NZ793890A - Substituted pyridinone-containing tricyclic compounds, and methods using same - Google Patents

Abstract

The present invention includes substituted pyridinone-containing tricyclic compounds, and compositions comprising the same, that can be used to treat or prevent hepatitis B virus (HBV) infection in a patient. In certain embodiments, the compounds and compositions of the invention inhibit and/or reduce HBsAg secretion. uce HBsAg secretion.

Description

The present invention includes substituted pyridinone-containing tricyclic compounds, and compositions sing the same, that can be used to treat or prevent hepatitis B virus (HBV) infection in a patient. In n embodiments, the compounds and compositions of the invention inhibit and/or reduce HBsAg secretion.

NZ 793890 WO 85619 TITLE OF THE ION Substituted Pyridinone-Containing Tricyclic Compounds, and Methods Using Same CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to US. Provisional Applications No. 62/512,990, filed May 31, 2017, No. 62/506,325, filed May 15, 2017, and No. 62/418,478, filed November 7, 2016, all of which applications are incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION Hepatitis B is one of the world’s most prevalent diseases. Although most individuals resolve the infection following acute symptoms, approximately 30% of cases become chronic. 350-400 million people worldwide are estimated to have chronic hepatitis B, leading to 0.5-1 million deaths per year, due largely to the development of hepatocellular carcinoma, cirrhosis and/or other complications. Hepatitis B is caused by hepatitis B virus (HBV), a noncytopathic, liver tropic DNA virus belonging to Hepadnaviridae family.

A limited number of drugs are tly approved for the management of chronic tis B, including two ations of alpha-interferon (standard and pegylated) and five nucleoside/nucleotide analogues (lamivudine, adefovir, entecavir, udine, and tenofovir) that t HBV DNA polymerase. At present, the first-line ent choices are entecavir, tenofovir or peg-interferon alfa-2a. However, peg-interferon alfa-2a achieves desirable serological milestones in only one third of treated patients, and is frequently associated with severe side effects. vir and tenofovir e long-term or possibly lifetime stration to continuously suppress HBV ation, and may eventually fail due to emergence of drug- resistant viruses.

HBV is an ped virus with an unusual mode of replication, centering on the establishment of a covalently closed ar DNA (cchNA) copy of its genome in the host cell nucleus. Pregenomic (pg) RNA is the template for reverse transcriptional replication ofHBV DNA. The encapsidation of pg RNA, together with viral DNA polymerase, into a nucleocapsid is essential for the subsequent viral DNA synthesis.

Aside from being a critical structural component of the virion, the HBV envelope is a major factor in the disease process. In chronically infected individuals, serum levels ofHBV surface antigen (HBsAg) can be as high as 400 ug/ml, driven by the propensity for ed cells to secrete non-infectious subviral particles at levels far in excess of ious (Dane) particles.

HBsAg ses the principal antigenic determinant in HBV infection and is composed of the small, middle and large surface antigens (S, M and L, tively). These proteins are produced from a single open reading frame as three separate N-glycosylated polypeptides through utilization of alternative transcriptional start sites (for L and MS mRNAs) and initiation codons (for L, M and S).

Although the viral polymerase and HBsAg perform distinct functions, both are essential proteins for the virus to te its life cycle and be infectious. HBV lacking HBsAg is completely defective and cannot infect or cause ion. HBsAg protects the virus nucleocapsid, begins the infectious cycle, and es morphogenesis and secretion of newly forming virus from the infected cell.

People chronically infected with HBV are usually characterized by y detectable levels of circulating antibody specific to the viral capsid (HBc), with little, if any detectable levels of antibody to HBsAg. There is evidence that chronic carriers produce antibodies to HBsAg, but these antibodies are complexed with the circulating HBsAg, which can be present in mg/mL amounts in a chronic carrier’s circulation. Reducing the amount of circulating levels of HBsAg might allow any present anti-HBsA to manage the infection. Further, even if nucleocapsids free of HBsAg were to be expressed or secreted into circulation (perhaps as a result of cell death), the high levels of anti-HBc would quickly complex with them and result in their clearance. s have shown that the presence of subviral particles in a culture of infected hepatocytes may have a transactivating function on viral genomic replication, and the ating surface antigen suppresses virus-specific immune response. Furthermore, the scarcity of virus- 1c cytotoxic T lymphocytes (CTLs), that is a hallmark of chronic HBV ion, may be due to repression of MHC I tation by intracellular expression of L and M in infected hepatocytes. Existing FDA-approved therapies do not significantly affect HBsAg serum levels.

There is thus a need in the art for novel nds and/or compositions that can be used to treat and/or prevent HBV infection in a subject. In certain embodiments, the compounds reduce or minimizing levels of HBsAg, hepatitis B e-antigen (HBeAg), hepatitis B core protein, and/or pg RNA, in a HBV-infected subject. In other embodiments, the compounds can be used in patients that are HBV infected, patients who are at risk of becoming HBV, and/or patients that are infected with drug-resistant HBV. The present invention addresses this need.

BRIEF SUTVIMARY OF THE INVENTION The invention es certain compounds, as well as pharmaceutical itions comprising at least one compound of the invention and a pharmaceutically acceptable carrier.

The invention further provides a method of treating or preventing hepatitis virus infection in a subject. The invention further es a method of reducing or zing HBsAg levels in a HBV-infected subject. The invention r provides a method of reducing or minimizing HBeAg levels in a HBV-infected subject. The invention further provides a method of reducing or minimizing hepatitis core protein levels in a fected subject. The invention r provides a method of reducing or minimizing pg RNA levels in a HBV-infected subject.

The invention further provides a nd of formula (IIIa), or a salt, solvate, stereoisomer, geometric isomer, tautomer, or any mixtures thereof: wherein: R1 is selected from the group consisting of H, halo, -OR8, (R9)OR8, -C(=O)R8, - C(=O)OR8; -C(=O)NH-OR8, -C(=O)NHNHR8; -C(=O)NHNHC(=O)R8; -C(=O)NHS(=O)2R8; — CH2C(=O)OR8, -CN; -NH2, C(=O)H, -N(R8)C(=O)R10, C(=O)OR10, — N(R8)C(=O)NHR8; -NR98(=O)2R10; -P(=O)(OR8)2, -B(OR8)2, 2,5-dioxo-pyrrolidin-l-yl, 2H- tetrazolyl, 3-hydroxy-isoxazolyl, l,4-dihydrooxo-5H-tetrazol-l-yl, pyridinyl optionally substituted with C1-C6 alkyl, pyrimidinyl optionally substituted with C1-C6 alkyl, (pyridinyl)methyl, (pyrimidinyl)methyl, (pyrimidinyl)amino, bis-(pyrimidinyl)- amino, 5-R8-l,3,4,-thiadiazolyl, 5-thioxo-4,5-dihydro-lH-l,2,4-triazolyl, lH-l,2,4-triazol- -yl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and l,2,4-oxadiazolyl, R2 is selected from the group ting of =0, =NR9, =N(OR9), and =N(NR9R9), or R1 and R2 combine to form =N-O-C(=O)- or =N-N(R9)-C(=O)-, wherein the =N group is bound to the ring carbon atom marked “*”, X1 is selected from the group consisting of CR61 and N, X2 is selected from the group consisting of CR611 and N, X3 is selected from the group consisting of CR6111 and N, X4 is selected from the group consisting of CR61V and N, or either X3 and X4, or X1 and X2, combine to form - 8-, n 1-2 substituents selected from the group consisting of X1, X2, X3 and X4 are N, each of which, if present, is ally alkylated with C1-C6 alkyl if the nt carbon atom in the ring is substituted with -OH, R61, R611, R6111 and R61V are independently selected from the group consisting of H, halo, - CN, pyrrolidinyl, ally substituted C1-C6 alkyl, optionally tuted C1-C6 l, optionally tuted C3-C8 cycloalkyl, optionally substituted heterocyclyl, -OR, C1-C6 haloalkoxy, -N(R)(R), -N02, -S(=O)2N(R)(R), acyl, and C1-C6 alkoxycarbonyl, wherein each occurrence ofR is independently selected from the group consisting of H, C1-C6 alkyl, R’- substituted C1-C6 alkyl, C1-C6 hydroxyalkyl, optionally substituted (C1-C6 alkoxy)-C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, wherein each occurrence of R’ is ndently selected from the group consisting of -NH2, -C6 alkyl), -N(C1-C6 alkyl)(C1-C6 , - NHC(=O)OtBu, -N(C1-C6 alkyl)C(=O)OtBu, or a 5- or 6-membered heterocyclic group, which is optionally N—linked, or X2 is CR6H, X3 is CR“, and R611 and R6111 combine to form a divalent group selected from the group consisting of -O(CHF)O-, -O(CF2)O-, -O(CR9R9)O-, - O(CH2)(CH2)O- and -O(CH2)(CR”R”)(CH2)O-, R7 is selected from the group consisting of H, OH, halo, C1-C6 alkoxy, and optionally tuted C1-C6 alkyl, R8 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, each occurrence of R9 is independently selected from the group consisting ofH and C1-C6 alkyl, R10 is selected from the group consisting of optionally substituted C1-C6 alkyl and optionally substituted phenyl, and, each occurrence of R11 is independently selected from the group consisting of H, OH, C1- C6 alkyl, C1-C6 alkoxy, alkoxy-Cl-C6 alkyl and alkoxy-Cl-C6 alkoxy, wherein two R11 groups bound to the same carbon atom are not simultaneously OH, or two R11 groups combine with the carbon atom to which they are bound to form a moiety selected from the group consisting of C=O, C=CH2 and oxetane-3,3-diyl.

The invention further provides a compound of formula (Ia), or a salt, solvate, stereoisomer, geometric isomer, tautomer,r or any mixtures thereof: wherein: Y is selected from the group consisting of CHR5 and 0, each occurrence of R5 is independently selected from the group consisting of H, ally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, R1 is selected from the group consisting of H, halo, -OR8, -C(R9)(R9)OR8, -C(=O)R8, - C(=O)OR8; -C(=O)NH-OR8, -C(=O)NHNHR8; -C(=O)NHNHC(=O)R8; -C(=O)NHS(=O)2R8; — CH2C(=O)OR8, -CN; -NH2, -N(R8)C(=O)H, C(=O)R10, -N(R8)C(=O)OR10, — N(R8)C(=O)NHR8; -NR98(=O)2R10; -P(=O)(OR8)2, -B(OR8)2, 2,5-dioxo-pyrrolidin-l-yl, 2H- tetrazolyl, 3-hydroxy-isoxazolyl, l,4-dihydrooxo-5H-tetrazol-l-yl, pyridinyl optionally substituted with C1-C6 alkyl, pyrimidinyl optionally tuted with C1-C6 alkyl, (pyridinyl)methyl, (pyrimidinyl)methyl, (pyrimidinyl)amino, bis-(pyrimidinyl)- amino, 5-R8-l ,3,4,-thiadiazolyl, 5-thioxo-4,5-dihydro-lH-l,2,4-triazolyl, lH-l,2,4-triazol- -yl, oxadiazolyl, oxadiazolyl, and 3-R10-l,2,4-oxadiazolyl, R2 is selected from the group consisting of =0, =NR9, =N(OR9), and R9), or R1 and R2 combine to form =N-O-C(=O)- or =N-N(R9)-C(=O)-, wherein the =N group is bound to the ring carbon atom marked “*”, R3, R3,, R4 and R4, are each independently selected from the group consisting of H, alkyl- substituted oxetanyl, optionally substituted C1-C6 alkyl and ally substituted C3-C8 cycloalkyl, or one pair selected from the group consisting of R3 / R3,, R4 / R4,, and R3 / R4 combine to form a divalent group selected from the group consisting of C1-C6 alkanediyl, - (CH2)n0(CH2)n-, -(CH2)nNR9(CH2)n-, -(CH2)nS(CH2)n-, -(CH2)nS(=O)(CH2)n-, and - (CH2)nS(=O)2(CH2)n-, wherein each occurrence of n is independently ed from the group consisting of l and 2 and each divalent group is optionally substituted with at least one C1-C6 alkyl or halo, X1 is selected from the group consisting of CR61 and N, X2 is selected from the group consisting of CR611 and N, X3 is ed from the group consisting of CR6111 and N, X4 is selected from the group consisting of CR61V and N, or either X3 and X4, or X1 and X2, combine to form - 8-, wherein 0-2 substituents selected from the group consisting of X1, X2, X3 and X4 are N, each WO 85619 of which, if present, is optionally alkylated with C1-C6 alkyl if the adjacent carbon atom in the ring is substituted with -OH, R61, R611, R6111 and R61V are independently selected from the group consisting of H, halo, - CN, pyrrolidinyl, optionally substituted C1-C6 alkyl, optionally tuted C1-C6 alkenyl, optionally tuted C3-C8 cycloalkyl, optionally substituted heterocyclyl, -OR, C1-C6 haloalkoxy, -N(R)(R), -N02, -S(=O)2N(R)(R), acyl, and C1-C6 alkoxycarbonyl, wherein each occurrence ofR is independently selected from the group ting of H, C1-C6 alkyl, R’- substituted C1-C6 alkyl, C1-C6 hydroxyalkyl, optionally substituted (C1-C6 alkoxy)-C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, wherein each occurrence of R’ is independently selected from the group ting of -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), - NHC(=O)OtBu, -N(C1-C6 alkyl)C(=O)OtBu, or a 5- or 6-membered heterocyclic group, which is optionally N—linked, or X2 is CR6H, X3 is CR“, and R611 and R6111 combine to form a nt group selected from the group consisting of -O(CHF)O-, -O(CF2)O-, -O(CR9R9)O-, - O(CH2)(CH2)O- and )(CR”R”)(CH2)O-, R7 is ed from the group consisting of H, OH, halo, C1-C6 alkoxy, and optionally tuted C1-C6 alkyl, R8 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, each occurrence of R9 is independently selected from the group consisting ofH and C1-C6 alkyl, R10 is ed from the group consisting of optionally tuted C1-C6 alkyl and optionally substituted phenyl, and, each occurrence of R11 is independently selected from the group consisting of H, OH, C1- C6 alkyl, C1-C6 alkoxy, alkoxy-Cl-C6 alkyl and alkoxy-Cl-C6 alkoxy, wherein two R11 groups bound to the same carbon atom are not simultaneously OH, or two R11 groups combine with the carbon atom to which they are bound to form a moiety ed from the group consisting of C=O, C=CH2 and oxetane-3,3-diyl.

The invention further provides a compound selected from the group consisting of formula (I), (II), and (III), or a salt, solvate, stereoisomer, geometric isomer, tautomer or any mixtures thereof.

In certain embodiments, for compounds of formulas (I), (11), and/or (111), R1 is selected from the group consisting of H, halo, -OR8, -C(R9)(R9)OR8 (such as, for e, -CH20R8, such as, for example, -CH20H), -C(=O)R8, -C(=O)OR8 (such as, for e, -C(=O)OH or - C(=O)O-C1-C6 alkyl), -C(=O)NH-OR8 (such as, for example, -C(=O)NH-OH), - C(=O)NHNHR8, -C(=O)NHNHC(=O)R8; -C(=O)NHS(=O)2R8; -CH2C(=O)OR8, -CN; -NH2, — N(R8)C(=O)H; -N(R8)C(=O)R10, -N(R8)C(=O)OR10, -N(R8)C(=O)NHR8, -NR98(=O)2R10; — P(=O)(OR8)2, -B(OR8)2, 2,5-dioxo-pyrrolidin-l-yl, razolyl, oxy-isoxazolyl, l,4-dihydrooxo-5H-tetrazol-l-yl, pyridinyl optionally substituted with C1-C6 alkyl, pyrimidinyl optionally substituted with C1-C6 alkyl, (pyridinyl)methyl, (pyrimidin yl)methyl, (pyrimidinyl)amino, yrimidinyl)-amino, 5-R8-l,3,4,-thiadiazolyl, 5- thioxo-4,5-dihydro-lH-l,2,4-triazolyl, ,4-triazolyl, 1,3,4-oxadiazolyl, 1,2,4- oxadiazolyl, and 3-R10-l,2,4-oxadiazolyl.

In certain embodiments, for compounds of formulas (I), (II), and/or (III), R2 is selected from the group consisting of =0, =NR9, =N(OR9), and =N(NR9R9), or R1 and R2 combine to form =N-O-C(=O)— or =N-N(R9)-C(=O)-, wherein the =N group is bound to the ring carbon atom marked “*”.

In certain embodiments, for compounds of formulas (I), (II), and/or (III), X1 is ed from the group ting of CR61 and N, X2 is selected from the group consisting of CR611 and N, X3 is selected from the group consisting of CR and N, X4 is selected from the group consisting of CR61V and N, or either X3 and X4, or X1 and X2, combine to form -S-, wherein 0-2 substituents selected from the group consisting of X1, X2, X3 and X4 are N, each of which, if present, is optionally alkylated with C1-C6 alkyl if the nt carbon atom in the ring is substituted with —OH.

In certain ments, for compounds of formulas (I), (II), and/or (III), R61, R611, R6111 and R61V are independently selected from the group consisting of H, halo, -CN, pyrrolidinyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, ally substituted C3-C8 cycloalkyl, optionally substituted heterocyclyl, -OR, C1-C6 haloalkoxy, -N(R)(R), -N02, - S(=O)2N(R)(R), acyl, and C1-C6 alkoxycarbonyl, wherein each occurrence ofR is independently selected from the group consisting of H, C1-C6 alkyl, R’-substituted C1-C6 alkyl, C1-C6 yalkyl, optionally substituted (C1-C6 alkoxy)-C1-C6 alkyl, and optionally substituted C3- Cg cycloalkyl, wherein each occurrence of R’ is independently selected from the group consisting of -NH2, -NH(C1-C6 alkyl), -N(C1-C6 (C1-C6 alkyl), -NHC(=O)OtBu, -N(C1-C6 alkyl)C(=O)OtBu, or a 5- or 6-membered heterocyclic group, which is optionally N—linked, or X2 is CR6H, X3 is CR“, and R611 and R6111 e to form a divalent group selected from the group consisting of -O(CHF)O-, -O(CF2)O-, R9)O-, -O(CH2)(CH2)O- and — O(CH2)(CR”R”)(CH2)O-.

In certain embodiments, for compounds of formulas (I), (II), and/or (III), R7 is selected from the group consisting of H, OH, halo, C1-C6 alkoxy, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl.

In certain embodiments, for compounds of formulas (I), (II), and/or (III), R8 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted C3- Cg cycloalkyl.

In certain embodiments, for compounds of formulas (I), (II), and/or (III), each ence of R9 is independently selected from the group consisting ofH and C1-C6 alkyl.

In certain embodiments, for compounds of formulas (I), (II), and/or (III), R10 is selected from the group consisting of optionally substituted C1-C6 alkyl and optionally substituted phenyl.

In certain embodiments, for compounds of formulas (I), (II), and/or (III), each occurrence of R11 is independently selected from the group consisting of H, OH, C1-C6 alkyl, C1-C6 alkoxy, alkoxy-Cl-Cs alkyl and alkoxy-Ci-Cs alkoxy, n two R11 groups bound to the same carbon atom are not simultaneously OH, or two R11 groups combine with the carbon atom to which they are bound to form a moiety ed from the group consisting of C=O, C=CH2 and oxetane-3,3- diyl.

In certain embodiments, the compound of formula (I) is wherein: bond a is a single or double bond, wherein: (i) if bond a is a single bond, then: Y is C(=O), and M is ed from the group consisting of C(R4)(R4’) and NR8, or Y is selected from the group ting of CHRS, o, s, S(=O), S(=O)2, and NR5, and M is C(R4)(R4’), wherein, if Y is selected from the group consisting of CHRS, O, and NR5, R4 and R4, optionally combine with each other to form =0, or Y is CH, M is C(R4)(R4’), R4, is CH2, and Y and R4, form a single bond to generate cyclopropyl, (ii) if bond a is a double bond, then Y is selected from the group ting of CR5 and N, M is C(R4)(R4’), and R4, is absent, R3, R3,, R4 and R4, are each ndently selected from the group consisting of H, alkyl- substituted oxetanyl, optionally substituted C1-C6 alkyl (e.g., optionally substituted with 1-3 groups independently selected from the group consisting of F, Cl, Br, I, OH, and OMe) and optionally substituted C3-C8 lkyl (e.g., optionally substituted with 1-3 groups independently selected from the group consisting of F, Cl, Br, I, OH, and OMe), or one pair selected from the group consisting of R3 / R3,, R4 / R4,, and R3 / R4 combine to form a divalent group selected from the group consisting of C1-C6 alkanediyl, -(CH2)nO(CH2)n-, - (CH2)nNR9(CH2)n-, -(CH2)nS(CH2)n-, -(CH2)nS(=O)(CH2)n-, and -(CH2)nS(=O)2(CH2)n-, wherein each occurrence of n is independently selected from the group consisting of l and 2 and each divalent group is optionally substituted with at least one C1-C6 alkyl or halo, each ence of R5 is independently selected from the group consisting of H, ally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl.

In certain embodiments, the compound of formula (I) is a compound of formula (Ia).

In certain ments, the compound of formula (II) is wherein: R3 and R3, are each independently selected from the group consisting of H, alkyl-substituted oxetanyl, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, or R3 and R3, combine to form a divalent group selected from the group consisting of C1-C6 alkanediyl, -(CH2)nO(CH2)n-, -(CH2)nNR9(CH2)n-, -(CH2)nS(CH2)n-, -(CH2)nS(=O)(CH2)n-, and - (CH2)nS(=O)2(CH2)n-, wherein each occurrence of n is independently ed from the group 2O consisting of l and 2 and each nt group is ally substituted with at least one C1-C6 alkyl or halo.

In certain embodiments, the nd of a (III) is: wherein: R3 and R3, are each independently selected from the group consisting of H, alkyl-substituted oxetanyl, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, or R3 and R3, combine to form a divalent group selected from the group consisting of C1-C6 alkanediyl, -(CH2)nO(CH2)n-, -(CH2)nNR9(CH2)n-, -(CH2)nS(CH2)n-, -(CH2)nS(=O)(CH2)n-, and - S(=O)2(CH2)n-, wherein each occurrence of n is ndently selected from the group consisting of l and 2 and each divalent group is ally substituted with at least one C1-C6 alkyl or halo.

In certain embodiments, the compound of formula (III) is a compound of formula (IIIa) wherein 1-2 substituents selected from the group consisting of X1, X2, X3 and X4 are N. In certain embodiments, the compound of a (III) is a compound of formula (IIIb) wherein at least one applies: R1 is not -C(=O)OR8, R2 is not =0. In certain embodiments, the compound of formula (III) is a compound of formula (IIIc) embodiments, the compound of a (III) is a compound of formula (IIId) wherein X2 is CR6H, X3 is CR“, and R611 and R6111 combine to form a divalent group selected from the group consisting of -O(CHF)O-, -O(CF2)O-, -O(CR9R9)O-, -O(CH2)(CH2)O- and - O(CH2)(CRHRH)(CH2)O-. In certain ments, the compound of formula (III) is a compound of formula (IIIe) wherein R3 and R3, are each independently selected from the group consisting of H, alkyl-substituted yl, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, or R3 and R3, combine to form a divalent group selected from the group consisting of C1-C6 diyl, -(CH2)nO(CH2)n-, - (CH2)nNR9(CH2)n-, -(CH2)nS(CH2)n-, -(CH2)nS(=O)(CH2)n-, and -(CH2)nS(=O)2(CH2)n-, wherein each occurrence of n is independently selected from the group consisting of l and 2, and each nt group is optionally tuted with at least one C1-C6 alkyl or halo.

In certain embodiments, each occurrence of alkyl or cycloalkyl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, halo, -OR’ ’, phenyl and -N(R’ ’)(R’ ’), wherein each occurrence of R” is ndently H, C1-C6 alkyl or C3-C8 cycloalkyl.

In certain embodiments, each occurrence of aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, -CN, -OR, -N(R”)(R”), -N02, -S(=O)2N(R”)(R”), acyl, and C1-C6 alkoxycarbonyl, wherein each occurrence of R” is independently H, C1-C6 alkyl or C3-C8 cycloalkyl.

In certain embodiments, the compound of formula (III) or (IIIa) is selected from the (1110), and (IIIq).

In certain ments, the compound of formula (I) or (Ia) is selected from the group R4 (1y).

(Ih), and (11).

In certain embodiments, the nd of formula (II) is selected from the group consisting of: (11h), and (Hi).

In n embodiments, the compound of formula (III) is selected from the group (111p), and In certain embodiments, R1 is selected from the group consisting of optionally substituted triazolyl, optionally substituted oxadiazolyl, -C(=O)OH, -C(=O)OMe, -C(=O)OEt, -C(=O)O-nPr, -C(=O)O-iPr, -C(=O)O-cyclopentyl, and -C(=O)O-cyclohexyl.

In certain embodiments, R2 is selected from the group consisting of O, N(OH), N(Me), , and N(NH2).

In certain embodiments, R3 and R3, are each independently selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, hydroxymethyl, 2-hydroxy-ethyl, 2-methoxy-ethyl, methoxymethyl, and 2-methyl-l-methoxy- -yl. In certain embodiments, R3 and R3,, and R4 and R4,, are each independently ed from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tyl, t- butyl, ymethyl, 2-hydroxy-ethyl, 2-methoxy-ethyl, methoxymethyl, and 2-methyl-lmethoxy-propyl.

In certain embodiments, at least one applies: R3 is H, R3, is isopropyl, R3 is H, R3, is tert-butyl, R3 is methyl, R3, is isopropyl, R3 is methyl, R3, is tert-butyl, R3 is methyl, R3, is methyl, R3 is methyl, R3, is ethyl, and R3 is ethyl, R3, is ethyl. In certain embodiments, R3 and R3 are not H. In certain embodiments, R4 and R4, are H. In certain embodiments, R4 and R4, are not H. In certain embodiments, R3 / R3, combine to form a divalent group selected from the group consisting of C1-C6 alkanediyl, -(CH2)nO(CH2)n-, nNR9(CH2)n-, -(CH2)nS(CH2)n-, - (CH2)nS(=O)(CH2)n-, and -(CH2)nS(=O)2(CH2)n-, wherein each occurrence of n is ndently selected from the group consisting of l and 2 and wherein each divalent group is optionally substituted with at least one C1-C6 alkyl or halo.

In certain embodiments, when present, R61, R611, R6111 and R61V are independently selected from the group consisting of H, F, Cl, Br, I, CN, amino, methylamino, dimethylamino, methoxyethylamino, idinyl, methoxy, ethoxy, n-propoxy, isopropoxyl, n-butoxy, secbutoxy , oxy, t-butoxy, 2-methoxy-ethoxy, 2-hydroxy-ethoxy, 3 -methoxy-prop- l -yl, 3 - hydroxy-prop-l-yl, 3-methoxy-prop-l-oxy, 3-hydroxy-prop-l-oxy, 4-methoxy-but-l-yl, 4- y-but-l-yl, 4-methoxy-but-l-oxy, 4-hydroxy-but-l-oxy, 2-hydroxy-ethoxy, 3-hydroxyprop-l-yl , 4-hydroxy-but-l-yl, oxy-2,2-dimethyl-prop-l-oxy, cyclopropylmethoxy, 2,2,2- trifluoroethoxy, 2-(2-haloethoxy)-ethoxy, 2-(N-morpholino)—ethyl, 2-(N—morpholino)-ethoxy, 3- (N-morpholino)-prop-l-yl, 3-(N-morpholino)—prop-l-oxy, 4-(N-morpholino)-but-l-yl, 4-(N- morpholino)—butl-oxy, o-ethyl, 2-(NHC(=O)OtBu)-ethyl, 2-amino-ethoxy, 2- (NHC(=O)OtBu)-ethoxy, o-prop-l-yl, 3-(NHC(=O)OtBu)-prop-l-yl, 3-amino-prop-l-oxy, 3 -(NHC(=O)OtBu)-prop- l -oxy, 4-amino-but- l -yl, 4-(NHC(=O)OtBu)-but- l -yl, 4-amino-but- l - oxy, and 4-(NHC(=O)OtBu)-but- l -oxy.

In certain embodiments, X1 is CH or N. In certain ments, X4 is CH. In certain embodiments, X2 is CR6H, R611 is not H, X3 is CR“, and R6111 is not H. In certain embodiments, X1 is CH, X2 is CR6H, X3 is CR“, and X4 is CH, and one of the following applies: R611 is methoxy, R6111 is 3-methoxy-propoxy, R611 is , R6111 is oxy-propoxy; R611 is isopropyl, R6111 is 3-methoxy-propoxy, R611 is y, R6111 is methoxy, R611 is chloro, R6111 is methoxy, and R611 is cyclopropyl, R6111 is methoxy. In certain embodiments, X1 is N, X2 is CR6H, X3 is CR“, and X4 is CH, and one of the following applies: R611 is methoxy, R6111 is 3-methoxy- propoxy, R611 is chloro, R6111 is 3-methoxy-propoxy, R611 is cyclopropyl, R6111 is 3-methoxy- propoxy, R611 is methoxy, R6111 is methoxy, R611 is chloro, R6111 is methoxy, and R611 is cyclopropyl, R6111 is methoxy. In certain embodiments, X2 is CR6H, X3 is CR“, and R611 and R6111 combine to form a nt group ed from the group consisting of -O(CHF)O-, -O(CF2)O-, -O(CR9R9)O-, -O(CH2)(CH2)O-, and -O(CH2)(CR”R”)(CH2)O. In n embodiments, R7 is selected from the group consisting of H, methyl, ethyl, and fluoro.

In certain embodiments, the pharmaceutical compositions further comprise at least one additional agent useful for treating hepatitis Virus infection. In other embodiments, the at least one additional agent comprises at least one selected from the group consisting of reverse transcriptase inhibitor, capsid inhibitor, cchNA formation inhibitor, sAg ion inhibitor, oligomeric nucleotide targeted to the Hepatitis B genome, and immunostimulator. In yet other embodiments, the oligomeric nucleotide comprises one or more . In yet other embodiments, the one or more siRNAs comprise a siRNA comprising a sense sequence of nucleotide sequence of SEQ ID N01 and an antisense ce of nucleotide sequence of SEQ ID NO:2, a siRNA comprising a sense sequence of nucleotide sequence of SEQ ID N03 and an antisense sequence of nucleotide sequence of SEQ ID N04, and a siRNA comprising a sense sequence of tide ce of SEQ ID N05 and an antisense sequence of nucleotide sequence of SEQ ID NO:6. In yet other embodiments, the one or more siRNAs comprise a siRNA comprising a sense sequence of nucleotide sequence of SEQ ID N07 and an antisense sequence of nucleotide sequence of SEQ ID NO:8, a siRNA sing a sense sequence of nucleotide sequence of SEQ ID N09 and an antisense sequence of nucleotide ce of SEQ ID NO: 10, and a siRNA comprising a sense sequence of nucleotide sequence of SEQ ID NO: 11 and an antisense sequence of tide sequence of SEQ ID NO: 12. In yet other embodiments, the one or more siRNAs are formulated in a lipid rticle.

In certain embodiments, the method comprises administering to the t in need f a therapeutically effective amount of at least one nd of the invention or at least one pharmaceutical composition of the invention. In other embodiments, the at least one compound is administered to the subject in a pharmaceutically acceptable composition. In yet other embodiments, the subject is further administered at least one additional agent useful for treating the hepatitis virus ion. In yet other embodiments, the at least one additional agent ses at least one selected from the group consisting of reverse transcriptase inhibitor, capsid inhibitor, cchNA formation inhibitor, sAg secretion inhibitor, oligomeric nucleotide targeted to the Hepatitis B genome, and immunostimulator. In yet other embodiments, the oligomeric nucleotide comprises one or more siRNAs. In other embodiments, the one or more siRNAs comprise a siRNA comprising a sense sequence of nucleotide sequence of SEQ ID N01 and an antisense sequence of nucleotide sequence of SEQ ID NO:2, a siRNA comprising a sense sequence of nucleotide sequence of SEQ ID N03 and an antisense sequence of nucleotide sequence of SEQ ID N04, and a siRNA comprising a sense sequence of nucleotide sequence of SEQ ID N05 and an antisense sequence of nucleotide sequence of SEQ ID NO:6. In yet other embodiments, the one or more siRNAs comprise a siRNA comprising a sense sequence of nucleotide sequence of SEQ ID N07 and an antisense sequence of tide sequence of SEQ 2O ID NO:8, a siRNA sing a sense sequence of nucleotide sequence of SEQ ID N09 and an nse sequence of nucleotide sequence of SEQ ID NO: 10, and a siRNA comprising a sense sequence of nucleotide sequence of SEQ ID N011 and an antisense sequence of nucleotide sequence of SEQ ID NO: 12. In yet other embodiments, the one or more siRNAs are formulated in a lipid nanoparticle.

In certain embodiments, the subject is co-administered the at least one compound and the at least one additional agent. In other embodiments, the at least one compound and the at least one additional agent are coformulated. In yet other embodiments, the virus comprises hepatitis B virus (HBV).

In certain ments, the compound is at least one selected from the group consisting of es 20-26, 86-88, 108-118, 142-143, 152-167, and 171, or a salt, solvate, stereoisomer, tautomer, geometric isomer, or any es thereof. In certain embodiments, the compound is at least one ed from the group consisting of es 1-14, 15-19, 27-83, 104, 134-141, 150-151, and 168-170, or a salt, solvate, stereoisomer, tautomer, geometric isomer, or any mixtures thereof. In certain embodiments, the nd is at least one selected from the group consisting of Examples 1-88, 90-173, or a salt, e, stereoisomer, tautomer, geometric isomer, or any mixtures thereof. In certain embodiments, the compound is Example 172 or 173, or a salt, solvate, stereoisomer, tautomer, geometric isomer, or any es f. In certain embodiments, the compound is Example 89, or a salt, solvate, stereoisomer, tautomer, geometric isomer, or any mixtures thereof. In certain embodiments, the compound is any of the Examples in Tables l-3.

DETAILED DESCRIPTION OF THE INVENTION The invention s, in certain aspects, to the discovery of certain tuted tricyclic compounds that are useful to treat and/or t HBV infection and d conditions in a subject. In certain embodiments, the compounds inhibit and/or reduce HBsAg secretion in a HBV-infected subject. In other embodiments, the compounds reduce or minimize levels of at least one ed from the group consisting of HB sAg, HBeAg, hepatitis B core protein, and pg RNA, in a HBV-infected subject.

Definitions As used herein, each of the following terms has the meaning associated with it in this section.

Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the lature used herein and the laboratory procedures in animal pharmacology, pharmaceutical science, separation science and organic chemistry are those well- known and commonly employed in the art. It should be understood that the order of steps or order for performing certain actions is immaterial, so long as the t teachings remain operable. er, two or more steps or actions can be conducted simultaneously or not.

The following non-limiting abbreviations are used herein: cchNA, covalently closed circular DNA, HBc, hepatitis B capsid, HBV, hepatitis B virus, HBeAg, hepatitis B e-antigen, HBsAg, hepatitis B virus surface antigen, pg RNA, pregenomic RNA.

As used herein, the articles “a” and “an” refer to one or to more than one (1'.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

As used herein, the term “alkenyl,” employed alone or in combination with other terms, means, unless otherwise stated, a stable monounsaturated or diunsaturated straight chain or branched chain hydrocarbon group haVing the stated number of carbon atoms. Examples include Vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, l,3-pentadienyl, l,4-pentadienyl, and the higher homologs and isomers. A functional group representing an alkene is exemplified by -CH2-CH=CH2.

As used herein, the term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group haVing the designated number of carbon atoms, as defined elsewhere herein, connected to the rest of the molecule Via an oxygen atom, such as, for example, methoxy, ethoxy, l-propoxy, 2-propoxy (or isopropoxy) and the higher gs and isomers. A c example is (C1-C3)alkoxy, such as, but not limited to, ethoxy and methoxy.

As used herein, the term “alkyl” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon haVing the number of carbon atoms ated (1'.e., C1-C10 means one to ten carbon atoms) and includes straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, pyl, butyl, yl, lerl—butyl, , neopentyl, hexyl, and cyclopropylmethyl. A specific embodiment is )alkyl, such as, but not d to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmethyl.

As used herein, the term yl” employed alone or in combination with other terms means, unless otherwise stated, a stable straight chain or branched chain hydrocarbon group with a triple carbon-carbon bond, haVing the stated number of carbon atoms. Non-limiting examples e ethynyl and propynyl, and the higher homologs and isomers. The term “propargylic” refers to a group exemplified by -CH2-CECH. The term “homopropargylic” refers to a group exemplified by -CH2CH2-CECH.

As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and haVing aromatic character, i.e., having (4n+2) delocalized 1: (pi) electrons, where ‘n’ is an integer.

As used herein, the term “aryl” employed alone or in combination with other terms means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be ed together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl and naphthyl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more ted or lly saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5- trienyl, or indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.

As used herein, the term “aryl-(C1-C6)alkyl” refers to a functional group wherein a one to six carbon alkanediyl chain is attached to an aryl group, e.g., -CH2CH2-phenyl or -CH2-phenyl (or benzyl). Specific examples are aryl-CH2- and aryl-CH(CH3)-. The term “substituted aryl- (C1-C6)alkyl” refers to an aryl-(Cl-C6)alkyl functional group in which the aryl group is substituted. A specific example is substituted aryl(CH2)-. Similarly, the term “heteroaryl-(C1- C6)alkyl” refers to a functional group wherein a one to three carbon alkanediyl chain is attached to a heteroaryl group, e.g., -CH2CH2-pyridyl. A specific example is heteroaryl-(CH2)-. The term “substituted heteroaryl-(Cl-C6)alkyl” refers to a heteroaryl-(Cl-C6)alkyl onal group in which the heteroaryl group is substituted. A specific example is substituted heteroaryl-(CH2)-.

In one aspect, the terms “co-administered” and “co-administration” as relating to a subject refer to administering to the subject a nd and/or composition of the invention along with a compound and/or composition that may also treat or prevent a disease or disorder plated herein. In certain embodiments, the co-administered compounds and/or compositions are administered separately, or in any kind of combination as part of a single therapeutic approach. The co-administered compound and/or composition may be formulated in any kind of combinations as mixtures of solids and s under a variety of solid, gel, and liquid formulations, and as a solution.

As used herein, the term “cycloalkyl” by itself or as part of another substituent refers to, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (1'.e., C3-C6 refers to a cyclic group comprising a ring group consisting of three to six carbon atoms) and es ht, branched chain or cyclic substituent groups. Examples of (C3-C6)cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl rings can be optionally substituted. Non-limiting examples of cycloalkyl groups include: ropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, entadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, methylcyclopentyl, 3,5-dichlorocyclohexyl, 4- ycyclohexyl, 3,3,5-trimethylcyclohex-l-yl, octahydropentalenyl, octahydro- 1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-indenyl, decahydroazulenyl, bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro- lH—fluorenyl. The term “cycloalkyl” also includes bicyclic hydrocarbon rings, miting examples of which include, bicyclo-[2. l . l]hexanyl, bicyclo[2.2. l]heptanyl, bicyclo[3 . l . anyl, l,3-dimethyl[2.2. l] heptanyl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

As used herein, a “disease” is a state of health of a t wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject’s health continues to deteriorate.

As used herein, a “disorder” in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject’s state of health.

As used herein, the term “halide” refers to a halogen atom bearing a negative charge.

The halide anions are fluoride (F_), chloride (Cl_), bromide (Br_), and iodide (1—).

As used , the term “halo” or en” alone or as part of another substituent refers to, unless ise stated, a fluorine, ne, bromine, or iodine atom.

As used herein, the term “heteroalkenyl” by itself or in combination with another term refers to, unless otherwise stated, a stable straight or branched chain saturated or diunsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples include -CH=CH- O-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, and -CH2-CH=CH- As used herein, the term “heteroalkyl” by itself or in combination with another term refers to, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quatemized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including n the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the alkyl group. Examples include: -OCH2CH2CH3, -CH2CH2CH20H, -CH2CH2NHCH3, - CHZSCHZCHg, and -CH2CHZS(=O)CH3. Up to two heteroatoms may be utive, such as, for example, -CH2NH-OCH3, or -CH2CH2$SCH3.

As used herein, the term “heteroaryl” or “heteroaromatic” refers to a heterocycle haVing aromatic character. A clic heteroaryl may include one or more rings that are partially saturated. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuryl.

As used herein, the term “heterocycle” or “heterocyclyl” or “heterocyclic” by itself or as part of another substituent refers to, unless otherwise stated, an unsubstituted or substituted, stable, mono- or multi-cyclic heterocyclic ring system that comprises carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quatemized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure. A heterocycle may be aromatic or omatic in . In certain embodiments, the heterocycle is a heteroaryl.

Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, ydrofuran, thiophane, dine, l,2,3,6-tetrahydropyridine, l,4-dihydropyridine, piperazine, morpholine, rpholine, pyran, hydropyran, ydropyran, l,4-dioxane, l,3-dioxane, homopiperazine, peridine, l,3-dioxepane, 4,7-dihydro-l,3-dioxepin and thyleneoxide.

Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, lyl, isothiazolyl, l,2,3-triazolyl, l,2,4-triazolyl, l,3,4-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, l,2,3-oxadiazolyl, l,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4-, -, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, l- and 5-isoquinolyl), l,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, l,8-naphthyridinyl, 1,4- benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, l,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not d to, othiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.

The entioned listing of heterocyclyl and heteroaryl moieties is intended to be representative and not limiting.

As used herein, the term “pharmaceutical composition” or “composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a subject.

As used herein, the term aceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound useful within the invention, and is relatively non-toxic, 1'. e., the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or orting a compound useful within the invention within or to the subject such that it may perform its intended function. lly, such constructs are d or transported from one organ, or portion of the body, to another organ, or portion of the body.

Each carrier must be “acceptable” in the sense of being compatible with the other ients of the formulation, including the compound useful within the invention, and not injurious to the subject. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, e and sucrose, starches, such as corn starch and potato , cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl ose and ose acetate, powdered anth, malt, n, talc, excipients, such as cocoa butter and suppository waxes, oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols, such as propylene glycol, polyols, such as in, sorbitol, mannitol and polyethylene , esters, such as ethyl oleate and ethyl laurate, agar, buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; ate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

As used herein; “pharmaceutically acceptable carrier” also includes any and all coatings; cterial and antifungal agents; and tion delaying agents; and the like that are ible with the activity of the compound useful within the invention; and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described; for example in Remington’s ceutical Sciences (Genaro; Ed; Mack Publishing Co.; 1985; ; PA); which is incorporated herein by reference.

As used herein; the language “pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and/or bases; including inorganic acids; inorganic bases; c acids; inorganic bases; solvates (including hydrates) and clathrates thereof.

As used herein; a “pharmaceutically effective amount; 77 (4therapeutically effective ” or “effective amount” of a compound is that amount of compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered.

The term “prevent; 77 (Lpreventing” or “prevention” as used herein means avoiding or delaying the onset of symptoms associated with a disease or condition in a subject that has not developed such ms at the time the stering of an agent or compound commences.

Disease; condition and er are used interchangeably herein.

By the term “specif1cally bind” or “specifically binds” as used herein is meant that a first molecule preferentially binds to a second le (e.g.; a ular receptor or enzyme); but does not necessarily bind only to that second molecule.

As used herein; the terms “subject” and idual” and “patient” can be used interchangeably and may refer to a human or non-human mammal or a bird. Non-human mammals include; for example; livestock and pets; such as ovine; bovine; porcine; canine; feline and murine mammals. In certain embodiments; the subject is human.

As used herein, the term “substituted” refers to that an atom or group of atoms has replaced hydrogen as the substituent attached to r group.

As used herein, the term “substituted ” “substituted cycloalkyl,” “substituted alkenyl” or “substituted alkynyl” refers to alkyl, cycloalkyl, alkenyl or alkynyl, as defined elsewhere herein, substituted by one, two or three substituents independently selected from the group consisting of halogen, -OH, alkoxy, tetrahydroH-pyranyl, -NH2, -NH(C1-C6 alkyl), - N(C1-C6 alkyl)2, l-methyl-imidazolyl, pyridinyl, nyl, pyridinyl, -C(=O)OH, - C(=O)O(C1-C6)alkyl, trifluoromethyl, -CEN, -C(=O)NH2, -C(=O)NH(C1-C6)alkyl, - C(=O)N((C1-C6)alkyl)2, -SOzNH2, -SOZNH(C1-C6 alkyl), C1-C6 alkyl)2, -C(=NH)NH2, and -N02, in certain embodiments containing one or two tuents independently selected from n, -OH, alkoxy, -NH2, romethyl, -N(CH3)2, and -C(=O)OH, in certain embodiments independently ed from halogen, alkoxy and -OH. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and 3- chloropropyl.

For aryl, aryl-(Cl-C3)alkyl and heterocyclyl groups, the term “substituted” as applied to the rings of these groups refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In certain embodiments, the substituents vary in number between one and four. In other ments, the substituents vary in number between one and three. In yet another embodiments, the substituents vary in number between one and two. In yet other ments, the substituents are independently selected from the group consisting of C1-C6 alkyl, -OH, C1-C6 alkoxy, halo, amino, acetamido and nitro. As used herein, where a tuent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic.

Unless otherwise noted, when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R2 and R3 taken together with the nitrogen to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., l to 3) onal heteroatoms independently selected from nitrogen, oxygen, or sulfur. The ring can be saturated or partially saturated, and can be optionally substituted.

Whenever a term or either of their prefix roots appear in a name of a substituent the name is to be interpreted as including those limitations provided herein. For example, whenever the term ” or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, mino) the name is to be interpreted as including those tions given elsewhere herein for “alkyl” and “aryl” respectively.

In certain embodiments, substituents of nds are disclosed in groups or in .

It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2- C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

The terms “treat,77 (Ltreating” and “treatment,” as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a t by virtue of administering an agent or compound to the subject.

Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and y and should not be construed as an ble limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range.

For example, ption of a range such as from 1 to 6 should be ered to have specifically sed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 2O 3 to 6 etc., as well as individual and partial numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

Compounds The invention includes certain compound recited herein, as well as any salt, solvate, geometric isomer (such as, in a non-limiting example, any geometric isomer and any mixtures thereof, such as, in a non-limiting e, mixtures in any proportion of any geometric isomers thereof), stereoisomer (such as, in a non-limiting example, any enantiomer or diastereoisomer, and any mixtures thereof, such as, in a miting example, mixtures in any proportion of any enantiomers and/or diastereoisomers thereof), tautomer (such as, in a non-limiting example, any tautomer and any mixtures thereof, such as, in a non-limiting e, mixtures in any proportion of any tautomers thereof), and any mixtures thereof.

The invention includes a compound of formula (I), or a salt, e, geometric isomer, stereoisomer, tautomer, and any mixtures thereof: YIM’ (I), wherein: A is selected from the group consisting of null (1'.e., the two atoms bonded to A are ly bonded through a chemical bond) and CR9R9, R1 is ed from the group consisting of H, halo, -OR8, -C(R9)(R9)OR8 (such as, for example, -CH20R8, such as, for example, -CH20H), -C(=O)R8, OR8 (such as, for example, -C(=O)OH or -C(=O)O-C1-C6 alkyl), -C(=O)NH-OR8 (such as, for example, - C(=O)NH-OH), -C(=O)NHNHR8; -C(=O)NHNHC(=O)R8; -C(=O)NHS(=O)2R8; — CH2C(=O)OR8, -CN; -NH2, -N(R8)C(=O)H, -N(R8)C(=O)R10, -N(R8)C(=O)OR10, — N(R8)C(=O)NHR8; -NR98(=O)2R10; -P(=O)(OR8)2, -B(OR8)2, 2,5-dioxo-pyrrolidin-l-yl, 2H- tetrazolyl, 3-hydroxy-isoxazolyl, l,4-dihydrooxo-5H-tetrazol-l-yl, pyridinyl optionally substituted with C1-C6 alkyl, pyrimidinyl ally tuted with C1-C6 alkyl, (pyridinyl)methyl, idinyl)methyl, (pyrimidinyl)amino, bis-(pyrimidinyl)- amino, 5-R8-l,3,4,-thiadiazolyl, 5-thioxo-4,5-dihydro-lH-l,2,4-triazolyl, lH-l,2,4-triazol- 5-yl, l,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 3-R10-l,2,4-oxadiazolyl, R2 is selected from the group consisting of =0, =NR9, =N(OR9), and =N(NR9R9), or R1 and R2 combine to form =N—O-C(=O)- or =N—N(R9)-C(=O)-, wherein the =N group is bound to the ring carbon atom marked “*”, M is selected from the group ting of C(R4)(R4’) and NR8, bond a is a single or double bond, wherein: (i) if bond at is a single bond, then: Y is C(=O), and M is selected from the group consisting of C(R4)(R4’) and NR8, or Y is selected from the group consisting of CHRS, O, S, S(=O), S(=O)2, and NR5, and M is C(R4)(R4’), wherein, if Y is selected from the group consisting of CHRS, O, and NR5, R4 and R4, optionally combine with each other to form =0, or Y is CH, M is C(R4)(R4’), R4, is CH2, and Y and R4, form a single bond to generate cyclopropyl, (ii) if bond a is a double bond, then Y is selected from the group consisting of CR5 and N, M is R4’), and R4, is absent; R3, R3,, R4 and R4, are each independently selected from the group consisting of H, alkyl- substituted oxetanyl, optionally substituted C1-C6 alkyl (e.g., optionally substituted with 1-3 groups independently ed from the group consisting of F, Cl, Br, I, OH, and OMe) and optionally substituted C3-C8 cycloalkyl (e.g., optionally substituted with 1-3 groups independently selected from the group consisting of F, Cl, Br, I, OH, and OMe), or one pair selected from the group consisting of R3 / R3,, R4 / R4,, and R3 / R4 combine to form a divalent group selected from the group consisting of C1-C6 alkanediyl, -(CH2)nO(CH2)n-, -(CH2)nNR9(CH2)n-, nS(CH2)n-, -(CH2)nS(=O)(CH2)n-, and - (CH2)nS(=O)2(CH2)n-, wherein each occurrence of n is independently selected from the group consisting of l and 2 and each divalent group is ally substituted with at least one C1-C6 alkyl or halo, each occurrence of R5 is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally tuted C3-C8 cycloalkyl, X1 is selected from the group consisting of CR61 and N, X2 is selected from the group consisting of CR611 and N, X3 is selected from the group consisting of CR6111 and N, X4 is selected from the group consisting of CR61V and N, or either X3 and X4, or X1 and X2, combine to form -S-, wherein 0-2 substituents selected from the group consisting of X1, X2, X3 and X4 are N, each of which, if present, is ally alkylated with C1-C6 alkyl if the adjacent carbon atom in the ring is substituted with -OH, R61, R611, R6111 and R61V are ndently selected from the group consisting of H, halo, -CN, pyrrolidinyl, ally substituted C1-C6 alkyl (e.g., C1-C6 hydroxyalkyl, alkoxy-Cl-C6 alkyl, and/or C1-C6 haloalkyl), optionally substituted C1-C6 alkenyl, optionally substituted C3-C8 cycloalkyl, optionally substituted heterocyclyl (e.g., morpholinyl), -OR, C1-C6 haloalkoxy, - ), -N02, -S(=O)2N(R)(R), acyl, and C1-C6 alkoxycarbonyl, wherein each occurrence ofR is independently selected from the group ting of H, C1-C6 alkyl, R’-substituted C1-C6 alkyl, C1-C6 hydroxyalkyl, optionally substituted WO 85619 (C1-C6 )-C1-C6 alkyl, and ally substituted C3-C8 cycloalkyl, wherein each occurrence of R’ is independently selected from the group consisting of -NH2, -C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NHC(=O)OtBu, -N(C1-C6 alkyl)C(=O)OtBu, or a 5- or ered heterocyclic group (such as, but not limited to, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and so forth), which is optionally N- linked; or X2 is CR6H, X3 is CR“, and R611 and R6111 combine to form a divalent group selected from the group consisting of -O(CHF)O-, -O(CF2)O-, -O(CR9R9)O-, - O(CH2)(CH2)O- and -O(CH2)(CR”R”)(CH2)O-; R7 is selected from the group consisting of H, OH, halo, C1-C6 alkoxy, optionally substituted C1-C6 alkyl (e. g., optionally tuted with 1-3 independently selected halo groups), and optionally substituted C3-C8 cycloalkyl, R8 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, each occurrence of R9 is independently ed from the group consisting ofH and C1-C6 alkyl (e. g., methyl or ethyl), R10 is selected from the group consisting of optionally substituted C1-C6 alkyl and optionally tuted phenyl, and, each occurrence of R11 is independently selected from the group consisting of H, OH, C1-C6 alkyl, C1-C6 alkoxy, alkoxy-Cl-C6 alkyl and alkoxy-Cl-C6 alkoxy, wherein two R11 groups bound to the same carbon atom are not simultaneously OH, or two R11 groups combine with the carbon atom to which they are bound to form a moiety selected from the group consisting of C=O, C=CH2 and oxetane-3,3-diyl.

In n embodiments, the compound of formula (I) is a compound of formula (Ia), or a salt, solvate, geometric , stereoisomer, tautomer, and any mixtures thereof: (Ia), wherein: Y is selected from the group consisting of CHR5 and O, and R7 is ed from the group consisting of H, OH, halo, C1-C6 alkoxy, and optionally substituted C1-C6 alkyl.

In certain embodiments, the compound of formula (I) is a compound of formula compound of formula R6IV Y ‘ R4' formula (I) is a compound of formula R4 compound of formula (I) is a compound of formula embodiments, the compound of formula (I) is a compound of formula In yet other ments, the nd of formula (I) is a compound of formula compound of formula formula (I) is a compound of formula (Ii).

In certain embodiments, the compound of formula (I) is a compound of formula of formula R4 (1k). In yet other embodiments, the nd of formula (I) is a compound of formula R4 (11). In yet other embodiments, the compound of formula (I) is a compound of formula the compound of formula (I) is a compound of formula ments, the compound of formula (I) is a compound of formula (Io). In yet other embodiments, the compound of formula (I) is a nd of formula (Ip). In yet other embodiments, the compound of formula (I) is a -3 2- compound of formula (Iq).

In certain embodiments, the compound of formula (I) is a compound of formula of formula is a compound of formula formula (I) is a compound of formula (Iu). In yet other embodiments, the compound of formula (I) is a compound of a other embodiments, the compound of formula (I) is a compound of formula compound of formula a (I) is a compound of formula (1y).

The invention includes a compound of formula (II), or a salt, solvate, geometric isomer, stereoisomer, tautomer and any mixtures thereof: (11), n: R1 is selected from the group consisting of H, halo, -OR8, -C(R9)(R9)OR8 (such as, for example, -CH20R8, such as, for example, -CH20H), -C(=O)R8, -C(=O)OR8 (such as, for example, -C(=O)OH or -C(=O)O-C1-C6 alkyl), -C(=O)NH-OR8 (such as, for example, - C(=O)NH-OH), -C(=O)NHNHR8; -C(=O)NHNHC(=O)R8; -C(=O)NHS(=O)2R8; n CH2C(=O)OR8, -CN; -NH2, -N(R8)C(=O)H, -N(R8)C(=O)R10, -N(R8)C(=O)OR10, — N(R8)C(=O)NHR8; -NR98(=O)2R10; -P(=O)(OR8)2, -B(OR8)2, 2,5-dioxo-pyrrolidin-l-yl, 2H- tetrazolyl, 3-hydroxy-isoxazolyl, l,4-dihydrooxo-5H-tetrazol-l-yl, pyridinyl optionally tuted with C1-C6 alkyl, pyrimidinyl optionally substituted with C1-C6 alkyl, (pyridinyl)methyl, (pyrimidinyl)methyl, (pyrimidinyl)amino, bis-(pyrimidinyl)- amino, 5-R8-l,3,4,-thiadiazolyl, 5-thioxo-4,5-dihydro-lH-l,2,4-triazolyl, lH-l,2,4-triazol- -yl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 3-R10-l,2,4-oxadiazolyl, R2 is selected from the group consisting of =0, =NR9, =N(OR9), and =N(NR9R9), or R1 and R2 combine to form =N—O-C(=O)- or 9)-C(=O)-,wherein the =N group is bound to the ring carbon atom marked “*”, R3 and R3, are each independently selected from the group consisting of H, alkyl-substituted oxetanyl, optionally substituted C1-C6 alkyl (e.g., optionally substituted with 1-3 groups independently selected from the group consisting of F, Cl, Br, I, OH, and OMe) and optionally substituted C3-C8 cycloalkyl (e.g., optionally substituted with 1-3 groups independently selected from the group consisting of F, Cl, Br, I, OH, and OMe), or R3 and R3, combine to form a divalent group selected from the group consisting of C1-C6 alkanediyl, -(CH2)nO(CH2)n-, nNR9(CH2)n-, -(CH2)nS(CH2)n-, - (CH2)nS(=O)(CH2)n-, and -(CH2)nS(=O)2(CH2)n-, wherein each occurrence of n is ndently selected from the group consisting of l and 2 and each nt group is ally substituted with at least one C1-C6 alkyl or halo, X1 is selected from the group consisting of CR61 and N, X2 is selected from the group consisting of CR611 and N, X3 is selected from the group consisting of CR6111 and N, X4 is selected from the group consisting of CR61V and N, or either X3 and X4, or X1 and X2, combine to form -S-, wherein 0-2 tuents selected from the group ting of X1, X2, X3 and X4 are N, each of which, if t, is optionally alkylated with C1-C6 alkyl if the adjacent carbon atom in the ring is substituted with -OH, R61, R611, R6111 and R61V are independently selected from the group consisting of H, halo, -CN, pyrrolidinyl, optionally substituted C1-C6 alkyl (e.g., C1-C6 hydroxyalkyl, alkoxy-Cl-C6 alkyl, and/or C1-C6 haloalkyl), optionally substituted C1-C6 alkenyl, optionally substituted C3-C8 lkyl, optionally substituted heterocyclyl (e.g., morpholinyl), -OR, C1-C6 haloalkoxy, - ), -N02, 2N(R)(R), acyl, and C1-C6 alkoxycarbonyl, wherein each occurrence ofR is independently selected from the group consisting of H, C1-C6 alkyl, R’-substituted C1-C6 alkyl, C1-C6 hydroxyalkyl, optionally substituted (C1-C6 alkoxy)-C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, wherein each occurrence of R’ is independently selected from the group consisting of -NH2, -NH(C1-C6 alkyl), C6 alkyl)(C1-C6 alkyl), -NHC(=O)OtBu, -N(C1-C6 alkyl)C(=O)OtBu, and a 5- or 6-membered heterocyclic group (such as, but not limited to, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and so forth), which is optionally N—linked, or X2 is CR6H, X3 is CR6111 and R611 and R6111 e to form a divalent group selected from the group consisting of -O(CHF)O-, -O(CF2)O-, -O(CR9R9)O-, - (CH2)O- and -O(CH2)(CR”R”)(CH2)O-, R7 is selected from the group consisting of H, OH, halo, C1-C6 alkoxy, optionally substituted C1-C6 alkyl (e. g., optionally tuted with 1-3 independently selected halo groups), and optionally substituted C3-C8 cycloalkyl, R8 is ed from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, each occurrence of R9 is independently selected from the group consisting ofH and C1-C6 alkyl (e. g., methyl or ethyl), R10 is selected from the group consisting of optionally substituted C1-C6 alkyl, and optionally substituted phenyl, and, each occurrence of R11 is independently selected from the group consisting of H, OH, C1-C6 alkyl, C1-C6 alkoxy, alkoxy-Cl-C6 alkyl and alkoxy-Cl-C6 alkoxy, wherein two R11 groups bound to the same carbon atom are not simultaneously OH, or two R11 groups combine with the carbon atom to which they are bound to form a moiety selected from the group consisting of C=O, C=CH2 and e-3,3-diyl.

In certain embodiments, the nd of formula (II) is a compound of formula -3 6- of formula is a compound of formula of formula (II) is a compound of formula the compound of formula (II) is a compound of formula (He). In yet other ments, the compound of formula (II) is a compound of formula compound of formula RGM’L§ formula (II) is a compound of formula R3' (IIh).

The invention includes a compound of a (III), or a salt, solvate, geometric isomer, stereoisomer, tautomer and any mixtures thereof: (111), wherein: R1 is selected from the group consisting of H, halo, -OR8, -C(R9)(R9)OR8 (such as, for example, -CH20R8, such as, for example, -CH20H), -C(=O)R8, -C(=O)OR8 (such as, for example, OH or -C(=O)O-C1-C6 alkyl), -C(=O)NH-OR8 (such as, for example, - C(=O)NH-OH), -C(=O)NHNHR8; -C(=O)NHNHC(=O)R8; -C(=O)NHS(=O)2R8; — CH2C(=O)OR8, -CN; -NH2, -N(R8)C(=O)H, -N(R8)C(=O)R10, C(=O)OR10, — N(R8)C(=O)NHR8; -NR98(=O)2R10; -P(=O)(OR8)2, -B(OR8)2, oxo-pyrrolidin-l-yl, 2H- tetrazolyl, 3-hydroxy-isoxazolyl, l,4-dihydrooxo-5H-tetrazol-l-yl, pyridinyl ally substituted with C1-C6 alkyl, pyrimidinyl optionally tuted with C1-C6 alkyl, (pyridinyl)methyl, (pyrimidinyl)methyl, (pyrimidinyl)amino, bis-(pyrimidinyl)- amino, 5-R8-l,3,4,-thiadiazolyl, 5-thioxo-4,5-dihydro-lH-l,2,4-triazolyl, lH-l,2,4-triazol- -yl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 3-R10-l,2,4-oxadiazolyl, R2 is selected from the group consisting of =0, =NR9, ), and =N(NR9R9), or R1 and R2 e to form =N—O-C(=O)- or =N—N(R9)-C(=O)-,wherein the =N group is bound to the ring carbon atom marked “*”, R3 and R3, are each independently selected from the group consisting of H, substituted oxetanyl, optionally substituted C1-C6 alkyl (e.g., optionally substituted with 1-3 groups independently selected from the group consisting of F, Cl, Br, I, OH and OMe), and optionally substituted C3-C8 cycloalkyl (e.g., optionally substituted with 1-3 groups ndently selected from the group consisting of F, Cl, Br, I, OH and OMe), or R3 and R3, combine to form a divalent group selected from the group consisting of C1-C6 alkanediyl, -(CH2)nO(CH2)n-, -(CH2)nNR9(CH2)n-, -(CH2)nS(CH2)n-, - (CH2)nS(=O)(CH2)n-, and -(CH2)nS(=O)2(CH2)n-, wherein each occurrence of n is independently selected from the group consisting of l and 2 and each divalent group is optionally substituted with at least one C1-C6 alkyl or halo, X1 is ed from the group consisting of CR61 and N, X2 is selected from the group consisting of CR611 and N, X3 is selected from the group consisting of CR6111 and N, X4 is selected from the group consisting of CR61V and N, or either X3 and X4, or X1 and X2, combine to form -S-, wherein 0-2 substituents ed from the group consisting of X1, X2, X3 and X4 are N, each of which, if present, is optionally alkylated with C1-C6 alkyl if the adjacent carbon atom in the ring is substituted with -OH, R61, R611, R6111 and R61V are independently selected from the group consisting of H, halo, -CN, pyrrolidinyl, optionally substituted C1-C6 alkyl (e.g., C1-C6 hydroxyalkyl, alkoxy-Cl-C6 alkyl, and/or C1-C6 haloalkyl), ally substituted C1-C6 alkenyl, ally substituted C3-C8 cycloalkyl, optionally substituted heterocyclyl (e.g., morpholinyl), -OR, C1-C6 haloalkoxy, - N(R)(R), -N02, -S(=O)2N(R)(R), acyl, and C1-C6 alkoxycarbonyl, wherein each ence ofR is independently selected from the group consisting of H, C1-C6 alkyl, stituted C1-C6 alkyl, C1-C6 hydroxyalkyl, optionally substituted (C1-C6 alkoxy)-C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, wherein each occurrence of R’ is selected from the group consisting of -NH2, - NH(C1-C6 alkyl), C6 alkyl)(C1-C6 alkyl), -NHC(=O)OtBu, -N(C1-C6 alkyl)C(=O)OtBu, and a 5- or 6-membered heterocyclic group (such as, but not limited to, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and so forth), which is optionally or X2 is CR6H, X3 is CR6111 and R611 and R6111 combine to form a divalent group ed from the group consisting of -O(CHF)O-, -O(CF2)O-, -O(CR9R9)O-, - O(CH2)(CH2)O- and -O(CH2)(CR”R”)(CH2)O-, R7 is selected from the group consisting of H, OH, halo, C1-C6 alkoxy, ally substituted C1-C6 alkyl (e. g., optionally substituted with 1-3 independently selected halo groups), and optionally substituted C3-C8 cycloalkyl, R8 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, and ally substituted C3-C8 cycloalkyl, each occurrence of R9 is independently selected from the group consisting ofH and C1-C6 alkyl (e. g., methyl or ethyl), R10 is selected from the group consisting of optionally substituted C1-C6 alkyl and optionally substituted phenyl, and, each occurrence of R11 is ndently selected from the group consisting of H, OH, C1-C6 alkyl, C1-C6 alkoxy, alkoxy-Cl-C6 alkyl and -Cl-C6 alkoxy, wherein two R11 groups bound to the same carbon atom are not simultaneously OH, or two R11 groups combine with the carbon atom to which they are bound to form a moiety selected from the group consisting of C=O, C=CH2 and oxetane-3,3-diyl, wherein at least one of the following conditions is present: (a) R1 is not -C(=O)OR8, (b) R2 is selected from the group consisting of =NR9, =N(OR9), and R9), or R1 and R2 combine to form =N—O-C(=O)— or =N—N(R9)-C(=O)-, wherein the =N group is bound to the ring carbon atom marked “*”, (c) either X3 and X4, or X1 and X2, combine to form -S-, (d) 1-2 substituents selected from the group consisting of X1, X2, X3 and X4 are N, (e) X2 is CR6H, X3 is CR“, and R611 and R6111 combine to form a divalent group selected from the group consisting of -O(CHF)O-, )O-, -O(CR9R9)O-, - O(CH2)(CH2)O- and -O(CH2)(CR”R”)(CH2)O-; and/or (f) R3 and R3, are each independently selected from the group consisting of alkyl- substituted yl, optionally tuted C1-C6 alkyl (e.g., optionally substituted with 1-3 groups independently selected from the group consisting of F, Cl, Br, I, OH and OMe), and optionally substituted C3-C8 cycloalkyl (e.g., optionally substituted with 1-3 groups independently selected from the group consisting of F, Cl, Br, I, OH and OMe), or R3 and R3, combine to form a divalent group ed from the group consisting of C1-C6 alkanediyl, -(CH2)nO(CH2)n-, - (CH2)nNR9(CH2)n-, -(CH2)HS(CH2)n-, -(CH2)HS(=0)(CH2)n-, and - (CH2)nS(=O)2(CH2)n-, wherein each occurrence of n is independently selected from the group consisting of l and 2 and each divalent group is optionally substituted with at least one C1-C6 alkyl or halo.

In n embodiments, the compound of formula (III) is the compound of formula (IIIa), or a salt, solvate, geometric , stereoisomer, tautomer and any mixtures thereof: (IIIa), wherein: each of X1, X2, X3, and X4 are independently selected from the group consisting of CR61 and wherein 1-2 substituents selected from the group consisting of X1, X2, X3 and X4 are N, each of which is optionally alkylated with C1-C6 alkyl if the adjacent carbon atom in the ring is substituted with -OH, or either X3 and X4, or X1 and X2, combine to form -S-.

In certain embodiments, the compound of formula (III) is the compound of formula (IIIb), or a salt, solvate, geometric isomer, stereoisomer, tautomer and any mixtures f: (IIIb), wherein at least one s: R1 is ed from the group consisting of H, halo, -OR8, -C(R9)(R9)OR8, -C(=O)R8, - C(=O)NH-OR8, -C(=O)NHNHR8; -C(=O)NHNHC(=O)R8; -C(=O)NHS(=O)2R8; -CN; -NH2, — N(R8)C(=O)H; C(=O)R10, -N(R8)C(=O)OR10, -N(R8)C(=O)NHR8, -NR98(=O)2R10; — P(=O)(OR8)2, -B(OR8)2, 2,5-dioxo-pyrrolidin-l-yl, 2H-tetrazolyl, l,4-dihydrooxo-5H- tetrazol-l-yl, pyridinyl optionally substituted with C1-C6 alkyl, pyrimidinyl optionally substituted with C1-C6 alkyl, (pyrimidinyl)amino, bis-(pyrimidinyl)-amino, 5-R8-l,3,4,- thiadiazolyl, 5-thioxo-4,5-dihydro-lH-l,2,4-triazolyl, lH-l,2,4-triazolyl, 1,3,4- oxadiazolyl, oxadiazolyl, and l,2,4-oxadiazolyl, R2 is selected from the group consisting of =NR9, ), and =N(NR9R9), or R1 and R2 combine to form =N—O-C(=O)- or =N—N(R9)-C(=O)-, wherein the =N group is bound to the ring carbon atom marked “*”.

In certain embodiments, the compound of formula (III) is a compound of formula (IIIc), or a salt, solvate, geometric isomer, stereoisomer, tautomer and any mixtures thereof: (IIIc), wherein: X3 and X4, or X1 and X2, combine to form -S-, In certain embodiments, the compound of formula (III) is the nd of a (IIId), or a salt, solvate, geometric isomer, stereoisomer, tautomer and any mixtures thereof:: (IIId), wherein: X2 is CR6H, X3 is CR“, and R611 and R6111 combine to form a divalent group ed from the group consisting of )O-, -O(CF2)O-, -O(CR9R9)O-, -O(CH2)(CH2)O- and - O(CH2)(CR”R”)(CH2)O-.

In certain embodiments, the compound of formula (III) is a compound of formula (IIIe): (IIIe), n: R3 and R3, are each independently selected from the group consisting of H, alkyl-substituted oxetanyl, optionally tuted C1-C6 alkyl (e.g., optionally substituted with 1-3 groups independently selected from the group ting of F, Cl, Br, I, OH and OMe), and optionally substituted C3-C8 cycloalkyl (e.g., optionally substituted with 1-3 groups independently selected from the group consisting of F, Cl, Br, I, OH and OMe), or R3 and R3, combine to form a divalent group selected from the group consisting of C1-C6 alkanediyl, -(CH2)nO(CH2)n-, - (CH2)nNR9(CH2)n-, -(CH2)nS(CH2)n-, -(CH2)nS(=O)(CH2)n-, and -(CH2)nS(=O)2(CH2)n-, wherein each occurrence of n is independently selected from the group ting of l and 2 and each divalent group is optionally substituted with at least one C1-C6 alkyl or halo.

In certain embodiments, the compound of formula (III) is a compound of formula compound of formula formula (III) is a compound of formula . In yet other embodiments, the compound of a (III) is a compound of formula (IIIi). In yet other embodiments, the nd of formula (III) is a compound of formula compound of formula formula (III) is a compound of formula the compound of formula (III) is a compound of a (IIIm). In yet other embodiments, the compound of formula (III) is a compound of formula (IIIn). In yet other embodiments, the compound of formula (III) is a compound of formula formula (III) is a compound of formula the nd of formula (III) is a compound of formula (IIIq).

In certain embodiments, each occurrence of alkyl, alkenyl, or cycloalkyl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, halo, -OR”, phenyl (thus yielding, in miting examples, optionally substituted phenyl-(C1-C3 alkyl), such as, but not limited to, benzyl or substituted benzyl) and -N(R’ ’)(R’ ’), wherein each occurrence of R” is independently H, C1-C6 alkyl or C3-C8 cycloalkyl.

In certain embodiments, each occurrence of aryl or heteroaryl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, -CN, -OR”, -N(R”)(R”), -N02, -S(=O)2N(R”)(R”), acyl, and C1-C6 alkoxycarbonyl, wherein each occurrence of R” is independently H, C1-C6 alkyl or C3-C8 lkyl.

In certain embodiments, each occurrence of aryl or heteroaryl is independently optionally tuted with at least one substituent selected from the group ting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halo, -CN, -OR”, -N(R”)(R”), and C1-C6 alkoxycarbonyl, wherein each occurrence of R” is independently H, C1-C6 alkyl or C3-C8 cycloalkyl.

In n embodiments, A is null. In certain embodiments, A is CR9R9.

In certain embodiments, R1 is selected from the group consisting of H, halo, -OR8, - C(R9)(R9)OR8; R8, -C(=O)OR8; -C(=O)NH-OR8, -C(=O)NHNHR8; — C(=O)NHNHC(=O)R8; -C(=O)NHS(=O)2R8; -CH2C(=O)OR8, -CN; -NH2, -N(R8)C(=O)H, — N<R8)C(=0)R10; -N(R8)C(=0)OR10; -N(R8)C(=0)NHR8; -NR98(=0)2R10; (0R8)2; - B(OR8)2, 2,5-dioxo-pyrrolidin-l-yl, 2H-tetrazolyl, 3-hydroxy-isoxazolyl, l,4-dihydro oxo-5H-tetrazol-l-yl, pyridinyl optionally substituted with C1-C6 alkyl, pyrimidinyl optionally substituted with C1-C6 alkyl, (pyridinyl)methyl, (pyrimidinyl)methyl, (pyrimidinyl)amino, bis-(pyrimidinyl)-amino, 5-R8-l,3,4,-thiadiazolyl, 5-thioxo-4,5- dihydro-lH-l,2,4-triazolyl, lH-l,2,4-triazolyl, 1,3,4-oxadiazolyl, l,2,4-oxadiazolyl, and 3-R10-l,2,4-oxadiazolyl.

In certain embodiments, R1 is H. In certain embodiments, R1 is halo. In certain embodiments, R1 is -OR8. In certain embodiments, R1 is -C(R9)(R9)OR8 (such as, for e, - CHZORS, such as, for example, -CH20H). In certain embodiments, R1 is -C(=O)R8. In certain embodiments, R1 is OR8 (such as, for example, OH or -C(=O)O-C1-C6 alkyl). In certain embodiments, R1 is -C(=O)NH-OR8 (such as, for example, -C(=O)NH-OH). In certain embodiments, R1 is -C(=O)NHNHR8. In certain embodiments, R1 is -C(=O)NHNHC(=O)R8. In n embodiments, R1 is -C(=O)NHS(=O)2R8. In certain embodiments, R1 is -CH2C(=O)OR8.

