WO2019169539A1

WO2019169539A1 - Novel oxa-and aza-tricyclic 4-pyridone-3-carboxylic acid for treatment and prophylaxis of hepatitis b virus infection

Info

Publication number: WO2019169539A1
Application number: PCT/CN2018/078063
Authority: WO
Inventors: Ping Chen; Ding Zhou; Dawei Cui; Xingzhu GAO; Yuanchao BAI
Original assignee: Pharmaresources (Shanghai) Co., Ltd.
Priority date: 2018-03-05
Filing date: 2018-03-05
Publication date: 2019-09-12

Abstract

Provided herein are oxa- and aza-tricyclic 4-pyridone-3-carboxylic acid compounds, their manufacture, pharmaceutical compositions comprising them, and their use as medicaments for inhibiting HBsAg secretion and HBV DNA production, and for treatment and/or prophylaxis of hepatitis B infection.

Description

NOVEL OXA-AND AZA-TRICYCLIC 4-PYRIDONE-3-CARBOXYLIC ACID FOR TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION

FIELD OF THE INVENTION

This application relates to novel oxa-and aza-tricyclic 4-pyridone-3-carboxylic acid compounds, their manufacture, pharmaceutical compositions comprising them, and their use as medicaments for inhibiting HBsAg secretion and HBV DNA production, and thereby useful for treatment and/or prophylaxis of hepatitis B infection.

BACKGROUND OF THE INVENTION

Chronic hepatitis B (CHB) virus infection is a global public health problem, affecting more than 400 million people worldwide with more than 75 thousand deaths attributed annually to HBV-related complications (Lavanchy D. J Viral Hepat. 2004; 11: 97–107; Lok AS, McMahon BJ. Hepatology. 2007; 45: 507–539) . There are two different treatment strategies used as standard of care (SOC) for patients with CHB infection: therapies of finite duration using immunomodulators such as interferon-α and the long-term treatment with the nucleos (t) ide analogs. In principle, these treatment strategies consist of boosting innate immune system, suppressing active HBV DNA replication (Liaw YF, Sung JJ, Chow WC, et al. N Engl J Med. 2004; 351: 1521–1531) . With the advent of oral nucleos (t) ide analogues (NUCs) , HBV replication can be effectively suppressed (Lee CI, Kwon SY, Kim JH, et al. Gut Liver. 2014; 8: 64–69; Kwon DH, Kim IH, Choung BS, et al. Gut Liver. 2013; 7: 712–718) , and serum HBV DNA concentrations have been a surrogate marker for HBV replication during antiviral therapy. However, increasing rates of resistance to antiviral therapy necessitates consideration of combination therapy, and research for novel mechanism treatments.

Studies have suggested that HBsAg titers in the sera might reflect the amount of covalently closed circular DNA (cccDNA) in infected hepatocytes (Wursthorn K, et al. Hepatology. 2006; 44: 675–684; Volz T, et al. Gastroenterology. 2007; 133: 843–852) . Recent studies have investigated the correlation between serum HBsAg titers and HBV DNA concentrations (Ganji A et al. Hepat Mon. 2011; 11: 342–345; Lee J-H et al. J Clin Pathol. 2010; 63: 1027–1031) and shown a significant correlation between HBsAg titers and HBV DNA concentrations across distinct phases of CHB (Nguyen T et al. J Hepatol. 2010; 52: 508–513; Chan HL et al. Hepatology. 2010; 52: 1232–1241; Jaroszewicz J, et al. J Hepatol. 2010; 52: 514– 522; Thompson AJ, et al. Hepatology. 2010; 51: 1933–1944; Won Kim, et al. Gut Liver. 2015; 9 (5) : 657–664; Idilman R et al. J Viral Hepat. 2012; 19 (3) : 220-6) . Current therapy for HBV is aimed at achieving suppression of HBV replication at levels below detection. Although this can be accomplished in almost all patients, long-term management of CHB remains a challenge. Treatment options for HBV therapy include PEGylated interferon-alpha (pegIFN-α) and direct inhibition of the viral polymerase through nucleos (t) ide analogues. PEGylated interferon-alpha (pegIFN-α) can induce viral suppression in approximately 25%of patients but is always accompanied by severe side effects in most cases. (Marcellin, P.; Lau, G.K. et al. New England Journal of Medicine (2004) , 351, 1206–1217. Hoofnagle, J. H. et al. New England Journal of Medicine (1997) , 336, 347–356; Mailliard, M.E.; et al. Annual Review of Medicine (2006) , 57, 155–166) . Nucleos (t) ides can inhibit HBV DNA production while offering advantages over pegIFN-α like oral bioavailability, low toxicity, and efficacy in almost all patients. However, these nucleos (t) ides could not significantly reduce HBsAg level even with prolonged therapy to get complete clearance of infection. (Jassen et al. Lancet (2005) , 365, 123-129; Marcellin et al. New England Journal of Medicine (2004) , 351, 1206-1217; Buster et al. Hepatology (2007) , 46, 388-394) . Failure to achieve sustained response and HBV persistence is related to the viral factors and inadequate induction of immune response that are seen in acute HBV patients, which naturally clears the infection.

Advancement in the understanding of the basis of HBV persistence has guided the development of strategies that could lead to a functional cure for HBV infection. The goal of CHB treatment is the loss of hepatitis B surface antigen (HBsAg) with the development of hepatitis B surface antibody (anti-HBs) , which is associated with favorable clinical outcomes (Idilman R, Cinar K, Seven G, et al. J Viral Hepat. 2012; 19: 220–226; European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol. 2009; 50: 227–242) .

HBV persistence results from an ineffective anti-viral immune response towards the virus. The suppression of innate immune response can also be mediated by direct interference of HBV antigens with host cells. Elevated levels of HBsAg in the range of 400 μg/ml (0.4%of total serum protein) have been demonstrated in HBV infected patients (Dougherty AM, et al. Antimicrobial Agents Chemother. 2007; 51 (12) : 4427–4437; Heermann KH et al. J. Virol. 1984; 52 (2) : 396–402; Yu W, Goddard C, Clearfield E, et al. J. Med. Chem. 2011; 54 (16) : 5660–5670) and are thought to play a key role in suppressing the HBV-specific immune response. In this regard, recent reports have suggested that HBsAg acts directly on dendritic (DC) cells and natural killer (NK) cells to limit cytokine production (Op den Brouw et al. Virology. 2009; 393 (1) : 84–90; Xu et al. Mol. Immunol. 2009; 46 (13) : 2640–2646) . Current therapy such as nucleos (t) ide analogues can inhibit HBV DNA synthesis but are not directed at reducing HBsAg level. Therefore, targeting HBsAg together with HBV DNA levels in CHB patients may significantly improve CHB patient immune reactivation and remission (Wieland, S. F. &F. V. Chisari, J Virol, 2005, 79, 9369-80; Kumar et al. J Virol, 2011, 85, 987-95; Woltman et al. PLos One, 2011, 6, e15324; Op den Brouw et al. Immunology, 2009, 126, 280-9) .

HBsAg inhibitors can improve CHB patients'immune reactivation and remission, and therefore can be used in combination therapy with nucleos (t) ide drugs or other anti-HBV drugs for treatment and/or prophylaxis of HBV infection. Several classes of drugs have been reported to reduce HBsAg secretion (Korba BE, Montero AB, Farrar K, et al. Antiviral Res. 2008; 77 (1) : 56–63) , or to inhibit HBsAg (Roche, WO2015/173164A1, US2015/0210682, US2016/0122344) .

SUMMARY OF INVENTION

The present invention relates to a compound of formula (I)

wherein:

R ¹ is hydrogen, halogen, C _1-6alkyl, C _1-6alkoxy, N (C _1-6alkyl) ₂, or NH-C _1-6alkyl;

R ² is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, haloC _1-6alkoxy, O (CH ₂) _q-phenyl, CN, or C _3-7cycloalkyl;

R ³ is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, O (CH ₂) _q-phenyl, CN, amino, C _3-7cycloalkyl, O (CH ₂) _wR ⁶, O (CH ₂) _mO (CH ₂) _nR ⁶, or O-C _1-6alkyl-R ⁶;

R ⁴ is hydrogen, halogen, C _1-6alkyl, C _1-6alkoxy or CN;

X is O, or NR ⁷;

R ⁵ is hydrogen, C _1-6alkyl, haloC _1-6alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, C _1-6alkyl-OH, or C _1-6alkyl-O-C _1-6alkyl;

each R ⁶ is independently OH, C _1-6alkoxy, C _3-7cycloalkyl, CN, C _2-6alkenyl, C _2-6alkynyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, SC _1-6alkyl, S (=O) ₂C _1-6alkyl, NR _aR _b, C (=O) OH, C (=O) OC _1-6alkyl, or C (=O) NR _aR _b;

R ⁷ is hydrogen, C _1-4alkyl, CD ₃, haloC _1-4alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, (CH ₂) _q-monocyclic heteroaryl, C _1-4alkyl-OH, or C _1-4alkyl-O-C _1-4alkyl; or R ⁷ and R ⁵ together optionally form a 5 to 7-membered heterocyclic ring, which ring contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C ₁-C ₄) alkyl, C _3-7cycloalkyl, OH, C _1-4alkoxy, haloC _1-4alkoxy, phenyl, benzyl and monocyclic heteroaryl;

each occurrence of R _a and R _b is independently hydrogen or C _1-6alkyl, or R _a and R _b, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C ₁-C ₄) alkyl, phenyl and benzyl;

each q is independently 0-6;

w is 1-6; and

m and n are each independently 2-6, or a pharmaceutically acceptable salt or enantiomer thereof.

The invention also relates to their manufacture, pharmaceutical compositions comprising them, and their use as medicaments for inhibiting HBsAg secretion and HBV DNA production. Accordingly, the compounds of formula (I) are useful for treatment and/or prophylaxis of hepatitis B virus.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

DETAILED DESCRIPTION OF THE INVENTION

One embodiment herein provides compounds, and their pharmaceutically acceptable forms, including, but not limited to, salts, hydrates, solvates, isomers, enantiomers, prodrugs, and isotopically labeled derivatives thereof.

Another embodiment herein provides methods of treating and/or managing various diseases and disorders, which comprises administering to a patient a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable form (e.g., salts, hydrates, solvates, isomers, enantiomers, prodrugs, and isotopically labeled derivatives) thereof. Non-limiting examples of diseases and disorders are described herein.

Another embodiment herein provides methods of preventing various diseases and disorders, which comprises administering to a patient in need of such prevention a prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable form (e.g., salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof. Non-limiting examples of diseases and disorders are described herein.

In other embodiments, a compound provided herein, or a pharmaceutically acceptable form (e.g., salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof, can be administered in combination with another drug ( "second active agent" ) or treatment. Second active agents include small molecules and large molecules (e.g., proteins and antibodies) , non-limiting examples of which are provided herein, as well as stem cells. Other methods or therapies that can be used in combination with the administration of compounds provided herein include, but are not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy, and other non-drug based therapies presently used to treat, prevent or manage various disorders described herein.

Also provided herein are pharmaceutical compositions (e.g., single unit dosage forms) that can be used in the methods provided herein. In one embodiment, pharmaceutical compositions comprise a compound provided herein, or a pharmaceutically acceptable form (e.g., salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof, and optionally one or more second active agents.

While specific embodiments have been discussed, the specification is illustrative only and not restrictive. Many variations of this disclosure will become apparent to those skilled in the art upon review of this specification.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this specification pertains.

Definitions

As used in the specification and claims, the singular form "a" , "an" and "the" includes plural references unless the context clearly dictates otherwise.

As used herein, "agent" or "biologically active agent" or "second active agent" refers to a biological, pharmaceutical, or chemical compound or another moiety. Non-limiting examples include simple or complex organic or inorganic molecules, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, an antibody fragment, a vitamin, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound, and metabolites thereof. Various compounds can be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides) , and synthetic organic compounds based on various core structures. In addition, various natural sources can provide active compounds, such as plant or animal extracts, and the like. A skilled artisan can readily recognize that there is no limit as to the structural natureof the agents of this disclosure.

“Administration” of a disclosed compound encompasses the delivery to a subject of a compound as described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, as discussed herein.

The term "co-administration, " "administered in combination with, " and their grammatical equivalents, as used herein, encompasses administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at separate times in separate compositions, or administration in a composition in which both agents are present.

The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or pharmaceutical composition described herein that is sufficient to affect the intended application including, but not limited to, disease treatment, as illustrated below. In some embodiments, the amount is that effective for detectable inhibition ofHBsAg secretion and HBV DNA production. The therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo) , or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a response in target cells, e.g., reduction of cell migration. The specific dose will vary depending on, for example, the compounds chosen, the species of subject and their age/existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

As used herein, the terms "treatment" , "treating" , "palliating" “managing” and "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and/or compositions can be administered to a patient at risk of developing a disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

A "therapeutic effect, " as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

"Subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult) ) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys) ; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys.

The term "in vivo" refers to an event that takes place in a subject’s body. In vivo also includes events occurring in rodents, such as rats, mice, guinea pigs, and the like.

The term "in vitro" refers to an event that takes places outside of a subject’s body. For example, an in vitro assay encompasses any assay conducted outside of a subject. In vitro assays encompass cell-based assays in which cells, alive or dead, are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable saltsof the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of a parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4alkyl) ⁴ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

As used herein, the term "solvate" refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate" . Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term "compound" as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood) . In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.

The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985) , pp. 7-9, 21-24 (Elsevier, Amsterdam) . A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems, " A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the digestive tract, or it can enhance drug stability for long-term storage.

The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject. Prodrugs of an active compound, as described herein, can be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like. Other examples of prodrugs include compounds that comprise –NO, -NO ₂, -ONO, or –ONO ₂moieties. Prodrugs can typically be prepared using well known methods, such as those described in Burger’s Medicinal Chemistryand Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995) , and Designof Prodrugs (H. Bundgaard ed., Elselvier, New York, 1985) .

For example, if a disclosed compound or a pharmaceutically acceptable form of the compound contains a carboxylic acid functional group, a prodrug can comprise a pharmaceutically acceptable ester formed by the replacement of the hydrogen atom of the acid group with a group such as (C _1-8) alkyl, (C _1-12) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having from 5 to 10 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N- (C _1-2) alkylamino (C _2-3) alkyl (such as [3-dimethylaminoethyl) , carbamoyl- (C _1-2) alkyl, N, N-di (C _1-2) alkylcarbamoyl- (C _1-2) alkyl and piperidino-, pyrrolidino-or morpholino (C _2-3) alkyl.

Similarly, if a disclosed compound contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (C _1- ₆) alkanoyloxymethyl, 1- ( (C _1-6) alkanoyloxy) ethyl, 1-methyl-1- ( (C _1-6) alkanoyloxy) ethyl, (C _1- ₆) alkoxycarbonyloxymethyl, N- (C _1-6) alkoxycarbonylaminomethyl, succinoyl, (C _1-6) alkanoyl, α-amino (C _1-4) alkanoyl, arylacyl, and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α- aminoacyl group is independently selected from the naturally occurring L-amino acids, -P (O) (OH) ₂, -P (O) (O (C _1-6) alkyl) ₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate) .

If a disclosed compound incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR’-carbonyl where R and R’are each independently selected from (C _1–10) alkyl, (C _3- ₇) cycloalkyl, benzyl, a natural α-aminoacyl or natural α-aminoacyl-natural-α-aminoacyl, -C (OH) C (O) OY ¹ wherein Y ¹ is H, (C _1-6) alkyl or benzyl; -C (OY ²) Y ³ whereinY ² is (C _1-4) alkyl and Y ³ is (C _1-6) alkyl, carboxy (C _1-6) alkyl, amino (C _1-4) alkyl or mono-N-or di-N, N- (C _1- ₆) alkylaminoalkyl; and -C (Y ⁴) Y ⁵ wherein Y ⁴ is H or methyl andY ⁵ is mono-N-or di-N- (C ₁ ₆) alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

In certain embodiments, the disclosed compounds may encompassan isomer. "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomers" include geometric double bond cis-and trans-isomers, also termed E-and Z-isomers; R-and S-enantiomers; diastereomers, (d) -isomers and (l) -isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure.

Geometric isomers can be represented by the symbol -----which denotes a bond that can be a single, double or triple bond as described herein. Provided herein are various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration wherein the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers.

