Pyrido [3, 4-D] pyrimidinone and pyrimidine aromatic hydrocarbon receptor antagonist and application thereof

Abstract

Disclosed herein are compounds useful as modulators of the aromatic hydrocarbon receptor (AHR). Further disclosed herein are methods of treating diseases and disorders, such as cancer and viral infections, using the compounds disclosed herein.

Description

Technical Field

[0001] This disclosure relates to compounds used as antagonists of aryl hydrocarbon receptor (AHR) activity, pharmaceutical formulations thereof, and methods of using the compounds to treat diseases and disorders such as cancer. Background Technology

[0002] Aromatic hydrocarbon receptors (AHRs) are ligand-dependent transcription factors that regulate gene expression in a variety of cells, including epithelial and immune cells. Emerging evidence suggests 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 cell lines, indicating that AHRs are activated in tumors and promote tumor growth. Immune evasion is increasingly recognized as a hallmark of cancer. Links between AHRs and the immune system have been identified, and AHRs are considered immunosuppressive effectors of different types of immune cells. Certain cancers can evade immune recognition via AHR signaling pathways. Overall, modulating AHR activity in intratumoral cancer cells, immune cells, stromal cells, fibroblasts, and endothelial cells can slow disease progression.

[0003] AHR is expressed at high levels and remains persistently active in hematologic malignancies (such as T-cell leukemia and lymphoma) and solid tumors (such as glioblastoma, ovarian cancer, lung cancer, liver cancer, and head and neck cancer). Detecting AHR activity in the tumor microenvironment is considered a potentially effective diagnostic indicator of tumor invasiveness. Depending on the cancer type, outcomes in both types are associated with AHR activity and prognosis. Evidence suggests that in hormone-dependent breast cancer, AHR activation is associated with reduced invasiveness and a better prognosis. Conversely, higher 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 confirmed the role of AHR as a regulator of intrinsic, innate, and adaptive immune responses to viral infections. The activation of AHR is thought to affect host resistance to a variety of viral infections, including influenza, coronaviruses (such as SARS-CoV-1, SARS-CoV-2, and MERS-CoV), flaviviruses (such as Zika virus), retroviruses (such as HIV), and herpesviruses.

[0005] Therefore, new compounds are needed as AHR antagonists to provide new and effective therapies for diseases and disorders such as cancer and viral infections. Summary of the Invention

[0006] This article provides compounds of formula (I) or formula (II): (I) or (II) The substituents are discussed below. These compounds are useful as aromatic hydrocarbon acceptor modulators. Detailed Implementation

[0007] This article provides Equation (I): (I) or (II): (II) compounds, wherein L and R 1 R N Ar 1 and Ar 2 As described herein, they can act as modulators of AHR activity. For example, the compounds disclosed herein can increase or decrease AHR activity.

[0008] The compounds disclosed herein This article provides compounds having the structure of formula (I) or formula (II) or pharmaceutically acceptable salts thereof: (I) or (II) in, L represents the bond, C(O), C 2-3 imide or C 2-3 Ethyne group; Ar 1 For phenyl, C 3-8 Cycloalkyl or 4- to 8-membered aromatic heterocycles or non-aromatic heterocycles having 1 to 3 cyclic heteroatoms selected from O, N, and S, and Ar 1 The optional replacement has one or two Rs. A ; Each R A 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; Each R N Independently H or C 1-6 alkyl; Ar 2 It is a 5- to 10-membered aromatic or non-aromatic ring having 0 to 3 cyclic heteroatoms selected from O, N, and S, and Ar 2 The optional replacement can be one, two, or three Rs. B; Each R B Independent of 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 cyclic heteroatoms selected from N, O, and S, and optionally substituted with 1, 2, or 3 R atoms. C ; Each R C Independently halogen, OH, =O, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NR N R N C(O)NR N R N CO2R N C(O)R N or SO2-C 1-6 alkyl; R 1 C 1-6 Alkyl, C 1-6 Alkylene-R D C 1-6 Alkylene-C(O)R D C 1-6 Alkylene-NHSO2 cyclopropyl or C 1-6 Alkylene-NR N -C(O)R N ;as well as R D OR N or NR N R N ; The conditions are: (i) For compounds of formula (I), when L is a bond, then (a) Ar 2 The substitute has at least one selected from Het, C(O)-C 0-2 Alkylene-Het and N(R) N )-C 0-3Alkylene-C(O)-C 0-3 R of alkylene-Het B , or (b)Ar 2 This includes 8- to 10-membered bicyclic aromatic or non-aromatic rings with 1 to 3 cyclic heteroatoms, and with 0 to 3 R substitutions. B ;as well as (ii) For compounds of formula (II), when L is a bond, Ar 2 It is a phenyl or a 6-membered aromatic heterocycle, Ar 2 Replacement has 1 R B And R B When it is Het, then (a) Het is attached to Ar via the carbon atom of Het. 2 Or (b) Het replaces one, two or three Rs. C .

[0009] In some cases, each R N Independently, it is H or CH3. In some cases, R N For H. In some cases, R N C 1-6 Alkyl group. In some cases, R N It is a methyl group.

[0010] In some cases, R 1 C 1-6 Alkyl or C 1-6 Alkylene-R D In some cases, R D OR N In some cases, R D It is OH. In some cases, R 1 for , , ,or In some cases, R 1 for In some cases, R 1 for .

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

[0012] In many cases, Ar 1 It can be a heterocyclic group containing a total of 4 to 8 ring atoms, of which 1 to 3 ring atoms are selected from O, N, and S. In many cases, Ar 1 For phenyl, C 3-8Cycloalkyl or pyrazole. In some cases, Ar 1 It is unreplaced. In some cases, Ar 1 Replacement has 1 or 2 R A For example, at least one R A C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkyl group. In some cases, at least one R A It is a methyl group.

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

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

[0015] In many cases, L represents the bond. In some cases, L represents the C bond. 2-3 Alkenyl group. In some cases, L is C. 2-3 Alynyl group.

[0016] In various implementations, Ar 2 It is phenyl or naphthyl. In various embodiments, Ar 2 It is a 5- to 10-membered aromatic or non-aromatic ring having 1 to 3 cyclic heteroatoms selected from O, N, and S. In some cases, Ar 2 It is isoindoline, tetrahydroisoquinoline, tetrahydroquinoline, indazole or pyrazolo[4,3- c ]Pyridine. In various embodiments, Ar 2 It is unreplaced. In some cases, Ar 2 The replacement has 1, 2 or 3 Rs. B 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 many cases, at least one R B For Het, C(O)-C 0-2 Alkylene-Het or N(R) N )-C 0-3 Alkylene-C(O)-C 0-3Alkylene-Het. In some cases, Het includes phenyl, pyridine, pyridin-2-one, pyrimidine, piperidine, piperazine, morpholine, azepane, 1,4-diazacycloheptane, pyrrolidine, tetrahydropyran, dihydropyran, or 8-oxa-3λ. 2 -Azabicyclo[3.2.1]octane. In some cases, Het is unsubstituted. In many cases, Het is substituted with one or two R atoms. C In some cases, at least one R C Halogen, OH, =O, C 1-6 Alkyl, CO2R N NR N R N or SO2-C 1-6 Alkyl group. In some cases, Het is... , , , , , , , , , , , , , , , , , , , , , or .

[0017] In various cases used for compounds of formula (I), Ar 2 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0018] In various cases used for compounds of formula (II), Ar 2 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0019] The specific compounds disclosed herein include those listed in Table 1 or their pharmaceutically acceptable salts.

[0020] Table 1.

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033] Unless otherwise stated, the structures described herein are also intended to include all isomeric forms of such structures (e.g., enantiomers, diastereomers, cis-trans, conformations, and rotations). For example, unless only one isomer is specifically indicated, this disclosure covers every asymmetric center. R and S Configuration, ( Z )and( EDouble bond isomers, and ( Z )and( E Conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as enantiomers, diastereomers, cis / trans, and mixtures of conformations and rotations, are all within the scope of this disclosure. In some cases, the compounds disclosed herein are stereoisomers. "Stereoisomer" refers to a compound with one or more stereocenters of different chirality. Stereoisomers include enantiomers and diastereomers. The compounds disclosed herein may exist as single stereoisomers or as mixtures of stereoisomers. Unless otherwise discussed, the stereochemistry of the compounds shown herein refers to relative stereochemistry, not absolute stereochemistry. As indicated herein, a single stereoisomer, diastereomer, or enantiomer means a compound comprising at least 50% of the indicated stereoisomer, diastereomer, or enantiomer, and in some cases, at least 90% or 95% of the indicated stereoisomer, diastereomer, or enantiomer.

[0034] The compounds disclosed in this article can be found in sp. 3 The carbon atoms can have any stereochemical configuration. In some cases, the compounds of this disclosure are optically pure. As used herein, "optically pure" means that when multiple stereochemical configurations are possible, the compound exists in only one enantiomer (detection limit). In many cases, the chiral moiety present in the compounds of this disclosure is derived from native or non-native amino acids or sugars.

