Treatment of genetic neurodevelopmental, neurosensory and / or weight control disorders

Abstract

The present invention relates to (E)-N-(3-(2-(2H-tetrazol-5-yl)vinyl)phenyl)-3',4- difluoro-[1,1'-biphenyl]-3-carboxamide, or a pharmaceutically acceptable salt and / or solvate thereof. This compound is useful for the treatment of genetic neurodevelopmental, neurosensory and / or weight control disorders.

Description

TREATMENT OF GENETIC NEURODEVELOPMENTAL, NEUROSENSORYAND / OR WEIGHT CONTROL DISORDERSFIELD OF INVENTION

[0001] The present invention relates to (£)-7V-(3-(2-(2J / -tetrazol-5-yl)vinyl)phenyl)- 3',4-difluoro-[l,T-biphenyl]-3-carboxamide, or a pharmaceutically acceptable salt and / or solvate thereof. This compound is useful for the treatment of genetic neurodevelopmental and / or neurosensory disorders, as well as weight control disorders.BACKGROUND OF INVENTION

[0002] The Hedgehog (Hh) signaling pathway plays a crucial role in neurodevelopment. During embryonic development, sonic hedgehog (SHH) is essential for establishing the ventral spinal cord, inducing basal lamina formation, and generating motor neurons. It mediates the ventral patterning, proliferation, and differentiation of precursor cells in the central nervous system, including the telencephalon, thereby coordinating the size, shape, and cell types of developing neural structures.

[0003] Glil plays a crucial role as a transcriptional effector and target gene in the Hh signaling pathway, particularly in neurodevelopment. As a transcription factor, Glil functions exclusively as an activator, lacking the N-terminal repressor domain found in other Gli proteins. It is both a target and a mediator of Hh signaling, creating a positive feedback loop that amplifies the pathway's response.

[0004] Maintaining Glil transcription levels is thus important for proper regulation of Hh signaling, which plays a crucial role in cell proliferation, differentiation, and tissue patterning during embryonic development. Abnormal Glil regulation can lead to neurodevelopmental disorders.

[0005] Conversely, enhancing Glil activity can be beneficial in tissue regeneration and repair, and in neurodevelopment. Activation of the Hedgehog pathway may promote stem cell proliferation and tissue healing in contexts like chronic wounds or neurological disorders such as Parkinson’s disease or spinal cord injuries.

[0006] Glil+ mesenchymal stem cells (MSCs) are a specialized population of stem cells that play crucial roles in tissue development, regeneration, and repair. They are primarily located in perivascular areas of various tissues, beneath cartilage in bones, in the limbal stroma of the cornea, and within the bone marrow. For instance, Gli 1+ MSCs contribute significantly to osteoblast production in subchondral bone during postnatal development, support craniofacial bone homeostasis, and are involved in the repair of fibrosis in organs such as the heart, liver, lung, and spinal cord, and play a key role in corneal fibrosis repair after injury. Clinically, they present promising therapeutic potential, such as in reducing corneal fibrosis and promoting bone regeneration in the mandible, and may serve as a target in bone marrow fibrosis treatments. For example, Guo et al. showed that Gli P MSCs exhibited active bone morphogenetic protein (BMP) signaling at the skull suture, and conditional downregulation of Hh signaling caused suture stenosis (Guo et al., Bone Research, 2018, 6:30). In mice with skull defects, Hh agonists were found to restore morphological and functional cranial disorders and promote skull healing.

[0007] It is herein evidenced that one specific compound, (E)-7V-(3-(2-(2 / / -tetrazol-5- yl)vinyl)phenyl)-3',4-difluoro-[l,l'-biphenyl]-3-carboxamide (Compound 1), is particularly advantageous for the treatment of neurodevelopmental, neurosensory and weight control disorders. Especially, it is evidenced that Compound 1 can activate Hedgehog signaling, especially by increasing expression levels of GLI1 and / or PTCH transcripts.

[0008] Hh genes are expressed in the adult mouse hypothalamus, in particular in the differentiated neurons important for the regulation of feeding behavior; that pathway activity is regulated at the transcriptional level by fasting. It is known that downregulation of hippocampal Hh signaling leads to neuronal apoptosis and cognitive deficits in HFD- fed mice; also that SHH signal is neuroprotective in obesity and that the use of a Hh agonist can relieve anxiety-like behavior through reducing mitochondrialfragmentation (Qin et al., Behav. Brain Res., 2019 Jul 23:367:91-100; Sun et al., Brain Res. Bull., 2023 Apr: 195:25-36). However, Hh signaling contribution to feeding behavior remains complex and unclear. In the present disclosure shows that Compound 1 increases GLI1 and PTCH expressions, which would have a positive impact on hyperphagia and feeding behavior dysregulation.

[0009] The present invention is thus directed to Compound 1 or a pharmaceutically acceptable salt and / or solvate, and, in particular, to Compound 1 for use in the treatment of neurodevelopmental, neurosensory and weight control disorders.SUMMARY

[0010] This invention thus relates to a compound which is (E)-N-(3-(2-(2H-tetrazol-5- yl)vinyl)phenyl)-3',4-difluoro-[l,T-biphenyl]-3-carboxamide (Compound 1), or a pharmaceutically acceptable salt and / or solvate thereof.

[0011] The invention further relates to a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable carrier.

[0012] The invention also provides Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, for use as a medicament.

[0013] The invention also provides Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of a neurodevelopmental disorder, a neurosensory disorder, or a weight control disorder, in a subject in need thereof.

[0014] In one embodiment, the treated disorder is selected from cerebral palsy, epilepsy, X fragile syndrome, Down syndrome, Rett syndrome, tuberous sclerosis complex, autism, Angelman syndrome, trisomy 13 (Patau syndrome), trisomy 18 (Edwards syndrome), 5p deletion syndrome (cri du chat syndrome), Lesch-Nyhan syndrome, mucopolysaccharidoses, adrenoleukodystrophy, Apert syndrome, Cornelia de Lange syndrome, Rubinstein-Taybi syndrome, Smith-Magenis syndrome, Coffin-Lowrysyndrome, dysfunctions of central control of satiety, hyperphagia, Bardet-Biedl syndrome (BBS), Prader-Willi syndrome (PWS), early-onset forms of glaucoma, and genetic obesity conditions.

[0015] In one embodiment, the genetic obesity conditions are selected from proopiomelanocortin (POMC) deficiency, proprotein convertase subtilisin / kexin type 1 (PCSK1) deficiency, leptin receptor (LEPR) deficiency, monogenic obesity MOI, CHOPS syndrome, WAGR syndrome, pseudohypoparathyroidism type la (PHP la), Schaaf-Yang syndrome, Bbrjeson-Forssman-Lehmann syndrome, Carpenter syndrome, Chung-Jansen syndrome, Cohen syndrome, 2q37 deletion syndrome, Smith-Magenis syndrome, Kabuki syndrome, MEHMO syndrome, MORM syndrome, short bowel intestinal dysmotility, and diarrhea syndrome (SBIDDS).

