Substituted arylmethyl ureas and heteroarylmethyl ureas, analogs thereof, and methods of using the same

Abstract

The present invention includes substituted arylmethyl ureas and heteroarylmethyl ureas useful for treating or preventing hepatitis B virus (HBV) infection in a patient, and compositions comprising the same.

Description

[0001] Cross-references to related applications

[0002] Pursuant to 35 USC §119(e), this application claims priority to U.S. Provisional Patent Application No. 62 / 778,471, filed December 12, 2018, and U.S. Provisional Patent Application No. 62 / 896,237, filed September 5, 2019, the entirety of which is incorporated herein by reference. Background Technology

[0003] Hepatitis B is one of the most prevalent diseases in the world and is listed as a priority area by the National Institute of Allergic Infectious Diseases (NIAID) in the United States. Although most people resolve the infection after experiencing acute symptoms, approximately 30% of cases become chronic. It is estimated that 350-400 million people worldwide have chronic hepatitis B, which causes 500,000-1 million deaths annually, primarily due to the development of hepatocellular carcinoma, cirrhosis, and / or other complications.

[0004] Currently, the number of approved drugs for the treatment of chronic hepatitis B is limited, including two formulations of alpha-interferon (standard and pegylated) and five nucleoside / nucleotide analogs that inhibit hepatitis B virus (HBV) DNA polymerase (lamivudine, adefovir, entecavir, telbivudine, and tenofovir). Currently, the first-line treatment options are entecavir, tenofovir, and / or pegylated interferon alpha-2a. However, pegylated interferon alpha-2a achieves the desired serological milestones in only one-third of treated patients and is often accompanied by serious side effects. Entecavir and tenofovir are effective HBV inhibitors, but require long-term or potentially lifelong administration to sustain HBV replication suppression and may eventually fail due to the emergence of drug-resistant viruses. Therefore, there is an urgent need to introduce novel, safe, and effective therapies for chronic hepatitis B.

[0005] HBV is a non-cytopathic, hepatotropic DNA virus belonging to the Hepatoviridae family. The pregenomic (pg) RNA, along with viral DNA polymerase, capsidates into a nucleocapsid, which is crucial for subsequent viral DNA synthesis. Inhibiting pg RNA capsidation may prevent HBV replication and provide novel therapeutic approaches for HBV treatment. Capsid inhibitors exert their effects by directly or indirectly inhibiting the expression and / or function of capsid proteins: for example, they can inhibit capsid assembly, induce the formation of non-capsid polymers, promote excessive or misdirected capsid assembly, affect capsid stability, and / or inhibit RNA capsidation. Capsid inhibitors can also exert their effects by inhibiting capsid function in one or more downstream events during replication, such as, but not limited to, viral DNA synthesis, translocation of loose circular DNA (rcDNA) into the nucleus, formation of covalently closed circular DNA (cccDNA), viral maturation, budding, and / or release.

[0006] Clinically, inhibiting pgRNA capsidation, or more generally, inhibiting nucleocapsid assembly, may offer certain therapeutic advantages. On the one hand, inhibiting pgRNA capsidation can complement current medications by providing options for patient subgroups that cannot tolerate or benefit from current drugs. On the other hand, based on its unique antiviral mechanism, inhibition of pgRNA capsidation can effectively resist HBV variants resistant to currently available DNA polymerase inhibitors. Furthermore, combination therapy with pgRNA capsidation inhibitors and DNA polymerase inhibitors can synergistically inhibit HBV replication and prevent the development of drug resistance, thus providing a more effective treatment for chronic hepatitis B infection.

[0007] Hepatitis D virus (HDV) is a small, circular enveloped RNA virus that can only replicate in the presence of HBV. Specifically, HDV requires HBV surface antigen protein to replicate. Infection with both HBV and HDV leads to more severe complications compared to HBV infection alone. These complications include a greater likelihood of experiencing liver failure in acute infection and rapid progression to cirrhosis, and an increased chance of developing liver cancer in chronic infection. When combined with hepatitis B, hepatitis D has the highest mortality rate among all hepatitis infections. The transmission routes of HDV are similar to those of HBV. Infection is primarily limited to high-risk groups for HBV infection, particularly those who inject drug users and receive clotting factor concentrates.

[0008] Currently, there are no effective antiviral therapies available for treating acute or chronic hepatitis D. Weekly administration of interferon-alpha for 12 to 18 months is the only licensed treatment for hepatitis D. Response to this therapy is limited, as only about a quarter of patients have undetectable serum HDV RNA 6 months after treatment.

[0009] Clinically, inhibiting pgRNA capsidation, or more generally, inhibiting nucleocapsid assembly, may offer certain therapeutic advantages for the treatment of hepatitis B and / or hepatitis D. On one hand, inhibiting pgRNA capsidation can complement current medications by providing options to patient subgroups that cannot tolerate or benefit from current drugs. On the other hand, based on its unique antiviral mechanism, inhibition of pgRNA capsidation can effectively resist HBV and / or HDV variants resistant to currently available DNA polymerase inhibitors. Furthermore, combination therapy with pgRNA capsidation inhibitors and DNA polymerase inhibitors can synergistically inhibit HBV and / or HDV replication and prevent the development of drug resistance, thus providing a more effective treatment for chronic hepatitis B and / or hepatitis D infection.

[0010] Therefore, there is a need in the art to identify novel compounds that can be used to treat and / or prevent HBV and / or HDV infection in subjects. In some embodiments, the novel compounds inhibit HBV and / or HDV nucleocapsid assembly. In other embodiments, the novel compounds can be used in patients infected with HBV and / or HBV-HDV, patients at risk of HBV and / or HBV-HDV infection, and / or patients infected with drug-resistant HBV and / or HDV. The present invention addresses this need. Summary of the Invention

[0011] This invention provides compounds of formula (I), or salts, solvates, prodrugs, stereoisomers, tautomers, or isotopically labeled derivatives thereof, or any mixture thereof:

[0012]

[0013] where R 1 R 2 R 3 R 4a R 4b and R 5 As defined elsewhere herein. The invention further provides pharmaceutical compositions comprising at least one compound described herein and a pharmaceutically acceptable carrier. The invention further provides a method for treating or preventing hepatitis B virus (HBV) infection in a subject. The invention further provides a method for directly or indirectly inhibiting the expression and / or function of viral capsid proteins in a subject infected with hepatitis B virus. In some embodiments, the method comprises administering a therapeutically effective amount of at least one compound described herein to a subject in need of it. Attached Figure Description

[0014] The accompanying drawings illustrate various embodiments of the invention by way of example rather than limitation.

[0015] Figure 1 It is the ORTEP representation of (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea (compound 14). Detailed Implementation

[0016] In some aspects, the present invention relates to certain substituted urea-containing compounds that can be used to treat and / or prevent hepatitis B virus (HBV) and / or hepatitis D virus (HDV) infection and related conditions in subjects. In some embodiments, the compounds of the present invention are viral capsid inhibitors.

[0017] definition

[0018] As used herein, each of the following terms has its corresponding meaning in this section. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Generally, the nomenclature used herein, as well as laboratory procedures in animal pharmacology, pharmaceutical science, separation science, and organic chemistry, are well-known and commonly used in the art. It should be understood that the order of steps or the order in which certain actions are performed is not important as long as this teaching remains operational. Any use of section headings is intended to aid in reading the document and should not be construed as restrictive; information relating to a section heading may occur within or outside that particular section. All publications, patents, and patent documents cited in this document are incorporated herein by reference in their entirety as if they were individually incorporated by reference.

[0019] In this application, when a described element or component is included in and / or selected from the list of listed elements or components, it should be understood that the element or component can be any one of the listed elements or components and can be selected from two or more of the listed elements or components.

[0020] In the methods described herein, actions can be performed in any order unless the timing or sequence of operations is explicitly stated. Furthermore, specified actions can be performed simultaneously unless the explicit declaration language states that they are performed separately. For example, claimed action X and claimed action Y can be performed simultaneously in a single operation, and the resulting process will fall within the literal scope of the claimed process.

[0021] In this document, unless the context clearly indicates otherwise, the terms “a,” “an,” or “the” are used to include one or more. Unless otherwise stated, the term “or” is used to indicate a non-exclusive “or.” The statements “at least one of A and B” or “at least one of A or B” have the same meaning as “A, B, or A and B.”

[0022] As used herein, the term “about” will be understood by one of ordinary skill in the art and will vary to some extent in the context in which it is used. As used herein, when “about” refers to a measurable value such as a quantity, duration of time, etc., it is intended to cover variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are suitable for performing the disclosed methods.

[0023] As used herein, unless otherwise stated, the term "alkenyl" alone or in combination with other terms refers to a stable monounsaturated or diunsaturated straight-chain or branched hydrocarbon group having a specified number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher homologues and isomers. Examples of functional groups representing alkenes are -CH2-CH=CH2.

[0024] As used herein, unless otherwise stated, the term "alkoxy" alone or in combination with other terms refers to an alkyl group having a specified number of carbon atoms, as defined elsewhere herein, that is attached via an oxygen atom to the remainder of the molecule, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (or isopropoxy), and higher homologues and isomers. Specific examples are (C1-C3)alkoxy groups, such as, but not limited to, ethoxy and methoxy.

[0025] As used herein, unless otherwise stated, the term "alkyl" on its own or as part of another substituent refers to having a specified number of carbon atoms (i.e., C1-C2). 10 This refers to a straight-chain or branched hydrocarbon (containing 1 to 10 carbon atoms), and includes straight-chain, branched, or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. Specific embodiments are (C1-C6) alkyl groups, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl.

[0026] As used herein, unless otherwise stated, the term "alkynyl" alone or in combination with other terms refers to a stable straight-chain or branched hydrocarbon group having a specified number of carbon atoms and a carbon-carbon triple bond. Non-limiting examples include ethynyl and propynyl, as well as higher homologues and isomers. The term "propargylic" refers to a group exemplified by -CH2-C≡CH. The term "homopropargylic" refers to a group exemplified by -CH2CH2-C≡CH.

[0027] As used herein, the term "aromatic" refers to a carbon ring or heterocycle having one or more polyunsaturated rings and exhibiting aromatic characteristics, namely having (4n+2) delocalized π(pi) electrons (where 'n' is an integer).

[0028] As used herein, unless otherwise stated, the term "aryl" alone or in combination with other terms refers to a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), wherein these rings may be linked together in a side-chain manner, such as biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracene, and naphthyl. Aryl also includes, for example, a benzene or naphthalene ring fused to one or more saturated or partially saturated carbocyclic rings (e.g., bicyclic [4.2.0] octa-1,3,5-trienyl or indanyl), which may be substituted at one or more carbon atoms of the aromatic ring and / or the saturated or partially saturated ring.

[0029] As used herein, the term "aryl-(C1-C6)alkyl" refers to a functional group in which one to six carbonyl chains are attached to an aryl group, such as -CH2CH2-phenyl or -CH2-phenyl (or benzyl). Specific examples are aryl-CH2- and aryl-CH(CH3)-. The term "substituted aryl-(C1-C6)alkyl" refers to an aryl-(C1-C6)alkyl functional group in which the aryl group is substituted. A specific example is substituted aryl(CH2)-. Similarly, the term "heteroaryl-(C1-C6)alkyl" refers to a functional group in which one to three carbonyl chains are attached to a heteroaryl group, such as -CH2CH2-pyridyl. A specific example is heteroaryl-(CH2)-. The term "substituted heteroaryl-(C1-C6)alkyl" refers to a heteroaryl-(C1-C6)alkyl functional group in which the heteroaryl group is substituted. A specific example is the substituted heteroaryl-(CH2)-.

[0030] In one respect, the terms "co-administered" and "co-administration" in relation to a subject refer to the administration of the compounds and / or compositions of the present invention to the subject, as well as compounds and / or compositions that may also treat or prevent the diseases or disorders considered herein. In some embodiments, the co-administered compounds and / or compositions are administered alone or in any kind of combination as part of a single treatment method. The co-administered compounds and / or compositions can be formulated into mixtures of solids and liquids, as well as solutions, of various solid, gel, and liquid formulations in any kind of combination.

[0031] As used herein, unless otherwise stated, the term "cycloalkyl" itself, or as part of another substituent, refers to a cyclic hydrocarbon having a specified number of carbon atoms (i.e., C3-C6 refers to a cyclic group comprising a cyclic group of 3 to 6 carbon atoms) and includes straight-chain, branched, or cyclic substituents. Examples of (C3-C6) cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl ring may optionally be substituted. Non-limiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazyl; bicyclo[6.2.0]decyl, decahydronaphthyl, and dodecahydro-1H-fluorenyl. The term "cycloalkyl" also includes bicyclic hydrocarbon rings, with non-limiting examples including bicyclic [2.1.1]hexyl, bicyclic [2.2.1]heptyl, bicyclic [3.1.1]heptyl, 1,3-dimethyl [2.2.1]heptane-2-yl, bicyclic [2.2.2]octyl and bicyclic [3.3.3]undecanyl.

[0032] As used in this article, “disease” refers to the health status of the subject in which the subject is unable to maintain homeostasis and whose health continues to deteriorate if the disease is not improved.

[0033] As used in this article, "disorder" in subjects refers to a state of health in which subjects are able to maintain homeostasis, but whose health is worse than that without disorder. Disorders do not necessarily lead to a further decline in a subject's health if left untreated.

[0034] As used herein, the term "halide" refers to a negatively charged halogen atom. The halide anion is the fluoride ion (F...). - ), chloride ions (Cl) - ), bromide ions (Br) - ) and iodide ions (I - ).

[0035] As used herein, unless otherwise stated, the terms “halo” or “halogen” alone or as part of another substituent refer to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0036] As used herein, unless otherwise stated, the term "heteroalkenyl" on its own or in combination with another term refers to a stable straight-chain or branched monounsaturated or diunsaturated hydrocarbon group consisting of a specified number of carbon atoms and one or two heteroatoms selected from O, N, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples include -CH=CH-O-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, and -CH2-CH=CH-CH2-SH.

[0037] As used herein, unless otherwise stated, the term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched alkyl group consisting of a specified number of carbon atoms and one or two heteroatoms selected from O, N, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) may be located at any position on the heteroalkyl group, including between the remainder of the heteroalkyl group and the segments to which it is attached, as well as at the most distal carbon atom attached to the heteroalkyl group. Examples include: -OCH2CH2CH3, -CH2CH2CH2OH, -CH2CH2NHCH3, -CH2SCH2CH3, and -CH2CH2S(=O)CH3. At most two heteroatoms may be consecutive, such as, for example, -CH2NH-OCH3 or -CH2CH2SSCH3.

[0038] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocycle that possesses aromatic properties. Polycyclic heteroaryls may include one or more partially saturated rings. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuranyl.

[0039] As used herein, unless otherwise stated, the terms "heterocycle," "heterocyclyl," or "heterocyclic" themselves, or as part of another substituent, refer to an unsubstituted or substituted, stable monocyclic or polycyclic heterocyclic system comprising a carbon atom and at least one heteroatom selected from N, O, and S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. Unless otherwise stated, the heterocyclic system may be attached to any heteroatom or carbon atom that provides a stable structure. The heterocycle may be aromatic or non-aromatic in nature. In some embodiments, the heterocycle is a heteroaryl group.

[0040] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, ethylene oxide, thiirane, aziridine, oxacyclobutane, thiobutane, pyrrolidine, pyrrololine, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxane, 4,7-dihydro-1,3-dioxepin, and hexamethylene oxide.

[0041] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (e.g., but not limited to 2- and 4-pyrimidinyl), pyridazinyl, thiopheneyl, furanyl, pyrroleyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiazolyl, and 1,3,4-oxadiazolyl.

[0042] Examples of polycyclic heterocycles include indolyl (e.g., but not limited to 2-, 3-, 4-, 5-, 6-, and 7-indolyl), dihydroindolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl (e.g., but not limited to 1- and 5-isoquinolinyl), 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, quinoxalinyl (e.g., but not limited to 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthidyl, 1,4-benzodioxane, coumarin, dihydrocoumarin, 1,5-naphthidyl, benzofuranyl (e.g., but not limited to 3-, 4-... 5-, 6- and 7-benzofuranyl), 2,3-dihydrobenzofuranyl, 1,2-benzoxazolyl, benzothiopheneyl (e.g., but not limited to 3-, 4-, 5-, 6- and 7-benzothiopheneyl), benzoxazolyl, benzothiazolyl (e.g., but not limited to 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbaolinyl, acridineyl, pyrrolizidinyl, and quinolizidinyl.

[0043] The above list of heterocyclic and heteroaryl moieties is intended to be representative, not restrictive.

[0044] As used herein, the term "pharmaceutical composition" or "composition" refers to a mixture of at least one compound useful in the present invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates the administration of the compound to a subject.

[0045] As used herein, the term “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of the compounds useful in this invention and is relatively non-toxic, meaning that the material can be administered to a subject without causing adverse biological effects or interacting in a harmful manner with any component of the composition comprising it.

[0046] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that participates in carrying or transporting, in or to a subject, a compound useful in this invention, so that it can perform its intended function. Typically, such an construct is carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" and harmless to the subject in the sense of compatibility with other components of the formulation, including compounds useful in this invention. Some examples of materials that can be used as pharmaceutically acceptable carriers 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 gum; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic, compatible substances used in pharmaceutical preparations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delay agents that are compatible with the activity of the compounds useful in this invention and are physiologically acceptable to the subject. Supplemental active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of compounds useful in this invention. Other additional ingredients that may be included in pharmaceutical compositions used in the practice of this invention are known in the art and are described, for example, in *Remington Pharmaceutical Sciences* (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0047] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of an applied compound prepared from a pharmaceutically acceptable, non-toxic acid and / or base, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates (including hydrates) and their clathrates.

[0048] As used herein, a “pharmaceuticalally effective amount,” “therapeutically effective amount,” or “effective amount” of a compound is an amount of the compound sufficient to provide a beneficial effect to a subject administering the compound.

[0049] As used herein, the terms “prevent,” “preventing,” and “prevention” refer to the avoidance or delay of the onset of symptoms associated with a disease or condition in subjects who have not developed such symptoms at the time of initiation of administration of a drug or compound. Disease, condition, and disorder are used interchangeably in this document.

[0050] As used herein, the terms “specifically bind” or “specifically binds” mean that a first molecule preferentially binds to a second molecule (e.g., a specific receptor or enzyme), but not necessarily only to that second molecule.

[0051] As used herein, the terms "subject," "individual," and "patient" are used interchangeably and can refer to humans or non-human mammals or birds. Non-human mammals include, for example, livestock and pets, such as sheep, bovine, swine, canine, feline, and rodent mammals. In some implementations, the subject is a human.

[0052] As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as a substituent attached to another group.

[0053] As used herein, the terms “substituted alkyl,” “substituted cycloalkyl,” “substituted alkenyl,” or “substituted alkynyl” mean alkyl, cycloalkyl, alkenyl, or alkynyl as defined elsewhere herein, independently selected from halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, 1-methyl-imidazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, -C(=O)O(C1-C6)alkyl, trifluoromethyl, -C≡N, -C(= The substituted alkyl groups include one, two, or three substituents selected from halogens, -C(=O)NH(C1-C6)alkyl, -C(=O)N((C1-C6)alkyl)2, -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)2, -C(=NH)NH2, and -NO2. In some embodiments, the substituted alkyl groups contain one or two substituents independently selected from halogens, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(=O)OH. In other embodiments, the substituted alkyl groups are independently selected from halogens, alkoxy, and -OH. Examples of substituted alkyl groups include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

[0054] For aryl, aryl-(C1-C3)alkyl, and heterocyclic groups, the term "substituted" applied to the ring of these groups refers to any level of substitution where such substitution is permitted, i.e., mono, di, tri, tetra, or penta-substituted. The substituents are chosen independently, and substitution can occur at any chemically accessible position. In some embodiments, the number of substituents varies between 1 and 4. In other embodiments, the number of substituents varies between 1 and 3. In yet another embodiment, the number of substituents varies between 1 and 2. In still other embodiments, the substituents are independently selected from C1-C6 alkyl, -OH, C1-C6 alkoxy, halogen, amino, acetamino, and nitro. As used herein, when the substituent is alkyl or alkoxy, the carbon chain can be branched, linear, or cyclic.

[0055] Unless otherwise stated, when two substituents together form a ring having a specified number of ring atoms (e.g., R...), 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring having 3 to 7 ring members, which may have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen, oxygen, or sulfur. The ring may be saturated or partially saturated and may optionally be substituted.

[0056] Whenever a term or any of its prefixes appears in the name of a substituent, that name shall be interpreted to include the limitations provided herein. For example, whenever the term “alkyl” or “aryl” or any of its prefixes appears in the name of a substituent (e.g., arylalkyl, alkylamino), that name shall be interpreted to include the limitations given elsewhere herein for “alkyl” and “aryl”, respectively.

[0057] In some embodiments, the substituents of the compound are disclosed by groups or ranges. Specifically, it is expected that the description includes each and each individual subcombination of members of these groups and ranges. For example, the term "C" 1-6 "alkyl" is explicitly intended to separately disclose C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0058] As used in this article, the terms “treat,” “treating,” and “treatment” refer to the reduction of the frequency or severity of symptoms of a disease or condition experienced by a subject through the administration of a drug or compound.

[0059] Some abbreviations used in this article are as follows: cccDNA, covalently closed circular DNA; DMSO, dimethyl sulfoxide; HBsAg, HBV surface antigen; HBV, hepatitis B virus; HDV, hepatitis D virus; HPLC, high-performance liquid chromatography; LCMS, liquid chromatography-mass spectrometry; NARTI or NRTI, reverse transcriptase inhibitor; NMR, nuclear magnetic resonance; NtARTI or NtRTI, nucleotide analog reverse transcriptase inhibitor; pg RNA, pregenomic RNA; rcDNA, loose circular DNA; RT, retention time; sAg, surface antigen; TLC, thin-layer chromatography.

[0060] Scope: Throughout this disclosure, various aspects of the invention may be presented in a scope format. It should be understood that the scope format is for convenience and brevity only and should not be construed as a rigid limitation on the scope of the invention. Therefore, a scope description should be considered as explicitly disclosing all possible sub-scopes and individual values ​​within that scope. For example, a description of a scope such as 1 to 6 should be considered as explicitly disclosing sub-scopes such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual values ​​within that scope, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. For example, a scope of "about 0.1% to about 5%" or "about 0.1% to 5%" should be considered as including not only about 0.1% to about 5%, but also individual values ​​within the indicated scope (e.g., 1%, 2%, 3%, and 4%) and sub-scopes (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). Unless otherwise stated, the statement "about X to Y" has the same meaning as "about X to about Y". Similarly, unless otherwise stated, the statement "about X, Y, or Z" has the same meaning as "about X, about Y, or about Z". This applies regardless of the breadth of the scope.

[0061] compound

[0062] This invention includes compounds of formula (I), or salts, solvates, prodrugs, isotopically labeled derivatives, stereoisomers (e.g., in non-limiting examples, enantiomers or diastereomers and / or any mixture thereof, e.g., in non-limiting examples, mixtures of their enantiomers and / or diastereomers in any proportion), tautomers and any mixture thereof, and / or geometric isomers and any mixture thereof:

[0063] In (I):

[0064] R 1 Selected from optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl and -(CH2)(optionally substituted heteroaryl);

[0065] R 2 Each occurrence of is independently selected from H and C1-C6 alkyl groups;

[0066] R 3 Selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, wherein the alkyl or cycloalkyl group is selected from C1-C6 alkyl, C3-C8 cycloalkyl, halogen, cyano, -OH, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, -C(=O)OR6 -OC(=O)R 6 -SR 6 -S(=O)R 6 -S(=O)2R 6 -S(=O)2NR 6 R 6 -N(R) 6 )S(=O)2R 6 -N(R) 6 )C(=O)R 6 -C(=O)NR 6 R 6 and -NR 6 R 6 At least one substituent may be optionally substituted;

[0067] R 4a Selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, and phenyl, wherein the alkyl, cycloalkyl, or phenyl is selected from C1-C6 alkyl, C3-C8 cycloalkyl, halogen, cyano, -OH, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, -NR 6 R 6 At least one substituent of the optionally substituted phenyl group is optionally substituted;

[0068] R 4b Selected from H and optionally substituted C1-C6 alkyl groups;

[0069] R 5 Selected from:

[0070] Each ring A is independently selected from benzene, pyridine, pyrimidine, pyridazine, and pyrazine;

[0071] R 6 Each occurrence of the is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, and optionally substituted heteroaryl;

[0072] R 7 Each occurrence of the substance is independently selected from H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy and optionally substituted C3-C8 cycloalkoxy.

[0073] R 8Each occurrence of is independently selected from H, halogen, -CN, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 cycloalkoxy, heterocyclic, heteroaryl, -S (optionally substituted C1-C6 alkyl), -SO (optionally substituted C1-C6 alkyl), -SO2 (optionally substituted C1-C6 alkyl), -C(=O)OH, -C(=O)O (optionally substituted C1-C6 alkyl), -C(=O)O (optionally substituted C3-C8 cycloalkyl), -O (optionally substituted C1-C6 alkyl), -O (optionally substituted C3-C8 cycloalkyl), -NH2, -NH (optionally substituted C1-C6 alkyl), -NH (optionally substituted C3-C8 cycloalkyl) -N (optionally substituted C1-C6 alkyl), -N (optionally substituted C3-C8 cycloalkyl), -N (optionally substituted C1-C6 alkyl), -C(=O)NH2, -C(=O)NH (optionally substituted C1-C6 alkyl), -C(=O)NH (optionally substituted C3-C8 cycloalkyl), -C(=O)N (optionally substituted C1-C6 alkyl), -C(=O)N (optionally substituted C3-C8 cycloalkyl), and -C(=O)N (optionally substituted C1-C6 alkyl).

[0074] R 9 Each occurrence of the substance is independently selected from H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy and optionally substituted C3-C8 cycloalkoxy.

[0075] Each occurrence of n is independently 0, 1, 2, 3, or 4; and

[0076] R 10 It is selected from H, optionally substituted C1-C6 alkyl groups and optionally substituted C3-C8 cycloalkyl groups.

[0077] In some embodiments, the compound of formula (I) is the compound of formula (Ia):

[0078]

[0079] In some embodiments, the compound of formula (I) is the compound of formula (Ib):

[0080]

[0081] In some embodiments, the compounds of formula (I) are selected from:

[0082]

[0083] In some embodiments, the compounds of formula (I) are selected from:

[0084]

[0085] In some embodiments, the compounds of formula (I) are selected from:

[0086]

[0087] In some implementations, R 5 Selected from:

[0088]

[0089] In some implementations, R 5 Selected from:

[0090]

[0091] In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 Yes. In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes In some implementations, R 5 yes

[0092] In some embodiments, each occurrence of an alkyl, alkenyl, ynyl, or cycloalkyl group is independently substituted by at least one substituent selected from: C1-C6 alkyl, C3-C8 cycloalkyl, halogen, cyano (-CN), -OR a Optionally substituted phenyl groups (thus resulting, in non-limiting examples, optionally substituted phenyl-(C1-C3 alkyl), such as, but not limited to, benzyl or substituted benzyl), optionally substituted heteroaryl groups, optionally substituted heterocyclic groups, -C(=O)OR a -OC(=O)R a -SR a 、-S(=O)R a -S(=O)2R a -S(=O)2NR a R a -N(R) a )S(=O)2R a -N(R) a )C(=O)R a -C(=O)NR a R a and -N(R) a (R) a ), where R a Each occurrence of R is independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, or two R a The groups combine with the N atoms they are bonded to to form heterocycles.

[0093] In some embodiments, each occurrence of the aryl or heteroaryl group is independently selected from C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, C1-C6 hydroxyalkyl, (C1-C6 alkoxy)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, -CN, -OR b -N(R)b (R) b -NO2, -C(=O)N(R) b (R) b -C(=O)OR b -OC(=O)R b -SR b -S(=O)R b -S(=O)2R b -N(R) b )S(=O)2R b -S(=O)2N(R) b (R) b At least one substituent of the acyl group and the C1-C6 alkoxycarbonyl group is optionally substituted, wherein R b Each occurrence of is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein in R b In this configuration, the alkyl or cycloalkyl group is optionally substituted with at least one substituent selected from halogens, -OH, C1-C6 alkoxy groups, and heteroaryl groups; or the substituents on two adjacent carbon atoms combine to form -O(CH2). 1-3 O-.

[0094] In some embodiments, each occurrence of the aryl or heteroaryl group is independently selected from C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, C1-C6 hydroxyalkyl, (C1-C6 alkoxy)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, -OR b -C(=O)N(R) b (R) b -C(=O)OR b -OC(=O)R b -SR b -S(=O)R b -S(=O)2R b and -N(R) b )S(=O)2R b At least one substituent may be substituted, wherein R b Each occurrence of is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein in R b In this configuration, the alkyl or cycloalkyl group is optionally substituted with at least one substituent selected from halogens, -OH, C1-C6 alkoxy groups, and heteroaryl groups; or the substituents on two adjacent carbon atoms combine to form -O(CH2). 1-3 O-.

[0095] In some embodiments, the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclic, aryl, or benzyl groups are optionally substituted with at least one group selected from C1-C6 alkyl; C1-C6 alkoxy; C1-C6 haloalkyl; C1-C6 haloalkoxy; -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), halogen, -OH; -CN; phenoxy, -NHC(=O)H, -NHC(=O)C1-C6 alkyl, -C(=O)NH2, -C(=O)NHC1-C6 alkyl, -C(=O)N(C1-C6 alkyl)(C1-C6 alkyl), tetrahydropyranyl, morpholinyl, -C(=O)CH3, -C(=O)CH2OH, -C(=O)NHCH3, -C(=O)CH2OMe, or their N-oxides.

[0096] In some embodiments, each occurrence of the heteroaryl group is independently selected from quinolinyl, imidazo[1,2-a]pyridyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, indolyl (e.g., but not limited to 2-, 3-, 4-, 5-, 6- and 7-indolyl), oxadiazolyl (including 1,2,3-, 1,2,4-, 1,2,5- and 1,3,4-oxadiazole), and triazolyl (e.g., 1,2,3-triazolyl and 1,2,4-triazolyl).

[0097] In some embodiments, each occurrence of the heterocyclic group is independently selected from tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazineyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, 1-oxobridged-thiomorpholinyl, 1,1-dioxobridged-thiomorpholinyl, oxazolidinyl, azacyclic butyl and their corresponding oxo analogs (wherein the methylene ring group is substituted with a carbonyl group).

[0098] In some implementations, R 1 It is an optionally substituted C3-C8 cycloalkyl group. In other embodiments, R 1 It is cyclobutyl. In other embodiments, R 1 It is cyclopentyl. In other embodiments, R 1 It is cyclohexyl. In other embodiments, R 1 It is a cycloheptyl group.

[0099] In some implementations, R 1The group is selected from optionally substituted phenyl, optionally substituted benzyl, and -(CH2) (optionally substituted heteroaryl), wherein the phenyl, benzyl, or heteroaryl group is optionally substituted by at least one of the following substituents: C1-C6 alkyl (e.g., methyl, ethyl, and isopropyl), halogen (e.g., F, Cl, Br, and I), C1-C3 haloalkyl (e.g., monofluoromethyl, difluoromethyl, and trifluoromethyl), and –CN.

[0100] In some implementations, R 1 Selected from: benzyl, 1-phenylethyl, 4-fluorophenylmethyl, 3,4-difluorophenylmethyl, 3-chloro-4-fluorophenylmethyl, 3,4,5-trifluorophenylmethyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3,5-dichlorophenyl, 3 5-Difluorophenyl, 3-Chloro-5-fluorophenyl, 3,4-Dichlorophenyl, 3-Chloro-4-fluorophenyl, 4-Chloro-3-fluorophenyl, 4-Chloro-3-methylphenyl, 3-Chloro-4-methylphenyl, 4-Fluoro-3-methylphenyl, 3-Fluoro-4-methylphenyl, 4-Chloro-3-methoxyphenyl, 3-Chloro-4-methoxyphenyl, 4-Fluoro-3-methoxyphenyl, 3-Fluoro-4-methoxyphenyl, 3-Trifluoromethylphenyl, 4-Trifluoromethylphenyl, 3-Trifluoromethyl -4-fluorophenyl, 4-trifluoromethyl-3-fluorophenyl, 2,3-difluorophenyl, 2,3,4-trifluorophenyl, 3,5-dichloro-4-fluorophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-cyano-4-fluorophenyl, 4-cyano-3-fluorophenyl, 3-difluoromethyl-4-fluorophenyl, 4-difluoromethyl-3-fluorophenyl, benzo[d][1,3]m-dioxacyclopenten-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, benzyl 3-Fluorobenzyl, 4-Fluorobenzyl, 3-Chlorobenzyl, 4-Chlorobenzyl, 2-Pyridyl, 4-Methyl-2-pyridyl, 5-Methyl-2-pyridyl, 6-Methyl-2-pyridyl, 3-Pyridyl, 2-Methyl-3-pyridyl, 3-Methyl-3-pyridyl, 4-Pyridyl, 2-Methyl-4-pyridyl, 2-Fluorobenzyl, 2-Chlorobenzyl, 2-Trifluoromethyl-4-pyridyl, 6-Methyl-4-pyridyl, and 1H-Indole-6-yl.

