Pyrido[3,4-D]pyrimidinone and pyrimidine aromatic hydrocarbon receptor antagonists and their uses

Abstract

This disclosure relates to compounds that can be used as aromatic hydrocarbon acceptor (AHR) modulators. Furthermore, this disclosure describes methods for treating diseases and disorders, such as cancer and viral infections, using the compounds described herein.

Description

[Technical Field]

[0001] This disclosure relates to compounds used as aromatic hydrocarbon receptor (AHR) activity antagonists, pharmaceutical formulations thereof, and methods for treating diseases and disorders such as cancer using the same. [Background technology]

[0002] Aromatic hydrocarbon receptors (AHRs) are ligand-dependent transcription factors that regulate gene expression in various cells (e.g., epithelial cells and immune cells). New evidence reveals that AHRs play a role in the initiation, promotion, progression, invasion, and metastasis of cancer cells. High AHR expression is observed in various tumor types and tumor cell lines, indicating that AHRs are activated within tumors and promote tumor growth. Immune evasion is increasingly recognized as a characteristic of cancer. The link between AHRs and the immune system is recognized, and AHRs are thought to be immunosuppressive effectors of different types of immune cells. Some cancers can evade immune recognition via the AHR signaling pathway. Taken together, regulating AHR activity in cancer cells, immune cells, matrix cells, fibroblasts, and endothelial cells within tumors may slow disease progression.

[0003] AHR is expressed at high levels and is chronically activated in hematological malignancies (e.g., T-cell leukemia, lymphoma) and solid tumors (e.g., glioblastoma, ovarian cancer, lung cancer, liver cancer, head and neck cancer). Detecting AHR activity in the tumor microenvironment is thought to be a potentially useful diagnostic indicator of tumor invasiveness. Depending on the type of cancer, two different outcomes are associated between AHR activity and prognosis. In hormone-dependent breast cancer, there is evidence that AHR activation is associated with reduced invasiveness and a favorable prognosis. Conversely, high AHR activity is thought to be associated with increased invasiveness and a poor prognosis in non-small cell lung cancer.

[0004] Recent reports have also demonstrated the role of AHR as a modulator of endogenous, innate, and adaptive immune responses to viral infections. The role of AHR activation is thought to influence the host's resistance to a variety of viral infections, including influenza, coronaviruses (e.g., SARS-CoV-1, SARS-CoV-2, MERS-CoV), flaviviruses (e.g., Zika virus), retroviruses (e.g., HIV), and herpesviruses.

[0005] Therefore, novel compounds are needed to be used as AHR antagonists in order to provide novel and effective therapies for diseases and disorders (e.g., cancer and viral infections). [Overview of the project]

[0006] This disclosure includes formula (I) or formula (II) A compound named JPEG2026515766000001.jpg30170 is provided. The substituents are as follows. These compounds are useful as aromatic hydrocarbon acceptor modulators. [Modes for carrying out the invention]

[0007] JPEG2026515766000002.jpg70170 can be used. For example, the compounds described herein can improve or decrease AHR activity.

[0008] Compounds of the Disclosure This disclosure provides compounds having the structure of formula (I) or formula (II) or pharmaceutically acceptable salts thereof, JPEG2026515766000003.jpg31170 However, L is bond, C(O), C 2-3 Alkenylene group or C 2-3 It is an alkynylene group, Ar 1 is a phenyl group, C 3-8a cycloalkyl group or a 4- to 8-membered aromatic or non-aromatic heterocyclic ring having 1 to 3 ring heteroatoms selected from O, N and S, Ar 1 is optionally substituted with one or two R A ; R A is each independently halogen, OH, =O, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyclopropyl, NR N R N ; C(O)NR N R N ; CO2R N ; C(O)R N ; or SO2-C 1-6 alkyl; R N is each independently H or C 1-6 alkyl; Ar 2 is a 5- to 10-membered aromatic or non-aromatic ring having 0 to 3 ring heteroatoms selected from O, N and S; Ar 2 is optionally substituted with one, two or three R B ; R B is each independently halogen, CN, C 1-6 alkyl, OH, =O, C 1-6 hydroxyalkyl, C(O)R N ; CO2R N ; C(O)NR N R N ; Het; C(O)-C 0-2 alkylene-Het; or N(R N )-C 0-3 alkylene-C(O)-C 0-3 alkylene-Het; Het is a 4- to 8-membered aromatic or non-aromatic ring having 0 to 3 ring heteroatoms selected from N, O and S, and is optionally substituted with one, two or three R C ; R CThese are, independently, halogen, OH, =O, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR N R N , C(O)NR N R N CO2R N , C(O)R N or SO2-C 1-6 It is alkyl, R 1 C 1-6 Alkyl alkyl group, C 1-6 Alkilen-R D , C 1-6 Alkylene-C(O)R D , C 1-6 Alkylene-NHSO2 cyclopropyl group, or C 1-6 Alkilen-NR N -C(O)R N And, R D is OR N or NR N R N And, The conditions are as follows: (i) In a compound of formula (I), if L is a bond, then (a) Ar 2 Het, C(O)-C 0-2 Alkylene-Het and N(RN)-C 0-3 Alkylene-C(O)-C 0-3 at least one R selected from alkylene-Het B It is replaced by (b)Ar 2 It contains an 8- to 10-membered bicyclic aromatic ring or a non-aromatic ring with 1 to 3 ring heteroatoms, and 0 to 3 R B It is replaced by (ii) In the compound of formula (II), if L is a bond, Ar 2 is a phenyl group or a 6-membered aromatic heterocycle, and Ar 2 is one R B It is replaced by, and furthermore, R BWhen it is Het, (a) Het is bonded to Ar through a carbon atom of Het 2 or (b) Het is substituted with one, two or three R C .

[0009] In some cases, R N are each independently H or CH3. In some cases, R N is H. In some cases, R N is a C 1-6 alkyl group. In some cases, R N is a methyl group.

[0010] In some cases, R 1 is a C 1-6 alkyl group or a C 1-6 alkylene group - R D . In some cases, R D is OR N . In some cases, R D is OH. In some cases, JPEG2026515766000004.jpg42170.

[0011] In some cases, the compound has a structure of formula (Ia) or formula (IIa). JPEG2026515766000005.jpg34170

[0012] In various cases, Ar 1 is a heterocyclic group containing a total of 4 to 8 ring atoms, and 1 to 3 of the ring atoms are selected from O, N, S. In various cases, Ar 1 is a phenyl group, a C 3-8 cycloalkyl group or a pyrazole group. In some cases, Ar 1 is unsubstituted. In some cases, Ar 1 is substituted with one or two R A , for example, at least one R A is a C 1-6 alkyl group, a C 1-6 haloalkyl group, or a C 1-6 alkoxy group. In some cases, at least one R AIt is methyl.

[0013] In some cases, the compound has the structure of formula (Ib) or formula (IIb). JPEG2026515766000006.jpg50170

[0014] In some cases, the compound has the structure of formula (Ic) or formula (IIc). JPEG2026515766000007.jpg43170

[0015] In various cases, L is a compound. In some cases, L is C 2-3 It is an alkenylene group. In some cases, L is C 2-3 It is an alkynylene group.

[0016] In multiple embodiments, Ar 2 is a phenyl group or a naphthyl group. In several embodiments, Ar 2 It is a 5- to 10-membered aromatic or aromatic ring having 1 to 3 ring heteroatoms selected from O, N, and S. In some cases, Ar 2 is isoindoline, tetrahydroisoquinoline, tetrahydroquinoline, indazole, or pyrazolo[4,3-c]pyridine. In various embodiments, Ar 2 It is a non-substitution. In some cases, Ar 2 This is 1, 2, or 3 R B It is replaced by. In some cases, at least one R B Halogen, CN, C 1-6 alkyl, OH, =O, C 1-6 Hydroxyalkyl, C(O)R N CO2R N or C(O)NR N R N In various cases, at least one R B Het, C(O)-C 0-2 Alkylene-Het or N(R) N )-C 0-3 Alkylene-C(O)-C 0-3Alkylene-Het is, in some cases, a phenyl group, pyridine, pyridine-2-one, pyrimidine, piperidine, piperazine, morpholine, azepane, 1,4-diazepane, pyrrolidine, tetrahydropyran, dihydropyran, or 8-oxa-3λ 2 -Contains azabicyclo[3.2.1]octane. In some cases, Het is unsubstituted. In various cases, Het has one or two R C It is replaced by. In some cases, at least one R C is a halogen, OH, =O, C 1-6 Alkyl, CO2R N , NR N R N or SO2-C 1-6 It can also be alkyl. In some cases, Het is JPEG2026515766000008.jpg106170

[0017] In various cases used in compounds of formula (I), Ar 2 teeth JPEG2026515766000009.jpg106170JPEG2026515766000010.jpg78170JPEG2026515766000011.jpg136170JPEG2026515766000012.jpg50170

[0018] In various cases of the compound of formula (II), Ar 2 teeth, JPEG2026515766000013.jpg29170JPEG2026515766000014.jpg140170JPEG2026515766000015.jpg102170JPEG2026515766000016.jpg104170

[0019] The specific compounds described in this disclosure include the compounds listed in Table 1 or their pharmaceutically acceptable salts. [Table 1] JPEG2026515766000018.jpg215170JPEG2026515766000019.jpg215170JPEG2026515766000020.jpg222170JPEG2026515766000021.jpg222170JPEG2026515766000022.jpg222170JPEG2026515766000023.jpg222170JPEG2026515766000024.jpg222170JPEG2026515766000025.jpg222170JPEG2026515766000026.jpg222170JPEG2026515766000027.jpg222170JPEG2026515766000028.jpg222170JPEG2026515766000029.jpg196170

[0020] Unless otherwise specified, the structures described herein are also intended to include all isomeric forms of the structure (e.g., enantiomers, diastereomers, cis-trans, conformational, and rotational forms). For example, unless only one specific isomer is shown, this disclosure encompasses the R and S configurations of each chiral center, the (Z) and (E) double bond isomers, and the (Z) and (E) conformational isomers. Thus, single stereoisomers of the compounds described herein, as well as mixtures of enantiomers, diastereomers, cis / trans, conformational, and rotational forms, are within the scope of this disclosure. In some cases, the compounds described herein are stereoisomers. “Stereoisomer” means a compound that differs in chirality at one or more stereocenters. Stereoiomers include enantiomers and diastereomers. The compounds described herein may exist in the form of a single stereoisomer or in the form of a mixture of stereoisomers. The stereochemistry of the compounds described herein is relative stereochemistry, not absolute stereochemistry, unless otherwise discussed. As described herein, a single stereoisomer, diastereomer, or enantiomer means a compound that is at least 50% or more of the stereoisomer, diastereomer, or enantiomer shown, and in some cases, a compound that is at least 90% or 95% of the stereoisomer, diastereomer, or enantiomer shown.

