Imidoursulfone inhibitors of enpp1

Abstract

The present disclosure relates generally to inhibitors of ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1), compositions thereof, and methods of using the compounds and compositions thereof. More particularly, the present disclosure relates to sulfoximine-based inhibitors of ENPP1 of Formula (I) and methods for using the same for the treatment of diseases mediated by ENPP1.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to U.S. Provisional Application No. 63 / 019,853, filed May 4, 2020, and U.S. Provisional Application No. 63 / 093,709, filed October 19, 2020, the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to inhibitors of exonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1), compositions thereof, and methods of using said compounds and compositions thereof. More specifically, this disclosure relates to sulfoxide-based inhibitors of ENPP1 and methods of using them to treat diseases mediated by ENPP1. Background Technology

[0004] In certain human diseases, the maintenance of phosphorylated nucleotides can be dysregulated, leading to poor prognosis, serious complications, and even death. Exonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1), also known as ARHR2, COLED, M6S1, NPP1, NPPS, PC-1, PCA1, and PDNP1, is an enzyme that hydrolyzes phosphorylated nucleotides, including adenosine triphosphate (ATP) and 2',3'-cyclic adenosine monophosphate-guanidine monophosphate (cGAMP). In some cases, ENPP1 depletes its substrate, thereby inhibiting its disease-regressing effect. The accompanying increase in hydrolysates can also have detrimental effects. Therefore, inhibitors of ENNP1 enzyme activity would have beneficial effects on certain human diseases.

[0005] Cells detecting abnormal DNA in the cytoplasm produce cGAMP, an activator of the immune response via the STING pathway. ATP activates immune cells via purine receptor signaling. ENPP1 can be expressed as a mechanism for degrading cGAMP and ATP and evading the immune response. This expression of ENPP1 has been identified in cancers with particularly poor prognoses. Therefore, ENPP1 inhibition may be an effective treatment for cancer, especially in cases of high ENPP1 expression or elevated cytoplasmic DNA levels. Adenosine monophosphate (AMP) is also a product of the hydrolysis of ATP and cGAMP. Adenosine is produced from AMP by enzymes such as CD73, and this adenosine further suppresses the immune response and supports tumor survival via the adenosine receptor pathway.

[0006] ENPP1 is also involved in bacterial or viral infections, insulin resistance and type II diabetes, chondrocalcinosis and osteoarthritis, calcium pyrophosphate deposition disorder (CPPD), hypophosphatase disorder, and soft tissue calcification disorders (such as cardiac calcification after heart injury). Therefore, ENPP1 inhibition can be used to treat any of these conditions. Summary of the Invention

[0007] This disclosure provides compounds of formula (I), compositions thereof, and methods of using said compounds and compositions thereof to treat diseases or ailments related to ENPP1. In one aspect, a compound of formula (I) is provided:

[0008]

[0009] Or its pharmaceutically acceptable salt, wherein W is

[0010] Ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which may or may not be substituted;

[0011] R 1a and R 2a Each is independently hydrogen, and each C is optionally substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocyclic alkyl, or optionally substituted C 1-6 Halogenated alkyl groups;

[0012] Y is either -N- or -CH-;

[0013] X 1 Yes -CR 1b -or -N-;

[0014] X 2 Yes -CR 2b -or -N-;

[0015] X 3 Yes -CR 3b -or -N-;

[0016] X 4 Yes -CR 4b -or -N-;

[0017] X 5 Yes -CR 5b -or -N-;

[0018] X 6 Yes -CR 6b -or -N-;

[0019] R1b -R 6b Each of the following is an independent C-type carbon atom containing hydrogen, halogen, hydroxyl group, or optionally substituted with one or more halogen substituents. 1-4 Alkoxy, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, nitro, -NR 1c R 2c -NHC(O)R 3c or -C(O)NR 4c R 5c ;

[0020] L represents a bond, -O-, -C(O)-, -NR 6c -or-OCR 7c -*, where * indicates AND The connection point;

[0021] R 1c -R 7c Each is independently hydrogen or C 1-3 alkyl;

[0022] a 1 a 2 b 1 and c 4 Each is independently 0, 1, 2, or 3; and

[0023] b 2 c 1 -c 3 d 1 -d 4 e 1 and e 2 Each can be 1, 2, or 3 independently.

[0024] In another aspect, a pharmaceutical composition is provided comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0025] In another aspect, a method for inhibiting ENPP1 is provided, which includes contacting cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0026] In another aspect, a method is provided for treating a subject in need of cancer, bacterial and / or viral infection, insulin resistance, type II diabetes, chondrocalcinosis, osteoarthritis, soft tissue calcification, calcium pyrophosphate deposition, or hypophosphoesterase syndrome, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Detailed Implementation

[0027] The following description is presented to enable those skilled in the art to make and use the various embodiments. The descriptions of specific apparatuses, techniques, and applications are provided by way of example only. Those skilled in the art will understand various modifications to the examples described herein, and the general principles defined herein can be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Therefore, the various embodiments are not intended to be limited to the examples described and shown herein, but are to be accorded the scope consistent with the claims.

[0028] As used in this specification, the following words and phrases are generally intended to have the meanings set forth below, unless otherwise indicated in the context in which they are used.

[0029] Throughout this application, unless the context otherwise indicates, references to compounds of formula (I) include all subgroups of formula (I) as defined herein, such as formulas (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), including all substructures, subgenus, preferences, embodiments, examples, and specific compounds as defined and / or described herein. In some embodiments, references to compounds of formula (I) and their subgroups (such as (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig)) include their ionic form, polymorph, pseudopolymorph, amorphous form, solvate, cocrystal, chelate, isomer, tautomer, oxide (e.g., N oxide, S oxide), ester, prodrug, isotope and / or protected form. In some embodiments, references to compounds of formula (I) and their subgroups (such as (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig)) include their polymorphs, solvates, cocrystals, isomers, tautomers and / or oxides. In some embodiments, references to compounds of formula (I) and their subgroups (such as formulas (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig)) include their polymorphs, solvates and / or eutectics. In some embodiments, references to compounds of formula (I) and their subgroups (such as (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig)) include their isomers, tautomers and / or oxides.In some embodiments, references to compounds of formula (I) and their subgroups (such as (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig)) include their solvates.

[0030] "alkyl" encompasses straight-chain and branched carbon chains having a specified number of carbon atoms, such as 1 to 20 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C 1-6 Alkyl groups encompass straight-chain and branched alkyl groups having 1 to 6 carbon atoms. When naming alkyl residues having a specific number of carbon atoms, it is intended to cover all branched and straight-chain forms having said number of carbon atoms; thus, for example, "propyl" includes n-propyl and isopropyl; and "butyl" includes n-butyl, sec-butyl, isobutyl, and tert-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0031] When a range of values ​​is given (e.g., C), 1-6 Alkyl), including every value in the range and all intermediate ranges. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 2-6 C 3-6 C 4-6 C 5-6 C 1-5 C 2-5 C 3-5 C 4-5 C 1-4 C 2-4 C 3-4 C 1-3 C 2-3 and C 1-2 alkyl.

[0032] "Alkenyl" refers to an unsaturated branched or straight-chain alkyl group having a specified number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group may be in a cis or trans configuration (Z or E configuration) around the double bond. Alkenyl groups include, but are not limited to, vinyl, propenyl (e.g., propen-1-en-1-yl, propen-2-yl, propen-2-en-1-yl (allyl), propen-2-en-2-yl) and butenyl (e.g., buten-1-en-1-yl, buten-2-yl, 2-methyl-propen-1-en-1-yl, buten-2-en-1-yl, buten-2-en-2-yl, buten-1,3-dien-1-yl, buten-1,3-dien-2-yl).

[0033] "Alynyl" refers to an unsaturated branched or straight-chain alkyl group having a specified number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl), and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl).

[0034] “Cycloalkyl” refers to a non-aromatic, fully saturated carbocyclic ring having a specified number of carbon atoms, such as 3 to 10, 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged and cage-like ring groups (e.g., norcamphene, bicyclic [2.2.2]octane). Additionally, one ring of a polycyclic cycloalkyl group can be aromatic, provided that the polycyclic cycloalkyl group is bonded to the parent structure via a non-aromatic carbon atom. For example, 1,2,3,4-tetrahydronaphth-1-yl (wherein the portion is bonded to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphth-5-yl (wherein the portion is bonded to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups composed of cycloalkyl groups fused with aromatic rings are described below.

[0035] "Cycloalkenyl" means a non-aromatic carbon ring containing a specified number of carbon atoms (e.g., 3 to 10, 3 to 8, or 3 to 6 cyclic carbon atoms) and at least one carbon-carbon double bond. Cycloalkenyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as bridged and cage-like cyclic groups (e.g., bicyclic [2.2.2]octene). Additionally, one ring of a polycyclic cycloalkenyl group can be aromatic, provided that the polycyclic cycloalkenyl group is bonded to the parent structure via a non-aromatic carbon atom. For example, inden-1-yl (where the portion is bonded to the parent structure via a non-aromatic carbon atom) is considered a cycloalkenyl group, while inden-4-yl (where the portion is bonded to the parent structure via an aromatic carbon atom) is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups composed of cycloalkenyl groups fused with aromatic rings are described below.

[0036] "Aryl" refers to an aromatic carbon ring having a specified number of carbon atoms, such as 6 to 12 or 6 to 10 carbon atoms. Aryl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of a polycyclic aryl group are aromatic rings (e.g., naphthyl). In other cases, a polycyclic aryl group may include a non-aromatic ring fused to an aromatic ring, provided that the polycyclic aryl group is bonded to the parent structure via atoms in the aromatic ring. Therefore, 1,2,3,4-tetrahydronaphth-5-yl (wherein the portion is bonded to the parent structure via aromatic carbon atoms) is considered an aryl group, while 1,2,3,4-tetrahydronaphth-1-yl (wherein the portion is bonded to the parent structure via non-aromatic carbon atoms) is not considered an aryl group. Similarly, 1,2,3,4-tetrahydroquinoline-8-yl (where the moiety is bonded to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinoline-1-yl (where the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not encompass or overlap with "heteroaryl" as defined herein, regardless of its connection point (e.g., both quinoline-5-yl and quinoline-2-yl are heteroaryl groups). In some cases, the aryl group is phenyl or naphthyl. In some cases, the aryl group is phenyl. Other examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.

[0037] "Heteroaryl" refers to an aromatic ring containing a specified number of atoms (e.g., 5 to 12 or 5 to 10-membered heteroaryls), said atoms being composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms) and the remaining ring atoms being carbon. Heteroaryls do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in a heteroaryl does not exceed 2. In some embodiments, the total number of S and O atoms in a heteroaryl does not exceed 1. Unless otherwise specified, heteroaryls may be bonded to the parent structure via carbon or nitrogen atoms, where valence allows. For example, "pyridinyl" includes 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl, and "pyrroleyl" includes 1-pyrroleyl, 2-pyrroleyl, and 3-pyrroleyl.

[0038] In some cases, heteroaryl monocyclic compounds are used. Examples include pyrrole, pyrazole, imidazole, triazoles (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazolium, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine), and tetrazine.

[0039] In some cases, both rings of a polycyclic heteroaryl group are aromatic rings. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benziisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benziisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine. 3H-Imidazolo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furano[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furano[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furano[2,3-c]pyridine Pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furano[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3- [c]pyridine, thiazo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnamoline, quinazoline, quinoxaline, phthalazine, naphthidine (e.g., 1,8-naphthidine, 1,7-naphthidine, 1,6-naphthidine, 1,5-naphthidine, 2,7-naphthidine, 2,6-naphthidine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole.

[0040] In other cases, polycyclic heteroaryl groups may include non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocyclic alkyl, heterocyclic alkenyl) fused to a heteroaryl ring, provided that the polycyclic heteroaryl group is bonded to the parent structure via atoms in the aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (wherein the portion is bonded to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the portion is bonded to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups composed of heteroaryl rings fused to non-aromatic rings are described below.

[0041] "Heterocyclic alkyl" refers to a non-aromatic, fully saturated ring (e.g., 3 to 10 or 3 to 7-membered heterocyclic alkyl) having a specified number of atoms, wherein the atoms consist of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms) and the remaining ring atoms are carbon. Heterocyclic alkyl can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocyclic alkyl include ethylene oxide, aziridinyl, azirmonobutyl, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Additionally, one ring of a polycyclic heterocyclic alkyl group may be an aromatic ring (e.g., aryl or heteroaryl), provided that the polycyclic heterocyclic alkyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom. For example, 1,2,3,4-tetrahydroquinoline-1-yl (wherein the moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocyclic alkyl group, while 1,2,3,4-tetrahydroquinoline-8-yl (wherein the moiety is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocyclic alkyl group. Examples of polycyclic heterocyclic alkyl groups composed of heterocyclic alkyl groups fused with aromatic rings are described below.

[0042] "Heterocyclic alkenyl" refers to a non-aromatic ring (e.g., 3 to 10 or 3 to 7-membered heterocyclic alkyl group) having a specified number of atoms and at least one double bond, wherein the atoms consist of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms) and the remaining ring atoms are carbon atoms, wherein the double bond is obtained by removing a hydrogen molecule from an adjacent carbon atom, an adjacent nitrogen atom, or an adjacent carbon atom and a nitrogen atom of the corresponding heterocyclic alkyl group. Heterocyclic alkenyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocyclic alkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazoyl (e.g., 2,3-dihydro-1H-imidazoyl, 4,5-dihydro-1H-imidazoyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridyl (e.g., 1,2,3,4-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). Furthermore, one ring of a polycyclic heterocyclic alkenyl group can be an aromatic ring (e.g., aryl or heteroaryl), provided that the polycyclic heterocyclic alkenyl group is bonded to the parent structure via a non-aromatic carbon atom or nitrogen atom. For example, 1,2-dihydroquinoline-1-yl (wherein the portion is bonded to the parent structure via a non-aromatic nitrogen atom) is considered a heterocyclic alkenyl group, while 1,2-dihydroquinoline-8-yl (wherein the portion is bonded to the parent structure via an aromatic carbon atom) is not considered a heterocyclic alkenyl group. Examples of polycyclic heterocyclic alkenyl groups composed of heterocyclic alkenyl groups fused with an aromatic ring are described below.

[0043] Examples of polycyclic compounds composed of aromatic rings (e.g., aryl or heteroaryl) fused with non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthyl, benzo[1,3]-m-dioxacyclopentenyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxacyclohexadienyl, indololinyl, isoyindololinyl, 2,3-dihydro-1H-inzolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isooxazolyl, 2,3-dihydrobenzo[d]isooxazolyl, 2,3-dihydrobenzo[d]oxazolyl, and 2,3-dihydrobenzo[d]oxazolyl. Azolyl, 2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopentathiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl, 4,5,6,7-tetrahydrothiazo[5,4-c]pyridyl, indoline-2-one, indoline-3-one, isoindolin-1-one, 1,2-dihydroindazole-3-one, 1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran- 3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazole-3(1H)-one, benzo[d]isoxazole-3(2H)-one, benzo[d]oxazole-2(3H)-one, benzo[b]thiophene-2(3H)-one, benzo[b]thiophene-3(2H)-one, benzo[c]thiophene-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinoline-4(3H)-one, quinazolino-4(3H)-one, quinazol Phosphoro-2,4(1H,3H)-dione, quinoxalo-2(1H)-one, quinoxalo-2,3(1H,4H)-dione, cyclophosphine-4(3H)-one, pyridin-2(1H)-one, pyrimidine-2(1H)-one, pyrimidine-4(3H)-one, pyridazine-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-d]thiazolyl-3-one and 4,5-dihydropyrrolo[3,4-d]thiazolyl-6-one.As discussed herein, whether each ring is considered aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is determined by the atoms through which the said portion is bonded to the parent structure.

[0044] "Halogen" or "halogenated group" refers to a fluorine group, a chlorine group, a bromine group, or an iodine group.

[0045] Unless otherwise specified, the compounds disclosed and / or described herein include all possible enantiomers, diastereomers, meso isomers, and other stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures thereof. Enantiomers, diastereomers, meso isomers, and other stereoisomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless otherwise stated, when the compounds disclosed and / or described herein contain an olefinic double bond or other geometrically asymmetric center, it is anticipated that the compounds include E and Z isomers. When the compounds described herein contain a tautomerizable moiety, unless otherwise stated, it is anticipated that the compounds include all possible tautomers.

[0046] The term "protecting group" has the meaning commonly associated with organic synthesis: a group that selectively blocks one or more reactive sites in a multifunctional compound, thereby allowing a chemical reaction to occur selectively at another unprotected reactive site, and which can be readily removed after the selective reaction is complete. Various protecting groups are disclosed, for example, in TH Greene and PGM Watts, *Protective Groups in Organic Synthesis*, 3rd edition, John Wiley & Sons, New York (1999). For example, a "hydroxyl-protected form" contains at least one hydroxyl group protected by a hydroxyl protecting group. Similarly, amines and other reactive groups can be similarly protected.

[0047] The term “pharmaceutically acceptable salt” refers to a salt of any compound known to be non-toxic and commonly used in pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of a compound retains the biological efficacy of the compound described herein and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0048] If the compound described herein is obtained in the form of an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the compound is a free base, the addition salt, especially a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with acid, according to conventional procedures for preparing acid addition salts from base compounds (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize the various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0049] "Solvates" are formed through the interaction of a solvent and a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having a ratio of any compound to water, such as monohydrates, dihydrates, and hemihydrates.

[0050] The term "substituted" means that the specified group or portion carries one or more substituents, including but not limited to alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azide, haloyl, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocyclic alkyl, heterocyclic alkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, etc. The term "unsubstituted" means that the specified group does not carry any substituents. When the term "substituted" is used to describe a structural system, substitution means any position on the system where the valence is allowed. When a group or portion carries more than one substituent, it should be understood that the substituents may be the same as or different from each other. In some embodiments, the substituted group or portion carries one to five substituents. In some embodiments, the substituted group or portion carries one substituent. In some embodiments, the substituted group or portion carries two substituents. In some embodiments, the substituted group or portion carries three substituents. In some embodiments, the substituted group or portion carries four substituents. In some embodiments, the substituted group or portion carries five substituents.

[0051] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and the description includes both the scenario where the event or situation occurs and the scenario where it does not occur. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. For any group containing one or more substituents, those skilled in the art will understand that such groups are not intended to introduce any substitution or substitution pattern that is spatially impractical, synthetically infeasible, and / or inherently unstable. It should also be understood that this disclosure includes embodiments in which the group or portion is optionally substituted and embodiments in which the group or portion is not substituted, when the group or portion is optionally substituted.

[0052] The compounds disclosed and / or described herein may be in enriched isotopic form, for example, in highly enriched forms. 2 H, 3 H, 11 C 13 C and / or 14C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be prepared, for example, by the methods described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds can enhance the efficacy of the compounds disclosed and / or described herein and increase the duration of their action. Deuterium-substituted compounds can be synthesized using various methods, such as those described in the following literature: Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0053] The terms "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and agents for pharmaceutical active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in pharmaceutical compositions is considered. Additional active ingredients may also be incorporated into pharmaceutical compositions.

[0054] The terms "patient," "individual," and "subject" refer to animals, such as mammals, birds, or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cattle, and humans. In some embodiments, the patient, individual, or subject is a person, such as a person who has been or will be the subject of treatment, observation, or experimentation. The compounds, compositions, and methods described herein are for human therapeutic and veterinary applications.

[0055] The term "therapeutic effective amount" or "effective amount" means an amount of a compound disclosed and / or described herein that is sufficient to achieve the treatment as defined herein when administered to a patient in need of such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease in response to ENPP1 regulation (e.g., inhibition). Therapeuticly effective amounts will vary depending on factors such as the subject being treated and the disease condition, the subject's weight and age, the severity of the disease condition, the specific compound, the dosing regimen to be followed, the time of administration, and the route of administration, all of which can be readily determined by one of ordinary skill in the art. A therapeutically effective amount may be determined experimentally, for example, by measuring the blood concentration of the chemical entity, or theoretically by calculating bioavailability.

[0056] "Treatment" (and related terms such as "treat / treated / treating") includes one or more of the following: inhibiting a disease or condition; slowing or halting the development of clinical symptoms of a disease or condition; and / or alleviating a disease or condition (i.e., causing relief or resolution of clinical symptoms). The term encompasses both total and partial relief of a disease or condition and total and partial relief of clinical symptoms of a disease or condition. Therefore, the compounds described and / or disclosed herein may prevent the exacerbation of an existing disease or condition, assist in the management of said disease or condition, or alleviate or eliminate said disease or condition.

[0057] It should be understood that the implementation described herein as “includes” includes “consisting of the implementation” and / or “substantially consisting of the implementation”.

[0058] compound

[0059] This document describes in detail the compounds and their salts (such as pharmaceutically acceptable salts), as included in the summary and appended claims. Uses of all the compounds described herein and methods for preparing such compounds are also provided. These compounds include any and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and mixtures thereof in any ratio, including racemic mixtures, salts, and solvates of the compounds described herein. Any compound described herein may also be called a drug.

[0060] In one aspect, compounds of formula (I) are provided:

[0061]

[0062] Or its pharmaceutically acceptable salt, wherein:

[0063] W is

[0064] Ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which may or may not be substituted;

[0065] R 1a and R 2a Each is independently hydrogen, and each C is optionally substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocyclic alkyl, or optionally substituted C 1-6 Halogenated alkyl groups;

[0066] Y is either -N- or -CH-;

[0067] X 1 Yes -CR 1b -or -N-;

[0068] X 2 Yes -CR 2b -or -N-;

[0069] X 3 Yes -CR 3b -or -N-;

[0070] X 4 Yes -CR 4b -or -N-;

[0071] X 5 Yes -CR 5b -or -N-;

[0072] X 6 Yes -CR 6b -or -N-;

[0073] R 1b -R 6b Each of the following is an independent C-type carbon atom containing hydrogen, halogen, hydroxyl group, or optionally substituted with one or more halogen substituents. 1-4 Alkoxy, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, nitro, -NR 1c R 2c -NHC(O)R 3c or -C(O)NR 4c R 5c ;

[0074] L represents a bond, -O-, -C(O)-, -NR 6c -or-OCR 7c -*, where * indicates AND The connection point;

[0075] R 1c -R 7cEach is independently hydrogen or C 1-3 alkyl;

[0076] a 1 a 2 b 1 and c 4 Each is independently 0, 1, 2, or 3; and

[0077] b 2 c 1 -c 3 d 1 -d 4 e 1 and e 2 Each can be 1, 2, or 3 independently.

[0078] In some embodiments of formula (I) or its pharmaceutically acceptable salts, the compound is not (9-imino-9-oxobridge-1-oxa-9λ) 6 -Thia-4-azaspiro[5.5]undecane-4-yl)(2-methylquinoline-4-yl)methyl ketone. In some embodiments, W is not In some implementations, when W is When W contains a fused ring structure, two or more rings share a single bond. In some embodiments, when W is When A is not a heterocyclic alkyl group. In some embodiments, when W is... When W contains a fused ring structure, two or more rings share a single bond. In some embodiments, when W is At that time, W contains a fused ring structure.

[0079] In some implementation schemes, R 1b -R 6b It is not morpholino or pyrazolyl. In some embodiments, R 1b -R 6b It is not a heterocyclic alkyl or heteroaryl group. In some embodiments, L is not -C(O)N(CH3)-*, where * indicates a group with... The connection point.

[0080] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is Among them, rings A and b 1 and R 1a As defined for formula (I) or any variation or implementation thereof. In some implementations, W is... In some such implementations, b 1 It is 0. In some such implementations, b 1It is 1. In some such implementations, b 1 It is 2. In some implementations, b 1 It is 3. In some implementations, W is In some implementation schemes, W is

[0081] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is Among them, rings A and b 1 and R 1a As defined for formula (I) or any variation or implementation thereof. In some implementations, W is... In some such implementations, b 1 It is 0. In some such implementations, b 1 It is 1. In some such implementations, b 1 It is 2. In some implementations, b 1 It is 3. In some implementations, W is In some implementation schemes, W is In some implementation schemes, W is

[0082] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is Among them, rings A and b 1 and b 2 As defined for formula (I) or any variation or implementation thereof. In some implementations, W is... In some such implementations, b 1 It is 1, and b 2 It is 2. In some implementations, W is

[0083] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is Among them, rings A and b 1 b 2 and R 1a As defined for formula (I) or any variation or implementation thereof. In some implementations, W is... In some such implementations, b 1 It is 1, and b 2 It is 2. In some implementations, W is In some implementation schemes, W is

[0084] In some embodiments of formula (I) or a pharmaceutically acceptable salt thereof, ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each substituted or unsubstituted. In some embodiments, ring A is C 6-14 Aryl, 4- to 14-membered heteroaryl, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3- to 18-membered heterocyclic alkyl, or 3- to 18-membered heterocyclic alkenyl, each substituted or unsubstituted. In some embodiments, ring A is a 4- to 14-membered heteroaryl, 3- to 18-membered heterocyclic alkyl, or 3- to 18-membered heterocyclic alkenyl, each substituted or unsubstituted, wherein said 4- to 14-membered heteroaryl, 3- to 18-membered heterocyclic alkyl, or 3- to 18-membered heterocyclic alkenyl contains one, two, three, four, five, or six heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen, and sulfur.

