Aryl hydrocarbon receptor agonist prodrugs and methods of use thereof

Abstract

Provided herein are compounds that may act as agonists of aryl hydrocarbon receptors (AHR). Further disclosed herein are methods for treating inflammatory and autoimmune diseases and disorders, such as diseases or disorders of the gastrointestinal tract, skin, lung, central nervous system, pancreas, eye, bone, osteoarticular, neuroinflammatory diseases or neurodegenerative diseases.

Description

Technical Field

[0001] The present disclosure relates to prodrug analogs of compounds that act as aryl hydrocarbon receptor (AHR) agonists, pharmaceutical formulations thereof, and methods of using these compounds to treat diseases and disorders, such as inflammatory and autoimmune diseases and disorders. Background Art

[0002] Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that regulates gene expression in a variety of cells (such as epithelial cells and immune cells). Activation of AHR can cause changes in the inflammatory cytokine spectrum and antioxidant response in the cellular environment, and can promote the healing process of diseased tissues. AHR signal transduction can play a key role in maintaining skin and eye homeostasis by regulating the skin immune network, keratinocyte differentiation, skin barrier function and pigmentation, retinal epithelial cells, rod photoreceptors, choroidal endothelial cells, choroidal neovascularization and responses to oxidative stress. Cells expressing AHR found in the skin and eyes include keratinocytes, sebaceous gland cells, fibroblasts, melanocytes, endothelial cells, Langerhans cells, choroidal endothelial cells, retinal pigment epithelial cells, rod photoreceptors and immune cells present in the skin and eyes. Therefore, the regulation of the AHR signal transduction pathway is related to the pathology of various diseases and disorders of the skin and eyes.

[0003] AHR signaling is known to regulate the composition and function of different cell types in the gastrointestinal tract, and therefore plays a prominent role in maintaining the balance between health and disease. AHR is involved in several physiological processes, including the regulation of homeostasis and immunity at the epithelial barrier (such as the barrier formed by intestinal epithelial cells (IEC)). Effective immune responses in vivo occur in the intestine, and therefore, people are very interested in clarifying the molecular mechanisms of the effects of AHR in intestinal mucosal cells, including IEC and various immune cells, such as B cells, T cell receptor γδT cells (TCRγδ), T helper 17 cells (Th17), regulatory T cells (Treg), type 1 regulatory T cells (Tr1), innate lymphocytes (ILC), macrophages (MQ), intraepithelial lymphocytes (IEL), dendritic cells (DC) and neutrophils. Therefore, abnormal AHR activity is related to several intestinal pathologies (such as intestinal inflammation, infection and cancer).

[0004] It is known that AHR signaling plays a major role in bone remodeling by altering the interaction between bone-forming osteoblasts and bone-resorbing osteoclasts. The overall effect of AHR activation in osteoblasts is to inhibit cell differentiation, and AHR excitement has a dose-dependent effect on osteoblasts, in which high and low activation inhibit and promote bone formation, respectively. The AHR pathway is associated with both stimulation and damage to osteoclast differentiation. Therefore, the AHR pathway is an attractive target for treating various human diseases in which osteoblasts and osteoclasts participate in the pathogenesis, including bone-destructive diseases such as osteoporosis and cancer.

[0005] Therefore, compounds that modulate the AHR pathway may be useful in treating diseases or disorders of the gastrointestinal tract, skin, lung, central nervous system, pancreas, eye, bone, osteoarticular, neuroinflammatory diseases, and neurodegenerative diseases. Summary of the invention

[0006] Provided herein are compounds having the structure of Formula (I):

[0007] Where: A is -Y 1 -Z 1 or a fused bicyclic heteroaryl having 8-10 total ring atoms and 1, 2 or 3 heteroatoms selected from N, O or S, and the heteroaryl is optionally substituted by 1, 2 or 3 R a Replace; Y 1 yes O, S, SO or SO2; Z 1 is phenyl or a 5- to 6-membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the phenyl group or the heteroaryl group is optionally substituted by 1, 2 or 3 R a Replace; X 1 Yes N, CR 3 or COLR 2 ; R 1 It is C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Hydroxyalkyl, OC 1-5 Alkyl, C 3-6 Cycloalkyl, N(R N )2、C(=O)C 1-5 Alkyl or C(=CH)C 1-4 Alkyl; each R 2 Independently SO2-R 4 , PO(R 4 )2、CO2H、N(R N )2. N(H)-C 2-6 Alkylene-N(R N )2. N(H)-C2-6 Polyoxyalkylene-N(R N )2、NHCH(R 5 )CO2H、NH-C 1-6 Alkylene -CH (NH2) CO2H, sugar or NH-phenyl, wherein the phenyl group is optionally substituted by 1, 2 or 3 R b Replacement; R 3 Is halogenated, C 1-6 Alkoxy, OH or N(R N )2; each L is independently C(O), C(O)-W n -C(O), C(O)-W n or C(O)NH-W n , or when R 2 SO2-R 4 , PO(R 4 )2 or a sugar, L may be a bond; each W is independently CH2, C 2-3 Alkylene-O or OC 2-3 Alkylene; n is 1, 2, 3, 4, 5 or 6; each R 4 are independently OH or NH2; each R 5 Independently H, C 1-6 Alkyl or C 1-6 Alkylene-R 6 ; R 6 It is CO2H, CO2C 1-3 Alkyl, CON(R N )2、OH、OCH3、N(R N )2, NHC(NH)NH2, a heteroaryl or phenyl group containing 5 or 6 total ring atoms and 1, 2 or 3 heteroatoms selected from N, O and S, wherein the heteroaryl or the phenyl group is optionally replaced by 1, 2, 3, 4 or 5 C 0-2 Alkylene-R b Substituent substitution; each R a are independently halogenated, C 1-6 Alkyl, CO2H, CO2C 1-3 Alkyl, CON(R N )2. OH, OC 1-3 Alkyl or N(R N )2; Each R b Independently, CO2H, CO2C 1-3 alkyl or OH; and each R N independently H or C 1-3 or a pharmaceutically acceptable salt thereof, provided that when Y 1 yes Z 1 is an unsubstituted phenyl group, and R1 When X is isopropyl, 1 Is N or CR 3 , and R 3 Is halogenated, C 1-6 Alkoxy or N(R N )2.

[0008] Further provided herein are pharmaceutical compositions comprising a compound as disclosed herein. Also provided is a method of treating or preventing a disease or condition associated with aberrant aryl hydrocarbon receptor (AHR) activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein.

[0009] By reviewing the following specific embodiments in conjunction with the accompanying drawings, other aspects and advantages will be apparent to those of ordinary skill in the art. Although the compounds and methods disclosed herein allow for various forms of situations, the following description includes specific situations, and it should be understood that the present disclosure is illustrative and is not intended to limit the present invention to the specific situations described herein. DETAILED DESCRIPTION

[0010] Novel aryl hydrocarbon receptor (AHR) agonists are needed to provide new and effective therapies for diseases and conditions, such as inflammatory and autoimmune diseases and conditions. Provided herein are compounds that can act as AHR agonists, such as compounds of formula (I): Among them, A, X 1 , R 1 , R 2 and L are as described herein.

[0011] Compounds of the Disclosure

[0012] Disclosed herein are compounds having the structure of Formula (I): Where: A is -Y 1 -Z 1 or a fused bicyclic heteroaryl having 8-10 total ring atoms and 1, 2 or 3 heteroatoms selected from N, O or S, and the heteroaryl is optionally substituted by 1, 2 or 3 R a Replace; Y 1 yes O, S, SO or SO2; Z 1 is phenyl or a 5- to 6-membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the phenyl group or the heteroaryl group is optionally substituted by 1, 2 or 3 R a Replace; X 1 Yes N, CR 3 or COLR 2 ; R 1 It is C 1-5 Alkyl, C1-5 Haloalkyl, C 1-5 Hydroxyalkyl, OC 1-5 Alkyl, C 3-6 Cycloalkyl, N(R N )2、C(=O)C 1-4 Alkyl or C(=CH)C 14 Alkyl; each R 2 Independently SO2-R 4 , PO(R 4 )2、CO2H、N(R N )2. N(H)-C 2-6 Alkylene-N(R N )2. N(H)-C 2-6 Polyoxyalkylene-N(R N )2、NHCH(R 5 )CO2H、NH-C 1-6 Alkylene -CH (NH2) CO2H, sugar or NH-phenyl, wherein the phenyl group is optionally substituted by 1, 2 or 3 R b Replacement; R 3 Is halogenated, C 1-6 Alkoxy, OH or N(R N )2; each L is independently C(O), C(O)-W n -C(O), C(O)-W n or C(O)NH-W n , or when R 2 SO2-R 4 , PO(R 4 )2 or a sugar, L may be a bond; each W is independently CH2, C 2-3 Alkylene-O or OC 2-3 Alkylene; n is 1, 2, 3, 4, 5 or 6; each R 4 are independently OH or NH2; each R 5 Independently H, C 1-6 Alkyl or C 1-6 Alkylene-R 6 ; R 6 It is CO2H, CO2C 1-3 Alkyl, CON(R N )2、OH、OCH3、N(R N )2, NHC(NH)NH2, a heteroaryl or phenyl group containing 5 or 6 total ring atoms and 1, 2 or 3 heteroatoms selected from N, O and S, wherein the heteroaryl or the phenyl group is optionally replaced by 1, 2, 3, 4 or 5 C 0-2 Alkylene-R b Substituent substitution; each R a are independently halogenated, C1-6 Alkyl, CO2H, CO2C 1-3 Alkyl, CON(R N )2. OH, OC 1-3 Alkyl or N(R N )2; Each R b Independently, CO2H, CO2C 1-3 alkyl or OH; and each R N independently H or C 1-3 or a pharmaceutically acceptable salt thereof, provided that when Y 1 yes Z 1 is an unsubstituted phenyl group, and R 1 When X is isopropyl, 1 Is N or CR 3 , and R 3 Is halogenated, C 1-6 Alkoxy or N(R N )2.

[0013] In the compound of formula (I), A may be -Y 1 -Z 1 or a fused bicyclic heteroaryl having 8-10 total ring atoms and 1, 2 or 3 heteroatoms selected from N, O or S, and the heteroaryl is optionally substituted by 1, 2 or 3 R a In each case, A is -Y 1 -Z 1 In the compound of formula (I), Y 1 Can O, S, SO or SO2. In each case, Y 1 yes In some cases, Y 1 is S, SO or SO2. In the compound of formula (I), Z 1 It may be phenyl or a 5- to 6-membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the phenyl or heteroaryl group is optionally substituted by 1, 2 or 3 R a In each case, Z 1 is phenyl. In some cases, Z 1 is a 5- to 6-membered heteroaryl. 1 is pyridine, pyrazole, imidazole or pyrimidine. 1 is unsubstituted. In some cases, Z 1 By 1 or 2 R a Replace; wherein each R a are independently halogenated, C 1-3 In each case, the substituted Z1 At least one R a In each case, the substituted Z 1 At least one R a is OH. In some cases, the substituted Z 1 At least one R a is CO2H. In some cases, the substituted Z 1 At least one R a It is CO2C 1-3 In some cases, the substituted Z 1 At least one R a It is CON(R N )2. In some cases, the substituted Z 1 At least one R a It's OC 1-3 In some cases, the substituted Z 1 At least one R a is N(R N )2.

[0014] In various cases, A is a fused bicyclic heteroaryl. In some cases, A is a 10-membered heteroaryl. In some cases, A is isoquinoline, quinoline, or quinazoline. In some cases, A is Or if R 2 SO2-R 4 or PO(R 4 )2, A is In some cases, A is unsubstituted. In each case, A is replaced by 1 or 2 R a Replace; wherein each R a are independently halogenated, C 1-3 In each case, at least one R of the substituted A a In each case, at least one R of the substituted A a is OH. In some cases, at least one R of the substituted A a is CO2H. In some cases, at least one R of the substituted A a It is CO2C 1-3 In some cases, at least one R of the substituted A is a It is CON(R N )2. In some cases, at least one R of the substituted A a It's OC 1-3 In some cases, at least one R of the substituted A is a is N(R N )2.

[0015] In some cases, A or Z 1 1, 2 or 3 R a In some cases, A or Z 1 By 1 or 2 R a In the compound of formula (I), each R a can be independently halogenated, C 1-6 Alkyl, CO2H, CO2C 1-3 Alkyl, CON(R N )2. OH, OC 1-3 Alkyl or N(R N )2. In each case, at least one R a is halogenated. In each case, at least one R a is OH. In some cases, at least one R a is CO2H. In some cases, at least one R a It is CO2C 1-3 In some cases, at least one R a It is CON(R N )2. In some cases, at least one R a It's OC 1-3 In some cases, at least one R a is N(R N )2.

[0016] In the compound of formula (I), X 1 Can be N, CR 3 or COLR 2 In each case, X 1 is N. In each case, X 1 Yes CR 3 In the compound of formula (I), R 3 Can be halogenated, OH or N(R N )2. In some cases, R 3 is F or OH. In some cases, R 3 is N(R N )2. In each case, X 1 It is COLR 2 In each case, X 1 It is COR 2 In each case, X 1 It is C-OSO2-R 4 or C-OPO(R 4 )2.

[0017] In the compound of formula (I), R 1 Can be C1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Hydroxyalkyl, OC 1-5 Alkyl, C 3-6 Cycloalkyl, N(R N )2、C(=O)C 1-4 Alkyl or C(=CH)C 1-4 In each case, R 1 It is C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 In some cases, R 1 It is C 1-3 In each case, R 1 is a C3 alkyl group. 1 It's OC 1-5 Alkyl, N(R N )2 or C(=O)C 1-4 alkyl.

[0018] In the compounds of formula (I), each L can independently be C(O), C(O)-W n -C(O), C(O)-W n or C(O)NH-W n , or when R 2 SO2-R 4 , PO(R 4 )2 or a sugar, L can be a bond. In various cases, L is a bond. In some cases, each L is independently C(O), C(O)- n -C(O), C(O)-W n or C(O)NH-W n In the compound of formula (I), each W can be independently CH2, C 2-3 Alkylene-O or OC 2-3 In each case, W is CH2 or C 2-3 In the compounds of formula (I), n may be 1, 2, 3, 4, 5 or 6. In each case, n is 1 or 2.

[0019] In the compound of formula (I), each R 2 Can be independently SO2-R 4 , PO(R 4 )2、CO2H、N(R N )2. N(H)-C 2-6 Alkylene-N(R N )2. N(H)-C 2-6 Polyoxyalkylene-N(R N)2、NHCH(R 5 )CO2H、NH-C 1-6 Alkylene -CH (NH2) CO2H, sugar or NH-phenyl, wherein the phenyl group is optionally substituted by 1, 2 or 3 R b Replace; wherein each R b Can be CO2H, CO2C independently 1-3 Alkyl or OH. In each case, at least one R b is CO2H or OH. In the compound of formula (I), each R N Can be independently H or C 1-3 In each case, R 2 SO2-R 4 or PO(R 4 )2. In each case, R 2 is SO2H or PO(OH)2. In some cases, R 2 It is N(H)-C 2-6 Alkylene-N(R N )2. N(H)-C 2-6 Polyoxyalkylene-N(R N )2、NHCH(R 5 )CO2H or NH-C 1-6 Alkylene -CH(NH2)CO2H. In some cases, R 2 It is N(H)-C 2-6 Alkylene-N(R N )2 or NH-C 1-6 Alkylene -CH(NH2)CO2H. In some cases, R 2 is NHCH(R 5 )CO2H. In each case, at least one R 2 It is NH-phenyl.

