Phosphodiesterase Inhibitors and Uses

Abstract

The present invention provides compounds that can inhibit ENPP1 and are therefore useful for treating disorders associated with ENPP1. The present invention further provides pharmaceutical compositions containing these compounds and methods of using these compounds for treating or preventing disorders associated with ENPP1.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 904,501, filed September 23, 2019, and U.S. Provisional Patent Application No. 62 / 968,755, filed January 31, 2020, the disclosures of each of which are incorporated herein by reference in their entireties.

[0002] The present invention relates generally to compounds and compositions that may be useful as phosphodiesterase inhibitors. [Background technology]

[0003] The ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family consists of seven members, ENNP1-7, which are membrane-bound glycoproteins or ectoenzymes with active sites or soluble proteins in body fluids. Among them, ENPP1 (also known as plasma cell membrane glycoprotein, PC-1) is involved in many physiological processes such as development, formation and transport as well as pathophysiological conditions. ENPP1 can use nucleotides and nucleotide derivatives as substrates and hydrolyze them to form nucleoside-5' monophosphates. ATP is an identified substrate of ENPP1, which is hydrolyzed to AMP and PPi. Another known substrate, 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP), is an intracellular second messenger produced in response to cytoplasmic dsDNA. In addition, the artificial phosphates p-nitrophenyl 5'-thymidine monophosphate (TMP-pNP) and p-nitrophenyl 5'-adenosine monophosphate (AMP-pNP) are also incorporated as substrates by ENPP1.

[0004] ENPP1 is a type II transmembrane glycoprotein initially identified as a negative regulator of bone mineralization. It is expressed in the extracellular membrane of osteoblasts and chondrocytes and hydrolyzes extracellular ATP to generate AMP and diphosphate, an inhibitor of bone mineralization (Terkeltaub, R et,al. Purinergic Signaling 2006, 2, 371-377; Vaingankar, SM et,al. Cell Physiol. 2004, 286, C1177-C1187). ENPP1 is involved in many different biological processes. In lymphoid organs, ENPP1 hydrolysis generates AMP, which is then metabolized by the ecto-5'-nucleotidase CD73 to the immunosuppressive adenosine (Ferretti, E., Immunol. Lett. 2018, 3, 307). In animal models, ENPP1 inhibits insulin receptor tyrosine kinase activity, the primary target of insulin action, in peripheral tissues (Abate, N. et al. Nature Clin. Pract. Endocrinol. Metab. 2006, 2, 694-701).Aberrant ENPP1 expression has also been reported in breast cancer, Hodgkin's lymphoma, hepatocellular carcinoma follicular lymphoma, glioblastoma and other malignant tumor tissues.

[0005] In recent years, ENPP1 has been found to play an important role in cancer immunity. Li et al. reported that ENPP1 is the dominant 2'3'-cGAMP hydrolase, which degrades it into 5'-AMP and 5'-GMP. 2'3'-cGAMP is the most potent natural agonist for the Stimulator of Interferon Genes (STING) pathway, a central pathway in antiviral and anticancer innate immunity. 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) functions as an endogenous second messenger in response to cytoplasmic double-stranded DNA. It binds to and activates STING, which then stimulates the production of type I interferon (IFN) and other cytokines that trigger antiviral and antitumor immune responses (Manas Sharma, et,al. Int J cell Sci & Mol Biol., 2018, 5, 555655). Thus, ENPP1 inhibitors prevent 2'3'-cGAMP hydrolysis, substantially enhance cGAMP-induced STING pathway activation, and stimulate antitumor immune responses.

[0006] Thus, there is a need to develop ENPP inhibitors for treatment. [Brief description of the drawings]

[0007] [Fig. 1A-1E] The percent increase measured for IFN-β in cells treated with representative compounds 12, 48, 89, 103 and 121 compared to IFN-β in untreated cells is shown. Summary of the Invention

[0008] In some embodiments, a compound of formula (A): [ka] wherein each variable is as defined herein. or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof is provided.

[0009] Formulas (I) to (VI): [ka] [ka] [ka] wherein each variable is as defined herein. or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof is also disclosed.

[0010] In some embodiments, the compound of Formula (A) or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof is of Formulas (I)-(VI) described herein.

[0011] In another embodiment, a method of treating or preventing an ENPP1 associated uncontrolled cell proliferation disorder, a skeletal and soft tissue calcification associated disorder, a disorder associated with an ENPP1 genetic alteration, a viral infection and / or cancer is provided.

[0012] In some embodiments, methods are provided for treating or preventing a disorder or disease, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (A), including a compound of Formulas (I)-(VI) or a pharma-ceutically acceptable salt, stereoisomer, or solvate thereof.

[0013] Also provided are pharmaceutical compositions comprising (A) a compound described herein, e.g., a compound of Formula (A), including a compound of Formulas (I)-(VI) or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and (B) a pharma- ceutically acceptable carrier or excipient. Also provided are kits comprising a compound described herein or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof and, optionally, instructions for use.

[0014] The compounds described herein or their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs are provided for use as medicines.The compounds described herein or their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs are also provided for the manufacture of medicines for the treatment or prevention of uncontrolled cell proliferation disorders associated with ENPP1, such as cancer.

[0015] Detailed Description definition For purposes of this specification, unless expressly indicated otherwise, use of the terms "a," "an," etc. refers to one or more.

[0016] Reference herein to "about" a value or parameter includes (and describes) an embodiment that relates to the value or parameter itself. For example, a description of "about X" includes a description of "X."

[0017] "Alkyl" means an alkyl group having a specified number of carbon atoms (i.e., C1-C 10 means 1 to 10 carbon atoms), or a combination thereof. Particular alkyl groups include those having 1 to 20 carbon atoms ("C1-C 20 alkyl) having 1 to 10 carbon atoms ("C1-C 10 alkyl) having 6 to 10 carbon atoms ("C6-C 10 having from 1 to 6 carbon atoms ("C1-C6 alkyl"), having from 2 to 6 carbon atoms ("C2-C6 alkyl"), or having from 1 to 4 carbon atoms ("C1-C4 alkyl"). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0018] As used herein, unless otherwise specified, "cycloalkyl" refers to a cycloalkyl group having a specified number of carbon atoms (i.e., C-C 10 means 3 to 10 carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. Cycloalkyls containing more than one ring can be fused, spiro, or bridged, or combinations thereof. Particular cycloalkyl groups are those having 3 to 12 ring carbon atoms. Preferred cycloalkyls are cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"), 3 to 6 carbon atoms ("C3-C6 cycloalkyl"), or 3 to 4 ring carbon atoms ("C3-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0019] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having 1-14 ring carbon atoms and at least one ring heteroatom, such as, but not limited to, nitrogen, oxygen, and sulfur. Heteroaryl groups can contain a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl), which may or may not be fused with an aromatic ring. Particular heteroaryl groups are 5-14 membered rings having 1-12 ring carbon atoms and 1-6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, 5-10 membered rings having 1-8 ring carbon atoms and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-, 6-, or 7-membered rings having 1-5 ring carbon atoms and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one example, certain heteroaryl groups are monocyclic aromatic 5-, 6-, or 7-membered rings having 1-6 ring carbon atoms and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another example, certain heteroaryl groups are polycyclic aromatic rings having 1-12 ring carbon atoms and 1-6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryl groups having two or more rings, where at least one ring is non-aromatic, may be attached to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one example, heteroaryl groups having two or more rings, where at least one ring is non-aromatic, may be attached to the parent structure at an aromatic ring position. Heteroaryl groups may be attached to the parent structure at a ring carbon atom or a ring heteroatom.

[0020] As used herein, "heterocycle", "heterocyclic" or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings and containing nitrogen, sulfur, or oxygen, etc. Heterocycles containing more than one ring can be fused, bridged, or spiro, or any combination thereof, excluding heteroaryl groups. Heterocyclyl groups can be optionally substituted independently with one or more substituents described herein. Particular heterocyclyl groups are a 3- to 14-membered ring having 1 to 13 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 12-membered ring having 1 to 11 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 10-membered ring having 1 to 9 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3- to 8-membered ring having 1 to 7 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 3- to 6-membered ring having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one example, heterocyclyl includes a monocyclic 3-, 4-, 5-, 6-, or 7-membered ring having 1-2, 1-3, 1-4, 1-5, or 1-6 ring carbon atoms and 1-2, 1-3, or 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another example, heterocyclyl includes a polycyclic non-aromatic ring having 1-12 ring carbon atoms and 1-6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0021] "Halo" or "halogen" refers to the group 17 elements having atomic numbers 9-85. Preferred halo groups include fluorine, chlorine, bromine, and iodine radicals. When a residue is substituted with more than one halogen, it may be referred to by utilizing a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryls and alkyls substituted with two ("di") or three ("tri") halo groups, not necessarily the same halogens; thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a "perhaloalkyl." A preferred perhaloalkyl group is trifluoromethyl (-CF3).

[0022] "Oxo" refers to the moiety ═O.

[0023] Unless otherwise specified, "optionally substituted" means that a group can be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, which may be the same or different. In some embodiments, the optionally substituted group has one substituent. In other embodiments, the optionally substituted group has two substituents. In other embodiments, the optionally substituted group has three substituents. In other embodiments, the optionally substituted group has four substituents. In some embodiments, the optionally substituted group has 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, or 2-5 substituents. In some embodiments, the optionally substituted group is unsubstituted.

[0024] A "pharmaceutically acceptable salt" is a salt that maintains at least some biological activity of the free (non-salt) compound and can be administered to an individual as a drug or medicine. Such salts include, for example, (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc.; (2) salts formed by replacing an acidic proton, when present in the parent compound, with a metal ion, for example, an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or by coordinating with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, etc. Acceptable inorganic bases that can be used to prepare salts include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. Pharmaceutically acceptable salts may be prepared in situ during a manufacturing process or by separately reacting a compound of the invention in its purified free acid or base form with a suitable organic or inorganic base or acid, respectively, and then isolating the salt so formed during purification.

[0025] "Pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0026] The term "excipient" as used herein means an inactive or non-active substance that can be used in a drug or pharmaceutical product, such as a tablet containing a compound of the present invention as an active ingredient. A variety of substances can be encompassed by the term excipient, including, but not limited to, any substance used as a binder, disintegrant, coating agent, compression / encapsulation aid, cream or lotion agent, lubricant, parenteral solution, chewable tablet material, sweetener or flavoring agent, suspending / gelling agent, or wet granulation agent. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coatings include, for example, cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, and the like; chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), and the like; suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, and the like; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, and the like; and wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, and the like.

[0027] As used herein, "treatment" or "treated" is an approach to obtain beneficial or desired results, including clinical results. For example, beneficial or desired results may be, but are not limited to, one or more of the following: reduction of symptoms resulting from a disease, improvement in the quality of life of people with a disease, reduction in the dose of other medications required to treat the disease, delay in progression of the disease, and / or prolonged survival of an individual. In some embodiments, "treatment" of a disorder does not include prevention of the disorder, and "prevention" is understood to refer to the prophylactic administration of a drug to substantially reduce the likelihood or severity of the disorder or its biological symptoms, or to delay the onset of such disorder or its biological symptoms.

[0028] As used herein, an "effective dosage" or "effective amount" of a compound or salt thereof, or pharmaceutical composition is an amount sufficient to produce a beneficial or desired result. For prophylactic use, a beneficial or desired result includes eliminating or reducing the risk, reducing the severity of the disease, or delaying the onset of the disease, including the biochemical, histological and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes manifested during the development of the disease. For therapeutic use, a beneficial or desired result includes improving, mitigating, reducing, delaying or reducing one or more symptoms resulting from the disease, improving the quality of life of people with the disease, enhancing the effect of another medication, such as through reducing the dose of another medication required to treat the disease, targeting, delaying the progression of the disease, and / or extending survival. In some embodiments, an effective amount is an amount sufficient to delay onset. In some embodiments, an effective amount is an amount sufficient to prevent or delay recurrence. An effective dosage may be administered in one or more administrations. For purposes of this invention, an effective dosage of a compound or salt thereof, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. It is intended and understood that the dosage of compound or its salt or pharmaceutical composition may or may not be achieved in combination with another drug, compound or pharmaceutical composition.Therefore, "effective dosage" may be considered in the context of the administration of one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if it can or does achieve a desired result in combination with one or more other agents.

[0029] The term "subject" as used herein refers to a mammal, including humans.Subjects include, but are not limited to, humans, cows, horses, cats, dogs, rodents, or primates.In some embodiments, subjects include humans (adults and children).

[0030] Unless otherwise specified, "substantially pure" intends a composition containing 10% or less impurities, e.g., less than about 9%, less than about 7%, less than about 5%, less than about 3%, less than about 1%, less than about 0.5% impurities.

[0031] It is understood that the embodiments and examples described herein also include "consisting of" and / or "consisting essentially of" embodiments and examples.

[0032] All references throughout this specification, including publications, patents, patent applications and published patent applications, are incorporated by reference in their entirety.

[0033] compound In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: [ka] [During the ceremony, L1 is a bond, O, CR1R2, NR3, or *CR1R2NR3, where the * indicates the point of attachment to ring A; L2 is a bond, CR1R2 or C(=O); Q1, Q2, Q3, Q4 and Q5 are independently N, C or CE; A2, A3, A4 and A5 are independently N or CR4; X is S, O, CR1R2, CE, N or NR3; Z is SO2NHR5, SO2R5, C(O)OH, C(O)NHR5, C(O)NHOR5, P(O)(OR5)2, or B(OH)2; E, at each occurrence, is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SO2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; -C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, N(C1-C6 alkyl)2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, 3-8 membered heterocyclyl, -C(O)-C1-C4 alkoxy, -C(O)-NH2 and -S(O)2-C1-C6 alkyl; R1 and R2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl and C3-C8 cycloalkyl, wherein said C1-C6 alkyl and C3-C8 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy, or R1 and R2 together form C3-C6 cycloalkyl; R3 and R3' are independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; R4 is selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SON2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy; R5, at each occurrence, is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, and -C(=O)-C1-C6 alkyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclyl are independently optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; Ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 aryl or 5-10 membered heteroaryl, wherein ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 The aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens; [ka] indicates that ring B is fully unsaturated or partially unsaturated. The present invention provides the compound, a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0034] In some embodiments, the compound of Formula (A) has Formula (I): [ka] [During the ceremony, L1 is a bond, O, CR1R2, NR3, or *CR1R2NR3, where the * indicates the point of attachment to ring A; L2 is a bond, CR1R2 or C(=O); Q1 is N or CE; A2, A3, A4 and A5 are independently N or CR4; X is S, O, CR1R2 or NR3; Z is SO2NHR5, SO2R5, C(O)OH, C(O)NHR5, C(O)NHOR5, P(O)(OR5)2 or B(OH)2; E is selected from the group consisting of hydrogen, deuterium, halogen, oxo, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SO2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, N(C1-C6 alkyl)2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, 3-8 membered heterocyclyl, -C(O)-C1-C4 alkoxy, -C(O)-NH2 and -S(O)2-C1-C6 alkyl; R1 and R2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl and C3-C8 cycloalkyl, wherein said C1-C6 alkyl and C3-C8 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy, or R1 and R2 together form C3-C6 cycloalkyl; R3 and R3' are independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; R4 is selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SON2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy; R5, at each occurrence, is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, and -C(=O)-C1-C6 alkyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclyl are independently optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; Ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 aryl or 5-10 membered heteroaryl, wherein ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 The aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH, C1-C3 alkyl, and C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens. or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein Q2 is C, Q3 is CE where E is oxo, Q4 is N and Q5 is C, such that the compound is

[0035] In some embodiments, the compound of Formula (A) has the formula (II): [ka] [During the ceremony, L1 is a bond, O, CR1R2, NR3, or *CR1R2NR3, where the * indicates the point of attachment to ring A; L2 is a bond, CR1R2 or C(=O); Q1 is N or CE; A2, A3, A4 and A5 are independently N or CR4; Z is SO2NHR5, SO2R5, C(O)OH, C(O)NHR5, C(O)NHOR5, P(O)(OR5)2, or B(OH)2; E, at each occurrence, is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SO2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; -C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, N(C1-C6 alkyl)2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, 3-8 membered heterocyclyl, -C(O)-C1-C4 alkoxy, -C(O)-NH2 and -S(O)2-C1-C6 alkyl; R1 and R2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl and C3-C8 cycloalkyl, wherein said C1-C6 alkyl and C3-C8 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy, or R1 and R2 together form C3-C6 cycloalkyl; R3 and R3' are independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; R4 is selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SON2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy; R5, at each occurrence, is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, and -C(=O)-C1-C6 alkyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclyl are independently optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; Ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 aryl, or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 The aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH, C1-C3 alkyl, and C1-C4 alkoxy ring A, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens. wherein Q2 is C, Q3 is CE, Q4 is N, Q5 is C and X is N, such that the compound is

[0036] In some embodiments, the compound of Formula (A) has the formula (III): [ka] [During the ceremony, L1 is a bond, O, CR1R2, NR3, or *CR1R2NR3, where the * indicates the point of attachment to ring A; L2 is a bond, CR1R2 or C(=O); Q1 is N or CE; Q3 is N or CE; A2, A3, A4 and A5 are independently N or CR4; Z is SO2NHR5, SO2R5, C(O)OH, C(O)NHR5, C(O)NHOR5, P(O)(OR5)2, or B(OH)2; E, at each occurrence, is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SO2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; -C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, N(C1-C6 alkyl)2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, 3-8 membered heterocyclyl, -C(O)-C1-C4 alkoxy, -C(O)-NH2 and -S(O)2-C1-C6 alkyl; R1 and R2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl and C3-C8 cycloalkyl, wherein said C1-C6 alkyl and C3-C8 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy, or R1 and R2 together form C3-C6 cycloalkyl; R3 and R3' are independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; R4 is selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SON2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy; R5, at each occurrence, is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, and -C(=O)-C1-C6 alkyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclyl are independently optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; Ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 aryl or 5-10 membered heteroaryl, wherein ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 The aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH, C1-C3 alkyl, and C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens. wherein Q2 is C, Q4 is N, Q5 is C and X is CE, such that the compound is

[0037] In some embodiments, the compound of Formula (A) has Formula (IV): [ka] [During the ceremony, L1 is a bond, O, CR1R2, NR3, or *CR1R2NR3, where the * indicates the point of attachment to ring A; L2 is a bond, CR1R2 or C(=O); Q1 is N or CE; A2, A3, A4 and A5 are independently N or CR4; Z is SO2NHR5, SO2R5, C(O)OH, C(O)NHR5, C(O)NHOR5, P(O)(OR5)2, or B(OH)2; E is selected from the group consisting of hydrogen, deuterium, halogen, oxo, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SO2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; nyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, N(C1-C6 alkyl)2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, 3-8 membered heterocyclyl, -C(O)-C1-C4 alkoxy, -C(O)-NH2 and -S(O)2-C1-C6 alkyl; R1 and R2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl and C3-C8 cycloalkyl, wherein said C1-C6 alkyl and C3-C8 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy, or R1 and R2 together form C3-C6 cycloalkyl; R3 and R3' are independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; R4 is selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SON2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy; R5, at each occurrence, is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, and -C(=O)-C1-C6 alkyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclyl are independently optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; Ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 aryl, or 5-10 membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 The aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH, C1-C3 alkyl, and C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens. or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, is provided, wherein Q2 is C, Q3 is N, Q4 is N, Q5 is C and X is N, such that the compound is

[0038] In some embodiments, the compound of Formula (A) has the formula (V): [ka] [During the ceremony, L1 is a bond, O, CR1R2, NR3, or *CR1R2NR3, where the * indicates the point of attachment to ring A; L2 is a bond, CR1R2 or C(=O); Q1 and X are independently N or CE; A2, A3, A4 and A5 are independently N or CR4; Z is SO2NHR5, SO2R5, C(O)OH, C(O)NHR5, C(O)NHOR5, P(O)(OR5)2, or B(OH)2; E is selected from the group consisting of hydrogen, deuterium, halogen, oxo, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SO2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; nyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, N(C1-C6 alkyl)2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, 3-8 membered heterocyclyl, -C(O)-C1-C4 alkoxy, -C(O)-NH2 and -S(O)2-C1-C6 alkyl; R1 and R2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl and C3-C8 cycloalkyl, wherein said C1-C6 alkyl and C3-C8 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy, or R1 and R2 together form C3-C6 cycloalkyl; R3 and R3' are independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; R4 is selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SON2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy; R5, at each occurrence, is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, and -C(=O)-C1-C6 alkyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclyl are independently optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; Ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 aryl, or 5-10 membered heteroaryl, where ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 The aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens. or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, such that Q2 is C, Q3 is N, Q4 is C and Q5 is N, such that

[0039] In some embodiments, the compound of Formula (A) has the formula (VI): [ka] [During the ceremony, L1 is a bond, O, CR1R2, NR3, or *CR1R2NR3, where the * indicates the point of attachment to ring A; L2 is a bond, CR1R2 or C(=O); Q1, Q3 and X are independently N or CE; A2, A3, A4 and A5 are independently N or CR4; Z is SO2NHR5, SO2R5, C(O)OH, C(O)NHR5, C(O)NHOR5, P(O)(OR5)2, or B(OH)2; E, at each occurrence, is independently selected from the group consisting of hydrogen, deuterium, halogen, oxo, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SO2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 3-8 membered heterocyclyl; -C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, N(C1-C6 alkyl)2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, 3-8 membered heterocyclyl, -C(O)-C1-C4 alkoxy, -C(O)-NH2 and -S(O)2-C1-C6 alkyl; R1 and R2 are independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6 alkyl and C3-C8 cycloalkyl, wherein said C1-C6 alkyl and C3-C8 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy, or R1 and R2 together form C3-C6 cycloalkyl; R3 and R3' are independently selected from the group consisting of hydrogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl, and 3- to 8-membered heterocyclyl, wherein said C1-C6 alkyl and C3-C6 cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; R4 is selected from the group consisting of hydrogen, deuterium, halogen, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SON2NR3R3', C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy; R5, at each occurrence, is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, and -C(=O)-C1-C6 alkyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclyl are independently optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; Ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 aryl or 5-10 membered heteroaryl, wherein ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14 The aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH, C1-C3 alkyl, and C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens. or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, such that Q2 is N, Q4 is C and Q5 is C, such that the compound is

[0040] In some embodiments, provided herein is a compound of formula (A) in which the ring is fully unsaturated, such as a compound of formula (I)-(VI) or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof. In other embodiments, ring B is partially unsaturated. In some embodiments, ring B is a 5-membered aryl or 5-membered heteroaryl. In other embodiments, ring B is a 5-membered heterocyclyl or 5-membered cycloalkyl.

[0041] In some embodiments, provided herein is a compound of Formula (A), e.g., a compound of Formulas (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein A2, A3, A4, and A5 are independently N or CR4, wherein R4, at each occurrence, is independently hydrogen, deuterium, halogen, -CN, -OR3, -NO2, -NR3R3', -C(O)R3, -C(O)OR3, -C(O)NR3R3', -SO2R3, -SO2NR3R3', C1-C6 alkyl. , C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 3-8 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl and C1-C3 haloalkoxy. In some embodiments, A2, A3, A4 and A5 are CR4, wherein said R4 is, independently of each other and independently at each occurrence, H, C1-C4 alkoxy or CN. In some embodiments, A2 is CH, A3 is C-C1-C4 alkoxy, A4 is C-C1-C4 alkoxy and A5 is CH. In some embodiments, A2 is CH, A3 is C-OMe, A4 is C-OMe, and A5 is CH. In some embodiments, A2 is CH, A3 is C-C1-C4 alkoxy, A4 is CH, and A5 is CH. In some embodiments, A2 is CH, A3 is C-OMe, A4 is CH, and A5 is CH. In some embodiments, A2 is CH, A3 is CH, A4 is C-C1-C4 alkoxy, and A5 is CH. In some embodiments, A2 is CH, A3 is CH, A4 is C-OMe, and A5 is CH. In some embodiments, A2 is CH, A3 is CH, A4 is C-OMe, and A5 is CH. In some embodiments, A2 is CH, A3 is C-C1-C4 alkoxy, A4 is CN, and A5 is CH.In some embodiments, A2 is CH, A3 is C-OMe, A4 is CN, and A5 is CH. In some embodiments, A2 is CH, A3 is C-C1-C4 alkoxy, A4 is N, and A5 is CH. In some embodiments, A2 is CH, A3 is C-OMe, A4 is N, and A5 is CH. In some embodiments, A2 is N, A3 is C-C1-C4 alkoxy, A4 is CH, and A5 is CH. In some embodiments, A2 is N, A3 is C-OMe, A4 is CH, and A5 is CH. In some embodiments, A2 is CH, A3 is C-OMe, A4 is CH, and A5 is CH. In some embodiments, A2 is CH, A3 is C-C1-C4 alkoxy, A4 is CH, and A5 is N. In some embodiments, A2 is CH, A3 is C-OMe, A4 is CH, and A5 is N. In some embodiments, A2 is CH, A3 is C-C1-C4 alkoxy, A4 is N, and A5 is CH. In some embodiments, A2 is CH, A3 is C-OMe, A4 is N, and A5 is CH. In some embodiments, A2 is N, A3 is C-C1-C4 alkoxy, A4 is C-halogen, and A5 is CH. In some embodiments, A2 is N, A3 is C-OMe, A4 is C-Cl, and A5 is CH.

