4-HYDROXY-2-OXO-1 ,2-DIHYDRO-l ,8-NAPHTHYRIDINE-3-CARBOXAMIDE DERIVATIVES AS

CANNABINOID CB2 RECEPTOR MODULATORS FOR THE TREATMENT OF CANCER

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application Serial Number 62/275,193, filed November 3, 2021, the contents of which are hereby incorporated by reference in their entirety.

FIELD

[0002] Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds for the treatment of conditions, diseases, or disorders that would benefit from reduction or inhibition of cannabinoid receptor CB2 activity.

BACKGROUND

[0003] Cannabinoid CB2 receptors (CBzR) modulate immune responses during inflammatory processes, in the tumor microenvironment. Endogenous and exogenous cannabinoids exert immunosupressive properties in a variety of ways, including induction of apoptosis of T cells, NK cells and B cells; inhibition of T, NK and B cells proliferation; inhibition of immunostimulatory cytokine and chemokine production, and induction of immunosuppressive cytokine production and regulatory T cells. Therefore, CB ₂ R antagonism should restore T, NK and B cells function and relieve innate and adaptive immunosuppression caused by the endocannabinoids. Developing CB2 receptor antagonists constitute a novel approach to treat cancer by enhancing antitumor immune response.

SUMMARY

[0004] The present disclosure, in one embodiment, provides a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, selected from Table 1. Compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and solvates thereof, are CB2 receptor (CB ₂ R) modulators. In some embodiments, the CB ₂ R modulators are CB ₂ R antagonists. In some embodiments, the CB ₂ R modulators are CB ₂ R inverse agonists.

[0005] In another aspect, described herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0006] In another aspect, described herein is a method of modulating the activity of the cannabinoid 2 receptor (CB ₂ R) in a mammal comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0007] In another aspect, described herein is a method of treating a disease or disorder in a mammal that is mediated by the action of the cannabinoid 2 receptor (CB ₂ R) comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate or stereoisomer thereof. DETAILED DESCRIPTION

Definitions

[0008] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of die present disclosure but is instead provided as a description of exemplary embodiments.

[0009] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0010] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH ₂ is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.

[0011] The prefix “C _u-v ” indicates that the following group has from u to v carbon atoms. For example, “C _1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0012] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, die term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless tiie context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0013] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C _1-20 alkyl), 1 to 8 carbon atoms (ie., C _1-8 alkyl), 1 to 6 carbon atoms (i.e., C _1-6 alkyl), or 1 to 4 carbon atoms (i.e., CM alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2- hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. -(CH ₂ ) ₃ CH ₃ ), sec-butyl (i.e. -CH(CH ₃ )CH ₂ CH ₃ ), isobutyl (i.e. -CH ₂ CH(CH ₃ ) ₂ ) and tert-butyl (i.e. -C(CH ₃ ) ₃ ); and “propyl” includes n-propyl (i.e. -(CH ₂ ) ₂ CH ₃ ) and isopropyl (i.e. -CH(CH ₃ ) ₂ ).

[0014] “Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (te., C _2-20 alkenyl), 2 to 8 carbon atoms (i.e., C _2-8 alkenyl), 2 to 6 carbon atoms (i.e., C _2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C _2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl). [0015] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy.

[0016] The term “alkylamine” refers to -NH( alkyl), or -N(alkyl) ₂ .

[0017] “Alkylthio” refers to the group “alkyl-S-.”

[0018] “Acyl” refers to a group -C(O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0019] “Amido” refers to both a “C-amido” group which refers to the group -C(O)NR ^y R ^z and an “N- amido” group which refers to the group -NR ^y C(O)R ^z , wherein R ^y and R ^z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0020] “Amino” refers to the group -NR ^y R ^z wherein R ^y and R ^z are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted.

[0021] “Amidino” refers to -C(NH)(NH ₂ ).

[0022] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C _6-20 aryl), 6 to 12 carbon ring atoms (i.e., C ₆ -n aryl), or 6 to 10 carbon ring atoms (i.e., C _6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.

[0023] “ Azido” refers to —Ns.

[0024] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NR ^y R ^z and an “N-carbamoyl” group which refers to the group -NR ^y C(O)OR ^z , wherein R ^y and R ^z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.

[0025] “Carboxyl” refers to -C(O)OH.

[0026] “Carboxyl ester” refers to both -OC(O)R and -C(O)OR, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0027] “Cyano” or “carbonitrile” refers to the group -CN.

[0028] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C _3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C _3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C _{3- 10} cycloalkyl), 3 to 8 ring carbon atoms (i.e., C _3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C _3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0029] “Cycloalkylene” refers to -cycloalkyl-, i.e., a cycloalkyl ring as defined herein which is bonded to two groups.

[0030] “1,4-dioxanyl ring fused to ring C” refers to

[0031] “Deuteroalkyl” refers to an alkyl group as defined herein, in which at least one H is replaced by an isotope of hydrogen, i.e., by deuterium ( ² H) or tritium ( ³ H).

[0032] “Deuteroalkoxy” refers to an alkoxy group as defined herein, in which at least one H is replaced by an isotope of hydrogen, i.e., by deuterium ( ² H) or tritium ( ³ H).

[0033] “Guanidino” refers to -NHC(NH)(NH ₂ ).

[0034] “Hydrazino” refers to -NHNH ₂ .

[0035] “Imino” refers to a group -C(NR)R, wherein each R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.

[0036] “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF ₂ ) and trifluoromethyl (-CF ₃ ).

[0037] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a C ₁ -C ₆ fluoioalkyl.

[0038] “Fluoroalkoxy” refers to an alkoxy group as defined herein, in which at least one H is replaced by a fluorine atom.

[0039] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.

[0040] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, - S(O)-, -S(O) ₂ -, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH ₃ , - CH ₂ OCH ₃ , -SCH ₃ , -CH ₂ SCH ₃ , -NRCH ₃ , and -CH ₂ NRCH ₃ , where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. [0041] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C _1-20 heteroaryl), 3 to 12 ring carbon atoms (e.e., C _3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C _3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from ni trogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0042] “Heterocyclyl” or “heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heteroalixyclic” refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e. the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused- heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C _2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C _2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C _2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C _2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C _3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C _3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C _3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term “bridged-heterocyclyl” refers to a four- to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g. 1 or 2) four- to ten-membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, bridged- heterocyclyl includes bicyclic and tricyclic ring systems. Also used herein, the term “spiro-heterocyclyl” refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to tenmembered heterocyclyl. Examples of the spiro-heterocyclyl rings include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1- azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1, 2,3,4- tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0043] In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine -2, 5-dithionyl, pyrrolidine-2, 5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In some embodiments, the sulfur atom in a heterocycloalkyl is not oxidized. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a Cr-C ₁₀ heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4- C ₁₀ heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[0044] “Hydroxy” or “hydroxyl” refers to the group -OH.

[0045] “Oxo” refers to the group (=O) or (O).

[0046] “Nitro” refers to the group -NO ₂ .

[0047] “Sulfonyl” refers to the group -S(O) ₂ R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methyl sulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0048] “Alkylsulfonyl” refers to the group -S(O) ₂ R, where R is alkyl.

[0049] “Alkylsulfinyl” refers to the group -S(O)R, where R is alkyl.

[0050] “Thiocyanate” refers to the group -SCN.

[0051] “Thiol” refers to the group -SH.

[0052] “Thioxo” or “thione” refer to the group (=S) or (S).

[0053] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0054] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0055] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. [0056] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target. In some embodiments, “modulate” means to interact with a target either directly or indirectly so as to decrease or inhibit receptor activity,

[0057] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, or combinations thereof. In some embodiments, a modulator is an antagonist. Receptor antagonists are inhibitors of receptor activity. Antagonists mimic ligands that bind to a receptor and prevent receptor activation by a natural ligand. Preventing activation may have many effects. If a natural agonist binding to a receptor leads to an increase in cellular function, an antagonist that binds and blocks this receptor decreases the function.

[0058] Some of the compounds may exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0059] Any formula or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to, ² H (deuterium, D), ³ H (tritium), ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, ^1S F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, and ¹²⁵ I. Various isotopically labeled compounds of the present disclosure, for example, are those into which radioactive isotopes such as ³ H and ¹⁴ C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single -photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0060] The disclosure also includes “deuterated analogs” of compounds in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. [0061] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An ¹⁸ F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.

[0062] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0063] In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

[0064] Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0065] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, mafic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH ₂ (alkyl)), dialkyl amines (i.e., HN(alkyl) ₂ ), trialkyl amines (i.e., N(alkyl)s), substituted alkyl amines (i.e., NH ₂ (substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl);), tri(substituted alkyl) amines (i.e., N(substituted alkyl);), alkenyl amines (i.e., NH ₂ (alkenyl)), dialkenyl amines (i.e., HN( alkenyl) 2), trialkenyl amines (i.e., N(alkenyl) ₃ ), substituted alkenyl amines (i.e., NH ₂ (substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl^), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl);, mono-, di- or tri- cycloalkyl amines (i.e., NH ₂ (cycloalkyl), HN(cycloalkyl) ₂ , N(cycloalkyl) ₃ ), mono-, di- or tri- arylamines (i.e., NH ₂ (aryl), HN(aryl) ₂ , N(aryl) ₃ ), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0066] The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidine, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc. ) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions tire not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyi, aryl, or heteroaryl, each of which is unsubstituted.

[0067] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0068] A “solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

List of Abbreviations and Acronyms

Abbreviation Meaning

°C Degree Celsius

ACN acetonitrile aq. Aqueous

Brettphos Pd G ; [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl- 1 , 1 '-biphenyl)-2-(2'-amino- 1,1' - biphenyl)]palladium(II) methanesulfonate methanesulfonate g Grams h or hrs Hours

M Molar mg Milligram

MHz Megahertz ml/mL Milliliter mM Millimolar mmol Millimole nL Nanoliter nm Nanometer μL/ μl Microliter μM Micromolar μm Micrometer

CDCI ₃ Chloroform, deuterated

CH ₃ COOH or HOAc Acetic acid or AcOH

DCE Dichloroethane

DCM Dichloromethane DMSO Dimethyl sulfoxide

DMF Dimethyl formamide

DMA Dimethylacetamide

DIEA or DIPEA Diisopropyl ethyl amine

EA or EtOAc Ethyl Acetate

EtOH Ethanol

FA Formic acid H ₂ O water

H ATU 1 - [B is(dimethylamino)methylene] - 1 H- 1 ,2 , 3 -triazolo[4, 5 - b]pyridinium 3-oxid hexafluorophosphate

LiHMDS Lithium bis(trimethylsilyl)amide

Me OH Methanol

NaBH ₃ CN Sodium cyanoborohydride

NaOMe Sodium methoxide

PE Petroleum ether

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

Rt Retention time

THF Tetrahydrofuran

TLC Thin Layer Chromatography

TsOH Para-Toluene sulfonic acid mL *2 or mL *3 Twice or thrice respectively

Compounds

[0069] In one aspect, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Formula (I) wherein,

R ¹ is -OH, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ deuteroalkyl, C ₁ -C ₄ deuteroalkoxy, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, C ₁ -C ₄ heteroalkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ heterocycloalkyl containing 1-2 N atom and 0 or 1 O or S atom, or a C ₃ -C ₆ heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom;

L ¹ is absent, C ₁ -C ₄ alkylene, or C ₃ -C ₅ cycloalkylene;

R ² is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 R ^a ; ring A is C ₃ -C ₆ heterocycloalkyl containing 1-2 N atom and 0 or 1 O or S atom, C ₃ -C ₆ heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom, phenyl, C ₃ -C ₁₀ cycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl; each R ^a is independently selected from the group consisting of halogen, -CN, -OH, -OR ¹² , -SR ¹² , -S(=O)R ¹² , -S(=O) ₂ R ¹² , -S(=O) ₂ N(R ¹³ ) ₂ , -NR ¹³ S(=O) ₂ R ¹² , -N(R ¹³ ) ₂ , - OC(=O)(R ¹² ), -CO ₂ R ¹³ , -C(=O)N(R ¹² ) ₂ , -NR ¹³ C(=O)(R ¹² ), -NR ¹³ C(=O)O(R ¹² ), -OC(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)N(R ¹³ ) ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ - C ₄ deuteroalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyl, or substituted or unsubstituted monocyclic C ₃ -C ₆ heterocycloalkyl;

R ³ is H or C ₁ -C ₄ alkyl;

R ⁴ is -L ² -R ⁵ ;

L ² is absent or -CR ¹⁰ R ⁿ -;

R ⁵ is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 R ^b ; ring B is C ₃ - C ₁₂ cycloalkyl, C ₂ -C ₁₀ heterocycloalkyl, phenyl, naphthyl, or heteroaryl; each R ^b is independently selected from the group consisting of halogen, -CN, -OH, -N(R ¹³ ) ₂ , -OC(=O)(R ¹² ), -CO ₂ R ¹³ , -C(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)(R ¹² ), -NR ¹³ C(=O)O(R ¹² ), -OC(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)N(R ¹³ ) ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ deuteroalkyl, C ₁ -C ₄ deuteroalkoxy, C ₁ - C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, C ₁ -C ₄ heteroalkyl, or substituted or unsubstituted monocyclic C ₃ -C ₆ heterocycloalkyl; or two R ^b that are attached to the same carbon atom are taken together with the carbon atom to form a C ₃ -C ₆ cycloalkyl or a C ₃ -C ₆ heterocycloalkyl;

R ¹⁰ and R ¹¹ are independently selected from H or -CH ₃ ; or R ¹⁰ and R ¹¹ are taken together with the carbon atom to which they are attached to form a C ₁ -C ₆ cycloalkyl;

R ⁶ is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 R ^c ; ring C is phenyl, naphthyl, heteroaryl, C ₃ -C ₁₂ cycloalkyl, or C ₂ -C ₁₀ heterocycloalkyl; or R ⁶ is hydrogen, halogen, -CN, -OH, -OR ¹² , -SR ¹² , -S(=O)R ¹² , -S(=O) ₂ R ¹² , -S(=O) ₂ N(R ¹³ ) ₂ , - NR ¹³ S(=O) ₂ R ¹² , -N(R ¹³ ) ₂ , -OC(=O)(R ¹² ), -CO ₂ R ¹³ , -C(=O)N(R ¹³ ) ₂ ,

-NR ¹³ C(=O)(R ¹² ), -NR ¹³ C(=O)O(R ¹² ), -OC(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)N(R ¹³ ) ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ deuteroalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyl, or substituted or unsubstituted monocyclic C ₃ -C ₆ heterocycloalkyl; each R ^c is independently selected from the group consisting of halogen, -CN, -OH, -OR ¹² , -SR ¹² , -S(=O)R ¹² , -S(=O) ₂ R ¹² , -S(=O) ₂ N(R ¹³ ) ₂ , -NR ¹³ S(=O) ₂ R ¹² , -N(R ¹³ ) ₂ , - OC(=O)(R ¹² ), -CO ₂ R ¹³ , -C(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)(R ¹² ), -NR ¹³ C(=O)O(R ¹² ), -OC(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)N(R ¹³ ) ₂ , C ₁ -c ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ - C ₄ deuteroalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ hetcroalkyl. substituted or unsubstituted C ₃ - C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₇ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl or a 1 ,4- dioxanyl ring fused to ring C;

R ⁷ is H, halogen, -CN, -OH, -N(R ¹³ ) ₂ , C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ deuteroalkyl, C ₁ -C ₄ deuteroalkoxy, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, or C ₁ -C ₄ heteroalkyl or C ₃ -C ₆ heterocycloalkyl;

X ¹ is N; and X ² is CR ⁸ or N; or X ¹ is CR ⁸ or N; and X ² is N;

R ⁸ is H, halogen, -CN, -OH, -N(R ¹³ ) ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ deuteroalkyl, C ₁ -C ₄ deuteroalkoxy, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ heteroalkyl or C ₃ -C ₆ heterocycloalkyl; each R ¹² is independently selected from the group consisting of C ₁ -C ₄ alky 1, C ₁ -C ₄ deuteroalkyl, C ₁ -Cbfluoroalkyl. C ₁ -C ₄ heteroalkyl, substituted or unsubstituted Ch-C ₆ cycloalkyl, substituted or unsubstituted C ;-C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; each R ¹³ is independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ deutcioalkyl, C -Cbfluoroalkyl. C ₁ -C ₄ heteroalkyl, substituted or unsubstituted Ch- C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; provided that when R ⁶ is H, R ⁴ is not cyclohexyl, 4-methylcyclohexyl, or cycloheptyl.

[0070] In another aspect, described herein is a compound that has the structure of Formula (X), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

Formula (X) wherein,

R ¹ is hydrogen, -OH, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ deuteroalkyl, C ₁ -C ₄ deuteroalkoxy, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, C ₁ -C ₄ heteroalkyl, C ₃ -C ₆ cycloalkyl, C--C ₆ heterocycloalkyl containing 1 N atom and 0 or 1 O or S atom, or a C ₃ -C ₆ heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom;

L ¹ is absent, C ₁ -C ₄ alkylene, or C ₃ -C ₆ cycloalkylene;

R ² is a ring A that is unsubstituted or is substituted with 1, 2, 3, or 4 R ^a ; ring A is C ₃ -C ₆ heterocycloalkyl containing 1-2 N atom and 0 or 1 O or S atom, C ₃ -C ₆ heterocycloalkyl containing 0 or 1 N atom and 1 O or S atom, phenyl, C ₃ -C ₁₀ cycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl; each R ^a is independently selected from the group consisting of halogen, -CN, -OH, -OR ¹² , -SR ¹² , -S(=O)R ¹² , -S(=O) ₂ R ¹² , -S(=O)2N(R ¹³ ) ₂ , -NR ¹³ S(=O) ₂ R ¹² , -N(R ¹³ ) ₂ , - OC(=O)(R ¹² ), -CO ₂ R ¹³ , -C(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)(R ¹² ), -NR ¹³ C(=O)O(R ¹² ), -OC(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)N(R ¹³ ) ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ - C ₄ deuteroalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyk or substituted or unsubstituted monocyclic C ₃ -C ₆ heterocycloalkyl;

R ³ is H or C ₁ -C ₄ alkyl;

R ⁴ ; u is 1 or 2; v is 1 or 2; or R ⁴ is -L ² -R ⁵ ;

L ² is absent or -CR ¹⁰ R ⁿ -;

R ¹⁰ is -CH ₃ ;

R ¹¹ is H or -CH ₃ ; or R ¹⁰ and R ¹¹ are taken together with the carbon atom to which they are attached to form a cyclopropyl- 1 , 1 -diyl;

R ⁵ is a ring B that is unsubstituted or is substituted with 1, 2, 3, or 4 R ^b ; ring B is bridged C5-C ₁ 2 cycloalkyl, phenyl, naphthyl, or heteroaryl; each R ^b is independently selected from the group consisting of halogen, -CN, -OH, -N(R ¹³ ) ₂ , -OC(=O)(R ¹² ), -CO ₂ R ¹³ , -C(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)(R ¹² ), -NR ¹⁵ C(=O)O(R ¹² ), -OC(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)N(R ¹³ ) ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ deuteroalkyl, C ₁ -C ₄ deuteroalkoxy, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, C ₁ -C ₄ heteroalkyl, or substituted or unsubstituted monocyclic C ₃ -C ₆ heterocycloalkyl; or two R ^b that are attached to the same carbon atom are taken together with the carbon atom to form a C ₃ -C ₆ cycloalkyl or a C ₃ -C ₆ heterocycloalkyl;

R ⁶ is a ring C that is unsubstituted or is substituted with 1, 2, 3, or 4 R ^c ; ring C is phenyl, naphthyl, heteroaryl, C ₃ -C ₁₂ cycloalkyl, or C ₂ -C ₁₀ heterocycloalkyl; or R ⁶ is hydrogen, halogen, -CN, -OH, -OR ¹² , -SR ¹² , -S(=O)R ¹² , -S(=O) ₂ R ¹² ,

-S(=O) ₂ N(R ¹³ ) ₂ , -NR ¹³ S(=O) ₂ R ¹² , -N(R ¹³ ) ₂ , -OC(=O)(R ¹² ), -CO ₂ R ¹³ , -C(=O)N(R ¹³ ) ₂ ,

-NR ^1S C(=O)(R ¹² ), -NR ¹³ C(=O)O(R ¹² ), -OC(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)N(R ¹³ ) ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ deuteroalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyl, or substituted or unsubstituted monocyclic C ₃ -C ₆ heterocycloalkyl; each R ^c is independently selected from the group consisting of halogen, -CN, -OH,

-OR ¹² , -SR ¹² , -S(=O)R ¹² , -S(=O) ₂ R ¹² , -S(=O)2N(R ¹³ ) ₂ , -NR ¹³ S(=O) ₂ R ¹² , -N(R ¹³ ) ₂ , - OC(=O)(R ¹² ), -CO ₂ R ¹³ , -C(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)(R ¹² ), -NR ¹³ C(=O)O(R ¹² ), -OC(=O)N(R ¹³ ) ₂ , -NR ¹³ C(=O)N(R ¹³ ) ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ - C ₄ deuteroalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyl. substituted or unsubstituted C ₃ - C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted monocyclic heteroaryl or a 1 ,4- dioxanyl ring fused to ring C;

R ⁷ is H, halogen, -CN, -OH, -N(R ¹³ ) ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ deuteroalkyl, C ₁ -C ₄ deuteroalkoxy, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, or C ₁ -C ₄ heteroalkyl;

X ¹ is N; and X ² is CR ⁸ or N; or X ¹ is CR ⁸ or N; and X ² is N;

R ⁸ is H, halogen, -CN, -OH, -N(R ¹³ ) ₂ , C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ deuteroalkyl, C ₁ -C ₄ deuteroalkoxy, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkoxy, or C -C ₄ heteroalkyl: each R ¹² is independently selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ deuteroalkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ heteroalkyl, substituted or unsubstituted C ₃ - C ₆ cycloalkyl, substituted or unsubstituted -C ₃ -heterocycioalkyl. substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl; each R ¹³ is independently selected from the group consisting of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ deuteroalkyl, C ₁ -C ₄ fluoroalkyl. C ₁ -C ₄ heteroalkyl, substituted or unsubstituted C ₃ - C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted monocyclic heteroaryl provided that when R ¹ is H, R ⁴ is not cyclohexyl substituted by 0, 1, 2, 3 or 4 methyl groups. [0071] In some embodiments, provided herein is a compound selected from Table 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, provided herein is a compound that is not disclosed in WO2021/226206.

Table 1

Treatment Methods and Uses

[0072] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g. , decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.

[0073] “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0074] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0075] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition associated with modulation of CB2 receptors. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.

[0076] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and/or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art. [0077] The compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are useful for the modulation of cannabinoid receptors. In some embodiments, the cannabinoid receptor modulated by the compounds and methods is the cannabinoid 2 receptor (CB ₂ R). [0078] Provided herein are CB ₂ R modulators that are useful for treating one or more diseases or disorders associated with or that would benefit from modulation of CB ₂ R activity.

[0079] In some embodiments, described herein are methods for treating a disease or disorder, wherein the disease or disorder is cancer, a hyperproliferative disorder, an autoimmune disorder, or inflammatory disorder.

[0080] In some embodiments, provided herein is a method of modulating the activity of the cannabinoid 2 receptor (CB ₂ R) in a mammal comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0081] In some embodiments, provided herein is a method of treating a disease or disorder in a mammal that is mediated by the action of the cannabinoid 2 receptor (CB ₂ R) comprising administering to the mammal a compound described herein, or any pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0082] In one aspect, a CB ₂ R modulator described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, reduces, ameliorates or inhibits immunosuppression and cell proliferation associated with cancers.

[0083] In some embodiments, provided herein is a method for treating cancer in a mammal, the method comprising administering to the mammal a selective cannabinoid 2 receptor (CB ₂ R) modulator. In some embodiments, the selective cannabinoid 2 receptor (CB ₂ R) modulator is a selective cannabinoid 2 receptor (CB ₂ R) antagonist. In some embodiments, the selective cannabinoid 2 receptor (CB ₂ R) modulator is a selective cannabinoid 2 receptor (CB ₂ R) inverse agonist.

[0084] The term “cancer” as used herein, refers to an abnormal growth of cells that tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). Types of cancer include, but are not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, liver, uterus, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma or basal cell cancer) or hematological tumors (such as the leukemias and lymphomas) at any stage of the disease with or without metastases.

[0085] In some embodiments, a mammal treated with a compound described herein has a disease or disorder that is or is associated with a cancer or tumor. Thus, in some embodiments, the mammal is a human that is an oncology patient. Such diseases and disorders and cancers include carcinomas, sarcomas, benign tumors, primary tumors, tumor metastases, solid tumors, non-solid tumors, blood tumors, leukemias and lymphomas, and primary and metastatic tumors.

[0086] In some embodiments, the CB2 receptor modulators described herein are used in the treatment of solid tumours. A solid tumor is an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign (not cancer), or malignant (cancer). Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are carcinomas, sarcomas, and lymphomas.

[0087] Carcinomas include, but are not limited to, esophageal carcinoma, hepatocellular carcinoma, basal cell carcinoma, squamous cell carcinoma, bladder carcinoma, bronchogenic carcinoma, colon carcinoma, colorectal carcinoma, gastric carcinoma, lung carcinoma, including small cell carcinoma and non-small cell carcinoma of the lung, adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma, breast carcinoma, ovarian carcinoma, prostate carcinoma, adenocarcinoma, renal cell carcinoma, Wilm's tumor, cervical carcinoma, uterine carcinoma, testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, and nasopharyngeal carcinoma.

[0088] Sarcomas include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, chordoma, osteogenic sarcoma, osteosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, and other soft tissue sarcomas.

[0089] Leukemias include, but are not limited to, a) chronic myeloproliferative syndromes (neoplastic disorders of multipotential hematopoietic stem cells); b) acute myelogenous leukemias; c) chronic lymphocytic leukemias (CLL), including B-cell CLL, T-cell CLL prolymphocyte leukemia, and hairy cell leukemia; and d) acute lymphoblastic leukemias (characterized by accumulation of lymphoblasts). Lymphomas include, but are not limited to, B-cell lymphomas (e.g., Burkitt's lymphoma); Hodgkin's lymphoma; and the like.

[0090] Benign tumors include, e.g., hemangiomas, hepatocellular adenoma, cavernous hemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas and pyogenic granulomas.

[0091] Primary and metastatic tumors include, e.g., lung cancer; breast cancer; colorectal cancer; anal cancer; pancreatic cancer; prostate cancer; ovarian carcinoma; liver and bile duct carcinoma; esophageal carcinoma; bladder carcinoma; carcinoma of the uterus; glioma, glioblastoma, medulloblastoma, and other tumors of the brain; kidney cancers; cancer of the head and neck; cancer of the stomach; multiple myeloma; testicular cancer; germ cell tumor; neuroendocrine tumor; cervical cancer; carcinoids of the gastrointestinal tract, breast, and other organs.

[0092] In some or any of the preceding embodiments, the cancer is a solid tumor.

[0093] In some or any of the preceding embodiments, the cancer is bladder cancer, colon cancer, brain cancer, breast cancer, endometrial cancer, heart cancer, kidney cancer, lung cancer, liver cancer, uterine cancer, blood and lymphatic cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, or skin cancer.

[0094] In some or any of the preceding embodiments, the cancer is prostate cancer, breast cancer, colon cancer, or lung cancer.

[0095] In some or any of the preceding embodiments, the cancer is a sarcoma, carcinoma, or lymphoma. [0096] In some embodiments, the mammal is a human.

Combination Therapies

[0100] In some or any of the preceding embodiments, the methods comprise administering at least one additional therapy to the mammal.

[0097] In some or any of the preceding embodiments, the methods comprise administering at least one immune checkpoint inhibitor to the mammal. In some or any of the preceding embodiments, the immune checkpoint inhibitor is an anti-PD-1 agent or an anti-PD-Ll agent. In some or any of the preceding embodiments, the anti-PD-1 agent or anti-PD-Ll agent is nivolumab, pembrolizumab, cemiplimab, labrolizumab, avelumab, durvalumab or atezolizumab.

Anti-PD-l/Anti-PD-Ll Agents

[0098] In some embodiments, a compound described herein (i.e. a CB ₂ R antagonist or inverse agonist), or a pharmaceutically acceptable salt thereof, is administered in combination with an immune checkpoint inhibitor. Immune checkpoint inhibitors include, but are not limited to, anti-PD-1, anti-PD- Ll, or anti-ligand 2 of programmed cell death protein 1 (PD-L2) agents/inhibitors. In some embodiments, immune checkpoint inhibitors include, but are not limited to anti-PD-1, anti-PD-Ll, or anti-ligand 2 of programmed cell death protein 1 (PD-L2) antibodies.

[0099] As used herein, “PD-1” or “PD1” refers to the Programmed Death 1 (PD-1) receptor. Other names include programmed cell death protein 1 and CD279 (cluster of differentiation 279). PD-1 has two ligands, PD-L1 and PD-L2. In some embodiments, targeting PD-1 restores immune function in the tumor microenvironment.

[0100] As used herein, “PD-L1” or “PDL1” refers to the programmed death ligand 1 (PD-L1). [0101] As used herein, “PD-L2” or “PDL2” refers to the programmed death ligand 2 (PD-L2).

[0102] In some embodiments, the anti-PD-1 or anti-PDL-1 agent is an antibody, a peptide, a small molecule or a nucleic acid.

[0103] In some embodiments, a compound described herein (i.e. a CBzR antagonist or inverse agonist), or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-PD-1 or anti-PD-Ll agent. In some embodiments, the anti-PD-1 agent is an anti-PD-1 antibody. In some embodiments, the anti-PD-Ll agent is an anti-PD-Ll antibody.

[0104] In some embodiments, the anti PD-1 agent for use in combination with compound described herein (i.e. a CB ₂ R antagonist or inverse agonist), or a pharmaceutically acceptable salt thereof, is nivolumab, pembrolizumab, atezolizumab, durvalumab, pidilizumab, avelumab, TSR-042, PDR-001, tislelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI- 754091, IBL3O8, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN- 2034, CSIOOI, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK-301, AK 104, or GLS-010, BGB-108, SHR-1210, PDR-001, PF-06801591, STI-1110, mDX-400, Spartalizumab (PDR001), Camrelizumab (SHR1210), Sintilimab (IBI3O8), Tislelizumab (BGB-A317), Toripalimab (JS 001), Dostarlimab (TSR-042, WB P-285), INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680). [0105] In some embodiments, the anti PD-1 agent is an anti PD-1 antibody.

[0106] “Anti-PD- 1 antibody” refers to an antibody directed towards programmed death protein 1 (PD1). In some embodiments, an anti-PD-1 antibody binds an epitope of PD-1 which blocks the binding of PD-1 to any one or more of its putative ligands. In some embodiments, an anti-PDl antibody binds an epitope of a PD-1 protein which blocks the binding of PD-1 to PD-L1 and/or PD-L2.

[0107] Exemplary anti-PD-1 antibodies include but are not limited to: nivolumab/MDX-1106/BMS- 9300/ONO1152, a fully human lgG4 anti-PD-1 monoclonal antibody; pidilizumab (MDV9300/CT-011), a humanized IgGl monoclonal antibody; pembrolizumab (MK-3475/ pembrolizumab/lambrolizumab), a humanized monoclonal IgG4 antibody; durvalumab (MEDI-4736) and atezolizumab.

[0108] In some embodiments, the anti-PD-1 antibody is nivolumab (OPDIVO®, Bristol-Myers Squibb), pembrolizumab (KEYTRUDA®, Merck), cemiplimab (Libtayo), labrolizumab (Merck), or BGB-A317.

[0109] In some embodiments, the anti-PDl antibody is an antibody set forth in U.S. Patent Nos. 7,029,674, 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,617,546, 8,709,417, or WO2014/179664.

[0110] The terms “antibody” and “antibodies” as used herein is inclusive of all types of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE, or fragments thereof, that may be appropriate for the medical uses disclosed herein. The antibodies may be monoclonal or polyclonal and may be of any species of origin, including, for example, mouse, rat, rabbit, horse, or human. Antibody fragments that retain specific binding to the protein or epitope, for example, PD-L1 or PD-1, bound by the antibody used in the present disclosure are included within the scope of the term “antibody.” The antibodies may be chimeric or humanized, particularly when they are used for therapeutic purposes. Antibodies and antibody fragments may be obtained or prepared using various methods.

[0111] In some embodiments, the anti PD-1 agent for use in combination with a compound described herein (i.e. a CB ₂ R antagonist or inverse agonist), or a pharmaceutically acceptable salt thereof, is atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX- 072, BMS-936559, KN035, CK-301 (Checkpoint Therapeutics), AUNP12, CA-170 (Aurigene/Curis), MEDI4736, MSB0010718C, MDX 1105-01, and BMS-986189.

[0112] In some embodiments, the anti PD-L1 agent is an anti PD-L1 antibody.

[0113] “Anti-PD-Ll antibody” refers to an antibody directed towards programmed death ligand 1 (PD-L1).

[0114] Anti-PD-Ll antibodies for use in combination with a compound described herein (i.e. a CB ₂ R antagonist or inverse agonist), or a pharmaceutically acceptable salt thereof, include: avelumab; BMS- 936559, a fully human IgG4 antibody; atezolizumab (MPDL3280A/RG-7446), a human monoclonal antibody; MEDI4736; MSB0010718C, and MDX 1105-01.

[0115] In some embodiments, the anti-PD-Ll antibody is avelumab (Bavencio®, Merck KGA/Pfizer), durvalumab (AstraZeneca) and atezolizumab (TECENTRIQ®, Roche). [0116] Additional exemplary antibodies include, but are not limited to, the antibodies set forth in U.S. Patent Nos. 8,217,149, 8,383,796, 8,552,154 and 8,617,546.

[0117] Peptide anti-PD-l/PD-Ll agents include AUNP12 (a 29-mer peptide by Aurigene and Laboratoires Pierre Fabre), CA-170 (Aurigene/Curis), BMS-986189 (a macrocyclic peptide by BMS). [0118] Small molecule anti-PD-l/PD-Ll agents include those described in WO/2020/086556, WO/2020/014643, WO/2019/204609, WO/2019/160882, WO/2018/195321, WO2018026971, US20180044329, US20180044305, US20180044304, US20180044303, US20180044350, US20180057455, US20180057486, US20180045142, WO20180044963, WO2018044783, W02018009505, WO20180044329, WO2017066227, WO2017087777, US20170145025, WO2017079669, W02017070089, US2017107216, WO2017222976, US20170262253, WO2017205464, US20170320875, WO2017192961, WO2017112730, US20170174679, WO2017106634, WO2017202744, WO2017202275, WO2017202273, WO2017202274, WO2017202276, WO2017180769, WO2017118762, W02016041511, WO2016039749, WO2016142835, WO2016142852, WO2016142886, WO2016142894, and WO2016142833.

Kits

[0119] Provided herein are also kits that include a compound of the disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and suitable packaging. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein. [0120] Provided herein are also articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.

Pharmaceutical Compositions and Modes of Administration

[0121] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0122] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0123] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0124] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0125] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents.

[0126] The compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. [0127] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0128] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0129] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

Dosing

[0130] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.

[0131] The daily dosage may also be described as a total amount of a compound described herein administered per dose or per day. Daily dosage of a compound of Formula I may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.

[0132] When administered orally, the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day.

[0133] The compounds of the present application or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.

[0134] In a particular embodiment, the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week.

Synthesis of the Compounds

General synthetic methods

[0135] Typical embodiments of compounds described herein may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. In general, compounds described herein are typically stable and isolatable at room temperature and pressure.

