Patent Application
20230012560
This present disclosure is related to a phenyl-carboxamide derivative, a pharmaceutical composition thereof and the use of same in the treatment of hepatitis B.
The hepatitis B virus (HBV) causes liver inflammation and injury that over several decades can further lead to serious complications, including cirrhosis and hepatocellular carcinoma. Hepatitis B is a significant public health threat, with over 250 million people living with hepatitis B worldwide. Nearly one million people die each year from hepatitis B and related diseases.
HBV is an enveloped DNA virus with an icosahedral core. The protein shell of the core, the capsid, is a self-assembling complex of 120 core protein homodimer. The correct assembly of the core proteins into a structurally and functionally relevant form is a key step for biological process to be carried out successfully. The capsid encloses the HBV DNA and a DNA polymerase that has reverse transcriptase activity. HBV replication is highly dependent on the accurate assembly of the capsid, which is also associated with the covalently closed circular DNA (cccDNA) reservoir for persistent infection. In addition to capsid assembly, core protein also has multiple roles in HBV lifecycle, making it an attractive drug target.
Interferons (IFNs) & nucleos(t)ide analogues (NAs) are currently available drugs for treatment of chronic HBV infection. However, the currently available treatments are suboptimal. There is a need in the art for the identification of novel compounds that can be used to treat and/or prevent HBV infection in a subject.
The present disclosure relates to a phenyl-carboxamide derivative as a class of hepatitis B virus inhibitors. Unexpectedly, these compounds showed effective anti-HBV activity.
Provided herein is a compound of Formula (I) below, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof:
In this formula, each of Ra, Rb, Rc, and Rd, independently, is hydrogen, halogen, CN, OH, C1-6 alkyl, C2-6 alkenyl, or C1-6 alkoxy, wherein each of C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy is optionally substituted with 1 to 4 moieties of halogen, OH, or CN;
each of X1 and X2, independently is C or N;
each of R1 and R2, independently, is hydrogen, CN, OH, halogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, C5-14 heteroaryl, wherein each of C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of deuterium, halogen, OH, CN, C1-6 alkyl, C1-6 alkoxy, or C3-12 carbocyclyl;
R3 is hydrogen, halogen, or C1-6 alkyl optionally substituted with 1 to 4 moieties of deuterium or halogen;
or R1 and R3, together with the adjacent atom to which they are each attached, form C3-12 carbocyclyl, C3-12 heterocyclyl, or C5-14 heteroaryl, wherein each of C3-12 carbocyclyl, C3-12 heterocyclyl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of halogen, OH, CN, NH2, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl;
W is absent or NR5;
R5 is hydrogen, C1-6 alkyl optionally substituted with 1 to 4 halogens;
Z is C3-12 heterocyclyl, C3-12 carbocyclyl, C1-6 alkyl(C3-12 carbocyclyl), C1-6 alkyl(C3-12 heterocyclyl), wherein each of C3-12 heterocyclyl, C3-12 carbocyclyl, C1-6 alkyl(C3-12 carbocyclyl), and C1-6 alkyl(C3-12 heterocyclyl) is optionally substituted with 1 to 4 moieties of halogen, CN, C1-6 alkyl optionally substituted with 1 to 4 moieties of halogen, or C1-6 alkoxy optionally substituted with 1 to 4 halogens;
L is —S(O)2—, —NHS(O)2—, —S(O)2NH—, —NHS(O)2NH—, —S(O)2N(CH3)—, —NHS(O)2N(CH3)—, —(C═O)2—, —NH(C═O)—, NH(C═O)NH—, —NH(C═O)2—, —(C═O)2NH—, —NH(C═O)2NH—, —(C═O)2N(CH3)— or —NH(C═O)2N(CH3)—;
R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl, wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of halogen, OH, CN, carboxy, C1-6 alkyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl;
the dotted line in the ring represents a single bond or a double bond;
with the proviso that, when L is —S(O)2—, R4 is not C1-6 alkyl.
Also provided herein are pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula (I), including a stereoisomer, or enantiomer thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition can be used for treating HBV infection or diseases associated with HBV.
Further provided herein is a method of treating, preventing, or ameliorating HBV infection, or one or more symptoms of a HBV-mediated disorder, disease, or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, e.g., a compound of Formula (I), including a stereoisomer, or enantiomer thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In related embodiments, the method may further comprise administering a compound disclosed herein, e.g., a compound of Formula (I), including a stereoisomer, or enantiomer thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in combination with one or more additional therapeutic agents, wherein a compound disclosed herein and one or more additional therapeutic agents are administered either together in a single formulation, or administered separately in different formulations, and wherein the administration of the compound disclosed herein and the additional therapeutic agents is done concomitantly, or in series.
Additionally provided herein is a method of preparing a compound disclosed herein, e.g., a compound of Formula (I), including a stereoisomer, or enantiomer variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
The term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%,/and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
The terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.
The terms “patient”, “individual” or “subject” refers to a human or a non-human mammal. In one embodiment, the patient, individual, or subject is human.
The term “therapeutically effective amount” refers to the amount of an active compound is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluents, solvent, or encapsulating material, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effect or interacting in a deleterious manner with any of the components of the composition in which it is contained. See, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.
The term “one or more” refers to either one or a number above one (e.g. 2, 3, 4, 5, 6 or 7).
The term “halo” or “halogen” alone or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom.
The term “carboxy” refers to a moiety of formula —C(O)OR′, wherein R′ is a hydrogen, C1-6 alkyl, C3-12 cycloalkyl, C2-6 alkenyl, C3-12 cycloalkenyl, C2-6 alkynyl, aryl (e.g., benzyl), or C5-14 heteroaryl group.
The term “C1-6 alkyl” (alone or in combination with another term) refers to a straight- or branched-chain saturated hydrocarbyl substituent containing 1 to 6 (e.g., 1 to 4, 1 to 3) carbon atoms. Examples of C1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and the like.
The term “C2-6 alkenyl” (alone or in combination with another term) refers to a straight- or branched-chain hydrocarbyl substituent containing 2 to 6 (e.g., 2 to 4, 2 to 3) carbon atoms and one or more double bonds. Examples of C2-6 alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, and the like.
The term “C2-6 alkynyl” (alone or in combination with another term) refers to a straight- or branched-chain hydrocarbyl substituent containing 2 to 6 (e.g., 2 to 4, 2 to 3) carbon atoms and one or more triple bonds. Examples of C2-6 alkynyl include ethynyl, propynyl, butynyl, pentynyl, and the like.
The term “C1-6 alkoxy” (alone or in combination with another term) refers to the group —OR″ wherein R″ is C1-6 alkyl. Examples of C1-6 alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
The term “carbocyclyl” refers to a saturated (i.e., “cycloalkyl”) or partly unsaturated (i.e., “cycloalkenyl”) monocyclic or bicyclic (fused, bridged, or spiro) ring containing from 3 to 12 (C3-12) ring atoms. In certain embodiments, the carbocyclyl has from 3 to 10 (C3-10), from 3 to 8 (C3-8), from 4 to 8 (C4-8), from 3 to 6 (C3-6), from 4 to 6 (C4-6), or from 5 to 6 (C5-6) ring atoms. Examples of such carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, norbornyl, and norbornenyl.
The term “heterocyclyl” refers to a saturated (i.e., “heterocycloalkyl”) or partly unsaturated (i.e., “heterocycloalkenyl” monocyclic or bicyclic (fused, bridged, or spiro) ring containing from 3 to 12 (C3-12) ring atoms which can comprise one, two or three heteroatoms selected from O, S, and N. In certain embodiments, the heterocyclyl has from 3 to 10 (C3-10), from 3 to 8 (C3-8), from 4 to 8 (C4_8), from 3 to 6 (C3-6), from 4 to 6 (C4-6), or from 5 to 6 (C5-6) ring atoms. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclyl include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and tetrahydrofuryl.
The term “aryl” refers to a monovalent monocyclic aromatic group and/or monovalent polycyclic aromatic group that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 14 (C6-14), or from 6 to 10 (C6-10) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
The term “heteroaryl” refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring can contain one, two, three or four heteroatoms independently selected from O, S, and N in the ring. Heteroaryl groups are bonded to the rest of a molecule through the aromatic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20 (C5-20), from 5 to 14 (C5-14), or from 5 to 10 (C5-10) ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
The term “amino protecting group” refers to a chemical group which is attached to the amino group and is easily removed in a certain condition. It includes but is not limited to alkoxycarbonyls, acyls, alkyls; for example tert-butyloxycarbonyl, benzyloxycarbonyl, fluorene-methoxycarbonyl, allylloxycarbonyl, phthalyl, benzyl, para-methoxybenzyl, triphenylmethyl or the like. It can be appropriately selected and manipulated by those skilled in the art with reference to the conventional textbook in the art, such as Greene's Protective Groups in Organic Synthesis (4th edition).
The term “solvate” refers to a complex formed between an active compound and a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.
The disclosure provides herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof:
wherein
each of Ra, Rb, Rc, and Rd, independently, is hydrogen, halogen, CN, OH, C1-6 alkyl, C2-6 alkenyl, or C1-6 alkoxy, wherein each of C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy is optionally substituted with 1 to 4 moieties of halogen, OH, or CN;
each of X1 and X2, independently is C or N;
each of R1 and R2, independently, is hydrogen, CN, OH, halogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, C5-14 heteroaryl, wherein each of C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of deuterium, halogen, OH, CN, C1-6 alkyl, C1-6 alkoxy, or C3-12 carbocyclyl;
R3 is hydrogen, halogen, or C1-6 alkyl optionally substituted with 1 to 4 moieties of deuterium or halogen;
or R1 and R3, together with the adjacent atom to which they are each attached, form C3-12 carbocyclyl, C3-12 heterocyclyl, or C5-14 heteroaryl, wherein each of C3-12 carbocyclyl, C3-12 heterocyclyl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of halogen, OH, CN, NH2, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl;
W is absent or NR5;
R5 is hydrogen, C1-6 alkyl optionally substituted with 1 to 4 halogens;
Z is C3-12 heterocyclyl, C3-12 carbocyclyl, C1-6 alkyl(C3-12 carbocyclyl), C1-6 alkyl(C3-12 heterocyclyl), wherein each of C3-12 heterocyclyl, C3-12 carbocyclyl, C1-6 alkyl(C3-12 carbocyclyl), and C1-6 alkyl(C3-12 heterocyclyl) is optionally substituted with 1 to 4 moieties of halogen, CN, C1-6 alkyl optionally substituted with 1 to 4 moieties of halogen, or C1-6 alkoxy optionally substituted with 1 to 4 halogens;
L is —S(O)2—, —NHS(O)2—, —S(O)2NH—, —NHS(O)2NH—, —S(O)2N(CH3)—, —NHS(O)2N(CH3)—, —(C═O)2—, —NH(C═O)—, NH(C═O)NH—, —NH(C═O)2—, —(C═O)2NH—, —NH(C═O)2NH—, —(C═O)2N(CH3)— or —NH(C═O)2N(CH3)—;
R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl, wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of halogen, OH, CN, carboxy, C1-6 alkyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl;
the dotted line in the ring represents a single bond or a double bond;
with the proviso that, when L is —S(O)2—, R4 is not C1-6 alkyl.
