CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 63/110,816, filed on Nov. 6, 2020, the entire disclosure of which is hereby incorporated by reference herein.

FIELD OF THE DISCLOSURE

The present disclosure is in the field of pharmaceutical compounds and preparations and method of their use in the treatment of disease. In particular, the present disclosure is in the field of THR-β modulators and their use.

BACKGROUND OF THE DISCLOSURE

In parallel with the global increase in obesity, nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of chronic liver disease and liver transplantation worldwide [1,2]. NAFLD is believed to affect 30% of the adult population and 70-80% of individuals who are obese and diabetic. NAFLD is defined as excess liver fat accumulation greater than 5% induced by causes other than alcohol intake. NAFLD progresses to liver inflammation (nonalcoholic steatohepatitis, NASH) and fibrosis in a variable proportion of individuals, ultimately leading to liver failure and hepatocellular carcinoma (HCC) in susceptible individuals [3].

In the United States alone, NASH is the third most common indication for liver transplantation and is on a trajectory to become the most common [4]. The most important medical need in patients with NAFLD and NASH is an effective treatment to halt the progression and possibly reverse fibrosis, which is the main predictor of liver disease evolution [5,6].

Thyroid hormone (TH) is essential for normal development, growth and metabolism of all vertebrates. Its effects are mediated principally through triiodothyronine (T3), which acts as a ligand for the TH receptors (TRs, or THRs) β1, β2 and α1 [7]. In the absence of ligand, TR first binds as a heterodimer or homodimer on TH response elements (TRE) located in the promoter regions of target genes, where it interacts with corepressors. Upon ligand binding, the TR homodimers are dissociated in favor of heterodimer formation with the retinoid-X receptor (RXR), resulting in release of the corepressors and recruitment of coactivators. This new complex attracts a large number of proteins which engage the RNA polymerase II in the transcription of the targeted genes.

Two different genetic loci, denoted THRA and THRB, are responsible for encoding multiple interrelated TR isoforms that have distinct tissue distributions and biological functions. The two major isoforms with the broadest level of tissue expression are TRα1 and TRβ1 [8]. While TRα1 is expressed first during fetal development and is widely expressed in adult tissues, TRβ1 appears later in development and displays highest expression in the adult liver, kidney, and lung [9]. TRα1 is a key regulator of cardiac output, whereas TRβ1 helps in the control of metabolism in the liver. Importantly, the natural thyroid hormone T3 activates both TRα1 and TRβ1 without any significant selectivity.

Design of thyromimetic small molecule agents led to the identification of TR (or THR) agonists with varying levels of TRβ selectivity despite high structural similarity between the ligand-binding domains for TRβ and TRα. TRβ selectivity achieved by some of these compounds resulted in an improved therapeutic index for lipid lowering relative to cardiac effects such as heart rate, cardiac hypertrophy, and contractility [10-12].

Another strategy to avoid activation of TRα in cardiac tissue is to design prodrugs of phosphonate-containing TR agonists that are specifically converted to the active agonist in the liver but remain stable as an inactive prodrug in blood and extrahepatic tissues, including the heart [13]. TRα and TRβ agonists are also used in indications other than liver-related disorders, as has been known in the art. For example, TRβ selective agonists may be useful in the treatment of X-linked adrenoleukodystrophy [14, 15].

SUMMARY

Provided herein, in one aspect, are compounds of Formula I:

[Image Omitted]

or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

R¹and R²together with the carbon atoms to which they are attached form a C₄-C₇monocyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen, C₁-C₆alkyl, and C₃-C₅cycloalkyl optionally substituted with 1-3 halogens; or

R¹and R²together with the carbon atoms to which they are attached form a polycyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen, C₁-C₆alkyl, and C₃-C₅cycloalkyl optionally substituted with 1-3 halogens;

R³and R⁴are each independently selected from halogen, —CN, optionally substituted C₁-C₃alkyl, optionally substituted C₁-C₂alkoxy, optionally substituted C₂-C₃alkenyl, and cyclopropyl;