[0136] The compounds of Formula (I) and/or (X) are prepared as described in the schemes below. [0137] Scheme 1 shows an embodiment for preparing compounds of Formula (I) and/or Formula (X). Scheme 1

[0138] Starting with compound 1-1, wherein X ¹ and X ² is as defined herein, and R may be H, halo or a triflate group, or any other suitable leaving group, reaction with ethyl 3-chloro-3-oxopropanoate provides compound 1-2 which can be cyclized in the presence of a base and a protic solvent to provide compound 1-3 which can be converted to compounds of Formula (I) and/or Formula (X). Examples of suitable bases for the cyclization include sodium methoxide, sodium ethoxide and the like. Suitable solvents include methanol, ethanol and the like.

[0139] Scheme 2 shows a further embodiment for the preparation of compounds of Formula (I) and/or Formula (X).

Scheme 2

[0140] Starting with compound 2-1, wherein R may be H, halo or a triflate group, or any other suitable leaving group, reaction with dibenzyl malonate provides compound 2-2 which can be converted to compounds of Formula (I) and/or Formula (X).

[0141] Scheme 3 shows an embodiment for the preparation of compounds of Formula (X).

Scheme 3

[0142] Starting with compound 3-1, wherein X ¹ and X ² are as defined herein, and R may be H, halo or a triflate group, or any other suitable leaving group, reaction with diethyl malonate in the presence of a base (e.g., piperidine) provides compound 3-2 which can be cyclized in the presence of a metal (e.g., Fe) and an acid (e.g., acetic acid) to provide compound 3-3 which can be converted to compounds of Formula (X). [0143] Scheme 4 shows an embodiment wherein R ¹ is H or OH, and compounds 1 -3 and/or 2-3 and/or 3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of Formula (I) and/or Formula (X).

Scheme 4

[0144] Starting with compound 1-3, or 2-3, or 3-3, collectively summarized as compound 4-1, wherein X ¹ and X ² are as defined herein and R may be H, halo or a triflate group, or any other suitable leaving group, and R’ is a C ₁ -C ₃ alkyl or benzyl, a reaction of compound 4-1 with compound 4-2 provides compound 4-3. Any suitable base may be used for this reaction (e.g., K ₂ CO ₃ , CS ₂ CO ₃ ). R ² in compound 4-2 is as defined herein and LG may be any suitable leaving group (e.g., halo). The ester in compound 4- 3 is hydrolyzed to provide compound 4-4. Coupling of compound 4-4 with compound 4-5 under any suitable amide coupling conditions (e.g., HATU, EDCI) provides compound 4-6. R ⁴ in compound 4-5 is as defined herein. Compound 4-6 is converted to compound 4-7 using any suitable borylating agent.

Each R” in compound 4-7 is independently H, C ₁ -C ₃ alkyl, or phenyl, or, the two R” together with the atoms to which they are attached, form a dioxaborolane ring. Compound 4-7 is coupled with a suitable compound 4-8 to provide compounds of Formula (I) or Formula (X). In compound 4-8, R ⁶ is as defined herein and LG” is any suitable leaving group (e.g., halo). The coupling reaction between compounds 4- 7 and 4-8 may be mediated by any suitable palladium catalyst or any other similar organometallic coupling method known to one of skill in the art. [0145] Scheme 5 shows an embodiment wherein R ¹ is H or OH, and compounds 1 -3 and/or 2-3 and/or 3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of Formula (I) and/or Formula (X).

Scheme 5

Formula (I) and/or Formula (X)

[0146] Starting with compound 1-3, or 2-3, or 3-3, collectively summarized as compound 4-1, wherein X ¹ and X ² are as defined herein and R may be H, halo or a triflate group, or any other suitable leaving group, and R’ is a C ₁ -C ₃ alkyl or benzyl, a reaction of compound 4-1 with compound 4-2 provides compound 4-3. Any suitable base may be used for this reaction (e.g., K ₂ CO ₃ , CS ₂ CO ₃ ). R ² in compound 4-2 is as defined herein and LG may be any suitable leaving group (e.g., halo). Compound 4-3 is converted to compound 5-1 using any suitable borylating agent. Each R” in compound 5-1 is independently H, C ₁ -C ₃ alkyl, or phenyl, or, the two R” together with the atoms to which they are attached, form a dioxaborolane ring. Compound 5-1 is coupled with a suitable compound 4-8 to provide a compound 5-2. The coupling reaction between compounds 5-1 and 4-8 may be mediated by any suitable palladium catalyst or any other similar organometallic coupling method known to one of skill in the art. In compound 4-8, R ⁶ is as defined herein and LG” is any suitable leaving group (e.g., halo). The ester in compound 5-2 is hydrolyzed to provide compound 5-3. Compound 5-3 is coupled with compound 4-5 under any suitable amide coupling conditions (e.g., HATU, EDO) to provide compounds of Formula (I) and/or Formula (X). [0147] Scheme 6 shows an embodiment wherein R ¹ is H or OH, and compounds 1 -3 and/or 2-3 and/or

3-3 shown above (collectively summarized as compound 4-1) can be converted to compounds of Formula

(I) and/or Formula (X).

Scheme 6

Formula (I) and/or Formula (X)

[0148] Starting with compound 1-3, or 2-3, or 3-3, collectively summarized as compound 4-1, wherein X ¹ and X ² is as defined herein and R may be H, halo or a triflate group, or any other suitable leaving group, and R’ is a C ₁ -C ₃ alkyl or benzyl, reaction with 2-bromo- 1,1 -diethoxyethane provides compound 6-2. Compound 6-2 is coupled with a boronate 6-3 to provide compound 6-4. In compound 6- 3, R ⁶ is as defined herein. In compound 6-3, each R” is independently H, C ₁ -C ₃ alkyl, or phenyl, or, the two R’ ’ together with the atoms to which they are attached, form a dioxaborolane ring. The coupling reaction between compounds 6-2 and 6-3 may be mediated by any suitable palladium catalyst or any other similar organometallic coupling method known to one of skill in the art. Compound 6-4 is converted to an amide 6-5 via a reaction with compound 4-5, wherein R ⁴ is as defined herein. The ketal in compound 6-5 is hydrolyzed under acidic conditions (e.g., HCl) to provide the aldehyde 6-6 which is aminated with compound 6-7 to provide compounds of Formula (I) and/or (X). R ² in compound 6-7 is as defined herein.

[0149] Scheme 7 shows an embodiment for preparation of compounds of Formula (I) and/or (X) wherein R ¹ is alkyl. Scheme 7

Formula (I) and/or Formula (X)

[0150] Starting with compound 7-1, wherein X ¹ and X ² is a defined herein and R may be H, halo or a triflate group, or any other suitable leaving group, conversion to a Weinreb amide provides compound 7- 2. Reaction with a suitable Grignard reagent provides compound 7-3 which is converted to compound 7- 4 by reaction with ethyl 3-chloro-3-oxopropanoate. Compound 7-4 is cyclized in the presence of a base to provide compound 7-5 which can be converted to compounds of Formula (I) and/or (X) using the methods described in Schemes 4-6.

[0151] Scheme 8 shows an embodiment for preparation of compounds of Formula (I) and/or (X) wherein R ¹ is alkoxy.

Scheme 8

Formula (I) and/or Formula (X)

[0152] Compound 8-1, wherein X ¹ and X ² is as defined herein and R may be H, halo or a triflate group, or any other suitable leaving group, and R’ is a C ₁ -C ₃ alkyl or benzyl is reacted with an alkylating agent to provide compound 8-2 wherein R’” is C ₁ -C ₆ alkyl, which can be converted to compounds of Formula (I) and/or (X) using the using the methods described in Schemes 4-6. By way of example, reaction of compound 8-1 with DMSO gives R”’ methyl, reaction of compound 8-1 with propyl iodide gives R’ ’ ’ isopropyl.

[0153] Any combination of steps described above may be used in the preparation of compounds described herein, including any procedures described in the Examples section.

[0154] The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0155] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.

[0156] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[0157] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Suppiementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5 ^th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0158] The compounds described herein may be prepared using the methods disclosed herein and/or by using methods described in PCT/US2021/030838, and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.

EXAMPLES

[0159] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[0160] General methods Preparative HPLC was performed on a Shimadzu LC-20AP. The preparative system was fitted with a Phenomenex Luna C18 150*25111111* 10μm reverse-phase column at 22 degree Celsius. The mobile phase consisted of a mixture of solvent 0.1% TFA in water and MeCN(TFA condition); 0.225% FA in water and MeCN (FA condition). A constant gradient from 100% aqueous/0% organic to 0% aqueous/100% organic mobile phase over the course of 25 minutes was utilized. The flow rate was constant at 25 mL/min.

EXAMPLE 1 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-1-(2-(4-methylpiperazin-1-yl)et hyl)-2- oxo-N-(spiro[2.3]hexan-5-yl)-1,2-dihydro-1,8-naphthyridine-3 -carboxamide (Compound 1)

[0161] Step 1. Preparation of ethyl 6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate

[0162] To a solution of the bromide (2 g, 6.39 mmol, 1 eq) and (4-fluorophenyl)boronic acid (1.07 g, 7.67 mmol, 1.2 eq) in EtOH (20 mL) and H ₂ O (5 mL) was added K ₃ PO ₄ (2.71 g, 12.78 mmol, 2 eq) and Brettphos Pd G ₃ (579.04 mg, 638.77 μmol, 0.1 eq). The mixture was stirred at 80°C for 4 h under N2. The resulting solid was collected by filtration. The filter cake was triturated with MeOH (10 mL) to give ethyl 6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1,2-dihydro-1,8-naphthyridine-3-carboxylate (2 g, crude).

[0163] LCMS (ESI+): m/z 329.1 [M+H] ⁺ , Rt:2.049 min. [0164] Step 2. Preparation of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2- dihydro- 1,8-naphthyridine-3-carboxamide

[0165] To a solution of ethyl 6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3- carboxylate (2 g, 6.09 mmol, 1 eq) and spiro[2.3]hexan-5-amine (976.82 mg, 7.31 mmol, 1.2 eq, HQ) in toluene (1 mL) was added DIEA (1.57 g, 12.18 mmol, 2.12 mL, 2 eq). The mixture was stirred at 100°C for 12 h. The mixture was concentrated. The residue was triturated with MeOH (20 mL) to give 6-(4- fhiorophenyl)-4-hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (2 g, 86.53% yield).

[0166] ¹ H NMR (400 MHz, DMSO) δ = 0.38-0.58 (m, 4H), 2.34-2.43 (m, 4H), 4.52-4.65 (m, 1H), 7.29-7.42 (m, 2H), 7.79-7.93 (m, 2H), 8.42-8.59 (m, 1H), 8.95-9.09 (m, 1H), 10.42-10.61 (m, 1H).

[0167] Step 3. Preparation of 6-(4-fluorophenyl)-4-hydroxy-1-(2-(4-methylpiperazin-1-yl)et hyl)- 2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0168] To a solution of spiro[2.3]hexan-5-yl 6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate (50 mg, 131.79 μmol, 1 eq) in DMF (1 mL) was added CS ₂ CO ₃ (343.52 mg, 1.05 mmol, 8 eq) and 1-(2-chloroethyl)-4-methyl-piperazine (31.49 mg, 158.15 μmol, 1.2 eq, HQ) at 20°C. The mixture was stirred at 50°C for 3 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (0.04%HCl)-ACN]; B%: 30%-60%, 8min) to give Compound 1 (6.3 mg, 11.90 μmol. 9.03% yield, 95.5% purity, HCl).

[0169] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.43 - 0.62 (m, 4 H), 2.25 - 2.55 (m, 4 H), 2.92 (br s, 3 H), 3.43 - 3.65 (m, 4 H), 3.90 - 4.23 (m, 6 H), 4.62 - 4.83 (m, 1 H), 5.00 (br s, 2 H), 7.19 - 7.24 (m, 2 H), 7.62 (br dd, J=8.19, 5.32 Hz, 2 H), 8.64 (s, 1 H), 8.84 (br s, 1 H), 10.11 (br d, J=6.25 Hz, 1 H), 13.80 - 13.93 (m, 1 H). LCMS for product (ESI+): m/z 506.1 (M+H) ⁺ , Rt:2.458 min. EXAMPLE 2 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-(pyridin-4-yl)ethyl) -N- (spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 2)

[0171] To a solution of methyl 5-bromo-2-chloronicotinate (400 mg, 1.60 mmol, 1 eq) in DMSO (5 mL) was added 2-(4-pyridyl) ethanamine (351.17 mg, 2.87 mmol, 347.69 μL, 1.8 eq). The mixture was stirred at 100°C for 10 h. The mixture was poured into water (50 mL), extracted with ethyl acetate (3x30 mL), separated, the organic layer was washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated to give crude product, which was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate=50: 1 , 0:1)) to give methyl 5-bromo-2-((2-(pyridin-4-yl)ethyl)amino)nicotinate (390 mg, 1.16 mmol, 72.64% yield).

[0172] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 2.98 (t, J=7.13 Hz, 2 H), 3.74 - 3.83 (m, 2 H), 3.87 (s, 3 H), 7.23 (d, J=5.88 Hz, 2 H), 8.00 (br d, J=4.25 Hz, 1 H), 8.20 (d, J=2.50 Hz, 1 H), 8.31 (d, J=2.50 Hz, 1 H), 8.54 (d, J=5.75 Hz, 2 H).

[0173] Step 2. Preparation of ethyl 6-bromo-4-hydroxy-2-oxo-1-(2-(pyridin-4-yl)ethyl)- 1,2- dihydro- 1,8-naphthyridine-3-carboxylate

[0174] To a solution of methyl 5-bromo-2-((2-(pyridin-4-yl)ethyl)amino)nicotinate (380 mg, 1.13 mmol, 1 eq) in DCE (5 mL) was added ethyl 3-chloro-3-oxo-propanoate (510.55 mg, 3.39 mmol, 425.46 μL, 3 eq). The mixture was stirred at 85°C for 10 h. The mixture was concentrated to give methyl 5- bromo-2-[(3-ethoxy-3-oxo-propanoyl)-[2-(4-pyridyl) ethyl] amino] pyridine-3-carboxylate (500 mg, crude). To a solution of methyl 5-bromo-2-[(3-ethoxy-3-oxo-propanoyl)-[2-(4-pyridyl) ethyl] amino] pyridine-3-carboxylate (480 mg, 1.07 mmol, 1 eq) in MeOH (5 mL) was added sodium methanolate (384.00 mg, 7.11 mmol, 6.67 eq). The mixture was stirred at 25°C for 12 h. The mixture was concentrated to give crude product, to which was added ethyl acetate (5 mL), the mixture was filtered, and the filter cake was washed with ethyl acetate and dried to give ethyl 6-bromo-4-hydroxy-2-oxo-1-(2- (pyridin-4-yl)ethyl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate (250 mg, 597.74 μmol, 56.07% yield). [0175] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 1.28 - 1.34 (m, 3 H), 2.94 - 3.05 (m, 2 H), 4.27 (q, J=7.13 Hz, 2 H), 4.54 - 4.65 (m, 2 H), 7.32 (d, J=6.00 Hz, 2 H), 8.35 (d, J=6.00 Hz, 2 H), 8.47 (s, 1 H) δ.51 (s, 1 H). [0176] Step 3. ethyl 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-(pyridin-4-yl)ethyl) - 1,2-dihydro- l,8-naphthyridine-3-carboxylate

[0177] To a solution of ethyl 6-bromo-4-hydroxy-2-oxo-1-(2-(pyridin-4-yl)ethyl)- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate (200.00 mg, 478.19 μmol, 1 eq) in dioxane (2 mL) and water (0.2 mL) was added (4-fluorophenyl)boronic acid (80.29 mg, 573.83 μmol. 1.2 eq), K ₂ CO ₃ (198.27 mg, 1.43 mmol, 3 eq), and Pd(dppf)Cl ₂ (34.99 mg, 47.82 μmol, 0.1 eq) under N ₂ . The mixture was stirred at 100°C for 3 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (0.04%HCl)-ACN]; B%: 20%-45%, 8min) to give ethyl 6-(4- fluorophenyl)-4-hydroxy-2-oxo-1-(2-(pyridin-4-yl)ethyl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate (50 mg, 115.36 μmol, 24.12% yield, HCl).

[0178] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 1.50 - 1.54 (m, 3 H), 3.40 (hr s, 2 H), 4.56 (q, J=6.92 Hz, 2 H), 4.85 (br s, 2 H), 7.18 - 7.26 (m, 2 H), 7.56 - 7.66 (m, 2 H), 7.91 (br s, 2 H), 8.51 - 8.75 (m, 3 H), 8.86 (br s, 1 H), 14.43 (s, 1 H).

[0179] Step 4. Preparation of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-(pyridin-4-yl)ethyl) -N- (spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide [0180] To a solution of ethyl 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-(pyridin-4-yl)ethyl) - 1,2- dihydro- 1,8-naphthyridine-3-carboxylate (50 mg, 106.41 μmol. 1 eq, HCl) in toluene (1 mL) was added DIEA (55.01 mg, 425.63 μmol, 74.14 uL, 4 eq) and spiro[2.3]hexan-5-amine (17.06 mg, 127.69 μmol, 1.2 eq, HCl). The mixture was stirred at 120°C for 5 h. The mixture was concentrated to give crude product, which was triturated with methanol (2 mL). The mixture was filtered, and the filter cake was dried to give product. The product was dissolved in MeOH (0.5 mL) and then HCl was added (11.85 mg, 117.05 μmol, 11.62 μL, 36% purity, 1.1 eq), and the mixture was blow-dried and lyophilized to give 6- (4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-(pyridin-4-yl)ethyl)-N -(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8- naphthyridine-3-carboxamide (27.5 mg, 52.05 μmol, 48.91% yield, 98.6% purity, HCl).

[0181] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.47 - 0.53 (m, 2 H), 0.54 - 0.61 (m, 2 H), 2.36 - 2.43 (m, 2 H), 2.44 - 2.51 (m, 2 H), 3.38 (br t, J=7.00 Hz, 2 H), 4.68 - 4.79 (m, 1 H), 4.87 (br t, J=7.00 Hz, 2 H), 7.20 - 7.26 (m, 2 H), 7.63 (dd, J=8.5O, 5.13 Hz, 2 H), 7.86 (br s, 2 H), 8.59 - 8.70 (m, 3 H), 8.86 (d, J=2.13 Hz, 1 H), 10.26 (br d, J=7.38 Hz, 1 H). LCMS for product (ESI+): m/z 485.1 (M+H) ⁺ , Rt:2.588 min.

EXAMPLE 3 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxo-2-(pyridin-3-yl) ethyl)-N- (spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 3)

[0182] Preparation of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxo-2-(pyridin-3-yl) ethyl)-N-

(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0183] To a solution of spiro[2.3]hexan-5-yl 6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate (100 mg, 263.59 μmol, 1 eq) in DMF (1 mL) was added K ₂ CO ₃ (546.46 mg, 3.95 mmol, 15 eq) and 2-chloro-1-(3-pyridyl)ethanone (506.20 mg, 2.64 mmol, 10 eq, HCl) at 20°C. The mixture was stirred at 50°C for 12 h. The mixture was filtered, and the filtrate was purified by prep- HPLC (column: Phenomenex Luna 80*30mm*3 μm; mobile phase: [water (0.04%HCl)-ACN]; B%: 50%-80%, 8min) to give 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxo-2-(pyridin-3-yl) ethyl)-N- (spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (6.5 mg, 11.58 μmol, 4.39% yield, 95.3% purity, HCl).

[0184] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.42 - 0.49 (m, 2 H), 0.51 - 0.56 (m, 2 H), 2.38 (br d, J=7.38 Hz, 2 H), 2.43 (br d, J=7.88 Hz, 2 H), 4.64 - 4.79 (m, 1 H), 5.99 (br s, 2 H), 7.21 (br t, J=8.38 Hz, 2 H), 7.60 (br dd, .1=7.94. 5.19 Hz, 2 H), 7.87 (br s, 1 H), 8.65 (s, 1 H), 8.68 - 8.79 (m, 2 H), 8.89 - 9.10 (m, 1 H), 9.34 - 9.60 (m, 1 H), 10.15 (br d, .1=6.25 Hz, 1 H). LCMS for product (ESI+): m/z 499.1 (M+H) ⁺ , Rt:3.105 min.

EXAMPLE 4 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-(pyrrolidin-1-yl)eth yl)-N- (spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 4)

[0185] Preparation of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-(pyrrolidin-1-yl)eth yl)-N-

(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0186] To a solution of spiro[2.3]hexan-5-yl 6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate (70 mg, 184.51 μmol, 1 eq) in DMF (1 mL) was added CS ₂ CO (480.93 mg, 1.48 mmol, 8 eq) and 1-(2-chloroethyl)pyrrolidine (37.66 mg, 221.41 jimol, 18.90 μL. 1.2 eq, HCl) at 20°C. The mixture was stirred at 50°C for 3 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3μm;mobile phase: [water(0.04%HCl)-ACN];B%: 30%-60%,8min) to give Compound 4 (3.7 mg, 7.21 μmol, 3.91% yield, 100% purity, HCl).

[0187] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.43 - 0.66 (m, 4 H), 2.05 - 2.16 (m, 2 H), 2.25 - 2.35 (m, 2 H), 2.37 - 2.50 (m, 4 H), 2.91 - 3.12 (m, 2 H), 3.33 - 3.54 (m, 2 H), 3.86 - 4.19 (m, 2 H), 4.73 (q, J=7.80 Hz, 1 H), 5.03 (br t, J=7.25 Hz, 2 H), 7.20 - 7.24 (m, 2 H), 7.59 - 7.65 (m, 2 H), 8.62 (d, J=2.25 Hz, 1 H), 8.91 (d, J=2.50 Hz, 1 H), 10.10 - 10.40 (m, 1 H), 12.79 - 13.05 (m, 1 H). LCMS for product (ESI+): m/z 477.1 (M+H) ⁺ , Rt:2.525 min. EXAMPLE 5 Synthesis of 1-(4-fluorobenzyl)-6-(4-fluorophenyl)-4-hydroxy-2-oxo-N- (spiro[2.3]hexan-5-yl)-1,2-dihydro-1,8-naphthyridine-3-carbo xamide (Compound 5) [0188] Preparation of 1-(4-fluorobenzyl)-6-(4-fluorophenyl)-4-hydroxy-2-oxo-N- (spiro[2.3]hexan-5-yl)-1,2-dihydro-1,8-naphthyridine-3-carbo xamide [0189] To a solution of spiro[2.3]hexan-5-yl 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8- naphthyridine-3-carboxylate (50 mg, 131.79 mol, 1 eq) in DMF (1 mL) was added Cs ₂ CO ₃ (343.52 mg, 1.05 mmol, 8 eq) and 1-(chloromethyl)-4-fluoro-benzene (22.86 mg, 158.15 mol, 18.90 L, 1.2 eq) at 20°C, the mixture was stirred at 50°C for 3 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3 m; mobile phase: [water (0.04%HCl)-ACN]; B%: 55%-85%, 8min) to give Compound 5 (16.3 mg, 31.11 mol, 23.60% yield, 100% purity, HCl). [0190] ¹ H NMR (400 MHz, CDCl ₃ )δ= 0.050.4 (m3, 2 H), 0.53 (s, 2 H), 2.43 (dd, J=7.82, 2.31 Hz, 4 H), 4.58 - 4.92 (m, 1 H), 5.72 (s, 2 H), 6.99 (t, J=8.63 Hz, 2 H), 7.21 (t, J=8.63 Hz, 2 H), 7.46 (dd, J=8.44, 5.69 Hz, 2 H), 7.58 - 7.66 (m, 2 H), 8.61 (d, J=2.38 Hz, 1 H), 8.90 (d, J=2.38 Hz, 1 H), 10.42 (br d, J=5.75 Hz, 1 H). LCMS for product (ESI+): m/z 488.1 (M+H) ⁺ , Rt:3.533 min. EXAMPLE 6 Synthesis of 6-(4-fluorophenyl)-4-hydroxy-1-(2-(3-methoxyazetidin-1-yl)et hyl)-2- oxo-N-(spiro[2.3]hexan-5-yl)-1,2-dihydro-1,8-naphthyridine-3 -carboxamide (Compound 6) [0191] Step 1. Preparation of 1-(2,2-diethoxyethyl)-6-(4-fluorophenyl)-4-hydroxy-2-oxo-N-

(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0192] To a solution of spiro[2.3]hexan-5-yl 6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate (1.5 g, 3.95 mmol, 1 eq) in DMF (20 mL) was added CS ₂ CO ₃ (12.88 g, 39.54 mmol, 10 eq) and 2-bromo- 1,1 -diethoxy-ethane (1.56 g, 7.91 mmol, 1.19 mL, 2 eq) at 20°C, and the mixture was stirred at 100°C for 10 h. The mixture was filtered, and the filtrate was purified by prep- HPLC (column: Phenomenex Titank Cl 8 Bulk 250*70mm lOu; mobile phase: [water (lOmM NH ₄ HCO ₃ )-ACN]; B%: 70%-95%, 20min) to give 1-(2,2-diethoxyethyl)-6-(4-fluorophenyl)-4-hydroxy- 2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (450 mg, 908.10 μmol. 22.97% yield).

[0193] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.41 - 0.60 (m, 4 H), 1.11 (t, J=7.00 Hz, 6 H), 2.36 - 2.50 (m, 4 H), 3.53 (dq, J=9.49, 7.01 Hz, 2 H), 3.79 (dq, J=9.51, 7.05 Hz, 2 H), 4.64 - 4.80 (m, 3 H), 5.09 (t, J=5.69 Hz, 1 H), 7.15 - 7.23 (m, 2 H), 7.60 - 7.67 (m, 2 H), 8.60 (d, J=2.50 Hz, 1 H), 8.91 (d, J=2.50 Hz, 1 H), 10.49 (br d, J=7.13 Hz, 1 H).

[0194] Step 2. Preparation of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N- (spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0195] To a solution of 1-(2,2-diethoxyethyl)-6-(4-fluorophenyl)-4-hydroxy-2-oxo-N- (spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (440 mg, 887.92 μmol. 1 eq) in THF (4 mL) was added HCl (4 M, 4.5 mL, 20 eq) at 20°C, and the mixture was stirred at 60°C for 10 h. The mixture was filtered, and the filter cake was dried to give 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2- oxoethyl)-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (340 mg, 742.55 μmol, 83.63% yield, HCl).

[0196] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.42 - 0.48 (m, 2 H), 0.49 - 0.54 (m, 2 H), 2.27 - 2.33 (m, 2 H), 2.37 - 2.43 (m, 2 H), 4.51 - 4.65 (m, 1 H), 5.33 (s, 2 H), 7.36 (t, J=8.88 Hz, 2 H), 7.86 - 7.92 (m, 2 H), 8.63 (d, J=2.50 Hz, 1 H), 9.07 (d, J=2.38 Hz, 1 H), 9.73 (s, 1 H), 10.17 - 10.43 (m, 1 H). [0197] Step 3. Preparation of 6-(4-fluorophenyl)-4-hydroxy-1-(2-(3-methoxyazetidin-1-yl)et hyl)-

2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0198] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 118.65 μmol, 1 eq) and 3 -methoxy azetidine (17.59 mg, 142.38 μmol, 1.2 eq, HCl) in MeOH (1 mL) was added NaOAc (29.20 mg, 355.94 μmol, 3 eq) to make the pH=7, then NaBH ₃ CN was added (22.37 mg, 355.94 μmol, 3 eq), and the mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filter cake was washed with DMF (0.5 mL), water (0.5 mL) and dried to give product, which was dissolved in MeOH (0.5 mL) and HCl was added (13.22 mg, 130.51 μmol, 12.96 μL, 36% purity, 1.1 eq), and the mixture was blow-dried and lyophilized to give Compound 6 (20.7 mg, 37.92 μmol, 31.96% yield, 96.9% purity, HCl).

[0199] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.45 - 0.52 (m, 2 H), 0.53 - 0.60 (m, 2 H), 2.36 - 2.50 (m, 4 H), 3.35 (s, 3 H), 3.48 - 3.62 (m, 2 H), 3.67 - 3.86 (m, 2 H), 4.27 - 4.46 (m, 1 H), 4.59 - 4.81 (m, 3 H), 4.85 (br t, J=6.19 Hz, 2 H), 7.21 (t, J=8.57 Hz, 2 H), 7.62 (dd, J=8.63, 5.25 Hz, 2 H), 8.62 (d, J=2.25 Hz, 1 H), 8.88 (d, J=2.25 Hz, 1 H), 10.19 (br d, J=7.38 Hz, 1 H), 12.83 (br d, J=3.00 Hz, 1 H). LCMS for product (ESI+): m/z 493.1 (M+H) ⁺ , Rt:2.493 min.

Example 7 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-1-(2-(3-hydroxyazetidin-1-yl)et hyl)-2-oxo- N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 7) [0200] Preparation of 6-(4-fluorophenyl)-4-hydroxy-1-(2-(3-hydroxyazetidin-1-yl)et hyl)-2-oxo-N-

(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0201] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 118.65 jimol, 1 eq) and azetidin-3-ol (15.60 mg, 142.38 μmol, 1.2 eq, HCl) in MeOH (1 mL) was added NaOAc (29.20 mg, 355.94 μmol, 3 eq) to make the pH=7, then NaBH ₃ CN was added (22.37 mg, 355.94 μmol, 3 eq), and the mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filter cake was washed with DMF (0.5 mL), water (0.5 mL) and dried to give product, which was dissolved in MeOH (0.5 mL) then HCl was added (13.22 mg, 130.51 μmol, 12.96 μL. 36% purity, 1.1 eq), and the mixture was blow-dried and lyophilized to give Compound 7 (12.5 mg, 25.46 μmol, 19.44% yield, 95% purity, HCl).

[0202] ¹ H NMR (400 MHz, CDCI ₃ δ = 0.46 - 0.52 (m, 2 H), 0.53 - 0.59 (m, 2 H), 2.36 - 2.53 (m, 4 H), 3.46 - 3.65 (m, 2 H), 3.75 - 3.93 (m, 1 H), 4.18 (br d, J=5.38 Hz, 1 H), 4.35 - 4.62 (m, 2 H), 4.64 - 4.77 (m, 2 H), 4.80 (br t, J=5.19 Hz, 2 H), 7.17 - 7.23 (m, 2 H), 7.59 - 7.66 (m, 2 H), 8.61 (dd, J=7.82, 2.06 Hz, 1 H), 8.84 - 8.94 (m, 1 H), 10.12 - 10.23 (m, 1 H), 11.63 - 12.14 (m, 1 H). LCMS for product (ESI+): m/z 479.1 (M+H) ⁺ , Rt:2.422 min.

EXAMPLE 8 - Synthesis of 1-(2-(l,4-oxazepan-4-yl)ethyl)-6-(4-fluorophenyl)-4-hydroxy- 2-oxo-N- (spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 8) [0203] Preparation of 1-(2-(l,4-oxazepan-4-yl)ethyl)-6-(4-fluorophenyl)-4-hydroxy- 2-oxo-N-

(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0204] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 118.65 μmol, 1 eq) and 1 ,4-oxazepane (14.40 mg, 142.38 μmol, 1.2 eq) in MeOH (1 mL) was added NaOAc (29.20 mg, 355.94 μmol, 3 eq) to make the pH=7, then NaBH ₃ CN was added (22.37 mg, 355.94 μmol, 3 eq), and the mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filter cake was washed with DMF (0.5 mL), water (0.5 mL) and dried to give product, which was dissolved in MeOH (0.5 mL) then HCl was added (13.22 mg, 130.51 μmol, 12.96 μL, 36% purity, 1.1 eq), and the mixture was blow-dried and lyophilized to give Compound 8 (25.8 mg, 43.43 μmol, 36.60% yield, 91.4% purity, HCl).

[0205] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.46 - 0.52 (m, 2 H), 0.53 - 0.59 (m, 2 H), 2.05 - 2.24 (m, 1

H), 2.36 - 2.50 (m, 4 H), 2.84 - 3.04 (m, 1 H), 3.18 - 3.35 (m, 1 H), 3.38 - 3.62 (m, 3 H), 3.66 - 4.06 (m, 5 H), 4.25 (br dd, J=14.20, 9.82 Hz, 1 H), 4.66 - 4.84 (m, 1 H), 5.05 (br t, J=6.69 Hz, 2 H), 7.20 - 7.25 (m, 2 H), 7.62 (dd, J=8.69, 5.19 Hz, 2 H), 8.62 (d, J=2.00 Hz, 1 H), 8.88 (d, J=2.13 Hz, 1 H), 10.20 (br d, J=7.25 Hz, 1 H), 13.12 (br d, J=2.63 Hz, 1 H). LCMS for product (ESI+): m/z 507.1 (M+H) ⁺ , Rt:2.465 min.

EXAMPLE 9 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-1-(2-(4-hydroxypiperidin-1-yl)e thyl)-2- oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 9) [0206] Preparation of 6-(4-fluorophenyl)-4-hydroxy-1-(2-(4-hydroxypiperidin-1-yl)e thyl)-2-oxo-

N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0207] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 118.65 μmol, 1 eq) and piperidin-4-ol (14.40 mg, 142.38 μmol, 1.2 eq) in MeOH (1 mL) was added NaOAc (9.73 mg, 118.65 μmol, 1 eq) to make the PH=7, then NaBH ₃ CN was added (22.37 mg, 355.94 μmol, 3 eq), and the mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (HCl)-ACN];B%: 25%-55%,8min) to give Compound 9 (22.5 mg, 41.43 μmol, 34.92% yield, 100% purity, HCl).

[0208] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.45 - 0.52 (m, 2 H), 0.52 - 0.60 (m, 2 H), 1.96 (br d, J=13.88 Hz, 2 H), 2.34 - 2.47 (m, 4 H), 2.53 - 3.08 (m, 2 H), 3.10 - 3.50 (m, 4 H), 3.60 (br d, J=10.26 Hz, 2 H), 4.29 (br s, 1 H), 4.59 - 4.80 (m, 1 H), 4.91 - 5.12 (m, 2 H), 7.21 (t, J=8.5O Hz, 2 H), 7.61 (dd, J=8.38, 5.25 Hz, 2 H), 8.60 (d, J=2.00 Hz, 1 H), 8.88 (s, 1 H), 10.14 - 10.26 (m, 1 H), 12.08 - 12.42 (m, 1 H). LCMS for product (ESI+): m/z 507.1 (M+H) ⁺ , Rt:2.422 min.

EXAMPLE 10 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1-(2- (tetrahydro-2H-pyran-4-yl)ethyl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 10)

[0209] Step 1. Preparation of 4-(2-chloroethyl)tetrahydro-2H-pyran [0210] To a solution of the alcohol (200 mg, 1.54 mmol, 1 eq) in DCE (5 mL) was added SOCk (548.31 mg, 4.61 mmol, 334.34 μL, 3 eq). The mixture was stirred at 85°C for 12 h. The mixture was concentrated to give 4-(2-chloroethyl)tetrahydro-2H-pyran (50 mg, 336.41 μmol, 21.90% yield), which was used into next step directly.

[0211] Step 2. Preparation of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1-(2- (tetrahydro-2H-pyran-4-yl)ethyl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0212] To a solution of spiro[2.3]hexan-5-yl 6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate (50 mg, 131.79 μmol, 1 eq) in DMF (1 mL) was added CS ₂ CO ₃ (343.53 mg, 1.05 mmol, 8 eq) and 4-(2-chloroethyl)tetrahydropyran (31.71 mg, 171.33 μmol, 1.3 eq, HCl) at 20°C. The mixture was stirred at 50°C for 12 h. The mixture was filtered, and the filtrate was purified by prep- HPLC (column: Phenomenex Luna 80*30mm*3|u.m; mobile phase: [water (0.04%HCl)-ACNJ; B%: 50%-80%, 8min) to give 6-(4-fluorophenyl)-4-hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1-(2-(tetrahydro- 2H-pyran-4-yl)ethyl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (4.7 mg, 8.90 μmol, 6.75% yield, 100% purity, HCl).

