4-aminopiperidines as selective modulators of potassium channels

Abstract

Selective modulators of Kv7 potassium channels that are useful for the treatment of a range of channelopathies, including epilepsy, developmental and epileptic encephalopathy, pain, tinnitus, cancer, cardiovascular disease, and neurodegeneration.

Description

[0001] 4-AMINOPIPERIDINES AS SELECTIVE MODULATORS OF POTASSIUM CHANNELS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 531,090, filed August 7, 2023, which is incorporated herein by reference.

[0003] BACKGROUND

[0004] The Kv7 (also referred to as KCNQ) potassium channel family of transmembrane proteins, encoded by KCNQ genes, plays a critical role in cell excitability. They belong to the voltage-gated ion channel super- family, are non-inactivating channels, and contribute both to the maintenance of the resting membrane potential and the control of excitability in cells. The KCNQ gene family is comprised of 5 isoforms, Kv7.1-5, and assembles as either homo- or heterotetramers (i.e. Kv7.2 / 3, Kv7.3 / 5, or Kv7.4 / 5). Each isoform has a specific distribution within the body, and specific mutations within the gene family have been implicated in human diseases. Accordingly, the search for isoform-specific, potent chemical probes aimed at the mechanistic function of Kv7 channels in various tissues remains an area of high interest.

[0005] Kv7.2 channels are located both in the central and peripheral nervous system, showing a high density in the neocortex and hippocampus. High-current amplitude Kv7.2 / 3 heterotetramers are the most abundant Kv7.2 channel assembly compared to the less abundant low-current amplitude homomeric channels and Kv7.4 or Kv7.5 hetero tetramers. Particular attention has been given to Kv7.2 / 3 channels for their M- current contributions in neuronal tissue. Among other functions, the homomeric Kv7.2 isoform has been implicated in the patho-physiology of epilepsy, wherein the heteromeric Kv7.2 / 3 isoform has been associated with the induction and prolongation of tinnitus.

[0006] SUMMARY

[0007] Disclosed herein is a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0008]

[0009] Formula I wherein X is N or C;

[0010] Y is N or C;

[0011] Z is N or C;

[0012] W is N or C;

[0013] R1is H;

[0014] R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl ;

[0015] R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0016] R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0017] R5is H;

[0018] R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;

[0019] R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;

[0020] R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;

[0021] R10is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, or oxo; and where each bond represented by - is a single or double bond as needed to satisfy valence requirements.

[0022] Also disclosed herein is a compound of Formula II, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0023] Formula II wherein X is N;

[0024] Y is C;

[0025] Z is C;

[0026] W is C;

[0027] R1is H;

[0028] R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0029] R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0030] R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0031] R5is H;

[0032] R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and

[0033] R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

[0034] Further disclosed herein is a method comprising administering to a subject in need of treatment for epilepsy, developmental or epileptic encephalopathy, pain, tinnitus, cancer, cardiovascular disease, neurodegeneration, fibromyalgia, arthritis, hyperalgesia, depression, schizophrenia, bipolar disorder, traumatic brain injury, smooth muscle disorders, erectile dysfunction, myotonic congenita, or inflammatory airway diseases, a therapeutically effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0035] Formula I wherein X is N or C;

[0036] Y is N or C;

[0037] Z is N or C;

[0038] W is N or C;

[0039] R1is H;

[0040] R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl ;

[0041] R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0042] R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl ;

[0043] R5is H;

[0044] R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;

[0045] R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo; R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;

[0046] R10is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, or oxo; and where each bond represented by - is a single or double bond as needed to satisfy valence requirements.

[0047] Additionally disclosed herein is a method comprising administering to a subject in need of treatment for epilepsy, developmental or epileptic encephalopathy, pain, tinnitus, cancer, cardiovascular disease, neurodegeneration, fibromyalgia, arthritis, hyperalgesia, depression, schizophrenia, bipolar disorder, traumatic brain injury, smooth muscle disorders, erectile dysfunction, myotonic congenita, or inflammatory airway diseases, a therapeutically effective amount of a compound of Formula II, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0048] Formula II wherein X is N;

[0049] Y is C;

[0050] Z is C;

[0051] W is C;

[0052] R1is H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0053] R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0054] R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0055] R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0056] R5is H; R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and

[0057] R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

[0058] DETAILED DESCRIPTION

[0059] Terminology

[0060] The following explanations of terms and methods are provided to better describe the present compounds, compositions and methods, and to guide those of ordinary skill in the art in the practice of the present disclosure. It is also to be understood that the terminology used in the disclosure is for the purpose of describing particular embodiments and examples only and is not intended to be limiting.

[0061] “Acyl” refers to a group having the structure -C(O)R, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. “Lower acyl” groups are those that contain one to six carbon atoms.

[0062] “Acyloxy” refers to a group having the structure -OC(O)R-, where R may be, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. “Lower acyloxy” groups contain one to six carbon atoms.

[0063] “Administration” as used herein is inclusive of administration by another person to the subject or self-administration by the subject.

[0064] The term "aliphatic" is defined as including alkyl, alkenyl, alkynyl, halogenated alkyl and cycloalkyl groups. A "lower aliphatic" group is a branched or unbranched aliphatic group having from 1 to 10 carbon atoms.

[0065] “Alkanediyl,” “cycloalkanediyl,” “aryldiyl,” “alkanearyldiyl” refers to a divalent radical derived from aliphatic, cycloaliphatic, aryl, and alkanearyl hydrocarbons.

[0066] “Alkenyl” refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and contains one or more double bonds that may or may not be conjugated. Alkenyl groups may be unsubstituted or substituted. “Lower alkenyl” groups contain one to six carbon atoms.

[0067] The term “alkoxy” refers to a straight, branched or cyclic hydrocarbon configuration and combinations thereof, including from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms (referred to as a “lower alkoxy”), more preferably from 1 to 4 carbon atoms, that include an oxygen atom at the point of attachment. An example of an “alkoxy group” is represented by the formula - OR, where R can be an alkyl group, optionally substituted with an alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, alkoxy or heterocycloalkyl group. Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy cyclopropoxy, cyclohexyloxy, and the like.

[0068] “Alkoxycarbonyl” refers to an alkoxy substituted carbonyl radical, -C(O)OR, wherein R represents an optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl or similar moiety.

[0069] The term “alkyl” refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, / -butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. A “lower alkyl” group is a saturated branched or unbranched hydrocarbon having from 1 to 6 carbon atoms. Preferred alkyl groups have 1 to 4 carbon atoms. Alkyl groups may be “substituted alkyls” wherein one or more hydrogen atoms are substituted with a substituent such as halogen, cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl. For example, a lower alkyl or (Ci-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C3-Ce)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C3-C6)cycloalkyl(Ci-Ce)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl; (Ci-Ce)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C2-Ce)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,- pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5- hexenyl; (C2-Ce)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2 -pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5- hexynyl; (Ci-Ce)alkanoyl can be acetyl, propanoyl or butanoyl; halo(Ci-C6)alkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2- fluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl; hydroxy(Ci-Ce)alkyl can be hydroxymethyl, 1 -hydroxy ethyl, 2-hydroxyethyl, 1 -hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- hydroxybutyl, 4-hydroxybutyl, 1 -hydroxypentyl, 5 -hydroxypentyl, 1-hydroxyhexyl, or 6- hydroxyhexyl; (Ci-C6)alkoxy carbonyl can be methoxy carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy carbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (Ci-Ce)alkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio; (C2-Ce)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoy loxy. “Alkynyl” refers to a cyclic, branched or straight chain group containing only carbon and hydrogen, and unless otherwise mentioned typically contains one to twelve carbon atoms, and contains one or more triple bonds. Alkynyl groups may be unsubstituted or substituted. “Lower alkynyl” groups are those that contain one to six carbon atoms.

[0070] The term “amine” or “amino” refers to a group of the formula -NRR', where R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, heterocycloalkyl, or carboxyl group. For example, an “alkylamino” or “alkylated amino” refers to -NRR', wherein at least one of R or R' is an alkyl. A suitable amine or amino group is acetamido.

[0071] The term "aminoalkyl" refers to alkyl groups as defined above where at least one hydrogen atom is replaced with an amino group (e.g, -CH2-NH2).

[0072] “Aminocarbonyl” alone or in combination, means an amino substituted carbonyl (carbamoyl) radical, wherein the amino radical may optionally be mono- or di-substituted, such as, for example, with alkyl, aryl, acyl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like. For example, an aminocarbonyl may be represented by the formula -C(O)NRR', where R and R' independently can be, for example, a hydrogen, alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group.

[0073] An “analog” is a molecule that differs in chemical structure from a parent compound, for example a homolog (differing by an increment in the chemical structure or mass, such as a difference in the length of an alkyl chain or the inclusion of one of more isotopes), a molecular fragment, a structure that differs by one or more functional groups, or a change in ionization. An analog is not necessarily synthesized from the parent compound. A derivative is a molecule derived from the base structure.

[0074] An “animal” refers to living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term mammal includes both human and non-human mammals. Similarly, the term “subject” includes both human and non-human subjects, including birds and non-human mammals. Illustrative non-human mammals include animal models (such as mice), non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats. The term subject applies regardless of the stage in the organism’s life-cycle. Thus, the term subject applies to an organism in utero or in ovo, depending on the organism (that is, whether the organism is a mammal or a bird, such as a domesticated or wild fowl).

[0075] The term "aralkyl" refers to an alkyl group wherein an aryl group is substituted for a hydrogen of the alkyl group. An example of an aralkyl group is a benzyl group. “Aryl” refers to a monovalent unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which can optionally be unsubstituted or substituted. A “heteroaryl group,” is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorous. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like. The aryl or heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl or heteroaryl group can be unsubstituted.

[0076] “Aryloxy” or “heteroaryloxy” refers to a group of the formula -OAr, wherein Ar is an aryl group or a heteroaryl group, respectively.

[0077] "Bicyclic" or "bicyclyl", as used here, in refers to a ring assembly of two rings where the two rings are fused together, linked by a single bond or linked by two bridging atoms. The rings may be a carbocyclyl, a heterocyclyl, or a mixture thereof.

[0078] A “carbonylamino” group may be -N(R)-C(O)-R (wherein each R is independently a substitution group such as, for example, alkyl, alkenyl, alkynyl, acyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group, or H). A suitable carbonylamino group is acetamido.

[0079] The term “carboxylate” or “carboxyl” refers to the group -COO' or -COOH. The carboxyl group can form a carboxylic acid. “Substituted carboxyl” refers to -COOR where R is alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group. For example, a substituted carboxyl group could be a carboxylic acid ester or a salt thereof (e.g., a carboxylate).

[0080] The term “co-administration” or “co-administering” refers to administration of a compound disclosed herein with at least one other therapeutic agent or therapy within the same general time period, and does not require administration at the same exact moment in time (although coadministration is inclusive of administering at the same exact moment in time). Thus, coadministration may be on the same day or on different days, or in the same week or in different weeks. In some embodiments, the co-administration of two or more agents or therapies is concurrent. In other embodiments, a first agent / therapy is administered prior to a second agent / therapy. Those of skill in the art understand that the formulations and / or routes of administration of the various agents or therapies used may vary. The appropriate dosage for co- administration can be readily determined by one skilled in the art. In some embodiments, when agents or therapies are co-administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone. Thus, co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent and / or lowers the frequency of administering the potentially harmful (e.g., toxic) agent. “Co-administration” or “co-administering” encompass administration of two or more active agents to a subject so that both the active agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active agents are present.

[0081] The term “cycloalkyl” refers to a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term “heterocycloalkyl group” is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorous.

[0082] The term “ester” refers to a carboxyl group-containing moiety having the hydrogen replaced with, for example, a Ci-ealkyl group (“carboxylCi -ealky 1” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on. CCECijalkyl groups are preferred, such as for example, methylester (CO zMe), ethylester (COzEt) and propylester (COzPr) and includes reverse esters thereof (e.g. -OCOMe, -OCOEt and -OCOPr).

[0083] "Halo" or "halogen", as used herein, refers to fluoro, chloro, bromo, and iodo.

[0084] The terms "halogenated alkyl" or "haloalkyl group" refer to an alkyl group with one or more hydrogen atoms present on these groups substituted with a halogen (F, Cl, Br, I).

[0085] The term “heterocyclic” refers to a closed-ring compound, or radical thereof as a substituent bonded to another group, particularly other organic groups, where at least one atom in the ring structure is other than carbon, and typically is oxygen, sulfur and / or nitrogen.

[0086] The term “hydroxyl” is represented by the formula -OH.

[0087] The term "hydroxy alkyl" refers to an alkyl group that has at least one hydrogen atom substituted with a hydroxyl group. The term "alkoxyalkyl group" is defined as an alkyl group that has at least one hydrogen atom substituted with an alkoxy group described above.

[0088] “Inhibiting” refers to inhibiting the full development of a disease or condition. “Inhibiting” also refers to any quantitative or qualitative reduction in biological activity or binding, relative to a control.

[0089] “N-heterocyclic” refers to mono or bicyclic rings or ring systems that include at least one nitrogen heteroatom. The rings or ring systems generally include 1 to 9 carbon atoms in addition to the heteroatom(s) and may be saturated, unsaturated or aromatic (including pseudoaromatic). The term "pseudoaromatic" refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings. Aromatic includes pseudoaromatic ring systems, such as pyrrolyl rings.

[0090] Examples of 5-membered monocyclic N-heterocycles include pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls) isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1 ,2,3- and 1 ,3,4-triazolyls), tetrazolyl, thiadiazolyl (including 1 ,2,3 and 1 ,3,4 thiadiazolyls), and dithiazolyl. Examples of 6-membered monocyclic N-heterocycles include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and triazinyl. The heterocycles may be optionally substituted with a broad range of substituents, and preferably with Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(Ci-6alkyl)amino. The N-heterocyclic group may be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl.

[0091] Examples of 8, 9 and 10-membered bicyclic heterocycles include 1H thieno|2,3- c]pyrazolyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, and the like. These heterocycles may be optionally substituted, for example with C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di(Ci-6alkyl)amino. Unless otherwise defined optionally substituted N-heterocyclics includes pyridinium salts and the N-oxide form of suitable ring nitrogens.

[0092] The term “subject” includes both human and non-human subjects, including birds and nonhuman mammals, such as non-human primates, companion animals (such as dogs and cats), livestock (such as pigs, sheep, cows), as well as non-domesticated animals, such as the big cats. The term subject applies regardless of the stage in the organism’s life-cycle. Thus, the term subject applies to an organism in ulero or in ovo, depending on the organism (that is, whether the organism is a mammal or a bird, such as a domesticated or wild fowl).

[0093] “Substituted” or “substitution” refers to replacement of a hydrogen atom of a molecule or an R-group with one or more additional R-groups. Unless otherwise defined, the term “optionally- substituted” or “optional substituent” as used herein refers to a group which may or may not be further substituted with 1, 2, 3, 4 or more groups, preferably 1, 2 or 3, more preferably 1 or 2 groups. The substituents may be selected, for example, from Ci-ealkyl, C2-e lkenyl, Cb-ealkynyl, C3- scycloalkyl, hydroxyl, oxo, Ci-6alkoxy, aryloxy, Ci-6alkoxyaryl, halo, Ci-6alkylhalo (such as CF3 and CHF2), Ci -ealkoxy halo (such as OCF3 and OCHF2), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketones, amides, aminoacyl, substituted amides, disubstituted amides, thiol, alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamides, substituted sulfonamides, disubstituted sulfonamides, aryl, arCi-ealkyl, heterocyclyl and heteroaryl wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groups containing them may be further optionally substituted. Optional substituents in the case N-heterocycles may also include but are not limited to Chalky! i.e. iV-Ci-3alkyl, more preferably methyl, particularly A-methyl.

[0094] A "therapeutically effective amount" refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, a therapeutically effective amount of an agent is an amount sufficient to inhibit or treat the disease or condition without causing a substantial cytotoxic effect in the subject. The therapeutically effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the therapeutic composition.

[0095] “Treatment” refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop. As used herein, the term “ameliorating,” with reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. The phrase “treating a disease” refers to inhibiting the full development of a disease, for example, in a subject who is at risk for a disease. A “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing a pathology or condition, or diminishing the severity of a pathology or condition.

[0096] “Pharmaceutical compositions” are compositions that include an amount (for example, a unit dosage) of one or more of the disclosed compounds together with one or more non-toxic pharmaceutically acceptable additives, including carriers, diluents, and / or adjuvants, and optionally other biologically active ingredients. Such pharmaceutical compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA (19th Edition). The terms “pharmaceutically acceptable salt or ester” refers to salts or esters prepared by conventional means that include salts, e.g., of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. “Pharmaceutically acceptable salts” of the presently disclosed compounds also include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide. These salts may be prepared by standard procedures, for example by reacting the free acid with a suitable organic or inorganic base. Any chemical compound recited in this specification may alternatively be administered as a pharmaceutically acceptable salt thereof. “Pharmaceutically acceptable salts” are also inclusive of the free acid, base, and zwitterionic forms. Descriptions of suitable pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002). When compounds disclosed herein include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. Such salts are known to those of skill in the art. For additional examples of “pharmacologically acceptable salts,” see Berge et al., J. Pharm. Sci. 66:1 (1977).

[0097] “Pharmaceutically acceptable esters” includes those derived from compounds described herein that are modified to include a carboxyl group. An in vivo hydrolysable ester is an ester, which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Representative esters thus include carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl, optionally substituted by, for example, halogen, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy) or amino); sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); or amino acid esters (for example, L- valyl or L-isoleucyl). A “pharmaceutically acceptable ester” also includes inorganic esters such as mono-, di-, or triphosphate esters. In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group, optionally substituted as shown in the definition of carbocycylyl above. Pharmaceutically acceptable esters thus include C1-C22 fatty acid esters, such as acetyl, t-butyl or long chain straight or branched unsaturated or omega-6 monounsaturated fatty acids such as palmoyl, stearoyl and the like. Alternative aryl or heteroaryl esters include benzoyl, pyridylmethyloyl and the like any of which may be substituted, as defined in carbocyclyl above. Additional pharmaceutically acceptable esters include aliphatic L-amino acid esters such as leucyl, isoleucyl and especially valyl.

[0098] For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0099] The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

[0100] The compounds containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

[0101] The term “addition salt” as used hereinabove also comprises the solvates which the compounds described herein are able to form. Such solvates are for example hydrates, alcoholates and the like. The term “quaternary amine” as used hereinbefore defines the quaternary ammonium salts which the compounds are able to form by reaction between a basic nitrogen of a compound and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.

[0102] Prodrugs of the disclosed compounds also are contemplated herein. A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into an active compound following administration of the prodrug to a subject. The term “prodrug” as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds described herein. Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo. Prodrugs of a compounds described herein may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. F or a general discussion of prodrugs involving esters see Svensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard, Design of Prodrugs, Elsevier (1985).

[0103] The term “prodrug” also is intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when the prodrug is administered to a subject. Since prodrugs often have enhanced properties relative to the active agent pharmaceutical, such as, solubility and bioavailability, the compounds disclosed herein can be delivered in prodrug form. Thus, also contemplated are prodrugs of the presently disclosed compounds, methods of delivering prodrugs and compositions containing such prodrugs. Prodrugs of the disclosed compounds typically are prepared by modifying one or more functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound. Prodrugs may include compounds having a phosphonate, hydroxy, thio and / or amino group functionalized with any group that is cleaved in vivo to yield the corresponding amino, hydroxy, thio and / or phosphonate group, respectively. Examples of prodrugs can include, without limitation, compounds having an acylated amino group and / or a phosphonate ester or phosphonate amide group. Protected derivatives of the disclosed compounds also are contemplated. A variety of suitable protecting groups for use with the disclosed compounds are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis', 3rd Ed.; John Wiley & Sons, New York, 1999.