[0085] In some embodiments, ring A is an aryl group (e.g., phenyl). In some embodiments, ring A is a phenyl group substituted with a halogen group (e.g., fluoro group). In some embodiments, ring A is a heteroaryl group. In some embodiments, ring A is a pyridyl group (e.g., 2-pyridyl or 3-pyridyl). In some embodiments, ring A is a cycloalkyl group (e.g., cyclopentyl). In some embodiments, ring A is a heterocyclic alkyl group (e.g., piperidinyl). In some embodiments, ring A is...

[0086]

[0087] In some implementations, ring A is In some implementations, ring A is

[0088] In some embodiments, ring A is independently selected from halogen groups, hydroxyl groups, C groups, and so on. 3-10 cycloalkyl or C 1-6 Alkyl substituents. In some embodiments, ring A is a C-shaped group substituted with a halogen group. 6-14 Aryl. In some embodiments, ring A is a fluoro-substituted phenyl group. In some embodiments, ring A is a bromo-substituted phenyl group. In some embodiments, ring A is a 3- to 18-membered heterocyclic alkyl group substituted with a hydroxyl group. In some embodiments, ring A is a piperidinyl group substituted with a hydroxyl group. In some embodiments, ring A is a C-substituted... 3-10 Cycloalkyl-substituted 3- to 18-membered heterocyclic alkyl groups. In some embodiments, ring A is replaced by C. 3-10 Cycloalkyl-substituted piperidinyl groups.

[0089] It should be understood that when the portion described herein is bonded to more than one location on the rest of the molecule, the orientation of said portion can be indicated by showing distinguishing symbols (such as wavy lines). and dotted lines The position of such bonds relative to the rest of the molecule is indicated by ) . For example, when W is Where ring A is This indicates that the nitrogen-containing heterocyclic butane ring is indicated by a wavy line. The key shown corresponds to Some sections use wavy lines The keys shown provide part of the information.

[0090] In some embodiments of formula (I) or its pharmaceutically acceptable salts, R 1a It is C 1-6 Alkyl, wherein the C 1-6 Alkyl groups are optionally replaced by halogen groups, hydroxyl groups, C... 1-3 Alkoxy or C 3-6 Cycloalkyl substitution. In some embodiments of formula (I) or its pharmaceutically acceptable salts, R 1a It is C 1-6 Alkyl group. In some embodiments, R 1a It is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R 1a It is methyl. In some embodiments, R 1a It is a C that has been replaced by a hydroxyl group. 1-6 Alkyl group. In some embodiments, R 1a It is a hydroxyl-substituted methyl, a hydroxyl-substituted ethyl, a hydroxyl-substituted n-propyl, a hydroxyl-substituted isopropyl, a hydroxyl-substituted n-butyl, a hydroxyl-substituted isobutyl, a hydroxyl-substituted sec-butyl, or a hydroxyl-substituted tert-butyl. In some embodiments, R 1a It was C 1-3 alkoxy-substituted C 1-6 Alkyl group. In some embodiments, R 1a It was C 1-3 Alkoxy-substituted methyl groups, C 1-3 Alkoxy-substituted ethyl, C 1-3 Alkoxy-substituted n-propyl, C 1-3 Alkoxy-substituted isopropyl, C 1-3 Alkoxy-substituted n-butyl, C 1-3 Alkoxy-substituted isobutyl, C 1-3 Alkoxy-substituted sec-butyl or C 1-3 Alkoxy-substituted tert-butyl. In some embodiments, R 1aIt is a methoxy-substituted methyl or a methoxy-substituted ethyl. In some embodiments, R 1a It was C 3-6 Cycloalkyl-substituted C 1-6 Alkyl group. In some embodiments, R 1a It was C 3-6 Cycloalkyl-substituted methyl groups, C 3-6 Cycloalkyl-substituted ethyl, C 3-6 cycloalkyl-substituted n-propyl, C 3-6 Cycloalkyl-substituted isopropyl, C 3-6 cycloalkyl-substituted n-butyl, C 3-6 Cycloalkyl-substituted isobutyl, C 3-6 Cycloalkyl-substituted sec-butyl or C 3-6 Cycloalkyl-substituted tert-butyl. In some embodiments, R 1a It is a methyl group that has been replaced by a cyclopropyl group.

[0091] In some implementation schemes, R 1a and R 2a It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-6 Halogenated alkyl groups. In some embodiments, R 1a and R 2a Optionally selected by one, two, three, four, five or more groups, each independently selected from halogen, hydroxyl, C 1-3 Alkoxy, C 3-6 Substituents of cycloalkyl and acyl groups. In some embodiments, the acyl group is -C(O)R. 1a1 , where R 1a1 Is it H or C? 1-6 Alkyl group. In some embodiments, R 1a and R 2a Optionally substituted by one, two, three, four, five or more substituents, each independently selected from fluorine, chloro, methoxy, ethoxy, cyclopropyl and -C(O)CH3.

[0092] In some embodiments of formula (I) or its pharmaceutically acceptable salts, b 1 It is 0, 1, or 2. In some implementations, b 1 It is 0. In some implementations, b 1 It is 1. In some implementations, b 1 It is 2. In some implementations, b 1 It is 3.

[0093] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is Where c1 -c 4 Y and R 2a As defined for formula (I) or any variation or implementation thereof. In some implementations, Y is -N-. In some implementations, Y is -CH-. In some implementations, c 1 It is 2 and c 2 It is 2. In some implementations, c 3 It is 1 and c 4 It is 1. In some implementations, c 3 It is 2 and c 4 It is 1. In some implementations, c 1 It is 2, c 2 It is 2, c 3 It is 1, and c 4 It is 1. In some implementations, c 1 It is 2, c 2 It is 2, c 3 It is 2, and c 4 It is 1. In some implementations, c 4 It is 0. In some implementations, c 1 It is 2, c 2 It is 2, c 3 It is 1, and c 4 It is 0.

[0094] In some implementation schemes, W is In some implementation schemes, R 2a It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-6 Halogenated alkyl groups. In some embodiments, R 2a It is methyl. In some embodiments, R 2a It is optionally surrounded by one, two, three, four, five or more groups selected from halogen groups, hydroxyl groups, C 1-3 Alkoxy, C 3-6 Cycloalkyl and -C(O)R 1a1 The group is substituted, wherein R is a group that is substituted. 1a1 Is it H or C? 1-6 Alkyl group. In some embodiments, R 2a C is optionally replaced by a hydroxyl group. 1-6 alkyl.

[0095] In some implementation schemes, W is

[0096] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is Where c 1 -c 4 Y, b 1 and R 2a As defined for formula (I) or any variation or implementation thereof. In some implementations, Y is -N-. In some implementations, Y is -CH-. In some implementations, c 1 It is 2 and c 2 It is 2. In some implementations, c 3 It is 1 and c 4 It is 1. In some implementations, c 3 It is 2 and c 4 It is 1. In some implementations, c 1 It is 2, c 2 It is 2, c 3 It is 1, and c 4 It is 1. In some implementations, c 1 It is 2, c 2 It is 2, c 3 It is 2, and c 4 It is 1. In some implementations, c 1 It is 1 and c 2 It is 1. In some implementations, c 1 It is 1, c 2 It is 1, c 3 It is 1, and c 4 It is 1.

[0097] In some implementation schemes, W is In some implementation schemes, R 2a It is hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-6 Halogenated alkyl groups. In some embodiments, R 2a It is methyl. In some embodiments, R 2a Optionally, it may be selected from one, two, three, four, five or more halogen groups, hydroxyl groups, C... 1-3 Alkoxy, C 3-6 Cycloalkyl and -C(O)R 1a1 The group is substituted, wherein R is a group that is substituted. 1a1 Is it H or C? 1-6 Alkyl group. In some embodiments, R 2a C is optionally replaced by a hydroxyl group. 1-6 Alkyl group. In some embodiments, W is...

[0098] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is Where d 1 -d 4 As defined for formula (I) or any variation or implementation thereof. In some implementations, d 1 It is 2 and d 2 It is 2. In some implementations, d 1 It is 1 and d 2 It is 1. In some implementations, d 3 It is 2 and d 4 It is 1. In some implementations, d 3 It is 1 and d 4 It is 1. In some implementations, d 1 It is 2, d 2 It is 2, d 3 It is 2, and d 4 It is 1. In some implementations, d 1 It is 1, d 2 It is 1, d 3 It is 1, and d 4 It is 1. In some implementations, W is

[0099] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is Among them, Y, e 1 and e 2 As defined for formula (I) or any variation or implementation thereof. In some implementations, Y is -N-. In some implementations, Y is -CH-. In some implementations, e 1 It is 2 and e 2 It is 2. In some implementations, e 1 It is 1 and e 2 It is 2. In some implementations, e 1 It is 3 and e 2 It is 2. In some implementations, W is In some implementation schemes, W is

[0100] In another aspect, the compound of formula (I) is a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig):

[0101]

[0102]

[0103] Or a pharmaceutically acceptable salt thereof, wherein rings A and R 1a R 2a Y, X 1 -X 6 R 1b -R 6b L, R 1c -R 6c a 1 a 2 b 1 b 2 c 1 -c 4 d 1 -d 4 e 1 and e 2 As defined for formula (I) or any variant or implementation thereof.

[0104] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or their pharmaceutically acceptable salts, X 1 Yes -CR 1b - In some implementations, X 1 Yes -N-. In some implementations, X 2 Yes -CR 2b - In some implementations, X 2 Yes -N-. In some implementations, X 3 Yes -CR 3b - In some implementations, X 3 Yes -N-. In some implementations, X 4 Yes -CR 4b - In some implementations, X 4 Yes -N-. In some implementations, X 5 Yes -CR 5b - In some implementations, X 5 Yes -N-. In some implementations, X 6 Yes -CR 6b - In some implementations, X 6 Yes -N-. In some implementations, X 1 Yes -CR 1b -, X 2 Yes -CR 2b -, X 3 Yes -CR 3b -, X4 Yes -CR 4b -, X 5 Yes -CR 5b - and X 6 Yes -CR 6b - In some implementations, X 1 It is -N-, X 2 Yes -CR 2b -, X 3 Yes -CR 3b -, X 4 Yes -CR 4b -, X 5 Yes -CR 5b - and X 6 Yes -CR 6b - In some implementations, X 1 Yes -CR 1b -, X 2 It is -N-, X 3 Yes -CR 3b -, X 4 Yes -CR 4b -, X 5 Yes -CR 5b - and X 6 Yes -CR 6b - In some implementations, X 1 Yes -CR 1b -, X 2 Yes -CR 3b -, X 3 It is -N-, X 4 Yes -CR 4b -, X 5 Yes -CR 5b - and X 6 Yes -CR 6b - In some implementations, X 1 Yes -CR 1b -, X 2 Yes -CR 2b -, X 3 Yes -CR 3b -, X 4 It is -N-, X 5 Yes -CR 5b - and X 6 Yes -CR 6b - In some implementations, X 1 Yes -CR 1b -, X 2 Yes -CR 2b -, X 3 Yes -CR 3b -, X 4Yes -CR 4b -, X 5 It is -N-, and X 6 Yes -CR 6b - In some implementations, X 1 Yes -CR 1b -, X 2 Yes -CR 2b -, X 3 Yes -CR 3b -, X 4 Yes -CR 4b -, X 5 Yes -CR 5b - and X 6 It is -N-.

[0105] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or their pharmaceutically acceptable salts, The portion is quinoline-4-yl, 1,5-naphthidyl-4-yl, 1,6-naphthidyl-4-yl, 1,7-naphthidyl-4-yl, 1,8-naphthidyl-4-yl, cenline-4-yl, or quinazolin-4-yl, each substituted or unsubstituted. In some embodiments, Part of it is 6,7-dimethoxyquinoline-4-yl. In some embodiments, Part of it is 7-methoxyquinoline-4-yl.

[0106] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or their pharmaceutically acceptable salts, Part of it is In some implementations, formula (I) Part of it is

[0107] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or their pharmaceutically acceptable salts, X 2It is R 2b And X 3 It is R 3b , where R 2b and R 3b It is a methoxy group. In some embodiments, X 1 It is R 1b X 2 It is R 2b X 3 It is R 3b And X 4 It is R 4b , where R 2b and R 3b It is a methoxy group, and R 1b and R 4b It is hydrogen. In some implementations, X 1 It is R 1b X 2 It is R 2b X 3 It is R 3b And X 4 It is R 4b , where R 3b It is a methoxy group, and R 1b R 2b and R 4b It is hydrogen.

[0108] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, Part of it is In some implementation schemes, Part of it is In some implementation schemes, Part of it is In some implementation schemes, Part of it is

[0109] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or their pharmaceutically acceptable salts, Part of it is

[0110] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or their pharmaceutically acceptable salts, formula (I) Part of it is

[0111] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or their pharmaceutically acceptable salts, Part of it is

[0112] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or their pharmaceutically acceptable salts, formula (I) Part of it is In some implementations, formula (I) Part of it is

[0113] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or their pharmaceutically acceptable salts, formula (I) Part of it is

[0114] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) or their pharmaceutically acceptable salts, L is a bond, -O-, C(O)-, -NR 6c -or-OCR 7c -*, where R 6cAs defined for formula (I) or any variation or implementation thereof, and where * denotes as... The connection point. In some implementations, L is a key. In some implementations, L is -O-. In some implementations, L is -C(O)-. In some implementations, L is -NR. 6c In some implementations, L is -NH-. In some implementations, L is -N(CH3)-. In some implementations, L is -OCR. 7c -*, where * indicates AND The connection point. In some implementations, L is -OC(CH3)-*.

[0115] In some embodiments of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ib), (Ic), (Id), (Ie), (If), or (Ig) or their pharmaceutically acceptable salts, a 1 and a 2 Each is independently 0, 1, or 2. In some implementations, a 1 It is 0. In some implementations, a 1 It is 1. In some implementations, a 1 It is 2. In some implementations, a 2 It is 0. In some implementations, a 2 It is 1. In some implementations, a 2 It is 2. In some implementations, a 1 It is 0, and a 2 It is 0. In some implementations, a 1 It is 0, and a 2 It is 1. In some implementations, a 1 It is 0, and a 2 It is 2. In some implementations, a 1 It is 1, and a 2 It is 0. In some implementations, a 1 It is 2, and a 2 It is 0.

[0116] In some embodiments of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) or a pharmaceutically acceptable salt thereof, The part is a bond, -CH2-, -CH2CH2-, -O-, -OCH2-, -CH2O-, -CH2OCH2-, -C(O)-, -C(O)CH2-, -CH2C(O)-, -NH-, -NHCH2-, or -CH2NH-, where the left side of each listed part is bonded to the rest of the molecule by a wavy line. On one side of the representation, and the right side of each listed portion is bonded to the rest of the molecule by On one side represented by the dotted line.

[0117] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is And equation (I) Part of it is In some implementations, formula (I) Part of it is In some implementations, formula (I) Part of it is In some implementations, formula (I) Part of it is

[0118] In some implementations, formula (I) Partial or pharmaceutically acceptable salts In some implementations, formula (I) Part of it is In some implementations, formula (I) Part of it is In some implementations, formula (I) Part of it is

[0119] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is And equation (I) Part of it is In some implementations, formula (I) Part of it is

[0120] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is And equation (I) Part of it is

[0121] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is And equation (I) Part of it is. In some implementations, formula (I) Part of it is In some implementations, formula (I) Part of it is

[0122] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is And equation (I) Part of it is In some implementations, formula (I) Part of it is

[0123] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is And equation (I) Part of it is

[0124] In some embodiments of formula (I) or its pharmaceutically acceptable salt, W is And equation (I) Part of it is

[0125] In one aspect, compounds of formula (Ia-1) are provided:

[0126]

[0127] Or a pharmaceutically acceptable salt thereof, wherein R 2b R 3b a 1 a 2 Ring A, b 1 and R 1a As defined for formula (I) or any variant or implementation thereof.

[0128] In one aspect, compounds of formula (Ia-2) are provided:

[0129]

[0130] Or a pharmaceutically acceptable salt thereof, wherein R 1a and b 1 As defined for formula (I) or any variant or implementation thereof.

[0131] In one aspect, compounds of formula (Ia-3) are provided:

[0132]

[0133] Or a pharmaceutically acceptable salt thereof, wherein R 1a and b 1 As defined for formula (I) or any variant or implementation thereof.

[0134] In one aspect, compounds of formula (Ia-4) are provided:

[0135]

[0136] Or a pharmaceutically acceptable salt thereof, wherein R 1a b 1 X 1 X 2 X 3 X 4 X 5 and X 6 As defined for formula (I) or any variant or implementation thereof.

[0137] In one aspect, compounds of formula (Ia-5) are provided:

[0138]

[0139] Or a pharmaceutically acceptable salt thereof, wherein R 1a b 1 X 1 X 2 X 3 X 4 X 5 and X 6 As defined for formula (I) or any variant or implementation thereof.

[0140] In one aspect, compounds of formula (Ia-6) are provided:

[0141]

[0142] Or a pharmaceutically acceptable salt thereof, wherein R 1a X 1 X 2 X 3 X 4 X 5 and X 6 As defined for formula (I) or any variant or implementation thereof.

[0143] In one aspect, compounds of formula (Ie-1) are provided:

[0144]

[0145] Or a pharmaceutically acceptable salt thereof, wherein R 2a b 1 X 1 X 2 X 3 X 4 X 5 and X 6 As defined for formula (I) or any variant or implementation thereof.

[0146] In one aspect, a compound of formula (Ie-2) is provided:

[0147]

[0148] Or a pharmaceutically acceptable salt thereof, wherein R 2a b 1 X 1 X 2 X 3 X 4 X 5 and X 6 As defined for formula (I) or any variant or implementation thereof.

[0149] In another aspect, the compound of formula (I) is the compound of formula (I-1):

[0150]

[0151] Or its pharmaceutically acceptable salt, wherein:

[0152] W is

[0153] Ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which may or may not be substituted;

[0154] R 1a and R 2a Each is independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-6 Halogenated alkyl groups;

[0155] Y is either -N- or -CH-;

[0156] X 1 Yes -CR 1b -or -N-;

[0157] X 2 Yes -CR 2b -or -N-;

[0158] X3 Yes -CR 3b -or -N-;

[0159] X 4 Yes -CR 4b -or -N-;

[0160] X 5 Yes -CR 5b -or -N-;

[0161] X 6 Yes -CR 6b -or -N-;

[0162] R 1b -R 6b Each of the following is an independent C-type carbon atom containing hydrogen, halogen, hydroxyl group, or optionally substituted with one or more halogen substituents. 1-4 Alkoxy, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, nitro, -NR 1c R 2c -NHC(O)R 3c or -C(O)NR 4c R 5c ;

[0163] L is a bond, -O-, -C(O)-, or -NR. 6c -;

[0164] R 1c -R 6c Each is independently either hydrogen or C. 1-3 alkyl;

[0165] a 1 a 2 and b 1 Each is independently 0, 1, or 2; and

[0166] b 2 c 1 -c 4 d 1 -d 4 e 1 and e 2 Each can be 1, 2, or 3 independently.

[0167] In another aspect, the compound of formula (I) is the same as the compound of formula (I-2):

[0168]

[0169] Or its pharmaceutically acceptable salt, wherein:

[0170] W is

[0171] Ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which may or may not be substituted;

[0172] R 1a and R 2a Each is independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups are optionally replaced by hydroxyl groups, C 1-3 Alkoxy or C 3-6 Cycloalkyl substitution;

[0173] Y is either -N- or -CH-;

[0174] X 1 Yes -CR 1b -or -N-;

[0175] X 2 Yes -CR 2b -or -N-;

[0176] X 3 Yes -CR 3b -or -N-;

[0177] X 4 Yes -CR 4b -or -N-;

[0178] X 5 Yes -CR 5b -or -N-;

[0179] X 6 Yes -CR 6b -or -N-;

[0180] R 1b -R 6b Each of the following is an independent C-type carbon atom containing hydrogen, halogen, hydroxyl group, or optionally substituted with one or more halogen substituents. 1-4 Alkoxy, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, nitro, -NR 1c R 2c -NHC(O)R 3c or -C(O)NR 4c R 5c ;

[0181] L is a bond, -O-, -C(O)-, or -NR. 6c -;

[0182] R 1c -R 6c Each is independently hydrogen or C 1-3 alkyl;

[0183] a 1 a 2 and b 1 Each is independently 0, 1, 2, or 3; and

[0184] b 2 c 1 -c 4 d 1 -d 4 e 1 and e 2 Each can be 1, 2, or 3 independently.

[0185] In one aspect, compounds of formula (I-3) are provided:

[0186]

[0187] Or its pharmaceutically acceptable salt, wherein:

[0188] W is

[0189] Ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which may or may not be substituted;

[0190] R 1a and R 2a Each is independently hydrogen, and each C is optionally substituted. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocyclic alkyl, or optionally substituted C 1-6 Halogenated alkyl groups;

[0191] Y is either -N- or -CH-;

[0192] X 1 Yes -CR 1b -or -N-;

[0193] X 2 Yes -CR 2b -or -N-;

[0194] X 3 Yes -CR 3b -or -N-;

[0195] X 4 Yes -CR 4b -or -N-;

[0196] X 5Yes -CR 5b -or -N-;

[0197] X 6 Yes -CR 6b -or -N-;

[0198] R 1b -R 6b Each of the following is an independent C-type carbon atom containing hydrogen, halogen, hydroxyl group, or optionally substituted with one or more halogen substituents. 1-4 Alkoxy, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, nitro, -NR 1c R 2c -NHC(O)R 3c or -C(O)NR 4c R 5c ;

[0199] L is -OCR 7c -*, where * indicates AND The connection point;

[0200] R 1c -R 5c and R 7c Each is independently hydrogen or C 1-3 alkyl;

[0201] a 1 a 2 b 1 and c 4 Each is independently 0, 1, 2, or 3; and

[0202] b 2 c 1 -c 3 d 1 -d 4 e 1 and e 2 Each can be 1, 2, or 3 independently.

[0203] In one aspect, compounds of formula (I-4) are provided:

[0204]

[0205] Or its pharmaceutically acceptable salt, wherein:

[0206] W is

[0207] R 2a It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 3-6Cycloalkyl, optionally substituted 3-6 membered heterocyclic alkyl, or optionally substituted C 1-6 Halogenated alkyl groups;

[0208] Y is either -N- or -CH-;

[0209] X 1 Yes -CR 1b -or -N-;

[0210] X 2 Yes -CR 2b -or -N-;

[0211] X 3 Yes -CR 3b -or -N-;

[0212] X 4 Yes -CR 4b -or -N-;

[0213] X 5 Yes -CR 5b -or -N-;

[0214] X 6 Yes -CR 6b -or -N-;

[0215] R 1b -R 6b Each of the following is an independent C-type carbon atom containing hydrogen, halogen, hydroxyl group, or optionally substituted with one or more halogen substituents. 1-4 Alkoxy, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, nitro, -NR 1c R 2c -NHC(O)R 3c or -C(O)NR 4c R 5c ;

[0216] L represents a bond, -O-, -C(O)-, -NR 6c -or-OCR 7c -*, where * indicates AND The connection point;

[0217] R 1c -R 7c Each is independently hydrogen or C 1-3 alkyl;

[0218] a 1 a 2 b 1 and c 4 Each is independently 0, 1, 2, or 3; and

[0219] c 1 -c 3 Each can be 1, 2, or 3 independently.

[0220] In one aspect, compounds of formula (I-5) are provided:

[0221]

[0222] Or its pharmaceutically acceptable salt, wherein:

[0223] W is

[0224] Ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which may or may not be substituted;

[0225] R 1a and R 2a Each is an independent C group that has been replaced by a halogenated group. 1-6 Alkyl or acyl-substituted 3-6 membered heterocyclic alkyl groups;

[0226] Y is either -N- or -CH-;

[0227] X 1 Yes -CR 1b -or -N-;

[0228] X 2 Yes -CR 2b -or -N-;

[0229] X 3 Yes -CR 3b -or -N-;

[0230] X 4 Yes -CR 4b -or -N-;

[0231] X 5 Yes -CR 5b -or -N-;

[0232] X 6 Yes -CR 6b -or -N-;

[0233] R 1b -R 6b Each of the following is an independent C-type carbon atom containing hydrogen, halogen, hydroxyl group, or optionally substituted with one or more halogen substituents. 1-4 Alkoxy, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, nitro, -NR 1c R 2c -NHC(O)R3c or -C(O)NR 4c R 5c ;

[0234] L represents a bond, -O-, -C(O)-, -NR 6c -or-OCR 7c -*, where * indicates AND The connection point;

[0235] R 1c -R 7c Each is independently hydrogen or C 1-3 alkyl;

[0236] a 1 a 2 b 1 and c 4 Each is independently 0, 1, 2, or 3; and

[0237] b 2 c 1 -c 3 d 1 -d 4 e 1 and e 2 Each can be 1, 2, or 3 independently.