[0042] In some embodiments, provided herein are compounds of formula (I) or pharma- ceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, wherein A2 is CH, A3 is C-C1-C4 alkoxy, A4 is C-C1-C4 alkoxy, and A5 is CH. In some embodiments, provided herein are compounds of formula (I) or pharma- ceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, wherein A2 is CH, A3 is C-OMe, A4 is C-OMe, and A5 is CH. In some embodiments, provided herein are compounds of formula (II) or pharma- ceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, wherein A2 is CH, A3 is C-C1-C4 alkoxy, A4 is C-C1-C4 alkoxy, and A5 is CH. In some embodiments, provided herein is a compound of formula (II) or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein A2 is N, A3 is C-OMe, A4 is C-OMe, and A5 is CH. In some embodiments, provided herein is a compound of formula (II) or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein A2 is N, A3 is C-C1-C4 alkoxy, A4 is CH, and A5 is CH. In some embodiments, provided herein is a compound of formula (II) or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein A2 is N, A3 is C-OMe, A4 is CH, and A5 is CH.

[0043] In some embodiments, provided herein is a compound of Formula (A), e.g., a compound of Formulas (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein Ring A is C-C cycloalkyl, 3- to 12-membered heterocyclyl, C-C 14 aryl or 5-10 membered heteroaryl, wherein ring A is C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C 14The aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens.

[0044] In some embodiments, provided herein is a compound of formula (A), e.g., a compound of formula (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein ring A is C3-C8 cycloalkyl, wherein said C3-C8 cycloalkyl of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogen. In some embodiments, ring A is cyclobutyl.

[0045] In some embodiments, provided herein is a compound of formula (A), e.g., a compound of formula (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein ring A is a 3-12 membered heterocyclyl, wherein said 3-12 membered heterocyclyl of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogen. In some embodiments, ring A is a 4-8 membered heterocyclyl. In some embodiments, ring A is a 5- or 6-membered heterocyclyl. In some embodiments, ring A is piperazinyl. In some embodiments, ring A is azetidinyl. In certain embodiments, ring A is piperidinyl. In other embodiments, ring A is pyrrolidinyl.

[0046] In some embodiments, provided herein is a compound of Formula (A), e.g., a compound of Formulas (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein Ring A is a C6-C 14 aryl, wherein the C6-C 14 The aryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH, C1-C3 alkyl, and C1-C4 alkoxy, wherein the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens. In some embodiments, ring A is a C6-C 10 In some embodiments, ring A is aryl. In some embodiments, ring A is phenyl. In some embodiments, ring A is phenyl, wherein said phenyl of ring A is optionally substituted with one or more halogen, CN, C1-C3 alkyl or C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogen. In some embodiments, halogen is F.

[0047] In some embodiments, provided herein is a compound of formula (A), e.g., a compound of formula (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein ring A is a 5-10 membered heteroaryl, wherein said 5-10 membered heteroaryl of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogen. In some embodiments, ring A is a 5- or 6-membered heteroaryl. In some embodiments, ring A is a 6-membered heteroaryl. In some embodiments, ring A is pyridinyl. In other embodiments, ring A is pyrimidinyl. In some embodiments, ring A is pyridinyl or pyrimidinyl, wherein said pyridinyl or pyrimidinyl of ring A is optionally substituted with one or more halogen, CN, C1-C3 alkyl or C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogen. In some embodiments, halogen is F. In some embodiments, ring A is dihydroisoquinolinyl.

[0048] In some embodiments, provided herein is a compound of formula (A), e.g., a compound of formula (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein L1 is a bond, O, CR1R2, NR3, or *CR1R2NR3, where the * indicates the point of attachment to ring A. In some embodiments, L1 is a bond. In other embodiments, L1 is O, CR1R2, NR3, or *CR1R2NR3, where the * indicates the point of attachment to ring A. In some embodiments, L1 is O. In certain embodiments, L1 is CR1R2. In some embodiments, L1 is CR1R2, where R1 and R2 are independently selected from H and C1-C6 alkyl. In some embodiments, L1 is CR1R2, where R1 and R2 are independently selected from H and methyl. In some embodiments, L1 is CR1R2, where R1 and R2 are both H. In some embodiments, L1 is CR1R2, where one of R1 and R2 is H and the other of R1 and R2 is C1-C6 alkyl. In some embodiments, L1 is CR1R2, where one of R1 and R2 is H and the other of R1 and R2 is methyl. In other embodiments, L1 is NR3. In some embodiments, L1 is NR3, where R3 is H or C1-C6 alkyl. In some embodiments, L1 is NR3, where R3 is H. In other embodiments, L1 is NR3, where R3 is methyl. In some embodiments, L1 is *CR1R2NR3, where * indicates the point of attachment to ring A. In certain embodiments, L1 is *CR1R2NR3, where * indicates the point of attachment to ring A and where R1 and R2 are both H.

[0049] In some embodiments, provided herein is a compound of Formula (A), e.g., a compound of Formulas (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein L is a bond, O, CR, R, NR, or *CR, R, NR, where * indicates a point of attachment to Ring A, and Ring A is a C-C 14 aryl, wherein the C6-C 14 The aryl may be optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein said C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens.

[0050] In some embodiments, L is a bond and Ring A is C6-C 14 aryl, wherein the C6-C 14 The aryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogen. In some embodiments, L1 is a bond, ring A is phenyl, and the phenyl of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogen.

[0051] In some embodiments, L1 is CR1R2, where R1 and R2 are independently selected from C1-C6 alkyl and Ring A is a C6-C 14 aryl, wherein the C6-C 14The aryl is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogen. In some embodiments, L1 is CR1R2, wherein the R1 and R2 are independently selected from H and C1-C6 alkyl, and ring A is phenyl, wherein the phenyl of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogen. In certain embodiments, L1 is *CR1R2NR3, where the * indicates the point of attachment to ring A, where each of R1, R2 and R3 is H, and ring A is phenyl, where the phenyl of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl and C1-C4 alkoxy, where the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens.

[0052] In some embodiments, L1 is a bond and ring A is a 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens. In some embodiments, L1 is a bond and ring A is a 6 membered heteroaryl, wherein the 6 membered heteroaryl of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, wherein the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens. In some embodiments, L1 is a bond and Ring A is pyridinyl or pyrimidinyl, wherein the pyridinyl or pyrimidinyl of Ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl and C1-C4 alkoxy, wherein the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens.

[0053] In some embodiments, L1 is CR1R2, where R1 and R2 are independently selected from the group consisting of H and C1-C6 alkyl, and ring A is a 5-10 membered heteroaryl, where the 5-10 membered heteroaryl of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, where the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogen. L1 is CR1R2, where R1 and R2 are independently selected from the group consisting of H and C1-C6 alkyl, and ring A is a 6 membered heteroaryl, where the 6 membered heteroaryl of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, where the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogen. In some embodiments, L1 is CR1R2, where R1 and R2 are independently selected from H and C1-C6 alkyl, and ring A is pyridinyl or pyrimidinyl, where the pyridinyl or pyrimidinyl of ring A is optionally substituted with one or more substituents selected from halogen, CN, OH, NH2, C1-C3 alkyl, and C1-C4 alkoxy, where the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens. In certain embodiments, L1 is *CR1R2NR3, where the * indicates the point of attachment to ring A, where each of R1, R2 and R3 is H, and ring A is pyridinyl or pyrimidinyl, where the pyridinyl or pyrimidinyl of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH2, C1-C3 alkyl and C1-C4 alkoxy, where the C1-C3 alkyl and C1-C4 alkoxy are independently optionally substituted with one or more halogens.In some embodiments, provided herein is a compound of Formula (A), e.g., a compound of Formula (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein L2 is a bond, CR1R2, or C(=O). In some embodiments, L2 is a bond. In some embodiments, L2 is O. In certain embodiments, L2 is CR1R2. In some embodiments, L2 is CR1R2, wherein said R1 and R2 are independently selected from H and C1-C6 alkyl. In some embodiments, L2 is CR1R2, wherein said R1 and R2 are independently selected from H and methyl. In some embodiments, L2 is CR1R2, wherein said R1 and R2 are both H. In some embodiments, L2 is CR1R2, wherein one of R1 and R2 is H and the other of R1 and R2 is C1-C6 alkyl. In some embodiments, L2 is CR1R2, where one of R1 and R2 is H and the other of R1 and R2 is methyl. In some embodiments, L2 is C(=O).

[0054] In some embodiments, provided herein are compounds of formula (A), e.g., compounds of formula (I)-(VI), or pharma- ceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, as applicable, wherein X is S, O, CR1R2, CE, N, or NR3. In some embodiments, X is O, CR1R2, CE, N, or NR3. In some embodiments, X is O. In certain embodiments, X is N. In some embodiments, X is NR3. In other embodiments, X is NR3 and R3 is H or C1-C6 alkyl. In some embodiments, X is CE. In some embodiments, X is CE, wherein E is H or C1-C6 alkyl, wherein E is C1-C6 alkyl, optionally substituted with one or more OH, halogen, C1-C4 alkoxy, or 3-8 membered heterocyclyl. In some embodiments, X is N or CE.

[0055] In some embodiments, provided herein is a compound of Formula (A), e.g., a compound of Formula (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein Z is SO2NHR5, SO2R5, C(O)OH, C(O)NHR5, C(O)NHOR5, P(O)(OR5)2, or B(OH). In some embodiments, Z is SO2NHR5, where R5 is H, C1-C6 alkyl, or -C(O)-C1-C6 alkyl. In some embodiments, Z is SO2NHR5, where R5 is H. In some embodiments, Z is SO2R5. In certain embodiments, Z is C(O)OH, C(O)NHR5, or C(O)NHOR5. In certain embodiments, Z is C(O)OH. In some embodiments, Z is C(O)NHOR5, where R5 is H. In some embodiments, Z is C(O)NHR5, where R5 is H. In some embodiments, Z is B(OH)2. In some embodiments, Z is P(O)(OR5)2, where each R5 is independently H or C1-C6 alkyl. In some embodiments, Z is P(O)(OR5)2, where each R5 is independently H.

[0056] Representative compounds are listed in Table 1. In some embodiments, provided herein is a compound of formula (A), e.g., a compound of formula (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein L1 is a bond and Z is SONHR5, wherein said R5 is H, C1-C6 alkyl, or -C(O)-C1-C6 alkyl. In some embodiments, L1 is a bond and Z is SONHR5, wherein said R5 is H. In other embodiments, L1 is a bond and Z is SONHR5, wherein said R5 is C1-C6 alkyl. L1 is NR3, wherein said R3 is H, and Z is SONHR5, wherein said R5 is H, C1-C6 alkyl, or -C(O)-C1-C6 alkyl. In some embodiments, L1 is NR3, wherein said R3 is H, and Z is SONHR5, wherein said R5 is H. In some embodiments, L1 is CR1R2, where R1 and R2 are independently selected from H and C1-C6 alkyl, and Z is SON2NHR5, where R5 is H, C1-C6 alkyl, or -C(O)-C1-C6 alkyl. In some embodiments, L1 is CR1R2, R1 and R2 are independently selected from H and C1-C6 alkyl, and Z is SON2NHR5, where R5 is H. In some embodiments, L1 is a bond and Z is P(O)(OR5)2, where each R5 is independently H or C1-C6 alkyl. In some embodiments, L1 is a bond and Z is B(OH)2. In some embodiments, L1 is a bond and Z is C(O)OH, C(O)NHR5, or C(O)NHOR5. In some embodiments, L1 is a bond and Z is C(O)OH, C(O)NHR5, or C(O)NHOR5, where each R5 is independently H.

[0057] Representative compounds are listed in Table 1. [Table 1-1] [Table 1-2]

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

[0058] In some embodiments, the compound of Formula (A) or the compound of Formulas (I)-(VI) is not an analog of the following, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof: [ka] [ka]

[0059] In some embodiments, the compound of Formula (A) or the compound of Formulas (I)-(VI) is not an analog of the following, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof: [ka] [ka]

[0060] In some embodiments, provided herein is a compound set forth in Table 1, or a pharma- ceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0061] In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts.In some embodiments, the methods described herein include methods of treating disease by administering such pharmaceutically acceptable salts.In some embodiments, the methods described herein include methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0062] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the salt so formed.

[0063] Examples of pharma- ceutically acceptable salts include salts prepared by reacting the compounds described herein with an inorganic acid, an organic acid, or an inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfite, hydrogen sulfite, bromide, butyrate, butyne-1,4-dioic acid, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioic acid, hydroxybenzoate, g-hydroxybutyrate, hydrochloride, or the like. The salts include, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate and xylenesulfonate.

[0064] Additionally, the compounds described herein may be used with, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxybenzoic acid, 1,2-dimethylphenylsulfonic ... They may be prepared as pharma- ceutically acceptable salts formed by reacting the free base form of the compound with pharma- ceutically acceptable inorganic or organic acids, including sietanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0065] In some embodiments, the compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxide, carbonate, bicarbonate, sulfate, ammonia, or pharma- ceutically acceptable organic primary, secondary, tertiary, or quaternary amines of pharma- ceutically acceptable metal cations.Representative salts include alkali or alkaline earth salts such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts.Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4 and the like.

[0066] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0067] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, with each center being present in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms and their corresponding mixtures. In addition to the embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers resulting from a single preparative step, combination or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, separable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on solubility agents. In some embodiments, the optically pure enantiomers are then recovered along with the resolving agent.

[0068] In some embodiments, the compounds described herein exist as solvates.The present invention further provides a method for treating a disease by administering such a solvate.The present invention further provides a method for treating a disease by administering such a solvate as a pharmaceutical composition.

[0069] Solvates include stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during the process of crystallization with pharma- ceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed. Solvates of the compounds described herein can be conveniently produced or formed during the process described herein. As an example, hydrates of the compounds described herein can be conveniently produced by recrystallization from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0070] Prodrugs of the compounds described herein are also provided. In some embodiments, the prodrugs can be converted to a compound of Formula (A) or Formulas (I)-(VI) when administered to a subject, for example, by metabolic processing of the prodrug.

[0071] The following prodrugs are examples using compound 40 for illustrative purposes. In some embodiments, similar analogs can be made using sulfonamides as handles. [ka]

[0072] Pharmaceutical Compositions and Formulations Pharmaceutical compositions of any of the compounds described herein or their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs are encompassed by the present invention. Thus, the present invention includes pharmaceutical compositions comprising the compounds described herein or their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs and pharmaceutically acceptable carriers or excipients. In some embodiments, the pharmaceutically acceptable salts are acid addition salts, for example, salts formed with inorganic or organic acids. Pharmaceutical compositions can be formulated for specific routes of administration, such as oral administration, parenteral administration and topical administration. In some embodiments, pharmaceutical compositions can be in a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or in a form suitable for administration by inhalation.

[0073] The compounds described herein or their pharma- ceutically acceptable salts, stereoisomers, solvates or prodrugs may be in purified form in some embodiments, and compositions comprising the compounds in purified form are described herein.Compositions comprising the compounds described herein or their salts, such as compositions comprising substantially pure compounds, are provided.In some embodiments, the compositions comprising the compounds described herein or their salts are in substantially pure form.

[0074] In one embodiment, the compounds herein are synthetic compounds prepared for administration to an individual. In another embodiment, a composition is provided that includes the compound in a substantially pure form. In another embodiment, the present invention encompasses a pharmaceutical composition that includes the compound described herein or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof and a pharma- ceutically acceptable carrier. In another embodiment, a method of administering the compound is provided. The purified form, pharmaceutical composition and method of administering the compound are appropriate for any compound or form described herein.

[0075] The compounds described herein or their pharma- ceutically acceptable salts, stereoisomers, solvates or prodrugs can be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery. The compounds or their salts can be formulated with suitable carriers to provide delivery forms, including, but not limited to, tablets, dragees, capsules (e.g., hard or soft gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, poultices, pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0076] One or several of the compounds described herein or their pharma- ceutically acceptable salts, stereoisomers, solvates or prodrugs can be used to prepare formulations, such as pharmaceutical preparations, by combining one or more of the compounds or their salts as active ingredients with pharma- ceutically acceptable carriers, such as the above-mentioned carriers. Depending on the therapeutic form of the system (e.g., transdermal patch and oral tablet), the carrier can be in various forms. In addition, the pharmaceutical preparations include preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, colorants, regulators and salts for regulating osmotic pressure, buffers, coating agents or antioxidants. The formulations containing the compounds also include other substances that have useful therapeutic properties. The pharmaceutical preparations can be prepared by known formulation methods. Suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated by reference.

[0077] Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and may be prepared in the form of tablets, pills, powders, suspensions, emulsions, solutions, syrups and capsules. Oral compositions may contain a mixture of the active ingredient with non-toxic pharma- ceutically acceptable excipients suitable for the manufacture of tablets. The tablets may be uncoated or coated to delay disintegration and absorption in the digestive tract, thereby providing a sustained action over a longer period of time. Formulations for oral use may be present as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0078] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.

[0079] Suitable compositions for transdermal application comprise an effective amount of the compound of the present invention together with suitable carrier.Suitable carrier for transdermal delivery comprises absorbable pharmacologically acceptable solvent to support passage through the skin of host.For example, transdermal device is in the form of a bandage, comprising a backing member, a reservoir that comprises the compound, optionally together with carrier, optionally a rate-controlling barrier for delivering the compound to the skin of host at a controlled and predetermined rate over an extended period of time, and a means for fixing the device to the skin.

[0080] Compositions suitable for topical application, e.g., to the skin and eyes, include, e.g., aqueous solutions, suspensions, ointments, creams, gels or spray formulations for delivery by aerosol, etc. Such topical delivery systems are particularly suitable for transdermal applications, e.g., prophylactic use in the treatment of skin cancer, e.g., sun creams, lotions, sprays, and the like.

[0081] As used herein, topical application may also refer to inhalation or intranasal application.They may conveniently be delivered in the form of dry powder (alone or in mixtures, for example, dry blends with lactose, or as mixed component particles, for example, with phospholipids) from a dry powder inhaler, in the form of an aerosol spray from a pressurized container, pump, spray, atomizer or nebulizer, with or without the use of a suitable propellant.

[0082] The present invention further provides pharmaceutical compositions and dosage forms that contain one or more substances that slow the rate at which the compounds of the present invention as an active ingredient decompose. Such substances, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.

[0083] Methods and Therapeutic Uses In addition to the compounds described herein, their pharma- ceutically acceptable salts, stereoisomers, solvates and compositions, and combinations comprising these compounds, the present invention includes methods of using them, as further described herein.

[0084] The compound of formula (A) or formula (I)-(VI) or its pharmaceutically acceptable salt, prodrug or solvate can be used for the treatment of STING pathway mediated diseases or disorders. In some embodiments, a method of inhibiting ENPP1 activity using the compound of formula (A) or formula (I)-(VI) or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug is provided. In some embodiments, the compound of formula (A) or formula (I)-(VI) or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug has desirable physicochemical properties, such as water solubility.

[0085] The ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family consists of seven members, ENNP1-7, which are membrane-bound glycoproteins or exoenzymes with active sites or soluble proteins in body fluids. ENPP1 is involved in many different biological processes. In animal models, it was reported that overexpressed ENPP1 inhibits insulin receptor tyrosine kinase activity in peripheral tissues, the primary target of insulin action (Abate, N. et,al. Nature Clin. Pract. Endocrinol. Metab. 2006, 2, 694-701). ENPP1 is also expressed on the outer cell membrane of osteoblasts and chondrocytes and has a profound effect on bone mineralization (Terkeltaub, R et al. Purinergic Signalling 2006, 2, 371-377; Vaingankar, SM et al. Cell Physiol. 2004, 286, C1177-C1187).

[0086] In recent years, ENPP1 has been shown to play an important role in cancer immunotherapy and autoimmune diseases. ENPP1 hydrolyzes 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) and breaks it down into 5'-AMP and 5'-GMP. cGAMP activates the stimulator of interferon genes (STING) pathway, leading to the production of type I interferon (IFN) and other cytokines that trigger immune responses (Manas Sharma, et al. Int J cell Sci & Mol Biol., 2018, 5, 555655). Therefore, ENPP1 inhibitors that prevent cGAMP hydrolysis and induce sting activity could be used to increase immune responses. As with checkpoint inhibitors such as anti-PD-1 or PD-L1, which are promising immunotherapeutic agents against a variety of cancers, activation of the STING pathway by these inhibitors has become even more important for tumor control in cancer immunotherapy.

[0087] Additionally, Lau WM and Kominsky SL [2013, PLoS ONE 8(7)] found that "Enpp1 was increased in human breast cancer cell lines known to give rise to bone metastases in animal models compared to nonmetastatic and normal breast epithelial cell lines." They further showed that ENPP1 levels were significantly elevated in human primary breast tumors compared to normal mammary epithelium in clinical specimens, with the highest levels observed in breast-bone metastases.

[0088] In certain aspects, the present invention provides a method of treating a disorder mediated by inappropriate ENPP1 activity comprising administering a safe and effective dose of a compound of Formula (A) or Formulas (I)-(VI), or a pharma-ceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0089] In some embodiments, the ENPP1 mediated disease or disorder is selected from the group consisting of diseases associated with skeletal and soft tissue mineralization, T2D, cardiovascular disease, cancer, autoimmune diseases and osteoarthritis.

[0090] In some embodiments, the ENPP1 mediated disease or disorder is an autoimmune disease such as asthma, type I diabetes, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD) and lupus.

[0091] In some embodiments, the compounds described herein can be used to treat the cancer mediated by inappropriate ENPP1 activity.In certain embodiments, the disease is hematological malignancy.In some embodiments, the disease is solid tumor.In some embodiments, the efficacy is to treat the solid tumor with abnormal ENPP1 expression, such as astrocyte brain tumor, and glioblastoma stem-like cell and breast cancer metastasis.

[0092] The potency of compounds as inhibitors of enzyme activity (or other biological activity) can be established by determining the concentration at which each compound inhibits the activity to a given degree and then comparing the results. The "IC 50" or "IC 90 " may be determined by the concentration that inhibits 50% or 90% of the activity in a biochemical assay, which may be accomplished using conventional techniques known in the art, including those described in the Examples below. As used herein, "inhibition of ENPP1 activity" or variations thereof refers to a decrease in ENPP1 activity as a direct or indirect response to the presence of a compound of Formula (A) or Formulas (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, compared to ENPP1 in the absence of the compound of Formula (A) or Formulas (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0093] In some embodiments, the compound of Formula (A) or Formulas (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, may be combined with one or more additional therapeutic agents to treat cancer or inflammatory disorders. The one or more additional therapeutic agents may be chemotherapeutic agents, radiotherapy, targeted therapy, immunotherapy, or any current best therapy, either as small molecules or biological properties.

[0094] According to their mechanism of action, chemotherapeutic agents are classified into alkylating agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors and cytotoxic agents. The compounds of formula (A) or formulas (I)-(VI) or their pharma-ceutically acceptable salts, stereoisomers, solvates or prodrugs may be used in combination with chemotherapeutic agents to enhance or improve the efficacy of the particular chemotherapeutic agent for treating blood or solid tumors.