[0104] In general, protecting groups are removed under conditions that will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. One preferred method involves the removal of an ester, such as cleavage of a phosphonate ester using Lewis acidic conditions, such as in TMS-Br mediated ester cleavage to yield the free phosphonate. A second preferred method involves removal of a protecting group, such as removal of a benzyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxy-based group, including t-butoxy carbonyl protecting groups can be removed utilizing an inorganic or organic acid, such as HC1 or trifluoroacetic acid, in a suitable solvent system, such as water, dioxane and / or methylene chloride. Another exemplary protecting group, suitable for protecting amino and hydroxy functions amino is trityl. Other conventional protecting groups are known and suitable protecting groups can be selected by those of skill in the art in consultation with Greene and Wuts, Protective Groups in Organic Synthesis', 3rd Ed.; John Wiley & Sons, New York, 1999. When an amine is deprotected, the resulting salt can readily be neutralized to yield the free amine. Similarly, when an acid moiety, such as a phosphonic acid moiety is unveiled, the compound may be isolated as the acid compound or as a salt thereof.

[0105] Particular examples of the presently disclosed compounds may include one or more asymmetric centers; thus the compounds described can exist in different stereoisomeric forms. Accordingly, compounds and compositions may be provided as individual pure enantiomers or as stereoisomeric mixtures, including racemic mixtures. In certain embodiments the compounds disclosed herein may be synthesized in or may be purified to be in substantially enantiopure form, such as in a 90% enantiomeric excess, a 95% enantiomeric excess, a 97% enantiomeric excess or even in greater than a 99% enantiomeric excess, such as in enantiopure form.

[0106] The presently disclosed compounds can have at least one asymmetric center or geometric center, cis-trans center(C=C, C=N). All chiral, diasteromeric, racemic, meso, rotational, conformational and geometric isomers of the structures are intended unless otherwise specified. The compounds can be isolated as a single isomer or as mixture of isomers by methods utilizing specific chiral resolving agents like quinine, Chiral HPLC, SFC (super critical fluid chromatography) etc. All tautomers of the compounds are also considered part of the disclosure. The presently disclosed compounds also include all isotopes of atoms present in the compounds, which can include, but are not limited to, deuterium, tritium,13C,18F, stable and radioisotope, etc. Compounds

[0107] Disclosed herein are novel and selective modulators of Kv7 potassium channels that are useful for the treatment of a range of channelopathies, including epilepsy, developmental and epileptic encephalopathy, pain, tinnitus, cancer, cardiovascular disease, and neurodegeneration.

[0108] In particular, disclosed herein are Kv7 potassium channel modulators of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0109] Formula I wherein X is N or C;

[0110] Y is N or C;

[0111] Z is N or C;

[0112] W is N or C;

[0113] R1is H;

[0114] R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl ;

[0115] R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0116] R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0117] Rsis H; R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;

[0118] R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;

[0119] R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;

[0120] R10is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, or oxo; and where each bond represented by - is a single or double bond as needed to satisfy valence requirements.

[0121] It certain embodiments, the compound is of Formula la, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0122] Formula la wherein X is N or C;

[0123] Y is N or C;

[0124] Z is N or C;

[0125] W is N or C;

[0126] R1is H;

[0127] R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;

[0128] R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0129] R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0130] Rsis H;

[0131] R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;

[0132] R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;

[0133] R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo; and

[0134] R10is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo.

[0135] Also disclosed herein are Kv7 potassium channel modulators of Formula II, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0136] Formula II wherein X is N;

[0137] Y is C;

[0138] Z is C;

[0139] W is C;

[0140] R1is H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0141] R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0142] R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0143] R5is H;

[0144] R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and

[0145] R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

[0146] In certain embodiments, at least one of X, Y, Z or W is N. In certain embodiments, X is N. In certain embodiments, X is N and Y, Z and W are each C.

[0147] In certain embodiments, R1is H.

[0148] In certain embodiments, R3is alkyl. In certain embodiments, R3is (Ci-Ce) alkyl, particularly methyl.

[0149] In certain embodiments, R4is alkyl or cycloalkyl. In certain embodiments, R4is (Ci-Ce) alkyl, particularly propyl. In certain embodiments, R4is (C3-C6) cycloalkyl, particularly cyclopropyl.

[0150] In certain embodiments, R6is H or alkoxy.

[0151] In certain embodiments, R7is H or alkoxy. In certain embodiments, R7is (Ci-Ce) alkoxy, particularly methoxy.

[0152] In certain embodiments, at least one of R6, R7, R9, R10is halo.

[0153] In certain embodiments, R8is arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl. In certain embodiments, R8is phenyl-substituted alkyl, particularly benzyl.

[0154] Illustrative compounds include:

[0155]

[0156] 10

[0157]

[0158] 10 and their stereoisomers.

[0159] Pharmaceutical Compositions and Methods of Use

[0160] The compounds disclosed herein may be used for treating Kv7-mediated diseases. For example, the compounds disclosed herein may be used for treating epilepsy, developmental and epileptic encephalopathy, pain (e.g., neuropathic pain, migraine), tinnitus, cancer, cardiovascular disease, neurodegeneration (e.g., Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington’s disease), fibromyalgia, arthritis, hyperalgesia, depression, schizophrenia, bipolar disorder, traumatic brain injury, smooth muscle disorders, erectile dysfunction, myotonic congenita, and inflammatory airway diseases.

[0161] In some embodiments, the methods disclosed herein involve administering to a subject in need of treatment a pharmaceutical composition, for example a composition that includes a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds disclosed herein. The compounds may be administered orally, parenterally (including subcutaneous injections (SC or depo-SC), intravenous (IV), intramuscular (IM or depo-IM), intrastemal injection or infusion techniques), sublingually, intranasally (inhalation), intrathecally, topically, ophthalmically, or rectally. The pharmaceutical composition may be administered in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and / or vehicles. The compounds are preferably formulated into suitable pharmaceutical preparations such as tablets, capsules, or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. Typically the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art.

[0162] In some embodiments, one or more of the disclosed compounds are mixed or combined with a suitable pharmaceutically acceptable carrier to prepare a pharmaceutical composition. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to be suitable for the particular mode of administration. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21stEdition (2005), describes exemplary compositions and formulations suitable for pharmaceutical delivery of the compounds disclosed herein. In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.

[0163] Upon mixing or addition of the compound(s) to a pharmaceutically acceptable carrier, the resulting mixture may be a solution, suspension, emulsion, or the like. Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. Where the compounds exhibit insufficient solubility, methods for solubilizing may be used. Such methods are known and include, but are not limited to, using cosolvents such as dimethylsulfoxide (DMSO), using surfactants such as Tween®, and dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts or prodrugs may also be used in formulating effective pharmaceutical compositions. The disclosed compounds may also be prepared with carriers that protect them against rapid elimination from the body, such as time-release formulations or coatings. Such carriers include controlled release formulations, such as, but not limited to, microencapsulated delivery systems.

[0164] The disclosed compounds and / or compositions can be enclosed in multiple or single dose containers. The compounds and / or compositions can also be provided in kits, for example, including component parts that can be assembled for use. For example, one or more of the disclosed compounds may be provided in a lyophilized form and a suitable diluent may be provided as separated components for combination prior to use. In some examples, a kit may include a disclosed compound and a second therapeutic agent (such as an anti-retroviral agent) for coadministration. The compound and second therapeutic agent may be provided as separate component parts. A kit may include a plurality of containers, each container holding one or more unit dose of the compound. The containers are preferably adapted for the desired mode of administration, including, but not limited to tablets, gel capsules, sustained-release capsules, and the like for oral administration; depot products, pre-filled syringes, ampoules, vials, and the like for parenteral administration; and patches, medipads, creams, and the like for topical administration.

[0165] The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the subject treated. A therapeutically effective concentration may be determined empirically by testing the compounds in known in vitro and in vivo model systems for the treated disorder. In some examples, a therapeutically effective amount of the compound is an amount that lessens or ameliorates at least one symptom of the disorder for which the compound is administered. Typically, the compositions are formulated for single dosage administration. The concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.

[0166] In some examples, about 0. 1 mg to 1000 mg of a disclosed compound, a mixture of such compounds, or a physiologically acceptable salt or ester thereof, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form. The amount of active substance in those compositions or preparations is such that a suitable dosage in the range indicated is obtained. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. In some examples, the compositions are formulated in a unit dosage form, each dosage containing from about 1 mg to about 1000 mg (for example, about 2 mg to about 500 mg, about 5 mg to 50 mg, about 10 mg to 100 mg, or about 25 mg to 75 mg) of the one or more compounds. In other examples, the unit dosage form includes about 0.1 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or more of the disclosed compound(s).

[0167] The disclosed compounds or compositions may be administered as a single dose, or may be divided into a number of smaller doses to be administered at intervals of time. The therapeutic compositions can be administered in a single dose delivery, by continuous delivery over an extended time period, in a repeated administration protocol (for example, by a multi-daily, daily, weekly, or monthly repeated administration protocol). It is understood that the precise dosage, timing, and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. In addition, it is understood that for a specific subject, dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only.

[0168] When administered orally as a suspension, these compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners / flavoring agents. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants. If oral administration is desired, the compound is typically provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

[0169] Oral compositions will generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules. For the purpose of oral therapeutic administration, the active compound or compounds can be incorporated with excipients and used in the form of tablets, capsules, or troches. Pharmaceutically compatible binding agents and adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches, and the like can contain any of the following ingredients or compounds of a similar nature: a binder such as, but not limited to, gum tragacanth, acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose, starch, or lactose; a disintegrating agent such as, but not limited to, alginic acid and com starch; a lubricant such as, but not limited to, magnesium stearate; a gildant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, or fruit flavoring.

[0170] When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials, which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings, and flavors.

[0171] When administered orally, the compounds can be administered in usual dosage forms for oral administration. These dosage forms include the usual solid unit dosage forms of tablets and capsules as well as liquid dosage forms such as solutions, suspensions, and elixirs. When the solid dosage forms are used, it is preferred that they be of the sustained release type so that the compounds need to be administered only once or twice daily. In some examples, an oral dosage form is administered to the subject 1, 2, 3, 4, or more times daily. In additional examples, the compounds can be administered orally to humans in a dosage range of 1 to 1000 mg / kg body weight in single or divided doses. One illustrative dosage range is 0.1 to 200 mg / kg body weight orally (such as 0.5 to 100 mg / kg body weight orally) in single or divided doses. For oral administration, the compositions may be provided in the form of tablets containing about 1 to 1000 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0172] Injectable solutions or suspensions may also be formulated, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3 -butanediol, water, Ringer’s solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, and the like, or a synthetic fatty vehicle such as ethyl oleate, and the like, polyethylene glycol, glycerine, propylene glycol, or other synthetic solvent; antimicrobial agents such as benzyl alcohol and methyl parabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, and phosphates; and agents for the adjustment of tonicity such as sodium chloride and dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass, plastic, or other suitable material. Buffers, preservatives, antioxidants, and the like can be incorporated as required.

[0173] Where administered intravenously, suitable carriers include physiological saline, phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol, polypropyleneglycol, and mixtures thereof. Liposomal suspensions including tissue-targeted liposomes may also be suitable as pharmaceutically acceptable carriers.

[0174] The compounds can be administered parenterally, for example, by IV, IM, depo-IM, SC, or depo-SC. When administered parenterally, a therapeutically effective amount of about 0.1 to about 500 mg / day (such as about 1 mg / day to about 100 mg / day, or about 5 mg / day to about 50 mg / day) may be delivered. When a depot formulation is used for injection once a month or once every two weeks, the dose may be about 0.1 mg / day to about 100 mg / day, or a monthly dose of from about 3 mg to about 3000 mg.

[0175] The compounds can also be administered sublingually. When given sublingually, the compounds should be given one to four times daily in the amounts described above for IM administration.

[0176] The compounds can also be administered intranasally. When given by this route, the appropriate dosage forms are a nasal spray or dry powder. The dosage of the compounds for intranasal administration is the amount described above for IM administration. When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents.

[0177] The compounds can be administered intrathecally. When given by this route, the appropriate dosage form can be a parenteral dosage form. The dosage of the compounds for intrathecal administration is the amount described above for IM administration.

[0178] The compounds can be administered topically. When given by this route, the appropriate dosage form is a cream, ointment, or patch. When administered topically, an illustrative dosage is from about 0.5 mg / day to about 200 mg / day. Because the amount that can be delivered by a patch is limited, two or more patches may be used. The compounds can be administered rectally by suppository. When administered by suppository, an illustrative therapeutically effective amount may range from about 0.5 mg to about 500 mg. When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and / or dissolve in the rectal cavity to release the drug.

[0179] It should be apparent to one skilled in the art that the exact dosage and frequency of administration will depend on the particular compounds administered, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular subject, and other medication the individual may be taking as is well known to administering physicians or other clinicians who are skilled in therapy of retroviral infections, diseases, and associated disorders.

[0180] Certain embodiments are described in the following numbered clauses:

[0181] 1. A compound of Formula II, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0182] Formula II wherein X is N;

[0183] Y is C;

[0184] Z is C;

[0185] W is C;

[0186] R1is H;

[0187] R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0188] R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0189] R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0190] R5is H; R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and

[0191] R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

[0192] 2. The compound of clause 1, wherein R2is -C(O)O-R8.

[0193] 3. The compound of clause 1 , wherein R2is -C(O)NH-R8.

[0194] 4. The compound of any one of clauses 1 to 3, wherein R3is alkyl.

[0195] 5. The compound of any one of clauses 1 to 3, wherein R3is (Ci-Cs) alkyl.

[0196] 6. The compound of any one of clauses 1 to 5, wherein R4is alkyl or cycloalkyl.

[0197] 7. The compound of any one of clauses 1 to 5, wherein R4is (Ci-Ce) alkyl.

[0198] 8. The compound of any one of clauses 1 to 7, wherein R6is H or alkoxy.

[0199] 9. The compound of any one of clauses 1 to 8, wherein R7is H or alkoxy.

[0200] 10. The compound of any one of clauses 1 to 9, wherein R8is arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl.

[0201] 11. The compound of any of clauses 1 to 9, wherein R8is phenyl-substituted alkyl

[0202] 12. The compound of any of clauses 1 to 9, wherein R8is benzyl.

[0203] 13. A pharmaceutical composition comprising at least one pharmaceutically acceptable additive and a compound of any of clauses 1 to 12.

[0204] 14. A method comprising administering to a subject in need of treatment for epilepsy, developmental or epileptic encephalopathy, pain, tinnitus, cancer, cardiovascular disease, neurodegeneration, fibromyalgia, arthritis, hyperalgesia, depression, schizophrenia, bipolar disorder, traumatic brain injury, smooth muscle disorders, erectile dysfunction, myotonic congenita, or inflammatory airway diseases, a therapeutically effective amount of a compound of Formula II, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0205] Formula II wherein X is N;

[0206] Y is C;

[0207] Z is C;

[0208] W is C;

[0209] R1is H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0210] R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0211] R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0212] R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0213] R5is H;

[0214] R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and

[0215] R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

[0216] 15. A method comprising administering to a subject in need of treatment for a Kv7- mediated disease a therapeutically effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0217] Formula I wherein X is N;

[0218] Y is C;

[0219] Z is C;

[0220] W is C;

[0221] R1is H, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0222] R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0223] R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0224] R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

[0225] Rsis H;

[0226] R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; and

[0227] R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

[0228] 16. The method of clause 14 or 15, wherein R1is H.

[0229] 17. The method of any one of clauses 14 to 16, wherein R is (Ci-Ce) alkyl.

[0230] 18. The method of any one of clauses 14 to 17, wherein R4is alkyl or cycloalkyl.

[0231] 19. The method of any one of clauses 14 to 17, wherein R4is (Ci-Ce) alkyl.

[0232] 20. The method of any one of clauses 14 to 19, wherein R6is H or alkoxy. 21. The method of any one of clauses 14 to 20, wherein R7is H or alkoxy.

[0233] 22. The method of any one of clauses 14 to 21, wherein R8is arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl.

[0234] 23. The method of any one of clauses 14 to 21, wherein R8is phenyl-substituted alkyl

[0235] 24. The method of any of one clauses 14 to 21 , wherein R8is benzyl.

[0236] Examples

[0237] Assay 1.

[0238] Biological screens for assessing compounds against KCNQ2, KCNQ2 / 3, KCNQ4, KCNQ4 / 5 and KCNQ5 were performed in agonist mode in the FLIPR assay.

[0239] The FLIPR Potassium Assay Kit exploits the permeability of thallium ions (T1+) through both voltage- and ligand-gated potassium (K+) channels. In this assay, a novel, highly-sensitive T1+ indicator dye is utilized which produces a bright fluorescent signal upon the binding to T1+ conducted through potassium channels.

[0240] Protocol: Human Kv cells are harvested, counted and seeded in black, clear-bottomed 96 well plates at a density of 50,000 cells per well in 1 OOu 1 volume and incubated overnight. Next day, media is removed and replaced with 40ul of loading buffer (4.895ml HBSS:HEPES, 5 Ou I probenecid, 50pl power load, 5p 1 FluxOR reagent) and incubated at room temperature for 30 minutes. After incubation loading buffer is removed and 40pl of assay buffer added (4.45ml HBSS:HEPES, 500,u 1 FluxOR assay buffer and 50,u 1 probenecid) and incubated for 10 minutes. The plates are placed in the FLIPR, after incubation with assay buffer, and fluorescence monitored every 1 second. After 20 seconds FLIPR then adds lOpl of stimulus buffer along with either vehicle, test compound or reference agonist and fluorescence monitored for 5 minutes at ex / emm: 488nm / 510-570nm. The following activities were obtained with this assay:

[0241] Assay 2.

[0242] CYL8059QB hKv7.2 / 7.3 Potassium Channel Agonist Assay- Qube APC. Data readout:

[0243] After whole cell configuration is achieved, the cell is held at -120 mV. Then the cell is depolarized to -40 mV for 1 s and then back to -120 mV. This paradigm is delivered once every 20s to monitor the current amplitude. The current amplitude in the presence of Test compound is normalized to that under the Control 0.33% DMSO concentration and reported as percent relative to the reference Control Retigabine.

[0244] All compounds were tested in the presence of 0. 1 % Pluronic F-68 Non-Ionic Surfactant and at approximately room temperature.