In one embodiment, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof:
wherein
each of Ra, Rb, Rc, and Rd, independently, is hydrogen, halogen, CN, OH, C1-6 alkyl, C2-6 alkenyl, or C1-6 alkoxy, wherein each of C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy is optionally substituted with 1 to 4 moieties of halogen, OH, or CN;
each of R1 and R2, independently, is hydrogen, CN, OH, halogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, C5-14 heteroaryl, wherein each of C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of deuterium, halogen, OH, CN, C1-6 alkyl, C1-6 alkoxy, or C3-12 carbocyclyl;
R3 is hydrogen, halogen, or C1-6 alkyl optionally substituted with 1 to 4 moieties of deuterium, or halogen;
or R1 and R3, together with the adjacent atom to which they are each attached, form C3-12 carbocyclyl, C3-12 heterocyclyl, or C5-14 heteroaryl, wherein each of C3-12 carbocyclyl, C3-12 heterocyclyl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of halogen, OH, CN, NH2, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl;
W is absent or NR5;
R5 is hydrogen, C1-6 alkyl optionally substituted with 1 to 4 halogens;
Z is C3-12 heterocyclyl, C3-12 carbocyclyl, C1-6 alkyl(C3-12 carbocyclyl), C1-6 alkyl(C3-12 heterocyclyl), wherein each of C3-12 heterocyclyl, C3-12 carbocyclyl, C1-6 alkyl(C3-12 carbocyclyl), and C1-6 alkyl(C3-12 heterocyclyl) is optionally substituted with 1 to 4 moieties of halogen, CN, C1-6 alkyl optionally substituted with 1 to 4 moieties of halogen, or C1-6 alkoxy optionally substituted with 1 to 4 halogens;
L is —S(O)2—, —NHS(O)2—, —S(O)2NH—, —NHS(O)2NH—, —S(O)2N(CH3)—, —NHS(O)2N(CH3)—, —(C═O)2—, —NH(C═O)—, NH(C═O)NH—, —NH(C═O)2—, —(C═O)2NH—, —NH(C═O)2NH—, —(C═O)2N(CH3)— or —NH(C═O)2N(CH3)—;
R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl, wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of halogen, OH, CN, carboxy, C1-6 alkyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl;
with the proviso that, when L is —S(O)2—, R4 is not C1-6 alkyl.
In yet another embodiment, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof:
wherein
each of Ra, Rb, Rc, and Rd, independently, is hydrogen, halogen, CN, OH, C1-6 alkyl, C2-6 alkenyl, or C1-6 alkoxy, wherein each of C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy is optionally substituted with 1 to 4 moieties of halogen, OH, or CN;
R2 is hydrogen, CN, OH, halogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, C5-14 heteroaryl, wherein each of C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of deuterium, halogen, OH, CN, C1-6 alkyl, or C1-6 alkoxy;
is a C3-12 heterocyclyl containing one or two nitrogen atoms, wherein said C3-12 heterocyclyl is optionally substituted with 1 to 4 moieties of halogen, OH, CN, NH2, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl. In one embodiment,
is a C4-8 heterocyclyl containing one nitrogen atom, wherein said C4-8 heterocyclyl is optionally substituted with 1 to 4 moieties of halogen, OH, CN, C1-6 alkyl, C2-6 alkenyl, or C1-6 alkoxy. In another embodiment.
is
wherein each of the heterocyclyl moieties is optionally substituted with 1 to 4 moieties of halogen, OH. CN, C1-6 alkyl, C2-6 alkenyl, or C1-6 alkoxy. In yet another embodiment,
is
wherein each of the heterocyclyl moieties is optionally substituted with 1 to 4 moieties of halogen, OH, CN, C1-6 alkyl, C2-6 alkenyl, or C1-6 alkoxy.
W is absent or NR5;
R5 is hydrogen, C1-6 alkyl optionally substituted with 1 to 4 halogens;
Z is C3-12 heterocyclyl, C3-12 carbocyclyl, C1-6 alkyl(C3-12 carbocyclyl), C1-6 alkyl(C3-12 heterocyclyl), wherein each of C3-12 heterocyclyl, C3-12 carbocyclyl, C1-6 alkyl(C3-12 carbocyclyl), and C1-6 alkyl(C3-12 heterocyclyl) is optionally substituted with 1 to 4 moieties of halogen, CN, C1-6 alkyl optionally substituted with 1 to 4 moieties of halogen, or C1-6 alkoxy optionally substituted with 1 to 4 halogens;
L is —S(O)2—, —NHS(O)2—, —S(O)2NH—, —NHS(O)2NH—, —S(O)2N(CH3)—, —NHS(O)2N(CH3)—, —(C═O)2—, —NH(C═O)—, NH(C═O)NH—, —NH(C═O)2—, —(C═O)2NH—, —NH(C═O)2NH—, —(C═O)2N(CH3)— or —NH(C═O)2N(CH3)—;
R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl, wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of halogen, OH, CN, carboxy, C1-6 alkyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl;
with the proviso that, when L is —S(O)2—, R4 is not C1-6 alkyl.
In other embodiment, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof:
each of Ra, Rb, Rc, and Rd, independently, is hydrogen, halogen, CN, OH, C1-6 alkyl, C2-6 alkenyl, or C1-6 alkoxy, wherein each of C1-6 alkyl, C2-6 alkenyl, and C1-6 alkoxy is optionally substituted with 1 to 4 moieties of halogen, OH, or CN;
each of R1 and R2, independently, is hydrogen, CN, OH, halogen, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, C5-14 heteroaryl, wherein each of C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of deuterium, halogen, OH, CN, C1-6 alkyl, C1-6 alkoxy, or C3-12 carbocyclyl;
R3 is hydrogen, halogen, or C1-6 alkyl optionally substituted with 1 to 4 moieties of deuterium, or halogen;
or R1 and R3, together with the adjacent atom to which they are each attached, form C3-12 carbocyclyl, C3-12 heterocyclyl, or C5-14 heteroaryl, wherein each of C3-12 carbocyclyl, C3-12 heterocyclyl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of halogen, OH, CN, NH2, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl;
R5 is hydrogen, C1-6 alkyl optionally substituted with 1 to 4 halogens;
is a C3-12 heterocyclyl containing one or two nitrogen atoms, wherein said C4-8 heterocyclyl is optionally substituted with 1 to 4 moieties of halogen or C1-6 alkyl optionally substituted with 1 to 4 halogens. In one embodiment,
is a C4-8 heterocyclyl containing one or two nitrogen atoms, wherein said C4-8 heterocyclyl is optionally substituted with 1 to 4 moieties of halogen or C1-6 alkyl optionally substituted with 1 to 4 halogens. In another embodiment,
is a C4-8 heterocyclyl containing one nitrogen atom, wherein said C4-8 heterocyclyl is optionally substituted with 1 to 4 moieties of halogen or C1-6 alkyl optionally substituted with 1 to 4 halogens. In yet another embodiment,
is
wherein each of the heterocyclyl moieties is optionally substituted with 1 to 4 moieties of halogen or C1-6 alkyl optionally substituted with 1 to 4 halogens. In other embodiment,
is
wherein each of the heterocyclyl moieties is optionally substituted with 1 to 4 moieties of halogen or C1-6 alkyl optionally substituted with 1 to 4 halogens.
L is —S(O)2—, —NHS(O)2—, —S(O)2NH—, —NHS(O)2NH—, —S(O)2N(CH3)—, —NHS(O)2N(CH3)—, —(C═O)2—, —NH(C═O)—, NH(C═O)NH—, —NH(C═O)2—, —(C═O)2NH—, —NH(C═O)2NH—, —(C═O)2N(CH3)— or —NH(C═O)2N(CH3)—;
R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl, wherein each of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of halogen, OH, CN, carboxy, C1-6 alkyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl;
with the proviso that, when L is —S(O)2—, R4 is not C1-6 alkyl.
The following embodiments are inclusive of definitions for Formula (I), (II), (III) and/or (IV).
In one embodiment, each of Ra, Rb, Rc, and Rd, independently, is hydrogen, halogen, CN, or C1-6 alkyl optionally substituted with 1 to 4 halogens. In another embodiment, each of Ra, Rb, Rc, and Rd, independently, is hydrogen, halogen, CN, or C1-6 alkyl optionally substituted with 1 to 4 moieties of fluoro. In yet another embodiment, each of Ra, Rb, Rc, and Rd, independently, is hydrogen, fluoro, chloro, bromo, CN, or C1-6 alkyl optionally substituted with 1 to 4 moieties of fluoro.
In one embodiment, each of R1 and R2, independently, is hydrogen, CN, halogen, C1-6 alkyl, C2-6 alkenyl, or C3-12 carbocyclyl, wherein each of C1-6 alkyl, C2-6 alkenyl, and C3-12 carbocyclyl is optionally substituted with 1 to 4 moieties of halogen, CN, or C3-12 carbocyclyl. In another embodiment, each of R1 and R2, independently, is hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, or C3-6 carbocyclyl, wherein each of C1-6 alkyl, C2-6 alkenyl and C3-6 carbocyclyl, is optionally substituted with 1 to 4 moieties of halogen or C3-12 carbocyclyl. In yet another embodiment, each of R1 and R2, independently, is hydrogen, fluoro, chloro, bromo, C1-6 alkyl, C2-6 alkenyl, or C3-6 carbocyclyl, wherein C1-6 alkyl is optionally substituted with 1 to 4 moieties of halogen or C3-6 carbocyclyl.
In one embodiment, R1 is hydrogen, CN, halogen, C1-6 alkyl, C2-6 alkenyl, or C3-12 carbocyclyl, wherein each of C1-6 alkyl, C2-6 alkenyl, and C3-12 carbocyclyl is optionally substituted with 1 to 4 moieties of halogen, CN, or C3-12 carbocyclyl. In another embodiment, R1 is hydrogen, halogen, C1-6 alkyl, or C2-6 alkenyl, wherein each of C1-6 alkyl and C2-6 alkenyl is optionally substituted with 1 to 4 moieties of halogen or C3-12 carbocyclyl. In yet another embodiment, R1 is hydrogen, fluoro, chloro, bromo, C1-6 alkyl, or C2-6 alkenyl, wherein C1-6 alkyl and C2-6 alkenyl is optionally substituted with 1 to 4 moieties of halogen or C3-6 carbocyclyl.
In one embodiment, R2 is hydrogen, CN, halogen, or C1-6 alkyl optionally substituted with 1 to 4 halogens. In another embodiment, R2 is hydrogen, fluoro, chloro, bromo, or C1-6 alkyl. In yet another embodiment, R2 is fluoro, chloro, or bromo.
In one embodiment, R3 is hydrogen, halogen, or C1-6 alkyl optionally substituted with 1 to 4 halogens. In another embodiment, R3 is hydrogen, halogen, or C1-6 alkyl optionally substituted with 1 to 4 moieties of fluoro. In yet another embodiment, R3 is hydrogen, fluoro, chloro, bromo, or C1-6 alkyl optionally substituted with 1 to 4 moieties of fluoro.