Substituents around a carbon-carbon double bond alternatively can be referred to as "cis" or "trans, " where “cis" represents substituents on the same side of the double bond and "trans" represents substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be designated as "cis" or "trans. " The term "cis" represents substituents on the same side of the plane of the ring, and the term "trans" represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated "cis/trans. "

"Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportion can be known as a "racemic" mixture. The term " (±) " is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro-or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry at each asymmetric atom, as (R) -or (S) -. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures. Optically active (R) -and (S) -isomers can be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

The "enantiomeric excess" or "%enantiomeric excess" of a composition can be calculated using the equation shown below. In the example shown below, a composition contains 90%of one enantiomer, e.g., the S enantiomer, and 10%of the other enantiomer, e.g., the R enantiomer.

ee= (90-10) /100=80%.

Thus, a composition containing 90%of one enantiomer and 10%of the other enantiomer is said to have an enantiomeric excess of 80%. Some compositions described herein contain an enantiomeric excess of at least about 50%, about 75%, about 90%, about 95%, or about 99%of the S enantiomer. In other words, the compositions contain an enantiomeric excess of the S enantiomer over the R enantiomer. In other embodiments, some compositions described herein contain an enantiomeric excess of at least about 50%, about 75%, about 90%, about 95%, or about 99%of the R enantiomer. In other words, the compositions contain an enantiomeric excess of the R enantiomer over the S enantiomer.

For instance, an isomer/enantiomer can, in some embodiments, be provided substantially free of the corresponding enantiomer, and can also be referred to as "optically enriched, " "enantiomerically enriched, " "enantiomerically pure" and "non-racemic, " as used interchangeably herein. These terms refer to compositions in which the percent by weight of one enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (e.g., greater than 1: 1 by weight) . For example, an enantiomerically enriched preparation of the S enantiomer means a preparation of the compound having greater than about 50%by weight of the S enantiomer relative to the R enantiomer, such as at least about 75%by weight, further such as at least about 80%by weight. In some embodiments, the enrichment can be much greater than about 80%by weight, providing a "substantially enantiomerically enriched, " "substantially enantiomerically pure" or a "substantially non-racemic" preparation, which refers to preparations of compositions which have at least about 85%by weight of one enantiomer relative to other enantiomer, such as at least about 90%by weight, and further such as at least about 95%by weight. In certain embodiments, the compound provided herein can be made up of at least about 90%by weight of one enantiomer. In other embodiments, the compound can be made up of at least about 95%, about 98%, or about 99%by weight of one enantiomer.

In some embodiments, the compound is a racemic mixture of (S) -and (R) -isomers. In other embodiments, provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S) -or (R) -isomeric configuration. For example, the compound mixture has an (S) -enantiomeric excess of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more. In other embodiments, the compound mixture has an (S) -enantiomeric excess of greater than about 55%to about 99.5%, greater than about 60%to about 99.5%, greater than about 65%to about 99.5%, greater than about 70%to about 99.5%, greater than about 75%to about 99.5%, greater than about 80%to about 99.5%, greater than about 85%to about 99.5%, greater than about 90%to about 99.5%, greater than about 95%to about 99.5%, greater than about 96%to about 99.5%, greater than about 97%to about 99.5%, greater than about 98%to greater than about 99.5%, greater than about 99%to about 99.5%, or more. In other embodiments, the compound mixture has an (R) -enantiomeric purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%or more. In some other embodiments, the compound mixture has an (R) -enantiomeric excess of greater than about 55%to about 99.5%, greater than about 60%to about 99.5%, greater than about 65%to about 99.5%, greater than about 70%to about 99.5%, greater than about 75%to about 99.5%, greater than about 80%to about 99.5%, greater than about 85%to about 99.5%, greater than about 90%to about 99.5%, greater than about 95%to about 99.5%, greater than about 96%to about 99.5%, greater than about 97%to about 99.5%, greater than about 98%to greater than about 99.5%, greater than about 99%to about 99.5%or more.

In other embodiments, the compound mixture contains identical chemical entities except for their stereochemical orientations, namely (S) -or (R) -isomers. For example, if a compound disclosed herein has a-CH (R) -unit, and R is not hydrogen, then the -CH (R) -is in an (S) -or (R) - stereochemical orientation for each of the identical chemical entities. In some embodiments, the mixture of identical chemical entities is a racemic mixture of (S) -and (R) -isomers. In another embodiment, the mixture of the identical chemical entities (except for their stereochemical orientations) , contain predominately (S) -isomers or predominately (R) -isomers. For example, the (S) -isomers in the mixture of identical chemical entities are present at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more, relative to the (R) -isomers. In some embodiments, the (S) -isomers in the mixture of identical chemical entities are present at an (S) -enantiomeric excess of greater than about 55%to about 99.5%, greater than about 60%to about 99.5%, greater than about 65%to about 99.5%, greater than about 70%to about 99.5%, greater than about 75%to about 99.5%, greater than about 80%to about 99.5%, greater than about 85%to about 99.5%, greater than about 90%to about 99.5%, greater than about 95%to about 99.5%, greater than about 96%to about 99.5%, greater than about 97%to about 99.5%, greater than about 98%to greater than about 99.5%, greater than about 99%to about 99.5%or more.

In another embodiment, the (R) -isomers in the mixture of identical chemical entities (except for their stereochemical orientations) , are present at about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more, relative to the (S) -isomers. In some embodiments, the (R) -isomers in the mixture of identical chemical entities (except for their stereochemical orientations) , are present at a (R) -enantiomeric excess greater than about 55%to about 99.5%, greater than about 60%to about 99.5%, greater than about 65%to about 99.5%, greater than about 70%to about 99.5%, greater than about 75%to about 99.5%, greater than about 80%to about 99.5%, greater than about 85%to about 99.5%, greater than about 90%to about 99.5%, greater than about 95%to about 99.5%, greater than about 96%to about 99.5%, greater than about 97%to about 99.5%, greater than about 98%to greater than about 99.5%, greater than about 99%to about 99.5%, or more.

Enantiomers can be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) , the formation and crystallization of chiral salts, or prepared by asymmetric syntheses. See, for example, Enantiomers, Racemates and Resolutions (Jacques, Ed., Wiley Interscience, New York, 1981) ; Wilen et al., Tetrahedron 33: 2725 (1977) ; Stereochemistry of Carbon Compounds (E.L. Eliel, Ed., McGraw-Hill, NY, 1962) ; and Tables ofResolvingAgents andOptical Resolutions p. 268 (E.L. ElM, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972) .

Optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, e.g., by formation of diastereoisomeric salts, by treatment with an optically active acid or base. Examples of appropriate acids include, but are not limited to, tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid. The separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts affords separation of the isomers. Another method involves synthesis of covalent diastereoisomeric molecules by reacting disclosed compounds with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically enriched compound. Optically active compounds can also be obtained by using active starting materials. In some embodiments, these isomers can be in the form of a free acid, a free base, an ester or a salt.

In certain embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" is a type of isomer that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa) . "Tautomerization" includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" involves the migration of a proton accompanied by changes in bond order. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Where tautomerization is possible (e.g., in solution) , a chemical equilibrium of tautomers can be reached. Tautomerizations (i.e., the reaction providing a tautomeric pair) can be catalyzed by acid or base, or can occur without the action or presence of an external agent. Exemplary tautomerizations include, but are not limited to, keto-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to- (a different) enamine tautomerizations. A specific example of keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers.

Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C-or ¹⁴C-enriched carbon are within the scope of this disclosure.

The disclosure also embraces pharmaceutically acceptable forms that are “isotopically labeledderivatives” which are compounds that are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Certain isotopically-labeled disclosed compounds (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can allow for ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) . Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, provided herein are compounds that can also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. All isotopic variations of the compounds as disclosed herein, whether radioactive or not, are encompassed within the scope of the present disclosure. In some embodiments, radiolabeled compounds are useful for studying metabolism and/or tissue distribution of the compounds or to alter the rate or path of metabolism or other aspects of biological functioning

"Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The pharmaceutically acceptable carrier or excipient does not destroy the pharmacological activity of the disclosed compound and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions as disclosed herein is contemplated. Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; releasing agents; coating agents; sweetening, flavoring and perfuming agents; preservatives; antioxidants; ion exchangers; alumina; aluminum stearate; lecithin; self emulsifying drug delivery systems (SEDDS) such as d-atocopherol polyethyleneglycol 1000 succinate; surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices; serum proteins such as human serum albumin; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; polyacrylates; waxes; and polyethylene-polyoxypropylene-block polymers. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2-and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein.

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sansalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5th ed., John Wiley &Sons, Inc., NewYork, 2001; Larock, Comprehensive Organic Transformations, VCHPublishers, Inc., NewYork, 1989; and Carruthers, Some ModernMethods of Organic Synthesis, 3rd ed., Cambridge University Press, Cambridge, 1987.

When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, "C _1-6 alkyl" is intended to encompass, C ₁, C ₂, C ₃, C ₄, C ₅, C ₆, C _1-6, C _1-5, C _1-4, C _1-3, C _1-2, C _2-6, C _2-5, C _2-4, C _2-3, C _3-6, C _3-5, C _3-4, C _4-6, C _4-5, and C _5-6 alkyl.

"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., C _1-10 alkyl) . Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; e.g., "1 to 10 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, “alkyl” can be a C _1-6 alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more of substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si (R ^a) ₃ , -OR ^a, -SR ^a, -OC (O) -R ^a, -N (R ^a) ₂, -C (O) R _a, -C (O) OR ^a, -OC (O) N (R ^a) ₂, -C (O) N (R ^a) ₂, -N (R ^a) C (O) OR ^a, -N (R ^a) C (O) R ^a, -N (R ^a) C (O) N (R ^a) ₂, -N (R ^a) C (NR ^a) N (R ^a) ₂, -N (R ^a) S (O) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In a non-limiting embodiment, a substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

"Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., C _2-10 alkenyl) . Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range; e.g., "2 to 10 carbon atoms" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to six carbon atoms (e.g., C _2-6 alkenyl) . The alkenyl is attached to the parent molecular structure by a single bond, for example, ethenyl (i.e., vinyl) , prop-1-enyl (i.e., allyl) , but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like. The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl) . Examples of C _2-4 alkenyl groups include ethenyl (C ₂) , 1-propenyl (C ₃) , 2-propenyl (C ₃) , 1-butenyl (C ₄) , 2-butenyl (C ₄) , 2-methylprop-2-enyl (C ₄) , butadienyl (C ₄) and the like. Examples of C _2-6 alkenyl groups include the aforementioned C _2-4 alkenyl groups as well as pentenyl (C ₅) , pentadienyl (C ₅) , hexenyl (C ₆) , 2, 3-dimethyl-2-butenyl (C ₆) and the like. Additional examples of alkenyl include heptenyl (C ₇) , octenyl (C ₈) , octatrienyl (C ₈) and the like. Unless stated otherwise in the specification, an alkenyl group can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si (R ^a) ₃ , -OR ^a, -SR ^a, -OC (O) -R ^a, -N (R ^a) ₂, -C (O) R _a, -C (O) OR ^a, -OC (O) N (R ^a) ₂, -C (O) N (R ^a) ₂, -N (R ^a) C (O) OR ^a, -N (R ^a) C (O) R ^a, -N (R ^a) C (O) N (R ^a) ₂, -N (R ^a) C (NR ^a) N (R ^a) ₂, -N (R ^a) S (O) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

"Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., C _2-10 alkynyl) . Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range; e.g., "2 to 10 carbon atoms" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to six carbon atoms (e.g., C _2-6 alkynyl) . The alkynyl is attached to the parent molecular structure by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, 3-methyl-4-pentenyl, hexynyl, and the like. Unless stated otherwise in the specification, an alkynyl group can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si (R ^a) ₃ , -OR ^a, -SR ^a, -OC (O) -R ^a, -N (R ^a) ₂, -C (O) R _a, -C (O) OR ^a, -OC (O) N (R ^a) ₂, -C (O) N (R ^a) ₂, -N (R ^a) C (O) OR ^a, -N (R ^a) C (O) R ^a, -N (R ^a) C (O) N (R ^a) ₂, -N (R ^a) C (NR ^a) N (R ^a) ₂, -N (R ^a) S (O) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

"Alkoxy" refers to the group -O-alkyl, including from 1 to 10 carbon atoms of a straight, branched, saturated cyclic configuration and combinations thereof, attached to the parent molecular structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, cyclopropyloxy, cyclohexyloxy and the like. "Lower alkoxy" refers to alkoxy groups containing one to six carbons. In some embodiments, C _1-4alkoxy is an alkoxy group which encompasses both straight and branched chain alkyls of from 1 to 4 carbon atoms. Unless stated otherwise in the specification, an alkoxy group can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si (R ^a) ₃ , -OR ^a, -SR ^a, -OC (O) -R ^a, -N (R ^a) ₂, -C (O) R _a, -C (O) OR ^a, -OC (O) N (R ^a) ₂, -C (O) N (R ^a) ₂, -N (R ^a) C (O) OR ^a, -N (R ^a) C (O) R ^a, -N (R ^a) C (O) N (R ^a) ₂, -N (R ^a) C (NR ^a) N (R ^a) ₂, -N (R ^a) S (O) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. The terms "alkenoxy" and "alkynoxy" mirror the above description of "alkoxy" wherein the prefix "alk" is replaced with "alken" or "alkyn" respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein.

"Aromatic" or "aryl" refers to a radical with 6 to 14 ring atoms (e.g., C _6-14 aromatic or C _6- ₁₄ aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl) . In some embodiments, the aryl is a C _6-10 aryl group. For example, bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. In other embodiments, bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in"-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as "6 to 14aryl “refers to each integer in the given range; e.g., "6 to 14 ring atoms" means that the aryl group can consist of 6 ring atoms, 7 ring atoms, etc., up to and including 14 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In a multi-ring group, only one ring is required to be aromatic, so groups such as indanyl are encompassed by the aryl definition. Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl, indanyl, and the like. Unless stated otherwise in the specification, an aryl moiety can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si (R ^a) ₃ , -OR ^a, -SR ^a, -OC (O) -R ^a, -N (R ^a) ₂, -C (O) R _a, -C (O) OR ^a, -OC (O) N (R ^a) ₂, -C (O) N (R ^a) ₂, -N (R ^a) C (O) OR ^a, -N (R ^a) C (O) R ^a, -N (R ^a) C (O) N (R ^a) ₂, -N (R ^a) C (NR ^a) N (R ^a) ₂, -N (R ^a) S (O) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

"Cycloalkyl" and "carbocyclyl" each refer to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated or partially unsaturated. Partially unsaturated cycloalkyl groups can be termed "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C _3-13 cycloalkyl) . Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range; e.g., "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In some embodiments, “cycloalkyl” can be a C _3-8 cycloalkyl radical. In some embodiments, “cycloalkyl” can be a C _3-5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: C _3-6 carbocyclyl groups include, without limitation, cyclopropyl (C ₃) , cyclobutyl (C ₄) , cyclopentyl (C ₅) , cyclopentenyl (C ₅) , cyclohexyl (C ₆) , cyclohexenyl (C ₆) , cyclohexadienyl (C ₆) and the like. Examples of C _3-7 carbocyclyl groups include norbornyl (C ₇) . Examples of C _3-8 carbocyclyl groups include the aforementioned C _3-7 carbocyclyl groups as well as cycloheptyl (C ₇) , cycloheptadienyl (C ₇) , cycloheptatrienyl (C ₇) , cyclooctyl (C ₈) , bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl, and the like. Examples of C _3-13 carbocyclyl groups include the aforementioned C _3-8 carbocyclyl groups as well as octahydro-1H indenyl, decahydronaphthalenyl, spiro [4.5] decanyl and the like. Unless stated otherwise in the specification, a cycloalkyl group can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si (R ^a) ₃ , -OR ^a, -SR ^a, -OC (O) -R ^a, -N (R ^a) ₂, -C (O) R _a, -C (O) OR ^a, -OC (O) N (R ^a) ₂, -C (O) N (R ^a) ₂, -N (R ^a) C (O) OR ^a, -N (R ^a) C (O) R ^a, -N (R ^a) C (O) N (R ^a) ₂, -N (R ^a) C (NR ^a) N (R ^a) ₂, -N (R ^a) S (O) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. The terms “cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl" wherein the prefix "alk" is replaced with "alken" or "alkyn" respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

"Halo" , "halide" , or, alternatively, "halogen" means fluoro, chloro, bromo or iodo. The terms "haloalkyl, " "haloalkenyl, " "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof, preferably substituted with one, two, or three halo groups. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, -O-CHF ₂, and the like. Each of the alkyl, alkenyl, alkynyl and alkoxy groups are as defined herein and can be optionally further substituted as defined herein.

"Heteroaryl" or, alternatively, "heteroaromatic" refers to a refers to a radical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic and the like) aromatic ring system (e.g., having 6, 10 or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ( "5-18 membered heteroaryl") . Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range; e.g., "5 to 18 ring atoms" means that the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. In some instances, a heteroaryl can have 5 to 14 ring atoms. In some embodiments, the heteroaryl has, for example, bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-ene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylene.