[0021] The compounds described herein are sp 3 The carbon atoms may have any stereochemical configuration. In some cases, the compounds of this disclosure are optically pure. As used in this disclosure, “optically pure” means that if multiple stereochemical configurations are possible, the compound contains only one enantiomer (detection limit). In various cases, the chirality moieties present in the compounds of this disclosure are derived from natural amino acids, unnatural amino acids, or sugars.

[0022] Unless otherwise specified, all tautomeral forms of the compounds disclosed herein are included within the scope of this disclosure.

[0023] Furthermore, unless otherwise specified, the structures described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, hydrogen may be substituted with deuterium or tritium, or carbon may be substituted with deuterium or tritium. 13 C- or 14 Compounds having the structure of the disclosure, other than those in which carbon atoms are substituted with C-- enriched carbon atoms, are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. Such compounds, in particular deuterium analogs, are also useful for therapeutic applications. Accordingly, the disclosure further discloses deuterated compounds or salts in which one or more hydrogen isotopes in formula (I) are substituted with deuterium.

[0024] The compounds of this disclosure are defined herein by their chemical structures and / or chemical names. If a compound is referred to by both its chemical structure and chemical name, and there is a conflict between the two, the compound shall be determined by its chemical structure.

[0025] In this specification, “alkyl group” means a linear and branched saturated hydrocarbon group containing 1 to 30 carbon atoms, for example, 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6). The term Cn means that the alkyl group has “n” carbon atoms. For example, C3 alkyl group means an alkyl group with 3 carbon atoms. 1-6 An alkyl group refers to an alkyl group having a number of carbon atoms that includes the entire range (i.e., 1 to 6 carbon atoms) and all subgroups (e.g., 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 3 to 4, 3 to 5, 3 to 5, 4 to 6, 1, 2, 3, 4, 5, and 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), and tert-butyl (1,1-dimethylethyl). Unless otherwise specified, alkyl groups may be unsubstituted or substituted alkyl groups.

[0026] In this specification, "alkylene group" means a divalent saturated aliphatic group. The term Cn means that the alkylene group has "n" carbon atoms. For example, C 1-6 As explained above regarding the "alkyl" group, an alkylene group refers to an alkylene group that has a number of carbon atoms that includes the entire range and all subgroups.

[0027] In this specification, the term "haloalkyl group" means an alkyl group in which one or more hydrogen atoms are substituted with a halogen. Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2-fluoroethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl groups. Haloalkyl groups may be further substituted or unsubstituted, and in some cases, haloalkyl groups having, for example, 1 to 6 carbon atoms, e.g., C 1-6 This refers to a haloalkyl group.

[0028] In this specification, the term "hydroxyalkyl" means an alkyl group in which one or more hydrogen atoms are substituted with a hydroxyl group (OH). Such groups include, but are not limited to, hydroxymethyl groups and hydroxyethyl groups. Hydroxyalkyl groups may be further substituted or unsubstituted, and in some cases, for example, hydroxyalkyl groups having 1 to 6 carbon atoms, e.g., C 1-6 It means hydroxyalkyl group.

[0029] In this specification, the term "cycloalkyl group" means an aliphatic cyclic hydrocarbon group containing 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 carbon atoms). The term Cn means that the cycloalkyl group has "n" carbon atoms. For example, a C5 cycloalkyl group means a cycloalkyl group having 5 carbon atoms in the ring. A C3-C8 cycloalkyl group means a cycloalkyl group having carbon atoms in the entire range (e.g., 3 to 8 carbon atoms) and all subgroups (e.g., 3-4, 3-5, 3-6, 3-7, 3-8, 4-5, 4-6, 4-7, 4-8, 5-6, 5-7, 5-8, 6-7, 6-8, 7-8, 3, 4, 5, 6, 7, and 8 carbon atoms). Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. The cycloalkyl groups described herein may be used alone or in combination with other cycloalkyl groups, heterocycloalkyl groups, aryl groups, and / or heteroaryl groups. When a cycloalkyl group is combined with another cycloalkyl group, each cycloalkyl group may contain 3 to 8 carbon atoms unless otherwise specified. Unless otherwise specified, cycloalkyl groups may be unsubstituted or substituted.

[0030] In this specification, the term “heterocyclic group” means a monocyclic, fused, spirocyclic, or bridging ring system which may contain saturated or one or more unsaturated units, or may be aromatic (i.e., heteroaryl), and have a total of 4 to 12 (or 4 to 10, or 4 to 8, as shown herein) ring atoms, where 1 to 3 (e.g., 1 to 3, or 1, 2, or 3) ring atoms are heteroatoms selected from N, S, and O. When the heterocyclic group is a spiro ring, it may include, for example, a 4-membered ring and a spiro-5-membered ring, a 4-membered ring and a spiro-6-membered ring, a 4-membered ring and a spiro-7-membered ring, a 5-membered ring and a spiro-6-membered ring, a 5-membered ring and a spiro-7-membered ring, a 6-membered ring and a spiro-6-membered ring, a 6-membered ring and a spiro-7-membered ring, or a 7-membered ring and a spiro-7-membered ring, and each ring in the spiro ring system may contain at least one ring heteroatom, or only one ring may contain at least one ring heteroatom while the other ring is a carbon ring. In some cases, the heterocyclic group contains 5 to 6 ring members. In some cases, the heterocyclic group contains 5 ring members. In some cases, the heterocyclic group contains 6 ring members.Heterocyclo groups include oxetanyl, azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazepanyl, thiazepanyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino (e.g., including 3-morpholino and 4-morpholino), 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, and 1 This includes, but is not limited to, -pyrrolidinil, 2-pyrrolidinil, 3-pyrrolidinil, pyrrolidine-2-one, 1-tetrahydropiperazinil, 2-tetrahydropiperazinil, 3-tetrahydropiperazinil, 1-piperidinil, 2-piperidinil, 3-piperidinil, 1-pyrazolinil, 3-pyrazolinil, 4-pyrazolinil, 5-pyrazolinil, 1-piperidinil, 2-piperidinil, 3-piperidinil, 4-piperidinil, 2-thiazolidinil, 3-thiazolidinil, 4-thiazolidinil, 1-imidazolidinil, 2-imidazolidinil, 4-imidazolidinil, 5-imidazolidinil, and 1,3-dihydroimidazole-2-one. In some cases, the heterocyclic group is oxetanyl, azetidinyl, diazepanyl (such as 1,4-diazepanyl), azepanyl, piperidinyl (such as 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, or 4-piperidinyl), or pyrrolidinyl (such as 1-pyrrolidinyl, 2-pyrrolidinyl, or 3-pyrrolidinyl). In some cases, the heterocyclic group is oxetanyl, azetidinyl, diazepanyl, or azepanyl. In some cases, the heterocyclic group is diazepanyl or azepanyl. In some cases, the heterocyclic group is 1,4-diazepanyl or azepanyl. In some cases, the heterocyclic group is 1,4-diazepanyl. In some cases, the heterocyclic group is azepanyl. The heterocyclic group may be unsubstituted or substituted, as described herein.

[0031] In this specification, the term “aromatic ring” means a monocyclic or dicyclic aromatic group having 5 to 10 ring atoms, where all ring atoms are carbocyclic atoms (i.e., aryl) or where 1 to 3 ring heteroatoms (i.e., heteroaryl) are included. Unless otherwise specified, aromatic rings may be unsubstituted or substituted. Aromatic rings may be unsubstituted or substituted, as described elsewhere in this specification.

[0032] In this specification, the term “heteroaryl” means an aromatic heterocyclic group having a total of 5 to 12 ring atoms (e.g., a monocyclic aromatic ring having a total of 5 to 6 ring atoms), and the aromatic ring contains 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms. Unless otherwise specified, heteroaryls may be unsubstituted or substituted. Heteroaryls may be isolated (e.g., pyridyl) or condensed to other heteroaryls (e.g., purinyl), cycloalkyl groups (e.g., tetrahydroquinolinyl), non-aromatic heterocyclic groups (e.g., dihydronaphthilidinyl) and / or aryls (e.g., benzothiazolyl and quinolyl). Heteroaryls include, but are not limited to, pyrazolyl, thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl. When a heteroaryl is condensed with another heteroaryl, each ring may contain a total of 5 or 6 ring atoms, and the aromatic ring may contain 1 to 3 heteroatoms.

[0033] In this specification, the term "alkoxy" means the "-O-alkyl" group.

[0034] In this specification, the term "haloalkoxy group" means an "-O-haloalkyl group".

[0035] In this specification, the term "halogen / halogenated" means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) group.

[0036] A "substituted" functional group (e.g., a substituted heterocyclic group, aromatic ring, or heteroaryl group) is a functional group in which at least one hydrogen is substituted with a non-hydrogen group (i.e., a substituent). Non-hydrogen groups (or substituents) include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, ether, aryl, heteroaryl, heterocyclic alkyl, hydroxy, oxy (or oxo), alkoxy, ester, thioester, acyl, carboxy, cyano, nitro, amino, mercapto, and halogen. Substitutions are discussed herein in relation to specific functional groups or parts.

[0037] Pharmaceutically acceptable salts The compounds described herein may be in free form or, where appropriate, in the form of salts. These pharmaceutically acceptable salts are of particular interest because they are useful when administering the compounds described herein for medical purposes. Pharmaceutically unacceptable salts are useful in manufacturing processes for separation and purification, and in some cases are useful for separating stereoisomers of the compounds disclosed herein or their intermediates.

[0038] In this specification, the term “pharmaceutically acceptable salt” means a salt of a compound that, within reasonable medical judgment, is suitable for use in contact with human and lower animal tissues without inappropriate side effects (e.g., toxicity, irritation, allergic reactions, etc.) and is commensurate with a reasonable return / risk ratio.

[0039] Pharmacopoeia-acceptable salts are well known in the field. For example, SMBerge et al. describe in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmacopoeia-acceptable salts of the compounds described herein include salts derived from appropriate inorganic and organic acids and bases. These salts can be prepared in situ during the final separation and purification process of the compounds.

[0040] If the compounds described herein contain a basic group or are bioisosters with sufficient basicity, the acid addition salt can be prepared by the following steps: 1) reacting the purified compound in its free base form with a suitable organic or inorganic acid; 2) separating the resulting salt. In practice, the acid addition salt is a more convenient form of use, and using the salt is equivalent to using its free base form.

[0041] Pharmaceutically acceptable and non-toxic acid addition salts include amino salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts produced by other methods commonly used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptaneate, hexanoate, hydrochloride, hydrobromide, hydroiodide, and 2-hydroxyethane. This includes sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, salicylates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valersates, and others.