In one embodiment, R1 and R3, can together with the adjacent atom to which they are each attached, form C3-12 heterocyclyl optionally substituted with 1 to 4 moieties of halogen, CN, or C1-6 alkyl. In another embodiment, R1 and R3, together with the adjacent atom to which they are each attached, form C5-6 heterocyclyl optionally substituted with 1 to 4 moieties of halogen, CN, or C1-6 alkyl. In yet another embodiment, R1 and R3, together with the adjacent atom to which they are each attached, form pyrrolidine or piperidine, wherein each of pyrrolidine and piperidine is optionally substituted with 1 to 4 moieties of halogen, CN, or C1-6 alkyl.
In one embodiment, W is NR5; R5 is hydrogen, C1-6 alkyl optionally substituted with 1 to 4 halogens. In another embodiment, W is NR5; R5 is hydrogen.
In one embodiment, Z is C3-12 heterocyclyl, or C3-12 carbocyclyl, wherein each of C3-12 heterocyclyl and C3-12 carbocyclyl is optionally substituted with 1 to 4 moieties of halogen, CN, or C1-6 alkyl optionally substituted with 1 to 4 halogens. In another embodiment, Z is C3-12 heterocyclyl containing one or two nitrogen, or C3-12 carbocyclyl, wherein each of C3-12 heterocyclyl, and C3-12 carbocyclyl is optionally substituted with 1 to 4 moieties of halogen, CN, or C1-6 alkyl optionally substituted with 1 to 4 halogens. In yet another embodiment, Z is C4-8 heterocyclyl containing one or two nitrogen, wherein said C4-8 heterocyclyl is optionally substituted with 1 to 4 moieties of halogen or C1-6 alkyl optionally substituted with 1 to 4 halogens. In other embodiment, Z is C4-8 heterocyclyl containing one or two nitrogen, wherein said C4-8 heterocyclyl is optionally substituted with 1 to 4 moieties of halogen or C1-6 alkyl optionally substituted with 1 to 4 halogens; and L is linked to nitrogen atom of said C4-8 heterocyclyl.
In one embodiment, Z is
wherein each of the heterocyclyl moieties is optionally substituted with 1 to 4 moieties of halogen or C1-6 alkyl optionally substituted with 1 to 4 halogens. In another embodiment, Z is
wherein each of the heterocyclyl moieties is optionally substituted with 1 to 4 moieties of halogen or C1-6 alkyl optionally substituted with 1 to 4 halogens. In yet another
embodiment, Z is
wherein each of the heterocyclyl moieties is optionally substituted with 1 to 4 moieties of halogen or C1-6 alkyl optionally substituted with 1 to 4 halogens.
In one embodiment, L is —S(O)2—, —S(O)2NH—, —S(O)2N(CH3)—, —NHS(O)2NH—, —(C═O)2NH—, or —NH(C═O)2NH—. In another embodiment, L is —S(O)2NH—, —S(O)2N(CH3)—, —(C═O)2NH—, or —NH(C═O)2NH—. In yet another embodiment, L is —S(O)2NH— or —S(O)2N(CH3)—. In other embodiment, L is —(C═O)2—, —NH(C═O)—, —NH(C═O)NH—, —NH(C═O)2—, —(C═O)2NH—, —NH(C═O)2NH—, —(C═O)2N(CH3)— or —NH(C═O)2N(CH3)—. In other embodiment, L is —(C═O)2—, —NH(C═O)2—, —(C═O)2NH—, —NH(C═O)2NH—, —(C═O)2N(CH3)— or —NH(C═O)2N(CH3)—. In other embodiment, L is (C═O)2NH— or —NH(C═O)2NH—.
In one embodiment, R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, or C5-14 heteroaryl, wherein each of C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, aryl, and C5-14 heteroaryl is optionally substituted with 1 to 4 moieties of halogen, OH, CN, carboxy, C1-6 alkyl, C1-6 alkoxy, or aryl. In another embodiment, R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, or aryl, wherein each of C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C3-12 carbocyclyl, C3-12 heterocyclyl, and aryl is optionally substituted with 1 to 4 moieties of halogen, CN, carboxy, C1-6 alkyl, C1-6 alkoxy, or aryl.
In one embodiment, the compound provided herein is selected from:
, and a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.
The compounds provided herein are intended to encompass all possible stereoisomers, unless a particular stereochemistry is specified. Where the compound provided herein contains an alkenyl or alkenylene group, the compound may exist as one or a mixture of geometric cis/trans (or Z/E) isomers. Where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.
When the compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically acceptable salt. The pharmaceutically acceptable salts are generally prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentane propionate, diethylacetic, digluconate, dihydrochloride, dodecylsulfanate, edetate, edisylate, estolate, esylate, ethanesulfonate, formic, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, phosphate/diphosphate, pimelic, phenylpropionic, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate, valerate and the like. Suitable bases for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, sodium hydroxide, primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, tromethamine and the like.
The compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound, for example, of Formula (I), and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
Provided herein are pharmaceutical compositions comprising a compound provided herein, e.g., a compound of Formula (I), as an active ingredient, including a stereoisomer, or diastereomer thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more pharmaceutically acceptable carriers or excipients.
Suitable carriers or excipients are well known to those skilled in the art, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form.
The pharmaceutical compositions of the present disclosure comprise a compound provided herein (e.g., a compound of Formula (I), including a stereoisomer, or diastereomer thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof) as an active ingredient, one or more pharmaceutically acceptable carriers/excipients and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art.
The pharmaceutical compositions provided herein can be provided in a unit-dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unit-dosage form include an ampoule, syringe, and individually packaged tablet and capsule. For example, a 100 mg unit dose contains about 100 mg of an active ingredient in a packaged tablet or capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.
The pharmaceutical compositions provided herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
The pharmaceutical compositions provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, syrups, liposomes, micelles, microspheres, nanosystems, sustained release formulations, and the like. In addition to the active ingredient(s), the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches; gelatin; sugars; natural and synthetic gums, such as acacia, alginic acid, alginates, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP); celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses; and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing.
Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses; wood products; natural sponge; cation-exchange resins; alginic acid; gums; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose; starches; clays; aligns; and mixtures thereof.
Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels; and mixtures thereof.
Suitable glidants include, but are not limited to, colloidal silicon dioxide and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration. The pharmaceutical compositions provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science.
The pharmaceutical compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequcarboxying or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases. Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.
The pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration. The pharmaceutical compositions provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. The topical formulation of the pharmaceutical compositions provided herein can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof. Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequcarboxying or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
Also provided herein is a combination of a compound disclosed herein, e.g., a compound of Formula (I), including a stereoisomer, or enantiomer thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof with one or more additional therapeutic agents (including, but not limited to, a second and different anti-HBV infection agent). For instance, the compounds of this disclosure can be combined with one or more anti-HBV agents selected from the group consisting of reverse transcriptase inhibitors, capsid inhibitors, cccDNA formation inhibitors, HbsAg release inhibitors, oligomeric nucleotides targeted to the Hepatitis B genome, immunostimulators, and agents of distinct or unknown mechanism. In one embodiment, the compounds of this disclosure are also useful in combination with one or more additional therapeutic agents for simultaneous, separate or sequential administration.
In one embodiment, the reverse transcriptase inhibitors include, but are not limited to entecavir, clevudine, telbivudine, lamivudine, adefovir, tenofovir, adefovir dipovoxil, emtricitabine, abaccavir, elvucitabine, ganciclovir, lobucavir, famciclovir, penciclovir, amdoxovir, and the like.
In one embodiment, the capsid inhibitors may include, but is not limited to, any compound that inhibits capsid assembly, induces formation of non-capsid polymers, promotes excess capsid assembly or misdirected capsid assembly, affects capsid stabilization, or inhibits encapsidation of RNA (pgRNA).
In one embodiment, the cccDNA formation inhibitors include compounds that are capable of inhibiting the formation and/or stability of cccDNA either directly or indirectly. For example, a cccDNA formation inhibitor may include, but is not limited to, any compound that inhibits capsid disassembly, relaxed circular DNA (rcDNA) entry into the nucleus, or the conversion of rcDNA into cccDNA.
In one embodiment, HB sAg release inhibitors include compounds that are capable of inhibiting, either directly or indirectly, the secretion of sAg (S, M and/or L surface antigens) bearing subviral particles and/or DNA containing viral particles from HBV-infected cells.
In one embodiment, oligomeric nucleotides targeted to the Hepatitis B genome include, but are not limited to, isolated, double stranded, siRNA molecules, that each include a sense strand and an antisense strand that is hybridized to the sense strand, such as Arrowhead-ARC-520.
In one embodiment, immunostimulators include, but are not limited to, agonists of stimulator of IFN genes (STING) and interleukins, interferons, TLR-7 agonists (such as, but not limited to, GS-9620, RG-7795), T-cell stimulators (such as, but not limited to, GS-4774), RIG-1 inhibitors (such as, but not limited to, SB-9200), or SMAC-mimetics (such as, but not limited to, Birinapant).
Also provided herein a kit comprising a compound disclosed herein, e.g., a compound of Formula (I), including a stereoisomer, or enantiomer thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The kit may further comprise instructions for use, e.g., for use in treating a HBV infection. The instructions for use are generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable.
Described below are the procedures used to synthesize the exemplary compounds.
All the reagents and solvents were purchased from commercial sources and used without further purification unless otherwise indication. All the reactions were carried out under dry nitrogen or argon atmosphere and monitored by thin layer chromatography (TLC) using Merck Silica Gel 60 F254 glass-backed plate. Column chromatography was performed by Merck Silica Gel 60 (0.040-0.063 mm, 230-400 mesh). 1H NMR and 13C NMR spectra were measured by Varian Mercury-300 and Varian Bruker AVIII-500 spectrometers, and the chemical shifts (δ) were reported in parts per million (ppm) relative to the resonance of the solvent peak. Multiplicities are reported with the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), quin (quinete), m (multiplet), or br (broad). Low-resolution mass spectra were measured by HP Hewlett Packard 1100 series.
The following scheme I was followed for synthesizing the compounds of Formula (I).
In one embodiment, a compound of Formula (I) can be prepared as shown in Scheme 1. Compound I-1 is first converted to compound I-2 by reacting with R1-Y. Compound I-2 then reacts with compound I-3 to form compound I-4. Subsequently, compound I-4 reacts with trimethylsilyl chlorosulfonate to form compound I-5, which is then treated with SOCl2 to form compound I-6. Compound I-6 is converted to compound I-8 by reacting with compound I-7. Compound I-8 is deprotected and then reacts with compound I-9 to obtain compound I-10.
For the compounds shown in Scheme 1, wherein Ra, Rb, Rc, Rd, R1, R2, R3, R4 and R5 are defined as in any of the embodiments described herein. PG is an amino protecting group.
The disclosure will be further understood by the following non-limiting example.
