ARYL HYDROCARBON RECEPTOR (AHR) AGONISTS AND USES THEREOF

The present invention provides AHR agonists, compositions thereof, and methods of using the same.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful for activating aryl hydrocarbon receptor (AHR). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.

BACKGROUND

The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that mediates a number of important biological and pharmacological processes. AHR agonists have been shown to be potentially useful for treating disorders such as cancer (U.S. Pat. No. 8,604,067, Wang et al., 2013, Cheng et al., 2015), obesity (U.S. Pat. No. 7,419,992), and conditions related to imbalanced actions of the immune system (Quintana et al., 2010, Nugent et al., 2013). AHR has also been shown to be involved in immune regulation, hematopoiesis, cell cycle, carcinogenesis and in the maintenance of intestinal barrier integrity and homeostasis.

SUMMARY OF THE INVENTION

It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as AHR agonists. In one aspect, the instant invention provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with AHR. Such diseases, disorders, or conditions include, for example, cancer, obesity, and inflammatory disorders as described herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

1. General Description of Certain Embodiments of the Invention

Compounds of the present invention, and pharmaceutical compositions thereof, are useful as AHR agonists. Without wishing to be bound by any particular theory, it is believed that compounds of the present invention, and pharmaceutical compositions thereof, may activate AHR and thus treat certain diseases, disorders, or conditions associated with AHR, such as those described herein.

It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as AHR agonists. In one aspect, the present invention provides a compound of Formula (I):

2. Compounds and Definitions

As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:

As used herein, the term “bivalent C1-8(or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure:

Each R●is independently selected from C1-4aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R●is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from ═O, ═S, ═NNR*2, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)2R*, ═NR*, ═NOR*, —O(C(R*2))2-3O—, or —S(C(R*2))2-3S—, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is —O(CR*2)2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C1-6aliphatic or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

When R* is C1-6aliphatic, R* is optionally substituted with halogen, —R●, -(haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —NH2, NHR●, —NR●2, or —NO2, wherein each R●is independently selected from C1-4aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.

An optional substituent on a substitutable nitrogen is independently —R†, —NR†2, —C(O)R†, —C(O)OR†, —C(O)C(O)R†, —C(O)CH2C(O)R†, —S(O)2R†, —S(O)2NR†2, —C(S)NR†2, —C(NH)NR†2, or —N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1-6aliphatic, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of RJ, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R†is C1-6aliphatic, R†is optionally substituted with halogen, —R●, -(haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —NH2, —NHR●, —NR●2, or —NO2, wherein each R●is independently selected from C1-4aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.

As used herein, the term “agonist” is defined as a compound that binds to and/or activates AHR with measurable affinity. In certain embodiments, an agonist has an IC50and/or binding constant of less than about 100 μM, less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

The terms “measurable affinity” and “measurably activate,” as used herein, means a measurable change in AHR activity between a sample comprising a compound of the present invention, or composition thereof, and AHR, and an equivalent sample comprising AHR, in the absence of said compound, or composition thereof.

3. Description of Exemplary Embodiments

As defined generally above, Ring A is an optionally substituted 5-membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S.

In some embodiments, Ring A is an unsubstituted 5-membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, Ring A is a 5-membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, or S, which is substituted 1 or 2 times by R12, wherein each R12is independently an optional substituent as defined above and described in embodiments herein.

In some embodiments, Ring A is an unsubstituted 5-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N or S. In some embodiments, Ring A is a 5-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N or S, which is substituted 1 or 2 times by R12, wherein each R12is independently an optional substituent as defined above and described in embodiments herein.

In some embodiments, Ring A is an unsubstituted 5-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N or O. In some embodiments, Ring A is a 5-membered heteroaromatic ring having 1, 2, or 3 heteroatoms independently selected from N or O, which is substituted 1 or 2 times by R12, wherein each R12is independently an optional substituent as defined above and described in embodiments herein.

In some embodiments, Ring A is optionally substituted

In some embodiments, Ring A is unsubstituted

In some embodiments, Ring A is

each of which is substituted 1 or 2 times by R12, wherein each R12is independently an optional substituent as defined above and described in embodiments herein.

In some embodiments, Ring A is

In some embodiments, Ring A is

wherein each R12is independently an optional substituent as defined above and described in embodiments herein.

In some embodiments, Ring A is

wherein each of R7and R8is independently an optional substituent as defined above and described in embodiments herein.

In some embodiments, R7is halogen. In some embodiments, R7is —CN. In some embodiments, R7is —NO2. In some embodiments, R7is RWas defined below and described in embodiments herein. In some embodiments, R7is —C(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R7is —C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R7is —N(RW)—C(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R7is —N(RW)—C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R7is —OC(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R7is —OC(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R7is —S(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R7is —N(RW)—S(O)2—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R7is —OS(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R7is —S(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R7is —N(RW)—S(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R7is —OS(O)—RW, wherein RWis as defined below and described in embodiments herein.

In some embodiments, R7is

In some embodiments, R8is halogen. In some embodiments, R8is —CN. In some embodiments, R8is —NO2. In some embodiments, R8is RWas defined below and described in embodiments herein. In some embodiments, R8is —C(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R8is —C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R8is —N(RW)—C(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R8is —N(RW)—C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R8is —OC(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R8is —OC(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R8is —S(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R8is —N(RW)—S(O)2—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R8is —OS(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R8is —S(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R8is —N(RW)—S(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R8is —OS(O)—RW, wherein RWis as defined below and described in embodiments herein.