R⁵is selected from:

[Image Omitted]

R⁶is H or C₁-C₃alkyl;

R⁷is H or C₁-C₃alkyl;

R⁸is selected from H, halogen, —CN, optionally substituted C₁-C₃alkyl, and optionally substituted C₁-C₂alkoxy; or

R³and R⁸together with the carbon atoms to which they are attached form a 4-, 5-, or 6-membered partially unsaturated carbocyclic ring; a 4-, 5-, or 6-membered partially unsaturated heterocyclic ring; a C₆-C₁₀aryl ring; or a 5- or 6-membered heteroaryl ring;

Q is selected from N, CH, and CF; and

X is O or CH₂;

wherein when R¹and R²together with the carbon atoms to which they are attached form a C₆aromatic monocyclic ring, R⁵is selected from:

[Image Omitted]

and

wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).

In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₄-C₇monocyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen, C₁-C₆alkyl, and C₃-C₅cycloalkyl optionally substituted with 1-3 halogens. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₄-C₇monocyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₆alkyl. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₅monocyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₆alkyl. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₆monocyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₆alkyl. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₄-C₇monocyclic ring optionally substituted with C₃-C₅cycloalkyl optionally substituted with 1-3 halogens. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₅monocyclic ring optionally substituted with C₃-C₅cycloalkyl optionally substituted with 1-3 halogens. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₆monocyclic ring optionally substituted with C₃-C₅cycloalkyl optionally substituted with 1-3 halogens. In some embodiments, the monocyclic ring is not aromatic. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a polycyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen, C₁-C₆alkyl, and C₃-C₅cycloalkyl optionally substituted with 1-3 halogens. In some embodiments, R³and R⁴are each independently selected from halogen; —CN; C₁-C₃alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₆alkoxy; C₁-C₂alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen; and C₂-C₃alkenyl optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₆alkoxy; and cyclopropyl. In some embodiments, R³and R⁴are each independently selected from halogen and C₁-C₃alkyl. In some embodiments, R³and R⁴are both halogen. In some embodiments, R³and R⁴are both C₁. In some embodiments, R³and R⁴are both methyl. In some embodiments, R⁸is selected from H; halogen; —CN; C₁-C₃alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₂alkoxy; and C₁-C₂alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen. In some embodiments, R⁸is H. In some embodiments, R³and R⁸together with the carbon atoms to which they are attached form a 4-, 5-, or 6-membered partially unsaturated carbocyclic ring; a 4-, 5-, or 6-membered partially unsaturated heterocyclic ring; a C₆-C₁₀aryl ring; or a 5- or 6-membered heteroaryl ring. In some embodiments, R⁵is

[Image Omitted]

In some embodiments, X is CH₂. In some embodiments, X is O. In some embodiments, R⁷is H. In some embodiments, R⁷is C₁-C₃alkyl. In some embodiments, Q is CH. In some embodiments, Q is N.

Provided herein, in another aspect, is a compound selected from the group consisting of:

(R)-6-amino-2-(3,5-dichloro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

(S)-6-amino-2-(3,5-dichloro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(4-chloro-5-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl-2,6-d2)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(5-((7-cyclopropyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)-4-methylbicyclo[4.2.0]octa-1,3,5-trien-2-yl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((7-ethyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((7-cyclopropyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((7-(3,3-difluorocyclobutyl)-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((4′-oxo-3′,4′,6′,7′-tetrahydrospiro[cyclopentane-1,5′-cyclopenta[d]pyridazin]-1′-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((4-oxo-3,4,6,7-tetrahydrospiro[cyclopenta[d]pyridazine-5,1′-cyclopropan]-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((4′-oxo-3′,4′,6′,7′-tetrahydrospiro[cyclobutane-1,5′-cyclopenta[d]pyridazin]-1′-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((5-methyl-4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((5-ethyl-4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((5-cyclopropyl-4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((5,5-dimethyl-4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((5,5-diethyl-4-oxo-3,4,5,6,7,8-hexahydrophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((5-oxo-3,4-diazabicyclo[4.2.0]octa-1(6),2-dien-2-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((7,7-dimethyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((7,7-diethyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((4-oxo-3,4,4b,5,5a,6-hexahydrocyclopropa[3,4]cyclopenta[1,2-d]pyridazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((5-methyl-4-oxo-3,4,5,6,7,8-hexahydro-5,8-ethanophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((9-methyl-1-oxo-2,5,6,7,8,9-hexahydro-1H-cyclohepta[d]pyridazin-4-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl-2-d)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-4-((7-cyclopropyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl-2-d)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(3,5-dichloro-2-fluoro-4-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

6-amino-2-(4-chloro-6-methyl-5-((7-methyl-1-oxo-2,5,6,7-tetrahydro-1H-cyclopenta[d]pyridazin-4-yl)oxy)pyridin-2-yl)-1,2,4-triazine-3,5(2H,4H)-dione; and

6-amino-2-(3,5-dichloro-4-((4-oxo-3,4,5,6,7,8-hexahydro-5,8-methanophthalazin-1-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

Provided herein, in another aspect, is a pharmaceutical composition comprising a compound disclosed herein and at least one pharmaceutically acceptable excipient.

Provided herein, in another aspect, is a method of treating a disorder or disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a therapeutically effective amount of a pharmaceutical composition disclosed herein, wherein the disorder or disease is selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroid cancer.

Provided herein, in another aspect, is a use of a compound disclosed herein for the manufacture of a medicament for the treatment of a disorder or disease is selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroid cancer.

Provided herein, in another aspect, is a compound disclosed herein for use in treating a disorder or disease is selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroid cancer.

Provided herein, in another aspect, is a composition disclosed herein for use in treating a disorder or disease is selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroid cancer.

Provided herein, in another aspect, is a method of treating a thyroid hormone receptor related disorder in a patient, the method comprising the steps of identifying a patient in need of treatment for the thyroid hormone receptor related disorder, and administering to the patient, or contacting the patient with, a compound disclosed herein or a therapeutically effective amount of a pharmaceutical composition disclosed herein. In some embodiments, the thyroid hormone receptor related disorder is selected from non-alcoholic steatohepatitis (NASH), obesity, hyperlipidemia, hypercholesterolemia, diabetes, liver steatosis, atherosclerosis, cardiovascular diseases, hypothyroidism, and thyroid cancer.

Provided herein, in another aspect, is a method of selectively modulating the activity of a thyroid hormone receptor beta (THR-β) comprising contacting a compound disclosed herein with the thyroid hormone receptor. In some embodiments, the contacting is in vitro or ex vivo. In some embodiments, the contacting is in vivo.

Provided herein, in another aspect, is a compound disclosed herein for use in selectively modulating the activity of a thyroid hormone receptor beta (THR-β).

Provided herein, in another aspect, is a composition disclosed herein for use in selectively modulating the activity of a thyroid hormone receptor beta (THR-β).

DETAILED DESCRIPTION
Definitions

Various embodiments are described hereinafter. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment(s).

As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.

The use of the terms “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

In the definition of chemical substituents, each of Rx and Ry is independently hydrogen, alkyl, carbocyclic ring, heterocyclic ring, aryl, or heteroaryl, all of which, except hydrogen, are optionally substituted.

Unless otherwise indicated, the abbreviations “TR” and “THR” refer to thyroid hormone receptors.

As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to a patient to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Base-formed salts include, without limitation, ammonium salt (NH₄⁺); alkali metal, such as, without limitation, sodium or potassium, salts; alkaline earth, such as, without limitation, calcium or magnesium, salts; salts of organic bases such as, without limitation, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, without limitation, arginine and lysine. Useful acid-based salts include, without limitation, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, methane-sulfonates, ethanesulfonates, p-toluenesulfonates and salicylates.