For example, an N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. One or more heteroatom (s) in the heteroaryl radical can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally quaternized. Heteroaryl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridinyl N-oxides. The heteroaryl is attached to the parent molecular structure through any atom of the ring (s) .

"Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment to the parent molecular structure is either on the aryl or on the heteroaryl ring, or wherein the heteroaryl ring, as defined above, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment to the parent molecular structure is on the heteroaryl ring. For polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl and the like) , the point of attachment to the parent molecular structure can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl) . In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ( "5-10 membered heteroaryl" ) . In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ( "5-8 membered heteroaryl" ) . In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ( "5-6 membered heteroaryl" ) . In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur.

Examples ofheteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1, 3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo [d] thiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, benzo [b] [1, 4] oxazinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzopyranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl) , benzothieno [3, 2-d] pyrimidinyl, benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, cyclopenta [d] pyrimidinyl, 6, 7-dihydro-5H-cyclopenta [4, 5] thieno [2, 3-d] pyrimidinyl, 5, 6-dihydrobenzo [h] quinazolinyl, 5, 6-dihydrobenzo [h] cinnolinyl, 6, 7-dihydro-5H benzo [6, 7] cyclohepta [1, 2-c] pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo [3, 2 -c] pyridinyl, 5, 6, 7, 8, 9, 10-hexahydrocycloocta [d] pyrimidinyl, 5, 6, 7, 8, 9, 10-hexahydrocycloocta [d] pyridazinyl, 5, 6, 7, 8, 9, 10-hexahydrocycloocta [d] pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5, 8-methano-5, 6, 7, 8-tetrahydroquinazolinyl, naphthyridinyl, 1, 6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5, 6, 6a, 7, 8, 9, 10, 10a-octahydrobenzo [h] quinazolinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo [3, 4-d] pyrimidinyl, pyridinyl, pyrido [3, 2-d] pyrimidinyl, pyrido [3, 4-d] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5, 6, 7, 8-tetrahydroquinazolinyl, 5, 6, 7, 8-tetrahydrobenzo [4, 5 ] thieno [2, 3 -d] pyrimdinyl, 6, 7, 8, 9-tetrahydro-5H-cyclohepta [4, 5] thieno [2, 3-d] pyrimidinyl, 5, 6, 7, 8-tetrahydropyrido [4, 5-c] pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno [2, 3-d] pyrimidinyl, thieno [3, 2-d] pyrimidinyl, thieno [2, 3-c] pridinyl, and thiophenyl (i.e., thienyl) . Unless statedotherwise in the specification, a heteroaryl moiety can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si (R ^a) ₃ , -OR ^a, -SR ^a, -OC (O) -R ^a, -N (R ^a) ₂, -C (O) R _a, -C (O) OR ^a, -OC (O) N (R ^a) ₂, -C (O) N (R ^a) ₂, -N (R ^a) C (O) OR ^a, -N (R ^a) C (O) R ^a, -N (R ^a) C (O) N (R ^a) ₂, -N (R ^a) C (NR ^a) N (R ^a) ₂, -N (R ^a) S (O) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

"Heterocyclyl" , "heterocycloalkyl" or “heterocarbocyclyl" each refer to any 3 to 18-membered non-aromatic radical monocyclic or polycyclic moiety comprising at least one heteroatom selected from nitrogen, oxygen, phosphorous and sulfur. A heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the polycyclic ring systems can be a fused, bridged or spiro ring system. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. A heterocyclyl group can be saturated or partially unsaturated. Partially unsaturated heterocycloalkyl groups can be termed "heterocycloalkenyl" if the heterocyclyl contains at least one double bond, or "heterocycloalkynyl" if the heterocyclyl contains at least one triple bond. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range; e.g., "5 to 18 ring atoms" means that the heterocyclyl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. For example, bivalent radicals derived from univalent heterocyclyl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-ene" to the name of the corresponding univalent radical, e.g., a piperidine group with two points of attachment is a piperidylene.

An N-containing heterocyclyl moiety refers to a non-aromatic group in which at least one of the ring atoms is a nitrogen atom. The heteroatom (s) in the heterocyclyl radical can be optionally oxidized. One or more nitrogen atoms, if present, can be optionally quaternized. Heterocyclyl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as piperidinyl N-oxides. The heterocyclyl is attached to the parent molecular structure through any atom of any of the ring (s) .

"Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment to the parent molecular structure is on the heterocyclyl ring. In some embodiments, a heterocyclyl group is a 5-14 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ( "5-14 membered heterocyclyl" ) . In some embodiments, a heterocyclyl group is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ( "3-10 membered heterocyclyl" ) . In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ( "5-8 membered heterocyclyl" ) . In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ( "5-6 membered heterocyclyl" ) . In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen phosphorous and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorous and sulfur.

Exemplary 3-membered heterocyclyls containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyls containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyls containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyls containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, thiazolidinyl, and dithiolanyl. Exemplary 5-membered heterocyclyls containing 3 heteroatoms include, without limitation, triazolinyl, diazolonyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6 membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, and triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, benzothianyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, 3-1H-benzimidazol-2-one, (1-substituted) -2-oxo-benzimidazol-3-yl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1, 8-naphthyridinyl, octahydropyrrolo [3, 2 -b] pyrrole, phenanthridinyl, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo [e] [1, 4] diazepinyl, 1, 4, 5, 7-tetrahydropyrano [3, 4-b] pyrrolyl, 5, 6-dihydro-4H-furo [3, 2-b] pyrrolyl, 6, 7-dihydro-5H-furo [3, 2- b] pyranyl, 5, 7-dihydro-4H-thieno [2, 3-c] pyranyl, 2, 3-dihydro-lH-pyrrolo [2, 3-b] pyridinyl, hydrofuro [2, 3-b] pyridinyl, 4, 5, 6, 7 tetrahydro-1H-pyrrolo [2, 3-b] pyridinyl, 4, 5, 6, 7-tetrahydrofuro [3, 2-c] pyridinyl, 4, 5, 6, 7-tetrahydrothieno [3, 2-b] pyridinyl, 1, 2, 3, 4-tetrahydro-1, 6-naphthyridinyl, and the like.

Unless stated otherwise in the specification, a heterocyclyl moiety can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si (R ^a) ₃ , -OR ^a, -SR ^a, -OC (O) -R ^a, -N (R ^a) ₂, -C (O) R _a, -C (O) OR ^a, -OC (O) N (R ^a) ₂, -C (O) N (R ^a) ₂, -N (R ^a) C (O) OR ^a, -N (R ^a) C (O) R ^a, -N (R ^a) C (O) N (R ^a) ₂, -N (R ^a) C (NR ^a) N (R ^a) ₂, -N (R ^a) S (O) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

Where substituent groups are specified by their conventional chemical Formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH ₂O-is equivalent to -OCH ₂-.

A "leaving group or atom" is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable non-limiting examples of such groups unless otherwise specified include halogen atoms, mesyloxy, p-nitrobenzensulphonyloxy, trifluoromethyloxy, and tosyloxy groups.

"Protecting group" has the meaning conventionally associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete. Non-limiting embodiments of functional groups that can be masked with a protecting group include an amine, hydroxy, thiol, carboxylic acid, and aldehyde. For example, a hydroxy protected form is where at least one of the hydroxy groups present in a compound is protected with a hydroxy protecting group. A variety of protecting groups are disclosed, for example, in T.H. Greene and R G.M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley &Sons, New York (1999) , incorporated herein by reference in its entirety. For additional background information on protecting group methodologies (materials, methods and strategies for protection and deprotection) and other synthetic chemistry transformations useful in producing the compounds described herein, see in R. Larock, Comprehensive organic Transformations, VCH Publishers (1989) ; T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons (1999) ; L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994) ; and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) . These references are incorporated herein by reference in their entirety.

The terms "substituted" or "substitution" mean that at least one hydrogen present on a group atom (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution for the hydrogen results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group can have a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. Substituents include one or more group (s) individually and independently selected from acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si (R ^a) ₃ , -OR ^a, -SR ^a, -OC (O) -R ^a, -N (R ^a) ₂, -C (O) R _a, -C (O) OR ^a, -OC (O) N (R ^a) ₂, -C (O) N (R ^a) ₂, -N (R ^a) C (O) OR ^a, -N (R ^a) C (O) R ^a, -N (R ^a) C (O) N (R ^a) ₂, -N (R ^a) C (NR ^a) N (R ^a) ₂, -N (R ^a) S (O) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. For example, a cycloalkyl substituent can have a halide substituted at one or more ring carbons, and the like. The protecting groups that can form the protective derivatives of the above substituents are known to those of skill in the art and can be found in references such as Greene and Wuts, above.

Suitable substituents include, but are not limited to, haloalkyl and trihaloalkyl, alkoxyalkyl, halophenyl, -M-heteroaryl, -M-heterocycle, -M-aryl, -M-OR ^a, -M-SR ^a , -M-N (R ^a) ₂, -M-OC (O) N (R ^a) ₂, -M-C (=NR ^a) N (R ^a) ₂, -M-C (=NR ^a) OR ^a, -M-P (O) (R ^a) ₂, Si (R ^a) ₃, -M-NR ^aC (O) R ^a, -M-NR ^aC (O) OR ^a, -M-C (O) R ^a, -M-C (=S) R ^a, -M-C (=S) NR ^aR ^a, -M-C (O) N (R ^a) ₂, -M-C (O) NR ^a-M-N (R ^a) ₂, -M-NR ^aC (NR ^a) N (R ^a) ₂, -M-NR ^aC (S) N (R ^a) ₂, -M-S (O) ₂R ^a, -M C (O) R ^a, -M-OC (O) R ^a, - MC (O) SR ^a, -M-S (O) ₂N (R ^a) ₂, -C (O) -M-C (O) R ^a, -MCO ₂R ^a, -MC (=O) N (R ^a) ₂, -M-C (=NH) N (R ^a) ₂, and -M-OC (=NH) N (R ^a) ₂ (wherein M is a C _1-6 alkyl group) .

When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl) is substituted with several substituents varying within an expressly defined range, it is understood that the total number of substituents does not exceed the normal available valencies under the existing conditions. Thus, for example, a phenyl ring substituted with "p" substituents (where "p" ranges from 0 to 5) can have 0 to 5 substituents, whereas it is understood that a pyridinyl ring substituted with "p" substituents has several substituents ranging from 0 to 4. The maximum number of substituents that a group in the disclosed compounds can have can be easily determined. The substituted group encompasses only those combinations of substituents and variables that result in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one that, among other factors, has stability sufficient to permit its preparation and detection. In some embodiments, disclosed compounds are sufficiently stable that they are not substantially altered when kept at a temperature of 40℃ or less, in the absence of moisture (e.g., less than about 10%, less than about 5%, less than about 2%, less than about 1%, or less than about 0.5%) or other chemically reactive conditions, for e.g., at least about 3 days, at least about a week, at least about 2 weeks, at least about 4 weeks, or at least about 6 weeks.

The terms “combine, combining, to combine, combination” refer to the action of adding at least one chemical substance to another chemical substance (s) either sequentially or simultaneously. In some embodiments, bringing these chemical substances together can result in transformation of the initial chemical substances into one or more different chemical substances. This transformation can occur through one or more chemical reactions, e.g., where covalent bonds are formed, broken, rearranged and the like. A non-limiting example can include hydrolysis of an ester into an alcohol and carboxylic acid which can result from the combination of the ester with a suitable base. In another non-limiting example, an aryl fluoride can be combined with an amine to provide an aryl amine through a substitution process. These terms also include changes in association of charged chemical substances and creation of charged chemical substances, such as, but not limited to, N-oxide formation, acid addition salt formation, basic addition salt formation, and the like. These terms include the creation and/or transformation of radical chemical substances and isotopically labeled chemical substances.

The terms “convert, converting, to convert, conversion” refer to a subset of “combination” and its grammatical equivalents, where the action of one or more reagents transforms one or more functional groups on a chemical substance to another functional group (s) . For example, a conversion includes, but is not limited to, transforming a nitro functional group on a chemical substance to an amine with a reducing agent. Conversions also include changes in charged chemical substances, radical chemical substances and isotopically labeled chemical substances. However, the term “convert” does not include alteration of conserved bonds in disclosed genuses and compounds.

Compounds

In one aspect, the present invention relates to a compound of Formula (I) :

wherein:

R ⁴ is hydrogen, halogen, C _1-6alkyl, C _1-6alkoxy or CN;

X is O, or NR ⁷;

each q is independently 0-6;

w is 1-6; and

In some embodiments, the compound of Formula (I) can be a compound of Formula (Ia) :

wherein:

R ⁴ is hydrogen, halogen, C _1-6alkyl, C _1-6alkoxy or CN;

each q is independently 0-6;

w is 1-6; and

In some embodiments, the compound of Formula I can be a compound of Formula (Ib) :

wherein:

R ⁴ is hydrogen, halogen, C _1-6alkyl, C _1-6alkoxy or CN;

each q is independently 0-6;

w is 1-6; and

In certain embodiments, R ¹ is hydrogen. In certain other embodiments, R ¹ is halogen. In some embodiments, R ⁴ is hydrogen.

In some embodiments, the compound of Formula I can be a compound of Formula (Ic) :

wherein:

R ²is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, haloC _1-6alkoxy, O (CH ₂) _q-phenyl, CN, or C _3-7cycloalkyl;

R ³hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, O (CH ₂) _q-phenyl, CN, amino, C _3- ₇cycloalkyl, O (CH ₂) _wR ⁶, O (CH ₂) _mO (CH ₂) _nR ⁶, or O-C _1-6alkyl-R ⁶;

R ⁵is hydrogen, C _1-6alkyl, haloC _1-6alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, C _1-6alkyl-OH, or C _1-6alkyl-O-C _1-6alkyl;

each q is independently 0-6;

w is 1-6; and

In some embodiments, the compound of Formula I can be a compound of Formula (Id) :

wherein:

R ² is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, O (CH ₂) _q-phenyl, CN, or C _3- ₇cycloalkyl;

R ³ is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, haloC _1-6alkoxy, O (CH ₂) _q-phenyl, CN, amino, C _3-7cycloalkyl, O (CH ₂) _wR ⁶, O (CH ₂) _mO (CH ₂) _nR ⁶, or O-C _1-6alkyl-R ⁶;

each q is independently 0-6;

w is 1-6; and

In certain embodiments, R ³ isC _1-6alkoxy. In certainother embodiments, R ³ is O (CH ₂) _q-phenyl. In yet other embodiments, R ³ is O (CH ₂) _wR ⁶. In certainother embodiments, R ³ is O (CH ₂) _mO (CH ₂) _nR ⁶. In yetother embodiments, R ³ is O-C _1-6alkyl-R ⁶.

In certain embodiments, R ⁶ is OH. In certainother embodiments, R ⁶ is C _1-6alkoxy. In yet other embodiments, R ⁶ is methoxy. In yet other embodiments, R ⁶ is C _3-7cycloalkyl.

In some embodiments, the compound of Formula I can be a compound of Formula (Ie) :

wherein:

R ⁸ is hydrogen, C _1-6alkyl, C _3-7cycloalkyl, C _2-6alkenyl, C _2-6alkynyl, or phenyl;

each q is independently 0-6; and

x is 1-5, or a pharmaceutically acceptable salt or enantiomer thereof.

In some embodiments, the compound of Formula I can be a compound of Formula (If) :

wherein:

R ⁷ is hydrogen, C _1-4alkyl, CD ₃, haloC _1-4alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, (CH ₂) _q-monocyclic heteroaryl, C _1-4alkyl-OH, or C _1-4alkyl-O-C _1-4alkyl;

each q is independently 0-6; and

x is 1-5, or a pharmaceutically acceptable salt or enantiomer thereof.

In certain embodiments, R ⁸ is methyl. In certain other embodiments, R ⁸ is ethyl. In certain embodiments, R ⁸ is hydrogen.

In certain embodiments, x is 1. In certain other embodiments, x is 2.

In certain embodiments, R ⁷ is hydrogen. In certain other embodiments, R ⁷ isC _1-4alkyl. In certain embodiments, R ⁷ is methyl or ethyl. In certain other embodiments, R ⁷ is CD ₃. In certain embodiments, R ⁷ ishaloC _1-4alkyl. In certain other embodiments, R ⁷ is C _3-7cycloalkyl. In certain embodiments, R ⁷ is (CH ₂) _q-phenyl. In certain other embodiments, R ⁷ is monocyclic heterocycloalkyl. In certain embodiments, R ⁷ is (CH ₂) _q-monocyclic heteroaryl. In certain other embodiments, R ⁷ is C _1-4alkyl-O-C _1-4alkyl.