[0035] Unless otherwise stated, all tautomer forms of the compounds disclosed herein are within the scope of this disclosure.

[0036] Furthermore, unless otherwise stated, the structures described herein are also intended to encompass compounds distinguished solely by the presence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or where carbon is enriched... 13 C- or 14 Compounds having the structure disclosed herein, other than carbon substitution of C-, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. Such compounds, especially deuterium analogs, can also be used for therapeutic applications. Therefore, deuterated compounds or salts of formula (I) in which one or more hydrogen isotopes are substituted with deuterium are further disclosed herein.

[0037] The compounds disclosed herein are defined by their chemical structure and / or chemical name. When a compound is mentioned by both its chemical structure and chemical name, and there is a conflict between the two, the chemical structure shall determine the identity of the compound.

[0038] As used herein, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group containing 1 to 30 carbon atoms, such as 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. The term Cn signifies that an alkyl group has "n" carbon atoms. For example, a C3 alkyl group refers to an alkyl group having 3 carbon atoms. 1-6 An alkyl group is defined as an alkyl group having a number of carbon atoms covering 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 6, 4 to 5, 4 to 6, 5 to 6, 1, 2, 3, 4, 5, and 6 carbon atoms). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), and tert-butyl (1,1-dimethylethyl). Unless otherwise specified, an alkyl group may be an unsubstituted alkyl group or a substituted alkyl group.

[0039] As used herein, "alkylene" refers to a divalent saturated aliphatic group. Term C n This means that an alkylene group has "n" carbon atoms. For example, C 1-6 Alkylene refers to an alkylene group having a number of carbon atoms that covers the entire range and all subgroups, as previously described for the "alkyl" group.

[0040] As used herein, the term "haloalkyl" refers to 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. Haloalkyl groups may be further substituted or unsubstituted, and in some cases, refer to haloalkyl groups having, for example, 1 to 6 carbon atoms, such as C6. 1-6 Halogenated alkyl groups.

[0041] As used herein, the term "hydroxyalkyl" refers to 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, hydroxyethyl, etc. Hydroxyalkyl groups may be further substituted or unsubstituted, and in some cases, refer to hydroxyalkyl groups having, for example, 1 to 6 carbon atoms, such as C 1-6 Hydroxyalkyl.

[0042] As used herein, the term "cycloalkyl" refers to an aliphatic cyclic hydrocarbon group containing 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 carbon atoms). The term C... nThis means that the cycloalkyl group has "n" carbon atoms. For example, a C5 cycloalkyl group is a cycloalkyl group having 5 carbon atoms in the ring. C3-C8 cycloalkyl groups are cycloalkyl groups having a number of carbon atoms covering the entire range (e.g., 3 to 8 carbon atoms) and all subgroups (e.g., 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 5 to 6, 5 to 7, 5 to 8, 6 to 7, 6 to 8, 6 to 8, 7 to 8, 3, 4, 5, 6, 7, and 8 carbon atoms). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl groups described herein can be isolated or fused to another cycloalkyl group, heterocycloalkyl group, aryl group, and / or heteroaryl group. When a cycloalkyl group is fused to another cycloalkyl group, each cycloalkyl group may contain 3 to 8 carbon atoms unless otherwise specified. Unless otherwise indicated, cycloalkyl groups may be unsubstituted or substituted.

[0043] As used herein, the term "heterocyclic group" refers to a monocyclic, fused-ring, spirocyclic, or bridged-ring system that may be saturated or contain one or more unsaturated units, or may be aromatic (i.e., heteroaryl) having a total number of 4 to 12 (or 4 to 10, or 4 to 8, as indicated in this disclosure) ring atoms, wherein 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 spirocyclic, the group may include, for example: a 4-membered ring with a spiro-5-membered ring, a 4-membered ring with a spiro-6-membered ring, a 4-membered ring with a spiro-7-membered ring, a 5-membered ring with a spiro-6-membered ring, a 5-membered ring with a spiro-7-membered ring, a 6-membered ring with a spiro-6-membered ring, a 6-membered ring with a spiro-7-membered ring, or a 7-membered ring with a spiro-7-membered ring; and each ring of the spirocyclic system may contain at least one cyclic heteroatom, or only one ring may contain at least one cyclic heteroatom, while the other ring may be 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 other cases, the heterocyclic group contains 6 ring members. Examples of heterocyclic groups include, but are not limited to: oxetanyl, azetidinyl, piperidinyl, piperazine, pyrrolyl, pyrazolyl, imidazoyl, azepanyl, diazepanyl, triazepanyl, oxazolidinyl, isoxazolidinyl, thiazoyl, isothiazolyl, oxazepanyl, thiazepanyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl (including, for example, 3- Morpholino, 4-morpholino), 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, pyrrolidin-2-one, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolyl, 3-thiazolyl, 4-thiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, and 1,3-dihydro-imidazolyl-2-one. In some cases, the heterocyclic group is oxetyl, azirhepyl, diazahepyl (e.g., 1,4-diazahepyl), azirhepyl, piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, or 4-piperidinyl), or pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, or 3-pyrrolidinyl). In some cases, the heterocyclic group is oxetyl, azirhepyl, diazahepyl, or azirhepyl. In some cases, the heterocyclic group is diazahepyl or azirhepyl. In some cases, the heterocyclic group is 1,4-diazahepyl or azirhepyl.In some cases, the heterocyclic group is 1,4-diazaheptanyl. In other cases, the heterocyclic group is azaheptanyl. The heterocyclic ring can be unsubstituted or substituted, as described herein.

[0044] As used herein, the term "aromatic ring" refers to a monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, and all ring atoms are carbocyclic atoms (i.e., aryl) or may include 1 to 3 heterocyclic atoms (i.e., heteroaryl). Unless otherwise stated, aromatic rings may be unsubstituted or substituted, as described elsewhere herein.

[0045] As used herein, the term "heteroaryl" refers to 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 stated, heteroaryl groups can be unsubstituted or substituted. Heteroaryl groups can be isolated (e.g., pyridinyl) or fused to another heteroaryl group (e.g., purinyl), cycloalkyl group (e.g., tetrahydroquinolinyl), non-aromatic heterocyclic group (e.g., dihydronaphthidyl), and / or aryl group (e.g., benzothiazolyl and quinolinyl). Examples of heteroaryl groups include, but are not limited to, pyrazolyl, thiophene, furanyl, pyridinyl, pyrroleyl, oxazolyl, quinolinyl, thiophene, isoquinolinyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazoleyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl. When a heteroaryl group is fused with another heteroaryl group, each ring may contain a total of 5 or 6 ring atoms and may contain 1 to 3 heteroatoms in its aromatic ring.

[0046] As used herein, the term "alkoxy" refers to the "-O-alkyl" group.

[0047] As used herein, the term “haloalkoxy” refers to the “-O-haloalkyl” group.

[0048] As used herein, the term "halogen / halogenated" refers to a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) group.

[0049] A “substituted” functional group (e.g., a substituted heterocyclic, aromatic, or heteroaryl group) is a functional group having at least one hydrogen atom replaced by a non-hydrogen group (i.e., a substituent). Examples of non-hydrogen groups (or substituents) include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, ether, aryl, heteroaryl, heterocycloalkyl, hydroxyl, oxygen (or oxo), alkoxy, ester, thioester, acyl, carboxyl, cyano, nitro, amino, mercapto, and halogen. Substitution is discussed in relation to a specific functional group or portion herein.

[0050] Pharmaceutically acceptable salts The compounds described herein may exist in free form or, where appropriate, in the form of salts. 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 the production process, for separation and purification purposes, and in some cases for isolating stereoisomers of the disclosed compounds or their intermediates.

[0051] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound that, within reasonable medical judgment, is suitable for contact with human and lower animal tissues without undue side effects (such as toxicity, irritation, allergic reactions, etc.) and in proportion to a reasonable benefit / risk ratio.

[0052] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.

[0053] When the compounds described herein contain a basic group, or are bioisosteres with sufficient basicity, acid addition salts can be prepared by the following steps: 1) reacting the purified compound in its free basic form with a suitable organic or inorganic acid; 2) separating the resulting salt. In practice, acid addition salts may be a more convenient form of use, as using the salt is equivalent to using its free basic form.