[0245] CYL8059QB hKv7.2 / 7.3 Potassium Channel Agonist Assay- Qube APC. Data calculation and analysis:

[0246] The parameters measured were the maximum peak current evoked on stepping from -120mV to - 40mV. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of activity was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean hKv7.2 / Kv7.3 current amplitude collected 10 seconds at the end of the control period; Test compound data is the mean hKv7.2 / Kv7.3 current amplitude collected 10 seconds at the end of test concentration application for each concentration. The following activities were obtained for representative compounds with this assay:

[0247] Cpd K ol Activity

[0248] A

[0249] Retigabine

[0250] A4 High

[0251] BIO-1 Medium

[0252] B9-1 Low

[0253] B31 No agonist activity

[0254] B2-2 ent-B32

[0255] General Synthetic Methods. All reaction solvents were dried prior to use. THF was freshly distilled from a sodium / benzophenone radical anion solution and CH2Cl2. acetonitrile, and toluene were freshly distilled over (Cafh). EtjN, DIPEA, and pyridine were distilled (CaLK When necessary, degassed solvents were prepared by freeze-pump-thaw techniques. Unless stated otherwise, all reactions were performed under an atmosphere of N2 that was passed through a short cartridge (10 x 2 cm) of drierite®. All glassware and stir bars were flame-dried prior to use. Reactions were monitored by TLC analysis (pre-coated silica gel 60 F254) and spots were visualized (UV lamp 254 nm and 395 nm). IR spectra were obtained using a PerkinElmer 100 IR-ATR spectrometer. Melting points were obtained using a Mel-Temp instrument and are uncorrected.]H / nC NMR spectra were recorded on Broker Avance 300 / 76 MHz, Broker Avance 400 / 100 MHz, Broker Avance 500 / 126 MHz, Broker Avance 601 / 151 MHz, or Broker Avance 701 MHz instruments. High resolution mass spectra were obtained on a Micromass UK Limited, Q-TOF Ultima API or a Thermo Scientific Exactive Orbitrap LC-MS. Chemical shifts were reported in parts per million (ppm) with the residual solvent peak (CDC13: 7.26 ppm for]H, 77.16 ppm for13C; DMSO-d6: 2.50 ppm for1H, 39.52 ppm for13C) used as the internal standard. Chemical shifts were tabulated as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, h = sextet, dd = doublet of doublet, dt = doublet of triplet, ddd = doublet of doublet of doublet, tt = triplet of triplet, dtd = double of triplet of doublet, dddd = doublet of doublet of doublet of doublet, dddt = doublet of doublet of doublet of triplet, dtdd = doublet of triplet of doublet of doublet, ddtd = doublet of doublet of triplet of doublet, dtt = doublet of doublet of triplet, m = multiplet, brs = broad singlet, AB = second order AB spin system doublet of doublet, app = apparent), coupling constants ), and integration.

[0256] The purity of final products was assessed using an Agilent Technologies 1260 Infinity II LC at 220 nm UV absorption (Waters XBridge BEH Cis 2.1 x 50 mm, 2.5 nm) or an Agilent Technologies 385-ELSD (Microsolv Cogent 2.0 Bidentate Cis 2.1 x 50 mm, 2.2 pm; ELSD conditions: evaporator and nebulizer set at 45 °C; gas flow set at 1.80 standard liter / min). All final assay samples showed a purity >95% by LCMS analysis with UV (220 nm) and ELS detection.

[0257] General Procedure A for the Povarov Reaction with (R)-2,6-bis(4-chlorophenyl)-4-hydroxy- 8,9,10,l l,12,13,14,15-octahydrodinaphtho[2,l-d:r,2'-f][l,3,2]dioxaphosphepine 4-oxide ((R)- CPA). (Kazancioglu, M. Z.; Quirion, K.; Wipf, P.; Skoda, E. M. “Enantioselective Synthesis and Selective Functionalization of 4- Aminotetrahydroquinolines as Novel GLP-1 Secretagogues." Chirality 2021, 34, 521-536).

[0258] To a solution of the aldehyde (0.52 mmol, 1.0 eq) in dry CH2Q2 (2.6 mL, 0.2 M) at room temperature under an inert gas atmosphere was added the amine (0.52 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 30 min, cooled to 0 °C and treated with (R)-CPA (30 mg, 0.052 mmol, 10 mol%) and a solution of the ene-carbamate (0.52 mmol, 1.0 eq) in dry CH2Cl2(2.6 mL, 0.2 M). The mixture was allowed to warm to room temperature over 15 h, concentrated in vacuo, and the residue was purified by chromatography on SiCL to yield the desired tetrahydroquinoline as a colorless solid that was recrystallized (EtOAc / hexanes) for final purification. Enantiomeric excess was analyzed by HPLC using a Chiralpak IA column (46 mm D x 250 mm L / 5 pm) using as mobile phase 85: 15 Hexanes / EtOH at 1.0 mL / min.

[0259] 4-Bromobenzyl ((2R,3R,4S)-2-cyclopentyl-3-methyl-l,2,3,4-tetrahydroquinolin-4- yl)carbamate. Prepared according to General Procedure A: HRMS (ES+) m / z calcd for C23H28N2O2Br ([M + H]+) 433.1329, found 443.1323.

[0260]

[0261] Benzyl ((27?,3R,4S)-2-cyclopentyl-3-methyl-l,2,3,4-tetrahydroquinolin-4-yl)carbamate. Prepared according to General Procedure A. HRMS (ES+) m / z calcd for C23H29N2O2([M + H]+) 365.2223, found 365.2218.

[0262] Benzyl ((2R,3R,4S)-2-isopropyl-6-methoxy-3-methyl- 1,2,3, 4-tetrahydro-l, 5-naphthyridin-4- yljcarbamate (Al). Prepared according to General Procedure A. Mp 163 °C;]H NMR (500 MHz, CDC13) 5 7.41-7.29 (m, 5 H), 6.84 (d, J = 8.5 Hz, 1 H), 6.46 (d, J = 8.5 Hz, 1 H), 5.23, 5.14 (AB, J = 12.0 Hz, 1 H), 4.97 (brs, 1 H), 4.56 (app t, J = 9.6 Hz, 1 H), 3.69 (s, 3 H), 3.00 (d, J = 9.0 Hz, 1 H), 2.11-2.04 (m, 1 H), 1.83-1.75 (m, 1 H), 1.11 (d, J = 6.5 Hz, 3 H), 1.04 (d, J = 7.0 Hz, 3 H), 0.88

[0263] (d, J = 6.5 Hz, 3 H); HRMS (ES+) m / z calcd for C21H28N3O3([M + H]+) 370.2125, found 370.2127. Chiral HPLC (Chiralpak IA, EtOH / Hex 15:85, 254 nm) er = 97: (flow rate = 1.0 mL / min) major isomer: tR = 9.76 min; minor isomer: t = 13.06 min

[0264] Benzyl ((27?,3R,4Sj-6,8-dichloro-2-cyclopentyl-3-methyl- 1,2,3, 4-tetrahydroquinolin-4- yljcarbamate. Prepared according to General Procedure A followed by chlorination with 1,3- dichloro-5,5-dimethylhydantoin. (Xiong, X.; Yeung, Y.-Y. Angew. Chem. Int. Ed. 2016, 55(52), 16101-16105). HRMS (ES+) m / z calcd for C23H27N3O2CI2 ([M + H]+) 433.1444, found 433.1440.

[0265]

[0266] (±)-4-Bromobenzyl((2RS, RS.4SR)-6.8-dichloro-2-cyclopentyl-3-methyl-l, 2,3,4- tetrahydroquinolin-4-yl)carbamate. Prepared according to General Procedure A followed by chlorination with l,3-dichloro-5,5-dimethylhydantoin. (Xiong, X.; Yeung, Y.-Y. Angew. Chem. Ini. Ed. 2016, 55(52), 16101-16105) HRMS (ES+) m / z calcd for C23H26N2O2BrC12 ([M + H]+) 511.0549, found 511.0551.

[0267] General Procedure B for the Povarov Reaction with Diphenyl Hydrogen Phosphate.

[0268] To a solution of the aldehyde (0.52 mmol, 1.0 eq) in dry CH2Cl2(2.6 mL, 0.2 M) at room temperature under an argon atmosphere was added the aniline (0.52 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 30 min, cooled to 0 °C and treated with diphenyl hydrogen phosphate (13.0 mg, 0.052 mol, 10 mol%) and a solution of the ene-carbamate (0.52 mmol, 1.0 eq) in dry CH2Cl2(2.6 mL, 0.2 M). The reaction mixture was allowed to warm to room temperature, heated at 60 °C for 15 h, and concentrated in vacuo. The residue was purified by chromatography on SiO2to yield the desired tetrahydroquinoline as a colorless solid that was recrystallized (EtOAc / hexanes) for final purification. Reactions provided a racemic mixture of products which were analyzed on a Chiralpak IA column (4.6 mm D x 250 mm L; 5 pm) using 85: 15 Hexanes / EtOH at 1.0 mL / min. Analogous conditions were used for preparative resolutions of racemic mixtures on a semi -prep Chiralpak IA column (20 mm D x 250 mm L; 5 pm) with 85:15 Hexanes / EtOH at 6.0 mL / min. (±)-Benzyl ((2RS,3RS,4SR)-2-cyclopentyl-3-methyl- 1 ,2,3,4-tetrahydro- 1 ,5-naphthyridin-4- yl)carbamate. Prepared according to General Procedure B. Mp 128.5 °C;1H NMR (400 MHz, CDC13) 5 7.92 (d, J = 4.8 Hz, 1 H), 7.43-7.29 (m, 5 H), 6.96 (dd, J = 8.0, 4.4 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 5.27 (brs, 1 H), 5.23, 5.12 (AB, J = 12.0 Hz, 2 H), 4.53 (app t, 7= 7.6 Hz, 1 H), 3.84 (s, 1 H), 3.14 (brs, 1 H), 2.32-2.23 (m, 1 H), 2.05-1.97 (m, 1 H), 1.77-1.51 (m, 6 H), 1.35-1.23 (m, 2 H), 1.12 (d, J = 6.4 Hz, 3H);13C NMR (100 MHz, CDC13) 5 170.9, 157.1, 140.3, 138.3, 136.9, 128.4, 128.0, 127.9, 123.3, 120.6, 66.7, 59.2, 55.7, 41.9, 36.9, 29.2, 26.6, 25.9, 25.5, 16.3; HRMS (ES+) m / z calcd for C22H28N3O2([M + H]+) 366.2176, found 366.2173

[0269] (+)-4-Bromobenzyl ((2RS,3RS,4SR)-2-cyclopentyl-3-methyl- 1 ,2,3,4-tetrahydro- 1 ,5-naphthyridin-4- yljcarbamate.

[0270] Prepared according to General Procedure B.

[0271] (±)-4-(Trifluoromethyl)benzyl naphthyridin-4-yl)carbamate.

[0272] Prepared according to General Procedure B. HRMS (ES+ ) m / z. calcd for C23H27N3O2F3([M + H]+) 434.2049, found 434.2047.

[0273]

[0274] (±)-Benzyl ((2RS,3RS,4SR)-2-ethyl-6-methoxy-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4- yl)carbamate. Prepared according to General Procedure B. Mp 174.3 °C; 'H NMR (400 MHz, CDCl3) δ 7.43-7.30 (m, 5 H), 6.81 (d, J = 8.5 Hz, 1 H), 6.46 (d, J = 8.5 Hz, 1 H), 5.24, 5.13 (AB, J = 12.5 Hz, 2 H), 4.91 (d, J = 8.0 Hz, 1 H), 4.64 (brs, 1 H), 4.56 (t, J = 9.6 Hz, 1 H), 3.69 (s, 3 H), 3.11-3.03 (m, 1 H), 1.79-1.48 (m, 3 H), 1.11 (d, J = 6.4 Hz, 3 H), 1.97 (t, 7= 7.2 Hz, 3 H);13C NMR (100 MHz, CDCh) 5 158.2, 156.6, 136.9, 136.7, 128.6, 128.3, 128.1, 127.9, 126.3, 110.1, 67.0, 66.7, 57.7, 52.9, 37.8, 25.8, 14.9, 8.8; HRMS (ES+) m / z. calcd for C20H26N3O3(|M + HJ+) 356.1969, found

[0275] 356.1965.

[0276] (±)-Benzyl ((2RS,3RS,4SR)-2-ethyl-3-methyl-l,2,3,4-tetrahydroquinolin-4-yl)carbamate.

[0277] Prepared according to General Procedure B. HRMS (ES+) m / z. calcd for C20H25N2O2([M + H]+)

[0278] 325.1911, found 325.1907. Benzyl ((2R,3R,4S)-2-cyclopropyl-6-methoxy-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin- 4- yl)carbamate (A2). Prepared according to General Procedure B. HRMS (ES+) m / z calcd for C21H26N3O3([M + H]+) 368.1969, found 368.1969.

[0279] (±)-Benzyl((2P.S\3 / ?.S 4.S' / ?)-2-cyclopropyl-3-methyl- 1 ,2,3,4-tetrahydro- 1 ,5-naphthyridin-4- yl)carbamate.

[0280] Prepared according to General Procedure B. Mp 1 3.6-139.5 °C; NMR (500 MHz, CDC13) 8 7.91 (d, J = 3.5 Hz, 1 H), 7.44-7.29 (m, 5 H), 6.99-6.94 (m, 1 H), 6.81-6.76 (m, 1 H), 5.45 (brs, 1 H), 5.23, 5.13 (AB, J = 12.3 Hz, 2 H), 4.56 (app t, J = 9.0 Hz, 1 H), 4.00 (brs, 1 H), 2.33 (t, J = 9.0 Hz, 1 H), 1,94 (brs, 1 H), 1.26 (d, J = 6.5 Hz, 3 H), 0.93-0.83 (m, 1 H), 0.75-0.69 (m, 1 H), 0.58- 0.52 (m, 1 H), 0.46-0.42 (m, 1 H), 0.26-0.19 (m, 1 H); HRMS (ES+) m / z calcd for C20H24N3O2([M + H]+) 338.1863, found 338.1865.

[0281] (±)-Benzyl((2RS,3RS,4SR)-2-ethyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)carbamate.

[0282] Prepared according to General Procedure B. Mp 133.3-145.2 °C; ' H NMR (300 MHz, CDCh) 8 7.91 (dd, J = 4.5, 1.2 Hz, 1 H), 7.43-7.29 (m, 5 H), 6.94 (ddd, J = 8.1, 4.5, 0.5 Hz, 1 H), 6.81-6.75 (dd, J = 8.1, 1.5 Hz, 1 H), 5.37 (brs, 1 H), 5.23, 5.15 (AB, J = 12.6 Hz, 2 H), 4.59 (t, J = 9.7 Hz, 1 H), 3.79 (brs, 1 H), 3.22-3.14 (m, 1 H), 1.83-1.68 (m, 2 H), 1.57 (app h, J = 7.2 Hz, 1 H), 1.12 (d, 7 = 6.6 Hz, 3 H), 0.97 (t, J = 7.5 Hz, 3 H); LCMS (ES+) m / z. calcd for C19H24N3O2([M + H]+) 326.19, found 326.15.

[0283] (+)-Benzyl ((2 / ?.S',3 / ?.S',4.S' / ?)-2,3-dimelhyl- l ,2,3,4-tetrahydro- l ,5-naphthyridin-4-yl)carbamate.

[0284] Prepared according to General Procedure B. Mp 118.4-122.6 °C;1H NMR (500 MHz, CDCl3) 57.91 (dd, J = 4.6, 1.0 Hz, 1 H), 7.32-7.29 (m, 5 H), 6.95 (dd, J = 7.9, 4.7 Hz, 1 H), 6.75 (dd, J = 8.0, 1.0 Hz, 1 H), 5.35 (bs, 1 H), 5.23, 5.14 (AB, J = 12.3 Hz, 2 H), 4.59 (t, J = 9.7 Hz, 1 H), 3.70 (brs, 1 H), 3.32-3.26 (m, 1 H), 1.64- 1.57 (m, 1 H), 1.25 (d, J = 6.5 Hz, 3 H), 1.14 (d, 7= 6.5 Hz, 3 H);13C NMR (125 MHz, CDCI3) 5 157.9, 141.3, 140.5, 138.5, 137.0, 128.6, 128.2, 128.1, 123.2, 119.9, 66.9, 56.2, 52.7, 40.7, 20.8, 15.1; HRMS (ES+) m / z calcd for C18H22N3O2([M + H]+) 312.1707, found 312.1708. Chiral HPLC (Chiralpak IA, EtOH / Hexanes 15:85, 254 nm, flow rate = 1.0 mL / min) isomer 1: tR = 14.72 min; isomer 2: t = 25.99 min.

[0285] (-)-Benzyl ((2R,3R,4S )-2.3-dimethyl- l,2,3,4-tctrahydro- l,5-naphthyridin-4-yl)carhamatc (A6): [α]D25-32.0 (c 0.13, MeOH); Chiral HPLC (Chiralpak IA, EtOH / Hexanes 15:85, 254 nm, flow rate = 1.0 mL / min): tR = 14.72 min; isomer 2: t = 25.99 min; er >99:1.

[0286] (+)-Bcnzyl ('('2.S',3.S’,4A)-2,3-dimcthyl- 1 ,2,3.4-tctrahydro- 1 ,5-naphthyridin-4-yl)carbarnatc: [α]D25+35.1 (c 0.19, MeOH); Chiral HPLC (Chiralpak IA, EtOH / Hexanes 15:85, 254 nm, flow rate = 1.0 mL / min): tR = 25.99 min; er 98:2.

[0287] (+)-Benzyl((2RS,3RS,4SR )-2-isopropyl-3-methyl- 1 ,2,3,4-tetrahydro- 1 ,5-naphthyridin-4- yl)carbamate.

[0288] To an oven-dried round bottom flask was added isobutyraldehyde (69 μL, 0.74 mmol) in CH2Cl2(2.5 mL). The mixture was placed under nitrogen, treated with 3 -aminopyridine (68 mg, 0.72 mmol), and allowed to stir at room temperature for 30 min. The solution was then cooled to 0 °C, treated with diphenyl hydrogen phosphate (21 mg, 0.083 mmol) and a solution of (ZT)-prop- l -en- 1 - ylcarbamate (150 mg, 0.78 mmol) in CH2Cl2(2.5 mL), warmed to room temperature (~2 h) and heated at 60 °C overnight under reflux conditions. After 23 h, the reaction mixture was cooled and concentrated. The crude residue was purified by chromatography on SiCH (1 :1 Hexanes:EtOAc) and then triturated with CHiCHHexanes (1 :3) to give pure (±)-benzyl ((2 / ?S,3 / ?.S',4.S7?)-2-isopropyl- 3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)carbamate (47 mg, 20%) as a colorless solid:]H NMR (300 MHz, CDCh) 57.91 (dd, J = 4.6, 1.3 Hz, 1 H), 7.43-7.29 (m, 5 H), 6.95 (dd, J = 7.8, 4.6 Hz, 1 H), 6.77 (dd, 7 = 8.1 , 1.5 Hz, 1 H), 5.42 (brs, 1 H), 5.23, 5.14 (AB, 7 = 12.3 Hz, 2 H), 4.60 (t, 7 = 9.0 Hz, 1 H), 3.75 (brs, 1 H), 3.07 (dd, 7 = 9.3, 3.0 Hz, 1 H), 2.15-2.03 (m, 1 H), 1.92- 1.80 (m, 1 H), 1.11 (d, J = 6.6 Hz, 3 H), 1.05 (d, J = 7.2 Hz, 3 H), 0.86 (d, 7= 6.9 Hz, 3 H);13C NMR (125 MHz, CDCh) 5 157.7, 140.9, 140.8, 138.1, 136.8, 128.4, 128.0, 127.9, 123.2, 120.2, 66.7, 61.2, 56.1, 36.2, 28.6, 20.1, 14.9, 14.6; HRMS (ES+) m / z calcd for C20H26N3O2([M + H]+) 340.2019, found 340.2027; Chiral HPLC (Chiralpak IA, EtOH / Hexanes 15:85, 254 nm) (flow rate = 1.0 mL / min).

[0289] Benzyl ((2R,3R,45)-2-isopropyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)carbamate (A3): tR = 10.34 min; er = 98:2. Benzyl ((25, 3S\4R)-2-isopropyl-3-methyl- 1,2,3, 4-tetrahydro- 1,5- naphthyridin-4-yl)carbamate (A7): tR = 12.92 min; er = 99: 1.