As used herein, “pharmaceutically acceptable ester” refers to an ester of a compound that does not cause significant irritation to a patient to which it is administered. The ester is metabolized in the body to result in the parent compound, e.g., the claimed compound. Accordingly, the ester does not abrogate the biological activity and properties of the compound. Pharmaceutical esters can be obtained by reaction of a compound disclosed herein with an alcohol. Methyl, ethyl, and isopropyl esters are some of the common esters to be prepared. Other esters suitable are well-known to those skilled in the art (see, for example Wuts, P. G. M., Greene's Protective Groups in Organic Synthesis, 5^thEd., John Wiley & Sons, New York, N.Y., 2014, which is incorporated herein by reference in its entirety).

Where the compounds disclosed herein have at least one chiral center, they may exist as a racemate or as individual enantiomers. It should be noted that all such isomers and mixtures thereof are included in the scope of the present disclosure. Thus, the illustration of a chiral center without a designation of R or S signifies that the scope of the disclosure includes the R isomer, the S isomer, the racemic mixture of the isomers, or mixtures where one isomer is present in greater abundance than the other.

Where the processes for the preparation of the compounds disclosed herein give rise to mixtures of stereoisomers, such isomers may be separated by conventional techniques such as preparative chiral chromatography. The compounds may be prepared in racemic form or individual enantiomers may be prepared by stereoselective synthesis or by resolution. The compounds may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary.

Unless otherwise indicated, when a substituent is deemed to be “optionally substituted” it is meant that the substituent is a group that may be substituted with one or more (e.g., 1 or 2, or 1 to 3, or 1 to 4 or 1 to 5, or 1 to 6) group(s) individually and independently selected, without limitation, from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, is O-cyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino (e.g., —NR_xR_y), including mono- and di-substituted amino groups, and the protected derivatives thereof. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Wuts, above.

As used herein, a “carbocyclic ring” is an aromatic or non-aromatic ring structure in which all the atoms in the ring are carbon atoms. As such, the ring structure may be fully saturated, fully unsaturated, or partially saturated. If any of the atoms in the ring is anything other than a carbon atom, then the ring is a “heterocyclic ring.” Examples of atoms that are within a ring include sulfur, oxygen, and nitrogen. A carbocyclic ring or a heterocyclic ring may be polycyclic, e.g., a fused ring system, a spirocyclic ring system, or a bridged ring system. These polycyclic rings include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Additional non-limiting examples include bicyclic rings such as but not limited to:

[Image Omitted]

As used herein, “aryl” refers to a carbocyclic (all carbon) ring that has a fully delocalized pi-electron system. The “aryl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the aryl is a fused ring system, then the ring that is connected to the rest of the molecule has a fully delocalized pi-electron system. The other ring(s) in the fused ring system may or may not have a fully delocalized pi-electron system. Further, the other ring(s) may or may not contain one or more heteroatoms (e.g., O, N, or S). Examples of aryl groups include, without limitation, the radicals of benzene, naphthalene and azulene. Additional non-limiting examples include:

[Image Omitted]

As used herein, “heteroaryl” refers to a ring that has a fully delocalized pi-electron system and contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur in the ring. The “heteroaryl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the heteroaryl is a fused ring system, then the ring that is connected to the rest of the molecule has a fully delocalized pi-electron system. The other ring(s) in the fused ring system may or may not have a fully delocalized pi-electron system. Examples of heteroaryl rings include, without limitation, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine.

Wherever “hetero” is used it is intended to mean a group as specified, such as an alkyl or an aryl group, where at least one carbon atom has been replaced with a heteroatom selected from nitrogen, oxygen and sulfur.

