 5R)-Bicyclo[3.l .0]hexan-2-one To a solution of (1S,2S,5R)-bicyclo[3.1.0]hexan-2-ol (24.0 g, 245 mmol) in 5 anhydrous CH 2 Cl2 (1500 mL), was added 4-methylmorpholine-N-oxide (45.8 g, 391 mrnol) and 50 g of 3A molecular sieves. The reaction was placed in a water bath, tetrapropylammonium perruthenate (4.4 g, 12.5 mmol) was added, and the reaction was stirred at room temperature for 18 h. The reaction was filtered through a pad of Celite, the filtrate was poured into a separatory funnel and washed successively with 2 M aqueous HCI 10 solution (200 mL) and water (100 mL). The combined aqueous layers were back-extracted with CH 2 C1 2 (2 x 100 mL). The combined organic layers were dried over Na 2

SO

4 , filtered through a plug of silica gel, rinsing with 25% diethyl ether/CH 2 Cl 2 , and concentrated under reduced pressure. The residue was then purified by vaccuum distillation. The title compound distilled at 60-65 *C at a vacuum of 10 mm Hg (9.36 g, 44% yield). 'H NMR 15 (400 MHz, CDCl 3 ) 6 2.18-1.98 (m, 5H), 1.80-1.74 (in, 1H), 1.23-1.16 (m, 1H), 0.93 (q, J= 4.0 Hz, 1H). (1R,5S)-Bicyclot3.1.0]hexan-2-one 0 20 (JR, 5S)-bicyclo[3.1.0]hexan-2-one was prepared as using the same procedure described for (1S, 5R)-bicyclo[3.1 .0]hexan-2-one, replacing (S)-2-(chloromethyl)oxirane with (R)-2-(chloromethyl)oxirane in Step 1. The 1 H NMR is identical to (1S, 5R) bicyclo[3.1.0]hexan-2-one. 25 Preparation of Examples EXAMPLE 1 (±)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9', 1 0'-dihydro-2'H spiro [bicyclo[2.2.1 ]heptane-2,3'-imidazo [5,1-a] [2,6]naphthyridine] -1 ',5',7'(8'H)-trione WO 2012/058173 PCT/US2011/057557 69 H 0 OH 0 N'Me F )(>NMethylarnine hydrochloride F N NN C1 / N OMe EDC, HOBT, DIPEA, DMF C x N OMe 0 OMe 0 OMe Intermediate B HH0 0 N.'M 0 o Me O 'Me N HBr/AcOH F--N HNH F N C N N H 2 S04 N NO Ci 0 N N 0 OH 0 OH 5 Step 1: 6-(3-Chloro-4-fluorobenzyl)-3,4-dimethoxy-N-methyl-5-oxo-5,6,7,8 tetrahydro-2,6-naphthyridine- 1 -carboxamide A mixture of Intermediate B (5.0 g, 12.7 mmol), methylamine hydrochloride (1.5 equiv), EDCI (1.5 equiv), HOAt (1.5 equiv) and NN-diisopropylethylamine (2.5 equiv) 10 in DMF (0.2 M) was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with water (2x), brine, dried over Na 2

SO

4 and filtered. The solution was concentrated under reduced pressure. Trituration with EtOAc afforded a beige solid. MS (+ESI) m/z = 408. 15 Step 2: 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N-methyl-3,5-dioxo-2,3,5,6,7,8 hexahydro-2,6-naphthyridine- 1 -carboxamide A solution of the amide from Step 1 (4.11 g, 10.0 mmol) in HBr (33% in AcOH, 0.2 M) was heated at 50 'C for 30 minutes. The reaction was cooled to room 20 temperature, diluted with EtOAc and concentrated under reduced pressure. The resulting solid was triturated with EtOH, filtered and washed with a mixture of EtOH and hexanes to afford a beige solid (3.62 g, 95% yield). MS (+ESI) m/z = 380 Step 3: (±)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9',10'-dihydro-2'H 25 spiro[bicyclo[2.2.1]heptane-2,3'-imidazo[5,1-a][2,6]naphthyridine] 1',5',7(8'H)-trione WO 2012/058173 PCT/US2011/057557 70 A mixture of amide from Step 2 (200 mg, 0.53 mmol), (±)-norcamphor (30 equiv) and sulfuric acid (catalytic, 0.05 equiv) in 1,4-dioxane (0.1 M) was heated at 100 "C for 18 h (note: the reaction mixture became homogeneous at 100 'C). The reaction was 5 cooled to room temperature, diluted with saturated aqueous NaHCO 3 and extracted with

CH

2 C1 2 (3x). The combined organic layers were dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography using a Cig column, eluting with 10% MeCN in H20 (+0.1% formic acid) to 90% MeCN in H20 (+0.1% formic acid) as a gradient to afford a yellow solid as a 2:1 10 mixture of diastereomers (52 mg, 21% yield). MS (+ESI) m/z = 472 for both diastereomers. EXAMPLE 2 (±)-8-(3-Chloro-4-fluorobenzyl)-6-hydroxy-2,3-dimethyl-2,3,9,1 0-tetrahydroimidazo[5,1 a][2,6]naphthyridine-1,5,7(8H)-trione O OH H MeAN 0 F N Methylamine hydrochloride F -t CI N OMe EDCl, HOBT, DIPEA, DMF CN N OMe 0 OMe 0 OMe 15 Intermediate B EtO OEt o Me Me F) N>-NMe HBr/AcOH N 0 OH Step 1: 6-(3-Chloro-4-fluorobenzyl)-3,4-dimethoxy-N-methyl-5-oxo-5,6,7,8 tetrahydro-2,6-naphthyridine- 1 -carboxamide 20 The title compound was prepared according to the procedure described in Step 1 of Example 1: Step 2: (±)-8-(3-Chloro-4-fluorobenzyl)-6-hydroxy-2,3-dimethyl-2,3,9,10 25 tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione WO 2012/058173 PCT/US2011/057557 71 A solution of amide from Step 1 (500 ing, 1.23 mmol) and acetaldehyde diethyl acetal (5 equiv) in HBr (33% in AcOH, 0.2 M) was heated. at 50 0 C for I h. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative reverse phase chromatography through a C s 5 column, eluting with 10% MeCN in H20 (+0.1% formic acid) to 90% MeCN in H20 (+0.1% formic acid) as a gradient. The solid was triturated with EtOH/hexanes to afford a gray/green solid (275 mg, 55% yield). MS (+ESI) m/z = 406. 'H NMR (400 MHz, DMSO d) 13.57 (s, 114), 7.60 (d, J= 7.2 Hz, 1H), 7.45-7.35 (in, 2H), 5.68-5.61 (m, 114), 4.80 4.64 (m, 2 H), 3.60-3.53 (m, 2H), 3.36-3.14 (in, 2H), 2.96 (s, 3H), 1.62 (d,,J= 5.7 Hz, 3H). 10 EXAMPLE 3 (S)-8-(3-Chloro-4-fluorobenzyl)-2,3-dicyclopropyl-6-hydroxy-2,3,9, 10 tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione H0 O OPiv 0 NOK F H2NH2 -N FN NHH CIN OPiv C1 O 0 OPiv 0 OH Intermediate A O 0 N N F separate F C1N O enantiomers N N 15 .0 OH 0 OH Step 1: 6-(3-Chloro-4-fluorobenzyl)-N-cyclopropyl-4-hydroxy-3,5-dioxo-2,3,5,6,7,8 hexahydro-2,6-naphthyridine-1-carboxamide A 3.0 L flask was charged with dry THF (1.5 L) and Intermediate A (124 g, 20 200 mmol). Cyclopropylamine (114 g, 2000 mmol) was then added under nitrogen at 0 'C and the resulting slurry was then stirred at 20 C for 18 h. The slurry was cooled in an ice bath and concentrated aqueous HCI was added until the pH of the suspension was 1. Water was added and a white precipitate formed. The suspension was stirred at room temperature for 2 h, then filtered with successive rinses of water, ethanol and ethyl acetate. The resulting 25 solid was dried under vaccum to afford the title compound (75 g, 92% yield). MS (+ESI) m/z = 406.

WO 2012/058173 PCT/US2011/057557 72 Step 2: (S)-8-(3-Chloro-4-fluorobenzyl)-2,3-dicyclopropyl-6-hydroxy-2,3,9,10 tetrahydroimidazo[5,1-a[2,6]naphthyridine-1,5,7(8H)-trione A mixture of the amide from Step 1 (60 g, 150 mmol) in 1,4-dioxane (2000 5 mL) was added cyclopropanecarbaldehyde (115 g, 1500 mmol) and concentrated sulfuric acid (1 mL) under nitrogen at 0 C, then the mixture was heated to 100 *C for 18 h. After cooling, a solution of NaHCO 3 in water was added, and the resulting mixture was extracted with CH 2 C1 2 (3 x 500 mL), the combined organics were washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. The residue was 10 recrystallized with MeOH to afford the racemic compound (48 g, 69% yield). The racemic mixture (32 g) was separated by chiral SFC to afford the enantiopure example 3 (12.0 g, first eluting enantiomer, >99% ee). Preparative chiral separation of the enantiomers was achieved using a ChiralPak AD-H column (250 x 30 mm ID. 20 um), eluting with CO 2 plus methanol:acetonitrile (2: 2: 1 + 0.05% Et 2 NH) at a flow rate of 80 mL/minute and a 15 column temperature of 38 0 C. MS (+ESI) m/z = 458. 'H NMR (400 MHz, CDCl 3 ) 6 13.58 (s, 1K), 7.41-7.37 (m, 1H), 7.30-7.12 (in, 2H), 4.98-4.93 (m, 1H), 4.77 (d, J= 15 Hz, 1H), 4.64 (d, J= 15 Hz, 1H), 3.55-3.43 (m, 3H), 3.31-3.20 (m, 1H), 2.77-2.70 (m, 111), 1.28 1.14 (m, 2H), 1.08-1.00 (m, 1K), 0.97-0.85 (m, 1H), 0.86-0.69 (m, 4H), 0.65-0.57 (m, 1H). 20 EXAMPLE 4 (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclobutyl-6-hydroxy-2-(2-methoxyethyl)-2,3,9,10 tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione O NH 2 0 F /NH Me CI / N N o H 2 SO4 0 OH Intermediate D OMe S NH OMe 0 F Br 'N / N Me C1 O NaH Cl O O OH O OH WO 2012/058173 PCT/US2011/057557 73 Step 1: (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclobutyl-6-hydroxy-2,3,9,10 tetrahydroimidazo[5,1-a] [2,6]naphthyridine- 1,5,7(8R)-trione A mixture of Intermediate D (2.50 g, 5.13 mmol), cyclobutyl methyl ketone 5 (5 equiv) and concentrated sulfuric acid (catalytic, 0.05 equiv) in 1,4-dioxane (25 mL, 0.2 M) was heated at 100 'C for 18 h (note: the reaction mixture became homogeneous at 100 *C). The reaction was cooled to room temperature, diluted with EtOAc and the resulting solid was filtered to afford the desired aminal as a light yellow solid (2.68 g, 85% yield). 10 Step 2: (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclobutyl-6-hydroxy-2-(2-methoxyethyl) 2,3,9,1 0-tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione A solution of aminal from Step 1 (200 mg, 0.45 mmol), 2-bromoethyl methyl 15 ether (5 equiv) and sodium hydride (60 wt% in oil, 5 equiv) in DMF (1.8 mL, 0.25 M) was stirred at room temperature for 18 h. The solution was directly loaded onto a preparative reverse phase C18 column and eluted with 10% MeCN in H20 (+ 0.1% formic acid) to 90% MeCN in H 2 0 (+ 0.1% formic acid) as a gradient. The resulting solid was further purified by trituration using EtOAc/hexanes to afford a beige solid. MS (+ESI) m/z = 504. 20 EXAMPLE 5 (±)-3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-8,8-dimethyl-2,3,8,9, 10,11-hexahydro-7aH pyrido[2',1':2,3]imidazo[5,1-a][2,6]naphthyridine-4,6,13(1H)-trione H Me Me O OH O N OH Me Me F /N H 2 N OH F / N N N CN OMe EDC, HOBT, C N OMe O OMe DIPEA, DMF 0 OMe 25 WO 2012/058173 PCT/US2011/057557 74 H Me Me O N O Dess-Martin F N HBr/AcOH periodinane C N OMe O OMe 0 N F / N Me Me Ci N g O O OH Step 1: 6-(3-Chloro-4-fluorobenzyl)-N-(5-hydroxy-4,4-dimethylpentyl)-3,4 dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide 5 The title compound was prepared according to the procedure described in Step 1 of Example I using 5-amino-2,2-dimethylpentanol (1.5 equiv) as the source of amine. The reaction was quenched with 10% aqueous HCI and extracted with EtOAc (3x), The organic layer was washed with saturated -aqueous NaHCO 3 , dried over Na 2

SO

4 , filtered and concentrated under reduced pressure to afford a yellow oil. The product was used 10 unpurified in the subsequent reaction. MS (+ESI) m/z = 508. Step 2: 6-(3-Chloro-4-fluorobenzyl)-N-(4,4-dimethyl-5-oxopentyl)-3,4-dimethoxy-5 oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide 15 Dess-Martin periodinane (1.5 equiv) was added to a solution of alcohol (1.28 g, 2.52 mmol) in CH 2 C1 2 (13 mL, 0.2 M). The reaction was stirred at room temperature for 2 h. Solid Na 2

S

2 0 3 (25 g) was added and the solution was diluted with saturated aqueous NaHCO 3 (100 mL) and EtOAc. The solution was stirred until solid materials were dissolved (10 minutes). The layers were separated and the organic layer was washed with 20 saturated aqueous NaHCO 3 . The aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to afford a colorless foam. The product was used unpurified in the next reaction. MS (+ESI) m/z = 506. 25 Step 3: (±)-3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-8,8-dimethyl-2,3,8,9, 10,11 hexahydro-7aH-pyrido[2',1':2,3]imidazo[5,1-a][2,6]naphthyridine 4,6,13(lH)-trione WO 2012/058173 PCT/US2011/057557 75 The title compound was prepared according to the procedure described in Step 2 of Example 2. Trituration from EtOH afforded the desired product as a yellow solid (604 mg, 52% yield over 2 steps). MS (+ESI) m/z = 460. 'H NMR (400 MHz, d6-DMSO) S 5 13.62 (s, 1H), 7.64-7.59 (m, 1H), 7.45-7.37 (m, 2H), 5.64 (s, 1H), 4.76 (d, J= 15 Hz, 1H), 4.67 (d, J= 15 Hz, 1H), 4.19-4.11 (m, 1H), 3.60-3.53 (in, 2H), 3.43-3.30 (m, IfH), 3.20-3.10 (m, 1H), 3.00-2.90 (m, 1H), 1.80-1.69 (m, 1H), 1.58-1.42 (m, 3H), 1.24 (s, 3H), 0.51 (s, 31). 10 EXAMPLE 6 (±)-3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3,7a,8,9,10 hexahydropyrrolo[2',1':2,3]imidazo[5,1-a][2,6]naphthyridine-4,6,12(I H)-trione 0 0 OH ci 0 CI N C 1 O Me F N N_ _ F----- . KI 1 N I OMe C N I OMe KOH 0 OMe 0 OMe HO O N Me N F HBr/AcOH FNN Me >N N Mex Ci OMe C1 0 15 0 OMe 0 OH Step 1: 6-(3-Chloro-4-fluorobenzyl)-3,4-dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6 naphthyridine- 1 -carbonyl chloride Oxalyl chloride (1.1 equiv) was added to a solution of Intermediate B (1.00 g, 20 2.53 mmol) in THF (10 mL, 0.25 M). DMF (catalytic, 0.05 equiv) was added (note: reaction began to bubble) and the solution was stirred at room temperature for I h. The reaction was concentrated under reduced pressure and the acid chloride was used unpurified in the subsequent reaction. An aliquot was diluted with MeOH to form the methyl ester in order to confirm the presence of the acid chloride. MS (+ESI) of the corresponding methyl 25 ester m/z = 409.

WO 2012/058173 PCT/US2011/057557 76 Step 2: (3-Chloro-4-fluorobenzyl)-3,4-dimethoxy-5-oxo-N-(4-oxopentyl)-5,6,7,8 tetrahydro-2,6-naphthyridine- 1 -carboxamide The reaction was performed as outlined in J Org. Chem. 1984, 49, 4067 5 4070. Unpurified acid chloride (1.04 g, 2.52 mmol) was added to a solution of 2-methyl-I pyrroline (10 equiv) and 10% aqueous KOH (7 mL, 5 equiv) and THF (10 mL, 0.25 M). The reaction was stirred at room temperature for 2 h. The reaction was then diluted with

CH

2 Cl 2 and water. The layers were separated and the organic layer was washed with 10% aqueous HCl, dried over Na 2 S04, filtered and concentrated under reduced pressure to afford 10 an orange oil. The resulting ketone was used unpurified in the next reaction. MS (+ESI) m/z = 478. Step 3: (±)-3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3,7a,8,9,10 hexahydropyrrolo[2', 1':2,3]imidazo[5,1-a] [2,6]naphthyridine-4,6,12(1H) 15 trione The title compound was prepared according to the procedure described in Step 2 of Example 2 using the ketone from Step 2 above (1.20 g, 2.52 mmol). After concentrating the reaction under reduced pressure, the resulting oil was placed in the freezer 20 for 18 h. The product became a mixture of solid and oil. After the addition of EtOAc, a solid precipitated from the solution. The solid was filtered and washed with EtOAc and then with EtOH to afford a brown solid. MS (+ESI) m/z = 432. 'H NMR (400 MHz, CDCl 3 ) S 13.60 (s, IH), 7.41-7.37 (m, IH), 7.27-7.14 (m, 2H), 4.78-4.64 (m, 2H), 3.87-3.78 (in, iH), 3.54-3.45 (in, 2H), 3.40-3.31 (m, 3H), 2.75-2.67 (m, iH), 2.36-2.26 (m, 2H), 1.88 25 1.75 (m, 4H). EXAMPLE 7 (±)-3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3,8,9,10,11-hexahydro-7aH pyrido[2',1':2,3]imidazo[5,1-a][2,6]naphthyridine-4,6,13(1H)-trione o Ci 0 0 N?/ silica F / N H 2 N Me F / N Me gel C1 N OMe DIPEA CN OMe 30 0 OMe 0 OMe WO 2012/058173 PCT/US2011/057557 77 H 0 N Me O N N WN HBr/AcOH N e N I N CI )C - N' OMe N I 0 OMe 0 OH Step 1: 2-(3-Chloro-4-fluorobenzyl)-7,8-dimethoxy-5-[(6-methyl-3,4 dihydropyridin- 1 (2H)-yl)carbonyl}-3,4-dihydro-2,6-naphthyridin- I (2H)-one 5 A solution of amine (730 mg, 4.81 mmol), acid chloride (1.04 g, 2.52 nmol, prepared according to Example 6, Step 1) and NN-diisopropylethylamine (3 equiv) in THF (10 mL, 0.25 M) was stirred at room temperature for 18 h. The reaction was diluted with 10% aqueous HC1 and was extracted with dichloromethane (3 x 25 mL). The organic layer was washed with saturated aqueous NaHCO 3 , dried over Na 2

SO

4 , filtered and concentrated 10 under reduced pressure to afford a yellow oil. The enamine was used unpurified in the next reaction. MS (+ESI) m/z = 474. Step 2: 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-N-(5-oxohexyl) 2,3,5,6,7,8-hexahydro-2,6-naphthyridine- 1 -carboxamide 15 The reaction was performed as outlined in Advanced Synthesis and Catalysis, 1990, 351, 2081-2085. A large spatula of silica gel (~, g) was added to a solution of enamine (1.19 g , 2.51 ninol) in CH 2 01 2 (10 mL, 0.25 M). The reaction was stirred at room temperature for 18 h. The silica gel was filtered off and was washed with 50% MeOH in 20 CH 2 Cl 2 . The crude product was purified by preparative reverse phase chromatography through a C18 column, eluting with 10% MeCN in H 2 0 (+0.1% formic acid) to 90% MeCN in H 2 0 (+0.1% formic acid) to afford a yellow oil. MS (+ESI) m/z= 492. Step 3: (±)-3-(3-Chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3,8,9,10,11 25 hexahydro-7aH-pyrido[2',1':2,3]imidazo[5,1-a][2,6]naphthyridine 4,6,13(1H)-trione The title compound was prepared according to the procedure described in Step 2 of Example 2 using the ketone described in the previous step (329 mg, 0.67 mmol). 30 Trituration with EtOAc and then EtOH afforded a yellow solid. MS (+ESI) m/z = 446.

WO 2012/058173 PCT/US2011/057557 78 EXAMPLE 8 (±)-3 -(3 -Chloro-4-fluorobenzyl)-7a-ethyl-5 -hydroxy-2,3,8,9,10,11 -hexahydro-7aH pyrido[2', 1':2,3]imidazo[5, 1 -a] [2,6]naphthyridine-4,6,13(1H)-trione NBoc EtMgBr Me TFA , Me N_

~H

2 NMe N H 0 CI Me 0 N Me F NN F CI N OMe C1 OMe 5 0 OMe 0 OMe 0 N HBr/AcOH F N C x N M 0 OH Step 1: 7-Aminoheptan-3-one 10 The reaction was performed as outlined in J Org. Chem. 2006, 71, 4525 4529. To a solution of N-tert-butylcarboxycarbamoyl-piperidin-2-one (260 mg, 1.31 mmol) in THF (2.6 mL, 0.5 M) at -78 *C was added ethylmagnesium bromide (1.2 mL, 3.59 mmol). The reaction was stirred for 2 h during which the reaction slowly warmed up to room temperature. The reaction was quenched with saturated aqueous NaHCO 3 and 15 extracted with EtOAc (3 x 25 mL). The organic layer was dried over Na 2

SO

4 , filtered and concentrated under reduced pressure to afford a colorless oil. The ketone was used unpurified in the next reaction. MS (+ESI) m/z = 252 (M + Na) t Step 2: 6-Ethyl-2,3,4,5-tetrahydropyridine 20 The reaction was performed as outlined in J. Org. Chem. 2006, 71, 4525 4529. A solution of ketone (300 mg, 1.31 mmol) in CH 2 Cl2/TFA (4:1, 0.5 M) was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to afford a yellow oil. The enamine was used unpurified in the next reaction. MS (+ESI) m/z = 112.