[0290] General Procedure C for the Povarov Reaction with (S)-2,6-bis(4-chlorophenyl)-4-hydroxy- 8,9,10,l l,12,13,14,15-octahydrodinaphtho[2,l-< :l’,2'- |[l,3,2]dioxaphosphepine 4-oxide ((S)-CPA)

[0291] To a solution of the aldehyde (0.52 mmol, 1.0 eq) in dry CH2Q2 (2.6 mL, 0.2 M) at room temperature under an argon atmosphere was added the aniline (0.52 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 30 min, cooled to 0 °C and treated with (S)-CPA (30 mg, 0.052 mmol, 10 mol%) and a solution of the ene-carbamate (0.52 mmol, 1.0 eq) in dry CH2Cl2(2.6 mL, 0.2 M). The mixture was allowed to warm to room temperature over 15 h, concentrated in vacuo, and the residue was purified by chromatography on SiCL to yield the desired tetrahydroquinoline as a colorless solid that was recrystallized (EtOAc / hexanes) for final purification. Enantiomeric excess was analyzed by HPLC using a Chiralpak IA column (46 mm D x 250 mm L; 5 pm) using 85:15 Hexanes / EtOH at 1.0 mL / min as the mobile phase.

[0292]

[0293] Benzyl((2S,3S,4R)-2-isopropyl-6-methoxy-3-methyl-l ,2,3,4-tetrahydro-l,5-naphthyridin-4- yljcarbamate (A4).

[0294] Prepared according to General Procedure C. Mp 162 °C; 'H NMR (500 MHz, CDCh) 5 7.41-7.29 (m, 5 H), 6.82 (d, J = 8.6 Hz, 1 H), 6.46 (d, J = 8.6 Hz, 1 H), 5.24, 5.14 (AB, J = 12.5 Hz, 2 H), 4.97 (brd, J = 7.5 Hz, 1 H), 4.57 (app t, J = 9.6 Hz, 1 H), 3.69 (s, 3 H), 3.38 (bs, 1 H), 3.00 (d, J = 8.5 Hz, 1 H), 2.09-2.05 (m, 1 H), 1.78 (h, 7= 6.5 Hz, 1 H), 1.11 (d, J = 6.5 Hz, 3 H), 1.04 (d, J = 7.0 Hz, 3 H), 0.88 (d, J = 6.5 Hz, 3 H);13C NMR (125 MHz, CDCI3) 5 158.3, 156.7, 137.1, 136.6, 135.2, 128.6, 128.2, 128.1, 126.5, 110.2, 66.8, 61.6, 56.5, 53.1, 36.5, 28.3, 20.3, 14.8, 14.4; LCMS (ES+) m / z calcd for C21H28N3O3([M + H]+) 370.21 , found 370.20. Chiral HPLC (Chiralpak 1 A, EtOH / Hexanes, 15:85, 254 nm) er - 98:2 (flow rate = 1.0 mL / min); minor isomer: tR = 9.76 min; major isomer: tR = 13.06 min.

[0295] General Procedure D.

[0296] Benzyl ((2SR,3SR,4RS)-7-chloro-2-isopropyl-3-methyl- 1,2,3, 4-tetrahydro- 1 , 5-naphthyridin-4- yl )carbamate Bl. A flame dried round bottom flask under inert atmosphere was charged with isobutyraldehyde (72 μL, 0.78 mmol) and CH2Q2 (2 mL). The solution was treated with 5-chloro- 3-aminopyridine (0.10 g, 0.78 mmol) and allowed to stir at room temperature for 4 h. The mixture was then cooled to 0 °C and treated sequentially with diphenyl hydrogen phosphate (0.019 g, 0.08 mmol), and a solution of benzyl (E)-propyl-l-en-l-ylcarbamate (0.15 g, 0.78 mmol) in CH2Q2 (1 mL). The reaction mixture was stirred at 0 °C for 5 min and allowed to slowly warm to room temperature before heating at reflux for 36 h. The solution was then cooled, concentrated, and purified by chromatography on SiO2(30-50% EtOAc in Hexanes) to yield benzyl ((2SR,3SR,4RS)- 7-chloro-2-isopropyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)carbamate Bl (172.3 mg, 59%) as white crystals: m.p. 123.9 °C;]H NMR (400 MHz, CDCh) 5 7.81 (d, J = 1.8 Hz, 1H), 7.36 (m, 5H), 6.78 (d, J = 1.8 Hz, 1H), 5.22, 5.14 (AB, J = 12.2 Hz, 2H), 5.22 (brs, 1H), 4.55 (t, J = 9.2 Hz, 1H), 3.84 (brs, 1H), 3.08 (d, J = 8.9 Hz, 1H), 2.14 - 2.02 (m, 1H), 1.92 - 1.73 (m, 1H), 1.10 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H);13CNMR (101 MHz, CDCh) 157.7, 141.4, 139.4, 136.8, 136.3, 131.1, 128.6, 128.1, 119.3, 66.9, 61.3, 55.8, 36.0, 28.5, 20.2, 14.8, 14.5; HRMS (ES+) m z calcd for C20H25N3O2CI ([M + H]+) 374.1629, found 374.1644; ATR- IR (cm’1) 3371 , 2965, 1702, 1683, 1453, 1251 , 1029.

[0297] Benzyl ((2SR,3SR,4RS)-7-chloro-2-isopropyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4- yl)carbamate Bl was resolved by chiral SFC (Chiralpak AD-H column 250 x 30 mm, 48% MeOH, flow rate = 75 mL / min, 100 bar, 35.0 °C).

[0298] (2R,3R,4S)-Enantiomer Bl-1 (first eluting peak): Chiral SFC Rt= 3.94 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. : > 99.5 : 0.5; [α]D25-68.8 (c 0.06, CH2Cl2); θ at λ330nm-3602 (c 0.08, MeOH).

[0299] (2S,3S,4R)-Enanliomer Bl-2 (second eluting peak): Chiral SFC Rt= 4.88 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. -. > 99.5 : 0.5; [α]D2543.9 (c 0.04, CH2C12); θ at λ330nm5295 (c 0.08, MeOH).

[0300] Benzyl ((2SR,3SR,4RS)-2-cyclopentyl-3-methyl- 1,2,3, 4-tetrahydro-l, 5-naphthyridin-4- yl)carbamate B2. Synthesized according to General Procedure D with a 4 h pre-stir of 3- aminopyridine (531 mg, 5.64 mmol) and cyclopentanecarboxaldehyde (602 μL, 5.64 mmol). The reaction mixture was warmed to rt then heated at reflux for 13 h. Purification by chromatography on SiO2(15% EtOAc in Hexanes) followed by recrystallization (EtOAc / Hexanes) provided benzyl ((2SR,3SR,4RS)-2-cyclopentyl-3-methyl- 1 ,2,3,4-tetrahydro-l ,5-naphthyridin-4-yl)carbamate B2 (987.3 mg, 48%) as a white solid: m.p. 132.4 °C;1H NMR (400 MHz, CDCh) 5 7.84 (d, J = 4.1 Hz, 1H), 7.44 - 7.28 (m, 5H), 6.95 (dd, J = 8.0, 4.6 Hz, 1H), 6.74 (d, 7= 7.2 Hz, 1H), 6.17 (brs, 1H), 5.15 (s, 2H), 4.73 (dd, J = 10.6, 5.4 Hz, 1H), 3.84 (s, 1H), 3.33 (brs, 1H), 2.81 (s, 1H), 1.94 - 1.75 (m, 3H), 1.72 - 1.55 (m, 8H), 1.35 - 1.24 (m, 3H);13CNMR (101 MHz, CDCh) 156.9, 140.5, 140.1, 137.4, 136.8, 128.6, 128.3, 128.1, 123.5, 120.1, 66.8, 55.5, 50.4, 45.7, 33.8, 31.7, 29.3, 25.6, 25.6; HRMS (ES+) m z calcd for C21H26N3O2([M + H]+) 352.2020, found 352.2012; ATR-IR (cm" 1) 3355, 2954, 1688, 1524,1253, 1013.

[0301] Benzyl ((2SR,3SR,4RS )-2-cyclopentyl-3-methyl- 1,2, 3, 4-tetrahydro-l, 5-naphthyridin-4- yl)carbamate B2 was resolved by chiral SFC.

[0302] (2R,3R,4S)-Enantiomer B2-1 (first eluting peak): [α]D25-12.9 (c 0.04, MeOH); θ at λ330nm-4827 (c 0.08, MeOH).

[0303] (2S,3S,4R )-Enantiomer B2-2 (second eluting peak): [α]D2518.6 (c 0.04, MeOH); θ at λ330nm5149 (c 0.08, MeOH).

[0304] Benzyl ((2SR,3SR,4RS)-7-bromo-2-cyclopentyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4- yl)carbamate B3. Synthesized according to General Procedure D with a 2 h pre-stir of 5-bromo-3- aminopyridine (411 mg, 2.37 mmol) and cyclopentanecarboxaldehyde (255 μL, 2.37 mmol). The reaction mixture was stirred at 0 °C for 1 h then allowed to warm to rt and stirred for an additional 12 h. Purification by chromatography on SiO2(10-20% EtOAc in Hexanes) provided benzyl ((2SR,3SR,4RS)-7-bromo-2-cyclopentyl-3-methyl- 1,2,3, 4-tetrahydro-l, 5-naphthyridin-4- yl)carbamate B3 (437.9 mg, 41 %) as a white solid: m.p. 166.2 °C;!H NMR (400 MHz, CDCI3) δ 7.91 (d, J = 1.8 Hz, 1H), 7.46 - 7.28 (m, 5H), 6.93 (d, J = 1.8 Hz, 1H), 5.22, 5.12 (AB, J = 12.3 Hz, 2H), 5.17 (s, 1H), 4.47 (t, 7= 7.8 Hz, 1H), 3.92 (s, 1H), 3.15 (brs, 1H), 2.27 (m, 1H), 2.01 - 1.87 (m, 1H), 1.79 - 1.50 (m, 6H), 1.35 - 1.20 (m, 2H), 1.11 (d, J = 6.5 Hz, 3H);13CNMR (151 MHz, CDCh) 157.3, 141.4, 139.1, 138.6, 136.8, 128.6, 128.1, 122.2, 1 19.8, 66.9, 59.2, 55.5, 41.8, 36.7, 29.3, 26.4, 25.9, 25.6, 16.1 ; HRMS (ES+) m / z calcd for C22H27N3O2Br ([M + H]+) 444.1281, found 444.1273; ATR-IR (cm!) 3332, 2953, 1695, 1577,1452, 1247, 1039. Benzyl ((6SR,7SR,8RS)-6-isopropyl-2-methoxy-7-methyl-5,6,7,8-tetrahydropyrido|3,2- d]pyrimidin-8-yl)carbamate B4. Synthesized according to General Procedure D with a 4 h pre-stir of 2-methoxy-5-aminopyrimidine (98.2 mg, 0.78 mmol) and isobutyraldehyde (72 μL, 0.78 mmol). The reaction mixture was heated at reflux for 36 h. Purification by chromatography on SiCT (30- 80% EtOAc in Hexanes) followed by recrystallization (EtOAc / Hexanes) provided benzyl ((6SR,7SR,8RS)-6-isopropyl-2-methoxy-7-methyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidin-8- yl)carbamate B4 (74.5 mg, 26%) as a yellow crystalline solid: m.p. 185.7 °C;1H NMR (400 MHz, CDCh) 5 7.84 (s, 1H), 7.45 - 7.28 (m, 5H), 5.20, 5.16 (AB, J = VIA Hz, 2H), 5.12 - 5.03 (m, 1H), 4.55 (t, J= 9.7 Hz, 1H), 3.81 (s, 3H), 3.05 (d, J = 9.0 Hz, 1H), 2.25 - 2.05 (m, 1H), 1.83 - 1.71 (m, 2H), 1.11 (d, J = 6.5 Hz, 3H), 1.06 (d, J = 7.1 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H);13CNMR (101 MHz, CDCh) 158.9, 157.8, 150.9, 144.5, 136.7, 134.3, 128.6, 128.2, 66.9, 61.5, 55.9, 54.5, 35.9, 28.4, 20.3, 14.5, 14.1 ; HRMS (ES+) m / z calcd for C20H26N4O3([M + H]+) 371.2077, found 371.2075; ATR-IR (cm1) 3350, 2965, 1703, 1528, 1467, 1248, 1051.

[0305] Benzyl ((6SR,7SR,8RS)-6-isopropyl-2-methoxy-7-methyl-5,6,7,8-tetrahydropyrido[3,2- d|pyrimidin-8-yl)carbamate B4 was resolved by chiral SFC (Chiralpak AD-H column 250 x 30 mm, 48% MeOH, flow rate = 70 mL / min, 100 bar, 35.0 °C).

[0306] (2R,3R,4S)-Enantiomer B4-1 (first eluting peak): Chiral SFC Rt= 2.29 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. : > 99.5: 0.5; [α]D25-66.8 (c 0.06, CH2Cl2); θ at λ330nm: -917 (c 0.08, MeOH).

[0307] (2S,3S,4R)-Enantiomer B4-2 (second eluting peak): Chiral SFC Rt= 5.45 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. -. > 99.5: 0.5; [α]D2543.9 (c 0.08, CH2Cl2); θ at λ330nm: 1327 (c 0.08, MeOH).

[0308] 2,2,6,6-Tetramethylpiperidin-l-yl ((2SR,3.S7?,4 / ?.S')-6-bromo-2-isopropyl-3-methyl- l ,2,3,4- tetrahydroquinolin-4-yl)carbamate B5. Synthesized according to General Procedure D with a 3 h pre-stir of 8 -bromoaniline (358 mg, 2.08 mmol) and isobutyraldehyde (190 μ L, 2.08 mmol). The reaction mixture was stirred at rt for 14 h. Purification by chromatography on SiO2(10% EtOAc in Hexanes) provided 2,2,6,6-tetramethylpiperidin-l-yl ((2.S' / ?,3.S' / ?,4 / ?.S')-6-bromo-2-isopropyl-3- methyl- 1,2, 3, 4-tetrahydroquinolin-4-yl)carbamate B5 (808.0 mg, 83%) as a white solid: m.p. 165.8 C; *H NMR (400 MHz, CDCh) 57.24 (s, 1 H), 7.09 (d, J = 6.9 Hz, 1H), 6.82 (s, 1H), 6.42 (d, J = 8.5 Hz, 1H), 4.79 (t, J = 10.3 Hz, 1H), 3.77 (s, 1H), 2.96 (dd, J = 9.8, 2.5 Hz, 1H), 2.13 - 2.03 (m, 1H), 1.85 (d, J= 6.2 Hz, 1H), 1.81 - 1.35 (m, 10H), 1.26 (d, J = 5.5 Hz, 6H), 1.20 (s, 3H), 1.16 (s,

[0309] 5 3H), 1.06 (d, 6.8 Hz, 3H), 1.03 (d, 6.6 Hz, 3H), 0.91 (d, J= 6.8 Hz, 3H);13CNMR (125 MHz, CDCh) 159.2, 144.4, 131.6, 130.9, 123.9, 116.0, 109.2, 61.2, 61.1, 61.0, 54.3, 39.8, 39.7, 37.3, 32.5, 32.3, 28.0, 20.9, 20.7, 20.3, 16.8, 14.4, 14.1; HRMS (ES+) m / z. calcd for C23H37N3O2Br[M + H]+) 466.2064, found 466.2079; ATR-IR (cm l) 3299, 2968, 1701, 1489.

[0310] 10 2,2,6,6-Tetramethylpiperidin-l-yl ((2SR,3SR,4RS)-6-bromo-2-isopropyl-3-methyl-l, 2,3,4- tetrahydroquinolin-4-yl)carbamate B5 was resolved by chiral SFC (Chiralpak AD-H column 250 x 30 mm, 30% MeOH, flow rate = 70 mL / min, 100 bar, 35.0 °C).

[0311] (27?,37?,45)-Enantiomer B5-1 (first eluting peak): Chiral SFC Rt= 2.90 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 20% MeOH, 3.0 mL / min); e.r.: 98:2; [α]D2562.3 (c 0.06,

[0312] 15 CH2CI2), θ at λ330nm: -1625 (c 0.08, MeOH).

[0313] (25,35,47?)-Enantiomer B5-2 (second eluting peak): Chiral SFC Rt= 5.45 min 3.79 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 20% MeOH, 3.0 mL / min); e.r.: 98:2; [α]D25-46.9 (c 0.07, CH2CI2); θ at λ330nm: 2600 (c 0.08, MeOH).

[0314] 20

[0315] Benzyl ((257?,357?,47?5)-7-bromo-2-isopropyl-3-methyl- 1 ,2,3 ,4-tetrahydro- 1 ,5-naphthyridin-4- yl)caibamale B6. Synthesized according to General Procedure D with a 3 h pre-stir of 5-bromo-3- aminopyridine (0.14 g, 0.78mmol) and isobutyraldehyde (72 pL, 0.78 mmol). The reaction mixture was warmed to rt then heated at reflux for 16 h. Purification by chromatography on SiO2(15%

[0316] 25 EtOAc in Hexanes) followed by recrystallization (EtOAc / Hexanes) provided benzyl

[0317] ((2SR,3SR,4RS)-7-bromo-2-isopropyl-3-methyl-l, 2, 3, 4- tetrahydro-1, 5-naphthyridin-4-yl)carbamate B6 (254 mg, 77%) as a yellowish solid: m.p. 162.3 °C; 1H NMR (400 MHz, CDCh) 57.90 (d, J = 1.6 Hz, 1H), 7.36 (ddt, J = 20.4, 13.7, 6.8 Hz, 5H), 6.94 (d, J= 1.5 Hz, 1H), 5.23, 5.13 (AB, J = 12.2 Hz, 2H), 5.22 (brs, 1H), 4.53 (t, J = 9.3 Hz, 1H), 3.84 (s, 1H), 3.07 (d, J= 8.2 Hz, 1H), 2.16 -

[0318] 30 2.03 (m, 1H), 1.87 - 1.75 (m, 1H), 1.09 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H);13CNMR (125 MHz, CDCh) 157.7, 141.8, 139.7, 138.5, 136.8, 128.6, 128.1, 122.1, 119.7, 66.9, 61.3, 55.9, 35.9, 28.5, 20.2, 14.8, 14.5; HRMS (ES+) m / z calcd for C20H25N3O2Br ([M + H]+) 418.1125, found 418.1111; ATR-IR (cm 1) 3349, 2967, 1689, 1576, 1452, 1231, 1028.

[0319] Benzyl ((2SR,3SR,4RS)-7-bromo-2-isopropyl-3-methyl-l,2,3,4-tetrahydro-l ,5-naphthyridin-4- yljcarbamate B6 was resolved by chiral SFC (Chiralpak OJ-H column 250 x 20 mm, 30% MeOH, flow rate = 65 mL / min, 100 bar, 35.0 °C).

[0320] (2S,3S,4R)-Enantiomer B6-1 (first eluting peak): Chiral SFC Rt= 4.48 min (Chiralpak OJ-H column 250 x 4.6 mm, mobile phase 30% MeOH, 3.0 mL / min); e.r. : > 99.5: 0.5; [α]D2591.0 (c 0.09, CH2Cl2); θ at λ330nm: 6150 (c 0.08, MeOH).

[0321] (2R,3R,4S)-Enantiomer B6-2 (second eluting peak): Chiral SFC Rt= 6.35 min (Chiralpak OJ-H column 250 x 4.6 mm, mobile phase 30% MeOH, 3.0 mL / min); e.r. -. > 99.5: 0.5; [α]D25-23.1 (c 0.08, CH2Cl2); θ at λ330nm: -4158 (c 0.08, MeOH).