[0054] Examples of pharmaceutically acceptable and non-toxic acid addition salts include: amino salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts prepared using other methods commonly used in the art (such as ion exchange). Other pharmaceutically acceptable salts include: adipates, alginates, ascorbic acid salts, aspartate salts, benzenesulfonates, benzoates, hydrogen sulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionate, diglucuronide, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucohepanoate, glycerophosphates, glycolates, glucuronide, glycolates, hemisulfate, heptarate, hexanoate, hydrochloride, and hydrobromide. Hydroiodide, 2-hydroxy-ethanesulfonate, orotate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmitoleate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0055] When the compounds described herein contain a carboxyl group or a bioisostere with sufficient acidity, a base addition salt can be prepared by the following steps: 1) reacting the purified compound in its acidic form with a suitable organic or inorganic base; 2) separating the resulting salt. In practice, using a base addition salt may be more convenient, and using the salt form is equivalent to using its free acidic form. Salts derived from suitable bases include: alkali metal salts (e.g., sodium, lithium, and potassium), alkaline earth metal salts (e.g., magnesium and calcium), ammonium salts, and N2+ salts. + (C 1-4 Alkyl)4 salts. This disclosure also covers the quaternization of any basic nitrogen-containing group in the compounds disclosed herein. Such quaternization yields water-soluble, oil-soluble, or dispersible products.

[0056] Base addition salts include pharmaceutically acceptable metal salts and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium, and aluminum salts. Sodium and potassium salts are generally preferred. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium salts, quaternary ammonium salts, and amine cation salts formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions. 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 commonly used in medicinal chemistry due to their low toxicity and medical applicability. Examples include ammonia, ethylenediamine, N-methylglucosamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenylethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephedrine, dehydroabimethamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine, etc.

[0057] Other acids and bases, although not pharmaceutically acceptable on their own, can also be used to prepare salts that can serve as intermediates for obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

[0058] It should be understood that the compounds disclosed herein may exist in the form of mixtures / combinations of different pharmaceutically acceptable salts. Mixtures / combinations of compounds in their free form and pharmaceutically acceptable salts are also considered.

[0059] Pharmaceutical preparations This document also provides pharmaceutical formulations comprising an effective amount of the disclosed compound and one or more pharmaceutically acceptable excipients. As used herein, the terms "formulation" and "composition" are used interchangeably.

[0060] "Effective amount" includes "therapeutic effective amount" and "preventive effective amount." The term "therapeutic effective amount" refers to the amount that effectively treats and / or improves a subject's disease or condition. The term "preventive effective amount" refers to the amount that effectively prevents and / or significantly reduces a subject's chance of developing a disease or condition. As used herein, the terms "patient" and "subject" are used interchangeably and refer to animals such as dogs, cats, cows, horses, sheep (i.e., non-human animals) as well as humans. Specific patients or subjects are mammals (e.g., humans). Both the terms "patient" and "subject" include males and females.

[0061] As used herein, the term “excipient” means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient other than the active pharmaceutical ingredient (API), appropriately selected according to the intended form of administration and in accordance with standard pharmaceutical practice.

[0062] The disclosed compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. Furthermore, the compounds can be administered all at once (e.g., by rapid bolus injection), administered multiple times (e.g., by a series of tablets), or delivered substantially uniformly over a period of time (e.g., using transdermal delivery). It should also be noted that the dosage of the compounds can vary over time.

[0063] The compounds disclosed herein, and other pharmaceutically active compounds, may be administered to a subject or patient (if desired) via any suitable route, such as orally, topically, rectally, parenterally (e.g., subcutaneously, intravenously, intramuscularly, intrasternally, and intrathecally), or as an oral, inhaled, or nasal spray. Administration may provide systemic effects (e.g., enteric or parenterally). All methods of administering the pharmaceutically active agents that are available to those skilled in the art are contemplated. In some cases, the disclosed formulations may be administered orally or topically.

[0064] Suitable oral compositions or formulations according to this disclosure include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules 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 manufacturing.

[0065] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, 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 (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, and aroma agents.

[0066] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or a) fillers or extenders (such as starch, lactose, sucrose, glucose, mannitol, and silica), b) binders (such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic), c) humectants (e.g., glycerin), d) disintegrants (such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate), e) solution retarding agents (such as paraffin), f) absorption enhancers (such as quaternary ammonium compounds), g) wetting agents (such as cetyl alcohol and glyceryl monostearate), h) absorbents (such as kaolin and bentonite), and i) lubricants (such as 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 contain a buffer.

[0067] Similar solid compositions can also be used as fillers in soft and hard-filled 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, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field. They may optionally contain light-blocking agents and may also be compositions in which the active ingredient is optionally released in a delayed manner only or preferably in a portion of the intestine. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0068] The active compound may also be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical formulation 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 also contain additional substances besides inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain buffers. They may optionally contain light-blocking agents and may also be compositions in which they optionally release the active ingredient in a delayed manner only or preferably in a portion of the intestine. Examples of encapsulation compositions that can be used include polymers and waxes.

[0069] The pharmaceutical compositions and formulations described herein may also be administered topically or transdermally, particularly when the therapeutic target includes areas or organs easily accessible through topical application, including diseases of the eyes, skin, or lower intestine. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application to the lower intestine may be made, for example, in rectal suppository formulations or suitable enema formulations. Dosage forms for topical or transdermal application of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, suppositories, or patches.

[0070] For topical application, the pharmaceutical composition may be formulated as a suitable ointment, cream, lotion, or gel containing the active ingredient suspended or dissolved in one or more carriers, and any preservatives or buffers that may be required. Carriers for topical application of the compounds disclosed herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the 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 wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0071] It is also anticipated that ophthalmic formulations, ear drops, and eye drops are also within the scope of this disclosure. Furthermore, the use of transdermal patches is contemplated, offering the additional advantage of controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the amount of compound penetrating the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0072] Injectable formulations can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques, such as sterile injectable aqueous or oily suspensions. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. For acceptable carriers and solvents, water, Ringer's solution, USP, and isotonic sodium chloride solutions can be used. Furthermore, sterile, fixed oils are commonly used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids, such as oleic acid, are used in injectable formulations.

[0073] For example, injectable formulations can be sterilized by filtering with a bacterial trap or by adding a sterilizing agent in the form of a sterile solid composition, wherein the sterile solid composition can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0074] To prolong the effects of the compounds described herein, it is generally necessary to slow the absorption of compounds administered subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of a compound depends on its dissolution rate, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of parenteral-administered forms of compounds is achieved by dissolving or suspending the compound in an oil carrier. Injectable long-acting depot forms are prepared by forming microcapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolic acid. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Long-acting injectable formulations can also be prepared by encapsulating the compound in tissue-compatible liposomes or microemulsions.

[0075] Compositions for rectal or vaginal application are particularly suppositories, which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers (such as cocoa butter, polyethylene glycol, or suppository wax), wherein these excipients or carriers are solid at ambient temperature but liquid at body temperature, thus melting in the rectal or vaginal cavity and releasing the active compound.

[0076] The sterile injectable forms of the compositions described herein can be aqueous or oily suspensions. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Water, Ringer's solution, and isotonic sodium chloride solution can be used as acceptable carriers and solvents. Furthermore, sterile non-volatile 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 and its glycerol derivatives, can be used in the preparation of injections, as well as pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially their polyoxyethylene forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants, which are commonly used in pharmaceutically acceptable dosage forms, including emulsions and suspensions. For formulation purposes, other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, may also be used.

[0077] The pharmaceutical composition can also be administered via nasal aerosol or inhalation. This composition is prepared according to techniques well-known in the pharmaceutical formulation field and can be formulated as a solution in saline using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0078] The compounds used in the methods of this disclosure may be formulated into unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for a subject receiving treatment, wherein each unit contains a predetermined amount of active substance calculated to produce the desired therapeutic effect and optionally bound to a suitable drug carrier. A unit dosage form may be one of a single daily dose or multiple daily doses (e.g., about 1 to 4 or more times per day). When using multiple daily doses, the unit dosage form for each dose may be the same or different.

[0079] The disclosed compounds can be administered to subjects or patients at dose levels of about 0.1 mg to about 3000 mg per day. For a normal adult weighing about 70 kg, a dose of about 0.01 mg to about 100 mg per kilogram of body weight is generally sufficient. The specific dose and dose range to be used may potentially depend on many factors, including the needs of the subject or patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of the specific dose range and optimal dose for a subject or patient is within the scope of ordinary skill in the art.

[0080] Treatment The compounds disclosed in this paper modulate aryl hydrocarbon receptors (AHRs). AHRs are ligand-activated transcription factors associated with a variety of conditions, involved in regulating the immune system during homeostasis as well as during infection and inflammation. The AHR pathway has been recognized to play a role in the pathogenesis of diseases and dysregulations, including cancer and viral infections.

[0081] It was also found 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 a variety of viral infections, such as influenza. Inhibition of AHR is also associated with reduced viral particle production in vivo, such as in dengue fever. AHR appears to play a role in controlling lipid biogenesis (a hallmark of hepatitis C (HCV) infection). The role of AHR in regulating host immune responses against many viruses makes AHR modulation an attractive therapeutic target for viral infections.