WO 2012/058173 PCT/US2011/057557 79 Step 3: 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-N-(5-oxoheptyl) 2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 5 To a solution of acid chloride (539 mg, 1.30 mmol, prepared according to Example 6, Step 1) and NN-diisopropylethylamine (3 equiv) in THIF (5.2 mL, 0.25 M) was added 6-ethyl-2,3,4,5-tetrahydropyridine (1 equiv). The reaction was stirred at room temperature for 18 h. LCMS indicated a mixture of carboxylic acid and desired ketone. The reaction was diluted with 10% aqueous HCI and extracted with CH 2 C1 2 (3 x 25 mL). The 10 organic layer was washed with saturated aqueous NaHCO 3 , dried over Na 2

SO

4 , filtered and concentrated under reduced pressure to afford a yellow oil. The ketone was used unpurified in the next reaction. MS (+ESI) m/z= 506. Step 4: (±)-3-(3-Chloro-4-fluorobenzyl)-7a-ethyl-5-hydroxy-2,3,8,9,10,11 15 hexahydro-7aH-pyrido [2', 1':2,3 ]imidazo[5,1-a] [2,6]naphthyridine 4,6,13(1H)-trione The title compound was prepared according to the procedure described in Step 2 of Example 2 using the ketone described in the previous step (660 mg, 1.30 mmol). 20 Trituration with EtOAc and then EtOH afforded a yellow solid. MS (+ESI) m/z = 460. EXAMPLE 9 (±)-8-(4-Fluorobenzyl)-6-hydroxy-2-methyl-3-(propan-2-yl)-2,3,9,10 tetrahydroimidazo[5, 1-a] [2,6]naphthyridine-1,5,7(8H)-trione o Me 0 Me N, Me N, Me F N MePd(OH) 2 on carbon F NN Me I 4 -- N me CN N> O e H 2 (40-50 psi) N M 25 0 OH 0 OH A 200 mL Parr vessel equipped with a stir bar was charged with the aryl chloride (prepared according to general procedure in Example 1, 200 mg, 0.46 mmol), Pearlman's catalyst (20 wt% on carbon, 2 equiv), AcOH (16 equiv) and EtOH/CH 2 Cl 2 (5:1, 0.03 M). The vessel was purged with nitrogen then placed under vacuum (repeat 3 x). The 30 vessel was then filled with hydrogen (40-50 psi) and was vigorously shaken at room temperature for 5 h. The reaction was diluted with CH 2 Cl 2 , filtered over a pad of Celite and was washed with CH 2

CI

2 and MeOH to afford a gray/green foam. MS (+ESI) mz= 400. I WO 2012/058173 PCT/US2011/057557 80 NMR (400 MHz, CDCl 3 ) 8 13.70 (s, 1H), 7.36-7.29 (m, 2H), 7.11-7.02 (m, 2H), 5.57 (bs, 1H), 4.78 (d, J = 14.5 Hz, 1H), 4.69 (d, J = 14.5 Hz, 1H), 3.52-3.38 (m, 3H), 3.35-3.23 (m, IH), 3.21-3.05 (m, 4H), 1.21 (d, J=7.0 Hz, 3H), 0.71 (d, J= 6.5 Hz, 3H). 5 EXAMPLE 10 8'-(2-Bromo-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9',10'-dihydro-2'H-spiro[cyclopentane 1,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(8'H)-trione o Me F Br O e N AN NN AN Br F AN HN 0 KOt-Bu N N O 0 OH Br 0 OH Intermediate C Intermediate C (100 mg, 0.33 mmol), 2-bromo-4-fluorobenzyl bromide (3 10 equiv) and potassium tert-butoxide (5 equiv) were dissolved in DMSO (1 mL, 0.3 M) and stirred at room temperature for 2.5 h. The reaction was quenched with AcOH/20 and extracted with CH 2

CJ

2 . The organic layer was dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography through silica gel, eluting with 0 to 10% MeOH in CH 2 C1 2 as a gradient to afford the title compound as a 15 yellow solid. MS (+ESI) m/z= 490. 'H NMR (500 MHz, d 6 -DMSO) 6 13.44 (s, 1H), 7.69 7.65 (m, 1H), 7.45-7.40 (in, 1H), 7.29-7.24 (in, 1H), 4.74 (s, 2H), 3.61-3.55 (m, 2H), 2.97 (s, 3H), 2.58-2.50 (in, 2H), 2.20-2.11 (m, 3H), 2.00-1.93 (m, 2H), 1.90-1.83 (m, 3H). EXAMPLE 11 20 (±)-8-(3.-Chloro-4-fluorobenzyl)-2-cyclopropyl-6-hydroxy-3-(2-(methylsulfonyl)ethyl) 2,3,9,10-tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione WO 2012/058173 PCT/US2011/057557 81 7O 0 NH N SMe F -,O SMe F Cl N N H 2

SO

4 , dioxane C ' N o 0 OH 100 *C, 6 h 0 OH Example 3, step I 0 N ,, m-CPBA F N Me

CH

2 C1 2 C ' N O 0 0 OH Step I: (±)-8-(3-Chloro-4-fluorobenzyl)-2-cyclopropyl-6-hydroxy-3-(2 5 (methylthio)ethyl)-2,3,9,1 0-tetrahydroimidazo [5, 1 -a][2,6]naphthyridine 1,5,7(8H)-trione A solution of cyclopropylamide (from Example 3, Step 1) (1.14 g , 2.81 mmol) in 1,4-dioxane (14 mL) was treated with 3-(methylthio)propionaldehyde (2.81 mL, 10 28.1 mmol) and concentrated sulfuric acid (0.03 mL, 0.562 mmol, 20 mol%). The solution was heated at 100 *C for 6 h and then cooled to room temperature. The mixture was poured into a 250 mL separatory funnel, diluted with saturated aqueous NaHCO 3 solution (100 mL) and extracted with CH 2

CI

2 (2 x 50 mL). The combined organics were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure. Purification by 15 column chromatography through silica gel, eluting with 10% MeOH in CH 2 Cl 2 afforded the title compound as a yellow oil (1.23 g, 89% yield). MS (+ESI) m/z= 492, Step 2: (±)-8-(3-Chloro-4-fluorobenzyl)-2-cyclopropyl-6-hydroxy-3-(2 (methylsulfonyl)ethyl)-2,3,9,1 0-tetrahydroimidazo[5,1-a] [2,6]naphthyridine 20 1,5,7(8H)-trione A solution of the sulfide from Step 1 (1.5 g, 3.05 minol) in CH 2

CI

2 (15 mL) was cooled to 0 *C in an ice bath. The solution was treated with m-CPBA (3.16 g, 9.15 mrol) and the resulting mixture warmed to room temperature and stirred for 16 h. The 25 reaction mixture was poured into a 250 mL separatory funnel containing saturated aqueous NaHCO 3 (100 mL) and extracted with CH 2 C1 2 (2 x 50 mL). The combined organic layers were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced WO 2012/058173 PCT/US2011/057557 82 pressure. Purification by reverse-phase C18 column chromatography, eluting with 20% MeCN in water (+0.1% TFA) to 90% MeCN in water (+0.1% TFA) afforded the title compound (130 mg, 8% yield). MS (+ESI) m/z = 524. 5 EXAMPLE 12 (S)-2,3-Dicyclopropyl-8-(4-fluorobenzyl)-6-hydroxy-2,3,9,10-tetrahydroimidazo{5,1 a] [2,6]naphthyridine-1,5,7(8H)-trione O O N N F N ~ K! Pd(OH) 2 on carbon F N N N CN O H 2 O 0 OH O OH Example 3 10 The first eluting enantiomer from Example 3 (12 g, 26 mmol) was placed in dry MeOH (150 mL) and 3.5 g of 10 wt% palladium on carbon was added under nitrogen. The mixture was stirred under a balloon of H2 for 24 h at room temperature. The mixture was filtered through a syringe filter, and the filtrate was concentrated under reduced 15 pressure. Purification by column chromotography through silica gel, eluting with dichloromethane, afforded the title compound (6.5 g, 60% yield) as light yellow solid. MS (+ESI) m/z = 424. 'H NMR (400 MHz, CDCl 3 ) 6 13.71 (s, 1H), 7.34-7.30 (m, 2H), 7.09 7.05 (in, 2H), 4.96 (d, J= 8.0 Hz, 1H), 4.78-4.69 (m, 2H), 3.27-3.20 (in, 4H), 2.75-2.73 (in, 1H), 1.22-1.21 (in, 2H), 1.05-1.03 (in, 2H), 0.79-0.60 (in, 5H). 20 EXAMPLE 13 Sodium (S)-2,3-dicyclopropyl-8-(4-fluorobenzyl)-1,5,7-trioxo-1,2,3,5,7,8,9,10 octahydroimidazo[5,1-a] [2,6] naphthyridin-6-olate N 0 N N, F / N"K NaOH (1.0 equiv) F / N N N O MeCN, 23 *C, 1 h O 0 OH 0 O=Na Example 12 25 WO 2012/058173 PCT/US2011/057557 83 Into a 250 mL round-bottom flask equipped with a magnetic stirbar was added Example 12 (2.00 g, 4.72 mmol) and acetonitrile (15 mL). The solution was treated with a 1.0 M aqueous NaOH solution (4.96 mL, 4.96 mmol) and stirred at room temperature for 30 minutes. The reaction was transfered to a lyophilizer jar using water (5 mL), frozen 5 with dry-ice/acetone to the sides and placed on the lyophilizer for 16 h. The title compound was isolated as a slight greenish-white solid (1.94 g, 92% yield). MS (+ESI) m/z = 424. EXAMPLE 14 8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-2-methoxy-9',10'-dihydro-l'H-spiro[cyclopentane 10 1,3'-imidazo[5,1-a][2,6]naphthyridine]-',5',7'(2'H,8'H)-trione 0 OMe 0 NH 2 OMe NH F .XHF N x N N H 2

SO

4 C1 N N O 0 OH 0 OH fourth eluting enantiomer intermediate D To a mixture of Intermediate D (344 mg, 3.65 mmol) in anhydrous DMA (15 mL) was added 2-methoxycyclopentanone (4.1 g, 35.9 mnmol) and concentrated sulfuric acid (0.194 mL, 3.65 mmol). The reaction vial was sealed and stirred at 105 C for 18 h. After 15 cooling, the reaction was poured into a separatory funnel, diluted with ethyl acetate (50 mL) and washed with water (3 x 15 mL). The organic layer was dried over Na 2

SO

4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse phase chromatography through a SunFire C 18 10 gM 50 x 250 mm column. The compound was loaded with DMSO and methanol, and eluted with 25% MeCN in H20 (+ 0.1% TFA) to 20 70% MeCN in H20 (+ 0.1% TFA) over 35 minutes to afford the racemic title compound (530 mg, 32% yield). The racemic mixture was separated by chiral SFC to afford the enantiopure title compound, Example 14 (fourth eluting enantiomer). Preparative chiral separation of the enantiomers was achieved using a ChiralPak OD-H, 250 x 30 mm I.D. 5 gm column, eluting with CO 2 plus methanol:acetonitrile (70:20:10 + 0.1% Et 2 NH) at a flow 25 rate of 80 mL/min. The purified material was partitioned between daqueous IM HCl and ethyl acetate and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over Na 2 S04, filtered, and concentrated under reduced pressure to afford the title compound. MS (+ESI) m/z= 462. 'H NMR (400 MHz, d 6 -DMSO) 6 13.49 (s, 1H), 9.77 (s, 1H), 7.61 (d, J= 7.2 Hz, 1H), 7.42-7.37 (m, 2H), 4.75-4.65 (m, 2H), 3.76 (dd, J= 11.1, 30 7.0 Hz, 111), 3.55 (t, J= 6.6 Hz, 2H), 3.28-3.22 (m, 21), 3.14 (s, 311), 2.96-2.88 (m, 111), WO 2012/058173 PCT/US2011/057557 84 2.37-2.28 (m, 111), 2.15-2.06 (m, 1H), 1.98-1.90 (in, 1H), 1.88-1.80 (m, 1H), 1.68-1.57 (m, 1H-). EXAMPLES 15 AND 16 5 (1S,5R)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-9',10'-dihydro-1'H spiro[bicyclo[3.1 .0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione 0 0

NH

2 F N a CIN o H 2 SO4 0 OH Intermediate D 0 NH 0 NH F .- NA F II N NN N 0 OH 0 H Example 15 Example 16 first eluting diastereomer second eluting diastereomer To a mixture of intermediate D (500 mg, 1.37 mmol) in anhydrous DMA (4 mL) was added (1S, 5R)-bicyclo[3.1.O]hexan-2-one (526 mg, 5.47 mmol) and sulfuric acid 10 (73 gL, 1.37 mmol). The reaction vial was sealed and stirred at 105 *C for 18 h. After cooling to room temperature, the reaction was poured into a separatory funnel, diluted with ethyl acetate (50 mL) and washed with water (2 x 15 mL) and brine (20 mL). The organic layer was dried over Na 2 S04, filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse phase chromatography through a SunFire C18 10 s.M 50 15 x 250 mm column. The compound was loaded with DMSO, methanol, and water and eluted with 25% MeCN in H 2 0 (+ 0.1% TFA) to 65% MeCN in H 2 0 (+ 0.1% TFA) over 35 minutes to afford the separated diastereomers of the title compound. Example 15 is the first eluting diastereomer (102 mg, 17% yield). MS (+ESI) m/z = 444. 'H NMR (400 MHz, d 6 -DMSO) 6 13.48 (s, 1H), 9.55 (s, 1H), 7.59 (dd, J= 7.2, 2.0 Hz, 1H), 20 7.44-7.35 (m, 211), 4.75-4.67 (m, 2H), 3.55 (t, J = 6.4 Hz, 2H), 3.26 (t, J= 6.4 Hz, 2 H), 2.68-2.56 (in, 1H), 2.18-2.11 (in, 111), 1.88-1.71 (in, 2H), 1.69-1.63 (m, 1H), 1.53-1.47 (m, 1 H), 0.65-0.57 (i, 1H), 0.51 (q, J = 4.5 Hz, 1H). Example 16 is the second eluting diastereomer (135 mg, 22% yield). MS (+ESI) m/z = 444. 'H NMR (400 MHz, d 6 -DMSO) 8 13.46 (s, 1H), 9.95 (s, 1H), 7.59 (dd, J= 7.2, 2.0 Hz, WO 2012/058173 PCT/US2011/057557 85 1H), 7.43-7.35 (m, 2H), 4.75-4.67 (m, 2H), 3.55 (t, J= 6.5 Hz, 2H), 3.35-3.21 (m, 2H), 2.80 (td, J= 12.4, 8.0 Hz, 1H), 2.14-2.02 (m, 1H), 1.80 (dd, J= 12.4, 7.9 Hz, 1H), 1.51-1.43 (m, 2H), 1.34 (dd, J= 13.0, 7.9 Hz, iH), 1.25-1.19 (m, 1H), 0.78-0.70 (m, iH). 5 EXAMPLES 17 AND 18 (iR, 5S)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-9', 1 0'-dihydro-1'H spirojbicyclo[3.1 .0]hexane-2,3'-imidazo[5,1-a] [2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione 0 O

NH

2 F / NH C / N 0 O H 2 S0 4 0 OH Intermediate D 0 0 N H NH A N N N N NI 0 CID 1- 0 0 OH 0 OH Example 17 Example 18 first eluting diastereomer second eluting diastereomer The separated diastereomers of the title compound were prepared as 10 described for (1S, 5R)-8'-(3 -chloro-4-fluorobenzyl)-6'-hydroxy-9', 1 0'-dihydro- 1'H spiro [bicyclo [3.1 .0]hexane-2,3'-imidazo[5,1 -a] [2,6]naphthyridine]- 1',5',7'(2'H,8

'

H)-trione (Examples 15 & 16) replacing (1S,5R)-bicyclo[3.1.0]hexan-2-one with (1R,5S) bicyclo[3.1.0]hexan-2-one. Example 17 is the first eluting diastereomer and the 'H NMR is identical to Example 15. Example 18 is the second eluting diastereomer and the 'H NMR is 15 identical to Example 16. EXAMPLE 19 8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-2'-[(I-hydroxycyclopropyl)methyl]-9',1 0'-dihydro 2'H-spiro[cyclopentane-1,3'-imidazo[5,1-a] [2,6]naphthyridine]-1',5',7'(8'H)-trione WO 2012/058173 PCT/US2011/057557 86 H 0 OPiv NH0 N " OH 0 HO N F; -- N F N NH

SNH

2

S

4 C1 OPiv 0 0 OPiv 0 OH Intermediate A OH 0

N

N x N ' 0 OH Step 1: 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N-[(1-hydroxycyclopropyl)methyl] 3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine- 1 -carboxamide 5 A 250 mL flask was charged with dry THF (54 mL) and Intermediate A (5.0 g, 8.1 mmol). 1-(Aminomethyl)cyclopropanol (0.9 g, 10.5 mmol) was then added and the resulting mixture was stirred at room temperature for 10 minutes. Methylamine (33% in EtOH; 5.4 mL, 40.4 nmol) was added and the mixture was stirred at room temperature for 10 20 minutes. The reaction mixture was diluted with EtOAc (500 mL), washed with a saturated solution of NaHCO 3 in water (200 mL) and then aqueous 1 N HCi (2 x 200 mL). The organic layer containing a suspension was separated and filtered, and the solid was dried under vacuum to afford the title compound (2.9 g, 83% yield) as a white solid. MS (+ESI) m/z = 436. 15 Step 2: 8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-2'-[(1-hydroxycyclopropyl)methyl] 9',10'-dihydro-2'I-spiro[cyclopentane-1,3'-imidazo[5,1 a][2,6}naphthyridine]-l',5',7'(8'H)-trione 20 A mixture of the amide from Step 1 (420 mg, 1.0 mmol) in 1,4-dioxane (2.4 mL) was added cyclopentanone (810 mg, 10.0 mmol) and concentrated sulfiric acid (0.1 mL) under nitrogen at room temperature, then the mixture was heated to 100 "C for 18 h. After cooling, the reaction mixture was diluted with EtOAc (100 mL) and washed with a saturated aqueous solution of NaHCO 3 (20 mL) and water (20 mL), and the organic layer 25 was separated. The organic layer was dried over MgSO 4 , filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire C18 5 jim 30 x 150 mm column, eluting with 35-75% MeCN in H20 with (+0.1% TFA) as a WO 2012/058173 PCT/US2011/057557 87 gradient over 20 minutes to afford the title compound. HRMS (+ESI) m/z = 502.1551 found, 502.1540 required. 'H NMR (500 MHz, acetone) 6 13.65 (s, 1H), 7.62 (d, J= 7.0 Hz, IH), 7.47 (d, J= 7.4 Hz, 1H), 7.33 (t, J= 8.9 Hz, 1H), 4.83 (s, 2H), 4.42 (s, 2H), 3.68 (t, J= 6.4 Hz, 2H), 3.35 (t, J= 6.4 Hz, 2H), 2.71-2.61 (m, 4H), 2.22 (m, 2H), 2.02 (m, 2H), 1.83 5 (m, 2H), 1.07 (t, J= 7.2 Hz, 211). EXAMPLE 20 (+)or (-)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(2-{methyl[(1-methyl 1 H-pyrazol-4-yl)methyl] amino} ethyl)-2,3,9, 1 0-tetrahydroimidazo [5,1 -a] [2,6]naphthyridine 10 1,5,7(8H)-trione 0 OPiv OH F H2N -- OH 0 NH O CI N OPiv F N

H

2 SO4 O OPiv C1 OH 0 OH Intermediate A 0 OH OH O-S-Me 00 N Cl-S-Me O N 0 F >NF N N O N N O OH 0 OH 15 N N' Me MeN MeN M e ' N - M e O H 1 N' F // N separate N enantiomers 0 OH WO 2012/058173 PCT/US2011/057557 88 N'NMe MeN N 0 N F /N CF N 0 OH chiral - second eluting enantiomer Step 1: 6-(3-Chloro-4-fluorobenzyl)-3,4-dihydroxy-N-(2-hydroxyethyl)-5-oxo 5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide 5 Into a 300-mL flask was added Intermediate A (8.00 g, 12.92 mmol) and THF (100 mL). The solution was treated with ethanolamine (4.74 g, 78 mmol) then stirred at room temperature for 2 h. There was a thick, white precipitate present after 1 h. The solid was filtered and washed with THF and dried under vacuum. The solid was then 10 suspended in methanol (60 mL)/water (80 mL) and acidified with concentrated HC1 to pH = 1. This suspension was stirred for 1 h and then the solid was filtered through Whatman #1 filter paper on a Buchner funnel under vacuum. The solid was washed with water (2 x 80 mL), methanol (20 mL) and ethyl ether (2 x 30 mL) then dried under vacuum to afford the title compound (4.89 g, 92% yield). MS (+ESI) mn/z = 410. 15 Step 2: (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(2 hydroxyethyl)-2,3,9,10-tetrahydroimidazo[5,1-a][2,6]naphthyridine 1,5,7(8H)-trione 20 The solid amido alcohol from Step 1 (2.86 g, 6.98 mmol) was suspended in 1,4-dioxane (30 mL) in a 100 mL round-bottom flask equipped with a reflux condenser. To this suspension was added cyclopropanecarboxaldehyde (1.96 g, 27.9 mmol) and concentrated sulfuric acid (0.05 ml, 0.7 mmol). A stir bar was added and the suspension was stirred at 100 oC under reflux for 3 h. The light green colored suspension was cooled to 25 room temperature and the solid was filtered, washed with 1,4-dioxane followed by methanol. The resulting solid was dried under vacuum, affording the title compound. (2.58 g, 80% yield). MS (+ESI) m/z = 462.

WO 2012/058173 PCT/US2011/057557 89 Step 3: (±)-2-[8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-1,5,7-trioxo 1,5,7,8,9,1 0-hexahydroimidazo[5,1-a] [2,6]naphthyridin-2(3H)-yl]ethyl methanesulfonate 5 The alcohol from Step 2 (500 mg, 1.08 mmol) was suspended in CH 2 Cl 2 (10 mL) and triethylamine (0.15 ml, 1.08 mmol) was added. Methanesulfonyl chloride (0.08 mL, 1.08 mmol) was added drop-wise via syringe over 15 minutes and the resulting suspension was stirred at room temperature for 4 h. This reaction was used directly (unpurified) in the next Step. MS (+ESI) m/z = 540. 10 Step 4: (+) or (-)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(2 {methyl[(i-methyl-1 H-pyrazol-4-yl)methyl]amino} ethyl)-2,3,9,10 tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione 15 To the unpurified material from Step 3 (585 mg, 1.08 mmol) was further added triethylamine (0.76 ml, 5.42 mmol). N-Methyl-l-(1-methyl-1H-pyrazol-4 yl)methanamine (542 mg, 4.33 mmol) was added and the mixture stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by preparative reverse phase chromatography through a SunFire C18 10 gM 30 x 150 mm column. The 20 compound was loaded with DMSO/methanol, and eluted with 40% MeCN in H20 (+0.1% TFA) to 90% MeCN in H20 (+0.1% TFA) over 30 minutes at a flow rate of 35 mL/min. The title compound was recovered after concentration as a racemic, TFA salt (190 mg, 26% yield). MS (+ESI) nz = 569.2094. The racemic mixture (190 mg) was separated by chiral SFC to afford the enantiopure Example 20 (36 mg, second eluting enantiomer). Preparative 25 chiral separation of the enantiomers was achieved using a ChiralPak AD-H column (250 x 30 mm. LD), eluting with CO 2 plus methanol:acetonitrile (49:35:16 + 0.1% Et 2 NH) at a flow rate of 50 mL/min. MS (+ESI) n/z = 569. 'H NMR (400 MHz, CD 3 0D) 6 7.84 (m, 11), 7.75 (in, 1H), 7.50 (dd, J= 7.0, 6.5 Hz, 1H), 7.36 (m, 1H), 7.27 (t, J= 6.5 Hz, 1H), 7.40 (d, J= 8.0 Hz, 1H), 4.85-4.82 (m, IH), 4.50 (in, 4H), 3.91 (m, 5H), 3.54 (m, 4H), 2.94 (s, 3H), 30 1.15 (in, 1H), 0.83 (in, 4H). EXAMPLE 21 (±)-N-{2-[8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-1,5,7-trioxo-1,5,7,8,9,10 hexahydroimidazo[5,1-a][2,6]naphthyridin-2(3H)-yljethyl}-N-methylethanesulfonamide WO 2012/058173 PCT/US2011/057557 90 Me'NBoc O OPiv Me F N ,XN H 2 N N 0 NH ciC N OPiv F NH TFA O OPiv CN N Intermediate A 0 OH O Me'NH N'CBz 0,~ F HO , F O F 0 NH 0 NH CBzCI, TEA F F) -- - - -- - -- O FNH / NH H 2

SO

4 CIN N O oCi N N O O OH 0 OH Me, Me N-CBz NH 0 HC1 0 O N/ HC1,0 N CI-S F N Pd(OH) 2 F N \-Me N C N N N O O OH 0 OH Me o N- S O N-Me N N N 5 0 OH Step 1: tert-Butyl [2-({[6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo 2,3,5,6,7,8-hexahydro-2,6-naphthyridin- 1 yl]carbonyl}amino)ethyl]methylearbamate 10 A solution of Intermediate A (2.50 g, 4.04 mmol) in tetrahydrofuran (27 mL) was treated with tert-butyl (2-aminoethyl)methylcarbamate (0.844 g, 4.85 mmol) and stirred at room temperature for 20 minutes. Methylamine (33 % wt. solution in methanol, 3.26 mL, 24.2 nmol) was added and the mixture stirred at room temperature for 16 h. The mixture 15 was acidified to pH -8 with 1 N aqueous HCl and partitioned between water (40 mL) and EtOAc (400 mL). The organic phase was dried over Na 2

SO

4 , filtered and concentrated to WO 2012/058173 PCT/US2011/057557 91 afford the title compound, which was used in subsequent steps without purification. MS (+ESI) m/z = 523. Step 2: 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N-[2-(methylamino)ethyl]-3,5-dioxo 5 2,3,5,6,7,8-hexahydro-2,6-naphthyridine- 1 -carboxamide trifluoroacetate A solution of secondary anide from Step 1 (2.23 g, 4.26 mmol) in dichloromethane (28 mL) was treated with trifluoroacetic acid (3.29 mL, 42.6 mmol) and 10 stirred at room temperature for 2 h. The mixture was concentrated to afford the title compound, which was used in subsequent steps without purification. MS (+ESI) m/z= 423. Step 3: Benzyl [2-({[6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8 hexahydro-2,6-naphthyridin-1-yljcarbonyl}amino)ethyllmethylearbamate 15 A solution of the secondary amine from Step 2 (1.95 g, 3.63 mmol) in dichloromethane (18.2 mL) was treated with benzyl chloroformate (0.52 mL, 3.63 mmol) and triethylamine (2.53 mL, 18.2 mmol). After stirring at room temperature for 16 h, the mixture was poured into a 250 mL separatory funnel and partitioned between water (100 20 mL) and EtOAc (300 mL). The organic phase was hazy and was concentrated without drying over MgSO 4 or filtration. The residue was suspended in 50 mL of 10:1