[0322] Benzyl ((2SR,3SR,4RS)-2-isopropyl-7-methoxy-3-methyl-l ,2,3,4-tetrahydro-l ,5-naphthyridin-4- yl)carbamate B7. Synthesized according to General Procedure D with a 4 h pre-stir of 5-methoxy- 3-aminopyridine (0.097 g, 0.78mmol) and isobutyraldehyde (72 μL, 0.78 mmol). The reaction mixture was warmed to rt then heated at reflux for 16 h. Purification by chromatography on SiCL (20-40% EtOAc in Hexanes) followed by recrystallization (EtOAc / Hexanes) provided benzyl ((2SR,3SR,4RS)-2-isopropyl-7-methoxy-3-methyl- 1,2,3, 4-tetrahydro-l, 5-naphthyridin-4- yl)carbamate B7 (78.4 mg, 27%) as a yellow solid: m.p. 169.5 °C;1H NMR. (400 MHz, CDCI3) δ 7.65 (d, J = 2.2 Hz, 1H), 7.45 - 7.27 (m, 5H), 6.32 (d, J = 2.2 Hz, 1H), 5.24, 5.11 (AB, J= 12.4 Hz, 2H), 5.19 (brs, 1 H), 4.54 (t, J = 8.8 Hz, 1 H). 3.78 (s, 4H). 3.03 (d, J = 7.0 Hz, 1H), 2.16 - 2.00 (m, 1H), 1.93 - 1.79 (m, 1H), 1.09 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 0.86 (d, .7 = 6.8 Hz, 3H);13CNMR (125 MHz, CDCI3) 157.7, 156.1, 141.3, 136.9, 133.6, 128.6, 128.1, 128.0, 126.0, 105.1, 66.8, 61.4, 55.8, 55.6, 36.5, 28.6, 20.2, 15. HRMS (ES+) m / z calcd for C21H27N3O3([M + H]+) 370.2125, found 370.2122; ATR-IR (cm1) 3372, 2964, 1701, 1592, 1454, 1211, 1028.

[0323] Benzyl ((2SR,3SR,4RS)-2-isopropyl-7-methoxy-3-methyl-l ,2,3,4-tetrahydro-l ,5-naphthyridin-4- yl)carbamate B7 was resolved by chiral SFC (Chiralpak AD-H column 250 x 30 mm, 35% MeOH (0.1% DEA), flow rate = 70 mL / min, 100 bar, 35.0 °C, followed by second purification using a DAICEL DCpak SFC-B column 250 x 30 mm, 40% MeOH, flow rate = 60 mL / min, 100 bar, 35.0 °C).

[0324] (2S,3 S,4R )-Enanliomer B7-1 (first eluting peak): Chiral SFC Rt= 2.99 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. : > 99.5: 0.5; [α]D25-7.9 (c 0.09, CH2Cl2); θ at λ330nm: 3119 (c 0.08, MeOH).

[0325] (2R,3R,4lS')-Enantiomer B7-2 (second eluting peak): Chiral SFC Rt= 5.71 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 30% MeOH, 3.0 mL / min); e.r. : > 99.5: 0.5; [α]D2523.1 (c 0.08, CH2Cl2); θ at λ330nm: - 1878 (c 0.08, MeOH).

[0326] Benzyl ((2SR,3SR,4RS)-2-cyclopentyl-3-methyl-8-oxo-l,2,3,4,7,8-hexahydro-l,7-naphthyridin-4- yl)carbamate B8. Synthesized according to General Procedure D with a 6 h pre-stir of 3- aminopyridin-2-one (259 mg, 2.35 mmol) and cyclopentylcarboxaldehyde (251 μL, 2.35 mmol). The reaction mixture was warmed to rt then heated at reflux for 16 h. Purification by chromatography on SiO2(100% EtOAc) provided benzyl ((2SR,3SR,4RS )-2-cyclopentyl-3-methyl- 8-oxo-l,2,3,4,7,8-hexahydro-l,7-naphthyridin-4-yl)carbamate B8 (78.9 mg, 9%) as a white solid: m.p. 154.0 °C; H NMR (400 MHz, CDCl3) 5 7.41 - 7.29 (m, 5H), 6.67 (d. J = 6.8 Hz, 1H), 6.17 (d, J = 6.8 Hz, 1H), 5.18, 5. 11 (AB, J = 12.5 Hz, 2H ), 4.32 (d, J = 7.8 Hz. 1H), 3.13 (app t, 1 H), 2.41 - 2.31 (m, 1H), 1.95 - 1.31 (m, 1H), 1.76 - 1.53 (m, 6H), 1.47 - 1.36 (m, 2H), 1.03 (d, 6.8

[0327] Hz, 3H);13CNMR (101 MHz, MeOD) 159.2, 158.7, 138.5, 135.8, 129.5, 129.0, 128.8, 123.4, 120.1, 109.2, 67.5, 59.9, 54.3, 42.4, 36.9,30.1, 27.3, 26.8, 26.6, 16.3; HRMS (ES+) m / z calcd for C22H28N3O3([M + H]+) 382.2125, found 382.2117; ATR-IR (cm1) 3289, 2938, 1695, 1533, 1248, 1045.

[0328] Benzyl ((2SR,3SR ,4RS)-2-cyclopentyl-3-methyl-8-oxo-l,2,3,4,7,8-hexahydro-l,7-naphthyridin-4- yl)carbamate B8 was resolved by chiral SFC (Chiralpak AD-H column 250 x 30 mm, 42% MeOH (0.1% DEA), flow rate = 70 mL / min, 100 bar, 35.0 °C, followed by second purification using a DAICEL DCpak SFC-B column 250 x 30 mm, 40% MeOH, flow rate = 60 mL / min, 100 bar, 35.0 °C). (2R,3R,4S)-Enantiomer B8-1 (first eluting peak): Chiral SFC Rt= 4.09 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. : > 99.5: 0.5; [α]D25-53.3 (c 0.08, CH2Cl2); θ at λ330nm: -1904 (c 0.08, MeOH).

[0329] (2S,3S,4R)-Enantiomer B8-2 (second eluting peak): Chiral SFC Rt= 5.20 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. '. 97: 3; [α]D2538.6 (c 0.10, CH2Cl2); θ at λ330nm: 2143 (c 0.08, MeOH).

[0330] Benzyl ((2SR,3SR ,4RS )-2-cyclohexyl-3-methyl- 1 ,2, 3, 4- tetrahydro- 1 ,5-naphthyridin-4-yl)carbamate B9. Synthesized according to General Procedure D with a 6 h pre-stir of 3 -aminopyridine (98.0 mg, 1.05 mmol) and cyclohexanecarbaldehyde (127 μL, 1.05 mmol). The reaction mixture was warmed to rt then heated at reflux for 16 h. Purification by chromatography on SiO2(20% EtOAc in Hexanes) provided benzyl ((2SR,3SR,4RS)-2-cyclohexyl-3-methyLl,2,3,4-tetrahydro-l,5- naphthyridin-4-yl)carbamate B9 (165 mg, 42%) as a white solid: m.p. 148.5 °C;1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 4.4 Hz, 1H), 7.42 - 7.26 (m, 5H), 6.94 (dd, J = 8.0, 4.6 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.32 (d, J = 6.9 Hz, 1H), 5.24, 5.11 (AB, 7 = 12.3 Hz, 2H), 4.59 (t, 7 - 8.7 Hz. 1H), 3.82 (s, 1H), 3.03 (d, 7 - 6.7 Hz, 1H), 1.96 (m, 1H), 1.86 - 1.54 (m, 7H), 1.38 - 1.12 (m, 6H), 1.09 (d, 7 = 6.3 Hz, TH);13CNMR (125 MHz, CDCh) 157.7, 140.9, 140.8, 138.2, 136.9, 128.6, 128.1, 128.0, 123.3, 120.3, 66.9, 61.2, 56.2, 39.3, 35.4, 30.9, 26.8, 26.7, 26.3, 25.7, 15.3; HRMS (ES+) m / z calcd for C23H30N3O2(|M + HJ+) 380.2333, found 380.2331 ; ATR-1R (cm1) 3310, 2926, 1713, 1519,1229, 1028.

[0331] Benzyl ((2SR,3SR,4RS)-2-cyclohexyl-3-methyl- 1 ,2, 3, 4- tetrahydro- 1 ,5-naphthyridin-4-yl)carbamate B9 was resolved by chiral SFC (Chiralpak IC column 250 x 20 mm, 32% MeOH (0.1% DEA), flow rate = 60 mL / min, 100 bar, 35.0 °C).

[0332] (2S,3S,4R)-Enantiomer B9-1 (first eluting peak): Chiral SFC Rt- 4.30 min (Chiralpak IC column 250 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. > 99.5: 0.5; [α]D2581.0 (c 0.11, CH2Cl2); θ at λ330nm: 5960 (c 0.08, MeOH).

[0333] (2R,3R,45)-Enantiomer B9-2 (second eluting peak): Chiral SFC Rt= 5.75 min (Chiralpak IC column 250 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. > 99.5: 0.5; [α]D25-29.1 (c 0.07, CH2Cl2); θ at λ330nm: -9505 (c 0.08, MeOH).

[0334] Benzyl ((2SR,3SR,4RS )-3-methyl-2-neopentyl-l,2,3,4-tetrahydro-L5-naphthyridin-4-yl)carbamate B10. Synthesized according to General Procedure D with a 4 h pre-stir of 3 -aminopyridine (98.0 mg, 1.05 mmol) and 3,3-dimethylbutanal (229.7 μL, 1.83 mmol). The reaction mixture was warmed to rt then heated at reflux for 16 h. Purification by chromatography on SiCL (10% EtOAc in Hexanes) provided benzyl ((2SR,3SR,4RS)-3-methyl-2-neopentyl-l,2,3,4-tetrahydro-L5- naphthyridin-4-yl)carbamate B10 (296 mg, 44%) as an off-white solid: m.p. 186.9 °C;1H NMR (400 MHz, CDCI3) 5 7.90 (dd, 7= 4.4, 0.7 Hz, 1H), 7.44 - 7.28 (m, 5H), 6.93 (ddd, 7= 8.1, 4.6, 0.5

[0335] Hz, 1H), 6.70 (dd, J = 8.1 , 1.4 Hz, 1H), 5.39 (d, J = 7.5 Hz, 1H), 5.24, 5.14 (AB, J = 12.3 Hz, 2H),

[0336] 4.57 (t, J = 8.7 Hz, 1H), 3.84 (s, 1 H), 3.24 (t, J = 8.3 Hz, 1H), 1.80 - 1.68 (m, 2H), 1.28 (dd, J = 14.7, 8.1 Hz, 1H), 1.1 1 (d, . / = 6.5 Hz, 3H), 1.00 (s, 9H):13CNMR (125 MHz, CDCI3) 157.6, 140.6, 139.9, 138.2, 136.9, 128.6, 128.2, 128.0, 123.3, 119.9, 66.9, 59.9, 54.2, 48.2, 39.3, 30.9, 30.2, 16.3;

[0337] HRMS (ES+) m / z calcd for C22H30N3O2([M + H]+) 368.2333, found 368.2331; ATR-IR (cm l) 3414, 2967, 1721, 1505,1220, 1007.

[0338] Benzyl ((2SR,3SR,4RS)-3-methyl-2-neopentyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)carbamate B10 was resolved by chiral (Chiralpak IC column 250 x 20 mm, 30% MeOH (0.1% DEA), flow rate = 70 mL / min, 100 bar, 35.0 °C).

[0339] (2S,3S,4R)-Enanliomer B10-1 (first eluting peak): Chiral SFC Rt= 2.71 min (Chiralpak IC column 250 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. : > 99.5: 0.5; [α]D2516.8 (c 0.11, CH2Cl2); θ at λ330nm: 5378 (c 0.08, MeOH).

[0340] (2R,3R,4S)-Enantiomer B10-2 (second eluting peak): Chiral SFC Rt= 3.36 min (Chiralpak IC column 250 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. : > 99.5: 0.5; [α]D25-23.5 (c 0.07, CH2Cl2); θ at λ330nm: -4810 (c 0.08, MeOH). Benzyl ((2SR,3SR,4RS)-2-cyclobutyl-3-methyl- 1 ,2, 3, 4- tetrahydro- 1 ,5-naphthyridin-4-yl)carbamate Bll. Synthesized according to General Procedure A with a 6 h pre-stir of 3 -aminopyridine (98.0 mg, 1.05 mmol) and 3,3-dimethylbutanal (229.7 μL, 1.83 mmol). The reaction mixture was warmed to rt then heated at reflux for 16 h. Purification by chromatography on SiCh (20-30% EtOAc in Hexanes) provided benzyl ((2S / ?,3S7?,47?S)-2-cyclobutyl-3-methyl-l,2,3,4-tetrahydro-l,5- naphthyridin-4-yl)carbamate Bll (186.2 mg, 41%) as an off-white solid: m.p. 178.6 °C;]H NMR (400 MHz, CDCh) 5 7.92 (d, . / = 4.0 Hz, 1 H), 7.42 - 7.26 (m, 5H), 6.94 (dd, J = 8.0, 4.6 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1 H), 5.24 (hrs, 1 H), 5.22, 5.1 1 (AB, 7 = 12.2 Hz, 2H), 4.55 (t, J = 8.5 Hz, 1 H), 3.83 (s, 1H), 3.07 (t, 7 - 7.9 Hz, 1H), 2.60 - 2.50 (m, 1H), 2.07 - 1.74 (m, 8H), 1.08 (d, 7- 6.6 Hz, 3H);13CNMR (125 MHz, CDCI3) 157.6, 140.9, 140.3, 138.5, 136.9, 128.5, 128.1, 128.0, 123.3, 120.4, 66.9, 60.8, 55.9, 39.6, 38.0, 26.5, 24.8, 18.3, 15.7; HRMS (ES+) m / z calcd for C21H26N3O2([M + H]+) 352.2020, found 352.2024; ATR-IR (cm1) 3414, 2971, 1720, 1513,1222, 1026.

[0341] Benzyl ((2SR,3SR,4RS)-2-cyclobutyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)carbamate Bll was resolved by chiral (Chiralpak IC column 250 x 20 mm, 30% MeOH (0.1% DEA), flow rate = 70 mL / min, 100 bar, 35.0 °C).

[0342] (2S',3S,4R)-Enantiomer Bll-1 (first eluting peak): Chiral SFC Rt= 4.01 min (Chiralpak IC column 50 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. : > 99.5: 0.5; [(X]D25-19.2 (c 0.13, CH2Cl2); θ at λ330nm: 6994 (c 0.08, MeOH).

[0343] (2R,3R,4S)-Enantiomer Bll-2 (second eluting peak): Chiral SFC Rt= 5.50 min (Chiralpak IC column 250 x 4.6 mm, mobile phase 40% MeOH (0.1% DEA), 3.0 mL / min); e.r. : > 99.5: 0.5; [α]D258.5 (c 0.38, CH2Cl2); θ at λ330nm: -6517 (c 0.08, MeOH).

[0344] Benzyl ((2SR,3SR,4RS)-2-cyclopentyl-5-fluoro-3-methyl-l,2,3,4-tetrahydro-l,7-naphthyridin-4- yl)carbamate B12. Synthesized according to General Procedure D with a with a 2.5 h pre-stir of 5- fluoro- 3 -aminopyridine (88 mg, 0.78 mmol) and cyclopentanecarbaldehyde (84 μL, 0.78 mmol). The reaction mixture was warmed to rt over 16 h. Purification by chromatography on SiO2(30% EtOAc in Hexanes) provided benzyl ((2SR,3SR,4RS)-2-cyclopentyl-5-fluoro-3-methyl-l,2,3,4- tetrahydro-l,7-naphthyridin-4-yl)carbamate B12 (217.8 mg, 72%) as an off-white solid: m.p. 164.5 °C;]H NMR (400 MHz, CDCI3) 5 7.75 (d, J = 2.1 Hz, 1H), 7.42 - 7.28 (m, 5H), 6.50 (dd, 7 = 10.0, 2.3 Hz, 1H), 5.22, 5.11 (AB, J = 12.3 Hz, 2H), 5.19 (s, 1H), 4.50 (t, J = 7.7 Hz, 1H), 3.98 (s, 1H), 3.15 (brs, 1H), 2.35 - 2.17 (m, 1H), 2.02 - 1.93 (m, 1H), 1.77 - 1.48 (m, 8H), 1.36 - 1.24 (m, 2H), 1.11 (d, J = 6.5 Hz, 3H);13CNMR (101 MHz, CDCb) 159.9 ( C-F = 255 Hz), 157.3, 141.5 (3JC-F= 6 Hz), 136.8, 136.5 (4JC-F= 2 Hz), 128.6, 128.2, 128.1, 125.9 (2JC-F= 24 Hz), 106.7 (2JC-F= 21 Hz), 66.9, 59.3, 55.6, 41.9, 36.8, 30.1, 29.3, 26.6, 25.9, 25.6, 16.2;19FNMR (376 MHz, CDC13) -129.2; HRMS (ES+) m / z calcd for C22H27N3O2F([M + H]+) 384.2082, found 384.2075; ATR-IR (cm1) 3308, 2952, 1698, 1453,1240, 1020.

[0345] Benzyl ((2SR,3SR,4RS)2-cyclohexyl-5-fluoro-3-melhyl- 1,2,3, 4-tetrahydro-l, 7-naphthyridin-4- yl)carbamate B13. Synthesized according to General Procedure D with a 1 h pre-stir of 5-fluoro-3- aminopyridine (0.11 g, 0.95 mmol) and cyclohexanecarbaldehyde (0.12 mL, 0.95 mmol). The reaction mixture was warmed to rt over 16 h. Purification by chromatography on SiO2(20% EtOAc in Hexanes) provided benzyl ((2lS'R,3l5’R,4RS )-2-cyclohexyl-5-fluoro-3-methyl-l,2,3,4-tetrahydro- l,7-naphthyridin-4-yl)carbamate B13 (134.5 mg, 35%) as a white solid: m.p. 182.4 °C; H NMR (400 MHz, CDCI3) 5 7.73 (s, 1H), 7.54 - 7.28 (m, 5H), 6.48 (d, J = 8.4 Hz, 1H), 5.24, 5.12 (AB, J = 12.7 Hz, 2H), 5.21 (s, 1H), 4.53 (app t, 1H), 3.93 (s, 1H), 3.04 (d, J = 6.4 Hz, 1H), 1.99 - 1.55 (m, 8H), 1.36 - 1.10 (m, 8H), 1.08 (d, J = 5.7 Hz, 3H);13CNMR (101 MHz, CDCI3) , 159.9 (]JC-F= 254 Hz), 157.6, 141.8 (4JC-F= 7 Hz), 136.9 (3JC-F= 12 Hz), 128.6, 128.2, 128.1, 125.7 (2JC-F= 25 Hz), 106.5 (2JC-F= 22 Hz), 66.9, 61.2, 55.9, 39.2, 35.2, 30.9, 26.8, 26.6, 26.3, 25.6, 15.1 ;19FNMR (376 MHz, CDCI3) -129.5; HRMS (ES+) m / z calcd for C23H29N3O2F ([M + H]+) 398.2238, found 398.2231 ; ATR-IR (cm1) 3267, 2894, 1687, 1437, 1189, 1052.