In certain embodiments, R1 is —CN. In certain embodiments, R1 is -NH2. In certain embodiments, R1 is -N(R8)C(=O)H. In certain embodiments, R1 is -N(R8)C(=O)R10. In certain embodiments, R1 is -N(R8)C(=O)OR10. In certain embodiments, R1 is -N(R8)C(=O)NHR8. In certain embodiments, R1 is -NRQS(=O)2R10. In certain ments, R1 is (OR8)2. In certain embodiments, R1 is -B(OR8)2. In certain ments, R1 is oxo-pyrrolidin-l-yl.

In certain embodiments, R1 is 2H-tetrazolyl. In certain ments, R1 is 3-hydroxy- isoxazolyl. In n embodiments, R1 is l,4-dihydrooxo-5H-tetrazol-l-yl. In certain embodiments, R1 is pyridinyl optionally substituted with C1-C6 alkyl. In n embodiments, R1 is pyrimidinyl optionally substituted with C1-C6 alkyl. In certain embodiments, R1 is (pyridinyl)methyl. In certain embodiments, R1 is (pyrimidinyl)methyl.

In certain embodiments, R1 is (pyrimidinyl)amino. In certain embodiments, R1 is bis- (pyrimidinyl)-amino. In certain embodiments, R1 is ,3,4,-thiadiazolyl. In certain embodiments, R1 is 5-thioxo-4,5-dihydro-lH-l,2,4-triazolyl. In n embodiments, R1 is lH-l,2,4-triazolyl. In certain embodiments, R1 is l,3,4-oxadiazolyl. In n embodiments, R1 is 1,2,4-oxadiazolyl. In certain embodiments, R1 is 3-R10-l,2,4-oxadiazol yl. In certain embodiments, R1 is selected from the group consisting of -C(=O)OH, -C(=O)OMe, -C(=O)OEt, -C(=O)O-nPr, -C(=O)O-iPr, -C(=O)O-cyclopentyl, and -C(=O)O-cyclohexyl.

In certain embodiments, R2 is O. In certain embodiments, R2 is N(OH). In certain embodiments, R2 is N(Me). In certain embodiments, R2 is N(OMe). In certain embodiments, R2 is N(NHZ). In certain embodiments, R2 is =NR9. In certain embodiments, R2 is =N(OR9). In certain ments, R2 is =N(NR9R9). In certain embodiments, R1 and R2 combine to form =N—O-C(=O)-, wherein the =N group is bound to the ring carbon atom marked “*”. In certain embodiments, R1 and R2 combine to form =N—N(R9)-C(=O)-, wherein the =N group is bound to the ring carbon atom marked “*”.

In n embodiments, M is C(R4)(R4’). In certain embodiments, M is NR8.

In certain embodiments, bond a is a single bond. In other embodiments, bond a is a double bond.

In certain embodiments, bond a is a single bond, and Y is C(=O), and M is selected from the group ting of C(R4)(R4’) and NR8. In certain embodiments, bond a is a single bond, and Y is selected from the group consisting of CHRS, O, S, S(=O), S(=O)2, and NR5, and M is C(R4)(R4’). In certain embodiments, if Y is selected from the group consisting of CHRS, O, and NR5, R4 and R4, optionally combine with each other to form =0. In certain embodiments, Y is CH, M is C(R4)(R4’), R4, is CH2, and Y and R4, form a single bond to generate cyclopropyl. In certain embodiments, bond a is a double bond, and Y is selected from the group consisting of CR5 and N, M is C(R4)(R4’), and R4, is absent.

In certain embodiments, R3 is H. In certain embodiments, R3 is not H. In n embodiments, R3 is alkyl-substituted oxetanyl. In certain embodiments, R3 is optionally substituted C1-C6 alkyl. In certain embodiments, R3 is optionally substituted C3-C8 cycloalkyl.

In certain embodiments, R3, is H. In certain ments, R3 is not H. In certain embodiments, R3, is substituted yl. In certain ments, R3, is optionally substituted C1-C6 alkyl. In certain embodiments, R3, is optionally substituted C3-C8 cycloalkyl. In n embodiments, R4 is H. In certain embodiments, R4 is alkyl-substituted oxetanyl. In certain embodiments, R4 is optionally substituted C1-C6 alkyl. In certain embodiments, R4 is optionally substituted C3-C8 cycloalkyl. In n ments, R4, is H. In certain ments, R4, is alkyl-substituted oxetanyl. In certain embodiments, R4, is optionally substituted C1-C6 alkyl. In certain embodiments, R4, is optionally substituted C3-C8 cycloalkyl. In certain embodiments, the C1-C6 alkyl is optionally substituted with 1-3 groups independently selected from the group consisting of F, Cl, Br, I, OH, and OMe. In certain embodiments, the C3-C8 cycloalkyl is ally substituted with 1-3 groups independently selected from the group ting of F, Cl, Br, I, OH, and OMe. In certain embodiments, R3 is H and R3, is isopropyl. In n embodiments, R3 is H and R3, is utyl. In certain embodiments, R3 is methyl and R3, is isopropyl. In certain embodiments, R3 is methyl and R3, is tert-butyl. In certain embodiments, R3 is methyl and R3, is methyl. In certain embodiments, R3 is methyl and R3, is ethyl. In certain embodiments, R3 is ethyl and R3, is ethyl.

In certain embodiments, one pair selected from the group consisting of R3 / R3,, R4 / R4,, and R3 / R4 combine to form C1-C6 alkanediyl. In certain embodiments, one pair selected from the group ting of R3 / R3,, R4 / R4,, and R3 / R4 combine to form -(CH2)nO(CH2)n-, which is optionally substituted with at least one C1-C6 alkyl or halo, and wherein each occurrence of n is independently selected from the group consisting of l and 2. In certain embodiments, one pair selected from the group consisting of R3 / R3,, R4 / R4,, and R3 / R4 combine to form - NR9(CH2)n-, which is optionally substituted with at least one C1-C6 alkyl or halo, and wherein each occurrence of n is independently selected from the group consisting of l and 2. In certain embodiments, one pair selected from the group consisting of R3 / R3,, R4 / R4,, and R3 / R4 combine to form nS(CH2)n-, which is optionally substituted with at least one C1-C6 alkyl or halo, and wherein each occurrence of n is ndently selected from the group consisting of l and 2. In certain embodiments, one pair selected from the group consisting of R3 / R3,, R4 / R4,, 2O and R3 / R4 combine to form -(CH2)nS(=O)(CH2)n-, which is optionally tuted with at least one C1-C6 alkyl or halo, and n each occurrence of n is ndently selected from the group consisting of l and 2. In certain embodiments, one pair selected from the group consisting of R3 / R3,, R4 / R4,, and R3 / R4 combine to form -(CH2)nS(=O)2(CH2)n-, which is optionally substituted with at least one C1-C6 alkyl or halo, and wherein each occurrence of n is independently selected from the group consisting of l and 2. In certain embodiments, R3 and R3, are independently selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, hydroxymethyl, oxy-ethyl, 2-methoxy-ethyl, methoxymethyl, 2-methyl-l-methoxy-propyl, 2-methyl-l-hydroxy-propyl, and trifluoroethyl. In certain embodiments, R4 and R4, are independently selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, l, hydroxymethyl, 2-hydroxy-ethyl, 2-methoxy-ethyl, methoxymethyl, and 2-methyl-l-methoxy- WO 85619 propyl. In certain embodiments, R4 is selected from the group ting of H, methyl, ethyl, 2-hydroxy-ethyl, and 2-methoxy-ethyl. In certain embodiments, R3 and R3, combine to form l,l- methanediyl (1'.e.., an exocyclic double bond). In certain embodiments, R3 and R3, combine to form 1,2-ethanediyl. In certain embodiments, R3 and R3, combine to form 1,3-propanediyl. In n embodiments, R3 and R3, combine to form l,4-butanediyl. In certain embodiments, R3 and R3, combine to form l,5-pentanediyl. In certain embodiments, R3 and R3, combine to form l,6-hexanediyl. In certain ments, R3 and R4 combine to form 1,2-ethanediyl. In certain embodiments, R3 and R4 e to form l,3-propanediyl. In n embodiments, R3 and R4 combine to form l,3-propanediyl. In certain ments, R3 and R4 combine to form (1- or 2- methyl)-l,4-butanediyl. In certain embodiments, R3 and R4 combine to form (l,l-, 1,2-, 1,3-, or 2,2-dimethyl)-l,3-propanediyl. In certain embodiments, R3 and R4 combine to form 1,5- pentanediyl. In certain embodiments, R3 and R4 combine to form l,6-hexanediyl.

In certain embodiments, R5 is H. In certain ments, R5 is optionally tuted C1- C6 alkyl. In certain embodiments, R5 is optionally substituted C3-C8 cycloalkyl.

In certain embodiments, X1 is CR6. In certain embodiments, X1 is N. In n embodiments, X2 is CR611. In certain embodiments, X2 is N. In certain embodiments, X3 is CR6IH. In certain embodiments, X3 is N. In certain embodiments, X4 is CR6IV. In certain embodiments, X4 is N. In certain embodiments, X3 and X4 combine to form -S-. In certain embodiments, X1 and ne to form -S-.

In certain embodiments, none of X1, X2, X3 and X4 is N. In certain embodiments, only one from the group consisting of X1, X2, X3 and X4 is N. In certain embodiments, only two from the group consisting of X1, X2, X3 and X4 are N. In certain embodiments, X1 is N. In certain embodiments, X2 is N. In certain embodiments, X3 is N. In n embodiments, X4 is N. In certain embodiments, if at least one N is present in the ring comprising Xl-X4, the at least one N is optionally alkylated with C1-C6 alkyl if the adjacent carbon atom in the ring is substituted with —OH. In certain embodiments, X1 is CH. In certain ments, X4 is CH. In certain embodiments, X1 is N. 6H In n embodiments, X4 is N. In certain embodiments, X2 is CR wherein R611 is not H. In certain embodiments, X3 is CR6IH, wherein R6111 is not H.

In certain embodiments, R61 is H. In certain embodiments, R61 is halo. In certain embodiments, R61 is —CN. In certain embodiments, R61 is pyrrolidinyl. In certain embodiments, R61 is optionally substituted C1-C6 alkyl (e.g., C1-C6 hydroxyalkyl, alkoxy-Cl-C6 alkyl, and/or C1-C6 haloalkyl). In certain embodiments, R61 is optionally substituted C1-C6 alkenyl. In certain embodiments, R61 is optionally substituted C3-C8 cycloalkyl. In n embodiments, R61 is optionally substituted heterocyclyl (e.g., morpholinyl). In n embodiments, R61 is —OR. In certain embodiments, R61 is C1-C6 haloalkoxy. In certain embodiments, R61 is -N(R)(R). In certain embodiments, R61 is -N02. In certain ments, R61 is -S(=O)2N(R)(R). In certain embodiments, R61 is acyl. In n embodiments, R61 is C1-C6 alkoxycarbonyl.

In certain embodiments, R611 is H. In certain embodiments, R611 is halo. In certain embodiments, R611 is —CN. In certain embodiments, R611 is pyrrolidinyl. In certain embodiments, R611 is optionally substituted C1-C6 alkyl (e. g., C1-C6 hydroxyalkyl, alkoxy-Cl-C6 alkyl, and/or C1-C6 kyl). In certain embodiments, R611 is optionally substituted C1-C6 alkenyl. In certain embodiments, R611 is optionally substituted C3-C8 cycloalkyl. In certain ments, R611 is optionally substituted heterocyclyl (e.g., morpholinyl). In certain embodiments, R611 is —OR. In n embodiments, R611 is C1-C6 haloalkoxy. In certain ments, R611 is -N(R)(R). In certain embodiments, R611 is -N02. In certain embodiments, R611 is -S(=O)2N(R)(R). In certain embodiments, R611 is acyl. In certain embodiments, R611 is C1-C6 alkoxycarbonyl.

In certain ments, R6111 is H. In n embodiments, R6111 is halo. In certain embodiments, R6111 is —CN. In certain embodiments, R6111 is idinyl. In certain ments, R6111 is optionally substituted C1-C6 alkyl (e.g., C1-C6 hydroxyalkyl, alkoxy-Cl-C6 alkyl, and/or C1-C6 haloalkyl). In certain embodiments, R6111 is optionally substituted C1-C6 alkenyl. In n embodiments, R6111 is optionally substituted C3-C8 cycloalkyl. In certain embodiments, R6111 is optionally substituted heterocyclyl (e.g., morpholinyl). In certain embodiments, R6111 is —OR. In certain embodiments, R6111 is C1-C6 haloalkoxy. In certain embodiments, R6111 is -N(R)(R). In certain embodiments, R6111 is -N02. In certain embodiments, R6111 is -S(=O)2N(R)(R). In n embodiments, R6111 is acyl. In certain embodiments, R6111 is C1-C6 alkoxycarbonyl.

In certain embodiments, R61V is H. In n embodiments, R61V is halo. In certain embodiments, R61V is —CN. In certain embodiments, R61V is idinyl. In certain embodiments, R61V is optionally substituted C1-C6 alkyl (e.g., C1-C6 hydroxyalkyl, alkoxy-Cl-C6 alkyl, and/or C1-C6 haloalkyl). In certain embodiments, R61V is optionally substituted C1-C6 alkenyl. In certain embodiments, R61V is optionally substituted C3-C8 cycloalkyl. In certain embodiments, R61V is optionally substituted heterocyclyl (e.g., morpholinyl). In certain embodiments, R61V is —OR. In n embodiments, R61V is C1-C6 haloalkoxy. In n embodiments, R61V is -N(R)(R). In certain embodiments, R61V is -N02. In certain embodiments, R61V is -S(=O)2N(R)(R). In certain embodiments, R61V is acyl. In certain embodiments, R61V is C1-C6 alkoxycarbonyl.

In certain ments, R61 is ed from the group consisting of H, F, Cl, Br, I, CN, amino, methylamino, dimethylamino, methoxyethylamino, pyrrolidinyl, y, ethoxy, n- propoxy, isopropoxyl, n-butoxy, sec-butoxy, isobutoxy, t-butoxy, 2-methoxy-ethoxy, 2-hydroxy- ethoxy, 3-methoxy-prop-l-yl, 3-hydroxy-prop-l-yl, 3-methoxy-prop-l-oxy, 3-hydroxy-prop-l- oxy, oxy-but-l-yl, 4-hydroxy-but-l-yl, 4-methoxy-but-l-oxy, 4-hydroxy-but-l-oxy, 2- hydroxy-ethoxy, 3-hydroxy-prop-l-yl, 4-hydroxy-but-l-yl, oxy-2,2-dimethyl-prop-l-oxy, cyclopropylmethoxy, 2,2,2-trifluoroethoxy, 2-(2-haloethoxy)—ethoxy, 2-(N—morpholino)-ethyl, 2- pholino)-ethoxy, 3-(N-morpholino)-prop-l-yl, 3-(N-morpholino)-prop-l-oxy, 4-(N- morpholino)-but-l-yl, 4-(N-morpholino)-butl-oxy, 2-amino-ethyl, 2-(NHC(=O)OtBu)-ethyl, 2- amino-ethoxy, 2-(NHC(=O)OtBu)-ethoxy, 3-amino-prop-l-yl, 3-(NHC(=O)OtBu)-prop-l-yl, 3- amino-prop- l -oxy, 3 -(NHC(=O)OtBu)-prop- l -oxy, o-but- l -yl, 4-(NHC(=O)OtBu)-but- l - yl, 4-amino-but-l-oxy, and 4-(NHC(=O)OtBu)-but-l-oxy. In certain embodiments, R611 is selected from the group consisting of H, F, Cl, Br, I, CN, amino, methylamino, dimethylamino, methoxyethylamino, idinyl, methoxy, ethoxy, n-propoxy, isopropoxyl, n-butoxy, secbutoxy , isobutoxy, t-butoxy, 2-methoxy-ethoxy, 2-hydroxy-ethoxy, 3 -methoxy-prop- l -yl, 3 - hydroxy-prop-l-yl, oxy-prop-l-oxy, 3-hydroxy-prop-l-oxy, 4-methoxy-but-l-yl, 4- hydroxy-but-l-yl, 4-methoxy-but-l-oxy, 4-hydroxy-but-l-oxy, 2-hydroxy-ethoxy, 3-hydroxyprop-l-yl , 4-hydroxy-but-l-yl, 3-hydroxy-2,2-dimethyl-prop-l-oxy, cyclopropylmethoxy, 2,2,2- trifluoroethoxy, 2-(2-haloethoxy)-ethoxy, 2-(N-morpholino)—ethyl, 2-(N—morpholino)-ethoxy, 3- (N-morpholino)-prop-l-yl, 3-(N-morpholino)-prop-l-oxy, 4-(N-morpholino)—but-l-yl, 4-(N- morpholino)—butl-oxy, 2-amino-ethyl, 2-(NHC(=O)OtBu)-ethyl, 2-amino-ethoxy, 2- (NHC(=O)OtBu)-ethoxy, 3-amino-prop-l-yl, 3-(NHC(=O)OtBu)-prop-l-yl, 3-amino-prop-l-oxy, 3 -(NHC(=O)OtBu)-prop- l -oxy, 4-amino-but- l -yl, 4-(NHC(=O)OtBu)-but- l -yl, 4-amino-but- l - oxy, and 4-(NHC(=O)OtBu)-but-l-oxy. In certain ments, R6111 is selected from the group consisting of H, F, Cl, Br, I, CN, amino, methylamino, dimethylamino, methoxyethylamino, pyrrolidinyl, methoxy, ethoxy, n-propoxy, isopropoxyl, n-butoxy, sec-butoxy, isobutoxy, tbutoxy , 2-methoxy-ethoxy, 2-hydroxy-ethoxy, 3 -methoxy-prop- l -yl, 3 -hydroxy-prop- l -yl, 3 - methoxy-propoxy, 3 -hydroxy-propoxy, oxy-buty1, oxy-but— 1 -y1, 4- methoxy-but-l -oxy, 4-hydroxy-butoxy, oxy-ethoxy, 3 -hydroxy-propy1, 4-hydroxy- buty1, 3 -hydroxy-2,2-dimethy1-propoxy, cyclopropylmethoxy, 2,2,2-trifluoroethoxy, 2-(2- hoxy)—ethoxy, 2-(N-morpholino)—ethy1, 2-(N—morpholino)-ethoxy, 3 -(N-morpholino)-prop- 1-y1, 3 -(N-morpholino)-propoxy, 4-(N-morpholino)-buty1, 4-(N-morpholino)—but1-oxy, 2- amino-ethyl, 2-(NHC(=O)OtBu)-ethy1, 2-amino-ethoxy, 2-(NHC(=O)OtBu)-ethoxy, 3-amino- prop— 1 -y1, 3 -(NHC(=O)OtBu)-propy1, 3 -amino-propoxy, 3 -(NHC(=O)OtBu)-propoxy, 4- amino-buty1, 4-(NHC(=O)OtBu)-buty1, 4-amino-butoxy, and 4-(NHC(=O)OtBu)-but oxy. In n embodiments, R61V is selected from the group consisting of H, F, Cl, Br, I, CN, amino, methylamino, dimethylamino, methoxyethylamino, pyrrolidinyl, y, ethoxy, n- propoxy, isopropoxyl, n-butoxy, toxy, oxy, t-butoxy, 2-methoxy-ethoxy, 2-hydroxy- ethoxy, 3 -methoxy-propy1, 3 -hydroxy-propy1, 3 xy-propoxy, 3 -hydroxy-prop oxy, 4-methoxy-buty1, 4-hydroxy-buty1, 4-methoxy-butoxy, 4-hydroxy-butoxy, 2- hydroxy-ethoxy, 3 -hydroxy-propy1, 4-hydroxy-buty1, 3 -hydroxy-2,2-dimethy1-prop-1 -oxy, cyclopropylmethoxy, 2,2,2-trifluoroethoxy, 2-(2-haloethoxy)—ethoxy, 2-(N-morpholino)-ethy1, 2- (N-morpholino)-ethoxy, 3 -(N-morpholino)-propy1, 3 -(N-morpholino)-propoxy, 4-(N- morpholino)-buty1, 4-(N-morpholino)-but1-oxy, 2-amino-ethy1, 2-(NHC(=O)OtBu)-ethyl, 2- amino-ethoxy, 2-(NHC(=O)OtBu)-ethoxy, 3 -amino-propy1, 3 -(NHC(=O)OtBu)-propy1, 3 - amino-propoxy, 3 -(NHC(=O)OtBu)-propoxy, o-buty1, 4-(NHC(=O)OtBu)-but yl, 4-amino-butoxy, and 4-(NHC(=O)OtBu)-butoxy.

In certain embodiments, X1 is CR“, X2 is CR6H, X3 is CR“, and X4 is CR6IV. In certain embodiments, R61 is H, R611 is methoxy, R6111 is 3 -methoxy-propoxy, and R61V is H. In certain embodiments, R61 is H, R611 is chloro, R6111 is 3 -methoxy-propoxy, and R61V is H. In certain embodiments, R61 is H, R611 is isopropyl, R6111 is 3-methoxy-propoxy, and R61V is H. In certain ments, R61 is H, R611 is methoxy, R6111 is methoxy, and R61V is H. In certain embodiments, R61 is H, R611 is chloro, R6111 is methoxy, and R61V is H. In certain embodiments, R61 is H, R611 is cyclopropyl, R6111 is y, and R61V is H.

In certain embodiments, X1 is N, X2 is CR6H, X3 is CR“, and X4 is CR6IV. In certain embodiments, R611 is methoxy, R6111 is 3-methoxy-propoxy, and R61V is H. In certain embodiments, R611 is chloro, R6111 is 3-methoxy-propoxy, and R61V is H. In certain embodiments, R611 is cyclopropyl, R6111 is 3-methoxy-propoxy, and R61V is H. In certain embodiments, R611 is methoxy, R6111 is methoxy, and R61V is H. In certain embodiments, R611 is chloro, R6111 is methoxy, and R61V is H. In certain embodiments, R611 is cyclopropyl, R6111 is methoxy, and R61V is H.

In n embodiments, each occurrence ofR is independently selected from the group consisting of H, C1-C6 alkyl, R’-substituted C1-C6 alkyl, C1-C6 hydroxyalkyl, optionally substituted (C1-C6 alkoxy)—C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl. In certain embodiments, each occurrence of R’ is independently ed from the group consisting of - NHz, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NHC(=O)OtBu, -N(C1-C6 alkyl)C(=O)OtBu, or a 5- or 6-membered heterocyclic group (such as, but not limited to, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and so forth), which is optionally N—linked.

In certain embodiments, X2 is CR6H, X3 is CR“, and R611 and R6111 e to form a divalent group selected from the group consisting of -O(CHF)O-, -O(CF2)O-, -O(CR9R9)O-, - O(CH2)(CH2)O- and -O(CH2)(CR”R”)(CH2)O-.

In certain embodiments, R7 is H. In n embodiments, R7 is OH. In certain embodiments, R7 is halo. In certain ments, R7 is C1-C6 alkoxy. In certain embodiments, R7 is optionally substituted C1-C6 alkyl (e.g., optionally substituted with 1-3 independently selected halo groups). In certain embodiments, R7 is optionally substituted C3-C8 cycloalkyl. In certain embodiments, R7 is H. In certain embodiments, R7 is F. In certain embodiments, R7 is methoxy. In certain ments, R7 is ethoxy. In certain embodiments, R7 is methyl. In certain embodiments, R7 is ethyl. In n embodiments, R7 is yl. In certain embodiments, R7 is isopropyl.

In certain embodiments, R8 is ed from the group consisting of H, optionally substituted C1-C6 alkyl, and ally substituted C3-C8 cycloalkyl.

In n embodiments, each occurrence of R9 is independently selected from the group consisting ofH and C1-C6 alkyl (e. g., methyl or ethyl).

In certain embodiments, R10 is ed from the group ting of optionally substituted C1-C6 alkyl and optionally substituted phenyl.

In certain embodiments, each occurrence of R11 is independently selected from the group consisting of H, OH, C1-C6 alkyl, C1-C6 alkoxy, alkoxy-Cl-C6 alkyl and alkoxy-Cl-C6 alkoxy, wherein two R11 groups bound to the same carbon atom are not simultaneously OH, or two R11 groups e with the carbon atom to which they are bound to form a moiety selected from the group consisting of C=O, C=CH2 and oxetane-3,3-diyl.

In n embodiments, the compounds of the invention, or a salt, solvate, stereoisomer (such as, in a non-limiting e, an enantiomer or diastereoisomer thereof), any mixture of one or more stereoisomers (such as, in a non-limiting example, mixtures in any proportion of omers thereof, and/or mixtures in any proportion of diastereoisomers thereof), tautomer, and/or any mixture of ers thereof, are recited in Tables 1-3.

The nds of the invention disclosed in the present application were screened to evaluate their potency and toxicity profiles. Several compounds having desirable potency and toxicity profiles were identified in these screens. For example, Example 22 was cleared relatively slowly from blood plasma in dogs, and, as measured in a Langendorff assay (Bell, et al., Retrograde heartperfusion: The Langendorfltechnique ofisolated heartperfusion, J. Mol.

Cell. Cardiol. 2011, 940-950, Guo, et al. Validation ofa guinea pig dorflheart model for assessingpotential cardiovascular liability ofdrug ates, J. col. l.

Methods, 2009, 130—151), that compound showed no effect on any of the measured electrocardiogram parameters at any of the concentrations tested. These results suggest that Example 22 can be ped as an HBV therapeutic agent that is stered to human subjects in need thereof once per day, and that is unlikely to have undesirable cardiac side effects.

The compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the (R) or (5) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. The compounds described herein ass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable , including by way of non-limiting e, by resolution of the racemic form with recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. A compound illustrated herein by the racemic formula further represents either of the two enantiomers or mixtures thereof, or in the case where two or more chiral center are present, all diastereomers or mixtures thereof.

In certain embodiments, the compounds of the invention exist as tautomers. All tautomers are ed within the scope of the nds recited herein.

WO 85619 nds described herein also include isotopically d compounds n one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to 2H, 3H, 11C, 13C, 14C, 36Cl’ 18F, 1231’ 1251’ 13N, 15N, 150, 170, 180’ 32F, and 358. In certain embodiments, substitution with heavier isotopes such as deuterium affords greater chemical stability. Isotopically labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically labeled reagent in place of the non-labeled t otherwise employed.

IO In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

In all of the ments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention. The compounds of the invention may contain any of the substituents, or combinations of tuents, ed .

Salts The compounds described herein may form salts with acids or bases, and such salts are included in the present invention. The term “salts” embraces addition salts of free acids or bases that are useful within the methods of the invention. The term “pharmaceutically acceptable salt” refers to salts that s toxicity profiles within a range that affords utility in pharmaceutical ations. In certain embodiments, the salts are pharmaceutically acceptable salts.

Pharmaceutically unacceptable salts may eless s properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the invention.

Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include sulfate, hydrogen sulfate, hloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate c acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, , c, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (or pamoic), methanesulfonic, sulfonic, benzenesulfonic, pantothenic, sulfanilic, 2- hydroxyethanesulfonic, trifluoromethanesulfonic, p-toluenesulfonic, cyclohexylaminosulfonic, stearic, alginic, B-hydroxybutyric, salicylic, galactaric, galacturonic acid, ophosphonic acids and saccharin (e.g., saccharinate, rate). Salts may be comprised of a fraction of one, one or more than one molar equivalent of acid or base with respect to any compound of the invention.

Suitable ceutically acceptable base addition salts of compounds of the ion include, for example, ammonium salts and metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, ibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (or N—methylglucamine) and procaine.

All of these salts may be ed from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.

Combination Therapies In one aspect, the compounds of the invention are useful within the methods of the invention in combination with one or more additional agents useful for treating HBV infections.

These additional agents may comprise compounds or compositions identif1ed herein, or compounds (e.g., commercially available compounds) known to treat, prevent, or reduce the symptoms ofHBV ions.

Non-limiting examples of one or more additional agents useful for treating HBV infections include: (a) reverse transcriptase tors, (b) capsid inhibitors, (c) cchNA formation inhibitors, (d) sAg secretion tors, (e) oligomeric nucleotides targeted to the Hepatitis B genome, and (f) immunostimulators. (a) Reverse Transcriptase Inhibitors In certain embodiments, the e transcriptase tor is a e-transcriptase inhibitor (NARTI or NRTI). In other embodiments, the reverse transcriptase inhibitor is a nucleotide analog reverse-transcriptase inhibitor (NtARTI or NtRTI).

Reported reverse transcriptase inhibitors include, but are not limited to, entecavir, clevudine, telbivudine, lamivudine, adefovir, and tenofovir, tenofovir oxil, tenofovir alafenamide, adefovir dipovoxil, (lR,2R,3R,5R)(6-amino-9Hpurinyl)fluoro (hydroxymethyl)methylenecyclopentanol (described in U. S. Patent No. 8, 8 1 6,074, incorporated herein in its ty by reference), itabine, ir, elvucitabine, ganciclovir, lobucavir, famciclovir, penciclovir, and amdoxovir.

Reported reverse transcriptase inhibitors r include, but are not limited to, entecavir, lamivudine, and (lR,2R,3R,5R)(6-amino-9Hpurinyl)fluoro(hydroxymethyl) methylenecyclopentanol.

Reported reverse transcriptase inhibitors further include, but are not d to, a covalently bound phosphoramidate or phosphonamidate moiety of the above-mentioned reverse transcriptase inhibitors, or as described in for example US. Patent No. 8,816,074, US Patent Application Publications No. US 2011/0245484 A1, and US 2008/0286230Al, all of which incorporated herein in their entireties by reference.

Reported reverse transcriptase inhibitors further include, but are not d to, nucleotide analogs that comprise a phosphoramidate moiety, such as, for example, methyl ((((lR,3R,4R,5R)(6-amino-9H-purinyl)fluorohydroxymethylenecyclopentyl) methoxy)(phenoxy) phosphoryl)-(D or L)-alaninate and methyl ((((lR,2R,3R,4R)-3 -fluoro hydroxymethylene(6-oxo- l ydro-9H-purinyl)cyclopentyl)methoxy)(phenoxy) phosphoryl)-(D or L)—alaninate. Also included are the individual diastereomers thereof, which include, for e, methyl ((R)-(((lR,3R,4R,5R)(6-amino-9H-purinyl)fluoro hydroxymethylenecyclopentyl)methoxy)(phenoxy)phosphoryl)-(D or ninate and methyl ((S)-(((lR,3R,4R,5R)—3-(6-amino-9H-purinyl)fluorohydroxymethylenecyclopentyl) methoxy)(phenoxy)phosphoryl)-(D or L)—alaninate.

Reported reverse riptase inhibitors further include, but are not limited to, compounds comprising a phosphonamidate moiety, such as, for example, vir alafenamide, as well as those described in US. Patent Application Publication No. US 2008/0286230 A1, orated herein in its entirety by reference. Methods for preparing stereoselective phosphoramidate or phosphonamidate containing actives are described in, for example, US.

Patent No. 8,816,074, as well as US. Patent Application Publications No. US 2011/0245484 A1 and US 2008/0286230 A1, all of which incorporated herein in their entireties by reference. (b) Capsid Inhibitors As described herein, the term “capsid inhibitor” includes compounds that are capable of inhibiting the sion and/or function of a capsid protein either directly or indirectly. For example, a capsid inhibitor may include, but is not limited to, any compound that ts capsid assembly, induces formation of non-capsid polymers, promotes excess capsid ly or misdirected capsid assembly, affects capsid ization, and/or ts encapsidation ofRNA (pgRNA). Capsid inhibitors also include any compound that inhibits capsid function in a downstream event(s) within the replication process (e.g., viral DNA synthesis, transport of relaxed circular DNA (rcDNA) into the nucleus, covalently closed circular DNA (cchNA) formation, virus maturation, budding and/or release, and the like). For example, in certain embodiments, the inhibitor detectably inhibits the expression level or biological ty of the capsid protein as measured, e.g., using an assay described herein. In certain embodiments, the inhibitor inhibits the level of rcDNA and downstream products of viral life cycle by at least 5%, at least 10%, at least 20%, at least 50%, at least 75%, or at least 90%.

Reported capsid inhibitors include, but are not limited to, compounds described in International Patent ations Publication Nos WO 2013006394, WO 2014106019, and W02014089296, all of which incorporated herein in their entireties by reference.

Reported capsid tors also include, but are not d to, the following compounds and pharmaceutically acceptable salts and/or solvates thereof: Bay4109 (see Int’l Patent Application Publication No. WO 2013144129), AT-61 (see Int’l Patent Application Publication No. WO 1998033501, and King, el al., 1998, Antimicrob. Agents Chemother. 42(12):3179— 3186), DVR-01 and DVR-23 (see Int’l Patent Application Publication No. WO 2013006394, and Campagna, el al., 2013, J. Virol. 87(12):6931, all of which incorporated herein in their entireties by reference.

In addition, reported capsid tors include, but are not d to, those generally and cally described in US. Patent ation Publication Nos. US 2015/0225355, US 2015/0132258, US 2016/00833 83, US 2016/0052921 and Int’l Patent Application Publication Nos. WO 2013096744, WO 2014165128, WO 2014033170, WO 2014033167, WO 2014033176 WO 2014131847, WO 2014161888, WO 4350, WO 2014184365, WO 2015059212, WO 2015011281, WO 2015118057, WO 2015109130, WO 2015073774, WO 2015180631, WO 2015138895, WO 2016089990, WO 2017015451, WO 2016183266, WO 2017011552, WO 2017048950, WO2017048954, WO 2017048962, WO 2017064156 and are incorporated herein in their entirety by reference. (0) cchNA Formation Inhibitors Covalently closed circular DNA ) is generated in the cell nucleus from viral rcDNA and serves as the transcription template for viral mRNAs. As described herein, the term “cchNA formation inhibitor” includes compounds that are capable of inhibiting the formation and/or ity of cchNA either directly or indirectly. For example, a cchNA formation inhibitor may include, but is not limited to, any compound that inhibits capsid disassembly, rcDNA entry into the nucleus, and/or the sion of rcDNA into cchNA. For example, in certain embodiments, the inhibitor detectably inhibits the formation and/or ity of the cchNA as measured, e.g., using an assay described herein. In certain embodiments, the inhibitor inhibits the ion and/or stability of cchNA by at least 5%, at least 10%, at least %, at least 50%, at least 75%, or at least 90%.

Reported cchNA ion inhibitors include, but are not limited to, compounds described in Int’l Patent Application Publication No. WO 2013130703, and are incorporated herein in their entirety by reference.

In addition, reported cchNA formation inhibitors include, but are not limited to, those lly and specifically described in US. Patent Application Publication No. US 2015/003 8515 A1, and are incorporated herein in their entirety by reference. (d) sAg Secretion Inhibitors As described herein, the term “sAg secretion inhibitor” includes compounds that are capable of inhibiting, either directly or indirectly, the secretion of sAg (S, M and/or L surface antigens) bearing subviral particles and/or DNA ning viral les from HBV-infected cells. For example, in certain embodiments, the inhibitor detectably inhibits the secretion of sAg as measured, e.g., using assays known in the art or described , e.g., ELISA assay or by Western Blot. In certain ments, the inhibitor inhibits the secretion of sAg by at least 5%, at least 10%, at least 20%, at least 50%, at least 75%, or at least 90%. In certain embodiments, the inhibitor s serum levels of sAg in a patient by at least 5%, at least 10%, at least 20%, at least 50%, at least 75%, or at least 90%.

Reported sAg secretion inhibitors include compounds described in US. Patent No. 8,921,381, as well as compounds described in US. Patent ation Publication Nos. US 2015/0087659 and US 2013/0303552, all of which are incorporated herein in their entireties by reference.

In addition, reported sAg secretion inhibitors include, but are not limited to, those generally and specifically described in Int’l Patent ation Publication Nos. WO 2015113990, WO 2015173164, US 2016/0122344, WO 2016107832, WO 2016023877, WO 2016128335, WO 2016177655, WO 2016071215, WO 2017013046, WO 2017016921, WO 2017016960, WO 2017017042, WO 2017017043, WO 2017102648, WO 2017108630, WO 2017114812, WO 2017140821 and are orated herein in their entirety by reference. (e) stimulators The term “immunostimulator” includes compounds that are e of ting an immune response (e.g., ate an immune response (e.g., an adjuvant)). Immunostimulators include, but are not limited to, polyinosinic:polycytidylic acid (poly 1C) and interferons.

Reported immunostimulators include, but are not limited to, agonists of ator of IFN genes (STING) and interleukins. Reported immunostimulators further include, but are not limited to, HBsAg e inhibitors, TLR—7 agonists (such as, but not limited to, 0, RG- 7795), T-cell stimulators (such as, but not limited to, GS-4774), RIG-1 inhibitors (such as, but not limited to, 0), and SMAC-mimetics (such as, but not limited to, Birinapant). 09 Oligomeric Nucleotides ed oligomeric nucleotides targeted to the Hepatitis B genome include, but are not limited to, Arrowhead-ARC-520 (see US. Patent No. 8,809,293, and Wooddell el al., 2013, Molecular Therapy 21(5):973—985, all of which incorporated herein in their entireties by reference).

In certain embodiments, the oligomeric nucleotides can be designed to target one or more genes and/or transcripts of the HBV genome. Oligomeric nucleotide targeted to the Hepatitis B genome also include, but are not limited to, isolated, double stranded, siRNA molecules, that each include a sense strand and an antisense strand that is hybridized to the sense . In certain embodiments, the siRNA target one or more genes and/or transcripts of the HBV genome.

A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429- 453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each equation referred to elsewhere herein may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.

The corresponding graphs associated with the equations referred to elsewhere herein are the concentration-effect curve, ogram curve and combination index curve, respectively.

Synthesis The present invention further provides s of preparing the compounds of the present invention. Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the ture, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard tic methods and procedures for the preparation of organic les and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It should be plated that the invention includes each and every one of the synthetic schemes described and/or depicted herein.

It is iated that where typical or preferred process conditions (1'.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, and so forth) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by e zation procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the e of optimizing the formation of the compounds described herein.

The processes bed herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear ic resonance spectroscopy (e.g., 1H or 13C), ed spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

Preparation of the compounds can involve tion and ection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of ting groups can be found, for example, in Greene, el al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire sure of which is incorporated by reference herein for all purposes.

The reactions or the processes described herein can be carried out in suitable solvents that can be readily selected by one d in the art of organic synthesis. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, 1'. e., temperatures that can range from the solvent’ s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular on step, suitable solvents for a particular reaction step can be selected.

In certain embodiments, a compound of the ion can be prepared, for example, ing to the illustrative synthetic s outlined in Scheme 1: co Me2 co Me2 co H BnBr,K2003 2 R {3: R {3: aq.LiOH SOCI2 x X —>R {:E X —> OH OBn 14 1-2 1-3 O O O R9 o/\ CO2Et z COCI | | | NMe2 0 _. MEI RX 1. LHMDS, THF OBn AcOH, EtOH 1 4_ 2. Et o,a2 q .HCI 1_5 o o COZEt COgEt H2! PM; Pth, DIAD, N RC N RC Rx —>Rx —> RX —> Eth,THF OBn R9 OH OH R9 OH 1-6 1-7 chiral SFC separation Rx Scheme 1.

In certain embodiments, a compound of the invention can be prepared, for example, according to the rative synthetic methods outlined in Scheme 11: OH OMs l: Et3N, MsCI RC NHBoc RC NHBoc 2-1 2-2 CH0 OMS K2003, DMF CH0 HCI, CHZCIZ \N RX + RX —>RX OH RC NHBoc o j—RC 2-3 2-2 COZEt ranil RC —> chiral SFC separation RX Scheme 11.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme III: o o wo/\ COZEt / NHBOC I I COCI fl: SOCI2 NMe2 o —» RX RX Br 1. LHMDS Br AcOH, EtOH 2. HCI 3_2 3_3 1. 9-BBN, THF 2. Pd(dppf)C|2, 082003 chiral SFC separation 3-7A 3-7B Scheme III.

In certain ments, a compound of the ion can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme IV: CI N RbBrfiSzCOerMF CI N 25% MeONa/MeOH /o N Pd2(dba)3rXantphosr / / \ | | t—BuONa \ \ / HO Br RbO Br RbO Br 4-1 4-2 4-3 Rcll\ o N o N o N J300 Br2,NaOAc, / \ O / \ / \ NH | “”2 (30°)2OvEtSN ,NaBH3CN | | aceticacid / / / RbO RC —> Rbo RC—>RbO RC —> 4-4 4-5 4-6 300 n-BuLi; then DMF | /0w, /0 IN\ Boc TFA,CH20I2 \— NH, /o |N\ \N / / / RbO Rc Rbo R° RbO RC 4-7 4-8 4-9 OEt OEt p-Chloranil LiOH, MeOH/HZO Scheme IV.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme V: /S"o o / OEt Ra N | F LIOH- \ \ N I OEt RbO "'RC an2, CchN -1 5-2 5-3 Scheme V.

In certain embodiments, a nd of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme VI: aco Me2 CI co M2 e CI co M2 e SOZCIZ, CHZCIZ fl BnBr, K2003 LiOH, MeOH HO OH HO OH BnO1:1OBn 6-1 6-2 6-3 0 o O O H2N IIIRC CIUCO H2 CI COCI C | H SOCI2 NMe2 o —, U —, BnO OBn BnO OBn BnO OBn LiHMDS, THF, ACOH, EtOH -78 lo 15 0C 6-4 6-5 6-6 0 0 CI OEt l l H2, Pd/C PPhg, DEAD .,,Rc LiOH, 1,4—dioxane/H 20 Scheme VI.

In certain ments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods ed in Scheme VII: OEt OEt RbBr, K2003, DMF RaBF3K or RaB(OH)2 )2, XPhos Scheme VII.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme VIII: aCO Me2 Br Br CO Me Brz, AcOH 1:1CO Me2 BnBr, K2003 RaBFaK or RaB(OH)2 —> U — HO OH HO OH BnO OBn Pd(OAc)2, XPhos 8-1 8-2 8-3 Ra COgMe Ra R LiOH, MeOH 002“ 000' SOCI2 INMez —> —> BnO OBn BnO OBn BnO OBn LiHMDS THF 3-4 8-5 8-6 —78 to 15 °C {3”chH H2, Pd/C AcOH, EtOH RbBr, K2003, DMF LiOH, 1,4—dioxane/H20 Scheme VIII.

In certain embodiments, a nd of the invention can be ed, for example, according to the illustrative synthetic methods outlined in Scheme IX: PhNTf2, TEA RUN” —> —> LiOH, MeOH/HZO 9-3 9-4 Scheme IX.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme X: O\B BIO N 1 _ . 0’ \O a a HOWARCH, R N\ R Pd(dppf)C|2 N\ I2, NaZCO3 Ra N\ I Rg 10-5 | | —> | / / Rho Br Rho / 2- H202 RbO OH DIAD,PPh3 1°" 10-2 10-3 Scheme X.

In certain ments, a compound of the invention can be prepared, for example, according to the illustrative synthetic s outlined in Scheme XI: Rh, WW K2003, Nal m" EtOH, AcOH Ra “1IWOHN SOCI2,EtOH “:ng PdBr2,KOAc \ —> —> Scheme XI.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XII: 1.n—BuLi Dos/IO O O 0/» o’ ‘N—Boc 1 ( RI )ijOEt RI 0 I RC \N / \ Ri' / EtO Ri' —’ S —’ S Re 2. HCI, 1,4-dioxane/H20 EtOH 12-1 12-2 aq. NaOH 12-3 12-4 12-5 Scheme XII.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XIII: BOCHN NH2 BocHN N/ OH N/ (Boc)2O,TEA N/ n—BuLi,R°CHO | MsCI, TEA | | — —’ \ \ \ Rbo R° Rbo Rbo 13-1 13-2 0 o BocHN / \ EtoJE/k N/ Eto OMS N/ NH | 1.HC| NBS N\ | | —> b \ —> \ —> Rbo R° R O Rc R Ob Rc EtOH 2. Ncho3 13-4 13-5 p—chloranil 13-7 13-8 Scheme XIII.

In certain embodiments, a nd of the invention can be prepared, for example, according to the rative synthetic methods outlined in Scheme XIV: 09 ’IO 0 O 0 N’BOO /\/OH 0 1.n—BuLi CE CHO /2 l\ I N N N \ OEt N —* N / \ HHI MeOAl #PTSA s MeO 2. HCI, 1,4-dioxane/HZO s s RC EtOH HO—</s 14-1 14-2 14-3 p-chloranil H0—(’ 14-6 14.7 Scheme XIV.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative tic methods outlined in Scheme XV: 1. n—BuLi o o 0°84) o/ ‘N’Boc OH O ‘—< 2Kfkoa HO/\/ OEt CH0 /2 RC N \N _, N . / \ \ PTSA RJ,4 RJ—</ 2. HCI,1,4-dioxane/H20 3 RC EtOH 8 3 -1 15-2 15-3 0 0 I p—chloranll. NaOH N —> —.

. N RJ—</ l RJ—</_ S RC 154 15-5 15-6 Scheme XV.

In n embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XVI: mom BnO NH4OAc, NaBchN B BnO RC BnOnomz BnO Br Pd2(dba)3, Xamphos, RC t—BUONa 16-1 16-2 0 16-3 B 3| BnO RC BnO RC 16-4 16-5 002Et N p—chloranil BnO Rc 16-6 16-7 16-8 Scheme XVI.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XVII: v X o o RKCR” HO R° K2003, DMF 17—1 17—2 Rk' + 17-3 17-3A 17-3B Scheme XVII.

In certain embodiments, a compound of the invention can be prepared, for example, ing to the illustrative synthetic s outlined in Scheme XVIII: O O 18-1 13-2 1. H202 O 2. BH3.THF, < Scheme XVIII.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods ed in Scheme XIX: COzEt THPO{ COzEt COzEt || Br N N| N| ch03 DMF HO R° : R° —>HO‘<: R° 19-1 19-2 19-3 0 0 00sz COzH o | | o | | NaH, R'Br or R'I N LiOH N —, R'o R'o O R0 0 RC Scheme XIX.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XX: o 0 )ka0m Ra COCI Rho N/ CI 1.LHMDS,THF 2. HCI Scheme XX.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic s outlined in Scheme XXI: 0 (PF;OEt OH POEt Rm CH2(co2H)2 Ra H2804,MeOH Ra MeP(O)(OEt)2 _. —.

Rho Re Rho Re n-BuLi THF 21-1 21-2 21-3 21-4 0“ ,OEl Me2NCH(OMe)2 MeOH OEtE a a NI p-chloranil :EQE a NI TMSI R _. R R Ra NIO RbO RC RbO RbO TMSCI o o IPIPOEI | | OH RbO Rc Scheme XXI.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative tic methods outlined in Scheme XXII: 1. NHZNHZ 2. )3 Scheme XXII.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XXIII: o HN’N PCI5 or SOCI2 Scheme XXIII.

In certain ments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XXIV: 24-5 0 DPPA, K-OtBu, t—BuOH 24-9 24-10 24-8 Scheme XXIV.

In certain embodiments, a compound of the ion can be prepared, for example, according to the illustrative synthetic methods ed in Scheme XXV: Pd(PPh3)4 I I —> R3 RSSnBu3 -1 25-2 25-3 Scheme XXV.

In certain ments, a compound of the invention can be ed, for example, according to the illustrative synthetic methods outlined in Scheme XXVI: 26-1 26-5 NaOR4/R4OH, DPPA, K-OtBu, Pd(PPh3)4 R4SnBu3 t—BuOH HCI, NaNOz, KI Ra . ”RC -3 26-4 0‘ lo IB—B\ o o Pd(PPh3)4, K2C03 Scheme XXVI.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XXVII: Scheme XXVII.

In n embodiments, a compound of the ion can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XXVIII: 23-1 28-2 Scheme XXVIII.

In certain embodiments, a compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XXIX. In certain ments, compound 29-3 is the E geometric isomer.

Scheme XXIX.

A compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XXX: WO 85619 0 O EtOJj)K 1. EC 2. p—chloranil Scheme XXX.

A compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XXXI: Mel, K2003 Scheme XXXI.

A compound of the invention can be ed, for example, according to the illustrative synthetic methods outlined in Scheme XXXII: chiral SFC separation Scheme XXXII.

A compound of the invention can be prepared, for example, according to the illustrative tic methods outlined in Scheme XXXIII: a Br2, NaOAc, R /N R{11 /N NHBoc R8 /N Br N aceticacid NHBoc I —> HCI I HIRC —> I -iiRC \ .

Rbi Br \ \ 2- Pd(dI0Pf)C|2 Rb‘ Rb' 33-1 NHBoc 33-2 33-3 VII/RC o o :m.”RC r N / P(t Bu)3 Pd G2 | MR0 EtOH AcOH Rb' KOAc 33-4 33-5 33-6 Scheme XXXIII.

A compound of the ion can be prepared, for e, according to the illustrative synthetic methods outlined in Scheme XXXIV: NHB CI) \0 NHB Ru N\ HojfkRgc NH /NH-HC| Rb'lWBoc()CngsiHCI wad [ll R80 b .i RC” —> / —) RC” R RC HATU n—BuLi 0 O Ga(OTf)3 34-1 34-2 34-3 34-4 Ra N Ra N Br 80620 | ”HES? BrziNaOAC- \ | NHggc nBuLi; then DMF —' / R” / RC" r R“ Re" @306 34-5 34-6 34-7 0 o Bow/K HCI Ra |N\ 1. EtO LIOH.

Rb' Rd 2.p-chloranil 34-3 34-9 Scheme XXXIV.

A compound of the invention can be prepared, for example, according to the illustrative synthetic methods outlined in Scheme XXXV: HZN£33k Ra N\ Br Ra Ra RVMgBr Or N\ —. :rLN15b (LN I flI . / b b \ | 2 (RV)ZZn R T? o R" 0 -1 35-2 35-3 Ra N Br I lo PdBr2 KOAc / NH2 Ra EtOH AcOH Scheme XXXV.

The invention provides a method of treating or preventing hepatitis virus infection in a subject. In certain embodiments, the infection comprises hepatitis B virus (HBV) infection. In other embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of at least one compound of the invention. In yet other embodiments, the compound of the invention is the only antiviral agent administered to the subject. In yet other ments, the at least one compound is administered to the subject in a ceutically acceptable composition. In yet other embodiments, the subject is further administered at least one additional agent useful for treating the hepatitis virus infection. In yet other ments, the at least one additional agent comprises at least one selected from the group consisting of e transcriptase inhibitor, capsid inhibitor, cchNA formation inhibitor, sAg secretion inhibitor, oligomeric nucleotide targeted to the Hepatitis B genome, and immunostimulator. In yet other embodiments, the subject is co-administered the at least one nd and the at least one additional agent. In yet other embodiments, the at least one compound and the at least one additional agent are coformulated.

The invention further provides a method of inhibiting and/or reducing HBV surface antigen (HBsAg) ion either directly or indirectly in a subject. The ion further provides a method of reducing or minimizing levels of at least one selected from the group consisting of HBsAg, HBeAg, hepatitis B core protein, and pg RNA, in a HBV-infected subject.

In certain embodiments, the method ses administering to the subject in need thereof a therapeutically effective amount of at least one compound of the invention. In other embodiments, the at least one compound is administered to the subject in a pharmaceutically acceptable ition. In yet other embodiments, the compound of the invention is the only antiviral agent administered to the subject. In yet other embodiments, the subject is further administered at least one onal agent useful for treating HBV infection. In yet other embodiments, the at least one additional agent comprises at least one selected from the group consisting of e transcriptase inhibitor, capsid inhibitor, cchNA formation inhibitor, sAg secretion inhibitor, oligomeric nucleotide targeted to the Hepatitis B genome, and immunostimulator. In yet other ments, the subject is co-administered the at least one nd and the at least one additional agent. In yet other embodiments, the at least one compound and the at least one additional agent are coformulated.

In certain embodiments, the subject is a mammal. In other ments, the mammal is a human.

Pharmaceutical Compositions and Formulations The ion provides ceutical compositions comprising at least one compound of the invention or a salt or solvate thereof, which are useful to practice methods of the invention. Such a pharmaceutical composition may consist of at least one compound of the invention or a salt or solvate thereof, in a form suitable for administration to a subject, or the ceutical composition may comprise at least one compound of the invention or a salt or e thereof, and one or more pharmaceutically acceptable carriers, one or more additional ients, or some combination of these. At least one compound of the invention may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art.

In certain embodiments, the pharmaceutical compositions useful for practicing the method of the invention may be administered to deliver a dose of between 1 ng/kg/day and 100 mg/kg/day. In other embodiments, the pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of between 1 ng/kg/day and 1,000 mg/kg/day.

The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any onal ients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the ition is to be stered. By way of example, the composition may se between 0.1% and 100% (w/w) active ingredient.

Pharmaceutical compositions that are useful in the methods of the ion may be suitably developed for nasal, inhalational, oral, rectal, vaginal, pleural, peritoneal, parenteral, topical, transdermal, ary, intranasal, buccal, lmic, epidural, intrathecal, intravenous or another route of stration. A composition useful within the methods of the invention may be directly administered to the brain, the brainstem, or any other part of the central nervous system of a mammal or bird. Other contemplated formulations include projected nanoparticles, microspheres, liposomal preparations, coated particles, polymer conjugates, resealed erythrocytes containing the active ingredient, and immunologically-based formulations.

In certain embodiments, the compositions of the invention are part of a pharmaceutical matrix, which allows for manipulation of ble materials and improvement of the bioavailability thereof, development of controlled or sustained release products, and generation of homogeneous compositions. By way of example, a pharmaceutical matrix may be prepared using hot melt extrusion, solid solutions, solid dispersions, size reduction technologies, molecular complexes (e.g., cyclodextrins, and others), microparticulate, and le and formulation coating processes. Amorphous or crystalline phases may be used in such processes.

The route(s) of administration will be readily apparent to the d artisan and will depend upon any number of factors including the type and severity of the disease being treated, the type and age of the veterinary or human patient being treated, and the like.

The formulations of the pharmaceutical compositions described herein may be ed by any method known or hereafter developed in the art of pharmacology and pharmaceutics. In general, such preparatory methods include the step of bringing the active ingredient into ation with a carrier or one or more other accessory ingredients, and then, if necessary or ble, shaping or packaging the product into a desired single-dose or multi-dose unit.

As used herein, a “unit dose” is a discrete amount of the pharmaceutical ition comprising a predetermined amount of the active ingredient. The amount of the active ient is generally equal to the dosage of the active ingredient that would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

Although the descriptions of pharmaceutical compositions provided herein are pally directed to pharmaceutical compositions suitable for ethical administration to , it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant s such as cattle, pigs, horses, sheep, cats, and dogs.

In n embodiments, the compositions of the invention are formulated using one or more pharmaceutically acceptable ents or rs. In certain embodiments, the pharmaceutical compositions of the invention comprise a therapeutically ive amount of at least one compound of the invention and a ceutically able carrier.

Pharmaceutically acceptable carriers, which are useful, include, but are not limited to, glycerol, water, saline, ethanol, recombinant human albumin (e.g., RECOMBUTVIIN®), solubilized gelatins (e.g., GELOFUSINE®), and other pharmaceutically acceptable salt ons such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

The r may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, ene , and liquid polyethylene glycol, and the like), recombinant human albumin, solubilized gelatins, suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal , for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, isotonic , for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, are ed in the composition. Prolonged absorption of the able compositions may be brought about by including in the ition an agent that delays absorption, for example, aluminum monostearate or gelatin.

Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, tional, intravenous, subcutaneous, transdermal enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or fragrance- conferring substances and the like. They may also be combined where desired with other active agents, e.g., other sic, ytics or hypnotic agents. As used herein, “additional ingredients” include, but are not limited to, one or more ingredients that may be used as a ceutical carrier.

The composition of the invention may comprise a preservative from about 0.005% to 2.0% by total weight of the ition. The preservative is used to prevent spoilage in the case of exposure to contaminants in the environment. Examples of preservatives useful in accordance with the invention e but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and combinations thereof. One such preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5% sorbic acid.

The composition may include an antioxidant and a chelating agent which inhibit the degradation of the nd. Antioxidants for some compounds are BHT, BHA, alpha- tocopherol and ic acid in the exemplary range of about 0.01% to 0.3%, or BHT in the range of 0.03% to 0. l% by weight by total weight of the composition. The ing agent may be present in an amount of from 0.01% to 0.5% by weight by total weight of the composition.

Exemplary chelating agents include edetate salts (e.g. disodium edetate) and citric acid in the weight range of about 0.01% to 0.20%, or in the range of 0.02% to 0.10% by weight by total weight of the composition. The chelating agent is useful for chelating metal ions in the composition that may be detrimental to the shelf life of the formulation. While BHT and disodium edetate are ary antioxidant and chelating agent, respectively, for some compounds, other suitable and lent antioxidants and chelating agents may be substituted therefore as would be known to those d in the art.

Liquid suspensions may be prepared using conventional methods to e suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water, and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, , or t oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further se one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting , emulsifying agents, ents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl ose.

Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as in, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a l ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, in, acacia, and ionic or non ionic surfactants. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl para-hydroxybenzoates, ascorbic acid, and sorbic acid.

Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and rin.

Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent. As used herein, an “oily” liquid is one which comprises a -containing liquid molecule and which ts a less polar character than water. Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water, and isotonic . Oily solvents e, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

Powdered and ar formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill es, or to prepare an aqueous or oily suspension or solution by addition of an s or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a ding agent, ionic and non-ionic surfactants, and a preservative. onal excipients, such as fillers and sweetening, flavoring, or coloring agents, may also be included in these ations.

A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of -water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.

Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a e, methods of incorporating a chemical composition into the structure of a material during the sis of the material (1'.e., such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying. Methods for mixing components include physical milling, the use of pellets in solid and sion ations and mixing in a transdermal patch, as known to those skilled in the art.

Administration/Dosing The regimen of administration may affect what constitutes an ive amount. The therapeutic formulations may be stered to the patient either prior to or after the onset of a disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

Administration of the compositions of the present invention to a patient, such as a mammal, such as a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder contemplated herein. An ive amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to s such as the activity of the particular compound ed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, nds or materials used in combination with the compound, the state of the disease or disorder, age, sex, , condition, general health and prior medical history of the patient being treated, and like factors nown in the medical arts. Dosage ns may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an ive dose range for a therapeutic compound of the invention is from about 0.01 mg/kg to 100 mg/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the ination regarding the effective amount of the therapeutic compound t undue experimentation.

The compound may be administered to an animal as frequently as several times daily, or it may be stered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. It is understood that the amount of compound dosed per day may be administered, in non- limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. The frequency of the dose is readily apparent to the skilled artisan and depends upon a number of factors, such as, but not limited to, type and ty of the e being treated, and type and age of the animal.

Actual dosage levels of the active ingredients in the ceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to e the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

A medical doctor, e.g., ian or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical ition required. For example, the physician or veterinarian could start doses of the compounds of the invention ed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially ageous to formulate the compound in dosage unit form for ease of stration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated, each unit ning a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the tions nt in the art of compounding/formulating such a therapeutic compound for the treatment of a disease or er in a t.

In certain embodiments, the compositions of the invention are administered to the t in dosages that range from one to five times per day or more. In other embodiments, the compositions of the invention are administered to the t in range of dosages that include, but are not limited to, once every day, every two days, every three days to once a week, and once every two weeks. It will be readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention will vary from subject to subject depending on many factors ing, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient will be determined by the attending physician taking all other factors about the patient into account.

Compounds of the invention for administration may be in the range of from about 1 mg to about 7,500 mg, about 20 mg to about 7,000 mg, about 40 mg to about 6,500 mg, about 80 mg to about 6,000 mg, about 100 mg to about 5,500 mg, about 200 mg to about 5,000 mg, about 400 mg to about 4,000 mg, about 800 mg to about 3,000 mg, about 1 mg to about 2,500 mg, about 2 mg to about 2,000 mg, about 5 mg to about 1,000 mg, about 10 mg to about 750 mg, about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about 150 mg, and any and all whole or partial increments there-in-between.

In some ments, the dose of a compound of the invention is from about 0.5 mg and about 5,000 mg. In some embodiments, a dose of a nd of the invention used in compositions described herein is less than about 5,000 mg, or less than about 4,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

In certain embodiments, the present invention is directed to a packaged pharmaceutical ition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent, and ctions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder in a patient.

The term iner” includes any receptacle for holding the pharmaceutical composition or for managing stability or water uptake. For example, in certain embodiments, the ner is the packaging that contains the pharmaceutical composition, such as liquid (solution and suspension), semisolid, lyophilized solid, solution and powder or lyophilized formulation present in dual chambers. In other embodiments, the container is not the ing that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition. Moreover, packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional onship to the packaged product.

However, it should be tood that the instructions may contain information pertaining to the compound’s ability to perform its intended function, e.g., treating, ting, or reducing a disease or disorder in a patient.

Administration Routes of administration of any of the compositions of the invention include inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, l, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and ginally), (intra)nasal, and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, emulsions, dispersions, suspensions, ons, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the t invention are not limited to the ular formulations and compositions that are described herein.

Oral Administration For oral application, ularly suitable are s, s, liquids, drops, es, caplets and gelcaps. Other ations suitable for oral administration include, but are not limited to, a powdered or granular formulation, an aqueous or oily suspension, an aqueous or oily solution, a paste, a gel, toothpaste, a mouthwash, a coating, an oral rinse, or an emulsion. The compositions ed for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic, lly recognized as safe (GRAS) pharmaceutically excipients which are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose, granulating and disintegrating agents such as cornstarch, binding agents such as starch; and lubricating agents such as ium stearate.

Tablets may be non-coated or they may be coated using known s to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in US. Patents Nos. 4,256,108, 452, and 4,265,874 to form osmotically controlled release tablets. Tablets may further comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for ceutically elegant and ble preparation. Hard es comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. The capsules comprise the active ingredient, and may further comprise additional ingredients including, for e, an inert solid diluent such as m carbonate, calcium phosphate, or kaolin.

Hard capsules comprising the active ingredient may be made using a physiologically degradable composition, such as gelatin. Such hard capsules comprise the active ingredient, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium ate, or kaolin.

Soft gelatin capsules sing the active ingredient may be made using a physiologically degradable composition, such as gelatin from animal-derived collagen or from a hypromellose, a modified form of cellulose, and manufactured using optional mixtures of n, water and plasticizers such as sorbitol or glycerol. Such soft capsules comprise the active ingredient, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

For oral administration, the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents, fillers, lubricants, egrates, or wetting agents. If desired, the tablets may be coated using le methods and coating als such as ® film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY® OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY® White, 32K18400). It is understood that similar type of film coating or polymeric products from other companies may be used.

A tablet comprising the active ingredient may, for example, be made by compressing or molding the active ingredient, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable , the active ingredient in a free- flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a e active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to moisten the mixture.

Pharmaceutically acceptable excipients used in the cture of tablets include, but are not limited to, inert diluents, granulating and disintegrating , binding agents, and ating agents. Known dispersing agents include, but are not limited to, potato starch and sodium starch glycolate. Known surface-active agents include, but are not limited to, sodium lauryl sulphate.

Known diluents include, but are not limited to, calcium ate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate. Known granulating and disintegrating agents include, but are not limited to, corn starch and alginic acid. Known binding agents include, but are not d to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricating agents include, but are not limited to, magnesium stearate, c acid, silica, and talc.

Granulating techniques are well known in the pharmaceutical art for ing starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a “granulation.” For e, solvent-using “wet” ation ses are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions ing in the formation of a wet granulated mass from which the solvent must then be evaporated.

Melt granulation generally consists in the use of materials that are solid or semi-solid at room temperature (1'.e., having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid ts. The low melting solids, when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium. The liquefied solid s itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together. The resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form.

Melt ation improves the dissolution rate and bioavailability of an active (i.e., drug) by forming a solid sion or solid solution.

US. Patent No. 5,169,645 discloses directly compressible waX-containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow ing additives, ed by cooling and granulation of the admixture. In certain ments, only the waX itself melts in the melt combination of the waX(es) and additives(s), and in other cases both the waX(es) and the additives(s) will melt.

The present invention also includes a layer tablet comprising a layer providing for the delayed release of one or more compounds useful within the methods of the invention, and a further layer providing for the immediate release of one or more compounds useful within the methods of the invention. Using a waX/pH-sensitive polymer miX, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.

Liquid preparation for oral stration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as ding agents (e.g., ol syrup, methyl cellulose or hydrogenated edible fats), emulsifying agent (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol), and preservatives (e.g., methyl or propyl para-hydroxy benzoates or sorbic acid). Liquid formulations of a pharmaceutical composition of the invention which are le for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.

Parenteral Administration As used herein, “parenteral administration” of a pharmaceutical composition includes any route of stration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition h a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrastemal injection, and kidney dialytic infusion techniques.

Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for uous administration. able formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multidose containers containing a preservative. able formulations may also be prepared, ed, or sold in devices such as patient-controlled analgesia (PCA) devices. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable ned-release or biodegradable formulations. Such ations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a ation for parenteral administration, the active ingredient is provided in dry (1'. e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be ed using a non-toxic parenterally acceptable diluent or solvent, such as water or l,3-butanediol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer’s solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form in a inant human albumin, a fluidized n, in a liposomal preparation, or as a component of a biodegradable polymer system. itions for sustained release or tation may comprise ceutically able ric or hydrophobic als such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.

Topical stration An obstacle for topical administration of pharmaceuticals is the stratum corneum layer of the epidermis. The stratum corneum is a highly resistant layer comprised of protein, cholesterol, sphingolipids, free fatty acids and various other lipids, and includes comif1ed and living cells.

One of the factors that limit the penetration rate (flux) of a compound through the stratum m is the amount of the active substance that can be loaded or applied onto the skin surface. The greater the amount of active substance which is applied per unit of area of the skin, the greater the concentration gradient between the skin surface and the lower layers of the skin, and in turn the greater the diffusion force of the active nce through the skin. Therefore, a formulation ning a greater concentration of the active substance is more likely to result in penetration of the active substance through the skin, and more of it, and at a more consistent rate, than a formulation having a lesser concentration, all other things being equal.

Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid preparations such as liniments, lotions, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes, and solutions or sions. Topically strable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient may be as high as the lity limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ients described herein. 2O Enhancers of tion may be used. These materials increase the rate of ation of drugs across the skin. Typical enhancers in the art include ethanol, glycerol monolaurate, PGML (polyethylene glycol urate), dimethylsulfoxide, and the like. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar , or N—methylpyrrolidone.

One acceptable vehicle for l delivery of some of the compositions of the invention may contain liposomes. The composition of the liposomes and their use are known in the art (i.e., US. Patent No. 6,323,219).

In alternative embodiments, the lly active pharmaceutical composition may be optionally combined with other ingredients such as adjuvants, anti-oxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifying agents, viscosif1ers, buffering agents, preservatives, and the like. In other embodiments, a permeation or penetration enhancer is included in the composition and is effective in improving the percutaneous penetration of the active ingredient into and through the m corneum with respect to a composition lacking the permeation enhancer. Various tion enhancers, ing oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, or N- methylpyrrolidone, are known to those of skill in the art. In another aspect, the composition may further comprise a hydrotropic agent, which functions to se disorder in the structure of the m corneum, and thus allows increased transport across the stratum corneum. Various hydrotropic agents such as isopropyl alcohol, propylene glycol, or sodium xylene sulfonate, are known to those of skill in the art.

The topically active pharmaceutical composition should be applied in an amount effective to affect desired changes. As used herein “amount effective” shall mean an amount sufficient to cover the region of skin surface where a change is desired. An active compound should be present in the amount of from about 0.0001% to about 15% by weight volume of the composition. For example, it should be present in an amount from about 0.0005% to about 5% of the composition, for example, it should be present in an amount of from about 0.001% to about 1% of the composition. Such compounds may be synthetically-or naturally d.

Buccal Administration A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) of the active ingredient, the balance comprising an orally dissolvable or degradable composition and, optionally, one or more of the additional ingredients described herein. Altemately, formulations suitable for buccal stration may comprise a powder or an aerosolized or atomized on or suspension sing the active ingredient. Such ed, lized, or aerosolized formulations, when dispersed, may have an e particle or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein. The examples of formulations described herein are not exhaustive and it is understood that the ion includes onal modifications of these and other formulations not described herein, but which are known to those of skill in the art.

Rectal Administration A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for rectal administration. Such a composition may be in the form of, for example, a suppository, a retention enema preparation, and a solution for rectal or c irrigation.

Suppository ations may be made by combining the active ingredient with a non-irritating pharmaceutically acceptable excipient which is solid at ordinary room temperature (i. e., about 20 C) and which is liquid at the rectal temperature of the subject (i. e., about 37 C in a healthy human). Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycols, and various glycerides. Suppository formulations may further comprise various additional ingredients including, but not limited to, antioxidants, and preservatives.

Retention enema preparations or solutions for rectal or colonic irrigation may be made by combining the active ingredient with a pharmaceutically able liquid carrier. As is well known in the art, enema ations may be administered using, and may be packaged within, a delivery device adapted to the rectal anatomy of the subject. Enema preparations may further comprise various additional ingredients including, but not limited to, idants, and preservatives.

Additional Administration Forms Additional dosage forms of this invention include dosage forms as bed in US.

Patents Nos. 6,340,475, 6,488,962, 6,451,808, 389, 5,582,837, and 5,007,790. Additional dosage forms of this invention also include dosage forms as described in US. Patent ations Nos. 20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and 20020051820. Additional dosage forms of this invention also include dosage forms as bed in PCT Applications Nos. WO 03/35041, WO 03/35040, WO 03/35029, WO 03/35177, WO 03/35039, WO 02/96404, WO 02/32416, WO 01/97783, WO 01/56544, WO 01/32217, WO 98/55107, WO 98/11879, WO 97/47285, WO 93/18755, and WO 90/11757.

Controlled e Formulations and Drug Delivery Systems: In certain embodiments, the itions and/or formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, ned release, delayed e and pulsatile release formulations.

The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not arily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.

For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use the method of the invention may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.

In certain embodiments of the invention, the compounds useful within the ion are administered to a subject, alone or in ation with another pharmaceutical agent, using a sustained release formulation.

The term delayed release is used herein in its tional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that may, although not necessarily, include a delay of from about 10 minutes up to about 12 hours.

The term ile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to e pulsed plasma profiles of the drug after drug administration. 2O The term immediate release is used in its tional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.

As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 s, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or l increments thereof after drug stration.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous lents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims ed hereto. For example, it should be understood, that modifications in reaction conditions, including but not d to on times, reaction size/volume, and mental reagents, such as solvents, sts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

It is to be understood that, wherever values and ranges are ed herein, the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, all values and ranges encompassed by these values and ranges are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The description of a range should be ered to have specifically sed all the possible sub- ranges as well as individual numerical values within that range and, when appropriate, partial integers of the numerical values within ranges. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as dual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the 2O range.

The following examples further illustrate aspects of the present invention. r, they are in no way a limitation of the teachings or disclosure of the present invention as set forth herein.

EXAMPLES The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only, and the invention is not limited to these Examples, but rather encompasses all variations that are t as a result of the teachings provided herein.

Materials & Methods The following procedures can be utilized in preparing and/or testing exemplary compounds of the invention. For those compounds for which absolute chemistries are disclosed herein, the assignment of ity is based on X-ray crystallographic terization of the compound, or use of an enantiomerically and/or diastereoisomerically pure chiral intermediate in the compound synthesis.

EXAMPLE 1: 2-Chlor0is0pr0pylmethoxy0x0-6,7-dihydr0-1 1H- Benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid CIUCOZMG Methyl 2—(benzyloxy)chl0r0meth0xybenz0ate M90 OBn A mixture of methyl 5-chlorohydroxymethoxybenzoate (10.83 g, 50 mmol, prepared according to US. Pat. Appl. Publ. U820100168080), benzyl bromide (9.4 mL, 55 mmol) and potassium carbonate (13.8 g, 100 mmol) in DMF (100 ml) were stirred at room temperature overnight. The system was filtered, and ts d under vacuum. The residue was dissolved in dichloromethane (200 mL), washed with water and dried over sodium sulfate, and solvents removed to give methyl 2-(benzyloxy)chloromethoxybenzoate as a white solid that was used without further purification (l3.8g, 90% yield, m/z: 307 [M+H]+ observed). 1H NMR (300 MHz, : 5 7.82 (d, J: 2.5 Hz, 1 H), 7.56-7.35 (m, 5 H), 7.10 (d, J=2.5 Hz, 1 H), 5.25 (s, 2H), 3.91 (s, 3 H) and 3.82 (s, 3 H).

CIUCOZH 2-(Benzyloxy)—5-chlor0meth0xybenz0ic acid M90 OB“ 2O To a solution of methyl 2-(benzyloxy)chloromethoxybenzoate (12.28 g, 40 mmol) in dioxane (250 mL), aq. LiOH (40 mL of 2 M solution) was added and stirred at room temperature overnight. Solvents were removed under vacuum, and the contents were acidified with 1N aq.

HCl (90 mL). The precipitate was filtered, washed with water (100 mL) and air-dried to h 2-(benzyloxy)chloromethoxybenzoic acid as a white solid, which was used t further purification (ll.6g, 98% yield, m/z: 293 [M+H]+ observed). 1H NMR (300 MHZ, CDCl3): 5 12.60 (bs, 1H), 7.70 (s, 1 H), 7.48-7.30 (m, 5 H), 6.95 (s, 1 H), 5.20 (s, 2H) and 3.85 (s, 3 H).