[0016] In one embodiment, the treated disorder is hyperphagia. In one embodiment, the subject treated for hyperphagia suffers from Bardet-Biedl syndrome (BBS), Rett syndrome, and / or Prader-Willi syndrome (PWS).

[0017] In one embodiment, the treated disorder is early-onset forms of glaucoma affecting children and young adults or adult on-set glaucoma. In one embodiment, the subject treated for early-onset forms of glaucoma affecting children and young adults, suffers from juvenile open-angle glaucoma, anterior segment dysgenesis, congenital glaucoma, and / or familial normal -tension glaucoma. In one embodiment, the subject treated for adult on-set glaucoma, suffers from primary open-angle glaucoma (POAG), adult-onset normal tension glaucoma (NTG), pseudoexfoliation glaucoma, and / or primary angle-closure glaucoma.

[0018] In one embodiment, the treated disorder results from deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: POMC, PCSK1, MC4R, LEP, LEPR, MYT1L, MRAP2, BDNF, SIM1, ADCY3, NTRK2, SH2B1, MAGEL2, HDAC4, TUB, KSR2, SRC1, TRAPPC9, MYOC, PITX2, FOXCI, PAX6, CY1B1, LTBP2, OPTN, TBK1, FNDC3B, COL8A2, CHSY1, HS3ST3B1 / PMP22, ZNF469, RXRA / COL5A1, FGF9 / SGCG, LCN12 / PTGDS, CWC27 / ADAMTS6, TGP1,GPR15, FOXO1, LRRK1, USP37, AKAP13, SKYL1 / LTBP3, CDC7 / TGFBR3, SIX1, SIX6, CAV1, CAV2, TMCO1, GAS7, CDKN2BAS, 8q22, DCLK1, and ATOH7.

[0019] The invention also relates to Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, for use in increasing Hedgehog signaling, in a subject in need thereof. In one embodiment, Hedgehog signaling is increased by increasing levels of GLI1 and / or PTCH.

[0020] In one embodiment, the compound is to be administered orally, topically or parenterally.

[0021] The invention also relates to a process of manufacturing Compound 1, comprising the formation of the tetrazole moiety by addition of an azide salt to (E)-N-(3- (2-cyanovinyl)phenyl)-3',4-difluoro-[l,T-biphenyl]-3-carboxamide. In one embodiment, (E)-N-(3-(2-cyanovinyl)phenyl)-3',4-difluoro-[l, l'-biphenyl]-3-carboxamide is obtained by amide coupling between (E)-3-(3-aminophenyl)acrylonitrile and 3',4-difluoro-[l,l'- biphenyl]-3-carboxylic acid.DEFINITIONS

[0001] The definitions and explanations below are for the terms as used throughout the entire application, including both the specification and the claims.

[0002] The terms “a” and “an” refer to one or to more than one (z.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Similarly, the expressions “at least one” and “one or more” are interchangeable.

[0003] “About” preceding a figure encompasses plus or minus 10%, or less, of the value of said figure. It is to be understood that the value to which the term “about” refers is itself also specifically, and preferably, disclosed.

[0004] “Administering”, or a variant thereof (e.g., “administration"), refers to a means of providing an agent or a composition containing the agent to a subject in need thereofin a manner that results in the agent being inside the subject’s body. Such an administration can be by any route including, without limitation, oral, injection (e.g., subcutaneous, intravenous, parenterally, intraperitoneally, into the CNS), transdermal (e.g., vagina, rectum, oral mucosa), or inhalation (e.g., oral or nasal). Pharmaceutical preparations are, of course, given by forms suitable for each administration route.

[0005] “Pharmaceutically acceptable” means that the component is not deleterious to the subject to which it is administered and is compatible with any other component administered together.

[0006] “Pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical excipients or carriers, especially excipients or carriers that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, preferably a human. This includes any and all solvents, dispersion media, carriers such as a phosphate buffered saline solution, water, and emulsions such as an oil / water or water / oil emulsion, and various types of stabilizers, preservatives, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents and other similar ingredients. For examples of carriers, stabilizers and adjuvants, see Remington’s Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000). For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by the regulatory offices such as the FDA (US Food and Drug Administration) or EMA (European Medicines Agency).

[0007] “Pharmaceutically acceptable salt” refers to a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.

[0008] “Solvate” refers to a molecular complex comprising a compound and contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptablesolvent molecule such as ethanol. The term “hydrate” refers to when said solvent is water.

[0009] “Subject” refers to a mammal, preferably a human. According to the present invention, a subject is a mammal, preferably a human, suffering from the targeted disease and / or prone to develop the targeted disease. In one embodiment, the subject is a “patient”, i.e., a mammal, preferably a human, who / which is awaiting the receipt of, or is receiving medical care or was / is / will be the object of a medical procedure or is monitored for the development of the targeted disease.

[0010] “Suffering” as it relates to the term “treatment” refers to a patient or individual who has been diagnosed with the disease. The term “suffering” as it relates to the term “prevention” refers to a patient or individual who is predisposed to the disease. A patient may also be referred to being “at risk of suffering” from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease. A patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease.

[0011] “Therapeutically effective amount” or “effective amount” refers to an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, and the route of administration. It is understood, however, that specific doses of the compound as disclosed herein for any particular subject depend upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. Treatment dosages generally may be titrated to optimize safety and efficacy. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks. Consistent with this definition, as used herein, the term“therapeutically effective amount” is an amount sufficient to treat (e.g., improve) one or more symptoms associated with the targeted disease ex vivo, in vitro or in vivo.

[0012] “Treatment” or “treating” refers to a therapeutic treatment, to a prophylactic (or preventative) treatment, or to both a therapeutic treatment and a prophylactic (or preventative) treatment, wherein the object is to prevent, reduce, alleviate, and / or slow down (lessen) one or more of the symptoms or manifestations of a disease, in a subject in need thereof. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented. A subject or mammal is successfully “treated” for a disease if, after receiving a therapeutic amount of the compound as disclosed herein, the subject or mammal shows, (1) delayed or prevented onset of the disease; (2) slowed down or stopped progression, aggravation, or deterioration of one or more symptoms of the disease; (3) ameliorations of one or more symptoms of manifestations of the disease; (4) reduction of the severity or incidence of the disease; or (5) curing the disease. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician. In one embodiment, “treating” or “treatment” refers to a therapeutic treatment. In another embodiment, “treating” or “treatment” refers to a prophylactic or preventive treatment. In yet another embodiment, “treating” or “treatment” refers to both a prophylactic (or preventive) treatment and a therapeutic treatment.DETAILED DESCRIPTION

[0013] This invention thus relates to a specific compound (Compound 1) and, in particular, its use in the treatment of neurodevelopmental and / or neurosensory and / or weight control disorders. In all of its various aspects, the invention relates to Compound 1 or pharmaceutically acceptable salts and / or solvates thereof.Compound

[0014] In a first aspect, the present invention thus relates to Compound 1, which is (E)- 7V-(3-(2-(2J / -tetrazol-5-yl)vinyl)phenyl)-3',4-difluoro-[l,r-biphenyl]-3-carboxamide, and has the following formula:

[0015] The compound was named using ChemDraw Professional 23.1.1.3 (Revvity Signals Software, Inc.).