In some embodiments, R12is halogen. In some embodiments, R12is —CN. In some embodiments, R12is —NO2. In some embodiments, R12is RWas defined below and described in embodiments herein. In some embodiments, R12is —C(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R12is —C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R12is —N(RW)—C(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R12is —N(RW)—C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R12is —OC(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R12is —OC(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R12is —S(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R12is —N(RW)—S(O)2—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R12is —OS(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R12is —S(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R12is —N(RW)—S(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R12is —OS(O)—RW, wherein RWis as defined below and described in embodiments herein.

In some embodiments, R12is-CH3,

In some embodiments, Ring A is selected from those depicted in Table 1-a, below.

In some embodiments, R1is halogen. In some embodiments, R1is —CN. In some embodiments, R1is —NO2. In some embodiments, R1is RWas defined below and described in embodiments herein. In some embodiments, R1is —C(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R1is —C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R1is —N(RW)—C(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R1is —N(RW)—C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R1is —OC(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R1is —OC(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R1is —S(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R1is —N(RW)—S(O)2—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R1is —OS(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R1is —S(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R1is —N(RW)—S(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R1is —OS(O)—RW, wherein RWis as defined below and described in embodiments herein.

In some embodiments, R2is halogen. In some embodiments, R2is —CN. In some embodiments, R2is —NO2. In some embodiments, R2is RWas defined below and described in embodiments herein. In some embodiments, R2is —C(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R2is —C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R2is —N(RW)—C(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R2is —N(RW)—C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R2is —OC(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R2is —OC(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R2is —S(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R2is —N(RW)—S(O)2—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R2is —OS(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R2is —S(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R2is —N(RW)—S(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R2is —OS(O)—RW, wherein RWis as defined below and described in embodiments herein.

In some embodiments, R3is halogen. In some embodiments, R3is —CN. In some embodiments, R3is —NO2. In some embodiments, R3is RWas defined below and described in embodiments herein. In some embodiments, R3is —C(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R3is —C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R3is —N(RW)—C(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R3is —N(RW)—C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R3is —OC(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R3is —OC(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R3is —S(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R3is —N(RW)—S(O)2—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R3is —OS(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R3is —S(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R3is —N(RW)—S(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R3is —OS(O)—RW, wherein RWis as defined below and described in embodiments herein.

In some embodiments, R4is halogen. In some embodiments, R4is —CN. In some embodiments, R4is —NO2. In some embodiments, R4is RWas defined below and described in embodiments herein. In some embodiments, R4is —C(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R4is —C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R4is —N(RW)—C(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R4is —N(RW)—C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R4is —OC(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R4is —OC(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R4is —S(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R4is —N(RW)—S(O)2—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R4is —OS(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R4is —S(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R4is —N(RW)—S(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R4is —OS(O)—RW, wherein RWis as defined below and described in embodiments herein.

In some embodiments, R6is halogen. In some embodiments, R6is —CN. In some embodiments, R6is —NO2. In some embodiments, R6is RWas defined below and described in embodiments herein. In some embodiments, R6is —C(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R6is —C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R6is —N(RW)—C(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R6is —N(RW)—C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R6is —OC(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R6is —OC(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R6is —S(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R6is —N(RW)—S(O)2—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R6is —OS(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R6is —S(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R6is —N(RW)—S(O)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R6is —OS(O)—RW, wherein RWis as defined below and described in embodiments herein.

In some embodiments, each of R1, R2, R3, R4, and R6is independently selected from those depicted in Table 1-a, below.

As defined generally above, R5is —R, —C(O)—RW, —C(═NRW)—RW, —S(O)2—RW, or —S(O)—RW, wherein each RWis independently as defined below and described in embodiments herein.

In some embodiments, R5is —R, wherein R is as defined below and described in embodiments herein. In some embodiments, R5is —C(O)—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R5is —C(═NRW)—RW, wherein each RWis independently as defined below and described in embodiments herein. In some embodiments, R5is —S(O)2—RW, wherein RWis as defined below and described in embodiments herein. In some embodiments, R5is —S(O)—RW, wherein RWis as defined below and described in embodiments herein.

In some embodiments, R5is selected from those depicted in Table 1-a, below.

In some embodiments, RWis —R, wherein R is as defined below and described in embodiments herein. In some embodiments, RWis —N(R)2, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, RWis —NR—OR, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, RWis —N(R)—N(R)2, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, RWis —N(OR)—N(R)2, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, RWis —N(R)—N(OR)R, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, RWis —OR, wherein R is as defined below and described in embodiments herein. In some embodiments, RWis —O—N(R)2, wherein each R is independently as defined below and described in embodiments herein. In some embodiments, RWis —SR, wherein R is as defined below and described in embodiments herein.

In some embodiments, RWis selected from those depicted in Table 1-a, below.

As defined generally above, R is hydrogen, optionally substituted C1-6aliphatic, an optionally substituted 3-7 membered carbocyclic ring, or an optionally substituted 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S, or two R's together with the nitrogen to which they attach form an optionally substituted 5-7 membered heterocyclic ring having 0-2 heteroatoms independently selected from N, O, or S in addition to the nitrogen to which the two R's attach.