CH

2 C1 2 /MeOH and filtered through a fine fitted sintered glass funnel. The filtrate was concentrated to afford the title compound (1.53 g, 76% yield). MS (+ESI) m/z = 557. 25 Step 4: (±)-Benzyl {2-[8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-1,5,7 trioxo-1,5,7,8,9,10-hexahydroimidazo[5,1-a][2,6]naphthyridin-2(3H) yl] ethyl }methylcarbamate A solution of CBz-protected amine from Step 3 (2.00 g, 3.59 mmol) and 30 cyclopropanecarboxaldehyde (2.52 g, 35.9 mmol) in 1,4-dioxane (12 mtL) was treated with concentrated sulfuric acid (0.29 mL, 5.4 mmol) and heated to 70 *C for 40 minutes. The residue was purified by preparative reverse phase chromatography through a SunFire C18 5 4m 50 x 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 30% MeCN in H2O (+0.1% TFA) to 90% MeCN in H2O (+0.1% TFA) as a gradient 35 over 30 minutes at a flow rate of 35 mL/min. The purified material was poured into a 250 mL separatory funnel and partitioned between water (50 mL) and EtOAc (200 mL). The WO 2012/058173 PCT/US2011/057557 92 organic phase was dried over Na 2 S04, filtered and concentrated to afford the title compound (400 mg, 18 % yield). MS (+ESI) m/z = 609. Step 5: (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[2 5 (methylamino)ethyl]-2,3,9,10-tetrahydroimidazo[5,1-a][2,6]naphthyridine 1,5,7(8H)-trione hydrochloride A solution of compound from Step 4 (400 mg, 0.66 mmol) in EtOAc (6.5 mL) was treated with 20 mol% Pd(OH)2 on carbon (92 mg, 0.13 mmol). The flask was 10 evacuated and backfilled with H2 (gas) three times and stirred under a H 2 atmosphere (x I atm) at room temperature overnight. During the reaction, MeOH and a few drops of concentrated HCI solution were added to the reaction mixture to enable solubility. The mixture was filtered through a pad of Celite and the filter cake was washed with MeOH. The filtrate was concentrated to afford the title compound (309 mg, 99% yield). MS (+ESI) 15 m/z = 475. Step 6: (±)-N-{2-[8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-1,5,7 trioxo-1,5,7,8,9,10-hexahydroimidazo[5,1-a] [2,6]naphthyridin-2(3H) yl] ethyl }-N-methylethanesulfonamide 20 A suspension of compound from Step 5 (21 mg, 0.044 mmol) in dichloromethane (442 pL) was treated with triethylamine (18 VL, 0.133 mmol) and ethane sulfonyl chloride (8.5 mg, 0.066 mmol). The mixture was stirred at room temperature for 10 minutes. The residue was purified by preparative reverse phase chromatography through a 25 SunFire C18 5 pum 50 x 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 50% MeCN in H 2 0 (+0.1% TFA) to 90% MeCN in H 2 0 (+0.1% TFA) as a gradient over 30 minutes at a flow rate of 35 mL/min. Pure fractions were concentrated to afford the title compound (7.7 mg, 31% yield). MS (+ESI) m/z = 567. IH NMR (500 MHz, d-acetone) 13.71 (s, JH), 7.63 (dd, J= 7.1, 2.3 Hz, 1H), 7.50-7.46 (m, 30 1H), 7.33 (t, J= 8.9 Hz, 1H), 5.27 (d, J = 8.7 Hz, 11H), 4.83 (d, J = 2.8 Hz, 2H), 4.18-4.11 (m, 1H), 3.70-3.61 (m, 4H), 3.48-3.41 (m, 2H), 3.30 (dt, J= 16.3, 7.1 Hz, 1H), 3.05 (d, J= 7.4 Hz, 2H), 2.97 (s, 3 H), 1.25 (t, J= 7.4 Hz, 3H), 1.20-1.15 (m, 1H), 0.96-0.89 (m, 1H), 0.80-0.70 (m, 3H). 35 EXAMPLES 22 AND 23 (2R) or (2S)-(JS, 5R)-8'-(3,4-difluorobenzyl)-6'-hydroxy-9', I 0'-dihydro- 1'H spiro [bicyclo [3.1.0]hexane-2,3'-imidazo[5 ,1-a] [2,6]naphthyridine]- 1',5',7'(2'H,8'H)-trione WO 2012/058173 PCT/US2011/057557 93 0 OH 0 OH F)( B O OH NaH, KOt-Bu O F -- N DMSO, 0 2 (gas) N F Co 'N N OMe HN OMe KOt-Bu, t-BuOH 0 OMe 0 OMe Intermediate B 0 OH 0 NH 2 F NNH 4 0H F N OMe HATUDMF N OMe 0 OMe 0 OMe 0 NH 2 0 HBr in AcOH F r NH 50 OCN F N O 0 DMA, H 2 SO4 105 *C 0 OH 0 0 NHAj NH F ' N /N OF' N N 0 OH 0 OH Example 22 Example 23 first eluting diastereomer second eluting diastereomer 5 Step 1: 3,4-Dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-l-carboxylic acid Into an oven dried flask under an atmosphere of nitrogen was added sodium hydride (95 wt%, 102 mg, 4.05 mmol) and anhydrous DMSO (20 mL). The suspension was stirred at room temperature for 10 minutes. To this was added Intermediate B (1.0 g, 2.53 10 mmol) and the reaction was stirred at room temperature for 30 minutes. Oxygen was then bubbled into the reaction via a gas dispersion tube, followed by addition of potassium tert butoxide (568 mg, 5.07 mmol). As the reaction stirred at room temperature, oxygen was continually bubbled into the suspension in the flask. After 15 minutes, additional potassium tert-butoxide (568 mg, 5.07 mmol) was added to drive the reaction to completion. The 15 reaction was quenched with 2 M aqueous HCl solution (7.5 mL), diluted with brine, poured into a separatory funnel and extracted with CH2CL 2 (3 x 30 mL). The combined organic layers were dried over Na 2

SO

4 , filtered, and concentrated under reduced pressure. The WO 2012/058173 PCT/US2011/057557 94 residue was purified by preparative reverse phase chromatography through a SunFire C18 10 tM 50 x 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 5% MeCN in H 2 0 (+ 0.1% TFA) to 50% MeCN in H20 (+ 0.1% TFA) over 30 minutes to afford the title compound (450 mg, 70% yield), MS (+ESI) m/z = 253. 5 Step 2: 6-(3,4-Difluorobenzyl)-3,4-dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6 naphthyridine-1 -carboxylic acid Into a 10 mL vial equipped with a magnetic stirbar was added the secondary 10 aide from Step 1 (50 mg, 0.198 mmol) and tert-butanol (2 mL). The solution was treated with 2.4 equiv of potassium tert-butoxide (53 mg, 0.476 mmol). The resulting yellow suspension was stirred at room temperature for 10 minutes and then treated with 3,4 difluorobenzyl chloride (65 mg, 0.396 mmol). The mixture was stirred for 10 minutes at room temperature and then heated to 60 'C for 1 h. The cooled reaction mixture was diluted 15 with aqueous 1 M HCl solution until the pH of the solution was 2. The aqueous mixture was poured into a phase separator cartridge and extracted with dichloromethane (3 x 5 mL). The combined organics were concentrated under reduced pressure. The compound was purified by column chromatography through silica gel (12 g), eluting with 25% EtOAc in hexanes to 100% EtOAc in hexanes as a gradient. The title product was isolated as a light 20 yellow foam (51 mg, 68% yield). MS (+ESI) m/z = 379. Step 3: 6-(3,4-Difluorobenzyl)-3,4-dimethoxy-5-oxo-5,6,7,8-tetrahydro-2,6 naphthyridine- 1 -carboxamide 25 Into a 100 mL round-bottom flask equipped with a magnetic stirbar was added the carboxylic acid from Step 2 (401 mg, 1.06 mmol), HATU (564 mg, 1.48 mmol), and DMF (5 mL). The solution was treated with EtN(iPr) 2 (0.37 mL, 2.12 mmol) and concentrated aqueous ammonium hydroxide solution (0.13 mL, 3.18 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was poured into a 125 mL 30 separatory funnel containing 1 M aqueous HCl (75 mL) and the mixture extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over MgS04, filtered and the solvent was evaporated under reduced pressure. The compound was purified by column chromatography through silica gel (40 g), eluting with 75% EtOAc in hexanes to 100% EtOAc in hexanes as a gradient. The title compound was isolated as a 35 light yellow solid (406 mg, >99% yield). MS (+ESI) m/z = 378.

WO 2012/058173 PCT/US2011/057557 95 Step 4: 6-(3,4-Difluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6 naphthyridine- 1 -carboxamide Into a 100 mL round-bottom flask equipped with a magnetic stirbar was 5 added the carboxamide from Step 3 (400 mg, 1.060 mmol). The solid was treated with a solution of 25% HBr in acetic acid (4 mL, 73.7 mmol). The red-orange solution was heated to 50 'C for 2 h. The reaction mixture was concentrated under reduced pressure, using toluene as a co-solvent to remove all the AcOH and HBr. The resulting red solid was purified by preparative reverse phase chromatography through a SunFire C18 10 kM 50 x 10 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 20% MeCN in H20 (+0.1% TFA) to 90% MeCN in H20 (+0.1% TFA) over 30 minutes at a flow rate of 85 mL/min. The desired product was collected and concentrated under reduced pressure to afford a white solid (192 mg, 52% yield). MS (+ESI) m/z = 350. 15 Step 5: (2R) or (2S)-(S,5R)-8'-(3,4-difluorobenzyl)-6-hydroxy-9',10'-dihydro-1'H spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine] I',5,7'(2H,8'H)-trione Into a 25 mL salable pressure vial equipped with a magnetic stir-bar was 20 added the carboxamide from Step 4 (190 mg, 0.544 mmol), (1S, 5R)-bicyclo[3.1.0]hexan-2 one (209 ing, 2.17 mmol), DMA (4 mL) and concentrated sulfuric acid (0.14 mL). The vial was sealed and heated in an oil bath at 105 *C for 16 h. The reaction mixture was concentrated and purified by preparative reverse phase chromatography through a SunFire C18 10 gM 50 x 250 mm column. The compound was loaded with DMSO/methanol, and 25 eluted with 25% MeCN in H20 (+0.1% TFA) to 70% MeCN in H20 (+0.1% TFA) over 30 minutes at a flow rate of 85 mL/min. The desired products were collected and concentrated under reduced pressure. The first eluting diastereomer (Example 22) was isolated as an off-white solid (43 mg, 18% yield). MS (+ESI) n/z = 428. 'H NMR (400 MHz, CDC1 3 ) 6 7.86 (bs, 1H), 7.17-7.15 (m, 30 211), 7.07-7.05 (bs, 1H), 4.74-4.70 (in, 2H), 3.50-3.37 (in, 4H), 2.89 (m, 1H), 2.36-2.32 (m, 11), 1.92-1.90 (in, 3H), 1.58-1.57 (in, 1H), 0.78-0.77 (in, 1H), 0.38-0.36 (i, 1H). The second eluting diastereomer (Example 23) was isolated as a light yellow solid (56 mg, 24% yield). MS (+ESI) n/z = 428. '1H NMR (400 MHz, CDC 3 ) 6 8.21 (bs, 1H), 7.15-7.07 (m, 3H), 4.73 (d, J= 15 Hz, 1H), 4.67 (d, J=15 Hz, 1H), 3.49-3.39 (m, 4H), 3.05 (q, J= 6.0 35 Hz, 11), 2.03-2.01 (in, 21), 1.72-1.70 (in, 1H), 1.60-1.58 (m, 1H), 1.47-1.44 (m, 1H), 1.25 1.20 (in, 1H), 0.90-0.87 (m, 1H).

WO 2012/058173 PCT/US2011/057557 96 EXAMPLES 24 AND 25 (IS,5R)-8'-(2,4-difluorobenzyl)-6'-hydroxy-9',10'-dihydro-2'H-spiro[bicyclo[3.1.0]hexane 2,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(8'H)-trione F CI FF.PhSO 2 Me Fr HNNN NaH, DMF NHMDS S 11 0 F 0 F 0 0 5 BuO 0 N 0 OEt Na 2 00 3 F v0 Qt FN Toluene N 150 0 O days N N F O H 2 0 F 0 OH O OEt 0 OEt

TMSCHN

2 F N TFAA, CH 2 Cl 2 F N N

CH

2 Cl 2 /MeOH N urea H 2 0 2 N F 0 OMe F 0 OMe 0 OEt 0 OH Ac 2 O F N LiOH F N Toluene 115 *C N N0 Me EtOH/H 2 0 N OH F 0 OMe F 0 OMe 10 WO 2012/058173 PCT/US2011/057557 97 0 0 NH 2 O NH HATU, NH 4 0H F / ''N F /N I EtN(iPr)2 N OH DMA, H 2 SO NO F 0 OMe F 0 OMe NH NH NCI F N F N' DMF 0 F 0 OH F 0 OH Example 24 Example 25 first eluting diastereomer second eluting diastereomer Step 1: 1 -2,4-Difluorobenzyl)piperidin-2-one 5 To a solution of valerolactam (15.0 g, 150 mmol) in DMF (750 nL) at 0 *C was added sodium hydride (60 wt%, 6.6 g, 165 mmol). The solution was stirred at 0 'C for 30 minutes and then 2,4-difluorobenzyl chloride (25 g, 152 mmol) in DMF (50 mL) was added drop-wise. The ice bath was removed and the solution stirred for 16 h at room temperature. The reaction was quenched with water (5000 mL), poured into a separatory 10 funnel and extracted with EtOAc (3 x 500 mL). The combined organics were washed with water and the combined organic layers were dried over Na 2

SO

4 , filtered and concentrated under reduced pressure, affording 31 g of the unpurified desired product. MS (+ESI) m/z= 226. 15 Step 2: 1-(2,4-Difluorobenzyl)-3-(phenylsulfinyl)piperidin-2-one 1-(2,4-Difluorobenzyl)piperidin-2-one (31 g, 140 mmol) in THF (300 mL) was cooled to -10 'C and a solution of lithium bis(trimethylsilyl)amide (300 ml, 300 mmol, 1.0 M in THF) was added drop-wise. After the addition was complete the solution was 20 stirred for 40 minutes at -10 *C. Methyl benzenesulfinate (22 ml, 170 mmol) was added drop-wise at -10 'C. After 1 h, the reaction was quenched with an aqueous solution of saturated NH 4 Cl (200 mL) and brine (200 mL). The aqueous layer was poured into a separatory funnel and extracted with EtOAc (2 x 100 mL). The combined organics were washed with brine, dried over Na 2

SO

4 , filtered and concentrated under reduced pressure.

WO 2012/058173 PCT/US2011/057557 98 The crude product (obtained in quantitative yield) was not purified at this stage. MS (+ESI) mz = 350. Step 3: 1-(2,4-Difluorobenzyl)-5,6-dihydropyridin-2(1H)-one 5 A solution of 1-(2,4-Difluorobenzyl)-3-(phenylsulfinyl)piperidin-2-one (64 g, 183 mmol) in toluene (425 mL) was treated with sodium carbonate (85 g, 806 mmol) and stirred at 95 *C for 12 h. After cooling to room temperature the solution was poured into a separatory funnel, quenched with water (250 mL) and extracted with EtOAc (3 x 300 mL). 10 The combined organics were dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. The dihydropyridinone was purified by column chromatography through silica gel (330 g), eluting with 50% EtOAc in hexanes to afford the title compound (20.4 g, 50% yield). MS (+ESI) m/z = 224. 15 Step 4: Ethyl 6-(2,4-difluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6 naphthyridine- 1 -carboxylate A solution of 1-(2,4-difluorobenzyl)-5,6-dihydropyridin-2(1H)-one (20.4 g, 91 mmol) and ethyl 5-butoxy-1,3-oxazole-2-carboxylate (27.3 g, 128 mmol, procedure 20 described in patent WO 2005/087768 Al) in water (2.5 mL, 137 mmol) was stirred at 150 *C for 6 days. After cooling to room temperature, methanol (20 mL) was added. The yellow solid was filtered and the resulting solid was triturated in hot CH 2 C1 2 (100 mL). Filtration afforded 17 g of the desired product. The combined filtrates were concentrated under reduced pressure. Purification of the filtrate by column chromatography through 25 silica gel (220 g), eluting with 5% MeOH in CH 2 C1 2 provided an additional 10 g of desired compound (combined yield: 27 g, 82% yield). MS (+ESI) m/z = 363. Step 5: Ethyl 6-(2,4-difluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6 naphthyridine- 1 -carboxylate 30 To a solution of ethyl 6-(2,4-difluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8 tetrahydro-2,6-naphthyridine-I-carboxylate (17 g, 47 mmol) in MeOH (100 mL) and CH 2 C1 2 (200 mL) at 0 *C was added trimethylsilyl-diazomethane (35 mL, 70 mmol. 2.0 M solution in diethyl ether). The ice bath was removed and the solution stirred at room temperature for 35 14 h. Concentration under reduced pressure afforded an oil, which was purified by column chromatography on silica gel (220 g), eluting with 5% MeOH in CH 2 Cl 2 to afford the desired methyl phenol ether (16.8 g, 95% yield). MS (+ESI) m/z = 377.

WO 2012/058173 PCT/US2011/057557 99 Step 6: Ethyl 6-(2,4-difluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6 naphthyridine-1-carboxylate 2-oxide 5 To a solution of ethyl ester from Step 5 (10.5 g, 27.9 mmol) in CH 2 Cl 2 (175 mL) at 0 *C was added urea hydrogen peroxide (5.25 g, 55.8 mmol) followed by drop-wise addition of trifluoroacetic anhydride (8.28 mL, 58.6 mmol). The ice bath was removed and the solution stirred for 14 h at room temperature. Saturated aqueous K 2

HPO

4 solution was added to the mixture until the pH was 7. The solution was cooled to 0 *C and solid sodium 10 bisulfite (5 g) was added. After stirring at room temperature for 1 h, water (250 mL) was added. The mixture was poured into a separatory funnel, and the aqueous layer was extracted with CH 2 C1 2 (250 mL). The organic layer was washed with brine, dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. The crude N-oxide 10.9 g was used directly in the next step without purification. MS (+ESI) m/z = 393. 15 Step 7: Ethyl 3-(acetyloxy)-6-(2,4-difluorobenzyl)-4-methoxy-5-oxo-5,6,7,8 tetrahydro-2,6-naphthyridine- 1 -carboxylate To a solution of N-oxide from Step 6 (10.9 g, 27.8 mmol) in toluene (125 20 mL) was added acetic anhydride (18.0 mL, 200 nmol). The resulting mixture was refluxed for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Additional toluene (25 mL) was added and the solution was concentrated twice more to remove any residual acetic anhydride. The resulting acylated product (12.4 g) was used directly in the next step without further purification. MS (+ESI) m/z = 435. 25 Step 8: 6-(2,4-Difluorobenzyl)-3-hydroxy-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6 naphthyridine- 1 -carboxylic acid To a solution of ethyl ester from Step 7 (12.3 g, 28.3 mmol) in ethanol (125 30 mL) was added a solution of lithium hydroxide (4.47 g, 187 mmol) in water (25 ml). The resulting solution was stirred at room temperature for 12 h. The solution was concentrated under reduced pressure and then acidified with aqueous 1 M HCl. The resulting yellow product was filtered through filter paper on a Hirsch funnel under vacuum, affording the title compound (9.6 g, 93% yield). MS (+ESI) mz = 365. 35 Step 9: 6-(2,4-Difluorobenzyl)-3-hydroxy-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6 naphthyridine- 1 -carboxamide WO 2012/058173 PCT/US2011/057557 100 A solution of carboxylic acid from Step 8 (3.6 g, 10 mmol) in DMF (100 mL) was treated with HATU (5.3 g, 14 mmol), N,N'-diisopropylethylamine (3.5 mL, 20 mmol), and concentrated ammonium hydroxide (1.2 mL, 30 mmol). Progess of the reaction was 5 checked by LCMS and additional equivalent of reagents were added as necessary (approx 3 times). After 12 h, the reaction was quenched with a saturated aqueous solution of NH4Cl (100 mL) and the mixture was poured into a separators funnel. The aqueous layer was extracted with EtOAc (3 x x 150 mL) and the combined organics layers were dried over MgSO 4 , filtered and concentrated under reduced pressure affording 1.5 g of the primary 10 amide. MS (+ESI) m/z = 364. Step 10: (1S,5R)-8'-(2,4-Difluorobenzyl)-6'-methoxy-9',10'-dihydro-2'H spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a] [2,6]naphthyridine] l',5',7'(8'H)-trione 15 To a solution of amide from Step 9 (0.72 g, 2.0 mnol) in DMA (5.0 mL) was added (IS, 5R)-bicyclo[3.1.0]hexan-2-one (0.58 g, 6.0 mmol) and concentrated sulfuric acid (0.10 ml, 2.0 mmol). The mixture was heated to 100 C for 4 h. After cooling to room temperature, a saturated solution of NaJC0 3 in water was added, the resulting mixture was 20 poured into a separatory funnel and extracted with CH 2 C1 2 (3 x 25 mL). The combined organic layers were washed with water and brine, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. The title compound (0.66 g) was used directly in the next step without purification. MS (+ESI) m/z= 442. 25 Step 11: (1S,5R)-8'-(2,4-Difluorobenzyl)-6'-hydroxy-9', I 0'-dihydro-2'H spiro[bicyclo[3.1 .0]hexane-2,3'-imidazo[5 ,1-a] [2,6]naphthyridine] l',5',7'(8'H)-trione To a solution of compound from Step 10 (0.66 g, 30 1.5 mmol) in DMF (15 mL) was added lithium chloride (0.19 g, 4.5 mmol) and the solution heated at 100 0 C for 2 h. After cooling to room temperature the reaction mixture was diluted with water (15 nL), poured into a separatory funnel and extracted with EtOAc (3 x 10 mL). The organic layer was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. Purification by preparative reverse phase chromatography through a SunFire C 18 35 10 4M 30 x 150 mm column, eluting with 25% MeCN in H20 (+0.1% TFA) to 95% MeCN in H20 (+0.1% TFA) over 12 minutes at a flow rate of 25 ml/min, afforded Example 24 WO 2012/058173 PCT/US2011/057557 101 (0.156 g, the first eluting diastereomer) and Example 25 (0.172 g, the second eluting diastereomer). Example 24 (first eluting diastereomer): MS (+ESI) m/z = 428. 'H NMR (400 MHz, d DMSO) 6 13.45 (s, 1H), 9.53 (s, 1H), 7.50-7.43 (in, 1H), 7.31-7.22 (in, 1H), 7.13- 7.04 (m, 5 1H), 4.73 (s, 2H), 3.61-3.54 (in, 2H), 3.29-3.22 (m, 2H), 2.68-2.57 (m, 1H), 2.19-2.12 (m, 1H), 1.87-1.71 (m, 2H), 1.69-1.63 (in, 1H), 1.54-1.47 (in, 1H), 0.63-0.48 (m, 2H). Example 25 (second eluting diastereomer): MS (+ESI) m/z = 428. 'H NMR (400 MHz, d6 DMSO) 8 13.43 (s, 1H), 9.94 (s, 1H), 7.57-7.43 (m, 1H), 7.27-7.22 (in, 1H), 7.11- 7.06 (m, IH), 4.73 (s, 2H), 3.60-3.52 (in, 2H), 3.32-3.24 (in, 2H), 2.83-2.75 (m, 1H), 2.18-2.05 (mo, 10 1H), 1.82-1.76 (m, 1H), 1.53-1.42 (m, 2H), 1.39-1.33 (m, 1H), 1.24-1.19 (m, 1H), 0.80 0.71 (m, 1H). EXAMPLE 26 (+) or (-)-N-{2-[8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-1,5,7-trioxo 15 1,5,7,8,9,1 0-hexahydroimidazo[5,1-a][2,6]naphthyridin-2(3H)-yl]ethyl}-N methylmethanesulfonamide Me' NCBz MeNc 0 OPiv Me FO H2N N O Ph 0 NH O AN 0 F - N A N HN~ Ci OPiv

H

2 SO4 o OPiv ciN O Intermediate A 0 OH Me Me NCBz NCBz 0 J'0 'N N N N NPd(OH) 2 F AN separate F N IN O enantiomers A N O O OH 0 OH first efuting enantiomer 20 WO 2012/058173 PCT/US2011/057557 102 Me Me 0 NH N-S N HC CI-S-Me N F XN0 F X N 1 x N N _ 0 OH 0 OH chiral Step I: tert-Butyl [2-({[6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo 2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1 5 yl]carbonyl}amino)ethyl]methylcarbamate A solution of Intermediate A (11.0 g, 17.8 mmol) in THF (118 ml) was treated with benzyl (2-aminoethyl)methylcarbamate (4.81 g, 23.1 mmol), triethylamine (4.95 mL, 35.5 mmol) and stirred at room temperature for 20 minutes. Methylamine (33 wt% 10 solution in methanol, 9.56 mL, 71.1 mmol) was added and the mixture stirred at room temperature for 16 h. The mixture was acidified to pH -8 with 1 M aqueous HCl solution, poured into a 1 L separatory funnel and partitioned between water (200 mL) and EtOAc (800 mL). The organic phase was dried over Na 2

SO

4 , filtered and concentrated to afford the title compound which was used in subsequent steps without purification. MS (+ESI) m/z = 15 557. Step 2: (R) or (S)-Benzyl {2-[8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy 1,5,7-trioxo-1,5,7,8,9,10-hexahydroimidazo[5,1-a][2,6]naphthyridin-2(3H) ylJethyl} methylearbamate 20 A solution of secondary amide from Step 1 (9.9 g, 17.8 mmol) and cyclopropanecarboxaldehyde (7.47 g, 107 mmol) in 1,4-dioxane (59 mL) was treated with concentrated sulfuric acid (1.42 mL, 26.7 mmol) and heated to 70 *C for 3 h. The reaction mixture was concentrated and purified by preparative reverse phase chromatography through 25 a SunFire C18 10 p.M 50 x 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 50% MeCN in H 2 0 (+0.1% TFA) to 90% MeCN in H 2 0 (+0.1% TFA) over 30 minutes at a flow rate of 85 mL/min. The desired product fractions were partitioned between water (100 mL) and EtOAc (500 mL). The organic phase removed, dried over Na 2

SO

4 , filtered and concentrated to afford the racemic compound (5.5 30 g, 51 % yield). The racemic mixture (5.5 g) was separated by chiral SFC to afford enantiopure title compound (2.15 g, first eluting enantiomer, >95% ee). Preparative chiral WO 2012/058173 PCT/US2011/057557 103 separation of the enantiomers was achieved using a ChiralPak OD-H, 250 x 30 mm I.D. 20 pim column, eluting with CO 2 plus methanol:acetonitrile (60 : 26.7: 13.3 + 0.1% Et 2 NH) at a flow rate of 80 mL/min. MS (+ESI) m/z = 609. 5 Step 3: (R) or (S)-8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[2 (methylamino)ethyl]-2,3,9,10-tetrahydroimidazo[5, 1-a][2,6]naphthyridine 1,5,7(8t)-trione hydrochloride A solution of chiral CBz-protected amide from Step 2 (1.00 g, 1.64 mmol) in 10 EtOAc (16.4 mL) was treated with 20 wt% Pd(OH) 2 on carbon (231 mg, 0.131 mmol). The flask was evacuated and backfilled with H 2 (gas) three times and stirred under a H 2 atmosphere (~ I atm) at 50 'C for 2 h. At this time, an additional 20 wt% Pd(OH)2 on carbon was added (165 mg, 0.065 mmol). The flask was evacuated and backfilled with H 2 (gas) three times and stirred under a H 2 atmosphere (z 1 atm) at 50 C for an additional 4 h. 15 Methanol and a few drops of concentrated HCi solution were added to the suspension to aid in solubility of the compound. The mixture was filtered through a pad of Celite and the filter cake was washed with MeOH. The filtrate was concentrated to afford the title compound (700 mg, 83% yield). MS (+ESI) m/z 475. 20 Step 4: (R) or (S)-N-{2-[8-(3-chloro-4-tluorobenzyl)-3-cyclopropyl-6-hydroxy-1,5,7 trioxo-1,5,7,8,9,10-hexahydroimidazo[5,1-a][2,6]naphthyridin-2(3H) yl] ethyl} -N-methylmethanesulfonamide A suspension of secondary amine from Step 3 (488 mg, 1.03 mmol) in 25 dichloromethane (10 mL) was cooled to 0 C and treated with triethylamine (0.86 mL, 6.17 mmol) followed by methane sulfonyl chloride (0.20 mL, 2.57 mmol). The mixture was stirred and warmed to room temperature over 25 minutes. The mixture was concentrated, diluted with tetrahydrofuran (10 mL) and treated with 4 N aqueous LiOH solution (2.57 mL, 10.3 mmol). The resulting mixture was stirred at room temperature for 1 h. The mixture 30 was poured into a 250 mL separators funnel and partitioned between 1 M aqueous HCI (50 mL) and EtOAc (200 mL). The organic phase was removed and concentrated under reduced pressure. The reaction mixture was purified by preparative reverse phase chromatography through a SunFire C 18 10 gM 50 x 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 5% MeCN in H20 (+0.1% TFA) to 95% MeCN in H20 35 (+0.1% TFA) over 30 minutes at a flow rate of 85 mL/min. Pure fractions were partitioned between water (50 mL) and EtOAc (200 mL). The organic phase was removed, dried over Na 2