[0082] Therefore, this disclosure provides a method for modulating aryl hydrocarbon receptors (AHRs) in cells, comprising: contacting cells with a therapeutically effective amount of the disclosed compound or salt or an formulation thereof in an amount effective in treating the AHR. In some cases, the contact occurs in vitro. In some cases, the contact occurs in vivo. In some cases, the contact includes administration to a subject in need (e.g., suffering from a disease or disorder associated with abnormal AHR activity). As used herein, the terms “patient” and “subject” are used interchangeably and are intended to refer to animals such as dogs, cats, cattle, horses, and sheep (i.e., non-human animals) and humans. A specific patient is a mammal (e.g., a human).

[0083] Another aspect of this disclosure provides a method for treating a subject's disease or disorder, comprising administering a therapeutically effective amount of the disclosed compound or salt or a combination thereof to the subject. In some cases, the terms "treating," "treat," or "treatment" may include preventative (e.g., prophylactic) and palliative treatments.

[0084] 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, and neuroinflammatory 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 many cases, skin diseases or disorders are selected from the group consisting of atopic dermatitis, acne, psoriasis, and vitiligo. In some cases, eye diseases or disorders include abnormal eye movements, inflammatory eye diseases, autoimmune eye diseases, hereditary eye diseases, degenerative eye diseases, vascularized 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 many cases, lung diseases or disorders include pulmonary fibrosis, asthma, or chronic obstructive pulmonary disease (COPD). In some cases, bone and joint diseases or disorders include osteoporosis, rheumatoid arthritis, or bone cancer. In many cases, diseases or disorders include diabetes, cancer, viral infections, or bacterial infections. In some cases, bacterial infections include lung infections, gastrointestinal infections, skin infections, ear infections, or sepsis.

[0085] In some cases, the disease or disorder is cancer. Cancers treated with the compounds and methods described herein include, but are not limited to: hematologic malignancies, lymphoma, myeloma, leukemia, nervous system cancers, skin cancer, breast cancer, prostate cancer, respiratory cancers, reproductive organ cancers, digestive tract cancers, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, genitourinary cancers, bone cancer, kidney cancer, and vascular cancer. In some cases, the cancer is a fluid or solid tumor, hematologic malignancies, lymphoma, myeloma, leukemia, sarcoma, eye cancer, thyroid cancer, parathyroid cancer, nervous system cancer, skin cancer, breast cancer, endocrine cancer, uterine cancer, endometrial cancer, prostate cancer, colorectal cancer, lung cancer, head and neck cancer, gastrointestinal cancer, liver cancer, pancreatic cancer, genitourinary cancer, bone cancer, kidney cancer, or vascular cancer. In some cases, the cancer is bone cancer. Possible bone cancers include, but are not limited to, histiocytoma of the bone. In some cases, the cancer is an endocrine carcinoma. Possible endocrine carcinomas include, but are not limited to, multiple endocrine adenoma syndrome, adrenal carcinoma (such as, but not limited to, adrenocortical carcinoma, adrenocortical tumor, or adrenocortical sebaceous adenoma), thyroid carcinoma (such as, but not limited to, undifferentiated thyroid carcinoma), and parathyroid carcinoma. In some cases, the cancer is breast cancer. Possible breast cancers include, but are not limited to, triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ. In some cases, the cancer is a respiratory tract cancer. Possible respiratory tract cancers include, but are not limited to, bronchial cancer, lung cancer (such as, but not limited to, small cell lung cancer and non-small cell lung cancer), as well as bronchial adenoma and pleural pulmonary blastoma. In some cases, the cancer is a central nervous system cancer. Possible central nervous system cancers include, but are not limited to, spinal axis tumors, neurofibromatosis type 1-associated malignant peripheral nerve sheath tumor (MPNST), and brain cancer. In some cases, the cancer is brain cancer. Considerable brain cancers include, but are not limited to, gliomas, low-grade gliomas, astrocytomas (e.g., Grade I—pilocytic astrocytoma, Grade II—low-grade astrocytoma, Grade III—anaplastic astrocytoma, Grade IV—glioblastoma (GBM)), glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, moderately differentiated pineal parenchymal tumors, pineal tumors, hemangioblastomas, acoustic neuromas, oligodendrogliomas, meningiomas, melanomas, neuroblastomas, olfactory neuroblastomas, or retinoblastomas, medullary carcinomas, brainstem and pituitary gliomas, cerebellar and cerebral astrocytomas, and neuroectodermal and pineal tumors, chordomas, mixed gliomas, optic gliomas, subependymal tumors, metastatic brain tumors, pituitary adenomas, primitive neuroectodermal tumors (PNETs), or schwannomas.In some cases, the cancer is a type more common in children than adults, such as brainstem glioma, juvenile pilocytic astrocytoma, optic nerve glioma, pineal gland tumor, primitive neuroectodermal tumor (PNET), or rhabdoid tumor. In some cases, the patient is an adult human. In some cases, the patient is a child or a 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, embryonal carcinoma, seminoma, penile cancer, prostate cancer, and testicular cancer. In some cases, the cancer is a cancer of the female reproductive organs. Cancers of the female reproductive organs that may be considered include, but are not limited to, ovarian epithelial cancer, fallopian tube cancer, papillary serous uterine carcinoma (UPSC), choriocarcinoma, endometrial cancer, 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 cystadenocarcinomas, endometrioid tumors, mucinous cystadenocarcinomas, granulosa cell tumors, Sertoli-Leydig cell tumors, and arrhenoblastomas. In some cases, the cancer may be cervical cancer. Cervical cancers that may be considered include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumors, hyalinoid carcinoma, and villonodular adenocarcinoma. In some cases, the cancer may be a cancer of the digestive tract. Cancers of the digestive tract that may be considered include, but are not limited to, anal cancer, colon cancer, colon tumors, colorectal cancer, esophageal cancer, stomach cancer, gallbladder cancer, gastrointestinal cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), duodenal cancer, gastric cancer, pancreatic cancer, rectal cancer, small bowel cancer, and salivary gland cancer. In some cases, the cancer may be esophageal cancer. Possible esophageal cancers 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. Possible gastric cancers include, but are not limited to, intestinal-type and diffuse gastric adenocarcinoma. In some cases, the cancer is pancreatic cancer. Possible pancreatic cancers include, but are not limited to, pancreatic ductal carcinoma, pancreatic adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, and pancreatic endocrine tumors. In some cases, the cancer is urinary tract cancer. Possible urinary tract cancers include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureteral cancer, urethral cancer, and human papillary renal carcinoma. In some cases, the cancer is kidney cancer. Possible kidney cancers include, but are not limited to, renal cell carcinoma, renal pelvis tumor, urothelial carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal eosinophilic tumor, Bellini duct carcinoma, renal clear cell sarcoma, mesodermal nephroma, and Wilms' tumor. In some cases, the cancer referred to is bladder cancer. Possible types of bladder cancer include, but are not limited to, bladder tumors, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma. In some cases, the cancer is eye cancer. Possible types of eye cancer include, but are not limited to, intraocular melanoma and retinoblastoma.In some cases, the cancer is liver cancer. Possible liver cancers include, but are not limited to, cystadenoma, hepatocellular carcinoma, cholangiocarcinoma, extrahepatic cholangiocarcinoma, hepatobiliary (liver and bile duct) carcinoma, hepatoblastoma, hepatocellular carcinoma (with or without fibrolamellar variants), cholangioma (intrahepatic cholangioma), hepatocholangiocarcinoma, and mixed hepatocellular cholangiocarcinoma. In some cases, the cancer is skin cancer. Possible skin cancers 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 skin cancer, and non-melanoma skin cancer. In some cases, the cancer is head and neck cancer. Possible head and neck cancers 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 cavity cancer, and squamous cell carcinoma. In some cases, the cancer is lymphoma. Considerable lymphomas include, but are not limited to, lymphocytic lymphoma, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphomas of the central nervous system. In some cases, the cancer is a sarcoma. Considerable sarcomas include, but are not limited to, soft tissue sarcoma, fibrosarcoma, neurofibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. In some cases, the cancer is leukemia. Leukemias that may be considered include, but are not limited to, acute leukemias (such as, but not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocyticle leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, and acute erythroleukemia), chronic leukemias (such as, but not limited to, chronic myeloid leukemia and chronic myeloid leukemia), and hairy cell leukemia.

[0086] Other cancers that may be considered for treatment with the compounds disclosed herein and the methods described herein are selected from: for example, urothelial carcinoma, including but not limited to bladder cancer and all transitional cell carcinomas; squamous cell carcinoma of the head and neck; melanoma, including but not limited to uveal melanoma; ovarian cancer, including but not limited to serous subtypes of ovarian cancer; renal cell carcinoma, including but not limited to clear cell renal cell carcinoma; cervical cancer; gastrointestinal / gastric (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 squamous cell carcinoma of the head and neck. 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 subtypes of ovarian cancer. In some cases, the cancer is renal cell carcinoma. In some cases, the cancer is clear cell renal cell carcinoma. 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.