[0095] Immunotherapeutic agents that may be suitable for use in combination with a compound of Formula (A) or Formulas (I)-(VI) or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof include, but are not limited to, therapeutic antibodies, small molecules and vaccines suitable for treating a patient; for example, IDO1 and TDO2 inhibitors, A2A receptor inhibitors, arginase inhibitors, Toll-like receptor agonists, chemokine regulators (including the CCR and CXCR families), STING agonists, checkpoint inhibitory antibodies, such as antibodies that regulate PD-1, PD-L1, CTLA-4, OX40-OX40 ligand, LAG3, TIM3, or any combination thereof.

[0096] Radiation therapy is part of cancer treatment to control or kill malignant cells, and is generally applied to cancer tumors because of its ability to control cell proliferation. The compound of formula (A) or formula (I)-(VI), or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug, can be combined with radiation therapy to improve the efficacy of radiation therapy for treating blood or solid tumors, or can be combined with surgery, chemotherapy, immunotherapy and combinations of the four.

[0097] Targeted therapies that may be suitable for use in combination in a combination therapy include, but are not limited to, inhibitors against cyclin-dependent kinases (CDKs) such as PI3K, CDK1, CDK2, CDK4 / 6, CDK7 and CDK9, Janus kinases (JAKs) such as JAK1, JAK2 and / or JAK3, spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), mitogen-activated protein kinases (MEKs) such as MEK1 and MEK2, bromodomain-containing protein inhibitors (BRDs) such as BRD4, isocitrate dehydrogenases (IDHs) such as IDH1, histone deacetylases (HDACs) or any combination thereof.

[0098] In some embodiments, a compound of Formula (A) or Formulas (I)-(VI), or a pharma- ceutically acceptable salt, stereoisomer, solvate or prodrug thereof, may be used in combination with one or more additional therapeutic agents to treat patients who are substantially refractory to at least one chemotherapy treatment or who have relapsed following treatment with chemotherapy.

[0099] The dosage of pharmaceutical composition or combination depends on body weight, age and individual condition, the disorder or disease to be treated or its severity.Effective dosage is determined by a doctor or clinician to prevent, treat or inhibit the progression of disorder or disease.In some embodiments, a safe and effective dosage is sufficient to treat the condition of the patient, but low enough to avoid serious side effects.Safe and effective dosage can vary with the specific compound selected (e.g., considering the potency, efficacy and half-life of the compound); the route of administration selected; the disorder to be treated; the severity of the disorder to be treated; the age, height, weight and physical condition of the patient to be treated; the medical history of the patient to be treated; the duration of treatment; the nature of the combination therapy; the desired therapeutic effect; and similar factors.

[0100] In carrying out the method of the present invention, a therapeutically effective amount of any one of the compounds of the present invention or any combination of the compounds of the present invention or pharma- ceutically acceptable salts, stereoisomers, solvates or prodrugs thereof is administered alone or in combination by any of the conventional and accepted methods known in the art. Thus, the compounds or compositions may be administered orally (e.g., buccal), sublingually, parenterally (e.g., intramuscularly, intravenously or subcutaneously), rectally (e.g., by suppository or lavage), transdermally (e.g., skin electroporation) or by inhalation (e.g., aerosol), in the form of solid, liquid or gaseous dosages, including tablets and suspensions. Administration may be performed continuously in a single unit dosage form or in a single dose treatment, as appropriate. The therapeutic composition may also be in the form of an oil emulsion or dispersion with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained release composition for subcutaneous or intramuscular administration.

[0101] The pharmaceutical compositions may be administered in single or multiple doses. The compounds of formula (A) or formulas (I)-(VI), or pharma- ceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, may be formulated to provide a desired release schedule of the active ingredient based on the objective of the therapeutic treatment.

[0102] The pharmaceutical compositions are preferably prepared in the form of dosage units containing a specific amount of active ingredient in the form of tablets, pills, powders, suspensions, emulsions, solutions, syrups and capsules. For example, they may contain the active ingredient in an amount of about 0.1 to 1000 mg, preferably about 0.1 to 500 mg. Suitable daily doses for humans or other mammals may vary widely depending on the condition of the patient and other factors, but again can be determined using routine methods. The daily dose may be administered in 1 to 4 doses per day. For therapeutic purposes, the active compounds of the invention are usually combined with one or more adjuvants suitable for the indicated dropwise administration route, suitable for administration to the eye, ear or nose. Suitable topical doses of the active ingredients of the compounds of the invention are 0.1 mg to 150 mg, administered 1 to 4 times a day, preferably 1 or 2 times. For topical administration, the active ingredient may be from 0.001% to 10% w / w, for example from 1% to 2% by weight of the formulation, preferably up to 5% w / w of the formulation, more preferably from 0.1% to 1% by weight of the formulation.

[0103] The compound or composition of the present invention can be administered to an individual according to an effective dosing regimen for a desired time or period, for example, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more. In one example, the compound is administered daily or on an intermittent schedule. The compound can be administered to an individual continuously (e.g., at least once a week) during the period. The dosing frequency can be less than once a week, for example, about once a week. The dosing frequency can be more than once a week, for example, twice a week or three times a week. The dosing frequency can also be intermittent, including "drug holidays" (e.g., seven days of once a day dosing followed by seven days of no dosing repeated in any 14 day period, for example, about two months, about four months, about six months, or more). Any dosing frequency can be utilized with any compound described herein, together with any dosage amount described herein.

[0104] In certain embodiments, the method includes administering to the subject an initial daily dose of 0.1-500 mg of a compound of Formula (A) or Formulas (I)-(VI) and increasing the dose by incremental escalation until a clinical response 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 a week or three times a week.

[0105] Manufacturing and Kit Instructions The present invention further includes the product of manufacture, which comprises the compound of the present invention or its salt, composition and unit dose described herein in suitable packaging.In certain embodiments, the product of manufacture is for use in any of the methods described herein.Suitable packaging is known in the art, and includes, for example, vial, container, ampoule, bottle, jar, flexible packaging, etc.The product of manufacture is further sterilized and / or sealed.

[0106] The present specification further provides a kit for carrying out the method of the present invention, comprising one or more compounds described herein or a composition comprising a compound described herein.The kit may utilize any compound described herein.In one example, the kit utilizes a compound described herein or a pharma-ceutically acceptable salt, stereoisomer, solvate or prodrug thereof.The kit may be used for any one or more of the uses described herein, and therefore may include instructions for treating the diseases described herein.

[0107] The kit generally includes suitable packaging. The kit may include one or more containers that contain any of the compounds described herein. Each component (if there are two or more components) may be packaged in separate containers, or some components may be combined in one container, if cross-reactivity and shelf life permit.

[0108] The kit can be in unit dosage form, bulk packaging (e.g., multi-dose packaging) or sub-unit dose. For example, a kit can be provided that includes a sufficient dosage of the herein described and / or second pharmacoactive compound useful for the herein described disease (e.g., hypertension) to provide an effective treatment of an individual for an extended period of time, e.g., for any of 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months or more. The kit can also include multiple unit doses of the compound and instructions for use, and can be packaged in sufficient quantities for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0109] The kit may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic or optical disks) containing the instructions, relating to the use of one or more components of the methods of the invention. The instructions included in the kit generally include information about the components and their administration to an individual.

[0110] The present invention may be further understood by reference to the following examples, which are offered by way of illustration and are not meant to be limiting. EXAMPLES

[0111] Synthesis Examples Reagents and solvents used below can be obtained from commercial sources. 1 H-NMR spectra were recorded on Bruker 400 and 600 MHz NMR spectrometers. Prominent peaks are listed in order of multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broadened singlet), coupling constant in Hertz (Hz), and number of protons. Mass spectrometry results are reported as mass-to-charge ratio and relative abundance of each ion (in parentheses). Electrospray ionization (ESI) mass spectrometry was performed on an Agilent 1100 LC / MSD electrospray mass spectrometer.

[0112] The terms "solvent", "inert organic solvent" or "inert solvent" refer to a solvent that is inert under the reaction conditions described therein, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), ethyl acetate (EA or EtOAc), dichloromethane (DCM), diethyl ether, methanol, pyridine, and the like. Unless otherwise specified, the solvents used in the reactions of the present invention are inert organic solvents and the reactions are carried out under an inert gas, preferably nitrogen and argon.

[0113] Formula (I)-Formula (VI) can be prepared using the methods described herein and their routine modifications, which are clearly known in the art, as disclosed herein and the methods are known. Conventional and known synthetic methods can be used in addition to those described herein. Representative synthesis of the compounds described herein can be achieved as described in the following examples. Where available, reagents can be purchased commercially, for example, from Sigma Aldrich or other chemical distributors.

[0114] General method: Example 1 4-((7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (1) [ka] Step 1: Synthesis of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile A stirred mixture of 4-hydroxy-6,7-dimethoxyquinoline-3-carbonitrile (550 mg, 2.39 mmol) and 10 mL of POCl3 was heated at reflux for 3 h. Volatiles were removed under reduced pressure at about 70 °C. The residue was stirred with methylene chloride and H2O at 0 °C, and solid K2CO3 was carefully added until the pH was 8-9. After stirring at 25 °C for 30 min, the organic layer was separated, washed with H2O, dried, filtered through Celite, and concentrated to give the crude product. The residue was purified by flash column chromatography (0-30% EA in PE) to give the product 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 2 as a light yellow solid (600 mg, 95% yield). LCMS (ESI) [M+H] + =249.

[0115] Step 2: Synthesis of 4-(((3-cyano-6,7-dimethoxyquinolin-4-yl)amino]methyl)-benzenesulfonamide A solution of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile (550 mg, 2.21 mmol), 4-(aminomethyl)benzenesulfonamide hydrochloride (591 mg, 2.65 mmol) and potassium carbonate (1.528 g, 11.06 mmol) in DMF (15 ml). The reaction mixture was stirred at 70° C. for 16 h and monitored by LCMS. After filtration, the organic layer was concentrated in vacuo and the residue was purified by recrystallization from DCM / MeOH (10:1) to give the product 4-(((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)methyl)benzenesulfonamide as a yellow solid (800 mg, 72.6% yield). LCMS (ESI) [M+H] + =399.

[0116] Step 3: Synthesis of 6,7-dimethoxy-4-(((4-sulfamoylphenyl)methyl)amino)quinoline-3-carboxylic acid To a solution of 4-(((3-cyano-6,7-dimethoxyquinolin-4-yl)amino)methyl)benzenesulfonamide (500 mg, 1.255 mmol) in EtOH (5 ml) was added KOH (1734 mg, 12.55 mmol, dissolved in 5 ml water). The reaction mixture was heated at reflux for 16 h. The solution was concentrated in vacuo and the crude product was purified by preparative HPLC to give the product 6,7-dimethoxy-4-(((4-sulfamoylphenyl)methyl)amino)quinoline-3-carboxylic acid as a white solid (90 mg, 16% yield). LCMS (ESI) [M+H] + =418.

[0117] Step 4: Synthesis of 4-((7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzene-sulfonamide To a solution of 6,7-dimethoxy-4-(((4-sulfamoylphenyl)methyl)amino)quinoline-3-carboxylic acid (20 mg, 0.048 mmol) in t-BuOH (2 ml) was added triethylamine (5.8 mg, 0.057 mmol) and DPPA (15.8 mg, 0.057 mmol). Under nitrogen, the reaction mixture was stirred at 100° C. for 16 h. The solution was concentrated to dryness and purified by preparative HPLC to give the product 4-((7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzene-sulfonamide (1) as a white solid (5 mg, 21% yield). LCMS (ESI) [M+H] + =415; 1 H NMR (400MHz, DMSO)δ 11.58(br, 1H), 8.51(s, 1H), 8.17(s, 1H), 7.79(d, J=8.3Hz, 2H), 7.45(d, J=8 .3Hz, 2H), 7.31(s, 2H), 6.95(s, 1H), 5.63(s, 2H), 3.84(s, 3H), 3.59(s, 3H).

[0118] Example 2 Preparation of 2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl (General Method 1) [ka] A similar synthetic method (W, Huang et al, Eur. J. Org. Chem. 2018, 1572-1580) was applied to obtain the title analogue from known starting material (4-chloro-6,7-dimethoxyquinolin-3-amine, prepared according to literature method, Fuchss, Thomas et al, PCT International Application No. 2012028233).

[0119] Preparation of 2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl (General Method 2) [ka] Preparation of 1H-imidazo[4,5-c]quinoline (General Method 3) [ka] Preparation of 1H-[1,2,3]triazolo[4,5-c]quinolines (General Method 4) [ka] A similar synthetic method (A. Boullilot, WO 2011 / 054846 A1) was applied to obtain the title analogues (general methods 2, 3 and 4) from known starting material (4-chloro-3-nitro-6,7-dimethoxyquinoline, prepared according to literature method, Fuchss, Thomas et al, PCT International Application No. 2012028233).

[0120] Preparation of 1H-[1,2,3]triazolo[4,5-c]quinolines (General Method 5) [ka] A similar synthetic method (A Gopalsamy et al, Journal of Medicinal Chemistry 2007, 50, 5547-5549) was applied to obtain the title analogue from 4-chloro-6,7-dimethoxyquinoline-3-carbaldehyde.

[0121] Preparation of 1H-[1,2,3]triazolo[4,5-c]quinolines (General Method 6) [ka] A similar synthetic method (By A. Jeffrey S. et al, PCT International Application No. 2014152029) was applied to obtain the title analogue from 3,4-dimethoxyaniline.

[0122] Example 3 4-((7,8-dimethoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (2) [ka] A similar synthetic method (W, Huang et al, Eur. J. Org. Chem. 2018, 1572-1580) was applied to give the title analogue 2 from the known starting material (4-chloro-6,7-dimethoxyquinolin-3-amine, prepared according to literature method, Fuchss, Thomas et al, PCT International Application No. 2012028233). LCMS (ESI) [M+H] + =428; 1 H NMR(400MHz, DMSO)δ LCMS[M+H] + =429; 1 H NMR (600MHz, DMSO-d6) δ ppm 3.62(d, J=4.03Hz, 6H), 3.86-3.93(m, 3H), 5.76(s, 2H), 7.04(s, 1H), 7.33(s , 2H), 7.41(s, 1H), 7.50(d, J=8.44Hz, 2H), 7.78-7.81(m, 2H), 8.95(brs, 1H).

[0123] Example 4 (R)-4-(1-(7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)benzenesulfonamide (3a) and (S)-4-(1-(7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)benzenesulfonamide (3b) General method 2 is followed to prepare (R)-4-(1-(7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)benzenesulfonamide (3a) and (S)-4-(1-(7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)benzenesulfonamide (3b) from the known compounds (R)-4-(1-aminoethyl)benzenesulfonamide and (S)-4-(1-aminoethyl)benzenesulfonamide (Canales et al, PCT International Application No. 2010002998).

[0124] Example 5 4-((7,8-dimethoxy-2-oxooxazolo[5,4-c]quinolin-1(2H)-yl)methyl)benzenesulfonamide (4) Following general procedure 6, 4-((7,8-dimethoxy-2-oxooxazolo[5,4-c]quinolin-1(2H)-yl)methyl)benzenesulfonamide is prepared.

[0125] Example 6 6-((7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-3-sulfonamide (5) General method 2 is followed to prepare 6-((7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-3-sulfonamide from the known compound, 6-(aminomethyl)pyridine-3-sulfonamide (J. Bakonyi, et al, US Patent Publication No. 20150291607).

[0126] Example 7 5-((7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-2-sulfonamide (6) General method 2 is followed to prepare 5-((7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-2-sulfonamide from the known compound, 5-(aminomethyl)pyridine-2-sulfonamide (A. Macleod, et al, PCT International Application No. 2009024585).

[0127] Example 8 3-((7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (7) Following general procedure 2, 3-((7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-benzenesulfonamide is prepared from 3-(aminomethyl)benzenesulfonamide.

[0128] Example 9 (R)-4-(1-(7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)benzene-sulfonamide (8) Prepare (R)-4-(1-(7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)benzene-sulfonamide in a similar manner to compound 1. LCMS (ESI) [M+H] + =399; 1 H NMR (600MHz, DMSO-d6) δ ppm 1.98(brd, J=6.97Hz, 4H), 3.85(s, 3H), 6.28(q, J=7.21Hz, 1H), 7.01(brs, 1H), 7.33- 7.39(m, 3H), 7.54(d, J=8.07Hz, 2H), 7.78-7.83(m, 2H), 8.66(s, 1H), 11.62(brs, 1H).

[0129] Example 10 4-((7,8-dimethoxy-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (9) Following general procedure 3, 4-((7,8-dimethoxy-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide is prepared using triethyl orthoacetate.

[0130] Example 11 5-((7,8-dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-2-sulfonamide (10) 5-((7,8-dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-2-sulfonamide was prepared according to general method 3. LCMS (ESI) [M+H]+ =400; 1 H NMR (600MHz, DMSO-d6) δ ppm 3.70-3.76(m, 4H), 3.94(s, 3H), 6.31(s, 2H), 7.25(s, 1H), 7.47(s, 2H), 7.61(s, 1H), 7.72(dd, J =8.44, 2.20Hz, 1H), 7.87(d, J=8.07Hz, 1H), 8.71(d, J=1.83Hz, 1H), 8.84(s, 1H), 9.53(brs, 1H).

[0131] Example 12 (R)-4-(1-(7,8-dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)benzenesulfonamide (11a) and (S)-4-(1-(7,8-dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)benzenesulfonamide (11b) Following general method 3, (R)-4-(1-(7,8-dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)benzenesulfonamide (11a) and (S)-4-(1-(7,8-dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)benzenesulfonamide (11b) were prepared. 11a: LCMS (ESI) [M+H] + =413; 1 H NMR (600MHz, DMSO-d6) δ ppm 2.15(d, J=6.60Hz, 3H), 3.77-3.84(m, 4H), 3.90-3.97(m, 4H), 6.73-6.81(m, 1H), 7.34(s, 2H), 7 .40(brd, J=8.44Hz, 3H), 7.64(brs, 1H), 7.79(d, J=8.80Hz, 2H), 9.16(brs, 1H), 9.67(brs, 1H). 11b:LCMS(ESI)[M+H] + =413.

[0132] Example 13 6-((7,8-dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-3-sulfonamide (12) Following general method 3, 6-((7,8-dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-3-sulfonamide (12) was prepared. LCMS [M+H] + =400; 1 H NMR (600MHz, DMSO-d6) δ ppm 1.16(s, 1H), 2.09(s, 1H), 3.77(s, 3H), 3.94(s, 3H), 6.33(s, 2H), 7.39(s, 1H), 7. 58(s, 3H), 8.21(dd, J=8.44, 2.20Hz, 1H), 8.80(brs, 1H), 8.84(d, J=1.83Hz, 1H).

[0133] Example 14 4-((7,8-dimethoxy-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (13) Compound 13 was prepared according to general method 4. LCMS [M+H] + =400; 1 H NMR (600MHz, DMSO-d6) δ ppm 3.78(s, 3H), 3.93(s, 3H), 6.56(s, 2H), 7.33(d, J=12.10Hz, 3H), 7.37(d, J=8 .80Hz, 2H), 7.64(s, 1H), 7.80(d, J=8.44Hz, 2H), 9.43(s, 1H), 11.69(s, 1H). Example 15 Compounds 14a, 14b, 15 and 16 are prepared according to general method 4. Example 16 Compounds 17, 18, 19a, 19b, 20 and 21 are prepared according to general method 5.

[0134] Example 17 4-((7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-2-fluorobenzenesulfonamide (22) According to general method 2, 4-((7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-2-fluorobenzenesulfonamide (22) is prepared from 4-(aminomethyl)-2-fluorobenzenesulfonamide (prepared according to S. Yamamoto et al., PCT International Application No. 2018030550).

[0135] Example 18 Preparation of 3-(aminomethyl)azetidine-1-sulfonamide, 3-(aminomethyl)pyrrolidine-1-sulfonamide and 4-(aminomethyl)piperidine-1-sulfonamide [ka] Step 1. Boc diamine (0.8 mmol, 1 equiv.) was dissolved in DCM (4.4 mL, 0.2 M) and (tert-butoxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (262 mg, 1 equiv.) was added. The mixture was stirred at room temperature for 18 h. After completion, the mixture was concentrated in vacuo. The crude was purified by FCC using hexane / THF (100% / 0% to 60% / 40%) to give the product.

[0136] Step 2. The above product (1 eq.) was dissolved in DCM (5 mL, 0.1 M) and then cooled to 0° C. TFA (5 mL, 0.1 M) was added to the mixture, then the cooling bath was removed and the mixture was stirred at room temperature for 2 h. After completion, the mixture was concentrated in vacuo, neutralized with NaHCO3, and extracted with DCM. The crude was used in the next step without further purification.

[0137] Example 19 4-((7,8-dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)piperidine-1-sulfonamide (32) 4-((7,8-dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)piperidine-1-sulfonamide was prepared from the intermediate 4-(aminomethyl)piperidine-1-sulfonamide according to general method 3. LCMS (ESI) [M+H] + =406; 1 H NMR (600MHz, DMSO-d6) δ ppm 1.22-1.28(m, 2H), 1.41-1.50(m, 2H), 1.65(brd, J=11.37Hz, 2H), 2.01-2.10(m, 1H), 2.41-2.48(m, 2H), 3.40-3.52(m, 6H) ), 3.99(s, 3H), 4.01-4.07(m, 3H), 4.72(brd, J=6.97Hz, 2H), 6.63-6.69(m, 2H), 7.60(s, 1H), 7.66(s, 1H), 8.53(brs, 1H). Example 20 Compounds 23-31 are prepared from the above intermediates according to general methods 2-6.

[0138] Example 21 4-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,6]naphthyridin-1-yl)methyl)benzenesulfonamide (33). [ka] In a manner similar to the preparation of compound 1, 4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,6]naphthyridin-1-yl)methyl)benzenesulfonamide is prepared from ethyl 4-chloro-7-methoxy-1,6-naphthyridine-3-carboxylate.

[0139] Example 22 4-((8-cyano-7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (34) In a manner similar to the preparation of compound 1, 4-((8-cyano-7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide is prepared from ethyl 4-chloro-6-cyano-7-methoxyquinoline-3-carboxylate.

[0140] Example 23 4-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-benzenesulfonamide (35) 4-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-benzenesulfonamide was prepared according to general method 2. LCMS (ESI) [M+H] + =385; 1 H NMR (600MHz, DMSO-d6) δ ppm 3.85(s, 3H), 5.59(s, 2H), 7.10(dd, J=9.35, 2.75Hz, 1H), 7.31(s, 2H), 7.37(d, J=2.57Hz, 1H), 7. 42(d, J=8.80Hz, 2H), 7.77(d, J=7.91Hz, 2H), 7.82(d, J=9.54Hz, 1H), 8.66(s, 1H), 11.63(s, 1H).

[0141] Example 24 4-((8-Methoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (36) 4-((8-Methoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide was prepared according to general method 3. LCMS (ESI) [M+H] + =369; 1 H NMR (600MHz, DMSO-d6) δ ppm 3.71(s, 4H), 6.20(s, 2H), 7.28(d, J=2.57Hz, 1H), 7.32-7.38(m, 5H), 7.7 9(d, J=7.76Hz, 2H), 8.08(d, J=9.17Hz, 1H), 8.75(s, 1H), 9.33(brs, 1H).

[0142] Example 25 3-((7,8-dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (37) 3-((7,8-dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide was prepared according to general method 3. LCMS (ESI) [M+H] + =399; 1 H NMR (600MHz, DMSO-d6) δ ppm 0.83-0.90(m, 3H), 0.99-1.09(m, 2H), 1.15(d, J=5.87Hz, 3H), 1.18-1.23(m, 5H), 1.23- 1.36(m, 4H), 1.39-1.50(m, 2H), 1.79(dd, J=13.94, 2.93Hz, 1H), 3.38-3.44(m, 19H), 3. 44-3.56(m, 7H), 3.69-3.74(m, 3H), 3.89-3.94(m, 3H), 6.20(s, 2H), 7.28(s, 1H), 7.35( d, J=8.07Hz, 1H), 7.38(s, 2H), 7.54-7.59(m, 2H), 7.74(s, 1H), 7.77(d, J=7.70Hz, 1H).