[0020] In the compound of formula (I), each R 4 can be independently OH or NH2. In each case, at least one R 4 is OH. In some cases, at least one R 4 It's NH2.

[0021] In the compound of formula (I), each R 5 Independently H, C 1-6 Alkyl or C 1-6 Alkylene-R 6 In each case, each R 5 Independently C 1-6 Alkyl or C 1-6 Alkylene-R 6 .

[0022] In the compound of formula (I), each R 6 Independently, CO2H, CO2C 1-3 Alkyl, CON(R N )2、OH、OCH3、N(R N )2, NHC(NH)NH2, a heteroaryl or phenyl group containing 5 or 6 total ring atoms and 1, 2 or 3 heteroatoms selected from N, O and S, wherein the heteroaryl or the phenyl group is optionally replaced by 1, 2, 3, 4 or 5 C 0-2 Alkylene-R b In each case, R 6 It is CO2H, CO2CH3, CONH2, OH, OCH3, NH2, NHC(NH)NH2, imidazolyl, phenyl or 4-hydroxy-phenyl.

[0023] In each case, at least one R 2 is NH-phenyl; wherein the phenyl group is replaced by 1 or 2 R b In some cases, each R 2 and / or R 6 1 to 5 R b In the compound of formula (I), each R b Can be CO2H, CO2C independently 1-3 Alkyl or OH. In each case, at least one R b is CO2H or OH. In the compound of formula (I), each R N Can be independently H or C 1-3 In each case, each R N is H. In some cases, at least one R N is CH3. In some cases, at least one R N It is CH2CH3.

[0024] In some cases, the compound of formula (I) is (E)-2-isopropyl-5-styrylpyridin-3-yl hydrogen sulfate, (E)-2-isopropyl-5-styrylpyridin-3-yl dihydrogen phosphate, 3-hydroxy-2-isopropyl-5-(isoquinolin-3-yl)phenyl hydrogen sulfate, 3-hydroxy-2-isopropyl-5-(isoquinolin-3-yl)phenyl dihydrogen phosphate, 3-hydroxy-2-isopropyl-5-(quinolin-3-yl)phenyl hydrogen sulfate, 3-hydroxy-2-isopropyl-5-(quinolin-3-yl)phenyl dihydrogen phosphate, 2-isopropyl-5-(quinolin-3-yl)-1,3-phenylenebis(hydrogen sulfate), 2-isopropyl-5-(quinolin-3-yl)-1,3-phenylenebis(hydrogen sulfate), 3-yl)-1,3-phenylenebis(dihydrogen phosphate), (E)-5-(2-fluorostyryl)-2-isopropylpyridin-3-yl hydrogen sulfate, (E)-5-(2-fluorostyryl)-2-isopropylpyridin-3-yl dihydrogen phosphate, (E)-5-(3-fluorostyryl)-2-isopropylpyridin-3-yl hydrogen sulfate, (E)-5-(3-fluorostyryl)-2-isopropylpyridin-3-yl dihydrogen phosphate, (E)-5-(4-fluorostyryl)-2-isopropylpyridin-3-yl hydrogen sulfate, (E)-5-(4-fluorostyryl)-2-isopropylpyridin-3-yl dihydrogen phosphate, 5-(2-amino-5-fluoroquinazoline-7 -yl)-3-hydroxy-2-isopropylphenyl hydrogen sulfate, 5-(2-amino-5-fluoroquinazolin-7-yl)-3-hydroxy-2-isopropylphenyl dihydrogen phosphate, 5-(2-amino-5-fluoroquinazolin-7-yl)-2-isopropyl-1,3-phenylene bis(hydrogen sulfate); 5-(2-amino-5-fluoroquinazolin-7-yl)-2-isopropyl-1,3-phenylene bis(dihydrogen phosphate); 5-(6-fluoroquinolin-2-yl)-3-hydroxy-2-isopropylphenyl hydrogen sulfate, 5-(6-fluoroquinolin-2-yl)-3-hydroxy-2-isopropylphenyl dihydrogen phosphate, 5-(6-fluoroquinolin-2-yl)-2-isopropyl-1,3-phenylene bis(hydrogen sulfate), 5-(6-fluoroquinolin-2-yl)-2-isopropyl-1,3-phenylene bis(dihydrogen phosphate), (E)-3-fluoro-2-propyl-5-phenylvinylphenyl hydrogen sulfate, (E)-3-fluoro-2-propyl-5-phenylvinylphenyl dihydrogen phosphate, (E)-3-fluoro-2-isopropyl-5-phenylvinylphenyl hydrogen sulfate, (E)-3-fluoro-2-isopropyl-5-phenylvinylphenyl dihydrogen phosphate, 3-fluoro-2-isopropyl-5-phenylvinylphenyl dihydrogen phosphate, 3-fluoro-2-isopropyl-5-(4-methylquinolin-7-yl)phenyl hydrogen sulfate or 3-fluoro-2-isopropyl-5-(4-methylquinolin-7-yl)phenyl dihydrogen phosphate, or a pharmaceutically acceptable salt of any one of the foregoing.

[0025] In some cases, the compound of formula (I) is 2-isopropyl-5-(quinolin-3-yl)-1,3-phenylene bis(dihydrogen phosphate), 2-isopropyl-5-(quinolin-3-yl)-1,3-phenylene bis(hydrogen sulfate), (E)-5-(2-fluorostyryl)-2-isopropylpyridin-3-yl hydrogen sulfate, (E)-5-(2-fluorostyryl)-2-isopropylpyridin-3-yl dihydrogen phosphate, (E)-3-fluoro-2-propyl-5-styrylphenyl hydrogen sulfate, (E)-3-fluoro-2-propyl-5-phenylvinylphenyl dihydrogen phosphate, (E)-3-fluoro-2-isopropyl-5-phenylvinylphenyl dihydrogen phosphate, (E)-3-fluoro-2-isopropyl-5-phenylvinylphenyl dihydrogen phosphate, 3-fluoro-2-isopropyl-5-(4-methylquinolin-7-yl)phenyl hydrogen sulfate or 3-fluoro-2-isopropyl-5-(4-methylquinolin-7-yl)phenyl dihydrogen phosphate or a pharmaceutically acceptable salt of any one of the foregoing.

[0026] In some cases, the compound of formula (I) is or a pharmaceutically acceptable salt thereof. In some cases, the compound of formula (I) is or a pharmaceutically acceptable salt thereof.

[0030] Unless otherwise indicated, the structures depicted herein are also meant to include all isomeric (e.g., enantiomers, diastereomers, cis-trans, conformation and rotation) forms of the structure. For example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in the present disclosure unless only one isomer in the isomer is specifically indicated. Therefore, single stereochemical isomers of the compounds of the present invention as well as enantiomers, diastereomers, cis / trans, conformation and rotation mixtures are within the scope of the present disclosure. In some cases, the compounds disclosed herein are stereoisomers. "Stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds disclosed herein may exist as single stereoisomers or as mixtures of multiple stereoisomers. The stereochemistry of the compounds shown herein indicates relative stereochemistry, rather than absolute stereochemistry, unless otherwise discussed. As indicated herein, a single stereoisomer, diastereomer or enantiomer refers to a compound that is at least greater than 50% of the indicated stereoisomer, diastereomer or enantiomer, and in some cases at least 90% or 95% of the indicated stereoisomer, diastereomer or enantiomer.

[0031] The compounds disclosed herein having double bonds can be 1 In some cases, the compound of formula (I) exhibits E or Z (not shown) stereochemistry at the double bond of Y 1 In each case, the compounds of formula (I) exhibit Z stereochemistry at the double bond. The compounds of formula (I) exhibit Z stereochemistry at any sp 3 The carbon atoms may have any stereochemical configuration. In some cases, the compounds of the present disclosure are optically pure. As used herein, "optically pure" means that if multiple stereochemical configurations can exist (e.g., at least 99% enantiomeric excess), then there is predominantly one enantiomer in the compound.

[0032] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0033] The compounds of the present disclosure are defined herein by their chemical structure and / or chemical name. When a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure determines the identity of the compound.

[0034] As used herein, "alkyl" refers to straight and branched chain saturated hydrocarbon groups containing from one to thirty carbon atoms, for example, from one to four carbon atoms (e.g., 1, 2, 3 or 4). n It means that the alkyl group has "n" carbon atoms. For example, C3 alkyl refers to an alkyl group with 3 carbon atoms. 1-4 Alkyl refers to an alkyl group having a carbon number covering the entire range (i.e., 1 to 4 carbon atoms) and all subranges (e.g., 1-2, 1-3, 2-3, 2-4, 1, 2, 3, and 4 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.

[0035] As used herein, "alkylene" refers to a divalent saturated aliphatic group. n This means that the alkylene group has "n" carbon atoms. For example, C 1-6 Alkylene refers to alkylene groups having a number of carbon atoms covering the entire range, and all subranges, as previously described for "alkyl" groups. As used herein, "polyoxyalkylene" refers to alkylene groups having ether bonds present at the terminal ends and optionally within the alkylene chain. 2-6Non-limiting examples of polyoxyalkylene groups include polyethylene glycol moieties and polypropylene glycol moieties, such as C2 polyoxyalkylene groups (eg, -CH2CH2OCH2CH2O- and -CH2CH2CH2OCH2CH2CH2O-).

[0036] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by 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.

[0037] As used herein, the term "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group (OH). Such groups include, but are not limited to, hydroxymethyl, hydroxyethyl, and the like.

[0038] As used herein, the term "heteroaryl" refers to a cyclic aromatic ring having a heteroatom in the ring (e.g., a monocyclic aromatic ring having 5-6 total ring atoms or a fused bicyclic ring having 10 total ring atoms) and containing one to three heteroatoms selected from nitrogen, oxygen and sulfur atoms in the aromatic ring. Unless otherwise indicated, a heteroaryl group may be unsubstituted or substituted. A heteroaryl group may be isolated (e.g., pyridyl) or fused to another heteroaryl group (e.g., purinyl), cycloalkyl (e.g., tetrahydroquinolinyl), heterocycloalkyl (e.g., dihydronaphthyridinyl) and / or aryl (e.g., benzothiazolyl, quinolinyl, isoquinolinyl or quinazolinyl). Examples of contemplated heteroaryl groups include, but are not limited to, pyrazolyl, thienyl, furanyl, pyridinyl, pyrrolyl, oxazolyl, quinolyl, thienyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.

[0039] As used herein, a fused bicyclic heteroaryl refers to a heteroaryl fused to another heteroaryl, and each ring may contain five or six total ring atoms and one to three heteroatoms in its aromatic ring. Examples of fused bicyclic heteroaryls include, but are not limited to, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, indolizinyl, purinyl, benzofuranyl, benzimidazolyl, quinolyl, isoquinolyl, naphthyridinyl, and pyridopyrazinyl.

[0040] As used herein, the term "halo" refers to a fluoro (F), chloro (Cl), bromo (Br), or iodo (I) group.

[0041] As used herein, "substituted" functional groups are functional groups having at least one hydrogen group substituted 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, cycloalkyl, alkynyl, ether, aryl, heteroaryl, heterocycloalkyl, hydroxyl, oxy (or oxo), alkoxy, ester, thioester, acyl, carboxyl, cyano, nitro, amino, sulfhydryl, and halo. When the substituted alkyl includes more than one non-hydrogen group, the substituent may be combined with the same carbon or two or more different carbon atoms.

[0042] As used herein, the sugar may be any sugar known in the art, such as a monosaccharide (e.g., a sugar having the general formula C6H 12 06 monosaccharides), disaccharides (e.g., sugars comprising two monosaccharides linked together by glycosidic bonds), oligosaccharides (e.g., sugars comprising 3-10 monosaccharides linked together by glycosidic bonds), polysaccharides (e.g., sugars comprising seven or more monosaccharides linked together by glycosidic bonds), or amino sugars (e.g., sugars in which the hydroxyl groups have been replaced by amino groups). As used herein, a glycosidic bond is a bond between a hemiacetal or hemiketal group of a sugar (or a molecule derived from a sugar) and a hydroxyl group of a second sugar. Each glycosidic bond can independently be an α-glycosidic bond (e.g., the carbon atoms of each partner of the glycosidic bond have the same stereochemistry) or a β-glycosidic bond (e.g., the carbon atoms of each partner of the glycosidic bond have different stereochemistry). In some cases, an oligosaccharide comprises an α-glycosidic bond. In some embodiments, the sugar is a monosaccharide, a disaccharide, an oligosaccharide, or an amino sugar. Conceived monosaccharides include, but are not limited to, glucose, fructose, galactose, ribose, and xylose. In some embodiments, the sugar is an oligosaccharide comprising 3-10 monosaccharide units. In various embodiments, the oligosaccharide comprises an α-1,4 glycosidic bond. In some cases, the oligosaccharide is a cyclic oligosaccharide having 5-8 pyranose units. In some embodiments, the pyranose unit comprises glucose. In various embodiments, the oligosaccharide comprises a cyclodextrin. In some cases, at least one -OLR 2 yes

[0043]

[0044] Pharmaceutically acceptable salts

[0045] As used herein, the term "pharmaceutically acceptable salt" refers to salts of compounds that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue adverse effects (e.g., toxicity, irritation, allergic response, etc.) and are commensurate with a reasonable benefit / risk ratio.

[0046] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe 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 appropriate inorganic and organic acids and bases. These salts can be prepared in situ during the final separation and purification of the compound.

[0047] In the case where the compounds described herein contain a basic group or a sufficiently basic bioisostere, an acid addition salt can be prepared by 1) reacting the purified compound in free base form with a suitable organic or inorganic acid, and 2) isolating the salt thus formed. In practice, the acid addition salt may be a more convenient form for use, and use of the salt is equivalent to use of the free base form.

[0048] Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by an amino group with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or an organic acid (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucose heptanoate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- Hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0049] In the case where the compounds described herein contain a carboxyl group or a sufficiently acidic bioisostere, base addition salts can be prepared by 1) reacting the purified compound in acid form with a suitable organic or inorganic base, and 2) isolating the salt thus formed. In practice, it may be more convenient to use base addition salts, and the use of the salt form is essentially equivalent to the use of the free acid form. Salts derived from appropriate bases include alkali metals (e.g., sodium, lithium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium and N + (C1-4 The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. By such quaternization, water-soluble or oil-soluble or dispersible products can be obtained.

[0050] Base addition salts include pharmaceutically acceptable metal salts and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum. Sodium salts and potassium salts are usually preferred. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates when appropriate. Suitable inorganic base addition salts are prepared from metal bases, including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, etc. Suitable amine base addition salts are prepared from amines, which are often used in pharmaceutical chemistry because of their low toxicity and acceptability for medical use. Ammonia, ethylenediamine, N-methyl-glucosamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietinamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylamine, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine, etc.

