RU2800292C2 - Chemical compounds - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein W is N; Y is C; R¹ is absent; R² is either halogen, hydroxy or cycloalkyl; R³ is -OR¹²; R⁴ is H; R⁵ is H; R⁶ and R⁷ together form a 3- to 8-membered cycloalkyl ring, optionally substituted with R¹⁵, R^15', R¹⁶ and/or R^16'; R⁸ is H; R⁹ is H; R¹⁰ is -COOH; R¹¹ is H; R¹² is C_1-6 alkyl substituted with methoxy or cyclopropyl; and R¹⁵, R¹⁵, R¹⁶ and/or R¹⁶' are independently C_1-6 alkyl. The invention also relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I.

EFFECT: obtaining new compounds and a pharmaceutical composition based on them which can be used in medicine as effective agents for the treatment of hepatitis B.

8 cl, 3 tbl, 36 ex

Description

FIELD OF TECHNOLOGY

[0001] The present invention relates to compounds useful in the treatment of diseases caused by the hepatitis B virus in animals, in particular for the treatment of diseases caused by the hepatitis B virus in humans.

PRIOR ART

[0001] Hepatitis B is a viral disease transmitted parenterally through contaminated material such as blood and blood products, contaminated needles, sexually and vertically from an infected mother or carrier mother to her children. In regions of the world where the disease is common, vertical transmission at an early age results in a high proportion of infected people becoming chronic carriers of hepatitis B. The World Health Organization estimates that more than 2 billion people are infected worldwide, there are about 4 million acute cases per year, 1 million deaths per year, and there are 350-400 million chronic carriers. Approximately 25% of carriers die from chronic hepatitis, cirrhosis, or liver cancer, and nearly 75% of chronic carriers are Asians. Hepatitis B virus (HBV) is the second most important carcinogen after tobacco, causing 60% to 80% of all cases of primary liver cancer. HBV is 100 times more contagious than HIV.

[0002] HBV is transmitted through dermal or parenteral contact with infected blood, body fluids, and sexual intercourse. HBV can remain on any surface it comes in contact with for up to a week, such as countertops, razor blades, blood stains, without losing its infectivity. However, HBV cannot cross the skin or mucosal barrier. Transmission requires some breakthrough of this barrier, which can be minimal and negligible.

[0003] HBV is a small enveloped DNA virus belonging to the hepadnavirus family. The virus replicates through an intermediate form of RNA by reverse transcription, which in practice associates them with retroviruses such as HIV. Although replication takes place in the liver, the virus spreads through the blood, where viral proteins and antibodies against them are found in infected people. HBV is many times more contagious than HIV due to the higher concentrations of HBV virus found in the bloodstream at any given time.

[0004] HBV infection results in the formation of two different particles: 1) the HBV virus itself (or Dane particle), which includes a viral capsid assembled from the HBV core antigen (HBcAg) protein and coated with hepatitis B surface antigen (HBsAg) capable of re-infecting cells; and 2) subviral particles (or SHF), which are high-density lipoprotein-like particles composed of lipids, cholesterol, cholesterol esters, and small and medium forms of hepatitis B surface antigen (HBsAg), which are non-infectious. For every virus particle produced, between 1,000 and 10,000 microwaves enter the bloodstream. Thus, SHFs (and the HBsAg protein they carry) represent the vast majority of viral protein in the blood. HBV-infected cells also secrete a soluble proteolytic product of a pre-core protein called HBV e-antigen (HBeAg).

[0005] Hepatitis D virus (HDV) uses HBsAg to form its viral structure (Taylor, 2006, Virology, 344: 71-76), and therefore, HDV infection can only occur in subjects co-infected with HBV. While the incidence of HBV co-infection in asymptomatic HBV carriers and HBV-associated chronic liver disease is low in countries with low HBV incidence, it is a serious complication in HBV-infected subjects in countries with high HBV incidence and may increase the rate of progression of liver disease to fulminant hepatitis. Thus, the apparent unmet medical need for the treatment of HBV infection becomes even more relevant for subjects with HBV/HDV co-infection.

[0006] Current conventional treatments for HBV include immunotherapy based on interferon or thymosin α1 and suppression of viral production through inhibition of HBV polymerase (eg, "nuclei"). HBV polymerase inhibitors are effective in reducing viral production, but have little or no effect on rapidly lowering blood levels of HBsAg or may slowly lower HBsAg with long-term treatment in a limited number of patients (as is the case with tenofovir disoproxil fumarate). Interferon-based immunotherapy can lead to reduced viral production and early removal of HBsAg from the blood, but only in a small percentage of treated patients. The generally accepted role of HBsAg in the blood is to isolate anti-HBsAg antibodies and allow infectious viral particles to elude immune detection, which is likely one of the reasons HBV infection remains a chronic disease. In addition, HBsAg, HBeAg, and HBcAg have immunoinhibitory properties, as discussed below, and the persistence of these viral proteins in the blood of patients following administration of any of the currently available HBV treatments as described above is likely to have a significant impact on the difficulty patients achieve immunological control of their HBV infection.

[0007] Although all three major HBV proteins (HBsAg, HBeAg and HBcAg) have immunoinhibitory properties (see below), HBsAg makes up the vast majority of the HBV protein circulating in the blood of HBV infected subjects. In addition, although HBeAg clearance (via seroconversion) or reduction in serum viremia does not correlate with development of sustained control of HBV infection after treatment, serum HBsAg clearance (and seroconversion) in HBV infection is generally accepted as an excellent prognostic indicator of antiviral response to treatment that will control HBV infection after treatment (although this occurs only in a small proportion of patients receiving immunotherapy). Thus, while reduction of all three major HBV proteins (HBsAg, HBeAg, and HBcAg) may result in optimal reversal of the inhibitory effect, removal of HBsAg alone may be sufficient on its own to reverse the major part of viral suppression of immune function in subjects with HBV infection.

[0008] Therefore, in the absence of any current treatment regimen that can restore immunological control of HBV in a significant proportion of patients, it is necessary to provide effective treatment for HBV infection and HBV/HDV co-infection that can restore immunological control in the majority of patients.

[0009] Hepatitis B viral infections in association with hepatitis D viral infections are an ongoing medical problem because, like any rapidly replicating infectious agent, they generate mutations that help certain HBV subpopulations become resistant to current treatment regimens. Currently, there are no effective therapies for the treatment of people infected with hepatitis B and/or hepatitis D virus (HDV) that result in seroconversion of the virus in the body, or that result in a 90% decrease in antigen levels from baseline in people with hepatitis B virus infection. Currently, treatments for chronic HBV and/or HDV infection recommended by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) include interferon alfa (IFNα), pegylated interferon alfa-2a (Peg-IFN2a), entecavir, and tenofovir. However, typical interferon therapy lasts 48 weeks and leads to serious and unpleasant side effects, and HBeAg seroconversion 24 weeks after stopping therapy varies only in the range of 27-36%. Seroconversion of HBsAg is even lower - immediately after the cessation of treatment, only 3% is observed, and after 5 years it increases to 12%.

[0010] Nucleoside and nucleotide therapies with entecavir and tenofovir are successful in reducing viral load, but levels of HBeAg seroconversion and loss of HBsAg are even lower than with IFNα therapy. Other similar therapies are also used, including lamivudine (3TC), telbivudine (LdT), and adefovir, but for nucleoside/nucleotide therapy in general, the occurrence of resistance limits therapeutic efficacy.

[0011] Recent clinical studies have found a correlation between seroconversion and HBeAg reduction (Fried et al. (2008) Hepatology 47: 428) and HBsAg reduction (Moucari et al. (2009) Hepatology 49: 1151). The decrease in antigen levels could allow immunological control of HBV infection, as high levels of antigens are thought to induce immunological tolerance. Current HBV nucleoside therapies are able to drastically reduce serum HBV levels, but have little effect on HBeAg and HBsAg levels. Antisense therapy differs from nucleoside therapy in that it can directly act on antigen transcripts and thereby reduce serum levels of HBeAg and HBsAg. But antisense therapy is expensive and requires intravenous administration.

[0012] Thus, there is a need in the art for the discovery and development of new antiviral therapies. In particular, there is a need for new HBV therapies that can increase HBeAg and HBsAg seroconversion rates. These serum markers indicate immunological control of HBV infection and lead to improved prognosis, i.e. prevention of liver disease and progression of cirrhosis, prevention of liver failure, prevention of hepatocellular cancer (HCC), prevention of transplantation associated with liver disease, and prevention of death.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

[0013] Embodiments of the present invention are compounds of Formula I:

Where

[0014] W and Y are independently C or N, provided that W and Y are not both C;

wherein

[0015] if W is C, then R ¹ is hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio or substituted thio, alkyl or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered heterocycloalkyl or substituted from 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, -C _x H _2x -phenyl, -O _- C x H _2x -phenyl, or -(C _1-6 alkyl)NC _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5, 6; or -OR ¹² ; And

[0016] if Y is C, then R ₄ is hydrogen, hydroxy, halogen, cyano, amino, or substituted amino, thio, or substituted thio, alkyl, or substituted alkyl, alkoxy, or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered heterocycloalkyl or substituted from 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, -C _x H _2x -phenyl, -O-C _x H _2x -phenyl, or -(C _1-6 alkyl)N-C _x H _2x -phenyl, while x is 0, 1, 2, 3, 4, 5, 6; or -OR ¹² ;

wherein

[0017] if W is N, then R ¹ is absent; And

[0018] if Y is N, then R ₄ is absent;

[0019] R ₂ and R ₃ are independently a group selected from hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio or substituted thio, alkyl or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered heterocycloalkyl or substituted from 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, -C x H _2x -phenyl, O _- C _x H _2x -phenyl, or -(C _1-6 alkyl) N -C _x H _2x -phenyl, while x is 0, 1, 2, 3, 4, 5, 6; or -OR ¹² ; R ⁵ and R ⁶ are independently hydrogen, hydroxy, halogen, cyano, amino alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted aryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[0020] R ⁷ and R ⁸ are independently hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[0021] or R ⁵ and R ⁶ together are a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring, wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' , wherein said 3- to 8-membered heterocycloalkyl ring is optionally substituted nym R ¹³ , R ^13' , R ¹⁴ and/or R ^14' ;

[0022] or R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring or a heterocycloalkyl ring comprising one heteroatom or two or more heteroatoms optionally substituted with R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' , wherein said one heteroatom in said heteroalkyl ring is NR ²⁰ and said two or more heteroatoms are a group selected from N, NR ²² , O, S, SR ²² and SR ²² R ²² ';

[0023] or R ⁷ and R ⁸ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with R ¹⁷ , R ¹⁷ ', R ¹⁸ and/or R ¹⁸ ', wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ²² ';

[0024] R ⁹ is a bond, hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, while x is 0, 1, 2, 3, 4, 5 or 6;

[0025] R ¹⁰ is a substituent shown in Table 2 or a tautomer thereof;

[0026] or R ⁹ is a bond and R ⁹ and R ¹⁰ together form an oxaborol ring;

[0027] R ¹¹ is hydrogen, hydroxy, halogen, piano, amino, alkyl, or substituted alkyl; alkenyl or substituted alkenyl; alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; heterocycloalkyl or substituted heterocycloalkyl, aryl, heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[0028] R ¹² is hydrogen; alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl;

[0029] R ¹³ , R ^13' , R ¹⁴ and R ¹⁴ ' are independently hydrogen, hydroxy, halogen, amino, aminoalkyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, carbonyl, carboxamide, amide; or R ¹³ and R ^13' or R ¹⁴ and R ^14' together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C 3-8 cycloalkyl, C _2-6 alkenyl or C _1-6 alkoxy, wherein said the heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, ^{SR 22} _or SR ²² R ²² ';

[0030] R ¹⁵ , R ^15' , R ¹⁶ and R ^16' are independently hydrogen, hydroxy, halogen, amino, cyano, C _1-6 alkyl, or C _1-6 alkoxy; or R ¹⁵ and R ^15' or R ¹⁶ and R ^16' together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl or C _1-6 alkoxy, wherein said hetero an atom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' ;

[0031] R ¹⁷ , R ^17' , R ¹⁸ and R ^18' are independently hydrogen, hydroxy, halogen, amino, cyano, C _1-6 alkyl, or C _1-6 alkoxy; or R ¹⁷ and R ¹⁸ or R ^17' and R ^18' together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl or C _1-6 alkoxy, wherein said the heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' ;

[0032] R ¹⁹ , R ^19' and R ^19" are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C 2-6 alkenyl, C _1-6 alkoxy, phenyl, C _1-6 alkylimidazole, C _1-6 alkyltriazole, C _1-6 alkyltetrazole, C _1-6 alkylthiazole, C _1-6 alkyloxazole, C _1-6 alkyldioxazole, _{C 1-6 alkyloxazolidone} , and

[0033] R ²⁰ and R ²¹ are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, phenyl, C _1-6 alkylimidazole, C _1-6 alkyltriazole, C _1-6 alkyltetrazole, C _1-6 alkylthiazole, C _1-6 alkyloxazole, C _1-6 alkyldioxazole; C _1-6 alkyloxazolidone or R ²⁰ and R ²¹ together with the nitrogen to which they are attached form an unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl; or form a carboxyl-substituted pyrrolidinyl, carboxyl-substituted piperidinyl or carboxyl-substituted morpholinyl; And

[0034] R ²² and R ^22' are independently a group selected from hydrogen, oxygen, C _1-6 alkyl or substituted C _1-6 alkyl, C _1-6 alkoxy or substituted C _1-6 alkoxy, C _3-8 cycloalkyl or substituted C _3-8 cycloalkyl, C _2-6 alkenyl or substituted C _2-6 alkenyl, aryl or substituted aryl, including substituted or unsubstituted C _1-6 alkylimidazole, substituted or unsubstituted C 1-6 alkyltriazole, C _{1-6 alkyltetrazole, C 1-6 alkylthiazole} , substituted or unsubstituted _{C 1-6 alkyloxazole} , C _1-6 alkyldioxazole; C _1-6 alkyloxazolidone; -COR ¹⁹ , -COOR ^19' , -CSOR ^19" , -CONR ²⁰ R ²¹ ,

or a pharmaceutically acceptable salt thereof.

[0035] Another embodiment provides a compound of Formula IA or Formula IB:

[0036]

wherein

[0037] C* is a stereocenter at a carbon atom that has the configuration being (R) or (S);

[0038] W and Y are independently C or N, provided that W and Y are not both C;

[0039] wherein if W is C, then R ¹ is hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio or substituted thio, alkyl or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered heterocycloalkyl or substituted from 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, -C _x H _2x -phenyl, -O-C _x H _2x -phenyl, or -(C _1-6 alkyl)NC _x H _2x -phenyl, while x is 0, 1, 2, 3, 4, 5, 6; or -OR ¹² ; And

[0040] if Y is C, then R ⁴ is hydrogen, hydroxy, halo, cyano, amino, or substituted amino, thio, or substituted thio, alkyl, or substituted alkyl, alkoxy, or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered heterocycloalkyl or substituted from 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, -C _x H _2x -phenyl, -O-C _x H _2x -phenyl, or -(C _1-6 alkyl)NC _x H _2x -phenyl, while x is 0, 1, 2, 3, 4, 5, 6; or -OR ¹² ;

wherein

[0041] if W is N, then R ¹ is absent; And

[0042] if Y is N, then R ⁴ is absent;

[0043] R ² and R ³ are independently a group selected from hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio or substituted thio, alkyl or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; from 3- to 8-membered heterocycloalkyl or substituted from 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, -C _x H _2x -phenyl, -O-C _x H _2x -phenyl, or -(C _1-6 alkyl) N _- C x H _2x -phenyl, while x is 0, 1, 2, 3, 4, 5, 6; or -OR ¹² ;

[0044] R ⁵ and R ⁶ are independently hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted aryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[0045] R ⁷ and R ⁸ are independently hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[0046] or R ⁵ and R ⁶ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring, wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' , wherein said 3- to 8-membered heterocycloalkyl ring is optionally substituted with R ¹³ , R ^13' , R ¹⁴ and/or R ^14' ;

[0047] or R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring or a heterocycloalkyl ring containing one heteroatom or two or more heteroatoms optionally substituted with R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' , wherein said one heteroatom in said heteroalkyl ring is NR ²⁰ and said two or more heteroatoms are a group selected from N, NR ²² , O, S, SR ²² and SR ²² R ^22' ;

[0048] or R ⁷ and R ⁸ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with R ¹⁷ , R ^17' , R ¹⁸ and/or R ^18' , wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' ;

[0049] R ⁹ is a bond, hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, while x is 0, 1, 2, 3, 4, 5 or 6;

[0050] R ¹⁰ is a substituent shown in Table 2, or a tautomer thereof;

[0051] or R ⁹ is a bond and R ⁹ and R ¹⁰ together form an oxaborol ring;

[0052] R ¹¹ is hydrogen, hydroxy, halo, cyano, amino, alkyl, or substituted alkyl; alkenyl or substituted alkenyl; alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; heterocycloalkyl or substituted heterocycloalkyl, aryl, heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[0053] R ¹² is hydrogen; alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl;

[0054] R ¹³ , R ^13' , R ¹⁴ and R ^14' are independently hydrogen, hydroxy, halogen, amino, aminoalkyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, carbonyl, carboxamide, amide; or R ¹³ and R ^13' or R ¹⁴ and R ^14' together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _{3-8 cycloalkyl, C 2-6 alkenyl} or C _1-6 alkoxy, wherein said hetero an atom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' ;

[0055] R ¹⁵ , R ^15' , R ¹⁶ and R ^16' are independently hydrogen, hydroxy, halogen, amino, cyano, C _1-6 alkyl, or C _1-6 alkoxy; or R ¹⁵ and R ^15' or R ¹⁶ and R ^16' together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl or C _1-6 alkoxy, wherein said hetero an atom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ²² ';

[0056] R ¹⁷ , R ^17' , R ¹⁸ and R ^18' are independently hydrogen, hydroxy, halogen, amino, cyano, C _1-6 alkyl, or C _1-6 alkoxy; or R ¹⁷ and R ¹⁸ or R ^17' and R ^18' together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl or C _1-6 alkoxy, wherein said the heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ²² ';

[0057] R ¹⁹ , R ^19' and R ^19" are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C 2-6 alkenyl, C _1-6 alkoxy, phenyl, C _1-6 alkylimidazole, C _1-6 alkyltriazole, C _1-6 alkyltetrazole, C _1-6 alkylthiazole, C _1-6 alkyloxazole, C _1-6 alkyldioxazole, _{C 1-6 alkyloxazolidone} , and

[0058] R ²⁰ and R ²¹ are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, phenyl, C _1-6 alkylimidazole, C _1-6 alkyltriazole, C _{1-6 alkyltetrazole, C 1-6 alkylthiazole} , C _1-6 alkyloxazole, C _1-6 alkyldioxazole; C _1-6 alkyloxazolidone, or R ²⁰ and R ²¹ together with the nitrogen to which they are attached, form an unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl; or form a carboxyl-substituted pyrrolidinyl, a carboxyl-substituted piperidinyl or a carboxyl-substituted morpholinyl; And

[0059] R ²² and R ^22' are independently a group selected from hydrogen, oxygen, C _1-6 alkyl or substituted C _1-6 alkyl, C _1-6 alkoxy or substituted C _1-6 alkoxy, C _3-8 cycloalkyl or substituted C _3-8 cycloalkyl, C _2-6 alkenyl or substituted C _2-6 alkenyl, aryl or substituted aryl, including substituted or unsubstituted C _1-6 alkylimidazole, substituted or unsubstituted C 1-6 alkyltriazole, C _{1-6 alkyltetrazole, C 1-6 alkylthiazole} , substituted or unsubstituted _{C 1-6 alkyloxazole} , C _1-6 alkyldioxazole; C _1-6 alkyloxazolidone; -COR ¹⁹ , -COOR ^19' , CSOR ^19" , -CONR ²⁰ R ²¹ ,

or a pharmaceutically acceptable salt thereof.

[0060] In another specific embodiment, the present invention provides compounds of Formula I, Formula IA, or Formula IB described herein, including their salts and prodrugs,

[0061] while

R ¹⁰ is selected from the group -CO ₂ H, -B(OH) ₂ , -NHSO ₂ R ^25' , -NCO ₂ R ²⁵ ,

wherein

[0062] R ²³ and R ^23' are independently a group selected from H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl

[0063] R ²⁴ and R ^{24 '} independently are a group selected from H, hydroxilia, amino or replaced by amino, alkyl or replaced by alkyl, cycloalkil or replaced cycloil, alkeenil or replaced by alkenil, thiol or thioalalkil, heterocylcuciallceline or replaced heterocilles, arila or substituted arila, gutes, guts Roarila or replaced by heteroaril; And

[0064] R ²⁵ and R ^25' are independently a group selected from H, OH, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, and heteroaryl or substituted heteroaryl; or their pharmaceutically acceptable salt.

[0065] In another specific embodiment, the present invention provides compounds of Formula I, Formula IA, or Formula IB, including salts and prodrugs thereof, wherein

[0066] R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ and R ¹¹ are groups as defined herein;

[0067] R ⁸ is isopropyl; And

R ¹⁰ is selected from the group -CO ₂ H, -B(OH) ₂ , -NHSO ₂ R ^25' , -NCO ₂ R ²⁵ ,

wherein

[0068] R ²³ and R ^23' are independently a group selected from H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl,

[0069] R ²⁴ and R ^{24 '} independently are a group chosen from n, hydroxilia, amino or replaced by amino, alkyl or replaced by alkyl, cycloalkil or replaced cycloilkil, alkenil, thiol or thioalalkil, heterocylcucial orplane heterocilles, arila or substituted arila, guts Roarila or replaced by heteroaril; And

[0070] R ²⁵ and R ^25' are independently a group selected from H, OH, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, and heteroaryl or substituted heteroaryl; or their pharmaceutically acceptable salt.

[0071] In another embodiment, a Formula I, Formula IA, or Formula IB compound, including salts and prodrugs thereof, is provided, wherein

[0072] R ¹ , R ² , R ³ , R ⁴ , R ⁹ and R ¹¹ as defined herein;

[0073] R ⁵ , R ⁶ and R ⁷ are H;

[0074] R ⁸ is isopropyl;

R ¹⁰ is selected from the group -CO ₂ H, -B(OH) ₂ , -NHSO ₂ R ^25' , -NCO ₂ R ²⁵ ,

wherein

[0075] R ²³ and R ^23' are independently a group selected from H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl,

[0076] R ²⁴ and R ^{24 '} independently are a group selected from H, hydroxilia, amino or replaced by amino, alkyl or replaced by alkyl, cycloalkil or replaced cycloil, alkenil, thiol or thioalalkil, heterocylcucilla or replaced heterocilles, arila or substituted arila, gut Roarila or replaced by heteroaril; And

[0077] R ²⁵ and R ^25' are independently a group selected from H, OH, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, and heteroaryl or substituted heteroaryl; or their pharmaceutically acceptable salt.

[0078] In specific embodiments, a method of treating a hepatitis B infection or a hepatitis B and hepatitis D co-infection is provided, in particular a method of treating a hepatitis B infection or a hepatitis B and hepatitis D co-infection in a human, comprising administering to a subject in need of such treatment a compound of Formula I, IA, or IB described herein.

[0079] In yet another embodiment, the present invention provides a method of treating hepatitis B infection or hepatitis B and hepatitis D co-infection, in particular a method of treating hepatitis B infection or hepatitis B and hepatitis D co-infection in a human, comprising administering to a subject in need of such treatment a first pharmaceutically acceptable agent comprising a compound of Formula I, Formula IA, or Formula IB as described herein, in combination with a second pharmaceutically acceptable agent that stimulates immune function and a third pharmaceutically acceptable agent containing antivirus connection.

[0080] In yet another embodiment, administration of a compound of Formula I, IA, or IB as described herein inhibits the release of hepatitis B surface antigen (HBsAg), HB core antigen protein (HBcAg), and/or the hepatitis B pre-core protein known as HBV antigen e antigen (HBeAg) from infected hepatocytes.

BRIEF DESCRIPTION OF THE FIGURES

[0081] Embodiments of the present invention include compounds that inhibit levels of HBe and/or HBs antigens in a subject infected with hepatitis B virus and therefore useful in the treatment of human hepatitis B virus infections and diseases and symptoms associated with such viral infections. The features of the present invention will be explained in more detail with reference to the following detailed description with reference to the attached Tables, in which:

[0082] Table 1 lists compounds of Formula I as described herein,

[0083] Table 2 lists the R ¹⁰ substituents for compounds of Formula I as described herein.

[0084] Table 3 shows the results of an ELISA study of HepAD38 HBsAg cells and a cytotoxicity study showing the EC ₅₀ values measured for the tested compounds against HBs antigens (HBsAg).

DETAILED DESCRIPTION OF SPECIFIC IMPLEMENTATION OPTIONS

[0085] This application makes reference to various embodiments relating to compounds, compositions and methods. The various embodiments described are intended to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather, it should be noted that the descriptions of the various embodiments provided herein may have overlapping scope. The embodiments discussed herein are illustrative only and are not intended to limit the scope of the present invention.

[0086] It should be understood that the terminology used herein is only intended to describe specific embodiments and is not intended to limit the scope of the present invention. In this description and in the following claims, reference will be made to a number of terms which are to have the following meanings.

[0087] As used herein, unless otherwise indicated, "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 14 carbon atoms and, in some embodiments, 1 to 6 carbon atoms. The term "alkyl" includes by way of example linear and branched hydrocarbon groups such as methyl (CH ₃ -), ethyl-(CH ₃ CH ₂ -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH _{3 ) 2 CH-} ), n-butyl (CH ₃ CH ₂ CH ₂ CH ₂ -), isobutyl ((CH ₃ ) ₂ CHCH ₂ -), sec- butyl ((CH ₃ ) (CH ₃ CH ₂ ) CH-), t-butyl ((CH ₃ ) ₃ C-), n-pentyl (CH _{3 CH 2} CH ₂ CH ₂ CH ₂ -), and neopentyl ((CH ₃ ) ₃ CCH ₂ -). Alkyl groups may also be substituted, for example, with one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halogen or haloalkyl substituents.

[0088] "Alkoxy" or "alkoxy" refers to an -O-alkyl group, where alkyl is a group as defined herein. Alkoxy includes by way of example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, morpholinylpropoxy, piperidinylethoxy. Alkoxy groups may also be substituted, for example, with one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halogen or haloalkyl substituents.

[0089] "Amino" refers to a group -NR ^a R ^b , where R ^a and R ^b are independently a group selected from hydrogen, hydroxy, alkyl or substituted alkyl, alkenyl or substituted alkenyl, aryl or substituted aryl, cycloalkyl or substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, heteroaryl or substituted heteroaryl, and optionally R ^a and R ^b , combined with nitrogen, form a heterocyclic group. When R ^a is hydrogen and R ^b is alkyl, said amino group sometimes refers to alkylamino or aminoalkyl. When R ^a and R ^b are alkyl, said amino group is sometimes referred to as daalkylamino. When referring to a monosubstituted amino, this means that either R ^a or R ^b is hydrogen, but not both. When referring to disubstituted amino, this means that neither R ^a nor R ⁶ is hydrogen.

[0090] "Aryl" refers to an aromatic group formed from 5 to 14 carbon atoms with no ring heteroatoms and having one ring (eg phenyl) or multiple fused rings (eg naphthyl or anthryl). For multiple ring systems, including fused, bridged, and spiro rings, containing aromatic and non-aromatic rings that do not contain heteroatoms in the ring, the term "aryl" or "Ar" is used when the point of attachment is an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalen-2-yl is an aryl group in which its point of attachment is position 2 on the aromatic phenyl ring). Aryl groups may also be substituted, for example, with one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halogen or haloalkyl substituents.

[0091] "Cycloalkyl" refers to a saturated or partially saturated cyclic group formed from 3 to 14 carbon atoms, containing no ring heteroatoms, and having one or more rings, including fused, bridged, and spiro ring systems. For multi-ring systems having aromatic and non-aromatic rings that do not contain heteroatoms in the ring, the term "cycloalkyl" is used when the point of attachment is a non-aromatic carbon atom (eg 5,6,7,8-tetrahydronaphthalen-5-yl). The term "cycloalkyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of cycloalkyl groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicycloostyl and the like. Cycloalkyl groups may also be substituted, for example, with one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halogen or haloalkyl substituents.

[0092] "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0093] "Haloalkyl" refers to substituted alkyl groups with 1 to 9 (e.g., when said alkyl group has 4 carbon atoms, such as a t-butyl group fully substituted with halogen) or in some embodiments, 1 to 3 halogen groups (e.g., trifluoromethyl).

[0094] "Hydroxy" or "hydroxyl" refers to the -OH group.

[0095] "Heteroaryl" refers to an aromatic group formed from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, sulfur, phosphorus, silicon, and boron, and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl and benzimidazol-6-yl). For multiple ring systems, including fused, bridged, and spiro ring systems containing aromatic and non-aromatic rings, the term "heteroaryl" is used if at least one ring heteroatom is present and the point of attachment is an aromatic ring atom (e.g., 1,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl). In some embodiments, said nitrogen and/or sulfur ring atoms of said heteroaryl group are optionally oxidized to form an N-oxide (N→O), sulfinyl, or sulfonyl. More specifically, the term heteroaryl includes, but is not limited to, pyridine, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, purinyl, phthalazyl, naphthyl, naphthylpyridyl, oxazolyl, quinolyl, benzofuranyl, tetra hydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, indolizinyl, dihydroindolyl, indazolyl, indolinyl, benzoxazolyl, quinolyl, isoquinolyl, quinolisyl, chianazolyl, quinoxalyl, tetrahydroquinolinyl, isoquinolyl, quinazolinonyl, but not limited to benzimidazolyl, benzisoxazolyl, benzothienyl, benzopyridazinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, and phthalimidyl. Heteroaryl groups may also be substituted, for example, with one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halogen or haloalkyl substituents.

[0096] "Heterocyclic" or "heterocycle" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated cyclic group containing 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, sulfur, phosphorus, or oxygen, and having a single ring and a multiple ring system, including fused, bridged, and spiro ring systems. Для систем с множеством колец, имеющих ароматические и/или неароматические кольца, термины "гетероциклический, "гетероцикл", "гетероциклоалкил" или "гетероциклил" применяют, когда имеется по меньшей один гетероатом в кольце, а местом присоединения является атом неароматического кольца (например, 1,2,3,4-тетрагидрохинолин-3-ил, 5,6,7,8-тетрагидрохинолин-6-ил, и декагидрохинолин-6-ил). В одном варианте осуществления атомы азота, фосфора и/или серы указанной гетероциклической группы необязательно окислены с получением N-оксида, фосфинан оксида, сульфинильного, сульфонильного остатков. Более конкретно указанный гетероциклил включает тетрагидропиранил, пиперидинил, пиперазинил, 3-пирролидинил, 2-пирролидон-1-ил, морфолинил, и пирролидинил, но не ограничиваются ими. Префикс, указывающий количество атомов углерода (например, С ₃ -С ₁₀ ) относится к общему количеству атомов углерода в части указанной гетероциклильной группы, не включающему количество гетероатомов. Гетероциклил или алкильные группы гетероцикла также могут быть замещены, например, одним или более алкилом, циклоалкилом, гетероциклоалкилом, алкокси, амино, аминоалкилом, тиолом, тиоалкилом, арилом, гетероарилом, галогенными или галогеналкильными заместителями.

[0097] Examples of heterocyclic and heteroaryl groups include azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolisinol, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazoliperoline, imidazolidine, imidazolidine, naphrazoline, phthalimide, quinoline, 1,2,3,4 tetrahydroisoquinoline, 4,5,6,7-tetra hydrobenzo[b]thiophene, thiazole, cyclopentathiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholine, thiomorpholine (also called thiamorpholine), piperidine, pyrrolidine, and tetrahydrofuranyl.

[0098] "Fused heterocyclic" or "fused heterocyclyl" refers to a 3 to 10 membered cyclic substituent formed by substitution of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure, as in the following cyclopentathiazole structure:

Fused heterocyclyl groups may also be substituted, for example, with one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halogen or haloalkyl substituents.

[0099] "Fused aryl" and "fused heteroaryl" refers to a 5 to 6 membered aryl structure or a heteroaryl structure fused to a 5 to 6 membered aryl, heteroaryl, or cycloalkyl ring of different carbon atoms in said aryl structure or said heteroaryl structure, which may be substituted on one of the carbon atoms in said fused aryl or fused heteroaryl structure, and connected with the core of the molecule at different carbon atoms, as in the following structures of cyclopentylthiazole, quinoline or naphthalene, given as an example:

Fused aryl and fused heteroaryl groups may also be substituted, for example, with one or more alkyl, cycloalkyl, heterocycloalkyl, alkoxy, amino, aminoalkyl, thiol, thioalkyl, aryl, heteroaryl, halogen or haloalkyl substituents.

[00100] The terms "compound", "compounds", "chemical compound", and "chemical compounds" as used herein refer to a compound characterized by the general Formula given herein, any subtypes of said general Formula, and any forms of compounds included in said Formula and subtypes of said Formula, including racemates, stereoisomers, and tautomers of said compound or compounds.

[00101] The term "heteroatom" means nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen such as N(O) {N ⁺ -O ^- } and sulfur such as S(O) and S(O) ₂ and the quaternary form of any basic nitrogen.

[00102] "Oxazole" and "oxazolyl" refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms, and also contains three carbon atoms and may substitute for one of three carbon atoms and may be bonded to another molecule at the other of three carbon atoms, as illustrated by any of the following structures, wherein the oxazolidinone groups shown herein are bonded to the parent molecule as indicated by a wavy line in connection with the parent molecule:

[00103] "Oxopyrrolidine" and "oxopyrrolidinyl" refers to a 5-membered heterocyclic ring containing nitrogen and 4 carbon atoms, which replaces one of the carbon atoms in the heterocyclic ring through a carbonyl and may be bonded to another substituent on another carbon atom in the heterocyclic ring, as in the structure below by way of example:

[00104] "Pyridine" and "pyridinyl" refer to 6-membered heteroaryl rings containing one nitrogen and 5 carbon atoms, which may also be substituted on one or more carbon atoms in the heteroaryl ring, and may be bonded to another substituent on another carbon in the heteroaryl ring, as in the structure below by way of example:

[00105] "Thiazol" and "thiazolyl" refer to 5-membered heteroaryls containing one sulfur atom and one nitrogen atom in the heteroaryl ring and 3 carbon atoms in the heteroaryl ring, which may also be substituted for one or more carbon atoms in the heteroaryl ring, and may be bonded to another substituent on a different carbon atom in the heteroaryl ring, as in the structure below by way of example:

[00106] "Pyrimidine" and "pyrimidinyl" refers to a 6-membered heteroaryl ring containing two nitrogens in the heteroaryl ring and 4 carbon atoms in the heteroaryl ring, which may be substituted at one or more carbon atoms in the heteroaryl ring, and may be connected to another substituent at a different carbon atom in the heteroaryl ring, as in the structure below by way of example:

[00107] "Racemates" refers to a mixture of enantiomers. In one embodiment of the present invention, the compounds of Formula I, or a pharmaceutically acceptable salt thereof, are enantiomerically enriched in one enantiomer wherein all of said chiral carbon atoms are in the same configuration. In general, reference to an enantiomerically enriched compound or salt means that said enantiomer will comprise more than 50% by weight of the total weight of all enantiomers of the compound or salt.