[0042] If the compounds described herein contain a carboxyl group or a bioisoster having sufficient acidity, the base addition salt can be prepared by the following steps: 1) reacting the purified compound in acid form with a suitable organic or inorganic base; 2) separating the resulting salt. In practice, it is more convenient to use the base addition salt, and using its salt form is equivalent to using its free acid form. Salts derived from suitable bases include alkali metal salts (e.g., sodium, lithium, potassium), alkaline earth metal salts (e.g., magnesium, calcium), ammonium salts, and N +(C 1-4 This includes alkyl) tetrasalts. The disclosure also includes quaternary ammonium treatment of any of the basic nitrogen atom-containing groups in the compounds described herein. This quaternary ammonium treatment can yield water-soluble, oil-soluble, or dispersible products.

[0043] Base addition salts include pharmaceutically acceptable metal salts and amine salts. Suitable metal salts include salts of sodium, potassium, calcium, barium, zinc, magnesium, and aluminum. Sodium and potassium salts are generally preferred. Other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cation salts formed with counterions such as halogen ions, hydroxide ions, carboxylate ions, sulfate ions, phosphate ions, nitrate ions, lower alkyl sulfonate ions, and aryl sulfonate ions, where appropriate. Suitable inorganic base addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, and zinc hydroxide. Suitable amine base addition salts are prepared from amines that are commonly used in pharmacochemistry because they have low toxicity and are acceptable for medical use. Examples include ammonia, ethylenediamine, N-methylglucosamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tri(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabiethylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, and dicyclohexylamine.

[0044] Other acids and bases, although not pharmaceutically acceptable themselves, can be used to prepare salts used as intermediates for obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

[0045] It should be understood that the compounds described herein may exist as mixtures / combinations of different pharmaceutically acceptable salts. Mixtures / combinations of the free form of the compound with pharmaceutically acceptable salts are also possible.

[0046] Pharmaceutical preparations This specification also provides pharmaceutical formulations comprising an effective amount of the compounds of this disclosure and one or more pharmaceutically acceptable excipients. In this specification, the terms “formulation” and “composition” may be used interchangeably.

[0047] "Effective dose" includes "therapeutically effective dose" and "preventively effective dose." The term "therapeutically effective dose" means an amount effective in treating and / or improving a subject's disease or condition. The term "preventively effective dose" means an amount effective in preventing and / or significantly reducing a subject's disease or condition. In this specification, the terms "patient" and "subject" are interchangeable and refer to animals such as dogs, cats, cattle, horses, and sheep (i.e., non-human animals) and humans. A specific patient or subject is a mammal (e.g., human). The terms "patient" and "subject" include both males and females.

[0048] In this specification, the term “excipient” means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other component other than the active pharmaceutical ingredient (API). These are appropriately selected according to the intended dosage form and in accordance with conventional pharmaceutical practice.

[0049] The compounds of this disclosure may be administered alone or as part of a pharmaceutically acceptable composition or formulation. Furthermore, the compounds may be administered all at once (e.g., by rapid intravenous bolus injection), multiple times (e.g., by a series of tablets), or substantially uniformly over a period of time (e.g., by transdermal administration). It should also be noted that the dosage of the compounds may change over time.

[0050] The compounds disclosed herein and other pharmaceutically active compounds (as needed) may be administered to subjects or patients by any suitable route, such as orally, topically, rectally, parenterally (e.g., by subcutaneous injection, intravenous, intramuscular, intrasternal and intrasacral injection or infusion techniques), or orally, inhaled, or as a nasal spray. Administration may provide systemic effects (e.g., intestinal or parenterally). All methods of administering pharmaceutically active agents that can be used by those skilled in the art are foreseeable. In some cases, the disclosed formulations may be administered orally or topically.

[0051] Suitable oral compositions or formulations relating to this disclosure include, but are not limited to, tablets, Trotsch, Rozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions or formulations suitable for oral administration can be prepared according to any method known in the field of pharmaceutical composition production.

[0052] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsifies, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain, in addition to the active compound, inert diluents commonly used in the industry, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. In addition to the inert diluent, the oral composition may contain adjuvants such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavoring agents, and tasters.

[0053] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid preparations, the active compound is at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or a) filler or bulking agent (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid), b) binder (e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic), c) humectant (e.g., glycerol), d) disintegrant (e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates, and sodium carbonate), e) solution retarding agent. f) an absorption enhancer (e.g., a quaternary ammonium compound), g) a wetting agent (e.g., cetyl alcohol and glyceryl monostearate), h) an absorbent (e.g., kaolin and bentonite clay), and i) a lubricant (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof). In the case of capsules, tablets, and pills, the dosage form may also include a buffer.

[0054] Similar types of solid compositions can also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated pills, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical field. These may optionally contain light-shielding agents and may optionally be compositions that release the active ingredient only in a specific part of the intestine, or preferably with a delay. Embedding compositions that can be used include polymers and waxes. Similar types of solid compositions can also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0055] The active compound may be in the form of microcapsules, along with one or more excipients as described above. Solid dosage forms of tablets, sugar-coated pills, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical field. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Conventionally, such dosage forms may contain additional substances other than inert diluents, such as compression lubricants such as magnesium stearate and microcrystalline cellulose, and other compression aids. In the case of capsules, tablets, and pills, the dosage form may further contain buffers. These may optionally contain light-shielding agents and may optionally be compositions that release the active ingredient only to a certain part of the intestine, or preferably with a delay. Usable embedding compositions include, for example, polymers and waxes.

[0056] The pharmaceutical compositions and formulations described herein may also be administered topically or percutaneously, particularly when the therapeutic target includes areas or organs that can be easily reached by topical application, including diseases of the eyes, skin, or lower intestine. Appropriate topical formulations can be readily prepared for each of these areas or organs. Topical administration to the lower intestine can be carried out, for example, by rectal suppositories or appropriate enema formulations. Dosage forms for topical or percutaneous administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, suppositories, or patches.

[0057] For topical application, the pharmaceutical composition may be formulated into a suitable ointment, cream, lotion, or gel containing an active ingredient suspended or dissolved in one or more carriers, and any preservatives or buffers that may be necessary. Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutical composition may be formulated into a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetyl stearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0058] It is anticipated that ophthalmic formulations, ear drops, and eye drops are also included in the scope of this disclosure. Furthermore, the disclosure envisions the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may be used to increase the amount of compound that passes through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0059] Injectable formulations can be formulated using appropriate dispersants or wetting agents and suspending agents based on known techniques, for example, sterile injectable aqueous or oily suspensions. Sterile injectable formulations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable carriers and solvents include water, Ringer's solution, USP, and isotonic sodium chloride solutions. Sterile, non-volatile (fixed) oils are commonly used as solvents or suspension media. For this purpose, any mild non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Fatty acids such as oleic acid can also be used in injectable formulations.

[0060] Injectable formulations can be sterilized, for example, by filtration through a bacterial capture filter, or by adding a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0061] To extend the effects of the compounds described herein, it is generally desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. The absorption rate of a compound depends on its dissolution rate, which depends on the crystal size and crystalline form. Alternatively, delaying the absorption of compounds administered parenterally is achieved by dissolving or suspending the compound in an oil-based carrier. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polyactide-polyglycolide. The release rate of the compound can be controlled depending on the ratio of the compound to the polymer and the properties of the specific polymer used. Other biodegradable polymers include, for example, poly(orthoester) and poly(acid anhydride). Depot-injectable formulations can also be prepared by embedding the compound in liposomes or microemulsions that are compatible with body tissues.

[0062] Compositions for rectal or vaginal administration are, in particular, suppositories, which can be prepared by mixing the compounds described herein with a suitable non-irritating excipient or carrier (e.g., cocoa butter, polyethylene glycol, or suppository wax), where these excipients or carriers are solid at ambient temperature but liquid at body temperature, and thus dissolve in the rectal or vaginal cavity to release the active compound.

[0063] The sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions can be formulated using appropriate dispersants or wetting agents and suspending agents according to art known techniques. The sterile injectable formulations may be sterile injectable solutions or suspensions in non-toxic, orally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solutions. Sterile non-volatile oils are also commonly used as solvents or suspension media. For this purpose, any mild non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Fatty acids, such as oleic acid and its glyceride derivatives, are used in the manufacture of injectable formulations, as are naturally pharmaceutically acceptable oils such as olive oil or castor oil, particularly their polyoxyethylene-formulated forms. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. For formulation purposes, other common surfactants such as Tween and Span, and other emulsifiers or bioavailability enhancers commonly used to prepare pharmaceutically acceptable solids, liquids, or other dosage forms may also be used.

[0064] Pharmaceutical compositions may also be administered by nasal spray or inhalation. Such compositions may be prepared according to techniques well known in the field of pharmaceutical formulation and may be prepared as salt solutions using benzyl alcohol or other suitable preservatives, absorption enhancers to improve bioavailability, fluorocarbon compounds and / or other conventional solubilizers or dispersants.

[0065] The compounds used in the methods of this disclosure can be formulated as unit dosage forms. The term "unit dosage form" means a physically discrete unit suitable as a unit dose for a subject receiving treatment, where each unit contains a predetermined amount of active substance which may be combined with an appropriate pharmaceutical carrier to obtain the desired therapeutic effect by calculation. A unit dosage form may be a single daily dose or one of several daily doses (e.g., about 1 to 4 or more times per day). If multiple daily doses are used, the unit dosage forms for each dose may be the same or different.

[0066] The compounds disclosed herein can be administered to subjects or patients at dose levels ranging from approximately 0.1 mg to approximately 3000 mg per day. For a normal adult weighing approximately 70 kg, a dose of approximately 0.01 mg to approximately 100 mg per kg of body weight is usually sufficient. The specific dose and dose range used may potentially depend on many factors, including the needs of the subject or patient, the severity of the medical condition or disease being treated, and the pharmacological activity of the compound being administered. Determining the specific dose range and optimal dose for a particular subject or patient is within the scope of the ordinary art.

[0067] treatment method The compounds described herein can modulate aromatic hydrocarbon receptors (AHRs). AHRs are ligand-activated transcription factors associated with various pathological conditions that are involved in modulating the immune system during steady state and during infections and inflammation. The AHR pathway is recognized to play a role in the pathogenesis of diseases and disorders, including cancer and viral infections.

[0068] Furthermore, it has become clear that many viral infections involve AHR signaling. AHR is involved in regulating immune responses, and AHR activation is associated with impaired adaptive immune responses and adverse health outcomes in various viral infections (e.g., influenza). Inhibition of AHR is also associated with reduced viral particle production in the body (e.g., dengue fever). AHR appears to play a role in regulating lipid biogenesis (e.g., a characteristic of hepatitis C (HCV) infection). The role of AHR in regulating host immune responses to many viruses makes AHR regulation an attractive therapeutic target for viral infections.

[0069] Accordingly, this disclosure provides a method for modulating aromatic hydrocarbon receptors (AHRs) in cells, the method comprising contacting cells with a compound or salt, or formulation thereof, described herein, in an amount effective to modulate the AHRs. In some cases, the contact is performed extracorporeally. In some cases, the contact is performed intracorporeally. In some cases, the contact involves administration to a subject in need (e.g., suffering from a disease or disorder associated with abnormal AHR activity). As herein, the terms “patient” and “subject” are interchangeable and mean animals such as dogs, cats, cattle, horses, and sheep (i.e., non-human animals) and humans. A specific patient is a mammal (e.g., human).

