Phosphodiesterase inhibitors and uses thereof

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 to treat or prevent disorders associated with ENPP1.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 904,501, filed on September 23, 2019, and U.S. Provisional Patent Application No. 62 / 968,755, filed on January 31, 2020, the disclosures of each of which are incorporated herein by reference in their entireties. Technical Field

[0003] The present disclosure generally relates to compounds and compositions useful as phosphodiesterase inhibitors. Background Art

[0004] The ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family consists of seven members (ENNP1-7), which are membrane-bound glycoproteins or exoenzymes with active sites or as soluble proteins in body fluids. Among them, ENPP1 (plasmacytic membrane glycoprotein, also known as PC-1) is involved in many physiological processes (such as development, formation and transportation) and pathophysiological conditions. ENPP1 may use nucleotides and nucleotide derivatives as substrates and hydrolyze them to form nucleoside-5' monophosphate. ATP is an identified ENPP1 substrate, 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, ENPP1 also uses artificial phosphates p-nitrophenyl 5'-thymidine monophosphate (TMP-pNP) and p-nitrophenyl 5'-adenosine monophosphate (AMP-pNP) as substrates.

[0005] ENPP1 is a type II transmembrane glycoprotein originally identified as a negative regulator of bone mineralization. It is expressed on the extracellular membrane of osteoblasts and chondrocytes and hydrolyzes extracellular ATP to produce AMP and diphosphate (a bone mineralization inhibitor) (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 produces AMP, which is then metabolized by the ecto-5'-nucleotidase CD73 to immunosuppressive adenosine (Ferretti, E., Immunol. Lett. 2018, 3, 307). In animal models, ENPP1 inhibits insulin receptor tyrosine kinase activity in peripheral tissues, which are the main targets of insulin action (Abate, N. et al. Nature Clin. Pract. Endocrinol. Metab. 2006, 2, 694-701). Abnormal ENPP1 expression has also been reported in breast cancer, Hodgkin's lymphoma, hepatocellular carcinoma, follicular lymphoma, glioblastoma and other malignant tumor tissues.

[0006] In recent years, it has been found that ENPP1 plays an important role in cancer immunity. Li et al. reported that ENPP1 is the main 2'3'-cGAMP (which breaks it down into 5'-AMP and 5'-GMP) hydrolase. 2'3'-cGAMP is the most effective natural agonist of the interferon gene stimulator (STING) pathway, which is a central pathway for antiviral and anticancer innate immunity. 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) acts as an endogenous second messenger in response to cytoplasmic double-stranded DNA. It binds and activates STING to stimulate the production of type I interferon (IFN) and other cytokines, followed by antiviral and anti-tumor immune responses (Manas Sharma et al. Int J cell Sci&Mol Biol., 2018, 5, 555655). Therefore, ENPP1 inhibitors block 2'3'-cGAMP hydrolysis, subsequently enhance cGAMP-induced STING pathway activation and stimulate anti-tumor immune responses.

[0007] Therefore, there is a need to develop ENPP inhibitors for use as therapeutic agents. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figures 1A, 1B, 1C, 1D, and 1E show the % increase in IFN-β measured in cells treated with representative compounds 12, 48, 89, 103, and 121 relative to untreated cells. Summary of the invention

[0009] In one aspect, provided is a compound of formula (A):

[0010]

[0011] or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein each variable is as detailed herein.

[0012] Also disclosed herein are compounds of formula (I)-(VI):

[0013]

[0014]

[0015]

[0016] or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein each variable is as detailed herein.

[0017] In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof has Formula (I)-(VI) as detailed herein.

[0018] In another aspect, a method of treating or preventing an ENPP1-related disorder of uncontrolled cell proliferation, a bone and soft tissue mineralization-related disorder, a disorder associated with ENPP1 gene alterations, a viral infection, and / or cancer is provided.

[0019] In some embodiments, a method of treating a disorder or disease is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (A) (including compounds of formula (I)-(VI)) or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0020] Also provided are pharmaceutical compositions comprising: (A) a compound as described in detail herein, such as a compound of formula (A), including a compound of formula (I)-(VI), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; and (B) a pharmaceutically acceptable carrier or excipient. Also provided are kits comprising a compound as described in detail herein or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof and optionally instructions for use.

[0021] Compounds as detailed herein or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof are provided for use as medicaments. Compounds as detailed herein or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof are also provided for use in the manufacture of medicaments for treating or preventing disorders of uncontrolled cell proliferation associated with ENPP1, such as cancer. DETAILED DESCRIPTION

[0022] definition

[0023] As used herein, the use of the terms "a," "an," etc. means one or more than one, unless expressly indicated otherwise.

[0024] References herein to "about" a value or parameter include (and describe) embodiments directed to that value or parameter itself. For example, description referring to "about X" includes description of "X".

[0025] Unless otherwise indicated, as used herein, "alkyl" refers to and includes saturated straight chain (ie, unbranched) or branched monovalent hydrocarbon chains, or combinations thereof, having a specified number of carbon atoms (ie, C 1 -C 10 Specific alkyl groups are groups having 1 to 20 carbon atoms (“C 1 -C 20 alkyl”), having 1 to 10 carbon atoms (“C 1 -C 10 alkyl”), having 6 to 10 carbon atoms (“C 6 -C 10 alkyl”), having 1 to 6 carbon atoms (“C 1 -C 6 alkyl”), having 2 to 6 carbon atoms (“C 2 -C 6 alkyl") or having 1 to 4 carbon atoms ("C 1 -C 4 Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0026] Unless otherwise indicated, as used herein, "cycloalkyl" refers to and includes a saturated cyclic monovalent hydrocarbon structure having the specified number of carbon atoms (i.e., C 3 -C 10Cycloalkyl groups may be composed of one ring (such as cyclohexyl) or multiple rings (such as adamantyl). Cycloalkyl groups containing more than one ring may be fused, spirocyclic or bridged, or a combination thereof. Specific cycloalkyl groups are those having from 3 to 12 ring carbon atoms. Preferred cycloalkyl groups are those having from 3 to 8 ring carbon atoms ("C 3 -C 8 cycloalkyl”), having 3 to 6 carbon atoms (“C 3 -C 6 cycloalkyl”), or having from 3 to 4 ring carbon atoms (“C 3 -C 4 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0027] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having from 1 to 14 ring carbon atoms and at least one ring heteroatom (including but not limited to heteroatoms, such as nitrogen, oxygen and sulfur). Heteroaryl can have a monocyclic ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl), which may or may not be aromatic. Specific heteroaryl is a 5 to 14-membered ring with 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5 to 10-membered ring with 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5, 6 or 7-membered ring with 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, specific heteroaryl is a monocyclic aromatic 5, 6 or 7 rings with 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, specific heteroaryl is a polycyclic aromatic ring with 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. Heteroaryl with more than one ring can be connected to the parent structure at an aromatic ring position or a non-aromatic ring position, wherein at least one ring is non-aromatic. In a variation, heteroaryl with more than one ring is connected to the parent structure at an aromatic ring position, wherein at least one ring is non-aromatic. Heteroaryl can be connected to the parent structure at a ring carbon atom or a ring heteroatom.

[0028] As used herein, "heterocycle", "heterocyclic" or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having a single ring or multiple fused rings and having from 1 to 14 ring carbon atoms and from 1 to 6 ring heteroatoms (such as nitrogen, sulfur or oxygen), etc. Heterocycles containing more than one ring may be fused, bridged or spirocyclic or any combination thereof, but do not include heteroaryl. Heterocyclyl may be optionally substituted independently by one or more substituents described herein. Particular heterocyclyl groups are 3 to 14 membered rings having 1 to 13 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12 membered rings having 1 to 11 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10 membered rings having 1 to 9 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8 membered rings having 1 to 7 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6 membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, heterocyclyl includes monocyclic 3, 4, 5, 6, or 7 membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 ring carbon atoms and 1 to 2, 1 to 3, or 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0029] "Halo" or "halogen" refers to an element of the Group 17 series with an atomic number of 9 to 85. Preferred halides include groups of fluorine, chlorine, bromine and iodine. When a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached, for example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halides, which may be, but are not necessarily, the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced by a halide is referred to as a "perhaloalkyl group". A preferred perhaloalkyl group is trifluoromethyl (-CF 3 ).

[0030] "Oxo" refers to the moiety =0.

[0031] Unless otherwise specified, "optionally substituted" means that the group can be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for the group, wherein the substituents can be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In some embodiments, the optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In some embodiments, the optionally substituted group is unsubstituted.

[0032] "Pharmaceutically acceptable salts" are those salts that retain at least some of the biological activity of the free (non-salt) compound and can be administered to an individual as a drug or pharmaceutical. 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 when an acid proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or coordinated 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 can be prepared in situ during the manufacturing process, or by reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during a subsequent purification process.

[0033] "Pharmaceutically acceptable carrier" refers to ingredients in a pharmaceutical formulation other than the active ingredient that are non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers or preservatives.

[0034] As used herein, the term "excipient" means an inert or inactive substance that can be used to produce a drug or pharmaceutical product (such as a tablet containing the compound of the present invention as an active ingredient). The term excipient can include a variety of substances, including but not limited to any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, material for chewable tablets, sweetener or flavoring agent, suspending agent / 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, cross-linked sodium carboxymethylcellulose, gellan gum, sodium starch glycolate, etc.; lactose Pastes or lotions include, for example, maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, for example, dextrose, fructose DC, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending agents / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, fructose, sorbitol, sucrose DC, etc.; and wet granulating agents include calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0035] As used herein, "treatment" or "treating" is a method for obtaining beneficial or desired results (including clinical results). For example, beneficial or desired results include, but are not limited to, one or more of the following: reducing symptoms caused by the disease, improving the quality of life of patients with the disease, reducing the dose of other drugs required to treat the disease, delaying the progression of the disease, and / or prolonging the survival of the 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 significantly reduce the likelihood or severity of a disorder or its biological manifestations, or to delay the onset of such a disorder or its biological manifestations.

[0036] As used herein, an "effective dose" or "effective amount" of a compound, or salt thereof, or pharmaceutical composition is an amount sufficient to achieve a beneficial or desired result. For prophylactic use, beneficial or desired results include results such as: eliminating or reducing risk, reducing severity, or delaying the onset of the disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presented during the development of the disease. For therapeutic use, beneficial or desired results include results such as: improving, alleviating, alleviating, delaying, or reducing one or more symptoms caused by the disease; improving the quality of life of those suffering from the disease; reducing the dose of other drugs required to treat the disease; such as enhancing the effect of another drug via targeting, delaying the progression of the disease, and / or prolonging survival. In some embodiments, an effective amount is an amount sufficient to delay development. In some embodiments, an effective amount is an amount sufficient to prevent or delay recurrence. The effective dose may be administered in one or more administrations. For the purposes of this disclosure, an effective dose of a compound, or salt thereof, or pharmaceutical composition is an amount sufficient to accomplish a prophylactic or therapeutic treatment directly or indirectly. It is contemplated and understood that an effective dose of a compound or salt thereof or pharmaceutical composition may or may not be achieved in combination with another drug, compound or pharmaceutical composition. Thus, an "effective dose" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if the desired result can be achieved or achieved in combination with one or more other agents.

[0037] As used herein, the term "subject" is a mammal, including a human. Subjects include, but are not limited to, humans, cattle, horses, cats, dogs, rodents, or primates. In some embodiments, the subject is a human (including adults and children).

[0038] Unless otherwise indicated, "substantially pure" refers to a composition containing no more than 10% impurities, such as a composition containing less than about 9%, 7%, 5%, 3%, 1%, 0.5% impurities.

[0039] It should be understood that the aspects and variations described herein also include "consisting of" and / or "consisting essentially of" the aspects and variations.

[0040] All references cited throughout the text, such as publications, patents, patent applications, and published patent applications, are incorporated herein by reference in their entirety.

[0041] Compound

[0042] In one aspect, the present invention provides a compound of formula (A):

[0043]

[0044] or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein:

[0045] L 1 Yes key, O, CR 1 R 2 NR 3 or *CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A;

[0046] L 2 Yes key, CR 1 R 2 or C(=O);

[0047] Q 1 , Q 2 , Q 3 , Q 4 and Q 5 are independently N, C or CE,

[0048] A 2 , A 3 , A 4 and A 5 Independently N or CR 4 ;

[0049] X is S, O, CR 1 R 2 , CE, N or NR 3 ;

[0050] Z is SO 2 NHR 5 、SO 2 R 5 、C(O)OH、C(O)NHR 5 、C(O)NHOR 5 、P(O)(OR 5 ) 2 or B(OH) 2 ;

[0051] E is independently selected at each occurrence from hydrogen, deuterium, halogen, oxo, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 4 Alkoxy, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 、N(C 1 -C 6 alkyl) 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, 3-8 membered heterocyclic group, -C(O)-C 1 -C 4 Alkoxy, -C(O)-NH 2 and -S(O) 2 -C 1 -C 6 alkyl;

[0052] R 1 and R 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl, wherein the C 1 -C 6 Alkyl and C 3 -C 8 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy, or R 1 and R 2 Together they form C 3 -C 6 Cycloalkyl;

[0053] R 3 and R 3 ' is independently selected from hydrogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl and 3-8 membered heterocyclic group, wherein the C 1 -C 6 Alkyl and C 3 -C 6 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0054] R 4 Selected from hydrogen, deuterium, halogen, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0055] R 5 is independently selected at each occurrence from hydrogen, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group and -C(=O)-C 1 -C 6 Alkyl, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are independently optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 haloalkoxy; and

[0056] Ring A is C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 aryl or 5- to 10-membered heteroaryl, wherein the C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 Aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 The alkoxy groups are independently optionally substituted with one or more halogens; and

[0057] Indicates whether Ring B is fully unsaturated or partially unsaturated.

[0058] In some embodiments, provided herein is a compound of formula (A), wherein Q 2 It's C, Q 3 is CE, where E is an oxo group, Q 4 is N and Q 5 is C, such that the compound of formula (A) is a compound of formula (I):

[0059]

[0060] or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein:

[0061] L 1 Yes key, O, CR 1 R 2 NR 3 or *CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A;

[0062] L 2 Yes key, CR 1 R 2 or C(=O);

[0063] Q 1 is N or CE;

[0064] A 2 , A 3 , A 4 and A 5 Independently N or CR 4 ;

[0065] X is S, O, CR 1 R 2 or NR 3 ;

[0066] Z is SO 2 NHR 5 、SO 2 R 5 、C(O)OH、C(O)NHR 5、C(O)NHOR 5 、P(O)(OR 5 ) 2 or B(OH) 2 ;

[0067] E is selected from hydrogen, deuterium, halogen, oxo, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 4 Alkoxy, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 、N(C 1 -C 6 alkyl) 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, 3-8 membered heterocyclic group, -C(O)-C 1 -C 4 Alkoxy, -C(O)-NH 2 and -S(O) 2 -C 1 -C 6alkyl;

[0068] R 1 and R 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl, wherein the C 1 -C 6 Alkyl and C 3 -C 8 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy, or R 1 and R 2 Together they form C 3 -C 6 Cycloalkyl;

[0069] R 3 and R 3 ' is independently selected from hydrogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl and 3-8 membered heterocyclic group, wherein the C 1 -C 6 Alkyl and C 3 -C 6 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0070] R 4 Selected from hydrogen, deuterium, halogen, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R3 ',-SO 2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0071] R 5 is independently selected at each occurrence from hydrogen, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group and -C(=O)-C 1 -C 6 Alkyl, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are independently optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3Haloalkyl and C 1 -C 3 haloalkoxy; and

[0072] Ring A is C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 aryl or 5- to 10-membered heteroaryl, wherein the C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 Aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy groups are independently optionally substituted with one or more halogens.

[0073] In some embodiments, provided herein is a compound of formula (A), wherein Q 2 It's C, Q 3 Yes CE, Q 4 Yes N, Q 5 is C and X is N, such that the compound of formula (A) is a compound of formula (II):

[0074]

[0075] or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein:

[0076] L 1 Yes key, O, CR 1 R 2 NR 3 or *CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A;

[0077] L 2 Yes key, CR 1 R 2 or C(=O);

[0078] Q 1 is N or CE;

[0079] A 2 , A3 , A 4 and A 5 Independently N or CR 4 ;

[0080] Z is SO 2 NHR 5 、SO 2 R 5 、C(O)OH、C(O)NHR 5 、C(O)NHOR 5 、P(O)(OR 5 ) 2 or B(OH) 2 ;

[0081] E is independently selected at each occurrence from hydrogen, deuterium, halogen, oxo, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 4 Alkoxy, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 、N(C 1 -C 6 alkyl) 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, 3-8 membered heterocyclic group, -C(O)-C 1 -C 4 Alkoxy, -C(O)-NH 2 and -S(O) 2 -C 1 -C 6 alkyl;

[0082] R 1 and R 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl, wherein the C 1 -C 6 Alkyl and C 3 -C 8 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy, or R 1 and R 2 Together they form C 3 -C 6 Cycloalkyl;

[0083] R 3 and R 3 ' is independently selected from hydrogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl and 3-8 membered heterocyclic group, wherein the C 1 -C 6 Alkyl and C 3 -C 6 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3Haloalkoxy;

[0084] R 4 Selected from hydrogen, deuterium, halogen, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0085] R 5 is independently selected at each occurrence from hydrogen, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group and -C(=O)-C 1 -C 6 Alkyl, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are independently optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 haloalkoxy; and

[0086] Ring A is C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 aryl or 5- to 10-membered heteroaryl, wherein the C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 Aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy groups are independently optionally substituted with one or more halogens.

[0087] In some embodiments, a compound of formula (A) is provided, wherein Q 2 It's C, Q 4 Yes N, Q 5 is C and X is CE, such that the compound of formula (A) is a compound of formula (III):

[0088]

[0089] or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein:

[0090] L 1 Yes key, O, CR 1 R 2 NR 3 or *CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A;

[0091] L 2 Yes key, CR 1 R 2 or C(=O);

[0092] Q 1 is N or CE;

[0093] Q 3 is N or CE;

[0094] A 2 , A 3 , A 4 and A 5 Independently N or CR 4 ;

[0095] Z is SO 2 NHR 5 、SO 2 R 5 、C(O)OH、C(O)NHR 5 、C(O)NHOR 5 、P(O)(OR 5 ) 2 or B(OH) 2 ;

[0096] E is independently selected at each occurrence from hydrogen, deuterium, halogen, oxo, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 4 Alkoxy, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 、N(C 1 -C 6 alkyl) 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, 3-8 membered heterocyclic group, -C(O)-C 1 -C 4 Alkoxy, -C(O)-NH 2 and -S(O) 2 -C 1 -C 6 alkyl;

[0097] R 1 and R 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl, wherein the C 1 -C 6 Alkyl and C 3 -C 8 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy, or R 1 and R 2 Together they form C 3 -C 6 Cycloalkyl;

[0098] R 3 and R 3 ' is independently selected from hydrogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl and 3-8 membered heterocyclic group, wherein the C 1 -C 6Alkyl and C 3 -C 6 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0099] R 4 Selected from hydrogen, deuterium, halogen, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0100] R 5is independently selected at each occurrence from hydrogen, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group and -C(=O)-C 1 -C 6 Alkyl, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are independently optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 haloalkoxy; and

[0101] Ring A is C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 aryl or 5- to 10-membered heteroaryl, wherein the C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 Aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy groups are independently optionally substituted with one or more halogens.

