FIELD OF THE INVENTION

The present invention relates to ligands of lanthionine synthetase C-like (LANCL) proteins, including LANCL2 and LANCL3, and methods of treating diseases and disorders with same.

BACKGROUND

The lanthionine synthetase C-like (LANCL) family of proteins is comprised of three signaling proteins (LANCL1, LANCL2, and LANCL3) that are at the interface of immunity and metabolism. While LANCL1 is localized to the central nervous system, LANCL2 and LANCL3 are more widely expressed throughout the body. LANCL3 is most highly expressed in immune cells, endocrine tissues, and squamous epithelial cells, as well as hepatocytes and fibroblasts. LANCL1 is a glutathione transferase that functions in the prevention of oxidative stress in part through regulation of SIRT proteins [1, 2]. LANCL2 has been characterized as the mammalian receptor for abscisic acid for the promotion of glycemic control and is differentially expressed in regulatory CD4+ T cells with its activity associated with increased stability and suppressive function of these cells [3-5]. Unlike LANCL1 and LANCL2, which are expressed on the plasma membrane, LANCL3 is associated with the mitochondria. As such, the loss of LANCL3 is associated with impaired mitochondrial metabolism as well as increased inflammatory responses in immune cells.

There are clear clinical needs for safe, efficacious treatments for diseases in which LANCL2 and LANCL3 are implicated. LANCL3 has been identified to be downregulated in unbiased transcriptomic studies of ulcerative colitis [6] and systemic lupus erythematosus [7], among others. Due to low efficacy and poor safety, current autoimmune treatments require frequent monitoring, shifting treatment paradigms, and complex delivery methods. Thus, new treatments capable of being dosed orally for long-term management of disease are needed. In infectious diseases, high mutation rates in various microbes necessitate the development of novel non-antimicrobial treatments that spare the use of antibacterials, antifungals, and antivirals. Further, new strains and epidemic infections create a lag period between the emergence of a pathogen and the availability of microbe-specific interventions, creating a need for novel host-targeted therapeutics. Given the epidemic of infectious and autoimmune diseases as a whole, the LANCL pathways have the potential to significantly impact millions of patients.

Natural compounds have been identified to bind to the LANCL family of proteins. In particular, abscisic acid (“ABA”) is a natural compound found to bind to LANCL2 [5]. ABA has been shown to elicit anti-inflammatory effects and improvement of glycemic control dependent on signaling through LANCL2 [8, 9]. Binding domains for glutathione have been identified in LANCL1 [1]. Further, LANCL1 has been demonstrated to have affinity for other signaling proteins in vitro [10]. Previously, synthetic compounds, such as BT-11, have been developed to target LANCL2 (U.S. Pat. No. 9,556,146).

The present invention provides compounds that have been developed by novel medicinal chemistry approaches, and screened using in silico, in vitro, and in vivo techniques, to maximize their ability to bind to the LANCL family of proteins and thus to induce a beneficial response in various disease conditions.

SUMMARY OF THE INVENTION

The invention provides compounds of Formula (I):


or a salt or ester thereof, wherein:

A1and A6are each C;

A2, A3, A4, A5, A7, A8, A9, A10, A11, A12, A13, A20, A21, A22, A23, and A24are each independently N or C(R2);

A14and A15are each C(O) or N(RL), with the proviso that A14and A15are not both C(O) and are not both N(RL);

A16, A17, A18, and A19are each independently selected from O, N(R2), S, N, and C(R2), with the proviso that one and only one of A16, A17, A18, and A19is O, N(R2), or S;

- - - represents delocalized pi bonds;