[0016] The present invention also relates to the pharmaceutically acceptable salts of Compound 1. Pharmaceutically acceptable salts of Compound 1 include the acid addition salts and base addition salts thereof.

[0017] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts.

[0018] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)- morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts.

[0019] Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. When the compound may also form internal salts, it is also within the scope of the invention.

[0020] Pharmaceutically acceptable salts may be prepared by one or more of these methods:(i) by reacting the compound with the desired acid;(ii) by reacting the compound with the desired base;(iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and / or(iv) by converting one salt of the compound to another by reaction with an appropriate acid or by means of a suitable ion exchange column.

[0021] All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

[0022] The present invention further relates to the pharmaceutically acceptable solvates of Compound 1.

[0023] In one embodiment, the invention relates to (E)-7V-(3-(2-(2J / -tetrazol-5- yl)vinyl)phenyl)-3',4-difluoro-[l,T-biphenyl]-3-carboxamide, or a pharmaceutically acceptable salt and / or solvate thereof.

[0024] Compound 1 can be prepared by methods known in the art.

[0025] In one embodiment, Compound 1 can especially be prepared by a process comprising the formation of the tetrazole moiety by addition of an azide salt to nitrile intermediate C:(Intermediate C)

[0026] Intermediate C thus corresponds to (£)-7V-(3-(2-cyanovinyl)phenyl)-3',4- difluoro-[ 1 , 1 '-biphenyl]-3 -carboxamide.

[0027] In one embodiment, the azide salt used in the process to prepare Compound 1 is sodium azide.

[0028] In one embodiment, Intermediate C can be obtained by amide coupling between Intermediate A and Intermediate B:(Intermediate A)(Intermediate B)

[0029] Intermediate A thus corresponds to (E)-3-(3-aminophenyl)acrylonitrile. Intermediate B thus corresponds to 3',4-difluoro-[l,l'-biphenyl]-3-carboxylic acid.

[0030] In one embodiment, Compound 1 is prepared as detailed in the experimental part as detailed below.Medical indications

[0031] In a second aspect, the invention relates to the medical use of Compound 1, or of a pharmaceutically acceptable salt and / or solvate thereof.

[0032] Especially, Compound 1, pharmaceutically acceptable salts and / or solvates thereof, and pharmaceutical compositions containing the same, described herein are useful in the treatment of neurodevelopmental and / or neurosensory and / or weight control disorders. In one embodiment, Compound 1, pharmaceutically acceptable salts and / or solvates thereof, and pharmaceutical compositions containing the same, described hereinare useful in the treatment of neurodevelopmental disorders, neurosensory disorders, or weight control disorders.

[0033] In a third aspect, the present invention thus provides a compound for use in the treatment of neurodevelopmental and / or neurosensory and / or weight control disorders in a subject in need thereof, wherein the compound is (£)-7V-(3-(2-(2Z7-tetrazol-5- yl)vinyl)phenyl)-3',4-difluoro-[l,r-biphenyl]-3-carboxamide (Compound 1) or a pharmaceutically acceptable salt and / or solvate thereof. In one embodiment, the present invention thus provides a compound for use in the treatment a neurodevelopmental disorder, a neurosensory disorder, or a weight control disorder in a subject in need thereof, wherein the compound is Compound 1 or a pharmaceutically acceptable salt and / or solvate thereof.

[0034] Also provided is a method for treating neurodevelopmental and / or neurosensory and / or weight control disorders in a subject in need thereof, the method comprising administering to the subject an effective amount of (E)-7V-(3-(2-(2Z7-tetrazol-5- yl)vinyl)phenyl)-3',4-difluoro-[l,r-biphenyl]-3-carboxamide (Compound 1) or a pharmaceutically acceptable salt and / or solvate thereof. Further provided is the use of (E)-A-(3-(2-(2Z7-tetrazol-5-yl)vinyl)phenyl)-3',4-difluoro-[l,r-biphenyl]-3- carboxamide (Compound 1) or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment of neurodevelopmental and / or neurosensory and / or weight control disorders in a subject in need thereof or for use in a method of treating neurodevelopmental and / or neurosensory and / or weight control disorders in a subject in need thereof. Further provided is a pharmaceutical composition for use in the treatment of neurodevelopmental and / or neurosensory and / or weight control disorders in a subject in need thereof, said pharmaceutical composition comprising (E)- 7V-(3-(2-(2Z7-tetrazol-5-yl)vinyl)phenyl)-3',4-difluoro-[l,r-biphenyl]-3-carboxamide (Compound 1) or a pharmaceutically acceptable salt and / or solvate thereof and optionally at least one pharmaceutically acceptable excipient.

[0035] In one embodiment, the invention relates to a method for treating a neurodevelopmental disorder, a neurosensory disorder, or a weight control disorder, in a subject in need thereof, the method comprising administering to the subject an effectiveamount of Compound 1 or a pharmaceutically acceptable salt and / or solvate thereof. Further provided is the use of Compound 1 or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment of a neurodevelopmental disorder, a neurosensory disorder, or a weight control disorder in a subject in need thereof or for use in a method of treating a neurodevelopmental disorder, a neurosensory disorder, or a weight control disorder in a subject in need thereof. Further provided is a pharmaceutical composition for use in the treatment of a neurodevelopmental disorder, a neurosensory disorder, or a weight control disorder in a subject in need thereof, said pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt and / or solvate thereof and optionally at least one pharmaceutically acceptable excipient.

[0036] In a preferred embodiment, the neurodevelopmental and / or neurosensory and / or weight control disorders are genetic neurodevelopmental disorders and / or genetic neurosensory disorders and / or genetic weight control disorders.