[0101] In some implementations, R 1 It is phenyl. In other embodiments, R 1 It is benzyl. In other embodiments, R 1 It is 1-phenylethyl. In other embodiments, R 1It is 4-fluorophenylmethyl. In other embodiments, R 1 It is 3,4-difluorophenylmethyl. In yet other embodiments, R 1 It is 3-chloro-4-fluorophenylmethyl. In other embodiments, R 1 It is 3,4,5-trifluorophenylmethyl. In other embodiments, R 1 It is 3,4-difluorophenyl. In yet other embodiments, R 1 It is 3-difluoromethyl-4-fluorophenyl. In other embodiments, R 1 It is 3-chlorophenyl. In other embodiments, R 1 It is 3-chloro-4-fluorophenyl. In other embodiments, R 1 It is 4-chloro-3-fluorophenyl. In other embodiments, R 1 It is 3-fluoro-4-methylphenyl. In other embodiments, R 1 It is 4-fluoro-3-methylphenyl. In other embodiments, R 1 It is 3-cyano-4-fluorophenyl. In other embodiments, R 1 It is 3-difluoromethyl-4-fluorophenyl. In other embodiments, R 1 It is 2-fluorophenyl. In other embodiments, R 1 It is 2,3-difluorophenyl. In yet other embodiments, R 1 It is 3-fluorophenyl. In other embodiments, R 1 It is 4-fluorophenyl. In other embodiments, R 1 It is 4-chlorophenyl. In other embodiments, R 1 It is 4-bromophenyl. In other embodiments, R 1 It is 3,5-dichlorophenyl. In other embodiments, R 1 It is 3,5-dichloro-4-fluorophenyl. In yet other embodiments, R 1 It is 2,3,4-trifluorophenyl. In other embodiments, R 1 It is 4-pyridyl. In other embodiments, R 1 It is 2-chloro-4-pyridyl. In other embodiments, R 1 It is 2-trifluoromethyl-4-pyridyl. In other embodiments, R 1 It is 1H-indole-6-yl.

[0102] In some implementations, R 2 Each occurrence of is independently selected from H and methyl. In other embodiments, R 2 It is H. In other embodiments, R 2 It is a methyl group.

[0103] In some implementations, R 3 Selected from H, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, isopropylmethyl, -(CH2) 2-6 OH, -(CH2) 2-6 O (C1-C6 alkyl), optionally substituted benzyl, and optionally substituted phenyl.

[0104] In some implementations, R 3 It is H. In other embodiments, R 3 It is a methyl group. In other embodiments, R 3 It is trideuterated methyl. In other embodiments, R 3 It is ethyl. In yet another embodiment, R 3 It is 1-(2,2-difluoroethyl). In yet other embodiments, R 3 It is 1-(2,2,2-trifluoroethyl). In yet other embodiments, R 3 It is 1-pentadeuteroethyl. In other embodiments, R 3 It is isopropyl. In other embodiments, R 3 It is cyclopropyl. In other embodiments, R 3 It is 1-propyl. In other embodiments, R 3 It is cyclopropylmethyl. In other embodiments, R 3 It is 1-butyl. In other embodiments, R 3 It is isobutyl.

[0105] In some implementations, R 3 It is a methoxymethyl group. In some embodiments, R 3 It is ethoxymethyl. In some embodiments, R 3 It is (acetamido)methyl. In some embodiments, R 3 It is (aminocarbonyl)methyl. In some embodiments, R 3 It is (methylaminocarbonyl)methyl. In some embodiments, R 3 It is (dimethylaminocarbonyl)methyl. In some embodiments, R 3 It is cyanomethyl. In some embodiments, R 3 It is a methylsulfonyl methyl group. In some embodiments, R 3 It is an aminosulfonylmethyl group. In some embodiments, R 3 It is (tetrahydro-2H-pyran-4-yl)methyl. In some embodiments, R3 It is (tetrahydrofuran-2-yl)methyl. In some embodiments, R 3 It is (tetrahydrofuran-3-yl)methyl. In some embodiments, R 3 It is cyclopentylmethyl. In some embodiments, R 3 It is cyclohexylmethyl. In some embodiments, R 3 It is (1-methylpiperidin-4-yl)methyl. In some embodiments, R 3 It is (4-hydroxycyclohexyl)methyl. In some embodiments, R 3 It is (1H-1,2,3-triazol-4-yl)methyl. In some embodiments, R 3 It is (4H-1,2,4-triazol-3-yl)methyl. In some embodiments, R 3 It is (2,2-dimethyl-1,3-dioxane-5-yl)methyl. In some embodiments, R 3 It is pyridin-2-ylmethyl. In some embodiments, R 3 It is pyridin-3-ylmethyl. In some embodiments, R 3 It is pyridin-4-ylmethyl. In some embodiments, R 3 It is thiazol-2-ylmethyl. In some embodiments, R 3 It is thiazol-4-ylmethyl. In some embodiments, R 3 It is pyrimidin-5-ylmethyl. In some embodiments, R 3 It is pyrimidin-4-ylmethyl. In some embodiments, R 3 It is thiazolyl-5-methyl.

[0106] In some implementations, R 3 It is 1-(2-amino)ethyl. In other embodiments, R 3 It is 1-(2-hydroxy)ethyl. In yet another embodiment, R 3 It is 1-(2-methoxy)ethyl. In other embodiments, R 3 It is 1-(2-ethoxy)ethyl. In yet other embodiments, R 3 It is 1-(2-acetamido)ethyl. In yet another embodiment, R 3 It is 1-(2-aminocarbonyl)ethyl. In other embodiments, R 3 It is 1-(2-methylaminocarbonyl)ethyl. In other embodiments, R 3 It is 1-(2-dimethylaminocarbonyl)ethyl. In yet other embodiments, R 3 It is 1-(2-cyano)ethyl. In yet other embodiments, R 3It is 1-(2-methylsulfonyl)ethyl. In other embodiments, R 3 It is 1-(2-aminosulfonyl)ethyl. In yet other embodiments, R 3 It is 1-(2-(2-methoxyethoxy))ethyl. In yet other embodiments, R 3 It is 1-(2-(2,2-difluoroethyl)amino)ethyl. In yet other embodiments, R 3 It is 1-(2-(2,2,2-trifluoroethyl)amino)ethyl. In yet other embodiments, R 3 It is 1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl. In yet other embodiments, R 3 It is 1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl. In yet other embodiments, R 3 It is 1-(2-carboxy)ethyl.

[0107] In some implementations, R 3 It is 1-(3-amino)propyl. In other embodiments, R 3 It is 1-(3-hydroxy)propyl. In other embodiments, R 3 It is 1-(3-methoxy)propyl. In other embodiments, R 3 It is 1-(3-ethoxy)propyl. In other embodiments, R 3 It is 1-(3-acetamido)propyl. In other embodiments, R 3 It is 1-(3-aminocarbonyl)propyl. In other embodiments, R 3 It is 1-(3-methylaminocarbonyl)propyl. In other embodiments, R 3 It is 1-(3-dimethylaminocarbonyl)propyl. In other embodiments, R 3 It is 1-(3-cyano)propyl. In other embodiments, R 3 It is 1-(3-methylsulfonyl)propyl. In other embodiments, R 3 It is 1-(3-aminosulfonyl)propyl. In other embodiments, R 3 It is 1-(3-hydroxy-2,2-dimethyl)propyl. In other embodiments, R 3 It is 1-(2-hydroxy)propyl. In other embodiments, R 3 It is 1-(3-carboxy)propyl. In other embodiments, R 3 It is 1-(3-hydroxy-2-hydroxymethyl)propyl.

[0108] In some implementations, R 3 It is 1-(4-amino)butyl. In other embodiments, R 3It is 1-(4-hydroxy)butyl. In some embodiments, R 3 It is 1-(4-methoxy)butyl. In some embodiments, R 3 It is 1-(4-ethoxy)butyl. In some embodiments, R 3 It is 1-(4-acetamido)butyl. In some embodiments, R 3 It is 1-(4-aminocarbonyl)butyl. In some embodiments, R 3 It is 1-(4-methylaminocarbonyl)butyl. In some embodiments, R 3 It is 1-(4-dimethylaminocarbonyl)butyl. In some embodiments, R 3 It is 1-(4-cyano)butyl. In some embodiments, R 3 It is 1-(4-methylsulfonyl)butyl. In some embodiments, R 3 It is 1-(4-aminosulfonyl)butyl. In some embodiments, R 3 It is 1-(3-hydroxy)butyl. In some embodiments, R 3 It is 1-(4-carboxy)butyl. In some embodiments, R 3 It is benzyl.

[0109] In some implementations, R 4a Selected from H, methyl, ethyl, isopropyl, n-propyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, isopropylmethyl, -(CH2) 2-6 OH, -(CH2) 2-6 O (C1-C6 alkyl), optionally substituted benzyl, optionally substituted phenyl, fluoromethyl, difluoromethyl and trifluoromethyl.

[0110] In some implementations, R 4a It is H. In other embodiments, R 4a It is a methyl group. In other embodiments, R 4a It is trifluoromethyl. In some embodiments, R 4a It is ethyl. In some embodiments, R 4a It is cyclopropyl. In some embodiments, R 4a It is isopropyl. In some embodiments, R 4a It is 1-propyl. In some embodiments, R 4a It is a phenyl group. In some embodiments, R... 4a It is 2-hydroxyethyl.

[0111] In some implementations, R 4b Selected from H and methyl. In other embodiments, R 4b It is H. In other embodiments, R4b It is a methyl group.

[0112] In some implementations, R 7 It is H. In other embodiments, R 7 It is a methyl group.

[0113] In some implementations, R 8 It is H. In other embodiments, R 8 It is a methoxy group. In other embodiments, R 8 It is ethoxylated. In other embodiments, R 8 It is a methyl group. In other embodiments, R 8 It is ethyl. In yet another embodiment, R 8 It is 2-hydroxyethoxy. In other embodiments, R 8 It is an amino group. In other embodiments, R 8 It is methylamino. In other embodiments, R 8 It is ethylamino. In other embodiments, R 8 It is dimethylamino. In other embodiments, R 8 It is (2-hydroxyethyl)amino. In yet another embodiment, R 8 It is 2-aminoethyl)amino. In other embodiments, R 8 It is a triazole group. In other embodiments, R 8 It is a triazolylmethoxy group. In other embodiments, R 8 It is (N-methyltriazolyl)methyl. In other embodiments, R 8 It is triazolylmethylamino. In other embodiments, R 8 It is (N-methyltriazolyl)methylamino. In yet another embodiment, R 8 It is CN. In other embodiments, R 8 It is hydroxymethyl. In other embodiments, R 8 It is a carboxyl group. In other embodiments, R 8 It is an amino carbonyl group. In other embodiments, R 8 It is a methylaminocarbonyl group. In other embodiments, R... 8 It is dimethylaminocarbonyl. In other embodiments, R 8 It is a methanesulfonyl group. In other embodiments, R 8 It is piperidinylmethoxy.

[0114] In some implementations, R 9 It is H. In other embodiments, R 9 It is Cl. In other embodiments, R 9It is F. In other embodiments, R 9 It is Br. In other embodiments, R 9 It is a methoxy group. In other embodiments, R 9 It is an ethoxy group.

[0115] In some implementations, R 10 It is H. In other embodiments, R 10 It is a methyl group. In other embodiments, R 10 It is ethyl. In yet another embodiment, R 10 It is 1-(2,2,2-trifluoroethyl). In yet other embodiments, R 10 It is 1-propyl. In other embodiments, R 10 It is isopropyl. In other embodiments, R 10 It is cyclopropyl. In other embodiments, R 10 It is 1-(2-hydroxy)ethyl. In yet another embodiment, R 10 It is 1-(2-methoxy)ethyl. In other embodiments, R 10 It is 1-(3-hydroxy)propyl. In other embodiments, R 10 It is 1-(3-methoxy)propyl. In other embodiments, R 10 It is a triazolylmethyl group.

[0116] In some embodiments, the compounds of the present invention are any compounds disclosed herein, or their salts, solvates, prodrugs, isotopically labeled, stereoisomers, any mixtures of stereoisomers, tautomers, and / or any mixtures of tautomers.

[0117] In some embodiments, the compound is at least one compound selected from Table 4, or a salt, solvate, prodrug, isotopically labeled, stereoisomer, any mixture of stereoisomers, tautomers and / or any mixture of tautomers thereof.

[0118] In some embodiments, the compound is selected from at least one of the following: (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)-1-methylurea; (R)-3-(4-fluoro-3-methylphenyl)-1-((1-methoxyisoquinoline-4-yl)methyl) (S)-3-(4-fluoro-3-methylphenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)-1-methylurea; (R)-1-(4-fluoro-3-methylphenyl)-3-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-1-(4-fluoro-3-methylphenyl)-3-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (R)-3-(4-fluoro-3-methylphenyl)-1-methyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-3-(4-fluoro-3-methylphenyl)-1-methyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea ; (R)-1-(3-chloro-4-fluorophenyl)-3-((1-methoxyisoquinoline-4-yl)methyl)urea; (S)-1-(3-chloro-4-fluorophenyl)-3-((1-methoxyisoquinoline-4-yl)methyl)urea; (R)-1-(4-fluoro-3-methylphenyl)-3-((1-methoxyisoquinoline-4-yl)methyl)urea; (S)-1-(4-fluoro-3-methylphenyl)-3-((1-methoxyisoquinoline-4-yl)methyl)urea; (R)-1-(3-chloro-4-fluorophenyl)-3-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-1-(3-chloro-4-fluorophenyl)-3-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (R)-1-(3-chloro-4-fluorophenyl)-3-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-1-(3-chloro-4-fluorophenyl)-3-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea;(S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(isoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-ethoxyisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-((1-ethoxyisoquinoline-4-yl)methyl)-1-ethylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-isopropyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-isopropyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-isopropyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)-1-propylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)-1-propylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (S) (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-isopropyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-isopropyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea;(R)-3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)-1-propylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)-1-propylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-(2-hydroxyethoxy)) (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-(2-hydroxyethoxy)isoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (R)-3-(4-fluoro-3-methylphenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(4-fluoro-3-methylphenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-butyl-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (S)-1-butyl-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea (S)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (R)-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-propylurea; (S)-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-propylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinoline-4-yl)propyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinoline-4-yl)propyl)urea;(R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)propyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)propyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropyl(1-methoxyisoquinoline-4-yl)methyl)-1-ethylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropyl(1-methoxyisoquinoline-4-yl)methyl)-1-ethylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropyl(1-methoxyisoquinoline-4-yl)methyl)-1-ethylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-((1-methoxyisoquinoline- (S)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (R)-3-(4-fluoro-3-methylphenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-propylurea; (S)-3-(4-fluoro-3-methylphenyl)-1-(1-(1-)-(4-)-(2-methoxyethyl)-1-(2-) ... (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinoline-4-yl)-2-methylpropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinoline-4-yl)-2-methylpropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinoline-4-yl)-2-methylpropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropyl(1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)-1-ethylurea; (S)-3-( 3-Chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)-1-(3-methoxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)-1-(3-methoxypropyl)urea; (R)-1-benzyl-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (S)-1-benzyl-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea;(S)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(3-methoxypropyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-methoxypropyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (R)-1-butyl-3-(3-chloro-4-fluorophenyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-1-butyl-3-(3-chloro-4-fluorophenyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2-methyl-1-(1-oxo-1,2-dihydroisoquinoline-4-yl)propyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2-methyl-1-(1-oxo-1,2-dihydroisoquinoline-4-yl)propyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-methoxyisoquinoline-4-yl)(phenyl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-methoxyisoquinoline-4-yl)(phenyl)methyl)urea; (R)-1-butyl-3-(3-chloro-4-fluorophenyl) (S)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (S)-1-butyl-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea;(S)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)(phenyl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(( 1-O-1,2-dihydroisoquinoline-4-yl)(phenyl)methyl)urea; (R)-1-(3-chloro-4-fluorophenyl)-3-(3-hydroxy-1-(1-methoxyisoquinoline-4-yl)propyl)urea; (S)-1-(3-chloro-4-fluorophenyl)-3-(3-hydroxy-1-(1-methoxyisoquinoline-4-yl)propyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)- 1-Ethyl-1-(2,2,2-trifluoro-1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2,2,2-trifluoro-1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2,2,2-trifluoro-1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2,2,2-trifluoro-1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(3-methoxypropyl)-1 -(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-methoxypropyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)-1-(3-methoxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)-1-(3-methoxypropyl)urea; (R)-1-butyl-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea;(S)-1-Butyl-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-((1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)methyl)urea; (S)-3-(3- (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-((1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-((1-(pyridin-2-ylmethoxy)isoquinoline-4-yl)methyl)urea; (R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4,5-trifluorophenyl)urea; (S)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4,5-trifluorophenyl)urea; (R)-3- (3,4-Difluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3,4-difluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(2-chloropyridin-4-yl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea;(S)-3-(2-chloropyridin-4-yl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea; (S)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2,2-difluoroethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2,2-difluoroethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-(2,2-difluoroethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-1-(2,2-difluoroethyl)-3-(4-fluoro-3-methylphenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-(2,2-difluoroethyl)-3-(4-fluoro-3-methylphenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-1-(2,2-difluoroethyl)-3-(4-fluoro-3-methylphenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-cyano-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-cyano-4-fluorophenyl)-1-methyl-1-(1-( 1-O-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(ethyl-d5)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(ethyl-d5)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-N-(2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea)ethyl)acetamide; (S)-N-(2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)acetamide) (R)-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)urea; (S)-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydro-2,7-diazanaphthyl-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydro-2,7-diazanaphthyl-4-yl)ethyl)urea;(R)-3-(3-chloro-4-fluorophenyl)-1-(2-cyanoethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-cyanoethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureoyl)-N-methylpropionamide; (S)-3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureoyl)-N-methylpropionamide; (R)- 3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)-N,N-dimethylpropionamide; (S)-3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)-N,N-dimethylpropionamide; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-(methylsulfonyl)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-(methylsulfonyl)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline- (R)-3-(3-chloro-4-fluorophenyl)-1-(2-ethoxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-ethoxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydro-2,7-diazanaphth-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydro-2,7-diazanaphth-4-yl)ethyl)urea (Ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(3-cyanopropyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-cyanopropyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureoyl)-N-methylacetamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureoyl)-N-methylacetamide;(R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-(2-methoxyethoxy)ethyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-(2-methoxyethoxy)ethyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea (R)-3-(3-chloro-4-fluorophenyl)-1-(2-(2-methoxyethoxy)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-(2-methoxyethoxy)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-ethoxyethyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-ethoxyethyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydro-2,6-diazanaphthyl-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydro-2,6-diazanaphthyl-4-yl)ethyl)urea; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea)acetamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea)acetamide; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea)acetamide; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)urea;(R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(5-(methylamino)pyridino[3,4-b]pyrazin-8-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(5-(methylamino)pyridino[3,4-b]pyrazin-8-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(5-methoxypyridino[3,4-b]pyrazin-8-yl)ethyl)-1-methylurea; (S)-3-( (3-Chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea; (R)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-2-(3- (3-Chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)-N,N-dimethylacetamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)-N,N-dimethylacetamide; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(5-oxo-5,6-dihydropyridino[3,4-b]pyrazin-8-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(5-oxo-5,6-dihydropyridino[3,4-b]pyrazin-8-yl)ethyl)urea;(R)-3-(3-chloro-4-fluorophenyl)-1-(4-hydroxybutyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(4-hydroxybutyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(8-oxo-7,8-dihydro-1,7-diazanaphthyl-5-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(8-oxo-7,8-dihydro-1,7-diazanaphthyl-5-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(8-oxo-7,8-dihydro-1,7-diazanaphthyl-5-yl)ethyl)urea; (S)-1-isobutyl-1-(1-(1-oxo-1,2-dihydro-2,7-diazanaphthyl-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydro-2,7-diazanaphthyl-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(((R)-tetrahydrofuran-2-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1(S)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(((R)-tetrahydrofuran-2-yl)methyl)urea; (R)-1-(3-aminopropyl) (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-oxo-1,2-dihydro-2,7-diazanaphth-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-oxo-1,2-dihydro-2,7-diazanaphth-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1(S)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)urea;(R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(((S)-tetrahydrofuran-3-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1(S)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; Quinoline-4-yl)ethyl)-1-((((S)-tetrahydrofuran-3-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(((R)-tetrahydrofuran-3-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1(S)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(((R)-tetrahydrofuran-3-yl)methyl)urea; (R)-1-(1-(8-chloro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(8-chloro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-chloro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-chloro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-chloro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7-methoxy-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7-methoxy-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-methoxy-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-methoxy-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea;(R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-ethyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-ethyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)- 1-Methyl-1-(1-(2-propyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-propyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-isopropyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-isopropyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-isopropyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; 1-O-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-cyclopropyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(2-(2-methoxyethyl)-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(2-(2-methoxyethyl)-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopentylmethyl)-1-(1-(1-(1-oxo- 1,2-Dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopentylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclohexylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclohexylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea;(S)-3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-((2,2-difluoroethyl)amino)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-((2,2-difluoroethyl)amino)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(2-(3-methoxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(2-(3-methoxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-1-((1-acetylpiperidin-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-1-((1-acetylpiperidin-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-((1-(methanesulfonyl)) (S)-3-(3-chloro-4-fluorophenyl)-1-((1-(methylsulfonyl)piperidin-4-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(2-(2-hydroxyethyl)-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(2-(2-hydroxyethyl)-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(2-(2-hydroxyethyl)-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(2-(3-hydroxypropyl)-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-((1-methylpiperidin-4-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-((1-methylpiperidin-4-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea;(R)-3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea)propionic acid; (S)-3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea)propionic acid; (R)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; 3-(3-chloro-4-) 3-(3-chloro-4-fluorophenyl)-1-((R)-3-hydroxybutyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((R)-3-hydroxybutyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((S)-3-hydroxybutyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((S)-3-hydroxybutyl)-1-(1(S)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)- 1-((R)-2-hydroxypropyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((R)-2-hydroxypropyl)-1-((S)1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((S)-2-hydroxypropyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((S)-2-hydroxypropyl)-1-(1(S)-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-(3-chloro-4-fluorophenyl)-1- (1-(1-O-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)-N-methylpropane-1-sulfonamide; (S)-3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-O-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)-N-methylpropane-1-sulfonamide; (R)-3-(3-chloro-4-fluorophenyl)-1-(((1r,4r)-4-hydroxycyclohexyl)methyl)-1-(1-(1-O-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(((1r,4r)-4-hydroxycyclohexyl)methyl)-1-(1-(1-O-1,2-dihydroisoquinoline-4-yl)ethyl)urea;(R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(3-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(3-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-((4-cis-hydroxycyclohexyl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-((4-cis-hydroxycyclohexyl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-4-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea)butyric acid; (S)-4-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea)butyric acid; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-2-(2,2,2-trifluoroethyl)- 1,2-Dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(4-fluoro-3-methylphenyl)-1-methyl-1-(1-(3-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(4-fluoro-3-methylphenyl)-1- Methyl-1-(1-(3-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(methylamino)isoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(methylamino)isoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(dimethylamino)isoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(dimethylamino)isoquinoline-4-yl)ethyl)urea;(R)-3-(4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(4-fluoro-3-methylphenyl)-1-methyl-1-(1-(3-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(4-fluoro-3-methylphenyl)-1-methyl-1-(1-(3-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-(1-(1-aminoisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-aminoisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-(1-(ethylamino)isoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-(1-(ethylamino)isoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-(1-(ethylamino)isoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-(1-(2-hydroxyethyl)amino) (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-((2-hydroxyethyl)amino)isoquinoline-4-yl)ethyl)-1-methylurea; (R)-1-(1-(1-((2-aminoethyl)amino)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-((2-aminoethyl)amino)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(((1-methyl-1H-1,2,4-triazole-) 3-yl)methyl)amino)isoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(((1-methyl-1H-1,2,4-triazol-3-yl)methyl)amino)isoquinoline-4-yl)ethyl)urea; (R)-1-(1-(1-(((1H-1,2,4-triazol-3-yl)methyl)amino)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-(((1H-1,2,4-triazol-3-yl)methyl)amino)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea;(R)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; (S)-1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; (R)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)urea; (S)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)-3-( 3-Chloro-4-fluorophenyl)-1-(3-hydroxypropyl)urea; (R)-1-(1-(1-(((2H-1,2,3-triazol-4-yl)methyl)amino)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-(((2H-1,2,3-triazol-4-yl)methyl)amino)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(5-methoxy-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(5- Methoxy-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-1-((1H-1,2,3-triazol-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-1-((1H-1,2,3-triazol-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-((4H-1,2,4-triazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea;(S)-1-((4H-1,2,4-triazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-(1-(2-((1H-1,2,4-triazol-3-yl)methyl)-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(2-((1H-1,2,4-triazol-3-yl)methyl)-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-1-(1-(7-chloro-1-oxo-1) ,2-Dihydroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(7-chloro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-((2,2-dimethyl-1,3-dioxane-5-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-((2,2-dimethyl-1,3-dioxane-5-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-((2,2-dimethyl-1,3-dioxane-5-yl)methyl)-3-(4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-1-((2,2-dimethyl-1,3-dioxane-5-yl)methyl)-3-(4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-((2,2-dimethyl-1,3-dioxane-5-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-1-((2,2-dimethyl-1,3-dioxane-5-yl)methyl)-1- (1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-phenylurea; (R)-1-(1-(2-((1H-1,2,3-triazol-4-yl)methyl)-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(2-((1H-1,2,3-triazol-4-yl)methyl)-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea;(S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-isobutylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-isobutylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-isobutylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-((2,2-dimethyl-1,3-dioxane-5-yl)methyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-isobutylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-((2,2-dimethyl-1,3-dioxane-5-yl)methyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxy-2-(hydroxymethyl)propyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxy-2-(hydroxymethyl)propyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-(3-hydroxypropyl)urea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-(3-hydroxypropyl)urea; (R)-3-(4-chlorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea;(S)-3-(4-chlorophenyl)-1-methyl-1-(1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(4-bromophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(4-bromophenyl)-1-methyl-1-(1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(3-hydroxy-2-(hydroxymethyl)propyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(3-hydroxy-2-(hydroxymethyl)propyl)urea; (R)-1-(1-(1-(1H-1,2,4-triazol-1-yl)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-(1H-1,2,4-triazol-1-yl)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-1,3-dimethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-1,3-dimethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-cyclopentyl-1 (S)-3-Cyclopentyl-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-(1-(1-(1H-1,2,4-triazol-1-yl)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-isobutylurea; (S)-1-(1-(1-(1H-1,2,4-triazol-1-yl)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-isobutylurea; (R)-1-(1-(1-(1H-1,2,4-triazol-1-yl)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-isobutylurea; (R)-1-(1-(1-(1H-1,2,4-triazol-1-yl)isoquinoline-4-yl)ethyl)-3-(4-fluorophenyl) (S)-1-(1-(1-(1H-1,2,4-triazol-1-yl)isoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(pyridin-2-ylmethyl)urea;(S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(pyridin-2-ylmethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(pyridin-3-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(pyridin-3-ylmethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(pyridin-3-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(pyridin-4-ylmethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(thiazolyl-2-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(thiazolyl-2-ylmethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(thiazolyl-2-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(thiazolyl-4-ylmethyl)urea; (S) (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(thiazo-4-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(1-(methanesulfonyl)isoquinoline-4-yl)ethyl)urea; (R)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylurea)ethyl)-N-methylisoquinoline-1-carboxamide; (S)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylurea)ethyl) (R)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylureoyl)ethyl)-N,N-dimethylisoquinoline-1-carboxamide; (S)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylureoyl)ethyl)-N,N-dimethylisoquinoline-1-carboxamide; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(pyrimidin-5-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(pyrimidin-5-ylmethyl)urea;(R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(pyrimidin-4-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(pyrimidin-4-ylmethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(thiazolyl-5-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(thiazolyl-5-ylmethyl)urea; (R)- 4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylurea)ethyl)isoquinoline-1-carboxylic acid; (S)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylurea)ethyl)isoquinoline-1-carboxylic acid; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-(1-(hydroxymethyl)isoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-(1-(hydroxymethyl)isoquinoline-4-yl)ethyl)-1-methylurea; (R)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylurea)ethyl)isoquinoline-1-carboxamide; (S)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylurea)ethyl)isoquinoline-1-carboxamide; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-cyanoisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-cyanoisoquinoline-4-yl)ethyl)-1-methylurea;(R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-isobutylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-isobutylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea ;(R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-isobutylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-isobutylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-methylisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-methylisoquinoline-4-yl)ethyl)urea; (R)-1-(1-(1-(1H-1,2,3-triazol-1-yl)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea;(S)-1-(1-(1-(1H-1,2,3-triazol-1-yl)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-1-(1-(1-(1H-1,2,3-triazol-1-yl)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-isobutylurea; (S)-1-(1-(1-(1H-1,2,3-triazol-1-yl)isoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-isobutylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl Urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-isobutylurea; (S (R)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)-6,7-difluoroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)-6,7-difluoroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R ... -Difluoroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)urea; (S)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)-6,7-difluoroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(3-hydroxypropyl)urea;(R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; (S)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro- (4-Fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (R)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; (S)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; (R)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; (R)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; (S)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-(3-hydroxypropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-hydroxy-1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-hydroxy-1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(2-hydroxy-1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide;(R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (R)-2-(1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)ureo)ethane-1-sulfonamide; (S)-2-(1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl) (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (R)-2-(3-(4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (S)-2-(3-(4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (R)-2-(3-(4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (S)-2-(3-(4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1- (8-Fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)ureo)ethane-1-sulfonamide; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-phenylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-phenylurea; (R)-3-(4-chlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(4-chlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea;(R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-ethyl-3-(4-fluorophenyl)urea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-ethyl-3-(4-fluorophenyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-ethyl-3-(4-fluorophenyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-ethyl-3-(4-fluorophenyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-ethyl-3-phenylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-ethyl-3-phenylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-ethyl-3-phenylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-ethyl-3-phenylurea; Fluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-ethylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-ethylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-fluorophenyl)-1-methylurea; (R)-3-(3-chlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluoro) (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorophenyl)urea; (R)-3-(3,5-dichlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3,5-dichlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(2-chloropyridin-4-yl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea;(S)-3-(2-chloropyridin-4-yl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2-fluorophenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2-fluorophenyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2-fluorophenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-ethylurea; (S)-1-(1-(6,7- (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluoro-3-methylphenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluoro-3-methylphenyl)-1-methylurea; (R)-3-(3-cyano-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-cyano-4-fluorophenyl) (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2,3-difluorophenyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2,3-difluorophenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2,3-difluorophenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; (S ... (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-phenylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-phenylurea;(R)-3-(3,5-dichloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3,5-dichloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluoro-3-methylphenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluoro-3-methylphenyl)-1-methylurea; (R)-1 (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorophenyl)urea; (R)-3-(4-chlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorophenyl)urea; (R)-3-(4-chlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(4-chlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-( 6,8-Difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-isobutylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-isobutylurea; (R)-3-(3,5-dichlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3,5-dichlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl) (S)-1-methyl-3-(pyridin-4-yl)urea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-(pyridin-4-yl)urea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-(pyridin-3-yl)urea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-(pyridin-3-yl)urea; (R)-3-(3,5-dichloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea;(S)-3-(3,5-dichloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-benzyl-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-benzyl-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(2-chloropyridin-4-yl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(2-chloropyridin-4-yl) -1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-fluorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-fluorophenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-fluorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2-fluorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2-fluorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline- (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2,3-difluorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2,3-difluorophenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2,3-difluorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-chlorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-chlorophenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-ethylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-ethylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-ethylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorophenyl)-1-ethylurea;(R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-phenyl-1-ethylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-phenyl-1-ethylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-ethylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-ethylurea; (R)-3-(3-cyano-4-fluorophenyl)-1 -(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-cyano-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(methyl)urea; (R)-3-(3-chloro-4-fluorophenyl) (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(methyl-d3)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(methyl)urea; (R)- 3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(methyl-d3)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(methyl-d3)urea; (R)-3-(3-chlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(methyl)urea; (S)-3-(3-chlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(methyl)urea;(R)-3-(3-chlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(methyl-d3)urea; (S)-3-(3-chlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-(methyl-d3)urea; 1-(1(R)-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-((S)-1-phenethyl)urea; 1-(1(S)-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-((S)-1-phenethyl)urea; (R)-1-(1- (6,7-Difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorobenzyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorobenzyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorobenzyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorobenzyl)-1-methylurea; 1-(1(R)-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorobenzyl)-1-methylurea; 1-(1(R)-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorobenzyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-((R)-1-phenylethyl)urea; (R)-1-(3-chloro-4-fluorophenyl)-3-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-1-(3-chloro-4-fluorophenyl)-3-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; 4,5-Trifluorobenzyl)urea; (S)1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorobenzyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-(3-chloro-4-fluorobenzyl)urea; (S)1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-(3-chloro-4-fluorobenzyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(1H-indol-6-yl)-1-methylurea;(S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(1H-indol-6-yl)-1-methylurea; 1-(1(R)-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-((S)-1-phenethyl)urea; 1-(1(S)-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-((S)-1-phenethyl)urea; 1-(1(R)-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-((S)-1-phenethyl)urea; 1-(1(S)-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-((R ... (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methyl-3-((R)-1-phenethyl)urea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorobenzyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4-difluorobenzyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(4-fluorobenzyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline)ethyl)-3-(4-fluorobenzyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline)ethyl)-3-(4-fluorobenzyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline)ethyl)-3-(4-fluorobenzyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4,5-trifluorobenzyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3,4,5-trifluorobenzyl)-1-methylurea; (R)-1-(3-cyano-4-fluorophenyl)-3-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-1-(3-cyano-4-fluorophenyl)-3-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorobenzyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorobenzyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(1H-indol-6-yl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(1H-indol-6-yl)-1-methylurea;(R)-1-(3-chloro-4-fluorophenyl)-3-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-1-(3-chloro-4-fluorophenyl)-3-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl) (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-methylurea; or salts, solvates, prodrugs, isotopically labeled, stereoisomers, any mixtures of stereoisomers, tautomers and / or any mixtures of tautomers thereof.

[0119] In some embodiments, the compound is at least one selected from the group consisting of: (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(4-fluoro-3-methylphenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-propylurea; (R)-3-(4-fluoro-3-methylphenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-propylurea; (R)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-1-propylurea; (R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3,4,5-trifluorophenyl)urea; (R)-3-(3,4-difluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea (R)-3-(3-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(2-chloropyridin-4-yl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2,2-difluoroethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-1-(2,2-difluoroethyl)-3-(4-fluoro-3-methylphenyl) (R)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-cyano-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(ethyl-d5)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)urea; (R)-3-(4-chlorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea;And (R)-3-(4-bromophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea; or its salts, solvates, prodrugs, isotopically labeled, stereoisomers, any mixtures of stereoisomers, tautomers and / or any mixtures of tautomers.