SO

4 , filtered and concentrated to yield the desired material of 90 % ee (287 mg, 50% WO 2012/058173 PCT/US2011/057557 104 yield). This material was further purified by chiral SFC to afford enantiopure Example 26 (189 mg, second eluting enantiomer, >99% ee). Preparative chiral separation of the enantiomers was achieved using a ChiralPak OD-H, 20 x 250 mm LD. column, eluting with

CO

2 plus methanol:acetonitrile (65:23.5:11.5 + 0.1% Et 2 NH) at flow rate of 50 mL/min. 5 MS (+ESI) m/z = 553. IH NMR (400 MHz, CDC 3 ) 6 7.34 (dd, J = 6.8, 2.2 Hz, 1H), 7.18 (ddd, J= 8.5, 4.5, 2.2 Hz, 1H), 7.10 (t, J= 8.6 Hz, IH), 5.14-5.10 (m, 1H), 4.66 (d, J= 4.3 Hz, 2 H), 4.11-4.01 (m, 1H), 3.62 (dt, J= 14.4, 5.7 Hz, 1 H), 3.48-3.37 (m, 3H), 3.36 (t, J = 5.8 Hz, 1H), 3.28 (ddd, J= 14.9, 8.0, 5.9 Hz, 2H), 2.91 (s, 3H), 2.76 (s, 3H), 1.28 (dd, J= 9.6, 5.0 Hz, 1H), 0.80-0.73 (m, 3H), 0.61-0.55 (m, 1H). 10 EXAMPLES 27 AND 28 (+) and (-) - N-{2-[8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7'-trioxo-1',5',7',8',9',10' hexahydro-2'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridin]-2' yl]ethyl } -N-methylmethanesulfonamide 15 0 NH 2 O F N H F F)( _ _ _

-

_ _ _ NH N C / N t O H 2 S0 4 , DMA C X N O NaH, DMF 0 OH 0 OH Intermediate D Me Me C e H N-Szro MeMe , 0 separate NA 0'0 N diastereomers F N NaH, THF F N separate N O CIN O enantiomers O OH 0 OH Me Me Me Me N-SzO N-S*O 0 0 0 0 N N F / N N C" N0 ci 0 0 OH 0 OH Example 27 Example 28 First eluting diastereomer First eluting diastereomer 20 First eluting enantiomer Second eluting enantiomer WO 2012/058173 PCT/US2011/057557 105 Step 1: (±)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-9', 1 0'-dihydro-2'H spiro[bicyclo[3.l.0]hexane-2,3'-imidazo[5,1-a] [2,6]naphthyridine] l',5',7'(8'H)-trione 5 A 250 mL flask was charged with dry DMA (65 mL), Intermediate D (6.00 g, 16.3 mmol), racemic bicyclo[3.1.0]hexan-2-one (6.23 g, 65.2 mmol) and concentrated sulfuric acid (1.9 mL). The resulting mixture was heated to 105 C under an atmosphere of

N

2 for 6 h. After cooling, the reaction mixture was poured into a 1 L separatory funnel, diluted with EtOAc (500 mL), washed with water (2 x 200 mL) and brine (200 mL), and the 10 organic layer was separated. The organic layer was dried over MgS04, filtered and concentrated to afford the title compound. MS (+ESI) m/z = 444. Step 2: (±)-2'-(2-Chloroethyl)-8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-9', 0' dihydro-2'1--spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1 15 a] [2,6]naphthyridine]-l',5',7'(8'I)-trione A 250 mL flask was charged with dry DMF (45 mL) and the compound from Step 1 (4.0 g, 9.0 mmol). Sodium hydride (95 wt%, 1.1 g, 45 mmol) was added to the mixture portion-wise at room temperature, followed by the addition of 1-bromo-2 20 chloroethane (6.5 g, 45 mmol) and the resulting mixture was stirred at room temperature. After I h, the reaction was recharged with 1 -bromo-2-chloroethane (6.5 g, 45 mmol) and sodium hydride (95 wt%, 1.1 g, 45 mmol). The same process was repeated 2-times until the alkylation was complete by LCMS analysis. The reaction mixture was poured into a I L separatory funnel, diluted with EtOAc (500 mL), washed with aqueous 1 N HCI (100 mL), a 25 saturated solution of NaHCO 3 in water (100 mL) and water (8 x 100 mL). The organic layer was separated, dried over MgSO 4 , filtered and concentrated to afford the title compound (4.3 g, 95% yield) as a yellow solid. MS (+ESI) m/z = 506. Step 3: (+) and (-)-N-{2-[8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-l',5',7'-trioxo 30 1',5',7',8,9',10'-hexahydro-2'H-spiro[bicyclo[3.1.0]hexane-2,3'imidazo[5,1 a] [2,6]naphthyridin}-2'-yl]ethyl} -N-methylmethanesulfonamide To a solution of N-methylmethanesulfonamide (1.3 g, 11.9 mmol) in dry THF (5 mL) was added sodium hydride (60 wt%, 415 mg, 10.4 mmol) at room temperature. 35 The resulting suspension was stirred at room temperature for 30 minutes, at which point a solution of the chloroethyl-compound from Step 2 (750 mg, 1.5 mmol) in dry THF (5 mL) was added in a single portion. The resulting mixture was heated to 100 *C for 16 h. After WO 2012/058173 PCT/US2011/057557 106 cooling, the reaction mixture was poured into a 500 mL separatory funnel, diluted with EtOAc (200 mL) and washed with IM aqueous HCl solution (50 mL) and water (50 mL). The organic layer was separated, dried over MgSO 4 , filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire Cl 8 5 pm 50 x 5 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 30% MeCN in H 2 0 (+0.1% TFA) to 70% MeCN in H20 (+0.1% TFA) as a gradient over 30 minutes at a flow rate of 35 nL/min. First eluting diastereomer (240 mg, 28% yield), yellow solid. HRMS (+ESI) m/z = 579.1452 found, 579.1452 required. !H NMR (500 MHz, acetone) 6 13.69 (s, 1H), 7.62 (dd, J= 7.1, 10 2.3 Hz, 1H), 7.47 (ddd, J= 8.5, 4.6, 2.2 Hz, 1H), 7.33 (t, J= 8.9 Hz, 1H), 4.83 (s, 2H), 3.99-3.92 (m, 1H), 3.67 (t, J= 6.4 Hz, 2H), 3.55-3.47 (m, 4K), 3.43-3.38 (m, 2H), 2.99 (s, 3K), 2.88 (s, 3H), 2.86-2.78 (m, 1H), 2.21 (dt, J= 15.4, 9.3 Hz, 1H), 1.90-1.80 (m, 2H), 1.50 (q, J= 6.0 Hz, 1H), 0.94-0.88 (in, 211). Second eluting diastereomer (198 mg, 23% yield), yellow solid. HRMS (+ESI) m/z 15 579.1452 found, 579.1452 required. 'H NMR (500 MHz, acetone) 6 13.69 (s, 1H), 7.62 (dd, J= 7.1, 2.3 Hz, 1 H), 7.47 (ddd, J= 8.6, 4.7, 2.2 Hz, 1H), 7.33 (t, J= 8.9 Hz, 1H), 4.83 (s, 2H), 3.85-3.77 (m, 2K), 3.68 (t, J= 6.4 Hz, 2H), 3.53-3.42 (m, 3H), 3.41-3.32 (m, 2H), 3.00 (s, 3K), 2.89-(s, 311, 2.35 (m, 1H), 2.04 (m, 1H), 1.92 (t, J= 4.6 Hz, 1H), 1.85 (s, 1H), 1.76 (in, 1H), 1.39 (dt, J= 8.7, 4.5 Hz, 111), 0.90-0.79 (m, 1H). 20 The racemic mixture of the first eluting diastereomer (240 mg) was separated by chiral SFC to afford enantiopure Example 27 (83 mg, first eluting enantiomer, >99% ee) and Example 28 (89 mg, second eluting enantiomer). Preparative chiral separation of the enantiomers was achieved using a ChiralPak OD-H, 20 x 250 mm I.D. column, eluting with CO 2 plus ethanol (60:40 + 0.1% Et 2 NH) at a flow rate of 50 mL/min. HRMS (+ESI) m/z = 579.1454 found, 25 579.1452 required. IH NMR (399 MHz, CDC 3 ) 6 7.37 (dd, J= 8.7, 2.4 Hz, 1H), 7.21 (ddd, J= 9.9, 4.9, 2.3 Hz, 1H), 7.14 (t, J= 8.5 Hz, 1 H), 4.69 (s, 2H), 3.98 (t, J= 9.6 Hz, 111), 3.55-3.46 (in, 4H), 3.39 (t, J= 9.3 Hz, 411), 3.00 (s, 3H), 2.83 (s, 3K), 2.05 (m, 41), 1.92 1.84 (m, 1H), 0.96 (q, J= 7.4 Hz, 1H), 0.76 (q, J= 4.8 Hz, 1H). 30 EXAMPLE 29 (1S,5R)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-2'-(2-methoxyethyl)-9',10'-dihydro-I'H spiro[bicyclo[3.1 .0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine] -1 ',57'(2'H,8'H)-trione WO 2012/058173 PCT/US2011/057557 107 OMe NH ON F NYNaH, Br& O'Me F N NN N C N N 0 OH 0 OH Example 15 first eluting diastereomer first eluting diastereomer To an oven dried vial under an atmosphere of nitrogen was added (IS, 5R)-8' (3-chloro-4-fluorobenzyl)-6'-hydroxy-9',10'-dihydro-1'H-spiro[bicyclo[3.1.0]hexane-2,3' imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione (Example 15) (102 mg, 0.23 5 mmol) and anhydrous DMF (4 mL). To this solution was added sodium hydride (95 wt%, 29 mg, 1.15 mmol) and the reaction was stirred at room temperature for 45 minutes. 1 Bromo-2-methoxyethane (86 pL, 0.92 mmol) was then added and the reaction was stirred at room temperature for 18 h. The reaction was quenched with 1 M aqueous HCl solution (1.5 mL) and stirred at room temperature for 90 minutes. This solution was purified by 10 preparative reverse phase chromatography through a SunFire C18 10 fiM 50 x 250 mm column, eluting with 35% MeCN in H20 (+ 0.1% TFA) to 85% MeCN in H20 (+ 0.1% TFA) over 25 minutes to afford the title compound (37 mg, 32 % yield). MS (+ESI) m/z= 502. 'H NMR (499 MHz, d 6 -DMSO) 8 13.45 (s, 1H), 7.58 (d, J= 7.1 Hz, 1H), 7.43-7.34 (m, 2H), 4.75-4.67 (m, 2H), 3.81-3.73 (m, 1H), 3.61-3.47 (m, 5H), 3.32-3.26 (m, 5H), 2.68 15 2.60 (m, 1H), 2.22-2.11 (m, 1H), 1.97-1.88 (m, 1H), 1.80-1.71 (m, 2H), 1.39 (m, 1H), 0.85 0.77 (m, 2H). EXAMPLE 30 (+) or (-)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(3-methoxy-3 20 methylbutyl)-2,3,9, 1 0-tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione WO 2012/058173 PCT/US2011/057557 108 Me Me H Me 0 O OPiv 0 N Me

H

2 N OH F NN N F N NH OH H 2

S

4 CI N OPiv CI 0 O OPiv 0 OH Intermediate A Me Me Me 0 Me OMe N N F N HC, MeOH, F N separate CI N 0C1 X N N enantiomers O OH 0 OH Me Me O OMe N C N N NH first eluting enantiomer Step 1: 6-(3-Chloro-4-fluorobenzyl)-4-bydroxy-N-(3-hydroxy-3-methylbutyl)-3,5 dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide 5 4-amino-2-methylbutan-2-ol (0.372 g, 2.42 mmol) was added to a stirring solution of Intermediate A (1.50 g, 2.42 mmol) in THF (16 mL). Triethylamine (1.35 mL, 9.69 nmol) was added, and the reaction mixture was stirred at room temperature for 2 h. Next, a 33 wt% EtOH solution of methylamine (1.96 mL, 14.54 mmol) was added, and the 10 reaction mixture was stirred for an additional 1 h. The reaction mixture was poured into a 500 mL separators funnel, diluted with EtOAc (150 mL) and washed sequentially with saturated aqueous NaHCO 3 solution (150 mL) and brine (150 mL). The combined organics layers were dried over MgS04, filtered, and concentrated under reduced pressure to afford the title compound as a light yellow semi-solid. The overall yield was not determined, and 15 the isolated material was used in the subsequent step without further purification assuming quantitative conversion. MS (+ESI) m/z= 452.

WO 2012/058173 PCT/US2011/057557 109 Step 2: (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(3-methylbut-2 en-1-yl)-2,3,9, 1 0-tetrahydroimidazo[5,1-a] [2,6]naphthyridine- 1,5,7(8H) trione 5 Concentrated sulfuric acid (0.34 mL, 6.09 mmol) was added drop-wise to a stirring suspension of the amide compound from Step 1 (1.10 g, 2.42 mmol) and cyclopropane-carboxaldehyde (1.71 g, 24.34 mmol) in 1,4-dioxane (12 mL) in a 25 mL pressure vessel. The vessel was sealed, and the reaction mixture was heated to 85 'C for 1 h. The reaction mixture was diluted with EtOAc (120 mL) and washed sequentially with 10 saturated aqueous NaHCO 3 solution (120 mL) and brine (120 mL). The combined organics were dried over MgS04, filtered, and concentrated under reduced pressure to afford the crude title compound as a light yellow semi-solid. The resulting gum was purified by preparative reverse phase chromatography through a SunFire C18 10 jiM 30 x 150 mm column. The compound was loaded with DMSO/methanol, and eluted with 5% MeCN in 15 H20 (+ 0.1% TFA) to 95% MeCN in H20 (+ 0.1% TFA) to afford the racemic compound as a light yellow gum (398 mg, 34% over 2 Steps). MS (+ESI) m/z = 486. Step 3: (+) or (-)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(3 methoxy-3- methylbutyl)-2,3,9,1 0-tetrahydroimidazo [5,1-a] [2,6]naphthyridine- 1,5,7(8H) 20 trione The alkene from Step 2 (0.398 g, 0.82 mmol) was treated with 3M HCl in MeOH (13.7 mL) in a 25-mL pressure vessel. The vessel was sealed, and the reaction mixture was heated to 75 *C for 16 h. The reaction mixture was cooled to room temperature 25 and the solvent removed under reduced pressure. The resulting brown gum was purified by preparative reverse phase chromatography through a SunFire C18 10 jiM 30 x 150 mm column. The compound was loaded with DMSO, and eluted with 5% MeCN in H20 (+ 0.1% TFA) to 95% MeCN in H20 (+ 0.1% TFA) to afford the racemic title compound as a light yellow gum (250 mg, 59% yield). The racemic mixture (250 mg) was separated by 30 chiral SFC to afford the enantiopure title compound (99 mg, first eluting enantiomer, >99% ee). Preparative chiral separation of the enantiomers was achieved using a ChiralCel OD-H, 250 x 30 mm I.D. 5 ptm column, eluting with CO 2 plus methanol (1:1 + 0.1% Et 2 NH) at a flow rate of 80 mL/min., column temperature = 38 'C. MS (+ESI) m/z = 518. '1H NMR (500 MHz, CDCl 3 ) 8 13.68 (s, 1H), 7.61 (d, J= 7.1 Hz, 1H), 7.49-7.45 (m, 1H), 7.33 (t, J= 8.9 35 Hz, 114), 5.16 (d, J= 8.8 Hz, 1H), 4.83 (td, J= 14.9, 12.7 Hz, 2H), 3.91 (ddd, J= 13.9, 11.5, 5.13 Hz, 1H), 3.72-3.65 (m, 2H), 3.56-3.41 (m, 2H), 3.33-3.27 (m, 1H), 3.20 (s, 3H), 1.99 (ddd, J= 13.9, 7.1,4.4 Hz, 1H), 1.80 (ddd, J= 13.9, 8.1, 5.6, 1H), 1.21 (s, 6H), 1.20-1.15 WO 2012/058173 PCT/US2011/057557 110 1.21 (s, 6H), 1.20-1.15 (m, 1H), 0.92-0.87 (m, 1H), 0.80-0.71 (m, 3H). EXAMPLE 31 (+)or (-)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[(cis)-2 5 (methoxymethyl)cyclopropyl]-2,3,9,1 0-tetrahydroimidazo [5,1-a] [2,6]naphthyridine 1,5,7(8H)-trione H o OPiv H2N OH 0 NOHO F N EtNN-, F N /- NHH2O C1Oiv Cl 0 O OPiv 0 OH Intermediate A OH OMe O O N Mel N F N X7 N1 FtN4 2 FNNaH F -~N separate N N enantiomers Cl O C1 N O OH 0 OH 10 OMe F N pN NN N 0 OH O OH 15 0 0 first eluting diastereomer first eluting enantiomer Step 1: 6 3 -Chloro-4-fluorobenzyl)y4-hydroxy-N-[(cis)-2 (hydroxymethyl)cyclopropyl]-3 ,5 -dioxo-2,3 ,5 ,6,7,8-hexahydro-2,6 naphthyridine-l1-carboxamide 15 A 100 mL flask was charged with dry THF (2 7 mL) and Intermediate A (2.5 g, 4.0 mmol). [(Cis)-2-aminocyclopropyl]methanol hydrochloride (0.7 g, 5.3 mmol) and triethylamine (1.1 mL, 8.1 mmol) were then added and the resulting mixture was stirred at room temperature for 30 minutes. Methylamine (33 wt% in EtOH, 2.7 mL, 20.2 mmol) was 20 added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into a 500 mL separatory funnel, diluted with EtOAc (200 mL), washed with a WO 2012/058173 PCT/US2011/057557 Ill with a saturated solution NaHCO 3 in water (50 mL) and 1 M aqueous HCi solution (2 x 50 mL). The organic layer containing a suspension was separated and filtered, and the solid was dried under vacuum to afford the title compound (1 6 g, 91% yield) as a white solid. MS (+ESI) m/z = 436. 5 Step 2: (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[(cis)-2 (hydroxymethyl)cyclopropyl]-2,3,9, 1 0-tetrahydroimidazo[5,1 a] [2,6]naphthyridine- 1,5,7(8H)-trione 10 To a mixture of the amide from Step 1 (1.2 g, 2.7 mmol) in 1,4-dioxane (9.1 mL) was added cyclopropanecarboxaldehyde (1.9 g, 27 mmol) and concentrated sulfuric acid (0.3 mL) under nitrogen at room temperature. The resulting mixture was heated to 80 C for 30 minutes. After cooling, the reaction mixture was poured into a 250 mL separatory funnel, diluted with EtOAc (200 mL) and washed with a saturated solution of NaHCO 3 in 15 water (50 mL), water (50 mL), and the organic layer was separated. The organic layer was dried over MgSO 4 , filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire Ci8 5pm 50 x 250 mm column. The compound was loaded with DMSO/methanol and eluted with 30% MeCN in H20 (+0.1% TFA) to 75% MeCN in H20 (+0.1% TFA) as a gradient over 30 minutes to afford the title 20 compound. MS (+ES) m/z =488. Step 3: (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[(cis)-2 (methoxymethyl)cyclopropyl]-2,3,9,10-tetrahydroimidazo[5,1 a] [2,6]naphthyridine-1,5,7(8H)-trione 25 To a stirring solution of the alcohol from Step 2 (280 mg, 0.6 mmol) in dry DMF (2.9 mL) was added sodium hydride (60 wt%, 69 mg, 1.7 mmol) at room temperature followed by the addition of iodomethane (244 mg, 1.7 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into a 250 mL 30 separatory funnel and diluted with EtOAc (100 mL), washed with I M aqueous HCI (20 mL), a saturated solution of NaHCO 3 in water (20 mL) and water (2 x 20 mL). The organic layer was separated, dried over MgSO 4 , filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire C18 5 ptm 50 x 250 mm column. The compound was loaded with DMSO/methanol, and eluted with 35% MeCN in 35 H20 (+0.1% TFA) to 85% MeCN in H20 (+0.1% TFA) as a gradient over 30 minutes to afford both diastereomers of the title compound.

WO 2012/058173 PCT/US2011/057557 112 First eluting diastereomer (204 mg, 71% yield), yellow solid, HRMS (+ESI) m/z= 502.1543 found, 502.1540 required. IH NMR (500 MHz, d-acetone) 6 13.71 (s, 1H), 7.62 (dd, J= 7.1, 2.1 Hz, lH), 7.49-7.45 (in, 1H), 7.33 (t, J= 8.9 Hz, 1H), 5.14 (d, J= 7.8 Hz, 1H), 4.90-4.75 (m, 2H), 3.81 (dd, J= 10.5, 4.7 Hz, 1H), 3.68 (t, J= 6.3 Hz, 2H), 3.45 (dt, J 5 = 16.4, 5.8 Hz, 1H), 3.30-3.21 (m, 1H), 3.20 (s, 3H), 2.98 (t, J= 9.7 Hz, 1H), 2.86 (td, J= 7.4, 4.7 Hz, 1H), 1.63-1.57 (m, 1H), 1.16-0.95 (in, 4H), 0.77-0.64 (in, 3H). Second eluting diastereomer (28 mg, 10% yield), yellow solid. HRMS (+ESI) m/z = 502.1536 found, 502.1540 required. IH NMR (500 MHz, d-acetone) 6 13.71 (s, 1H), 7.61 (dd, J= 7.1, 2.2 Hz, 1H), 7.47 (ddd, J= 8.5, 4.6, 2.2 Hz, 1H), 7.33 (t, J= 8.9 Hz, 1H), 5.10 10 (d, J= 8.7 Hz, IH), 4.89-4.77 (m, 2H), 3.70-3.64 (m, 3H), 3.47 (dt, J= 16.4, 5.8 Hz, IH), 3.27 (s, 3H), 3.27-3.21 (in, 1K), 2.95-2.83 (m, 2H), 1.47-1.39 (m, 1H), 1.31 (ddd, J= 9.2, 7.5, 6.1 Hz, 1H), 1.11-1.06 (m, IH); 1.04-0.96 (m, 2H), 0.91-0.83 (m, 1H), 0.74-0.65 (m, 2H). 15 Step 4: (+) or (-)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[(cis)-2 (methoxymethyl)cyclopropyl]-2,3,9,1 0-tetrahydroimidazo[5, 1 a] [2,6]naphthyridine-1,5,7(8J-)-trione The racemic mixture of the first eluting diastereomer (150 mg) was separated 20 by chiral SFC to afford enantiopure Example 31 (43 mg, first eluting enantiomer, >99% ee) and enantiomer B (42 mg, second eluting enantiomer, >99% ee). Preparative chiral separation of the enantioners was achieved using a ChiralPak OD-H, 20 x 250 mm I.D. column, eluting with CO 2 plus methanol (55:45 + 0.1% Et 2 NH) at a flow rate of 50 mL/min., detection at 254 nm. HRMS (+ESI) m/z = 502.1550 found, 502.1540 required. 'H 25 NMR analysis was identical to racemic material in Step 3. EXAMPLE 32 (S) or (R)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[(1R,2R)-2 methoxycyclohexyl]-2,3,9,10-tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione WO 2012/058173 PCT/US2011/057557 113 HC1 H OH 0 OPiv 0 N,

H

2 N OH OsA F N AN Et 3 N F N NH H 2 SO4 ci A N N 0 N No C1OPiv C1 O 0 OPiv 0 OH Intermediate A 0 O N OH Mel N OMe F N NF A N N NaH N 0 OH 0 OH first eluting diastereomer Step 1: 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-N-[(1S,2S)-2-hydroxycyclohexyl] 5 3,5 -dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine- I -carboxamide A 50 mL flask was charged with dry THF (5.4 mL) and Intermediate A (500 mg, 0.8 mmol). (1R,2R)-2-aminocyclohexanol hydrochloride (0.2 g, 1.1 mmol) and triethylamine (0.2 nL, 1.6 mmol) were then added and the resulting mixture was stirred at 10 room temperature for 10 minutes. Methylamine (33 wt% in EtOH, 0.5 mL, 4.0 mmol) was added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into a 250 mL separatory funnel, diluted with EtOAc (100 mL), washed with a saturated solution NaHCO 3 in water (20 mL) followed by aqueous IM HCI solution (2 x 20 mL). The organic layer containing a suspension was separated and filtered, and the solid 15 was dried under vacuum to afford the title compound (303 mg, 81% yield) as a white solid. MS (+ESI) m/z = 464. Step 2: (S) and (R)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2 [(1 R,2R)-2-hydroxycyclohexyl]-2,3,9,1 0-tetrahydroimidazo[5, 1 20 a][2,6]naphthyridine-1,5,7(8H)-trione A mixture of the amide from Step 1 (200 mg, 0.4 mmol) in 1,4-dioxane (1.4 mL) was added cyclopropanecarboxaldehyde (300 mg, 4.3 mmol) and concentrated sulfuric acid (0.07 mL) under nitrogen at room temperature, then the mixture was heated to 100 4C 25 for 45 minutes. After cooling, the reaction mixture was poured into a 125 mL separatory WO 2012/058173 PCT/US2011/057557 114 funnel, diluted with EtOAc (50 mL) and washed with a saturated solution of NaHCO 3 in water (10 mL), water (10 mL), and the organic layer was separated. The organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by preparative reverse phase chromatography through a SunFire C18 5 vum 30 x 150 5 mm column. The compound was loaded with DMSO/methanol, and eluted with 35% MeCN in H 2 0 (+0.1% TFA) to 75% MeCN in H20 (+0.1% TFA) as a gradient over 25 minutes to separate the diastereomers of the title compound. First eluting diastereromer (33 mg, 15% yield): HRMS (+ESI) m/z = 516.1693 found, 516.1696 required. 'H NMR (500 MHz, d6-acetone) 6 13.68 (s, 111), 7.62 (dd, J= 7.1, 2.2 10 Hz, 1H), 7.49-7.45 (m, 1H), 7.33 (t, J = 8.9 Hz, 1H), 5.40 (d, J= 8.2 Hz, 1H), 4.90-4.76 (m, 2H), 4.21-4.14 (m, 1H), 3.79 (td, J= 10.6, 5.5 Hz, 1 H), 3.68 (t, J= 6.4 Hz, 2 H), 3.45 (dt, J = 16.4, 5.6 Hz, 1 H), 3.31-3.22 (m, IH), 2.12 (d, J= 8.0 Hz, 111), 1.95 (s, 211), 1.75 (s, 2H), 1.37-1.26 (m, 4H), 1.08-1.02 (in, 1H), 0.76-0.63 (m, 3H). Second eluting diastereomer (37 mg, 17% yield): HRMS (+ESI) m/z = 516.1703 found, 15 516.1696 required. Step 3: (S) or (R)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[(cis)-2 (methoxymethyl)cyclopropyl] -2,3,9,1 0-tetrahydroimidazo[5, 1 a][2,6]naphthyridine-1,5,7(8H)-trione 20 To a stirring solution of the first eluting diastereomer from Step 2 (10 mg, 0.02 mmol) in dry DMF (0.2 mL) was added sodium hydride (60 wt%, 3.1 mg, 0.08 mmol) at room temperature. This was followed by the addition of iodomethane (11.0 mg, 0.08 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. The 25 reaction mixture was poured into a 50 mL separatory funnel, diluted with EtOAc (10 mL), washed with aqueous 1 M HCI (1 mL) and a saturated solution of NaHCO 3 in water (1 mL). The organic layer was separated, dried over MgSO 4 , filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire C18 5 gim 30 x 150 mm column. The compound was loaded with DMSO/methanol and eluted with 35% 30 MeCN in H20 (+0.1% TFA) to 90% MeCN in H20 (+0.1% TFA) as a gradient over 15 minutes to afford the title compound, Example 32. HRMS (+ESI) m/z= 530.1853 found, 530.1853 required. IH NMR (500 MHz, d6-acetone) 6 13.70 (s, 1H), 7.62 (dd, J= 7.1, 2.1 Hz, 1H), 7.50-7.46 (m, 1H), 7.33 (t, J= 8.9 Hz, 1H), 5.25 (d, J= 8.1 Hz, 1H), 4.83 (d, J = 7.0 Hz, 2H), 3.95 (s, 1H), 3.82-3.75 (m, 1H), 3.69 (t, J= 6.4 Hz, 2H), 3.45 (dt, J= 16.4, 5.7 35 Hz, 1H), 3.30 (s, 4H), 2.35 (d, J= 12.5 Hz, 111), 1.97-1.92 (m, 211), 1.80-1.76 (m, 2H), 1.37-1.25 (m, 3H), 1.15 (q, J= 11.7 Hz, 1H), 1.07-1.00 (m, 1H), 0.74-0.62 (in, 3H).