[0037] “Neurodevelopmental disorders (NDDs)” refer to a class of disorders affecting brain development and function and are characterized by wide genetic and clinical variability. NDDs are characterized by an inability to reach cognitive, emotional, and motor developmental milestones. They have a heterogeneous etiology and lead to impaired cognition, communication, adaptive behavior, and psychomotor skills. In terms of genetics, different types of mutation have been associated with NDDs, including chromosomal rearrangements, copy number variations, small indels, and point mutations. Methods for identifying, detecting, or characterizing neurodevelopmental disorders are well known in the art and include, for example, whole-exome sequencing (WES), DNA microarrays to detect gross chromosomal aberrations otherwise not detectable with conventional WES, and various additional methods to detect epigenetic changes, such as PCR, tandem mass spectrometry, and southern blot. In one embodiment, the treated neurodevelopmental disorders are genetic neurodevelopmental disorders, i.e. neurodevelopmental disorders having a genetic cause. In another embodiment, the treated neurodevelopmental disorders have no genetic cause, and are for example due to fetal alcoholism.

[0038] “Neurosensory disorders” refer to a class of disorders that result from anormal activation of nerves that commonly signal visual, auditory, touch, smell, taste, pain, pressure or temperature sensation. Neurosensory disorders include taste change, a wide array of pain syndromes including nerve pain (numbness, tingling, pain), mucosal sensitivity, altered hearing and altered sight. Methods for identifying, detecting, or characterizing neurosensory disorders are well known in the art and include, for example, reports of symptoms from patients completed by investigations of the causes. In one embodiment, the treated neurosensory disorders are genetic neurosensory disorders, i.e. neurosensory disorders having a genetic cause.

[0039] “Weight control disorders” refer to a class of disorders related to abnormal regulation of body weight, either through excessive weight gain or severe weight loss, often associated with metabolic, behavioral, or psychological factors. Methods for identifying, detecting, or characterizing weight control disorders are well known in the art and include, for example, genetic screening, metabolic assessments, body mass index (BMI) calculations, and behavioral evaluations. In one embodiment, the treated weight control disorders are genetic weight control disorders, i.e. weight control disorders having a genetic cause.

[0040] In one embodiment, the treatment of neurodevelopmental, neurosensory, or weight control disorders, especially of genetic neurodevelopmental, neurosensory, or weight control disorders, by Compound 1 occurs at least by increasing Hedgehog signaling, and especially by increasing levels of GLI1 and / or PTCH. Examples of neurodevelopmental, neurosensory, or weight control disorders, especially of genetic neurodevelopmental, neurosensory, or weight control disorders, that can be treated by increasing Hedgehog signaling, and especially by increasing levels of GLI1 and / or PTCH, include cerebral palsy, epilepsy, X fragile syndrome, Down syndrome, Rett syndrome, tuberous sclerosis complex, autism, and Angelman syndrome. In one embodiment, the treated neurodevelopmental, neurosensory, or weight control disorders, especially genetic neurodevelopmental, neurosensory, or weight control disorders, are selected from cerebral palsy, epilepsy, X fragile syndrome, Down syndrome, tuberous sclerosis complex, autism, and Angelman syndrome.

[0041] In one embodiment, the neurodevel opmental disorders are linked to chromosomal abnormalities, such as numerical (such as trisomies) or genomic structural variation (deletion, duplication, and others). Examples of neurodevelopmental disorders linked to chromosomal abnormalities include trisomy 13 (Patau syndrome), trisomy 18 (Edwards syndrome), and 5p deletion syndrome (cri du chat syndrome). In one embodiment, the neurodevelopmental disorders are selected from trisomy 13 (Patau syndrome), trisomy 18 (Edwards syndrome), and 5p deletion syndrome (cri du chat syndrome).

[0042] In one embodiment, the neurodevelopmental disorders are linked to metabolic disorders. Examples of neurodevelopmental disorders linked to metabolic disorders include Lesch-Nyhan syndrome, mucopolysaccharidoses, adrenoleukodystrophy, Cornelia de Lange syndrome, Rubinstein-Taybi syndrome, Smith-Magenis syndrome, Coffin-Lowry syndrome, and Bardet-Biedl syndrome (BBS). In one embodiment, the neurodevelopmental disorders are selected from Lesch-Nyhan syndrome, mucopolysaccharidoses, adrenoleukodystrophy, Cornelia de Lange syndrome, Rubinstein-Taybi syndrome, Smith-Magenis syndrome, Coffin-Lowry syndrome, and Bardet-Biedl syndrome (BBS).

[0043] In one embodiment, the neurodevelopmental, neurosensory, or weight control disorders are dysfunctions of central control of satiety. The dysfunctions of central control of satiety can occur in the central nervous system (CNS), in peripheral sensory organs, in hypothalamus, or in a combination thereof. Dysfunctions of central control of satiety can result in hyperphagia. In one embodiment, the neurodevelopmental, neurosensory, or weight control disorders are selected from dysfunctions of central control of satiety and hyperphagia.

[0044] In one embodiment, the hyperphagia is treated in patients with Bardet-Biedl syndrome (BBS), Rett syndrome, and / or Prader-Willi syndrome (PWS).

[0045] In one embodiment, the treated disorder is selected from other genetic obesity conditions, such as for example pro-opiomelanocortin (POMC) deficiency, proprotein convertase subtilisin / kexin type 1 (PCSK1) deficiency, leptin receptor (LEPR)deficiency, monogenic obesity MOI, CHOPS syndrome, WAGR syndrome, pseudohypoparathyroidism type la (PHPla), Schaaf-Yang syndrome, Borjeson- Forssman-Lehmann syndrome, Carpenter syndrome, Chung-Jansen syndrome, Cohen syndrome, 2q37 deletion syndrome, Smith-Magenis syndrome, Kabuki syndrome, MEHMO syndrome, MORM syndrome, short bowel intestinal dysmotility, and diarrhea syndrome (SBIDDS).

[0046] In one embodiment, the treated disorder is early-onset forms of glaucoma.

[0047] In one embodiment, the early-onset forms of glaucoma is affecting children and young adults. Preferably, children are 6 months to 18 years old and young adults are 18 to 40 years old. In one embodiment, the treated disorder is early-onset forms of glaucoma affecting children and young adults. In one embodiment, the early-onset forms of glaucoma affecting children and young adults are treated in patients suffering from juvenile open-angle glaucoma, anterior segment dysgenesis, congenital glaucoma, and / or familial normal-tension glaucoma. In one embodiment, the early-onset forms of glaucoma affecting children and young adults result from deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: MYOC, PITX2, FOXCI, PAX6, CY1B1, LTBP2, OPTN, and TBK

[0048] In another embodiment, the early-onset forms of glaucoma is affecting adults and is referred to as adult on-set glaucoma. Usually, adult on-set glaucoma is affecting adults above 40 years old, preferably above 50 years old. In one embodiment, the treated disorder is early-onset forms of glaucoma affecting adults, also referred to as adult on-set glaucoma. In one embodiment, the adult on-set glaucoma is treated in patients suffering from primary open-angle glaucoma (POAG), adult-onset normal tension glaucoma (NTG), pseudoexfoliation glaucoma, and / or primary angle-closure glaucoma. In one embodiment, the adult on-set glaucoma results from deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: FNDC3B, COL8A2, CHSY1, HS3ST3B1 / PMP22, ZNF469, RXRA / COL5A1, FGF9 / SGCG, LCN12 / PTGDS, CWC27 / ADAMTS6, TGP1, GPR15, F0X01, LRRK1, USP37, AKAP13, SKYL1 / LTBP3, CDC7 / TGFBR3, SIX1, SIX6, CAV1, CAV2, IMC01, GAS7, CDKN2BAS, 8q22, DCLK1, and ATOH7.