[0143] Example 26 4-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (38) [ka] Step 1. 6-Methoxypyridin-2-amine (9.8 g, 78.9 mmol, 1.1 equiv) was dissolved in ethyloxymethylene diethylmalonate (15.5 g, 71.8 mmol, 1 equiv). The mixture was heated at 95° C. under reduced pressure for 1 h. Upon completion, the mixture was cooled to 45° C. and hexane was added. The mixture was further cooled and precipitated with dry ice. The resulting precipitate was filtered and dried (14.8 g, 70%). The crude product was used without further purification.

[0144] Step 2. Diethyl 2-(((6-methoxypyridin-2-yl)amino)methylene)malonate (14.8 g, 50.3 mmol) was added to a diphenyl ether solution (125 mL, 0.4 M) at 260° C. After addition, the mixture was heated at reflux temperature for an additional 45 minutes. After completion, the mixture was cooled to 85° C. and hexane was added. Cooled to room temperature, the solid was filtered and purified by FCC to give the product.

[0145] Step 3. Ethyl 4-hydroxy-7-methoxy-1,8-naphthyridine-3-carboxylate (130 mg, 0.52 mmol, 1 equiv) was dissolved in DCM (2.6 mL, 0.2 M) and oxylyl chloride (53 μL, 0.63 mmol, 1.2 equiv) and DMF (1 drop) were added. The mixture was heated at reflux for 5 min. After completion, the mixture was cooled to room temperature and concentrated in vacuo. The crude was used without further purification.

[0146] Step 4. Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (0.26 mmol, 1 eq) and 4-(aminomethyl)benzenesulfonamide HCl (75 mg, 0.34 mmol, 1.3 eq) were dissolved in DMF (2.6 mL, 0.1 M) and DIEA (226 μL, 1.3 mmol, 5 eq) was added. The mixture was heated at 60° C. After completion, the mixture was cooled to room temperature and then water was added. The resulting precipitate was filtered and dried (21 mg, 19%).

[0147] Step 5. Ethyl 7-methoxy-4-((4-sulfamoylbenzyl)amino)-1,8-naphthyridine-3-carboxylate (21 mg, 0.05 mmol, 1 eq) was dissolved in THF / MeOH (1 mL / 0.3 ml) and then cooled to 0° C. Aqueous LiOH (1 M, 0.5 mmol, 10 eq) was added to the mixture. The resulting mixture was heated to 50° C. Upon completion, the mixture was cooled to room temperature and diluted with water. The aqueous layer was washed with EtOAc and then the aqueous layer was acidified to pH 4 with 2N HCl. The resulting precipitate was filtered and dried (14 mg, 74%).

[0148] Step 6. 7-Methoxy-4-((4-sulfamoylbenzyl)amino)-1,8-naphthyridine-3-carboxylic acid (14 mg, 0.04 mmol, 1 eq) was dissolved in DMF (2 ml) and DPPA (9.3 μL, 0.043 mmol, 1.2 eq) was added. The resulting mixture was heated at 110° C. After completion, the mixture was cooled to room temperature and concentrated in vacuo. The crude was purified by FCC to give the product (8.8 mg, 44%). LCMS [M+H] + =386; 1 H NMR (600MHz, DMSO-d6) δ ppm 4.00(s, 3H), 5.63(s, 2H), 7.00-7.06(m, 1H), 7.06-7.11(m, 1H), 7.13-7.18(m, 1H), 7.25-7.31(m, 1H) , 7.34(s, 2H), 7.43(d, J=8.44Hz, 2H), 7.77(d, J=8.44Hz, 2H), 8.29(brd, J=9.35Hz, 1H), 8.74(s, 1H).

[0149] Example 27 5-Chloro-2-methoxy-6-nitro-1,8-naphthyridine (Intermediate B): [ka] Step 1. A mixture of Meldrum's acid (13.36 g, 92.6 mmol) and triethyl orthoformate (35.8 g, 3.0 equiv.) was heated at 92° C. for 90 min, followed by the addition of 6-methoxypyridin-2-amine (10 g, 80.6 mmol) in portions over 5 min at 70° C. The reaction mixture was then stirred for 20 min, cooled, and filtered to give 5-(((6-methoxypyridin-2-yl)imino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione as a grey solid (19.27 g, 75%).

[0150] Step 2. The above solid (19.2 g, 69 mmol) was added in portions to diphenyl ether (30 ml) heated at 260° C., then the resulting mixture was stirred at 260° C. for 40 minutes and then cooled to room temperature. Hexane (100 ml) was added and the solid was filtered, washed with hexane and dried (11.25 g, 93%).

[0151] Step 3. A solution of the above solid (1.0 g, 5.7 mmol) in CH3CH2CO2H (35 ml) was treated dropwise with fuming HNO3 (0.59 ml) and then stirred for 2 h. The resulting solid was filtered, washed and dried (725 mg, 58%).

[0152] Step 4. A solution of the above solid (725 mg, 3.3 mmol) in DCM (20 ml) was treated with SOCl2 (0.60 ml) and 2 drops of DMF. After 6 h, the reaction mixture was concentrated and purified by combiflash (DCM / EtOAc) to give a white solid (578 mg, 74%).

[0153] Example 28 4-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (39) [ka] Step 1. A mixture of intermediate B (90 mg, 0.38 mmol), 4-(aminomethyl)benzenesulfonamide HCl salt (100 mg, 1.2 equiv), Hunig's base (0.33 mL, 5.0 equiv) and MeCN (4 ml) was heated at 80° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated and treated with water (5 ml). The resulting solid was filtered, washed with water and dried (107 mg, 73%). LCMS [M+H] + =390.

[0154] Step 2. A solution of the above solid (107 mg, 0.28 mmol) in MeOH (5 ml) and EtOAc (5 ml) was heated at 65° C., then Pd / C (10%, 10 mg) was added. The reaction mixture was stirred overnight under a H2 balloon. After cooling to room temperature, the reaction mixture was filtered, concentrated and purified by combiflash (DCM / MeOH) to give a yellow solid (49 mg, 49%). LCMS [M+H] + =360.

[0155] Step 3. The above solid (49 mg, 0.17 mmol) was added to a mixture of DMF (1.1 ml) and triethyl orthoformate (2.2 ml), then stirred at 120° C. for 8 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by combiflash (DCM / MeOH) to give a yellow solid (41 mg, 65%). LCMS [M+H] + =370; 1 H NMR (500MHz, DMSO-d6) δ ppm 3.98(s, 3H), 6.08(s, 2H), 7.18(d, J=9.00Hz, 1H), 7.24(d, J=8.39Hz, 2H), 7.28( s, 2H), 7.69(d, J=8.39Hz, 2H), 8.44(d, J=9.16Hz, 1H), 8.76(s, 1H), 9.51(s, 1H).

[0156] Example 29 6-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (40) 6-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide was prepared from intermediate B and 6-(aminomethyl)pyridine-3-sulfonamide HCl salt in a similar manner to compound 39. LCMS [M+H] + =371; 1H NMR (500MHz, DMSO-d6) δ ppm 4.02-4.09(m, 3H), 6.27(s, 2H), 7.26(m, J=9.16Hz, 1H), 7.59(s, 2H), 7.64(d, J=8.24Hz, 1H), 8.20( dd, J=8.32, 2.36Hz, 1H), 8.58(m, J=9.00Hz, 1H), 8.75(d, J=2.14Hz, 1H), 8.81(s, 1H), 9.57(s, 1H).

[0157] Example 30 5-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-2-sulfonamide (41) 5-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-2-sulfonamide was prepared from intermediate B and 5-(aminomethyl)pyridine-2-sulfonamide HCl salt in a similar manner to compound 39. LCMS [M+H] + =371; 1 H NMR (500MHz, DMSO-d6) δ ppm 3.99(s, 4H), 6.15(s, 2H), 7.21(d, J=9.16Hz, 1H), 7.40(s, 2H), 7.60(dd, J=8.16, 2.21Hz, 1H), 7 .76(d, J=8.09Hz, 1H), 8.54(d, J=9.16Hz, 1H), 8.61(d, J=1.83Hz, 1H), 8.77(s, 1H), 9.52(s, 1H).

[0158] Example 31 4-((8,9-dimethoxypyrazolo[1,5-c]quinazolin-1-yl)methyl)benzenesulfonamide (42) [ka] Ethyl 8,9-dimethoxypyrazolo[1,5-c]quinazolin-1-carboxylate (prepared according to known methods by Feng, H., RSC Adv., 2016, 6, 95774) is converted to the corresponding alcohol by a reducing agent such as LiBH4. The bromo analog is prepared by treating the alcohol with PBr3. Palladium-catalyzed coupling with (4-sulfamoylphenyl)boronic acid gives 4-((8,9-dimethoxypyrazolo[1,5-c]quinazolin-1-yl)methyl)benzenesulfonamide (42).

[0159] Example 32 (R)-6-(1-(7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)ethyl)pyridine-3-sulfonamide (43) (R)-6-(1-(7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)ethyl)pyridine-3-sulfonamide was prepared from intermediate B and (R)-6-(1-(-aminoethyl)pyridine-3-sulfonamide HCl salt in a similar manner to compound 39. LCMS [M+H] + =385; 1 H NMR (600MHz, DMSO-d6)δ ppm:2.08(d, J=6.97Hz, 3H), 3.99(s, 4H), 6.67(q, J=6.91Hz, 1H), 7.24(d, J=9.17Hz, 1H), 7.51(s, 2H), 7.68(d, J=8.2 5Hz, 1H), 8.13(dd, J=8.25, 2.38Hz, 1H), 8.68(brd, J=8.80Hz, 1H), 8.74(d, J=2.38Hz, 1H), 9.02(s, 1H), 9.55(s, 1H).

[0160] Example 33 4-((7,8-dimethoxy-2λ 2 ,10λ 4 -[1,2,4]Triazolo[4,3-a]quinoxalin-1-yl)methyl)benzenesulfonamide (44) [ka] Step 1. 2-Chloro-6,7-dimethoxyquinoxaline (0.28 g, 1.24 mmol, 1 equiv) was dissolved in reagent alcohol (6.2 mL, 0.2 M) and hydrazine monohydrate (6.2 mL, 0.2 M) was added. The mixture was heated at 80° C. for 2 h. Upon completion, the mixture was cooled to room temperature and then water was added. The resulting precipitate was filtered and dried (206 mg, 75%).

[0161] Step 2. 2-Hydrazinyl-6,7-dimethoxyquinoxaline (50 mg, 0.22 mmol, 1 eq.) and 2-(4-bromophenyl)acetaldehyde (53 mg, 0.264 mmol, 1.2 eq.) were dissolved in reagent alcohol (2.2 mL, 0.1 M). The mixture was heated at reflux for 1 h. After completion, the mixture was cooled to room temperature and then water was added. The resulting precipitate was filtered and dried (88 mg, 99%).

[0162] Step 3. 2-(2-(2-(4-bromophenyl)ethylidene)hydrazinyl)-6,7-dimethoxyquinoxaline (88 mg, 0.22 mmol, 1 equiv) was dissolved in DCM (4.4 mL, 0.05 M) and iodobenzene diacetate (78 mg, 0.24 mmol, 1.1 equiv) was added. The mixture was stirred at room temperature for 3 h. Upon completion, the mixture was concentrated in vacuo. The resulting oil was triturated with hexanes and then used without further purification.

[0163] Step 4. 1-(4-Bromobenzyl)-7,8-dimethoxy-2λ 2 ,10λ 4-[1,2,4]Triazolo[4,3-a]quinoxaline (0.22 mmol, 1 equiv), Pd(dba)2 (13 mg, 0.022 mmol, 0.1 equiv) and Xantphos (13 mg, 0.022 mmol, 0.1 equiv) were dissolved in dioxane and DIEA (153 μL, 0.44 mmol, 2 equiv) was added. The mixture was purged with nitrogen for 1 min and benzyl mercaptan (28 μL, 0.24 mmol, 1.1 equiv) was added. The mixture was heated at 100° C. for 4 h. After completion, the mixture was cooled to room temperature and water was added. The aqueous layer was extracted with EtOAc (3×2 ml). The combined organic layers were dried and concentrated in vacuum. The crude was purified by FCC to give the product (97 mg, 99%).

[0164] Step 5. 1-(4-(benzylthio)benzyl)-7,8-dimethoxy-2λ 2 ,10λ 4 -[1,2,4]Triazolo[4,3-a]quinoxaline (97 mg, 0.22 mmol, 1 equiv) was dissolved in MeCN (2.27 mL, 0.1 M) and AcOH (86 μL, 2.57 M) and water (56 μL, 3.9 M) were added. The mixture was cooled to 0 °C and 1,3-dichloro-5,5-dimethylhydantoin (52 mg, 0.264 mmol, 1.2 equiv) was added. The mixture was stirred at 0 °C. After completion, the mixture was diluted with EtOAc and basified with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2 x 2 ml). The combined organic layers were cooled to 0 °C and NH4OH (2 ml) was added. The mixture was stirred at 0 °C for 1 h. After completion, the mixture was acidified to pH 2 using 2N HCl. The separated layers and the aqueous layer were extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo. The crude was triturated with Et2O to give product 44 (18 mg, 20%). LCMS [M+H] + =400; 1 H NMR (600MHz, DMSO-d6) δ ppm 3.70(s, 3H), 3.90(s, 3H), 5.17(s, 2H), 7.32(d, J=7.15Hz, 3H), 7.39(d, J=8.44Hz, 2H), 7.59(s, 1H), 7.76-7.79(m, 2H), 9.25(s, 1H).

[0165] Example 34 4-((7-Methoxy-2λ 2 ,10λ 4 -Imidazo[3,4-a]quinoxalin-1-yl)methyl)benzenesulfonamide (45) [ka] 2-(4-Bromophenyl)acetonitrile is converted to 2-(4-bromobenzyl)-1H-imidazole by treatment with ethylenediamine. This material is reacted with 1-fluoro-4-methoxy-2-nitrobenzene, and the resulting product is then cyclized to give 1-(4-bromobenzyl)-7-methoxy-2λ 2 ,10λ 4 -imidazo[3,4-a]quinoxaline. A similar transformation as in 44 is used to convert the bromo to the sulfonamide.

[0166] Example 35 4-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl sulfamide (46) [ka] 4-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)aniline was prepared from intermediate B and 4-(aminomethyl)aniline HCl salt in a similar manner to compound 39. 4-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)aniline (41 mg, 0.13 mmol) was dissolved in MeCN (2 ml) and then treated with 4-nitrophenyl sulfamate (44 mg, 1.5 equiv.) followed by Hunig's base (0.046 mL, 2.0 equiv.). After stirring overnight at room temperature, the reaction mixture was worked up and purified by reverse phase HPLC (MeCN / H2O / 0.1% TFA) to give a white solid (1.5 mg). LCMS [M+H] + =385.

[0167] Example 36 4-((7-Methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (47) [ka] A solution of 4-(((3-amino-7-methoxy-1,8-naphthyridin-4-yl)amino)methyl)benzenesulfonamide (18 mg, 0.05 mmol) in toluene (1 ml) and pyridine (1 ml) was treated with trifluoroacetic anhydride (0.0081 mL, 1.15 equiv) and then heated at 140° C. overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (MeCN / H2O / 0.1% TFA) to give a white solid (5.5 mg). LCMS [M+H] + =438; 1 H NMR (500MHz, DMSO-d6) δ ppm 3.99-4.05(m, 3H), 4.46(d, J=5.80Hz, 1H), 6.18(s, 2H), 7.13(d, J=9.00Hz, 1H), 7.27(d, J=8 .39Hz, 2H), 7.32-7.36(m, 3H), 7.76(d, J=8.39Hz, 2H), 8.36(d, J=9.16Hz, 1H), 9.50(s, 1H).

[0168] Example 37 4-((7-Methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (48) [ka] 4-((7-Methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide was prepared from 4-(((3-amino-7-methoxy-1,8-naphthyridin-4-yl)amino)methyl)benzenesulfonamide and ethyl orthoacetate in a similar manner to compound 39. LCMS [M+H] + =384; 1H NMR (500MHz, DMSO-d6) δ ppm 2.66-2.72(m, 3H), 4.06(s, 3H), 6.10(s, 2H), 7.26(brd, J=8.24Hz, 3H), 7.36 (s, 2H), 7.77 (brd, J=7.42Hz, 2H), 8.55 (brd, J=8.70Hz, 1H), 9.50 (brs, 1H).

[0169] Example 38 4-((7-Methoxy-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl)benzenesulfonamide (49) [ka] 4-Chloro-7-methoxy-3-nitro-1,5-naphthyridine was prepared from 5-methoxypyridin-3-amine in a similar manner to intermediate B; then 4-((7-methoxy-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl)benzenesulfonamide (49) was prepared from 4-chloro-7-methoxy-3-nitro-1,5-naphthyridine and 4-(aminomethyl)benzenesulfonamide in a similar manner to compound 39. LCMS [M+H] + =371; 1 H NMR (600MHz, DMSO-d6) δ ppm 3.97-4.00(m, 3H), 6.19(s, 2H), 7.28(s, 2H), 7.49(m, J=8.25Hz, 2H), 7.74(m, J=8.2 5Hz, 2H), 7.97(d, J=2.75Hz, 1H), 8.65(s, 1H), 8.75(d, J=2.75Hz, 1H), 9.29(s, 1H).

[0170] Example 39 4-((7-Methoxy-1H-imidazo[4,5-c][1,6]naphthyridin-1-yl)methyl)benzenesulfonamide (50) [ka] 4-((7-Methoxy-1H-imidazo[4,5-c][1,6]naphthyridin-1-yl)methyl)benzenesulfonamide was prepared from the known compound 8-bromo-7-methoxy-1,6-naphthyridin-4-ol (Morgentin, Remy et al, Tetrahedron, 2008, 64, 2772-2782). LCMS [M+H] + =371; 1 H NMR (500MHz, DMSO-d6) δ ppm 3.94(s, 3H), 6.16(s, 2H), 7.30-7.37(m, 5H), 7.79(d, J=8.39Hz, 2H), 8.66(s, 1H), 9.10-9.17(m, 1H), 9.43(s, 1H).

[0171] Example 40 4-(7,8-Dimethoxy-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)benzyl sulfamide (51) [ka] Step 1. 2-Hydrazinyl-6,7-dimethoxyquinoxaline (50 mg, 0.22 mmol, 1 eq.) and tert-butyl (4-formylbenzyl)carbamate (57 mg, 0.24 mmol, 1.1 eq.) were dissolved in reagent alcohol (2.2 mL, 0.1 M). The mixture was heated at reflux for 1 h. After completion, the mixture was cooled to room temperature and then water was added. The resulting precipitate was filtered and dried (96 mg, 99%).

[0172] Step 2. tert-Butyl-(4-((2-(6,7-dimethoxyquinoxalin-2-yl)hydrazinylidene)methyl)-benzyl)-carbamate (96 mg, 0.22 mmol, 1 equiv) was dissolved in DCM (4.4 mL, 0.05 M) and iodobenzene diacetate (78 mg, 0.24 mmol, 1.1 equiv) was added. The mixture was stirred at room temperature for 3 h. Upon completion, the mixture was concentrated in vacuo. The resulting oil was triturated with hexanes and then used without further purification.

[0173] Step 3. tert-Butyl (4-(7,8-dimethoxy-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)benzyl)carbamate (96 mg, 0.22 mmol, 1 equiv) was dissolved in DCM (0.55 mL, 0.4 M) and then cooled to 0° C. TFA (0.55 mL, 0.4 M) was added to the mixture. The mixture was allowed to warm to room temperature and stirred for 1 h. Upon completion, the mixture was concentrated in vacuo. The crude was dissolved in DCM / DMF (1:1, 8 ml) and Et3N (276 μL, 1.98 mmol, 9 equiv) and sulfamoylating reagent (73 mg, 0.242 mmol, 1.1 equiv) were added. The mixture was heated at 60° C. for 1 h. Upon completion, the mixture was concentrated in vacuo. The crude was passed through a silica plug and then used without further purification.

[0174] Step 4. tert-Butyl (N-(4-(7,8-dimethoxy-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)benzyl)sulfamoyl)-carbamate (0.22 mmol, 1 eq) was dissolved in DCM (1 ml) and then cooled to 0° C. TFA (1 ml) was added to the mixture. The mixture was allowed to warm to room temperature and stirred for 0.5 h. Upon completion, the mixture was concentrated in vacuo. The crude was purified by FCC to give the product (11 mg, 10%). LCMS [M+H] + =415; 1 H NMR (600MHz, DMSO-d6) δ ppm 3.38-3.40(m, 3H), 3.91(s, 3H), 4.25(d, J=6.24Hz, 2H), 6.71(s, 2H), 6.86(s, 1H), 7.28(brt, J=6.42Hz, 1H) 7.61(s, 1H), 7.68(m, J=8.07Hz, 2H), 7.77(m, J=8.07Hz, 2H), 9.31(s, 1H).

[0175] Example 41 3-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)azetidine-1-sulfonamide (52) 3-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)azetidine-1-sulfonamide was prepared from intermediate B and 3-(aminomethyl)azetidine-1-sulfonamide in a similar manner to compound 39. LCMS [M+H] + =349; 1 H NMR (600MHz, DMSO-d6) δ ppm 3.08-3.17(m, 2H), 3.59(brdd, J=8.34, 5.59Hz, 8H), 3.78-3.84(m, 3H), 4.12(s, 3H), 4.97(d, J=7. 34Hz, 2H), 6.90(s, 2H), 7.43(d, J=8.99Hz, 1H), 8.83(s, 1H), 8.95(d, J=9.17Hz, 1H), 9.60(s, 1H).

[0176] Example 42 7-(7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (53) 7-(7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide was prepared from intermediate B and 7-amino-3,4-dihydroisoquinoline-2(1H)-sulfonamide in a similar manner to compound 39. LCMS [M+H] + =411; 1 H NMR (600MHz, DMSO-d6) δ ppm 3.10(brs, 2H), 4.06(s, 3H), 4.31(brs, 2H), 7.01(s, 2H), 7.19(d, J=8.99Hz, 1H), 7.51-7.5 6(m, 1H), 7.56-7.59(m, 1H), 7.65(s, 1H), 7.78(d, J=9.17Hz, 1H), 8.72(s, 1H), 9.58(s, 1H).

[0177] Example 43 (R)-4-(1-(7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)ethyl)benzenesulfonamide (54) (R)-4-(1-(7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)ethyl)benzenesulfonamide was prepared from intermediate B and (R)-4-(1-aminoethyl)benzenesulfonamide in a similar manner to compound 39. LCMS [M+H] + =384; 1 H NMR (600MHz, DMSO-d6) δ ppm 2.12(d, J=6.97Hz, 3H), 4.05(s, 3H), 6.64(q, J=6.91Hz, 1H), 7.28(d, J=9.17Hz, 1H), 7.34(s, 2H) ), 7.40(d, J=8.44Hz, 2H), 7.75-7.79(m, 2H), 8.65(d, J=9.17Hz, 1H), 9.07(s, 1H), 9.62(s, 1H).

[0178] Example 44 (4-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl)boronic acid (55) [ka] 1-(4-Bromobenzyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridine was prepared from intermediate B and 4-bromobenzylamine in a similar manner to compound 39. A solution of 1-(4-bromobenzyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridine (10 mg, 0.027 mmol) in a mixture of dioxane / DMF (0.5 / 0.5 ml) was treated with bis(pinacolato)diboron (10 mg, 1.5 equiv.), Pd(dppf)2Cl2 (2.2 mg, 10%) and KOAc (8 mg, 3.0 equiv.), and the reaction mixture was purged with N2 for 2 min and then stirred at 100 °C for 2 h. After cooling to room temperature, the reaction mixture was treated with NaIO4 (17 mg, 3.0 equiv), NHOAc (6 mg, 3.0 equiv) and water (1 ml) for 1 h. After workup, the residue was purified by reverse phase HPLC (MeCN / H2O / 0.1% TFA) to give a white solid as (4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl)boronic acid. LCMS [M+H]+ =335.

[0179] Example 45 4-(8,9-Dimethoxypyrazolo[1,5-c]quinazoline-1-carbonyl)piperazine-1-sulfonamide (58) [ka] Ethyl 8,9-dimethoxypyrazolo[1,5-c]quinazoline-1-carboxylate (prepared according to the known method by Feng, H., RSC Adv., 2016, 6, 95774) is converted to the corresponding acid by saponification with LiOH in THF. Coupling of piperazine-1-sulfonamide with HATU gives 4-(8,9-dimethoxypyrazolo[1,5-c]quinazoline-1-carbonyl)piperazine-1-sulfonamide (58).