[0238] In some implementations, the compounds and their salts described in Table 1 are provided herein.

[0239] Table 1.

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303] In some variants, any of the compounds described herein, such as compounds of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or any variant thereof, or the compounds of Table 1, may be deuterated (e.g., hydrogen atoms are replaced by deuterium atoms). In some variants of these variants, the compound is deuterated at a single site. In other variants, the compound is deuterated at multiple sites. The deuterated compound can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding undeuterated compound. Other methods known in the art can also be used to replace hydrogen atoms with deuterium atoms.

[0304] It is intended that any formula given herein, such as formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), represents a compound having the structure described by the structural formula, as well as certain variants or forms. Specifically, compounds of any formula given herein may have an asymmetric center and thus exist in different enantiomers or diastereomers. All optical and stereoisomers of the general formula and mixtures thereof in any ratio are considered to be within the scope of the general formula. Therefore, it is intended that any formula given herein represents a racemic compound, one or more enantiomers, one or more diastereomers, one or more transisomers, and mixtures thereof in any ratio. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or blocked trans isomers. Additionally, any formula given herein is intended to refer to any of the hydrates, solvates, amorphous forms, and polymorphic forms of such compounds, or mixtures thereof, even if such forms are not explicitly listed. In some embodiments, the solvent is water and the solvate is a hydrate.

[0305] Representative examples of the compounds detailed herein, including intermediates and final compounds, are depicted in tables and other places herein. It should be understood that, in one aspect, any of the compounds described herein can be used in the methods detailed herein, including intermediate compounds that are separable and administerable to an individual where appropriate.

[0306] Even if salts are not described herein, the compounds described herein may exist in salt form, and it should be understood that the compositions and methods provided herein include all salts and solvates of the compounds described herein, as well as non-salt and non-solvent forms of the compounds, as well as those well known to those skilled in the art. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0307] In one variant, the compounds described herein are synthetic compounds prepared for individual administration. In another variant, a composition comprising the compound in its substantially pure form is provided. In yet another variant, a pharmaceutical composition comprising the compound detailed herein and a pharmaceutically acceptable carrier is provided. In yet another variant, a method of administering the compound is provided. The purified form, pharmaceutical composition, and method of administering the compound are applicable to any of the compounds or their forms detailed herein.

[0308] The W, ring A, and a provided in this article 1 a 2 b 1 b 2 c 1 c 2 c 3 c 4 d 1 d 2 d 3 d 4 e 1 e 2 Y, X 1 X 2 X 3 X 4 X 5 X 6 R 1a R 2a R 1a1 R 1b R 2b R 3b R 4b R 5b R 6b R 1c R 2c R 3c R 4c R 5c R 6c R 7c Any variant or implementation of L can be used with W, ring A, a 1 a 2 b 1 b 2 c 1 c 2 c3 c 4 d 1 d 2 d 3 d 4 e 1 e 2 Y, X 1 X 2 X 3 X 4 X 5 X 6 R 1a R 2a R 1a1 R 1b R 2b R 3b R 4b R 5b R 6b R 1c R 2c R 3c R 4c R 5c R 6c R 7c Each other variant or combination of implementations in L, as each combination has been described individually and specifically.

[0309] As used in this article, when any variable appears more than once in a chemical formula, its definition for each occurrence is independent of its definition for each other occurrence.

[0310] Formula (I) includes all its sub-formulas. For example, formula (I) includes compounds of formulas (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig).

[0311] The compound names provided herein (including those in Table 1) are provided by ChemDraw Professional 19.1. Those skilled in the art will understand that various recognized nomenclature systems and symbols can be used to name or identify compounds. For example, compounds can be named or identified using common names, systematic names, or non-systematic names. Recognized nomenclature systems and symbols in the field of chemistry include, for example, the Chemical Abstracts Service (CAS), ChemBioDraw Ultra, and the International Union of Pure and Applied Chemistry (IUPAC).

[0312] Composition

[0313] Compositions, such as pharmaceutical compositions, are also provided, comprising compounds disclosed and / or described herein and one or more other medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, etc. Suitable medicinal agents and pharmaceutical agents include those described herein. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, sodium carboxymethyl cellulose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, compositions, such as pharmaceutical compositions, are provided containing one or more compounds described herein or pharmaceutically acceptable salts thereof.

[0314] In some embodiments, pharmaceutically acceptable compositions are provided comprising compounds of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or compounds of Table 1, or pharmaceutically acceptable salts thereof. In some aspects, the composition may contain a synthetic intermediate that can be used to prepare the compounds described herein. The compositions described herein may contain any other suitable active or inactive agent.

[0315] Any composition described herein may be sterile or contain sterile components. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more substantially pure compounds.

[0316] Also provided are packaged pharmaceutical compositions comprising the pharmaceutical compositions described herein and instructions for use in treating patients suffering from the diseases or ailments described herein.

[0317] How to use

[0318] As described herein, the compounds disclosed are inhibitors of ENPP1 enzyme activity. In one aspect, the compounds and pharmaceutical compositions herein can be used to inhibit ENPP1. In another aspect, the compounds and pharmaceutical compositions herein can be used to treat or prevent an individual's disease or ailment.

[0319] The inhibitory activity of the compounds described herein against ENPP1 can be determined and measured by methods known in the art, including but not limited to inhibiting the ENPP1 hydrolysis of 2',3'-cGAMP (cyclic guanosine monophosphate-adenosine monophosphate) (Mardjuki, R. et al. (2020), Journal of Biological Chemistry, 295(15), 4881-4892), inhibiting the ENPP1 hydrolysis of pNP-TMP (p-nitrophenylthymidine 5'-monophosphate), or inhibiting the ENPP1 hydrolysis of pNP-AMP (p-nitrophenyladenosine 5'-monophosphate) (Lee, S. et al. (2017), Frontiers in Pharmacology 8, 54).

[0320] In one aspect, this document provides a method for inhibiting ENPP1, comprising contacting cells with an effective amount of the compounds or pharmaceutical compositions described herein. In some embodiments, this document provides a method for inhibiting ENPP1, the method comprising contacting cells with an effective amount of a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides a method for inhibiting ENPP1, the method comprising contacting cells with an effective amount of a pharmaceutical composition comprising a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. In one variation of the foregoing embodiments, the cells are contacted in vitro. In other variations of the foregoing embodiments, the cells are contacted in vivo.

[0321] In another aspect, the compounds and pharmaceutical compositions described herein can be used to treat or prevent diseases or conditions in an individual, including by administering an effective amount of the compounds or pharmaceutical compositions described herein. When used in a preventative manner, the compounds disclosed and / or described herein can prevent the development of a disease or condition in an individual at risk of developing said disease or condition, or reduce the severity of a disease or condition that may develop.

[0322] In some embodiments, this document provides a method for treating or preventing a disease or ailment in an individual, the method comprising administering to a subject a therapeutically effective amount of a compound or pharmaceutical composition as described herein. In some embodiments, this document provides a method for treating or preventing a disease or ailment in an individual, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, this document provides a method for treating or preventing a disease or ailment in an individual, the method comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments, the disease or ailment is mediated by ENPP1. In some embodiments, the disease or ailment is cancer. In some embodiments, the disease or ailment is a bacterial or viral infection. In some embodiments, the disease or ailment is a bacterial infection. In some other embodiments, the disease or ailment is a viral infection. In some embodiments, the disease or ailment is insulin resistance. In some embodiments, the disease or ailment is type 2 diabetes. In some embodiments, the disease or ailment is chondrocalcinosis. In some embodiments, the disease or ailment is osteoarthritis. In some embodiments, the disease or ailment is soft tissue calcification. In some embodiments, the disease or ailment is cardiac calcification following cardiac injury. In some embodiments, the disease or ailment is calcium pyrophosphate deposition syndrome (CPPD). In some embodiments, the disease or ailment is hypophosphatase syndrome (HPP).

[0324] In some embodiments, a method of treating or preventing cancer in an individual is provided, the method comprising administering to an individual in need a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, a method of treating or preventing cancer in a subject in need is provided, comprising administering to the subject a therapeutically effective amount of at least one of the chemical entities described herein. This document also provides the use of compounds of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig) or compounds of Table 1 or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a disease in a subject.

[0325] In some embodiments, this document provides a method for treating cancer, the method comprising administering to an individual in need a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. This document also provides the use of compounds of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig) or compounds of Table 1 or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of cancer.

[0326] In some embodiments, a method for treating an individual with bacterial and / or viral infections is provided, the method comprising administering to the individual in need a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. This document also provides the use of compounds of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig) or compounds of Table 1 or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of bacterial and / or viral infections.

[0327] In some embodiments, a method for treating or preventing insulin resistance in an individual is provided, the method comprising administering to an individual in need a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. This document also provides the use of compounds of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig) or compounds of Table 1 or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of insulin resistance.

[0328] In some embodiments, a method for treating type 2 diabetes is provided, the method comprising administering to an individual in need a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. This document also provides the use of compounds of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig) or compounds of Table 1 or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of type II diabetes.

[0329] In some embodiments, a method for treating or preventing chondrocalcinosis in an individual is provided, the method comprising administering to an individual in need a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. This document also provides the use of compounds of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig) or compounds of Table 1 or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of chondrocalcinosis.

[0330] In some embodiments, a method for treating or preventing osteoarthritis in an individual is provided, the method comprising administering to an individual in need a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. This document also provides the use of compounds of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig) or compounds of Table 1 or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of osteoarthritis.

[0331] In some embodiments, a method is provided for treating or preventing soft tissue calcification in an individual, the method comprising administering to an individual in need a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the soft tissue calcification is cardiac calcification following cardiac injury. This document also provides the use of compounds of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or compounds of Table 1, or pharmaceutically acceptable salts thereof, in the manufacture of medicaments for treating soft tissue calcification. In some embodiments, soft tissue calcification is cardiac calcification following cardiac injury.

[0332] In some embodiments, a method is provided for treating or preventing calcium pyrophosphate deposition syndrome (CPPD) in an individual, the method comprising administering to an individual in need a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. This document also provides the use of compounds of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig) or compounds of Table 1 or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of calcium pyrophosphate deposition syndrome (CPPD).

[0333] In some embodiments, a method for treating or preventing hypophosphatase syndrome (HPP) in an individual is provided, the method comprising administering to an individual in need a compound of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1 or a pharmaceutically acceptable salt thereof. This document also provides the use of compounds of formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If) or (Ig) or compounds of Table 1 or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment of hypophosphatase syndrome (HPP).

[0334] dose

[0335] The compounds and / or compositions disclosed and / or described herein are administered at therapeutically effective doses, such as doses sufficient to provide treatment for a disease state. Although human dose levels have not been optimized for the chemical entities described herein, generally, the daily dose range is from about 0.01 to 100 mg / kg body weight; in some embodiments, it is from about 0.05 to 10.0 mg / kg body weight, and in some embodiments, it is from about 0.10 to 1.4 mg / kg body weight. Thus, in some embodiments, for administration to a 70 kg person, the dose range would be from about 0.7 to 7000 mg per day; in some embodiments, it is from about 3.5 to 700.0 mg per day, and in some embodiments, it is from about 7 to 100.0 mg per day. The amount of chemical entity administered will depend, for example, on the subject being treated and the disease state, the severity of the condition, the manner and schedule of administration, and the judgment of the prescribing physician. For example, exemplary dose ranges for oral administration are from about 5 mg to about 500 mg per day, and exemplary dose ranges for intravenous administration are from about 5 mg to about 500 mg per day, each depending on the pharmacokinetics of the compound.

[0336] The compounds and compositions disclosed and / or described herein may be administered via any acceptable therapeutic route, including but not limited to oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, percutaneous, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compounds or compositions are administered orally or intravenously. In some embodiments, the compounds or compositions disclosed and / or described herein are administered orally.

[0337] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories, and aerosols. The compounds disclosed and / or described herein may also be administered in extended-time sustained-release or controlled-release dosage forms (e.g., controlled / sustained-release pills, long-acting injections, osmotic pumps, or transdermal (including electrotransport) patches) and / or via pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for a precise single-dose administration.

[0338] The compounds disclosed and / or described herein may be administered alone or in combination with one or more conventional drug carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). Where necessary, the pharmaceutical composition may also contain small amounts of non-toxic excipients, such as wetting agents, emulsifiers, solubilizers, pH buffers, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitol monolaurate, triethanolamine acetate, triethanolamine oleate). Typically, depending on the intended administration method, the pharmaceutical composition will contain about 0.005% to 95% or about 0.5% to 50% by weight of the compounds disclosed and / or described herein. Practical methods for preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0339] In some embodiments, the composition will be in the form of pills or tablets, and therefore the composition may contain one or more of the following together with the compounds disclosed and / or described herein: a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include powders, pellets, solutions, or suspensions (e.g., in propylene carbonate, vegetable oil, or triglycerides) encapsulated in gelatin capsules.

[0340] Liquid, drug-applied compositions may be prepared, for example, by dissolving, dispersing, or suspending the compounds disclosed and / or described herein, and optional pharmaceutical additives, in a carrier (e.g., water, saline, aqueous dextran solution, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectable formulations may be prepared in conventional forms, such as liquid solutions or suspensions, emulsions, or solid forms suitable for dissolution or suspension in a liquid prior to injection. The percentage of compounds contained in such parenteral compositions depends, for example, the physical properties of the compounds, the activity of the compounds, and the needs of the subject. However, an active ingredient percentage of 0.01% to 10% in the solution may be used, and if the composition is a solid, the percentage may be higher, subsequently diluted to another concentration. In some embodiments, the composition will contain about 0.2% to about 2% of the compounds disclosed and / or described herein in the solution.

[0341] Pharmaceutical compositions of the compounds disclosed and / or described herein may also be administered to the respiratory tract, alone or in combination with an inert carrier such as lactose, in the form of an aerosol or solution for use in a nebulizer or as a fine powder for inhalation. In this case, the particle diameter of the pharmaceutical composition may be less than 50 micrometers, or in some embodiments, less than 10 micrometers.

[0342] In addition, pharmaceutical compositions may comprise compounds disclosed and / or described herein and one or more other pharmaceutical agents, drug agents, adjuvants, etc. Suitable pharmaceutical agents and drug agents include those described herein.

[0343] medicine box

[0344] Articles and packaging boxes containing any of the compounds or pharmaceutical compositions provided herein are also provided. The articles may include labeled containers. Suitable containers include, for example, bottles, vials, and test tubes. Containers may be formed from a variety of materials, such as glass or plastic. Containers may contain the pharmaceutical compositions provided herein. Labels on the containers may indicate that the pharmaceutical composition is intended for the prevention, treatment, or suppression of the diseases described herein, and may also indicate instructions for in vivo or in vitro use.

[0345] In one aspect, this document provides a kit containing a compound or composition described herein and instructions for use. The kit may contain instructions for use in treating any of the diseases or ailments described herein in an individual in need. The kit may additionally contain any materials or devices that can be used to administer the compound or composition, such as vials, syringes, or IV bags. The kit may also contain sterile packaging.

[0346] combination

[0347] The compounds and compositions described and / or disclosed herein may be administered alone or in combination with other therapies and / or treatments available for the treatment of the aforementioned conditions.

[0348] The compounds and compositions described and / or disclosed herein may be combined with one or more other therapies to treat the diseases or conditions described herein, including but not limited to cancer, bacterial and / or viral infections, insulin resistance, type II diabetes, chondrocalcinosis, osteoarthritis, calcium pyrophosphate deposition disorder (CPPD), hypophosphatase disorder, and soft tissue calcification disorders (such as cardiac calcification following heart injury).

[0349] General synthesis methods

[0350] Compounds of formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) will now be described by reference to the illustrative synthetic schemes for their general preparation and subsequent specific examples. Those skilled in the art will recognize that, in order to obtain the various compounds described herein, starting materials can be suitably selected such that the desired final substituent will be carried by the reaction scheme, either protected or unprotected, as appropriate, to produce the desired product. Alternatively, it may be necessary or desirable to substitute a suitable group for the desired final substituent, which can be carried by the reaction scheme and replaced with the desired substituent as appropriate. Furthermore, those skilled in the art will recognize that protecting groups can be used to protect certain functional groups (amino, carboxyl, or side-chain groups) from the effects of reaction conditions and, where appropriate, to remove such groups under standard conditions. Unless otherwise specified, the variables are defined as in the above reference expressions (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig).

[0351] When a specific enantiomer of a compound is required, the enantiomer can be separated or resolved using any suitable conventional procedure from the corresponding enantiomer mixture. Thus, for example, diastereomeric derivatives can be produced by reacting an enantiomer, such as a racemic compound, with a suitable chiral compound. The diastereomeric compound can then be separated by any conventional means, such as crystallization, and the desired enantiomer recovered. In another resolution process, the racemic compound can be separated using chiral high-performance liquid chromatography. Alternatively, if desired, the specific enantiomer can be obtained by using a suitable chiral intermediate in one of the described processes.

[0352] When it is necessary to obtain a specific isomer of a compound or to purify reaction products in other ways, chromatography, recrystallization and other conventional separation procedures can also be used for intermediates or final products.

[0353] General methods for preparing the compounds described herein are described in the following exemplary methods. The variable groups in the schemes provided herein are as defined for formulas (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or any variant thereof. Other compounds described herein can be prepared by similar methods.

[0354] In some embodiments, the compounds provided herein can be synthesized according to Scheme 1, Scheme 2, Scheme 3 and / or Scheme 4.

[0355] Option 1.

[0356]

[0357] Scheme 1 outlines an exemplary route for synthesizing compounds of general formula IV, wherein the group W 1 Compounds of general formula III have structures a, b, c, or d. They are formed by a heteroaryl chloride of general formula I and an alcohol or phenol of general formula II via Ullman-type coupling or S... N The Ar reaction is prepared under heating, either as a pure mixture or in a suitable solvent such as isopropanol (reaction step a). The compound of general formula III is then oxidized with, for example, PhI(OAc)₂ in the presence of an ammonia source such as ammonium acetate to provide the compound of general formula IV (reaction step b).

[0358] Option 2.

[0359]

[0360] Scheme 2 summarizes an exemplary route for preparing compounds of general formula VIII, where A is an aryl or heteroaryl ring or bicyclic ring. The preparation is achieved by reacting a heteroaryl bromide of general formula V with a boric acid or borate ester of general formula VI (wherein the group W) under heating (e.g., between 80°C and 120°C) in the presence of a palladium catalyst (such as Pd(PPh3)4 or Pd(dppf)Cl2) and a base (such as Na2PO4, Na2CO3, or CsCO3). 2 (a, b, or c) cross-coupling (reaction step c) yields compound of general formula VII. Compound of general formula VIII sulfoxide imine can be prepared from compound of general formula VII via the conditions described in Scheme 1 for the preparation of general formula III (reaction step b).

[0361] Option 3.

[0362]

[0363] Compounds of general formula XI can be prepared as described in Scheme 3. Using a suitable base such as K₂CO₃, Et₃N, or iPr₂NEt in a polar solvent such as DMF, a heteroaryl chloride of general formula I reacts with an amine of general formula IX in S… N The reaction proceeds under Ar conditions (reaction step d), including heating (e.g., between 80°C and 100°C), to yield compound X. Compound X can be used to prepare sulfoxide imine of formula XI from compound X via the conditions described in scheme 1 for the preparation of III (reaction step b). Various amines can be used in this route. For example, amine of formula IX (where W...) 3 (en) will provide its corresponding sulfoxide imine XIV.

[0364] Option 4.

[0365]

[0366] It can be produced via intermediate general formula XIII from general formula XII carboxylic acid and general formula IX amine (where W 3 The preparation of general formula XIV amides is described in step e). Various standard condensation reactions can be used (reaction step e). For example, carbodiimide reagents such as DCC or EDC can be used with acyl transfer reagents such as HOBt, HOAt, or DMAP. Urea salts (such as HATU or TBTU) can also be used with bases (such as iPr2NEt). General formula XIV sulfoxide imides can be prepared from general formula XIII intermediates via the conditions described in Scheme 1 for the preparation of III (reaction step b).

[0367] abbreviation:

[0368] dppf: 1,1'-bis(diphenylphosphine)ferrocene

[0369] de: Excess diastereomers (% major diastereomers - % minor diastereomers)

[0370] DAST: Diethylaminosulfonium trifluoride

[0371] DCC: Dicyclohexylcarbodiimide

[0372] DMF-DMA: Dimethylformamide dimethyl acetal

[0373] EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0374] ee: Enantiomer excess (% major enantiomer - % minor enantiomer)

[0375] HOBt: Hydroxybenzotriazole

[0376] HOAt: 1-Hydroxy-7-azabenzotriazole

[0377] DIAD: Diisopropyl azodicarboxylate

[0378] DMAP: 4-(dimethylamino)pyridine

[0379] HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)

[0380] TBDMS: tert-butyl-dimethylsilyl

[0381] T-buxphos-Pd-G3: [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate

[0382] TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyltetrafluoroborate ammonium

[0383] TFA: Trifluoroacetic acid

[0384] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthanium

[0385] List of implementation plans

[0386] 1. A compound of formula (I)

[0387]

[0388] Or its pharmaceutically acceptable salt, wherein:

[0389] W is

[0390] Ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which may or may not be substituted;

[0391] R 1a and R 2a Each is independently hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or C 1-6 Halogenated alkyl groups, wherein the C 1-6 Alkyl groups are optionally replaced by hydroxyl groups, C 1-3 Alkoxy or C 3-6 Cycloalkyl substitution;

[0392] Y is either -N- or -CH-;

[0393] X 1 Yes -CR 1b-or -N-;

[0394] X 2 Yes -CR 2b -or -N-;

[0395] X 3 Yes -CR 3b -or -N-;

[0396] X 4 Yes -CR 4b -or -N-;

[0397] X 5 Yes -CR 5b -or -N-;

[0398] X 6 Yes -CR 6b -or -N-;

[0399] R 1b -R 6b Each of the following is an independent C-type carbon atom containing hydrogen, halogen, hydroxyl group, or optionally substituted with one or more halogen substituents. 1-4 Alkoxy, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, nitro, -NR 1c R 2c -NHC(O)R 3c or -C(O)NR 4c R 5c ;

[0400] L is a bond, -O-, -C(O)-, or -NR. 6c -;

[0401] R 1c -R 6c Each is independently either hydrogen or C. 1-3 alkyl;

[0402] a 1 a 2 and b 1 Each is independently 0, 1, 2, or 3; and

[0403] b 2 c 1 -c 4 d 1 -d 4 e 1 and e 2 Each can be 1, 2, or 3 independently.

[0404] 2. The compound as described in Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein W is

[0405] 3. The compound as described in Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein W is

[0406] 4. The compound as described in Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein W is

[0407] 5. The compound as described in Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein W is

[0408]

[0409] 6. The compound of any one of embodiments 2-5 or a pharmaceutically acceptable salt thereof, wherein A is an aryl group.

[0410] 7. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 2-5, wherein A is a heteroaryl group.

[0411] 8. The compound of any one of embodiments 2-5 or a pharmaceutically acceptable salt thereof, wherein A is a heterocyclic alkyl group.

[0412] 9. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 2-5, wherein A is

[0413] 10. The compound or a pharmaceutically acceptable salt thereof as described in Embodiment 3, wherein A is

[0414] 11. The compound as described in Embodiment 5 or a pharmaceutically acceptable salt thereof, wherein A is

[0415] 12. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 2-11, wherein R 1a It is C 1-6 alkyl.

[0416] 13. The compound as described in embodiment 12 or a pharmaceutically acceptable salt thereof, wherein R 1a It is a methyl group.

[0417] 14. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 2-13, wherein b 1 It is 0.

[0418] 15. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 2-13, wherein b 1 It is 2.

[0419] 16. The compound as described in Embodiment 3 or a pharmaceutically acceptable salt thereof, wherein W is

[0420] 17. The compound as described in embodiment 4 or a pharmaceutically acceptable salt thereof, wherein W is

[0421] 18. The compound as described in embodiment 5 or a pharmaceutically acceptable salt thereof, wherein W is

[0422] 19. The compound as described in Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein W is

[0423] 20. The compound as described in embodiment 19 or a pharmaceutically acceptable salt thereof, wherein W is

[0424] 21. The compound or a pharmaceutically acceptable salt thereof as described in embodiment 19 or 20, wherein R 2a It is C 1-6 alkyl.

[0425] 22. The compound or a pharmaceutically acceptable salt thereof as described in embodiment 15, wherein R 2a It is a methyl group.