[0049] In one embodiment, the treated disorder is selected from cerebral palsy, epilepsy, X fragile syndrome, Down syndrome, Rett syndrome, and tuberous sclerosis complex, autism, Angelman syndrome, trisomy 13 (Patau syndrome), trisomy 18 (Edwards syndrome), 5p deletion syndrome (cri du chat syndrome), Lesch-Nyhan syndrome, mucopolysaccharidoses, adrenoleukodystrophy, Cornelia de Lange syndrome, Rubinstein-Taybi syndrome, Smith-Magenis syndrome, Coffin-Lowry syndrome, dysfunctions of central control of satiety, hyperphagia, Bardet-Biedl syndrome (BBS), Prader-Willi syndrome (PWS), early-onset forms of glaucoma including early-onset forms of glaucoma affecting children and young adults and early-onset forms of glaucoma affecting adults (as adult on-set glaucoma), and genetic obesity conditions, such as proopiomelanocortin (POMC) deficiency, proprotein convertase subtilisin / kexin type 1 (PCSK1) deficiency, leptin receptor (LEPR) deficiency, monogenic obesity MOI, CHOPS syndrome, WAGR syndrome, pseudohypoparathyroidism type la (PHP la), Schaaf-Yang syndrome, Bbrjeson-Forssman-Lehmann syndrome, Carpenter syndrome, Chung-Jansen syndrome, Cohen syndrome, 2q37 deletion syndrome, Smith-Magenis syndrome, Kabuki syndrome, MEHMO syndrome, MORM syndrome, short bowel intestinal dysmotility, and diarrhea syndrome (SBIDDS).

[0050] In one embodiment, the neurodevelopmental and / or neurosensory and / or weight control disorders have a genetic cause. Especially, genetic neurodevelopmental and / or neurosensory and / or weight control disorders may result from the deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes. In one embodiment, the genetic disorder may be dominant or recessive. In one embodiment, the genetic disorder is recessive, in particular autosomal recessive. In one embodiment, the genetic neurodevelopmental or neurosensory disorder may be dominant or recessive. In one embodiment, the genetic neurodevelopmental or neurosensory disorder is recessive, in particular autosomal recessive.

[0051] In one embodiment, the treated genetic disorders result from deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: POMC, PCSK1, MC4R, LEP, LEPR, MYT1L, MRAP2, BDNF, SIM1, ADCY3, NTRK2, SH2B1, MAGEL2, HDAC4, TUB, KSR2, SRC1, and TRAPPC9.

[0052] In another embodiment, the treated genetic disorders result from deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: MYOC, PITX2, FOXCI, PAX6, CY1B1, LTBP2, OPTN, and TBK1.

[0053] In another embodiment, the treated genetic disorders result from deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: FNDC3B, COL8A2, CHSY1, HS3ST3B1 / PMP22, ZNF469, RXRA / COL5A1, FGF9 / SGCG, LCN12 / PTGDS, CWC27 / ADAMTS6, TGP1, GPR15, F0X01, LRRK1, USP37, AKAP13, SKYL1 / LTBP3, CDC7 / TGFBR3, SIX1, SIX6, CAV1, CAV2, TMCO1, GAS7, CDKN2BAS, 8q22, DCLK1, and ATOH7.

[0054] In one embodiment, the treated genetic disorders result from deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: POMC, PCSK1, MC4R, LEP, LEPR, MYT1L, MRAP2, BDNF, SIM1, ADCY3, NTRK2, SH2B1, MAGEL2, HDAC4, TUB, KSR2, SRC1, TRAPPC9, MYOC, PITX2, FOXCI, PAX6, CY1B1, LTBP2, OPTN, TBK1, FNDC3B, COL8A2, CHSY1, HS3ST3B1 / PMP22, ZNF469, RXRA / COL5A1, FGF9 / SGCG, LCN12 / PTGDS, CWC27 / ADAMTS6, TGP1, GPR15, F0X01, LRRK1, USP37, AKAP13, SKYL1 / LTBP3, CDC7 / TGFBR3, SIX1, SIX6, CAV1, CAV2, TMCO1, GAS7, CDKN2BAS, 8q22, DCLK1, and ATOH7.

[0055] Deletions, mutations and loss of functions causing genetic neurodevelopmental and / or neurosensory and / or weight control disorders can be biallelic or monoallelic. As used herein, by “biallelic”, it is meant that the deletions, mutations and loss of functions are present in / affect both alleles of the gene(s), with the deletions, mutations and loss of functions on each allele being either identical or different. As used herein, by “monoallelic”, it is meant that the deletions, mutations and loss of functions are present in / affect only one allele of the gene(s).

[0056] In one embodiment, the present invention also provides a compound for use in increasing Hedgehog signaling, especially by increasing levels of GLI1, in a subject in need thereof, wherein the compound is (E)-A-(3-(2-(2Z7-tetrazol-5-yl)vinyl)phenyl)-3',4- difluoro-[l,l'-biphenyl]-3-carboxamide (Compound 1) or a pharmaceutically acceptable salt and / or solvate thereof.

[0057] Also provided is a method for increasing Hedgehog signaling, especially by increasing levels of GI 1, in a subject in need thereof, the method comprising administering to the subject an effective amount of (E)-7V-(3-(2-(2Z7-tetrazol-5- yl)vinyl)phenyl)-3',4-difluoro-[l,r-biphenyl]-3-carboxamide (Compound 1) or a pharmaceutically acceptable salt and / or solvate thereof. Further provided is the use of (E)-A-(3-(2-(2Z7-tetrazol-5-yl)vinyl)phenyl)-3',4-difluoro-[l,r-biphenyl]-3- carboxamide (Compound 1) or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for increasing Hedgehog signaling, especially by increasing levels of GI 1, in a subject in need thereof or for use in a method of increasing Hedgehog signaling, especially by increasing levels of GI 1, in a subject in need thereof. Further provided is a pharmaceutical composition for use in increasing Hedgehog signaling, especially by increasing levels of GI 1, in a subject in need thereof, said pharmaceutical composition comprising (E)-7V-(3-(2-(2Z7-tetrazol-5-yl)vinyl)phenyl)- 3',4-difluoro-[l,r-biphenyl]-3-carboxamide (Compound 1) or a pharmaceutically acceptable salt and / or solvate thereof and optionally at least one pharmaceutically acceptable excipient.