[0213] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.44 - 0.50 (m, 2 H), 0.52 - 0.59 (m, 2 H), 1.39 - 1.52 (m, 2 H), 1.64 - 1.75 (m, 3 H), 1.79 (br d, J=13.23 Hz, 2 H), 2.43 (dd, 1=7.81, 2.56 Hz, 4 H), 3.43 (td, J=11.71, 1.73 Hz, 2 H), 4.00 (dd, J=11.09, 3.10 Hz, 2 H), 4.52 - 4.60 (m, 2 H), 4.67 - 4.81 (m, 1 H), 7.19 - 7.25 (m, 2 H), 7.60 - 7.65 (m, 2 H), 8.60 (d, J=2.50 Hz, 1 H), 8.90 (d, J=2.50 Hz, 1 H), 10.49 (hr d, J=7.15 Hz, 1 H). LCMS for product (ESI+): m/z 492.1 [M+H] ⁺ , Rt:3.512 min.

EXAMPLE 11 - Synthesis of 1-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-6-(4-fluorophe nyl)-4- hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 11) [0214] Preparation of 1-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-6-(4-fluorophe nyl)-4- hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0215] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 118.65 μmol, 1 eq) and 2-oxa-6- azaspiro[3.3]heptane (14.11 mg, 142.38 μmol, 1.2 eq) in MeOH (1 mL) was added NaOAc (9.73 mg, 118.65 μmol, 1 eq) to make the pH=7, then NaBH ₃ CN was added (22.37 mg, 355.94 μmol, 3 eq), and the mixture was stirred at 20°C for 3 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna Cl 8 75*30mm*3μm; mobile phase: [water (FA)-ACN];B%: 30%- 70%,8min) to give Compound 11 (2.4 mg, 4.27 μmol, 3.60% yield, 98% purity, FA).

[0216] ¹ H NMR (400 MHz, MeOD) δ = 0.45 - 0.51 (m, 2 H), 0.53 - 0.59 (m, 2 H), 2.26 (s, 2 H), 2.40 - 2.51 (m, 2 H), 2.79 - 3.06 (m, 2 H), 3.62 (br d, J=2.63 Hz, 4 H), 4.51 - 4.61 (m, 2 H), 4.61 - 4.69 (m, 1 H), 4.73 (s, 4 H), 7.26 (br t, J=8.69 Hz, 2 H), 7.73 - 7.80 (m, 2 H), 8.57 - 8.71 (m, 1 H), 8.93 - 9.05 (m, 1 H). LCMS for product (ESI+): m/z 505.1 (M+H) ⁺ , Rt:2.438 min.

EXAMPLE 12 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-1-(2-(l-methylpiperidin-4-yl)et hyl)-2- oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 12) [0217] Preparation of 6-(4-fluorophenyl)-4-hydroxy-1-(2-(l-methylpiperidin-4-yl)et hyl)-2-oxo-N-

(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0218] To a solution of spiro[2.3]hexan-5-yl 6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate (50 mg, 131.79 jimol. 1 eq) in DCM (1 mL) was added 2-(l-methyl-4- piperidyl)ethanol (52.10 mg, 289.94 μmol, 2.2 eq, HCl) and PPhg (76.05 mg, 289.94 jimol, 2.2 eq). The mixture was stirred at 20°C for 15 min under N2, a solution of DIAD (58.63 mg, 289.94 jimol, 56.37 J1L. 2.2 eq) in DCM (1 mL) was added into the mixture at 20°C. The mixture was stirred at 20°C for 12 h. The mixture was concentrated to give crude product, which was purified by TLC (ethyl acetate) and prep-HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (HCl)-ACNJ; B%: 25%- 55%, 8min) to give Compound 12 (6.3 mg, 11.38 jimol, 8.63% yield, 97.7% purity, HCl).

[0219] 'HNMR (400 MHz, MeOD) δ = 0.45 - 0.51 (m, 2 H), 0.55 - 0.60 (m, 2 H), 1.43 - 1.60 (m, 2 H), 1.61 - 1.73 (m, 1 H), 1.74 - 1.86 (m, 2 H), 2.21 (br d, J=14.26 Hz, 2 H), 2.30 - 2.37 (m, 2 H), 2.42 - 2.49 (m, 2 H), 2.86 (s, 3 H), 2.93 - 3.06 (m, 2 H), 3.53 (br d, J=12.88 Hz, 2 H), 4.62 (br t, J=7.25 Hz, 2 H), 4.68 (t, J=7.82 Hz, 1 H), 7.28 (t, J=8.76 Hz, 2 H), 7.75 - 7.79 (m, 2 H), 8.68 (d, J=2.25 Hz, 1 H), 9.02 (d, J=2.50 Hz, 1 H). LCMS for product (ESI+): m/z 505.2 (M+H) ⁺ , Rt: 2.607 min.

EXAMPLE 13 - Synthesis of (S)-6-(4-fluorophenyl)-4-hydroxy-1-(2-(2-methylmorpholino)et hyl)-2- oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 13) [0220] Preparation of (S)-6-(4-fluorophenyl)-4-hydroxy-1-(2-(2-methylmorpholino)et hyl)-2-oxo-

N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0221] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 109.20 μmol, 1 eq, HCl) and (2S)-2- methylmorpholine (13.25 mg, 131.04 μmol, 1.2 eq) in MeOH (1 mL) was added NaOAc (8.96 mg, 109.20 μmol, 1 eq) to make the pH=7, then NaBH ₃ CN was added (34.31 mg, 545.99 μmol, 5 eq). The mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filter cake was washed with MeOH (1 mL) and dried to give product. The product was dissolved in MeOH (0.5 mL) then HCl was added (12.17 mg, 120.12 jimol, 11.93 μL, 36% purity, 1.1 eq), and the mixture was blow-dried and lyophilized to give Compound 13 (24.3 mg, 42.20 μmol, 38.64% yield, 94.3% purity, HCl).

[0222] ¹ H NMR (400 MHz, MeOD) δ = 0.45 - 0.52 (m, 2 H), 0.54 - 0.60 (m, 2 H), 1.26 (d, J=6.13 Hz, 3 H), 2.25 - 2.38 (m, 2 H), 2.42 - 2.54 (m, 2 H), 2.66 - 2.99 (m, 1 H), 3.01 - 3.21 (m, 1 H), 3.48 - 3.62 (m, 2 H), 3.66 - 3.86 (m, 4 H), 4.05 - 4.18 (m, 1 H), 4.66 - 4.73 (m, 1 H), 4.92 - 4.97 (m, 2 H), 7.28 (t, J=8.57 Hz, 2 H), 7.78 (br dd, J=8.38, 5.25 Hz, 2 H), 8.72 (s, 1 H), 9.04 (d, J=1.63 Hz, 1 H). LCMS for product (ESI+): m/z 507.1 (M+H) ⁺ , Rt:2.496 min.

EXAMPLE 14 - Synthesis of 1-(2-(4-oxa-7-azaspiro[2.5]octan-7-yl)ethyl)-6-(4-fluorophen yl)-4- hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 14) [0223] Preparation of 1-(2-(4-oxa-7-azaspiro[2.5]octan-7-yl)ethyl)-6-(4-fluorophen yl)-4-hydroxy-

2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0224] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 109.20 μmol, 1 eq, HCl) and 4-oxa-7- azaspiro[2.5]octane (19.61 mg, 131.04 μmol, 1.2 eq, HCl) in MeOH (1 mL) was added NaOAc (44.79 mg, 545.99 μmol, 5 eq) to make the pH=7, then NaBH ₃ CN was added (34.31 mg, 545.99 μmol, 5 eq), and the mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filter cake was washed with MeOH (1 mL) and dried to give product, which was dissolved in MeOH (0.5 mL), then HO was added (12.17 mg, 120.12 μmol, 11.93 μL, 36% purity, 1.1 eq), and the mixture was blow-dried and lyophilized to give Compound 14 (21.6 mg, 35.88 μmol, 32.86% yield, 92.2% purity, HCl).

[0225] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.46 - 0.53 (m, 2 H), 0.53 - 0.61 (m, 2 H), 0.72 - 1.25 (m, 4 H), 2.23 - 2.38 (m, 2 H), 2.42 - 2.56 (m, 2 H), 3.35 - 3.54 (m, 2 H), 3.60 - 3.80 (m, 4 H), 3.83 - 4.06 (m, 2 H), 4.66 - 4.75 (m, 1 H), 4.93 (br s, 2 H), 7.29 (t, .1=8.50 Hz, 2 H), 7.78 (br dd, J=8.19, 5.19 Hz, 2 H), 8.74 (s, 1 H), 9.04 (d, J=1.50 Hz, 1 H). LCMS for product (ESI+): m/z 519.1 (M+H) ⁺ , Rt:2.514 min.

EXAMPLE 15 - Synthesis of 1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-6-(4-fluor ophenyl)- 4-hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 15) [0226] Preparation of 1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-6-(4-fhior ophenyl)-4- hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0227] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 109.20 μmol, 1 eq, HCl) and 2-oxa-5- azabicyclo[2.2.1]heptane (17.77 mg, 131.04 μmol, 1.2 eq, HCl) in MeOH (1 mL) was added NaOAc (44.79 mg, 545.99 μmol, 5 eq) to make the pH=7, then NaBPLCN was added (34.31 mg, 545.99 μmol, 5 eq), and the mixture was stirred at 20°C for 2 h. The mixture was filtered and the filter cake was washed with MeOH (1 mL) and dried to give product, which was dissolved in MeOH (0.5 mL) then HCl was (12.17 mg, 120.12 μmol, 11.93 μL, 36% purity, 1.1 eq), and the mixture was blow-dried and lyophilized to give Compound 15 (18.7 mg, 31.73 μmol, 29.06% yield, 91.8% purity, HCl).

[0228] 1H NMR (400 MHz, MeOD) 0.45 - 0.52 (m, 2 H), 0.54 - 0.61 (m, 2 H), 2.16 - 2.53 (m, 6 H), 3.50 - 3.68 (m, 1 H), 3.74 - 3.87 (m, 2 H), 3.87 - 4.03 (m, 2 H), 4.64 - 4.75 (m, 2 H), 4.80 (br s, 2 H), 4.91 - 4.95 (m, 2 H), 7.29 (t, J=8.57 Hz, 2 H), 7.78 (dd, J=8.00, 5.38 Hz, 2 H), 8.73 (br s, 1 H), 9.05 (s, 1 H). LCMS for product (ESI+): m/z 505.1 (M+H) ⁺ , Rt:2.442 min.

EXAMPLE 16 - Synthesis of (R)-6-(4-fluorophenyl)-4-hydroxy-1-(2-(2-methylmorpholino)et hyl)-2- oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 16) [0229] Preparation of (R)-6-(4-fluorophenyl)-4-hydroxy-1-(2-(2-methylmorpholino)et hyl)-2-oxo-

N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0230] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 109.20 μmol, 1 eq, HCl) and (2R)-2- methylmorpholine (13.25 mg, 131.04 μmol, 1.2 eq) in MeOH (1 mL) was added NaOAc (8.96 mg, 109.20 μmol, 1 eq) to make the pH=7, then NaBH ₃ CN was added (34.31 mg, 545.99 μmol, 5 eq), and the mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filter cake was purified by prep- HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (HCl)-ACN]; B%: 30%-50%, 8min) to give Compound 16 (28.5 mg, 52.48 μmol, 48.06% yield, 100% purity, HCl).

[0231] ¹ H NMR (400 MHz, MeOD) δ = 0.45 - 0.52 (m, 2 H), 0.53 - 0.62 (m, 2 H), 1.28 (d, J=6.25 Hz, 3 H), 2.27 - 2.38 (m, 2 H), 2.42 - 2.52 (m, 2 H), 2.79 - 3.00 (m, 1 H), 3.07 - 3.22 (m, 1 H), 3.63 (br s, 2 H), 3.73 - 3.91 (m, 4 H), 4.08 - 4.21 (m, 1 H), 4.66 - 4.74 (m, 1 H), 4.93 - 4.98 (m, 2 H), 7.29 (t, J=8.69 Hz, 2 H), 7.75 - 7.81 (m, 2 H), 8.74 (d, J=2.38 Hz, 1 H), 9.05 (d, J=2.50 Hz, 1 H). LCMS for product (ESI+): m/z 507.1 (M+H) ⁺ , Rt:2.499 min.

EXAMPLE 17 - Synthesis of (R)-6-(4-fluorophenyl)-4-hydroxy-1-(2-(3-methylmorpholino)et hyl)-2- oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 17) [0232] Preparation of (R)-6-(4-fluorophenyl)-4-hydroxy-1-(2-(3-methylmorpholino)et hyl)-2-oxo-

N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0233] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 109.20 μmol, 1 eq, HCl) and (3R)-3- methylmorpholine (13.25 mg, 131.04 μmol, 1.2 eq) in MeOH (1 mL) was added NaOAc (8.96 mg, 109.20 μmol, 1 eq) to make the pH=7, then NaBH ₃ CN was added (34.31 mg, 545.99 μmol, 5 eq), and the mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filter cake was purified by prep- HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (HCl)-ACN]; B%: 35%-75%, 8min) to give Compound 17 (20.1 mg, 37.01 μmol, 33.90% yield, 100% purity, HCl).

[0234] ¹ HNMR (400 MHz, MeOD) δ = 0.43 - 0.51 (m, 2 H), 0.53 - 0.62 (m, 2 H), 1.26 - 1.58 (m, 3 H), 2.29 - 2.37 (m, 2 H), 2.40 - 2.50 (m, 2 H), 3.43 - 3.63 (m, 4 H), 3.79 - 4.16 (m, 5 H), 4.68 - 4.71 (m, 1 H), 4.94 - 5.11 (m, 2 H), 7.24 - 7.31 (m, 2 H), 7.74 - 7.81 (m, 2 H), 8.70 - 8.75 (m, 1 H), 9.05 (d, J=2.38 Hz, 1 H). LCMS for product (ESI+): m/z 507.1 (M+H) ⁺ , Rt:2.491 min min.

EXAMPLE 18 - Synthesis of (S)-6-(4-fluorophenyl)-4-hydroxy-1-(2-(3-methylmorpholino)et hyl)-2- oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 18)

[0235] Preparation of (S)-6-(4-fluorophenyl)-4-hydroxy-1-(2-(3-methylmorpholino)et hyl)-2-oxo-

N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide [0236] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 109.20 μmol, 1 eq, HCl) and (3S)-3- methylmorpholine (13.25 mg, 131.04 μmol, 1.2 eq) in MeOH (1 mL) was added NaOAc (8.96 mg, 109.20 μmol, 1 eq) to make the pH=7, then NaBH ₃ CN was added (34.31 mg, 545.99 μmol, 5 eq). The mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filter cake was purified by prep- HPLC (column: Phenomenex Luna 80*30mm*3jim; mobile phase: [water (HCl)-ACN]; B%: 35%-75%, 8min) to give Compound 18 (20.4 mg, 37.57 μmol. 34.40% yield, 100% purity, HCl).

[0237] ¹ H NMR (400 MHz, MeOD) δ = 0.45 - 0.52 (m, 2 H), 0.54 - 0.60 (m, 2 H), 1.40 (br s, 3 H), 2.28 - 2.37 (m, 2 H), 2.42 - 2.50 (m, 2 H), 3.42 - 3.65 (m, 4 H), 3.79 - 4.22 (m, 5 H), 4.70 (t, J=7.69 Hz, 1 H), 4.92 - 5.00 (m, 2 H), 7.29 (t, J=8.69 Hz, 2 H), 7.75 - 7.82 (m, 2 H), 8.73 (d, J=2.38 Hz, 1 H), 9.06 (d, J=2.38 Hz, 1 H). LCMS for product (ESI+): m/z 507.1 (M+H) ⁺ , Rt:2.492 min.

EXAMPLE 19 - Synthesis of 1-(2-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)ethyl)-6-(4-fluoro phenyl)-4- hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 19)

[0238] Preparation of 1-(2-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)ethyl)-6-(4-fluoro phenyl)-4- hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0239] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 109.20 μmol, 1 eq, HCl) and 2-oxa-5- azabicyclo[2.2.2]octane (26.63 mg, 131.04 μmol. 1.2 eq, oxalic acid) in MeOH (1 mL) was added NaOAc (44.79 mg, 545.99 μmol, 5 eq) to make the pH=7, then NaBHgCN was added (34.31 mg, 545.99 μmol, 5 eq), and the mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filter cake was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3jim; mobile phase: [water (HCl)- ACN]; B%: 20%-60%, 8min) to give Compound 19 (27.4 mg, 49.37 μmol, 45.21% yield, 100% purity, HCl).

[0240] 'HNMR (400 MHz, MeOD) δ = 0.44 - 0.52 (m, 2 H), 0.53 - 0.61 (m, 2 H), 1.73 - 1.97 (m, 1

H), 1.99 - 2.28 (m, 3 H), 2.30 - 2.38 (m, 2 H), 2.43 - 2.52 (m, 2 H), 3.55 - 3.94 (m, 4 H), 3.99 - 4.31 (m, 4 H), 4.66 - 4.72 (m, 1 H), 4.95 (br s, 2 H), 7.29 (br t, J=8.69 Hz, 2 H), 7.78 (br dd, J=8.5O, 5.25 Hz, 2 H), 8.74 (s, 1 H), 9.05 (br s, 1 H). LCMS for product (ESI+): m/z 519.1 (M+H) ⁺ , Rt:2.479 min.

EXAMPLE 20 - Synthesis of 1-(2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)-6-(4-fluorophen yl)-4- hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 20)

[0241] Preparation of 1-(2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)-6-(4-fluorophen yl)-4-hydroxy-

2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0242] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 109.20 μmol, 1 eq, HCl), 7-oxa-4- azaspiro[2.5]octane (19.61 mg, 131.04 μmol, 1.2 eq, HCl) in MeOH (1 mL) was added NaOAc (44.79 mg, 545.99 μmol, 5 eq) to make the pH=7, then NaBH ₃ CN was added (34.31 mg, 545.99 μmol, 5 eq), and the mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Waters Xbridge BEH Cl 8 100*30mm*10pm;mobile phase: [water( NH ₄ HCO ₃ )- ACN];B%: 50%-80%,8min) to give product, which was dissolved in MeOH(0.5 mL) then HCl was added (12.17 mg, 120.12 μmol, 11.93 μL, 36% purity, 1.1 eq), and the mixture was blow-dried and lyophilized to give Compound 20 (2.3 mg, 4.14 μmol, 3.79% yield, 100% purity, HCl).

[0243] ¹ H NMR (400 MHz, MeOD) δ = 0.44 - 0.52 (m, 2 H), 0.54 - 0.61 (m, 2 H), 0.86 - 1.01 (m, 4 H), 1.26 - 1.38 (m, 2 H), 2.27 - 2.39 (m, 2 H), 2.41 - 2.55 (m, 2 H), 3.45 - 3.50 (m, 2 H), 3.52 - 3.73 (m, 4 H), 3.82 - 4.09 (m, 2 H), 4.65 - 4.71 (m, 1 H), 5.19 - 5.30 (m, 2 H), 7.23 - 7.33 (m, 2 H), 7.78 (dd, J=8.5O, 5.25 Hz, 2 H), 8.66 - 8.75 (m, 1 H), 9.04 (d, J=2.13 Hz, 1 H). LCMS for product (ESI+): m/z 519.2 (M+H) ⁺ , Rt:2.579 min.

EXAMPLE 21 - Synthesis of 1-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)ethyl)-6-(4-fluor ophenyl)-

4-hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 21)

[0244] Preparation of 1-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)ethyl)-6-(4-fluor ophenyl)-4- hydroxy-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0245] To a solution of 6-(4-fluorophenyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2 .3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (50 mg, 109.20 μmol, 1 eq, HCl) and 3-oxa-6- azabicyclo[3.1.1]heptane (17.77 mg, 131.04 μmol, 1.2 eq, HCl) in MeOH (1 mL) was added NaOAc (44.79 mg, 545.99 μmol, 5 eq) to make the pH=7, then NaBPLCN was added (34.31 mg, 545.99 μmol, 5 eq), and the mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filter cake was purified by prep-HPLC (column: Phenomenex Luna Cl 8 150*30mm*5um; mobile phase: [water (FA)- ACN]; B%: 30%-70%, 8min) to give Compound 21 (6.5 mg, 12.01 μmol, 11.00% yield, 100% purity, HCl).

[0246] ¹ H NMR (400 MHz, MeOD) δ = 0.43 - 0.51 (m, 2 H), 0.52 - 0.61 (m, 2 H), 1.94 (br d, J=9.01 Hz, 1 H), 2.24 - 2.35 (m, 2 H), 2.38 - 2.47 (m, 2 H), 2.60 - 2.81 (m, 1 H), 3.13 (br s, 2 H), 3.72 (br d, J=4.25 Hz, 2 H), 3.81 (br d, J=11.01 Hz, 2 H), 4.40 (br d, J=11.13 Hz, 2 H), 4.60 (br d, J=6.38 Hz, 2 H), 4.66 (br d, J=7.63 Hz, 1 H), 7.25 (br t, J=8.5O Hz, 2 H), 7.75 (br dd, J=7.88, 5.13 Hz, 2 H), 8.62 (s, 1 H), 8.97 (s, 1 H). LCMS for product (ESI+): m/z 505.0 (M+H) ⁺ , Rt:2.530 min. EXAMPLE 22 - Synthesis of 1-((l,3-dioxan-2-yl)methyl)-6-(4-fluorophenyl)-4-hydroxy-2-o xo-N- (spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 22)

[0247] Step 1. Preparation of ethyl 1-((l,3-dioxan-2-yl)methyl)-6-(4-fluorophenyl)-4-hydroxy-2- oxo- 1 ,2-dihydro- 1 ,8-naphthyridine-3-carboxylate

[0248] To a solution of the diethyl acetal (100 mg, 225.00 μmol, 694.44 μL, 1 eq) in propane-1, 3-diol (1.05 g, 13.80 mmol, 1.00 mL, 61.33 eq) was added 4-methylbenzenesulfonic acid (100.74 mg, 584.99 μmol, 2.6 eq). The mixture was stirred at 20°C for 10 h. The mixture was triturated with water (6 mL) and the mixture was filtered, and the filtrate cake was dried to give ethyl 1-((l,3-dioxan-2-yl)methyl)-6- (4-fluorophenyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate (70 mg, 163.40 μmol, 72.62% yield).

[0249] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 1.28 - 1.36 (m, 1 H), 1.51 (t, J=7.13 Hz, 3 H), 2.19 (dt, J=13.20, 5.03 Hz, 1 H), 3.74 (td, J=12.16, 2.31 Hz, 2 H), 4.10 (dd, J=10.88, 5.00 Hz, 2 H), 4.53 (q, J=7.13 Hz, 2 H), 4.74 (d, J=5.38 Hz, 2 H), 5.12 (t, J=5.32 Hz, 1 H), 7.18 - 7.24 (m, 2 H), 7.58 - 7.64 (m, 2 H), 8.55 (d, J=2.50 Hz, 1 H), 8.94 (d, J=2.50 Hz, 1 H)..

[0250] Step 2. Preparation of 1-((l,3-dioxan-2-yl)methyl)-6-(4-fluorophenyl)-4-hydroxy-2-o xo-N- (spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0251] To a solution of ethyl 1-((l,3-dioxan-2-yl)methyl)-6-(4-fluorophenyl)-4-hydroxy-2-o xo- 1,2- dihydro- 1,8-naphthyridine-3-carboxylate (50 mg, 107.56 μmol, 1 eq, HCl) in toluene (1 mL) was added DIEA (55.60 mg, 430.23 μmol, 74.94 μL, 4 eq) and spiro[2.3]hexan-5-amine (17.25 mg, 129.07 μmol, 1.2 eq, HCl). The mixture was stirred at 120°C for 2 h. The mixture was concentrated to give crude product, which was triturated with DMF (2 mL), and the mixture was filtered, the filter cake was washed with H ₂ O (1 mL) and dried to give Compound 22 (23.7 mg, 49.43 μmol, 45.95% yield, 100% purity). [0252] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.42 - 0.50 (m, 2 H), 0.51 - 0.60 (m, 2 H), 1.34 (br d, J= 13.57 Hz, 1 H), 2.23 (tdd, J=12.85, 12.85, 7.55, 5.14 Hz, 1 H), 2.42 (d, J=7.83 Hz, 4 H), 3.75 (td, J=12.20, 2.26 Hz, 2 H), 4.14 (dd, J=11.07, 4.83 Hz, 2 H), 4.69 - 4.78 (m, 3 H), 5.09 (t, J-5.20 Hz, 1 H), 7.17 - 7.24 (m, 2 H), 7.60 - 7.65 (m, 2 H), 8.60 (d, .1=2.45 Hz, 1 H), 8.93 (d, 1=2.57 Hz, 1 H), 10.46 (br d, J=7.46 Hz, 1 H). LCMS for product (ESI+): m/z 478.2 (M-H)', Rt:2.821 min.

EXAMPLE 23 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-1-((4-methyl- 1,3-dioxan-2-yl)methyl)-2- oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 23)

[0253] Step 1. Preparation of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-((4-methyl- 1,3-dioxan-2- yl)methyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate

[0254] To a solution of the diethyl acetal (100 mg, 225.00 μmol, 694.44 μL, 1 eq) in butane-1, 3-diol (1.24 g, 13.80 mmol, 1 mL, 61.33 eq) was added 4-methylbenzenesulfonic acid (100.74 mg, 584.99 μmol, 2.6 eq). The mixture was stirred at 20°C for 10 h. The mixture was triturated with water (6 mL) and the mixture was filtered, and the filtrate cake was dried to give the desired product (70 mg, 158.21 μmol, 70.32% yield).

[0255] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 1.22 (d, J=6.25 Hz, 3 H), 1.48 - 1.53 (m, 3 H), 1.71 - 1.82 (m, 1 H), 3.64 (td, J=12.01, 2.50 Hz, 1 H), 3.75 - 3.86 (m, 1 H), 4.00 - 4.09 (m, 1 H), 4.50 - 4.60 (m, 3 H), 4.98 (dd, J=13.20, 6.69 Hz, 1 H), 5.12 (dd, J=6.82, 3.94 Hz, 1 H), 7.19 - 7.24 (m, 2 H), 7.59 - 7.63 (m, 2 H), 8.55 (d, J=2.50 Hz, 1 H), 8.94 (d, J=2.50 Hz, 1 H). [0256] Step 2. Preparation of 6-(4-fluorophenyl)-4-hydroxy-1-((4-methyl- 1,3-dioxan-2- yl)methyl)-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0257] To a solution of ethyl 6-(4-fluorophenyl)-44iydroxy-1-((4-methyl- 1,3-dioxan-2-yl)niethyl)-2- oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate (50 mg, 104.41 μmol, 1 eq, HCl) in toluene (1 mL) was added DIEA (53.97 mg, 417.63 μmol, 72.74 μL, 4 eq) and spiro[2.3]hexan-5-amine (16.74 mg, 125.29 μmol, 1.2 eq, HCl). The mixture was stirred at 120°C for 2 h. The mixture was concentrated to give crude product, which was triturated with methanol (2 mL) and the mixture was filtered, and the filter cake was concentrated to give Compound 23 (32.2 mg, 64.07 μmol, 61.37% yield, 98.2% purity).

[0258] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.43 - 0.49 (m, 2 H), 0.51 - 0.60 (m, 2 H), 1.26 (d, J=6.13 Hz, 3 H), 1.42 (br d, J=13.01 Hz, 1 H), 1.80 (br dd, J=12.19, 4.31 Hz, 1 H), 2.42 (d, J=7.75 Hz, 4 H), 3.57 - 3.72 (m, 1 H), 3.76 - 3.90 (m, 1 H), 4.08 (dd, J=11.57, 4.57 Hz, 1 H), 4.55 (dd, J=13.32, 3.81 Hz, 1 H), 4.68 - 4.79 (m, 1 H), 4.96 (dd, J=13.32, 6.69 Hz, 1 H), 5.09 (dd, J=6.69, 3.81 Hz, 1 H), 7.21 (t, J=8.57 Hz, 2 H), 7.63 (dd, J=8.50, 5.25 Hz, 2 H), 8.60 (d, J=2.38 Hz, 1 H), 8.93 (d, J=2.38 Hz, 1 H), 10.47 (br d, J=7.13 Hz, 1 H). LCMS for product (ESI+): m/z 492.3 (M-H)’, Rt:3.049 min.

EXAMPLE 24 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-1-((5-methyl- 1,3-dioxan-2-yl)methyl)-2- oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 24)

[0259] Step 1. Preparation of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-((5-methyl- 1,3-dioxan-2- yl)methyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate [0260] To a solution of the diethyl acetal (100 mg, 225.00 μmol, 694.44 μL, 1 eq) in 2-methylpropane- 1, 3-diol (1.24 g, 13.80 mmol, 1.0 mL, 61.33 eq) was added 4-methylbenzenesulfonic acid (100.74 mg, 584.99 μmol, 2.6 eq). The mixture was stirred at 20°C for 10 h. The mixture was triturated with water (6 mL) and the mixture was filtered, and the filtrate cake was dried to give the desired product (70 mg, 158.21 μmol, 70.32% yield).

[0261] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.67 (d, J=6.75 Hz, 2 H), 1.31 (d, J=7.00 Hz, 1 H), 1.47 - 1.53 (m, 3 H), 2.18 (br dd, J=11.07, 4.57 Hz, 1 H), 3.26 (t, J=11.19 Hz, 1 H), 3.74 - 4.07 (m, 3 H), 4.53 (q, J=7.09 Hz, 2 H), 4.76 (br d, J=5.25 Hz, 2 H), 4.98 - 5.13 (m, 1 H), 7.21 (br t, J=8.44 Hz, 2 H), 7.61 (td, J=5.75, 2.13 Hz, 2 H), 8.55 (d, J=2.38 Hz, 1 H), 8.89 - 8.96 (m, 1 H).

[0262] Step 2. Preparation of 6-(4-fluorophenyl)-4-hydroxy-1-((5-methyl- 1,3-dioxan-2- yl)methyl)-2-oxo-N-(spiro[2.3]hexan-5-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0263] To a solution of ethyl 6-(4-fluorophenyl)-44iydroxy-1-((5-methyl- 1,3-dioxan-2-yl)methyl)-2- oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate (50.00 mg, 104.41 μmol, 1 eq, HCl) in toluene (1 mL) was added DIEA (53.97 mg, 417.63 μmol, 72.74 μL, 4 eq) and spiro[2.3]hexan-5-amine (16.74 mg, 125.29 μmol, 1.2 eq, HCl). The mixture was stirred at 120°C for 2 h. The mixture was concentrated to give crude product, which was triturated with methanol (2 mL). The mixture was filtered, and the filter cake concentrated to give Compound 24 (34.3 mg, 67.76 μmol, 64.90% yield, 97.5% purity).

[0264] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.42 - 0.49 (m, 2 H), 0.50 - 0.57 (m, 2 H), 0.68 (d, J=6.72 Hz, 2 H), 1.34 (d, J=7.09 Hz, 1 H), 2.02 - 2.31 (m, 1 H), 2.42 (d, J=7.83 Hz, 4 H), 3.19 - 3.86 (m, 2 H), 3.88 - 4.11 (m, 2 H), 4.68 - 4.80 (m, 3 H), 4.97 - 5.10 (m, 1 H), 7.21 (t, J=8.56 Hz, 2 H), 7.61 - 7.66 (m, 2 H), 8.58 - 8.62 (m, 1 H), 8.93 (d, J=2.45 Hz, 1 H), 10.46 (br d, J=6.85 Hz, 1 H). LCMS for product (ESI+): m/z 492.3 (M-H)-, Rt:3.056 min.

EXAMPLE 25 - Synthesis of 6-(4-fluorophenyl)-1-(2-(4-fluoropiperidin-1-yl)ethyl)-4-hyd roxy-N- (1-(hydroxymethyl)cyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 25)

[0265] Step 1. Preparation of 1-(2,2-diethoxyethyl)-6-(4-fhiorophenyl)-4-hydroxy-N-(l-

(hydroxymethyl)cyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0266] To a solution of the diethyl acetal (300 mg, 674.99 μmol, 1 eq) in toluene (3 mL) was added DIEA (174.47 mg, 1.35 mmol, 235.14 μL, 2 eq) and (l-aminocyclohexyl)methanol (134.18 mg, 809.99 (j. mol, 11.98 μL, 1.2 eq, HCl). The mixture was stirred at 110°C for 10 h. The mixture was concentrated to give crude product, which was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate=50:l to 1:1) to give the desired product (60 mg, 113.73 μmol, 16.85% yield).

[0267] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 1.11 (t, J=7.03 Hz, 6 H), 1.38 - 1.45 (m, 2 H), 1.62 - 1.73 (m, 6 H), 2.09 - 2.17 (m, 2 H), 3.52 - 3.58 (m, 2 H), 3.75 - 3.82 (m, 4 H), 4.31 (br d, J=5.38 Hz, 1 H), 4.76 (d, J=5.75 Hz, 2 H), 5.09 (t, J=5.81 Hz, 1 H), 7.21 - 7.24 (m, 2 H), 7.62 - 7.65 (m, 2 H), 8.59 (d, J=2.44 Hz, 1 H), 8.92 (d, J=2.44 Hz, 1 H).

[0268] Step 2. Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-(1-(hydroxymethyl)cyclohexyl) -2- oxo-1-(2-oxoethyl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide [0269] To a solution of 1-(2,2-diethoxyethyl)-6-(4-fluorophenyl)-4-hydroxy-N-(l- (hydroxymethyl)cyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (5 mg, 9.48 μmol, 1 eq) in THF (0.1 mL) was added hydrochloric acid (2 M, 0.1 mL, 20 eq) at 20°C. The mixture was stirred at 20°C for 1 h. The mixture was concentrated to give the desired product (4 mg, 8.82 μmol, 93.08% yield).

[0270] LCMS for product (ESI+): m/z 452.2 (M-H) , Rt: 0.859 min.

[0271] Step 3. Preparation of 6-(4-fluorophenyl)-1-(2-(4-fluoropiperidin-1-yl)ethyl)-4-hyd roxy-N- (1-(hydroxymethyl)cyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0272] To a solution of 6-(4-fluorophenyl)-4-hydroxy-N-(1-(hydroxymethyl)cyclohexyl) -2-oxo-1-(2- oxoethyl)-!, 2-dihydro- 1,8-naphthyridine-3-carboxamide (4 mg, 8.16 μmol. 1 eq, HCl) and 4- fluoropiperidine (1.37 mg, 9.80 jimol, 1.2 eq, HCl) in MeOH (1 mL) was added NaOAc (6.70 mg, 81.65 μmol, 10 eq) to make the pH=7, then NaBI OCX was added (5.13 mg, 81.65 μmol, 10 eq). The mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (HCl)-ACN]; B%: 25%-70%, 8min) to give Compound 25 (1.1 mg, 1.91 μmol, 23.35% yield, 100% purity, HCl).

[0273] ¹ H NMR (400 MHz, CDCI ₃ ) δ 1.26 - 1.43 (m, 3 H), 1.46 - 1.51 (m, 3 H), 1.63 - 1.73 (m, 4 H), 2.10 - 2.29 (m, 4 H), 3.14 - 3.30 (m, 2 H), 3.33 - 3.50 (m, 2 H), 3.72 - 3.84 (m, 4 H), 4.89 - 5.11 (m, 3 H), 7.22 (t, J=8.38 Hz, 2 H), 7.58 - 7.66 (m, 2 H), 8.64 (s, 1 H), 8.88 (d, J=0.98 Hz, 1 H), 10.29 (br d, J=2.45 Hz, 1 H). LCMS for product (ESI+): m/z 541.1 (M+H) ⁺ , Rt:2.489 min.