[0102] In some embodiments, a compound of formula (A) is provided, wherein Q 2 It's C, Q 3 Yes N, Q 4 Yes N, Q 5 is C and X is N, such that the compound of formula (A) is a compound of formula (IV):

[0103]

[0104] or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein:

[0105] L 1 Yes key, O, CR 1 R 2 NR 3 or *CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A;

[0106] L 2 Yes key, CR 1 R 2 or C(=O);

[0107] Q 1 is N or CE;

[0108] A 2 , A 3 , A 4 and A 5 Independently N or CR 4 ;

[0109] Z is SO 2 NHR 5 、SO 2 R 5 、C(O)OH、C(O)NHR 5 、C(O)NHOR 5 、P(O)(OR 5 ) 2 or B(OH) 2 ;

[0110] E is selected from hydrogen, deuterium, halogen, oxo, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C2 -C 6 Alkynyl, C 1 -C 4 Alkoxy, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 、N(C 1 -C 6 alkyl) 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, 3-8 membered heterocyclic group, -C(O)-C 1 -C 4 Alkoxy, -C(O)-NH 2 and -S(O) 2 -C 1 -C 6 alkyl;

[0111] R 1 and R 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl, wherein the C 1 -C 6 Alkyl and C 3 -C 8 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy, or R 1 and R2 Together they form C 3 -C 6 Cycloalkyl;

[0112] R 3 and R 3 ' is independently selected from hydrogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl and 3-8 membered heterocyclic group, wherein the C 1 -C 6 Alkyl and C 3 -C 6 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0113] R 4 Selected from hydrogen, deuterium, halogen, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0114] R 5 is independently selected at each occurrence from hydrogen, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group and -C(=O)-C 1 -C 6 Alkyl, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are independently optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 haloalkoxy; and

[0115] Ring A is C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 aryl or 5- to 10-membered heteroaryl, wherein the C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 Aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1-C 4 Alkoxy groups are independently optionally substituted with one or more halogens.

[0116] In some embodiments, a compound of formula (A) is provided, wherein Q 2 It's C, Q 3 Yes N, Q 4 It is C and Q 5 is N, such that the compound of formula (A) is a compound of formula (V):

[0117]

[0118] or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein:

[0119] L 1 Yes key, O, CR 1 R 2 NR 3 or *CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A;

[0120] L 2 Yes key, CR 1 R 2 or C(=O);

[0121] Q 1 and X are independently N or CE;

[0122] A 2 , A 3 , A 4 and A 5 Independently N or CR 4 ;

[0123] Z is SO 2 NHR 5 、SO 2 R 5 、C(O)OH、C(O)NHR 5 、C(O)NHOR 5 、P(O)(OR 5 ) 2 or B(OH) 2 ;

[0124] E is selected from hydrogen, deuterium, halogen, oxo, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 4 Alkoxy, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 、N(C 1 -C 6 alkyl) 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, 3-8 membered heterocyclic group, -C(O)-C 1 -C 4 Alkoxy, -C(O)-NH 2 and -S(O) 2 -C 1 -C 6 alkyl;

[0125] R 1 and R 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl, wherein the C 1 -C 6 Alkyl and C 3 -C 8The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy, or R 1 and R 2 Together they form C 3 -C 6 Cycloalkyl;

[0126] R 3 and R 3 ' is independently selected from hydrogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl and 3-8 membered heterocyclic group, wherein the C 1 -C 6 Alkyl and C 3 -C 6 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0127] R 4 Selected from hydrogen, deuterium, halogen, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0128] R 5 is independently selected at each occurrence from hydrogen, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group and -C(=O)-C 1 -C 6 Alkyl, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are independently optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 haloalkoxy; and

[0129] Ring A is C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 aryl or 5- to 10-membered heteroaryl, wherein the C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C6 -C 14 Aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy groups are independently optionally substituted with one or more halogens.

[0130] In some embodiments, a compound of formula (A) is provided, wherein Q 2 Yes N, Q 4 It is C and Q 5 is C, such that the compound of formula (A) is a compound of formula (VI):

[0131]

[0132] or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein:

[0133] L 1 Yes key, O, CR 1 R 2 NR 3 or *CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A;

[0134] L 2 Yes key, CR 1 R 2 or C(=O);

[0135] Q 1 , Q 3 and X are independently N or CE;

[0136] A 2 , A 3 , A 4 and A 5 Independently N or CR 4 ;

[0137] Z is SO 2 NHR 5 、SO 2 R 5 、C(O)OH、C(O)NHR 5 、C(O)NHOR 5 、P(O)(OR5 ) 2 or B(OH) 2 ;

[0138] E is independently selected at each occurrence from hydrogen, deuterium, halogen, oxo, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 4 Alkoxy, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 、N(C 1 -C 6 alkyl) 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl, C 1 -C 3 Haloalkoxy, 3-8 membered heterocyclic group, -C(O)-C 1 -C 4 Alkoxy, -C(O)-NH 2 and -S(O) 2 -C 1 -C 6 alkyl;

[0139] R 1 and R 2 are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl and C 3 -C 8 Cycloalkyl, wherein the C 1 -C 6 Alkyl and C 3 -C 8 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy, or R 1 and R 2 Together they form C 3 -C 6 Cycloalkyl;

[0140] R 3 and R 3 ' is independently selected from hydrogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl and 3-8 membered heterocyclic group, wherein the C 1 -C 6 Alkyl and C 3 -C 6 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0141] R 4 Selected from hydrogen, deuterium, halogen, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO2 R 3 、-SO 2 NR 3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 Haloalkoxy;

[0142] R 5 is independently selected at each occurrence from hydrogen, C 1 -C 6 Alkyl, C 3 -C 8 Cycloalkyl, 3-8 membered heterocyclic group and -C(=O)-C 1 -C 6 Alkyl, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are independently optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1-C 3 haloalkoxy; and

[0143] Ring A is C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 aryl or 5- to 10-membered heteroaryl, wherein the C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 Aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy groups are independently optionally substituted with one or more halogens.

[0144] In some embodiments, provided herein is a compound of formula (A) (e.g., a compound of formula (I)-(VI)) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein the ring is fully unsaturated. 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 a 5-membered cycloalkyl.

[0145] In some embodiments, provided herein is a compound of formula (A) (eg, a compound of formula (I)-(VI)) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein A 2 , A 3 , A 4 and A 5 Each independently is N or CR 4 , where R 4 is independently selected at each occurrence from hydrogen, deuterium, halogen, -CN, -OR 3 、-NO 2 、-NR 3 R 3 '、-C(O)R 3 、-C(O)OR 3 、-C(O)NR 3 R 3 ',-SO 2 R 3 、-SO 2 NR3 R 3 '、C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 8 Cycloalkyl and 3-8 membered heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl, phenyl, C 1 -C 4 Alkoxy, C 1 -C 3 Haloalkyl and C 1 -C 3 In some embodiments, A 2 , A 3 , A 4 and A 5 Each is independently CR 4 , where R 4 Independently of each other and independently at each occurrence are H, C 1 -C 4 Alkoxy or CN. In some embodiments, A 2 It is CH, A 3 Yes CC 1 -C 4 Alkoxy, A 4 Yes CC 1 -C 4 Alkoxy and A 5 is CH. In some embodiments, A 2 It is CH, A 3 Is C-OMe, A 4 is C-OMe and A 5 is CH. In some embodiments, A 2 It is CH, A 3 Yes CC 1 -C 4 Alkoxy, A 4 is CH and A 5is CH. In some embodiments, A 2 It is CH, A 3 Is C-OMe, A 4 is CH and A 5 is CH. In some embodiments, A 2 It is CH, A 3 It is CH, A 4 Yes CC 1 -C 4 Alkoxy and A 5 is CH. In some embodiments, A 2 It is CH, A 3 It is CH, A 4 is C-OMe and A 5 is CH. In some embodiments, A 2 It is CH, A 3 Yes CC 1 -C 4 Alkoxy, A 4 is CN and A 5 is CH. In some embodiments, A 2 It is CH, A 3 Is C-OMe, A 4 is CN and A 5 is CH. In some embodiments, A 2 It is CH, A 3 Yes CC 1 -C 4 Alkoxy, A 4 is N and A 5 is CH. In some embodiments, A 2 It is CH, A 3 Is C-OMe, A 4 is N and A 5 is CH. In some embodiments, A 2 Yes N, A 3 Yes CC 1 -C 4 Alkoxy, A 4 is CH and A 5 is CH. In some embodiments, A 2 Yes N, A 3 Is C-OMe, A 4 is CH and A 5 is CH. In some embodiments, A 2 It is CH, A 3 Yes CC 1 -C 4 Alkoxy, A 4 is CH and A 5is N. In some embodiments, A 2 It is CH, A 3 Is C-OMe, A 4 is CH and A 5 is N. In some embodiments, A 2 It is CH, A 3 Yes CC 1 -C 4 Alkoxy, A 4 is N and A 5 is CH. In some embodiments, A 2 It is CH, A 3 Is C-OMe, A 4 is N and A 5 is CH. In some embodiments, A 2 Yes N, A 3 Yes CC 1 -C 4 Alkoxy, A 4 is a C-halogen and A 5 is CH. In some embodiments, A 2 Yes N, A 3 Is C-OMe, A 4 is C-Cl and A 5 It is CH.

[0146] In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein A 2 It is CH, A 3 Yes CC 1 -C 4 Alkoxy, A 4 Yes CC 1 -C 4 Alkoxy and A 5 In some embodiments, provided herein is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein A 2 It is CH, A 3 Is C-OMe, A 4 is C-OMe and A 5 In some embodiments, provided herein is a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein A 2 It is CH, A 3 Yes CC 1 -C 4 Alkoxy, A 4 Yes CC 1 -C 4 Alkoxy and A5 In some embodiments, provided herein is a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein A 2 Yes, A 3 Is C-OMe, A 4 is C-OMe and A 5 In some embodiments, provided herein is a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein A 2 Yes N, A 3 Yes CC 1 -C 4 Alkoxy, A 4 is CH and A 5 In some embodiments, provided herein is a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein A 2 Yes N, A 3 Is C-OMe, A 4 is CH and A 5 It is CH.

[0147] In some embodiments, provided herein is a compound of formula (A) (e.g., a compound of formula (I)-(VI)) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein ring A is C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 aryl or 5- to 10-membered heteroaryl, wherein the C 3 -C 8 Cycloalkyl, 3 to 12 membered heterocyclic group, C 6 -C 14 Aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy groups are independently optionally substituted with one or more halogens.

[0148] In some embodiments, provided herein is a compound of formula (A) (e.g., a compound of formula (I)-(VI)) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein ring A is C 3 -C8 Cycloalkyl, wherein the C 3 -C 8 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. In some embodiments, Ring A is cyclobutyl.

[0149] In some embodiments, provided herein is a compound of formula (A) (e.g., a compound of formula (I)-(VI)) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein ring A is a 3- to 12-membered heterocyclic group, wherein the 3- to 12-membered heterocyclic group of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted by one or more halogens. In some embodiments, ring A is a 4 to 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.

[0150] In some embodiments, provided herein is a compound of formula (A) (e.g., a compound of formula (I)-(VI)) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein ring A is C 6 -C 14 Aryl, wherein the C of the ring A 6 -C 14 The aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. 6 -C 10 In some embodiments, ring A is phenyl. In some embodiments, ring A is phenyl, wherein the phenyl group of ring A is optionally substituted with one or more halogen, CN, C 1 -C 3 Alkyl or C 1 -C 4 Alkoxy substituted, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. In some embodiments, the halogen is F.

[0151] In some embodiments, provided herein is a compound of formula (A) (e.g., a compound of formula (I)-(VI)) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein ring A is a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group of ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. 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 a pyridinyl. In other embodiments, Ring A is a pyrimidinyl. In some embodiments, Ring A is a pyridinyl or pyrimidinyl, wherein the pyridinyl or pyrimidinyl of Ring A is optionally substituted with one or more halogens, CN, C 1 -C 3 Alkyl or C 1 -C 4 Alkoxy substituted, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. In some embodiments, the halogen is F. In some embodiments, Ring A is dihydroisoquinolinyl.

[0152] In some embodiments, provided herein is a compound of formula (A) (eg, a compound of formula (I)-(VI)) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein L 1 Yes key, O, CR 1 R 2 NR 3 or *CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A. In some embodiments, L 1 is a bond. In other embodiments, L 1 Yes O, CR 1 R 2 NR 3 or *CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A. In some embodiments, L 1 is O. In certain embodiments, L 1 Yes CR 1 R 2 In some embodiments, L 1 Yes CR 1 R 2 , where R 1 and R 2 Independently selected from H and C 1 -C 6 In some embodiments, L 1 Yes CR 1 R 2 , where R 1 and R 2 In some embodiments, L 1 Yes CR 1 R 2 , where R 1 and R 2 are H. In some embodiments, L 1 Yes CR 1 R 2 , where R 1 and R 2 One of them is H and R 1 and R 2 The other one is C 1 -C 6 In some embodiments, L 1 Yes CR 1 R 2 , where R 1 and R 2 One of them is H and R 1and R 2 In other embodiments, L 1 YesNR 3 In some embodiments, L 1 YesNR 3 , where R 3 Is H or C 1 -C 6 In some embodiments, L 1 YesNR 3 , where R 3 is H. In other embodiments, L 1 YesNR 3 , where R 3 In some embodiments, L 1 Yes*CR 1 R 2 NR 3 , wherein * indicates the point of attachment to ring A. In certain embodiments, L 1 Yes*CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A, where R 1 and R 2 All are H.

[0153] In some embodiments, provided herein is a compound of formula (A) (eg, a compound of formula (I)-(VI)) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein L 1 Yes key, O, CR 1 R 2 NR 3 or *CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A, and ring A is C 6 -C 14 Aryl, wherein the C of the ring A 6 -C 14 The aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy groups are independently optionally substituted with one or more halogens.

[0154] In some embodiments, L1 is a bond and ring A is C 6 -C 14 Aryl, wherein the C of the ring A 6 -C 14 The aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. 1 is a bond and Ring A is phenyl, wherein the phenyl of Ring A is optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy groups are independently optionally substituted with one or more halogens.

[0155] In some embodiments, L 1 Yes CR 1 R 2 , where R 1 and R 2 Independently selected from H and C 1 -C 6 alkyl, and ring A is C 6 -C 14 Aryl, wherein the C of the ring A 6 -C 14 The aryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. 1 Yes CR 1 R 2 , where R1 and R 2 Independently selected from H and C 1 -C 6 alkyl, and ring A is phenyl, wherein the phenyl of ring A is optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. 1 Yes*CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A, where R 1 , R 2 and R 3 Each is H, and Ring A is phenyl, wherein the phenyl of Ring A is optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy groups are independently optionally substituted with one or more halogens.

[0156] In some embodiments, L 1 is a bond and Ring A is a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl of Ring A is optionally substituted with one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. 1 is a bond and Ring A is a 6-membered heteroaryl, wherein the 6-membered heteroaryl of Ring A is optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1-C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. 1 is a bond and Ring A is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl of Ring A is optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy groups are independently optionally substituted with one or more halogens.

[0157] In some embodiments, L 1 Yes CR 1 R 2 , where R 1 and R 2 Independently selected from H and C 1 -C 6 alkyl, and ring A is a 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl of ring A is optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. 1 Yes CR 1 R 2 , where R 1 and R 2 Independently selected from H and C 1 -C 6 alkyl, and ring A is a 6-membered heteroaryl, wherein the 6-membered heteroaryl of ring A is optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. 1 Yes CR 1 R 2 , where R 1 and R 2 Independently selected from H and C 1 -C 6 alkyl, and ring A is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl of ring A is optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is independently optionally substituted with one or more halogens. 1 Yes*CR 1 R 2 NR 3 , where * indicates the point of attachment to ring A, where R 1 , R 2 and R 3 Each is H, and Ring A is pyridinyl or pyrimidinyl, wherein the pyridinyl or pyrimidinyl of Ring A is optionally substituted by one or more substituents selected from the group consisting of halogen, CN, OH, NH 2 , C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy, wherein the C 1 -C 3 Alkyl and C 1 -C 4 Alkoxy is 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 pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein L 2 Yes key, CR 1 R 2 or C(═O). In some embodiments, L 2 is a bond. In some embodiments, L 2 is O. In certain embodiments, L 2 Yes CR 1 R2 In some embodiments, L 2 Yes CR 1 R 2 , where R 1 and R 2 Independently selected from H and C 1 -C 6 In some embodiments, L 2 Yes CR 1 R 2 , where R 1 and R 2 In some embodiments, L 2 Yes CR 1 R 2 , where R 1 and R 2 are H. In some embodiments, L 2 Yes CR 1 R 2 , where R 1 and R 2 One of them is H and R 1 and R 2 The other one is C 1 -C 6 In some embodiments, L 2 Yes CR 1 R 2 , where R 1 and R 2 One of them is H and R 1 and R 2 In some embodiments, L 2 It is C(=O).

[0158] In some embodiments, provided herein is a compound of formula (A) (such as a compound of formula (I)-(VI), as the case may be) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein X is S, O, CR 1 R 2 , CE, N or NR 3 In some embodiments, X is O, CR 1 R 2 , CE, N or NR 3 In some embodiments, X is O. In certain embodiments, X is N. In some embodiments, X is NR 3 In other embodiments, X is NR 3 , where R 3 Is H or C 1 -C 6In some embodiments, X is CE. In some embodiments, X is CE, wherein E is H or C 1 -C 6 Alkyl, wherein the C 1 -C 6 The alkyl group is optionally substituted with one or more OH, halogen, C 1 -C 4 In some embodiments, X is N or CE.