[00108] "Solvate" or "solvates" of a compound refers to those compounds, as defined above, that are associated with a stoichiometric or non-stoichiometric amount of solvent. Solvates of a compound include solvates of all forms of the compound. In some embodiments, the solvents are volatile, non-toxic, and/or suitable for human administration in trace amounts. Suitable solvates include water.

[00109] "Stereoisomer" or "stereoisomers" refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

[00110] "Tautomer" refers to alternative forms of the compound that differ in the position of the proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing a ring atom attached to both the -NH- ring moiety and the =N- ring moiety, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[00111] "Thio" or "thiol" refers to the group -SR, where R is selected from the group of hydrogen, alkyl, alkenyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycle. When R is H, said thio group is sometimes referred to as a thiol group, and when R is alkyl, said thio group is sometimes referred to herein as a thioalkyl group or an alkylthio group. Said sulfur atom may also be bonded to another carbon atom or atom in the same molecule to form a heterocyclic group.

[00112] A "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counterions well known in the art and includes, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkyl ammonium, and when the molecule contains a basic functional group, organic or inorganic acid salts such as hydrochloride, hydrobromide, tartrate, mesylate, acetate , maleate and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.

[00113] "Patient" or "subject" refers to mammals and includes humans and non-human mammals.

[00114] "Treatment" of a disease in a patient refers to 1) preventing the onset of the disease in a patient who is predisposed or not yet symptomatic of the disease; 2) suppression of the disease or stop its development; or 3) alleviation or regression of the disease.

[00115] If dashed lines occur adjacent to single bonds indicated by solid lines, then the dashed line represents an optional double bond at that position. Similarly, wherever dotted circles appear in ring structures, indicated by solid lines or solid circles, the dotted circles represent one to three optional double bonds arranged according to their proper valence, considering whether there are any optional substitutions around the ring known to one of ordinary skill in the art. For example, the dotted line in the structure below could indicate either a double bond at that position or a single bond at that position:

[00116] Similarly, ring A below can be a cyclohexyl ring without any double bonds, or it can also be a phenyl ring having three double bonds located in any position that still reflects the correct valence of the phenyl ring. Similarly, in ring B below, any of X1-X5 can be a group selected from: C, CH, or CH ₂ , N, or NH, and the dotted circle means that ring B can be a cyclohexyl or phenyl ring, or an N-containing heterocycle without double bonds, or an N-containing heteroaryl ring with one to three double bonds located in any position that still reflects the correct valency:

[00117] If specific compounds or general Formulas are shown that have aromatic rings, such as those with aryl or heteroaryl, then one skilled in the art will appreciate that the particular aromatic arrangement of any double bonds is a mixture of equivalent positions even if they are drawn in different places from compound to compound or Formula to Formula. For example, in the two pyridine rings (A and B) below, the double bonds are drawn in different places, however, as you know, they have the same structure and represent the same compound:

[00118] Unless otherwise indicated, substituent nomenclature that is not explicitly defined herein is achieved by denoting a terminal portion of functionality followed by adjacent functional groups in the direction of the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)(alkyl)OC(O). In terms such as "-C(Rx) ₂ ", it is to be understood that the two Rx groups may be the same or they may be different if Rx is defined as having more than one possible identity. In addition, some substituents are designated as -RxRy, where "-" indicates a bond adjacent to the original molecule, and Ry represents the terminal part of the functionality. Similarly, it is understood that the above definitions are not intended to include invalid substitution schemes (eg substitution with 5 fluoro groups). Such invalid substitution patterns are well known to the person skilled in the art.

[00119] In accordance with one embodiment of the present invention, compounds of Formula I, or salts or prodrugs thereof, are provided,

wherein

[00120] W and Y are independently C or N, provided that W and Y are not both C;

wherein

[00121] if W is C, then R ¹ is hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio or substituted thio, alkyl or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered heterocycloalkyl or substituted from 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, -C _x H _2x -phenyl, -O-C _x H _2x -phenyl, or -(C _1-6 alkyl)N-C _x H _2x -phenyl, while x is 0, 1, 2, 3, 4, 5, 6; or -OR ¹² ; And

[00122] if Y is C, then R ⁴ is hydrogen, hydroxy, halo, cyano, amino, or substituted amino, thio, or substituted thio, alkyl, or substituted alkyl, alkoxy, or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered heterocycloalkyl or substituted from 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, -C _x H _2x -phenyl, -O-C _x H _2x -phenyl, or -(C _1-6 alkyl)NC _x H _2x -phenyl, while x is 0, 1, 2, 3, 4, 5, 6; or -OR ¹² ;

wherein

[00123] if W is N, then R ¹ is absent; And

[00124] if Y is N, then R ⁴ is absent;

[00125] R ² and R ³ are independently a group selected from hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio or substituted thio, alkyl or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or substituted with cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered heterocycloalkyl or substituted from 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, -C _x H _2x -phenyl, -O-C _x H _2x -phenyl, or -(C _1-6 alkyl)NC _x H _2x -phenyl, while x is 0.1, 2, 3.4, 5, 6; or -OR ¹² ;

[00126] R ⁵ and R ⁶ are independently hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[00127] R ⁷ and R ⁸ are independently hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[00128] or R ⁵ and R ⁶ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring, wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' , wherein said 3- to 8-membered heterocycloalkyl ring is optionally substituted with R ¹³ , R ^13' , R ¹⁴ and/or R ^14' ;

[00129] or R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring or a heterocycloalkyl ring containing one heteroatom or two or more heteroatoms optionally substituted with R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' , wherein said one heteroatom in said heteroalkyl ring is NR ²⁰ and said two or more heteroatoms is a group selected one of N, NR ²² ,O, S, SR ²² and SR ²² R ^22' ;

[00130] or R ⁷ and R ⁸ together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with R ¹⁷ , R ^17' , R ¹⁸ and/or R ^18' , wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ^{22 R22'} ;

[00131] R ⁹ is a bond, hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O- C _x H _2x is phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[00132] R ¹⁰ is a substituent shown in Table 2, or a tautomer thereof;

[00133] or R ⁹ is a bond and R ⁹ and R ¹⁰ together form an oxaborol ring;

[00134] R ¹¹ is hydrogen, hydroxy, halo, cyano, amino, alkyl, or substituted alkyl; alkenyl or substituted alkenyl; alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; heterocycloalkyl or substituted heterocycloalkyl, aryl, heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[00135] R ¹² is hydrogen; alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl;

[00136] R ¹³ , R ^13' , R ¹⁴ and R ^14' are independently hydrogen, hydroxy, halogen, amino, aminoalkyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, carbonyl, carboxamide, amide; or R ¹³ and R ^13' or R ¹⁴ and R ^14' together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _{3-8 cycloalkyl, C 2-6 alkenyl} or C _1-6 alkoxy, wherein said the heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' ;

[00137] R ¹⁵ , R ^15' , R ¹⁶ and R ¹⁶ ' independently are hydrogen, hydroxy, halogen, amino, cyano, C _1-6 alkyl or C _1-6 alkoxy; or R ¹⁵ and R ^15' or R ¹⁶ and R ^16' together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl or C _1-6 alkoxy, wherein said the heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' ;

[00138] R ¹⁷ , R ^17' , R ¹⁸ and R ^18' are independently hydrogen, hydroxy, halogen, amino, cyano, C _1-6 alkyl, or C _1-6 alkoxy; or R ¹⁷ and R ¹⁸ or R ^17' and R ^18' together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl or C _1-6 alkoxy, wherein said the heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' ;

[00139] R ¹⁹ , R ^19' and R ^19" are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C 2-6 alkenyl, C _1-6 alkoxy, phenyl, C _1-6 alkylimidazole, C _{1-6 alkyltriazole, C 1-6 alkyltetrazole} , C _1-6 alkylthiazole, C _1-6 alkyloxazole, C _1-6 alkyldioxazole, _{C 1-6 alkyloxazolidone} , and

[00140] R ²⁰ and R ²¹ are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, phenyl, C _1-6 alkylimidazole, C _{1-6 alkyltriazole, C 1-6 alkyltetrazole} , C _1-6 alkylthiazole, C _1-6 alkyloxa ash, C _1-6 alkyldioxazole; C _1-6 alkyloxazolidone, or R ²⁰ and R ²¹ together with the nitrogen to which they are attached form an unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl; or form a carboxyl-substituted pyrrolidinyl, carboxyl-substituted piperidinyl or carboxyl-substituted morpholinyl; And

[00141] R ²² and R ^22' are independently a group selected from hydrogen, oxygen, C _1-6 alkyl or substituted C _1-6 alkyl, C _1-6 alkoxy or substituted C _1-6 alkoxy, C _3-8 cycloalkyl or substituted C _3-8 cycloalkyl, C _2-6 alkenyl or substituted C _2-6 alkenyl, aryl, or substituted aryl, including substituted or unsubstituted C _1-6 alkylimidazole, substituted or unsubstituted C 1-6 alkyltriazole, C _1-6 alkyltetrazole, C _1-6 alkylthiazole, substituted or unsubstituted _{C 1-6 alkyloxazole} , C _1-6 alkyldioxazole; C _1-6 alkyloxazolidone; -COR ¹⁹ , -COOR ^19' , -CSOR ^19" , -CONR ²⁰ R ²¹ ,

or a pharmaceutically acceptable salt thereof.

[00142] One particular embodiment provides a compound according to Formula I, Formula IA, or Formula IB as described herein, wherein:

[00143] R ¹ is selected from the group of hydrogen, hydroxy, halogen, cyano, amino, pyrrolidinyl, unsubstituted C _1-6 alkyl or halo-substituted C _1-6 alkyl, unsubstituted C _1-6 alkoxy, or halogen-substituted C _1-6 alkyloxy; C _3-7 cycloalkyl or halogenated C _3-7 cycloalkyl; N-containing monocyclic heterocycloalkyl, pyrrolidinyl, -C _x H _2x -phenyl, -O- _{C x} H _2x -phenyl, or -(C _1-6 alkyl)N - C _x H _2x -phenyl, while x is 0, 1, 2, 3, 4, 5 or 6; or -OR ¹² ;

[00144] R ² and R ³ are independently OR ¹² ;

[00145] R ⁴ is selected from the group of hydrogen, hydroxy, halogen, piano, amino, pyrrolidinyl, unsubstituted C _1-6 alkyl or halo-substituted C _1-6 alkyl, unsubstituted C _1-6 alkoxy, or halogen-substituted C _1-6 alkyloxy; C _3-7 cycloalkyl or halogenated C _3-7 cycloalkyl; N-containing monocyclic heterocycloalkyl, pyrrolidinyl, -C _x H _2x -phenyl, -O-C _x H _2x -phenyl, or -(C _1-6 alkyl)N-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6; or -OR ¹² ;

[00146] R⁶ and R⁷ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring containing one heteroatom or two or more heteroatoms, optionally substituted with R¹⁵, R^15', R¹⁶ and/or R^16', wherein said one heteroatom in said heteroalkyl ring is NR²⁰ and said two or more heteroatoms are a group selected from N, NR²², O, S, SR^22"SR²²R^22'; R^eleven is hydrogen; R¹² - as given in the present description; and R¹⁵ and R¹⁶ or R^15' and R^16' together form a 3- to 8-membered cycloalkyl ring or a heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C_1-6 alkyl, C_3-8 cycloalkyl, C_2-6 alkenyl or C_1-6 alkoxy, wherein said heteroatom in said heteroalkyl ring is O, N, NR²², S, SR²² or SR²²R^22', or a pharmaceutically acceptable salt thereof.

[00147] Another embodiment provides a compound of Formula I, Formula IA, or Formula IB as described herein, R ⁹ is as described herein and R ¹⁰ is a substituent shown in Table 2, or R ⁹ is a bond and R ⁹ and R ¹⁰ together form an oxaborol ring; or a pharmaceutically acceptable salt thereof.

[00148] Another specific embodiment provides a compound of Formula I, Formula IA, or Formula IB as described herein, R ⁹ is as described herein and R ¹⁰ is a substituent shown in Table 2, or R ⁹ is a bond and R ⁹ and R ¹⁰ together form an oxaborol ring; and R ¹² is unsubstituted C _1-6 alkyl; or a pharmaceutically acceptable salt thereof.

[00149] Yet another specific embodiment provides a compound of Formula I, Formula IA, or Formula IB as described herein, wherein W and Y are as described herein, R ¹ , R ² , R ³ and R ⁴ are independently OR ¹² ; R ⁹ is as described herein and R ¹⁰ is the substituent shown in Table 2, or R ⁹ is a bond and R ⁹ and R ¹⁰ together form an oxaborol ring; and R ¹² - as described in the present description; or a pharmaceutically acceptable salt thereof.

[00150] Another embodiment of the present invention provides a compound of Formula I, Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, as described herein, wherein R ⁹ is a bond and R ⁹ and R ¹⁰ together form an oxaborol ring.

[00151] Another embodiment of the present invention provides a compound of Formula I, Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, as described herein, wherein

[00152] W and Y - as described in the present description;

[00153] R ¹ and R ⁴ - as described;

[00154] R ² and R ³ are independently a group selected from hydrogen, hydroxy, halogen, cyano, amino, thio, C _1-6 alkyl or substituted C _1-6 alkyl, C _1-6 alkoxy or substituted C _1-6 alkoxy; C _3-8 cycloalkyl or substituted C _3-8 cycloalkyl; C _2-8 alkenyl or substituted C _2-8 alkenyl; 3- to 8-membered heterocycloalkyl or substituted 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, or —OR ¹² ;

[00155] R ⁵ and R ⁶ are independently hydrogen, hydroxy, halogen, cyano, amino, C _1-6 alkyl or substituted C _1-6 alkyl, C _1-6 alkoxy or substituted C _1-6 alkoxy, C _3-8 cycloalkyl or substituted C _3-8 cycloalkyl, C _2-8 alkenyl or substituted C _2-8 al kenyl; aryl or substituted aryl, heteroaryl or substituted aryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[00156] R ⁷ and R ⁸ are independently hydrogen, hydroxy, halogen, cyano, amino, C _1-6 alkyl or substituted C _1-6 alkyl, C _1-6 alkoxy or substituted C _1-6 alkoxy, C _3-8 cycloalkyl or substituted C _3-8 cycloalkyl, C _2-8 alkenyl or substituted C _2-8 al kenyl; aryl or substituted aryl, heteroaryl or substituted aryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[00157] or R ⁵ and R ⁶ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring, wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ²² ', wherein said 3- to 8-membered heterocycloalkyl ring is optionally substituted with R ¹³ , R ^13' , R ¹⁴ and/or R ^14' ;

[00158] R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring or a heterocycloalkyl ring containing one heteroatom or two or more heteroatoms, optionally substituted with R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' , wherein said one heteroatom in said heteroalkyl ring is NR ²⁰ and said two or more heteroatoms are a group selected from N, NR ²² , O, S, SR ²² and SR ²² R ^22' ;

[00159] or R ⁷ and R ⁸ together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with R ¹⁷ , R ^17' , R ¹⁸ and/or R ^18' , wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ^{22 R22'} ;

[00160] R ⁹ is a bond, hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O- C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[00161] R ¹⁰ is a substituent shown in Table 2, or a tautomer thereof;

[00162] or R ⁹ is a bond and R ⁹ and R ¹⁰ together form an oxaborol ring;

[00163] R ¹¹ is hydrogen, hydroxy, halogen, cyano, amino, C _1-6 alkyl or replaced with _1-6 alkyl, C _1-6 alcohox or replaced with _1-6 alkoxy, with _3-8 cycloal oxyl or replaced with _3-8 cycliclol, with _2-8 alkenil or noticeable with _2-8 alkenil; aryl or substituted aryl, heteroaryl or substituted aryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[00164] R ¹² is hydrogen; C _1-6 alkyl or substituted C _1-6 alkyl, C _1-6 alkoxy or substituted C _1-6 alkoxy, C _3-8 cycloalkyl or substituted C _3-8 cycloalkyl, C _3-8 heterocycloalkyl or substituted C _3-8 heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl; And

[00165] R ²² and R ^22' are independently a group selected from hydrogen, oxygen, C _1-6 alkyl or substituted C _1-6 alkyl, C _1-6 alkoxy or substituted C _1-6 alkoxy, C _3-8 cycloalkyl or substituted C _3-8 cycloalkyl, C _2-6 alkenyl or substituted C _2-6 alkenyl, aryl, or substituted aryl, -COR ¹⁹ , -COOR ^19' , -CSOR ^19" , -CONR ²⁰ R ²¹ .

[00166] Another embodiment of the present invention provides a compound of Formula I, Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, as described herein, wherein W and Y are each N.

[00167] A specific embodiment of the present invention provides a compound of Formula I, Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, as described herein, wherein

[00168] W and Y - as described in the present description;

[00169] R ¹ , R ² , R ³ and R ⁴ are independently H or OR ¹² ; And

[00170] R ⁵ and R ⁶ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring, wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² , or SR ²² R ^22' , wherein said 3- to 8-membered heterocycloalkyl ring is optionally substituted with R ¹³ , R ^13' , R ¹⁴ and/or R ^14' .

[00171] Another embodiment of the present invention provides a compound of Formula I, Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, as described herein, wherein

[00172] W and Y - as described in the present description;

[00173] R ² and R ³ are independently H or OR ¹² ; And

[00174] R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring or a heterocycloalkyl ring containing one heteroatom or two or more heteroatoms optionally substituted with R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' , wherein said one heteroatom in said heteroalkyl ring is NR ²⁰ and said two or more heteroatoms are a group selected from N, NR ²² , O, S, SR ²² and SR ²² R ^22' .

[00175] Another embodiment of the present invention provides a compound of Formula I, Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, as described herein, wherein

[00176] R ¹ , R ² , R ³ and R ⁴ are independently H or OR ¹² ; And

[00177] R ⁷ and R ⁸ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with R ¹⁷ and R ¹⁸ , wherein said heteroatom in said heterocycloalkyl ring is selected from the group O, N, NR ²² , S, SR ²² or SR ²² R ^22' .

[00178] Another specific embodiment provides a compound of Formula I, Formula IA, or Formula IB as described herein, wherein R ² and R ³ are independently OR ¹² ; R ⁵ and R ⁶ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with R ¹³ and R ¹⁴ , said heteroatom in said heteroalkyl ring being O, N, NR ²² , S, SR ²² or SR ²² R ^22' ; R ¹⁰ is a substituent shown in Table 2, or R ⁹ is a bond and R ⁹ and R ¹⁰ together form an oxaborol ring; R ¹¹ is H; R ¹² is unsubstituted C _1-6 alkyl; and R ¹³ and R ¹⁴ or R ^13' and R ^14' together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C 3-8 cycloalkyl, C _2-6 alkenyl or C _1-6 alkoxy, wherein said the heteroatom in said heteroalkyl ring is O, N, NR ²² , S, ^{SR 22} _or SR ²² R ^22' ; or a pharmaceutically acceptable salt thereof.

[00179] Another specific embodiment provides a compound of Formula I, Formula IA, or Formula IB as described herein, wherein R ² and R ³ are independently OR ¹² ; R ⁷ and R ⁸ together form a 3- to 8-membered ring, optionally substituted with R ¹⁷ and R ¹⁸ ; R ¹⁰ is a substituent shown in Table 2, or R ⁹ is a bond and R ⁹ and R ¹⁰ together form an oxaborol ring; R ¹¹ is H; R ¹² is unsubstituted C _1-6 alkyl; and R ¹⁷ and R ¹⁸ or R ^17' and R ^18' together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl or C _1-6 alkoxy, wherein said the heteroatom in said heteroalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' ; or a pharmaceutically acceptable salt thereof.

[00180] Another specific embodiment provides a compound of Formula I, Formula IA, or Formula IB as described herein, wherein R ² and R ³ are independently OR ¹² ; and R ⁵ and R ⁶ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with R ¹³ , R ¹⁴ , R ^13' and/or R ¹⁴ ' , wherein said heteroatom in said heteroalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' , or its pharmaceutically acceptable salt.

[00181] Another specific embodiment of the present invention provides a compound of Formula I, Formula IA, or Formula IB as described herein, wherein R ² and R ³ are independently OR ¹² ; and R ⁷ and R ⁸ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with R ¹⁷ , R ¹⁸ , R ^17' and/or R ^18' , wherein said heteroatom in said heteroalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' , or its pharmaceutically acceptable salt.

[00182] Yet another specific embodiment of the present invention provides a compound of Formula I, Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof, as described herein, wherein

[00183] R ¹ , R ² , R ³ and R ⁴ as described herein; And

[00184] (A) R ⁵ and R ⁶ are independently hydroxy, halo, cyano, amino alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6; or R ⁵ and R ⁶ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with R ¹³ , R ^13' , R ¹⁴ and/or R ^14' , wherein said heteroatom in said heterocycloalkyl ring is selected from the group O, N, NR ²² , S, SR ²² or SR ²² R ^22' ; And

[00185] R ⁷ and R ⁸ are independently hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6; or

[00186] (B) R ⁵ and R ⁸ are independently hydrogen, hydroxy, halogen, cyano, amino alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6; And

[00187] R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring containing one heteroatom or two or more heteroatoms, optionally substituted with R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' , wherein said one heteroatom in said heteroalkyl ring is NR ²⁰ and said two or more heteroatoms are a group selected from N, NR ²² , O, S, SR ²² and SR ²² R ^22' ; or

[00188] (C) R ⁵ and R ⁶ are independently hydrogen, hydroxy, halogen,

cyano, amino alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6; And

[00189] R ⁷ and R ⁸ are independently hydroxy, halo, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6; or R ⁷ and R ⁸ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with R ¹⁷ , R ^18' , R ¹⁷ and/or R ^18' , said heteroatom in said heterocycloalkyl ring being selected from the group O, N, NR ²² , S, SR ²² or SR ²² R ^22' .

[00190] In another specific embodiment, the present invention provides a compound of Formula I, Formula IA, or Formula IB as described above, wherein said compound is selected from the group of compounds shown in Table 1, wherein R ¹⁰ is as given herein, or a substituent shown in Table 2, or a tautomer thereof.

[00191] In specific embodiments, the present invention provides a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein W is N; Y is C; R ¹ is absent; R ² and R ³ are independently a group selected from the group represented by hydrogen, hydroxy, halogen, C _1-6 alkyl or substituted C _1-6 alkyl, C _1-6 alkoxy or substituted C _1-6 alkoxy, C _3-8 cycloalkyl or substituted C _3-8 cycloalkyl, C _2-8 alkenyl or substituted C _2-8 alkenyl, or - OR ¹² , R ⁴ is H; R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring optionally substituted with R ¹⁵ , R ¹⁵ ', R ¹⁶ and/or R ¹⁶ '; R ¹¹ is H; and R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' are independently hydrogen, hydroxy, halogen, amino, cyano, C _1-6 alkyl, or C _1-6 alkoxy.

[00192] In a specific embodiment, the present invention provides a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein W is N; Y is C; R ¹ is absent; R ² is halogen; R ³ is OR ¹² ; and R ⁴ is H.

[00193] In another specific embodiment, the present invention provides a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein W is N; Y is C; R ¹ is missing; R ² is halo and R ³ is -OR ¹² ; R ⁴ is H; R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring optionally substituted with R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' ; R ¹¹ is H; and R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' are independently C _1-6 alkyl.

[00194] In another specific embodiment, the present invention provides a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein: R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring optionally substituted with R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' .

[00195] In another specific embodiment, the present invention provides a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, wherein: R ⁷ and R ⁸ together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with R ¹⁷ and R ¹⁸ , wherein said heteroatom in said heterocycloalkyl ring is selected from the group O, N, NR ^{2 2} , S, SR ²² or SR ²² R ^22' .

[00196] In one specific embodiment, the present invention provides a compound selected from the group consisting of the following compounds:

[00197] (4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;

[00198] (4bS,7aR)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;

[00199] (4bR,7aS)-2-cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;

[00200] 2-cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;

[00201] (7aR)-2-cyclopropyl-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;

[00202] (7aR)-2-chloro-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;

[00203] (7aR)-2-chloro-4b-methoxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;

[00204] (4bR,7aS)-2-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;

[00205] (4bR,7aS)-2-chloro-3-hydroxy-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;

[00206] 2-chloro-6-(1-hydroxy-2-methylpropan-2-yl)-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00207] (S)-6-(t-bugyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00208] (S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00209] (S)-6-(tert-butyl)-3-(3-methoxypropoxy)-2-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00210] (S)-6-(tert-butyl)-2-cyclopropyl-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00211] (S)-6-(t-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00212] (R)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00213] (S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-digadro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00214] (S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-hydroxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00215] (S)-6-(tert-butyl)-2-methoxy-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00216] (S)-6-(tert-butyl)-2-hydroxy-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00217] (S)-6-(t-butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00218] (S)-6-(tert-butyl)-2-isopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00219] (S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00220] (S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00221] (s)-6-(t-butyl)-2-cyclopropyl-11-hydroxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00222] (2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00223] (2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00224] 2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00225] 2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00226] 6-(t-bugyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid;

[00227] 2'-chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid;

[00228] 2',3'-dimethoxy-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid;

[00229] 6-isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylic acid;

[00230] 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid;

[00231] 3'-(cyclopropylmethoxy)-2,-(difluoromethyl)-11'-fluoro-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid;

[00232] 2'-(difluoromethyl)-11'-fluoro-10'-oxo-3'-((tetrahydrofuran-3-yl)methoxy)-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid;

[00233] (S)-3-(cyclopropylmethoxy)-2-(difluoromethyl)-11-fluoro-6-isopropyl-6-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; And

[00234] (6S)-2-(difluoromethyl)-11-fluoro-6-isopropyl-6-methyl-10-oxo-3-((tetrahydrofuran-3-yl)methoxy)-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid; or a pharmaceutically acceptable salt or tautomer thereof.

[00235] In one specific embodiment, the present invention provides a compound selected from the group of compounds:

or

or a pharmaceutically acceptable salt thereof.

[00236] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00237] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00238] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00239] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00240] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00241] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00242] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00243] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00244] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00245] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00246] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00247] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00248] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00249] In a specific embodiment, the present invention provides a compound having the following structure:

or a pharmaceutically acceptable salt thereof.

[00250] According to one embodiment, the present invention provides a compound having the structure of Formula I, IA, or IB, said compound being selected from the group of compounds:

[00251]

wherein W and Y are independently N or C, provided that W and Y are not both C, and that R ¹⁰ is as given herein or the substituent shown in Table 2 and

Y' represents heterocycle or substituted heterocycle, heteroaryl or substituted heteroaryl, wherein R and R' are independently alkyl or substituted alkyl.

[00252] In specific embodiments, the present invention provides compounds of Formula I, IA, or IB, said compound being selected from the group:

wherein W and Y are independently N or C, provided that W and Y are not both C, and that R ¹⁰ is as given herein or the substituent shown in Table 2.

[00253] In other specific embodiments, the present invention provides a compound of Formula I, IA, or IB, said compound being selected from the group:

wherein W and Y are independently N or C, provided that W and Y are not both C, and wherein R ¹⁰ is a substituent as described herein or a substituent shown in Table 2, and R is H, alkyl, or substituted alkyl.

[00254] In another embodiment of the present invention, the compound of Formula I, Formula IA or Formula IB is selected from the group:

wherein W and Y are independently N or C, provided that W and Y are not both C, and wherein R ¹⁰ is a substituent as described herein or a substituent shown in Table 2, and R is hydrogen, hydroxy, heterocycloalkyl or substituted heterocycloalkyl, heteroaryl or substituted heteroaryl, wherein R' and R'' are independently alkyl or substituted alkyl.

[00255] In another embodiment, the present invention provides a Formula I, Formula IA, or Formula IB compound as shown below:

[00256] при этом R ¹ , R ² , R ³ , R ⁴ , R ⁹ и R ¹¹ - как описано в настоящем документе, W и Y независимо являются N или С, при условии, что W и Y оба не являются С, и при этом R ¹⁰ - как приведено в настоящем описании или группа, выбранная из заместителей, показанных в Таблице 2, и R' и R независимо являются группой, выбранной из водорода, гидроксила, галогена, алкила или замещенного алкила, алкиломена или замещенного алкиломена, карбоцикла или замещенного карбоцикла, гетероциклоалкила или замещенного гетероциклоалкила, арила или замещенного арила, гетероарила или замещенного гетероарила, при этом указанные замещенные группы R и R' могут быть замещены гидроксилом, галогеном, алкилом, алкиломеном, циклоалкилом, гетероциклом, арилом, гетероарилом, or R and R' together form a spiro, fused or bridged carbocyclic or heterocyclic ring.

[00257] In another embodiment, the present invention provides a compound having the structure of Formula I, IA, or IB, said compound being selected from the group:

wherein W and Y are independently N or C, provided that W and Y are not both C, and wherein R ¹⁰ is as defined herein or selected from the group of substituents shown in Table 2, R and R' are independently H, hydroxyl, alkyl, or substituted alkyl, acyl, ester, carbamoyl, sulfonylurea, or urea, and wherein Z is H, OH, NH ₂ , SH, or substituted with C, O, N, or S.

[00258] In another specific embodiment, the present invention provides a compound of Formula I, IA or IB as follows:

while R ⁴ , R ⁵ , R ⁶ , R ⁹ , and R ¹¹ - as described herein, W and Y are independently N or C, provided that W and Y are not both C, and while R ¹⁰ - as given in the present description or selected from the group of substituents shown in Table 2, R ¹ - as defined herein, R ² and R ³ are independently a group selected from:

[00259] An embodiment of the present invention provides a compound of Formula I, Formula IA, or Formula IB as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[00260] (A) R ⁵ and R ⁶ are independently hydroxy, halo, cyano, amino alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0.1.2, 3.4, 5 or 6; or R ⁵ and R ⁶ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with R ¹³ , R ^13' , R ¹⁴ and/or R ^14' , said heteroatom in said heterocycloalkyl ring being selected from the group O, N, NR ²² , S, SR ²² or SR ²² R ^22' ; And

[00261] R ⁷ and R ⁸ are independently hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -OC _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6; or

[00262] (B) R ⁵ and R ⁸ are independently hydrogen, hydroxy, halogen, cyano, amino alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6; And

[00263] R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring containing one heteroatom or two or more heteroatoms, optionally substituted with R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' , wherein said one heteroatom in said heteroalkyl ring is NR ²⁰ and said two or more heteroatoms are selected from the group N, NR ²² , O, S, SR ²² and SR ²² R ^22' ; or

[00264] (C) R ⁵ and R ⁶ are independently hydrogen, hydroxy, halogen, cyano, amino alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6; And

[00265] R ⁷ and R ⁸ are independently hydroxy, halo, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6; or R ⁷ and R ⁸ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with R ¹⁷ , R ^18' , R ¹⁷ and/or R ^18' , wherein said heteroatom in said heterocycloalkyl ring is selected from the group O, N, NR ²² , S, SR ²² or SR ²² R ^22' .

[00266] In one embodiment, the present invention provides a compound of Formula I, Formula IA, or Formula IB as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group of compounds in Table 1, and wherein R ¹⁰ is as given herein or is a substituent shown in Table 2, or a tautomer thereof.

[00267] In one embodiment, the present invention provides a method of treating or preventing a viral infection in a subject susceptible to or suffering from said viral infection, comprising administering to said subject an HBe or HBs antigen inhibitor, said inhibitor being a compound of Formula I, Formula IA, or Formula IB as described herein.

[00268] In one embodiment, the present invention provides a method of treating or preventing a hepatitis B viral infection in a subject susceptible to or suffering from said hepatitis B viral infection, comprising administering to said subject an inhibitor of HBe or HBs antigens, said inhibitor being a compound of Formula I, Formula IA, or Formula IB as described herein.

[00269] In one embodiment, the present invention provides a method of treating or preventing hepatitis B virus infection in a subject susceptible to or suffering from said hepatitis B virus infection, comprising administering to said subject an inhibitor of HBe or HBs antigens, said inhibitor comprising a compound from Table 1, wherein R ¹⁰ is a substituent shown in Table 2, or a tautomer thereof, or wherein said inhibitor is a compound from Table IB.

[00270] In one embodiment, the present invention provides a method for inhibiting the level of HBe or HBs antigens in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I, Formula IA, or Formula IB described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[00271] In a specific embodiment, the present invention provides a method for inhibiting the level of HBe or HBs antigens in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of Formula I, Formula IA, or Formula IB described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein said mammal is a human.

[00272] In one embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula I, Formula IA, or Formula IB described herein.

[00273] In one embodiment, the present invention provides a Formula I, Formula IA, or Formula IB compound described herein, or a pharmaceutical composition thereof, for use in said therapy.

[00274] In one embodiment, the present invention provides a Formula I, Formula IA, or Formula IB compound described herein, or a pharmaceutical composition thereof, for use in the treatment of a viral infection.

[00275] In one embodiment, the present invention provides a Formula I, Formula IA, or Formula IB compound as described herein, or a pharmaceutical composition thereof, for use in the treatment of a viral infection, said viral infection being a hepatitis B virus infection.

[00276] In one embodiment, the present invention provides the use of a Formula I, Formula IA, or Formula IB compound as described herein, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in the treatment of human hepatitis B virus infection.

[00277] In one embodiment, the present invention provides a Formula I, Formula IA, or Formula IB compound described herein, or a pharmaceutical composition thereof, for use in medical therapy.

[00278] In one embodiment, the present invention provides a Formula I, Formula IA, or Formula IB compound described herein, or a pharmaceutical composition thereof, for use in the treatment of preventing hepatitis B virus infection in a human.

[00279] In one embodiment, the present invention provides a Formula I, Formula IA, or Formula IB compound described herein, or a pharmaceutical composition thereof, for use in inhibiting the level of HBe or HBs antigens in a mammalian HBsAg in vitro.

[00281] The compounds described herein may exist in particular geometric or stereoisomeric forms. The present invention includes all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the present invention. Additional asymmetric carbon atoms may be present on substituents such as an alkyl group. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

[00282] Optically active (R) - and (S)-isomers and D and L-isomers can be obtained using chiral synthons or chiral reagents, or can be separated using conventional techniques. If, for example, it is desired to obtain a particular enantiomer of a compound of the present invention, it can be obtained by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved off to obtain the pure desired enantiomers. Alternatively, if the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation of the diastereomers thus obtained, by fractional crystallization or by chromatographic methods known in the art, and subsequent isolation of the pure enantiomers. In addition, separation of enantiomers and diastereomers is often carried out using chromatography using chiral stationary phases, optionally in combination with chemical derivatization (eg, formation of carbamates from amines).

[00283] In another embodiment, the present invention provides a compound of Formula I, Formula IA, or Formula IB for use in said therapy.

[00284] In another embodiment, the present invention provides a compound of Formula I, Formula IA, or Formula IB, for use in the treatment of a viral infection.

[00285] In another embodiment, the present invention provides the use of a compound of Formula I, Formula IA, or Formula IB for the manufacture of a medicament for use in the treatment of a human viral infection.