CIUCOCIOBn 2-(Benzyloxy)—5-chl0r0meth0xybenz0yl chloride M90 A mixture of zyloxy)chloromethoxybenzoic acid (5.84 g, 20 mmol) and thionyl chloride (15 mL) was stirred at 80 0C for 4h. The reaction mixture was trated under vacuum, and the crude was subjected to azeotropic distillation with toluene (2 x 20 mL) and then dried under high vacuum for 2h to yield 2-(benzyloxy)chloromethoxybenzoyl chloride that was used without further purification (5.85g, quantitative). 2-(2-(Benzyloxy)chl0r0meth0xyphenyl)-4H-pyran0ne MeO OBn To a solution of LiHMDS (36 ml, 34 mL, 1.06 M in THF) in anhydrous THF (50 mL) at -78 °C (dry ice/acetone bath ) under argon, a solution of ethyl (Z)((dimethylamino)methylene) anoate (2.78 g, 15 mmol) and zyloxy)chloromethoxybenzoyl chloride (4.67 g, mmol) in 50 mL anhydrous THF was added dropwise over 10 min. The dry ice/acetone bath was d and the solution was warmed to room temperature over a 30 min period. Diethyl ether (100 mL) was added to the reaction mixture, followed by 3N aq. HCl (60 mL, 180 mmol) and stirred the contents overnight. Organic ts were removed under vacuum at below 20 oC and the contents were treated with saturated aqueous bicarbonate on until the aqueous layer reached basic pH, and the system was stirred vigorously for 10 min. The precipitate was filtered, washed with water, dissolved in dichloromethane, dried over sodium sulfate and concentrated to give dark orange residue (6.5 g). The residue was purified by normal phase SiOz chromatography (10% to 100% EtOAc/hexanes) to furnish 2-(2-(benzyloxy)chloro methoxyphenyl)-4H-pyranone as an orange solid, which upon crystallization from methanol (30 mL) yielded 2-(2-(benzyloxy)chloromethoxyphenyl)-4H-pyranone as a white solid (2.49g, 40% yield, m/z: 415 [M+H]+ observed). 1H NMR (400 MHz, : 5 8.54 (s, 1 H), 7.74 (s, 1H), 7.45—7.32 (m, 5 H), 7.20 (s, 1H), 6.57 (s, 1H), 5.25 (s, 2 H), 4.37 (q, J=2.4 Hz, 2 H), 3.85 (s, 3 H) and 1.30 (t, J=2.4Hz, 3H).

Ethyl 6-(2-(benzyloxy)chlor0meth0xyphenyl)(1-hydr0xy—3—methylbutanyl)-4—0x0- WO 85619 o o C' 0“ | I MeO 2 < 1,4-dihydr0pyridinecarb0xylate OH To a mixture of 2-(2-(benzyloxy)chloromethoxyphenyl)-4H-pyranone (208 mg, 0.5 mmol) in AcOH/EtOH (10 mL, 2:3 ratio), D,L-valinol (76 mg, 0.75 mmol) was added and the contents were refluxed for 4h. The reaction e was concentrated under vacuum, and the residue was purified by normal phase Si02 chromatography (0% to 10% MeOH/CHzClz) to h ethyl 6-(2-(benzyloxy)chloromethoxyphenyl)(1-hydroxy-3 -methylbutanyl) 4-dihydropyridinecarboxylate as an orange solid, which was collected upon crystallization from methanol (30 mL) yielded ethyl 6-(2-(benzyloxy)chloro methoxyphenyl)(1-hydroxy-3 -methylbutanyl)oxo-1,4-dihydropyridine-3 -carboxylate as a white foam (125 mg, 50% yield, m/z: 500 [M+H]+ observed). 1H NMR (300 MHz, CDCl3): 5 8.36 (s, 1 H), 7.63 (s, 1H), 7.40-7.28 (m, 5 H), 7.15 (d, J=3.0 Hz, 1H), 6.10 (d, J=3.0 Hz, 1 H), .20 (bs, 2 H), 4.25 (q, J=2.0 Hz, 2 H), 3.95 (s, 3 H), 3.80-3.85 (m, 1H), 3.60-3.45 (m, 2H), 2.45- 2.20 (m, 1H), 1.30 (t, J=2.0Hz, 3H), 0.95-0.92 (dd, J=2.2 &1.0 Hz, 3H) and 0.75-0.67 (dd, J=6.0 & 2.2 Hz, 3H).

Ethyl 6—(5-chl0r0hydr0xy—4—methoxyphenyl)(1-hydr0xy-3—methylbutanyl)-4—0x0-1,4- o 0 dihydropyridinecarb0xylate A mixture of ethyl 6-(2-(benzyloxy)chloromethoxyphenyl)(1-hydroxymethyl butan- 2-yl)oxo-1,4-dihydropyridinecarboxylate (100 mg, 0.20 mmol) and 10% Pd/C (50 mg) in ethanol (10 mL) were hydrogenated at 2 psi for 5 min using Parr-shaker apparatus. The on mixture was filtered through celite, concentrated under vacuum to give ethyl 6-(5-chloro hydroxymethoxyphenyl)(1-hydroxy-3 -methylbutanyl)oxo-1,4-dihydropyridine-3 - carboxylate, which was used without further ation (82 mg, 99% yield, m/z: 410 [M+H]+ observed). 1H NMR (300 MHz, DMSO-d6): 6 8.24 (s, 1 H), 7.20 (s, 1H), 6.64 (s, 1H), 6.04 (s, 1 H), 4.20 (q, J=2.4 Hz, 2 H), 3.93-3.86 (m, 1H), 3.79 (s, 3 H), 3.60-3.45 (m, 2H), 1.23 (t, J=2.4Hz, 3H), 0.85-0.81 (m, 1H), 0.59 (s, 3H) and 0.52 (s, 3H).

Ethyl 2-chl0r0- 7-is0pr0pyl—3—meth0xy—11-0x0-6, 7-dihydr0—11H—benz0[flpyrid0[1,2-d][1,4] oxazepine-l 0—carb0xylate To a mixture of ethyl 6-(5-chlorohydroxymethoxyphenyl)(1-hydroxymethylbutan yl)oxo-1,4-dihydropyridinecarboxylate (60 mg, 0.15 mmol) and Ph3P (78 mg, 0.3 mmol) and triethylamine (0.2 mL) in anhydrous dichloromethane (20 mL) at 0 CC, DIAD (60 uL, 0.3 mmol) was added dropwise and the ts were d at rt for 6h under argon. Additional P Ph3 (78 mg) and DIAD (60 uL, 0.3 mmol) were added and stirred for another 16 h. The reaction mixture was concentrated under vacuum, and the residue was purified by normal phase Si02 chromatography (0% to 10% MeOH/CHzClz) to furnish ethyl 2-chloroisopropylmethoxy- -6,7-dihydro-11H-benzo[f]pyrido[1,2-d][1,4]oxazepine- 10-carboxylate (27 mg, 50% yield, m/z: 392 [M+H]+ observed). 1H NMR (300 MHz, : 5 8.14 (s, 1 H), 7.50 (s, 1 H), 6.67 (s, 1H), 6.59 (s, 1 H), 4.70-4.50 (m, 2 H), 4.43-4.35 (q, J=2.4 Hz, 2 H), 3.93 (s, 3H), 3.75- 3.66 (m, 1 H), 2.10-1.98 (m, 1H), 1.40 (t, z, 3H), 1.65 (d, J=2.2 Hz, 3H) and 0.88 (d, J: 2.2 Hz, 3H).

EXAMPLE 2: 2-Chlor0is0pr0pylmethoxy0x0-6,7-dihydr0-1 1H- benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid To a mixture of ethyl 2-chloroisopropylmethoxyoxo-6,7-dihydro-11H- benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylate (16 mg, 0.04 mmol) in dioxane (3 mL), aqueous LiOH (7 mg in 0.2 mL, 0.4 mmol) was added and stirred at room temperature overnight.

The reaction mixture was concentrated under vacuum, and the residue was dissolved in water (2 mL), cooled to 10 oC, acidified with 1N aq. HCl to pH 2-3. The precipitate was filtered and washed with 2 mL of water, and the precipitate was vacuum-dried to furnish 2-chloro isopropylmethoxy-1 1-oxo-6,7-dihydro-1 1H-benzo[f]pyrido[1,2-d][1,4]oxazepine carboxylic acid as a white solid (13 mg, 87% yield, m/z: 364 [M+H]+ observed). 1H NMR (300 MHz, DMSO-d6): 5 8.76 (s, 1 H), 7.73 (s, 1 H), 7.00 (s, 1H), 6.86 (s, 1 H), 4.68 (brd, J=1 Hz, 1 H), 4.53 (brd, J=3.5 Hz, 1 H), 3.89 (s, 3H), 3.33 (bs, 1 H), 1.81 (bs, 1H), 0.95 (d, J: 2.2 Hz, 3H) WO 85619 and 0.68 (d, J: 2.2 Hz, 3H).

EXAMPLE 3: (R)Chlor0is0pr0pylmeth0xy-1 1-0x0-6,7-dihydr0-1 1H- benzo[f]pyrido [1,2-d][1,4]oxazepine—lO-carboxylic acid EXAMPLE 4: (S)Chlor0is0pr0pylmethoxy0x0-6,7-dihydr0-11H- O O benzo[f] pyrido [1,2-d][1,4]oxazepine—lO-carboxylic acid 100 mg of the mixture of enantiomers was separated by SFC (supercritical fluid chromatography) on an AD-H column using 40% EtOH (0.1% aq. NH3) as a r to give (R)chloroisopropylmethoxy-1 1-oxo-6,7-dihydro-1 zo[f]pyrido[1,2- d][1,4]oxazepinecarboxylic acid as a white solid (faster eluting enantiomer, 17.6 mg, 17%, m/z: 364 [M+H]+ observed) and (S)chloroisopropylmethoxyoxo-6,7-dihydro-11H- benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylic acid as a white solid (slower eluting enantiomer, 11 mg, 11%, m/z: 364 [M+H]+ observed).

Example 3: (R)Chlor0is0pr0pylmeth0xy0x0-6,7-dihydr0-11H-benz0[f]pyrid0 [1,2-d][1,4]0xazepinecarb0xylic acid. m/z: 364 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6): 5 8.76 (s, 1 H), 7.73 (s, 1 H), 7.00 (s, 1H), 6.86 (s, 1 H), 4.68 (brd, J=1 Hz, 1 H), 4.53 (brd, J=3.5 Hz, 1 H), 3.89 (s, 3H), 3.33 (bs, 1 H), 1.81 (bs, 1H), 0.95 (d, J: 2.2 Hz, 3H) and 0.68 (d, J: 2.2 Hz, 3H).

Example 4: (S)Chlor0is0pr0pylmethoxy0x0-6,7-dihydr0-11H-benz0[f]pyrid0 [1,2-d][1,4]0xazepinecarb0xylic acid. m/z: 364 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6): 5 8.76 (s, 1 H), 7.73 (s, 1 H), 7.00 (s, 1H), 6.86 (s, 1 H), 4.68 (brd, J=1 Hz, 1 H), 4.53 (brd, J=3.5 Hz, 1 H), 3.89 (s, 3H), 3.33 (bs, 1 H), 1.81 (bs, 1H), 0.95 (d, J: 2.2 Hz, 3H) and 0.68 (d, J: 2.2 Hz, 3H).

The following example were prepared in a similar manner as (R)chloroisopropyl methoxy-l l-oxo-6,7-dihydro-l lH-benzo[f]pyrido ] [ l ,4]oxazepine- l O-carboxylic acid and (S)—2-chloroisopropyl-3 -methoxy-l l-oxo-6,7-dihydro-l lH-benzo[f]pyrido[ l ,2-d] [ l ,4] oxazepine- l O-carboxylic acid from 2-(2-(benzyloxy)chloromethoxyphenyl)-4H-pyran one and an appropriate amine.

EXAMPLE 5: 2-Chl0r0is0butylmeth0xy-1 6,7-dihydr0-1 1H-benz0 [f] pyrido [1,2- 0 o d] [1,4]oxazepine-lO-carboxylic acid m/z: 378 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.74 (s, 1H), 7.78 (s, 1H), .98 (m, 2H), 4.62 (m, 3H), 3.93 (s, 3H), 1.61 (m, 2H), 1.46 (m, 2H), 0.81 (m, 6H).

EXAMPLE 6: (S)Chlor0is0butylmethoxy-l1-0x0-6,7-dihydr0-11H- benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid EXAMPLE 7: (R)Chlor0is0butylmethoxy0x0-6,7-dihydr0-11H- o o CI OH l I benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid o—jNH”)\ 84 mg of the mixture of omers was separated by SFC (supercritical fluid chromatography) on an AS column using 35% EtOH (0.1% aq. NH3) as a modifier to give (S)—2-chloroisobutylmethoxy-l l-oxo-6,7-dihydro-l zo[f]pyrido[ l ,2-d] [ l ,4]oxazepine- l O-carboxylic acid as a white solid (faster eluting enantiomer, 42 mg, 50%, m/z: 378 [M+H]+ observed) and (R) chloroisobutyl-3 -methoxy-l l-oxo-6,7-dihydro-l lH-benzo[f]pyrido[ l ,2-d] [ l ,4]oxazepine- l O- carboxylic acid as a white solid r eluting enantiomer, 40 mg, 47%, m/z: 378 [M+H]+ observed).

Example 6: (S)Chlor0isobutylmeth0xy0x0-6,7-dihydr0-1 1H- benzo[f]pyrido[1,2-d][1,4]oxazepine—lO-carboxylic acid. m/z: 378 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.74 (s, 1H), 7.78 (s, 1H), 6.99~6.98 (m, 2H), 4.62 (m, 3H), 3.93 -lO3- (s, 3H), 1.61 (m, 2H), 1.46 (m, 1H), 0.81 (m, 6H). e 7: Chlor0is0butylmeth0xy0x0-6,7-dihydr0-11H- benzo[flpyrido[1,2-d][1,4]oxazepine—lO-carboxylic acid. m/z: 378 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 6 8.74 (s, 1H), 7.78 (s, 1H), 6.99~6.98 (m, 2H), 4.62 (m, 3H), 3.93 (s, 3H), 1.61 (m, 2H), 1.46 (m, 1H), 0.81 (m, 6H).

EXAMPLE 8: 2-Chlor0ethylmethoxy0x0-6,7-dihydr0-11H-benz0[f] pyrido [1,2- d] [1,4]oxazepine-lO-carboxylic acid m/z: 350 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.70 (s, 1H), 7.77 (s, 1H), 7.00 (s, 1H), 6.99 (s, 1H), 4.61 (m, 3H), 3.93 (s, 3H), 1.82 (m, 2H), 0.87~0.83 (t, J=7.2 Hz, 3H).

EXAMPLE 9: 2-Chlor0(hydr0xymethyl)—3-methoxy0x0-6,7-dihydr0-11H- O O benzo[f] pyrido[1,2-d] xazepine-lO-carboxylic acid OH m/z: 352 [M+H]+ observed . 1H NMR (400MHz, DMSO-d6): 5 16.31 (s, 1H), 8.94 (s, 1H), 7.76 (s, 1H), 7.04 (s, 1H), 6.95 (s, 1H), 5.47 (bs, 1H), 4.63-4.50 (m, 3H), 3.92 (s, 3H), 3.87-3.84 (m, EXAMPLE 10: 2-Chlor0cyclobutylmeth0xy0x0-6,7-dihydr0-11H- benzo[f] pyrido[1,2-d] [1,4]oxazepine—lO-carboxylic acid m/z: 376 [M+H]+ observed . 1HN1\/1R(4001\/1Hz,DMSO-d6): 16.30 (s, 1H), 8.50 (bs, 1H), 7.75 (s, 1H), 6.99 (s, 1H), 6.95 (s, 1H), 4.66 (m, 1H), 4.47 (t, J=12.0 Hz, 1H), 4.44 (m, 1H), 3.92 (s, 3H), 2.91 (m, 1H), 2.03 (m, 1H), 1.87-1.78 (m, 3H), 1.75-1.74 (m, 2H). —104— EXAMPLE 1 1: r0(is0pr0p0xymethyl)—3-methoxy-1 1-0x0-6,7-dihydr0-1 1H- benzo[f] pyrido[1,2-d] [1,4]oxazepine—lO-carboxylic acid m/z: 394 [M+H]+ observed . 1H NMR (400MHz, CDC13): 5 15.60 (s, 1H), 8.92 (s, 1H), 7.49 (s, 1H), 6.74 (s, 2H), .66 (m, 1H), 4.47-4.41 (m, 2H), 3.95-3.93 (m, 4H), 3.84-3.80 (m, 1H), 3.70-3.64 (m, 1H), 1.27-1.25 (d, J=6.0 Hz, 3H), .18 (d, J=6.0 Hz, 3H).

EXAMPLE 12: 6-(Tert-buljyl)—2-chlor0meth0xy—1 1-0x0-6,7-dihydr0-1 1H- 0 0 CI OH I I benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid KT m/z: 378 [M+H]+ observed. 1H NMR: (300 MHz, 6): 5 10.41 (s, 1H), 8.43 (s, 1H), 7.17 (s, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 6.25 (m, 1H), 5.88 (m, 2H), 3.66 (s, 3H) and 0.74 (s, 9H).

EXAMPLE 13: 11-Ch10r0methoxy-Z-oxo-Sa,6,7,7a-tetrahydr0-2H— o 3 benz0[f] cyclobuta[b]pyrid0[1,2-d] [1,4]0xazepine—3-carb0xylic acid m/z: 348 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 6 8.75 (s 1H), 7.80 (s, 1H), 7.10 (s, 1H), 6.93 (s, 1H), 5.20-5.05 (m, 2H), 3.95 (s, 3H), 2.36-2.15 (m, 4H).

EXAMPLE 14: 12-Chlor0-1l-methoxy-Z-ox0-5a,7,8,8a-tetrahydr0-2H,6H- CI OH I I benz0[f] cyclopenta[b]pyrid0[1,2-d] [1,4]0xazepine—3-carb0xylic acid “G m/z: 362 [M+H]+ observed . 1HNMR (400 MHz, CDC13): 6 8.61 (s, 1H), 7.48 (s, 1H), 6.73-6.72 (m, 2H), .95 (m, 1H), 4.55—4.42 (m, 1H), 3.94 (s, 3H), 2.28-1.70 (m, 6H).

EXAMPLE 15: 2-Fluor0is0pr0pylmeth0xy0x0-6,7-dihydr0-11H- benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid lerl—butyl N—(l-hydroxymethylbutanyl)carbamate (600 mg, 2.95 mmol) and triethylamine (1.2 mL, 8.85 mmol) were dissolved in anhydrous THF (30 mL). Methanesulfonyl chloride (473 mg 4.13 mmol) was added drop-wise and the mixture was stirred overnight at RT. The reaction was diluted with H20 (25 mL) and extracted with EtOAc (2x25 mL). The combined organic fractions were washed with sat. aqueous brine solution (10 mL), dried over sodium sulfate and concentrated under vacuum to give crude Zerl-butyl N—[1-(methanesulfonyloxy)methylbutan- 2-yl]carbamate as a white solid that was used without further purification (0.73 g, 89% yield, m/z: 282 [M+H]+ observed).

Tert-buljyl flu0r0f0rmyl—5-meth0xyphen0xy)methylbutan-2—yl)carbamate MeOFUCHOO EHBOC -Fluorohydroxymethoxybenzaldehyde (200 mg 0.56 mmol) and cesium carbonate (840 mg 2.59 mmol) were ded in anhydrous DMF (5 mL) and stirred at rt for 15 minutes.

Tert-butyl N—[1-(methanesulfonyloxy)—3-methylbutanyl]carbamate (662 mg, 2.35 mmol) and potassium iodide (20 mg, 0.12 mmol) in DMF (1 mL) were added and the reaction mixture was heated at 55 0C for 36 hours. The reaction was diluted with H20 (15 mL) and extracted with EtOAc (2x25 mL). The combined organic ons were washed with sat. aqueous brine solution (10 mL), dried over sodium sulfate and trated under vacuum. The residue was d by normal phase SiOz tography (5% to 45% EtOAc/hexanes) to furnish lerl—butyl N—[l-(4- -lO6- fluoroformylmethoxyphenoxy)-3 lbutanyl]carbamate as a light yellow solid (175 mg, 42% yield, m/z: 356 [M+H]+ observed). 7-Flu0r0is0pr0pyl—8—meth0xy—2,3-dihydr0benz0[fl[l,4]0xazepine hydrochloride lerl-butyl N-[ 1 -(4-fluoroformylmethoxyphenoxy)-3 -methylbutanyl ] carbamate (175 mg, 0.49 mmol) was dissolved in anhydrous CHzClz (2 mL) and a hydrogen chloride on (4M in 1,4-dioxane, 0.62 mL, 2.46 mmol) was added. The mixture was stirred at rt overnight. The mixture was concentrated under vacuum and further azeotroped with THF (2x5 mL), then dried over sodium sulfate and concentrated under vacuum to give 7-fluoro-3 -isopropylmethoxy-2,3- dihydro-1,4-benzoxazepine, hydrochloride salt as a light green solid that was used without further purification (0.11 g, 80% yield, m/z: 238 [M+H]+ observed). 1H NMR (300 MHz, CDCl3) ppm 8.51-8.67 (m, 1 H) 7.35—7.49 (m, 1 H) 6.69-6.78 (m, 1 H) 4.63-4.79 (m, 1 H) 4.02 (s, 5 H) 1.96-2.12 (m, 1 H) 1.12—1.31 (m, 6 H).

Ethyl Z-fluoro- 7-is0pr0pyl—3-meth0xy—11-0x0-6, 7,12,12a—tetrahydr0—11H-benz0[flpyrid0[1,2— o o d][1, 4]0xazepine—1 0—carb0xylate 7-fluoro-3 -isopropylmethoxy-2,3-dihydro-1,4-benzoxazepine hydrochloride, (50 mg, 0.18 mmol) and ethyl (2E)(ethoxymethylidene)oxobutanoate (100 mg, 0.55 mmol) were dissolved in anhydrous EtOH (1 mL) and the mixture was heated at 115 0C in a microwave reactor for 2 hours. The mixture was concentrated to give the crude product ethyl 2-fluoro isopropyl-3 xy-1 1-oxo-6,7,12,12a-tetrahydro-1 zo[f]pyrido[1,2-d][1,4]oxazepine- boxylate as a yellow oil that was used in the next step t further purification (0.07 g, >100% yield, m/z: 378 [M+H]+ observed).

Ethyl Z-fluoro- r0pyl—3-meth0xy—11-0x0-6, 7-dihydr0—11H—benz0[flpyrid0[1,2— d][1, 4]0xazepine—1 0—carb0xylate The crude ethyl 2-fluoroisopropylmethoxyoxo-6,7,12,12a-tetrahydro-11H- benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylate (0.07 g, 0.19 mmol) was dissolved in 2-Me- THF (1 mL) and p-chloranil (54 mg 0.22 mmol) was added. The mixture was heated at 70 0C for 3 hours. The reaction was diluted with EtOAc (15 mL) and washed with sat. aqueous sodium bicarbonate solution (15 mL), H20 (10 mL), sat. aqueous brine solution (10 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by reverse phase HPLC. The pure fractions were combined, extracted with EtOAc (3x30 mL) and concentrated under vacuum to afford ethyl 2-fluoroisopropylmethoxyoxo-6,7-dihydro-11H- benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylate as a yellow solid (0.02 g, 25% yield, m/z: 376 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 5 ppm 9.15—9.21 (m, 1 H), 7.32 (s, 1 H), 7.25 (s, 1 H), 6.69 (d, J=7.33 Hz, 1 H), 4.70 (bs, 2 H), 4.42-4.56 (m, 2 H), 4.06-4.23 (m, 1 H), 3.97 (s, 3 H), 2.07-2.18 (m, 1 H), 1.43 (t, J=7.04 Hz, 3 H), 1.15 (d, J=6.74 Hz, 3 H), 0.86 (d, J=6.45 Hz, 3 H). 2-Flu0r0- 7-is0pr0pyl—3—meth0xy—11-0x0-6, 7-dihydr0—11H—benz0[flpyrid0[1,2— d][1,4]0xazepine—10-carb0xylic acid Ethyl 2-fluoroisopropylmethoxy-1 1-oxo-6,7-dihydro-1 zo[f]pyrido[1,2- ]oxazepinecarboxylate (17 mg, 0.05 mmol) and m hydroxide monohydrate (6 mg, 0.14 mmol) were suspended in a THF/MeOH/HZO mixture (3: 1 : 1, 1 mL) and the reaction was d at rt for 2 hours. The reaction was ied by the addition of aqueous 1N HCl (10 mL) and ted with EtOAc (3x15 mL). The combined organic fractions were dried over sodium sulfate and concentrated under vacuum to give 2-fluoroisopropylmethoxyoxo-6,7- dihydro-11H-benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylic acid (9 mg, 57% yield, m/z: 348 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 6 ppm 8.58 (s, 1 H), 7.24 (d, J=11.43 Hz, 1 H), 6.90 (s, 1 H), 6.70 (d, J=7.33 Hz, 1 H), 4.53-4.66 (m, 2 H), 3.95 (s, 4 H), 2.07-2.18 (m, 1 H), 1.09 (d, J=6.45 Hz, 3 H), 0.86 (d, J=6.45 Hz, 3 H).

The following example was prepared in a similar manner as 2-fluoroisopropyl-3 -methoxy-1 1- oxo-6,7-dihydro-1 1H-benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylic acid from 2-hydroxy- WO 85619 4-methoxybenzaldehyde and an appropriate te.

EXAMPLE 16: r0pylmeth0xy-1 1-0x0-6,7-dihydr0-1 1H-benz0 [f] pyrido [1,2- d][1,4]oxazepine-lO-carboxylic acid m/z: 330 [M+H]+ observed). 1H NMR (300 MHz, CDC13) 5 ppm 8.48-8.58 (m, 1 H), 7.39-7.48 (m, 1 H), .95 (m, 1 H), 6.75-6.85 (m, 1 H), 6.62 (br. s., 1 H), 4.60 (bs, 2 H), 3.87 (bs, 4 H), 2.03-2.10 (m, 1 H), 1.04-1.13 (m, 3 H), 0.80-0.88 (m, 3 H).

EXAMPLE 17: (R)Is0pr0pylmeth0xy0x0-6,7-dihydr0-11H-benz0[f]pyrid0 [1,2- 0 OH d][1,4]oxazepine-lO-carboxylic acid OJWI( m/z: 330 [M+H]+ observed). 1H NMR (300 MHz, CDC13) 5 ppm 8.48-8.58 (m, 1 H), 7.39-7.48 (m, 1 H), 6.88-6.95 (m, 1 H), 6.75-6.85 (m, 1 H), 6.62 (br. s., 1 H), 4.60 (bs, 2 H), 3.87 (bs, 4 H), 2.03-2.10 (m, 1 H), 1.04-1.13 (m, 3 H), 0.80-0.88 (m, 3 H).

EXAMPLE 18: (S)Is0pr0pylmeth0xy0x0-6,7-dihydr0-11H-benz0[f] pyrid0[1,2- o OH d][1,4]oxazepine-lO-carboxylic acid m/z: 330 [M+H]+ observed). 1H NMR (300 MHz, CDC13) 5 ppm 8.48-8.58 (m, 1 H), 7.39-7.48 (m, 1 H), 6.88-6.95 (m, 1 H), 6.75-6.85 (m, 1 H), 6.62 (bs, 1 H), 4.60 (bs, 2 H), 3.87 (bs, 4 H), 2.03-2.10 (m, 1 H), 1.04-1.13 (m, 3 H), 0.80-0.88 (m, 3 H).

EXAMPLE 19: 6-Isopr0pyl-10,11-dimeth0xy0x0-2,6,7,8-tetrahydr0benzo[c] pyrid0[1,2- WO 85619 MeO OH l I a]azepinecarb0xylic acid MeOmCOCIBr 0-4,5-dimeth0xybenz0yl chloride M60 A mixture of 2-bromo-4,5-dimethoxybenzoic acid (5.22g, 20 mmol) and thionyl chloride (20 mL) were d for 3h. Excess thionyl chloride was removed under vacuum and the crude product was azeotroped from 50 mL toluene, followed by high vacuum drying for 2h to give the desired t 2-bromo-4,5-dimethoxybenzoyl chloride as a clear oil that was used without further purification (5.6g, quantitative yield).

Ethyl 6-(2-br0m0-4,5-dimeth0xyphenyl)0x0-4H-pyran-3—carboxylate MeO Br To a solution of LiHMDS (24 mmol, 22.6 mL, 1.06 M in THF) in anhydrous THF (30 mL) at - 78 oC (dry ice/acetone bath) under argon, a solution of ethyl (Z)((dimethylamino)methylene)- 3-oxobutanoate (1.85 g, 10 mmol) and 2-bromo-4,5-dimethoxybenzoyl chloride (2.79 g, 10 mmol) in 50 mL anhydrous THF was added dropwise over 10 min. The dry ice/acetone bath was removed and the solution was warmed for 15 min period. Diethyl ether (100 mL) was added to the reaction mixture followed by 3N aq. HCl (30 mL, 90 mmol), and the contents were stirred overnight. The reaction mixture was poured slowly into a saturated aqueous onate solution (600 mL) with vigorous stirring, and additional solid sodium bicarbonate was added until the aqueous layer was d basic pH. The resulting system was stirred vigorously for 10 min.

The precipitate was filtered, washed with water, dissolved in dichloromethane, dried over sodium sulfate and concentrated to give a dark orange e (6.5 g). Purification by normal phase SiOz chromatography (10% to 100% EtOAc/hexanes) yielded the desired product as an orange solid (2.1 g), which upon crystallization from methanol (20 mL) furnished ethyl 6-(2- bromo-4,5-dimethoxyphenyl)oxo-4H-pyrancarboxylate as a light orange solid (1.56 g, 40% yield, m/z: 383/385 [M+H]+ observed). 1H NMR (300 MHz, CDCl3): 5 8.20 (s, 1 H), 7.30 (s, 1H), 7.10 (s, 1 H), 6.42 (s, 1 H), 4.37 (q, J=2.4 Hz, 2 H), 3.85 (m, 6 H) and 1.35 (t, J=2.4Hz, Ethyl 6-(2-br0m0-4,5-dimeth0xyphenyl)—1-(4-methylpent—1-enyl)0x0-1,4-dihydr0 o o MeO O/\ l I pyridine-3—carb0xylate <—< To a mixture of ethyl 6-(2-bromo-4,5-dimethoxyphenyl)oxo-4H-pyran-3 -carboxylate (383 mg, 1 mmol) in tOH (18 mL, 5:1 ratio), N—Bocmethylpentenamine (300 mg, 1.5 mmol) was added and refluxed at 120 0C for 12h. The crude reaction mixture was concentrated under vacuum, and the residue was purified on normal phase SiOz chromatography (0% to 10% MeOH/CHzClz) to give ethyl 6-(2-bromo-4,5-dimethoxyphenyl)(4-methylpent enyl)oxo-1,4-dihydropyridinecarboxylate as a yellow oil (139 mg, 30% yield, m/z: 6 [M+H]+ observed). 1H NMR (300 MHz, CDC13): 6 8.28 (s, 1 H), 7.11 (d, J=2.2 Hz, 1 H), 6.70 (d, J=9.3 Hz, 1 H), 6.42 (d, J=3.5 Hz, 1 H), 6.05-5.85 (m, 1 H), 5.45-4.85 (m, 2 H), 4.41 (q, J = 3.5 Hz, 2H), 3.95-3.70(m, 7H), 2.20-2.05 (m, 1 H), 1.41 (t, J: 3.5Hz, 3H) and .79 (m, 6H).

Ethyl 6-is0pr0pyl—1 0,11-dimeth0xy—2—0x0—2, 6, 7, 8-tetrahydrobenz0[c]pyrid0[1,2-alazepine O 0 M60 O/\ l l carboxylate To a stirred solution of ethyl 6-(2-bromo-4,5-dimethoxyphenyl)(4-methylpenten-3 -yl) oxo-1,4-dihydropyridinecarboxylate (93 mg, 0.2 mmol) in anhydrous THF (20 mL) under argon, 9-BBN (1.2 mL, 0.6 mmol, 0.5 M on in THF) was added dropwise and the system was heated at 60 0C for 3 hours. Aqueous cesium carbonate (1 mL, 2 M solution, 2 mmol) and Pd(dppf)C12 (16 mg, 0.020 mmol) were added and refluxed overnight. Solvents were removed and the crude product was d on normal phase SiOz chromatography (0%-10% MeOH/CHzClz) to give ethyl 6-isopropyl-10,11-dimethoxyoxo-2,6,7,8-tetrahydro benzo[c]pyrido[1,2-a]azepinecarboxylate as a white foam (40 mg, 52% yield, m/z: 386 [M+H]+ observed). 1H NMR (300 MHz, CDC13): 5 8.20 (s, 1 H), 7.18 (s, 1 H), 6.97 (s, 1 H), 6.94 (s, 1 H), 5.60 (s, 1 H), 5.27 (s, 1 H), 4.38 (q, I = 2.5 Hz, 2H), 4.10—3.93 (m, 7H), 1.90—1.75 (m, 2 H), 1.70-1.60 (m, 1H), 1.30—1.20 (m, 1H), 1.39 (t, J: 2.5Hz, 3H), 0.90 (d, J: 2.2 Hz, 3H) and 0.83 (d, J: 2.2 Hz, 3H). r0pyl—1 imeth0xy-2—0x0—2, 6, trahydrobenz0[c]pyrid0[1,2-alazepine O O MeO OH I I carboxylic acid To a mixture of compound ethyl 6-isopropyl-10,11-dimethoxyoxo-2,6,7,8- tetrahydrobenzo[c]pyrido[1,2-a]azepinecarboxylate (16 mg, 0.04 mmol) in dioxane (3 mL), aq. LiOH (3.5 mg in 0.2 mL, 0.2 mmol) was added and stirred at room temperature overnight.

The reaction mixture was concentrated under vacuum, and the residue was dissolved in water (2 mL) and acidified with 1N aq. HCl to pH 2-3. The precipitate was filtered, washed with 2 mL of water and dried under high vacuum to furnish 6-isopropyl-10,11-dimethoxyoxo-2,6,7,8- tetrahydrobenzo[c]pyrido[1,2-a]azepinecarboxylic acid as a white solid (9 mg, 60% yield, m/z: 358 [M+H]+ observed). 1H NMR (300 MHz, DMSO-d6): 5 8.81 (s, 1 H), 7.57 (bs, 2 H), 7.26 (s, 1 H), 5.87 (s, 1 H), 5.36 (s, 1 H), 5.00 (d, J = 2.7 Hz, 1H), 3.91 (bs, 7H), 2.45 (bs, 1 H), 1.71 (bs, 1 H), 0.77 (bs, 6H).

EXAMPLE 20: 6-Is0pr0pylmeth0xy(3-meth0xypr0p0xy)—10-0x0-5,10-dihydr0-6H- pyrid0[1,2-h] [1,7]naphthyridine—9-carb0xylic acid -Br0m0chl0r0—3—(3-meth0xypr0p0xy)pyridine MGOM To a stirred on of 5-bromochloropyridinol (7. lg, 34.3 mmol) in DMF (50 mL) was added Cs2C03 (16.7g, 51.4 mmol) followed by omethoxypropane (6.29g, 41.4 mmol) at room temperature, and the reaction mixture was stirred at rt for 4h. The reaction was monitored by TLC. The reaction mixture was diluted with water (80mL) and extracted in EtOAc (3 x 70mL). The organic fractions were combined, dried over sodium e, evaporated under vacuum, and the residue was purified by normal phase SiOz chromatography (0% to 30% EtOAc/hexanes) to furnish 5-bromochloro(3 -methoxypropoxy)pyridine as an off-white solid (6.11g, 64% yield, m/z: 280/282 [M+H]+ observed). 1H NMR (400 MHZ, DMSO-d6) 5 8.13 (d, J=1.2 Hz, 1H), 7.89 (d, J=1.2Hz, 1H), 4.21-4.18 (t, J=6.4Hz, 2H), 3.49 -3.46 (t, J=6.4 Hz, 2H), 3.25 (s, 3H), 2.01—1.95 (m, 2H). /0 N \O/\/\O / -Br0m0meth0xy—3—(3-methoxypropoxgy)pyridine Br To a stirred solution of 5-bromochloro(3 -methoxypropoxy)pyridine (7g, 25 mmol) was added NaOMe (25% solution in MeOH, 57 mL, 251 mmol), and the reaction mixture was heated at 80 0C for 3h. The reaction was monitored by TLC and LCMS. The reaction mixture was cooled to room temperature and diluted with water (80mL), then ted with EtOAc (3 x 70mL). The organic fractions were combined, dried over sodium sulfate and evaporated under vacuum to give 5-bromomethoxy(3 -methoxypropoxy)pyridine as a yellow gum that was used without further purification (6.8g, 98% yield, m/z: 276/278 [M+H]+ observed). 1H NMR (400 MHZ, DMSO-d6) 5 7.77 (d, J=2.0 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 4.05-4.02 (t, J=6.4 Hz, 2H), 3.82 (s, 3H), 3.44—3.41 (t, J=6.4 Hz, 2H), 3.22 (s, 3H), 1.96-1.91 (m, 2H). 1-(6-Meth0xy—5—(3-meth0xypr0p0xy)pyridin-3—yl)methylbutan—2—0ne /0 IN\ 0 \oMo / To a stirred solution of 5-bromomethoxy-3 -(3-methoxypropoxy)pyridine (1 g, 3.63 mmol) and 3-methylbutanone (0.94g, 10.9 mmol) in THF (10 mL) was added NaOtBu (1 . 15g, 12 mmol).

The reaction mixture was degassed at room temperature using an argon balloon for 30 min.

Then Xantphos (42mg, 0.072 mmol) was added to the reaction mixture followed by a)3 (33mg, 0.036 mmol) at room ature. The reaction mixture was warmed to 80°C and stirred for 2h. The reaction was monitored by TLC. The reaction mixture was cooled to room ature, evaporated in vacuum, diluted with water (10 mL) and extracted with EtOAc (3 x mL). The organic fractions were combined, dried over sodium sulfate, evaporated under vacuum and the e was d by normal phase SiOz chromatography (0% to 30% EtOAc/hexanes) to furnish ethoxy(3 -methoxypropoxy)pyridinyl)methylbutan one as a yellow oil (7.4 g, 73% yield from 10x1 g scale reactions, m/z: 282 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 5 7.51 (d, J=1.6 Hz, 1H), 6.93 (d, J=1.6 Hz, 1H), 4.09—4.05 (t, J=6.4 Hz, 2H), 3.98 (s, 3H), 3.64 (s, 2H), 3.55 (t, J=6.0 Hz, 2H), 3.33 (s, 3H), 2.73 (m, 1H), 2.11 (m, WO 85619 2H), 1.13 (d, J=6.8 Hz, 6H). 1-(6-Meth0xy—5—(3-meth0xypr0p0xy)pyridin-3—yl)methylbutan—2—amine /o |N\ NH2 To a stirred solution of l-(6-methoxy(3-methoxypropoxy)pyridinyl)methylbutanone (7.4g, 26.3 mmol) in MeOH (60 mL) at room temperature was added ammonium acetate (30.4g, 395 mmol). The reaction mixture was cooled to 0°C, and NaCNBH3 (3.26g, 52.6 mmol) was added to the reaction mixture n-wise and stirred at room temperature for 16h. The reaction was monitored by TLC. The reaction e was evaporated under , diluted with ice cold water (80 mL) and extracted in EtOAc (3 x 100 mL). The organic fractions were dried over sodium sulfate and evaporated in vacuo to obtain l-(6-methoxy(3-methoxypropoxy)pyridin yl)—3-methylbutanamine as a brown oil that was used without further purification (8.2g, >100% yield, m/z: 283 [M+H]+ observed). 1H NMR (400 MHz, 6) 5 7.51 (s, 1H), 7.18 (s, 1H), 4.9 (bs, 2H), 4.01-3.98 (t, J=6.4 Hz, 2H), 3.81 (s, 3H), 3.46-3.43 (t, J=6.0 Hz, 2H), 3.23 (s, 3H),2.95-2.91 (m, 1H), 2.85-2.81 (m, 1H), 2.69-2.65 (s, 1H), 1.97—1.91 (m, 2H), 1.70-1.66 (m,lH), 0.85-0.95 (m, 6H).

Tert-buljyl meth0xy-5—(3-methoxyprop0x32)pyridin—3—yl)methylbutan-Z-yl)carbamate /O N\ Boc To a stirred solution of l-(6-methoxy(3-methoxypropoxy)pyridinyl)methylbutan amine (8.2g, 29 mmol) in CHzClz (60 mL) was added triethylamine (10 mL, 73 mmol), followed by di-tert-butyl dicarbonate (7.6g, 35 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3h, and the reaction was monitored by TLC. The reaction e was diluted with water (90 mL) and extracted in CHzClz (3 x 50 mL). The combined organic fractions were dried over sodium sulfate and evaporated under vacuum, and the residue was purified by normal phase SiOz chromatography (0% to 20% EtOAc/hexanes) to furnish tert-butyl (l-(6-methoxy (3 xypropoxy)pyridin-3 -yl)methylbutanyl)carbamate as an off white solid (7.6g, 68%, m/z: 383 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 5 7.49 (s, 1H), 6.98 (s, 1H), 4.34 (d, J=9.6 Hz, 1H), 4.11 (t, J=6.4 Hz, 2H), 3.99 (s, 3H), 3.68 (bs, 1H), 3.58 (t, J=6.4 Hz, 2H), 3.37 (s, 3H), 2.73 (dd, J=14.2, 6.1 Hz, 1H), 2.59 (dd, J=14.2, 8.4 Hz, 1H), 2.13 (m, 2H), 1.75 (m, —114— 1H), 1.38 (s, 9H), 0.96 (dd, J=18.0, 6.8 Hz, 6H).

Tert-buljyl (1-(2-br0m0meth0xy(3-meth0xypr0p0xy)pyridin-3—yl)methylbutan—2— o N BrNH,BOC \ / yDcarbamate To a stirred on of tert-butyl (1-(6-methoxy(3 -methoxypropoxy)pyridinyl) butanyl)carbamate (6.6g, 17 mmol) in acetic acid (50 mL) at room temperature was added sodium acetate (1.41 g, 17.3 mmol) ed by bromine (0.88 mL, 17 mmol) and the reaction was stirred for 1h. The reaction was monitored by TLC and LCMS. The reaction mixture was basif1ed using saturated aqueous NaHCO3 solution until reaching a pH of 10-12.

The reaction mixture was extracted with CHzClz (3 x 50 mL). The organic phase washed with saturated aqueous NaHC03 solution (75 mL), dried over sodium sulfate and evaporated under vacuum. The residue was d by normal phase SiOz chromatography (0-15% hexanes) to afford tert-butyl bromomethoxy(3 -methoxypropoxy) pyridin yl)methylbutanyl)carbamate as brown gum (4.1g, 52%, m/z: 3 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 5 7.02 (s, 1H), 4.44 (d, J=8.8 Hz, 1H), 4.10 (t, J=6.4 Hz, 2H), 3.96 (s, 3H), 3.78-3.74 (m, 1H), 3.57 (t, J=6.3 Hz, 2H), 3.34 (s, 3H), 2.85 (dd, J=14.2, 4.5 Hz, 1H), 2.66-2.6 (m, 1H), 2.11 (t, J=6.0 Hz, 2H), 1.85 (d, J=6.0 Hz, 1H), 1.37 (s, 9H), 1.05—0.91 (m, 6H).

Tert-buljyl (1-(2-f0rmylmeth0xy—5-(3-meth0xypr0p0xy)pyridin-3—yl)methylbutan—2— yDcarbamate Tert-butyl (1 -(2-bromomethoxy-5 -(3 -methoxypropoxy)pyridin-3 -yl)-3 -methylbutanyl) carbamate (500 mg, 1.08 mmol) was dissolved in anhydrous THF (25 mL), and the solids were completely dissolved by gently warming the solution with a heat gun. The reaction was cooled to -78 oC (dry ice/acetone bath) and n-BuLi (1.6M on in hexanes, 1.69 mL, 2.71 mmol) was added dropwise. The mixture was stirred at -78°C for 15 minutes. ylformamide (0.12 mL, 1.63 mmol) was added dropwise and the reaction was stirred at -78 0C for 10 minutes, then warmed to room temperature and stirred for an additional 10 minutes. The reaction mixture was added dropwise to ice water (150 mL) with vigorous stirring. The precipitate was filtered to give a white solid. The filter cake was washed off with EtOAc (2 x 5 mL), and the residue was extracted with EtOAc (3 X 10 mL) to remove residual water. The EtOAc solution was dried with sodium sulfate and concentrated under vacuum to give tert-butyl (1-(2-formylmethoxy(3- methoxypropoxy) pyridinyl)methylbutanyl)carbamate as a white solid that was used without further purification (455 mg, 92%, m/z: 411 [M+H]+ observed). 6-Is0pr0pyl—2—meth0xy—3—(3-meth0xypr0p0xy)-5, 6—dihydr0—1, 7-naphthyridine Tert-butyl (1 -(2-formylmethoxy-5 -(3 -methoxypropoxy)pyridin-3 -yl)-3 -methylbutan bamate (450 mg, 1.10 mmol) was dissolved in CHzClz (10 mL) at room temperature and hydrogen chloride, (4M on in 1,4-dioxane, 822 uL, 3.29 mmol) (4M/dioxane) was added.

The on mixture was stirred at room ature for 2 hours. The reaction mixture was concentrated, then treated with water (30 mL), and basified using ted aqueous NaHC03 solution until pH 10-12. The mixture was extracted with CHzClz (3 x 50 mL), the combined c fractions was dried over anhydrous sodium sulfate, evaporated under vacuum and the residue was purified by normal phase SiOz chromatography (5-60% EtOAc/hexanes) to give 6- isopropylmethoxy(3 -methoxypropoxy)-5,6-dihydro-1,7-naphthyridine as a yellow oil that was used without further purification (129 mg, 41%, m/z: 293 [M+H]+ observed).

Ethyl 6-is0pr0pyl—2—meth0xy—3—(3-meth0xypr0p0xy)—1 0-0x0-5,1 0,11,11a-tetrahydr0—6H- O O pyrid0[1,2-h][1, 7Inaphthyridinecarb0xylate 6-Isopropylmethoxy(3-methoxypropoxy)-5,6-dihydro-1,7-naphthyridine (129 mg, 0.441 mmol) and ethyl (2E)—2-(ethoxymethylidene)oxobutanoate (247 mg, 1.32 mmol) were ved in anhydrous EtOH (3 mL), and the mixture was heated at 80 0C for 8 hours. LC/MS after 8 hours showed ~25% of imine starting material ing. An additional 2 equivalents of ethyl (2E)(ethoxymethylidene)oxobutanoate (164 mg, 0.882 mmol) were added, and the mixture was further d at 80 0C for another 8 hours. The reaction mixture was concentrated under reduced pressure to give the ethyl 6-isopropylmethoxy(3 -methoxypropoxy)oxo- ,10,11,11a-tetrahydro-6H-pyrido[1,2-h][1,7]naphthyridinecarboxylate as a brown oil that was used without further purification (191mg, 100%, m/z: 433 [M+H]+ observed). -ll6- Ethyl r0pyl—2—meth0xy—3—(3-meth0xypr0p0xy)0x0-5,10-dihydr0-6H—pyrid0[1,2- O O h][1, 7Inaphthyridinecarb0xylate Ethyl 6-isopropylmethoxy-3 -(3 -methoxypropoxy)oxo-5, 10,1 1,1 1a-tetrahydro-6H- pyrido[1,2-h][1,7]naphthyridinecarboxylate (191mg, 0.441 mmol) from the step above and iodine (112 mg 0.441 mmol) were dissolved in 2-MeTHF (3 mL) and stirred at 70°C for 1h.

The reaction mixture was evaporated under vacuum and the residue was purified by normal phase Si02 chromatography (SO-100% EtOAc/hexanes, then 0% to 7% MeOH/CHzClz) to give ethyl 6-isopropylmethoxy-3 -(3 -methoxypropoxy)oxo-5,10-dihydro-6H-pyrido[1,2- h][1,7]naphthyridinecarboxylate as a brown foam (90 mg, 47% yield over 3 steps, m/z: 431 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 6 8.36 (s, 1H), 7.36 (s, 1H), 6.95 (s, 1H), 4.22 (m, 3H), 4.11 (m, 2H), 3.95 (s, 3H), 3.48 (t, J=6.2 Hz, 2H), 3.32-3.23 (m, 4H), 3.14 (d, J=16.7 Hz, 1H), 2.00 (m, 2H), 1.70 (m, 1H), 1.27 (t, J=7.1 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H), 0.72 (d, J=6.7 Hz, 3H). 6-Is0pr0pyl—2—meth0xy—3—(3-meth0xypr0p0xy)-1 0-0x0-5,1 0-dihydr0—6H—pyrid0[1,2—h[[1, 7I naphthyridine—9—carb0xylic acid Ethyl 6-isopropylmethoxy-3 -(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2-h]1,7- naphthyridinecarboxylate, (230 mg, 0.53 mmol) and lithium ide drate (90 mg, 2.14mmol) were suspended in THF/MeOH/H20 e (3: 1 : 1, 2 mL), and the reaction was stirred at room temperature for 1 hour. THF and MeOH were removed under reduced pressure and the crude residue was diluted with water (40 mL), extracted with 2x50ml EtOAc (2 x 50 mL) to get rid of some impurities. The remaining s solution was acidified to pH 2 with aqueous 1N HCl and ted with EtOAc (3 x 50 mL). The combined organic fractions were dried with sodium sulfate, then concentrated under vacuum to give a crude light brown solid.

The solid was further washed with EtOAc/hexanes mixture (4: 1, 10 mL), filtered and dried to give 6-isopropylmethoxy-3 -(3 -methoxypropoxy)oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7] naphthyridinecarboxylic acid as a light tan solid (105mg, 49%, m/z: 403 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 16.52 (s, 1H), 8.82 (s, 1H), 7.42 (s, 1H), 7.37 (s, 1H), 4.51— 4.47 (dd, J: 5.6Hz, J: 8.8 Hz, 1H), 4.11 (m, 2H), 3.96 (s, 3H), 3.48 (t, J=6.4 Hz, 2H), 3.44—3.40 (m, 1H), 3.34 (s, 3H), 3.22 (m, 1H), 2.00 (m, 2H), 1.73 (m, 1H), 0.88 (d, J = 6.4 Hz, 3H), 0.72 (d, J = 6.4 Hz, 3H).

EXAMPLE 21: Is0pr0pylmeth0xy(3-methoxypropoxy)—10-0x0-5,10-dihydr0- o o 6H-pyrid0[1,2-h] [1,7]naphthyridine—9-carb0xylic acid EXAMPLE 22: Isopropyl-Z-methoxy(3-meth0xypr0p0xy)—10-0x0-5,10-dihydr0- 6H-pyrid0[1,2-h] [1,7]naphthyridine—9-carb0xylic acid 325 mg of the mixture of enantiomers was separated by SFC (supercritical fluid chromatography) on an CHIRALCEL OX-H column using liquid C02 and IPA:CH3CN (1:1) and 0.1% diethylamine as modifier to give: (R)isopropylmethoxy(3 -methoxypropoxy) oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridinecarboxylic acid as a light brown solid (faster eluting enantiomer, 105 mg, 32%, m/z: 403 [M+H]+ observed) and (S)isopropyl methoxy-3 -(3 -methoxypropoxy)oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine carboxylic acid as a light brown solid r eluting enantiomer, 104 mg, 32%, m/z: 403 [M+H]+ ed).

Example 21: (R)Is0propyl-Z-methoxy(3-meth0xypr0p0xy)—10-0x0-5,10-dihydr0-6H- pyrido[1,2-h][1,7]naphthyridine—9-carboxylic acid. m/z: 403 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 6 16.52 (s, 1H), 8.82 (s, 1H), 7.42 (s, 1H), 7.37 (s, 1H), 4.51-4.47 (dd, J: .6Hz, J: 8.8 Hz, 1H), 4.11 (m, 2H), 3.96 (s, 3H), 3.48 (t, J=6.4 Hz, 2H), 3.44-3.40 (m, 1H), 3.34 (s, 3H), 3.22 (m, 1H), 2.00 (m, 2H), 1.73 (m, 1H), 0.88 (d, J = 6.4 Hz, 3H), 0.72 (d, J = 6.4 Hz, 3H).

Example 22: (S)Is0pr0pylmeth0xy(3—methoxypropoxy)—10-0x0-5,10-dihydr0-6H- pyrido[1,2-h][1,7]naphthyridine—9-carboxylic acid. m/z: 403 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 16.52 (s, 1H), 8.82 (s, 1H), 7.42 (s, 1H), 7.37 (s, 1H), 4.51—4.47 (dd, J: .6Hz, J: 8.8 Hz, 1H), 4.11 (m, 2H), 3.96 (s, 3H), 3.48 (t, J=6.4 Hz, 2H), 3.44 —3.40 (m, 1H), 3.34 (s, 3H), 3.22 (m, 1H), 2.00 (m, 2H), 1.73 (m, 1H), 0.88 (d, J = 6.4 Hz, 3H), 0.72 (d, J = 6.4 Hz, 3H).

The following examples were prepared in a similar manner as (R)isopropylmethoxy(3- methoxypropoxy)-lO-oxo-S,lO-dihydro-6H-pyrido[l,2-h][l,7]naphthyridinecarboxylic acid and (S)isopropylmethoxy-3 -(3 xypropoxy)- l O-oxo-S, l dro-6H-pyrido[ l ,2- h][1,7]naphthyridinecarboxylic acid from 5-bromo-2,3-dimethoxypyridine and an appropriate ketone.

E 23: 6-Is0pr0pyl-2,3-dimeth0xy0x0-5,10-dihydr0-6H-pyrid0[1,2- h] [1,7]naphthyridine—9-carb0xylic acid m/z: 345 [M+H]+ observed . 1HNMR (400 MHz, CDC13): 5 16.45 (s, 1H), 8.82 (s, 1H), 7.41 (s, 1H), 7.37 (s, 2H), 4.52 — 4.48 (m, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.42 — 3.36 (m, 1H), 3.21 — 3.17 (m, 1H), 1.77 = 4.8 Hz, 3H), 0.89 = 6.8 Hz, 3H). — 1.72 (m, 1H), 1.04 — 1.02 (d, J — 0.87 (d, J EXAMPLE 24: 6-Is0pr0pyl-2,3-dimeth0xy0x0-5,10-dihydr0-6H-pyrid0[1,2- h][1,7]naphthyridine—9-carb0xylic acid (single enantiomer 1) EXAMPLE 25: 6-Is0pr0pyl-2,3-dimeth0xy0x0-5,10-dihydr0-6H-pyrid0[1,2- h] [1,7]naphthyridine—9-carb0xylic acid (single enantiomer II) 425 mg of the mixture of enantiomers was separated by SFC (supercritical fluid -ll9- WO 85619 chromatography) on an OX-H column using 45% i-PrOH:CH3CN (1:1, 0.1% DEA) to give 6- isopropyl-2,3 -dimethoxyoxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridinecarboxylic acid (single enantiomer I) as an off-white solid (faster eluting enantiomer, 140 mg, 33%, m/z: 345 [M+H]+ observed) and 6-isopropyl-2,3-dimethoxyoxo-5,10-dihydro-6H-pyrido[1,2- h][1,7]naphthyridinecarboxylic acid e enantiomer II) as an off-white solid (slower eluting enantiomer, 100 mg, 24%, m/z: 345 [M+H]+ observed).

Example 24: 6-Is0pr0pyl-2,3-dimethoxy0x0-5,10-dihydr0-6H-pyrid0[1,2- h][1,7]naphthyridine—9-carboxylic acid (single enantiomer I). m/z: 370 [M+H]+ ed). 1HNMR (400 MHz, CDC13): 6 16.45 (s, 1H), 8.82 (s, 1H), 7.41 (s, 1H), 7.37 (s, 2H), 4.52 - 4.48 (m, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.42 - 3.36 (m, 1H), 3.21 - 3.17 (m, 1H), 1.77 - 1.72 (m, 1H), 1.04 = 4.8 Hz, 3H), 0.89 = 6.8 Hz, 3H). - 1.02 (d, J - 0.87 (d, J Example 25: 6-Is0pr0pyl-2,3-dimethoxy0x0-5,10-dihydr0-6H—pyrid0[1,2- h] [1,7]naphthyridine—9-carboxylic acid (single enantiomer II). m/z: 370 [M+H]+ observed). 1HNMR (400 MHz, CDC13): 6 16.45 (s, 1H), 8.82 (s, 1H), 7.41 (s, 1H), 7.37 (s, 2H), 4.52 - 4.48 (m, 1H), 3.95 (s, 3H), 3.86 (s, 3H), 3.42 - 3.36 (m, 1H), 3.21 - 3.17 (m, 1H), 1.77 - 1.72 (m, 1H), 1.04 = 4.8 Hz, 3H), 0.89 = 6.8 Hz, 3H). - 1.02 (d, J - 0.87 (d, J EXAMPLE 26: (S)Flu0r0isopr0pylmethoxy(3-meth0xypr0p0xy)—10-0x0-5,10- dihydr0-6H-pyrid0[1,2-h] [1,7]naphthyridine—9-carb0xylic acid pyrid0[1,2-h][1, 7Inaphthyridinecarb0xylate A solution of zinc iodide (327 mg, 1.03 mmol) and (6S)—6-isopropylmethoxy(3- methoxypropoxy)-5,6-dihydro-1,7-naphthyridine (300 mg, 1 mmol) in dry acetonitrile (3 mL) was heated to 50 0C. A on of ethyl (2Z)(ethoxymethylidene)-4,4-difluoro [(trimethylsilyl)oxy]butenoate (1.81 g 6.16 mmol, prepared according to the procedure in W02017140821) in DMF (4 mL) was added into above solution via a glass pipet under nitrogen.

The reaction was stirred at 50 oC overnight. EtOAc (30 mL) and H20 (30 mL) were added to reaction and the layers separated. The organic layer was washed with H20 (2X20 mL), followed by sat. aqueous brine on (20 mL). The organic layer was dried over sodium sulfate and concentrated under . The residue was purified by normal phase SiOz chromatography (0% to 6% MeOH/CHzClz) to furnish ethyl (6S)fluoroisopropylmethoxy(3- methoxypropoxy)oxo-5H,6H-pyrido[1,2-h]1,7-naphthyridinecarboxylate as a brown solid (0.35 g, 76% yield, m/z: 449 [M+H]+ ed).

(S)Flu0r0is0pr0pyl—2—meth0xy—3-(3-meth0xypr0p0xy)-1 0-0x0-5,1 0-dihydr0—6H- pyrid0[1,2-h][1, 7Inaphthyridinecarb0xylic acid Ethyl (6 S)— 1 1-fluoroisopropylmethoxy-3 -(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2- naphthyridinecarboxylate (350 mg, 0.78 mmol), lithium ide monohydrate (65 mg, 1.6 mmol) were dissolved in 1,4-dioxane:HzO mixture (5 mL, 1:1). The reaction was stirred at rt for 2h. CH2C12 (10mL) and H20 (10 mL) were added and layers separated. The aqueous layer was washed with CHzClz (2X10 mL). The pH of the aqueous layer was adjusted to 5 using 1N HCl. CHzClz (10 mL) was added and the layers separated. The aqueous layer was washed with CHzClz (3X10mL). The combined organic layers were dried over sodium sulfate and trated under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 5% MeOH/CHzClz) to furnish (6S)—11-fluoroisopropylmethoxy(3- methoxypropoxy)oxo-5H,6H-pyrido[1,2-h]1,7-naphthyridinecarboxylic acid as a light brown solid (53 mg, 16% yield, m/z: 421 [M+H]+ observed). 1H NMR (400 MHZ, CDCl3): 5 8.48 (s, 1H), 6.96 (s, 1H),4.25-4.11 (m, 2H), 4.01—4.03 (m, 4H), 3.56 (tt, J=6.1, 3.0 Hz, 2H), 3.47—3.37 (m, 1H), 3.35 (s, 3H), 3.06 (dd, J=16.5, 1.7 Hz, 1H), 2.14 (p, J=6.2 Hz, 2H), 1.85 (dt, J=9.9, 6.7 Hz, 1H), 0.95 (d, J=6.7 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H).

EXAMPLE 27: (R)Chlor0isopropyl(3-meth0xypr0p0xy)—11-0x0-6,7-dihydr0-11H- o o MeO’\/\ benzo[f] pyrido[1,2-d] xazepine-lO-carboxylic acid o}""( CIflCOZMeOH Methyl 5-chlor0-2,4-dihydr0xybenz0ate HO To a stirred solution of methyl 2,4-dihydroxybenzoate (8 g, 48 mmol) in CHZCIZ (500 mL) at 0 0C was added sulfuryl chloride (4 mL, 49 mmol). The reaction mixture was warmed to room temperature and stirred for 36 h. The reaction was followed by TLC. Saturated aqueous NaHCO3 solution (150 mL) was added, and the reaction mixture was extracted with CHzClz (2x500 mL). The combined organic phase was washed with saturated s brine solution (2x200 mL), dried over sodium sulfate, filtered and concentrated under . The residue was purified by normal phase Si02 tography (10% to 30% petroleum ether) to afford methyl 5-chloro-2,4-dihydroxybenzoate as a white solid (3.8 g, 40% yield, m/z: 203 [M+H]+ observed).

OlmCOZMeOBn Methyl 2,4-bis(benzyloxy)—5-chl0r0benz0ate BnO A solution of methyl 5-chloro-2,4-dihydroxybenzoate (3.8 g, 19 mmol), benzyl bromide (4.9 mL, 4127 mmol) and potassium carbonate (6.2 g, 45 mmol) in anhydrous DMF (10 mL) was stirred at 60 0C for 12 h. The reaction was followed by TLC. The mixture was poured into ice-water (120 mL) and extracted with EtOAc (2x200 mL). The combined c fractions were washed with saturated s brine solution (2x50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The e was purified by normal phase SiOz chromatography (0% to 10% EtOAc/petroleum ether) to afford methyl 2,4-bis(benzyloxy)—5-chlorobenzoate as a white solid (6.0 g, 84% yield).

CIKICOZHOBn 2,4-Bis(benzyloxy)—5-chlor0benz0ic acid BnO A solution of methyl 2,4-bis(benzyloxy)chlorobenzoate (5 g, 13 mmol) and lithium hydroxide monohydrate (2.74 g, 65.3 mmol) in MeOH (50 mL) and H20 (30 mL) was stirred at 70 CC for 4 -l22- h. The on was monitored by TLC. The reaction mixture was concentrated in vacuum. 2N aqueous HCl solution was added to reach pH = 3 to yield a precipitate, which was filtered, washed with water (10 mL) and dried to give 2,4-bis(benzyloxy)chlorobenzoic acid as a white solid. That solid was used t further ation (4 g, 83% yield, m/z: 369 [M+H]+ observed).

CIUCOCI 2,4-Bis(benzyloxy)—5-chl0r0benz0yl chloride BnO OBn A mixture of 2,4-bis(benzyloxy)chlorobenzoic acid (4 g, 11 mmol) in thionyl chloride (50 mL, 0.69 mol) was stirred at 80 0C for 2 h. The reaction was followed by TLC. The reaction mixture was concentrated under vacuum to give 2,4-bis(benzyloxy)chlorobenzoyl chloride as a yellow oil that was used without further purification (4g, 95% yield).

Ethyl 6-(2,4-bis(benzyloxy)chlorophenyl)0x0-4H-pyran-3—carboxylate O 0 l l BnO OBn To a solution of ethyl (Z)((dimethylamino)methylene)oxobutanoate (1.9 g, 10 mmol) in anhydrous THF (50 mL) at -78 oC (dry ice/acetone bath) was added DS (l M solution in THF, 25 mL, 25 mmol). After stirring for 30 min, 2,4-bis(benzyloxy)chlorobenzoyl chloride (4 g, 10 mmol) was added over 10 min to the mixture while keeping the temperature at -78 oC.

Following complete addition, the reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was followed by TLC. 2N aqueous HCl solution (20 mL) was added to the mixture, and the aqueous phase was extracted with EtOAc (2x400 mL). The combined organic fractions were washed with saturated aqueous brine solution (2x150 mL), dried over sodium sulfate, filtered and trated under vacuum. The e was purified by normal phase SiOz chromatography (10% to 40% EtOAc/petroleum ether) to afford ethyl 6-(2,4-bis(benzyloxy) phenyl)oxo-4H-pyrancarboxylate as a yellow solid (3.5 g, 69% yield, m/z: 491 [M+H]+ ed). 1H NMR (400 MHz, DMSO-d6) 5 8.76 (s, 1 H), 7.83 (s, 1 H), 7.50—7.37 (m, 10 H), 7.23 (s, 1 H), 6.91 (s, 1 H), 5.35—5.30 (m, 4 H), 4.26-4.20 (q, J=10.8, 7.2 Hz, 2H), 1.28- 125 (t, J=7.2 Hz, 3 H).

Ethyl (R)-6—(2,4-bis(benzyl0xy)—5-chl0r0phenyl)(1-hydr0xymethylbutan-Z-yl)0x0-1,4- -l23- BnO OBnI dihydropyridinecarb0xylate OH To a solution of ethyl 6-(2,4-bis(benzyloxy)chlorophenyl)oxo-4H-pyrancarboxylate (10 g, 20 mmol) in glacial AcOH (85 mL) and EtOH (100 mL) at room temperature was added (R)- 2-amino-3 -methylbutanol (2.71 g, 26.3 mmol). The reaction mixture was warmed to 80 oC and stirred for 16 h. The reaction was monitored by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with CHzClz (500 mL), washed with saturated aqueous NaHCO3 solution (500 mL), and the aqueous layer was extracted with CHzClz (500 mL). The ed organic fractions were dried over sodium sulfate, filtered and concentrated under reduced vacuum. The residue was purified by normal phase SiOz chromatography (0% to 10% MeOH/ CHzClz) to afford ethyl (R)—6-(2,4- bi yloxy)-5 -chlorophenyl)(1-hydroxy-3 -methylbutanyl)oxo-1,4-dihydropyridine- 3-carboxylate as a yellow solid (7.5 g, 64% yield, m/z: 576 [M+H]+ observed).

Ethyl (5-chlor0-2,4-dihydr0xyphenyD(1-hydr0xymethylbutanyl)0x0-1,4- dihydropyridinecarb0xylate To a solution of ethyl (R)(2,4-bis(benzyloxy)chlorophenyl)(1-hydroxy-3 -methylbutan- 2-yl)oxo-1,4-dihydropyridinecarboxylate (3.0 g, 5.2 mmol) in EtOH (100 mL) was added palladium on carbon (10% on carbon, 1 g, 94 mmol). The suspension was degassed under vacuum and lled with hydrogen-gas 2 times. The mixture was stirred under H2 (15 psi) at room temperature for 15 min. The reaction was followed by TLC. The reaction mixture was d, washed with EtOH (3x50 mL) and the filtrate concentrated under reduced pressure. The residue was dissolved in THF (50 mL) and concentrated under vacuum (repeated 3 times) to give ethyl (R)(5 o-2,4-dihydroxyphenyl)(1-hydroxy-3 -methylbutanyl)oxo-1,4- opyridinecarboxylate as a yellow solid that was used without r purification (1.72 g, 83% yield, m/z: 396 [M+H]+ observed).

Ethyl (R)chlor0-3—hydr0xy— 7-is0pr0pyl—11-0x0—6, 7-dihydr0—11H-benz0[flpyrid0[1,2— —124— CI I d][1, 4]0xazepine—1 0-carb0xylate oJNw'( To a solution of ethyl (R)(5-chloro-2,4-dihydroxyphenyl)(1-hydroxymethylbutanyl)- 4-oxo-1,4-dihydropyridinecarboxylate (3.3 g, 8.3 mmol) and PPh3 (10.9 g, 41.8 mmol) in THF (600 mL) was added dropwise a solution of diethyl azodicarboxylate (40% wt in toluene, 3 mL, 42 mmol, 5 eq) in THF (70 mL) at -10°C under N2. The e was stirred at -10 0C for 2 h and followed by TLC. Water (100 mL) was added to the reaction e, and the aqueous phase was extracted with EtOAc (2x200 mL). The combined organic phase was washed with saturated aqueous brine solution (2x150 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The e was purified by normal phase SiOz chromatography (30% to 100% EtOAc/hexanes, then 0% to 10% MeOH/CHzClz) to afford ethyl (R)chloro yisopropyl-1 1-oxo-6,7-dihydro-1 1H-benzo[f]pyrido[1,2-d][1,4]oxazepine carboxylate as a light yellow solid (2.0 g, 64% yield, m/z: 378 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 11 (s, 1H), 8.35 (s, 1H), 7.54 (s, 1H), 6.64 (s, 1H), 6.40 (s, 1H), 4.57—4.53 (m7 2H), 4.23-4.18 (m, 3H), 1.74 (m, 1H), .24 (t, J=6.8 Hz, 3H), 0.93—0.91 (d, J=6.4 Hz, 3H), 0.70-0.69 (d, J=6.4 Hz, 3H).

Ethyl (R)chl0r0- 7-is0pr0pyl—3—(3-meth0xypr0p0xgy)0x0-6, 7-dihydr0—11H- O O benz0[flpyrid0[1,2-d][1,4]0xazepine—1 0-carb0xylate To a solution of ethyl (R)chlorohydroxyisopropyloxo-6,7-dihydro-11H-benzo[f] pyrido[1,2-d][1,4]oxazepinecarboxylate (3.5 g, 9.3 mmol) and K2C03 (2.56 g, 18.6 mmol) in DMF (50 mL) was added 1-bromomethoxypropane (2.82 g, 18.6 mmol), and the mixture was stirred at 80 0C for 2 hr. The on was followed by TLC. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic fractions were washed with sat. aq. brine solution (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal phase SiOz tography (0% to 10% EtOAc/MeOH) to afford ethyl (R)chloroisopropyl(3-methoxypropoxy)oxo- 6,7-dihydro-11H-benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylate as a white solid (3.9 g, 94% yield, m/z: 450 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 8.36 (s, 1H), 7.63 (s, 1H), 6.87 (s, 1H), 6.44 (s, 1H), 4.62-4.59 (m, 2H), 4.24-4.12 (m, 5H), 3.50-3.47 (t, J=6.4Hz, 2H), 3.25 (s, 3H), 2.01-1.94 (m, 2H), 1.75 (m, 1H), .25 (t, J=7.2 Hz, 3H), .93 (d, J=6.4 Hz, 3H) 0.71-0.70 (d, J=6.40, 3H).

(R)Chloro- 7-is0pr0pyl—3—(3-meth0xypr0p0xy)0x0-6, 7-dihydr0—11H—benz0[flpyrid0 [1,2- MeO’\/\OCI d][1,4]0xazepine—10-carb0xylic acid To a solution of ethyl (R)chloroisopropyl(3 -methoxypropoxy)-l l-oxo-6,7-dihydro-l lH- benzo[f]pyrido[l,2-d][l,4]oxazepine-lO-carboxylate (3.3 g, 7.35 mmol) in l,4-dioxane (10 mL) and H20 (10 mL) was added lithium ide monohydrate (1.54g, 36.7 mmol). The reaction mixture was stirred at room temperature for 1 h and followed by TLC. The reaction mixture was concentrated under reduced pressure, and 1N aq. HCl solution was added to reach pH = 2-3. The mixture was extracted with EtOAc (3x20 mL), and the combined c fractions were washed with sat. aq. brine on (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (R)chloroisopropyl(3 xypropoxy)-1 1-oxo-6,7-dihydro- 11H-benzo[f]pyrido[l,2-d][l,4]oxazepinecarboxylic acid as a light yellow solid (5.25 g, 85% yield from 2x3.3g scale reactions, m/z: 422 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 5 15.64 (s, 1H), 8.39 (s, 1H), 7.45 (s, 1H), 6.78 (s, 1H), 6.59 (s, 1H), 4.55-4.46 (m, 2H), 4.11-4.08 (m, 2H), 3.82-3.78 (m, 1H), 3.55—3.52 (m, 2H), 3.30 (s, 3H), 2.09—2.03 (m, 3H), 1.02— 1.01 (d, J=6.4 Hz, 3H), 0.80-0.79 (d, J=6.4 Hz, 3H).

The following examples were prepared in a similar manner as (R)chloroisopropyl(3- methoxypropoxy)-l l-oxo-6,7-dihydro-l lH-benzo[f]pyrido [1,2-d][1,4]oxazepine-lO-carboxylic acid from ethyl 2-chloro-3 -hydroxyisopropyl-l l-oxo-6,7-dihydro-l lH-benzo[f]pyrido[ l ,2- d][l,4]oxazepine-lO-carboxylate and an riate bromide.

EXAMPLE 28: (S)Chlor0is0pr0pyl(3-methoxypropoxy)—1 1-0x0-6,7-dihydr0-1 1H- -l26- MeO’\/\ benzo[f] pyrido[1,2-d] xazepine-lO-carboxylic acid m/z: 422 [M+H]+ observed. 1H NMR (400 MHz, CDC13) 6 15.64 (s, 1H), 8.39 (s, 1H), 7.45 (s, 1H), 6.78 (s, 1H), 6.59 (s, 1H), 4.55-4.46 (m, 2H), 4.11-4.08 (m, 2H), 3.82-3.78 (m, 1H), 3.55- 3.52 (m, 2H), 3.30 (s, 3H), 2.09-2.03 (m, 3H), 1.02-1.01 (d, J=6.4 Hz, 3H), 0.80-0.79 (d, J=6.4 Hz, 3H).

E 29: 2-Chlor0isopropyl(2-meth0xyeth0xy)—11-0x0-6,7-dihydr0-11H- o o benzo[f] [1,2-d] [1,4]oxazepine-lO-carboxylic acid m/z: 408 [M+H]+ observed . 1HNMR (400 MHz, DMSO-d6): 6 8.73 (bs, 1 H), 7.77 (s, 1 H), 6.98 (bs, 1 H), 6.92 (s, 1H), 4.70 (s, 2 H), 4.52 (s, 1 H), 4.28 (m, 2 H), 3.71 (t, J=4.4 Hz, 2 H), 3.34 (s, 3 H), 1.82 (bs, 1 H), 0.99 (d, J=6.4 Hz, 3 H), 0.71 (d, J=6.4 Hz, 3 H).

EXAMPLE 30: (R)Chlor0is0pr0pyl(2-meth0xyeth0xy)—11-0x0-6,7-dihydr0-11H- o o o—jN" benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid ( ; EXAMPLE 31: (S)Chlor0is0pr0pyl(2-meth0xyeth0xy)—1 1-0x0-6,7-dihydr0-1 1H- benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid 66 mg of the mixture of enantiomers was separated by SFC (supercritical fluid chromatography) on an AD-3 column using 40% EtOH (0.1% aq. NH3) as a modifier to give (R)chloro isopropy1(2-methoxyethoxy)-1 1-oxo-6,7-dihydro-1 1H-benzo[f]pyrido[1,2-d][1,4]oxazepine- boxy1ic acid as a white solid (faster eluting enantiomer, 17.9 mg, 26%, m/z: 408 [M+H]+ observed) and (S)—2-chloroisopropyl(2-methoxyethoxy)oxo-6,7-dihydro-11H- benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylic acid as a white solid (slower eluting enantiomer, 20.5 mg, 31%, m/z: 408 [M+H]+ observed).

