This application is a continuation U.S. application Ser. No. 18/363,195, now allowed, which is a continuation of International Patent Application No. PCT/US2023/069762, filed Jul. 7, 2023, which claims priority to U.S. Provisional Application No. 63/359,715, filed 8 Jul. 2022 and to U.S. Provisional Application No. 63/385,282, filed 29 Nov. 2022. The entire content of each of these United States Provisional Patent Applications is hereby incorporated herein by reference.

FIELD

This disclosure relates to pharmaceutical compositions that act as antagonists of both wildtype TRPV4 channels and of TRPV4 channels that carry disease-causing activating mutations.

BACKGROUND

The transient receptor potential vanilloid type 4, TRPV4, is a member of the Transient Receptor Potential (TRP) super family (Venkatachalam and Craig Montell 2007 Annual Reviews Biochemistry). The TRPV4 gene encodes a non-selective cation channel highly permeable to calcium. TRPV4 is activated by a variety of different stimuli including heat, mechanical stress, and chemicals including arachidonic acid metabolites. TRPV4 is expressed in a number of different tissues including the brain, bladder, skin, heart, lung and musculoskeletal tissues, among others.

The TRPV4 channel is widely expressed in diverse human cell types. In particular, TRPV4 is expressed in epithelial and endothelial cells, fibroblasts, chondrocytes, neurons, and various inflammatory cells (Koivisto et al 2021 NRDD). TRPV4 has been directly implicated in epithelial and endothelial barrier function with relevance to lung injury and has been further associated with respiratory diseases through TRPV4-induced ATP release (Koivisto). Genetic and pharmacologic studies have implicated TRPV4 as therapeutic target for chronic cough, pulmonary edema, chronic obstructive pulmonary disease, and pulmonary fibrosis (Grace et al 2017, Pharmacology and Therapeutics). Genetic knockout of TRPV4 results in decreased osteoclast function and calcium regulation and is critical for bone homeostasis, suggesting a role for TRPV4 in osteoporosis and other joint diseases. Inflammatory hyperalgesia and mechanical pain are reduced in TRPV4 knockout mice (J. Neurosci. 2004, 18, 4444-4452, Qu, et al., 2016 BioMed Research International) and a variety of functional studies have demonstrated TRPV4 signaling in neuropathic pain. TRPV4 is also expressed in urothelium and detrusor muscles of the bladder and activation causes muscle contraction (Birder et al 2007 J. Pharmacol. Exp. Ther.). Consistent with a role for TRPV4 in bladder related conditions, it has been shown that inhibition of TRPV4 improves bladder function in mice and rat models of cyclophosphamide-induced cystitis (Prog. Biophys. Mol. Biol. 2010, 1, 2-17). This provides evidence for TRPV4 as a therapeutic target in multiple diseases, including respiratory disease, joint diseases, pain, and bladder dysfunction.

Additionally, activating pathogenic mutations in TRPV4 have been shown to cause multiple severe Mendelian diseases including a set of skeletal dysplasias (Nishimura et al 2012 AJMG) and a peripheral neuropathy (Landoure et al. Nature Genetics 2009). All disease-causing mutations appear to contribute to risk of disease by increasing calcium influx into cells (Toft-Beterlsen and MacAulay 2021 Cells) suggesting therapeutic benefit of TRPV4 inhibitors.

These observations suggest a benefit of inhibition of TRPV4 in genetic diseases due to activating mutations, in addition to a number of different common diseases resulting from activation of the wildtype receptor.

GSK2798745 advanced to Phase II clinical trials. Further exploration uncovered a circulating active metabolite (ACS Med. Chem. Lett. 2021, 12, 9, 1498-1502) and a lower safety margin established by a three month dog toxicity study resulted in a 4.8-fold decrease in the maximum clinically administered dose (Am. J. Cardiovasc. Drugs 2019, 19, 335-342).

GSK2798745 failed to show efficacy across several human disease indications. Currently there is a need for agents that are useful for antagonizing TRPV4. In particular, there is a need for agents with lower toxicity, improved potency, improved metabolic stability (e.g., against CYP3A4), lower levels of active circulating metabolites, and/or a higher safety margin.

SUMMARY OF THE DISCLOSURE

In one aspect, the disclosure provides compounds that are useful for antagonizing TRPV4.