EXAMPLE 26 - Synthesis of N-(bicyclo[l.l.l]pentan-1-yl)-2-(6-(4-fluorophenyl)-4-hydrox y-1-(2- morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridin-3-yl)acetamide (Compound 26) [0274] Step 1. Preparation of methyl 5-bromo-2-(4-methoxy-4-oxobutanamido)nicotinate

[0275] To a solution of the pyridyl amine (5 g, 21.64 mmol, 1 eq) in dioxane (60 mL) was added TEA (2.19 g, 21.64 mmol, 3.01 mL, 1 eq). The mixture was stirred at 0°C for 15 min. Then ethyl 4-chloro-4- oxo-butanoate (3.92 g, 23.80 mmol, 3.38 mL, 1.1 eq) was added into the mixture at 0°C. The mixture was stirred at 20°C for 10 h. The mixtures was poured into water (200 mL) and extracted with ethyl acetate (3x50 mL), separated, the organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give crude product which was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate=50:l to 1:1) to give the desired product (2 g, 5.57 mmol, 25.73% yield).

[0276] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 1.28 (d, J=1.88 Hz, 3 H), 2.74 - 2.81 (m, 2 H), 2.99 (t, J=6.75 Hz, 2 H), 3.97 (s, 3 H), 4.15 - 4.21 (m, 3 H), 8.42 (d, J=2.50 Hz, 1 H), 8.60 (d, J=2.50 Hz, 1 H), 10.73 (br s, 1 H).

[0277] Step 2. Preparation of ethyl 3-bromo-5,8-dioxo-6,7,8,9-tetrahydro-5H-pyrido[2,3- b]azepine-6-carboxylate

[0278] To a solution of methyl 5-bromo-2-(4-methoxy-4-oxobutanamido)nicotinate (2 g, 5.57 mmol, 1 eq) in THF (20 mL) was added potassium 2-methylpropan-2-olate (1 M, 16.71 mL, 3 eq). The mixture was stirred at 70°C for 1 h. The mixture was concentrated to give the desired product (1.5 g, 4.59 mmol, 82.35% yield).

[0279] LCMS for product (ESI+): m/z 326.9, 328.9 (M+H) ⁺ , Rt: 1.878 min.

[0280] Step 3. Preparation of 2-(6-bromo-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridin-3- yl)acetic acid

[0281] A solution of ethyl 3-bromo-5,8-dioxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine -6- carboxylate (1.5 g, 4.59 mmol, 1 eq) in KOH aqueous solution (2.57 g, 4.59 mmol, 15 mL, 10% purity) was stirred at 100°C for 2 h. The mixture was acidified by adding 2 N hydrochloric acid dropwise to pH = 2 at 0°C, the mixture was filtered, and the filter cake was washed with water and dried to give the desired product (800 mg, 2.67 mmol, 58.34% yield).

[0282] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 3.48 - 3.52 (m, 2 H), 8.42 (d, J=2.13 Hz, 1 H), 8.55 (d, J=2.26 Hz, 1 H), 11.80 (br s, 1 H). [0283] Step 4. Preparation of N-(bicyclo[l.l.l]pentan-1-yl)-2-(6-bromo-4-hydroxy-2-oxo- 1,2- dihydro- 1,8-naphthyridin-3-yl)acetamide

[0284] To a solution of 2-(6-bromo-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridin-3-yl)acetic acid (400 mg, 1.34 mmol, 1 eq) in DMF (4 mL) was added HATU (610.24 mg, 1.60 mmol, 1.2 eq), bicyclofl. l.l]pentan-1-amine (175.94 mg, 1.47 mmol, 1.1 eq, HCl) and TEA (406.00 mg, 4.01 mmol, 558.47 μL, 3 eq). The mixture was stirred at 20°C for 2 h. The mixture was used in the next step directly.

[0285] LCMS for product (ESI+): m/z 364.1, 366.1 (M+H) ⁺ , Rt:0.646 min.

[0286] Step 5. Preparation of N-(bicyclo[l.l.l]pentan-1-yl)-2-(6-bromo-4-hydroxy-1-(2- morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridin-3-yl)acetamide

[0287] To the previous mixture was added CS ₂ CO ₃ (3.44 g, 10.54 mmol, 8 eq) and 4-(2- chloroethyl)morpholine (538.78 mg, 2.90 mmol, 2.20 eq, HCl) at 80°C. The mixture was stirred at 80°C for 12 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (HCl)-ACN]; B%: 20%-50%, 8min) to give N- (bicyclofl .1.1 ]pentan- 1 -yl)-2-(6-bromo-4-hydroxy- 1 -(2-morpholinoethyl)-2-oxo-l ,2-dihydro- 1 ,8- naphthyridin-3-yl)acetamide (50 mg, 104.74 μmol, 7.95% yield).

[0288] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 2.13 (s, 6 H), 2.48 (br d, >9.76 Hz, 2 H), 2.73 (br s, 1 H), 3.02 - 3.12 (m, 2 H), 3.45 (br d, J=1.75 Hz, 2 H), 3.74 (s, 2 H), 3.81 (br d, J=12.01 Hz, 2 H), 4.03 - 4.10 (m, 2 H), 4.12 - 4.21 (m, 2 H), 4.87 - 4.96 (m, 2 H), 8.50 (d, J=2.25 Hz, 1 H), 8.55 (d, J=2.38 Hz, 1 H), 10.82 - 11.37 (m, 1 H), 12.71 - 13.67 (m, 1 H). [0289] Step 6. Preparation of N-(bicyclo[l.l.l]pentan-1-yl)-2-(6-(4-fluorophenyl)-4-hydrox y-1-(2- morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridin-3-yl)acetamide

[0290] To a solution of N-(bicyclo[l.l.l]pentan-1-yl)-2-(6-bromo-4-hydroxy-1-(2-morp holinoethyl)- 2-oxo- 1,2-dihydro- 1,8-naphthyridin-3-yl)acetamide (50 mg, 104.74 μmol. 1 eq) in dioxane (0.5 mL) and H ₂ O (0.1 mL) was added (4-fluorophenyl)boronic acid (17.59 mg, 125.69 μmol, 1.2 eq), K ₂ CO ₃ (43.43 mg, 314.23 μmol, 3 eq) and Pd(dppf)Cl ₂ (7.66 mg, 10.47 μmol, 0.1 eq) under N2. The mixture was stirred at 100°C for 2 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (HCl)-MEOH]; B%: 25%-50%, 8min) to give Compound 26 (5.1 mg, 10.03 μmol, 9.58% yield, 96.9% purity).

[0291] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 2.17 (s, 6 H), 2.50 (s, 1 H), 2.96 - 3.19 (m, 2 H), 3.38 - 3.59 (m, 2 H), 3.74 - 3.88 (m, 2 H), 3.94 - 4.13 (m, 4 H), 4.25 - 4.49 (m, 2 H), 4.95 - 5.18 (m, 2 H), 7.21 (br t, J=8.13 Hz, 2 H), 7.59 (br dd, J=6.44, 4.82 Hz, 2 H), 8.50 - 8.83 (m, 3 H), 12.79 - 13.10 (m, 1 H). LCMS for product (ESI+): m/z 493.1 (M+H) ⁺ , Rt:2.305 min.

EXAMPLE 27 - Synthesis of methyl 1-(6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamido)cyclohexane-1-carboxylate (Compound 27)

[0292] Preparation of methyl 1-(6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2- dihydro- 1,8-naphthyridine-3-carboxamido)cyclohexane-1-carboxylate

[0293] To a solution of the ethyl ester (400 mg, 836.97 μmol, 1 eq,) in toluene (4 mL) was added

DIEA (324.51 mg, 2.51 mmol, 437.35 μL, 3 eq) and methyl 1 -aminocyclohexanecarboxylate (171.05 mg, 1.09 mmol, 1.3 eq). The mixture was stirred at 120°C for 4 h. The mixture was concentrated to give crude product, which was triturated with methanol (3 mL) and the mixture was filtered, and the filter cake concentrated to give Compound 27 (325 mg, 588.14 μmol, 70.34% yield). 25 mg of Compound 27 was dissolved in MeOH (0.5 mL) then HCl was added (6 mg, 59.24 μmol, 5.88 μL, 36% purity), and the mixture was blow-dried and lyophilized to give Compound 27 HCl salt (21.2 mg, 35.02 μmol, 4.18% yield, 97.3% purity).

[0294] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 1.27 - 1.45 (m, 1 H), 1.56 (br d, J=2.00 Hz, 2 H), 1.68 - 1.81 (m, 3 H), 1.85 - 2.03 (m, 2 H), 2.21 (br d, J=13.88 Hz, 2 H), 3.09 (br d, J=10.63 Hz, 2 H), 3.41 (br s, 2 H), 3.76 (s, 5 H), 4.03 (br d, J=11.13 Hz, 2 H), 4.41 (br t, J=11.88 Hz, 2 H), 5.07 (br t, J=7.00 Hz, 2 H), 7.22 (t, J=8.63 Hz, 2 H), 7.57 - 7.66 (m, 2 H), 8.61 (d, J=2.38 Hz, 1 H), 8.90 (d, J=2.50 Hz, 1 H), 10.39 (s, 1 H), 13.62 (br s, 1 H). LCMS for product (ESI+): m/z 553.1 (M+H) ⁺ , Rt:2.482 min.

EXAMPLE 28 - Synthesis of N-(4,4-dimethylcyclohexyl)-6-(4-fluorophenyl)-4-hydroxy-1-(2 - morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 28) [0295] Preparation of N-(4,4-dimethylcyclohexyl)-6-(4-fluorophenyl)-4-hydroxy-1-(2 - morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0296] To a solution of the ethyl ester (50 mg, 104.62 μmol, 1 eq, HCl) in toluene (1 mL) was added DIEA (40.56 mg, 313.87 μmol, 54.67 μL, 3 eq) and 4,4-dimethylcyclohexanamine (15.97 mg, 125.55 μmol, 1.2 eq). The mixture was stirred at 120°C for 4 h. The mixture was concentrated to give product, which was triturated with methanol (3 mL), and the mixture was filtered, and the filter cake was dried to give product. The product was dissolved in MeOH (0.5 mL) then HCl was added (8.66 mg, 115.08 μmol, 11.43 μL, 36% purity, 1.1 eq), and the mixture was blow-dried and lyophilized to give Compound 28 HCl salt (31.5 mg, 56.34 μmol, 53.85% yield, 100% purity).

[0297] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.98 (d, J=8.38 Hz, 6 H), 1.31 - 1.41 (m, 2 H), 1.44 - 1.58 (m, 4 H), 1.84 - 1.95 (m, 2 H), 2.99 - 3.16 (m, 2 H), 3.41 (br s, 2 H), 3.73 (br d, J=11.63 Hz, 2 H), 3.83 - 3.96 (m, 1 H), 4.03 (br d, J=11.63 Hz, 2 H), 4.39 (br t, .1= 12.07 Hz, 2 H), 5.05 (br t, .1=6.69 Hz, 2 H), 7.22 (t, J=8.57 Hz, 2 H), 7.62 (dd, J=8.63, 5.25 Hz, 2 H), 8.62 (d, J=2.25 Hz, 1 H), 8.88 (d, J=2.38 Hz, 1 H), 9.95 (br d, J=7.50 Hz, 1 H), 13.44 - 13.66 (m, 1 H). LCMS for product (ESI+): m/z 523.2 (M-H) , Rt:2.724 min.

EXAMPLE 29 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-N-(5-(hydroxymethyl)spiro[2.3]h exan- 5-yl)-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 29) [0298] Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-(5-(hydroxymethyl)spiro[2.3]h exan-5-yl)- 1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0299] To a solution of the ethyl ester (40 mg, 90.61 μmol, 1 eq) and (5- aminospiro [2.3] hexan- 5-yl) methanol (12.68 mg, 99.67 μmol, 1.1 eq) in toluene (1 mL) was added DIEA (11.71 mg, 90.61 μmol,

15.78 μL, 1 eq). The mixture was stirred at 120°C for 12 h. The mixture was concentrated and purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water(HCl)-ACN];B%:

25%-55%,8min) to give Compound 29 HCl salt (11.1 mg, 18.15 μmol, 20.03% yield, 91.4% purity).

[0300] ¹ H NMR (400 MHz, MeOD) δ = 9.05 (d, J = 2.3 Hz, 1H), 8.73 (d, J = 2.4 Hz, 1H), 7.78 (br dd,

J = 5.3, 8.6 Hz, 2H), 7.28 (br t, J = 8.7 Hz, 2H), 4.94 (br d, J = 5.4 Hz, 4H), 4.11 (br s, 2H), 4.00 (s, 2H), 3.88 - 3.74 (m, 4H), 3.67 (br t, J = 5.7 Hz, 2H), 2.60 (br d, J = 12.9 Hz, 2H), 2.26 - 2.19 (m, 2H), 0.57 -

0.46 (m, 4H). LCMS for product (ESI+): m/z 523.1 (M+H) ⁺ , Rt:2.641 min.

EXAMPLE 30 - Synthesis of N-(l-carbamoylcyclohexyl)-6-(4-fluorophenyl)-4-hydroxy-1-(2- morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 30)

[0301] Step 1. Preparation of 1-(6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2- dihydro- 1,8-naphthyridine-3-carboxamido)cyclohexane-1-carboxylic acid [0302] To a solution of Compound 27 (130 mg, 220.69 μmol, 1 eq, HO) in DMSO (1 mL) was added NaOH (2 M, 0.3 mL, 3 eq). The mixture was stirred at 25°C for 2 h. The mixture was poured into water (10 mL), and the mixture was acidified by adding 2N hydrochloric acid drop wise to pH = 2 at 0 °C. The mixture was filtered, and the filter cake was washed with water and dried to give the desired carboxylic acid (100 mg, 185.68 μmol, 84.13% yield).

[0303] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 1.27 - 1.54 (m, 3 H), 1.56 - 1.75 (m, 3 H), 1.76 - 1.89 (m, 2 H), 2.11 (br d, J=13.51 Hz, 2 H), 2.53 - 2.64 (m, 2 H), 3.06 - 3.25 (m, 2 H), 3.41 - 3.79 (m, 6 H), 4.38 - 4.99 (m, 2 H), 7.38 (br t, J=8.76 Hz, 2 H), 7.91 (dd, J=8.63, 5.38 Hz, 2 H), 8.64 (br d, J=3.50 Hz, 1 H), 9.17 (d, J=2.38 Hz, 1 H), 10.26 - 10.83 (m, 1 H).

[0304] Step 2. Preparation of N-(l-carbamoylcyclohexyl)-6-(4-fluorophenyl)-4-hydroxy-1-(2- morpholmoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0305] To a solution of the carboxylic acid (30 mg, 55.70 μmol, 1 eq) in DMF (0.5 mL) was added NH ₄ HCO ₃ (8.81 mg, 111.41 μmol, 9.17 μL, 2 eq), HATU (31.77 mg, 83.55 μmol, 1.5 eq), and DIEA (14.40 mg, 111.41 μmol, 2 eq). The mixture was stirred at 25°C for 2 h. The mixture was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water (HCl)-ACN]; B%: 10%-60%, 8min) to give Compound 30 HCl salt (7.9 mg, 13.76 μmol, 24.71% yield, 100% purity).

[0306] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 1.27 - 1.55 (m, 2 H), 1.68 - 1.83 (m, 4 H), 1.92 - 2.02 (m, 2 H), 2.31 (br d, J=13.20 Hz, 2 H), 2.90 - 3.06 (m, 2 H), 3.46 (br s, 2 H), 3.85 - 4.08 (m, 4 H), 4.29 - 4.46 (m, 2 H), 5.02 (br s, 2 H), 5.37 (br d, J=2.32 Hz, 1 H), 7.20 - 7.24 (m, 2 H), 7.61 (dd, J=8.5O, 5.20 Hz, 2 H), 8.64 (d, J=1.59 Hz, 1 H), 8.84 (d, J=1.34 Hz, 1 H), 10.42 (s, 1 H), 12.23 - 12.81 (m, 1 H). LCMS for product (ESI+): m/z 538.1 (M+H) ⁺ , Rt:2.200 min. EXAMPLE 31 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-N-(1-(methylcarbamoyl)cyclohexy l)-1-

(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 31)

[0307] Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-(1-(methylcarbamoyl)cyclohexy l)-1-(2- morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0308] To a solution of methanamine (7.52 mg, 111.40 μmol, 2 eq, HCl) in DMF (0.5 mL) was added the carboxylic acid (30 mg, 55.70 μmol, 1 eq), HATU (31.77 mg, 83.55 μmol, 1.5 eq), and DIEA (28.8 mg, 222.80 μmol, 4 eq). The mixture was stirred at 25°C for 2 h. The mixture was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3μm;mobile phase: [water(HCl)-ACN];B%: 10%-50%,8min) to give Compound 31 HCl salt (9.7 mg, 16.49 μmol, 29.61% yield, 100% purity).

[0309] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 1.23 - 1.60 (m, 2 H), 1.69 - 1.86 (m, 4 H), 1.92 - 2.03 (m, 2 H), 2.18 - 2.32 (m, 2 H), 2.81 (br s, 3 H), 3.00 (br s, 2 H), 3.47 (br d, J=4.28 Hz, 2 H), 3.83 - 4.18 (m, 4 H), 4.30 - 4.50 (m, 2 H), 5.02 (br s, 2 H), 7.22 (br t, J=8.31 Hz, 2 H), 7.61 (br dd, J=7.95, 5.13 Hz, 2 H), 8.63 (s, 1 H), 8.83 (br s, 1 H), 10.36 (br s, 1 H), 12.27 - 12.56 (m, 1 H). LCMS for product (ESI+): m/z 552.1 (M+H) ⁺ , Rt:2.263 min. EXAMPLE 32 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N- (spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 32)

[0310] Preparation of 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo-N-

(spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0311] To a solution of the ethyl ester (20 mg, 45.31 μmol, 1 eq) and spiro[2.5]octan-6-amine (8.06 mg, 49.84 μmol, 1.1 eq, HCl) in toluene (1 mL) was added DIEA (5.86 mg, 45.31 μmol, 7.89 μL, 1 eq). The mixture was stirred at 120°C for 2 h. The mixture was concentrated. The mixture was triturated with MeOH (1 mL) for 30 min. The resulting solid was collected by filtration and dried to give Compound 32 HCl salt (9.1 mg, 16.34 μmol, 36.06% yield, 100% purity).

[0312] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.30 - 10.18 (m, 1H), 9.94 - 9.74 (m, 1H), 9.14 (d, J = 2.4 Hz, 1H), 8.66 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 5.3, 8.7 Hz, 2H), 7.39 (t, J = 8.8 Hz, 2H), 4.79 (br s, 2H), 4.08 - 3.95 (m, 3H), 3.76 - 3.62 (m, 4H), 3.42 (br d, J = 1.8 Hz, 1H), 3.28 - 3.13 (m, 3H), 1.96 - 1.87 (m, 2H), 1.65 - 1.48 (m, 4H), 1.25 - 1.13 (m, 2H), 0.37 - 0.23 (m, 4H). LCMS for product (ESI+): m/z 521.2 (M+H) ⁺ , Rt:2.615 min.

EXAMPLE 33 - Synthesis 1-(2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)-4-hydroxy-2-oxo -N- (spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 33) [0313] Step 1. Preparation of methyl 2-(3-ethoxy-3-oxopropanamido)nicotinate

[0314] To a solution of methyl 2-aminonicotinate (2 g, 13.14 mmol, 1 eq) in DCM (20 mL) was added TEA (1.33 g, 13.14 mmol, 1.83 mL, 1 eq). To the mixture was added ethyl 3-chloro-3-oxo- propanoate (1.98 g, 13.14 mmol, 1.65 mL, 1 eq) at 0°C. The mixture was stirred at 25°C for 2 h. The mixture was concentrated to give methyl 2-(3-ethoxy-3-oxopropanamido)nicotinate (3 g, 11.27 mmol, 85.72% yield).

[0315] Step 2. Preparation of ethyl 4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3- carboxylate

[0316] To a solution of methyl 2-(3-ethoxy-3-oxopropanamido)nicotinate (3 g, 11.27 mmol, 1 eq) in MeOH (30 mL) was added NaOMe (2.43 g, 45.07 mmol, 4 eq). The mixture was stirred at 60°C for 2 h. The mixture was acidified by adding 2 M hydrochloric acid drop wise to pH = 6, the resulting solid was collected by filtration, and dried under high vacuum to give ethyl 4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate (1.9 g, 8.11 mmol, 72.00% yield).

[0317] ¹ H NMR (400 MHz, MeOD) 3 = 8.37 (q, J = 1.8 Hz, 1H), 8.36 (s, 1H), 7.13 - 7.08 (m, 1H), 4.25 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0318] Step 3. Preparation of ethyl 1-(2,2-diethoxyethyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate

[0319] To a solution of ethyl 4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate (800 mg, 3.42 mmol, 1 eq) and 2 -bromo- 1,1 -diethoxy -ethane (1.35 g, 6.83 mmol, 1.03 mL, 2 eq) in DMSO (20 mL) was added CS ₂ CO ₃ (11.13 g, 34.16 mmol, 10 eq). The mixture was stirred at 100 °C for 12 h. The mixture was diluted with water (100 mL) and acidified by adding 2 M hydrochloric acid drop wise to pH = 6, the resulting solid was collected by filtration, and dried under high vacuum to give ethyl 1-(2,2- diethoxyethyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate (670 mg, 1.91 mmol, 55.98% yield). [0320] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 312.95 - 12.73 (m, 1H), 8.73 (dd, J = 1.9, 4.6 Hz, 1H), 8.42 (dd, J = 1.8, 7.9 Hz, 1H), 7.36 (dd, J = 4.7, 7.9 Hz, 1H), 4.94 (t, J = 5.7 Hz, 1H), 4.48 (d, J = 5.8 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.65 - 3.60 (m, 2H), 3.40 - 3.35 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.0 Hz, 6H).

[0321] Step 4. Preparation of ethyl 1-(2,2-diethoxyethyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate

[0322] To a solution of ethyl 1-(2,2-diethoxyethyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3- carboxylate (300 mg, 856.25 μmol, 1 eq) and the cyclohexyl amine (166.12 mg, 1.03 mmol, 1.2 eq, HCl) in toluene (1 mL) was added DIEA (110.66 mg, 856.25 jimol, 149.14 μL, 1 eq). The mixture was stirred at 120°C for 12 h. The mixture was concentrated to give ethyl 1-(2,2-diethoxyethyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate (300 mg, 698.47 μmol, 81.57% yield).

[0323] Step 5. Preparation of 4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2.5]octan-6-yl)- 1,2- dihydro- 1,8-naphthyridine-3-carboxamide

[0324] To a solution of ethyl 1-(2,2-diethoxyethyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3- carboxylate (400 mg, 931.30 μmol, 1 eq) in THF (4 mL) was added HCl (2 M, 4 mL, 8.59 eq). The mixture was stirred at 60°C for 1 h. The mixture was concentrated to give 4-hydroxy-2-oxo-1-(2- oxoethyl)-N-(spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (300 mg, 844.15 μmol, 90.64% yield).

[0325] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.15 (br d, J = 2.4 Hz, 1H), 9.70 (s, 1H), 8.75 (dd, J = 1.8, 4.6 Hz, 1H), 8.50 (dd, J = 1.8, 7.9 Hz, 1H), 7.46 (dd, J = 4.6, 7.9 Hz, 1H), 5.29 (s, 2H), 4.04 - 3.90 (m, 1H), 1.88 (br dd, J = 3.6, 8.6 Hz, 2H), 1.62 - 1.47 (m, 4H), 1.20 - 1.10 (m, 2H), 0.34 - 0.22 (m, 4H). [0326] Step 6. Preparation of 1-(2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)-4-hydroxy-2-oxo -N-

(spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0327] To a solution of 4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8- naphthyridine-3-carboxamide (50 mg, 140.69 μmol, 1 eq) and 7-oxa-4-azaspiro[2.5]octane (25.26 mg, 168.83 μmol, 1.2 eq, HCl) in MeOH (1 mL) was added NaOAc (11.54 mg, 140.69 μmol, 1 eq) and NaBH ₃ CN (53.05 mg, 844.15 μmol, 6 eq). The mixture was stirred at 25°C for 1 h. The mixture was purified by prep-HPLC (column: Waters Xbridge BEH Cl 8 100*30mm*10μm;mobile phase: [water( NH ₄ HCO ₃ )-ACN];B%: 70%-95%,10min) to give Compound 33 (3.3 mg, 6.34 μmol, 4.51% yield, 94% purity).

[0328] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 13.25 - 13.04 (m, 1H), 10.01 (br d, J = 7.3 Hz, 1H), 8.71 (dd, J = 1.8, 4.8 Hz, 1H), 8.50 (dd, J = 1.8, 7.9 Hz, 1H), 7.31 (dd, J = 4.7, 7.9 Hz, 1H), 5.37 - 5.24 (m, 1H), 4.85 (br t, J = 10.6 Hz, 1H), 4.21 - 4.08 (m, 3H), 4.07 - 3.98 (m, 1H), 3.88 - 3.78 (m, 1H), 3.69 - 3.60 (m, 2H), 3.58 - 3.49 (m, 1H), 3.26 - 3.16 (m, 1H), 2.37 - 2.24 (m, 1H), 2.03 - 1.96 (m, 2H), 1.79 - 1.71 (m, 2H), 1.69 - 1.63 (m, 2H), 1.55 (br s, 1H), 1.18 - 1.08 (m, 2H), 1.06 - 0.97 (m, 1H), 0.95 - 0.83 (m, 1H), 0.40 - 0.25 (m, 4H). LCMS for product (ESI+): m/z 453.3 (M+H) ⁺ , Rt:2.641 min.

EXAMPLE 34 - Synthesis 1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-4-hydroxy- 2-oxo-N- (spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 34) [0329] Preparation of 1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-4-hydroxy- 2-oxo-N-

(spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0330] To a solution of 4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8- naphthyridine-3-carboxamide and 2-oxa-5-azabicyclo[2.2.1]heptane (13.74 mg, 101.30 pinol. 1.2 eq, HQ) in MeOH (1 mL) was added NaOAc (6.92 mg, 84.42 μmol, 1 eq) and NaBH ₃ CN (15.91 mg, 253.25 μmol. 3 eq). The mixture was stirred at 25°C for 1 h. The mixture was purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3μm;mobile phase: [water(HCl)-ACN];B%: 25%-55%,8min) to give Compound 34 HCl salt (11 mg, 20.84 μmol, 24.69% yield, 90% purity).

[0331] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 10.26 - 10.10 (m, 1H), 8.70 (dd, J = 1.9, 4.6 Hz, 1H), 8.48 (dd, J = 1.8, 7.8 Hz, 1H), 7.25 (br s, 1H), 4.83 - 4.61 (m, 2H), 4.50 (br s, 1H), 4.24 - 3.89 (m, 3H), 3.75 - 3.67 (m, 1H), 3.40 - 2.72 (m, 4H), 2.07 - 1.97 (m, 3H), 1.91 - 1.84 (m, 1H), 1.72 (br d, J = 10.6 Hz, 4H), 1.22 - 1.04 (m, 2H), 0.38 - 0.24 (m, 4H). LCMS for product (ESI+): m/z 439.1 (M+H)+, Rt:2.315 min.

[0332] EXAMPLE 35 - Synthesis 1-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)ethyl)-4-hydroxy- 2- oxo-N-(spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 35)

[0333] Preparation of 1-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)ethyl)-4-hydroxy- 2-oxo-N-

(spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide [0334] To a solution of 4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8- naphthyridine-3-carboxamide and 2-oxa-5-azabicyclo[2.2.1]heptane (60 mg, 168.83 μmol, 1 eq) and 3- oxa-6-azabicyclo[3.1.1]heptane (27.47 mg, 202.60 μmol, 1.2 eq, HCl) in MeOH (1 mL) was added NaOAc (41.55 mg, 506.49 μmol, 3 eq) to make the pH=7. NaBEhCN (42.44 mg, 675.32 μmol, 4 eq) was added into the mixture, the mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna Cl 8 150*30mm*5um; mobile phase: [water (FA)-ACN]; B%: 20%-60%, 8min) to give Compound 35 fumaric acid (FA) salt (12.5 mg, 25.80 μmol, 15.28% yield, 100% purity, FA).

[0335] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.24 - 0.31 (m, 2 H), 0.32 - 0.39 (m, 2 H), 1.13 (br d, J=13.13 Hz, 2 H), 1.50 - 1.63 (m, 4 H), 1.92 (d, J=8.5O Hz, 1 H), 1.97 - 2.09 (m, 2 H), 2.66 - 2.85 (m, 1 H), 3.06 (br t, J=7.38 Hz, 2 H), 3.63 - 3.84 (m, 4 H), 3.92 - 4.11 (m, 1 H), 4.37 (d, J=11.01 Hz, 2 H), 4.50 - 4.68 (m, 2 H), 7.23 - 7.26 (m, 1 H), 8.48 (dd, J=7.88, 1.88 Hz, 1 H), 8.69 (dd, J=4.63, 2.00 Hz, 1 H), 10.23 (br d, J=8.00 Hz, 1 H). LCMS for product (ESI+): m/z 439.1 (M+H) ⁺ , Rt:2.367 min.

EXAMPLE 36 - Synthesis 1-(2-(4-fhioropiperidin-1-yl)ethyl)-4-hydroxy-2-oxo-N-(spiro [2.5]octan- 6-yl)- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 36)

[0336] Preparation of 1-(2-(4-fluoropiperidin-1-yl)ethyl)-4-hydroxy-2-oxo-N-(spiro [2.5]octan-6- yl)- 1 ,2-dihydro- 1 ,8-naphthyridine-3-carboxamide

[0337] To a solution of 4-hydroxy-2-oxo-1-(2-oxoethyl)-N-(spiro[2.5]octan-6-yl)- 1,2-dihydro- 1,8- naphthyridine-3-carboxamide and 2-oxa-5-azabicyclo[2.2.1]heptane (30 mg, 84.42 μmol, 1 eq) and 4- fluoropiperidine (14.14 mg, 101.30 μmol, 1.2 eq, HCl) in MeOH (1 mL) was added NaOAc (20.77 mg, 253.25 μmol, 3 eq) to make the pH=7, then NaBH ₃ CN (21.22 mg, 337.66 μmol, 4 eq) was added into the mixture, and the mixture was stirred at 20°C for 2 h. The mixture was filtered, and the filtrate was purified by prep-HPLC (column: Phenomenex Luna Cl 8 150*30mm*5um; mobile phase: [water (HCl)- ACN]; B%: 30%-70%, 8min) to give Compound 36 HCl salt (13.5 mg, 27.73 μmol, 32.85% yield, 98.4% purity).

[0338] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 0.25 - 0.31 (m, 2 H), 0.31 - 0.38 (m, 2 H), 1.15 (br d, J=13.01 Hz, 2 H), 1.52 - 1.61 (m, 2 H), 1.67 - 1.77 (m, 2 H), 1.92 - 2.05 (m, 2 H), 2.13 - 2.28 (m, 2 H), 2.54 - 2.86 (m, 2 H), 3.23 (br d, .1=5.00 Hz, 2 H), 3.37 (br t, .1=6.94 Hz, 2 H), 3.67 (br d, J= 10.88 Hz, 2 H), 3.92 - 4.16 (m, 1 H), 4.95 - 5.10 (m, 3 H), 7.31 (dd, J=7.88, 4.75 Hz, 1 H), 8.50 (dd, J=7.88, 1.75 Hz, 1 H), 8.69 (dd, J=4.63, 1.75 Hz, 1 H), 10.00 (br d, J=7.13 Hz, 1 H), 12.63 (br d, J=2.00 Hz, 1 H). LCMS for product (ESI+): m/z 443.1 (M+H) ⁺ , Rt:2.434 min.

EXAMPLE 37 - Synthesis 4-hydroxy-N-((ls,4s)-4-methylcyclohexyl)-1-(2-morpholinoethy l)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 37)

[0339] Step 1. Preparation of ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxylate

[0340] To a solution of ethyl 4-hydroxy-2-oxo-lH- 1,8-naphthyridine-3-carboxylate (500 mg, 2.13 mmol, 1 eq) in DMF (10 mL) was added CS ₂ CO ₃ (5.56 g, 17.08 mmol, 8 eq) at 20 °C for 1 h. Then 4-(2- chloroethyl)morpholine (638.83 mg, 4.27 mmol, 2 eq) was added. The mixture was heated to 140 °C and stirred for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was triturated with petroleum ether: ethyl acetate (10 ml/ 10 ml) at 20 °C for 0.5 h. The resulting (precipitated) solid was collected by filtration to give ethyl 4-hydroxy-1-(2- morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxylate (650 mg, 1.87 mmol, 87.65% yield).

[0341] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 8.36 (dd, J = 1.8, 4.6 Hz, 1H), 8.16 (dd, J = 1.7, 7.5 Hz, 1H), 6.99 (dd, J = 4.7, 7.5 Hz, 1H), 4.38 - 4.26 (m, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.56 (br t, J = 4.5 Hz, 4H), 3.33 (br s, 2H), 2.45 (br d, J = 5.3 Hz, 4H), 1.19 (t, J = 7.1 Hz, 3H). [0342] Step 2. Preparation of 4-hydroxy-N-((ls,4s)-4-methylcyclohexyl)-1-(2-morpholinoethy l)-2- oxo- 1 ,2-dihydro- 1 ,8-naphthyridine-3-carboxamide

[0343] To a mixture of ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine- 3-carboxylate (80 mg, 230.31 μmol. 1 eq) in toluene (2 mL) was added DIPEA (74.42 mg, 575.78 μmol, 100.29 juL, 2.5 eq) and 4-methylcyclohexanamine (34.47 mg, 230.31 μmol, 1 eq, HCl) in one portion at 20 °C under N2. The mixture was then heated to 120 °C and stirred for 2 hours. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition, column: Phenomenex Synergi Cl 8 150*25mm* 10μm; mobile phase: [water(0.225%FA)-ACN];B%: 15%- 45%, 10 min) and lyophilized to obtain Compound 37 (28 mg, 67.55 μmol, 29.33% yield).

[0344] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.56 (br d, J = 6.3 Hz, 1H), 8.82 (dd, J = 1.5, 4.5 Hz, 1H), 8.46 (br d, J = 6.8 Hz, 1H), 7.44 - 7.42 (m, 1H), 4.56 (br t, J = 6.9 Hz, 2H), 4.21 - 3.99 (m, 1H), 3.52 (t, J = 4.4 Hz, 4H), 2.58 (br t, J = 6.9 Hz, 2H), 2.48 (br s, 4H), 1.81 - 1.71 (m, 2H), 1.68 - 1.58 (m, 4H), 1.57 - 1.48 (m, 1H), 1.24 - 1.10 (m, 2H), 0.94 (d, J = 6.5 Hz, 3H). LCMS for product (ESI+): m/z 415.2 [M+H] ⁺ , Rt: 0.777 min.

EXAMPLE 38 - Synthesis 1-(4-fluorobenzyl)-4-hydroxy-N-(1-(hydroxymethyl)cyclohexyl) -2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 38)

[0345] Step 1. Preparation of ethyl l-[(4-fluorophenyl) methyl]-4-hydroxy-2-oxo- 1, 8- naphthyridine-3-carboxylate [0346] To a solution of ethyl 4-hydroxy-2-oxo-lH- 1,8-naphthyridine-3-carboxylate (500 mg, 2.13 mmol, 1 eq) in DMF (10 mL) was added CS ₂ CO ₃ (5.56 g, 17.08 mmol, 8 eq) at 20 °C for 1 h, then (bromomethyl)-4-fluoro-benzene (807.08 mg, 4.27 mmol, 527.50 μL, 2 eq) was added to the mixture. The mixture was stirred at 90 °C for 16 h. Then CS ₂ CO ₃ (1.39 g, 4.27 mmol, 2 eq) and 1- (bromomethyl) - 4-fluoro-benzene (403.54 mg, 2.13 mmol, 263.06 μL, 1 eq) was added, the mixture was stirred at 90 °C for another 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether: ethyl acetate (10 ml/10 ml) at 20 oC for 0.5 h. The cake was purified by reverser-phase HPLC (0.05% FA condition; water/ ACN=45%/55%) and lyophilized to give ethyl l-[(4-fluorophenyl) methyl] -4-hydroxy-2-oxo- 1, 8-naphthyridine-3-carboxylate

(170 mg, 496.61 μmol, 23.26% yield).