[00286] In another embodiment, the present invention provides a pharmaceutical dosage form containing a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound described by Formula I, Formula IA, or Formula IB.

[00287] In one embodiment, said pharmaceutical dosage form containing a compound of Formula I, Formula IA, or Formula IB, or a salt thereof, is a dosage form adapted for parenteral administration. In another embodiment, said dosage form is a long acting dosage form. In yet another embodiment, said dosage form is a nanoparticulate dosage form.

[00288] In one embodiment, said pharmaceutical dosage form containing a compound of Formula I, Formula IA, or Formula IB, or a salt thereof, is a dosage form adapted for oral, rectal, topical, or intravenous administration, wherein said pharmaceutical dosage form optionally contains any one or more pharmaceutically acceptable carrier, adjuvant, or excipient.

[00289] In one embodiment of the present invention, said compound of Formula I, Formula IA, or Formula IB is in an oral dosage form, and may be administered as a conventional preparation, for example, any solid agent dosage form such as tablets, powders, granules, capsules, and the like; water agent; oil suspension; or a liquid remedy such as syrup and elixir. In one embodiment, said compound of Formula I, Formula IA, or Formula IB is in the form of a parenteral dosage form, and may be administered as an aqueous or oily suspension for injection or nasal drops. When preparing a parenteral dosage form with a compound of Formula I, Formula IA or Formula IB, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be used optionally. As an antiviral drug, an oral agent is particularly preferable. A formulation of a Formula I, Formula IA, or Formula IB compound may be prepared by combining (eg, mixing) a therapeutic amount of a Formula I, Formula IA, or Formula IB compound with a pharmaceutically acceptable carrier or diluent.

[00290] A pharmaceutical dosage form adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; foams, edible or whipped; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[00291] For example, for oral administration in the form of a tablet or capsule, said compound of Formula I, Formula IA, or Formula IB may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders are prepared by grinding said compound of Formula I, Formula IA or Formula IB to a suitable fine size and mixing with a similarly divided pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol. A flavoring agent, preservative, dispersing agent and coloring agent may also be present.

[00292] Capsules are made by preparing a powder mixture as described above and filling formed gelatin shells. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol may be added to the powder mixture prior to the filling operation. A disintegrant or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug upon swallowing the capsule.

[00293] In addition, if desired or necessary, suitable binders, lubricants, disintegrants and colorants can also be included in the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated into dosage forms, for example, by preparing a powder mixture, granulating or impact compacting, adding a lubricant and a disintegrant, and compressing into tablets. A powder mixture is prepared by mixing said compound, suitably milled, with a diluent or base as described above and optionally with a binder such as carboxymethylcellulose, aligate, gelatin or polyvinylpyrrolidone, a dissolution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorbent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia gum or solutions of cellulosic or polymeric materials and forcing through a sieve. As an alternative to granulation, the powder mixture can be passed through a tablet machine, resulting in poorly formed ingots being broken into granules. The granules can be lubricated to prevent sticking to tablet molds by adding stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. Said compound of the present invention can also be combined with a free-flowing inert carrier and directly compressed into tablets, bypassing the steps of granulation or impact compaction. A transparent or opaque protective coating may be provided, consisting of a sealing layer of shellac, a coating of sugar or polymeric material, and a polishing coating of wax. Dyes can be added to these coatings to distinguish between different standard dosages.

[00294] Oral liquids such as solutions, syrups, and elixirs may be formulated in unit dosage form such that a given amount of liquid contains a given amount of said compound. Syrups can be prepared by dissolving said compound in an appropriately tasting aqueous solution, and elixirs using a non-toxic alcoholic carrier. Suspensions can be prepared by dispersing said compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and sorbitol polyoxyethylene ethers, preservatives, flavoring agents such as peppermint oil or natural sweeteners, saccharin or other artificial sweeteners, and the like may also be added.

[00295] If necessary, the unit dosage form for oral administration may be microencapsulated. Said dosage form of the compounds of Formula I, Formula IA or Formula IB may also be formulated into a sustained or sustained release form of said compound, for example by coating or encapsulating the particulate material in polymers, wax or the like.

[00296] Said compound of Formula I, Formula IA or Formula IB or a salt, solvate or hydrate thereof may also be administered in the form of liposomal delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as cholesterol, stearylamine, or phosphatidylcholines.

[00297] Said compound of Formula I, Formula IA, or Formula IB, or salts, solvates or hydrates thereof, can also be delivered using monoclonal antibodies as individual carriers to which the molecules of said compound are linked. Said compound may also be associated with soluble polymers as target drug carriers. Such polymers may include polyvinylpyrrolidone, a pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or palmitoyl substituted with polysethylene oxide polylysine moieties. Furthermore, said compound may be associated with a class of biodegradable polymers useful for achieving controlled drug release, e.g., polylactic acid, polepsilone-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers, hydrogels.

[00298] A pharmaceutical dosage form adapted for transdermal administration may be presented as separate patches designed to remain in close contact with the recipient's epidermis for an extended period of time. For example, said compound of Formula I, Formula IA or Formula IB can be delivered from a patch using iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

[00299] A pharmaceutical dosage form adapted for topical use may be in the form of ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. In the manufacture of the dosage form in the form of an ointment, the active ingredient can be used with either a paraffin or water-soluble ointment base. Alternatively, the active ingredient may be added to an oil-in-water or water-in-oil cream.

[00300] A pharmaceutical dosage form adapted for rectal administration may be presented as suppositories or enemas.

[00301] A pharmaceutical dosage form adapted for nasal administration, when the carrier is a solid, including a coarse powder having a particle size, for example, in the range of 20 to 500 microns, can be administered in the same way as snuff, that is, by rapid inhalation through the nasal passage from a container of powder brought close to the nose. Suitable dosage form, when the carrier is a liquid, which can be administered as a nasal spray or nasal drops, includes aqueous or oily solutions of the active ingredient.

[00302] Pharmaceutical dosage forms adapted for administration by inhalation include fine particles of dust or spray, which can be generated using various types of pressurized metered aerosols, nebulizers or insufflators.

[00303] A pharmaceutical dosage form adapted for parenteral administration includes aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostatics, and solutes that render the dosage form isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Said dosage form may be presented in single-use or multi-dose containers, such as sealed ampoules and vials, and may be stored in a lyophilized state requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Injectable solutions and suspensions for immediate administration can be prepared from sterile powders, granules and tablets.

[00304] It should be understood that in addition to the ingredients specifically mentioned above, the dosage form described herein may include other agents conventional in the art, taking into account the type of dosage form in question, for example, dosage forms suitable for oral administration may include flavorings.

[00305] Therapeutic effective amounts of a compound of Formula I, Formula IA, or Formula IB will depend on a number of factors, including the age and weight of the human or other animal, the exact condition requiring treatment and its severity, the nature of the disease, the dosage form and route of administration, and will ultimately be at the discretion of the attending physician or veterinarian. An effective amount of a salt or hydrate may be defined as a proportion of the effective amount of said compound of Formula I, Formula IA or Formula IB, or salts, solvates or hydrates thereof, as such.

[00306] Embodiments of the present invention provide for administering compounds of Formula I, Formula IA, or Formula IB to a healthy or virus-infected patient either as a single agent or in combination with (a) another agent that is effective in treating or preventing hepatitis B virus or hepatitis D virus, (b) another agent that improves immune response and resistance, or (c) another agent that reduces inflammation and/or pain.

[00307] Said compound of Formula I, Formula IA, or Formula IB, or a salt, solvate, or hydrate thereof, is believed to have activity in preventing, terminating, or reducing the effects of the Hepatitis B virus by inhibiting HBe and/or HBs antigens, thereby preventing or preventing the presence of the virus in the host cell and rendering the virus incapable of replication.

[00308] Accordingly, a method of treating hepatitis B virus and/or hepatitis D virus is carried out by administering to a mammal a therapeutically effective amount of a compound of Formula I, Formula IA, or Formula IB, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, said mammal is a human.

[00309] In another aspect, the present invention provides a method for reducing the level of HBe and/or HBs antigens in a mammal by administering to said mammal a therapeutically effective amount of a compound of Formula I, Formula IA, or Formula IB, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, said mammal is a human.

[00310] In other embodiments, the implementation of the specified connection according to the present invention can be used in combination with one or more antiviral therapeutic agents or anti-inflammatory agents useful in the prevention or treatment of viral diseases or associated pathophysiology. Thus, said compound of the present invention and its salt, solvate or other suitable derivatives thereof may be used alone or in combination with other antiviral or anti-inflammatory therapeutic agents.

[00311] Said compound of the present invention and any other pharmaceutically active agent(s) may be administered together or separately, and when administered separately, said administration may occur simultaneously or sequentially, in any order. The amounts of said compound of the present invention and other pharmaceutically active agent(s) and the relative time of administration are chosen to achieve the desired combined therapeutic effect. Administration in combination of a compound of the present invention and a salt, solvate or other pharmaceutically acceptable derivative thereof with other therapeutic agents may be carried out in combination by simultaneous administration as: (1) a single pharmaceutical composition comprising both compounds; or (2) separate pharmaceutical compositions, each of which contains one specified connection.

[00312] Alternatively, said combination may be administered separately in a sequential manner, with one beneficial agent administered first and the other second, or vice versa. Such sequential administration may be close in time or remote in time. The amounts of said compound(s) of Formula I, Formula IA or Formula IB or a salt thereof and other pharmaceutically active agent(s) and relative timing of administration are chosen to achieve the desired combined therapeutic effect.

[00313] More specifically, embodiments of the present invention provide a method as described herein, comprising administering an additional agent selected from the group consisting of an antiviral agent, an antibiotic, an analgesic, a non-steroidal anti-inflammatory (NSAED) agent, an antifungal agent, an antiparasitic agent, an anti-nausea agent, an antidiarrheal agent, or an immunosuppressant. In some embodiments of the present invention, said antiviral agent is an anti-hepatitis B agent or an anti-hepatitis C agent. Even more specifically, the additional agent is administered as part of a single dosage of said pharmaceutical dosage form or as a separate dosage form.

[00314] The present invention is directed to a compound, composition and pharmaceutical composition that can be used as novel treatments and/or prophylactic therapies for viral infections. Without wishing to be bound by any particular theory, it is believed that the compounds of the present invention are capable of inhibiting the levels of HBe and HBs antigens in a human infected with hepatitis B virus or suffering from chronic hepatitis B virus infection. By lowering the levels of HBe and HBs antigens in a patient infected with hepatitis B virus, the compounds described herein are effective in treating hepatitis B virus infections and secondary diseases such as liver cirrhosis, liver failure and liver cancer, which are often associated with hepatitis B virus infections.

[00315] Thus, in another embodiment, the present invention provides a method for treating or preventing a hepatitis virus infection in a subject suffering from an HBV infection, comprising administering to said subject an inhibitor of HBe and/or HBs antigens, said inhibitor being a compound of Formula I, Formula IA, or Formula IB.

[00316] Another embodiment of the present invention is a method of treating hepatitis B viral infection and/or hepatitis D virus infection in a subject suffering from said viral infection, comprising administering to said subject a compound from Table 1.

[00317] In some embodiments, a method of treating a viral infection in a subject mediated at least in part by a virus of the hepatitis B family and or the hepatitis D family, comprising administering to said subject a composition comprising a compound of any Formula I, Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof.

[00318] In another aspect, another embodiment of the present invention provides a method of inhibiting the progression of a viral infection in a subject at risk of infection with hepatitis B virus and/or hepatitis D virus, comprising administering to said subject a therapeutically effective amount of said compound of Formula I, Formula IA or Formula IB, or a pharmaceutically acceptable salt thereof.

[00319] In yet another aspect, another embodiment of the present invention provides a method of preventing a viral infection in a subject at risk of contracting hepatitis B virus and/or hepatitis D virus, comprising administering to said subject a therapeutically effective amount of said compound of Formula I or Formula IA, or a pharmaceutically acceptable salt thereof.

[00320] In yet another aspect, another embodiment of the present invention provides a method of treating a viral infection in a subject suffering from said viral infection, comprising administering to said subject a therapeutically effective amount of said compound of Formula I, Formula IA, or Formula IB, or a pharmaceutically acceptable salt thereof.

[00321] Disclosed herein are compounds, methods, and pharmaceutical compositions for treating viral infections by administering compounds of Formula I, Formula IA, or Formula IB in therapeutically effective amounts. Also disclosed are methods for preparing compounds of Formula I, Formula IA or Formula IB and methods for using said compound and pharmaceutical compositions thereof. In particular, the treatment and prevention of viral infections such as those caused by hepatitis B and/or hepatitis D are described.

[00322] In other embodiments, said compound described herein is useful in treating infections in a subject, said infection being caused by a multidrug-resistant strain of hepatitis B virus and/or hepatitis D virus.

[00323] In additional embodiments of the present invention, said compound of the present invention, or a practically acceptable salt thereof, is selected from said compound shown in Table 1.

EXAMPLES

[00324] Synthesis schemes

[00325] Said compound of the present invention having Formula I, Formula IA, or Formula IB

[00326] or its corresponding pharmaceutically acceptable salts are obtained using traditional methods of organic synthesis, while:

[00327] C* is a stereocenter at a carbon atom that has the (R) or (S) configuration;

[00328] W and Y are independently C or N, provided that W and Y are not both C;

wherein

[00329] if W is C, then R ¹ is hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio or substituted thio, alkyl or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered heterocycloalkyl or substituted from 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, -C _x H _2x -phenyl, -O-C x H _2x -phenyl, or -(C _1-6 alkyl) N _- C _x H _2x -phenyl, while x is 0, 1, 2, 3, 4, 5, 6; or -OR ¹² ; And

[00330] if Y is C, then R ⁴ is hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio or substituted thio, alkyl or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered heterocycloalkyl or substituted from 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, -C _x H _2x -phenyl, -O-C x H _2x -phenyl, or -(C _1-6 alkyl) N _- C _x H _2x -phenyl, while x is 0, 1, 2, 3, 4, 5, 6; or -OR ¹² ;

wherein

[00331] if W is N, then R ¹ is absent; And

[00332] if Y is N, then R ⁴ is absent;

[00333] R ² and R ³ are independently a group selected from hydrogen, hydroxy, halogen, cyano, amino or substituted amino, thio or substituted thio, alkyl or substituted alkyl, alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; alkenyl or substituted alkenyl; 3- to 8-membered heterocycloalkyl or substituted from 3- to 8-membered heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, pyrrolidinyl, -C _x H _2x -phenyl, -O-C _x H _2x -phenyl, or -(C _1-6 alkyl) N -C _x H _2x -phenyl, while x is 0.1 , 2, 3, 4, 5, 6; or -OR ¹² ;

[00334] R ⁵ and R ⁶ are independently hydrogen, hydroxy, halogen, cyano, amino alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl or substituted aryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[00335] R ⁷ and R ⁸ are independently hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl; aryl or substituted aryl, heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[00336] or R ⁵ and R ⁶ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring, wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' , wherein said 3- to 8-membered heterocycloalkyl ring is optionally substituted with R ¹³ , R ^13' , R ¹⁴ and/or R ^14' ;

[00337] or R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring or a heterocycloalkyl ring containing one heteroatom or two or more heteroatoms, optionally substituted with R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' , wherein said one heteroatom in said heteroalkyl ring is NR ²⁰ and said two or more heteroatoms are selected from the group N, NR ²² , O, S, SR ²² and SR ²² R ^22' ;

[00338] or R ⁷ and R ⁸ together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with R ¹⁷ , R ^17' , R ¹⁸ and/or R ^18' , wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ^{22 R22'} ;

[00339] R ⁹ is a bond, hydrogen, hydroxy, halogen, cyano, amino, alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, alkenyl or substituted alkenyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[00340] R ¹⁰ is a substituent shown in Table 2 or a tautomer thereof;

[00341] or R ⁹ is a bond and R ⁹ and R ¹⁰ together form an oxaborol ring;

[00342] R ¹¹ is hydrogen, hydroxy, halo, cyano, amino, alkyl, or substituted alkyl; alkenyl or substituted alkenyl; alkoxy or substituted alkoxy; cycloalkyl or substituted cycloalkyl; heterocycloalkyl or substituted heterocycloalkyl, aryl, heteroaryl, -C _x H _2x -phenyl or -O-C _x H _2x -phenyl, wherein x is 0, 1, 2, 3, 4, 5 or 6;

[00343] R ¹² is hydrogen; alkyl or substituted alkyl, alkoxy or substituted alkoxy, cycloalkyl or substituted cycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl;

[00344] R ¹³ , R ^13' , R ¹⁴ and R ^14' are independently hydrogen, hydroxy, halogen, amino, aminoalkyl, cyano, C _1-6 alkyl, C _1-6 alkoxy, carbonyl, carboxamide, amide; or R ¹³ and R ^13' or R ¹⁴ and R ^14' together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _{3-8 cycloalkyl, C 2-6 alkenyl} or C _1-6 alkoxy, wherein said the heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' ;

[00345] R ¹⁵ , R ^15' , R ¹⁶ and R ^16' are independently hydrogen, hydroxy, halogen, amino, cyano, C _1-6 alkyl, or C _1-6 alkoxy; or R ¹⁵ and R ^15' or R ¹⁶ and R ^16' together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl or C _1-6 alkoxy, wherein said the heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' ;

[00346] R ¹⁷ , R ^17' , R ¹⁸ and R ^18' are independently hydrogen, hydroxy, halogen, amino, cyano, C _1-6 alkyl, or C _1-6 alkoxy; or R ¹⁷ and R ¹⁸ or R ^17' and R ^18' together form a 3 to 8 membered cycloalkyl ring or a 3 to 8 membered heterocycloalkyl ring optionally substituted with oxygen, halogen, hydroxy, amino, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl or C _1-6 alkoxy, wherein said the heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' ;

[00347] R ¹⁹ , R ^19' and R ^19'' are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, phenyl, C _1-6 alkylimidazole, C 1-6 alkyltriazole, C _1-6 alkyltetrazole, C _1-6 alkylthiazole, _{C 1-6 alkyloxazole} , C _1-6 alkyldioxazole; C _1-6 alkyloxazolidone; And

[00348] R ²⁰ and R ²¹ are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _1-6 alkoxy, phenyl, C _1-6 alkylimidazole, C _{1-6 alkyltriazole, C 1-6 alkyltetrazole} , C _1-6 alkylthiazole, C _1-6 alkyloxa ash, C _1-6 alkyldioxazole; C _1-6 alkyloxazolidone, or R ²⁰ and R ²¹ together with the nitrogen to which they are attached form an unsubstituted pyrrolidinyl, unsubstituted piperidinyl, or unsubstituted morpholinyl; or form a carboxyl-substituted pyrrolidinyl, a carboxyl-substituted piperidinyl or a carboxyl-substituted morpholinyl; And

[00349] R ²² and R ^22' are independently a group represented by hydrogen, oxygen, C _1-6 alkyl or substituted C _1-6 alkyl, C _1-6 alkoxy or substituted C _1-6 alkoxy, C _3-8 cycloalkyl or substituted C _3-8 cycloalkyl, C _2-6 alkenyl or substituted C _2-6 alkenyl, aryl or substituted aryl, including substituted or unsubstituted C _1-6 alkylimidazole, substituted or unsubstituted C 1-6 alkyltriazole, C _1-6 alkyltetrazole, C _1-6 alkylthiazole, substituted or unsubstituted C _1-6 alkyloxazole, _{C 1-6 alkyldioxazole} ; C _1-6 alkyloxazolidone; -COR ¹⁹ , -COOR ^19' , -CSOR ^19'' , -CONR ²⁰ R ²¹ ,

or a pharmaceutically acceptable salt thereof.

[00350] In other embodiments, compounds of Formula I, Formula IA, or Formula IB, or pharmaceutically acceptable salts thereof, are provided herein, wherein:

[00351] R ⁵ and R ⁶ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring, wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² , or SR ²² R ^22' , wherein said 3- to 8-membered heterocycloalkyl ring is optionally substituted with R ¹³ , R ^13' , R ¹⁴ and/or R ^14' .

[00352] Other specific embodiments of the present invention provide compounds of Formula I, Formula IA, or Formula IB, or pharmaceutically acceptable salts thereof, as described herein, wherein:

[00353] R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring or a heterocycloalkyl ring containing one heteroatom or two or more heteroatoms, optionally substituted with R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' , wherein said one heteroatom in said heteroalkyl ring is NR ²⁰ and said two or more heteroatoms are selected from the group N, NR ²² , O, S, SR ²² and SR ²² R ^22' .

[00354] Other specific embodiments of the present invention provide compounds of Formula I, Formula IA, or Formula IB, or pharmaceutically acceptable salts thereof, as described herein, wherein:

[00355] R ⁷ and R ⁸ together form a 3- to 8-membered cycloalkyl ring or a 3- to 8-membered heterocycloalkyl ring optionally substituted with R ¹⁷ , R ^17' , R ¹⁸ and/or R ^18' , wherein said heteroatom in said heterocycloalkyl ring is O, N, NR ²² , S, SR ²² or SR ²² R ^22' .

[00356] Suitable synthetic routes are depicted below in the following general reaction schemes. The skilled artisan will appreciate that if a substituent described herein is incompatible with the synthetic methods described, the substituent may be protected with an appropriate protecting group that is stable under the reaction conditions. The protecting group may be removed at an appropriate time in the reaction sequence to give the desired intermediate or target compound. Suitable protecting groups and methods for protecting and deprotecting various substituents using such suitable protecting groups are well known to those skilled in the art; examples of these can be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999). In some cases, the substituent may be specifically chosen to be reactive under the reaction conditions employed. Under these conditions, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate or is the desired substituent in the target compound.

[00357] Abbreviations

[00358] When describing the examples, the chemical elements are identified in accordance with the Periodic Table of the Elements. The abbreviations and symbols used in this document correspond to the usual use of such abbreviations and symbols by those skilled in the art of chemistry. The following abbreviations are used in this document:

AcOH - acetic acid

AC ₂ O - acetic anhydride

aq - water

B4 - (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(trifluoromethyl)piperidin-1-yl)propanoic acid

BOC (Boc) - N-tert-butoxycarbonyl or tert-butyloxycarbonyl

CBz - carboxybenzyl

dba - dibenzylideneacetone or dibenzalacetone

DCE - dichloroethane

DCM - dichloromethane

DCM/EA - dichloromethane/ethanol

DDQ - 2,3-dichloro-5,6-dicyanobenzoquinone

DIPEA (or DIEA) - N,N-diisopropylethylamine, or Hunig's Base

DME - dimethoxyethane

DMEM - Dulbecco's Needle Medium

DMF - dimethylformamide

DMP - Dess-Martin Periodinan

DMSO-d6 - deuterated dimethyl sulfoxide

DMSO - dimethyl sulfoxide

DPPA - diphenylphosphoryl azide

EU ₅₀ - 50% effective concentration

EDTA - ethylenediaminetetraacetic acid

Et - ethyl

Et ₂ O - diethyl ether

EtOH - ethanol

EtOAc, EA, AcOEt - ethyl acetate

GlutaMAX™ Cell Culture Supplement from Life Technologies

h - hour(s)

HEPES - 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

HPLC - high performance liquid chromatography

IC ₅₀ - 50% inhibitory concentration

iPrOH - isopropyl alcohol or isopropanol

LCMS - liquid chromatography - mass spectroscopy

LDA - lithium diisopropylamide

Me - methyl

MeOH - methanol

NBS - N-bromosuccinimide

NCS - N-chlorosuccinimide

NIS - N-iodosuccinimide

NXS - N-halosuccinimide

NaBH(OAc) ₃ - sodium triacetoxyborohydride

NMR - nuclear magnetic resonance spectroscopy

Pd ₂ (dba) ₃ - tris (dibenzylideneacetone) dipalladium (0)

PE - petroleum ether

PPh ₃ - triphenylphosphine

Pr - propyl

RB - round bottom

rt or r.t. - room temperature

RT - retention time

SFC - supercritical phase liquid chromatography

SO ₃ pyr - a complex of sulfur trioxide and pyridine of the formula C ₅ H ₅ NSO ₃

SPhos - 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl or dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)

t-BuOMe - methyl t-butyl ether

Т3Р - solution of 1-propanephosphonic anhydride, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatrifphosphorinan-2,4,6-trioxide

TFA, TFA - trifluoroacetic acid

THF, THF - tetrahydrofuran

UV - ultraviolet.

[00359] Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise noted, all temperatures are in °C (degrees Celsius). Unless otherwise indicated, all reactions were carried out under an inert atmosphere at ambient temperature.

[00360] All temperatures are in degrees Celsius, all solvents are of the highest purity available, and all reactions are run under anhydrous conditions under an argon (Ar) or nitrogen (N ₂ ) atmosphere, as appropriate.

[00361] The following examples illustrate the present invention. These examples are not intended to limit the scope of the present invention, but rather serve as a guide to the skilled artisan in the preparation and use of said compound, compositions and methods according to the present invention.

[00362] While specific embodiments of the present invention have been described, the skilled artisan will appreciate that various changes and modifications may be made without departing from the spirit and scope of the present invention.

[00363] [00363] As used herein, the symbols and conventions used in the processes, schemes, and examples are consistent with those used in current scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.

[00364] All references to ether refer to diethyl ether; saline refers to a saturated aqueous solution of NaCl. Unless otherwise noted, all temperatures are in °C (degrees Celsius). All reactions are carried out under an inert atmosphere at room temperature, unless otherwise indicated, and all solvents are of the highest purity available, unless otherwise indicated.

[00365] ¹ H NMR spectra (hereinafter also "NMR") were recorded on a Varian Unity-400 spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). The interaction constants are expressed in hertz (Hz). Splitting patterns describe apparent multiplicity and are denoted as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).

[00366] Liquid chromatography was performed on Merck Silica Gel 60 (230-400 mesh) or Teledyne Isco ^Combiflash® Companion with redi- ^Sep® normal phase disposable flash columns. Mass spectra were taken on an open access LC-MS system with electrospray ionization. Low resolution analytical mass spectra (MS) were recorded on a Waters SQD instrument. UPLC analysis was performed on a ^{Phenomenex® Kinetex®} 1.7 µm, 2.1×50 mm XB-C18 column at 40CSQ using a gradient elution method. Solvent A: 0.2% formic acid (FA) in water; solvent B: 0.15% FA in acetonitrile; gradient 1% - 99% solvent B in 1.1 minutes and a constant hold at 99% solvent B for another 0.4 minutes at a flow rate of 1 ml/min.

[00367] Obtaining compounds through synthesis

[00368] General protocols for obtaining the compounds described in the present description, shown below in Schemes 1-15.

[00369] Scheme 1

Designations: heat - heating, water - water, catalyst - catalyst, acid or base hydrolysis - acid or alkaline hydrolysis.

[00370] The specific compounds described herein may be prepared according to Scheme 1. For example, compound 4 may be prepared by reacting compound 1 with an appropriately substituted 4-pyranone as shown in acetic acid or ethanol with heating. Reductive cyclization of compound 2 by treating compound 2 with a Pd(II) catalyst with a suitable base such as potassium acetate in a suitable solvent such as N,N-dimethylacetamide (DMA) or N,N-dimethylformamide (DMF) at 90-120° C. results in the formation of a fused tricyclic carboxylate compound 3. Compound 3 is then subjected to hydrolysis of the ester bond under acidic or basic conditions to form a carbox ylic acid 4. Further chemical manipulations with said carboxylic acid may lead to the introduction of additional R ¹⁰ groups.

[00371] Alternatively, the compounds described herein can be prepared according to Scheme 2.

[00372] Scheme 2

where X represents Br or I, and W, Y, R ⁵ , R ⁶ , R ⁷ and R ⁸ - as specified in this document.

Designations: heat - heating, catalyst - catalyst, acid or base hydrolysis - acid or alkaline hydrolysis.

[00373] As shown in Scheme 2, Compound 2 can be prepared by reacting Compound 1 with an appropriately substituted 4-pyranone as shown in acetic acid or ethanol with heating. Reductive cyclization of compound 2 by treating compound 2 with a Pd(II) catalyst with a suitable base such as potassium acetate in a suitable solvent such as N,N-dimethylacetamide (DMA) or N,N-dimethylformamide (DMF) at 90-120° C. results in the formation of a fused tricyclic carboxylate compound 3. Compound 3 is then subjected to hydrolysis of the ester bond under acidic or basic conditions to form said carbox ylic acid 4. As in Scheme 1, further chemical manipulation of said carboxylic acid may lead to the introduction of additional R ¹⁰ groups.

[00374] Scheme 3 Obtaining the compound of Example 1 (Compound 220)

Designations: reflux - heating under reflux, water - water, room temperature - room temperature, cis / trans - cis / trans, overnight - during the night, dioxane - dioxane, chiral resolution - chiral separation.

[00375] Example 1 Preparation A (Compound 220)

[00376] (4bR,7aS)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,71naphthyridine-10-carboxylic acid

[00377] Step 1: 5-(6-Chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclo-pentanone

[00378] A mixer, 5-Brom-2-chlor-3-methoxypyridin (16.5 g, 74.2 mmol), Tris (dibenzilidenaceton) of dipalladium (1.02 g, 1.11 mmol), xanthos (1.16 g, 2.00 gmol), and tributotoxide sodium (12.6 g, sodium were placed in the flask. 131 mmol). The specified flask was purged with a stream of nitrogen for 30 minutes. Tetrahydrofuran (THF) (300 ml) was degassed with nitrogen for 30 minutes. 2,2-dimethylcyclopentan-1-one (11.2 ml, 89 mmol) was added to the indicated degassed tetrahydrofuran (THF) (300 ml) and this solution was added to the indicated nitrogen purged flask containing the starting compound. This mixture was heated under reflux under nitrogen atmosphere for 3 hours. This mixture was allowed to cool to room temperature and filtered through a silicon plug under nitrogen. This plug was washed with tetrahydrofuran and the resulting filtrate was concentrated. The resulting precipitate was dissolved in a minimum amount of dichloromethane and injected into a silica column. This column was eluted 1 minute with hexanes followed by a fast gradient (3 minutes) to 20% ethyl acetate/hexanes followed by isocratic 20% ethyl acetate/hexanes until the product eluted. Fractions were concentrated to give 5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-one (10.7 g, 42.1 mmol, 56.8% yield) as an oil. LCMS (ESI) m/z 254.2 (M+1).

[00379] Step 2: 5-(6-Chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentanamine (cis/trans mixture)

[00380] A stirred mixture of 5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-one (cis/trans) (10.7 g, 42.2 mmol) and ammonium acetate (32.5 g, 422 mmol) in methanol (200 ml) was degassed with a stream of nitrogen for 25 minutes. Sodium cyanoborohydride (5.30 g, 84 mmol) was added and the mixture was heated at 65° C. over the weekend. The reflux condenser was removed and the oil bath was heated at 80° C., to a concentration of the specified reaction mixture up to ~70% of the initial volume for 4 hours. The reflux condenser was attached back and the specified mixture was heated strongly under reflux overnight (oil bath at 80°C). This mixture was concentrated and the resulting residue was suspended in ~300 ml of dichloromethane. This mixture was vigorously shaken for ~30 minutes. The solid was filtered off and the filter cake was washed with dichloromethane. The resulting filtrate was concentrated to give 22 g of crude 5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine (cis/trans). This crude material was purified by silica chromatography eluting with a gradient of 0% to 10% 2M ammonia/methanol in dichloromethane. Fractions were concentrated to give 5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine (cis/trans) (9.04 g, 35.5 mmol, 84% yield). LCMS (ESI) m/z 255.2 (M+1).

[00381] Stage 3: 5-(2-Amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol (cis/trans mixture)

[00382] Boron tribromide (6.71 mL, 71.0 mmol) was slowly added dropwise to a vigorously stirred solution of 5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine (cis/trans) (9.04 g, 35.5 mmol) in 1,2-dichloroethane (DCE) (175 mL ). This mixture was shaken at room temperature for 30 minutes and then heated at 70° C. overnight. This mixture was cooled in an ice bath and then carefully quenched by slow addition of methanol. Additional methanol (100 ml) was added. This mixture was warmed to room temperature, stirred for 30 minutes, and concentrated to give ~17 g of crude 5-(2-amino-3,3-dimethylcyclopentyl)-2-chloropyridin-3-ol (cis/trans). Water (200 ml) was added to this crude material and mixed with a stirrer. Potassium carbonate (24.5 g, 177 mmol) was added in portions slowly and carefully to control foaming. This mixture was shaken for 10 minutes after complete addition of potassium carbonate. Said aqueous mixture was checked with a pH paper to ensure that said mixture was alkaline. This aqueous mixture was extracted once with 100 ml of dichloromethane. LC-MS revealed impurities only in the organic phase, and only 5-(2-amino-3,3-dimethylcyclopentyl)-2-chlorohydroxridin-3-ol (cis/trans mixture) in the aqueous phase. This organic phase was discarded and this aqueous phase was transferred from the separating funnel to a round bottom flask before adding iodine (18.0 g, 71.0 mmol). This mixture was shaken overnight at room temperature. Excess sodium sulfate (~4 equiv.) was added in portions. 2-Methyltetrahydrofuran (100 ml) was added and the mixture was stirred. An excess of acetic acid was carefully added to neutralize said aqueous phase while controlling foaming. Solid sodium chloride was added to said aqueous phase. This mixture was extracted 3 times with 2-methyltetrahydrofuran. The combined organic phases were washed 2 times with brine. The specified organic phase was dried over sodium sulfate, concentrated and received 12.6 g of the crude material. This material was purified by chromatography on silica eluting with a gradient of 0% to 20% 2M ammonia/methanol in dichloromethane. Fractions were concentrated to give 5-(2-amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol (cis/trans) (6.6 g, 18 mmol, 50.7% yield). LCMS (ESI) m/z 367.1 (M+1).

[00383] Step 4: Ethyl 1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (cis/trans mixture)

[00384] 5-(2-Amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol (cis/trans mixture) (6.6 g, 18 mmol) and ethyl 4-oxo-4H-pyran-3-carboxylate (3.94 g, 23.4 mmol) in acetic acid (150 ml) were stirred at 100°C for 3 hours. This mixture was allowed to cool to room temperature and concentrated to dryness in vacuo. Toluene was added and evaporated on the rotor several times to get rid of residual acetic acid. Final evaporation gave crude ethyl 1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate. LCMS (ESI) m/z 517.1 (M+1). The crude ethyl 1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate was dissolved in N,N-dimethylformamide (DMF) (75 ml) before adding potassium carbonate (12.4 g, 90 mmol) and 1-bromo-3-methoxypropane (4.05 ml, 36.0 mmol). This mixture was allowed to stir at room temperature for 15 minutes and then heated at 60° C. for 1 hour. The resulting reaction mixture was cooled in an ice bath and quenched with water. The solid phase was precipitated. This mixture was extracted 3 times with ethyl acetate. The solids floated at the interface and this mixture was extracted 1 time with dichloromethane. The solid fraction was dissolved and the product was found in the specified organic phase. The combined organic phases were washed 2 times with 5% lithium chloride, washed 1 time with brine, dried over sodium sulfate, and concentrated. The resulting precipitate was suspended in ethyl ether and the precipitate was collected by filtration. The specified sediment was dried in the air and received ethyl-1- (5- (6-chlor-2-yod-5- (3-methoxy) pyridin-3-il) -2.2-dimethylcyclopentil) -4-oxso-1,4-dihydropyridine-3-carboxylate (5.21 g, 8.85 mmol, 49.1% exit) in the form of pale brown brigies) Country solid. LCMS (ESI) m/z 589.2 (M+1). The resulting filtrate was concentrated and the resulting residue was purified by chromatography on silica eluting with a gradient of 0% to 10% methanol in dichloromethane. Fractions were concentrated to give ethyl 1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (cis/trans) (2.59 g, 3.08 mmol, 17.1% yield, 70% purity). LCMS (ESI) m/z 589.2 (M+1).