As used herein, “alkyl” refers to a straight or branched chain fully saturated (no double or triple bonds) hydrocarbon group. An alkyl group of the presently disclosed compounds may comprise from 1 to 20 carbon atoms. An alkyl group herein may also be of medium size having 1 to 10 carbon atoms. An alkyl group herein may also be a lower alkyl having 1 to 5 carbon atoms or 1 to 6 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, sec-butyl, t-butyl, amyl, t-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.

An alkyl group of the presently disclosed compounds may be substituted or unsubstituted. When substituted, the substituent group(s) can be one or more group(s) independently selected from cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, amino (e.g., —NR_xR_y) and protected amino.

As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group of the presently disclosed compounds may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above regarding alkyl group substitution, or with regard to optional substitution.

As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group of the presently disclosed compounds may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above regarding alkyl group substitution, or with regard to optional substitution.

As used herein, “acyl” refers to an “R_xC(═O)—” group.

As used herein, “cycloalkyl” refers to a completely saturated (no double bonds) hydrocarbon ring. In some embodiments, cycloalkyl refers to a hydrocarbon ring containing no double bonds or one or more double bonds provided that they do not form a fully delocalized pi-electron system in the ring. Cycloalkyl groups of the presently disclosed compounds may range from C₃to C₈. A cycloalkyl group may be unsubstituted or substituted. If substituted, the substituent(s) may be selected from those indicated above regarding substitution of an alkyl group. The “cycloalkyl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the cycloalkyl is a fused ring system, then the ring that is connected to the rest of the molecule is a cycloalkyl as defined above. The other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heterocycloalkyl.

As used herein, “cycloalkenyl” refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be “aryl,” as defined herein). A cycloalkenyl group of the presently disclosed compounds may unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above regarding alkyl group substitution. The “cycloalkenyl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the cycloalkenyl is a fused ring system, then the ring that is connected to the rest of the molecule is a cycloalkenyl as defined above. The other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heterocycloalkyl.

The term “alkylene” refers to an alkyl group, as defined herein, which is a biradical and is connected to two other moieties. Thus, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—), isopropylene (IUPAC: (methyl)ethylene) (—CH₂—CH(CH₃)—), and isobutylene (IUPAC: 2-(methyl)propylene) (—CH₂—CH(CH₃)—CH₂—) are examples, without limitation, of an alkylene group. Similarly, the term “cycloalkylene” refers to a cycloalkyl group, as defined here, which binds in an analogous way to two other moieties. If the alkyl and cycloalkyl groups contain unsaturated carbons, the terms “alkenylene” and “cycloalkenylene” are used.

As used herein, “heterocycloalkyl,” “heteroalicyclic,” or “heteroali-cyclyl” refers to a ring having in the ring system one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. The ring may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system in the rings. The ring defined herein can be a stable 3- to 18-membered ring that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocycloalkyl, groups of the presently disclosed compounds may be unsubstituted or substituted. When substituted, the substituent(s) may be one or more groups independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, amino, protected amino, carboxamide, protected carboxamide, alkylsulfonamido and trifluoromethane-sulfonamido. The “heterocycloalkyl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the heterocycloalkyl is a fused ring system, then the ring that is connected to the rest of the molecule is a heterocycloalkyl as defined above. The other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heterocycloalkyl.

As used herein, “aralkyl” refers to an alkylene substituted with an aryl group.

As used herein, “carbocyclic alkyl” or “(carbocyclic)alkyl” refers to an alkylene substituted with a carbocyclic group.

As used herein, “heterocyclicalkyl” or (heterocyclic)alkyl” refers to an alkylene substituted with a heterocyclic group. Similarly, “(heterocycloalkyl)alkyl” refers to an alkylene substituted with a heterocycloalkyl group.

As used herein, “heteroarylalkyl” or “(heteroaryl)alkyl” refers to an alkylene substituted with a heteroaryl group.

An “O-carboxy” group refers to a “R_xC(═O)O—” group.