[0070] Another aspect of this disclosure provides a method for treating a disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound or salt or composition thereof described in this disclosure. In some cases, terms such as “treating,” “treat,” or “treatment” may include prophylactic (e.g., preventive) treatment and paliative treatment.

[0071] Diseases or disorders associated with abnormal AHR activity include inflammatory diseases or disorders, cancer, and viral infections. They also include diseases and / or disorders of the gastrointestinal tract, skin, lungs, central nervous system, pancreas, eyes, bones, or joints, neuroinflammatory diseases, or neurodegenerative diseases. In some cases, gastrointestinal diseases or disorders are selected from the group consisting of colitis, inflammatory bowel disease, Crohn's disease, celiac disease, necrotizing enterocolitis, irritable bowel syndrome, chronic idiopathic constipation, traveler's diarrhea, and colorectal cancer. In various cases, skin diseases or disorders are selected from the group consisting of atopic dermatitis, acne, psoriasis, and vitiligo. In some cases, eye diseases or ataxias are abnormal eye movements, inflammatory eye diseases, autoimmune eye diseases, hereditary eye diseases, degenerative eye diseases, neovascular eye diseases, dry and wet age-related macular degeneration ("AMD"), uveitis, retinitis pigmentosa ("RP"), primary open-angle glaucoma ("POAG"), primary congenital glaucoma, Behcet's disease, or Leber congenital amaurosis ("LCA"). In various cases, lung diseases or ataxias are pulmonary fibrosis, asthma, or chronic obstructive pulmonary disease. In some cases, bone and joint diseases or ataxias are osteoporosis, rheumatoid arthritis, or bone cancer. In various cases, diseases or ataxias are diabetes mellitus, cancer, viral infections, or bacterial infections. In some cases, bacterial infections are lung infections, gastrointestinal infections, skin infections, ear infections, or sepsis.

[0072] In some cases, the disease or disorder is cancer. Cancers treated with the compounds and methods described herein include, but are not limited to, hematological cancers, lymphomas, myelomas, leukemias, neurological cancers, skin cancers, breast cancers, prostate cancers, respiratory cancers, reproductive cancers, gastrointestinal cancers, colorectal cancers, lung cancers, head and neck cancers, gastrointestinal cancers, liver cancers, pancreatic cancers, genitourinary cancers, bone cancers, kidney cancers, and vascular cancers. In some cases, cancer is a liquid or solid tumor, hematological cancer, lymphoma, myeloma, leukemia, sarcoma, eye cancer, thyroid cancer, parathyroid cancer, neurological cancer, skin cancer, breast cancer, endocrine cancer, uterine cancer, endometrial cancer, prostate cancer, colorectal cancer, lung cancer, head and neck cancers, gastrointestinal cancers, liver cancer, pancreatic cancer, genitourinary cancers, bone cancers, kidney cancers, or vascular cancers. In some cases, cancer is bone cancer. Bone cancers that may be considered include, but are not limited to, histiocytoma of bone. In some cases, cancer is endocrine cancer. Endocrine cancers that may be considered include, but are not limited to, multiple endocrine adenoma syndrome, adrenal cancer (e.g., adrenocortical carcinoma, adrenocorticoma, or adrenosebaceous adenoma), thyroid cancer (e.g., anaplastic thyroid carcinoma), and parathyroid cancer. In some cases, cancer is breast cancer. Breast cancers that may be considered include, but are not limited to, trinegative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma, and lobular carcinoma. In some cases, cancer is respiratory cancer. Respiratory cancers that may be considered include, but are not limited to, bronchial cancer, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), bronchioadenoma, and pleuropulmonary blastoma. In some cases, cancer is central nervous system cancer. Central nervous system cancers that may be considered include, but are not limited to, spinal axial tumors, neurofibromatosis type 1-associated malignant peripheral nerve schwannosis (MPNST), and brain cancer. In some cases, the cancer is brain cancer.Brain cancers that may be considered include glioma, low-grade glioma, astrocytoma (e.g., Grade I - pilar cell astrocytoma, Grade II - low-grade astrocytoma, Grade III - interdegenerative astrocytoma, Grade IV - glioblastoma (GBM)), pleomorphic glioblastoma (GBM, also called glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, moderately differentiated pineal parenchymal tumor, pinealoma, and hematocystoma. This includes, but is not limited to, ductal blastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, olfactory neuroblastoma, or retinoblastoma, medullary carcinoma, brainstem and pituitary glioma, cerebellar and cerebral astrocytoma, as well as neuroectodermal tumors and pineal tumors, chordoma, mixed glioma, optic glioma, subependymal tumor, metastatic brain tumor, pituitary tumor, pituitary adenoma, primitive neuroectodermal tumor (PNET), or schwannoma. In some cases, the cancer is of a type more common in children than in adults, such as brainstem glioma, juvenile pilocytic astrocytoma, optic glioma, pineal tumor, primitive neuroectodermal tumor (PNET), or rhabdomyoid tumor. In some cases, the patient is an adult human. In some cases, the patient is a child or pediatric patient. In some cases, the cancer is a cancer of the male reproductive organs. Cancers of the male reproductive organs that may be considered include, but are not limited to, embryonic carcinoma, seminomas, penile cancer, prostate cancer, and testicular cancer. In some cases, the cancer is of the female reproductive organs. Cancers of the female reproductive organs that may be considered include, but are not limited to, ovarian epithelial carcinoma, fallopian tube cancer, papillary serous carcinoma of the uterus (UPSC), choriocarcinoma, endometrial carcinoma, cervical cancer, ovarian cancer, vaginal cancer, and vulvar cancer, as well as uterine sarcoma. In some cases, the cancer is ovarian cancer. Ovarian cancers that may be considered include, but are not limited to, serous tumors, papillary serous cystadenocarcinoma, endometrioid tumors, mucinous cystadenocarcinoma, granulosa cell tumors, Sertoli-Leydig cell tumors, and androcytoma (arrhenoblastoma). In some cases, the cancer is cervical cancer. Cervical cancers that may be considered include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma, neuroendocrine tumors, vitreous cell carcinoma, and chorioadenocarcinoma. In some cases, the cancer is a cancer of the gastrointestinal tract.Cancers of the gastrointestinal tract that may be considered include, but are not limited to, anal cancer, colon cancer, colorectal cancer, colon tumors, esophageal cancer, stomach cancer, gallbladder cancer, gastrointestinal cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), duodenal cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer. In some cases, the cancer is esophageal cancer. Cancers of the esophageal tract that may be considered include, but are not limited to, esophageal cell carcinoma and adenocarcinoma, as well as squamous cell carcinoma, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, and lymphoma. In some cases, the cancer is gastric cancer. Cancers of the gastric tract that may be considered include, but are not limited to, intestinal and diffuse gastric adenocarcinoma. In some cases, the cancer is pancreatic cancer. Cancers of the pancreatic tract that may be considered include, but are not limited to, pancreatic ductal carcinoma, pancreatic adenodenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, and pancreatic endocrine tumors. In some cases, cancer is cancer of the urinary tract. Cancers of the urinary tract that may be considered include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureteral cancer, urethral cancer, and human papillary renal cell carcinoma. In some cases, cancer is kidney cancer. Cancers of the kidney that may be considered include, but are not limited to, renal cell carcinoma, renal pelvis tumor, urothelial cell carcinoma, juxtaglomerular cell carcinoma (reninoma), angiomyolipoma, renal eosinophilia, Bellini duct carcinoma, clear cell sarcoma, mesenchymal nephroma, and Wilms' tumor. In some cases, the following cancers are bladder cancer. Cancers of the bladder that may be considered include, but are not limited to, bladder tumors, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma. In some cases, cancer is eye cancer. Cancers of the eye that may be considered include, but are not limited to, intraocular melanoma and retinoblastoma. In some cases, cancer is liver cancer. Liver cancers that may be considered include, but are not limited to, cystadenoma, hepatocellular carcinoma, cholangiocarcinoma, extrahepatic cholangiocarcinoma, hepatobiliary (liver and bile duct) carcinoma, hepatoblastoma, hepatocellular carcinoma (with or without fibrous laminae mutation), cholangiomoma (intrahepatic cholangiomoma), hepatocholangiocarcinoma, and mixed hepatocellular carcinoma. In some cases, the cancer is skin cancer. Skin cancers that may be considered include, but are not limited to, basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell carcinoma, and non-melanoma skin cancer.In some cases, the cancer is a head and neck cancer. Head and neck cancers that may be considered include, but are not limited to, squamous cell carcinoma of the head and neck, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, salivary gland cancer, lip and oral cancer, and squamous cell carcinoma. In some cases, the cancer is a lymphoma. Lymphomas that may be considered include, but are not limited to, lymphocytic lymphoma, AIDS-associated lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and central nervous system lymphoma. In some cases, the cancer is a sarcoma. Sarcomas that may be considered include, but are not limited to, soft tissue sarcoma, fibrosarcoma, neurofibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endosarcoma, lymphangiosarcoma, lymphangiosarcoma, synoviomas, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. In some cases, cancer is leukemia. Leukemias that may be considered include, but are not limited to, acute leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, and acute erythroleukemia), chronic leukemia (e.g., chronic myeloid leukemia and chronic myeloid leukemia), and hairy cell leukemia.

[0073] Other cancers that may be treated with the compounds of this disclosure and the methods described herein may be selected from, for example, urothelial carcinoma (including, but not limited to, bladder cancer and all transitional cell carcinomas), head and neck squamous cell carcinoma, melanoma (including, but not limited to, uveal melanoma), ovarian cancer (including, but not limited to, serous subtype ovarian cancer), renal cell carcinoma (including, but not limited to, clear cell renal cell carcinoma molecular subtypes), cervical cancer, gastrointestinal / stomach (GIST) cancer (including, but not limited to, gastric cancer); non-small cell lung cancer (NSClC); acute myeloid leukemia (AML); and esophageal cancer. In some cases, the cancer is urothelial carcinoma. In some cases, the cancer is bladder cancer. In some cases, the cancer is transitional cell carcinoma. In some cases, the cancer is head and neck squamous cell carcinoma. In some cases, the cancer is melanoma. In some cases, the cancer is uveal melanoma. In some cases, the cancer is ovarian cancer. In some cases, the cancer is serous subtype ovarian cancer. In some cases, the cancer is renal cell carcinoma. In some cases, the cancer is the clear cell renal cell carcinoma molecular subtype. In some cases, the cancer is cervical cancer. In some cases, the cancer is gastrointestinal / stomach (GIST) cancer. In some cases, the cancer is stomach cancer. In some cases, the cancer is non-small cell lung cancer (NSClC). In some cases, the cancer is advanced and / or metastatic NSCLC. In some cases, the cancer is esophageal cancer.