[0120] The compounds of the present invention may have one or more stereocenters, and each stereocenter may exist independently in an (R) or (S) configuration. In some embodiments, the compounds described herein are present in optical or racemic forms. The compounds described herein include racemic, optical, regioisomeric, and stereoisomeric forms or combinations thereof having the therapeutically useful properties described herein. Preparation of the optical form is achieved in any suitable manner, including, as non-limiting examples, resolution of the racemic form by recrystallization, synthesis from optically active raw materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. The compounds described herein by racemic formulation further represent two enantiomers or any mixture thereof, or, in the presence of two or more chiral centers, all diastereomers or any mixture thereof.

[0121] In some embodiments, the compounds of the present invention are present as tautomers. All tautomers are included within the scope of the compounds described herein.

[0122] The compounds described herein also include isotopically labeled compounds, wherein one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from those normally found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include, but are not limited to, those... 2 H, 3 H, 11 C 13 C 14 C 36 Cl, 18 F, 123 I, 125 I, 13 N、 15 N、 15 O. 17 O. 18 O. 32 P and 35 S. In some embodiments, substitution with a heavier isotope, such as deuterium, provides greater chemical stability. Isotope-labeled compounds can be prepared by any suitable method or by using a suitable isotope-labeled reagent instead of an unlabeled reagent.

[0123] In some embodiments, the compounds described herein are labeled in other ways, including but not limited to using chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0124] Examples of suitable optional substituents in all embodiments provided herein are not intended to limit the scope of the claimed invention. Compounds of the present invention may contain any substituents or combinations thereof provided herein.

[0125] Salt

[0126] The compounds described herein can form salts with acids or bases, and such salts are included in this invention. The term "salt" includes addition salts of free acids or bases useful in the methods of this invention. The term "pharmaceutically acceptable salt" refers to a salt having toxicity characteristics within the range useful in pharmaceutical applications. In some embodiments, the salt is a pharmaceutically acceptable salt. However, pharmaceutically unacceptable salts may have properties such as high crystallinity, which are useful in the practice of this invention, such as in the synthesis, purification, or formulation of compounds useful in the methods of this invention.

[0127] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include sulfates, hydrogen sulfates, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid (including hydrogen phosphate and dihydrogen phosphate). Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic acid, and sulfonic acid organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pyric acid (or pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, sulfanilic acid, 2-hydroxyethanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactopyric acid, galacturonic acid, glycerophosphonic acid, and saccharin (e.g., saccharinate, saccharate). With respect to any compound of the present invention, the salt may consist of a portion of 1 molar equivalent, 1 or more molar equivalent of an acid or base.

[0128] Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, ammonium salts and metal salts, including alkali metal, alkaline earth metal, and transition metal salts, such as, for example, calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts prepared from basic amines such as, for example, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (or N-methylglucosamine), and procaine. All these salts can be prepared from the respective compounds, for example, by reacting them with a suitable acid or base.

[0129] Combination therapy

[0130] In one aspect, the compounds of the present invention are used in combination with one or more additional agents for treating HBV and / or HDV infection in the methods of the present invention. These additional agents may include compounds or compositions identified herein, or compounds known for treating, preventing, or alleviating symptoms of HBV and / or HDV infection (e.g., commercially available compounds).

[0131] Non-limiting examples of one or more other agents for the treatment of HBV and / or HDV infection include: (a) reverse transcriptase inhibitors; (b) capsid inhibitors; (c) cccDNA formation inhibitors; (d) RNA destabilizers; (e) oligonucleotides targeting the HBV genome; (f) immunostimulants, such as checkpoint inhibitors (e.g., PD-L1 inhibitors); and (g) GalNAc-siRNA conjugates targeting the HBV gene transcriptome.

[0132] (a) Reverse transcriptase inhibitors

[0133] In some embodiments, the reverse transcriptase inhibitor is a reverse transcriptase inhibitor (NARTI or NRTI). In other embodiments, the reverse transcriptase inhibitor is a nucleotide analog reverse transcriptase inhibitor (NtARTI or NtRTI).

[0134] The reported reverse transcriptase inhibitors include, but are not limited to, entecavir, clavidine, telbivudine, lamivudine, adefovir and tenofovir, tenofovir disoproxil, tenofovir alafenamide, adefovir dipovoxil, (1R,2R,3R,5R)-3-(6-amino-9H-9-purinyl)-2-fluoro-5-(hydroxymethyl)-4-methylenecyclopentan-1-ol (described in U.S. Patent No. 8,816,074, which is incorporated herein by reference in its entirety), emtricitabine, abacavir, elvucitabine, ganciclovir, lobucavir, famciclovir, penciclovir, and amdoxovir.

[0135] The reported reverse transcriptase inhibitors further include, but are not limited to, entecavir, lamivudine, and (1R,2R,3R,5R)-3-(6-amino-9H-9-purinyl)-2-fluoro-5-(hydroxymethyl)-4-methylenecyclopentanol.

[0136] The reported reverse transcriptase inhibitors further include, but are not limited to, the covalently bound aminophosphate or phosphonamide moiety of the reverse transcriptase inhibitors mentioned above, or as described, for example, in U.S. Patent No. 8,816,074, U.S. Patent Application Publication No. US2011 / 0245484 A1, and US2008 / 0286230A1, all of which are incorporated herein by reference in their entirety.

[0137] The reported reverse transcriptase inhibitors further include, but are not limited to, nucleotide analogs comprising an aminophosphate moiety, such as, for example, ((((1R,3R,4R,5R)-3-(6-amino-9H-purin-9-yl)-4-fluoro-5-hydroxy-2-methylenecyclopentyl)methoxy)methyl(phenoxy)phosphoryl)-(D or L)-alanine ester and ((((1R,2R,3R,4R)-3-fluoro-2-hydroxy-5-methylene-4-(6-oxo-1,6-dihydro-9H-purin-9-yl)cyclopentyl)methoxy)methyl(phenoxy)phosphoryl)-(D or L)-alanine ester. It also includes its individual diastereomers, including, for example, ((R)-(((1R,3R,4R,5R)-3-(6-amino-9H-purin-9-yl)-4-fluoro-5-hydroxy-2-methylenecyclopentyl)methoxy)methyl(phenoxy)phosphoryl)-(D or L)-alanine ester and ((S)-(((1R,3R,4R,5R)-3-(6-amino-9H-purin-9-yl)-4-fluoro-5-hydroxy-2-methylenecyclopentyl)methoxy)methyl(phenoxy)phosphoryl)-(D or L)-alanine ester.

[0138] The reported reverse transcriptase inhibitors further include, but are not limited to, compounds comprising a phosphonamide moiety, such as, for example, tenofovir alafenamide, and those described in U.S. Patent Application Publication No. 2008 / 0286230 A1, which are incorporated herein by reference in their entirety. Methods for preparing active ingredients containing stereoselective aminophosphates or phosphonamides are described, for example, in U.S. Patent No. 8,816,074 and U.S. Patent Application Publications Nos. 2011 / 0245484 A1 and 2008 / 0286230 A1, all of which are incorporated herein by reference in their entirety.

[0139] (b) Capsid inhibitors

[0140] As described herein, the term "capsid inhibitor" includes compounds capable of directly or indirectly inhibiting the expression and / or function of capsid proteins. For example, capsid inhibitors may include, but are not limited to, any compound that inhibits capsid assembly, induces the formation of non-capsid polymers, promotes excessive or misdirected capsid assembly, affects capsid stability, and / or inhibits RNA (pgRNA) capsidation. Capsid inhibitors also include any compound that inhibits capsid function in one or more downstream events of the replication process (e.g., viral DNA synthesis, translocation of loose circular DNA (rcDNA) to the nucleus, formation of covalently closed circular DNA (cccDNA), viral maturation, budding, and / or release, etc.). For example, in some embodiments, the inhibitor detectably inhibits the expression level or biological activity of capsid proteins, as measured, for example, using the assays described herein. In some embodiments, the inhibitor inhibits the levels of rcDNA and downstream products of the viral life cycle by at least 5%, at least 10%, at least 20%, at least 50%, at least 75%, or at least 90%.

[0141] The reported capsid inhibitors include, but are not limited to, the compounds described in International Patent Application Publication Nos. WO 2013006394, WO2014106019 and WO2014089296, all of which are incorporated herein by reference in their entirety.

[0142] The reported capsid inhibitors also include, but are not limited to, the following compounds and their pharmaceutically acceptable salts and / or solvates: Bay-41-4109 (see International Patent Application Publication No. WO 2013144129), AT-61 (see International Patent Application Publication No. WO 1998033501; and King et al., 1998, Antimicrob. Agents Chemother. 42(12):3179–3186), DVR-01 and DVR-23 (see International Patent Application Publication No. WO 2013006394; and Campagna et al., 2013, J. Virol. 87(12):6931, all of which are incorporated herein by reference in their entirety.

[0143] In addition, reported capsid inhibitors include, but are not limited to, those in US patent application publications US 2015 / 0225355, US 2015 / 0132258, US 2016 / 0083383, US 2016 / 0052921 and international patent application publications WO2013096744, WO 2014165128, WO 2014033170, WO 2014033167, WO 2014033176, WO2014131847, WO 2014161888, WO 2014184350, WO 2014184365, WO 2015059212, WO2015011281, WO 2015118057, WO 2015109130, WO Those generally and specifically described in WO 2015073774, WO 2015180631, WO 2015138895, WO 2016089990, WO 2017015451, WO 2016183266, WO 2017011552, WO 2017048950, WO 2017048954, WO 2017048962, and WO 2017064156, are incorporated herein by reference in their entirety.

[0144] (c) cccDNA formation inhibitors

[0145] Covalently blocked circular DNA (cccDNA) is produced in the cell nucleus of viral rcDNA and serves as a transcription template for viral mRNA. As described herein, the term "cccDNA formation inhibitor" includes compounds capable of directly or indirectly inhibiting the formation and / or stability of cccDNA. For example, cccDNA formation inhibitors may include, but are not limited to, any compound that inhibits capsid disintegration, rcDNA entry into the cell nucleus, and / or conversion of rcDNA into cccDNA. For example, in some embodiments, the inhibitor may suppress cccDNA formation and / or stability, as measured, for example, using the assays described herein. In some embodiments, the inhibitor inhibits cccDNA formation and / or stability by at least 5%, at least 10%, at least 20%, at least 50%, at least 75%, or at least 90%.

[0146] The reported cccDNA formation inhibitors include, but are not limited to, the compounds described in International Patent Application Publication No. WO 2013130703, which are incorporated herein by reference in their entirety.

[0147] In addition, the reported cccDNA formation inhibitors include, but are not limited to, those generally and specifically described in U.S. Patent Application Publication No. US 2015 / 0038515 A1, which are incorporated herein by reference in their entirety.

[0148] (d) RNA destabilizers

[0149] As used herein, the term "RNA destabilizer" refers to a molecule or its salt or solvation that reduces the total amount of HBV RNA in mammalian cell cultures or in live human subjects. In non-limiting examples, RNA destabilizers reduce the amount of RNA transcripts (one or more) encoding one or more of the following HBV proteins: surface antigen, core protein, RNA polymerase, and e antigen. In some embodiments, RNA destabilizers reduce the total amount of HBV RNA in mammalian cell cultures or in live human subjects by at least 5%, at least 10%, at least 20%, at least 50%, at least 75%, or at least 90%.

[0150] The reported RNA destabilizers include compounds described in U.S. Patent No. 8,921,381, and compounds described in U.S. Patent Application Publication Nos. US 2015 / 0087659 and US 2013 / 0303552, all of which are incorporated herein by reference in their entirety.

[0151] In addition, reported RNA destabilizers include, but are not limited to, those mentioned in international patent application publication numbers WO 2015113990, WO 2015173164, US 2016 / 0122344, WO 2016107832, WO 2016023877, WO 2016128335, WO2016177655, WO 2016071215, WO 2017013046, WO 2017016921, WO 2017016960, WO2017017042, WO 2017017043, WO 2017102648, WO 2017108630, WO 2017114812, WO2017140821, WO Those generally and specifically described in 2018085619 are incorporated herein by reference in their entirety.

[0152] (e) Oligonucleotides targeting the HBV genome

[0153] Reported oligonucleotides targeting the HBV genome include, but are not limited to, Arrowhead-ARC-520 (see U.S. Patent No. 8,809,293; and Wooddell et al., 2013, Molecular Therapy 21(5):973–985, all of which are incorporated herein by reference in their entirety).

[0154] In some embodiments, oligonucleotides may be programmed to target one or more genes and / or transcripts of the HBV genome. Oligonucleotides targeting the HBV genome also include, but are not limited to, isolated double-stranded siRNA molecules, each siRNA molecule comprising a sense strand and an antisense strand hybridized to the sense strand. In some embodiments, the siRNA targets one or more genes and / or transcripts of the HBV genome.

[0155] (f) Immunostimulants

[0156] Checkpoint inhibitors

[0157] As described herein, the term "checkpoint inhibitor" includes any compound capable of inhibiting immune checkpoint molecules that act as regulators of the immune system (e.g., stimulating or inhibiting immune system activity). For example, some checkpoint inhibitors block inhibitory checkpoint molecules, thereby stimulating immune system function, such as stimulating T cell activity against cancer cells. A non-limiting example of a checkpoint inhibitor is a PD-L1 inhibitor.

[0158] As described herein, the term "PD-L1 inhibitor" includes any compound capable of directly or indirectly inhibiting the expression and / or function of the programmed death-ligand 1 (PD-L1) protein. PD-L1, also known as differentiation cluster 274 (CD274) or B7 homologue 1 (B7-H1), is a type 1 transmembrane protein that plays an important role in suppressing the adaptive arms of the immune system during pregnancy, tissue allogeneic transplantation, autoimmune diseases, and hepatitis. PD-L1 binds to its receptor, the inhibitory checkpoint molecule PD-1 (found on activated T cells, B cells, and bone marrow cells), to modulate the activation or suppression of the adaptive arms of the immune system. In some embodiments, the PD-L1 inhibitor inhibits the expression and / or function of PD-L1 by at least 5%, at least 10%, at least 20%, at least 50%, at least 75%, or at least 90%.

[0159] Reported PD-L1 inhibitors include, but are not limited to, compounds described in one of the following patent application publications: US2018 / 0057455; US 2018 / 0057486; WO 2017 / 106634; WO 2018 / 026971; WO 2018 / 045142; WO2018 / 118848; WO 2018 / 119221; WO 2018 / 119236; WO 2018 / 119266; WO 2018 / 119286; WO2018 / 121560; WO 2019 / 076343; WO 2019 / 087214; and are incorporated herein by reference in their entirety.

[0160] (g) GalNAc-siRNA conjugate targeting the HBV gene transcript

[0161] "GalNAc" is an abbreviation for N-acetylgalactosamine, and "siRNA" is an abbreviation for small interfering RNA. In the GalNAc-siRNA conjugate useful in the practice of this invention, siRNA targeting the HBV gene transcript is covalently bound to GalNAc. While not wishing to be bound by theory, it is believed that GalNAc binds to the desialylate glycoprotein receptor on hepatocytes, thereby promoting siRNA targeting and infection of HBV-infected hepatocytes. The siRNA enters the infected hepatocytes and stimulates the disruption of the HBV gene transcript through RNA interference.

[0162] Examples of GalNAc-siRNA conjugates useful in the practice of this aspect of the invention are set forth in published international application PCT / CA2017 / 050447 (PCT application publication number WO / 2017 / 177326, published on October 19, 2017), which is incorporated herein by reference in its entirety.

[0163] For example, suitable methods, such as Sigmoid-E, can be used. maxThe synergistic effect was calculated using the equations (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the Loewe additivity equation (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326), and the median effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each equation mentioned elsewhere in this paper can be applied to experimental data to generate corresponding curves to help evaluate the effects of the drug combination. The corresponding curves associated with the equations mentioned elsewhere in this paper are concentration-effect curves, equivalence plots, and combination exponent curves, respectively.

[0164] synthesis

[0165] The present invention further provides a method for preparing the compounds of the present invention. The compounds of this teaching can be prepared from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, according to the procedures outlined herein, using standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and the transformation and manipulation of functional groups are readily available from relevant scientific literature or standard textbooks in the art.

[0166] It should be understood that, unless otherwise stated, other process conditions may be used even when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and sequence of the presented synthetic steps can be altered for the purpose of optimizing the formation of the compounds described herein.

[0167] The process described herein can be monitored using any suitable method known in the art. For example, product formation can be monitored using spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) Monitoring can be performed using infrared spectroscopy, spectrophotometry (e.g., UV-Vis), mass spectrometry, or chromatographic methods such as high-performance liquid chromatography (HPLC), gas chromatography (GC), gel permeation chromatography (GPC), or thin-layer chromatography (TLC).

[0168] The preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of suitable protecting groups, can be readily determined by those skilled in the art. The chemical properties of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 2nd edition (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference for all purposes.

[0169] The reactions or methods described herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. At the temperatures at which the reaction takes place, i.e., within the range of the solvent's freezing temperature to its boiling temperature, suitable solvents generally do not react substantially with the reactants, intermediates, and / or products. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a suitable solvent can be selected for that particular reaction step.

[0170] Compound (I) can be prepared from commercially available or previously documented starting materials according to the synthetic methods outlined, for example, in Scheme 1. The (un)substituted isoquinoline-1(2H)-one (II) can be commercially available or synthesized according to the methods outlined, for example, in Tetrahedron, 2002, 58:5761-5766. In a non-limiting example, perbrominated pyridine is used as described in J. Med. Chem., 2014, 57:1299-1322. N-bromosuccinimide bromide II, as described in Angew. Chem. Int. Ed., 2011, 50:8416-8419, provides III. In a non-limiting example, as described in Bioorg. Med. Chem. Lett., 2017, 27:217-222, III is chlorinated with phosphoryl chloride, followed, in a non-limiting example, as exemplified in WO200472033, the chloride is replaced with, for example, an alcohol in the presence of a base (Y=O), to provide IV. Exchange of a halide metal with the heteroaryl bromide of IV, followed by quenching of the resulting heteroaryl anion with a suitable electrophile, such as, but not limited to, DMF, carbon dioxide, dialkyl dicarbonate, acid anhydrides, aldehydes, ketones, and / or Weinreb amides, or treatment of bromine using transition metal catalytic coupling techniques, provides V. Reductive alkylation of V subsequently provides VI. When V is an aldehyde or ketone, reductive alkylation can be achieved by reacting the compound with a primary amine to form an imine, which is then reacted with a reducing agent such as, but not limited to, sodium borohydride, or a carbon-based nucleophile such as, but not limited to, a Grignard reagent or an alkyl / aryl lithium. Alternatively, when V is an aldehyde or ketone, reductive alkylation can be achieved by reacting the compound with a primary sulfinamide to form a sulfinimine, which is then reacted with a reducing agent such as, but not limited to, sodium borohydride, or a carbon-based nucleophile such as, but not limited to, a Grignard reagent or an alkyl / aryl lithium. In some embodiments, the primary sulfinamide may be racemic, scaly, or enantiopure, and may be used to influence the stereochemical outcome of the reduction of the sulfinimine. In the presence of a base such as, but not limited to, sodium hydride, the resulting secondary sulfinamide may be further functionalized with an electrophile such as, but not limited to, an alkyl halide, and the sulfonamido may be removed to provide VI. Under certain conditions, the removal of the sulfinylamino group can be accompanied by R'-dealkylation to directly provide VIII. Alternatively, when V is an aldehyde or ketone, the compound can be reduced to the corresponding primary or secondary alcohol using a reducing agent such as, but not limited to, sodium borohydride. The primary or secondary alcohol can be functionalized, for example, with p-toluenesulfonyl chloride to provide the corresponding toluenesulfonate, or converted to an alkyl halide using, for example, thionyl chloride, and subsequently reacted with a primary amine to provide VI. Functionalization of VI with various electrophilic agents (e.g., isocyanates) provides VII. Alternatively, acid-mediated O-dealkylation (Y=O) of VI using, for example, hydrochloric acid or hydrobromic acid provides VIII, which can be functionalized with various electrophilic agents such as isocyanates to provide IX. Alternatively, ketone XX can be synthesized from bromoisoquinolinone III via palladium-catalyzed coupling with vinyltinane followed by hydrolysis to obtain an enol ether. Reductive alkylation using a primary amine can then provide VIII, which can be functionalized to provide IX (Scheme 2).Examples of the synthesis of representative compounds of the present invention are incorporated herein by way of illustration. Similar compounds can be synthesized in a manner similar to those illustrated using appropriately substituted intermediates and reagents.

[0171]

[0172] method

[0173] This invention provides a method for treating or preventing hepatitis virus infection in a subject. In some embodiments, the infection includes hepatitis B virus (HBV) infection. In other embodiments, and still others, the method includes administering a therapeutically effective amount of at least one compound of the invention to a subject in need of it. In still others, at least one compound of the invention is the only antiviral agent administered to the subject. In still others, at least one compound is administered to the subject in a pharmaceutically acceptable composition. In still others, at least one additional agent for treating hepatitis infection is further administered to the subject. In still others, at least one additional agent comprises at least one agent selected from reverse transcriptase inhibitors; capsid inhibitors; cccDNA formation inhibitors; RNA destabilizers; oligonucleotides targeting the HBV genome; immune enhancers, such as checkpoint inhibitors (e.g., PD-L1 inhibitors); and GalNAc-siRNA conjugates targeting the HBV gene transcriptome. In still others, at least one compound and at least one additional agent are co-administered to the subject. In still others, at least one compound and at least one additional agent are co-formulated.

[0174] The present invention further provides a method for directly or indirectly inhibiting the expression and / or function of viral capsid proteins in a subject. In some embodiments, the method includes administering a therapeutically effective amount of at least one compound of the present invention to a subject in need of it. In other embodiments, at least one compound is administered to the subject in a pharmaceutically acceptable composition. In still other embodiments, at least one compound of the present invention is the sole antiviral agent administered to the subject. In still other embodiments, at least one additional agent for treating HBV infection is further administered to the subject. In still other embodiments, at least one additional agent comprises at least one agent selected from reverse transcriptase inhibitors; capsid inhibitors; cccDNA formation inhibitors; RNA destabilizers; oligonucleotides targeting the HBV genome; immune enhancers, such as checkpoint inhibitors (e.g., PD-L1 inhibitors); and GalNAc-siRNA conjugates targeting the HBV gene transcriptome. In still other embodiments, at least one compound and at least one additional agent are co-administered to the subject. In still other embodiments, at least one compound and at least one additional agent are co-formulated.

[0175] In some implementations, the subject is a mammal. In other implementations, the mammal is a human.

[0176] Pharmaceutical compositions and formulations

[0177] This invention provides pharmaceutical compositions comprising at least one compound of the present invention or a salt or solvation thereof, for use in practicing the methods of the present invention. Such pharmaceutical compositions may consist of at least one compound of the present invention, or a salt or solvation thereof, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least one compound of the present invention, or a salt or solvation thereof, and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or any combination thereof. As is well known in the art, at least one compound of the present invention may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, such as in combination with a physiologically acceptable cation or anion.

[0178] In some embodiments, the pharmaceutical composition used in practicing the methods of the present invention may be administered to deliver a dose between 1 ng / kg / day and 100 mg / kg / day. In other embodiments, the pharmaceutical composition used in practicing the present invention may be administered to deliver a dose between 1 ng / kg / day and 1,000 mg / kg / day.

[0179] The relative amounts of the active ingredient, pharmaceutically acceptable carrier, and any other components in the pharmaceutical compositions of the present invention will vary depending on the identity, size, and condition of the subject being treated, and further on the route of administration of the composition. For example, the composition may include the active ingredient in amounts between 0.1% and 100% (w / w).

[0180] The pharmaceutical compositions used in the methods of the present invention can be suitably developed for administration via nasal, inhalation, oral, rectal, vaginal, pleural, peritoneal, parenteral, topical, percutaneous, pulmonary, intranasal, sublingual, intraocular, epidural, intrathecal, intravenous, or other routes of administration. The compositions used in the methods of the present invention can be administered directly to the brain, brainstem, or any other part of the central nervous system of mammals or birds. Other formulations considered include projected nanoparticles, microspheres, liposome formulations, coated particles, polymer conjugates, resealed red blood cells containing the active ingredient, and immunologically based formulations.

[0181] In some embodiments, the compositions of the present invention are part of a pharmaceutical matrix that allows for the processing of insoluble materials and improvement of their bioavailability, development of controlled-release or sustained-release products, and the production of homogeneous compositions. For example, pharmaceutical matrices can be prepared using hot melt extrusion, solid solutions, solid dispersions, size reduction techniques, molecular complexes (e.g., cyclodextrins), microparticles, and particle and formulation coating methods. Amorphous or crystalline phases can be used in such processes.

[0182] The route of administration (one or more) is obvious to the technician and will depend on many factors, including the type and severity of the disease being treated, the type and age of the veterinary or human patient being treated, etc.

[0183] The formulations of the pharmaceutical compositions described herein can be prepared by any method known or subsequently developed in the fields of pharmacology and pharmaceutical science. Typically, such preparation methods involve the following steps: combining the active ingredient with a carrier or one or more other auxiliary ingredients, and then, if necessary or desired, shaping or packaging the product into the desired single-dose or multi-dose units.

[0184] As used herein, a “unit dose” is a pharmaceutical composition comprising a discrete amount of a predetermined amount of active ingredient. The amount of active ingredient is typically equal to the dose of active ingredient to be administered to a subject, or a convenient portion of such a dose, such as, for example, half or one-third of such a dose. The unit dosage form may be one of a single-dose daily dose or a multiple-dose daily dose (e.g., about 1 to 4 or more times per day). When using multiple-dose daily doses, the unit dosage form for each administration may be the same or different.

[0185] Although the description of the pharmaceutical compositions provided herein is primarily directed toward pharmaceutical compositions suitable for ethical administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to a wide variety of animals. Modifications to pharmaceutical compositions suitable for human administration are well known to make them suitable for administration to a wide variety of animals, and such modifications can be designed and performed by a veterinary pharmacist of ordinary skill through routine experiments. Subjects intended to administer the pharmaceutical compositions of the present invention include, but are not limited to, humans and other primates, mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs.

[0186] In some embodiments, the compositions of the present invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In some embodiments, the pharmaceutical compositions of the present invention comprise a therapeutically effective amount of at least one compound of the present invention and a pharmaceutically acceptable carrier. Useful pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, saline, ethanol, recombinant human albumin (e.g., ), soluble gels (e.g., Other pharmaceutically acceptable salt solutions, such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

[0187] The carrier can be a solvent or dispersion medium, comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), recombinant human albumin, soluble gelatin, suitable mixtures thereof, and vegetable oils. For example, coatings such as lecithin can be used to maintain the desired particle size in the presence of a dispersion, and suitable flowability can be maintained by using surfactants. Microbial action can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, the composition includes isotonic agents, such as sugars, sodium chloride, or polyols, such as mannitol and sorbitol. Extended absorption of injectable compositions can be achieved by including agents that delay absorption, such as aluminum monostearate or gelatin, in the composition.

[0188] The formulations can be mixed with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, inhalation, intravenous, subcutaneous, transdermal enteric, or any other suitable route of administration known in the art. The pharmaceutical formulations can be sterilized and, if desired, can be mixed with excipients such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, colorants, flavoring agents, and / or aroma-imparting substances. They can also be combined with other active agents, such as other analgesics, anxiolytics, or hypnotics, when desired. As used herein, “additional ingredients” include, but are not limited to, one or more ingredients that can be used as a drug carrier.

[0189] The compositions of the present invention may include from about 0.005% to 2.0% preservatives by weight of the total composition. In the event of exposure to environmental contaminants, the preservatives serve to prevent deterioration. Examples of preservatives useful according to the present invention include, but are not limited to, those selected from benzyl alcohol, sorbic acid, p-hydroxybenzoic acid, imidurium, and any combination thereof. One such preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05-0.5% sorbic acid.

[0190] The composition may include antioxidants and chelating agents that inhibit the degradation of the compound. For some compounds, the antioxidants are BHT, BHA, α-tocopherol, and ascorbic acid, in exemplary ranges of about 0.01% to 0.3% by weight of the total composition, or BHT in the range of 0.03% to 0.1% by weight. The amount of chelating agent present may be 0.01% to 0.5% by weight of the total composition. Exemplary chelating agents include ethylenediaminetetraacetic acid (e.g., disodium ethylenediaminetetraacetate) and citric acid in the range of about 0.01% to 0.20% by weight or in the range of 0.02% to 0.10% by weight of the total composition. Chelating agents can be used to chelate metal ions in the composition, which may be detrimental to the shelf life of the formulation. For some compounds, although BHT and disodium ethylenediaminetetraacetate are exemplary antioxidants and chelating agents, as those skilled in the art will know, other suitable and equivalent antioxidants and chelating agents may be substituted.

[0191] Liquid suspensions can be prepared using conventional methods to suspend the active ingredient in an aqueous or oily medium. Aqueous media include, for example, water and isotonic saline. Oily media include, for example, almond oil, oily esters, ethanol, vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further include one or more additional components, including but not limited to suspending agents, dispersants or wetting agents, emulsifiers, modifiers, preservatives, buffers, salts, flavoring agents, coloring agents, and sweeteners. Oily suspensions may further include thickeners. Known suspending agents include, but are not limited to, sorbitol syrups, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragali, gum arabic, and cellulose derivatives such as sodium carboxymethyl cellulose, methylcellulose, and hydroxypropyl methylcellulose. Known dispersants or wetting agents include, but are not limited to, naturally occurring phospholipids such as lecithin, and condensation products of olefinic oxygen with fatty acids, with long-chain aliphatic alcohols, with esters derived from fatty acids and hexitols, or with esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene stearate, heptadecetylacetyl cetyl alcohol, polyoxyethylene sorbitan monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifiers include, but are not limited to, lecithin, gum arabic, and ionic or nonionic surfactants. Known preservatives include, but are not limited to, methylparaben, ethylparaben, or n-propylparaben, ascorbic acid, and sorbic acid. Known sweeteners include, for example, glycerin, propylene glycol, sorbitol, sucrose, and saccharin.

[0192] Liquid solutions of active ingredients in aqueous or oily solvents can be prepared in essentially the same manner as liquid suspensions, the main difference being that the active ingredient is dissolved rather than suspended in the solvent. As used herein, an "oily" liquid is a liquid comprising carbon-containing liquid molecules and exhibiting less polarity than water. Liquid solutions of the pharmaceutical compositions of the present invention may contain each of the components described with respect to liquid suspensions; it should be understood that a suspending agent does not necessarily aid in the dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethanol, vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

[0193] Powdered and granular formulations of the pharmaceutical preparations of the present invention can be prepared using known methods. Such formulations can be administered directly to a subject, for example, for forming tablets, filling capsules, or for preparing aqueous or oily suspensions or solutions by adding an aqueous or oily medium. Each of these formulations may further include one or more of dispersants or wetting agents, suspending agents, ionic and nonionic surfactants, and preservatives. Additional excipients, such as fillers and sweeteners, flavoring agents, or coloring agents, may also be included in these formulations.

[0194] The pharmaceutical compositions of the present invention can also be prepared, packaged, or sold in the form of oil-in-water emulsions or water-in-oil emulsions. The oil phase can be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a combination thereof. Such compositions may further comprise one or more emulsifiers, such as naturally occurring gums such as gum arabic or gum tragali; naturally occurring phospholipids such as soybean or lecithin; esters or metaesters derived from combinations of fatty acids and hexyl anhydrides, such as sorbitan monooleate, and condensation products of such metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients, including, for example, sweeteners or flavorings.

[0195] Methods of impregnating or coating materials with chemical compositions are known in the art, and include, but are not limited to, methods of depositing or incorporating chemical compositions onto surfaces, methods of incorporating chemical compositions into the material structure during the synthesis of materials (i.e., using physiologically degradable materials), and methods of absorbing aqueous or oily solutions or suspensions into absorbent materials, followed by drying or without drying. Methods of mixing components include physical grinding, the use of pellets in solid and suspension formulations, and mixing in transdermal patches, as known to those skilled in the art.

[0196] Application / Dosage

[0197] The dosing regimen may affect the composition of the effective dose. The therapeutic agent may be administered to the patient before or after the onset of the disease or disorder. Furthermore, several separate doses may be administered daily or sequentially, as well as alternating doses, or the dose may be administered continuously by infusion or by bolus injection. Additionally, the dose of the therapeutic agent may be increased or decreased proportionally depending on the urgency of the treatment or prevention situation.

[0198] The compositions of the present invention can be administered to patients, such as mammals, such as humans, at doses and durations appropriate for the effective treatment of the diseases or disorders considered herein, using known procedures. The effective amount of the therapeutic compound necessary to achieve a therapeutic effect can vary depending on factors such as the activity of the specific compound used; the time of administration; the rate of excretion of the compound; the duration of treatment; other drugs, compounds, or materials used in combination with the compound; the state of the disease or disorder; the age, sex, weight, condition, general health status, and medical history of the patient being treated; and similar factors well known in the medical field. Dosing regimens can be adjusted to provide an optimal therapeutic response. For example, as indicated by an emergency situation in the treatment, several separate doses may be administered daily, or the dose may be proportionally reduced. A non-limiting example of an effective dose range for the therapeutic compounds of the present invention is from about 0.01 mg / kg to 100 mg / kg body weight per day. Those skilled in the art will be able to investigate the relevant factors and determine the effective amount of the therapeutic compound without excessive experimentation.

[0199] The compound can be administered to animals frequently, several times a day, or less frequently, such as once daily, once a week, once every two weeks, once a month, or even less frequently, such as once every few months, or even once a year or less. It should be understood that, in non-limiting instances, the amount of the compound administered daily can be once daily, every other day, every two days, every three days, every four days, or every five days. For example, once-every-other-day administration could begin with a 5 mg daily dose on Monday, followed by the first subsequent 5 mg daily dose on Wednesday, the second subsequent 5 mg daily dose on Friday, and so on. The frequency of dosing is obvious to a person skilled in the art and depends on many factors, such as, but not limited to, the type and severity of the disease being treated and the type and age of the animal.