[00385] Step 5: Ethyl 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate (cis/trans mixture)

[00386] Round bottom flask containing stirrer, ethyl 1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (cis/trans mixture) (5.57 g, 9.46 mmol), potassium acetate (4.6 4 g, 47.3 mmol) and palladium(II) bromide (0.504 g, 1.89 mmol) were purged with nitrogen for 20 minutes using a retractable and retractable needle membrane. N,N-Dimethylformamide (DMF) (75 ml) was purged with nitrogen for 20 minutes before being added to the reaction flask. The specified flask with the reaction mixture was placed in an oil bath, preheated to 100°C, and the specified mixture was stirred over night. This mixture was allowed to cool to room temperature and filtered through a Celite pad. Said Celite pad was washed with dichloromethane and the resulting filtrate was concentrated. The resulting residue was purified by chromatography on silica eluting with a gradient of 0% to 10% methanol in dichloromethane. The fractions were concentrated to give ethyl 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate (cis/trans mixture) (3.15 g, 6.83 mmol, 72.2% yield) as a pale brown solid. LCMS (ESI) m/z 461.3 (M+1).

[00387] Step 6: (4bR,7aS)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00388] To a solution of ethyl 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate (cis/trans mixture) (3.15 g, 6.83 mmol) in 1, 4-dioxane (40 ml) was added a solution of lithium hydroxide monohydrate (1.434 g, 34.2 mmol) in water (30 ml). This mixture was heated at 70°C for 3 hours. LC-MS showed complete conversion to the desired racemic cis product. This mixture was allowed to cool to room temperature and diluted with 0.5 M hydrochloric acid (100 ml). This precipitate was collected by filtration and the filter cake was thoroughly washed with water. The filter cake was dried in air for several hours using vacuum on a Buchner funnel until the solid fraction contained no moisture by visual inspection. The filter cake was dissolved in 150 ml of dichloromethane. For complete dissolution, stirring was required for several minutes. This solution was dried over sodium sulfate and concentrated to give 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (racemate cis) (2.6 g, 6.01 mm ol, 88% yield).

[00389] The indicated racemate was purified in several steps using the following conditions: Column = Chiralpak IC, 10 mm × 250 mm (5u); Mobile phase = 3:1 MeOH/EtOH+0.1% TFA; Flow rate = 10 ml/min; Injection volume = 500 µl (concentration 30 mg/ml, DCM used as injection solvent); Detection wavelength = 254 nm. Fractions corresponding to peak 1 were concentrated. The resulting precipitates were suspended in ethyl ether, sonicated, stirred for 10 minutes, and then this stirred mixture was cooled in an ice bath. The solid was collected by vacuum filtration, air dried, and dried under high vacuum to give (4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (1.24 g, 2.87 mmol, 42% yield) as a white solid. LCMS (ESI) m/z 433.2 (M+1). ¹ Н ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 8,62 (s, 1 H), 7,63 (s, 1 H), 7,43 (s, 1 H), 4,72 (d, J=8,98 Hz, 1 H), 4,19-4,39 (m, 2 H), 3,94 (td, J=8,68, 3,32 Hz, 1 H), 3,51 (t, J=6,05 Hz, 2 H), 3,26 (s, 3 H), 2,35-2,46 (m, 1 H), 2,19-2,31 (m, 1 H), 2,03 (quin, J=6,25 Hz, 2 H), 1,55-1,67 (m, 1 H), 1,40-1,50 (m, 1 H), 1,15 (s, 3 H), 0,40 (s, 3 H).

Scheme 4 - Alternative Synthesis of Compound 220 Example 1

Designations: step - stage, water - water, cis/trans - cis/trans, chiral resolution - chiral separation.

[00390] Example 1 Preparation B (Compound 220)

[00391] (4bR,7aS)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00392] Step 1: 5-(6-Chloro-5-methoxypyridin-3-yl)-2,2-dimethyldiclopentan-1-one

[00393] To a solution of 5-bromo-2-chloro-3-methoxypyridine (100 g, 449 mmol) in THF (2 L) were added NaOtBu (76.02 g, 791 mmol), xanthos (7.01 g, 12.1 mmol) and 2,2-dimethylcyclopentan-1-one (65.56 g, 584.6 mmol). The resulting reaction mixture was degassed with nitrogen for 30 minutes. Pd ₂ (aba) ₃ was added to this reaction mixture and the resulting reaction mixture was agitated at 70° C. for 3 hours. After completion of the reaction, the resulting reaction mixture was filtered through a pad of silica gel (60-120) and washed with THF. This solvent was removed under reduced pressure and this crude product was purified using column chromatography (230-400 silica gel) using 0-30% ethyl acetate in petroleum ether as eluent. Fractions were collected and concentrated to give the title compound (61 g, 54% yield), LCMS (ESI) m/z 253.9 (M+1).

[00394] Stage 2: 5-(6-Chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine (cis/trans mixture)

[00395] To a solution of 5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-one (60 g, 236.5 mmol) in methanol (1.2 L) was added NH ₄ OAc (182 g, 2365 mmol). The resulting reaction mixture was degassed with nitrogen for 30 minutes. NaBH ₃ CN (29.7 g, 473 mmol) was added to the resulting reaction mixture, and the resulting reaction mixture was agitated at 65° C. for 3 days. After completion of the reaction, this solvent was removed under reduced pressure to give the crude title compound (55 g). LCMS (ESI) m/z: 255.7(M+1). This compound was used in the next step without further purification.

[00396] Step 3: Preparation of 5-(2-amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol (cis/trans mixture)

[00397] To a solution of 5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine (60 g, 236 mmol) in 1,2-dichloroethane (DCE) (1300 ml) was added BBr ₃ (22.27 ml, 236 mmol) and the resulting reaction mixture was agitated at 70°C for 16 h After completion of the reaction, methanol (1.5 L) was added slowly dropwise to the reaction mixture at 0° C., and stirred at room temperature for 30 minutes. The resulting reaction mixture was concentrated and the resulting precipitate was taken up in water (1 L) and adjusted to a basic pH using potassium carbonate (325 g, 2355 mmol). The specified aqueous phase was washed with DCM (200 ml). Iodine (120 g, 471 mmol) was added to this aqueous phase and stirred at room temperature for 16 hours. After completion of the reaction, sodium sulfate (200 g) was added to neutralize excess iodine. Added acetic acid (250 ml) and was extracted with 2-methyl-THF (2×1 l). The specified organic phase was separated and dried over sodium sulfate. The indicated solvent was removed under reduced pressure and the indicated crude product was triturated with 20% dichloromethane in hexane (2 x 600 ml). The resulting solid was filtered off and dried to give the title compound (35 g, 21.89% yield). LCMS (54%) (ESI) m/z: 367 (M+1).

[00398] Step 4: Ethyl 1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethyl-vdclopentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (cis/trans mixture)

[00399] A suspension of 5-(2-amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol (87 g, 237 mmol), ethyl 4-oxo-4H-pyran-3-carboxylate (45.9 g, 273 mmol) and acetic acid (1.8 L) was agitated at 100°C for 3 hours. After completion of the reaction the resulting reaction mixture was concentrated and co-evaporated with toluene (4 x 200 ml). The resulting residue was purified using a column chromatography (230-400 silica gel) using 10~15% MeOH in DCM as eluent. Fractions were collected and concentrated to give the title compound (51 g, 22% yield) as a dark brown solid. LCMS (53%) (ESI) m/z: 517 (M+1).

[00400] Step 5: Ethyl 1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclopentyl)-oxo-1,4-dihydropyridine-3-carboxylate (cis/trans mixture)

[00401] To a solution of ethyl 1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (51 g, 99 mmol) in N,N-dimethylformamide (580 ml) was added K ₂ CO ₃ (68.2 g, 493 mmol) and 1-bromo-3-methoxypropane (30.2 g, 197 mmol). The resulting reaction mixture was agitated at 60° C. for 1 hour. After completion of the reaction, the resulting reaction mixture was quenched with ice water (1500 ml) and extracted with DCM (2 L). The combined organic phases were washed with brine (500 ml), dried over Na ₂ SO ₄ and concentrated. The crude material was purified using column chromatography (230-400 silica gel) using 0~10% methanol in DCM as eluent. Fractions were collected and concentrated to give the title compound (52 g, 84% yield). LCMS (ESI) m/z: 588.8 (M+1).

Step 6: Ethyl 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-][1,7]naphthyridine-10-carboxylate (cis/trans mixture)

[00402] Potassium acetate (43.3 g, 44 2 mmol). The resulting reaction mixture was degassed with nitrogen for 20 minutes. Palladium (II) bromide (4.70 g, 17.66 mmol) was added to the resulting reaction mixture and the resulting reaction mixture was agitated at 100° C. for 16 hours. After completion of the reaction, the resulting reaction mixture was filtered through celite and washed with DCM. The specified organic phase was washed with water (250 ml), dried over Na ₂ SO ₄ and concentrated. The crude material was purified using column chromatography (230-400 silica gel) using 2~5% MeOH in DCM as eluent. Fractions were collected and concentrated to give the title compound (20 g, 42% yield). LCMS (ESI) m/z: 461.1 (M+1).

[00403] Step 7: (4bR,7aS)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00404] To a solution of ethyl 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate (17.5 g, 38 mmol) in 1,4-dioxane (150 mL) ) and water (150 ml) were added lithium hydroxide (7.9 g, 190.14 mmol). The resulting reaction mixture was heated to 70° C. for 2 hours. After completion of the reaction, the resulting reaction mixture was concentrated and the resulting precipitate was taken up in DCM (250 ml). To this mixture was added 1.5 N HCl until pH=6 was established. The specified organic phase was separated and dried over Na ₂ SO ₄ and concentrated to obtain 15 g (yield: 91%) of the racemic mixture. This racemic mixture was purified by preparative HPLC to give the title compound (5.5 g, 73% yield) as a pale yellow solid. Chiral HPLC method: Chiralpak IC (21*250), 5 mics, Mobile phase A: 0.1% TFA in methanol, B: 0.1% TFA in ethanol; A: B:75:25, Flow rate: 2 5 ml/min. First peak retention time: 5.4. ¹ Н ЯМР 400 MHz, DMSO-d ₆ : δ 8,62 (s, 1Н), 7,63 (s, 1H), 7,43 (s, 1H), 4,73 (d, J=8,96 Hz, 1H), 4,33-4,28 (m, 2H), 3,95-3,94 (m, 1H), 3,53-3,50 (m, 2H), 3,27 (s, 3H), 2,39-2,38 (m, 1H), 2,28-2,27 (m, 1H), 2,04-2,01 (m, 2H), 1,61-1,60 (m, 1H), 1,47-1,44 (m, 1H), 1,15 (s, 3H), 0,40 (s, 3H). LCMS (ESI) m/z: 432.9 (M+1).

[00405] Example 2 (Compound 221)

[00406] (4bS,7aR)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00407] Step 1: (4bS,7aR)-2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00408] 2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexagadrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (racemate cis) (500 mg) was purified by chiral chromatography. Column = Chiralpak IC, 10 mm × 250 mm (5u), Mobile phase = 3:1 MeOH/EtOH + 0.1% TFA, Flow rate = 10 ml/min, Injection volume = 500 μl (30 mg/ml concentration); DCM was used as injection solvent, detection wavelength = 254 nm. Peak 2 was concentrated to give (4bS,7aR)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (190 mg, 0.438 mmol, 38% yield) as a white solid. LCMS (EST) m/z 433.3 (M+1). ¹ Н ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 8,59 (s, 1 H), 7,60 (s, 1 H), 7,40 (s, 1 H), 4,69 (d, J=8,98 Hz, 1 H), 4,18-4,36 (m, 2 H), 3,84-3,96 (m, 1 H), 3,48 (t, J=6,25 Hz, 2 H), 3,23 (s, 3 H), 2,30-2,43 (m, 1 H), 2,18-2,28 (m, 1 H), 2,00 (quin, J=6,15 Hz, 2 H), 1,53-1,64 (m, 1 H), 1,37-1,48 (m, 1 H), 1,12 (s, 3 H), 0,37 (s, 3 H).

[00409] Example 3: (Compound 222)

[00410] (4bR,7aS)-2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1.2-h][1,7]naphthyridine-10-carboxylic acid

[00411] Step 1: (4bR,7aS)-2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexagadrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00412] Reaction vial containing stirrer, (4bR,7aS)-2-xnop-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (81 mg, 0.19 mmol), potassium carbonate (103 mg, 0.748 mmol), cyclopropylboronic acid (32.1 mg, 0.374 mmol) and tetrakis(triphenylphosphine)palladium(0) (43.2 mg, 0.037 mmol) were thoroughly purged with nitrogen flow (retractable/retractable needle). Added 1,4-dioxane (2 ml) and the specified reaction vial was placed in a heating block, preheated to 100°C. This mixture was heated at 100° C. overnight. The resulting reaction mixture was allowed to cool to room temperature and then diluted with 2-methyltetrahydrofuran and water. Acetic acid was added slowly and carefully (due to foaming) until the Specified aqueous phase was neutralized. This mixture was extracted 2 times with 2-methyltetrahydrofuran. The combined organic phases were washed with brine and concentrated. The resulting precipitate was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). The fractions were combined and concentrated until a white precipitate formed. A small amount of acetonitrile was added and this solution became clear. This solution was lyophilized to give (4bR,7aS)-2-cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (67 mg, 0.151 mmol, 81% yield ) as a white powder. LCMS (ESI) m/z 439.1 (M+1). ¹ Н ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 8,54 (s, 1 Н), 7,46 (s, 1 Н), 7,31 (s, 1 Н), 4,64 (d, J=8,98 Hz, 1 H), 4,08-4,33 (m, 2 H), 3,79-3,91 (m, 1 H), 3,50 (t, J=6,25 Hz, 2 H), 3,24 (s, 3 H), 2,39-2,45 (m, 1 Н), 2,16-2,38 (m, 2 Н), 2,01 (quin, J=6,15 Hz, 2 H), 1,51-1,63 (m, 1 H), 1,32-1,45 (m, 1 H), 1,12 (s, 3 H), 0,92-1,05 (m, 4 H), 0,34 (s, 3 H).

[00413] Example 4: (Compound 223)

[00414] 2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (racemate cis)

[00415] Step 1: 2-Cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexadrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (racemate cis)

[00416] Reaction vial containing stirrer, ethyl 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-b][1,7]naphthyridine-10-carboxylate (racemate cis) (200 mg, 0 .434 mmol), potassium carbonate (240 mg, 1.74 mmol), cyclopropylboronic acid (74.5 mg, 0.868 mmol), and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087 mmol) were thoroughly purged with nitrogen flow (retractable/retractable needle). Added 1,4-dioxane (4 ml) and the specified reaction vial was placed in a heating block, preheated to 100°C. This mixture was heated at 100° C. for 3 hours. Additionally, cyclopropylboronic acid (74.5 mg, 0.868 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087 mmol) were added and the mixture continued to be heated at 100°C for 2 hours. This mixture was allowed to cool and filtered through a Celite plug. Said Celite plug was washed with ethyl acetate. The resulting filtrate was concentrated to give crude ethyl 2-cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate. The crude intermediate was dissolved in methanol (2 ml) before a solution of lithium hydroxide monohydrate (182 mg, 4.34 mmol) in water (2 ml) was added. This mixture was heated at 60°C for 3 hours and cooled to room temperature. This mixture was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). Fractions were lyophilized to give 2-cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]-pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (racemate cis) (50 mg, 0.114 mmol, 26.3 % yield) as a pale brown powder. LCMS (ESI) m/z 439.3 (M+1). ¹ Н ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 8,54 (s, 1 H), 7,46 (s, 1 H), 7,31 (s, 1 H), 4,64 (d, J=8,98 Hz, 1 H), 4,11-4,28 (m, 2 H), 3,79-3,91 (m, 1 H), 3,50 (t, J=6,25 Hz, 2 H), 3,24 (s, 3 H), 2,39-2,45 (m, 1 H), 2,16-2,38 (m, 2 H), 1,96-2,04 (m, 2 H), 1,51-1,64 (m, 1 H), 1,34-1,44 (m, 1 H), 1,12 (s, 3 H), 0,93-1,06 (m, 4 H), 0,34 (s, 3 H).

[00417] Scheme 5 - Preparation of compounds such as Example 5

[00418] Example 5: (Compound 224)

[00419] (7aR)-2-Cyclopropyl-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00420] Step 1: (7aR)-2-Cyclopropyl-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00421] Potassium tert-butoxide (13.3 mg, 0.119 mmol) was added to a solution of (4bR,7aS)-2-cyclopropyl-3-(3-methoxyteopoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10 -carboxylic acid (13 mg, 0.030 mmol) in dimethyl sulfoxide (DMSO) (0.5 ml) at room temperature and stirred overnight. This mixture was loaded onto a reverse phase medium pressure column and eluted (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). Fractions were lyophilized to give (7aR)-2-cyclopropyl-4b-hadroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (single isomer) (6 mg, 0.013 mmol, 43.6% yield) as an off-white powder. LC-MS and NMR confirmed the desired product. LCMS (ESI) m/z 455.3 (M+1). ¹ H ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 8,68 (s, 1 H), 7,50 (s, 2 H), 6,11 (s, 1 H), 4,62 (s, 1 H), 4,12-4,35 (m, 2 H), 3,51 (t, J=6,05 Hz, 2 H), 3,24 (s, 3 H), 2,57-2,68 (m, 1 H), 2,11-2,24 (m, 1 H), 2,02 (quin, J=6,15 Hz, 2 H), 1,56-1,70 (m, 1 H), 1,13-1,26 (m, 4 H), 0,97-1,10 (m, 4 H), 0,24 (s, 3 H).

[00422] Example 6: (Compound 225)

[00423] (7aR)-2-Chloro-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00424] Step 1: (7aR)-2-Chloro-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00425] Potassium tert-butoxide (15.5 mg, 0.139 mmol) was added to a solution of (4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-car boxylic acid (15 mg, 0.035 mmol) in dimethyl sulfoxide (DMSO) (1 ml) at room temperature and stirred for 2 hours. This mixture was loaded onto a reverse phase medium pressure column and eluted (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). The fractions were lyophilized to give (7aR)-2-chloro-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahadrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (7 mg, 0.015 mmol, 44.6 % yield) as a white powder. LCMS (ESI) m/z 449.1 (M+1). ¹ Н ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 8,74 (s, 1 H), 7,78 (s, 1 H), 7,44 (s, 1 H), 6,28 (s, 1 H), 4,70 (s, 1 H), 4,18-4,43 (m, 2 H), 3,49 (t, J=6,25 Hz, 2 H), 3,24 (s, 3 H), 2,59-2,73 (m, 1 H), 2,21 (dt, J=13,47, 8,88 Hz, 1 H), 2,01 (quin, J=6,15 Hz, 2 H), 1,58-1,71 (m, 1 H), 1,21-1,29 (m, 1 H), 1,18 (s, 3 H), 0,27 (s, 3 H).

[00426] Example 7: (Compound 226)

[00427] (7aR)-2-Chloro-4b-methoxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00428] Step 1: (7aR)-2-Chloro-4b-methoxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexagadrocyclopenta[f]pyrido[1,2-b][1,71naphthyridine-10-carboxylic acid

[00429] Sodium hydride (60% in mineral oil) (1.87 mg, 0.047 mmol) was added to a stirred solution of (7aR)-2-chloro-4b-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]-pyrido[1,2-h][1 ,7]naphthyridine-10-carboxylic acid (7 mg, 0.016 mmol) and methyl iodide (2.9 μl, 0.047 mmol) in N,N-dimethylformamide (DMF) (0.5 ml). This mixture was shaken for 2 hours. This mixture was heated to 80°C for 2 hours. This mixture was allowed to cool to room temperature and quenched with water. This mixture was stirred for 20 minutes. This mixture was injected into a medium pressure reverse phase chromatography column (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). Fractions were lyophilized to give (4bS,7aR)-2-chloro-4b-methoxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahadrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid as an off-white powder. LCMS (ESI) m/z 463.2 (M+1). ¹ Н ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 8,79 (s, 1 H), 7,78 (s, 1 H), 7,46 (s, 1 H), 4,92 (s, 1 H), 4,26-4,42 (m, 2 H), 3,49 (t, J=6,25 Hz, 2 H), 3,24 (s, 3 H), 2,94 (s, 3 H), 2,66 (dt, J=13,56, 6,68 Hz, 1 H), 2,19-2,33 (m, 1 H), 2,01 (quin, J=6,15 Hz, 2 H), 1,63-1,74 (m, 1 H), 1,28-1,40 (m, 1 H), 1,19 (s, 3 H), 0,29 (s, 3 H).

[00430] Example 8 (Compound 227) and Example 9 (Compound 228)

[00431] (4bR,7aS)-2-Hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00432] (4bR,7aS)-2-Chloro-3-hydroxy-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid

[00433]

[00434] A mixture of (4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (61 mg, 0.141 mmol) in sodium hydroxide (2M ) (4 ml, 8 mmol) was heated at 150°C in a microwave reactor for 1 hour. This mixture was injected onto a reverse phase medium pressure column chromatography and eluted (C18/acetonitrile/water/0.1% formic acid/0% to 100% gradient). The 2 sets of fractions were lyophilized separately to give:

[00435] Example 8: (4bR,7aS)-2-Hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (20 mg, 0.048 mmol, 34 % yield). LCMS (ESI) m/z 415.2 (M+1). ¹ H ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 11,15-11,71 (m, 1 H), 8,53 (s, 1 H), 7,44 (s, 1 H), 6,97-7,27 (m, 1 H), 4,61 (d, J=8,98 Hz, 1 H), 4,00-4,19 (m, 2 H), 3,73 (br. s., 1 H), 3,45 (t, J=6,05 Hz, 2 H), 3,23 (s, 3 H), 2,11-2,33 (m, 2 H), 1,96 (quin, J=6,25 Hz, 2 H), 1,50-1,61 (m, 1 H), 1,31-1,45 (m, 1 H), 1,11 (s, 3 H), 0,42 (s, 3 H).

[00436] Example 9: (4bR,7aS)-2-Chloro-3-hydroxy-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (8 mg, 0.022 mmol, 15.6% yield). LCMS (ESI) m/z 361.1 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.85 (br. s, 1 H), 8.57 (s, 1 H), 7.37 (s, 1 H), 7.24 (s, 1 H), 4.66 (d, J=8.98 Hz, 1 H), 3.80-3.94 (m, 1 H), 2.25- 2.43(m, 2H), 1.94-2.08(m, 1H), 1.52-1.64(m, 1H), 1.38-1.49(m, 1H), 1.11(s, 3H), 0.37(s, 3H).

[00437] Example 10: (Compound 229)

[00438] 2-Chloro-6-(1-hydroxy-2-methylpropan-2-yl)-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00439] Step 1: 4-(Benzyloxy)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one

[00440] A stirrer, 5-bromo-2-chloro-3-methoxypyridine (5.8 g, 26 mmol), tris(dibenzylideneacetone) dipalladium(0) (0.358 g, 0.391 mmol), and sodium tert-butoxide (4.41 g, 45.9 mmol) were placed in the flask. This flask was purged with a stream of nitrogen before adding 4-(benzyloxy)-3,3-dimethylbutan-2-one (5.45 g, 26.4 mmol) in tetrahydrofuran (THF) (100 ml). This mixture was heated under reflux for 3 hours. This mixture was allowed to cool to room temperature and diluted with water. This mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated. The resulting residue was purified by silica chromatography eluting with a gradient of 0% to 50% ethyl acetate in hexanes. The resulting fractions were concentrated to give 4-(benzyloxy)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one (5.62 g, 16.2 mmol, 62% yield) as a pale yellow oil. LCMS (ESI) m/z 348.2 (M+1). ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.70 (d, J=1.95 Hz, 1 H), 7.21-7.39 (m, 5 H), 7.01 (d, J=1.56 Hz, 1 H), 4.49 (s, 2 H), 3.79 (s, 5 H), 3.52 (s, 2 H), 1, 22 (s, 6 H).

[00441] Step 2: 4-(Benzyloxy)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amine

[00442] A mixture of 4-(benzyloxy)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one (3 g, 8.6 mmol) and ammonium acetate (9.97 g, 129 mmol) in methanol (50 mL) was stirred at room temperature overnight. Sodium cyanoborohydride (1.08 g, 17.3 mmol) was added and the mixture was heated at 60° C. overnight. This mixture was allowed to cool to room temperature, concentrated to -15 ml, quenched with 1M sodium hydroxide, and extracted 3 times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, concentrated to give crude 4-(benzyloxy)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amine (2.84 g, 5.62 mmol, 65% yield). LCMS (ESI) m/z 349.3 (M+1).

[00443] Step 3: 5-(2-Amino-4-hydroxy-3,3-dimethylbutyl)-2-chloropyridin-3-ol

[00444] Boron tribromide (2.66 ml, 28.1 mmol) was added dropwise to a solution of 4-(benzyloxy)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amine (2.84 g, 5.62 mmol) in 1,2-dichloromethane (DCE) (100 ml) at 0°C. This mixture was allowed to warm to room temperature and stirred for 4 hours. An oily solid precipitated at the bottom of the flask. This solid was scraped off the walls of the flask and this mixture was vigorously stirred at room temperature overnight. An oily solid precipitated at the bottom of the flask. This liquid phase was decanted and poured onto ice. The precipitate in the original reaction flask was suspended in fresh 1,2-dichloroethane (DCE) (100 ml) and stirred while 1 ml (~2 eq) fresh boron tribromide was added dropwise at room temperature. The specified mixture was heated at 70°C for 4 hours, and then left to cool to room temperature. This mixture was cooled in an ice bath, quenched by slow careful addition of 100 ml of methanol warmed to room temperature and stirred for 1 hour. This mixture was concentrated and the resulting residue was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/0% to 20% gradient). Fractions were lyophilized to give 5-(2-amino-4-hadroxy-3,3-dimethylbutyl)-2-chloropyridin-3-ol (910 mg, 3.72 mmol, 66.2% yield) as a white powder. LCMS (ESI) m/z 245.2 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.80 (d, J=1.95 Hz, 1 H), 7.59 (br. s., 3 H), 7.25 (d, J=1.95 Hz, 1 H), 3.31-3.38 (m, 2 H), 3.19-3.29 (m, 1 H), 2.9 2-3.02(m, 1H), 2.53-2.63(m, 1H), 0.95(s, 3H), 0.90(s, 3H).

[00445] Step 4: 5-(2-Amino-4-hydroxy-33-dimethylbutyl)-2-chloro-6-iodopyridin-3-ol

[00446] Iodine (233 mg, 0.919 mmol) was added to a stirred mixture of 5-(2-amino-4-hydroxy-3,3-dimethylbutyl)-2-chloropyridin-3-ol (225 mg, 0.919 mmol) and potassium carbonate (381 mg, 2.76 mmol) in water (10 ml). This mixture was agitated at room temperature for 2 hours. Solid sodium sulfate was added in portions to this mixture until the color disappeared. This aqueous mixture was injected onto a C18 medium pressure reverse phase column and then eluted with a gradient of 0% to 50% acetonitrile/water/0.1% formic acid. The combined fractions were lyophilized to give 5-(2-amino-4-hydroxy-3,3-dimethylbutyl)-2-chloro-6-iodopyridin-3-ol (164 mg, 0.443 mmol, 48.1% yield) as a white solid. LCMS (ESI) m/z 371.0 (M+1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.23 (s, 1 H), 7.20 (s, 1 H), 3.13-3.41 (m, 2 H), 2.70-2.88 (m, 2 H), 2.29-2.39 (m, 1 H), 0.92 (s, 3 H), 0.84 (s, 3H).

[00447] Step 5: Ethyl 1-(4-acetoxy-1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate

[00448] 5-(2-Амино-4-гадрокси-3,3-диметилбутил)-2-хлор-6-йодпиридин-3-ол (164 мг, 0,443 ммоль) и этил-4-оксо-4Н-пиран-3-карбоксилат (83 мг, 0,494 ммоль) в уксусной кислоте (4 мл) перемешивали при 100°С в течение 4 часов. This mixture was allowed to cool to room temperature and concentrated. The resulting precipitate was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/0% to 100% gradient). The 2 sets of fractions were concentrated separately to give ethyl 1-(1-(6-chloro-5-yl)oxy-2-iodopyridin-3-yl)-4-hydroxy-3,3-dimethylbutan-2-yl)-4-oxo-1,4-digadropyridine-3-carboxylate (83 mg, 0.16 mmol, 36% yield) and ethyl 1-(4-acetoxy-1-(6-chloro -5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (27 mg, 0.048 mmol, 11% yield). LCMS (EST) m/z 563.2 (M+1).

[00449] Step 6: Ethyl 1-(4-acetoxy-1-(6-chloro-2-iodo-5-(3-methoxypropoxy)-pyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate

[00450] Ethyl 1-(4-acetoxy-1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (27 mg, 0.048 mmol), potassium carbonate (26.5 mg, 0.192 mmol), and 1-bromo-3-methoxypro pan (19 mg, 0.124 mmol) was stirred at room temperature overnight. This mixture was quenched with water and extracted 2 times with ethyl acetate. The combined organic phases were washed with brine, washed with 5% lithium chloride (wave), and concentrated. The resulting precipitate was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). The fractions were lyophilized to give ethyl 1-(4-acetoxy-1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-digropyridine-3-carboxylate (15 mg, 0.024 mmol, 49.2% yield) as a white powder. LCMS (ESI) m/z 635.9 (M+1).

[00451] Step 7: 2-Chloro-6-(1-hydroxy-2-methylpropan-2-yl)-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[004S2] Round bottom flask containing stirrer, ethyl 1-(4-acetoxy-1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (14 mg, 0.022 mmol), potassium acetate (4.33 mg , 0.044 mmol), and palladium(II) bromide (1.2 mg, 4.4 µmol) was purged with nitrogen for 15 minutes. N,N-Dimethylacetamide (DMA) (1 ml) was purged with nitrogen for 5 minutes before being added to the reaction flask. The specified flask with the reaction mixture was placed in an oil bath, pre-heated to 90°C and the specified mixture was stirred for 3 hours. This mixture was allowed to cool to room temperature, filtered through celite, and the resulting filtrate was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). Fractions were combined and made basic with 1M sodium hydroxide. This mixture was heated at 60° C. overnight, cooled to room temperature, and concentrated. The resulting precipitate was dissolved in water and acidified to pH=3-4 with 1M hydrochloric acid. This mixture was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/0% to 100% gradient). Fractions were lyophilized to give 2-chloro-6-(1-hydroxy-2-methylpropan-2-yl)-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (3 mg, 6.9 µmol, 31% yield). LCMS (ESI) m/z 437.2 (M+1).

[00453]

[00454] General scheme 6 to obtain compounds of Examples 11-25

[00455] Example 11 (Compound 230)

[00456] (S)-6-(tert-Butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00457] Step 1: (R)-N-((S)-1-(6-Chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-methylpropan-2-sulfinamide

[00458] A solution of 1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one (2.54 g, 10.50 mmol), (R)-2-methylpropan-2-sulfinamide (2.55 g, 21.00 mmol) and Ti(OEt) ₄ (5.99 g, 26.3 mmol) in toluene (8.5 ml) ) was shaken for 10 minutes at 60°C, and then the indicated vessel was evaporated. The resulting reaction mixture was agitated at 60° C. under vacuum for 24 hours. The vessel was filled with nitrogen and toluene (5 ml) and THF (35 ml) were added. A solution of LiBH ₄ (15.8 ml, 2M in THF, 31.5 mmol) was added slowly. The resulting reaction mixture was shaken at room temperature overnight. The resulting reaction mixture was diluted with THF (130 ml) and brine (3 ml), stirred for 30 min, and then filtered through celite. The resulting filtrate was evaporated and purified by silica gel chromatography (0-100% EtOAc/hexanes) to give (R)-N-((S)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-methylpropan-2-sulfinamide (2.58 g, 71%) as the main diastereomer. LCMS (m/z, ES+)=346.9, 348.1 (M+1).

[00459] Step 2: (S)-5-(2-Amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol

[00460] A solution of (R)-N-((S)-1-(6-chloro-5-methoxy-1-iridin-3-yl)-3,3-dimethylbutan-2-yl)-2-methylpropan-2-sulfinamide (2.56 g, 7.38 mmol) in 1,2-dichloroethane (36.9 ml) was agitated at 0°C. Boron tribromide (4.88 mL, 51.7 mmol) was added slowly. The resulting reaction mixture was removed from the cooling bath and stirred overnight at room temperature. This solution was cooled to 0° C. and quenched by slow addition of MeOH. The resulting suspension was evaporated. EtOAc was added and the resulting solid was collected by filtration, washed with EtOAc and dried to give (S)-5-(2-amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol as HBr bis salt. (2.89 g, calc.) LCMS (m/z, ES+)=229.1.231.1 (M+1).

[00461] Step 3: (S)-tert-Butyl (1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate

[00462] Triethylamine (0.95 ml, 6.85 mmol) was added to a stirred suspension of (S)-5-(2-amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol 2HBr (1.36 g, 3.42 mmol) and Boc anhydride (0.87 ml, 3.73 mmol) in THF (34.2 ml) and the resulting reaction the mixture was shaken at 60° C. for 1 h and then evaporated to dryness. The resulting solid residue was suspended in diethyl ether, separated by filtration, and then partitioned between EtOAc and water. This aqueous phase was extracted with CH ₂ Cl ₂ (4x) and the combined organic phases were dried (Na ₂ SO ₄ ), filtered and evaporated to give (S)-tert-butyl (1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate (estimated calc.). LCMS (m/z, ES+)=329.6, 331.2 (M+1).

[00463] Step 4: (S)-tert-Butyl (1-(6-chloro-5-hadroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate

[00464] Iodine (0.87 g, 3.42 mmol) was added to a stirred solution of tert-butyl-(S)-(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate (1.13 g, 3.42 mmol) and K ₂ CO ₃ (1.42 g, 10.26 mmol) in water (8 .6 ml) and 1,4-dioxane (8.6 ml). The resulting reaction mixture was shaken overnight at room temperature. Additional iodine (0.20 g, 0.79 mmol) and K ₂ CO ₃ (0.40 g, 7.23 mmol) were added and the resulting reaction mixture was heated at 40°C for 5 hours. Solid Na ₂ SO ₃ was added with stirring until the indicated solution was no longer dark brown. This solution was diluted with brine and EtOAc. This aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na ₂ SO ₄ ), filtered and evaporated to give (S)-tert-butyl-(1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate as a yellow foam (1.56 g, calc.). LCMS (m/z, ES+)=455.1.457.1 (M+1).