[0074] Other cancers that may be considered include polycythemia vera, Waldenström macroglobulinemia, multiple myeloma, heavy chain disease, epithelial carcinoma, appendiceal cancer, atypical teratoid / rhabdomyoid tumor, atypical teratoid / rhabdomyoid tumor of the central nervous system, germ cell tumor of the central nervous system, bronchial tumor, carcinoid tumor, cancer of unknown primary origin, central nervous system cancer, childhood cancer, chordoma, chronic myeloproliferative disorder, ductal carcinoma in situ (DCIS), and germ cell tumor. Endometrial cancer, ependymoblastoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous germ cell tumor, gestational trophoblastic disease, cardiac cancer, histiocytosis, Langerhans cell carcinoma, hypopharyngeal cancer, islet cell tumor, Langerhans cell histiocytosis, laryngeal cancer, lip and oral cancer, non-invasive lobular carcinoma (LCIS), macroglobulinemia, medullary epithelioma, Merkel cell carcinoma, NUT gene-associated midline carcinoma, oral cancer (mouth cancer) This includes, but is not limited to, cancer, multiple endocrine adenoma syndrome, plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, myeloma, chronic myeloproliferative disorder, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, papillomatosis, paraganglioma, paranasal sinus cancer, nasal cavity cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma, plasma cell tumor, pleuropulmonary blastoma, transitional cell carcinoma, Sézary syndrome, supratentorial primitive neuroectodermal tumor, laryngeal cancer, thymoma, thymic carcinoma, transitional cell gestational trophoblastoma, cancer of unknown primary origin, unusual cancer of childhood, or diffuse large B-cell lymphoma (DLBCL).

[0075] The present invention also provides methods and compositions for the diagnosis, prognosis, and treatment of virus-related cancers, which include virus-related tumors in human immunodeficiency virus (HIV)-related autosomal tumors, human papillomavirus (HPV)-16-positive incurable autosomal tumors, and adult T-cell leukemia (which is caused by human T-cell leukemia virus type 1 (HTLV-I) and is a highly invasive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemia cells), gastric cancer, nasopharyngeal cancer, cervical cancer, vaginal cancer, vulvar cancer, head and neck squamous cell carcinoma, and Merkel cell carcinoma.

[0076] In some cases, the compounds or compositions thereof of this disclosure can be used to treat viral infections. In some cases, viral infections treated with the compounds and methods described herein include, but are not limited to, coronavirus infections and flavivirus infections.

[0077] In some cases, a viral infection is a coronavirus infection. In this specification, the term “coronavirus infection” means the disease caused by a coronavirus infection. Coronaviruses are a family of viruses that cause disease in mammals and birds. Coronaviruses belong to the subfamily Orthocoroninae of the family Coronaviridae in the order Nidovirales. There are four main genera of coronaviruses, called α, β, γ, and δ. Coronaviruses that affect humans include human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), severe acute respiratory syndrome-associated coronavirus (SARS-CoV), human coronavirus NL63 (HCoV-NL63, New Haven coronavirus), human coronavirus HKU1, Middle East respiratory syndrome-associated coronavirus (MERS-CoV, formerly known as novel coronavirus 2012, HCoV-EMC), and SARS-CoV-2 (also known as 2019-nCoV).

[0078] In some cases, viral infections are flavivirus infections. In this specification, the term “flavivirus infection” means a disease caused by a flavivirus infection.

[0079] Flaviviruses are a family of viruses that cause disease in mammals and insects. They belong to the order Amarillovirales, family Flaviviridae. Flaviviruses have an unsegmented, positive-sense single-stranded RNA genome approximately 10–11 kbp long. In humans, flaviviruses cause hemorrhagic fever, encephalitis, and congenital microcephaly. Flavivirus infections range from asymptomatic to fatal. Vaccines or antiviral drugs exist to prevent or treat some, but not all, human flavivirus infections. Non-exclusive examples of flaviviruses include West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus, and several other viruses that can cause encephalitis. Therefore, in some cases, the compounds of this disclosure (e.g., the compounds of formula (I), the compounds in Table 1, and their salts) or pharmaceutically acceptable salts thereof can be used to treat flavivirus infections such as West Nile fever, dengue fever, tick-borne encephalitis, yellow fever, and Zika fever (i.e., West Nile virus infection, dengue virus infection, tick-borne encephalitis virus infection, yellow fever virus infection, and Zika virus infection, respectively).

[0080] Another aspect of the present disclosure provides applications for the treatment of diseases or disorders associated with abnormal AHR activity in which the compounds or salts of the present disclosure or compositions comprising the compounds or salts of the present disclosure are used.

[0081] Furthermore, the use of the compounds or salts of the disclosed herein, or compositions comprising the compounds or salts of the disclosed herein, in the preparation of pharmaceuticals for the treatment of diseases or disorders associated with abnormal AHR activity should also be considered.

[0082] Furthermore, the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof for the treatment of diseases or disorders associated with abnormal AHR activity in subjects should also be considered. In addition, the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment of the above-mentioned conditions should also be considered.

[0083] In some cases, the compounds of this disclosure or pharmaceutically acceptable salts thereof may be administered in combination with other therapeutic agents to treat diseases or disorders associated with abnormal AHR activity. Thus, in any method of this disclosure, treatment of the disease or disorder may include the co-administration of the compounds of this disclosure or pharmaceutically acceptable salts thereof with another therapeutic agent. In some cases, the therapeutic agent is an anti-inflammatory agent. Anti-inflammatory agents that may be considered include, but are not limited to, mesalazine, naproxen, ibuprofen, diclofenac, celecoxib, sulindac, oxaprozine, piroxicam, indomethacin, meloxicam, fenoprofen, diflunisal, etodolac, ketrolac tromethamine, meclofenamete, nabumetone, salisalate, or any combination thereof. In some cases, the therapeutic agent is an immune checkpoint inhibitor. Immune checkpoint inhibitors include PD1 or PDL1 antibodies such as pembrolizumab, nivolumab, cemiplimab, atezolizumab, dostarlimab, durvalumab, or avelumab.

[0084] Synthesis of the Compounds Disclosed The compounds of this disclosure can be synthesized by any method known in the art. For example, the compounds of this disclosure can be synthesized as described in the following examples.

[0085] A general scheme for synthesizing the compounds of this disclosure is shown below. Further information regarding specific reaction conditions is provided in detail in the Examples section. JPEG2026515766000030.jpg172170

[0086] The following synthesis scheme provides additional routes for preparing the compounds of this disclosure. JPEG2026515766000031.jpg227170