In certain embodiments, R ² is halogen. In certain other embodiments, R ² is C _1-6alkoxy. In certain embodiments, R ² is haloC _1-6alkoxy. In certain other embodiments, R ² is Cl. R ² is F. In certain embodiments, R ² is -OCHF ₂. In certain other embodiments, R ² is methoxy.

In certain embodiments, R ⁵ is C _1-6alkyl. In certain other embodiments, R ⁵ is iso-propyl. R ⁵ is (S) -iso-propyl. In certain embodiments, R ⁵ is t-butyl. In certain other embodiments, R ⁵ is C _3-7cycloalkyl. In certain embodiments, R ⁵ is cyclopropyl or cyclobutyl. In certain other embodiments, R ⁵ is (CH ₂) _q-phenyl. In certain embodiments, R ⁵ is phenyl. In certain other embodiments, R ⁵ is monocyclic heteroaryl. In certain embodiments, R ⁵ is pyridyl, thiophenyl, or thiozolyl. In certain other embodiments, R ⁵ is C _1-6alkyl-OH. In certain embodiments, R ⁵ is C _1- ₆alkyl-O-C _1-6alkyl. In certain other embodiments, R ⁵ is -C (CH ₃) ₂CH ₂OH or -C (CH ₃) ₂CH ₂OCH ₃.

In certain embodiments, each haloC _1-6alkyl, haloC _1-4alkyl, and haloC _1-6alkoxy mentioned above independently contains one, two or three halogens. In certain other embodiments, each haloC _1-6alkyl, haloC _1-4alkyl, and haloC _1-6alkoxy mentioned above independently contains one, two or three fluorines.

In some embodiments, the compound of the present invention is selected from:

2-Chloro-3- (3-methoxypropoxy) -6-methyl-10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

(S) -2-chloro-6-isopropyl-3- (3-methoxy-propoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

(R) -2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido - [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-6-cyclopropyl-3- (3-methoxypropoxy) -10-oxo -6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-6-cyclobutyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6-phenyl-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6- (pyridin-4-yl) -6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

(6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-6-isopropyl-3- (2-methoxyethoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

(6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid) ,

(S) - (6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid) ,

(R) - (6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid) ,

2-fluoro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydrobenzo - [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H -pyrido [1, 2-c] quinazoline-9-carboxylic acid,

6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6- (1-methoxy-2-methylpropan-2-yl) -3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6- (1-hydroxy-2-methylpropan-2-yl) -3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6-phenyl-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6- (thiazol-2-yl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6- (thiophen-2-yl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-fluoro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

(2-chloro-6- (1-methoxy-2-methylpro -pan-2-yl) -3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-5-ethyl-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6-isopropyl-5- (2-methoxyethyl) -3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5- (2, 2, 2-trifluoro -ethyl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

5-benzyl-2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5- (pyridin-4-ylmethyl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-fluoro-6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-3- (3-methoxypropoxy) -5-methyl-10-oxo-6- (thiazol-2-yl) -5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-3- (3-methoxypropoxy) -5- (methyl-d3) -10-oxo-6- (thiazol-2-yl) -5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-5- (2-methoxyethyl) -3- (3-methoxypropoxy) -10-oxo-6- (thiazol-2-yl) -5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

5- (Azetidin-3-yl) -2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-5-cyclobutyl-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-6-isopropyl-3- (3-methoxypropoxy) -5- (oxetan-3-yl) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-5-cyclopropyl-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-5, 6-diisopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2- (Difluoromethoxy) -6-isopropyl-5- (2-methoxyethyl) -3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

5- (Tert-butyl) -2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydrobenzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

6- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid, and

2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid; or a pharmaceutically acceptable salt or enantiomer thereof.

In some embodiments, the compound of the present invention is selected from:

5- (Tert-butyl) -2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid, and

10-chloro-11- (3-methoxypropoxy) -7-oxo-2, 3, 3a, 7-tetrahydro-1H-pyrido [1, 2-c] pyrrolo [1, 2-a] quinazoline-6-carboxylic acid; or a pharmaceutically acceptable salt or enantiomer thereof.

In certain embodiments, the compound of the invention is (S) -2-chloro-6-isopropyl-3- (3-methoxy-propoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid, or a pharmaceutically acceptable salt thereof.

In certain other embodiments, the compound of the invention is (S) - (6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid) , or a pharmaceutically acceptable salt thereof.

In certain other embodiments, the present invention relates to a compound of Formula (I) , (Ia) , (Ib) , (Ic) , (Id) , (Ie) , or (If) described herein, wherein one or more hydrogen atoms are replaced by deuterium.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound described herein, and a pharmaceutically acceptable carrier.

In another aspect, the present invention relates to a method for treatment and/orprophylaxis of hepatitis B infection in a subject in need thereof, comprising administering an effective amount of a compound described herein to the subject.

General Synthetic Methods

The compounds of the present invention can be prepared by any conventional methods. The process to make these compounds as well as their starting materials are listed in the below schemes. All substituents, in particular, R ¹ to R ⁵ and X are defined above unless otherwise indicated. All reactions, reaction conditions, abbreviations and symbols have the well-known meaning to a well skilled person in organic chemistry.

General synthetic route for Compounds of Formula (Ia) :

Scheme 1

The compound of formula I can be prepared according Scheme 1. Coupling Compound II with pinacol borane in the presence of Pd catalyst gives Compound III, which was then oxidized in the presence of oxone to afford phenol IV. Bromination with NBS on the phenol IV gives Compound V. Protection of phenol of Compound VI with MOMCl gives Compound VI. Coupling Compound VI with pinacol borane in the presence of Pd catalyst gives Compound VII. Using Suzuki coupling reaction, Compound VII reacts with substituted 2-chloro-pyridine to get Compound VIII, which was de-protected in the acidic condition to afford CompoundVIIII. Compound VIIII reacts with substituted 1, 1-dibromo-alkane or other related reagents to give Compound X. Hydrolyzation of Compound X with a base affords compound of formula Ia.

General synthetic route for Compounds I-1:

Scheme 2

The compound of formula I-1 can be prepared according Scheme 2. Reduction of Compound XI with Fe gives aniline XII. Bromination with NBS on the aniline XII gives Compound XIII. Coupling Compound XIII with pinacol borane in the presence of Pd catalyst gives Compound XIV. Using Suzuki coupling reaction, Compound XIV reacts with substituted 2-chloro-pyridine to get Compound XV, which was de-protected in the acidic condition to afford Compound XVI. Compound XVI reacts with different aldehyde to give Compound XVII. Hydrolyzation of Compound XVII with a base affords compound of formula I-1.

General synthetic route for Compounds Ib:

Scheme 3

The compound of formula I-2 can be prepared according Scheme 3. Compound XVII reacted with different halides or sulphonates etc. affords Compound XVIII. Hydrolyzation of Compound XVIII with a base affords compound of formula I-2.

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION

The compounds utilized in the methods described herein may be formulated together with a pharmaceutically acceptable carrier or adjuvant into pharmaceutically acceptable compositions prior to be administered to a subject. In another embodiment, such pharmaceutically acceptable compositions further comprise additional therapeutic agents in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein.

The term “pharmaceutically acceptable carrier or adjuvant” refers to a carrier or adjuvant that may be administered to a subject, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2-and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.

The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

When the compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95%of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.

The compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the mode of administration. A typical preparation will contain from about 5%to about 95%active compound (w/w) . Alternatively, such preparations contain from about 20%to about 80%active compound.

Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.

Upon improvement of a subject’s condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

The pharmaceutical compositions described above comprising a compound of formula I may further comprise another therapeutic agent useful for the treatment and prophylaxis of hepatitis B virus.

INDICATIONS AND METHODS OF TREATMENT

The compounds of the invention can inhibit HBsAg secretion or production, and inhibit HBV DNA production and HBV gene expression. Therefore, the compounds of the invention are useful for the treatment and/or prophylaxis of HBV infection.

The invention relates to a method for the treatment or prophylaxis of HBV infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I, a stereoisomer or pharmaceutically acceptable salts thereof.

COMBINATION THERAPY

The compounds of the present invention can be combined with other anti-HBV agents such as INFs (INF-2, INF-2, pegINF-, etc. ) ; nucleos (t) ide analogues (ribavirin, lamivuldine, entecavir, tenofovir, telbivudine, adefovir, tenofovir disoproxil fumarate (TDF) , tenofovir alafenamide fumarate (TAF) , CMX157 etc. ) ; or other anti-HBV agents such as HBV RNA replication inhibitors, HBsAg secretion inhibitors, HBV capsid modulators, antisense oligomers, siRNA, HBV vaccine, HBV antibody therapy, TLR 2, 3, 7, 8 and 9 agonists and Rig-1 agonists for treatment and/or prophylaxis of HBV. The compounds of the present inventioncan also be combined with agents that target PD-1 or PD-L1. Exemplary PD-1 agents include, but not limited to, Pembrolizumab, Nivolumab, Pidilizumab, AMP-224, AMP-514, and PDR001. Exemplary PD-L1 agents include, but not limited to, Atezolizumab, Avelumab, Durvalumab, and BMS-936559.

The invention will be more understood by reference to the following examples, but they should not limit the scope of the invention.

Abbreviations used herein are as follows:

BBr ₃ borontribromide

Cs ₂CO ₃ cesium carbonate

DCM dichloromethame

DMSO dimethyl sulfoxide

DMF N, N-dimethylformamide

EtOAc ethyl acetate

HCl hydrochloride

K ₂CO ₃ potassium carbonate

K ₃PO ₄ potassium phosphate

KOAc potassium acetate

MeOH methanol

MTBE methyl t-butyl ether

MOMCl chloromethyl methyl ether

NaH sodium hydride

NBS N-bromosuccinimide

Oxone potassium peroxomonosulphate

PE petroleum ether

Pd (dppf) Cl ₂ [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium

Pd (PPh ₃) ₄ tetrakis (triphenylphosphine) palladium

i-PrOH propan-2-ol

THF tetrahydrofuran

TFA trifluoroacetic acid

GENERAL EXPERIMENTAL CONDITIONS

In the following examples, the reagents (chemicals) were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company) , and used without further purification. Analytical and preparative thin layer chromatography (TLC) plates were HSGF 254 (0.15-0.2 mm thickness, Shanghai Anbang Company, China) . Nuclear magnetic resonance (NMR) spectra were obtained on a Brucker AMX-400 NMR (Brucker, Switzerland) . Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were given with electrospray ionization (ESI) from a Shimadzu LCMS-2020 Mass Spectrometer (Shimadzu, Japan) . HPLC chromatographs were recorded on a Shimadzu LC-2010A HT Liquid Chromatography (Shimadzu, Japan column: Ultimate 4.6mmx250 mm, 5μm, mobile phase A: 0.1%formic acid in water; mobile phase B: acetonitrile) . Microwave reactions were run on an Initiator 2.5 Microwave Synthesizer (Biotage, Sweden) . Chiral HPLC chromatographs were recorded on a Shimadzu LC-20AD Liquid Chromatography (Column AY-H, 150*4.6mm, 5um; mobile phase: Hexane/EtOH =60/40 (V/V) )

PREPARATIVE EXAMPLES

Example 1: 2-Chloro-3- (3-methoxypropoxy) -6-methyl-10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid

Step 1: Preparation of 4-bromo-1-chloro-2- (3-methoxy-propoxy) benzene)

To a mixture of 5-bromo-2-chlorophenol (15.0 g, 72.81 mmol) in DMF (200 mL) at r.t. were added 1-bromo-3-methoxypropane (13.2 g, 87.37 mmol) and K ₂CO ₃ (15.07 g, 109.22 mmol) . The reaction mixture was stirred at r.t. for 16 hr then quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 10/1) to afford the desired product (18.1 g, 89.1%yield) .

Step 2: Preparation of 2- (4-chloro-3- (3-methoxypropoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane

To a mixture of 4-bromo-1-chloro-2- (3-methoxypropoxy) benzene in1, 4-dioxane (200 mL) (10 g, 30.67 mmol) under N ₂were added 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (10.9 g, 43.16 mmol) , Pd (dppf) Cl ₂ (1.31 g, 1.79 mmol) andKOAc (10.57 g, 107.9 mmol) . The reaction mixture was stirred at 90℃ overnight then filtered through Celite. The filtrate was collected and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 10/1) to afford the desired product (8.2 g, 70.1%yield) . LC-MS: m/z 327 (M+H) ⁺.

Step 3: Preparation of 4-chloro-3- (3-methoxypropoxy) phenol

To a mixture of 2- (4-chloro-3- (3-methoxypropoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (8.2 g, 25.15 mmol) in acetone (75 mL) and water (75 mL) at 0℃ was added oxone (30.88 g, 50.3 mmol) . The reaction mixture was stirred at 0℃ for 1hr then quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was directly used in the next step without any further purification. LC-MS: m/z 217.2 (M+H) ⁺.

Step 4: Preparation of 2-bromo-4-chloro-5- (3-methoxypropoxy) phenol

To a mixture of 4-chloro-3- (3-methoxypropoxy) phenol (5.8 g, 26.85 mmol) in DCM (100 mL) at0℃ was added NBS (4.78 g, 26.85 mmol) . The reaction mixture was stirred at 0℃ for 0.5 hr then quenched with water and extracted by DCM. The combined organic layers were dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 5/1) to afford the desired product (5.2 g, 66%%yield) . LC-MS: m/z 295.1 (M+H) ⁺.

Step 5: Preparation of 1-bromo-5-chloro-2- (methoxymethoxy) -4- (3-methoxy -propoxy) benzene

To a mixture of 2-bromo-4-chloro-5- (3-methoxypropoxy) phenol (5.2 g, 17.62 mmol) in THF (100 mL) at 0℃was added NaH (1.4 g, 35.2 mmol) . The reaction mixture was stirred at 0℃ for 0.5 hr followed by addition of MOMCl (2.83 g, 35.2 mmol) . The resulting mixture was stirred at r.t. for 2 hr then quenched with ice water and extracted with DCM. The combined organic layers were dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 6/1) to afford the desired product (5.0 g, 83.7%yield) . LC-MS: m/z 361.2 (M+Na) ⁺.

Step 6: Preparation of 2- (5-chloro-2- (methoxymethoxy) -4- (3-methoxypropoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane

To a mixture of 1-bromo-5-chloro-2- (methoxymethoxy) -4- (3-methoxy-propoxy) benzene (5 g, 14.79 mmol) in dioxane (100 mL) under N ₂ were added 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (4.5 g, 17.75 mmol) , Pd (dppf) Cl ₂ (540 mg, 0.73 mmol) and KOAc (4.35 g, 44.37 mmol) . The reaction mixture was stirred at 90℃ under N ₂ overnight then filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 5/1) to afford the desired product (3 g, 52.6%yield) . LC-MS: m/z 409.1 (M+Na) ⁺.

Step 7: Preparation of methyl 6- (5-chloro-2- (methoxymethoxy) -4- (3-methoxypro poxy) phenyl) -4-methoxynicotinate

To a mixture of 2- (5-chloro-2- (methoxymethoxy) -4- (3-methoxypropoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (3 g, 7.77 mmol) in dioxane (30 mL) and water (5 mL) under N ₂were added methyl 6-chloro-4-methoxynicotinate (1.87 g, 9.32 mmol) , Pd (PPh ₃) ₄ (448 mg, 0.46 mmol) and Na ₂CO ₃ (2.47 g, 23.3 mmol) . The reaction mixture was stirred at 120℃ under N ₂ for 2 hr then filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 3/1) to afford the desired product (1.4 g, 42.4%yield) . LC-MS: m/z 426 (M+H) ⁺.

Step 8: Preparation of methyl 6- (5-chloro-2-hydroxy-4- (3-methoxypropoxy) phenyl) -4-hydroxynicotinate

To a mixture of methyl 6- (5-chloro-2- (methoxymethoxy) -4- (3-methoxypropoxy) phenyl) -4-methoxy-nicotinate (1.3 g, 3.05 mmol) in dry DCM (40 mL) at -78℃ under N ₂ was slowly added BBr ₃ (0.82 mL, 9.15 mmol) . The reaction mixture was stirred at -78℃ under N ₂for 2 hr then quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: DCM) to afford the desired product (520 mg, 46.4%yield) . LC-MS: m/z 368.0 (M+H) ⁺.

Step 9: Preparation of methyl 2-chloro-3- (3-methoxypropoxy) -6-methyl -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylate

To a mixture of methyl 6- (5-chloro-2-hydroxy-4- (3-methoxypropoxy) phenyl) -4-hydroxy-nicotinate (50 mg, 0.136 mmol) in dry DMF (5 mL) at r.t. under N ₂ were added Cs ₂CO ₃ (133 mg, 0.408 mmol) and 1, 1-dibromoethane (127 mg, 0.68 mmol) . The reaction mixture was stirred at 100℃ under N ₂ overnight then quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the desired product (25 mg, 46.7%yield) . LC-MS: m/z 394.0 (M+H) ⁺.