In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C1-6aliphatic. In some embodiments, R is optionally substituted C1-6alkyl. In some embodiments, R is unsubstituted —C1-6aliphatic. In some embodiments, R is unsubstituted —C1-6alkyl. In some embodiments, R is —C1-6aliphatic which is substituted by —CH3, —CF3, —OH, —OCH3, —OCF3, —N(CH3)2, —N+(CH3)3,

In some embodiments, R is —C1-6aliphatic substituted 1-6 times by halogen. In some embodiments, R is —C1-6alkyl substituted 1-6 times by halogen. In some embodiments, R is —C1-6alkyl substituted 1-6 times by F. In some embodiments, R is —CH3. In some embodiments, R is —CH2CH3. In some embodiments, R is —CH2CH2CH3. In some embodiments, R is —CH(CH3)2. In some embodiments, R is —CH2CH2CH2CH3. In some embodiments, R is —CH2CH(CH3)2. In some embodiments, R is —C(CH3)3. In some embodiments, R is —CF3.

some embodiments, R is an optionally substituted

In some embodiments, R is an optionally substituted 6-membered heterocyclic ring having 1 or 2 heteroatoms independently selected from N, O, or S. In some embodiments, R is optionally substituted or

In some embodiments, R is optionally substituted

In some embodiments, R is

In some embodiments, two R's together with the nitrogen to which they attach form an optionally substituted 5-7 membered heterocyclic ring having 0-2 heteroatoms independently selected from N, O, or S in addition to the nitrogen to which the two R's attach. In some embodiments, two R's together with the nitrogen to which they attach form an optionally substituted 5-7 membered heterocyclic ring having 0 or 1 heteroatom independently selected from N, O, or S in addition to the nitrogen to which the two R's attach. In some embodiments, —N(R)2is optionally substituted

In some embodiments, R is selected from those depicted in Table 1-a, below.

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination.

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of Formula (I-a), or a pharmaceutically acceptable salt thereof, wherein R7is —C(O)—RW, each of RW, R1, R2, R3, R4, R5, R6, and R8is independently as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of Formula (I-a), or a pharmaceutically acceptable salt thereof, wherein R7is —C(O)—OR or —C(O)O—N(R)2, each of R, R1, R2, R3, R4, R5, R6, and R8is independently as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound of Formulas (I-a), or a pharmaceutically acceptable salt thereof, wherein R7is —C(O)—N(R)2, —C(O)—NR—OR, —C(O)—N(R)—N(R)2, —C(O)—N(OR)—N(R)2, or —C(O)—N(R)—N(OR)R, each of R, R1, R2, R3, R4, R5, R6, and R8is independently as defined above and described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound selected from Formulas (I-b) to (I-h):

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination.

Exemplary compounds of the invention are set forth in Table 1-a, below.

In some embodiments, the present invention provides a compound set forth in Table 1-a above, or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of the present invention is not

In some embodiments, a compound of the present invention is not

The compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein. In some embodiments, the present invention provides a compound or an intermediate compound as described in the Examples, or a salt thereof.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably activate AHR, or a mutant thereof, in a biological sample or in a patient. The amount of compound in compositions of this invention is such that is effective to measurably activate AHR, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably activate AHR, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably activate AHR, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an active metabolite or residue thereof.

As used herein, the term “active metabolite or residue thereof” means that a metabolite or residue thereof also activates AHR, or a mutant thereof. The term “active metabolite or residue thereof” also means that a metabolite or residue thereof activates AHR, or a variant or mutant thereof.

Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

It should also be understood that a specific dosage and treatment regimen for any particular patient depends upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition also depends upon the particular compound in the composition.

In some embodiments, the present invention provides a method of using a compound as described herein for treating a disease or disorder associated with AHR. In some embodiments, a disease or disorder associated with AHR is an angiogenesis implicated disorder as described herein. In some embodiments, a disease or disorder associated with AHR is a cancer as described herein. In some embodiments, a disease or disorder associated with AHR is an inflammatory disorder as described herein. In some embodiments, a disease or disorder associated with AHR is a disease or disorder as described in Gutiérrez-Vázquez C. et al.Immunity2018, 48(1): 19-33, and Rothhammer V., et al.,Nat Rev Immunol.2019; 19(3): 184-197, each of which is incorporated herein by reference in its entirety.

Angiogenesis Implicated Disorders

In one aspect, the present invention provides a method for treating or preventing or reducing the risk of an angiogenesis implicated disorder in a patient comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, an angiogenesis implicated disorder is associated with a reduced expression or activation of an AHR.

In some embodiments, an angiogenesis implicated disorder is a retinopathy, psoriasis, rheumatoid arthritis, obesity, or cancer (for example, as described below).

Cancer

In some embodiments, the present invention provides a method for treating or preventing or reducing the risk of cancer in patient comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, a cancer is associated with a reduced expression or activation of an aryl hydrocarbon receptor (AHR).

The cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.

In some embodiments, a cancer is acoustic neuroma, astrocytoma (e.g. Grade I—Pilocytic Astrocytoma, Grade II—Low-grade Astrocytoma, Grade III—Anaplastic Astrocytoma, or Grade IV—Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.

Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkins's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

In some embodiments, a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas. In some embodiments, the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

In some embodiments, a cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

In some embodiments, a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papillomavirus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma. (See https://clinicaltrials.gov/ct2/show/study/NCT02488759; see also https://clinicaltrials.gov/ct2/show/study/NCT0240886; https://clinicaltrials.gov/ct2/show/NCT02426892)

In some embodiments, a cancer is melanoma cancer. In some embodiments, a cancer is breast cancer. In some embodiments, a cancer is lung cancer. In some embodiments, a cancer is small cell lung cancer (SCLC). In some embodiments, a cancer is non-small cell lung cancer (NSCLC). In some embodiments, a cancer is selected from prostate cancer, liver cancer, and ovarian cancer.

Inflammatory Disorders

In some embodiments, the present invention provides a method for treating or preventing or reducing the risk of an inflammatory disorder in patient comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, an inflammatory disorder is associated with a reduced expression or activation of an aryl hydrocarbon receptor (AHR). In some embodiments, an inflammatory disorder is associated with a reduced expression or reduced activation of an aryl hydrocarbon receptor (AHR).

Inflammatory disorders include a large number of disorders or conditions that are involved in a variety of diseases, including those involving the immune system, including those demonstrated in allergic reactions and myopathies, or non-immune diseases with causal origins in inflammatory processes including, but not limited to cancer, atherosclerosis, and ischemic heart disease. Non-limiting examples of disorders associated with inflammation include, but are not limited to, acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, inflammatory bowel diseases, interstitial cystitis, otitis, pelvic inflammatory disease, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, and vasculitis.

The term “inflammatory bowel disease” or “IBD” as used herein is a collective term describing inflammatory disorders of the gastrointestinal tract, the most common forms of which are ulcerative colitis and Crohn's disease. Other forms of IBD that can be treated with the presently disclosed compounds, compositions and methods include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behget's disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, Crohn's (granulomatous) colitis, irritable bowel syndrome, mucositis, radiation induced enteritis, short bowel syndrome, celiac disease, stomach ulcers, diverticulitis, pouchitis, proctitis, and chronic diarrhea.

As used herein, treating or preventing an inflammatory disease also includes ameliorating or reducing one or more symptoms of the inflammatory disease. Where the inflammatory disease or disorder is IBD, the term “symptoms of IBD” can refer to detected symptoms such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite, and other more serious complications, such as dehydration, anemia and malnutrition. A number of such symptoms are subject to quantitative analysis (e.g., weight loss, fever, anemia, etc.). Some symptoms are readily determined from a blood test (e.g., anemia) or a test that detects the presence of blood (e.g., rectal bleeding). The term “wherein said symptoms are reduced” refers to a qualitative or quantitative reduction in detectable symptoms, including but not limited to, a detectable impact on the rate of recovery from disease (e.g, rate of weight gain). The diagnosis is typically determined by way of an endoscopic observation of the mucosa, and pathologic examination of endoscopic biopsy specimens. The course of IBD varies, and is often associated with intermittent periods of disease remission and disease exacerbation. Various methods have been described for characterizing disease activity and severity of IBD as well as response to treatment in subjects having IBD. Treatment according to the present methods is generally applicable to a subject having IBD of any level or degree of disease activity.

In some embodiments, the present invention provides a method for treating or preventing or reducing the risk of an angiogenesis implicated disorder, cancer, or an inflammatory disorder, such as those described above, comprising administering to the patient a compound selected from:

or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Co-Administration with One or More Other Therapeutic Agent(s)

Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, can also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.

A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.

One or more other therapeutic agent(s) can be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agent(s) may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent(s) and a compound or composition of the invention can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent(s) and a compound or composition of the invention are administered as a multiple dosage regimen within greater than 24 hours apart.

As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of a compound of the invention and one or more other therapeutic agent(s) (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Preferably, a composition of the invention should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of a compound of the invention can be administered.

In those compositions which comprise one or more other therapeutic agent(s), the one or more other therapeutic agent(s) and a compound of the invention can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01-1,000 g/kg body weight/day of the one or more other therapeutic agent(s) can be administered.

The amount of one or more other therapeutic agent(s) present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the phrase “normally administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert.

The compounds of this invention, or pharmaceutical compositions thereof, can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention.

Exemplary Other Therapeutic Agents

In some embodiments, the one or more other therapeutic agents is an anti-inflammatory agent. Anti-inflammatory agents include but are not limited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate. Non-limiting examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors (i.e., a compound that inhibits COX-2 with an IC50 that is at least 50-fold lower than the IC50 for COX-1) such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.

In a further embodiment, the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent can also be a corticosteroid. For example, the corticosteroid can be chosen from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone. In some embodiments, the anti-inflammatory therapeutic agent is a gold compound such as gold sodium thiomalate or auranofin.

In some embodiments, the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydroo rotate dehydrogenase inhibitor, such as leflunomide.

In some embodiments, the anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist, such as entanercept, or infliximab, which is an anti-TNF alpha monoclonal antibody.

Included herein are methods of treatment in which a compound described herein, is administered in combination with an immunosuppressant. In some embodiments, the immunosuppressant is methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Unless otherwise stated, one or more tautomeric forms of compounds of the examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms of compounds of the examples described hereafter should be considered to be disclosed. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.