[0087] This Disclosure Embodiment 1. Compounds having the structure of formula (I) or formula (II), or pharmaceutically acceptable salts thereof: JPEG2026515766000032.jpg37170 where L is merged, C(O), C 2-3 It is an alkenylene group or a C2-3 alkynylene group, Ar 1 is a phenyl group, C 3-8 A cycloalkyl group or a 4- to 8-membered aromatic heterocycle or non-aromatic heterocycle having a ring heteroatom selected from 1 to 3 O, N, and S, and further, Ar 1 is 1 or 2 R A It may be replaced with, R A These are, independently, halogen, OH, =O, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyclopropyl, NR N R N , C(O)NR N R N CO2R N , C(O)R N or SO2-C 1-6 It is alkyl, R N Each is independently H or C 1-6 It is alkyl, Ar 2 It is a 5- to 10-membered aromatic or aromatic ring having 0 to 3 ring heteroatoms selected from O, N, and S, and Ar 2 This is 1, 2, or 3 R B It may be replaced with, R B These are halogen, CN, and C, respectively, independently. 1-6 alkyl, OH, =O, C 1-6 Hydroxyalkyl, C(O)R N CO2R N , C(O)NR N RN ,Het,C(O)-C 0-2 Alkylene-Het, or N(R) N )-C 0-3 Alkylene-C(O)-C 0-3 It is alkylene-Het. Het is a 4- to 8-membered aromatic or aromatic ring having 0 to 3 ring heteroatoms selected from N, O, and S, and 1, 2, or 3 R C It may be replaced with, R C These are, independently, halogen, OH, =O, CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, NR N R N , C(O)NR N R N CO2R N , C(O)R N or SO2-C 1-6 It is alkyl, R 1 C 1-6 Alkyl alkyl group, C 1-6 Alkilen-R D , C 1-6 Alkylene-C(O)R D , C 1-6 Alkylene-NHSO2 cyclopropyl group, or C 1-6 Alkilen-NR N -C(O)R N And, R D is OR N or NR N R N And, The conditions are as follows: (i) In a compound of formula (I), if L is a bond, then (a) Ar 2 Het, C(O)-C 0-2 Alkylene-Het and N(R) N )-C 0-3 Alkylene-C(O)-C 0-3At least one R selected from the group consisting of alkylene-Het B It is replaced by (b)Ar 2 It contains an 8- to 10-membered bicyclic aromatic ring or a non-aromatic ring with 1 to 3 ring heteroatoms, and 0 to 3 R B It is replaced by (ii) In the compound of formula (II), if L is a bond, Ar 2 is a phenyl group or a 6-membered aromatic heterocycle, and Ar 2 is one R B It is replaced by, and furthermore, R B If is Het, then (a) Het can be transmitted through the carbon atoms of Het via Ar 2 (b) Het is bonded to R C It has been replaced with. 2.R N The compound or salt described in Embodiment 1, wherein each is independently H or methyl. 3.R 1 C 1-6 Alkyl alkyl group or C 1-6 Alkylene group-R D The compound or salt described in Embodiment 1 or 2. 4.R D is OR N The compound or salt described in Embodiment 3. JPEG2026515766000033.jpg19170 The compound or salt described in Embodiment 3. JPEG2026515766000034.jpg271707.Having the structure of formula (Ia), JPEG2026515766000035.jpg331708.Having the structure of formula (IIa), JPEG2026515766000036.jpg451709.Ar 1 The compound or salt according to any one of Embodiments 1 to 8, wherein the compound is a heterocyclic group containing a total of 4 to 8 ring atoms, 1 to 3 of which are selected from O, N, and S. 10.Ar 1 is 1 or 2 R AA compound or salt according to any one of Embodiments 1 to 9, which is substituted with [the compound or salt]. 11. Ar 1 The compound or salt according to Embodiment 9, wherein is unsubstituted. 12.Ar 1 is a phenyl group, C 3-8 A compound or salt according to any one of Embodiments 1 to 11, which is a cycloalkyl group or a pyrazole. 13. Having the structure of formula (Ib), JPEG2026515766000037.jpg6317014.Having the structure of formula (IIb), JPEG2026515766000038.jpg6417015. At least one R A However, C 1-6 Alkyl alkyl group, C 1-6 Haloalkyl group or C 1-6 It is an alkoxy group, or at least one R A The compound or salt according to any one of embodiments 9, 10 and 12-14, wherein is a methyl group. 16. Having the structure of formula (Ic), JPEG2026515766000039.jpg4617017.Having the structure of formula (IIc), A compound or salt according to any one of Embodiments 1 to 17, wherein JPEG2026515766000040.jpg5617018.L is a bond. 19. L is C 2-3 A compound or salt according to any one of Embodiments 1 to 17, which is an alkenylene group. 20.L is C 2-3 A compound or salt according to any one of Embodiments 1 to 17, which is an alkylylene group. 21.Ar 2 The compound or salt according to any one of Embodiments 1 to 20, wherein is a phenyl group or a naphthyl group. 22.Ar 2 The compound or salt according to any one of Embodiments 1 to 20, wherein is a 5- to 10-membered aromatic or non-aromatic ring having 1 to 3 ring heteroatoms selected from O, N, and S. 23. Ar 2The compound or salt according to Embodiment 22, wherein is an 8- to 10-membered bicyclic aromatic or non-aromatic ring having 1 to 3 ring heteroatoms selected from O, N, and S. 24.Ar 2 The compound or salt according to Embodiment 23, wherein isoindoline, tetrahydroisoquinoline, tetrahydroquinoline, indazole, or pyrazolo[4,3-c]pyridine. 25.Ar 2 A compound or salt according to any one of Embodiments 1 to 24, wherein is unsubstituted. 26.Ar 2 This is 1, 2, or 3 R B A compound or salt according to any one of Embodiments 1 to 24, which is substituted with [the compound or salt]. 27. At least one R B Halogen, CN, C 1-6 alkyl, OH, =O, C 1-6 Hydroxyalkyl, C(O)R N CO2R N or C(O)NR N R N The compound or salt described in Embodiment 26. 28. At least one R B Het, C(O)-C 0-2 Alkylene-Het or N(R) N )-C 0-3 Alkylene-C(O)-C 0-3 The compound or salt according to embodiment 26 or 27, which is alkylene-Het. 29. Het is a compound or salt according to Embodiment 28, comprising a phenyl group, pyridine, pyridine-2-one, pyrimidine, piperidine, piperazine, morpholine, azepane, 1,4-diazepane, pyrrolidine, tetrahydropyran, dihydropyran, or 8-oxa-3-azabicyclo[3.2.1]octane. 30. The compound or salt according to Embodiment 28 or 29, wherein Het is unsubstituted. 31. Het has one or two R C The compound or salt according to Embodiment 28 or 29, which is substituted with 32. At least one R Cis a halogen, OH, =O, C 1-6 Alkyl, CO2R N , NR N R N or SO2-C 1-6 A compound or salt according to Embodiment 31, which is alkyl. 33. At least one R C The compound or salt according to Embodiment 32, wherein is F, Cl, OH, =O, methyl, CO2H, NH2, or SO2CH3. 34. Het is JPEG2026515766000041.jpg112170 or salt. 35. Ar 2 teeth A compound or salt according to any one of Embodiments 1 to 20, wherein the images are JPEG2026515766000042.jpg55170, JPEG2026515766000043.jpg237170, and JPEG2026515766000044.jpg56170. 36. Ar 2 teeth JPEG2026515766000045.jpg171170JPEG2026515766000046.jpg214170 A compound or salt described in any one of items 1 to 20. 37. Compounds listed in Table 1 or pharmaceutically acceptable salts thereof. 38. A pharmaceutical preparation comprising a compound or salt described in any one of Embodiments 1 to 37 and a pharmaceutically acceptable excipient. 39. A method for treating or preventing a disease or disorder related to abnormal aromatic hydrocarbon receptor (AHR) activity in a subject, comprising administering to the subject a therapeutically effective dose of a compound or salt described in any one of Embodiments 1 to 37. 40. The method according to Embodiment 39, wherein the disease or disorder is an inflammatory disease or disorder. 41. The method according to Embodiment 39, wherein the disease or disorder is a disease or disorder of the gastrointestinal tract, skin, lungs, central nervous system, pancreas, eyes, bones, or joints, a neuroinflammatory disease, or a neurodegenerative disease. 42. The gastrointestinal disorder or disorder is selected from the group consisting of colitis, inflammatory bowel disease, Crohn's disease, celiac disease, necrotizing enterocolitis, irritable bowel syndrome, chronic idiopathic constipation, traveler's diarrhea, and colorectal cancer, according to Embodiment 41. 43. The method according to Embodiment 41, wherein the skin disease or disorder is selected from the group consisting of atopic dermatitis, acne, psoriasis and vitiligo. 44. The method according to Embodiment 41, wherein the eye disease or ataxia is abnormal eye movement, inflammatory eye disease, autoimmune eye disease, hereditary eye disease, degenerative eye disease, neovascular eye disease, dry and wet age-related macular degeneration ("AMD"), uveitis, retinitis pigmentosa ("RP"), primary open-angle glaucoma ("POAG"), primary congenital glaucoma, Bethet's disease, or Leber's congenital amaurosis ("LCA"). 45. The method according to Embodiment 41, wherein the lung disease or disorder is pulmonary fibrosis, asthma, or chronic obstructive pulmonary disease. 46. ​​The method according to Embodiment 41, wherein the disease or ataxia of the bone and joint is osteoporosis, rheumatoid arthritis, or bone cancer. 47. The method according to Embodiment 39, wherein the disease or disorder is diabetes, cancer, viral infection, or bacterial infection. 48. The method according to Embodiment 47, wherein the viral infection is a flavivirus infection or a coronavirus infection. 49. The method according to Embodiment 47, wherein the bacterial infection is a lung infection, gastrointestinal infection, skin infection, ear infection, or sepsis. 50. The method according to any one of embodiments 39 to 49, further comprising administering a therapeutic agent to a patient. 51. The method according to Embodiment 50, wherein the therapeutic agent is an anti-inflammatory agent. 52. The method according to Embodiment 51, wherein the anti-inflammatory agent is selected from the group consisting of mesalazine, naproxen, ibuprofen, diclofenac, celecoxib, sulindac, oxaprozin, piroxicam, indomethacin, meloxicam, fenoprofen, diflunisal, etodolac, ketrolac tromethamine, meclofename, nabumetone, salsalate, or any combination thereof. 53. The method according to Embodiment 50, wherein the therapeutic agent is an immune checkpoint inhibitor. 54. A compound or salt according to any one of Embodiments 1 to 37, used to treat or prevent a disease or disorder associated with abnormal aromatic hydrocarbon receptor (AHR) activity. 55. Uses of any one of the compounds or salts described in Embodiments 1 to 37 for the treatment or prevention of diseases or disorders related to abnormal aromatic hydrocarbon receptor (AHR) activity.

[0088] [Examples] Abbreviation Preparation of 3-amino-6-chloro-2-iodoisonicotinic acid (A-2) JPEG2026515766000047.jpg218170 JPEG2026515766000048.jpg331705-amino-2-chloroisonicotinic acid (1.0 g, 5.82 mmol) was added to a solution of DMF (30 mL) with NIS (2.6 g, 11.64 mmol). The reaction mixture was stirred at 60°C for 48 hours. The desired molecular weight was detected by LC-MS. Next, the residue was quenched with water, extracted with siRNA, washed with saturated brine, dried over Na2SO4, filtered and concentrated to obtain yellow solid A-2 (830.0 mg, yield: 48.0%). LCMS(ESI):C6H4ClIN2O2[M+H] + The calculated value for m / z was 299.4, and the measured value was 299.0.

[0089] Preparation of (S)-3-amino-6-chloro-N-(1-hydroxypropan-2-yl)-2-iodoisonicotinamide (A-4) To a 30 mL solution of A-2 (830.0 mg, 2.78 mmol) in DMF, EDCI (640.0 mg, 3.33 mmol), HOBT (440.0 mg, 3.33 mmol), and TEA (420.0 mg, 4.17 mmol) were added. After 30 minutes, A-3 (230.0 mg, 3.05 mmol) was added, and the reaction mixture was stirred at 60°C for 12 hours. The desired molecular weight was detected by LC-MS. The residue was extracted with  (50 mL), the organic layer was washed with saline, dried over Na2SO4, and concentrated by filtration. The residue was purified by silica gel chromatography (elution with PE / Â, from 100 / 0 to 50 / 50 in 30 minutes) to obtain a brown solid A-4 (530.0 mg, yield: 53.6%). LCMS(ESI):C9H 11 ClIN3O2[M+H] + The calculated value for m / z was 356.5, and the measured value was 356.1.

[0090] Preparation of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-iodopyrido[3,4-d]pyrimidine-4(3H)-one (A-6) Triethoxymethane (330.0 mg, 2.23 mmol) was added to a solution of A-4 (530.0 mg, 1.49 mmol) in AcOH (50 mL). The mixture was heated in a microwave reactor under an N2 atmosphere at 150°C for 1 hour. The desired molecular weight was detected by LC-MS. The residual mixture was then quenched in ice water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (elution with PE / ethyl acetate, 100 / 0 to 80 / 20 over 30 minutes) to obtain brown solid A-6 (230.1 mg, yield: 42.2%). LC-MS (ESI):C 10 H9ClIN3O2[M+H] + The calculated value for m / z was 366.5, and the measured value was 366.0.

[0091] Preparation of (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazole-4-yl)pyrido[3,4-d]pyrimidine-4(3H)-one (A) To a solution of A-6 (230.1 mg, 0.86 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL), A-7 (115.3 mg, 0.94 mmol), Pd(dppf)Cl2 (125.7 mg, 0.17 mmol), and K2CO3 (237.7 mg, 1.72 mmol) were added. The mixture was stirred at 80°C for 12 hours under an N2 atmosphere. The desired molecular weight was detected by LC-MS. The residue was extracted with siRNA (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (elution with PE / Â, from 100 / 0 to 80 / 20 over 30 minutes) to obtain brown solid A (124.9 mg, yield: 62.1%). LCMS(ESI):C 14 H 14 ClN5O2[M+H] + The calculated value for m / z was 320.7, and the measured value was 320.2.

[0092] Preparation of compounds 1-13 JPEG2026515766000052.jpg44170 Intermediate A (1.0 eq) was dissolved in dioxane (6 mL) / H2O (2 mL) and boric acid or borate ester (1.1 eq), K2CO3 (2.0 eq), and Pd(dppf)Cl2 (0.05 eq) were added. The reaction mixture was stirred at 90°C for 3 hours. The desired molecular weight was detected by LC-MS. The residue was quenched with ice water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over Na2SO4, and concentrated under vacuum. The residue was concentrated in C 18 The final compound was obtained by eluting with column chromatography (ACN-H2O (0.1% NH3.H2O), eluting from 5 / 95 to 80 / 20 over 30 minutes).