Step 10: Preparation of 2-chloro-3- (3-methoxypropoxy) -6-methyl-10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid

To a mixture of methyl 2-chloro-3- (3-methoxypropoxy) -6-methyl -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylate (25 mg, 0.063 mol) in MeOH (5 mL) at r.t. were added LiOH (8.1 mg, 0.19 mol) and H ₂O (1 mL) . The reaction mixture was stirred at r.t. for 16he then poured into ice water. The resulting mixture was adjusted to pH 1-2 with aqueous HCl (4M) then extracted with DCM. The combined organic layers were dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the desired product (10 mg, 41.6%yield) . ¹H NMR (400 MHz, CDCl ₃) : δ 8.50 (s, 1H) , 7.70 (s, 1H) , 6.93 (s, 1H) , 6.67 (s, 1H) , 5.81-5.80 (m, 1H) , 4.20-4.17 (t, 2H) , 3.61-3.58 (t, 2H) , 3.49 (s, 3H) , 2.15-2.11 (t, 2H) , 1.86-1.85 (d, 3H) . LC-MS: m/z 380.1 (M+H) ⁺.

The following analogs were prepared by a method analogous to the procedures described herein, starting from the appropriate starting materials.

Example 2: 2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid

¹H NMR (400 MHz, CDCl ₃) : δ 8.38 (s, 1H) , 7.69 (s, 1H) , 6.93 (s, 1H) , 6.67 (s, 1H) , 5.35-5.33 (d, 1H) , 4.19-4.17 (d, 2H) , 3.61-3.58 (t, 2H) , 3.37 (s, 3H) , 2.41-2.31 (m, 1H) , 2.15-2.11 (t, 2H) , 1.10-1.08 (d, 3H) , 0.86-0.88 (d, 3H) . LC-MS: m/z 408.0 (M+H) ⁺.

Example 3: (S) -2-chloro-6-isopropyl-3- (3-methoxy-propoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid and (R) -2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido - [1, 2-c] [1, 3] oxazine-9-carboxylic acid

Two enantiomers were separated by chiral HPLC.

Isomer A: ¹H NMR (400 MHz, CDCl ₃) : δ 8.38 (s, 1H) , 7.69 (s, 1H) , 6.93 (s, 1H) , 6.67 (s, 1H) , 5.35-5.33 (d, 1H) , 4.19-4.17 (d, 2H) , 3.61-3.58 (t, 2H) , 3.37 (s, 3H) , 2.41-2.31 (m, 1H) , 2.15-2.11 (t, 2H) , 1.10-1.08 (d, 3H) , 0.86-0.88 (d, 3H) . LC-MS: m/z 408.0 (M+H) ⁺. [Chiral HPLC retention time: 20.18 min]

Isomer B: ¹H NMR (400 MHz, CDCl ₃) : δ 8.38 (s, 1H) , 7.69 (s, 1H) , 6.93 (s, 1H) , 6.67 (s, 1H) , 5.35-5.33 (d, 1H) , 4.19-4.17 (d, 2H) , 3.61-3.58 (t, 2H) , 3.37 (s, 3H) , 2.41-2.31 (m, 1H) , 2.15-2.11 (t, 2H) , 1.10-1.08 (d, 3H) , 0.86-0.88 (d, 3H) . LC-MS: m/z 408.0 (M+H) ⁺. [Chiral HPLC retention time: 12.94 min]

Example 4: 2-chloro-6-cyclopropyl-3- (3-methoxypropoxy) -10-oxo -6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid

¹H NMR (400 MHz, CDCl ₃) : δ 8.78 (s, 1H) , 7.63 (s, 1H) , 6.87 (s, 1H) , 6.64 (s, 1H) , 4.75 (m, 1H) , 4.14-4.10 (m, 2H) , 3.55-3.52 (m, 2H) , 3.30 (s, 3H) , 2.20-2.09 (m, 2H) , 1.90-1.87 (m, 1H) , 1.18-1.16 (m, 2H) , 1.04-1.00 (m, 2H) . LC-MS: m/z 406 (M+H) ⁺.

Example 5: 2-chloro-6-cyclobutyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid

¹H NMR (400 MHz, CDCl ₃) : δ 8.40 (s, 1H) , 8.00 (s, 1H) , 6.92 (s, 1H) , 6.65 (s, 1H) , 5.55-5.52 (m, 1H) , 4.20-4.16 (m, 2H) , 3.63-3.57 (m, 2H) , 3.37 (s, 3H) , 3.10-3.00 (m, 1H) , 2.10-1.86 (m, 8H) . LC-MS: m/z 420 (M+H) ⁺.

Example 6: 2-chloro-3- (3-methoxypropoxy) -10-oxo-6-phenyl-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid

¹H NMR (400 MHz, CDCl ₃) : δ 8.20 (s, 1H) , 7.68 (s, 1H) , 7.51-7.48 (m, 3H) , 7.31-7.29 (m, 2H) , 6.99 (s, 1H) , 6.68 (s, 1H) , 6.60 (s, 1H) , 4.16-4.13 (t, 2H) , 3.59-3.56 (t, 2H) , 3.34 (s, 3H) , 2.12-2.09 (t, 2H) . LC-MS: m/z 442.2 (M+H) ⁺.

Example 7: 2-chloro-3- (3-methoxypropoxy) -10-oxo-6- (pyridin-4-yl) -6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 9.05 (s, 1H) , 8.64 (d, 2H, J = 4.0 Hz) , 8.28 (s, 1H) , 7.75 (s, 1H) , 7.57 (s, 1H) , 7.27-7.21 (m, 3H) , 4.24 (t, 2H, J = 6.4 Hz) , 3.53 (t, 2H, J = 6.4 Hz) , 3.30 (s, 3H) , 2.05-2.02 (m, 2H) . LC-MS: m/z 443.1 (M+H) ⁺.

Example 8: (6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid

¹H NMR (400 MHz, CDCl ₃) : δ 8.32 (s, 1H) , 7.54-7.52 (d, 1H) , 6.90 (s, 1H) , 6.72-6.70 (d, 1H) , 6.54 (s, 1H) , 5.29-5.26 (d, 1H) , 4.07-4.04 (t, 2H) , 3.50-3.47 (t, 2H) , 3.29 (s, 3H) , 2.24-2.23 (m, 1H) , 2.04-1.98 (m, 2H) , 1.02 (d, J = 6.0 Hz, 3H) , 0.82 (d, J = 6.4 Hz, 3H) . LC-MS: m/z 374.0 (M+H) ⁺.

Example 9: 2-chloro-6-isopropyl-3- (2-methoxyethoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid

¹H NMR (400 MHz, CDCl ₃) : δ 8.31 (s, 1H) , 7.61 (s, 1H) , 6.86 (s, 1H) , 6.63 (s, 1H) , 5.28-5.26 (d, 1H) , 4.18-4.16 (m, 2H) , 3.78-3.78 (t, 2H) , 3.41 (s, 3H) , 2.21-2.10 (m, 1H) , 1.02 (d, J = 6.8 Hz, 3H) , 0.84 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 394.0 (M+H) ⁺.

Example 10: (6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid)

Step 1: Preparation of 4-bromo-1-methoxy-2- (3-methoxypropoxy) benzene

To a mixture of 5-bromo-2-methoxyphenol (15.0 g, 73.9 mmol) and K ₂CO ₃ (20.4 g, 148 mmol) in dry DMF (100 mL) at r.t. was added 1-bromo-3-methoxypropane (13.6 g, 88.7 mmol) . The reaction mixture was stirred at 80 ℃ for 2 hr then filtered through Celite. The filtrate was diluted with water and extracted with MTBE. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 50/1) to afford the desired product (20 g, 98.4%yield) . LC-MS: m/z 275.0 (M+H) ⁺.

Step 2: Preparation of 2- (4-methoxy-3- (3-methoxypropoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2 -dioxaborolane

To a mixture of 4-bromo-1-methoxy-2- (3-methoxypropoxy) benzene (20.0 g, 72.7 mmol) in dioxane (300 mL) at r.t. under N ₂ were added 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (22.1 g, 87.2 mmol) , Pd (dppf) Cl ₂ (2.7 g, 3.6 mmol) and KOAc (21.4 g, 218.2 mmol) . The reaction mixture was stirred at 90℃ under N ₂ overnight then filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 50/1 to 5/1) to afford the desired product (22 g, 93.7%yield) . LC-MS: m/z 323.0 (M+H) ⁺.

Step 3: Preparation of 4-methoxy-3- (3-methoxypro -poxy) phenol

To a mixture of 2- (4-methoxy-3- (3-methoxypropoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2 –dioxaborolane (23.0 g, 71.4 mmol) in MeOH (150 mL) and H ₂O (150 mL) at 0℃ was added oxone (43.8 g, 71.4 mmol) . The reaction mixture was stirred at r.t. for 30 min then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 4/1) to afford the desired product (15.0 g, quant. yield) . LC-MS: m/z 213 (M+H) ⁺.

Step 4: Preparation of 2-bromo-4-methoxy-5- (3-methoxypropoxy) phenol

To a mixture of 4-methoxy-3- (3-methoxypropoxy) phenol (17.0 g, 80.0 mmol) in DCM (300 mL) at0℃ was added NBS (13.5 g, 76 mmol) . The reaction mixture was stirred at 0℃ for 10 min then quenched with ice water and extracted with DCM. The combined organic layers were dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 4/1) to afford the desired product (7.0 g, 30.0%yield) . LC-MS: m/z 291 (M+H) ⁺.

Step 5: Preparation of 1-bromo-5-methoxy-2- (methoxymethoxy) -4- (3-methoxy -propoxy) benzene

To a mixture of 2-bromo-4-methoxy-5- (3-methoxypropoxy) phenol (7.5 g, 25.9 mmol) in THF (150 mL) at 0℃ was added NaH (1.5 g 38.8 mmol) . The reaction mixture was stirred at 0℃ for 10 min followed by addition of MOMCl (2.5 g 31.0 mmol) . The resulting mixture was stirred at r.t. for 2 hr then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 8/1) to afford the desired product (7.0 g, 81%yield) . LC-MS: m/z 335 (M+H) ⁺.

Step 6: Preparation of 2- (5-methoxy-2- (methoxymethoxy) -4- (3-methoxypropoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane

To a mixtureof1-bromo-5-methoxy-2- (methoxymethoxy) -4- (3-methoxypropoxy) benzene (900 mg, 2.7 mmol) in dioxane (10 mL) at r.t. under N ₂ were added 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (1 g, 4 mmol) , Pd (dppf) Cl ₂ (100 mg, 0.13 mmol) and KOAc (660 mg, 6.8 mmol) . The reaction mixture was stirred at 100℃ under N ₂ overnight then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 5/1) to afford the desired product (530 mg, 51.3%yield) . LC-MS: m/z 383 (M+H) ⁺.

Step 7: Preparation of methyl 4- (benzyloxy) -6- (5-methoxy-2- (methoxymethoxy) -4- (3-methoxypropoxy) phenyl) nicotinate

To a mixture of 2- (5-methoxy-2- (methoxymethoxy) -4- (3-methoxypropoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (500 mg, 1.3 mol) in 1, 4-dioxane (5 mL) and H ₂O (1 mL) at r.t. under N ₂ were added methyl 4- (benzyloxy) -6-chloronicotinate (365 mg, 1.3 mmol) , Pd (PPh ₃) ₄ (100 mg, 0.087 mmol) and Na ₂CO ₃, (400 mg, 3.8 mmol) . The reaction mixture was stirred at 120℃ under N ₂ for 3 hr then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 2/1) to afford the desired product (450 mg, 69.5%yield) . LC-MS: m/z 498 (M+H) ⁺.

Step 8: Preparation of methyl 6- (5-methoxy-2- (methoxymethoxy) -4- (3-methoxy -propoxy) phenyl) -4-oxo-1, 4-dihydropyridine-3-carboxylate

To a mixture of methyl 4- (benzyloxy) -6- (5-methoxy-2- (methoxymethoxy) -4- (3-methoxypropoxy) phenyl) nicotinate (450 mg, 0.9 mmol) in MeOH (40 mL) under N ₂ was added Pd/C (50 mg) . The resulting mixture was stirred under H ₂ at 30℃ for 16 hr then filtered through Celite. The filtrate was concentrated under reduced pressure to afford the crude product (350 mg, 95.3%crude yield) which was used directly in the next step without any further purification. LC-MS: m/z 408 (M+H) ⁺.

Step 9: Preparation of methyl 4-hydroxy-6- (2-hydroxy-5-methoxy-4- (3-methoxypropoxy) phenyl) -nicotinate

To a mixtureof methyl 6- (5-methoxy-2- (methoxymethoxy) -4- (3-methoxy-propoxy) phenyl) -4-oxo-1, 4-dihydropyridine-3-carboxylate (300 mg, 0.74 mmol) in DCM (5 mL) at r.t. was added TFA (5 mL) . The reaction mixture was stirred at 30℃ for 3 hr, then adjusted to pH 6 with saturated aqueous NaHCO ₃ and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: DCM/MeOH=30/1) to afford the desired product (300 mg, 96.0%yield) . LC-MS: m/z 364 (M+H) ⁺.

Step 10: Preparation of 6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydrobenzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid

To a mixture of methyl 4-hydroxy-6- (2-hydroxy-5-methoxy-4- (3-methoxypropoxy) phenyl) -nicotinate (500 mg, 1.37 mmol) in dry DMF (50 mL) at r.t. under N ₂ were added CS ₂CO ₃ (1.25 g, 3.85mmol) and 1, 1-dibromo-2-methylpropane (3.88 g, 18 mmol) . The reaction was stirred at 100℃ under N ₂ overnight then quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elute DCM/MeOH=35/1) to afford the desired product (350 mg, 45%yield) . ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.81 (s, 1H) , 7.54 (s, 1H) , 7.47 (s, 1H) , 6.88 (s, 1H) , 6.11 (d, J = 9.6 Hz, 1H) , 4.10 (dd, J = 13.4, 6.4 Hz, 2H) , 3.86 (s, 3H) , 3.51 –3.45 (m, 2H) , 3.25 (s, 3H) , 2.19 (m, 1H) , 2.04 –1.87 (m, 2H) , 1.00 (d, J = 6.4 Hz, 3H) , 0.76 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 404.0 (M+H) ⁺.

Example 11: (S) - (6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid) and (R) - (6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid)

Two enantiomers were separated by chiral HPLC.

Isomer A: ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.81 (s, 1H) , 7.54 (s, 1H) , 7.47 (s, 1H) , 6.88 (s, 1H) , 6.11 (d, J = 9.6 Hz, 1H) , 4.10 (dd, J = 13.4, 6.4 Hz, 2H) , 3.86 (s, 3H) , 3.51 –3.45 (m, 2H) , 3.25 (s, 3H) , 2.19 (m, 1H) , 2.04 –1.87 (m, 2H) , 1.00 (d, J = 6.4 Hz, 3H) , 0.76 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 404.0 (M+H) ⁺. [Chiral HPLC retention time: 26.83 min]

Isomer B: 1H NMR (400 MHz, DMSO-d ₆) : δ 8.81 (s, 1H) , 7.54 (s, 1H) , 7.47 (s, 1H) , 6.88 (s, 1H) , 6.11 (d, J = 9.6 Hz, 1H) , 4.10 (dd, J = 13.4, 6.4 Hz, 2H) , 3.86 (s, 3H) , 3.51 –3.45 (m, 2H) , 3.25 (s, 3H) , 2.19 (m, 1H) , 2.04 –1.87 (m, 2H) , 1.00 (d, J = 6.4 Hz, 3H) , 0.76 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 404.0 (M+H) ⁺. [Chiral HPLC retention time: 19.98 min]

Example 12: 2-fluoro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydrobenzo - [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.83 (s, 1H) , 8.10 (d, J = 12 Hz, 1H) , 7.37 (s, 1H) , 7.10 (d, J = 7.2Hz, 1H) , 6.16 (d, J = 9.6 Hz, 1H) , 4.35 –3.92 (m, 2H) , 3.53 –3.45 (m, 2H) , 3.26 (s, 3H) , 2.17 m, 1H) , 1.99 (m, 2H) , 1.01 (d, J = 6.4 Hz, 3H) , 0.76 (d, J = 6.4 Hz, 3H) . LC-MS: m/z 392.0 (M+H) ⁺.