[0180] Example 46 4-(7-Methoxy-1H-imidazo[4,5-c][1,6]naphthyridin-1-yl)benzyl sulfamide (59) In a manner similar to the preparation of compound 43, 4-(7-methoxy-1H-imidazo[4,5-c][1,6]naphthyridin-1-yl)benzyl sulfamide (59) was prepared.

[0181] Example 47 Synthesis of intermediates: 4-Bromo-2-(trifluoromethyl)benzenesulfonamide [ka] 4-Bromo-2-(trifluoromethyl)benzenesulfonyl chloride (2.5 g, 7.73 mmol, 1 equiv) was dissolved in THF (40 mL, 0.2 M) and added dropwise to the stirring solution of NH4OH at -20°C, keeping the internal temperature below -10°C during the addition. After addition, the reaction mixture was stirred at -10°C for 10 min. After completion, at 0°C, the mixture was poured into 2M HCl (250 ml) and EtOAc (100 ml). The phases were separated and the aqueous layer was extracted with EtOAc (2 x 100 ml). The combined organic layers were dried over Na2SO4 and concentrated to give the product (2.3 g, 98%).

[0182] The following intermediates were prepared in a similar manner to 4-bromo-2(trifluoromethyl)-benzenesulfonamide: 4-Bromo-2,3-difluorobenzenesulfonamide 4-Bromo-3,5-difluorobenzenesulfonamide 4-Bromo-2-(trifluoromethoxy)benzenesulfonamide 4-Bromo-3-(trifluoromethyl)benzenesulfonamide

[0183] 4-(Aminomethyl)-2,6-difluorobenzenesulfonamide HCl [ka] Step 1. At 0° C., thionyl chloride (7.5 mL, 103.2 mmol, 4.3 equiv) was added dropwise to a flask containing water (45 mL, 2.3 M). The resulting mixture was stirred at 22° C. for 18 hours. At 0° C., concentrated HCl (24 mL, 1 M) was added to 4-bromo-2,6-difluoroaniline (5 g, 24 mmol, 1 equiv) and the resulting mixture was heated at 50° C. for 1 hour and then cooled to −5° C. (internal temperature). To the reaction mixture was added a solution of NaNO2 (1.77 g, 25.7 mmol, 1.07 equiv) in water (7 ml). The internal temperature was kept below 0° C. during the addition. After the addition, the mixture was stirred at −5° C. for an additional 10 minutes. The aqueous thionyl chloride mixture was cooled to −5° C. (internal temperature) and CuCl (24 mg, 0.24 mmol, 0.01 equiv) was added. The newly formed diazonium mixture was slowly added to the aqueous thionyl chloride mixture while maintaining the internal temperature below 0°C. After addition, the mixture was stirred at -5°C for an additional 20 min. The resulting precipitate was filtered and dissolved in THF (100 ml). A solution of the sulfonyl chloride in THF was slowly added to stirring NH4OH (82 ml) at -10°C (internal temperature). The internal temperature was maintained below -5°C during the addition. After addition, the mixture was poured into 2M HCl (600 ml). At pH 2, the aqueous layer was extracted with EtOAc (3 x 100 ml). The combined organic layers were dried over Na2SO4 and concentrated to give the product (5.34 g, 82%).

[0184] Step 2. 4-Bromo-2,6-difluorobenzenesulfonamide (2 g, 7.35 mmol, 1 eq), Zn(CN)2 (518 mg, 4.41 mmol, 0.6 eq), and Pd(PPh3)4 (424 mg, 0.37 mmol, 0.05 eq) were suspended in DMF (37 mL, 0.2 M). The mixture was purged with nitrogen for 1 min and heated at 100 °C for 5 h. After completion, the mixture was cooled to 22 °C and poured into water. The resulting ligand precipitate was filtered. The filtrate was acidified to pH 2 using 2 M HCl and extracted with EtOAc (3 x 100 ml). The combined organic layers were dried over Na2SO4 and concentrated to give the product (1.4 g, 88%).

[0185] Step 3. 4-Cyano-2,6-difluorobenzenesulfonamide (844 mg, 3.87 mmol, 1 equiv) was dissolved in MeOH (39 mL, 0.1 M) and then added to a flask containing 10% Pd / C (844 mg) under nitrogen atmosphere. Concentrated HCl (355 μL, 4.3 mmol, 1.1 equiv) was added and the mixture was purged with hydrogen (3 cycles). The resulting mixture was stirred at 22° C. for 1 h. Upon completion, the mixture was filtered through a pad of Celite. The filtrate was concentrated. The residue was triturated several times with EtOAc to give the product (903 mg, 90%). LCMS [M+H] + =223.

[0186] The following intermediates were prepared in a similar manner to 4-(aminomethyl)-2,6-difluorobenzenesulfonamide HCl: 4-(Aminomethyl)-2,5-difluorobenzenesulfonamide HCl 4-(Aminomethyl)-2,3-difluorobenzenesulfonamide HCl 4-(Aminomethyl)-3,5-difluorobenzenesulfonamide HCl 4-(Aminomethyl)-2-(trifluoromethyl)benzenesulfonamide HCl 4-(Aminomethyl)-2-(trifluoromethoxy)benzenesulfonamide HCl 4-(Aminomethyl)-3-(trifluoromethyl)benzenesulfonamide HCl

[0187] (4-Bromo-2,6-difluorophenyl)methanamine [ka] step 1. To a mixture of 4-bromo-2,6-difluoro-benzaldehyde (2.5 g, 11.31 mmol, 1 equiv) in ethanol (40 ml) was added hydroxylamine hydrochloride (1.10 g, 15.84 mmol, 1.40 equiv) and potassium acetate (1.30 g, 13.24 mmol, 1.17 equiv) in one portion over 1 h at 22° C. After completion, water (40 ml) was added to the mixture at 0° C. and washed with 1:1 EtOH / water to give the product (2.5 g, 94%).

[0188] Step 2. (E)-4-Bromo-2,6-difluoro-benzaldehyde oxime (2.5 g, 10.59 mmol, 1 eq) was dissolved in AcOH (60 ml). At 65° C., Zn (5.54 g, 84.74 mmol, 8 eq) was added in one portion. The mixture was stirred at 65° C. for 2 h. After completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in water (50 ml) and washed with diethyl ether (3×50 ml). The combined organic layers were back-extracted with water (2×50 mL, containing 2 drops of AcOH) and the two aqueous layers were combined and neutralized with NaHCO3. The basic aqueous layer was extracted with EtOAc (3×50 ml). The EtOAc layers were combined and dried over Na2SO4. After concentration, the product was obtained without further purification (1.46 g, 62%). LCMS [M+H] + =222.

[0189] The product was prepared following the procedure for step 3. (4-bromo-2,6-difluorophenyl)-methanamine. LCMS [M+H] + =240.

[0190] (R)-6-(1-aminoethyl)pyridine-3-sulfonamide HCl [ka] Step 1. 6-Cyanopyridine-3-sulfonamide (1.4 g, 7.65 mmol, 1 eq) was dissolved in THF (60 ml) and then cooled to 0° C. MeMgCl (3.0 M, 7.6 mL, 22.95 mmol, 3 eq) was added to the reaction mixture. After addition, the mixture was stirred at 22° C. for 2 h. After completion, the mixture was quenched with saturated NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc (2×50 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by FCC to give the product (1.14 g, 76%)

[0191] Step 2. 6-Acetylpyridine-3-sulfonamide (1.14 g, 5.69 mmol, 1 eq) was dissolved in THF (14 mL, 0.4 M) and (R)-2-methylpropane-2-sulfinamide (828 mg, 6.83 mmol, 1.2 eq) was added. To the mixture was added Ti(OEt)4 (1.72 mL, 11.38 mmol, 2 eq) and the mixture was heated at reflux for 18 h. After completion, the mixture was cooled to 0° C. and quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by FCC using a DCM / THF gradient to give the product (0.97 g, 56%).

[0192] Step 3. (E)-6-(1-((tert-Butylsulfinyl)imino)ethyl)pyridine-3-sulfonamide (0.97 g, 3.2 mmol, 1 equiv) was dissolved in THF (11 mL, 0.3 M) and then cooled to 0° C. To the mixture was added 9-BBN (0.5 M, 8.3 mL, 4.2 mmol, 1.3 equiv). The mixture was stirred at 0° C. for 2 h. After completion, the mixture was quenched with MeOH (11 ml) and HCl-EtOH solution (1.25 M, 11 ml) was added. The mixture was stirred at 0° C. for an additional 30 min and then concentrated. The resulting residue was triturated several times with EtOAc to give the product (613 mg, 81%). LCMS [M+H] + =202.

[0193] Compounds 60-69 and 129 were prepared from the amine intermediate in a manner similar to the preparation of compound 39.

[0194] Example 48 16 mg of (R)-6-(1-(7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)ethyl)pyridine-3-sulfonamide (60) was prepared. LCMS [M+H] + =385; 1 H NMR (600MHz, DMSO-d6) δ ppm 2.08(d, J=6.97Hz, 3H), 3.99(s, 4H), 6.67(q, J=6.91Hz, 1H), 7.24(d, J=9.17Hz, 1H), 7.51(s, 2H), 7.68(d, J=8.25H) z, 1H), 8.13(dd, J=8.25, 2.38Hz, 1H), 8.68(brd, J=8.80Hz, 1H), 8.74(d, J=2.38Hz, 1H), 9.02(s, 1H), 9.55(s, 1H).

[0195] Example 49 15 mg of 2-fluoro-4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (61) was prepared. LCMS [M+H] + =388.

[0196] Example 50 24.2 mg of 3-fluoro-4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (62) was prepared. LCMS [M+H] + =388.

[0197] Example 51 0.5 mg of 2-cyano-6-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (63) was prepared. LCMS [M+H] + =396; 1H NMR (600MHz, DMSO-d6) δ ppm 1.08(s, 6H), 2.02(s, 1H), 3.98(s, 3H), 6.22(s, 2H), 7.16(brd, J=9.17Hz, 1H), 7.60-7.75(m, 1H), 8 .44(d, J=8.07Hz, 1H), 8.54(brd, J=8.99Hz, 2H), 8.73(brs, 1H), 9.04(brs, 1H), 9.39-9.51(m, 1H).

[0198] Example 52 4.1 mg of 2-methoxy-4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (64) was prepared. LCMS [M+H] + =400; 1 H NMR (600MHz, DMSO-d6) δ ppm 3.93(s, 3H), 5.68(s, 1H), 6.19(s, 2H), 7.17(dd, J=3.30, 1.65Hz, 1H), 7.28(s, 2H), 7.45(d, J=8.99Hz, 1H), 7.52(d, J =8.62Hz, 2H), 7.68-7.74(m, 2H), 7.97(dd, J=3.30, 2.20Hz, 1H), 8.94(d, J=8.99Hz, 1H), 9.93(s, 1H), 13.70(brs, 1H).

[0199] Example 53 7.6 mg of 4-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-(trifluoromethyl)benzenesulfonamide (65) was prepared. LCMS [M+H] + =438; 1 H NMR (600MHz, DMSO-d6) δ ppm 4.06(s, 3H), 6.23(s, 2H), 7.25(d, J=9.17Hz, 1H), 7.39(d, J=8.44Hz, 1H), 7.70(s, 2H), 7.94(s, 1H), 8.03(d, J=8.25Hz, 1H), 8.56(d, J=9.17Hz, 1H), 8.81(s, 1H), 9.58(s, 1H).

[0200] Example 54 3.7 mg of 4-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-(trifluoromethoxy)-benzene-sulfonamide (66) was prepared. LCMS [M+H] + =454.

[0201] Example 55 3.1 mg of 4-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-3-(trifluoromethyl)-benzenesulfonamide (67) was prepared. LCMS [M+H] + =438.

[0202] Example 56 214 mg of 3-bromo-4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (68) was prepared. LCMS [M+H] + =449; 1 H NMR (300MHz, DMSO-d6) δ ppm 4.03(s, 3H), 6.08(s, 2H), 6.61-6.68(m, 1H), 7.15-7.24(m, 1H), 7.48(s, 2H), 7.56 -7.60(m, 1H), 8.15(s, 1H), 8.18(d, J=8.79Hz, 1H), 8.64(s, 1H), 9.47-9.54(m, 1H).

[0203] Example 57 6.7 mg of 3-cyano-4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (69) was prepared. LCMS [M+H] + =395; 1H NMR (300MHz, DMSO-d6) δ ppm 4.05(s, 3H), 6.36(s, 2H), 6.90(d, J=8.21Hz, 1H), 7.20(d, J=9.38Hz, 1H), 7.58(s, 2H), 7.85(dd , J=8.21, 2.34Hz, 1H), 8.32(d, J=1.76Hz, 1H), 8.44(d, J=8.79Hz, 1H), 8.71(s, 1H), 9.58(s, 1H).

[0204] Example 58 29.4 mg of 3,5-difluoro-4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (129). LCMS [M+H] + =406; 1 H NMR (400MHz, DMSO-d6) δ ppm 4.04(s, 3H), 6.16(s, 2H), 7.34(d, J=9.00Hz, 1H), 7.52(s, 1H), 7.54(s, 1H), 7.65(s, 2H), 8.64(s, 1H), 8.83(d, J=9.00Hz, 1H), 9.47(s, 1H). Compounds 70-73 and 130 were prepared from the amine intermediate in a similar manner to compound 39, using ethyl orthoacetate instead of triethyl orthoformate in the final step.

[0205] Example 59 3.7 mg of 2,5-difluoro-4-((7-methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (70) was prepared. LCMS [M+H] + =420.

[0206] Example 60 2.3 mg of 2-fluoro-4-((7-methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (71) was prepared. LCMS [M+H] + =402; 1H NMR (300MHz, DMSO-d6) δ ppm 2.69(s, 3H), 4.06(s, 3H), 6.09(s, 2H), 6.98(d, J=7.62Hz, 1H), 7.17-7.34(m, 2H), 7.64-7.76(m, 3H), 8.54(d, J=9.38Hz, 1H), 9.54(s, 1H).

[0207] Example 61 3.4 mg of 6-((7-Methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (72) was prepared. LCMS [M+H] + =385; 1 H NMR (300MHz, DMSO-d6) δ ppm 2.69(s, 3H), 4.04(s, 3H), 6.15-6.21(m, 2H), 7.16-7.30(m, 1H), 7.55(s, 2H), 7.70(d, J= 8.79Hz, 1H), 8.17-8.24(m, 1H), 8.57-8.67(m, 1H), 8.71-8.74(m, 1H), 9.40-9.42(m, 1H).

[0208] Example 62 6 mg of 5-((7-Methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-2-sulfonamide (73) was prepared. LCMS [M+H] + =385.

[0209] Example 63 14 mg of 3,5-difluoro-4-((7-methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (130) was prepared. LCMS [M+H] + =420.

[0210] Example 64 6-((2-Cyclopropyl-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (74) [ka] step 1. At 22°C, to a mixture of cyclopropanecarboxylic acid (6.21 mg, 72.14 μmol, 5.70 μL, 1.3 eq) in DMF (0.3 ml) was added HATU (27.43 mg, 72.14 μmol, 1.3 eq) and DIEA (27.97 mg, 216.43 μmol, 37.70 μL, 3.9 eq) in one portion. The mixture was stirred at 22°C for 1 h. Then, 6-(((3-amino-7-methoxy-1,8-naphthyridin-4-yl)amino)methyl)pyridine-3-sulfonamide (20 mg, 55.50 μmol, 1 eq) was added to the reaction mixture, which was then stirred at 22°C for 18 h. After completion, water was added to the reaction mixture and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated. The crude product was used in the next step without further purification.

[0211] Step 2. At 22° C., to a solution of 6-((2-cyclopropyl-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide in EtOH / water=4:1 (1 ml) was added K2CO3 (23.01 mg, 166.49 μmol, 3 eq.). The reaction was stirred at 65° C. for 18 h. Upon completion, the mixture was concentrated. The crude was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give the product (2.5 mg, 9%). LCMS [M+H] + =411.

[0212] Example 65 1.0 mg of 6-((7-methoxy-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (75) was prepared in a similar manner to the preparation of compound 74. LCMS [M+H] + =455.

[0213] Example 66 N-((2-fluoro-4-((7-methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-phenyl)sulfonyl)acetamide (76) was isolated as a by-product of the final step in the preparation of compound 71. LCMS [M+H] + =444; 1 H NMR (300MHz, DMSO-d6) δ ppm 1.92(s, 3H), 2.70(s, 3H), 4.08(s, 3H), 6.10-6.17(m, 2H), 7.10(d, J=8.21Hz, 1H), 7.25(d, J=11. 14Hz, 1H), 7.33(d, J=8.79Hz, 1H), 7.83(t, J=7.91Hz, 1H), 8.55-8.61(m, 1H), 9.59-9.62(m, 1H).

[0214] Example 67 N-((6-((7-Methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridin-3-yl)-sulfonyl)acetamide (77) was isolated as a by-product of the final step in the preparation of compound 72. LCMS [M+H] + =427; 1 H NMR (300MHz, DMSO-d6) δ ppm 1.89(s, 3H), 2.71(s, 3H), 4.07(s, 3H), 6.25(s, 2H), 7.27(brd, J=4.10Hz, 1H), 7.85(s , 1H), 8.30-8.40(m, 1H), 8.69(d, J=9.38Hz, 1H), 8.77(d, J=2.34Hz, 1H), 9.53(s, 1H).

[0215] Example 68 In a similar manner to the preparation of compound 39, 9.7 mg of 4-((2,7-dimethoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-fluorobenzenesulfonamide (78) was prepared using tetraethyl orthocarbonate in the final step. LCMS [M+H] + =418; 1H NMR (300MHz, DMSO-d6) δ ppm 4.06(s, 3H), 4.27(s, 3H), 5.88(s, 2H), 7.11(d, J=8.21Hz, 1H), 7.30-7.35(m, 1 H), 7.64(s, 2H), 7.71(brt, J=7.62Hz, 2H), 8.50(d, J=8.79Hz, 1H), 9.39(s, 1H).

[0216] Example 69 2-Fluoro-4-((7-methoxy-2-(methoxymethyl)-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-benzenesulfonamide (79) [ka] Step 1. 4-(((3-amino-7-methoxy-1,8-naphthyridin-4-yl)amino)methyl)-2-fluorobenzenesulfonamide (70 mg, 0.185 mmol, 1 equiv) was dissolved in DMF (1.85 mL, 0.1 M) and chloroacetic anhydride (35 mg, 0.204 mmol, 1.1 equiv) was added. The mixture was stirred at 22° C. for 4 days. After completion, the mixture was partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×3 ml). The combined organic layers were dried over Na2SO4 and concentrated to give 4-((2-(chloromethyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-fluorobenzenesulfonamide (47.4 mg, 59%) without further purification.

[0217] Step 2. 4-((2-(chloromethyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-fluorobenzenesulfonamide (17 mg, 0.039 mmol, 1 equiv) was dissolved in MeOH (0.4 mL, 0.1 M) and 25 wt% NaOMe (286 μL) was added. The mixture was stirred at 22° C. for 1 h. Upon completion, the mixture was quenched with saturated NH4Cl and concentrated. The crude was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give the product (10 mg, 59%). LCMS [M+H]+ =432; 1 H NMR (300MHz, DMSO-d6) δ ppm 4.03(s, 3H), 4.84(s, 2H), 6.09(s, 2H), 6.88-6.99(m, 1H), 7.15-7.23(m, 2H) , 7.61(s, 2H), 7.67(t, J=7.62Hz, 1H), 8.34-8.45(m, 1H), 9.47-9.56(m, 1H).

[0218] Example 70 2-Fluoro-4-((7-methoxy-2-(morpholinomethyl)-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-benzenesulfonamide (80) [ka] 4-((2-(chloromethyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-fluorobenzenesulfonamide (10 mg, 0.023 mmol, 1 eq) was dissolved in DMF (0.46 mL, 0.05 M) and morpholine (10 μL, 0.115 mmol, 5 eq) was added. The mixture was stirred at 22° C. for 1 h. After completion, the mixture was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give the product (4 mg). LCMS [M+H] + =487; 1 H NMR (300MHz, DMSO-d6) δ ppm 2.58-2.74(m, 4H), 3.78(brs, 2H), 4.04(s, 3H), 4.13-4.24(m, 2H), 6.14(s, 2H), 6.92(s, 1H), 7.13-7.2 1(m, 1H), 7.24(d, J=8.79Hz, 1H), 7.65(s, 2H), 7.68-7.71(m, 1H), 8.43(d, J=9.38Hz, 1H), 9.53(s, 1H).

[0219] Example 71 2-Fluoro-4-((7-methoxy-2-((methylsulfonyl)methyl)-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)-methyl)benzenesulfonamide (81) [ka] Step 1. 4-((2-(chloromethyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-fluorobenzenesulfonamide (17.7 mg, 0.041 mmol, 1 equiv) was dissolved in EtOH (0.82 mL, 0.05 M) and then NaSMe (9 mg, 0.123 mmol, 3 equiv) was added. The mixture was stirred at 22° C. for 3 h. After completion, the mixture was concentrated to give the product. The crude product was used in the next step without further purification.

[0220] Step 2. 2-Fluoro-4-((7-methoxy-2-((methylthio)methyl)-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide was dissolved in THF (0.18 ml) followed by the addition of a solution of oxone (11 mg, 0.018 mmol, 1 eq) in water (0.18 ml). The mixture was stirred at 22° C. for 3 h. After completion, the mixture was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give the product (5.3 mg, 31%). LCMS [M+H] + =480; 1 H NMR (300MHz, DMSO-d6) δ ppm 3.26(s, 3H), 4.02(s, 3H), 5.26(s, 2H), 6.21(s, 2H), 6.93(d, J=7.86Hz, 1H), 7.10(d, J=11.14Hz, 1H ), 7.18(d, J=8.79Hz, 1H), 7.61(s, 2H), 7.67(t, J=7.91Hz, 1H), 8.37(d, J=9.38Hz, 1H), 9.53(s, 1H).

[0221] Example 72 4-((2-(cyanomethyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-fluorobenzene-sulfonamide (82) [ka] 4-((2-(chloromethyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-fluorobenzenesulfonamide (11.3 mg, 0.026 mmol, 1 eq) was dissolved in DMSO (0.26 mL, 0.1 M) and then NaCN (2.5 mg, 0.052 mmol, 2 eq) was added. The mixture was heated at 80° C. for 10 min. After completion, the mixture was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give the product (2.6 mg, 24%). LCMS [M+H] + =427.

[0222] Example 73 Methyl 2-(1-(3-fluoro-4-sulfamoylbenzyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-2-yl)-acetate (83) [ka] 4-(((3-amino-7-methoxy-1,8-naphthyridin-4-yl)amino)methyl)-2-fluorobenzenesulfonamide (80 mg, 0.212 mmol, 1 eq) was dissolved in DMF (4.24 mL, 0.05 M) and then Et3N (35 μL, 0.254 mmol, 1.2 eq) was added. The mixture was cooled to 0° C. and methyl malonyl chloride (24 μL, 0.223 mmol, 1.05 eq) was added. The mixture was stirred at 0° C. for 1 h and then heated at 100° C. for 3 h. After completion, the mixture was partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×5 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by FCC using DCM / THF to give the product (26 mg, 27%). LCMS [M+H] + =460.

[0223] Example 74 2-(1-(3-fluoro-4-sulfamoylbenzyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-2-yl)acetamide (84) [ka] Methyl 2-(1-(3-fluoro-4-sulfamoylbenzyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-2-yl)acetate (10 mg, 0.022 mmol, 1 eq) was dissolved in 2N ammonia-MeOH (0.21 ml). The mixture was heated at 65° C. for 2 h. Additional 2N ammonia-MeOH (0.42 ml) solution was added and heated at 65° C. for 3 h. Upon completion, the mixture was concentrated. The crude was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give the product (3.8 mg, 39%). LCMS [M+H] + =445; 1 H NMR (300MHz, DMSO-d6) δ ppm 4.03(s, 3H), 6.11(s, 2H), 7.01(s, 1H), 7.11-7.18(m, 1H), 7.18-7.24(m, 2H), 7 .60(s, 2H), 7.65-7.70(m, 1H), 7.75(brs, 1H), 8.38-8.43(m, 1H), 9.48(s, 1H).