[0051] While other acids and bases are not in themselves pharmaceutically acceptable, they may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

[0052] 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 free forms of the compounds and pharmaceutically acceptable salts are also envisioned.

[0053] Drug formulations

[0054] Also provided herein are pharmaceutical formulations comprising an effective amount of a compound of the present disclosure and one or more pharmaceutically acceptable excipients. As used herein, the term "formulation" is used interchangeably with "composition."

[0055] "Effective amount" includes "therapeutically effective amount" and "prophylactically effective amount". The term "therapeutically effective amount" refers to an amount that effectively treats and / or improves a disease or condition in a subject. The term "prophylactically effective amount" refers to an amount that is effective in preventing and / or significantly reducing the chance of a subject developing a disease or condition. As used herein, the terms "patient" and "subject" can be used interchangeably and mean animals such as dogs, cats, cows, horses and sheep (i.e., non-human animals) and humans. A specific patient or subject is a mammal (e.g., a human). The terms "patient" and "subject" include males and females.

[0056] As used herein, the term "excipient" means any pharmaceutically acceptable additive, carrier, diluent, adjuvant or other ingredient other than the active pharmaceutical ingredient (API), which is appropriately selected according to the intended administration form and in accordance with conventional pharmaceutical practice.

[0057] The compounds of the present disclosure may be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds may be administered all at once (e.g., by bolus injection), multiple times (e.g., by a series of tablets), or substantially uniformly over a period of time (e.g., using transdermal delivery). It should also be noted that the dosage of the compound may vary over time.

[0058] If desired, the compounds disclosed herein and other pharmaceutically active compounds can be administered to a subject or patient by any suitable route, such as orally, topically, rectally, parenterally (e.g., subcutaneously, intravenously, intramuscularly, intrasternal and intrathecal injection or infusion techniques), or as an oral spray, inhalation spray or nasal spray. Administration can be intended to provide a systemic effect (e.g., enterally or parenterally). All methods that one skilled in the art can use to administer a pharmaceutically active agent are contemplated. In some cases, the disclosed formulations can be administered orally or topically.

[0059] Suitable oral compositions or formulations according to the present disclosure include, but are not limited to, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions or formulations suitable for oral use can be prepared according to any method known in the art for making pharmaceutical compositions.

[0060] 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, the liquid dosage form can also 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-butylene glycol, dimethylformamide, oil (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and aromatics.

[0061] 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 starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarder, such as paraffin; f) absorption promoter, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) adsorbents, 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.

[0062] Solid compositions of similar types 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 of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as other coatings known in the field of enteric coatings and pharmaceutical formulations. The dosage form can optionally contain an emulsifier and its composition can also make the dosage form release the active ingredient only or preferentially in a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of similar types 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.

[0063] The active compound can also be in microencapsulated form with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells (such as enteric coatings, release control coatings and other coatings known in the field of drug formulation). In such solid dosage forms, the active compound can be mixed with at least one inert diluent (such as sucrose, lactose or starch). Under normal circumstances, in addition to inert diluents, such dosage forms can also include other substances, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can also include a buffer. The dosage form can optionally contain an emulsifier and its composition can also make the dosage form only or preferentially release the active ingredient in a delayed manner in a specific part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0064] The pharmaceutical compositions and formulations described herein can also be administered topically or transdermally, especially when the therapeutic target includes areas or organs that are easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations for each of these areas or organs are readily prepared. Topical administration to the lower intestinal tract can be achieved, for example, with a rectal suppository formulation or with a suitable enema formulation. Dosage forms for topical or transdermal administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, suppositories, or patches.

[0065] For topical application, the pharmaceutical composition can be formulated into suitable ointments, creams, emulsions or gels (which contain active components suspended or dissolved in one or more carriers) and any desired preservatives or buffers that may be needed. The carrier for topical application of the disclosed compound includes but is not limited to mineral oil, liquid paraffin oil, white paraffin oil, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated into suitable lotions or creams, which contain active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, hexadecyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0066] Ophthalmic formulations, ear drops and eye drops are also considered to be within the scope of the present disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of enabling the compound to be delivered to the body in a controlled manner. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. Rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or a gel.

[0067] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are routinely used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, injectables are prepared using fatty acids such as oleic acid.

[0068] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable vehicle prior to use.

[0069] In order to prolong the effect of the compounds described herein, it is generally desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injections. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. Thus, the absorption rate of the compound depends on its dissolution rate, which in turn can depend on crystal size and crystal form. Alternatively, delayed absorption of the compound form administered parenterally is achieved by dissolving or suspending the compound in an oily vehicle. Injectable reservoir-type (depot) forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. According to the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir-type injectable formulations are also prepared by trapping the compound in a liposome or microemulsion compatible with human tissue.

[0070] Compositions for rectal or vaginal administration are particularly suppositories which can be prepared by mixing a compound described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at room temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0071] The sterile injectable form of the composition described herein can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, for example in the form of solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and their glyceride derivatives can be used to prepare injectables, as can natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used to prepare pharmaceutically acceptable dosage forms (including emulsions and suspensions). For the purposes of formulation, other commonly used surfactants (eg, Tweens, Spans) and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used.

[0072] The pharmaceutical compositions can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulations and can be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0073] The compounds used in the methods of the present disclosure can be formulated into unit dosage forms. The term "unit dosage form" refers to a single dose suitable for a subject to be treated, each unit comprising a predetermined amount of active material calculated to produce a desired therapeutic effect associated with an optionally suitable pharmaceutical carrier. The unit dosage form can be a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.

[0074] The compounds of the present disclosure can be administered to a subject or patient at a dosage level of about 0.1 to about 3,000 mg per day. For a normal adult weighing about 70 kg, a dosage of about 0.01 to about 100 mg per kilogram of body weight is generally sufficient. The specific dosage and dosage range to be used may 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 administered compound. It is within the ordinary skill of the art to determine the dosage range and optimal dosage for a particular subject or patient.

[0075] Treatment

[0076] Compounds disclosed herein (e.g., compounds of formula (I)) and pharmaceutically acceptable salts thereof can act as agonists of the aryl hydrocarbon receptor (AHR) pathway. The AHR is a ligand-activated transcription factor that is associated with a variety of pathologies, including by regulating the immune system during steady state and during infection and inflammation. The AHR pathway is recognized for its role in the pathogenesis of: inflammatory skin diseases such as atopic dermatitis, acne, psoriasis, and vitiligo; intestinal pathologies such as inflammatory bowel disease, necrotizing enterocolitis, and other autoimmune diseases, and colorectal cancer; diseases and conditions of bones and joints, including rheumatoid arthritis; diseases of the eye, such as age-related macular degeneration; and lung diseases, such as pulmonary fibrosis, chronic obstructive pulmonary disease. The AHR pathway is also recognized for its role in the pathogenesis of diseases and conditions, including neuroinflammatory diseases and conditions, neurodegenerative diseases and conditions, cancer, diabetes, viral and bacterial infections.

[0077] Thus, the present disclosure provides a method of regulating an aryl hydrocarbon receptor (AHR) in a cell, the method comprising contacting the cell with a therapeutically effective amount of a compound or salt disclosed herein (e.g., a compound of formula (I) and a pharmaceutically acceptable salt of any of the foregoing) or a formulation thereof that is effective in regulating AHR. In some cases, the contact occurs in vitro. In some cases, the contact occurs in vivo. In some cases, the contact comprises administration to a subject in need. As used herein, the terms "patient" and "subject" may be used interchangeably and refer to animals such as dogs, cats, cattle, horses and sheep (i.e., non-human animals) and humans. A particular patient is a mammal (e.g., a human). In some cases, the subject suffers from an inflammatory disease or condition. In some cases, the subject suffers from a disease or condition of the gastrointestinal tract, skin, lungs, eyes, or bone and joints. In some cases, the subject suffers from cancer or a viral infection.

[0078] Another aspect of the present disclosure provides a method for treating a disease or condition of a subject, the method comprising administering to the subject a therapeutically effective amount of a compound or salt disclosed herein (e.g., a compound of formula (I)) or a formulation thereof. In some cases, the term "treating / treat / treatment" and the like may include preventive (e.g., prophylactic) and palliative treatments. In some cases, the disease or condition is an inflammatory disease or condition. In some cases, the disease or condition is a disease or condition of the gastrointestinal tract, skin, lung, central nervous system (CNS), pancreas, eye, bone, or osteoarticular, a neuroinflammatory disease, or a neurodegenerative disease. In some cases, the disease or condition is diabetes, cancer, a viral infection, or a bacterial infection.

[0079] In some cases, the disease or illness of the gastrointestinal tract is colitis, inflammatory bowel disease, Crohn's disease, celiac disease, necrotizing enterocolitis, irritable bowel syndrome, chronic idiopathic constipation, traveler's diarrhea or colorectal cancer. In some cases, the disease or illness of the skin is atopic dermatitis, acne, psoriasis or vitiligo. In some cases, the disease or illness of the eye 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, Behcet's disease (Behcet'sdisease) or Leber congenital amaurosis (" LCA "). In some cases, the disease or illness of the lung is pulmonary fibrosis, asthma or chronic obstructive pulmonary disease. In some cases, the disease or condition of the bone or bone joint is osteoporosis, rheumatoid arthritis, or bone cancer. In some cases, the disease or condition of the central nervous system is Alzheimer's disease and other memory disorders, amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease, or motor neuron disease). In some cases, the disease or condition of the pancreas is type 1 diabetes. In some instances, the autoimmune disease or disorder is hidradenitis suppurativa, systemic sclerosis, lupus nephritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis (NR-Ax-SpA), rheumatoid arthritis, juvenile idiopathic arthritis (JIA), Crohn's disease, ulcerative colitis, systemic lupus erythematosus, atopic dermatitis, chronic obstructive pulmonary disease, severe asthma, psoriasis, Sjogren's disease, chronic spontaneous urticaria, cutaneous lupus erythematosus, Still's Disease, idiopathic pulmonary fibrosis, dermatomyositis, sarcoidosis, psoriatic arthritis, pustular psoriasis of bone, osteoarthritis, alopecia areata, giant cell arteritis (GCA), ANCA vasculitis, vasculitis, eosinophilic esophagitis, acute respiratory distress syndrome, severe acne, or lichen planus. In some cases, the neuroinflammatory disease or disorder is multiple sclerosis, Rasmussen's encephalitis, acute disseminated encephalomyelitis (ADEM), autoimmune encephalitis, transverse myelitis (TM) or anti-NMDA receptor encephalitis. In some cases, the neurodegenerative disease or disorder is uveitis, optic neuritis, neuromyelitis optica spectrum disorder (NMOSD) or age-related macular degeneration (AMD).

[0080] In some cases, the disease or condition is diabetes (e.g., type 1 diabetes or type 2 diabetes). In some cases, the disease or condition is cancer. Conceived cancers that can be treated using the compounds and methods described herein include, but are not limited to, blood cancers, lymphomas, myelomas, leukemias, nervous system cancers, skin cancers, breast cancers, prostate cancers, respiratory cancers, reproductive cancers, digestive tract cancers, colorectal cancers, lung cancers, head and neck cancers, gastrointestinal cancers, liver cancers, pancreatic cancers, urogenital cancers, bone cancers, kidney cancers, and vascular cancers.

[0081] In some cases, the disease or illness is a viral infection. In some cases, the compounds of the present disclosure (such as compounds of formula (I) and any of the foregoing pharmaceutically acceptable salts or compositions thereof) can 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 (e.g., SARS, MERS and COVID-19, such as SARS-CoV infection, MERS-CoV and SARS-CoV-2 infection, respectively) and flavivirus infections (e.g., West Nile virus infection, dengue virus infection, tick-borne encephalitis virus infection, yellow fever virus infection, Zika virus infection and several other viruses that may cause encephalitis).

[0082] In some cases, the disease or condition is a bacterial infection. In some cases, the compounds of the present disclosure (such as compounds of formula (I) and any of the foregoing pharmaceutically acceptable salts or compositions thereof) can be used to treat bacterial infections. In some cases, bacterial infections treated using the compounds and methods described herein include but are not limited to lung infections, gastrointestinal infections, skin infections, ear infections or sepsis.

[0083] Another aspect of the present disclosure provides the use of a compound disclosed herein, such as a compound of formula (I), a pharmaceutically acceptable salt thereof, or a formulation comprising a compound or salt disclosed herein, in the treatment of inflammatory diseases or disorders, such as diseases or disorders of the gastrointestinal tract, skin, lung, central nervous system, pancreas, eye, bone or osteoarticular, neuroinflammatory diseases and disorders, or neurodegenerative diseases and disorders.

[0084] Also contemplated is the use of a compound disclosed herein, such as a compound of formula (I), a pharmaceutically acceptable salt thereof, or a formulation comprising a compound or salt disclosed herein, in the manufacture of a medicament for treating inflammatory diseases or disorders, such as diseases or disorders of the gastrointestinal tract, skin, lungs, central nervous system, pancreas, eyes, bones or osteoarticular diseases and disorders, neuroinflammatory diseases and disorders, or neurodegenerative diseases and disorders.

[0085] Also contemplated is the use of the compounds disclosed herein, such as compounds of Formula (I), pharmaceutically acceptable salts thereof, or formulations comprising the compounds or salts disclosed herein, to treat inflammatory diseases or disorders, such as diseases or disorders of the gastrointestinal tract, skin, lungs, central nervous system, pancreas, eyes, bones or osteoarticular, neuroinflammatory diseases and disorders, or neurodegenerative diseases and disorders.

[0086] In some cases, formula (I) compounds as disclosed herein or their pharmaceutically acceptable salts can be administered in combination with another therapeutic agent to treat a disease or condition, such as a disease or condition disclosed herein. In some cases, combination therapy can be used to treat inflammatory diseases or conditions (e.g., diseases or conditions of the gastrointestinal tract, skin, eyes, lungs or osteoarticular). As used herein, the term "co-administered", "administered with..." or "administered in combination with..." etc. covers the administration of the selected therapeutic agent to a single patient, and is intended to include a treatment regimen in which the agent is administered by the same or different routes of administration or at the same or different times. Therefore, in any method disclosed herein, treating a disease or condition disclosed herein, such as an inflammatory disease or condition (e.g., a gastrointestinal tract, skin, lungs, central nervous system, pancreas, eyes, bone or osteoarticular disease or condition, neuroinflammatory disease and condition or neurodegenerative disease and condition) includes co-administering a compound of the present disclosure, such as a compound of formula (I), a pharmaceutically acceptable salt thereof, or a formulation comprising a compound disclosed herein or a salt combined with another therapeutic agent. In some cases, other therapeutic agents are anti-inflammatory agents. Contemplated anti-inflammatory agents for co-administration with the compounds of the present disclosure include, for example, mesalamine, naproxen, ibuprofen, diclofenac, celecoxib, sulindac, oxaprozin, piroxicam, indomethacin, meloxicam, fenoprofen, difunisal, etodolac, ketorolac tromethamine, meclofenac, nabumetone, salicylic acid, or any combination of the foregoing.