Example 1: Synthesis of Exemplary Compounds

Certain exemplary compounds are prepared following the following schemes.

To a solution of 4-methyl-1H-indole (2 g, 15.25 mmol, 1 eq) in THF (20 mL) was added drop-wise (COCl)2(1.97 g, 15.55 mmol, 1.36 mL, 1.02 eq) at 0-5° C. under N2. The mixture was stirred at 0-5° C. for 3 h. The reaction mixture was concentrated to yield crude 2-(4-methyl-1H-indol-3-yl)-2-oxo-acetyl chloride (3.38 g, crude) as a yellow solid which was used in the next step without further purification.

To a solution of 4-methoxycarbonylthiazole-2-carboxylic acid (300 mg, 1.57 mmol, 1 eq) in DCM (6 mL) was added (COCl)2(797.50 mg, 6.28 mmol, 550.00 μL, 4 eq) dropwise at 0° C. And DMF (114.81 mg, 1.57 mmol, 120.85 μL, 1 eq) was added the mixture. The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under reduced pressure to yield methyl 2-chlorocarbonylthiazole-4-carboxylate (300 mg, crude) as a yellow solid which was used in the next step without further purification.

To a stirred solution of 2-(1H-indole-3-carbonyl)thiazole-4-carboxylic acid (200 mg, 734.54 μmol, 1 eq) in THF (30 mL) was added SOCl2(6.56 g, 55.14 mmol, 4 mL, 75.07 eq) and DMF (53.69 mg, 734.54 μmol, 56.52 μL, 1 eq). The reaction mixture was stirred at 25° C. for 2 h. TLC (PE/EtOAc=3/1, Rf=0.50) showed starting material was almost consumed and one new spot was detected. The reaction mixture was concentrated to yield 2-(1H-indole-3-carbonyl)thiazole-4-carbonyl chloride (210 mg, crude) as a yellow solid which was used in the next step without further purification.

To a solution of (4-bromothiazol-2-yl)-[1-(2-trimethylsilylethoxymethyl)indol-3-yl]methanone (400 mg, 868.72 μmol, 1 eq) in DCM (5 mL) was added TFA (6.65 g, 58.32 mmol, 4.32 mL, 67.14 eq). The mixture was stirred at 25° C. for 1 h. TLC (PE/EtOAc=3/1, Rf=0.22) indicated the starting material was consumed completely and one new spot formed. The mixture was dissolved in MeOH (10 mL), adjusted pH to 9 by addition of Na2CO3(92.07 mg, 868.72 μmol, 1 eq) in water (2 mL). The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield (4-bromothiazol-2-yl)-(1H-indol-3-yl)methanone (350 mg, 518.45 μmol, 59.6% yield, 45.5% purity) as a yellow solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) δ ppm 9.04 (s, 1H), 8.36-8.33 (m, 2H), 7.67-7.61 (m, 1H), 7.36-7.32 (m, 2H); ES-LCMS m/z 306.8, 308.8 [M+H]+.

To a solution of methyl 2-aminothiazole-4-carboxylate (1.5 g, 9.48 mmol, 1 eq) in DCM (25 mL) was added NBS (2.03 g, 11.38 mmol, 1.2 eq). The mixture was stirred at 20° C. for 12 h under N2. TLC (PE/EtOAc=1/1, Rf=0.22) indicated starting material was consumed completely and one new spot formed. The mixture was concentrated and then water (80 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to yield a residue which was purified by flash silica gel chromatography (From PE/EtOAc=1/0 to 1/1, Rf=0.22) to yield methyl 2-amino-5-bromo-thiazole-4-carboxylate (2 g, 7.82 mmol, 82.5% yield, 92.7% purity) as a red solid.1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3H); ES-LCMS m/z 237.1, 238.1 [M+H]+.

To a solution of methyl 2-aminothiazole-4-carboxylate (5 g, 31.61 mmol, 1 eq) in DCM (50 mL) was added NIS (8.53 g, 37.93 mmol, 1.2 eq). The mixture was stirred at 20° C. for 12 h. The reaction mixture was quenched by addition of water (50 mL), extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield methyl 2-amino-5-iodo-thiazole-4-carboxylate (18 g, crude) as red oil, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ ppm 5.68 (s, 3H); ES-LCMS m/z 285.0, 286.9 [M+H]+.

To a solution of methyl 2-amino-5-chloro-thiazole-4-carboxylate (1.89 g, 7.14 mmol, 72.9%, 1 eq) in THF (30 mL) was added tert-butyl nitrite (1.10 g, 10.71 mmol, 1.27 mL, 1.5 eq). The mixture was stirred at 60° C. for 1 h. TLC (PE/EtOAc=3:1, Rf=0.1) showed starting material was remained and one new spot was detected. The reaction mixture was quenched by addition of water (100 mL), extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue which was purified by flash silica gel chromatography (from PE/EtOAc=1/0 to 3/1, TLC:PE/EtOAc=3/1, Rf=0.50) to yield methyl 5-chlorothiazole-4-carboxylate (580 mg, 3.10 mmol, 43.4% yield, 95.0% purity) as a yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.67 (s, 1H), 3.99 (s, 3H).