[0224] Example 75 4-((2-(azetidin-3-yl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-fluorobenzene-sulfonamide (85) [ka] tert-Butyl 3-(1-((3-fluoro-4-sulfamoyl-phenyl)methyl)-7-methoxy-imidazo[4,5-c][1,8]naphthyridin-2-yl)azetidine-1-carboxylate (43 mg, 79.25 μmol, 1 eq.) obtained according to the synthesis of compound 74 was dissolved in DCM (1 ml), then cooled to 0° C. and TFA (308.00 mg, 2.70 mmol, 0.2 mL, 34.08 eq.) was added. The cooling bath was removed and the mixture was stirred at 22° C. for 1 h. After completion, the mixture was concentrated to give the product TFA salt (44 mg, 99%). LCMS [M+H] + =443; 1H NMR (300MHz, DMSO-d6) δ ppm 4.02(s, 3H), 4.29-4.43(m, 4H), 4.45-4.57(m, 1H), 5.95(s, 2H), 6.95(d, J=8.21Hz, 1H), 7.15-7.22( m, 2H), 7.64(s, 2H), 7.70(t, J=7.91Hz, 1H), 8.42(d, J=8.79Hz, 1H), 8.98-9.15(m, 1H), 9.51(s, 1H).

[0225] Example 76 2-Fluoro-4-((7-methoxy-2-(1-(methylsulfonyl)azetidin-3-yl)-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (86) [ka] 4-[[2-(azetidin-3-yl)-7-methoxy-imidazo[4,5-c][1,8]naphthyridin-1-yl]methyl]-2-fluoro-benzenesulfonamide (19.1 mg, 34.32 μmol, 1 eq, TFA) was dissolved in DMF (0.34 ml) and then cooled to 0° C. To the mixture was added Et3N (2M, 17.16 μL, 1 eq), followed by MsCl (2M, 17.16 μL, 1 eq). The mixture was stirred at 0° C. for 0.5 h. The mixture was allowed to warm to 22° C. and stirred for 1.5 h. Cooled to 0° C. and additional Et3N (2M, 17.16 μL, 1 eq) and MsCl (2M, 17.16 μL, 1 eq) were added and stirred at 0° C. for 30 min. The mixture was stirred at 22° C. for 18 h. After completion, the mixture was concentrated. The crude was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give the product (1.7 mg, 10%). LCMS [M+H] + =521.

[0226] Example 77 Intermediate 4-chloro-7-methoxy-2-methyl-3-nitro-1,8-naphthyridine [ka] Step 1. To 6-Methoxy-2-amino-pyridine (5 g, 40.3 mmol, 1 eq) and methyl acetoacetate (43 mL, 400.3 mmol, 10 eq) was added PPA (13 g). The mixture was heated at 190° C. for 3 h. After completion, the mixture was cooled to 22° C., diluted with water, and then washed with EtOAc (2×50 ml) to remove excess ethyl acetoacetate. To the aqueous layer was added EtOAc (100 ml) and the pH was adjusted to 8 with 2M NaOH under stirring. The resulting ppt was filtered and dried to give the product (2.7 g, 35%).

[0227] Step 2. 7-Methoxy-2-methyl-1,8-naphthyridin-4-ol (1 g, 5.26 mmol, 1 eq) was dissolved in sulfuric acid (50 ml) and then cooled to 0° C. At 0° C., fuming nitric acid (3.70 g, 58.72 mmol, 2.5 mL, 11.17 eq) was slowly added dropwise to the mixture. The mixture was stirred at 0° C. for 0.5 h. The cooling bath was removed and the mixture was stirred at 22° C. for 18 h. The mixture was heated at 60° C. for 5 h. After completion, the mixture was cooled to 22° C. and then poured into stirring ice water. The resulting ppt was filtered and dried to give the product (432 mg, 34%).

[0228] Step 3. 7-Methoxy-2-methyl-3-nitro-1,8-naphthyridin-4-ol (423 mg, 1.80 mmol, 1 eq) was suspended in POCl3 (5.94 g, 38.74 mmol, 3.6 mL, 21.54 eq) and heated at 80° C. for 1.5 h. After completion, the mixture was concentrated and dissolved in DCM. The organic layer was washed with saturated NaHCO3 (3×10 ml). The organic layer was dried over Na2SO4 and concentrated to give the product (447 mg, 98%).

[0229] Compounds 87 and 88 were prepared from the intermediate 4-chloro-7-methoxy-2-methyl-3-nitro-1,8-naphthyridine in a manner similar to the preparation of compound 39.

[0230] Example 78 11.9 mg of 6-((7-Methoxy-4-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (87) was prepared. LCMS [M+H] + =385; 1 H NMR (300MHz, DMSO-d6) δ ppm 2.86(s, 3H), 3.94(s, 3H), 6.14(s, 2H), 6.94(d, J=8.79Hz, 1H), 7.43(d, J=8.21Hz, 1H), 7.48- 7.60(m, 2H), 8.10-8.15(m, 1H), 8.31(d, J=8.79Hz, 1H), 8.50(s, 1H), 8.79(d, J=2.34Hz, 1H).

[0231] Example 79 7 mg of 2-fluoro-4-((7-methoxy-4-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (88) was prepared. LCMS [M+H] + =370; 1 H NMR (500MHz, DMSO-d6) δ ppm 3.94(s, 3H), 6.16(s, 2H), 7.30-7.37(m, 5H), 7.79(d, J=8.39Hz, 2H), 8.66(s, 1H), 9.10-9.17(m, 1H). Compounds 89 and 90 were prepared from the intermediate 4-chloro-7-methoxy-2-methyl-3-nitro-1,8-naphthyridine in a manner similar to the preparation of compound 39 using ethyl orthoformate.

[0232] Example 80 1.4 mg of 6-((7-Methoxy-2,4-dimethyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (89) was prepared. LCMS [M+H] + =399; 1H NMR (300MHz, DMSO-d6) δ ppm 2.69(s, 3H), 4.06(s, 3H), 6.19(s, 2H), 7.17-7.29(m, 1H), 7.57(s, 2H), 7.68 -7.78(m, 1H), 8.17-8.26(m, 1H), 8.58-8.67(m, 1H), 8.70(d, J=2.34Hz, 1H).

[0233] Example 81 12.1 mg of 2,5-difluoro-4-((7-methoxy-2,4-dimethyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-benzenesulfonamide (90) was prepared. LCMS [M+H] + =434; 1 H NMR (300MHz, DMSO-d6) δ ppm 2.68(s, 3H), 3.04(s, 3H), 4.08(s, 3H), 6.08(s, 2H), 6.85-6.95(m, 1H), 7.28(d, J =8.79Hz, 1H), 7.66(dd, J=9.08, 5.57Hz, 1H), 7.80(s, 2H), 8.56(d, J=8.79Hz, 1H).

[0234] Example 82 2-((7-Methoxy-2,4-dimethyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyrimidine-5-sulfonamide (91a) and 2-((6-chloro-7-methoxy-2,4-dimethyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyrimidine-5-sulfonamide (91b) [ka] Step 1. 4-Chloro-7-methoxy-2-methyl-3-nitro-1,8-naphthyridine (200 mg, 788.51 μmol, 1 eq.) was dissolved in NH3-MeOH solution (2M, 8 mL, 20.29 eq.) and stirred at 22° C. for 3 days. After completion, the mixture was concentrated and the resulting precipitate was triturated with water. The resulting precipitate was filtered and dried to give the product (184 mg, 99%).

[0235] Step 2. 7-Methoxy-2-methyl-3-nitro-1,8-naphthyridin-4-amine (184 mg, 785.62 μmol, 1 eq) was suspended in MeOH (8 ml) followed by the addition of 10% palladium on carbon (184 mg, 172.84 μmol, 0.22 eq) and HCl (12M, 65.47 μL, 1 eq). The mixture was purged with hydrogen (3 cycles) and stirred under a hydrogen balloon at 22° C. for 3 h. Upon completion, the mixture was filtered through a pad of Celite. The cake was washed with MeOH / Et3N (90% / 10%) and the filtrate was concentrated to give the product (160 mg, 99%).

[0236] Step 3. 7-Methoxy-2-methyl-1,8-naphthyridine-3,4-diamine (157 mg, 768.75 μmol, 1 eq) was dissolved in DMF (8 ml) followed by the addition of triethyl orthoacetate (3.47 g, 21.41 mmol, 3.92 mL, 27.85 eq) and acetic acid (55.40 mg, 922.50 μmol, 52.76 μL, 1.2 eq). The vial was sealed and heated at 80° C. for 8 hours. Upon completion, the mixture was concentrated. The resulting residue was triturated with saturated NaHCO3 and the brown precipitate was filtered. The aqueous layer was allowed to stand at 22° C. for 2 hours and a light yellow solid began to precipitate out which was dried to give the product (48 mg, 27%).

[0237] Step 4. 7-Methoxy-2,4-dimethyl-1H-imidazo[4,5-c][1,8]naphthyridine (44 mg, 192.77 μmol, 1 eq) and 5-bromo-2-(bromomethyl)pyrimidine (58.27 mg, 231.33 μmol, 1.2 eq) were dissolved in DMF (1 ml). The vial was sealed and heated at 50° C. for 4 hours. Additional 5-bromo-2-(bromomethyl)pyrimidine (58.27 mg, 231.33 μmol, 1.2 eq) was added and heated at 50° C. for 2 hours. Additional 5-bromo-2-(bromomethyl)pyrimidine (58.27 mg, 231.33 μmol, 1.2 eq) was added and stirred at 50° C. for hours. Upon completion, 3 drops of TFA were added to the mixture. The mixture was purified by Biotage C18 Duo 12 g column with a water / MeCN (0.1% TFA) gradient. The product fractions were combined and basified with saturated NaHCO3. The aqueous layer was extracted with EtOAc (3 x 5 ml). The combined organic layers were dried over Na2SO4 and concentrated to give the product (33 mg, 43%).

[0238] Step 5. 1-((5-Bromopyrimidin-2-yl)methyl)-7-methoxy-2,4-dimethyl-imidazo[4,5-c][1,8]naphthyridine (33 mg, 82.66 μmol, 1 eq.), Pd(dba)2 (4.75 mg, 8.27 μmol, 0.1 eq.), Xantphos (4.78 mg, 8.27 μmol, 0.1 eq.) and DIEA (32.05 mg, 247.97 μmol, 43.19 μL, 3 eq.) were dissolved in dioxane (0.8 ml). The mixture was purged with nitrogen for 20 s and sealed. Heat at 80 °C for 30 s and cooled to 22 °C. To the mixture was added benzyl mercaptan (11.29 mg, 90.92 μmol, 10.65 μL, 1.1 equiv) and the mixture was purged with nitrogen for 20 seconds. The vial was sealed and heated at 80° C. for 1 hour. Upon completion, the mixture was diluted with water and extracted with EtOAc (3×5 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by FCC using a Biotage Sfar 5 g silica column with a DCM / MeOH (100% / 0% to 80% / 20%) gradient to give the product (21.3 mg, 58%).

[0239] Step 6. 1-((5-benzylsulfanylpyrimidin-2-yl)methyl)-7-methoxy-2,4-dimethyl-imidazo[4,5-c][1,8]naphthyridine (21.3 mg, 48.13 μmol, 1 eq) was dissolved in MeCN (0.5 ml) and HO (12.14 mg, 673.85 μmol, 12.14 μL, 14 eq) and AcOH (20.23 mg, 336.92 μmol, 19.27 μL, 7 eq) were added, then cooled to 0° C. 1,3-Dichloro-5,5-dimethyl-imidazolidine-2,4-dione (13.28 mg, 67.38 μmol, 1.4 eq) was added and stirred at 0° C. for 1 h. Additional 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (13.28 mg, 67.38 μmol, 1.4 equiv) was added and stirred at 0° C. for 10 min. At 0° C., the mixture was added to NH4OH (0.5 ml) and stirred for 10 min. The pH of the resulting mixture was adjusted to 8 with 2M HCl. The mixture was concentrated. The crude was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give 91a (3.3 mg, 13%). LCMS [M+H] + = 400; 91b, LCMS [M + H] + =434; 1 H NMR (400MHz, DMSO-d6) δ ppm 2.78(s, 3H), 3.39(brs, 3H), 3.70(s, 3H), 5.77(s, 2H), 6.59(brs, 2H), 7.53(d, J=9.00Hz, 1H), 7.78(s, 2H).

[0240] Compounds 92 to 93 were produced in the same manner as in the production of compound 94.

[0241] Example 83 23.1 mg of 4-((2-((dimethylamino)methyl)-7-methoxy-4-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2,5-difluorobenzenesulfonamide (92) was prepared. LCMS [M+H] + =477; 1H NMR (300MHz, DMSO-d6) δ ppm 2.93(brs, 6H), 3.03-3.05(m, 3H), 4.04(s, 3H), 4.81(brs, 2H), 6.10(s, 2H), 6.85(dd, J=9.67, 5.57 Hz, 1H), 7.20(d, J=9.38Hz, 1H), 7.67(dd, J=9.38, 5.86Hz, 1H), 7.82(s, 2H), 8.39(d, J=9.38Hz, 1H).

[0242] Example 84 18.8 mg of 2,5-difluoro-4-((7-methoxy-2-(2-methoxyethyl)-4-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (93) was prepared. LCMS [M+H] + =478; 1 H NMR (300MHz, DMSO-d6) δ ppm 3.06(s, 3H), 3.14(s, 3H), 3.76-3.80(m, 2H), 4.08(s, 3H), 6.13(s, 2H), 6.72-6.84(m , 1H), 7.28(d, J=9.38Hz, 1H), 7.62-7.72(m, 1H), 7.80(s, 2H), 8.51(d, J=8.79Hz, 1H).

[0243] Example 85 2,5-Difluoro-4-((2-(hydroxymethyl)-7-methoxy-4-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (94) [ka] Step 1. 4-[[(3-amino-7-methoxy-2-methyl-1,8-naphthyridin-4-yl)amino]methyl]-2,5-difluoro-benzenesulfonamide (25 mg, 61.06 μmol, 1 eq) was dissolved in DMF (0.6 ml) and then cooled to 0° C. and (2-chloro-2-oxo-ethyl) acetate (8.34 mg, 61.06 μmol, 6.56 μL, 1 eq) was added. The mixture was stirred at 0° C. for 1 h. After completion, at 0° C., the mixture was quenched with water and saturated NaHCO3 was added. The aqueous layer was extracted with EtOAc (3×2 ml). The combined organic layers were dried over Na2SO4 and concentrated to give the product. The crude product was used in the next step without further purification.

[0244] Step 2. (2-((4-((2,5-difluoro-4-sulfamoyl-phenyl)methylamino)-7-methoxy-2-methyl-1,8-naphthyridin-3-yl)amino)-2-oxo-ethyl) acetate (31 mg, 60.85 μmol, 1 eq) was dissolved in EtOH (1.2 ml) followed by addition of NaOH (2M, 45.63 μL, 1.5 eq). The vial was sealed and heated at 60° C. for 1.5 h. Upon completion, the mixture was cooled to 22° C. and neutralized with 2M HCl (46 μL). The mixture was concentrated. The crude was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give the product (19.5 mg, 57%). LCMS [M+H] + =450; 1 H NMR (300MHz, DMSO-d6) δ ppm 3.06-3.07(m, 3H), 4.08(s, 3H), 4.88(s, 2H), 6.16(s, 2H), 6.69(dd, J=9.96, 5.86Hz, 1H), 7 .28(d, J=8.79Hz, 1H), 7.66(dd, J=9.08, 5.57Hz, 1H), 7.79(s, 2H), 8.44(d, J=9.38Hz, 1H).

[0245] Following the synthesis of compound 38, the following compounds were prepared:

[0246] Example 86 16.1 mg of 2,3-difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-benzenesulfonamide (95) was prepared. LCMS [M+H] + =422.

[0247] Example 87 0.8 mg of 5-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-2-sulfonamide (96) was prepared. LCMS [M+H] + =387. 1 H NMR (400MHz, DMSO-d6) δ ppm 3.93(s, 3H), 5.54(s, 2H), 6.99(d, J=9.00Hz, 1H), 7.11-7.21(m, 2H), 7.60(dd, J=9 .39, 5.48Hz, 1H), 7.78(s, 2H), 8.19(d, J=9.00Hz, 1H), 8.63(s, 1H), 11.72(s, 1H).

[0248] Example 88 34.5 mg of 2-fluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-benzenesulfonamide (98) was prepared. LCMS [M+H] + =404. 1 H NMR (400MHz, DMSO-d6) δ ppm 3.88-3.94(m, 3H), 5.54(s, 2H), 6.95(d, J=9.00Hz, 1H), 7.08(dd, J=8.02, 1.37Hz, 1H), 7.34(d, J=11. 04Hz, 1H), 7.61(s, 2H), 7.68(t, J=8.02Hz, 1H), 8.14(d, J=9.39Hz, 1H), 8.63(s, 1H), 11.73(brs, 1H).

[0249] Example 89 26 mg of 6-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (99) was prepared. LCMS [M+H] + =387. 1 H NMR (400MHz, DMSO-d6) δ ppm 3.95(s, 3H), 5.69(s, 2H), 7.02(d, J=9.39Hz, 1H), 7.55(s, 2H), 7.62(d, J=8.22Hz, 1H), 8.14(dd, J =8.41, 2.15Hz, 1H), 8.32(d, J=9.00Hz, 1H), 8.67(s, 1H), 8.74(d, J=2.35Hz, 1H), 11.95(brs, 1H).

[0250] Example 90 37.3 mg of 2,6-difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-benzenesulfonamide (100) was prepared. LCMS [M+H] + =422; 1 H NMR (400MHz, DMSO-d6) δ ppm 3.92(s, 3H), 5.51(s, 2H), 6.99(d, J=9.00Hz, 1H), 7.16-7.21(m, 2H), 7.95(s, 2H), 8.13(d, J=9.00Hz, 1H), 8.64(s, 1H).

[0251] Example 91 58 mg of (R)-4-(1-(7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)ethyl)benzene-sulfonamide (101) was prepared. LCMS [M+H] + =400; 1H NMR (400 MHz, chloroform-d) δ ppm 1.84-1.87 (m, 3H), 3.87-3.88 (m, 3H), 6.19-6.25 (m, 1H), 6.56-6.69 (m, 1H), 7.07-7.15 (m, 1H), 7.16-7.23 (m, 1H), 7.43-7.45 (m, 2H), 7.74-7.77 (m, 2H), 8.43-8.51 (m, 1H).

[0252] Example 92 3-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)cyclobutyl sulfamate (97) [ka] At 0° C., formic acid (4.90 mg, 106.56 μmol, 4.02 μL, 2 eq.) was added dropwise to chlorosulfonyl isocyanate (15.08 mg, 106.56 μmol, 9.25 μL, 2 eq.). The resulting mixture was stirred for 18 h to form sulfamoyl chloride. At 0° C., sulfamoyl chloride was added dropwise to a mixture of 1-((3-hydroxycyclobutyl)methyl)-7-methoxy-1,3-dihydro-2H-imidazo[4,5-c][1,8]-naphthyridin-2-one (16 mg, 0.053 mmol, 1 eq., obtained according to the preparation of compound 38) in DMA (0.5 ml). The reaction mixture was allowed to warm to 22° C. and stirred for 3 h. After completion, the solution was subjected to preparative HPLC using water / MeCN (0.1% TFA) to give the product (1.9 mg, 9%). LCMS [M+H] + =380.

[0253] Example 93 32.7 mg of 3-fluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-benzenesulfonamide (102) was prepared. LCMS [M+H] + =404.

[0254] Example 94 8.4 mg of 3,5-difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (103) was prepared. LCMS [M+H] + =422; 1 H NMR (400MHz, DMSO-d6) δ ppm 3.93(s, 3H), 5.58(s, 2H), 6.99(d, J=9.00Hz, 1H), 7.43(d, J=6.95Hz, 2H), 8.54-8.57(m, 2H).

[0255] Example 95 21.9 mg of 2,3,5-trifluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-benzenesulfonamide (112) was prepared. LCMS [M+H] + =440; 1 H NMR (300MHz, DMSO-d6) δ ppm 4.06(s, 3H), 5.70(s, 2H), 7.23-7.31(m, 1H), 7.39-7.50(m, 1H), 8.01(s, 2H), 8.67-8.77(m, 1H), 8.82-8.87(m, 1H).

[0256] Example 96 12.4 mg of 3,5-difluoro-4-((7-methoxy-4-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (113) was prepared. LCMS [M+H] + =436; 1 H NMR (300MHz, DMSO-d6) δ ppm 2.61(s, 3H), 3.91-3.98(m, 3H), 5.56-5.68(m, 2H), 6.92-7.08(m, 1H), 7.43-7.56(m, 2H), 7.56-7.64(m, 2H), 8.47-8.62(m, 1H).

[0257] Example 97 Sodium acetyl((3,5-difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl)sulfonyl)amide (104) [ka] Step 1. 3,5-Difluoro-4-((7-methoxy-2-oxo-3H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (50 mg, 118.66 μmol, 1 eq.) was dissolved in DMF (0.6 ml) and Et3N (30.02 mg, 296.65 μmol, 41.29 μL, 2.5 eq.), DMAP (1.45 mg, 11.87 μmol, 0.1 eq.) and acetic anhydride (30.28 mg, 296.65 μmol, 27.78 μL, 2.5 eq.) were added. The mixture was stirred at 22° C. for 1 h. The mixture was concentrated and dissolved in MeOH. 2M NaOH (5 eq.) was added and stirred for 5 min. The pH of the mixture was adjusted to 4 with 2M HCl. The resulting precipitate was filtered. The crude was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient. The product fractions were combined, the pH was adjusted to 4, and then extracted with EtOH / CHCl3 (3:1). The combined organic layers were concentrated to give the product (31 mg, 56%).

[0258] Step 2. N-(3,5-difluoro-4-((7-methoxy-2-oxo-3H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl)sulfonylacetamide (30 mg, 64.74 μmol, 1 eq) was suspended in MeOH (1 ml) followed by the addition of NaOH (0.2 M, 323.68 μL, 1 eq). The mixture became homogenous and was stirred at 22° C. for 5 min. After completion, the mixture was concentrated to give the product (30.6 mg, 97%). LCMS [M+H] + = 464; LCMS [M + H] + =422; 1H NMR (300MHz, DMSO-d6) δ ppm 1.62-1.67(m, 3H), 3.96(s, 3H), 5.56(s, 2H), 6.97-7.09(m, 1H), 7.32(d, J=8.21Hz, 2H), 8.56-8.62(m, 2H), 11.51-11.62(m, 1H).

[0259] Example 98 Following the synthesis of compound 104, 16.6 mg of sodium ((3,5-difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl)sulfonyl)(propionyl)amide (105) was prepared. LCMS [M+H] + =478; 1 H NMR (300MHz, DMSO-d6) δ ppm 0.80(t, J=7.62Hz, 3H), 1.88(q, J=7.62Hz, 2H), 3.95(s, 3H), 5.54(s, 2H), 6.95-7.07(m, 1H), 7.28(d, J=8.21Hz, 2H), 8.53-8.60(m, 2H).

[0260] Example 99 Following the synthesis of compound 104, 25.6 mg of sodium butyryl((3,5-difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl)sulfonyl)amide (106) was prepared. LCMS [M+H] + =492; 1 H NMR (300MHz, DMSO-d6) δ ppm 0.70(t, J=7.33Hz, 3H), 1.25-1.39(m, 2H), 1.81-1.87(m, 2H), 3.94(s, 3H) ), 5.53(s, 2H), 6.92-7.02(m, 1H), 7.25-7.30(m, 2H), 8.49-8.56(m, 2H).

[0261] Example 100 2 mg of 3,5-difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-N-methylbenzenesulfonamide (107) was prepared according to the preparation of compound 38. LCMS [M+H] + =436; 1 H NMR (300MHz, DMSO-d6) δ ppm 2.76(s, 3H), 3.75-3.81(m, 3H), 6.48-6.58(m, 2H), 7.43-7.50(m, 1H), 7.72-7.81(m, 2H), 8.77-8.86(m, 1H), 9.02-9.09(m, 2H).