[0058] In one embodiment, the invention also relates to the use of Compound 1 as a benchmark in diagnostic methods. In another embodiment, the invention also relates to the use of Compound 1 as a benchmark in therapeutic methods.Subject

[0059] In one embodiment, the subject is a human.

[0060] In one embodiment, the subject is a male. In one embodiment, the subject is a female.

[0061] In one embodiment the subject is an adult; e.g. of an age above 18 years old. In another embodiment, the subject is a child; e.g., of an age from 0 to 18 years old, e.g., from 1 to 15 years old, or from 1 to 5 years old, or from 5 to 10 years old, or from 10 to 15 years old. In another embodiment, the subject is a young adult; e.g., of an age from 18 to 40 years old.

[0062] In one embodiment, the subject is diagnosed with a neurodevel opmental and / or neurosensory disorder. In one embodiment, the subject is diagnosed with a neurodevel opmental and / or neurosensory disorder and suffers from a manifestation of a neurodevelopmental and / or neurosensory disorder selected from hyperphagia. In one embodiment, the subject is diagnosed with a neurodevelopmental, a neurosensory disorder, or a weight control disorder. In one embodiment, the subject is diagnosed with a neurodevelopmental, a neurosensory disorder, or a weight control disorder and suffers from a manifestation of a neurodevelopmental, a neurosensory disorder, or a weight control disorder.

[0063] As mentioned above, neurodevelopmental and / or neurosensory and / or weight control disorders are often associated with one or more genetic mutations. In some embodiments, the subject is diagnosed with having a neurodevelopmental disorder, a neurosensory disorder, or a weight control disorder, and is also diagnosed to have a particular genetic mutation, for example, one that is known to be a cause of the neurodevelopmental, neurosensory, or weight control disorder in question, although it often cannot be proven that a particular patient’s disease or disorder is caused by the particular mutation that a person has been diagnosed with having. In some embodiments, the subject is diagnosed with having a neurodevelopmental and / or neurosensory disorder and is also diagnosed to have a particular genetic mutation, for example, one that is known to be a cause of the neurodevelopmental and / or neurosensory disorder in question, although it often cannot be proven that a particular patient’s disease or disorder is caused by the particular mutation that a person has been diagnosed with having. As used in this manner, the term “diagnosed to have a particular genetic mutation” means that a subject or patient has been tested, e.g., by DNA or RNA sequencing, protein profiling, or other suitable means, and found to have the mutation in question.

[0064] In one embodiment, the subject is diagnosed with a deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: POMC, PCSK1, MC4R, LEP, LEPR, MYT1L, MRAP2, BDNF, SIM1, ADCY3, NTRK2, SH2B1, MAGEL2, HDAC4, TUB, KSR2, SRC1, and TRAPPC9.

[0065] In another embodiment, the subject is diagnosed with a deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: MYOC, PITX2, FOXCI, PAX6, CY1B1, LTBP2, OPTN, and TBK1.

[0066] In another embodiment, the subject is diagnosed with a deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: FNDC3B, COL8A2, CHSY1, HS3ST3B1 / PMP22, ZNF469, RXRA / COL5A1, FGF9 / SGCG, LCN12 / PTGDS, CWC27 / ADAMTS6, TGP1, GPR15, F0X01, LRRK1, USP37, AKAP13, SKYL1 / LTBP3, CDC7 / TGFBR3, SIX1, SIX6, CAV1, CAV2, TMCO1, GAS7, CDKN2BAS, 8q22, DCLK1, and ATOH7.

[0067] In one embodiment, the subject is diagnosed with a deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: POMC, PCSK1, MC4R, LEP, LEPR, MYT1L, MRAP2, BDNF, SIM1, ADCY3, NTRK2, SH2B1, MAGEL2, HDAC4, TUB, KSR2, SRC1, TRAPPC9, MYOC, PITX2, FOXCI, PAX6, CY1B1, LTBP2, OPTN, TBK1, FNDC3B, COL8A2, CHSY1, HS3ST3B1 / PMP22, ZNF469, RXRA / COL5A1, FGF9 / SGCG, LCN12 / PTGDS, CWC27 / ADAMTS6, TGP1, GPR15, F0X01, LRRK1, USP37, AKAP13, SKYL1 / LTBP3, CDC7 / TGFB.R3, SIX1, SIX6, CAV1, CAV2, TMCO1, GAS7, CDKN2BAS, 8q22, DCLK1, and ATOH7

[0068] In one embodiment, the subject carries a biallelic deletion, mutation, or loss of function. As used herein, by “carrying a biallelic deletion, mutation, or loss of function”, it is meant that the subj ect carries a deletion, mutation, or loss of function in / of both alleles of the gene(s), with the deletions, mutations, or loss of functions on each allele being either identical or different. In one embodiment, the subject carries a monoallelic deletion, mutation, or loss of function. As used herein, by “carrying a monoallelic deletion, mutation, or loss of function”, it is meant that the subject carries a deletion, mutation, or loss of function in / of only one allele of the gene(s).

[0069] The uses of the invention may be beneficial for subj ects who have been diagnosed with a neurodevelopmental disorder, a neurosensory disorder, or a weight control disorder, but are not yet experiencing the typical symptoms associated with the disease state. In one embodiment, the uses of the invention may be beneficial for subjects whohave been diagnosed with a neurodevelopmental and / or neurosensory disorder but are not yet experiencing the typical symptoms associated with the disease state. Uses of the invention may also be beneficial for subjects who are at risk of developing a neurodevelopmental disorder, a neurosensory disorder, or a weight control disorder (in particular a neurodevelopmental and / or neurosensory disorder) due to, for example, a mutation in the subject or the subject’s family lineage known to cause a neurodevelopmental disorder, a neurosensory disorder, or a weight control disorder. In one embodiment of the uses described herein, the subject has been diagnosed as being at risk of developing said neurodevelopmental disorder, neurosensory disorder, or weight control disorder, and Compound 1 as described herein prevents or delays the onset and / or development of the neurodevelopmental disorder, neurosensory disorder, or weight control disorder in the subject. In embodiments, the subject has been diagnosed as being at risk of developing said neurodevelopmental disorder, neurosensory disorder, or weight control disorder by virtue of having a mutation in a gene as described herein.Pharmaceutical compositions

[0070] In any one of the uses according to the invention detailed above, the compound is preferably administered within a pharmaceutical composition.

[0071] In a fifth aspect, the invention thus further relates to a pharmaceutical composition comprising (£)-7V-(3-(2-(2J / -tetrazol-5-yl)vinyl)phenyl)-3',4-difluoro-[l,r- biphenyl]-3 -carboxamide (Compound 1), or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0072] The pharmaceutically acceptable excipient can be any such excipient known in the art including those described in, for example, Remington’s Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000). Pharmaceutical compositions may be prepared by conventional means known in the art including, for example, mixing Compound 1 as described herein, or a pharmaceutically acceptable salt and / or solvate thereof, with a pharmaceutically acceptable excipient.