A “C-carboxy” group refers to a “—C(═O)OR_x” group.

An “acetyl” group refers to a CH₃C(═O)— group.

A “C-amido” group refers to a “—C(═O)NR_xR_y” group.

An “N-amido” group refers to a “R_yC(═O)NR_x—” group.

The term “perhaloalkyl” refers to an alkyl group in which all the hydrogen atoms are replaced by halogen atoms.

Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxy group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well-known to those skilled in the art (see, for example Wuts, above).

It is understood that, in any compound of the presently disclosed compounds having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be R or S or a mixture thereof. In addition, it is understood that, in any compound of the presently disclosed compounds having one or more double bond(s) generating geometrical isomers that can be defined as E or Z each double bond may independently be E or Z, or a mixture thereof.

It is understood that the disclosure of a compound herein inherently includes the disclosure of a tautomer thereof, if applicable. For instance, the disclosure of:

[Image Omitted]

also includes the disclosure of:

[Image Omitted]

and vice versa, even if only one of the two structures is disclosed.

Throughout the present disclosure, when a compound is illustrated or named, it is understood that the isotopically enriched analogs of the compound are also contemplated. For example, a compound may have a deuterium incorporated instead of a hydrogen, or a carbon-13 instead of carbon with natural isotopic distribution. The isotopic enrichment may be in one location on the compound, i.e., only one hydrogen is replaced by a deuterium, or in more than one location. The present disclosure also encompasses compounds where all the similar atoms are replaced by their less common isotope, for example, a perdeutero compound where all the hydrogen atoms are replaced by a deuterium. The isotopically enriched compounds are useful when obtaining NMR spectra or when making use of an isotope effect in managing the kinetics of the reaction the compound undergoing.

The term “pharmaceutical composition” refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

The term “carrier” defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.

The term “diluent” defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.

In certain embodiments, the same substance can act as a carrier, diluent, or excipient, or have any of the two roles, or have all three roles. Thus, a single additive to the pharmaceutical composition can have multiple functions.

The term “pharmaceutically acceptable” defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.

Compounds

In one aspect, provided herein are compounds of Formula I:

[Image Omitted]

or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

R¹and R²together with the carbon atoms to which they are attached form a C₄-C₇monocyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen, C₁-C₆alkyl, and C₃-C₅cycloalkyl optionally substituted with 1-3 halogens; or

R¹and R²together with the carbon atoms to which they are attached form a polycyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen, C₁-C₆alkyl, and C₃-C₅cycloalkyl optionally substituted with 1-3 halogens; R³and R⁴are each independently selected from halogen, —CN, optionally substituted C₁-C₃alkyl, optionally substituted C₁-C₂alkoxy, optionally substituted C₂-C₃alkenyl, and cyclopropyl;

R⁵is selected from:

[Image Omitted]

R⁶is H or C₁-C₃alkyl;

R⁷is H or C₁-C₃alkyl optionally substituted with 1-5 halogens;

R⁸is selected from H, halogen, —CN, optionally substituted C₁-C₃alkyl, and optionally substituted C₁-C₂alkoxy; or

R³and R⁸together with the carbon atoms to which they are attached form a 4-, 5-, or 6-membered partially unsaturated carbocyclic ring; a 4-, 5-, or 6-membered partially unsaturated heterocyclic ring; a C₆-C₁₀aryl ring; or a 5- or 6-membered heteroaryl ring;

Q is selected from N, CH, and CF; and

X is O or CH₂;

wherein when R¹and R²together with the carbon atoms to which they are attached form a C₆aromatic monocyclic ring, R⁵is selected from:

[Image Omitted]

wherein 0 to 10 hydrogen atoms that are attached to one or more carbon atoms are replaced with deuterium atom(s).