[0159] In some embodiments, provided herein is a compound of formula (A) (eg, a compound of formula (I)-(VI)) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein Z is SO 2 NHR 5 、SO 2 R 5 、C(O)OH、C(O)NHR 5 、C(O)NHOR 5 、P(O)(OR 5 ) 2 or B(OH) 2 In some embodiments, Z is SO 2 NHR 5 , where R 5 It is H, C 1 -C 6 Alkyl or -C(O)-C 1 -C 6 In some embodiments, Z is SO 2 NHR 5 , where R 5 is H. In some embodiments, Z is SO 2 R 5 In certain embodiments, Z is C(O)OH, C(O)NHR 5 or C(O)NHOR 5 In certain embodiments, Z is C(O)OH. In certain embodiments, Z is C(O)NHOR 5 , where R 5 is H. In some embodiments, Z is C(O)NHR 5 , where R 5 is H. In some embodiments, Z is B(OH) 2 In some embodiments, Z is P(O)(OR 5 ) 2 , where each R 5 independently H or C 1 -C 6In some embodiments, Z is P(O)(OR 5 ) 2 , where each R 5 Independently H.

[0160] Representative compounds are listed in Table 1. In some embodiments, provided herein is a compound of formula (A) (eg, a compound of formula (I)-(VI)) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, wherein L 1 is a key and Z is SO 2 NHR 5 , where R 5 It is H, C 1 -C 6 Alkyl or -C(O)-C 1 -C 6 In some embodiments, L 1 is a key and Z is SO 2 NHR 5 , where R 5 is H. In other embodiments, L 1 is a key and Z is SO 2 NHR 5 , where R 5 It is C 1 -C 6 Alkyl. 1 YesNR 3 , where R 3 is H, and Z is SO 2 NHR 5 , where R 5 It is H, C 1 -C 6 Alkyl or -C(O)-C 1 -C 6 In some embodiments, L 1 YesNR 3 , where R 3 is H, and Z is SO 2 NHR 5 , where R 5 is H. In some embodiments, L 1 Yes CR 1 R 2 , where R 1 and R 2 Independently selected from H and C 1 -C 6 alkyl, and Z is SO 2 NHR 5 , where R 5 It is H, C 1 -C6 Alkyl or -C(O)-C 1 -C 6 In some embodiments, L 1 Yes CR 1 R 2 , where R 1 and R 2 Independently selected from H and C 1 -C 6 alkyl, and Z is SO 2 NHR 5 , where R 5 is H. In some embodiments, L 1 is a bond and Z is P(O)(OR 5 ) 2 , where each R 5 independently H or C 1 -C 6 In some embodiments, L 1 is a bond and Z is B(OH) 2 In some embodiments, L 1 is a bond and Z is C(O)OH, C(O)NHR 5 or C(O)NHOR 5 In some embodiments, L 1 is a bond and Z is C(O)OH, C(O)NHR 5 or C(O)NHOR 5 , where each R 5 Independently H.

[0161] Representative compounds are listed in Table 1.

[0162] Table 1

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194] In some embodiments, the compound of Formula (A) or the compound of Formula (I)-(VI) is not an analog of:

[0195] or a pharmaceutically acceptable salt, stereoisomer or solvate thereof.

[0196] In some embodiments, the compound of Formula (A) or the compound of Formula (I)-(VI) is not an analog of:

[0197] or a pharmaceutically acceptable salt, stereoisomer or solvate thereof.

[0198] In some embodiments, provided herein are compounds described in Table 1, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof.

[0199] In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0200] In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base and isolating the salt thus formed.

[0201] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with mineral, organic acids or inorganic bases, such salts include acetates, acrylates, adipates, alginate, aspartates, benzoates, benzenesulfonates, bisulfates, bisulfites, bromides, butyrates, butyne-1,4-dioates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, digluconates, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, gluconate heptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyne-1,6-dioates, hydroxybenzoates, g-hydroxybutyrates, hydrochlorides, hydrobromides ...

[0013] The invention further comprises the following: iodate, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, 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 undeconate, and xylenesulfonate.

[0202] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphophosphoric 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, l,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptanoic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid.

[0203] In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base (e.g., hydroxide, carbonate, bicarbonate, sulfate) of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium and magnesium, and aluminum salts, etc. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C I-4 alkyl) 4 wait.

[0204] Representative organic amines useful for forming 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-soluble or oil-soluble or dispersible products can be obtained by such quaternization.

[0205] In some embodiments, the compounds described herein exist in the form of geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, synonymous, antisense, opposite side (E) and same side (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in R configuration or S configuration. The compounds described herein include all diastereoisomers, enantiomers and diastereoisomers and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, the enantiomers and / or mixtures of diastereoisomers produced by a single preparation step, combination or mutual conversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared into their individual stereoisomers in the following manner: the racemic mixture of the compound is reacted with an optically active resolving agent to form a pair of diastereoisomer compounds, the diastereoisomers are separated, and optically pure enantiomers are recovered. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.), and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography or preferably by separation / resolution techniques based on solubility differences. In some embodiments, optically pure enantiomers and resolving agents are then recovered.

[0206] In some embodiments, the compounds described herein exist in the form of solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0207] Solvates contain stoichiometric or non-stoichiometric amounts of solvents, and in some embodiments, are formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the process of the methods described herein. By way of example only, hydrates of compounds described herein can be conveniently prepared by recrystallization from a water / organic solvent mixture using organic solvents including but not limited to dioxane, tetrahydrofuran or methanol. In addition, compounds provided herein can exist in non-solvated and solvated forms. Generally, for the purposes of compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0208] Also provided are prodrugs of the compounds described herein. In some embodiments, when administered to a subject, the prodrug can be converted to a compound of Formula (A) or Formula (I)-(VI), for example, following metabolic processing of the prodrug.

[0209] The following prodrugs are examples for illustrative purposes using compound 40. In some embodiments, similar analogs can be made using sulfonamides as handles.

[0210]

[0211] Pharmaceutical compositions and formulations

[0212] The present disclosure encompasses pharmaceutical compositions of any of the compounds described in detail herein or their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs. Therefore, the present disclosure includes pharmaceutical compositions comprising compounds as described in detail herein or their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs and pharmaceutically acceptable carriers or excipients. On the one hand, the pharmaceutically acceptable salts are acid addition salts, such as 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, etc. 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 providing inhalation administration.

[0213] The compounds as detailed herein or their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs can be in purified form on the one hand, and compositions comprising the compounds in purified form are described in detail herein. Compositions comprising the compounds as detailed herein or their salts are provided, such as compositions of substantially pure compounds. In some embodiments, compositions containing the compounds as detailed herein or their salts are in substantially pure form.

[0214] In one variation, the compound herein is a synthetic compound prepared for administration to an individual. In another variation, a composition containing the compound in substantially pure form is provided. In other variations, the disclosure encompasses pharmaceutical compositions of the compound or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug described in detail herein and a pharmaceutically acceptable carrier. In another variation, a method of administering the compound is provided. The purified form, pharmaceutical composition and method of administering the compound are applicable to any compound or form thereof described in detail herein.

[0215] The compounds or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs described herein 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 forms. The compounds or their salts can be formulated with a suitable carrier to provide a delivery form including, but not limited to, tablets, caplets, capsules (e.g., hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, poultices (pastes), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalants), gels, suspensions (e.g., aqueous liquid suspensions or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0216] One or more compounds described herein or their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs can be used to prepare formulations, such as pharmaceutical formulations, by combining one or more compounds or their salts as active ingredients with pharmaceutically acceptable carriers (such as those mentioned above). Depending on the treatment form of the system (e.g., transdermal patch and oral tablets), the carrier can be in various forms. In addition, the pharmaceutical formulation can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators and salts, buffers, coating agents or antioxidants for regulating osmotic pressure. The formulation containing the compound can also contain other substances with valuable therapeutic properties. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pennsylvania, 20th edition. (2000), which is incorporated herein by reference.

[0217] Compositions for oral use are prepared according to any method known in the art for preparing pharmaceutical compositions, and can be prepared in the form of tablets, pills, powders, suspensions, emulsions, solutions, syrups and capsules. Oral compositions can contain active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for making tablets. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a longer sustained effect. Preparations for oral use can be presented in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or in the form of soft gelatin capsules, wherein the active ingredient is mixed with water or an oily medium (e.g., peanut oil, liquid paraffin or olive oil).

[0218] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.

[0219] Suitable compositions for transdermal applications include an effective amount of a compound of the invention and a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to aid in permeation through the host's skin. For example, a transdermal device is in the form of a bandage comprising a backing member, a reservoir containing the compound and an optional carrier, an optional rate-controlling barrier (for delivering the compound to the host's skin at a controlled and predetermined rate over an extended period of time) and a means for fixing the device to the skin.

[0220] Suitable compositions for topical application (e.g., to the skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels or spray formulations (e.g., for delivery by aerosol, etc.). Such topical delivery systems will be particularly suitable for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sunscreens, lotions, sprays, etc.

[0221] As used herein, topical application may also refer to inhalation or intranasal application. They can be conveniently delivered in dry powder form (alone, as a mixture (e.g., dry blend with lactose) or mixed component particles (e.g., with phospholipids)) from a dry powder inhaler or in an aerosol spray presentation from a pressurized container, pump, sprayer, atomizer or nebulizer (with or without a suitable propellant).

[0222] The present invention further provides such pharmaceutical compositions and dosage forms, which contain one or more agents that reduce the decomposition rate of the compounds of the present invention as active ingredients. Such agents are referred to herein as "stabilizers" and include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers, etc.

[0223] Methods and therapeutic uses

[0224] In addition to the compounds as disclosed herein, their pharmaceutically acceptable salts, stereoisomers, solvates, and compositions and combinations comprising these compounds, the present invention includes methods of using the same, as further described herein.

[0225] The compound of formula (A) or formula (I)-(VI) or a pharmaceutically acceptable salt, prodrug or solvate thereof can be used to treat a disease or disorder mediated by the STING pathway. In some embodiments, provided herein is a method of inhibiting ENPP1 activity using a compound of formula (A) or formula (I)-(VI) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof. In some embodiments, the compound of formula (A) or formula (I)-(VI) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof has a desired physicochemical property, such as solubility in water.

[0226] The ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family consists of seven members (ENNP1-7), which are membrane-bound glycoproteins or exoenzymes with active sites or as soluble proteins in body fluids. ENPP1 is involved in many different biological processes. In animal models, it is reported that overexpressed ENPP1 inhibits insulin receptor tyrosine kinase activity in peripheral tissues, which are the main targets of insulin action (Abate, N. et al. Nature Clin. Pract. Endocrinol. Metab. 2006, 2, 694-701). ENPP1 is also expressed on the cell membrane of osteoblasts and chondrocytes, and it has a great effect on bone mineralization. (Terkeltaub, R et al. Purinergic Signalling 2006, 2, 371-377; Vaingankar, SM et al. Cell Physiol. 2004, 286, C1177-C1187).

[0227] Recently, 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), breaking it down into 5'-AMP and 5'-GMP. cGAMP activates the stimulator of interferon genes (STING) pathway, leading to the production of type I interferons (IFNs) and other cytokines that trigger immune responses. (Manas Sharma et al. Int J Cell Sci & Mol Biol., 2018, 5, 555655). Therefore, ENPP1 inhibitors that block cGAMP hydrolysis and induce STING activity can potentially be used to increase immune responses. Similar to checkpoint inhibitors (such as anti-PD-1 or PD-L1, which are promising immunotherapeutic drugs for various cancers), activation of the STING pathway by these inhibitors becomes more critical for tumor control in cancer immunotherapy.

[0228] In addition, Lau WM and Kominsky SL [2013, PLoS ONE 8(7)] found that "expression of Enpp1 was elevated in human breast cancer cell lines known to produce bone metastases in animal models compared with non-metastatic and normal breast epithelial cell lines." They further demonstrated that in clinical specimens, levels of ENPP1 were significantly elevated in human primary breast tumors relative to normal breast epithelium, with the highest levels observed in breast-bone metastases.

[0229] In one aspect, the present invention provides a method for treating a disorder mediated by inappropriate ENPP1 activity, comprising administering a safe and effective dose of a compound of formula (A) or formula (I)-(VI) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0230] In some embodiments, the ENPP1 -mediated disease or disorder is selected from a disease related to bone and soft tissue mineralization, T2D, cardiovascular disease, cancer, an autoimmune disease, and osteoarthritis.

[0231] 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.

[0232] In some embodiments, the compounds described herein can be used to treat cancers mediated by inappropriate ENPP1 activity. In certain embodiments, the disease is a hematological malignancy. In some embodiments, the disease is a solid tumor. In some embodiments, treatment of solid tumors with abnormal ENPP1 expression, such as astrocytic brain tumors and glioblastoma stem-like cells and metastases of breast cancer is indicated.

[0233] The potency of a compound as an inhibitor of enzyme activity (or other biological activity) can be established by determining the concentration at which each compound inhibits activity to a predetermined degree and then comparing the results. The "IC50" or "IC90" of an inhibitor can be determined by the concentration that inhibits 50% or 90% of the activity in a biochemical assay, which can 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 refers to a decrease in ENPP1 activity as a direct or indirect reaction to the presence of a compound of Formula (A) or Formula (I)-(VI) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, relative to the activity of ENPP1 in the absence of a compound of Formula (A) or Formula (I)-(VI) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0234] In some embodiments, a compound of Formula (A) or Formula (I)-(VI), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, can be used in combination with one or more additional therapeutic agents to treat cancer or inflammatory disorders. The one or more additional therapeutic agents can be chemotherapeutic agents, radiotherapy, targeted therapy, immunotherapeutic agents, or any current best care treatment, either small molecule or biological in nature.

[0235] Chemotherapeutic agents can be classified according to their mechanism of action as: alkylating agents, antimetabolites, anti-microtubule agents, topoisomerase inhibitors and cytotoxic agents. The compounds of formula (A) or formula (I)-(VI) or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof can be used in combination with chemotherapeutic agents to sensitize or improve the efficacy of certain chemotherapeutic agents to treat hematological tumors or solid tumors.

[0236] Immunotherapeutic agents that may be suitable for use in combination with a compound of Formula (A) or Formula (I)-(VI) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof include, but are not limited to, therapeutic antibodies, small molecules and vaccines suitable for treating patients; such as IDO1 and TDO2 inhibitors, A2A receptor inhibitors, arginase inhibitors, toll-like receptor agonists, chemokine (including CCR and CXCR family) regulators, STING agonists, checkpoint blocking antibodies such as antibodies that regulate PD-1, PD-L1, CTLA-4, OX40-OX40 ligands, LAG3, TIM3 or any combination thereof.

[0237] Radiation therapy is part of cancer treatment to control or kill malignant cells and is often applied to cancerous tumors due to its ability to control cell growth. The compounds of Formula (A) or Formula (I)-(VI) or pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof can be used in combination with radiation therapy to improve the efficacy of radiation therapy for treating hematological tumors or solid tumors, or in combination with surgery, chemotherapy, immunotherapy and a combination of the four.

[0238] Targeted therapies that may be suitable for combination therapy include, but are not limited to, inhibitors of PI3K, cyclin-dependent kinases (CDKs) (such as CDK1, CDK2, CDK4 / 6, CDK7, and CDK9), Janus kinases (JAKs) (such as JAK1, JAK2, and / or JAK3), spleen tyrosine kinases (SYKs), Bruton's tyrosine kinases (BTKs), 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.

[0239] In some embodiments, a compound of Formula (A) or Formula (I)-(VI), or a pharmaceutically 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 chemotherapeutic treatment or who have relapsed after treatment with chemotherapy.

[0240] The dosage of the pharmaceutical composition or combination depends on body weight, age and individual condition, the disorder or disease being treated or its severity. The effective dose is determined by a physician or clinician to prevent, treat or inhibit the progression of the disorder or disease. In some embodiments, a safe and effective dose is an amount sufficient to treat the patient's condition but low enough to avoid serious side effects. A safe and effective dose may vary with the following factors: the specific compound selected (e.g., considering the efficacy, efficacy and half-life of the compound); the selected route of administration; the disorder being treated; the severity of the disorder being treated; the age, size, weight and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of treatment; the nature of concurrent therapy; the desired therapeutic effect; and similar factors.

[0241] In the practice of the method of the present invention, any of the compounds of this invention or any combination of the compounds of this invention or its pharmaceutically acceptable salt, stereoisomer, solvate or prodrug of therapeutically effective amount is administered alone or in combination via any commonly used and acceptable method known in the art. Therefore, compound or composition can be administered orally (for example, through buccal cavity), sublingually, parenterally (for example, intramuscularly, intravenously or subcutaneously), rectum (for example, by suppository or lotion), transdermally (for example, skin electroporation) or by inhalation (for example, by aerosol) and in the form of solid, liquid or gaseous dosage form (including tablet and suspension). Administration can be carried out in a single unit dosage form of continuous therapy or arbitrarily carried out with single dose therapy. Therapeutic composition can also be in the form of an oil emulsion or dispersion combined with a lipophilic salt (such as pamoic acid), or in the form of a biodegradable sustained release composition for subcutaneous or intramuscular administration.

[0242] The pharmaceutical composition may be administered in a single dose or multiple doses.The compound of formula (A) or formula (I)-(VI) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof may be formulated to provide a desired release schedule of the active ingredient for therapeutic treatment purposes.

[0243] The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a specific amount of active ingredient, in the form of tablets, pills, powders, suspensions, emulsions, solutions, syrups and capsules. For example, these can contain an active ingredient in an amount from about 0.1 to 1000 mg, preferably from about 0.1 to 500 mg. Depending on the patient's condition and other factors, the suitable daily dose for humans or other mammals may vary greatly, but can be determined using conventional methods again. The daily dose can be applied in one to four doses per day. For therapeutic purposes, the active compound of the present invention is usually combined with one or more adjuvants suitable for the indicated route of application of drops that are suitable for application to the eye, ear or nose. The suitable topical dose of the active ingredient of the compound of the present invention is 0.1 mg to 150 mg, applied one to four times a day, preferably once or twice. For topical application, the active ingredient can contain from 0.001% to 10% w / w, such as from 1% to 2% of the weight of the preparation, preferably no more than 5% w / w, and more preferably from 0.1% to 1% of the weight of the preparation.

[0244] The compound or composition of the present invention can be administered to an individual according to an effective dosing regimen, for a desired time period or duration, such as 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 longer, which may last for the duration of an individual's life in some variations. In one variation, 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 day) over a period of time. The frequency of administration can also be less than once a day, for example, administered approximately once a week. The frequency of administration can be more than once a day, for example, twice or three times a day. The frequency of administration can also be intermittent, including a "drug-free period" (e.g., once a day administration for 7 days, then no administration for 7 days, repeating any 14-day time period, such as about 2 months, about 4 months, about 6 months or longer). Any administration frequency can be used with any compound described herein and any dosage described herein.

[0245] In certain embodiments, the method comprises administering to the subject an initial daily dose of about 0.1 to 500 mg of a compound of Formula (A) or Formula (I)-(VI), and increasing the dose in increments until clinical efficacy is achieved. The dose may be increased in increments of about 5, 10, 25, 50, or 100 mg. The dose may be increased daily, every other day, twice a week, or once a week.