WO 2012/058173 PCT/US2011/057557 115 EXAMPLE 33 (1 S,5R)-2-Cyclopropyl-8'-(4-fluorobenzyl)-6'-hydroxy-.9',10'-dihydro-2'H spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a] [2,6]naphthyridine]-1',5',7'(8 t H)-trione 0 o F N >-B(OH)2 F N N1 0 C1N Cu(OAc) 2 C1N 0 O 0 OH 0 OH Example 15 0 Pd(OH) 2 on C F N N N

H

2 N0~ 0 OH 5 Step 1: (1S,5R)-8-(3-Chloro-4-fluorobenzy1)-2'-cyclopropyl-6'-hydroxy-9', 10' dihydro-2'H-spiro[bicyclo[3.1 .0]hexane-2,3'-imidazo[5,1 a] [2,6]naphthyridine]- 1',5',7'(8'H)-trione 10 To a suspension of Example 15 (0.18 g, 0.40 mmol), cyclopropylboronic acid (0.07 g, 0.80 mmol), and sodium carbonate (0.08 g, 0.80 mmol) in 1,2-dichloroethane (4.0 mL) was added a suspension of copper (II) acetate (0.07 g, 0.40 mmol) and 2,2'-bipyridine (0.06 g, 0.40 mmol) in hot 1,2-dichloroethane (2 mL). The mixture was heated at 70 *C for 2 h, open to air. The reaction was incomplete and another equivalent of reagents (Cu, ligand 15 and cyclopropyl boronic acid) were added. After 2 h the solution was cooled to room temperature and an aqueous saturated N4C1 solution was added (5 mL). The mixture was poured into a separatory funnel and the aqueous layer was extracted with CH2Cl 2 (3 x 10 mL). The combined organic layers were dried over Na 2 S04, filtered and concentrated under reduced pressure. The reaction mixture was purified by preparative reverse phase 20 chromatography through a SunFire C18 10 piM 30 x 150 rmm column. The compound was loaded onto the column with DMSO, and eluted with 25% MeCN in 1120 (+ 0.1% TFA) to 95% MeCN in H20 (+ 0.1% TFA) over 12 minutes at a flow rate of 25 mL/Umin. The title compound was isolated after concentration (0.03 g, 16% yield). MS (+ESI) m/z= 484. 'H NMR (400 MHz, CDCl 3 ) & 13.58 (s, 1H), 7.41-7.37 (in, 1H), 7.30-7.12 (m, 2H), 4.98-4.93 25 (in, 111), 4.77 (d, J= 15 Hz, 1H), 4.64 (d, J= 15 Hz, 1H), 3.55-3.43 (m, 3H), 3.31-3.20 (m, 1H), 2.77-2.70 (m, 1H), 1.28-1.14 (m, 2H), 1.08-1.00 (m, 1H), 0.97-0.85 (m, 1H), 0.86 0.69 (m, 4H), 0.65-0.57 (m, 1H).

WO 2012/058173 PCT/US2011/057557 116 Step 2: (1S,5R)-2'-cyclopropyl-8'-(4-fluorobenzyl)-6'-hydroxy-9',10'-dihydro-2'H spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine] l',5',7'(8'H)-trione 5 To a solution of compound from Step 1 (25 mg, 0.052 mmol) in methanol (10 mL) under nitrogen was added 20 wt% Pd(OH) 2 on carbon (19 mg, 0.027 mmol) and the suspension was hydrogenated on a Parr apparatus at 50 psi for 12 h. The resulting mixture was filtered through a pad of Celite and washed with methanol. The filtrate was 10 concentrated under reduced pressure and purified by preparative reverse phase chromatography through a SunFire C18 10 gM 30 x 150 mm column. The compound was loaded onto the column with DMSO/methanol, and eluted with 25% MeCN in H20 (+ 0.1% TFA) to 95% MeCN in H20 (+ 0.1% TFA) over 12 minutes at a flow rate of 25 mL/min. The title compound was isolated after concentration (7 mg, 30% yield). MS (+ESI) m/z= 15 450. iH NMR (400 MHz, CDCl 3 ) 6 13.58 (s, 1H), 7.41-7.37 (in, 1H), 7.30-7.12 (m, 2H), 4.98-4.93 (in, 1H), 4.77 (d,,J= 15 Hz, 1H), 4.64 (d, J= 15 Hz, 1H), 3.55-3.43 (m, 3H), 3.31-3.20 (in, 1H), 2.77-2.70 (m, 11), 1.28-1.14 (m, 2H), 1.08-1.00 (in, 1H), 0.97-0.85 (in, 1H), 0.86-0.69 (m, 4H), 0.65-0.57 (in, 111). 20 EXAMPLE 34 (+)-or (-)-(S, 5R)-8'-(4-Fluorobenzyl)-6', 1 0'-dihydroxy-2'-(2-methoxyethyl)-9', 1 0'-dihydro 1'H-spiro[bicyclo[3.1 .0]hexane-2,3'-imidazo[5,1-a] [2,6]naphthyridine]-1',5',7'(2'H,8'H) trione WO 2012/058173 PCT/US2011/057557 117 Me 0 0 0 NN NaH MN F, FD C1 x N 0 BK-,- 0 -Me C1 ' N 0 0 OH 0 OH Example 16 second eluting diastereomer Me 0 O N NaH, DMSO, Pd(OH) 2 , H 2 F KOtBu, 02 N No 0 OH Me, O OH NN FN N 0 0 OH second eluting diastereomer single enantiomer Step 1: (1S, 5R)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-2'-(2-methoxyethyl)-9', 10' dihydro- 1H-spiro [bicyclo [3.1.0]hexane-2,3'-imidazo [5,1 a] [2,6]naphthyridine]- 1',5',7'(2'H, 8'f)-trione 5 The title compound was prepared as in Example 29 replacing (1S, 5R)-8'-(3 chloro-4-fluorobenzyl)-6'-hydroxy-9', 1 0'-dihydro- 'H-spiro [bicyclo [3.1.0]hexane-2,3' imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione - Example 15 with Example 16. MS (+ESI) m/z= 502. 10 Step 2: (1S, 5R)-8'-(4-Fluorobenzyl)-6'-hydroxy-2'-(2-methoxyethyl)-9', 1 0'-dihydro 1'H-spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a] [2,6]naphthyridine] 1',5',7'(2'H,8'H)-trione WO 2012/058173 PCT/US2011/057557 118 To a solution of compound from Step 1 (80 mg, 0.16 mmol) in methanol (20 mL) sparged with nitrogen gas, was added palladium hydroxide catalyst (15-20 wt% on carbon, 20 mg). The reaction was fitted with a balloon filled with hydrogen and stirred at room temperature. After 3 h, the reaction was filtered through a 0.45 micron filter and 5 concentrated under reduced pressure. The residue was purified by preparative reverse phase chromatography through a SunFire C18 10 gM 30 x 150 mm column. The compound was loaded with DMSO, and eluted with 30% MeCN in H20 (+ 0.1% TFA) to 80% MeCN in H20 (+ 0.1% TFA) over 14 minutes to afford the title compound. MS (+ESI) m/z = 468. 10 Step 3: (+)-or (-)-(]S',5R)-8'-(4-Fluorobenzyl)-6',1 0'-dihydroxy-2'-(2-methoxyethyl) 9',1 0'-dihydro- 1'H-spiro[bicyclo [3. 1. 0]hexane-2,3'-imidazo[5, 1 a] [2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione In an oven dried flask under an atmosphere of nitrogen was added the 15 compound from Step 2 (30 mg, 0.064 mmol) and anhydrous DMSO (3 mL). To this was added sodium hydride (95 wt%, 3 mg, 0.12 mmol) and the reaction was stirred at room temperature for 10 minutes. Oxygen was then bubbled into the reaction via a pipette, followed by addition of solid potassium tert-butoxide (29 mg, 0.26 mmol). As the reaction stirred at room temperature, oxygen was continually bubbled into the suspension. After 45 20 minutes, more potassium tert-butoxide (50 mg, 0.41 mmol) was added to drive the reaction to completion. The reaction was quenched with IM aqueous HCl solution (3 mL), diluted with water (5 mL), and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over Na 2 S0 4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse phase chromatography through a SunFire C18 10 25 pM 30 x 150 mm column. The compound was loaded with DMSO, and eluted with 35% MeCN in H20 (+ 0.1% TFA) to 70% MeCN in H20 (+ 0.1% TFA) over 20 minutes to afford the separated diastereomers. The later eluting diastereomer is the title compound (5 mg, 16% yield). MS (+ESI) m/z = 484. 1H NMR (400 MHz, d 6 -DMSO) 8 13.6 (s, IH), 7.42 (dd, J= 8.4, 5.5 Hz, 2 H), 7.18 (t, J= 8.8 Hz, 2H), 5.67 (s, 11), 5.43 (bs, 1H), 4.76 30 4.65 (m, 2H), 3.76-3.50 (m, 6H), 3.29 (s, 3H), 3.17-3.08 (m, 114), 2.25-2.14 (in, 1H), 1.96 1.89 (m, 1H), 1.81-1.75 (in, 2H), 1.74-1.67 (m, 1H), 1.29-1.22 (m, 11), 0.87-0.81 (m, 1H). EXAMPLES 35 AND 36 (R) or (S)-(1R,5S)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-1-methyl-9',10'-dihydro-2'H 35 spiro [bicyclo [3.1. 0]hexane-2,3'-imidazo [5,1-a] [2,6]naphthyridine]- 1',5',7'(8'H)-trione WO 2012/058173 PCT/US2011/057557 119 OH Ph ,Ph Ph 4Ph O Ph Oh 0 (S'S) Me OH 0 O Et 2 Zn Me MeA Me PPTS, Toluene 0 NH 2 F ' N C N /OH 0 Me. 0 OH NH t Intermediate D FN CIN N N O DMA, H 2

SO

4 0 OH first eluting diastereomer Step 1: (2S,3S)-6-Methyl-2,3-diphenyl-1,4-dioxaspiro[4.4]non-6-ene 5 A solution of 2-methyl-2-cyclopenten-1-one (11.49 mL, 117 mmol) in toluene (600 mL) was added (SS)-(-)-hydrobenzoin (25 g, 117 mmol) and pyridinium p toluenesulfonate (2.94 g, 11.70 mmol). The mixture was refluxed under nitrogen for 4 days azeotropically removing water with a Dean-Stark trap. The solution was cooled to room 10 temperature, diluted with diethyl ether and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. The resulting ketal was purified by column chromatography through silica gel (330 g), eluting with 10% EtOAc in hexanes (16.2 g, 47% yield). 15 Step 2: (lR,4'S,5S,5'S)-I-Methyl-4',5'-diphenylspiro[bicyclo[3.1 .O]hexane-2,2' [1,3]dioxolane] A solution of (2S,3S)-6-methyl-2,3-diphenyl-1,4-dioxaspiro[4.4]non-6-ene (16.23 g, 55.5 mmol) in CHJ- 2 C1 2 (56 mL) was cooled to 0 'C and then diethylzinc (117 mL, 20 117 mmol) was added drop-wise. To the resulting mixture was added diiodomethane (9.40 mL, 117 mmol) drop-wise over 30 minutes. The ice bath was removed and the slurry stirred for 16 h at room temperature. The reaction was carefully quenched with 1 M aqueous HCI solution (100 mL), poured into a separatory funnel and diluted with EtOAc (500 mL). The organic layer was separated, washed with brine, dried over Na 2

SO

4 , and WO 2012/058173 PCT/US2011/057557 120 concentrated under reduced pressure. The product was purified by column chromatography through silica gel (330 g), eluting with 20% EtOAc in hexanes. The enriched diastereomeric mixture (15 g) was further purified by chiral SFC to afford the enantiopure title compound (10.1 g, first eluting diastereomer, >99% ee). Preparative chiral 5 separation of the diastereomers was achieved using a ChiralPak AD-H, 250 x 30 mm I.D.20 gim column. The compound was eluted with CO 2 plus methanol (85:15 + 0.1% Et 2 NH) at a flow rate of 80 mL/minute and column temperature of 38 'C. Step 3: (R) or (S)-(1 R,5S)-8'-(3 -chloro-4-fluorobenzyl)-6'-hydroxy- 1 -methyl-9', 10' 10 dihydro-2'H-spiro [bicyclo [3.1.0]hexane-2,3'-imidazo[5, 1 a] [2,6]naphthyridine] -1 ,5',7'(8'H)-trione A solution of Intennediate D (4.0 g, 11 mmol) in DMA (28 mL) was added (1R,4'S,5S,5'S)-1-methyl-4',5'-diphenylspiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane) (10.0 15 g, 33 mmol) and concentrated sulfuric acid (0.58 mL). The mixture was heated to 100 C for 18 h. After cooling, a solution of saturated NaHCO 3 in water (150 mL) was added, and the resulting mixture was poured into a separatory funnel and extracted with CH 2

CI

2 (3 x 200 mL). The combined organic layers were washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. The diastereomers were resolved 20 by preparative reverse phase chromatography using a SunFire C18 50 x 250 mm, eluting with 30% MeCN in H 2 0 (+0.1% TFA) to 75% MeCN in H20 (+0.1% TFA) at a flow rate of 85 mL/min. The desired compound ws obtained as a solid (0.22 g, 4% yield, first eluting diastereomer). MS (+ESI) m/z = 458. 'H NMR (400 MHz, CDC 3 ) 8 13.58 (s, 1H), 7.42 7.37 (in, 1H), 7.24-7.20 (in, 114), 7.18-7.10 (m, 1H), 6.53 (s, 1H), 4.75-4.63 (m, 2H), 3.53 25 3.46 (m, 2H), 3.41-3.35 (in, 2H), 2.94-2.86 (in, 1H), 2.39-2.32 (in, 1H), 1.95-1.87 (m, 1H), 1.84-1.74 (m, 2H), 0.94 (s, 3H), 0.60-0.54 (m, 1H), 0.45-0.40 (in, 1H). EXAMPLE 36 (R) or (S)-(1S,5R)-8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-1-methyl-9',10'-dihydro-2'H 30 spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(8'H()-trione Ph Ph 0 NH 2 O O N N NN OH NN Ol cI l N >OH DMA, H 2 SO4 N O OH 0 OH Intermediate D second eluting diastereomer WO 2012/058173 PCT/US2011/057557 121 Step 1: (R) or (S)-(IS,5R)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-1-methyl-9',10' dihydro-2'H- spiro[bicyclo[3.1.0]hexane-2,3'-imidazo[5,1 a][2,6]naphthyridine]-1',5',7'(8'H)-trione 5 A solution of Intermediate D (4.0 g, 11 mmol) in DMA (31 mL) was added (1S,4'S,5R,5'S)-1-methyl-4',5'-diphenylspiro[bicyclo[3.1.0]hexane-2,2'-[1,3]dioxolane] (11 g, 33 mmol) (prepared in an identical manner to Example 35 beginning with (RR)-(+) hydrobenzoin) and concentrated sulfuric acid (0.66 mL). The mixture was heated to 100 C for 18 h. After cooling to room temperature, a solution of NaHCO 3 in water was added, the 10 mixture was poured into a separatory funnel and extracted with CH 2 C1 2 (3 x 200 mL). The combined organic layers were washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. The diastereomers were resolved by preparative reverse phase chromatography using a SunFire C18 50 x 250 mm, eluting with 30% MeCN in H20 (+0.1% TFA) to 75% MeCN in H20 (+0.1% TFA) at a flow rate of 85 ml/min. The 15 desired compound ws obtained as a solid (0.21 g, 4% yield, second eluting diastereomer). MS (+ESI) m/z = 458. 'H NMR (400 MHz, CDCl3) 6 13.58 (s, 1H), 7.40-7.36 (m, 111), 7.24-7.20 (m, 1H), 7.18-7.11 (m, 1H), 6.40 (s, 111), 4.73-4.68 (m, 2H), 3.53-3.46 (m, 2H), 3.41-3.35 (m, 2H), 3.16-3.05 (m, 111), 1.98-1.90 (m, 3H), 1.53-1.47 (m, 1H), 1.37-1.32(m, 1H), 1.03 (s, 31), 0.84-0.79 (m, 1H). 20 EXAMPLE 37 (±)-Methyl 2-{2-[8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-1,5,7-trioxo 1,5,7,8,9,1 0-hexahydroimidazo[5,1 -a] [2,6]naphthyridin-2(3H)-yl]ethyl}pyridine-3 carboxylate trifluoroacetate 0 MeO HO 0 MeO 0 o OPiv H Intermediate A 0 OH MeO / 0 N ON O

H

2

SO

4 F 0N 0 NF IN O HO F 25 0 OH F WO 2012/058173 PCT/US2011/057557 122 Step 1: Methyl 2-[2-({ [6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8 hexahydro-2,6-naphthyridin-1-yljcarbonyl}amino)ethyl]pyridine-3 carboxylate 5 A 50 mL flask was charged with dry THF (5.4 mL) and Intermediate A (500 mg, 0.8 mmol). Methyl 2-(2-aninoethyl)pyridine-3-carboxylate ethanedioate (280 mg, 1.1 mmol) and triethylamine (0.2 mL, 1.6 mmol) were then added and the resulting mixture was stirred at room temperature for 10 minutes. Methylanine (33% in EtOH; 0.5 mL, 4.0 mmol) was added and the mixture was stirred at room temperature for 20 minutes. The 10 reaction mixture was poured into a 125 mL separatory funnel and diluted with EtOAc (100 mL), washed with a saturated solution NaHCO 3 in water (20 mL) and aqueous 1 M HCi solution (2 x 20 mL). The organic layer containing a suspension was separated and filtered, and the solid was dried under vacuum to afford the title compound (366 mg, 86% yield) as a white solid. MS (+ESI) m/z= 529. 15 Step 2: (±)-Methyl 2-{2-[8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy 1,5,7-trioxo-1,5,7,8,9,10-hexahydroimidazo[5,1-a][2,6]naphthyridin-2(3H) yl]ethyl } pyridine-3 -carboxylate trifluoroacetate 20 A mixture of the amide from Step 1 (300 mg, 0.6 mmol) in 1,4-dioxane (1.9 mL) was added cyclopropanecarboxaldehyde (400 mg, 5.7 mmol) and concentrated sulfuric acid (0.06 mL) under nitrogen at room temperature. The mixture was heated to 100 'C for 45 minutes. After cooling, the reaction mixture was poured into a 125 mL separatory funnel, diluted with EtOAc (50 mL) and washed with a solution of NaHCO 3 in water (10 25 mL), water (10 mL), and the organic layer was separated. The organic layer was dried over MgSO 4 , filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire Prep C18 5 tm 30 x 150 mm column. The compound was loaded with DMSO or methanol and eluted with 20% MeCN in H20 (+0.1% TFA) to 70% MeCN in H20 (+0.1% TFA) as a gradient over over 25 minutes to afford the title 30 compound (103 mg, 26% yield). HRMS (+ESI) m/z = 581.1600 found, 581.1598 required. 1 H NMR (500 MHz, d-acetone) 8 13.72 (s, 1H), 8.77 (d, J= 5.0 Hz, 1H), 8.43 (d, J= 7.9 Hz, 1H), 7.63-7.55 (m, 211), 7.47-7.44 (in, 1H), 7.32 (t, J = 8.8 Hz, 1H), 5.30 (d, J= 8.7 Hz, 1H), 4.89-4.74 (m, 2H), 4.35 (dt, J= 14.2, 7.2 Hz, 1H), 3.94 (s, 3H), 3.76-3.69 (m, 1H), 3.66 (t, J = 6.4 Hz, 3H), 3.57-3.50 (m, 1H), 3.38 (dt, J= 16.4, 5.7 Hz, IH), 3.25-3.15 (m, 35 1H), 1.15-1.09 (m, 1H), 1.04-0.96 (m, 1H), 0.78-0.68 (m, 3H).