[0262] Example 101 3,5-Difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzoic acid (108) [ka] Step 1. At 22° C., to a mixture of 1-(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,3-dihydro-2H-imidazo[4,5-c][1,8]naphthyridin-2-one (84 mg, 198 μmol, 1 eq.) in MeOH (1 ml) was added Et3N (60.23 mg, 595.23 μmol, 82.85 μL, 3 eq.) and Pd(dppf)Cl2 (14.52 mg, 19.84 μmol, 0.1 eq.) in one portion. The mixture was degassed with a CO balloon and stirred at 65° C. for 1 h. After completion, the mixture was concentrated. The crude was purified by FCC using a Biotage C18 Duo 12 g column with a water / MeCN (0.1% TFA) gradient to give the product (62 mg, 78%). LCMS [M+H] + =401.

[0263] Step 2. At 22° C., LiOH (1M, 1.62 mL, 10 eq.) was added in one portion to a mixture of methyl 3,5-difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzoate (62 mg, 155 μmol, 1 eq.) in THF / MeOH (2 ml). The mixture was stirred at 55° C. for 1 h. Upon completion, the mixture was concentrated. The crude was purified by FCC using a Biotage C18 Duo 12 g column with a water / MeCN (0.1% TFA) gradient to give compound 108 (2.4 mg, 4%). LCMS [M+H] + =387. 1 H NMR (300MHz, DMSO-d6) δ ppm 4.04(s, 3H), 5.69(s, 2H), 7.24(d, J=9.38Hz, 1H), 7.51-7.58(m, 2H), 8.71(s, 1H), 8.77(d, J=9.38Hz, 1H), 12.15(brs, 1H).

[0264] Example 102 3,5-Difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-benzamide (109) [ka] Methyl 3,5-difluoro-4-((7-methoxy-2-oxo-3H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzoate (50 mg, 124.90 μmol, 1 eq.) was dissolved in a solution of NH3 in MeOH (2M, 2.50 mL, 40 eq.). The vial was sealed and heated at 65° C. for 2 h. An additional solution of NH3 in MeOH (2M, 2.50 mL, 40 eq.) was added and heated at 65° C. for 18 h. Upon completion, the mixture was concentrated. The resulting precipitate was triturated with saturated NaHCO3. The precipitate was filtered. The crude was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give compound 109 (9.3 mg, 15%). LCMS [M+H] + =386; 1H NMR (300MHz, DMSO-d6) δ ppm 4.05(s, 3H), 5.68(s, 2H), 7.27(d, J=9.38Hz, 1H), 7.54(d, J=8.79Hz, 2H), 7.63 (brs, 1H), 8.07(brs, 1H), 8.72(s, 1H), 8.80(d, J=9.38Hz, 1H), 12.23(brs, 1H).

[0265] Example 103 3,5-Difluoro-N-hydroxy-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzamide (110) [ka] Methyl 3,5-difluoro-4-((7-methoxy-2-oxo-3H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzoate (50 mg, 124.90 μmol, 1 equiv) was dissolved in MeOH (2.5 ml) and then hydroxylamine hydrochloride (86.79 mg, 1.25 mmol, 10 equiv) was added. The mixture was sonicated until the hydroxylamine was dissolved and then cooled to 0° C. To the mixture was added NaOMe (4.4 M, 369.01 μL, 13 equiv) in one portion. The mixture was stirred at 22° C. for 2 h. Upon completion, the mixture was stored at −20° C. for 18 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The crude was triturated with saturated NaHCO3 and the resulting precipitate was filtered. The crude was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give compound 110 (29.4 mg, 46%). LCMS [M+H] + =402; 1 H NMR (300MHz, DMSO-d6) δ ppm 4.04(s, 3H), 5.66(s, 2H), 7.22-7.26(m, 1H), 7.43(d, J=8.79Hz, 2H), 8.71( s, 1H), 8.77(brd, J=8.79Hz, 1H), 11.24-11.50(m, 1H), 12.02-12.28(m, 1H). LCMS[M+H] + =387.

[0266] Example 104 (3,5-Difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl)boronic acid (111) [ka] Step 1. 1-((4-Bromo-2,6-difluoro-phenyl)methyl)-7-methoxy-3H-imidazo[4,5-c][1,8]naphthyridin-2-one (400 mg, 949.68 μmol, 1 eq.) was dissolved in DMF (2.5 ml), followed by addition of Boc2O (298.46 mg, 1.37 mmol, 314.17 μL, 1.44 eq.) and Cs2CO3 (464.13 mg, 1.42 mmol, 1.5 eq.). The mixture was stirred at 22° C. for 2 hours. After completion, the mixture was added to water and the resulting precipitate was filtered and dried to give the product (463 mg, 94%).

[0267] Step 2. tert-Butyl 1-((4-bromo-2,6-difluoro-phenyl)methyl)-7-methoxy-2-oxo-imidazo[4,5-c][1,8]naphthyridine-3-carboxylate (260 mg, 498.74 μmol, 1 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (151.98 mg, 598.49 μmol, 1.2 eq.), KOAc (146.84 mg, 1.50 mmol, 3 eq.) and Pd(dppf)Cl2DCM complex (40.73 mg, 49.87 μmol, 0.1 eq.) were suspended in dioxane (2.5 ml). The mixture was purged with nitrogen for 30 seconds and sealed. The mixture was heated at 80° C. for 2 h. After completion, the mixture was cooled to 22° C. and diluted with water. The mixture was extracted with EtOAc (3×5 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by FCC using a Biotage Sfar 5 g silica column with a DCM / MeOH (100% / 0% to 80% / 20%) gradient to give the product (198 mg, 70%).

[0268] Step 3. tert-Butyl 1-((2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl)-7-methoxy-2-oxo-imidazo[4,5-c][1,8]naphthyridine-3-carboxylate (50 mg, 87.97 μmol, 1 eq) was dissolved in acetone (1.35 ml) and HO (0.9 ml) followed by the addition of NaIO (56.45 mg, 263.91 μmol, 14.62 μL, 3 eq) and NHOAc (20.34 mg, 263.91 μmol, 3 eq). The mixture was stirred at 22° C. for 4 hours. Upon completion, the mixture was filtered through a pad of Celite and concentrated. The residue was suspended in 1:1 DCM:TFA (2 ml) and stirred at 22° C. for 10 minutes. The mixture was concentrated. The crude was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give compound 111 (23.6 mg, 54%). LCMS [M+H] + =387; 1 H NMR (300MHz, DMSO-d6) δ ppm 4.04(s, 3H), 5.65(s, 2H), 7.25(d, J=8.79Hz, 1H), 7.35(d, J=8.79Hz, 2H), 8.41(brs, 1H), 8.71-8.76(m, 2H), 12.21(brs, 1H).

[0269] Example 105 3,5-Difluoro-4-((7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (114) [ka] Step 1.0° C. To a mixture of 1-((4-bromo-2,6-difluoro-phenyl)methyl)-7-methoxy-3H-imidazo[4,5-c][1,8]naphthyridin-2-one (110 mg, 261.16 μmol, 1 equiv.) in DMF (2.5 ml) was added MeI (44.48 mg, 313.39 μmol, 19.51 μL, 1.2 equiv.) and NaH (12.54 mg, 313.39 μmol, 60% purity, 1.2 equiv.) in one portion. The mixture was stirred at 0° C. for 1 h. After completion, water (10 ml) was added to the reaction mixture. The aqueous layer was extracted with EtOH / CHCl3=1:3. The organic layer was dried over Na2SO4 and concentrated. The crude was purified on a Biotage Sfar 10 g silica column with DCM / EtOAc to give the product (28 mg, 25%).

[0270] Step 2. To a mixture of 1-((4-bromo-2,6-difluoro-phenyl)methyl)-7-methoxy-3-methyl-imidazo[4,5-c][1,8]naphthyridin-2-one (70 mg, 160.84 μmol, 1 equiv.) in DMF (2 ml) was added DIEA (74.83 mg, 579.02 μmol, 100.85 μL, 3.6 equiv.), Xantphos (9.31 mg, 16.08 μmol, 0.1 equiv.) and Pd(dba)2 (9.25 mg, 16.08 μmol, 0.1 equiv.) in one portion under N2 at 22° C. The mixture was stirred at 80° C. for 10 min. Benzyl mercaptan (23.97 mg, 193.01 μmol, 22.61 μL, 1.2 equiv) was added to the reaction and heated at 80° C. for 2 h. Upon completion, the mixture was concentrated. The crude was purified on a Biotage Sfar 5 g silica column with DCM / MeOH to give the product (60 mg, 78%).

[0271] Step 3. At 0° C., to a mixture of 1-((4-benzylsulfanyl-2,6-difluoro-phenyl)methyl)-7-methoxy-3-methyl-imidazo[4,5-c][1,8]naphthyridin-2-one (30 mg, 62.69 μmol, 1 eq.) in THF (2 ml) and MeCN (1 ml) was added AcOH (26.35 mg, 438.86 μmol, 25.10 μL, 7 eq.) and HO (15.82 mg, 877.72 μmol, 15.82 μL, 14 eq.) in one portion. Then, at 0° C., 1,3-dichloro-5,5-dimethylhydantoin (17.29 mg, 87.77 μmol, 1.4 eq.) was added to the reaction mixture. The mixture was stirred at 0° C. for 2 h. NH4OH (659.15 mg, 18.81 mmol, 724.34 μL, 300 equiv) was cooled to 0° C. The reaction mixture was added dropwise to NH4OH (659.15 mg, 18.81 mmol, 724.34 μL, 300 equiv) and stirred at 0° C. for 1 h. Upon completion, the mixture was acidified to pH=1 and concentrated. The crude was purified by Biotage C18 Duo 12 g column with water / MeCN (0.1% TFA) to give the product (28.6 mg, 83%). LCMS [M+H] + =436; 1 H NMR (300MHz, DMSO-d6) δ ppm 3.51(brs, 3H), 4.08(s, 3H), 5.72(s, 2H), 7.31(d, J=9.38Hz, 1H), 7.45-7.54(m, 2H), 7.63(s, 2H), 8.93(d, J=9.38Hz, 1H), 9.05(s, 1H).

[0272] Following the preparation of compound 114, the following compounds were prepared:

[0273] Example 106 Following the synthesis of compound 114, 9.9 mg of 3,5-difluoro-4-((3-(2-hydroxyethyl)-7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (115) was prepared. LCMS [M+H] + =466.

[0274] Example 107 Following the synthesis of compound 114, 29.5 mg of 3,5-difluoro-4-((7-methoxy-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (131) was prepared. LCMS [M+H] + =504; 1 H NMR (400MHz, DMSO-d6) δ ppm 3.99(s, 3H), 5.00(d, J=9.00Hz, 2H), 5.71(s, 2H), 7.17-7.20(m, 1H), 7.46(d, J=7.43Hz, 2H), 7.61(s, 2H), 8.74(d, J=9.00Hz, 1H), 9.04(s, 1H).

[0275] Example 108 Following the synthesis of compound 114, 30 mg of 3,5-difluoro-4-((7-methoxy-3-(2-methoxyethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (132) was prepared. LCMS [M+H] + =480; 1 H NMR (400MHz, chloroform-d) δ ppm 3.21-3.22(m, 3H), 3.63-3.67(m, 2H), 4.02-4.10(m, 3H), 4.18-4.24(m, 2H), 5.69-5.77(m, 2H), 7.23-7.33(m, 1H), 7.46-7.53(m, 2H), 7.61-7.68(m, 2H), 8.82-8.90(m, 1H), 8.99-9.05(m, 1H).

[0276] Example 109 Following the synthesis of compound 114, 29.5 mg of 3,5-difluoro-4-((3-(3-hydroxypropyl)-7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (133) was prepared. LCMS [M+H] + =480; 1H NMR (400MHz, DMSO-d6) δ ppm 1.82(t, J=6.85Hz, 2H), 3.41-3.42(m, 2H), 4.02-4.07(m, 5H), 5.69-5.73(m, 2H), 7.2 0-7.28(m, 1H), 7.47(d, J=7.43Hz, 2H), 7.62(s, 2H), 8.76-8.85(m, 1H), 9.01(s, 1H).

[0277] Example 110 Following the synthesis of compound 114, 6.6 mg of 3,5-difluoro-4-((7-methoxy-3-(oxetan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (139) was prepared. LCMS [M+H] + =478.

[0278] Example 111 4-((7-Methoxy-1H-pyrazolo[4,3-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (116) [ka] Step 1. Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (276 mg, 1.03 mmol, 1 eq) was dissolved in DCM (10 mL, 0.1 M) and then cooled to -78 °C. 1 M DIBAL-cyclohexane solution (2.4 mL, 2.4 mmol, 2.4 eq) was added to the mixture. After completion, the mixture was warmed to 0 °C and quenched with saturated NH4Cl. The aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were dried over Na2SO4 and concentrated. The product was used in the next step without further purification.

[0279] Step 2. (4-Chloro-7-methoxy-1,8-naphthyridin-3-yl)methanol from the previous step was dissolved in DCM (10 ml) and then MnO2 (870 mg, 10 mmol, 10 equiv) was added. The mixture was stirred at 22° C. for 2 h. Upon completion, the mixture was filtered through a pad of Celite and the filtrate was concentrated to give the product (132 mg, 2 steps, 59%).

[0280] Step 3. 4-Chloro-7-methoxy-1,8-naphthyridine-3-carbaldehyde (122 mg, 0.55 mmol, 1 eq) was dissolved in MeOH (11 mL, 0.05 M) followed by the addition of hydrazine monohydrate (32 μL, 0.66 mmol, 1.2 eq). The vial was sealed and heated at 90° C. for 24 h. Upon completion, the mixture was cooled to 22° C. and concentrated. The crude was dissolved in EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2×20 ml). The combined organic layers were dried over Na2SO4 and concentrated to give the product (100 mg, 91%).

[0281] Step 4. 7-Methoxy-1H-pyrazolo[4,3-c][1,8]naphthyridine (20 mg, 0.1 mmol, 1 eq) was dissolved in DMF (1 mL, 0.1 M) followed by the addition of 60% NaH (5 mg, 0.12 mmol. 1.2 eq) and 4-(bromomethyl)benzenesulfonamide (30 mg, 0.12 mmol, 1.2 eq). The mixture was stirred at 22° C. for 3 h and at 40° C. for 1 h. The mixture was purified by preparative HPLC using water / MeCN (0.1% TFA) to give the product (7.3 mg, 20%). LCMS [M+H] + =370; 1 H NMR (300MHz, DMSO-d6) δ ppm 3.98(s, 3H), 6.26(s, 2H), 7.34(s, 2H), 7.61(d, J=8.79Hz, 3H), 7.75-7.79(m, 3H), 7.99-8.11(m, 1H), 8.90(d, J=8.79Hz, 1H), 10.29(s, 1H).

[0282] Example 112 2-Fluoro-4-((7-methoxy-1H-pyrazolo[4,3-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (122a) and 2-fluoro-4-((7-methoxy-2H-pyrazolo[4,3-c][1,8]naphthyridin-2-yl)methyl)benzenesulfonamide (122b): Following the synthesis of 4-((7-methoxy-1H-pyrazolo[4,3-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide, the two products were prepared in 35% yield, 66 mg and 10 mg, respectively. 122a: LCMS [M+H] + =388; 1 H NMR (300MHz, DMSO-d6) δ ppm 4.06(s, 3H), 5.93(s, 2H), 7.29(brd, J=8.79Hz, 1H), 7.33(brd, J=8.21Hz, 1H), 7.43(brd, J=11.14Hz, 1 122b:LCMS[M+H] + =388; 1 H NMR (300MHz, DMSO-d6) δ ppm 3.95(s, 3H), 6.25(s, 2H), 7.58(d, J=8.79Hz, 1H), 7.75(t, J=7.91Hz, 1H), 7.84-7.93(m, 1H), 7 .93-7.98(m, 2H), 8.07-8.13(m, 1H), 8.67-8.72(m, 1H), 8.91(d, J=8.79Hz, 1H), 10.26(s, 1H).

[0283] Example 113 6-((7-Methoxy-1H-pyrazolo[4,3-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (135a) and 6-((7-Methoxy-2H-pyrazolo[4,3-c][1,8]naphthyridin-2-yl)methyl)pyridine-3-sulfonamide (135b): The products were prepared according to the synthesis of 4-((7-Methoxy-1H-pyrazolo[4,3-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide, 4.8 mg and 2.6 mg, respectively. 135a: LCMS [M+H] + =371; 135b: LCMS [M+H] + =371.

[0284] Example 114 4-((7-Methoxy-1H-pyrrolo[3,2-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (117) [ka] Step 1. 5-Chloro-2-methoxy-1,8-naphthyridine (527 mg, 2.7 mmol, 1 equiv), tert-butyl carbamate (380 mg, 3.25 mmol, 1.2 equiv), Pd(dba)2 (78 mg, 0.135 mmol, 0.05 equiv), XPhos (129 mg, 0.27 mmol, 0.1 equiv) and Cs2CO3 (1.76 g, 5.4 mmol, 2 equiv) were suspended in dioxane (14 mL, 0.2 M). The mixture was purged with nitrogen for 1 h and heated at 100 °C under nitrogen atmosphere for 5 h. Upon completion, the mixture was cooled to 22 °C and poured into water. The resulting precipitate was filtered and dried. The crude product was used in the next step without further purification.

[0285] Step 2. The (7-methoxy-1,8-naphthyridin-4-yl)carbamate from the previous step was dissolved in DCM (5.4 mL, 0.5 M), then cooled to 0° C. and 4M HCl-dioxane solution (2.7 ml) was added. The mixture was stirred at 22° C. until all starting material was consumed. After completion, the mixture was concentrated to give the product. The product was used in the next step without further purification.

[0286] Step 3. 7-Methoxy-1,8-naphthyridin-4-amine HCl was dissolved in AcOH (14 mL, 0.2 M) and then cooled to 0° C. Bromine (153 μL, 2.97 mmol, 1.1 equiv) was added to the mixture. The mixture was stirred at 22° C. until no starting material was observed on LCMS. After completion, the mixture was poured into water. The resulting precipitate was filtered and dried to give the product (459 mg, 3 steps, 67%).

[0287] Step 4. 3-Bromo-7-methoxy-1,8-naphthyridin-4-amine (455 mg, 1.79 mmol, 1 eq), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (709 mg, 3.58 mmol, 2 eq), Pd(OAc)2 (12 mg, 0.05 mmol, 0.03 eq), SPhos (55 mg, 0.133, 0.075 eq) and K3PO4 (760 mg, 3.58 mmol, 2 eq) were dissolved in 4:1 MeCN / H2O (10 mL, 0.18 M). The mixture was purged with nitrogen for 1 h and heated at 110 °C. After completion, the mixture was cooled to 22 °C and poured into saturated NH4Cl. The aqueous layer was extracted with EtOAc (3 x 30 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by FCC using DCM / MeOH to give the product (280 mg, 64%).

[0288] Step 5. (E)-3-(2-ethoxyvinyl)-7-methoxy-1,8-naphthyridin-4-amine (280 mg, 1.14 mmol, 1 eq) was dissolved in 1.25M HCl-EtOH solution (14 ml). The mixture was heated to 75° C. Upon completion, the mixture was cooled to 22° C. and concentrated to give the product (259 mg, 97%).

[0289] Step 6. 7-Methoxy-1H-pyrrolo[3,2-c][1,8]naphthyridine HCl (50 mg, 0.212 mmol, 1 eq) was dissolved in DMF (3 ml) followed by the addition of 4-(bromomethyl)benzenesulfonamide (64 mg, 0.255 mmol, 1.2 eq) and K2CO3 (88 mg, 0.64 mmol, 3 eq). The mixture was heated to 60° C. Upon completion, the mixture was cooled to 22° C. and concentrated. The crude was purified by preparative HPLC using water / MeCN (0.1% TFA) to give the product (22.7 mg, 22%). LCMS [M+H] + =369; 1 H NMR (600MHz, DMSO-d6) δ ppm 3.99(s, 3H), 6.08(s, 2H), 6.93-6.97(m, 1H), 7.21(brd, J=9.35Hz, 2H), 7.59(s , 2H), 7.65(t, J=7.89Hz, 1H), 8.43(d, J=9.17Hz, 1H), 8.75(s, 1H), 9.52(s, 1H).

[0290] Example 115 2-Fluoro-4-((7-methoxy-1H-pyrazolo[4,3-c]cinnolin-1-yl)methyl)benzenesulfonamide (118) [ka] Step 1. At -78 °C, DIBAL (1M, 3.37 mL, 3 eq) was added dropwise to a solution of ethyl 4-chloro-7-methoxy-cinnoline-3-carboxylate (300 mg, 1.12 mmol, 1 eq) in THF (10 ml). The -78 °C mixture was stirred at -78 °C for 3 h. After completion, saturated NaHCO3, potassium sodium tartrate, EtOAc were added to the reaction mixture and stirred at 22 °C for 18 h. The aqueous layer was washed with EtOAc (3 x 20 ml). The organic layers were combined, dried over Na2SO4 and concentrated. The crude residue was dissolved in DCM (10 ml). At 22 °C, MnO2 (978.03 mg, 11.25 mmol, 10 eq) was added to the reaction mixture. The reaction was stirred at 22 °C for 3 h. After completion, the reaction was filtered through a pad of celite and concentrated. The crude was purified by FCC to give the product (156 mg, 63%).

[0291] Step 2. To a mixture of 4-chloro-7-methoxy-cinnoline-3-carbaldehyde (156 mg, 700.72 μmol, 1 eq) in MeOH (15 ml) at 22° C., hydrazine (40.42 mg, 1.26 mmol, 45.63 μL, 1.8 eq) was added in one portion. The mixture was stirred at 65° C. for 18 h. After completion, the mixture was concentrated. The crude was purified by FCC to give the product (87 mg, 62%).

[0292] step 3. At 22°C, NaH (8.39 mg, 209.79 μmol, 60% purity, 1.2 eq) was added in one portion to a mixture of 7-methoxy-1H-pyrazolo[4,3-c]cinnoline (35 mg, 174.83 μmol, 1 eq) in DMF (1 ml). The mixture was stirred at 22°C for 5 min. 4-(Bromomethyl)-2-fluoro-benzenesulfonamide (56.25 μg, 0.21 μmol, 1.20e-3 eq) was added to the reaction mixture and stirred for 2 h. Upon completion, the reaction was quenched with 1N HCl (2 ml). A solid was allowed to precipitate out of the solution. The precipitate was filtered. The filtrate was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give the product (3.8 mg, 5.6%). LCMS [M+H] + =388; 1 H NMR (300MHz, DMSO-d6) δ ppm 3.96(s, 3H), 6.25(s, 2H), 7.41-7.53(m, 2H), 7.58(brd, J=7.62Hz, 1H), 7.63(s, 2H) ), 7.75(brt, J=7.91Hz, 1H), 7.93(brs, 1H), 8.91(d, J=8.79Hz, 1H), 10.25(s, 1H).

[0293] Example 116 6-((7-Methoxy-1H-[1,2,3]triazolo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (119) [ka] NaNO2 (4.82 mg, 69.92 μmol, 1.2 equiv) was dissolved in water (0.1 ml). At 0° C., to a mixture of 6-(((3-amino-7-methoxy-1,8-naphthyridin-4-yl)amino)methyl)pyridine-3-sulfonamide (21 mg, 58.27 μmol, 1 equiv) in HCl (2M, 291.35 μL, 10 equiv) was added NaNO2 (4.82 mg, 69.92 μmol, 1.2 equiv) solution in one portion. The mixture was stirred at 0° C. for 30 min. After completion, the solution was subjected to preparative HPLC using water / MeCN (0.1% TFA) to give the product (6.2 mg, 29%). LCMS [M+H] + =372; 1 H NMR (300MHz, DMSO-d6) δ ppm 4.02(s, 3H), 6.60(s, 2H), 7.19(d, J=8.79Hz, 1H), 7.53(s, 2H), 7.64(d, J=8.21Hz, 1H), 8. 19(dd, J=8.21, 2.34Hz, 1H), 8.61(d, J=8.79Hz, 1H), 8.71(d, J=2.34Hz, 1H), 9.66(s, 1H).