[0073] The pharmaceutical composition or dosage form is formulated to provide, when administered, an amount of the compound of interest sufficient to treat neurodevelopmental and / or neurosensory and / or weight control disorders or a manifestation of neurodevelopmental and / or neurosensory and / or weight control disorders.

[0074] In one embodiment, the compound is to be administered by systemic administration, e.g., via a parenteral or a non-parenteral route. In one embodiment, the route of administration is oral (enteral). In another embodiment, the route of administration is parenteral, e.g., by injection, such as by intravenous, intramuscular, intrathecal or subcutaneous injection. In another embodiment, the compound is to be administered by local administration, e.g., by topical administration.

[0075] In a preferred embodiment, Compound 1, or a pharmaceutically acceptable salt and / or solvate thereof, is to be administered orally.

[0076] The dosage form comprising the compound or the pharmaceutical composition comprising the compound can be an oral dosage form, a parenteral dosage form, a topical or rectal dosage form, an intranasal dosage form. Preferably, the dosage form is an oral dosage form. The oral dosage form is for example a pill, capsule, caplet, tablet, dragee, powder, granule, film, lozenge or liquid. Alternatively, the dosage form can be a topical dosage form including, but not limited to, eye drops.

[0077] In one embodiment, the compound is to be administered as the sole active agent. Alternatively, a second pharmaceutically active agent can be concurrently administered. In one embodiment, the second active agent is capable of treating neurodevelopmental and / or neurosensory and / or weight control disorders. The second active agent can be administered in the same pharmaceutical composition or dosage form as the compound as disclosed herein. Alternatively, the second active agent can be administered in a different pharmaceutical composition or dosage form.

[0078] Generally, the agents and compositions described herein are to be administered in an effective amount or quantity sufficient to treat or prevent neurodevelopmentaland / or neurosensory and / or weight control disorders in a subject. Typically, the dose can be adjusted within this range based on, e.g., age, physical condition, body weight, sex, diet, time of administration, and other clinical factors. Determination of an effective amount is well within the capability of those skilled in the art.

[0079] In the treatment of neurodevelopmental and / or neurosensory and / or weight control disorders, an appropriate dosage level will generally be about 0.01 to 250 mg per kg patient body weight per day (mg / kg per day) which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 100 mg / kg per day, such as ranging from 0.1 to 50 mg / kg per day. For oral administration, the compositions are preferably provided in dosage forms containing 1.0 to 1000 mg of the active ingredient. The compound may be administered as a single daily dose, divided over one or more daily doses, for example on a regimen of 1 to 4 times per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.BRIEF DESCRIPTION OF THE DRAWINGS

[0080] Figure l is a graph showing the expression of GLI1 transcript upon addition of Compound 1 relative to change in expression levels when treated with vehicle (DMSO), in two control cell lines 1 and 2, and in two cell lines issued from patients with mutations m BBSl or BBS10.

[0081] Figure 2 is a graph showing the expression of PTCH transcript upon addition of Compound 1 relative to change in expression levels when treated with vehicle (DMSO), in two control cell lines 1 and 2, and in two cell lines issued from patients with mutations m BBSl or BBS10.EXAMPLES

[0082] The present invention is further illustrated by the following examples.

[0083] Abbreviations:CyHex: cyclohexyl;DCM: dichloromethane;DIPEA: diisopropylethylamine;DMF: dimethylformamide; eq.: equivalent;EtOAc: ethyl acetate;MeOH: methanol;MW: microwave; r.t. : room temperature;TLC: thin layer chromatography.Example 1 : Synthesis of compound 1Intermediate A: (£)-3-(3-aminophenyl)acrylonitrile

[0084] In a MW vial, 3-iodoaniline (200 mg, 0.913 mmol), acrylonitrile (145 mg, 2.74 mmol, 3 eq.) , palladium acetate (10 mg, 0.0457 mmol, 5 mol%) and tri(2-tolyl)phosphine (28 mg, 0.0913 mmol, 10 mol%) were charged and the mixture was flushed with argon for 5 min. Degassed DMF (1.8 mL, [C] = 0.5M) followed by triethylamine (0.38 mL, 2.74 mmol, 3 eq.) were added and the resulting mixture was stirred at 95 °C for 20h. After cooling to r.t., the mixture was filtered on a Whatman filter and the mixture was poured into water / EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with aqueous saturated NH4Q, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC on silica gel (CyHex. / EtOAc, 7 / 3) to give the tittle compound Intermediate A, 88mg (53% yield) as a yellow solid. The product was obtained as a 4 / 1 mixture of trans / cis isomers respectively. HPLC / MS (acid): m / z (ES+) = 145.1 (M+H)+.Intermediate C: (£')-A-(3-(2-cyanovinyl)phenyl)-3',4-difluoro-[l,l'-biphenyl]-3- carboxamide

[0085] To a stirred solution of Intermediate A, (£)-3-(3-aminophenyl)acrylonitrile (40 mg, 0.277 mmol), and Intermediate B, 3',4-difluoro-[l,T-biphenyl]-3-carboxylic acid (78 mg, 0.333 mmol, 1.2 eq.) in DMF (1.4 mL, [C] = 0.2M) were added DIPEA (0.12 mL, 0.694 mmol, 2.5 eq.), l,(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (64 mg, 0.333 mmol, 1.2 eq.) and 2-hydroxypyridine 1-oxide (34 mg, 0.305 mmol, 1.1 eq.) at r.t. and the resulting mixture was stirred at r.t. for 20h and then at 60 °C for 4h. The mixture was poured into water and extracted with EtOAc (2x). The combined organic extracts were washed with aqueous IN HC1, brine, dried (Na2SC>4), filtered and concentrated. The residue was purified by preparative TLC on silica gel (CyHex. / EtOAc, 7 / 3) to give the title compound Intermediate C, 74 mg (74% yield) as a light yellow oil. The product was obtained as a 4 / 1 mixture of trans / cis isomers respectively. HPLC / MS (acid): m / z (ES+) = 361.1 (M+H)+.Compound 1: ( / :)- \-(3-(2-(2 / / -tetrazol-5-yl)vinyl)phenyl)-3'.4-dinuoro-| 1.1 '- biphenyl]-3-carboxamide