[0347] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.70 (dd, J = 1.6, 4.6 Hz, 1H), 8.43 (dd, J = 1.7, 7.9 Hz, 1H), 7.38 - 7.35 (m, 1H), 7.34 - 7.29 (tn, 2H), 7.09 (t, J = 8.8 Hz, 2H), 5.51 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H).

[0348] Step 2. Preparation of 1-(4-fluorobenzyl)-4-hydroxy-N-(1-(hydroxymethyl)cyclohexyl) -2- oxo- 1 ,2-dihydro- 1 ,8-naphthyridine-3-carboxamide

[0349] To a solution of ethyl l-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo- 1,8-naphthyridine-3- carboxylate (40 mg, 116.85 μmol, 1 eq) and (l-aminocyclohexyl)methanol (21.29 mg, 128.53 μmol. 1.1 eq, HCl) in toluene (1.5 mL) was added DIEA (37.75 mg, 292.12 μmol, 50.88 μL, 2.5 eq). The mixture was stirred at 120 °C for 1.5 hr. The reaction mixture was directly concentrated. The residue was first purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10μm; mobile phase: [water (0.225 %FA)-ACN]; B%: 68%-88%, lOmin) and lyophilized. Then the crude product was second purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150 ^i:: 25mnr ^;: 10μm; mobile phase: [water (0.225%FA)-ACN]; B%: 74%-94%, 8min) and lyophilized to give Compound 38 (8.6 mg, 20.11 μmol, 17.21% yield, 99.48% purity).

[0350] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.43 - 10.13 (m, 1H), 8.85 - 8.65 (m, 1H), 8.47 (br d, J = 5.7 Hz, 1H), 7.46 - 7.37 (m, 1H), 7.29 (br d, J = 4.9 Hz, 2H), 7.09 (br s, 2H), 5.59 (br s, 2H), 4.99 - 4.65 (m, 1H), 3.61 (s, 2H), 2.10 (br s, 2H), 1.53 (br s, 3H), 1.41 (br s, 6H), 1.23 (br s, 2H). LCMS for product (ESI+): m/z 426.0 [M+H] ⁺ , Rt: 1.066 min. EXAMPLE 39 - Synthesis 4-hydroxy-N-(1-(hydroxymethyl)cyclohexyl)-1-(2-morpholinoeth yl)-2- oxo-1, 2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 39)

[0351] Preparation of 4-hydroxy-N-(1-(hydroxymethyl)cyclohexyl)-1-(2-morpholinoeth yl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0352] To a mixture of ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,8-naphthyridine-3-carboxylate (80 mg, 230.31 μmol, 1 eq) in toluene (2 mL) was added (l-aminocyclohexyl)methanol hydrochloride (30.52 mg, 184.24 μmol, 0.8 eq) and DIPEA (89.30 mg, 690.92 μmol, 120.35 μL, 3 eq) in one portion at 20 °C. The mixture was heated to 120 °C and stirred at 120 °C for 2 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition, column: Phenomenex Synergi Cl 8 150*25mm* 10μm; mobile phase: [water (0.225%FA)-ACN];B%: 9%- 39%,10min). Compound 39 (40 mg, 92.92 μmol, 40.34% yield) was obtained.

[0353] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.30 (br d, J = 1.0 Hz, 1H), 8.80 (br s, 1H), 8.45 (br d, J = 7.9 Hz, 1H), 8.14 (s, 0.74H, HCOOH), 7.44 - 7.41 (m, 1H), 4.99 - 4.68 (m, 1H), 4.54 (br t, J = 6.4 Hz, 2H), 3.63 (s, 2H), 3.54 - 3.50 (m, 4H), 2.56 (br t, J = 6.9 Hz, 2H), 2.48 (br s, 4H), 2.13 (br d, J = 6.0 Hz, 2H), 1.57 (br d, J = 4.0 Hz, 3H), 1.44 - 1.42 (m, 4H), 1.27 (br d, J = 2.1 Hz, 1H). LCMS for product (ESI+): m/z 431.1 [M+H] ⁺ , Rt: 0.720 min. EXAMPLE 40 - Synthesis N-cyclohexyl-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxamide (Compound 40)

[0354] Preparation of N-cyclohexyl-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxamide

[0355] To a mixture of ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,8-naphthyridine-3-carboxylate (50 mg, 143.94 μmol, 1 eq) and cyclohexanamine hydrochloride (19.52 mg, 143.94 μmol, 1 eq) in toluene (2 mL) was added DIEA (55.81 mg, 431.82 μmol, 75.22 μL, 3 eq) in one portion at 20 °C. The mixture was then heated to 120 °C and stirred for 2 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition, column: Phenomenex Synergi Cl 8 150*25mm* 10μm; mobile phase: [water(FA)-ACN];B%: 15% -45 %,10min) and lyophilized to obtain desired product. Compound 40 (20 mg, 49.94 μmol, 34.70% yield) was obtained.

[0356] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.27 (br s, 1H), 8.81 - 8.80 (m, 1H), 8.45 (dd, J = 1.5, 7.9 Hz, 1H), 7.42 (dd, J = 4.6, 7.8 Hz, 1H), 4.52 (br t, J = 7.2 Hz, 2H), 3.86 (br d, J = 2.0 Hz, 1H), 3.53 (br t, J = 4.3 Hz, 4H), 2.56 - 2.53 (m, 2H), 2.47 (br s, 4H), 1.88 (br s, 2H), 1.68 (br s, 2H), 1.61 - 1.51 (m, 1H), 1.38 (br t, J = 8.9 Hz, 4H), 1.31 - 1.13 (m, 1H). LCMS for product (ESI+): m/z 401.1 [M+H] ⁺ , Rt: 0. 0.844 min. EXAMPLE 41 - Synthesis N-cycloheptyl-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxamide (Compound 41)

[0357] Preparation of N-cycloheptyl-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8- naphthyridine-3-carboxamide

[0358] To a mixture of ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,8-naphthyridine-3-carboxylate (60 mg, 172.73 μmol, 1 eq) and cycloheptanamine (23.46 mg, 207.27 μmol, 26.39 μL, 1.2 eq) in toluene (3 mL) was added DIPEA (66.97 mg, 518.19 μmol, 90.26 μL, 3 eq) in one portion at 20 °C. The mixture was then heated to 120 °C and stirred for 2 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition; column: Unisil 3-100 Cl 8 Ultra 150*50mm*3 μm; mobile phase: [water(FA)-ACN];B%: 15%-45%,10min) and lyophilized to obtain desired product. Compound 41 (10 mg, 24.13 μmol, 13.97% yield) was obtained.

[0359] ¹ H NMR (400 MHz, DMSO-ds) δ = 10.46 - 10.37 (m, 1H), 8.77 (br s, 1H), 8.45 (br d, J = 7.8 Hz, 1H), 7.44 - 7.35 (m, 1H), 4.60 (br t, J = 6.8 Hz, 2H), 4.14 - 4.07 (m, 1H), 3.54 - 3.52 (m, 4H), 2.61 (br t, J = 6.9 Hz, 2H), 2.48 (br s, 4H), 2.01 - 1.88 (m, 2H), 1.73 - 1.48 (m, 10H). LCMS for product (ESI+): m/z 415.2 [M+H] ⁺ , Rt: 0.782 min.

EXAMPLE 42 - Synthesis 1-(2-(4-fluoropiperidin-1-yl)ethyl)-4-hydroxy-N-((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 42)

[0360] Step 1. Preparation of ethyl l-allyl-4-hydroxy-2-oxo- 1, 8-naphthyridine-3-carboxylate

[0361] To a mixture of ethyl 4-hydroxy-2-oxo-lH- 1,8-naphthyridine-3-carboxylate (4 g, 17.08 mmol, 1 eq) in DMF (40 mL) was added LiHMDS (1 M, 34.2 mL, 2 eq) dropwise at 0 °C under Nz. The mixture was stirred at 0 °C for 0.5 h, then warmed to 20 °C and stirred for 0.5 h, then 3 -bromoprop- 1-ene (3.10 g, 25.62 mmol, 1.5 eq) was added, and the mixture was stirred at 20 °C for 16 h. After reacting 16 h, LiHMDS (1 M, 17.08 mL, 1 eq) and 3 -bromoprop- 1-ene (1.03 g, 8.54 mmol, 0.5 eq) were added in turn, the reaction mixture was stirred at 20 °C for another 24 h. The reaction mixture was quenched by water 20 mL, then concentrated to obtain a solution (removed DMF). The solution was diluted with 80 mL 1 M HCl solution and stirred at 20 °C for 16 h, filtered and washed with water 10 mL, and the filter cake was dried by reduced pressure. The crude product ethyl l-allyl-4-hydroxy-2-oxo- 1, 8-naphthyridine-3- carboxylate (3.5 g, 12.76 mmol, 74.72% yield) was used into the next step without further purification. [0362] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 13.53 - 12.58 (m, 1H), 8.72 (dd, J = 1.8, 4.6 Hz, 1H), 8.33 (dd, J = 1.7, 8.0 Hz, 1H), 7.36 (dd, J = 4.6, 7.9 Hz, 1H), 5.97 - 5.87 (m, 1H), 5.07 - 4.99 (m, 2H), 4.94 - 4.93 (m, 2H), 4.36 - 4.30 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H). LCMS for product (ESI+): m/z 275.1 [M+H] ⁺ , Rt: 0.783 min.

[0363] Step 2. Preparation of l-allyl-4-hydroxy-N-(4-methylcyclohexyl)-2-oxo- 1,8-naphthyridine- 3-carboxamide [0364] To a mixture of ethyl l-allyl-4-hydroxy-2-oxo- 1,8-naphthyridine-3-carboxylate (3.5 g, 12.76 mmol, 1 eq) and (cis)-4-methylcyclohexanamine (1.91 g, 12.76 mmol, 1 eq, HCl) in toluene (50 mL) was added DIPEA (4.95 g, 38.28 mmol, 6.67 mL, 3 eq) in one portion at 20 °C under N2. The mixture was then heated to 110 °C and stirred for 24 h. The reaction mixture was concentrated to obtain a residue, the residue was dissolved in EA (150 mL), then washed with water (50 mL *2), dried by Na ₂ SO ₄ , filtered and concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g epaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) and concentrated to obtain desired product. Compound 1 -allyl-4-hydroxy-N-(4- methylcyclohexyl)-2-oxo- 1,8-naphthyridine-3-carboxamide (2.4 g, 7.03 mmol, 55.09% yield) was obtained.

[0365] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.51 (br d, J = 7.5 Hz, 1H), 8.81 - 8.80 (m, 1H), 8.47 (br d, J = 7.3 Hz, 1H), 7.44 (dd, J = 4.7, 7.9 Hz, 1H), 6.00 - 5.93 (m, 1H), 5.08 - 4.95 (m, 4H), 4.14 - 4.12 (m, 1H), 1.77 - 1.51 (m, 7H), 1.23 - 1.14 (m, 2H), 0.93 (d, J = 6.6 Hz, 3H). LCMS for product (ESI+): m/z 342.2 [M+H] ⁺ , Rt: 1.045 min.

[0366] Step 3. Preparation of 1-(2,3-dihydroxypropyl)-4-hydroxy-N-(4-methylcyclohexyl)-2-o xo- l,8-naphthyridine-3-carboxamide

[0367] To a mixture of l-allyl-4-hydroxy-N-(4-methylcyclohexyl)-2-oxo- 1,8-naphthyridine-3- carboxamide (2.4 g, 7.03 mmol, 1 eq) in THF (20 mL) and H ₂ O (20 mL) was added K ₂ OSO ₄ 2H ₂ O (1.30 g, 3.51 mmol, 0.5 eq) and NaICU (1.50 g, 7.03 mmol, 1 eq) in one portion at 0 °C. After addition, the mixture was warmed to 20 °C for 1 h. The reaction mixture was filtered and concentrated to obtain a solution. The solution was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 1 -(2 , 3 -dihydroxypropyl) -4-hydroxy-N-(4-methylcyclohexyl) -2-oxo- 1,8- naphthyridine-3-carboxamide (2.0 g, 5.33 mmol, 75.78% yield) was obtained.

[0368] ¹ H NMR (400 MHz, DMSO-d6) δ = 10.57 (br d, J = 7.9 Hz, 1H), 8.79 (dd, J = 1.7, 4.6 Hz, 1H), 8.44 (dd, J = 1.4, 7.8 Hz, 1H), 7.41 (dd, J = 4.6, 7.9 Hz, 1H), 4.74 - 4.51 (m, 3H), 4.33 (dd, J = 5.3, 13.0 Hz, 1H), 4.18 - 4.08 (m, 1H), 3.99 (td, J = 5.4, 8.1 Hz, 1H), 3.46 - 3.34 (m, 2H), 1.78 - 1.49 (m, 7H), 1.28 - 1.09 (m, 2H), 0.93 (d, J = 6.5 Hz, 3H). LCMS for product (ESI+): m/z 376.1 [M+H] ⁺ , Rt: 0.859 min. [0369] Step 4. Preparation of 4-hydroxy-N-(4-methylcyclohexyl)-2-oxo-1-(2-oxoethyl)- 1,8- naphthyridine-3-carboxamide

[0370] To a mixture of 1-(2,3-dihydroxypropyl)-4-hydroxy-N-(4-methylcyclohexyl)-2-o xo- 1,8- naphthyridine-3-carboxamide (1 g, 2.66 mmol, 1 eq) in THF (20 mL) and HiO (20 mL) was added NaICU (170.92 mg, 799.11 μmol, 44.28 μL. 0.3 eq) at 0 °C, the mixture was then warmed to 20 °C and stirred for 2h, then NaIO4 (170.92 mg, 799.11 μmol, 44.28 μL, 0.3 eq) was added and stirred for 2 h. NaICU (227.90 mg, 1.07 mmol, 59.04 μL, 0.4 eq) was added, and stirred for 16 h. NaIO4 (113.95 mg, 532.74 μmol, 29.52 μL, 0.2 eq) was added, and stirred at 20 °C for 2 h. The reaction mixture was filtered and the filtrate was dried by reduced pressure. The crude product 4-hydroxy-N-(4-methylcyclohexyl)-2-oxo-1-(2- oxoethyl)- 1,8-naphthyridine-3-carboxamide (850 mg, 2.48 mmol, 92.93% yield) was used into the next step without further purification.

[0371] ¹ H NMR (400 MHz, DMSO-d6) δ = 10.35 (br s, 1H), 9.70 (s, 1H), 8.74 (br d, J = 3.1 Hz, 1H),

8.49 (dd, J = 1.8, 7.9 Hz, 1H), 7.46 (dd, J = 4.7, 7.8 Hz, 1H), 5.30 (s, 2H), 4.16 - 4.13 (m, 1H), 1.75 -

1.49 (m, 7H), 1.18 - 1.09 (m, 2H), 0.93 (d, J = 6.7 Hz, 3H). LCMS for product (ESI+): rn/z 344.1 [M+H] ⁺ , Rt: 0.927 min.

[0372] Step 5. Preparation of 1-(2-(4-fluoropiperidin-1-yl)ethyl)-4-hydroxy-N-((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0373] To a solution of 4-hydroxy-N-(4-methylcyclohexyl) -2-oxo-1-(2-oxoethyl) -1, 8-naphthyridine-

3 -carboxamide (50 mg, 145.61 μmol, 1 eq) and 4-fluoropiperidine (24.39 mg, 174.74 μmol, 1.2 eq, HCl) in MeOH (2 mL) was added AcOH (17.49 mg, 291.23 μmol, 16.66 μL, 2 eq) and NaBH ₃ CN (45.75 mg, 728.06 μmol, 5 eq). The mixture was stirred at 60 °C for 15 hr. 5 mL MeOH and 2 mL DMF was added to the mixture and stirred at 20 °C for 10 min. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition, column: Phenomenex Synergi Cl 8 150*25 mm* 10μm; mobile phase: [water (FA) -ACN]; B%: 21%-51%, 10 min) and lyophilized to give crude product. The crude product was second purified by prep-HPLC (FA condition, column: Phenomenex Synergi Cl 8 150*25 mm* 10pm;mobile phase: [water (FA) -ACN];B%: 21%-48%, 9 min) and lyophilized to give Compound 42 (5 mg, 9.69 μmol, 6.65% yield, 92.32% purity, FA salt).

[0374] ¹ H NMR (400 MHz, Methanol-d ₄ ) δ = 8.71 (br d, J = 2.0 Hz, 1H), 8.52 (dd, J = 1.8, 7.8 Hz, 1H), 8.49 (s, 1H), 7.38 - 7.29 (m, 1H), 4.73 (br t, J = 7.0 Hz, 2H), 4.61 (br dd, J = 3.5, 10.2 Hz, 1H), 4.27 - 4.20 (m, 1H), 2.95 - 2.82 (m, 4H), 2.77 (br d, J = 3.4 Hz, 2H), 2.01 - 1.78 (m, 6H), 1.73 - 1.59 (m, 5H), 1.53 (dt, J = 3.0, 6.7 Hz, 1H), 1.27 (br d, J = 12.3 Hz, 2H), 0.98 (d, J = 6.5 Hz, 3H). LCMS for product (ESI+): m/z 431.1 [M+H] ⁺ , Rt: 0.853 min.

EXAMPLE 43 - Synthesis 4-hydroxy-N-(3-methylcyclopentyl)-1-(2-morpholinoethyl)-2-ox o- 1,2- dihydro- 1,8-naphthyridine-3-carboxamide (Compound 43)

[0375] Step 1. Preparation of N-benzyl-3-methyl-cyclopentanamine

[0376] To a mixture of 3 -methylcyclopentanone (1 g, 10.19 mmol, 1.09 mL, 1 eq) and phenylmethanamine (1.09 g, 10.19 mmol, 1.11 mL, 1 eq) in MeOH (10 mL) and CH ₃ COOH (1 mL) was added sodium triacetoxyborohydride (4.32 g, 20.38 mmol, 2 eq) in one portion at 20 °C. The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to obtain a residue, the residue was dissolved in EA (80 mL), then washed with water (40 mL *2) and brine (40 mL), dried by Na2SOr, filtered and concentrated to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate/Petroleum ethergradient @ 50 mL/rnin) and concentrated to obtain desired product. The product N-benzyl-3-methyl-cyclopentanamine (1.4 g, 7.40 mmol, 72.58% yield) was obtained.

[0377] ¹ H NMR (400 MHz, CHLOROFORM-d) 3 = 7.49 - 7.44 (m, 5H), 4.13 - 4.03 (m, 2H), 3.51 - 3.40 (m, 1H), 2.29 - 2.12 (m, 1H), 2.05 - 2.01 (m, 2H), 1.85 - 1.73 (m, 2H), 1.47 - 1.35 (m, 1H), 1.29 - 1.24 (m, 1H), 1.08 - 1.07 (m, 2H), 0.99 - 0.97 (m, 1H). LCMS for product (ESI+): m/z 190.2 [M+H] ⁺ , Rt: 0.318 min. [0378] Step 2. Preparation of 3-methylcyclopentanamine

[0379] To a solution of N-benzyl-3-methyl-cyclopentanamine (1.5 g, 7.92 mmol, 1 eq) in MeOH (15 mL) and HCI (0.5 mL, 37.5% purity) was added Pd/C (150 mg, 10% purity) under Nz. The suspension was degassed under vacuum and purged with Hz three times. The mixture was stirred under Hz (15 psi) at 20 °C for 16 h. The reaction mixture was filtered and washed with MeOH (10 mL), then concentrated to obtain a residue. The crude product 3-methylcyclopentanamine (180 mg, 1.81 mmol, 22.90% yield) was used into the next step without further purification.

[0380] ¹ H NMR (400 MHz, DMSO-d6) δ = 3.51 - 3.33 (m, 1H), 2.17 - 2.06 (m, 1H), 1.74 - 1.66 (m, 2H), 1.55 - 1.24 (m, 2H), 1.02 - 0.88 (m, 5H).

[0381] Step 3. Preparation of 4-hydroxy-N-(3-methylcyclopentyl)-1-(2-morpholinoethyl)-2-ox o- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0382] To a mixture of ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,8-naphthyridine-3-carboxylate (385.58 mg, 1.11 mmol, 1 eq) and 3-methylcyclopentanamine (150 mg, 1.11 mmol, 1 eq, HCI) in toluene (3 mL) was added DIPEA (430.38 mg, 3.33 mmol, 580.03 μL, 3 eq) in one portion at 20 °C, then the mixture was heated to 120 °C for 2 h. The reaction mixture was concentrated to obtain a crude product. The crude product was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10μm; mobile phase: [water(FA)-ACN];B%: 16%-46%,10min) and lyophilized to obtain desired product. Compound 43 (45 mg, 112.37 μmol, 10.12% yield) was obtained.

[0383] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.41 - 10.34 (m, 1H), 8.76 (br s, 1H), 8.44 (dd, J = 1.7, 7.8 Hz, 1H), 7.38 (br d, J = 0.6 Hz, 1H), 4.55 (br t, J = 7.0 Hz, 2H), 4.39 - 4.25 (m, 1H), 3.57 - 3.51 (m, 4H), 2.60 (br t, J = 6.9 Hz, 2H), 2.49 - 2.46 (m, 4H), 2.35 - 2.13 (m, 2H), 2.03 - 1.74 (m, 2H), 1.35 - 1.29 (m, 2H), 1.09 - 0.93 (m, 4H). LCMS for product (ESI+): m/z 401.1 [M+H] ⁺ , Rt: 0.740 min. EXAMPLE 44 - Synthesis 4-hydroxy-N-(4-methylcycloheptyl)-1-(2-morpholinoethyl)-2-ox o- 1,2- dihydro-1, 8-naphthyridine-3-carboxamide (Compound 44)

[0384] Preparation of 4-hydroxy-N-(4-methylcycloheptyl)-1-(2-morpholinoethyl)-2-ox o- 1,2- dihydro-1, 8- naphthyridine-3-carboxamide

[0385] To a mixture of ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,8-naphthyridine-3-carboxylate (150.17 mg, 432.30 μmol, 1.1 eq) and 4-methylcycloheptanamine (50 mg, 393.00 μmol, 1 eq) in toluene

(4 mL) was added DIPEA (152.38 mg, 1.18 mmol, 205.36 μL, 3 eq) in one portion at 20 °C. The mixture was then heated to 120 °C for 2 h. The reaction mixture was concentrated to obtain desired product. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10μm; mobile phase: [water(FA)-ACN];B%: 20%-50%,10min) and lyophilized to obtain desired product.

Compound 44 (48 mg, 112.01 μmol, 28.50% yield) was obtained.

[0386] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.37 - 10.28 (m, 1H), 8.81 (br d, J = 3.2 Hz, 1H), 8.45 (br d, J = 7.8 Hz, 1H), 7.43 (br dd, J = 4.9, 7.2 Hz, 1H), 4.54 (br s, 2H), 4.17 - 3.95 (m, 1H), 3.53 (br s, 4H),

2.47 (br s, 6H), 2.06 - 1.29 (m, 9H), 1.27 - 1.07 (m, 2H), 0.92 (br d, J = 5.9 Hz, 3H). LCMS for product

(ESI+): m/z 429.1 [M+H] ⁺ , Rt: 0.782 min.

EXAMPLE 45 - Synthesis 1-(2-(2,2-dimethylmorpholino)ethyl)-4-hydroxy-N-((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 45) [0387] Preparation of 1-(2-(2,2-dimethylmorpholino)ethyl)-4-hydroxy-N-((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0388] To a solution of 4-hydroxy-N-(4-methylcyclohexyl) -2-oxo-1-(2-oxoethyl) -1, 8-naphthyridine-

3-carboxamide (50 mg, 145.61 μmol, 1 eq) and 2,2-dimethylmorpholine (26.50 mg, 174.74 jnnol, 1.2 eq, HQ) in MeOH (3 mL) was added NaBHgCN (91.50 mg, 1.46 mmol, 10 eq) and AcOH (17.49 mg, 291.23 μmol, 16.66 μL, 2 eq). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was quenched by addition of water (2 mL) at 25 °C, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10pm; mobile phase: [water (FA) -ACN];B%: 23%-53%, 10 min) and lyophilized. The crude product was second purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10μm;mobile phase: [water (FA) -ACN];B%: 29%-49%, 8 min) and lyophilized to give Compound 45 (3.4 mg, 6.72 μmol, 4.62% yield, 96.59% purity, FA).

[0389] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 11.17 - 10.35 (m, 1H), 8.82 - 8.56 (m, 1H), 8.43 (br d, J = 7.5 Hz, 1H), 8.22 (s, 1H), 7.38 - 7.19 (m, 1H), 4.58 - 4.50 (m, 2H), 4.12 (br s, 1H), 3.48 (br s, 2H), 2.56 (br s, 2H), 2.36 (br s, 2H), 2.22 (s, 2H), 1.76 - 1.69 (m, 2H), 1.67 - 1.49 (m, 6H), 1.27 - 1.21 (m, 2H), 1.04 (s, 6H), 0.94 (br d, J = 6.1 Hz, 3H). LCMS for product (ESI+): m/z 443.1 [M+H] ⁺ , Rt: 0.856 min.

EXAMPLE 46 - Synthesis 1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-4-hydroxy- N-((ls,4s)-

4-methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 46) [0390] Preparation of 1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-4-hydroxy- N-((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0391] To a mixture of 4-hydroxy-N-(4-methylcyclohexyl)-2-oxo-1-(2-oxoethyl)- 1,8-naphthyridine-3- carboxamide (50 mg, 145.61 μmol, 1 eq) and 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (19.74 mg, 145.61 μmol, 1 eq) in MeOH (3 mL) and CH ₃ COOH (1 mL) was added NaBH ₃ CN (27.45 mg, 436.84 μmol. 3 eq) in one portion at 20 °C, the mixture was heated to 60 °C for 3 h. The reaction mixture was concentrated to obtain a residue, the residue was dissolved in 40 mL EA, then washed with water (40 mL *3), the organic layer was dried by Na ₂ SO ₄ , filtered and concentrated to obtain the crude product. The crude product was purified by PRE-HPLC (0.5% FA condition, H ₂ O/CH ₃ CN=3:1) and lyophilized to obtain desired product. Compound 46 (6.5 mg, 15.24 μmol, 10.47% yield) was obtained.

[0392] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.60 (br d, J = 4.3 Hz, 1H), 8.82 (br d, J = 2.8 Hz, 1H), 8.45 (br d, J = 7.0 Hz, 1H), 7.44 - 7.41 (m, 1H), 4.47 (br d, J = 4.8 Hz, 2H), 4.33 (br s, 1H), 4.13 (br s, 1H), 3.76 (br d, J = 7.6 Hz, 1H), 3.57 (br s, 1H), 3.49 (br d, J = 7.0 Hz, 2H), 2.89 (br d, J = 9.5 Hz, 1H), 2.77 (br d, J = 3.1 Hz, 2H), 1.874 - 1.55 (m, 9H), 1.21 - 1.13 (m, 2H), 0.94 (d, J = 6.5 Hz, 3H). LCMS for product (ESI+): m/z 427.0 [M+H] ⁺ , Rt: 0.838 min.

EXAMPLE 47 - Synthesis 1-(2-((3R,5S)-3,5-dimethylmorpholino)ethyl)-4-hydroxy-N-((ls ,4S)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 47)

[0393] Preparation of 1-(2-((3R,5S)-3,5-dimethylmorpholino)ethyl)-4-hydroxy-N-((ls ,4S)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0394] To a mixture of 4-hydroxy-N-(4-methylcyclohexyl)-2-oxo-1-(2-oxoethyl)- 1,8-naphthyridine-3- carboxamide (50 mg, 145.61 μmol, 1 eq) and (3S,5R)-3,5-dimethylmorpholine (16.77 mg, 145.61 μmol,

1 eq) in MeOH (3 mL) and CH ₃ COOH (0.1 mL)was added NaBH ₃ CN (27.45 mg, 436.84 μmol, 3 eq) in one portion at 20 °C. The mixture was stirred at 60°C for 16 h. The reaction mixture was concentrated to obtain a residue. The residue was dissolved in 40 mL EA, then washed with water (40 mL *3), dried by Na ₂ SO ₄ , filtered and concentrated to obtain a crude product. The residue was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 47 (2.5 mg, 5.65 μmol, 3.88% yield) was obtained.

[0395] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.69 - 10.67 (m, 1H), 8.82 (br s, 1H), 8.47 - 8.42 (m, 1H), 7.495 - 7.342 (m, 1H), 4.47 - 4.42 (m, 2H), 4.14 - 4.11 (m, 1H), 3.64 (br d, J = 10.1 Hz, 2H), 3.02 (br t, J = 10.5 Hz, 2H), 2.81 - 2.79 (m, 2H), 2.67 (br s, 1H), 2.34 (td, J = 1.8, 3.6 Hz, 1H), 1.68 - 1.58 (m, 7H), 1.17 (br d, J = 12.1 Hz, 2H), 1.11 (br d, J = 5.6 Hz, 6H), 0.93 - 0.92 (m, 3H). LCMS for product (ESI+): m/z 443.2 [M+H] ⁺ , Rt: 0.781 min.

EXAMPLE 48 - Synthesis 4-hydroxy-1-(2-(4-methoxypiperidin-1-yl)ethyl)-N-((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 48) [0396] Preparation of 4-hydroxy-1-(2-(4-methoxypiperidin-1-yl)ethyl)-N-((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0397] To a mixture of 4-hydroxy-N-(4-methylcyclohexyl)-2-oxo-1-(2-oxoethyl)- 1,8-naphthyridine-3- carboxamide (50 mg, 145.61 μmol, 1 eq) and 4-methoxypiperidine (16.77 mg, 145.61 μmol, 1 eq) in

MeOH (3 mL) and CH ₃ COOH (0.1 mL) was added NaBH ₃ CN (27.45 mg, 436.84 μmol, 3 eq) in one portion at 20 °C. The mixture was then heated to 60 °C and stirred for 2 h. The reaction mixture was concentrated to obtain a residue, the residue was dissolved in EA (40 ml), then washed with water (40 mL *3), the organic layer was dried by NajSCL. filtered and concentrated to obtain a crude product. The crude product was purified by prep-HPLC (0.5% FA condition) and lyophilized to obtain desired product. Compound 48 (5 mg, 11.30 μmol, 7.76% yield) was obtained.

[0398] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.83 - 10.78 (m, 1H), 8.70 (br s, 1H), 8.44 (br d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 7.37 - 7.24 (m, 1H), 4.53 (br t, J = 6.5 Hz, 2H), 4.13 (br s, 1H), 3.22 (br s, 4H), 2.82 - 2.73 (m, 2H), 2.58 (br t, J = 6.5 Hz, 2H), 2.19 (br t, J = 9.4 Hz, 2H), 1.66 - 1.40 (m, 9H), 1.41 - 1.33 (m, 2H), 1.28 - 1.20 (m, 2H), 0.95 (br d, J = 6.1 Hz, 3H). LCMS for product (ESI+): m/z 443.2 [M+H] ⁺ , Rt: 0.773 min.

EXAMPLE 49 - Synthesis 1-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)ethyl)-4-hydroxy- N-((ls,4s)- 4-methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 49) [0399] Preparation of 1-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)ethyl)-4-hydroxy- N-((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0400] To a solution of 4-hydroxy-N-(4-methylcyclohexyl) -2-oxo-1-(2-oxoethyl) -1, 8-naphthyridine- 3-carboxamide (50 mg, 145.61 μmol, 1 eq) and 3-oxa-6-aza-bicyclo[3.1.1]heptane 4- methylbenzenesulfonic acid (47.41 mg, 174.73 μmol, 1.2 eq) in MeOH (2 mL) was added NaBH ₃ CN (27.45 mg, 436.83 μmol, 3 eq) and AcOH (26.23 mg, 436.83 μmol, 24.98 μL, 3 eq). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was acidified to pH = 3 by dropwise addition of 1 M HCl and added to ethyl acetate (10 mL), then extracted with water (10 mL *3). The combined organic layers were washed with brine 10 mL (10 mL *2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10μm;mobile phase: [water (FA) -ACN];B%: 19%-49%, 10 min) and lyophilized. Compound 49 (15 mg, 31.06 μmol, 21.33% yield, 97.84% purity, FA salt).

[0401] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.71 - 10.48 (m, 1H), 8.81 (hr s, 1H), 8.46 (br d, J = 7.5 Hz, 1H), 8.15 (s, 1H), 7.50 - 7.35 (m, 1H), 4.42 (br s, 2H), 4.17 (br d, J = 10.9 Hz, 3H), 3.62 (br d, J = 10.3 Hz, 2H), 3.55 (br d, J = 4.0 Hz, 2H), 2.88 (br s, 2H), 1.79 - 1.43 (m, 9H), 1.22 - 1.10 (m, 2H), 0.93 (d, J = 6.5 Hz, 3H). LCMS for product (ESI+): m/z 427.0 [M+H] ⁺ , Rt: 0.844 min.

EXAMPLE 50 - Synthesis 1-(2-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)ethyl)-4-hydroxy-N -((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 50) [0402] Preparation of 1-(2-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)ethyl)-4-hydroxy-N -((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0403] To a solution of 4-hydroxy-N-(4-methylcyclohexyl) -2-oxo-1-(2-oxoethyl) -1, 8-naphthyridine- 3-carboxamide (50 mg, 145.61 μmol, 1 eq) and 2-oxa-5-azabicyclo[2.2.2]octane (25.33 mg, 160.17 μmol, 1.1 eq, 0.5 oxalic acid) in MeOH (2 mL) was added NaBPLCN (27.45 mg, 436.83 prnol, 3 eq) and AcOH (26.23 mg, 436.83 μmol, 24.98 μL, 3 eq). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was acidified to pH = 3 by dropwise addition of 1 M HCl, added to 10 mL water and extracted with ethyl acetate (10 mL *3). The combined organic layers were washed with brine (10 mL *2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10μm;mobilc phase: [water (FA) -ACN];B%: 20%-50%, 10 min) and lyophilized. The crude product was second purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* lOpimmobile phase: [water (FA) -ACN];B%: 18%-48%, 10 min) and lyophilized to give Compound 50 (25 mg, 56.75 μmol, 38.97% yield, 100% purity).

[0404] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.72 - 10.34 (m, 1H), 8.81 (br d, J = 3.2 Hz, 1H), 8.49 - 8.38 (m, 1H), 7.42 (br dd, J = 4.6, 7.6 Hz, 1H), 4.60 - 4.39 (m, 2H), 4.12 (br s, 1H), 4.03 (br d, J = 8.9 Hz, 1H), 3.71 - 3.63 (m, 2H), 3.13 - 2.94 (m, 2H), 2.90 - 2.71 (m, 3H), 1.93 - 1.80 (m, 2H), 1.78 - 1.70 (m, 2H), 1.68 - 1.50 (m, 8H), 1.23 - 1.11 (m, 2H), 0.93 (d, J = 6.5 Hz, 3H). LCMS for product (ESI+): m/z 441.1 [M+H] ⁺ , Rt: 0.851 min.