To a stirred solution of 2-(1H-indole-3-carbonyl)-5-methyl-thiazole-4-carboxylic acid (100 mg, 349.28 μmol, 1 eq) in THF (5 mL) was added SOCl2(415.54 mg, 3.49 mmol, 253.38 μL, 10 eq). The reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated to yield 2-(1H-indole-3-carbonyl)-5-methyl-thiazole-4-carbonyl chloride (110 mg, crude, HCl) as a yellow solid, which was used in the next step without further purification. ES-LCMS m/z 305.1, 307.1 [M+H]+.

To a mixture of 4-isopropylthiazole-2-carboxylic acid (200 mg, 1.17 mmol, N/A purity, 1 eq) in DMF (0.01 mL) and DCM (3 mL) was added (COCl)2(725.00 mg, 5.71 mmol, 500 μL, 4.89 eq) dropwise at 25° C. The mixture was stirred at 25° C. for 1.5 h. TLC (PE/EtOAc=5/1, Rf=0.50) showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to yield 4-isopropylthiazole-2-carbonyl chloride (220 mg, 1.16 mmol, 99.30% yield, N/A purity) as a yellow solid, which was used in the next step without further purification.

POCl3(16.42 g, 107.12 mmol, 9.95 mL, 2.32 eq) was slowly added dropwise to DMF (50 mL). The mixture was stirred at 0° C. for 30 min. Then, DMF (12.43 g, 170.06 mmol, 13.08 mL, 3.68 eq) solution of 6-nitro-1H-indole (7.5 g, 46.25 mmol, 1 eq) was added dropwise to the reaction system. The mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched by addition of ice water (50 mL) and 10% aq. NaOH, adjusted the reaction system pH to 7-8 and continue to stir to a lot of white solid precipitation, filtered to give a residue which was added PE/EA (5/1, 500 mL), and stirred at 15° C. for 2 h. The slurry was filtered, and the cake was rinsed with PE (2×30 mL). The solid was collected and dried in vacuo to yield 6-nitro-1H-indole-3-carbaldehyde (7 g, 35.14 mmol, 76.0% yield, 95.5% purity) as a yellow solid. ES-LCMS m/z 191.2 [M+H]+.

To a solution of ethyl 4-isopropylthiazole-2-carboxylate (1 g, 5.02 mmol, 1 eq) in AcOH (10 mL) was added Br2(4.01 g, 25.09 mmol, 1.29 mL, 5 eq) at 0° C. The mixture was stirred at 0° C. for 1 h. TLC (PE/EtOAc=10/1, Rf=0.48) indicated 30% of the starting materials was remained and one new spot formed. The reaction mixture was concentrated under reduced pressure to yield a residue. The mixture was diluted with water (100 mL), basified with aqueous Na2CO3until pH=7-8 and extracted with ethyl acetate (80 mL×3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to yield ethyl 5-bromo-4-isopropyl-thiazole-2-carboxylate (1 g, crude) as yellow oil, which was used in the next step without further purification.1H NMR (500 MHz, CDCl3) δ ppm 4.54-4.42 (m, 2H), 3.35-3.22 (m, 1H), 1.43 (q, J=7.3 Hz, 3H), 1.37-1.31 (m, 6H).

To a solution of 4-nitro-1H-indole (1 g, 6.17 μmol, 1 eq) in THF (10 mL) was added oxalyl dichloride (2.35 g, 18.50 μmol, 1.62 mL, 3 eq) under 0° C. The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated to yield 2-(4-nitro-1H-indol-3-yl)-2-oxo-acetyl chloride (1.1 g, crude) as a brown solid which was used in the next step without further purification; ES-LCMS no desired m/z was detected on LCMS.

To a solution of 5-bromo-2-[1-(2-trimethylsilylethoxymethyl)indole-3-carbonyl]thiazole-4-carboxamide (580 mg, 603.60 μmol, 50.0% purity, 1 eq) in DCM (15 mL) was added TEA (727.00 mg, 1 mL) and TFAA (1.51 g, 1 mL) at 0° C. under N2atmosphere. The mixture was stirred at 0° C. for 1 h. The mixture was allowed to warm to room temperature (25° C.) with stirred under N2atmosphere for 8 h. TLC (PE/EtOAc=3/1, Rf=0.5) showed that new point was formed and start material was consumed completely. The reaction mixture was quenched by addition saturated aqueous NaHCO3(20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (from PE/EtOAc=100/1 to 10/1, TLC:PE/EtOAc=10/1, Rf=0.40) to yield 5-bromo-2-[1-(2-trimethylsilylethoxymethyl)indole-3-carbonyl]thiazole-4-carbonitrile (380 mg, 575.22 μmol, 95.3% yield, 70.0% purity) as a white solid. ES-LCMS m/z 464.1 [M+H]+.

To a solution of methyl 5-bromothiazole-4-carboxylate (3.16 g, 13.51 mmol, 95.0% purity, 1 eq) in THF (15 mL) was added LiOH.H2O (1 M, 15 mL, 1.1 eq). The mixture was stirred at 25° C. for 2 h. TLC (PE/EtOAc=3/1, Rf=0.1) showed that new point was formed and start material was consumed completely. The reaction mixture was quenched by addition H2O (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 5-bromothiazole-4-carboxylic acid (2.5 g, 11.42 mmol, 84.5% yield, 95.0% purity) as a white solid, which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ=13.35 (s, 1H), 9.14 (s, 1H).