[0346] Benzyl ((2SR,3SR,4RS)-2-cyclobutyl-3-propyl- 1 ,2,3,4-tetrahydro- 1 ,5-naphthyridin-4-yl)carbamate B14. Synthesized according to General Procedure D with a 1 h pre-stir of 3 -aminopyridine (171 mg, 1.24 mmol) and cyclobutanecarbaldehyde (139 μL, 1.82 mmol) followed by addition of benzyl (E)-pent- l -en- 1 -ylcarbamate (300 mg, 1.36 mmol). The reaction mixture was warmed to rt then heated at reflux for 20 h. Purification by chromatography on SiO2(20% EtOAc in Hexanes) provided benzyl ((2SR,3SR , 4RS)-2-cyclobutyl-3-propyl-l ,2,3,4-tetrahydro-l ,5-naphthyridin-4- yl)carbamate B14 (265.9 mg, 39%) as an off-white solid: m.p. 126.8 °C; 'H NMR (601 MHz, DMSO) 57.72 (s, 1H), 7.37 (dd, J = 7.2, 4.9 Hz, 2H), 7.32 - 7.17 (m, 1H), 6.96 - 6.87 (m, 1H), 5.89 (s, 1H), 5.10, 5.03 (AB, J = 12.6 Hz, 2H), 4.33 (d, J = 5.4 Hz, 1H), 3.00 (s, 1H), 2.72 - 2.62 (m, 1H), 1.92 (s, 1H), 1.84 (s, 1H), 1.80 - 1.64 (m, 2H), 1.40 (s, 1H), 1.32 (d, J = 5.6 Hz, 1H), 1.25 - 1.09 (m, 1 H), 0.85 (t, J = 6.6 Hz, 1H);13CNMR (101 MHz, CDC13) 156.4, 139.7, 139.0, 136.9, 128.6, 128.2, 128.1, 123.7, 121.4, 66.7, 59.0, 53.9, 38.9, 38.5, 33.9, 26.6, 25.5, 20.2, 17.7, 14.4; HRMS (ES+) m / z calcd for C24H32N3O2([M + H]+) 394.2489 found 294.2486; ATR-IR (cm1) 3373, 2965, 1701, 1455, 1212, 1028.

[0347] Benzyl ((2SR,3SR , 4RS )-2-cyclopentyl-3-propyl- 1 ,2,3,4-tetrahydro- 1 ,5-naphthyridin-4-yl)carbamate B15. Synthesized according to General Procedure D with a 3 h pre-stir of 3 -aminopyridine (117 mg, 1.24 mmol) and cyclopentanecarbaldehyde (133 μL, 1.24 mmol) followed by addition of benzyl (E)-penl- 1 -en- 1 -ylcarbamate (300 mg, 1.36 mmol). The reaction mixture was warmed to rt then heated at reflux for 20 h. Purification by chromatography on SiO2(30-50% EtOAc in Hexanes) provided benzyl ((2SR,3SR , 4RS )-2-cyclopentyl-3-propyl-l,2,3,4-tetrahydro-l,5- naphthyridin-4-yl)carbamate B15 (253.7 mg, 52%) as an off-white solid: m.p. 174.7 °C;]H NMR (400 MHz, CDCI3) 5 7.94 (d, J = 4.1 Hz, 1H), 7.46 - 7.27 (m, 5), 6.97 (dd, J = 7.9, 4.5 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.20, 5.07 (AB, J = 11.8 Hz, 2H), 5.09 (s, 1H), 4.56 (s, 1H), 4.05 (brs, 1H), 2.92 (d, J = 7.3 Hz, 1H), 2.36 (s, 1H), 2.22 - 2.08 (m, 1H), 1.93 - 1.02 (m, 14H), 0.90 (t, J = 6.4 Hz, 3H);nCNMR (101 MHz, CDCI3) 156.2, 139.7, 139.2, 138.8, 136.8, 128.5, 128.2, 123.9, 121.4, 66.6, 58.5, 53.9, 43.1, 39.3, 34.4, 30.9, 29.6, 25.6, 25.5, 20.2, 14.4; HRMS (ES+) m / z calcd for C24H32N3O2([M + H]+) 394.2489, found 294.2486; ATR-IR (cm1) 3378, 2954, 1691, 1528,1464,1256, 1048.

[0348] Benzyl ((2SR,3SR,4RS)-2-cyclopentyl-3-cyclopropyl- 1 ,2, 3, 4- tetrahydro- 1 ,5-naphthyridin-4- yl)carbamate B16. Synthesized according to General Procedure D with a 2 h pre-stir of 3- aminopyridine (130 mg, 1.38 mmol) and cyclopentanecarbaldehyde (147 μL, 1.38 mmol) followed by addition of benzyl (£)-(2-cyclopropyl vinyl) carbamate (300 mg, 1.38 mmol). The reaction mixture was warmed to rt over 16 h. Purification by chromatography on SiO2(20% EtOAc in Hexanes) provided benzyl ((2SR.3SR, 4RS )-2-cyclopentyl-3-cyclopropyl- 1,2,3, 4-tetrahydro- 1,5- naphthyridin-4-yl)carbamate B16 (173.9 mg, 32%) as a white solid: m.p. 183.7 °C;1H NMR (400 MHz, CDCh) 5 7.96 (d, J = 3.7 Hz, 1H), 7.41 - 7.27 (m, 5H), 6.99 (dd, J = 8.1, 4.5 Hz, 1H), 6.82 (d, J = 7.3 Hz, 1H), 5.18, 5.05 (AB, J = 12.3 Hz, 2H), 5.08 (brs, 1H), 4.79 (brs, 1H), 4.14 (s, 1H),

[0349] 3.08 (d, J = 8.6 Hz, 1H), 2.28 - 2.17 (m, 1H), 1.83 - 1.75 (m, 1H), 1.70 - 1.45 (m, 7H), 1.22 - 1.10 (m, 2H), 0.80 - 0.40 (m, 4H), 0.22 - 0.13 (m, 1H);13CNMR (101 MHz, CDCh) 156.1, 138.8,

[0350] 138.9, 136.9, 128.6, 128.2, 123.9, 121.4, 66.6, 60.1, 54.6, 45.3, 43.2, 31.1, 29.8, 25.62, 14.6, 5.1, 4.6; HRMS (ES+) m / z calcd for C24H30N3O2([M + H]+) 392.2333, found 392.2323; ATR-IR (cm1) 3354, 2952, 1688, 1522, 1252, 1005.

[0351] Benzyl ((2SR,4RS)-2-cyclopentyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)carbamate B17.

[0352] Synthesized according to General Procedure A with a 4 h pre-stir of 3 -aminopyridine (193 mg, 2.05 mmol) and cyclopentanecarbaldehyde (219 μL, 2.05 mmol) followed by addition of benzyl vinylcarbamate (427 mg, 2.05 mmol). The reaction mixture was warmed to rt over 18 h.

[0353] Purification by chromatography on SiO2(15% EtOAc in Hexanes) to provide benzyl ((2SR, 4RS )-2- cyclopentyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)carbamate B17 (42.1 mg, 6%) as a white solid: m.p. 132.4 °C;]H NMR (400 MHz, CDCI3) 5 7.84 (d, J = 4.1 Hz, 1H), 7.44 - 7.28 (m, 5H), 6.95 (dd, J = 8.0, 4.6 Hz, 1H), 6.74 (d, J = 7.2 Hz, 1H), 6.17 (brs, 1H), 5.15 (s, 2H), 4.73 (dd, J = 10.6, 5.4 Hz, 1H), 3.84 (s, 1H), 3.33 (brs, 1H), 2.81 (s, 1H), 1.94 - 1.75 (m, 3H), 1.72 - 1.55 (m, 8H), 1.35 - 1.24 (m, 3H);13CNMR (101 MHz, CDCh) 156.9, 140.5, 140.1, 137.4, 136.8, 128.6, 128.3, 128.1, 123.5, 120.1, 66.8, 55.5, 50.4, 45.7, 33.8, 31.7, 29.3, 25.6, 25.6; HRMS (ES+) m / z calcd for C21H26N3O2([M + H]+) 352.2020, found 352.2012; ATR-IR (cm1) 3355, 2954, 1688, 1524,1253, 1013.

[0354] Benzyl ((2SR,3SR,4RS)-2-cyclopentyl-6-methoxy-3-methyl- 1,2,3, 4-tetrahydro- 1 , 5-naphthyridin-4- yl)carbamate B19. Synthesized according to General Procedure D with a 1 h pre-stir of 5-amino-2- methoxypyridine (62 μL, 0.78 mmol) and cyclopentanecarbaldehyde (84 μL, 0.78 mmol). The reaction mixture was warmed to rt over 20 h. Purification by chromatography on SiO2(10 - 20% EtOAc in Hexanes) followed by recrystallization in EtOAc / Hexanes provided benzyl ((2SR.3SR, 4RS)-2-cyclopentyl-6-methoxy-3-methyl- 1 ,2, 3, 4-tetrahydro- 1 ,5-naphthyridin-4- yl)carbamate B19 (207.8 mg, 67%) as a white solid: m.p. 175.9 °C;1H NMR (400 MHz, CDCh) 5 7.44 - 7.27 (m, 1H), 6.81 (d, J = 8.6 Hz, 1H), 6.46 (d, J = 8.5 Hz, 1H), 5.22, 5.14 (AB, J = 12.2 Hz, 2H), 5.00 (d, J = 7.3 Hz, 1H), 4.49 (t, J = 8.4 Hz, 1H), 3.71 (s, 3H), 3.46 (s, 1H), 3.07 (brs, 1H), 2.31 - 2.21 (m, 1H), 1.90 - 1.81 (m, 1H), 1.73 - 1.49 (m, 5H), 1.41 - 1.22 (m, 2H), 1.12 (d, J = 6.5 Hz, 3H);13CNMR (101 MHz, CDCl3) 157.8, 156.6, 137.0, 136.1 , 134.9, 128.6, 128., 2, 128.1 , 126.6, 110.4, 66.7, 59.4, 56.0, 53.1, 41.5, 37.3, 29.3, 26.0, 25.7, 16.1 ; HRMS (ES+) m / z. calcd for C23H30N3O3([M + H]+) 396.2282, found 396.2275; ATR-IR (cm’1) 3275, 2957, 1216, 1541, 1477,

[0355] 1242, 1018.

[0356] General Procedure E. jV-((2SR,3SR,4SR)-2-Cyclopentyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)-l- phenylmethanesulfonamide B22. A round bottom flask was charged with benzyl ((2SR,3.S7?,4 / ?.S')-2- cyclopentyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)carbamate (794 mg, 2.17 mmol) and cooled to 0 °C. A solution of 30% HBr in AcOH ( 11.4 mL, 76.0 mmol) was added slowly to the solid starting material with rapid stirring. The solution was stirred for 3 h at 0 °C. Cold ether was added dropwise until a cloudy precipitate formed. The suspension was stirred for ~1 h at 0 °C then filtered. The product was washed with cold Et2O (4 x 20 mL) to afford the deprotected amine as the HBr salt. The deprotection was confirmed by LCMS and1H NMR analysis, and the HBr salt was used without further purification: 'H NMR (300 MHz, DMSO-d6) 5 8.27 (brs, 3H), 8.00 (d, J = 3.2 Hz, 1H), 7.84 (dd, J = 4.4, 1.4 Hz, 1H), 7.17 - 7.62 (m, 1H), 4.16 - 4.06 (m, 1H), 3.23 (dd, J = 9.6, 3.0 Hz, 1H), 2.34 - 2.22 (m, 1H), 1.87 - 1.27 (m, 10H), 1.12 (d, J = 6.5 Hz, 3H); LCMS Rt= 3.65 min, m / z ([M + H]+) 232.1.

[0357] A flame dried round bottom flask was charged with the HBr salt (0.10 g, 0.32 mmol) and CH2CI2(15 mL). The suspension was cooled to 0 °C and treated dropwise with N,N-diisopropylethylamine (0.22 mL, 1.3 mmol). When the solution became homogenous, phenylmethanesulfonyl chloride (51 μL, 0.35 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 3 h, allowed to warm to room temperature, and stirred for an additional 13 h. The mixture was quenched with sat. NaHCO3(20 mL) and extracted with CH2Cl2(3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried (MgSCL) and purified by chromatography on SiOz (2% MeOH in CH2Cl2) followed by trituration (CH2Cl2 / Hexanes) to afford A-((2SR,3SR,4SR)-2-cyclopcntyl-3- methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)-l-phenylmethanesulfonamide B22 (78.3 mg, 63%) as an off-white solid: m.p. 173.9 °C;1H NMR (300 MHz, DMSO) 5 7.57 (dd, J = 4.2, 1.7 Hz, 1H), 7.54 - 7.40 (m, 4H) 7.43 - 7.38 (m, 2H) 7.27 - 7.20 (m, 3H), 6.95 - 6.85 (m, 2H), 6.32 (brs, 1H), 4.66, 4.50 (AB, J = 13.7 Hz, 2H), 4.60 (brs, 1H), 4.22 (t, J = 8.3 Hz, 1H), 3.04 (app t, 1H), 2.30 - 2.16 (m, 1H), 1.94 - 1.85 (m, 1H), 1.78 - 1.67 (m, 1H), 1.63 - 1.22 (m, 8H), 0.82 (d, J = 6.7 Hz, 3H);13CNMR (101 MHz, CDCI3) 140.7, 140.1, 131.2, 129.9, 128.6, 128.4, 123.9, 120.6, 59.6, 59.2, 58.7, 42.1, 38.1, 29.4, 26.4, 25.9, 25.7, 16.5; HRMS (ES+) m / z calcd for C21H28SN302([M + H]+) 386.1897, found 386.1891.

[0358] A-((2SR,3SR,4SR)-2-Cyclopentyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)-l- phenylmethanesulfonamide B22 was resolved by chiral SFC (Chiralpak AD-H column 250 x 30 mm, 35% MeOH (0.1% DEA), flow rate = 70 mL / min, 100 bar, 35 °C).

[0359] (2R,3R,4S)-Enantiomer B22-1 (first eluting peak): Chiral SFC Rt= 6.07 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 25% MeOH (0.1% DEA), 3.0 mL / min); e.r. : > 99.5: 0.5; [α]D2582.9 (c 0.10, CH2Cl2); θ at λ330nm: -11086 (c 0.08, MeOH).

[0360] (2S,3S,4R)-Enantiomer B22-2 (second eluting peak): Chiral SFC Rt= 7.51 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 25% MeOH (0.1% DEA), 3.0 mL / min); e.r. -. > 99.5: 0.5; [α]D25-125.0 (c 0.08, CH2Cl2); θ at λ330nm: 8421 (c 0.08, MeOH).

[0361] Benzyl ((2SR.3S / ?,4RS )-2-cyclobiityl-3-meihyl- 1 ,2,3,4-tetrahydro- 1 ,5-naphthyridin-4-yl)carbamate B23. Synthesized according to General Procedure E using the HBr salt (50 mg, 0.16 mmol), N,N- diisopropylethylamine (84 mL, 0.48 mmol), and 3-phenylpropanoyl chloride (24 μL, 0.16 mmol). The reaction mixture was stirred at -78 °C for 2.5 h, then allowed to warm to rt over 13 h. Chromatography on SiO2(100% EtOAc) provided benzyl ((2SR,3SR,4RS)-2-cyclobulyl-3-melhyl- l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)carbamate B23 (32.8 mg, 56%) as a pale green solid: m.p. 152.8 °C;1H NMR (400 MHz, CDCh) 5 7.89 (d, J~ 3.6 Hz, 1 H), 7.29 - 7.15 (m, 5H), 6.97 (dd, J = 8.0, 4.6 Hz, 1H), 6.78 (d, J= 7.1 Hz, 1H), 5.94 (d, J = 7 Hz, 1H), 4.78 (t, J = 7.7 Hz, 1H), 3.86 (s, 1H), 3.13 (app t, 1H), 3.04 (t. J = 7.9 Hz, 2H), 2.75 - 2.52 (m, 2H), 2.28 - 2.17 (m, 1H), 1.99 - 1.90 (m, 1 H), 1.79 - 1.50 (m, 9H), 1.33 - 1.23 (m, 2H), 1.04 (d, J = 6.8 Hz, 3H);13CNMR (101 MHz, CDCh) 172.8, 141.3, 140.6, 140.6, 138.1, 128.6, 128.5, 126.2, 123.4, 120.5, 59.3, 53.8, 42.1, 38.7, 36.9, 31.8, 29.4, 26.6, 25.9, 25.6, 16.4; HRMS (ES+) m / z calcd for C23H30N3O ([M + H]+) 364.2383, found 364.2381 ; ATR-IR (cm1) 3275, 2954, 1633, 1462, 1360.

[0362] Benzyl ((2SR,3SR,4RS)-2-cyclopentyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)-2- phenylacetamide B24. Synthesized according to General Procedure E using the HBr salt (100 mg, 0.32 mmol), N,N-diisopropylethylamine (0.30 mL, 1.7 mmol), and 2-phenylacetyl chloride (46 μL, 0.35 mmol). The reaction mixture was stirred at rt for 13 h. Chromatography on S1O2(100% EtOAc) provided benzyl ((2SR,3SR,4RS)-2-cyclopentyl-3-methyl- 1,2,3, 4-tetrahydro- 1,5- naphthyridin-4-yl)-2-phenylacetamide B24 (50.2 mg, 45%) as an off-white solid: m.p. 168.3 °C; H NMR (400 MHz, CDCh) δ 7.88 (d, J = 4.6 Hz, 1H), 7.39 - 7.27 (m, 4H), 6.96 (dd, J = 7.9, 4.7 Hz, 1H), 6.78 (d, J = 7.0 Hz, 1H), 5.96 (brs, 1H), 5.30 (s, 2H), 4.78 (t, J = 7.6 Hz, 1H), 3.88 (brs, 1H), 3.70 (s, 2H), 3.12 - 2.90 (m, 2H), 2.14 - 2.05 (m, 1H), 1.99 - 1.92 (m, 1H), 1.66 - 1.43 (m, 6H), 1.31 - 1.18 (m, 3H), 1.03 (d, 7 - 6.8 Hz, 3H);13CNMR (101 MHz, CDCh) 171.5, 140.4, 138.4, 135.3, 129.7, 128.9, 127.2, 123.4, 120.4, 59.5, ,53.9, 44.3, 42.1, 36.8, 29.4, 27.1, 25.9, 25.6, 16.2; HRMS (ES+) m / z calcd for C22H28N3O ([M + H]+) 350.2227, found 350.2223; ATR-IR (cm1) 3308, 2956, 1635, 1533, 1463, 1362.

[0363] Benzyl ((2SR,3SR ,4RS )-2-cyclopentyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)-2- phenylacetamide B24 was resolved by chiral SFC (Chiralpak AD-H column 150 x 20 mm, 30% MeOH (0.1% DEA), flow rate = 60 mL / min, 100 bar, 35.0 °C).

[0364] (2S,3S,4R)-Enantiomer B24-1 (first eluting peak): Chiral SFC Rt= 2.08 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 40% MeOH (0.1 % DEA), 3.0 mL / min); e.r. -. > 99.5: 0.5; [α]D25-23.4 (c 0.08, CH2Cl2); θ at λ330nm: 7907 (c 0.08, MeOH).

[0365] (2R,3R,4S)-Enantiomer B24-2 (second eluting peak): Chiral SFC Rt- 7.51 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 25% MeOH (0.1% DEA), 3.0 mL / min); e.r. -. > 99.5: 0.5; [α]D2518.2 (c 0.07, CH2Cl2); θ at λ330nm: -6140 (c 0.08, MeOH).