R1, R2, and RLin each instance are independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, hydroxyl, carboxyl, optionally substituted alkyloxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted cycloalkyloxy, optionally substituted cycloalkenyloxy, thiol, optionally substituted alkylthio, optionally substituted alkenylthio, optionally substituted alkynylthio, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted alkylsulfonyloxy, optionally substituted cycloalkylthio, optionally substituted cycloalkyl sulfinyl, optionally substituted cycloalkyl sulfonyl, optionally substituted cycloalkylsulfonyloxy, optionally substituted cycloalkenylthio, optionally substituted cycloalkenylsulfinyl, optionally substituted cycloalkenylsulfonyl, optionally substituted cycloalkenylsulfonyloxy, optionally substituted amino, acyl, optionally substituted alkyloxycarbonyl, optionally substituted alkenyloxycarbonyl, optionally substituted alkynyloxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted carbamoyl, optionally substituted sulfamoyl, cyano, nitro, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfinyl, optionally substituted arylsulfonyl, optionally substituted arylsulfonyloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heteroarylthio, optionally substituted heteroarylsulfinyl, optionally substituted heteroarylsulfonyl, optionally substituted heteroarylsulfonyloxy, or an optionally substituted non-aromatic heterocyclic group.

In some versions, A8is N. In some versions, at least one of A11and A13is N. In some versions, A17is N, A18is N(R2), or A17is N and A18is N(R2). In some versions, R1is hydroxyl or optionally substituted alkyloxy. In some versions:

each optionally substituted alkyl, optionally substituted alkyloxy, optionally substituted alkylthio, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted alkylsulfonyloxy, and optionally substituted alkyloxycarbonyl, when substituted, is independently substituted with one to three substituent(s) selected from the group consisting of cycloalkyl, alkylene optionally containing one or two heteroatom(s), hydroxyl, oxo, alkyloxy optionally substituted with a substituent group A at one to three position(s), thiol, alkylthio, halogen, nitro, cyano, carboxyl, alkyloxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, acyl, aryl optionally substituted with a substituent group B at one to three position(s), heteroaryl optionally substituted with a substituent group C at one to three position(s), an optionally substituted non-aromatic heterocyclic ring group optionally substituted with a substituent group C at one to three position(s), aryloxy optionally substituted with a substituent group B at one to three position(s), and alkylsulfonyl;

each optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted alkenylthio, optionally substituted alkynylthio, optionally substituted alkenyloxycarbonyl, optionally substituted alkynyloxycarbonyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkyloxy, optionally substituted cycloalkenyloxy, optionally substituted cycloalkylthio, optionally substituted cycloalkenylthio, optionally substituted cycloalkyl sulfinyl, optionally substituted cycloalkenyl sulfinyl, optionally substituted cycloalkyl sulfonyl, optionally substituted cycloalkenyl sulfonyl, optionally substituted cycloalkylsulfonyloxy, optionally substituted cycloalkenylsulfonyloxy, and optionally substituted alkylene optionally containing one or two heteroatom(s), when substituted, is independently substituted with one or more substituent(s) selected from the group consisting of alkyl optionally substituted with a substituent group D at one to three position(s), cycloalkyl, hydroxyl, oxo, alkyloxy optionally substituted with a substituent group A at one to three position(s), thiol, alkylthio, halogen, nitro, cyano, carboxyl, alkyloxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, acyl, acyloxy, aryl optionally substituted with a substituent group B at one to three position(s), heteroaryl optionally substituted with a substituent group C at one to three position(s), non-aromatic heterocyclic group optionally substituted with a substituent group C at one to three position(s), aryloxy optionally substituted with a substituent group C at one to three position(s), and alkyl sulfonyl;

each optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryloxycarbonyl, optionally substituted arylthio, optionally substituted arylsulfinyl, optionally substituted arylsulfonyl, optionally substituted arylsulfonyloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heteroarylthio, optionally substituted heteroarylsulfinyl, optionally substituted heteroarylsulfonyl, optionally substituted heteroarylsulfonyloxy, and optionally substituted non-aromatic heterocyclic group, when substituted, are each independently substituted with one or more substituent(s) selected from the group consisting of alkyl optionally substituted with a substituent group D at one to three position(s), oxo, cycloalkyl, alkenyl, alkynyl, hydroxyl, alkyloxy optionally substituted with a substituent group A at one to three position(s), aryloxy optionally substituted with a substituent group B at one to three position(s), thiol, alkylthio, halogen, nitro, cyano, carboxyl, alkyloxycarbonyl, acyl, alkylsulfonyl, optionally substituted amino, optionally substituted carbamoyl, aryl optionally substituted with a substituent group B at one to three position(s), heteroaryl optionally substituted with a substituent group C at one to three position(s), and non-aromatic heterocyclic group optionally substituted with a substituent group C at one to three position(s);