[0087] Other cancers to consider include, but are not limited to: polycythemia vera, Waldenström macroglobulinemia, multiple myeloma, heavy chain disease, epithelial carcinoma, appendiceal cancer, atypical teratoid / rhabdoid tumor, atypical teratoid / rhabdoid tumor of the central nervous system, embryonal tumors of the central nervous system, bronchial tumors, carcinoid tumors, cancers of unknown primary origin, cancers of the central nervous system, childhood cancers, chordoma, chronic myeloproliferative disorders, ductal carcinoma in situ (DCIS), embryonal tumors, endometrial cancer, ependymoblastoma, extracranial germ cell tumors, gonadal germ cell tumors, ocular cancer, fibroblastic germ cell tumors, gestational trophoblastic tumors, cardiac cancer, histiocytosis, Langerhans cell carcinoma, hypopharyngeal cancer, islet cell tumors, Langerhans cell histiocytosis, laryngeal cancer, lip and oral cavity cancer, lobular carcinoma in situ (LCIS), macroglobulinemia, medullary epithelioma, Merkel cell carcinoma, NUT gene-associated mid-trap carcinoma, and mouth cancer. 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, papilloma, paraganglioma, paranasal sinus cancer, nasal cavity cancer, pharyngeal cancer, pheochromocytoma, pineal blastoma, plasma cell tumor, pleural pulmonary blastoma, transitional cell carcinoma, Sezary syndrome, supratentorial primitive neuroectodermal tumor, laryngeal cancer, thymoma, thymic carcinoma, transitional cell gestational trophoblastic tumor, cancer of unknown primary origin, rare childhood cancers, or diffuse large B-cell lymphoma (DLBCL).

[0088] Methods and compositions for the diagnosis, prognosis, and treatment of virus-associated cancers are also provided, including: human immunodeficiency virus (HIV)-associated solid tumors, human papillomavirus (HPV)-16-positive incurable solid tumors, and adult T-cell leukemia caused by human T-cell leukemia virus type I (HTLV-I), which is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I into leukemic cells; as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, head and neck squamous cell carcinoma, and Merkel cell carcinoma.

[0089] In some cases, the compounds or combinations thereof disclosed herein may be used to treat viral infections. In some cases, the viral infections to be treated using the compounds and methods described herein include, but are not limited to, coronavirus infections and flavivirus infections.

[0090] In some cases, viral infections are coronavirus infections. The term "coronavirus infection" as used in this article refers to illness caused by a coronavirus. Coronaviruses are a family of viruses that cause disease in mammals and birds. Coronaviruses belong to the subfamily Orthocoronaviruses of the family Coronaviridae in the order Nematovirales. 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 and HCoV-EMC), and SARS-CoV-2 (also known as 2019-nCoV).

[0091] In some cases, viral infections are flavivirus infections. The term "flavivirus infection" as used in this article refers to illness caused by flavivirus infection.

[0092] Flavivirs are a family of viruses that cause disease in mammals and insects. They belong to the family Flaviviridae within the order Amarillovirales. Flavivirs have a positive-sense, single-stranded RNA genome that is unsegmented and approximately 10-11 kbp in length. In humans, flaviviruses cause hemorrhagic fever, encephalitis, and microcephaly. Flavivir infection can range from asymptomatic to fatal. Vaccines and antiviral drugs exist to prevent or treat some, but not all, human flavivirus infections. Non-limiting examples of flaviviruses include West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus, and several other viruses that may cause encephalitis. Therefore, in some cases, the compounds of this disclosure (such as the compounds of formula (I), the compounds in Table 1 and their salts) or their pharmaceutically acceptable salts may 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).

[0093] Another aspect of this disclosure provides the use of the compounds or salts disclosed herein, or compositions comprising the compounds or salts disclosed herein, in the treatment of diseases or disorders associated with abnormal AHR activity.

[0094] The use of the compounds or salts disclosed herein, or compositions comprising the compounds or salts disclosed herein, in the preparation of medicaments for treating diseases or disorders associated with abnormal AHR activity is also considered.

[0095] The use of the compounds disclosed herein or pharmaceutically acceptable salts thereof for the treatment of diseases or disorders associated with abnormal AHR activity in subjects has also been considered. Furthermore, the use of the compounds disclosed herein or pharmaceutically acceptable salts thereof for the preparation of medicaments for the treatment of the aforementioned conditions has been considered.

[0096] In some cases, the compounds disclosed herein or pharmaceutically acceptable salts thereof may be administered in combination with another therapeutic agent to treat diseases or disorders associated with aberrant AHR activity. Therefore, in any of the methods disclosed herein, treatment of a disease or disorder may include the co-administration of a combination of the disclosed compounds or pharmaceutically acceptable salts thereof with another therapeutic agent. In some cases, the therapeutic agent is an anti-inflammatory agent. Possible anti-inflammatory agents include, but are not limited to, mesalazine, naproxen, ibuprofen, diclofenac, celecoxib, sulindac, oxapazine, piroxicam, indomethacin, meloxicam, fenofurin, desflunixa, etodoxacin, ketorolac tromethamine, meclofenac, nabumetone, salsalate, or any combination thereof. In some cases, the therapeutic agent is an immune checkpoint inhibitor. Non-limiting examples of immune checkpoint inhibitors include PD1 or PDL1 antibodies, such as pembrolizumab, nivolumab, cemiplimab, atezolizumab, dostarlimab, durvalumab, or avelumab.

[0097] Synthesis of the compounds disclosed herein The compounds disclosed herein can be synthesized by any method known in the art. For example, the compounds disclosed herein can be synthesized according to the following examples.

[0098] The general scheme for synthesizing the disclosed compound is shown below. Further information regarding specific reaction conditions is provided in detail in the Examples section.

[0099]

[0100] The following synthetic scheme provides an additional route for preparing the compounds disclosed herein.

[0101]

[0102]

[0103] Implementation of this disclosure 1. Compounds having the structure of formula (I) or formula (II) or pharmaceutically acceptable salts thereof: (I) or (II) L represents the bond, C(O), C 2-3 imide or C 2-3 Ethyne group; Ar 1 For phenyl, C 3-8 Cycloalkyl or 4- to 8-membered aromatic heterocycles or non-aromatic heterocycles having 1 to 3 cyclic heteroatoms selected from O, N, and S, and Ar 1 The optional replacement has one or two Rs. A ; Each R A 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; Each R N Independently H or C 1-6 alkyl; Ar 2 It is a 5- to 10-membered aromatic or non-aromatic ring having 0 to 3 cyclic heteroatoms selected from O, N, and S, and Ar 2 The optional replacement can be one, two, or three Rs. B ; Each R B Independent of 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 cyclic heteroatoms selected from N, O, and S, and optionally substituted with 1, 2, or 3 R atoms.C ; Each R C Independently halogen, OH, =O, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NR N R N C(O)NR N R N CO2R N C(O)R N or SO2-C 1-6 alkyl; R 1 C 1-6 Alkyl, C 1-6 Alkylene-R D C 1-6 Alkylene-C(O)R D C 1-6 Alkylene-NHSO2 cyclopropyl or C 1-6 Alkylene-NR N -C(O)R N ;as well as R D OR N or NR N R N ; The conditions are: (i) For compounds of formula (I), when L is a bond, then (a) Ar 2 The substitute has at least one selected from Het, C(O)-C 0-2 Alkylene-Het and N(R) N )-C 0-3 Alkylene-C(O)-C 0-3 R of alkylene-Het B , or (b)Ar 2 This includes 8- to 10-membered bicyclic aromatic or non-aromatic rings with 1 to 3 cyclic heteroatoms, and with 0 to 3 R substitutions. B ;as well as (ii) For compounds of formula (II), when L is a bond, Ar 2 It is a phenyl or a 6-membered aromatic heterocycle, Ar 2 Replacement has 1 R B And R B When it is Het, then (a) Het is attached to Ar via the carbon atom of Het. 2 Or (b) Het replaces one, two or three Rs. C .

[0104] 2. The compound or salt according to embodiment 1, wherein each R N It can be H or methyl on its own.

[0105] 3. The compound or salt according to embodiment 1 or 2, wherein R 1 C 1-6 Alkyl or C 1-6 Alkylene-R D .

[0106] 4. The compound or salt according to embodiment 3, wherein R D OR N .

[0107] 5. The compound or salt according to embodiment 3, wherein R 1 for , , or .

[0108] 6. The compound or salt according to any one of embodiments 1 to 42, wherein R 1 for .

[0109] 7. The compound or salt according to embodiment 1 or 2 has the structure of formula (Ia): (Ia).

[0110] 8. The compound or salt according to embodiment 1 or 2 has the structure of formula (IIa): (IIa).