[0246] Products and kits

[0247] The present disclosure further provides articles of manufacture comprising compounds of the present disclosure or salts thereof, compositions and unit doses as described herein in suitable packaging. In certain embodiments, the articles of manufacture are used in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampoules, bottles, cans, flexible packaging, etc. The articles of manufacture may further be sterilized and / or sealed.

[0248] The disclosure further provides a kit for implementing the method of the disclosure, the kit comprising one or more compounds described herein or a composition comprising a compound described herein. The kit may employ any compound disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof. The kit may be used for any one or more of the purposes described herein, and accordingly may contain instructions for treating a disease described herein.

[0249] The kit generally includes suitable packaging. The kit may include one or more containers containing any compound described herein. Each component (if there is more than one component) may be packaged in a separate container, or some components may be combined in one container when cross-reactivity and shelf life permit.

[0250] The kit can be in unit dosage form, bulk packaging (e.g., multi-dose packaging) or subunit dosage. For example, a kit containing a sufficient dose of a compound as disclosed herein and / or a second pharmaceutically active compound that can be used for a disease (e.g., hypertension) described herein can be provided to provide effective treatment of an individual for an extended period of time, such as one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months or any one of longer periods. The kit can also include multiple unit doses of the compound and instructions for use, and is packaged in an amount sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy and a compounding pharmacy).

[0251] The kit may optionally include a set of instructions for use of one or more components of the methods of the invention, typically written instructions, although electronic storage media (e.g., magnetic or optical disks) containing the instructions are also acceptable. The instructions included in the kit typically include information about the components and their administration to an individual.

[0252] The invention may be further understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting.

[0253] Example

[0254] Synthesis Example

[0255] The reagents and solvents used below can be obtained from commercial sources. Spectra were recorded on Bruker 400 and 600 MHz NMR spectrometers. 1 H-NMR spectra. Significant peaks are listed in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), coupling constant and number of protons in Hertz (Hz). Mass spectrometry results are reported as mass-to-charge ratios followed by the relative abundance of each ion (in parentheses). Electrospray ionization (ESI) mass spectrometry was performed on an Agilent 1100 LC / MSD electrospray mass spectrometer.

[0256] The term "solvent", "inert organic solvent" or "inert solvent" refers to a solvent that is inert under the reaction conditions described in connection therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), ethyl acetate (EA or EtOAc), dichloromethane (DCM), ether, methanol, pyridine, etc.). Unless otherwise specified, the solvent used in the reaction of the present invention is an inert organic solvent, and the reaction is carried out under an inert gas, preferably nitrogen and argon.

[0257] Compounds of formula (I)-(VI) can be prepared using methods disclosed herein and conventional modifications thereof, which will be apparent in view of the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can also be used. The synthesis of representative compounds described herein can be accomplished as described in the following examples. If available, reagents can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0258] General procedure:

[0259] Example 1

[0260] 4-((7,8-Dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (1)

[0261]

[0262] Step 1: Synthesis of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile

[0263] 4-Hydroxy-6,7-dimethoxyquinoline-3-carbonitrile (550 mg, 2.39 mmol) and 10 mL of POCl 3 The stirred mixture was heated under reflux for 3 h. The volatile materials were removed under vacuum at about 70 °C. The residue was mixed with dichloromethane and H at 0 °C. 2 O and carefully add solid K 2 CO 3 After stirring at 25 °C for 30 min, the organic layer was separated and the mixture was heated to 40 °C with H 2 O, dried over celite and concentrated to give the crude product. The residue was purified by flash column chromatography (0 to 30% EA in PE) to give the product of 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile 2 as a light yellow solid (600 mg, 95% yield). LCMS (ESI) [M+H] + =249.

[0264] Step 2: Synthesis of 4-(((3-cyano-6,7-dimethoxyquinolin-4-yl)amino]methyl)-benzenesulfonamide

[0265] To 4- chloro-6,7-dimethoxyquinoline-3-carbonitrile (550mg, 2.21mmol), 4- (aminomethyl) benzenesulfonamide hydrochloride (591mg, 2.65mmol) and potassium carbonate (1.528g, 11.06mmol) in DMF (15ml) solution. The reaction mixture was stirred at 70 ° C for 16h 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 obtain the product of 4- (((3- cyano-6,7-dimethoxyquinoline-4-yl) amino) methyl) benzenesulfonamide (800mg, 72.6% yield) as a yellow solid. LCMS (ESI) [M + H] + =399.

[0266] Step 3: Synthesis of 6,7-dimethoxy-4-(((4-sulfamoylphenyl)methyl)amino)quinoline-3-carboxylic acid

[0267] 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 to reflux for 16 h. The solution was concentrated in vacuo and the crude product was purified by preparative HPLC to give the product of 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.

[0268] Step 4: Synthesis of 4-((7,8-dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzene-sulfonamide

[0269] 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). The reaction mixture was stirred at 100 ° C for 16 h under nitrogen. The solution was concentrated to dryness and purified by preparative HPLC to give the product of 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 HNMR(400MHz,DMSO)δ11.58(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).

[0270] Example 2

[0271] Preparation of 2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl (General Procedure 1)

[0272]

[0273] Similar synthetic methods (W, Huang et al., Eur. J. Org. Chem. 2018, 1572-1580) were adapted to provide the title analogs from known starting materials (4-chloro-6,7-dimethoxyquinolin-3-amine, prepared according to literature procedures, Fuchss, Thomas et al., PCT International Application 2012028233).

[0274] Preparation of 2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl (General Procedure 2)

[0275]

[0276] Preparation of 1H-imidazo[4,5-c]quinoline (General Procedure 3)

[0277]

[0278] Preparation of 1H-[1,2,3]triazolo[4,5-c]quinoline (General Procedure 4)

[0279]

[0280] Similar synthetic methods (A. Boullilot, WO 2011 / 054846 Al) were adapted to provide the title analogs (General Procedures 2, 3 and 4) from known starting materials (4-chloro-3-nitro-6,7-dimethoxyquinoline, prepared according to literature procedures, Fuchss, Thomas et al., PCT Intl Appl 2012028233).

[0281] Preparation of 1H-[1,2,3]triazolo[4,5-c]quinoline (General Procedure 5)

[0282]

[0283] A similar synthetic method (A Gopalsamy et al., Journal of Medicinal Chemistry 2007, 50, 5547-5549) was adapted to provide the title analog from 4-chloro-6,7-dimethoxyquinoline-3-carbaldehyde.

[0284] Preparation of 1H-[1,2,3]triazolo[4,5-c]quinoline (General Procedure 6)

[0285]

[0286] A similar synthetic method (by A. Jeffrey S. et al., PCT International Application 2014152029) was adapted to provide the title analogs from 3,4-dimethoxyaniline.

[0287] Example 3

[0288] 4-((7,8-Dimethoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (2)

[0289]

[0290] A similar synthetic method (W, Huang et al., Eur. J. Org. Chem. 2018, 1572-1580) was adapted from known starting materials (4-chloro-6,7-dimethoxyquinolin-3-amine, prepared according to literature procedures, Fuchss, Thomas et al., PCT International Application 2012028233) to provide the title analog 2. LCMS (ESI) [M+H] + =428; 1 H NMR(400MHz, DMSO)δLCMS[M+H]+=429; 1H NMR(600MHz,DMSO-d6)δppm 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(br s,1H).

[0291] Example 4

[0292] (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)

[0293] (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) were prepared according to General Procedure 2 from known compounds (R)-4-(1-aminoethyl)benzenesulfonamide and (S)-4-(1-aminoethyl)benzenesulfonamide (Canales et al., PCT International Application 2010002998).

[0294] Example 5

[0295] 4-((7,8-Dimethoxy-2-oxooxazolo[5,4-c]quinolin-1(2H)-yl)methyl)benzenesulfonamide (4)

[0296] 4-((7,8-Dimethoxy-2-oxooxazolo[5,4-c]quinolin-1(2H)-yl)methyl)benzenesulfonamide was prepared according to General Procedure 6.

[0297] Example 6

[0298] 6-((7,8-Dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-3-sulfonamide (5)

[0299] 6-((7,8-Dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-3-sulfonamide was prepared according to General Procedure 2 from the known compound 6-(aminomethyl)pyridine-3-sulfonamide (J. Bakonyi et al., U.S. Patent Application Publication 20150291607).

[0300] Example 7

[0301] 5-((7,8-Dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-2-sulfonamide (6)

[0302] 5-((7,8-Dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-2-sulfonamide was prepared according to General Procedure 2 from the known compound 5-(aminomethyl)pyridine-2-sulfonamide (A. Macleod et al., PCT Intl Appl 2009024585).

[0303] Example 8

[0304] 3-((7,8-Dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (7)

[0305] 3-((7,8-Dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1 yl)methyl)-benzenesulfonamide was prepared according to General Procedure 2 from 3-(aminomethyl)benzenesulfonamide.

[0306] Example 9

[0307] (R)-4-(1-(7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)benzene-sulfonamide (8)

[0308] (R)-4-(1-(7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)benzene-sulfonamide was prepared in a similar manner to compound 1. LCMS (ESI) [M+H] + =399; 1H NMR (600MHz, DMSO-d6) δppm 1.98 (br d, J=6.97Hz, 4H) 3.85 (s, 3H) 6.28 (q, J=7.21Hz, 1H) 7.01 (br s,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(br s,1H).

[0309] Example 10

[0310] 4-((7,8-Dimethoxy-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (9)

[0311] 4-((7,8-Dimethoxy-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide was prepared according to General Procedure 3 using triethyl orthoacetate.

[0312] Embodiment 11

[0313] 5-((7,8-Dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-2-sulfonamide (10)

[0314] 5-((7,8-Dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-2-sulfonamide was prepared according to General Procedure 3. LCMS (ESI) [M+H] + =400; 1 H NMR(600MHz,DMSO-d6)δppm 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(br s,1H).

[0315] Example 12

[0316] (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)

[0317] (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 according to General Procedure 3. 11a: LCMS (ESI) [M+H] + =413; 1 H NMR (600MHz, DMSO-d6) δppm 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 (br d,J=8.44Hz,3H)7.64(br s,1H)7.79(d,J=8.80Hz,2H)9.16(br s,1H)9.67(br s,1H). 11b:LCMS(ESI)[M+H] + =413.

[0318] Embodiment 13

[0319] 6-((7,8-Dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-3-sulfonamide (12)

[0320] 6-((7,8-Dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)pyridine-3-sulfonamide (12) was prepared according to General Procedure 3. LCMS [M+H] + =400; 1 H NMR(600MHz,DMSO-d6)δppm 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(br s,1H)8.84(d,J=1.83Hz,1H).

[0321] Embodiment 14

[0322] 4-((7,8-Dimethoxy-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (13)

[0323] Compound 13 was prepared according to General Procedure 4. LCMS [M+H] + =400; 1H NMR(600MHz,DMSO-d6)δppm3.78(s,3H)3.93(s,3H)6.56(s,2H)7.33(d,J=12.10Hz,3 H)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).

[0324] Embodiment 15

[0325] Compounds 14a, 14b, 15 and 16 were prepared according to General Procedure 4.

[0326] Example 16

[0327] Compounds 17, 18, 19a, 19b, 20 and 21 were prepared according to General Procedure 5.

[0328] Embodiment 17

[0329] 4-((7,8-Dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-2-fluorobenzenesulfonamide (22)

[0330] 4-((7,8-Dimethoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-2-fluorobenzenesulfonamide (22) was prepared according to General Procedure 2 from 4-(aminomethyl)-2-fluorobenzenesulfonamide (prepared according to S. Yamamoto et al., PCT International Application No. 2018030550).

[0331] Embodiment 18

[0332] Preparation of 3-(aminomethyl)azetidine-1-sulfonamide, 3-(aminomethyl)pyrrolidine-1-sulfonamide and 4-(aminomethyl)piperidine-1-sulfonamide

[0333]

[0334] Step 1. Boc diamine (0.8 mmol, 1 eq) was dissolved in DCM (4.4 mL, 0.2 M) followed by the addition of (tert-butyloxycarbonyl)((4-(dimethylimino)pyridin-1(4H)-yl)sulfonyl)amide (262 mg, 1 eq). The mixture was stirred at room temperature for 18 h. Upon completion, the mixture was concentrated in vacuo. The crude was purified by FCC using Hex / THF (100% / 0% to 60% / 40%) to give the product.

[0335] Step 2. The above product (1 equivalent) 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 and the cold water bath was removed. The mixture was stirred at room temperature for 2 h. After completion, the mixture was concentrated in vacuo and purified by NaHCO 3 Neutralized and extracted with DCM. The crude product was used in the next step without further purification.

[0336] Embodiment 19

[0337] 4-((7,8-Dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)piperidine-1-sulfonamide (32)

[0338] 4-((7,8-Dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)piperidine-1-sulfonamide was prepared from intermediate 4-(aminomethyl)piperidine-1-sulfonamide according to General Procedure 3. LCMS (ESI) [M+H] + =406; 1 H NMR(600MHz,DMSO-d6)δppm 1.22-1.28(m,2H)1.41-1.50(m,2H)1.65(br d,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(br s,1H).

[0339] Embodiment 20

[0340] Compounds 23-31 were prepared from the above intermediates according to general procedures 2-6.

[0341] Embodiment 21

[0342] 4-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,6]naphthyridin-1-yl)methyl)benzenesulfonamide (33).

[0343]

[0344] 4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,6]naphthyridin-1-yl)methyl)benzenesulfonamide was prepared in a similar manner to compound 1 from ethyl 4-chloro-7-methoxy-1,6-naphthyridine-3-carboxylate.

[0345] Embodiment 22

[0346] 4-((8-Cyano-7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (34)

[0347] 4-((8-Cyano-7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide was prepared in a similar manner to compound 1 from ethyl 4-chloro-6-cyano-7-methoxyquinoline-3-carboxylate.

[0348] Embodiment 23

[0349] 4-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-benzenesulfonamide (35)

[0350] 4-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)methyl)-benzenesulfonamide was prepared according to General Procedure 2. LCMS (ESI) [M+H] + =385; 1 H NMR(600MHz,DMSO-d6)δppm 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).

[0351] Embodiment 24

[0352] 4-((8-Methoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (36)

[0353] 4-((8-Methoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide was prepared according to General Procedure 3. LCMS (ESI) [M+H] + =369; 1 H NMR(600MHz,DMSO-d6)δppm 3.71(s,4H)6.20(s,2H)7.28(d,J=2.57Hz,1H)7.32-7.38(m,5H)7.79(d,J=7.76Hz,2H)8.08(d,J=9.17Hz,1H)8.75(s,1H)9.33(br s,1H).

[0354] Embodiment 25

[0355] 3-((7,8-Dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide (37)

[0356] 3-((7,8-Dimethoxy-1H-imidazo[4,5-c]quinolin-1-yl)methyl)benzenesulfonamide was prepared according to General Procedure 3. LCMS (ESI) [M+H] + =399; 1 H NMR(600MHz,DMSO-d6)δppm 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).

[0357] Embodiment 26

[0358] 4-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (38)

[0359]

[0360] Step 1. 6-methoxypyridine-2-amine (9.8 g, 78.9 mmol, 1.1 equivalents) was dissolved in diethyl ethoxymethylene malonate (15.5 g, 71.8 mmol, 1 equivalent). The mixture was heated to 95 ° C for 1 h under vacuum. After completion, the mixture was cooled to 45 ° C and hexane was added. The mixture was further cooled by dry ice to induce precipitation. The resulting precipitate was filtered and dried (14.8 g, 70%). The crude product was used without further purification.

[0361] Step 2. Diethyl 2-(((6-methoxypyridin-2-yl)amino)methylene)malonate (14.8 g, 50.3 mmol) was added to a solution of diphenyl ether (125 mL, 0.4 M) at 260°C. After addition, the mixture was heated at reflux for another 45 min. Upon completion, the mixture was cooled to 85°C and hexanes were added. Once cooled to room temperature, the solid was filtered and purified by FCC to give the product.

[0362] Step 3. 4-Hydroxy-7-methoxy-1,8-naphthyridine-3-carboxylic acid ethyl ester (130 mg, 0.52 mmol, 1 eq) was dissolved in DCM (2.6 mL, 0.2 M) followed by addition of oxalyl chloride (53 μL, 0.63 mmol, 1.2 eq) and DMF (1 drop). The mixture was heated to reflux for 5 min. After completion, the mixture was cooled to room temperature and concentrated in vacuo. The crude product was used without further purification.

[0363] 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 to 60 °C. After completion, the mixture was cooled to room temperature and then added to water. The resulting precipitate was filtered and dried (21 mg, 19%).

[0364] Step 5. 7-methoxy-4-((4-sulfamoylbenzyl)amino)-1,8-naphthyridine-3-carboxylic acid ethyl ester (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 solution (1 M, 0.5 mmol, 10 eq) was added to the mixture. The resulting mixture was heated to 50°C. After completion, the mixture was cooled to room temperature and diluted with water. The aqueous layer was washed with EtOAc and then acidified to pH 4 with 2N HCl. The resulting precipitate was filtered and dried (14 mg, 74%).

[0365] 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) followed by the addition of DPPA (9.3 μL, 0.043 mmol, 1.2 eq). The resulting mixture was heated to 110°C. Upon completion, the mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by FCC to give the product (8.8 mg, 44%). LCMS [M+H] +=386; 1 H NMR(600MHz,DMSO-d6)δppm 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(br d,J=9.35Hz,1H)8.74(s,1H).

[0366] Embodiment 27

[0367] Synthesis of 5-chloro-2-methoxy-6-nitro-1,8-naphthyridine (Intermediate B):

[0368]

[0369] 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, then 6-methoxypyridin-2-amine (10 g, 80.6 mmol) was added portionwise 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 (19.27 g, 75%) as a grey solid.

[0370] Step 2. The above solid (19.2 g, 69 mmol) was added portionwise to heated diphenyl ether (30 mL) at 260°C, and the mixture was stirred at 260°C for 40 min 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%).

[0371] Step 3. Install CH 3 CH 2 CO 2 The above solid (1.0 g, 5.7 mmol) in H (35 mL) was dropwise treated with fuming HNO 3 (0.59 mL) and then stirred for 2 h. The resulting solid was filtered, washed and dried (725 mg, 58%).

[0372] Step 4. The above solid (725 mg, 3.3 mmol) in DCM (20 mL) was treated with SOCl 2(0.60 mL) and then treated with 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%).

[0373] Embodiment 28

[0374] 4-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (39)

[0375]

[0376] Step 1. Intermediate B (90 mg, 0.38 mmol), 4-(aminomethyl)benzenesulfonamide HCl salt (100 mg, 1.2 eq), hunig base (0.33 mL, 5.0 eq) and MeCN (4 mL) were heated to 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.