EXAMPLE 51 - Synthesis 4-hydroxy-1-(2-(3-methoxyazetidin-1-yl)ethyl)-N-((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 51) [0405] Preparation of 4-hydroxy-1-(2-(3-methoxyazetidin-1-yl)ethyl)-N-((ls,4s)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0406] To a solution of 4-hydroxy-N-(4-methylcyclohexyl)-2-oxo-1-(2-oxoethyl) -1,8-naphthyridine- 3-carboxamide (60 mg, 174.74 μmol, 1 eq) and 3-methoxyazetidine;hydrochloride (23.75 mg, 192.21 μmol, 1.1 eq) MeOH (2 mL) was added NaBH ₃ CN (32.94 mg, 524.21 μmol, 3 eq) and AcOH (31.48 mg, 524.21 μmol, 29.98 μL, 3 eq). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was quenched by addition IM HCl (10 mL) at 25 °C, and extracted with ethyl acetate (10 mL *3). The combined organic layers were washed with brine (10 mL *2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by re versed-phase HPLC (0.05% FA condition, Water/ ACN = 80%/20%) and lyophilized to give Compound 51 (8 mg, 19.30 μmol, 11.05% yield, 100% purity).

[0407] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.72 - 10.29 (m, 1H), 8.82 (dd, J = 1.7, 4.6 Hz, 1H), 8.46 (dd, J = 1.8, 7.9 Hz, 1H), 7.44 (dd, J = 4.6, 7.9 Hz, 1H), 4.43 (br t, J = 6.2 Hz, 2H), 4.19 - 4.09 (m, 1H), 3.95 (quin, J = 5.2 Hz, 1H), 3.74 - 3.60 (m, 2H), 3.14 (s, 3H), 3.09 - 2.94 (m, 2H), 2.90 - 2.77 (m, 2H), 1.79 - 1.71 (m, 2H), 1.68 - 1.58 (m, 4H), 1.53 (ddd, J = 3.4, 6.4, 9.8 Hz, 1H), 1.17 (br d, J = 12.0 Hz, 2H), 0.94 (d, J = 6.5 Hz, 3H). LCMS for product (ESI+): m/z 415.0 [M+H] ⁺ , Rt: 0.848 min.

EXAMPLE 52 - Synthesis 1-(4-fluorobenzyl)-4-hydroxy-N-((ls,4s)-1-(hydroxymethyl)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 52)

[0408] Step 1. Preparation of ((ls,4s)-1-amino-4-methylcyclohexyl)methanol [0409] L1AIH ₄ (72.43 mg, 1.91 mmol, 3 eq) was placed in a 50 mL round-bottom flask under N2 atmosphere at 0 °C and THF (3 mL) was added. Then (ls,4s)-1-amino-4-methylcyclohexane-1- carboxylic acid (100 mg, 636.09 μmol, 1 eq) was added in small portions as a solid, The mixture was stirred at 70 °C for 15 h under N2 atmosphere. The mixture was cooled to 0 °C, treated slowly with NaiCO; (10 mL), warmed to 20 °C and stirred at 20 °C for 2 h. A white precipitate formed, which was separated by filtration, washed with THF (20 mL) and twice with EtOAc (20 mL). The filtrate was concentrated in vacuo. The residue was dissolved in DCM (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give ((ls,4s)-1-amino-4-methylcyclohexyl)methanol (60 mg, 418.92 μmol, 65.86% yield).

[0410] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 4.54 - 4.15 (m, 1H), 3.22 (s, 2H), 1.60 - 1.53 (m, 2H), 1.52 - 1.45 (m, 2H), 1.35 (s, 1H), 1.15 - 1.06 (m, 2H), 1.01 - 0.92 (m, 2H), 0.85 (d, J = 6.7 Hz, 3H).

[0411] Step 2. Preparation of 1-(4-fluorobenzyl)-4-hydroxy-N-((ls,4s)-1-(hydroxymethyl)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridme-3-carboxamide

[0412] To a solution of ethyl l-[(4-fluorophenyl) methyl]-4-hydroxy-2-oxo- 1, 8-naphthyridine-3- carboxylate (50 mg, 146.06 μmol, 1 eq) and ((ls,4s)-1-amino-4-methylcyclohexyl)methanol (23.01 mg, 160.67 μmol, 1.1 eq) in toluene (1.5 mL) was added DIEA (47.19 mg, 365.15 μmol, 63.60 μL, 2.5 eq). The mixture was stirred at 120 °C for 1.5 hr. The mixture was directly concentrated. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10pm; mobile phase: [water (FA) -ACN]; B%: 76%-96%, 10 min) and lyophilized to give Compound 52 (16 mg, 36.26 μmol, 24.82% yield, 99.59% purity).

[0413] ¹ H NMR (400 MHz, DMSO-d6) δ = 10.34 - 10.18 (m, 1H), 8.77 (br d, J = 1.7 Hz, 1H), 8.52 - 8.42 (m, 1H), 7.47 - 7.38 (m, 1H), 7.29 (br dd, J = 5.7, 8.3 Hz, 2H), 7.10 (br t, J = 8.7 Hz, 2H), 5.59 (s, 2H), 5.00 - 4.78 (m, 1H), 3.69 (br d, J = 5.1 Hz, 2H), 3.30 (br s, 1H), 2.01 - 1.79 (m, 5H), 1.60 - 1.53 (m, 2H), 1.18 - 1.09 (m, 2H), 0.90 (br d, J = 6.2 Hz, 3H). LCMS for product (ESI+): m/z 440.0 [M+H] ⁺ , Rt: 1.095 min. EXAMPLE 53 - Synthesis 1-(4-fluorobenzyl)-4-hydroxy-N-((lr,4r)-1-(hydroxymethyl)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 53)

[0414] Step 1. Preparation of ((lr,4r)-1-amino-4-methylcyclohexyl)methanol

[0415] L1AIH ₄ (144.85 mg, 3.82 mmol, 3 eq) was added in a 50 mL round-bottom flask under Ni at 0 °C, THF was added (8 mL), and (lr,4r)-1-amino-4-methyl-cyclohexanecarboxylic acid (200 mg, 1.27 mmol, 1 eq) was added in small portions as a solid. Upon completion addition, the mixture was heated to 80 °C for 16 h. The mixture was cooled to 0 °C, treated slowly with saturated Na2CO; solution (5 mL), warmed to 20 °C, and stirred for 2 h. A white precipitate formed, which was separated by filtration, washed with THF (10 mL), and washed twice with EtOAc (10 mL). The filtrate was concentrated in vacuo. The residue was dissolved in DCM (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. Compound (lr,4r)-(l-amino-4-methyl-cyclohexyl)methanol (100 mg, 698.20 μmol, 54.88% yield) was obtained.

[0416] ¹ H NMR (400 MHz, DMSO-d6) δ = 4.73 - 4.08 (m, 1H), 3.40 - 3.30 (m, 2H), 3.05 (br s, 2H), 1.40 - 1.33 (m, 2H), 1.24 (br d, J = 6.2 Hz, 6H), 0.86 (br d, J = 5.3 Hz, 3H).

[0417] Step 2. Preparation of 1-(4-fhiorobenzyl)-4-hydroxy-N-((lr,4r)-1-(hydroxymethyl)-4- methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0418] To a mixture of ethyl l-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo- 1,8-naphthyridine-3- carboxylate (60 mg, 175.27 μmol, 1 eq) and (lr,4r)-(l-amino-4-methyl-cyclohexyl)methanol (25.10 mg, 175.27 μmol, 1 eq) in toluene (3 mL) was added DIPEA (67.96 mg, 525.82 μmol, 91.59 μL, 3 eq) in one portion at 20 °C. the mixture was then heated to 120 °C for 2 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10pm; mobile phase: [water(FA)-ACN];B%: 70%-100%,10min) and lyophilized to obtain desired product. Compound 53 (28 mg, 63.71 μmol, 36.35% yield) was obtained.

[0419] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.16 (s, 1H), 8.90 - 8.74 (m, 1H), 8.49 (br d, J = 7.9 Hz, 1H), 7.45 (dd, J = 4.7, 7.8 Hz, 1H), 7.33 (dd, J = 5.6, 8.4 Hz, 2H), 7.11 (t, J = 8.8 Hz, 2H), 5.62 (s, 2H), 4.80 (br s, 1H), 3.61 (d, J = 5.9 Hz, 2H), 2.20 (br d, J = 13.4 Hz, 2H), 1.58 (br d, J = 12.1 Hz, 2H), 1.43 - 1.30 (m, 3H), 1.18 - 1.00 (m, 2H), 0.85 (d, J = 6.5 Hz, 3H). LCMS for product (ESI+): m/z 440.2 [M+H] ⁺ , Rt: 1.007 min.

EXAMPLE 54 - Synthesis 6-(4-fluorophenyl)-4-hydroxy-N-((ls,4s)-1-(hydroxymethyl)-4- methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 54)

[0420] Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-((ls,4s)-1-(hydroxymethyl)-4- methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0421] To a solution of ethyl 6-(4-fluorophenyl) -4-hydroxy-1-(2-morpholinoethyl) -2-oxo- 1, 8- naphthyridine-3-carboxylate (50 mg, 113.26 μmol, 1 eq) and (ls,4s)-(l-amino-4-methyl-cyclohexyl) methanol (17.84 mg, 124.59 μmol, 1.1 eq) in toluene (1.5 mL) was added DIEA (36.60 mg, 283.16 μmol,

49.32 jrL, 2.5 eq). The mixture was stirred at 120 °C for 1.5 hr. The reaction mixture was directly concentrated. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10μm;mobile phase: [water (FA) -ACN];B%: 28%-48%, 10 min) and lyophilized to give Compound 54 (30 mg, 52.49 μmol, 46.34% yield, 94.24% purity).

[0422] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.56 - 10.15 (m, 1H), 9.13 (br s, 1H), 8.58 (br s, 1H), 7.88 (br s, 2H), 7.35 (br s, 2H), 5.00 - 4.83 (m, 1H), 4.62 - 4.42 (m, 2H), 3.66 (br d, J = 3.3 Hz, 2H), 3.54 (br s, 4H), 2.52 (br d, J = 1.9 Hz, 6H), 1.93 (br s, 4H), 1.57 (br d, J = 2.1 Hz, 3H), 1.21 - 1.08 (m, 2H), 0.91 (br s, 3H). LCMS for product (ESI+): m/z 539.0 [M+H] ⁺ , Rt: 0.903 min.

EXAMPLE 55 - Synthesis 6-(4-fluorophenyl)-4-hydroxy-N-((lr,4r)-1-(hydroxymethyl)-4- methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 55)

[0423] Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-((lr,4r)-1-(hydroxymethyl)-4- methylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0424] To a mixture of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,8- naphthyridine-3-carboxylate (100 mg, 226.53 μmol, 1.08 eq) and (lr,4r)-(l-amino-4-methyl- cyclohexyl)methanol (33.00 mg, 230.41 μmol, 1.1 eq) in toluene (3 mL) was added DIEA (81.21 mg, 628.38 |Ltmol, 109.45 μL, 3 eq) in one portion at 20 °C. The mixture was then heated to 120 °C for 2 h, then the mixture was added DMF (0.5 mL) and stirred at 120 °C for 4 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 55 (9 mg, 16.71 μmol, 7.98% yield) was obtained.

[0425] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.28 (br d, J = 3.3 Hz, 1H), 9.14 (br s, 1H), 8.60 (s, 1H), 7.89 (br d, J = 5.4 Hz, 2H), 7.37 (br t, J = 8.6 Hz, 2H), 4.83 (br s, 1H), 4.58 (br s, 2H), 3.63 (br s, 2H), 3.54 (br s, 4H), 3.29 - 3.28 (m, 1H), 2.62 (br d, J = 6.0 Hz, 2H), 2.53 (br s, 4H), 2.21 (br d, J = 13.1 Hz, 2H), 1.60 (br d, J = 12.5 Hz, 2H), 1.44 - 1.33 (m, 3H), 1.15 - 1.06 (m, 2H), 0.88 (br d, J = 6.1 Hz, 3H). LCMS for product (ESI+): m/z 539.2 [M+H] ⁺ , Rt: 0.805 min.

EXAMPLE 56 - Synthesis of 6-(4-fluorophenyl)-1-(2-(4-fluoropiperidin-1-yl)ethyl)-4-hyd roxy-N- ((ls,4s)-4-methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 56)

[0426] Step 1. Preparation of ethyl 6-(4-fluorophenyl)-4-hydroxy-2-oxo-lH- 1,8-naphthyridine-3- carboxylate

[0427] To a mixture of ethyl 6-bromo-4-hydroxy-2-oxo-lH- 1,8-naphthyridine-3-carboxylate (2 g, 6.39 mmol, 1 eq) and (4-fluorophenyl)boronic acid (1.07 g, 7.67 mmol, 1.2 eq) in EtOH (20 mL) and H ₂ O (5 mL) was added BrettPhos Pd G ₃ (579.04 mg, 638.77 μmol, 0.1 eq) and K ₃ PO ₄ (2.71 g, 12.78 mmol, 2 eq) in one portion at 20 °C under N2. The mixture was then heated to 80 °C and stirred for 16 h. The reaction mixture was filtered, the filter cake was triturated with MeOH (20 mL), and stirred at 20 °C for 30 min, then filtered and the filter cake was dried by reduced pressure. The crude product ethyl 6-(4- fluorophenyl)-4-hydroxy-2-oxo-lH- 1,8-naphthyridine-3-carboxylate (2.5 g, crude) was used into the next step without further purification.

[0428] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.12 (s, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 7.72 (br dd, J = 5.6, 8.4 Hz, 2H), 7.31 (br t, J = 8.8 Hz, 2H), 4.10 - 3.98 (m, 2H), 1.26 - 1.09 (m, 3H). LCMS for product (ESI+): m/z 329.1 [M+H] ⁺ , Rt: 0.822. [0429] Step 2. Preparation of ethyl l-allyl-6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1,8- naphthyridine-3-carboxylate

[0430] To a mixture of ethyl 6-(4-fluorophenyl)-4-hydroxy-2-oxo-lH- 1,8-naphthyridine-3-carboxylate (2.35 g, 7.16 mmol, 1 eq) in DMF (30 mL) was added LiHMDS (I M, 7.16 mL, 1 eq) dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 0.5 h, then warmed to 20 °C, and 3-bromoprop-1-ene (1.04 g, 8.59 mmol, 1.2 eq) was added, and the mixture was stirred at 20 °C for 16 h. The reaction mixture was quenched by water (10 mL), then concentrated to obtain a residue. The residue was dissolved in 50 mL 1 M HCl solution and stirred at 20 °C for 0.5 h, then filtered and washed with water (10 mL), and dried by reduced pressure to obtain desired product. Compound ethyl 1 -allyl-6-(4- fluorophenyl)-4-hydroxy-2-oxo- 1,8-naphthyridine-3-carboxylate (2.2 g, 5.97 mmol, 83.43% yield) was obtained.

[0431] ¹ H NMR (400 MHz, DMSO- d ₆ ) 8 = 8.95 (d, J = 2.4 Hz, 1H), 8.59 (d, J = 2.3 Hz, 1H), 7.88 -

7.78 (m, 2H), 7.35 (t, J = 8.8 Hz, 2H), 6.07 - 5.85 (m, 1H), 5.13 - 4.90 (m, 4H), 4.26 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). LCMS for product (ESI+): m/z 368.9 [M+H] ⁺ , Rt: 1.018 min.

[0432] Step 3. Preparation of l-allyl-6-(4-fluorophenyl)-4-hydroxy-N-(4-methylcyclohexyl)- 2- oxo-1, 8-naphthyridine-3-carboxamide

[0433] To a mixture of ethyl l-allyl-6-(4-fluorophenyl)-4-hydroxy-2-oxo- 1,8-naphthyridine-3- carboxylate (2.2 g, 5.97 mmol, 1 eq) and 4-methylcyclohexanamine (893.84 mg, 5.97 mmol, 1.14 mL, 1 eq, HCl) in toluene (40 mL) was added DIPEA (2.32 g, 17.92 mmol, 3.12 mL, 3 eq) in one portion at 20 °C. The mixture was then heated to 110 °C and stirred for 72 h. The reaction mixture was concentrated to obtain a residue, the residue was dissolved in EA (80 mL), then washed with water (50 mL *3), dried by Na ₂ SO ₄ . filtered and concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate/Petroleum ethergradient @50 mL/min) and concentrated to obtain desired product. Compound 1- allyl-6-(4-fluorophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-2- oxo- 1,8-naphthyridine-3-carboxamide (1.7 g, 3.90 mmol, 65.36% yield) was obtained.

[0434] ¹ H NMR (400 MHz, DMSO- d ₆ ) 8 = 10.52 (br d, J = 7.4 Hz, 1H), 9.12 (br d, J = 1.1 Hz, 1H),

8.60 (br s, 1H), 7.89 (br dd, J = 5.5, 8.0 Hz, 2H), 7.36 (br t, J = 8.7 Hz, 2H), 6.11 - 5.89 (m, 1H), 5.17 -

4.94 (m, 4H), 4.15 (br d, J = 3.9 Hz, 1H), 1.80 - 1.54 (m, 7H), 1.30 - 1.18 (m, 2H), 0.94 (d, J = 6.5 Hz,

3H). LCMS for product (ESI+): m/z 436.2 [M+H] ⁺ , Rt: 1.150 min.

[0435] Step 4. Preparation of 1-(2,3-dihydroxypropyl)-6-(4-fluorophenyl)-4-hydroxy-N-(4- methylcyclohexyl)-2-oxo- 1,8-naphthyridine-3-carboxamide

[0436] To a mixture of l-allyl-6-(4-fluorophenyl)-4-hydroxy-N-(4-methylcyclohexyl)- 2-oxo- 1,8- naphthyridine-3-carboxamide (1.7 g, 3.90 mmol, 1 eq) in THF (20 mL) and HzO (20 mL) was added KzOsO^HzO (719.16 mg, 1.95 mmol, 0.5 eq) and NaIO4 (834.96 mg, 3.90 mmol, 1 eq) in one portion at 20 °C. The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to obtain a solution, then filtered, the filter cake was triturated with 10 mL THF/H ₂ O (1:1), filtered and the filter cake was dried by reduced pressure to obtain desired product. The crude product 1 -(2,3- dihydroxypropyl)-6-(4-fluorophenyl)-4-hydroxy-N-(4-methylcyc lohexyl)-2-oxo- 1,8-naphthyridine-3- carboxamide (1.05 g, 2.24 mmol, 57.30% yield) was used into the next step without further purification.

[0437] ¹ H NMR (400 MHz, DMSO- d ₆ ) 8 = 10.61 (s, 1H), 9.09 (br s, 1H), 8.58 (s, 1H), 7.87 (br s, 2H), 7.35 (br t, J = 8.3 Hz, 2H), 4.72 - 4.58 (m, 2H), 4.44 - 4.32 (m, 1H), 4.18 - 3.96 (m, 2H), 1.83 - 1.48 (m, 7H), 1.28 - 1.12 (m, 2H), 0.94 (br d, J = 6.2 Hz, 3H). LCMS for product (ESI+): m/z 470.1 [M+H] ⁺ , Rt: 0.790 min.

[0438] Step 5. Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-2-oxo-1- (2- oxoethyl)- 1,8-naphthyridine-3-carboxamide

[0439] To a mixture of 1-(2,3-dihydroxypropyl)-6-(4-fluorophenyl)-4-hydroxy-N-(4- methylcyclohexyl)-2-oxo- 1,8-naphthyridine-3-carboxamide (950 mg, 2.02 mmol, 1 eq) in THF (10 mL) and H ₂ O (10 mL) was added NalCL (432.79 mg, 2.02 mmol, 1 eq) in one portion at 20 °C. The mixture was stirred at 20 °C for 2 h, then a second portion of NalCL (216.39 mg, 1.01 mmol, 0.5 eq) was added and stirred for 2 h, then a third portion of NalCL (216.39 mg, 1.01 mmol, 0.5 eq) was added, the mixture was stirred at 20 °C for 2 h, then a fourth portion of NalCL (216.39 mg, 1.01 mmol, 0.5 eq) was added and stirred for 2 h. The reaction mixture was filtered and washed with water (20 mL), then concentrated to obtain desired product. The crude product 6-(4-fluorophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-2- oxo-1-(2-oxoethyl)- 1,8-naphthyridine-3-carboxamide (590 mg, 1.35 mmol, 66.66% yield) was used into the next step without further purification.

[0440] ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.42 (m, 1H), 9.79 (br s, 1H), 9.12 (br s, 1H), 8.68 (br s, 1H), 7.94 (br s, 2H), 7.41 (br t, J = 7.9 Hz, 2H), 5.40 (br s, 2H), 4.21 (br s, 1H), 1.93 - 1.53 (m, 7H), 1.39

- 1.12 (m, 2H), 0.97 (br d, J = 6.5 Hz, 3H). LCMS for product (ESI+): m/z 438.1 [M+H] ⁺ , Rt: 1.052 min.

[0441] Step 6. Preparation of 6-(4-fluorophenyl)-1-(2-(4-fluoropiperidin-1-yl)ethyl)-4-hyd roxy-N- ((ls,4s)-4-methylcyclohexyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0442] To a mixture of 6-(4-fluorophenyl)-4-hydroxy-N-(4-methylcyclohexyl)-2-oxo-1- (2-oxoethyl)- l,8-naphthyridine-3-carboxamide (80 mg, 182.87 μmol, 1 eq) and 4-fluoropiperidine hydrochloride (18.86 mg, 182.87 μmol, 1 eq) in MeOH (3 mL) and CH ₃ COOH (0.1 mL) was added NaBH ₃ CN (34.48 mg, 548.62 μmol, 3 eq) in one portion at 20 °C. The mixture was then heated to 60 °C and stirred for 2 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition) and lyophilized to obtain crude product, the crude product was purified by prep-HPLC (HCl condition, column: 3_Phenomenex Luna C1875*30mm*3pm; mobile phase: [water(HCl)-ACN];B%: 47%-67%,7min) and lyophilized to obtain desired product. Compound 56 (25 mg, 47.66 μmol, 26.06% yield) was obtained.

[0443] ¹ H NMR (400 MHz, Methanol- d ₄ ) δ = 10.49 (br d, J = 7.4 Hz, 1H), 9.99 - 9.71 (m, 1H), 9.19 (d, J = 2.4 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 7.95 (dd, J = 5.4, 8.8 Hz, 2H), 7.43 (t, J = 8.9 Hz, 2H), 5.13 - 4.93 (m, 1H), 4.86 (br s, 2H), 4.28 - 4.18 (m, 1H), 3.91 - 3.71 (m, 2H), 3.63 - 3.49 (m, 2H), 3.31 - 3.14 (m, 2H), 2.36 - 2.00 (m, 4 H), 1.82 - 1.49 (m, 7H), 1.29 - 1.16 (m, 2H), 0.99 (d, J = 6.5 Hz, 3H). LCMS for product (ESI+): m/z 525.3 [M+H] ⁺ , Rt: 0.855 min. EXAMPLE 57 - Separation of 4-hydroxy-N-(4-methylcycloheptyl)-1-(2-morpholinoethyl)-2-ox o- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 57A and 57B)

[0444] Separation of 4-hydroxy-N-(4-methylcycloheptyl)-1-(2-morpholinoethyl)-2-ox o- 1,2- dihydro- 1,8-naphthyridine-3-carboxamide

[0445] Compound 44 (48 mg, 112.02 μmol ) was separated into two fractions by SFC. column: Daicel ChiralPak lG (250*30mm, 10μm);mobile phase: [0.1%NH ₃ H ₂ O MeOH];B%: 40%-40%,5.7 min; 200 min, and then concentrated to obtain Compound 57A with a retention time of 1.245 min. (8 mg, 18.67 μmol, 16.67% yield) and Compound 57B with a retention time of 1.559 min. (18 mg, 42.00 μmol, 37.50% yield).

[0446] Compound 57A: ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.58 - 10.31 (m, 1H), 8.78 (hr s, 1H), 8.55 - 8.38 (m, 1H), 7.40 (br d, J = 1.9 Hz, 1H), 4.53 (br s, 2H), 4.15 - 3.96 (m, 1H), 3.53 (br s, 4H), 2.50 - 2.39 (m, 6H), 1.83 - 1.33 (m, 9H), 1.14 (br t, J = 7.2 Hz, 2H), 0.92 (br d, J = 5.8 Hz, 3H). LCMS for product (ESI+): m/z 429.1 [M+H] ⁺ , Rt: 0.869 min.

[0447] Compound 57B: ¹ H NMR (400 MHz, DMSO- d ₆ ) 3 = 10.54 - 10.10 (m, 1H), 8.80 (br s, 1H), 8.45 (br d, J = 7.5 Hz, 1H), 7.42 (br s, 1H), 4.53 (br s, 2H), 4.02 (br d, J = 2.6 Hz, 1H), 3.53 (br s, 4H), 2.53 - 2.36 (m, 6H), 1.85 - 1.45 (m, 9H), 1.27 - 1.16 (m, 2H), 0.91 (br s, 3H). LCMS for product (ESI+): m/z 429.1 [M+H] ⁺ , Rt: 0.864 min.

EXAMPLE 58 - Synthesis N-(4,4-difluorocyclohexyl)-4-hydroxy-1-(2-morpholinoethyl)-2 -oxo- 1,2- dihydro- 1,8-naphthyridine-3-carboxamide (Compound 58) [0448] Step 1. Preparation of ethyl l-allyl-4-hydroxy-2-oxo- 1, 8-naphthyridine-3-carboxylate

[0449] To a mixture of ethyl 4-hydroxy-2-oxo-lH- 1,8-naphthyridine-3-carboxylate (4 g, 17.08 mmol, 1 eq) in DMF (40 mL) was added LiHMDS (1 M, 34.2 mL, 2 eq) dropwise at 0 °C under Nz. The mixture was stirred at 0 °C for 0.5 h, then warmed to 20 °C and stirred for 0.5 h, then 3 -bromoprop- 1-ene (3.10 g, 25.62 mmol, 1.5 eq) was added, and the mixture was stirred at 20 °C for 16 h. After reacting 16 h, LiHMDS (1 M, 17.08 mL, 1 eq) and 3 -bromoprop- 1-ene (1.03 g, 8.54 mmol, 0.5 eq) were added in turn, the reaction mixture was stirred at 20 °C for another 24 h. The reaction mixture was quenched by water (20 mL), then concentrated to obtain a solution (removed DMF). The solution was diluted with 80 mL 1 M HCl solution and stirred at 20 °C for 16 h, filtered and washed with water (10 mL), and the filter cake was dried by reduced pressure. The crude product ethyl l-allyl-4-hydroxy-2-oxo- 1,8-naphthyridine-3- carboxylate (3.5 g, 12.76 mmol, 74.72% yield) was taken to the next step without further purification.

[0450] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 13.53 - 12.58 (m, 1H), 8.72 (dd, J = 1.8, 4.6 Hz, 1H), 8.33 (dd, J = 1.7, 8.0 Hz, 1H), 7.36 (dd, J = 4.6, 7.9 Hz, 1H), 5.97 - 5.87 (m, 1H), 5.07 - 4.99 (m, 2H), 4.94 - 4.93 (m, 2H), 4.36 - 4.30 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H). LCMS for product (ESI+): m/z 275.1 [M+H] ⁺ , Rt: 0.783 min.

[0451] Step 2. Preparation of l-allyl-N-(4, 4-difluorocyclohexyl) -4-hydroxy-2-oxo- 1, 8- naphthyridine-3-carboxamide

[0452] To a solution of ethyl l-allyl-4-hydroxy-2-oxo- 1,8-naphthyridine-3-carboxylate (1.3 g, 4.74 mmol, 1 eq) and 4,4-difluorocyclohexanamine (813.43 mg, 4.74 mmol, 1 eq, HCl) in toluene (15 mL) was added DIPEA (1.53 g, 11.85 mmol, 2.06 mL, 2.5 eq). The mixture was stirred at 110 °C for 15 hr. To the reaction mixture was added IM HCl 1 mL and directly concentrated. The residue was purified by silica gel chromatography (SiOz, Petroleum ether/Ethyl acetate = 1/0 to 4/1, product came out at Petroleum ether/Ethyl acetate = 4/1) to give l-allyl-N-(4, 4-difluorocyclohexyl) -4-hydroxy-2-oxo- 1, 8- naphthyridine-3-carboxamide (1.1 g, crude).

[0453] LCMS for product (ESI+) : m/z 363.9 [M+H] ⁺ , RT: 1.042 min. [0454] Step 3. Preparation of N-(4, 4-difluorocyclohexyl) -1-(2, 3-dihydroxypropyl) -4-hydroxy-2- oxo-1, 8-naphthyridine-3-carboxamide

[0455] To a solution of l-allyl-N-(4, 4-difluorocyclohexyl) -4-hydroxy-2-oxo- 1, 8-naphthyridine-3- carboxamide (1.1 g, 3.03 mmol, 1 eq) in THF (10 mL) and H ₂ O (10 mL) was added NaIC>4 (647.51 mg, 3.03 mmol, 167.75 μL, 1 eq) and K ₂ OSO ₄ 2H ₂ O (223.09 mg, 605.46 μmol, 0.2 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to remove THF, and the precipitation was collected by filtration to obtain desired product. The filtrate was purified by reversed flash (0.05% FA condition, water/ ACN = 80%/20%) and lyophilized to give desired product. N-(4, 4-difluorocyclohexyl) -1-(2, 3-dihydroxypropyl) -4-hydroxy-2-oxo- 1, 8-naphthyridine-3- carboxamide (550 mg, 1.84 mmol, 60.68% yield) was obtained.

[0456] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.35 (br d, J = 7.0 Hz, 1H), 8.79 (br d, J = 3.4 Hz, 1H), 8.44 (br d, J = 7.8 Hz, 1H), 7.41 (dd, J = 4.6, 7.8 Hz, 1H), 4.66 (br d, J = 5.3 Hz, 1H), 4.64 - 4.59 (m, 1H), 4.56 (br t, J = 5.7 Hz, 1H), 4.31 (br dd, J = 5.1, 12.8 Hz, 1H), 4.04 (br dd, J = 6.8, 13.6 Hz, 1H), 3.97 (td, J = 5.5, 7.8 Hz, 1H), 3.44 - 3.37 (m, 2H), 2.12 - 1.93 (m, 7H), 1.66 (br d, J = 7.5 Hz, 2H).

[0457] Step 4. Preparation of 4-hydroxy- N-(4, 4-difluorocyclohexyl) -4-hydroxy-2-oxo-1-(2- oxoethyl) -1, 8-naphthyridine-3-carboxamide

[0458] To a solution of N-(4, 4-difluorocyclohexyl) -1-(2, 3-dihydroxypropyl) -4-hydroxy-2-oxo- 1, 8- naphthyridine-3-carboxamide (550 mg, 1.38 mmol, 1 eq) in THF (5 mL) and H ₂ O (5 mL) was added NalCL (148.02 mg, 692.05 μmol, 38.35 μL, 0.5 eq) and stirred for 1 h, then NalCL (148.02 mg, 692.05 μmol, 38.35 μL, 0.5 eq) was added. The mixture was stirred at 20 °C for 14 hr. The reaction mixture was cooled to 0 °C for 10 min, whereupon precipiration formed. The precipitated solid was collected by filtration. N-(4, 4-difluorocyclohexyl) -4-hydroxy-2-oxo-l -(2 -oxoethyl) -1, 8-naphthyridine-3- carboxamide (480 mg, 1.31 mmol, 94.93% yield) was obtained. [0459] ¹ H NMR (400 MHz, DMSO-J6) δ = 10.15 - 9.99 (m, 1H), 9.69 (s, 1H), 8.75 (dd, J = 1.6, 4.6 Hz, 1H), 8.50 (dd, J = 1.6, 7.9 Hz, 1H), 7.46 (dd, J = 4.7, 7.9 Hz, 1H), 5.29 (s, 2H), 4.11 - 4.02 (m, 1H), 2.10 - 1.93 (m, 9H), 1.73 - 1.59 (m, 3H).

[0460] Step 5. Preparation of N-(4,4-difluorocyclohexyl)-4-hydroxy-1-(2-morpholinoethyl)-2 -oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0461] To a solution of N-(4,4-difluorocyclohexyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)- 1,8- naphthyridine-3-carboxamide (60 mg, 164.23 μmol, 1 eq) and morpholine (15.74 mg, 180.65 μmol, 15.90 μL, 1.1 eq) in MeOH (2 mL) was added NaBH ₃ CN (30.96 mg, 492.69 μmol, 3 eq) and AcOH (29.59 mg, 492.69 μmol, 28.18 μL, 3 eq). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was quenched by addition IM HCl (10 mL) at 25 °C, and then diluted with water (10 mL), and extracted with ethyl acetate (10 mL *3). The combined organic layers were washed with brine (10 mL *2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10μm;mobile phase: [water (FA) -ACN];B%: 16%-46%, 10 min) and lyophilized to give Compound 58 (22 mg, 50.31 μmol, 30.63% yield, 99.80% purity).

[0462] ¹ H NMR (400 MHz, Methanol-d ₄ ) δ = 10.41 - 10.17 (m, 1H), 8.81 (br s, 1H), 8.45 (br d, J = 7.5 Hz, 1H), 7.43 (br s, 1H), 4.53 (br t, J = 6.3 Hz, 2H), 4.13 - 3.96 (m, 1H), 3.52 (br s, 4H), 2.52 (br d, J = 2.0 Hz, 2H), 2.47 - 2.43 (m, 4H), 2.02 (br d, J = 16.9 Hz, 6H), 1.74 - 1.57 (m, 2H). LCMS for product (ESI+): m/z 437.0 [M+H] ⁺ , Rt: 0.791 min.

EXAMPLE 59 - Synthesis of 1-(2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)-N-(4,4- difluorocyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 59) [0463] Preparation of 1-(2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)-N-(4, 4-difhiorocyclohexyl)-4- hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0464] To a solution of N-(4,4-difluorocyclohexyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)- 1,8- naphthyridine-3-carboxamide (60 mg, 164.23 μmol, 1 eq) and 7-oxa-4-azaspiro[2.5]octane (20.44 mg, 180.65 μmol, 1.1 eq) in MeOH (2 mL) was added NaBH ₃ CN (30.96 mg, 492.69 μmol, 3 eq) and AcOH (29.59 mg, 492.69 μmol, 28.18 μL, 3 eq). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was quenched by addition IM HCl (10 mL) at 25 °C, and then diluted with water (10 mL), and extracted with ethyl acetate (10 mL *3). The combined organic layers were washed with brine (10 mL *2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10μm;mobile phase: [water (FA) -ACN];B%: 23%-53%, 10 min) and lyophilized to give Compound 59 (23 mg, 49.43 μmol, 30.10% yield, 99.40% purity).

[0465] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.43 - 10.17 (m, 1H), 8.80 (hr s, 1H), 8.44 (br d, J = 7.1 Hz, 1H), 7.42 (br s, 1H), 4.38 (br s, 2H), 4.05 (br dd, J = 2.0, 3.5 Hz, 1H), 3.58 (br s, 2H), 3.26 (br s, 2H), 2.89 (br s, 2H), 2.84 (br s, 2H), 2.00 (br d, J = 1.6 Hz, 6H), 1.67 (br d, J = 6.1 Hz, 2H), 0.38 (br d, J = 7.1 Hz, 4H). LCMS for product (ESI+): m/z 463.0 [M+H] ⁺ , Rt: 0.815 min.

EXAMPLE 60 - Synthesis of 1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-N-(4,4- difluorocyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 60) [0466] Preparation of 1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-N-(4,4- difluorocyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0467] To a solution of N-(4,4-difluorocyclohexyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)- 1,8- naphthyridine-3-carboxamide (60 mg, 164.23 μmol, 1 eq) and (IS, 4S)-2-oxa-5- azabicyclo[2.2.1]heptane;hydrochloride (24.50 mg, 180.65 μmol, 1.1 eq) in MeOH (2 mL) was added NaBH ₃ CN (30.96 mg, 492.69 μmol, 3 eq) and AcOH (29.59 mg, 492.69 μmol, 28.18 μL, 3 eq). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was quenched by addition IM HCl (10 mL) at 25 °C, and then diluted with water (10 mL), and extracted with ethyl acetate (10 mL *3). The combined organic layers were washed with brine (10 mL *2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10μm;mobile phase: [water (FA) -ACN];B%: 14%-44%, 10 min) and lyophilized to give Compound 60 (22 mg, 48.63 μmol, 29.61% yield, 99.14% purity).