For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Centigrade). All reactions conducted at room temperature unless otherwise noted. Synthetic methodologies herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.
The starting materials used in the examples described herein are either commercially available or can be prepared by a method known to one of skill in the art.
1-(1-Fluoro-5,11-dihydro-10-thia-dibenzo[a,d]cyclohepten-5-yl)-5-hydroxy-3,3-cyclopropyl-2,3-dihydro-1H-pyrido[1,2-b]pyridazine-4,6-dione (Compound 1)
Compound 1-ii was first prepared from commercially available 3-Fluoro-1H-pyrrole-2-carboxylic acid ethyl carboxylate via intermediate 1-i, following the scheme shown below:
To a solution of Ethyl 3-fluoro-1H-pyrrole-2-carboxylate (30 g, 191 mmole) in dry DMF (600 mL) was added Sodium hydride (9.16 mg, 229 mmole, 60% in mineral oil) at 0° C., the mixture was stirred for 30 min, then Methyl iodide (30 mL, 482 mmole) was added dropwise at ice bath over 15 min, the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was acidified with 1 N HCl(aq) and concentrated. The residue was dissolved in H2O/EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The obtained crude compound 1-i was dissolved in THF/MeOH (200/150 mL) and 2N NaOH(aq) (350 mL, 4.0 eq) was added at room temperature, the mixture was heated to 50° C. for 3 hours. After hydrolysis finished, evaporated to remove solvent and the aqueous was acidified with con. HCl (pH=2˜3), the precipitate was collected by filtration, dried under vacuum to afford compound 1-ii as an off-white solid (27.2 g, yield=99.5% in two steps).
To a solution of compound 1-ii (9 g, 62.9 mmole) in dry DMF (300 mL) was added HATU (35.9 g, 94.4 mmole) at room temperature, the mixture was stirred for 15 min. Then 3,4-Difluoroaniline (12.2 g, 94.5 mmole) and N,N-Diisopropylethylamine (54.8 mL, 314.6 mmole) were added sequentially, the reaction mixture was heated to 70° C. until reaction was completed by checking with LC-MS. Then the mixture was diluted with EtOAc, washed with 1 N HCl(aq), H2O and brine sequentially. The organic layer was dried over MgSO4, filtered and concentrated. The obtained residue was purified by column chromatography on silica gel eluting with EtOAc/Hexanes (1:9) to give compound 1-iii as an off-white solid (12.0 g, yield=75%).
To a solution of compound 1-iii (6.0 g, 23.6 mmole) in dry CH2Cl2 (240 mL) was added Trimethylsilyl chlorosulfonate (6.6 g, 35.0 mmole) at 0° C., the mixture was stirred under ice-water bath for 1 hour to afford compound 1-iv as a light yellow solid, which was suspension in CH2Cl2. After reaction completed, SOCl2 (17.0 mL, 234 mmole) and dry DMF (3.6 mL, 46.5 mmole) were added to the above solution, kept the solution clear and heated to 40° C. for 2 hours. The reaction mixture was concentrated, and the obtained dark yellow oil was subjected to silica gel column chromatography using EtOAc as eluant, the product fractions were concentrated and recrystallized in CH2Cl2/Hexanes to give compound 1-v as an off-white solid (6.0 g, yield=72% in two steps).
Compound 1 was prepared via intermediates 1-v to 1-vii as follows. A solution of compound 1-v (1.5 g, 4.3 mmole) in CH2Cl2 (20 mL) were added (R)-3-Amino-N-Boc-pyrrolidine (1.0 g, 5.4 mmole) and N,N-Diisopropylethylamine (1.5 mL, 8.6 mmole) at ice-water bath, the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. Quenched the reaction with 1 N HCl(aq), washed the mixture with H2O and brine. The organic layer was dried over MgSO4, filtered and concentrated. The obtained residue was purified by column chromatography on silica gel using a gradient from 10 to 50% EtOAc in Hexanes to afford compound 1-vi as an off-white solid (2.1 g, yield=97%).
The compound 1-vi (2.1 g, 4.2 mmole) was dissolved in CH2Cl2/MeOH (1:1, 20 mL) was added 4 N HCl/1,4-dioxane (5.4 mL, 21.6 mmole), and the mixture was stirred at room temperature for 3 hours, evaporated to give the deprotected compound 1-vii as a pale yellow hydrochloride salt (quantitative yield).
To a solution of compound 1-vii (100 mg, 0.23 mmole) in CH2Cl2 (5 mL) was added NEt3 (0.16 mL, 1.15 mmole) at ice-water bath, then cyclopropanesulfonyl chloride (50 mg, 0.36 mmole) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hour, and quenched reaction with 1 N HCl(aq), washed the mixture with H2O and brine. The organic layer was dried over MgSO4, filtered and concentrated. The obtained residue was purified by column chromatography (EtOAc/Hexanes= 3/7 as eluent), and the product fractions were concentrated and recrystallized in CH2Cl2/Hexanes system to afford compound 1 as an off-white solid (90 mg, yield=77%). MS: m/z 507.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.30 (s, 1H), 8.10 (s, 1H), 7.86-7.78 (m, 1H), 7.54 (d, 1H), 7.43-7.40 (m, 2H), 3.80 (s, 3H), 3.78-3.76 (m, 1H), 3.48-3.39 (m, 1H), 3.36-3.25 (m, 3H), 3.19-3.14 (m, 1H), 2.71-2.63 (m, 1H), 2.10-2.02 (m, 1H), 1.90-1.81 (m, 1H), 0.99-0.91 (m, 4H).
Each of Compounds 2-100 was similarly prepared following the scheme as set forth above and the protocols described in the preparation of Compound 1.
Analytical data of Compounds 2-100 are listed below:
Compound 2: MS: m/z 521.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.29 (s, 1H), 8.11 (d, 1H), 7.85-7.78 (m, 1H), 7.53 (d, 1H), 7.45-7.40 (m, 2H), 3.80 (s, 3H), 3.79-3.77 (m, 1H), 3.48-3.41 (m, 2H), 3.33 (s, 3H), 3.21-3.16 (m, 2H), 2.11-2.02 (m, 1H), 1.91-1.82 (m, 1H), 1.13-1.09 (m, 2H), 0.83-0.79 (m, 2H).
Compound 3: MS: m/z 535.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.29 (s, 1H), 8.08 (s, 1H), 7.85-7.78 (m, 1H), 7.53 (d, 1H), 7.45-7.40 (m, 2H), 3.80 (s, 3H), 3.78-3.74 (m, 1H), 3.72-3.61 (m, 1H), 3.47-3.41 (m, 1H), 3.37-3.24 (m, 2H), 3.19-3.13 (m, 1H), 2.10-2.01 (m, 2H), 1.99-1.90 (m, 2H), 1.88-1.70 (m, 2H), 1.67-1.58 (m, 2H), 1.57-1.49 (m, 2H).
Compound 4: MS: m/z 525.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.29 (s, 1H), 8.07 (s, 1H), 7.85-7.78 (m, 1H), 7.53 (d, 1H), 7.45-7.40 (m, 2H), 3.80 (s, 3H), 3.77-3.71 (m, 1H), 3.66-3.62 (m, 2H), 3.46-3.41 (m, 1H), 3.38-3.28 (m, 4H), 3.25 (s, 3H), 3.14-3.07 (m, 1H), 2.06-2.00 (m, 1H), 1.86-1.79 (m, 1H).
Compound 5: MS: m/z 496.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 8.04 (d, 1H), 7.82-7.74 (m, 1H), 7.48 (d, 1H), 7.41-7.36 (m, 2H), 6.99 (dd, 1H), 3.76-3.70 (m, 4H), 3.34-3.29 (m, 1H), 3.26-3.15 (m, 1H), 3.12-3.07 (m, 1H), 3.01-2.96 (m, 1H), 2.47 (s, 3H), 2.06-1.99 (m, 1H), 1.80-1.70 (m, 1H).
Compound 6: MS: m/z 514.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.36 (s, 1H), 8.09 (d, 1H), 7.62-7.52 (m, 3H), 7.02 (dd, 1H), 3.78-3.72 (m, 4H), 3.35-3.31 (m, 1H), 3.27-3.19 (m, 1H), 3.16-3.08 (m, 1H), 3.02-2.97 (m, 1H), 2.48 (s, 3H), 2.09-1.99 (m, 1H), 1.83-1.74 (m, 1H).
Compound 7: MS: m/z 503.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.37 (s, 1H), 8.15 (dd, 1H), 8.09 (d, 1H), 7.96-7.90 (m, 1H), 7.55-7.49 (m, 2H), 7.02 (dd, 1H), 3.79-3.72 (m, 4H), 3.36-3.31 (m, 1H), 3.27-3.19 (m, 1H), 3.16-3.08 (m, 1H), 3.02-2.97 (m, 1H), 2.48 (s, 3H), 2.09-1.99 (m, 1H), 1.83-1.74 (m, 1H).
Compound 8: MS: m/z 576.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.44 (s, 1H), 8.32 (d, 1H), 7.82-7.75 (m, 1H), 7.45-7.38 (m, 2H), 7.02 (dd, 1H), 3.82-3.77 (m, 4H), 3.37-3.20 (m, 2H), 3.19-3.07 (m, 1H), 3.01-2.96 (m, 1H), 2.46 (s, 3H), 2.07-2.00 (m, 1H), 1.84-1.74 (m, 1H).
Compound 9: MS: m/z 510.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.29 (s, 1H), 8.10 (s, 1H), 7.85-7.78 (m, 1H), 7.53 (d, 1H), 7.45-7.40 (m, 2H), 3.80 (s, 3H), 3.77-3.73 (m, 1H), 3.40-3.31 (m, 2H), 3.28-3.18 (m, 1H), 3.13-3.08 (m, 1H), 2.72 (s, 6H), 2.11-2.00 (m, 1H), 1.88-1.79 (m, 1H).
Compound 10: MS: m/z 522.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 9.88 (s, 1H), 8.02 (d, 1H), 7.83-7.76 (m, 1H), 7.43-7.38 (m, 2H), 7.06-7.02 (m, 1H), 4.26-4.22 (m, 2H), 3.78-3.74 (m, 1H), 3.37-2.98 (m, 6H), 2.71 (s, 3H), 2.49-2.34 (m, 2H), 2.06-1.97 (m, 1H), 1.81-1.74 (m, 1H).
Compound 11: MS: m/z 536.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.14 (s, 1H), 7.93 (d, 1H), 7.81-7.74 (m, 1H), 7.40-7.35 (m, 2H), 7.04-6.99 (m, 1H), 4.10 (t, 2H), 3.72-3.68 (m, 1H), 3.28-3.06 (m, 3H), 2.99-2.94 (m, 1H), 2.89-2.85 (m, 2H), 2.46 (d, 3H), 2.05-1.95 (m, 1H), 1.86-1.81 (m, 2H), 1.78-1.69 (m, 3H).