[0366] Benzyl ((2SR,3SR,4RS )-2-cyclopentyl-3-methyl- 1 ,2,3,4-tetrahydro- 1 ,5-naphthyridin-4- yl)benzamide B25. Synthesized according to General Procedure E using the HBr salt (100 mg, 0.32 mmol), N, N-diisopropylethylamine (0.30 mL, 1.7 mmol), and benzoyl chloride (41 μL, 0.35 mmol). The reaction mixture was stirred at rt for 13 h. Chromatography on SiO2(100% EtOAc) provided benzyl ((2SR,3SR,4RS)-2-cyclopentyL3-methyl- 1 ,2,3,4-tetrahydro- 1 ,5-naphthyridin-4- yl)benzamide B25 (52.9 mg, 49%) as an off-white solid: m.p. 153.8 °C;1H NMR (400 MHz, CDCh) 5 7.90 - 7.82 (m, 3H), 7.52 - 7.39 (m, 3H), 6.97 (dd, J = 8.1, 4.5 Hz, 1H), 6.86 (brs, 1H) 6.83 (s, 1H), 6.81 (dd, 8.2, 1.0 Hz, 1H), 4.96 (t, J = 7.5 Hz, 1H), 3.94 (s, 1H), 3.72 - 3.58 (m, 1H), 3.19 (t, J = 6.4 Hz, 1H) 3.12 - 3.05 (m, 1H), 3.08 (dt. J = 11 .3, 7.4 Hz, 1H), 2.37 - 2.27 (m, 1H), 2.20 - 2.11 (m, 1H), 1.80 - 1.47 (m, 13H), 1.44 (d, J = 6.6 Hz, 1H). 1.38 - 1.27 (m, 1H), 1.16 (d, J = 6.8 Hz, IH);13CNMR (101 MHz, CDCh) 168.3, 140.6, 140.5, 138.2, 135.0, 131.5, 128.6, 127.2, 123.5, 120.5, 59.4, ,54.2, 42.2, 37.0, 29.4, 26.8, 25.9, 25.6, 16.6; HRMS (ES+) m / z calcd for C21H26N3O ([M + H]+) 336.2070, found 336.2067; ATR-IR (cm1) 3309, 2960, 1628, 1532, 1463, 1296. Benzyl ((2SR,3SR,4RS)-2-cyclopentyl-3-methyl- 1 ,2,3,4-tetrahydro- 1 ,5-naphthyridin-4- yl)benzamide B25 was resolved by chiral SFC (Chiralpak AD-H column 250 x 30 mm, 30% MeOH (0.1% DEA), flow rate = 60 mL / min, 100 bar, 35.0 °C, followed by second purification using a DAICEL DCpak SFC-B column 250 x 30 mm, 40% MeOH, flow rate = 60 mL / min, 100 bar, 35 °C).

[0367] (2 / ?,3 / ?,4.S)- Enantiomer B25-1 (first eluting peak): Chiral SFC Rt= 3.67 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 25% MeOH (0.1% DEA), 3.0 mL / min); e.r. > 99.5: 0.5; [α]D2529.3 (c 0.08, CH2CI2; θ at λ330nm: -8841 (c 0.08, MeOH).

[0368] (2S,3S,4R)-Enantiomer B25-2 (second eluting peak): Chiral SFC Rt= 4.52 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 25% MeOH (0.1% DEA), 3.0 mL / min); e.r. > 99.5: 0.5; [α]D25-28.9 (c 0.12, CH2C12); θ at λ330nm: 10531 (c 0.08, MeOH).

[0369] Neopentyl ((2>S'R,3S7?,4RlS’2-cyclopentyl-3-methyl- 1 ,2,3 ,4-tetrahydro- 1 ,5-naphthyridin-4- yl)carbamate B26. Synthesized according to General Procedure E using the HBr salt (100 mg, 0.32 mmol), N,N-diisopropylethylamine (0.30 mL, 1.7 mmol), and neopentyl chloroformate (72 μL, 0.47 mmol). The reaction mixture was stirred at rt for 13 h. Chromatography on SiO2(100% EtOAc) provided neopentyl ((2SR,3SR,4RS2-cyclopentyl-3-methyl- l ,2,3,4-tetrahydro- l ,5- naphthyridin-4-yl)carbamate B26 (49.9 mg, 45%) as an off-white solid: m.p. 144.6 °C;1H NMR (300 MHz, CDCh) 5 7.93 (dd, J = 4.6, 1.3 Hz, 1H), 6.97 (dd, J = 8.0, 4.7 Hz, 1H), 6.82 - 6.77 (m, 1H), 4.48 (d, J = 6.7 Hz, 1H), 3.96 - 3.85 (m, 2H), 3.77 - 3.69 (m, 1H), 3.12 (brs, 1H), 2.37 - 2.20 (m, 2H), 2.07 (s, 2H), 1.82 - 1.46 (m, 6H), 1.36 - 1.25 (m, 2H), 1.12 (d, 7= 6.8 Hz, 3H), 0.94 (s, 9H);13CNMR (101 MHz, CDCl3) 157.8, 140.4, 138.5, 123.4, 120.6, 595, 55.6, 42.3, 36.8, 31.7, 29.4, 27.0, 26.6, 25.9, 25.6, 16.6; HRMS (ES+) m / z calcd for C20H32N3O2([M + H]+) 346.2489, found 346.2488; ATR-IR (cm’1) 3332, 2954, 1739, 1526, 1253, 1038.

[0370] Neopentyl ((2SR,3SR,4RS2-cyclopentyl-3-methyl- 1 ,2,3 ,4-tetrahydro- 1 ,5-naphthyridin-4- yl)carbamate B26 was resolved by chiral SFC (Chiralpak AD-H column 250 x 30 mm, 20% MeOH (0.1% DEA), flow rate = 70 mL / min, 100 bar, 35.0 °C, followed by second purification using a DAICEL DCpak SFC-B column 250 x 30 mm, 40% MeOH, flow rate = 60 mL / min, 100 bar, 35 °C). (2R,3R,4S)-Enantiomer B26-1 (first eluting peak): Chiral SFC Rt= 3.41 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 15% MeOH (0.1% DEA), 3.0 mL / min); e.r. : 97:3; [α]D25-52.5 (c 0.05, CH2Cl2); θ at λ330nm: -5205 (c 0.08, MeOH).

[0371] (2S,3S,4R)-Enantiomer B26-2 (second eluting peak): Chiral SFC Rt= 4.39 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 15% MeOH (0.1% DEA), 3.0 mL / min); e.r. > 99.5: 0.5; [α]D2583.8 (c 0.08, CH2Cl2); θ at λ330nm: 5948 (c 0.08, MeOH).

[0372] Tert-butyl ((2SR,3SR,4RS)-2-cyclopentyL3-methyl- 1,2,3, 4-tetrahydro- 1 , 5-naphthyridin-4- yl)carbamate B27. Synthesized according to General Procedure E using the HBr salt (80 mg, 0.26 mmol), A,A-diisopropylethylamine (0.18 mL, 1.0 mmol), and di- te -butyl dicarbonate (62 mg, 0.28 mmol). The reaction mixture was stirred at rt for 13 h. Chromatography on SiO2(2% MeOH in CH2Cl2) followed by trituration (CftCL / Hexanes) afforded tert-butyl ((2SR,3SR,4RS)-2- cyclopentyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)carbamate B27 (51.3 mg, 60%) as an off-white solid: m.p. 138.9 °C;]H NMR (400 MHz, CDCI3) 5 7.93 (d, J = 3.7 Hz, 1H), 6.99 (dd, J = 8.0, 4.6 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 5.15 (brs, 1H), 4.41 (s, 1H), 3.94 (s, 1H), 3.07 (s, 1H), 2.35 - 2.24 (m, 1H), 2.21 - 2.12 (m, 1H), 1.85 - 1.52 (m, 8H), 1.47 (s, 9H), 1.36 - 1.21 (m, 3H), 1.10 (d, J = 6.8 Hz, 3H);13CNMR (101 MHz, CDCI3) 156.5, 140.5, 140.3, 138.4, 123.4, 120.5, 55.2, 42.4, 36.3, 29.4, 28.6, 27.6, 25.9, 25.6, 16.9; HRMS (ES+) m / z. calcd for C19H30N3O2([M + H]+) 332.2333, found 332.2331 ; ATR-IR (cm1) 3362, 2957, 1698, 1261, 1364, 1247, 1165.

[0373] Tert-butyl ((2SR,3SR,4RS)-2-cyclopentyl-3-methyl- 1,2, 3, 4-tetrahydro- l,5-naphthyridin-4- yl)carbamate B27 was resolved by chiral SFC (Chiralpak AD-H column 250 x 30 mm, 20% MeOH (0.1% DEA), flow rate = 70 mL / min, 100 bar, 35.0 °C, followed by second purification using a DAICEL DCpak SFC-B column 250 x 30 mm, 40% MeOH, flow rate = 60 mL / min, 100 bar, 35 °C).

[0374] (25,35,47?)-Enantiomer B27-1 (first eluting peak): Chiral SFC Rt= 2.74 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 25% MeOH (0.1% DEA), 3.0 mL / min); e.r. 98:2; [CI]D25-26.4 (c 0.06, CH2Cl2); θ at λ330nm: 7250 (c 0.08, MeOH). (2R,3R,4S)-Enantiomer B27-2 (second eluting peak): Chiral SFC Rt- 3.81 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 25% MeOH (0.1% DEA), 3.0 mL / min); e.r. '. 98:2; [α]D2599.8 (c 0.05, CH2Cl2); θ at λ330nm: -5421 (c 0.08, MeOH).

[0375] N-((2SR,3SR,4RS)-2-Cyclopentyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)-3,3- dimethylbutanamide B28. Synthesized according to General Procedure E using the HBr salt (100 mg, 0.32 mmol), A / A-diisopropylethylamine (0.22 mL, 1.3 mmol), and 3,3-dimethylbutanoyl chloride (49 μL, 0.35 mmol). The reaction mixture was stirred at 0 °C, and then slowly warmed to rt over 20 h. Chromatography on SiO2(2% MeOH in CH2Cl2) provided N- (2SR,3SR,4RS)-2- cyclopentyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)-3,3-dimethylbutanamide B28 (73.9 mg, 70%) as a yellow solid: m.p. 170.6 °C;!H NMR (400 MHz, CDCh) 57.88 (dd, J = 4.5, 1.0 Hz ,1H), 6.95 (dd, J = 7.8, 5.3 Hz ,1H), 6.77 (d, J = 7.7 Hz, 1H), 5.94 (brs, 1H), 4.78 (t, J = 8.0 Hz, 1H), 3.83 (s, 1H), 3.18 (dd, J = 7.3, 6.4 Hz, 1H), 2.33 - 2.25 (m, 1H), 2.22, 2.18 (AB, J = 13.3 Hz, 2H), 1.96 - 1.87 (m, 1H), 1.81 - 1.73 (m, 1H), 1.68 - 1.52 (m, 5H), 1.36 - 1.27 (m, 2H), 1.12 (d, 7 = 6.8 Hz, 3H), 1.10 (s, 9H).;13CNMR (101 MHz, CDCh) 172.8, 141.1, 140.9, 137.8, 123.3, 120.4, 59.3, 51.1, 41.9, 37.4, 31.1, 30.1, 29.5, 26.1, 26.0, 25.7, 16.3; HRMS (ES+) m / z calcd for C20H32N3O ([M + H]+) 330.2539, found 330.2538; ATR-IR (cm1) 3279, 2949, 1538, 1238, 13.64, 1258.

[0376] A-((2SR,3SR,4RS)-2-Cyclopentyl-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)-3,3- dimethylbutanamide B28 was resolved by chiral SFC (Chiralpak AD-H column 250 x 30 mm, 40% MeOH (0.1% DEA), flow rate = 70 mL / min, 100 bar, 35.0 °C, followed by second purification using a DAICEL DCpak SFC-B column 250 x 30 mm, 40% MeOH, flow rate = 60 mL / min, 100 bar, 35 °C).

[0377] (2S,3S,4R)-Enantiomer B28-1 (first eluting peak): Chiral SFC Rt= 2.99 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 15% MeOH (0.1% DEA), 3.0 mL / min); e.r. '. > 99.5: 0.5; [α ]D25-30.1 (c 0.06, CH2Cl2); θ at λ330nm: 6377 (c 0.08, MeOH).

[0378] (2R,3R,4S)-Enantiomer B28-2 (second eluting peak): Chiral SFC Rt= 5.01 min (Chiralpak AD-H column 250 x 4.6 mm, mobile phase 15% MeOH (0.1 % DEA), 3.0 mL / min); e.r. '. > 99.5: 0.5; [α]D2519.7 (c 0.06, CH2Cl2); θ at λ330nm: -8208 (c 0.08, MeOH).

[0379] lV-(2.S' / ?,3.S' / ?,4 / ?.S')-2-Cyclopentyl-3-propyl- l ,2,3,4-tetrahydro- 1 ,5-naphthyridin-4-yl)-2- phenylethane- 1 -sulfonamide B30. Synthesized according to General Procedure E using the HBr salt of benzyl ((257?, 3SR, 47?5)-2-cyclopentyl-3 -propyl- 1,2,3, 4-tetrahydro-l, 5-naphthyridin-4- yl)carbamate (120 mg, 0.35 mmol), A,A-diisopropylethylamine 0.31 mL, 1.8 mmol), and phenylethanesulfonyl chloride (78 mL, 0.46 mmol). The reaction mixture was stirred for 6 h at 0 °C, then at rt over 13 h. Chromatography on SiO2(50% EtOAc in Hexanes) provided N- (257?,357?,47?5)-2-cyclopentyl-3-propyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)-2-phenylethane- 1-sulfonamide B30 (85.9 mg, 57%) as a white solid: m.p. 174.8 °C;1H NMR (400 MHz, CDCh) 5 7.93 (dd, 7 = 4.5, 1.2 Hz, 1H), 7.35 - 7.19 (m, 5H), 7.00 (dd, J = 8.1 , 4.5 Hz, 1H), 6.81 (dd, 7 = 8.1, 1.2 Hz, 1H), 4.65 (d, 7 = 6.6 Hz, 1H), 4.28 (dd, J = 6.5, 3.7 Hz, 1H), 4.O1 (s, 1H), 3.76 (ddd, 7 = 13.8, 12.2, 4.8 Hz, 1H), 3.48 (ddd, 7 = 13.8, 12.2, 4.6 Hz, 1H), 3.30 (ddd, 7 = 13.1, 12.3, 4.8 Hz, 1H), 3.14 (ddd, 7 = 12.9, 12.4, 3.2 Hz, 1H), 2.97 (d, 7 = 8.9 Hz, 1H), 2.33 - 2.66 (m, 1H), 2.22 - 2.11 (m, 1H), 2.05 - 1.95 (m, 1H), 1.84- 1.74 (m, 1H), 1.70 - 1.60 (m, 3H), 1.50 - 1.32 (m, 4H), 1.28 - 1.15 (m, 3H), 0.92 (t, 7 = 6.8 Hz, 3H);nCNMR (101 MHz, CDCh) 139.8, 139.5, 138.8, 138.7, 128.8, 128.7, 126.8, 124.1, 121.4, 58.7, 56.4, 53.5, 42.9, 41.9, 34.4, 30.5, 30.1, 29.7, 25.7, 25.6, 20.1, 14.3; HRMS (ES+) m / z calcd for C24H34SN3O2([M + H]+) 428.2366 found 428.2356; ATR-IR (cm ' ) 3388, 2956, 1587, 1319, 1146, 1057.

[0380] General Procedure F.

[0381] Benzyl ((25, 3S, 47?)-7-bromo-2-cyclohexyl-3-methyl-l, 2, 3, 4-tetrahydro-l, 5-naphthyridin-4- yl)carbamate B31. A flame-dried round bottom flask under inert atmosphere was charged with cyclohexanecarbaldehyde (118 μL, 0.95 mmol) and CH2Cl2(5 mL). The solution was treated with 3-amino-5-bromopyridine (0.17 g, 0.95 mmol) and allowed to stir at room temperature for 1 h. The solution was then cooled to 0 °C and treated sequentially with (1 lb5)-2,6-bis(4-chlorophenyl)-4- hydroxy-8,9,10,l l,12,13,14,15-octahydrodinaphtho[2,l-7: l',2'- |[l,3,2]dioxaphosphepine 4-oxide ((S)-CPA, 0.033 g, 0.057 mmol) and a solution of (E)-propyl- 1-en-l-ylcarbamate (0.20 g, 1.0 mmol) in CH2Q2 (3 mL). The reaction mixture was stirred at 0 °C for 5 min, allowed to slowly warm to rt, and stirred for 4 d. The reaction mixture was then concentrated and purified by chromatography on SiO2(20% EtOAc in Hexanes) to provide benzyl ((2.S'.3.S',4 / ?)-7-bromo-2- cyclohexyl-3-methyl-l ,2,3,4-tetrahydro-l ,5-naphthyridin-4-yl)carbamate B31 (127 mg, 29%) as a white powder: m.p. 173.8 °C;1H NMR (601 MHz, CDCh) 5 7.90 (d, 7 = 1.8 Hz, 1H), 7.45 - 7.26 (m, 5H), 6.92 (d, J = 1.7 Hz, 1H), 5.23, 5.13 (AB, 7 = 12.3 Hz, 2H), 5.18 (s, 1H), 4.52 (t, 7 = 8.8 Hz, 1H), 3.89 (s, 1H), 3.04 (d, 7 = 7.3 Hz, 1H), 1.95 - 1.89 (m, 1H), 1.83 (d, 7 = 12.8 Hz, 1H), 1.78 (d, 7 = 13.0 Hz, 1H), 1.74 - 1.65 (m, 2H), 1.65 - 1.54 (m, 2H), 1.36 - 1.02 (m, 6H), 1.09 (d, 7 = 6.4 Hz, 3H);nCNMR (151 MHz, CDCh) 157.6, 141.6, 139.6, 138.5, 136.8, 128.6, 128.1, 121.9, 119.7, 66.9, 61.2, 55.9, 39.1, 35.1, 30.9, 26.8, 26.6, 26.2, 25.5, 15.1; HRMS (ES+) m / z calcd for C23H29N3O2Br ([M + H]+) 458.1438, found 458.1451; ATR-IR (cm’1) 3328, 1918, 1702, 1525, 1253, 1036; |a|D2529.7 (c 0.17, CH2Cl2); θ at λ330nm: 2813 (c 0.08, MeOH).

[0382] Benzyl ((2R,3R,45)-2-cyclopentyl-3-methyl-l,2,3,4-tetrahydroquinolin-4-yl)carbamate B32.

[0383] Synthesized according to General Procedure F with a 50 min pre-stir of aniline (95 μL, 1.05 mmol) and cyclopentanecarbaldehyde (112 μL, 1.05 mmol). The reaction mixture was warmed to rt and stirred for 16 h. Purification by chromatography on SiCb (10-20 % EtOAc in Hexanes) followed by recrystallization in EtOAc / Hexanes provided benzyl ((2 / ?,3 / ?,4.S')-2-cyclopentyl-3-methyl- 1 ,2,3,4- tetrahydroquinolin-4-yl)carbamate B32 (176 mg, 46%) as a white solid: m.p. 107.5 °C;1H NMR (500 MHz, CDCh) 5 7.45 - 7.29 (m, 5H), 7. 13 (d, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.65 (t, 7 = 7.4 Hz, 1H), 6.50 (d, 7 = 7.9 Hz, 1H), 5.20, 5.15 (AB, 7 = 12.3 Hz, 2H), 4.83 (d, 7 = 8.7 Hz, 1H), 4.58 (t, 7 = 8.3 Hz, 1H), 3.88 (brs, 1H), 3.07 (t, 7= 6.4 Hz, 1H), 2.33 - 2.16 (m, 1H), 1.94 - 1.87 (m, 1H), 1.74 - 1.49 (m, 7H), 1.47 - 1.21 (m, 2H), 1.06 (d, 7 = 6.7 Hz, 3H);13C NMR (125 MHz, CDCh) 156.8, 144.5, 136.8, 128.8, 128.7, 128.5, 128.2, 128.1, 120.9, 117.4, 114.3, 66.9, 59.5, 54.9, 42.2, 37.3, 29.3, 26.8, 25.9, 25.7, 16.4; HRMS (ES+) m / calcd for C23H29N2O2([M + H]+) 365.2224, found 365.2236; ATR-IR (cm1) 3382, 2954,1712, 1512, 1460,1238, 1027; [«]D25- 3.93 (c 0.76, CH2Cl2).