[0200] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be changed to obtain an amount of active ingredient that effectively achieves the therapeutic response required for a particular patient, composition, and route of administration, while being non-toxic to the patient.

[0201] Physicians or veterinarians with common skills in the art can readily determine and prescribe the required effective amount of the pharmaceutical composition. For example, a physician or veterinarian may begin with a dose of the compound of the invention used in the pharmaceutical composition at a level lower than required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0202] In specific embodiments, formulating compounds in dosage units is particularly advantageous for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suitable as a unit dose for a patient to be treated; each unit contains a predetermined amount of the therapeutic compound, which is calculated to bind with a desired drug carrier to produce the desired therapeutic effect. The dosage unit form of the present invention is determined by and directly depends on (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the field of formulating / preparing such therapeutic compounds for treating a patient's disease or disorder.

[0203] In some embodiments, the compositions of the present invention are administered to a patient at doses ranging from 1 to 5 times or more per day. In other embodiments, the compositions of the present invention are administered to a patient at doses ranging from once daily, once every two days, once every three days to once a week, and once every two weeks. It will be apparent to those skilled in the art that the frequency of administration of the various combinations of the present invention will vary from subject to subject, depending on many factors, including but not limited to age, disease or disorder to be treated, sex, overall health condition, and other factors. Therefore, the present invention should not be construed as limited to any particular dosage regimen, and the precise dose and composition to be administered to any patient will be determined by the attending physician taking into account all other factors of the patient.

[0204] The compounds of the present invention used for application may be in the following ranges: about 1 μg to about 7,500 mg, about 20 μg to about 7,000 mg, about 40 μg to about 6,500 mg, about 80 μg to about 6,000 mg, about 100 μg to about 5,500 mg, about 200 μg to about 5,000 mg, about 400 μg to about 4,000 mg, about 800 μg to about 3,000 mg, about 1 mg to about 2,500 mg, about 2 mg to about 2,000 mg, about 5 mg to about 1,000 mg, about 10 mg to about 750 mg, about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about 150 mg, and any full and partial increments therebetween.

[0205] In some embodiments, the dosage of the compound of the present invention is about 0.5 μg and about 5,000 mg. In some embodiments, the dosage of the compound of the present invention used in the compositions described herein is less than about 5,000 mg, or less than about 4,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dosage of the second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any full and partial increments thereof.

[0206] In some embodiments, the present invention relates to packaged pharmaceutical compositions comprising a container holding a therapeutically effective amount of the compound of the present invention, alone or in combination with a second drug; and instructions for using the compound to treat, prevent, or alleviate one or more symptoms of a patient’s disease or disorder.

[0207] The term "container" includes any receptor used to contain a pharmaceutical composition or to manage stability or water absorption. For example, in some embodiments, a container is a package containing a pharmaceutical composition, such as a liquid (solution and suspension), semi-solid, lyophilized solid, solution, powder, or lyophilized formulation present in a two-chamber container. In other embodiments, a container is not a package containing a pharmaceutical composition; that is, a container is a receptor, such as a box or vial containing a packaged or unpackaged pharmaceutical composition and instructions for use of the pharmaceutical composition. Furthermore, packaging techniques are well known in the art. It should be understood that instructions for use of the pharmaceutical composition may be included on the package containing the pharmaceutical composition, and thus, the instructions for use form an additional functional relationship with the packaged product. However, it should be understood that the instructions for use may contain information about the compound's ability to perform its intended function, such as treating, preventing, or alleviating a patient's disease or disorder.

[0208] application

[0209] The routes of administration for any composition of the present invention include inhalation, oral administration, nasal administration, rectal administration, parenteral administration, sublingual administration, transdermal administration, transmucosal administration (e.g., sublingual, lingual, sublingual, urethral, ​​vaginal administration (e.g., vaginal and perivasal), nasal administration and rectal administration, intravesical administration, intrapulmonary administration, intraduodenal administration, intragastric administration, intrathecal administration, intrathecal administration, intradural administration, intrapleural administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intradermal administration, intraarterial administration, intravenous administration, intrabronchial administration, inhalation, and topical administration.

[0210] Suitable compositions and dosage forms include, for example, tablets, capsules, pouches, pills, soft capsules, lozenges, emulsions, dispersants, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, emulsions (magma), lozenges, creams, pastes, plasters, lotions, tablets (discs), suppositories, liquid sprays for nasal or oral administration, dry powder or nebulized formulations for inhalation, and compositions and formulations for intravesical administration. It should be understood that the formulations and compositions that can be used in this invention are not limited to the specific formulations and compositions described herein.

[0211] Oral administration

[0212] For oral administration, tablets, lozenges, liquids, drops, capsules, pouches, and soft capsules are particularly suitable. Other formulations suitable for oral administration include, but are not limited to, powder or granule formulations, aqueous or oily suspensions, aqueous or oily solutions, pastes, gels, toothpastes, mouthwashes, coatings, oral rinsings, or emulsions. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions may contain one or more agents selected from inert, non-toxic, and generally considered safe (GRAS) pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate.

[0213] Tablets may be uncoated or coated using known methods to achieve delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. For example, tablets may be coated using materials such as glyceryl monostearate or glyceryl distearate. Further, tablets may be coated using methods described in U.S. Patent Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotic controlled-release tablets. Tablets may further contain sweeteners, flavoring agents, coloring agents, preservatives, or some combination thereof to provide a pharmaceutically elegant and palatable formulation. Hard capsules containing the active ingredient may be prepared using physiologically degradable compositions such as gelatin. Capsules contain the active ingredient and may further include additional components, including, for example, inert solid diluents such as calcium carbonate, calcium phosphate, or kaolin.

[0214] Hard capsules containing active ingredients can be prepared using physiologically degradable compositions such as gelatin. These hard capsules contain the active ingredients and may further include additional components, such as inert solid diluents like calcium carbonate, calcium phosphate, or kaolin.

[0215] Soft capsules containing active ingredients can be prepared using physiologically degradable compositions such as gelatin derived from animal collagen or hydroxypropyl methylcellulose (a modified form of cellulose), and manufactured using an optional mixture of gelatin, water, and plasticizers such as sorbitol or glycerin. Such soft capsules contain active ingredients that can be mixed with an aqueous or oily medium such as peanut oil, liquid paraffin, or olive oil.

[0216] For oral administration, the compounds of the present invention may be in the form of tablets or capsules prepared by conventional methods with pharmaceutically acceptable excipients such as binders, fillers, lubricants, disintegrants, or wetting agents. If desired, suitable methods and coating materials may be used, for example, those available from Colorcon, West Point, Pa. (e.g., OY type, OYC type, organic enteric-coated OY-P type, water-based enteric-coated OY-A type, OY-PM type and White, 32K18400) The film coating system coats tablets. It should be understood that similar types of film coatings or polymer products from other companies can be used.

[0217] Tablets containing an active ingredient can be prepared, for example, by compression or molding the active ingredient, optionally together with one or more other ingredients. Compressed tablets can be prepared by compressing the active ingredient, in a free-flowing form such as a powder or granules, in a suitable apparatus, optionally mixed with one or more binders, lubricants, excipients, surfactants, and dispersants. Molded tablets can be prepared by molding a mixture of the active ingredient, a pharmaceutically acceptable carrier, and a liquid sufficient to wet the mixture in a suitable apparatus. Pharmaceutically acceptable excipients for manufacturing tablets include, but are not limited to, inert diluents, granulators and disintegrants, binders, and lubricants. Known dispersants include, but are not limited to, potato starch and sodium hydroxymethyl starch. Known surfactants include, but are not limited to, sodium lauryl sulfate. Known diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, dicalcium phosphate, and sodium phosphate. Known granulators and disintegrants include, but are not limited to, corn starch and alginic acid. Known binders include, but are not limited to, gelatin, gum arabic, pregelatinized corn starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Known lubricants include, but are not limited to, magnesium stearate, stearic acid, silica, and talc.

[0218] Granulation technology is well-known in the pharmaceutical industry for modifying starting powders or other particulate materials of active ingredients. The process of mixing powder with a binder material to form larger, permanently free-flowing agglomerates or particles is generally called "granulation." For example, a typical characteristic of a solvent-based "wet" granulation process is that powder is mixed with a binder material and wetted under certain conditions with water or an organic solvent to form wet granular material, from which the solvent must then be evaporated.

[0219] Melt granulation typically involves granulating powders or other materials using materials that are solid or semi-solid at room temperature (i.e., have a relatively low softening or melting point range) without the addition of water or other liquid solvents. When heated to a temperature within the melting point range, the low-melting-point solid liquefies to act as a binder or granulation medium. The liquefied solid disperses itself onto the surface of the powdery material it contacts and, upon cooling, forms solid granular material in which the initial material is bound together. The resulting melt granules can then be fed to a tableting machine or encapsulated to prepare oral dosage forms. Melt granulation improves the dissolution rate and bioavailability of active substances (i.e., drugs) by forming solid dispersions or solid solutions.

[0220] U.S. Patent No. 5,169,645 discloses directly compressible wax-containing particles with improved flow properties. Particles are obtained by mixing wax with certain flow-improving additives in a melt, then cooling and granulating the mixture. In some embodiments, only the wax itself melts in the molten composition of the wax (one or more) and the additive (one or more), while in other cases, both the wax (one or more) and the additive (one or more) melt.

[0221] The present invention also includes multilayer tablets comprising a layer providing a delayed release of one or more compounds useful in the methods of the present invention, and other layers providing an immediate release of one or more compounds useful in the methods of the present invention. Using a wax / pH-sensitive polymer mixture, a gastric insoluble composition can be obtained, in which the active ingredient is entrapped, thereby ensuring its delayed release.

[0222] Liquid formulations for oral administration can be in the form of solutions, syrups, or suspensions. Liquid formulations can be prepared using conventional methods with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous mediators (e.g., almond oil, oily esters, or ethanol); and preservatives (e.g., methylparaben, propylparaben, or sorbic acid). Liquid formulations of the pharmaceutical compositions of the present invention suitable for oral administration can be prepared, packaged, and sold in liquid form or as a dried product intended to be reconstituted with water or another suitable carrier prior to use.

[0223] External application

[0224] As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical destruction of the subject’s tissues and administration of the pharmaceutical composition through destruction of the tissues. Therefore, parenteral administration includes, but is not limited to, administration of the pharmaceutical composition by injection, administration through a surgical incision, administration through a non-surgical wound that penetrates tissue. In particular, parenteral administration is intended to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection, and renal dialysis infusion techniques.

[0225] Formulations of pharmaceutical compositions suitable for parenteral administration include an active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations can be prepared, packaged, or marketed in a form suitable for bolus or continuous administration. Injectable formulations can be prepared, packaged, or marketed in unit dosage forms, such as ampoules containing preservatives or multi-dose containers. Injectable formulations can also be prepared, packaged, or marketed in devices such as patient-controlled analgesia (PCA) devices. Parenteral administration formulations include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous media, ointments, and implantable sustained-release or biodegradable formulations. Such formulations may further contain one or more additional ingredients, including, but not limited to, suspending agents, stabilizers, or dispersants. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e., powder or granules) form to be reconstituted with a suitable media (e.g., sterile pyrogen-free water), and then the reconstituted composition is administered parenterally.

[0226] Pharmaceutical compositions can be prepared, packaged, or sold as sterile, injectable aqueous or oily suspensions or solutions. These suspensions or solutions can be formulated according to known techniques and may contain additional components besides the active ingredient, such as dispersants, wetting agents, or suspending agents as described herein. Such sterile injectable formulations can be prepared using non-toxic, parenterally acceptable diluents or solvents, such as, for example, water or 1,3-butanediol. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and non-volatile oils such as synthetic monoglycerides or diglycerides. Other useful parenterally applicable formulations include those containing an active ingredient in microcrystalline form as a component of recombinant human albumin, fluidized gelatin, liposome formulations, or biodegradable polymer systems. Compositions for sustained release or implantation may include pharmaceutically acceptable polymers or hydrophobic materials, such as emulsions, ion exchange resins, microsoluble polymers, or microsoluble salts.

[0227] Topical application

[0228] The barrier to topical drug formulations is the stratum corneum of the epidermis. The stratum corneum is a highly resistant layer composed of proteins, cholesterol, sphingolipids, free fatty acids, and various other lipids, and includes keratinized cells and living cells. One factor limiting the permeability (flux) of compounds across the stratum corneum is the amount of active substance that can be loaded or applied to the skin surface. The greater the amount of active substance applied per unit area of ​​skin, the greater the concentration gradient between the skin surface and the subcutaneous layer, and consequently, the greater the diffusion force of the active substance across the skin. Therefore, formulations containing higher concentrations of active substances are more likely to result in more active substances penetrating the skin at a more consistent rate compared to formulations with lower concentrations, all other things being equal.

[0229] Formulations suitable for topical application include, but are not limited to, liquid or semi-liquid formulations, such as liniments, lotions, oil-in-water or water-in-oil emulsions, such as creams, ointments, or pastes, as well as solutions or suspensions. Although the concentration of the active ingredient may be the same as the solubility limit of the active ingredient in the solvent, a formulation suitable for topical application may, for example, include about 1% to about 10% (w / w) of the active ingredient. Formulations for topical application may further include one or more of the additional ingredients described herein.

[0230] Penetration enhancers can be used. These materials increase the rate at which drugs penetrate the skin. Typical enhancers in the art include ethanol, glyceryl monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, etc. Other enhancers include oleic acid, oleyl alcohol, ethoxyethylene glycol, lauryl ketone, alkyl carboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone.

[0231] An acceptable medium for local delivery of some of the compositions of the present invention may comprise liposomes. The composition of liposomes and their uses are known in the art (i.e., U.S. Patent No. 6,323,219).

[0232] In optional embodiments, the topical active pharmaceutical composition may optionally be combined with other ingredients such as adjuvants, antioxidants, chelating agents, surfactants, foaming agents, wetting agents, emulsifiers, thickeners, buffers, preservatives, etc. In other embodiments, a penetration enhancer or permeation improver is included in the composition and is effective for improving the penetration of the active ingredient into the skin and across the stratum corneum compared to a composition lacking a penetration enhancer. Various penetration enhancers, including oleic acid, oleyl alcohol, ethoxyethylene glycol, lauryl azone, alkanolide, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone, are known to those skilled in the art. In another aspect, the composition may further contain a water-soluble adjuvant that increases the disorder of the stratum corneum structure and thus allows for increased transport across the stratum corneum. Various water-soluble adjuvants, such as isopropanol, propylene glycol, or sodium xylenesulfonate, are known to those skilled in the art.

[0233] The topical active pharmaceutical composition should be applied in an amount that effectively affects the desired change. As used herein, "effective amount" means an amount sufficient to cover the skin surface area requiring alteration. The active compound should be present in an amount of about 0.0001% to about 15% by weight and volume of the composition. For example, it should be present in an amount of about 0.0005% to about 5% of the composition; for example, it should be present in an amount of about 0.001% to about 1% of the composition. Such compounds may be synthetic or natural.

[0234] Sublingual administration

[0235] The pharmaceutical compositions of the present invention can be prepared, packaged, or sold as formulations suitable for sublingual administration. Such formulations may be, for example, in the form of tablets or lozenges prepared using conventional methods, and may contain, for example, 0.1 to 20% (w / w) of the active ingredient, the balance comprising an orally soluble or biodegradable composition, and optionally one or more additional ingredients described herein. Optionally, formulations suitable for sublingual administration may comprise a powder, aerosolized, or atomized solution, or suspension containing the active ingredient. When dispersed, such powdered, aerosolized, or atomized formulations may have an average particle or droplet size in the range of about 0.1 to about 200 nanometers, and may further comprise one or more additional ingredients described herein. The examples of formulations described herein are not exhaustive, and it should be understood that the invention includes additional modifications of these and other formulations not described herein but known to those skilled in the art.

[0236] Rectal administration

[0237] The pharmaceutical compositions of the present invention can be prepared, packaged, or sold in formulations suitable for rectal administration. Such compositions may be in the form of, for example, suppositories, retention enema formulations, and solutions for rectal or colonic irrigation.

[0238] Suppositories can be prepared by mixing the active ingredient with a non-irritating, pharmaceutically acceptable excipient that is solid at normal room temperature (i.e., about 20°C) and liquid at the rectal temperature of the subject (i.e., about 37°C in a healthy human body). Suitable pharmaceutically acceptable excipients include, but are not limited to, cocoa butter, polyethylene glycol, and various glycerides. Suppositories may further contain a variety of additional ingredients, including but not limited to antioxidants and preservatives.

[0239] Retention enema formulations or solutions for rectal or colonic lavage can be prepared by mixing the active ingredient with a pharmaceutically acceptable liquid carrier. As is well known in the art, the enema formulation can be administered using a delivery device adapted to the rectal anatomy of the subject, and the enema formulation can be packaged in the delivery device. The enema formulation may further contain a variety of additional ingredients, including but not limited to antioxidants and preservatives.

[0240] Other forms of application

[0241] Further dosage forms of the present invention include those described in U.S. Patent Nos. 6,340,475, 6,488,962, 6,451,808, 5,972,389, 5,582,837, and 5,007,790. Further dosage forms of the present invention also include those described in U.S. Patent Application Nos. 20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and 20020051820. Other dosage forms of the present invention include those described in PCT application numbers WO 03 / 35041, WO03 / 35040, WO 03 / 35029, WO 03 / 35177, WO 03 / 35039, WO 02 / 96404, WO 02 / 32416, WO 01 / 97783, WO 01 / 56544, WO 01 / 32217, WO 98 / 55107, WO 98 / 11879, WO 97 / 47285, WO 93 / 18755 and WO 90 / 11757.

[0242] Controlled-release formulations and drug delivery systems:

[0243] In some embodiments, the compositions and / or formulations of the present invention may be, but are not limited to, short-term, rapid-compensation, and controlled, such as sustained-release, delayed-release, and pulsatile-release formulations.

[0244] The term sustained release, in its conventional sense, refers to a pharmaceutical preparation that releases the drug gradually over an extended period of time, although not necessarily, but which results in a substantially constant blood level of the drug over that extended period. This period can be as long as a month or longer, and should be longer than the release achieved by administering the same amount via bolus injection.

[0245] For sustained release, the compound can be formulated with a suitable polymer or hydrophobic material that provides sustained release properties. Thus, the compound used in the method of the present invention can be administered in particulate form by, for example, injection, or in wafer or disc form by implantation.

[0246] In some embodiments of the present invention, a sustained-release formulation is used to administer the useful compounds of the present invention, alone or in combination with another pharmaceutical formulation, to a subject.

[0247] The term delayed release, in its conventional sense, refers to a pharmaceutical preparation that provides the initial release of the drug after a certain delay following drug administration, and although not mandatory, may range from about 10 minutes to about 12 hours.

[0248] In its conventional sense, the term pulsed release refers to a pharmaceutical formulation that delivers drug release in a manner that produces a pulsed plasma distribution after drug administration.

[0249] The term immediate release, in its conventional sense, refers to a pharmaceutical preparation that delivers the drug immediately after administration.

[0250] As used herein, "short term" means any time period following drug administration, up to and including approximately 8 hours, approximately 7 hours, approximately 6 hours, approximately 5 hours, approximately 4 hours, approximately 3 hours, approximately 2 hours, approximately 1 hour, approximately 40 minutes, approximately 20 minutes, or approximately 10 minutes after drug administration, and any or all of these whole or partial increments.

[0251] As used herein, rapid compensation refers to any time period following drug administration, up to and including approximately 8 hours, approximately 7 hours, approximately 6 hours, approximately 5 hours, approximately 4 hours, approximately 3 hours, approximately 2 hours, approximately 1 hour, approximately 40 minutes, approximately 20 minutes, or approximately 10 minutes, as well as any full and partial increments thereof.

[0252] Using only conventional experiments, those skilled in the art will recognize or be able to identify many equivalents of the specific procedures, implementation methods, claims, and embodiments described herein. Such equivalents are considered to be within the scope of the invention and are covered by the appended claims. For example, it should be understood that modifications to reaction time, reaction size / volume, and experimental reagents such as solvents, catalysts, pressure, atmospheric conditions such as nitrogen atmosphere, and reaction conditions involving reducing agents / oxidizing agents, using alternatives recognized in the art and employing only conventional experiments, are all within the scope of this application.

[0253] It should be understood that wherever numerical values ​​and ranges are provided herein, the description of the range format is for convenience and brevity only and should not be construed as a rigid limitation on the scope of the invention. Therefore, all values ​​and ranges covered by these values ​​and ranges are intended to be covered within the scope of the invention. Furthermore, this application also considers all values ​​falling within these ranges, as well as the upper or lower limits of the range of such values. The description of the range should be considered as explicitly disclosing all possible subranges and individual numerical values ​​within that range, and, where appropriate, partial integers of the numerical values ​​within that range. For example, a description of a range from 1 to 6 should be considered as explicitly disclosing subranges from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and individual numerical values ​​within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0254] The following examples further illustrate aspects of the invention. However, they are by no means intended to limit the teachings or disclosure of the invention as set forth herein.

[0255] Example

[0256] The invention will now be described with reference to the following embodiments. These embodiments are provided for illustrative purposes only, and the invention is not limited to these embodiments, but covers all variations that will become apparent from the teachings provided herein.

[0257] Materials & Methods

[0258] The following procedure can be used to evaluate and select compounds that can inhibit hepatitis B virus infection.

[0259] HepDE19 assay using HBV rcDNA bDNA quantification:

[0260] The HepDE19 cell culture system is a HepG2 (human liver cancer) derived cell line that supports HBV DNA replication and cccDNA formation via tetracycline (Tet) regulation, and produces HBV rcDNA and detectable reporter molecules dependent on cccDNA production and maintenance (Guo et al., 2007, J.Virol. 81:12472-12484).

[0261] HepDE19 cells (50,000 cells / well) were seeded in 96-well collagen-coated microtiter plates in DMEM / F12 medium supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin, and 1 μg / mL tetracycline, and incubated overnight at 37°C and 5% CO2 under humidification. The next day, cells were transferred to fresh tetracycline-free medium and incubated at 37°C and 5% CO2 for 4 hours. Cells were then treated with fresh Tet-free medium, starting at a concentration of 25 μM, in a continuous 1 / 2 log, 8-point titration series, in duplicate. The final DMSO concentration in the assay was 0.5%. The plates were incubated for 7 days at 37°C and 5% CO2 under humidification. After 7 days of incubation, the levels of rcDNA present in inhibitor-treated wells were measured using the Quantigene 2.0bDNA assay kit (Affymetrix, Santa Clara, CA), in conjunction with a custom probe kit specific to HBV and the manufacturer's instructions. Simultaneously, the effect of the compounds on cell viability was assessed using replication plates. Plates were seeded at a density of 5,000 cells / well and incubated for 4 days to determine ATP content as a measure of cell viability using cell titer glo reagent (CTG; Promega Corporation, Madison, WI) according to the manufacturer's instructions. Plates were read using a Victor luminescence plate reader (PerkinElmer Model 1420 Multilabel counter), and the relative luminescence units (RLU) generated per well were calculated as the percentage of inhibition in untreated control wells. Analysis was performed using the XL-Fit module in Microsoft Excel to determine EC using a 4-parameter curve fitting algorithm. 50 and EC 90 (bDNA) and CC 50 The value of (CTG).

[0262] LCMS method:

[0263] LCMS Method A: Waters Acquity UPLC system, using a Waters Acquity UPLC BEH C18, 1.7 μm, 50 × 2.1 mm column, with a solvent gradient based on acetonitrile-water solution of 2-98% CH3CN / H2O (0.05% TFA) over 9.5 min. Flow rate = 0.8 mL / min.

[0264] LCMS Method B: Shimadzu UFLC system, using an ACE UltraCore Super PhenylHexyl, 2.5 μm, 50 × 2.1 mm column, with a solvent gradient based on acetonitrile-water solution of 5-100% CH3CN / H2O (0.05% formic acid) over 4.0 min, followed by maintenance in 100% CH3CN (0.05% formic acid) for 1 min. Flow rate = 1.0 mL / min.

[0265] As described herein, “enantiomer I” or “diastereomer I” refers to the first enantiomer or diastereomer that escapes from the chiral column under the specific chiral analytical conditions detailed elsewhere in this document; “enantiomer II” or “diastereomer II” refers to the second enantiomer or diastereomer that escapes from the chiral column under the specific chiral analytical conditions detailed elsewhere in this document. For these compounds, this nomenclature does not imply or assign any specific relative and / or absolute configuration.

[0266] Example 1: Compound

[0267] 4-Bromoisoquinoline-1(2H)-one (IIIa)

[0268]

[0269] At room temperature, 225 g (703 mmol, 1.02 eq.) of pyridine perbromide was added to a solution of 100.0 g (690 mmol, 1.0 eq.) isoquinoline-1(2H)-one (IIa) in 2 L of dichloromethane. Hydrobromide was added, and the mixture was stirred at room temperature for 3 hours. The mixture was then filtered, and the filtrate was alkalized with a saturated sodium bicarbonate solution. The precipitated solid was collected by filtration, washed with 4 × 500 mL of water and 2 × 400 mL of petroleum ether, and then dried under high vacuum to provide 130 g (583 mmol, 84%) of 4-bromoisoquinoline-1(2H)-one (IIIa). LCMS: m / z measured 223.9 / 225.9 [M+H] + ; 1H NMR (400MHz, CDCl3): δ10.52 (bs, 1H), 8.43 (dd, 1H), 7.89 (d, 1H), 7.78-7.82 (m, 1H), 7.57-7.61 (m, 1H), 7.41 (s, 1H).

[0270] 4-Bromo-1-chloroisoquinoline

[0271]

[0272] A solution of 100.0 g (447 mmol, 1.0 eq.) of 4-bromoisoquinoline-1(2H)-one (IIIa) in 250 mL of phosphoric acid was heated at 100 °C for 3 hours. The mixture was cooled to room temperature, and the evaporation was evaporated under reduced pressure. The residue was suspended in 1 L of ice-cold water and stirred for 10 min. The precipitated solid was collected by filtration, washed with 500 mL of water and 500 mL of petroleum ether, and dried under high vacuum to provide 96.0 g (397 mmol, 88%) of 4-bromo-1-chloroisoquinoline. LCMS: m / z measured 241.9 / 243.9; 1 H NMR (400MHz, CDCl3): δ 8.49 (s, 1H), 8.36 (d, 1H), 8.20 (d, 1H), 7.88 (dd, 1H), 7.77 (dd, 1H).

[0273] 4-Bromo-1-methoxyisoquinoline (IVa)

[0274]

[0275] At 0 °C, 32.1 g (1.19 mol, 4.0 eq.) of sodium methoxide was added in portions over approximately 30 min to a solution of 96.0 g (397 mmol, 1.0 eq.) of 4-bromo-1-chloroisoquinoline in 750 mL of methanol, and the mixture was then heated under reflux for 16 h. The mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was suspended in 2 L of ice-cold water and stirred for 10 min. The precipitated solid was collected by filtration, washed with 2 × 500 mL of water, and dried under high vacuum to provide 78 g (329 mmol, 82%) of 4-bromo-1-methoxyisoquinoline (IVa). LCMS: m / z measured 237.9 / 239.9 [M+H] + ; 1 H NMR (500MHz, CDCl3): δ 8.24-8.26 (m, 1H), 8.18 (s, 1H), 8.06 (d, 1H), 7.76-7.95 (m, 1H), 7.59-7.62 (m, 1H), 4.11 (s, 3H).

[0276] 1-Methoxyisoquinoline-4-carboxaldehyde (Va)

[0277]

[0278] Under a nitrogen atmosphere, at -78 °C, 26 mL (42.0 mmol, 2.0 eq.) of a 1.6 M n-butyllithium solution in hexane was added to a solution of 5.0 g (21.0 mmol, 1.0 eq.) of 4-bromo-1-methoxyisoquinoline (IVa) in 50 mL of anhydrous THF. The mixture was stirred at -78 °C for 1 hour, and then 6.8 mL (98.5 mmol, 4.7 eq.) of anhydrous DMF was added. The mixture was stirred at -78 °C for another 1.5 hours, and then quenched by adding 50 mL of saturated ammonium chloride solution. The mixture was diluted with 500 mL of ethyl acetate, and the layers were separated. The organic phase was washed with 200 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by rapid chromatography (SiO2, eluting with a linear gradient of 0-30% ethyl acetate / hexane) to provide 2.5 g (13.4 mmol, 64%) of 1-methoxyisoquinoline-4-carboxaldehyde (Va). LCMS: m / z determined 188.2 [M+H] + ; 1 ¹H NMR (400 MHz, CDCl₃): δ 10.16 (s, ¹H), 9.18 (d, ¹H), 8.47 (s, ¹H), 8.32 (d, ¹H), 7.82–7.99 (m, ¹H), 7.62–7.68 (m, ¹H), 4.24 (s, ³H). The above detailed reactions were performed in multiple batches at a scale of 5 grams, and the results were consistent.

[0279]

[0280] (1-Methoxyisoquinoline-4-yl)methanol (Xa)

[0281]

[0282] At 0 °C, 0.61 g (16.04 mmol, 3.0 eq.) of sodium borohydride was added to a solution of 1.0 g (5.35 mmol, 1.0 eq.) of 1-methoxyisoquinoline-4-carboxaldehyde (Va) in 20 mL of 1:1 (v / v) MeOH:THF. The mixture was heated to room temperature and stirred for 2 hours. The solvent was removed under vacuum, and the residue was purified by rapid chromatography (SiO2, eluting with a linear gradient of 0–20% ethyl acetate / hexane) to provide 0.60 g (3.17 mmol, 59%) (1-methoxyisoquinoline-4-yl)methanol (Xa). LCMS: m / z measured 190.2 [M+H]+ ; 1 H NMR (400MHz, CDCl3): δ 8.29 (d, 1H), 8.08 (d, 1H), 7.97 (s, 1H), 7.72-7.76 (m, 1H), 7.55-7.59 (m, 1H), 4.99 (m, 2H), 4.11 (s, 3H).

[0283] 4-(chloromethyl)-1-methoxyisoquinoline (XIa)

[0284]

[0285] At 0 °C, 0.4 mL (6.34 mmol, 2.0 eq.) of thionyl chloride was added to a solution of 0.6 g (3.17 mmol, 1.0 eq.) of (1-methoxyisoquinoline-4-yl)methanol (Xa) in 6 mL of dichloromethane. The mixture was heated to room temperature and stirred for 3 hours. The volatiles were removed under vacuum, and the residue was dried under high vacuum to provide 0.7 g of 4-(chloromethyl)-1-methoxyisoquinoline (XIa). 1 H NMR (400MHz, CDCl3): δ 8.23-8.26 (d, 1H), 8.16 (s, 1H), 8.10 (d, 1H), 7.87-7.91 (m, 1H), 7.61-7.72 (m, 1H), 5.18 (s, 2H), 4.07 (s, 3H).

[0286] N-((1-Methoxyisoquinoline-4-yl)methyl)ethylamine (VIa)

[0287]

[0288] 0.7 g (3.4 mmol, 1.0 eq.) 4-(chloromethyl)-1-methoxyisoquinoline (XIa) was added to a pressure vessel with 14 mL of a 2 M THF solution of ethylamine. The vessel was sealed and heated at 70 °C for 16 hours. The mixture was cooled to room temperature, diluted with 20 mL of water, and extracted with 3 × 30 mL of ethyl acetate. The combined organic extracts were dried (Na₂SO₄), filtered, and the solvent was removed under vacuum to provide 0.42 g (1.9 mmol, 60% from Xa) N-((1-methoxyisoquinoline-4-yl)methyl)ethylamine (VIa). LCMS: m / z determined 217.3 [M+H] + ; 1H NMR (400MHz, CDCl3): δ 8.26 (d, 1H), 8.15 (s, 1H), 8.12 (m, 1H), 7.82 (dd, 1H), 7.59 (dd, 1H), 4.36 (s, 2H), 4.09 (s, 3H), 2.88 (q, 2H), 1.37 (t, 3H).

[0289] 3-(3-Chloro-4-fluorophenyl)-1-ethyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea (Compound 15)

[0290]

[0291] At 0 °C, 0.38 mL (2.77 mmol, 2.0 eq.) of trimethylamine was added to a solution of 0.3 g (1.38 mmol, 1.0 eq.) of N-((1-methoxyisoquinoline-4-yl)methyl)ethylamine (VIa) in 10 mL of THF, followed by the addition of 0.24 g (1.38 mmol, 1.0 eq.) of 4-fluoro-3-chloro-phenyl isocyanate. The mixture was heated to room temperature and stirred for 6 hours. The solvent was removed under vacuum, and the residue was redissolved in 50 mL of dichloromethane. The organic solution was washed with 20 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by semi-preparative HPLC to provide 90 mg (0.23 mmol) of 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea (compound 15). LCMS: Measured m / z value 388.2 / 390.2 [M+H] + RT = 5.09 min (Method A); 1 H NMR (400MHz, DMSO-d6): δ8.57 (s, 1H), 8.32 (d, 1H), 8.08 (d, 1H), 7.73 (s, 1H), 7.79-7.83 (m, 2H), 7.63-7.67 (d d, 1H), 7.47-7.51 (m, 1H), 7.28-7.33 (dd, 1H), 4.88 (s, 2H), 4.06 (s, 3H), 3.22-3.27 (q, 2H), 0.99-1.03 (t, 3H).

[0292] 4-((ethylamino)methyl)isoquinoline-1(2H)-one (VIIIa)

[0293]

[0294] A solution of 0.42 g (1.9 mmol, 1.0 eq.) N-((1-methoxyisoquinoline-4-yl)methyl)ethylamine (VIa) in 4.2 mL of 47% aqueous hydrobromic acid was heated at 80 °C for 6 hours. The mixture was cooled to room temperature and the solvent was removed under vacuum to provide crude 4-((ethylamino)methyl)isoquinoline-1(2H)-one (VIIIa), which could be used later in the next step without further purification. LCMS: m / z 203.1 [M+H] + .