[0111] 9. The compound or salt according to any one of embodiments 1 to 8, wherein Ar 1 It is a heterocyclic group containing a total of 4 to 8 ring atoms, of which 1 to 3 ring atoms are selected from O, N and S.

[0112] 10. A compound or salt according to any one of embodiments 1 to 9, wherein Ar 1 Replacement has 1 or 2 R A .

[0113] 11. The compound or salt according to embodiment 9, wherein Ar 1 It is not replaced.

[0114] 12. The compound or salt according to any one of embodiments 1 to 11, wherein Ar 1 For phenyl, C 3-8 Cycloalkyl or pyrazole.

[0115] 13. The compound or salt according to any one of embodiments 1 to 7, 9 and 10 has the structure of formula (Ib): (Ib).

[0116] 14. The compound or salt according to any one of embodiments 1 to 6, 8, 9 and 10 has the structure of formula (IIb): (IIb).

[0117] 15. A compound or salt according to any one of embodiments 9, 10, and 12 to 14, wherein at least one R A C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 alkoxy; or at least one R A It is a methyl group.

[0118] 16. The compound or salt according to embodiment 1 or 2 has the structure of formula (Ic): (Ic).

[0119] 17. The compound or salt according to embodiment 1 or 2 has the structure of formula (IIc): (IIc).

[0120] 18. A compound or salt according to any one of embodiments 1 to 17, wherein L is a bond.

[0121] 19. A compound or salt according to any one of embodiments 1 to 17, wherein L is C 2-3 Alkenyl group.

[0122] 20. A compound or salt according to any one of embodiments 1 to 17, wherein L is C 2-3 Alynyl group.

[0123] 21. The compound or salt according to any one of embodiments 1 to 20, wherein Ar 2 It can be phenyl or naphthyl.

[0124] 22. The compound or salt according to any one of embodiments 1 to 20, wherein Ar 2 It is a 5- to 10-membered aromatic or non-aromatic ring having 1 to 3 cyclic heteroatoms selected from O, N and S.

[0125] 23. The compound or salt according to embodiment 22, wherein Ar 2It is an 8- to 10-membered bicyclic aromatic ring or non-aromatic ring having 1 to 3 cyclic heteroatoms selected from O, N and S.

[0126] 24. The compound or salt according to embodiment 23, wherein Ar 2 It is isoindoline, tetrahydroisoquinoline, tetrahydroquinoline, indazole, or pyrazolo[4,3-c]pyridine.

[0127] 25. The compound or salt according to any one of embodiments 1 to 24, wherein Ar 2 It is not replaced.

[0128] 26. The compound or salt according to any one of embodiments 1 to 24, wherein Ar 2 The replacement has 1, 2 or 3 Rs. B .

[0129] 27. The compound or salt according to embodiment 26, wherein 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 .

[0130] 28. The compound or salt according to embodiment 26 or 27, wherein at least one R B For Het, C(O)-C 0-2 Alkylene-Het or N(R) N )-C 0-3 Alkylene-C(O)-C 0-3 Alkylene-Het.

[0131] 29. The compound or salt according to embodiment 28, wherein Het includes phenyl, pyridine, pyridin-2-one, pyrimidine, piperidine, piperazine, morpholine, azacycloheptane, 1,4-diazacycloheptane, pyrrolidine, tetrahydropyran, dihydropyran or 8-oxa-3-azabicyclo[3.2.1]octane.

[0132] 30. The compound or salt according to embodiment 28 or 29, wherein Het is unsubstituted.

[0133] 31. The compound or salt according to embodiment 28 or 29, wherein Het is substituted with one or two R atoms. C .

[0134] 32. The compound or salt according to embodiment 31, wherein at least one R CHalogen, OH, =O, C 1-6 Alkyl, CO2R N NR N R N or SO2-C 1-6 alkyl.

[0135] 33. The compound or salt according to embodiment 32, wherein at least one R C The possible values ​​are F, Cl, OH, =O, methyl, CO2H, NH2, or SO2CH3.

[0136] 34. The compound or salt according to embodiment 28 or 29, wherein Het is , , , , , , , , , , , , , , , , , , , , , or .

[0137] 35. A compound or salt according to any one of embodiments 1 to 20, wherein Ar 2 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0138] 36. The compound or salt according to any one of embodiments 1 to 20, wherein Ar 2 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0139] 37. The compounds listed in Table 1 or their pharmaceutically acceptable salts.

[0140] 38. A pharmaceutical preparation comprising a compound or salt according to any one of embodiments 1 to 37, and a pharmaceutically acceptable excipient.

[0141] 39. A method for treating or preventing a disease or disorder associated with abnormal aryl hydrocarbon receptor (AHR) activity in a subject, comprising administering to the subject a therapeutically effective amount of any one of embodiments 1 to 37, or a salt thereof.

[0142] 40. The method according to embodiment 39, wherein the disease or disorder is an inflammatory disease or disorder.

[0143] 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.

[0144] 42. The method according to embodiment 41, wherein the gastrointestinal disease 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.

[0145] 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.

[0146] 44. The method according to embodiment 41, wherein the eye disease or disorder is abnormal eye movement, inflammatory eye disease, autoimmune eye disease, hereditary eye disease, degenerative eye disease, vascularized eye disease, dry and wet age-related macular degeneration (“AMD”), uveitis, retinitis pigmentosa (“RP”), primary open-angle glaucoma (“POAG”), primary congenital glaucoma, Bechtel disease, or Leber congenital amaurosis (“LCA”).

[0147] 45. The method according to embodiment 41, wherein the disease or disorder of the lung is pulmonary fibrosis, asthma, or chronic obstructive pulmonary disease.

[0148] 46. ​​The method according to embodiment 41, wherein the disease or disorder of the joint is osteoporosis, rheumatoid arthritis or bone cancer.

[0149] 47. The method according to embodiment 39, wherein the disease or disorder is diabetes, cancer, viral infection or bacterial infection.

[0150] 48. The method according to embodiment 47, wherein the viral infection is a flavivirus infection or a coronavirus infection.

[0151] 49. The method according to embodiment 47, wherein the bacterial infection is a lung infection, gastrointestinal infection, skin infection, ear infection, or sepsis.

[0152] 50. The method according to any one of embodiments 39 to 49 further includes administering a therapeutic agent to the patient.

[0153] 51. The method according to embodiment 50, wherein the therapeutic agent is an anti-inflammatory agent.

[0154] 52. The method according to embodiment 51, wherein the anti-inflammatory agent is selected from mesalazine, naproxen, ibuprofen, diclofenac, celecoxib, sulindac, oxapazine, piroxicam, indomethacin, meloxicam, fenprofen, diclofenac, etodoxacin, ketorolac tromethamine, meclofenac, nabumetone, disalicylate, or any combination thereof.

[0155] 53. The method according to embodiment 50, wherein the therapeutic agent is an immune checkpoint inhibitor.

[0156] 54. The compound or salt according to any one of embodiments 1 to 37, for the treatment or prevention of diseases or disorders related to abnormal aromatic hydrocarbon receptor (AHR) activity.

[0157] 55. Use of the compound or salt according to any one of embodiments 1 to 37 for the treatment or prevention of diseases or disorders associated with abnormal aromatic hydrocarbon receptor (AHR) activity.

[0158] Example abbreviation

[0159] Preparation of 3-amino-6-chloro-2-iodoisonicotinic acid (A-2)

[0160] NIS (2.6 g, 11.64 mmol) was added to a DMF (30 mL) solution of 5-amino-2-chloroisonicotinic acid (1.0 g, 5.82 mmol). The reaction mixture was stirred at 60 °C for 48 h. The desired molecular weight was determined by LC-MS. The residue was then quenched with water, extracted with EtOAc, the organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated to give a yellow solid A-2 (830.0 mg, yield: 48.0%). LCMS (ESI): C6H4ClIN2O2[M+H] + m / z, calculated value 299.4, measured value 299.0.

[0161] Preparation of (S)-3-amino-6-chloro-N-(1-hydroxypropyl-2-yl)-2-iodoisonicotinamide (A-4)

[0162] EDCI (640.0 mg, 3.33 mmol), HOBT (440.0 mg, 3.33 mmol), and TEA (420.0 mg, 4.17 mmol) were added to a DMF (30 mL) solution of A-2 (830.0 mg, 2.78 mmol). 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 determined by LC-MS. The residue was extracted with EtOAc (50 mL), the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with PE / EtOAc, from 100 / 0 to 50 / 50 over 30 minutes) to give a brown solid A-4 (530.0 mg, yield: 53.6%). LCMS (ESI): C9H 11 ClIN3O2[M+H] + m / z, calculated value 356.5, measured value 356.1.