[0087] In jurisdictions that prohibit patenting of methods practiced on humans, the meaning of "administering" a composition to a human subject or patient shall be limited to prescribing a controlled substance to be self-administered by the human subject or patient by any technique (e.g., oral, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with the law or regulation defining patentable subject matter is intended. In jurisdictions that do not prohibit patenting of methods practiced on humans, "administration" of a composition includes both methods practiced on humans as well as the aforementioned activities.

[0088] Synthesis of Compounds of the Disclosure

[0089] The compounds of the present disclosure can be synthesized by any method known in the art. For example, the compounds of the present disclosure (compounds of formula (I)) can be synthesized according to Schemes 1, 2, 3 and 4.

[0090] As shown in Scheme 1 below, compounds wherein A is an optionally substituted fused bicyclic heteroaryl having 8-10 total ring atoms and 1, 2 or 3 heteroatoms selected from N, O or S can be synthesized by, for example, Suzuki coupling.

[0091] Solution 1

[0092]

[0093] Coupling the desired phenyl or pyridyl moiety a with the desired fused bicyclic heteroaryl (Het) conjugated to an organoboronic acid b yields compounds c of the present disclosure. Note that while the above scheme shows an "OLR 2 " part is already in place, but an alternative synthesis could include an organoboronic acid aromatic coupling and then introduce the "OLR 2 ” Sidechain.

[0094] As shown in Scheme 2 below, the following compounds can be synthesized by, for example, the Horner-Wadsworth-Emmons reaction: of the present disclosure.

[0095] Solution 2

[0096]

[0097] Reaction of the desired aldehyde a' with the desired phenyl or heteroaryl ("Ph / Het") b' and diethyl benzoylphosphonate produces compounds c' of the present disclosure. Note that while the above scheme shows "OLR 2 " part is already in place, but an alternative synthesis could include an acid Horner-Wadsworth-Emmons coupling and then introduce the "OLR 2 ” Sidechain.

[0098] As shown in Scheme 3 below, the Y 1 A compound of the present disclosure that is O, S, S═O, or SO 2 .

[0099] Solution 3

[0100]

[0101] In a nucleophilic aromatic substitution reaction, the 5-fluoro-2-nitrobenzene moiety a" (shown attached to OLR 2moiety, which may alternatively be subsequently inserted downstream in the synthesis) is coupled with the desired heteroaryl or phenyl group ("Het / Ph") conjugated with OH or SNa("Y") b" to produce compound c", which can be synthesized using standard methods known in the art in the presence of NO2 groups, OLR 2 Group, X 1 The compound of the present disclosure, structure d" is derived from the group and / or the Y group to obtain the compound of the present disclosure, structure d".

[0102] The compounds of the present disclosure are characterized by one or two OLRs 2 A group, which can be synthesized according to Scheme 4 below. A group wherein X 1 It is COLR 2 of the present disclosure.

[0103] Solution 4

[0104]

[0105] Compounds of formula (I) can be synthesized using the procedure shown in Scheme 4. Reaction of a hydroxy substituted benzene or pyridine compound a"' with a nucleophilic R derivative compound b"' produces a compound as described herein, ie, compound c"' of formula (I).

[0106] As used herein, LG refers to any suitable part known in the art that can be replaced by a nucleophile. Examples of leaving groups include, but are not limited to, halides (e.g., chlorides, bromides, iodides), sulfonates (e.g., toluenesulfonates, mesylates, trifluoromethanesulfonates), sulfides (e.g., SCH3), carboxylic acid coupling reagent derivatives (e.g., N-hydroxysuccinimide, N-hydroxybenzotriazole), activated carboxylic acids (e.g., acyl chlorides), or acidic hydroxyls activated by Mitsunobu conditions. Nucleophiles are known in the art and include amines, alcohols, and thiols.

[0107] The coupling of compounds a' and b' can be catalyzed or promoted by appropriate reagents selected based on the precise nature of compounds a and b. For example, when compound b' is a phosphoryl compound (i.e., when R 2 When R is a phosphate group), the coupling of compound a' and phosphoryl compound b'' can be catalyzed by a base (e.g., triethylamine). Sometimes, the coupling reaction may not require a catalyst, or the solvent used for the reaction may be a catalyst, for example, when compound b'' is a sulfur trioxide pyridine complex and the solvent is pyridine (i.e., when R is a phosphate group), the coupling of compound a'' and phosphoryl compound b'' can be catalyzed by a base (e.g., triethylamine). 2 is a sulfate group).

[0108] Embodiments of the present disclosure

[0109] 1. A compound having a structure of formula (I):

[0110]

[0111] in:

[0112] A is -Y 1 -Z 1 or a fused bicyclic heteroaryl having 8-10 total ring atoms and 1, 2 or 3 heteroatoms selected from N, O or S, and the heteroaryl is optionally substituted by 1, 2 or 3 R a replace;

[0113] Y 1 yes O, S, SO or SO2;

[0114] Z 1 is phenyl or a 5- to 6-membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the phenyl group or the heteroaryl group is optionally substituted by 1, 2 or 3 R a replace;

[0115] X 1 Yes N, CR 3 or COLR 2 ;

[0116] R 1 It is C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Hydroxyalkyl, OC 1-5 Alkyl, C 3-6 Cycloalkyl, N(R N )2、C(=O)C 1-4 Alkyl or C(=CH)C 1-4 alkyl;

[0117] Each R 2 Independently SO2-R 4 , PO(R 4 )2、CO2H、N(R N )2. N(H)-C 2-6 Alkylene-N(R N )2. N(H)-C 2-6 Polyoxyalkylene-N(R N )2、NHCH(R 5 )CO2H、NH-C 1-6 Alkylene -CH (NH2) CO2H, sugar or NH-phenyl, wherein the phenyl group is optionally substituted by 1, 2 or 3 R b replace;

[0118] R 3 Is halogenated, C 1-6 Alkoxy, OH or N(R N )2;

[0119] Each L is independently C(O), C(O)-W n -C(O), C(O)-W n or C(O)NH-W n , or when R 2 SO2-R 4 , PO(R 4 )2 or a sugar, L may be a bond;

[0120] Each W is independently CH2, C 2-3 Alkylene-O or OC 2-3 Alkylene;

[0121] n is 1, 2, 3, 4, 5, or 6;

[0122] Each R 4 independently OH or NH2;

[0123] Each R 5 Independently H, C 1-6 Alkyl or C 1-6 Alkylene-R 6 ;

[0124] Each R 6 Independently, CO2H, CO2C 1-3 Alkyl, CON(R N )2、OH、OCH3、N(R N )2, NHC(NH)NH2, a heteroaryl or phenyl group containing 5 or 6 total ring atoms and 1, 2 or 3 heteroatoms selected from N, O and S, wherein the heteroaryl or the phenyl group is optionally replaced by 1, 2, 3, 4 or 5 C 0-2 Alkylene-R b Substituent substitution;

[0125] Each R a are independently halogenated, C 1-6 Alkyl, CO2H, CO2C 1-3 Alkyl, CON(R N )2. OH, OC 1-3 Alkyl or N(R N )2;

[0126] Each R b Independently, CO2H, CO2C 1-3 Alkyl or OH; and

[0127] Each R N independently H or C 1-3 alkyl;

[0128] or a pharmaceutically acceptable salt thereof,

[0129] The condition is that when Y 1 yes Z 1 is an unsubstituted phenyl group, and R 1 When X is isopropyl, 1 Is N or CR 3 , and R 3 Is halogenated, C 1-6 Alkoxy or N(R N )2.

[0130] 2. The compound or salt according to embodiment 1, wherein A is Y 1 -Z 1 .

[0131] 3. The compound or salt according to embodiment 2, wherein Y 1 yes

[0132] 4. The compound or salt according to embodiment 2, wherein Y 1 It is S, SO or SO2.

[0133] 5. A compound or salt according to any one of embodiments 2 to 4, wherein Z 1 It is phenyl.

[0134] 6. A compound or salt according to any one of embodiments 2 to 4, wherein Z 1 It is a 5- to 6-membered heteroaryl group.

[0135] 7. The compound or salt according to embodiment 6, wherein Z 1 is pyridine, pyrazole, imidazole or pyrimidine.

[0136] 8. A compound or salt according to any one of embodiments 5 to 7, wherein Z 1 is unreplaced.

[0137] 9. A compound or salt according to embodiments 5 to 7, wherein Z 1 By 1 or 2 R a Group substitution.

[0138] 10. The compound or salt according to embodiment 9, wherein each R a are independently halogenated, C 1-3 Alkyl or NH2.

[0139] 11. The compound or salt of embodiment 1, wherein A is a fused bicyclic heteroaryl.

[0140] 12. The compound or salt of embodiment 11, wherein A is a 10-membered heteroaryl.

[0141] 13. The compound or salt of embodiment 11 or 12 wherein A is isoquinoline, quinoline or quinazoline.

[0142] 14. The compound or salt according to embodiment 13, wherein A is or

[0143] When R 2 SO2-R 4 or PO(R 4 )2, A can be

[0144] 15. The compound or salt of any one of Embodiments 11 to 14, wherein A is unsubstituted.

[0145] 16. A compound or salt according to any one of embodiments 11 to 14, wherein A is replaced by 1 or 2 R a Group substitution.

[0146] 17. The compound or salt according to embodiment 16, wherein each R a are independently halogenated, C 1-3 Alkyl or NH2.

[0147] 18. A compound or salt according to any one of embodiments 1 to 17, wherein X 1 It is N.

[0148] 19. A compound or salt according to any one of embodiments 1 to 17, wherein X 1 Yes CR 3 .

[0149] 20. The compound or salt according to embodiment 19, wherein R 3 It is F or OH.

[0150] 21. A compound or salt according to any one of embodiments 1 to 17, wherein X 1 It is COLR 2 .

[0151] 22. The compound or salt according to embodiment 21, wherein X 1 It is COR 2 .

[0152] 23. The compound or salt according to embodiment 22, wherein X1 It is C-OSO2-R 4 or C-OPO(R 4 )2.

[0153] 24. A compound or salt according to any one of embodiments 1 to 23, wherein R 1 It is C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 Hydroxyalkyl.

[0154] 25. The compound or salt according to embodiment 24, wherein R 1 It is C 1-5 alkyl.

[0155] 26. The compound or salt according to embodiment 25, wherein R 1 It is a C3 alkyl group.

[0156] 27. A compound or salt according to any one of embodiments 1 to 23, wherein R 1 It's OC 1-5 Alkyl, N(R N )2 or C(=O)C 1-4 alkyl.

[0157] 28. The compound or salt of any one of Embodiments 1 to 27, wherein L is a bond.

[0158] 29. A compound or salt according to any one of embodiments 1 to 27, wherein L is C(O), C(O)-W n -C(O), C(O)-W n or C(O)NH-W n .

[0159] 30. The compound or salt according to embodiment 29, wherein each W is independently CH2 or C 2-3 Alkylene-O.

[0160] 31. The compound or salt of embodiment 29 or 30, wherein n is 1 or 2.

[0161] 32. A compound or salt according to any one of embodiments 1 to 31, wherein R 2 SO2-R 4 or PO(R 4 )2.

[0162] 33. The compound or salt according to embodiment 32, wherein R 2 It is SO2H or PO(OH)2.

[0163] 34. A compound or salt according to any one of embodiments 1 to 31, wherein R 2 It is N(H)-C 2-6 Alkylene-N(R N )2. N(H)-C 2-6 Polyoxyalkylene-N(R N )2、NHCH(R 5 )CO2H or NH-C 1-6 Alkylene -CH(NH2)CO2H.

[0164] 35. The compound or salt according to embodiment 34, wherein R 2 It is N(H)-C 2-6 Alkylene-N(R N )2 or NH-C 1-6 Alkylene -CH(NH2)CO2H.

[0165] 36. The compound or salt according to embodiment 35, wherein R 2 is NHCH(R 5 )CO2H.

[0166] 37. The compound or salt according to embodiment 36, wherein R 5 It is C 1-6 Alkyl or C 1-6 Alkylene-R 6 .

[0167] 38. The compound or salt according to embodiment 37, wherein R 6 It is CO2H, CO2CH3, CONH2, OH, OCH3, NH2, NHC(NH)NH2, imidazolyl, phenyl or 4-hydroxy-phenyl.

[0168] 39. A compound or salt according to any one of embodiments 1 to 31, wherein at least one R 2 It is NH-phenyl.

[0169] 40. The compound or salt according to embodiment 39, wherein the phenyl group is replaced by 1 or 2 R b Group substitution.

[0170] 41. A compound or salt according to any one of embodiments 1 to 40, wherein each R N are independently H or CH3.

[0171] 42. A compound or salt according to embodiment 1 selected from the group consisting of:

[0172] (E)-2-isopropyl-5-phenylvinylpyridin-3-yl hydrogen sulfate,

[0173] (E)-2-isopropyl-5-phenylvinylpyridin-3-yl dihydrogen phosphate,

[0174] 3-Hydroxy-2-isopropyl-5-(isoquinolin-3-yl)phenyl hydrogen sulfate,

[0175] 3-Hydroxy-2-isopropyl-5-(isoquinolin-3-yl)phenyl dihydrogen phosphate,

[0176] 3-Hydroxy-2-isopropyl-5-(quinolin-3-yl)phenyl hydrogen sulfate,

[0177] 3-Hydroxy-2-isopropyl-5-(quinolin-3-yl)phenyl dihydrogen phosphate,

[0178] 2-Isopropyl-5-(quinolin-3-yl)-1,3-phenylene bis(hydrogen sulfate),

[0179] 2-Isopropyl-5-(quinolin-3-yl)-1,3-phenylenebis(dihydrogen phosphate),

[0180] (E)-5-(2-fluorophenylvinyl)-2-isopropylpyridin-3-yl hydrogen sulfate,

[0181] (E)-5-(2-fluorophenylvinyl)-2-isopropylpyridin-3-yl dihydrogen phosphate,

[0182] (E)-5-(3-fluorophenylvinyl)-2-isopropylpyridin-3-yl hydrogen sulfate,

[0183] (E)-5-(3-fluorophenylvinyl)-2-isopropylpyridin-3-yl dihydrogen phosphate,

[0184] (E)-5-(4-Fluorophenylvinyl)-2-isopropylpyridin-3-yl hydrogen sulfate,

[0185] (E)-5-(4-Fluorophenylvinyl)-2-isopropylpyridin-3-yl dihydrogen phosphate,

[0186] 5-(2-amino-5-fluoroquinazolin-7-yl)-3-hydroxy-2-isopropylphenyl hydrogen sulfate,

[0187] 5-(2-amino-5-fluoroquinazolin-7-yl)-3-hydroxy-2-isopropylphenyl dihydrogen phosphate,

[0188] 5-(2-amino-5-fluoroquinazolin-7-yl)-2-isopropyl-1,3-phenylene bis(hydrogen sulfate);

[0189] 5-(2-amino-5-fluoroquinazolin-7-yl)-2-isopropyl-1,3-phenylenebis(dihydrogen phosphate);

[0190] 5-(6-Fluoroquinolin-2-yl)-3-hydroxy-2-isopropylphenyl hydrogen sulfate,

[0191] 5-(6-Fluoroquinolin-2-yl)-3-hydroxy-2-isopropylphenyl dihydrogen phosphate,

[0192] 5-(6-Fluoroquinolin-2-yl)-2-isopropyl-1,3-phenylene bis(hydrogen sulfate),

[0193] 5-(6-Fluoroquinolin-2-yl)-2-isopropyl-1,3-phenylenebis(dihydrogen phosphate),

[0194] (E)-3-Fluoro-2-propyl-5-phenylvinylphenyl hydrogen sulfate,

[0195] (E)-3-fluoro-2-propyl-5-phenylvinylphenyl dihydrogen phosphate,

[0196] (E)-3-Fluoro-2-isopropyl-5-phenylvinylphenyl hydrogen sulfate,

[0197] (E)-3-Fluoro-2-isopropyl-5-phenylvinylphenyl dihydrogen phosphate,

[0198] 3-Fluoro-2-isopropyl-5-(4-methylquinolin-7-yl)phenyl hydrogen sulfate, and

[0199] 3-Fluoro-2-isopropyl-5-(4-methylquinolin-7-yl)phenyl dihydrogen phosphate.