[0295] 3-(3-Chloro-4-fluorophenyl)-1-ethyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (Compound 9)

[0296]

[0297] 1.17 mL (8.43 mmol) of trimethylamine was added to a solution of crude VIIIa in 20 mL of dichloromethane, described elsewhere in this document, at 0 °C, followed by 0.18 g (1.05 mmol) of 4-fluoro-3-chloro-phenyl isocyanate. The mixture was heated to room temperature and stirred for 6 hours. The solvent was removed under vacuum, and the residue was redissolved in 50 mL of dichloromethane. The organic solution was washed with 20 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by semi-preparative HPLC to provide 75 mg (0.20 mmol, 20% from VIIIa) 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea (compound 9). LCMS: m / z determined 374.3 / 376.3 [M+H] + RT = 3.91 min (Method A); 1 H NMR (400MHz, DMSO-d6): δ11.22 (d, 1H), 8.54 (s, 1H), 8.23 ​​(d, 1H), 7.08-7.82 (m, 2H), 7.71-7.75 (m, 1 H), 7.47-7.53(m, 2H), 7.28-7.32(dd, 1H), 7.13(d, 1H), 4.63(s, 2H), 3.30(t, 2H), 0.99-1.02(t, 3H).

[0298] (1-Methoxyisoquinoline-4-yl)methylamine (VIh)

[0299]

[0300] A solution of 0.38 g (1.8 mmol, 1.0 eq.) 4-(chloromethyl)-1-methoxyisoquinoline (XIa) in 10 mL of 35% ammonia was heated at 70 °C for 16 hours. The mixture was cooled to room temperature and the volatiles were removed under vacuum to provide 0.35 g of crude (1-methoxyisoquinoline-4-yl)methylamine (VIh), which was used directly in the subsequent synthetic steps.

[0301] 1-(3-Chloro-4-fluorophenyl)-3-((1-methoxyisoquinoline-4-yl)methyl)urea (Compound 6)

[0302]

[0303] Add 0.45 g (1.53 mmol, 0.8 eq.) of triphosgene to a solution of 0.33 g (2.23 mmol, 1.2 eq.) of 3-chloro-4-fluoroaniline in 10 mL of toluene, and heat the mixture at 80 °C for 4 hours. Cool the mixture to room temperature, and then add a pre-cooled solution of 0.35 g of crude (1-methoxyisoquinoline-4-yl)methylamine (VIh) at 0 °C and 0.78 mL (5.58 mmol, 3.0 eq.) of triethylamine in 10 mL of DMF. Heat the resulting mixture to room temperature and stir for 6 hours. Quench the reaction mixture with 20 mL of water and extract with 3 × 30 mL of ethyl acetate. Wash the combined organic extracts with 10 mL of saturated sodium bicarbonate solution, dry (Na₂SO₄), filter, and remove the solvent under vacuum. The residue was purified by preparative HPLC to provide 1-(3-chloro-4-fluorophenyl)-3-((1-methoxyisoquinolin-4-yl)methyl)urea (compound 6). LCMS: m / z measured 360.0 / 362.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ1H NMR: 9.00 (bs, 1H), 8.22 (d, 1H), 8.09 (d, 1H), 7.98 (s, 1H), 7.81-7.85 (m, 1H), 7.78 (d d, 1H), 7.63-7.67 (m, 1H), 7.22-7.27 (m, 2H), 7.02 (bs, 1H), 4.59 (d, 2H), 4.05 (s, 3H).

[0304] 1-(3-Chloro-4-fluorophenyl)-3-((1-O-1,2-dihydroisoquinoline-4-yl)methyl)urea (Compound 8)

[0305]

[0306] 0.10 g (0.42 mmol, 2.5 eq.) of boron tribromide was added to a solution of 0.06 g (0.17 mmol, 1.0 eq.) of 1-(3-chloro-4-fluorophenyl)-3-((1-methoxyisoquinoline-4-yl)methyl)urea (compound 6) in 5 mL of anhydrous THF at 0 °C. The mixture was heated to room temperature and then heated at 70 °C for 12 hours. The mixture was cooled to room temperature and quenched by adding 5 mL of ice water. The mixture was extracted with 3 × 20 mL of ethyl acetate, and the combined organic extracts were dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by rapid chromatography (SiO2, linear gradient elution with a 0-10% methanol solution in dichloromethane) to provide 0.04 g (0.12 mmol, 70%) of 1-(3-chloro-4-fluorophenyl)-3-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea (compound 8). LCMS: m / z determined 346.0 / 348.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ 1 H NMR: 11.23 (d, 1H), 8.92 (s, 1H), 8.23 ​​(dd, 1H), 7.74-7.81 (m, 3H), 7.50-7.53 (m, 1H), 7.22-7.28 (m, 2H), 7.15 (d, 1H), 6.69 (s, 1H), 4.36 (d, 2H).

[0307] 1-(4-Fluoro-3-methylphenyl)-3-((1-Methoxyisoquinoline-4-yl)methyl)urea (Compound 7)

[0308]

[0309] 1-(4-fluoro-3-methylphenyl)-3-((1-methoxyisoquinoline-4-yl)methyl)urea (compound 7) was synthesized from 3-methyl-4-fluoroaniline and (1-methoxyisoquinoline-4-yl)methylamine (VIh) in a similar manner to that described above. LCMS: m / z measured 340.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6)δ 1 H NMR8.55(s, 1H), 8.22(d, 1H), 8.08(d, 1H), 7.98(s, 1H), 7.81-7.85(m, 1H), 7.63-7.67(m, 1H), 7. 29(dd, 1H), 7.17-7.21(m, 1H), 6.97(t, 1H), 6.73(d, 1H), 4.59(d, 2H), 4.05(s, 3H), 2.17(d, 3H).

[0310] 1-(4-Fluoro-3-methylphenyl)-3-((1-O-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 4)

[0311]

[0312] 1-(4-fluoro-3-methylphenyl)-3-((1-methoxyisoquinoline-4-yl)methyl)urea (compound 7) and boron tribromide were synthesized in a similar manner to that described above. LCMS: m / z measured 326.4 [M+H] + ; 1 H NMR (400MHz, DMSO-d6)δ 1 H NMR11.21(s, 1H), 8.38(s, 1H), 8.23(dd, 1H), 7.74-7.81(m, 2H), 7.50-7.53(m, 1H), 7.2 7-7.29 (m, 1H), 7.13-7.20 (m, 2H), 6.97 (t, 1H), 6.43 (t, 1H), 4.36 (d, 2H), 2.17 (d, 3H).

[0313] 1-(1-Methoxyisoquinoline-4-yl)-N-methylmethylamine (VIi)

[0314]

[0315] A solution of 0.50 g (2.4 mmol, 1.0 eq.) of 4-(chloromethyl)-1-methoxyisoquinoline (XIa) in 10 mL of THF was added to a 2 M THF solution of methylamine (9.6 mmol, 4.0 eq.), and the mixture was heated at 70 °C for 16 hours. The mixture was then cooled to room temperature, and volatiles were removed under vacuum. The resulting solid was washed with 10 mL of diethyl ether and dried under high vacuum to provide 0.30 g (1.5 mmol, 63%) of 1-(1-methoxyisoquinoline-4-yl)-N-methylmethylamine (VIi). 1 H NMR (400MHz, DMSO-d6) δ 8.28 (d, 1H), 8.07 (d, 2H), 7.78 (d, 1H), 7.58 (t, 1H), 4.29 (d, 2H), 4.10 (s, 3H), 2.53 (s, 3H).

[0316] 3-(4-fluoro-3-methylphenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)-1-methylurea (compound 3)

[0317]

[0318] 3-(4-fluoro-3-methylphenyl)-1-((1-methoxyisoquinoline-4-yl)-N-methylmethylamine (VIi) was synthesized in a similar manner to that described above. LCMS: m / z measured 354.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.34 (s, 1H), 8.22 (dd, 1H), 8.11 (d, 1H), 7.93 (s, 1H), 7.79-7.82 (m, 1H), 7.63-7.66 (m, 1H), 7.40 (dd, 1H), 7.30-7.33 (m, 1H), 7.01 (t, 1H), 4.85 (s, 2H), 4.05 (s, 3H), 2.85 (s, 3H), 2.19 (d, 3H).

[0319] 3-(3-Chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)-1-methylurea (Compound 2)

[0320]

[0321] To a solution of 0.05 g (0.24 mmol, 1.0 eq.) 1-(1-methoxyisoquinoline-4-yl)-N-methylmethylamine (VIi) in 5 mL of LDM, 0.1 mL (0.74 mmol, 3.0 eq.) of triethylamine was added, followed by 0.05 g (0.29 mmol, 1.2 eq.) of 2-chloro-1-fluoro-4-isocyanate benzene, and the mixture was stirred at room temperature for 16 hours. The mixture was then diluted with 10 mL of water and extracted with 3 × 15 mL of ethyl acetate. The combined organic extracts were washed with 10 mL of saturated sodium bicarbonate solution, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by preparative HPLC to provide 0.04 g (0.11 mmol, 46%) of 3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)-1-methylurea (compound 2). LCMS: Measured m / z value 374.2 / 376.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ8.95 (s, 1H), 8.23 ​​(d, 1H), 8.09 (d, 1H), 7.94 (s, 1H), 7.79-7.83 (m, 2H ), 7.63-7.69(m, 1H), 7.46-7.49(s, 1H), 7.31(t, 1H), 4.86(s, 2H), 4.06(s, 3H), 2.87(s, 3H).

[0322] 3-(3-Chloro-4-fluorophenyl)-1-((1-ethoxyisoquinoline-4-yl)methyl)-1-ethylurea (Compound 17)

[0323]

[0324] 3-(3-chloro-4-fluorophenyl)-1-((1-ethoxyisoquinoline-4-yl)methyl)ethylamine (VIj) and benzene 2-chloro-1-fluoro-4-isocyanate were synthesized in a similar manner to that described above. LCMS: m / z measured 402.2 / 404.2 [M+H] + RT = 5.40 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ8.56 (s, 1H), 8.23-8.25 (d, 1H), 8.05-8.08 (d, 1H), 7.90 (s, 1H), 7.78-7.83 (m, 2H), 7.64-7.68 (t, 1H), 7.46-7.50(m, 1H), 7.28-7.33(t, 1H), 4.87(s, 2H), 4.49-4.54(q, 2H), 3.27-3.32(q, 2H), 1.42-1.45(t, 3H), 0.968-1.02(t, 3H)

[0325] 4-((methylamino)methyl)isoquinoline-1(2H)-one (VIIIaf)

[0326]

[0327] A solution of 0.45 g (2.2 mmol, 1.0 eq.) 1-(1-methoxyisoquinoline-4-yl)-N-methylmethylamine (VIi) in 5 mL of 47% HBr aqueous solution was heated at 80 °C for 6 hours. The mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was prepared with diethyl ether and dried under high vacuum to provide 0.35 g (1.9 mmol, 84%) 4-((methylamino)methyl)isoquinoline-1(2H)-one (VIIIaf). 1H NMR (400MHz, DMSO-d6) δ 11.55 (s, 1H), 8.63 (s, 1H), 8.26 (dd, 1H), 7.95 (d, 1H), 7.80-7.84 (m, 1H), 7.48 (d, 1H), 4.30 (t, 2H), 2.61 (d, 3H).

[0328] 3-(4-fluoro-3-methylphenyl)-1-methyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 5)

[0329]

[0330] 3-(4-fluoro-3-methylphenyl)-1-methyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 5) was synthesized from 3-methyl-4-fluoroaniline and 4-((methylamino)methyl)isoquinoline-1(2H)-one (VIIIaf) in a similar manner to that described above. LCMS: m / z measured 340.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.27 (d, 1H), 8.32 (s, 1H), 8.23 ​​(dd, 1H), 7.84 (d, 1H), 7.71-7.74 (m, 1H), 7.50 (d d, 1H), 7.39 (dd, 1H), 7.29-7.32 (m, 1H), 7.13 (d, 1H), 7.01 (t, 1H), 4.60 (s, 2H), 2.84 (s, 3H), 2.19 (d, 3H).

[0331] 3-(3-Chloro-4-fluorophenyl)-1-methyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (Compound 1)

[0332]

[0333] 3-(3-chloro-4-fluorophenyl)-1-methyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 1) was synthesized from 4-((methylamino)methyl)isoquinoline-1(2H)-one (VIIIaf) and 2-chloro-1-fluoro-4-isocyanate benzene in a similar manner to that described above. LCMS: m / z measured 360.0 / 362.0 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ11.29 (1H, d), 8.56 (s, 1H), 8.23 ​​(dd, 1H), 7.80-7.83 (m, 2H), 7. 71-7.75(m, 1H), 7.45-7.52(m, 2H), 7.30(t, 1H), 7.15(d, 1H), 4.61(s, 2H), 2.85(s, 3H).

[0334] 1-Chloroisoquinoline-4-carboxaldehyde

[0335]

[0336] A solution of 3.0 g (12.5 mmol, 1.0 eq.) of 4-bromo-1-chloroisoquinoline in 30 mL of anhydrous THF was added to 15.5 mL (24.8 mmol, 2.0 eq.) of 1.6 M n-butyllithium in hexane at -78 °C under a nitrogen atmosphere. The mixture was stirred at -78 °C for 30 min and 3.62 g (49.6 mmol, 4.0 eq.) of anhydrous DMF was added. Stirring was continued at -78 °C for 1 h, and the reaction mixture was quenched with 50 mL of saturated ammonium chloride solution. The resulting solution was extracted with 3 × 100 mL of ethyl acetate, and the combined organic extracts were washed with 100 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by rapid chromatography (SiO₂, eluted with a linear gradient of 0–18% ethyl acetate / petroleum ether) to provide 1.3 g (6.80 mmol, 55%) of 1-chloroisoquinoline-4-carboxaldehyde. LCMS: m / z measured value 191.9 / 193.9 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ10.36 (s, 1H), 9.25-9.27 (m, 1H), 8.71 (s, 1H), 8.47-8.49 (m, 1H), 7.95-7.99 (m, 1H), 7.79-7.84 (m, 1H).

[0337] (1-Chloroisoquinoline-4-yl)methanol

[0338]

[0339] 0.26 g (6.80 mmol, 1.0 eq.) of sodium borohydride was added to a solution of 1.3 g (6.80 mmol, 1.0 eq.) of 1-chloroisoquinoline-4-carboxaldehyde in 13 mL of methanol at 0 °C. The mixture was heated to room temperature and stirred for 1 hour. The solvent was removed under vacuum, and the residue was resuspended in 50 mL of water and extracted with 3 × 50 mL of ethyl acetate. The combined organic extracts were dried (Na₂SO₄), filtered, and the solvent was removed under vacuum to provide 1.3 g (6.71 mmol, 98%) (1-chloroisoquinoline-4-yl) methanol. LCMS: m / z measured 194.2 / 196.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ 8.39 (d, 1H), 8.27 (s, 1H), 8.17 (d, 1H), 7.83-7.85 (m, 1H), 7.70-7.71 (m, 1H), 5.09 (s, 2H), 1.96 (bs, 1H).

[0340] 1-Chloro-4-(chloromethyl)isoquinoline

[0341]

[0342] 4.1 g (33.67 mmol, 5.0 eq.) of thionyl chloride was added to a solution of 1.3 g (6.73 mmol, 1.0 eq.) of (1-chloroisoquinoline-4-yl)methanol in 13 mL of dichloromethane at 0 °C. The mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was quenched by slow addition of 20 mL of water and extracted with 3 × 30 mL of dichloromethane. The combined organic extracts were dried (Na₂SO₄), filtered, and the solvent was removed under vacuum to provide 1.3 g (6.13 mmol, 91%) of 1-chloro-4-(chloromethyl)isoquinoline. LCMS: m / z found 212.3 / 214.3 / 216.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ 8.41 (d, 1H), 8.31 (s, 1H), 8.15 (d, 1H), 7.86-7.90 (m, 1H), 7.73-7.77 (m, 1H), 4.96 (s, 2H).

[0343] 1-(1-Chloroisoquinoline-4-yl)-N-methylmethylamine

[0344]

[0345] To a sealed tube, 1.1 g (5.19 mmol, 1.0 eq.) of 1-chloro-4-(chloromethyl)isoquinoline in 11 mL of THF was added to 7.8 mL (15.6 mmol, 3.0 eq.) of 2 M methylamine in THF. The container was sealed and the mixture was stirred at room temperature for 16 hours. Volatiles were removed under vacuum, and the residue was purified by rapid chromatography (SiO2, eluting with a linear gradient of 0–10% methanol in dichloromethane) to provide 0.9 g (4.35 mmol, 84%) of 1-(1-chloroisoquinoline-4-yl)-N-methylmethylamine. LCMS: m / z determined 207.2 / 209.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ 8.37 (d, 1H), 8.22 (s, 1H), 8.18 (d, 1H), 7.78-7.82 (m, 1H), 7.67-7.71 (m, 1H), 4.12 (s, 2H), 2.54 (s, 3H), 1.69 (bs, 1H).

[0346] 3-(3-chloro-4-fluorophenyl)-1-((1-chloroisoquinoline-4-yl)methyl)-1-methylurea

[0347]

[0348] 1.51 g (11.65 mmol, 3.0 eq.) of N,N-diisopropylethylamine was added to a solution of 0.8 g (3.88 mmol, 1.0 eq.) of 1-(1-chloroisoquinoline-4-yl)-N-methylmethylamine in 8 mL of dichloromethane at 0 °C, followed by the addition of 0.66 g (3.88 mmol, 1.0 eq.) of 4-fluoro-3-chloro-phenyl isocyanate, and the mixture was stirred at 0 °C for 1 hour. The mixture was then diluted with 30 mL of water and extracted with 3 × 40 mL of ethyl acetate. The combined organic extracts were washed with 30 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum to provide 0.6 g (1.58 mmol, 41%) of 3-(3-chloro-4-fluorophenyl)-1-((1-chloroisoquinoline-4-yl)methyl)-1-methylurea. LCMS: Measured m / z value 378.4 / 380.4 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.42 (d, 1H), 8.22 (d, 1H), 8.18 (s, 1H), 7.83 (t, 1H), 7.73 (t, 1H), 7 .58-7.61 (m, 1H), 7.19-7.23 (m, 1H), 7.07 (t, 1H), 6.39 (s, 1H), 5.01 (s, 2H), 2.92 (s, 3H).

[0349] 3-(3-Chloro-4-fluorophenyl)-1-methyl-1-((1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)methyl)urea (compound 87)

[0350]

[0351] In a nitrogen atmosphere, 64 mg (1.59 mmol, 2.0 eq.) of a dispersion of 60% sodium hydride in mineral oil was added to a solution of 0.3 g (0.79 mmol, 1.0 eq.) of 3-(3-chloro-4-fluorophenyl)-1-((1-chloroisoquinoline-4-yl)methyl)-1-methylurea in 5 mL of anhydrous THF, followed by the addition of 180 mg (1.59 mol, 2.0 eq.) of (1-methyl-1H-1,2,4-triazol-3-yl)methanol. The mixture was heated at 60 °C for 8 hours, quenched with 25 mL of ice-cold water, and extracted with 3 × 40 mL of ethyl acetate. The combined organic extracts were washed with 20 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by rapid chromatography (SiO2, linear gradient elution with a 0-10% methanol solution in dichloromethane) to provide 0.14 g (0.30 mmol, 38%) of 3-(3-chloro-4-fluorophenyl)-1-methyl-1-((1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinoline-4-yl)methyl)urea (compound 87). LCMS: m / z measured 455.1 / 457.2 [M+H] + RT = 5.31 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ8.60 (s, 1H), 8.47 (s, 1H), 8.18 (d, 1H), 8.11 (d, 1H), 7.94 (s, 1H), 7.80-7.85 (m , 2H), 7.65(t, 1H), 7.46-7.51(m, 1H), 7.31(t, 1H), 5.53(s, 2H), 4.87(s, 2H), 3.87(s, 3H), 2.89(s, 3H).

[0352] 3-(3-Chloro-4-fluorophenyl)-1-methyl-1-((1-(pyridin-2-ylmethoxy)isoquinoline-4-yl)methyl)urea (compound 88)

[0353]

[0354] 3-(3-chloro-4-fluorophenyl)-1-((1-chloroisoquinoline-4-yl)methyl)-1-methylurea and pyridin-2-ylmethanol were synthesized in a similar manner to that described above. LCMS: m / z measured 451.1 / 453.2 [M+H] + RT = 5.00 min (Method A); 1 HNMR (400MHz, DMSO-d6) δ8.58-8.61 (m, 2H), 8.36 (d, 1H), 8.13 (d, 1H), 7.93 (s, 1H), 7.80-7.87 (m, 3H), 7.69 (t, 1H), 7.58 (d, 1H), 7.46-7.50 (m, 1H), 7.28-7.37 (m, 2H), 5.65 (s, 2H), 4.87 (s, 2H), 2.88 (s, 3H).

[0355] 1-((1-(2-((tert-butyldimethylsilyl)oxy)ethoxy)isoquinoline-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-ethylurea (VIIb)

[0356]

[0357] 1-((1-(1-chloroisoquinoline-4-yl)methyl)-1-ethylurea and 2-((tert-butyldimethylsilyl)oxy)ethoxy)isoquinoline-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-ethylurea (VIIb) were synthesized in a similar manner to that described above. LCMS: m / z measured 532.5 / 534.5 [M+H] + .

[0358] 3-(3-Chloro-4-fluorophenyl)-1-ethyl-1-((1-(2-hydroxyethoxy)isoquinoline-4-yl)methyl)urea (compound 29)

[0359]

[0360] To a solution of 250 mg of 1-((1-(1-(2-(tert-butyldimethylsilyl)oxy)ethoxy)isoquinoline-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-ethylurea (VIIb) in 4 mL of THF, 2.5 mL (2.5 mmol) of 1 M tetra-n-butylammonium fluoride in THF was added, and the mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum, and the residue was purified by reversed-phase chromatography (C18, eluting with a linear gradient of 0–50% [0.1% formic acid aqueous solution] / acetonitrile) to provide 45 mg of 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-(2-hydroxyethoxy)isoquinoline-4-yl)methyl)urea (compound 29). LCMS: m / z measured 418.2 / 420.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.60 (s, 1H), 8.31 (d, 1H), 8.07 (d, 1H), 7.91 (s, 1H), 7.79-7.84 (m, 2H), 7.65 (t, 1H), 7 .49-7.53 (m, 1H), 7.31 (t, 1H), 4.95 (t, 1H), 4.88 (s, 2H), 4.47 (t, 2H), 3.83 (q, 2H), 3.29 (q, 2H), 1.01 (t, 3H).

[0361]

[0362] 1-Cyclopropyl-N-((1-Methoxyisoquinoline-4-yl)methyl)methylamine (VIb)

[0363]

[0364] Add 0.11 g (1.55 mmol, 3.0 eq.) of cyclopropylmethylamine to a solution of 0.10 g (0.52 mmol, 11.0 eq.) of 1-methoxyisoquinoline-4-carboxaldehyde (Va) in 3 mL of 1,2-dichloroethane. Stir the mixture at room temperature for 10 min and add 0.33 g (1.55 mmol, 3.0 eq.) of solid sodium triacetoxyborohydride. Then, stir the mixture vigorously at room temperature for 18 hours. Dilute the mixture with 5 mL of dichloromethane and 10 mL of saturated sodium carbonate solution, and stir vigorously for another 15 min. Separate the layers and extract the aqueous phase with 5 mL of dichloromethane. Dry the combined organic extracts (Na₂SO₄), filter, and remove the solvent under vacuum to provide 0.11 g of crude 1-cyclopropyl-N-((1-methoxyisoquinoline-4-yl)methyl)methylamine (VIb), which is ready for use without further purification. LCMS: m / z measured value 243.2 [M+H] + .

[0365] 3-(3-Chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea (compound 31)

[0366]

[0367] 0.08 g (0.5 mmol) of 4-fluoro-3-chlorophenyl isocyanate was added to a solution of 0.11 g of crude N-(cyclopropylmethyl)-1-(1-methoxy-4-isoquinolinyl)methylamine in 1.5 mL of dichloromethane, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum, and the residue was purified by rapid chromatography (eluting with a linear gradient of 10–35% ethyl acetate / hexane over 10 min) to provide 0.15 g (0.37 mmol, 71% from Va) 3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-((1-methoxyisoquinolinyl-4-yl)methyl)urea (compound 31). LCMS: m / z determined 414.1 / 416.1 [M+H] + RT = 6.33 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ8.63 (s, 1H), 8.11-8.37 (m, 1H), 7.94-8.07 (m, 1H), 7.72-7.91 (m, 3H), 7.63 (m, 1H), 7.46 (m, 1H), 7.29 (t, 1H), 4.96 (s, 2H), 4.03 (d, 3H), 3.18 (d, 2H), 1.02 (td, 1H), 0.27-0.42 (m, 2H), 0.07-0.23 (m, 2H).

[0368] 4-(((cyclopropylmethyl)amino)methyl)isoquinoline-1(2H)-keto hydrochloride (VIIIam)

[0369]

[0370] A solution of 0.25 g (1.03 mmol, 1.0 eq.) 1-cyclopropyl-N-((1-methoxyisoquinoline-4-yl)methyl)methylamine (VIb) in 3 mL of 4 M HCl in p-dioxane was heated at 60 °C for 2 h. The mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was prepared with 10 mL of n-pentane and dried under high vacuum to provide 0.25 g (0.94 mmol, 91%) 4-(((cyclopropylmethyl)amino)methyl)isoquinoline-1(2H)-one hydrochloride (VIIIam). LCMS: m / z measured 229.3 [M+H] + .

[0371] 3-(3-Chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 53)

[0372]

[0373] 3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 53) was synthesized from 4-(((cyclopropylmethyl)amino)methyl)isoquinoline-1(2H)-one hydrochloride (VIIIam) and 2-chloro-1-fluoro-4-isocyanate benzene in a similar manner to that described above. LCMS: m / z measured 400.1 / 402.1 [M+H] + RT = 4.34 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ11.24 (bs, 1H), 8.61 (s, 1H), 8.24 (d, 1H), 7.72-7.81 (m, 3H), 7.45-7.54 (m, 2H), 7. 31 (t, 1H), 7.06 (s, 1H), 4.72 (s, 2H), 3.20 (d, 2H), 1.01-1.07 (m, 1H), 0.36-0.42 (m, 2H), 0.17-0.22 (m, 2H).

[0374] N-((1-Methoxyisoquinoline-4-yl)methyl)propyl-2-amine (VIc)

[0375]

[0376] To a solution of 2.0 g (10.69 mmol, 1.0 eq.) of 1-methoxyisoquinoline-4-carboxaldehyde (Va) in 20 mL of methanol, 2 g of solid sodium sulfate and 2.6 mL (32.1 mmol, 3.0 eq.) of isopropylamine were added at room temperature. The mixture was stirred at room temperature for 16 hours, and 0.61 g (16.0 mmol, 1.5 eq.) of sodium borohydride was added in portions. The mixture was stirred at room temperature for another 16 hours, and the solvent was removed under vacuum. The residue was suspended in 100 mL of ice-cold water and extracted with 3 × 80 mL of ethyl acetate. The combined organic extracts were washed with 80 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum to provide 1 g of crude N-((1-methoxyisoquinoline-4-yl)methyl)propyl-2-amine (VIc), which was ready for use without further purification. LCMS: m / z 231.22 [M+H] + .

[0377] 3-(3-Chloro-4-fluorophenyl)-1-isopropyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea (Compound 19)

[0378]

[0379] 1.2 mL (8.7 mmol) of trimethylamine was added to a solution of 1 g of crude N-((1-methoxyisoquinoline-4-yl)methyl)propyl-2-amine (VIc) in 10 mL of THF at 0 °C, followed by the addition of 0.74 g (4.6 mmol) of 4-fluoro-3-chlorophenyl isocyanate. The mixture was heated to room temperature and stirred for 16 hours. The solvent was removed under vacuum, and the residue was redissolved in 110 mL of dichloromethane. The organic solution was washed with 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by preparative HPLC to provide 3-(3-chloro-4-fluorophenyl)-1-isopropyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea (compound 19); LCMS: m / z 402.2 / 404.2 [M+H] + RT = 5.18 min (Method A); 1 H NMR (400MHz, DMSO-d6): δ8.54 (s, 1H), 8.23 ​​(d, 1H), 8.09 (d, 1H), 7.84 (t, 1H), 7.73-7.75 (m, 2H), 7.6 7(t, 1H), 7.40-7.44(m, 1H), 7.24-7.28(m, 1H), 4.85(s, 2H), 4.53(q, 1H), 4.02(s, 3H), 1.14(d, 6H).

[0380] 4-((isopropylamino)methyl)isoquinoline-1(2H)-one (VIIIc)

[0381]

[0382] A suspension of 0.5 g of N-((1-methoxyisoquinoline-4-yl)methyl)propyl-2-amine (VIc) in 5 mL of 48% aqueous hydrobromic acid was heated at 80 °C for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to provide 0.55 g of crude 4-((isopropylamino)methyl)isoquinoline-1(2H)-one (VIIIc), which was ready for use without further purification. LCMS: m / z measured 217.19 [M+H] + .

[0383] 3-(3-Chloro-4-fluorophenyl)-1-isopropyl-1-((1-O-1,2-dihydroisoquinoline-4-yl)methyl)urea (Compound 26)

[0384]

[0385] At 0 °C, 0.64 mL (4.32 mmol) of trimethylamine was added to a solution of 0.5 g of crude 4-((isopropylamino)methyl)isoquinoline-1(2H)-one (VIIIc) in 10 mL of anhydrous THF, followed by 0.4 g (2.31 mmol) of 4-fluoro-3-chlorophenyl isocyanate. The mixture was heated to room temperature and stirred for 4 hours. The solvent was removed under vacuum, and the residue was redissolved in 100 mL of dichloromethane. The organic solution was washed with 50 mL of brine, dried (Na2SO4), filtered, and the solvent was removed under vacuum. The residue was purified by reversed-phase chromatography to provide 0.18 g (0.46 mmol, 21% from VIIIc) 3-(3-chloro-4-fluorophenyl)-1-isopropyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 26). LCMS: Measured m / z value 388.1 / 390.1 [M+H] + RT = 4.04 min (Method A); 1 H NMR (400MHz, DMSO-d6): δ11.13 (d, 1H), 8.51 (s, 1H), 8.25 (d, 1H), 7.73-7.84 (m, 3H), 7.55 (t, 1 H), 7.40-7.44(m, 1H), 7.27(t, 1H), 6.78(d, 1H), 4.57(s, 2H), 4.46-4.49(m, 1H), 1.13(d, 6H).

[0386] N-((1-Methoxyisoquinoline-4-yl)methyl)propyl-1-amine (VIk)

[0387]

[0388] To a solution of 3.8 g (20.3 mmol, 1.0 eq.) of 1-methoxyisoquinoline-4-carboxaldehyde (Va) in 40 mL of methanol, 1.7 g (30.5 mmol, 1.5 eq.) of n-propylamine was added, followed by 3.8 g of sodium sulfate. The mixture was stirred at room temperature for 16 hours, and 0.76 g (20.3 mmol, 1.0 eq.) of sodium borohydride was added. The mixture was stirred at room temperature for 16 hours, and volatiles were removed under vacuum. The residue was resuspended in 200 mL of ice-cold water and extracted with 3 × 100 mL of ethyl acetate. The combined organic extracts were washed with 100 mL of water and 100 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum to provide 3.8 g of crude N-((1-methoxyisoquinoline-4-yl)methyl)propyl-1-amine (VIk), which was ready for use without further purification. LCMS: Measured m / z value 231.2 [M+H] + .

[0389] 3-(3-Chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)-1-propylurea (Compound 20)

[0390]

[0391] 3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)prop-1-amine (VIk) and benzene 2-chloro-1-fluoro-4-isocyanate were synthesized in a similar manner to that described above. LCMS: m / z measured 402.2 / 404.2 [M+H] + RT = 5.46 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ8.56 (s, 1H), 8.21-8.24 (d, 1H), 8.05-8.07 (d, 1H), 7.91 (s, 1H), 7.71-7.83 (m, 2H), 7.63-7.67 (t, 1H) ), 7.45-7.49(m, 1H), 7.28-7.33(t, 1H), 4.89(s, 2H), 4.06(s, 3H), 3.18-3.22(m, 2H), 1.46-1.51(m, 2H), 0.77-0.81(t, 3H).

[0392] 4-((propylamino)methyl)isoquinoline-1(2H)-one (VIIIag)

[0393]

[0394] To a solution of 1.0 g (4.35 mmol, 1.0 eq.) N-((1-methoxyisoquinoline-4-yl)methyl)propyl-1-amine (VIk) in 10 mL of acetonitrile, 1.9 g (13.04 mmol, 3.0 eq.) sodium iodide was added, followed by 2.3 g (21.7 mmol, 5.0 eq.) trimethylsilyl chloride, and the mixture was stirred at room temperature for 16 hours. Volatile substances were removed under vacuum, and the residue was suspended in 100 mL of water and extracted with 3 × 80 mL of 10% methanol in dichloromethane. The combined organic extracts were washed with 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by preparation with diethyl ether to provide 0.5 g (2.31 mmol, 53%) 4-((propylamino)methyl)isoquinoline-1(2H)-one (VIIIag). 1 H NMR (400MHz, CDCl3): δ10.20-10.80 (bs, 1H), 8.43 (dd, 1H), 7.83 (d, 1H), 7.72 (td, 1H), 7.51(m, 1H), 7.16(s, 1H), 3.89(s, 2H), 2.69(t, 2H), 1.56(m, 2H), 0.94(t, 3H).

[0395] (3-Chloro-4-fluorophenyl)carbamate 4-nitrophenyl ester

[0396]

[0397] At 0 °C, 4.8 g (61.8 mmol, 3.0 eq.) of pyridine was added to a solution of 3.0 g (20.6 mmol, 1.0 eq.) of 3-chloro-4-fluoroaniline in 30 mL of 1,2-dichloroethane, followed by 5.0 g (24.7 mmol, 1.2 eq.) of 4-nitrophenyl chloroformate. The mixture was heated to room temperature and stirred for 5 hours. The solvent was removed under vacuum, and the residue was resuspended in 20 mL of cold water. The solid was collected by filtration, washed with 250 mL of water followed by 125 mL of ethyl acetate, and dried under high vacuum to provide 3.6 g (11.6 mmol, 57%) of (3-chloro-4-fluorophenyl)carbamate 4-nitrophenyl ester. 1 H NMR (400MHz, DMSO-d6): δ 10.70 (s, 1H), 8.31-8.40 (d, 2H), 7.73-7.75 (d, 1H), 7.55-7.57 (d, 2H), 7.40-7.49 (dd, 2H).