Example 30: Chl01‘0is0pr0pyl(2-meth0xyeth0xy)—11-0x0-6,7-dihydr0-11H- benzo[flpyrido[1,2-d][1,4]oxazepine—lO-carboxylic acid. m/z: 408 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.73 (bs, 1 H), 7.77 (s, 1 H), 6.98 (bs, 1 H), 6.92 (s, 1H), 4.70 (s 2 H), 4.52 (s, 1 H), 4.28 (m, 2 H), 3.71 (t, J=4.4 Hz, 2 H), 3.34 (s, 3 H), 1.82 (bs, 1 H), 0.99 (d, J=6.4 Hz, 3 H), 0.71 (d, J=6.4 Hz, 3 H).

Example 31: (S)Chlor0is0pr0pyl(2-methoxyethoxy)—11-0x0-6,7—dihydr0-11H- benzo[flpyrido[1,2-d][1,4]oxazepine—lO-carboxylic acid. m/z: 378 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.73 (bs, 1 H), 7.77 (s, 1 H), 6.98 (bs, 1 H), 6.92 (s, 1H), 4.70 (s 2 H), 4.52 (s, 1 H), 4.28 (m, 2 H), 3.71 (t, J=4.4 Hz, 2 H), 3.34 (s, 3 H), 1.82 (bs, 1 H), 0.99 (d, J=6.4 Hz, 3 H), 0.71 (d, J=6.4 Hz, 3 H).

EXAMPLE 32; Ethyl r0hydr0xyisopropyl-l 1-0x0-6,7-dihydr0-1 1H- benzo [f] pyrido [1,2-d] [1,4]oxazepine—lO-carboxylate m/z: 378 [M+H]+ observed. 1H NMR (400 MHz, DMSO-d6) 6 11 (s, 1H), 8.35 (s, 1H), 7.54 (s, 1H), 6.64 (s, 1H), 6.40 (s, 1H), 4.57-4.53 (m, 2H), 4.23-4.18 (m, 3H), 1.74 (m,1H), 1.28-1.24 (t, J=6.8 Hz, 3H), .91 (d, J=6.4 Hz, 3H), 0.70-0.69 (d, J=6.4 Hz, 3H).

EXAMPLE 33: 2—Chlor0is0pr0pyl(3-methoxypropoxy)—1 1-0x0-6,7—dihydr0-1 1H- 0 O MeO’\/\O benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid 0JNY m/z: 422 [M+H]+ observed. 1H NMR (400 MHz, CDC13) 5 15.64 (s, 1H), 8.39 (s, 1H), 7.45 (s, 1H), 6.78 (s, 1H), 6.59 (s, 1H), 4.55-4.46 (m, 2H), 4.11-4.08 (m, 2H), 3.82-3.78 (m, 1H), 3.55— 3.52 (m, 2H), 3.30 (s, 3H), 2.09—2.03 (m, 3H), 1.02—1.01 (d, J=6.4 Hz, 3H), 0.80-0.79 (d, J=6.4 Hz, 3H). -l28- E 34: (R)Chlor0isopropyl0x0(2,2,2-triflu0r0eth0xy)—6,7-dihydr0- O O 11H-benzo[f] pyrido[1,2-d] [1,4]oxazepine—lO-carboxylic acid m/z: 432 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.80 (s, 1 H), 7.82 (s, 1 H), 7.07 (s, 2 H), 4.97 (m, 2 H), 4.72 (m, 2 H), 4.57 (d, J=10 Hz, 1 H), 1.81 (m, 1 H), 0.98 (d, J=6.8 Hz, 3 H), 0.71 (d, J=6.4 Hz, 3 H).

EXAMPLE 35: (R)Chlor0(cyclopropylmethoxy)—7-is0pr0pyl0x0-6,7-dihydr0- O O 11H-benzo[f] pyrido[1,2-d] [1,4]oxazepine—lO-carboxylic acid m/z: 404 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.78 (s, 1 H), 7.74 (s, 1 H), 7.02 (s, 1 H), 6.84 (s, 1 H), 4.69 (m, 2 H), 4.54 (br d, J=10.8 Hz, 1 H), 4.00 (m, 2 H), 1.82 (br s, 1 H), 1.26 (m, 1 H), 0.97 (d, J=6.4 Hz, 3 H), 0.70 (d, J=6.4 Hz, 3 H), 0.59 (m, 2 H), 0.37 (m, 2 H).

EXAMPLE 36: (R)Chlor0(3-hydr0xypr0p0xy)—7-is0pr0pyl0x0-6,7-dihydr0-11H- o o benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid m/z: 408 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.78 (s, 1 H), 7.74 (s, 1 H), 7.02 (s, 1 H), 6.88 (s, 1 H), 4.71 (m, 2 H), 4.54 (bd, J=104. Hz, 2 H), 4.20 (m, 2 H), 3.58 (t, J=6 Hz, 2 H), 1.88 (m, 3 H), 0.98 (d, J=6.8 Hz, 3 H), 0.70 (d, J = 6.4 Hz, 3 H).

EXAMPLE 37: (R)Chlor0(3-hydroxy-2,2-dimethylpr0p0xy)—7-isopropyl0x0-6,7- dihydro—l 1H-benz0 [f] pyrido [1,2-d] [1,4]0xazepine—10-carb0xylic acid m/z: 436 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.78 (s, 1 H), 7.74 (s, 1 H), 7.02 (s, 1 H), 6.85 (s, 1 H), 4.69 (m, 2 H), 4.54 (m, 1 H), 3.83 (m, 2 H), 3.30 (m, 2 H), 1.84 (s, 1 H), 0.97 (m, 9 H), 0.70 (d, J=6.8 Hz, 3 H).

EXAMPLE 38: (R)Chlor0is0pr0pyl(4-meth0xybut0xy)—1 1-0x0-6,7-dihydr0-1 1H- 0 O benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid ( m/z: 436 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 6 8.78 (s, 1 H), 7.74 (s, 1 H), 7.02 (s, 1 H), 6.87 (s, 1 H), 4.69 (m, 2 H), 4.55 (bd, J=10.4 Hz, 1 H), 4.14 (m, 2 H), 3.39 (t, J=6.4 Hz, 2 H), 3.23 (s, 3 H), 1.79 (m, 3 H), 1.68 (m, 2 H), 0.97 (d, J=6.4 Hz, 3 H), 0.71 (d, J=6.8 Hz, 3 H).

EXAMPLE 39: Chlor0(4-hydr0xybut0xy)—7-isopropyl-l1-0x0-6,7-dihydr0-11H- o o OJ w( benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid m/z: 422 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.78 (s, 1 H), 7.74 (s, 1 H), 7.02 (s, 1 H), 6.88 (s, 1 H), 4.70 (s, 2 H), 4.55 (m, 1 H), 4.18-4.09 (m, 2 H), 3.46 (t, J=6.4Hz, 3 H), 1.78 (m, 3 H), 1.60 (m, 2 H), 0.97 (d, J=6.4 Hz, 3 H), 0.70 (d, J=6.4 Hz, 3 H).

EXAMPLE 40: (R)Chlor0is0pr0pyl(3-m0rpholin0pr0p0xy)—11-0x0-6,7-dihydr0- o o oflN/\/\ \J N 1 1H-benzo [f] pyrido ] [1,4]oxazepine-lO-carboxylic acid ( m/z: 477 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 10.03 (s, 1 H), 8.79 (s, 1 H), 7.77 (s, 1 H), 7.02 (s, 1 H), 6.90 (s, 1 H), 4.71 (m, 2 H), 4.58 (bd, J=10 Hz, 1 H), 4.22 (m, 2 H), 4.01 (bd, J=12 Hz, 2 H), 3.67 (m, =11.6 Hz, 2 H), 3.51 (bd, J=12 Hz, 2 H), 3.30 (t, J=7.2 Hz, 2 H), 3.13 (m, 2 H), 2.20 (m, 2 H), 1.83 (bs, 1 H), 0.98 (d, J=6.4 Hz, 3 H), 0.73—0.71 (d, J=6.4 Hz, 3 EXAMPLE 41: (R)(2-(2-Br0m0ethoxy)eth0xy)—2-chlor0is0pr0pyl0x0-6,7-dihydr0- o o 11H-benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid m/z: 499, 501 [M+H]+ observed . 1HNMR (300 MHz, CDC13): 6 8.56 (s, 1H), 7.52 (s, 1H), 6.97 (s, 1H), 6.69 (s, 1H), 4.68-4.50 (m, 2H), 4.26-4.24 (m, 1H) 3.98-3.96 (m, 6H), 3.51 (t, J=6.0 Hz, 2H), 2.06-2.10 (m, 1H), 1.09 (d, J=6.5 Hz, 3H), 0.86 (d, J=6.5 Hz, 3H).

EXAMPLE 42: (R)(3-((tert-Butoxycarb0nyl)amin0)pr0p0xy)chlor0is0pr0pyl-1 1- 0x0-6,7-dihydr0-1 1H-benz0 [f] pyrido [1,2-d] [1,4]0xazepinecarb0xylic acid 0 O X 40 CI OH m/z: 507 [M+H]+ observed . 1H NMR (300 MHz, CDC13): 5 8.48 (s, 1H), 7.50 (d, J=1.2 Hz, 1H), 6.85 (s, 1H), 6.62 (s, 1H), 5.01 (d, J=5.3 Hz, 1H), 4.65 (dd, J=12.7, 5.7 Hz, 2H), 4.56 (dd, , 2.9 Hz, 1H), .05 (m, 2H), 3.38 (q, J=6.2 Hz, 2H), 2.13—2.00 (m, 2H), 1.43 (s, 9H), 1.25 —1.24 (m, 1H), 1.09 (d, J=6.5 Hz, 3H), 0.86 (d, J=6.5 Hz, 3H).

EXAMPLE 43: (R)Chlor0(2-hydr0xyethyl)—3-(3-methoxypropoxy)—1 1-0x0-6,7- o-l 1H-benz0 [f] pyrido [1,2-d] [1,4]0xazepinecarb0xylic acid m/z: 424 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 16.36 (s, 1H), 8.67 (s, 1H), 7.74 (s, 1H), 6.96 (s, 2H), 4.81-4.72 (m, 2H), 4.61-4.50 (m, 2H), 4.17 (t, J=6.0 Hz, 2H), 3.49-3.46 (m, 2H), 3.37—3.42 (m, 1H), 3.24 (s, 3H), 1.98 (m, 2H), 1.95-1.85 (m, 2H), 1.32 (s, 1H) EXAMPLE 44: (R)Cycl0pr0pylisobutoxyis0pr0pyl0x0-6,7-dihydr0-11H- benzo[f] pyrido[1,2-d] xazepine-lO-carboxylic acid Ethyl (R)chl0r0is0but0xy- 7-is0pr0pyl—11-0x0-6, 7-dihydr0—11H—benz0[flpyrid0[1,2— d][1, 4]0xazepine—1 0—carb0xylate Ethyl (R)chloro-3 -hydroxyisopropyl-1 1-oxo-6,7-dihydro-1 1H-benzo[f]pyrido[1,2- d][1,4]oxazepinecarboxylate (200 mg, 0.53 mmol), K2C03 (219 mg 1.59 mmol) and isobutyl bromide (73 mg, 0.53 mmol) were dissolved in DMF (1 mL) and heated to 80 0C for 16 hours. The reaction was diluted with EtOAc (50 mL) and washed with H20 (2X15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was d by normal phase Si02 chromatography (0% to 10% MeOH/CHzClz) to afford (R)chloroisobutoxyisopropyl-1 1-oxo-6,7-dihydro—1 1H-benzo[f]pyrido[1,2- d][1,4]oxazepinecarboxylate as a yellow solid (130 mg, 57% yield, m/z: 434 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 5 8.14 (s, 1H), 7.47 (s, 1H), 6.65 (s, 1H), 6.56 (s, 1H), 4.55 (m, 2H), 4.37 (m, 2H), 3.79 (m, 3H), 2.17 (m, 1H), 2.02 (m, 1H), 1.38 (t, J=7.2 Hz, 3H), 1.05 (m, 9H), 0.86 (d, J=6.8 Hz, 3H).

Ethyl (R)cyclopr0pyl—3—is0butoxy- 7-is0pr0pyl—11-0x0—6, 7-dihydr0—11H—benz0[flpyrid0[1,2— d][1, 4]0xazepine—1 0—carb0xylate In a microwave vial, Cs2C03 (98 mg, 0.30 mmol), (R)chloroisobutoxyisopropyloxo- 6,7-dihydro-11H-benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylate (45 mg 0.10 mmol) and potassium cyclopropyltrifluoroborate (22 mg 0.15 mmol) were added. A e of toluene/HzO (0.6 mL, 5: 1) was added. The solution was purged with argon for 1 min, ed by the addition of Xphos (9.5 mg, 0.021 mmol) and palladium(II)acetate (2 mg, 0.01 mmol). The microwave vial was sealed. The reaction was stirred at 110 0C for 60 min with microwave irradiation. LCMS showed complete conversion. The vial was opened and the reaction mixture concentrated under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 7% HzClz) to afford ethyl (R)—2-cyclopropyl-3 -isobutoxyisopropyl-l l-oxo- 6,7-dihydro-l lH-benzo[f]pyrido[l,2-d][l,4]oxazepinecarboxylateas as a yellow solid (35 mg, 77% yield, m/z: 440 [M+H]+ observed).

(R)Cyclopropyl—3-is0but0xy— r0pyl—11-0x0-6, 7-dihydr0—11H—benz0[flpyrid0[1,2- O O ]0xazepine—10-carb0xylic acid OJN'”( Ethyl (R)cyclopropyl-3 -isobutoxyisopropyl-l l-oxo-6,7-dihydro-l lH-benzo[f]pyrido[ l ,2- d][l,4]oxazepine-lO-carboxylateas (30 mg, 0.068 mmol) and lithium hydroxide monohydrate (5.1 mg, 0.12 mmol) were dissolved in dioxane/HZO (1 mL, 1:1) and stirred at rt for 16h. The pH was changed to 5 by the dropwise addition of 1N HCl. A white sticky solid formed. The aqueous layer was extracted with EtOAc (4x5 mL). The combined organic phase was washed dried over sodium sulfate, filtered and concentrated under vacuum. The residue was d by reverse phase HPLC to afford (R)cyclopropyl-3 -isobutoxyisopropyl-l l-oxo-6,7-dihydro-l lH- benzo[f]pyrido[l,2-d][l,4]oxazepine-l0-carboxylic acid as white solid (15 mg, 55% yield, m/z: 412 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 8.77 (s, 1H), 7.04 (s, 1H), 6.97 (s, 1H), 6.66 (s, 1H), 4.62 (m, 2H), 4.48 (m, 1H), 3.84 (m, 2H), 2.06 (m, 2H), 1.78 (bs, 1H), 1.03 (d, J=6.8 Hz, 6H), 0.96 (d, J=6.4 Hz, 3H), 0.89 (m, 2H), 0.77 (m, 2H), 0.67 (d, J=6.8 Hz, 3H).

The following example were ed in a similar manner as (R)—2-cyclopropyl-3 -isobutoxy isopropyl-l 6,7-dihydro-l lH-benzo[f]pyrido[ l ,2-d] [ l ,4]oxazepine- l 0-carboxylic acid from Ethyl (R)chlorohydroxyisopropyl-l l-oxo-6,7-dihydro-l lH-benzo[f]pyrido[l,2- d][l,4]oxazepine-lO-carboxylate and an appropriate bromide, ed by a suitable organoboron species.

EXAMPLE 45: (R)Cycl0propylisopropyl(3-meth0xypr0p0xy)—11-0x0-6,7-dihydr0- -l33- WO 85619 11H-benzo[f] pyrido[1,2-d] [1,4]oxazepine—lO-carboxylic acid OJW( m/z: 428 [M+H]+ observed . 1HNMR (300 MHz, CDC13): 6 8.47 (d, J=1.7 Hz, 1H), 6.93 (d, J=1.6 Hz, 1H), 6.81 (d, J=1.6 Hz, 1H), 6.54 (d, J=1.5 Hz, 1H), 4.55 (dd, J=11.3, 4.5 Hz, 2H), 4.11 (td, J=6.2, 1.4 Hz, 2H), 3.97-3.81 (m, 1H), 3.66-3.49 (m, 2H), 3.36 (d, J=1.6 Hz, 3H), 2.21- 1.91 (m, 4H), 1.06 (dd, J=6.5, 1.6 Hz, 3H), 0.98-0.89 (m, 2H), 0.83 (d, J=6.5 Hz, 3H), 0.72-0.50 (m, 2H).

EXAMPLE 46: Is0propyl(3-methoxypropoxy)—2-methyl0x0-6,7-dihydr0-11H- o o benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid OJHU( m/z: 402 [M+H]+ observed . 1H NMR (300 MHz, CDC13): 5 8.49 (s, 1H), 7.21(s, 1H), 6.85 (s, 1H), 6.53 (d, J=1.4 Hz, 1H), 4.54 (td, , 11.5, 4.5 Hz, 2H), 4.15-4.03 (m, 2H), 3.98-3.85 (m, 1H), 3.57 (td, J=6.0, 1.3 Hz, 2H), 3.36 (d, J=1.3 Hz, 3H), 2.20 (s, 3H), 2.17-1.92 (m, 3H), 1.05 (d, J=6.6 Hz, 3H), 0.86-0.77 (m, 3H).

EXAMPLE 47: (R)Ethylis0pr0pyl(3-methoxypropoxy)—11-0x0-6,7-dihydr0-11H- o o benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid OJW( m/z: 416 [M+H]+ observed . 1H NMR (300 MHz, CDC13): 5 8.56 (s, 1H), 7.26 (s, 1H), 7.04 (s, 1H), 6.55 (s, 1H), 4.64 (dd, J=12.8, 5.7 Hz, 1H), 4.58-4.47 (m, 1H), 4.09 (t, J=6.1 Hz, 2H), 3.96 (s, 1H), 3.59 (dd, J=6.6, 5.4 Hz, 2H), 3.37 (d, J=1.2 Hz, 3H), 2.71-2.55 (m, 2H), 2.18-2.03 (m, 3H), 1.21 (td, J=7.4, 1.2 Hz, 3H), 1.08 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.5 Hz, 3H).

EXAMPLE 48: (R)Is0propyl(3-methoxypropoxy)—11-0x0vinyl-6,7-dihydr0-1 1H- —134— benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid OJHH( m/z: 414 [M+H]+ observed . 1HNMR (300 MHz, CDC13): 6 8.45 (s, 1H), 7.55 (s, 1H), 7.01-6.84 (m, 2H), 6.59 (s, 1H), 5.75 (dd, J: 17.7, 1.2 Hz, 1H), 5.32 (dd, J: 11.2, 1.2 Hz, 1H), 4.65-4.49 (m, 2H), 4.13 (t, J: 6.3 Hz, 2H), 3.86 (m, 1H), 3.58 (t, J: 6.0 Hz, 2H), 3.37 (s, 3H), 2.16-2.08 (m, J: 6.1 Hz, 3H), 1.08 (d, J: 6.5 Hz, 3H), 0.86 (d, J: 6.6 Hz, 3H).

EXAMPLE 49: (R)(Cycl0pr0pylmeth0xy)—7-is0propyl-Z-methyl0x0-6,7-dihydr0- o o 11H-benzo[f] [1,2-d] [1,4]oxazepine-lO-carboxylic acid OJHU( m/z: 384 [M+H]+ observed . 1H NMR (300 MHz, CDC13): 5 8.47 (s, 1H), 7.24 (s, 1H), 6.85 (s, 1H), 6.48 (s, 1H), 4.54 (td, , 11.1, 4.3 Hz, 2H), 3.96-3.80 (m, 3H), 2.23 (d, J=0.9 Hz, 3H), 2.08 (bs, 1H), 1.35-1.21 (m, 1H), 1.05 (d, J=6.5 Hz, 3H), 0.82 (d, J=6.5 Hz, 3H), 0.73-0.60 (m, 2H), 0.39 (dd, J=6.0, 4.6 Hz, 2H).

EXAMPLE 50: (Cycl0pr0pylmethoxy)—2-ethylisopropyl0x0-6,7-dihydr0-11H- o o V0 1}. benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid 0 W( m/z: 398 [M+H]+ observed . 1H NMR (300 MHz, CDC13): 5 8.61 (s, 1H), 7.26 (s, 1H), 7.12 (s, 1H), 6.49 (s, 1H), 4.65 (dd, J=13.5, 5.7 Hz, 1H), 4.52 (d, J=12.7 Hz, 1H), 4.03-3.98 (m, 1H), 3.86 (d, J=6.7 Hz, 2H), 2.66 (hept, J=7.5 Hz, 2H), 2.11-2.00 (m, 1H), 1.24 (td, J=7.5, 1.4 Hz, 3H), 1.09 (d, J=6.4 Hz, 3H), 0.85 (d, J=6.4 Hz, 3H), 0.66 (dd, J=7.2, 5.5 Hz, 2H), 0.44-0.32 (m, 2H).

EXAMPLE 51: (R)Is0butoxyis0pr0pyl-Z-methyl0x0-6,7-dihydr0-11H- benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid OJWI( m/z: 386 [M+H]+ observed . 1H NMR (300 MHz, CDC13): 5 8.68 (s, 1H), 7.25 (s, 1H), 7.13 (s, 1H), 6.51 (s, 1H), 4.68 (dd, J=13.0, 5.1 Hz, 1H), 4.55 (d, J=12.6 Hz, 1H), 4.10 (d, J=10.5 Hz, 1H), 3.84-3.69 (m, 2H), 2.23 (s, 3H), 2.12 (dd, J=13.0, 6.6 Hz, 2H), 1.25-1.05 (m, 9H), 0.82 (d, J=6.5 Hz, 3H).

EXAMPLE 52: (R)Ethylis0but0xyis0pr0pyl0x0-6,7-dihydr0-11H- o o benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid OJWI( m/z: 400 [M+H]+ observed . 1H NMR (300 MHz, CDC13): 6 8.62 (s, 1H), 7.25 (d, J=4.5 Hz, 1H), 7.08 (s, 1H), 6.51 (s, 1H), 4.64 (s, 1H), 4.56 (s, 1H), 4.03 (s, 1H), 3.84-3.69 (m, 2H), 2.75-2.54 (m, 2H), 2.15 (dp, , 6.5 Hz, 2H), 1.23 (t, J=7.5 Hz, 3H), 1.08 (t, J=7.2 Hz, 9H), 0.84 (d, J=6.4 Hz, 3H).

EXAMPLE 53: (R)(3-((tert-Butoxycarbonyl)amino)propoxy)—2-cyclopr0pylisopropyl- 1 1-0x0-6,7-dihydr0-1 1H-benz0 [f]pyrido [1,2-d] [1,4]0xazepine—10-carb0xylic acid 0 o o—J""( m/z: 513 [M+H]+ ed . 1H NMR (300 MHz, CDC13): 5 8.47 (s, 1H), 6.98 (s, 1H), 6.82 (s, 1H), 6.52 (s, 1H), 5.00-5.02 (m, 1H), 4.56 (qd, J=12.4, 4.4 Hz, 2H), 4.18-4.04 (m, 2H), .84 (m, 1H), 3.39 (q, J=4.5, 2.8 Hz, 2H), 2.11-1.94 (m, 3H), 1.65 (d, J=7.5 Hz, 1H), 1.43 (s, 9H), 1.31-1.19 (m, 2H), 1.11-0.92 (m, 4H), 0.83 (d, J=6.5 Hz, 3H), 0.63 (ddd, J=9.4, 6.4, 3.7 Hz, 1H).

EXAMPLE 54: (R)Cyclopr0pylis0pr0pyl-1 1-0x0(2,2,2-triflu0r0eth0xy)—6,7- dihydro—l 1H-benz0 [f] pyrido [1,2-d] [1,4]0xazepine—10-carb0xylic acid oj"”( m/z: 438 [M+H]+ observed . 1H NMR (300 MHz, : 5 8.55 (s, 1H), 7.03-6.98 (m, 2H), 6.51 (s, 1H), 4.63-4.52 (m, 2H), 4.42 (q, J =7.9 Hz, 2H), 3.94 (s, 1H), 2.08 (s, 2H), 1.04 (m 5H), 0.90-0.81 (m, 3H), 0.71-0.65 (m, 2H).

EXAMPLE 55: (R)(2-Eth0xyeth0xy)—7-isopropyl-Z-methyl0x0-6,7—dihydr0-11H- o o benzo[f] pyrido[1,2-d] [1,4]oxazepine—lO-carboxylic acid OJIW( m/z: 402 [M+H]+ ed . (400 MHz, DMSO-d6): 5 8.76 (s, 1H), 7.45 (s, 1H), 6.96 (s, 1H), 6.68 (s, 1H), 4.65 (d, J=3.2 Hz, 2H), 4.52 (bd, J=11.2 Hz, 1H), 4.17 (m, 2H), 3.72 (t, J=4.4 Hz, 2H), 3.51 (m, 2H), 2.14 (s, 3H), 1.81 (bs, 1H), 1.13 (t, J=6.8 Hz, 3H), 0.96 (d, J=6.4 Hz, 3H), 0.67 (d, J=6.4 Hz, 3H).

EXAMPLE 56: (R)Ethyl(3-hydroxyprop0xy)—7-is0pr0pyl0x0-6,7-dihydr0-11H- o o benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid OJHH( m/z: 402 [M+H]+ observed . (400 MHz, DMSO-d6): 5 8.76 (s, 1H), 7.40 (s, 1H), 6.99 (s, 1H), 6.66 (s, 1H), 4.66 (d, J=3.6 Hz, 2H), 4.52 (bd, J=12 Hz, 1H) 4.09 (m, 2H), 3.58 (t, J=6.4 Hz, 2H), 2.53 (m, 2H), 1.88 (m, 2H), 1.80 (m, 1H), 1.15 (t, J=7.2 Hz, 3H), 0.98-0.96 (d, J=6.4 Hz, 3H), 0.69-0.68 (d, J=6.4 Hz, 3H).

EXAMPLE 57: (R)(2-Eth0xyeth0xy)—2-ethylisopropyl0x0-6,7-dihydr0-11H- benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid m/z: 416 [M+H]+ ed . (400 MHz, DMSO-d6): 5 8.76 (s, 1H), 7.40 (s, 1H), 6.99 (s, 1H), 6.68 (s, 1H), 4.65 (d, J=3.2 Hz, 2H), 4.52 (bd, J=10.4 Hz, 1H), 4.16 (m, 2H), 3.72 (t, J: 4.4 Hz, 2H), 3.52 (q, J=14, 7.2, 2H), 2.55 (m, 2H), 1.81 (s, 1H), 1.11 (m, 6H), 0.94 (d, J=6.4 Hz, 3H), 0.68 (d, J=6.4 Hz, 3H).

EXAMPLE 58: (R)Ethylis0pr0pyl0x0(2,2,2-triflu0r0eth0xy)—6,7-dihydr0-11H- benzo[f] pyrido[1,2-d] [1,4]oxazepine-lO-carboxylic acid OJWI( m/z: 426 [M+H]+ observed . (400 MHz, DMSO-d6): 5 8.78 (s, 1 H), 7.48 (s, 1 H), 7.03 (s, 1 H), 6.83 (s, 1 H), 4.87 (m, 2 H), 4.68 (d, J=3.2 Hz, 2 H), 4.55 (bd, J=10.4 Hz, 1 H), 2.58 (m, 2 H), 1.77 (bs, 1 H), 1.16 (t, J=7.2 Hz, 3 H), 0.97 (d, J=6.8 Hz, 3 H), 0.69 (d, J=6.8 Hz, 3 H).

EXAMPLE 59: (R)Isopropyl-Z-methyl-l1-0x0(2,2,2-triflu0r0ethoxy)—6,7-dihydr0- 1 zo [f] pyrido [1,2-d] [1,4]oxazepine-lO-carboxylic acid BrUConeOH Methyl 5-br0m0-2,4-dihydr0xybenz0ate HO To a stirred solution of methyl 2,4-dihydroxybenzoate (10 g, 60 mmol) in AcOH (150 mL) was added a solution of Brz (3 mL, 60 mmol) in AcOH (50 mL) drop-wise. The reaction mixture was stirred at 10 0C for 12 h. The pH of the reaction mixture was adjusted to 8 by the addition of saturated aqueous NaHCO3 (300 mL) and the reaction was extracted with EtOAc (2x200 mL).

The combined organic phase was washed with saturated aqueous brine solution (300 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was washed with 100 mL zz petroleum ether = 10:1) to give methyl o-2,4-dihydroxybenzoate as a white solid (9.5 g, 65% yield, m/z: 246, 248 [M+H]+ observed).

BrUCOZMeOBn Methyl 2,4-bis(benzyloxy)—5-br0m0benz0ate BnO To a stirred on of 5-bromo-2,4-dihydroxybenzoate (8.0 g, 33 mmol) in CH3CN (80 mL) was added K2CO3 (18 g, 130 mmol), followed by benzyl e (9.7 mL, 81 mmol). The e was stirred at 80 0C for 12 h. The reaction mixture was quenched by the addition of H20 (200 mL) and extracted with EtOAc (2x300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2S04, filtered and concentrated under vacuum. The residue was washed with 100 mL (PE: EA: 20 :1) to give methyl 2,4-bis(benzyloxy)bromobenzoate as a white solid (12 g, 87% yield, m/z: 426, 428 [M+H]+ observed). 1H NMR (400 MHz, CD3Cl) 8.11 (s, 1H), 7.39 (m, 10H), 6.54 (s, 1H), 5.12 (s, 2H), 5.11 (s, 2H), 3.88 (s, 3H).

Methyl 2,4-bis(benzyloxy)—5-methylbenz0ate BnOUCOZMEOBn To a stirred solution of 2,4-bis(benzyloxy)bromobenzoate (2.0 g, 4.7 mmol) in oxane (20 mL) and H20 (4 mL) was added trimethylboroxine solution (4 M in THF, 2 mL, 8 mmol), Pd(OAc)2 (74 mg, 0.33 mmol), SPhos (289 mg, 0.7 mmol) and K2C03 (2.6 g, 19 mmol). The mixture was stirred at 90 0C for 16 hours. The reaction mixture was diluted H20 (20 mL) and extracted with EtOAc (3x15 mL). The combined organic layers were separated, dried over Na2S04, filtered and concentrated under vacuum. The e was purified by normal phase SiOz chromatography (5% to 20% EtOAc/petroleum ether) to afford methyl s(benzyloxy)- ylbenzoate as a light yellow solid (1.5 g, 88% yield, m/z: 363 [M+H]+ observed). 1H NMR (400 MHz, CD3Cl) 5 7.72 (s, 1H), 7.41 (m, 10H), 6.52 (s, 1H), 5.13 (s, 2H), 5.06 (s, 2H), 3.88 (S, 3H), 2.21 (S, 3H).

UCOOHOBn 2,4-Bis(benzyloxy)—5-methylbenz0ic acid BnO To a stirred solution of methyl 2,4-bis(benzyloxy)methylbenzoate (1 g, 4.7 mmol) in THF (10 mL), MeOH (10 mL) and H20 (10 mL) was added lithium hydroxide monohydrate (590 mg, 14 mmol). The mixture was stirred at 60 0C for 4 hours. The reaction mixture was concentrated under vacuum to remove the organic solvents. The aqueous solution was acidified with 1N HCl (10 mL) to pH = 3. The resulting white solid was collected by filtration and washed with H20 (2x10 mL) to give 2,4-bis(benzyloxy)methylbenzoic acid (0.9 g, 94% yield, m/z: 349 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 12.17 (s, 1H), 7.46 (m, 11H), 6.89 (s, 1H), 5.20 (s, 2H), 5.15 (s, 2H), 2.11 (s, 3H).

UCOCIOBn 2,4-Bis(benzyloxy)—5-methylbenz0yl chloride BnO A mixture of 2,4-bis(benzyloxy)methylbenzoic acid (0.9 g, 2.58 mmol) in thionyl chloride (2.6 mL, 36 mmol) was stirred at 80 0C for 2 hours. The mixture was concentrated under vacuum to remove the organic solvent to give 2,4-bis(benzyloxy)methylbenzoyl de as a light yellow solid that was used without further purification (0.9 g, 96% yield).

Ethyl 6-(2,4-bis(benzyloxy)methylphenyl)0x0-4H-pyran-3—carboxylate o o | | To a solution of at -78 oC (dry ice/acetone bath) was added the mixture of 2,4-bis (benzyloxy) methylbenzoyl chloride (0.9 g, 2.5 mmol) and ethyl (Z)((dimethylamino) methylene) oxobutanoate (455 mg, 2.45 mmol) in THF (6 mL) at -78 0C was added LiHMDS (1 M in THF, .9 mL, 5.9 mmol). The reaction mixture warmed to 0 CC over 30 min. Then MTBE (2.5 mL) and 3N HCl (7.5 mL) was added to the mixture and the solution was d at room temperature for 1.5 hours. The pH of the on mixture was adjusted to 8 by addition of saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered and concentrated under . The residue was purified by normal phase Si02 chromatography (5% to 50% EtOAc/petroleum ether) to afford ethyl 6-(2,4-bis(benzyloxy)methylphenyl)oxo-4H-pyrancarboxylate as a yellow solid (0.85 g, 73% yield, m/z: 471 [M+H]+ observed). 1H NMR (400 MHz, CD3Cl) 5 8.54 (s, 1H), 7.50 (s, 1H), 7.40 (m, 10H), 7.16 (s, 1H), 6.53 (s, 1H), 5.14 (s, 2H), 5.04 (s, 2H), 4.44 (q, J=14.4, 7.2 Hz, 2H), 2.23 (s, 3H), 1.40 ~1.37 (t, J=7.2 Hz, 3H).

Ethyl (R)(2,4-bis(benzyloxy)—5—methylphenyl)(1-hydr0xy—3—methylbutanyl)-4—0x0-1,4- O O opyridinecarb0xylate OH To a solution of ethyl 6-(2,4-bis(benzyloxy)methylphenyl)oxo-4H-pyrancarboxylate (0.5 g, 1.1 mmol) in EtOH (1.5 mL) and glacial AcOH (1.0 mL) was added (R)amino —140— methylbutanol (0.16 g, 1.6 mmol, 1.50 eq). The mixture was stirred at 90 °C for 4 hours. The pH of the on mixture was adjusted to 8 by addition of ted aqueous NaHC03 (15 mL) and extracted with EtOAc (3x30 mL). The combined c layers were separated, dried over NaZSO4, filtered and concentrated under vacuum. The residue was purified by normal phase Si02 chromatography (20% to 50% EtOAc/petroleum ether) to afford ethyl (2,4- bis(benzyloxy)methylphenyl)(1-hydroxy-3 -methylbutanyl)oxo-1,4-dihydropyridine- 3-carboxylate as a light yellow solid that was used without further purification (0.4 g, 68% yield, m/z: 557 [M+H]+ observed).

Ethyl (R)(2,4-dihydr0xy—5-methylphenyl)(1-hydr0xymethylbutanyl)0x0-1,4- dihydropyridinecarb0xylate To a mixture of ethyl (R)(2,4-bis(benzyloxy)methylphenyl)(1-hydroxy-3 lbutan- 2-yl)oxo-1,4-dihydropyridinecarboxylate (3 00 mg, 0.54 mmol) in absolute EtOH (20 mL) was added ium on carbon (10% on carbon, 100 mg, 9.3 mmol). The mixture was stirred at room temperature for 15 min under H2 (15 Psi). The reaction was followed by TLC. The reaction mixture was filtered, washed with EtOH (3x50 mL) and the filtrate concentrated under reduced pressure. The residue was diluted with H20 (20 mL) and extracted with EtOAc (3x30 mL). The combined organic fractions were dried over sodium sulfate, filtered and concentrated under vacuum to yield ethyl (R)(2,4-dihydroxymethylphenyl)(1-hydroxy-3 - methylbutanyl)oxo-1,4-dihydropyridine-3 -carboxylate a yellow solid that was used without further purification (0.19 g, 94% yield, m/z: 376 [M+H]+ observed).

Ethyl hydr0xy— 7-is0pr0pyl—2—methyl—11-0x0-6, 7-dihydr0—11H-benz0[flpyrid0[1,2— o o d][1, 4]0xazepine—1 0—carb0xylate o—)NW( To a solution of ethyl (R)(2,4-dihydroxymethylphenyl)(1-hydroxymethylbutanyl)- 4-oxo-1,4-dihydropyridinecarboxylate (0.19 g, 0.51 mmol) in THF (70 mL) was added PPh3 (0.66 g, 2.5 mmol), ed by diethyl azodicarboxylate (40% wt in toluene, 0.2 mL, 2.5 mmol) (440 mg, 2.53 mmol, 5.00 eq). The reaction mixture was stirred at rt for 12 hours. The mixture —141— was concentrated under vacuum and the residue was diluted with H20 (50 mL). The mixture was extracted with EtOAc (2x200 mL). The combined organic layers were separated, dried over NaZSO4, filtered and concentrated under vacuum. The residue was d by normal phase SiOz chromatography (10% to 50% petroleum ether) to afford ethyl (R)hydroxy isopropylmethyl-1 1-oxo-6,7-dihydro-1 1H-benzo[f]pyrido[1,2-d][1,4]oxazepine carboxylate as a yellow solid that was used without further purification (0.12 g, 66% yield, m/z: 358 [M+H]+ observed).

Ethyl (R)— 7-is0pr0pyl—2—methyl—11-0x0(2,2,2-triflu0r0eth0xy)-6, 7-dihydr0—11H— o o benz0[flpyrid0[1,2-d][l,4/0xazepine-1 0—carb0xylate OJNHH( To the mixture of ethyl (R)hydroxyisopropylmethyloxo-6,7-dihydro-11H- benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylate (0.12 g, 0.34 mmol) in DMF (4 mL) was added 2-bromo-1,1,1-trifiuoroethane (0.11 g, 0.66 mmol) and K2C03 (0.12 g, 0.84mmol). The reaction mixture was stirred at 80 0C for 2 hours. Then the reaction mixture was diluted with H20 (50 mL) and extracted with EtOAc (3x60 mL). The combined organic layers were separated, dried over NaZSO4, filtered and concentrated under vacuum to afford ethyl (R) isopropylmethyl-1 1-oxo-3 -(2,2,2-trifiuoroethoxy)-6,7-dihydro- 1 1H-benzo[f]pyrido[1,2- d][1,4]oxazepinecarboxylate as a light yellow solid that was used without further purification (0.11 g, 74% yield, m/z: 440 [M+H]+ ed).

(R)— r0pyl—2—methyl—11-0x0(2,2,2-triflu0r0eth0xy)-6, 7-dihydr0—11H— benz0[flpyrid0[1,2-d][1,4/0xazepinecarb0xylic acid o—)NHH( To a solution of ethyl (R)isopropylmethyloxo(2,2,2-trifluoroethoxy)-6,7-dihydro- 11H-benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylate (110 mg, 0.25 mmol, ) in dioxane (3 mL) and H20 (2 mL) was added lithium hydroxide monohydrate (52 mg, 1.25 mmol). The reaction e was d at rt for 16 hours. The e was concentrated under vacuum. The residue was diluted with H20 (10 mL), acidified to pH 2 with 1N HCl on (10 mL) and the mixture was extracted with CHzClz (3x20 mL). The combined organic layers were separated, —142— WO 85619 dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by reverse phase HPLC to afford isopropylmethyloxo(2,2,2-trifluoroethoxy)-6,7-dihydro- 11H-benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylic acid as white solid (49 mg, 48% yield, m/z: 412 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 8.78 (s, 1H), 7.53 (s, 1H), 6.99 (s, 1H), 6.84 (s, 1H), 4.88 (m, 2H), 4.68 (d, J=3.2 Hz, 2H), 4.54 (d, J=10.4 Hz, 1H), 2.16 (s, 3H), 1.77 (bs, 1H), 0.97 (d, J=6.4 Hz, 3H), 0.69 (d, J=6.4 Hz, 3H).

The following example were prepared in a similar manner as (R)isopropylmethyloxo(2,2,2-trifluoroethoxy)-6,7-dihydro- 1 zo[f]pyrido[1,2-d][1,4]oxazepinecarboxylic acid from methyl 2,4-bis(benzyloxy)—5-bromobenzoate and an appropriate organoboron species.

EXAMPLE 60: (R)(3-Hydroxyprop0xy)—7-is0pr0pylmethyl0x0-6,7-dihydr0-11H- O O benzo[f] pyrido[1,2-d] [1,4]oxazepine—lO-carboxylic acid m/z: 388 [M+H]+ observed . 1H NMR (300 MHz, CDCl3): 5 8.76 (s, 1H), 7.44 (s, 1H), 6.95 (s, 1H), 6.65 (s, 1H), 4.66 (d, J=3.6 Hz, 2H), 4.52 (d, J=11.2 Hz, 1H), 4.09 (m, 2H), 3.58 (t, J=6.0 Hz, 2H), 2.13 (s, 3H), 1.89 (m, 3H), 1.81 (bs, 1H), 0.97 (d, J=6.4 Hz, 3H), 0.69 (d, J=6.4 Hz, EXAMPLE 61: (R)Chlor0is0pr0pyl((3-methoxypropyl)amin0)0x0-6,7-dihydr0- o o MeO’\/\ N 1 1H-benzo [f] pyr1do[1,2-d] [1,4]oxazep1ne—10-carb0xyllc ac1d. . . . 09% Ethyl (R)chl0r0- 7-is0pr0pyl—3—((3-meth0xypr0pyl)amin0)0x0-6, 7-dihydr0—11H— benz0[flpyrid0[1,2-d][l,4]0xazepine—1 0—carb0xylate To a solution of ethyl chloro-3 -hydroxyisopropyl-1 1-oxo-6,7-dihydro-1 1H- —143— benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylate (1 g, 2.7 mmol) and N—phenyl- ifiuoromethanesulfonimide) (1.14 g, 3.18 mmol) in CHzClz (20 mL) was added TEA (0.74 mL, 5.3 mmol, 2.00 eq). The reaction mixture was stirred for 16 h at rt. The reaction mixture was d H20 (20 mL) and extracted with CHzClz (3x10 mL). The combined organic layers were ted, dried over Na2SO4, filtered and concentrated under vacuum. The residue was d by normal phase Si02 chromatography (0% to 10% MeOH/CHzClz) to afford ethyl chloro- 7-isopropyl-1 1-oxo(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-1 1H-benzo[f]pyrido[1,2- d][1,4]oxazepinecarboxylate as a white solid (1 g, 74% yield) that was used ly in the next step.

A on of ethyl (R)chloroisopropyloxo(((trifiuoromethyl)sulfonyl)oxy)-6,7- o-11H-benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylate (700 mg, 1.37 mmol), 3— methoxypropanwl ~amine (184 mg, 2.06 mmol) and cesium carbonate (895 mg, 2.75 mmol) in toluene (30 mL) was flushed with nitrogen (3 times). Then palladium(II) acetate (62 mg, 0.275 mmol), BINAP (513 mg, 0.825 mmol) and bis(dibenzylideneacetone)palladium(0) (79 mg, 0.138 mmol) were added and the reaction mixture was heated at 100 0C for 16 h. The reaction mixture was concentrated under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 5% MeOH/CHzClz) to afford ethyl (R)chloroisopropyl((3- methoxypropyl)amino)-1 1-oxo-6,7-dihydro-1 1H-benzo[f]pyrido[1,2-d][1,4]oxazepine carboxylate as a light yellow oil (200 mg, 32% yield, m/z: 449 [M+H]+ observed).

(R)Chloro- 7-is0pr0pyl—3—((3-meth0xypr0pyl)amin0)0x0-6, 7-dihydr0—11H- MeO’\/\ N benz0[flpyrid0[1,2-d][1,4]0xazepine—10-carb0xylic acid O‘)"H( To a mixture of ethyl (R)chloroisopropyl((3-methoxypropyl)amino)oxo-6,7- dihydro-11H-benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylate (100 mg, 0.216 mmol) in MeOH (2 mL) and H20 (2 mL) was added lithium hydroxide monohydrate (37 mg, 0.89 mmol) and stirred at rt for 10 hr. The reaction mixture was concentrated under vacuum. The residue was purified by reverse phase HPLC to afford (R)chloroisopropyl((3- methoxypropyl)amino)-1 1-oxo-6,7-dihydro-1 1H-benzo[f]pyrido[1,2-d][1,4]oxazepine carboxylic acid as white solid (19 mg, 20% yield, m/z: 421 [M+H]+ observed). 1H NMR (400 —144— WO 85619 MHz, DMSO-d6) 5 8.73 (s, 1H), 7.55 (s, 1H), 6.92 (s, 1H), 6.33 (s, 1H), 6.21 (bs, 1H), 4.63 (d, J=3.2 Hz, 2H), 4.52 (m, 1H), 3.40 (t, J=6 Hz, 2H), 3.25 (m, 5H), 1.89 (bs, 1H), 1.79 (m, 2H), 0.98 (d, J=6.4 Hz, 3H), 0.69 (d, J=6.4 Hz, 3H).

The following example were prepared in a similar manner as (R)chloroisopropyl((3- methoxypropyl)amino)-1 6,7-dihydro-1 1H-benzo[f]pyrido[1,2-d][1,4]oxazepine carb oxylic acid from ethyl (R)chlorohydroxyisopropyl-1 1-oxo-6,7-dihydro-1 1H- benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylate and an appropriate amine.

EXAMPLE 62: (R)Chlor0is0pr0pylm0rpholin00x0-6,7-dihydr0-11H- benzo[f] pyrido[1,2-d] [1,4]oxazepine—lO-carboxylic acid m/z: 419 [M+H]+ observed . 1H NMR (300 MHz, DMSO-d6): 5 8.78 (s, 1 H), 7.71 (s, 1 H), 7.03 (s, 1 H), 6.77 (s, 1 H), 4.69 (d, J=3.6 Hz, 2 H), 4.55 (bd, J=10.4 Hz, 1 H), 3.74 (t, J=4.4 Hz, 4 H), 3.13 (m, 2 H), 3.04 (m, 2 H), 1.83 (bs, 1 H), 0.98 (d, J=6.8 Hz, 3 H), 0.72 (d, J=6.4 Hz, 3 H).

EXAMPLE 63: (R)Chlor0is0pr0pyl((3-methoxypropyl)(methyl)amin0)—1 1-0x0-6,7- dihydro-l z0 [f] pyrid0[1,2-d][1,4]0xazepine—10-carb0xylic acid 0 O m/z: 435 [M+H]+ observed . 1H NMR (300 MHz, DMSO-d6): 5 8.77 (s, 1H), 7.65 (s, 1H), 7.00 (s, 1H), 6.73 (s, 1H), 4.67 (m, J=3.6 Hz, 2H), 4.55 (bd, J=9.6 Hz, 1H), 3.32 (t, J=6 Hz, 2H), 3.2 (m, 5H), 2.80 (s, 3H), 1.80 (m, 3H), 0.99 (d, J=6 Hz, 3H), 0.71 (d, J=6.8 Hz, 3H).

EXAMPLE 64: (R)Chlor0is0pr0pyl((2-methoxyethyl)amin0)—11-0x0-6,7-dihydr0- —145— 11H-benzo[f] pyrido[1,2-d] [1,4]oxazepine—lO-carboxylic acid m/z: 407 [M+H]+ ed . 1H NMR (300 MHz, DMSO-d6): 5 8.73 (s, 1 H), 7.56 (s, 1 H), 6.93 (s, 1 H), 6.42 (s, 1 H), 6.00 (bs, 1 H), 4.63 (m, 2 H), 4.51 (bd, J=10.8 Hz, 1 H), 3.50 (t, J=5.2 Hz, 2 H), 3.36 (m, 2 H), 3.27 (s, 3 H), 1.89 (bs, 1 H), 0.98 (d, J=6.4 Hz, 3 H), 0.70 (d, J=6.4 Hz, 3 E 65: (R)Chlor0is0pr0pyl((2-methoxyethyl)(methyl)amin0)0x0-6,7- dihydro-l1H-benz0[f]pyrid0[1,2-d][1,4]0xazepine—10-carb0xylic acid 0 O m/z: 421 [M+H]+ observed . 1H NMR (300 MHz, DMSO-d6): 5 8.78 (s, 1H), 7.64 (s, 1H), 7.02 (s, 1H), 6.73 (s, 1H), 4.68 (d, J=3.2 Hz, 2H), 4.55 (d, J=10.8 Hz, 1H), 3.57 (t, J=6 Hz, 2H), 3.37 (t, J=6 Hz, 2H), 3.21 (s, 3H), 2.86 (s, 3H), 1.84 (bs, 1H), 0.98 (d, J=6.4 Hz, 3H), 0.71 (d, J=6.4 Hz, 3H).

EXAMPLE 66: (R)(Tert-butyl)chlor0-3—(3-meth0xypr0p0xy)—11-0x0-6,7-dihydr0- 6-Chloro(3-methoxyprop0xy)pyridin-3—0l \0/\/\ A solution of 5-bromochloro(3-methoxypropoxy)pyridine (10 g, 36 mmol), bis(pinacolato)diboron (10.9 g, 42.8 mmol), Pd(dppf)C12.CH2C12 (1.45 g, 1.78 mmol) and potassium acetate (10.5 g, 107 mmol) in dioxane (100 mL) was purged with nitrogen and then heated for 16 hours at 85°C. The solution was diluted with EtOAc (150 mL) and washed with aqueous sat. NaHC03 solution (200 mL). The organic phase was dried over ium sulfate, WO 85619 d and concentrated under reduced vacuum. To a stirred solution of crude ro(3- methoxypropoxy)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyridine in THF (100 mL) at room temperature was added 30% en peroxide (30% (w/w) in H20, 3.6 mL, 120 mmol) dropwise and stirring was continued for 4 hours. Additional hydrogen de (30% (w/w) in H20, 3.6 mL, 120 mmol) was added and the reaction mixture stirred overnight. Upon completion, the solution was trated under reduced vacuum to remove THF. The aqueous mixture was diluted with EtOAc (100 mL), washed with aqueous sat. NaHCO3 solution (100 mL) and then aqueous sat. brine solution (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced vacuum. The residue was purified by normal phase Si02 chromatography (25% to 75% EtOAc/ hexanes) to afford 6-chloro(3- methoxypropoxy)pyridinol as a yellow oil (3.3 g, 42% yield, m/z: 218 [M+H]+ observed).

CI N I 6—Chl0r0i0d0(3-methoxyprop0xy)pyridin-3—0l OH To a solution of 6-chloro(3-methoxypropoxy)pyridinol (1.5 g, 6.9 mmol) and sodium ate (1.5 g, 14 mmol) in H20 (75 mL) was added iodine (1.8 g, 6.9 mmol). The reaction mixture was stirred at rt for 2 hours then the pH was adjusted to to 7.5-8 with sat. aqueous ammonium chloride (~50 mL). The solution was ted with EtOAc (2 x 100 mL) and the combined organic fractions were dried on magnesium sulfate, d and concentrated under reduced vacuum. The residue was purified by normal phase Si02 chromatography (25% to 100% EtOAc/ hexanes) to afford 6-chloroiodo(3-methoxypropoxy)pyridin-3 -ol as a yellow solid (2 g, 85% yield, m/z: 344 [M+H]+ observed).

Tert-buljyl (R)—1-(1-hydr0xy—3,3-dimethylbutan-2—yl)0x0-1,4-dihydr0pyridine—3—carb0xylate A solution of tert-butyl 4-oxopyran-3 -carboxylate (1.5 g, 7.7 mmol) and (R)amino-3,3- dimethylbutanol (2.1 mL, 16 mmol) in anhydrous ethanol (30 mL) was refluxed overnight.

The reaction mixture was concentrated under reduced vacuum. The residue was purified by normal phase SiOz chromatography (0% to 15% MeOH/ CHzClz) to afford tert-butyl (R)(1- hydroxy-3,3-dimethylbutanyl)oxo-1,4-dihydropyridinecarboxylate as a yellow solid —147— (650 mg, 29% yield).

Tert-buljyl (R)—1—(1-((6-chlor0i0d0(3-meth0xypr0p0xy)pyridin-3—yl)0xy)-3,3- dimethylbutanyl)0x0—1,4-dihydr0pyridine—3—carboxylate o 0 \OMOUOJM’< N\ I WOK To a solution of 6-chloroiodo(3 -methoxypropoxy)pyridinol (760 mg, 2.2 mmol), tert- butyl (R)(1-hydroxy-3,3-dimethylbutanyl)oxo-1,4-dihydropyridinecarboxylate (650 mg, 2.2 mmol) and triphenylphosphine (1.2 g, 4.4 mmol) in toluene (25 mL) was slowly added diisopropyl azodicarboxylate (1.3 mL, 6.6 mmol). The solution was heated to 55°C for 2 hours then concentrated under reduced vacuum. The residue was purified by normal phase SiOz chromatography (0% to 15% MeOH/ CHzClz) to afford tert-butyl (R)(1-((6-chloroiodo (3 -methoxypropoxy)pyridin-3 -yl)oxy)-3 , 3 -dimethylbutanyl)oxo-1,4-dihydropyridine-3 - ylate as a yellow solid (575 mg, 42%, m/z: 621 [M+H]+ observed).

Tert-buljyl (R)— 7-(tert-buljyl)-2—chl0r0—3—(3-meth0xypr0p0xy)—11-0x0—6, 7-dihydr0—11H- dipyrid0[1,2-d.°2 ',3 '-fl[1,4]0xazepine—1 0—carb0xylate A on of tert-butyl (R)(1-((6-chloroiodo(3 -methoxypropoxy)pyridin-3 -yl)oxy)-3,3- dimethylbutanyl)oxo-1,4-dihydropyridine-3 -carboxylate (580 mg, 0.93 mmol), palladium bromide (120 mg, 0.45 mmol) and potassium e (180 mg, 1.9 mmol) in MN- dimethylacetamide (10 mL) was purged with nitrogen and d for 16h at 120°C in a sealed reaction vessel. Additional PdBrz (25mg, 0.1 mmol) was added and heating was continued for another 24h. Upon completion, the d product and the t-butyl ester hydrolysis product were both observed. The solution was poured into H20 (100 mL) and extracted with EtOAc (5 x 75 mL). The combined extracts were washed with sat. aqueous brine solution (2 X 100 mL), dried over magnesium sulfate, d and concentrated under d vacuum. The residue was purified by normal phase Si02 chromatography (0% to 5% MeOH/ CHzClz) to afford a mixture of desired tert-butyl (R)(tert-butyl)—2-chloro(3-methoxypropoxy)oxo-6,7-dihydro-11H- dipyrido[1,2-d:2',3'-f][1,4]oxazepinecarboxylate and the ester hydrolysis t (R)(tert- butyl)chloro-3 -(3 -methoxypropoxy)-l l-oxo-6,7-dihydro-l lH-dipyrido[ l ,2-d:2',3 '- f][l,4]oxazepine-lO-carboxylic acid. The mixture was used in the next step without further purification (85 mg, 19% yield, m/z: 493 [M+H]+ observed).

(R)- 7-(Tert-buljyl)chlor0(3-meth0xypr0p0xy)0x0—6, 7-dihydr0—11H-dipyrid0[1,2- (1:2 ',3 '-fl[1,4]0xazepine—1 0-carb0xylic acid A solution of utyl (R)(tert-butyl)—2-chloro(3 -methoxypropoxy)-l l-oxo-6,7-dihydro- llH-dipyrido[l,2-d:2',3'-f][l,4]oxazepine-lO-carboxylate (85 mg crude, 0.17 mmol) in romethane/trifluoroacetic acid solution (2:1, 10 mL) was d overnight at rt. The on was concentrated under reduced vacuum and azeotroped with toluene (3x) to remove all residual trifluoroacetic acid. The residue was purified by normal phase SiOz chromatography (0% to 15% MeOH/ CHzClz), followed by precipitation from ol (2 mL) to afford (R) (tert-butyl)chloro-3 -(3 -methoxypropoxy)-l l-oxo-6,7-dihydro-l lH-dipyrido[ l ,2-d:2',3 '- f][l,4]oxazepine-lO-carboxylic acid as a white solid (4.2 mg, 6% yield, m/z: 437 [M+H]+ ed). 1H NMR (300 MHz, CDCl3): 5 8.39 (s, 1H), 8.13 (s, 1H), 6.83 (s, 1H), 4.99 (dd, J=l4.0, 4.9 Hz, 1H), 4.48-4.32 (m, 1H), 4.18 (q, J=6.2, 5.6 Hz, 3H), 3.59 (t, J=5.8 Hz, 2H), 3.36 (s, 3H), 2.14 (p, J=6.1 Hz, 2H), 1.05 (s, 9H).

EXAMPLE 67: (R)(Tert-butyl)—2-cyclopr0pyl(3-methoxypropoxy)—11-0x0-6,7- dihydro-l1H-dipyrid0[1,2—d:2',3'-f] [1,4]0xazepine—10-carb0xylic acid O O MeO’\/\ b.°1 0—) 6 ', 3 '-e][1,4]0xazepine—10-carb0xylate To a mixture of ethyl(7R)—7-tert-butylchloro-3 -(3 -methoxypropoxy)-l l-oxo-6,7- —149— dihydrodipyrido[5,3-b:1',3'-e][1,4]oxazepinecarboxylate (200 mg, 0.43 mmol) and potassium cyclopropyltrifiuoroborate (96 mg, 0.65 mmol) in e (3 mL) and H20 (3 mL) was added cesium carbonate (562 mg, 1.72 mmol) of , palladium(II) acetate (10 mg, 0.043mol) and XPhos 61.52 mg (62 mg, 0.129 mmol). The mixture was stirred at 120 CC for 16 hr. The reaction mixture was diluted with H20 (10 mL) and extracted with EtOAc (3x5 mL). The combined organic layers were washed with sat. aqueous brine solution (2.5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to give ethyl(7R)—7-tert-butylcyclopropyl(3-methoxypropoxy)oxo- 6,7-dihydrodipyrido[5,3-b:1',3'-e][1,4]oxazepinecarboxylate as a yellow solid (140 mg, 59% yield, m/z: 471 [M+H]+ observed). (7R)- 7- Tert-bulfyl-Z-cyclopropyl—3—(3-meth0xypr0p0xy)—11-0x0-6, 7-dihydr0dipyrid0[5,3- b.°1 ',3 ,4]0xazepine—10-carb0xylic acid To a mixture of ethyl (7R)tert-butylcyclopropyl (3-methoxypropoxy)oxo-6,7- dihydrodipyrido[5,3-b:1',3'-e][1,4]oxazepinecarboxylate (150 mg, 0.32 mmol) in THF (1 mL) and H20 (1 mL) was added m hydroxide monohydrate (67mg, 1.6 mmol) in one portion under N2. The e was d at 20 0C for 16 hr. The reaction mixture was adjusted to pH 7 with aqueous sodium carbonate solution and extracted with 3 x 5 mL of EtOAc (3x5 mL). The mixture was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to afford the (7R)—7-tert-butyl cyclopropyl(3-methoxypropoxy)-1 1-oxo-6,7 -dihydrodipyrido[5,3-b:1',3'-e][1,4]oxazepine- -carboxylic acid as a yellow solid (37 mg, 26% yield, m/z: 443 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 8.61 (s, 1H), 7.81 (s, 1H), 7.02 (s, 1H), 4.94-4.87 (m, 2H), 4.55—4.52 (d, J=13.6 Hz, 1H), 4.18-4.15 (t, J=6.4 Hz, 2H), 3.65-3.62 (t, J=6 Hz, 2H), 3.26 (s, 3H), 2.43—2.40 (m, 1H), 2.05-1.98 (m, 2H), 1.04-0.86 (m, 13H).

The following example were ed in a similar manner as (R)(tert-butyl)chloro(3- methoxypropoxy)oxo-6,7-dihydro-11H-dipyrido[1,2-d:2',3'—f][1,4]oxazepinecarboxylic acid from 6-chloroiodo(3 -methoxypropoxy)pyridin-3 -ol, tert-butyl 4-oxopyran ylate and an appropriate amine.

WO 85619 EXAMPLE 68: (R)Chlor0is0pr0pyl(3-meth0xypr0p0xy)—11-0x0-6,7-dihydr0-11H— dipyrido[1,2-d:2',3'-f] [1,4] oxazepine-lO-carboxylic acid m/z: 423 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.78 (s, 1H), 7.51 (s, 1H), 7.32 (s, 1H), 4.90 (dd, J=11.8, 5.2 Hz, 1H), 4.79 (dd, J=11.1, 5.1 Hz, 1H), 4.67 (d, J=13.7 Hz, 1H), 4.24 (t, J=5.8 Hz, 2H), 3.49 (t, J=6.2 Hz, 2H), 3.26 (s, 3H), 2.04-1.96 (q, J=6.2 Hz, 2H), 1.94- 1.84 (m, 1H), 1.07 (d, J=6.5 Hz, 3H), 0.75 (d, J=6.6 Hz, 3H).

EXAMPLE 69: 2'-Chlor0-3'-(3-meth0xypr0p0xy)—11'-0x0-6'H,11'H—spir0[cyclohexane- 1,7'-dipyrido[1,2-d:2',3'-f] [1,4]oxazepine]-10'-carb0xylic acid 1-[1-(Hydroxymethyl)cyclohexyll0x0-pyridinecarboxylic acid PICK/O To a solution of of tert-butyl 4-oxopyrancarboxylate (1 .67g, 8.51 mmol) in EtOH (6 mL) and AcOH (4 mL) was added 1-amino(hydroxyethyl)cyclohexane (1g, 7.7 mmol). The mixture was stirred at 90 0C for 16 hr. The reaction mixture was concentrated under d re to give 1-[1-(hydroxy methyl)cyclohexyl]oxo-pyridinecarboxylic acid as a white solid (1.1 g, 51% yield, m/z: 252 [M+H]+ ed). 0 0 1-[1-(hydroxymethyl)cyclohexyll0x0-pyridinecarb0xylate HOVO To a mixture of 1-[1-(hydroxymethyl)cyclohexyl]oxo- pyridinecarboxylic acid (1 g, 4 mmol) of in EtOH (10 mL) was added sulfuric acid (5 mL, 94 mmol). The mixture was stirred at 60 0C for 5 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to afford l-[l-(hydroxymethyl) cyclohexyl]oxo- pyridine carboxylate as a yellow oil (1.1 g, 99% yield, m/z: 280 [M+H]+ observed).

Ethyl [6-chlor0i0d0—5—(3-meth0xypr0p0xy)pyridyl]0xymethyl]cyclo hexyll0x0- o 0 U N\ | W03 MeO/\/\O o pyridine-3—carb0xylate b To a solution of 6-chloroiodo(3 -methoxypropoxy)pyridin ol (1g, 2.9 mmol), ethyl 1-[1- (hydroxymethyl)cyclohexyl] oxo-pyridinecarboxylate (988 mg, 3.53 mmol) and PPh3 (1.73 g, 5.89 mmol) in THF (25 mL) was added a solution of diisopropyl azodicarboxylate (1.2 mL, 5.82 mmol) in THF (6 mL) dropwise at 25 0C under N2. The reaction mixture was stirred at 45 0C for 20 h under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by normal phase SiO2 chromatography (0% to 10% MeOH/CH2Cl2) to afford ethyl 1-[1-[[6-chloroiodo(3 -methoxypropoxy)-3 yl]oxy methyl]cyclohexyl] oxo-pyridinecarboxylate as a white solid (700 mg, 39% yield, m/z: 605 [M+H]+ observed).

Ethyl 2-chlor0(3-meth0xypr0p0xy)—11-0x0-spir0[6H-dipyrid0[5,3-b.°3 ',1 '-d][1,4] oxazepine - 7,1 0hexane]—10-carb0xylate To a mixture of ethyl 1-[1-[[6-chloroiodo(3-methoxypropoxy) l]oxymethyl]cyclohexyl]oxo-pyridinecarboxylate (950 mg, 1.6 mmol) and potassium acetate (308 mg, 3.14 mmol) in N,N—dimethylacetamide (25 mL) was added palladium(II) bromide (126 mg, 0.472 mmol) under N2. The mixture was heated to 120 oC and stirred for 16 hours under N2. The mixture was diluted with H20 (200 mL) and extracted with EtOAc (2x150 mL). The combined organic layers were concentrated under reduced re.

The residue was purified by e phase HPLC to afford ethyl 2- chloro-3 -(3- methoxypropoxy)oxo-spiro[6H-dipyrido[5,3-b:3',1'-d][1,4]oxazepine-7,1'-cyclohexane] carboxylate as a light yellow solid (140 mg, 19% yield, m/z: 477 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 8 8.51 (s, 1H), 7.53 (s, 1H), 6.75 (s, 1H), 4.40 (s, 1H), 4.36-4.31 (m, 2H), 4.10-4.07 (t, J=6.0 Hz, 2H), 3.54-3.51 (t, J=6.0 Hz, 2H), 3.30 (s, 3H), 2.09-2.05 (m, 2H), 1.93 (m, 2H), 1.86-1.80 (m, 5H), 1.75-1.56 (m, 4H), 1.33-1.31 (m, 3H). 2-Chlor0(3-meth0xypr0p0xy)—11-0x0-spir0[6H—dipyrid0[5,3-b.°3 ',1 '-d][1,4]0xazepine— 7,1 '- Me0’\/\OCI cyclohexanel-l 0-carb0xylic acid To a mixture of ethyl 2-chloro(3 -methoxypropoxy) oxo-spiro[6H-dipyrido[5,3-b:3',1'- d][1,4]oxazepine-7,1'-cyclohexane]carboxylate (140 mg, 0.29 mmol) in H20 (4 mL) and (4 mL) was added lithium hydroxide drate (37 mg, 0.882 mmol). The mixture was stirred for 16 hours at 25 oC. The mixture was acidized with 1 N hydrogen chloride solution until pH to 2 and extracted with EtOAc (2x10 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase HPLC to afford 2-chloro(3- ypropoxy)oxo-spiro[6H-dipyrido[5,3-b:3',1'-d][1,4]oxaze pine-7,1'-cyclohexane] carboxylic acid as a light solid (46 mg, 34% yield, m/z: 449 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 6 8.77 (s, 1H), 7.53 (s, 1H), 7.33 (s, 1H), 4.69 (s, 2H), 4.26-4.23 (t, J=6.0 Hz, 2H), 3.51-3.48 (t, J=6.0 Hz, 2H), 3.26 (s, 3H), 2.07-1.98 (m, 6H), 1.71 (m, 2H), 1.61-1.59 (m, 3H), 1.35 (m, 1H).

The following examples were prepared in a similar manner as 2-chloro(3 -methoxypropoxy)- 11-oxo-spiro[6H-dipyrido[5,3-b:3',1'-d][1,4]oxazepine-7,1'-cyclohexane]carboxylic acid from tert-butyl 4-oxopyrancarboxylate and an appropriate amino alcohol.

E 70: 2'-Chloro-3'-(3-methoxypropoxy)—1 1'-oxo-6'H,1 1'H—spir0[cyclopentane— 1,7'-dipyrido[1,2-d:2',3'-f] [1,4]oxazepine]-10'-carb0xylic acid m/z: 435 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.63 (s, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 4.65 (s, 2H), 4.25 (t, J=8.0 Hz, 2H), 3.50 (t, J=8.0 Hz, 2H), 3.26 (s, 3H), 2.15 (m, 2H), 2.01 (m, 4H), 1.69 (m, 4H).

EXAMPLE 71: r0(3-methoxypropoxy)—1 1-0x0-6H,1 r0 [dipyrido [1,2-d:2',3'- f] [1,4]oxazepine—7,3'-oxetane]carb0xylic acid -l53- WO 85619 m/z: 423 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.67 (s, 1H), 7.54 (s, 1H), 6.88 (s, 1H), 5.11 (m, 2H), 4.79 (s, 2H), 4.27—4.22 (m, 4H), 3.49-3.46 (t, J=6.4 Hz, 2H), 3.24 (s, 3H), 2.03—1.97 (m, 2H).

EXAMPLE 72: 2'-Chlor0-3'-(3-meth0xypr0p0xy)—3,3-dimethyl-11'-0x0-6'H,11'H- spir0[cyclobutane-1,7'-dipyrid0[1,2-d:2',3'-f][1,4]oxazepine]-10'-carboxylic acid 0 O m/z: 449 [M+H]+ ed . 1H NMR (400 MHz, CDC13): 5 15.90 (s, 1 H), 8.65 (s, 1H), 7.17 (s, 1H), 7.02 (s, 1H), 4.63 (s, 2H), 4.23—4.20 (t, J: 6 Hz, 2H), 3.62 (t, J=6 Hz, 2H), 3.39 (s, 3H), 2.38-2.14 (m, 4H), 2.06-2.02 (m, 2H), 1.19 (s, 3H), 1.09 (s, 3H).

EXAMPLE 73: 2'-Chlor0-3'-(3-meth0xypr0p0xy)—3,3-dimethyl-11'-0x0-6'H,11'H- spir0[cyclobutane-1,7'-dipyrid0[1,2-d:2',3'-f][1,4]oxazepine]-10'-carboxylic acid m/z: 435 [M+H]+ observed . 1H NMR (mixture of cis/lrans, 400 MHz, DMSO-d6): 5 8.73 (s, 0.5H), 8.50 (s, 0.5 H), 7.52-7.48 (m, 1H), 6.94-6.91 (m, 1H), 4.83-4.78 (m, 2H), 4.27-4.23 (m, 2H), 3.26 (s, 3H), 2.20 (m, 2H), .98 (m, 2H), 1.82-1.80 (m, 1H), 1.30-1.25 (m, 2H), 1.38- 1.23 (m, 1H), 1.05-0.96 (m, 3H), 0.89-0.85 (m, 1H).

EXAMPLE 74: 2-Chlor0(3-methoxypropoxy)—1 1-0x0-2',3',5',6'-tetrahydr0-6H,1 1H- spiro[dipyrid0[1,2-d:2',3'-f] [1,4]0xazepine-7,4'-thi0pyran]carb0xylic acid m/z: 467 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.73 (s, 1H), 7.58 (s, 1H), 7.33 (s, 1H), 4.78 (s, 2H), 4.27—4.24 (t, J=6 Hz, 2H), 3.52—3.49 (t, J: 6 Hz, 2H), 3.26 (s, 3H), 3.08- —154— 3.02 (t, J=13.2 Hz, 2H), 2.77—2.73 (d, J=14.4, 2H), 2.37(s, 2H) 2.33—2.30 (d, J=13.2, 2H), 2.05— 2.00 (7, J=6 Hz, 2H).

EXAMPLE 75: Chlor0is0pr0py1—3-meth0xy-1 1-0x0-6,7-dihydr0-1 1H- 0 OH dipyrido[1,2-d:2',3'-f] [1,4] oxazepine-lO-carboxylic acid m/z: 365 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.78 (s, 1H), 7.52 (s, 1H), 7.32 (s, 1H), 4.91 (dd, J=12.0, 4.0 Hz, 1H), 4.85 (m, 1H), 4.69 (d, J=16.0 Hz, 1H), 3.97 (s, 3H), 1.85 (m, 1H), 1.15 (d, J=8.0 Hz, 3H), 0.75 (d, J=8.0 Hz, 3H).

EXAMPLE 76: (R)Cycl0pr0pylisobutoxyis0pr0pyl0x0-6,7-dihydr0-11H- dipyrido[1,2-d:2',3'-f] [1,4] oxazepine-lO-carboxylic acid OJWI( m/z: 413 [M+H]+ observed . 1H NMR (400 MHz, CDC13): 5 8.48-8.43 (m, 1H), 8.28-8.22 (m, 1H), 6.96 (s, 1H), 4.89 (d, J=12.3 Hz, 1H), 4.63 (d, J=13.4 Hz, 1H), 3.98 (d, J=9.3 Hz, 1H), 3.81- 3.67 (m, 2H), 2.47 (s, 1H), 2.09 (s, 2H), .14 (m, 5H), 1.08-1.05 (m, 8H), 0.91 (d, J=6.6 Hz, 3H).

EXAMPLE 77: (R)(Benzyloxy)—2—chlor0isopr0pyl-1 1-0x0-6,7-dihydr0- 1 1H- dipyrido[1,2-d:2',3'-f] [1,4]oxazepine—lO-carboxylic acid m/z: 441 [M+H]+ observed . 1HNMR (400 MHz, CDC13): 6 8.51 (s, 1H), 8.27 (s, 1H), .34 (m, 5H), 6.99 (s, 1H), 5.13-5.03 (m, 2H), 4.95 (s, 1H), 4.78-4.59 (m, 1H), 4.07 (dd, J=11.3, 5.2 Hz, 1H), 2.03 (dd, J=12.0, 6.1 Hz, 1H), 1.15 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H).

EXAMPLE 78: (R)Chlor0hydr0xyisopropyl-1 1-0x0-6,7-dihydr0-1 1H-dipyrid0 [1,2- d:2',3'-f] [1,4]oxazepine—lO-carboxylic acid m/z: 351 [M+H]+ observed . 1H NMR (400 MHz, CDC13): 5 8.48 (s, 1H), 8.14 (s, 1H), 7.03 (s, 1H), 5.04 (dd, J=13.4, 5.2 Hz, 1H), 4.77 (d, J=13.4 Hz, 1H), 4.04 (dd, J=11.2, 5.1 Hz, 1H), 2.06 (dt, J=11.8, 6.4 Hz, 1H), 1.17 (d, J=6.5 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H).

EXAMPLE 79: (R)Chl0r0is0but0xyis0pr0pyl-1 1-0x0-6,7-dihydr0-1 1H- dipyrido[1,2-d:2',3'-f] [1,4] oxazepine-lO-carboxylic acid m/z: 407 [M+H]+ ed . 1H NMR (400 MHz, CDC13): 5 8.44 (s, 1H), 8.24 (s, 1H), 6.99 (s, 1H), 4.92 (m, 1H), 4.68 (d, J=13.3 Hz, 1H), 3.94 (m, 1H), 3.79 (ddd, J=27.2, 8.5, 6.5 Hz, 2H), 2.28-2.08 (m, 1H), 2.02-2.01(m, 1H), 1.16 (d, J=6.6 Hz, 3H), 1.07 (dd, J=6.7, 1.8 Hz, 6H), 0.95 (d, J=6.6 Hz, 3H).