[00465] Step 5: (S)-tert-Butyl (1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate

[00466]

[00467] Раствор трет-бутил-(S)-(1-(6-хлор-5-гидрокси-2-йодпиридин-3-ил)-3,3-диметилбутан-2-ил)карбамата (0,83 г, 1,84 ммоль), К ₂ СО ₃ (0,76 г, 5,51 ммоль) и 1-бром-3-метоксипропана (0,56 г, 3,67 ммоль) в ДМФА (12,2 мл) нагревали при 80°С в течение 3 ч. Полученную реакционную смесь упаривали досуха и полученный осадок переносили в CH ₂ Cl ₂ и Н ₂ О. Указанную водную фазу экстрагировали CH ₂ Cl ₂ (2х) и объединенные органические фазы осушали (Na ₂ SO ₄ ), отфильтровывали, и упаривали с получением трет-бутил-(S)-(1-(6-хлор-2-йод-5-(3-метоксипропокси)пиридин-3-ил)-3,3-диметилбутан-2-ил)карбамата (0,97 г, рассчетн.) в виде серовато-белого твердого вещества. LCMS (m/z, ES+)=527.2, 529.2 (M+1).

[00468] Step 6: (S)-Ethyl-1-(1-(6-chloro-2-iodo-5-(3-methoxytheopoxy)pyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate

[00469] 4M Hydrochloric acid in dioxane (6.89 ml, 27.5 mmol) was added to a solution of tert-butyl-(S)-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate (967 mg, 1.84 mmol) in CH ₂ Cl ₂ (7 ml). The resulting reaction mixture was shaken at room temperature for 3 h and evaporated to dryness. The resulting solid residue was dissolved in CH ₂ Cl ₂ (1 ml) and Et ₃ N (1 ml) and then evaporated to dryness. The resulting precipitate was taken up in saturated NaHCO ₃ and CH ₂ Cl ₂ . This aqueous phase was extracted with CH ₂ Cl ₂ (2x) and the combined organic phases were dried (Na ₂ SO ₄ ), filtered and evaporated to give (S)-1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-2-amine. A solution of the above amine and ethyl 4-oxo-4H-pyran-3-carboxylate (340 mg, 2.02 mmol) in acetic acid (18.4 ml) was agitated at 100° C. for 7 h. 1% formic acid)) to give ethyl ( _S )-1-(1-(6-chloro-2-iodo-5-(3- _{methoxypropoxy} )pyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-ditidropyridine-3-carboxylate (593 mg, 56%) as a light brown solid. LCMS (m/z, ES+)=577.7, 579.2 (M+1).

[00470] Step 7: (S)-Ethyl-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate

[00471] Flask containing ethyl-(S)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (0.59 g, 1.03 mmol), potassium acetate (0.20 g, 2.06 mmol) ) and palladium(II) bromide (0.055 g, 0.21 mmol) were purged with nitrogen. Degassed N,N-dimethylacetamide (DMA) (10.3 mL) was added and the resulting reaction mixture was heated at 90° C. for 24 h. The solvent was removed by evaporation and the resulting residue was purified by reverse phase chromatography (5-100% CH ₃ CN/H ₂ O (0.1% formic acid)) to give ethyl-(S)-6-(t-butyl )-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (326 mg, 71%) as an off-white solid. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,18 (s, 1 Н), 7,49 (s, 1 Н), 7,02 (s, 1 Н), 4,40 (q, J=7,0 Hz, 2 H), 4,13-4,26 (m, 2 H), 3,93 (d, J=6,6 Hz, 1 H), 3,62 (m, 2 H), 3,42-3,51 (m, 1 H), 3,38 (s, 3 H), 3,17-3,25 (m, 1 H), 2,15 (quin, J=6,0 Hz, 2 H), 1,41 (t, J=7,2 Hz, 3 H), 0,86 (s, 9 H); LCMS (m/z, ES+)=449.3.451.3 (M+1).

[00472] Step 8: (S)-6-(tert-Butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00473] A solution of ethyl (S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (42 mg, 0.094 mmol) in 1 M LiOH (1.7 ml) and MeOH (1.7 ml) shaken at 50°C for 1.5 hours Added 1M citric acid (2 ml) and the resulting reaction mixture was shaken for several minutes. This white matter was collected by filtration, washed with water and dried to give (S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (35.5 mg, 90%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 16.31 (s, 1 H), 8.81 (s, 1 H), 7.75 (s, 1 H), 7.30 (s, 1 H), 4.68 (d, J=6.3 Hz, 1 H), 4.19-4.32 (m, 2 H), 3.40-3.60 (m, 4 H), 3.26 (s, 3 H), 2.04 (quin, J=6.2 Hz, 2 H), 0.75 (s, 9 H); LCMS (m/z, ES+)=421.3, 423.2 (M+1).

[00474] Example 12 (Compound 231)

[00475] (S)-6-(tert-Butyl)-3-(cyclopropylmethoxy)-2-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00476] Step 1: (S)-tert-Butyl-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethidebutan-2-yl)carbamate

[00477] Раствор трет-бутил-(S)-(1-(6-хлор-5-гидрокси-2-йодпиридин-3-ил)-3,3-диметилбутан-2-ил)карбамата (0,73 г, 1,60 ммоль), K ₂ СО ₃ (0,66 г, 4,78 ммоль) и (бромметил)циклопропана (0,43 г, 3,19 ммоль) в ДМФА (10,6 мл) нагревали при 80°С в течение 3 ч. Полученную реакционную смесь упаривали досуха и полученный осадок переносили в CH ₂ Cl ₂ и Н ₂ О. Указанную водную фазу экстрагировали CH ₂ Cl ₂ (2х) и объединенные органические фазы осушали (Na ₂ SO ₄ ), отфильтровывали и упаривали с получением трет-бутил-(S)-(1-(6-хлор-5-(циклопропилметокси)-2-йодпиридин-3-ил)-3,3-диметилбутан-2-ил)карбамата (0,81 г, рассчетн.) в виде серовато-белого твердого вещества. LCMS (m/z, ES+)=508.8, 511.1 (M+1).

[00478] Step 2: (S)-Ethyl-1-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate

[00479] 4 М Соляную кислоту в диоксане (5,98 мл, 23,9 ммоль) добавляли к раствору трет-бутил (S)-(1-(6-хлор-5-(циклопропилметокси)-2-йодпиридин-3-ил)-3,3-диметилбутан-2-ил)карбамата (812 мг, 1,60 ммоль) в CH ₂ Cl ₂ (6 мл). The resulting reaction mixture was shaken at room temperature for 3 h and evaporated to dryness. The resulting solid residue was dissolved in CH ₂ Cl ₂ (1 ml) and Et ₃ N (1 ml) and then evaporated to dryness. The resulting precipitate was taken up in saturated NaHCO ₃ and CH ₂ Cl ₂ . This aqueous phase was extracted with CH ₂ Cl ₂ (2x) and the combined organic phases were dried (Na ₂ SO ₄ ), filtered and evaporated to give (S)-1-(6-chloro-2-iodo-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbutan-2-amine. LCMS (m/z, ES+)=409.1.411.1 (M+1).

[00480] A solution of the above amine and ethyl 4-oxo-4H-pyran-3-carboxylate (295 mg, 1.76 mmol) in acetic acid (16.0 ml) was agitated at 100° C. for 7 h. _{H 2} O (0.1% formic acid)) to give ethyl (S)-1-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (453 mg, 51%) as a light brown solid. LCMS (m/z, ES+)=559.4, 561.1 (M+1).

[00481] Stage 3: (S)-Ethyl-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate

[00482] A flask containing ethyl-(S)-1-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (0.45 g, 0.81 mmol), potassium acetate (0.16 g, 1.62 mmol), and palladium (II) bromide (0.043 g, 0.16 mmol), purged with nitrogen. Degassed N,N-dimethylacetamide (DMA) (8.1 ml) was added and the resulting reaction mixture was heated at 90°C for 24 h. The indicated solvent was removed by evaporation and the resulting precipitate was taken up in CH ₂ Cl ₂ and water and filtered through celite. This organic phase was evaporated to dryness and the resulting residue was purified by reverse phase chromatography (10-100% CH ₃ CN/H ₂ O (0.1% formic acid)) to give ethyl-(S)-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h] [1,7]naphthyridine-9-carboxylate (216 mg, 62%) as an off-white solid. LCMS (m/z, ES+)=431.2.433.2 (M+1); >97% enantiomeric excess by chiral HPLC.

[00483] Step 4: (S)-6-(tert-Butyl)-3-(cyclopropylmethoxy)-2-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00484]

[00485] Ethyl (S)-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate solution (52.7 mg, 0.12 mmol), Pd(PPh ₃ ) ₄ (28 mg, 0.024 mmol ), potassium carbonate (34 mg, 0.25 mmol), and trimethylboroxine (46 mg, 0.37 mmol) in 1,4-dioxane (0.61 ml) were heated at 100° C. overnight. The resulting reaction mixture was diluted with CH ₂ Cl ₂ and filtered through celite. The resulting filtrate was evaporated and the resulting residue was purified by reverse phase chromatography (5-100% CH ₃ CN/H ₂ O (0.1% formic acid)) to give (S)-ethyl-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naf thyridine-9-carboxylate (36.5 mg, 73%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.18 (s, 1 H), 7.56 (s, 1 H), 6.80 (s, 1 H), 4.40 (q, J=7.0 Hz, 2 H), 3.87 (s, 3 H), 3.39-3.48 (m, 1 H), 3.10-3.18 (m, 1 H), 2.50 (s, 3 H), 1.41 (t, J=7.0 Hz, 3 H), 0.69 (m, 2 H), 0.40 (m, 2 H); LCMS (m/z, ES+)=411.4 (M+1).

[00486] A solution of the above ester in 1M LiOH (0.9 ml) and MeOH (0.9 ml) was heated at 50°C for 1.5 hours. 1M citric acid (1.2 ml) was added and the resulting reaction mixture was agitated for 15 minutes. The resulting solid was collected by filtration, washed with water and dried to give (S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-p][1,7]naphthyridine-9-carboxylic acid (27.7 mg, 59% for 2 steps) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 16.53 (br. s., 1 H), 8.77 (s, 1 H), 7.44 (s, 1 H), 7.42 (s, 1 H), 4.58-4.69 (m, 1 H), 3.98 (m, 2 H), 3.46-3.55 (m, 2 H), 2.43 (s, 3H), 1.22-1.36 (m, 1 H), 0.73 (s, 9 H), 0.65-0.55 (m, 2 H), 0.33-0.44 (m, 2 H); LCMS (m/z, ES+)=383.2 (M+1).

[00487] Example 13 (Compound 232)

[00488] (S)-6-(tert-Butyl)-3-(3-methoxypropoxy)-2-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00489]

[00490] Ethyl (S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate solution (47.7 mg, 0.11 mmol), Pd(PPh ₃ ) ₄ (25 mg, 0.02 1 mmol), potassium carbonate (29 mg, 0.21 mmol) and trimethylboroxine (40 mg, 0.32 mmol) in 1,4-dioxane (0.53 ml) were heated at 100° C. overnight. The resulting reaction mixture was diluted with CH ₂ Cl ₂ and filtered through celite. The resulting filtrate was evaporated and the resulting residue was purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in hexanes) to give (S)-ethyl-6-(tert-butyl)-3-(3-methoxypropoxy)-2-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]on phthyridine-9-carboxylate (41.3 mg, 91%) as a white solid. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,17 (s, 1 H), 7,27 (s, 1 H), 6,86 (s, 1 H), 4,39 (q, J=7,0 Hz, 2 H), 4,05-4,17 (m, 2 H), 3,91 (d, J=6,6 Hz, 1 H), 3,63-3,55 (m, 2 H), 3,49-3,41 (m, 1 H), 3,38 (s, 3 H), 3,15 (d, J=16,8 Hz, 1 H), 2,46 (s, 3 H), 2,12 (quin, J=6,1 Hz, 2 H), 1,40 (t, J=7,0 Hz, 3 H), 0,84 (s, 9 H); LCMS (m/z, ES+)=429.4 (M+1).

[00491] A solution of the above ester in 1M LiOH (1 ml) and MeOH (1 ml) was heated at 50°C for 1.5 hours. 1M citric acid (1.2 ml) was added and the resulting reaction mixture was agitated for 15 minutes. The resulting solid was collected by filtration, washed with water and dried to give (S)-6-(tert-butyl)-3-(3-methoxypropoxy)-2-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (27.6 mg, 65% for 2 steps) as a white solid . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 16.53 (s, 1 H), 8.77 (s, 1 H), 7.46 (s, 1 H), 7.44 (s, 1 H), 4.64 (d, J=6.3 Hz, 1 H), 4.09-4.23 (m, 2 H), 3.47-3.56 (m, 3 H), 3.38-3.32 (m, 1H), 3.26 (s, 3 H), 2.42 (s, 3 H), 2.02 (quin, J=6.2 Hz, 2 H), 0.74 (s, 9 H); LCMS (m/z, ES+)=401.2 (M+1).

[00492] Example 14 (Compound 233)

[00493] (S)-6-(tert-Butyl)-2-cyclopropyl-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00494]

[00495] Ethyl (S)-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate solution (53 mg, 0.12 mmol), Pd(PPh ₃ ) ₄ (28 mg, 0.025 mmol), potassium carbonate (51 mg, 0.37 mmol) and cyclopropylboronic acid (21 mg, 0.25 mmol) in 1,4-dioxane (1.2 ml) were heated at 100° C. overnight. The resulting reaction mixture was diluted with CH ₂ Cl ₂ and filtered through celite. The resulting filtrate was evaporated and the resulting residue was purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in hexanes) to give (S)-ethyl-6-(tert-butyl)-2-cyclopropyl-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrvdo[1,2-h][1,7]naphthyr idine-9-carboxylate (53.3 mg, 99%) as a white solid. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,14 (s, 1 Н), 7,42 (s, 1 Н), 6,77 (s, 1 Н), 4,38 (q, J=7,3 Hz, 2 H), 3,88 (m, J=6,8,2,1 Hz, 2 H), 3,43 (dd, J=16,8, 7,0 Hz, 1 H), 3,11 (d, J=16,8 Hz, 1 H), 2,56-2,47 (m, 1 H), 1,39 (t, J=7,0 Hz, 3 H), 1,35-1,29 (m, 1 H), 1,22-1,29 (m, 1 H), 1,04-1,19 (m, 2 H), 0,93-1,01 (m, 2 H), 0,82 (s, 9 H), 0,63-0,73 (m, 2 H), 0,44-0,38 (m, 2 H); LCMS (m/z, ES+)=437.4 (M+1).

[00496] A solution of the above ester in 1M LiOH (1.2 ml) and MeOH (1.2 ml) was heated at 50°C for 2 hours. 1M citric acid (1.5 ml) was added and the resulting reaction mixture was agitated for 15 minutes. The resulting solid was collected by filtration, washed with water and dried to give (S)-6-(tert-butyl)-2-cyclopropyl-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (38.8 mg, 77% for 2 steps) as a white solid. ¹ Н ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 16,53 (s, 1 Н), 8,76 (s, 1 Н), 7,38 (s, 1 Н), 7,35 (s, 1 Н), 4,62 (d, J=6,3 Hz, 1 H), 4,05-3,94 (m, 2 H), 3,42-3,55 (m, 1 H), 3,30-3,28 (m, 1H), 1,26-1,44 (m, 1 H), 0,93-1,06 (m, 4 H), 0,72 (s, 9 H), 0,65-0,59 (m, 2 H), 0,43-0,5 (m, 2 H); LCMS (m/z, ES+)=409.2 (M+1).

[00497] Example 15 (Compound 234)

[00498] (S)-6-(tert-Butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00499]

[00500] Ethyl (S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate solution (46 mg, 0.10 mmol), Pd(PPh ₃ ) ₄ , (24 mg, 0.02 0 mmol), potassium carbonate (42 mg, 0.31 mmol) and cyclopropylboronic acid (18 mg, 0.21 mmol) in 1,4-dioxane (1.0 ml) were heated at 100° C. overnight. The resulting reaction mixture was diluted with CH ₂ Cl ₂ and filtered through celite. The resulting filtrate was evaporated and the resulting residue was purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in hexanes) to give (S)-ethyl-6-(tert-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1.7] naphthyridine-9-carboxylate (43.6 mg, 94%) as a white solid. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,16 (s, 1 Н), 7,45 (s, 1 Н), 6,83 (s, 1 Н), 4,39 (q, J=7,0 Hz, 2 H), 4,13 (m, 2 H), 3,89 (d, J=6,6 Hz, 1 H), 3,62 (m, 2 H), 3,39-3,46 (m, 1 H), 3,38 (s, 3 H), 3,13 (d, J=16,8 Hz, 1 H), 2,40-2,50 (m, 1 H), 2,15 (quin, J=6,1 Hz, 2 H), 1,40 (t, J=7,0 Hz, 3 H), 1,14-1,22 (m, 1 H), 1,04-1,12 (m, 1 H), 0,93-1,02 (m, 2 H), 0,83 (s, 9 H); LCMS (m/z, ES+)=455.5 (M+1).

[00501] A solution of the above ester in 1 M LiOH (1.2 ml) and MeOH (1.2 ml) was heated at 50°C for 2 hours. 1 M citric acid (1.5 ml) was added and the resulting reaction mixture was agitated for 15 minutes. The resulting solid was collected by filtration, washed with water, and dried to give (S)-6-(tert-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (27.2 mg, 62%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 16.53 (s, 1 H), 8.76 (s, 1 H), 7.43 (s, 1 H), 7.35 (s, 1 H), 4.62 (d, J=6.3 Hz, 1 H), 4.11-4.24 (m, 2 H), 3.42-3.57 (m, 4 H), 3.26 (s, 3 H), 2.41-2.46 (m, 1 H), 2.05 (quin, J=6.2 Hz, 2 H), 0.94-1.06 (m, 4 H), 0.73 (s, 9 H); LCMS (m/z, ES+)=427.2 (M+1).

[00502] Example 16 (Compound 235)

[00503] (R)-6-(tert-Butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00504]

[00505] Step 1: (S)-N-((R)-1-(6-Chloro-5-methoxytfidin-3-yl)-3,3-dimethylbutan-2-yl)-2-methylpropan-2-sulfinamide and (S)-N-((S)-1-(6-Chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-methylpro pan-2-sulfinamide

[00506]

[00507] A solution of 1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one (2.56 g, 10.57 mmol), (S)-2-methylpropan-2-sulfinamide (2.56 g, 21.14 mmol), Ti(OEt) ₄ (6.03 g, 26.4 mmol) in toluene (8.5 ml) was shaken for 10 minutes at 60°C and the specified vessel was evaporated. The resulting reaction mixture was agitated at 60°C under vacuum for 24 h. The indicated vessel was filled with nitrogen, toluene (5 ml) and Ti(OEt) ₄ (2.4 g, 10.5 mmol) were added and the resulting reaction mixture was agitated under vacuum for 4 h.

The indicated vessel was filled with nitrogen, toluene (5 ml) was added and the resulting reaction mixture was agitated under vacuum for an additional 3 hours. The indicated viscous reaction mixture was then transferred into THF (70.5 ml), additional Ti(OEt) ₄ (2.4 g, 10.5 mmol) was added and the indicated NaBH ₄ solution (1.20 g, 31.7 mmol), cooled to -30 ° C, was added in portions . The resulting reaction mixture was then allowed to slowly warm to room temperature overnight. The resulting reaction mixture was diluted with THF (130 ml) and brine (3 ml), stirred for 30 min, and then filtered through celite. The resulting filtrate was evaporated and purified by silica gel chromatography to give the two indicated diastereomers.

[00508] The main diastereomer is a white solid: (S)-N-((R)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-methylpropan-2-sulfinamide (1.8 g, 50%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.81 (d, J=2.0 Hz, 1 H), 7.40 (d, J=2.0 Hz, 1 H), 3.97 (s, 3 H), 3.26 (m, 1 H), 3.06-3.15 (m, 2 H), 2.72 (dd, J=14.8, 8, 2 Hz, 1 H), 1.17 (s, 9 H), 0.99 (s, 9 H); LCMS (m/z, ES+)=346.8, 348.5 (M+1).

[00509] The other diastereomer is a clear oil: (S)-N-((S)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-methylpropan-2-sulfinamide (1.2 g, 33%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.77 (d, J=1.6 Hz, 1 H), 7.07 (d, J=1.6 Hz, 1 H), 3.93 (s, 3 H), 3.19-3.33 (m, 2 H), 3.02 (dd, J=14.1, 2.7 Hz, 1 H), 2.5 5 (dd, J=14.1, 10.5 Hz, 1 H), 1.08 (s, 9 H), 0.98 (s, 9 H); LCMS (m/z, ES+)=346.8, 348.0 (M+1).

[00510] Step 2: (R)-5-(2-Amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol

[00511]

[00512] A solution of (S)-N-((R)-1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-methylpropan-2-sulfinamide (1.82 g, 5.26 mmol) in 1,2-dichloroethane (26.3 ml) was agitated at 0°C. Boron tribromide (3.48 mL, 36.8 mmol) was added slowly. The resulting reaction mixture was removed from the cooling bath and stirred overnight at room temperature. This solution was cooled to 0° C. and quenched by slow addition of MeOH. The resulting suspension was evaporated. EtOAc was added and the resulting solid was collected by filtration, washed with EtOAc and dried to give (S)-5-(2-amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol, as HBr bis salt. (2.1 g, calc.) LCMS (m/z, ES+)=229.2, 231.2 (M+1).

[00513] Step 3: (R)-tert-Butyl (1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate

[00514]

g, 2.51 mmol) and Boc anhydride (0.80 g, 3.67 mmol) in THF (25.1 ml) were agitated at 60°C for 1.5 h. THF (10 ml) and triethylamine (0.35 ml, 2.51 mmol) were added and the resulting reaction mixture was agitated for an additional 30 minutes. Additional triethylamine (0.35 ml, 2.51 mmol) was added and the resulting reaction mixture was agitated at 60° C. for 1 hour. This solution was then evaporated to dryness. The resulting solid residue was suspended in diethyl ether, separated by filtration and washed with additional diethyl ether. The resulting solid was taken up in EtOAc and washed with dilute aqueous NaHCCO ₃ and brine. This organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated to give (R)-tert-butyl (1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate (1.01 g, 99%) as a light yellow solid. LCMS (m/z, ES+) = 329.2, 331.2 (M+1).

[00516] Step 4: (R)-tert-Butyl-(1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate

[00517]

[00518] Iodine (0.64 g, 2.51 mmol) was added to a stirred solution of tert-butyl-(R)-(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate (0.83 g, 2.51 mmol) and K ₂ CO ₃ (1.04 g, 7.53 mmol) in water (6, 3 ml) and 1,4-dioxane (6.3 ml). The resulting reaction mixture was shaken at room temperature for 1.5 h.

[00519] Solid Na ₂ SO ₃ was added with stirring until the solution was no longer dark brown. This solution was diluted with brine and EtOAc. This aqueous phase was extracted with EtOAc. The combined organic phases were dried (Na ₂ SO ₄ ), filtered and evaporated to give (R)-tert-butyl-(1-(6-chloro-5-hadroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate as a yellow foam (0.38 g, 34%). LCMS (m/z, ES+) = 455.4.457.1 (M+1).

[00520] Step 5: (R)-tert-Butyl-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate

[00521]

[00522] Раствор трет-бутил-(R)-(1-(6-хлор-5-гидрокси-2-йодпиридин-3-ил)-3,3-диметилбутан-2-ил)карбамата (0,3819 г, 0,840 ммоль), K ₂ СО ₃ (0,35 г, 2,52 ммоль) и (бромметил)циклопропана (0,23 г, 1,68 ммоль) в ДМФА (5,6 мл) нагревали при 80°С в течение 3 ч. Полученную реакционную смесь упаривали досуха и полученный осадок переносили в CH ₂ Cl ₂ и Н ₂ О. Указанную водную фазу экстрагировали CH ₂ Cl ₂ (2х) и объединенные органические фазы осушали (Na ₂ SO ₄ ), отфильтровывали и упаривали с получением трет-бутил-(E)-(1-(6-хлор-5-(1щклопропилметокси)-2-йодпиридин-3-ил)-3,3-диметилбутан-2-ил)карбамата (415,4 мг, 97%) в виде серовато-белого твердого вещества. LCMS (m/z, ES+) = 509.2, 511.2 (M+1).

[00523] Step 6: Ethyl-(R)-1-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate

[00524]

[00525] 4 M Hydrochloric acid in dioxane (3.06 ml, 12.25 mmol) was added to a solution of tert-butyl (R)-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate (0.42 g, 0.82 mmol) in CH ₂ Cl ₂ (3 ml). The resulting reaction mixture was shaken at room temperature for 3 h and evaporated to dryness. The resulting solid residue was dissolved in CH ₂ Cl ₂ (1 ml) and Et ₃ N (1 ml), stirred, and then evaporated to dryness. The resulting precipitate was taken up in saturated NaHCO ₃ and CH ₂ Cl ₂ . This aqueous phase was extracted with CH ₂ Cl ₂ (2x) and the combined organic phases were dried (Na ₂ SO ₄ ), filtered and evaporated to give (R)-1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylbutan-2 -amine. A solution of the above amine and ethyl 4-oxo-4H-pyran-3-carboxylate (151 mg, 0.90 mmol) in acetic acid (8.2 ml) was agitated at 100° C. for 7 h. % formic acid)) to give ethyl ( _R )-1-(1-(6-chloro-5-( _{cyclopropylmethoxy} )-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (389 mg, 85%) as a light brown solid. LCMS (m/z, ES-) = 575.2, 577.2 (M-1).

[00526] Step 7: (R)-Ethyl-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate

[00527]

[00528] A flask containing ethyl-(R)-1-(1-(6-chloro-5-(cyclopropylmethoxy)-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (0.39 g, 0.70 mmol), potassium acetate (0.14 g, 1.39 mmol), and palladium (P) bromide (0.037 g, 0.14 mmol), purged with nitrogen. Degassed N, _N -dimethylacetamide (DMA) (7.0 ml ₎ was added and the resulting reaction mixture was heated at 90° C. for 24 h. hydroxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (167 mg, 56%). ¹ H ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,18 (s, 1Н), 7,49 (s, 1Н), 6,96 (s, 1Н), 4,40 (q, J=7,3 Hz, 2Н), 3,96 (d, J=7,0 Hz, 2H), 3,93 (d, J=6,6 Hz, 1H), 3,46 (dd, J=17,0, 6,8 Hz, 1H), 3,19 (d, J=16,8 Hz, 1H), 1,41 (t, 7=7,0 Hz, 3H), 1,30-1,37 (m, 1H), 0,85 (s, 9H), 0,76-0,70 (m, 2H), 0,41-0,48 (m, 2 H); LCMS (m/z, ES-) = 429.4.431.4 (M-1).

[00529] Step 8: (R)-6-(tert-Butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00530]

[00531] Ethyl (R)-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate solution (33 mg, 0.077 mmol), NaB(OMe) ₄ (36 mg, 0.23 mmol), tBuX Phos (6.5 mg, 0.015 mmol) and Pd ₂ (dba) ₃ (7.0 mg, 7.66 μmol) in DMF (0.77 ml) were heated at 80°C for 2 hours. The resulting reaction mixture was filtered through celite and the specified celite was washed with EtOAc and CH ₂ Cl ₂ . The resulting filtrate was evaporated and the resulting residue was purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in hexanes) to give ethyl-(R)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naf thyridine-9-carboxylate (27 mg, 83%). ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,17 (s, 1Н), 7,42 (s, 1Н), 6,80 (s, 1Н), 4,39 (q, 7=7,0 Hz, 2H), 4,05 (s, 3H), 3,94-3,85 (m, 3H), 3,42 (dd, 7=16,6,6,8 Hz, 1H), 3,09 (d, J=16,8 Hz, 1H), 1,37-1,40 (t, 7=7,2 Hz, 4H), 1,27-1,37 (m, 1H), 0,85 (s, 9H), 0,66-0,75 (m, 2H), 0,42-0,37 (m, 2H); LCMS (m/z, ES+) = 427.4 (M+1).

[00532] A solution of the above ester in 1M LiOH (1 ml) and MeOH (1 ml) was heated at 50°C for 2 hours. The resulting reaction mixture was filtered through an Acrodisc filter to remove remaining fine particles, and 1M citric acid (1 ml) was added to this clean filtrate. The precipitate was collected by filtration, washed with water and dried to give (R)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (19 mg, 62% for 2 steps) as an off-white solid substances. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 16.53 (s, 1H), 8.77 (s, 2H), 7.40 (s, 2H), 7.36 (s, 2H), 4.62 (d, J=6.8 Hz, 1H), 3.97 (s, 3H), 3.96-3.89 (m, 2 H), 3.49-3.40 (m, 1H), 1.22-1.32 (m, 1H), 0.75 (s, 9H), 0.57-0.65 (m, 2H), 0.31-0.40 (m, 2H); LCMS (m/z, ES+) = 399.2 (M+1).

[00533] Example 17 (Compound 236)

[00534] (S)-6-(tert-Butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00535]

[00536] Ethyl (S)-6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-b][1,7]naphthyridine-9-carboxylate solution (52 mg, 0.12 mmol), NaB(OMe) ₄ (57 mg, 0.36 mmol), tBuXP hos (10.3 mg, 0.024 mmol) and Pd ₂ (dba) ₃ (11.0 mg, 0.012 mmol) in DMF (1.2 ml) were heated at 80° C. for 2 h. The resulting reaction mixture was filtered through celite and said celite was washed with EtOAc and CH ₂ Cl ₂ . The resulting filtrate was evaporated and the resulting residue was purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in hexanes) to give ethyl-(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naf giridine-9-carboxylate (32 mg, 62%). ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,17 (s, 1Н), 7,44 (s, 1Н), 6,80 (s, 1Н), 4,40 (q, 7=7,2 Hz, 2H), 4,06 (s, 3H), 3,89 (m, 3H), 3,42 (dd, 7=16,8, 7,0 Hz, 1H), 3,09 (d, J=16,4 Hz, 1H), 1,40 (t, 7=7,0 Hz, 3H), 1,31-1,37 (m, 1H), 0,84 (s, 9H), 0,68-0,75 (m, 2H), 0,36-0,43 (m, 2 H); LCMS (m/z, ES+) = 427.4 (M+1).

[00537] A solution of the above ester in 1 M LiOH (0.75 ml) and MeOH (0.75 ml) was heated at 50° C. for 2 h, 1 M citric acid (0.75 ml) was added to the resulting reaction mixture, and the precipitate was collected by filtration, washed with water and dried to give (S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy- 10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (26.5 mg, 55% for 2 steps) as a white solid. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 16,11 (s, 1H), 8,45 (s, 1H), 7,65 (s, 1H), 6,83 (s, 1H), 4,08 (s, 3H), 4,04 (d,.7=6,8 Hz, 1H), 3,92 (m, 2H), 3,48 (dd, J=17,1, 7,3 Hz, 1H), 3,16 (d, J=17,1 Hz, 1H), 1,31-1,43 (m, 1H), 0,86 (s, 9H), 0,69-0,78 (m, 2H), 0,41 (m, 2 H); LCMS (m/z, ES+) = 399.3 (M+1).

[00538] Example 18 (Compound 237)

[00539] (S)-6-(tert-Butyl)-3-(cyclopropylmethoxy)-2-hydroxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1.7]naphthyridine-9-carboxylic acid

[00540]

[00541] A demethylated product was formed as a by-product of the reaction in which ethyl-(S)-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-methoxy-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate was obtained and was collected as mixed fractions, which were then combined. Repurification by reverse phase chromatography (10-100% CH ₃ CN/H ₂ O (0.1% formic acid)) gave (S)-ethyl-6-(tert-butyl)-3-(cyclopropylmethoxy)-2-hydroxy-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (8.3 mg, 17%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.18 (s, 1H), 6.85 (s, 1H), 6.55 (s, 1H), 4.37 (q, J=7.0 Hz, 2H), 3.83-3.97 (m, 3H), 3.33 (dd, J=16.8, 6.6 Hz, 1H), 2.95 (d, J=17.2 Hz, 1H), 1.33-1.42 (m, 4H), 0.65-0.74 (m, 2H), 0.40 (m, 2H); LCMS (m/z, ES+) = 413.3 (M+1).

[00542] A solution of the above ester in 1M LiOH (0.5 ml) and MeOH (0.5 ml) was heated at 50°C for 2 hours. 1M citric acid (0.5 ml) was added to the resulting reaction mixture and this solution was purified using reverse phase chromatography (5-100% CH ₃ CN/H ₂ O (0.1% formic acid)) to obtain (S) -6-(tert-butyl)-3-(cyclopropylmethoxy)-2-hydroxy-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (6.4 mg, 14% for 2 steps) as a yellow solid. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 15,72 (br. s., 1H), 8,44 (s, 1H), 7,38 (s, 1H), 6,66 (s, 1H), 4,04 (d, J=4,9 Hz, 1H), 3,96 (d, J=6,8 Hz, 2H), 3,40-3,53 (m, 1H), 3,04 (d, J=17,1 Hz, 1H), 1,34-1,45 (m, 1H), 0,89 (s, 9H), 0,77-0,72 (m, 2H), 0,47-0,42 (m, 2 H); LCMS (m/z, ES+) = 385.2 (M+1).

[00543] Example 19 (Compound 238)

[00544] (S)-6-(tert-Butyl)-2-methoxy-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1.2-h][1,7]naphthyridine-9-carboxylic acid

[00545]

[00546] Ethyl (8)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-b][1,7]naphthyridine-9-carboxylate solution (46.8 mg, 0.10 mmol), NaB(OMe)4 (49 mg, 0.31 mmol), tBuXPhos (8.9 mg, 0.021 mmol) and Pd ₂ (dba) ₃ (9.6 mg, 0.010 mmol) in DMF (1.0 ml) were heated at 80° C. for 2 h. The resulting reaction mixture was filtered through celite and said celite was washed with CH ₂ Cl ₂ . The resulting filtrate was evaporated and the resulting precipitate was used under the same conditions of the indicated reaction mixture with additional reagents: NaB(OMe) ₄ (49 mg, 0.31 mmol), tBuXPhos (8.9 mg, 0.021 mmol) and Pd ₂ (dba) ₃ (9.6 mg, 0.010 mmol) in DMF (1.0 ml) at 80°C for an additional 3 hours. the reaction mixture was filtered through celite and said celite was washed with CH ₂ Cl ₂ . The resulting filtrate was evaporated and the resulting residue was purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in hexanes) to give ethyl-(S)-6-(tert-butyl)-2-methoxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1.7 ]naphthyridine-9-carboxylate as a light brown solid. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,18 (s, 1Н), 7,44 (s, 1Н), 6,86 (s, 1Н), 4,40 (q, 7=7,3 Hz, 2H), 4,19 - 4,12 (m, 2H), 4,05 (s, 3H), 3,90 (d, J=6,6 Hz, 1H), 3,61-3,55 (m, 2H), 3,42 (dd, J=16,8, 7,0 Hz, 1H), 3,37 (s, 3H), 3,11 (d, J=16,8 Hz, 1H), 2,15 (quin, J=6,2 Hz, 2H), 1,40 (t, J=7,0 Hz, 3H), 0,86 (s, 9H); LCMS (m/z, ES+) = 445.0 (M+1).