WO 2012/058173 PCT/US2011/057557 123 EXAMPLE 38 (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(pyridin-3-yl)-2,3,9,10 tetrahydroimidazo[5,1 -a][2,6]naphthyridine-1,5,7(8H)-trione 0 NH 2 0 F H N NH C N cat. H 2

SO

4 O OH dioxane Intermediate D NH N ON F N C N N CuI K 2 CO3, NMP O OH C0 O 0 OH 5 Step 1: (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2,3,9,1 0 tetrahydroimidazo[5, 1-a] [2,6]naphthyridine- 1,5,7(8H)-trione This compound was prepared from Intermediate D and cyclopropylcarboxaldehyde using the procedure described in Example 4, Step 1. 10 Step 2: (±)-8-(3-Chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(pyridin-3-yl) 2,3,9,1 0-tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione A 2 mL microwave vial was charged with compound from Step 1 (40 mg, 0.1 15 mmol), 3-iodopyridine (39 mg, 0.2 mmol), anhydrous potassium carbonate (53 mg, 0.4 mmol), and copper(I) iodide (18 mg, 0.1 mmol) in NMP (0.7 mL). The mixture was degassed, purged with nitrogen, and the resulting mixture was heated in a microwave reactor at 180 C for 20 minutes. The reaction mixture was poured into a 50 mL separatory funnel, diluted with EtOAc (20 mL) and washed with water (5 mL), and the organic layer was 20 separated. The organic layer was dried over MgSO 4 , filtered and concentrated. The residue was purified by preparative reverse phase chromatography through a SunFire Prep C18 5 im 30 x 150 mm column. The compound was loaded with DMSO or methanol and eluted with 20% MeCN in H20 (+0.1% TFA) to 75% MeCN in H20 (+0.1% TFA) as a gradient over 20 minutes to afford title compound (19 mg, 35% yield). HRMS (+ESI) m/z = 25 495.1242 found, 495.1230 required. 'H NMR (499 MHz, d 6 -DMSO) 8 8.86 (s, 1H), 8.51 8.48 (in, 1H), 8.07 (d, J= 8.2 Hz, 1H), 7.66-7.18 (m, 4H), 6.25-6.19 (m, 1H), 4.80-4.67 (m, WO 2012/058173 PCT/US2011/057557 124 1H), 4.62-4.47 (m, 1H), 1.23 (s, 2H), 0.76-0.69 (m, 1H), 0.56-0.54 (m, 1H), 0.40 (s, 1H), 0.23 (s, 2H), 0.10 (s, 2H). EXAMPLE 39 5 (+)and (-)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-N-methyl-1',5,7'-trioxo-l',5',7',8',9',10' hexahydro-2'H-spiro[cyclopentane-1,3'-imidazo[5,1-a][2,6]naphthyridine]-2-carboxamide 0 NH 2 0 0 OMe O NH NOMe FN NN C1 OHN O OH DMA, H 2

SO

4 CI o 0 OH Intermediate D O OH 0 NH NaOH FN CI N O O OH Me O NH 0 NH BOP, EtN(iPr) 2 F N methylamine C N N o OH 10 Step 1: (±)-Methyl 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7'-trioxo 1',5',7',8',9',10'-hexahydro-2'H-spiro[cyclopentane-1,3'-imidazo[5,1 a][2,6]naphthyridine]-2-carboxylate 15 A solution of Intermediate D (2.2 g, 6.0 mmol) in 1,4-dioxane (30 mL) was treated with methyl cyclopentanone-2-carboxylate (2.2 mL, 18 mmol) and concentrated sulfuric acid (0.06 mL, 1.2 nmol). The mixture was heated to 100 C for 18 h. After cooling, an aqueous solution of NaHCO 3 in water was added, and the resulting mixture was poured into a separatory funnel and extracted with CH 2 Cl 2 (3 x 200 mL). The combined 20 organic layers were washed with water and brine, dried over Na 2

SO

4 , filtered and WO 2012/058173 PCT/US2011/057557 125 concentrated under reduced pressure. The ester was purified by preparative reverse phase chromatography through a SunFire Prep C18 5 pm 30 x 250 mm column. The compound was loaded with DMSO or methanol and eluted with 30% MeCN in H20 (+0.1% TFA) to 75% MeCN in H 2 0 (+0.1% TFA) at a flow rate of 85 mL/min. over 35 minutes to afford the 5 desired product (290 mg, 10% yield). MS (+ESI) m/z = 490. Step 2: (±)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-1',5,7'-trioxo-l',5',7',8',9',10' hexahydro-2'H-spiro[cyclopentane-1,3'-imidazo[5,1-a][2,6]naphthyridine]-2 carboxylic acid 10 The ester from Step 1 (0.13 g, 0.25 mmol) in a mixture of THF (1.5 mL)/MeOH (0.5 mL)/water (0.5 mL) was treated with 2 M aqueous sodium hydroxide solution (0.25 mL, 0.5 mmol). The solution was stirred at room temperature for 2 h and then neutralized with an aqueous solution of 2 N HCI (0.25 mL, 0.5 mmol). The resulting 15 carboxylic acid was concentrated under reduced pressure, dissolved in CH 2

CI

2 /MeOH (90/10) and filtered. The acid was concentrated again and used directly without purification. MS (+ESI) m/z = 476. Step 3: (±)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-N-methyl-1',5',7'-trioxo 20 1',5',7',8',9',10'-hexahydro-2'H-spiro[cyclopentane-1,3'-imidazo[5,1 a] [2,6]naphthyridine]-2-carboxamide To a solution of the acid from Step 2 (35 mg, 0.074 mmol) in CH 2 Cl 2 (7 mL) was added BOP (36 mg, 0.081 mmol) followed by methylamine hydrochloride (6 mg, 0.088 25 mmol) and NN-diisopropylethylamine (0.064 mL, 0.368 mmol). The solution was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by preparative reverse phase chromatography through a SunFire Prep C 18 5 [tm 30 x 150 mm column. The compound was loaded with DMSO or methanol and eluted with 25% MeCN in H20 (+0.1% TFA) to 95% MeCN in H20 (+0.1% TFA) at a flow rate of 25 mL/min over 12 30 minutes to afford the desired product as a mixture of diastereomers (10 mg, 28% yield). MS (+ESI) m/z = 489. 35 WO 2012/058173 PCT/US2011/057557 126 EXAMPLE 40 (±)-2-[8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7'-trioxo-1',5',7',8',9' 1 0'-hexahydro-2'H spiro[cyclopentane-1,3'-imidazo[5,1-a] [2,6]naphthyridin]-2-yl]-N-methylacetamide 0 Et 0 NH 2 0 F OEt NH CI NOH N 0 OH DMA, H 2

SO

4 CI 0 Intermediate D 0 OH OH o 0 NH NaOH F/ N BOP, EtN(iPr) 2 CI 0 methylamine O OH NHMe O 0 NH FN N O OH 5 Step 1: (±)-Ethyl [8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy- ',5',7'-trioxo 1',5',7',8',9',10'-hexahydro-2'H-spiro[cyclopentane-1,3'-imidazo[5,1 a] [2,6]naphthyridin]-2-yljacetate A solution of Intermediate D (1.1 g, 3.0 mmol) in DMA (7.5 mL) was treated 10 with ethyl (2-oxocyclopentyl)acetate (2.0 g, 12 mmol) and concentrated sulfuric acid (0.16 mL, 3.0 mmol). The mixture was heated to 100 "C for 18 h. After cooling, an aqueous solution of NaHCO 3 was added, the mixture poured into a separatory funnel, and the resulting mixture extracted with CH 2

C

2 (3 x 200 mL). The combined organic layers were washed with water and brine, dried over Na 2

SO

4 , filtered and concentrated under reduced 15 pressure. The diastereomers were resolved by preparative reverse phase chromatography through a SunFire Prep C 18 5 Rm 30 x 250 mm column. The compound was loaded with DMSO or methanol and eluted with 30% MeCN in H20 (+0.1% TFA) to 75% MeCN in WO 2012/058173 PCT/US2011/057557 127

H

2 0 (+0.1% TFA) at a flow rate of 85 mL/min over 35 minutes. The diastereomerically enriched fractions were concentrated to afford the first eluting diastereomer (100 mg) and the second eluting diastereomer (60 mg). MS (+ESI) m/z = 518 (both diastereomers). 5 Step 2: (±)-[8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7'-trioxo-l',5',7',8',9',1 0' hexahydro-2'H-spiro[cyclopentane-1,3'-imidazo[5,1-a][2,6]naphthyridin]-2 yl]acetic acid A solution of first eluting diastereomeric ethyl ester from Step 1 (50 mg, 10 0.096 mmol) in a mixture of THF (0.15 mL)/MeOH (0.5 mL)/water (0.5 mL) was treated with 2 M aqueous sodium hydroxide solution (0.10 mL, 0.19 mmol). The solution was stirred at room temperature for 2 h and then neutralized with aqueous 2 M HCL solution (0.10 mL, 0.19 mmol). The crude acid was concentrated under reduced pressure, dissolved in CH 2 Cl 2 /MeOH (90/10) and filtered. The acid was concentrated again and used directly 15 without further purification. MS (+ESI) m/z = 490. Step 3: (±)-2-[8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-l',5',7'-trioxo-l',5',7',8',9',10' hexahydro-2'H-spiro[cyclopentane-1,3'-imidazo[5,1 -a][2,6]naphthyridin]-2 yl]-N-methylacetamide 20 To a solution of carboxylic acid from Step 2 (20 mg, 0.041 mmol) in CH 2 C1 2 (0.4 mL) was added BOP (20 mg, 0.045 mmol) followed by methylamine (0.022 mL, 0.045 mmol) and N,N-diisopropylethylamine (0.037 ml, 0.20 mmol). The solution was stirred at room temperature for 2 h, concentrated under reduced pressure, and purified by preparative 25 reverse phase chromatography through a SunFire Prep C18 5 pm 30 x 150 mm column. The compound was loaded with DMSO or methanol and eluted with 25% MeCN in H 2 0 (+0.1% TFA) to 95% MeCN in H 2 0 (+0.1% TFA) at a flow rate of 25 mL/min over 12 minutes. The title compound was obtained as an oil (9 mg, 44% yield). MS (+ESI) m/z= 503, 30 EXAMPLE 41 (±)-2-(8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7'-trioxo-2',5',7',8',9',I 0'-hexahydro- 1'H spiro[cyclohexane-1,3'-imidazo[5,1-a] [2,6]naphthyridin]-2-yl)-N-isopropylacetamide WO 2012/058173 PCT/US2011/057557 128 0 OEt O o NH 2 0 0 OEt NH N NH FFe~ N C1, N ' 0 FeCI 3 C!"" N 0N O OH MeCN 0 OH Intermediate D 0 0 0 ~ OH O NH C1 C1 NaOH F N 0 EtOH C N N cat. DMF C1 0 O OH O Me 0 Me O C1 H 2 N 0 N Me NH Me NH H NNA N N N. C, N 'N O OH 0 OH 5 Step 1: (±)-Ethyl 2-(8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7'-trioxo 2',5',7',8',9',10'-hexahydro-1 'H-spiro[cyclohexane-1,3'-imidazo[5,1 a] [2,6]naphthyridinj-2-yl)acetate Intermediate D (1.0 g, 2.73 mmol) was suspended in acetonitrile (20 mL) and 10 treated with ethyl 2-cyclohexanoneacetate (2.02 g, 10.94 mmol) followed by ferric (III) chloride (0.443 g, 2.73 mmol). The mixture was heated to 90 'C for 48 h under stirring. The reaction mixture was diluted with 1M aqueous HCl (8 mL) and the mixture was stirred at room temperature for 90 min. The mixture was diluted with dichloromethane (30 mL) and washed with aqueous IM HCl solution (2 x 20 mL), dried over Na 2

SO

4 , filtered and 15 evaporated to give a light brown solid. This was tritterated with hexanes and filtered to give the title compound (1.33 g, 91% yield). MS (+ESI) m/z = 532. Step 2: (±)-2-(8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7'-trioxo-2',5',7',8',9',10' hexahydro-1'H-spiro[cyclohexane-1,3'-imidazo[5,1-a][2,6]naphthyridin]-2 20 yl)acetic acid WO 2012/058173 PCT/US2011/057557 129 The ester from Step 1 (1.03 g, 1.94 mmol) was suspended in ethanol (9.7 ml) and treated with 1 M aqueous NaOH solution (7.76 mL, 7.76 mmol) and stirred at room temperature for 18 h. The reaction contents were evaporated under vacuum to give a residue which was suspended in 1 M aqueous HCl (10 mL) and filtered to give the title compound as 5 a yellow solid (0.861 g, 88% yield). MS (+ESI) m/z = 504. Step 3: (±)-2-(8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7'-trioxo-2',5',7',8'9', 10' hexahydro- I'H-spiro[cyclohexane- 1,3'-imidazo [5,1-a] [2,6]naphthyridin]-2 yl)acetic acid 10 The acid from Step 2 (0.30 g, 0.595 mmol) was suspended in dichloromethane (3 ml) and treated with oxalyl chloride (0.146 mL, 1. 67 imol) followed by DMF (14 piL). The reaction mixture was stirred at room temperature for 30 min. The reaction contents were evaporated in vacuo to afford the the title compound (0.311 g). 15 Step 4: (±)-2-(8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7-trioxo-2',5',7',8',9',10' hexahydro-1'H-spiro[cyclohexane-1,3'-imidazo[5,1-a][2,6]naphthyridin]-2 yl)-N-isopropylacetamide 20 The acid chloride from Step 3 (50 mg, 0.096 mmol) was dissolved in dichloromethane (480 pl) and treated with isopropylamine (49.2 11, 0.574 mmol) followed by N,N'-diisopropylethylamine (50.2 pl, 0.287 mmol) and stirred at room temperature for 18 h. The reaction contents were diluted with CH 2 C1 2 (1 mL), washed with with aqueous 1 M HCl solution (1 mL), dried by filtering through a hydrophobic frit and evaporating to afford 25 a residue. This residue was purified by preparative reverse phase chromatography through a SunFire C18 10 pM 30 x 150 mm column. The compound was loaded with DMSO or methanol, and eluted with 10% MeCN in H20 (+ 0.1% TFA) to 95% MeCN in H20 (+ 0.1% TFA) to afford the racemic title compound as a light yellow solid (16 mg, 31 % yield). MS (+ESI) m/z= 545. 'H NMR (400 MHz, d 6 -DMSO) 6 13.50 (s, 1H), 9.93 (s, 1H), 7.60 (m, 30 2H), 7.41 (in, 211), 4.77 (d, J= 15 Hz, 1H), 4.66 (d, J= 15 Hz, 1H), 3.70 (m, 2H), 3.55 (in, 2H), 3.35 (in, 111), 3.27 (in, 2H), 3.00 (m, 2H), 1.66 (in, 4H), 1.48 (d, J= 13 Hz, 1H), 1.27 (in, 2H), 0.97 (d, J= 6.5 Hz, 3H), 0.91 (d, J= 6.5 Hz, 3H). EXAMPLE 42 35 (+) or (-)-8'-(3-Chloro-4-fluorobenzyl)-6'-hydroxy-2,2-dimethyl-9', 1 0'-dihydro- 'H spiro[cyclopentane-1,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(2'H,8'H)-trione WO 2012/058173 PCT/US2011/057557 130 0 0 NH 2 Me 0 Me Me NH F -NHMe F X x N O o FeCl 3 M N NN 0 OH 0 OH Intermediate D second eluting enantiomer To a sealable reaction vial, was added Intermediate D (2.0 g, 5.47 mmol), anhydrous acetonitrile (40 mL), 2,2-dimethylcyclopentanone (3.43 mL, 27.3 mmol) and iron(III) choride (890 mg, 5.47 mmol). The vial was sealed and heated at 90 *C for 18 h. 5 The reaction was diluted with ethyl acetate (10 mL) and treated with 0.1 M aqueous disodium EDTA solution (8.5 mmol) and concentrated HCt (2 mL). The mixture was stirred at room temperature for 2 h and the grey precipitate was filtered through a pad of Celite. The filtrate was washed sucessively with acidified aqueous disodium EDTA, water, and brine. The combined organic layers were dried over Na 2 S0 4 , filtered, and concentrated 10 under reduced pressure. The residue was purified by preparative reverse phase chromatography through a SunFire C18 10 jiM 50 x 250 mm column. The compound was loaded with DMSO or methanol, and eluted with 25% MeCN in H20 (+ 0.1% TFA) to 80% MeCN in H20 (+ 0.1% TFA) over 30 minutes to afford the racemic title compound. The racemic mixture was separated by preparative chiral SFC to afford enantiopure title 15 compound (second eluting enantiomer). Preparative chiral separation of the enantiomers was achieved using a Chiralcel OD, 250 x 20 mm I.D column, eluting with 75 % CO 2 : 25% methanol:acetonitrile (2:1 + 0.1% Et 2 NH) at a flow rate of 50 mL/min. The purified material was partitioned between I M aqueous HCl and ethyl acetate and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over Na 2

SO

4 , filtered, and 20 concentrated under reduced pressure to afford the title compound. MS (+ESI) m/z = 460. 'H NMR (400 MHz, d 6 -DMSO) 8 13.47 (s, 1H), 9.56 (s, 1H), 7.60 (d, J= 7.2 Hz, 1H), 7.43 7.37 (m, 2H), 4.74 (d, J= 15.1 Hz, 1H), 4.68 (d, J= 15.1 Hz, 111), 3.55 (t, J= 6.4 Hz, 2H), 3.34-3.20 (in, 2H), 2.99-2.90 (m, 1H), 2.41-2.31 (m, 1H), 2.05-1.90 (m, 2H), 1.89-1.77 (in, 1H), 1.64-1.56 (m, 1H), 0.98 (s, 3 H), 0.75 (s, 3H). 25 EXAMPLES 43 TO 177 The compounds of Examples 43 to 177 were prepared in accordance with the procedures described above for the compounds of Examples 1 to 42. Table B below provides the structure, name, preparative method, and [M+1]- value for each of the 30 compounds of the present invention, numbered 1-177. Diastereomers were purified using reverse phase HPLC through a C18 column, and the final compounds are described WO 2012/058173 PCT/US2011/057557 131 according to their relative retention times on the C 18 column (e.g., first eluting or second eluting diastereomer). In all cases enantiomers were purified using normal phase SFC chromatography through an AD, AS or OD-based column, and the final compounds are described according to their relative retention times (e.g. first eluting or second eluting 5 enantiomer). In cases where starting materials required for the synthesis of these examples are not commercially available, the synthesis of the ketone or amine building blocks is described above herein. Table B Example Structure Preparative Method(s) 'ES No. SrcueUsed(ET [M+1] O Me F- NNXD 1 C Example 1 472 O OH racemic O M N 2 N N eExample 2 406 CI1 0 O OH racemic 0 N 3 N Example 3 458 N > O OH chra/i - (S) O Me 0 N 4 N N Me Example 4 504 x1 N 'N 0 O OH racemic WO 2012/058173 PCT/US2011/057557 132 N F N Me 5 Me Example 5 460 SN N SN O OH racemic 0 N 6N N Me Example 6 432 Cl ) "N;0 O OH racemic 0 N 7N Me Example 7 446 8 NMe Example 8 460 No O OH racemic 0 M N O ,Me F>A 9 N Me Example 9 400 0 OH racemic O Me N 10 F N Example 10 490 SN N SN o Br O OH o OH racemic O Me N, N0 FMe Examplel 11540 N S 0 O OH racemic WO 2012/058173 PCT/US2011/057557 133 0 N 12 F N N Example 12 424 C 0 0 OH chiral - (S) 0 N F N 13 Example 13 424 NN O OE Na ( chiral - (S) O MeO NH F N 14 N N N OExamplei4 462 O OH chiral - fourth eluting enantiomer by SFC 0 F N 15 N N Example 15 444 O OH chiral - first eluting diastereomer 0 NH F>N 16 N N Example 16 444 O OH chiral - second eluting diastereomer 0 NH F> 17 N. N N Example 17 O OH chiral - first eluting diastereomer WO 2012/058173 PCT/US2011/057557 134 0 N H ' F>N 18 N N Example 18 444 o OH chiral - second eluting diastereomer OH O N 19 F / N Example 19 502 C1 N O O OH MeN N 0 20 N Example 20 569 F / N O 0 OH chiral - second eluting enantiomer Me Et N-S4 0 0 O N 21 F N Example 21 567 C N O O OH racemic 0 NH F A N'K 22 N Example 22 428 O OH chiral - first eluting diastereomer WO 2012/058173 PCT/US2011/057557 135 0 F N 23 N / Example 23 428 O OH chiral - second eluting diastereomer ONH F // N'K 24 N O Example 24 428 F 0 OH chiral - first eluting diastereomer 0 25 F N N Example 25 428 F 0 OH chiral - second eluting diastereomer Me Me N- SsO O N 26 F N Example 26 553 CI N N O OH chiral - second eluting enantiomer Me, Me N-S O~ NI O 0 N 27 N / NN Example 27 579 O OH chiral first eluting diastereomer first eluting enantiomer WO 2012/058173 PCT/US2011/057557 136 Me Me N-SO O 0 N 28 N>N Example 28 579 O OH chiral first eluting diastereomer second eluting enantiomer OMe O 29 F X N IExample 29 502 C N O O OH chiral - first eluting diastereomer Me Me OMe N 30 F N Example 30 518 CI /4 N 4 O O OH chiral - first eluting enantiomer OMe 0 N F XN 31 C x N O Example 31 502 O OH chiral first eluting diastereomer first eluting enantiomer WO 2012/058173 PCT/US2011/057557 137 N OMe 32 C N N Example 32 530 cl: N > O OH chiral first eluting diastereomer 0 F~ N' 33F N N O Example 33 450 N 0 OH chiral - first eluting diastereomer OMe 0 OH N F N N Example 34 484 3 4 q0 O OH chiral second eluting diastereomer O Me NH 5C N NOExample 35 458 O OH chiral - first eluting diastereomer O Me NH F -~N u 36 N N Example 36 458 O OH chiral - second eluting diastereomer WO 2012/058173 PCT/US2011/057557 138 MeO O N 0 N 37 F N Example 37 581 N0 Fr C N o HO F O OH F racemic O\N 0 N 38 F N Example 38 495 C N O O OH racemic o NHMe NH 39F N Example 39 489 N 0 O OH racemic MeHN 00 N H 40 N N Example 40 503 40 N 0. O OH racemic second eluting diastereomer 0 NHiPr 0 NH 41 F N Exam ple4 l 545 N1 N . O OH racemic - mixture WO 2012/058173 PCT/US2011/057557 139 O Me Me NH F AA 42 N N O Example 42 460 0 OH chiral - second eluting enantiomer O Me N Me 43F N Me Example 1, Steps I & 2, 434 CN NthenExample 3, Step 2 O OH racemic O me N 44 FNN Me Example 420 A I) ,N t O OH OMe 0 N Me 45 F N Example 1, Step 1, then 47g A N Me Example 3, Step 2 O OH racemic O ,Me N N Me F N Me Example 1, Steps 1 & 2, 46 CIN OMe then Example 3, Steps 2 448 C N 0 & O OH racemic 0 N N N Example 5 432 NI 0 O OH racemic WO 2012/058173 PCT/US2011/057557 140 OMe Example 1, Step 1, wherein the bis-hydroxy O acid resulting from the hydrolysis of 48 F N Me Intermediate A was used 450 N as starting material for Ci x N O the coupling reaction, O OH then Example 2, Step 2 racemic with sulfuric acid/1,4 dioxane O Me N NMe F / N MMe Example 1, Steps 1 &2, 49 NMe then Example 3, Steps 2 448 O OH chiral - first elating enantiomer O Me N NMe F w N M e Example 1, Steps I & 2, 50 N Me then Example 3, Steps 2 448 C1 0 & 3 O OH chiral - second elating enantiomer O ,Me N Me F1N N OExample 2 420 N ' O OH racemic 0 NH Me F / N Me 52 N N Me Example 4, Step 1 434 O OH racemic 0 NH Me Me 53 N N OMe Example 4, Step 1 476 O OH racemic WO 2012/058173 PCT/US2011/057557 141 0 Me NH F5N -xN MeExample St1 420 ci 'N N 'N o OH 0 NH SN N EMeMe 4 57 N 0 Example 4, Step 1 432 O OH racemic O Me 0 y F N ' 56 N - Example 1 446 x N > O OH 0 NH F SN t Example 4, Step 1 432 0 OH racemic O Me N F58 F N Examplel1 460 58o O OH O jMe F59 N Example I CI > '-N 0N O OH O Me F6N0 M Examplel146 600 racemic WO 2012/058173 PCT/US2011/057557 142 O Me N 61FNN MeMe Example 1 434 mI N 0 0 OH racemic O Me N F Me 62 C N Me Example 1 448 O OH racemic O Me N 63 NN Example 1 464 O OH racemic 64 Ci "N 0 e Examplel1 460 mixture of diastereomers at amninal center Me O ) N Example 1, Steps 1 &2, F N Me then Example 2, Step 2 420 65 With sulfuric acid/1,4 Ci NO 0 dioxane O OH racemic O Me N 66 N -N Me Example 1 474 O O H 0 OH WO 2012/058173 PCT/US2011/057557 143 OEt 0 O0/ N Example 1, Steps 1 & 2, F MeN then Example 2, Step2 478 67 N with sulfuric acid/1,4 C1 N 0 dioxane O OH racemic O Me N 68 N N o Example 1 500 O OH O Me N Me N Example 1, Steps 1 & 2, 448 69C N N then Example 3, Step 2 O OH racemic O Me N Et 7 ~ N Et Example 1, Steps 1 & 2, 462 70 C N N O then Example 3, Step 2 O OH racemic N O Me F N Example 1, Steps 1 & 2, 460 71 GI N N then Example 3, Step 2 O OH racemic Me 0 N Me F / N Example 1, Steps 1 & 2, 4 72 C 1 then Example 3, Step 2 cN N N O OH racemic WO 2012/058173 PCT/US2011/057557 144 O NH CF 3 73 N / N Me Example 4, Step 1 474 0 OH racemic Me O N 74 F 460 74 N N Example 1 N 0N 0 OH 0 NH 75 N N Example 4, Step 1 432 ci NC N O OH Me Me 0 IN N Me Example 1, Steps 1 & 2, 490 76 F N OMMe then Example 3, Step 2 CID: N 0Me 0 OH racemic O Me Me N Me 77 N;/ NO Example 1 488 NI N- N 0 O OH racemic OMe 0 N 0 F N Example 1, Steps 1 & 2, 490 78 Nthen Example 3, Step 2 O OH racemic WO 2012/058173 PCT/US2011/057557 145 Me Me 0 N 79 F Example 1 488 N 10 Cl NCIO O OH o Me NH N 80 NN Example 4, Step 1 446 'N N 0 O OH racemic SMe O F Me Example 1, Steps 1 & 2, 508 81 C x NWN Me then Example 3, Step 2 O OH racemic SMe 0 N F N Example 1, Steps 1 & 2, 492 82 then Example 3, Step 2 GI N 0 O OH racemic 0 N F83NN Me Example 4 500 83 NM O OH racemic 0 N F N Example 3, Step 1, then 472 84 N Example 1, Step 3 ' N OH 0 OH WO 2012/058173 PCT/US2011/057557 146 OH O OH N Example3, Step 1,then 486 86 F N Example 1,Step3 C1 N CIDO - 0 O OH 0 U 0 0 O $TFA 87 N Example 3 531 CI> N0 O OH racemnic N OTF 88 N Example 3 529 F N N 0 O OH racemic WO 2012/058173 PCT/US2011/057557 147 0 o TFA 89 N Example 3 545 F NN CI N O 0 OH racemic OH 0 N 90FN N Example 3 488 90 O OH chiral - first eluting enantiomer 0 N OH 91N N N Example3 516 C[ xt -N? N O OH chiral, first eluting diastereomer N OH 92FN N Example 3 516 x1 N > 0 OH chiral, first eluting diastereomer 0 Os O :S-NMe2 N 93 F /N Example 3 C011 N O O OH racemic WO 2012/058173 PCT/US2011/057557 148 Me N'N \H N NH O TFA N Example 3, followed by 529 94 Examplel12 F N ' N O OH racemic OH