[0377] Step 2. The above solid (107 mg, 0.28 mmol) in MeOH (5 mL) and EtOAc (5 mL) was heated to 65 °C and then Pd / C (10%, 10 mg) was added. The reaction mixture was stirred under H 2 Stirred under balloon overnight. 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.

[0378] 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) and then heated to 120°C for 8 h. 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)δppm 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).

[0379] Embodiment 29

[0380] 6-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (40)

[0381] 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; 1 H NMR(500MHz,DMSO-d6)δppm 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).

[0382] Embodiment 30

[0383] 5-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-2-sulfonamide (41)

[0384] 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)δppm 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).

[0385] Embodiment 31

[0386] 4-((8,9-Dimethoxypyrazolo[1,5-c]quinazolin-1-yl)methyl)benzenesulfonamide (42)

[0387]

[0388] By reducing agents such as LiBH 4 ) 8,9-dimethoxypyrazolo[1,5-c]quinazoline-1-carboxylic acid ethyl ester (prepared according to a procedure known from Feng, H., RSC Adv., 2016, 6, 95774) was converted to the corresponding alcohol. The alcohol was reacted with PBr 3 Workup to prepare the bromo analog. Coupling with (4-sulfamoylphenyl)boronic acid under palladium catalyst provides 4-((8,9-dimethoxypyrazolo[1,5-c]quinazolin-1-yl)methyl)benzenesulfonamide (42).

[0389] Embodiment 32

[0390] (R)-6-(1-(7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)ethyl)pyridine-3-sulfonamide (43)

[0391] (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 manner similar to that of compound 39. LCMS [M+H] + =385; 1 H NMR (600MHz, DMSO-d6) δppm: 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=8.25Hz,1H)8.13(dd,J=8.25,2.38Hz,1H)8.68(br d,J=8.80Hz,1H)8.74(d,J=2.38Hz,1H)9.02(s,1H)9.55(s,1H).

[0392] Embodiment 33

[0393] 4-((7,8-dimethoxy-2λ 2 ,10λ 4 -[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)methyl)benzenesulfonamide (44)

[0394]

[0395] Step 1. 2-Chloro-6,7-dimethoxyquinoxaline (0.28 g, 1.24 mmol, 1 eq) was dissolved in reagent alcohol (6.2 mL, 0.2 M) followed by the addition of hydrazine monohydrate (6.2 mL, 0.2 M). The mixture was heated to 80 °C for 2 h. Upon completion, the mixture was cooled to room temperature and then added to water. The resulting precipitate was filtered and dried (206 mg, 75%).

[0396] Step 2. 2-Hydrazino-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 to reflux for 1 h. Upon completion, the mixture was cooled to room temperature and then added to water. The resulting precipitate was filtered and dried (88 mg, 99%).

[0397] Step 3. 2-(2-(2-(4-bromophenyl)ethylidene)hydrazino)-6,7-dimethoxyquinoxaline (88 mg, 0.22 mmol, 1 eq) was dissolved in DCM (4.4 mL, 0.05 M) followed by the addition of iodobenzene diacetate (78 mg, 0.24 mmol, 1.1 eq). 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 used without further purification.

[0398] Step 4. Reaction of 1-(4-bromobenzyl)-7,8-dimethoxy-2λ 2 ,10λ 4 -[1,2,4]triazolo[4,3-a]quinoxaline (0.22 mmol, 1 equivalent), Pd(dba) 2 4-(4-(4-(4-(4-piperidin-2-yl)-2-yl)-1-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene (10-nitropropene)-2-nitropropene

[0399] 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 eq) was dissolved in MeCN (2.27 mL, 0.1 M), followed by the addition of AcOH (86 μL, 2.57 M) and water (56 μL, 3.9 M). The mixture was cooled to 0 °C, followed by the addition of 1,3-dichloro-5,5-dimethylhydantoin (52 mg, 0.264 mmol, 1.2 eq). The mixture was stirred at 0 °C. Upon completion, the mixture was diluted with EtOAc and washed with saturated NaHCO 3 The aqueous layer was extracted with EtOAc (2 x 2 mL). The combined organic layers were cooled to 0 °C and then NH 4 OH (2 mL). The mixture was stirred at 0 °C for 1 h. Upon completion, the mixture was acidified to pH 2 with 2N HCl. The layers were separated and the aqueous solution was extracted with EtOAc. The combined organic layers were dried and concentrated in vacuo. The crude product was mixed with Et 2 O were triturated to yield the product 44 (18 mg, 20%). LCMS [M+H] + =400; 1 H NMR(600MHz,DMSO-d6)δppm 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).

[0400] Embodiment 34

[0401] 4-((7-methoxy-2λ 2 ,10λ 4 -imidazo[3,4-a]quinoxalin-1-yl)methyl)benzenesulfonamide (45)

[0402]

[0403] 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 to 44 was used to convert the bromine to the sulfonamide.

[0404] Embodiment 35

[0405] 4-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenylsulfamide (46)

[0406]

[0407] 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 manner similar to that of preparing 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-nitrophenylaminosulfonate (44 mg, 1.5 equivalents) followed by hunig base (0.046 mL, 2.0 equivalents). After spending the night at room temperature, the reaction mixture was post-processed and purified by reverse phase HPLC (MeCN / H 2 O / 0.1% TFA) to give a white solid (1.5 mg). LCMS [M+H] + =385.

[0408] Embodiment 36

[0409] 4-((7-Methoxy-2-(trifluoromethyl)-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (47)

[0410]

[0411] 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 to 140° C. overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (MeCN / H 2 O / 0.1% TFA) to give a white solid (5.5 mg). LCMS [M+H] + =438; 1 H NMR(500MHz,DMSO-d6)δppm3.99-4.05(m,3H)4.46(d,J=5.80Hz,1H)6.18(s,2H)7.13(d,J=9.00Hz,1 H)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).

[0412] Embodiment 37

[0413] 4-((7-Methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (48)

[0414]

[0415] 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 triethyl orthoacetate in a manner similar to that of compound 39. LCMS [M+H] + =384; 1 H NMR(500MHz, DMSO-d6)δppm 2.66-2.72(m,3H)4.06(s,3H)6.10(s,2H)7.26(br d,J=8.24Hz,3H)7.36(s,2H)7.77(br d,J=7.42Hz,2H)8.55(br d,J=8.70Hz,1H)9.50(br s,1H).

[0416] Embodiment 38

[0417] 4-((7-Methoxy-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl)benzenesulfonamide (49)

[0418]

[0419] 4-Chloro-7-methoxy-3-nitro-1,5-naphthyridine was prepared from 5-methoxypyridin-3-amine in a manner similar to that of intermediate B; 4-((7-methoxy-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl)benzenesulfonamide (49) was then prepared from 4-chloro-7-methoxy-3-nitro-1,5-naphthyridine and 4-(aminomethyl)benzenesulfonamide in a manner similar to that of compound 39. LCMS [M+H] + =371; 1 H NMR(600MHz,DMSO-d6)δppm 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).

[0420] Embodiment 39

[0421] 4-((7-Methoxy-1H-imidazo[4,5-c][1,6]naphthyridin-1-yl)methyl)benzenesulfonamide (50)

[0422]

[0423] 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) in a manner similar to the preparation of compound 39. LCMS [M+H] + =371; 1 H NMR (500MHz, DMSO-d6) δppm 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).

[0424] Embodiment 40

[0425] 4-(7,8-Dimethoxy-[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)benzylsulfamide (51)

[0426]

[0427] Step 1. 2-Hydrazino-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 to reflux for 1 h. After completion, the mixture was cooled to room temperature and then added to water. The resulting precipitate was filtered and dried (96 mg, 99%).

[0428] Step 2. Tert-butyl (4-((2-(6,7-dimethoxyquinoxalin-2-yl)hydrazono)methyl)-benzyl)-carbamate (96 mg, 0.22 mmol, 1 eq) was dissolved in DCM (4.4 mL, 0.05 M) followed by the addition of iodobenzene diacetate (78 mg, 0.24 mmol, 1.1 eq). 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 used without further purification.

[0429] 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 eq) was dissolved in DCM (0.55 mL, 0.4 M) and cooled to 0 °C. TFA (0.55 mL, 0.4 M) was added to the mixture. The mixture was warmed 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) followed by the addition of Et 3 N (276 μL, 1.98 mmol, 9 eq) and sulfamoylating agent (73 mg, 0.242 mmol, 1.1 eq). The mixture was heated to 60 °C for 1 h. Upon completion, the mixture was concentrated in vacuo. The crude product was pushed through a plug of silica and used without further purification.

[0430] 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 cooled to 0°C. TFA (1 mL) was added to the mixture. The mixture was warmed to room temperature and stirred for 0.5 h. After 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)δppm3.38-3.40(m,3H)3.91(s,3H)4.25(d,J=6.24Hz,2H)6.71(s,2H)6.86(s,1H)7.28(br t,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).

[0431] Embodiment 41

[0432] 3-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)azetidine-1-sulfonamide (52)

[0433] 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 manner similar to the preparation of compound 39. LCMS [M+H] + =349; 1H NMR(600MHz,DMSO-d6)δppm 3.08-3.17(m,2H)3.59(br dd,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).

[0434] Embodiment 42

[0435] 7-(7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (53)

[0436] 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 manner similar to that for compound 39. LCMS [M+H] + =411; 1 H NMR(600MHz,DMSO-d6)δppm 3.10(br s,2H)4.06(s,3H)4.31(brs,2H)7.01(s,2H)7.19(d,J=8.99Hz,1H)7.51-7.56(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).

[0437] Embodiment 43

[0438] (R)-4-(1-(7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)ethyl)benzenesulfonamide (54)

[0439] (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 manner similar to that of compound 39. LCMS [M+H] + =384; 1H NMR(600MHz,DMSO-d6)δppm 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,2 H)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).

[0440] Embodiment 44

[0441] (4-((7-Methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl)boronic acid (55)

[0442]

[0443] 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. 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 reacted with bis(pinacolato)diboron (10 mg, 1.5 equiv), Pd(dppf) and 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). 2 Cl 2 (2.2 mg, 10%) and KOAc (8 mg, 3.0 eq.) and the reaction mixture was washed with N 2 Purge for 2 min and then heat to 100 °C for 2 h. After cooling to room temperature, the reaction mixture was washed with NaIO 4 (17 mg, 3.0 eq.), NH 4 OAc (6 mg, 3.0 eq.) and water (1 mL) were treated for 1 h. Workup and the residue was purified by reverse phase HPLC (MeCN / H 2 O / 0.1% TFA) to give (4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)phenyl)boronic acid as a white solid. LCMS [M+H] + =335.

[0444] Embodiment 45

[0445] 4-(8,9-Dimethoxypyrazolo[1,5-c]quinazoline-1-carbonyl)piperazine-1-sulfonamide (58)

[0446]

[0447] Ethyl 8,9-dimethoxypyrazolo[1,5-c]quinazoline-1-carboxylate (prepared according to known procedures by Feng, H., RSC Adv., 2016, 6, 95774) was converted to the corresponding acid by saponification with LiOH solution in THF. Coupling with piperazine-1-sulfonamide in the presence of HATU provided 4-(8,9-dimethoxypyrazolo[1,5-c]quinazoline-1-carbonyl)piperazine-1-sulfonamide (58).

[0448] Embodiment 46

[0449] 4-(7-Methoxy-1H-imidazo[4,5-c][1,6]naphthyridin-1-yl)benzylsulfamide (59)

[0450] 4-(7-Methoxy-1H-imidazo[4,5-c][1,6]naphthyridin-1-yl)benzylsulfamide (59) was prepared in a similar manner to compound 43.

[0451] Embodiment 47

[0452] Synthesis of intermediates:

[0453] 4-Bromo-2-(trifluoromethyl)benzenesulfonamide

[0454]

[0455] 4-Bromo-2-(trifluoromethyl)benzenesulfonyl chloride (2.5 g, 7.73 mmol, 1 eq.) was dissolved in THF (40 mL, 0.2 M) and added dropwise to NH 4 OH, keeping the internal temperature below -10 °C during the addition. After addition, the reaction mixture was stirred at -10 °C for another 10 min. After completion, the mixture was poured into 2M HCl (250 mL) and EtOAc (100 mL) at 0 °C. The layers were separated and the aqueous layer was extracted with EtOAc (2x100 mL). The combined organic layers were purified by Na 2 SO 4 Drying and concentration gave the product (2.3 g, 98%).

[0456] The following intermediate was prepared in the same manner as 4-bromo-2(trifluoromethyl)-benzenesulfonamide:

[0457] 4-Bromo-2,3-difluorobenzenesulfonamide

[0458] 4-Bromo-3,5-difluorobenzenesulfonamide

[0459] 4-Bromo-2-(trifluoromethoxy)benzenesulfonamide

[0460] 4-Bromo-3-(trifluoromethyl)benzenesulfonamide

[0461] 4-(Aminomethyl)-2,6-difluorobenzenesulfonamide HCl

[0462]

[0463] Step 1. To a flask containing water (45 mL, 2.3 M) was added thionyl chloride (7.5 mL, 103.2 mmol, 4.3 eq) dropwise at 0°C. The reaction mixture was stirred at 22°C for 18 h. 4-Bromo-2,6-difluoroaniline (5 g, 24 mmol, 1 eq) was added concentrated HCl (24 mL, 1 M) at 0°C and the resulting mixture was heated to 50°C for 1 h and then cooled to -5°C (internal temperature). NaNO 2 A solution of (1.77 g, 25.7 mmol, 1.07 eq.) dissolved in water (7 mL) was added to the reaction mixture. During the addition, the internal temperature was kept below 0 ° C. After the addition, the mixture was stirred for another 10 min at -5 ° C. The aqueous thionyl chloride mixture was cooled to -5 ° C (internal temperature) and CuCl (24 mg, 0.24 mmol, 0.01 eq.) was added. The freshly formed diazo mixture was slowly added to the aqueous thionyl chloride mixture while keeping the internal temperature below 0 ° C. After the addition, the mixture was stirred for another 20 min at -5 ° C. The resulting precipitate was filtered and dissolved in THF (100 mL). At -10 ° C (internal temperature), the sulfonyl chloride in THF was slowly added to the NH 4 OH (82 mL). During the addition, the internal temperature was kept below -5 °C. After the addition, the mixture was poured into 2M HCl (600 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL) at pH 2. The combined organic layers were washed with water and then evaporated to room temperature. 2 SO 4 Drying and concentration gave the product (5.34 g, 82%).

[0464] 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(PPh 3 ) 4The ligand precipitate was filtered. The filtrate was acidified to pH 2 with 2M HCl and extracted with EtOAc (3x100mL). The combined organic layers were purified by evaporation of 4% paraformaldehyde (40% ethanol, 0.2% sodium hydroxide) and stirred for 2 h. The precipitate was stirred for 3 hours. The precipitate was stirred for 2 hours. The precipitate was stirred for 3 hours. The precipitate was stirred for 2 hours. The precipitate was stirred for 3 hours. The precipitate was stirred for 2 hours. The precipitate was stirred for 3 hours. The precipitate was stirred for 2 hours. The precipitate was stirred for 3 hours. 2 SO 4 Dry and concentrate to give the product (1.4 g, 88%). Step 3. 4-cyano-2,6-difluorobenzenesulfonamide (844 mg, 3.87 mmol, 1 eq) was dissolved in MeOH (39 mL, 0.1 M) and then added to a flask containing 10% Pd / C (844 mg) under a nitrogen atmosphere. Concentrated HCl (355 μL, 4.3 mmol, 1.1 eq) was added and the mixture was purged with hydrogen (3 cycles). The reaction mixture was stirred at 22 ° C for 1 h. After completion, the mixture was filtered through a celite pad. The filtrate was concentrated. The residue was ground several times with EtOAc to give the product (903 mg, 90%). LCMS [M + H] + =223.

[0465] The following intermediate was prepared in the same manner as 4-(aminomethyl)-2,6-difluorobenzenesulfonamide HCl:

[0466] 4-(Aminomethyl)-2,5-difluorobenzenesulfonamide HCl

[0467] 4-(Aminomethyl)-2,3-difluorobenzenesulfonamide HCl

[0468] 4-(Aminomethyl)-3,5-difluorobenzenesulfonamide HCl

[0469] 4-(Aminomethyl)-2-(trifluoromethyl)benzenesulfonamide HCl

[0470] 4-(Aminomethyl)-2-(trifluoromethoxy)benzenesulfonamide HCl

[0471] 4-(Aminomethyl)-3-(trifluoromethyl)benzenesulfonamide HCl

[0472] (4-Bromo-2,6-difluorophenyl)methanamine

[0473]

[0474] Step 1. To a mixture of 4-bromo-2,6-difluoro-benzaldehyde (2.5 g, 11.31 mmol, 1 eq) in ethanol (40 mL) was added hydroxylamine hydrochloride (1.10 g, 15.84 mmol, 1.40 eq) and potassium acetate (1.30 g, 13.24 mmol, 1.17 eq) at 22°C in one portion for 1 h. After completion, water (40 mL) was added to the reaction mixture at 0°C and stirred for 1 h. The resulting precipitate was filtered and washed with cold 1:1 EtOH / water to give the product (2.5 g, 94%).

[0475] Step 2. (E)-4-bromo-2,6-difluoro-benzaldehyde oxime (2.5 g, 10.59 mmol, 1 eq) was dissolved in AcOH (60 mL). Zn (5.54 g, 84.74 mmol, 8 eq) was added at 65 °C in one go. 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 x 50 mL). The combined organic layer was back extracted with water (2 x 50 mL with 2 drops of AcOH), the two aqueous layers were combined, and the reaction mixture was purified by NaHCO 3 The basic aqueous layer was extracted with EtOAc (3 x 50 mL). The EtOAc layers were combined and purified by Na 2 SO 4 After drying, the product (1.46 g, 62%) was obtained without further purification. LCMS [M+H] + =222.

[0476] Step 3. The product was prepared according to the procedure of (4-bromo-2,6-difluorophenyl)-methylamine. LCMS [M+H] + =240.

[0477] (R)-6-(1-Aminoethyl)pyridine-3-sulfonamide HCl

[0478]

[0479] 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 washed with saturated NH 4 Cl was quenched. The layers were separated and the aqueous solution was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with Na 2 SO 4Dry and concentrate. The crude was purified by FCC to give the product (1.14 g, 76%).

[0480] Step 2. 6-Acetylpyridine-3-sulfonamide (1.14 g, 5.69 mmol, 1 eq) was dissolved in THF (14 mL, 0.4 M) followed by the addition of (R)-2-methylpropane-2-sulfenamide (828 mg, 6.83 mmol, 1.2 eq). Ti(OEt) 4 (1.72mL, 11.38mmol, 2 equivalents) was added to the mixture and the mixture was heated to reflux for 18h. 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 (2x50mL). The combined organic layers were purified by Na 2 SO 4 Dried and concentrated. The crude was purified by FCC using a DCM / THF gradient to yield the product (0.97 g, 56%).