To a solution of 5-bromothiazole-4-carboxylic acid (2.5 g, 10.82 mmol, 90.0% purity, 1.0 eq) and NH4Cl (867.79 mg, 16.22 mmol, 1.5 eq) in DCM (20 mL) was added HATU (4.93 g, 12.98 mmol, 1.2 eq) and Et3N (3.28 g, 32.45 mmol, 4.52 mL, 3.0 eq). The mixture was stirred at 25° C. for 3 h. TLC (PE/EtOAc=1/1, Rf=0.4) showed that new point was formed and start material was consumed completely. The reaction mixture was quenched by addition of H2O (100 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 5-bromothiazole-4-carboxamide (2.5 g, 9.66 mmol, 89.3% yield, 80.0% purity) as a white solid, which was used in the next step without further purification. ES-LCMS: no desired MS found.

To a solution of methyl 5-(benzhydrylideneamino)-2-[hydroxy-[7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-5-yl]methyl]thiazole-4-carboxylate (60 mg, 75.03 μmol, 75% purity, 1 eq) in CHCl3(5 mL) was added MnO2(195.69 mg, 2.25 mmol, 30 eq). The mixture was stirred at 70° C. for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to yield methyl 5-(benzhydrylideneamino)-2-[7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-5-carbonyl]thiazole-4-carboxylate (30 mg, 40.15 μmol, 53.5% yield, 80.0% purity) as a white solid, which was used in the next step without further purification. ES-LCMS m/z 563.2 [M+H]+.

Example 2. In Vitro Assay

AHR binds to Dioxin Responsive Elements (DRE) upstream of genes that it activates. One measure of AHR activity is activation of a reporter gene, such as luciferase, downstream of one or multiple DRE elements. Luciferase activity will reflect activation and inhibition of AHR in the cells expressing this reporter.

Murine Hepa1-6 or Hepa-1c1c7 or other murine cell line with a DRE-luciferase reporter either stably or transiently transfected are plated in media in plates (96-well, 384-well or other plates) and incubated overnight at 37 C in a CO2 incubator. Likewise, human HepG2 or other human cell line with a DRE-luciferase reporter either stably or transiently transfected are plated in media in plates (96-well, 384-well or other plates) and incubated overnight at 37 C in a CO2incubator.

The next day, an AHR agonist compound is added. Cells are incubated for 6, 16 or 24 hours or another time point and then lysed for determination of luciferase activity as a read-out of the AHR activation. Luciferase can be measured with a commercial kit such as the Promega Luciferase kit or any kit or reagents that provide the luciferin substrate for measuring luciferase activity. The level of luciferase with only activating ligand (e.g. such as TCDD, kynurenine, ITE (2-(1H-indole-3-ylcarbonyl)-4-thiazolecarboxylic methyl ester), VAF347, BNF (beta-naphthoflavone), ICZ (6-formylindolo(3,2-b) carbazole or other AHR ligands) added is the maximum signal while the luciferase with no ligand is the minimum signal. EC50s can be determined as the concentration which activates half of the maximum luciferase activity.

In some embodiments, compounds have an EC50>1 μM. In some embodiments, compounds have an EC50<1 μM. In some embodiments, compounds have an EC50<0.1 μM. In some embodiments, compounds have an EC50<0.01 μM.

AHR binds to Dioxin Responsive Elements (DRE) upstream of genes that it activates. One measure of AHR activity is P450 CYP1A1 protein levels determined by measuring CYP1A1 enzyme activity using a luminogenic CYP1A1 luciferin-based substrate. Luciferase activity will reflect CYP1A1 activity resulting from activation of AHR in the cells.

Murine Hepa1-6 or Hepa-1c1c7 or other murine cell line, human HepG2 or other human cell line are plated in media (96-well, 384-well or other plates) and incubated overnight at 37 C in a CO2 incubator.

The next day, an AHR agonist compound is added. Cells are incubated for 6, 16 or 24 hours or another time point and then lysed and incubated with a CYP1A1 luciferase-based substrate (e.g., Luciferin-CEE) for 3, 6, or 12 hours of another time point. Determination of luciferase activity as a read-out of CYP1A1 enzyme activity can be measured with a commercial kit such as the Promega P450 Glo CYP1A1 detection reagent or any kit or reagents that provide for measuring luciferase activity. The level of luciferase with only activating ligand (e.g., such as TCDD, kynurenine, ITE (2-(1H-indole-3-ylcarbonyl)-4-thiazolecarboxylic methyl ester), VAF347, BNF (beta-naphthoflavone), ICZ (6-formylindolo(3,2-b) carbazole or other AHR ligands) added is the maximum signal while the luciferase with no ligand is the minimum signal. EC50s can be determined as the concentration which activates half of the maximum luciferase activity.

Example 3. Liver and Colon Pharmacodynamics (PD) Assays and Methods

C57BL/6N mice are weighed and randomized into treatment groups with group size of 3-5 mice. On study Day 1, treatment is initiated and necropsies follow on day 1 at 4 and 12 hours post-dose and on Day 2, 24 hours post-dose.