HF

2 C 0 N 95 N N> Example 3 512 C I N 'N O OH chiral - second eluting enantiomer second eluting diastereomer 0 N OH 96 F N Example3 502 Cl N 0 O OH racemic OH O N -N Example 3, followed by 468 97 N O Example 12 O OH racemic 0 N OH F / N Example 3, followed by 468 98 N Example 12 0 OH chiral - second eluting enantiomer WO 2012/058173 PCT/US2011/057557 149 HN-t-Bu 0 1 N 0 99 F N Example 4 531 CI N 0 O OH 0 N Me O Me 100 N, Example 4 559 ciN E O OH 0 N 0 1 101 N 0 Example 4 547 F ci N N O OH 0 DD N 0 10N 0 Example 4 561 102/1 N N O OH iHN -Me 0 r Me N, 0Example 4 561 103 F> N '0 0 OH WO 2012/058173 PCT/US2011/057557 150 0 0 N 0 104 F Example 4. 557 NN O OH chiral 0 Me' NQ O Me 105 F Example 4 573 ? N N O OH racemic Me N® & HN N 0 106 Example 4 566 N N TFA O OH 0 / ND 0 N 0 107 F N Example 4 545 N O O OH racemic 0 N OH 108FN Example 4 502 N1 N o 0 OH chiral - second eluting enantiomer WO 2012/058173 PCT/US2011/057557 151 NMe 2 0 N 0 F 1NN Example 4 503 109 C1N 0 0 OH chiral - second eluting enantiomer NMe 2 N 0 110 N N Example 4 531 N1 N 0 O OH racemic O Me N F 111 N N Example4 446 O OH chiral - third product from chiral SFC separation NO 112 F Example 4 515 C N N N > O OH chiral - second eluting enantiomer 0 NH FO N N N.O Example 4 480 113 X N 0 O OH racemic WO 2012/058173 PCT/US2011/057557 152 N 114 N Example 4 484 o OH chiral - second eluting enantiomer j OMe NH 15 NN Example 4 490 115 N N 0N O OH racemic mixture of diastereomers Me 0 0 NH 116FNN Example4 488 Cl 0 O OH racemic, mixture of diastereomers 0 o OEt NH F17 N N Example 4 518 C N N 'N 0 O OH chiral, first eluting diastereomer first eluting enantiomer 0 ON OEt NH 118F N N Example4 518 Ci ' N N 0 0 OH chiral, second eluting diastereomer first eluting enantiomer WO 2012/058173 PCT/US2011/057557 153 0 ' N OEt NH F19 N N OExample4 518 119N w O OH chiral, second eluting diastereomer second eluting enantiomer 0 Me OEt 0t N 120 F N NO Example 4 532 cr N 0 O OH racemic, first eluting diastereomer 0 Me OEt N 121 F N N Example4 532 C1N 0 O OH racemic, second eluting diastereomer o OMe NH 122 N N Example4 502 CI)O N 0 xml O OH racemic, mixture of diastereomers H O o N t-Bu NH 123 F N Example 4 531 N N 0 O OH racemic, single diastereomer WO 2012/058173 PCT/US2011/057557 154 OMe O 124 F - N Example 4 486 Ft N O o OH chiral, first eluting diastereomer 0 O Me OMe NH 125 FN > N Example4 518 C1N 0 O OH racemic, mixture

CO

2 Et 0 N 126 FN - N Example 4 530 C IN O OH racemic - first eluting diastereomer NH F N. 127 N N Example 4 458 O OH racemic - first eluting diastereomer MeO 0 O- N 128 N N Example 4 490 N NN 0 OH racemic, first eluting diastereomer WO 2012/058173 PCT/US2011/057557 155 0 OH racemic 0 N 0 Oo/ N 130 F-N Example 4 571 N 'N O O OH racemic first eluting diastereomer 0 N N 131 F Example 4 571 cl N N O O OH racemic, second eluting diastereomer HN-t-Bu 0= F ~ N 132 F N N Example 4 557 c N N 'N O OH racemic, first eluting diastereomer WO 2012/058173 PCT/US2011/057557 156 HN-t-Bu 0 F ~ N\ 133 N Example 4 557 NI N N CIDO , 0 0 OH racemic, second eluting diastereomer 0 N Me O Me 0 N 134 F N Example 4 585 C N O OH racemic, first eluting diastereomer ( 0 N Me O Me 05 N 135 F Example 4 585 C1 N N O OH racemic, second outing diastereomer NMe 2 N 136 F Example 4 followed by 469 N6NExample 12 N N N 0 OH chiral - second eluting enantiomer WO 2012/058173 PCT/US2011/057557 157 O Me NH F / N Example 4 (second eluting product from 137 N ' chiral SFC used for 412 O OH subsequent reduction) followed by Example 12 chiral - derived from second eluting product in chiral SFC separation of chioro analog O Me NH F / N Example 4 (third eluting product from chiral SFC 138 N 0 used for subsequent 412 O OH reduction) followed by Example 12 chiral - derived from third eluting product in chiral SFC separation of chioro analog o Me NH F / N Example 4 (fourth eluting product from 139 N O chiral SFC used for 412 O OH subsequent reduction) followed by Example 12 chiral - derived from fourth eluting product in chiral SFC separation of chloro analog O Me NH 14F N Example 4 followed by 426 140N > Example 12 O OH racemic, mixture 0 NH F N N Example 4 followed by 424 141 Example 12 O OH O Me Me NH F AA NExample 42 followed by 426 142'N, N ~ 0 Examplel12 0 OH chiral - second elating enantiorner WO 2012/058173 PCT/US2011/057557 158 OMe O Me Example 42 then 143 F / N Example 4, Step 2 484 N N followed by Example 12 0 O OH chiral - first eluting enantiomer OMe 0 Me Example 42 then 144 F / N Example 4, Step 2 484 F 1 N O followed by Example 12 0 O OH chiral - second eluting enantiomer 0 N 145 F N Example 4 followed by 510 N Me Example 12 'N N " 0 O OH racemic 0 0 N 146F Example 4 followed by 482 N Example 12 N N 0 O OH racemic O Me F.47 N Example 4 followed by 424 147 N N N Example 12 O OH chiral - first eluting diastereomer WO 2012/058173 PCT/US2011/057557 159 o Ye Me N F F4I Example 4 followed by 438 148 ' N O Example 12 O OH chiral - first eluting diastereomer O Me NH F l9 NN Example 4 followed by 424 19N? N o Example 12 O OH chiral - first eluting diastereomer 0 NH ''= 150F N Example 17 followed by 410 Example 12 0 OH chiral - first eluting diastereomer 0 NH F N 15 F N O O OExample 15 followed by 410 151 N N 0 Examp e 12 0 OH chiral - first eluting diastereomer 0 N H 15F NN Example 8 followed by 410 152 'N N0 Examplel12 O OH chiral - second eluting diastereomer 0 15 N Example 16 followed by 410 153'N ' Examplel12 O OH chiral - second elating diastereomer WO 2012/058173 PCT/US2011/057557 160 O OMe N H F N Example 14 (using the 154 N third eluting enantiomer) 428 O followed by Example 12 O OH third eluting compound by chiral SFC Me.

NH

2 0 $ ®TFA N 155 F N Example 20 475

C

1 N N O OH racemic Et\ (D

NH

2 O $ TFA N 156 F N Example 20 489 CI N O 0 OH racemic F F

NH

2 O $ TFA 157 N Example 20 525 F CI N N 0 0 O OH racemic WO 2012/058173 PCT/US2011/057557 161 F HD F HN O 6 TFA 158 F Example 20 551 C N > N O OH chiral F 6 F HN O $ TFA 159 N Example 20 551 F N 0 O OH racemic Me Me Me N 16 NEamle2 545 160 F Examiple 21 o OH racemic Me O-Me OsO N 161 F Example 21 533 C1 N 0 O OH racemic WO 2012/058173 PCT/US2011/057557 162 Me Me N-st N 162 F N Example 21 517 N O O OH racemic H Me Me N N- Me 0O N 163 FN Example 21 560 CI N N O OH racemic 0 NH F N 164 N N Example 22 428 F OH chiral - first eluting diastereomer 0 F N 165 FN N Example 23 428 O OH chiral - second eluting diastereomer O 0 0 N 166 N N Example 27 569 C1 N0 0 OH racemic - first eluting diastereomer WO 2012/058173 PCT/US2011/057557 163 0 O 0 N 167 N / N Example 27 569 C1 0 N N O OH racemic - second eluting diastereomer O N NN N 168 N / NN Example 27 584 cl):IN N 0 O OH racemic - first eluting diastereomer ON N$ N 169 F NN Example 27 584 C I ) N N O OH racemic - second eluting diastereomer Me9 N-S-Me 0 N Me Example 42, followed 170 F by Example 27 (Step 2 to 595 N Step 3) Ci N N N O OH racemic WO 2012/058173 PCT/US2011/057557 164 0 O $MeO N Me Example 42, followed 171 e by Example 27 (Step 2 to 585 F N Step 3) C1tO OH 0 0H racemic O 00 N Me Example 42, followed 172 by Example 27 (Step 2 to 607 F N Step 3) C N O O OH racemic OMe O F N jExample 29 followed by 468 173 NN Example 12 N ZN O OH chiral - first eluting diastereomer 0 0 N 174 F Example 31 followed by 468 N? N Example 12 O OH racemic O- Me NH 9 175 A N Example 35 followed by 424 17$N ~.Examplel12 0 OH chiral - first eluting diastereromer WO 2012/058173 PCT/US2011/057557 165 o Me N H 7' FN N Example 35 followed by 424 176 N O Example 12 O OH chiral - second eluting diastereromer HN O 0 NH 177 F Example 40 543 Ci N N O O OH racemic, mixture of diastereomers EXAMPLE 178 Assay for inhibition of HIV replication Assays for the inhibition of acute HIV-I infection of T-lymphoid cells (i.e., 5 MT4 cells) were conducted in accordance with Vacca, J..P. et al., Proc. Natl. Acad. Sci. USA 1994, 91: 4096. MT-4 cells (250,000 cells/mL) were bulk-infected with HIV (H9111B strain) at low multiplicity of infection (MOI) in + 10% FBS for 24 hours. Cells were then washed twice in serum free Roswell Park Memorial Institute medium (RPMI) and resuspended in RPMI + 10 or 50% normal human serum (NHS). Test compounds were serial-diluted in 10 DMS0 and then diluted in 10 or 50% NHS. MT-4 cells and compounds were added to a 384-well TC-treated polystyrene plate (12,000 cells and 0.25% DMSO final) using an automated liquid handler (Agilent Bravo). After 72 hours of incubation, the cell/virus suspension was mixed and samples were lysed. Viral growth was determined by HIV-1 p24 gag AlphaLISA assay (384-well Bravo automated format, Z'=0.5-0.9). Percent viral growth 15 inhibition was calculated by [I -(Signal-Min)/(Max-Min)]*100, where Min is complete inhibition by an HIV anti-viral compound and Max is viral growth in DMSO. Compound

IC

95 or IC 50 was determined by a 4-pararmeter dose response curve analysis. Representative compounds of the present invention exhibit inhibition of HIV replication in this assay (also referred to herein as the "spread assay"). For example, the compounds of Examples 1 to 9 20 and 11 to 177were tested in this assay in 50% NHS and found to have the IC95 values in Table C. The compound of Example 10 was tested in 10% NHS and its IC50 value is provided in Table C. Table C WO 2012/058173 PCT/US2011/057557 166 Cell Assay Example No. (wild type) IC95 (nM) 1 1530 2 9768 3 1070 4 227 5 1487 6 5624 7 613 8 1312 9 4463 10 *ICo= 80 (10% NIS) 11 226 12 83 13 57 14 90 15 124 16 239 17 233 18 241 19 270 20 80 21 162 22 93 23 163 24 42 25 199 26 100 27 85 28 21 29 100 30 141 WO 2012/058173 PCT/US2011/057557 167 31 42 32 67 33 89 34 44 35 126 36 83 37 261 38 1807 39 181 40 148 41 217 42 207 43 3818 44 990 45 783 46 4701 47 3477 48 4516 49 1599 50 7793 51 6834 52 3946 53 966 54 1051 55 431 56 1234 57 8339 58 1406 59 8599 60 294 61 313 62 432 WO 2012/058173 PCT/US2011/057557 168 63 1252 64 9995 65 7852 66 3411 67 3175 68 1016 69 2982 70 1853 71 7726 72 506 73 1537 74 2044 75 1623 76 550 77 601 78 507 79 1295 80 175 81 467 82 340 83 738 84 1448 85 6958 86 786 87 153 88 229 89 183 90 165 91 61 92 45 93 76 94 140 WO 2012/058173 PCT/US2011/057557 169 95 78 96 38 97 106 98 103 99 236 100 195 101 182 102 204 103 219 104 233 105 244 106 247 107 57 108 116 109 212 110 243 111 214 112 141 113 249 114 186 115 137 116 236 117 216 118 127 119 90 120 197 121 208 122 81 123 243 124 169 125 102 126 155 WO 2012/058173 PCT/US2011/057557 170 127 212 128 34 129 20 130 26 131 54 132 85 133 100 134 54 135 67 136 190 137 206 138 151 139 109 140 228 141 209 142 48 143 71 144 74 145 143 146 183 147 41 148 56 149 31 150 56 151 92 152 164 153 172 154 198 155 170 156 141 157 117 158 213 WO 2012/058173 PCT/US2011/057557 171 159 168 160 201 161 246 162 220 163 177 164 137 165 214 166 32 167 74 168 45 169 57 170 58 171 49 172 69 173 42 174 70 175 23 176 63 177 178 EXAMPLE 179 Cytotoxicity Cytotoxicity was determined by microscopic examination of the cells in each 5 well in the spread assay, wherein a trained analyst observed each culture for any of the following morphological changes as compared to the control cultures: pH imbalance, cell abnormality, cytostatic, cytopathic, or crystallization (i.e., the compound is not soluble or forms crystals in the well). The toxicity value assigned to a given compound is the lowest concentration of the compound at which one of the above changes is observed. 10 Representative compounds of the present invention that were tested in the spread assay (see Table C of Example 178) were examined for cytotoxicity up to a concentration of 10 micromolar, and no cytotoxicity was exhibited. While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, the practice of the WO 2012/058173 PCT/US2011/057557 172 invention encompasses all of the usual variations, adaptations and/or modifications that come within the scope of the following claims.

Claims (14)

1. A compound of Formula I: RSA 0 R RIA R2B R3B N R 2 A ~ N N R1BRN N R6 R1c 0 OH (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 A and R 1 B are each independently: (1) H, (2) C1-6 alkyl, (3) OH, (4) 0-C 1-6 alkyl, (5) C1-6 haloalkyl, (6) O-C1-6 haloalkyl, (7) halogen, (8) CN, (9) N(RA)RB, (10) C(O)N(RA)RB, (11) C(O)RA, (12) C(O)ORA, (13) SRA, (14) S(O)RA, (15) SO 2 RA, (16) N(RA)SO 2 RB, (17) N(RA)SO 2 N(RA)RB, (18) N(RA)C(O)RB, or (19) N(RA)C(O)C(O)N(RA)RB; or alternatively RIA and RIB are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy; RIC is: (1) H, (2) C1-6 alkyl, WO 2012/058173 PCT/US2011/057557 174 (3) O-C 1-6 alkyl, (4) C1 -6 haloalkyl, (5) 0-C1-6 haloalkyl, or (6) halogen; R2A and R2B are each independently: (1) H, (2) C1-8 alkyl, (3) C1-8 haloalkyl, or (4) C 1-8 alkyl substituted with OH, C(O)N(RA)RB, C(O)RA, CO 2 RA, or C(O)-N(RA)-C2-8 alkylene-ORB; or alternatively R2A and R2B together form oxo; R3A and R3B are each independently: (1) H, (2) fluoro, (3) C1-8 alkyl, optionally substituted with OH, O-C1-8 alkyl, O-C1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, C(O)-N(RA)-C2-8 alkylene -ORB, SRA, S(O)RA, SO 2 RA, SO 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)SO 2 RB, N(RA)SO 2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB; (4) Cl-8 haloalkyl, or (5) OH, 0-C1-8 alkyl, O-C1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, C(O)-N(RA)-C2-8 alkylene -ORB, SRA, S(O)RA, SO 2 RA, S0 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)SO2RB, N(RA)SO 2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB; alternatively R3A and R3B together form oxo; R 4 , R 5 and R 6 are defined as set forth in Part A, Part B or Part C below: (A) R 4 is: (1) H, (2) CI-g alkyl, (3) CI-8 haloalkyl, (4) C-8 alkyl substituted with OH, 0-C1-8 alkyl, O-C1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, C(O)-HetP, CO 2 RA, C(O)-N(RA)-C2-8 alkylene-ORB, SRA, S(O)RA, SO 2 RA, SO 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)SO 2 RB, N(RA)SO 2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB, (5) CycA, (6) Cl-8 alkyl substituted with CycA, WO 2012/058173 PCT/US2011/057557 175 (7) C1 -8 alkyl substituted with AryA, (8) C1-8 alkyl substituted with HetA, (9) CI -8 alkyl substituted with HetP; (10) C-8 hydroxyalkyl substituted with C1-8 haloalkyl or CycA; or (11) Het A R 5 and R 6 are each independently: (1) H, (2) C1 -8 alkyl, (3) Cl-s haloalkyl, or (4) Ci -8 alkyl substituted with OH, O-C1-8 alkyl, O-C1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, C(O)-N(RA)-C2-8 alkylene-ORB, SRA, S(O)RA, SO 2 RA, S0 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO 2 RB, N(RA)S0 2 RB, N(RA)S02N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB, (5) CycB, (6) AryB, (7) HetB, (8) CI-8 alkyl substituted with CycB, (9) CI -8 alkyl substituted with AryB, (10) Ci-s alkyl substituted with HetB, or (11) Cl-8 alkyl substituted with HetQ; or (B) R 4 and R 5 together with the atoms to which they are attached form a 4- to 8 membered fused azacycloalkyl ring which is optionally substituted with from I to 4 substituents each of which is independently: (1) CI-g alkyl, (2) C1 -8 haloalkyl, or (3) Ci-8 alkyl substituted with OH, Q-Ci-8 alkyl, O-C1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, C(O)-N(RA)-C2-8 alkylene-ORB, SRA, S(O)RA, SO 2 RA, S0 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO 2 RB, N(RA)SO2RB, N(RA)SO2N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB, (4) CycB, (5) AryB, (6) HetB, (7) C1 -8 alkyl substituted with CycB, WO 2012/058173 PCT/US2011/057557 176 (8) CI -S alkyl substituted with AryB, (9) C1 -8 alkyl substituted with HetB, or (10) CI -8 alkyl substituted with HetQ; R 6 is: (1) H, (2) C1 -8 alkyl, (3) Cl-8 haloalkyl, or (4) C1-8 alkyl substituted with OH, O-C1-8 alkyl, O-C1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, Co2RA, C(O)-N(RA)-C2-8 alkylene-ORB, SRA, S(O)RA, SO2RA, S0 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO 2 RB, N(RA)SO 2 RB, N(RA)SO 2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB, (5) CycB, (6) AryB, (7) HetB, (8) C1-8 alkyl substituted with CycB, (9) Ci-8 alkyl substituted with AryB, (10) C1-8 alkyl substituted with HetB, or (11) C1-8 alkyl substituted with HetQ; or (C) R 4 is: (1) H, (2) Cl-8 alkyl, (3) C1-8 haloalkyl, or (4) C1-8 alkyl substituted with OH, 0-C 1-8 alkyl, 0-C1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(0)RA, CO 2 RA, -C(O)HetA, C(O)N(RA)HetP, -C(O)N(R^)HetP, C(O)-N(RA)-C2-8 alkylene-ORB, SRA, S(O)RA, SO 2 RA, S0 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)SO 2 RB, N(RA)SO 2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB, (5) CycA, (6) C1-8 alkyl substituted with CycA, (7) Cl-8 alkyl substituted with AryA, (8) C1-8 alkyl substituted with HetA, or (9) Cj-8 alkyl substituted with HetP; WO 2012/058173 PCT/US2011/057557 177 R 5 and R 6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 4- to 8-membered cycloalkyl, which can be optionally fused to a benzene ring or a 5 or 6-membered heteroaryl ring, (ii) a 6- to 10-membered fused or bridged bicycloalkyl, or (iii) a 5- to 8 membered heterocyclylalkyl in which the ring heteroatom is selected from N, o and S where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted on a ring carbon with oxo and is optionally substituted with from 1 to 4 substituents each of which is independently: (1) C1-8 alkyl, (2) C1-8 haloalkyl, or (3) C1 -8 alkyl substituted with OH, 0-C1 -8 alkyl, 0-C1-8 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, C(O)-N(RA)-C2-8 alkylene-ORB, SRA, S(O)RA, SO 2 RA, S0 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)SO 2 RB, N(RA)SO 2 N(RA)RB, N(RA)C(O)N(RA)RB, or OC(O)N(RA)RB, (4) CycB, (5) AryB, (6) HetB, (7) C 1-8 alkyl substituted with CycB, (8) C1-g alkyl substituted with AryB, (9) Cl -g alkyl substituted with HetB, or (10) C1-8 alkyl substituted with HetQ; AryA is an aryl which is optionally substituted with from I to 5 substituents, wherein: (A) each of the substituents is independently: (1) C1-6 alkyl, (2) C1-6 alkyl substituted with OH, O-C1-6 alkyl, O-C1-6 haloalkyl, CN, N02, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, SRA, S(O)RA, SO 2 RA, SO 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO 2 RB, N(RA)SO 2 RB, N(RA)SO2N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB, (3) 0-C 1-6 alkyl, (4) C 1-6 haloalkyl, (5) 0-C1 -6 haloalkyl, (6) OH, (7) halogen, WO 2012/058173 PCT/US2011/057557 178 (8) CN, (9) N02, (10) N(RA)RB, (11) C(O)N(RA)RB, (12) C(O)RA, (13) C(O)-C1-6 haloalkyl, (14) C(O)ORA, (15) OC(O)N(RA)RB, (16) SRA, (17) S(O)RA, (18) SO 2 RA, (19) S0 2 N(RA)RB, (20) N(RA)SO 2 RB, (21) N(RA)SO 2 N(RA)RB, (22) N(RA)C(O)RB, (23) N(RA)C(O)N(RA)RB, (24) N(RA)C(O)C(O)N(RA)RB, or (25) N(RA)CO2RB; or (B) when there are two or more substituents on the aryl, two of the substituents are respectively located on adjacent carbons on the aryl ring and together form methylenedioxy or ethylenedioxy, and other substituents, if any, are each independently one of groups (1) to (25) as set forth in (A) above; each AryB independently has the same definition as AryA; CycA is a 3- to 8-membered monocyclic or bicyclic cycloalkyl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, OH, C 1-6 alkyl, 0-C1 -6 alkyl, C 1-6 alkyl substituted with -01-1, 0-C 1-6 alkyl, C 1-6 haloalkyl, or O-C 1-6 haloalkyl; each CycB independently has the same definition as CycA; HetA is a heteroaryl which is optionally substituted with from I to 5 substituents, each of which is independently: (1) C1-6 alkyl, (2) C1-6 alkyl substituted with OH, O-C1-6 alkyl, O-C1-6 haloalkyl, CN, N02, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, SRA, S(O)RA, S0 2 RA, S0 2 N(RA)RB, N(RA)C(O)RB, N(RA)CO2RB, N(RA)SO 2 RB, N(RA)SO 2 N(RA)RB, OC(O)N(RA)RB, N(RA)C(O)N(RA)RB, or N(RA)C(O)C(O)N(RA)RB, (3) O-C1-6 alkyl, WO 2012/058173 PCT/US2011/057557 179 (4) C1 -6 haloalkyl, (5) 0-Cl-6 haloalkyl, (6) OH, (7) halogen, (8) CN, (9) N02, (10) N(RA)RB, (11) C(0)N(RA)RB, (12) C(O)RA, (13) C(O)-C1-6 haloalkyl, (14) C(O)ORA, (15) OC(O)N(RA)RB, (16) SRA, (17) S(0)RA, (18) SO 2 RA, (19) S0 2 N(RA)RB, (20) N(RA)SO 2 RB, (21) N(RA)SO 2 N(RA)RB, (22) N(RA)C(O)RB, (23) N(RA)C(O)N(RA)RB, (24) N(RA)C(O)C(O)N(RA)RB, or (25) N(RA)CO 2 RB; each HetB independently has the same definition as HetA; HetP is (i) a 4- to 7-membered, saturated or mono-unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, 0 and S, where each S is optionally oxidized to S(O) or S(0)2 or (ii) a 6- to 10 membered saturated or mono-unsaturated, bridged or fused heterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, 0 and S, where each S is optionally oxidized to S(O) or S(0)2; and wherein the saturated or mono unsaturated heterocyclic or heterobicyclic ring is optionally substituted with a total of from I to 4 substituents, each of which is independently halogen, C1-6 alkyl, C1-6 haloalkyl, 0-C1-6 alkyl, 0-C1-6 haloalkyl, oxo, C(O)N(RA)RB, C(O)C(O)N(RA)RB, C(O)RA, Co 2 RA, SRA, S(0)RA, SO 2 RA, or S0 2 N(RA)RB; each HetQ independently has the same definition as HetP; each RA is independently H, C1-6 alkyl or C1-6 haloalkyl; each RB is independently H, C1-6 alkyl or C1-6 haloalkyl; WO 2012/058173 PCT/US2011/057557 180 each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic; and each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, 0 and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 1 0-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, 0 and S, wherein either one or both of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(0)2.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: AryA is phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently: (1) C 1-6 alkyl, (2) 0-C 1-6 alkyl, (3) Cl -6 haloalkyl, (4) O-C 1-6 haloalkyl, (5) OH, (6) halogen, (7) CN, (8) N(RA)RB, (9) C(0)N(RA)RB, (10) S(O)RA, (11) SO 2 RA, (12) N(RA)SO2RB, (13) N(RA)SO 2 N(RA)RB, (14) N(RA)C(0)RB, or (15) N(RA)C(O)C(O)N(RA)RB; and each AryB independently has the same definition as AryA; CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently OH, C1-6 alkyl, 0-C1-6 alkyl, or C1-6 alkyl substituted with O-C1-6 alkyl; WO 2012/058173 PCT/US2011/057557 181 each CycB independently has the same definition as CycA; HetA is a 5- or 6-membered heteroaromatic ring containing a total of from 1 to 3 heteroatoms independently selected from N, S and 0, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently C 1-4 alkyl, OH, 0-CI-4 alkyl, halogen, CN, C(0)N(RA)RB, C(O)RA, C(O)ORA, or SO 2 RA; each HetB independently has the same definition as HetA; HetP is a 5- or 6-membered saturated heterocyclic ring containing a total of from I to 2 heteroatoms selected from 1 to 2 N atoms, zero to 1 0 atom, and zero to 1 S atom, wherein the S atom is optionally S(0) or S02, wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently C 1-4 alkyl, oxo, C(O)N(RA)RB, C(O)RA, C0 2 RA, or S0 2 RA; and each HetQ independently has the same definition as HetP.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of Formula II: O R 4 R3A N RRA 2 A N N N R 6 R 5 16 R 0 OH (II) R1A and RIB are each independently: (1) H, (2) C1 -6 alkyl, (3) OH, (4) 0-C1 -6 alkyl, (5) C1-6 haloalkyl, (6) 0-C 1-6 haloalkyl, (7) halogen, (8) CN, (9) N(RA)RB, (10) C(0)N(RA)RB, WO 2012/058173 PCT/US2011/057557 182 (11) C(0)RA, (12) C(O)ORA, (13) SRA, (14) S(O)RA, (15) SO 2 RA; or or alternatively RIA and RIB are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy; RIC is: (1) H, (2) C1-6 alkyl, (3) 0-C1-6 alkyl, (4) C1-6 haloalkyl, (5) 0-C1 -6 haloalkyl, or (6) halogen; R2A and R3A are each independently H, fluoro, or C1-6 alkyl; R4, R 5 and R 6 are defined as set forth in Part A, Part B or Part C below: (A) R 4 is: (1) H, (2) C1-8 alkyl, (3) C1 -6 haloalkyl, (4) C1 -6 alkyl substituted with 0-C 1-6 alkyl, C(O)N(RA)RB, C(O)RA, CO 2 RA, SRA, S(O)RA, SO 2 RA, or S0 2 N(RA)RB, (5) CycA, or (6) C 1-6 alkyl substituted with CycA, one of R 5 and R 6 is H or C1-6 alkyl, and the other of R 5 and R 6 is: (1) H, (2) C1-8 alkyl, (3) C1 -6 haloalkyl, (4) C1 -6 alkyl substituted with 0-C 1-6 alkyl, C(O)N(RA)RB, C(O)RA, C0 2 RA, S(O)RA, SO 2 RA, or S0 2 N(RA)RB, (5) CycB, or (6) C1 -6 alkyl substituted with CycB; WO 2012/058173 PCT/US2011/057557 183 or (B) R 4 and R 5 together with the atoms to which they are attached form a 5- to 7 membered fused azacycloalkyl ring which is optionally substituted with from 1 to 3 substituents each of which is independently: (1) C1-6 alkyl, (2) C1 -6 haloalkyl, or (3) Ci -6 alkyl substituted with OH, 0-Ci -6 alkyl, 0-Ci-6 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO2RA, SRA, S(O)RA, or SO 2 RA, (4) CycB, or (5) C1 -6 alkyl substituted with CycB; R 6 is: (1) H, (2) Ci -8 alkyl, (3) C1-6 haloalkyl, or (4) C1-6 alkyl substituted with OH, O-CI-6 alkyl, O-C-6 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, SRA, S(O)RA, SO 2 RA, or SO 2 N(RA)RB; or (C) R 4 is as defined in Part A: R 5 and R 6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to