Compound 12: MS: m/z 556.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.16 (s, 1H), 7.97 (d, 1H), 7.66-7.58 (m, 2H), 7.05-7.00 (m, 1H), 4.25-4.20 (m, 2H), 3.76-3.70 (m, 1H), 3.29-3.20 (m, 2H), 3.15-3.00 (m, 4H), 2.43 (s, 3H), 2.41-2.36 (m, 2H), 2.05-1.95 (m, 1H), 1.83-1.74 (m, 1H).
Compound 13: MS: m/z 561.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.27 (s, 1H), 7.87-7.76 (m, 4H), 7.49-7.34 (m, 5H), 5.72 (s, 3H), 3.51-3.46 (m, 1H), 3.33-3.26 (m, 1H), 3.23-3.14 (m, 1H), 3.03-2.94 (m, 1H), 2.88-2.78 (m, 1H), 1.76-1.67 (m, 1H), 1.44-1.36 (m, 1H).
Compound 14: MS: m/z 569.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.27 (s, 1H), 8.06 (d, 1H), 7.85-7.80 (m, 1H), 7.78-7.72 (m, 2H), 7.49 (d, 1H), 7.44-7.38 (m, 3H), 7.34 (s, 1H), 7.29 (s, 1H), 3.76 (s, 3H), 3.74-3.72 (m, 1H), 3.45-3.39 (m, 1H), 3.37-3.31 (m, 2H), 3.29-3.22 (m, 2H), 3.20-3.12 (m, 1H), 2.04-1.96 (m, 1H), 1.86-1.77 (m, 1H).
Compound 15: MS: m/z 530.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 9.88 (s, 1H), 8.09 (d, 1H), 7.67-7.59 (m, 1H), 7.53 (d, 1H), 7.34 (t, 1H), 7.03 (dd, 1H), 3.79-3.72 (m, 4H), 3.36-3.20 (m, 2H), 3.17-3.11 (m, 1H), 3.03-2.98 (m, 1H), 2.47 (s, 3H), 2.10-1.97 (m, 1H), 1.84-1.75 (m, 1H).
Compound 16: MS: m/z 528.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.27 (s, 1H), 8.05 (d, 1H), 8.00-7.97 (m, 1H), 7.79-7.76 (m, 1H), 7.49 (d, 1H), 7.38 -6.98 (m, 3H), 3.77-3.71 (m, 4H), 3.36-3.20 (m, 2H), 3.18-3.07 (m, 1H), 3.02-2.96 (m, 1H), 2.47 (s, 3H), 2.06-1.98 (m, 1H), 1.83-1.74 (m, 1H).
Compound 17: MS: m/z 541.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.07 (d, 1H), 7.84-7.76 (m, 1H), 7.56 (d, 1H), 7.43-7.38 (m, 2H), 7.02 (dd, 1H), 4.22 (dd, 2H), 3.76 (dd, 1H), 3.35-3.08 (m, 3H), 3.01-2.96 (m, 1H), 2.47 (s, 3H), 2.07-1.98 (m, 1H), 1.83-1.74 (m, 1H) 7.27 (t, 3H).
Compound 18: MS: m/z 517.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 9.99 (s, 1H), 7.96 (d, 1H), 7.56 (dd, 1H), 7.48-7.42 (m, 2H), 7.09 (t, 1H), 3.77 (s, 3H), 3.59 (dd, 1H), 3.42 (d, 1H), 3.16-3.14 (m, 1H), 2.76-2.47 (m, 3H), 2.21 (s, 3H), 1.74-1.72 (m, 2H), 1.46-1.26 (m,2H), 0.97-0.79 (m, 4H).
Compound 19: MS: m/z 524.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.13 (s, 1H), 7.84-7.76 (m, 1H), 7.69 (d, 1H), 7.45-7.38 (m, 3H), 7.12-7.07 (m, 1H), 3.85 (s, 3H), 3.32-3.24 (m, 3H), 2.76-2.25 (m, 5H), 1.72-1.39 (m, 3H), 0.94-0.72 (m, 3H).
Compound 20: MS: m/z 524.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 7.83-7.56 (m, 1H), 7.55 (s, 1H), 7.48 (d, 1H), 7.42-7.40 (m, 2H), 7.09-7.07 (m, 1H), 3.77 (s, 3H), 3.32-3.17 (m, 2H), 2.84 (d, 1H), 2.71-2.64 (m, 1H), 2.45 (s, 3H), 1.69-1.30 (m, 4H), 0.86 (s, 3H).
Compound 21: MS: m/z 542.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 8.15 (s, 1H), 7.96 (d, 1H), 7.89 (d, 1H), 7.59 (dd, 1H), 7.52 (d, 1H), 7.46 (d, 1H), 7.13 (dd, 1H), 3.80 (s, 3H), 3.49 (dd, 1H), 3.30-3.27 (m, 1H), 3.24-3.08 (m, 1H), 2.62-2.56 (m, 1H), 2.49 (d, 3H), 2.42 (d, 1H), 1.73-1.69 (m, 2H), 1.48-1.37 (m, 1H), 1.32-1.21 (m, 1H).
Compound 22: MS: m/z 524.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.30 (s, 1H), 7.94 (d, 1H), 7.86-7.78 (m, 1H), 7.57 (d, 1H), 7.45-7.40 (m, 2H), 7.12 (d, 1H), 4.23 (q, 2H), 3.49 (dd, 1H), 3.33-3.29 (m, 1H), 3.24-3.07 (m, 1H), 2.59-2.56 (m, 1H), 2.49 (d, 3H), 2.46 (d, 1H), 1.74-1.70 (m, 2H), 1.46-1.32 (m, 2H), 1.28 (t, 3H).
Compound 23: MS: m/z 538.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 7.83-7.76 (m, 2H), 7.42 (d, 1H), 7.43-7.38 (m, 2H), 7.08 (d, 1H), 3.78 (s, 3H), 3.38-3.15 (m, 3H), 2.71-2.64 (m, 3H), 1.78-1.75 (m, 2H), 1.51-1.41 (m, 2H), 1.07 (s, 3H), 1.5 (s, 3H).
Compound 24: MS: m/z 535.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 7.89-7.76 (m, 2H), 7.70-7.38 (m, 3H), 3.78 (s, 3H), 3.56-3.51 (m, 2H), 3.27-3.23 (m, 1H), 3.03-2.96 (m, 2H), 1.78-1.74 (m, 2H), 1.48-1.40 (m, 2H), 1.35 (s, 3H), 1.12-1.08 (m, 1H), 0.79-0.75 (m, 1H).
Compound 25: MS: m/z 524.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.21 (s, 1H), 7.83-7.76 (m, 1H), 7.48-7.38 (m, 4H), 7.03-7.00 (m, 1H), 3.77 (s, 3H), 3.10-2.94 (m, 4H), 2.48 (s, 3H), 1.98-1.94 (m, 2H), 1.51-1.43 (m,2H), 1.17 (m, 3H).
Compound 26: MS: m/z 521.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 8.26 (s, 1H), 7.85-7.78 (m, 1H), 7.52 (d, 1H), 7.45-7.40 (m, 2H), 3.80 (s, 3H), 3.04-2.97 (m, 4H), 2.91-2.84 (m, 1H), 2.08-1.93 (m, 2H), 1.35-1.29 (m, 2H), 1.16 (t, 3H), 1.01-0.98 (m, 1H), 0.59-0.55 (m, 1H).
Compound 27: MS: m/z 546.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 8.31 (d, 1H), 7.82-7.75 (m, 1H), 7.44-7.33 (m, 3H), 7.25 (dd, 1H), 3.75-3.61 (m, 4H), 3.58-3.42 (m, 1H), 3.34 (d, 1H), 3.29-3.15 (m, 1H), 2.97-2.90 (m, 1H), 2.45 (d, 3H), 1.73-1.64 (m, 2H).
Compound 28: MS: m/z 581.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.13 (s, 1H), 7.77 (d, 1H), 7.66-7.59 (m, 2H), 4.26-4.21 (m, 2H), 3.50-3.43 (m, 2H), 3.22-3.19 (m, 1H), 3.05-3.00 (m, 2H), 2.94-2.87 (m, 2H), 2.42-2.39 (m, 3H), 1.77-1.74 (m, 2H), 1.55-1.44 (m, 2H), 0.99-0.88 (m, 4H).
Compound 29: MS: m/z 524.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.20 (s, 1H), 7.83-7.74 (m, 2H), 7.45-7.38 (m, 3H), 6.88 (d, 1H), 6.58 (dd, 1H), 3.76 (s, 3H), 3.02-2.98 (m, 1H), 2.87-2.84 (m, 1H), 2.35 (d, 3H), 1.97 (d, 1H), 1.77 (d, 1H), 1.61 (t, 2H), 1.21-0.94 (m, 4H).
Compound 30: MS: m/z 520.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.35 (s, 1H), 8.10 (S, 1H), 7.63-7.51 (m, 3H), 3.82-3.68 (m, 4H), 3.46-3.33 (m, 2H), 3.30-3.15 (m, 2H), 2.85-2.80 (m, 6H), 2.05-2.02 (m, 1H), 1.88-1.77 (m, 1H).
Compound 31: MS: m/z 538.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.24 (d, 1H), 8.93 (t, 1H), 8.03 (s, 1H), 7.76 (dd, 1H), 7.47 (t, 1H), 7.43-7.32 (m, 2H), 6.20-5.78 (m, 1H), 3.80-3.66 (m, 5H), 3.64-3.54 (m, 1H), 3.51-3.40 (m, 3H), 3.39-3.30 (m, 1H), 2.03-1.73 (m, 2H).
Compound 32: MS: m/z 532.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.25 (d, 1H), 8.55 (t, 1H), 8.03 (s, 1H), 7.78 (dd, 1H), 7.50-7.42 (m, 1H), 7.41-7.33 (m, 2H), 3.81-3.71 (m, 5H), 3.69-3.59 (m, 1H), 3.57-3.41 (m, 1H), 3.38-3.24 (m, 3H), 3.23-3.16 (m, 5H), 2.04-1.72 (m, 2H).
Compound 33: MS: m/z 514.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.21 (s, 1H), 8.60 (s, 1H), 8.01 (s, 1H), 7.76 (dd, 1H), 7.48 (d, 1H), 7.40-7.33 (m, 2H), 3.77-3.70 (m, 5H), 3.68-3.55 (m, 1H), 3.50-3.38 (m, 1H), 3.35-3.21 (m, 1H), 2.70-2.63 (m, 1H), 2.04-1.74 (m, 2H), 0.65-0.50 (m, 4H).
Compound 34: MS: m/z 512.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.24 (d, 1H), 9.02 (t, 1H), 8.04 (d, 1H), 7.78 (dd, 1H), 7.49 (t, 1H), 7.45-7.34 (m, 2H), 3.86-3.83 (m, 2H), 3.77-3.69 (m, 5H), 3.67-3.59 (m, 1H), 3.53-3.40 (m, 1H), 3.38-3.27 (m, 1H), 3.08-3.05 (m, 1H), 2.05-1.76 (m, 2H).