E 80: (R)Chlor0(2-hydr0xyethyl)—3-(3-meth0xypr0p0xy)—11-0x0-6,7- dihydro-l1H-dipyrid0[1,2—d:2',3'-f] [1,4]0xazepine—10-carb0xylic acid m/z: 425 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 16.51 (s, 1H), 8.67 (s, 1H), 7.47 (s, 1H), 7.33 (s, 1H),5.15-5.13 (m, 1H), 4.77—4.75 (m, 2H), 4.65 (d, J=13.6 Hz, 1H), 4.23 (t, J=12.0 Hz, 2H), 3.50—3.47 (m, 3H), 3.25 (s, 3H), 2.03-1.98 (m, 2H), 1.93-1.88 (m, 1H), 1.79— 1.73 (m, 2H).

EXAMPLE 81: r0(3-meth0xypr0p0xy)—12,12-dimethyl0x0-9a,11,12,12a- tetrahydr0-3H,10H-cyclopenta[b]dipyrid0[1,2-d:2',3'-f] [1,4]oxazepine-Z-carboxylic acid -((6-Chlor0-2—i0d0—5—(3-meth0xypr0p0xy)pyridinyl)0xy)-2,2—dimethylcyclopentan-l-one CI N\ I MeOMoUO’bLo To a mixture of 6-chloroiodo(3-methoxypropoxy)pyridinol (7g, 20 mmol) and 5- bromo-2,2-dimethyl-cyclopentanone (4.2g, 22 mmol in acetone (100 mL) was added ium ate (5.7g, 41 mmol) and sodium iodide (1.5g, 10 mmol) in one portion under N2. The mixture was stirred at 60 0C for 16 hours. The mixture was diluted with water (100 mL) and the aqueous phase was ted with ethyl acetate (2x100 mL). The combined organic phase was washed with sat. aqueous brine solution (100 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by normal phase SiOz chromatography (10% to 40% EtOAc/petroleum ether) to afford 5-((6-chloroiodo(3- ypropoxy)pyridinyl)oxy)-2,2-dimethylcyclopentanone as a yellow solid (6.8 g, 74% yield, m/z: 454 [M+H]+ observed). -[[6-Chlor0i0d0—5—(3-methoxypropoxy)pyridyl]0xy]—2,Z-dimethyl-cyclopentanamine CI N\ I MeOMOI/IofiH2N To a mixture of 5-((6-chloroiodo(3 -methoxypropoxy)pyridinyl)oxy)-2,2- dimethylcyclopentan-l-one (6.8g, 15 mmol) in EtOH (80 mL) was added ammonium acetate (17 .3 g, 224 mmol) and sodium cyanoborohydride (1.9g, 30 mmol) in one portion under N2. The mixture was stirred at 90 0C for 16 hours. The mixture was diluted with H20 (10 mL) and the pH was adjusted to 10-11 by the on of 1 M sodium ide solution. The residue was extracted with CHzClz (3x50 mL). The combined organic phase was washed with sat. aqueous brine solution (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was d by normal phase SiOz chromatography (10% to 100% EtOAc/petroleum ether) to afford 5-[[6-chloroiodo(3 -methoxypropoxy)pyridyl]oxy]- 2,2-dimethyl-cyclopentanamineas a yellow oil (3.7 g, 54% yield, m/z: 455 [M+H]+ observed).

Ethyl 1-(5-((6-chlor0i0d0—5-(3-meth0xypr0p0xy)pyridinyl)0xy)-2,Z-dimethylcyclopenleD- O O CIINII N meOMO / 0% 4-0x0-1,4-dihydr0pyridinecarb0xylate A mixture of 5-[[6-chloroiodo(3 -methoxypropoxy) pyridyl]oxy]-2,2-dimethyl- entanamine (6.4g, 15 mmol) and tert-butyl 4-oxopyrancarboxylate (3.52 g, 18 mmol) in EtOH (25 mL) and AcOH (25 mL) was stirred at 100 0C for 16 hours. The mixture was concentrated in vacuum to afford 1-[5-[[6-chloroiodo(3-methoxypropoxy)pyridyl]oxy]- 2,2-dimethyl-cyclopentyl]oxo-pyridinecarboxylic acid as a yellow solid that was used in the next step without further purification (4.2g, 62%).

To a mixture of 1-[5-[[6-chloroiodo(3-methoxypropoxy)pyridyl]oxy]-2,2-dimethyl- cyclopentyl]oxo-pyridinecarboxylic acid (4.2g, 7.3 mmol) in EtOH (100 mL) was added thionyl chloride (2.7 mL, 36.5 mmol) over 5 min under N2. The mixture was d at 60 0C for 16 hours. The mixture was concentrated in vacuum. The residue was purified by normal phase Si02 chromatography (10% to 100% EtOAc/petroleum ether) to afford ethyl 1-[5-[[6-chloro iodo(3-methoxypropoxy)pyridyl]oxy]-2,2-dimethyl- cyclopentyl]oxo-pyridine carboxylate as a yellow oil (3.0 g, 68% yield, m/z: 605 [M+H]+ observed). 1H NMR (mixture of rotamers, 400 MHz, CDC13) 6 8.33-8.32 (m, 1 H), 7.80-7.77 (m, 1 H), 6.74 (m, 1 H), 6.40-6.38 (m, 1 H), 5.31 (m, 1H), 4.32-4.27 (m, 2 H), 4.11-4.08 (m, 2 H), 3.93 (m, 1 H), .53 (m, 2 H), 3.33 (s, 3 H), .94 (m, 6 H), 1.33-1.31 (m, 3 H), 1.29-1.22 (m, 6 H).

Ethyl 19—chlor0-1 5-(3-meth0xypr0p0xy)—23,23-dimethyl—13-0x00xa—24,25— diazatetracyclooctadeca—4(16),5(14), 6(1 7),]5(19),18(24)-pentaene—1 7-carb0xylate To a mixture of ethyl 1-[5-[[6-chloroiodo(3 -methoxypropoxy) pyridyl]oxy]-2,2- dimethyl-cyclopentyl]oxo-pyridinecarboxylate (3 g, 4.96 mmol) in N,N—dimethylacetamide (50 mL) was added potassium e (0.975 g, 9.93 mmol) and palladium(II) bromide (660 mg, 2.5 mmol) under N2. The mixture was d at 120 0C for 16 hours. The mixture was filtered and the residue was diluted with H20 (20 mL). The s phase was extracted with ethyl acetate (2x20 mL). The combined organic phase was washed with sat. aqueous brine solution (10 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse phase HPLC to afford ethyl l9-chloro(3 -methoxypropoxy)-23,23- yl- l 3 -oxooxa-24,25- diazatetracyclooctadeca-4(l6),5(l4),6(l7),15(19),18(24)- pentaene-l7-carboxylate as a yellow solid (0.5 g, 21% yield, m/z: 477 [M+H]+ observed). 6—Chloro- 7-(3-meth0xypr0p0xy)—12,12—dimethyl—3—0x0—9a,11,12,12a—tetrahydr0—3H,1 0H- cyclopenta[b]dipyrid0[1,2-d.°2 ',3 '-f][1,4]0xazepine—2—carb0xylic acid To a mixture of ethyl l9-chloro-l5-(3 xypropoxy)- 23,23-dimethyl-l3-oxooxa-24,25- diazatetracyclooctadeca-4(l6),5(l4),6(l7),15(19),l8(24)-pentaene-l7-carboxylate (50 mg, 0.105 mmol) in H20 (1 mL) and THF (1 mL) was added lithium hydroxide monohydrate (13 mg, 0.3 14 mmol) in one portion at 25°C under N2. The mixture was d at 25 0C for 1 hr. The mixture was diluted 1 M hydrogen chloride solution to pH 4 and the aqueous phase was extracted with EtOAc (2x20 mL). The combined organic phase was washed with sat. aqueous brine solution (10 mL), dried with anhydrous sodium sulfate, d and concentrated in vacuum. The residue was purified by reverse phase HPLC to afford 6-chloro(3-methoxypropoxy)-12,12-dimethyl oxo-9a, l 1, l2, trahydro-3H, l0H-cyclopenta[b]dipyrido[ l ,2-d:2',3 '-f] [ l ,4]oxazepine carboxylic acid as a yellow solid (11 mg, 23% yield, m/z: 449 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 15.99 (s, 1H), 8.80 (s, 1H), 7.55 (s, 1 H), 6.99 (s, 1 H), 5.46-5.40 (m, 1 H), .97 (d, J=9.2 Hz, 1 H), 4.33—4.29 (m, 1 H), 4.24—4.22 (m, 1 H), 3.52—3.49 (t, J=6 Hz, 2 H), 3.26 (s, 3 H), 2.16-2.00 (m, 4 H), 1.35-1.28 (m, 1 H), .05 (m, 1 H), 1.02 (s, 3 H), 0.33 (s, 3 EXAMPLE 82: 6-Chl0r0(3-meth0xypr0p0xy)—12,12-dimethyl0x0-9a,11,12,12a- tetrahydr0-3H,10H-cyclopenta[b]dipyrid0[1,2-d:2',3'-f] [1,4]oxazepine-Z-carboxylic acid -l59- (single enantiomer 1) EXAMPLE 83: r0(3-meth0xypr0p0xy)—12,12-dimethyl0x0-9a,11,12,12a- tetrahydr0-3H,10H-cyclopenta[b]dipyrid0[1,2-d:2',3'-f] [1,4]oxazepine-Z-carboxylic acid (single enantiomer II) 150 mg of the mixture of enantiomers was ted by SFC (supercritical fluid chromatography) on an OD-3 column using 30% MeOH (0.05% diethylamine as a modifier) to give 6-chloro(3-methoxypropoxy)-12,12-dimethy1oxo-9a,1 1,12,12a-tetrahydro-3H,10H- cyclopenta[b]dipyrido[1,2-d:2',3'-f][1,4]oxazepinecarboxy1ic acid e enantiomer I) as a white solid (faster eluting enantiomer, 36 mg, 24%, m/z: 449 [M+H]+ observed) and 6-chloro (3 -methoxypropoxy)-12,12-dimethy1-3 -oxo-9a, 1 1,12,12a-tetrahydro-3H,10H- cyclopenta[b]dipyrido[1,2-d:2',3'-f][1,4]oxazepinecarboxy1ic acid (single enantiomer II) as a white solid (slower g enantiomer, 33 mg, 22%, m/z: 449[M+H]+ observed).

Example 82: 6-Chlor0(3-methoxypropoxy)—12,12-dimethyl0x0-9a,11,12,12a- tetrahydr0-3H,10H-cyclopenta[b]dipyrid0[1,2-d:2',3'-f] [1,4]oxazepine-Z-carboxylic acid (single omer I). m/z: 449 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 15.99 (s, 1 H), 8.80 (s, 1 H), 7.55 (s, 1 H), 6.99 (s, 1 H), .40 (m, 1 H), 4.99-4.97 (d, J=9.2 Hz, 1 H), .29 (m, 1 H), 4.24-4.22 (m, 1 H), 3.52-3.49 (t, J=6 Hz, 2 H), 3.26 (s, 3 H), 2.16-2.00 (m, 4 H), 1.35-1.28 (m, 1 H), 1.12-1.05 (m, 1 H), 1.02 (s, 3 H), 0.33 (s, 3 H).

Example 83: 6-Chl0r0(3-meth0xypr0p0xy)—12,12-dimethyl0x0-9a,11,12,12a- tetrahydr0-3H,10H-cyclopenta[b]dipyrid0[1,2-d:2',3'-f] [1,4]oxazepine-Z-carboxylic acid (single enantiomer II). m/z: 449 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 15.99 (s, 1 H), 8.80 (s, 1 H), 7.55 (s, 1 H), 6.99 (s, 1 H), 5.46-5.40 (m, 1 H), 4.99-4.97 (d, J=9.2 Hz, 1 H), 4.33-4.29 (m, 1 H), 4.24-4.22 (m, 1 H), 3.52-3.49 (t, J=6 Hz, 2 H), 3.26 (s, 3 H), 2.16-2.00 (m, 4 H), 1.35-1.28 (m, 1 H), 1.12-1.05 (m, 1 H), 1.02 (s, 3 H), 0.33 (s, 3 H).

EXAMPLE 84: S-Isopropyl0x0-4,9-dihydr0-5H-thien0[3,2-a]quinolizine-S-carboxylic 6—Is0pr0pyl—6,7-dihydr0thien0[3,2-clpyridine S A solution of 2-(thiophenyl)-1,3-dioxolane (0.97 g, 6.2 mmol) in anhydrous THF (5 mL) was cooled to -78 oC (dry ice/acetone bath), followed by the drop-wise addition of n-BuLi (2.5 M in THF, 2.7 mL, 6.8 mmol). The mixture was stirred at -78 CC for 2h. Tert-butyl 4-isopropyl-1,2,3- azolidinecarboxylate 2,2-dioxide (prepared according to the procedure by Guo, el al., 2010, J. Org. Chem. 75:937) (1.5g, 5.7 mmol) in THF (7 mL) was added drop-wise at -78 oC and the resulting mixture was slowly warmed up to rt and stirred for 16 h. The reaction mixture was concentrated under vacuum. The residue was diluted with HCl (4N in 1,4-dioxane, 20 mL), H20 (2 mL) at rt and stirred for 1 h. The on mixture was diluted with CHzClz (30 mL) and ed with 1M aqueous Na2CO3 solution (10 mL). The on mixture was extracted with CHzClz (2 x 20 mL), washed with H20 (15 mL) and sat. aqueous brine solution (10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The e was purified by normal phase SiOz chromatography (20% to 80% EtOAc/hexanes) to afford 6-isopropyl-6,7- dihydrothieno[3,2-c]pyridine as a colorless oil (300 mg, 27% yield, m/z: 180 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 5 8.33-8.32 (d, J=3.2 Hz, 1H), 7.10-7.08 (d, J=6.0 Hz, 1H), 7.03— 7.02 (d, J=5.2 Hz, 1H), 3.46-3.40 (m, 1H), 2.91-2.86 (dd, J=16.8, 6.8Hz, 1H), .65 (t, J=16.0 Hz, 1H), 2.14—2.09 (m, 1H), 1.09-1.07(d, J=6.8 Hz, 3H), 1.06-1.04 (d, J=6.8 Hz, 3H).

Ethyl 5-is0pr0pyl—9—0x0—4, 9,1 0,1 0a-tetrahydr0—5H-thien0[3,2-a]quinolizine—8—carb0xylate O 0 To a solution of 6-isopropyl-6,7-dihydrothieno[3,2-c]pyridine (380 mg, 2.12 mmol) in ethanol (20 mL) was added ethyl (2E)—2-acetyl-3 -ethoxypropenoate (1.18 g, 6.36 mmol) and the reaction mixture was stirred at 100 0C for 16h. The on mixture was concentrated under -l6l- vacuum. The residue was purified by normal phase Si02 chromatography (0% to 5% MeOH/CHzClz) to afford ethyl 5-isopropyloxo-4,9,10,10a-tetrahydro-5H-thieno[3,2- a]quinolizinecarboxylate as a light brown syrup (250 mg, 37% yield, m/z: 320 [M+H]+ observed). 1H NMR (400MHz, : 8.28 (s, 1H),7.20-7.19 (d, J=5.2 Hz, 1H), .78 (d, J=5.2 Hz, 1H), 4.74—4.70 (dd, J=3.2, 15.6 Hz, 1H), 4.29—4.24 (q, J=6.8 Hz, 2H), 3.55—3.50 (m, 1H), 3.22-3.18 (m, 2H), 2.85-2.80 (dd, J=4.4, 15.6 , 2.58-2.50 (m, 1H), 1.88-1.82 (m, 1H), 1.35—1.31 (t, J=7.2 Hz, 3H), 0.97—0.95 (d, J=6.8 Hz, 3H), 0.92—0.90 (d, J=6.8 Hz, 3H).

Ethyl 5-is0pr0pyl—9—0x0—4,9-dihydr0—5H-thien0[3,2-alquin0lizinecarb0xylate To a stirred solution of ethyl 5-isopropyloxo-4,9,10,10a-tetrahydro-5H-thieno[3,2-a] quinolizinecarboxylate (250 mg, 0.783 mmol) in 1,2-dimethoxyethane (10 mL) was added p- chloranil (193 mg, 0.783 mmol). The reaction mixture was stirred at 100 °C for 2h. The reaction mixture was cooled to rt and resulting itate was filtered and washed with EtOAc (2x25 mL). The filtrate was washed with H20 (10 mL) and sat. aqueous brine solution (10 mL). The c layer was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by normal phase Si02 chromatography (0% to 5% MeOH/CHzClz) to afford ethyl 5-isopropyloxo-4,9-dihydro-5H-thieno[3,2-a]quinolizinecarboxylate as a brown syrup (180 mg, 73% yield, m/z: 318 [M+H]+ observed). 1H NMR (400MHz, DMSO-D6): 5 8.38 (s, 1H), 7.54—7.53 (d, J=5.2 Hz, 1H), 7.49-7.48 (d, J=5.2 Hz, 1H), 6.66 (s, 1H),4.21-4.15 (q, J=6.4 Hz, 2H), 3.40—3.34 (m, 3H), .84 (m, 1H), 1.22—1.20 (t, J=4.0 Hz, 3H), 0.85-0.84 (d, J=6.8 Hz, 3H), 0.69-0.68 (d, J=6.8 Hz, 3H).

-Is0pr0pyl—9—0x0—4, 9-dihydr0—5H-thien0[3,Z-alquinolizine—8—carb0xylic acid To a solution of ethyl ropyloxo-4,9-dihydro-5H-thieno[3,2-a]quinolizinecarboxylate carboxylate (180 mg, 0.56 mmol) in 1,4-dioxane (2 mL) was added 10% aqueous NaOH solution (1.5 mL) at rt and stirred for 2 hours. The reaction mixture was cooled to 0°C, acidified with aqueous 2N HCl solution to pH 2 and stirred for 1 h at rt. The resulted solids were filtered, washed with H20 (5 mL) and diethyl ether (5 mL) to give 5-isopropyloxo-4,9-dihydro-5H- thieno[3,2-a]quinolizinecarboxylic acid as a light brown solid (90mg, 55% yield, m/z: 290 [M+H]+ observed). 1H NMR (400MHz, DMSO-d6): 5 8.82 (s, 1H), 7.67-7.66 (d, J=5.2 Hz, 1H), 7.56-7.55 (d, J=5.2 Hz, 1H), 7.18 (s, 1H), 4.61-4.58 (t, J=7.2 Hz, 1H), 3.47—3.43 (m, 2H), 1.82- 1.76 (m, 1H), 0.87-0.85 (d, J=6.8 Hz, 3H), 0.67-0.66 (d, J=6.8 Hz, 3H).

EXAMPLE 85: 2-Chloro-S-isopr0pyl0x0-4,9-dihydro-SH-thieno[3,2-a]quinolizine o o carboxylic acid m/z: 324 [M+H]+ observed. 1H NMR z, DMSO-d6): 6 8.71 (s, 1H), 8.27 (s, 1H), 8.06 (s. 1H), 5.07 (m, 1H), 3.97 (m, 2H), 1.83 (m, 1H), 0.67 (d, J=6.8 Hz, 3H), 0.49 (d, J=6.8 Hz, 3H).

E 86: 6-is0pr0pylmeth0xy0x0-5,10-dihydr0-6H-pyrid0[2,1-a] [2,7] naphthyridine—9-carb0xylic acid Tert-buljyl ((6-methoxy—4-methylpyridin-3—yl)methyl)carbamate (l) To a solution of hoxymethylpyridinyl)methanamine (1 g, 6.6 mmol) in CHzClz (10 mL) was added di-tert—butyl decarbonate (1.72 g, 7.88 mmol) and triethylamine (1.28 mL, 9.20 mmol) at 0 oC. The mixture was warmed to rt and stirred for 12 h. H20 (10 mL) was added to the mixture and ted with CHzClz (2x15 mL), washed with sat. aqueous brine solution (15 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by normal phase Si02 chromatography (0% to 15% EtOAc/hexanes) to afford tert-butyl ((6- methoxymethylpyridinyl)methyl)carbamate as a white solid (1.3 g, 78% yield, m/z: 253 [M+H]+ observed).

Tert-buljyl ((4-(2-hydr0xy—3-methylbu920meth0xypyridinyl)methyl)carbamate -l63- To a solution of tert-butyl ((6-methoxymethylpyridinyl)methyl) (1.1 g, 4.36 mmol) in THF (10 mL) at -78 oC (dry ice/acetone bath) was added n-BuLi (2.5 M in hexanes, 5 mL, 12 mmol) and stirred for 1 hour at -78 oC. Isovelaraldehyde (1.3 mL, 12 mmol) was added at -78 oC and the reaction mixture stirred for 30 min. The temperature was slowly raised to rt and stirred for 4h. Sat. aqueous NH4Cl solution (10 mL) was added to the reaction mixture at 0 oC. The aqueous phase was extracted with EtOAc (2 x 15 mL) and washed with sat. aqueous brine solution (15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under . The residue was purified by normal phase SiOz tography (0% to 30% EtOAc/hexanes) to afford tert-butyl ((4-(2-hydroxy-3 -methylbutyl) methoxypyridinyl)methyl)carbamate as a white solid (0.8 g, 57% yield, m/z: 325 [M+H]+ observed). 1H NMR (400MHz, DMSO-d6): 5 7.90 (s, 1H), 7.18 (m, 1H), 6.65 (s, 1H), 4.50—4.49 (d, J=6.0 Hz, 1H), 4.16-4.03 (m, 2H), 3.78 (s, 3H), 3.40—3.39 (m, 1H), 2.68-2.64 (m, 1H), 1.65- 1.60 (m, 1H), 1.36 (s, 9H), .89 (d, J=2.4 Hz, 3H), 0.88-0.87 (d, J=2.4 Hz, 3H). 1-(5-(((tert-Butoxgycarbonyl)amino)methyl)meth0xypyridin-4—yl)methylbutan-2—yl BocHN N/ OMS methanesulfonate | To a solution of l—butyl hydroxymethylbutyl)methoxypyridinyl)methyl carbamate (0.2 g, 0.62 mmol) in CH2C12 (3 mL) was added trimethylamine (0.13 mL, 0.92 mmol) and methanesulfonyl chloride (0.07 mL, 0.92 mmol) at 0 oC. The ant mixture was stirred for 3 hours at 0 oC. H20 (5 mL) was added, extracted with EtOAc (2 x 15 mL), washed with sat. aqueous brine on (10 mL), dried over sodium e, filtered and concentrated under vacuum. The residue was purified by normal phase Si02 chromatography (0% to 30% EtOAc/hexanes) to afford 1-(5-(((tert-butoxycarbonyl)amino)methyl)methoxypyridinyl) methylbutanyl methanesulfonate as a pale yellow syrup (190 mg, 77% yield). 1H NMR (400MHz, CDCl3): 5 8.05 (s, 1H), 6.63 (s, 1H), 4.84-4.77 (m, 2H), 4.29-4.28 (d, J=5.2 Hz, 2H), 3.91 (s, 3H), 2.98-2.92 (m, 2H), 2.66 (s, 3H), 2.10—2.09 (m, 1H), 1.44 (s, 9H), 1.07—1.05 (d, J=7.2 Hz, 6H).

N/ NH 3-Is0pr0pyl—6—meth0xy—1,2,3,4-tetrahydr0—2,7-naphthyridine | To a solution of 1-(5-(((tert-butoxycarbonyl)amino)methyl)methoxypyridinyl) methylbutanyl methanesulfonate (190 mg, 0.47 mmol) in e (3 mL) was added 6N HCl (3 mL) at 0 oC. The reaction mixture was warmed to rt and d for 3 h. Sat. aqueous NaHCO3 solution (10 mL) was added to the mixture dropwise to adjust the pH to 8-9 and stirred for 2 h.

The mixture was extracted with EtOAc (2 x 15 mL), washed with sat. aqueous brine solution (10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 10% MeOH/CHzClz) to afford 3- isopropylmethoxy-1,2,3,4-tetrahydro-2,7-naphthyridine as a ess oil (85 mg, 88% yield). 1H NMR (400MHz, DMSO-d6): 5 7.82 (s, 1H), 6.51 (s, 1H), 3.91-3.87 (d, J=15.6 Hz, 1H), 3.73— 3.71 (m, 5H), 2.65-2.61 (m, 1H), 2.41-2.38 (m, 1H), .58 (m, 1H), 0.94-0.83 (m, 6H).

N/ \N 3-Is0pr0pyl—6—meth0xy—3,4-dihydr0—2,7-naphthyridine | To a solution of 1,2,3,4-tetrahydroisopropylmethoxy-2,7-naphthyridine (80 mg, 0.39 mmol) in CHzClz (2 mL) at 0 0C was added N—bromosuccinamide (140 mg, 0.77 mmol) and the reaction mixture stirred for 2 h. Sat. aqueous NaHC03 solution (3 mL) was added to e and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with sat. aqueous brine solution (10 mL), dried over sodium sulfate, filtered and concentrated under . The residue was purified by normal phase Si02 chromatography (0% to 50% EtOAc/hexanes) to afford 3-isopropylmethoxy-3,4-dihydro-2,7-naphthyridine as a colorless oil (55 mg, 69% yield, m/z: 205 [M+H]+ observed).

Ethyl 6—is0pr0pyl—3—meth0xy-1 0—0x0-5,1 0,11,11a—tetrahydro—6H-pyrid0[2,1- a][2, 7/11uphthyridine—9—carb0xylate A mixture of 3-isopropylmethoxy-3,4-dihydro-2,7-naphthyridine (50 mg, 0.24 mmol) and ethyl (2E)—2-acetyl-3 -ethoxypropenoate (0.14 g, 0.73 mmol) in EtOH (4 mL) was d at 100 0C for 12 h. The reaction e was concentered under vacuum to give ethyl 6-isopropylmethoxy- 1 0-oxo-5, 10,1 1,1 1a-tetrahydro-6H-pyrido[2,1-a][2,7]naphthyridinecarboxylate as a brown oil which was used without further purification (90 mg, >100%, m/z: 345 [M+H]+ observed).

Ethyl 6—is0pr0pyl—3-meth0xy-1 0—0x0-5,1 0—dihydr0—6H-pyrid0[2,1-a][2, 7Inaphthyridine ylate To a solution of ethyl 6-isopropylmethoxyoxo-5,10, 1 1,1 1a-tetrahydro-6H-pyrido[2,1- a] [2,7]naphthyridinecarboxylate (85 mg, 0.25 mmol) in 1,2-dimethoxyethane (2 mL) was added p-chloranil (71 mg, 0.29 mmol) and the reaction mixture d at 100 CC for 4h. The reaction mixture was concentrated under vacuum to give to give ethyl 6-isopropylmethoxy- -oxo-5, 10,1 1,1 1a-tetrahydro-6H-pyrido[2,1-a][2,7]naphthyridinecarboxylate which was used without further purification (90 mg, >100%). 6-Is0pr0pyl—3-meth0xy—1 0-0x0-5,10-dihydr0—6H-pyrid0[2,1-a][2, 7Inaphthyridinecarb0xylic To a solution of ethyl 6-isopropylmethoxyoxo-5,10, 1 1,1 rahydro-6H-pyrido[2,1- a] [2,7]naphthyridinecarboxylate (85 mg, 0.25 mmol) in MeOH (2 mL) was added a 10% s NaOH (2 mL) and stirred at rt for 4h. The reaction mixture was washed with l ether (2x4 mL) and the pH of the aqueous layer adjusted to 1-2 with 2M HCl. The resultant solids were filtered, washed with l ether (2x4 mL) and recrystallized from EtOH to give pure 6-isopropyl-3 -methoxyoxo-5,10-dihydro-6H-pyrido[2,1-a][2,7]naphthyridine carboxylic acid as a white solid (20 mg, 26% yield, m/z: 315 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 5 8.87 (s, 1H), 8.79 (s, 1H), 7.47 (s, 1H), 6.95 (s, 1H), 4.51—4.47 (m, 1H), 3.91 (s, 3H), 3.35—3.30 (m, 2H), 1.54-1.48 (m,1H), 0.85-0.83 (d, J=6.8 Hz, 3H), 0.70-0.68 (d, J=6.8 Hz, EXAMPLE 87: S-Isopr0pylmeth0xy0x0-4,9-dihydr0-5H-thiazolo[4,5-a] quinolizine— MeO—</ 0xylic acid MeO/<S\{0 4-(1,3-Di0x0lan-2—yl)meth0xythiaz0le A mixture of 2-methoxythiazolecarbaldehyde (500 mg, 3.49 mmol) in benzene (20 mL), triethyl orthoformate (0.70 ml, 4.2 mmol), ethylene glycol (1.2 ml, 21 mmol) and p- toluenesulfonic acid monohydrate (6 mg, 0.034 mmol) was heated to 40 0C for 2 h. The on mixture was cooled to rt and quenched with aqueous NaHC03 (10 mL) and extracted with EtOAc (2x20 mL). The combined organic ts were washed with sat. aqueous brine solution (10 mL), dried over sodium sulfate and concentrated under vacuum. The residue was d by normal phase SiOz chromatography (5% to 20% hexanes) to afford 4-(1,3-dioxolan yl)methoxythiazole as a colorless oil (450 mg, 69% yield). 1H NMR (400MHz, CDCl3): 5 6.78 (s, 1H), 5.81 (s, 1H), 4.15—4.12 (m, 2H), 4.09 (s, 3H), 4.04—4.00 (m, 2H).

HO/(M\ NN 6-Is0pr0pyl—6, 7-dihydr0thiaz0l0[4,5-clpyridin0l 3 To a stirred solution of 4-(1,3-dioxolanyl)methoxythiazole (0.45 g, 2.4 mmol) in dry THF (10 mL) at -78°C (dry ice/acetone bath) was added n-BuLi (2.5 M in hexanes, 1.2 mL, 2.9 mmol) drop-wise and the mixture allowed to stir for 2 h. l—Butyl 4-isopropyl-1,2,3- oxathiazolidinecarboxylate 2,2-dioxide (640 mg, 2.4 mmol) in THF (5 mL) was added drop- wise and the resulting mixture was slowly warmed to rt and stirred for 16 h. The reaction e was concentrated under reduced pressure and treated with HCl (4N in 1,4-dioxane, 20 mL), followed by H20 (1.5 mL) at rt and allowed to stir for 1 h. The reaction mixture was diluted with CHzClz (20 mL) and basif1ed with 1M aqueous NazCO3 solution. The layers were separated and the aqueous portion was extracted with CHzClz (2 x 20 mL), washed with H20 (15 mL), sat. aqueous brine solution (10 mL), dried over sodium sulfate and concentrated under . The residue was purified by normal phase Si02 chromatography (5% to 50% hexanes) to afford 6-isopropyl-6,7-dihydrothiazolo[4,5-c]pyridinol as a colorless oil (330 mg, 70% yield). 1H NMR (400MHz, CDCl3): 8 7.26 (s, 1H), 3.79-3.75 (m, 1H), 3.66-3.62 (m, 1H), 3.51-3.43 (m, 1H), 2.13-2.06 (m, 1H), 1.05-l.O4(d,J= 6.8 Hz, 3H), l.O3-l.Ol(d, J: 6.8 Hz, 3H). 2-Hydr0xy—5-is0pr0pyl—9—0x0—5, 9,1 0, 1 0a—tetrahydr0—4H-thiaz0l0[4, 5-alquinolizine O O Ho—(/N N carboxylate To a solution of 6-isopropyl-6,7-dihydrothiazolo[4,5-c]pyridinol (330 mg, 1.68 mmol) in ethanol (20 mL) was added ethyl (2E)acetylethoxypropenoate (880 mg, 4.7 mmol) at rt and resultant mixture was stirred at 100 0C for 16h. The solvent was removed under vacuum and the residue was purified by normal phase Si02 chromatography (0% to 5% HzClz) to afford 2-hydroxy-5 -isopropyloxo-5,9, l O, l Oa-tetrahydro-4H-thiazolo[4, inolizine carboxylate as a light brown solid (120 mg, 21% yield, m/z: 337 [M+H]+ observed). 1H NMR (400MHz, DMSO-d6): 11.24 (s, 1H), 8.32 (s, 1H), 4.53—4.49 (d, J=14.8 Hz, 1H), 4.08-4.02 (q, J=7.2 Hz, 2H), 3.89-3.85 (dd, J=10.0, 4.8, 1H), 2.85-2.78 (m, 1H), 2.74-2.64 (m, 2H), 1.84-1.82 (m, 1H), 1.18-1.14 (t, J=7.2 Hz, 4H), 0.90-0.88 (d, J=6.8 Hz, 3H), 0.80-0.78 (d, J=6.4 Hz, 3H).

Ethyl 2-hydr0xy—5-is0pr0pyl—9—0x0—4,9-dihydr0—5H-thiaz0l0[4, 5-alquinolizine—8—carb0xylate To a solution of oxyisopropyloxo-5,9, lO,lOa-tetrahydro-4H-thiazolo[4,5- a]quinolizinecarboxylate (120 mg, 0.36 mmol) in l,2-dimethoxyethane (20 mL) was added p- nil (88 mg, 0.36 mmol) and the mixture was stirred at 100 0C for 2h. The reaction was cooled to rt. The resulting solids collection by filtration and washed with EtOAc (25 mL). The 2O filtrate was washed with H20 (10 mL), sat. s brine solution (10 mL), dried over sodium sulfate and concentrated under vacuum. The e was purified by normal phase Si02 chromatography (0% to 5% MeOH/CHzClz) to afford ethyl 2-hydroxyisopropyloxo-4,9- dihydro-5H-thiazolo[4,5-a]quinolizinecarboxylate as a light yellow solid (60 mg, 50% yield, m/z: 335 [M+H]+ observed). 1H NMR (400MHz, DMSO-d6): 11.87 (s, 1H), 8.36 (s, 1H), 6.49 (s, 1H), 5.73 (s, 1H), 4.43 (m, 1H), 4.29 (m, 1H), 4.17-4.16 (q, 2H), 1.99—1.97 (m, 1H), 1.27—1.21 -l68- (t, J: 6.8 Hz, 3H), 0.89-0.87 (d, J: 6.4 Hz, 3H), 0.72-0.70 (d, J: 6.8 Hz, 3H).

Ethyl 5-is0pr0pyl-2—methoxy0x0—4,9-dihydr0—5H-thiaz0l0[4,5-alquinolizine—8—carb0xylate To a solution of ethyl 2-hydroxyisopropyloxo-4,9-dihydro-5H-thiazolo[4,5-a]quinolizine- 8-carboxylate (60 mg, 0.18 mmol) in acetone (10 mL) was added potassium carbonate (160 mg, 1.2 mmol), followed by drop-wise addition of methyl iodide (0.12 mL, 1.9 mmol). The reaction mixture was stirred at rt for 24h. The reaction mixture was diluted with EtOAc (2 x 20 mL), washed with H20 (10 mL) and sat. aqueous brine solution (10 mL). The c layer was dried over sodium sulfate and concentrated under . The residue was purified by normal phase Si02 chromatography (0% to 10% MeOH/CHzClz) to afford ethyl ropylmethoxyoxo- 4,9-dihydro-5H-thiazolo[4,5-a]quinolizinecarboxylate as a light yellow solid (30 mg, 48% yield, m/z: 349 [M+H]+ observed). r0pyl—2—meth0xy—9-0x0-4,9-dihydr0—5H-thiaz0l0[4, 5-alquinolizine—8—carb0xylic acid To a solution of ethyl 5-isopropylmethoxyoxo-4,9-dihydro-5H-thiazolo[4,5-a]quinolizine- 8-carboxylate (30 mg, 0.086 mmol) in 1,4-dioxane (2 mL) was added 10% aqueous NaOH solution (1.5 mL) at rt and stirred for 2 h. The reaction the mixture was cooled to 0 oC, acidified with aqueous 2NHCl to pH 1-2 and d for 1 h at rt. The resulting solids were filtered, washed with H20 (5 mL), followed by diethyl ether (5 mL) and dried to give 5-isopropyl methoxyoxo-4,9-dihydro-5H-thiazolo[4,5-a]quinolizinecarboxylic acid as pale yellow solid (20 mg, 73% yield, m/z: 321 [M+H]+ observed). 1H NMR (400MHz, 6): 5 16.02 (bs, 1H), 8.81 (s, 1H), 6.95 (s, 1H), 4.52—4.50 (d, J=9.2 Hz, 1H), 3.38 (s, 3H), 3.20 (s, 2H), 2.09—2.07 (m, 1H), 0.92—0.91 (d, J=6.4 Hz, 3H), 0.77-0.76 (d, J=6.4 Hz, 3H).

EXAMPLE 88: S-Is0pr0pyl-Z-(methoxymethyl)0x0-4,9-dihydro-SH-thiazolo[4,5- olizine—S-carboxylic acid MeOJf—O 4-(1,3-Di0x0lan—2—yl)-2—(methoxymethyDthiazole S A mixture of 2-(methoxymethyl)thiazolecarbaldehyde (700 mg, 4.46 mmol) in benzene (20 mL), triethyl orthoformate (0.9 ml, 5.4 mmol), ne glycol (1.2 ml, 20.75 mmol) and p- toluene sulfonic acid monohydrate (8 mg, 0.044 mmol) was heated to 40 0C for 2 h. The reaction mixture was cooled to rt and quenched with aqueous NaHCO3 (15 mL) and extracted with EtOAc (2x30 mL). The combined organic extracts were washed with sat. aqueous brine solution (10 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by normal phase Si02 tography (5% to 25% EtOAc/hexanes) to afford 4-(1,3-dioxolan yl)(methoxymethyl)thiazole as a colorless oil (600 mg, 67% yield). 1H NMR (400MHz, : 5 7.41 (s, 1H), 5.98 (s, 1H), 4.74 (s, 3H), 4.16-4.13 (m, 2H), 4.06-4.02 (m, 2H), 3.49 (s, MeO\/< \ 6-is0pr0pyl—2—(methoxymethyD-6, dr0thiaz0l0[4, 5-clpyridine 3 To a stirred solution of 4-(1,3-dioxolanyl)methoxythiazole (0.6 g, 3 mmol) in dry THF (10 mL) at -78 0C was added drop wise n-BuLi (2.5 M in hexanes, 1.43 mL, 3.58 mmol) and the mixture stirred for 2 h at -78 CC. Z-Butyl 4-isopropyl-1,2,3-oxathiazolidinecarboxylate 2,2- dioxide (800 mg, 3 mmol) in THF (5 mL) was added drop-wise, and then the resulting mixture was slowly warmed up to 20 oC and d for 16 h. The reaction mixture was trated under reduced pressure and treated with HCl (4N in 1,4-dioxane, 24 mL), followed by H20 (2 mL) at rt and allowed to stir for 1 h. The reaction mixture was diluted with CHzClz (30 mL) and basif1ed with 1M aqueous NazCO3 solution. The layers were separated and the aqueous portion was ted with CHzClz (2 x 20 mL), washed with H20 (15 mL), sat. aqueous brine solution (10 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by normal phase SiOz chromatography (5% to 50% EtOAc/hexanes) to afford 6-isopropyl (methoxymethyl)-6,7-dihydrothiazolo[4,5-c]pyridine as a colorless oil (290 mg, 43% yield, m/z: 225 [M+H]+ observed). 1H NMR (400MHz, CDC13): 8 8.45 (s, 1H), 4.70 (s, 2H), 3.53-3.51 (m, 1H), 3.49 (s, 3H), 3.99-3.93 (m, 1H), 2.80-2.72 (m, 1H), 2.14-2.09 (m, 1H), 1.09-1.07 (d, J=6.8 Hz, 3H), .05 (d, J=6.8 Hz, 3H).

Ethyl 5-is0pr0pyl—2—(methoxymethyD-9—0x0—4, 9,1 0,1 0a-tetrahydro—5H-thiazolo[4, 5- O O MeO N \_</ N alquinolizine-8—carb0xylate To a stirred solution of 6-isopropyl(methoxymethyl)-6,7-dihydrothiazolo[4,5-c]pyridine (290 mg, 1.3 mmol) in ethanol (20 mL) was added ethyl (2E)acetylethoxypropenoate (722 mg, 3.88 mmol) at 20 OC and the resultant mixture was stirred at 100 0C for 16h. The solvent was removed under vacuum and the residue was purified by normal phase SiOz chromatography (50% to 100% EtOAc/hexanes) to afford ethyl 5-isopropyl(methoxymethyl)oxo- 4,9,10,10a-tetrahydro-5H-thiazolo[4,5-a]quinolizinecarboxylate as a light brown syrup (250 mg, 53% yield, m/z: 365 [M+H]+ observed). 1H NMR (400MHz, CDCl3): 8.27 (s, 1H), 4.78 (m, 1H), 4.75 (s, 2H), 4.27—4.25 (q, J=7.2 Hz, 2H), 3.49 (m, 5H), 3.19—3.09 (m, 3H), 1.86-1.83 (m, 1H), 1.33—1.31 (t, J=7.2 Hz, 3H), .95 (d, J=6.8 Hz, 3H), .92 (d, J=6.8 Hz, 3H).

Ethyl r0pyl—2—(methoxymethyD-9—0x0—4, 9-dihydr0—5H—thiazolo[4, 5-alquinolizine ylate To a stirred solution of ethyl 5-isopropyl(methoxymethyl)oxo-4,9,10,10a-tetrahydro-5H- thiazolo[4,5-a]quinolizinecarboxylate (250 mg, 0.69 mmol) in l,2-dimethoxyethane (20 mL) was added p-chloranil (170 mg, 0.69 mmol) and the mixture was stirred at 100 0C for 2h. The on was cooled to rt. The resulting solids collection by filtration and washed with EtOAc (25 mL). The filtrate was washed with H20 (10 mL), sat. aqueous brine solution (10 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by normal phase Si02 chromatography (0% to 5% MeOH/CHzClz) to afford ethyl 5-isopropyl(methoxymethyl) oxo-4,9-dihydro-5H-thiazolo[4,5-a]quinolizinecarboxylate as a light yellow solid (150 mg, -l7l- WO 85619 60% yield, m/z: 363 [M+H]+ observed). 1H NMR (400MHz, DMSO-d6): 8.41 (s, 1H), 6.63 (s, 1H), 4.71 (s, 2H), 4.41-4.37 (q, J=6.8 Hz, 2H), 4.21-4.16 (m, 3H), 3.40 (s, 3H), 1.84-1.79 (m, 1H), 1.22-1.20 (t, J=7.2 Hz, 3H), 0.85-0.84 (d, J=6.8 Hz, 3H), .69 (d, J=6.4 Hz, 3H).

-Is0pr0pyl—2—(methoxymethyD-9—0x0—4,9-dihydr0—5H-thiaz0l0[4,5-alquinolizine—8—carb0xylic To a solution of ethyl 5-isopropyl(methoxymethyl)oxo-4,9-dihydro-5H-thiazolo[4,5- a]quinolizinecarboxylate (150 mg, 0.41 mmol) in 1,4-dioxane (3 mL) was added 10% aqueous NaOH on (2.0 mL) at rt and stirred for 2 h. The reaction the mixture was cooled to 0 oC, acidified with aqueous 2NHC1 to pH 1-2 and stirred for 1 h at rt. The crude mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and trated under vacuum. The residue was purified by preparative TLC to give 5- isopropyl(methoxymethyl)oxo-4,9-dihydro-5H-thiazolo[4,5-a]quinolizinecarboxylic acid as a pale yellow solid (70 mg, 51% yield, m/z: 335.0 [M+H]+ observed). 1H NMR (400MHz, DMSO-d6): 5 16.18 (bs, 1H), 8.88 (s, 1H), 7.03 (s, 1H), 4.74 (s, 2H), .65 (m, 1H), 3.64-3.59 (m, 1H), 3.52-3.46 (m, 1H), 3.42 (s, 3H), 1.89-1.82 (m, 1H), 0.87-0.86 (d, J=6.8 Hz, 3H), 0.70-0.68 (d, J=6.8 Hz, 3H).

EXAMPLE 89: Ethyl 6-(tert-butyl)—9,10-dihydroxy-Z-ox0-6,7-dihydr0-2H-pyrid0[2,1- COZEt 21] isoquinolinecarb0xylate B Onm 1-(3,4-Bis(benzyl0xy)phenyl)—3,3-dimethylbutan-2—0ne BnO t-Bu To a solution of (((4-bromo-1,2-phenylene)bis(oxy))bis(methylene))dibenzene (50 g, 0.14 mol) and 3,3-dimethylbutanone (51 mL, 0.41 mol) in 1,4-dioxane (600 mL) was added sodium tert- butoxide (43 g, 0.448 mol), Xantphos (7.86 g, 13.5 mmol) and tris(dibenzylideneacetone)dipalladium(0) (6.22 g, 6.79 mmol). The mixture was stirred at 100 0C for 3 hrs. The e was filtered through Celite®, washed with ethyl acetate (3x80 mL) and concentrated under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 20% petroleum ether/ EtOAc) to afford 1-(3,4-bis(benzyloxy) phenyl)-3,3- dimethylbutanone as a yellow solid (31.5 g, 60% yield, m/z: 389 [M+H]+ observed). 1H NMR (400 MHz, CDC13): 5 7.48-7.42 (m, 4 H), 7.40-7.28 (m, 6 H), 6.89 (d, J=8.0 Hz, 1 H), 6.82 (s, 1 H), 6.72-6.69 (m, 1 H), 5.15 (d, J=4.8 Hz, 4 H), 3.70 (s, 2 H), 1.14 (s, 9 H). 1-(3, 4-Bis(benzyl0xy)phenyl)-3,3-dimethylbutan-2—amine BnO t-Bu To a solution of 1-(3,4-bis(benzyloxy)phenyl)-3,3-dimethylbutanone (13.5 g, 34.8 mmol) in MeOH (40 mL) was added NH4OAc (26.8 g, 348 mol) and the mixture was d at rt for12 hr.

The on mixture was cooled to 0 oC and sodium cyanoborohydride (3.5 g, 55.7 mmol) was added and contents of the flask was stirred at 40 0C for 30 hr. The mixture was concentrated under vacuum. The residue was diluted H20 (100 mL), ted with CHzClz (3x300 mL) and washed with sat. aqueous brine solution (2x100 mL). The combined organic layers were dried over Na2S04, d and concentrated under vacuum to give 1-(3,4-bis(benzyloxy)phenyl)-3,3- dimethylbutanamine as a yellow oil that was used without further purification (13 .7 g, >100% yield, m/z: 390 [M+H]+ observed).

Bnomjm N—(1-(3,4-bis(benzyl0xy)phenyl)-3,3-dimethylbutan-Z-nyormamide BnO t'BU To a solution of 1-(3,4-bis(benzyloxy)phenyl)-3,3-dimethylbutanamine (13.7 g, 35.2 mmol) in 1,4-dioxane (140 mL) was added formic acid (40 mL, 1.06 mol). The mixture was stirred at 120 0C for 50 hrs. The reaction mixture was concentrated under vacuum. The residue was purified by normal phase SiOz chromatography (10% to 50% petroleum ether/ EtOAc) to afford 3,4- bis(benzyloxy)phenyl)-3,3-dimethylbutanyl)formamide as a yellow solid (6.2 g, 42% yield, m/z: 418 [M+H]+ observed). 1H NMR (400 MHz, CDCl3, e of rotamers): 5 7.94-7.28 (m, H), 6.90 -6.78 (m, 1 H), 6.72-6.66 (m, 2 H), 5.88-5.06 (m, 5 H), 4.21-2.87 (m, 2 H), 2.34—2.22 (m, 1 H), 0.99 (d, J=3.6 Hz, 9 H). 6, 7-Bis(benzyl0xy)-3—(tert-buljyl)-3,4-dihydr0is0quin0line BnO t-Bu To a solution ofN—(l-(3,4-bis(benzyloxy)phenyl)-3,3-dimethylbutanyl)formamide (10 g, 24 mmol) in CHzClz (120 mL) was added phosphorus(V) oxychloride (6 mL, 65 mmol) dropwise and the mixture was stirred at 40 0C for 12 hr. The mixture was poured into aqueous ammonium hydroxide solution (10%, 60 mL). The reaction e was extracted with CHzClz (3x80 mL).

The combined organic layers were dried over Na2S04, filtered and concentrated under vacuum to afford 6,7-bis(benzyloxy)(tert-butyl)-3,4-dihydroisoquinoline as a yellow gum that was used without further purification (9.2 g, >100% yield, m/z: 400 [M+H]+ observed).

Ethyl 9,1 0-bis(benzyloxy)—6-(tert-buljyl)-2—0x0—6, 7-dihydr0—2H-pyrid0[2,1-alis0quin0line COzEt carboxylate BnO t'BU A mixture of 6,7-bis(benzyloxy)(tert-butyl)-3,4-dihydroisoquinoline (9.2 g, 23 mmol) and ethyl (E)—2-(ethoxymethylene)—3-oxobutanoate (18.6 g, 83.9 mmol) in EtOH (80.00 mL) was stirred at 100 0C for 60 hr. The reaction mixture was concentrated under vacuum to give ethyl 9,10-bis(benzyloxy)(tert-butyl)oxo-1,6,7,1 1b-tetrahydro-2H-pyrido[2,1-a]isoquinoline-3 - carboxylate as brown gum that was used in the next step without further ation (30.7 g, >100% yield, m/z: 540 [M+H]+ observed).

To a on of crude ethyl 9,10-bis(benzyloxy)(tert-butyl)oxo-1,6,7,11b-tetrahydro-2H- pyrido[2,1-a]isoquinolinecarboxylate (12.4 g) in 1,2-dimethoxyethane (180 mL) was added p- chloranil (6 g, 24 mmol). The mixture was stirred at 70 0C for 3 hr and concentrated to ~120 mL under vacuum. The reaction mixture was cooled to 5 oC. The mixture, filtered and washed with cooled methoxyethane (3x8 mL) to give a first crop of the desired product. The filtrate was trated to about 80 mL and cooled to 0 oC. The mixture was filtered and filter solid was washed with cooled DME (6 mL * 3) to give a second crop of the desired product. The 2 crops were combined to give ethyl 9,10-bis(benzyloxy)(tert-butyl)oxo-6,7-dihydro-2H- pyrido[2,1-a]isoquinolinecarboxylate as a yellow solid (7 g, 54% yield, m/z: 538 [M+H]+ observed). 1H NMR (400 MHz, CDC13): 5 8.73 (s, 1 H), 7.51 (d, J=2.4 Hz, 2 H), 7.49—7.44 (m, 4 H), 7.42-7.28 (m, 6 H), 7.22 (s, 1 H), 5.296. 18 (m, 4 H), 4.57 (bd, J=6.4 Hz, 1 H), 4.30 (dd, J=14 Hz, 7.2 Hz, 2H), 3.42—3.34 (m, 1 H), .21 (m, 1 H), 1.30 (m, 3 H), 0.71 (s, 9 H).

Ethyl 6-(tert-buzjyl)-9,1 0—dihydr0xy—2—0x0—6, 7-dihydr0—2H-pyrid0[2,1-alis0quin0line —174— COzEt carboxylate H0 “3“ A mixture of ethyl 9,10-bis(benzyloxy)(tert-butyl)oxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinolinecarboxylate (2 g, 3.7 mmol) and palladium on carbon (10%, 300 mg, 37 mmol) under H2 (30 psi) in EtOH (50 mL) was stirred at rt for 6 hrs. The reaction mixture was filtered through Celite® and washed with ethanol (5x30 mL). The filtrate was concentrated under vacuum to give ethyl 6-(tert-butyl)-9,10-dihydroxyoxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinolinecarboxylate as a brown solid (1.16 g, 87% yield, m/z: 538 [M+H]+ observed). 1HN1\/1R(400 MHz, DMSO-d6): 5 10.14 (br s, 1 H), 9.66 (br s, 1 H), 8.73 (s, 1 H), 7.33 (bs, 1 H), 7.21 (s, 1 H), 6.81 (s, 1 H), 4.54 (bd, J=6.4 Hz, 1 H), 4.29 (m, 2 H), 3.32 (m, 1 H), 3.14 (m, 1 H), 1.29 (m, 3 H), 0.73 (s, 9 H).

EXAMPLE 90: 6-(Tert-butyl)—2-0x0-6,7,11,12-tetrahydr0-2H,10H-[1,4]di0xepin0[2,3- O | | C N g] pyrido[2,1-a]isoquinoline—3-carb0xylic acid o t-Bu To a mixture of ethyl 6-(tert-butyl)-9,10-dihydroxyoxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinolinecarboxylate (500 mg, 1.4 mmol) and K2C03 (680 mg, 4.9 mmol) in EtOH (20 mL) was added 1,3-dibromopropane (0.28 mL, 2.80 mmol). The e was stirred at 100 0C for 12 hr. The reaction mixture was concentrated under vacuum. To the residue was added H20 (80 mL) and extracted with and CHzClz (500 mL). The pH was adjusted to 1 with 1N HCl. The organic phase was washed sat. aqueous brine on (2x100 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford ethyl t-butyl)oxo-6,7,11,12-tetrahydro- 2H,10H-[1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylate as brown solid that was used in the next step without further ation in the next step (600 mg, >100% yield, m/z: 398 [M+H]+ observed).

To a mixture of crude ethyl 6-(tert-butyl)oxo-6,7,11,12-tetrahydro-2H,10H-[1,4]dioxepino [2,3-g]pyrido[2,1-a]isoquinolinecarboxylate and t-butyl)oxo-6,7,11,12-tetrahydro- 2H,10H-[1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylic acid (516.6 mg) in a -l75- mixture of H20 (10 mL) and THF (10 mL) was added LiOH.HzO (200. mg, 4.8 mmol). The mixture was stirred at rt for 12 hrs. The pH of the reaction mixture was adjusted to 1 using aqueous HCl (2N) at 0 oC. The e was extracted with CHzClz (3x100 mL). The combined organic phase was washed with saturated aqueous brine solution (2x60 mL), dried over sodium sulfate, filtered and concentrated under . The residue was purified by normal phase Si02 chromatography (0% to 10% MeOH/CHzClz) and further recrystallized from toluene/EtOH (1:1, 2 mL) to furnish 6-(tert-butyl)oxo-6,7,11,12-tetrahydro-2H,10H-[1,4]dioxepino[2,3- do[2,1-a]isoquinolinecarboxylic acid as a white solid (90 mg, 17% yield, m/z: 370 [M+H]+ observed). 1H NMR (400 MHz, 6): 5 8.71 (s, 1 H), 7.64 (s, 1 H), 7.29 (s, 1 H), 7.03 (s, 1 H), 4.57 (d, J: 5.6 Hz, 1 H), 4.32—4.09 (m, 4 H), 3.36-3.21 (m, 2 H), 2.19—2.09 (m, 2 H), 0.71 (s, 9 H).

EXAMPLE 91: 6-(Tert-butyl)—2-0x0-6,7,11,12-tetrahydr0-2H,10H-[1,4]dioxepino[2,3- O I I C N g]pyrido[2,1-a]isoquinolinecarb0xylic acid (single enantiomer I) 0 H3“ EXAMPLE 92: 6-(Tert-butyl)—2-0x0-6,7,11,12-tetrahydr0-2H,10H-[1,4]dioxepino[2,3- o I I C N g]pyrido[2,1-a]isoquinolinecarb0xylic acid (single enantiomer II) o t—Bu 45 mg of the mixture of enantiomers was separated by SFC (supercritical fluid chromatography) on an OD column using 40% CH3CN to give 6-(tert-butyl)oxo-6,7,11,12-tetrahydro-2H,10H- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylic acid (single enantiomer I) as a white solid r eluting enantiomer, 10.1 mg, 22%, m/z: 370 [M+H]+ observed) and 6-(tert- butyl)oxo-6,7,11,12-tetrahydro-2H,10H-[1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline carboxylic acid (single enantiomer II)as a white solid r eluting enantiomer, 10.4 mg, 22%, m/z: 370 [M+H]+ observed).

Example 91: 6-(Tert-butyl)—2-0x0-6,7,11,12-tetrahydr0-2H,10H—[1,4]dioxepino[2,3- g]pyrido[2,1-a]isoquinolinecarb0xylic acid (single enantiomer I). m/z: 370 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6): 8 8.71 (s, 1 H), 7.64 (s, 1 H), 7.29 (s, 1 H), 7.03 (s, 1 H), 4.57 (d, J: 5.6 Hz, 1 H), 4.32-4.09 (m, 4 H), 3.36-3.21 (m, 2 H), 2.19-2.09 (m, 2 H), 0.71 (s, 9 H).

Example 92: 6-(Tert-butyl)—2-0x0-6,7,11,12-tetrahydr0-2H,10H—[1,4]di0xepin0[2,3- g]pyrido[2,1-a]isoquinolinecarb0xylic acid (single enantiomer II). m/z: 370 [M+H]+ observed). 1HNMR (400 MHz, DMSO-d6): 6 8.71 (s, 1 H), 7.64 (s, 1 H), 7.29 (s, 1 H), 7.03 (s, 1 H), 4.57 (d, J: 5.6 Hz, 1 H), 4.32-4.09 (m, 4 H), 3.36-3.21 (m, 2 H), 2.19-2.09 (m, 2 H), 0.71 (s, 9 H).

The following examples were prepared in a r manner as (R)(tert-buty1)—2-oxo-6,7,11,12- tetrahydro-2H,1OH-[1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxy1ic acid and (5)6- (tert-buty1)oxo-6,7, 1 1,12-tetrahydro-2H,10H-[1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline- 3-carboxylic acid from ethyl 6-(tert-buty1)-9,10-dihydroxyoxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinolinecarboxy1ate and an appropriate di-bromide, di-mesylate or di-chloride.

EXAMPLE 93: 6'-(Tert-butyl)—2'-0x0-6',7'-dihydr0-2'H,10'H,12'H-spir0[oxetane—3,11'- o o O | | [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline]-3'-carb0xylic acid m/z: 412 [M+H]+ observed . 1H NMR (400 MHz, 6): 8.71 (s, 1 H), 7.66 (s, 1 H), 7.32— 7.27 (m, 1 H), 7.06 (s, 1 H), .33 (m, 9 H), 3.29 (m, 1 H), 3.28-3.20 (m, 1 H), 0.70 (s, 9 H).

EXAMPLE 94: 6'-(Tert-butyl)—2'-0x0-6',7'-dihydr0-2'H,10'H,12'H-spir0[oxetane—3,11'- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline]-3'-carb0xylic acid single enantiomer I 0 || 00C N EXAMPLE 95: 6'-(Tert-butyl)—2'-0x0-6',7'-dihydr0-2'H,10'H,12'H-spir0[oxetane—3,11'- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline]-3'-carb0xylic acid (single enantiomer II) 0 || 0% N 174 mg of the mixture of enantiomers was separated by SFC (supercritical fluid chromatography) on an OD-3 column using 40% EtOH (0.1% aq. NH3) to give 6'-(tert-butyl)-2'- oxo-6',7'-dihydro-2'H,10'H,12'H-spiro[oxetane-3,1 1'-[1,4]dioxepino[2,3-g]pyrido[2,1- a]isoquinoline]—3'-carboxylic acid (single enantiomer I) as an yellow solid (faster eluting enantiomer, 37 mg, 21%, m/z: 412 [M+H]+ observed) and 6'-(tert-butyl)-2'-oxo-6',7'-dihydro- 2'H,10'H,12'H-spiro[oxetane-3,11'-[1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline]-3'-carboxylic acid (single enantiomer II) as an off-white solid (slower eluting enantiomer, 20 mg, 11%, m/z: 412 [M+H]+ observed). e 94: 6'-(Tert-butyl)—2'-0x0-6',7'-dihydr0-2'H,10'H,12'H-spir0[oxetane—3,11'- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline]-3'-carboxylic acid (single enantiomer I). m/z: 412 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6): 8.71 (s, 1 H), 7.66 (s, 1 H), 7.32- 7.27 (m, 1 H), 7.06 (s, 1 H), 4.59-4.33 (m, 9 H), 3.29 (m, 1 H), 3.28-3.20 (m, 1 H), 0.70 (s, 9 H).

Example 95: 6'-(Tert-butyl)—2'-0x0-6',7'-dihydr0-2'H,10'H,12'H-spir0[oxetane—3,11'- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline]-3'-carb0xylic acid (single enantiomer II). m/z: 412 [M+H]+ observed). 1H NMR (400 MHz, 6): 8.71 (s, 1 H), 7.66 (s, 1 H), 7.32- 7.27 (m, 1 H), 7.06 (s, 1 H), 4.59-4.33 (m, 9 H), 3.29 (m, 1 H), 3.28-3.20 (m, 1 H), 0.70 (s, 9 H).

EXAMPLE 96: 6-(Tert-butyl)—11-(methoxymethyl)—2-0x0-6,7,11,12-tetrahydr0-2H,10H- ioxepino[2,3-g]pyrido[2,1-a]isoquinoline—3-carb0xylic acid 0 O O I I /—< N m/z: 414 [M+H]+ ed . 1H NMR (400 MHz, CDCl3): 5 8.44 (s, 1H), 7.28 (s, 1H), 7.01 (s, 1H), 6.80 (s, 1H), 4.38~4.16 (m, 4H), 4.00~3.98 (m, 1H), 3.52~3.47 (m, 2H), 3.38 (s, 3H), 3.38~3.30 (m, 1H), 3.17~3.13 (m, 1H), 2.62~2.60 (m, 1H), 0.81 (s, 9H). -l78- EXAMPLE 97: 6-(Tert-butyl)—11-(2-methoxyethoxy)—2-0x0-6,7,11,12-tetrahydr0-2H,10H- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline—3-carb0xylic acid 0 O O | | o~< N / O m/z: 444 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.73-8.66 (m, 1 H), 7.63-7.57 (m, 1 H), 7.32—7.27 (m, 1 H), 7.02-6.96 (m, 1 H), 4.52-4.58 (m, 1 H) 4.43—4.01 (m, 4 H), 3.63- 3.71 (m, 2 H), 3.59 (bs, 1 H), 3.46 (m, 2 H), 3.30—3.19 (m, 5 H), 0.72 (s, 9 H).

EXAMPLE 98: 6-(Tert-butyl)—11-methylene0x0-6,7,11,12-tetrahydr0-2H,10H- :< N [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline—3-carb0xylic acid m/z: 382 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.70 (s, 1 H), 7.64 (s, 1 H), 7.30 (s, 1 H), 7.01 (s, 1 H), 5.20 (bd, J=14.0 Hz, 2 H), 4.90-4.72 (m, 4H), 4.56 (bd, J=5.6 Hz, 1 H), 3.30 (bs, 1 H), 3.27-3.20 (m, 1 H), 0.72 (s, 9 H).

E 99: 6-(Tert-butyl)—1 1,1 1-bis(meth0xymethyl)—2—0x0-6,7,1 1,12-tetrahydr0- 2H,10H- [1,4] dioxepino [2,3—g] pyrido ]is0quin01ine—3-carb0xylic O O o | | MeOMeO:><O m/z: 458 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 5 8.68 (s, 1H), 7.59 (s, 1H), 7.26 (s, 1H), 6.99 (s, 1H), 4.55-4.53 (d, 1H), .00 (m, 4H), 3.39-3.37 (d, 4H), 3.26 (s, 6H), 3.24 (s, 1H), 3.22 (s, 1H), 0.69 (s, 9H).

EXAMPLE 100: 6-(Tert-butyl)—1-methyl0x0-6,7,11,12-tetrahydr0-2H,10H- WO 85619 C N [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline—3-carb0xylic acid m/z: 384 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6): 8 8.68 (s, 1 H), 7.39 (s, 1 H), 7.10 (s, 1H), 4.59—4.53 (m, 1 H), 4.32—4.15 (m, 4 H), 3.26-3.14 (m, 2 H), 2.32 (s, 3 H), 2.20—2.15 (m, 2 H), 0.66 (s, 9 H).

EXAMPLE 101: 6-(Tert-butyl)—3-(hydr0xymethyl)methylene-6,7,11,12-tetrahydr0- O I I :< N 2H,10H-[1,4]dioxepino[2,3-g]pyrido[2,1-a]is0quinolin0ne O t-Bu Methyl 6-(tert-buljyl)methylene—2—0x0—6, 7,11,12-tetrahydr0—2H, 1 0H-[1,4]di0xepin0[2,3— COzMe O I I :< N g]pyrid0[2,1-a]is0quinolinecarb0xylate o t-Bu To a suspension of 6-(tert-butyl)-1 1-methyleneoxo-6,7,1 1,12-tetrahydro-2H,10H- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylic acid (1.3 g, 3.30 mmol) and thane (1.0 mL, 16 mmol) in CH3CN (80 mL) was added potassium carbonate (800 mg, .8 mmol). The mixture was d at rt for 12 hr. Then, additional CH3CN (50 mL) and iodomethane (1.0 mL, 16 mmol) were added and the mixture was stirred at rt for another 12 hr.

The mixture was d through Celite® and the filtrate was concentrated under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 10% MeOH/CHzClz) to afford methyl 6-(tert-butyl)methyleneoxo-6,7,11,12-tetrahydro-2H,10H- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylate as a yellow solid (1.2 g, 92% yield, m/z: 396 [M+H]+ observed). 6—(Tert-buljyl)(hydroxymethyD-l1-methylene—6, 7,11,12—tetrahydr0—2H,1 0H- [1,4]di0xepin0[2,3-g]pyrid0[2,1-alis0quinolin0ne 0 “3” To a solution of methyl 6-(tert-butyl)methyleneoxo-6,7,11,12-tetrahydro-2H,10H-[1,4] dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylate (100 mg, 0.25 mmol) in THF (5 mL) was added H202 (30 wt% in H20, 0.07 mL, 0.76 mmol) at 0 oC. The mixture was stirred at rt for 2 hr. Borane tetrahydrofuran complex solution (1 M in THF, 0.3 mL, 0.3 mmol) and aqueous NaOH solution (2.5 M, 0.3 mL, 0.76 mmol) were added at 0 oC. The mixture was stirred at rt for hrs. H20 (2 mL) was added to quench the reaction. CHzClz (30 mL) and H20 (10 mL) were added. The pH was adjusted to 3 with 1N HCl (0.5 mL). The mixture was separated and the c phase was washed a sat. aqueous sodium sulfite solution (15 mL), sat. aqueous brine on (2x15 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-TLC (10% MeOH/CHzClz) to afford 6-(tert-butyl)(hydroxy methyl)-1 1-methylene-6,7, 1 1,12-tetrahydro-2H,10H-[1,4]dioxepino[2,3-g]pyrido[2,1-a] nolinone as a light yellow solid (20 mg, 21% yield, m/z: 368 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 8.02 (s, 1 H), 7.43 (s, 1 H), 7.04-6.98 (m, 2 H), 5.21 (d, J=12.8 Hz, 2 H), 4.89-4.74 (m, 4 H), 4.51—4.39 (m, 3 H), 3.26 (br s, 1 H), 3.223 18 (m, 1 H), 0.73 (s, 9 EXAMPLE 102: 6-(Tert-butyl)—11-meth0xy0x0-6,7,11,12-tetrahydr0-2H,10H- Meo~< N [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarb0xylic acid Ethyl 6-(tert-buljyl)—2—0x0—11-((tetrahydro—ZH—pyranyl)0xy)-6, 7,11,12-tetrahydr0—2H, 1 0H- COgEt THPO{ N [1,4]di0xepin0[2,3-g]pyrid0[2,1-a]is0quinoline—3-carb0xylate To a solution of ethyl 6-(tert-butyl)-9,10-dihydroxyoxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinolinecarboxylate (800 mg, 2.2 mmol) in DMF (15 mL) was added K2C03 (1.24 g, 8.96 mmol), then the mixture was heated to 100 0C. To this mixture was added a solution of 2- omochloropropanyl)oxy)tetrahydro-2H-pyran red according to the procedure by rnann, el al., 2007, Helv. Chim. Acta 90: 1006) (803 mg, 3.14 mmol) in DMF (1mL) drop-wise. The mixture was stirred at 120 0C for 12 hrs. The mixture was poured into ice water (60 mL) and diluted with CHzClz (300 mL). The pH was adjusted to 6 with sat. aqueous 1N HCl (12 mL). The mixture was separated and the organic phase was washed with sat. aqueous brine solution (2x50 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 10% MeOH/CHzClz) to afford ethyl 6-(tert-butyl)oxo((tetrahydro-2H-pyranyl)oxy)-6,7,11,12-tetrahydro- 2H,10H-[1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylate as a brown solid (790 mg, 71% yield, m/z: 498 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 5 8.20-8.14 (m, 1 H), 7.27— 7.20 (m, 1 H), 6.91-6.82 (m, 1 H), 6.80-6.71 (m, 1 H), 4.92—4.71 (m, 1 H), .24 (m, 8 H), .80 (m, 3 H), 3.57 (bs, 1 H), 3.40—3.25 (m, 1 H), 3.10 (bd, J=16.8 Hz, 1 H), 1.85 (m, 2 H), 1.75 (m, 3 H), 1.65 (m, 2 H), 0.80 (br s, 9 H).

Ethyl 6-(tert-buljyl)hydr0xy—2—0x0—6, 7,11,12-tetrahydr0—2H, 1 0H-[1,4]di0xepin0[2,3- g]pyrid0[2,1-a]is0quinoline—3-carb0xylate; 6—(tert-buljyl)hydr0xy—2—0x0—6, 7,11, 12- tetrahydr0-2H,1 0H-[1,4]di0xepin0[2,3-g]pyrid0[2,1-a]is0quinolinecarb0xylic acid 0 O COzEt COzH O | | o | | HO{ N HO{ N 0 t-Bu o A on of ethyl 6-(tert-butyl)oxo((tetrahydro-2H-pyranyl)oxy)-6,7,11,12- tetrahydro-2H,10H-[1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylate (440 mg, 0.88 mmol) in aqueous HCl (1 N, 4.40 mL, 4.4 mmol) and THF (15 mL) was stirred at rt for 12 hrs.

The mixture was diluted with CHzClz (80 mL) and H20 (20 mL). The mixture was separated and the organic phase was washed H20 (40 mL), sat. aqueous brine solution (2x40 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give a mixture of ethyl t-butyl)- 1 1-hydroxyoxo-6,7, 1 1,12-tetrahydro-2H,10H-[1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline- 3-carboxylate and 6-(tert-butyl)hydroxyoxo-6,7,11,12-tetrahydro-2H,10H- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylic acid as a yellow solid used in the next step without further purification (351 mg, 96% yield, m/z: 414 [M+H]+ observed).

Methyl 6-(tert-buljyl)meth0xy-2—0x0—6, 7,11,12—tetrahydr0—2H,1 0H-[1,4]di0xepin0[2,3- 002Me O | | Me0{ N g]pyrido[Z,1-a]is0quinolinecarb0xylate o t—Bu To a solution of ethyl 6-(tert-butyl)-1 1-hydroxyoxo-6,7,1 1,12-tetrahydro-2H,1OH- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylate and 6-(tert-butyl)—11-hydroxy oxo-6,7, 1 1,12-tetrahydro-2H,1OH-[l,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylic acid (300 mg) in DMF (4 mL) at 0 CC was added NaH (60% in mineral oil, 100 mg, 2.5 mmol).

The ice bath was removed and the mixture was stirred at rt for 1hr. Iodomethane (0.3 mL, 4.82 mmol) was added and the mixture was d at rt for 12 hrs. The mixture was cooled to 0 OC and aqueous HCl (1N, 0.5 mL) was added to quench the reaction. The mixture was concentrated under vacuum. The residue was purified by preparative TLC to give methyl 6-(tert-butyl)—1 1- methoxyoxo-6,7, 1 etrahydro-2H,1OH-[1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline carboxylate as a yellow solid (170 mg, 57% yield, m/z: 414 [M+H]+ observed). 6—(Tert-buleD-l1-meth0xy—2-0x0—6, 7,11,12-tetrahydr0—2H,1 0H-[1,4]di0xepin0[2,3- O | | Me0{ N g]pyrid0[2,1-a]is0quinoline—3-carb0xylic acid o t-Bu A solution of methyl 6-(tert-butyl)-1 1-methoxyoxo-6,7,1 1,12-tetrahydro-2H,1OH- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylate (170 mg, 0.411 mmol) in H20 (2 mL) and THF (1 mL) was added lithium hydroxide drate (86 mg, 2.06 mmol). The mixture was d at rt for 12 hrs. The mixture was cooled to 0 OC and aqueous HCl (1N, 2 mL) was added to adjust the pH to 1. The resulting precipitate was collected by filtration to give 127 mg of crude product. The crude solid was recrystallized from e:EtOH (1.2 mL:1 mL) to 2O afford 6-(tert-butyl)-1 1-methoxyoxo-6,7,1 1,12-tetrahydro-2H,10H-[1,4]dioxepino[2,3- g]pyrido[2,1-a]isoquinolinecarboxylic acid as a white solid (38 mg, 23% yield, m/z: 400 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 8.70 (s, 1 H), 7.61 (s, 1 H), 7.30 (bs, 1 H), 7.01 (s, 1 H), 4.56 (bd, J=5.2 Hz, 1 H), .13 (m, 4 H) 3.95-3.85 (m, 1 H), 3.34 (d, J=10.4 Hz, 3 H), 3.29 (bd, J=6.8 Hz, 1 H), 3.26-3.19 (m, 1 H), 0.71 (s, 9 H).

EXAMPLE 103: 6-(Tert—butyl)—11-hydr0xy0x0-6,7,11,12-tetrahydr0-2H,10H- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinoline—3-carb0xylic acid o | | HO{ N o t—Bu A solution of ethyl 6-(tert-butyl)hydroxyoxo-6,7,11,12-tetrahydro-2H,10H- [1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylate and t-butyl)hydroxy oxo-6,7, 1 1,12-tetrahydro-2H,10H-[1,4]dioxepino[2,3-g]pyrido[2,1-a]isoquinolinecarboxylic acid (600 mg, 1.45 mmol) in THF (6 mL) and H20 (10 mL) was added lithium hydroxide drate (305 mg, 7.26 mmol). The mixture was stirred at rt for 16 hrs. The mixture was cooled to 0 oC and aqueous 1N HCl was added to adjust the pH to 3. The mixture was extracted with CHzClz (100 mL) and the organic phase was washed with sat. s brine solution (2x20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by normal phase Si02 chromatography (0% to 20% MeOH/CHzClz) to afford 6-(tert- butyl)-1 oxyoxo-6,7,1 1,12-tetrahydro-2H,10H-[1,4]dioxepino[2,3 -g]pyrido[2,1- a]isoquinolinecarboxylic acid as a yellow solid (96 mg, 17% yield, m/z: 386 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 8.70 (s, 1 H), 7.61 (s, 1 H), 7.29 (s, 1 H), 7.00 (s, 1 H), 4.57—4.55 (m, 1 H), 4.44—4.25 (m, 2 H), 4.20—4.11 (m, 1 H), 4.09—3.95 (m, 2 H), 3.35-3.28 (m, 1 H), 3.27-3.18 (m, 1 H), 0.71 (m, 9 H).