[0384] 4-Bromobenzyl ((2R,3R,4>S')-2-cyclopentyl-3-methyl-l,2,3,4-tetrahydroquinolin-4-yl)carbamate B33. Synthesized according to General Procedure F with a 3 h pre-stir of aniline (81 μL, 0.89 mmol) and cyclopentanecarbaldehyde (95 μL, 0.89 mmol). The reaction mixture was treated with 4-bromobenzyl-(E)-propyl-l-en-l-ylcarbamate (240 mg, 0.89 mmol) in CH2Q2 (3.0 mL), warmed to rt, and stirred for 17 h. Purification by chromatography on SiO2(10-20% EtOAc in Hexanes) followed by recrystallization in EtOAc / Hexanes provided 4-bromobenzyl ((27?,3R,4S)-2- cyclopentyl-3-methyl-l,2,3,4-tetrahydroquinolin-4-yl)carbamate B33 (137.5 mg, 35%) as a white solid: m.p. 166.7 °C;]H NMR (500 MHz, CDCh) 6 7.39 (d, J = 8.4 Hz, 2 H), 7.16 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 7.6 Hz, 1H), 6.93 (t, J = 7.9 Hz, 1H), 6.55 (t, 7 = 7.4 Hz, 1H), 6.40 (d, 7 = 7.9 Hz, 1H), 5.04, 4.98 (AB, 7 = 12.5 Hz, 2H), 4.74 (d, 7 = 8.9 Hz, 1H), 4.46 (t, 7 = 8.2 Hz, 1H), 3.78 (brs, 1H), 2.96, (app t, 7 = 6.15, 1H), 2.18-2.09 (m, 1H), 1.84-1.77 (m, 1H), 1.62-1.40 (m, 6H), 1.31-1.14 (m, 2H), 0.95 (d, 7 = 6.8 Hz, 3H);13C NMR (125 MHz, CDCh)156.6, 144.5, 135.9, 131.8, 129.8, 128.8, 128.6, 122.2, 120.7, 117.5, 114.4, 66.0, 59.5, 53.9, 42.2, 37.3, 29.3, 26.9, 25.9, 25.7, 16.5; HRMS (ES+) m / z calcd for C23H28N2O2Br ([M + H]+) 443.1329, found 443.1344; ATR-IR (cm1) 3382, 2954, 1711, 1512, 1460, 1238, 1026; [α]D25-6.14 (c 0.22, CH2Cl2).

[0385] Benzyl ((2R,3R,4S)-6,8-dichloro-2-cyclopentyl-3-methyl-l,2,3,4-tetrahydroquinolin-4-yl) carbamate B34. To an oven-dried pressure flask under inert atmosphere was added dichlorohydantoin (35 mg, 0.18mol) and THF (0.5 mL). A solution of benzyl ((2R,3R,4S)-2- cyclopentyl-3-methyl-l,2,3,4-tetrahydroquinolin-4-yl)carbamate (65 mg, 0.18 mmol) in THF (0.6 mL) was added drop wise. The flask was sealed and heated at 65 °C for 3.5 h. The reaction mixture was cooled to rt and quenched with 30% aqueous NaOH. The organic layer was separated, dried (MgSOfl, and purified by SiOz chromatography (10% EtOAc in Hexanes) to afford benzyl ((2R,3R,4S)-6,8-dichloro-2-cyclopentyl-3-methyl-l,2,3,4-tetrahydroquinolin-4-yl)carbamate B34 (48.8 mg, 63%) as a white solid: m.p. 135.4 °C;1H NMR (400 MHz, CDCh) 5 7.41-7.32 (m, 5H), 7.13 (d, 7 = 1.8 Hz, 1 H), 7.03 (s, 1H), 5.21, 5.16 (AB, 7= 12.1 Hz, 2H), 4.79 (d, 7 = 9.2 Hz, 1H), 4.57 (t, 8.8 Hz, 1H), 4.48 (brs, 1H), 3.16 (app t, J = 7.2 Hz, 1H), 2.31-2.21 (m, 1H), 2.18-1.59 (m, 8H), 1.43-1.31 (m, 2H), 1.06 (d, 7 = 6.7 Hz, 3H);13C NMR (125 MHz, CDCI3) 156.7, 139.4, 136.5, 128.7, 128.4, 128.2, 127.9, 126.6, 123.4, 120.7, 118.4, 67.2, 59.3, 53.8, 41.8, 36.8, 29.4, 26.4, 26.1, 25.8, 15.9; HRMS (ES+) m / z calcd for C23H27N2O2CI2 ([M + H]+) 433.1444, found 433.1448; ATR-IR (cm1) 3276, 2956, 1688, 1543, 1491, 1249, 1037; [α]D25-2.75 (c 0.02, CH2Cl2).

[0386] General Procedure G.

[0387] Benzyl ((25R,3S’R,4RlS’)-2-cyclopentyl-7-(4-methoxyphenyl)-3-methyl-l,2,3,4-tetrahydro-l,5- naphthyridin-4-yl)carbamate B35. To a flame-dried pear shaped Schlenk flask was added sequentially benzyl ((2SR,3SR ,4RS ')-7-bromo-2-cyclopentyl-3-methyl-l,2,3,4-tetrahydro-l,5- naphthyridin-4-yl)carbamate (0.10 g, 0.23 mmol), dioxane:water (2: 1, 2.5 mL) Ietrakis(triphenylphosphine)palladium(0) (0.014 g, 0.011 mmol), 4-methoxyphenylboronic acid (0.045 g, 0.29 mmol), and NazCOs (0.048 g, 0.45 mmol). The reaction vessel was evacuated and backfilled between each addition. The reaction mixture was heated to 55 °C for 13 h before being cooled to rt and diluted with water (20 mL) and CH2Q2 (20 mL). The aqueous layer was extracted with CH2Cl2(2 x 20 mL) and the combined organic layers were washed with brine (25 mL), dried (MgSCU), filtered, concentrated, and purified by chromatography on SiO2(50% EtOAc in Hexanes) to afford benzyl ((25R,3S7?,4R>S')-2-cyclopentyl-7-(4-methoxyphenyl)-3-methyl- 1 ,2,3,4-tetrahydro- l,5-naphthyridin-4-yl)carbamate B35 (62.6 mg, 59%) as a yellow powder: m.p. 151.9 °C; 'H NMR (601 MHz, CDCh) 5 8.11 (s, 1H), 7.49 - 7.29 (m, 4H), 6.96 (d, J = 8.5 Hz, 2H), 5.27 (brs, 1H), 5.24, 5.11 (AB, 7 = 12.3 Hz, 2H), 4.57 (app t, 1H), 3.93 (s, 1H), 3.84 (s, 3H), 3.15 (s, 1H), 2.33 - 2.23 (m, 1H) 2.08 - 1.99 (m, 1H), 1.75 - 1.50 (m, 7H), 1.36 - 1.23 (m, 2H), 1.13 (d, 7 = 6.0 Hz, 3H);13CNMR (151 MHz, CDCh) 159.7, 157.3, 140.4, 139.8, 136.9, 136.4, 135.2, 130.7, 130.7, 129.8, 128.6, 128.2, 128.1, 118.5, 114.5,66.9, 59.4, 55.6, 55.5, 42.0, 37.0, 29.4, 26.8, 26.0, 25.7, 16.4; HRMS (ES+) m z calcd for C29H34N3O3([M + H]+) 472.2595, found 472.2593; ATR-IR (cm"]) 3365, 2953, 1708, 1523, 1246, 1028.

[0388] Benzyl ((2SR,3SR,4RS)-2-cyclopentyl-3-methyl-7-(4-(trifluoromethyl)phenyl)-l,2,3,4-tetrahydro- l,5-naphthyridin-4-yl)carbamate B36. Synthesized following General Procedure G with benzyl ((2SR,3SR,4RS)-7-bromo-2-cyclopentyl-3-methyl- 1,2,3, 4-tetrahydro-l, 5-naphthyridin-4- yl)carbamate (0.10 g, 0.23 mmo) and 4-(trifhioromethyl)phenylboronic acid (86 mg, 0.45 mmol). The mixture was purified by chromatography on SiO2(30% EtOAc in Hexanes) to afford benzyl ((2SR,3SR,4RS)-2-cyclopentyl-3-methyl-7-(4-(trifluoromethyl)phenyl)-l, 2, 3, 4-tetrahydro-l, 5- naphthyridin-4-yl)carbamate B36 (68.2 mg, 59 %) as a colorless powder: m.p. 173.2 °C;]H NMR (400 MHz, DMSO-d6) 5 8.09 (s, 1H), 7.86 - 7.69 (m, 4H), 7.41 - 7.30 (m, 6H), 5.75 (brs, 1H), 5.12, 5.06 (AB, J = 12.6 Hz, 2H), 4.36 (t, J = 8.9 Hz, 1H), 3.15 (dd, J = 7.8, 4.6 Hz, 1 H), 2.35 - 2.26 (m, 1H), 1.93 - 1.83 (m, 1H), 1.69 - 1.45 (m, 7H), 1.44 - 1.32 (m, 1H), 0.98 (d, J = 6.4 Hz, 3H);13CNMR (151 MHz, CDCI3) 157.2, 128.6, 128.2, 128.1, 127.4, 126.1, 124.3, 119.9, 67.1, 59.1, 55.2, 41.6, 36.6, 29.8, 29.3, 26.9, 25.6, 15.7;19FNMR (376 MHz, CDCh) -62.5; HRMS (ES+) m / z calcd for C29H31N3O2F3 ([M + H]+) 510.2363, found 510.2365; ATR-IR (cm1) 3352, 2956, 1713, 1328, 1112, 1017.

[0389] Benzyl ((2S,3S,4R)-2-cyclohexyl-6-fluoro-3-methyl- 1,2, 3, 4-tetrahydro-l, 5-naphthyridin-4- yl)carbamate B41. Synthesized according to General Procedure F with a 1 h pre-stir of 5-amino-2- fluoropyridine (81 mg, 0.71 mmol) and cyclohexanecarbaldehyde (88 μL, 0.71 mmol). The reaction mixture was warmed to rt and stirred for 16 h. Purification by chromatography on SiO (40 % EtOAc in Hexanes) provided benzyl ((2S,3S,4R)-2-cyclohexyl-6-fluoro-3-methyl-l,2,3,4- tetrahydro-l,5-naphthyridin-4-yl)carbamate B41 (65.2 mg, 23%) as a white solid:1H NMR (400 MHz, CDCh) 5 7.94 (d, J = 4.4 Hz, 1H), 7.43 - 7.29 (m, 5H), 6.97 (dd, J = 8.1, 5.0 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 5.30 (s, 1H), 5.25, 5. 12 (AB, J = 12. 1 Hz, 2H), 4.58 (t, J = 8.3 Hz, 1H), 3.77 (s, 1H), 3.12 (brs, 1H), 2.23 - 1.96 (m, 4H), 1.84 - 1.40 (m, 10H), 1.11 (d, J = 6.2 Hz, 3H);19F NMR (282 MHz, CDCh) 5 -80.3; HRMS (ES+) m / z calcd for C23H29N3O2F([M + H]+) 398.2238, found 398.2232.

[0390] Benzyl ((2RS,,3SR ,4RS)-2-(bicyclo[ 1.1.0]butan- 1 -yl)-6-methoxy-3-propyl- 1 ,2,3 ,4-tetrahydro- 1,5- naphthyridin-4-yl)carbamate B42. Synthesized according to General Procedure D with a 1.5 h prestir of 3 -amino-5 -methoxypyridine (164 μL, 2.08 mmol) and bicyclo[1.1.0]butane-l-carbaldehyde (200 mL, 2.08 mmol). The reaction mixture was warmed to rt over 14 h. Purification by chromatography on SiO2(20-40% EtOAc in Hexanes) provided benzyl ((2RS,3SR,4RS)-2- (bicyclo[ 1. 1.0]butan-l -yl)-6-methoxy-3-propyl-l ,2,3,4-tetrahydro- 1 ,5-naphthyridin-4-yl)carbamate B42 (63.2 mg, 7%) as a tan solid:!H NMR (500 MHz, DMSO-d6) 8 7.40 - 7.24 (m, 7H), 6.95 (d, 7 = 8.6 Hz, 1H), 6.44 (d, J = 8.5 Hz, 1H), 5.22 (s, 1H), 5.11, 5.05 (AB, J = 12.8 Hz, 2H), 4.42 (t, J = 8.8 Hz, 1H), 3.61 (s, 3H), 3.06 (brs, 1H), 1.76 - 1.69 (m, 1H), 1.62 - 1.54 (m, 1H), 1.48 - 1.21 (m, 10H), 0.89 (t, J = 7.0 Hz, 3H), 0.85 (t, J = 6.7 Hz, 3H); HRMS (ES+) m / z calcd for C25H32N3O3([M + H]+) 422.2438, found 422.2436.

[0391] Benzyl ((2SR,3SR,4RS)-2-(4,4-difhiorocyclohexyl)-3-methyl- 1 ,2,3,4-tetrahydro- 1 ,5-naphthyridin- 4-yl)carbamate B43. Synthesized according to General Procedure D with a 1 h pre-stir of 3- aminopyridine (81 mg, 0.86 mmol) and 4,4-difluorocyclohexanecarbaldehyde (121 μL, 0.86 mmol). The reaction mixture was warmed to rt over 14 h then heated at reflux for 24 h. Purification by chromatography on SiO2(5% MeOH in CH2CI2) provided benzyl ((2SR,3SR,4RS)-2- ,4- difluorocyclohexyl)-3-methyl-l,2,3,4-tetrahydro-l,5-naphthyridin-4-yl)carbamate B43 (72.9 mg, 21%) as a yellow solid: H NMR (400 MHz, CDCh) 5 7.44 - 7.28 (m, 5H), 6.88 (dd, J = 8.5, 7.1 Hz, 1H), 6.60 (dd, J = 8.5, 2.9 Hz, 1H), 5.12, 5.16 (AB, J = 12.1 Hz, 2H), 5.06 (d, J = 7.5 Hz, 1H), 4.53 (t, J = 8.4 Hz, 1H), 3.73 (brs, 1H), 2.99 (d, J = 8.0 Hz, 1H), 2.03 - 1.89 (m, 1H), 1.87 - 1.57

[0392] (m, 6H), 1.38 - 1.11 (m, 5H), 1.08 (d, J = 6.5 Hz, 3H);19F NMR (282 MHz, CDCI3) 5 -91.5 (d, J = 237 Hz, IF), - 102.9 (d, J = 237 Hz, IF).

[0393] In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only preferred examples of the invention and should not be taken as limiting the scope of the invention.

Claims

What is claimed is:

1. A compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:Formula I wherein X is N or C;Y is N or C;Z is N or C;W is N or C;R1is H;R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl ;R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R5is H;R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R10is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, or oxo; and where each bond represented by - is a single or double bond as needed to satisfy valence requirements.

2. The compound of claim 1 , wherein the compound is:Formula la wherein X is N or C;Y is N or C;Z is N or C;W is N or C;R1is H;R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R5is H;R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R10is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo.

3. The compound of claim 1 or 2, wherein R2is -C(O)O-R8.

4. The compound of claim 1 or 2, wherein R2is -C(O)NH-R8.

5. The compound of any one of claims 1 to 4, wherein R3is alkyl.

6. The compound of any one of claims 1 to 4, wherein R3is (Ci-Ce) alkyl.

7. The compound of any one of claims 1 to 6, wherein R4is alkyl or cycloalkyl.

8. The compound of any one of claims 1 to 6, wherein R4is (Ci-Ce) alkyl.

9. The compound of any one of claims 1 to 8, wherein R6is H or alkoxy.

10. The compound of any one of claims 1 to 9, wherein R7is H or alkoxy.

11. The compound of any one of claims 1 to 10, wherein R8is arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl.

12. The compound of any one of claims 1 to 10, wherein R8is phenyl-substituted alkyl13. The compound of any one of claims 1 to 10, wherein R8is benzyl.

14. The compound of any one of claims 1 to 13, wherein at least one of X, Y, Z or W isN.

15. The compound of any one of claims 1 to 13, wherein X is N.

16. The compound of claim 15, wherein Y, Z and W are each C.

17. The compound of any one of claims 1 to 16, wherein at least one of R6, R7, R9or R10is halo.

18. The compound of any one of claims 1 to 16, wherein R6is halo.

19. The compound of any one of claims 1 to 16, wherein R7is halo.

20. The compound of any one of claims 1 to 16, wherein R9is halo.

21. The compound of any one of claims 1 to 16, wherein R10is halo.

22. The compound of claim 1 , wherein R10is oxo.

23. A compound of Formula II, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:Formula II wherein X is N;Y is C;Z is C;W is C;R1is H;R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R5is H;R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; andR7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

24. A pharmaceutical composition comprising at least one pharmaceutically acceptable additive and a compound of any of claims 1 to 23.

25. A method comprising administering to a subject in need of treatment for epilepsy, developmental or epileptic encephalopathy, pain, tinnitus, cancer, cardiovascular disease, neurodegeneration, fibromyalgia, arthritis, hyperalgesia, depression, schizophrenia, bipolar disorder, traumatic brain injury, smooth muscle disorders, erectile dysfunction, myotonic congenita, or inflammatory airway diseases, a therapeutically effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:Formula I wherein X is N or C;Y is N or C;Z is N or C;W is N or C;R1is H;R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8,wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-Rs, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl ;R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl ;R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;Rsis H;R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R10is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, or oxo; and where each bond represented by - is a single or double bond as needed to satisfy valence requirements.

26. A method comprising administering to a subject in need of treatment for a Kv7- mediated disease a therapeutically effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt, solvate, or hydrate thereof:Formula I wherein X is N or C;Y is N or C;Z is N or C;W is N or C;R1is H;R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R4is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R5is H;R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R10is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, or oxo; and where each bond represented by - is a single or double bond as needed to satisfy valence requirements.

27. The method of claim 25 or 26, wherein the compound is:Formula la wherein X is N or C;Y is N or C;Z is N or C;W is N or C;R1is H;R2is -C(O)O-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)NH-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -S(O)(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl, or R2is -C(O)-R8, wherein R8is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl ;R3is alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R4is alkyl, substituted alkyl, cycloalky], aryl, substituted aryl, heteroaryl, or substituted heteroaryl;R5is H;R6is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R7is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R9is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo;R10is H, alkoxy, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or halo.

28. The method of any one of claims 25 or 27, wherein R1is H.

29. The method of any one of claims 25 to 28, wherein R3is (Ci-Ce) alkyl.

30. The method of any one of claims 25 to 29, wherein R4is alkyl or cycloalkyl.

31. The method of any one of claims 25 to 29, wherein R4is (Ci-Ce) alkyl.

32. The method of any one of claims 25 to 31, wherein R6is H or alkoxy.

33. The method of any one of claims 25 to 32, wherein R7is H or alkoxy.

34. The method of any one of claims 25 to 33, wherein R8is arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl.

35. The method of any of claims 25 to 33, wherein Rsis phenyl-substituted alkyl36. The method of any of claims 25 to 33, wherein R8is benzyl.

37. The method of any of claims 25 to 36, wherein at least one of X, Y, Z or W is N.

38. The method of any one of claims 25 to 36, wherein X is N.

39. The method of claim 38, wherein Y, Z and W are each C.40 The method of any one of claims 25 to 39, wherein at least one of R6, R7, R9or R10is halo.

41. The method of any one of claims 25 to 39, wherein R6is halo.

42. The method of any one of claims 25 to 39, wherein R7is halo.

43. The method of any one of claims 25 to 39, wherein R9is halo.

44. The method of any one of claims 25 to 39, wherein R10is halo.

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