Example 13: 2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H -pyrido [1, 2-c] quinazoline-9-carboxylic acid

Step 1: Preparation of 1-chloro-2- (3-methoxypropoxy) -4-nitrobenzene

To a mixture of 2-chloro-5-nitrophenol (10.0 g, 57.8 mmol) in dry DMF (100 mL) at 20 ℃ was added K ₂CO ₃ (16.0 g, 0.116 mol) , followed by addition of 1-bromo-3-methoxypropane (10.5 g, 69.4 mmol) . The reaction mixture was stirred at 60℃ for 2 hr then filtered through Celite. The filtrate was diluted with water and extracted with MTBE. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 50/1 to 10/1) to afford the desired product (13.6 g, 95.8%yield) . LC-MS: m/z 246.0 (M+H) ⁺.

Step 2: Preparation of 4-chloro-3- (3-methoxypropoxy) aniline

To a mixture of 1-chloro-2- (3-methoxypropoxy) -4-nitrobenzene (13.6 g, 55.5 mmol) in H ₂O (150 mL) and MeOH (150 mL) at 20 ℃ were added Fe powder (15.5 g, 0.277 mol) and NH ₄Cl (16.0 g, 0.297 mol) . The reaction mixture was stirred at reflux for 2 hr then cooled to r.t. and filtered through Celite. The filtrate was concentrated under reduced pressure to remove most of MeOH, then diluted with water and extracted with MTBE. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue (11.9 g, quant. crude yield) was directly used in the next step without any further purification. LC-MS: m/z 216.0 (M+H) ⁺.

Step 3: Preparation of 2-bromo-4-chloro-5- (3-methoxypropoxy) aniline

To a mixture of 4-chloro-3- (3-methoxypropoxy) aniline (11.9 g, 55.3 mmol) in DCM (240 mL) and MeOH (120 mL) at 0 ℃ was added (n-Bu) ₄NBr ₃ (28.0 g, 58.1 mmol) . The reaction mixture was stirred at 0℃ for 15 min, then quenched with saturated aqueous Na ₂S ₂O ₃ and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 5/1 to 4/1) to afford the desired product (13.0 g, 80.2%yield) . LC-MS: m/z 294.0 (M+H) ⁺.

Step 4: Preparation of 4-chloro-5- (3-methoxypropoxy) -2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan -2-yl) aniline

To a mixture of 2-bromo-4-chloro-5- (3-methoxypropoxy) aniline (11.0 g, 37.5 mmol) in DMSO (100 mL) at r.t. under N ₂ were added 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (11.5 g, 45.1 mmol) , Pd (dppf) Cl ₂ (1.4 g, 1.85 mmol) and KOAc (11 g, 113 mmol) . The reaction mixture was stirred at 85℃ under N ₂ overnight then filtered through Celite. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 5/1) to afford the desired product (10.5 g, 82.7%yield) . LC-MS: m/z: 342.0 (M+H) ⁺.

Step 5: Preparation of methyl 6- (2-amino-5-chloro-4- (3-methoxypropoxy) phenyl) -4-methoxynicotinate

To a mixture of 4-chloro-5- (3-methoxypropoxy) -2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan -2-yl) aniline (100 mg, 0.293 mol) in DMF (5 mL) at r.t. under N ₂ were added methyl 6-chloro-4-methoxynicotinate (65.0 mg, 0.322 mmol) , Pd (PPh ₃) ₄ (20 mg, 0.0173 mmol) and K ₃PO ₄ (186 mg, 0.879 mmol) . The reaction mixture was stirred at 85℃ under N ₂ for 18 小时hr then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 10/1) to afford the desired product (80 mg, 72.0%yield) . LC-MS: m/z: 381.0 (M+H) ⁺.

Step 6: Preparation methyl 6- (2-amino-5-chloro-4- (3-methoxypropoxy) -phenyl) -4-oxo-1, 4-dihydropyridine-3-carboxylate

To a mixture of methyl 6- (2-amino-5-chloro-4- (3-methoxypropoxy) phenyl) -4-methoxynicotinate (1.00 g, 2.63 mmol) in dry DCM (50 mL) at 0℃ was added BBr ₃ (0.8 mL, 8.64 mmol) . The reaction mixture was stirred at 0℃ for 1 hr then quenched in sequence with MeOH (1 mL) and water. The resulting mixture was extracted with a mixed solvent of DCM and i-PrOH (V: V=5: 1) . The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/DCM/EtOAc=2/1/2) to afford the desired product (200 mg, 20.8%yield) . LC-MS: m/z: 367.0 (M+H) ⁺.

Step 7: Preparation of methyl 2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylate

To a mixture of methyl 6- (2-amino-5-chloro-4- (3-methoxypropoxy) -phenyl) -4-oxo-1, 4-dihydropyridine-3-carboxylate (460 mg, 1.26 mmol) in MeOH (20 mL) was added isobutyraldehyde (1 mL) . The reaction mixture was stirred at 50℃ for 18 hr then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: DCM/MeOH=20/1) to afford the desired product (530 mg, quant. yield) . LC-MS: m/z: 421.0 (M+H) ⁺.

Step 8: Preparation of 2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo -5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

To a mixture of methyl 2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylate (50 mg, 0.119 mmol) in MeOH (10 mL) and H ₂O (10 mL) at r.t. was added NaOH (100 mg, 2.5 mmol) . The mixture was stirred at 20℃ for 1hr then concentrated under reduced pressure. The residue was adjusted to pH 6 with diluted aqueous HCl (1N) , then adjusted to pH 8 with saturated aqueous NaHCO ₃ and extracted with a mixed solvent of DCM and i-PrOH (V: V=5: 1) . The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the desired product (25 mg, 52%yield) . ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.79 (s, 1H) , 8.05 (s, 1H) , 7.80-7.84 (brs, 1H) , 7.26 (s, 1H) , 6.60 (s, 1H) , 5.47-5.52 (m, 1H) , 4.05-4.15 (m, 2H) , 3.46-3.53 (m, 2H) , 3.26 (s, 3H) , 1.97-2.10 (m, 3H) , 0.89 (d, J = 6.8 Hz, 3H) , 0.72 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 407.0 (M+H) ⁺.

The followinganalogs were prepared via a method analogous to theprocedures described herein, starting from the appropriate starting materials.

Example 14: 6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.69 (s, 1H) , 7.97 (s, 1H) , 7.75-7.79 (brs, 1H) , 7.24 (s, 1H) , 6.56 (s, 1H) , 5.60-5.65 (m, 1H) , 4.05-4.14 (m, 2H) , 3.46-3.53 (m, 2H) , 3.32 (s, 3H) , 1.97-2.03 (m, 2H) , 0.82 (s, 9H) . LC-MS: m/z 421.0 (M+H) ⁺.

Example 15: 2-chloro-6- (1-methoxy-2-methylpropan-2-yl) -3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.52 (s, 1H) , 7.97 (s, 1H) , 7.64-7.67 (brs, 1H) , 7.21 (s, 1H) , 6.60 (s, 1H) , 5.69 (d, J = 3.6 Hz, 1H) , 4.05-4.14 (m, 2H) , 3.46-3.53 (m, 2H) , 3.256 (s, 3H) , 3.12 (s, 3H) , 2.83-3.09 (m, 2H) , 1.97-2.03 (m, 2H) , 0.91 (s, 3H) , 0.67 (s, 3H) . LC-MS: m/z 451.0 (M+H) ⁺.

Example 16: 2-chloro-6- (1-hydroxy-2-methylpropan-2-yl) -3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) δ 8.63 (s, 1H) , 7.96 (s, 1H) , 7.61 (d, J = 3.2 Hz, 1H) , 7.22 (s, 1H) , 6.61 (s, 1H) , 5.69 (d, J = 3.6 Hz, 1H) , 4.09 (qd, J = 15.6, 8.0 Hz, 2H) , 3.50 (t, J = 6.0 Hz , 2H) , 3.26 (s, 3H) , 3.19 (d, J = 11.2 Hz, 2H) , 3.04 (d, J = 10.8 Hz, 2H) , 2.09 –1.86 (m, 2H) , 0.84 (s, 3H) , 0.63 (s, 3H) . LC-MS: m/z 437.0 (M+H) ⁺.

Example 17: 2-chloro-3- (3-methoxypropoxy) -10-oxo-6-phenyl-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.83 (s, 1H) , 8.31 (d, J=3.2 Hz, 1H) , 8.03 (s, 1H) , 7.39-7.31 (m, 4H) , 7.15 (d, J=6.8 Hz, 2H) , 6.95 (d, J=2.8 Hz, 1H) , 6.61 (s, 1H) , 4.11-4.06 (m, 2H) , 3.48 (t, J=6.0 Hz, 2H) , 3.24 (s, 3H) , 1.98 (t, J=6.0 Hz, 2H) . LC-MS: m/z 441.1 (M+H) ⁺.

Example 18: 2-chloro-3- (3-methoxypropoxy) -10-oxo-6- (thiazol-2-yl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 9.03 (s, 1H) , 8.56 (s, 1H) , 8.04 (s, 1H) , 7.72 (s, 2 H) , 7.37 (s, 1H) , 7.29 (s, 1H) , 6.70 (s, 1H) , 4.15-4.06 (m, 2H) , 3.50 (t, J=6.0 Hz, 2H) , 3.26 (s, 3H) , 2.05 (t, J=6.0 Hz, 2H) . LC-MS: m/z 448.1 (M+H) ⁺.

Example 19: 2-chloro-3- (3-methoxypropoxy) -10-oxo-6- (thiophen-2-yl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.94 (s, 1H) , 8.28 (d, J=3.2 Hz, 1H) , 8.09 (s, 1H) , 7.48 (dd, J=0.8, 4.8 Hz, 1H) , 7.33 (s, 1H) , 7.26 (d, J=3.2 Hz, 1H) , 7.03 (d, J=3.2 Hz, 1H) , 6.97 (dd, J=4, 4.8 Hz, 1H) , 6.64 (s, 1H) , 4.14-4.10 (m, 2H) , 3.50 (t, J=6.0 Hz, 2H) , 3.26 (s, 3H) , 2.01 (t, J=6.4 Hz, 2H) . LC-MS: m/z 447.1 (M+H) ⁺.

Example 20: 2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) δ 8.79 (s, 1H) , 7.79 (s, 1H) , 7.74 (s, 1H) , 7.21 (s, 1H) , 7.19 (s, 0.22H) , 7.00 (s, 0.47H) , 6.81 (s, 0.24H) , 6.60 (s, 1H) , 5.49 (d, J = 6.4 Hz, 1H) , 4.31 –3.94 (m, 2H) , 3.60 –3.42 (m, 2H) , 3.25 (s, 3H) , 2.08 (dd, J = 15.2, 6.8 Hz, 1H) , 2.05 –1.88 (m, 2H) , 0.91 (d, J = 6.8Hz, 3H) , 0.72 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 439 (M+H) ⁺.

Example 21: 2-fluoro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d6) : δ 8.79 (s, 1H) , 7.87 (d, J = 12.4 Hz, 1H) , 7.59 (d, J = 2.4 Hz, 1H) , 7.19 (s, 1H) , 6.61 (d, J = 7.6 Hz, 1H) , 5.47 (dd, J = 9.2, 3.2 Hz, 1H) , 4.11 (m, 2H) , 3.48 (t, J = 6.4 Hz, 2H) , 3.26 (s, 3H) , 2.13 –2.04 (m, 1H) , 2.00 (m, 2H) , 0.90 (d, J = 6.4 Hz, 3H) , 0.71 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 391 (M+H) ⁺.

Example 22: 2-chloro-6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

Step 1: methyl 2-chloro-6-isopropyl-3- (3-methoxy -propoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylate

To a mixture of methyl 2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylate (50 mg, 0.119 mmol) in dry DMF (5 mL) was addedNaH (100 mg, 2.5 mmol) , followed by addition of MeI (0.5 mL, 8.08 mmol) . The mixture was stirred at r.t. for 1hr then directly used in the next step. LC-MS: m/z 435.0 (M+H) ⁺.

Step 2: 2-chloro-6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

The above mixture was quenched with crushed ice, followed by addition of NaOH (100 mg, 2.5 mmol) . The reaction mixture was stirred at r.t. for 1 hr then adjusted pH to 6 with diluted aqueous HCl (1N) . The resulting mixture was adjusted to pH 8 with saturated aqueous NaHCO ₃, then extracted with a mixed solvent of DCM and i-PrOH (V: V=5: 1) . The combined organic layers were washed with brine, dried over anhydrous Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the desired product (7 mg, 14.0%yield) . ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.79 (s, 1H) , 8.18 (s, 1H) , 7.53 (s, 1H) , 6.76 (s, 1H) , 5.71 (d, J = 9.6 Hz, 1H) , 4.27-4.36 (m, 2H) , 3.56-3.63 (m, 2H) , 3.35 (s, 3H) , 3.30 (s, 3H) , 2.06-2.18 (m, 3H) , 0.96 (d, J = 6.8 Hz, 3H) , 0.77 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 421.0 (M+H) ⁺.

The following analogs were prepared via a method analogous to theprocedures described herein, starting from the appropriate starting materials.

Example 23: 6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.63 (s, 1H) , 8.04 (s, 1H) , 7.26 (s, 1H) , 6.66 (s, 1H) , 5.78 (s, 1H) , 4.20-4.26 (m, 2H) , 3.50-3.55 (m, 2H) , 3.27 (s, 3H) , 3.26 (s, 3H) , 2.00-2.04 (m, 2H) , 0.79 (s, 9H) . LC-MS: m/z 435.0 (M+H) ⁺.

Example 24: (2-chloro-6- (1-methoxy-2-methylpro -pan-2-yl) -3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.50 (s, 1H) , 8.03 (s, 1H) , 7.22 (s, 1H) , 6.67 (s, 1H) , 5.82 (s, 1H) , 4.19-4.26 (m, 2H) , 3.49-3.54 (m, 2H) , 3.25 (s, 3H) , 3.23 (s, 3H) , 3.17 (s, 3H) , 2.77-3.05 (m, 2H) , 1.98-2.04 (m, 2H) , 0.87 (s, 3H) , 0.63 (s, 3H) . LC-MS: m/z 465.0 (M+H) ⁺.

Example 25: 2-chloro-5-ethyl-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.83 (s, 1H) , 8.11 (s, 1H) , 7.27 (s, 1H) , 6.88 (s, 1H) , 5.63 (d, J = 9.6 Hz, 1H) , 4.23-4.17 (m, 2H) , 3.80 (t, J=7.2 Hz, 1H) , 3.51 (t, J=6.4 Hz, 2H) , 3.32-3.30 (m, 1H) , 3.28 (s, 3H) , 2.03-1.95 (m, 3H) , 1.10 (t, J=7.2 Hz, 3H) , 0.88 (d, J = 6.8 Hz, 3H) , 0.68 (d, J = 6.8 Hz, 3H) . LC-MS: m/z: 435.0 (M+H) ⁺.

Example 26: 2-chloro-6-isopropyl-5- (2-methoxyethyl) -3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.77 (s, 1H) , 8.10 (s, 1H) , 7.26 (s, 1H) , 6.97 (s, 1H) , 5.80 (d, J = 9.6 Hz, 1H) , 4.22-4.02 (m, 3H) , 3.51 (t, J = 6.0 Hz, 3H) , 3.41-3.38 (m, 2H) , 3.26 (s, 3H) , 3.02 (s, 3H) , 2.03-1.88 (m, 3H) , 0.90 (d, J = 6.8 Hz, 3H) , 0.67 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 465.0 (M+H) ⁺.

Example 27: 2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5- (2, 2, 2-trifluoro -ethyl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.81 (s, 1H) , 8.17 (s, 1H) , 7.35 (s, 1H) , 7.13 (s, 1H) , 5.66 (d, J = 10 Hz, 1H) , 4.96-4.91 (m, 1H) , 4.22-4.19 (t, 2H) , 4.11-4.05 (m, 1H) 3.52 (t, 2H) , 3.26 (s, 3H) , 2.04-1.89 (m, 3H) , 0.91 (d, J = 6.8 Hz, 3H) , 0.70 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 489.0 (M+H) ⁺.

Example 28: 5-benzyl-2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.83 (s, 1H) , 8.20 (s, 1H) , 7.34-7.30 (m, 6H) , 7.04 (s, 1H) , 5.90 (d, J = 9.6 Hz, 1H) , 5.22 (d, J = 15.6 Hz, 1H) , 4.62 (d, J = 15.6 Hz, 1H) , 4.36-4.33 (m, 1H) , 4.19-4.17 (m, 1H) , 3.61-3.58 (t, 2H) , 3.37 (s, 3H) , 2.14-2.03 (m, 3H) , 1.07 (d, J = 6.4 Hz, 3H) , 0.82 (d, J = 6.4 Hz, 3H) . LC-MS: m/z 497.0 (M+H) ⁺.