[0093] Preparation of compounds 14-17 In a reaction vial, intermediate A (1.0 eq), cyclic amine (1.5 eq), and DIEA (3.0 eq) were dissolved in DMSO (3 mL). The mixture was reacted with microwaves at 170°C for 4 hours. The desired molecular weight was detected by LC-MS. The residue was quenched with ice water and extracted with pharmaceutically acceptable ammonium compounds. The organic phases were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was then converted to C 18 The final compound was obtained by eluting with column chromatography (ACN-H2O (0.1% NH3.H2O), eluting from 5 / 95 to 80 / 20 in 30 minutes).

[0094] The compounds listed in the table below were prepared in the same manner as described above. JPEG2026515766000054.jpg213170JPEG2026515766000055.jpg209170JPEG20265157660 00056.jpg188170JPEG2026515766000057.jpg151170JPEG2026515766000058.jpg151170 JPEG2026515766000059.jpg175170JPEG2026515766000060.jpg163170JPEG20265157660 00061.jpg178170JPEG2026515766000062.jpg169170JPEG2026515766000063.jpg109170

[0095] Preparation of 1-methyl-1H-pyrazole-4-carboxymidamide (AA-2) JPEG2026515766000064.jpg441701-methyl-1H-pyrazole-4-carbonitrile, i.e., AA-1 (4.0 g, 37.37 mmol), was dissolved in methanol (40 mL) and 28% sodium methoxide was dissolved in methanol (6.6 mL). After stirring at 25°C for 3 hours, ammonium chloride (12.0 g, 226.42 mmol) was added. The mixture was stirred at 90°C for 1 hour. The desired molecular weight was detected by LC-MS. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was purified by flash chromatography (elution with DCM / MeOH, from 100 / 0 to 70 / 30 over 20 minutes) to obtain a white solid AA-2 (4.0 g, yield: 86.3%). LCMS(ESI):C5H9N4[M+H] + The calculated m / z value was 125.1, and the measured value was 125.2.

[0096] Preparation of 6-hydroxy-2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-4-carboxylic acid (AA-4) JPEG2026515766000065.jpg58170 To a solution of AA-3 (8.2 g, 38.71 mmol) in 80 mL of water, a solution of sodium hydroxide (3.1 g, 77.42 mmol) in 3 mL of water was added. After 10 minutes, AA-2 (4.0 g, 32.24 mmol) was added. The reaction mixture was stirred at 70°C for 16 hours. The desired molecular weight was detected by LC-MS. After cooling to room temperature, the reaction solution was adjusted to pH=4 with 6 M HCl. The solid was filtered and collected to obtain the brown solid product AA-4 (3.0 g, yield: 42.3%). LCMS(ESI):C9H9N4O3[M+H] + The calculated value for m / z was 221.1, and the measured value was also 221.1.

[0097] Preparation of 6-hydroxy-2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-4-carboxylate methyl (AA-5) JPEG2026515766000066.jpg49170AA-4 (3.0 g, 13.63 mmol) was dissolved in MeOH (30 mL) and sulfuric acid (2 mL) was added. The mixture was stirred at 70°C for 2 hours. The desired molecular weight was detected by LC-MS. The reaction mixture was filtered and the solid was collected to obtain the white solid product AA-5 (2.8 g, yield: 97.7%). LCMS(ESI):C 10 H 11 N4O3[M+H] + The calculated value for m / z was 235.1, and the measured value was 235.2.

[0098] Preparation of 6-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-4-carboxylate methyl (AA) To a solution of AA-5 (2.8 g, 11.96 mmol), phosphorus oxychloride (60 mL) was added. The mixture was stirred at 100°C for 1 hour. The desired molecular weight was detected by LC-MS. The reaction solution was concentrated under reduced pressure, adjusted to pH=7 with saturated sodium bicarbonate solution, and extracted with siRNA. The organic layer was concentrated to obtain the crude product AA (2.2 g, yield: 93.9%) as a white solid. LC-MS (ESI):C 10 H 10 N4O3[M+H] + The calculated m / z value was 253.0, and the measured value was 253.2.

[0099] Preparation of compound (C-3) Compound (B1-x) (1.0 eq), compound (C-1) (1.2 eq), potassium acetate (1.5 eq), and Pd(dppf)Cl2 (0.01 eq) were dissolved in a solution of 1,4-dioxane (10 mL). The reaction mixture was stirred at 130 °C for 16 hours under an N2 atmosphere. The desired molecular weight was detected by LC-MS, and compound (AA) (0.8 eq), potassium carbonate (2.0 eq), Pd(dppf)Cl2 (0.01 eq), and H2O (3 mL) were added. The reaction mixture was stirred at 100 °C for 16 hours under an N2 atmosphere. The desired molecular weight was detected by LC-MS. The solvent was removed under vacuum. The residue was purified by flash chromatography (elution with DCM / MeOH, from 100 / 0 to 90 / 10 in 30 minutes) to obtain compound (C-3).

[0100] Preparation of compound (C-4) JPEG2026515766000069.jpg52170 Sodium hydroxide (2.0 eq) was added to a solution of compound (C-3) (1.0 eq) (methanol:THF:H2O = 6:3:1, 10 mL). The mixture was stirred at room temperature for 4 hours. The desired molecular weight was detected by LC-MS. The reaction solution was concentrated under reduced pressure and adjusted to pH = 4 with 2N HCl. The solution was filtered, and the solid was collected to obtain compound (C-4).

[0101] Preparation of Compounds in this Disclosure JPEG2026515766000070.jpg48170 Compound (C-4) (1.0 eq) was dissolved in DMF (5 mL), to which HATU (2.0 eq) and DIEA (3.0 eq) were added. After 30 minutes, compound (C-5) was added. The reaction mixture was stirred at room temperature for 2 hours. The desired molecular weight was detected by LC-MS. The reaction mixture was quenched with H2O, extracted with siRNA, washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (eluted with DCM / MeOH, from 100 / 0 to 90 / 10 in 30 minutes) to obtain the desired compound.

[0102] Preparation of compound (D-2) JPEG2026515766000071.jpg49170 Compound (D-1) (1.2 eq) and DIEA (3.0 eq) were added to a solution of compound AA (1.0 eq) in DMF (5 mL). The reaction mixture was stirred at 80°C for 2 hours. The desired molecular weight was detected by LC-MS. The reaction mixture was quenched with H2O, extracted with ethyl acetate, washed with saturated saline, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (eluted with DCM / MeOH, from 100 / 0 to 90 / 10 in 30 minutes) to obtain compound (D-2).

[0103] Preparation of compound (D-3) JPEG2026515766000072.jpg56170 Sodium hydroxide (2.0 eq) was added to a solution of compound (D-2) (1.0 eq) (methanol:THF:H2O = 6:3:1, 10 mL). The mixture was stirred at room temperature for 4 hours. The desired molecular weight was detected by LC-MS. The reaction solution was concentrated under reduced pressure and adjusted to pH = 4 with 2N HCl. The solution was filtered, and the solid was collected to obtain compound (D-3).

[0104] Preparation of Compounds in this Disclosure JPEG2026515766000073.jpg51170 Compound (D-3) (1.0 eq) was added to a solution of DMF (5 mL) with HATU (2.0 eq) and DIEA (3.0 eq). After 30 minutes, compound (C-5) was added. The reaction mixture was stirred at room temperature for 2 hours. The desired molecular weight was detected by LC-MS. The reaction mixture was quenched with H2O, extracted with Âi, washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (eluted with DCM / MeOH, from 100 / 0 to 90 / 10 in 30 minutes) to obtain the desired compound.

[0105] The compounds listed in the table below were prepared in the same manner as described above. JPEG2026515766000074.jpg195170JPEG2026515766000075.jpg255156JPEG2026515766000076.jpg123170 Preparation of compound (E-2) JPEG2026515766000077.jpg57170 Compound (C-4) (1.0 eq) was dissolved in DMF (5 mL), to which HATU (2.0 eq) and DIEA (3.0 eq) were added. After 30 minutes, compound (E-1) was added. The reaction mixture was stirred at room temperature for 2 hours. The desired molecular weight was detected by LC-MS. The reaction mixture was quenched with H2O, extracted with ethyl acetate, washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (eluted with DCM / MeOH, from 100 / 0 to 90 / 10 in 30 minutes) to obtain compound (E-2).

[0106] Preparation of compound (X) JPEG2026515766000078.jpg52170 Compound (E-2) (1.0 eq) was dissolved in DMF (5 mL), to which compound (E-5) (1.2 eq) and K2CO3 (3.0 eq) were added. The reaction mixture was stirred at 80°C for 2 hours. The desired molecular weight was detected by LC-MS. The reaction mixture was quenched with H2O, extracted with ethyl acetate, washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (elution with DCM / MeOH, from 100 / 0 to 90 / 10 in 30 minutes) to obtain compound (X).

[0107] Preparation of compound (F-2) JPEG2026515766000079.jpg56170 Compound (D-3) (1.0 eq) was added to a solution of DMF (5 mL) with HATU (2.0 eq) and DIEA (3.0 eq). After 30 minutes, compound (F-1) was added. The reaction mixture was stirred at room temperature for 2 hours. The desired molecular weight was detected by LC-MS. The reaction mixture was quenched with H2O, extracted with ethyl acetate, washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (eluted with DCM / MeOH, from 100 / 0 to 90 / 10 in 30 minutes) to obtain the desired compound (F-2).

[0108] Preparation of compound (X) JPEG2026515766000080.jpg55170 Sodium hydroxide (2.0 eq) was added to a solution of compound (F-5) (1.0 eq) (MeOH:THF:H2O = 6:3:1, 10 mL). The mixture was stirred at room temperature for 4 hours. The desired molecular weight was detected by LC-MS. The reaction solution was concentrated under reduced pressure and adjusted to pH = 4 with 2N HCl. The solution was filtered, and the solid was collected to obtain compound (X).

[0109] The compounds listed in the table below were prepared in the same manner as described above. JPEG2026515766000081.jpg207170JPEG2026515766000082.jpg178170

[0110] synthesis biological measurements AhR reporting gene analysis was performed according to the protocol of the Human Aromatic Hydrocarbon Receptor (AhR) Reporting Gene Analysis System (INDIGO Bioscience, #IB06001-32). AhR reporting cells were thawed and pre-cultured in cell recovery medium (CRM) for 6 hours. Next, the medium was removed and the cells were incubated for 24 hours in compound screening medium (CSM) supplemented with 200 μM kynurenic acid if the test compound was absent (negative control) or present at 10 nM. For the positive inhibitory control, cells activated with 200 μM kynurenic acid were incubated in the presence of literature-listed AHR antagonists. Alternatively, inactivated cells were used as the positive inhibitory control. After 24 hours of incubation, the medium was removed and luciferase detection reagent (LDR) was added. Firefly luciferase activity was quantified using a plate reader. Results were standardized by positive and negative controls.