[0398] 3-(3-Chloro-4-fluorophenyl)-1-((1-O-1,2-dihydroisoquinoline-4-yl)methyl)-1-propylurea (Compound 28)

[0399]

[0400] 1.0 g (3.47 mmol, 1.5 eq.) of 4-((propylamino)methyl)isoquinoline-1(2H)-one (VIIIag) in 5 mL of THF was added to a sealed tube. The container was sealed and the mixture was heated at 80 °C for 16 hours. The solvent was removed under vacuum and the residue was purified by semi-preparative HPLC to provide 101 mg (0.26 mmol, 11%) of 3-(3-chloro-4-fluorophenyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)-1-propylurea (compound 28). LCMS: m / z measured 388.3 / 390.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ11.25 (s, 1H), 8.53 (s, 1H), 8.24 (d, 1H), 7.72-7.81 (m, 3H), 7.52 (d, 1H), 7.45-7.50 (m, 1H), 7.30 (t, 1H), 7.11 (d, 1H), 4.64 (s, 2H), 3.21 (t, 2H), 1.47 (m, 2H), 0.80 (t, 3H).

[0401] N-((1-methoxyisoquinoline-4-yl)methyl)cyclopropylamine (VIm)

[0402]

[0403] To a solution of 0.2 g (1.07 mmol, 1.0 eq.) of 1-methoxyisoquinoline-4-carboxaldehyde (Va) in 4 mL of methanol, 0.22 mL (3.21 mmol, 3.0 eq.) of cyclopropylamine was added, followed by 0.2 g of sodium sulfate. The mixture was stirred at room temperature for 16 hours, and 0.08 g (2.13 mmol, 2.0 eq.) of sodium borohydride was added. The mixture was stirred at room temperature for 2 hours, and volatiles were removed under vacuum. The residue was resuspended in 20 mL of ice-cold water and extracted with 2 × 50 mL of ethyl acetate. The combined organic extracts were washed with 50 mL of water and 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum to provide 0.2 g of N-((1-methoxyisoquinoline-4-yl)methyl)cyclopropylamine (VIm). LCMS: m / z measured 229.5 [M+H]+ .

[0404] 3-(3-Chloro-4-fluorophenyl)-1-cyclopropyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea (compound 34)

[0405]

[0406] 3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-((1-methoxyisoquinoline-4-yl)methyl)urea (Compound 34) was synthesized from N-((1-methoxyisoquinoline-4-yl)methyl)cyclopropylamine (VIm) and 2-chloro-1-fluoro-4-isocyanate benzene in a similar manner to that described above. LCMS: m / z measured 400.2 / 402.2 [M+H] + RT = 5.40 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ8.54(bs, 1H), 8.23(d, 1H), 8.06(d, 1H), 7.97(s, 1H), 7.79-7.85(m, 2H), 7.62-7.67( m, 1H), 7.48-7.53 (m, 1H), 7.29-7.35 (m, 1H), 4.84 (s, 2H), 4.06 (s, 3H), 2.27-2.33 (m, 1H), 0.83-0.92 (m, 4H).

[0407] 4-((cyclopropylamino)methyl)isoquinoline-1(2H)-ketohydrobromide (VIIIah)

[0408]

[0409] A solution of 0.5 g (2.19 mmol, 1.0 eq) of N-((1-methoxyisoquinoline-4-yl)methyl)cyclopropylamine (VIm) in 5 mL of 40% HBr aqueous solution was stirred at 80 °C for 3 hours. The mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was prepared with 20 mL of diethyl ether and dried under high vacuum to provide 0.3 g of 4-((cyclopropylamino)methyl)isoquinoline-1(2H)-one hydrobromide (VIIIah). LCMS: m / z measured 215.3 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.93 (bs, 2H), 8.27 (d, 1H), 7.97 (d, 1H), 7.82 (t, 1H), 7 .53-7.60 (m, 2H), 4.42 (t, 2H), 2.09 (bs, 1H), 1.79 (s, 1H), 0.73-0.91 (m, 4H).

[0410] 3-(3-Chloro-4-fluorophenyl)-1-cyclopropyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 42)

[0411]

[0412] 3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 42) was synthesized from 4-((cyclopropylamino)methyl)isoquinoline-1(2H)-one hydrobromide (VIIIah) and 2-chloro-1-fluoro-4-isocyanate benzene in a similar manner to that described above. LCMS: m / z measured 386.2 / 388.2 [M+H] + RT = 4.13 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ11.28 (bd, 1H), 8.54 (bs, 1H), 8.25 (d, 1H), 7.82-7.86 (m, 1H), 7.71-7.80 (m, 2H), 7.47-7.54(m, 2H), 7.32(t, 1H), 7.14(d, 1H), 4.60(s, 2H), 2.26-2.32(m, 1H), 0.77-0.92(m, 4H).

[0413] N-((1-Methoxyisoquinoline-4-yl)methyl)but-1-amine (VIn)

[0414]

[0415] To a solution of 0.5 g (2.67 mmol, 1.0 eq.) of 1-methoxyisoquinoline-4-carboxaldehyde (Va) in 5 mL of methanol, 0.49 g (8.02 mmol, 3.0 eq.) of n-butylamine was added, followed by 0.5 g of sodium sulfate. The mixture was stirred at room temperature for 16 hours, and 0.30 g (8.02 mmol, 3.0 eq.) of sodium borohydride was added. The mixture was then stirred at room temperature for another 2 hours, and volatiles were removed under vacuum. The residue was resuspended in 50 mL of ice-cold water and extracted with 2 × 50 mL of ethyl acetate. The combined organic extracts were washed with 50 mL of water and 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum to provide 0.56 g (2.27 mmol, 85%) of N-((1-methoxyisoquinoline-4-yl)methyl)but-1-amine (VIn). LCMS: m / z 245.4 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.27 (d, 1H), 8.03 (d, 1H), 7.93 (s, 1H), 7.68-7.72 (m 1H), 7.51-7.55(m, 1H), 4.12(s, 3H), 4.05(s, 2H), 2.71(t, 2H), 1.47-1.53(m, 2H), 1.32-1.38(m, 2H), 1.31(bs, 1H), 0.92(t, 3H).

[0416] 1-Butyl-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea (compound 33)

[0417]

[0418] 1-Butyl-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)but-1-amine (VIn) and benzene 2-chloro-1-fluoro-4-isocyanate were synthesized in a similar manner to that described above. LCMS: m / z measured 416.2 / 418.2 [M+H] + , RT=6.02min (method A); 1 H NMR (400MHz, DMSO-d6) δ8.57 (s, 1H), 8.21-8.24 (m, 1H), 8.05-8.06 (m, 1H), 7.91 (s, 1H), 7.77-7.84 (m, 2H), 7.63-7.67 (m, 1H), 7.4 5-7.49 (m, 1H), 7.28-7.33 (m, 1H), 4.89 (s, 2H), 4.06 (s, 3H), 3.22-3.26 (m, 2H), 1.44-1.49 (m, 2H), 1.17-1.27 (m, 2H), 0.82 (t, 3H).

[0419] 4-((Butylamino)methyl)isoquinoline-1(2H)-one (VIIIai)

[0420]

[0421] To a solution of 0.55 g (2.25 mmol, 1.0 eq.) N-((1-methoxyisoquinoline-4-yl)methyl)but-1-amine (VIn) in 10 mL of acetonitrile, 1.22 g (11.3 mmol, 5.0 eq.) of trimethylsilyl chloride was added at room temperature, followed by 1.0 g (6.76 mmol, 3.0 eq.) of sodium iodide, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with 15 mL of saturated sodium bicarbonate solution and extracted with 3 × 60 mL of ethyl acetate. The combined organic extracts were washed with 30 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by preparation with diethyl ether to provide 0.45 g of 4-((butylamino)methyl)isoquinoline-1(2H)-one (VIIIai). LCMS: m / z 230.9 [M+H] + .

[0422] 1-Butyl-3-(3-chloro-4-fluorophenyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (Compound 52)

[0423]

[0424] 1-Butyl-3-(3-chloro-4-fluorophenyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 52) was synthesized from 4-((butylamino)methyl)isoquinoline-1(2H)-one (VIIIai) and 2-chloro-1-fluoro-4-isocyanate benzene in a similar manner to that described above. LCMS: m / z measured 402.1 / 404.1 [M+H] + RT = 4.62 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ11.25 (bs, 1H), 8.54 (s, 1H), 8.24 (dd, 1H), 7.72-7.80 (m, 3H), 7.47-7.54 (m, 2H) , 7.30 (t, 1H), 7.11 (s, 1H), 4.64 (s, 2H), 3.24 (t, 2H), 1.39-1.48 (m, 2H), 1.16-1.27 (m, 2H), 0.82 (t, 3H).

[0425] 2-((tert-butyldimethylsilyl)oxy)-N-((1-methoxyisoquinoline-4-yl)methyl)ethyl-1-amine (VIo)

[0426]

[0427] To a solution of 0.4 g (2.13 mmol, 1.0 eq.) 1-methoxyisoquinoline-4-carboxaldehyde (Va) in 5 mL of methanol, 1.2 g (6.38 mmol, 3.0 eq.) 2-((tert-butyldimethylsilyl)oxy)ethyl-1-amine was added, followed by 0.4 g of sodium sulfate. The mixture was stirred at room temperature for 16 hours, and 0.12 g (3.19 mmol, 1.0 eq.) of sodium borohydride was added. The mixture was stirred at room temperature for another 2 hours, and volatiles were removed under vacuum. The residue was resuspended in 50 mL of ice-cold water and extracted with 3 × 50 mL of ethyl acetate. The combined organic extracts were washed with 100 mL of water and 100 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by rapid chromatography (SiO2, eluting with a linear gradient of 0-25% ethyl acetate / hexane) to provide 0.4 g (1.15 mmol, 54%) of 2-((tert-butyldimethylsilyl)oxy)-N-((1-methoxyisoquinoline-4-yl)methyl)ethyl-1-amine (VIo). LCMS: m / z determined 347.3 [M+H] + .

[0428] 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea (VIIa)

[0429]

[0430] 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea (VIIa) was synthesized from 2-((tert-butyldimethylsilyl)oxy)ethyl)-N-((1-methoxyisoquinoline-4-yl)methyl)urea (VIIa) in a similar manner to that described above. LCMS: m / z measured 518.3 / 520.3 [M+H] + .

[0431] 3-(3-Chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea (Compound 21)

[0432]

[0433] To a solution of 300 mg of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea (VIIa) in 3 mL of THF, 1.7 mL (1.74 mmol, 3.0 eq.) of 1 M tetrabutylammonium fluoride in THF was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum, and the residue was purified by rapid chromatography (SiO2, eluting with a linear gradient of 40–70% ethyl acetate / hexane) to provide 75 mg (0.19 mmol, 21% from VIIa) of 3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea (compound 21). LCMS: m / z determined 404.2 / 406.2 [M+H] + RT = 4.44 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ8.89 (s, 1H), 8.23 ​​(d, 1H), 8.06 (d, 1H), 7.93 (s, 1H), 7.82 (t, 1H), 7.76 (dd, 1H), 7.66 (t, 1 H), 7.35-7.38(m, 1H), 7.31(t, 1H), 5.19-5.21(m, 1H), 4.93(s, 2H), 4.06(s, 3H), 3.46(q, 2H), 3.33-3.39(m, 2H).

[0434] 3-(3-Chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 27)

[0435]

[0436] To a solution of 300 mg of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea (VIIa) in 3 mL of dichloromethane, 0.24 g (2.9 mmol, 5.0 eq.) of 47% HBr aqueous solution was added, and the mixture was stirred at room temperature for 6 hours. The mixture was then diluted with 100 mL of ethyl acetate, washed with 50 mL of saturated sodium bicarbonate solution and 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by reversed-phase chromatography (eluting with a linear gradient of 10–40% [0.1% formic acid aqueous solution] / acetonitrile) to provide 0.036 g (0.09 mmol, 11% from VIo) 3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea (compound 27). LCMS: m / z determined 390.2 / 392.1 [M+H] + RT = 3.39 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ11.28 (s, 1H), 8.87 (s, 1H), 8.24 (d, 1H), 7.74-7.81 (m, 3H), 7.52 (t, 1H), 7.35-7 .36(m, 1H), 7.31(t, 1H), 7.12(d, 1H), 5.19(bs, 1H), 4.68(s, 2H), 3.44–3.47(m, 2H), 3.32-3.37(m, 2H).

[0437] 2-Methoxy-N-((1-Methoxyisoquinoline-4-yl)methyl)ethyl-1-amine (VIp)

[0438]

[0439] To a solution of 1.0 g (5.3 mmol, 1.0 eq.) 1-methoxyisoquinoline-4-carboxaldehyde (Va) in 10 mL of methanol, 1.19 g (15.9 mmol, 3.0 eq.) 2-methoxyethyl-1-amine was added, followed by 1.0 g sodium sulfate. The mixture was stirred at room temperature for 16 hours, and 0.47 g (12.7 mmol, 2.4 eq.) sodium borohydride was added. The mixture was then stirred at room temperature for another 4 hours, and volatiles were removed under vacuum. The residue was resuspended in 50 mL of ice-cold water and extracted with 2 × 50 mL ethyl acetate. The combined organic extracts were washed with 50 mL of water and 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum to provide 1.2 g (4.9 mmol, 91%) 2-methoxy-N-((1-methoxyisoquinoline-4-yl)methyl)ethyl-1-amine (VIp). LCMS: Measured m / z value 247.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.27 (d, 1H), 8.04 (d, 1H), 7.94 (s, 1H), 7.69-7.73 (m 1H), 7.51-7.56(m, 1H), 4.11(s, 3H), 4.08(s, 2H), 3.52(t, 2H), 3.34(s, 3H), 2.88(t, 2H), 1.69(bs, 1H).

[0440] 3-(3-Chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea (Compound 41)

[0441]

[0442] 3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-((1-methoxyisoquinoline-4-yl)methyl)ethyl-1-amine (VIp) and benzene 2-chloro-1-fluoro-4-isocyanate were synthesized in a similar manner to that described above. LCMS: m / z measured 418.2 / 420.2 [M+H] + RT = 5.36 min (Method A); 1H NMR (400MHz, DMSO-d6) δ8.65 (bs, 1H), 8.23 ​​(m, 1H), 8.04 (d, 1H), 7.90 (s, 1H), 7.76-7.85 (m, 2H), 7.63- 7.68 (m, 1H), 7.38-7.44 (m, 1H), 7.31 (t, 1H), 4.94 (s, 2H), 4.06 (s, 3H), 3.41-3.47 (m, 4H), 3.21 (s, 3H).

[0443] 4-(((2-methoxyethyl)amino)methyl)isoquinoline-1(2H)-one hydrochloride (VIIIaj)

[0444]

[0445] A solution of 0.60 g (2.44 mmol, 1.0 eq.) of 2-methoxy-N-((1-methoxyisoquinoline-4-yl)methyl)ethyl-1-amine (VIp) in 2.5 mL of methanol was added to a 5 mL solution of 4 M HCl in p-dioxane. The container was sealed, and the mixture was heated at 80 °C for 6 hours. The mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was prepared with 10 mL of n-pentane and dried under high vacuum to provide 0.55 g (2.0 mmol, 84%) of 4-(((2-methoxyethyl)amino)methyl)isoquinoline-1(2H)-one hydrochloride (VIIIaj). LCMS: m / z measured 233.3 [M+H] + ; 1 HNMR (400MHz, DMSO-d6) δ11.57 (bd, 1H), 8.89 (bs, 2H), 8.26 (d, 1H), 7.90-7.92 (m, 1H), 7.80-7.84 (m, 1H ), 7.55-7.59(m, 1H), 7.48(d, 1H), 4.27-4.30(m, 2H), 3.61-3.64(m, 2H), 3.31(s, 3H), 3.16-3.22(m, 2H).

[0446] 3-(3-Chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 50)

[0447]

[0448] 3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 50) was synthesized from 4-(((2-methoxyethyl)amino)methyl)isoquinoline-1(2H)-one hydrochloride (VIIIaj) and benzene 2-chloro-1-fluoro-4-isocyanate in a similar manner to that described above. LCMS: m / z measured 404.1 / 406.1 [M+H] + RT = 4.15 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ11.29 (d, 1H), 8.62 (bs, 1H), 8.24 (d, 1H), 7.72-7.78 (m, 3H), 7.50-7.54 (m, 1H), 7. 38-7.43 (m, 1H), 7.31 (t, 1H), 7.09 (d, 1H), 4.68 (d, 2H), 3.45-3.48 (m, 2H), 3.38-3.41 (m, 2H), 3.21 (s, 3H).

[0449] 2-Methoxy-N-((1-Methoxyisoquinoline-4-yl)methyl)propyl-1-amine (VIq)

[0450]

[0451] To a solution of 1.0 g (5.3 mmol, 1.0 eq.) 1-methoxyisoquinoline-4-carboxaldehyde (Va) in 20 mL of methanol, 1.42 g (3.21 mmol, 3.0 eq.) 2-methoxypropyl-1-amine was added, followed by 1.0 g sodium sulfate. The mixture was stirred at room temperature for 16 hours, and 0.30 g (8.0 mmol, 1.5 eq.) sodium borohydride was added. The mixture was then stirred at room temperature for another 4 hours, and volatiles were removed under vacuum. The residue was resuspended in 30 mL of ice-cold water and extracted with 2 × 60 mL of ethyl acetate. The combined organic extracts were washed with 50 mL of water and 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was prepared with 20 mL of n-pentane to provide 1.1 g (4.2 mmol, 79%) 2-methoxy-N-((1-methoxyisoquinoline-4-yl)methyl)propyl-1-amine (VIq). LCMS: Measured m / z value 261.4 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.28 (dd, 1H), 8.05 (d, 1H), 7.93 (s, 1H), 7.68-7.72 (m, 1H), 7.51-7.56 (m, 1 H), 4.11(s, 3H), 4.06(d, 2H), 3.44(t, 2H), 3.30(s, 3H), 2.80(t, 2H), 1.80(m, 2H), 1.68(bs, 1H).

[0452] 3-(3-Chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)-1-(3-methoxypropyl)urea (Compound 47)

[0453]

[0454] 3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)prop-1-amine (VIq) and benzene 2-chloro-1-fluoro-4-isocyanate were synthesized in a similar manner to that described above. LCMS: m / z measured 432.3 / 434.2 [M+H] + RT = 5.52 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ8.57 (s, 1H), 8.23 ​​(d, 1H), 8.06 (d, 1H), 7.91 (s, 1H), 7.78-7.85 (m, 2H), 7.66 (t, 1H), 7.42-7.47 (m, 1H), 7.31 (t, 1H), 4.89 (s, 2H), 4.06 (s, 3H), 3.26-3.31 (m, 4H), 3.17 (s, 3H), 1.67-1.74 (m, 2H).

[0455] 4-(((2-Methoxypropyl)amino)methyl)isoquinoline-1(2H)-one hydrochloride (VIIIak)

[0456]

[0457] Add 5 mL of 4 M HCl in p-dioxane to a 5 mL methanol solution of 0.50 g (2.44 mmol, 1.0 eq.) 2-methoxy-N-((1-methoxyisoquinoline-4-yl)methyl)propyl-1-amine (VIq) in a sealed tube. Seal the container and heat the mixture at 80 °C for 6 hours. Allow the mixture to cool to room temperature and remove the solvent under vacuum. Prepare the residue with 10 mL of diethyl ether and dry under high vacuum to provide 0.4 g (1.42 mmol, 58%) 4-(((2-methoxypropyl)amino)methyl)isoquinoline-1(2H)-one hydrochloride (VIIIak). LCMS: m / z measured 247.5 [M+H] + .

[0458] 3-(3-Chloro-4-fluorophenyl)-1-(2-methoxypropyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 51)

[0459]

[0460] 3-(3-chloro-4-fluorophenyl)-1-(2-methoxypropyl)-1-((1-oxo-1,2-dihydroisoquinoline-4-yl)methyl)urea (compound 51) was synthesized from 4-(((2-methoxypropyl)amino)methyl)isoquinoline-1(2H)-one hydrochloride (VIIIak) and benzene 2-chloro-1-fluoro-4-isocyanate in a similar manner to that described above. LCMS: m / z measured 418.2 / 420.2 [M+H] + RT = 4.15 min (Method A); 1 H NMR (400MHz, DMSO-d6) δ11.14 (bd, 1H), 8.54 (bs, 1H), 8.25 (d, 1H), 7.71-7.81 (m, 3H), 7.42-7.55 ( m, 2H), 7.31 (t, 1H), 7.11 (d, 1H), 4.64 (s, 2H), 3.26-3.31 (m, 4H), 3.17 (s, 3H), 1.65-1.72 (m, 2H).

[0461] N-Benzyl-1-(1-Methoxyisoquinoline-4-yl)methylamine (VIr)

[0462]

[0463] Add 0.32 μL (0.29 mmol, 1.1 eq.) benzylamine and 0.05 g sodium sulfate to a solution of 0.05 g (0.27 mmol, 1.0 eq.) 1-methoxyisoquinoline-4-carboxaldehyde (Va) in 3 mL of 1,2-dichloroethane. Stir the mixture at room temperature for 16 hours, and then add a stirred solution of 0.039 g (1.03 mmol, 3.8 eq.) sodium borohydride in 1 mL of methanol. Stir the mixture at room temperature for 30 min, dilute with 0.5 mL of acetone, and stir for another 20 min. Remove the solvent under vacuum, and partition the residue between 5 mL of ethyl acetate and 5 mL of saturated sodium carbonate solution. Separate the layers, and extract the aqueous phase with 5 mL of ethyl acetate. Dry the combined organic extracts (Na₂SO₄), filter, and remove the solvent under vacuum to provide 0.07 g N-benzyl-1-(1-methoxyisoquinoline-4-yl)methylamine (VIr). LCMS: m / z measured value 279.2 [M+H] + RT = 2.90 min (Method A).

[0464] 1-Benzyl-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea (Compound 48)

[0465]

[0466] 1-Benzyl-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinoline-4-yl)methyl)urea (compound 48) was synthesized from N-benzyl-1-(1-methoxyisoquinoline-4-yl)methylamine (VIr) and 4-fluoro-3-chlorophenyl isocyanate in a similar manner to that described above. LCMS: m / z measured 450.4.1 / 452.1 [M+H] + RT = 6.11 min (Method A).

[0467] Isoquinoline-4-carboxaldehyde

[0468]

[0469] At -78 °C under a nitrogen atmosphere, 30 mL (48.1 mmol, 2.0 eq.) of a solution of 4-bromoisoquinoline in 100 mL of a 1:3 v / v diethyl ether:THF solution was added. The mixture was stirred at -78 °C for 30 min, and then 4.5 mL (60.1 mmol, 2.5 eq.) of DMF was added. The mixture was stirred at -78 °C for another 30 min, quenched with 50 mL of saturated ammonium chloride solution, and extracted with 2 × 100 mL of ethyl acetate. The combined organic extracts were washed with 50 mL of water and 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by rapid chromatography (SiO2, eluting with a linear gradient of 10–15% ethyl acetate / petroleum ether) to provide 1.0 g (6.4 mmol, 26%) of isoquinoline-4-carboxaldehyde. LCMS: m / z 158.0 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ10.40 (s, 1H), 9.44 (s, 1H), 9.21 (d, 1H), 9.0 (d, 1H), 8.10 (d, 1H), 7.92 (t, 1H), 7.75 (t, 1H).

[0470] N-(isoquinoline-4-ylmethyl)ethylamine

[0471]

[0472] To a solution of 1.0 g (6.36 mmol, 1.0 eq.) isoquinoline-4-carboxaldehyde in 10 mL of methanol, 10 mL (20.0 mmol, 3.1 eq.) of 2 M ethylamine in THF was added, followed by the addition of 1.0 g of sodium sulfate. The mixture was stirred at room temperature for 16 hours, and then 0.24 g (6.36 mmol, 1.0 eq.) of sodium borohydride was added. The mixture was stirred at room temperature for another 4 hours, and then diluted with 30 mL of ice-cold water. The mixture was extracted with 3 × 70 mL of ethyl acetate, and the combined organic extracts were washed with 50 mL of water and 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum to provide 0.8 g (4.30 mmol, 67%) of N-(isoquinoline-4-ylmethyl)ethylamine. 1 H NMR (400MHz, CDCl3) δ9.18 (s, 1H), 8.48 (s, 1H), 8.15 (d, 1H), 8.00 (d, 1H), 7.77 (t, 1H), 7.61 (t, 1H), 4.20 (s, 2H), 2.80 (q, 2H), 1.20 (t, 3H).

[0473] 3-(3-Chloro-4-fluorophenyl)-1-ethyl-1-(isoquinoline-4-ylmethyl)urea (Compound 16)

[0474]

[0475] 0.83 g (2.68 mmol, 1.0 eq.) of 4-nitrophenyl-(3-chloro-4-fluorophenyl)carbamate was added to a stirred solution of 0.5 g (2.68 mmol, 1.0 eq.) N-(isoquinoline-4-ylmethyl)ethylamine in 10 mL of anhydrous THF, and the mixture was heated at 80 °C for 16 h. The reaction mixture was quenched with 50 mL of water and extracted with 3 × 50 mL of water. The combined organic extracts were washed with 50 mL of water and 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by rapid chromatography (SiO₂, eluted with a linear gradient of 20–30% ethyl acetate / hexane) to provide 0.14 g (0.64 mmol, 26%) of 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(isoquinoline-4-ylmethyl)urea (compound 16). LCMS: Measured m / z value 358.2 / 360.2 [M+H] + RT = 2.86 min (Method A); 1 H NMR (300MHz, DMSO-d6) δ9.27 (s, 1H), 8.62 (s, 1H), 8.39 (s, 1H), 8.17 (d, 2H), 7.79-7.87 (m, 2H ), 7.72(t, 1H), 7.46-7.52(m, 1H), 7.30(t, 1H), 5.02(s, 2H), 3.33-3.39(q, 2H), 1.04(t, 3H).

[0476] 1-Methoxyisoquinoline-4-carboxylic acid (Vd)

[0477]

[0478] A solution of 10.0 g (42 mmol, 1.0 eq.) of 4-bromo-1-methoxyisoquinoline (IVa) in 600 mL of anhydrous THF was added to 52.5 mL (84 mmol, 1.5 eq.) of 1.6 M n-butyllithium. The mixture was stirred at -78 °C for 2 hours, and then crushed dry ice was poured in and the temperature was raised to room temperature. The mixture was diluted with 1.5 L of water and acidified with 10% citric acid solution. The resulting precipitate was collected by filtration and dried under high vacuum to provide 5.3 g (26.1 mmol, 61%) of 1-methoxyisoquinoline-4-carboxylic acid (Vd). LCMS: m / z 204.0 [M+H] + ;1 ¹H NMR (400MHz, DMSO-d6): δ 13.02 (bs, ¹H), 8.93–8.95 (d, ¹H), 8.73 (s, ¹H), 8.26–8.29 (d, ¹H), 7.86–7.92 (dd, ¹H), 7.67–7.72 (dd, ¹H), 4.14 (s, ³H). The above detailed reaction was performed in multiple batches at a scale of 10 g, and the results were consistent.

[0479] N,1-Dimethoxy-N-methylisoquinoline-4-carboxamide (Ve)

[0480]

[0481] To a solution of 10.6 g (52.2 mmol, 1.0 eq.) 1-methoxyisoquinoline-4-carboxylic acid (Vd) in 50 mL of anhydrous DMF, 14 mL (156.6 mmol, 3.0 eq.) of N,N-diisopropylethylamine was added, followed by 3.81 g (78.3 mmol, 1.5 eq.) of N,O-dimethylhydroxylamine and 14.9 g (78.3 mmol, 1.5 eq.) of HATU. The mixture was stirred at room temperature for 16 hours. The mixture was then diluted with 100 mL of water and extracted with 3 × 50 mL of ethyl acetate. The combined organic extracts were washed with 50 mL of brine, dried (Na2SO4), filtered, and the solvent was removed under vacuum. The residue was purified by rapid chromatography (SiO2, eluting with a linear gradient of 0-20% ethyl acetate / hexane) to provide 9.0 g (36.6 mmol, 70%) of N-1-dimethoxy-N-methylisoquinoline-4-carboxamide (Ve). LCMS: m / z determined 247.05 [M+H] + ; 1 H NMR (400MHz, CDCl3): δ 8.29 (d, 1H), 8.14 (s, 1H), 7.87 (d, 1H), 7.71 (dd, 1H), 7.57 (dd, 1H), 4.16 (s, 3H), 3.56 (s, 3H), 3.42 (s, 3H).

[0482] 1-(1-Methoxyisoquinoline-4-yl)ethyl-1-one (Vf)

[0483]

[0484] A solution of 9.0 g (36.6 mmol, 1.0 eq.) of N-1-dimethoxy-N-methylisoquinoline-4-carboxamide (Ve) in 90 mL of anhydrous THF was added to 60.9 mL (182.9 mmol, 5 eq.) of 3.0 M methyl magnesium bromide in THF. The mixture was heated to room temperature and stirred for 16 hours. The reaction mixture was slowly quenched with 750 mL of saturated ammonium chloride solution and extracted with 3 × 250 mL of ethyl acetate. The combined organic extracts were washed with 250 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was prepared with n-pentane to provide 6.7 g (27.2 mmol, 91%) of 1-(1-methoxyisoquinoline-4-yl)ethyl-1-one (Vf). LCMS: m / z 202.3 [M+H] + ; 1 H NMR (300MHz, CDCl3): δ9.03 (d, 1H), 8.71 (s, 1H), 8.30 (d, 1H), 7.79 (dd, 1H), 7.59 (dd, 1H), 4.20 (s, 3H), 2.71 (s, 3H).

[0485] (1-(1-Methoxyisoquinoline-4-yl)ethylamine (VId)

[0486]

[0487] 1.64 g (23.7 mmol, 2.0 eq.) of hydroxylamine hydrochloride was added to a solution of 2.4 g (11.9 mmol, 1.0 eq.) of 1-(1-methoxyisoquinoline-4-yl)ethyl-1-one (Vf) in 24 mL of pyridine, and the mixture was stirred at room temperature for 4 hours. The solvent was removed under vacuum, and the residue was prepared with n-pentane to provide 1.2 g of 1-(1-methoxyisoquinoline-4-yl)ethyl-1-one oxime. LCMS: m / z measured 217.3 [M+H] + The residue was redissolved in 10 mL of ethanol, and 1.0 g of wet Raney nickel was added. The mixture was then stirred for 16 hours at room temperature under a hydrogen atmosphere (1 atm). The mixture was filtered and the pad was washed with 2 × 10 mL of ethanol. The solvent was removed under vacuum to provide 0.7 g of racemic 1-(1-methoxyisoquinoline-4-yl)ethylamine (VId). 1 H NMR (400MHz, CDCl3): δ 8.30 (d, 1H), 8.11 (s, 1H), 8.06 (d, 1H), 7.71 (t, 1H), 7.54 (t, 1H), 4.72 (q, 1H), 4.12 (s, 3H), 1.57 (d, 3H).

[0488] 4-(1-Aminoethyl)isoquinoline-1(2H)-one (VIIId)

[0489]

[0490] A solution of 0.5 g (2.47 mmol, 1.0 eq.) of 1-(1-methoxyisoquinoline-4-yl)ethyl-1-amine (VId) in 5 mL of 47% HBr aqueous solution was heated at 80 °C for 6 hours. The mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was dried under high vacuum to provide 0.5 g of 4-(1-aminoethyl)isoquinoline-1(2H)-one (VIIId).

[0491] 1-(3-chloro-4-fluorophenyl)-3-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea (compounds 10 & 11)

[0492]

[0493] At 0 °C, 1.9 mL (13.2 mmol, 3.0 eq.) of triethylamine was added to a solution of 0.5 g (2.65 mmol, 1.0 eq.) of racemic 4-(1-aminoethyl)isoquinoline-1(2H)-one (VIIId) in 20 mL of dichloromethane, followed by the addition of 0.27 g (1.59 mmol, 0.6 eq.) of 4-fluoro-3-chlorophenyl isocyanate. The mixture was heated to room temperature, stirred for 1 hour, and the solvent was removed under vacuum. The residue was redissolved in 50 mL of dichloromethane and washed with 20 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by preparation with n-pentane to provide 0.51 g (1.42 mmol, 53%) of racemic 1-(3-chloro-4-fluorophenyl)-3-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea. LCMS: m / z measured value 360.1 / 362.1 [M+H] + The enantiomers were then separated using an SFC-Waters SFC-200 column-Chiralpak IC (30×250mm), 5μm, 75% CO2:MeOH, at a flow rate of 100g / min.

[0494] 1-(3-chloro-4-fluorophenyl)-3-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea: enantiomer I (compound 10), 92 mg. LCMS: m / z measured 360.2 / 362.2 [M+H] + RT = 3.72 min (Method A); 1¹H NMR (400MHz, DMSO-d6): δ 11.25 (d, 1H), 8.53 (s, 1H), 8.25 (d, 1H), 7.76–7.79 (m, 3H), 7.50–7.54 (m, 1H), 7.27 (t, 1H), 7.18–7.22 (m, 1H), 7.11 (d, 1H), 6.62 (d, 1H), 5.17 (t, 1H), 1.47 (d, 3H); Chiral analysis: SFC, RT = 2.18 min, column: Chiralpak IC (150 × 4.6 mm) 3 μm, 70% CO₂: MeOH, flow rate = 3.0 g / min.

[0495] 1-(3-chloro-4-fluorophenyl)-3-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea: enantiomer II (compound 11), 93 mg. LCMS: m / z measured 360.2 / 362.2 [M+H] + RT = 3.72 min (Method A); 1 ¹H NMR (400MHz, DMSO-d6): δ 11.22 (d, 1H), 8.53 (s, 1H), 8.25 (d, 1H), 7.76–7.79 (m, 3H), 7.50–7.54 (m, 1H), 7.27 (t, 1H), 7.18–7.22 (m, 1H), 7.11 (d, 1H), 6.62 (d, 1H), 5.17 (t, 1H), 1.47 (d, 3H); Chiral analysis: SFC, RT = 3.15 min, column: Chiralpak IC (150 × 4.6 mm) 3 μm, 70% CO₂: MeOH, flow rate = 3.0 g / min.