9-membered fused or bridged bicycloalkyl, or (iii) a 5- to 7-membered heterocyclylalkyl in which the ring atom is selected from N, 0 and S, where the S is optionally oxidized to S(O) or S(0)2; wherein the spirocyclic ring is optionally substituted on a ring carbon with oxo and is optionally substituted with from I to 3 substituents each of which is independently: (1) Cl1-6 alkyl, (2) C1-6 haloalkyl, or (3) C1-6 alkyl substituted with OH, 0-C 1-6 alkyl, 0-C 1-6 haloalkyl, CN, N(RA)RB, C(O)N(RA)RB, C(O)RA, CO 2 RA, SRA, S(O)RA, SO 2 RA, or SO 2 N(RA)RB, (4) CycB, or (5) C1-6 alkyl substituted with CycB; WO 2012/058173 PCT/US2011/057557 184 CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from 1 to 3 substituents each of which is independently OH, C1-6 alkyl, O-C1-6 alkyl, or C1-6 alkyl substituted with O-C1-6 alkyl; and each CycB independently has the same definition as CycA; 4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein: RI A and R 1 B are each independently: (1) H, (2) C 1-4 alkyl, (3) OH, (4) O-Cf-4 alkyl, (5) CF3, (6) OCF3, (7) Cl, (8) Br, (9) F, (10) CN, (11) NH2, (12) N(H)-C1.4 alkyl, (13) N(C1.4 alkyl)2, (14) C(O)NH2, (15) C(O)N(H)-C1-3 alkyl, (16) C(O)N(CJ-3 alkyl)2, (17) CH(O), (18) C(O)-C1.4 alkyl, (19) CO2H, (20) C02-C 1-4 alkyl, (21) S02H, or (22) S02-C1.4 alkyl; RIC is: (1) H, (2) C1.4 alkyl, (3) 0-C1-4 alkyl, (4) CF3, WO 2012/058173 PCT/US2011/057557 185 (5) OCF3, (6) Cl, (7) Br, or (8) F; R2A and R3A are both H; R 4 , R 5 and R 6 are defined as set forth in Part A, Part B or Part C below: (A) R 4 is: (1) H, (2) C1-4 alkyl, (3) C1-4 fluoroalkyl, (4) C1-4 alkyl substituted with O-C1-4 alkyl, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, C(0)0-C1-4 alkyl, S-C1-4 alkyl, or S02-CI-4 alkyl, (5) CycA, or (6) CH2-CycA; one of R 5 and R 6 is H or C1-4 alkyl, and the other of R5 and R 6 is: (1) H, (2) C1-8 alkyl, (3) C -4 fluoroalkyl, (4) C1-6 alkyl substituted with O-C1 -6 alkyl, (5) CycB, or (6) CH2-CycB; or (B) R 4 and R 5 together with the atoms to which they are attached form a 5- or 6-membered fused azacycloalkyl ring which is optionally substituted with from 1 to 3 substituents each of which is independently: (1) Cl-4 alkyl, (2) C 1-4 fluoroalkyl, or (3) CJ-4 alkyl substituted with O-C1-4 alkyl; R 6 is (1) H, or (2) C1-4 alkyl; or WO 2012/058173 PCT/US2011/057557 186 (C) R 4 is as defined in Part A; R 5 and R 6 together with the carbon atom to which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl which is optionally substituted on a ring carbon with oxo, or (iii) a 5- or 6-membered heterocyclylalkyl in which the ring atom is selected from N, 0 and S, where the S is optionally oxidized to S(0) or S(0)2; wherein the spirocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently: (1) C1-4 alkyl, (2) C 1-4 fluoroalkyl, or (3) C 1.4 alkyl substituted with 0-C 1-4 alkyl; CycA is a 3- to 6-membered cycloalkyl which is optionally substituted with from I to 3 substituents each of which is independently C 1-4 alkyl, 0-C1 4 alkyl, or C 1 -4 alkyl substituted with 0-C 1-4 alkyl; and CycB independently has the same definition as CycA. 5. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein: R1A and RIB are each independently: (1) H, (2) CH3, (3) CH2CH3 (4) OH, (5) OCH3, (6) CF3, (7) OCF3, (8) C1, (9) Br, (10) F, (11) CN, (12) NH2, (13) N(H)CH3, (14) N(CH3)2, WO 2012/058173 PCT/US2011/057557 187 (15) C(O)NH2, (16) C(O)N(H)CH3, (17) C(O)N(CH3)2, (18) CH(O), (19) C(O)CH3, (20) CO2H, (21) CO2CH3, (22) SO2H, or (23) SO2CH3; RIC is: (1) H, (2) CH3, (3) OCH3, (4) CF3, (5) OCF3, (6) Cl, (7) Br, or (8) F; R 4 , R 5 and R 6 are defined as set forth in Part A, Part B or Part C below: (A) R 4 is: (1) H, (2) C1 -4 alkyl, (3) CF3, (4) CH2CF3, (5) (CH2)1-3-T, wherein T is C(O)NH2, C(O)NH(CH3), C(O)N(CH3)2, CO2H, C(O)OCH3, or S02CH3, (6) (CH2)2-3-U, wherein U is OCH3 or SCH3, (7) CycA, or (8) CH2-CycA; one of R 5 and R6 is H or C1 -4 alkyl, and the other of R 5 and R 6 is: (1) H, (2) C1-8 alkyl, (3) CF3, (4) CH2CF3, WO 2012/058173 PCT/US2011/057557 188 (5) CycB, or (6) CH2-CycB; or (B) R 4 and R 5 together with the atoms to which they are attached form a 5- or 6 membered fused azacycloalkyl ring which is optionally substituted with from 1 to 3 substituents each of which is independently: (1) C1.4 alkyl, (2) CF3, (3) CH2CF3, (3) C1.4 alkyl substituted with O-C1.4 alkyl; R 6 is (1) H, or (2) C1.4 alkyl; or (C) R 4 is as defined in Part A: R 5 and R 6 together with the carbon atom to. which they are both attached form a spirocyclic ring which is (i) a 5- to 7-membered cycloalkyl, (ii) a 7- to 9-membered fused or bridged bicycloalkyl which is optionally substituted on a ring carbon with oxo, or (iii) a 5- or 6-membered heterocyclylalkyl in which the ring atom is selected from N, 0 and S, where the S is optionally oxidized to S(0) or S(0)2; wherein the spirocyclic ring is optionally substituted with from I to 3 substituents each of which is independently: (1) C 1-4 alkyl, (2) CF3, or (3) CH2CF3; CycA is a 3- to 6-membered cycloalkyl; and CycB is a 3- to 6-membered cycloalkyl. 6. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein: R IA and RIB are each independently: (1) H, (2) CH3, WO 2012/058173 PCT/US2011/057557 189 (3) Cl, (4) Br, or (5) F; RIC is: (1) H, (2) CH3, (3) Cl, (4) Br, or (5) F; and provided that at least one of RIA, RIB and RIC is other than H; R 4 , R 5 and R6 are defined as set forth in Part A, Part B or Part C below: (A) R 4 is: (1) H, (2) CH3, (3) CH2CH3, (4) CH2CH2CH3, (5) CH(CH3)2, (6) CH2CH(CH3)2, (7) CH2CF3, (8) CH2C(O)OH, (9) CH2C(O)OCH3, (10) CH2C(O)OCH2CH3, (11) CH2CH20CH3, (12) CH2CH2SCH3, (13) CycA, or (14) CH2-CycA; R5 is: (1) H, (2) CH3, (3) CH2CH3, (4) CH2CH2CH3, (5) CH(CH3)2, (6) C(CH3)3, (7) CH(CH2CH3)2, (8) CH(CH3)CH2CH3, or WO 2012/058173 PCT/US2011/057557 190 (9) C(CH2CH3)3, (10) CH2CF3, or (11) CycB; R6 is H, CH3, or CH2CH3; or (B) R 4 and R 5 together with the atoms to which they are attached form a 5- or 6 membered fused azacycloalkyl ring which is: *-N *-N or ; wherein the azacycloalkyl ring is optionally substituted with 1 or 2 substituents each of which is independently methyl or ethyl; and each asterisk (*) denotes the point of attachment to the rest of the compound; R 6 is (1) H, (2) CH3, or (3) CH2CH3; or (C) R 4 is as defined in Part A: R 5 and R 6 together with the carbon atom to which they are both attached form a spirocyclic ring which is: XD *C OS or , ; wherein the spirocyclic ring is optionally substituted with 1 or 2 methyl groups; and each asterisk (*) denotes the point of attachment to the rest of the compound; CycA is cyclopropyl; and CycB is independently cyclopropyl, cyclobutyl, or cyclopentyl. WO 2012/058173 PCT/US2011/057557 191 7. A compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein: RIA is F in the para position of the benzyl moiety; RIB is H, Cl, or Br in the ortho or meta position of the benzyl moiety; and RIC is H. 8. A compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein: in part B of the definition of R 4 , R 5 and R6: R 4 and R 5 together with the atoms to which they are attached form a fused azacycloalkyl ring which is: *-N *-NP *--N CH *- *-N C3 *CH3 * CH3,or *-N * H0 H 3 H3C ;and R 6 is (1) H, (2) CH3, or (3) CH2CH3; and in part C of the definition of R 4 , R 5 and R 6 : R 4 is (1) H, (2) CH3, (3) CH2CH3, (4) CH2CH2CH3, (5) CH(CH3)2, (6) CH2CH(CH3)2, (7) CH2C(O)OH, (8) cyclopropyl, or (9) CH2-cyclopropyl; and R 5 and R6 together with the carbon atom to which they are both attached form a spirocyclic ring which is: O >o XD *C * *> * H 3 C H 3 0 CH 3 SOH 3 * *H, * or WO 2012/058173 PCT/US2011/057557 192 9. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of Formula III: o R4 N R1A R5 RI R1B NN OR6 0 OH (III) wherein: R1A is halo; RiB is H or halo; R is H, 3 to 8-membered cycloalkyl or C 1 . 8 alkyl, wherein said 3 to 8 membered cycloalkyl group can be optionally substituted with -OH and wherein said CI 8 alkyl group is substituted with -N(C 1 . 6 akyl)-SO 2 -(C1- 6 alkyl), -O-(Cs 6 alkyl) or 3 to 8 membered cycloalkyl, wherein said 3 to 8-membered cycloalkyl substituent can be optionally substituted with -OH; R is H; and Ri is cycloalkyl, or R5 and R6, together with the common carbon atom to which they are attached, combine to form a spirocyclic ring which is: (i) a 4 to 8 membered cycloalkyl group or (ii) a 6 to 10-membered fused or bridged bicycloalkyl group, wherein said spirocyclic rings (i) and (ii) can be optionally substituted with a -O-(C< 6 alkyl) group.

10. The compound according to claim 9, wherein RIA is F and R B is H or Cl; R4 is cyclopropyl or -CH 2 CH 2 N(CH 3 )SO 2 CH 3 ; R5 is H; and RW is cyclopropyl.

11. The compound according to claim 9, wherein R A is F and R B is H or Cl; R 4 is H, -CH 2 CH 2 N(CH 3 )SO 2 CH 3 , -CH 2 CH 2 0CH 3 or: OH ;and Rs and R 6 , together with the common carbon atom to which they are attached, combine to form a spirocyclic group having the structure: WO 2012/058173 PCT/US2011/057557 193 H 3 CO // or

12. A compound according to claim 1, or an individual enantiomer or diastereomer thereof, which is selected from the group consisting of: 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9', 1 0'-dihydro-2'H spiro[bicyclo[2.2.1]heptane-2,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(8'H)-trione; 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2,3-dimethyl-2,3,9,10 tetrahydroimidazo[5,1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-3-cyclobutyl-6-hydroxy-2-(2-methoxyethyl)-3 methyl-2,3,9,1 0-tetrahydroimidazo[5,1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 3-(3-chloro-4-fluorobenzyl)-5-hydroxy-8,8-dimethyl-2,3,8,9,10,11 hexahydro-7aH-pyrido[2',1':2,3]imidazo[5,1-a][2,6]naphthyridine-4,6,13(1H)-trione; 3-(3-chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3,7a,8,9,10 hexahydropyrrolo[2',1':2,3]imidazo[5,1-a] [2,6]naphthyridine-4,6,12(1H)-trione; 3-(3-chloro-4-fluorobenzyl)-5-hydroxy-7a-methyl-2,3,8,9, 10,11-hexahydro 7aH-pyrido[2',1':2,3]imidazo[5,1-a][2,6]naphthyridine-4,6,13(1H)-trione; -3 -(3 -chloro-4-fluorobenzyl)-7a-ethyl-5-hydroxy-2,3,8,9,10,11 -hexahydro 7al-pyrido[2',1':2,3]imidazo[5,1-a] [2,6]naphthyridine-4,6,13(1H)-trione; 8-(4-fluorobenzyl)-6-hydroxy-2-methyl-3-(1-methylethyl)-2,3,9, 10 tetrahydroimidazo[5,1-a] [2,6]naphthyridine-1,5,7(8H)-trione; 8'-(2-bromo-4-fluorobenzyl)-6'-hydroxy-2'-methyl-9', 1 0'-dihydro-2'H spiro [cyclopentane- 1,3'-imidazo [5,1-a] [2,6]naphthyridine] -1 ',5',7'(8'H)-trione; 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-3-(1 -methylethyl)-2,3,9,10 tetrahydroimidazo[5,1 -a] [2,6]naphthyridine-1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2,3,3-trimethyl-2,3,9,10 tetrahydroimidazo[5,1 -a] [2,6]naphthyridine-1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-(2-methoxyethyl)-3-(1 methylethyl)-2,3,9 1 0-tetrahydroimidazo[5,1 -a] [2,6]naphthyridine-1,5,7(8H)-trione; 3 -tert-butyl-8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-2,3,9, 10 tetrahydroimidazo[5,1-a] [2,6]naphthyridine- 1,5,7(8H)-trione; 3-(3-chloro-4-fluorobenzyl)-5-hydroxy-2,3,8,9,10,1 1-hexahydro-7aH pyrido[2',1':2,3]imidazo[5,1-a][2,6]naphthyridine-4,6,13(1H)-trione; 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-(2-methoxyethyl)-3-methyl 2,3,9,10-tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-2,3-dicyclopropyl-6-hydroxy-2,3,9, 10 tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione; 3-tert-butyl-8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-2,3,9,10 tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-3-ethyl-6-hydroxy-2-methyl-2,3,9,10 tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione; 3-tert-butyl-8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2,3,9,10 tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione; 8-(3-chloro-4-fluorobenzyl)-3-(1,1-diethylpropyl)-6-hydroxy-2,3,9,10 tetrahydroimidazo [5,1-a] [2,6]naphthyridine- 1,5,7(8H)-trione; WO 2012/058173 PCT/US2O1 1/057557 194 8'-(3-chloro-4-fluorobenzyl)-6 1 -hydroxy-2'-methyl-9', l O'-dihydro-2'H spiro [cyclobutane- I ,3'-imidazo [5,1I-a] [2,6]naphthyridine] - ,5,7'(8H)-trione; 8-(3-chloro-4-fluoroben-zyl)-3-ethyl-6-hydroxy-3-methyl-2,3,9, 10 tetrahydroimidazo [5,1I-a] [2,6]naphthyridine- 1 ,5,7(8H)-trione; 8'(-hoo4furbny)-'hdoy2-ely-' I 0'-dihydro-2'H spiro [cyclopentane- 1 ,3'-imidazo[5 ,1 -a] [2,6]naphthyridine] -1 ',5',7'(8'I-)-trione; 8-(3-chloro-4-fluorobenzyl)-3-cyclobutyl-6-hydroxy-2,3 ,9, 10 tetrahydroirnidazo [5,1-a] [2,6]naphthyridine- 1,5 ,7(8Hj)-trione; 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2'-methyI-9', I 0'-dihydro-2'H spiro[cyclohexane- I ,3'-iinidazo[5, 1-a] [2,6]naphthyridine]- 1 ',5',7'(ST{)-trione; 8'-(3 -chtoro-4-fluorobenzyl)-6'-hydroxy-2'-methyl -9', 1 0'-dihydro-2'H spiro [cycloheptane- 1,3 -imidazo [5,1 -a] [2,6]naphthyridine]-l1 ,5',7'(8'fl)-trione; 8-(3-chiloro-4-fluorobenzyl)-3-cyclohutyl-6-hydroxy-2,3-dimethyl-2,3,9, 10 tetrahydroimidazo [5,1-a] [2,6]naphthyridine- 1,5 ,7(SH)-trione; 8-(3-chloro-4-fluorobenzyl)-3 -ethyl-6-hydroxy-2,3 -dimethyl-2,3 ,9, 10 tetrahydroimidazo [5,1 -a] [2,6] naphthyridine- 1,5 ,7(SU)-trione; 8-(3-cloro-4-fluorobenzyl)-6-hydroxy-2,3-dimethyl-3-propyl-2,3,9, 10 tetrahydroimidazo [5,1I-a] [2,6]naphthyridine- 1,5 ,7(8I-)-trione; 8-(3 -chloro-4-fluorobeuzyl)-6-hydroxy-2-rnethyl-4,5',9, I 0-tetrahydro-2H spiro [imidazo [5, 1-a] [2,6] naphthyhidine-3 ,3'-thiophene]- 1,5 ,7(8H)-trione; S t -(3-chloro-4-fluaorohenzyl)-6'-hydroxy-2%,3-dimethyl-9', I 0'-dihydro-2'H spiro [cyclopentane- 1,3 '-imidazo [5,1I-a] [2,6]naphthyridine] -1',5',7'(8'H)-trione; 8-(3-chloro-4-fluorobenzyl)-2-ethyl-6-hydroxy-3 -methyl-2,3,9,1 0 tetrahydroimidazo[5,1 -a][2,6]naphthyridine-1 ,5,7(8H)-trione; 8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-2,4-dimethyl-9', I 0'-dihydro-2'H spiro[cyclohexane- 1,3 '-irnidazo [5, 1-a] [2,6]naphthyridine] -1 F,5',7'(8'H)-trione; ethyl [8-(3-cbloro-4-fluorobenzyl)-6-hydroxy-3-methyl-1 ,5,7-trioxo 1, 5,7,8,9,1 0-hexahydroimidazo [5, 1-a] [2,6]naphthyridin-2(3U)-yl] acetate 8-(3-ehloro-4-fluorobenzyl)-6-hydroxy-2-methyl-3a',4t,6 t ,6a',9, I 0-hexahydro I TJ,2H-spiro[imidazo[5, 1 -a] [2,6Jnaphthyridine-3 ,2'-pentalene]- 1,5,5 ',7(3'H,8H)-tetrone 8-(3-chloro-4-tluorobenzyl)-6-hydroxy-2-methyl-3 -(1. -methyipropyl) 2,3,9,1 0-tetrahydroimidazo[5, 1-a] [2,6]naphthyridine- 1,5 ,7(8H)-trione; 8-(3 -chloro-4-fluorobenzyl)-3-( 1 -ethylpropyl)-6-hydroxy-2-rnethyl-2,3 ,9, 10 tetrahydroimidazo[5, 1-a] [2,6]naphthyridine-1 ,5,7(8H)-trione; 8-(3 -chloro-4-fluorobenzyl)-3-cyclopentyl-6-hydroxy-2-methyl-2,3 ,9, 10 tetrahydroimidazo [5,1I-a] [2,6]naphthyridine-1I,5,7(8H)-trione; 8-(3 -chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-(2-methylpropyl) 2,3,9,1 O-tetrhydroimidazo[5,1 -a] [2,6]naphthyridine- 1,5 ,7(8I{-trione; 8-(3-chloro-4-fluorobenzyl)-6-hydroxy-3-methyl-3 -(2,2,2-trifluoroethyl) 2,3,9,1 0-tetrahydroimidazo [5, 1-a] [2,6]naphthyridine-1 ,5,7(8H)-trione; 8'-(3-chloro-4-fluorobenzyl)-2'-ethyl-6'-hydroxy-9', 1 0'-dihydro-2'H spiro[cyclopentane-1I,3 t -imidazo[5,1 -a] [2,6]naphthyridine] -1',5',7'(8'H)-trione; 8'-(3 -chloro-4-iluorobenzyl)-6'-hydroxy-9', I 0'-dihydro-2'H spiro [cyclopentane- 1,3 '-imidazo [5,1 -a] [2,6]naphthyridine]-l1',5%,7'(8'H)-trione; 3-tert-butyl-8-(3 -chloro-4-fluorobenzyl)-6-hydroxy-2-(2-methylpropyl) 2,3,9,1 0-tetrahydroimidazo [5,1-a] [2,6] naplithyridine- 1,5 ,7(8H)-trione; 8'-(3-chloro-4-fluorobenz-yl)-6'-hydroxy-2',3,3-trimethyl-9', 10'-dihydro-2'H spiro[cyclohexane- 1,3 t -imidazo[5,1 -a] [2,6]naphthy'ridine] -1'S ',7'(8'F1)-trione; WO 2012/058173 PCT/US2011/057557 195 methyl [8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-1,5,7-trioxo 1,5,7,8,9,1 0-hexahydroimidazo [5,1-a] [2,6]naphthyridin-2(3 H)-yl]acetate 8'-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-(2-methylpropyl)-9', 1 0'-dihydro 2'H-spiro[cyclopentane-1,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(8'H)-trione; 8'-(3 -chloro-4-fluorobenzyl)-6-hydroxy-2-methyl-9, 1 0'-dihydro-2'H spiro[cyclopentane-1,3'-imidazo[5,1-a][2,6]naphthyridine]-1',5',7'(8'H)-trione; 3-tert-butyl-8-(3-chloro-4-fluorobenzyl)-6-hydroxy-2-[2 (methylsulfanyl)ethyl] -2,3,9,1 0-tetrahydroimidazo [5,1-a] [2,6)naphthyridine- 1,5,7(8H) trione; 8-(3-chloro-4-fluorobenzyl)-3-cyclopropyl-6-hydroxy-2-[2 (methylsulfanyl)ethyl]-2,3,9,10-tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H) trione; 8-(3-chloro-4-fluorobenzyl)-3-cyclobutyl-2-(cyclopropylmethyl)-6-hydroxy 3-methyl-2,3,9,10-tetrahydroimidazo[5,1-a][2,6]naphthyridine-1,5,7(8H)-trione; 8'-(3-chloro-4-fluorobenzyl)-2'-cyclopropyl-6'-hydroxy-9',10'-dihydro-2'H spiro[cyclopentane-1,3'-imidazo[5,1-a][2,6]naphthyridine]-l',5',7'(8'H)-trione; [8'-(3-chloro-4-fluorobenzyl)-6'-hydroxy-1',5',7'-trioxo-l',5',7',8',9',10' hexahydro-2'H-spiro[cyclopentane- 1,3'-imidazo [5,1-a] [2,6]naphthyridin]-2'-yl] acetic acid 8'-(3-chloro-4-fluorobenzyl)-2'-(cyclopropylmethyl)-6'-hydroxy-9', 10' dihydro-2'-1-spiro[cyclopentane-1,3'-imidazo[5,1-a][2,6]naphthyridine]-l',5',7'(8'H)-trione; and pharmaceutically acceptable salts thereof.

13. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims I to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. A method for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof, which comprises administering to the subject an effective amount of the compound according to any one of claims I to 12 or a pharmaceutically acceptable salt thereof

15. The method according to claim 14, wherein the HIV is HIV-1.

16. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the inhibition of HIV integrase, for the treatment or prophylaxis of infection by HIV, or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof.

17. The use according to claim 12, wherein the HIV is IV-1. WO 2012/058173 PCT/US2011/057557 196

18. The pharmaceutical composition according to claim 13, further comprising one or more additional therapeutic agents selected from lamivudine, abacavir, ritonavir and lopinavir, wherein the amounts present of: (i) the compound according to any one of claims 1-10 and (ii) the one or more additional therapeutic agents are together effective for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in the subject in need thereof.

19. The method according to claim 14 or 15, further comprising administering to the patient one or more additional therapeutic agents selected from lamivudine, abacavir, ritonavir and lopinavir, wherein the amounts administered of: (i) the compound according to any one of claims 1-10 and (ii) the one or more additional therapeutic agents are together effective for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in the subject in need thereof.