Compound 35: MS: m/z 536.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 11.75 (d, 1H), 10.32 (d, 1H), 8.06 (d, 1H), 7.61-7.50 (m, 3H), 3.84-3.61 (m, 7H), 3.59-3.48 (m, 1H), 3.46-3.39 (m, 1H), 3.35-3.22 (m, 1H), 2.04-1.77 (m, 2H), 1.10 (dd, 3H).
Compound 36: MS: m/z 548.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.32 (s, 1H), 9.36 (d, 1H), 8.03 (s, 1H), 7.60-7.49 (m, 3H), 4.83-4.74 (m, 1H), 4.66-4.60 (m, 2H), 4.52-4.48 (m, 2H), 3.77-3.65 (m, 5H), 3.63-3.53 (m, 1H), 3.51-3.43 (m, 1H), 3.41-3.29 (m, 1H), 2.04-1.77 (m, 2H).
Compound 37: MS: m/z 536.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.32 (s, 1H), 8.46(t, 1H), 8.04 (s, 1H), 7.63-7.50 (m, 3H), 4.67 (t, 1H), 3.85-3.59 (m, 6H), 3.52-3.29 (m, 4H), 3.17-3.10 (m, 2H), 2.04-1.73 (m, 2H).
Compound 38: MS: m/z 600.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.34 (d, 1H), 8.72 (t, 1H), 8.06 (d, 1H), 7.60-7.50 (m, 3H), 4.00 (d, 2H), 3.80-3.68 (m, 5H), 3.66-3.46 (m, 1H), 3.42-3.67 (m, 1H), 3.30-3.24 (m, 3H), 2.05-1.77 (m, 5H).
Compound 39: MS: m/z 588.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.32 (d, 1H), 9.18 (dd, 1H), 8.08 (s, 1H), 7.60-7.50 (m, 3H), 4.60-4.50 (m, 1H), 3.77-3.59 (m, 5H), 3.57-3.41 (m, 2H), 3.38-3.22 (m, 1H), 2.05-1.76 (m, 2H), 1.25 (t, 3H).
Compound 40: MS: m/z 520.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.27 (d, 1H), 8.55-8.54 (m, 1H), 8.03-7.97 (m, 2H), 7.79-7.76 (m, 1H), 7.49 (t, 1H), 7.38-7.02 (m, 2H), 3.83-3.52 (m, 6H), 3.50-3.40 (m, 1H), 3.37-3.24 (m, 1H), 2.60-2.53 (m, 3H), 2.05-1.73 (m, 2H).
Compound 41: MS: m/z 504.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.22 (d, 1H), 8.54 (s, 1H), 8.03 (s, 1H), 7.93 (dd, 1H), 7.60-7.54 (m, 1H), 7.49 (t, 1H), 7.38 (t, 1H), 3.83-3.59 (m, 6H), 3.52-3.42 (m, 1H), 3.40-3.27 (m, 1H), 2.61-2.58 (m, 3H), 2.02-1.76 (m, 2H).
Compound 42: MS: m/z 511.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.66 (s, 1H), 8.65 (s, 1H), 8.56 (d, 1 H), 8.18-8.16 (m, 1H), 7.99-7.95 (m, 1H), 7.66 (d, 1H), 7.54 (t, 1H), 3.83-3.63 (m, 4H), 3.51-3.43 (m, 1H), 2.64-2.60 (m, 6H), 1.98-1.79 (m, 2H).
Compound 43: MS: m/z 540.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.50 (d, 1H), 8.55 (t, 1H), 8.37 (s, 1H), 7.58 (dd, 2H), 3.82-3.75 (m, 5H), 3.70-3.63 (m, 1H), 3.52-3.41 (m, 1H), 3.37-3.30 (m, 1H), 2.61-2.59 (m, 3H), 2.03-1.77 (m, 2H).
Compound 44: MS: m/z 502.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.31-10.18 (m, 1H), 8.63-8.50 (m, 1H), 7.98-7.77 (m, 2H), 7.48-7.33 (m, 2H), 3.84-3.72 (m, 2H), 3.69 (s, 3H), 3.66-3.59 (m, 2H), 3.48-3.41 (m, 1H), 3.27 (s, 3H), 2.59-2.55 (m, 3H), 2.07-1.80 (m, 2H).
Compound 45: MS: m/z 546.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 9.98 (s, 1H), 8.64 (t, 1H), 8.03 (s, 1H), 7.65-7.59 (m, 2H), 4.25 (t, 2H), 3.82-3.59 (m, 4H), 3.51-3.39 (m, 1H), 3.14-3.10 (m, 2H), 3.07-2.97 (m, 2H), 2.43-2.36 (m, 2H), 2.04-1.82 (m, 2H), 1.05-0.98 (dd, 3H).
Compound 46: MS: m/z 546.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.20 (d, 1H), 8.54 (d, 1H), 7.91 (s, 1H), 7.60-7.54 (m, 2H), 4.09 (t, 2H), 3.78-3.60 (m, 3H), 3.58-3.41 (m, 1H), 2.87-2.70 (m, 2H), 2.61-2.58 (m, 3H), 2.05-1.92 (m, 1H), 1.87-1.83 (m, 3H), 1.81-1.74 (m, 3H).
Compound 47: MS: m/z 548.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.15 (s, 1H), 8.57 (t, 1H), 7.95 (s, 1H), 7.65-7.60 (m, 2H), 4.23 (t, 2H), 3.82-3.63 (m, 3H), 3.50-3.30 (m, 2H), 3.04-3.00 (m, 2H), 2.66-2.61 (m, 3H), 2.44-2.37 (m, 2H), 2.00-1.78 (m, 2H).
Compound 48: MS: m/z 538.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.44 (s, 1H), 8.56 (s, 1H), 8.18 (s, 1H), 7.81-7.75 (m, 1H), 7.58 (s, 1H), 7.46-7.38 (m, 2H), 6.36 (t, 1H), 4.75 (t, 2H), 3.82-3.70 (m, 2H), 3.68-3.61 (m, 1H), 3.53-3.41 (m, 1H), 3.37-3.29 (m, 1H), 2.60 (s, 3H), 2.03-1.89 (m, 1H), 1.87-1.74 (m, 1H).
Compound 49: MS: m/z 514.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.42 (s, 1H), 8.56 (d, 1H), 8.03 (s, 1H), 7.85-7.79 (m, 1H), 7.44-7.39 (m, 3H), 3.83-3.70 (m, 3H), 3.67-3.57 (m, 1H), 3.51-3.40 (m, 1H), 3.37-3.25 (m, 1H), 2.61 (s, 3H), 2.02-1.91 (m, 1H), 1.86-1.73 (m, 1H), 0.92-0.81 (m, 4H).
Compound 50: MS: m/z 528.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.39 (s, 1H), 8.55 (s, 1H), 8.06 (s, 1H), 7.83-7.76 (m, 1H), 7.58 (s, 1H), 7.43-7.40 (m, 2H), 4.06 (d, 2H), 3.83-3.70 (m, 3H), 3.68-3.61 (m, 1H), 3.53-3.41 (m, 1H), 3.38-3.27 (m, 1H), 2.60 (s, 3H), 2.03-1.90 (m, 1H), 1.87-1.74 (m, 1H), 0.93-0.79 (m, 2H), 0.49-0.32 (m, 2H).
Compound 51: MS: m/z 516.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 8.57 (s, 1H), 8.03 (s, 1H), 7.83-7.75 (m, 1H), 7.55 (s, 1H), 7.46-7.38 (m, 2H), 4.17 (t, 2H), 3.81-3.70 (m, 2H), 3.68-3.60 (m, 1H), 3.52-3.43 (m, 1H), 3.40-3.26 (m, 1H), 2.60 (s, 3H), 2.02-1.93 (m, 1H), 1.89-1.78 (m, 1H), 1.69-1.57 (m, 2H), 0.76 (t, 3H).
Compound 52: MS: m/z 514.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.35 (s, 1H), 8.57 (d, 1H), 8.08 (s, 1H), 7.81-7.74 (m, 1H), 7.53 (d, 1H), 7.42-7.37 (m, 2H), 5.98-5.89 (m, 1H), 5.13 (d, 1H), 4.96 (d, 1H), 4.85 (d, 2H), 3.82-3.70 (m, 2H), 3.64-3.60 (m, 1H), 3.50-3.43 (m, 1H), 3.32-3.25 (m, 1H), 2.60 (s, 3H), 2.00-1.94 (m, 1H), 1.85-1.78 (m, 1H).
Compound 53: MS: m/z 542.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.50 (s, 1H), 8.57 (d, 1H), 8.03 (s, 1H), 7.82-7.76 (m, 1H), 7.50 (t, 1H), 7.43-7.38 (m, 2H), 5.04-4.98 (m, 1H), 3.81-3.70 (m, 2H), 3.64-3.58 (m, 1H), 3.52-3.40 (m, 1H), 3.33-3.29 (m, 1H), 2.60 (s, 3H), 2.08-1.94 (m, 3H), 1.81-1.73 (m, 3H), 1.62-1.57 (m, 2H), 1.26-1.20 (m, 2H).
Compound 54: MS: m/z 534.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 8.59 (dd, 1H), 8.05 (s, 1H), 7.64-7.58 (m, 2H), 7.52 (dd, 1H), 3.80 (s, 3H), 3.77-3.74 (m, 1H), 3.67-3.62 (m, 1H), 3.51-3.40 (m, 1H), 3.37-3.26 (m, 2H), 3.10 (q, 2H), 2.36-2.26 (m, 1H), 1.02 (t, 3H), 0.90 (d, 3H).
Compound 55: MS: m/z 518.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.29 (d, 1H), 8.51-8.50 (m, 2H), 7.61-7.53 (m, 3H), 4.02-3.53 (m, 6H), 3.38-3.19 (m, 1H), 2.59-2.54 (m, 3H), 1.69-1.60 (m, 1H), 0.95-0.92 (m, 1H), 0.54-0.49 (m, 1H).
Compound 56: MS: m/z 506.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.35 (s, 1H), 8.67 (t, 1H), 8.46 (s, 1H), 7.60-7.51 (m, 3H), 4.65-4.59 (m, 1H), 4.23-4.11 (m, 3H), 3.77 (s, 3H), 3.73-3.68 (m, 1H), 3.09-3.00 (m, 2H), 0.97 (t, 3H).
Compound 57: MS: m/z 536.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.65 (d, 1H), 8.56-8.50 (m, 1H), 7.87 (s, 1H), 7.66-7.59 (m, 3H), 4.18-3.94 (m, 1H), 3.78 (s, 3H), 3.70-3.52 (m, 1H), 2.99-2.86 (m, 1H), 2.73-2.60 (m, 4H), 1.84-1.80 (m, 1H), 1.69-1.66 (m, 1H), 1.46-1.24 (m, 3H).
Compound 58: MS: m/z 502.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.31 (s, 1H), 8.05 (d, 1H), 7.93 (s, 1H), 7.86-7.79 (m, 1H), 7.65 (d, 1H), 7.55 (d, 1H), 7.49-7.37 (m, 2H), 4.23 (q, 2H), 4.14 (dd, 1H), 3.96 (d, 1H), 3.78 (dd, 1H), 3.53 (d, 1H), 3.19-3.08 (m, 1H), 3.01-2.86 (m, 1H), 2.73-2.56 (m, 1H), 1.84-1.78 (m, 1H), 1.70-1.66 (m, 1H), 1.29 (t, 3H).