[0200] 43. A compound or salt according to embodiment 42 selected from the group consisting of:

[0201] 2-Isopropyl-5-(quinolin-3-yl)-1,3-phenylenebis(dihydrogen phosphate), 2-Isopropyl-5-(quinolin-3-yl)-1,3-phenylenebis(hydrogen sulfate), (E)-5-(2-fluorostyryl)-2-isopropylpyridin-3-yl hydrogen sulfate, (E)-5-(2-fluorostyryl)-2-isopropylpyridin-3-yl dihydrogen phosphate, (E)-3-fluoro-2-propyl-5-styrylphenyl dihydrogen phosphate, (E)-3-fluoro-2-propyl-5-phenylvinylphenyl dihydrogen phosphate, (E)-3-fluoro-2-isopropyl-5-phenylvinylphenyl dihydrogen phosphate, (E)-3-fluoro-2-isopropyl-5-phenylvinylphenyl dihydrogen phosphate, 3-fluoro-2-isopropyl-5-(4-methylquinolin-7-yl)phenyl dihydrogen phosphate.

[0202] 44. A pharmaceutical formulation comprising a compound or salt according to any one of embodiments 1 to 43 and a pharmaceutically acceptable excipient.

[0203] 45. A method of modulating aryl hydrocarbon receptor (AHR) activity in a subject, the method comprising contacting the AHR with a compound or salt of any one of embodiments 1 to 43 in an amount effective to modulate the AHR activity.

[0204] 46. ​​A method of treating or preventing a disease or condition associated with aberrant aryl hydrocarbon receptor (AHR) activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound or salt according to any one of embodiments 1 to 43.

[0205] 47. The method of embodiment 46, wherein said administration is topical.

[0206] 48. The method of embodiment 46, wherein said administration is oral or by injection or infusion.

[0207] 49. The method of embodiment 46, 47 or 48, wherein the disease or condition is an inflammatory disease or condition.

[0208] 50. The method of embodiment 46, 47 or 48, wherein the disease or disorder is a disease or disorder of the gastrointestinal tract, skin, lung, central nervous system, pancreas, eye, bone, osteoarticular, neuroinflammatory disease or neurodegenerative disease.

[0209] 51. The method of embodiment 50, wherein the disease or disorder of the gastrointestinal tract 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.

[0210] 52. The method of embodiment 50, wherein said disease or condition of said skin is selected from the group consisting of atopic dermatitis, acne, psoriasis, and vitiligo.

[0211] 53. The method of embodiment 50, wherein the disease or condition of the eye is abnormal eye movement, inflammatory eye disease, autoimmune eye disease, inherited eye disease, degenerative eye disease, vascular eye disease, 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").

[0212] 54. The method of embodiment 50, wherein the disease or condition of the lung is pulmonary fibrosis, asthma, or chronic obstructive pulmonary disease.

[0213] 55. The method of embodiment 50, wherein the disease or disorder of the bone joint is osteoporosis, rheumatoid arthritis, or bone cancer.

[0214] 56. The method of embodiment 46, 47 or 48, wherein the disease or condition is diabetes, cancer, a viral infection or a bacterial infection.

[0215] 57. The method of embodiment 56, wherein the viral infection is a flavivirus infection or a coronavirus infection.

[0216] 58. The method of embodiment 56, wherein the bacterial infection is a lung infection, a gastrointestinal infection, a skin infection, an ear infection, or sepsis.

[0217] 59. The method of any one of embodiments 46-58, further comprising administering a therapeutic agent.

[0218] 60. The method of embodiment 59, wherein the therapeutic agent is an anti-inflammatory agent.

[0219] 61. The method of embodiment 60, wherein the anti-inflammatory agent is selected from mesalazine, naproxen, ibuprofen, diclofenac, celecoxib, sulindac, oxaprozin, piroxicam, indomethacin, meloxicam, fenoprofen, diflunisal, etodolac, ketorolac tromethamine, meclofenamate, nabumetone, disalicylate, or any combination of the foregoing.

[0220] Examples

[0221] The following examples are provided for illustration and are not intended to limit the scope of the invention.

[0222] Preparation of {2-isopropyl-5-[(E)-2-phenylvinyl]pyridin-3-yl}oxyalkanesulfonic acid (Compound 1)

[0223]

[0224] To a solution of 5-hydroxypyridine-3-carboxylic acid methyl ester (5.0 g, 0.033 mol) in THF / H2O (50 ml / 50 ml) was added Na2CO3 (10.4 g, 0.098 mol) and I2 (20.8 g, 0.082 mol). The reaction mixture was stirred at 25 °C for 12 hours. The solvent was removed in vacuo to give a crude product which was purified by flash chromatography (eluted from 100 / 0 to 90 / 10 with DCM / MeOH in 30 minutes) to give compound A-2. LCMS (ESI): [M+H] for C7H6INO3 + m / z calculated: 280.0, found: 279.8.

[0225] A-3 (509.5 mg, 3.03 mmol) and Pd(PPh3)4 (292.0 mg, 2.53 mmol) and K2CO3 (697.3 mg, 5.05 mmol) were added to a solution of compound A-2 (705.0 mg, 2.53 mmol) in dioxane / H2O=10:1 (15 mL). The reaction mixture was stirred at 80°C for 12 hours under nitrogen. The solvent was removed in vacuo to give a crude product, which was purified by flash chromatography (eluted from 100 / 0 to 90 / 10 with DCM / MeOH in 30 minutes) to give compound A-4. LCMS (ESI): C 10 H 11 [M+H] of NO3 + m / z calcd. 194.0, found 194.0.

[0226] Pd / C (73.8 mg, 10%) was added to a solution of A-4 (134.0 mg, 0.69 mmol) in ethyl acetate (10 mL). The reaction mixture was stirred at 25 °C for 12 hours under 1 atm of hydrogen. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give compound A-5, which was used directly in the next step. LCMS (ESI): C 10 H 13 [M+H] of NO3 + m / z calcd. 196.0, found 196.0.

[0227] To a solution of A-5 (104.0 mg, 0.53 mmol) in THF (5 mL) was slowly added LiAlH4 (30.3 mg, 0.80 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The residue was quenched with water and removed by vacuum to give a crude product which was purified by flash chromatography (eluted with DCM / MeOH from 100 / 0 to 80 / 20 in 20 minutes) to give compound A-6. LCMS (ESI): C9H 13 [M+H] of NO2 + m / z calcd. 168.0, found 168.0.

[0228] PCC (154.7 mg, 0.72 mmol) was slowly added to a solution of A-6 (80.0 mg, 0.48 mmol) in DCM (5 mL) at 0 ° C. The reaction mixture was stirred at 25 ° C for 4 hours. The solvent was removed by vacuum to give a crude product, which was purified by flash chromatography (DCM / MeOH=100 / 0 to 80 / 20) to give compound A-7. LCMS (ESI): C9H 11 [M+H] of NO2 + m / z calcd. 166.0, found 166.0.

[0229] At 0°C, NaH (19.0 mg, 0.79 mmol, 60%) was added to a solution of diethyl benzylphosphonate (134.7 mg, 0.59 mmol) in THF (3 mL). After 2 hours, a solution of A-7 (65.0 mg, 0.39 mmol) in THF was added dropwise at 0°C. The reaction mixture was stirred at 25°C for 16 hours. After completion, the mixture was poured onto ice, extracted with EtOAc (10 mL × 3), and the combined organic layers were then washed with saturated NaCl (20 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EtOAc=100 / 0to 50 / 50) to obtain compound A-8.

[0230] To a solution of A-8 (100.0 mg, 0.42 mmol) in pyridine (5 ml) was added ClSO 3 H (193.9 mg, 1.68 mmol) dropwise. The reaction mixture was stirred at 25 °C for 2 hours. The desired mass was detected on LC-MS. The solvent was removed under reduced pressure. The reaction mixture was purified by C 18 The residue was purified by column (eluting with ACN-H2O (0.1% HCOOH) from 0:100 to 50:50 in 30.0 min) to give compound 1. LCMS (ESI): C 16 H17 NO4S [MH] - m / z calculated: 318.0, found: 317.9. 1 HNMR (400MHz, DMSO-d6, ppm) 8.55 (s, 1H), 8.23 ​​(s, 1H), 7.66 (d, J = 7.2Hz, 2H), 7. 41(t,J=7.6Hz,2H),7.36-7.30(m,3H),3.61-3.54(m,1H),1.24(d,J=7.2Hz,6H).

[0231] Preparation of [3-hydroxy-2-isopropyl-5-(isoquinolin-3-yl)phenyl]oxanesulfonic acid (Compound 2)

[0232]

[0233] To a solution of 5-bromo-2-isopropyl-1,3-dimethoxybenzene (200.0 mg, 0.77 mmol) in 1,4-dioxane (5 ml) was added B-2 (235.2 mg, 0.927 mmol), Pd (dppf) Cl2 (56.5 mg, 0.077 mmol) and potassium acetate (151.5 mg, 1.54 mmol). The reaction mixture was stirred at 100 ° C for 16 hours under nitrogen. The solvent was removed by vacuum. The residue was purified by silica gel chromatography (eluted from 50 / 1 to 10 / 1 with PE / EtOAc in 30 minutes) to obtain B-3. 1 HNMR (400MHz, DMSO-d6, ppm) 6.84 (s, 2H), 3.79-3.71 (m, 6H), 3.62-3.46 (m, 1H), 1.29 (s, 12H), 1.20 (d, J = 7.2Hz, 6H).

[0234] To a solution of 2-(4-isopropyl-3,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (120.0 mg, 0.39 mmol) in 1,4-dioxane / H2O=3:1 (8 ml) was added 3-bromoisoquinoline (97.8 mg, 0.47 mmol), K2CO3 (109.9 mg, 0.78 mmol) and Pd(dppf)Cl2 (28.7 mg, 0.039 mmol). The reaction mixture was stirred at 80°C under nitrogen for 12 hours. The solvent was removed by vacuum. The residue was purified by silica gel chromatography (eluted with PE / EtOAc from 50:1 to 10:1 in 30 minutes) to give B-5. LCMS (ESI): C 20 H 21 [M+H] of NO2 + m / z calculated = 308.1, found 307.9. 1H NMR (400MHz, DMSO-d6, ppm): 9.40 (s, 1H), 8.47 (s, 1H), 8.03 (d, J = 8.2Hz, 1H), 7.86 -7.62(m,3H),7.49(s,2H),3.90(s,6H),3.65-3.51(m,1H),1.27(d,J=7.2Hz,6H).

[0235] To a solution of B-5 (100.0 mg, 0.325 mmol) in DCM (5 ml) was added BBr3 (0.5 ml, 1 M in DCM) dropwise at 0 ° C. The reaction mixture was stirred at 25 ° C for 6 hours. The solvent was removed under reduced pressure. NaHCO3 aqueous solution (10 mL) was added to the solution and extracted with EtOAc (10 mL x 3). The organic phases were combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5um C18150 x21.2 mm, mobile phase: ACN-H2O (0.05% NH3.H2O), gradient: 35-50, 9.0 minutes) to obtain B-6. LCMS (ESI): C 18 H 17 [M+H]+ m / z calculated for NO2: 280.1, found: 280.1. 1 H NMR (400MHz, DMSO-d6, ppm): 9.34 (s, 1H), 9.18 (s, 2H), 8.16-8.06 (m, 1H), 8.03 (d, J = 8.2Hz, 2H), 7 .77(t,J=7.2Hz,1H),7.64(t,J=7.6Hz,1H),7.13(s,2H),3.55-3.42(m,1H),1.28(d,J=7.1Hz,6H).

[0236] To a solution of 2-isopropyl-5-(isoquinolin-3-yl)benzene-1,3-diol (100.0 mg, 0.358 mmol) in pyridine (5 ml) was added ClSO3H (207.6 mg, 1.79 mmol). The reaction mixture was stirred at 25°C for 2 hours. The desired mass was detected on LC-MS. The solvent was removed under reduced pressure. The reaction mixture was purified by C 18 The residue was purified by column (eluted with ACN-H2O (0.1% NH3.H2O) from 0:100 to 50:50 in 30.0 min) to give compound 2. LCMS (ESI): C 18 H 17 NO5S's [M+H] - m / z calcd. 360.1, found 360.1.1 H NMR (400MHz, DMSO-d6, ppm) 9.51 (s, 1H), 9.46 (s, 1H), 8.25 (d, J = 7.6Hz, 2H), 8.16 (d, J = 8.4Hz, 1H), 7.90 (t, J = 7 .6Hz,1H),7.75(t,J=7.6Hz,1H),7.61(d,J=1.6Hz,1H),7.33(s,1H),3.58-3.55(m,1H),1.28(d,J=7.2Hz,6H).

[0237] Preparation of [3-hydroxy-2-isopropyl-5-(quinolin-3-yl)phenyl]oxyethanesulfonic acid (Compound 3)

[0238]

[0239] 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (212.7 mg, 0.83 mmol), Pd(dppf)Cl2 (50.8 mg, 0.069 mmol) and K2CO3 (191.7 mg, 1.39 mmol) were added to a solution of 5-bromo-2-isopropyl-1,3-dimethoxybenzene (180.0 mg, 0.69 mmol) in 1,4-dioxane / H2O (4 mL / 4 mL). The reaction mixture was stirred at 100 ° C for 16 hours under nitrogen. LCMS showed that the desired MS was detected. The solvent was removed by vacuum. The residue was extracted with EtOAc (200 mL), and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography (eluted with PE / EtOAc from 100 / 0 to 40 / 60 in 30 minutes) to give C-2. LCMS (ESI): C 20 H 21 [M+H] of NO2 + m / z calculated: 308.1, found: 308.2.