[00547] A solution of the above ester in 1 M LiOH (0.75 ml) and MeOH (0.75 ml) was heated at 50° C. for 2 hours. 1 M citric acid (0.75 ml) was added to the resulting reaction mixture and this solution was purified using reverse phase chromatography (5-100% CH ₃ CN/H ₂ O (0.1% formic acid)) to obtain (S)-6-(tert-butyl)-2-methoxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (19.6 mg, 45% for 2 steps) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 16.12 (s, 1H), 8.46 (s, 1H), 7.65 (s, 1H), 6.90 (s, 1H), 4.24-4.13 (m, 2H), 4.06 (s, 1H), 3.63-3.55 (m, 2H), 3.4 9 (dd, J=16.6, 6.3 Hz, 1H), 3.38 (s, 3H), 3.18 (d, J=17.1 Hz, 1H), 2.16 (quin, J=6.1 Hz, 2H), 0.87 (s, 9H); LCMS (m/z, ES+) = 417.2 (M+1).

[00548] Example 20 (Compound 239)

[00549] (S)-6-(tert-Butyl)-2-hydroxy-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1.2-h][1.7]naphthyridine-9-carboxylic acid

[00550]

[00551] A demethylated product was formed as a by-product of the reaction in which ethyl (S)-6-(tert-butyl)-2-methoxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate was obtained and was collected as mixed fractions, which were then combined and subjected to hydrolysis without further purification. A solution of the indicated ester in 1M LiOH (0.5 ml) and MeOH (0.5 ml) was heated at 50°C for 2 hours. To the resulting reaction mixture was added 1M citric acid (0.5 ml) and the indicated solution was purified using reverse phase chromatography (5-100% CH ₃ CN/H ₂ O (0.1% formic acid)) to obtain (S)-6-(tert-but yl)-2-hydroxy-3-(3-methoxygfopoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (3.4 mg, 8% for 2 steps) as a yellow solid. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 15,76 (br. s., 1H), 8,42 (s, 1H), 7,47 (s, 1H), 6,70 (s, 1H), 4,20 (t, 7=6,1 Hz, 2H), 4,04 (d, J=6,3 Hz, 1H), 3,61-3,76 (m, 2H), 3,48 (dd, J=17,1, 6,8 Hz, 1H), 3,41 (s, 3H), 3,04 (d, J=17,1 Hz, 1H), 2,21 (quin, J=6,0 Hz, 2H), 0,89 (s, 9H); LCMS (m/z, ES+) = 403.2 (M+1).

[00552] Example 21 (Compound 240)

[00553] (S)-6-(tert-Butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00554]

[00555] Step 1: (S)-Ethyl-6-(tert-butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-6,10-dihydro-5H-pyrido[1.2-h][1.7]naphthyridine-9-carboxylate

[00556]

[00557] A solution of ethyl (S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (88.4 mg, 0.20 mmol), potassium isopropenyl trifluoroborate (58 mg, 0.39 mmol ), sodium carbonate (63 mg, 0.59 mmol) and Pd(PPh ₃ ) ₄ (23 mg, 0.020 mmol) in ethanol (2.0 ml) were shaken at 80° C. overnight. The resulting reaction mixture was diluted with CH ₂ Cl ₂ and filtered through celite. The resulting filtrate was evaporated and the resulting residue was purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in hexanes) to give ethyl-(S)-6-(tert-butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-5,10-dihydro-6H-pyrido[ 1,2-h][1,7]naphthyridine-9-carboxylate (87.5 mg, 98%) as a white solid. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,18 (s, 1Н), 7,54 (s, 1Н), 7,00 (s, 1Н), 5,91 (s, 1Н), 5,54 (s, 1Н), 4,39 (q, J=7,0 Hz, 2H), 4,07-4,22 (m, 2H), 3,93 (d, J=6,6 Hz, 1H), 3,61-3,56 (m, 2H), 3,48 (dd, J=17,0, 6,8 Hz, 1H), 3,37 (s, 3H), 3,19 (d, J=16,8 Hz, 1H), 2,25 (s, 3H), 2,13 (quin, J=6,1 Hz, 2H), 1,40 (t, 7=7,2 Hz, 3H), 0,85 (s, 9H); LCMS (m/z, ES+) = 455.9 (M+1).

[00558] Step 2: (S)-6-(tert-Butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00559]

[00560] The title compound was isolated as a by-product by hydrolysis under alkaline conditions during the oxidation reaction of ethyl-(S)-6-(tert-butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carbox ylate (30.3 mg, 0.067 mmol) with trimethylsulfoxonium iodide (31 mg, 0.14 mmol) and KOtBu (15 mg, 0.13 mmol) in DMSO (0.64 ml) and THF (0.27 ml). Purification of the resulting reaction mixture by reverse phase chromatography (5-100% CH ₃ CN/H ₂ O (0.1% formic acid)) gave (S)-6-(tert-butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-6,10-dihydro-5H-pyrido[1,2-h][1 ,7]naphthyridine-9-carboxylic acid (4.8 mg, 17%) as a white solid. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 16,16 (s, 1H), 8,47 (s, 1H), 7,78 (s, 1H), 7,04 (s, 1H), 5,95 (s, 1H), 5,59 (s, 1H), 4,26-4,12 (m, 2H), 4,07 (d, J=6,8 Hz, 1H), 3,62-3,57 (m, 2H), 3,53 (dd, J=17,3, 7,1 Hz, 1H), 3,38 (s, 3H), 3,26 (d, J=17,1 Hz, 1H), 2,26 (s, 3H), 2,15 (quin, J=6,0 Hz, 2H), 0,87 (s, 9H); LCMS (m/z, ES+) = 427.3 (M+1).

[00561] Example 22: (Compound 241)

[00562] (S)-6-(tert-Butyl)-2-isopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00563]

[00564] A solution of ethyl (S)-6-(tert-butyl)-3-(3-methoxypropoxy)-10-oxo-2-(prop-1-en-2-yl)-5,10-digadro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (11.9 mg, 0.026 mmol) and 10% Pd/ C (catalytic) in MeOH (1 ml) was agitated at 60 psi. inch H ₂ for 1.5 hours. The resulting reaction mixture was filtered through celite and evaporated to dryness to obtain the crude substance (S)-ethyl-6-(tert-butyl)-2-isopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate, which was used without further purification.

[00565] A solution of the above ester in 1 M LiOH (0.7 ml) and MeOH (0.7 ml) was heated at 50°C for 2 hours. 1 M citric acid (0.8 ml) was added and the resulting reaction mixture was agitated for 15 minutes. The precipitate was collected by filtration, washed with water and dried to give (S)-6-(tert-butyl)-2-isopropyl-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (9.3 mg, 83% for two steps) as an off-white solid th substance. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 16,26 (s, 1H), 8,46 (s, 1H), 7,83 (s, 1H), 6,91 (s, 1H), 4,08-4,21 (m, 2H), 4,05 (d, J=6,8 Hz, 1H), 3,66-3,58 (m, 2H), 3,41-3,55 (m, 2H), 3,38 (s, 3H), 3,22 (d, J=17,1 Hz, 1H), 2,14 (quin, J=6,0 Hz, 2H), 1,27 (d, J=6,8 Hz, 6 H), 0,85 (s, 9H); LCMS (m/z, ES+) = 429.3 (M+1).

[00566] Example 23: (Compound 243)

[00567] (S)-6-(tert-Butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-6,10-dihydro-5H-pyrido[1.2-h][1,7]naphthyridine-9-carboxylic acid

[00568]

[00569] Step 1: Ethyl 2-methyl-4-oxo-4H-pyran-3-carboxylate

[00570] A solution of ethyl 3-oxobutanoate (3.64 g, 28 mmol) in 20 ml THF was added via a syringe pump (dropwise) to a vial containing NaH (60% dispersion in mineral oil) (1.176 g, 29.4 mmol) which was cooled at 0°C during the addition. The resulting reaction mixture was agitated at room temperature for 1 h after the addition was complete and then cooled back to 0°C. A solution of 3-chloroacryloyl chloride (3.50 g, 28 mmol) in 20 ml of THF was slowly added to this cooled reaction mixture using a syringe pump over 1 h. After the addition was complete, the resulting reaction mixture was agitated at room temperature overnight and then heated under reflux for 2.5 hours, the resulting reaction mixture was diluted with water and was extracted with Et ₂ O (4x) and CH ₂ Cl ₂ (2x). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-100% EtOAc/hexanes) to give ethyl 2-methyl-4-oxo-4H-pyran-3-carboxylate (2.65 g, 52%) as a brown liquid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.66 (d, J=5.9 Hz, 1H), 6.36 (d, J=5.9 Hz, 1H), 4.39 (q, J=7.3 Hz, 2H), 2.38 (s, 3H), 1.38 (t, J=7.2 Hz, 3H); LCMS (m/z, ES+) = 183.1 (M+1).

[00571] Step 2: (S)-Ethyl-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbugan-2-yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate

[00572]

[00573] A solution of (S)-1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-2-amine, hydrochloric acid (196 mg, 0.42 mmol) and ethyl 2-methyl-4-oxo-4H-pyran-3-carboxylate (0.23 g, 1.27 mmol) in HOAc (4.2 ml) was shaken at 100°C for 10 h. The resulting reaction mixture was evaporated to dryness, dissolved in CH ₂ Cl ₂ and saturated NaHCO ₃ and stirred for 1 h. The specified organic phase was isolated, dried (Na ₂ SO ₄ ), filtered and evaporated. The resulting precipitate was shaken with additional ethyl 2-methyl-4-oxo-4H-pyran-3-carboxylate (200 mg, 1.10 mmol) in HOAc (4.2 ml) at 100° C. overnight. The resulting reaction mixture was evaporated to dryness and the resulting residue was purified by reverse phase chromatography (5-100% CH ₃ CN/H ₂ O (0.1% formic acid)) to give ethyl-(S)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-methyl -4-oxo-1,4-dihydropyridine-3-carboxylate (67.4 mg, 27%) as a brown solid. LCMS (m/z, ES+) = 591.2, 593.2 (M+1).

[00574] Stage 3: (S)-Ethyl-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate

[00575] Flask containing ethyl-(S)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-2-yl)-2-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (67.4 mg, 0.11 mmol), potassium acetate (22 mg, 0.23 mmol) and palladium(II) bromide (6.1 mg, 0.023 mmol) were purged with nitrogen. Degassed DMF (1.1 ml) was added and the resulting reaction mixture was heated at 90°C for 24 hours. The above solution was cooled to room temperature, additional palladium (II) bromide (6.1 mg, 0.023 mmol) was added and the resulting reaction mixture was heated at 90°C for an additional 6 hours. The indicated solvent was removed by evaporation and the resulting precipitate was purified by chromatography on silica. le (0-100% 3:1 (EtOAc/EtOH) in hexanes) to give ethyl-(S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (12.1 mg, 23 %) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.48 (s, 1H), 7.00 (s, 1H), 4.34-4.45 (m, 3H), 4.13-4.24 (m, 2H), 3.65-3.58 (m, 2H), 3.31-3.41 (m, 4H), 3.15 (d , J=16.8 Hz, 1H), 2.45 (s, 3H), 2.12-2.19 (m, 2H), 1.38 (t, J=7.2 Hz, 3H), 0.80 (s, 9H); LCMS (m/z, ES+) = 463.3.465.3 (M+1).

[00576] Step 4: (S)-6-(tert-Butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00577]

[00578] A solution of (S)-ethyl-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (12.1 mg, 0.026 mmol) in 1 M LiOH (0.5 ml) and MeOH (0 .5 ml) was heated at 50°C for 2 h, and then at 60°C for 2 h. 1M citric acid (0.7 ml) was added to the resulting reaction mixture. This solution was evaporated to dryness and the resulting residue was purified by reverse phase chromatography (5-90% CH ₃ CN/H ₂ O (0.1% formic acid)) to give (S)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-8-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][ 1,7]naphthyridine-9-carboxylic acid (7.0 mg, 62%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 17.61 (br. s., 1H), 7.82 (s, 1H), 7.05 (s, 1H), 4.81 (d, J=5.4 Hz, 1H), 4.15-4.28 (m, 2H), 3.67-3.57 (m, 2H), 3.4 9-3.41 (m, 1H), 3.38 (s, 3H), 3.25 (d, J=17.6 Hz, 1H), 3.18 (s, 3H), 2.17 (quin, 7=6.0 Hz, 2H), 0.81 (s, 9H); LCMS (m/z, ES+) = 435.2, 437.2 (M+1).

[00579] Example 24: (Compound 243)

[00580] (S)-6-(tert-Butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00581]

[00582] Step 1: (S)-tert-Butyl-(1-(5-(benzyloxy)-6-chloro-2-iodopyridin-3-yl)-3,3-dimethylbugan-2-yl)carbamate

[00583]

[00584] A solution of tert-butyl-(S)-(1-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate (2.18 g, 4.79 mmol), K ₂ CO ₃ (1.99 g, 14.38 mmol), (bromomethyl)benzene (0.86 ml, 7.19 mmol) in DMF (32.0 ml) was heated at 80° C. for 3 hours. The resulting reaction mixture was evaporated to dryness and the resulting precipitate was taken up in CH ₂ Cl ₂ and water. The specified aqueous phase was extracted with CH ₂ Cl ₂ (2x) and the combined organic phases were dried (Na ₂ SO ₄ ), filtered and evaporated to obtain tert-butyl-(S)-(1-(5-(benzyloxy)-6-chloro-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate (calculated amount), which was transferred to the next stage without further purification. LCMS (m/z, ES+) = 545.4, 547.0 (M+1).

[00585] Step 2: Ethyl-(S)-1-(1-(5-(benzyloxy)-6-chloro-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate

[00586]

[00587] HCl (4M in dioxane) (11.98 ml, 47.9 mmol) was added to a solution of tert-butyl-(S)-(1-(5-(benzyloxy)-6-chloro-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate (2.61 g, 4.79 mmol) in CH ₂ Cl ₂ (6 ml) and the resulting reaction mixture was agitated at room temperature for 3 hours. This mixture was evaporated to dryness and the resulting precipitate was taken up in saturated NaHCO ₃ and CH ₂ Cl ₂ . This aqueous phase was extracted with CH ₂ Cl ₂ (2x) and the combined organic phases were dried (Na ₂ SO ₄ ), filtered, evaporated to give a brown oil.

[00588] A solution of the above amine and ethyl 4-oxo-4H-pyran-3-carboxylate (0.89 g, 5.27 mmol) in HOAc ( ₂₄ ml) was agitated at 100° C. for 7 _h . within ₃₀ min. This aqueous phase was extracted with CH ₂ Cl ₂ (5×10 mL) and the combined organic phases were dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-100% (3:1 EtOAc:EtOH) in hexanes) to give ethyl-(S)-1-(1-(5-(benzyloxy)-6-chloro- 2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (1.39 g, 49%) as a brown solid. LCMS (m/z, ES+) = 596.1, 597.2 (M+1).

[00589] Step 3: Ethyl-(S)-3-(benzyloxy)-6-(tert-butyl)-2-chloro-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate

[00590]

[00591] Flask containing ethyl-(S)-1-(1-(5-(benzyloxy)-6-chloro-2-iodopyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (1.39 g, 2.34 mmol), potassium acetate (460 mg, 4.68 mmol), and bromine d palladium (II) (125 mg, 0.47 mmol) was purged with nitrogen. Degassed DMF (23.4 ml) was added and the resulting reaction mixture was heated at 90° C. for 24 hours. The indicated solvent was removed by evaporation and the resulting precipitate was dissolved in CH ₂ Cl ₂ , filtered through celite and purified using silica gel chromatography (0-100% 3:1 (EtOAc/EtOH) in hexanes) to give ethyl-(S )-3-(benzyloxy)-6-(tert-butyl)-2-chloro-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (706 mg, 65%) as a brown solid. LCMS (m/z, ES+) = 467.3.469.3 (M+1).

[00592] Step 4: Ethyl-(S)-3-(benzyloxy)-6-(tert-butyl)-10-oxo-2-vinyl-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate

[00593]

[00594] A solution of ethyl (S)-3-(benzyloxy)-6-(tert-butyl)-2-chloro-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (0.34 g, 0.74 mmol), trifluoro(vinyl)-14-borane potassium salt (0.20 g, 1 .48 mmol), sodium carbonate (0.24 g, 2.22 mmol) and Pd(PPh ₃ ) ₄ (85 mg, 0.074 mmol) in EtOH (7.4 ml) were shaken at 80° C. overnight. The resulting reaction mixture was diluted with CH ₂ Cl ₂ , filtered through celite, and evaporated. The resulting residue was purified by silica gel chromatography (0-100% 3:1 (EtOAc/EtOH) in hexanes) to give ethyl-(S)-3-(benzyloxy)-6-(tert-butyl)-10-oxo-2-vinyl-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carbox ylate (251 mg, 74%) as a grayish foam. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,21 (s, 1H), 7,39-7,73 (m, 7H), 7,00 (s, 1H), 6,59 (d, J=6,6 Hz, 1H), 5,54 (d, J=10,5 Hz, 1H), 5,09-5,24 (m, 2H), 4,40 (q, J=7,0 Hz, 2H), 3,90-4,01 (m, 1H), 3,39-3,55 (m, 1H), 3,13-3,24 (m, 1H), 1,41 (t, J=7,0 Hz, 3H), 0,84 (s., 9H); LCMS (m/z, ES+) = 459.1.460.4 (M+1).

[00595] Step 5: (S)-Ethyl-6-(tert-butyl)-3-hydroxy-2-(hydroxymethyl)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate

[00596]

[00597] To a solution of ethyl (S)-3-(benzyloxy)-6-(tert-butyl)-10-oxo-2-vinyl-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (251 mg, 0.55 mmol) in THF (5.5 ml) and water (1.4 ml) at 0°C was added potassium osmate dihydrate (20.2 mg, 0.055 mmol) followed by sodium periodate (468 mg, 2.19 mmol). After the addition was complete, the resulting reaction mixture was agitated at room temperature for 2 hours. The resulting reaction mixture was diluted with CH ₂ Cl ₂ and water, stirred and filtered through celite. The combined organic phases were dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-100% 3:1 (EtOAc/EtOH) in CH ₂ Cl ₂ ) to give ethyl-(S)-3-(benzyloxy)-6-(tert-butyl)-2-formyl-10-oxo-5,10-dihydro- 6Н-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (suggested calculation). LCMS (m/z, ES+) = 461.3 (M+1).

[00598] A solution of the above aldehyde and 10% Pd/C (catalytic) in EtOH (20 ml) was shaken at 60 psi. inch H ₂ during the night. The resulting reaction mixture was filtered through celite and evaporated to give ethyl (S)-6-(tert-butyl)-3-hydroxy-2-(hydroxymethyl)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (122.1 mg, 60%), which was taken to the next step without purification. LCMS (m/z, ES+) = 373.3 (M+1).

[00599] Step 6: Ethyl-(S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1.7]naphthyridine-9-carboxylate

[00600]

[00601] 1-Bromo-3-methoxypropane (44.3 µl, 0.39 mmol) was added to a solution of ethyl-(S)-6-(tert-butyl)-3-hydroxy-2-(hydroxymethyl)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (122.1 mg, 0.33 mmol) and potassium carbonate (136 mg, 0.98 mmol) in DMF (3.3 ml) and the resulting reaction mixture was agitated at room temperature overnight. Additional potassium carbonate (100 mg, 0.72 mmol) and 1-bromo-3-methoxypropane (44.3 μl, 0.39 mmol) were added and the resulting reaction mixture was heated at 40° C. for 2.5 h and then stirred at room temperature overnight. This solvent was evaporated and the resulting residue was diluted with CH ₂ Cl ₂ and brine. This organic phase was dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-100% 3:1 (EtOAc/EtOH) in CH ₂ Cl ₂ ) to give ethyl-(S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5 ,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (62.8 mg, 43%) as a yellow oil. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,18 (s, 1Н), 7,44 (s, 1Н), 6,98 (s, 1Н), 4,72 (s, 2Н), 4,39 (q, J=7,2 Hz, 2H), 4,22-4,12 (m, 2H), 3,90-4,06 (m, 2H), 3,61-3,53 (m, 3H), 3,37 (s, 3H), 3,21 (d, J=16,8 Hz, 1H), 2,11 (quin, J=6,0 Hz, 2H), 1,40 (t, J=7,2 Hz, 3H), 0,83 (s, 9H); LCMS (m/z, ES+) = 445.3 (M+1).

[00602] Step 7: (S)-6-(tert-Butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00603]

[00604] A solution of ethyl (S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (29 mg, 0.065 mmol) in 1 M LiOH (0.65 ml) and MeOH (0.65 ml) 65 ml) was heated at 50°C for 2 hours was Added 1M citric acid (1 ml) and the resulting reaction mixture was evaporated to dryness. The resulting residue was purified by reverse phase chromatography (5-90% CH ₃ CN/H ₂ O (0.1% formic acid)) to give (S)-6-(tert-butyl)-2-(hydroxymethyl)-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9 -carboxylic acid (18.5 mg, 68%) as a white solid. ¹ H ЯМР (400 MHz, CDCl ₃ ) δ ppm 15,96 (s, 1Н), 8,49 (s, 1Н), 7,74 (s, 1Н), 7,02 (s, 1Н), 4,79 (d, J=4,4 Hz, 2H), 4,14-4,27 (m, 2H), 4,10 (d, J=6,3 Hz, 1H), 3,90 (t, J=4,9 Hz, 1H), 3,62-3,53 (m, 3H), 3,37 (s, 3H), 3,29 (d, J=17,1 Hz, 1H), 2,13 (quin, J=5,9 Hz, 2H), 0,86 (s, 9H); LCMS (m/z, ES-) = 415.3 (M-1).

[00605] Example 25: (Compound 244)

[00606] (S)-6-(tert-Butyl)-2-cyclopropyl-11-hydroxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00607] Step 1: Ethyl 4-(benzyloxy)-2-((dimethylamino)methylene)-3-oxobutanoate

[00608] DMF-DMA (5.70 ml, 42.5 mmol) was added to a solution of ethyl 4-(benzyloxy)-3-oxobutanoate (6.70 g, 28.4 mmol) in toluene (30 ml) and the resulting reaction mixture was agitated overnight and evaporated to dryness. The resulting residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give ethyl 4-(benzyloxy)-2-((dimethylamino)methylene)-3-oxobutanoate (6.78 g, 82%) as a yellow oil. LCMS (m/z, ES+) = 292.6 (M+1).

[00609] Step 2: Ethyl 5-(benzyloxy)-4-oxo-4H-pyran-3-carboxylate

[00610] Ethyl formate (10.2 ml, 126 mmol) was slowly added to a suspension of potassium tert-butoxide (3.54 g, 31.6 mmol) in 24 ml THF at 0°C. After the addition was complete, the resulting reaction mixture was agitated for an additional 15 min at 0° C. and a solution of ethyl 4-(benzyloxy)-2-((dimethylamino)methylene)-3-oxobutanoate (4.6 g, 15.8 mmol) in 24 mL of THF was added dropwise using an additional funnel. After the addition was complete, the resulting reaction mixture was removed from the ice bath and stirred at room temperature overnight. Added 1 M HCl (50 ml) and the specified solution was extracted with EtOAc (2x). The combined organic phases were dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give ethyl 5-(benzyloxy)-4-oxo-4H-pyran-3-carboxylate (1.48 g, 34%) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.41 (s, 1H), 7.55 (s, 1H), 7.32-7.43 (m, 5H), 5.12 (s, 2H), 4.37 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H); LCMS (m/z, ES+) = 275.5 (M+1).

[00611] Step 3: (S)-Ethyl-5-(benzyloxy)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbugan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate

[00612]

[00613] A solution of the indicated (S)-1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-2-amine, hydrochloric acid (0.402 g, 0.87 mmol) and ethyl 5-(benzyloxy)-4-oxo-4H-pyran-3-carboxylate (0.38 g, 1.37 mmol) ol) in HOAc (8.7 ml) was shaken at 100°C for 10 h. The resulting reaction mixture was evaporated to dryness, taken up in CH ₂ Cl ₂ and saturated NaHCO ₃ and stirred for 1 h. This aqueous phase was extracted with CH ₂ Cl ₂ and EtOAc (2x). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and evaporated. The resulting precipitate was dissolved in EtOH (8 ml) and heated at 80° C. overnight. The resulting reaction mixture was evaporated to dryness and the resulting residue was purified by reverse phase chromatography (5-100% CH ₃ CN/H ₂ O (0.1% formic acid)) to give ethyl-(S)-5-(benzyloxy)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan- 2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (89.8 mg, 15%) as a brown solid. LCMS (m/z, ES+) = 683.7, 685.7 (M+1).

[00614] Step 4: (S)-Ethyl-11-(benzyloxy)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate

[00615] Flask containing ethyl-(S)-5-(benzyloxy)-1-(1-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-digadropyridine-3-carboxylate (89.8 mg, 0.13 mmol), potassium acetate (26 mg, 0.26 mmol) and palladium (II) bromide (7.0 mg, 0.03 mmol) were purged with nitrogen. Degassed DMF (1.3 ml) was added and the resulting reaction mixture was heated at 90° C. for 24 hours. The resulting reaction mixture was filtered through celite, the indicated solvent was removed by evaporation, and the resulting precipitate was purified by silica gel chromatography (0-100% 3:1 (EtOAc/EtOH) in hexanes) to give ethyl-(S)-11-(benzyl hydroxy)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (47.9 mg, 66%) as a brown oil. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,15 (s, 1H), 7,73 (d, J=6,2 Hz, 2H), 7,28-7,36 (m, 3H), 6,94 (s, 1H), 5,26 (br. s., 2H), 4,35 (q, J=6,4 Hz, 2H), 4,21-4,10 (m, 2H), 3,82-3,92 (m, 1H), 3,56-3,67 (m, 2H), 3,46-3,37 (m, 1H), 3,39 (s, 3H), 2,98 (d, J=16,0 Hz, 1H), 2,13 (quin, J=5,9 Hz, 2H), 1,40-1,31 (m, 3H), 0,71 (s, 9H); LCMS (m/z, ES+) = 555.4, 557.3 (M+1).

[00616] Step 5: (S)-Ethyl-11-(benzyloxy)-6-(tert-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate

[00617]

[00618] Ethyl (S)-11-(benzyloxy)-6-(tert-butyl)-2-chloro-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate solution (47.9 mg, 0.086 mmol), Pd(PPh ₃ ) ₄ (20 mg, 0.017 mmol), potassium carbonate (36 mg, 0.26 mmol) and cyclopropylboronic acid (15 mg, 0.17 mmol) in 1,4-dioxane (0.9 ml) were heated at 100° C. for 2 days. The resulting reaction mixture was diluted with CH ₂ Cl ₂ and filtered through celite. The resulting filtrate was evaporated and the resulting residue was purified by reverse phase chromatography (5-100% CH ₃ CN/H ₂ O (0.1% formic acid)) to give (S)-ethyl-11-(benzyloxy)-6-(tert-butyl)-2-cyclopropyl-3-(3-methoxypropoxy)-10-oxo-6,10-dihydro-5H-pyrido[ 1,2-h][1,7]naphthyridine-9-carboxylate (14.7 mg, 30%) as a white solid. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 8,18 (s, 1Н), 7,66 (d, J=7,0 Hz, 2H), 7,27-7,20 (m, 3H), 6,82 (s, 1H), 5,45 (d, J=10,9 Hz, 1H), 5,21 (d, J=10,9 Hz, 1H), 4,46-4,38 (m, 2H), 4,04-4,20 (m, 2H), 3,89 (d, J=5,5 Hz, 1H), 3,65-3,56 (m, 2H), 3,38 (s, 3H), 3,30 (dd, J=16,0, 6,2 Hz, 1H), 3,03 (d, J=16,0 Hz, 1H), 2,39-2,49 (m, 1H), 2,13 (quin, J=6,1 Hz, 2H), 1,42 (t, J=7,2 Hz, 3H), 1,07-1,15 (m, 1H), 0,96-1,04 (m, 1H), 0,88-0,96 (m, 1H), 0,80-0,86 (m, 1H), 0,77 (s, 9H); LCMS (m/z, ES+) = 561.8 (M+1).

[00619] Step 6: (S)-6-(tert-Butyl)-2-cyclopropyl-11-hydroxy-3-(3-methoxypropoxy)-10-oxo-5,10-digadro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00620] A solution of ethyl (S)-11-(benzyloxy)-6-(tert-butyl)-2-vdpsopropyl-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (14.7 mg, 0.026 mmol) and 10% P d/C (catalytic) in MeOH (5 ml) was shaken in 1 atm H ₂ for 1.5 h. The resulting reaction mixture was filtered through celite and evaporated to dryness. The resulting precipitate was taken up in MeOH (0.5 ml) and 1M LiOH (0.5 ml) and the indicated solution was heated at 50°C for 2 hours. 1M citric acid (1.5 ml) was added, the indicated mixture was evaporated to dryness and the resulting precipitate was purified using reverse phase chromatography (5-90% CH ₃ CN/H ₂ O (0.1% formic acid)) to obtain ( S)-6-(tert-butyl)-2-cyclopropyl-11-hydroxy-3-(3-methoxypropoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (6.3 mg, 54%) as a white solid. ¹ Н ЯМР (400 MHz, CDCl ₃ ) δ ppm 15,79 (s, 1Н), 13,96 (s, 1Н), 8,28 (s, 1Н), 7,08 (s, 1Н), 4,25-4,16 (m, 2Н), 4,06 (d, J=6,3 Hz, 1H), 3,58-3,69 (m, 2H), 3,51 (dd, J=17,1, 6,8 Hz, 1H), 3,39 (s, 3H), 3,25 (d, J=17,1 Hz, 1H), 2,49-2,59 (m, 1H), 2,18 (quin, J=6,1 Hz, 2H), 1,06-1,19 (m, 4H), 0,84 (s, 9H); LCMS (m/z, ES+) = 443.7 (M+1).

[00621] General scheme 7 to obtain compounds such as Examples 26, 27

[00622] Specific Synthesis Scheme 8 for Compounds of Example 26.2

[00623] Example 26: (Compound 245)

[00624] (2-Chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid - Isomer-1

[00625] Example 27: (Compound 246)

[00626] (2-Chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid - Isomer-2

[00627] Stage 1: Methyl 6-chloro-5-hydroxynicotinate

[00628] To a solution of methyl 5-hydroxynicotinate (100 g, 0.65 mol) in DMF (1000 ml), NCS (130.5 g, 0.97 mol) was added and the resulting reaction mixture was heated to 80°C for 16 hours. The resulting reaction mixture was cooled to room temperature and the indicated solvent was removed under reduced pressure. The resulting precipitate was taken up in EtOAc (2L) and washed with saturated sodium chloride solution (500 ml). The specified organic phase was dried over Na ₂ SO ₄ and concentrated. This crude product was purified using a 230-400 silica gel column chromatography using 0-30% ethyl acetate in petroleum ether as eluent. Fractions were collected and concentrated to give the title compound as a yellow oil (60 g, 49% yield), LCMS (ESI) m/z 187.9 (M+1).

[00629] Step 2: 2-Chloro-5-(hydroxymethyl)pyridin-3-ol

[00630] A solution of methyl 6-chloro-5-hydroxynicotinate (60 g, 0.32 mol) in THF (600 ml) was added dropwise to lithium aluminum hydride (160 ml, 0.32 mol, 2.0 M in THF) at -50°C under nitrogen atmosphere. The resulting reaction mixture was agitated at -25°C for 2 hours. EtOAc (1000 ml), water (50 ml) and saturated aqueous sodium and potassium tartrate solution (500 ml) were added to the resulting reaction mixture dropwise at -25°C. This mixture was filtered through a Celite pad, washed with 20% MeOH in DCM (500 ml). The resulting filtrate was concentrated under reduced pressure to give the title compound (40 g, 80% yield) as an off-white solid. LCMS (ESI) m/z 157.9 (M-H).

[00631] Step 3: 2-Chloro-5-(hydroxymethyl)-6-iodopyridin-3-ol

[00632] To a solution of 2-chloro-5-(hydroxymethyl)pyridin-3-ol (3.5 g, 22.01 mmol) in THF (35 ml) was added water (35 ml), K ₂ CO ₃ (6.1 g, 44.24 mmol) and iodine (5.84 g, 23.11 mmol) and the resulting reaction mixture was agitated at room temperature for 2 hours. The mixture was cooled to 0°C and quenched with an aqueous solution of sodium sulfate (50 ml). Ethyl acetate (150 ml) was added thereto, the organic layer was separated and discarded. The specified aqueous phase was acidified with 1.5 N aqueous HCl solution to pH=6 and was extracted with ethyl acetate (150 ml). The specified organic phase was separated, washed with water (25 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure to give the title compound as a greyish solid (4 g, 64.5% yield). LCMS (ESI) m/z: 283.7 (M-H).

[00633] Stage 4: (6-Chloro-2-iodo-5-methoxypyridin-3-yl)methanol

[00634] To a solution of 2-chloro-5-(hydroxymethyl)-6-iodopyridin-3-ol (4 g, 14.03 mmol) in acetonitrile (50 ml), was added K ₂ CO ₃ (3.87 g, 28.06 mmol) and methyl iodide (Mel) (5.97 g, 42.10 mmol) and the resulting reaction mixture was heated to 80°C for 2 hours in a sealed tube. The resulting reaction mixture was quenched with water (100 ml), acidified with 1.5N HCl (pH=6) and extracted with ethyl acetate (150 ml). The specified organic phase was washed with saline, dried over Na ₂ SO ₄ and concentrated. The crude material was purified using a 230-400 silica gel column chromatography using 0-30% ethyl acetate in petroleum ether as eluent. Fractions were collected and concentrated to give the title compound as a greyish solid (3.3 g, 80% yield). LCMS (ESI) m/z: 299.8 (M+1).

[00635] Step 5: 3-(Brommegyl)-6-chloro-2-iodo-5-methoxypyridine

[00636] To a solution of (6-chloro-2-iodo-5-methoxypyridin-3-yl)methanol (2.2 g, 7.35 mmol) in DCM (20 ml) was added CBr ₄ (3.6 g, 11.35 mmol) and PPh ₃ (2.3 g, 8.82 mmol) in THF (20 ml). The resulting reaction mixture was agitated at room temperature for 6 hours. The solvent was removed under reduced pressure to give a crude product. It was purified using a 60-120 mesh silica gel column chromatography using 0-20% EtOAc in petroleum ether as eluent. Fractions were collected and concentrated to give the title compound as a greyish solid (2.4 g, 92% yield). LCMS (ESI) m/z: 363.6 (M+H).