[0426] 23. The compound as described in Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein W is

[0427] 24. The compound as described in embodiment 23 or a pharmaceutically acceptable salt thereof, wherein W is

[0428] 25. The compound as described in Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein W is

[0429] 26. The compound as described in embodiment 25 or a pharmaceutically acceptable salt thereof, wherein W is

[0430] 27. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-26, wherein formula (I) Part of it is

[0431] 28. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-24, wherein formula (I) Part of it is

[0432] 29. The compound or a pharmaceutically acceptable salt thereof as described in embodiment 27 or 28, wherein R 2b and R 3b It is a methoxy group, and R 1b and R 4b It is hydrogen.

[0433] 30. The compound or a pharmaceutically acceptable salt thereof as described in embodiment 27 or 28, wherein R 3b It is a methoxy group, and R 1b R 2b and R 4b It is hydrogen.

[0434] 31. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-30, wherein L is a bond.

[0435] 32. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-30, wherein L is -O-.

[0436] 33. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-30, wherein L is -C(O)-.

[0437] 34. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-30, wherein L is -NR 6c -

[0438] 35. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-30, wherein L is -NH-.

[0439] 36. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-35, wherein a 1 It is 0.

[0440] 37. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-35, wherein a 1 It is 1.

[0441] 38. The compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-37, wherein a 2 It is 0.

[0442] 39. A compound or a pharmaceutically acceptable salt thereof as described in Embodiment 1, wherein the compound is selected from the group consisting of the compounds in Table 1.

[0443] 40. A pharmaceutical composition comprising a compound as described in any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0444] 41. A method for inhibiting ENPP1, comprising contacting cells with an effective amount of a compound as described in any one of embodiments 1-39 or a pharmaceutically acceptable salt thereof.

[0445] 42. A method of treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-39.

[0446] 43. A method for treating a subject with a bacterial and / or viral infection, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-39.

[0447] 44. A method for treating insulin resistance in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-39.

[0448] 45. A method of treating type II diabetes in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-39.

[0449] 46. ​​A method of treating chondrocalcinosis in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-39.

[0450] 47. A method of treating osteoarthritis in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-39.

[0451] 48. A method of treating a subject with soft tissue calcification, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-39.

[0452] 49. The method of embodiment 48, wherein the soft tissue calcification is cardiac calcification following cardiac injury.

[0453] 50. A method of treating a subject with calcium pyrophosphate deposition syndrome, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-39.

[0454] 51. A method of treating hypophosphatase syndrome in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 1-39.

[0455] Specific non-limiting embodiments are provided in the following embodiments section.

[0456] Example

[0457] The following examples are provided to illustrate, but do not limit, the compositions, uses, and methods provided herein. The compounds were prepared using the general methods described above.

[0458] Synthesis of intermediates

[0459] Synthesis of intermediate 4-chloro-6-fluoro-7-methoxy-quinoline

[0460]

[0461] Step 1: A mixture of 4-fluoro-3-methoxyaniline (10 g, 71 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (13 g, 92 mmol), trimethoxymethane (11 g, 99 mmol), and MeCN (150 mL) was degassed and purged with N2, and then stirred at 80 °C for 16 h under N2 atmosphere. The mixture was concentrated, and the residue was milled with petroleum ether at 25 °C for 30 min. The mixture was filtered and dried to provide 5-[(4-fluoro-3-methoxy-anilino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (16 g).

[0462] Step 2: Mix 5-[(4-fluoro-3-methoxy-aniline)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (16 g, 53 mmol) with Dowtherm The mixture of A (80 mL) was degassed and purged with N2, and then stirred at 220 °C under N2 atmosphere for 3 h. The mixture was ground with petroleum ether at 25 °C for 30 min, and the solid mixture was filtered and dried to give 6-fluoro-7-methoxy-quinoline-4-ol (10 g).

[0463] Step 3: POCl3 (60 mL, 644 mmol) was added to a mixture of 6-fluoro-7-methoxy-quinoline-4-ol (9.2 g, 48 mmol) and iPr2Net (20 mL, 115 mmol) in MeCN (100 mL). The mixture was then degassed and purged with N2, and stirred at 80 °C under N2 atmosphere for 12 hours. The reaction mixture was cooled and concentrated. The residue was dissolved in ethyl acetate (200 mL) and washed with a saturated aqueous solution of NaHCO3 (200 mL). The organic phase was washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated to provide 4-chloro-6-fluoro-7-methoxy-quinoline (9.8 g).

[0464] Synthesis of 4-chloro-7-methoxy-quinoline-6-nitrile

[0465]

[0466] 4-Chloro-7-methoxy-quinoline-6-onitrile was prepared from 4-amino-2-methoxy-benzonitrile in three steps, as described in the synthesis of the intermediate 4-chloro-6-fluoro-7-methoxy-quinoline.

[0467] Synthesis of intermediate 4-chloro-6-fluoro-7-methoxyquinazoline hydrochloride

[0468]

[0469] Step 1: Br2 (5.5 mL, 110 mmol) was slowly added to a mixture of 4-fluoro-3-methoxyaniline (15 g, 110 mmol), CH2Cl2 (240 mL), and K2CO3 (15 g, 110 mmol) at -15 °C. After stirring for 1 h, the mixture was diluted with H2O (150 mL) and extracted with CH2Cl2 (100 mL x 2). The organic phases were combined, extracted with brine (50 mL), dried over Na2SO4, filtered, concentrated, and ground at 20 °C with CH2Cl2 (40 mL) and hexane (50 mL) for 30 min to provide 2-bromo-4-fluoro-5-methoxyaniline (19 g).

[0470] Add (Boc)₂O (57 g, 260 mmol) to a mixture of 2-bromo-4-fluoro-5-methoxyaniline (24 g, 110 mmol), THF (250 mL), and stir at 20 °C for 12 h with DMAP (2.7 g, 22 mmol). Concentrate the mixture, dilute with H₂O (100 mL), and extract with EtOAc (80 mL x 2). Combine the extracts, wash with brine (50 mL), dry to Na₂SO₄, filter, concentrate, and purify by chromatography (10%–50% EtOAc in petroleum ether) to provide N-(2-bromo-4-fluoro-5-methoxy-phenyl)-N-tert-butoxycarbonylcarbamate tert-butyl ester (41 g).

[0471] Step 2: Add n-BuLi (2.5M in hexane, 29mL) to a mixture of N-(2-bromo-4-fluoro-5-methoxy-phenyl)-N-tert-butoxycarbonyl-carbamate tert-butyl ester (20g, 48mmol) and THF (150mL) at -78°C, and stir the mixture at -78°C for 1h. Add saturated NH4Cl aqueous solution (5.0mL) at 0°C, followed by H2O (100mL). Extract the mixture with EtOAc (70mL x 2), and combine the extracts, wash with brine (40mL), dry to Na2SO4, filter, concentrate, and purify by silica chromatography (10%-50% EtOAc in petroleum ether) to provide 2-((tert-butoxycarbonyl)amino)-5-fluoro-4-methoxybenzoate tert-butyl ester (16g).

[0472] Step 3: Add TFA (21 mL, 280 mmol) to a mixture of tert-butyl 2-(tert-butoxycarbonylamino)-5-fluoro-4-methoxybenzoate (9.0 g, 26 mmol) and CH2Cl2 (50 mL). Stir the mixture at 20 °C for 2 h, concentrate, dilute with H2O (40 mL), and extract with EtOAc (30 mL x 2). Wash the combined extracts with brine (20 mL), dry to Na2SO4, filter, concentrate, and purify by silica chromatography (10%-100% EtOAc in petroleum ether) to provide 2-amino-5-fluoro-4-methoxybenzoic acid (3.1 g).

[0473] Step 4: A mixture of 2-amino-5-fluoro-4-methoxybenzoic acid (1.0 g, 5.4 mmol) and formamide (9.1 mL, 230 mmol) was stirred at 160 °C for 5 h. The mixture was combined with H₂O (20 mL). The precipitate was filtered and ground with MeOH (8.0 mL) at 20 °C for 30 min to give 6-fluoro-7-methoxyquinazoline-4-ol (0.42 g).

[0474] Step 5: The mixture of 6-fluoro-7-methoxy-quinazoline-4-ol (0.40 g, 2.1 mmol) in SOCl2 (8.0 mL) and DMF (15 mg) was stirred at 80 °C for 12 h. The mixture was concentrated to provide 4-chloro-6-fluoro-7-methoxyquinazoline hydrochloride (0.55 g).

[0475] Synthesis of intermediate 4-chloro-3-fluoro-6,7-dimethoxyquinoline

[0476]

[0477] Step 1: Fuming nitric acid (98%, 7.5 mL, 210 mmol) was slowly added to a stirred mixture of 6,7-dimethoxyquinoline-4-ol (20 g, 97 mmol) and propionic acid (450 mL) at 20 °C. The mixture was stirred at 100 °C for 6 h, then cooled to 0 °C, and the resulting precipitate was filtered and washed with hexane. The solid was milled at 20 °C with a 1:5 mixture of MeOH / MTBE (300 mL) for 30 min to give 6,7-dimethoxy-3-nitroquinoline-4-ol (22 g).

[0478] Step 2: A mixture of 6,7-dimethoxy-3-nitroquinoline-4-ol (11 g, 44 mmol), SOCl2 (100 mL), and DMF (0.32 g, 4.4 mmol) was stirred at 90 °C for 12 h and then concentrated to provide 4-chloro-6,7-dimethoxy-3-nitroquinoline hydrochloride (13 g).

[0479] Step 3: SnCl2·2H2O (67 g, 300 mmol) was added to a mixture of 4-chloro-6,7-dimethoxy-3-nitroquinoline hydrochloride (13 g, 43 mmol), AcOH (29 mL), and EtOH (230 mL). The mixture was stirred at 80 °C for 12 h, then concentrated and combined with CH2Cl2 (400 mL) and NaOH (4 M, 80 mL). The mixture was filtered through diatomaceous earth and concentrated to provide 4-chloro-6,7-dimethoxy-quinoline-3-amine (10 g).

[0480] Step 4: HBF4 (40%, 9.8 mL, 63 mmol) was added dropwise to a mixture of 4-chloro-6,7-dimethoxy-quinoline-3-amine (5.0 g, 21 mmol) and THF (50 mL) at 0 °C. The mixture was stirred for 30 min, and NaNO2 (1.6 g, 23 mmol) in H2O (6.3 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, then filtered, and the filtrate was stirred at 170 °C for 1 h. The reactants were concentrated and purified by silica chromatography (0-50% MeOH in CH2Cl2) to give 4-chloro-3-fluoro-6,7-dimethoxyquinoline (0.24 g).

[0481] Synthesis of intermediate 4-chloro-8-ethoxyquinazoline

[0482]

[0483] Step 1: A degassed mixture of methyl 3-hydroxy-2-nitrobenzoate (15 g, 76 mmol), ethane iodide (24 g, 152 mmol), K₂CO₃ (21 g, 152 mmol), and DMF (75 mL) was stirred at 20 °C under a nitrogen atmosphere for 12 h. The mixture was poured into water (150 mL) and extracted with EtOAc (2 x 80 mL). The extract was washed with brine (50 mL), dried over Na₂SO₄, and concentrated to provide methyl 3-ethoxy-2-nitrobenzoate (17 g).

[0484] Step 2: A degassed mixture of methyl 3-ethoxy-2-nitrobenzoate (6.0 g, 27 mmol), NaOH (3.2 g, 80 mmol), H₂O (30 mL), and THF (30 mL) was stirred at 70 °C for 1 h, and then concentrated to remove THF. The mixture was extracted with EtOAc (30 mL), and the aqueous phase was acidified to pH 2 with HCl (4 N) and extracted with EtOAc (2 x 50 mL). The extract was washed with brine (30 mL), dried over anhydrous Na₂SO₄, and concentrated to provide 3-ethoxy-2-nitrobenzoic acid (5.0 g).

[0485] Step 3: The degassed mixture of 3-ethoxy-2-nitrobenzoic acid (5.0 g, 24 mmol), MeOH (50 mL), and 10% Pd / C (2.0 g, 4.7 mmol) was stirred for 12 h at 20 °C under H2 (15 psi). The mixture was filtered and the filtrate was concentrated to provide compound 2-amino-3-ethoxy-benzoic acid (2.8 g).

[0486] Step 4: The mixture of 2-amino-3-ethoxybenzoic acid (2.8 g, 15 mmol) and formamide (2.8 g, 62 mmol) was stirred at 165 °C for 4 h. The reaction mixture was poured into water (30 mL), and the resulting precipitate was filtered, washed with water (10 mL x 2), and dried to provide 8-ethoxyquinazoline-4-ol (1.5 g).

[0487] Step 5: A mixture of 8-ethoxyquinazoline-4-ol (0.29 g, 1.5 mmol), SOCl2 (5 mL, 69 mmol), and DMF (11 mg, 150 μmol) was stirred at 80 °C for 12 h. The mixture was concentrated to provide compound 4-chloro-8-ethoxyquinazoline (0.29 g).

[0488] Synthesis of intermediate 4-chloro-8-ethoxyquinoline-3-nitrile

[0489]

[0490] Step 1: Fe (19 g, 0.33 mol) and NH4Cl (14 g, 0.27 mol) were added to a mixture of methyl 3-ethoxy-2-nitrobenzene (7.5 g, 33 mmol) in EtOH (50 mL). The mixture was stirred at 70 °C for 12 h, then filtered and the filtrate was concentrated. The residue was combined with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined extracts were washed with brine (30 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (9%–17% EtOAc in petroleum ether) to provide methyl 2-amino-3-ethoxy-benzoate (6.0 g).

[0491] Step 2: The degassed mixture of methyl 2-amino-3-ethoxybenzoate (5.0 g, 26 mmol) and DMF-DMA (3.4 mL, 26 mmol) was stirred at 110 °C under a N2 atmosphere for 12 h. The mixture was concentrated to provide methyl 2-[(E)-dimethylaminomethyleneamino]-3-ethoxybenzoate (4.5 g).

[0492] Step 3: Add BuLi (2.5M, 13) to a mixture of CH3CN (1.7 mL, 32 mmol) and THF (25 mL) at -70 °C. After stirring for 0.5 h, add a solution of methyl 2-[(E)-dimethylaminomethyleneamino]-3-ethoxybenzoate (4.0 g, 16 mmol) in THF (30 mL) and stir the mixture at -70 °C for 1.5 h. Add HOAc (3.7 mL, 64 mmol) and pour the mixture into water (30 mL), then extract the resulting mixture with EtOAc (2 x 30 mL). Wash the combined extracts with brine (10 mL), dry to Na2SO4, filter, and concentrate to provide 8-ethoxy-4-hydroxy-quinoline-3-nitrile (2.1 g).

[0493] Step 4: The degassed mixture of 8-ethoxy-4-hydroxyquinoline-3-onitrile (0.25 g, 1.2 mmol), SOCl2 (5 mL, 69 mmol), and DMF (20 μL, 0.26 mmol) was stirred at 90 °C under a N2 atmosphere for 2 h. The mixture was concentrated to provide 4-chloro-8-ethoxyquinoline-3-onitrile (0.40 g).

[0494] Synthesis of intermediate 4-chloro-8-(fluoromethoxy)quinoline-3-nitrile

[0495]

[0496] Step 1: Add 65% NaH (1.4 g, 38 mmol) to a mixture of methyl 3-hydroxy-2-nitrobenzoate (3.0 g, 15 mmol) and DMF (30 mL) and stir at 0 °C for 0.5 h. Add fluoro(iodo)methane (2.9 g, 18 mmol) at 25 °C and stir the mixture for 12 h. Slowly add saturated NH4Cl aqueous solution (20 mL) and filter the mixture, concentrate it, combine it with EtOAc (50 mL), and wash with H2O (30 mL x 3). Combine the extracts, wash with brine (20 mL), dry with Na2SO4, filter, and concentrate to provide methyl 3-(fluoromethoxy)-2-nitrobenzoate (3.3 g).

[0497] Step 2: Pd / C (1.0 g, 10%) was added to methyl 3-(fluoromethoxy)-2-nitrobenzoate (4.9 g, 21 mmol) and EtOH (50 mL) under a nitrogen atmosphere. The suspension was degassed and then stirred at 20 °C for 8 h under H2 (15 psi). The mixture was filtered and the filtrate was concentrated to provide methyl 2-amino-3-(fluoromethoxy)benzoate (3.50 g).

[0498] Steps 3-5 are performed with 2-amino-3-(fluoromethoxy)benzoate in the manner described in steps 2-4 of the synthesis of intermediate 4-chloro-8-ethoxyquinoline-3-onitrile to provide 4-chloro-8-(fluoromethoxy)quinoline-3-onitrile.

[0499] Synthesis of intermediate 4-chloro-5-fluoro-8-methoxyquinoline-3-nitrile

[0500]

[0501] Step 1: A mixture of 5-fluoro-2-methoxyaniline (4.0 g, 28 mmol) and (Z)-2-cyano-3-ethoxy-prop-2-enoic acid ethyl ester (4.8 g, 28 mmol) was stirred at 150 °C for 2 h. The resulting solid was cooled and ground at 20 °C with petroleum ether (15 mL) for 30 min to obtain (E)-2-cyano-3-((5-fluoro-2-methoxyphenyl)amino)acrylate ethyl ester (7.0 g).

[0502] Step 2: A mixture of (E)-2-cyano-3-((5-fluoro-2-methoxyphenyl)amino)acrylate (1.0 g, 3.8 mmol) and Ph₂O (10 mL) was stirred at 250 °C for 6 h, followed by stirring at 280 °C for 6 h. The mixture was cooled, and the resulting precipitate was stirred with petroleum ether (30 mL) at 80 °C for 15 min, and then cooled to 40 °C. The suspension was filtered, and the filter cake was washed with petroleum ether (5 mL x 3) to give 5-fluoro-4-hydroxy-8-methoxyquinoline-3-nitrile (0.58 mg).

[0503] Step 3: A mixture of 5-fluoro-4-hydroxy-8-methoxyquinoline-3-onitrile (0.50 g, 2.3 mmol) and POCl3 (3.0 mL, 32 mmol) was stirred at 120 °C for 12 h. The mixture was concentrated, and saturated NaHCO3 (5 mL) was added to adjust its pH to 8. The solid was separated by filtration, and the filter cake was washed with water (0.5 mL x 3) and petroleum ether (3 mL). This solid was milled with MTBE (8 mL) at 70 °C for 15 min, cooled to 20 °C, filtered, and washed with MTBE (0.5 mL x 3) and petroleum ether (3 mL) to obtain 4-chloro-5-fluoro-8-methoxyquinoline-3-onitrile (0.47 g).

[0504] Synthesis of intermediate 4-chloro-8-methoxy-2-methylquinoline-3-nitrile

[0505]

[0506] Step 1: A degassed mixture of (E)-2-cyano-3-ethoxy-but-2-enoate (6.3 g, 34 mmol), 2-methoxyaniline (3.9 mL, 34 mmol), and EtOH (50 mL) was stirred at 90 °C under a N2 atmosphere for 4 h. The mixture was concentrated and purified by silica chromatography (0-25% EtOAc in petroleum ether) to provide (Z)-2-cyano-3-(2-methoxyphenylamino)but-2-enoate (2.7 g).

[0507] Step 2: Add (Z)-2-cyano-3-(2-methoxyphenylamino)but-2-enoic acid ethyl ester (2.5 g, 9.0 mmol) and DOWTHERM A (50 mL) was stirred at 280 °C for 10 h. The mixture was then ground with petroleum ether at 20 °C for 30 min to provide 4-hydroxy-8-methoxy-2-methyl-quinoline-3-nitrile (1.3 g).

[0508] Step 3: A degassed mixture of 4-hydroxy-8-methoxy-2-methylquinoline-3-onitrile (0.85 g, 3 mmol), DMF (4.3 μL, 55 μmol), and SOCl2 (10 mL) was stirred at 20 °C under a N2 atmosphere for 12 h. The mixture was concentrated and purified by silica chromatography (0-100% EtOAc in petroleum ether) to provide 4-chloro-8-methoxy-2-methylquinoline-3-onitrile (0.40 g).

[0509] Synthesis of intermediate 4-chloro-6,7-dimethoxy-3-methylzoline

[0510]

[0511] Step 1: EtMgCl (2M, 79mL) was slowly added to a mixture of 2-amino-4,5-dimethoxybenzonitrile (7.0g, 39mmol) and THF (70mL) at 0°C. The mixture was stirred at 50°C for 2h, an aqueous HCl solution (2N, 80mL) was added, and the pH was adjusted to 9 by adding a saturated aqueous NaHCO3 solution. The resulting mixture was extracted with EtOAc (2 x 100mL), the extracts were combined, washed with brine (50mL), dried over Na2SO4, concentrated, and purified by silica chromatography (5%-100% EtOAc in petroleum ether) to provide 1-(2-amino-4,5-dimethoxy-phenyl)propane-1-one (4.3g).

[0512] Step 2: NaNO2 (1.1 g, 16 mmol) in H2O (6.6 mL) was slowly added to a mixture of 1-(2-amino-4,5-dimethoxy-phenyl)prop-1-one (3.3 g, 16 mmol), concentrated HCl (53 mL), and H2O (6.6 mL) at -5 °C over 10 min. The mixture was stirred at -5 °C for 1 h, and then at 60 °C for 4 h. The solid was separated by filtration, washed with H2O (20.0 mL x 3), and dried to provide crude 6,7-dimethoxy-3-methyl-cenline-4-ol (4.4 g).

[0513] Step 3: A mixture of crude 6,7-dimethoxy-3-methyl-cenline-4-ol (4.3 g, ≤20 mmol), SOCl2 (30 mL), and DMF (0.15 mL, 2.0 mmol) was stirred at 80 °C under a N2 atmosphere for 2 h. The mixture was concentrated and purified by preparative HPLC (15%–45% aqueous solution of MeCN, 10 mM NH4CO3) to provide 4-chloro-6,7-dimethoxy-3-methylcenline (1.5 g).

[0514] Synthesis of intermediate 4-chloro-3-fluoro-8-methoxyquinoline

[0515]

[0516] Step 1: Add 2-fluoromalonic acid (1 g, 8.2 mmol) to POCl3 (60 mL) and heat the mixture to reflux for 30 min, then cool to 60 °C and slowly add 2-methoxyaniline (1.0 g, 8.2 mmol). Heat the mixture to 140 °C for 15 h, concentrate, and add ice water (5 g). After stirring for 0.5 h, add ammonia until the pH reaches 10. Collect the resulting precipitate by filtration and purify by silica chromatography (0-50% EtOAc in petroleum ether) to provide 2,4-dichloro-3-fluoro-8-methoxyquinoline (0.38 g).

[0517] Step 2: A mixture of 2,4-dichloro-3-fluoro-8-methoxyquinoline (0.38 g, 1.54 mmol), H₂O (2.5 mL), dioxane (5 mL), 10% Pd / C (0.2 g), Et₃N (3.9 mL, 28 mmol), and formic acid (0.23 μL, 6.2 mmol) was stirred at 90 °C for 16 h. The mixture was filtered, and the filtrate was concentrated and purified by silica chromatography (0-50% EtOAc in petroleum ether) to provide 4-chloro-3-fluoro-8-methoxyquinoline (0.12 g).

[0518] Synthesis of intermediate 4,6-dichloro-7-methoxyzoline hydrochloride

[0519]

[0520] Step 1: Add NCS (3.1 g, 23 mmol) to a mixture of 1-(2-amino-4-methoxy-phenyl)ethyl ketone (3.5 g, 21 mmol) and THF (60 mL). Stir the mixture at 60 °C for 2 h, pour into H2O (60 mL), and extract with EtOAc (2 x 40 mL). Wash the combined extracts with brine (10 mL), dry to Na2SO4, concentrate, and grind at 20 °C with CH2Cl2 / petroleum ether (5 mL) for 10 min to provide compound 1-(2-amino-5-chloro-4-methoxy-phenyl)ethyl ketone (2.8 g).

[0521] Step 2: A solution of NaNO2 (0.97 g, 14 mmol) in H2O (7.5 mL) was slowly added to 1-(2-amino-5-chloro-4-methoxy-phenyl)ethyl ketone (2.8 g, 14 mmol) in 12NHCl (60 mL) at -5 °C. The mixture was stirred for 1 h, and then stirred at 60 °C for 4 h. The resulting precipitate was filtered and washed with water (20 mL x 2) to provide 6-chloro-7-methoxy-porphyrin-4-ol hydrochloride (1.8 g).

[0522] Step 3: A degassed mixture of 6-chloro-7-methoxy-cynoline-4-ol hydrochloride (1.8 g, 8.5 mmol), DMF (62 mg, 0.85 mmol), and SOCl2 (49 g, 410 mmol) was stirred at 90 °C for 2 h. The mixture was concentrated to provide compound 4,6-dichloro-7-methoxy-cynoline hydrochloride (2.2 g).