[0240] Tribromoborane (0.6 ml, 1 M in DCM) was added dropwise to a solution of C-2 (160.0 mg, 0.56 mmol) in DCM (2 ml) at -78 °C. The reaction mixture was stirred at 25 °C for 12 hours. LCMS showed that the desired MS was detected. NaHCO3 aqueous solution was added to the solution and extracted with EtOAc (10 mL x 3). The organic phases were combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Gemini 5um C18150 x 21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 35-95, 12 minutes) to obtain C-3. LCMS (ESI): C18 H 17 [M+H] of NO2 + m / z calculated: 280.1, found: 280.2. 1 H NMR(400MHz, DMSO-d6,ppm)9.34(s,2H),9.03(d,J=2.4Hz,1H),8.37(d,J=2.0Hz,1H),8.09-7.98(m ,2H),7.81-7.71(m,1H),7.68-7.59(m,1H),6.68(s,2H),3.55-3.44(m,1H),1.28(d,J=8.0Hz,6H).

[0241] To a solution of C-3 (100.0 mg, 0.358 mmol) in DCM (5 ml) was added SO 3 .Py (284.8 mg, 1.79 mmol) and pyridine (452.5 mg, 5.73 mmol). The reaction mixture was stirred at 25 ° C for 6 hours. LCMS showed that the expected MS was detected. The expected mass was detected on LC-MS. The solvent was removed under reduced pressure. The reaction mixture was purified by C 18 The residue was purified by column (eluted with ACN-H2O (0.1% NH3.H2O) from 0:100 to 50:50 in 30.0 min) to give compound 3. LCMS (ESI): C 18 H 17 NO5S's [M+H] - m / z calculated: 360.0, found: 360.2. 1 H NMR(400MHz, CD3OD, ppm)9.14(d,J=2.0Hz,1H),8.65(d,J=1.6Hz,1H),8.06(d,J=8.4Hz,2H),7.81(t,J =7.6Hz,1H),7.68(t,J=7.6Hz,1H),7.45(s,1H),6.98(s,1H),3.72-3.62(m,1H),1.38(d,J=6.8Hz,6H).

[0242] Preparation of 2-isopropyl-3-(phosphonooxy)-5-(quinolin-3-yl)phenoxyphosphonic acid (Compound 4)

[0243]

[0244] To a solution of 2-isopropyl-5-(quinolin-3-yl)benzene-1,3-diol (400.0 mg, 1.43 mmol) in THF / DCM (1:1, 10 ml) was added POCl3 (724.6 mg, 4.73 mmol) and pyridine (869.4 mg, 8.59 mmol) dropwise. The reaction mixture was stirred at 25 °C for 2 hours. The desired mass was detected on LC-MS. The solvent was removed under reduced pressure. The reaction mixture was purified by C 18 The residue was purified by column (eluting with ACN-H2O (0.1% NH3.H2O) from 0:100 to 50:50 in 30.0 min) to give compound 4. LCMS (ESI): C 18 H 19 NO8P2's [M+H] - m / z calculated: 440.0, found: 440.2. 1 H NMR (400MHz, DMSO-d6, ppm) 9.09 (s, 1H), 8.46 (s, 1H), 8.06 (dd, J = 15.6, 8.0Hz, 2H), 7.75 (t, J = 7. 6Hz, 1H), 7.62 (t, J = 7.2Hz, 1H), 7.54 (s, 2H), 3.54-3.51 (m, J = 7.2Hz, 1H), 1.27 (d, J = 6.4Hz, 6H).

[0245] Preparation of {5-[(E)-2-(2-fluorophenyl)vinyl]-2-isopropylpyridin-3-yl}oxyalkanesulfonic acid (Compound 5)

[0246]

[0247] To a solution of diethyl [(2-fluorophenyl)methyl]phosphonate (131.9 mg, 0.536 mmol) in THF (5 mL) was added NaH (26.8 mg, 0.670 mmol, 60% in oil), and the reaction mixture was stirred at 25 ° C for 1 hour. 6-isopropyl-5-methoxypyridine-3-carboxaldehyde (80.0 mg, 0.446 mmol) was added to the mixture, and the reaction mixture was stirred at 25 ° C for 2 hours. Water (10 mL) was added to the mixture and extracted with EtOAc (20 mL x 3). The organic phases were combined and washed with brine, dried over Na2SO4, filtered out and concentrated in vacuo. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (eluted from 100 / 0 to 95 / 5 with PE / EtOAc in 20 minutes) to obtain D-3. LCMS (ESI): C 17 H 18 [M+H] by FNO + m / z calcd. 272.1, found 272.1.

[0248] To a solution of D-3 (60.0 mg, 0.221 mmol) in DCM (5 mL) was added BBr (554.0 mg, 2.21 mmol), and the mixture was stirred at 25 ° C for 16 hours. Water (10 mL) was added to the solution and extracted with DCM (10 mL x 3). The organic phases were combined and washed with NaHCO aqueous solution and brine, dried over Na2SO4, filtered out and concentrated in vacuo. The residue was purified by preparative HPLC (eluted from 70 / 30 to 5 / 95 with H2O (0.1% NH3.H2O) / MeCN in 40 minutes) to obtain D-4. LCMS (ESI): C 16 H 16 [M+H] by FNO + m / z calcd. 258.1, found 258.0. 1 H NMR(400MHz, DMSO-d6,ppm)9.83(s,1H),8.18(d,J=1.8Hz,1H),7.85-7.78(m,1H) ,7.36-7.29(m,2H),7.29-7.12(m,4H),3.41-3.35(m,1H),1.18(d,J=6.8Hz,6H).

[0249] To a solution of D-4 (200.0 mg, 0.777 mmol) in DCM (5 mL) at 0 °C, pyridine (122.8 mg, 1.55 mmol) and SO3Py (618.0 mg, 7.77 mmol) were added. The reaction mixture was stirred at 25 °C for 2 hours. The desired mass was detected on LC-MS. The solvent was removed under reduced pressure. The reaction mixture was purified by C 18 The residue was purified by column (eluted with ACN-H2O (0.1% NH3.H2O) from 20:80 to 60:40 in 30.0 min) to give compound 5. LCMS (ESI): C 16 H 17 FNO4S [M+H] + ms / z calculated value 338.2, found value 338.2. 1 H NMR (400MHz, CD3OD, ppm)8.48(s,1H),8.37(s,1H),7.73(t,J=7.6Hz,1H),7.46(d,J=16.8Hz,1H),7.36-7.27 (m,2H),7.20(t,J=7.6Hz,1H),7.13(dd,J=10.8,8.4Hz,1H),3.72(hept,J=7.2Hz,1H),1.33(d,J=7.2Hz,6H).

[0250] Preparation of {5-[(E)-2-(4-fluorophenyl)vinyl]-2-isopropylpyridin-3-yl}oxyalkanesulfonic acid (Compound 6)

[0251]

[0252] To a solution of diethyl [(4-fluorophenyl)methyl]phosphonate (54.0mg, 0.218mmol) in THF (5mL), NaH (60%) (16.0mg, 0.338mmol) was added. After 30 minutes, 6-isopropyl-5-methoxypyridine-3-carboxaldehyde (30.0mg, 0.167mmol) was added. The reaction mixture was stirred at 25°C for 2 hours. LCMS showed that the desired MS was detected. Water (10mL) was added to the mixture and extracted with EtOAc (20mL x 3). The organic phases were combined and washed with brine, dried over Na2SO4, filtered out and concentrated in vacuo. The residue was purified by silica gel chromatography (eluted from 100 / 0 to 95 / 5 with PE / EtOAc in 20 minutes) to obtain D-6. LCMS (ESI): C 17 H 19 [M+H] by FNO + m / z calcd. 272.1, found 272.1.

[0253] To a solution of D-6 (40.0 mg, 0.133 mmol) in DCM (5 mL) was added BBr3 (332.0 mg, 1.33 mmol), and the mixture was stirred at 25 ° C for 16 hours. Water (10 mL) was added to the solution and extracted with DCM (10 mL x 3). The organic phases were combined and washed with NaHCO3 (aqueous solution) and brine, dried over Na2SO4, filtered out and concentrated in vacuo. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5um C18150 x21.2 mm, mobile phase: ACN-H2O (0.1% FA), gradient: 20-95, 10.0 minutes) to obtain D-7. LCMS (ESI): C 16 H 17 [M+H] by FNO + m / z calcd. 258.1, found 258.1. 1 H NMR(400MHz, DMSO-d6,ppm)9.78(s,1H),8.16(d,J=1.8Hz,1H),7.66(m,2H),7.27(d, J=1.8Hz,1H),7.21(t,J=8.8Hz,2H),7.14(s,2H),3.36(m,1H),1.17(d,J=6.8Hz,6H).

[0254] SO3Py (804.0 mg, 5.05 mmol) and pyridine (160.0 mg, 2.02 mmol) were added to a solution of E-3 (260.0 mg, 1.01 mmol) in DCM (6 ml). The reaction mixture was then stirred at rt for 16 hours. The desired mass was detected on LC-MS. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Gemini5um C18150 x 21.2 mm, mobile phase: H2O-ACN (0.05% NH3.H2O), gradient: 80-20, 10.0 min) to obtain compound 6. LCMS (ESI): C 16 H 17 FNO4S [M+H] + ms / z calculated value 338.2, found value 338.1. 1 H NMR(400MHz,DMSO-d6,ppm)8.53(s,1H),8.20(s,1H),7.72(dd,J=8.8,5.6Hz,2H) ,7.39-7.30(m,2H),7.29-7.21(m,2H),3.64-3.48(m,1H),1.24(d,J=6.8Hz,6H).

[0255] Preparation of [5-(2-amino-5-fluoroquinazolin-7-yl)-3-hydroxy-2-isopropylphenyl]oxanesulfonic acid (Compound 7)

[0256]

[0257] 7-bromo-5-fluoroquinazoline-2-amine (870.9 mg, 3.5971 mmol), Pd(dppf)Cl2 (262.9 mg, 0.3597 mmol) and K2CO3 (994.3 mg, 7.1942 mmol) were added to a solution of 2-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzene-1,3-diol (1.0 g, 3.5971 mmol) in 1.4-dioxane (50 mL) and H2O (10 mL). The reaction mixture was stirred at 80 ° C for 12 hours under N2. The desired mass was detected on LC-MS. The mixed reaction was quenched with water, extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluted with PE / (EtOAc:DCM=1:1) from 50:50 to 10:90 in 30 min) to give E-3. LCMS (ESI): C 17 H 16 [M+H] of FN3O2 +ms / z calculated value 314.1, found value 314.2. 1 HNMR(400MHz,DMSO-d6,ppm)9.31(s,2H),9.22(s,1H),7.25(s,1H),7.13(s, 2H), 7.04 (d, J = 11.2Hz, 1H), 6.59 (s, 2H), 3.47 (m, 1H), 1.26 (d, J = 7.2Hz, 6H).

[0258] To a solution of E-3 (150.0 mg, 0.4787 mmol) in pyridine (5 mL) was added SO3Py (380.95 mg, 2.3935 mmol), and the mixture was stirred at 25 ° C for 12 hours. The desired mass was detected on LC-MS. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5um C18150 x 21.2 mm, mobile phase: H2O-ACN (0.05% NH3.H2O), gradient: 85-5, 11.0 minutes) to give [5-(2-amino-5-fluoroquinazolin-7-yl)-3-hydroxy-2-isopropylphenyl]oxanesulfonic acid. LCMS (ESI): C 17 H 18 FN3O5S[MH] - m / z calculated value 392.1, found value 392.3. 1 H NMR(400MHz,DMSO-d6,ppm)9.46(s,1H),9.27(s,1H),7.31(s,2H),7.26(d,J=1.6Hz,1H),7.20(s,1 H),7.11-7.07(m,2H),6.94(s,1H),6.85(d,J=2.0Hz,1H),3.55-3.47(m,1H),1.26(d,J=7.2Hz,6H).

[0259] Preparation of [5-(6-fluoroquinolin-2-yl)-3-hydroxy-2-isopropylphenyl]oxyethanesulfonic acid (Compound 8)

[0260]

[0261] 2-bromo-6-fluoroquinoline (400.0 mg, 1.77 mmol), Pd(dppf)Cl2 (129.5 mg, 0.18 mmol) and K2CO3 (489.2 mg, 3.54 mmol) were added to a solution of 2-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzene-1,3-diol (541.4 mg, 1.95 mmol) in 1,4-dioxane / H2O (16 mL / 4 mL). The reaction mixture was stirred at 80 ° C for 12 hours under nitrogen. The desired mass was detected on LC-MS. The solvent was removed by vacuum. The residue was quenched with water, extracted with EtOAc, and the combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by silica gel chromatography (eluting with PE / EtOAc from 100 / 0 to 40 / 60 in 30 min) and C 18 The residue was purified by column (eluting with 0.5% NH3.H2O / MeCN from 100:0 to 20:80 in 30 min) to give F-2. LCMS (ESI): C 18 H 16 [M+H] of FNO2 + ms / z calculated value 298.1, found value 298.3. 1 H NMR(400MHz, DMSO-d6,ppm)9.29(s,2H),8.40(d,J=8.8Hz,1H),8.04(dd,J=9.2,5.6Hz,1H),7.86(d,J=8.8Hz ,1H),7.79(dd,J=9.2,2.8Hz,1H),7.69-7.64(m,1H),7.14(s,2H),3.55-3.44(m,1H),1.28(d,J=7.2Hz,6H).

[0262] To a solution of F-2 (300.0 mg, 1.074 mmol) in DCM (5 ml) was added SO 3 .Py (854.4 mg, 5.37 mmol) and pyridine (1357.5 mg, 17.19 mmol). The reaction mixture was stirred at 25 °C for 6 hours. The desired mass was detected on LC-MS. The solvent was removed under reduced pressure. The reaction mixture was purified by C 18 Column (ACN-H2O (0.1% NH 3. The residue was purified by eluting with H2O from 0:100 to 60:40) and from 0:100 to 50:50) to give compound 8. LCMS (ESI): C 18 H 16 FNO5S's [M+H] -m / z calculated: 378.0, found: 378.3. 1 H NMR (400MHz, DMSO-d6, ppm) 9.46 (s, 1H), 8.46 (d, J = 8.8Hz, 1H), 8.10 (dd, J = 9.2, 5.6Hz, 1H), 7.91 (d, J = 8.8Hz, 1H) ,7.82(dd,J=9.6,2.8Hz,1H),7.72-7.65(m,2H),7.44(d,J=1.6Hz,1H),3.59-3.51(m,1H),1.27(d,J=6.8Hz,6H).