[00637] Step 6: Ethyl 2-((6-chloro-2-iodo-5-methoxypyridin-3-yl)methyl)-2,3-dimethylbutanoate

[00638] To a solution of diisopropylamine (2.43 ml, 17.38 mmol) in dry THF (20 ml) was added n-BuLi (10.86 ml, 17.38 mmol, 1.6 M in hexane) dropwise at -78°C. The resulting reaction mixture was agitated at the same temperature for 30 minutes. Ethyl 2,3-dimethylbutanoate (2.3 g, 16.57 mmol) in THF (20 ml) was added to the resulting reaction mixture, and the resulting reaction mixture was agitated at -78°C for 1 h. ) and the resulting reaction mixture was warmed to room temperature and stirred at room temperature for 1 h. The resulting reaction mixture was cooled to 0°C, quenched with saturated NH ₄ Cl solution (50 ml), diluted with water (20 ml) and extracted with EtOAc (3×50 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ and filtered. The solvents were removed under reduced pressure to give the crude product. This crude product was purified using a 230-400 mesh silica gel column chromatography using 0-10% EtOAc in petroleum ether as eluent. Fractions were collected and concentrated to give the title compound as a yellow oil (3 g, 85% yield). LCMS (ESI) m/z: 426 (M+H).

[00639] Step 7: 2-((6-Chloro-2-iodo-5-methoxypyridin-3-yl)methyl)-2,3-dimethylbutyric acid

[00640] To a solution of ethyl 2-((6-chloro-2-iodo-5-methoxypyridin-3-yl)methyl)-2,3-dimethylbutanoate (3 g, 7.05 mmol) in DMSO (9 ml) was added a solution of 5 M NaOH (21.6 ml, 98.11 mmol) and the resulting reaction mixture was agitated at 120°C for 6 hours. the mixture was cooled to 0°C, acidified with concentrated HCl to pH=1. After dilution with water (50 ml) it was extracted with EtOAc (2×100 ml). The combined organic phases were washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ and filtered. The indicated solvent was removed under reduced pressure to obtain the indicated crude product. This crude product was purified using a 230-400 silica gel column chromatography using 0-10% MeOH in DCM to give 2-((6-chloro-2-iodo-5-methoxypyridin-3-yl)methyl)-2,3-dimethylbutyric acid (500 mg, 18% yield) (LCMS (ESI) m/z: 397.8 (M+1)).

[00641] Step 8: 1-(6-Chloro-2-iodo-5-methoxypyridin-3-yl)-2,3-dimethylbutan-2-amine

[00642] To a solution of 2-((6-chloro-2-iodo-5-methoxypyridin-3-yl)methyl)-2,3-dimethylbutyric acid (1 g, 2.5 mmol) in toluene (30 ml) was added tristylamine (0.57 g, 5.5 mmol) and diphenyl phosphoryl azide (1.52 g, 5.5 mmol) and the resulting reaction mixture was shaken at 80°C for 2 hours. The resulting reaction mixture was cooled to room temperature and concentrated. HCl (8.4 ml) was added to the resulting reaction mixture dropwise over 30 min at 0°C. The resulting reaction mixture was agitated at 60°C for 2 hours. The resulting reaction mixture was cooled to 0°C and made basic with 1N NaOH aqueous solution to pH=10. The resulting reaction mixture was diluted with water (20 ml) and was extracted with EtOAc (2×50 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a brown rubbery solid. It was purified using a 230-400 silica gel column chromatography using 0-3% MeOH in DCM to give the title compound as a yellow oil (800 mg, 87% yield). LCMS (ESI) m/z: 368.8 (M+1).

[00643] Step 9: Ethyl 1-(1-(6-chloro-2-iodo-5-methoxypyridin-3-yl)-2,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate

[00644] To a solution of 1-(6-chloro-2-iodo-5-methoxypyridin-3-yl)-2,3-dimethylbutan-2-amine (800 mg, 2.17 mmol) in acetic acid (25 ml) was added ethyl 4-oxo-4H-pyran-3-carboxylate (0.547 g, 3.2 mmol) and the resulting reaction mixture was shaken at 100°C for 8 hours The resulting reaction mixture was cooled to room temperature. This solvent was removed under reduced pressure and the resulting residue was purified using a 230-400 silica gel column chromatography using 0-10% MeOH in DCM as eluent. Fractions were collected and concentrated to give the title compound (400 mg, 35% yield) as a brown solid. LCMS (ESI) m/z: 518.7 (M+1).

[00645] Step 10: Ethyl 2-chloro-6-isopropyl-3-methoxy-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate

[00646] To a solution of ethyl 1-(1-(6-chloro-2-iodo-5-methoxypyridin-3-yl)-2,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (300 mg, 0.57 mmol) in N,N-dimethylformamide (7.5 ml) was added potassium acetate (283 mg, 2.89 mmol). The resulting reaction mixture was degassed with nitrogen for 20 minutes. Palladium (II) bromide (30 mg, 0.11 mmol) was added to the resulting reaction mixture was agitated at 90° C. for 16 h. The resulting reaction mixture was cooled to room temperature, filtered through celite and washed with DCM. This solvent was removed under reduced pressure and the crude material was purified using a 230-400 silica gel column chromatography using 0-10% MeOH in DCM as eluent. Fractions were collected and concentrated to give the title compound (150 mg, 68% yield) as a brown solid. LCMS (ESI) m/z: 390.9 (M+1).

[00647] Step 11: 2-Chloro-3-hydroxy-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00648] To a solution of ethyl 2-chloro-6-isopropyl-3-methoxy-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (150 mg, 0.38 mmol) in 1,2-dichloroethane (DCE) (6.45 ml) was added BBr ₃ (288 mg , 1.15 mmol) and the resulting reaction mixture was agitated at 70°C for 16 hours. The resulting reaction mixture was cooled to -10°C, methanol (15 ml) was added dropwise to the reaction mixture, and then stirred at room temperature for 30 minutes. The resulting reaction mixture was concentrated to give the crude compound (150 mg) as a brown solid. LCMS (ESI) m/z: 348.9 (M+1). This crude product was used in the next Step.

[00649] Step 12: Methyl 2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate-Isomer-1 and methyl-2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5 ,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate - Isomer-2

[00650] To a solution of 2-chloro-3-hydroxy-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (150 mg, 0.43 mmol) in DMF (2 ml) was added K ₂ CO ₃ (594 mg, 4.3 mmol) and (bromomethyl )cyclopropane (464 mg, 3.44 mmol) and the resulting reaction mixture was agitated at 80°C for 5 h. The resulting reaction mixture was cooled to room temperature, the indicated solvent was removed under reduced pressure, and the resulting precipitate was agitated with MeOH (10 ml) at room temperature for 30 min. The solvent was removed under reduced pressure and diluted with DCM (20 ml). The organic layer was washed with water (15 ml) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a mixture of isomers, which were separated by chiral supercritical mobile phase chromatography (SFC). The resulting fractions of Isomer-1 (first elution peak) and Isomer-2 (second elution peak) were concentrated under reduced pressure to give methyl 2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate - Isomer-1 (50 mg, 2 8% yield) as a greyish solid LCMS (ESI) m/z: 417.9 (M+1) and methyl 2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate - Isomer-2 (50 mg, 28% yield) as grayish solid. LCMS (ESI) m/z: 417.9 (M+1).

[00651] Stage 13: (2-Chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid - Isomer-1

[00652] To a solution of methyl 2-chloro-3-(cyclopropylmethoxy)-6-isogfopyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate - Isomer-1 (50 mg, 0.11 mmol) in methanol (2 ml) and H ₂ O (0.5 ml) was added lithium hydroxide (25 mg, 0.59 mmol) and the resulting reaction mixture was agitated at room temperature for 2 hours. The indicated solvent was removed under reduced pressure and the resulting precipitate was dissolved in water (3 ml) and acidified with 1.5 N HCl to pH~3. The resulting solid was filtered off, washed with water (5 ml), dried in vacuo and purified by prep-HPLC to give the title compound (15 mg, 31.2% yield) as a greyish solid. LCMS (ESI) m/z: 403.1 (M+1). ¹ H NMR; 400 MHz, DMSO-d6: δ ppm 8.57 (s, 1H), 7.72 (s, 1H), 7.39 (s, 1H), 4.10-4.07 (m, 2H), 3.36-3.35 (m, 2H), 1.91-1.84 (m, 1H), 1.70 (s, 3H), 1.3 5-1.25(m, 1H), 0.85-0.82(m, 3H), 0.65-0.63(m, 5H), 0.42-0.39(m, 2H).

[00653] Stage 13 A: 2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid - Isomer-2

[00654] To a solution of methyl 2-chloro-3-(cyclopropylmethoxy)-6-isopropyl-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate - Isomer-2 (50 mg, 0.11 mmol) in methanol (2 ml) and H ₂ O (0.5 ml) was added hydroxide lithium (25 mg, 0.59 mol) and the resulting reaction mixture was agitated at room temperature for 2 hours. The indicated solvent was removed under reduced pressure and the resulting precipitate was dissolved in water (3 ml) and acidified with 1.5 N HCl to pH~3. The resulting solid was filtered off, washed with water (5 ml), dried under vacuum for 16 h to give the title compound as a greyish solid (30 g, 62% yield). LCMS (ESI) m/z: 402.9 (M+1). ¹ H NMR; 400 MHz, DMSO-d6: δ ppm 8.57 (s, 1H), 7.71 (s, 1H), 7.39 (s, 1H), 4.09-4.08 (m, 2H), 3.39-3.38 (m, 2H), 1.90-1.87 (m, 1H), 1.70 (s, 3H), 1.3 2-1.28 (m, 1H), 1.11-1.07 (m, 3H), 0.83-0.81 (m, 5H), 0.63-0.62 (m, 2H).

[00655] Example 28: (Compound 247)

[00656] 2-Cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid - Isomer-1

[00657] Example 29: (Compound 248)

[00658] 2-Cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid - Isomer-2

[00659] General Synthesis Scheme 9 for Compounds such as Example 28, 29:

[00660] Specific Synthesis Scheme 10 for Compounds of Example 28, 29:

[00661] Stage 1: Methyl 2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate - Isomer-1 and methyl-2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl- 10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate - Isomer-2

[00662] To a stirred solution of methyl 2-chloro-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (570 mg, 1.311 mmol) in 1,4-dioxane (11.4 ml) was added potassium carbonate (362 mg, 2.62 mmol) and purged with nitrogen for 5 min. Cyclopropylboronic acid (225 mg, 2.62 mmol) was added followed by Pd(PPh ₃ ) ₄ (303 mg, 0.262 mmol) and purged with nitrogen for 5 minutes. The resulting reaction mixture was heated to 100°C in a sealed tube for 16 hours. The resulting reaction mixture was concentrated completely under reduced pressure and the resulting precipitate was diluted with DCM (100 ml), washed with water (40 ml), brine (40 ml). The indicated organic phase was separated, dried over sodium sulfate, concentrated and the crude material was purified using Isolera™ silica gel chromatography and eluted with 3% MeOH in DCM. The collected fractions were concentrated completely to give the title compound as a mixture of isomers. This compound was then purified by preparative HPLC followed by chiral SFC. The collected fractions of Isomer-1 (first elution peak) and Isomer-2 (second elution peak) were concentrated separately under reduced pressure to give methyl 2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate - Isomer-1 (60 mg, 10.3% yield) as a colorless oil and methyl 2-cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate - Isomer-2 (90 mg, 13.97% yield) as a colorless oil. LCMS (ESI) m/z: 441.0 (M+1).

[00663] Stage 2: 2-Cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid - Isomer-1

[00664] Li OH (16.31 mg, 0.681 mmol) and water (0.60 ml) and the resulting reaction mixture was agitated at room temperature for 2 hours. The solvents from the resulting reaction mixture were removed under reduced pressure, and the resulting precipitate was dissolved in water (2 ml). This solution was acidified with 1.5 N HCl to pH 6 at 0°C. The resulting solid was filtered off, washed with water, n-pentane and dried to give the title compound as a pale brown solid (15 mg, 25.3%). LCMS (ESI) m/z: 427.2 (M+1). ¹ H NMR (400 MHz, DMSO-d6): δ ppm 8.54 (s, 1H), 7.44 (s, 2H), 4.19-4.18 (m, 2H), 3.53 (t, J=6 Hz, 2H), 3.29-3.27 (m, 5H), 2.05 (t, J=6 Hz, 2H), 1.8 4-1.82 (m, 1H), 1.68 (s, 3H), 1.03-1.01 (m, 4H), 0.82 (d, J=6.5 Hz 3H), 0.61 (d, J=6.6 Hz, 3H)

[00665] Stage 2A: 2-Cyclopropyl-6-isopropyl-3-(3-methoxypropoxy)-6-methyl-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid - Isomer-2

[00666] LiOH (2 4.46 mg, 1.021 mmol) and water (0.90 ml), and the resulting reaction mixture was agitated at room temperature for 2 hours. The solvents from the resulting reaction mixture were removed under reduced pressure, and the resulting precipitate was dissolved in water (2 ml). This solution was acidified with 1.5 N HCl to pH 6 at 0°C. The resulting solid was filtered off, washed with water, n-pentane and dried to give the title compound as a pale brown solid (26 mg, 29.3%). LCMS (ESI) m/z: 427.2 (M+1). ¹ H NMR (400 MHz, DMSO-d6): δ ppm 8.53 (s, 1H), 7.44 (s, 2H), 4.25-4.12 (m, 2H), 3.56-3.52 (m, 2H), 3.23-3.18 (m, 5H), 2.10-2.01 (m, 3H), 1.81- 1.62 (m, 4H), 1.05-0.99 (m, 4H), 0.85-0.81 (m, 3H), 0.65-0.61 (m, 3H).

[00667] General scheme 11 - Obtaining the type of compounds, such as Compound 249

[00668] Compound 249 can be prepared according to the general synthetic procedure described in Scheme 11 above and as described in more detail below.

[00669] Example 30 (Compound 249 (racemate))

[00670] 6-(tert-Butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00671] Step 1: 1-(6-Chloro-5-methoxytfidin-3-yl)-3,3-dimethylbutan-2-one

[00672] A stirrer, xanthos (0.225 g, 0.388 mmol), tris(dibenzylideneacetone) dipalladium(0) (0.198 g, 0.216 mmol), and sodium tert-butoxide (2.43 g, 25.3 mmol) were placed in the flask. This flask was purged with a stream of nitrogen before adding a solution of 5-bromo-2-chloro-3-methoxypyridine (3.2 g, 14.4 mmol) and 3,3-dimethylbutan-2-one (2.16 ml, 17.3 mmol) in tetrahydrofuran (THF) (50 ml). This mixture was heated at reflux overnight. This mixture was allowed to cool to room temperature and diluted with water. This mixture was extracted 3 times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, concentrated to give 1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one (3.07 g, 12.7 mmol, 88% yield). ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.74 (d, J=1.56 Hz, 1H), 7.10 (d, J=1.56 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 2H), 1.20 (s, 9H).

[00673] Step 2: 1-(6-Chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amine

[00674] A mixture of 1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-one (3.07 g, 12.7 mmol) and ammonium acetate (14.7 g, 191 mmol) in methanol (50 mL) was stirred for 1 hour at room temperature before sodium cyanoborohydride (2.00 g, 31.8 mmol) was added in batches ol). This mixture was agitated over the weekend at room temperature and then made basic with 1M sodium hydroxide. This mixture was extracted 3 times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, concentrated to give 1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amine (2.82 g) as a clear oil. The resulting material was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/0% to 100% gradient). The fractions were combined, made basic with 1M sodium hydroxide and extracted 3 times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, concentrated to give 1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amine (1.45 g, 5.97 mmol, 47.0% yield) as a clear oil. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.83 (d, J=1.56 Hz, 1H), 7.08 (d, J=1.56 Hz, 1H), 3.90 (s, 3H), 2.91 (dd, J=13.48,2.15 Hz, 1H), 2.62 (dd, J=10.94, 1.95 Hz, 1H), 2.22 (dd, J=13.48, 11.13 Hz, 1H), 1.12-1.36 (m, 2H), 0.98 (s, 9H).

LCMS(ES ⁺ )(w/z): 243, 245 (M+1).

[00675] Step 3: 5-(2-Amino-3,3-dimethylbugyl)-2-chloropyridin-3-ol

[00676] Boron tribromide (2.82 ml, 29.9 mmol) was added dropwise to a solution of 1-(6-chloro-5-methoxypyridin-3-yl)-3,3-dimethylbutan-2-amine (1.45 g, 5.97 mmol) in 1,2-dichloroethane (DCE) (30 ml) at 0°C. This mixture was allowed to warm to room temperature and stirred overnight. The LC-MS data showed significant conversion to the desired product, however starting material was still present. The solid fraction that formed during the night was crushed and the specified mixture was stirred for an additional 24 hours at room temperature. This mixture was cooled to 0° C. and carefully quenched by dropwise addition of methanol. After the excess BBr ₃ was completely quenched, additional methanol (100 ml) was added. This mixture was shaken for 1 hour and concentrated. The resulting precipitate was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/0% to 100% gradient). Fractions were lyophilized to give 5-(2-amino-3,3-dimethylbutyl)-2-chloropyridin-3-ol (1.33 g, 5.81 mmol, 97% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.21 (s, 1H), 7.83-8.16 (m, 2H), 7.74 (d, J=1.95 Hz, 1H), 7.21 (d, J=1.56 Hz, 1H), 2.82-3.02 (m, 2H), 2.35-2, 43 (m, 1H), 0.94 (s, 9H). LCMS(ES ⁺ )(m/z): 229.231 (M+1).

[00677] Step 4: tert-Butyl (1-(6-chloro-5-hydroxygofidin-3-yl)-3,3-dimethylbutan-2-yl)carbamate

[00678] Di-Trett-Buldicarbonate (1.52 g, 6.98 mmol) added to the mixed mixture of 5- (2-amino-3.3-deimethylbutil) -2-chlorgophydine-3-ola (1.33 g, 5.81 mmol) and trieylamine (2.43 ml, 17.4 mmol) in n-dimensamy (DM (DM DM) F) (30 ml). This mixture was agitated at room temperature for 1 hour. LC-MS data showed minimal conversion. This solid fraction did not completely dissolve. Added tetrahydrofuran (THF) (50 ml) and the specified solid fraction went into solution. This mixture was agitated for 2 hours, concentrated and the resulting residue was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). The fractions were concentrated and then the resulting precipitate was lyophilized (acetonitrile/water) to give tert-butyl-(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate (1.04 g, 3.16 mmol, 54.4% yield). ¹ H NMR (400 MHz, Temp.=80°C, DMSO-d ₆ ) δ ppm 9.81-10.14 (m, 1H), 7.68 (d, J=1.56 Hz, 1H), 7.15 (d, J=1.56 Hz, 1H), 6.13-6.46 (m, 1H), 3.24-3.4 6 (m, 1H), 2.76 (dd, J=14.05,2.34 Hz, 1H), 2.31-2.42 (m, 1H), 1.21 (br. s., 9H), 0.91 (s, 9H). LCMS(ES ⁺ )(/n/z): 329, 331 (M+1).

[00679] Step 5: tert-Butyl-(1-(2-bromo-6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbugan-2-yl)carbamate

[00680] Under nitrogen atmosphere, a solution of N-bromosuccinimide (471 mg, 2.65 mmol) in 2 ml of DMF was slowly added dropwise to a solution of tert-butyl-(1-(6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl) carbamate (791 mg, 2.405 mmol) in N ,N-dimethylformamide (DMF) (25 ml) and this mixture was stirred in the reaction vial, which was protected from light with aluminum foil. The temperature of the cooling bath was maintained between -25°C and -20°C for 30 minutes. This mixture was allowed to warm to room temperature and stirred overnight. This mixture was quenched with water and extracted 3 times with ethyl acetate. The combined organic phases were washed with brine and concentrated. The resulting precipitate was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 60% gradient, then 60% isocratic, then 60% to 100% gradient). Fractions were concentrated to give tert-butyl (1-(2-bromo-6-chloro-5-hydroxy-shridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate (485 mg, 1.19 mmol, 49.5% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.81 (br. s., 1H), 7.23 (s, 1H), 6.60 (d, J=10.15 Hz, 1H), 3.35-3.50 (m, 1H), 2.73-2.89 (m, 1H), 2.18-2.37 ( m, 1H), 1.15 (s, 9H), 0.83-0.91 (m, 9H). LCMS(ES ⁺ )(m/z): 407, 409, 411 (M+1).

[00681] Step 6: 1-(2-Bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbutan-2-amine

[00682] (Bromomethyl)cyclopropane (0.231 ml, 2.38 mmol) was added to a stirred mixture of tert-butyl-(1-(2-bromo-6-chloro-5-hydroxypyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate (485 mg, 1.19 mmol) and potassium carbonate (658 mg, 4.76 mmol) in N,N -dimethylformamide (DMF) (5 ml). This mixture was shaken at room temperature overnight. This mixture was quenched with water and extracted 2 times with ethyl acetate. The combined organic phases were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate, concentrated to give crude tert-butyl (1-(2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbutan-2-yl)carbamate. This intermediate was dissolved in dichloromethane (DCM) (5.00 ml) before hydrochloric acid (4M in dioxane) (5 ml, 20 mmol) was added. This mixture was agitated for 4 hours, concentrated to give a white solid. Saturated sodium bicarbonate solution was added and the mixture was extracted 2 times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated to give 1-(2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbutan-2-amine (423 mg, 1.17 mmol, 98% yield) as a clear oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.62 (s, 1H), 3.96 (d, J=7.03 Hz, 2H), 2.89 (dd, J=12.88, 1.95 Hz, 1H), 2.43-2.46 (m, 1H), 2.20-2.33 (m, 1H), 1.19-1.36 (m, 3H), 0.92 (s, 9H), 0.52-0.66 (m, 2H), 0.26-0.42 (m, 2H). LCMS(ES ⁺ )(m/z): 361, 363, 365 (M+1).

[00683] Step 7: Ethyl 1-(1-(2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-33-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate

[00684] 1-(2-Bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbutan-2-amine (375 mg, 1.04 mmol) and ethyl 4-oxo-4H-pyran-3-carboxylate (174 mg, 1.04 mmol) in acetic acid (10 ml) were stirred at 100°C for 4 hours. This mixture was allowed to cool to room temperature and concentrated. The resulting precipitate was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/0% to 100% gradient). The fractions were concentrated and the resulting precipitate was lyophilized (water/acetonitrile) to give ethyl 1-(1-(2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (420 mg, 0.821 mmol, 79% yield) as white powder. LCMS(ES ⁺ )(w/z): 511, 513, 515 (M+1).

[00685] Step 8: Ethyl 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate

[00686] Reaction vial containing stirrer, ethyl 1-(1-(2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate (395 mg, 0.772 mmol), potassium acetate (151 mg, 1.543 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (79 mg, 0.15 mmol) were purged with nitrogen for 15 minutes. N,N-Dimethylacetamide (DMA) (8 ml) was purged with nitrogen for 5 minutes before being added to this reaction mixture. This reaction vial was placed in a heating block preheated to 90° C. and this mixture was stirred overnight. The resulting reaction mixture was allowed to cool to room temperature, filtered through a cotton plug and purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). The fractions were concentrated and the resulting precipitate was azeotropically distilled with acetonitrile to remove any remaining water. The resulting residue was dissolved in dichloromethane and hexanes, then concentrated to give ethyl 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (140 mg, 0.325 mmol, 42.1% yield) as a pale -yellow solid. ¹ Н ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 8,38 (s, 1Н), 7,66 (s, 1Н), 6,90 (s, 1Н), 4,40 (d, J=6,25 Hz, 1H), 4,21 (q, J=7,03 Hz, 2H), 3,99-4,10 (m, 2H), 3,37-3,50 (m, 1H), 3,31-3,37 (m, 1H), 1,22-1,37 (m, 4H), 0,74 (s, 9H), 0,59-0,67 (m, 2H), 0,34-0,45 (m, 2H). LCMS(ES ⁺ )(m/z): 431, 433 (M+1).

[00687] Step 9: 6-(tert-Butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid

[00688] A solution of lithium hydroxide monohydrate (1.6 mg, 0.039 mmol) in water (1 mL) was added to a solution of ethyl 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dipso-5H-pyrido[1,2-11][1,7]naphthyridine-9-carboxylate (2.0 mg, 3.9 μmol) in methanol (1 ml) and the mixture was heated at 60° C. for 3 hours. This mixture was allowed to cool to room temperature and purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). The fractions were concentrated and the resulting residue was dried to give 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (1.2 mg, 2.9 µmol, 77% yield) as a white solid. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 8.70 (br. s., 1H), 7.54 (br. s., 1H), 7.47 (br. s., 1H), 4.44-4.55 (m, 1H), 3.97-4.14 (m, 2H), 3.39-3.61 (m, 2H), 1.33 (br. s., 1H), 1.12 (br. s., 1H), 0.83 (s, 9H), 0.63-0.71 (m, 2H), 0.34-0.50 (m, 2H). LCMS(ES ⁺ )(m/z): 403.405 (M+1).

[00689] Example 30-a (Compound 249 Isomer 1)

[00690] 6-(tert-Butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (isomer 1)

[00691] Step 1: Ethyl 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (isomer 1)

[00692] Ethyl 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-digadro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate racemate (153 mg) was purified by chiral chromatography using the following conditions: Column = Chiralpak IC, 10 mm × 250mm (5u); Mobile phase = 95:5 MeCN/H ₂ O + 0.1% formic acid; Flow rate = 10 ml/min: Injection volume = 300 µl (18 mg/ml concentration); Detection wavelength: 254 nm. Fractions were concentrated to give ethyl 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (isomer 1) (48 mg). LCMS(ES ⁺ )(m/z): 431.433 (M+1).

[00693] Stage 2: 6-(tert-Butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (isomer 1)

[00694] A solution of lithium hydroxide monohydrate (38.8 mg, 0.925 mmol) in water (2 ml) was added to a solution of ethyl 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (isomer 1) (4 8 mg, 0.092 mmol) in methanol (2 ml) and the mixture was heated at 60° C. for 3 hours. This mixture was cooled to room temperature and acidified with 3 ml of 1M hydrochloric acid. The solid fraction was collected by filtration. The resulting filtrate was injected into a medium pressure reverse phase chromatographic column. The collected solid was dissolved in DMF and injected into a reverse phase column. This column was eluted (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). Fractions were lyophilized to give 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (isomer 1) (33 mg, 0.082 mmol, 89% yield) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.75 (br. s., 1H), 7.66 (s, 1H), 7.24 (br. s., 1H), 4.55-4.68 (m, 1H), 3.93-4.10 (m, 2H), 3.39-3.54 (m, 2H), 1.27 (d, J=5.08 Hz, 1H), 0.70 (s, 9H), 0.55-0.62 (m, 2H), 0.30-0.39 (m, 2H). LCMS(ES ⁺ )(/w/z): 403.405 (M+1).

[00695] Example 30-b (Compound 249 Isomer 2)

[00696] 6-(tert-Butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6,10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (isomer 2)

[00697] Step 1: Ethyl 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (isomer 2)

[00698] Ethyl 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate racemate (153 mg) was purified by chiral chromatography using the following conditions: Column = Chiralpak IC, 10 mm x 2 50mm (5u); Mobile phase = 95:5 MeCN/H ₂ O + 0.1% formic acid; Flow rate = 10 ml/min: Injection volume = 300 µl (18 mg/ml concentration); Detection wavelength: 254 nm. Fractions were concentrated to give ethyl 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (isomer 2) (46 mg). LCMS(ES ⁺ )(m/z): 431.433 (M+1).

[00699] Stage 2: 6-(tert-Butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-6.10-dihydro-5H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (isomer 2)

[00700] A solution of lithium hydroxide monohydrate (37.2 mg, 0.886 mmol) in water (2 ml) was added to a solution of ethyl 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylate (isomer 2) (4 6 mg, 0.089 mmol) in methanol (2 ml) and the mixture was heated at 60° C. for 3 hours. This mixture was left to cool to room temperature and acidified with 3 ml of 1M hydrochloric acid. The solid fraction was collected by filtration. The resulting filtrate was injected into a medium pressure reverse phase chromatographic column. The collected solid was dissolved in DMF and also injected into the reverse phase column. This column was eluted (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). Fractions were lyophilized to give 6-(tert-butyl)-2-chloro-3-(cyclopropylmethoxy)-10-oxo-5,10-dihydro-6H-pyrido[1,2-h][1,7]naphthyridine-9-carboxylic acid (isomer 2) (34 mg, 0.084 mmol, 95% yield) as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.76 (s, 1H), 7.67 (s, 1H), 7.25 (s, 1H), 4.63 (d, J=6.64 Hz, 1H), 3.96-4.11 (m, 2H), 3.33-3.54 (m, 2H), 1.19 -1.33(m, 1H), 0.70(s, 9H), 0.56-0.62(m, 2H), 0.30-0.42(m, 2H). LCMS(ES ⁺ )(m/z): 403, 405 (M+1).

[00701] Scheme 12 - Preparation of Type YYYY Compounds (e.g. Compounds 250.251.255 and 256)

[00702] Example 31 (Compound 250)

2'-Chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid

[00703] Stage 1: 6-Bromo-2-chloro-5-methylpyridin-3-ol

[00704] 6-Bromo-5-methylpyridin-3-ol (10.4 g, 55.3 mmol) and NCS (8.12 g, 60.8 mmol) in N,N-dimethylformamide (DMF) (150 ml) were heated at 80°C for 2 hours. This mixture was allowed to cool to room temperature, quenched with brine and extracted 3 times with ethyl acetate. The combined organic phases were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate and concentrated. The resulting residue was purified by silica chromatography eluting with a gradient of 0% to 50% ethyl acetate in hexanes. The fractions were concentrated to give 6-bromo-2-chloro-5-methylpyridin-3-ol (7.85 g, 35.3 mmol, 63.8% yield) as a white powder. LCMS(ES ⁺ )(m/z): 222, 224, 226 (M+1).

[00705] Step 2: 2-Bromo-6-chloro-5-(cyclopropylmethoxy)-3-methylpyridine

[00706] 6-Bromo-2-chloro-5-methylpyridin-3-ol (1.1 g, 4.9 mmol), potassium carbonate (2.73 g, 19.8 mmol) and (bromomethyl)cyclopropane (1.01 ml, 10.4 mmol) in N,N-dimethylformamide (DMF) (10 ml) was stirred at room temperature overnight. This mixture was diluted with water and extracted 2 times with ethyl acetate. The combined organic phases were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate, concentrated to give 2-bromo-6-chloro-5-(cyclopropylmethoxy)-3-metaliridine (1.18 g, 4.27 mmol, 86% yield) as a white solid. LCMS(ES ⁺ )(m/z): 276, 278, 280 (M+1).

[00707] Step 3: 2-Bromo-3-(bromomethyl)-6-chloro-5-(cyclopropylmethoxy)pyridine

[00708] N-Bromosuccinimide (0.801 g, 4.50 mmol) and AIBN (0.049 g, 0.30 mmol) were added to a stirred solution of 2-bromo-6-chloro-5-(cyclopropylmethoxy)-3-methylpyridine (1.0 g, 3.0 mmol) in carbon tetrachloride (15 ml). This mixture was heated at 85°C for 5 hours. Additional AIBN (0.049 g, 0.300 mmol) was added and the mixture was allowed to warm overnight. This mixture was allowed to cool to room temperature and the solids were collected by filtration. The resulting filtrate was quenched with water and extracted 2 times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated. The resulting residue was purified by chromatography on silica eluting with 10% ethyl acetate in hexanes. Fractions were concentrated to give 2-bromo-3-(bromomethyl)-6-chloro-5-(cyclopropylmethoxy)pyridine (730 mg, 1.23 mmol, 60% purity, 41% yield). Said material was a ~60:40 mixture of the desired product/starting material. LCMS(ES ⁺ )(/w/z): 354, 356, 358 (M+1).

[00709] Step 4: Ethyl 1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutanecarboxylate

[00710] n-Butyl lithium (2.5 M in hexanes) (1.04 ml, 2.59 mmol) was added dropwise to a -78° C. cooled solution of diisopropylamine (0.369 ml, 2.59 mmol) in tetrahydrofuran (THF) (10 ml). This mixture was allowed to warm to room temperature and stirred for 15 minutes. This mixture was cooled to -78°C before adding ethylcyclobutanecarboxylate (0.317 ml, 2.46 mmol), which was added dropwise. This mixture was heated to 0° C. and stirred for 15 minutes. A solution of 2-bromo-3-(bromomethyl)-6-chloro-5-(cyclopropylmethoxy)pyridine (730 mg, 1.23 mmol) in tetrahydrofuran (THF) (3.33 ml) was added dropwise. This mixture was shaken for an additional 10 minutes at 0° C. and then quenched with saturated ammonium chloride. This mixture was extracted 2 times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated. The resulting precipitate was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). Fractions were concentrated to give ethyl 1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutan-1-carboxylate (350 mg, 0.869 mmol, 70.5% yield) as an oil. LCMS(ES ⁺ )(m/r): 402, 404, 406 (M+1).

[00711] Step 5: 1-((2-Bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutanecarboxylic acid

[00712] A solution of lithium hydroxide monohydrate (365 mg, 8.69 mmol) in water (3 mL) was added To a solution of ethyl 1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutan-1-carboxylate (350 mg, 0.869 mmol) in 1,4-dioxane (5 mL) and the mixture was heated at 60°C for 4 hours. This mixture was allowed to cool to room temperature, quenched with saturated ammonium chloride solution and extracted 3 times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, concentrated to give 1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutan-1-carboxylic acid (325 mg, 0.867 mmol, quantitative) as a white solid. LCMS(ES ⁺ )(m/z): 374, 376, 378 (M+1).

[00713] Step 6: 1-((2-Bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutanamine and 5-((1-aminocyclobutyl)methyl)-6-bromo-2-chloropyridin-3-ol

[00714] Diphenylphosphorazidate (0.394 ml, 1.83 mmol) was added dropwise to a stirred mixture of 1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutan-1-carboxylic acid (311 mg, 0.830 mmol) and triethylamine (0.255 ml, 1.83 mmol) in toluene (10 ml). This mixture was allowed to warm to room temperature and stirred for 15 minutes, then heated at 80° C. for 1 hour. LC-MS data showed a net conversion to 2-bromo-6-chloro-5-(cyclopropylmethoxy)-3-((1-isocyanatecyclobutyl)methyl)pyridine. This mixture was allowed to cool to room temperature before adding 5N hydrochloric acid (5 ml, 25 mmol) and 1,4-dioxane (10 ml). This mixture was heated at 80°C with vigorous shaking for 3 hours. This mixture was concentrated and the resulting residue was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). The two sets of fractions were concentrated separately to give the following products:

[00715] 5-((1-aminocyclobutyl)methyl)-6-bromo-2-chloropyridin-3-ol (170 mg, 0.583 mmol, 70.2% yield). LCMS(ES ⁺ )(m/z): 291, 293, 295 (M+1)

[00716] 1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutan-1-amine (50 mg, 0.145 mmol, 17.43% yield). LCMS(ES ⁺ )(/n/z): 345, 347, 349 (M+1).