[0523] Synthesis of intermediate 4,6-dichloro-7-methoxy-3-methylbenzyl hydrochloride

[0524]

[0525] Step 1: A degassed mixture of 2-amino-4-methoxy-benzonitrile (10 g, 67 mmol), NCS (9.9 g, 74 mmol), and THF (150 mL) was stirred at 60 °C under a nitrogen atmosphere for 12 h. The mixture was poured into a saturated aqueous solution of NaHCO3 (100 mL) and extracted with EtOAc (2 x 100 mL). The extract was washed with brine (50 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (5%–25% EtOAc in petroleum ether) to provide 2-amino-5-chloro-4-methoxy-benzonitrile (7.2 g).

[0526] Step 2: Add EtMgCl (2M in THF, 52mL) to a mixture of 2-amino-5-chloro-4-methoxy-benzonitrile (4.7g, 26mmol) and THF (20mL). Stir the mixture at 50°C for 12h and slowly add 50mL of 2M HCl. Add saturated NaHCO3 aqueous solution to adjust the pH to 9, and extract the resulting mixture with EtOAc (2 x 80mL). Wash the extract with brine (10mL), dry to Na2SO4, concentrate, and purify by silica chromatography (5%-17% EtOAc in petroleum ether) to provide 1-(2-amino-5-chloro-4-methoxy-phenyl)prop-1-one (3.2g).

[0527] Step 3: A solution of NaNO2 (1.0 g, 15 mmol) in 10 mL of H2O was slowly added at -5 °C to a mixture of 1-(2-amino-5-chloro-4-methoxy-phenyl)prop-1-one (3.2 g, 15 mmol), H2O (6 mL), and concentrated HCl (45 mL). After addition, the mixture was stirred for 1 h, and then stirred at 50 °C for 3 h. The resulting precipitate was filtered and washed with water (50 mL x 2) to provide 6-chloro-7-methoxy-3-methyl-boronin-4-ol (2.5 g).

[0528] Step 4: Stir a mixture of 6-chloro-7-methoxy-3-methyl-cinnamoline-4-ol (2.5 g, 11 mmol), SOCl2 (25 mL, 0.35 mol), and DMF (40 mg, 0.55 mol) at 80 °C for 2 h, and then concentrate to provide 4,6-dichloro-7-methoxy-3-methylcinnamoline hydrochloride (3.2 g).

[0529] Synthesis of intermediate 1-(3-((4-hydroxyphenyl)thio)azacyclobut-1-yl)ethyl-1-one

[0530]

[0531] Step 1: Add Et3N (7.3 mL, 52 mmol) and toluenesulfonyl chloride (5.0 g, 26 mmol) to a mixture of 1-(3-hydroxyazacyclobut-1-yl)acetone (2.0 g, 17 mmol), CH2Cl2 (20 mL) at 0 °C. Stir the mixture at 20 °C for 2 h, then pour it into water (30.0 mL) and extract with EtOAc (2 x 30 mL). Wash the combined extracts with brine (10.0 mL), dry to Na2SO4, concentrate, and purify by silica chromatography (0-100% EtOAc / petroleum ether) to provide (1-acetylazacyclobut-3-yl)4-methylbenzenesulfonate (4.35 g).

[0532] Step 2: A degassed mixture of (1-acetylazetrazol-3-yl)4-methylbenzenesulfonate (2.0 g, 7.4 mmol), DMSO (20 mL), Cs₂CO₃ (4.8 g, 15 mmol), and 4-methoxybenzenethiol (1.8 mL, 15 mmol) was stirred at 60 °C under a N₂ atmosphere for 12 h. The mixture was poured into water (30.0 mL) and extracted with EtOAc (30.0 mL x 2). The combined extracts were washed with brine (20.0 mL x 2), dried over Na₂SO₄, filtered, concentrated, and purified by silica chromatography (0-100% EtOAc / petroleum ether) to provide 1-[3-(4-methoxyphenyl)thioalkylazetrazol-1-yl]acetone (1.5 g).

[0533] Step 3: Add BBr3 (2.9 mL, 30 mmol) to a degassed mixture of 1-[3-(4-methoxyphenyl)thioalkylazacyclobut-1-yl]ethyl ketone (1.4 g, 6.0 mmol) and CH2Cl2 (20 mL) at -78 °C. Stir the mixture at 25 °C under a N2 atmosphere for 12 h, slowly add MeOH (5.0 mL), and concentrate the resulting mixture. Combine with water (10 mL) and extract with EtOAc (10.0 mL x 2). Wash the combined extracts with an aqueous solution of NaHCO3 (10 mL x 2), dry to Na2SO4, filter, and concentrate to provide 1-(3-((4-hydroxyphenyl)thio)azacyclobut-1-yl)ethane-1-one (1.4 g, 78% purity).

[0534] Synthesis of intermediate 6-(methylthio)pyridine-3-ol

[0535]

[0536] At -78 °C, t-BuLi solution (1.9 M, 3.2 mL, 6.0 mmol) was added dropwise to 2-bromo-5-hydroxypyridine (0.35 g, 2.0 mmol) and 10 mL THF. The mixture was stirred at -78 °C for 10 min, and dimethyl disulfide (0.36 mL, 4.0 mmol) was added slowly. The resulting mixture was stirred for 15 min, then warmed to room temperature and stirred for 2 h. Saturated NH4Cl aqueous solution and 2 M HCl were added until pH 3 was reached. The phases were separated, and the aqueous phase was extracted with EtOAc (3x). The initial organic phase was combined with the EtOAc extract, dried over Na2SO4, filtered, and concentrated to provide 6-(methylthio)pyridin-3-ol (0.22 g, 1.5 mmol).

[0537] Synthesis of intermediate 4-(cyclopropylthio)phenol

[0538]

[0539] Step 1: A mixture of 4-methoxyphenylthiol (0.37 g, 2.6 mmol), K₂CO₃ (0.54 g, 3.9 mmol), DMF (5 mL), and cyclopropyl bromide (0.27 mL, 3.4 mmol) was heated to 120 °C overnight under an Ar atmosphere. After cooling, cold water and EtOAc were added. The organic phase was separated and washed with cold water (4x) and brine. The organic layer was dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel chromatography (1%–25% EtOAc in heptane) to obtain 0.38 g of cyclopropyl(4-methoxyphenyl)thiol.

[0540] Step 2: BBr3 (1M, 11mL, 11mmol in CH2Cl2) was added to a mixture of cyclopropyl(4-methoxyphenyl)thione (0.36g, 2.0mmol) and CH2Cl2 (50mL) at 5°C. After stirring at room temperature for 2 days, additional BBr3 (1M, 11mL, 11mmol in CH2Cl2) was added, and the mixture was stirred overnight. A saturated aqueous solution of NaHCO3 (15mL) was added, followed by water, and the mixture was extracted with CH2Cl2 (3x). The combined extracts were dried over Na2SO4, filtered, and concentrated to provide 0.33g of 4-(cyclopropylthio)phenol.

[0541] Synthesis of intermediate (3-fluoro-5-(methylthio)phenyl)methanol

[0542]

[0543] Step 1: A mixture of 1-bromo-3,5-difluorobenzene (3.0 mL, 26 mmol), DMF (30 mL), and 93% NaSMe (1.8 mL, 26 mmol) was stirred at 20 °C for 12 h. The mixture was poured into a saturated aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (50 mL x 2). The combined extracts were washed with brine (20 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0–20% EtOAc / petroleum ether) to provide 1-bromo-3-fluoro-5-methylthioalkylbenzene (2.8 g).

[0544] Step 2: BuLi (1.6 M, 5.4 mL) was added to 1-bromo-3-fluoro-5-methylthioalkylbenzene (1.9 g, 8.6 mmol) in THF (10 mL) at -78 °C, and the mixture was stirred at -78 °C for 15 min. DMF (0.79 mL, 10 mmol) was added, and the mixture was stirred at -78 °C for 0.5 h. Saturated NH4Cl aqueous solution (10 mL) was added at -78 °C, and the mixture was then stirred at 25 °C for 30 min and extracted with EtOAc (20 mL x 3). The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-35% EtOAc / petroleum ether) to provide 3-fluoro-5-methylthioalkylbenzaldehyde (0.79 g).

[0545] Step 3: LiAlH4 (0.25 g, 6.5 mmol) was added to 3-fluoro-5-methylthioalkylbenzaldehyde (0.74 g, 4.4 mmol) in THF (20 mL) at 0 °C. The mixture was stirred at 20 °C for 2 h, and then 0.25 mL of H2O, 0.25 mL of NaOH aqueous solution (15%, NaOH), and another 0.25 mL of H2O were added slowly in sequence. The mixture was stirred at 20 °C for 10 min and then extracted with EtOAc (10 mL x 2). The combined extracts were dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-70% EtOAc / petroleum ether) to provide (3-fluoro-5-(methylthio)phenyl)methanol (0.47 g).

[0546] Synthesis of intermediate (4-(methylthio)furan-2-yl)methanol

[0547]

[0548] Step 1: A mixture of 4-bromofuran-2-carboxaldehyde (5.0 g, 29 mmol), EtOH (9 mL), ethyl orthoformate (6.6 g, 45 mmol), and NH4Cl (1.5 g, 29 mmol) was stirred at 90 °C for 12 h. The mixture was concentrated, combined with 20 mL of H2O, and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (5%–10% EtOAc in petroleum ether) to provide 4-bromo-2-(diethoxymethyl)furan (6.4 g, 26 mmol).

[0549] Step 2: A solution of n-BuLi (2.5 M, 3.8 mL, 9.5 mmol) was slowly added to a stirred mixture of 4-bromo-2-(diethoxymethyl)furan (2.0 g, 8.0 mmol) and THF (20 mL) at -70 °C. The mixture was stirred at -70 °C for 0.5 h, and (methyldithioalkyl)methane (0.91 g, 9.6 mmol) was added to THF (2 mL). The mixture was poured into saturated NH4Cl (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to provide 2-(diethoxymethyl)-4-methylthioalkylfuran (1.7 g), which was used without further purification.

[0550] Step 3: A mixture of 2-(diethoxymethyl)-4-methylthioalkylfuran (1.7 g, 7.9 mmol), THF (20 mL), and 2M HCl (20 mL, 40 mmol) was stirred at 20 °C for 0.5 h, then poured into water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, and concentrated to provide 4-methylthioalkylfuran-2-carboxaldehyde (1.1 g), which was used directly without purification.

[0551] Step 4: Add NaBH4 (590 mg, 15 mmol) to a mixture of 4-methylthiofuran-2-carboxaldehyde (1.1 g, 7.7 mmol) and MeOH (10 mL). Stir the mixture at 25 °C for 1 h, then concentrate, combine with H2O (30 mL), and extract with EtOAc (2 x 30 mL). Combine the extracts, wash with brine (10 mL), dry with Na2SO4, filter, concentrate, and purify by silica chromatography (10%-100% EtOAc in petroleum ether) to provide (4-(methylthio)furan-2-yl)methanol (0.7 g).

[0552] Synthesis of intermediate (3-cyclopropylthioalkylphenyl)methanol

[0553]

[0554] Step 1: A mixture of 3-thioalkylbenzoic acid (2.0 g, 13 mmol), DMSO (20 mL), t-BuOK (3.6 g, 32 mmol), and bromocyclopropane (1.6 mL, 20 mmol) was stirred at 80 °C for 24 h. HCl aqueous solution (1 M) was added to bring the pH to 2–3, and the mixture was extracted with EtOAc (20 mL x 2). The combined extracts were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated to provide 3-cyclopropylthioalkylbenzoic acid (2.4 g).

[0555] Step 2: 3-Cyclopropylthioalkylbenzoic acid (2.2 g, 11 mmol) in THF (20 mL) was slowly added to LiAlH4 (0.86 g, 23 mmol) and THF (10 mL) at 0 °C. The mixture was stirred at 20 °C for 12 h, and H2O (1 mL) was slowly added, followed by 15% NaOH (1 mL) and H2O (3 mL). The mixture was filtered, and the filtrate was concentrated, diluted with EtOAc (20 mL), washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (33%-50% EtOAc in petroleum ether) to provide (3-cyclopropylthioalkylphenyl)methanol (2.0 g).

[0556] Synthesis of intermediate (R)-1-(3-(methylthio)phenyl)ethanol-1-ol

[0557]

[0558] Step 1: A degassed mixture of (1R)-1-(3-bromophenyl)ethanol (5.0 g, 25 mmol), TBDMSCl (4.5 g, 30 mmol), imidazole (2.4 g, 35 mmol), and DMF (50 mL) was stirred at 20 °C under a N2 atmosphere for 16 h. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (2 x 60 mL). The organic phase was washed with brine (60 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (10%-20% EtOAc in petroleum ether) to provide [(1R)-1-(3-bromophenyl)ethoxy]-tert-butyl-dimethylsilane (7 g).

[0559] Step 2: A BuLi (2.5 M, 13 mL) solution was slowly added to [(1R)-1-(3-bromophenyl)ethoxy]-tert-butyl-dimethyl-silane (7.0 g, 22 mmol) in THF (50 mL) at -78 °C. After addition, the mixture was stirred for 30 min, and 1,2-dimethyl disulfide (2.2 mL, 24 mmol) was slowly added at -78 °C. The resulting mixture was stirred at 20 °C for 2 h, poured into a saturated NH4Cl aqueous solution (50 mL), and extracted with EtOAc (50 mL x 2). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to provide tert-butyl-dimethyl-[(1R)-1-(3-methylthioalkylphenyl)ethoxy]silane (6.5 g).

[0560] Step 3: A mixture of tert-butyl-dimethyl-[(1R)-1-(3-methylthiophenyl)ethoxy]silane (6.5 g, 23 mmol), EtOH (50 mL), and HCl (2 M, 50 mL) was stirred at 20 °C for 2 h. The mixture was concentrated and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (10%-25% EtOAc in petroleum ether) to provide (R)-1-(3-(methylthio)phenyl)ethane-1-ol (2.7 g).

[0561] Synthesis of intermediate (1r,4r)-4-(methylthio)cyclohexyl-1-ol

[0562]

[0563] Step 1: A degassed mixture of 7-oxabicyclo[2.2.1]heptane (1.0 g, 10 mmol), thiourea (1.2 g, 15 mmol), p-TsOH (2.9 g, 17 mmol), and EtOH (10 mL) was stirred at 90 °C for 12 h. NaOH (1.3 g, 33 mmol) and H2O (3 mL) were added, and the mixture was stirred at 90 °C for 2 h. The mixture was then concentrated, combined with H2O (20 mL), and extracted with EtOAc (2 x 20 mL). The extract was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (20%-50% EtOAc in petroleum ether) to provide 4-[(4-hydroxycyclohexyl)dithioalkyl]cyclohexanol (0.5 g).

[0564] Step 2: Add Bu3P (0.34 g, 1.7 mmol) to a mixture of 4-[(4-hydroxycyclohexyl)dithioalkyl]cyclohexanol (0.4 g, 1.5 mmol), THF (8 mL), and H2O (0.2 mL). Add MeI (0.86 g, 6.1 mmol) and K2CO3 (1.3 g, 9.1 mmol) to the solution. Stir the mixture at 25 °C for 12 h, pour it into H2O (30 mL), and extract the resulting mixture with EtOAc (2 x 30 mL), wash with brine (10 mL), dry to anhydrous Na2SO4, concentrate, and purify by silica chromatography (20%-50% EtOAc in petroleum ether) to give (1r,4r)-4-(methylthio)cyclohexyl-1-ol (0.22 g).

[0565] Synthesis of intermediate (1r,4s)-4-(methylthio)cyclohexyl-1-ol

[0566]

[0567] Step 1: Add DIAD (1.9 g, 9.6 mmol) to a mixture of (1r,4r)-4-(methylthio)cyclohexyl-1-ol (0.70 g, 4.8 mmol), 4-nitrobenzoic acid (1.2 g, 7.2 mmol), PPh3 (2.5 g, 9.6 mmol), and THF (30 mL). Stir the mixture at 20 °C for 12 h, pour into H2O (30 mL), and extract with EtOAc (2 x 30 mL). Wash the combined extracts with brine (10 mL), dry to Na2SO4, concentrate, and purify by silica chromatography (5%–17% EtOAc in petroleum ether) to provide (1s,4s)-4-(methylthio)cyclohexyl 4-nitrobenzoate (1.1 g).

[0568] Step 2: A mixture of (1s,4s)-4-(methylthio)-4-nitrobenzoate cyclohexyl ester (0.90 g, 3.0 mmol) in THF (9.0 mL), H₂O (3.0 mL), and LiOH·H₂O (0.64 g, 15 mmol) was stirred at 20 °C for 2 h. The mixture was poured into water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined extracts were washed with brine (10 mL), dried over Na₂SO₄, concentrated, and purified by silica chromatography (10%–50% EtOAc in petroleum ether) to provide (1r,4s)-4-(methylthio)cyclohexanol (0.50 g).

[0569] Synthesis of intermediate 6-((methylthio)methyl)-2-azaspiro[3.3]heptane trifluoroacetate

[0570]

[0571] Step 1: Et3N (5.3 g, 53 mmol) and MsCl (3.6 g, 32 mmol) were slowly added to a mixture of 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (6.0 g, 26 mmol) and CH2Cl2 (30 mL) at 0 °C. The mixture was stirred at 20 °C for 2 h, poured into a saturated NaHCO3 aqueous solution (100 mL), and extracted with EtOAc (2 x 100 mL). The combined extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated to provide 6-(methanesulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (12 g).

[0572] Step 2: Add 20% NaSMe aqueous solution (10 mL, 33 mmol) to a mixture of 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (5.0 g, 16 mmol) in EtOH (50 mL). Stir the mixture at 25 °C for 2 h, then concentrate and extract with EtOAc (2 x 30 mL). Wash the combined extracts with brine (30 mL), dry to Na2SO4, concentrate, and purify by silica chromatography (17%-50% EtOAc in petroleum ether) to provide 6-(methylthioalkylmethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.6 g).

[0573] Step 3: Add TFA (14 mL, 190 mmol) to a mixture of 6-(methylthioalkylmethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.6 g, 14 mmol) and CH2Cl2 (20 mL). Stir the mixture at 20 °C for 12 h and concentrate to provide 6-((methylthio)methyl)-2-azaspiro[3.3]heptane trifluoroacetate (6.8 g).

[0574] Synthesis of intermediate 2-(methylthio)-8-azaspiro[4.5]decane hydrochloride

[0575]

[0576] Step 1: PPh3 (6.2 g, 24 mmol) was added to a mixture of 3-hydroxy-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (4.0 g, 16 mmol), CBr4 (7.8 g, 24 mmol), and CH2Cl2 (50 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h, concentrated, and purified by silica chromatography (10%-20% EtOAc in petroleum ether) to obtain 3-bromo-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (3.0 g).

[0577] Step 2: Add 20% sodium methanethiol (4.9 g, 14 mmol) in H2O to a mixture of 3-bromo-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (3.0 g, 9.4 mmol) and EtOH (20 mL). Stir the mixture at 25 °C for 2 h, concentrate to a small volume, pour into H2O (30 mL), and extract with EtOAc (2 x 30 mL). Wash the organic phase with brine (10 mL), dry with Na2SO4, filter, and concentrate to provide 3-methylthioalkyl-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (2.6 g).

[0578] Step 3: Add HCl / EtOAc (4M, 5.0mL) to a mixture of 3-methylthioalkyl-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (0.26mg, 0.91mmol) and EtOAc (5.0mL). Stir the mixture at 25°C for 2h and concentrate to provide 2-(methylthio)-8-azaspiro[4.5]decane hydrochloride (200mg).

[0579] Synthesis of intermediate 4-(cyclopropylthioalkylmethyl)piperidine trifluoroacetate

[0580]

[0581] Step 1: A mixture of 4-(thioalkylmethyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.3 mmol), DMSO (15 mL), t-BuOK (1 M, 4.8 mL), and bromocyclopropane (0.58 g, 4.8 mmol) was stirred at 15 °C for 12 h. EtOAc (10 mL) was added, and the mixture was washed with H2O (5 mL x 3) and brine (5 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-50% EtOAc in petroleum ether) to provide 4-(cyclopropylthioalkylmethyl)piperidine-1-carboxylic acid tert-butyl ester (0.55 g).

[0582] Step 2: Add TFA (2.3 g, 20 mmol) to a mixture of 4-(cyclopropylthioalkylmethyl)piperidine-1-carboxylic acid tert-butyl ester (0.45 g, 1.7 mmol) and CH2Cl2 (4.5 mL). Stir the mixture at 15 °C for 2 h, then concentrate it, combine it with toluene (10 mL), and then concentrate it again to provide 4-(cyclopropylthioalkylmethyl)piperidine trifluoroacetate (0.45 g).

[0583] Synthesis of intermediate 4-((methylthio)methyl)piperidine-4-ol

[0584]

[0585] Step 1: Trimethyl sulfoxide (2.2 g, 10 mmol) was added to a mixture of 60% NaH (0.40 g, 10 mmol) and DMSO (10 mL) at 20 °C. After addition, the mixture was stirred for 2 h, and 4-oxopiperidin-1-carboxylic acid tert-butyl ester (2.0 g, 10 mmol) was slowly added to DMSO (10 mL). The resulting mixture was stirred at 55 °C for 2 h, diluted with H2O, and extracted with MTBE (30 mL x 2). The combined extracts were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated to provide 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (2.2 g).

[0586] Step 2: Add 20% NaSMe aqueous solution (3.4 mL, 11 mmol) to a mixture of 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid tert-butyl ester (1.5 g, 7.0 mmol) and EtOH (10 mL). Stir the mixture at 20 °C for 2 h, concentrate, dilute with H2O (30 mL), and extract with EtOAc (20 mL x 2). Wash the combined extracts with brine (20 mL), dry with Na2SO4, filter, and concentrate to provide 4-hydroxy-4-(methylthioalkylmethyl)piperidine-1-carboxylic acid tert-butyl ester (1.8 g).

[0587] Step 3: Add 4M HCl (4M, 13mL) from EtOAc to the mixture of 4-hydroxy-4-(methylthiomethyl)piperidine-1-carboxylic acid tert-butyl ester (1.8g, 6.9mmol) in EtOAc (8.0mL). Stir the mixture at 20°C for 2h and concentrate to provide 4-(methylthiomethyl)piperidine-4-ol hydrochloride (1.3g).

[0588] The intermediates in Table 2 were prepared using the reagents shown via the route described in the synthesis of intermediate 4-((methylthiomethyl)methyl)piperidine-4-ol.

[0589] Table 2

[0590]

[0591] Synthesis of intermediate 4-((cyclobutthio)methyl)piperidine-4-ol hydrochloride

[0592]

[0593] Step 1: A mixture of sodium sulfide nonahydrate (5.6 g, 23 mmol), MeOH (125 mL), and TsOH hydrate (7.1 g, 38 mmol) was stirred for 15 min at 0 °C under N2. Then, tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylic acid (2.0 g, 9.4 mmol) was added to MeOH (10 mL), and the mixture was stirred at 0 °C under N2 for 1 h, followed by stirring at 20 °C for 1 h. A saturated NaHCO3 aqueous solution (40 mL) was slowly added at 0 °C, followed by brine (40 mL). The mixture was extracted with EtOAc (50 mL x 3), and the extracts were combined, washed with brine (40 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-40% EtOAc in petroleum ether) to provide tert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylic acid (1.53 g).

[0594] Step 2: A mixture of tert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (1.2 g, 4.9 mmol), bromocyclobutane (0.60 g, 4.4 mmol), DMF (20 mL), and NaOMe (0.32 g, 5.9 mmol) was stirred at 50 °C under a nitrogen atmosphere for 5 h. A saturated aqueous solution of NH4Cl (40 mL) was added dropwise at 0 °C, followed by the addition of brine (40 mL). The mixture was extracted with EtOAc (50 mL x 3), and the combined extracts were washed with water (40 mL x 3) and brine (40 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-30% EtOAc in petroleum ether) to provide tert-butyl 4-((cyclobutyrothio)methyl)-4-hydroxypiperidine-1-carboxylate (0.80 g).

[0595] Step 3: Add HCl / MeOH (4M, 6.9mL) to a mixture of 4-((cyclobutylthio)methyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.40g, 1.3mmol) and MeOH (6mL). Stir the mixture at 20°C for 5h and concentrate to obtain 4-((cyclobutylthio)methyl)piperidine-4-ol hydrochloride (0.28g).

[0596] Synthesis of intermediate 8-((methylthio)methyl)-5-azaspiro[2.5]octyl-8-ol hydrochloride

[0597]

[0598] Step 1: A mixture of trimethyl sulfoxide (2.5 g, 12 mmol), DMSO (25 mL), and 60% NaH (0.60 g, 15 mmol) was stirred at 30 °C for 30 min, and 8-oxo-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester (0.90 g, 4.0 mmol) from DMSO (5 mL) was added dropwise, and the mixture was stirred at 20 °C for 12 h. A saturated aqueous solution of NH4Cl (5 mL) and water (50 mL) were then added. The mixture was extracted with EtOAc (2 x 50 mL), and the extracts were combined, washed with water (40 mL x 3) and brine (40 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-40% EtOAc in petroleum ether) to provide 5-oxa-9-azabispiro[2.0.24.43]decane-9-carboxylic acid tert-butyl ester (0.50 g).