[0481] Step 3. (E)-6-(1-((tert-butylsulfinyl)imino)ethyl)pyridine-3-sulfonamide (0.97 g, 3.2 mmol, 1 eq) was dissolved in THF (11 mL, 0.3 M) and then cooled to 0°C. 9-BBN (0.5 M, 8.3 mL, 4.2 mmol, 1.3 eq) was added to the mixture. The mixture was stirred at 0°C for 2 h. After completion, the mixture was quenched with MeOH (11 mL) and HCl (1.25 M, 11 mL) in EtOH was added. The mixture was stirred at 0°C for another 30 min and then concentrated. The resulting residue was triturated several times with EtOAc to yield the product (613 mg, 81%). LCMS [M+H] + =202.

[0482] Compounds 60-69 and 129 were prepared in a similar manner to the preparation of compound 39 from the amine intermediate.

[0483] Embodiment 48

[0484] Prepare 16 mg of (R)-6-(1-(7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)ethyl)pyridine-3-sulfonamide (60). LCMS [M+H] + =385; 1H NMR(600MHz,DMSO-d6)δppm 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=8.25Hz,1H)8.13(dd,J=8.25,2.38Hz,1H)8.68(br d,J=8.80Hz,1H)8.74(d,J=2.38Hz,1H)9.02(s,1H)9.55(s,1H).

[0485] Embodiment 49

[0486] Preparation of 15 mg of 2-fluoro-4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (61). LCMS [M+H] + =388.

[0487] Embodiment 50

[0488] Prepare 24.2 mg of 3-fluoro-4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (62). LCMS [M+H] + =388.

[0489] Embodiment 51

[0490] Preparation of 0.5 mg of 2-cyano-6-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (63). LCMS [M+H] + =396; 1 H NMR(600MHz,DMSO-d6)δppm 1.08(s,6H)2.02(s,1H)3.98(s,3H)6.22(s,2H)7.16(br d,J=9.17Hz,1H)7.60-7.75(m,1H)8.44(d,J=8.07Hz,1H)8.54(br d,J=8.99Hz,2H)8.73(br s,1H)9.04(br s,1H)9.39-9.51(m,1H).

[0491] Embodiment 52

[0492] Prepare 4.1 mg of 2-methoxy-4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (64). LCMS [M+H] + =400; 1H NMR(600MHz,DMSO-d6)δppm 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(br s,1H).

[0493] Embodiment 53

[0494] Prepare 7.6 mg of 4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-(trifluoromethyl)benzenesulfonamide (65). LCMS [M+H] + =438; 1 H NMR(600MHz,DMSO-d6)δppm 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).

[0495] Embodiment 54

[0496] Prepare 3.7 mg of 4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-(trifluoromethoxy)-benzene-sulfonamide (66). LCMS [M+H] + =454.

[0497] Embodiment 55

[0498] Prepare 3.1 mg of 4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-3-(trifluoromethyl)-benzenesulfonamide (67). LCMS [M+H] + =438.

[0499] Embodiment 56

[0500] Preparation of 214 mg of 3-bromo-4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (68). LCMS [M+H] + =449; 1H NMR(300MHz,DMSO-d6)δppm 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).

[0501] Embodiment 57

[0502] Preparation of 6.7 mg of 3-cyano-4-((7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzene-sulfonamide (69). LCMS [M+H] + =395; 1 H NMR(300MHz,DMSO-d6)δppm 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).

[0503] Embodiment 58

[0504] Prepared 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)δppm 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).

[0505] Compounds 70-73 and 130 were prepared from the amine intermediate in a similar manner to the preparation of compound 39 using triethyl orthoacetate instead of triethyl orthoformate in the final step.

[0506] Embodiment 59

[0507] Prepare 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). LCMS [M+H] + =420.

[0508] Embodiment 60

[0509] Prepare 2.3 mg of 2-fluoro-4-((7-methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (71). LCMS [M+H] + =402; 1 H NMR(300MHz,DMSO-d6)δppm 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).

[0510] Embodiment 61

[0511] Prepare 3.4 mg of 6-((7-methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (72). LCMS [M+H] + =385; 1 H NMR(300MHz,DMSO-d6)δppm 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).

[0512] Embodiment 62

[0513] Preparation of 6 mg of 5-((7-methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-2-sulfonamide (73). LCMS [M+H] + =385.

[0514] Embodiment 63

[0515] Prepare 14 mg of 3,5-difluoro-4-((7-methoxy-2-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (130). LCMS [M+H]+ =420.

[0516] Embodiment 64

[0517] 6-((2-Cyclopropyl-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (74)

[0518]

[0519] Step 1. 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 umol, 1.3 eq.) and DIEA (27.97 mg, 216.43 umol, 37.70 μL, 3.9 eq.) at 22°C 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 and then stirred at 22°C for 18 h. After completion, water was added to the reaction mixture and extracted by EtOAc. The organic layer was purified by Na 2 SO 4 Dry and concentrate. The crude product was used in the next step without further purification.

[0520] Step 2. To 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 K 2 CO 3 (23.01 mg, 166.49 μmol, 3 eq.). The reaction was stirred at 65 °C for 18 h. After completion, the mixture was concentrated. The crude product was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to yield the product (2.5 mg, 9%). LCMS [M+H] + =411.

[0521] Embodiment 65

[0522] In a similar manner to the preparation of compound 74, 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. LCMS [M+H] + =455.

[0523] Embodiment 66

[0524] 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 in the final step of the preparation of compound 71. LCMS [M+H] + =444; 1 H NMR(300MHz,DMSO-d6)δppm 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).

[0525] Embodiment 67

[0526] 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 in the final step of the preparation of compound 72. LCMS [M+H] + =427; 1 H NMR(300MHz,DMSO-d6)δppm 1.89(s,3H)2.71(s,3H)4.07(s,3H)6.25(s,2H)7.27(br d,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).

[0527] Embodiment 68

[0528] 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 last step. LCMS [M+H] + =418; 1H NMR (300MHz, DMSO-d6) δppm 4.06 (s, 3H) 4.27 (s, 3H) 5.88 (s, 2H) 7.11 (d, J = 8.21Hz, 1H) 7.30-7.35 (m, 1H) 7.64 (s, 2H) 7.71 (br t,J=7.62Hz,2H)8.50(d,J=8.79Hz,1H)9.39(s,1H).

[0529] Embodiment 69

[0530] 2-Fluoro-4-((7-methoxy-2-(methoxymethyl)-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-benzenesulfonamide (79)

[0531]

[0532] Step 1. 4-(((3-amino-7-methoxy-1,8-naphthyridin-4-yl)amino)methyl)-2-fluorobenzenesulfonamide (70 mg, 0.185 mmol, 1 eq) was dissolved in DMF (1.85 mL, 0.1 M) followed by the addition of chloroacetic anhydride (35 mg, 0.204 mmol, 1.1 eq). The mixture was stirred at 22 °C for 4 days. Upon completion, the mixture was partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 3 mL). The combined organic layers were purified by Na 2 SO 4 Drying and concentration without further purification yielded 4-((2-(chloromethyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-fluorobenzenesulfonamide (47.4 mg, 59%).

[0533] 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 eq) was dissolved in MeOH (0.4 mL, 0.1 M) followed by the addition of 25 wt% NaOMe (286 μL). The mixture was stirred at 22 °C for 1 h. After completion, the mixture was washed with saturated NH 4 Cl was quenched and concentrated. The crude product was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to yield the product (10 mg, 59%). LCMS [M+H] + =432; 1H NMR(300MHz,DMSO-d6)δppm 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).

[0534] Embodiment 70

[0535] 2-Fluoro-4-((7-methoxy-2-(morpholinomethyl)-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-benzenesulfonamide (80)

[0536]

[0537] 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) followed by the addition of morpholine (10 μL, 0.115 mmol, 5 eq). The mixture was stirred at 22 °C for 1 h. Upon completion, the mixture was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to yield the product (4 mg). LCMS [M+H] + =487; 1 H NMR(300MHz,DMSO-d6)δppm2.58-2.74(m,4H)3.78(br s,2H)4.04(s,3H)4.13-4.24(m,2H)6.14(s,2H)6.92(s,1H)7.13-7.21(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).

[0538] Embodiment 71

[0539] 2-Fluoro-4-((7-methoxy-2-((methylsulfonyl)methyl)-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)-methyl)benzenesulfonamide (81)

[0540]

[0541] 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 eq) was dissolved in EtOH (0.82 mL, 0.05 M) followed by the addition of NaSMe (9 mg, 0.123 mmol, 3 eq). The mixture was stirred at 22 °C for 3 h. Upon completion, the mixture was concentrated to yield the product. The crude product was used in the next step without further purification.

[0542] 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) and then added to 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. Upon completion, the mixture was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to yield the product (5.3 mg, 31%). LCMS [M+H] + =480; 1 H NMR(300MHz,DMSO-d6)δppm 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).

[0543] Embodiment 72

[0544] 4-((2-(Cyanomethyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-fluorobenzene-sulfonamide (82)

[0545]

[0546] 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) followed by the addition of NaCN (2.5 mg, 0.052 mmol, 2 eq). The mixture was heated to 80 °C for 10 min. Upon completion, the mixture was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to yield the product (2.6 mg, 24%). LCMS [M+H] + =427.

[0547] Embodiment 73

[0548] 2-(1-(3-Fluoro-4-sulfamoylbenzyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-2-yl)-acetic acid methyl ester (83)

[0549]

[0550] 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 Et 3 N (35 μL, 0.254 mmol, 1.2 eq.). The mixture was cooled to 0 °C and methylmalonyl chloride (24 μL, 0.223 mmol, 1.05 eq.) was added. The mixture was stirred at 0 °C for 1 h and then heated to 100 °C for 3 h. After completion, the mixture was partitioned between water and EtOAc. The layers were separated and the aqueous solution was extracted with EtOAc (3x5 mL). The combined organic layers were purified by Na 2 SO 4 Dried and concentrated. The crude was purified by FCC using DCM / THF to give the product (26 mg, 27%). LCMS [M+H] + =460.

[0551] Embodiment 74

[0552] 2-(1-(3-Fluoro-4-sulfamoylbenzyl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-2-yl)acetamide (84)

[0553]

[0554] 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 amine (0.21 mL) in MeOH. The mixture was heated to 65 °C for 2 h. Additional 2N ammonia (0.42 mL) in MeOH was added and heated to 65 °C for 3 h. After completion, the mixture was concentrated. The crude product 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)δppm 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(br s,1H)8.38-8.43(m,1H)9.48(s,1H).

[0555] Embodiment 75

[0556] 4-((2-(azetidin-3-yl)-7-methoxy-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-2-fluorobenzene-sulfonamide (85)

[0557]

[0558] 3-(1-((3-Fluoro-4-sulfamoyl-phenyl)methyl)-7-methoxy-imidazo[4,5-c][1,8]naphthyridin-2-yl)azetidine-1-carboxylic acid tert-butyl ester obtained according to the procedure for the synthesis of compound 74 (43 mg, 79.25 μmol, 1 eq) was dissolved in DCM (1 mL) and then cooled to 0 °C before 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. Upon completion, the mixture was concentrated to yield the product TFA salt (44 mg, 99%). LCMS [M+H] + =443; 1H NMR(300MHz,DMSO-d6)δppm 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).

[0559] Embodiment 76

[0560] 2-Fluoro-4-((7-methoxy-2-(1-(methylsulfonyl)azetidin-3-yl)-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (86)

[0561]

[0562] 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. Et 3 N (2M, 17.16 μL, 1 eq) was added to the mixture followed by MsCl (2M, 17.16 μL, 1 eq). The mixture was stirred at 0°C for 0.5 h. The mixture was warmed to 22°C and stirred for 1.5 h. Cooled to 0°C, additional Et 3 N (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 to 22°C over 18 hours. After completion, the mixture was concentrated. The crude product 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.

[0563] Embodiment 77

[0564] Synthesis of Intermediate 4-Chloro-7-methoxy-2-methyl-3-nitro-1,8-naphthyridine

[0565]

[0566] Step 1. PPA (13 g) was added to 6-methoxy-2-amino-pyridine (5 g, 40.3 mmol, 1 eq.) and methyl acetoacetate (43 mL, 400.3 mmol, 10 eq.). The mixture was heated to 190 ° C for 3 h. After completion, the mixture was cooled to 22 ° C, diluted with water and then washed with EtOAc (2x50 mL) to remove excess methyl acetoacetate. EtOAc (100 mL) was added to the aqueous layer and the pH was adjusted to 8 with 2M NaOH under stirring. The resulting ppt was filtered and dried to yield the product (2.7 g, 35%).

[0567] Step 2. 7-methoxy-2-methyl-1,8-naphthyridine-4-ol (1 g, 5.26 mmol, 1 eq) was dissolved in sulfuric acid (50 mL) and then cooled to 0 ° C. Fuming nitric acid (3.70 g, 58.72 mmol, 2.5 mL, 11.17 eq) was slowly added dropwise to the mixture at 0 ° C. 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 to 60 ° C for 5 h. After completion, the mixture was cooled to 22 ° C and then poured into stirred ice water. The resulting ppt was filtered and dried to give the product (432 mg, 34%).

[0568] Step 3. Suspend 7-methoxy-2-methyl-3-nitro-1,8-naphthyridin-4-ol (423 mg, 1.80 mmol, 1 eq.) in POCl 3 (5.94 g, 38.74 mmol, 3.6 mL, 21.54 equiv) and heated to 80 °C for 1.5 h. Upon completion, the mixture was concentrated and dissolved in DCM. The organic layer was washed with saturated NaHCO 3 The organic layer was washed with Na 2 SO 4 Drying and concentration gave the product (447 mg, 98%).

[0569] Compounds 87 and 88 were prepared in a similar manner to the preparation of compound 39 from the intermediate 4-chloro-7-methoxy-2-methyl-3-nitro-1,8-naphthyridine.

[0570] Embodiment 78

[0571] Prepared 11.9 mg of 6-((7-methoxy-4-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (87). LCMS [M+H] + =385; 1H NMR(300MHz,DMSO-d6)δppm 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).

[0572] Embodiment 79

[0573] Preparation of 7 mg of 2-fluoro-4-((7-methoxy-4-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (88). LCMS [M+H] + =370; 1 H NMR (500MHz, DMSO-d6) δppm 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).

[0574] Compounds 89 and 90 were prepared from the intermediate 4-chloro-7-methoxy-2-methyl-3-nitro-1,8-naphthyridine using triethyl orthoacetate in a similar manner to the preparation of compound 39.

[0575] Embodiment 80

[0576] Prepare 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). LCMS [M+H] + =399; 1 H NMR(300MHz,DMSO-d6)δppm 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).

[0577] Embodiment 81

[0578] Prepare 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). LCMS [M+H] + =434;1 H NMR(300MHz,DMSO-d6)δppm 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).

[0579] Embodiment 82

[0580] 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)

[0581]

[0582] Step 1. Dissolve 4-chloro-7-methoxy-2-methyl-3-nitro-1,8-naphthyridine (200 mg, 788.51 μmol, 1 eq.) in NH 3 (2M, 8 mL, 20.29 equiv) and stirred at 22°C for 3 days. Upon completion, the mixture was concentrated and the resulting precipitate was triturated with water. The resulting precipitate was filtered and dried to yield the product (184 mg, 99%).

[0583] 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 (12 M, 65.47 μL, 1 eq). The mixture was purged with hydrogen (3 cycles) and stirred for 3 h at 22 ° C under a hydrogen balloon. After completion, the mixture was filtered through a celite pad. The cake was washed with MeOH / Et 3 N (90% / 10%) and the filtrate was concentrated to give the product (160 mg, 99%).

[0584] 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 to 80 °C for 8 h. Upon completion, the mixture was concentrated. The resulting residue was mixed with saturated NaHCO 3 Triturate together and filter the brown precipitate. The aqueous layer was allowed to stand at 22°C for 2 h and a light yellow solid began to form. The light yellow precipitate was filtered and dried to yield the product (48 mg, 27%).

[0585] 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 to 50 °C for 4 h. Additional 5-bromo-2-(bromomethyl)pyrimidine (58.27 mg, 231.33 μmol, 1.2 eq) was added and heated to 50 °C for 2 h. Additional 5-bromo-2-(bromomethyl)pyrimidine (58.27 mg, 231.33 μmol, 1.2 eq) was added and stirred at 50 °C for 2 h. Upon completion, 3 drops of TFA were added to the mixture. The mixture was purified by Biotage C18 Duo 12 g column using a water / MeCN (0.1% TFA) gradient. The product fractions were combined and washed with saturated NaHCO 3 The aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic layers were purified by Na 2 SO 4 Drying and concentration gave the product (33 mg, 43%).

[0586] 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(4.75mg, 8.27μmol, 0.1 equivalent), Xantphos (4.78mg, 8.27μmol, 0.1 equivalent) and DIEA (32.05mg, 247.97μmol, 43.19μL, 3 equivalents) were dissolved in dioxane (0.8mL). The mixture was purged with nitrogen for 20 seconds and sealed. It was heated to 80°C for 30 seconds and then cooled to 22°C. Benzyl mercaptan (11.29mg, 90.92μmol, 10.65μL, 1.1 equivalents) was added to the mixture and the mixture was purged with nitrogen for 20 seconds. The vial was sealed and heated to 80°C for 1h. After completion, the mixture was diluted with water and extracted with EtOAc (3x5mL). The combined organic layer was purified by Na 2 SO 4 Dried and concentrated. The crude was purified by FCC using a DCM / MeOH (100% / 0% to 80% / 20%) gradient using a Biotage Sfar 5g silica column to yield the product (21.3 mg, 58%).

[0587] 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 then H 2 O (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 and 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 eq) was added and stirred at 0°C for 10 min. The mixture was added to NH 4 OH (0.5 mL) and stirred for 10 min. The pH of the resulting mixture was adjusted to 8 using 2M HCl. The mixture was concentrated. The crude product was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to yield 91a (3.3 mg, 13%). LCMS [M+H] + =400; 91b, LCMS [M+H] + =434; 1HNMR (400MHz, DMSO-d6) δppm 2.78 (s, 3H) 3.39 (br s, 3H) 3.70 (s, 3H) 5.77 (s, 2H) 6.59 (br s, 2H) 7.53 (d, J = 9.00Hz, 1H) 7.78 (s, 2H).

[0588] Compounds 92-93 were prepared in a similar manner to the preparation of compound 94.

[0589] Embodiment 83

[0590] Prepared 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). LCMS [M+H] + =477; 1 H NMR(300MHz,DMSO-d6)δppm 2.93(br s,6H)3.03-3.05(m,3H)4.04(s,3H)4.81(br s,2H)6.10(s,2H)6.85(dd,J=9.67,5.57Hz,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).