Example 29: 2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5- (pyridin-4-ylmethyl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) : δ 8.71 (s, 1H) , 8.42 (d, J=6.0 Hz, 2H) , 8.12 (s, 1H) , 7.29 (s, 1H) , 7.18 (d, J = 6.0 Hz, 2H) , 6.86 (s, 1H) , 5.73 (d, J = 9.6 Hz, 1H) , 5.15 (d, J = 16.4 Hz, 1H) , 4.52 (d, J = 16.8 Hz, 1H) , 4.32-4.11 (m, 1H) , 4.01-3.82 (m, 1H) , 3.45 (t, J = 6.4 Hz, 2H) , 3.24 (s, 3H) , 1.93-1.88 (m, 3H) , 0.94 (d, J = 6.8 Hz, 3H) , 0.69 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 498.2 (M+H) ⁺.

Example 30: 2-fluoro-6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) δ 8.71 (s, 1H) , 7.94 (d, J = 12.4 Hz, 1H) , 7.22 (s, 1H) , 6.76 (d, J = 7.2 Hz, 1H) , 5.58 (d, J = 9.6Hz, 1H) , 4.35 –4.03 (m, 2H) , 3.49 (t, J = 6.4 Hz, 2H) , 3.26 (s, 3H) , 3.20 (s, 3H) , 2.20 –1.77 (m, 3H) , 0.89 (d, J = 6.8 Hz, 3H) , 0.68 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 405.0 (M+H) ⁺.

Example 31: 2-Chloro-3- (3-methoxypropoxy) -5-methyl-10-oxo-6- (thiazol-2-yl) -5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) δ 8.94 (s, 1H) , 8.10 (s, 1H) , 7.75-7.72 (m, 2H) , 7.45 (s, 1H) , 7.34 (s, 1H) , 6.79 (s, 1H) , 4.24 (t, J = 6.4 Hz, 2H) , 3.50 (t, J = 6.0 Hz, 2H) , 3.32 (s, 3H) , 3.26 (s, 3H) , 2.0 (t, J = 6.0 Hz, 2H) . LC-MS: m/z 462.0 (M+H) ⁺.

Example 32: 2-Chloro-3- (3-methoxypropoxy) -5- (methyl-d3) -10-oxo-6- (thiazol-2-yl) -5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, CDCl ₃) δ 8.69 (s, 1H) , 7.64-7.63 (m, 2H) , 7.58 (s, 1H) , 7.19 (s, 1H) , 6.88 (s, 1H) , 6.54 (m, 1H) , 6.39 (s, 1H) , 4.14-4.13 (m, 2H) , 3.54 (t, J = 6.0 Hz, 2H) , 3.0 (s, 3H) , 2.08 (t, J = 6.0 Hz, 2H) . LC-MS: m/z 465.0 (M+H) ⁺.

Example 33: 2-Chloro-5- (2-methoxyethyl) -3- (3-methoxypropoxy) -10-oxo-6- (thiazol-2-yl) -5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) δ 9.00 (s, 1H) , 8.05 (s, 1H) , 7.69-7.66 (m, 2 H) , 7.46 (s, 1H) , 7.28 (s, 1H) , 7.12 (s, 1H) , 4.23-4.14 (m, 3H) , 3.53-3.51 (m, 1H) , 3.49-3.32 (m, 4H) , 3.26 (s, 1H) , 3.09 (s, 1H) , 2.01 (m, 2H) . LC-MS: m/z 506.1 (M+H) ⁺.

Example 34: 5- (Azetidin-3-yl) -2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) δ 9.01 (s, 1H) , 8.31 (s, 1H) , 8.15 (s, 1H) , 7.32 (s, 1H) , 6.82 (s, 1H) , 5.80 (d, J = 0.8 Hz, 1H) , 4.67 (m, 1H) , 4.26-4.20 (m, 2H) , 3.91 (m, 1H) , 3.71-3.49 (m, 5H) , 3.09 (s, 3H) , 2.03-1.89 (m, 3H) , 0.85 (d, J = 0.4 Hz, 3H) , 0.70 (d, J = 0.8 Hz, 3H) . LC-MS: m/z 462.1 (M+H) ⁺.

Example 35: 2-Chloro-5-cyclobutyl-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, CDCl ₃) δ 8.55 (s, 1H) , 7.66 (s, 1H) , 6.95 (s, 1H) , 6.60 (s, 1H) , 5.00 (m, 1H) , 4.17-4.15 (m, 2H) , 3.59 (t, J = 0.8 Hz, 2H) , 3.40 (m, 1H) , 3.35 (s, 3H) , 3.10 (m, 1H) , 2.14-1.98 (m, 3H) , 0.98-0.78 (m, 7H) , 0.53 (d, J = 0.4 Hz, 2H) , 0.19-0.14 (m, 2H) . LC-MS: m/z 461.2 (M+H) ⁺.

Example 36: 2-Chloro-6-isopropyl-3- (3-methoxypropoxy) -5- (oxetan-3-yl) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) δ 9.03 (s, 1H) , 8.15 (s, 1H) , 7.33 (s, 1H) , 6.78 (s, 1H) , 5.86 (d, J = 1.2 Hz, 1H) , 5.08-5.05 (m, 1H) , 4.90 (t, J = 0.8 Hz, 1H) , 4.75 (t, J = 0.8 Hz, 1H) , 4.68 (t, J = 0.8 Hz, 1H) , 4.40 (t, J = 0.8 Hz, 1H) , 4.24-4.18 (m, 1H) , 3.51 (t, J = 0.8 Hz, 1H) , 3.23 (s, 3H) , 2.03-1.91 (m, 3H) , 0.85 (d, J = 0.8 Hz, 3H) , 0.70 (d, J = 0.8 Hz, 3H) . LC-MS: m/z 463.2 (M+H) ⁺.

Example 37: 2-Chloro-5-cyclopropyl-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) δ 8.91 (s, 1H) , 8.09 (s, 1H) , 7.26 (s, 1H) , 6.92 (s, 1H) , 5.67 (d, J = 0.8 Hz, 1H) , 4.31-4.17 (m, 2H) , 3.53 (t, J = 0.8 Hz, 2H) , 3.27 (s, 3H) , 2.92-2.90 (m, 1H) , 2.25-2.00 (m, 3H) , 1.02-1.90 (m, 6H) , 0.70 (d, J = 0.8 Hz, 3H) , 0.45-0.42 (m, 1H) . LC-MS: m/z 447.2 (M+H) ⁺.

Example 38: 2-Chloro-5, 6-diisopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, CDCl ₃) δ 8.41 (s, 1H) , 7.61 (s, 1H) , 6.88 (s, 1H) , 6.61 (s, 1H) , 4.69 (d, J = 0.8 Hz, 1H) , 4.16-4.08 (m, 2H) , 3.76 (m, 1H) , 3.55 (t, J = 0.8 Hz, 2H) , 3.30 (s, 3H) , 2.09-2.05 (m, 2H) , 1.80 (m, 1H) , 1.30 (d, J = 0.8 Hz, 3H) , 0.89 (d, J = 0.8 Hz, 3H) , 0.81 (d, J = 0.8 Hz, 3H) , 0.72 (d, J = 0.8 Hz, 3H) . LC-MS: m/z 449.2 (M+H) ⁺.

Example 39: 2- (Difluoromethoxy) -6-isopropyl-5- (2-methoxyethyl) -3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) δ 8.77 (s, 1H) , 7.80 (s, 1H) , 7.28-6.80 (m, 3 H) , 5.55 (d, J = 0.8 Hz, 1H) , 4.17-4.14 (m, 3H) , 3.49 (d, J = 0.8 Hz, 2H) , 3.41-3.25 (m, 2H) , 3.25 (s, 3H) , 3.01 (s, 3H) , 2.00-1.97 (m, 3H) , 0.90 (d, J = 0.8 Hz, 3H) , 0.67 (d, J = 0.8 Hz, 3H) . LC-MS: m/z 497.2 (M+H) ⁺.

Example 40: 5- (Tert-butyl) -2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) δ 8.34 (s, 1H) , 7.62 (s, 1H) , 7.20-6.64 (m, 3 H) , 5.36 (m, 1H) , 4.21-4.14 (m, 2H) , 3.49 (d, J = 0.8 Hz, 2H) , 3.24 (s, 3H) , 2.01-1.96 (m, 3H) , 0.87 (d, J = 0.8 Hz, 3H) , 0.68 (d, J = 0.8 Hz, 3H) . LC-MS: m/z 456.2 (M+H) ⁺.

Example 41: 2-chloro-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydrobenzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid

¹H NMR (400 MHz, CDCl ₃) δ 8.48 (s, 1H) , 7.72 (s, 1H) , 6.93 (s, 1H) , 6.72 (s, 1H) , 5.60 (s, 2H) , 4.19 (t, J = 6.0 Hz, 2H) , 3.60 (t, J = 6.0 Hz, 2H) , 3.37 (s, 3H) , 2.21 –1.95 (m, 2H) . LC-MS: m/z 366.0 (M+H) ⁺.

Example 42: 6- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) δ 8.79 (s, 1H) , 7.87 (d, J = 12.4 Hz, 1H) , 7.59 (d, J = 2.4 Hz, 1H) , 7.19 (s, 1H) , 6.61 (d, J = 7.6 Hz, 1H) , 5.47 (dd, J = 9.2, 3.2 Hz, 1H) , 4.16-4.05 (m, 2H) , 3.48 (t, J = 6.4 Hz, 2H) , 3.26 (s, 3H) , 2.13 –2.04 (m, 1H) , 2.02-1.92 (m, 2H) , 0.90 (d, J = 6.4 Hz, 3H) , 0.71 (d, J = 6.8 Hz, 3H) . LC-MS: m/z 551.2 (M+H) ⁺.

Example 43: 2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid

¹H NMR (400 MHz, DMSO-d ₆) δ 8.71 (s, 1H) , 7.85 (s, 1H) , 7.24 (s, 1H) , 7.24 (s, 0.24H) , 7.23 (s, 1H) , 7.05 (s, 0.49H) , 6.86 (s, 0.25H) , 6.71 (s, 1H) , 5.61 (d, J = 9.6 Hz, 1H) , 4.21 (m, 2H) , 3.50 (t, J = 6.4 Hz, 2H) , 3.26 (s, 3H) , 3.21 (s, 3H) , 2.19 –1.85 (m, 3H) , 0.89 (d, J = 6.8 Hz, 3H) , 0.69 (d, J = 6.4 Hz, 3H) . LC-MS: m/z 453.2 (M+H) ⁺.

Example 44: 10-chloro-11- (3-methoxypropoxy) -7-oxo-2, 3, 3a, 7-tetrahydro-1H-pyrido [1, 2-c] pyrrolo [1, 2-a] quinazoline-6-carboxylic acid

1H NMR (400 MHz, DMSO-d6) : δ 8.30 (s, 1H) , 7.92 (s, 1H) , 6.77 (s, 1 H) , 6.50 (s, 1H) , 5.00 (s, 1H) , 4.19 (t, J=6.0 Hz, 2H) , 3.63-3.52 (m, 1H) , 3.50 (t, J=6.0 Hz, 3H) , 3.26 (s, 3H) , 2.76-2.62 (m, 1H) , 2.34-2.31 (m, 2H) , 2.25-2.06 (m, 1H) , 2.02-1.95 (m, 2H) .

BIOLOGICAL ASSAYS

Cells and Major Reagents

1) HepG2.2.15 cell

2) QIAamp 96 DNA Blood Kit (Qiagen-51162)

3) FastStart Universal Probe Master (Roche-04914058001)

4) HBsAg ELISA kit (Anto-CL0310)

5) CellTiter-Glo Luminescent Cell Viability Assay kit (Promega-G7573)

Instruments

1) 7500 Real Time PCR system (Applied Biosystems)

2) ABI Prism 7900HT (Applied Biosystems)

3) BioTek Synergy 2

Study Procedure

1) Seeding Cells: On day 0, HepG2.2.15 cell was seeded in 96-well plates at the density of 4.0X10 ⁴ cells/well (0.1 ml/well) . The cells were incubated at 37 ℃ and 5%CO ₂.

2) Compound Treatment: On day 1, test compounds were first diluted with DMSO, and further diluted with medium to reach final concentration; and the final volume per well was 200 μl. The final concentration of DMSO in the culture medium was 0.5%. The compounds were tested with 8 concentrations in duplicate. The test concentrations and dilution folds were determined by the client. The cells were cultured at 37 ℃ and 5%CO ₂ for 3 days. On day 4, the plates were refreshed with culture media containing compounds. On day 7, culture supernatants were collected for DNA isolation and HBsAg ELISA detection. In parallel, after collection of supernatants, Cell Titer-Glo reagent was added to the assay plates. The plates were incubated at room temperature for 10 min. Luminescence signal were read the by BioTek-Synergy 2.

HBsAg ELISA

The HBsAg in the cell culture supernatants was detected according to the manual of the ELISA kit. In brief, 50 μl of cell supernatants, standard or control samples was added to the ELISA plates, followed by addition of 50 μl enzyme conjugate into each well. The ELISA plates were incubated at 37℃ for 60 minutes, then washed for 5 times. 50 μl of enzyme substrate was added to the ELISA plates, followed by incubation at room temperature for 10 minutes. The luminescence signal was collected by BioTek Synergy 2. The measurement range for HBsAg was 0.05-250 IU/ml.

qPCR

Extracellular DNA was isolated with QIAamp 96 DNA Blood Kit per themanufacturer’s manual. A plasmid containing the HBV full-genome sequence (D type) is used as a standard sample for HBV DNA quantification. The range of the standard used is between 1.0×10 ¹ -1.0×10 ⁷ copies/μl. The PCR will be performed with 95 ℃ for 10 min, then cycling at 95 ℃ for 15 secs, 60 ℃ for 1 min for 40 cycles.

Data Analysis

The inhibition percent are calculated according to the equation below.

%HBV DNA inhibition= (Copy numbers of DMSO control -Copy numbers of sample) /Copy numbers of DMSO control X100%

%HBsAg inhibition= (HBsAg level of DMSO control -HBsAg level of sample) /HBsAg level of DMSO control X100%

The EC ₅₀ values for test compounds on inhibition of HBsAgsecretion and HBV DNA production are calculated using GraphPad Prism software.

The compounds of this invention were tested for their activity to inhibit HBsAgsecretionand DNA production as described herein. Results of HBsAg assay are given in table 1. Compounds with >～95%inhibition against HBsAg at 50 nM are submitted for EC ₅₀ test.

Table 1. Activity data in HBsAg assay

NA: not available

Results of HBV DNA assay are given in table 2.