[0496] (1-(1-methoxyisoquinoline-4-yl)ethyl)tert-butyl carbamate (VIe)

[0497]

[0498] Add 0.54 g (2.46 mmol, 1.0 eq.) of di-tert-butyl dicarbonate to a solution of 0.5 g (2.46 mmol, 1.0 eq.) of 1-(1-methoxyisoquinoline-4-yl)ethyl-1-one (VId) in 5 mL of methanol, and stir the mixture at room temperature for 16 hours. Remove the solvent under vacuum, and redissolve the residue in 50 mL of ethyl acetate. Wash the organic solution with 20 mL of brine, dry (Na2SO4), filter, and remove the solvent under vacuum to provide 0.40 g (1.32 mmol, 54%) of (1-(1-methoxyisoquinoline-4-yl)ethyl)carbamate tert-butyl ester (VIe). 1H NMR (400MHz, CDCl3): δ8.29 (d, 1H), 7.97-8.01 (m, 2H), 7.72 (t, 1H), 7.56 (t, 1 H), 5.41 (brs, 1H), 4.75-4.80 (m, 1H), 4.12 (s, 3H), 1.63 (d, 3H), 1.44 (s, 9H).

[0499] 1-(1-Methoxyisoquinoline-4-yl)-N-methylethyl-1-amine (VIf)

[0500]

[0501] 0.2 g (5.28 mmol, 4.0 eq.) of lithium aluminum hydride was added to a solution of 0.40 g (1.32 mmol, 1.0 eq.) of tert-butyl carbamate (VIe) in 10 mL of THF at 0 °C under a nitrogen atmosphere. The reaction mixture was then heated to 50 °C for 16 hours. The mixture was cooled to 0 °C and slowly quenched with an aqueous sodium sulfate solution. Filtration. The pad was washed with 2 × 10 mL THF and the solvent was removed under vacuum to provide 0.20 g (0.92 mmol, 70%) of 1-(1-methoxyisoquinoline-4-yl)-N-methylethyl-1-amine (VIf). LCMS: m / z measured 186.0 [M-NHMe] + ; 1 H NMR (400MHz, CDCl3): δ 8.30 (d, 1H), 8.15 (d, 1H), 8.06 (s, 1H), 7.69 (t, 1H), 7.53 (t, 1H), 4.26 (q, 1H), 4.12 (s, 3H), 2.41 (s, 3H), 1.52 (d, 3H).

[0502] 4-(1-(methylamino)ethyl)isoquinoline-1(2H)-one (VIIIf)

[0503]

[0504] A solution of 0.20 g (0.92 mmol, 1.0 eq.) of 1-(1-methoxyisoquinoline-4-yl)-N-methylethyl-1-amine (VIf) in 2.5 mL of 47% aqueous hydrobromic acid was heated at 80 °C for 6 hours. The mixture was cooled to room temperature and evaporated to dryness to provide 0.35 g of crude 4-(1-(methylamino)ethyl)isoquinoline-1(2H)-one hydrobromide (VIIIf). LCMS: m / z measured 172.16 [M-NHMe] + .

[0505] 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea (compounds 12, 13 & 14)

[0506]

[0507] At 0 °C, 1.2 mL (8.7 mmol) of triethylamine was added to a solution of 0.35 g of crude 4-(1-(methylamino)ethyl)isoquinoline-1(2H)-one hydrobromide (VIIIf) in 10 mL of a 1:1 (v / v) dichloromethane:DMF. Then, 0.30 g (1.73 mmol) of 4-fluoro-3-chlorophenyl isocyanate was added. The mixture was heated to room temperature and stirred for 2 hours. The solvent was removed under vacuum, and the residue was redissolved in 100 mL of ethyl acetate. The organic solution was washed with 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by preparative HPLC to provide 90 mg of racemic 1-(3-chloro-4-fluorophenyl)-3-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea (compound 12). LCMS: m / z measured value 374.1 / 376.1 [M+H] + The enantiomers were then separated by an SFC (Waters SFC-80) column, Chiralcel OD-H (21×250mm), 5μm, 85% CO2:MeOH, at a flow rate of 70g / min.

[0508] 3-(3-Chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea: enantiomer I (compound 13). LCMS: m / z measured 374.2 / 376.2 [M+H] + RT = 3.83 min (Method A); 1 ¹H NMR (400MHz, DMSO-d6): δ 11.45 (bs, 1H), 8.48 (bs, 1H), 8.24 (d, 1H), 7.87 (dd, 1H), 7.69–7.73 (m, 2H), 7.47–7.53 (m, 2H), 7.31 (t, 1H), 7.16 (s, 1H), 5.85 (q, 1H), 2.58 (s, 3H), 1.43 (d, 3H); Chiral analysis: SFC, RT = 4.13 min, column: Chiralcel OD-H (250 × 4.6 mm) 5 μm, 70% CO₂: MeOH, flow rate = 3.0 g / min.

[0509] 3-(3-Chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea: enantiomer II (compound 14). LCMS: m / z measured 374.2 / 376.2 [M+H] + RT = 3.83 min (Method A); 1 ¹H NMR (400MHz, DMSO-d6): δ 11.45 (bs, 1H), 8.48 (bs, 1H), 8.24 (d, 1H), 7.87 (dd, 1H), 7.69–7.73 (m, 2H), 7.47–7.53 (m, 2H), 7.31 (t, 1H), 7.16 (s, 1H), 5.85 (q, 1H), 2.58 (s, 3H), 1.43 (d, 3H); Chiral analysis: SFC, RT = 5.58 min, column: Chiralcel OD-H (250 × 4.6 mm) 5 μm, 70% CO₂: MeOH, flow rate = 3.0 g / min.

[0510] 1,3-Dimethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea (compound 298)

[0511]

[0512] In a nitrogen atmosphere, 0.3 g (1.48 mmol, 1.0 eq.) of a solution of 4-(1-(methylamino)ethyl)isoquinoline-1(2H)-one (VIIIf) in 3 mL of THF was added to a sealed tube, followed by 0.8 mL (4.45 mmol, 3.0 eq.) of N,N-diisopropylethylamine, and then 0.28 g (2.22 mmol, 1.5 eq.) of N-methyl-1H-imidazol-1-carboxamide. The mixture was heated at 100 °C for 16 hours. The mixture was cooled to room temperature, diluted with 20 mL of ice-cold water, and extracted with 3 × 100 mL of ethyl acetate. The combined organic extracts were washed with 80 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by preparative HPLC to provide 120 mg (0.46 mmol, 31%) of racemic 1,3-dimethyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea. LCMS: m / z 260.0 [M+H] + The enantiomers were then separated by an SFC (Waters SFC-80) column, Chiralcel OD-H (21×250mm), 5μm, 75% CO2:MeOH, at a flow rate of 70g / min.

[0513] 1,3-Dimethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea: enantiomer I (compound 298). LCMS: m / z measured 260.2 [M+H] + RT = 1.64 min (Method A); 1 ¹H NMR (400MHz, DMSO-d6) δ 11.30 (bs, 1H), 8.21–8.23 (m, 1H), 7.75 (d, 1H), 7.67–7.72 (m, 1H), 7.46–7.51 (m, 1H), 7.07 (s, 1H), 6.22 (m, 1H), 5.75–5.80 (m, 1H), 2.65 (d, 3H), 2.37 (s, 3H), 1.32 (d, 3H); Chiral analysis: SFC, RT = 2.98 min, column: Chiralcel OD-H (250 × 4.6 mm) 5 μm, 75% CO₂: MeOH, flow rate = 3.0 g / min.

[0514] 1,3-Dimethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea: enantiomer II. LCMS: m / z measured 260.2 [M+H] + RT = 1.64 min (Method A); 1 ¹H NMR (400MHz, DMSO-d6) δ 11.30 (bs, 1H), 8.21–8.23 (m, 1H), 7.75 (d, 1H), 7.67–7.72 (m, 1H), 7.46–7.51 (m, 1H), 7.07 (s, 1H), 6.22 (m, 1H), 5.75–5.80 (m, 1H), 2.65 (d, 3H), 2.37 (s, 3H), 1.32 (d, 3H); Chiral analysis: SFC, RT = 4.28 min, column: Chiralcel OD-H (250 × 4.6 mm) 5 μm, 75% CO₂: MeOH, flow rate = 3.0 g / min.

[0515] 3-Cyclopentyl-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea (compound 299)

[0516]

[0517] Racemic 3-cyclopentyl-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea was synthesized from 4-(1-(methylamino)ethyl)isoquinoline-1(2H)-one (VIIIf) and cyclopentyl isocyanate in a similar manner to that described above. The enantiomers were then separated by SFC (Waters SFC-80), Chiralcel OX-H column (21 × 250 mm), 5 μm, 75% CO2: MeOH, flow rate 70 g / min.

[0518] 3-Cyclopentyl-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea: enantiomer I (compound 299). LCMS: m / z measured 314.1 [M+H] + RT = 3.11 min (Method A); 1 ¹H NMR (400MHz, DMSO-d6) δ 11.30 (bs, 1H), 8.22 (d, 1H), 7.75 (d, 1H), 7.65–7.69 (m, 1H), 7.45–7.51 (m, 1H), 7.06 (d, 1H), 5.95 (bd, 1H), 5.75–5.80 (m, 1H), 3.98–4.05 (m, 1H), 2.37 (s, 3H), 1.79–1.89 (m, 2H), 1.57–1.66 (m, 2H), 1.34–1.51 (m, 4H), 1.33 (d, 3H); Chiral analysis: SFC, RT = 3.18 min, column: Chiralcel OX-3 (150×4.6mm) 3μm, 70% CO2:MeOH, flow rate = 3.0g / min.

[0519] 3-Cyclopentyl-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea: enantiomer II. LCMS: m / z measured 314.1 [M+H] + RT = 3.11 min (Method A); 1¹H NMR (400MHz, DMSO-d6) δ 11.30 (bs, 1H), 8.22 (d, 1H), 7.75 (d, 1H), 7.65–7.69 (m, 1H), 7.45–7.51 (m, 1H), 7.06 (d, 1H), 5.95 (bd, 1H), 5.75–5.80 (m, 1H), 3.98–4.05 (m, 1H), 2.37 (s, 3H), 1.79–1.89 (m, 2H), 1.57–1.66 (m, 2H), 1.34–1.51 (m, 4H), 1.33 (d, 3H); Chiral analysis: SFC, RT = 6.07 min, column: Chiralcel OX-3 (150×4.6mm) 3μm, 70% CO2:MeOH, flow rate = 3.0g / min.

[0520] 4-Acetylisoquinoline-1(2H)-one (XXa)

[0521]

[0522] A solution of 3.0 g (14.92 mmol, 1.0 eq.) of 1-(1-methoxyisoquinoline-4-yl)ethyl-1-one (Vf) in 30 mL of methanol was added to 15 mL of 4 M HCl in 1,4-dioxane. The mixture was then heated at 70 °C for 3 hours. The mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was prepared with diethyl ether and dried under high vacuum to provide 2.2 g (11.76 mmol, 78%) of 4-acetylisoquinoline-1(2H)-one (XXa). LCMS: m / z measured 188.2 [M+H] + ; 1 H NMR (300MHz, DMSO-d6): δ 12.00 (bs, 1H), 8.91 (d, 1H), 8.25 (d, 1H), 8.19 (d, 1H), 7.78 (t, 1H), 7.55 (t, 1H), 2.53 (s, 3H).

[0523] 4-(1-((cyclopentylmethyl)amino)ethyl)isoquinoline-1(2H)-one (VIIIb)

[0524]

[0525] In a nitrogen atmosphere, a solution of 0.5 g (2.67 mmol, 1.0 eq.) of 4-acetylisoquinoline-1(2H)-one (XXa) in 5 mL of isopropoxytitanium (IV) was added to a solution of 0.4 g (4.01 mmol, 1.5 eq.) of cyclopentylmethylamine in 5 mL of anhydrous THF, and the mixture was heated at 90 °C for 16 hours. The mixture was then cooled to room temperature and then further cooled to 0 °C. The mixture was diluted with 2 mL of methanol and 0.20 g (5.34 mmol, 2.0 eq.) of sodium borohydride was added. The mixture was then heated to room temperature and stirred for 1 hour. The reaction mixture was quenched by adding 20 mL of water and then... Filter. Wash the pad with 5 mL of ethyl acetate and extract the two-phase mixture with 2 × 30 mL of ethyl acetate. Dry the combined organic extracts (Na₂SO₄), filter, and remove the solvent under vacuum to provide 0.6 g (2.21 mmol, 82%) of 4-(1-((cyclopentylmethyl)amino)ethyl)isoquinoline-1(2H)-one (VIIIb). LCMS: m / z 271.1 [M+H] + ; 1 H NMR (300MHz, DMSO-d6): δ11.16 (bs, 1H), 8.21-8.25 (m, 1H), 8.02 (d, 1H), 7.67-7.73 (m, 1H), 7.45-7.49 (m, 1H), 7.15 (d, 1H), 3 .99-4.03 (m, 1H), 2.40-2.43 (m, 1H), 2.29-2.33 (m, 1H), 1.87-1.96 (m, 2H), 1.39-1.71 (m, 6H), 1.32 (d, 3H), 1.12-1.19 (m, 2H).

[0526] 3-(3-Chloro-4-fluorophenyl)-1-(cyclopentylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea (compounds 192 & 193)

[0527]

[0528] 0.27 mL (2.22 mmol, 1.0 eq.) of 2-chloro-1-fluoro-4-isocyanate benzene was added to a stirred solution of 0.6 g (2.21 mmol, 1.0 eq.) of 4-(1-((cyclopentylmethyl)amino)ethyl)isoquinoline-1(2H)-one (VIIIb) in 6 mL of dichloromethane at 0 °C under a nitrogen atmosphere. The mixture was heated to room temperature and stirred for 1 hour. The mixture was diluted with 10 mL of water and extracted with 2 × 20 mL of dichloromethane. The combined organic extracts were dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was redissolved in 5 mL of methanol, and 0.61 g (4.44 mmol, 2.0 eq.) of potassium carbonate was added. The resulting mixture was stirred at room temperature for 2 hours. Volatile substances were removed under vacuum, and the residue was suspended in 10 mL of water and extracted with 2 × 30 mL of ethyl acetate. The combined organic extracts were washed with 30 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by column chromatography (SiO₂, with a linear gradient elution of 0–5% methanol in dichloromethane) to provide 0.30 g (0.68 mmol, 31%) of racemic 3-(3-chloro-4-fluorophenyl)-1-(cyclopentylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea. LCMS: m / z 442.39 [M+H] + The enantiomers were then separated by SFC (Waters SFC-80), Lux Cellulose-2 column (30x250mm) 5μm, 70% CO2:MeOH, flow rate 70g / min, to provide 92mg and 89mg of separated enantiomers.

[0529] 3-(3-Chloro-4-fluorophenyl)-1-(cyclopentylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea: enantiomer I (compound 192). LCMS: m / z measured 442.3 / 444.3 [M+H] + RT = 7.72 min (Method A); 1¹H NMR (400MHz, DMSO-d6): δ 11.39 (br s, 1H), 8.45 (br s, 1H), 8.24 (d, 1H), 7.84–7.73 (m, 3H), 7.52–7.47 (m, 2H), 7.32 (t, 1H), 7.22 (d, 1H), 5.81–5.84 (m, 1H), 2.99–3.11 (m, 2H), 1.64–1.69 (m, 1H), 1.46 (d, 3H), 1.33–1.42 (m, 2H), 0.99–1.29 (m, 5H), 0.66–0.72 (m, 1H); Chiral analysis: SFC: RT = 7.07 min, column: Lux Cellulose-2 (250×4.6mm), 5μm, 70% CO2:MeOH, flow rate = 3.0mL / min.

[0530] 3-(3-Chloro-4-fluorophenyl)-1-(cyclopentylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea: enantiomer II (compound 193). LCMS: m / z measured 442.3 / 444.3 [M+H] + RT = 7.66 min (Method A); 1 ¹H NMR (400MHz, DMSO-d6): δ 11.39 (br s, 1H), 8.45 (br s, 1H), 8.24 (d, 1H), 7.84–7.73 (m, 3H), 7.52–7.47 (m, 2H), 7.32 (t, 1H), 7.22 (d, 1H), 5.81–5.84 (m, 1H), 2.99–3.11 (m, 2H), 1.64–1.69 (m, 1H), 1.46 (d, 3H), 1.33–1.42 (m, 2H), 0.99–1.29 (m, 5H), 0.66–0.72 (m, 1H); Chiral analysis: SFC: RT = 11.35 min, column: Lux Cellulose-2 (250×4.6mm), 5μm, 70% CO2:MeOH, flow rate = 3.0mL / min.

[0531] 4-(1-(isobutylamino)ethyl)isoquinoline-1(2H)-one (VIIIe)

[0532]

[0533] In a nitrogen atmosphere, 0.12 g (1.6 mmol, 1.5 eq.) of isobutylamine was added to a solution of 0.2 g (1.06 mmol, 1.0 eq.) of 4-acetylisoquinoline-1(2H)-one (XXa) in 5 mL of THF, followed by 2 mL of isopropoxytitanium (IV). The mixture was heated to 90 °C for 6 hours. The mixture was then cooled to room temperature and then further cooled to 0 °C. The mixture was then diluted with 2 mL of methanol and 0.08 g (2.13 mmol, 2.0 eq.) of sodium borohydride was added. The mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was quenched by adding 20 mL of water and then... Filter. Wash the pad with 5 mL of ethyl acetate and extract the two-phase mixture with 2 × 30 mL of ethyl acetate. Wash the combined organic extracts with 20 mL of brine, dry (Na₂SO₄), filter, and remove the solvent under vacuum to provide 0.25 g (1.02 mmol, 96%) of 4-(1-(isobutylamino)ethyl)isoquinoline-1(2H)-one (VIIIe). LCMS: m / z determined 245.1 / 247.1 [M+H] + ; 1 H NMR (300MHz, DMSO-d6): δ11.09 (br s 1H), 8.22-8.25(m, 1H), 8.02(d, 1H), 7.68-7.74(m, 1H), 7.48(t, 1H), 7.15(d, 1H), 3.99-4.06(m , 2H), 2.31-2.37(m, 1H), 2.16-2.22(m, 1H), 1.58-1.69(m, 1H), 1.33(d, 3H), 0.82-0.87(m, 6H).

[0534] 3-(3-Chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea (compounds 135, 143 & 144)

[0535]

[0536] 0.18 g (1.02 mmol, 1.0 eq.) of 2-chloro-1-fluoro-4-isocyanate benzene was added to a stirred solution of 0.25 g (1.02 mmol, 1.0 eq.) of racemic 4-(1-(isobutylamino)ethyl)isoquinoline-1(2H)-one (VIIIe) in 10 mL of dichloromethane at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 0 °C for 2 hours. The mixture was diluted with 10 mL of water and extracted with 2 × 30 mL of ethyl acetate. The combined organic extracts were washed with 30 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by preparation with 25 mL of methyl tert-butyl ether to provide 0.37 g (0.85 mmol, 83%) of racemic 3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea (compound 135). LCMS: m / z measured 416.1 / 418.1 [M+H] + The enantiomers were then separated by an SFC (Waters SFC-80) column, LuxCellulose-2 (30x250mm) 5μm, 65% CO2:MeOH, at a flow rate of 70g / min, to provide 86mg and 90mg of separated enantiomers.

[0537] 3-(3-Chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea: enantiomer I (compound 143). LCMS: m / z measured 416.3 / 418.3 [M+H] + RT = 6.91 min (Method A); 1 HNMR (400MHz, DMSO-d6): δ 11.40 (bd, 1H), 8.40 (bs, 1H), 8.23 ​​(d, 1H), 7.73–7.83 (m, 3H), 7.47–7.52 (m, 2H), 7.32 (t, 1H), 7.22 (d, 1H), 5.83–5.88 (m, 1H), 2.89–2.93 (m, 2H), 1.47 (d, 3H), 1.32–1.38 (m, 1H), 0.61 (d, 3H), 0.48 (d, 3H); Chiral analysis: SFC: RT = 1.09 min, column: CHIRALCEL OZ-3 (150mm×4.6mm) 3μm; 60% CO2:MeOH); Flow rate = 3.0mL / min.

[0538] 3-(3-Chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea: enantiomer II (compound 144). LCMS: m / z measured 416.3 / 418.3 [M+H] + RT = 6.91 min (Method A); 1 HNMR (400MHz, DMSO-d6): δ 11.40 (bd, 1H), 8.40 (bs, 1H), 8.23 ​​(d, 1H), 7.73–7.83 (m, 3H), 7.47–7.52 (m, 2H), 7.32 (t, 1H), 7.22 (d, 1H), 5.83–5.88 (m, 1H), 2.89–2.93 (m, 2H), 1.47 (d, 3H), 1.32–1.38 (m, 1H), 0.61 (d, 3H), 0.48 (d, 3H); Chiral analysis: SFC: RT = 1.49 min, column: CHIRALCEL OZ-3 (150mm×4.6mm) 3μm; 60% CO2:MeOH); Flow rate = 3.0g / min.

[0539] N-Ethyl-1-(1-Methoxyisoquinoline-4-yl)ethyl-1-amine (VIw)

[0540]

[0541] To a sealed tube, 1.2 g (6.0 mmol, 1.0 eq.) of a solution of 1-(1-methoxyisoquinoline-4-yl)ethyl-1-one (Vf) in 12 mL of methanol was added to 15 mL (30.0 mmol, 5.0 eq.) of 2 M ethylamine in THF, followed by 0.06 mL (1.19 mmol, 0.2 eq.) of acetic acid. The mixture was then heated at 70 °C for 24 hours. The mixture was cooled to room temperature, and 0.43 g (11.9 mmol, 2.0 eq.) of sodium borohydride was added. Stirring was continued for another 2 hours, and the solvent was removed under vacuum. The residue was diluted with 70 mL of ice-cold water and extracted with 3 × 70 mL of ethyl acetate. The combined organic extracts were washed with 50 mL of water and 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by chromatography (neutral alumina, eluted with a linear gradient of 0-10% ethyl acetate / hexane) to provide 0.78 g (3.39 mmol, 57%) of N-ethyl-1-(1-methoxyisoquinoline-4-yl)ethyl-1-amine (VIw). LCMS: m / z 231.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.30 (d, 1H), 8.15 (d, 1H), 8.09 (s, 1H), 7.69 (t, 1H), 7. 54(t, 1H), 4.41(q, 1H), 4.12(s, 3H), 2.64(q, 2H), 1.53(d, 3H), 1.12(t, 3H).

[0542] 3-(3-Chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea (compounds 22 & 23)

[0543]

[0544] 0.94 g (6.08 mmol, 2.0 eq.) of 4-nitrophenyl (3-chloro-4-fluorophenyl)carbamate was added to a solution of 0.7 g (3.04 mmol, 1.0 eq.) of N-ethyl-1-(1-methoxyisoquinoline-4-yl)ethyl-1-amine (VIw) in 7 mL of anhydrous THF, and the mixture was heated at 60 °C for 16 hours. The mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was redissolved in 100 mL of ethyl acetate, washed with 50 mL of water and 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue product was purified by semi-preparative HPLC to provide 0.39 g (0.98 mmol, 32%) of racemic 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea. LCMS: Measured m / z value 402.2 / 404.2 [M+H] + The enantiomers were then separated by an SFC (Waters SFC-80) column: Chiralpak IC (30×250mm) 5μm, 85% CO2: MeOH, at a flow rate of 100g / min, to provide 110mg and 105mg of separated enantiomers.

[0545] 3-(3-Chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea: enantiomer I (compound 22). LCMS: m / z measured 402.2 / 401.1 [M+H] + RT = 5.34 min (Method A); 1¹H NMR (400MHz, DMSO-d6): δ 8.39 (s, 1H), 8.23 ​​(d, 1H), 8.16 (s, 1H), 7.99 (d, 1H), 7.88 (dd, 1H), 7.82 (t, 1H), 7.63 (t, 1H), 7.52–7.56 (m, 1H), 7.33 (t, 1H), 6.15 (q, 1H), 4.09 (s, 3H), 3.11–3.16 (m, 2H), 1.60 (d, 3H), 0.55 (t, 3H); Chiral analysis SFC: RT = 2.78 min, column: Chiralpak IC (250 × 4.6 mm), 5 μL, 75% CO₂: MeOH, flow rate = 3.0 mL / min.

[0546] 3-(3-Chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea: enantiomer II (compound 23). LCMS: m / z measured 402.2 / 401.1 [M+H] + RT = 5.34 min (Method A); 1 ¹H NMR (400MHz, DMSO-d6): δ 8.39 (s, 1H), 8.23 ​​(d, 1H), 8.16 (s, 1H), 7.99 (d, 1H), 7.88 (dd, 1H), 7.82 (t, 1H), 7.63 (t, 1H), 7.52–7.56 (m, 1H), 7.33 (t, 1H), 6.15 (q, 1H), 4.09 (s, 3H), 3.11–3.16 (m, 2H), 1.60 (d, 3H), 0.55 (t, 3H); Chiral analysis SFC: RT = 3.84 min, column: Chiralpak IC (250 × 4.6 mm), 5 μL, 75% CO₂: MeOH, flow rate = 3.0 mL / min.

[0547] 4-(1-(ethylamino)ethyl)isoquinoline-1(2H)-one (VIIIaq)

[0548]

[0549] A solution of 0.78 g (3.39 mmol, 1.0 eq.) N-ethyl-1-(1-methoxyisoquinoline-4-yl)ethyl-1-amine (VIw) in 8 mL of 48% HBr aqueous solution was heated at 60 °C for 16 h. The mixture was cooled to room temperature, quenched with 200 mL of saturated sodium bicarbonate solution, and extracted with 3 × 75 mL of 10% methanol in dichloromethane. The combined organic extracts were washed with 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by preparation with n-pentane and diethyl ether to provide 0.68 g (3.15 mmol, 92%) 4-(1-(ethylamino)ethyl)isoquinoline-1(2H)-one (VIIIaq). LCMS: m / z 217.2 [M+H] + ; 1 H NMR (300MHz, DMSO-d6) δ11.19 (s, 1H), 8.23 ​​(d, 1H), 8.01 (d, 1H), 7.71 (t, 1H), 7.48 (t, 1H) ), 7.15(s, 1H), 4.05(q, 1H), 2.42-2.47(m, 2H), 1.92(bs, 1H), 1.31(d, 3H), 1.01(t, 3H).

[0550] 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea (compounds 24 & 25)

[0551]

[0552] At 0 °C, 0.7 mL (5.09 mmol, 2.0 eq.) of triethylamine was added to a solution of 0.55 g (2.55 mmol, 1.0 eq.) of 4-(1-(ethylamino)ethyl)isoquinoline-1(2H)-one (VIIIaq) in 10 mL of THF, followed by 0.43 g (2.55 mmol, 1.0 eq.) of benzene 2-chloro-1-fluoro-4-isocyanate. The mixture was heated to room temperature and stirred for 3 hours. The solvent was removed under vacuum, and the residue was redissolved in 100 mL of ethyl acetate, washed with 50 mL of water and 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by reverse-phase chromatography (C-18 column, eluting with a linear gradient of 10-40% [0.1% formic acid aqueous solution] / acetonitrile) to provide 0.33 g (0.84 mmol, 33%) of racemic 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea. LCMS: m / z determined 388.2 [M+H] +The enantiomers were then separated by an SFC (Waters SFC-80) column: Chiralcel OD-H (30×250mm) 5μm, 65% CO2: MeOH, at a flow rate of 90g / min, to provide 110mg and 93mg of separated enantiomers.

[0553] 3-(3-Chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea: enantiomer I (compound 24). LCMS: m / z measured 388.2 / 390.2 [M+H] + RT = 4.05 min (Method: A); 1H NMR (400 MHz, DMSO-d6): δ 11.41 (s, 1H), 8.36 (s, 1H), 8.24 (d, 1H), 7.87 (dd, 1H), 7.71–7.74 (m, 2H), 7.48–7.56 (m, 2H), 7.32 (t, 1H), 7.22 (d, 1H), 5.87 (q, 1H), 3.10–3.17 (m, 2H), 1.45 (d, 3H), 0.66 (t, 3H); Chiral analysis SFC: RT = 2.74 min, column: Chiralcel OD-H (250 × 4.6 mm), 5 μL, 65% CO2: MeOH, flow rate = 3.0 mL / min.

[0554] 3-(3-Chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea: enantiomer II (compound 25). LCMS: m / z measured 388.2 / 390.2 [M+H] + RT = 4.06 min (Method: A); 1H NMR (400 MHz, DMSO-d6): δ 11.41 (s, 1H), 8.36 (s, 1H), 8.24 (d, 1H), 7.87 (dd, 1H), 7.71–7.74 (m, 2H), 7.48–7.56 (m, 2H), 7.32 (t, 1H), 7.22 (d, 1H), 5.87 (q, 1H), 3.10–3.17 (m, 2H), 1.45 (d, 3H), 0.66 (t, 3H); Chiral analysis SFC: RT = 3.91 min, column: Chiralcel OD-H (250 × 4.6 mm), 5 μ, 65% CO2: MeOH, flow rate = 3.0 mL / min.

[0555] N-(1-(1-methoxyisoquinoline-4-yl)ethyl)cyclopropylamine (VIx)

[0556]

[0557] To a sealed tube containing a solution of 0.2 g (1.0 mmol, 1.0 eq.) of 1-(1-methoxyisoquinoline-4-yl)ethyl-1-one (Vf) in 5 mL of methanol, add 0.17 g (3.0 mmol, 3.0 eq.) of cyclopropylamine, followed by 0.01 mL (0.2 mmol, 0.2 eq.) of acetic acid and 0.2 g of sodium sulfate. The mixture is then heated at 50 °C for 16 hours. The mixture is cooled to room temperature, and 0.08 g (2.0 mmol, 2.0 eq.) of sodium borohydride is added. Stirring continues for another 30 min, and the solvent is removed under vacuum. The residue is diluted with 20 mL of ice-cold water and extracted with 3 × 40 mL of ethyl acetate. The combined organic extracts were washed with 50 mL of water and 50 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum to provide 0.2 g (0.82 mmol, 82%) of N-(1-(1-methoxyisoquinoline-4-yl)ethyl)cyclopropylamine (VIx). LCMS: m / z measured 243.5 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ8.30 (d, 1H), 8.17 (d, 1H), 8.05 (s, 1H), 7.66-7.70 (m, 1H), 7.51-7.55 (m, 1H) , 4.46-4.51(q, 1H), 4.12(s, 3H), 2.09-2.14(m, 1H), 1.68(bs, 1H), 1.55(d, 3H), 0.30-0.41(m, 4H).

[0558] 3-(3-Chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea (compounds 56 & 57)

[0559]

[0560] 0.14 g (0.82 mmol, 1.0 eq.) of benzene 2-chloro-1-fluoro-4-isocyanate was added to a stirred solution of 0.2 g (0.82 mmol, 1.0 eq.) of N-(1-(1-methoxyisoquinoline-4-yl)ethyl)cyclopropylamine (VIx) in 5 mL of dichloromethane at 0 °C. The mixture was then heated to room temperature and stirred for 16 hours. The solvent was removed under vacuum and the mixture was analyzed by reverse-phase chromatography (column: C18, the residue was purified by elution with a linear gradient of 10–70% [acetonitrile solution of 0.1% formic acid] / [aqueous solution of 0.1% formic acid] to provide 0.64 g (0.64 mmol, 77%) racemic 3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea. LCMS: m / z determined 414.5 / 416.5 [M+H] + The enantiomers were then separated by an SFC (Waters SFC-80) column: Chiralpak IG (30×250mm) 5μm, 85% CO2: MeOH, at a flow rate of 100g / min, to provide 40mg and 69mg of separated enantiomers.

[0561] 3-(3-Chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea: enantiomer I (compound 56). LCMS: m / z measured 414.2 / 416.1 [M+H] + RT = 5.61 min (Method: A); 1H NMR (400 MHz, DMSO-d6): δ 8.51 (bs, 1H), 8.24 (d, 1H), 8.15 (s, 1H), 7.87–7.92 (dd, 2H), 7.79–7.85 (m, 1H), 7.60–7.66 (m, 1H), 7.52–7.57 (m, 1H), 7.33 (t, 1H), 5.94 (q, 1H), 4.09 (s, 3H), 1.95–1.98 (m, 1H), 1.70 (d, 3H), 0.57–0.73 (m, 3H), 0.11–0.16 (m, 1H); Chiral analysis SFC: RT = 5.55 min, column: Chiralpak IG (250×4.6mm), 5μm, 75% CO2:MeOH, flow rate = 3.0mL / min.

[0562] 3-(3-Chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea: enantiomer II (compound 57). LCMS: m / z measured 414.2 / 416.1 [M+H] +RT = 5.61 min (Method: A); 1H NMR (400 MHz, DMSO-d6): δ 8.51 (bs, 1H), 8.24 (d, 1H), 8.15 (s, 1H), 7.87–7.92 (dd, 2H), 7.79–7.85 (m, 1H), 7.60–7.66 (m, 1H), 7.52–7.57 (m, 1H), 7.33 (t, 1H), 5.94 (q, 1H), 4.09 (s, 3H), 1.95–1.98 (m, 1H), 1.70 (d, 3H), 0.57–0.73 (m, 3H), 0.11–0.16 (m, 1H); Chiral analysis SFC: RT = 7.27 min, column: Chiralpak IG (250×4.6mm), 5μm, 75% CO2:MeOH, flow rate = 3.0mL / min.