[0468] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.43 - 10.22 (m, 1H), 8.93 - 8.72 (m, 1H), 8.45 (br d, J = 6.8 Hz, 1H), 7.52 - 7.33 (m, 1H), 4.44 (br s, 2H), 4.33 (br s, 1H), 4.11 - 3.96 (m, 1H), 3.75 (br d, J = 7.5 Hz, 1H), 3.57 (br s, 1H), 3.48 (br d, J = 6.7 Hz, 1H), 2.88 (br d, J = 9.5 Hz, 1H), 2.77 (br s, 2H), 2.55 (br d, J = 9.7 Hz, 1H), 2.00 (br s, 6H), 1.71 - 1.55 (m, 4H). LCMS for product (ESI+): m/z 449.0 [M+H] ⁺ , Rt: 0.802 min.

EXAMPLE 61 - Synthesis of N-(4,4-difluorocyclohexyl)-1-(2-(4-fluoropiperidin-1-yl)ethy l)-4- hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 61) [0469] Preparation of N-(4,4-difluorocyclohexyl)-1-(2-(4-fluoropiperidin-1-yl)ethy l)-4-hydroxy-2- oxo-1, 2-dihydro- 1,8-naphthyridine-3-carboxamide

[0470] To a solution of N-(4,4-difluorocyclohexyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)- 1,8- naphthyridine-3-carboxamide (60 mg, 164.23 μmol, 1 eq) and 4-fluoropiperidine;hydrochloride (25.22 mg, 180.66 μmol, 1.1 eq) in MeOH (2 mL) was added NaBHiCN (30.96 mg, 492.70 μmol, 3 eq) and AcOH (29.59 mg, 492.70 μmol, 28.18 μL, 3 eq). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was quenched by addition IM HCl (10 mL) at 25 °C, and then diluted with water (10 mL), and extracted with ethyl acetate (10 mL *3). The combined organic layers were washed with brine (10 mL *2), dried over NtoSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25 mm* 10pm; mobile phase: [water (FA) -ACN];B%: 17% -47%, 10 min) and lyophilized to obtained crude product. The crude product was second purified by prep-HPLC (FA condition, column: Phenomenex Synergi Cl 8 150*25 mm* 10μm;mobile phase: [water (FA) -ACN];B%: 16%-46%, 10 min) and lyophilized to give Compound 61 (40 mg, 88.40 μmol, 53.83% yield).

[0471] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.54 - 10.13 (m, 1H), 8.81 (br s, 1H), 8.45 (br d, J = 7.3 Hz, 1H), 7.42 (br s, 1H), 4.75 - 4.57 (m, 1H), 4.51 (br s, 2H), 4.11 - 3.97 (m, 1H), 2.68 - 2.59 (m, 2H), 2.56 (br d, J = 6.4 Hz, 2H), 2.39 (br s, 2H), 2.10 - 1.94 (m, 6H), 1.87 - 1.74 (m, 2H), 1.65 (br d, J = 2.9 Hz, 4H). LCMS for product (ESI+): m/z 453.2 [M+H] ⁺ , Rt: 0.749 min.

EXAMPLE 62 - Synthesis of 1-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)ethyl)-N-(4,4- difluorocyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 62) [0472] Preparation of 1-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)ethyl)-N-(4,4- difluorocyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0473] To a solution of N-(4,4-difluorocyclohexyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)- 1,8- naphthyridine-3-carboxamide (60 mg, 164.23 μmol, 1 eq) and 3-oxa-6-azabicyclo[3.1.1]heptane (44.56 mg, 164.23 μmol, 1 eq, TsOH) in MeOH (2 mL) was added NaBH ₃ CN (30.96 mg, 492.69 μmol, 3 eq) and AcOH (29.59 mg, 492.69 μmol, 28.18 μL, 3 eq). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was quenched by addition IM HCl (10 mL) at 25 °C, and then diluted with water (10 mL), and extracted with ethyl acetate (10 mL *3). The combined organic layers were washed with brine (10 mL *2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18 150*25 mm* 10μm;mobile phase: [water (FA) -ACN];B%: 15%-45%, 10 min) and lyophilized to give Compound 62 (16 mg, 35.47 μmol, 21.60% yield, 99.42% purity).

[0474] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.49 - 10.18 (m, 1H), 8.81 (br s, 1H), 8.46 (br d, J = 7.0 Hz, 1H), 7.50 - 7.33 (m, 1H), 4.39 (br s, 2H), 4.15 (br d, J = 10.6 Hz, 2H), 4.08 - 4.00 (m, 1H), 3.60 (br d, J = 9.9 Hz, 2H), 3.51 (br s, 2H), 2.84 (br s, 2H), 2.01 (br d, J = 4.4 Hz, 6H), 1.78 - 1.46 (m, 4H). LCMS for product (ESI+): m/z 449.0 [M+H] ⁺ , Rt: 0.799 min.

EXAMPLE 63 - Synthesis N-((ls,4s)-4-fluorocyclohexyl)-4-hydroxy-1-(2-morpholinoethy l)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 63)

[0475] Step 1. Preparation of trans-tert-butyl N-(4-fluorocyclohexyl)carbamate [0476] To a mixture of trans -tert-butyl N-(4-hydroxycyclohexyl)carbamate (5 g, 23.22 mmol, 1 eq) in DCM (50 mL) was added DAST (4.12 g, 25.55 mmol, 3.38 mL, 1.1 eq) in DCM (10 mL) at -78 °C dropwise. After addition, the mixture was stirred at -78 °C for 4 h. The reaction mixture was quenched by NaHCO: solution (100 mL), then the organic layer was separated, and washed by NaHCO: solution (100 mL *2), dried by NaiSOi. filtered and concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) and concentrated to obtain desired product. Compound trans-tert-butyl N-(4-fluorocyclohexyl)carbamate (600 mg, 2.76 mmol, 11.89% yield) was obtained.

[0477] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 6.80 (br d, J = 7.0 Hz, 1H), 4.79 - 4.67 (m, 1H), 3.29 (br d, J = 2.1 Hz, 1H), 1.93 - 1.82 (m, 2H), 1.64 - 1.54 (m, 3H), 1.52 - 1.41 (m, 3H), 1.38 (s, 9H).

[0478] Step 2. Preparation of trans-4-fluorocyclohexanamine

[0479] To a mixture of trans-tert-butyl N-(4-fluorocyclohexyl)carbamate (1.2 g, 5.52 mmol, 1 eq) in DCM (15 mL) was added TFA (9.24 g, 81.04 mmol, 6.00 mL, 14.67 eq) dropwise at 20 °C, and the mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to obtain desired product.

Compound trans-4-fluorocyclohexanamine (1.2 g, 5.19 mmol, 93.98% yield, TFA) was obtained.

[0480] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 7.82 (br s, 3H), 4.80 - 4.68 (m, 1H), 3.02 (br dd, J = 5.1, 9.7 Hz, 1H), 1.95 - 1.83 (m, 2H), 1.76 - 1.67 (m, 2H), 1.53 - 1.41 (m, 4H).

[0481] Step 3. Preparation of l-allyl-N-((ls,4s)-4-fluorocyclohexyl)-4-hydroxy-2-oxo- 1,8- naphthyridine-3-carboxamide

[0482] To a mixture of ethyl l-allyl-4-hydroxy-2-oxo- 1,8-naphthyridine-3-carboxylate (1.42 g, 5.19 mmol, 1 eq) and trans-4-fluorocyclohexanamine (1.2 g, 5.19 mmol, 1 eq, TFA) in toluene (20 mL) was added DIPEA (2.01 g, 15.57 mmol, 2.71 mL, 3 eq) in one portion at 20 °C. The mixture was then heated to 110 °C for 16 h. The reaction mixture was concentrated to obtain a residue, the residue was dissolved in 100 mL EA, then washed with brine (60 mL *2), dried by Na ₂ SO ₄ , filtered and concentrated to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) and concentrated to obtain desired product. Compound l-allyl-N-((ls,4s)-4-fluorocyclohexyl)-4- hydroxy-2-oxo- 1,8-naphthyridine-3-carboxamide (930 mg, 2.69 mmol, 51.88% yield) was obtained. [0483] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.31 (br d, J = 7.6 Hz, 1H), 8.81 (dd, J = 1.7, 4.5 Hz, 1H), 8.48 (dd, J = 1.6, 7.8 Hz, 1H), 7.45 (dd, J = 4.6, 7.8 Hz, 1H), 6.00 - 5.93 (m, 1H), 5.11 - 4.96 (m, 4H), 4.87 - 4.75 (m, 1H), 4.98 - 3.96 (m, 1H), 2.00 - 1.56 (m, 8H).

[0484] Step 4. Preparation of 1-(2,3-dihydroxypropyl)-N-((ls,4s)-4-fluorocyclohexyl)-4-hyd roxy- 2-oxo- 1,8-naphthyridine-3-carboxamide

[0485] To a mixture of l-allyl-N-((ls,4s)-4-fluorocyclohexyl)-4-hydroxy-2-oxo- 1,8-naphthyridine-3- carboxamide (930 mg, 2.69 mmol, 1 eq) in THF (10 mL) and HjO (10 mL) was added K ₂ OSO ₄ 2H ₂ O (198.43 mg, 538.56 μmol, 0.2 eq) and NaIO ₄ (575.96 mg, 2.69 mmol, 1 eq) in one portion at 20 °C. The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was filtered, and the filtrate was concentrated by reduce pressure at 30 °C whereupon a solid appeared, which was filtered and the filter cake was dried by reduced pressure to obtain desired product. The filtrate was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 1-(2,3-dihydroxypropyl)-N-((ls,4s)-4- fluorocyclohexyl)-4-hydroxy-2-oxo- 1,8-naphthyridine-3-carboxamide (710 mg, 1.87 mmol, 69.50% yield) was obtained.

[0486] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.38 (br d, J = 7.3 Hz, 1H), 8.80 - 8.79 (m, 1H), 8.45 (dd, J = 1.3, 7.8 Hz, 1H), 7.42 (dd, J = 4.6, 7.8 Hz, 1H), 4.87 - 4.75 (m, 1H), 4.68 - 4.56 (m, 3H), 4.33 (dd, J = 5.1, 12.9 Hz, 1H), 3.99 (td, J = 5.3, 7.9 Hz, 2H), 1.96 - 1.57 (m, 8H). LCMS for product (ESI+): m/z 380.1 [M+H] ⁺ , Rt: 0.775min.

[0487] Step 5. Preparation of N-((ls,4s)-4-fluorocyclohexyl)-4-hydroxy-2-oxo-1-(2-oxoethyl )- 1,8- naphthyridine-3-carboxamide

[0488] To a mixture of 1-(2,3-dihydroxypropyl)-N-((ls,4s)-4-fluorocyclohexyl)-44iyd roxy-2-oxo- 1,8- naphthyridine-3-carboxamide (550 mg, 1.45 mmol, 1 eq) in THF (8 mL) and HjO (8 mL) was added NaIO ₄ (310.08 mg, 1.45 mmol, 1 eq) in one portion at 20 °C, then the mixture was stirred at 20 °C for 6 h. The reaction mixture was filtered, and the filtrate was concentrated, whereupon a solid appeared, was filtered and the filter cake was dried by reduced pressure to obtain desired product. Compound N- ((1 s,4s)-4-fluorocyclohexyl)-4-hydroxy-2-oxo- 1 -(2-oxoethyl)- 1 ,8-naphthyridine-3-carboxamide (480 mg, 1.38 mmol, 95.32% yield) was obtained.

[0489] ¹ H NMR (400 MHz, DMSO-J6) δ = 10.19 - 10.13 (m, 1H), 9.70 (s, 1H), 8.75 (br s, 1H), 8.50 (br d, J = 7.8 Hz, 1H), 7.46 (br s, 1H), 5.29 (br s, 2H), 4.86 - 4.74 (m, 1H), 3.97 (br d, J = 5.1 Hz, 1H), 1.89 - 1.58 (m, 8H). LCMS for product (ESI+): m/z 347.8 [M+H] ⁺ , Rt: 0.922 min.

[0490] Step 6. Preparation of N-((ls,4s)-4-fluorocyclohexyl)-4-hydroxy-1-(2-morpholinoethy l)-2- oxo-1, 2-dihydro- 1,8-naphthyridine-3-carboxamide

[0491] To a mixture of N-(4-fluorocyclohexyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)- 1,8-naphthyridine-3- carboxamide (60 mg, 172.74 μmol, 1 eq) and morpholine (18.06 mg, 207.29 pinol. 18.24 p.L. 1.2 eq) in MeOH (3 mL) and CH ₃ COOH (0.1 mL) was added NaBH ₃ CN (32.57 mg, 518.22 μmol, 3 eq) in one portion at 20 °C. The mixture was then heated to 60 °C and stirred for 2 h. The reaction mixture was concentrated to obtain a residue, the residue was dissolved in 50 mL EA, then washed with brine (30 mL *3), the organic layer was dried by Na2SCL, filtered and concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 63 (18 mg, 43.01 jrmol. 24.90% yield) was obtained.

[0492] ¹ H NMR (400 MHz, Methanol-d/) δ = 10.34 - 10.33 (m, 1H), 8.82 (br d, J = 3.3 Hz, 1H), 8.46 (br d, J = 7.5 Hz, 1H), 7.44 (dd, J = 4.6, 7.8 Hz, 1H), 4.87 - 4.75 (m, 1H), 4.54 (br t, J = 6.7 Hz, 2H), 3.98 - 3.96 (m, 1H), 3.54 (br t, J = 3.9 Hz, 4H), 2.61 - 2.54 (m, 2H), 2.49 - 2.44 (m, 4H), 1.95 - 1.60 (m, 8H). LCMS for product (ESI+): m/z 419.0 [M+H] ⁺ , Rt: 0.785 min.

EXAMPLE 64 - Synthesis of 1-(2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)-N-((ls,4s)-4- fluorocyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 64) [0493] Preparation of 1-(2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)-N-((ls,4s)-4-fl uorocyclohexyl)-

4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0494] To a mixture of N-((ls,4s)-4-fluorocyclohexyl)-4-hydroxy-2-oxo-1-(2 -oxoethyl)-1, 8- naphthyridine-3-carboxamide (60 mg, 172.74 μmol, 1 eq) and 7-oxa-4-azaspiro[2.5]octane (25.7 mg, 172.74 μmol, 1 eq, HCl) in MeOH (3 mL) and CH ₃ COOH (0.1 mL) was added NaBH ₃ CN (32.57 mg, 518.22 μmol, 3 eq) in one portion at 20 °C. The mixture was then heated to 60 °C and stirred for 2 h. The reaction mixture was concentrated to obtain a residue, the residue was dissolved in 50 mL EA, then washed with brine (30 mL *3), the organic layer was dried by Na ₂ SO _g , filtered and concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 64 (23 mg, 51.74 μmol, 29.95% yield) was obtained.

[0495] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.32 (br d, J = 7.3 Hz, 1H), 8.81 (br d, J = 3.4 Hz, 1H), 8.45 (br d, J = 7.5 Hz, 1H), 7.42 (dd, J = 4.8, 7.8 Hz, 1H), 4.88 - 4.75 (m, 1H), 4.39 (br t, J = 7.1 Hz, 2H), 3.97 - 3.95 (m, 1H), 3.60 - 3.57 (m, 2H), 3.31 (br s, 1H), 3.27 (s, 2H), 2.93 - 2.88 (m, 2H), 2.85 (br t, J = 7.0 Hz, 2H), 1.94 - 1.60 (m, 8H), 0.38 (br d, J = 4.2 Hz, 4H). LCMS for product (ESI+): m/z 445.1 [M+H] ⁺ , Rt: 0.823 min.

EXAMPLE 65 - Synthesis of 1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-N-((ls,4s) -4- fluorocyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 65) [0496] Preparation of 1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-N-((ls,4s) -4- fluorocyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0497] To a mixture of N-((ls,4s)-4-fluorocyclohexyl)-4-hydroxy-2-oxo-1-(2 -oxoethyl)-!, 8- naphthyridine-3-carboxamide (60 mg, 172.74 μmol, 1 eq) and 2-oxa-5-azabicyclo[2.2.1 (heptane (23.42 mg, 172.74 μmol, 1 eq, HCl) in MeOH (3 mL) and CH ₃ COOH (0.1 mL) was added NaBH ₃ CN (32.57 mg, 518.22 μmol, 3 eq) in one portion at 20 °C. The mixture was then heated to 60 °C and stirred for 2 h. The reaction mixture was concentrated to obtain a residue, the residue was dissolved in 50 mL EA, then washed with brine (30 mL *3), the organic layer was dried by Na ₂ SO ₄ , filtered and concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 65 (13 mg, 30.20 μmol, 17.48% yield) was obtained.

[0498] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.42 - 10.32 (m, 1H), 8.83 (br s, 1H), 8.46 (br d, J = 7.2 Hz, 1H), 7.44 (br s, 1H), 4.87 - 4.75 (m, 1H), 4.47 (br s, 2H), 4.36 (br s, 1H), 4.03 - 3.89 (m, 1H), 3.77 (br d, J = 7.6 Hz, 1H), 3.62 (br s, 1H), 3.51 (br d, J = 6.8 Hz, 1H), 2.91 (br d, J = 9.5 Hz, 1H), 2.86 - 2.74 (m, 2H), 2.59 (br d, J = 9.9 Hz, 1H), 1.97 - 1.55 (m, 10H). LCMS for product (ESI+): m/z 431.1 [M+H] ⁺ , Rt: 0.788 min.

EXAMPLE 66 - Synthesis of N-((ls,4s)-4-fluorocyclohexyl)-1-(2-(4-fluoropiperidin-1-yl) ethyl)-4- hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 66) [0499] Preparation of N-((ls,4s)-4-fluorocyclohexyl)-1-(2-(4-fluoropiperidin-1-yl) ethyl)-4- hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0500] To a mixture of N-((ls,4s)-4-fhiorocyclohexyl)-44iydroxy-2-oxo-1-(2-oxoethyl )- 1,8- naphthyridine-3-carboxamide (60 mg, 172.74 μmol, 1 eq) and 4-fluoropiperidine;hydrochloride (24.11 mg, 172.74 jxmol, 1 eq) in MeOH (3 mL) and CH ₃ COOH (0.1 mL) was added NaBH ₃ CN (32.57 mg, 518.22 μmol, 3 eq) in one portion at 20 °C. The mixture was then heated to 60 °C and stirred for 2 h. The reaction mixture was concentrated to obtain a residue. The residue was dissolved in 50 mL EA, then washed with brine (30 mL *3), the organic layer was dried by Na ₂ SO ₄ , filtered and concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 66 (18 mg, 41.43 μmol, 23.98% yield) was obtained.

[0501] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.33 (br s, 1H), 8.83 (br d, J = 3.2 Hz, 1H), 8.47 (br d, J = 7.6 Hz, 1H), 7.45 (dd, J = 4.6, 7.6 Hz, 1H), 4.88 - 4.64 (m, 2H), 4.64 - 4.58 (m, 2H), 3.98 - 3.94 (m, 1H), 2.94 - 2.54 (m, 6H), 1.97 - 1.58 (m, 12H). LCMS for product (ESI+): m/z 434.9 [M+H]+, Rt: 0.819 min.

EXAMPLE 67 - Synthesis of 1-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)ethyl)-N-((ls,4s) -4- fluorocyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 67) [0502] Preparation of 1-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)ethyl)-N-((ls,4s) -4- fluorocyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0503] To a mixture of N-((ls,4s)-4-fluorocyclohexyl)-4-hydroxy-2-oxo-1-(2 -oxoethyl)-!, 8- naphthyridine-3-carboxamide (60 mg, 172.74 μmol, 1 eq) and 3-oxa-6-azabicyclo[3.1.1 (heptane (46.87 mg, 172.74 μmol, 1 eq, TsOH) in MeOH (3 mL) and CH ₃ COOH (0.1 mL) was added NaBHjCN (32.57 mg, 518.22 μmol, 3 eq) in one portion at 20 °C. The mixture was heated to 60 °C and stirred for 2 h. The reaction mixture was concentrated to obtain a residue, the residue was dissolved in 50 mL EA, then washed with brine (30 mL *3), the organic layer was dried by Na ₂ SO ₄ , filtered and concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 67 (13 mg, 30.20 umol, 17.48% yield) was obtained.

[0504] ¹ H NMR (400 MHz, Methanol-eL) δ = 8.72 - 8.69 (m, 1H), 8.62 - 8.56 (m, 1H), 8.51 (s, 1H), 7.36 - 7.35 (m, 1H), 4.83 - 4.62 (m, 7H), 4.37 - 4.34 (m, 1H), 4.12 - 3.90 (m, 4H), 2.03 - 1.64 (m, 10H). LCMS for product (ESI+): m/z 430.9 [M+H] ⁺ , Rt: 0.809 min.

EXAMPLE 68 - Synthesis of methyl (lr,4r)-1-(6-(4-fhiorophenyl)-4-hydroxy-1-(2- morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamido)-4-methylcyclohexane-1- carboxylate (Compound 68)

[0505] Step 1. Preparation of methyl (lr,4r)-1-amino-4-methylcyclohexane-1-carboxylate [0506] To a mixture of (trans)- l-amino-4-methyl-cyclohexanecarboxylic acid (100 mg, 636.09 μmol, 1 eq) in MeOH (2 mL) was added SOCb (328.00 mg, 2.76 mmol, 0.2 mL, 4.33 eq) dropwise at 0 °C, and after addition the mixture was heated to 60 °C and stirred at 60 °C for 6 h. The reaction mixture was concentrated to obtain a residue, which was dissolved in EA (20 mL), and stirred at 20 °C for 0.5 h, then concentrated to obtain product. The product methyl (lr,4r)-1-amino-4-methylcyclohexane-1-carboxylate (100 mg, 583.99 μmol, 91.81% yield) was used into the next step without further purification.

[0507] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.63 (br s, 2H), 3.76 (s, 3H), 2.00 - 1.78 (m, 4H), 1.57 (br d, J = 11.1 Hz, 2H), 1.49 - 1.32 (m, 3H), 0.91 (d, J = 5.8 Hz, 3H).

[0508] Step 2. Preparation of methyl (lr,4r)-1-(6-(4-fluorophenyl)-4-hydroxy-1-(2- morpholmoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamido)-4-methylcyclohexane-1- carboxylate

[0509] To a mixture of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,8- naphthyridine-3-carboxylate (255.05 mg, 577.76 μmol, 1.2 eq) and methyl (lr,4r)-1-amino-4- methylcyclohexane-1 -carboxylate (100 mg, 481.47 μmol, 1 eq, HCl) in toluene (4 mL) was added DIPEA (311.13 mg, 2.41 mmol, 419.32 μL, 5 eq) at 20 °C. The mixture was then heated to 120 °C and stirred for 16 h. The reaction was concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate/Petroleum ethergradient @ 50 mL/min) and concentrated to obtain a crude product, the crude product was dissolved in CH ₃ CN (5 mL) and water (10 mL), then lyophilized to obtain desired product. Compound 68 (80 mg, 141.19 μmol, 29.32% yield) was obtained.

[0510] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.76 (br s, 1H), 9.17 (d, J = 2.3 Hz, 1H), 8.59 (d, J = 2.2 Hz, 1H), 7.90 (dd, J = 5.4, 8.7 Hz, 2H), 7.37 (t, J = 8.8 Hz, 2H), 4.60 (br t, J = 6.7 Hz, 2H), 3.66 (s, 3H), 3.54 (br t, J = 4.3 Hz, 4H), 2.64 (br t, J = 6.7 Hz, 2H), 2.50 - 2.47 (m, 4H), 2.17 (br d, J = 13.3 Hz, 2H), 1.89 - 1.76 (m, 2H), 1.69 (br d, J = 11.5 Hz, 2H), 1.54 - 1.41 (m, 1H), 1.24 - 1.05 (m, 2H), 0.90 (d, J = 6.5 Hz, 3H). LCMS for product (ESI+): m/z 567.3 [M+H] ⁺ , Rt: 0.817 min. EXAMPLE 69 - Synthesis of (lr,4r)-1-(6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl )-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamido)-4-methylcyclohexane-1-carbo xylic acid (Compound 69)

[0511] Preparation of (lr,4r)-1-(6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl )-2-oxo- 1,2- dihydro- 1,8-naphthyridine-3-carboxamido)-4-methylcyclohexane-1-carbo xylic acid

[0512] To a mixture of Compound 68 (55 mg, 97.07 μmol, 1 eq) in dioxane (0.5 mL) and H ₂ O (0.5 mL) was added NaOH (77.65 mg, 1.94 mmol, 20 eq) at 20 °C, and the mixture was heated to 60 °C for 16 h. The reaction mixture was quenched by 6 M HCl solution (3 mL), filtered and washed with water (4 mL), and the filter cake was dried by reduced pressure to obtain a residue. The residue was purified by prep-HPLC (FA condition, column: Phenomenex Synergi Cl 8 150*25mm* 10μm: mobile phase: [water(FA)-ACN];B%: 20%-50%,10min) and lyophilized to obtain desired product. Compound 69 (50 mg, 90.48 μmol, 93.22% yield) was obtained.

[0513] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.73 - 10.53 (m, 1H), 9.18 (s, 1H), 8.63 (br s, 1H), 8.14 (s, 1H), 7.96 - 7.85 (m, 2H), 7.38 (br t, J = 8.8 Hz, 2H), 4.83 - 4.49 (m, 2H), 3.72 - 3.54 (m, 4H), 2.71 - 2.64 (m, 6H), 2.19 (br d, J = 13.9 Hz, 2H), 1.88 - 1.77 (m, 2H), 1.68 (br d, J = 11.5 Hz, 2H), 1.52 - 1.43 (m, 1H), 1.16 - 1.05 (m, 2H), 0.90 (d, J = 6.4 Hz, 3H). LCMS for product (ESI+): m/z 553.1 [M+H] ⁺ , Rt: 0.866 min. EXAMPLE 70 - Synthesis of methyl (ls,4s)-1-(6-(4-fluorophenyl)-4-hydroxy-1-(2- morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamido)-4-methylcyclohexane-1- carboxylate (Compound 70)

[0515] To a mixture of (cis)-1-amino-4-methyl-cyclohexanecarboxylic acid (200 mg, 1.27 mmol, 1 eq) in MeOH (5 mL) was added SOCL (756.76 mg, 6.36 mmol, 461.44 μL, 5 eq) dropwise at 0 °C. The mixture was then heated to 70 °C for 4 h. The reaction mixture was concentrated to obtain a residue, which was dissolved in EA (20 mL), then concentrated to obtain a crude product. The crude product methyl (ls,4s)-1-amino-4-methyl-cyclohexanecarboxylate (200 mg, 1.17 mmol, 91.81% yield) was used into the next step without further purification.

[0516] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 8.68 (br s, 3H), 3.76 (s, 3H), 2.11 (br d, J = 13.6 Hz, 2H), 1.76 - 1.57 (m, 4H), 1.44 - 1.32 (m, 1H), 1.27 - 1.11 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H)

[0517] Step 2. Preparation of methyl (ls,4s)-1-(6-(4-fluorophenyl)-4-hydroxy-1-(2- morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamido)-4-methylcyclohexane-1- carboxylate

[0518] To a mixture of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,8- naphthyridine-3-carboxylate (420.84 mg, 953.31 μmol, 0.9 eq) and methyl (ls,4s)-1-amino-4-methyl- cyclohexanecarboxylate (220 mg, 1.06 mmol, 1 eq, HCl) in toluene (5 mL) was added DIPEA (684.49 mg, 5.30 mmol, 922.50 μL, 5 eq) 20 °C. The mixture was heated to 120 °C for 16 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash Column, Eluent of 0-80% Ethyl acetate/Petroleum ethergradient @50 mL/min) and concentrated to obtain desired product. Compound 70 (240 mg, 423.56 μmol. 39.99% yield) was obtained.

[0519] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.64 (br s, 1H), 9.17 (br s, 1H), 8.59 (d, J = 2.3 Hz, 1H), 8.04 - 7.83 (m, 2H), 7.37 (t, J = 8.8 Hz, 2H), 4.58 (br t, J = 6.8 Hz, 2H), 3.66 (s, 3H), 3.61 - 3.51 (m, 4H), 2.64 - 2.56 (m, 4H), 2.35 - 2.22 (m, 2H), 1.79 - 1.54 (m, 6H), 1.38 - 1.21 (m, 3H), 0.93 (br d, J = 6.1 Hz, 3H). LCMS for product (ESI+): m/z 567.2 [M+H] ⁺ , Rt: 0.834 min.

EXAMPLE 71 - Synthesis of (ls,4s)-1-(6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl )-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamido)-4-methylcyclohexane-1-carbo xylic acid (Compound 71) [0520] Preparation of (ls,4s)-1-(6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl )-2-oxo- 1,2- dihydro-1, 8- naphthyridine-3-carboxamido)-4-methylcyclohexane-1-carboxyli c acid

[0521] To a mixture of Compound 70 (120 mg, 211.78 μmol, 1 eq) in dioxane (1 mL) and H ₂ O (1 mL) was added NaOH (338.83 mg, 8.47 mmol, 40 eq) at 20 °C, and the mixture was heated to 60 °C and stirred for 40 h. The reaction mixture was quenched by 6 M HCl solution (3 mL), then concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* lOpm; mobile phase: [water(FA)-ACN] ; B%: 20%-50%,10min ) and lyophilized to obtain desired product. Compound 71 (100 mg, 180.97 μmol, 85.45% yield)was obtained.

[0522] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.53 (br s, 1H), 9.16 (br s, 1H), 8.61 (br s, 1H), 7.89 (br d, J = 5.5 Hz, 2H), 7.37 (br t, J = 8.5 Hz, 2H), 4.65 (br s, 2H), 3.77 - 3.58 (m, 4H), 2.53 (br d, J = 1.8 Hz, 3H), 2.35 - 2.23 (m, 3H), 1.82 - 1.55 (m, 6H), 1.46 - 1.26 (m, 3H), 0.94 (br d, J = 6.1 Hz, 3H). LCMS for product (ESI+): m/z 553.1 [M+H] ⁺ , Rt: 0.874 min.

EXAMPLE 72 - Synthesis N-((lr,4r)-1-carbamoyl-4-methylcyclohexyl)-6-(4-fluorophenyl )-4- hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 72) [0523] Preparation of N-((lr,4r)-1-carbamoyl-4-methylcyclohexyl)-6-(4-fluorophenyl )-4- hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0524] To a mixture of Compound 69 (30 mg, 54.29 μmol, 1 eq) and NH ₄ Cl (8.71 mg, 162.87 μmol, 3 eq) in DMF (1 mL) was added HATU (30.96 mg, 81.43 umol, 1.5 eq) and DIPEA (35.08 mg, 271.45 μmol, 47.28 μL, 5 eq) at 20 °C, and the mixture was stirred at 20 °C for 16 h. The reaction mixture was purified by pre-HPLC (column: 3_Phenomenex Luna Cl 8 75*30mm*3pm; mobile phase: [water (HCl)- ACN]; B%: 32%-52%,min) and lyophilized to obtain desired product. Compound 72 (8 mg, 14.50 μmol, 26.71% yield) was obtained.

[0525] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.42 (br s, 2H), 9.17 (d, J = 2.3 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 7.92 (dd, J = 5.3, 8.7 Hz, 2H), 7.39 (br t, J = 8.9 Hz, 2H), 7.00 (br s, 1H), 4.84 (br s, 2H), 4.01 (br d, J = 10.6 Hz, 2H), 3.77 (br d, J = 12.8 Hz, 2H), 2.49 - 2.43 (m, 6H), 2.17 (br d, J = 13.1 Hz, 2H), 1.86 - 1.74 (m, 2H), 1.64 (br d, J = 11.6 Hz, 2H), 1.50 - 1.38 (m, 1H), 1.19 - 1.06 (m, 2H), 0.89 (d, J = 6.4 Hz, 3H). LCMS for product (ESI+): m/z 552.1 [M+H] ⁺ , Rt: 0.840 min.

EXAMPLE 73 - Synthesis 6-(4-fluorophenyl)-4-hydroxy-N-((lr,4r)-4-methyl-1- (methylcarbamoyl)cyclohexyl)-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3- carboxamide (Compound 73) [0526] Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-((lr,4r)-4-methyl-1-

(methylcarbamoyl)cyclohexyl)-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3- carboxamide

[0527] To a mixture of Compound 69 (30 mg, 54.29 μmol, 1 eq) and NH ₄ CI (8.71 mg, 162.87 μmol, 3 eq) in DMF (1 mL) was added HATU (20 mg, 36.19 μmol, 1 eq) and MeNH ₂ (7.48 mg, 108.58 μmol, 98% purity, 3 eq, HCl) in DMF (1 mL). To the mixture was added HATU (20.64 mg, 54.29 μmol, 1.5 eq) and DIPEA (23.39 mg, 180.97 μmol, 31.52 μL, 5 eq), and the mixture was stirred at 20 °C for 2 h. The reaction mixture was purified directly. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10μm; mobile phase: [water(FA)-ACN];B%: 24%- 44%,10min) and lyophilized to obtain desired product. Compound 73 (14 mg, 24.75 μmol, 68.39% yield) was obtained.

[0528] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 3 = 11.58 - 11.04 (m, 1H), 8.91 (br s, 1H), 8.61 (d, J = 2.0 Hz, 1H), 8.20 (s, 1H), 7.86 - 7.73 (m, 2H), 7.31 (br t, J = 8.7 Hz, 2H), 4.56 (br t, J = 6.5 Hz, 2H), 3.54 (br s, 4H), 2.61 (br d, J = 4.1 Hz, 6H), 2.53 - 2.52 (m, 3H), 2.24 (br d, J = 13.1 Hz, 2H), 1.80 - 1.69 (m, 2H), 1.55 (br d, J = 12.4 Hz, 2H), 1.44 - 1.34 (m, 1H), 1.26 - 1.11 (m, 2H), 0.84 (br d, J = 6.0 Hz, 3H). LCMS for product (ESI+): m/z 566.0 [M+H] ⁺ , Rt: 0.870 min.

EXAMPLE 74 - Synthesis N-((ls,4s)-1-carbamoyl-4-methylcyclohexyl)-6-(4-fluorophenyl )-4- hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 74) [0529] Preparation of N-((ls,4s)-1-carbamoyl-4-methylcyclohexyl)-6-(4-fluorophenyl )-4-hydroxy- 1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0530] To a mixture of Compound 71 (40 mg, 72.39 μmol, 1 eq) and NH ₄ CI (11.62 mg, 217.16 μmol, 3 eq) in DMF (1 mL) was added HATU (41.29 mg, 108.58 μmol, 1.5 eq) and DIPEA (46.78 mg, 361.93 μmol, 63.04 μL, 5 eq), and the mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition; column: 3_Phenomenex Luna Cl 8 75*30mm*3μm; mobile phase: [water(HCl)-ACN];B%: 32%-52%) and lyophilized to obtain desired product. Compound 74 (16 mg, 29.01 μmol, 40.07% yield) was obtained.

[0531] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.53 (br s, 2H), 9.16 (br s, 1H), 8.61 (br s, 1H), 7.89 (br d, J = 5.5 Hz, 2H), 7.37 (br t, J = 8.5 Hz, 2H), 7.02 (s, 1H), 4.65 (br s, 2H), 3.77 - 3.58 (m, 4H), 2.53 (br d, J = 1.8 Hz, 4H), 2.35 - 2.23 (m, 2H), 1.82 - 1.55 (m, 6H), 1.46 - 1.26 (m, 3H), 0.94 (br d, J = 6.1 Hz, 3H). LCMS for product (ESI+): m/z 552.1 [M+H] ⁺ , Rt: 0.841 min.