Table 2. Anti HBV DNA production activity

Claims

A compound of formula (I)

wherein:

R ¹is hydrogen, halogen, C _1-6alkyl, C _1-6alkoxy, N (C _1-6alkyl) ₂, or NH-C _1-6alkyl;

R ²is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, haloC _1-6alkoxy, O (CH ₂) _q-phenyl, CN, or C _3-7cycloalkyl;

R ³is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, O (CH ₂) _q-phenyl, CN, amino, C _3-7cycloalkyl, O (CH ₂) _wR ⁶, O (CH ₂) _mO (CH ₂) _nR ⁶, or O-C _1-6alkyl-R ⁶;

R ⁴is hydrogen, halogen, C _1-6alkyl, C _1-6alkoxy or CN;

X is O, or NR ⁷;

R ⁵is hydrogen, C _1-6alkyl, haloC _1-6alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, C _1-6alkyl-OH, or C _1-6alkyl-O-C _1-6alkyl;

each R ⁶ is independently OH, C _1-6alkoxy, C _3-7cycloalkyl, CN, C _2-6alkenyl, C _2-6alkynyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, SC _1-6alkyl, S (=O) ₂C _1-6alkyl, NR _aR _b, C (=O) OH, C (=O) OC _1-6alkyl, or C (=O) NR _aR _b;

R ⁷ is hydrogen, C _1-4alkyl, CD ₃, haloC _1-4alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, (CH ₂) _q-monocyclic heteroaryl, C _1-4alkyl-OH, or C _1-4alkyl-O-C _1-4alkyl; or R ⁷ and R ⁵ together optionally form a 5 to 7-membered heterocyclic ring, which ring contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C ₁-C ₄) alkyl, C _3-7cycloalkyl, OH, C _1-4alkoxy, haloC _1-4alkoxy, phenyl, benzyl and monocyclic heteroaryl;

each occurrence of R _a and R _b is independently hydrogen or C _1-6alkyl, or R _a and R _b, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additionalone or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C ₁-C ₄) alkyl, phenyl and benzyl;

each q is independently 0-6;

w is 1-6; and

m and n are each independently 2-6, or a pharmaceutically acceptable salt or enantiomer thereof.
The compound of claim 1, having the structure of formula (Ia) ,

wherein:

R ¹is hydrogen, halogen, C _1-6alkyl, C _1-6alkoxy, N (C _1-6alkyl) ₂, or NH-C _1-6alkyl;

R ²is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, haloC _1-6alkoxy, O (CH ₂) _q-phenyl, CN, or C _3-7cycloalkyl;

R ³is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, O (CH ₂) _q-phenyl, CN, amino, C _3-7cycloalkyl, O (CH ₂) _wR ⁶, O (CH ₂) _mO (CH ₂) _nR ⁶, or O-C _1-6alkyl-R ⁶;

R ⁴is hydrogen, halogen, C _1-6alkyl, C _1-6alkoxy or CN;

R ⁵is hydrogen, C _1-6alkyl, haloC _1-6alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, C _1-6alkyl-OH, or C _1-6alkyl-O-C _1-6alkyl;

each R ⁶ is independently OH, C _1-6alkoxy, C _3-7cycloalkyl, CN, C _2-6alkenyl, C _2-6alkynyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, SC _1-6alkyl, S (=O) ₂C _1-6alkyl, NR _aR _b, C (=O) OH, C (=O) OC _1-6alkyl, or C (=O) NR _aR _b; each occurrence of R _a and R _b is independently hydrogen or C _1-6alkyl, or R _a and R _b, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C ₁-C ₄) alkyl, phenyl and benzyl;

each q is independently 0-6;

w is 1-6; and

m and n are each independently 2-6.
The compound of claim 1, having the structure of formula (Ib) ,

wherein:

R ¹is hydrogen, halogen, C _1-6alkyl, C _1-6alkoxy, N (C _1-6alkyl) ₂, or NH-C _1-6alkyl;

R ²is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, haloC _1-6alkoxy, O (CH ₂) _q-phenyl, CN, or C _3-7cycloalkyl;

R ³is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, O (CH ₂) _q-phenyl, CN, amino, C _3-7cycloalkyl, O (CH ₂) _wR ⁶, O (CH ₂) _mO (CH ₂) _nR ⁶, or O-C _1-6alkyl-R ⁶;

R ⁴is hydrogen, halogen, C _1-6alkyl, C _1-6alkoxy or CN;

R ⁵is hydrogen, C _1-6alkyl, haloC _1-6alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, C _1-6alkyl-OH, or C _1-6alkyl-O-C _1-6alkyl;

each R ⁶ is independently OH, C _1-6alkoxy, C _3-7cycloalkyl, CN, C _2-6alkenyl, C _2-6alkynyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, SC _1-6alkyl, S (=O) ₂C _1-6alkyl, NR _aR _b, C (=O) OH, C (=O) OC _1-6alkyl, or C (=O) NR _aR _b;

R ⁷ is hydrogen, C _1-4alkyl, CD ₃, haloC _1-4alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, (CH ₂) _q-monocyclic heteroaryl, C _1-4alkyl-OH, or C _1-4alkyl-O-C _1-4alkyl; or R ⁷ and R ⁵ together optionally form a 5 to 7-membered heterocyclic ring, which ring contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C ₁-C ₄) alkyl, C _3-7cycloalkyl, OH, C _1-4alkoxy, haloC _1-4alkoxy, phenyl, benzyl and monocyclic heteroaryl;

each occurrence of R _a and R _b is independently hydrogen or C _1-6alkyl, or R _a and R _b, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C ₁-C ₄) alkyl, phenyl and benzyl;

each q is independently 0-6;

w is 1-6; and

m and n are each independently 2-6.
The compound of any one of claims 1-3, wherein R ¹ is hydrogen.
The compound of any one of claims 1-3, wherein R ¹ is halogen.
The compound of any one of claims 1-5, wherein R ⁴ is hydrogen.
The compound of claim 1, having the structure of formula (Ic) ,

wherein:

R ²is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, haloC _1-6alkoxy, O (CH ₂) _q-phenyl, CN, or C _3-7cycloalkyl;

R ³hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, O (CH ₂) _q-phenyl, CN, amino, C _3- ₇cycloalkyl, O (CH ₂) _wR ⁶, O (CH ₂) _mO (CH ₂) _nR ⁶, or O-C _1-6alkyl-R ⁶;

R ⁵is hydrogen, C _1-6alkyl, haloC _1-6alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, C _1-6alkyl-OH, or C _1-6alkyl-O-C _1-6alkyl;

each R ⁶ is independently OH, C _1-6alkoxy, C _3-7cycloalkyl, CN, C _2-6alkenyl, C _2-6alkynyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, SC _1-6alkyl, S (=O) ₂C _1-6alkyl, NR _aR _b, C (=O) OH, C (=O) OC _1-6alkyl, or C (=O) NR _aR _b;

each occurrence of R _a and R _b is independently hydrogen or C _1-6alkyl, or R _a and R _b, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C ₁-C ₄) alkyl, phenyl and benzyl;

each q is independently 0-6;

w is 1-6; and

m and n are each independently 2-6.
The compound of claim 1, having the structure of formula (Id) ,

wherein:

R ²is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, O (CH ₂) _q-phenyl, CN, or C _3- ₇cycloalkyl;

R ³is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, haloC _1-6alkoxy, O (CH ₂) _q-phenyl, CN, amino, C _3-7cycloalkyl, O (CH ₂) _wR ⁶, O (CH ₂) _mO (CH ₂) _nR ⁶, or O-C _1-6alkyl-R ⁶;

R ⁵is hydrogen, C _1-6alkyl, haloC _1-6alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, C _1-6alkyl-OH, or C _1-6alkyl-O-C _1-6alkyl;

each R ⁶ is independently OH, C _1-6alkoxy, C _3-7cycloalkyl, CN, C _2-6alkenyl, C _2-6alkynyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, SC _1-6alkyl, S (=O) ₂C _1-6alkyl, NR _aR _b, C (=O) OH, C (=O) OC _1-6alkyl, or C (=O) NR _aR _b;

R ⁷ is hydrogen, C _1-4alkyl, CD ₃, haloC _1-4alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, (CH ₂) _q-monocyclic heteroaryl, C _1-4alkyl-OH, or C _1-4alkyl-O-C _1-4alkyl; or R ⁷ and R ⁵ together optionally form a 5 to 7-membered heterocyclic ring, which ring contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C ₁-C ₄) alkyl, C _3-7cycloalkyl, OH, C _1-4alkoxy, haloC _1-4alkoxy, phenyl, benzyl and monocyclic heteroaryl;

each occurrence of R _a and R _b is independently hydrogen or C _1-6alkyl, or R _a and R _b, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of (C ₁-C ₄) alkyl, phenyl and benzyl;

each q is independently 0-6;

w is 1-6; and

m and n are each independently 2-6.
The compound of any one of claims 1-8, wherein R ³ isC _1-6alkoxy.
The compound of any one of claims 1-8, wherein R ³ is O (CH ₂) _q-phenyl.
The compound of any one of claims 1-8, wherein R ³ is O (CH ₂) _wR ⁶.
The compound of any one of claims 1-8, wherein R ³ is O (CH ₂) _mO (CH ₂) _nR ⁶.
The compound of any one of claims 1-8, wherein R ³ is O-C _1-6alkyl-R ⁶.
The compound of any one of claims 1-13, wherein R ⁶ is OH.
The compound of any one of claims 1-13, wherein R ⁶ is C _1-6alkoxy.
The compound of any one of claims 1-13, wherein R ⁶ is methoxy.
The compound of any one of claims 1-13, wherein R ⁶ is C _3-7cycloalkyl.
The compound of claim 1, having the structure of formula (Ie) ,

wherein:

R ²is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, haloC _1-6alkoxy, O (CH ₂) _q-phenyl, CN, or C _3-7cycloalkyl;

R ⁵is hydrogen, C _1-6alkyl, haloC _1-6alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, C _1-6alkyl-OH, or C _1-6alkyl-O-C _1-6alkyl;

R ⁸ is hydrogen, C _1-6alkyl, C _3-7cycloalkyl, C _2-6alkenyl, C _2-6alkynyl, or phenyl;

each q is independently 0-6; and

x is 1-5.
The compound of claim 1, having the structure of formula (If) ,

wherein:

R ²is hydrogen, halogen, C _1-6alkyl, haloC _1-6alkyl, OH, C _1-6alkoxy, haloC _1-6alkoxy, O (CH ₂) _q-phenyl, CN, or C _3-7cycloalkyl;

R ⁵is hydrogen, C _1-6alkyl, haloC _1-6alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, monocyclic heteroaryl, C _1-6alkyl-OH, or C _1-6alkyl-O-C _1-6alkyl;

R ⁷ is hydrogen, C _1-4alkyl, CD ₃, haloC _1-4alkyl, C _3-7cycloalkyl, (CH ₂) _q-phenyl, monocyclic heterocycloalkyl, (CH ₂) _q-monocyclic heteroaryl, C _1-4alkyl-OH, or C _1-4alkyl-O-C _1-4alkyl;

R ⁸ is hydrogen, C _1-6alkyl, C _3-7cycloalkyl, C _2-6alkenyl, C _2-6alkynyl, or phenyl;

each q is independently 0-6; and

x is 1-5.
The compound of claim 18 or 19, wherein R ⁸ is methyl.
The compound of claim 18 or 19, wherein R ⁸ is ethyl.
The compound of claim 18 or 19, wherein R ⁸ is hydrogen.
The compound of any one of claims 18-22, wherein x is 1.
The compound of any one of claims 18-22, wherein x is 2.
The compound of any one of claims 1-22, wherein R ⁷ is hydrogen.
The compound of any one of claims 1-22, wherein R ⁷ isC _1-4alkyl.
The compound of any one of claims 1-22, wherein R ⁷ is methyl or ethyl.
The compound of any one of claims 1-22, wherein R ⁷ is CD ₃.
The compound of any one of claims 1-22, wherein R ⁷ ishaloC _1-4alkyl.
The compound of any one of claims 1, 3, 8 and 19, wherein R ⁷ isC _3-7cycloalkyl.
The compound of any one of claims 1, 3, 8 and 19, wherein R ⁷ is (CH ₂) _q-phenyl.
The compound of any one of claims 1, 3, 8 and 19, wherein R ⁷ ismonocyclic heterocycloalkyl.
The compound of any one of claims 1, 3, 8 and 19, wherein R ⁷ is (CH ₂) _q-monocyclic heteroaryl.
The compound of any one of claims 1, 3, 8 and 19, wherein R ⁷ is C _1-4alkyl-O-C _1-4alkyl.
The compound of any one of claims 1-34, wherein R ² is halogen.
The compound of any one of claims 1-34, wherein R ² is C _1-6alkoxy.
The compound of any one of claims 1-34, wherein R ² is haloC _1-6alkoxy.
The compound of any one of claims 1-34, wherein R ² is Cl.
The compound of any one of claims 1-34, wherein R ² is F.
The compound of any one of claims 1-34, wherein R ² is -OCHF ₂.
The compound of any one of claims 1-34, wherein R ² is methoxy.
The compound of any one of claims 1-41, wherein R ⁵ isC _1-6alkyl.
The compound of any one of claims 1-41, wherein R ⁵ is iso-propyl.
The compound of any one of claims 1-41, wherein R ⁵ is (S) -iso-propyl.
The compound of any one of claims 1-41, wherein R ⁵ is t-butyl.
The compound of any one of claims 1-41, wherein R ⁵ isC _3-7cycloalkyl.
The compound of any one of claims 1-41, wherein R ⁵ is cyclopropyl or cyclobutyl.
The compound of any one of claims 1-41, wherein R ⁵ is (CH ₂) _q-phenyl.
The compound of any one of claims 1-41, wherein R ⁵ isphenyl.
The compound of any one of claims 1-41, wherein R ⁵ ismonocyclic heteroaryl.
The compound of any one of claims 1-41, wherein R ⁵ is pyridyl, thiophenyl, or thiozolyl.
The compound of any one of claims 1-41, wherein R ⁵ isC _1-6alkyl-OH.
The compound of any one of claims 1-41, wherein R ⁵ isC _1-6alkyl-O-C _1-6alkyl.
The compound of any one of claims 1-41, wherein R ⁵ is -C (CH ₃) ₂CH ₂OHor -C (CH ₃) ₂CH ₂OCH ₃.
The compound of any one of claims 1-54, wherein each said haloC _1-6alkyl, haloC _1-4alkyl, and haloC _1-6alkoxy independently contains one, two or three halogens.
The compound of any one of claims 1-54, wherein each said haloC _1-6alkyl, haloC _1-4alkyl, and haloC _1-6alkoxy independently contains one, two or three fluorines.
A compound selected from:

2-Chloro-3- (3-methoxypropoxy) -6-methyl-10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

(S) -2-chloro-6-isopropyl-3- (3-methoxy-propoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

(R) -2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido - [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-6-cyclopropyl-3- (3-methoxypropoxy) -10-oxo -6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-6-cyclobutyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6-phenyl-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6- (pyridin-4-yl) -6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

(6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-6-isopropyl-3- (2-methoxyethoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

(6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid) ,

(S) - (6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid) ,

(R) - (6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid) ,

2-fluoro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydrobenzo - [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H -pyrido [1, 2-c] quinazoline-9-carboxylic acid,

6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6- (1-methoxy-2-methylpropan-2-yl) -3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6- (1-hydroxy-2-methylpropan-2-yl) -3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6-phenyl-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6- (thiazol-2-yl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6- (thiophen-2-yl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-fluoro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

(2-chloro-6- (1-methoxy-2-methylpro -pan-2-yl) -3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-5-ethyl-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6-isopropyl-5- (2-methoxyethyl) -3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5- (2, 2, 2-trifluoro -ethyl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

5-benzyl-2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5- (pyridin-4-ylmethyl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-fluoro-6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-3- (3-methoxypropoxy) -5-methyl-10-oxo-6- (thiazol-2-yl) -5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-3- (3-methoxypropoxy) -5- (methyl-d3) -10-oxo-6- (thiazol-2-yl) -5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-5- (2-methoxyethyl) -3- (3-methoxypropoxy) -10-oxo-6- (thiazol-2-yl) -5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

5- (Azetidin-3-yl) -2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-5-cyclobutyl-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-6-isopropyl-3- (3-methoxypropoxy) -5- (oxetan-3-yl) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-5-cyclopropyl-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-5, 6-diisopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2- (Difluoromethoxy) -6-isopropyl-5- (2-methoxyethyl) -3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

5- (Tert-butyl) -2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydrobenzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

6- (1- (tert-butyldimethylsilyloxy) -2-methylpropan-2-yl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid, and

2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid; or a pharmaceutically acceptable salt or enantiomer thereof.
A compound selected from:

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

(S) -2-chloro-6-isopropyl-3- (3-methoxy-propoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid,

(6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid) ,

(S) - (6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid) ,

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H -pyrido [1, 2-c] quinazoline-9-carboxylic acid,

6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-3- (3-methoxypropoxy) -10-oxo-6- (thiazol-2-yl) -6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -10-oxo-6, 10-dihydro-5H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-chloro-6-isopropyl-3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

6- (tert-butyl) -2-chloro-3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

(2-chloro-6- (1-methoxy-2-methylpro -pan-2-yl) -3- (3-methoxypropoxy) -5-methyl-10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-3- (3-methoxypropoxy) -5-methyl-10-oxo-6- (thiazol-2-yl) -5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

2-Chloro-3- (3-methoxypropoxy) -5- (methyl-d3) -10-oxo-6- (thiazol-2-yl) -5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid,

5- (Tert-butyl) -2- (difluoromethoxy) -6-isopropyl-3- (3-methoxypropoxy) -10-oxo-5, 10-dihydro-6H-pyrido [1, 2-c] quinazoline-9-carboxylic acid, and

10-chloro-11- (3-methoxypropoxy) -7-oxo-2, 3, 3a, 7-tetrahydro-1H-pyrido [1, 2-c] pyrrolo [1, 2-a] quinazoline-6-carboxylic acid; or a pharmaceutically acceptable salt or enantiomer thereof.
The compound of claim 58, which is (S) -2-chloro-6-isopropyl-3- (3-methoxy-propoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid, or a pharmaceutically acceptable salt thereof.
The compound of claim 58, which is (S) - (6-isopropyl-2-methoxy-3- (3-methoxypropoxy) -10-oxo-6H, 10H-benzo [e] pyrido [1, 2-c] [1, 3] oxazine-9-carboxylic acid) , or a pharmaceutically acceptable salt thereof.
The compound of any one of claims 1-60, wherein one or more hydrogen atoms are replaced by deuterium.
A pharmaceutical composition comprising the compound of any one of claims 1-61, and a pharmaceutically acceptable carrier.
A method for treatment and/or prophylaxis of hepatitis B infection in a subject in need thereof, comprising administering an effective amount of a compound of any one of claims 1-61 to the subject.