EXAMPLE 104: 2-Chlor0is0pr0pylmethoxy0x0-6,7-dihydr0-11H-dipyrid0[1,2- d:3',2'-f] [1,4]oxazepine—lO-carboxylic acid Ethyl -dichlor0—6—meth0xypyridin—3—yl)—4-0x0-4H-pyran-3—carboxylate To a solution of LiHMDS (1M solution in THF, 22.6 mL, 24 mmol) in dry THF (30 ml) at -78 oC (dry ice/acetone bath) under argon, a solution of ethyl (@((dimethylamino) methylene) anoate (1.85 g, 10 mmol) and 2,5-dichloromethoxynicotinoyl chloride (2.4 g, 10 mmol, prepared from 2,5,6-trichloronicotinic acid by the methods in W02008130527 and W02010146351) in 50 mL THF was added dropwise over 10 min. The dry ice/acetone bath was removed and the solution warmed to rt over a 30 min. Diethyl ether (100 mL) was added to the reaction mixture followed by aqueous HCl (3N, 30 ml, 90 mmol) and the contents were stirred overnight. The organic solvents were removed under vacuum keep the bath ature below oC and the solids were treated with sat. aqueous sodium bicarbonate solution until to adjust the pH to 7-8 and stirred vigorously for 10 min. The precipitate was filtered, washed with H20 (25 mL), dissolved in CHzClz (50 mL), dried over sodium sulfate and concentrated under vacuum to give dark orange residue (6.5 g). The residue was purified by normal phase Si02 chromatography (10% to 100% EtOAc/hexanes), followed by recrystallization from methanol (20 mL) afforded ethyl -dichloromethoxypyridinyl)oxo-4H-pyrancarboxylate as a white solid (0.76 g, 20% yield, m/z: 344 [M+H]+ ed). 1H NMR (300 MHz, CDC13) 8 8.56 (s, 1H), 7.85 (d, J=1.5 Hz, 1H), 6.87 (d, J=1.5 Hz, 1H), 4.43—4.35 (m, 2H), 4.11 (s, 3H), .37 (m, 3H).

Ethyl 2 ',5 '-dichlor0(1-hydr0xy-3—methylbutanyl)-6 '-meth0xy0x0—1,4-dihydr0—[2,3 '- MeO N CI bipyridinelcarb0xylate OH To a mixture of ethyl 6-(2,5-dichloromethoxypyridin-3 -yl)oxo-4H-pyrancarboxylate ( 138 mg, 0.402 mmol) in AcOH/EtOH (2:3, 10 mL) was added DL-valinol (62 mg, 0.6 mmol).

The reaction was heated at 100 0C for 8 h. The reaction mixture was concentrated under vacuum and the residue was purified by normal phase SiOz tography (0% to 10% MeOH/CHzClz) to afford ethyl 2',5'-dichloro(1-hydroxy-3 -methylbutanyl)-6'-methoxyoxo-1,4-dihydro- [2,3'-bipyridine]carboxylate as a white foam (100 mg, 58% yield, m/z: 429 [M+H]+ observed). 1H NMR (300 MHz, CDCl3) 8 8.70 (s, 1H), 7.49 (s, 1H), 6.26 (s, 1H), 4.40-4.25 (m, 2H), 4.15 (s, 3H), .95 (m, 2H), 3.25 (m, 1H), 2.45 (m, 1H), 1.37 (m, 3H) and 1.05-0.85 (m, 2—Chloro- 7-is0pr0pyl-3—meth0xy—11-0x0-6, 7-dihydr0—11H—dipyrid0[1,2-d.°3 ',2 '- f][1,4]0xazepinecarb0xylic acid To a solution of ethyl 2',5'-dichloro-l-(l-hydroxymethylbutanyl)-6'-methoxyoxo-l,4- dihydro-[2,3'-bipyridine]carboxylate (86 mg, 0.2 mmol) in anhydrous THF (10 mL) at 0 CC was added sodium hydride (60% in mineral oil, 9 mg, 0.4 mmol). The on mixture was stirred at room temperature for 30 min and then refluxed for 4 h. The organic solvent was removed under reduced pressure and the reaction e was lized with aqueous HCl (IN, mL), ted with ethyl acetate (2 x 10 mL), washed with H20, dried over sodium sulfate and trated under vacuum. The residue was purified by reverse phase HPLC to afford 2-chloro— 7-isopropyl-3 -methoxy-l l-oxo-6,7-dihydro-l lH-dipyrido[l,2-d:3',2'—f][l,4]oxazepine carboxylic acid as white solid (25 mg, 34% yield, m/z: 365 [M+H]+ observed). 1H NMR (300 MHz, DMSO-d6) 5 8.54 (s, 1H), 7.45 (s, 1H), 6.94 (s ,1H), 5.53—5.43 (m, 2H), 4.08 (s, 3H), 4.04— 3.98 (m, 1H), 2.05 (m, 1H) and 1.05—0.95 (m, 6H).

EXAMPLE 105: Diethyl (6—(tert-butyl)—10-chl0r0(3-meth0xypr0p0xy)—2-0x0-6,7- 0 (I? | | OEt MeO/\/\O dihydro-ZH-pyrido [2,1-a] nolinyl)ph0sph0nate 2—(3-(Tert—buleD- 7-chl0r0(3-meth0xypr0p0xy)—1,2,3,4-tetrahydr0is0quinolinyl)acetic A mixture of 3-(tert-butyl)chloro(3-methoxypropoxy)-3,4-dihydroisoquinoline (3.5 g, 11 mmol, prepared according to the procedure in WO20151 13990Al) and malonic acid (1.18 g, 11.3 mmol) was heated at 120°C for 30 min. The reaction mixture was cooled to rt, diluted with CHzClz (50 mL) and washed with H20 (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuum to obtain crude 2-(3 -(tert-butyl)chloro(3- methoxypropoxy)-1 2 3 4-tetrahydroisoquinolinyl)acetic acid as a brown solid that was used7 7 7 without further purification (2.0 g, 48% yield, m/z: 370 [M+H]+ observed).

Methyl 2-(3-(tert-butyl)— 7-chl0r0(3-meth0xypr0p0xy)—1,2,3,4-tetrahydroisoquinolin-I- MeO/\/\O yl)acetate To a stirred on of 2-(3 -(tert-butyl)chloro(3 -methoxypropoxy)-1,2,3,4- tetrahydroisoquinolin-l-yl)acetic acid (2.0 g, 5.4 mmol) in MeOH (20 mL) at 0 0C was added conc. sulfuric acid (2 mL) and stirred at 70°C for 16h. The reaction mixture was evaporated in vacuum and basified using aqueous ammonium ide solution to adjust the pH to 8-9. The mixture was extracted with EtOAc (3 x 25 mL). The combined organic phase was dried over anhydrous sodium sulfate and evaporated in vacuum. The residue was purified by normal phase SiOz chromatography (5% to 15% hexanes) to afford methyl 2-(3-(tert-butyl)chloro (3-methoxypropoxy)-1,2,3,4-tetrahydroisoquinolinyl)acetate as a brown solid (1 g, 48% yield, m/z: 384 [M+H]+ observed).

Diethyl (3-(3-(tert-butyl)- 7-chl0r0(3-meth0xypr0p0xy)-1,2,3, 4-tetrahydr0is0quinolin-I-yl)- 0 93,03 Meo/\/\o 2—0x0pr0pyl)ph0sph0nate To a stirred solution of diethyl methylphosphonate (0.11 mL, 0.782 mmol) in dry THF (2 mL) was added n-BuLi (2.5 M in hexanes, 0.3 mL, 0.756 mmol) at -78°C (dry ice/acetone bath) and the mixture was stirred for 30 min. Then methyl tert-butyl)chloro(3- methoxypropoxy)-1,2,3,4-tetrahydroisoquinolinyl)acetate (0.1 g, 0.27 mmol) in THF (0.5 mL) was added to the reaction mixture and stirred at -78°C for 15 min. The temperature was raised to rt over 2 h. The reaction mixture was diluted with H20 (5 mL) and extracted in EtOAc (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated in vacuum to obtain crude diethyl (3-(3-(tert-butyl)chloro(3 xypropoxy)-1,2,3,4- tetrahydroisoquinolin-l-yl)oxopropyl)phosphonate as a brown gum that was used without r purification (115 mg, 88% yield, m/z: 504 [M+H]+ observed).

Diethyl (4-(3-(tert-buleD- 7-chl0r0(3-meth0xypr0p0xy)-1,2,3,4-tetrahydr0is0quinolin-I-yl)- MeO/\/\O 1-(dimethylamino)0x0butenyl)ph0sph0nate To a stirred solution of diethyl (3 -(3-(tert-butyl)chloro(3-methoxypropoxy)-1,2,3,4- tetrahydroisoquinolin-l-yl)—2-oxopropyl)phosphonate (0.31 g, 0.62 mmol) in toluene (1.5 mL) at rt was added N,N—dimethylformamide dimethyl acetal (0.12 mL, 0.924 mmol) and the reaction mixture was stirred at 100°C for 12 h. The reaction mixture was evaporated in vacuum to obtain crude diethyl (4-(3 -(tert-butyl)chloro(3 xypropoxy)-1,2,3,4-tetrahydroisoquinolin yl)(dimethylamino)oxobut-l-enyl)phosphonate as a brown gum that was used without further purification (0.3 g, 72% yield, m/z: 559 [M+H]+ observed).

Diethyl (6-(tert-buljyl)—1 0-chl0r0(3-meth0xypr0p0xy)0x0-1, 6, 7,11b-tetrahydr0—2H- 0 (I? F|’—OEt | OEt MeoMo pyrid0[2,1-a]is0quinolin—3-yl)ph0sph0nate A solution of diethyl (4-(3 -(tert-butyl)chloro(3 -methoxypropoxy)-1,2,3,4- tetrahydroisoquinolinyl)-1 -(dimethylamino)-3 tenyl)phosphonate (0.29 g, 0.52 mmol) in MeOH (3 mL) was stirred at rt for 16 h. The reaction was evaporated in vacuum to obtain crude diethyl (6-(tert-butyl)chloro(3-methoxypropoxy)oxo-1,6,7, 1 1b- tetrahydro-2H-pyrido[2,1-a]isoquinolinyl)phosphonate as a brown gum that was used without further purification (190 mg, 71% yield, m/z: 514 [M+H]+ observed).

Diethyl rt-buljyl)—1 0-chl0r0(3-meth0xypr0p0xy)0x0-6, 7-dihydr0-2H-pyrid0[2,1- 0 ll F|’—OEt | | OEt MeO/\/\O alisoquinolinyl)ph0sph0nate To a d solution of l (6-(tert-butyl)chloro(3-methoxypropoxy)oxo-1 6 7 11b- 7 7 7 tetrahydro-2H-pyrido[2,1-a]isoquinolinyl)phosphonate (0.14 g, 0.27 mmol) in DME (2 mL) at rt was added p-chloranil (0.134 g, 0.545 mmol) and the reaction mixture was stirred at 85°C for 2h. The reaction was ated in vacuum. The residue was purified by reverse phase HPLC to afford diethyl (6-(tert-butyl)chloro(3 -methoxypropoxy)oxo-6,7-dihydro-2H- pyrido[2,1-a]isoquinolinyl)phosphonate as a grey solid (13 mg, 10% yield, m/z: 512 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 8.08 (d, J=13.2 Hz, 1H), 7.99 (s, 1H), 7.25 (s, 1H), 6.81 (d, 1H), 4.38 (s, 1H), 4.22—4.14 (m, 2H), 4.08- 4.01 (m, 4H), 3. 51 (t, J=6 Hz, 2H), 3.33 (s, 2H), 3.26 (s, 3H), 2.01 (t, J=6 Hz, 2H), 1.24 (t, J=7.2 Hz, 6H), 0.72 (s, 9H).

EXAMPLE 106: Ethyl en (6-(tert-butyl)—10-chl0r0(3-meth0xypr0p0xy)—2-0X0- 0 PI I'D—OEt | | OH MeO/\/\O 6,7-dihydro-2H-pyrido[2,1-a]isoquinolinyl)ph0sph0nate To a stirred solution of diethyl (6-(tert-butyl)chloro(3 -methoxypropoxy)oxo-6,7- o-2H-pyrido[2,1-a]isoquinolinyl)phosphonate (0.15 g, 0.29 mmol) in CHzClz (4 mL) was added chlorotrimethylsilane (0.08ml, 0.6 mmol) at 0°C and stirred at rt for 16h. The reaction was evaporated in vacuum to obtain crude. The residue was purified by reverse phase HPLC to afford ethyl hydrogen (6-(tert-butyl)chloro(3 xypropoxy)oxo-6,7-dihydro-2H- pyrido[2,1-a]isoquinolinyl)phosphonate as a brown solid (20 mg, 15% yield, m/z: 484 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 .14 (d, J=11.6 Hz, 1H), 8.00 (s, 1H), 7.26 (s, 1H), 6.96 (s, 1H), 4.38 (s, 1H), 4.19—4.15 (m, 2H), 3.70-3.67 (m, 3H), 3.53—3.50 (m, 2H), 3.33 (s, 3H), 2.04-1.98 (t, J=6.4 Hz, 2H), 1.24 (s, 1H), 1.09—1.05 (t, J=7.2 Hz, 3H), 0.72 (s, 9H).

EXAMPLE 107: (6-(Tert-butyl)—10-chlor0(3-meth0xypr0p0xy)—2-0x0—6,7-dihydr0-2H- O ‘3 I'D—OH | | OH MeO/\/\O pyrido[2,l-a]isoquinolinyl)phosphonic acid To a stirred solution of diethyl (6-(tert-butyl)chloro(3 -methoxypropoxy)oxo-6,7- dihydro-2H-pyrido[2,1-a]isoquinolinyl)phosphonate (0.250 g, 0.49 mmol) in CHzClz (10 mL) was added imethylsilane (0.35 mL, 2.44 mmol) at rt and the reaction was stirred for 6h.

The reaction was evaporated in vacuum. The residue was purified by e phase HPLC to afford (6-(tert-butyl)chloro—9-(3 -methoxypropoxy)oxo-6,7-dihydro-2H-pyrido[2,1- a]isoquinolin-3 -yl)phosphonic acid as an off-white solid (20 mg, 15% yield, m/z: 456 [M+H]+ ed). 1H NMR (400 MHz, 6) 5 8.23-8.19 (d, J=11.2 Hz, 1H), 7.98 (s, 1H), 7.26 (s, 1H), 6.96 (s, 1H), 4.39 (s, 1H), 4.24—4.12 (m, 2H), 3.52—3.49 (t, J=6 Hz, 2H), 3.31—3.25 (m, 5H), 2.02—1.99 (t, J=6 Hz, 2H), 0.70 (s, 9H).

EXAMPLE 108: (S)Isopropyl-Z-meth0xy(3-meth0xypr0p0xy)—9-(S-methyl-1,3,4- thiadiaz01yl)-5,6-dihydr0-10H-pyrid0 [1,2-h] [1,7]naphthyridin0ne o N’N MeO/\/\O (6S)—6-isopropylmethoxy-3 -(3 -methoxypropoxy)—10-oxo-5H,6H-pyrido[1,2-h]1,7- naphthyridinecarboxylic acid (60 mg, 0.15 mmol) was dissolved in CHzClz (2 mL) and stirred at 0 oC. Phosphorus pentachloride (38 mg, 0.18 mmol) was added and the mixture stirred at 0 0C for 15min. Acetohydrazide (22 mg, 0.30 mmol) in (1 mL) was added into the above solution dropwise and the on stirred at rt for 3h. The solvent was removed under vacuum. Lawesson reagent (30 mg, 0.07 mmol) was added, followed by 1,4-dioxane (4 mL). The reaction was heated to 100 0C for 1h. Additional Lawesson reagent (30 mg, 0.07 mmol) was added. The reaction was stirred at 100 0C for 3 days. The reaction mixture was concentrated under vacuum.

The residue was purified by reverse phase HPLC to afford 1-[1-(hydroxymethyl) cyclohexyl] oxo- pyridinecarboxylate, ed by normal phase SiOz chromatography (0% to 10% HzClz) to afford (6S)—6-isopropylmethoxy-3 -(3 -methoxypropoxy)(5-methyl-1,3,4- azolyl)—5H,6H-pyrido[1,2-h]1,7-naphthyridinone as a light yellow solid (3.1 mg, 5% yield, m/z: 457 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 5 8.73 (s, 1H), 7.59 (s, 1H), 6.91 (s, 1H), 4.14—4.09 (m, 2H), 4.08 (s 3.91 (dd, J=9.6, 5.4 Hz, 1H), 3.58 (td, J=6.0, 1.6 Hz, , 3H), 2H), 3.40 (dd, J=16.3, 5.7 Hz, 1H), 3.36 (s, 3H), 3.06 (dd, J=16.5, 1.5 Hz, 1H), 2.80 (s, 3H), 2.15 (p, J=6.2 Hz, 2H), 2.03—1.92 (m, 1H), 0.97 (d, J=6.7 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H).

EXAMPLE 109: (S)Isopropyl-Z-meth0xy(3-meth0xypr0p0xy)—9-(5-thi0x0-4,5- -l90- o-1H-1,2,4-triazolyl) ihydr0-10H-pyrid0[1,2-h] [1,7]naphthyridin0ne MeO/\/\O (6 S)isopropylmethoxy-3 -(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2-h]1,7- naphthyridinecarboxylic acid (60 mg, 0.15 mmol) was dissolved in CHzClz (2 mL) and the mixture was stirred at 0 oC. orus pentachloride (37 mg, 0.18 mmol) was added and reaction was d at 0 0C for 15min. Hydrazinecarbothioamide (19 mg 0.21 mmol) was added into the above solution, followed by CH3CN/THF mixture (1 :1, 2 mL) to solubilize the thiohydrazide. The reaction was stirred at room temperature for 2h. The solvent was removed under vacuum. Sodium hydroxide (30 mg 0.75 mmol) was added, followed by H20 (3 mL) and the reaction was d at 100 0C for 16h. The mixture was cooled to rt and 1N HCl was added to adjust the pH to 4-5. The aqueous solution was extracted with CHzClz (3x5 mL). The combined organic fractions were dried over sodium sulfate and trated under vacuum. The residue was purified by reverse phase HPLC to afford (6S)isopropylmethoxy-3 -(3- methoxypropoxy)(5-sulfanylidene-1,4-dihydro-1,2,4-triazol-3 -yl)-5H,6H-pyrido[1,2-h]1,7- naphthyridinone as a yellow solid (13 mg, 18% yield, m/z: 458 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 5 8.73 (s, 1H), 7.74 (s, 1H), 6.91 (s, 1H), 4.29 (s, 1H), 4.16 (s, 2H), 4.00 (s, 3H), 3.57—3.59 (m, 3H), 3.37 (s, 3H), 3.08 (d, J=16.6 Hz, 1H), 2.23-2.06 (m, 2H), 2.01-1.80 (m, 1H), 0.93 (d, J=6.6 Hz, 3H), 0.81 (dd, J=17.1, 6.7 Hz, 3H).

EXAMPLE 110: (S)Isopropyl-Z-methoxy(3-meth0xypr0p0xy)—9-(1,3,4-0xadiazol o N’N l O>\ MeO/\/\O yl)—5,6-dihydr0-10H-pyrid0 [1,2-h] aphthyridin0ne '( To a solution of (6S)isopropylmethoxy(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2- h]1,7-naphthyridinecarboxylic acid (60 mg, 0.15 mmol) in CHzClz (2 mL) at 0 0C was added phosphorus pentachloride (47 mg 0.22 mmol). The reaction was stirred for 10 minutes. A solution hydrazine monohydrate (11 mg, 0.22 mmol) in CHzClz (0.5 mL) was added to the -l9l- reaction se. The mixture was stirred for 2h. Check LCMS. The mixture was concentrated under vacuum. Trimethyl orthoformate (0.8 mL, 7.5 mmol) was added and the reaction was stirred at 135 0C for 16h. The solvent was removed under vacuum. The residue was d by reverse phase HPLC to afford (6S)—6-isopropylmethoxy(3 -methoxypropoxy) (1,3,4-oxadiazolyl)-5H,6H-pyrido[1,2-h]1,7-naphthyridinone as a yellow solid (5 mg, 8% yield, m/z: 427 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 5 8.56 (s, 1H), 8.48 (s, 1H), 7.78 (s, 1H), 6.91 (s, 1H), 4.18 (d, J=5.0 Hz, 2H), 4.07 (s, 3H), 3.94 (s, 1H), 3.58 (t, J=5.9 Hz, 2H), 3.43 (d, J=12.9 Hz, 1H), 3.36 (s, 3H), 3.08 (d, J=16.4 Hz, 1H), 2.24-2.08 (m, 2H), 1.99 (d, J=7.4 Hz, 1H), 0.98 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H).

E 111: (S)is0pr0pyl-Z-methoxy(3-meth0xyprop0xy)(3-methyl-1,2,4- oxadiaz01yl)-5,6-dihydr0-10H-pyrid0 [1,2-h] [1,7] naphthyridin-lO-one MGOMO To a solution of (6S)isopropylmethoxy(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2- h]1,7-naphthyridinecarboxylic acid (60 mg, 0.15 mmol) in CHzClz (3 mL) at 0 0C was added phosphorus pentachloride (37 mg, 0.18 mmol). The reaction was stirred at 0 0C for 15 minutes.

N-hydroxyethanimidamide (13 mg, 0.18 mmol) was added to the reaction, followed by THF (2 mL). The reaction was stirred at room temperature for 16h. The solvent was removed under vacuum and the crude mixture was re-dissolved in DMF (2 mL). The reaction was heated to 110 0C for 24h. The DMF was removed under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 5% MeOH/CHzClz) to afford (6S)—6-isopropylmethoxy(3- ypropoxy)(3 -methyl-1,2,4-oxadiazol-5 -yl)-5H,6H-pyrido[1,2-h]1,7-naphthyridin one as a white solid (13 mg, 19% yield, m/z: 441[M+H]+ ed). 1H NMR (400 MHz, CDCl3) 8.29 (s, 1H), 7.51 (s, 1H), 6.89 (s, 1H), 4.16 (td, J=6.5, 4.5 Hz, 2H), 4.04 (s, 3H), 3.82 (dd, J=9.4, 5.3 Hz, 1H), 3.57 (td, J=6.1, 1.6 Hz, 2H), 3.43—3.37 (m, 1H), 3.36 (s, 3H), 3.04 (dd, J=16.6, 1.5 Hz, 1H), 2.47 (s, 3H), 2.14 (p, J=6.3 Hz, 2H), 1.94 (dt, J=9.5, 6.7 Hz, 1H), 0.96 (d, J=6.7 Hz, 3H), 0.85 (d, J=6.7 Hz, 3H).

EXAMPLE 112: (S)Isopropyl-Z-methoxy(3-methoxyprop0xy)(3-phenyl-1,2,4- oxadiaz01yl)-5,6-dihydr0-10H-pyrid0 [1,2-h] [1,7]naphthyridin0ne MeO/\/\O To a solution of (6S)isopropylmethoxy(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2- h]1,7-naphthyridinecarboxylic acid (60 mg, 0.15 mmol) in CHzClz (3 mL) at 0 0C was added phosphorus pentachloride (37 mg, 0.18 mmol). The reaction was stirred at 0 0C for 15 s.

N-hydroxybenzenecarboximidamide (24 mg, 0.18 mmol) was added to the reaction, followed by THF (2 mL). The on was stirred at room temperature for 16h. The solvent was removed under vacuum and the crude mixture was solved in DMF (2 mL). The reaction was heated to 110 0C for 24h. The DMF was removed under vacuum. The residue was purified by e phase HPLC to afford (S)—6-isopropylmethoxy(3 xypropoxy)(3 -phenyl-1,2,4- oxadiazolyl)-5,6-dihydro-10H-pyrido[1,2-h][1,7]naphthyridinone as a white solid (4 mg, % yield, m/z: 503 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 5 8.70 (s, 1H), 8.10 (dd, J=7.9, 1.8 Hz, 2H), 7.99 (s, 1H), 7.53—7.42 (m, 3H), 6.93 (s, 1H), 4.18 (tt, J=6.6, 3.3 Hz, 3H), 4.04 (s, 3H), 3.66-3.52 (m, 3H), 3.38 (d, J=0.5 Hz, 3H), 3.13 (d, J=16.7 Hz, 1H), 2.15 (p, J=6.3 Hz, 2H), 2.07—1.95 (m, 1H), 1.01 (d, J=6.6 Hz, 3H), 0.87 (d, J=6.7 Hz, 3H).

EXAMPLE 113: (S)Isopropyl-Z-methoxy(3-meth0xypr0p0xy)0x0-5,10-dihydr0- Meo/\/\o 6H-pyrid0 [1,2-h] [1,7] naphthyridine—9-carb0nitrile To a solution of 6-isopropylmethoxy(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2-h]1,7- naphthyridinecarboxylic acid (20 mg, 0.05 mmol) in CHzClz (1 mL) at 0 0C was added phosphorus pentachloride (12 mg 0.06 mmol). The reaction was at 0 oC stirred for 15 minutes. um hydroxide (28-23% in H20, 0.02 mL, 0.15 mmol) was added to reaction and the mixture was stirred at rt for 2h. The solvent was removed under reduced pressure. The e was purified by normal phase Si02 chromatography (0% to 5% MeOH/CHzClz) to afford -l93- the crude amide. The amide was dissolved in a e of CH3CN/HZO (1:1, 5 mL). Palladium de (4.4 mg, 0.02 mmol) was added and the reaction was stirred at 50 0C for 24h. The solvent was removed under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 5% MeOH/CHzClz) to afford (S)isopropylmethoxy-3 -(3- methoxypropoxy)oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridinecarbonitrile as a white solid (2.3 mg, 12% yield, m/z: 384 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 5 7.88-7.74 (m, 1H), 7.40 (s, 1H), 6.89 (s, 1H), 4.15 (td, J=6.5, 4.6 Hz, 2H), 4.01 (s, 3H), 3.78 (dd, J=9.7, 4.8 Hz, 1H), 3.56 (td, J=6.1, 1.7 Hz, 2H), 3.45—3.37 (m, 1H), 3.35 (s, 3H), 3.03 (dd, , 1.6 Hz, 1H), 2.24—2.04 (m, 2H), 1.91 (dt, J=9.6, 6.7 Hz, 1H), 0.96 (d, J=6.7 Hz, 3H), 0.84 (d, J=6.7 Hz, 3H).

EXAMPLE 114: 6-(Tert-butyl)—10-chlor0(3-methoxypr0p0xy)—3-(5-0x0-4,S-dihydro-1H- o N\ 0 Y ,,N | | MeO/\/\O tetrazol-l-yl)—6,7-dihydr0-2H-pyrid0[2,1-a]is0quinolin0ne A stream of argon gas was bubbled through a solution of 6-(tert-butyl)chloro(3- methoxypropoxy)oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinolinecarboxylic acid (84 mg, 0.2 mmol, synthesized by the procedure described in the patent W020151 13990) in anhydrous CHzClz (5 mL) for 5 min. Triethylamine (0.42 mL, 3 mmol), followed by yl phosphoryl azide (0.3 mL, 1.5 mmol) were added and stirred at rt overnight. The reaction mixture was concentrated under vacuum. The residue was purified by reverse phase HPLC to afford 6-(tert- butyl)chloro(3 -methoxypropoxy)-3 -(5 -oxo-4, 5 -dihydro-1H-tetrazolyl)-6,7-dihydro- 2H-pyrido[2,1-a]isoquinolinone as a grey solid (20 mg, 22% yield, m/z: 460 [M+H]+ observed). 1H NMR (300 MHz, CDCl3) 5 8.82 (s, 1H), 8.05 (s, 1H), 7.73 (s, 1H), 7.41 (s, 1H), 6.80 (s, 1H), .15 (m, 2H), 4.05 (d, J=6.6 Hz, 1H), 3.64-3.59 (m, 2H), 3.49-3.42 (m, 1H), 3.37 (s, 3H), 3.24-3.18 (m, 1H), .09 (m, 2H), and 0.83 (bs, 9H).

EXAMPLE 115: (S)Isopropyl-Z-methoxy(3-methoxypropoxy)—9-(1H-tetrazolyl)- —194— Me0M0 ,6-dihydr0-10H-pyrid0 [1,2-h] [1,7]naphthyridin0ne To a solution of (6S)isopropylmethoxy(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2- h]1,7-naphthyridinecarboxylic acid (70 mg, 0.17 mmol) in CHzClz (3 mL) at 0 0C was added phosphorus pentachloride (43 mg, 0.21 mmol). The on was stirred at 0 0C for 15 minutes.

Ammonium ide (28-30% in H20, 0.07 mL, 0.52 mmol) was added to the reaction and the mixture was stirred at rt for 2h. The solvent was evaporated under vacuum.

The residue was purified by normal phase SiOz chromatography (0% to 5% HzClz) and concentrated under vacuum. The crude amide product was dissolved in CH3CN:H20 (1:1, 5 mL), followed by the addition of palladium chloride (15 mg, 0.09 mmol) and the reaction was stirred at 50 0C for 24h. The t was removed under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 5% MeOH/CHzClz) and concentrated under vacuum. The crude cyano product was dissolved in e (1 mL), followed by the on of sodium azide (113 mg 1.74 mmol) and triethylamine hydrochloride (239 mg, 1.74 mmol). The reaction was refluxed for 16h. The pH of the reaction was acidified with 1N HCl to 4-5. The on mixture was extracted with EtOAc (3x5 mL). The combined organic fractions were dried over sodium sulfate and concentrated under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 5% MeOH/CHzClz) to afford 6-isopropylmethoxy(3- methoxypropoxy)(1H-1,2,3,4-tetrazolyl)-5H,6H-pyrido[1,2-h]1,7-naphthyridinone as a light brown solid (17 mg, 23% yield, m/z: 427 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 5 8.69 (s, 1H), 7.60 (s, 1H), 6.92 (s, 1H), 4.24—4.09 (m, 2H), 4.07 (s, 3H), 3.97 (dd, J=9.5, 5.4 Hz, 1H), 3.58 (td, J=6.1, 1.3 Hz, 2H), 3.43 (dd, J=16.4, 5.6 Hz, 1H), 3.36 (s, 3H), 3.08 (dd, J=16.6, 1.5 Hz, 1H), 2.15 (p, J=6.3 Hz, 2H), .92 (m, 1H), 0.98 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.7 Hz, 3H).

EXAMPLE 116: (S)Isopropyl-Z-methoxy(3-methoxypropoxy)—9-(1H-1,2,4-triazol -l95- Meo/\/\o yl)—5,6-dihydr0-10H-pyrid0 [1,2-h] [1,7]naphthyridin0ne To a solution of -isopropylmethoxy(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2- naphthyridinecarboxylic acid (60 mg, 0.15 mmol) in CHzClz (3 mL) at 0 0C was added phosphorus pentachloride (37 mg, 0.18 mmol) and the reaction was stirred for 30 min.

Ammonium hydroxide (28-30% in H20, 0.07 mL, 0.52 mmol) was added and the reaction stirred at rt for overnight. H20 (5 mL) was added and the layers separated. The organic phase was dried over sodium e and concentrated under vacuum. The crude amide t was dissolved in N, thylformamide dimethyl acetal (1 mL) and stirred at 90 0C for 30min. The N, N- dimethylformamide dimethyl acetal was removed under vacuum. Glacial acetic acid (2 mL) was added to reaction mixture followed by hydrazine monohydrate (0.03 mL, 0.75 mmol). The reaction was stirred at 95 0C for 30 minutes. The acetic acid was removed under vacuum. The residue was purified by normal phase Si02 chromatography (0% to 5% MeOH/CHzClz) to afford (6183-64sopropylmethoxy-3 -(3 -methoxypropoxy)(2H-1,2,4-triazol-3 -yl)-5H,6H-pyrido[1,2- h]1,7-naphthyridinone as a white solid (12 mg, 20% yield, m/z: 426 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 5 13.48 (s, 1H), 8.50 (s, 1H), 7.99 (s, 1H), 7.56 (s, 1H), 6.91 (s, 1H), 4.25—4.12 (m, 2H), 4.08 (s, 3H), 3.88 (dd, J=9.6, 5.4 Hz, 1H), 3.58 (td, J=6.1, 1.6 Hz, 2H), 3.36 (d, J=0.5 Hz, 4H), 3.05 (dd, J=16.4, 1.5 Hz, 1H), 2.15 (p, J=6.2 Hz, 2H), 1.97 (dt, J=9.3, 6.7 Hz, 1H), 0.96 (d, J=6.7 Hz, 3H), 0.85 (d, J=6.7 Hz, 3H).

EXAMPLE 117: Hydr0xyis0pr0pylmethoxy(3-methoxypropoxy)—10-0X0- ,10-dihydr0-6H-pyrid0 [1,2-h] [1,7]naphthyridine—9-carb0xamide MeOMO (6S)—6-Isopropylmethoxy-3 -(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2-h]1,7- naphthyridinecarboxylic acid (50 mg, 0.12 mmol) was dissolved in a mixture of CH2C12:thionyl chloride (1:1, 2 mL). The on was stirred at 40 0C for 30 min. The solvent -l96- was evaporated under vacuum. Residual thionyl chloride was removed by azeotropic evaporation from toluene (2x2 mL) to give a yellow foam. The yellow foam in CHzClz (1 mL) was added dropwise to a pre-formed mixture of hydroxylamine hydrochloride (0.03 mL, 0.62 mmol) in CHzClz (1 mL) and triethylamine (0.3 mL, 2 mmol). The reaction was stirred at 40 0C for 2h.

The solvent was removed under vacuum. The residue was d by normal phase Si02 chromatography (0% to 6% MeOH/CHzClz) to afford (6S)—N—hydroxyisopropylmethoxy (3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2-h] 1,7-naphthyridinecarboxamide as a white solid (14 mg, 27% yield, m/z: 418 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 5 12.67 (s, 1H), 8.37 (s, 1H), 7.44 (s, 1H), 6.89 (s, 1H), 4.15 (td, J=6.5, 4.5 Hz, 2H), 4.03 (s, 3H), 3.88 (dd, J=9.4, 5.4 Hz, 1H), 3.57 (td, J=6. 1, 1.2 Hz, 2H), .25 (m, 4H), 3.02 (dd, J=16.5, 1.5 Hz, 1H), 2.14 (p, J=6.2 Hz, 2H), 1.96-1.80 (m, 1H), 0.93 (d, J=6.7 Hz, 3H), 0.80 (d, J=6.7 Hz, 3H).

EXAMPLE 118: (S)Isopropyl-Z-methoxy(3-methoxypropoxy)—N-(methylsulfonyl)—10- -dihydr0-6H-pyrid0[1,2-h] [1,7] yridinecarb0xamide MGOMO (6S)—6-Isopropylmethoxy-3 -(3 xypropoxy)oxo-5H,6H-pyrido[1,2-h]1,7- naphthyridinecarboxylic acid (50 mg, 0.12 mmol) in a mixture of CH2C12:thionyl chloride (1:1, 2 mL) solution. The reaction was stirred at 40 0C for 30 min. The solvent was removed under vacuum. Residual thionyl chloride was removed by azeotropic evaporation from toluene (2x2 mL) to give a yellow foam. The yellow foam in CHzClz (1 mL) was added dropwise to a pre-formed mixture of methanesulfonamide (18 mg, 0.19 mmol) in CHzClz (1 mL) and triethylamine (0.3 mL, 2 mmol). The reaction was d at 40 0C for 2h. The solvent was removed under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 6% MeOH/CHzClz) to afford (6S)—6-isopropyl-N-methanesulfonylmethoxy(3- methoxypropoxy)oxo-5H,6H-pyrido[1,2-h]1,7-naphthyridinecarboxamide as a white solid (9 mg, 15% yield, m/z: 480 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 5 13.87 (s, 1H), 8.44 (s, 1H), 7.54 (s, 1H), 6.91 (s, 1H), 4.17 (td, J=6.5, 4.8 Hz, 2H), 4.05 (s, 3H), 3.92 (dd, J=9.6, .3 Hz, 1H), 3.57 (td, J=6.1, 1.7 Hz, 2H), 3.36 (m, 7H), 3.06 (dd, J=16.8, 1.6 Hz, 1H), 2.14 (q, WO 85619 J=6.1 Hz, 2H), 2.07-1.69 (m, 1H), 0.97 (d, J=6.7 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H).

EXAMPLE 119: Tert-butyl N-[6-tert-butylchlor0(3-meth0xypr0p0xy)—2-0x0- I I CI \g/ \|< MeO/\/\O 6H,7H-pyrido[2,1-a]isoquinolinyl]carbamate To a solution of 6-tert-butylchloro(3 -methoxypropoxy)oxo-6H,7H-pyrido[2,1- a]isoquinolinecarboxylic acid (250 mg, 0.60 mmol) in tert-butyl alcohol (5 mL) were added potassium xide (81mg, 0.71 mmol) and ylphosphoryl azide (200 mg, 0.71 mmol) under nitrogen atmosphere. The mixture was refluxed for 12 h, then cooled to room ature, and diluted with EtOAc (15 mL). The organic phase was washed with sat. aqueous NaHC03 solution (15 mL), then sat. aqueous brine, dried over ium sulfate and concentrated under reduced pressure to give a yellowish oil. The residue was purified by normal phase SiOz chromatography (0% to 5% MeOH/CHzClz) to afford Zerl-butyl N—[6-tert-butylchloro(3- ypropoxy)oxo-6H,7H-pyrido[2,1-a]isoquinolinyl]carbamate as a white solid (0.21 g, 73% yield, m/z: 491 [M+H]+ observed). 1H NMR (300 MHz, CDC13) 5 8.37 (s, 1H), 7.67 (d, J=15.7 Hz, 2H), 6.83-6.64 (m, 2H), 4.15 (d, J=6.8 Hz, 2H), 3.85 (d, J=6.3 Hz, 1H), 3.59 (t, J=5.6 Hz, 2H), 3.47—3.23 (m, 4H), 3.22—3.03 (m, 1H), 2.22—1.92 (m, 2H), .27 (m, 9H), 0.99—0.53 (m, 9H).

EXAMPLE 120: 3-Amin0tert-butylchlor0(3-meth0xypr0p0xy)-6H,7H- MeO/\/\O pyrldo[2,1-a]1s0qu1n011n0ne hydrochlorlde0 o o o o Terr-bury] N—[6-tert-butylchloro(3 -methoxypropoxy)oxo-6H,7H-pyrido[2,1- a]isoquinolinyl]carbamate (200 mg, 0.41 mmol) was dissolved in anhydrous CHzClz (4 mL) and hydrogen chloride solution (4N in 1,4-dioxane, 0.41 mL, 1.63 mmol) was added. The mixture was stirred at rt overnight. The resulting precipitate was filtered, washed with CHzClz (2x5 mL), then dried to give 3-aminotert-butylchloro(3 -methoxypropoxy)-6H,7H- -l98- pyrido[2,1-a]isoquinolinone, HCl salt as a dark pink solid (0.16 g, 99% yield, m/z: 391 [M+H]+ observed). 1H NMR (300 MHz, DMSO-d6) 8 ppm 7.79-7.89 (m, 1 H), 7.66-7.77 (m, 1 H), 7.49-7.61 (m, 1 H), 7.26-7.37 (m, 1 H), 5.66-6.00 (m, 2 H), 4.43-4.53 (m, 1 H), 4.05-4.24 (m, 2 H), 3.30-3.55 (m, 4 H), 3.22 (d, J=1.47 Hz, 3 H), 1.91-2.05 (m, 2 H), 0.71 (bs, 9 H).

EXAMPLE 121: N—[6-Tert—buljyl—l0-ch10r0(3-meth0xypr0p0xy)—2-0x0-6H,7H- CI 0 MeoMo pyrido [2,l-a]isoquinolinyl]acetamide 3 -aminoZerZ-butylchloro(3 xypropoxy)-6H,7H-pyrido[2,1-a]isoquinolinone, hydrochloride salt (15 mg 0.04 mmol) and ylamine (0.01 mL, 0.08 mmol) were dissolved in anhydrous CHzClz (1 mL) and cooled to 0 oC. Acetyl chloride (0.003 mL, 0.04 mmol) was added dropwise and the mixture was warmed to rt and stirred overnight. The solution was concentrated under vacuum and the crude residue was purified by preparative TLC to give N—[6- lerl-butyl- 1 0-chloro(3 -methoxypropoxy)—2-oxo-6H,7H-pyrido[2, 1-a]isoquinolin-3 - yl]acetamide as a white solid (11 mg, 72% yield, m/z: 433 [M+H]+ observed). 1H NMR (300 MHz, CDC13) 5 ppm 8.84 (s, 1 H), 8.48 (s, 1 H), 7.66 (s, 1 H), 6.83 (s, 1 H), 6.76 (s, 1 H), 4.16 (d, J=7.04 Hz, 2 H), .92 (m, 1 H), 3.60 (d, J=0.88 Hz, 2 H), 3.36 (d, J=1.47 Hz, 4 H), 3.08- 3.18 (m, 1 H), 2.20 (s, 3 H), 2.12 (t, J=6.01 Hz, 2 H), 0.80 (s, 9 H).

EXAMPLE 122: Methyl N-[6-tert-butylchlor0(3-methoxyprop0xy)—2-0x0-6H,7H- Meo/\/\o pyrido [2,l-a]isoquinolinyl]carbamate 3 -AminoZerZ-butylchloro(3 -methoxypropoxy)-6H,7H-pyrido[2,1-a]isoquinolinone, hloride salt (15 mg 0.04 mmol) and triethylamine (0.02 mL, 0.11 mmol) were dissolved in CHzClz (1 mL) and cooled to 0 oC. Methyl chloroformate (0.005 mL, 0.04 mmol) was added dropwise and the e was warmed to rt and stirred overnight. The on was concentrated under reduced pressured. The residue was purified by preparative TLC to give methyl N—[6-lerl— butyl- 1 O-chloro(3 -methoxypropoxy)oxo-6H,7H-pyrido[2, 1-a]isoquinolin-3 -yl]carbamate as a tan solid (14 mg, 89% yield, m/z: 449 [M+H]+ observed). 1H NMR (300 MHz, CDCl3) 5 ppm 8.42 (s, 1 H), 7.83-7.91 (m, 1 H), 7.61-7.68 (m, 1 H), 6.77-6.83 (m, 1 H), .77 (m, 1 H), 4.11-4.22 (m, 2 H), 3.83-3.90 (m, 1 H), 3.76 (s, 3 H), 3.56-3.65 (m, 2 H), 3.36 (s, 4 H), 3.06- 3.16 (m, 1 H), 2.12 (s, 2 H), 0.81 (s, 9 H).

The following examples were prepared in a similar manner as methyl N—[6-Zerl—butylchloro- 9-(3-methoxypropoxy)oxo-6H,7H-pyrido[2,1-a]isoquinolinyl]carbamate from 3-amino lerl-butyl- 1 O-chloro(3 xypropoxy)—6H,7H-pyrido[2,1-a]isoquinolinone, hydrochloride salt and an appropriate chloroformate.

EXAMPLE 123: Pyridin-Z-ylmethyl (6-(tert-butyl)—10-chlor0-9—(3-methoxypropoxy)—2-0X0- hydro-2H-pyrido[2,1-a]isoquinolinyl)carbamate O N/l MeO/\/\O m/z: 526 [M+H]+ observed. 1H NMR (300 MHz, CDCl3) 5 ppm 8.58-8.63 (m, 1 H), 8.43-8.48 (m, 1 H), 8.05-8.11 (m, 1 H), .78 (m, 1 H), 7.69 (s, 1 H), 7.39-7.45 (m, 1 H), 7.21-7.26 (m, 1 H), 6.85 (s, 1 H), 6.77 (s, 1 H), 5.34 (d, J=6.45 Hz, 2 H), 4.14-4.24 (m, 2 H), 3.86-3.92 (m, 1 H), 3.58-3.65 (m, 2 H), 3.38 (s, 4 H), 3.10-3.19 (m, 1 H), 2.14 (s, 2 H), 0.82 (s, 9 H). 2O EXAMPLE 124: tyl (6-(tert-butyl)—10-chlor0(3-methoxypropoxy)—2-0x0-6,7- Meo/\/\o dihydro-ZH-pyrido [2,1-a] isoquinolinyl)carbamate m/z: 505 [M+H]+ observed. 1H NMR (300 MHz, CDCl3) 5 ppm 8.43 (s, 1 H), 7.85-7.90 (m, 1 H), 7.64-7.68 (m, 1 H), 6.79-6.82 (m, 1 H), .77 (m, 1 H), 4.11-4.21 (m, 2 H), 3.79-3.90 (m, 3 H), 3.57-3.63 (m, 2 H), 3.36 (s, 4 H), 3.08-3.17 (m, 1 H), 2.07-2.17 (m, 2 H), 0.96 (s, 9 H), 0.81 (s, 9 H).

EXAMPLE 125: 1-[6-Tert-butylchlor0(3-methoxypr0p0xy)—2-0x0-6H,7H-pyrid0 MeO/\/\O [2,1-a]is0quinolinyl] pyrrolidine—2,5-di0ne Succinic anhydride (6 mg, 0.06 mmol) was dissolved in CHzClz (1 mL) and cooled to 0 oC. 3- aminotert—butylchloro(3 -methoxypropoxy)-6H,7H-pyrido[2, 1-a]isoquinolinone, hydrochloride salt (25 mg, 0.06 mmol) and triethylamine (0.003 mL, 0.18 mmol) in CHzClz (0.5 mL) was added dropwise and the reaction was warmed to rt and stirred overnight. Reaction was trated under reduced pressured. The residue was purified by preparative TLC to give methyl N—[6-lerl—butylchloro(3 -methoxypropoxy)oxo-6H,7H-pyrido[2,1-a]isoquinolin- 3-yl]carbamate as a white foam (10 mg, 43% yield, m/z: 473 [M+H]+ ed). 1H NMR (300 MHz, CDCl3) 5 ppm 7.65-7.68 (m, 1 H), 7.38-7.41 (m, 1 H), .88 (m, 1 H), .78 (m, 1 H), .23 (m, 2 H), 3.79-3.84 (m, 1 H), 3.61 (d, J=1.17 Hz, 2 H), 3.39—3.47 (m, 1 H), 3.37 (s, 3 H), 3.09-3.18 (m, 1 H), 2.93-3.06 (m, 2 H), 2.74-2.88 (m, 2 H), 2.13 (s, 2 H), 1.76-0.83 (s, 9 EXAMPLE 126: 3-Tert-butyl[6-tert—butylchl0r0(3-methoxypropoxy)—2-0x0- N N I I CI ‘5 6 MeO/\/\O 6H,7H-pyrid0[2,1-a]isoquinolinyl]urea 3 -Aminotert-butylchloro(3 -methoxypropoxy)-6H,7H-pyrido[2, 1-a]isoquinolinone, hloride salt (15 mg, 0.04 mmol), lerZ-butyl isocyanate (0.004 mL, 0.04 mmol) and ylamine ( 0.005 mL, 0.04 mmol) were dissolved in anhydrous THF (2 mL) and the mixture was heated at 80°C for 6 hours. The reaction was concentrated. The residue was purified by normal phase SiOz chromatography (50% to 100% EtOAc/hexanes) to furnish 3-tert-butyl[6- tert—butyl- l 0-chloro(3 -methoxypropoxy)oxo-6H,7H-pyrido[2, 1-a]isoquinolin-3 -yl]urea as a tan solid (5 mg, 25% yield, m/z: 491 [M+H]+ observed). 1H NMR (300 MHz, CDCl3): 5 ppm 8.94-8.99 (m, 1 H), 8.75-8.79 (m, 1 H), 7.55 (s, 1 H), 7.37-7.42 (m, 1 H), 6.71-6.78 (m, 2 H), 4.11—4.23 (m, 2 H), .96 (m, 1 H), 3.57-3.65 (m, 2 H), 3.37 (s, 4 H), 3.06-3.15 (m, 1 H), 2.07-2.18 (m, 2 H), 1.47 (s, 9 H), 0.81 (s, 9 H).

EXAMPLE 127: N-[6-Tert-butylchl0r0(3-methoxypr0p0xy)—2-0x0-6H,7H— pyrido ]isoquinolinyl]-2,2,2-trifluoroethanesulfonamide MeO/\/\O 3 -Aminotert-butyl- l 0-chloro(3 -methoxypropoxy)-6H,7H-pyrido[2, l-a]isoquinolinone, hydrochloride salt (20 mg, 0.05 mmol) and triethylamine (0.01 mL, 0.09 mmol) were dissolved in CHzClz (1 mL) and cooled to 0 oC. 2,2,2-trifluoroethanesulfonyl chloride (0.007 mL, 0.06 mmol) was added dropwise and the mixture was stirred ght at rt. Reaction was concentrated under reduce pressure. The residue was purified by e phase HPLC to afford N-[6-ZerZ-butyl- l 0-chloro(3 -methoxypropoxy)oxo-6H,7H-pyrido[2, l-a]isoquinolin-3 -yl]- 2,2,2-trifluoroethanesulfonamide as a white solid (5 mg, 18% yield, m/z: 537 [M+H]+ observed). 1H NMR (300 MHz, CDC13) 5 ppm 7.96-8.00 (m, 1 H), 7.74 (s, 1 H), 7.29 (s, 1 H), 6.81 (s, 1 H), 4.20 (d, J=5.86 Hz, 2 H), 4.00-4.06 (m, 2 H), .98 (m, 2 H), 3.62 (s, 2 H), 3.40-3.48 (m, 1 H), 3.38 (s, 3 H), 3.16-3.26 (m, 1 H), 2.14 (t, J=6.01 Hz, 2 H), 0.83 (s, 9 H).

The following example was prepared in a similar manner as N—[6-ZerZ-butyl-l0-chloro(3- methoxypropoxy)oxo-6H,7H-pyrido[2, l -a]isoquinolin-3 -yl]-2,2,2-trifluoroethanesulfonamide from 3-aminotert-butyl- l 0-chloro(3 -methoxypropoxy)-6H,7H-pyrido[2, l-a]isoquinolin one, hydrochloride salt and an riate sulfonyl chloride.

EXAMPLE 128: N-(6-(Tert-butyl)—10-chlor0(3-methoxyprop0xy)—2-0x0-6,7-dihydr0- 2H-pyrido[2,1-a]isoquinolinyl)—1,1,1-trifluoromethanesulfonamide O F F I I CI O// \O MeOMO m/z: 523 [M+H]+ observed. 1H NMR (300 MHz, CDC13) 5 8.03 (s, 1H), 7.72 (s, 1H), 7.29 (s, 1H), 6.81 (s, 1H), 4.29—4.12 (m, 2H), 4.05 (d, J=6.7 Hz, 1H), 3.63 (t, J=5.9 Hz, 2H), 3.46 (dd, J=16.8, 6.7 Hz, 1H), 3.38 (d, J=0.8 Hz, 3H), 3.23 (d, J=16.8 Hz, 1H), 2.14 (p, J=6.1 Hz, 2H), 0.82 (s, 9H).

EXAMPLE 129: 6-(Tert-butyl)—10-chlor0(3-methoxypr0p0xy)—3-(pyrimidinylamino)- I I I) 6 / Meo/\/\O 6,7-dihydr0-2H-pyrid0 [2,1-a] nolin0ne EXAMPLE 130: 6-(Tert-butyl)—10-chlor0(di(pyrimidinyl)amin0)—9-(3- methoxypr0p0xy)—6,7-dihydr0-2H-pyrid0 [2,1-a]isoquinolin0ne 3 -Aminotert-butyl- l 0-chloro(3 -methoxypropoxy)-6H,7H-pyrido[2, l-a]isoquinolinone, hydrochloride salt (20 mg, 0.05 mmol) and ro-pyrimidine (4 mg 0.12 mmol) were melted and heated neat at 90 0C for 3 minutes. The mixture was d by reverse phase HPLC to afford: Example 129: 6-(Tert—butyl)—10-chl0r0(3-methoxypr0p0xy)—3-(pyrimidinylamino)- 6,7-dihydr0-2H-pyrid0[2,1-a]isoquinolin0ne as a tan solid (8 mg, 37% yield, m/z: 469 [M+H]+ observed). 1H NMR (300 MHz, CDC13) 6 ppm 9.02-9.08 (m, 1 H), 8.44 (d, J=4.98 Hz, 3 H), 7.69 (s, 1 H), 6.91 (s, 1 H), 6.78 (s, 1 H), 6.72 (s, 1 H), 4.18 (d, J=6.45 Hz, 2 H), 4.00 (d, J=6.45 Hz, 1 H), .67 (m, 2 H), 3.40-3.50 (m, 1 H), 3.38 (s, 3 H), 3.17 (d, J=16.42 Hz, 1 H), 2.14 (t, J=6.01 Hz, 2 H), 0.85 (s, 9 H) and Example 130: 6-(Tert-butyl)—10-chlor0(di(pyrimidinyl)amin0)(3- methoxyprop0xy)—6,7-dihydr0-2H-pyrid0[2,1-a]is0quinolin0ne as a light green solid (2 mg, 8% yield, m/z: 547 [M+H]+ observed). 1H NMR (300 MHz, CDCl3) 5 ppm 8.59 (d, J=4.98 Hz, 4 H), 8.01-8.05 (m, 1 H), 7.92-7.95 (m, 1 H), 7.81-7.85 (m, 1 H), 6.99-7.08 (m, 2 H), 6.78- WO 85619 6.83 (m, 1 H), 4.15-4.26 (m, 2 H), 3.95—4.02 (m, 1 H), 3.59-3.67 (m, 2 H), 3.48-3.58 (m, 1 H), 3.39 (s, 3 H), 3.18-3.28 (m, 1 H), 2.10—2.21 (m, 2 H), 0.84 (s, 9 H).

EXAMPLE 131: 6-Tert-butylchlor0i0d0(3-methoxyprop0xy)-6H,7H—pyrid0[2,1- a]is0quinolinone 3 -Aminotert-butylchloro(3 -methoxypropoxy)-6H,7H-pyrido[2, 1-a]isoquinolinone, hydrochloride salt (40 mg, 0.09 mmol) was dissolved in HCl (12 N in H20, 2 mL) and the e was cooled to 0°C. Sodium nitrite (7 mg, 0.10 mmol) was added slowly and the mixture was d at 0°C for 15 min, followed by the on of a solution of potassium iodide (160 mg, 0.94 mmol) in H20 (1 mL). The reaction mixture was gradually warmed to rt and stirred for 16 h. The reaction was concentrated under reduced pressure. The residue was purified by normal phase Si02 chromatography (0% to 5% HzClz) to furnish 6-tert-butylchloroiodo- 9-(3-methoxypropoxy)-6H,7H-pyrido[2,1-a]isoquinolinone as a dark yellow solid (30 mg, 64% yield, m/z: 502 [M+H]+ observed). 1H NMR (300 MHz, CDCl3): 5 ppm 7.84-7.90 (m, 1 H), 7.68-7.74 (m, 1 H), 6.79 (bs, 2 H), 4.19 (bs, 2 H), 3.83 (bs, 1 H), 3.62 (bs, 2 H), 3.38 (bs, 4 H), 3.14 (d, J=15.24 Hz, 1 H), 2.13 (bs, 2 H), 0.82 (bs, 9 H).

EXAMPLE 132: 6-Tert-butylchlor0(3-meth0xypr0p0xy)—3-(pyrimidin-Z-yl)—6H,7H- ONéj\ | | pyrido[2,1-a]is0quinolin0ne 6-Terl—bulyl—10-chloro-3 -iodo(3 -methoxypropoxy)-6H,7H-pyrido[2,1-a]isoquinolinone (3 0 mg, 0.06 mmol), 2-(tributylstannyl)pyrimidine (0.03 mL, 0.08 mmol), and palladium- tetrakis(triphenylphosphine) (14 mg, 0.01 mmol) were dissolved in 1,4-dioxane (1 mL) in a ave reaction vial. The vessel was flushed with nitrogen gas, then sealed and heated at 90°C in a microwave reactor for 1 hour. The reaction was concentrated under reduced pressure.

The residue was purified by reverse phase HPLC to afford 6-lerl—butylchloro(3- —204— methoxypropoxy)(pyrimidinyl)-6H,7H-pyrido[2,1-a]isoquinolinone as a white solid (1.2 mg, 4% yield, m/z: 454 [M+H]+ observed). 1H NMR (300 MHz, CDCl3) 5 ppm 8.81-8.90 (m, 2 H), 8.35-8.43 (m, 1 H), .79 (m, 1 H), 7.18-7.25 (m, 1 H), 7.00-7.06 (m, 1 H), 6.79 (s, 1 H), 4.15—4.25 (m, 2 H), 4.04—4.11 (m, 1 H), 3.59-3.67 (m, 2 H), 3.40—3.49 (m, 1 H), 3.39 (s, 3 H), 3.15—3.24 (m, 1 H), 2.15 (s, 2 H), 0.86 (s, 9 H).

The following example was prepared in a similar manner as 6-ZerZ-butylchloro(3- methoxypropoxy)(pyrimidinyl)-6H,7H-pyrido[2,1-a]isoquinolinone from 6-lerl—butyl- -chloroiodo(3-methoxypropoxy)-6H,7H-pyrido[2,1-a]isoquinolinone and an appropriate organotin reagent.

EXAMPLE 133: 6-(Tert-butyl)—10-chl0r0(3-methoxyprop0xy)—3-(pyridinyl)-6,7- dihydro-ZH-pyrido[2,1-a]isoquinolin0ne m/z: 453 [M+H]+ observed. 1H NMR (300 MHz, CDCl3) 5 ppm 8.83-8.90 (m, 1 H), .62 (m, 2 H), 7.76 (s, 2 H), 7.17-7.25 (m, 1 H), 6.92-6.97 (m, 1 H), 6.79 (s, 1 H), 4.15-4.25 (m, 2 H), 4.03-4.13 (m, 1 H), 3.63 (s, 2 H), 3.39 (s, 4 H), 3.13-3.23 (m, 1 H), 2.15 (t, J=6.16 Hz, 2 H), 0.85 (s, 9 H).

EXAMPLE 134: Tert—butyl (R)-(2-chlor0is0pr0pyl(3-meth0xypr0p0xy)—11-0x0-6,7- dihydro-l zo [f] pyrido ] [1,4]oxazepin-lO-yl)carbamate To a solution of (R)chloroisopropyl(3-methoxypropoxy)oxo-6,7-dihydro-11H- benzo[f]pyrido[1,2-d][1,4]oxazepinecarboxylic acid (300 mg 0.71 mmol) in lerl—butyl alcohol (5 mL) were added potassium I—butoxide (98 mg, 0.85 mmol) and diphenyl phosphoryl azide (0.18 mL, 0.85 mmol) under nitrogen atmosphere. The mixture was refluxed for 12 h, cooled to room temperature, and diluted with EtOAc (10 mL). The organic phase was washed with sat. s NaHC03 solution (10 mL), then sat. aqueous brine solution (10 mL), dried over magnesium sulfate and concentrated under reduced pressure to a give a yellowish oil. The residue was purified by normal phase SiOz chromatography (0% to 5% MeOH/CHzClz) to furnish tert—butyl (R)-(2-chloroisopropyl(3-methoxypropoxy)oxo—6,7-dihydro-11H- benzo[f]pyrido[1,2-d][1,4]oxazepinyl)carbamate as an off-white foam (0.18 g, 53% yield, m/z: 493 [M+H]+ observed). 1H NMR (300 MHz, CDCl3): 5 ppm 8.38 (s, 1 H), 7.75 (s, 1 H), 7.51 (s, 1H), 6.60 (d, J=2.64 Hz, 2 H), 4.53 (s, 2 H), .20 (m, 2 H), 3.65-3.73 (m, 1 H), 3.61 (s, 2 H), 3.37 (s, 3 H), 2.12 (t, J=6.01 Hz, 2 H), 1.95—2.05 (m, 1 H), .57 (m, 9 H), 1.03 (d, J=6.45 Hz, 3 H), 0.87 (d, J=6.74 Hz, 3 H).

EXAMPLE 135: (R)Ch10r0isopropyl(3-meth0xypr0p0xy)—10-(pyrimidinyl)—6,7- dihydro-l 1H-benz0 [f] pyrido [1,2-d] [1,4] oxazepin-l 1-0ne E 136: (R)Chlor0isopropyl(3-meth0xypr0p0xy)-6,7-dihydr0-1 1H- benzo [f] pyrido [1,2-d] [1,4] oxazepin-l 1-0ne (R)-1 0chl0r0— 7-is0pr0pyl—3—(3-meth0xypr0p0xy)-6, 7-dihydr0—11H-benz0[flpyrid0 [1,2-d][1,4]0xazepin—11-0ne Terr-bury] (R)-(2-chloroisopropyl(3 -methoxypropoxy)-1 1-oxo-6,7-dihydro-1 1H- benzo[f]pyrido[1,2-d][1,4]oxazepinyl)carbamate (180 mg, 0.37 mmol) was dissolved in 4 ml anhydrous CHzClz (4 mL) and a solution of hydrogen chloride (4N in 1,4-dioxane, 0.46 mL, 1.8 mmol) was added. The mixture was d at rt overnight. The resulting precipitate was filtered, washed with CHzClz (5 mL), then dried to give (R)aminochloroisopropyl(3- methoxypropoxy)-6,7-dihydro-1 1H-benzo[f]pyrido[1,2-d][1,4]oxazepin-1 1-one, hydrochloride salt as a tan solid (155 mg, 99% yield, m/z: 393 [M+H]+ observed).

(R)Chl0r0-1 0-i0d0- 7-is0pr0pyl—3—(3-meth0xypr0p0xy)—6, 7-dihydr0—11H-benz0[flpyrid0[1,2— d][1,4]0xazepin0ne (R)Aminochloroisopropyl-3 -(3 -methoxypropoxy)-6,7-dihydro-1 1H- benzo[f]pyrido[1,2-d][1,4]oxazepinone, hydrochloride salt (81 mg, 0.19 mmol) was suspended in concentrated aqueous HCl solution (2 mL), cooled to 0°C, and sodium nitrite (17 mg 0.25 mmol) in H20 (0.5 mL) was added dropwise. The mixture was stirred at 0 0C for 15 min, then a solution of potassium iodide (313 mg, 1.89 mmol) in H20 (1 mL) was added dropwise. The reaction mixture was stirred at rt for 16 h. After concentration under vacuum, the e was purified by normal phase SiOz chromatography (0% to 5% HzClz) to furnish chloroiodoisopropyl-3 -(3 -methoxypropoxy)-6,7-dihydro-1 1H- benzo[f]pyrido[1,2-d][1,4]oxazepinone as a tan solid (95 mg, 100% yield, m/z: 504 [M+H]+ observed).

(R)Chloro- r0pyl—3—(3-meth0xypr0p0xy)—1 0—@yrimidin-Z-yD-6, dr0—11H- benz0[flpyrid0[1,2-d][1,4/0xazepin0ne; Chloro- 7-is0pr0pyl—3—(3-meth0xypr0p0xy)—6, 7-dihydr0—11H-benz0[flpyrid0[1,2— d][1,4]0xazepin—11-0ne (R)Chloroiodoisopropyl-3 -(3 -methoxypropoxy)-6,7-dihydro-1 1H-benzo[f]pyrido [1,2- d][1,4]oxazepinone (36 mg, 0.07 mmol), 2-(tributylstannyl)pyrimidine (0.04 mL 0.14 mmol), and palladium-tetrakis(triphenylphosphine) (8 mg, 0.01 mmol) were dissolved in 1,4- dioxane (1 mL) in a microwave reaction vial. The vessel was flushed with nitrogen gas, then sealed and heated at 90 0C in a microwave reactor for 1 hour. The reaction was concentrated under vacuum.

The residue was purified by e phase HPLC to afford (R)chloroisopropyl-3 -(3- methoxypropoxy)(pyrimidinyl)-6,7-dihydro-1 1H-benzo[f]pyrido[1,2-d][1,4]oxazepin-1 1- one as a white solid (3.1 mg, 10% yield), and and (R)chloroisopropyl(3- methoxypropoxy)-6,7-dihydro-11H-benzo[f]pyrido[1,2-d][1,4] oxazepin-l 1-one as an yellow oil (2.4 mg, 5% yield, m/z).

Example 135: (R)Chlor0is0pr0pyl(3-methoxypr0p0xy)—10-(pyrimidinyl)—6,7- o—l1H-benz0[f]pyrid0[1,2-d][1,4]0xazepin0ne, m/z: 456 [M+H]+, 1H NMR (300 MHz, CDCl3) 8 ppm 8.84 (d, J=4.98 Hz, 2 H), 8.22 (s, 1 H), 7.57 (s, 1 H), 7.15-7.21 (m, 1 H), 6.79 (s, 1 H), 6.60 (s, 1 H), 4.52-4.65 (m, 2 H), 4.09-4.19 (m, 2 H), 3.70-3.79 (m, 1 H), 3.60 (s, 2 H), 3.37 (s, 3 H), 2.05-2.17 (m, 3 H), 1.03-1.10 (m, 3 H), 0.89-0.95 (m, 3 H).

Example 136: (R)Chlorois0propyl(3-meth0xypr0p0xy)—6,7-dihydr0-11H- benz0[f]pyrid0[1,2-d][1,4] oxazepin-ll-one, m/z: 378 [M+H]+, 1H NMR (300 MHz, CDCl3) 5 ppm 7.41 (s, 1 H), 7.21 (m, 1 H), 6.5 (s, 2 H)k 6.24-6.28 (m, 1H)k 4.52-4.65 (m, 2 H)k 4.09- 4.19 (m, 2 H), 3.43-3.60 (m, 3 H), 3.25 (s, 3 H), .10 (m, 2 H), 1.85-1.99 (m, 1H), O.90-1.0 (m, 3 H), 0.75-0.85 (m, 3 H).

The following es were prepared in a similar manner as (R)chloroisopropyl(3- methoxypropoxy)- 1 O-(pyrimidinyl)—6,7-dihydro- 1 zo[f]pyrido[1,2-d][1,4]oxazepin-1 1- one from chloroiodoisopropyl-3 -(3 -methoxypropoxy)-6,7-dihydro-1 1H- benzo[f]pyrido[1,2-d][1,4]oxazepinone and an appropriate organotin reagent.

EXAMPLE 137 : (R)Chlor0isopropyl(3-meth0xypr0p0xy)—10-(3-methylpyridin yl)—6,7-dihydr0-1 1H-benz0 [f] pyrido [1,2-d] [1,4] oxazepin-l 1-0ne m/z: 469 [M+H]+ observed. 1H NMR (300 MHz, CDCl3) 5 ppm 8.45-8.50 (m, 1 H), 7.60 (d, J=2.35 Hz, 3 H), 7.18-7.25 (m, 1 H), 6.72 (s, 1 H), 6.61 (s, 1 H), 4.55-4.67 (m, 2 H), 4.11-4.20 (m, 2 H), 3.67-3.75 (m, 1 H), 3.62 (s, 2 H), 3.38 (s, 3 H), 2.39 (s, 3 H), 2.10-2.18 (m, 2 H), 2.01- 2.08 (m, 1 H), 1.06 (d, J=6.45 Hz, 3 H), 0.90 (d, J=6.45 Hz, 3 H).

EXAMPLE 138: (R)Chlor0isopropyl(3-meth0xypr0p0xy)—10-(pyridinyl)—6,7— OJ ”( dihydro-l1H-benz0[f]pyrid0[1,2-d][1,4]0xazepin0ne m/z: 455 [M+H]+ observed. 1H NMR (300 MHz, CDCl3) 5 ppm 8.81-8.89 (m, 1 H), 8.51-8.61 (m, 2 H), 7.74-7.82 (m, 1 H), 7.58 (s, 1 H), .26 (m, 1 H), 6.77 (s, 1 H), 6.62 (s, 1 H), 4.60 (d, J=2.64 Hz, 2 H), 4.15 (d, J=2.35 Hz, 2 H), 3.82-3.93 (m, 1 H), 3.62 (s, 2 H), 3.38 (s, 3 H), 2.13 (s, 3 H), 1.08 (d, J=6.74 Hz, 3 H), 0.91 (d, J=6.45 Hz, 3 H).

EXAMPLE 139: (R)Chlor0isopropylmeth0xy(3-methoxypropoxy)—6,7- dihydro-l z0 [f] pyrido ] [1,4]0xazepin-1 1-0ne o—J""( chloroiodoisopropyl-3 -(3 -methoxypropoxy)-6,7-dihydro-1 1H-benzo[f]pyrido[1,2- d][1,4]oxazepinone (25 mg, 0.05 mmol), copper(I) iodide (1.42 mg, 0.01 mmol) and sodium methoxide (11 mg 0.20 mmol) were suspended in MeOH (1 mL) and the mixture was heated at 100 0C in a microwave reactor for 10 minutes. Aqueous ammonium chloride solution (1M, 5 mL) was added and the e was extracted with EtOAc (3x 10 mL). The combined organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The reaction was concentrated under vacuum. The residue was purified by reverse phase HPLC to afford (R)chloroisopropylmethoxy(3-methoxypropoxy)-6,7-dihydro-11H- benzo[f]pyrido[1,2-d][1,4]oxazepinone as a white foam (2.8 mg, 14% yield, m/z: 408[M+H]+ observed). 1H NMR (300 MHz, CDC13) 5 7.50 (s, 1H), 7.32 (s, 1H), 7.04 (s, 1H), 6.59 (s, 1H), 4.74-4.61 (m, 1H), 4.56 (d, J=12.8 Hz, 1H), 4.13 (d, J=2.6 Hz, 2H), 3.87 (s, 4H), 3.60 (t, J=6.0 Hz, 2H), 3.37 (d, J=1.4 Hz, 3H), 2.12 (p, J=6.3 Hz, 3H), 1.08 (d, J=6.6 Hz, 3H), 0.84 (d, J=6.5 Hz, 3H).

EXAMPLE 140: (R)-(2-Chlor0is0pr0pyl(3-methoxypropoxy)—11-0x0-6,7-dihydr0- O OH MeO’\/\ 1 1H-benz0 [f] pyrido [1,2-d] [1,4]0xazepinyl)b0r0nic acid ( (R)Chloroiodoisopropyl-3 -(3 -methoxypropoxy)-6,7-dihydro-1 1H-benzo[f]pyrido[1,2- d][1,4]oxazepinone (27 mg, 0.054 mmol), bis(pinacolato)diboron (31.30 mg 0.12 mmol), palladium-tetrakis(triphenylphosphine) ( 3.10 mg 0.003 mmol) and potassium carbonate (17 mg, 0.12 mmol) were suspended in a mixture of 1,4-dioxane/water (4:1, 1 mL) and the reaction was heated at 70 0C in a microwave r for 10 minutes. The reaction was filtered through Celite® and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to afford -chloroisopropyl(3-methoxypropoxy)oxo-6,7-dihydro-11H- benzo[f]pyrido[1,2-d][1,4]oxazepinyl)boronic acid as a white foam (2.5 mg, 11% yield, m/z: 422[M+H]+ ed). 1H NMR (300 MHz, MeOH-d4) 5 7.95 (s, 1H), 7.72 (s, 1H), 7.18 (s, 1H), 6.83 (s, 1H), 4.85-4.76 (m, 1H), 4.69-4.57 (m, 1H), 4.43 (s, 1H), 4.19 (t, J=6.1 Hz, 2H), 3.61 (t, J=6.1 Hz, 2H), 3.38-3.32 (m, 3H), 2.18-1.95 (m, 3H), 1.11 (d, J=6.5 Hz, 3H), 0.77 (d, J=6.6 Hz, EXAMPLE 141: utyl (R)-(2-chlor0is0pr0pyl(3-meth0xypr0p0xy)0x0-6,7- dihydro-l 1H-benzo [f] pyrido[1,2-d] [1,4]oxazepinyl)(methyl)carbamate Terr-bury] (R)-(2-chloroisopropyl(3 -methoxypropoxy)-1 1-oxo-6,7-dihydro-1 1H- benzo[f]pyrido[1,2-d][1,4]oxazepinyl)carbamate (15 mg, 0.03 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to 0 oC. Sodium hydride (60% dispersion in mineral oil, 1.6 mg 0.04 mmol) was added under an argon stream and the e was stirred at 0 0C for 20 s. Methyl iodide (0.002 mL, 0.03 mmol) was added and the reaction was warmed to rt and stirred overnight. The mixture was purified by reverse phase HPLC. The pure fractions were ed, washed with sat. aqueous NaHCO3 solution (20 mL), and extracted with EtOAc (3x25 mL). The combined organic fractions were dried over sodium sulfate and concentrated under vacuum to give tert-butyl (R)-(2-chloroisopropyl(3-methoxypropoxy)oxo-6,7-dihydro- 11H-benzo[f]pyrido[1,2-d][1,4]oxazepinyl)(methyl)carbamate as a white foam (11 mg, 72% yield, m/z: 507[M+H]+ ed). 1H NMR (300 MHz, CDCl3) 5 ppm 7.51-7.54 (m, 1 H), 7.35- 7.44 (m, 1 H), 6.66 (s, 1 H), 6.61 (s, 1 H), 4.51-4.60 (m, 2 H), 4.11—4.19 (m, 2 H), 3.61 (t, J=5.86 Hz, 3 H), 3.38 (s, 3 H), 3.18 (s, 3 H), 2.09—2.17 (m, 2 H), 1.96-2.05 (m, 1 H), 1.45 (bs, 9 H), 1.05 (d, J=6.74 Hz, 3 H), 0.89 (d, J=6.45 Hz, 3 H).

EXAMPLE 142: 9-Acetylisopropyl-Z-methoxy(3-meth0xypr0p0xy)—5,6-dihydr0-10H- O O MeO/\/\O pyrido [1,2-h] [1,7] naphthyridin-lO-one EXAMPLE 143: 9-(2-Hydr0xypr0pan-Z-yl)—6-is0pr0pylmeth0xy(3-methoxypropoxy)— O OH MeO/\/\O ,6-dihydr0-10H-pyrid0 [1,2-h] [1,7]naphthyridin0ne Ethyl 6-isopropylmethoxy-3 -(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2-h]1,7- naphthyridinecarboxylate (59 mg, 0.14 mmol) and copper(I) iodide (57 mg, 0.30 mmol) were suspended in THF (2 mL), then cooled to -78°C (dry ice/acetone bath) and methylmagnesium bromide solution (3M in in diethyl ether, 0.05 mL, 0.14 mmol) was added dropwise. The mixture was stirred at -78°C for 1 hour, then another additional lent of methylmagnesium bromide solution (3M in in diethyl ether, 0.05 mL, 0.14 mmol) was added. The reaction was further stirred at -78°C for another 4 hours. The mixture was then warmed to 0 oC and quenched with sat. aqueous ammonium chloride solution (50 mL). The aqueous layer was extracted with EtOAc (3x50 mL). The combined organic fractions were washed with H20 (20 mL), sat. s brine solution (20 mL), dried over sodium sulfate and trated under vacuum. The residue was purified by reverse phase HPLC to afford 9-acetylisopropylmethoxy(3- methoxypropoxy)-5,6-dihydro-10H-pyrido[1,2-h][1,7]naphthyridinone as a yellow oil (1.6 mg, 3% yield), and ydroxypropanyl)isopropylmethoxy(3-methoxypropoxy)- 5,6-dihydro-10H-pyrido[1,2-h][1,7] naphthyridinone as an yellow foam (6.4 mg, 11% yield).