EXAMPLE 75 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-N-((ls,4s)-4-methyl-1- (methylcarbamoyl)cyclohexyl)-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3- carboxamide (Compound 75) [0532] Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-((ls,4s)-4-methyl-1-

(methylcarbamoyl)cyclohexyl)-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3- carboxamide

[0533] To a mixture of Compound 71 (30 mg, 54.29 μmol, 1 eq) and MeNEC (11.22 mg, 162.87 μmol, 98% purity, 3 eq, HCl) in DMF (2 mb) was added HATU (24.77 mg, 65.15 μmol, 1.2 eq) and DIPEA (35.08 mg, 271.45 μmol, 47.28 μL, 5 eq), and the mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi C18150*25mm* 10μm; mobile phase: [water(FA)-ACN];B%: 24%- 44%,10min) and lyophilized to obtain desired product. Compound 75 (8 mg, 14.14 μmol, 26.05% yield) was obtained.

[0534] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 11.30 - 10.91 (m, 1H), 8.89 (br s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 7.79 - 7.71 (m, 2H), 7.45 - 7.38 (m, 1H), 7.29 (t, J = 8.8 Hz, 2H), 4.53 (br t, J = 7.0 Hz, 2H), 3.51 - 3.50 (m, 4H), 2.64 - 2.56 (m, 6H), 2.38 - 2.28 (m, 3H), 1.76 - 1.56 (m, 6H), 1.34 - 1.24 (m, 3H), 0.91 (br d, J = 6.1 Hz, 3H). LCMS for product (ESI+): m/z 566.1 [M+H] ⁺ , Rt: 0.870 min.

EXAMPLE 76 - Synthesis of N-(4,4-dimethylcycloheptyl)-4-hydroxy-1-(2-morpholinoethyl)- 2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 76) [0535] Preparation of N-(4,4-dimethylcycloheptyl)-4-hydroxy-1-(2-morpholinoethyl)- 2-oxo- 1,2- dihydro- 1,8-naphthyridine-3-carboxamide

[0536] To a mixture of ethyl 4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,8-naphthyridine-3-carboxylate (15 mg, 43.18 μmol, 1 eq) and 4,4-dimethylcycloheptanamine (7.32 mg, 51.82 μmol. 1.2 eq) in toluene (1 mL) was added DIPEA (16.74 mg, 129.55 μmol, 22.56 μL, 3 eq) at 20 °C. The mixture was then heated to 120 °C for 2 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10μm; mobile phase: [water(FA)-ACN];B%: 29%-49%,10min) and lyophilized to obtain desired product. Compound 76 (6 mg, 13.56 μmol, 31.40% yield) was obtained.

[0537] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.15 - 10.94 (m, 1H), 8.56 (br d, J = 3.1 Hz, 1H), 8.46 - 8.38 (m, 1H), 8.34 (s, 2H), 7.25 - 7.21 (m, 1H), 4.51 (br t, J = 7.3 Hz, 2H), 4.02 - 3.91 (m, 1H), 3.59 - 3.48 (m, 4H), 2.62 - 2.54 (m, 2H), 2.49 (br s, 4H), 1.99 - 1.89 (m, 1H), 1.81 - 1.66 (m, 1H), 1.59 - 1.24 (m, 8H), 0.90 (br d, J = 10.3 Hz, 6H). LCMS for product (ESI+): m/z 443.0 [M+H] ⁺ , Rt: 0.873 min.

EXAMPLE 77 - Synthesis of N-(4,4-dimethylcyclohexyl)-4-hydroxy-1-(2-morpholinoethyl)-2 -oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 77) [0538] Preparation of N-(4,4-dimethylcyclohexyl)-4-hydroxy-1-(2-morpholinoethyl)-2 -oxo- 1,2- dihydro- 1,8-naphthyridine-3-carboxamide

[0539] To a mixture of l-allyl-N-(4,4-dimethylcyclohexyl)-4-hydroxy-2-oxo- 1,8-naphthyridine-3- carboxamide (800 mg, 2.25 mmol, 1 eq) in THF (4 mL) and H ₂ O (4 mL) was added K ₂ OSO ₄ 2H ₂ O (165.86 mg, 450.16 μmol, 0.2 eq) and NaIO4 (481.43 mg, 2.25 mmol, 124.72 p.L, 1 eq), and the mixture was stirred at 20 °C for 1 h. The residue was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 77 (600 mg, 1.54 mmol, 68.45% yield) was obtained.

[0540] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.32 (br d, J = 6.1 Hz, 1H), 8.79 (br d, J = 3.8 Hz, 1H), 8.45 (br d, J = 7.2 Hz, 1H), 7.41 (dd, J = 4.6, 7.8 Hz, 1H), 4.71 - 4.52 (m, 3H), 4.33 (br dd, J = 5.1, 13.0 Hz, 1H), 4.05 - 3.92 (m, 1H), 3.87 - 3.76 (m, 1H), 3.45 - 3.35 (m, 2H), 1.85 - 1.71 (m, 2H), 1.62 - 1.50 (m, 2H), 1.45 - 1.25 (m, 4H), 0.94 (d, J = 9.7 Hz, 6H). LCMS for product (ESI+): m/z 390.0 [M+H] ⁺ , Rt: 0.989 min.

EXAMPLE 78 - Synthesis of 1-(2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)-N-(4,4- dimethylcyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 78) [0541] Step 1. Preparation of ethyl 4-hydroxy-1-[2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl]-2-oxo - l,8-naphthyridine-3-carboxylate

[0542] To a mixture of ethyl 4-hydroxy-2-oxo-1-(2-oxoethyl)- 1,8-naphthyridine-3-carboxylate (50 mg, 181.00 μmol, 1 eq) and 7-oxa-4-azaspiro[2.5]octane (32.50 mg, 217.20 μmol, 1.2 eq, HCl) in MeOH (3 mL) and CH ₃ COOH (0.1 mL) was added NaBH ₃ CN (34.12 mg, 543.00 μmol, 3 eq) at 20 °C, then the reaction mixture was heated to 60 °C for 2 h. The reaction mixture was concentrated to obtain a residue. The crude product ethyl 4-hydroxy-1-[2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl]-2-oxo - 1,8- naphthyridine-3-carboxylate (50 mg, crude) was used into the next step without further purification.

[0543] LCMS for product (ESI+): m/z 374.2 [M+H] ⁺ , Rt: 0.641 min.

[0544] Step 2. Preparation of 1-(2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)-N-(4,4- dimethylcyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0545] To a mixture of ethyl 4-hydroxy-1-[2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl]-2-oxo - 1,8- naphthyridine-3-carboxylate (50 mg, 133.90 μmol, 1 eq) and 4,4-dimethylcyclohexanamine (17.04 mg, 133.90 μmol, 1 eq) in toluene (2 mL) was added DIPEA (86.53 mg, 669.52 μmol, 116.62 μL, 5 eq), and the mixture was heated to 120 °C for 2 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10μm;mobile phase: [water(FA)-ACN];B%: 39%-59%,10min) and lyophilized to obtain a crude product, the crude product was purified by prep-HPLC (neutral condition, column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH ₄ HCO ₃ )-ACN];B%: 80%-100%,7min) and lyophilized to obtain desired product. Compound 78 (5 mg, 11.00 μmol. 8.21% yield) was obtained. [0546] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.28 (br d, J = 7.1 Hz, 1H), 8.89 - 8.72 (m, 1H), 8.51 - 8.34 (m, 1H), 7.42 (dd, J = 4.7, 7.9 Hz, 1H), 4.40 (br t, J = 7.1 Hz, 2H), 3.90 - 3.77 (m, 1H), 3.64 - 3.57 (m, 2H), 3.28 (s, 2H), 2.96 - 2.81 (m, 4H), 1.77 (td, J = 4.2, 8.8 Hz, 2H), 1.64 - 1.51 (m, 2H), 1.43 - 1.20 (m, 4H), 0.95 (d, J = 9.8 Hz, 6H), 0.39 (br d, J = 6.7 Hz, 4H). LCMS for product (ESI+): m/z 455.1 [M+H] ⁺ , Rt: 0.913 min.

EXAMPLE 79 - Synthesis of 1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-N-(4,4- dimethylcyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 79)

[0547] Step 1. Preparation of ethyl 4-hydroxy-1-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]- 2-oxo- 1,8-naphthyridine-3-carboxylate

[0548] To a mixture of ethyl 4-hydroxy-2-oxo-1-(2-oxoethyl)- 1,8-naphthyridine-3-carboxylate (50 mg,

181.00 μmol, 1 eq) and 2-oxa-5-azabicyclo[2.2.1]heptane (29.45 mg, 217.20 μmol, 1.2 eq, HCl) in

MeOH (3 mL) and CH ₃ COOH (0.1 mL) was added NaBHgCN (34.12 mg, 543.00 μmol, 3 eq) at 20 °C.

The mixture was heated to 60 °C for 2 h. The reaction mixture was concentrated to obtain a residue. The crude product ethyl 4-hydroxy-1-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]- 2-oxo- 1,8- naphthyridine-3-carboxylate (50 mg, crude) was used into the next step without further purification.

[0549] LCMS for product (ESI+): m/z 360.2 [M+H] ⁺ , Rt: 0.607 min. [0550] Step 2. Preparation of 1-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)-N-(4,4- dimethylcyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0551] To a mixture of ethyl 4-hydroxy-1-[2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethyl]- 2-oxo- 1,8- naphthyridine-3-carboxylate (50 mg, 139.13 μmol, 1 eq) and 4,4-dimethylcyclohexanamine (21.24 mg, 166.96 μmol, 1.2 eq) in toluene (2 mL) was added DIPEA (89.91 mg, 695.65 μmol, 121.17 μL, 5 eq), and the mixture was heated to 120 °C for 2 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10μm; mobile phase: [water(FA)-ACN];B%: 22%-52%,10min) and lyophilized to obtain desired product. Compound 79 (10 mg, 22.70 μmol, 16.32% yield) was obtained.

[0552] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.29 (br d, J = 3.1 Hz, 1H), 8.82 (br d, J = 1.8 Hz, 1H), 8.46 (br d, J = 7.2 Hz, 1H), 7.44 (br s, 1H), 4.46 (br s, 2H), 4.36 (br s, 1H), 3.89 - 3.74 (m, 2H), 3.61 (br s, 1H), 3.51 (br d, J = 7.0 Hz, 1H), 2.91 (br d, J = 10.0 Hz, 1H), 2.80 (br s, 2H), 2.64 - 2.56 (m, 1H), 1.82

- 1.68 (m, 3H), 1.64 - 1.49 (m, 3H), 1.44 - 1.37 (m, 2H), 1.35 - 1.26 (m, 2H), 0.95 (br d, J = 9.4 Hz, 6H). LCMS for product (ESI+): m/z 441.2 [M+H] ⁺ .

EXAMPLE 80 - Synthesis of N-(4,4-dimethylcyclohexyl)-1-(2-(4-fluoropiperidin-1-yl)ethy l)-4- hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 80) [0553] Step 1. Preparation of l-allyl-N-(4,4-dimethylcyclohexyl)-4-hydroxy-2-oxo- 1,8- naphthyridine-3-carboxamide

[0554] To a mixture of ethyl l-allyl-4-hydroxy-2-oxo- 1,8-naphthyridine-3-carboxylate (2 g, 7.29 mmol, 1 eq) and 4,4-dimethylcyclohexanamine hydrochloride (1.39 g, 10.94 mmol, 1.5 eq) in toluene (20 mL) was added DIPEA (4.71 g, 36.46 mmol, 6.35 mL, 5 eq), the reaction mixture was heated to 110 °C for 36 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) and concentrated to obtain desired product. Compound l-allyl-N-(4,4-dimethylcyclohexyl)-4-hydroxy-2-oxo- 1,8-naphthyridine-3-carboxamide (800 mg, 2.25 mmol, 30.87% yield) was obtained.

[0555] ¹ H NMR (400 MHz, CDCI ₃ ) δ = 10.27 - 10.08 (m, 1H), 8.70 (dd, J = 2.0, 4.6 Hz, 1H), 8.49 (dd, J = 1.8, 7.8 Hz, 1H), 7.27 - 7.22 (m, 1H), 6.20 - 5.91 (m, 1H), 5.23 - 5.03 (m, 4H), 3.94 - 3.82 (m, 1H), , 1.93 - 1.83 (m, 2H), 1.61 - 1.43 (m, 2H), 1.40 - 1.24 (m, 2H), 1.21 - 1.08 (m, 2H), 0.96 (d, J = 1.5 Hz, 6H). LCMS for product (ESI+): m/z 355.9 [M+H] ⁺ , Rt: 1.143 min.

[0556] Step 2. Preparation of 1-(2,3-dihydroxypropyl)-N-(4,4-dimethylcyclohexyl)-4-hydroxy -2- oxo-1, 8-naphthyridine-3-carboxamide

[0557] To a mixture of l-allyl-N-(4,4-dimethylcyclohexyl)-4-hydroxy-2-oxo- 1,8-naphthyridine-3- carboxamide (800 mg, 2.25 mmol, 1 eq) in THF (4 mL) and H ₂ O (4 mL) was added K ₂ OSO ₄ 2H ₂ O (165.86 mg, 450.16 μmol, 0.2 eq) and NaIO4 (481.43 mg, 2.25 mmol, 124.72 μL, 1 eq), the mixture was stirred at 20 °C for 1 h. The residue was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 1-(2,3-dihydroxypropyl)-N-(4,4-dimethylcyclohexyl)-4-hydroxy -2-oxo- 1,8- naphthyridine-3-carboxamide (600 mg, 1.54 mmol, 68.45% yield) was obtained.

[0558] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.32 (br d, J = 6.1 Hz, 1H), 8.79 (br d, J = 3.8 Hz, 1H), 8.45 (br d, J = 7.2 Hz, 1H), 7.41 (dd, J = 4.6, 7.8 Hz, 1H), 4.71 - 4.52 (m, 3H), 4.33 (br dd, J = 5.1, 13.0 Hz, 1H), 4.05 - 3.92 (m, 1H), 3.87 - 3.76 (m, 1H), 3.45 - 3.35 (m, 2H), 1.85 - 1.71 (m, 2H), 1.62 - 1.50 (m, 2H), 1.45 - 1.25 (m, 4H), 0.94 (d, J = 9.7 Hz, 6H). LCMS for product (ESI+): m/z 390.0 [M+H] ⁺ , Rt: 0.989 min.

[0559] Step 3. Preparation of N-(4,4-dimethylcyclohexyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)- 1,8- naphthyridine-3-carboxamide

[0560] To a mixture of 1-(2,3-dihydroxypropyl)-N-(4,4-dimethylcyclohexyl)-4-hydroxy -2-oxo- 1,8- naphthyridine-3-carboxamide (600 mg, 1.54 mmol, 1 eq) in THF (6 mL) and HzO (6 mL) was added NaIC>4 (329.53 mg, 1.54 mmol, 85.37 μL. 1 eq) at 20 °C. The mixture was stirred at 20 °C for 6 h. The reaction mixture was filtered and the filter cake was dried by reduced pressure to obtain desired product. Compound N-(4,4-dimethylcyclohexyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)- 1,8-naphthyridine-3- carboxamide (200 mg, 559.59 μmol, 36.32% yield) was obtained.

[0561] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 9.79 (s, 1H), 8.84 (br d, J = 3.9 Hz, 1H), 8.59 (br d, J = 7.2 Hz, 1H), 7.55 (br dd, J = 4.8, 7.4 Hz, 1H), 5.38 (s, 2H), 3.92 (br d, J = 6.6 Hz, 2H), 1.95 - 1.79 (m, 2H), 1.71 - 1.60 (m, 2H), 1.49 - 1.34 (m, 2H), 1.03 (br d, J = 6.1 Hz, 6H). LCMS for product (ESI+): m/z 358.2 [M+H] ⁺ , Rt: 0.961 min.

[0562] Step 4. Preparation of N-(4,4-dimethylcyclohexyl)-1-(2-(4-fluoropiperidin-1-yl)ethy l)-4- hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0563] To a mixture of N-(4,4-dimethylcyclohexyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)- 1,8- naphthyridine-3-carboxamide (23 mg, 64.35 μmol, 1 eq) and 4-fluoropiperidine (7.96 mg, 77.22 μmol, 1.2 eq) in MeOH (2 mL) and CH ₃ COOH (0.1 mL) was added NaBH ₃ CN (4.04 mg, 64.35 μmol, 1 eq), and the mixture was heated to 60 °C for 2 h. The reaction mixture was concentrated to obtain a residue, which was dissolved in EA (50 mL), then washed with brine (40 mL *3), dried by Na ₂ SO ₄ . filtered and concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 80 (7 mg, 15.75 μmol, 24.47% yield) was obtained.

[0564] ¹ H NMR (400 MHz, Methanol-d ₄ ) δ = 8.72 (br s, 1H), 8.54 (br d, J = 7.5 Hz, 1H), 8.46 (s, 1H), 7.36 (br s, 1H), 4.84 - 4.66 (m, 3H), 3.92 (br d, J = 3.5 Hz, 1H), 3.02 (br s, 6H), 2.10 - 1.79 (m, 6H), 1.64 - 1.46 (m, 4H), 1.43 - 1.30 (m, 2H), 1.00 (br d, J = 11.6 Hz, 6H). LCMS for product (ESI+): rn/z 445.2 [M+H] ⁺ , Rt: 0.797 min.

EXAMPLE 81 - Synthesis of 1-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)ethyl)-N-(4,4- dimethylcyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 81)

[0565] Preparation of 1-(2-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)ethyl)-N-(4,4- dimethylcyclohexyl)-4-hydroxy-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide

[0566] To a mixture of N-(4,4-dimethylcyclohexyl)-4-hydroxy-2-oxo-1-(2-oxoethyl)- 1,8- naphthyridine-3-carboxamide (50 mg, 139.90 μmol, 1 eq) and 3-oxa-6-azabicyclo[3.1.1 (heptane (45.55 mg, 167.88 μmol, 1.2 eq, TsOH) in MeOH (3 mL) and CH ₃ COOH (0.1 mL) was added NaBH ₃ CN (26.37 mg, 419.69 μmol, 3 eq), and the mixture was heated to 60 °C for 4 h. The reaction mixture was concentrated to obtain a residue, which was dissolved in EA (50 mL), then washed with brine (30 mL *3), dried by Na2SCL, filtered and concentrated to obtain a crude product. The crude product was purified by prep-HPLC (FA condition) and lyophilized to obtain desired product. Compound 81 (3 mg, 6.81 μmol, 4.87% yield) was obtained.

[0567] ¹ H NMR (400 MHz, DMSO-d6) δ = 11.68 - 11.27 (m, 1H), 10.56 - 10.27 (m, 1H), 8.67 - 8.50 (m, 1H), 8.47 - 8.34 (m, 1H), 8.24 (s, 2H), 7.39 - 7.08 (m, 1H), 4.42 - 4.25 (m, 2H), 4.21 - 4.03 (m, 2H), 3.83 - 3.73 (m, 1H), 3.67 - 3.59 (m, 4H), 2.83 - 2.73 (m, 2H), 1.82 - 1.67 (m, 3H), 1.64 - 1.12 (m, 7H), 0.99 - 0.87 (m, 6H). LCMS for product (ESI+): m/z 441.2 [M+H] ⁺ , Rt: 0.778 min.

EXAMPLE 82 - Synthesis of 6-(4-fluorophenyl)-4-hydroxy-N-(1-(hydroxymethyl)-4,4- dimethylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide (Compound 82)

[0568] Step 1. Preparation of 8, 8-dimethyl- 1,3-diazaspiro[4.5]decane-2, 4-dione

[0569] To a mixture of 4,4-dimethylcyclohexanone (3 g, 23.77 mmol, 1 eq) in EtOH (25 mL) and H ₂ O

(25 mL) was added (NH ₄ ) ₂ CO ₃ (13.71 g, 142.64 mmol, 15.23 mL, 6 eq) and KCN (2.69 g, 41.25 mmol, 1.77 mL, 1.74 eq), and the mixture was then heated to 60 °C for 6 h. The reaction mixture was diluted with water (40 mL), then extracted with EA (80 mL *3), the combined organic layers were washed with brine (50 mL), dried by Na ₂ SCL. filtered and concentrated to obtain a residue. The water layer was filtered, the filter cake was added into 40 mL water and stirred at 20 °C for 10 min, and filtered. The filter cake was washed by water (100 mL), then dried by reduced pressure to obtain a residue. The filter cake and residue were mixed, and 8, 8-dimethyl- 1,3-diazaspiro[4.5]decane-2, 4-dione (4 g, 20.38 mmol, 85.74% yield) was obtained and used into the next step without further purification.

[0570] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 10.54 (br s, 1H), 8.40 (s, 1H), 1.81 - 1.70 (m, 2H), 1.51 - 1.26 (m, 6H), 0.91 (d, J = 4.9 Hz, 6H).

[0571] Step 2. Preparation of l-amino-4,4-dimethyl-cyclohexanecarboxylic acid

[0572] To a solution of NaOH (4.80 g, 120.00 mmol, 5.89 eq) in H ₂ O (40 mL) was added 8,8- dimethyl- 1,3-diazaspiro[4.5]decane-2, 4-dione (4 g, 20.38 mmol, 1 eq), and the mixture was heated to 100 °C and stirred for 96 h. The reaction mixture was cooled to 20 °C, then filtered and washed with water (40 mL), and the filter cake was dried by reduced pressure to obtain desired product. The crude product l-amino-4,4-dimethyl-cyclohexanecarboxylic acid (2 g, 11.68 mmol, 57.30% yield) was used into the next step without further purification.

[0573] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 3.42 (br s, 2H), 1.68 (dt, J = 4.0, 13.6 Hz, 2H), 1.38 (dt, J = 3.7, 13.5 Hz, 2H), 1.22 (br d, J = 13.1 Hz, 2H), 1.05 (br d, J = 13.0 Hz, 2H), 0.86 (br d, J = 3.1 Hz, 6H).

[0574] Step 3. Preparation of (l-amino-4,4-dimethyl-cyclohexyl)methanol

[0575] LiAlH ₄ (443.30 mg, 11.68 mmol, 5 eq) was placed in a 50 mL round-bottom flask under N2 atmosphere at 0 °C, and THF (20 mL) was added. l-Amino-4,4-dimethyl-cyclohexanecarboxylic acid (400 mg, 2.34 mmol, 1 eq) was added in small portions as a solid, and upon completion addition the mixture was heated to 80 °C for 16 h. The mixture was cooled to 0 °C, treated slowly with saturated aq NaiCOs (5 mL), warmed to 20 °C, and stirred for 2 h, whereupon a white precipitate formed, which was separated by filtration, washed with THF (10 mL), and washed twice with EtOAc (10 mL). The filtrate was concentrated in vacuo to obtain a residue. The residue was dissolved in DCM (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product (1-amino- 4,4-dimethyl-cyclohexyl)methanol (300 mg, crude) was used into the next step without further purification.

[0576] ¹ H NMR (400 MHz, DMSOd ₆ ) δ = 4.23 - 4.06 (m, 1H), 3.22 - 3.15 (m, 2H), 3.13 - 3.06 (m, 1H), 1.49 - 1.38 (m, 4H), 1.17 - 1.03 (m, 4H), 0.94 - 0.72 (m, 6H).

[0577] Step 4. Preparation of 6-(4-fluorophenyl)-4-hydroxy-N-(1-(hydroxymethyl)-4,4- dimethylcyclohexyl)-1-(2-morpholinoethyl)-2-oxo- 1,2-dihydro- 1,8-naphthyridine-3-carboxamide [0578] To a mixture of ethyl 6-(4-fluorophenyl)-4-hydroxy-1-(2-morpholinoethyl)-2-oxo- 1,8- naphthyridine-3-carboxylate (50 mg, 113.26 μmol, 1 eq) and (l-amino-4,4-dimethyl- cyclohexyl)methanol (21.37 mg, 135.92 μmol, 1.2 eq) in toluene (3 mL) was added DIPEA (73.19 mg, 566.31 μmol, 98.64 μL, 5 eq), and the mixture was heated to 120 °C for 2 h. The reaction mixture was concentrated to obtain a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Synergi Cl 8 150*25mm* 10μm; mobile phase: [water(FA)-ACN];B%: 25%-55%,10min) and lyophilized to obtain desired product. Compound 82 (28 mg, 50.67 μmol, 44.73% yield) was obtained.

[0579] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.30 (br s, 1H), 9.13 (d, J = 2.1 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 5.5, 8.4 Hz, 2H), 7.36 (t, J = 8.8 Hz, 2H), 4.88 (br s, 1H), 4.57 (br t, J = 6.8 Hz, 2H), 3.66 (br s, 2H), 3.54 (br t, J = 4.1 Hz, 4H), 2.60 (br t, J = 6.9 Hz, 2H), 2.49 (br s, 3H), 2.07 (br d, J = 13.6 Hz, 2H), 1.66 - 1.54 (m, 2H), 1.42 - 1.26 (m, 4H), 0.92 (s, 6H). LCMS for product (ESI+): m/z 553.3 [M+H] ⁺ , Rt: O.813min.

Biological Assays

The following examples describe biological assays for the compounds described herein.

Example B-l: CB1 and CB2 Receptor Binding Assays

[0580] The compounds were evaluated in CBiR and CBzR binding assays using membranes from HEK-293 cells transfected with cDNAs encoding the human recombinant CBiR (B _max = 2.5 μmol/mg protein) and human recombinant CB ₂ R (B _max = 4.7 μmol/mg protein) (Perkin-Elmer). These membranes were incubated with [ ³ H]-(— )-cis-3-[2-hydroxy-4-(l,l-dimethylheptyl)phenyl]-trans-4-(3- hydroxypropyl)cyclohexanol ([ ³ H]CP-55,940) (0.14 nM/Kd = 0.18 nM and 0.084 nM/Kd = 0.31 nM for CBiR and CB ₂ R, respectively) as high-affinity ligand and displaced with 100 nM (R)-(+)-[2,3-dihydro-5- methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]- 1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN-55,212-2) as heterologous competitor for nonspecific binding (Ki = 9.2 and 2.1 nM, respectively, for CBiR and CB ₂ R). Compounds were tested following the procedure described by the cell membrane manufacturer. CBiR binding protocol involves the use of the same solution buffer used for both incubation and washing reaction (Tris-HCl, 50 mM; EDTA, 2.5 mM; MgCF. 2.5 mM; BSA, 0.5 mg/mL at pH 7.4), 0.4 nM for [ ³ H]CP-55,940, test compounds (concentrations from 0.001 to 10 μM), and finally

8 pg/sample membrane in a total volume of 200 μL. CB ₂ R binding assays were carried out with two different buffers: incubation buffer (Tris-HCl, 50 mM; MgCh, 5 mM; CaCh 1 mM; BSA, 0.2% at pH 7.4) and washing buffer (Tris-HCl, 50 mM; NaCl 500 mM; BSA, 0.1% at pH 7.4). The assay mixture contained incubation buffer, 0.4 nM [ ³ H]CP-55,940, test substances (concentrations from 0.001 to 10 μM), and 4 pg/sample membrane in a total assay volume of 200 μL. Assays were performed in duplicate and incubated for 120 min at 37 °C. After the incubation, the assay mixture was filtered through 96 GF/C filter plates (Perkin Elmer #6005174) using Perkin Elmer Filtermate Harvester, and then washed four times with ice-cold washing buffer. The filters were dried for 1 hour at 50°C and [ ³ H] trapped on filter counted for radioactivity in Perkin Elmer Microscint 20 cocktail (#6013329) using Perkin Elmer MicroBeta2 Reader. The results were expressed as a percent inhibition of the control radioligand specific binding calculated using the following equation: %Inhibition=(l -(Assay well- Average_LC)/(Average_HC-Average_LC))x100%. Data were analyzed and IC50 was calculated using GraphPad Prism 5 and the model “log(inhibitor) vs. response - Variable slope”. The binding affinity of the compounds was determined by using the Cheng and Prusoff equation Ki = IC50/(l+ [radioligand] ZKd) .

Example B-2: CB2 Receptor cAMP Assay

[0581] cAMP Hunter CHO-K-1 cell lines expressing human CB ₂ receptor (Eurofins) are expanded from freezer stocks according to standard procedures. Cells are seeded in a total volume of 20 μL into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing. cAMP modulation in agonist, inverse agonist or antagonist format is determined using the DiscoverX HitHunter cAMP XS+ assay (Eurofins). For agonist determination, cells are incubated with sample in the presence of EC80 forskolin to induce response. Media is aspirated from cells and replaced with 15 μL 2:1 HBSS/lOmM Hepes: cAMP XS+ Ab reagent. Intermediate dilution of sample stocks is performed to generate 4X sample in assay buffer containing 4X EC80 forskolin. 5 μL of 4X sample is added to cells and incubated at 37°C or room temperature for 30 or 60 minutes. Final assay vehicle concentration is 1%. For inverse agonist determination, cells are preincubated with sample in the presence of EC20 forskolin. Media is aspirated from cells and replaced with 15μL 2: 1 HBSS/lOmM Hepes: cAMP XS+ Ab reagent. Intermediate dilution of sample stocks is performed to generate 4X sample in assay buffer containing 4X EC20 forskolin. 5 μL of 4X sample is added to cells and incubated at 37°C or room temperature for 30 or 60 minutes. Final assay vehicle concentration is 1%. For antagonist determination, cells are pre-incubated with sample followed by agonist challenge at the EC80 concentration. Media is aspirated from cells and replaced with 10 μL 1:1 HBSS/Hepes: cAMP XS+ Ab reagent. 5 μL of 4X compound is added to the cells and incubated at 37 °C or room temperature for 30 minutes. 5 μL of 4X EC80 agonist is added to cells and incubated at 37 °C or room temperature for 30 or 60 minutes. EC80 forksolin is included. After appropriate compound incubation, assay signal is generated through incubation with 20 μL cAMP XS+ ED/CL lysis cocktail for one hour followed by incubation with 20 μL cAMP XS+ EA reagent for three hours at room temperature. Microplates are read following signal generation with a PerkinElmer Envision instrument for chemiluminescent signal detection. Compound activity is analyzed using CBIS data analysis suite (Chemlnnovation, CA). For agonist mode assay, percentage activity is calculated using the following formula: % Activity = 100% x (1 - (mean RLU of test sample - mean RLU of MAX control) / (mean RLU of vehicle control - mean RLU of MAX control)). For inverse agonist mode assay, percentage activity is calculated using the following formula: % Inverse Agonist Activity =100% x ((mean RLU of test sample - mean RLU of EC20 forskolin) / (mean RLU of forskolin positive control - mean RLU of EC20 control)). For antagonist mode assay, percentage inhibition is calculated using the following formula: % Inhibition = 100% x (mean RLU of test sample - mean RLU of EC80 control) / (mean RLU of forskolin positive control - mean RLU of EC80 control). Data are analyzed and IC ₅₀ is calculated using GraphPad Prism 5 and the model “log(inhibitor) vs. response - Variable slope”. [0582] Illustrative binding affinities for representative compounds are described in Table 2. The potencies are divided into three criteria: + means that IC ₅₀ is greater than 1000 nM; ++ means IC ₅₀ is between 100 nM and 999 nM; +++ means IC ₅₀ is below 100 nM. In some embodiments, compounds with IC ₅₀ designated “+” may have IC ₅₀ S between 1 μM to 30 μM.

Table 2.

Example B-3: In vitro mixed lymphocyte reaction assay

[0583] Dendritic cells (DC) are generated by culturing monocytes isolated from freshly isolated human PBMC ₃ using a monocyte purification kit (Miltenyi Biotec) in vitro for 7 days with 500 U/mL interleukin-4 (IL-4) and 250 U/mL GM-CSF (R&D Systems). CD ⁴⁺ T cells (IxlO ⁵ ) and allogeneic DC ₃

(IxlO ⁴ ) are co-cultured with or without CBjR antagonists and/or anti-PD-(L)-! antibody added at the initiation of the assay. After 5 days, IFNy secretion in culture supernatants is analyzed by ELISA (BD Biosciences).

Example B-4: In vitro T cell exhaustion assay

[0584] Freshly isolated human PBMC ₃ from healthy donors are cultured for 3 days with or without CB ₂ R antagonists and/or anti-PD-(L)-l antibodies at the initiation of the assay together with serial dilutions of staphylococcal enterotoxin B (SEB; Toxin Technology). IL-2 levels in culture supernatants are measured by ELISA analysis (BD Biosciences).

Example B-5: In vivo B16F10 tumor growth inhibition study

[0585] C57BL/6 inbred female mice, aged at 8-9 week, are purchased from Charles River. On the day of inoculation (Day 0), B16F10 cells are harvested, washed and counted. Cells are re-suspended as single cell solution in PBS at a concentration of 5xl0 ⁶ cells/mL at the final step. Immediately, five hundred thousand (5xl0 ⁵ ) of B16F10 cells suspended in 0.1 mL PBS are injected in the right flank of C57BL/6 mice subcutaneously using 27G needles. When palpable, tumors are measured by a caliper and tumor volumes (mm ³ ) are calculated by length x width x height x 0.5236. Mice with the tumor size approximate to 100 mm ³ are randomly assigned into one of four groups (n=10). Each group received vehicle (BID), CB ₂ R antagonists at 1 mg/kg (QD) and/or mouse anti-PD-1 (RMP1-14) at 5 mg/kg (Q2D), intraperitoneally. Tumor size and body weight are determined every 2-3 days. Percent tumor growth inhibition (TGI) is defined as the difference between the Median Tumor Volume (MTV) of a test group and control group, using the formula: % TGI = ((MTVcontrol-MTVtreated/MTVcontrol)) x 100.

Example B-6: Combination with Anti-PD-l/anti-PD-Ll Agents

[0586] CB ₂ receptor antagonists can be used in combination with other therapies that further enhance the antitumor immune response. When PD-1 and PD-L1 join together, they form a biochemical shield protecting tumor cells from being destroyed by the immune system. In some embodiments, CB ₂ receptor antagonists are combined with anti-PD-l/anti-PD-Ll agents to treat cancer. Combination therapy is advantageous when efficacy is greater than either agent alone or when the dose required for either drug is reduced thereby improving the side effect profile.

Example B -7: In vivo PK

[0587] Compounds described herein are tested in vivo and PK parameters are determined, as follows. Test compound is administered to six male SD rats, IV (n=3) at a dose level of 1 mg/kg and (PO) at dose level of 5 mg/kg PO (n=3). The dosing solution for IV administration is prepared by dissolving the compound in DMSO/PEG400/Water =10:30:60 as a 0.5 mg/mL solution (2 mL/kg dose volume). The dosing suspension for oral administration is formulated in 0.5% Methylcellulose as a 1 mg/mL suspension for the 5 mg/kg oral dose level (5 mL/kg dose volume).

[0588] Blood samples are collected from rats via jugular vein cannulation into EDTA-K2 tubes. For the IV administration experiment, blood samples are collected pre-dose, at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h post-dose administration. For PO adiminstation, blood samples are collected predose, at 15 min, 30 min,, 1 h, 2 h, 4 h, 8 h, and 24 h post-dose administration. [0589] For the IV administration experiment, blood concentrations of the compound are determined using LC-MS/MS with a lower limit of quantitation of 10 ng/mL. For the PO administration experiment, plasma concentrations of the compound are determined using LC-MS/MS with a lower limit of quantitation of 1 ng/mL. The pharmacokinetic parameters are determined by non-compartmental analysis using WinNonlin.

[0590] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0591] The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including,” “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed.

[0592] Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification, improvement and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this invention. The materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention.

[0593] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0594] In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0595] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control. [0596] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.