[0163] Preparation of (S)-6-chloro-3-(1-hydroxypropyl-2-yl)-8-iodopyridano[3,4-d]pyrimidin-4(3H)-one (A-6)

[0164] 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 at 150 °C for 1 hour under N2 atmosphere. The desired molecular weight was determined by LC-MS. The residue mixture was then quenched to ice water and extracted with EtOAc. 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 (eluting with PE / EtOAc, from 100 / 0 to 80 / 20 over 30 minutes) to give a brown solid A-6 (230.1 mg, yield: 42.2%). LCMS (ESI): C 10 H9ClIN3O2[M+H] + m / z, calculated value 366.5, measured value 366.0.

[0165] Preparation of (S)-6-chloro-3-(1-hydroxypropyl-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (A)

[0166] A solution of A-6 (230.1 mg, 0.86 mmol) in 1,4-dioxane (10 mL) and H₂O (2 mL) was supplemented with 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). The mixture was stirred at 80 °C for 12 h under N₂ atmosphere. The desired molecular weight was determined by LC-MS. The residue was extracted with EtOAc (100 mL × 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 (eluting with PE / EtOAc, from 100 / 0 to 80 / 20 over 30 min) to give brown solid A (124.9 mg, yield: 62.1%). LCMS (ESI): C 14 H 14 ClN5O2[M+H] + m / z, calculated value 320.7, measured value 320.2.

[0167] Preparation of compounds 1 to 13

[0168] Boric acid or borate ester (1.1 eq), K₂CO₃ (2.0 eq), and Pd(dppf)Cl₂ (0.05 eq) were added to a solution of intermediate A (1.0 eq) in dioxane (6 mL) / H₂O (2 mL). The reaction mixture was stirred at 90 °C for 3 h. The desired molecular weight was determined by LC-MS. The residue was quenched with ice water and extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by C18 column chromatography (eluting with ACN-H₂O (0.1% NH₃·H₂O) from 5 / 95 to 80 / 20 over 30 min) to give the final compound.

[0169] Preparation of compounds 14 to 17

[0170] In a reaction flask, 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 in a microwave oven at 170 °C for 4 hours. The desired molecular weight was determined by LC-MS. The residue was quenched with ice water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by C18 column chromatography (eluting with ACN-H2O (0.1% NH3·H2O) from 5 / 95 to 80 / 20 over 30 min) to give the final compound.

[0171] Prepare the compounds in the table below in a manner similar to that described above.

[0172]

[0173] Preparation of 1-methyl-1H-pyrazole-4-formamidin (AA-2)

[0174] A methanol (40 mL) solution of 28% sodium methoxide in methanol (6.6 mL) was added to a methanol (4.0 g, 37.37 mmol) solution of 1-methyl-1H-pyrazole-4-onitrile, i.e., AA-1 (4.0 g, 37.37 mmol). 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 determined by LC-MS. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by rapid chromatography (eluting with DCM / MeOH, from 100 / 0 to 70 / 30 within 20 min) to give a white solid AA-2 (4.0 g, yield: 86.3%). LCMS (ESI): C5H9N4[M+H] + The calculated value of m / z is 125.1, and the measured value is 125.2.

[0175] Preparation of 6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylic acid (AA-4)

[0176] A solution of sodium hydroxide (3.1 g, 77.42 mmol) in water (3 mL) was added to an 80 mL solution of AA-3 (8.2 g, 38.71 mmol). 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 determined 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 give a brown solid product, AA-4 (3.0 g, yield: 42.3%). LCMS (ESI): C9H9N4O3[M+H] + m / z, calculated value 221.1, measured value 221.1.

[0177] Preparation of methyl 6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylic acid (AA-5)

[0178] Sulfuric acid (2 mL) was added to a MeOH (30 mL) solution of AA-4 (3.0 g, 13.63 mmol). The mixture was stirred at 70 °C for 2 hours. The desired molecular weight was determined by LC-MS. The reaction mixture was filtered and the solid was collected to give a white solid product AA-5 (2.8 g, yield: 97.7%). LCMS (ESI): C 10 H 11 N4O3[M+H] + m / z, calculated value 235.1, measured value 235.2.

[0179] Preparation of methyl 6-chloro-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxylate (AA)

[0180] Phosphorus oxychloride (60 mL) was added to a solution of AA-5 (2.8 g, 11.96 mmol). The mixture was stirred at 100 °C for 1 hour. The desired molecular weight was determined by LC-MS. The reaction solution was concentrated under reduced pressure and adjusted to pH = 7 with saturated sodium bicarbonate solution, followed by extraction with EtOAc. The organic layer was concentrated to give a white solid crude product AA (2.2 g, yield: 93.9%). LCMS (ESI): C 10 H 10 The calculated value of N4O3[M+H]+ m / z is 253.0, and the measured value is 253.2.

[0181] Preparation of compound (C-3)

[0182] 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 h under N2 atmosphere. The desired molecular weight was determined 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 h under N2 atmosphere. The desired molecular weight was determined by LC-MS. The solvent was removed by vacuum. The residue was purified by rapid chromatography (eluting with DCM / MeOH, from 100 / 0 to 90 / 10 within 30 min) to give compound (C-3).

[0183] Preparation of compound (C-4)

[0184] Sodium hydroxide (2.0 eq) was added to a solution of compound (C-3) (1.0 eq) in methanol:THF:H₂O = 6:3:1, 10 mL. The mixture was stirred at room temperature for 4 hours. The desired molecular weight was determined by LC-MS. The reaction solution was concentrated under reduced pressure and adjusted to pH = 4 with 2 N HCl. The solution was filtered, and the solid was collected to give compound (C-4).

[0185] Preparation of the compounds disclosed herein

[0186] HATU (2.0 eq) and DIEA (3.0 eq) were added to a DMF (5 ml) solution of compound (C-4) (1.0 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 determined by LC-MS. The reaction mixture was quenched with H2O, extracted with EtOAc, washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by rapid chromatography (eluting with DCM / MeOH, from 100 / 0 to 90 / 10 within 30 minutes) to give the desired compound.

[0187] Preparation of compound (D-2)

[0188] Compound (D-1) (1.2 eq) and DIEA (3.0 eq) were added to a DMF (5 ml) solution of compound AA (1.0 eq). The reaction mixture was stirred at 80 °C for 2 h. The desired molecular weight was determined by LC-MS. The reaction mixture was quenched with H2O, extracted with EtOAc, washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by rapid chromatography (eluting with DCM / MeOH, from 100 / 0 to 90 / 10 within 30 min) to give compound (D-2).

[0189] Preparation of compound (D-3)

[0190] Sodium hydroxide (2.0 eq) was added to a solution of compound (D-2) (1.0 eq) in methanol:THF:H₂O = 6:3:1, 10 mL. The mixture was stirred at room temperature for 4 hours. The desired molecular weight was determined by LC-MS. The reaction solution was concentrated under reduced pressure and adjusted to pH = 4 with 2 N HCl. The solution was filtered, and the solid was collected to give compound (D-3).

[0191] Preparation of the compounds disclosed herein

[0192] HATU (2.0 eq) and DIEA (3.0 eq) were added to a DMF (5 ml) solution of compound (D-3) (1.0 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 determined by LC-MS. The reaction mixture was quenched with H2O, extracted with EtOAc, washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by rapid chromatography (eluting with DCM / MeOH, from 100 / 0 to 90 / 10 within 30 minutes) to give the desired compound.

[0193] The compounds in the table below are prepared in a manner similar to that described above.

[0194]

[0195] Preparation of compound (E-2)

[0196] HATU (2.0 eq) and DIEA (3.0 eq) were added to a DMF (5 ml) solution of compound (C-4) (1.0 eq). After 30 minutes, compound (E-1) was added. The reaction mixture was stirred at room temperature for 2 hours. The desired molecular weight was determined by LC-MS. The reaction mixture was quenched with H2O, extracted with EtOAc, washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by rapid chromatography (eluting with DCM / MeOH, from 100 / 0 to 90 / 10 within 30 minutes) to give compound (E-2).

[0197] Preparation of compound (X)

[0198] Compound (E-5) (1.2 eq) and K₂CO₃ (3.0 eq) were added to a DMF (5 ml) solution of compound (E-2) (1.0 eq). The reaction mixture was stirred at 80 °C for 2 h. The desired molecular weight was determined by LC-MS. The reaction mixture was quenched with H₂O, extracted with EtOAc, washed with saturated brine, dried over Na₂SO₄, and concentrated. The residue was purified by rapid chromatography (eluting with DCM / MeOH, from 100 / 0 to 90 / 10 within 30 min) to give compound (X).

[0199] Preparation of compound (F-2)

[0200] HATU (2.0 eq) and DIEA (3.0 eq) were added to a DMF (5 ml) solution of compound (D-3) (1.0 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 determined by LC-MS. The reaction mixture was quenched with H2O, extracted with EtOAc, washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified by rapid chromatography (eluting with DCM / MeOH, from 100 / 0 to 90 / 10 within 30 minutes) to give the desired compound (F-2).