Example 142: 9-Acetylisopropyl-Z-methoxy(3-meth0xypr0p0xy)-5,6-dihydr0-10H- pyrid0[1,2-h][1,7]naphthyridin-lO-one, m/z: 401 [M+H]+, 1H NMR (400 MHz, CDC13) 5 8.14 (s, 1H), 7.45 (s, 1H), 6.88 (s, 1H), 4.23-4.09 (m, 2H), 4.06 (d, J=0.4 Hz, 3H), 3.77 (dd, J=9.4, 5.0 Hz, 1H), 3.57 (td, J=6.1, 1.5 Hz, 2H), 3.37-3.30 (m, 4H), 3.05-2.96 (m, 1H), 2.77 (d, J=0.4 Hz, 3H), 2.14 (p, J=6.2 Hz, 2H), 1.95-1.82 (m, 1H), 0.94 (d, J=6.7 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H).

Example 143: 9-(2-Hydr0xypr0panyl)is0pr0pylmeth0xy(3-methoxypropoxy)- ,6-dihydro-10H-pyrido[1,2-h][1,7]naphthyridin0ne, m/z: 417 [M+H]+, 1H NMR (400 MHz, CDC13) 8 7.34 (s, 1H), 7.25-7.22 (m, 1H), 6.89-6.84 (m, 1H), 4.20-4.06 (m, 3H), 4.04 (s, 3H), 3.72-3.64 (m, 1H), 3.57 (td, J=6.1, 1.3 Hz, 2H), 3.39-3.28 (m, 4H), 2.99 (dd, J=16.4, 1.6 Hz, 1H), 2.13 (p, J=6.2 Hz, 2H), 1.90 (dp, J=9.4, 6.6 Hz, 1H), 1.56 (s, 3H), 1.29-1.19 (m, 2H), 0.93 (d, J=6.7 Hz, 3H), 0.79 (d, J=6.7 Hz, 3H).

EXAMPLE 144: Methyl 6-tert-butylchlor0(hydr0xyimin0)(3-methoxypropoxy)- MeO/\/\O 6H,7H-pyrido [2,1-a] isoquinolinecarb0xylate Methyl —buty1chloro(3 -methoxypropoxy)oxo-6H,7H-pyrido[2,1-a]isoquinoline-3 - carboxylate (0.15 g 0.3 5mmol, prepared according to the procedure in W02015113990A1) was suspended in l chloride (1.3 mL, 17. 3 mmol) and the mixture was heated at 70°C for 2 hours. The volatile was removed under reduced pressure and the sample was azeotroped with e (2X5 mL). The crude -pyridinium salt was dissolved in DMF (3 mL) and cooled to 0°C. Hydroxylamine (50% solution in H20, 0.04 mL, 0.4 mmol) was added dropwise and the on was gradually warmed to rt and stirred overnight. The residue was purified by reverse phase HPLC to afford methyl 6-tert-buty1chloro(hydroxyimino)(3 -methoxypropoxy)— 6H,7H-pyrido[2,1-a]isoquinolinecarboxy1ate as a yellow solid (0.11 g, 71% yield, m/z: 449 [M+H]+ observed). 1H NMR (400 MHz, DMSO-d6) 5 11.49 (s, 1H), 8.79 (s, 1H), 8.19 (s, 1H), 7.63 (s, 1H), 7.31 (s, 1H), 4.63 (d, J: 5.2 Hz, 1H), 4.17 (tt, J: 9.7, 6.4 Hz, 2H), 3.87 (s, 3H), 3.47 (t, J = 6.1 Hz, 2H), 3.42—3.30 (m, 2H), 3.22 (s, 3H), 2.06-1.91 (m, 2H), 0.70 (s, 9H).

EXAMPLE 145: 6-Tert-butylchl0r0(hydroxyimin0)(3-methoxypropoxy)—6H,7H- MeO/\/\O [2,l-a]isoquinoline—3-carb0xylic acid Methyl 10-chloro(hydroxyimino)isopropyl (3 -methoxypropoxy)-6H,7H-pyrido[2, 1- a]isoquinolinecarboxylate (0.07 g, 0.16 mmol) was dissolved in 1,4-dioxane (2 mL) and a solution of sodium hydroxide ( 0.01 g 0.32 mmol) in H20 (1 mL) was added. The reaction was stirred at rt for 12 hours. The reaction was diluted with H20 (5 mL) and the solution was acidified with 1NHCl (20 mL). The aqueous layer was extracted with EtOAc (2X15 mL). The combined organic fractions were evaporated under d pressure. The residue was purified by reverse phase HPLC to afford 6-lerl—butylchloro(hydroxyimino)(3 -methoxypropoxy)- 6H,7H-pyrido[2,1-a]isoquinolinecarboxylic acid as a white solid (0.03 g, 40% yield, m/z: 435 [M+H]+ observed). 1H NMR (300 MHz, CDC13) 5 ppm 8.37-8.43 (m, 1 H), 7.81 (bs, 1 H), 7.45 (bs, 1H), 6.79-6.85 (m, 1 H), 4.17-4.26 (m, 2 H), 4.10-4.16 (m, 1 H), 3.60-3.66 (m, 2 H), 3.39 (bs, 3H), 3.18-3.28 (m, 2 H), 2.10—2.20 (m, 2 H), 0.81 (bs, 9 H).

EXAMPLE 146: 6-(Tert-butyl)—2-chlor0(3-meth0xypr0p0xy)—5,6-dihydr0-9H- MeO/\/\O isoxazolo[3',4':4,5]pyrid0[2,1-a]is0quinolin0ne 6-lerZ-butylchloro(hydroxyimino)(3 -methoxypropoxy)-6H,7H-pyrido[2,1- a]isoquinolinecarboxylic acid (30 mg, 0.07 mmol) was dissolved in anhydrous CHZCIZ (1 mL) and the mixture was cooled to 0 oC. Phosphorus hloride (16 mg, 0.08 mmol) was added portion-wise and the mixture was stirred at 0 0C until all solids dissolved (10 minutes). The on was gradually warmed to rt and stirred for 18 hours. The on mixture was trated under reduced pressure. The residue was purified by reverse phase HPLC to afford -2l3- WO 85619 6-(lerl-butyl)chloro-3 -(3 -methoxypropoxy)-5,6-dihydro-9H-isoxazolo[3',4':4,5]pyrido[2,1- a]isoquinolinone as a white solid (8 mg, 27% yield, m/z: 417 [M+H]+ observed). 1H NMR (300 MHz, CDCl3) 6 8.05-7.95 (m, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.03 (d, J=1.4 Hz, 1H), 6.79 (s, 1H), 4.19 (q, J=6.5, 6.0 Hz, 2H), 3.96 (d, J=6.3 Hz, 1H), 3.62 (tt, J=6.1, 1.8 Hz, 2H), 3.48-3.27 (m, 4H), 3.20 (d, J=16.6 Hz, 1H), 2.14 (tt, J=7.0, 3.5 Hz, 2H), 0.82 (d, J=1.6 Hz, 9H).

The ing examples were prepared in a r manner as 6-(lerl—butyl)chloro-3 -(3- methoxypropoxy)-5,6-dihydro-9H-isoxazolo[3',4':4,5]pyrido[2,1-a]isoquinolinone from methyl 6-ZerZ-butylchloro(3 -methoxypropoxy)oxo-6H,7H-pyrido[2, 1-a]isoquinoline-3 - carboxylate and an appropriate alkyl or alkoxy/hydroxyl amine.

EXAMPLE 147: 6-(Tert-butyl)—10-meth0xy(3-methoxypropoxy)—2-(methylimin0)-6,7- MeO/\/\O dihydro-ZH-pyrido[2,1-a]isoquinoline—3-carb0xylic acid m/z: 415 [M+H]+ observed. 1H NMR (300 MHz, CDCl3) 5 ppm 9.58-9.72 (bs, 1 H), 8.50 (bs, 1 H), 6.94-7.00 (m, 1 H), 6.77 (s, 1 H), 6.67 (s, 1 H), 4.03-4.12 (m, 2 H), 3.88-3.96 (m, 1 H), 3.84 (s, 3 H), 3.45 (s, 2 H), 3.18-3.29 (m, 4 H), 2.88-3.05 (m, 4 H), 2.02 (t, J=6.16 Hz, 2 H), 1.61-1.74 (m, 1 H), 0.80 (d, J=6.45 Hz, 3 H), 0.67 (d, J=6.74 Hz, 3 H).

EXAMPLE 148: Methyl 6-is0pr0pylmeth0xy—2-(meth0xyimin0)—9-(3-meth0xy propoxy)—6,7-dihydro-2H-pyrido[2,l-a]isoquinoline—3-carb0xylate MeO/\/\O m/z: 445 [M+H]+ observed. 1H NMR (300 MHz, CDC13) 5 ppm 7.66 (s, 1 H) 7.19 (s, 1 H) 7.07 (s, 1 H) 6.67 (s, 1 H) 4.15 (d, J=1.17 Hz, 2 H) 3.97 (s, 3 H) 3.93 (s, 3 H) 3.85 (s, 3 H) 3.54-3.62 —214— (m, 2 H) .47 (m, 1 H) 3.37 (s, 3 H) 3.14—3.24 (m, 1 H) 2.86-2.94 (m, 1 H) 2.14 (s, 2 H) .74 (m, 1 H) 0.87 (dd, J=6.60, 4.84 Hz, 6 H).

EXAMPLE 149: 6-(Tert-butyl)—10-meth0xy-2—(meth0xyimin0)—9-(3-meth0xypr0p0xy)—6,7- MeO/V\O dihydro-ZH-pyrido[2,1-a]isoquinoline—3-carb0xylic acid m/z: 431 [M+H]+ observed. 1H NMR (300 MHz, CDC13) 5 ppm 8.60-8.68 (m, 1 H), 7.23-7.25 (m, 1 H), 7.20-7.23 (m, 1 H), 6.81 (s, 1 H), 4.21 (d, J=1.76 Hz, 2 H), 4.03-4.13 (m, 1 H), 3.88- 4.00 (m, 6 H), 3.59 (d, J=1.17 Hz, 2 H), 3.37-3.43 (m, 4H), 3.03-3.14 (m, 1 H), 2.16 (t, J=6.16 Hz, 2 H), 1.75-1.89 (m, 1 H), 0.94 (d, J=6.74 Hz, 3 H), 0.81 (d, J=6.74 Hz, 3 H).

EXAMPLE 150: Ethyl 2-chlor0(hydr0xyimin0)is0pr0pylmeth0xy-6,7-dihydr0- 1 1H-benzo [f] pyrido [1,2-d] [1,4]oxazepine—lO-carboxylate m/z: 407 [M+H]+ observed. 1H NMR (300 MHz, CHLOROFORM-d) 5 ppm 12.58 (In, 1 H) 8.68 (d, J=9.38 Hz, 1 H) 7.81 (s, 1 H) 7.37-7.60 (m, 2 H) 6.71-6.85 (m, 1 H) 4.82-5.08 (m, 2 H) 4.57-4.79 (m, 2 H) 4.28 (s, 3 H) 2.09-2.39 (m, 1 H) 1.53-1.78 (m, 3 H) 1.31 (br. s., 3 H) 1.05 (br. s., 3 H) EXAMPLE 151: 2-Chlor0is0pr0pylmethoxy-6,7-dihydr0-10H-benz0[flisoxazolo [3',4':4,5]pyrid0[1,2-d][1,4]0xazepin0ne m/z: 361 [M+H]+ observed). 1H NMR (300 MHz, CDC13) 8 8.06 (d, J=3.6 Hz, 1H), 7.49 (d, J=3.8 Hz, 1H), 6.77 (d, J=3.5 Hz, 1H), 6.65 (d, J=3.7 Hz, 1H), 4.54 (d, J=4.6 Hz, 2H), 3.94 (d, J=4.0 Hz, 3H), 3.80 (d, J=10.5 Hz, 1H), 2.04 (s, 1H), 1.06 (dd, J=6.4, 3.6 Hz, 3H), 0.88 (dd, J=6.9, 3.5 Hz, 3H).

EXAMPLE 152: (6S,10)Hydrazinylidene—6-is0pr0pylmeth0xy(3-methoxy propoxy)—5H,6H-pyrid0[1,2-h]1,7-naphthyridine—9-carb0hydrazide ”“N o MeO/\/\O EXAMPLE 153: (S)—6-Is0pr0pylmeth0xy(3-meth0xypr0p0xy)—5,10-dihydr0pyrazolo MeO/\/\O [3',4' : 4,5] pyrid0[1,2-h] [1,7] naphthyridin-9(6H)—0ne To a solution of (6S)isopropylmethoxy(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2- h]1,7-naphthyridinecarboxylic acid (60 mg, 0.15 mmol) in CHzClz (3 mL) at 0 0C was added phosphorus pentachloride (47 mg, 0.22 mmol). The reaction was d for 10 min. The reaction mixture was transferred via pipet into a stirring solution of methanol in another round bottom flask. The reaction was stirred for 5 min, then quenched by adding sat. sodium bicarbonate solution (10 mL). The aqueous layer was extracted with CHzClz (2x15mL). The combined organic fractions were dried over sodium sulfate and trated under vacuum to give crude methyl (S)isopropylmethoxy-3 -(3 xypropoxy)oxo-5,10-dihydro-6H-pyrido[1,2- h][1,7]naphthyridinecarboxylate. The methyl isopropylmethoxy-3 -(3- methoxypropoxy)oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridinecarboxylate was dissolved in EtOH (2 mL) and hydrazine monohydrate (0.03 mL, 0.75 mmol) was added. The reaction was d for 10h. The solvent was removed under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 5% MeOH/CHzClz) to h: Example 152: (6S,10)Hydrazinylidene—6-is0pr0pylmeth0xy(3-methoxypropoxy)— 5H,6H-pyrid0[1,2-h]1,7-naphthyridinecarb0hydrazide as a white solid (28 mg, 44% yield, -2l6- m/z: 431 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 5 11.25—11.20 (m, 1H), 8.38 (s, 1H), 7.44 (s, 1H), 6.88 (s, 1H), 4.20—4.09 (m, 2H), 4.02 (d, J=0.4 Hz, 3H), 3.89-3.80 (m, 1H), 3.55 (td, J=6.1, 1.4 Hz, 2H), 3.34 (d, J=0.4 Hz, 4H), 3.01 (dd, , 1.5 Hz, 1H), 2.12 (p, J=6.2 Hz, 2H) 7 1.90 (dt, J=9.4, 6.7 Hz, 1H), 0.93 (d, J=6.7 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H) and Example 153: Isopropyl-Z-methoxy-3—(3-methoxypropoxy)—5,10-dihydr0pyrazolo [3',4':4,5]pyrid0[1,2-h][1,7]naphthyridin-9(6H)—0ne as an yellow solid (5 mg, 8% yield, m/z: 399 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 8 9.24 (s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 6.90 (s, 1H), 4.16 (td, J=6.6, 4.5 Hz, 2H), 4.08 (s, 3H), 3.83 (dd, J=9.4, 4.8 Hz, 1H), 3.58 (td, J=6.1, 1.6 Hz, 2H), 3.36 (s, 4H), 3.04 (dd, J=16.3, 1.7 Hz, 1H), 2.15 (p, J=6.2 Hz, 2H), 2.04-1.84 (m, 1H), 0.97 (d, J=6.7 Hz, 3H), 0.79 (d, J=6.7 Hz, 3H).

EXAMPLE 154: (6S)—N'-Acetylisopropyl-Z-methoxy(3-methoxypropoxy)—10-0X0- 5H,6H-pyrid0[1,2-h]1,7-naphthyridinecarb0hydrazide MeO/V\O To a solution of (6S)isopropylmethoxy(3 -methoxypropoxy)oxo-5H,6H-pyrido[1,2- h]1,7-naphthyridinecarboxylic acid (60 mg, 0.15 mmol) in CHzClz (3 mL) at 0 0C was added phosphorus pentachloride (37 mg, 0.18 mmol) and the reaction was stirred for 15min. ydrazide (0.002 mL, 0.30 mmol) in THF (1 mL) was added into above solution dropwise.

The reaction was stirred for 3h at rt. The t was removed under vacuum. The residue was purified by normal phase SiOz chromatography (0% to 5% MeOH/CHzClz) to furnish (6S,10E)- -hydrazinylideneisopropylmethoxy-3 -(3 -methoxypropoxy)-5H,6H-pyrido[1,2-h]1,7- naphthyridinecarbohydrazide as a white solid (5.5 mg, 8% yield, m/z: 459 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 9.27 (s, 1H), 7.93 (s, 1H), 6.98 (s, 1H), 4.21 (t, J=6.5 Hz, 2H), 3.99 (s, 3H), 3.76 (d, J=11.2 Hz, 1H), 3.58 (td, J=6.1, 1.9 Hz, 2H), 3.37-3.38 (m, 4H), 3.13 (d, J=16.6 Hz, 1H), 2.13—2.15 (d, J=12.3 Hz, 5H), 1.95-1.98 (m, 1H), 0.96 (d, J=6.7 Hz, 3H), 0.80 (d, J=6.7 Hz, 3H).

EXAMPLE 155: 6-Is0propyl-Z-methoxy(3-methoxypropoxy)—6-methyl0x0-5,10- 0-6H-pyrid0[1,2-h] [1,7]naphthyridine—9-carb0xylic acid 0 OH 1-[6-Meth0xy—5—(3-methoxyprop0xy)pyridinyl]—2,3-dimethylbutan-2—0l MeO N | OH MeO/V\O / Methylmagnesium bromide solution (3.0M in diethyl ether, 3.6 mL, 11 mmol) was added to anhydrous THF (15 mL) and the mixture was cooled to 0 oC. 1-[6-methoxy(3- methoxypropoxy)pyridinyl]—3-methylbutanone (1 g 3.6 mmol) in anhydrous THF (1 mL) was added drop-wise. The resulting e slowly warmed to rt over 2h and stirred for 30 min.

The mixture was then cooled to 0 oC and ed with sat. aqueous ammonium chloride solution (50 mL) and extracted with EtOAc (3x30 mL). The combined organic fractions were washed with H20, then washed with sat. aqueous brine solution, dried over sodium sulfate and concentrated under vacuum to give 1-[6-methoxy(3 -methoxypropoxy) pyridinyl]-2,3- ylbutanol (1.03 g, 97.4%) as a yellow oil that was used without further purification (1.03 g, 97% yield, m/z: 298 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 5 7.54 (d, J=1.9 Hz, 1H), 7.05 (d, J=1.9 Hz, 1H), 4.10 (td, J=6.8, 5.8 Hz, 2H), 3.99 (s, 3H), 3.56 (t, J=6.1 Hz, 2H), 3.35 (s, 3H), 2.71 (d, J=13.7 Hz, 1H), 2.61 (d, J=13.9 Hz, 1H), 2.10 (p, J=6.3 Hz, 2H), 1.71 (h, J=6.8 Hz, 1H), 1.03 (s, 3H), 0.99 (dd, J=6.8, 2.7 Hz, 6H).

N—{l-[6-Meth0xy—5—(3-meth0xypr0p0xy)pyridinyl]-2,3-dimethylbutanyl}acetamide MeO N\ CY | NH MeO/\/\O / 1-[6-methoxy(3-methoxypropoxy)pyridinyl]—2,3-dimethylbutanol, (520 mg 1.8 mmol) was dissolved in acetonitrile (5 mL) and concentrated sulfuric acid (0.48 mL 8.8 mmol) was added dropwise at 0°C. After stirring at room temperature for 18 hours the reaction mixture was diluted with H20 (30 mL) and extracted with EtOAc (3x30 mL). The combined organic ons were dried over sodium sulfate and concentrated under vacuum. The residue was d by normal phase Si02 chromatography (10% to 100% EtOAc/hexanes) to afford N—{ 1-[6-methoxy- -(3 -methoxypropoxy)pyridinyl]-2,3-dimethylbutanyl}acetamide as a clear oil (228 mg, 39% yield, m/z: 339 [M+H]+ observed).

N-{I-[Z-Bromo—6—meth0xy-5—(3-methoxyprop0xy)pyridin-3—yl]—2,3-dimethylbutan-2— MeO N\ BrOY | NH MeO/\/\O / yl}acetamide N—{1-[6-methoxy(3-methoxypropoxy)pyridinyl]-2,3-dimethylbutanyl}acetamide (130 mg 0.38 mmol) and sodium acetate (37 mg 0.45 mmol) were suspended in glacial acetic acid , , (2 mL), then cooled to 0 OC and bromine (0.02 mL 0.38 mmol) was added drop-wise. The mixture was stirred for 3 hours at rt. The mixture was added ise to a solution of ice water with us ng. The precipitate was filtered and dried to give N—{ 1-[2-bromomethoxy- 5-(3 -methoxypropoxy)pyridinyl]-2,3-dimethylbutanyl}acetamide that was used without further purification as a white solid (95 mg, 60% yield, m/z: 416/420 [M+H]+ observed).

N—{I-[Z-Formyl—6-meth0xy-5—(3-methoxyprop0xy)pyridin-3—yl]—2,3-dimethylbutan-2— MeO N\ O§f/ | NH MeO/\/\O / yl}acetamide N—{ 1-[2-bromomethoxy-5 -(3 -methoxypropoxy)pyridin-3 -yl]—2,3 -dimethylbutan yl}acetamide (67 mg 0.13 mmol) was dissolved in anhydrous THF (2 mL), then cooled to -78 oC (dry ice/acetone bath) and n-butyllithium(1.6 M in s, 0.20 mL 0.32 mmol) was added drop-wise. The reaction mixture was stirred at -78 0C for 60 min. Dimethylforrnamide (0.02 mL, 0.19 mmol) was a subsequently added drop-wise and the reaction was stirred at -78°C for 10 minutes, then warmed to rt and stirred for an additional 30 minutes. The reaction was diluted with H20 (5 mL) and extracted with EtOAc (3x15 mL). The combined organic fractions were washed with H20 (5 mL), sat. aqueous brine solution (5 mL), dried over sodium e and concentrated under vacuum to give a crude 2-formylmethoxy(3- methoxypropoxy)pyridinyl]-2,3-dimethylbutanyl}acetamide that was used without further purification as a yellow oil (47 mg, 60% yield, m/z: 367 [M+H]+ ed). 6-Is0pr0pyl—2—meth0xy—3—(3-meth0xypr0p0xy)-6—methyl-5H-1, 7-naphthyridine MeO N MeO/\/\O / To a solution of N—{ l-[2-formylmethoxy(3 -methoxypropoxy)pyridinyl]-2,3- dimethylbutanyl}acetamide (47 mg 0.08 mmol) in CHzClz (0.5 mL) was added hydrogen chloride on (4M in l,4-dioxane, 0.58 mL, 2.3 mmol). The reaction mixture was stirred at rt for 2 hours. The volatiles were evaporated under vacuum, then the residue was dissolved in H20 and the solution was adjusted to pH 10-12 with sat. aqueous sodium bicarbonate solution. The aqueous layer was then extracted with CHzClz (3 X 20 mL). The ed organic phase was dried over anhydrous sodium e and evaporated in vacuum. The residue was purified by normal phase Si02 chromatography (5% to 60% hexanes) to afford 6-isopropyl methoxy(3 -methoxypropoxy)methyl-5H-l,7-naphthyridine as a yellow oil (26 mg, 83% yield, m/z: 307 [M+H]+ observed). 1H NMR (400MHz, CDCl3): 5 8.21 (s, 1H), 6.83 (s, 1H), 4.14 (t, J=6.5 Hz, 2H), 4.01 (s, 3H), 3.56 (t, J=5.9 Hz, 2H), 3.35 (s, 3H), 2.87 (d, J=16.5 Hz, 1H), 2.49 (d, J=16.4 Hz, 1H), 2.12 (p, J=6.3 Hz, 2H), 1.96 (p, J=6.7 Hz, 1H), 1.08 (s, 3H), 0.98 (dd, J=19.2, 6.9 Hz, 6H).

Ethyl 6-is0pr0pyl—2—meth0xy—3—(3-meth0xypr0p0xy)methyl-1 0-0x0-5,1 dr0—6H— MeO/\/\O pyrid0[1,2-h][1, 7Inaphthyridinecarb0xylate 6-isopropylmethoxy(3-methoxypropoxy)methyl-5H-l,7-naphthyridine (26 mg, 0.08 mmol) and ethyl (2E)—2-(ethoxymethylidene)oxobutanoate (47 mg 0.25 mmol) were dissolved in anhydrous EtOH (1 mL) in a sealed tube. The reaction vessel was flushed with air, then sealed and heated at 90°C overnight. The reaction mixture was concentrated under reduced pressure to give crude ethyl 6-isopropylmethoxy-3 -(3 -methoxypropoxy)methyloxo- ,10, l 1,1 la-tetrahydro-6H-pyrido[1,2-h][l,7]naphthyridinecarboxylate as a brown oil that was used without further purification (23 mg, 61% yield).

The crude e from above and p-chloranil (23 mg, 0.09 mmol) were dissolved in 2-MeTHF (1 mL) and stirred at 75°C for 1h. The reaction mixture was concentrated under vacuum. The residue was ed by reverse phase HPLC to afford ethyl 6-isopropylmethoxy(3- methoxypropoxy)methyl-l0-oxo-5, l0-dihydro-6H-pyrido[l,2-h][1,7] naphthyridine carboxylate as a tan solid (25 mg, 66% yield, m/z: 445 [M+H]+ ed). 1H NMR (400 MHz, CDCl3) 8 8.42 (s, 1H), 7.58 (s, 1H), 6.85 (s, 1H), 4.40 (q, J=7.1 Hz, 2H), 4.20-4.07 (m, 2H), 4.05 (s, 3H), 3.57 (t, J=5.9 Hz, 2H), 3.36 (s, 3H), 3.12 (d, J=16.5 Hz, 1H), 3.01 (d, J=16.4 Hz, 1H), 2.13 (q, J=6.0 Hz, 2H), 2.10-2.05 (m, 1H), 1.63 (s, 3H), 1.40 (t, J=7.1 Hz, 3H), 0.87 (d, J=6.8 Hz, 3H), 0.72 (d, J=6.8 Hz, 3H). 6-Is0pr0pyl—2—meth0xy—3—(3-meth0xypr0p0xy)-6—methyl-1 0—0x0-5H-pyrid0[1,2-h]1, 7- O O MeO/\/\O naphthyridine—9—carb0xylic acid Ethyl 6-isopropylmethoxy-3 -(3 -methoxypropoxy)methyloxo-5H-pyrido[1,2-h]1,7- yridinecarboxylate (25 mg, 0.06 mmol) and lithium hydroxide monohydrate (9 mg 0.2 mmol) were suspended in a THFzMeOHszO mixture (3: 1 : 1, 2 mL) and the reaction was stirred at rt for 2 hours. The volatile organics were d under reduced pressure, H20 (3 mL) was added and the aqueous solution was extracted with EtOAc (3x10 mL). The remaining aqueous solution was acidified to pH 2 with aqueous 1M HCl solution, then extracted with EtOAc (2x10 mL). The organics were dried with sodium sulfate and concentrated to give 6-isopropyl methoxy-3 -(3 -methoxypropoxy)methyloxo-5H-pyrido[1,2-h] 1,7-naphthyridine carboxylic acid as a light brown oil (6.6 mg, 28%, m/z: 417 [M+H]+ observed). 1H NMR (400 MHz, CDC13) 5 8.65 (s, 1H), 7.73 (d, J=1.2 Hz, 1H), 6.89 (s, 1H), .12 (m, 2H), 4.06 (d, J=1.1 Hz, 3H), 3.58 (td, J=6.0, 1.6 Hz, 2H), 3.36 (s, 3H), 3.18 (d, J=16.5 Hz, 1H), 3.07 (d, J=16.6 Hz, 1H),2.17-2.13 (m, 2H), 2.12-2.08 (m, 1H), 1.69 (s, 3H), 0.89 (d, J=6.8 Hz, 3H), 0.71 (d, J=6.8 Hz, 3H).

EXAMPLE 156: 6-Is0propyl-Z-methoxy(3-methoxypropoxy)—6-methyl0x0-5,10- dihydr0-6H-pyrid0[1,2-h][1,7]naphthyridine—9-carb0xylic acid e enantiomer I) EXAMPLE 157: 6-Is0propyl-Z-methoxy(3-methoxypropoxy)—6-methyl0x0-5,10- WO 85619 dihydr0-6H-pyrid0[1,2-h][1,7]naphthyridinecarb0xylic acid (single enantiomer II) 23 mg of the mixture of enantiomers were separated by SFC (supercritical fluid chromatography) on a CHIRALPAK AD column using 30% IPA (0.2% diethylamine as modifier) to give 6- isopropy1methoxy-3 -(3 -methoxypropoxy)methy1oxo-5,10-dihydro-6H-pyrido[1,2- h][1,7]naphthyridinecarboxy1ic acid (single enantiomer I) as a yellow oil (faster eluting enantiomer, 8.3 mg, 36%, m/z: 417 [M+H]+ observed) and 6-isopropy1methoxy-3 -(3- methoxypropoxy)methy1oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine carboxylic acid (single enantiomer II) as a tan solid (slower eluting enantiomer, 7.7 mg, 33%, m/z: 417 [M+H]+ observed).

Example 156: 6—Is0pr0pylmeth0xy(3-methoxypropoxy)—6—methyl0x0-5,10- dihydr0-6H-pyrid0[1,2-h][1,7]naphthyridinecarb0xylic acid (single enantiomer I). m/z: 417 [M+H]+ ed. 1HNMR (400 MHz, CDC13) 6 8.65 (s, 1H), 7.73 (d, J=1.2 Hz, 1H), 6.89 (s, 1H), 4.22-4.12 (m, 2H), 4.06 (d, J=1.1 Hz, 3H), 3.58 (td, J=6.0, 1.6 Hz, 2H), 3.36 (s, 3H), 3.18 (d, J=16.5 Hz, 1H), 3.07 (d, J=16.6 Hz, 1H), .13 (m, 2H), 2.12-2.08 (m, 1H), 1.69 (s, 3H), 0.89 (d, J=6.8 Hz, 3H), 0.71 (d, J=6.8 Hz, 3H).

Example 157: 6—Is0pr0pylmeth0xy(3-methoxypropoxy)—6—methyl0x0-5,10- dihydr0-6H-pyrid0[1,2-h][1,7]naphthyridinecarb0xylic acid (single enantiomer II). m/z: 417 [M+H]+ ed. 1HNMR (400 MHz, CDC13) 6 8.65 (s, 1H), 7.73 (d, J=1.2 Hz, 1H), 6.89 (s, 1H), 4.22-4.12 (m, 2H), 4.06 (d, J=1.1 Hz, 3H), 3.58 (td, J=6.0, 1.6 Hz, 2H), 3.36 (s, 3H), 3.18 (d, J=16.5 Hz, 1H), 3.07 (d, J=16.6 Hz, 1H), 2.17-2.13 (m, 2H), 2.12-2.08 (m, 1H), 1.69 (s, 3H), 0.89 (d, J=6.8 Hz, 3H), 0.71 (d, J=6.8 Hz, 3H).

The ing examples were prepared in a similar manner as isopropy1methoxy(3- methoxypropoxy)methy1oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine carboxylic acid and (R)—6-isopropy1methoxy(3 -methoxypropoxy)methy1oxo-5,10- dihydro-6H-pyrido[1,2-h][1,7]naphthyridinecarboxy1ic acid using an appropriate ketone and Grignard reagent.

EXAMPLE 158: 6-(Tert-butyl)—2-methoxy(3-meth0xypr0p0xy)—6-methyl0x0-5,10- d1hydr0-6H-pyr1d0[1,2-h] [1,7]naphthyr1d1ne—9-carb0xyllc acld. o o o o o m/z: 431 [M+H]+ observed . 1H NMR (400 MHz, CDC13)6 8.65 (s, 1H), 7.75 (s, 1H), 6.83 (s, 1H), 4.24—4.09 (m, 2H), 4.05 (s, 3H), 3.58 (td, J=6.1, 1.5 Hz, 2H), 3.36 (s, 3H), 3.26 (s, 2H), 2.15 (p, J=6.3 Hz, 2H), 1.81 (s, 3H), 0.83 (s, 9H).

EXAMPLE 159: 6-(Tert-butyl)—2-methoxy(3-meth0xypr0p0xy)—6-methyl0x0-5,10- dihydr0-6H-pyrid0[1,2-h][1,7]naphthyridine—9-carb0xylic acid (single enantiomer I) EXAMPLE 160: 6-(Tert-butyl)—2-methoxy(3-meth0xypr0p0xy)—6-methyl0x0-5,10- dihydr0-6H-pyrid0[1,2-h][1,7]naphthyridine—9-carb0xylic acid (single enantiomer II) 0 O mg of the mixture of enantiomers was separated by SFC (supercritical fluid tography) on a CHIRALPAK AD column using 25% IPA (0.1% diethylamine as modifier) to give 6-(tert- butyl)methoxy-3 -(3 -methoxypropoxy)methyl- l O-oxo-S, lO-dihydro-6H-pyrido[ l ,2- h][l,7]naphthyridinecarboxylic acid (single enantiomer I) as a light brown solid (faster eluting omer, 1.5 mg, 30%, m/z: 431 [M+H]+ observed) and t—butyl)—2-methoxy-3 -(3- methoxypropoxy)methyl- l O-oxo-S, l O-dihydro-6H-pyrido[ l ,2-h] [ l ,7]naphthyridine carboxylic acid (single enantiomer II) as a light brown solid (slower eluting enantiomer, 1.3 mg, 26%, m/z: 431 [M+H]+ ed) Example 159: 6-(Tert-butyl)—2-methoxy(3-methoxypropoxy)—6-methyl0x0-5,10- dihydr0-6H-pyrid0[1,2-h][1,7]naphthyridine—9-carb0xylic acid (single enantiomer I). m/z: 431 [M+H]+ observed . 1H NMR (400 MHz, CDC13) 8 8.65 (s, 1H), 7.75 (s, 1H), 6.83 (s, 1H), 4.24-4.09 (m, 2H), 4.05 (s, 3H), 3.58 (td, J=6.1, 1.5 Hz, 2H), 3.36 (s, 3H), 3.26 (s, 2H), 2.15 (p, J=6.3 Hz, 2H), 1.81 (s, 3H), 0.83 (s, 9H).

Example 160: 6-(Tert-butyl)meth0xy(3-meth0xypr0p0xy)—6-methyl0x0-5,10- dihydr0-6H-pyrid0[1,2-h][1,7]naphthyridine—9-carb0xylic acid (single enantiomer II). m/z: 431 [M+H]+ observed . 1H NMR (400 MHz, CDC13) 8 8.65 (s, 1H), 7.75 (s, 1H), 6.83 (s, 1H), 4.24-4.09 (m, 2H), 4.05 (s, 3H), 3.58 (td, J=6.1, 1.5 Hz, 2H), 3.36 (s, 3H), 3.26 (s, 2H), 2.15 (p, J=6.3 Hz, 2H), 1.81 (s, 3H), 0.83 (s, 9H).

EXAMPLE 161: Ethyl 6,6-diethylmethoxy(3-methoxypropoxy)—10-0x0-5,10-dihydr0- O O 6H-pyrido [1,2-h] [1,7]naphthyridine—9-carb0xylate EXAMPLE 162: 6,6-Diethylmeth0xy—3-(3-meth0xypr0p0xy)—10-0x0-5,10-dihydr0-6H- MeO/V\O pyrid0[1,2-h] [1,7]naphthyridine—9-carb0xylic acid m/z: 417 [M+H]+ observed. 1H NMR (400 MHz, CDC13) 5 8.60 (s, 1H), 7.77 (s, 1H), 6.89 (s, 1H), 4.17 (t, J=6.5 Hz, 2H), 4.06 (s, 3H), 3.57 (t, J=5.9 Hz, 2H), 3.36 (s, 3H), 3.07 (s, 2H), 2.14 (p, J=6.2 Hz, 2H), 1.96 (q, J=7.4 Hz, 4H), 0.92 (t, J=7.4 Hz, 6H).

EXAMPLE 163: lis0pr0pylmeth0xy(3-methoxypropoxy)—10-0x0-5,10- 0-6H-pyrid0[1,2-h] [1,7]naphthyridine—9-carb0xylic acid 0 OH —224— m/z: 431 [M+H]+ observed. 1H NMR (400 MHz, CDC13) 5 8.55 (s, 1H), 7.79 (d, J=0.7 Hz, 1H), 6.89 (s, 1H), 4.23—4.12 (m, 2H), 4.06 (d, J=0.7 Hz, 3H), 3.58 (t, J=5.9 Hz, 2H), 3.36 (d, J=0.7 Hz, 3H), 3.23 (d, J=16.6 Hz, 1H), 2.97 (d, J=16.6 Hz, 1H), 2.31 (p, J=6.9 Hz, 1H), 2.22—2.10 (m, 3H), 0.97 (t, J=7.3 Hz, 3H), 0.89 (dd, J=13.4, 6.8 Hz, 6H).

EXAMPLE 164: ,3-Dihydroxyis0pr0pyl0x0-5H,6H—pyrid0[1,2-h]1,7- naphthyridine—9-carb0xylic acid (6S)—6-isopropyl-2,3 -dimethoxyoxo-5H,6H-pyrido[1,2-h]1,7-naphthyridinecarboxylic acid (150 mg, 0.44 mmol) was dissolved in anhydrous CHzClz (3 mL) and cooled to 0 oC. Boron mide solution (1M in CHzClz, 1.7 mL, 1.7 mmol) was added drop-wise and the mixture was stirred at 0 0C for 2 hours, then warmed to rt and heated at 50 0C for 1 hour. Methanol (2 mL) was added to the reaction and the mixture was concentrated to afford (6S)—2,3-dihydroxy isopropyloxo-5H,6H-pyrido[1,2-h]1,7-naphthyridinecarboxylic acid as a yellow solid which was used in the next step without further purification (135 mg, 97%, m/z: 317 [M+H]+ ed). 1H NMR (300 MHz, DMSO-d6) 5 ppm 10.25—10.33 (m, 1 H) 8.73-8.80 (m, 1 H) 7.24— 7.35 (m, 1 H) 6.87-6.98 (m, 1 H) 4.38-4.48 (m, 1 H) 3.32 (br. s., 2 H) 3.12—3.27 (m, 1 H) 2.94— 3.07 (m, 1 H) 1.75—1.90 (m, 1 H) 0.88 (d, J=6.45 Hz, 3 H) 0.69 (d, J=6.45 Hz, 3 H).

Methyl (6S)-6—is0pr0pyl—3—meth0xy—1-methyl-2,1 0-di0x0-5H, 6H-pyrid0[1,2-h]1, 7- O O nuphthyridine—9—carb0xylate (6S)—2,3 -Dihydroxyisopropyloxo-5H,6H-pyrido[1,2-h]1,7-naphthyridinecarboxylic acid (90 mg, 0.26 mmol) and potassium carbonate (177 mg, 1.28 mmol) were ded in DMF (3 mL) and the mixture was heated to 90 0C in an oil bath. Methyl iodide (0.8 mL, 1.3 mmol) in DMF (0.5 mL) was added dropwise and the mixture was stirred at 90 0C for 2 hours. The reaction was filtered through Celite® and the filtrate was concentrated under reduced pressure.

The residue was purified by reverse phase HPLC to afford methyl (6S)isopropylmethoxy- yl-2,10-dioxo-5H,6H-pyrido[1,2-h]l,7-naphthyridinecarboxylate as a white solid (70 mg, 76% yield, m/z: 359 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 5 8.71 (s, 1H), 7.16 (s, 1H), 6.53 (s, 1H), 4.14 (dd, J=9.8, 5.0 Hz, 1H), 3.95 (d, J=14.4 Hz, 6H), 3.72 (s, 3H), 3.31 (dd, J=17.4, 5.3 Hz, 1H), 2.97 (d, J=17.4 Hz, 1H), 2.16-2.05 (m, 1H), 0.99 (dd, J=23.3, 6.7 Hz, 6H).

EXAMPLE 165: (S)Is0pr0pylmethoxymethyl-2,10-di0x0-2,5,6,10-tetrahydr0-1H- o o pyrid0[1,2-h] [1,7]naphthyridine—9-carb0xylic acid Methyl (6S)—6-isopropyl-3 -methoxy-l-methyl-2,l0-dioxo-5H,6H-pyrido[1,2-h] l,7- naphthyridinecarboxylate (10 mg, 0.03 mmol) and lithium hydroxide monohydrate (10 mg, 0.14 mmol) were suspended in a l,4-dioxane/water mixture (1 : l, 1 mL) and the reaction was stirred at rt overnight. The reaction was concentrated under reduced re and the crude residue was taken up in H20 (5 mL), then extracted with EtOAc (2x10 mL) to get rid of impurities. The remaining s solution was acidified to pH 2 with s 1M HCl solution, then extracted with EtOAc (2x10 mL). The combined organic fractions were dried with sodium sulfate, then concentrated to give (S)—6-isopropyl-3 xy-l-methyl-2,10-dioxo- 2,5,6,l0-tetrahydro-lH-pyrido[l,2-h][l,7]naphthyridinecarboxylic acid as a white solid (5.6 mg, 58% yield, m/z: 345 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 5 8.52 (s, 1H), 6.90 (d7 J=1.2 Hz, 1H), 6.51 (s, 1H), 4.00-3.83 (m, 4H), 3.74 (d, J=1.2 Hz, 3H), 3.20 (dd, J=17.1, 5.2 Hz, 1H), 2.95 (d, J=17.2 Hz, 1H), 2.13—2.03 (m, 1H), 1.05—0.94 (m, 6H).

Ethyl 6-is0pr0pyl—3—(3-meth0xypr0p0xy)—2,10—di0x0-2, 5, 6,1 0—tetrahydr0—1H—pyrid0[1,2- O O MeO/V\O h][1, 7]nuphthyridine—9—carb0xylate A mixture of ethyl 6-isopropylmethoxy(3-methoxypropoxy)-lO-oxo-5,10-dihydro-6H- pyrido[l,2-h][l,7]naphthyridinecarboxylate (lg, 2.3 mmol) in hydrobromic acid (40% aqueous solution, 10 mL) was stirred at rt for 16 hours. The pH of the reaction mixture was adjusted to 8 with sat. aqueous NaHC03 (30 mL). The aqueous phase was extracted with CHzClz (5x40 mL). The combined organic layers were concentrated under reduced pressure to give ethyl 6-isopropyl-3 -(3 -methoxypropoxy)-2,10-dioxo-5,6-dihydro-1H-pyrido[1,2-h][1,7]naphthyridine- oxylate as a dark brown solid that was used in the next step without further purification (750 mg, 78% yield, m/z: 417 [M+H]+ observed). 6—is0pr0pyl—3—(3-meth0xypr0p0xy)—2,1 0-di0x0-2, 5, 6, 1 0-tetrahydr0—1H-pyrid0[1,2- MeOMO h][1, 7Inaphthyrldmecarb0xyllc aad. . . .

To a solution of ethyl 6-isopropyl(3-methoxypropoxy)-2,10-dioxo-5,6-dihydro-1H- [1,2-h][1,7]naphthyridinecarboxylate (700 mg, 1.68 mmol) in THF (7 mL) and H20 (7 mL) was added lithium hydroxide monohydrate (70 mg, 1.7 mmol). The mixture was stirred at rt for 16 hr. The reaction mixture was extracted with CHzClz (5x30 mL). The combined c phase was concentrated in vacuum and the pH was adjusted to 3 with 1NHCl (4 mL). The resulting solid was filtered and washed with CH3CN (3x3 mL) to afford 6-isopropyl-3 -(3- methoxypropoxy)-2,10-dioxo-2,5,6,10-tetrahydro-1H-pyrido[1,2-h][1,7]naphthyridine carboxylic acid as a white solid that was used in the next step without further purification (240 mg, 37% yield, m/z: 389 [M+H]+ observed).

EXAMPLE 166: 6-Is0propyl(3-meth0xypr0p0xy)-2,10-di0x0-2,5,6,10-tetrahydr0-1H- pyrid0[1,2-h][1,7]naphthyridinecarb0xylic acid (single enantiomer I) EXAMPLE 167: 6-Is0propyl(3-meth0xypr0p0xy)-2,10-di0x0-2,5,6,10-tetrahydr0-1H- pyrid0[1,2-h][1,7]naphthyridinecarb0xylic acid e enantiomer II) 240 mg of the mixture of 6-isopropyl(3-methoxypropoxy)-2,10-dioxo—2,5,6,10-tetrahydro-1H- pyrido[1,2-h][1,7]naphthyridinecarboxylic acid enantiomers was separated by SFC critical fluid tography) on a CHIRALCEL® OJ-3 column using 35% MeOH (0.1% NH4OH as modifier) to give 6-isopropyl(3 -methoxypropoxy)-2,10-dioxo-2,5,6, lO-tetrahydro- 1H-pyrido[1,2-h][1,7]naphthyridinecarboxylic acid (single enantiomer I) as an yellow solid (faster eluting omer, 84 mg, 35%, m/z: 389 [M+H]+ observed) and 6-isopropyl(3- methoxypropoxy)-2,10-dioxo-2,5,6,10-tetrahydro-1H-pyrido[1,2-h][1,7]naphthyridine carboxylic acid (single enantiomer II) as an yellow solid (slower eluting enantiomer, 92 mg, 38%, m/z: 389 [M+H]+ observed).

Example 166: r0pyl(3-meth0xypr0p0xy)—2,10-di0x0-2,5,6,10-tetrahydr0-1H- [1,2-h][1,7]naphthyridine—9-carb0xylic acid (single enantiomer I). m/z: 389 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6) 8 8.78 (s, 1H), 7.30 (s, 1H), 7.21 (s, 1H), 4.47-4.44 (m, 1H), 4.12-4.02 (m, 2H), 3.49-3.46 (t, J=6Hz, 2H), 3.25 (m, 4H), 3.11-3.07 (m, 1H), 2.02- 1.95 (m, 2H), 1.84-1.78 (m, 1H), 0.89-0.87 (d, J=6.4Hz, 3H), 0.70-0.68 (d, J=6.8Hz, 3H).

Example 167: 6-Is0pr0pyl(3-meth0xypr0p0xy)—2,10-di0x0-2,5,6,10-tetrahydr0-1H- pyrid0[1,2-h][1,7]naphthyridine—9-carb0xylic acid (single enantiomer II). m/z: 389 [M+H]+ observed . 1H NMR (400 MHz, DMSO-d6) 8 8.78 (s, 1H), 7.30 (s, 1H), 7.21 (s, 1H), 4.47-4.44 (m, 1H), 4.12-4.02 (m, 2H), 3.49-3.46 (t, J=6Hz, 2H), 3.25 (m, 4H), 3.11-3.07 (m, 1H), 2.02- 1.95 (m, 2H), 1.84-1.78 (m, 1H), 0.89-0.87 (d, J=6.4Hz, 3H), 0.70-0.68 (d, J=6.8Hz, 3H).

E 168: (S)Isopropyl-Z-methoxy(3-meth0xyprop0xy)—11-0x0-5,6,7,11- MeO’\/\O tetrahydrodipyrido[1,2-a:2',3'-c]azepine—lO-carboxylic acid uljyl N—[(3S)[6-meth0xy(3-methoxyprop0xy)pyridin-3—yl]methylpentan-3— yllcarbamate Me In a dry microwave vial, lerl—butyl N—[(3R)methylpenten-3 -yl]carbamate (289 mg, 1.45 mmol) was dissolved in THF (1 mL), followed by the addition of 9-borabicyclo[3.3.1]nonane (0.5 M in THF, 5.8 mL, 2.90 mmol) at O 0C. The reaction was warmed up to room temperature and stirred for 2 h. The solution was purged with nitrogen gas for 1 minute. 5-Bromo methoxy(3-methoxypropoxy)pyridine (400 mg, 1.45 mmol) was dissolved in THF (0.5 mL) and added into above solution via syringe. [1,1'-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) (118 mg, 0.14 mmol), cesium carbonate (0.94 g, 2.90 mmol) and H20 (0.5 mL) were added to the e. The reaction was stirred at room temperature for 16h.

The solvent was removed under reduced pressure. The residue was purified by normal phase SiOz chromatography (0% to 50% EtOAc/hexanes) to furnish tert-butyl N—[(3 6-methoxy- -(3-methoxypropoxy)pyridinyl]—4-methylpentanyl]carbamate as a light yellow oil (0.28 g, 49% yield, m/z: 397 [M+H]+ ed).

Tert-buljyl N—[(3S)[2-br0m0meth0xy(3-methoxyprop0xy)pyridinyl]—4—methylpentan- MeO N Br NHBoc I - I I I< arbamate MGOMO Sodium acetate (57 mg, 0.69 mmol), lerl-butyl N—[(3 S)[6-methoxy(3- methoxypropoxy)pyridinyl]—4-methylpentan-3 -yl]carbamate (280 mg, 0.71 mmol) and bromine (0.04 mL, 0.71 mmol) were dissolved in glacial acetic acid (2 mL) and the reaction was d at room temperature for 2 h. The reaction was quenched by the addition of sat. aqueous sodium bicarbonate solution (5 mL). The reaction mixture was extracted with CHZCIZ (2x5 mL).

The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by normal phase Si02 chromatography (0% to 40% EtOAc/hexanes) to furnish Ierl—butyl N—[(3 S)[2-bromomethoxy(3- methoxypropoxy)pyridinyl]—4-methylpentanyl]carbamate as a light yellow solid (210 mg, 63% yield, m/z: 474/476 [M+H]+ observed). (3S)[2-Br0m0meth0xy-5—(3-meth0xypr0p0xy)pyridinyl]methylpentanamine MeO /N Br NH2 I HI< MeO/\/\O \ To a solution of lerl—butyl N—[(3 S)[2-bromomethoxy(3 -methoxypropoxy)pyridin-3 -yl]- 4-methylpentan-3 -yl]carbamate (210 mg, 0.44 mmol) in CHzClz (2 mL) was added a on of HCl (4N in oxane, 0.2 mL, 0.88 mmol) was added and stirred at room temperature for 16h.

The reaction was quenched by adding 1N aqueous sodium hydroxide solution (2 mL). The aqueous layer was extracted with CHzClz (3x2 mL). The combined c layer was dried over sodium sulfate and concentrated under reduced pressure to give (3 S)[2-bromomethoxy (3 -methoxypropoxy)pyridin-3 -yl]methylpentanamine as a yellow solid that was used in the next step without r purification (0.13 g, 78% yield, m/z: 374/376 [M+H]+ observed). 1-[(3S)[2-Br0m0meth0xy(3-meth0xypr0p0xy)pyridin-3—yllmethylpentanyll o 0 MeO N Br W MeO/V\O \‘11,(W 0x0pyridine—3—carb0xylic acid -[2-Bromomethoxy(3 -methoxypropoxy)pyridin-3 -yl]—4-methylpentan-3 -amine (20 mg, 0.05 mmol) and lerl-butyl 4-oxopyrancarboxylate (10 mg, 0.05 mmol) were dissolved in ethanol/acetic acid (1:1, 0.2 mL) and heated to 90 0C for 4 h. The solvent was removed under reduced pressure. The residue was purified by reverse phase HPLC to afford 1-[(3S)[2-bromo- 6-methoxy(3 xypropoxy)pyridinyl]—4-methylpentan-3 -yl]—4-oxopyridine carboxylic acid as a white solid (11 mg, 44% yield, m/z: 497 [M+H]+ observed).

(S)- 7-Is0pr0pyl—2—meth0xy-3—(3-meth0xypr0p0xy)0x0-5, 6, 7,11-tetrahydr0dipyrid0[1,2- O OH MeO’\/\ (1:2 ',3 '-c]azepine—1 0-carb0xylic acid 1-[(3S)[2-bromomethoxy(3 -methoxypropoxy)pyridin-3 -yl]methylpentanyl] oxopyridinecarboxylic acid (27 mg, 0.05 mmol) and ium acetate (12 mg 0.12 mmol) were dissolved in dimethylacetamide (2 mL) in a microwave flask and sealed. The solution was purged with nitrogen for 2 min, followed by the addition of (chloro[(tri-tert-butylphosphine) (2-aminobiphenyl)] palladium(II)) (3 mg, 0.01 mmol). The on was heated at 125 0C in microwave reactor for 1h. The crude mixture was purified by reverse phase HPLC to afford (S)- 7-isopropylmethoxy(3-methoxypropoxy)-1 1-oxo-5,6,7,1 1-tetrahydrodipyrido[1,2-a:2',3'- c]azepinecarboxylic acid as a white solid (5 mg, 24% yield, m/z: 417 [M+H]+ observed). 1H NMR (300 MHz, CDCl3) 6 8.64 (s, 1H), 7.18 (s, 1H), 6.94 (s, 1H), 4.18 (t, J=6.5 Hz, 2H), 4.05 (d, J=1.0 Hz, 3H), 3.59-3.60 (m, 3H), 3.37 (t, J=1.1 Hz, 3H), 2.69 (bs, 1H), 2.49 (bs, 3H), 2.15 (m, 3H), .86 (m, 6H).

The following e was prepared in a similar manner as (S)isopropylmethoxy(3- methoxypropoxy)oxo-5,6,7,1 1-tetrahydrodipyrido[1,2-a:2',3'-c]azepinecarboxylic acid from 8-bromo-3,4-dihydro-2H-[1,4]dioxepino[2,3-b]pyridine and utyl N—[(3R)—4- methylpenten-3 -y1]carbamate.

EXAMPLE 169: (S)Is0pr0pyl0x0-2,6,7,8,12,13-hexahydr0-11H-[1,4]di0xepin0 [2',3':5,6]pyrido[2,3-c]pyrido[1,2-a]azepine—3-carb0xylic acid m/z: 371 [M+H]+ observed . 1H NMR (400 MHz, CDC13): 5 8.55 (s, 1H), 7.12 (s, 1H), 6.99 (s, 1H), 4.39 (d, J=30.7 Hz, 4H), 3.51 (bs, 1H), .75 (m, 6H), 1.36 (d, J=13.0 Hz, 1H), 0.97- 0.78 (m, 6H).

EXAMPLE 170: (S)Is0pr0pyl0x0-2,6,7,8,11,12-hexahydr0-[1,4]dioxino[2',3':5,6] [2,3-c]pyrido[1,2-a]azepine—3-carb0xylic acid EXAMPLE 171: 2'-Meth0xy-3'-(3-meth0xypr0p0xy)—10'-0x0-5',10'-dihydr0spir0 [cyclobutane—1,6'-pyrido[1,2-h] [1,7]naphthyridine]-9'-carboxylic acid /N‘ k \ Tert—buljyl N-[1-[meth0xy(methyl)carbamoyllcyclobunil/carbamate 1-(tert-Butoxycarbony1amino)cyclobutanecarboxylic acid (3 g, 13.9 mmol), HATU (6.36 g, 16.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.5 g, 15.3 mmol) were dissolved in DMF (45 mL). Then N, N—diisopropylethylamine (9.71 mL, 55.8 mmol) was added. The reaction was stirred at rt for 16 h. The mixture was diluted with EtOAc (100 mL) and poured into H20 (200 mL). The aqueous phase was separated and ted with EtOAc (2x50 mL). The combined organics were dried over sodium sulfate, filtered and trated under . The residue was purified by normal phase SiOz chromatography (5% to 50% EtOAc/petroleum ether) to give tert-butyl N—[1-[methoxy(methyl)carbamoyl]cyclobutyl]carbamate as a light yellow solid (2g, 56%, m/z: 259 [M+H]+ observed).

Tert-buljyl N-[l-[6-meth0xy—5—(3-meth0xypr0p0xy)pyridine—3—carb0nyllcycl0 rbamate MeO N \ NHBoc MeO/\/\O / To a mixture of 5-bromomethoxy(3-methoxypropoxy) pyridine (3 g, 11 mmol) in THF (30 mL) was added n-BuLi (2.5M in s, 6.1 mL, 15 mmol) dropwise at -70 0C under N2. The mixture was stirred at -70 0C for 1 h. Then a mixture of tert-butyl N—[l-[methoxy(methyl) carbamoyl]cyclobutyl]carbamate (0.37 mL, 5.76 mmol) in THF (10 mL) was added dropwise at - 70 0C under N2. The mixture was stirred at -70 0C for 3 h. The mixture was quenched with sat. aqueous ammonium de solution (200 mL) and extracted with EtOAc (3x100mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The e was purified by normal phase Si02 chromatography (10% to 35% EtOAc/petroleum ether) to give tert-butyl 6-methoxy(3-methoxy propoxy)pyridine carbonyl]cyclobutyl]carbamate as a yellow oil (500 mg, 22%, m/z: 395 [M+H]+ observed). 1-[[6-Meth0xy(3-meth0xypr0p0xy)pyridyl]methyl]cyclobutanamine MeO N\ l NH2 MeO/\/\O / To a mixture of tert-butyl N—[1-[6-methoxy(3-methoxypropoxy) pyridinecarbonyl] cyclobutyl]carbamate (500 mg, 1.3 mmol) and gadolinium(III) trifiuoromethanesulfonate (524 mg, 1.01 mmol) in 1,2-dichloroethane (10 mL) was added chlorodimethylsilane (600 mg, 6.3 mmol). The reaction was stirred at 80 0C for 16 hours. The pH of the reaction was adjusted to 8- 9 with sat. aqueous sodium bicarbonate solution. The aqueous layer was extracted with CHzClz (3x50 mL). The combined organics were dried over over sodium sulfate, filtered and concentrated under vacuum to give 1-[[6-methoxy(3 -methoxypropoxy)pyridyl]methyl] cyclobutanamine as a yellow oil that was used in the next step without further purification (360 mg, 99%, m/z: 281 [M+H]+ observed).

Tert-buljyl N—[l-[[6-meth0xy—5—(3-meth0xypr0p0xy)pyridyl]methyl]cycl0buljyl] carbamate MeO N \ NHBoc MeO/\/\O / To a mixture of 1-[[6-methoxy(3 xypropoxy)-3 -pyridyl]methyl] cyclobutanamine (360 mg, 1.28 mmol) and ylamine (0.45 mL, 3.2 mmol) in CHzClz (10 mL) was added di-Zerl— butyl dicarbonate (336.3 mg, 1.54 mmol). The reaction was stirred at rt for 16 hours. The reaction was quenched by adding H20 (20 mL). The s layer was extracted with CHzClz (3x10mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal phase Si02 chromatography (25% to 50% EtOAc/petroleum ether) to give Ierl—butyl N—[1-[[6-methoxy(3-methoxypropoxy) pyridyl]methyl]cyclobutyl]carbamate as a yellow solid (220 mg, 45%, m/z: 381 [M+H]+ observed).

Tert-buljyl N-[l-[[2-br0m0—6-meth0xy—5-(3-meth0xypr0p0xy)pyridyl]methyl] MeO N Br \ NHBoc /\/\ / MeO 0 utyl]carbamate To a mixture of lerl-butyl N—[1-[[6-methoxy(3-methoxypropoxy)pyridyl]methyl] cyclobutyl]carbamate (220 mg, 0.58 mmol) in CHzClz (1 mL) and sat. s NaHC03 solution (1 mL) at 0 0C under N2 was added a solution of bromine (0.03 mL, 0.64 mmol) in CHzClz (1 mL) se. The mixture was stirred at rt for 16 hours. The reaction mixture was quenched by the addition of sat. aqueous sodium bicarbonate solution (20 mL) and extracted with CHzClz (3x10 mL). The combined organic layers were dried over sodium e, filtered and concentrated under reduced pressure. The residue purified by normal phase Si02 chromatography (5% to 35% EtOAc/petroleum ether) to give Zerl-butyl N—[l-[[2-bromo methoxy(3 -methoxypropoxy) pyridyl] methyl]cyclobutyl]carbamate as a yellow oil (110 mg, 42%, m/z: 458/460 [M+H]+ observed). 1H NMR (400 MHz, CDCl3): 5 7.14 (s, 1H), 4.49 (s, 1H), 4.13—4.10 (m, 3H), 3.98 (s, 3H), 3.58-3.55 (m, 2H), 3.36 (s, 3H), 3.12 (m, 1H), 2.28-2.25 (m, 2H), 2.19—2.09 (m, 2H), 1.82-1.79 (m, 2H), 1.57—1.47 (m, 2H), 1.37 (s, 9H).

Tert-buljyl (1-((2-f0rmyl—6-meth0xy—5-(3-meth0xypr0p0xy)pyridin-3—yl)methyDcyclobulj/l) MeO N /800 |\ HN /\/\ / M60 0 carbamate Terr-bury]N-(1 -{ [2-bromomethoxy(3 -methoxypropoxy)pyridin-3 -yl]methyl } cyclobutyl) carbamate (110 mg, 0.24 mmol) was dissolved in anhydrous THF (5 mL). The reaction was cooled to -78 OC and n-Buli (1.6 M solution in hexanes, 0.45 mL, 0.72 mmol) was added dropwise. The reaction e was stirred at -78 0C for 15 minutes. Dimethylformamide (0.02 mL, 0.29 mmol) was added dropwise and the reaction was stirred at -78 0C for 10 minutes, then warmed to room temperature and stirred for an additional 10 minutes. The reaction mixture was quenched with H20 (5 mL) with vigorous stirring. The reaction was extracted with EtOAc (3x5 mL). The combined organics were dried with sodium sulfate and trated under vacuum to give tert-butyl N—(1-{ [2-formylmethoxy-5 -(3 -methoxypropoxy)pyridin-3 thyl} cyclobutyl)carbamate as a yellow oil that was used in the next step without further purification (98 mg, 100.0 %, m/z: 409 [M+H]+ observed). 2 '-Meth0xy-3 '-(3-meth0xypr0p0xy)—5 'H-spir0[cycl0butane-1, 6 '-[1, 7Inaphthyridine] MeO N MeO/\/\O / To a solution of lerl—butyl N—(1-{[2-formylmethoxy(3 -methoxypropoxy)pyridin yl]methyl}cyclobutyl)carbamate (98 mg, 0.24 mmol) in CHzClz (5 mL) was added hydrogen chloride (4N on in oxane, 0.12 mL, 0.48 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under vacuum, then treated with H20 (5 mL) and basified with sat. aqueous sodium bicarbonate solution until pH 10- 12. The mixture was extracted with CHzClz (3 x 5 mL). The combined organics were dried over anhydrous sodium sulfate and ated under vacuum. The residue was purified by normal phase Si02 chromatography (0-6% HzClz) to give 2-methoxy(3 -methoxypropoxy)- ro[1,7-naphthyridine-6,1'-cyclobutane] as a colorless oil that was used in the next step without further purification (25 mg, 36 %, m/z: 291 [M+H]+ observed). —234— Ethyl 2 '-meth0xy-3 '-(3-meth0xypr0p0xy)—1 0 '-0x0-5 ', 1 0 ',11 ', 11a '-tetrahydr0spir0[cycl0butune- O O MeO N\ N MeOMO / 1, 6 '-pyrid0[1,2—h][1, 7Inaphthyridinel-9 '-carb0xylate 2-Methoxy(3-methoxypropoxy)-5H-spiro[l,7-naphthyridine-6,l'-cyclobutane] (25 mg, 0.09 mmol) and ethyl (2E)—2-(ethoxymethylidene)oxobutanoate (48 mg, 0.26 mmol) were ved in anhydrous ethanol (3 mL) and the reaction mixture was heated at 80 0C for 16 hours. The reaction e was concentrated under reduced pressure to give ethyl 2'—methoxy- 3'-(3 -methoxypropoxy)-l 0'-oxo-l l',l l'a-dihydro-5'H-spiro[cyclobutane-l,6'—pyrido[l,2-h]1,7- naphthyridine]-9'—carboxylate as a brown foam that was used in the next step without further purification (37 mg, 100 %, m/z: 431 [M+H]+ observed).

Ethyl 2 '-meth0xy-3 '-(3-meth0xypr0p0xy)—1 0 '-0x0-5 ',1 0 '-dihydr0spir0[cyclobutune-1, 6 '- MeOMO pyrid0[1,2-h][1,7Inaphthyridinel- '-carb0xylate ethyl 2'-methoxy-3 '-(3 -methoxypropoxy)-10'-oxo-l l', l l'a-dihydro-5 'H-spiro[cyclobutane- l ,6'— pyrido[l,2-h]l,7-naphthyridine]-9'-carboxylate (37 mg, 0.09 mmol) and p-chloranil (25.4 mg, 0.10 mmol) were dissolved in 2-MeTHF (3 mL) and stirred at 70 CC for lh. The reaction mixture was evaporated under vacuum. The residue was d by normal phase Si02 chromatography (0% to 7% MeOH/CHzClz) to give ethyl hoxy-3'-(3 -methoxypropoxy)- l0'-oxo-5'H-spiro[cyclobutane-l,6'—pyrido[1,2-h]l,7-naphthyridine]-9'—carboxylate as a yellow solid that was used in the next step without further purification (8 mg, 22 %, m/z: 431 [M+H]+ observed). 2 '-Meth0xy-3 '-(3-meth0xypr0p0xy)—1 0 '-0x0-5 ',1 0 '-dihydr0spir0[cyclobutune-1, 6 d0[1,2- MeOMO h][1, thyridinel-9 '-carb0xylic acid To a solution of ethyl 2'—methoxy-3'—(3 -methoxypropoxy)-10'-oxo-5'H-spiro[cyclobutane-1,6'- [1,2-h]1,7-naphthyridine]-9'-carboxylate (8 mg, 0.02 mmol) in 1,4-dioxane/H20 (2:1 mixture, 2 mL) was added lithium hydroxide monohydrate (1.2 mg, 0.03 mmol). The reaction was stirred at rt for 6 hours. The pH of the reaction was adjusted to 5-6 by the addition of 1N HCl. EtOAc (2 mL) and H20 (2 mL) were added to the reaction mixture. The s layer was extracted with EtOAc (2x2 mL). The combined organic phase was dried over sodium sulfate and the solvent removed under . The e was purified by normal phase SiOz chromatography (0% to 4% MeOH/CHzClz) to afford 2'-methoxy-3'-(3 xypropoxy)-10'- oxo-5'H-spiro[cyclobutane-1,6'-pyrido[1,2-h]1,7-naphthyridine]-9'—carboxylic acid as a white solid (5 mg, 66 %, m/z: 401 [M+H]+ observed). 1H NMR (400 MHz, CDCl3) 5 8.53 (s, 1H), 7.74 (d, J=0.6 Hz, 1H), 7.00 (s, 1H), 4.55 (q, J=8.1 Hz, 1H), 4.19 (q, J=6.4 Hz, 2H), 4.06 (d, J=0.7 Hz, 3H), 3.65 (td, J=7.1, 3.3 Hz, 1H), 3.58 (dp, J=8.3, 2.9 Hz, 2H), 3.36 (d, J=0.7 Hz, 3H), 2.38 — 2.07 (m, 5H), 1.83 (tdd, J=15.6, 10.7, 7.4 Hz, 2H), 1.70 (dt, J=12.9, 7.9 Hz, 1H).

E 172: (R)- S-Isopropyl-Z-methoxy0x0—5,9-dihydr0pyrido[2,3-a]indolizine O O carboxylic acid (R,E)—N—((2-Br0m0—6-meth0xypyridine—3-yl)methylene)methylpr0pane—2—sulfinamide MeO N Br 70; k/ / N \ISI To a solution of 2-bromomethoxy-nicotinaldehyde (1.0 g, 4.6 mmol) and (R)-(+)methyl propanesulf1namide (0.84 g, 6.9 mmol) in CH2C12 (100 mL) was added boron trifluoride-diethyl ether complex (1.7 mL, 14 mmol) and the resulting mixture was stirred at rt for 24 h. The reaction mixture was then cooled to 0 OC and treated with s sodium bicarbonate solution (100 mL). After stirring for 30 min the biphasic mixture was filtered through a plug of Celite®.

The organic layer was separated, washed with sat. aqueous brine solution (100 mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by normal phase SiOz chromatography (0 to 10 % EtOAc/hexanes) to give (R,E)—N—((2- WO 85619 bromomethoxypyridineyl)methylene)methylpropanesulfinamide as white solid (1.1 g, 75% yield, m/z: 318/320 [M+H]+ observed). 1H NMR (300 MHz, CDCl3): 5 8.85 (s, 1H), 8.22 (d, J=9 Hz, 1H), 6.80 (d, J=6 Hz, 1H), 4.03 (s, 3H), 1.27 (s, 9H).

((R)(2-br0m0meth0xypyridine—3—yl)methylpr0pyl)methylpr0pane—2— MeO N Br 71);“\/ J< : \fi sulfinamide /\0 To a solution of diisopropyl zinc (1.0 M solution in toluene, 10.1 mL, 10.2 mmol) was added dropwise pyl magnesium chloride (2.0 M solution in THF, 4 mL, 8 mmol) and the mixture d to stirr at rt under argon for 20 min to give the triorganozincate reagent. The triorganozincate solution was transferred via cannula to a flask containing (R,E)-N—((2-bromo methoxypyridineyl)methylene)methylpropanesulfinamide (2.16 g, 6.79 mmol) in THF (50 mL) at — 78 oC and the mixture allowed to stir for further 3 h. Saturated aqueous ammonium chloride solution (50 mL) and EtOAc (50 mL) were added to the mixture and stirred at rt for 1 h.

The biphasic mixture was filtered through a pad of Celite® and the organic layer separated, washed with sat. s brine solution (100 mL) and dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced re and the resultant residue was purified by normal phase Si02 chromatography (10 to 20 % EtOAc/CHzClz) to give the major diastereomer (R)-N—((R)(2-bromomethoxypyridine-3 -yl)methylpropyl)methylpropane sulfinamide as white solid (0.92 g, 37% yield, m/z: 362/364 [M+H]+ ed). 1H NMR (300 MHz, CDC13): 5 7.50 (d, J=6 Hz, 1H), 6.74 (d, J=9 Hz, 1H), 4.39 (t, J=6 Hz, 1H), 3.94 (s, 3H), 3.69 (d, J=9 Hz, 1H), 2.22—2.15 (m, 1H), 1.23 (s, 9H), 1.04 (d, J=6 Hz, 3H), 0.91(d, J=6 Hz, 3H).

MeO N Br / NH2 (R)(Z-Bromometh0xypyridine—3—yl)methylpr0pane—1-amine /:\ To a stirred on of (R)-N—((R)(2-bromomethoxypyridine-3 -yl)methylpropyl) methylpropanesulfinamide (0.92 g, 2.5 mmol) in MeOH (50 mL) was added HCl solution (4N in 1,4-dioxane, 10 mL) and the e allowed to stir at rt for 15 h. The mixture was then concentrated to dryness under reduced pressure and the residue treated with aqueous saturated sodium bicarbonate solution (25 mL), extracted with EtOAc (2 x 30 mL) and the organic layer dried over anhydrous sodium sulfate. The organic solvent was d under reduced pressure to give (2-bromomethoxypyridine-3 -yl)methylpropaneamine as a yellow oil that was used in the next step without further purification (0.75 g, >100% yield, m/z: 258/260 [M+H]+ observed). 1H NMR (300 MHz, CDC13): 5 7.67 (d, J=9 Hz, 1H), 6.74 (d, J=6 Hz, 1H), 4.07 (d, J=6 Hz, 1H), 3.94 (s, 3H), .89 (m, 1H), 1.52 (bs, 2H), 1.01 (d, J=6 Hz, 3H), 0.89 (d, J=6 Hz, 3H).

(R)-Ethyl(1-(2—br0m0—6—meth0xypyridine—3-yl)methylpr0pyl)—4—0x0—1,4-dihydr0 pyridine- MeO Br O LLN /|N\ / 3-carb0xylate /=\ A mixture of (R)(2-bromomethoxypyridineyl)methylpropaneamine (0.65 g, 2.5 mmol) and ethyloxo-4H-pyrancarboxylate (0.42 g, 2.50 mmol, prepared according to W0201713046) in EtOH (20 mL) was d at 90 0C for 1 h. Acetic acid (3 mL) was then added and the mixture allowed to stir at 90 0C for further 6 h. The reaction mixture was then concentrated to s under reduced pressure and the residue treated with EtOAc (30 mL) and aqueous saturated sodium bicarbonate solution (25 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent distilled off under reduced pressure and the resultant residue was purified by normal phase SiOz chromatography (0 to 10 % MeOH/CHzClz) to give (R)-ethyl(1-(2-bromomethoxypyridine-3 -yl)methylpropyl)oxo-1,4-dihydro pyridinecarboxylate as yellow oil (0.79 g, 77% yield, m/z: 408/410 [M+H]+ observed). 1H NMR (300 MHz, CDC13): 5 8.26 (d, J=3 Hz, 1H), 7.67 (d, J=6 Hz, 1H), 7.32 (dd, J=6, 2 Hz, 1H), 6.86 (d, J=9 Hz, 1H), 6.48 (d, J=6 Hz, 1H), 4.83 (d, J=12 Hz, 1H), 4.38 (q, J=6 Hz, 2H), 3.97 (s, 3H), .51 (m, 1H), 1.39 (t, J=6 Hz, 3H), 1.01 (dd, J=9 Hz & 6 Hz, 6H).

(R)-ethylis0pr0pyl—2—meth0xy0x0-5,9-dihydr0pyrid0[2,3-alind0lizinecarb0xylate To a solution of (R)-ethyl(1-(2-bromomethoxypyridineyl)methylpropyl)oxo-1,4- dihydro pyridinecarboxylate (0.79 g, 1.9 mmol) in dry methyl acetamide (10 mL) was added ium acetate (0.38 g, 3.8 mmol) and degassed for 10 minutes with argon gas.

Palladium (II) bromide (0.051 mg, 0.19 mmol) was added under argon atmosphere and the degassing continued for 20 minutes. The reaction e was then stirred at 120 0C for 30 h.