[00717] Step 7: Ethyl 4-oxo-4H-pyran-3-carboxylate

[00718] Ethyl formate (23.6 ml, 292 mmol) was slowly added to a suspension of KOtBu (6.06 g, 54.0 mmol) in 50 ml THF at 0°C. The resulting reaction mixture was stirred for 15 min at 0°C and a pre-cooled (0°C) solution of ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (5 g, 27.0 mmol) in 45 ml THF was added via cannula. After the addition was complete, this solution was removed from the cooling bath, stirred at room temperature overnight, and quenched by adding 1M aqueous HCl (80 ml). This mixture was extracted with EtOAc (3×25 ml) and CH ₂ Cl ₂ (5×25 ml). These organic phases were combined, dried (Na ₂ SO ₄ ), filtered, evaporated and purified by silica gel chromatography (0-100% EtOAc/hexanes) to give ethyl 4-oxo-4H-pyran-3-carboxylate (1.8994 g, 41.8% yield) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.47 (d, J=0.78 Hz, 1H), 7.72 (dd, J=5.86, 0.78 Hz, 1H), 6.47 (d, J=5.86 Hz, 1H), 4.37 (q, J=7.29 Hz, 2H), 1.38 (t, J =7.03Hz, 3H). LCMS (ESI) m/z: 169.05 (M+1) ⁺ .

[00719] Step 8: Ethyl 1-(1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutyl)-4-oxo-1,4-dihydropyridine-3-carboxylate

[00720] 5-((1-Aminocyclobutyl)methyl)-6-bromo-2-chloropyridin-3-ol (170 mg, 0.583 mmol) and ethyl 4-oxo-4H-pyran-3-carboxylate (98 mg, 0.58 mmol) in acetic acid (5 mL) were stirred at 100°C for 4 hours. This mixture was allowed to cool to room temperature and concentrated. The resulting residue was diluted in toluene and the mixture was concentrated to remove the remaining acetic acid. The resulting precipitate was dissolved in N,N-dimethylformamide (DMF) (2 ml) before adding potassium carbonate (322 mg, 2.33 mmol) and (bromomethyl)cyclopropane (0.113 ml, 1.17 mmol). This mixture was agitated at room temperature for 6 hours to give a crude mixture of ethyl 1-(1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutyl)-4-oxo-1,4-dihydropyridine-3-carboxylate in DMF. In a separate reaction flask, stirred 1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutan-1-amine (50 mg, 0.145 mmol) and ethyl 4-oxo-4H-pyran-3-carboxylate (24.3 mg, 0.145 mmol) in acetic acid (1 ml) at 100° C. overnight. This mixture was allowed to cool to room temperature and then combined with the previous crude mixture of ethyl 1-(1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutyl)-4-oxo-1,4-dihydropyridine-3-carboxylate in DMF described above. This mixture was diluted with water and extracted 2 times with ethyl acetate. The combined organic phases were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate and concentrated. The resulting precipitate was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). The fractions were concentrated until they became cloudy. Acetonitrile was added until complete dissolution and the solution was lyophilized to give ethyl 1-(1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)pyridin-3-yl)methyl)cyclobutyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (100 mg, 0.202 mmol, 26% yield) as a pale yellow solid. LCMS(ES ⁺ )(/n/z): 495, 497.499 (M+1).

[00721] Step 9: Ethyl 2'-chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylate

[00722] A reaction vial containing a stirrer, ethyl 1-(1-((2-bromo-6-chloro-5-(cyclopropylmethoxy)tridin-3-yl)methyl)cyclobutyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (100 mg, 0.202 mmol), potassium acetate (39.6 mg, 0.403 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (20.7 mg, 0.040 mmol) was purged with nitrogen for 15 minutes. N,N-Dimethylacetamide (DMA) (2 ml) was purged with nitrogen for 5 minutes before being added to the indicated reaction mixture in the vial. This reaction vial was placed in a heating block preheated to 90° C. and this mixture was stirred overnight. The resulting reaction mixture was allowed to cool to room temperature, filtered through a cotton plug and purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). Fractions were lyophilized to give ethyl 2'-chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylate (30 mg, 0.072 mmol, 35.9% yield) as an off-white solid. LCMS(ES ⁺ )(m/z): 415, 417 (M+1).

[00723] Step 10: 2'-Chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,71naphthyridine]-9'-carboxylic acid

[00724] A solution of lithium hydroxide monohydrate (25.2 mg, 0.600 mmol) in water (1 ml) was added to a solution of ethyl 2'-chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylate (30 mg, 0.060 mmol) in methanol (1 ml) and the mixture was heated at 60° C. for 3 hours. This mixture was allowed to cool to room temperature and acidified with 1M hydrochloric acid. This mixture was diluted with DMF to dissolve the sample and then purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). The combined fractions were lyophilized to give 2,-chloro-3'-(1-cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid (22 mg, 0.056 mmol, 94% yield) as an off-white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.79 (s, 1H), 7.68 (s, 1H), 7.27 (s, 1H), 4.07 (d, J=7.03 Hz, 2H), 3.44 (s, 2H), 2.61-2.75 (m, 2H), 2.00-2.12 (m, 2H), 1.78-1.95 (m, 2H), 1.25-1.37 (m, 1H), 0.57-0.68 (m, 2H), 0.33-0.40 (m, 2H). LCMS(ES ⁺ )(m/z): 387, 389 (M+1).

[00725] Example 32 (Compound 251)

[00726] 2',3',-Dimethoxy-10'-oxo-5',10,-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid

[00727] Step 1: 2',3'-Dimethoxy-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid

[00728] 2'-Chloro-3'-(cyclopropylmethoxy)-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid (10 mg, 0.026 mmol) and sodium methoxide (0.5 M in methanol) (0.517 ml, 0.259 mmol) was heated at 65°C for 2 hours. Dioxane (0.5 ml) was added and the mixture was heated at 100°C. Said vial was initially left uncapped so that most of the methanol had evaporated. The specified reaction vial was closed with a lid and stirred at 100°C for 1.5 hours. This mixture was allowed to cool to room temperature, acidified with 1N HCl, purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). Fractions were lyophilized to give 2',3'-dimethoxy-10'-oxo-5',10'-dihydrospiro[cyclobutane-1,6'-pyrido[1,2-h][1,7]naphthyridine]-9'-carboxylic acid (1.5 mg, 4.03 µmol, 15.6% yield) as a white solid. ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.90 (s, 1H), 7.65 (s, 1H), 6.93 (s, 1H), 4.08 (s, 3H), 3.97 (s, 3H), 3.26 (s, 2H), 2.57-2.75 (m, 2H), 2.15-2.2 9 (m, 2H), 2.00-2.12 (m, 2H). LCMS(ES ^- )(w/z): 341 (M-1)-.

[00729] Scheme 13 - Preparation of compounds such as Example 33 (Compound 252)

[00730] Scheme 14 - Preparation of Example 33 (Compound 252)

[00731] Example 33 (Compound 252)

6-Isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylic acid

[00732] Stage 1: 2-Chloro-5.6-dimethylnicotinnitrile

[00733] A mixture of 2-hydroxy-5,6-dimethylnicogynnitrile (10 g, 67.5 mmol) in POCl ₃ (100 ml) was heated under reflux for 10 h and concentrated. The resulting precipitate was alkalized with 10% NaOH aqueous solution and filtered off. The filter cake was washed with H ₂ O. The resulting filtrate was extracted with DCM (200 ml x 2). These organic phases were combined, washed with brine (200 ml), dried over anhydrous Na ₂ SO ₄ , concentrated to give 9.8 g of crude 2-chloro-5,6-dimethylnicotinnitrile as a yellow solid. LCMS (ESI) m/z: 167.1, 169.1 (M/M+2) ⁺ .

[00734] Stage 2: 2-Chloro-5,6-dimethylnicotinaldehyde

[00735] To a cooled -78°C solution of 2-chloro-5,6-dimethylnicotinnitrile (1.6 g, 9.6 mmol) in DCM (20 ml) was added DIBAL-H (5.76 ml, 2 mol/l in hexane). The resulting mixture was agitated at the same temperature for 2 hours. This reaction mixture was quenched by adding ice water. Then the specified mixture was acidified with 1N HCl to pH=~6 and was extracted with DCM (100 ml × 2). These organic phases were combined, washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , concentrated to give 1.5 g of crude 2-chloro-5,6-dimethylnicotinaldehyde as a white solid. LCMS (ESI) m/z: 170.1, 172.1 (M/M+2) ⁺ .

[00736] Step 3: 2-Chloro-3-(1,3-dioxolan-2-yl)-5,6-dimethylpyridine

[00737] A mixture of 2-chloro-5,6-dimethylnicotinaldehyde (1.5 g, 8.84 mmol), ethane-1,2-diol (1.1 g, 17.68 mmol), PPTS (444.3 mg, 1.768 mmol) in toluene (20 mL) was refluxed for 12 h. The resulting reaction mixture was cooled to room temperature and extracted with E tOAc (100 ml × 2). These organic phases were combined, washed with aqueous NaHCO ₃ (50 ml), dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 0-50% EtOAc in PE) to give 2-chloro-3-(1,3-dioxolan-2-yl)-5,6-dimethylpyridine (1.35 g, 71.5% yield) as a colorless oil. LCMS (ESI) m/z: 214.1, 216.1(M/M+2) ⁺ .

[00738] Step 4: 1-(3-(1,3-Dioxolan-2-yl)-5,6-dimethylpyridin-2-yl)-3-methylbutan-2-one

[00739] A mixture of 2-chloro-3-(1,3-dioxolan-2-yl)-5,6-dimethylpyridine (1.35 g, 6.32 mmol), 3-methylbutan-2-one (653 mg, 7.58 mmol), Pd(dtbpf)Cl ₂ (411.9 mg, 0.632 mmol) and t-BuONa (1.52 g, 15.8 mmol) in THF (20 ml) was heated at 60° C. for 3 hours. The resulting reaction mixture was cooled to room temperature and filtered. The resulting filtrate was concentrated and the resulting residue was purified by flash column chromatography (silica gel, 0-70% EtOAc in PE) to give 1-(3-(1,3-daoxolan-2-yl)-5,6-dimethylpyridin-2-yl)-3-methylbutan-2-one (231 mg, 14% yield) as a yellow solid. LCMS (ESI) m/z: 264.3 (M+1) ⁺ .

[00740] Step 5: 1-(3-(1,3-Dioxolan-2-yl)-5,6-dimethylpyridin-2-yl)-3-methylbugan-2-amine

[00741] To a solution of 1-(3-(1,3-daoxolan-2-yl)-5,6-dimethylpyridin-2-yl)-3-methylbutan-2-one (231 mg, 0.878 mmol) in MeOH (10 ml) was added NH ₄ OAc (683.1 mg, 8.78 mmol) at room temperature. After stirring said mixture for 30 minutes, NaBH ₃ CN (82.8 mg, 1.317 mmol) was added to said mixture at 0°C. The resulting mixture was then shaken at 50° C. for 10 hours. The resulting reaction mixture was cooled to room temperature and concentrated. The precipitate obtained was diluted with H ₂ O (20 ml), alkalized to pH~10 with 10% NaOH solution. This aqueous mixture was extracted with DCM (2x). These organic phases were combined, washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 236 mg of crude 1-(3-(1,3-dioxolan-2-yl)-5,6-dimethylpyridin-2-yl)-3-methylbutan-2-amine. LCMS (ESI) m/z: 265.3 (M+1) ⁺ .

[00742] Stage 6: 7-Isopropyl-2,3-dimethyl-7,8-dihydro-1,6-naphthyridine

[00743] To a solution of 1-(3-(1,3-dioxolan-2-yl)-5,6-dimethylpyridin-2-yl)-3-methylbutan-2-amine (70 mg, 0.264 mmol) in THF (10 mL) was added 10% aqueous HCl (2 mL). The resulting mixture was heated at 50°C for 10 hours After cooling to room temperature, the mixture was concentrated. The resulting residue was purified using column chromatography (silica gel, 0-10% MeOH in DCM) to give 7-isopropyl-2,3-dimethyl-7,8-digadro-1,6-naphthyridine (20 mg, 37.3% yield). LCMS (ESI) m/z: 203.27 (M+1) ⁺ .

[00744] Step 7: Ethyl 6-isopropyl-2,3-dimethyl-10-oxo-5,10,11,11a-tetrahydro-6H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylate

[00745] A solution of 7-isopropyl-2,3-dimethyl-7,8-dihydro-1,6-naphthyridine (20 mg, 0.099 mmol) and ethyl 2-(ethoxymethylene)-3-oxo-butanoate (55.86 mg, 0.3 mmol) in EtOH (5 ml) was heated at 85°C for 10 h. irled. The resulting residue was purified using a column chromatography (silica gel, 0-10% MeOH in DCM) to give ethyl 6-isopropyl-2,3-dimethyl-10-oxo-5,10,11,11a-tetrahydro-6H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylate (20 mg, 58.9% yield). LCMS (ESI) m/z: 343.2 (M+1) ⁺ .

[00746] Step 8: Ethyl 6-isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylate

[00747] To a solution of ethyl 6-isopropyl-2,3-dimethyl-10-oxo-5,10,11,11a-tetrahydro-6H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylate (20 mg, 0.058 mmol) in DME (5 ml) was added p-chloranil (12.3 mg, 0.05 mmol). The specified mixture was heated at 80°C for 3 hours After cooling to room temperature, the specified mixture was concentrated. The resulting residue was purified using column chromatography (silica gel, 0-10% MeOH in DCM) to give ethyl 6-isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylate (15 mg, 76% yield). LCMS (ESI) m/z: 341.2 (M+1) ⁺ .

[00748] Step 9: 6-Isopropyl-2,3-dimethyl-10-oxo-5N0-dihydro-6H-pyrido[2,1-][1,6]naphthyridine-9-carboxylic acid

[00749] To a solution of ethyl 6-isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylate (15 mg, 0.044 mmol) in MeOH (5 ml) was added NaOH (7 mg, 0.176 mmol) dissolved in H ₂ O (1 ml). The resulting mixture was shaken at room temperature for 2 hours. The resulting reaction mixture was acidified to pH~5 with 1N HCl. Then the specified mixture was diluted with EtOAc (20 ml) and H ₂ O (20 ml), and then was extracted with EtOAc (20 ml × 2). The combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated. The resulting precipitate was purified by reverse phase HPLC (C18 column, 5%-100% MeCN in H ₂ O with 0.1% formic acid in H ₂ O) to give 6-isopropyl-2,3-dimethyl-10-oxo-5,10-dihydro-6H-pyrido[2,1-f][1,6]naphthyridine-9-carboxylic acid ( 5 mg, 36.3% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.87 (s, 1H), 8.25 (s, 1H), 7.43 (s, 1H), 4.63-4.58 (m, 1H), 3.56-3.50 (m, J=16.8, 5.3 Hz, 1H), 3.18 (d, J=16.6 Hz, 1H), 2.48 (s, 3H), 2.31 (s, 3H), 1.64-1.57 (m, 1H), 0.84 (d, J=6.6 Hz, 3H), 0.69 (d, J=6.7 Hz, 3H). LCMS (ESI) m/z: 313.2 (M+1) ⁺ .

[00750] Example 34 (Compound 253)

[00751] 2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (racemate cis)

[00752] Stage 1: 5-(6-Chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentanone

[00753] A stirrer, 5-bromo-2-chloro-3-methoxypyridine (9.9 g, 44 mmol), tris(dibenzylideneacetone) dipalladium(0) (0.611 g, 0.668 mmol), xanthos (0.695 g, 1.202 mmol) and sodium tert-butoxide (7.5 g, 78 mmol) were placed in the flask. This flask was purged with a stream of nitrogen before adding 2,2-dimethylcyclopentan-1-one (8.38 ml, 66.8 mmol) in tetrahydrofuran (THF) (200 ml). This mixture was heated under reflux for 3 hours. This mixture was allowed to cool to room temperature, filtered and the filter cake was washed with ethyl acetate. The resulting filtrate was diluted with additional ethyl acetate, washed with brine, concentrated, and the resulting residue was purified by chromatography on silica eluting with a gradient of 0% to 30% ethyl acetate in hexanes. Fractions were concentrated to give 5-(6-chloro-5-methoxy-pyridin-3-yl)-2,2-dimethyl-schiclopentan-1-one (4.6 g, 18 mmol, 41% yield) as an oil. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.82 (d, J=1.56 Hz, 1H), 7.13 (d, J=1.95 Hz, 1H), 3.91 (s, 3H), 3.36-3.47 (m, 1H), 2.45 (m, 1H), 1.96-2.17 (m, 2 H), 1.79-1.92 (m, 1H), 1.18 (s, 3H), 1.07 (s, 3H). LCMS(ES ⁺ )(m/z): 254.2 (M+1).

[00754] Step 2: 5-(6-Chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentanamine (cis/trans isomers)

[00755] A mixture of 5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-one (4.6 g, 18 mmol) and ammonium acetate (21 g, 270 mmol) in methanol (75 ml) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (2.28 g, 36.3 mmol) was added and the mixture was heated at 60° C. overnight and then at 65° C. for an additional 24 hours. This mixture was allowed to cool to room temperature, concentrated to ~20 ml, quenched with 1M sodium hydroxide and extracted 3 times with 2-methyltetrahydrofuran. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The resulting precipitate was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/0% to 100% gradient). Fractions were concentrated to give 5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine (2.63 g, 10.3 mmol, 57% yield) as a mixture of cis/trans isomers. LCMS(ES ⁺ )(m/z): 255.2 (M+1).

[00756] Step 3: 5-(2-Amino-3,3-dimethylcyclopentyl)-2-chloropyridin-3-ol(cis/trans isomers)

[00757] Boron tribromide (4.82 mL, 51.0 mmol) was slowly added dropwise to a vigorously stirred solution of 5-(6-chloro-5-methoxypyridin-3-yl)-2,2-dimethylcyclopentan-1-amine (2.6 g, 10.2 mmol) (cis/trans isomers). The specified mixture was heated at 70°C during the night. The specified mixture was left to cool to room temperature, and then cooled to 0°C. This mixture was carefully quenched by slow addition of methanol. Added an additional 50 ml of methanol and the specified mixture was stirred for 30 minutes, then concentrated. The resulting precipitate was purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/0% to 100% gradient). Fractions were lyophilized to give 5-(2-amino-3,3-dimethylcyclopentyl)-2-chloropyridin-3-ol (cis/trans isomers) (2.17 g, 9.01 mmol, 88% yield) as a white solid. LCMS(ES ⁺ )(m/z): 241.2 (M+1).

[00758] Step 4: 5-(2-Amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol (cis racemate) and 5-(2-amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol (trans racemate)

[00759] Iodine (2.29 g, 9.01 mmol) was added to a stirred mixture of 5-(2-amino-3,3-dimethylcyclopentyl)-2-chloropyridin-3-ol (2.17 g, 9.01 mmol) and potassium carbonate (3.74 g, 27.0 mmol) in water (40 mL). This mixture was agitated at room temperature for 2 hours. Solid sodium sulfate (2.39 g, 18.9 mmol) was added in portions and the mixture was stirred for 30 minutes. This aqueous mixture was adjusted to pH=~3 with 3N hydrochloric acid. This mixture was filtered. LC-MS data showed that the resulting solid contained a small amount of product and was discarded. The wash was concentrated to ~50 ml and injected onto a C18 ISCO medium pressure reversed phase column, which was eluted with acetonitrile/water/0.1% formic acid/gradient from 0% to 100%. 2 sets of fractions were lyophilized separately.

[00760] Peak 1 = 5-(2-amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol (racemate trans) (1.17 g, 3.19 mmol, 35% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.23 (s, 1H), 7.26 (s, 1H), 2.99-3.15 (m, 2H), 2.05-2.19 (m, 1H), 1.51-1.64 (m, 2H), 1.22-1.35 (m, 1H), 1.0 9 (s, 3H), 0.95 (s, 3H). LCMS(ES ⁺ )(m/z): 367.1 (M+1).

[00761] Peak 2 = 5-(2-amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol (racemate cis, contaminated with ~20% racemate trans) (924 mg, 2.01 mmol, 22% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.27 (s, 1H), 7.20 (s, 1H), 3.41-3.53 (m, 1H), 3.28 (d, J=5.86 Hz, 1H), 2.07-2.19 (m, 1H), 1.81-1.95 (m, 1H), 1.68-1.77(m, 1H), 1.47-1.57(m, 1H), 1.14(s, 3H), 1.08(s, 3H). LCMS(ES ⁺ )(m/z): 367.1 (M+1).

[00762] Step 5: Ethyl 1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (cis racemate)

[00763] 5-(2-Amino-3,3-dimethylcyclopentyl)-2-chloro-6-iodopyridin-3-ol (racemate cis) (924 mg, 2.02 mmol) (contaminated with ~20% racemate trans) and ethyl 4-oxo-4H-pyran-3-carboxylate (466 mg, 2.77 mmol) in acetic acid (1 3 ml) was stirred at 100°C for 4 hours. This mixture was allowed to cool to room temperature, diluted with water and extracted 2 times with dichloromethane. Saturated brine was added to said aqueous phase and said mixture was extracted 2 more times with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The resulting residue was purified by chromatography on silica eluting with a gradient of 0% to 10% methanol in dichloromethane. Fractions were concentrated to give ethyl 1-(5-(6-chloro-5-hadroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (cis racemate) (346 mg, 0.670 mmol, 33% yield). ¹ Н ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 10,92 (br. s., 1H), 7,78 (d, J=1,95 Hz, 1H), 7,43 (dd, J=7,81, 2,34 Hz, 1H), 7,07 (s, 1H), 6,04 (d, J=7,42 Hz, 1H), 4,54 (d, J=7,42 Hz, 1H), 4,03-4,17 (m, 2H), 3,82-3,95 (m, 1H), 2,15-2,27 (m, 2H), 1,99 (dt, J=13,66, 7,22 Hz, 1H), 1,74-1,87 (m, 1H), 1,24-1,31 (m, 3H), 1,14-1,23 (m, 3H), 0,92 (s, 3H). LCMS(ES ⁺ )(m/z): 517.1 (M+1).

[00764] Step 6: Ethyl 1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (cis racemate)

[00765] Ethyl 1-(5-(6-chloro-5-hydroxy-2-iodopyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-car (racemate cis) (346 mg, 0.670 mmol), potassium carbonate (463 mg, 3.35 mmol) and 1-bromo-3-methoxypropane (20 5 mg, 1.34 mmol) in N,N-dimethylformamide (DMF) (5 ml) was stirred at room temperature overnight. This mixture was quenched with water and extracted 3 times with ethyl acetate. The combined organic phases were washed with brine and concentrated. The resulting residue was purified by chromatography to give ethyl 1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (341 mg, 0.579 mmol, 86% yield). LCMS(ES ⁺ )(w/z): 589.2 (M+1).

[00766] Step 7: Ethyl 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate (cis racemate)

[00767] A round bottom flask with a septum and containing a stirrer, ethyl 1-(5-(6-chloro-2-iodo-5-(3-methoxypropoxy)pyridin-3-yl)-2,2-dimethylcyclopentyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (341 mg, 0.579 mmol), potassium acetate (114 mg, 1 .16 mmol) and palladium (II) bromide (30.8 mg, 0.116 mmol) were purged with nitrogen for 15 minutes. N,N-Dimethylacetamide (DMA) (5 ml) was purged with nitrogen for 5 minutes before being added to the reaction flask. The specified flask with the reaction mixture was placed in an oil bath, pre-heated to 90°C, and the specified mixture was stirred for 4 hours. The resulting reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and filtered through a cotton plug. This mixture was washed with brine, dried over sodium sulfate and concentrated. The resulting residue was purified by chromatography on silica eluting with a gradient of 0% to 10% methanol in dichloromethane. Fractions were concentrated. The desired product was isolated, but a significant amount of DMA was left. This product was then purified by medium pressure reverse phase chromatography (C18/acetonitrile/water/0.1% formic acid/10% to 100% gradient). The fractions were concentrated to give ethyl 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexadrocyclopenta[1]pyrido[1,2-h][1,7]naphthyridine-10-carboxylate (cis racemate) (150 mg, 0.325 mmol, 56% yield). ¹ Н ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 8,21 (s, 1H), 7,55 (s, 1H), 7,00 (s, 1H), 4,43 (d, J=8,98 Hz, 1H), 4,15-4,31 (m, 4H), 3,79-3,88 (m, 1H), 3,47 (t, J=6,05 Hz, 2H), 3,23 (s, 3H), 2,27-2,38 (m, 1H), 2,12-2,25 (m, 1H), 1,99 (quin, J=6,15 Hz, 2H), 1,50-1,60 (m, 1H), 1,35-1,45 (m, 1H), 1,24 (t, J=7,22 Hz, 3H), 1,11 (s, 3H), 0,39 (s, 3H). LCMS(ES ⁺ )(m/z): 461.3 (M+1).

[00768] Step 8: 2-Chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (racemate cis)

[00769] A solution of lithium hydroxide monohydrate (113 mg, 2.70 mmol) in water (2 ml) was added to a solution of ethyl 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[1]pyrido[1,2-h][1,7]naphthyridine-10- carboxylate (racemate cis) (150 mg, 0.270 mmol) in methanol (3 ml) and the mixture was heated at 65° C. for 1 hour. This mixture was left to cool, diluted with water, acidified with 1M HCl and extracted 3 times with 2-methyltetrahydrofuran. The combined organic phases were washed with brine and concentrated. The resulting residue was purified by chromatography on silica eluting with a gradient of 0% to 10% methanol in dichloromethane. The fractions were concentrated to give 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[1]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid (racemate cis) (95 mg, 0.219 mmol, 81% yield) as white solid. ¹ Н ЯМР (400 MHz, DMSO-d ₆ ) δ ppm 8,62 (s, 1H), 7,63 (s, 1H), 7,43 (s, 1H), 4,72 (d, J=9,37 Hz, 1H), 4,21-4,39 (m, 2H), 3,89-3,99 (m, 1H), 3,51 (t, J=6,05 Hz, 2H), 3,26 (s, 3H), 2,33-2,44 (m, 1H), 2,19-2,31 (m, 1H), 1,96-2,08 (m, 2Н), 1,55-1,66 (m, 1Н), 1,40-1,51 (m, 1Н), 1,15 (s, 3Н), 0,40 (s, 3Н). LCMS(ES ⁺ )(m/z): 433.3 (M+1).

[00770] Additional general synthetic protocols for the preparation of the compounds described herein are shown below in Scheme 15.

[00771] Scheme 15 - Compounds of the type Compounds in which R ₁₀ is selected from Table 2)

Biological Examples

[00772] Example 35 - Compound Treatment of Primary Human Hepatocytes Infected with HBV

[00773] HBV-Ag inhibitors

[00774] Vials with cryopreserved primary human hepatocytes were placed in a 37° C. water bath until thawed. These were pooled, gently resuspended in differentiation medium (Williams medium containing GlutaMax-1™ differentiation supplement and penicillin/streptomycin) and cells were counted using a hemacytometer. These cells were pelleted by centrifugation at 1000 g for 10 minutes and resuspended to a density of 5.5×10 ⁵ cells/ml in differentiation medium. 100 μl of cell suspension was placed in each well of a 96-well plate coated with collagen. These plates were incubated at 37°C and 5% CO ₂ for 2 days before infection.

[00775] HBV stock solutions were obtained by ultrafiltration of the medium from HepG2,2,15 cell culture. To obtain a working stock solution with a multiplicity of infection (MOI) of 100, HBV stock solutions were added to differentiation media containing 4% polyethylene glycol until an HBV DNA concentration of 5.5 x 10 ⁷ copies/mL was reached. The indicated cell medium was transferred with 100 μl of the working stock solution of the virus into columns 1-11 and with differentiation medium into column 12. These plates were incubated at 37°C and 5% CO ₂ for approximately 24 hours.

[00776] Compounds were resuspended in DMSO and serially diluted 3-fold in DMSO to obtain a 10-point dilution series at 200x the final desired concentrations. Columns 11 and 12 contained DMSO. Using a Biomek FX, 2.5 μl of each compound dilution was placed in 96-well U-bottomed plates in 3 replicates. Said compound plates were sealed and stored at -20°C. After warming to room temperature, these compound plates were diluted with 200x assay medium (differentiation medium plus 1 mm ABT). The medium in the cell plates was replaced with 150 µl of diluted compound solutions. The highest final compound concentration was 20 μM. These tablets were incubated at 37°C and 5% CO ₂ . This treatment with the compounds was repeated on the 4th and 9th day after the initial treatment. Readings were taken by ELISA using HBsAg and HBeAg on days 9 and 14.

[00777] On the 9th day after the initial treatment, this medium was transferred from each well of the plate to a U-bottomed plate and stored at -80°C. On day 14 after initial treatment, the cell plates were washed once with PBS and stored at -80°C.

[00778] ELISA using HBs Ag

[00779] Frozen plates containing collected media were allowed to warm to room temperature in a biosafety cabinet for approximately 30 minutes. The HBsAg ELISA kit was used according to the manufacturer's recommendations. Briefly, the ELISA plates and solutions were allowed to warm to room temperature for approximately 1 hour and the plates were washed once with 300 μl of 1x wash buffer. 100 µl of 1x conjugated enzyme solution, 120 µl of PBS containing 10% FBS, and 30 µl of the resulting medium were placed in each well. The assay plates were sealed and incubated at 37° C. for approximately 2 hours. These plates were washed 4 times with 195 ml of 1x wash buffer and dried thoroughly by inverting onto paper towels. 195 µl of the chromagen/substrate solution was added to each well and incubated at room temperature for approximately 5 minutes. 100 μl of stop solution was added to each well and these plates were read on a Molecular Devices SpectraMax® 384 Plus plate reader at 450 nm. IC ₅₀ values were determined using GraphPad Prism: four-parameter logistic curve with the equation Y=Bottom+(Top-Bottom)/(1+10 ^∧ ((LogIC50-X)*HillSlope)).

[00780] ELISA using HBe Ag

[00781] Frozen plates containing collected media were allowed to warm to room temperature in a biosafety cabinet for approximately 30 minutes. The HBeAg ELISA kit was used according to the manufacturer's recommendations. Briefly, said ELISA plates and solutions were allowed to warm to room temperature for approximately 1 hour and said plates were washed once with 300 μl of 1x wash buffer. 80 µl of PBS containing 10% FBS and 20 µl of collected medium were placed in each well. The assay plates were sealed and incubated at 37° C. for approximately 1 hour. The plates were washed twice with 300 ml of 1x wash buffer and dried thoroughly by inverting onto paper towels. 100 μl of 1x conjugated enzyme solution was placed in each well. The assay plates were sealed and incubated at 37° C. for at least 1 hour. The plates were washed 3 times with 300 ml 1x wash buffer and dried thoroughly by inverting onto paper towels. 100 µl of the chromagen/substrate solution was added to each well and incubated at room temperature for approximately 5 minutes. 100 μl stop solution was added to each well and the indicated plates were read on a Molecular Devices SpectraMax 384 Plus plate reader at 450 nm.

[00782] Data analysis

[00783] IC ₅₀ values were determined using GraphPad Prism: a four-parameter logistic curve with the equation Y=Bottom+(Top-Bottom)/(1+10 ^∧ ((LogIC50-X)*HillSlope)). The IC ₅₀ values for the 50% reduction in HBs and HBe antigens for the tested compounds are shown in Table 1 for days 9 and 14. As can be seen from these IC ₅₀ values, the compounds tested exhibited 50% inhibition of HBe and HBs antigens at concentrations between less than ~0.22 μM and 0.0069 μM.

[00784] The embodiments of the present invention described above are for illustrative purposes only; many variations and modifications are obvious to a person skilled in the art. Such variations and modifications as such are within the scope of the present invention as defined in the appended claims.

[00785] Example 36 HepAD38-HBsAg Cells ELISA and Cytotoxicity Assay

[00786] HepAD38 cells were maintained in collagen coated flasks in cell growth medium (DMEM/F12 containing 10% fetal bovine serum (FBS), GlutaMax-1, penicillin/streptomycin, non-essential amino acids, sodium pyruvate, 250 μg/ml genecitin, and 1 μg/ml doxycycline). Compound solutions were prepared in DMSO and compounds serially diluted to final concentrations of 4000, 1000.250, 62.5, 15.6, 3.91, 0.977, 0.244, 0.061, and 0.015 nM. These cells were then trypsinized and seeded at a concentration of 10,000 cells per well. The plates were incubated at 37°C, 5% CO ₂ for 4 days. The medium was replaced with new medium with processing compounds. Then these tablets were incubated at 37°C, 5% CO ₂ for 3 additional days to achieve a total processing time of 7 days. To assess the antiviral response, the HBsAg level was measured using the HBsAg ELISA kit (International Immuno-diagnostics) according to the instructions provided. For ELISA, 100 μl of cell medium samples were used. Optical absorbance was measured with a Spectramax® 384 plate reader (Molecular Devices) at 450 nm. CellTiter-Glo® Luminescent cell survival test reagent (Promega) was used to evaluate cellular cytotoxicity. Luminescence was measured with an Envision Multilabel Reader (Perkin Elmer). The obtained data were analyzed and compared with the DMSO control.

[00787] % inhibition = (1-(unknown/highest control value))*100

[00788] Mean % inhibition values from two replicate plate studies were plotted using GraphPad Prism to determine a single IC value: a four parameter logistic curve with the equation Y=Bottom+(Top-Bottom)/(1+10 ^∧ ((LogIC50-X)*HillSlope))

[00789] pIC ₅₀ =log(-IC ₅₀ in M)

ppi this:

Claims (41)

1. Compound of Formula I or a pharmaceutically acceptable salt thereof in which W is N; Y is C; R ¹ is missing; R ² is halogen, hydroxy or cycloalkyl; R ³ is -OR ¹² ; R ⁴ is H; R ⁵ is H; R ⁶ and R ⁷ together form a 3- to 8-membered cycloalkyl ring optionally substituted with R ¹⁵ , R ^15' , R ¹⁶ and/or R ^16' ; R ⁸ is H; R ⁹ is H; R ¹⁰ is -COOH; R ¹¹ is H; R ¹² is C _1-6 alkyl substituted with methoxy or cyclopropyl; And R ¹⁵ , R ¹⁵ , R ¹⁶ and/or R ^16' are independently C _1-6 alkyl. 2. The compound according to claim. 1 or its pharmaceutically acceptable salt, characterized in that R ² is halogen; R ⁸ is hydrogen; And R ¹² is C _1-6 alkyl substituted with methoxy or cyclopropyl. 3. The compound according to claim 1, selected from the specified group: (4bR,7aS)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid; (4bS,7aR)-2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid; (4bR,7aS)-2-cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid; 2-cyclopropyl-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid; (4bR,7aS)-2-hydroxy-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid; 2-chloro-3-(3-methoxypropoxy)-7,7-dimethyl-11-oxo-4b,5,6,7,7a,11-hexahydrocyclopenta[f]pyrido[1,2-h][1,7]naphthyridine-10-carboxylic acid; or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, selected from the group: or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, having the structure or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 1, having the structure or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 1, having the structure or a pharmaceutically acceptable salt thereof 8. Pharmaceutical composition for the treatment of hepatitis B, containing a pharmaceutically acceptable diluent and a therapeutically effective amount of the compound according to any one of paragraphs. 1-7 or a pharmaceutically acceptable salt thereof.