In some aspects, the disclosure provides a compound of formula I:

[Image Omitted]

or a salt thereof, wherein:

- L¹is CR^aR^b.
- L²is CR^cR^d;
- R^ais H, halo, cyano, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₃-C₅)cycloalkyloxy, or (C₃-C₅)cycloalkyl, wherein any (C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₃-C₅)cycloalkyloxy, and (C₃-C₅)cycloalkyl is optionally substituted with one or more fluoro;
- R^bis H, halo, cyano, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, or (C₃-C₅)cycloalkyl, wherein any (C₁-C₅)alkyl, (C₁-C₅)alkoxy, and (C₃-C₅)cycloalkyl is optionally substituted with one or more fluoro; or R^aand R^btaken together are oxo (═O) methylene (═CH₂), or R^aand R^btaken together with the atom to which they are attached form a spiro(C₃-C₅)cycloalkyl;
- R^cis H, halo, cyano, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₃-C₅)cycloalkyloxy, or (C₃-C₅)cycloalkyl, wherein any (C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₃-C₅)cycloalkyloxy, and (C₃-C₅)cycloalkyl is optionally substituted with one or more fluoro;
- R^dis H, halo, cyano, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, or (C₃-C₅)cycloalkyl, wherein any (C₁-C₅)alkyl, (C₁-C₅)alkoxy, and (C₃-C₅)cycloalkyl is optionally substituted with one or more fluoro;
- or R^cand R^dtaken together with the atoms to which they are attached form a fused cyclopropyl ring; or R^cand R^dtaken together are oxo (═O) or methylene (═CH₂),
- or R^cand R^dtaken together with the atom to which they are attached form a spiro(C₃-C₅)cycloalkyl;
- wherein at least one of R^a, R^b, R^c, and R^dis other than H;
- R¹is H, hydroxy, cyano, halo, methoxycarbonyl, cyclopropyl, (C₁-C₃)alkyl, or (C₁-C₃)alkoxy, wherein any cyclopropyl, (C₁-C₃)alkyl, and (C₁-C₃)alkoxy is optionally substituted with one or more groups independently selected from hydroxy, (C₁-C₃)alkoxy, benzyloxy, cyano, and fluoro,
- or R¹and R^ctaken together with the atoms to which they are attached form a fused cyclopropyl ring;
- each R²is independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C₁-C₃)alkylsulfonyl, cyclopropyl, (C₁-C₃)alkyl, and (C₁-C₃)alkoxy, wherein any cyclopropyl, (C₁-C₃)alkyl, and (C₁-C₃)alkoxy is optionally substituted with one or more fluoro;
- R⁴is (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, phenyl or a 6-membered heteroaryl, wherein any R⁴is optionally substituted with one or more R^x;
- each R^xis independently selected from the group consisting of hydroxy, halo, cyano, C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₃-C₅)cycloalkyloxy, and (C₃-C₇)cycloalkyl, wherein any (C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₃-C₅)cycloalkyloxy, and (C₃-C₅)cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano, C₁-C₅)alkyl, and hydroxy; and
- A is 0, 1, or 2;
  
  In some aspects, the disclosure provides a compound of formula I:

[Image Omitted]

or a salt thereof, wherein:

- L¹is CR^aR^b;
- L²is CR^cR^d;
- R^ais H, halo, cyano, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₃-C₅)cycloalkyloxy, or (C₃-C₅)cycloalkyl, wherein any (C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₃-C₅)cycloalkyloxy, and (C₃-C₅)cycloalkyl is optionally substituted with one or more fluoro;
- R^bis H, halo, cyano, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, or (C₃-C₅)cycloalkyl, wherein any (C₁-C₅)alkyl, (C₁-C₅)alkoxy, and (C₃-C₅)cycloalkyl is optionally substituted with one or more fluoro; or R^aand R^btaken together are oxo (═O) methylene (═CH₂),
- or R^aand R^btaken together with the atom to which they are attached form a spiro(C₃-C₅)cycloalkyl;
- R^cis H, halo, cyano, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₃-C₅)cycloalkyloxy, or (C₃-C₅)cycloalkyl, wherein any (C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₃-C₅)cycloalkyloxy, and (C₃-C₅)cycloalkyl is optionally substituted with one or more fluoro;
- R^dis H, halo, cyano, (C₁-C₅)alkyl, (C₁-C₅)alkoxy, or (C₃-C₅)cycloalkyl, wherein any (C₁-C₅)alkyl, (C₁-C₅)alkoxy, and (C₃-C₅)cycloalkyl is optionally substituted with one or more fluoro; or R^cand R¹taken together with the atoms to which they are attached form a fused cyclopropyl ring; or R^cand R^dtaken together are oxo (═O) or methylene (═CH₂),
- or R^cand R^dtaken together with the atom to which they are attached form a spiro(C₃-C₅)cycloalkyl;
- R¹is (C₁-C₃)alkyl that is substituted with one or more fluoro;
- each R²is independently selected from the group consisting of halo, cyano, hydroxy, ethynyl, (C₁-C₃)alkylsulfonyl, cyclopropyl, (C₁-C₃)alkyl, and (C₁-C₃)alkoxy, wherein any cyclopropyl, (C₁-C₃)alkyl, and (C₁-C₃)alkoxy is optionally substituted with one or more fluoro;
- R⁴is (C₁-C₇)alkyl, (C₃-C₇)cycloalkyl, phenyl or a 6-membered heteroaryl, wherein any R⁴is optionally substituted with one or more R^x;
- each R^xis independently selected from the group consisting of hydroxy, halo, cyano, C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₃-C₅)cycloalkyloxy, and (C₃-C₇)cycloalkyl, wherein any (C₁-C₅)alkyl, (C₁-C₅)alkoxy, (C₃-C₅)cycloalkyloxy, and (C₃-C₅)cycloalkyl is optionally substituted with one or more groups independently selected from halo, cyano, and hydroxy; and
- A is 0, 1, or 2.