[0563] 4-(1-(cyclopropylamino)ethyl)isoquinoline-1(2H)-one (VIIIar)

[0564]

[0565] A solution of 0.40 g (1.65 mmol, 1.0 eq.) N-(1-(1-methoxyisoquinoline-4-yl)ethyl)cyclopropylamine (VIx) in 10 mL of 48% HBr aqueous solution was heated at 80 °C for 4 h. The mixture was cooled to room temperature, quenched with 20 mL of saturated sodium bicarbonate solution, and extracted with 3 × 40 mL of 10% methanol in dichloromethane. The combined organic extracts were washed with 40 mL of brine, dried (Na₂SO₄), filtered, and the solvent was removed under vacuum. The residue was purified by preparation with n-pentane to provide 0.35 4-(1-(cyclopropylamino)ethyl)isoquinoline-1(2H)-one (VIIIar). LCMS: m / z 229.0 [M+H] + ; 1 H NMR (300MHz, DMSO-d6) δ9.91 (bs, 1H), 8.47 (dd, 1H), 7.92 (d, 1H), 7.69-7.74 (m, 1H), 7.49-7.54 (m, 1 H), 7.25 (d, 1H), 4.26-4.32 (m, 1H), 2.10-2.18 (m, 1H), 1.67 (bs, 1H), 1.48 (d, 3H), 0.32-0.46 (m, 4H).

[0566] 3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea (compounds 67 & 68)

[0567]

[0568] 0.24 g (1.4 mmol, 0.9 eq.) of 2-chloro-1-fluoro-4-isocyanate was added to a solution of 0.35 g of 4-(1-(cyclopropylamino)ethyl)isoquinoline-1(2H)-one (VIIIar) in 10 mL of dichloromethane, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under vacuum, and the residue was purified by semi-preparative HPLC to provide 0.32 g (0.80 mmol, 48% from VIx) of racemic 3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea. LCMS: m / z determined 400.2 / 402.2 [M+H] + The enantiomers were then separated by an SFC (Waters SFC-80) column: Chiralpak AD-H (30×250mm) 5μm, 90% CO2: MeOH, at a flow rate of 90 g / min, to provide 121 mg and 78 mg of separated enantiomers.

[0569] 3-(3-Chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea: enantiomer I (compound 67). LCMS: m / z measured 400.2 / 402.2 [M+H] + RT = 5.28 min (Method A); 1 ¹H NMR (400MHz, DMSO-d6): δ 11.37 (d, 1H), 8.49 (s, 1H), 8.24–8.27 (m, 1H), 7.88–7.91 (m, 1H), 7.73–7.77 (m, 1H), 7.63 (d, 1H), 7.48–7.56 (m, 2H), 7.30–7.35 (m, 1H), 7.18–7.19 (m, 1H), 5.63–5.69 (m, 1H), 1.98–2.02 (m, 1H), 1.55 (d, 3H), 0.66–0.71 (m, 3H), 0.23–0.26 (m, 1H); Chiral analysis: SFC: RT = 3.18 min, column: Chiralpak AD-3 (250×4.6mm), 5μm, 80% CO2:MeOH, flow rate = 3.0mL / min.

[0570] 3-(3-Chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-oxo-1,2-dihydroisoquinoline-4-yl)ethyl)urea: enantiomer II (compound 68). LCMS: m / z measured 400.2 / 402.2 [M+H] +RT = 5.28 min (Method A); 1 HNMR (400MHz, DMSO-d6): δ 11.37 (d, 1H), 8.49 (s, 1H), 8.24–8.27 (m, 1H), 7.88–7.91 (m, 1H), 7.73–7.77 (m, 1H), 7.63 (d, 1H), 7.48–7.56 (m, 2H), 7.30–7.35 (m, 1H), 7.18–7.19 (m, 1H), 5.63–5.69 (m, 1H), 1.98–2.02 (m, 1H), 1.55 (d, 3H), 0.66–0.71 (m, 3H), 0.23–0.26 (m, 1H); Chiral analysis: SFC: RT = 4.69 min, column: Chiralpak AD-3 (250×4.6mm), 5μm, 80% CO2:MeOH, flow rate = 3.0mL / min.

[0571] N-(cyclopropylmethyl)-1-(1-methoxyisoquinoline-4-yl)ethyl-1-amine (VIy)

[0572]

[0573] Add 0.53 g (3.0 mmol, 1.0 eq.) of cyclopropylmethylamine to a solution of 0.5 g (2.5 mmol, 1.0 eq.) of 1-(1-methoxyisoquinoline-4-yl)ethyl-1-one (Vf) in 20 mL of methanol, followed by 0.03 g (0.5 mmol, 0.2 eq.) of acetic acid. Heat the mixture at 60 °C for 16 hours. Cool the mixture to room temperature and add 0.19 g (5.0 mmol, 2.0 eq.) of sodium borohydride. Continue stirring for another 30 min and remove the solvent under vacuum. Dilute the residue with 20 mL of ice-cold water and extract with 3 × 40 mL of ethyl acetate. Wash the combined organic extracts with 50 mL of water and 50 mL of brine, dry (Na₂SO₄), filter, and remove the solvent under vacuum. Perform reversed-phase chromatography (…). Purify the residue using a C18 column with a linear gradient of 10–70% acetonitrile / water to provide 0.4 g (1.56 mmol, 82%) of N-(cyclopropylmethyl)-1-(1-methoxyisoquinoline-4-yl)ethyl-1-amine (VIy). LCMS: m / z 257.5 [M+H] + .

[0574] 3-(3-Chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea (compounds 63 & 64)

[0575]

[0576] Racemic 3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl-1-amine (VIy) and 2-chloro-1-fluoro-4-isocyanate benzene were synthesized in a similar manner to that described above. The enantiomers were then separated by SFC column: Chiralpak IC (30 × 250 mm) 5 μm, 85% CO2: MeOH, flow rate 70 g / min.

[0577] 3-(3-Chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea: enantiomer I (compound 63). LCMS: m / z measured 428.1 / 430.1 [M+H] + , RT=6.22min (Method: A); 1HNMR (400MHz, DMSO-d6): δ8.51 (bs, 1H), 8.23 ​​(d, 1H), 8.11 (s, 1H), 7.99 (d, 1H) ,7.86-7.90(m,1H),7.79-7.85(m,1H),7.60-7.66(m,1H),7.51-7.57(m,1H),7.30-7.36(m,1H),6.07- 6.15 (m, 1H), 4.08 (s, 3H), 3.03 (dd, 1H), 2.88 (dd, 1H), 1.63 (d, 3H), 0.49-0.56 (m, 1H), 0.15-0.23 (m, 1H), 0.01-0.041 (m, 1H), -0.14--0.19 (m, 1H), -0.62--0.67 (m, 1H); Chiral analysis SFC: RT = 5.55 min, column: Chiralpak IC (250 × 4.6 mm), 5 μ, 80% CO2: MeOH, flow rate = 3.0 mL / min.

[0578] 3-(3-Chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-methoxyisoquinoline-4-yl)ethyl)urea: enantiomer II (compound 64). LCMS: m / z measured 428.2 / 430.2 [M+H] +, RT=6.25min (Method: A); 1HNMR (400MHz, DMSO-d6): δ8.51 (bs, 1H), 8.23 ​​(d, 1H), 8.11 (s, 1H), 7.99 (d, 1H) ,7.86-7.90(m,1H),7.79-7.85(m,1H),7.60-7.66(m,1H),7.51-7.57(m,1H),7.30-7.36(m,1H),6.07- 6.15 (m, 1H), 4.08 (s, 3H)...

Claims

1. A compound of formula (I), or a salt, stereoisomer or isotope-labeled substance thereof, or any mixture thereof: Wherein in (I): R 1 is selected from optionally substituted phenyl, optionally substituted C3-C8 cycloalkyl, optionally substituted benzyl, optionally substituted heteroaryl, and -(CH2)(optionally substituted heteroaryl); Where R 1 The heteroaryl group is selected from pyridyl and indolyl; R 2 It is H; R 3 Selected from C1-C6 alkyl and C3-C8 cycloalkyl, Where R 3 wherein the alkyl or cycloalkyl is selected from C1-C6 alkyl, C3-C8 cycloalkyl, halogen, cyano, -OH, C1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 haloalkoxy, C3-C8 halocycloalkoxy, optionally substituted piperidinyl, optionally substituted triazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted thiazolyl, tetrahydrofuranyl, tetrahydropyranyl, optionally substituted 1,3-dioxanyl, -C(=O)OR 6 、-S(=O)2R 6 , -S(=O)2NR 6 R 6 、-N(R 6 )S(=O)2R 6 、-N(R 6 )C(=O)R 6 、-C(=O)NR 6 R 6 and-NR 6 R 6 is optionally substituted with at least one substituent; R 4a is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl and phenyl, Where R 4a wherein the alkyl, cycloalkyl or phenyl is optionally substituted by at least one substituent selected from C1-C6 alkyl, C3-C8 cycloalkyl, halogen, cyano, -OH, C1-C6 alkoxy and optionally substituted phenyl; R 4b It is H; R 5 Selected from: Where R 5 wherein each ring A is independently selected from benzene, pyridine and pyrazine; R 6 Each occurrence of is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted phenyl; R 7 is selected from H and optionally substituted C1-C6 alkyl; R 8 is selected from halogen, -CN, optionally substituted C1-C6 alkyl, optionally substituted triazolyl, -SO2(optionally substituted C1-C6 alkyl), -C(=O)OH, -O(optionally substituted C1-C6 alkyl), -O(optionally substituted C3-C8 cycloalkyl), -NH2, -NH(optionally substituted C1-C6 alkyl), -C(=O)NH2, -C(=O)NH(optionally substituted C1-C6 alkyl) and -C(=O)N(optionally substituted C1-C6 alkyl)(optionally substituted C1-C6 alkyl); R 9 Each occurrence of is independently selected from H, halogen, and C1-C6 alkoxy; Each occurrence of n is independently 0, 1, 2, 3, or 4; and R 10 is selected from H and optionally substituted C1-C6 alkyl; wherein each occurrence of optionally substituted phenyl or optionally substituted heteroaryl is independently selected from C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, C1-C6 hydroxyalkyl, (C1-C6 alkoxy)-(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, -CN, -OR b 、-N(R b )(R b )、-C(=O)N(R b )(R b )、-C(=O)OR b 、-OC(=O)R b 、-SR b 、-S(=O)R b 、-N(R b )S(=O)2R b and -S(=O)2N(R b )(R b ) is optionally substituted with at least one substituent, Where R b Each occurrence of is independently H, C1-C6 alkyl or C3-C8 cycloalkyl, wherein in R bwherein the alkyl or cycloalkyl is optionally substituted by at least one substituent selected from halogen and -OH; wherein each occurrence of optionally substituted benzyl is independently optionally substituted with at least one substituent selected from C1-C6 alkyl and halogen; wherein each occurrence of optionally substituted 1,3-dioxanyl is independently optionally substituted with at least one C1-C6 alkyl; wherein each occurrence of optionally substituted piperidinyl is independently optionally substituted with C1-C6 alkyl or -C(=O)CH3; wherein each occurrence of optionally substituted alkyl or optionally substituted cycloalkyl is independently selected from C1-C6 alkyl, C3-C8 cycloalkyl, halogen, cyano, -OR a , optionally substituted phenyl, -C(=O)OR a 、-OC(=O)R a 、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR a R a 、-N(R a )S(=O)2R a 、-N(R a )C(=O)R a 、-C(=O)NR a R a and -N(R a )(R a ) is optionally substituted with at least one substituent, Where R a Each occurrence of is independently H and optionally substituted C1-C6 alkyl.

2. The compound according to claim 1, wherein R 1 is phenyl optionally substituted by at least one substituent selected from the group consisting of C1-C6 alkyl, halogen, C1-C3 haloalkyl and -CN.

3. The compound according to claim 1, wherein R 1selected from the group consisting of phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 4-chloro-3-methylphenyl, 3-chloro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3-fluoro-4-methylphenyl, 4-chloro-3- phenyl, 3-chloro-4-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethyl-4-fluorophenyl, 4-trifluoromethyl-3-fluorophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-cyano-4-fluorophenyl, 4-cyano-3-fluorophenyl, 3-difluoromethyl-4-fluorophenyl and 4-difluoromethyl-3-fluorophenyl.

4. The compound according to claim 1, which is selected from:

5. The compound according to claim 1, which is selected from:

6. The compound according to claim 1, wherein R 5 Selected from:

7. A compound, or a salt, stereoisomer or isotope-labeled substance thereof, or any mixture thereof, selected from: 3-(3-chloro-4-fluorophenyl)-1-methyl-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinolin-4-yl)methyl)-1-methylurea; 3-(4-fluoro-3-methylphenyl)-1-((1-methoxyisoquinolin-4-yl)methyl)-1-methylurea; 3-(4-Fluoro-3-methylphenyl)-1-methyl-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-methoxyisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(isoquinolin-4-ylmethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((1-ethoxyisoquinolin-4-yl)methyl)-1-ethylurea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-isopropyl-1-((1-methoxyisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinolin-4-yl)methyl)-1-propylurea; 3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-((1-methoxyisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-isopropyl-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-1-propylurea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-(2-hydroxyethoxy)isoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-((1-methoxyisoquinolin-4-yl)methyl)urea; 3-(4-Fluoro-3-methylphenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-Butyl-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-((1-methoxyisoquinolin-4-yl)methyl)urea; (3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-propylurea; 3-(3-Chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinolin-4-yl)propyl)urea 3-(3-Chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)propyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(cyclopropyl(1-methoxyisoquinolin-4-yl)methyl)-1-ethylurea; 3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-((1-methoxyisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 3-(4-Fluoro-3-methylphenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-propylurea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinolin-4-yl)-2-methylpropyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(cyclopropyl(1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-1-ethylurea; 3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinolin-4-yl)methyl)-1-(3-methoxypropyl)urea; 1-Benzyl-3-(3-chloro-4-fluorophenyl)-1-((1-methoxyisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(3-methoxypropyl)-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 1-butyl-3-(3-chloro-4-fluorophenyl)-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2-methyl-1-(1-oxo-1,2-dihydroisoquinolin-4-yl)propyl)urea; 3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-methoxyisoquinolin-4-yl)(phenyl)methyl)urea; 1-Butyl-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)(phenyl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2,2,2-trifluoro-1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2,2,2-trifluoro-1-(1-methoxyisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(3-methoxypropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)-1-(3-methoxypropyl)urea; 1-Butyl-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-((1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-((1-(pyridin-2-ylmethoxy)isoquinolin-4-yl)methyl)urea; 3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(4-Fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-Methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4,5-trifluorophenyl)urea; 3-(3,4-difluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-Fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(2-chloropyridin-4-yl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea; 3-(3-chloro-4-fluorophenyl)-1-(2,2-difluoroethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-(2,2-difluoroethyl)-3-(4-fluoro-3-methylphenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-cyano-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(ethyl-d5)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; N-(2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethyl)acetamide; (3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(2-cyanoethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)-N-methylpropanamide; 3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)-N,N-dimethylpropanamide; 3-(3-chloro-4-fluorophenyl)-1-(2-(methylsulfonyl)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(2-ethoxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(3-cyanopropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)-N-methylacetamide; 2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; 3-(3-chloro-4-fluorophenyl)-1-(2-(2-methoxyethoxy)ethyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(2-(2-methoxyethoxy)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(2-ethoxyethyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydro-2,6-naphthyridin-4-yl)ethyl)urea; 2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)acetamide; 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(5-(methylamino)pyrido[3,4-b]pyrazin-8-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(5-methoxypyrido[3,4-b]pyrazin-8-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; 1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; 2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)-N,N-dimethylacetamide; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(5-oxo-5,6-dihydropyrido[3,4-b]pyrazin-8-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(4-hydroxybutyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(8-oxo-7,8-dihydro-1,7-naphthyridin-5-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(((R)-tetrahydrofuran-2-yl)methyl)urea; 1-(3-aminopropyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(((S)-tetrahydrofuran-2-yl)methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-((tetrahydrofuran-3-yl)methyl)urea; 1-(1-(8-chloro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6-chloro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(7-methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6-methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-ethyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-propyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-isopropyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-cyclopropyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(2-(2-methoxyethyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(cyclopentylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(cyclohexylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(2-((2,2-difluoroethyl)amino)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(2-(3-methoxypropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 1-((1-acetylpiperidin-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((1-(methylsulfonyl)piperidin-4-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(2-(2-hydroxyethyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(2-(3-hydroxypropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-((1-methylpiperidin-4-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)propanoic acid; 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((R)-3-hydroxybutyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((S)-3-hydroxybutyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((R)-2-hydroxypropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((S)-2-hydroxypropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)-N-methylpropane-1-sulfonamide; 3-(3-chloro-4-fluorophenyl)-1-(((1r,4r)-4-hydroxycyclohexyl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(3-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((4-cis-hydroxycyclohexyl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 4-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)butanoic acid; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(methylamino)isoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(dimethylamino)isoquinolin-4-yl)ethyl)urea; 3-(4-Fluorophenyl)-1-isobutyl-1-(1-(1-oxo-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(4-fluoro-3-methylphenyl)-1-methyl-1-(1-(3-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-(1-(1-aminoisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-(ethylamino)isoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-((2-hydroxyethyl)amino)isoquinolin-4-yl)ethyl)-1-methylurea; 1-(1-(1-((2-aminoethyl)amino)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(((1-methyl-1H-1,2,4-triazol-3-yl)methyl)amino)isoquinolin-4-yl)ethyl)urea; 1-(1-(1-(((1H-1,2,4-triazol-3-yl)methyl)amino)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; 1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)urea; 1-(1-(1-(((2H-1,2,3-triazol-4-yl)methyl)amino)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(5-methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 1-((1H-1,2,3-triazol-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-((4H-1,2,4-triazol-3-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-(1-(2-((1H-1,2,4-triazol-3-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; 1-(1-(7-chloro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-3-(4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-phenylurea; 1-(1-(2-((1H-1,2,3-triazol-4-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; 3-(3-chloro-4-fluorophenyl)-1-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(3-hydroxy-2-(hydroxymethyl)propyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-(3-hydroxypropyl)urea; 3-(4-chlorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(4-bromophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxy-2-(hydroxymethyl)propyl)urea; 1-(1-(1-(1H-1,2,4-triazol-1-yl)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; 3-Cyclopentyl-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-(1-(1-(1H-1,2,4-triazol-1-yl)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-isobutylurea; 1-(1-(1-(1H-1,2,4-triazol-1-yl)isoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyridin-2-ylmethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyridin-3-ylmethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyridin-4-ylmethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(thiazol-2-ylmethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(thiazol-4-ylmethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(methylsulfonyl)isoquinolin-4-yl)ethyl)urea; 4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylureido)ethyl)-N-methylisoquinoline-1-carboxamide; 4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylureido)ethyl)-N,N-dimethylisoquinoline-1-carboxamide; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyrimidin-5-ylmethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyrimidin-4-ylmethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(thiazol-5-ylmethyl)urea; 4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylureido)ethyl)isoquinoline-1-carboxylic acid; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-(hydroxymethyl)isoquinolin-4-yl)ethyl)-1-methylurea; 4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylureido)ethyl)isoquinoline-1-carboxamide; 3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(1-cyanoisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; 3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-methylisoquinolin-4-yl)ethyl)urea; 1-(1-(1-(1H-1,2,3-triazol-1-yl)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; 1-(1-(1-(1H-1,2,3-triazol-1-yl)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-isobutylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; 1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)-6,7-difluoroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; 1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)-6,7-difluoroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; 1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; 1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-(3-hydroxypropyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(2-hydroxy-1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; 2-(3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; 2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; 2-(1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)ureido)ethane-1-sulfonamide; 2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; 2-(3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; 2-(3-(4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; 2-(3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-phenylurea; 3-(4-chlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-ethyl-3-(4-fluorophenyl)urea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-ethyl-3-phenylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-ethylurea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-methylurea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-fluorophenyl)-1-methylurea; 3-(3-chlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorophenyl)urea; 3-(3,5-dichlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(2-chloropyridin-4-yl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(2-fluorophenyl)-1-methylurea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-ethylurea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluoro-3-methylphenyl)-1-methylurea; 3-(3-cyano-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(2,3-difluorophenyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-phenylurea; 3-(3,5-dichloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluoro-3-methylphenyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorophenyl)urea; 3-(4-chlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; 3-(3,5-dichlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(pyridin-4-yl)urea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(pyridin-3-yl)urea; 3-(3,5-dichloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-Benzyl-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(2-chloropyridin-4-yl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-fluorophenyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(2-fluorophenyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(2,3-difluorophenyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chlorophenyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-ethylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-ethylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-phenyl-1-ethylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-ethylurea; 3-(3-cyano-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(methyl-d3)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(methyl)urea; 3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(methyl-d3)urea; 3-(3-chlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(methyl)urea; 3-(3-chlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(methyl-d3)urea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-((S)-1-phenylethyl)urea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorobenzyl)-1-methylurea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorobenzyl)-1-methylurea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-((R)-1-phenylethyl)urea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorobenzyl)urea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(3-chloro-4-fluorobenzyl)urea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(1H-indol-6-yl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-((S)-1-phenylethyl)urea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-((R)-1-phenylethyl)urea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorobenzyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorobenzyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4,5-trifluorobenzyl)-1-methylurea; 3-(3-chloro-4-fluorobenzyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(1H-indol-6-yl)-1-methylurea; 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-methylurea; 1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-methylurea.

8. A compound, or a salt, stereoisomer or isotope-labeled substance thereof, or any mixture thereof, selected from: (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(4-fluoro-3-methylphenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-propylurea; (R)-3-(4-fluoro-3-methylphenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-propylurea; (R)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4,5-trifluorophenyl)urea; (R)-3-(3,4-difluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(2-chloropyridin-4-yl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(2-(trifluoromethyl)pyridin-4-yl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2,2-difluoroethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-1-(2,2-difluoroethyl)-3-(4-fluoro-3-methylphenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-cyano-4-fluorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(ethyl-d5)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)urea; (R)-3-(4-chlorophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(4-bromophenyl)-1-methyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinolin-4-yl)propyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinolin-4-yl)propyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)propyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)propyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinolin-4-yl)-2-methylpropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-methoxyisoquinolin-4-yl)-2-methylpropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropyl(1-methoxyisoquinolin-4-yl)methyl)-1-ethylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropyl(1-methoxyisoquinolin-4-yl)methyl)-1-ethylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropyl(1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-1-ethylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropyl(1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-1-ethylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2-methyl-1-(1-oxo-1,2-dihydroisoquinolin-4-yl)propyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2-methyl-1-(1-oxo-1,2-dihydroisoquinolin-4-yl)propyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-methoxyisoquinolin-4-yl)(phenyl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-methoxyisoquinolin-4-yl)(phenyl)methyl)urea; (R)-1-butyl-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (S)-1-butyl-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-cyclopropyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)(phenyl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-((1-oxo-1,2-dihydroisoquinolin-4-yl)(phenyl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2,2,2-trifluoro-1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2,2,2-trifluoro-1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2,2,2-trifluoro-1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(2,2,2-trifluoro-1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(3-methoxypropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-methoxypropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)-1-(3-methoxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)-1-(3-methoxypropyl)urea; (R)-1-butyl-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-1-butyl-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopropylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)-N,N-dimethylpropanamide; (S)-3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)-N,N-dimethylpropanamide; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-(methylsulfonyl)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-(methylsulfonyl)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-ethoxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-ethoxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-cyanoethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-cyanoethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(3-cyanopropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-cyanopropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)-N-methylpropanamide; (S)-3-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)-N-methylpropanamide; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-(2-methoxyethoxy)ethyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-(2-methoxyethoxy)ethyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-(2-methoxyethoxy)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-(2-methoxyethoxy)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-ethoxyethyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-ethoxyethyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)urea; (R)-N-(2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethyl)acetamide; (S)-N-(2-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethyl)acetamide; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(5-(methylamino)pyrido[3,4-b]pyrazin-8-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(5-(methylamino)pyrido[3,4-b]pyrazin-8-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(5-methoxypyrido[3,4-b]pyrazin-8-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(5-methoxypyrido[3,4-b]pyrazin-8-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)urea; (R)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)urea; (S)-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-methoxyisoquinolin-4-yl)ethyl)-1-(2,2,2-trifluoroethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-ethyl-1-(1-(1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(2-((2,2,2-trifluoroethyl)amino)ethyl)urea; (R)-1-(1-(8-chloro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(8-chloro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-chloro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-chloro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7-methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7-methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-ethyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-ethyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-propyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-propyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-isopropyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-isopropyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-cyclopropyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(2-cyclopropyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclopentylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclopentylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(cyclohexylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(cyclohexylmethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-((2,2-difluoroethyl)amino)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-((2,2-difluoroethyl)amino)ethyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-1-((1-acetylpiperidin-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-1-((1-acetylpiperidin-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-((1-(methylsulfonyl)piperidin-4-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-((1-(methylsulfonyl)piperidin-4-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((R)-3-hydroxybutyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((R)-3-hydroxybutyl)-1-(1(S)-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((S)-3-hydroxybutyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((S)-3-hydroxybutyl)-1-(1(S)-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((R)-2-hydroxypropyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((R)-2-hydroxypropyl)-1-((S)1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((S)-2-hydroxypropyl)-1-(1(R)-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 3-(3-chloro-4-fluorophenyl)-1-((S)-2-hydroxypropyl)-1-(1(S)-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(3-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(3-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-4-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)butanoic acid; (S)-4-(3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)butanoic acid; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(methylamino)isoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(methylamino)isoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(dimethylamino)isoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(dimethylamino)isoquinolin-4-yl)ethyl)urea; (R)-3-(4-fluoro-3-methylphenyl)-1-methyl-1-(1-(3-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(4-fluoro-3-methylphenyl)-1-methyl-1-(1-(3-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-1-(1-(1-aminoisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-aminoisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-(ethylamino)isoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-(ethylamino)isoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-((2-hydroxyethyl)amino)isoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-((2-hydroxyethyl)amino)isoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(((1-methyl-1H-1,2,4-triazol-3-yl)methyl)amino)isoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(((1-methyl-1H-1,2,4-triazol-3-yl)methyl)amino)isoquinolin-4-yl)ethyl)urea; (R)-1-(1-(1-(((1H-1,2,4-triazol-3-yl)methyl)amino)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-(((1H-1,2,4-triazol-3-yl)methyl)amino)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-isobutyl-1-(1-(1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)-1-(1-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)urea; (R)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)urea; (S)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)urea; (R)-1-(1-(1-(((2H-1,2,3-triazol-4-yl)methyl)amino)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-(((2H-1,2,3-triazol-4-yl)methyl)amino)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-1-((1H-1,2,3-triazol-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-1-((1H-1,2,3-triazol-4-yl)methyl)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-1-(1-(2-((1H-1,2,4-triazol-3-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(2-((1H-1,2,4-triazol-3-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-1-(1-(2-((1H-1,2,3-triazol-4-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(2-((1H-1,2,3-triazol-4-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-(3-hydroxypropyl)urea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-(3-hydroxypropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxy-2-(hydroxymethyl)propyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxy-2-(hydroxymethyl)propyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyridin-2-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyridin-2-ylmethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyridin-3-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyridin-3-ylmethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyridin-4-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyridin-4-ylmethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(thiazol-2-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(thiazol-2-ylmethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(thiazol-4-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(thiazol-4-ylmethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(methylsulfonyl)isoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-(methylsulfonyl)isoquinolin-4-yl)ethyl)urea; (R)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylureido)ethyl)-N-methylisoquinoline-1-carboxamide; (S)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylureido)ethyl)-N-methylisoquinoline-1-carboxamide; (R)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylureido)ethyl)-N,N-dimethylisoquinoline-1-carboxamide; (S)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylureido)ethyl)-N,N-dimethylisoquinoline-1-carboxamide; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyrimidin-4-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(pyrimidin-4-ylmethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(thiazol-5-ylmethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(thiazol-5-ylmethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-(hydroxymethyl)isoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-(hydroxymethyl)isoquinolin-4-yl)ethyl)-1-methylurea; (R)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylureido)ethyl)isoquinoline-1-carboxamide; (S)-4-(1-(3-(3-chloro-4-fluorophenyl)-1-methylureido)ethyl)isoquinoline-1-carboxamide; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-cyanoisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(1-cyanoisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; (R)-1-(1-(1-(1H-1,2,4-triazol-1-yl)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-isobutylurea; (S)-1-(1-(1-(1H-1,2,4-triazol-1-yl)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-isobutylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)isoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-methylisoquinolin-4-yl)ethyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-methyl-1-(1-(1-methylisoquinolin-4-yl)ethyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; (R)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)-6,7-difluoroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)-6,7-difluoroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)-6,7-difluoroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)urea; (S)-1-(1-(1-((1H-1,2,4-triazol-3-yl)methoxy)-6,7-difluoroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-(3-hydroxypropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; (S)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-(3-hydroxypropyl)urea; (R)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; (S)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-isobutylurea; (R)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-(3-hydroxypropyl)urea; (S)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-(3-hydroxypropyl)urea; (R)-3-(3-chloro-4-fluorophenyl)-1-(2-hydroxy-1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(2-hydroxy-1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (R)-2-(1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)ureido)ethane-1-sulfonamide; (S)-2-(1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)ureido)ethane-1-sulfonamide; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (R)-2-(3-(4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (S)-2-(3-(4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (R)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (S)-2-(3-(3-chloro-4-fluorophenyl)-1-(1-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)ureido)ethane-1-sulfonamide; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-phenylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-phenylurea; (R)-3-(4-chlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(4-chlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-ethyl-3-(4-fluorophenyl)urea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-ethyl-3-(4-fluorophenyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-ethyl-3-phenylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-ethyl-3-phenylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-ethylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-ethylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-fluorophenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-fluorophenyl)-1-methylurea; (R)-3-(3-chlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorophenyl)urea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorophenyl)urea; (R)-3-(3,5-dichlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3,5-dichlorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(2-chloropyridin-4-yl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(2-chloropyridin-4-yl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(2-fluorophenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(2-fluorophenyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-ethylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-ethylurea; (R)-1-(1-(1-(1H-1,2,3-triazol-1-yl)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (S)-1-(1-(1-(1H-1,2,3-triazol-1-yl)isoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluoro-3-methylphenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluoro-3-methylphenyl)-1-methylurea; (R)-3-(3-cyano-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-cyano-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(2,3-difluorophenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(2,3-difluorophenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-phenylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-phenylurea; (R)-3-(3,5-dichloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3,5-dichloro-4-fluorophenyl)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluoro-3-methylphenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluoro-3-methylphenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorophenyl)urea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorophenyl)urea; (R)-3-(4-chlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(4-chlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; (S)-3-(3-chloro-4-fluorophenyl)-1-(1-(6,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-isobutylurea; (R)-3-(3,5-dichlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3,5-dichlorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-3-(3,5-dichloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3,5-dichloro-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-fluorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-fluorophenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(2,3-difluorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(2,3-difluorophenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chlorophenyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chlorophenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-ethylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorophenyl)-1-ethylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-ethylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorophenyl)-1-ethylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-phenyl-1-ethylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-phenyl-1-ethylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-ethylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-chloro-4-fluorophenyl)-1-ethylurea; (R)-3-(3-cyano-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-cyano-4-fluorophenyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorobenzyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorobenzyl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorobenzyl)urea; (S) 1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(3,4,5-trifluorobenzyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(3-chloro-4-fluorobenzyl)urea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methyl-3-(3-chloro-4-fluorobenzyl)urea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(1H-indol-6-yl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(1H-indol-6-yl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorobenzyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4-difluorobenzyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorobenzyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(4-fluorobenzyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4,5-trifluorobenzyl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3,4,5-trifluorobenzyl)-1-methylurea; (R)-3-(3-chloro-4-fluorobenzyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (S)-3-(3-chloro-4-fluorobenzyl)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(1H-indol-6-yl)-1-methylurea; (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(1H-indol-6-yl)-1-methylurea; (R)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-methylurea; (S)-1-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-methylurea; (R)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-methylurea; and (S)-1-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)-3-(3-(difluoromethyl)-4-fluorophenyl)-1-methylurea.

9. A compound, or a salt, stereoisomer or isotope-labeled product thereof, or any mixture thereof, The compound is selected from: 1-(4-fluoro-3-methylphenyl)-3-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 1-(3-chloro-4-fluorophenyl)-3-((1-methoxyisoquinolin-4-yl)methyl)urea; 1-(4-fluoro-3-methylphenyl)-3-((1-methoxyisoquinolin-4-yl)methyl)urea; 1-(3-chloro-4-fluorophenyl)-3-((1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)urea; 1-(3-chloro-4-fluorophenyl)-3-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-(3-chloro-4-fluorophenyl)-3-(3-hydroxy-1-(1-methoxyisoquinolin-4-yl)propyl)urea; 1,3-Dimethyl-1-(1-(1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-(3-chloro-4-fluorophenyl)-3-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; 1-(3-cyano-4-fluorophenyl)-3-(1-(6,7-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea; and 1-(3-Chloro-4-fluorophenyl)-3-(1-(7,8-difluoro-1-oxo-1,2-dihydroisoquinolin-4-yl)ethyl)urea.

10. A pharmaceutical composition comprising at least one compound according to any one of claims 1 and 7-9 and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10, further comprising at least one additional agent for treating hepatitis infection.

12. A pharmaceutical composition according to claim 11, wherein the at least one additional agent comprises at least one agent selected from reverse transcriptase inhibitors, capsid inhibitors, cccDNA formation inhibitors, RNA destabilizers, oligonucleotides targeting the HBV genome, immunostimulants, and GalNAc-siRNA conjugates targeting HBV gene transcripts.

13. Use of at least one compound according to any one of claims 1 and 7-9 in the preparation of a medicament for treating or preventing hepatitis B virus infection in a subject.

14. The use according to claim 13, wherein the subject is further infected with hepatitis D virus.

15. Use of at least one compound according to any one of claims 1 and 7-9 in the preparation of a medicament for directly or indirectly inhibiting the expression and / or function of viral capsid proteins in a subject infected with hepatitis B virus.

16. The use according to claim 15, wherein the subject is further infected with hepatitis D virus.

17. The use according to any one of claims 13 and 15, wherein the subject is a mammal.

18. The use according to claim 17, wherein the mammal is a human.

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