On Day 1, mice are dosed orally with one dose of the AHR agonist compound(s) that are in a suspension and mixed well before dosing. At the designated time, animals are euthanized and plasma and tissue taken for compound levels (PK) and compound effect (PD) on gene expression. Liver samples and proximal colon are weighed and then frozen for subsequent RNA extraction and RT-PCR analysis. AHR activation is determined by measuring Cyp1a1 gene expression relative to a housekeeping gene, such as GAPDH or HPRT. Cyp1a1 expression levels in the liver are compared to Cyp1a1 levels in the colon to determine a colon:liver ratio, in order to assess the level of “GI-preferred” AHR activation.

Example 4: DSS IBD Study Method

On study day −1, C57Bl/6 mice are weighed and randomized into treatment groups based on body weight. On study day 0, treatment groups are given 2.5% DSS in drinking water and treatment is initiated on the same day, with either vehicle or AHR agonist compound(s).

On study day 7, DSS drinking water is replaced with normal drinking water for the remainder of the study. Body weight is measured daily during the entire study.

On study day 10, animals are anesthetized with Isoflurane and bled to exsanguination followed by cervical dislocation. The entire colon is removed and measured for length, weight, and weight per length. Overall efficacy of test AR agonist compounds is based on body weight, colon length, and colon histopathology.

Histopathology data is assessed for appropriate parameters, as determined by a pathologist and the parameters for these DSS studies can include inflammation, erosion, gland loss, edema, hyperplasia, neutrophil count, mucosal thickening, lymphoid aggregate count and lymphoid aggregate size. The different parameter scores can be added for a summed score for the study histopathology.

On Day 10, cell supernatant is collected and frozen for cytokine analysis. Cells are stimulated with 1× Cell Stimulation Cocktail (PMA and Ionomycin) for 5 hours. After 5 hours of stimulation, cells are stained for intracellular cytokines (human CD4, IL-17A, IL-22). Samples are run on BD LSR FORTESSA and analyzed in FLOWJO software.

On day 0, nave T cells from cryopreserved human derived PBMCs are isolated. These cells are plated in 48 well plate at 500,000 cells/mL concentration with human CD3/CD28 activation tetramer (12.5 μL/1×106cells) and differentiated into regulatory T cells (Tregs) with 1 ng/mL TGF-β and 5 ng/mL human recombinant IL-2 in the presence of DMSO or different concentrations of AHR agonist compounds.

On day 5, the Tregs are counted and washed. CD25-Effector T cells (Teffs) are isolated from the same human donor and labeled with Cell Trace Violet. The Tregs and Teffs are cocultured for 4 days in 96 well plate at 1:2 or 1:1 ratio with human CD3/CD28 tetramer (12.5 μL/1×106cells).

At the end of a 4 day co-culture, the cells are washed and stained with LiveDead stain. The cells are run on a flow cytometer and analyzed using FLOWJO software.

Example 7: T Cell Transfer IBD Model

On study day 0, donor Balb/C mice are terminated, and spleens obtained for CD4+CD45RBhighcell isolation (Using a SCID IBD Cell Separation Protocol). After cells have been sorted and obtained, each recipient SCID animal receives an IP injection of, at a minimum, 4×105cells (200 μl/mouse injections).

Also on study day 0, SCID mice are weighed and randomized into treatment groups based on body weight. On study day 14, AHR agonist compound treatments are initiated and dosed orally daily; the control group receiving anti-IL12 (0.5 mg/mouse) is dosed IP once a week.

On study day 49, animals are anesthetized with Isoflurane and bled to exsanguination followed by cervical dislocation. The entire colon is removed, measured, and weighed. Overall efficacy of AHR agonist compounds are based on a ratio of colon weight to length, and colon histopathology and colon cytokines (Th17 panel).

Example 8: IBD Ex Vivo Treat Methods

The studies described herein are to assess the effect of various AHR agonist compounds in human Crohn's and ulcerative colitis tissue cultures ex vivo. Following this culture, the resulting culture supernatant samples are collected for analysis of cytokine release. Briefly, Crohn's Disease or ulcerative colitis donor samples are obtained with full ethical consent from patients undergoing therapeutic resection for Crohn's disease or ulcerative colitis. A minimum of 18×5 mm2mucosal biopsies are taken using a scalpel. Three baseline biopsy samples are collected at time 0, and a minimum of 9 biopsies are incubated in 12 well culture plates. Tissues are placed apical (mucosal) side facing upwards on a Netwell filter. The biopsies are then cultured in either control media or media fortified with the appropriate AHR agonist compound in an incubator at 37° C. and high 02 atmospheric conditions (95% 02/5% CO2). To minimize variation, the biopsies are cultured in the presence of the inflammatory stimulant Staphylococcal Enterotoxin B (SEB) to normalize cytokine levels. The positive control BIRB796 (Selleck Chemicals catalogue No: S1574) is purchased as a powder. A 1 mM stock solution is prepared in DMSO and used at 1 μM. At approximately 18 hours post-culture start, media samples are collected, protease inhibitor is added and samples are stored at −80° C. Supernatant is collected at the 18-hour timepoint and divided into aliquots for cytokine analysis: analysis of cytokines, such as TNF-α, IFN-γ, IL-1β, IL17-α, IL-22, and IL-10) are performed in duplicate after completion of each set of 3 donors.