[0591] Embodiment 84

[0592] Prepare 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). LCMS [M+H] + =478; 1 H NMR(300MHz,DMSO-d6)δppm 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).

[0593] Embodiment 85

[0594] 2,5-Difluoro-4-((2-(hydroxymethyl)-7-methoxy-4-methyl-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (94)

[0595]

[0596] 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 followed by the addition of (2-chloro-2-oxo-ethyl)acetate (8.34 mg, 61.06 μmol, 6.56 μL, 1 eq). The mixture was stirred at 0°C for 1 h. Upon completion, the mixture was quenched with water at 0°C and saturated NaHCO 3 The aqueous layer was extracted with EtOAc (3 x 2 mL). The combined organic layers were purified by Na 2 SO 4 Drying and concentration gave the product. The crude product was used in the next step without further purification.

[0597] 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 the addition of NaOH (2M, 45.63 μL, 1.5 eq). The vial was sealed and heated to 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 product 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)δppm 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).

[0598] The following compounds were prepared according to the synthesis of compound 38.

[0599] Embodiment 86

[0600] Prepare 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). LCMS [M+H] + =422.

[0601] Embodiment 87

[0602] Prepare 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). LCMS [M+H] + =387. 1 H NMR(400MHz,DMSO-d6)δppm 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).

[0603] Embodiment 88

[0604] Preparation of 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). LCMS [M+H] + =404. 1 H NMR(400MHz,DMSO-d6)δppm 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(br s,1H).

[0605] Embodiment 89

[0606] Prepare 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). LCMS [M+H] + =387. 1H NMR(400MHz,DMSO-d6)δppm 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(d d,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(br s,1H).

[0607] Embodiment 90

[0608] Prepare 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). LCMS [M+H] + =422; 1 H NMR (400MHz, DMSO-d6) δppm3.92 (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).

[0609] Embodiment 91

[0610] Prepare 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). LCMS [M+H] + =400; 1 H 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).

[0611] Embodiment 92

[0612] 3-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)cyclobutylsulfamate (97)

[0613]

[0614] At 0 ° C, formic acid (4.90 mg, 106.56 μmol, 4.02 μL, 2 equivalents) was added dropwise to chlorosulfonyl isocyanate (15.08 mg, 106.56 μmol, 9.25 μL, 2 equivalents). The resulting mixture was stirred for 18 h to produce sulfamoyl chloride. 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]-naphthyridine-2-one (16 mg, 0.053 mmol, 1 equivalent, obtained according to the preparation of compound 38) in DMA (0.5 mL) at 0 ° C. The reaction mixture was slowly warmed to 22 ° C and stirred for 3 h. After completion, the solution was subjected to preparative HPLC using water / MeCN (0.1% TFA) to yield the product (1.9 mg, 9%). LCMS [M + H] + =380.

[0615] Embodiment 93

[0616] Prepare 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). LCMS [M+H] + =404.

[0617] Embodiment 94

[0618] Prepare 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). LCMS [M+H] + =422; 1 H NMR (400MHz, DMSO-d6) δppm 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).

[0619] Embodiment 95

[0620] Prepare 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). LCMS [M+H] + =440; 1H NMR(300MHz, DMSO-d6)δppm4.06(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).

[0621] Embodiment 96

[0622] Prepare 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). LCMS [M+H] + =436; 1 H NMR(300MHz,DMSO-d6)δppm 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).

[0623] Embodiment 97

[0624] 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)

[0625]

[0626] 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 then Et 3 N (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.). 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 using 2M HCl. The resulting precipitate was filtered. The crude product was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient. The product fractions were combined and the pH was adjusted to 4, then washed with EtOH / CHCl. 3The combined organic layers were concentrated to give the product (31 mg, 56%).

[0627] 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 homogeneous and was stirred at 22 °C for 5 min. After completion, the mixture was concentrated to yield the product (30.6 mg, 97%). LCMS [M+H] + =464; LCMS [M+H] + =422; 1 HNMR(300MHz,DMSO-d6)δppm 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).

[0628] Embodiment 98

[0629] According to the procedure for synthesizing 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)δppm 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).

[0630] Embodiment 99

[0631] According to the procedure for synthesizing 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; 1H NMR(300MHz,DMSO-d6)δppm 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).

[0632] Embodiment 100

[0633] According to the preparation of compound 38, 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. LCMS [M+H] + =436; 1 H NMR(300MHz,DMSO-d6)δppm 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).

[0634] Embodiment 101

[0635] 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)

[0636]

[0637] Step 1. 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 Et 3 N (60.23 mg, 595.23 μmol, 82.85 μL, 3 equiv) and Pd(dppf)Cl 2 (14.52 mg, 19.84 μmol, 0.1 eq.). The mixture was degassed by CO balloon and stirred at 65 °C for 1 hour. After completion, the mixture was concentrated. The crude product was purified by FCC using a water / MeCN (0.1% TFA) gradient using a Biotage C18 Duo 12g column to yield the product (62 mg, 78%). LCMS [M+H] + =401.

[0638] Step 2. 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) was added LiOH (1 M, 1.62 mL, 10 eq) in one portion at 22 °C. The mixture was stirred at 55 °C for 1 hour. Upon completion, the mixture was concentrated. The crude product was purified by FCC using a water / MeCN (0.1% TFA) gradient using a Biotage C18 Duo 12g column to yield compound 108 (2.4 mg, 4%). LCMS [M+H] + =387. 1 H NMR (300MHz, DMSO-d6) δppm 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 (br s, 1H).

[0639] Embodiment 102

[0640] 3,5-Difluoro-4-((7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)-benzamide (109)

[0641]

[0642] 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 NH 3 (2M, 2.50 mL, 40 equiv). The vial was sealed and heated to 65 °C for 2 h. Additional NH 3 (2M, 2.50 mL, 40 equiv) and heated to 65 °C for 18 h. After completion, the mixture was concentrated. The resulting precipitate was mixed with saturated NaHCO 3 Triturate together. Filter the precipitate. The crude product was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to yield compound 109 (9.3 mg, 15%). LCMS [M+H] + =386; 1H NMR (300MHz, DMSO-d6) δppm 4.05 (s, 3H) 5.68 (s, 2H) 7.27 (d, J = 9.38Hz, 1H) 7.54 (d, J = 8.79Hz, 2H) 7.63 (br s, 1H) 8.07 (br s,1H)8.72(s,1H)8.80(d,J=9.38Hz,1H)12.23(br s,1H).

[0643] Embodiment 103

[0644] 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)

[0645]

[0646] 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 MeOH (2.5 mL) followed by the addition of hydroxylamine hydrochloride (86.79 mg, 1.25 mmol, 10 eq). The mixture was sonicated until the hydroxylamine dissolved and then cooled to 0 °C. NaOMe (4.4 M, 369.01 μL, 13 eq) was added to the mixture in one go. The mixture was allowed to stir at 22 ° 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 product was mixed with saturated NaHCO 3 The resulting precipitate was triturated together and filtered. The crude product was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to yield compound 110 (29.4 mg, 46%). LCMS [M+H] + =402; 1 H NMR (300MHz, DMSO-d6) δppm 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 (br d,J=8.79Hz,1H)11.24-11.50(m,1H)12.02-12.28(m,1H). LCMS[M+H] + =387.

[0647] Embodiment 104

[0648] (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)

[0649]

[0650] 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) and then Boc 2 O (298.46 mg, 1.37 mmol, 314.17 μL, 1.44 equiv) and Cs 2 CO 3 (464.13 mg, 1.42 mmol, 1.5 eq.). The mixture was stirred at 22°C for 2 h. After completion, the mixture was added to water and the resulting precipitate was filtered and dried to yield the product (463 mg, 94%).

[0651] Step 2. 1-((4-Bromo-2,6-difluoro-phenyl)methyl)-7-methoxy-2-oxo-imidazo[4,5-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (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-dioxaborolan (151.98 mg, 598.49 μmol, 1.2 eq), KOAc (146.84 mg, 1.50 mmol, 3 eq) and Pd(dppf)Cl were added. 2 DCM complex (40.73 mg, 49.87 μmol, 0.1 equivalent) was suspended in dioxane (2.5 mL). The mixture was purged with nitrogen for 30 seconds and sealed. The mixture was heated to 80 ° C for 2 h. After completion, the mixture was cooled to 22 ° C and diluted with water. The mixture was extracted with EtOAc (3x5 mL). The combined organic layer was purified by Na 2 SO 4 Dried and concentrated. The crude was purified by FCC using a DCM / MeOH (100% / 0% to 80% / 20%) gradient using a Biotage Sfar 5g silica column to yield the product (198 mg, 70%).

[0652] Step 3. 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-carboxylic acid tert-butyl ester (50 mg, 87.97 μmol, 1 eq) was dissolved in acetone (1.35 mL) and H 2 O (0.9 mL), followed by the addition of NaIO 4 (56.45 mg, 263.91 μmol, 14.62 μL, 3 eq.) and NH 4 OAc (20.34 mg, 263.91 μmol, 3 eq.). The mixture was stirred at 22 ° C for 4 h. After completion, the mixture was filtered through a celite pad and concentrated. The residue was suspended in 1: 1 DCM: TFA (2 mL) and stirred at 22 ° C for 10 min. The mixture was concentrated. The crude product was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to yield compound 111 (23.6 mg, 54%). LCMS [M + H] + =387; 1 H NMR (300MHz, DMSO-d6) δppm 4.04 (s, 3H) 5.65 (s, 2H) 7.25 (d, J = 8.79Hz, 1H) 7.35 (d, J = 8.79Hz, 2H) 8.41 (br s, 1H) 8.71-8.76 (m, 2H) 12.21 (br s, 1H).

[0653] Embodiment 105

[0654] 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)

[0655]

[0656] Step 1. 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 eq) in DMF (2.5 mL) was added MeI (44.48 mg, 313.39 μmol, 19.51 μL, 1.2 eq) and NaH (12.54 mg, 313.39 μmol, 60% purity, 1.2 eq) in one portion at 0°C. The mixture was stirred at 0°C for 1 h. Upon completion, water (10 mL) was added to the reaction mixture. The aqueous layer was purified by EtOH / CHCl 3 =1:3 extraction. The organic layer was treated with Na2 SO 4 Dried and concentrated. The crude was purified by Biotage Sfar 10 g silica column using DCM / EtOAc to give the product (28 mg, 25%).

[0657] Step 2. In N 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 eq) in DMF (2 mL) at 22 °C were added DIEA (74.83 mg, 579.02 μmol, 100.85 μL, 3.6 eq), XantPhos (9.31 mg, 16.08 μmol, 0.1 eq) and Pd(dba) in one portion. 2 =Toluene-2-yl thiol (9.25 mg, 16.08 μmol, 0.1 eq.). The mixture was stirred at 80 °C for 10 min. Benzyl mercaptan (23.97 mg, 193.01 μmol, 22.61 μL, 1.2 eq.) was added to the reaction and then heated to 80 °C for 2 h. After completion, the mixture was concentrated. The crude product was purified by Biotage Sfar 5g silica column using DCM / MeOH to give the product (60 mg, 78%).

[0658] Step 3. 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) at 0 °C were added AcOH (26.35 mg, 438.86 μmol, 25.10 μL, 7 eq) and H 2 O (15.82 mg, 877.72 μmol, 15.82 μL, 14 eq.) Then 1,3-dichloro-5,5-dimethylhydantoin (17.29 mg, 87.77 μmol, 1.4 eq.) was added to the reaction mixture at 0°C. The mixture was stirred at 0°C for 2 h. 4 OH (659.15 mg, 18.81 mmol, 724.34 μL, 300 equiv) was cooled to 0° C. The reaction mixture was added dropwise to NH 4OH (659.15 mg, 18.81 mmol, 724.34 μL, 300 equiv) and stirred at 0 ° C for 1 h. After completion, the mixture was acidified to pH = 1 and concentrated. The crude product was purified by Biotage C18 Duo 12g column using water / MeCN (0.1% TFA) to yield the product (28.6 mg, 83%). LCMS [M+H] + =436; 1 H NMR(300MHz,DMSO-d6)δppm 3.51(br s,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).

[0659] According to the preparation of compound 114, the following compounds were prepared.

[0660] Embodiment 106

[0661] According to the procedure for 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.

[0662] Embodiment 107

[0663] According to the procedure for 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)δppm 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).

[0664] Embodiment 108

[0665] According to the procedure for 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 (400 MHz, 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).

[0666] Embodiment 109

[0667] According to the procedure for 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; 1 H NMR(400MHz,DMSO-d6)δppm 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).

[0668] Embodiment 110

[0669] According to the procedure for 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.

[0670] Embodiment 111

[0671] 4-((7-Methoxy-1H-pyrazolo[4,3-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (116)

[0672]

[0673] 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 in cyclohexane (2.4 mL, 2.4 mmol, 2.4 eq) was added to the mixture. Upon completion, the mixture was warmed to 0°C and washed with saturated NH 4 The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were purified by Na 2 SO 4 Dry and concentrate. The product was used in the next step without further purification.

[0674] Step 2. (4-chloro-7-methoxy-1,8-naphthyridin-3-yl)methanol from the previous step was dissolved in DCM (10 mL) followed by the addition of MnO 2 (870 mg, 10 mmol, 10 equiv). The mixture was stirred at 22 °C for 2 h. After completion, the mixture was filtered through a pad of celite and the filtrate was concentrated to give the product (132 mg, 59% over 2 steps).

[0675] 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 to 90 °C for 24 h. Upon completion, the mixture was cooled to 22 °C and concentrated. The crude product was dissolved in EtOAc and washed with saturated NaHCO 3 The aqueous layer was back extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with Na 2 SO 4 Drying and concentration gave the product (100 mg, 91%).

[0676] 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 then 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; 1HNMR(300MHz,DMSO-d6)δppm 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).

[0677] Embodiment 112

[0678] 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): According to the procedure for the synthesis of 4-((7-methoxy-1H-pyrazolo[4,3-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide, 66 mg and 10 mg of the two products were prepared, respectively, in 35% yield. 122a: LCMS [M+H] + =388; 1 H NMR(300MHz, DMSO-d6)δppm4.06(s,3H)5.93(s,2H)7.29(br d,J=8.79Hz,1H)7.33(br d,J=8.21Hz,1H)7.43(br d,J=11.14Hz,1H)7.65(s,2H)7.77-7.83(m,1H)8.74(d,J=8.79Hz,1H)9.33(s,1H)9.70(s,1H); 122b: LCMS[M+H] + =388; 1 H NMR(300MHz,DMSO-d6)δppm 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).

[0679] Embodiment 113

[0680] 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): According to the procedure for 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 of the products were prepared, respectively. 135a: LCMS [M+H] + =371; 135b: LCMS [M+H] + =371.

[0681] Embodiment 114

[0682] 4-((7-Methoxy-1H-pyrrolo[3,2-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (117)

[0683]

[0684] Step 1. 5-chloro-2-methoxy-1,8-naphthyridine (527 mg, 2.7 mmol, 1 eq.), tert-butyl carbamate (380 mg, 3.25 mmol, 1.2 eq.), Pd(dba) 2 (78 mg, 0.135 mmol, 0.05 eq), XPhos (129 mg, 0.27 mmol, 0.1 eq) and Cs 2 CO 3 (1.76 g, 5.4 mmol, 2 equivalents) was suspended in dioxane (14 mL, 0.2 M). The mixture was purged with nitrogen for 1 min and then heated to 100 ° C for 5 h under a nitrogen atmosphere. After 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.

[0685] Step 2. The (7-methoxy-1,8-naphthyridin-4-yl)carbamate from the previous step was suspended in DCM (5.4 mL, 0.5 M) and then cooled to 0 °C before adding 4 M HCl in dioxane (2.7 mL). The mixture was stirred at 22 °C until all the starting material was consumed. Upon completion, the mixture was concentrated to yield the product. The product was used in the next step without further purification.

[0686] Step 3. 7-methoxy-1,8-naphthyridine-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 eq) was added to the mixture. The mixture was stirred at 22 ° C until the starting material was no longer observed on LCMS. After completion, the mixture was poured into water. The resulting precipitate was filtered and dried to give the product (459 mg, 67% over 3 steps).

[0687] 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 K 3 PO 4 (760 mg, 3.58 mmol, 2 eq.) dissolved in 4:1 MeCN / H 2 O (10 mL, 0.18 M). The mixture was purged with nitrogen for 1 min and then heated to 110° C. Upon completion, the mixture was cooled to 22° C. and poured into saturated NH 4 The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were purified by Na 2 SO 4 Dried and concentrated. The crude was purified by FCC using DCM / MeOH to give the product (280 mg, 64%).

[0688] Step 5. (E)-3-(2-ethoxyvinyl)-7-methoxy-1,8-naphthyridin-4-amine (280 mg, 1.14 mmol, 1 eq) was dissolved in 1.25 M HCl (14 mL) in EtOH. The mixture was heated to 75° C. Upon completion, the mixture was cooled to 22° C. and concentrated to yield the product (259 mg, 97%).

[0689] 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 K 2 CO 3(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 product was purified by preparative HPLC using water / MeCN (0.1% TFA) to yield the product (22.7 mg, 22%). LCMS [M+H] + =369; 1 HNMR(600MHz,DMSO-d6)δppm 3.99(s,3H)6.08(s,2H)6.93-6.97(m,1H)7.21(br d,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).

[0690] Embodiment 115

[0691] 2-Fluoro-4-((7-methoxy-1H-pyrazolo[4,3-c]cinnolin-1-yl)methyl)benzenesulfonamide (118)

[0692]

[0693] Step 1. To a mixture of 4-chloro-7-methoxy-cinnoline-3-carboxylic acid ethyl ester (300 mg, 1.12 mmol, 1 eq.) in THF (10 mL) was added DIBAL (1 M, 3.37 mL, 3 eq.) dropwise at -78°C. The mixture was stirred at -78°C for 3 hours. After completion, saturated NaHCO 3 , potassium sodium tartrate, EtOAc were added to the reaction mixture and stirred at 22°C for 18 h. The aqueous layer was extracted with EtOAc (3 x 20 mL). The organic layers were combined and purified by Na 2 SO 4 Dry and concentrate. The crude residue was dissolved in DCM (10 mL). MnO 2 (978.03 mg, 11.25 mmol, 10 equiv) was added to the reaction mixture. The reaction was stirred at 22 °C for 3 hours. After completion, the reaction was filtered through a celite pad and concentrated. The crude product was purified by FCC to yield the product (156 mg, 63%).