[0294] Example 117 Following the synthesis of compound 119, 3.9 mg of 2-fluoro-4-((7-methoxy-1H-[1,2,3]triazolo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (120) was prepared. LCMS [M+H] + =389;1H NMR (400MHz, DMSO-d6)δ ppm 4.00(s, 3H), 6.46(s, 2H), 6.97(dd, J=8.22, 1.57Hz, 1H), 7.22(d, J=8.61Hz, 1H), 7.32(d, J=10.62Hz, 1H), 7.64(s, 2H), 7.68(t, J=8.02Hz, 1H), 8.58(d, J=9.00Hz, 1H), 9.67(s, 1H).

[0295] Example 118 Following the synthesis of compound 119, 3.2 mg of 6-((7-methoxy-4-methyl-1H-[1,2,3]triazolo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (136) was prepared. LCMS [M+H] + =386; 1 H NMR (300MHz, DMSO-d6) δ ppm 3.00(s, 3H), 4.00(s, 3H), 6.57(s, 2H), 7.09(d, J=8.79Hz, 1H), 7.53(s, 2H), 7.61 (d, J=8.21Hz, 1H), 8.18(d, J=8.21Hz, 1H), 8.50-8.56(m, 1H), 8.71-8.75(m, 1H).

[0296] Example 119 (2-Fluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl)phosphonic acid (121) [ka] Step 1. To a mixture of 1-ethoxyphosphonoyloxyethane (82.20 mg, 595.23 μmol, 76.82 μL, 6 eq.) and 1-((4-bromo-3-fluoro-phenyl)methyl)-7-methoxy-3H-imidazo[4,5-c][1,8]naphthyridin-2-one (40 mg, 99.21 μmol, 1 eq.) in DMF (1.2 ml) was added Et3N (30.12 mg, 297.62 μmol, 41.42 μL, 3 eq.) and Pd(dppf)Cl2 (7.26 mg, 9.92 μmol, 0.1 eq.) in one portion under N2 at 22° C. The mixture was stirred at 80° C. for 3 hours. Upon completion, the mixture was concentrated. The crude was purified on a Biotage Sfar 5 g silica column with DCM / MeOH to give the product (44 mg, 96%).

[0297] Step 2. At 22° C., to a mixture of 1-((4-diethoxyphosphoryl-3-fluoro-phenyl)methyl)-7-methoxy-3H-imidazo[4,5-c][1,8]naphthyridin-2-one (96 mg, 208.52 μmol, 1 eq) in DCM (10 ml) was added 2,6-lutidine (379.82 mg, 3.54 mmol, 412.85 μL, 17 eq) in one portion. The mixture was cooled to 0° C. and TMSBr (1.60 g, 10.43 mmol, 1.35 mL, 50 eq) was added dropwise to the reaction mixture. The reaction mixture was stirred at 22° C. for 5 h. After completion, MeOH (20 ml) was added to the reaction mixture and stirred for 30 min. The mixture was concentrated and the crude was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give the product (30 mg, 36%). LCMS [M+H] + =405; 1 H NMR (400MHz, DMSO-d6) δ ppm 3.92(s, 3H), 5.51(s, 2H), 6.93-7.04(m, 2H), 7.08-7.18(m, 1H), 7.51-7.63(m, 1H), 8.12-8.21(m, 1H), 8.61-8.68(m, 1H).

[0298] Compounds 124 to 127 were prepared according to the method for preparing Compound 121.

[0299] Example 120 Following the method for preparing compound 121, 9.1 mg of (3,5-difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-phenyl)phosphonic acid (124) was prepared. LCMS [M+H] + =423.

[0300] Example 121 (2,5-difluoro-4-((7-methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl)phosphonic acid (125): LCMS [M+H] + =421.

[0301] Example 122 (6-((7-Methoxy-2,4-dimethyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridin-3-yl)phosphonic acid (126): LCMS [M+H] + =400.

[0302] Example 123 Following the method for preparing compound 121, 8.1 mg of methyl hydrogen(2-fluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl)phosphonate (127) was prepared. LCMS [M+H] + =419.

[0303] Example 124 Following the preparation of compound 38, 14.6 mg of 3-fluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-1-yl)methyl)benzenesulfonamide (123) was prepared. LCMS [M+H] + =404; 1 H NMR (300MHz, DMSO-d6) δ ppm 3.95-3.97(m, 3H), 5.62(s, 2H), 7.37(d, J=1.76Hz, 1H), 7.40(d, J=2.34Hz, 1H), 7.49(s , 2H), 7.51(brd, J=1.76Hz, 2H), 7.67(dd, J=9.96, 1.76Hz, 1H), 7.96(d, J=9.38Hz, 1H).

[0304] Example 125 4-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-1-yl)methyl)benzene-sulfonamide (128) [ka] step 1. At 22° C., to a mixture of ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (77 mg, 288.74 μmol, 1 eq.) and (4-(aminomethyl)phenyl)methanesulfonamide (109.36 mg, 461.98 μmol, 1.6 eq., HCl) in MeCN (5 ml) was added DIEA (373.16 mg, 2.89 mmol, 502.91 μL, 10 eq.) in one portion. The mixture was stirred at 65° C. for 1 h. After completion, the mixture was concentrated. The resulting residue was triturated with EtOAc to give the product (112 mg, 90%).

[0305] Step 2. At 22° C., LiOH (1M, 2.60 mL, 10 eq.) was added in one portion to a mixture of ethyl 7-methoxy-4-[[4-(sulfamoylmethyl)phenyl]methylamino]-1,8-naphthyridine-3-carboxylate (112 mg, 260.18 μmol, 1 eq.) in EtOH / THF (2.6 ml). The mixture was stirred at 50° C. for 1 h. After completion, the organic solvent was removed under reduced pressure and then acidified to pH=4. The aqueous layer was acidified with EtOH / CHCl3=1:3. Both the aqueous and organic layers contained the product. All the solvents were combined and then concentrated. The resulting white solid was extracted with EtOH and filtered. The filtrate was concentrated to give the crude product. The product was used in the next step without further purification.

[0306] Step 3. At 22° C., to a solution of this crude product mixture in DMF (3 ml) was added DPPA (171.84 mg, 624.42 μmol, 135.31 μL, 2.4 equiv), Et3N (263.27 mg, 2.60 mmol, 362.13 μL, 10 equiv) in one portion. The mixture was stirred at 80° C. for 3 h. After completion, the mixture was concentrated. The crude was purified by DCM / MeOH to give the product (17 mg, 16%). LCMS [M+H] + =400; 1H NMR (400MHz, DMSO-d6) δ ppm 4.01(s, 3H), 4.19(s, 2H), 5.56(s, 2H), 6.79(s, 2H), 7.17(d, J=9.00Hz, 1H), 7.22-7.2 5(m, 2H), 7.27-7.30(m, 2H), 8.40(d, J=9.00Hz, 1H), 8.76(s, 1H), 12.16-12.50(m, 1H).

[0307] Example 126 Following the preparation of compound 38, 16.8 mg of 3-chloro-5-fluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (134) was prepared. LCMS [M+H] + =438.

[0308] Example 127 11 mg of 4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnoline-1-yl)methyl)benzene-sulfonamide (137) was prepared from ethyl 4-hydroxy-7-methoxycinnoline-3-carboxylate according to the preparation of compound 38. LCMS [M+H] + =386; 1 H NMR (300MHz, DMSO-d6) δ ppm 3.93-3.96(m, 3H), 5.62(s, 2H), 7.32(s, 2H), 7.36(dd, J=9.67, 2.64Hz, 1H), 7.45(d, J =2.34Hz, 1H), 7.50(d, J=8.21Hz, 2H), 7.75(d, J=8.21Hz, 2H), 7.91(d, J=9.38Hz, 1H).

[0309] Example 128 3,5-Difluoro-4-(7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfamide (138) [ka] Step 1. 1-((4-Bromo-2,6-difluoro-phenyl)methyl)-7-methoxy-3H-imidazo[4,5-c][1,8]naphthyridin-2-one (400 mg, 949.68 μmol, 1 eq.) was dissolved in DMF (2.5 ml), followed by addition of Boc2O (298.46 mg, 1.37 mmol, 314.17 μL, 1.44 eq.) and Cs2CO3 (464.13 mg, 1.42 mmol, 1.5 eq.). The mixture was stirred at 22° C. for 2 hours. After completion, the mixture was added to water and the resulting precipitate was filtered to give the product (463 mg, 94%).

[0310] Step 2. tert-Butyl 1-((4-bromo-2,6-difluoro-phenyl)methyl)-7-methoxy-2-oxo-imidazo[4,5-c][1,8]naphthyridine-3-carboxylate (60 mg, 115.09 μmol, 1 eq.), Pd(OAc)2 (1.29 mg, 5.75 μmol, 0.05 eq.), Xantphos (3.33 mg, 5.75 μmol, 0.05 eq.), Cs2CO3 (112.50 mg, 345.28 μmol, 3 eq.) and tert-butyl carbamate (26.97 mg, 230.19 μmol, 2 eq.) were dissolved in dioxane (0.8 ml). The mixture was purged with nitrogen for 30 seconds and sealed. The mixture was stirred at 100° C. for 1 hour. Upon completion, the mixture was cooled to 22° C. and diluted with water. The resulting precipitate was filtered and dried to give the product (55.5 mg, 60%).

[0311] Step 3. tert-Butyl 1-((4-(tert-butoxycarbonylamino)-2,6-difluoro-phenyl)methyl)-7-methoxy-2-oxo-imidazo[4,5-c][1,8]naphthyridine-3-carboxylate (108 mg, 193.71 μmol, 1 eq) was dissolved in DCM (0.5 ml) and then TFA (770.00 mg, 6.75 mmol, 0.5 mL, 34.86 eq) was added. The mixture was stirred at 22° C. for 1.5 h. Upon completion, the mixture was concentrated and then dissolved in DCM. The crude was free-based using saturated NaHCO3 and extracted with EtOAc (3×10 ml). The combined organics were dried over Na2SO4 and concentrated. The crude was purified by Biotage C18 Duo 12 g column with a water / MeCN (0.1% TFA) gradient to give the product (24 mg, 35%).

[0312] Step 4. 1-((4-amino-2,6-difluoro-phenyl)methyl)-7-methoxy-3H-imidazo[4,5-c][1,8]naphthyridin-2-one (24 mg, 67.17 μmol, 1 eq) was dissolved in DMA (0.7 ml) followed by the addition of sulfamoyl chloride (77.61 mg, 671.68 μmol, 10 eq). The mixture was stirred at 22° C. for 2 h. Et3N (135.93 mg, 1.34 mmol, 186.98 μL, 20 eq) was added and stirred at 22° C. for 18 h. After completion, the mixture was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to give the product (28.1 mg, 76%). LCMS [M+H] + =437.

[0313] Biological Examples Example B1: ENPP1 activity assay using p-nitrophenyl-5'-TMP as substrate ENPP1 is a transmembrane glycoprotein that hydrolyzes nucleotides and nucleotide derivatives to form nucleotide-5'-monophosphates. ENPP1 hydrolyzes the artificial phosphate thymidine 5'-monophosphate p-nitrophenyl ester (TMP-pNP) to nucleotide-5'-monophosphate and the color-developing product p-nitrophenol. The amount of p-nitrophenol product formed is measured using absorbance at 405 nm, which is directly proportional to the enzyme activity.

[0314] I C 50 For the determination of the OD value, eight different concentrations of each inhibitor were prepared in 50 mM Tris buffer (pH 9.5) containing 250 mM NaCl, with final assay concentrations starting from 1000 nM. A 50 μL solution of 20 ng of human soluble ENPP1 was loaded into the wells and incubated with 25 μL of inhibitor solution (4× final concentration) for 30 min at room temperature. Then, 25 μL of 2 mM TMP solution (2× final concentration) was added to the wells and incubated for 1 h at room temperature. The amount of p-nitrophenolate released was measured by reading the OD value at 405 nm.

[0315] The percent inhibition for each compound was calculated as follows: % Inhibition = (OD MAX -OD 化合物 ) / (OD MAX -OD MIN )*100 (no ENPP1 inhibitor control, MIN: blank control).

[0316] IC for percent inhibition vs. compound concentration 50 IC values ​​are determined by fitting inhibition curves with a four-parameter mixed slope model in GraphPad Prism® 8. Determined IC 50 The values ​​are listed in Table 2.

[0317] Example B2: ENPP1 activity assay using p-nitrophenyl-5'-AMP as substrate.

[0318] In some cases, ENPP-1 inhibitors can only minimally inhibit ATP hydrolysis and selectively inhibit the hydrolysis of 2'3'-cGAMP. Thus, the ATP analog p-nitrophenyl 5'-adenosine monophosphate (AMP-pNP) was shown to accurately reflect the hydrolysis of native ATP by various classes of ENPP1 inhibitors. AMP-pNP can be used as a substrate for ENPP-1. The hydrolysis products were nucleotide-5'-monophosphate and p-nitrophenol, which is also a color-developing product. The amount of p-nitrophenol product formed was measured using absorbance at 405 nm, which is directly proportional to the enzymatic activity of ENPP-1.

[0319] I C 50 For the determination of OD values, 12 different concentrations of each inhibitor were prepared at a final assay concentration starting from 9000 nM and serially diluted 3x with 50 mM Tris buffer (pH 9.5) containing 250 mM NaCl. A 50 μL solution of 35 ng of human soluble ENPP1 was loaded into the wells and incubated with 25 μL of inhibitor solution (4x final concentration) for 30 min at room temperature, after which 25 μL of 3 mM TMP solution (2x final concentration) was added to the wells and incubated for 1 h at room temperature. The amount of p-nitrophenolate released was measured by reading the OD value at 405 nm.

[0320] The percent inhibition for each compound was calculated as follows: % Inhibition = (OD MAX -OD 化合物 ) / (OD MAX -OD MIN )*100 (MAX: no NPP1 inhibitor control, MIN: blank control).

[0321] IC for percent inhibition vs. compound concentration 50 IC values ​​are determined by fitting inhibition curves with a four-parameter mixed slope model in GraphPad Prism® 8. Determined IC 50 The values ​​are listed in Table 2. [Table 2-1] [Table 2-2] [Table 2-3]

[0322] Example B3: Quantification of 2'3'-cGAMP hydrolysis When ENPP-1 uses 2'3'-cGAMP as a substrate, hydrolysis products of 5'-GMP and 5'-AMP are formed. In some cases, ENPP1 activity with the 2'3'-cGAMP substrate was measured using the AMP-Glo ​​assay to quantify the production of 5'-AMP. TM Measured using an assay kit (Promega). AMP-Glo TM The assay kit contains two reagents that are added sequentially: Reagent I converts the 5'-AMP produced in the reaction to 5'ADP, and Reagent II converts 5'-ADP to 5'-ATP, which reacts with the luciferase / luciferin pair to generate a luminescent signal.

[0323] The ENPP1 assay with 2'3'-cGAMP substrate is carried out in 50 mM Tris buffer (pH 9.5) containing 250 mM NaCl. 12 different concentrations of each inhibitor are prepared with a final assay concentration starting at 9000 nM and serially diluted 3x. Duplicate wells are prepared at each inhibitor concentration. The final assay volume is 18 μL per well in a 384 white assay plate containing 9 μL of inhibitor solution, 4.5 μL of human recombinant ENPP-1 protein (20 ng / well) and 4.5 μL of 2',3'-cGAMP at a final concentration of 20 μM. The assay is started by the addition of the substrate and after 2 h of incubation at room temperature, 5 μL is removed and mixed with 5 μL of Reagent I to stop the reaction. Then 10 μL of Reagent II is added and the wells are again incubated at room temperature for another 60 min. The luminescence signal is measured using a plate reader equipped with a luminometer.

[0324] The percent inhibition for each compound was calculated as follows: % Inhibition = (RLU MAX -RLU 化合物 ) / (RLU MAX -RLU MIN )*100 (MAX: no ENPP1 inhibitor control, MIN: blank control).

[0325] Example B4: Cellular enzyme assay of ENPP-1 inhibitors using TMP-pNP as substrate ENPP-1 is mainly expressed on the cell membrane surface, where it hydrolyzes 2'3'-cGAMP to form 5'-GMP and 5'-AMP. ENPP-1 also has the ability to hydrolyze the artificial phosphate ester TMP-pNP to the nucleotide-5'-monophosphate and the colored product p-nitrophenol. Therefore, TMP-pNP was used as a substrate to reflect the enzymatic activity of ENPP1 in cultured MDA-MB-231, HEK293 and / or Saos-2 cells. The amount of p-nitrophenol product formed was measured using absorbance at 405 nm, which is directly proportional to the enzymatic activity of ENPP-1. The lower the OD value at 405, the more effective the ENPP-1 inhibitor.

[0326] Eight different concentrations of each inhibitor were prepared with a final assay concentration starting at 20 μM. A 3× serial dilution with DMEM medium without FBS was applied. 75000 cells per well were incubated in DMEM for 24 hours at 37°C and 5% CO2 before adding the inhibitors. After removing the supernatant medium, 50 μL of inhibitor solution was added to each well with the cultured cells and incubated for 60 minutes at 37°C and 5% CO2. Then, 4 mM (2× final concentration) TMP-pNP solution was mixed with the inhibitors in each well for 5 hours, after which the OD values ​​at 405 nm were read using a plate reader.

[0327] IC for percent inhibition vs. compound concentration 50 Values ​​are determined by fitting inhibition curves with a four-parameter mixed slope model in GraphPad Prism® 8. [Table 3-1] [Table 3-2] [Table 4] [Table 5]

[0328] Example B5: ENPP1 inhibitor screening against cGAMP-activated THP-1 cells Count THP-1 cells from bulk culture and culture 5.5 x 10 6 THP-1 cells were suspended in RPMI 1640, 20% FBS, 2.5 mM L-alanyl-L-glutamine at a concentration of 1 × 10 cells / mL. Then, THP-1 cells were plated in a 96-well round-bottom plate at 180 μL / well (1 × 10 cells per well). 6 Cells) and incubated at 37°C, 5% CO2 for 1 hour.

[0329] Test compounds were screened in triplicate on THP-1 cells at a final concentration of 10 μM. Working dilutions were 0.2 mM. Each well contained 180 μL of THP-1 cell suspension, 10 μL (30 μM, 40 μM or 50 μM) of 2'3'-cGAMP (InvivoGen, Cat. No. tlrl-nacga23) solution (600 μM, 800 μM or 1000 μM) and 10 μL of test compound working solution. Incubated for 1 h.

[0330] Vehicle control wells contain 2'3'-cGAMP at concentrations of 30 μM and 50 μM without any test compound. Positive controls, 2'3'-cGAMP or 2',3'-cGAM(PS)2(Rp / Sp) (InvivoGen, Cat. No. tlrl-nacga2srs), are at 40 μM and 80 μM (final concentrations).

[0331] The final assay volume was 200 μL / well, containing: 1) THP-1 cells = 180 μL, 2) test compound = 10 μL, 3) 2'3'-cGAMP or 2'3'-cGAM(PS)2(Rp / Sp) or vehicle control = 10 μL.

[0332] After 24 h incubation at 37° C., 5% CO2, the supernatants were harvested at 200×g for 10 min. Cell culture supernatants were then transferred to clean plates and stored at −80° C. until ready for analysis of IFN-β levels. IFN-β levels in cell culture supernatants were determined by ELISA kit (PBL Assay Science, Cat. No. 41410) according to the manufacturer's instructions.

[0333] The % increase measured for IFN-β in cells treated with test compounds 12, 48, 89, 103 and 121 compared to untreated cells was examined (shown in Figures 1A-1E). The test compounds potently increased IFN-β levels at very high concentrations.

[0334] Example B6: Liver microsome stability A liver microsome assay was used to evaluate the metabolic stability of I-VI. Test substances at a concentration of 1 μM were incubated with 0.5 mg / mL liver microsomes in the presence of NADPH and UDPGA as cofactors for 0, 15, 30, 45 and 60 min. Incubation was performed at 37°C with 5% CO2 and saturated humidity. The disappearance of the test substances was monitored by LC / MS / MS. The elimination half-life (t 1 / 2 ), and intrinsic clearance and hepatic removal rates were determined. [Table 6]

[0335] Example B6: Pharmacokinetics in mice Dosing solutions of test samples were prepared at 1.0 mg / mL in 5% DMSO / 40% PEG400 / 55% water and administered to male CD-1 mice (4-6 weeks old, 20-30 grams, 3 animals per group) at 1 mg / kg by intravenous (IV) bolus and 5 mg / kg by oral gavage (PO). Blood samples (approximately 0.03 mL at each time point) were collected via the jugular vein into tubes containing sodium heparin as an anticoagulant at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after IV administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after PO administration. Blood samples were then centrifuged for 5 minutes in a centrifuge cooled to 4°C. The plasma samples obtained were analyzed using LC / MS / MS to determine the concentrations of the test samples. TM Pharmacokinetic (PK) parameters were calculated using a non-compartmental model with the Pharmacokinetics (Pharmacokinetics) Software (Version 8.0). The PK results are listed in Table 5. Compared with the quinoline analogue of compound 12, most of the naphthyridine analogues showed significant improvements in terms of clearance, AUC, half-life and oral bioavailability. [Table 7]

[0336] It should be understood that the present invention is not limited to the specific embodiments and aspects disclosed above, as variations of the specific embodiments and aspects may be made and still fall within the scope of the appended claims. All documents cited or referred to herein are expressly incorporated by reference.

Claims

1. Formula (I): 【Chemistry 1】 [During the ceremony, L １ is a bond; L ２ is CR １ R2, where R 1 and R 2 are independently selected from the group consisting of H and C 1 -C 6 alkyl; Q1 is CH; A 2 is N, A 3 is C-C 1 -C 4 alkoxy, A 4 is CH, and A 5 is CH; X is NR3, where R3 is H or C1-C6 alkyl; Z is P(O)(OR ５ )2, and R 5 is independently H or C 1 -C 6 alkyl; Ring A is phenyl, wherein said phenyl of Ring A is optionally selected from halogen, CN, C １ -C ３ Alkyl and C １ -C ４ alkoxy, wherein the C １ -C ３ Alkyl and C １ -C ４ The alkoxy may be independently optionally substituted with one or more halogens. or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

2. The compound according to claim 1, or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof, wherein A3 is C-OMe.

3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof, wherein R5 is H.

4. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof, wherein halogen is F.

5. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, wherein the compound is selected from the group consisting of: 【Chemistry 2】

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof and one or more pharma- ceutically acceptable carriers.

7. A pharmaceutical composition for treating an uncontrolled cell proliferation disorder associated with ENPP1, comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

8. A pharmaceutical composition for treating disorders associated with skeletal and soft tissue mineralization comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

9. A pharmaceutical composition for treating disorders associated with ENPP1 genetic alterations, including Cole's disease, infantile generalized arterial calcification and hypophosphatemic rickets, comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

10. A pharmaceutical composition for treating a subject having a viral infection, comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

11. The pharmaceutical composition according to claim 10, wherein the viral infection is caused by an RNA virus.

12. The pharmaceutical composition according to claim 10, wherein the viral infection is caused by a DNA virus.

13. The method of claim 10, wherein the viral infection is caused by a retrovirus. Pharmaceutical compositions.

14. A pharmaceutical composition for treating a subject having a bacterial infection, comprising a compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

15. The pharmaceutical composition of claim 14, wherein the bacterial infection is caused by a gram-positive bacterium.

16. The pharmaceutical composition of claim 14, wherein the bacterial infection is caused by a gram-negative bacterium.

17. A pharmaceutical composition for treating cancer, comprising a compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

18. 18. The pharmaceutical composition of claim 17, wherein the cancer is a hematological malignancy.

19. 19. The pharmaceutical composition of claim 18, wherein the hematological malignancy is leukemia, lymphoma or myeloma.

20. 20. The pharmaceutical composition of claim 19, wherein the hematological malignancy is a B-cell malignancy.

21. 20. The pharmaceutical composition of claim 19, wherein the hematological malignancy is a T-cell malignancy.

22. 20. The pharmaceutical composition of claim 19, wherein the hematological malignancy is multiple myeloma.

23. The pharmaceutical composition of claim 17 , wherein the cancer is a solid tumor in the subject.

24. 24. The pharmaceutical composition of claim 23, wherein the solid tumor is breast cancer, lung cancer, melanoma, pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, ovarian cancer, head and neck cancer or sarcoma.

25. The pharmaceutical composition according to claim 17, wherein the cancer is a recurrent or refractory cancer.

26. The pharmaceutical composition of claim 17, wherein the cancer is a metastatic cancer.

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