[0263] Preparation of {3-fluoro-5-[(E)-2-phenylvinyl]-2-propylphenyl}oxyethanesulfonic acid (Compound 9)

[0264]

[0265] MeONa (30%, 2.1 ml in MeOH) was added to 5-bromo-1,3-difluoro-2-iodobenzene (2.0 g, 6.3 mmol) in MeOH (20 ml). The reaction was stirred at 60 ° C for 16 hours. The reaction solvent was removed by vacuum to obtain a white solid. The solvent was diluted with DCM (20 mL) and water (20 mL). The aqueous phase was extracted with DCM (20 mL). The organic phases were combined and washed with brine, dried over anhydrous NaSO4 and concentrated to obtain a crude product, which was purified by flash chromatography (eluted from 100 / 0 to 98 / 2 with PE / EtOAc in 30 minutes) to obtain G-2. 1 H NMR (400 MHz, CDCl 3, ppm) 6.91 (dd, J = 7.2. 2.0 Hz, 1H), 6.76 (t, J = 1.6 Hz, 1H), 3.90 (s, 3H).

[0266] To a solution of compound G-2 (2.0 g, 6.04 mmol) in 1,4-dioxane / H2O (40 mL / 4 mL) was added G-3 (1.5 g, 9.07 mmol) and Pd(dppf)Cl2 (442.2 mg, 0.604 mmol) and K2CO3 (3.9 g, 12.08 mmol). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen. The solvent was removed by vacuum. The residue was purified by flash chromatography (eluted from 100 / 0 to 98 / 2 with PE / EA in 30 minutes) to obtain G-4. 1 H NMR (400 MHz, CDCl 3,ppm)6.90(dd,J=8.4,1.6Hz,1H).,6.82(t,J=1.6Hz 1H),5.35(dd,J=3.2,1.6Hz,1H),4.97-4.96(m,1H),3.82(s,3H),2.01(s,3H).

[0267] Pt / C (20.0 mg, 10 wt%) was added to a solution of G-4 (200.0 mg, 0.816 mmol) in EtOAc (5 ml). The reaction mixture was stirred under H2 (1 atm) at 25 °C for 16 hours. The solvent was removed by vacuum. The residue was purified by flash chromatography (eluted from 100 / 0 to 95 / 5 with PE / EA in 30 minutes) to obtain G-5. 1 H NMR (400MHz, CDCl3, ppm) 6.84 (dd, J=8.8, 1.6Hz, 1H)., 6.77 (t, J=1.6Hz 1H), 3.83-3.80 (m, 3H), 2.55 (td, J=7.6, 1.6Hz, 2H), 1.51 (dt, J=14.8, 7.6Hz, 2H), 0.91 (t, J=8.0Hz, 3H).

[0268] To a solution of G-5 (50.0 mg, 0.202 mmol) in 1,4-dioxane / H2O (2 mL / 0.2 mL), [(E)-2-phenylvinyl] boron diol (44.9 mg, 0.304 mmol), Pd(dppf)Cl2 (11.8 mg, 0.020 mmol) and K2CO3 (55.9 mg, 0.405 mmol) were added. The reaction mixture was stirred at 80 °C for 16 hours under nitrogen. LCMS showed that the desired MS was detected. The solvent was removed by vacuum. The residue was purified by flash chromatography (eluted from 100 / 0 to 95 / 5 with PE / EA in 30 minutes) to obtain G-7. 1 H NMR(400MHz,CD3OD,ppm)7.56(d,J=8.0Hz,2H),7.37-7.33(m,2H),7.27-7.23(m,1H),7.16-7.08(m ,2H),6.95-6.86(m,2H),3.90(s,3H),2.664-2.59(m,2H),1.60-1.51(m,2H),0.94(t,J=8.0Hz,3H).

[0269] To 1-fluoro-3-methoxy-5-[(E)-2-phenylvinyl]-2-propylbenzene (45.0 mg, 0.166 mmol) was added BBr3 (1 M in DCM, 5 mL), and the reaction was stirred at 25 ° C for 16 hours. Water (10 mL) was added to the solution and extracted with DCM (10 mL x 3). The organic phases were combined and washed with aqueous NaHCO3 and brine, dried over Na2SO4, filtered out and concentrated in vacuo. The solvent was removed under reduced pressure to give the crude product. The crude product was directly purified on a reverse phase column (eluted from 0 to 100 in 30 minutes with ACN-H2O (0.1% FA)) to give G-8. LCMS (ESI): C 17 H 17 FO's [M+H] + m / z calcd. 257.2, found 257.2. 1 H NMR(400MHz,DMSO-d6,ppm)9.79(s,1H),7.59(d,J=7.6Hz,2H),7.37(t,J=7.6Hz,2H),7.27(t,J=7.2Hz,1 H),7.13-7.09(m,2H),6.91-6.79(m,2H),1.59-1.42(m,2H),1.24(t,J=6.4Hz,2H),0.89(t,J=8.0Hz,3H).

[0270] To a solution of G-8 (200.0 mg, 0.781 mmol) in DCM (5 mL) was added Py (617.2 mg, 7.81 mmol) and SO 3 Py (1.24 g, 7.81 mmol), and the reaction mixture was stirred at 25 ° C for 2 hours. The desired mass was detected on LC-MS. The solvent was removed under reduced pressure. The reaction mixture was purified by C 18 The residue was purified by column (eluted with ACN-H2O (0.1% NH3.H2O) from 20:80 to 60:40 in 30.0 min) to give compound 9. LCMS (ESI): C 17 H 18 FO's [M+H] - ms / z calculated value 334.9, found value 334.9. 1 H NMR(400MHz, CD3OD, ppm)7.54(d,J=6.4Hz,3H),7.33(t,J=7.6Hz,2H),7.22(dd,J=16.4, 9.2Hz,1H),7.10(m,3H),2.71(t,J=7.6Hz,2H),1.68-1.55(m,2H),0.96(t,J=7.4Hz,3H).

[0271] Preparation of {3-fluoro-2-isopropyl-5-[(E)-2-phenylvinyl]phenyl}oxyethanesulfonic acid (Compound 10)

[0272]

[0273] To a solution of 5-bromo-3-fluoro-2-isopropylphenol (360.0 mg, 1.54 mmol) in 1,4-dioxane / H2O (10 mL / 1 mL) was added [(E)-2-phenylvinyl] boron diol (228.5 mg, 1.54 mmol), Pd(dppf)Cl2 (113.0 mg, 0.15 mmol) and K2CO3 (426.9 mg, 3.09 mmol). The reaction mixture was stirred at 80 ° C for 12 hours under nitrogen. The desired mass was detected on LC-MS. The solvent was removed by vacuum. The residue was quenched with water, extracted with EtOAc, and the combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. By silica gel chromatography (eluted from 100 / 0 to 40 / 60 with PE / EtOAc in 30 minutes) and C 18 The residue was purified by column (eluting with 0.5% NH3.H2O / MeCN from 100:0 to 30:70 in 30 min) to give H-2. LCMS (ESI): C 17 H 17 FO's [MH] + ms / z calculated value 255.1, found value 254.9. 1 H NMR (400MHz, DMSO-d6, ppm)9.79(s,1H),7.59(d,J=7.6Hz,2H),7.37(t,J=7.6Hz,2H),7.27(t,J=7.6 Hz,1H),7.10(s,2H),6.86(d,J=12.4Hz,1H),6.79(s,1H),3.39-3.34(m,1H),1.25(d,J=7.2Hz,6H).

[0274] To a solution of H-2 (100.0 mg, 0.39 mmol) in DCM (5 ml) was added SO3.Py (310.55 mg, 1.95 mmol) and pyridine (462.15 mg, 5.85 mmol). The reaction mixture was stirred at 25 °C for 6 hours. The desired mass was detected on LC-MS. The solvent was removed under reduced pressure. The reaction mixture was purified by C 18 The residue was purified by column (eluting with ACN-H2O (0.1% HCOOH) from 0:100 to 50:50 in 30.0 min) to give compound 10. LCMS (ESI): C 17 H 17 FO4S's [MH] -m / z calculated: 335.0, found: 335.2. 1 H NMR (400MHz, CD3OD, ppm)7.54(d,J=7.6Hz,2H),7.49(s,1H),7.33(t,J=7.6Hz,2H),7.23(t,J=7.2H z, 1H), 7.16 (d, J = 16.4Hz, 1H), 7.11-7.03 (m, 2H), 3.58 (hept, J = 7.2Hz, 1H), 1.32 (d, J = 7.2Hz, 6H).

[0275] Preparation of 3-fluoro-2-isopropyl-5-(4-methylquinolin-7-yl)phenyl dihydrogen phosphate (Compound 11)

[0276]

[0277] 3-Fluoro-2-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (151.4 mg, 0.54 mmol), Pd(dppf)Cl2 (36.6 mg, 0.05 mmol) and potassium carbonate (124.2 mg, 0.90 mmol) were added to a solution of 7-bromo-4-methylquinoline (100.0 mg, 0.45 mmol) in 1,4-dioxane / H2O=5:1 (3 mL). The reaction was stirred at 80 ° C for 12 hours under N2. The desired mass was detected on LC-MS. The solvent was removed under reduced pressure. The mixture was then quenched with water (10 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography (eluted with PE / EtOAc from 100 / 0 to 60 / 40 in 30 minutes) and concentrated under vacuum. The crude product was triturated with diethyl ether to give 1-3. LCMS (ESI): C 19 H 19 [M+H] by FNO + m / z calculated: 296.3, found: 296.2. 1 H NMR(400MHz, DMSO-d6,ppm)10.00(s,1H),8.78(d,J=4.4Hz,1H),8.18-8.13(m,2H),7.87-7.85(m,1 H),7.39(d,J=4.0Hz,1H),7.13-7.00(m,2H),3.46-3.39(m,1H),2.71(s,3H),1.30(d,J=7.2Hz,6H).

[0278] To a solution of I-3 (430.0 mg, 1.45 mmol) in THF (6 mL) was added POCl3 (733.7 mg, 4.79 mmol) and Et3N (880.4 mg, 8.70 mmol) dropwise. The reaction was stirred at 25 °C for 6 hours. The desired mass was detected on LC-MS. The solvent was removed under reduced pressure to give compound I-4, which was used directly in the next step. LCMS (ESI): C 19 H 18 [M+H] of ClFNO3P + m / z calculated: 394.0, found: 393.9.

[0279] To a solution of 3-fluoro-2-isopropyl-5-(4-methylquinolin-7-yl)phenyl hydrogen phosphate (400.0 mg, 1.02 mmol) in H2O (6 mL). The reaction was stirred at 40°C for 6 hours. The desired mass was detected on LC-MS. The residue was purified by preparative HPLC (column: Gemini 5um C18 150 x 21.2 mm, mobile phase: H2O-ACN (0.1% TFA), gradient: 90-50, 10.0 min) to give compound 11. LCMS (ESI): C 19 H 19 FNO4P's [M+H] + m / z calculated value 376.3, found value 376.2. 1 H NMR(400MHz,DMSO-d6,ppm):8.89(s,1H),8.35(s,1H),8.26(d,J=8.8Hz,1H),8.00(d,J=8.8H z,1H),7.65(s,1H),7.57-7.46(m,2H),3.51-3.44(m,1H),2.78(s,3H),1.32(d,J=7.2Hz,6H).

[0280] Caco-2 and S9 stability studies

[0281] Compounds were tested under typical Caco-2 and S9 assay conditions. Results are shown in Table A.

[0282] Table A

[0283]

[0284]

[0285]

[0286] In vitro release studies

[0287] The ability of the compounds of formula (I) to release active compounds in the small or large intestine was evaluated by introducing representative compounds of the present disclosure into the contents of the rodent small intestine or rodent large intestine for up to 24 hours at about 37°C. The amount of active drug released after the incubation period was determined by LC-MS / MS. Additional studies were conducted by incubating representative compounds of the present disclosure with human fecal samples.

[0288] In vitro anaerobic metabolism in fecal homogenates (relative to control)

[0289]

[0290] The structure of compound 1 is Its metabolites (as active AHR agents) are AHR reEC 50 (% activation of tapinarof at 1 μM) was measured to be 166.1 nM (69.5%), and AHR abEC 50 is 241.5 nM.

[0291] Compound 1 was dissolved in PBS (pH 7.4) to give a working solution of 200 μM. A 50 μL volume aliquot was spiked into each 450 μL fecal homogenate incubation sample to provide an incubation concentration at 20 μM.

[0292] The estimated 1 g to 2 g wet weight of fecal material from healthy mice and rats (respectively) was collected immediately in a pre-labeled 50 mL EP tube and stored at room temperature. Based on the weight of each fecal material, it was diluted with 0.01 M isotonic phosphate buffer (pH 7.0) to obtain a 12.5x diluted fecal homogenate. All fecal materials were stored at room temperature before being used for fecal homogenate preparation.

[0293] Under anaerobic conditions, by shaking and mixing with agitator, each kind of feces sample material collected in 0.01M isotonic phosphate buffer (pH7.0) is homogenized. To each batch of feces homogenate material, add the 0.01M isotonic phosphate buffer (pH 7.0) of appropriate volume, to obtain the feces homogenate diluted with 12.5X. Under anaerobic conditions in the nitrogen glove box to ensure oxygen level <1% under purging with high-purity nitrogen, the feces homogenate is transferred to a clean container and diluted with 3 volumes of brain heart infusion fermentation broth (BHI), to obtain the feces homogenate diluted with 50X. The diluted feces homogenate matrix of 0.45mL aliquots is distributed in 2-mL EP tubes, and then the compound 1 working solution of fresh preparation is incorporated in the feces homogenate sample vial, to incubate in the metabolic stability time course.

[0294] Compound 1 was incubated in each fecal homogenate at a target concentration of 20 μM over a time course of 0 hours, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours. Metabolic incubation was performed in triplicate at each time point. The sample was incubated in a 2-mL EP tube. 50 μL of compound 1 working solution was accurately dispensed into each pre-labeled sample vial, followed by the addition of 0.45 mL of pre-incubated fecal homogenate. The sample was capped, vortexed and incubated at 37 ° C in an anaerobic environment. At the end of each incubation time point, 1.0 mL of IS (internal standard) was added to each sample as a stop solvent, wherein the vortex was mixed to stop the metabolic reaction. Before the fecal homogenate and compound 1 were added, the sample was pretreated at 0 hour time point with the addition of IS stop solvent. Before LC-MS / MS determination, all samples were stored at -80 ° C. The sample was analyzed by LC-MS / MS. MS detection was performed using a Sciex API 5500+ instrument. Each compound was analyzed by reverse phase HPLC.

[0295] The results are shown in the table below.

[0296] Conversion of compound 1 into metabolites over time in rat or mouse fecal homogenates compared with controls

[0297]

[0298]

[0299] It should be understood that all combinations of the above-mentioned concepts and embodiments and additional concepts and embodiments discussed in more detail below are considered to be part of the inventive subject matter disclosed herein, and the benefits described herein can be achieved in any suitable combination. In particular, all combinations of the claimed subject matter appearing at the end of this disclosure are contemplated to be part of the inventive subject matter disclosed herein.

[0300] The foregoing description has been given only for clearness of understanding, and no unnecessary limitations should be understood therefrom, since modifications within the scope of the invention may be obvious to one skilled in the art.

[0301] Throughout this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or groups of integers or steps but not the exclusion of any other integer or step or groups of integers or steps.