[0599] Step 2: A mixture of 5-oxa-9-azabispiro[2.0.24.43]decane-9-carboxylic acid tert-butyl ester (0.50 g, 2.1 mmol), EtOH (20 mL), and NaSMe (0.33 g, 4.5 mmol) was stirred at 20 °C for 5 h. Water (10 mL) was added, and the mixture was extracted with EtOAc (2 x 20 mL). The extracts were combined, washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-40% EtOAc in petroleum ether) to provide 8-hydroxy-8-((methylthio)methyl)-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester (0.50 g).

[0600] Step 3: Stir a mixture of 0.50 g (1.7 mmol) of 8-hydroxy-8-((methylthio)methyl)-5-azaspiro[2.5]octane-5-carboxylic acid tert-butyl ester, 5 mL of MeOH, and HCl (4 M in MeOH, 5 mL) at 0 °C for 3 h while warming it to 20 °C. Concentrate the mixture to provide 0.39 g of 8-((methylthio)methyl)-5-azaspiro[2.5]octane-8-ol hydrochloride.

[0601] Intermediate imino(methyl)(2-(piperidin-4-yl)ethyl)-λ 6 Synthesis of thioketone hydrochloride

[0602]

[0603] Step 1: PPh3 (8.6 g, 32.8 mmol) and CBr4 (10.9 g, 32.9 mmol) were added in portions to a solution of 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 21.8 mmol) in CH2Cl2 (50 mL). After stirring at 20 °C for 20 h, the mixture was washed with brine (20 mL x 3), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (0-80% EtOAc / petroleum ether) to obtain 4-(2-bromoethyl)piperidine-1-carboxylic acid tert-butyl ester (6.0 g).

[0604] Step 2: NaSMe (1.65 g, 4.7 mmol, 20% aqueous solution) was added dropwise to a solution of 4-(2-bromoethyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.4 mmol) in EtOH (15 mL) at 20 °C, and the mixture was stirred at 20 °C for 12 h, concentrated, and dissolved in 30 mL of EtOAc. The solution was washed with brine (10 mL x 3) and concentrated, and purified by silica gel chromatography (0-30% EtOAc / petroleum ether) to give 4-(2-(methylthio)ethyl)piperidine-1-carboxylic acid tert-butyl ester (730 mg).

[0605] Step 3: PhI(OAc)₂ (1.5 g, 4.7 mmol) and NH₄OAc (270 mg, 3.5 mmol) were added to a solution of 4-(2-(methylthio)ethyl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.2 mmol) in EtOH (12 mL) at 20 °C. The mixture was stirred at 20 °C for 12 h, then concentrated and purified by silica gel chromatography (0-100% EtOAc in petroleum ether in 33% EtOH) to give 4-(2-(methylsulfonylimino)ethyl)piperidine-1-carboxylic acid tert-butyl ester (310 mg).

[0606] Step 4: Add HCl / EtOAc (4M, 1.24mL) to a solution of 4-(2-(S-methylsulfonylimino)ethyl)piperidine-1-carboxylic acid tert-butyl ester (310mg, 1.1mmol) in EtOAc (1.5mL) at 20°C. Stir the mixture at 20°C for 2h, then concentrate to obtain 4-(2-(methylsulfonylimino)ethyl)piperidine (260mg) as hydrochloride, which is used without purification.

[0607] The intermediates in Table 3 are synthesized via the thiols shown, targeting the synthetic intermediate imino(methyl)(2-(piperidin-4-yl)ethyl)-λ. 6 The thioalkyl ketone hydrochloride is prepared using the route described above.

[0608] Table 3

[0609]

[0610] Synthesis Example S-1

[0611] (4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)(imino)(methyl)-λ 6 Synthesis of thioketones (compound 1)

[0612] Step 1: Synthesis of 6,7-dimethoxy-4-(4-(methylthio)phenoxy)quinoline

[0613]

[0614] A mixture of 4-chloro-6,7-dimethoxyquinoline (500 mg, 2.24 mmol) and 4-(methylthio)phenol (942 mg, 3 equivalents, 6.72 mmol) was heated at 170 °C for 1 hour. The residue was diluted with saturated Na₂CO₃ (50 mL) / MeOH (15 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated. Purification by silica gel chromatography (0-50% EtOAc / petroleum ether) yielded 6,7-dimethoxy-4-(4-(methylthio)phenoxy)quinoline (400 mg, 1.15 mmol).

[0615] Step 2: (4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)(imino)(methyl)-λ 6 Synthesis of thioketones

[0616]

[0617] NH4OAc (94.0 mg, 1.2 mmol) and PhI(OAc)2 (295 mg, 3 equivalents, 916 μmol) were added to a solution of 6,7-dimethoxy-4-(4-(methylthio)phenoxy)quinoline (106 mg, 0.31 mmol) in EtOH (2 mL). The mixture was stirred at 20 °C for 12 h. The mixture was poured into H2O (50 mL) and extracted with EtOAc (20 mL x 3). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. It was purified by preparative HPLC (15%–35% [10 mM NH4HCO3] in aqueous solution of MeCN) to give (4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)(imino)(methyl)-λ 6-Thioketone (compound 1) (60 mg). ESI m / z: 359.1 (M+H). 1 H NMR(400MHz, DMSO-d6)δ:8.56(d,J=5.1Hz,1H),8.02(d,J=8.6Hz,2H),7.45-7.40( m, 4H), 6.69 (d, J = 5.1Hz, 1H), 4.28 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.10 (s, 3H).

[0618] Synthesis Example S-2

[0619] {4-[(6-fluoro-7-methoxyquinoline-4-yl)oxy]phenyl}(imino)methyl-λ 6 Synthesis of thioketones (compound 114)

[0620] Step 1: Synthesis of 6-fluoro-7-methoxy-4-(4-(methylthio)phenoxy)quinoline

[0621]

[0622] A mixture of 4-chloro-6-fluoro-7-methoxy-quinoline (2.0 g, 9.5 mmol) and 4-methylthioalkylphenol (2.7 g, 19 mmol) was degassed and purged with N2, and then stirred at 170 °C under N2 atmosphere for 2 hours. The mixture was combined with EtOAc (80 mL) and washed with NaOH (1 N, 30 mL x 4). The organic phase was washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated to provide 6-fluoro-7-methoxy-4-(4-methylthioalkylphenoxy)quinoline (2.0 g).

[0623] Step 2: {4-[(6-fluoro-7-methoxyquinoline-4-yl)oxy]phenyl}(imino)methyl-λ 6 Synthesis of thioketones

[0624]

[0625] A mixture of 6-fluoro-7-methoxy-4-(4-methylthioalkylphenoxy)quinoline (1.2 g, 3.8 mmol), PhI(OAc)2 (3.7 g, 11 mmol), NH4OAc (1.2 g, 15 mmol), and EtOH (20 mL) was degassed and purged with N2, and the mixture was stirred at 25 °C for 2 hours under N2 atmosphere. The mixture was concentrated and purified first by silica chromatography and then by preparative HPLC (column: Welch Xtimate C18 250*70mm#10µm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 18%-48%, 25 min) to give {4-[(6-fluoro-7-methoxyquinoline-4-yl)oxy]phenyl}(imino)methyl-λ 6 - Thionyl ketone (compound 114) (0.42g).

[0626] Compounds 10, 12, 18, 44, 78-80, 84, 103, 115-128 and 166-167 were prepared from aryl chloride and phenol derivatives indicated in Table 4 in a manner similar to that of compound 1 in Example S-1 and compound 114 in Example S-2.

[0627] Table 4

[0628]

[0629]

[0630]

[0631]

[0632]

[0633] Synthesis Example S-3

[0634] Imino({5-[(7-methoxyquinoline-4-yl)oxy]pyridin-2-yl})methyl-λ 6 Synthesis of thioketones (compound 101)

[0635] Step 1: Synthesis of 7-methoxy-4-((6-(methylthio)pyridin-3-yl)oxy)quinoline

[0636]

[0637] A mixture of 4-chloro-7-methoxyquinoline (50 mg, 0.26 mmol), 6-(methylthio)pyridin-3-ol (44 mg, 0.31 mmol), Cs₂CO₃ (0.13 g, 0.39 mmol), and 2 mL DMSO was stirred at 100 °C for 3 h. The mixture was then directly purified by reversed-phase HPLC (5%–100% MeCN in water (10 mM NH₄HCO₃)) to provide 7-methoxy-4-((6-(methylthio)pyridin-3-yl)oxy)quinoline (60 mg, 0.20 mmol).

[0638] Step 2: Imino({5-[(7-methoxyquinoline-4-yl)oxy]pyridin-2-yl})methyl-λ 6 Synthesis of thioketones

[0639]

[0640] Ammonium carbamate (24 mg, 0.30 mmol) and PhI(OAc)2 (140 mg, 0.42 mmol) were added to a mixture of 7-methoxy-4-((6-(methylthio)pyridin-3-yl)oxy)quinoline (60 mg, 0.20 mmol) and 2 mL of methanol. The mixture was stirred for 1 h and then purified directly by reversed-phase HPLC (5%–98% MeCN in water (10 mM NH4HCO3)) to provide imino({5-[(7-methoxyquinoline-4-yl)oxy]pyridin-2-yl})methyl-λ 6 -Thioketone (compound 101) (38 mg, 0.12 mmol). ESI MS m / z: 330.1 (M+H).

[0641] Compounds 22, 47, 50, 58, 60, 76, 77, 129-132 and 168 were prepared from aryl chlorides, phenol derivatives and bases indicated in Table 5, in the manner of steps 1 and 2 of Synthetic Example S-3.

[0642] Table 5

[0643]

[0644]

[0645]

[0646] Synthesis Example S-4

[0647] Imino(3-{[(7-methoxyquinoline-4-yl)oxy]methyl}phenyl)methyl-λ 6 Synthesis of thioketones (compound 133)

[0648] Step 1: Synthesis of 7-methoxy-4-((3-(methylthio)benzyl)oxy)quinoline

[0649]

[0650] NaH (0.26 g, 6.5 mmol, 60% of mineral oil) was added to a mixture of (3-methylthiophenyl)methanol (0.80 g, 5.2 mmol) and DMF (10 mL). The mixture was stirred at 0 °C for 30 min, and 4-chloro-7-methoxy-quinoline (0.50 g, 2.6 mmol) in DMF (5 mL) was added dropwise. The mixture was stirred at 20 °C for 12 h, water (5 mL) was added, and the mixture was extracted with EtOAc (20 mL x 2). The combined extracts were washed with brine (10 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether gradient) to provide 7-methoxy-4-[(3-methylthiophenyl)methoxy]quinoline (0.44 g).

[0651] Step 2: Imino(3-{[(7-methoxyquinoline-4-yl)oxy]methyl}phenyl)methyl-λ 6 Synthesis of thioketones

[0652]

[0653] PhI(OAc)₂ (1.2 g, 3.8 mmol) and NH₄OAc (0.40 mg, 5.0 mmol) were added to a mixture of 7-methoxy-4-[(3-methylthiophenyl)methoxy]quinoline (0.39 g, 1.3 mmol) in EtOH (1 mL). The reaction mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC (Kromasil C18 (250 x 50 mm x 10 μm); mobile phase: [water (10 mM NH₄HCO₃)-MeCN]; B%: 15%–45%) to provide imino(3-{[(7-methoxyquinoline-4-yl)oxy]methyl}phenyl)methyl-λ 6 - Thionyl ketone (compound 133) (101 mg). ESI m / z: 343.0 (M+H).

[0654] Compounds 14, 75, 134-138 and 169-178 were prepared from the aryl chlorides, alcohols and bases indicated in Table 6 in the manner described in Synthesis Example S-4.

[0655] Table 6

[0656]

[0657]

[0658]

[0659]

[0660]

[0661] Isolation of the diastereomeric 4-[(1-imino-1-oxobridged-3,4,5,6-tetrahydro-2H-thiaran-4-yl)methoxy]-7-methoxy-quinoline (compound 107)

[0662] By reversed-phase HPLC (Phenomenex Gemini- NX Separate the diastereomeric 4-[(1-imino-1-oxobridged-3,4,5,6-tetrahydro-2H-thiaran-4-yl)methoxy]-7-methoxy-quinoline (compound 107) in 150x30mm, 5um H2O (0.1% TFA) and 15%-45% MeCN to provide compound 107a (first elution) and compound 107b (second elution) as TFA salts.

[0663] Synthesis Example S-5

[0664] Imino({2-[1-(8-methoxyquinazoline-4-yl)piperidin-4-yl]ethyl})methyl-λ 6 -Thioketone

[0665] Synthesis of (Compound 72)

[0666]

[0667] iPrNEt2 (363.6 mg, 2.81 mmol) was added to a mixture of imino-methyl-oxo-[2-(4-piperidinyl)ethyl]-λ6-thion HCl (130 mg, 573 μmol) and 4-chloro-8-methoxy-quinazoline (113 mg, 0.58 mmol) in iPrOH (9 mL). The mixture was stirred at 90 °C for 12 h, then concentrated and purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 8%-38%, 8 min) to give imino({2-[1-(8-methoxyquinazoline-4-yl)piperidin-4-yl]ethyl})methyl-λ 6- Thionyl ketone (compound 72) (26.3 mg). ESI MS m / z: 349.1 (M+H).

[0668] Compounds 8, 43, 57, 69, 74, 139-152, 165 and 196-203 were prepared from aryl chlorides and amines under the conditions indicated in Table 7, in the manner of synthetic examples S-5.

[0669] Table 7

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677] Synthesis Example S-6

[0678] {2-[4-(6,7-dimethoxyquinazolin-4-yl)phenyl]ethyl}(imino)methyl-λ 6 Synthesis of thioketones (compound 153)

[0679] Step 1: Synthesis of 4-bromophenylethyl 4-methylbenzenesulfonic acid

[0680]

[0681] At 0 °C, pyridine (2.4 mL, 30 mmol) and toluenesulfonyl chloride (2.3 g, 12 mmol) were added to a mixture of 2-(4-bromophenyl)ethanol (1.4 mL, 10 mmol) and 20 mL CH2Cl2. The mixture was stirred at 20 °C for 12 h, poured into 30 mL of water, and extracted with CH2Cl2 (30.0 mL x 2). The extract was washed with saturated NaHCO3 aqueous solution (20.0 mL x 2) and brine (20.0 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (0-52% EtOAc / petroleum ether) to give 2-(4-bromophenyl)ethyl 4-methylbenzenesulfonic acid (2.4 g).

[0682] Step 2: Synthesis of (4-bromophenylethyl)(methyl)thion

[0683]

[0684] To a mixture of 2-(4-bromophenyl)ethyl 4-methylbenzenesulfonic acid (0.5 g, 1.4 mmol), NMP (1.5 mL), and THF (2.5 mL), NaSMe (20%, 0.67 mL, 2.11 mmol) was added. The mixture was stirred at 20 °C for 12 h, concentrated, diluted with an aqueous solution of Na₂CO₃ (20 mL), and extracted with EtOAc (10.0 mL x 2). The extract was washed with brine (10.0 mL x 2), dried over Na₂SO₄, filtered, and concentrated. Purification by silica gel chromatography (0-100% EtOAc / petroleum ether) yielded (4-bromophenylethyl)(methyl)thion (0.3 g).

[0685] Step 3: Synthesis of 4,4,5,5-Tetramethyl-2-(4-(2-(methylthio)ethyl)phenyl)-1,3,2-dioxoboronylcyclopentane

[0686]

[0687] Add Pd(dppf)Cl2·CH2Cl2 (88 mg, 0.11 mmol), KOAc (0.21 g, 2.2 mmol), and bis(pinacol)diborone (0.33 mg, 1.3 mmol) to a mixture of 1-bromo-4-(2-methylthioethyl)benzene (0.25 g, 1.1 mmol) and dioxane (10.0 mL). Degas the mixture and purge it three times with N2, then stir at 80 °C under N2 atmosphere for 3 hours. Pour the mixture into water (10.0 mL) and extract with EtOAc (10.0 mL x 2). The extract was washed with brine (10.0 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (0-35% EtOAc / petroleum ether) to give 4,4,5,5-tetramethyl-2-(4-(2-(methylthio)ethyl)phenyl)-1,3,2-dioxoboronylcyclopentane (0.22 g, 70% purity).

[0688] Step 4: Synthesis of 6,7-dimethoxy-4-(4-(2-(methylthio)ethyl)phenyl)quinazolino

[0689]

[0690] Add Pd(dppf)Cl2·CH2Cl2 (55 mg, 67 μmol), K2CO3 (190 mg, 1.3 mmol), and 4,4,5,5-tetramethyl-2-(4-(2-(methylthio)ethyl)phenyl)-1,3,2-dioxoboronylcyclohexane (180 mg, 0.65 mmol) to a mixture of 4-chloro-6,7-dimethoxyquinazoline (0.15 g, 0.668 mmol), dioxane (8.0 mL), and H2O (1.6 mL). Degas the mixture and purge it three times with N2 and stir it at 80 °C under N2 atmosphere for 12 h. Pour the mixture into water (10.0 mL) and extract with EtOAc (10.0 mL x 2). The combined extracts were washed with brine (10.0 mL x 2), dried over Na2SO4, filtered and concentrated to give crude product 6,7-dimethoxy-4-(4-(2-(methylthio)ethyl)phenyl)quinazoline (0.3 g, 50% purity).

[0691] Step 5: {2-[4-(6,7-dimethoxyquinazoline-4-yl)phenyl]ethyl}(imino)methyl-λ 6 Synthesis of thioketones

[0692]

[0693] As described for S-1, {2-[4-(6,7-dimethoxyquinazoline-4-yl)phenyl]ethyl}(imino)methyl-λ is prepared from 6,7-dimethoxy-4-(4-(2-(methylthio)ethyl)phenyl)quinazoline. 6 -Thioketone (compound 153). ESI MS m / z: 372.1 (M+H).

[0694] Compounds 88, 98, 154-155 and 204 were prepared from the aryl halides and borate esters indicated in Table 8, in the manner described in steps 4 and 5 of Synthetic Examples S-6.

[0695] Table 8

[0696]

[0697] Synthesis Example S-7

[0698] [8-(6,7-Dimethoxyquinazolin-4-yl)-2,8-diazaspiro[4.5]dec-2-yl](imino)methyl-λ 6 Synthesis of thioketones (compound 54)

[0699] Step 1: Synthesis of tert-butyl 8-(6,7-dimethoxyquinazoline-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid

[0700]

[0701] To a mixture of 2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.0 g, 4.2 mmol), iPr2NEt (3.0 mL, 17 mmol), and iPrOH (20 mL), 4-chloro-6,7-dimethoxyquinazoline (0.90 g, 4.0 mmol) was added and the mixture was stirred at 90 °C for 4 h. The reaction mixture was concentrated and milled at 25 °C with MTBE / iPrOH / H2O (3 / 1 / 1, 25 mL) for 15 min. The suspension was filtered to give compound 8-(6,7-dimethoxyquinazoline-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (2.0 g).

[0702] Step 2: Synthesis of 6,7-dimethoxy-4-(2,8-diazaspiro[4.5]dec-8-yl)quinazoline

[0703]

[0704] To a mixture of 2.0 g (4.7 mmol) of 8-(6,7-dimethoxyquinazoline-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (THF) and 10 mL of THF, HCl / EtOAc (4 M, 6 mL, 24 mmol) was added dropwise, and the mixture was stirred at 25 °C for 8 h. HCl / MeOH (4 M, 6 mL, 24 mmol) was added, and the mixture was stirred at 25 °C for another 12 h. The reaction mixture was concentrated, and the residue was dissolved in water (25 mL). Solid NaHCO3 (approximately 200 mg) was added to adjust the pH to 8, and NaCl (approximately 150 mg) was added until saturation was reached. The mixture was extracted with CH2Cl2 / iPrOH (3 / 1, 30 mL x 7). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was freeze-dried to obtain compound 6,7-dimethoxy-4-(2,8-diazaspiro[4.5]dec-8-yl)quinazoline (1.2 g).

[0705] Step 3: [8-(6,7-dimethoxyquinazoline-4-yl)-2,8-diazaspiro[4,5]dec-2-yl](imino)methyl-λ 6 Synthesis of thioketones

[0706]

[0707] Et3N (1.3 mL, 9.0 mmol) was added to a mixture of PPh3Cl2 (0.36 M, 21 mL) and CHCl3 (21 mL) at 0 °C with N2, and the mixture was stirred at 0 °C for 15 min. N-[tert-butyl(dimethyl)silyl]methanesulfonamide (0.67 g, 3.2 mmol) was added, and the mixture was stirred at 0 °C for 15 min, and then added at 0 °C with N2 to a mixture of 6,7-dimethoxy-4-(2,8-diazaspiro[4.5]dec-8-yl)quinazoline (0.70 g, 2.1 mmol), Et3N (1.4 mL, 10 mmol), and CHCl3 (21 mL). The mixture was stirred at 25°C for 5 h, then concentrated and purified by preparative HPLC (column: Phenomenex Luna C18 200*40mm*10um; mobile phase: [water (0.2% FA)-ACN]; B%: 1%-30%, 8 min) to provide [8-(6,7-dimethoxyquinazoline-4-yl)-2,8-diazaspiro[4,5]dec-2-yl](imino)methyl-λ as formate. 6- Thioketone (compound 54) (0.50 g). ESI MS m / z: 406.1 (M+H).

[0708] Synthesis Example S-8

[0709] [8-(6-fluoro-7-methoxyquinoline-4-yl)-2,8-diazaspiro[4.5]dec-2-yl](imino)methyl-λ 6 Synthesis of thioketones (compound 205)

[0710]

[0711] Step 1: A degassed mixture of 4-chloro-6-fluoro-7-methoxy-quinoline (75 g, 0.35 mol), 2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (85 g, 0.35 mol), iPr2 NEt (0.19 L, 1.1 mol), and n-BuOH (0.75 L) was stirred at 140 °C under a N2 atmosphere for 12 h. The mixture was concentrated and poured into H2O (3 L), and extracted with EtOAc (2 x 1.5 L). The combined extracts were washed with brine (500 mL), dried over Na2SO4, and concentrated to provide 8-(6-fluoro-7-methoxy-4-quinolinyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (295 g).

[0712] Step 2: 4M HCl (0.75L) from EtOAc was slowly added to a mixture of tert-butyl 8-(6-fluoro-7-methoxy-4-quinolinyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid (150g, 0.36mol) and EtOAc (0.4L) under stirring, and the mixture was stirred at 20°C for 12h. The mixture was concentrated and then mixed with 1L MeOH, and AmberLyst-21 was added until the pH reached 9. The mixture was filtered, concentrated, and milled at 20°C with petroleum ether / EtOAc (1:1, 1L) for 0.5h to obtain compound 8-(6-fluoro-7-methoxy-4-quinolinyl)-2,8-diazaspiro[4.5]decane (120g).

[0713] Step 3: A mixture of Ph3PCl2 (0.36 M, 0.53 L) and Et3N (29 g, 0.29 mol) was stirred at 0 °C for 0.25 h. N-[tert-butyl(dimethyl)silyl]methanesulfonamide (40 g, 190 mmol) was added at 0 °C, and the mixture was stirred for 0.25 h. This solution was then added dropwise at 0 °C to a mixture of 8-(6-fluoro-7-methoxy-4-quinolinyl)-2,8-diazaspiro[4.5]decane (30 g, 95 mmol), Et3N (19 g, 190 mmol), and CHCl3 (0.3 L), and stirred at 20 °C for 12 h. The mixture was concentrated, and EtOAc (2.5 L) was added, followed by an aqueous HCl solution (1 N, 1 L). The aqueous phase was adjusted to pH 8 with saturated NaHCO3. The precipitate was filtered, and the filter cake was washed with water (0.5 L x 2). The collected solids were dried to provide [8-(6-fluoro-7-methoxyquinoline-4-yl)-2,8-diazaspiro[4.5]dec-2-yl](imino)methyl-λ 6 - Thionyl ketone (compound 205) (120 g). ESI MS m / z: 393.2 (M+H).

[0714] Compounds 53, 55, 94, 156-160 and 206-226 were prepared from aryl halogens and amines under the conditions indicated in Table 9, in the manner of synthetic examples S-7 and S-8.