The disclosure also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

The disclosure also provides a method for treating a condition associated with TRPV4 modulation in an animal comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the animal.

The disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy.

The disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment a condition associated with TRPV4 modulation.

The disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a condition associated with TRPV4 modulation in an animal.

The disclosure also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I or a salt thereof.

Certain compounds of formula (I) demonstrate lower toxicity, improved potency, improved metabolic stability (e.g., against CYP3A4), lower levels of active circulating metabolites, and/or a higher safety margin.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows X-Ray Powder Diffraction (XRPD) data from Example 21.

DETAILED DESCRIPTION OF THE DISCLOSURE

The following definitions are used, unless otherwise described: halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.

The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C_1-5means one to five carbons). Examples include (C₁-C₅)alkyl, (C₂-C₅)alkyl, C₁-C₃)alkyl, (C₂-C₃)alkyl and (C₃-C₅)alkyl. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, and n-pentyl.

The term “alkoxy” refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”).

The term “carbocycle” refers to a saturated or partially unsaturated (non-aromatic) all carbon ring having the number of carbons designated.

The term 6-membered heteroaryl includes the following rings:

[Image Omitted]

As used herein a wavy line “ [Image Omitted] ” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.

The terms “treat,” “treatment,” or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition. The terms “treat,” “treatment,” or “treating” also refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For example, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treat,” “treatment,” or “treating” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented. In some embodiments, “treat”, “treatment”, or “treating” does not include preventing or prevention,

The phrase “therapeutically effective amount” or “effective amount” includes but is not limited to an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

In one aspect, the compounds of the present disclosure modulate TRPV4. In some embodiments, modulation is antagonism. In one aspect, the TRPV4 antagonists of the disclosure are useful for treating conditions associated with TRPV4 overactivation. Such conditions include diseases caused by activating mutations in TRPV4 including for example, but not limited to, congenital distal spinal motor neuropathy, scapuloperoneal spinal muscular atrophy, Charcot-Marie-Tooth disease type 2C (CMT2C), metatropic dysplasia (MD), spondylometaphyseal dysplasia Kozlowski type (SMDK), spondyloepiphyseal dysplasia, Maroteaux type, pseudo-Morquio syndrome type 2, parastremmatic dysplasia, autosomal dominant brachyolmia, and familial digital arthropathy-brachydactyly.

In one aspect, the TRPV4 antagonists of the disclosure may be useful for treating related conditions associated with elevated wildtype TRPV4 and/or with symptomology overlapping with diseases caused by TRPV4 activating mutations. Such conditions include, but are not limited to, skeletal dysplasia, bone dysplasia, osteoarthritis, reduced bone density, osteoporosis, peripheral neuropathies, inherited neuropathies, spinal muscular atrophies, Charcot-Marie-Tooth diseases, diseases of the bladder including but not limited to overactive bladder, urinary incontinence, interstitial cystitis, painful bladder syndrome, bladder urgency and neurogenic bladder.