[0694] Step 2. To a mixture of 4-chloro-7-methoxy-cinnoline-3-carboxaldehyde (156 mg, 700.72 μmol, 1 eq.) in MeOH (15 mL) was added hydrazine (40.42 mg, 1.26 mmol, 45.63 μL, 1.8 eq.) at 22 °C. The mixture was stirred at 65 °C for 18 h. After completion, the mixture was concentrated. The crude product was purified by FCC to give the product (87 mg, 62%).

[0695] Step 3. NaH (8.39 mg, 209.79 μmol, 60% purity, 1.2 eq.) was added to a mixture of 7-methoxy-1H-pyrazolo[4,3-c]cinnoline (35 mg, 174.83 μmol, 1 eq.) in DMF (1 mL) at 22 °C in one go. The mixture was stirred for 5 min at 22 °C. 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 hours. After completion, the reaction was quenched by 1N HCl (2 mL). The solid was decomposed from 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) δppm 3.96 (s, 3H) 6.25 (s, 2H) 7.41-7.53 (m, 2H) 7.58 (br d, J = 7.62Hz, 1H) 7.63 (s, 2H) 7.75 (br t, J = 7.91Hz, 1H) 7.93 (br s,1H)8.91(d,J=8.79Hz,1H)10.25(s,1H).

[0696] Embodiment 116

[0697] 6-((7-Methoxy-1H-[1,2,3]triazolo[4,5-c][1,8]naphthyridin-1-yl)methyl)pyridine-3-sulfonamide (119)

[0698]

[0699] NaNO 2 (4.82 mg, 69.92 μmol, 1.2 eq) was dissolved in water (0.1 mL). 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 eq) in HCl (2 M, 291.35 μL, 10 eq) at 0 °C was added NaNO in one portion.2 (4.82 mg, 69.92 μmol, 1.2 eq.) solution. The mixture was stirred at 0°C for 30 min. Upon completion, the solution was subjected to preparative HPLC using water / MeCN (0.1% TFA) to yield the product (6.2 mg, 29%). LCMS [M+H] + =372; 1 H NMR(300MHz,DMSO-d6)δppm 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)8.1 9(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).

[0700] Embodiment 117

[0701] According to 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) δppm 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).

[0702] Embodiment 118

[0703] According to 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)δppm 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).

[0704] Embodiment 119

[0705] (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)

[0706]

[0707] Step 1. In N 2 To a mixture of 1-ethoxyphosphonooxyethane (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) at 22 °C was added Et 3 N (30.12 mg, 297.62 μmol, 41.42 μL, 3 equiv) and Pd(dppf)Cl 2 (7.26 mg, 9.92 μmol, 0.1 eq.). The mixture was stirred at 80 °C for 3 hours. After completion, the mixture was concentrated. The crude was purified by Biotage Sfar 5g silica column using DCM / MeOH to yield the product (44 mg, 96%).

[0708] Step 2. 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) at 22°C 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 then stirred at 22°C for 5 h. Upon completion, MeOH (20 mL) was added to the reaction mixture and stirred for 30 min. The mixture was concentrated and the crude product was purified by preparative HPLC using a water / MeCN (0.1% TFA) gradient to yield the product (30 mg, 36%). LCMS [M+H] + =405; 1H NMR (400MHz, DMSO-d6) δppm 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).

[0709] Based on the preparation of compound 121, compounds 124-127 were prepared.

[0710] Embodiment 120

[0711] According to the procedure for synthesizing 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.

[0712] Embodiment 121

[0713] (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.

[0714] Embodiment 122

[0715] (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.

[0716] Embodiment 123

[0717] According to the procedure for the synthesis of 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.

[0718] Embodiment 124

[0719] According to 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; 1H NMR (300MHz, DMSO-d6) δppm 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 (br d,J=1.76Hz,2H)7.67(dd,J=9.96,1.76Hz,1H)7.96(d,J=9.38Hz,1H).

[0720] Embodiment 125

[0721] 4-((7-Methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]cinnolin-1-yl)methyl)benzene-sulfonamide (128)

[0722]

[0723] Step 1. 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) at 22 °C. The mixture was stirred at 65 °C for 1 hour. After completion, the mixture was concentrated. The resulting residue was triturated with EtOAc to give the product (112 mg, 90%).

[0724] Step 2. 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) was added LiOH (1 M, 2.60 mL, 10 eq) in one portion at 22°C. The mixture was stirred at 50°C for 1 hour. Upon completion, the organic solvent was removed under vacuum and then acidified to pH = 4. The aqueous layer was filtered through EtOH / CHCl 3 =1:3 extraction. Both the aqueous layer and the organic layer contained the product. All solvents were combined and then concentrated. The resulting white solid was extracted with EtOH and filtered. The filtrate was concentrated to yield the crude product. The product was used in the next step without further purification.

[0725] Step 3. To a mixture of this product in DMF (3 mL) at 22 °C were added DPPA (171.84 mg, 624.42 μmol, 135.31 μL, 2.4 equiv), Et 3N (263.27 mg, 2.60 mmol, 362.13 μL, 10 equiv.). The mixture was stirred at 80 °C for 3 h. After completion, the mixture was concentrated. The crude product was purified by DCM / MeOH to yield the product (17 mg, 16%). LCMS [M+H] + =400; 1 H NMR(400MHz, DMSO-d6)δppm4.01(s,3H)4.19(s,2H)5.56(s,2H)6.79(s,2H)7.17(d,J=9.00Hz, 1H)7.22-7.25(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).

[0726] Embodiment 126

[0727] According to 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.

[0728] Embodiment 127

[0729] According to the preparation of compound 38, 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 4-hydroxy-7-methoxycinnoline-3-carboxylic acid ethyl ester. LCMS [M+H] + =386; 1 H NMR(300MHz,DMSO-d6)δppm 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).

[0730] Embodiment 128

[0731] 3,5-Difluoro-4-(7-methoxy-2-oxo-2,3-dihydro-1H-imidazo[4,5-c][1,8]naphthyridin-1-yl)methyl)benzenesulfamide (138)

[0732]

[0733] 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) and then Boc 2 O (298.46 mg, 1.37 mmol, 314.17 μL, 1.44 equiv) and Cs 2 CO 3 (464.13 mg, 1.42 mmol, 1.5 eq.). The mixture was stirred at 22°C for 2 h. After completion, the mixture was added to water and the resulting precipitate was filtered and dried to yield the product (463 mg, 94%).

[0734] Step 2. 1-((4-bromo-2,6-difluoro-phenyl)methyl)-7-methoxy-2-oxo-imidazo[4,5-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (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.), Cs 2 CO 3 4-(4-(4-(4-(4-piperidin-2-yl)-2-nitropropene)-1 ...

[0735] Step 3. 1-((4-(tert-Butyloxycarbonylamino)-2,6-difluoro-phenyl)methyl)-7-methoxy-2-oxo-imidazo[4,5-c][1,8]naphthyridine-3-carboxylic acid tert-butyl ester (108 mg, 193.71 μmol, 1 eq) was dissolved in DCM (0.5 mL) followed by the addition of TFA (770.00 mg, 6.75 mmol, 0.5 mL, 34.86 eq). The mixture was stirred at 22 °C for 1.5 h. Upon completion, the mixture was concentrated and then dissolved in DCM. The crude product was purified by evaporation using saturated NaHCO 3 Free base and extract with EtOAc (3 x 10 mL). The combined organics were purified by Na 2 SO 4Dried and concentrated. The crude was purified by Biotage C18 Duo 12g column using a water / MeCN (0.1% TFA) gradient to give the product (24 mg, 35%).

[0736] 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. Et 3 N (135.93 mg, 1.34 mmol, 186.98 μL, 20 equiv) 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 yield the product (28.1 mg, 76%). LCMS [M+H] + =437.

[0737] Biological Examples

[0738] Example B1: ENPP1 activity assay using p-nitrophenyl-5'-TMP as substrate.

[0739] 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 p-nitrophenol, which is a chromogenic product. The amount of p-nitrophenol product formed is measured using its absorbance at 405 nm, which is proportional to the enzyme activity.

[0740] To determine the IC 50 8 different concentration points of each inhibitor were prepared with the final assay concentration starting at 1000 nM using 50 mM Tris buffer (pH 9.5) containing 250 mM NaCl. 20 ng of human soluble ENPP1 was loaded into a 50 μL well and incubated with 25 μL inhibitor solution (4X final concentration) for 30 min at room temperature. Then, 25 μL 2 mM TMP solution (2X final concentration) was added to the well and incubated for 1 hour at room temperature. The amount of p-nitrophenolate released was measured by reading the OD value at 405 nm.

[0741] The inhibition percentage of each compound was calculated as follows: Inhibition % = (OD MAX -OD 化合物 ) / (OD MAX -OD MIN)*100. (MAX: control without ENPP1 inhibitor, MIN: blank control).

[0742] By using the The inhibition curves were fitted with a four-parameter variable slope model in 8 to determine the IC for the percentage inhibition versus compound concentration. 50 value. The IC 50 The values ​​are listed in Table 2.

[0743] Example B2: ENPP1 activity assay using p-nitrophenyl-5'-AMP as substrate.

[0744] In some cases, inhibitors of ENPP-1 are able to selectively block the hydrolysis of 2'3'-cGAMP while only minimally inhibiting the hydrolysis of ATP. Thus, the ATP analog p-nitrophenyl 5'-adenosine monophosphate (AMP-pNP) has been shown to accurately reflect the hydrolysis of native ATP by different classes of ENPP1 inhibitors. AMP-pNP can be used as a substrate for ENPP-1. Its hydrolysis products are nucleotide-5'-monophosphate and p-nitrophenol (which is also a chromogenic product). The amount of p-nitrophenol product formed is measured using its absorbance at 405nm, which is proportional to the enzyme activity.

[0745] To determine the IC 50 The final assay concentration was used to prepare 12 points of different concentrations of each inhibitor, starting at 9000 nM and serially diluted 3X with 50 mM Tris buffer (pH 9.5) containing 250 mM NaCl. 35 ng of human soluble ENPP1 was loaded into a 50 μL well and incubated with 25 μL of inhibitor solution (4X final concentration) for 30 min at room temperature, and then 25 μL of 3 mM AMP solution (2X final concentration) was added to the well and incubated for 1 hour at room temperature. The amount of p-nitrophenolate released was measured by reading the OD value at 405 nm.

[0746] The inhibition percentage of each compound was calculated as follows: Inhibition % = (OD MAX -OD 化合物 ) / (OD MAX -OD MIN )*100. (MAX: control without ENPP1 inhibitor, MIN: blank control).

[0747] By using the The inhibition curves were fitted with a four-parameter variable slope model in 8 to determine the IC for the percentage inhibition versus compound concentration. 50 value. The IC 50The values ​​are listed in Table 2.

[0748] Table 2

[0749]

[0750]

[0751]

[0752]

[0753] *PF-QS1 is compound 1 in Bioorganic & Medicinal Chemistry Letters 19 (2009) 3339-3343, Snahel D. Patel et al.;

[0754] **MV0000658 is a representative compound in WO 2019 / 046778Al, Gallatin, WM et al.

[0755] Example B3: Quantification of 2'3'-cGAMP hydrolysis

[0756] When ENPP-1 uses 2'3'-cGAMP as a substrate, the hydrolysis products are 5'-GMP and 5'-AMP. In some cases, AMP-Glo TM The assay kit (Promega Corporation) measures ENPP1 activity with a 2'3'-cGAMP substrate to quantify 5'-AMP production. AMP-Glo TM The assay kit contains two reagents that are added sequentially. Reagent I converts the 5'-AMP produced in the reaction into 5'ADP. Reagent II converts 5'-ADP into 5'ATP, and allows the 5'-ATP to react with the luciferase / luciferin pair to produce a luminescent signal.

[0757] The ENPP1 assay with 2'3'-cGAMP substrate was performed in 50mM Tris buffer (pH 9.5) containing 250mM NaCl. 3X serial dilutions were made from 9000nM, and 12 different concentration points of each inhibitor were prepared with the final assay concentration. The wells were run in duplicate at each inhibitor concentration. The final assay volume was 18 μL / well in a 384 white assay plate, containing 9 μL inhibitor solution, 4.5 μL human recombinant ENPP-1 protein (20ng / well) and 4.5 μL 2', 3'-cGAMP in the wells, with a final concentration of 20 μM. The assay was started by adding substrate, and incubated at room temperature for 2 hours, then 5 μL was taken out and mixed with 5 μL reagent I to stop the reaction. Then 10 μL of reagent II was added, and the wells were incubated at room temperature for another 60 minutes. The luminescent signal was then measured using a plate reader with a luminometer.

[0758] The percentage inhibition of each compound was calculated as follows: % inhibition = (RLU MAX -RLU 化合物 ) / (RLU MAX -RLU MIN )*100. (MAX: control without ENPP1 inhibitor, MIN: blank control).

[0759] Example B4: Cellular enzyme assay of ENPP-1 inhibitors using TMP-pNP as substrate

[0760] ENPP-1 is mainly expressed on the cell membrane surface, where it hydrolyzes 2'3'-cGAMP to produce 5'-GMP and 5'-AMP. ENPP-1 also has the ability to hydrolyze artificial phosphate TMP-pNP into nucleotide-5'-monophosphate and p-nitrophenol (which is a chromogenic product). Therefore, in cultured MDA-MB-231, HEK293 and / or Saos-2 cells, TMP-pNP is used as a substrate to reflect the enzymatic activity of ENPP1. The amount of p-nitrophenol product formed in the culture medium is measured using its absorbance at 405nm, which is proportional to the activity of ENPP1. The lower the OD value at 405, the higher the potency of the ENPP-1 inhibitor.

[0761] Eight different concentration points of each inhibitor were prepared starting from 20 μM with the final assay concentration. 3X serial dilutions were performed using DMEM medium without FBS. 75,000 cells / well were cultured in DMEM at 37°C, 5% CO before adding inhibitors. 2 After removing the supernatant medium, 50 μL of the inhibitor solution was added to each well with cultured cells and incubated at 37°C, 5% CO 2Then, 4 mM (2X final concentration) TMP-pNP solution was mixed with inhibitors in each well for 5 hours, and then the OD value at 405 nm was read using a plate reader.

[0762] By using the The inhibition curves were fitted with a four-parameter variable slope model in 8 to determine the IC for the percentage inhibition versus compound concentration. 50 value.

[0763] Table 3-1 MDA-MB-231

[0764]

[0765]

[0766]

[0767] Table 3-2 HEK 293

[0768]

[0769]

[0770] Table 3-3 Saos-2

[0771] Compound ID <![CDATA[Relative to IC 50 (μM)]]> Inhibition % (at 20 μM) PF-QS1 - 50 Mv0000658 - 52 1 - 32 11a 1.2 87 12 1.0 87 35 5.6 76 36 2.0 48

[0772] Example B5: ENPP1 inhibitor screening on cGAMP-activated THP-1 cells

[0773] THP-1 cells from bulk cultures were counted and expressed as 5.5 x 10 6 The cells were suspended in RPMI 1640, 20% FBS, 2.5 mM L-alanyl-L-glutamine at a concentration of 1 x 10 cells / mL. THP-1 cells were then seeded in 96-well round-bottom plates at 180 μL / well (1 x 10 6 cells / well) at 37°C and 5% CO 2 Incubate for 1 hour.

[0774] The test compounds were screened in triplicate on THP-1 cells at a final concentration of 10 μM. 0.2 mM working solution. Each well contained 180 μL of THP-1 cell suspension, 10 μL (30 μM, 40 μM or 50 μM) 2'3'-cGAMP (InvivoGen, catalog number tlrl-nacga23) solution (600 μM, 800 μM or 1000 μM) and 10 μL of test compound working solution. Incubate for 1 hour.

[0775] Vehicle control wells contained 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) at 40 μM and 80 μM (final concentration).

[0776] 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.

[0777] At 37°C, 5% CO 2 After incubation at 400 °C for 24 hours, the supernatant was harvested at 200 × g for 10 minutes. The cell culture supernatant was then transferred to a clean plate and stored at -80 °C until ready to analyze IFN-β levels. According to the manufacturer's instructions, the IFN-β levels in the cell culture supernatant were determined by ELISA kit (PBL Assay Science, catalog number 41410).

[0778] The % increase measured by IFN-β in cells treated with test compounds 12, 48, 89, 103 and 121 relative to IFN-β in untreated cells was tested (as shown in Figures 1A-1E). The test compounds effectively increased IFN-β levels at very low concentrations.

[0779] Example B6: Liver microsome stability

[0780] The liver microsome assay was used to evaluate the metabolic stability of I-VI. Test articles 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 minutes. The cells were incubated at 37°C, 5% CO 2 The disappearance of the test article was monitored by LC / MS / MS. The disappearance half-life (t 1 / 2 ), intrinsic clearance, and hepatic extraction rate.

[0781] Table 4. Stability of selected compounds in liver microsomes

[0782]

[0783] Example B6: Pharmacokinetics in mice

[0784] The test sample dosing solution was 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 / group) via intravenous (IV) bolus of 1 mg / kg and oral gavage (PO) of 5 mg / kg. Blood samples (approximately 0.03 mL at each time point) were collected via the jugular vein into a test tube containing sodium heparin as an anticoagulant at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after intravenous administration and 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after oral gavage administration. The blood samples were then centrifuged in a refrigerated centrifuge for 5 minutes at 4°C. The resulting plasma samples were analyzed using LC / MS / MS to determine the concentration of the test sample. The concentration of the test sample was determined using a 40 μg / ml HPLC-MS / MS kit with WinNonlin (Phoenix TM , version 8.0) software to calculate the pharmacokinetic (PK) parameters. The PK results are listed in Table 5. Compared with the quinoline analogs of compound 12, most naphthyridine analogs showed significant improvements in clearance, AUC, half-life and oral bioavailability.

[0785] Table 5. Pharmacokinetic parameters in male CD-1 mice (1 mg / kg, intravenous)

[0786]

[0787]

[0788] *NT: Not tested

[0789] It should be understood that the present invention is not limited to the specific embodiments and aspects of the present disclosure described above, as variations may be made thereto and still fall within the scope of the appended claims. All documents cited or relied upon herein are expressly incorporated by reference.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: L1 is the key; L2 is CR1R2, R1 and R2 are hydrogen; Q1 is CE, E at each occurrence is independently selected from hydrogen and C1-C6 alkyl; A2 is N; A3 is CR4, R4 is -OR3, R3 is C1-C6 alkyl; A4 and A5 are CR4, R4 is hydrogen; X is NR3, R3 is hydrogen; Z is P(O)(OR5)2, R5 is hydrogen; Ring A is phenyl, wherein the phenyl group of ring A is optionally substituted by one or two halogens. 2 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the phenyl group of the ring A is optionally substituted by one or two fluorine groups.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein E is H.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each E is independently H or methyl.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A3 is CR4, R4 is -OR3, and R3 is methyl.

6. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 。 7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

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