[0715] Table 9

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723] Synthesis Example S-9

[0724] [7-(6,7-dimethoxyquinoline-4-yl)-1,2,3,4-tetrahydroisoquinoline-2-yl](imino)methyl-λ 6 Synthesis of thioketones (compound 161)

[0725] Step 1: Synthesis of tert-butyl 7-(6,7-dimethoxyquinazoline-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid

[0726]

[0727] A mixture of 4-chloro-6,7-dimethoxyquinoline (1.1 g, 4.6 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.0 g, 5.6 mmol), KOAc (0.91 g, 9.3 mmol), Pd(PPh3)4 (0.27 g, 0.23 mmol), dioxane (10 mL), and H2O (2 mL) was degassed and purged with N2, and then stirred at 110 °C under N2 atmosphere for 12 hours. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated, and purified by silica chromatography (petroleum ether / EtOAc, 9-100%) to provide tert-butyl 7-(6,7-dimethoxy-4-quinolinyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (1.1 g).

[0728] Step 2: [7-(6,7-dimethoxyquinoline-4-yl)-1,2,3,4-tetrahydroisoquinoline-2-yl](imino)methyl-λ 6 Synthesis of thioketones

[0729]

[0730] To a mixture of 7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.1 g, 3.1 mmol) and EtOAc (5 mL), 4 M HCl (12.7 mL) from EtOAc was added. The mixture was stirred at 20 °C for 2 h, then concentrated, and 30 mL of saturated NaHCO3 aqueous solution was added. The mixture was extracted with EtOAc (20 mL x 2), and the extracts were combined and washed with brine (20 mL), dried over Na2SO4, washed, filtered, and concentrated to provide 6,7-dimethoxy-4-(1,2,3,4-tetrahydroisoquinoline-7-yl)quinoline (0.54 g).

[0731] Et3N (0.33 mL, 2.3 mmol) was added dropwise to a mixture of Ph3PCl2 (0.36 M, 6.5 mL) and CHCl3 (3 mL) at 0 °C. The mixture was stirred at this temperature for 15 min, and N-[tert-butyl(dimethyl)silyl]methanesulfonamide (0.49 g, 2.3 mmol) was added, and the mixture was stirred at 0 °C for 15 min. 6,7-Dimethoxy-4-(1,2,3,4-tetrahydroisoquinoline-7-yl)quinoline (0.5 g, 1.6 mmol) and Et3N (1.1 mL, 7.8 mmol) were added at 0 °C. The resulting mixture was stirred at 20 °C for 1.5 h, then concentrated and purified by preparative HPLC (column: Phenomenex Luna C18 200*40mm*10um; mobile phase: [water (0.2% FA)-ACN]; B%: 1%-40%, 8 min) to provide [7-(6,7-dimethoxyquinoline-4-yl)-1,2,3,4-tetrahydroisoquinoline-2-yl](imino)methyl-λ 6 -Thioketone (compound 161) (71 mg). ESI MS m / z = 398.1 (M+H).

[0732] Compounds 37, 52 and 162-163 were prepared from the aryl halides and borate esters indicated in Table 10, as described in Synthetic Examples S-9.

[0733] Table 10

[0734]

[0735] Synthesis Example S-10

[0736] 1-Imine-4-[2-(7-methoxyquinoline-4-yl)acetyl]-1λ 6 Synthesis of 1-thiomorpholine-1-one (compound 26)

[0737] Step 1. Synthesis of methyl 2-(7-methoxyquinoline-4-yl)acetate

[0738]

[0739] 1 M LiHMDS (12 mL, 12 mmol) in THF was added to a stirred mixture of 7-methoxy-4-methylquinoline (0.52 g, 3.0 mmol), dimethyl carbonate (0.33 mL, 3.9 mmol), and THF (6.0 mL) at 0 °C. The mixture was warmed to ambient temperature and stirred for 1 h. A saturated aqueous solution of NH4Cl (10 mL) was added, and the mixture was stirred overnight. Water was added, and the mixture was extracted with CH2Cl2. The extract was dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (10%–70% EtOAc in heptane) to provide 0.66 g of methyl 2-(7-methoxyquinoline-4-yl)acetate.

[0740] Step 2. Synthesis of 2-(7-methoxyquinoline-4-yl)-1-thiomorpholinoacet-1-one

[0741]

[0742] Trimethylaluminum (2M in toluene; 0.12 mL, 0.24 mmol) was added to a stirred mixture of thiomorpholine (0.023 mL, 0.24 mmol) and toluene (3.0 mL). After stirring for 30 min, methyl 2-(7-methoxyquinoline-4-yl)acetate (0.046 g, 0.20 mmol) was added. The mixture was heated at 80 °C for 18 h, cooled to ambient temperature, and 10 drops of 1N HCl aqueous solution were added. Water was then added, the pH was adjusted to approximately 4 with a saturated NaHCO3 aqueous solution, and the mixture was extracted with CH2Cl2. The extract was dried over Na2SO4, filtered, concentrated, and purified by reversed-phase preparative HPLC (water, 5%–50% MeCN in 0.1% NH4HCO3) to provide 54 mg of 2-(7-methoxyquinoline-4-yl)-1-thiomorpholine-1-one.

[0743] Step 3. 1-Imine-4-[2-(7-methoxyquinoline-4-yl)acetyl]-1λ 6 Synthesis of 1-thiomorpholine-1-one

[0744]

[0745] A mixture of 2-(7-methoxyquinoline-4-yl)-1-thiomorpholinoacet-1-one (54 mg, 0.18 mmol), methanol (3.5 mL), ammonium carbamate (20 mg, 0.26 mmol), and PhI(OAc)2 (0.11 g, 0.35 mmol) was stirred for 3 hours. Additional ammonium carbamate (10 mg, 0.13 mmol) and PhI(OAc)2 (56 mg, 0.18 mmol) were added, and the mixture was stirred for 1 hour. After concentration, the mixture was purified by silica chromatography (0–3% MeOH in CH2Cl2) to provide 18 mg of 1-imino-4-[2-(7-methoxyquinoline-4-yl)acetyl]-1λ 6- Thiomorpholino-1-one (compound 26). ESI MS m / z: 334.1 (M+H).

[0746] Synthesis Example S-11

[0747] 1-Imine-4-(7-methoxyquinoline-4-carbonyl)-1λ 6 Synthesis of 1-thiomorpholine-1-one (compound 6)

[0748] Step 1: Synthesis of (7-methoxyquinoline-4-yl)(thiomorpholino) methyl ketone

[0749]

[0750] Thiomorpholine (25 mg, 0.24 mmol) was added to a stirred mixture of 7-methoxyquinoline-4-carboxylic acid (41 mg, 0.20 mmol), EDC (42 mg, 0.22 mmol), ethyl cyano(hydroxyamino)acetate (2.8 mg, 0.020 mmol), and DMF (3.0 mL). After stirring for 3 h, the mixture was directly purified by reversed-phase preparative HPLC (ReproSil column (5-40); 5%-40% MeCN in water, 0.1% NH4HCO3) to provide 52 mg of (7-methoxyquinoline-4-yl)(thiomorpholine) methyl ketone.

[0751] Step 2: 1-Imine-4-(7-methoxyquinoline-4-carbonyl)-1λ 6 Synthesis of 1-thiomorpholine-1-one

[0752]

[0753] 1-Imine-4-(7-methoxyquinoline-4-carbonyl)-1λ was prepared from (7-methoxyquinoline-4-yl)(thiomorpholino) methyl ketone in the manner described in step 3 of the synthesis of compound 26 (synthetic example S-10). 6-Thiomorpholino-1-one (compound 6). ESI MS m / z: 320.1 (M+H).

[0754] Synthesis Example S-12

[0755] (4-{[(6,7-dimethoxyquinazolin-4-yl)oxy]methyl}piperidin-1-yl)(imino)methyl-λ 6 Synthesis of thioketones (compound 164)

[0756]

[0757] The preparation of (4-{[(6,7-dimethoxyquinazolin-4-yl)oxy]methyl}piperidin-1-yl)(imino)methyl-λ was carried out in three steps. 6 -Thioketone. In step 1, 4-(((6,7-dimethoxyquinazoline-4-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester is prepared from 4-chloro-6,7-dimethoxyquinazoline in the manner described in step 1 of the synthesis of compound 133 (synthesis example S-4), except that DMF is used instead of EtOH as the solvent. In the same manner as steps 2 and 3 of the synthesis of compound 54 (synthesis example S-7), (4-{[(6,7-dimethoxyquinazoline-4-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester is prepared in two steps from 4-(((6,7-dimethoxyquinazoline-4-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester. 6 -Thioketone (compound 164). ESI MS m / z: 381.1 (M+H).

[0758] Compounds 229-230 were prepared from the aryl halides and alcohols indicated in Table 11 in the manner described in Synthesis Example S-12.

[0759] Table 11

[0760]

[0761] Synthesis Example S-13

[0762] 4-(4-{[imino(methyl)oxo-λ] 6 Synthesis of [-thioalkyl]methyl}piperidin-1-yl)-8-methoxyquinoline-3-nitrile (compound 179)

[0763]

[0764] Step 1: Add iPr2NEt (14 mL, 80 mmol) and 4-(methylthiomethyl)piperidine hydrochloride (2.9 g, 16 mmol) to a mixture of 4-chloro-8-methoxy-quinoline-3-onitrile hydrochloride (4.1 g, 16 mmol) and iPrOH (80 mL). Stir the mixture at 90 °C for 4 h, cool, concentrate, and grind with H2O (20 mL) for 30 min and then with MTBE (20 mL) for 30 min to provide 8-methoxy-4-[4-(methylthiomethyl)-1-piperidinyl]quinoline-3-onitrile (5.4 g).

[0765] Step 2: A mixture of 8-methoxy-4-[4-(methylthioalkylmethyl)-1-piperidinyl]quinoline-3-onitrile (5.9 g, 18 mmol), EtOH (50 mL), PhI(OAc)2 (17 g, 54 mmol), and NH4OAc (5.6 g, 72 mmol) was stirred at 20 °C for 2 h, concentrated, and ground with H2O (30 mL) for 30 min. The mixture was then purified by preparative HPLC (2%–25% MeCN / water (0.23% formic acid)) to obtain 8-methoxy-4-[4-[(methanesulfonylimino)methyl]-1-piperidinyl]quinoline-3-onitrile (2.7 g). ESI MS m / z: 359.1 (M+H).

[0766] Compounds 180-195 were prepared from aryl chlorides and amines under the conditions indicated in Table 12, in the manner described in Synthetic Examples S-13.

[0767] Table 12

[0768]

[0769]

[0770]

[0771]

[0772] Synthesis Example S-14

[0773] [8-(3-fluoro-6,7-dimethoxyquinoline-4-yl)-2,8-diazaspiro[4,5]dec-2-yl](imino)methyl-λ 6 Synthesis of thioketones (compound 227)

[0774]

[0775] Step 1: A mixture of 4-chloro-3-fluoro-6,7-dimethoxyquinoline (0.21 g, 0.85 mmol), dioxane (1.0 mL), Cs₂CO₃ (0.57 g, 1.7 mmol), Pd(OAc)₂ (19 mg), [1-(2-biphenylphosphyl-1-naphthyl)-2-naphthyl]-biphenylphosphine (54 mg, 87 μmol), and 2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl hydrochloride (0.24 g, 0.85 mmol) was stirred at 140 °C under a N₂ atmosphere for 12 h. The mixture was concentrated, combined with H₂O (10 mL), and extracted with EtOAc (10 mL x 2). The extracts were combined, washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (10%-100% EtOAc in petroleum ether) to provide 8-(3-fluoro-6,7-dimethoxyquinoline-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl hydrochloride (0.36 g).

[0776] Step 2: A mixture of tert-butyl 8-(3-fluoro-6,7-dimethoxy-4-quinolinyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid (0.36 g, 0.81 mmol), EtOAc (7.0 mL), and HCl / EtOAc (4 M, 3.6 mL) was stirred at 20 °C for 2 h and then concentrated to provide 3-fluoro-6,7-dimethoxy-4-(2,8-diazaspiro[4.5]dec-8-yl)quinoline (0.30 g).

[0777] Step 3: A mixture of Ph3PCl2 (0.36 M, 3.6 mL in CHCl3), CHCl3 (8.0 mL), and Et3N (0.27 mg, 2.6 mmol) was stirred at 0 °C for 0.5 h. 8-(3-fluoro-6,7-dimethoxy-4-quinolinyl)-2,8-diazaspiro[4.5]decane hydrochloride (0.25 mg, 0.66 mmol) was added at 0 °C, and the mixture was stirred for 0.5 h. N-[tert-butyl(dimethyl)silyl]methanesulfonamide (0.27 g, 1.3 mmol) and Et3N (0.27 g, 2.6 mmol) were added at 20 °C. After stirring for 1 h, the mixture was concentrated, and 1 M HCl (5.0 mL) was added to adjust the pH to 3, followed by the addition of H2O (5.0 mL). The mixture was extracted with EtOAc (15 mL), and the pH of the aqueous phase was adjusted to pH 7 with saturated NaHCO3 (5.0 mL). The solution was directly purified by preparative HPLC (1%–30% MeCN in H2O (0.2% formic acid)) to provide 3-fluoro-6,7-dimethoxy-4-(2-(S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)quinoline (compound 227) (69 mg). ESI MS m / z: 423.2 (M+H).

[0778] Synthesis Example S-15

[0779] [8-(6,7-Dimethoxy-3-methylcenolin-4-yl)-2,8-diazaspiro[4,5]dec-2-yl](imino)methyl-λ 6 Synthesis of thioketones (compound 228)

[0780]

[0781] Compound 228 was prepared in the same manner as compound 227 in synthetic example S-14, by replacing 4-chloro-3-fluoro-6,7-dimethoxy-3-methyl-cenline in step 1. ESI MS m / z: 420.3 (M+H).

[0782] Synthesis Example S-16

[0783] Imino({4-[(7-methoxyquinoline-4-yl)methoxy]phenyl})methyl-λ 6 Synthesis of thioketones (compound 231)

[0784]

[0785] Step 1: PPh3 (140 mg, 0.53 mmol) was added to a mixture of (7-methoxy-4-quinolinyl)methanol (50 mg, 0.26 mmol) and 4-methylthioalkylphenol (44 mg, 0.31 mmol) and THF (2.0 mL) at 0 °C, followed by dropwise addition of DIAD (110 mg, 0.52 mmol) in THF (0.5 mL). The resulting mixture was stirred at 25 °C for 12 h, H2O (5 mL) was added, and the mixture was extracted with 15 mL of EtOAc. The extract was washed with 10 mL of brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (10%-100% EtOAc in hexane) to provide 7-methoxy-4-[(4-methylthioalkylphenoxy)methyl]quinoline (40 mg).

[0786] Step 2: A mixture of 7-methoxy-4-[(4-methylthioalkylphenoxy)methyl]quinoline (40 mg, 0.13 mmol), EtOH (1.00 mL), PhIOAc2 (124 mg, 0.41 mmol), and NH4OAc (39 mg, 0.51 mmol) was stirred at 25 °C for 2 h. The reaction mixture was concentrated and purified by preparative HPLC (20%–40% aqueous solution of MeCN, 0.1%) to provide imino({4-[(7-methoxyquinoline-4-yl)methoxy]phenyl})methyl-λ 6 - Thionyl ketone (compound 231) (2.3 mg). ESIMS m / z: 343.0 (M+H).

[0787] Synthesis Example S-17

[0788] Imino({3-[(7-methoxyquinoline-4-yl)methoxy]phenyl})methyl-λ 6 Synthesis of thioketones (compound 232)

[0789]

[0790] As described in Synthesis Example S-16, imino({3-[(7-methoxyquinoline-4-yl)methoxy]phenyl})methyl-λ was prepared in two steps from (7-methoxy-4-quinoline)methanol and 4-methylthioalkylphenol. 6 -Thioketone (compound 232). ESI MS m / z: 343.0 (M+H).

[0791] Synthesis Example S-18

[0792] Imino[2-(7-methoxyquinoline-4-yl)-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]methyl-λ6 Synthesis of thioketones (compound 233)

[0793]

[0794] Step 1: A mixture of 4-chloro-7-methoxyquinoline (0.5 g, 2.6 mmol), 1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.63 g, 2.8 mmol), Xantphos (0.3 g, 0.52 mmol), K3PO4 (1.1 g, 5.2 mmol), Pd2(dba)3 (0.24 g, 0.26 mmol), and dioxane (10 mL) was heated in a microwave reactor at 140 °C for 2 h. The mixture was then poured into H2O (20 mL) and extracted with EtOAc (20.0 mL x 2). The combined extracts were washed with brine (20 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-100% EtOAc in petroleum ether) to provide tert-butyl 2-(7-methoxy-4-quinolinyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid (1.3 g, 85% purity).

[0795] Step 2: Add HCl / EtOAc (4M, 7.4mL) to a mixture of 2-(7-methoxy-4-quinolinyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.5g, 3.9mmol) and EtOAc (2.0mL), and stir the mixture at 25°C for 2h. Concentrate the mixture and combine it with MeOH (20mL) to add amberlyst-21 (2.0g). Filter the mixture and concentrate it to provide 7-methoxy-4-(4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-yl)quinoline (1.0g).

[0796] Step 3: Add Et3N (0.37 mL, 2.7 mmol) to Ph3PCl2 (0.36 M, 5.0 mL) in CHCl3 (2.0 mL) and stir the mixture at 0 °C for 10 min. Add N-[tert-butyl(dimethyl)silyl]methanesulfonamide (0.37 g, 1.8 mmol) and stir the mixture at 0 °C for 20 min. Then add 7-methoxy-4-(4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-2-yl)quinoline (0.5 g, 1.8 mmol) and Et3N (0.75 mL, 5.4 mmol) to CHCl3 (3 mL) at 0 °C. Stir the mixture at 25 °C for 90 min and concentrate. Combine the residue with MeOH (1.0 mL) and add 1 M HCl aqueous solution (40.0 mL, 40 mmol). The mixture was stirred at 20°C for 10 min, concentrated, and purified by reversed-phase HPLC (1-40% MeCN / water (0.2% formic acid)) to provide imino[2-(7-methoxyquinoline-4-yl)-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]methyl-λ 6 - Thionyl ketone (compound 233) (89 mg). ESI MS m / z: 358.1 (M+H).

[0797] Synthesis Example S-19

[0798] Imino({2-[1-(7-methoxyquinoline-4-yl)-1H-pyrazol-4-yl]ethyl})methyl-λ 6 Synthesis of thioketones (compound 234)

[0799]

[0800] Step 1: A mixture of 2-(1H-pyrazol-4-yl)ethanol (0.64 g, 5.7 mmol), 4-chloro-7-methoxyquinoline (1.0 g, 5.2 mmol), tBuONa (1.5 g, 16 mmol), T-buxphosPh-G3 (0.41 g, 0.52 mmol), and THF (10 mL) was degassed with bubbling N2 and then stirred at 110 °C under N2 atmosphere for 12 h. The mixture was poured into H2O (10 mL) and extracted with EtOAc (10.0 mL x 2). The combined extracts were washed with brine (10 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-100% EtOAc / petroleum ether) to provide 2-[1-(7-methoxy-4-quinolinyl)pyrazol-4-yl]ethanol (0.27 g).

[0801] Step 2: Add PPh3 (0.32 g, 1.2 mmol) and CBr4 (0.41 g, 1.2 mmol) to a mixture of 2-[1-(7-methoxy-4-quinolinyl)pyrazol-4-yl]ethanol (0.22 g, 0.82 mmol) and CH2Cl2 (5.0 mL) at 0 °C. Stir the mixture at 20 °C for 12 h, then concentrate it, pour it into water (10 mL), and extract with EtOAc (10.0 mL x 2). Wash the combined extracts with brine (10.0 mL x 2), dry them with Na2SO4, filter, and concentrate to provide 4-[4-(2-bromoethyl)pyrazol-1-yl]-7-methoxy-quinoline (0.27 g), which is used directly without purification.

[0802] Step 3: A mixture of 4-[4-(2-bromoethyl)pyrazol-1-yl]-7-methoxyquinoline (0.25 g, 0.75 mmol), EtOH (5 mL), and NaSMe aqueous solution (20%, 0.48 mL, 1.5 mmol) was stirred at 20 °C under N2 for 12 h. The mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL x 2). The combined extracts were washed with brine (10 mL x 2), dried over Na2SO4, filtered, concentrated, and purified by preparative TLC (SiO2, 10:1:1 CH2Cl2 / MeOH / EtOAc, then 4:1:1 petroleum ether / EtOAc / THF) to provide 7-methoxy-4-[4-(2-methylthioethyl)pyrazol-1-yl]quinoline (0.12 g).

[0803] Step 4: A mixture of 7-methoxy-4-[4-(2-methylthioethyl)pyrazol-1-yl]quinoline (0.10 g, 0.33 mmol), EtOH (2 mL), PhI(OAc)₂ (0.32 g, 1.0 mmol), and NH₄OAc (0.10 g, 1.3 mmol) was stirred at 20 °C for 1 h. The mixture was concentrated and purified by preparative TLC (SiO₂, 10:1CH₂Cl₂ / MeOH) to provide 7-methoxy-4-(4-(2-(S-methylsulfonylimino)ethyl)-1H-pyrazol-1-yl)quinoline (compound 234) (15 mg). ESIMS m / z: 331.2 (M+H)

[0804] Synthesis Example S-20

[0805] Imino({4-[(7-methoxyquinoline-4-yl)oxy]piperidin-1-yl})methyl-λ 6 Synthesis of thioketones (compound 235)

[0806]

[0807] Step 1: PPh3 (3.0 g, 11 mmol) was added to a mixture of 7-methoxyquinoline-4-ol (1.0 g, 5.7 mmol) and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.2 g, 5.7 mmol) in THF (25 mL), followed by dropwise addition of DIAD (2.2 mL, 11 mmol) in THF (5 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 12 h, then concentrated, combined with H2O (20 mL), and extracted with EtOAc (20.00 mL x 2). The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (10%–100% petroleum ether / EtOAc) to provide 4-[(7-methoxy-4-quinoline)oxy]piperidine-1-carboxylic acid tert-butyl ester (2.2 g).

[0808] Step 2: A mixture of 2.0 g (5.6 mmol) of 4-[(7-methoxy-4-quinolinyl)oxy]piperidine-1-carboxylic acid tert-butyl ester, 3 mL of EtOAc, and 30 mL (120 mmol) of 4 M HCl in EtOAc was stirred at 25 °C for 2 h. The mixture was concentrated to provide 1.9 g of 7-methoxy-4-(4-piperidineyloxy)quinoline hydrochloride.

[0809] Step 3: Add Et3N (1.4 mL, 9.6 mmol) to a mixture of Ph3PCl2 (0.36 M, 27 mL, 9.7 mmol) and CHCl3 (10 mL) at 0 °C. Stir the mixture for 15 min, then add N-[tert-butyl(dimethyl)silyl)methanesulfonamide (2.0 g, 9.7 mmol) and stir at 0 °C for 15 min. Add 7-methoxy-4-(4-piperidinyloxy)quinoline (1.0 g, 3.9 mmol) and Et3N (1.35 mL, 9.7 mmol) at 0 °C, and stir the resulting mixture at 20 °C for 1.5 h. Concentrate the mixture to give tert-butyl-[[[4-[(7-methoxy-4-quinolinyl)oxy]-1-piperidinyl]-methyl-oxo-λ 6[-thionyl]amino]-dimethyl-silane (1.8 g, crude), a portion of which (1.60 g, 3.5 mmol) was combined with MeOH (10.00 mL) and HCl aqueous solution (1 M, 8.0 mL, 8 mmol). The mixture was stirred at 25 °C for 30 min, and saturated NaHCO3 aqueous solution (15 mL) was added. The mixture was extracted with EtOAc (20 mL), and the extract was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by reversed-phase HPLC (H2O (0.2% formic acid) in 10%-30% MeCN) to give imino({4-[(7-methoxyquinoline-4-yl)oxy]piperidin-1-yl})methyl-λ 6 - Thionyl ketone (compound 235) (310 mg). ESI MS m / z: 336.0 (M+H).

[0810] Synthesis Example S-21

[0811] Imino[7-(8-methoxyquinazoline-4-yl)-2,7-diazaspiro[3,5]non-2-yl]methyl-λ 6 -

[0812] Synthesis of Thioketones (Compound 236)

[0813]

[0814] Step 1: Under nitrogen atmosphere, add Et3N (1.7 mL, 12 mmol) to a mixture of PPh3OCl2 (0.36 M, 26 mL) and CHCl3 (26 mL) at 0 °C and stir the mixture at 0 °C for 15 min. Add N-[tert-butyl(dimethyl)silyl]methanesulfonamide (0.9 g, 4.3 mmol) and stir the mixture at 0 °C for 15 min. Add this mixture at 0 °C to a solution of 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl hydrochloride (0.75 g, 2.9 mmol) and Et3N (1.7 mL, 12 mmol) in CHCl3 (25 mL) and stir the mixture at 0 °C for 0.5 h, and then at 25 °C for 1.5 h. The reaction mixture was concentrated and purified by silica gel chromatography (0-90% THF in (1:1 EtOAc / petroleum ether)) to provide tert-butyl 2-(S-methylsulfonylimino)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid (0.54 g).