[0201] Preparation of compound (X)

[0202] Sodium hydroxide (2.0 eq) was added to a solution of compound (F-5) (1.0 eq) in (MeOH:THF:H2O = 6:3:1, 10 mL). The mixture was stirred at room temperature for 4 hours. The desired molecular weight was determined by LC-MS. The reaction solution was concentrated under reduced pressure and adjusted to pH = 4 with 2 N HCl. The solution was filtered, and the solid was collected to give compound (X).

[0203] Prepare the compounds in the table below as described above.

[0204]

[0205] synthesis Biological assay AhR reporter gene analysis was performed according to the protocol of the Human Aromatic Hydrocarbon Receptor (AhR) Reporter Gene Analysis System (INDIGO Bioscience, #IB06001-32). AhR reporter cells were thawed and pre-cultured in cell recovery medium (CRM) for 6 hours. The medium was then removed, and cells were incubated for 24 hours in compound selection medium (CSM) supplemented with 200 μM kynurenic acid, either in the absence of the test compound (negative control) or in the presence of 10 nM test compound. For the positive inhibition control, cells activated with 200 μM kynurenic acid were incubated in the presence of the literature AHR antagonist; alternatively, unactivated cells were used as the positive inhibition control. After 24 hours of incubation, the medium was removed, and luciferase assay reagent (LDR) was added. Firefly luciferase activity was quantified using a plate reader. Results were normalized using positive and negative controls.

[0206] The results of AHR inhibition at 10 nM for the compounds disclosed in this paper are recorded in the table below.

[0207]

Claims

1. A compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof: (I) or (II), L represents the bond, C(O), C 2-3 imide or C 2-3 Ethyne group; Ar 1 For phenyl, C 3-8 Cycloalkyl or 4- to 8-membered aromatic heterocycles or non-aromatic heterocycles having 1 to 3 cyclic heteroatoms selected from O, N, and S, and Ar 1 The optional replacement has one or two Rs. A ; Each R A 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; Each R N Independently H or C 1-6 alkyl; Ar 2 It is a 5- to 10-membered aromatic or non-aromatic ring having 0 to 3 cyclic heteroatoms selected from O, N, and S, and Ar 2 The optional replacement can be one, two, or three Rs. B ; Each R B Independent of 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 cyclic heteroatoms selected from N, O, and S, and optionally substituted with 1, 2, or 3 R atoms. C ; Each R C Independently halogen, OH, =O, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, NR N R N C(O)NR N R N CO2R N C(O)R N or SO2-C 1-6 alkyl; R 1 C 1-6 Alkyl, C 1-6 Alkylene-R D C 1-6 Alkylene-C(O)R D C 1-6 Alkylene-NHSO2 cyclopropyl or C 1-6 Alkylene-NR N -C(O)R N ;as well as R D OR N or NR N R N ; in The conditions are: (i) For compounds of formula (I), when L is a bond, then (a) Ar 2 The substitute has at least one selected from Het, C(O)-C 0-2 Alkylene-Het and N(R) N )-C 0-3 Alkylene-C(O)-C 0-3 R of alkylene-Het B , or (b)Ar 2 This includes 8- to 10-membered bicyclic aromatic or non-aromatic rings with 1 to 3 cyclic heteroatoms, and with 0 to 3 R substitutions. B ; as well as (ii) For compounds of formula (II), when L is a bond, Ar 2 It is a phenyl or a 6-membered aromatic heterocycle, Ar 2 Replacement has 1 R B And R B When it is Het, then (a) Het is attached to Ar via the carbon atom of Het. 2 Or (b) Het replaces one, two or three Rs. C .

2. The compound or salt according to claim 1, wherein, Each R N It can be H or methyl on its own.

3. The compound or salt according to claim 1 or 2, wherein, R 1 C 1-6 Alkyl or C 1-6 Alkylene-R D .

4. The compound or salt according to claim 3, wherein, R D is OR N .

5. The compound or salt according to claim 3, wherein, R 1 for , , or .

6. The compound or salt according to any one of claims 1 to 42, wherein, R 1 for .

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

8. The compound or salt according to claim 1 or 2, having the structure of formula (IIa): (IIa)。 9. The compound or salt according to any one of claims 1 to 8, wherein, Ar 1 It is a heterocyclic group containing a total of 4 to 8 ring atoms, of which 1 to 3 ring atoms are selected from O, N and S.

10. The compound or salt according to any one of claims 1 to 9, wherein, Ar 1 Replacement has 1 or 2 R A .

11. The compound or salt according to claim 9, wherein, Ar 1 It is not replaced.

12. The compound or salt according to any one of claims 1 to 11, wherein, Ar 1 For phenyl, C 3-8 Cycloalkyl or pyrazole.

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

14. The compound or salt according to any one of claims 1 to 6, 8, 9 and 10, having the structure of formula (IIb): (IIb)。 15. The compound or salt according to any one of claims 9, 10, and 12 to 14, wherein, At least one R A C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 alkoxy; or at least one R A It is a methyl group.

16. The compound or salt according to claim 1 or 2, having the structure of formula (Ic): (Ic)。 17. The compound or salt according to claim 1 or 2, having the structure of formula (IIc): (IIc)。 18. The compound or salt according to any one of claims 1 to 17, wherein, L stands for bond.

19. The compound or salt according to any one of claims 1 to 17, wherein, L is C 2-3 Alkenyl group.

20. The compound or salt according to any one of claims 1 to 17, wherein, L is C 2-3 Alynyl group.

21. The compound or salt according to any one of claims 1 to 20, wherein, Ar 2 It can be phenyl or naphthyl.

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

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

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

25. The compound or salt according to any one of claims 1 to 24, wherein, Ar 2 It is not replaced.

26. The compound or salt according to any one of claims 1 to 24, wherein, Ar 2 The replacement has 1, 2 or 3 Rs. B .

27. The compound or salt according to claim 26, wherein, 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 .

28. The compound or salt according to claim 26 or 27, wherein, At least one R B For Het, C(O)-C 0-2 Alkylene-Het or N(R) N )-C 0-3 Alkylene-C(O)-C 0-3 Alkylene-Het.

29. The compound or salt according to claim 28, wherein, Het includes phenyl, pyridine, pyridin-2-one, pyrimidine, piperidine, piperazine, morpholine, aziridine, 1,4-diazacycloheptane, pyrrolidine, tetrahydropyran, dihydropyran or 8-oxa-3-azabicyclo[3.2.1]octane.

30. The compound or salt according to claim 28 or 29, wherein, Het is unsubstituted.

31. The compound or salt according to claim 28 or 29, wherein, Het replaces one or two Rs. C .

32. The compound or salt according to claim 31, wherein, At least one R C Halogen, OH, =O, C 1-6 Alkyl, CO2R N NR N R N or SO2-C 1-6 alkyl.

33. The compound or salt according to claim 32, wherein, At least one R C The possible values ​​are F, Cl, OH, =O, methyl, CO2H, NH2, or SO2CH3.

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

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

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

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

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

39. A method for treating or preventing a disease or disorder associated with abnormal aryl hydrocarbon receptor (AHR) activity in a subject, comprising administering to the subject a therapeutically effective amount of any one of claims 1 to 37, of the compound or salt.

40. The method according to claim 39, wherein, The disease or disorder mentioned is an inflammatory disease or disorder.

41. The method according to claim 39, wherein, The disease or disorder is a disease or disorder of the gastrointestinal tract, skin, lungs, central nervous system, pancreas, eyes, bones, joints, neuroinflammatory diseases, or neurodegenerative diseases.

42. The method according to claim 41, wherein, The gastrointestinal diseases or disorders mentioned 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.

43. The method according to claim 41, wherein, The skin diseases or disorders mentioned are selected from the group consisting of atopic dermatitis, acne, psoriasis, and vitiligo.

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

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

46. ​​The method according to claim 41, wherein, The diseases or disorders of the bones and joints mentioned are osteoporosis, rheumatoid arthritis, or bone cancer.

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

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

49. The method according to claim 47, wherein, The bacterial infection can be a lung infection, gastrointestinal infection, skin infection, ear infection, or sepsis.

50. The method according to any one of claims 39 to 49, further comprising administering a therapeutic agent to the patient.

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

52. The method according to claim 51, wherein, The anti-inflammatory agent is selected from mesalazine, naproxen, ibuprofen, diclofenac, celecoxib, sulindac, oxapazine, piroxicam, indomethacin, meloxicam, fenofosine, diclofenac, etodoxacin, ketorolac tromethamine, meclofenac, nabumetone, disalicylate, or any combination thereof.

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

54. The compound or salt according to any one of claims 1 to 37, for the treatment or prevention of diseases or disorders associated with abnormal aryl hydrocarbon receptor (AHR) activity.

55. Use of the compound or salt according to any one of claims 1 to 37 for the treatment or prevention of diseases or disorders associated with abnormal aryl hydrocarbon receptor (AHR) activity.

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