In one aspect, TRPV4 antagonists of the disclosure are useful to treat other bone disorders including bone infections, osteogenesis imperfecta, osteonecrosis, Paget's disease of bone, rickets, achondroplasia, dwarfism, short stature, hypochondroplasia, genetic diseases of the skeleton. In one aspect TRPV4 antagonists may be useful to treat other neuropathies including spinal muscle atrophies, neuropathic pain, pain, motor neuron disorders, chronic pain, intestinal pain and cramping. In one aspect, TRPV4 antagonists of the disclosure are useful to treat diseases with compromised barrier integrity and dysregulation of vascular permeability including but not limited to retinal edema, retinal leak, diabetic or other causes of macular edema, diabetic neuropathy, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, congestive heart failure, irritable bowel syndrome (IBS), Crohn's disease, diarrhea, intestinal irregularity (hyperreactivity/hyporeactivity), fecal incontinence, constipation, celiac disease, lactose intolerance, and flatulence, obesity and type-II diabetes (T2D), colitis/ulcerative colitis, hypertension, atherosclerosis, diseases with edema as a symptom, congestive heart failure, kidney disease or cirrhosis of the liver, kidney infections, urinary tract infections, and enlarged prostate. In one aspect, TRPV4 antagonists of the disclosure are useful to treat diseases of the lung including but not limited to pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, ventilator-associated lung parenchymal overdistension, high altitude induced pulmonary edema, acute respiratory distress syndrome, acute lung injury, pulmonary fibrosis, sinusitis/rhinitis, asthma, cough, chronic cough, bronchiectasis, sarcoidosis, and pulmonary hypertension. In one aspect, TRPV4 antagonists of the disclosure are useful to treat diseases of inflammation, including but not limited to sepsis, diseases with macrophage activation, microglial activation, neuroinflammation, Alzheimer's disease, Parkinson's disease, multiple sclerosis, as well as cardiac diseases, glaucoma, and viral and bacterial infections, infection, chronic inflammatory diseases (rheumatoid arthritis), tissue repair, multiple organ dysfunction/multiple organ failure, microbial infection, acute brain/lung/hepatic/renal injuries, neurodegenerative disorders, tumorigenesis, cardiovascular and metabolic diseases, and autoimmune diseases.

The term “mammal” as used herein refers to humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs, and cats. In some embodiments, the mammal is a human. The term “patient” as used herein refers to any animal including mammals. In one embodiment, the patient is a mammalian patient. In some embodiments, the patient is a human patient.

The compounds disclosed herein can exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the disclosure.

It is understood by one skilled in the art that this disclosure also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (²H or D). As a non-limiting example, a —CH₃group may be substituted with −CD₃. In some embodiments, the compound is enriched with deuterium at one position above naturally occurring isotopic ratio for deuterium. In some embodiments, the compound is enriched with deuterium at two positions above naturally occurring isotopic ratio for deuterium. In some embodiments, the compound is enriched with deuterium at one position by at least about 75%. In some embodiments, the compound is enriched with deuterium at two positions by at least about 75%. In some embodiments, the compound is enriched with deuterium at one position by at least about 95%. In some embodiments, the compound is enriched with deuterium at two positions by at least about 95%. The pharmaceutical compositions of the disclosure can comprise one or more excipients. When used in combination with the pharmaceutical compositions of the disclosure the term “excipients” refers generally to an additional ingredient that is combined with the compound of formula (I) or the pharmaceutically acceptable salt thereof to provide a corresponding composition. For example, when used in combination with the pharmaceutical compositions of the disclosure the term “excipients” includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes.

As used herein, the term “about” refers to a recited amount, value, or duration ±10% or less of said amount, value, or duration. In some embodiments, “about” refers to a recited amount, value, or duration ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5%. In other embodiments, “about” refers to a recited amount, value, or duration ±10%, ±8%, ±6%, ±5%, ±4%, or ±2%. In other embodiments, “about” refers to a recited amount, value, or duration ±5%. In some embodiments, “about” refers to a listed amount, value, or duration ±2% or ±1%. For example, in some embodiments, when the term “about” is used when reciting a temperature or temperature range, these terms refer to the recited temperature or temperature range ±5° C., ±2° C., or ±1° C. In other embodiments, the term “about” refers to the recited temperature or temperature range ±2° C.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the disclosure can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the disclosure, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present disclosure.

It will be appreciated by those skilled in the art that compounds of the disclosure having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present disclosure encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the disclosure, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.

When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. Bold-rectangles and dashed-rectangles ( [Image Omitted] ), designate relative stereochemistry. When a bond in a compound formula herein is drawn as a bold-wedge or a dashed-wedge (), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In some embodiments, the compound may be at least 51% the absolute stereoisomer depicted. In some embodiments, the compound may be at least 60% the absolute stereoisomer depicted. In some embodiments, the compound may be at least 80% the absolute stereoisomer depicted. In some embodiments, the compound may be at least 90% the absolute stereoisomer depicted. In some embodiments, the compound may be at least 95 the absolute stereoisomer depicted. In some embodiments, the compound may be at least 99% the absolute stereoisomer depicted.

Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded.

It is understood that, for a compound of the present disclosure, variables L¹, L², R^a, R^b, R^c, R^d, R¹, R², R⁴, and R^xcan each be, where applicable, selected from the groups described herein, and any group described herein for any of variables L¹, L², R^a, R^b, R^c, R^d, R¹, R², R⁴, and R^xcan be combined, where applicable, with any group described herein for one or more of the remainder of variables L¹, L², R^a, R^b, R^c, R^d, R¹, R², R⁴, and R^x.

Specifically, (C₁-C₅)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, or 3-pentyl; (C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and (C₁-C₅)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, or 3-pentoxy.