In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₄-C₇monocyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen, C₁-C₆alkyl, and C₃-C₅cycloalkyl optionally substituted with 1-3 halogens. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₄-C₇monocyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₆alkyl. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₅monocyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₆alkyl. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₆monocyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₆alkyl. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₄-C₇monocyclic ring optionally substituted with C₃-C₅cycloalkyl optionally substituted with 1-3 halogens. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₅monocyclic ring optionally substituted with C₃-C₅cycloalkyl optionally substituted with 1-3 halogens. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a C₆monocyclic ring optionally substituted with C₃-C₅cycloalkyl optionally substituted with 1-3 halogens. In some embodiments, the monocyclic ring is not aromatic.

In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a polycyclic ring optionally substituted with 1 to 3 substituents independently selected from halogen, C₁-C₆alkyl, and C₃-C₅cycloalkyl optionally substituted with 1-3 halogens. In some embodiments, R¹and R²together with the carbon atoms to which they are attached form a polycyclic ring optionally substituted with 1 to 3 substituents independently selected from C₁-C₆alkyl. In some embodiments, the polycyclic ring is a spirocyclic ring system. In some embodiments, the polycyclic ring is a fused ring system. In some embodiments, the polycyclic ring is a bridged ring system.

In some embodiments, R³and R⁴are each independently selected from halogen; —CN; C₁-C₃alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₆alkoxy; C₁-C₂alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen; and C₂-C₃alkenyl optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₆alkoxy; and cyclopropyl. In some embodiments, R³and R⁴are each independently selected from C₁; —CN; C₁-C₃alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₆alkoxy; C₁-C₂alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen; and C₂-C₃alkenyl optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₆alkoxy; and cyclopropyl. In some embodiments, R³and R⁴are each independently selected from halogen and C₁-C₃alkyl. In some embodiments, R³and R⁴are both halogen. In some embodiments, R³and R⁴are both C₁. In some embodiments, R³and R⁴are both methyl.

In some embodiments, R⁵is selected from:

[Image Omitted]

In some embodiments, R⁵is

[Image Omitted]

In some embodiments, R⁵is

[Image Omitted]

In some embodiments, R⁵is

[Image Omitted]

and R⁶is H. In some embodiments, R⁵is

[Image Omitted]

and R⁶is C₁-C₃alkyl.

In some embodiments, R⁵is

[Image Omitted]

In some embodiments, R⁵is

[Image Omitted]

In some embodiments, R⁵is

[Image Omitted]

In some embodiments, R⁵is

[Image Omitted]

In some embodiments, Q is CH, CD, or CF. In some embodiments, Q is CH. In some embodiments, Q is CD. In some embodiments, Q is CF. In some embodiments, Q is N.

In some embodiments, X is CH₂. In some embodiments, X is O.

In some embodiments, R⁷is H. In some embodiments, R⁷is C₁-C₃alkyl.

In some embodiments, R⁸is selected from H; halogen; —CN; C₁-C₃alkyl optionally substituted with 1 to 3 substituents independently selected from halogen and C₁-C₂alkoxy; and C₁-C₂alkoxy optionally substituted with 1 to 3 substituents independently selected from halogen. In some embodiments, R⁸is hydrogen or C₁-C₃alkyl. In some embodiments, R⁸is hydrogen.

In some embodiments, R³and R⁸together with the carbon atoms to which they are attached form a 4-, 5-, or 6-membered partially unsaturated carbocyclic ring; a 4-, 5-, or 6-membered partially unsaturated heterocyclic ring; a C₆-C₁₀aryl ring; or a 5- or 6-membered heteroaryl ring. In some embodiments, R³and R⁸together with the carbon atoms to which they are attached form a 4-, 5-, or 6-membered partially unsaturated carbocyclic ring. In some embodiments, R³and R⁸together with the carbon atoms to which they are attached form a 4-, 5-, or 6-membered partially unsaturated heterocyclic ring. In some embodiments, R³and R⁸together with the carbon atoms to which they are attached form a C₆-C₁₀aryl ring. In some embodiments, R³and R⁸together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaryl ring.