[0815] Step 2: TFA (1 mL, 14 mmol) was added to a mixture of 2-(S-methylsulfonylimino)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (0.49 g, 1.6 mmol) in CH2Cl2 (20 mL) at 0 °C. The mixture was stirred at 25 °C for 4 h and then concentrated to give 2-(S-methylsulfonylimino)-2,7-diazaspiro[3.5]nonane trifluoroacetate (0.58 mg).

[0816] Step 3: iPr2NEt (1.3 mL, 7.6 mmol) was added to a mixture of 2-(S-methylsulfonylimino)-2,7-diazaspiro[3.5]nonane trifluoroacetate (0.33 g, 1.0 mmol) and 4-chloro-8-methoxy-quinazoline hydrochloride (0.2 g, 0.86 mmol) in isopropanol (10 mL) and the mixture was stirred at 20 °C for 12 h. The mixture was concentrated and purified by reversed-phase HPLC (15%–35% MeCN in H2O (10 mM NH4HCO3)) to give imino[7-(8-methoxyquinazoline-4-yl)-2,7-diazaspiro[3.5]non-2-yl]methyl-λ 6 - Thionyl ketone (compound 236) (145 mg). ESI MS m / z: 362.2 (M+H).

[0817] Synthesis Example S-22

[0818] [8-(6,7-Dimethoxyquinazoline-4-yl)-8-azaspiro[4.5]dec-2-yl](imino)methyl-λ 6 Synthesis of thioketones (compound 237)

[0819]

[0820] Steps 1 and 2: A mixture of 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (0.90 g, 3.9 mmol), CH2Cl2 (15 mL), and TFA (4.5 mL, 61 mmol) was stirred at 25 °C for 2 h and then concentrated. The resulting residue, iPrOH (25 mL), iPr2NEt (6.1 mL, 35 mmol), and 4-chloro-6,7-dimethoxyquinazoline (1.6 g, 7.0 mmol) were stirred together at 80 °C for 2 h. The mixture was concentrated and purified by reversed-phase HPLC (alkaline conditions) to provide two batches of [2-(6,7-dimethoxyquinazoline-4-yl)-2-azaspiro[3.3]hept-6-yl]methanol (110 mg, 92% purity) (110 mg, 92% purity; 500 mg, 42% purity).

[0821] Step 2: A mixture of [2-(6,7-dimethoxyquinazoline-4-yl)-2-azaspiro[3.3]hept-6-yl]methanol (0.41 g, 1.3 mmol), CH2Cl2 (10 mL), Et3N (0.40 g, 3.9 mmol), and MsCl (0.30 g, 2.6 mmol) was stirred at 25 °C for 12 h, then concentrated and combined with H2O (15 mL), and extracted with EtOAc (15 mL x 2). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give [2-(6,7-dimethoxyquinazoline-4-yl)-2-azaspiro[3.3]hept-6-yl]methyl methanesulfonate (130 mg).

[0822] Step 4: A mixture of [2-(6,7-dimethoxyquinazoline-4-yl)-2-azaspiro[3.3]hept-6-yl]methyl methanesulfonate (0.11 g, 1.0 equivalent), EtOH (5 mL), and 20% NaSMe aqueous solution (0.15 mL) was stirred at 25 °C for 2 h, then concentrated, diluted with H2O (10 mL), and extracted with EtOAc (10 mL x 2). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to provide 6,7-dimethoxy-4-[6-(methylthiomethyl)-2-azaspiro[3.3]hept-2-yl]quinazoline (100 mg).

[0823] Step 5: A mixture of 6,7-dimethoxy-4-[6-(methylthioalkylmethyl)-2-azaspiro[3.3]hept-2-yl]quinazoline (90 mg, 0.26 mmol) in EtOH (5 mL) was mixed with DIB (251 mg, 0.78 mmol) and NH4OAc (80 mg, 1.0 mmol), stirred at 20 °C for 2 h, then concentrated and purified by preparative HPLC (1%-30% MeCN in H2O (10 mM NH4HCO3)) to provide 8-(6,7-dimethoxyquinazoline-4-yl)-8-azaspiro[4.5]dec-2-yl](imino)methyl-λ 6 - Thionyl ketone (compound 237) (24 mg). ESI MS m / z: 377.2 (M+H).

[0824] Compounds 238-239 were prepared from aryl halogens and alcohols under the conditions indicated in Table 13, in the manner described in Synthetic Examples S-22.

[0825] Table 13

[0826]

[0827]

[0828] Synthesis Example S-23

[0829] [8-(6,7-dimethoxyquinazoline-4-yl)-2,8-diazaspiro[4.5]dec-2-yl](2-hydroxy-2-methylpropyl)imino-λ 6 Synthesis of thioketones (compound 240)

[0830]

[0831] A solution of BuLi (2.5 M, 2.0 mL) was slowly added to a stirred mixture of 6,7-dimethoxy-4-(2-(S-methylsulfonylimino)-2,8-diazaspiro[4.5]dec-8-yl)quinazoline (0.04 g, 0.99 mmol) and THF (5 mL) at -78 °C. After stirring for 30 min, acetone (0.29 mL, 4.0 mmol) was slowly added at -78 °C. The reaction mixture was warmed to 25 °C, stirred for 1 h, concentrated, and purified by preparative HPLC (20%-40% MeCN / H2O (10 mM NH4HCO3)) to provide 1-[[8-(6,7-dimethoxyquinazoline-4-yl)-2,8-diazaspiro[4.5]dec-2-yl]sulfonylimino]-2-methyl-prop-2-ol (compound 240) (8.5 mg). ESI MS m / z: 464.3 (M+H).

[0832] Synthesis Example S-24

[0833] {8-[6-(fluoromethoxy)-7-methoxyquinazoline-4-yl]-2,8-diazaspiro[4,5]dec-2-yl}(imino)methyl-λ 6 Synthesis of thioketones (compound 241)

[0834]

[0835] Step 1: A degassed mixture of (4-hydroxy-7-methoxy-quinazoline-6-yl) acetate (5.0 g, 21 mmol), SOCl2 (50 mL, 690 mmol), and DMF (0.5 mL) was stirred at 85 °C under a N2 atmosphere for 12 h. The reactants were concentrated to provide (4-chloro-7-methoxy-quinazoline-6-yl) acetate (5.1 g).

[0836] Step 2: A degassed mixture of (4-chloro-7-methoxy-quinazoline-6-yl)acetate (2.4 g, 9.5 mmol), 2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.9 g, 7.9 mmol), Et3N (6.6 mL, 47 mmol), and CHCl3 (30 mL) was stirred at 20 °C under a N2 atmosphere for 12 h. The crude product was stirred together with a mixture of petroleum ether and ethyl acetate (7:1) at 20 °C for 30 min. The solids were filtered off, and the filtrate was concentrated and purified by silica chromatography (1:0:0:0 to 0:20:4:1 petroleum ether / EtOAc:CH2Cl2:MeOH) to provide 8-(6-acetoxy-7-methoxy-quinazoline-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (2.6 g).

[0837] Step 3: A degassed mixture of 8-(6-acetoxy-7-methoxy-quinazoline-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (2.3 g, 5.1 mmol), LiOH·H2O (0.65 g, 15 mmol), MeOH (94 mL), and H2O (47 mL) was stirred at 20 °C under a N2 atmosphere for 12 h. The mixture was concentrated and extracted with EtOAc (25 mL x 10), dried over Na2SO4, filtered, and concentrated to obtain 8-(6-hydroxy-7-methoxy-quinazoline-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.7 g).

[0838] Step 4: A mixture of 8-(6-hydroxy-7-methoxy-quinazoline-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.6 g, 3.9 mmol), DMF (20 mL), and 60% NaH (0.44 g, 11 mmol) at 0 °C was stirred for 0.5 h. Fluoroiodomethane (0.69 g, 4.3 mmol) was added, and the mixture was stirred at 20 °C for 12 h. A saturated aqueous solution of NH4Cl (20 mL) was added, the mixture was filtered, and the filtrate was concentrated and purified by silica chromatography (0-100% EtOAc in petroleum ether) to provide 8-[6-(fluoromethoxy)-7-methoxy-quinazoline-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.37 g).

[0839] Step 5: A mixture of 8-[6-(fluoromethoxy)-7-methoxy-quinazoline-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.3 g, 2.8 mmol), EtOAc (6 mL), and HCl (6 M in EtOAc, 15 mL) was stirred at 20 °C for 12 h. The mixture was concentrated to provide 4-(2,8-diazaspiro[4.5]dec-8-yl)-6-(fluoromethoxy)-7-methoxy-quinazoline hydrochloride (1.0 g).

[0840] Step 6: N-[tert-butyl(dimethyl)silyl]methanesulfonamide (1.1 g, 5.2 mmol) was added to Ph3PCl2 (0.36 M, 14 mL in CHCl3) at 0 °C. After stirring for 0.5 h, a mixture of 4-(2,8-diazaspiro[4.5]dec-8-yl)-6-(fluoromethoxy)-7-methoxy-quinazoline (0.60 g, 1.7 mmol), CH3Cl (5 mL), and Et3N (1.5 mL, 10 mmol) was added, and the mixture was stirred at 20 °C for 12 h. The mixture was concentrated and purified by preparative HPLC (1%-20% MeCN in H2O (0.2% formic acid)) to provide {8-[6-(fluoromethoxy)-7-methoxyquinazoline-4-yl]-2,8-diazaspiro[4.5]dec-2-yl}(imino)methyl-λ 6 - Thionyl ketone (compound 241) (75 mg). ESI MS m / z: 424.1 (M+H).

[0841] Synthesis Example S-25

[0842] Imino(methyl)[(1s,4s)-4-[(7-methoxyquinoline-4-yl)oxy]cyclohexyl]-λ 6 Synthesis of thioketones (compound 242)

[0843]

[0844] Step 1: Add DIAD (470 mg, 2.32 mmol, 2.0 equivalent) to a mixture of (1r,4r)-4-(methylthio)cyclohexyl-1-ol (0.17 g, 1.2 mmol), 7-methoxyquinoline-4-ol (0.24 g, 1.4 mmol), PPh3 (0.61 g, 2.3 mmol), and THF (7 mL). Stir the mixture at 20 °C for 12 h, concentrate, and purify by silica chromatography (50%–100% EtOAc in petroleum ether) to provide 7-methoxy-4-(4-methylthiocyclohexyloxy)quinoline (0.15 g).

[0845] Step 2: A mixture of 7-methoxy-4-(4-methylthiocyclohexyloxy)quinoline (0.15 mg, 0.49 mmol), EtOH (3 mL), PhI(OAc)2 (0.48 mg, 1.5 mmol), and NH4OAc (0.15 mg, 2.0 mmol) was prepared. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC (1%–30% MeCN / water (0.2% formic acid)) to provide imino(methyl)[(1s,4s)-4-[(7-methoxyquinoline-4-yl)oxy]cyclohexyl]-λ 6 - Thionyl ketone (compound 242) (36 mg). ESI MS m / z: 335.1.

[0846] Compounds 243-245 in Table 14 were prepared by means of aryl hydroxides and alcohols as indicated by the procedure described in Synthetic Example S-25.

[0847] Table 14

[0848]

[0849] Synthesis Example S-26

[0850] Imino({[1-(8-methoxyquinazoline-4-yl)-1,2,3,6-tetrahydropyridin-4-yl]methyl})methyl-λ 6 Synthesis of thioketones (compound 246)

[0851]

[0852] Step 1: A mixture of DAST (1.2 g, 7.6 mmol) and CH2Cl2 (10 mL) was slowly added to a stirred mixture of 4-hydroxy-4-(methylthiomethyl)piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 7.6 mmol) and CH2Cl2 (5.0 mL) at -70 °C. After stirring at -70 °C for 0.5 h, the resulting mixture was stirred at 20 °C for 12 h, then poured into water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (0-50% EtOAc in petroleum ether) to provide 4-fluoro-4-(methylthiomethyl)piperidine-1-carboxylic acid tert-butyl ester (1.0 g).

[0853] Step 2: A mixture of tert-butyl 4-fluoro-4-(methylthioalkylmethyl)piperidine-1-carboxylic acid (0.25 g, 0.95 mmol) and HCl / EtOAc (6 M, 5.0 mL) was stirred at 20 °C under a N2 atmosphere for 2 h. The mixture was concentrated to provide 4-fluoro-4-(methylthioalkylmethyl)piperidine hydrochloride (0.20 g).

[0854] Step 3: Add iPr2NEt (0.81 g, 6.2 mmol) and 4-chloro-8-methoxy-quinazoline (0.29 g, 1.2 mmol) to a mixture of 4-fluoro-4-(methylthiomethyl)piperidine hydrochloride (0.25 g, 1.2 mmol) and iPrOH (5.0 mL), and stir the resulting mixture at 20 °C for 2 h. Then concentrate the mixture, combine it with water (30 mL), and extract with EtOAc (2 x 30 mL). Wash the combined extracts with brine (10 mL), dry them with Na2SO4, and concentrate them to provide 4-[4-fluoro-4-(methylthiomethyl)-1-piperidinyl]-8-methoxy-quinazoline (0.47 g).

[0855] Step 4: A mixture of 4-[4-fluoro-4-(methylthioalkylmethyl)-1-piperidinyl]-8-methoxy-quinazoline (0.47 g, 1.4 mmol), PhI(OAc)2 (1.4 g, 4.3 mmol), and NH4OAc (0.45 g, 5.7 mmol) in EtOH (5.0 mL) was stirred for 2 h. The mixture was concentrated and purified by preparative HPLC (H2O, 0.2% formic acid, 1%–25% MeCN) to provide imino({[1-(8-methoxyquinazoline-4-yl)-1,2,3,6-tetrahydropyridin-4-yl]methyl})methyl-λ 6 - Thionyl ketone (compound 246) (20 mg). ESI MS m / z: 333.1 (M+H).

[0856] Table 15 describes the chiral separation conditions for a specific embodiment, wherein supercritical CO2 is a nonpolar cosolvent.

[0857] Table 15: SFC Separation Conditions

[0858]

[0859]

[0860] Table 16: Examples at 400MHz 1 H NMR data

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874] Biological Example B-1

[0875] Inhibition of ENPP1 hydrolysis of 2',3'-cGAMP

[0876] Assay 1: Plate the test compound in a 3x dilution in a 384-well plate. Add 2.5 μL of ENPP-1ECD (final concentration 2.5 nM) in assay buffer (Tris-HCl pH 8.0 (50 mM), NaCl (150 mM), and 0.01% Triton X-100 aqueous solution) to 50 nL of the test compound in DMSO. The enzyme was omitted in the control wells, which were reserved to define maximum inhibition (max). The control wells were reserved to define no inhibition (min), and DMSO was used instead of the compound solution. Centrifuge the plate for 30 s and incubate the mixture for 30 min. Add 2.5 μL of 2,3-cGAMP (final concentration: 24 μM; K) in assay buffer. M =24μM), and centrifuged the plate and incubated for 30 min. Add AMP-Glo TM Reagent I (Promega Corp.; 5 μL): Centrifuge the plate for 1 min and incubate for 60 min. Add AMP detection solution (100 μL) to each well, centrifuge the plate and incubate for 60 min. Measure luminescence using an Envision plate reader and calculate the inhibition percentage for each well as: (([max–min]–[test–min]) / [max–min]. IC50 The values ​​were calculated from the concentration versus inhibition % data using a four-parameter variable slope model and via the Cheng / Prusoff equation (K). I =IC 50 / (1+[substrate] / K) M Convert to K I Value. Known ENPP1 inhibitors have the following IC50 values ​​in assay 1. 50 value:

[0877] 8-(3-cyano-6-fluoro-7-methoxyquinoline-4-yl)-2,8-diazaspiro[4.5]decane-2-sulfonamide, 2.9 nM; 4-[(6,7-dimethoxyquinoline-4-yl)oxy]benzene-1-sulfonamide, 190 nM;

[0878] N-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}aminosulfonamide, 490 nM;

[0879] 7-(6,7-dimethoxyquinazoline-4-yl)-1,2,3,4-tetrahydroisoquinoline-2-sulfonamide, 11 nM;

[0880] N-{[4-(7-methoxyquinoline-4-yl)phenyl]methyl}aminosulfonamide, 29 nM;

[0881] N-{2-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]ethyl}aminosulfonamide, 31 nM.

[0882] K of compound 1 I The concentration was 5.1 nM. The IC50 of compound 1 was... 50 The IC50 of compound 8 is 17 nM. 50 The concentration was 6.9 nM. The IC50 of compound 80 was... 50 The IC50 of compound 161 is 1.4 nM. 50 The value is 1.3 nM. Other results are summarized in Tables 17 and 18.

[0883] Assay 2: Compared to the conditions in Assay 1, this assay has a wider dynamic range and ensures the system is under steady-state conditions by reducing the enzyme concentration in the assay. This allows for the differentiation of very effective compounds and allows for IC50 analysis. 50 Data converted to K I .

[0884] The test compound was plated in a 3x dilution scheme in a 384-well plate. 2.5 μL of ENPP-1ECD (final ENPP-1 concentration 0.25 nM) in assay buffer (Tris-HCl pH 8.0 (50 mM), NaCl (150 mM), and 0.01% Triton X-100 aqueous solution) was added to 50 nL of the test compound in DMSO. The enzyme was omitted in the control wells, which were reserved to define maximum inhibition (max). The control wells were reserved to define no inhibition (min), and DMSO was used instead of the compound solution. The plate was centrifuged for 30 s and the mixture was incubated for 30 min. 2.5 μL of 2,3-cGAMP (final concentration: 24 μM; K) was added to the assay buffer. M =24μM), and centrifuged the plate and incubated for 30 min. Add AMP-Glo TM Reagent I (Promega Corp.; 5 μL) was added, the plate was centrifuged for 1 min and incubated for 60 min. AMP detection solution (10 μL) was added to each well, the plate was centrifuged and incubated for 60 min. Emissions were measured using an Envision plate reader, and the inhibition percentage for each well was calculated as: (([max–min]–[test–min]) / [max–min]. IC 50 The values ​​were calculated from the concentration versus inhibition % data using a four-parameter variable slope model and via the Cheng / Prusoff equation (K). I =(IC 50 +[E] / 2) / (1+[substrate] / K M The transformation is K I Value. Known ENPP1 inhibitors have the following K values ​​in assay 2. I :

[0885] 8-(3-cyano-6-fluoro-7-methoxyquinoline-4-yl)-2,8-diazaspiro[4.5]decane-2-sulfonamide, 0.47 nM;

[0886] 4-[(6,7-dimethoxyquinoline-4-yl)oxy]benzene-1-sulfonamide, 32 nM;

[0887] N-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}aminosulfonamide, 70 nM;

[0888] N-{[4-(7-methoxyquinoline-4-yl)phenyl]methyl}aminosulfonamide, 4.9 nM;

[0889] N-{2-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]ethyl}aminosulfonamide, 2.3 nM

[0890] The results are summarized in Tables 17 and 18.

[0891] Biological Example B-2

[0892] Inhibition of ENPP1 hydrolysis of p-nitrophenyl ester AMP on MDA-MB-231 cells (assay 3)

[0893] ENPP1 is typically expressed in the human metastatic breast cancer cell line MDA-MB-231. In the supernatant of MDA-MB-231 cell culture, ENPP1 selectively catalyzes the hydrolysis of p-nitrophenyl AMP (pNP-AMP), the same electron configuration of ATP. The inhibition of pNP-AMP hydrolysis in MDA-MB-231 at pH 7.4 and 37°C provides a good model for the physiologically relevant activity of membrane-bound ENPP1 at disease-associated expression levels.

[0894] MDA-MB-231 cells were harvested using TypLE Express Enzyme digestion and resuspended in 100 μL Leibovitz L-15 medium, 20% FBS. Cells were seeded at 4.5 x 10⁴ cells / well in 96-well assay plates. Cells were incubated at 37°C and 1% CO₂ for 24 h. On separate dilution plates, 2x the highest dose of the compound was prepared in FBS-free phenol red 1640 medium and then serially diluted 1:3 in the same medium. Cell culture medium was carefully aspirated from the L15 medium, cells were washed once with PBS, and 50 μL / well of the test compound or DMSO blank was added to the assay plate. Substrate mixture (50 μL; 0.5 mM pNP-AMP in FBS-free phenol red 1640 medium) was added to a final pNP-AMP concentration of 0.25 mM. The system was incubated at 37°C for 3 h. The release of p-nitrophenol was measured by absorbance at 405 nM on an Envision plate reader, and the inhibition percentage for each well was then calculated as: (([max–min]–[test–min]) / [max–min]. IC 50 The values ​​were calculated from the concentration versus inhibition % data using a four-parameter variable slope model and via the Cheng / Prusoff equation (K). I,表观 =IC 50 / (1+[substrate] / K) M Convert to apparent K I (K I,表观 ) value. Known ENPP1 inhibitors have the following apparent K values ​​in assay 3. I :

[0895] 8-(3-cyano-6-fluoro-7-methoxyquinoline-4-yl)-2,8-diazaspiro[4.5]decane-2-sulfonamide, 24 nM;

[0896] 4-[(6,7-dimethoxyquinoline-4-yl)oxy]benzene-1-sulfonamide, 380 nM;

[0897] N-{4-[(6,7-dimethoxyquinoline-4-yl)oxy]phenyl}aminosulfonamide, 920 nM;

[0898] 7-(6,7-dimethoxyquinazoline-4-yl)-1,2,3,4-tetrahydroisoquinoline-2-sulfonamide, 23 nM;

[0899] N-{[4-(7-methoxyquinoline-4-yl)phenyl]methyl}aminosulfonamide, 330 nM;

[0900] N-{2-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]ethyl}aminosulfonamide, 120 nM

[0901] The results of Measurement 1 and Measurement 2 are summarized in Table 17 below. Table 17 Legend: Measurement 1 IC 50 Values, A: >1000 nM; B: ≤1000 but >10 nM; C: ≤10 nM; Measured at 2K I Values, D: >300nM; E: ≤300 but >3nM; F: ≤3nM.

[0902] Table 18 below provides a more detailed and expanded summary of the results of determinations 1, 2 and 3.

[0903] Table 17

[0904]

[0905]

[0906] Table 18

[0907]

[0908]

[0909]

[0910]

[0911] Biological Example B-3

[0912] Evaluation of the effects of ENPP1 inhibitors on mouse tumor growth models

[0913] EMT6 cells (ATCC, CRL-2755) were used. TMTumor cells were maintained in vitro as a monolayer in Waymouth medium at 37°C under a 5% CO2 atmosphere in air, supplemented with 15% heat-inactivated fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin. Tumor cells were routinely passaged twice weekly by trypsin-EDTA treatment. Cells grown to approximately 70%-80% confluence were harvested and counted for tumor inoculation. Two x 102 cells suspended in 0.1 mL of basal medium were subcutaneously inoculated into the right ventral region of each mouse. 5 EMT6 cells were used for tumor development, with n = 10 mice in each treatment group. Once the primary tumor size reached an average of 50 mm... 3 Animals can be randomized using block randomization performed in Excel based on tumor size. Then, the animals are administered once daily via tube feeding (10 mL / kg) either a mediator control (an aqueous solution of 0.5% methylcellulose and 1% Tween-80) or a suspension of the test compound in the mediator. Mice are continuously administered the medication, for example, once or twice daily, until individual tumors reach a size of 1,500 mm. 3 The experimental endpoint was reached after which the animals were euthanized and the tumors were harvested for downstream analysis.

[0914] While the foregoing written description of the compounds, uses, and methods described herein enables those skilled in the art to prepare and use the compounds, uses, and methods described herein, those skilled in the art will understand and appreciate that variations, combinations, and equivalents exist in the specific embodiments, methods, and examples described herein. Therefore, the compounds, uses, and methods provided herein should not be limited to the embodiments, methods, or examples described above, but should encompass all embodiments and methods within the scope and spirit of the compounds, uses, and methods provided herein.

[0915] All references published in this article are included in their entirety by way of citation.

Claims

1. A compound of formula (I) (I)， Or its pharmaceutically acceptable salt, wherein: W is , or ; R 2a It is methyl; Where equation (I) Part of it is , or , R 1b -R 6b Each of the following is an independent C-type carbon atom containing hydrogen, halogen, hydroxyl group, or optionally substituted with one or more halogen substituents. 1-4 Alkoxy, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, nitro, -NR 1c R 2c -NHC(O)R 3c or -C(O)NR 4c R 5c ; L is a bond; R 1c -R 5c Each is independently hydrogen or C 1-3 Alkyl; and a 1 and a 2 It is 0.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein formula (I) Part of it is , , or .

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein formula (I) Part of it is or .

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein formula (I) Part of it is or .

5. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

6. A pharmaceutical composition comprising a compound as described in any one of claims 1-5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

7. Use of the compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting ENPP1 in cells.

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