each optionally substituted amino, optionally substituted carbamoyl, and optionally substituted sulfamoyl, when substituted, is independently substituted with one or two substituent(s) selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkynyl, aryl, heteroaryl, acyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkyl sulfonyl, alkenyl sulfonyl, alkynylsulfonyl, aryl sulfonyl, and heteroarylsulfonyl;

each substituent group A is independently selected from the group consisting of halogen and phenyl optionally substituted with one to three substituent(s) selected from substituent group B;

each substituent group B is independently selected from the group consisting of halogen, alkyl, alkyloxy, cyano, and nitro;

each substituent group C is independently selected from the group consisting of halogen and alkyl; and

each substituent group D is independently selected from the group consisting of halogen and alkyloxy.

Additional embodiments are described elsewhere herein.

The compounds provided herein are ligands of LANCL3 and LANCL2.

Exemplary compounds include BT-108-1, BT-108-2, BT-108-3, BT-108-4, BT-108-5, BT-108-6, BT-108-7, BT-108-8, BT-108-9, BT-108-10, BT-108-11, BT-108-12, BT-108-13, BT-108-14, BT-108-15, BT-108-16, BT-108-17, BT-108-18, BT-108-19, BT-108-20, BT-108-21, BT-108-22, BT-108-23, BT-108-24, BT-108-25, BT-108-26, BT-108-27, BT-108-28, BT-108-29, BT-108-30, BT-108-31, BT-108-32, BT-108-33, BT-108-34, BT-108-35, BT-108-36, BT-108-37, BT-108-38, BT-108-39, BT-108-40, BT-108-41, BT-108-42, BT-108-43, BT-108-44, BT-108-45, BT-108-46, BT-108-47, BT-108-48, BT-108-49, BT-108-50, BT-108-51, BT-108-52, BT-108-53, BT-108-54, BT-108-55, BT-108-56, BT-108-57, BT-108-58, BT-108-59, BT-108-60, BT-108-61, BT-108-62, BT-108-63, BT-108-64, BT-108-65, BT-108-66, BT-108-67, BT-108-68, BT-108-69, and BT-108-70 as shown inFIGS. 1A-1R and 2A-2F, as well as salts of any of the foregoing.

The invention also provides methods of treating a condition in an animal with a compound as described herein. The methods comprise administering an effective amount of the compound to the animal. The condition may comprise at least one of an inflammatory disease, a metabolic disease, an autoimmune disease, cancer, and an infectious disease. In some versions, the condition comprises inflammatory conditions of the liver, such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and cirrhosis. In some versions, the condition comprises inflammatory conditions of the bile duct, such as primary biliary cholangitis, primary sclerosing cholangitis. In some versions, the condition comprises inflammatory bowel disease, such as Crohn's disease and ulcerative colitis. In some versions, the condition comprises lupus, such as systemic lupus erythematosus, lupus nephritis, and cutaneous lupus. In some versions, the condition comprises arthritis, such as rheumatoid arthritis. In some versions, the condition comprises hyperglycemia, such as type 1 diabetes, type 2 diabetes, and prediabetes, and, optionally, resulting complications such as atherosclerosis and diabetic kidney disease. In some versions, the condition comprises psoriasis. In some versions, the condition comprises multiple sclerosis.

The objects and advantages of the invention will appear more fully from the following detailed description of the preferred embodiment of the invention made in conjunction with the accompanying drawings.