[0111] The results of AHR inhibition at 10 nM of the compounds disclosed herein are shown in the table below. JPEG2026515766000083.jpg137170

Claims

1. A compound having the structure of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, However, L is a bond, C(O), C ２－３ Alkenylene group or C ２－３ It is an alkynylene group, Ar １ is a phenyl group, C ３－８ A 4- to 8-membered aromatic heterocycle or non-aromatic heterocycle having a cycloalkyl group or 1 to 3 ring heteroatoms selected from O, N, and S, and further, Ar １ is one or two R Ａ It may be replaced with, R Ａ is each independently halogen, OH, =O, CN, C １－６ alkyl, C １－６ haloalkyl, C １－６ hydroxyalkyl, C １－６ alkoxy, C １－６ haloalkoxy, cyclopropyl, NR Ｎ R Ｎ , C(O)NR Ｎ R Ｎ , CO ２ R Ｎ , C(O)R Ｎ or SO ２ -C １－６ alkyl, R Ｎ Each is independently H or C １－６ It is alkyl, Ar ２ Ar is a 5- to 10-membered aromatic or non-aromatic ring having 0 to 3 ring heteroatoms selected from O, N, and S, and Ar ２ This is one, two, or three R Ｂ It may be replaced with, R Ｂ These are, independently, halogen, CN, and C. １－６ Alkyl, OH, =O, C １－６ Hydroxyalkyl, C(O)R Ｎ CO ２ R Ｎ , C(O)NR Ｎ R Ｎ , Het, C(O)-C ０－２ Alkylene-Het, or N(R) Ｎ )-C ０－３ Alkylene-C(O)-C ０－３ It is alkylene-Het. Het is a 4- to 8-membered aromatic or aromatic ring having 0 to 3 ring heteroatoms selected from N, O, and S, and 1, 2, or 3 R Ｃ It may be replaced with, R Ｃ These are, independently, halogen, OH, =O, CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, NR Ｎ R Ｎ , C(O)NR Ｎ R Ｎ CO ２ R Ｎ , C(O)R Ｎ or SO ２ -C １－６ It is alkyl, R １ C １－６ Alkyl alkyl group, C １－６ Alkilen-R Ｄ , C １－６ Alkylene-C(O)R Ｄ , C １－６ Alkilen-NHSO ２ Cyclopropyl group, or C １－６ Alkylene-NR Ｎ -C(O)R Ｎ And, R Ｄ is OR Ｎ Or NR Ｎ R Ｎ And, The conditions are as follows: (i) In a compound of formula (I), if L is a bond, then (a) Ar ２ is Het, C(O)-C ０－２ Alkylene-Het and N(R) Ｎ )-C ０－３ Alkylene-C(O)-C ０－３ at least one R selected from alkylene-Het Ｂ (b) Ar ２ It comprises an 8- to 10-membered bicyclic aromatic ring or a non-aromatic ring having 1 to 3 ring heteroatoms, and 0 to 3 R Ｂ It is replaced by (ii) In the compound of formula (II), if L is a bond, Ar ２ is a phenyl group or a 6-membered aromatic heteroring, and Ar ２ is one R Ｂ It is replaced by, and furthermore, R Ｂ If it is Het, then (a) Het can be transmitted through the carbon atoms of Het to Ar ２ (b) R is bonded to (b) one, two or three Het Ｃ It is replaced by A compound or salt.

2. R Ｎ Each is independently either H or methyl. The compound or salt according to claim 1.

3. R １ C １－６ Alkyl alkyl group or C １－６ Alkylene group-R Ｄ That is, The compound or salt according to claim 1 or 2.

4. R Ｄ is OR Ｎ or a salt thereof, the compound according to claim 3.

5. The compound or salt according to claim 3.

6. The compound or salt according to any one of claims 1 to 42.

7. Having the structure of formula (Ia), The compound or salt according to claim 1 or 2.

8. Having the structure of formula (IIa), The compound or salt according to claim 1 or 2.

9. Ar １ This is a heterocyclic group containing a total of 4 to 8 ring atoms, where 1 to 3 of these ring atoms are selected from O, N, and S. The compound or salt according to any one of claims 1 to 8.

10. Ar １ is one or two R Ａ It is replaced by The compound or salt according to any one of claims 1 to 9.

11. Ar １ is non-substitutional, The compound or salt according to claim 9.

12. Ar １ is a phenyl group, C ３－８ It is a cycloalkyl group or pyrazole. The compound or salt according to any one of claims 1 to 11.

13. Having the structure of formula (Ib), The compound or salt according to any one of claims 1 to 7, 9, and 10.

14. Having the structure of formula (IIb), The compound or salt according to any one of claims 1 to 6, 8, 9, and 10.

15. At least one R Ａ is C １－６ alkyl group, C １－６ haloalkyl group or C １－６ alkoxy group, or at least one R Ａ is a methyl group, The compound or salt according to any one of claims 9, 10, and 12 to 14.

16. Having the structure of formula (Ic), The compound or salt according to claim 1 or 2.

17. Having the structure of formula (IIc), The compound or salt according to claim 1 or 2.

18. L is a combination. The compound or salt according to any one of claims 1 to 17.

19. L is C ２－３ It is an alkenylene group. The compound or salt according to any one of claims 1 to 17.

20. L is C ２－３ It is an alkynylene group. The compound or salt according to any one of claims 1 to 17.

21. Ar ２ is a phenyl group or a naphthyl group. The compound or salt according to any one of claims 1 to 20.

22. Ar ２ This is a 5- to 10-membered aromatic or aromatic ring having 1 to 3 ring heteroatoms selected from O, N, and S. The compound or salt according to any one of claims 1 to 20.

23. Ar ２ This is an 8- to 10-membered bicyclic aromatic or aromatic ring having 1 to 3 ring heteroatoms selected from O, N, and S. The compound or salt according to claim 22.

24. Ar ２ These are isoindoline, tetrahydroisoquinoline, tetrahydroquinoline, indazole, or pyrazolo[4,3-c]pyridine. The compound or salt according to claim 23.

25. Ar ２ is non-substitutional, The compound or salt according to any one of claims 1 to 24.

26. Ar ２ This is one, two, or three R Ｂ It is replaced by The compound or salt according to any one of claims 1 to 24.

27. at least one R Ｂ is halogen, CN, C １－６ Alkyl, OH, =O, C １－６ Hydroxyalkyl, C(O)R Ｎ CO ２ R Ｎ or C(O)NR Ｎ R Ｎ That is, The compound or salt according to claim 26.

28. at least one R Ｂ is Het, C(O)-C ０－２ Alkylene-Het or N(R) Ｎ )-C ０－３ Alkylene-C(O)-C ０－３ It is alkylene-Het. The compound or salt according to claim 26 or 27.

29. Het contains a phenyl group, pyridine, pyridine-2-one, pyrimidine, piperidine, piperazine, morpholine, azepane, 1,4-diazepane, pyrrolidine, tetrahydropyran, dihydropyran, or 8-oxa-3-azabicyclo[3.2.1]octane. The compound or salt according to claim 28.

30. Het is a non-substitution. The compound or salt according to claim 28 or 29.

31. Het has one or two R Ｃ It is replaced by The compound or salt according to any one of claims 28 or 29.

32. at least one R Ｃ is halogen, OH, =O, C １－６ Alkyl, CO ２ R Ｎ , NR Ｎ R Ｎ or SO ２ -C １－６ It is alkyl. The compound or salt according to claim 31.

33. at least one R Ｃ F, Cl, OH, =O, methyl, CO ２ H, NH ２ or SO ２ CH ３ That is, The compound or salt according to claim 32.

34. Het is, The compound or salt according to claim 28 or 29.

35. Ar ２ teeth, The compound or salt according to any one of claims 1 to 20.

36. Ar ２ teeth, The compound or salt according to any one of claims 1 to 20.

37. The compounds listed in Table 1 or their pharmaceutically acceptable salts.

38. A compound or salt according to any one of claims 1 to 37, and a pharmaceutically acceptable excipient, Pharmaceutical preparations.

39. A method for treating or preventing a disease or disorder related to abnormal aromatic hydrocarbon receptor (AHR) activity in a subject, The method comprises administering to the subject a therapeutically effective amount of the compound or salt described in any one of claims 1 to 37. method.

40. The aforementioned disease or disorder is an inflammatory disease or disorder. The method according to claim 39.

41. The aforementioned diseases or disorders include diseases or disorders of the gastrointestinal tract, skin, lungs, central nervous system, pancreas, eyes, bones, and joints, neuroinflammatory diseases, or neurodegenerative diseases. The method according to claim 39.

42. Gastrointestinal disorders or disorders are selected from the group consisting of colitis, inflammatory bowel disease, Crohn's disease, celiac disease, necrotizing enterocolitis, irritable bowel syndrome, chronic idiopathic constipation, traveler's diarrhea, and colorectal cancer. The method according to claim 41.

43. The aforementioned skin disease or disorder is selected from the group consisting of atopic dermatitis, acne, psoriasis, and vitiligo. The method according to claim 41.

44. The aforementioned eye diseases or ataxias include abnormal eye movements, inflammatory eye diseases, autoimmune eye diseases, hereditary eye diseases, degenerative eye diseases, neovascular eye diseases, dry and wet age-related macular degeneration ("AMD"), uveitis, retinitis pigmentosa ("RP"), primary open-angle glaucoma ("POAG"), primary congenital glaucoma, Bethet's disease, or Leber's congenital amaurosis ("LCA"). The method according to claim 41.

45. The aforementioned lung disease or disorder is pulmonary fibrosis, asthma, or chronic obstructive pulmonary disease. The method according to claim 41.

46. The aforementioned bone and joint disease or ataxia is osteoporosis, rheumatoid arthritis, or bone cancer. The method according to claim 41.

47. The aforementioned disease or disorder is diabetes, cancer, viral infection, or bacterial infection. The method according to claim 39.

48. The aforementioned viral infection is either a flavivirus infection or a coronavirus infection. The method according to claim 47.

49. The aforementioned bacterial infections include lung infections, gastrointestinal infections, skin infections, ear infections, or sepsis. The method according to claim 47.

50. This further includes administering therapeutic agents to patients. The method according to any one of claims 39 to 49.

51. The aforementioned therapeutic agent is an anti-inflammatory agent. The method according to claim 50.

52. The anti-inflammatory agent is selected from mesalazine, naproxen, ibuprofen, diclofenac, celecoxib, sulindac, oxaprozin, piroxicam, indomethacin, meloxicam, fenoprofen, diflunisal, etodolac, ketrolac tromethamine, meclofename, nabumetone, sarsalate, or any combination thereof. The method according to claim 51.

53. The aforementioned therapeutic agent is an immune checkpoint inhibitor. The method according to claim 50.

54. Used to treat or prevent diseases or disorders associated with abnormal aromatic hydrocarbon receptor (AHR) activity, The compound or salt according to any one of claims 1 to 37.

55. Uses of any one of the compounds or salts described in claims 1 to 37 for treating or preventing diseases or disorders related to abnormal aromatic hydrocarbon receptor (AHR) activity.

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