Compound 59: MS: m/z 532.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.31 (s, 1H), 8.54 (s, 1H), 8.35 (d, 1H), 7.62-7.51 (m, 3H), 4.17 (d, 1H), 3.62 (s, 3H), 3.60 (d, 1H), 3.06-2.98 (m, 1H), 2.79-2.70 (m, 1H), 2.61 (s, 3H), 1.96-1.94 (m, 1H), 1.59-1.49 (m, 1 H), 1.24 (d, 1H), 0.93-0.82 (m, 1H), 0.55-0.42 (m, 1H).
Compound 60: MS: m/z 514.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.30 (s, 1H), 7.60-7.55 (m, 3H), 7.17 (d, 1H), 6.78 (dd, 1H), 3.79 (s, 3H), 3.63 (dd, 1H), 3.40-3.23 (m, 2H), 3.18-3.10 (m, 1H), 3.03-2.98 (m, 1H), 2.39 (d, 3H), 2.06-2.00 (m, 1H), 1.75-1.69 (m, 1H).
Compound 61: MS: m/z 520.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 8.81 (d, 1H), 8.72 (t, 1H), 7.61-7.55 (m, 3H), 4.15 (dd, 1H), 3.78 (s, 3H), 3.39-3.30 (m, 2H), 3.23-3.02 (m, 4H), 2.05-1.91 (m, 2H), 0.97 (t, 3H).
Compound 62: MS: m/z 550.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.30 (s, 1H), 7.61-7.54 (m, 3H), 6.98 (d, 1H), 6.57 (dd, 1H), 3.79 (s, 3H), 3.39-3.35 (m, 2H), 3.03-3.01 (m, 1H), 2.61-2.54 (m, 2H), 2.38 (d, 3H), 1.88 (d, 2H), 1.50 (dd, 2H).
Compound 63: MS: m/z 534.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 8.76-8.71 (m, 2H), 7.60-7.53 (m, 3H), 3.78 (s, 3H), 3.63-3.50 (m, 3H), 3.15-3.06 (m, 2H), 2.51-2.40 (m, 2H), 1.71-1.61 (m, 4H), 1.00 (t, 3H).
Compound 64: MS: m/z 534.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 8.80 (t, 1H), 8.59 (d, 1H), 7.61-7.53 (m, 3H), 3.79-3.78 (m, 4H), 3.41-3.30 (m, 2H), 3.16-3.07 (m, 2H), 2.34 (t, 2H), 1.79-1.66 (m, 2H), 1.57-1.36 (m, 2H), 1.01 (t, 3H).
Compound 65: MS: m/z 520.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.35 (s, 1H), 8.62 (t, 1H), 7.59-7.54 (m, 3H), 3.79 (s, 3H), 3.58-3.55 (m, 4H), 3.13-3.04 (m, 2H), 2.97-2.46 (m, 4H), 0.99 (t, 3H).
Compound 66: MS: m/z 514.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 7.60-7.54 (m, 3H), 7.22 (dd, 1H), 3.79 (s, 3H), 3.16-3.14 (m, 4H), 3.03-3.01 (m, 4H), 2.48-2.47 (s, 3H).
Compound 67: MS: m/z 507.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.30 (s, 1H), 7.86-7.78 (m, 1H), 7.63 (d, 1H), 7.46-7.41 (m, 2H), 4.41 (q, 2H), 3.81 (s, 3H), 3.40-3.24 (m, 2H), 3.19-3.05 (m, 2H), 2.56-2.43 (m, 2H), 1.74-1.70 (m, 1H), 1.38-1.34 (m, 1H), 1.17 (t, 3H).
Compound 68: MS: m/z 506.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.32 (s, 1H), 8.03 (s, 1H), 7.91 (d, 1H), 7.61-7.56 (m, 3H), 7.48 (d, 1H), 4.00 (d, 1H), 3.77 (s, 3H), 3.64 (d, 1H), 3.31-3.30 (m, 1H), 3.09 (t, 1H), 2.83 (t, 1H), 1.76-1.73 (m, 2H), 1.40-1.29 (m, 2H).
Compound 69: MS: m/z 534.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.62 (t, 1H), 7.91 (d, 1H), 7.61-7.56 (m, 2H), 7.49 (d, 1H), 4.01 (d, 1H), 3.77 (s, 3H), 3.64 (d, 1H), 3.32-3.30 (m, 1H), 3.14-3.05 (m, 3H), 2.84 (t, 1H), 1.76-1.71 (m, 2H), 1.39-1.30 (m, 2H), 1.00 (t, 3H).
Compound 70: MS: m/z 532.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.61 (t, 1H), 7.90 (d, 1H), 7.60 (d, 1H), 7.54-7.47 (m, 2H), 7.14 (dd, 1H), 4.01 (d, 1H), 3.77 (s, 3H), 3.63 (d, 1H), 3.13-3.04 (m, 3H), 2.84 (t, 1H), 1.76-1.71 (m, 2H), 1.42-1.20 (m, 3H), 1.00 (t, 3H).
Compound 71: MS: m/z 512.2 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 9.98 (s, 1H), 8.61 (t, 1H), 7.85 (d, 1H), 7.57-7.53 (m, 1H), 7.46-7.41 (m, 2H), 7.08 (t, 1H), 4.01 (d, 1H), 3.75 (s, 3H), 3.63 (d, 1H), 3.33-3.23 (m, 1H), 3.13-3.04 (m, 3H), 2.84 (t, 1H), 2.18 (d, 3H), 1.76-1.72 (m, 2H), 1.39-1.29 (m, 2H), 0.99 (t, 3H).
Compound 72: MS: m/z 514.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.19 (s, 1H), 8.61 (t, 1H), 7.87 (d, 1H), 7.82-7.81 (m, 1H), 7.54 (d, 1H), 7.50 (d, 1H), 7.34 (t, 1H), 7.13 (dd, 1H), 4.00 (d, 1H), 3.76 (s, 3H), 3.63 (d, 1H), 3.29-3.23 (m, 1H), 3.12-3.03 (m, 3H), 2.83 (t, 1H), 1.75-1.71 (m, 2H), 1.42-1.21 (m, 2H), 0.99 (t, 3H).
Compound 73: MS: m/z 548.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.61 (t, 1H), 8.11 (s, 1H), 7.90-7.84 (m, 2H), 7.55 (t, 1H), 7.47-7.41 (m, 2H), 4.00 (d, 1H), 3.77 (s, 3H), 3.63 (d, 1H), 3.30-3.29 (m, 1H), 3.13-3.06 (m, 3H), 2.84 (t, 1H), 1.76-1.72 (m, 2H), 1.39-1.21 (m, 2H), 0.99 (t, 3H).
Compound 74: MS: m/z 550.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 9.84 (s, 1H), 8.62 (t, 1H), 7.91 (d, 1H), 7.66-7.58 (m, 1H), 7.48 (d, 1H), 7.32 (t, 1H), 4.01 (d, 1H), 3.77 (s, 3H), 3.63 (d, 1H), 3.31-3.30 (m, 1H), 3.13-3.04 (m, 3H), 2.84 (t, 1H), 1.76-1.72 (m, 2H), 1.39-1.30 (m, 2H), 1.00 (t, 3H).
Compound 75: MS: m/z 562.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 8.47 (d, 1H), 7.92 (d, 1H), 7.62-7.52 (m, 2H), 7.49 (d, 1H), 4.04-3.98 (m, 1H), 3.78 (s, 3H), 3.73-3.63 (m, 1H), 3.59 (d, 1H), 3.33-3.31 (m, 1H), 3.08 (t, 1H), 2.85 (dd, 1H), 1.75 (d, 2H), 1.44-1.23 (m, 4H), 0.94 (t, 3H), 0.79 (t, 3H).
Compound 76: MS: m/z 550.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.66 (s, 1H), 8.64 (t, 1H), 7.85 (d, 1H), 7.65-7.59 (m, 3H), 4.04 (d, 1H), 3.77 (s, 3H), 3.67 (d, 1H), 3.16-2.98 (m, 3H), 2.85 (t, 1H), 1.77-1.73 (m, 2H), 1.47-1.23 (m, 3H), 1.03 (t, 3H)
Compound 77: MS: m/z 572.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 9.94 (s, 1H), 8.72 (d, 1H), 7.87-7.85 (d, 1H), 7.65-7.59 (m, 2H), 4.25 (t, 2H), 4.01 (d, 1H), 3.61 (d, 1H), 3.37-3.20 (m, 1H), 3.14-2.97 (m, 3H), 2.90-2.83 (m, 1H), 2.71-2.65 (m, 1H), 2.43-2.38 (m, 2H), 1.76-1.71 (m, 2H), 1.39-1.30 (m, 2H), 0.67-0.61 (m, 2H), 0.47-0.44 (m, 2H).
Compound 78: MS: m/z 576.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.13 (s, 1H), 8.64 (t, 1H), 7.78 (d, 1H), 7.66-7.60 (m, 2H), 4.23 (t, 2H), 4.03 (d, 1H), 3.65 (d, 1H), 3.33-3.26 (m, 1H), 3.16-3.00 (m, 5H), 2.90-2.83 (m, 1H), 2.47-2.39 (m, 2H), 1.75-1.68 (m, 2H), 1.41-1.24 (m, 2H), 1.03 (t, 3H).
Compound 79: MS: m/z 556.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 9.99 (s, 1H), 8.62 (t, 1H), 7.57-7.45 (m, 3H), 4.10 (t, 2H), 3.99 (d, 1H), 3.62 (d, 1H), 3.18-2.98 (m, 4H), 2.95-2.89 (m, 2H), 2.85-2.81 (m, 1H), 2.38 (s, 3H), 1.75-1.57 (m, 3H), 1.35-1.22 (m, 3H), 1.00 (t, 3H).
Compound 80: MS: m/z 530.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.24 (t, 1H), 8.70-8.57 (m, 1H), 7.90-7.79 (m, 2H), 7.48-7.36 (m, 2H), 4.05-3.90 (m, 1H), 3.82-3.75 (m, 1H), 3.61 (s, 3H) 3.42-3.39 (m, 1H), 3.29-3.27 (m, 1H), 3.21-3.07 (m, 2H), 2.90-2.83 (m, 1H), 2.43 (s, 3H), 1.75-1.60 (m, 2H), 1.43-1.24 (m, 2H), 1.11-0.93 (m, 3H).
Compound 81: MS: m/z 613.9 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.50 (s, 1H), 8.61 (t, 1H), 8.15 (d, 1H), 7.61-7.56 (m, 2H), 4.03 (d, 1H), 3.77 (s, 3H), 3.66 (d, 1H), 3.31-3.30 (m, 1H), 3.15-3.03 (m, 3H), 2.83 (t, 1H), 1.41-1.32 (m, 2H), 1.18-1.13 (m, 2H), 1.01 (t, 3H).