The reaction mixture was cooled to rt, diluted with H20 (30 mL) and extracted with EtOAc (3x10 mL), washed with sat. s brine solution (10 mL), dried over sodium sulfate, filtered and concentrated under d pressure. The residue was purified by normal phase Si02 chromatography (0 to 15 % MeOH in EtOAc) to afford a yellow oil. The semi pure yellow oil was purified twice by preparative TLC (9:1 CHzClz/MeOH, followed by 9:1 EtOAc/MeOH) to give (R)-ethylisopropylmethoxyoxo-5,9-dihydropyrido[2,3-a]indolizinecarboxylate as an off-white solid (100 mg, 16% yield, m/z: 329 [M+H]+ observed). 1H NMR (300 MHz, CDCl3): 5 8.47 (s, 1H), 7.71 (d, J=9 Hz, 1H), 7.09 (s, 1H), 6.89 (d, J=9 Hz, 1H), 5.16 (d, J=6 Hz, 1H), 4.44—4.37 (m, 2H), 4.03 (s, 3H), 2.61-2.55 (m, 1H), 1.41 (t, J=9 Hz, 3H), 1.24 (d, J=6 Hz, 3H), 0.60 (d, J=6 Hz, 3H).

EXAMPLE 173: (R)Is0pr0pylmethoxy0x0-5,9-dihydr0pyrid0[2,3-a]indolizine carboxylic acid To a solution of hylisopropylmethoxyoxo-5,9-dihydropyrido[2,3-a]indolizine carboxylate (50 mg, 0.15 mmol) in MeOH (3 mL) was added a solution of sodium ide (0.018 g, 0.45 mmol) in H20 (3 mL) and the mixture allowed to stir at rt for 4 h. The t was removed under reduced pressure and the resulting residue was diluted with H20 (3 mL) and extracted with EtOAc (2x2 mL). The EtOAc extracts were discarded and the pH of the aqueous layer was adjusted to 5 using 1N HCl that resulted in the formation of a white precipitate. The white solid was collected by filtration, washed with H20 (3 mL) and dried under vacuum to give (R)- 5-isopropylmethoxyoxo-5,9-dihydropyrido[2,3-a]indolizinecarboxylic acid as a white solid (23 mg, 51% yield, m/z: 301 [M+H]+ observed). 1H NMR (300 MHz, CDCl3): 5 16.17 (s, 1H), 8.85 (s, 1H), 7.79 (d, J=9 Hz, 1H), 7.31 (s, 1H), 6.89 (d, J=9 Hz, 1H), 5.32 (d, J=3 Hz, 1H), 4.07 (s, 3H), 2.78-2.65 (m, 1H), 1.30 (d, J=6 Hz, 3H), 0.57 (d, J=6 Hz, 3H).

EXAMPLE 174: Biological Examples HBsAg Assay Inhibition of HBsAg was determined in HepG2.2. 15 cells. Cells were maintained in culture medium containing 10% fetal calf serum, G414, Glutamine, penicillin/streptomycin.

Cells were seeded in 96-well collagen-coated plate at a density of 30,000 cells/well. Serially diluted compounds were added to cells next day at the final DMSO concentration of 0.5%. Cells were incubated with compounds for 2-3 days, after which medium was removed. Fresh medium containing compounds was added to cells for additional 3-4 days. At day 6 after exposure of compounds, supernatant was collected, the HBsAg immunoassay (microplate-based uminescence immunoassay kits, CLIA, Autobio Diagnosics Co., Zhengzhou, China, Catalog # -2) was used to determine the level of HBsAg ing to manufactory instruction. Dose-response curves were generated and the EC50 value tive concentrations that achieved 50% inhibitory effect) were determined using XLflt software. In addition, cells were seeded at a y of 5,000 cells/well for ination of cell viability in the presence and absence of compounds by using CellTiter-Glo reagent (Promega). Tables 1-3 show EC 50 values obtained by the HBsAg assay for selected compounds. —240— Table 1.

Structure Nomenclature ethyl 2-chloroisopropy1-3 - methoxy-l 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d][1,4]oxazepinecarboxy1ate 2—chloroisopropy1-3 -methoxy-1 1- 7-dihydro-1 1H- f]pyiido[1,2- d] xazepinecarboxylic acid (R)chloroisopropy1-3 -methoxy- 1 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (5)chloroisopropy1-3 -methoxy- 1 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid 2—chloroisobuty1-3 -methoxy-1 1- 0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (S)chloroisobuty1-3 -methoxy- 1 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid —241— (R)chloroisobuty1-3 -methoxy- 1 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid 2—chloroethy1-3 -methoxy-1 l-oxo- 6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid 2-chloro(hydroxymethy1)-3 - methoxy-l 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid 2-chlorocyclobuty1-3 -methoxy- 1 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid ro(isopropoxymethyl) y-l 1-0X0-6,7-dihydro-1 1H- dipyrido[1,2—d:2',3'— f] [1,4]oxazepinecarboxylic acid 6-(teIT-buty1)chloro-3 -methoxy- 1 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid 2—fluoroisopropy1-3 xy-1 1- 0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid —242— 7-isopropy1-3 -methoxy-1 1-0X0-6,7- dihydro-l 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)isopropy1-3 -methoxy-1 1-0X0- 6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (S)isopropy1-3 -methoxy-1 l-oxo- 6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid 6-isopropy1-10,1 1-dimethoxyOXO- 2 6 7 8- tetrahydrobenzo ido [ 1 ,2- a]azepine-3 -carboxy1ic acid 2-chloroisopropy1-3 -(3 -methoxy y)-1 1 -OXO-6,7-dihyd1‘O-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)chloroisopropy1-3 -(3 - methoxypropoxy)-1 l-oxo-6,7- o-l 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid —243— (S)chloroisopropy1-3 -(3 - methoxypropoxy)-1 l-oxo-6,7- o-l 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid 2-chloroisopropy1-3 -(2-methoxy ethoxy)-1 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)chloroisopropy1-3 -(2- methoxyethoxy)-1 l-oxo-6,7- dihydro-l zo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (S)chloroisopropy1-3 -(2- methoxyethoxy)-1 l-oxo-6,7- dihydro-l 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid ethyl ro-3 -hydroxy-7 - isopropyl-l 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d][1,4]oxazepinecarboxy1ate (R)chloroisopropy1-1 l-oxo-3 - (2,2,2—trifluoroethoxy)-6,7-dihydro- 1 1H-benzo[f]pyiido[1,2- d] [ 1,4]oxazepinecarboxylic acid —244— (R)chloro -3 - (cyclopropylmethoxy)isopropy1- 1 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [ 1,4]oxazepinecarboxylic acid chloro-3 -(3 -hydroxypropoxy) - 7-isopropy1-1 1-0X0-6,7-dihydro- 1 1H-benzo[f]pyiido[1,2- d] [ 1,4]oxazepinecarboxylic acid (R)chloro-3 -(3 -hydroxy-2,2- dimethylpropoxy)isopropy1- 1 1- 0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [ 1,4]oxazepinecarboxylic acid (R)chloroisopropy1-3 -(4- methoxybutoxy)-1 l-oxo-6,7- dihydro-l 1H-benzo[f]pyiido[1,2- d] [ azepinecarboxy1ic acid (R)chloro-3 -(4-hydroxybutoxy)-7 isopropyl-l 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [ 1,4]oxazepinecarboxylic acid (R)chloroisopropy1-3 -(3 - linopropoxy)-1 1-0X0-6,7- dihydro-l 1H-benzo[f]pyiido[1,2- d] [ azepinecarboxy1ic acid (R)-3 -(2-(2-bromoethoxy)ethoxy)-2 - chloroisopropy1-1 1-0X0-6,7- dihydro-l 1H-benzo[f]pyiido[1,2- d] [ 1,4]oxazepinecarboxy1ic acid —245— (R)-3 -(3 -((teIt-butoxycarbonyl) amino)propoxy)chloro isopropyl-l 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [ 1,4]oxazepinecarboxylic acid (R)chloro(2-hydroxyethy1)-3 - (3 -methoxypropoxy)-1 6,7- dihydro-l 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)cyclopropy1-3 -isobutoxy pyl-l 6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid 1 l-chloro- 1 0-methoxyOXO- 5a,6,7,7a—tetrahydro-2H- benzo[flcyclobuta[b]pyiido[1,2- d] [1,4]oxazepine -3 -carboxylic acid 12-chloro-1 1-methoxyOXO- a,7, 8 6H- , 8a—tetrahydro-2H, benzo [f]cyclopenta[b]py1ido[ 1 ,2- d] [1,4]oxazepine -3 -carboxylic acid (R)chloroisopropy1-3 -methoxy- 1 1-0X0-6,7-dihydro-1 1H- dipyrido[1,2—d:2',3'— f] [1,4]oxazepinecarboxylic acid 2'-chloro-3 ethoxypropoxy)- 11'—oxo-6'H,11'H- spiro[cyclopentane-1,7'- dipyrido[1,2—d:2',3'— f][1,4]oxazepine]-10'-carboxy1ic acid 2'-chloro-3 '-(3-methoxypropoxy)- 1 1'-oxo -6'H, 1 1'H-spiro[cyclohexane- 1,7'-dipy1ido[1,2—d:2',3'— f] [1,4]oxazepine]—10'—carboxy1ic acid 2-chloro-3 -(3 -methoxypropoxy)-1 1- 0X0-6H,1 1H-spiro[dipyiido[1,2- d:2',3'—f] [1,4]oxazepine-7,3'— e]—10-carboxylic acid 2'-chloro-3 '-(3 -methoxypropoxy)- 3 ,3 -dimethy1-1 1'-0X0-6'H,1 l'H- spiro[cyclobutane-1,7'-dipy1ido[1,2- d:2',3 '-f] [1,4]oxazepine]— 1 0'- carboxylic acid 2'-chloro-3 '-(3 xypropoxy) -3 - methyl-1 1'-0X0-6'H,1 l'H- spiro[cyclobutane-1,7'-dipy1ido[1,2- d:2',3'—f] [1,4]oxazepine]— 1 0'- carboxylic acid ro-3 -(3 -methoxypropoxy)-1 1- 0X0-2',3 ',5 ',6'-tetrahydro-6H,1 1H- spiro[dipy1ido[1,2-d:2',3'— f] [1,4]oxazepine-7,4'—thiopyran] carboxylic acid —247— cyclopropy1-3 -isobutoxy isopropyl- 1 6,7-dihydro-1 1H- dipyrido[1,2—d:2',3'— f] [1,4]oxazepinecarboxylic acid (R)-3 -(benzyloxy)chloro isopropyl- 1 1-0X0-6,7-dihydro-1 1H- dipyrido[1,2—d:2',3'— f] [1,4]oxazepinecarboxylic acid (R)chloro-3 -hydroxyisopropyl- 1 1-0X0-6,7-dihydro-1 1H- dipyrido[1,2—d:2',3'— f] [1,4]oxazepinecarboxylic acid (R)chloro-3 -isobutoxy isopropyl- 1 1-0X0-6,7-dihydro-1 1H- dipyrido[1,2—d:2',3'— f] [1,4]oxazepinecarboxylic acid chloro(2-hydroxyethy1)-3 - (3 -methoxypropoxy)-1 1-0X0-6,7- dihydro-l 1H-dipy1ido[1,2—d:2',3'— fj [1,4]oxazepinecarboxylic acid 6-chloro(3 -methoxypropoxy) - 12, 12-dimethy1-3 -0X0-9a,1 1,12,12a— tetrahydro-3H, 1 0H- cyclopenta[b]dipyrido[1,2—d:2',3'- f] [1,4]oxazepinecarboxy1ic acid 6-chloro(3 -methoxypropoxy) - 12, 12-dimethy1-3 -0X0-9a,1 1,12,12a— tetrahydro-3H,10H- cyclopenta[b]dipyrido[1,2-d:2',3'- f] [1,4]oxazepinecarboxy1ic acid (single enantiomer I) 6-chloro(3 xypropoxy) - 12, 12-dimethy1-3 -0X0-9a,1 2a— ydro-3H,10H- cyclopenta[b]dipyrido[1,2-d:2',3'- f] [1,4]oxazepinecarboxy1ic acid (single enantiomer II) (R)cyclopropy1isopropy1(3- methoxypropoxy)-1 1-oxo-6,7- dihydro- 1 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)isopropy1—3 -(3 - methoxypropoxy)methy1-1 1 -OXO- 6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] xazepinecarboxylic acid (R)ethy1isopropy1—3 -(3 - methoxypropoxy)-1 1-oxo-6,7- dihydro- 1 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)isopropy1(3 - methoxypropoxy)-1 1-0X0Vinyl- 6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid —249— (R)-3 -(cyclopropylmethoxy) isopropy1methy1-1 l-oxo -6,7- dihydro-l 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)-3 -(cyclopropy1methoxy)ethy1- 7-isopropy1-1 1-0X0-6,7-dihydro- 1 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)-3 -isobutoxyisopropy1-2 - methyl-1 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] xazepinecarboxylic acid (R)ethy1-3 -isobutoxyisopropy1- 1 1-0X0-6,7-dihydro-1 1H- f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)(3-((tert- butoxycarbony1)amino)propoxy) cyclopropylisopropy1—1 l-oxo-6,7- o-l 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)cyclopropy1isopropy1-1 1- 0X0-3 -(2,2,2-trifluoroethoxy)-6,7- dihydro-l 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)-3 -(2-ethoxyethoxy)isopropy1- 2-methy1-1 1 -OXO-6,7-dihyd1‘0- 1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)ethy1-3 -(3 -hydroxypropoxy)-7 - isopropyl-l 1-0X0-6,7-dihydro-1 1H- f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)-3 -(2-ethoxyethoxy)ethy1-7 - isopropyl-l 1-0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid ethy1isopropy1-1 1-0X0-3 - (2,2,2-trifluoroethoxy)-6,7-dihydro- 1 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)isopropy1methyl -1 l-oxo -3 - (2,2,2—trifluoroethoxy)-6,7-dihydro- 1 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)-3 droxypropoxy) isopropy1methy1-1 l-oxo -6,7- dihydro-l 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)chloroisopropy1-3 -((3- methoxypropyl)amino)-1 1-0X0-6,7- dihydro-l 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)chloroisopropy1-3 - morpholino-l 1-0X0-6,7-dihydro - 1 1H-benzo[f]pyiido[1,2- d] xazepinecarboxylic acid (R)chloroisopropy1-3 -((3 - methoxypropyl)(methy1)amino)-1 1- 0X0-6,7-dihydro-1 1H- benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)chloroisopropy1-3 -((2- methoxyethy1)amino)-1 1 -OXO-6,7- dihydro-l 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)chloroisopropy1-3 -((2- methoxyethyl)(methyl)amino)-1 1- 7-dihydro-1 1H- f]pyiido[1,2- d] [1,4]oxazepinecarboxylic acid (R)(tert-buty1)chloro-3 -(3 - methoxypropoxy)-1 l-oxo-6,7- dihydro-l 1H-dipy1ido[1,2—d:2',3'— fj [1,4]oxazepinecarboxylic acid (R)(tert-butyl)cyclopropy1-3 - (3 xypropoxy)-1 1-0X0-6,7- dihydro-l 1H-dipy1ido[1,2—d:2',3'— fj [1,4]oxazepinecarboxylic acid (R)chloroisopropy1-3 -(3- methoxypropoxy)-1 l-oxo-6,7- dihydro-l 1H-dipy1ido[1,2—d:2',3'— f] [1,4]oxazepinecarboxylic acid 2-chloroisopropy1-3 xy-1 1- 0X0-6,7-dihydro-1 1H-dipyrido[1,2— d:3',2'—f] [1,4]oxazepine carboxylic acid teIt-butyl (R)-(2—chloroisopropy1(3 -methoxypropoxy)-1 1-0X0-6,7- dihydro-l 1H-benzo[f]pyiido[1,2- d] [1,4]oxazepiny1)carbamate (R)chloroisopropy1-3 -(3 - methoxypropoxy)(pyrimidin-2 - yl) -6, 7-dihydro-1 1H- benzo[f]py1ido[1,2-d][1,4]oxazepin- 1 l-one chloroisopropy1-3 -(3 - methoxypropoxy)-6,7-dihydro-1 1H- benzo[f]py1ido[1,2-d][1,4]oxazepin- 1 l-one WO 85619 (R)chloroisopropy1-3 -(3 - methoxypropoxy)(3 - methylpyridin-Z-y1)-6,7-dihydro- 1 1H-benzo[f]py1ido[ 1,2- d][1,4]oxazepin-1 l-one (R)chloroisopropy1-3 -(3 - methoxypropoxy)(pyridiny1)- hydro-1 1H- benzo[f]pyfido[1,2-d] [1,4]oxazepin- 1 l-one (R)chloroisopropy1 methoxy-3 -(3 -methoxypropoxy)-6,7- dihydro-l 1H-benzo[f]py1ido[ 1 ,2- d][1,4]oxazepin-1 l-one (R)-(2—chloroisopropy1(3- methoxypropoxy)-1 l-oxo-6,7- dihydro-l 1H-benzo[f]py1ido[ 1 ,2- d] [1,4]oxazepiny1)boronic acid teIt-butyl (R)-(2—chloroisopropy1(3 -methoxypropoxy)-1 1-0X0-6,7- dihydro-l 1H-benzo[f]py1ido[ 1 ,2- ]oxazepin y1)(methy1)carbamate ethyl 2-chloro-1 1-(hydroxyimino)-7 - isopropy1-3 -methoxy-6,7-dihydro- 1 1H-benzo[f]py1ido[ 1,2- d][1,4]oxazepinecarboxy1ate —254— 2—chloroisopropy1-3 -methoxy-6,7- dihydro-lOH- benzo[f]isoxazolo[3',4':4,5]py1ido[1, 2-d] [1,4]oxazepinone isopropylmethoxy-3 -(3 - methoxypropoxy)-1 1-0X0-5 ,6,7,1 1- ydrodipyiido[1,2-a:2',3'— c] azepine-l O-carboxylic acid (S)isopropy10X0-2,6,7,8,12,13- hexahydro-l 1H- [1,4]dioxepino [2',3':5,6]py1ido[2,3- c]pyiido[1,2-a]azepine-3 -carboxy1ic (S)isopropy10X0-2,6,7,8,11,12- hexahydro- [1,4]dioxino [2',3 ': 5,6]py1ido [2,3- c]pyiido[1,2-a]azepine-3 -carboxy1ic Table 2.

Nomenclature (R)-5 -isopropy1methoxyOXO- 3 -a] zine- , 9-dihydropyiido [2, 8-carboxylic acid ethyl (R)-5 -isopropy1methoxy 9-dihydropy1ido [2,3- a]indolizine-S-carboxylate Table 3.

Structure Nomenclature 6-isopropy1methoxy-3 -(3 - methoxypropoxy)oxo-5,10-dihydro- 6H-py1ido[1,2-h] [1,7]naphthy1idine carboxylic acid (R) isopropy1methoxy-3 -(3 - methoxypropoxy)oxo-5,10-dihydro- 6H-py1ido[1,2-h] [1,7]naphthy1idine carboxylic acid (S)isopropy1methoxy-3 -(3 - methoxypropoxy)oxo-5,10-dihydro- 6H-py1ido[1,2-h] [1,7]naphthy1idine ylic acid 6-isopropy1-2,3-dimethoxyoxo-5,10- dihydro-6H-py1ido [ 1 ,2- h] [1,7] naphthyiidinecarboxy1ic acid 6-isopropy1-2,3-dimethoxyoxo-5,10- dihydro-6H-py1ido [ 1 ,2- h] [1,7] naphthyiidinecarboxy1ic acid (single enantiomer I) 6-isopropy1-2,3-dimethoxyoxo-5,10- dihydro-6H-py1ido [ 1 ,2- h] [1,7] naphthyiidinecarboxy1ic acid (single enantiomer II) (S)-1 oisopropy1—2-methoxy-3 - (3 -mcthoxypropoxy)oxo-5,10- dihydro-6H-py1ido[1,2- h] [1,7] naphthyiidinecarboxy1ic acid -isopropy1oxo-4,9-dihydro-5H- thieno [3 ,2-a] quinolizine-S-carboxylic 2-chloroisopropy1oxo-4,9-dihydro- 5H-thieno [3 ,2-a] quinolizine-S- carboxylic acid ropy1-3 -methoxyoxo-5,10- dihydro-6H-py1ido [2, 1 - a] [2,7] naphthyiidinecarboxy1ic acid -isopropy1methoxyoX0-4,9- dihydro-SH-thiazolo[4,5-a]quinolizine- 8-carboxy1ic acid -isopropy1(methoxymcthyl)0X0- 4,9-dihydro-5H-thiazolo [4,5- a]quinolizinecarboxy1ic acid 6-(tcrt—butyl)oxo-6,7,11,12- tetrahydro-2H,10H-[1,4]dioxepino[2,3 - g]py1ido [2, 1-a] isoquinoline-3 -carboxy1ic 6-(tcrt—butyl)oxo-6,7,11,12- tetrahydro-2H,10H-[1,4]dioxepino[2,3 - g]py1ido [2, 1-a] noline-3 -carboxy1ic acid (single enantiomer I) t—butyl)oxo-6,7,11,12- tetrahydro-2H,10H-[1,4]dioxepino[2,3 - g]py1ido [2, 1-a] isoquinoline-3 -carboxy1ic acid (single enantiomer II) 6'—(tcrt-buty1)-2'-0X0-6',7'-dihydro- 2'H,10'H,12'H-spiro[oxetane-3,11'- [1,4]dioxepino [2,3 ido[2,1- a] isoquinoline] -3 '-carboxy1ic acid 6'—(tcrt-butyl) -2 '-0X0-6',7'-dihydro - 2'H,10'H,12'H-spiro[oxetane-3,11'- [1,4]dioxepino [2,3 -g]py1ido[2,1- a] noline] -3 '-carboxy1ic acid (single enantiomer I) 6'—(tcrt-buty1)-2'-0X0-6',7'-dihydro- 2'H,10'H,12'H-spiro[oxetane-3,11'- [1,4]dioxepino [2,3 -g]py1ido[2,1- a] isoquinoline] -3 '-carboxy1ic acid (single enantiomer II) 6-(tcrt—butyl)-1 1-(methoxymethyl) 0X0-6,7,11,12-tetrahydro-2H,10H- [1,4]dioxepino [2,3 -g]py1ido[2,1- a] isoquinoline-3 -carboxy1ic acid 6-(tert—buty1)-1 1-(2-methoxyethoxy) -2 - 0X0-6,7,11,12-tetrahydro-2H,10H- [1,4]dioxepino [2,3 -g]py1ido[2,1- a] isoquinoline-3 -carboxy1ic acid 6-(tert—buty1)-1 1-methylene0X0- 6,7,11,12-tetrahydro-2H,10H- [1,4]dioxepino [2,3 -g]py1ido[2,1- a] isoquinoline-3 -carboxy1ic acid 6-(tert—buty1)-11,11- bis(methoxymethy1)oxo-6,7,11,12- tetrahydro-2H,10H-[1,4]dioxepino[2,3 - g]py1ido [2, 1-a] isoquinoline-3 -carboxy1ic 6-(tcrt—butyl)methy1—2-oxo -6,7,11,12- ydro-2H,10H-[1,4]dioxepino[2,3 - g]py1ido [2, 1-a] isoquinoline-3 -carboxy1ic 6-(tcrt—butyl)-3 -(hydroxymethy1)-1 1- ene-6,7, 1 1, rahydro- -[1,4]dioxepino[2,3 - g]py1ido[2,1-a]isoquinolin—2-one 6-(tert—buty1)-1 1-Inethoxy0X0- 6,7,11,12-tetrahydro-2H,10H- [1,4]dioxepino [2,3 -g]py1ido[2,1- a] isoquinoline-3 -carboxy1ic acid 6-(tcrt—butyl)-1 1-hydroxy-2 -0X0- 6,7,11,12-tetrahydro-2H,10H- [1,4]dioxepino [2,3 -g]py1ido[2,1- a] isoquinoline-3 -carboxy1ic acid dicthyl (6-(tcrt-buty1)- 1 0-chloro(3 - methoxypropoxy)0X0-6,7-dihydro- 2H-py1ido[2,1-a]isoquinolin—3 - y1)phosphonate ethyl en (6-(tert-buty1) - 1 0-chloro- 9-(3 -methoxypropoxy) 0X0 -6,7- dihydro-2H-py1ido [2, 1 -a] isoquinolin—3 - sphonate (6-(tcrt-butyl)chloro-9 -(3 - methoxypropoxy)0X0-6,7-dihydro- 2H-py1ido[2,1-a]isoquinolin—3 - y1)phosphonic acid (S)isopropy1methoxy-3 -(3 - ypropoxy)(5 -methy1—1,3,4- thiadiazoly1)-5,6-dihydro-10H- pyiido[1,2-h] [1,7]naphthy1idin—10-one (S)isopropy1methoxy-3 -(3 - methoxypropoxy)(5 -thioxo-4,5 - dihydro- 1H- 1 ,2,4-t1iazol-3 ,6- dihydro- 10H-py1ido [ 1 ,2- h] [1,7]naphthyridin—10-one (S)isopropy1methoxy-3 -(3 - methoxypropoxy)( 1 , 3 ,4-oxadiazol y1)-5,6-dihydro-10H-pyn'do[1,2- h] [1,7]naphthyridin—10-one (S)isopropy1methoxy-3 -(3 - methoxypropoxy)(3 -methy1—1,2,4- oxadiazol-S-y1)-5,6-dihydro-10H- pyn'do[1,2-h] [1,7] naphthyn'din— 1 0 -one isopropy1methoxy-3 -(3 - methoxypropoxy)(3 -pheny1—1,2,4- oxadiazol-S-y1)-5,6-dihydro-10H- pyn'do[1,2-h] [1,7] naphthyn'din— 1 0 -one (S)isopropy1methoxy-3 -(3 - methoxypropoxy)oxo-5,10-dihydro- 6H-pyn'do[1,2-h] [1,7]naphthyn'dine carbonitn'le t—butyl)chloro(3 - methoxypropoxy)-3 -(5 -0X0-4, 5-dihydro- razol-l -y1) -6,7-dihydro-2H- pyn'do [2, 1-a] isoquinolin—Z-0me (S)isopropy1methoxy-3 -(3 - methoxypropoxy)(1H-tetrazol-5 -y1)- ,6-dihydro-10H-pyn'do[1,2- h] [1,7]naphthyridin—10-one (S)isopropy1methoxy-3 -(3 - methoxypropoxy)(1H-1,2,4-tn'azol-5 - y1)-5,6-dihydro-10H-pyn'do[1,2- h] [1,7]naphthyridin—10-one (S)-N-hydr0xyisopr0py1methoxy(3 -meth0xypr0p0xy)0X0-5,10- dihydro-6H-pyn'd0 [ 1 ,2- h] [1,7] naphthyridinecarb0Xamide (S)isopr0py1methoxy-3 -(3 - ypropoxy)-N-(methylsulf0ny1)- -0X0-5,10-dihydr0-6H-pyn'd0[1,2- h] [1,7] naphthyridinecarb0Xamide tert—butyl (6-(tert-buty1) - 1 O-chloro(3 - methoxypropoxy)0X0-6,7-dihydr0- 2H-pyn'd0[2, 1-a]isoquin01in—3 - y1)carbamate 3 (tert-buty1)-1O-chlor0(3 - methoxypropoxy)-6,7-dihydr0-2H- pyn'do [2, 1-a]isoquin01in—2-0ne N—(6-(tert-buty1)- 10 0-9 -(3 - methoxypropoxy)0X0-6,7-dihydr0- 2H-pyn'd0[2, 1-a]isoquin01in—3 - y1)acetamide methyl (6-(tert-buty1)chlor0(3 - methoxypropoxy)0X0-6,7-dihydr0- 2H-pyn'd0[2, 1-a]isoquin01in—3 - y1)carbamate pyn'din—2-y1methy1 (6-(tert-buty1)- 10- (3 -meth0xypr0p0xy)0X0- 6,7-dihydr0-2H-pyn'd0 [2, 1- a] isoquinolin—3 -y1)carbamate neopentyl (6-(tert—buty1)chlor0(3 - methoxypropoxy)0X0-6,7-dihydr0- 2H-pyn'd0[2, 1-a]isoquin01in—3 - y1)carbamate 1-(6-(tert-buty1)chlor0(3 - methoxypropoxy)0X0-6,7-dihydr0- 2H-pyn'd0[2, 1-a]isoquin01in—3 - y1)pyrrolidine-2,5-dione 1 -(tert—buty1)-3 -(6-(tert-buty1)- 10- chloro(3 xypr0p0xy)0X0- 6,7-dihydr0-2H-pyn'd0 [2, 1- a] isoquinolin—3 -y1)urea N—(6-(tert-buty1)chlor0-9 -(3 - methoxypropoxy)0X0-6,7-dihydr0- 2H-pyn'd0[2, 1-a]isoquin01in—3 -y1)-2,2,2- tn'fluor0ethane-1 -su1f0namide N—(6-(tert-buty1)chlor0-9 -(3 - methoxypropoxy)0X0-6,7-dihydr0- 2H-pyn'd0[2, 1-a]isoquin01in—3 -y1)-1,1,1- r0methanesulfonamide 6-(tert—butyl)chlor0(3 - methoxypropoxy) -3 -(pyn'mjdin-2 - ylamin0)-6,7-dihydr0-2H-pyn'd0[2,1- a] isoquinolin—2-0ne t—butyl)chlor0-3 -(di(pyn'midin— 2-y1)amin0)(3 -methoxypr0p0xy)-6,7- dihydro-2H-pyn'd0 [2, 1 -a] nolin—2- 6-(tert—butyl)Chlor0-3 -iod0(3 - methoxypropoxy)-6,7-dihydr0-2H- pyn'do [2, 1-a]isoquin01in—2-0ne 6-(tert—butyl)chlor0(3 - methoxypropoxy) -3 -(pyn'mjdin-2 -y1)- 6,7-dihydr0-2H-pyn'd0 [2, 1- a] isoquinolin—2-0ne 6-(tert—butyl)chloro(3 - methoxypropoxy)-3 -(pyn'din—2-y1)-6,7- dihydro-2H-pyn'do [2, 1 -a] isoquinolin—2- 9-acety1isopropy1methoxy-3 -(3- methoxypropoxy)-5,6-dihydro-10H- pyn'do[1,2-h] [1,7] yn'din— 1 0 -one 9-(2-hydroxypropan—2-y1)isopropy1- 2-methoxy-3 -(3 -methoxypropoxy)-5 ,6- dihydro-lOH-pyfido[1,2- h] [1,7] naphthyridin— 1 O-one methyl 6-(tert-buty1)chloro (hydroxyimino)(3 -methoxypropoxy)- 6,7-dihydro-2H-pyn'do [2, 1- a] isoquinoline-3 -carboxy1ate 6-(tert—butyl)chloro (hydroxyimino)(3 -methoxypropoxy)- hydro-2H-pyn'do [2, 1- a] isoquinoline-3 -carboxylic acid t—buty1)chloro-3 -(3 - methoxypropoxy)-5,6-dihydro-9H- isoxazolo [3 ',4' :4, 5]pyn'do [2, 1- a] isoquinolin—9-one 6-isopropy1methoxy(3 - methoxypropoxy)(methylimino)-6,7- dihydro-2H-pyn'do [2, 1-a]isoquinoline-3 - ylic acid methyl 6-isopropy1methoxy (methoxyimino)(3 xypropoxy)- 6,7-dihydro-2H-pyn'do [2, 1- a] isoquinoline-3 -carboxy1ate 6-isopropy1methoxy (methoxyimino)(3 -methoxypropoxy)- 6,7-dihydro-2H-pyn'do [2, 1- a] isoquinoline-3 -carboxylic acid (S)- 10-hydraziney1ideneisopropy1—2- methoxy-3 -(3 -methoxypropoxy)-5,10- dihydro-6H-pyn'do [ 1 ,2- h] [1,7] yn'dinecarbohydrazide (S)isopropy1methoxy-3 -(3 - methoxypropoxy)-5,10- dihydropyrazolo[3',4':4,5]pyn'do[1,2- h] [1,7] naphthyridin—9(6H)-one (S)-N'-acety1isopropy1methoxy-3 - (3 -methoxypropoxy)oxo-5, 10- dihydro-6H-pyn'do[1,2- h] [1,7] naphthyn'dinecarbohydrazide 6-isopropy1methoxy-3 -(3 - methoxypropoxy)methy1—10-oxo- ,10-dihydro-6H-py1ido[1,2- h] [1,7] naphthyiidinecarboxy1ic acid 6-isopropy1methoxy-3 -(3 - methoxypropoxy)methy1—10-oxo- ,10-dihydro-6H-py1ido[1,2- h] [1,7] naphthyiidinecarboxy1ic acid (single omer I) 6-isopropy1methoxy-3 -(3 - methoxypropoxy)methy1—10-oxo- ,10-dihydro-6H-py1ido[1,2- h] [1,7] naphthyiidinecarboxy1ic acid (single enantiomer II) 6-(tcrt—butyl) methoxy-3 -(3 - methoxypropoxy)methy1—10-oxo- ,10-dihydro-6H-py1ido[1,2- h] [1,7] yiidinecarboxy1ic acid 6-(tcrt—butyl) methoxy-3 -(3 - methoxypropoxy)methy1—10-oxo- ,10-dihydro-6H-py1ido[1,2- h] [1,7] naphthyiidinecarboxy1ic acid (single omer I) 6-(tcrt—butyl)methoxy-3 -(3- methoxypropoxy)methy1—10-oxo- ,10-dihydro-6H-py1ido[1,2- h] [1,7] naphthyiidinecarboxy1ic acid (single enantiomer II) ethylmethoxy-3 -(3 - methoxypropoxy)oxo-5,10-dihydro- 6H-py1ido[1,2-h] [1,7]naphthy1idine carboxylic acid (S)isopropyl-3 -methoxymethyl- 2,10-di0X0-2,5,6,10-tetrahydro-1H- pyiido[1,2-h] [1,7]naphthy1idine carboxylic acid 2, 3 -dihydroxyisopropyl0X0 -5,10- dihydro-6H-py1ido [ 1 ,2- h] [1,7] naphthyiidinecarboxylic acid 6-isopropyl-3 -(3 -methoxypropoxy)- 2,10-di0X0-2,5,6,10-tetrahydro-1H- pyiido[1,2-h] [1,7]naphthy1idine carboxylic acid (single omer I) 6-isopropyl-3 -(3 -methoxypropoxy)- 2,10-di0X0-2,5,6,10-tetrahydro-1H- pyiido[1,2-h] [1,7]naphthy1idine carboxylic acid (single enantiomer II) ethyl ethylmethoxy-3 -(3 - methoxypropoxy)oxo-5,10-dihydro- 6H-py1ido[1,2-h] [1,7]naphthy1idine carboxylate 6-ethylisopropylmethoxy-3 -(3 - ypropoxy)oxo-5,10-dihydro- 6H-pyrido[ 1,2-h] [l,7]naphthyridine carboxylic acid 2'-methoxy-3 '-(3 -methoxypropoxy)-10'- oxo-S ', 10 '-dihydrospiro [cyclobutane- l,6'—pyrido [ l ,2-h] [l,7]naphthyridine] -9'- carboxylic acid HBVproduction assay HepG2.2.15 cells were maintained and seeded as described above. After administration of test compounds for 6 days, supernatant was collected and clarified by low speed centrifugation. HBV DNA was released from virion in the supernatant by incubating in lysis buffer (Roche, Catalog # 07248431001). HBV DNA levels were quantified by qPCR/TaqMan assay. The nucleoside analog Entecavir (ETV) was used as a control to determine inhibition of HBV virion tion in the atant. Table 4 rates EC50 values obtained by the HBV production assay for selected compounds.

Table 4: Activity in HBV production assay Compound Compound 0 || C N o tBu single enantiomer II EXAMPLE 175: In vitro Combination Studies In vitro HBV infection studies in HepG2.2. 15 cells were performed using nds A and B of the present invention, in combination with certain lipid nanoparticles (LNP-l and LNP- 2), which encapsulate distinct siRNA mixtures (siRNA Mix 1 and siRNA Mix 2, respectively).

Compound A Compound B Lipid rticle ations: LNP-l and LNP-2 are lipid nanoparticle formulations of a mixture of three siRNAs targeting the HBV genome. The following lipid nanoparticle (LNP) product was used to deliver the HBV siRNAs in the experiments reported herein. The values shown in the table are mole percentages. Distearoylphosphatidylcholine is abbreviated as DSPC.

Table 5.

PEG-C-DMA Cationic lipid Cholesterol DSPC The cationic lipid has the ing structure: x“wflwwmmfl - “WM SiRNA The ces of three siRNAs comprised in LNP-l are: Table 6.

Sense Sequence (5'—3') Antisense ce (5’-3’) CCGUguGCACUuCGCuuCAw UGAAGCGAAGUgCACACgGfl (SEQ ID NO:1) (SEQ ID NO:2) CuggCUCAGUUUACuAgUGUfl CACUAgUAAACUgAgCCAGUU (SEQ ID NO:3) (SEQ ID NO:4) QCCgAuCCAUACugCGgAAUfl UUCCGCAgUAUGgAUCGgCUU (SEQ ID NO:5) (SEQ ID NO:6) lower case = 2'-O-methyl modification Underline = ed nucleobase analogue (UNA) moiety The sequences of three siRNAs comprised in LNP-2 are: Table 7.

Sense Sequence (5'—3') Antisense Sequence (5’-3’) rUmeUrGrCrArCrUmUrCmGrCm rUrGrArAmGrCmGrArAerUmGrCrAmCrAm UmUrCrArUrU CmGrGrUrU (SEQ ID NO:7) (SEQ ID NO:8) rCmUmeGrCmUrCrAerUrUmUrAmCm rCrArCrUrAmeUrArArAmCrUmGrAmGrCm UrAmeUmGrUrU CrArGrUrU (SEQ ID NO:9) (SEQ ID NO: 10) rAmCrCmUrCmUerCrCmUrAmArUmCrAr rGrArGrArUerArUmUrArGerCrAmGrAm UrCrUrCrUrU GrGrUrUrU (SEQ ID NO: 1 l) (SEQ ID NO: 12) rN = RNA of base N mN = 2'O-methyl modification of base N In vitro Combination Experimental Protocol: In vitro combination studies were conducted using the method of Prichard & Shipman, 1990, Antiviral Res. 14(4-5):181-205, and Prichard, el al., MacSynergy II). The HepG2.2. 15 cell culture system is a cell line derived from human hepatoblastoma HepG2 cells, that have been stably transfected with the adw2- subtype HBV genome (Sells, el al., 1987, Proc. Natl. Acad.

Sci. U. S. A 84: 009). HepG2.2.15 cells secrete Dane-like viral particles, produce HBV DNA, and produce the viral proteins, HBeAg and HBsAg.

Non-limiting examples ofHBV RNA destabilizers are Compound A and Compound B.

The EC50 values of these agents are shown in Table 12. Although inhibition ofHBV DNA, RNA and proteins can be determined in the presence of the compounds of the invention and LNPs (both referred to herein as “agents”), the assay that can quantitatively measure the level of HBsAg was used in this study. To test the agent combinations, HepG2.2. 15 (30,000 cells/well) were plated in 96 well tissue-culture d microtiter plates in DMEM+ L-Glutamine medium supplemented with 1% penicillin-streptomycin, 20 ug/mL cin (G418), 10% fetal bovine serum, and incubated in a humidified incubator at 37 oC and 5% C02 overnight. The next day, the cells were replenished with fresh medium ed by the addition of compound of the ion (dissolved in 100% DMSO), and LNP (dissolved in 100% RPMI medium). The agents were added to cells in a checkerboard fashion. The microtiter cell plates were incubated for a total duration of 6 days in a humidified incubator at 37 oC and 5% C02. On the 3rd day of incubation, the cells were replenished with fresh medium and agents. The serial dilutions spanned concentration ranges respective to the EC50 value of each agent, with the final DMSO concentration of the assay being 0.5%. In addition to combination testing of the agents in a checkerboard n, the nd and LNP were also tested alone.

Untreated positive l samples (0.5% DMSO in media) were included on each plate in le wells. Following a 6 day-incubation, media was removed from treated cells for use in an HBsAg chemiluminescence immunoassay (CLIA) (Autobio Diagnostics, Cat No. CL0310- 2). An HBsAg standard curve was generated to verify that the levels of HBsAg fication were within the detection limits of the assay. The remaining inhibitor-treated cells were assessed for cytotoxicity by ination of the intracellular adenosine triphosphate (ATP) using a Cell- Titer Glo reagent (Promega) as per manufacturers instructions and by copic analysis of the cells hout the duration of inhibitor treatment. Cell viability was calculated as a percentage of the untreated positive control wells.

The plates were read using an EnVision multimode plate reader (PerkinElmer Model 2104). The relative luminescence units (RLU) data generated from each well was used to ate HBsAg levels as %t inhibition of the untreated positive control wells and ed using the Prichard-Shipman combination model using the MacSynergyII program (Prichard & Shipman, 1990, Antiviral Res. 14(4-5):181-205, and Prichard, el al., MacSynergy II) to determine whether the combinations were synergistic, additive or antagonistic using the interpretive guidelines established by rd & Shipman as follows: synergy volumes <25 uM2% (log volume <2) at 95% CI: probably insignificant; 25-50 (log volume >2 and < 5) = minor but significant 50-100 (log volume >5 and <9) = moderate, may be important in viva, Over 100 (log volume >9) = strong synergy, probably important in viva, volumes approaching 1000 (log volume >90) = unusually high, check data. The RLU data from the single agent treated cells were analyzed using XL—Fit module in Microsoft Excel to determine EC 50 values using a 4-parameter curve fitting algorithm. ample 175.1: In vitro combination of Compound A and LNP-l Compound A ntration range of 0.1 uM to 0.000015 uM in a half-log, 3.16-fold dilution series and 9-point titration) was tested in combination with LNP-l (concentration range of 2.5 nM to 0.025 nM in a half-log, old dilution series and 5-point titration). The combination results were ted in duplicate with each assay consisting of 4 technical repeats. The measurements of synergy and antagonism s according to rd & Shipman, and interpretation, are shown in Table 12. The antiviral activity of this combination is shown in Table 8A, synergy and antagonism volumes are shown in Table 8B. The additive inhibition activity of this combination is shown in Table 8D. In this assay system, the combination results in ve inhibition of HBsAg secretion. No significant inhibition of cell viability or proliferation was observed by microscopy or Cell-Titer Glo assay (Table 8C).

Table 8A. Antiviral Activity of Compound A and LNP-l Combination.

Average percent inhibition versus negative control (n=4 samples per data point) 0.0025 85.62 87.78 90.23 92.7 94.43 97.25 9 63.75 72.77 75.74 81.16 88.16 89.54 Avg% 0.00025 38.19 48.06 51.51 64 78.69 93.07 Inhibition 7,913.05 17.82 30.39 36.54 52.99 72.55 93.07 2,513.05 11.11 24.54 31.68 47.94 68.95 92.62 3.16E—06 1.0E—05 3.171305 0.0001 16 0.1 ndA, ,uM Table 8B. MacSynergy Volume Calculations of Compound A and LNP-l Combination. 99.99% confidence interval (Bonferroni Adj. 96%) 0 -0.02 0 0 0. 00079 0 0 0 -3 .42 SYNERGY 0 0' 00025 Log vomme 0 _ O O O O Antagonism -3.44 Logvolume -0.86 0 06 3.16E—06 1.0E-05 3.17E-05 0.0001 0.000316 0.001 0.00316 0.1 Compound CompoundA, ,uM Table 8C. Cytotoxicity of Compound A and LNP-l Combination.

Average percent of cell viability vs control LNP-l, ,uM Avg % Cell 0.00079 85 87 82 91 95 93 111 Viability 100 114 121 121 119 125 123 138 138 133 --1.00E-06 3.16E-06 1.0E-05 3.171305 0.0001 0.000316 0.001 6 Table 8D. Antiviral Activity of Compound A and LNP-l Combination.

Additive percent inhibition versus negative control (n=4 samples per data point) 0.0025 88.17 86.83 88.04 89.01 95.14 97.75 98.62 98.9 0.00079 70.18 66.79 69.84 72.29 87.75 94.34 96.51 97.24 Additive "/0 0.00025 49.15 43.38 48.58 52.75 79.11 90.35 94.05 95.29 Inhibition 7.9E-05 32.39 24.71 31.63 37.17 72.23 87.16 92.09 93.74 2.5E-05 26.87 18 57 26.05 32.04 69.96 86.12 91.44 93.23 0 0 17.73 8.39 16.81 23.55 66.21 84.38 90.37 92.38 0 1.00E-06 3.16E-06 1. 0E-05 3.1 7E-05 0. 000316 0.001 0.00316 0.1 Sub-Example 175.2: In vitro combination of Compound A and LNP-2 Compound A (concentration range of 0.1 M to 0.000015 uM in a half-log, 3.16-fold dilution series and 9-point titration) was tested in combination with LNP-2 (concentration range of 2.5 nM to 0.025 nM in a og, 3.16-fold dilution series and 5-point titration). The combination results were completed in duplicate with each assay consisting of 4 cal repeats. The measurements of synergy and antagonism s according to Prichard & Shipman, and interpretation, are shown in Table 12. The antiviral activity of this ation is shown in Table 9A; synergy and antagonism s are shown in Table 9B. The ve inhibition activity of this combination is shown in Table 9D. In this assay system, the combination results in additive inhibition of HBsAg ion. No significant inhibition of cell viability or proliferation was observed by microscopy or Cell-Titer Glo assay (Table 9C). —274— Table 9A. Antiviral Activity of Compound A and LNP-Z Combination.

Average percent inhibition versus negative control (n=4 samples per data point) LNP-2,,uM 0.0025 88.13 91.38 93.76 95.84 98.19 Avg% 0.00079 44.43 69.47 74.68 86.09 96.27 Inhibition 0.00025 35.03 48.29 60.31 80.78 95.04 7.9E-05 28.58 37.14 53.07 76.86 93.73 2.5E-05 5.38 18.65 34.16 51.26 75.26 92.5 94.17 3.16E-06 1.0E-05 3.171505 0.0001 0.000316 0.1 ndA, ,uM Table 9B. MacSynergy Volume Calculations of nd A and LNP-Z Combination. 99.99% confidence interval (Bonferroni Adj. 96%) 0. 000 79 SYNERGY 0 0' 00025 Log vomme 0 _ O O O O nism 0 Logvolume 0 0 1.00E-06 3.16E-06 1.0E-05 3.17E-05 0.0001 16 0.001 0.00316 0.1 Compound CompoundA, ,uM Table 9C. Cytotoxicity of Compound A and LNP-Z Combination. e percent of cell viability vs control Avg % Cell 0.00025 100 95 92 83 85 92 85 103 108 Viability WO 85619 100 107 122 107 104 127 100 126 131 127 --1.00E-06 3.16E-06 1.0E-05 3.1 715.05 0.0001 0.000316 0.001 0.00316 Table 9D. Antiviral Activity of nd A and LNP-Z Combination: Additive percent inhibition versus ve control (n=4 samples per data point) 0.0025 87.55 88.24 89.25 90.28 . 96.24 98.13 98.82 99.07 0.00079 59.5 61.73 65.03 68.38 87.75 93.93 96.16 96.98 Additive "/0 0.00025 46.95 49.87 54.19 58.58 83.96 92.05 94.97 96.05 Inhibition 7.9E-05 27.6 31.58 37.48 43.47 78.11 89.15 93.14 94.6 2.5E-05 . 20.52 24.89 31.36 37.94 75.97 88.09 92.47 94.08 0 16 20.62 27.46 34.41 74.6 87.41 92.04 93.74 1.00E-06 3.16E-06 1. 0E—05 3.1 7E—05 0. 000316 0. 001 0.00316 0.1 ample 175.3: In vitro combination of Compound B and LNP-l Compound B (concentration range of 2 uM to 0.0002 M in a half-log, 3.16-fold dilution series and 9-point titration) was tested in combination with LNP-l (concentration range of 2.5 nM to 0.025 nM in a half-log, 3.16-fold dilution series and 5-point titration). The combination s were completed in duplicate with each assay consisting of 4 technical repeats. The measurements of synergy and antagonism volumes according to Prichard & Shipman, and retation, are shown in Table 12. The antiviral activity of this combination is shown in Table 10A; y and antagonism volumes are shown in Table 10B. The additive inhibition activity of this combination is shown in Table 10D. In this assay system, the combination results in additive tion of HBsAg secretion. No significant inhibition of cell viability or proliferation was observed by microscopy or Cell-Titer Glo assay (Table 10C).

Table 10A. Antiviral Activity of Compound B and LNP-l Combination.

Average percent inhibition versus negative control (n=4 samples per data point) 0.0025 91.04 92.72 94.9 96.62 97.16 0.00079 67.82 76.27 80.18 88.62 95.92 Avg% 0.00025 45.37 53.68 68.34 82.07 94.56 Inhibition 7,913.05 26.96 40.75 60.31 80.8 93.54 05 8.85 21.28 36.46 57.93 78.97 92.6 93.61 0.0006 0.002 0.006 0.02 0.06 0.20 0.63 2 Compound B, ,uM Table 10B. MacSynergy Volume Calculations of Compound B and LNP-l Combination. 99.99% confidence al (Bonferroni Adj. 96%) nism -9.98 Logvolume -2.49 0 0. 0002 0. 0006 0. 002 0. 006 0. 02 0. 06 0.20 0. 63 2 Compound Compound B, ,uM Table 10C. Cytotoxicity of Compound B and LNP-l Combination.

Average percent of cell viability vs control Avg%Cell 0.00079 92 87 87 89 90 92 91 Viability 102 103 98 85 98 101 92 104 88 97 Table 10D. ral ty of nd B and LNP-l Combination.

Additive percent inhibition versus negative control (n=4 samples per data point) 0.0025 90.42 90.69 91.47 92.72 97.67 98.8 99.11 99.22 0.00079 73.2 73.96 76.13 79.62 93.47 96.63 97.52 97.83 Additive "/0 5 47.79 49.26 53.5 60.3 87.28 93.44 95.17 95.77 Inhibition 7.9E-05 38.46 40.19 45.19 53.21 85.01 92.27 94.31 95.01 2.5E-05 . 27.07 29.12 35.04 44.54 . 82.23 90.84 93.25 94.08 0 19.99 22.24 28.73 39.16 80.51 89.95 92.6 93.51 0. 0002 0. 0006 0. 002 0. 006 . 0. 06 0.20 0. 63 2 Sub-Example 175.4: In vitro combination of Compound B and LNP-Z Compound B (concentration range of 2 uM to 0.0002 uM in a half-log, old dilution series and 9-point titration) was tested in combination with LNP-2 (concentration range of 2.5 nM to 0.025 nM in a half-log, 3.16-fold dilution series and 5-point titration). The combination results were completed in duplicate with each assay consisting of 4 technical repeats. The measurements of synergy and nism volumes according to Prichard & Shipman, and interpretation, are shown in Table 12. The ral activity of this combination is shown in Table 11A; synergy and nism volumes are shown in Table 11B. The additive inhibition activity of this combination is shown in Table 11D. In this assay system, the combination results in additive inhibition of HBsAg secretion. No significant inhibition of cell viability or proliferation was observed by microscopy or Cell-Titer Glo assay (Table 11C).

Table 11A. Antiviral Activity of Compound B and LNP-Z Combination.

Average percent inhibition versus negative control (n=4 samples per data point) LNP-Z, 0.0025 88.03 91.04 92.01 91.94 92.72 96.62 97.68 98.37 97.16 ,uM 0.00079 67.82 75.32 69.03 76.27 80.18 88.62 93.77 95.04 95.92 Avg% 5 45.37 41.55 45 53.68 68.34 82.07 90.67 93.78 94.56 Inhibition 7,913.05 26.96 29.45 34 40.75 60.31 80.8 89.24 93.06 93.54 2,513.05 8.85 21.28 24.16 30.18 36.46 57.93 78.97 89.18 92.6 93.61 0 0 19.99 22.24 28.73 39.16 61.93 80.51 89.95 92.6 93.51 0 0.0002 0.0006 0.002 0.006 0.02 0.06 0.20 0.63 2 Table 11B. MacSynergy Volume Calculations of Compound B and LNP-Z Combination. 99.99% confidence interval rroni Adj. 96%) LOgVOI‘mleO 0 -3.38 -0.18 -1.4 -2.49 0 0 0 0 Antagonism -16.95 Logvolume -4.23 0 0.0002 0.0006 0.002 0.006 0.02 0.06 0.20 0.63 2 Compound Compound B, ,uM Table 11C. Cytotoxicity of Compound B and LNP-Z Combination.

Average percent of cell Viability vs control 0.0025 127 115 114 105 117 103 104 102 99 108 0.00079 118 105 107 n 102 102 103 101 113 99 Avg%Cell 0.00025 103 100 101 94 107 111 110 107 113 118 Viability 7.913105 103 n 103 104 107 108 109 111 116 2,513.05 100 102 107 90 98 112 106 104 104 0 100 113 112 111 108 116 120 117 104 105 0.0002 0.0006 0.002 0.006 0.02 0.06 0.20 0.63 2 WO 85619 Table 11D. Antiviral Activity of Compound B and LNP-Z ation.

Additive percent inhibition versus ve control (n=4 samples per data point) 0.0025 86.19 88.42 90.56 93.36 96.54 98.97 0.00079 62.27 68.36 74.22 81.86 90.54 97.18 Additive"/o 0.00025 29.45 40.84 51.79 66.09 82.31 94.72 Inhibition 7,915.05 18.98 32.06 44.63 61.05 79.68 93.94 0.0006 0.002 0.006 0.02 0.06 0.20 0.63 2 Table 12. Summary of results of in vitro combination studies in HepG2.2.15 cell culture system with HBsAg quantitation by CLIA ls! 2nd S nery gy S nery gy Antagon'sl Antagon's1 Example 15‘ 2ml Inhibitor Inhibitor Volume Log 111 Volume 111 Log Interpretation Number Inhibitor Inhibitor ECso ECso (lle%) Volume (lle%)* Volume (11M) (Hg/mL) 175.1 Compound LNP-l 0.001 0.00039 0 0 -3 .44 -0.86 Additive 175.2 Compound LNP-Z 0.001 0.00054 0 0 0 0 Additive 175.3 Compound LNP-l 0.008 9 0 0 -9.98 -2.49 Additive 175.4 Compound LNP-Z 0.014 0.00048 0 0 -l6.95 -4.23 Additive *at 99.9% confidence interval The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.

While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and ions of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The ed claims are intended to be construed to e all such embodiments and equivalent variations.

Claims (29)

1. A compound of formula (Ia), or a salt, solvate, stereoisomer, geometric isomer, tautomer, or any mixtures thereof: (Ia), wherein: Y is selected from the group consisting of CHR5 and O; each occurrence of R5 is independently ed from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl; R1 is -C(=O)OR8; R2 is =O; R3, R3’, R4, and R4’ are each independently selected from the group consisting of H, alkyl-substituted oxetanyl, optionally tuted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl; or one pair selected from the group consisting of R3 / R3’, R4 / R4’, and R3 / R4 combine to form a divalent group selected from the group ting of C1-C6 alkanediyl, (CH2)nO(CH2)n-, -(CH2)nNR9(CH2)n-, nS(CH2)n- , -(CH2)nS(=O)(CH2)n-, and -(CH2)nS(=O)2(CH2)n-, wherein each occurrence of n is independently selected from the group consisting of 1 and 2 and each divalent group is optionally substituted with at least one C1-C6 alkyl or halogen; X1 is N, X2 is CR6II , X3 is CR6III , X4 is CR6IV, R6II, R6III, and R6IV are independently ed from the group consisting of H, halogen, -CN, pyrrolidinyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, ally substituted C3-C8 cycloalkyl, optionally tuted heterocyclyl, -OR, C1-C6 haloalkoxy, -N(R)(R), -NO2, -S(=O)2N(R)(R), acyl, and C1-C6 alkoxycarbonyl, wherein each ence of R is independently selected from the group ting of H, C1-C6 alkyl, R’-substituted C1-C6 alkyl, C1-C6 hydroxyalkyl, optionally substituted (C1-C6 alkoxy)-C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, wherein each occurrence of R’ is independently selected from the group ting of -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NHC(=O)OtBu, -N(C1-C6 C(=O)OtBu, and a 5- or 6-membered heterocyclic group, which is optionally N-linked; or R6II and R6III combine to form a divalent group selected from the group consisting of -O(CHF)O-, -O(CF2)O-, -O(CR9R9)O-, -O(CH2)(CH2)O-, and -O(CH2)(CR11R11)(CH2)O-; R7 is selected from the group consisting of H, OH, halogen, C1-C6 alkoxy, and optionally substituted C1-C6 alkyl; R8 is selected from the group ting of H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl; each occurrence of R9 is independently selected from the group consisting of H and C1-C6 alkyl; and each occurrence of R11 is independently selected from the group consisting of H, OH, C1-C6 alkyl, C1-C6 alkoxy, alkoxy-C1-C6 alkyl, and alkoxy-C1-C6 alkoxy, n two R11 groups bound to the same carbon atom are not simultaneously OH; or two R11 groups combine with the carbon atom to which they are bound to form a moiety selected from the group ting of C=O, C=CH2 and oxetane-3,3-diyl.

2. The compound of claim 1, wherein each occurrence of alkyl or cycloalkyl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, halogen, -OR’’, phenyl, and -N(R’’)(R’’), wherein each occurrence of R’’ is independently H, C1-C6 alkyl, or C3-C8 lkyl.

3. The compound of claim 1, wherein the compound of formula (Ia) is (In).

4. The compound of claim 1, wherein the compound of formula (Ia) is (Iv).

5. The compound of claim 1, wherein R1 is selected from the group consisting of - C(=O)OH, OMe, -C(=O)OEt, -C(=O)O-nPr, -C(=O)O-iPr, -C(=O)O-cyclopentyl, and - C(=O)O-cyclohexyl.

6. The compound of claim 1, wherein at least one applies: (a) R3 and R3’, and R4 and R4’, are each independently selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, hydroxymethyl, 2-hydroxy-ethyl, 2-methoxy-ethyl, methoxymethyl, and 2-methyl methoxy-propyl; (b) R3 is H, R3’ is isopropyl; (c) R3 is H, R3’ is utyl; (d) R3 is methyl, R3’ is pyl; (e) R3 is methyl, R3’ is tert-butyl; (f) R3 is methyl, R3’ is ; (g) R3 is methyl, R3’ is ethyl; (h) R3 is ethyl, R3’ is ethyl; (i) R3 and R3’ are not H; (j) R4 and R4’ are H; (k) R3 / R3’ combine to form a divalent group selected from the group consisting of C1-C6 alkanediyl, -(CH2)nO(CH2)n-, -(CH2)nNR9(CH2)n-, -(CH2)nS(CH2)n- , -(CH2)nS(=O)(CH2)n-, and nS(=O)2(CH2)n-, wherein each occurrence of n is independently ed from the group consisting of 1 and 2 and wherein each divalent group is ally substituted with at least one C1-C6 alkyl or halogen.

7. The compound of claim 1, wherein R6II, R6III and R6IV are independently selected from the group consisting of H, F, Cl, Br, I, CN, amino, amino, dimethylamino, methoxyethylamino, pyrrolidinyl, methoxy, ethoxy, n-propoxy, isopropoxyl, n-butoxy, secbutoxy , isobutoxy, t-butoxy, 2-methoxy-ethoxy, 2-hydroxy-ethoxy, 3-methoxy-propyl, 3- hydroxy-propyl, 3-methoxy-propoxy, 3-hydroxy-propoxy, 4-methoxy-butyl, 4- hydroxy-butyl, 4-methoxy-butoxy, 4-hydroxy-butoxy, 2-hydroxy-ethoxy, oxypropyl , 4-hydroxy-butyl, 3-hydroxy-2,2-dimethyl-propoxy, cyclopropylmethoxy, 2,2,2- trifluoroethoxy, aloethoxy)-ethoxy, 2-(N-morpholino)-ethyl, 2-(N-morpholino)-ethoxy, 3- (N-morpholino)-propyl, 3-(N-morpholino)-propoxy, 4-(N-morpholino)-butyl, 4-(N- morpholino)-butoxy, 2-amino-ethyl, 2-(NHC(=O)OtBu)-ethyl, 2-amino-ethoxy, 2- (NHC(=O)OtBu)-ethoxy, 3-amino-propyl, 3-(NHC(=O)OtBu)-propyl, 3-amino-propoxy, 3-(NHC(=O)OtBu)-propoxy, 4-amino-butyl, 4-(NHC(=O)OtBu)-butyl, 4-amino-but oxy, and 4-(NHC(=O)OtBu)-butoxy.

8. The compound of claim 1, wherein at least one applies: (a) X4 is CH; (b) X2 is CR6II, R6II is not H, X3 is CR6III, and R6III is not H; (c) X1 is N, X2 is CR6II, X3 is CR6III, and X4 is CH, and one of the following applies: R6II is y, R6III is 3-methoxy-propoxy; R6II is chloro, R6III is 3-methoxy-propoxy; R6II is cyclopropyl, R6III is oxy-propoxy; R6II is methoxy, R6III is methoxy; R6II is , R6III is methoxy; and R6II is cyclopropyl, R6III is methoxy; (d) X2 is CR6II, X3 is CR6III, and R6II and R6III combine to form a nt group selected from the group consisting of -O(CHF)O-, -O(CF2)O-, -O(CR9R9)O-, -O(CH2)(CH2)O-, and - O(CH2)(CR11R11)(CH2)O.

9. The compound of claim 1, wherein R7 is selected from the group consisting of H, , ethyl, and F.

10. A compound selected from the group consisting of: 2-chloro(isopropoxymethyl) methoxyoxo-6,7-dihydro-11H- dipyrido[1,2-d:2',3'-f][1,4]oxazepine carboxylic acid; (R)(tert-butyl)chloro(3- methoxypropoxy)oxo-6,7-dihydro- 11H-dipyrido[1,2-d:2',3'- f][1,4]oxazepinecarboxylic acid; (tert-butyl)cyclopropyl(3- methoxypropoxy)oxo-6,7-dihydro- 11H-dipyrido[1,2-d:2',3'- f][1,4]oxazepinecarboxylic acid; (R)chloroisopropyl(3- methoxypropoxy)oxo-6,7-dihydro- 11H-dipyrido[1,2-d:2',3'- f][1,4]oxazepinecarboxylic acid; 2'-chloro-3'-(3-methoxypropoxy)-11'- oxo-6'H,11'H-spiro[cyclohexane-1,7'- dipyrido[1,2-d:2',3'-f][1,4]oxazepine]- 10'-carboxylic acid; 2'-chloro-3'-(3-methoxypropoxy)-11'- oxo-6'H,11'H-spiro[cyclopentane-1,7'- do[1,2-d:2',3'-f][1,4]oxazepine]- 10'-carboxylic acid; 2-chloro(3-methoxypropoxy)oxo- 6H,11H-spiro[dipyrido[1,2-d:2',3'- f][1,4]oxazepine-7,3'-oxetane] carboxylic acid; 2'-chloro-3'-(3-methoxypropoxy)-3,3- dimethyl-11'-oxo-6'H,11'H- spiro[cyclobutane-1,7'-dipyrido[1,2- d:2',3'-f][1,4]oxazepine]-10'-carboxylic acid; 2'-chloro-3'-(3-methoxypropoxy) methyl-11'-oxo-6'H,11'H- spiro[cyclobutane-1,7'-dipyrido[1,2- d:2',3'-f][1,4]oxazepine]-10'-carboxylic acid; 2-chloro(3-methoxypropoxy)oxo- 2',3',5',6'-tetrahydro-6H,11H- spiro[dipyrido[1,2-d:2',3'- f][1,4]oxazepine-7,4'-thiopyran] carboxylic acid; chloroisopropylmethoxy oxo-6,7-dihydro-11H-dipyrido[1,2- d:2',3'-f][1,4]oxazepinecarboxylic acid; (R)cyclopropylisobutoxy isopropyloxo-6,7-dihydro-11H- dipyrido[1,2-d:2',3'-f][1,4]oxazepine carboxylic acid; (R)(benzyloxy)chloroisopropyl- 11-oxo-6,7-dihydro-11H-dipyrido[1,2- '-f][1,4]oxazepinecarboxylic acid; (R)chlorohydroxyisopropyl oxo-6,7-dihydro-11H-dipyrido[1,2- d:2',3'-f][1,4]oxazepinecarboxylic acid; (R)chloroisobutoxyisopropyl oxo-6,7-dihydro-11H-dipyrido[1,2- d:2',3'-f][1,4]oxazepinecarboxylic acid; (R)chloro(2-hydroxyethyl)(3- methoxypropoxy)oxo-6,7-dihydro- pyrido[1,2-d:2',3'- f][1,4]oxazepinecarboxylic acid; 6-chloro(3-methoxypropoxy)-12,12- dimethyloxo-9a,11,12,12a-tetrahydro- 3H,10H-cyclopenta[b]dipyrido[1,2- d:2',3'-f][1,4]oxazepinecarboxylic acid; 6-chloro(3-methoxypropoxy)-12,12- dimethyloxo-9a,11,12,12a-tetrahydro- 3H,10H-cyclopenta[b]dipyrido[1,2- d:2',3'-f][1,4]oxazepinecarboxylic acid (single enantiomer I); 6-chloro(3-methoxypropoxy)-12,12- dimethyloxo-9a,11,12,12a-tetrahydro- 3H,10H-cyclopenta[b]dipyrido[1,2- d:2',3'-f][1,4]oxazepinecarboxylic acid (single omer II); (S)isopropylmethoxy(3- methoxypropoxy)oxo-5,6,7,11- tetrahydrodipyrido[1,2-a:2',3'-c]azepine- 10-carboxylic acid; (S)isopropyloxo-2,6,7,8,12,13- dro-11H- [1,4]dioxepino[2',3':5,6]pyrido[2,3- c]pyrido[1,2-a]azepinecarboxylic acid; (S)isopropyloxo-2,6,7,8,11,12- hexahydro- [1,4]dioxino[2',3':5,6]pyrido[2,3- c]pyrido[1,2-a]azepinecarboxylic acid; or a salt, solvate, stereoisomer, tautomer, ric isomer, or any mixtures thereof.

11. A pharmaceutical composition comprising at least one compound of claim 1 and a ceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, further comprising at least one additional agent useful for treating hepatitis virus infection.

13. The pharmaceutical composition of claim 12, n the at least one additional agent comprises at least one selected from the group consisting of reverse transcriptase inhibitor; capsid inhibitor; cccDNA formation inhibitor; sAg secretion inhibitor; oligomeric nucleotide targeted to the Hepatitis B genome; and immunostimulator.

14. The pharmaceutical composition of claim 13, wherein the eric nucleotide ses one or more siRNAs.

15. A method of treating or ameliorating tis B virus (HBV) infection in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of at least one compound of formula (Ia), or a salt, solvate, stereoisomer, geometric isomer, tautomer, or any mixtures thereof: wherein: Y is selected from the group consisting of CHR5 and O; each occurrence of R5 is independently selected from the group ting of H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl; R1 is -C(=O)OR8; R2 is =O; R3, R3’, R4, and R4’ are each independently selected from the group consisting of H, alkyl-substituted oxetanyl, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl; or one pair selected from the group consisting of R3 / R3’, R4 / R4’, and R3 / R4 combine to form a divalent group selected from the group consisting of C1-C6 alkanediyl, O(CH2)n-, -(CH2)nNR9(CH2)n-, -(CH2)nS(CH2)n- , nS(=O)(CH2)n-, and -(CH2)nS(=O)2(CH2)n-, wherein each occurrence of n is ndently selected from the group consisting of 1 and 2 and each divalent group is optionally substituted with at least one C1-C6 alkyl or halogen; X1 is N; X2 is CR6II; X3 is CR6III; X4 is CR6IV; R6II, R6III, and R6IV are independently selected from the group consisting of H, n, -CN, pyrrolidinyl, optionally substituted C1-C6 alkyl, optionally tuted C1-C6 alkenyl, ally substituted C3-C8 cycloalkyl, ally substituted heterocyclyl, -OR, C1-C6 haloalkoxy, -N(R)(R), -NO2, -S(=O)2N(R)(R), acyl, and C1-C6 alkoxycarbonyl, wherein each occurrence of R is independently selected from the group ting of H, C1-C6 alkyl, R’-substituted C1-C6 alkyl, C1-C6 hydroxyalkyl, ally substituted (C1-C6 alkoxy)-C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl, n each occurrence of R’ is independently selected from the group consisting of -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NHC(=O)OtBu, -N(C1-C6 alkyl)C(=O)OtBu, and a 5- or 6-membered heterocyclic group, which is optionally N-linked; or R6II and R6III combine to form a divalent group ed from the group consisting of -O(CHF)O-, -O(CF2)O-, -O(CR9R9)O-, -O(CH2)(CH2)O-, and -O(CH2)(CR11R11)(CH2)O-; R7 is selected from the group consisting of H, OH, halogen, C1-C6 alkoxy, and optionally substituted C1-C6 alkyl; R8 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl; each occurrence of R9 is independently selected from the group consisting of H and C1-C6 alkyl; and each occurrence of R11 is independently selected from the group consisting of H, OH, C1- C6 alkyl, C1-C6 alkoxy, alkoxy-C1-C6 alkyl, and alkoxy-C1-C6 alkoxy, wherein two R11 groups bound to the same carbon atom are not simultaneously OH; or two R11 groups combine with the carbon atom to which they are bound to form a moiety selected from the group consisting of C=O, C=CH2 and oxetane-3,3-diyl.

16. The method of claim 15, wherein the at least one compound is administered to the subject in a ceutically acceptable composition.

17. The method of claim 15, wherein the subject is further administered at least one additional agent useful for treating the hepatitis B virus infection.

18. The method of claim 17, wherein the at least one additional agent comprises at least one selected from the group ting of reverse transcriptase inhibitor; capsid inhibitor; cccDNA ion tor; sAg secretion inhibitor; oligomeric nucleotide targeted to the Hepatitis B genome; and immunostimulator.

19. The method of claim 18, wherein the oligomeric nucleotide comprises one or more siRNAs.

20. The method of claim 17, n the subject is co-administered the at least one compound and the at least one additional agent.

21. The method of claim 20, wherein the at least one compound and the at least one additional agent are coformulated.

22. The method of claim 15, wherein the subject is a mammal.

23. A method of reducing or minimizing levels of at least one ed from the group ting of hepatitis B virus surface antigen (HBsAg), hepatitis B e-antigen (HBeAg), hepatitis B core protein, and pregenomic (pg) RNA, in a HBV-infected subject, the method comprising administering to the subject in need thereof a therapeutically ive amount of at least one compound of formula (Ia), or a salt, solvate, stereoisomer, geometric isomer, tautomer, or any mixtures thereof: wherein: Y is ed from the group consisting of CHR5 and O; each occurrence of R5 is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl; R1 is -C(=O)OR8; R2 is =O; R3, R3’, R4, and R4’ are each independently selected from the group consisting of H, alkyl-substituted oxetanyl, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl; or one pair selected from the group consisting of R3 / R3’, R4 / R4’, and R3 / R4 combine to form a divalent group ed from the group consisting of C1-C6 diyl, (CH2)nO(CH2)n-, -(CH2)nNR9(CH2)n-, -(CH2)nS(CH2)n- , -(CH2)nS(=O)(CH2)n-, and -(CH2)nS(=O)2(CH2)n-, n each occurrence of n is independently selected from the group consisting of 1 and 2 and each nt group is optionally substituted with at least one C1-C6 alkyl or halogen; X1 is N; X2 is CR6II; X3 is CR6III; X4 is CR6IV; R6II, R6III, and R6IV are independently selected from the group consisting of H, halogen, - CN, pyrrolidinyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, ally substituted C3-C8 cycloalkyl, optionally substituted heterocyclyl, -OR, C1-C6 haloalkoxy, -N(R)(R), -NO2, -S(=O)2N(R)(R), acyl, and C1-C6 alkoxycarbonyl, wherein each occurrence of R is independently selected from the group consisting of H, C1-C6 alkyl, R’-substituted C1-C6 alkyl, C1-C6 hydroxyalkyl, optionally substituted (C1-C6 alkoxy)-C1-C6 alkyl, and ally substituted C3-C8 cycloalkyl, wherein each occurrence of R’ is independently selected from the group consisting of -NH2, -NH(C1-C6 alkyl), -N(C1-C6 (C1-C6 alkyl), -NHC(=O)OtBu, -N(C1-C6 C(=O)OtBu, and a 5- or 6-membered heterocyclic group, which is optionally N-linked; or R6II and R6III combine to form a nt group selected from the group consisting of -O(CHF)O-, -O(CF2)O-, -O(CR9R9)O-, )(CH2)O-, and - O(CH2)(CR11R11)(CH2)O-; R7 is selected from the group consisting of H, OH, halogen, C1-C6 alkoxy, and optionally substituted C1-C6 alkyl; R8 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C8 cycloalkyl; each occurrence of R9 is independently selected from the group consisting of H and C1-C6 alkyl; and each occurrence of R11 is independently selected from the group ting of H, OH, C1- C6 alkyl, C1-C6 alkoxy, alkoxy-C1-C6 alkyl, and alkoxy-C1-C6 alkoxy, wherein two R11 groups bound to the same carbon atom are not aneously OH; or two R11 groups combine with the carbon atom to which they are bound to form a moiety selected from the group ting of C=O, C=CH2 and oxetane-3,3-diyl.

24. The method of claim 23, wherein the at least one compound is administered to the subject in a pharmaceutically acceptable composition.

25. The method of claim 23, wherein the t is further administered at least one additional agent useful for treating the viral infection.

26. The method of claim 25, wherein the at least one additional agent comprises at least one selected from the group consisting of reverse riptase inhibitor; capsid inhibitor; cccDNA formation inhibitor; sAg secretion inhibitor; oligomeric nucleotide targeted to the Hepatitis B genome; and immunostimulator.

27. The method of claim 25, wherein the subject is co-administered the at least one nd and the at least one additional agent.

28. The method of claim 27, wherein the at least one compound and the at least one additional agent are coformulated.

29. The method of claim 23, wherein the subject is a mammal. 20220906 WIPO Sequence g.TXT SEQUENCE LISTING <110> Arbutus Biopharma, Inc. Protiva Biotherapeutics, Inc. <120> Substituted Pyridinone‐Containing Tricyclic Compounds, and Methods Using Same <130> 367569‐7004WO1(00021) <150> US