[0302] Throughout the specification, unless otherwise described, when a composition is described as comprising a component or material, it is contemplated that the composition may also consist essentially of or consist of any combination of said components or materials. Similarly, unless otherwise described, when a method is described as comprising specific steps, it is contemplated that the method may also consist essentially of or consist of any combination of said steps. The invention illustratively disclosed herein may be suitably practiced in the absence of any element or step not specifically disclosed herein.

[0303] The practice of the method disclosed herein and its individual steps can be performed manually and / or by means of an electronic device or an automation provided by an electronic device. Although each process has been described with reference to a specific embodiment, it will be readily understood by those skilled in the art that other ways of performing the behavior associated with the method can be used. For example, unless otherwise described, the order of the various steps can be changed without departing from the scope or spirit of the method. In addition, some of the individual steps can be combined, omitted or further subdivided into other steps.

[0304] All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between the present disclosure and the incorporated patents, publications, and references, the present disclosure shall control.

Claims

1. A compound having a structure of formula (I): in: A is -Y 1 -Z 1 or a fused bicyclic heteroaryl having 8-10 total ring atoms and 1, 2 or 3 heteroatoms selected from N, O or S, and the heteroaryl is optionally substituted by 1, 2 or 3 R a replace; Y 1 yes O, S, SO or SO2; Z 1 is phenyl or a 5- to 6-membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the phenyl group or the heteroaryl group is optionally substituted by 1, 2 or 3 R a replace; X 1 is N, Cr 3 or C - O - L - R 2 ; R 1 It is C 1-45 Alkyl, C 1-5 Haloalkyl, C 1-5 Hydroxyalkyl, C 3-6 Cycloalkyl, OC 1-5 Alkyl, N(R N )2、C(=O)C 1-4 Alkyl or C(=CH)C 1-4 alkyl; Each R 2 Independently SO2-R 4 , PO(R 4 )2、CO2H、N(R N )2. N(H)-C 2-6 Alkylene-N(R N )2. N(H)-C 2-6 Polyoxyalkylene-N(R N )2、NHCH(R 5 )CO2H、NH-C 1-6 Alkylene -CH (NH2) CO2H, sugar or NH-phenyl, wherein the phenyl group is optionally substituted by 1, 2 or 3 R b replace; R 3 Is halogenated, C 1-6 Alkoxy, OH or N(R N )2; Each L is independently C(O), C(O)-W n -C(O), C(O)-W n or C(O)NH-W n , or when R 2 SO2-R 4 , PO(R 4 )2 or a sugar, L may be a bond; Each W is independently CH2, C 2-3 Alkylene-O or OC 2-3 Alkylene; n is 1, 2, 3, 4, 5, or 6; Each R 4 independently OH or NH2; Each R 5 Independently H, C 1-6 Alkyl or C 1-6 Alkylene-R 6 ; Each R 6 Independently, CO2H, CO2C 1-3 Alkyl, CON(R N )2、OH、OCH3、N(R N )2, NHC(NH)NH2, a heteroaryl or phenyl group containing 5 or 6 total ring atoms and 1, 2 or 3 heteroatoms selected from N, O and S, wherein the heteroaryl or the phenyl group is optionally replaced by 1, 2, 3, 4 or 5 C 0-2 Alkylene-R b Substituent substitution; Each R a are independently halogenated, C 1-6 Alkyl, CO2H, CO2C 1-3 Alkyl, CON(R N )2. OH, OC 1-3 Alkyl or N(R N )2; Each R b Independently, CO2H, CO2C 1-3 Alkyl or OH; and Each R N independently H or C 1-3 alkyl; or a pharmaceutically acceptable salt thereof, The condition is that when Y 1 yes Z 1 is an unsubstituted phenyl group, and R 1 When X is isopropyl, 1 Is N or CR 3 , and R 3 Is halogenated, C 1-6 Alkoxy or N(R N )2.

2. The compound or salt according to claim 1, wherein A is Y 1 -Z 1 .

3. The compound or salt according to claim 2, wherein Y 1 yes 4. The compound or salt according to claim 2, wherein Y 1 It is S, SO or SO2.

5. The compound or salt according to any one of claims 2 to 4, wherein Z 1 It is phenyl.

6. The compound or salt according to any one of claims 2 to 4, wherein Z 1 It is a 5- to 6-membered heteroaryl group.

7. The compound or salt according to claim 6, wherein Z 1 is pyridine, pyrazole, imidazole or pyrimidine.

8. A compound or salt according to any one of claims 5 to 7, wherein Z 1 is unreplaced.

9. The compound or salt according to claim 5 to 7, wherein Z 1 By 1 or 2 R a Group substitution.

10. The compound or salt according to claim 9, wherein each R a are independently halogenated, C 1-3 Alkyl or NH2.

11. The compound or salt of claim 1, wherein A is a fused bicyclic heteroaryl.

12. The compound or salt of claim 11, wherein A is a 10-membered heteroaryl.

13. The compound or salt according to claim 11 or 12, wherein A is isoquinoline, quinoline or quinazoline.

14. The compound or salt according to claim 13, wherein A is or When R 2 SO2-R 4 or PO(R 4 )2, A is 15. The compound or salt of any one of claims 11 to 14, wherein A is unsubstituted.

16. A compound or salt according to any one of claims 11 to 14, wherein A is replaced by 1 or 2 R a Group substitution.

17. The compound or salt according to claim 16, wherein each R a are independently halogenated, C 1-3 Alkyl or NH2.

18. A compound or salt according to any one of claims 1 to 17, wherein X 1 It is N.

19. A compound or salt according to any one of claims 1 to 17, wherein X 1 Yes CR 3 .

20. The compound or salt according to claim 19, wherein R 3 It is F or OH.

21. A compound or salt according to any one of claims 1 to 17, wherein X 1 It is COLR 2 .

22. The compound or salt according to claim 21, wherein X 1 It is COR 2 .

23. The compound or salt according to claim 22, wherein X 1 It is C-OSO2-R 4 or C-OPO(R 4 )2.

24. A compound or salt according to any one of claims 1 to 23, wherein R 1 It is C 1-5 Alkyl, C 1-5 Haloalkyl or C 1-5 Hydroxyalkyl.

25. The compound or salt according to claim 24, wherein R 1 It is C 1-5 alkyl.

26. The compound or salt according to claim 25, wherein R 1 It is a C3 alkyl group.

27. A compound or salt according to any one of claims 1 to 23, wherein R 1 It's OC 1-5 Alkyl, N(R N )2 or C(=O)C 1-4 alkyl.

28. A compound or salt according to any one of claims 1 to 27, wherein L is a bond.

29. A compound or salt according to any one of claims 1 to 27, wherein L is C(O), C(O)-W n -C(O), C(O)-W n or C(O)NH-W n .

30. The compound or salt of claim 29, wherein each W is independently CH2 or C 2-3 Alkylene-O.

31. The compound or salt of claim 29 or 30, wherein n is 1 or 2.

32. A compound or salt according to any one of claims 1 to 31, wherein R 2 SO2-R 4 or PO(R 4 )2.

33. The compound or salt according to claim 32, wherein R 2 It is SO2H or PO(OH)2.

34. A compound or salt according to any one of claims 1 to 31, wherein R 2 It is N(H)-C 2-6 Alkylene-N(R N )2. N(H)-C 2-6 Polyoxyalkylene-N(R N )2、NHCH(R 5 )CO2H or NH-C 1-6 Alkylene -CH(NH2)CO2H.

35. The compound or salt according to claim 34, wherein R 2 It is N(H)-C 2-6 Alkylene-N(R N )2 or NH-C 1-6 Alkylene -CH(NH2)CO2H.

36. The compound or salt according to claim 35, wherein R 2 is NHCH(R 5 )CO2H.

37. The compound or salt according to claim 36, wherein R 5 It is C 1-6 Alkyl or C 1-6 Alkylene-R 6 .

38. The compound or salt according to claim 37, wherein R 6 It is CO2H, CO2CH3, CONH2, OH, OCH3, NH2, NHC(NH)NH2, imidazolyl, phenyl or 4-hydroxy-phenyl.

39. A compound or salt according to any one of claims 1 to 31, wherein at least one R 2 It is NH-phenyl.

40. The compound or salt of claim 39, wherein the phenyl group is replaced by 1 or 2 R b Group substitution.

41. A compound or salt according to any one of claims 1 to 40, wherein each R N are independently H or CH3.

42. The compound or salt of claim 1 selected from the group consisting of: (E)-2-isopropyl-5-phenylvinylpyridin-3-yl hydrogen sulfate, (E)-2-isopropyl-5-phenylvinylpyridin-3-yl dihydrogen phosphate, 3-Hydroxy-2-isopropyl-5-(isoquinolin-3-yl)phenyl hydrogen sulfate, 3-Hydroxy-2-isopropyl-5-(isoquinolin-3-yl)phenyl dihydrogen phosphate, 3-Hydroxy-2-isopropyl-5-(quinolin-3-yl)phenyl hydrogen sulfate, 3-Hydroxy-2-isopropyl-5-(quinolin-3-yl)phenyl dihydrogen phosphate, 2-Isopropyl-5-(quinolin-3-yl)-1,3-phenylene bis(hydrogen sulfate), 2-Isopropyl-5-(quinolin-3-yl)-1,3-phenylenebis(dihydrogen phosphate), (E)-5-(2-fluorophenylvinyl)-2-isopropylpyridin-3-yl hydrogen sulfate, (E)-5-(2-fluorophenylvinyl)-2-isopropylpyridin-3-yl dihydrogen phosphate, (E)-5-(3-fluorophenylvinyl)-2-isopropylpyridin-3-yl hydrogen sulfate, (E)-5-(3-fluorophenylvinyl)-2-isopropylpyridin-3-yl dihydrogen phosphate, (E)-5-(4-Fluorophenylvinyl)-2-isopropylpyridin-3-yl hydrogen sulfate, (E)-5-(4-Fluorophenylvinyl)-2-isopropylpyridin-3-yl dihydrogen phosphate, 5-(2-amino-5-fluoroquinazolin-7-yl)-3-hydroxy-2-isopropylphenyl hydrogen sulfate, 5-(2-amino-5-fluoroquinazolin-7-yl)-3-hydroxy-2-isopropylphenyl dihydrogen phosphate, 5-(2-amino-5-fluoroquinazolin-7-yl)-2-isopropyl-1,3-phenylene bis(hydrogen sulfate); 5-(2-amino-5-fluoroquinazolin-7-yl)-2-isopropyl-1,3-phenylenebis(dihydrogen phosphate); 5-(6-Fluoroquinolin-2-yl)-3-hydroxy-2-isopropylphenyl hydrogen sulfate, 5-(6-Fluoroquinolin-2-yl)-3-hydroxy-2-isopropylphenyl dihydrogen phosphate, 5-(6-Fluoroquinolin-2-yl)-2-isopropyl-1,3-phenylene bis(hydrogen sulfate), 5-(6-Fluoroquinolin-2-yl)-2-isopropyl-1,3-phenylenebis(dihydrogen phosphate), (E)-3-Fluoro-2-propyl-5-phenylvinylphenyl hydrogen sulfate, (E)-3-fluoro-2-propyl-5-phenylvinylphenyl dihydrogen phosphate, (E)-3-Fluoro-2-isopropyl-5-phenylvinylphenyl hydrogen sulfate, (E)-3-Fluoro-2-isopropyl-5-phenylvinylphenyl dihydrogen phosphate, 3-Fluoro-2-isopropyl-5-(4-methylquinolin-7-yl)phenyl hydrogen sulfate, and 3-Fluoro-2-isopropyl-5-(4-methylquinolin-7-yl)phenyl dihydrogen phosphate.

43. The compound or salt of claim 42 selected from the group consisting of: 2-Isopropyl-5-(quinolin-3-yl)-1,3-phenylenebis(dihydrogen phosphate), 2-Isopropyl-5-(quinolin-3-yl)-1,3-phenylenebis(hydrogen sulfate), (E)-5-(2-fluorostyryl)-2-isopropylpyridin-3-yl hydrogen sulfate, (E)-5-(2-fluorostyryl)-2-isopropylpyridin-3-yl dihydrogen phosphate, (E)-3-fluoro-2-propyl-5-styrylphenyl dihydrogen phosphate, (E)-3-fluoro-2-propyl-5-phenylvinylphenyl dihydrogen phosphate, (E)-3-fluoro-2-isopropyl-5-phenylvinylphenyl dihydrogen phosphate, (E)-3-fluoro-2-isopropyl-5-phenylvinylphenyl dihydrogen phosphate, 3-fluoro-2-isopropyl-5-(4-methylquinolin-7-yl)phenyl dihydrogen phosphate.

44. A pharmaceutical formulation comprising a compound or salt according to any one of claims 1 to 43 and a pharmaceutically acceptable excipient.

45. A method of modulating aryl hydrocarbon receptor (AHR) activity in a subject, the method comprising contacting the AHR with an amount of a compound or salt according to any one of claims 1 to 43 effective to modulate the AHR activity.

46. ​​A method of treating or preventing a disease or condition associated with aberrant aryl hydrocarbon receptor (AHR) activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound or salt according to any one of claims 1 to 43.

47. The method of embodiment 46, wherein said administration is topical.

48. The method of embodiment 46, wherein said administration is oral or by injection or infusion.

49. The method of claim 46, 47 or 48, wherein the disease or condition is an inflammatory disease or condition.

50. The method of claim 46, 47 or 48, wherein the disease or disorder is a disease or disorder of the gastrointestinal tract, skin, lung, central nervous system, pancreas, eye, bone, osteoarticular, neuroinflammatory disease or neurodegenerative disease.

51. The method of claim 50, wherein the disease or disorder of the gastrointestinal tract 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.

52. The method of claim 50, wherein the disease or condition of the skin is selected from the group consisting of atopic dermatitis, acne, psoriasis, and vitiligo.

53. The method of claim 50, wherein the disease or condition of the eye is abnormal eye movement, inflammatory eye disease, autoimmune eye disease, inherited eye disease, degenerative eye disease, vascular eye disease, 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").

54. The method of claim 50, wherein the disease or disorder of the lung is pulmonary fibrosis, asthma, or chronic obstructive pulmonary disease.

55. The method of claim 50, wherein the disease or disorder of the bone joint is osteoporosis, rheumatoid arthritis, or bone cancer.

56. The method of claim 46, 47 or 48, wherein the disease or condition is diabetes, cancer, a viral infection or a bacterial infection.

57. The method of claim 56, wherein the viral infection is a flavivirus infection or a coronavirus infection.

58. The method of claim 56, wherein the bacterial infection is a lung infection, a gastrointestinal infection, a skin infection, an ear infection, or sepsis.

59. The method of any one of claims 46 to 58, further comprising administering a therapeutic agent.

60. The method of claim 59, wherein the therapeutic agent is an anti-inflammatory agent.

61. The method of claim 60, wherein the anti-inflammatory agent is selected from mesalazine, naproxen, ibuprofen, diclofenac, celecoxib, sulindac, oxaprozin, piroxicam, indomethacin, meloxicam, fenoprofen, diflunisal, etodolac, ketorolac tromethamine, meclofenamate, nabumetone, disalicylate, or any combination of the foregoing.

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