Compound 82: MS: m/z 548.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.30 (s, 1H), 8.56 (t, 1H), 7.61-7.49 (m, 4H), 3.77 (s, 3H), 3.68-3.61 (m, 1H), 3.48-3.23 (m, 2H), 3.17-3.05 (m, 3H), 1.90-1.88 (m, 2H), 1.47-1.35 (m, 2H), 1.19 (s, 3H), 0.83 (t, 3H).
Compound 83: MS: m/z 530.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.20 (s, 1H), 8.63-8.61 (m, 1H), 7.82-7.75 (m, 2H), 7.45-7.33 (m, 3H), 4.12 (d, 1H), 3.75 (s, 3H), 3.65 (d, 1H), 3.30-3.29 (m, 1H), 3.08-3.05 (m, 2H), 2.98-2.88 (m, 1H), 2.79-2.62 (m, 1H), 1.73-1.70 (m, 1H), 1.47-1.21 (m, 2H), 0.99 (t, 3H), 0.82-0.72 (m, 3H).
Compound 84: MS: m/z 564.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.66 (s, 1H), 8.61 (s, 1H), 7.74 (s, 1H), 7.64-7.57 (m, 3H), 3.99-3.94 (m, 1H), 3.75 (s, 3H), 3.36-3.32 (m, 2H), 3.11-3.07 (m, 3H), 1.73-1.61 (m, 4H), 1.23-1.15 (m, 3H), 1.01 (t, 3H).
Compound 85: MS: m/z 546.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.28 (d, 1H), 8.57 (q, 1H), 8.21 (d, 1H), 7.62-7.50 (m, 3H), 3.77 (s, 3H), 3.67-3.47 (m, 1H), 3.18-3.03 (m, 4H), 2.97-2.90 (m, 1H), 2.05-1.83 (m, 2H), 1.29-1.20 (m, 1H), 0.98 (t, 3H), 0.92-0.80 (m, 1H), 0.54-0.48 (m, 1H).
Compound 86: MS: m/z 562.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.28 (d, 1H), 8.61 (dd, 1H), 7.65-7.46 (m, 4H), 4.09-3.62 (m, 5H), 3.45-2.54 (m, 5H), 1.61-1.44 (m, 2H), 0.99 (t, 3H), 0.83-0.71 (m, 6H).
Compound 87: MS: m/z 598.2 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.64 (d, 1H), 8.68-8.61 (m, 1H), 7.81 (d, 1H), 7.63-7.58 (m, 3H), 3.75 (s, 3H), 3.70-3.67 (m, 1H), 3.48-3.36 (m, 2H), 3.19-3.03 (m, 4H), 1.64-1.53 (m, 2H), 1.01 (t, 3H), 0.86-0.84 (m, 1H), 0.52-0.43 (m, 3H).
Compound 88: MS: m/z 560.2 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.44 (t, 1H), 7.88 (d, 1H), 7.63-7.53 (m, 2H), 7.50 (d, 1H), 4.12 (s, 1H), 3.77 (s, 3H), 3.45-3.42 (m, 1H), 3.19-3.02 (m, 3H), 2.09 (s, 1H), 1.84-1.75 (m, 1H), 1.39-1.32 (m, 1H), 1.28-1.14 (m, 2H), 1.01 (t, 3H), 0.76-0.68 (m, 1H), 0.51-0.38 (m, 2H).
Compound 89: MS: m/z 566.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.42 (s, 1H), 8.63 (t, 1H), 7.99 (d, 1H), 7.83-7.75 (m, 1H), 7.51 (d, 1H), 7.44-7.39 (m, 2H), 6.36 (t, 1H), 4.80-4.71 (m, 2H), 4.02 (d, 1H), 3.65 (d, 1H), 3.14-3.00 (m, 4H), 2.87-2.80 (m, 1H), 1.75-1.72 (m, 2H), 1.40-1.30 (m, 2H), 1.01 (t, 3H).
Compound 90: MS: m/z 562.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.62 (s, 1H), 8.62 (t, 1H), 8.05 (s, 1H), 7.56-7.47 (m, 2H), 7.17-7.13 (m, 1H), 6.91 (dd, 1H), 6.80 (d, 1H), 4.01 (d, 1H), 3.16-3.04 (m, 4H), 2.87-2.79 (m, 1H), 1.78-1.72 (m, 3H), 1.43-1.25 (m, 3H), 1.00 (t, 3H).
Compound 91: MS: m/z 566.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.32 (d, 1H), 8.81-8.74 (m, 1H), 8.36 (d, 1H), 7.84-7.76 (m, 1H), 7.53-7.50 (m, 1H), 7.43-7.38 (m, 2H), 4.35-4.11 (m, 4H), 3.80-3.62 (m, 2H), 3.15-2.93 (m, 3H), 1.77-1.63 (m, 2H), 1.28 (t, 3H), 1.00 (t, 3H).
Compound 92: MS: m/z 580.1 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.21 (s, 1H), 9.54 (t, 1H), 8.33-8.32 (m, 1H), 7.81-7.75 (m, 1H), 7.44-7.33 (m, 3H), 4.84-4.73 (m, 1H), 4.68-4.74 (m, 2H), 4.45-4.41 (m, 3H), 4.38-3.60 (m, 5H), 3.39-2.94 (m, 2H), 1.77-1.50 (m, 2H).
Compound 93: MS: m/z 612.2 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.64 (s, 1H), 8.97 (d, 1H), 8.27 (d, 1H), 7.62-7.57 (m, 3H), 4.12 (d, 1H), 3.83 (s, 1H), 3.74 (s, 3H), 3.66 (d, 1H), 1.83-1.46 (m, 3H), 1.25 (s, 3H), 0.82 (d, 1H), 0.61 (s, 2H), 0.55-0.52 (m, 2H).
Compound 94: MS: m/z 552.0 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.28 (d, 1H), 8.34-8.76 (m, 1H), 8.39 (d, 1H), 7.85-7.78 (m, 1H), 7.48-7.40 (m, 3H), 4.37-4.23 (m, 1H), 4.17-4.13 (d, 1H), 3.91-3.60 (m, 4H), 3.30-3.23 (m, 1H), 3.16-3.12 (m, 2H), 3.10-2.99 (m, 1H), 1.80-1.68 (m, 2H), 1.03 (t, 3H).
Compound 95: MS: m/z 586.2 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.67 (s, 1H), 8.84-8.77 (m, 1H), 8.31 (d, 1H), 7.64-7.59 (m, 3H), 4.40-4.33 (m, 1H), 4.17-4.13 (d, 1H), 3.90-3.64 (m, 4H), 3.27-3.24 (m, 1H), 3.14-3.08 (m, 2H), 3.07-2.96 (m, 1H), 1.80-1.58 (m, 2H), 1.03 (t, 3H).
Compound 96: MS: m/z 534.2 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 8.65 (d, 1H), 8.16 (d, 1H), 7.83-7.75 (m, 1H), 7.47-7.35 (m, 3H), 4.81-4.42 (m, 1H), 4.22 (d, 1H), 3.78 (s, 3H), 3.58-3.44 (m, 1H), 3.15-3.06 (m, 2H), 2.82-2.72 (m, 1H), 1.74-1.59 (m, 2H), 1.34 (s, 2H), 1.03 (t, 3H).
Compound 97: MS: m/z 562.3 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.54-8.50 (m, 1H), 7.93 (d, 1H), 7.62-7.56 (m, 2H), 7.49 (d, 1H), 3.90-3.85 (m, 1H), 3.77 (s, 3H), 3.62-3.56 (m, 1H), 3.40 (s, 1H), 3.28-3.22 (m, 2H), 1.85 (d, 1H), 1.52 (d, 2H), 1.2 (s, 1H), 1.05-1.00 (m, 6H), 0.73 (t, 3H).
Compound 98: MS: m/z 584.2 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.35 (s, 1H), 8.81-8.75 (m, 1H), 8.39 (s, 1H), 7.61-7.56 (m, 2H), 7.48 (d, 1H), 4.42-4.09 (m, 2H), 3.87 (s, 1H), 3.77 (s, 3H), 3.30-3.25 (m, 2H), 3.06-2.97 (m, 2H), 1.78-1.74 (m, 2H), 1.44-1.37 (m, 2H), 0.80 (t, 3H).
Compound 99: MS: m/z 544.2 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.24 (d, 1H), 8.65 (dd, 1H), 7.82 (dd, 1H), 7.66 (d, 1H), 7.48-7.42 (m, 3H), 4.10 (d, 1H), 3.79 (s, 3H), 3.66 (d, 1H), 3.18-2.91 (m, 4H), 2.80-2.73 (m, 1H), 1.58-1.43 (m, 2H), 1.02 (t, 3H), 0.86-0.66 (m, 6H).
Compound 100: MS: m/z 518.2 (M+1); 1H NMR (300 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 8.53 (d, 1H), 7.90 (s, 1H), 7.60-7.51 (m, 3H), 4.01 (d, 1H), 3.92-3.86 (m, 1H), 3.76 (s, 3H), 3.70 (d, 1H), 3.56-3.50 (m, 1H), 2.59 (d, 3H), 2.30 (t, 1H), 1.88-1.81 (m, 1H), 1.78-1.74 (m, 1H).
HepAD38 cells were seeded and cultured on 96-well plates. After incubation for 2 days, cells were fed with compound-containing media without tetracycline. After compound treatment for 5 days, culture supernatants were collected. Extracellular DNA was then extracted using LabTurbo DNA mini kit, and quantified by real-time PCR.
Real-time PCR was performed using an ABI QuantStudio 3 system in a 96-well optical plate format. The PCR mixture containing forward primer (5′-ACATCAGGATTCCTAGGACC-3′) (SEQ ID NO.1), reverse primer (5′-GGTGAGTGATTGGAGGTTG-3′) (SEQ ID NO.2) and Luna Universal qPCR Master Mix in a final volume of 24 μl was incubated at 95° C. for 10 min followed by 45 cycle of incubation at 95° C. for 10 s and 60° C. for 10 s. Regression analysis was performed using GraphPad Prism 5 to calculate the 50% effective concentration (EC50) values.
Compound 1-100 were tested using the Real-time PCR Assay. It was observed that 83 test compounds (i.e., Compounds 1-2, 4-10, 12-13, 15-41, 43-45, 48-49, 51-52, 54-59, 64, 68-78, 80-81, and 83-100) exhibited EC50 values lower than 0.1 μM; 10 test compounds (i.e., Compound 3, 11, 14, 42, 46-47, 50, 63, 66, and 82) exhibited EC50 values of 0.1 to 0.3 μM; and 7 test compounds (i.e., Compound 53, 60-62, 65, 67, and 79) exhibited EC50 values of 0.3 to 1 μM.
All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a series of equivalent or similar features.
From the above description, one skilled in the art can easily ascertain the essential characteristics of the present disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications of the disclosure to adapt it to various usage and conditions. Thus, other embodiments are also within the scope of the following claims.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2020/049312 | 9/4/2020 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62895626 | Sep 2019 | US |