[0086] A MW vial was charged with Intermediate C, (£)-7V-(3-(2-cyanovinyl)phenyl)- 3',4-difluoro-[l,T-biphenyl]-3-carboxamide (74 mg, 0.205 mmol) and flushed with argon for 5 min. DMF (1.4 mL, [C] = 0.15M) followed by ammonium chloride (16 mg, 0.308mmol, 1.5 eq.) and sodium azide (20 mg, 0.308 mmol, 1.5 eq.) were added at r.t. and the resulting mixture was stirred at 110 °C for 20h. The mixture was poured into aqueous saturated NaHCCh and the aqueous layer was extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative HPLC (basic conditions) to give 8 mg as an orange oil. This fraction was purified by preparative TLC on silica gel (DCM / MeOH, 95 / 5) to give the title compound, Compound 1, 5 mg (91% purity, 4% yield) as a white solid. HPLC / MS (acid): m / z (ES+) = 404.2 (M+H)+; 1H-NMR (400 MHz, Methanol-d4) 58.10 (s, 1H), 8.03 (m, 1H), 7.86 (m, 1H), 7.78 - 7.66 (m, 2H), 7.55 -7.35 (m, 6H), 7.27 (d, J = 16.5 Hz, 1H), 7.13 (m, 1H).2: Expression of GLI1 and PTCH

[0087] This assay aims at evidencing the ability of Compound 1 to activate Hedgehog signaling, especially by increasing expression levels of GLIlo PTCH transcripts.Material and Methods

[0088] Primary derived fibroblasts from healthy controls (control cell lines 1 and 2) and from individuals with mutations in BBS1 and BBS10 genes were obtained by skin biopsy, then cultured in Dulbecco’s modified Eagle’s medium (DMEM) with Glutamax (Gibco) supplemented with 10% fetal calf serum (FCS) and 1% penicillin-streptomycin (PS) (Gibco). To induce sonic hedgehog (SHH) pathway stimulation, the fibroblasts were stimulated with smoothened agonist (SAG) at 100 nM for 48 h, with or without serum starvation (0.1% FCS). During the 48h incubation step, cells were exposed to Compound 1 at a final concentration of 0.2 pM or to DMSO vehicle only. RNA was extracted via QiaShredder and RNeasy Minikit (Qiagen) kits, RNA concentration was evaluated by spectrophotometry. cDNA was synthesized via an iScript cDNA Synthesis Kit according to the manufacturer’s instructions with 500 ng of RNA. Quantitative realtime PCR was carried out with an iQ SYBR Green Supermix in a Bio-Rad CFX96 / 384 Real-Time System in triplicate.

[0089] The normalized fold expression of the target gene (GLI1 and PTCH) was calculated using the comparative cycle threshold (Ct) method (2-AACt method) by normalizing target messenger RNA (mRNA) Ct to those for GAPDH reference gene, then relative expression was normalized to uninduced condition and vehicle-treated (DMSO) using CFX Manager Software and Microsoft Excel calculations.Results and conclusions

[0090] GLI1 Expression: When compared with unstimulated cells (reference expression = 1), in cells treated with Hh agonist SAG and DMSO only, the expression of GLI1 transcript was increased 15.0-fold and 10.5-fold in Control 1 and Control 2 cell lines, respectively (n=2); in BBS1 and BBS10 patient cells, DMSO treated cells yielded only a 2.5-fold increase and 2.4-fold, respectively (n=2). When BBSland BBS10 patient cells (stimulated with SAG), were additionally treated with Compound 1, expression of GLI1 was further to increased 9.9-fold and 9.4-fold, respectively (n=2). Results are shown in Figure 1.

[0091] PTCH Expression: When compared with unstimulated cells (reference expression =1), in cells treated with Hh agonist SAG and DMSO only, the expression of PTCH transcript was increased 6.0-fold and 6.6-fold in Control 1 and Control 2 cell lines, respectively (n=2); in BBS1 and BBS10 patient cells, DMSO treated cells yielded only a 2.0-fold increase and 2.3-fold, respectively (n=2). When BBS1 and BBS10 patient cells (stimulated with SAG), were additionally treated with Compound 1, expression of PTCH was further to increased 5.0-fold and 5.1-fold, respectively (n=2). Results are shown in Figure 2.

Claims

CLAIMS1. A compound which is (£)-A-(3-(2-(2#-tetrazol-5-yl)vinyl)phenyl)-3',4-difluoro- [1, l'-biphenyl]-3 -carboxamide, or a pharmaceutically acceptable salt and / or solvate thereof.

2. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt and / or solvate thereof, and at least one pharmaceutically acceptable carrier.

3. A compound according to claim 1, or a pharmaceutically acceptable salt and / or solvate thereof, for use as a medicament.

4. A compound according to claim 1, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of a neurodevelopmental disorder, a neurosensory disorder, or a weight control disorder, in a subject in need thereof.

5. The compound for use according to claim 4, wherein the disorder is selected from cerebral palsy, epilepsy, X fragile syndrome, Down syndrome, Rett syndrome, tuberous sclerosis complex, autism, Angelman syndrome, trisomy 13 (Patau syndrome), trisomy 18 (Edwards syndrome), 5p deletion syndrome (cri du chat syndrome), Lesch-Nyhan syndrome, mucopolysaccharidoses, adrenoleukodystrophy, Apert syndrome, Cornelia de Lange syndrome, Rubinstein- Taybi syndrome, Smith-Magenis syndrome, Coffin-Lowry syndrome, dysfunctions of central control of satiety, hyperphagia, Bardet-Biedl syndrome (BBS), Prader- Willi syndrome (PWS), early-onset forms of glaucoma, and genetic obesity conditions.

6. The compound for use according to claim 5, wherein the genetic obesity conditions are selected from pro-opiomelanocortin (POMC) deficiency, proprotein convertase subtilisin / kexin type 1 (PCSK1) deficiency, leptin receptor (LEPR) deficiency, monogenic obesity MOI, CHOPS syndrome, WAGR syndrome, pseudohypoparathyroidism type la (PHPla), Schaaf-Yang syndrome, Bbrjeson- Forssman-Lehmann syndrome, Carpenter syndrome, Chung-Jansen syndrome,Cohen syndrome, 2q37 deletion syndrome, Smith-Magenis syndrome, Kabuki syndrome, MEHMO syndrome, MORM syndrome, short bowel intestinal dysmotility, and diarrhea syndrome (SBIDDS).

7. The compound for use according to claims 4 or claim 5, wherein the disorder is hyperphagia.

8. The compound for use according to claim 7, wherein the subject treated for hyperphagia suffers from Bardet-Biedl syndrome (BBS), Rett syndrome, and / or Prader-Willi syndrome (PWS).

9. The compound for use according to claims 4 or claim 5, wherein the disorder is early-onset forms of glaucoma affecting children and young adults or adult on-set glaucoma.

10. The compound according to claim 9, wherein the subject treated for early-onset forms of glaucoma affecting children and young adults, suffers from juvenile openangle glaucoma, anterior segment dysgenesis, congenital glaucoma, and / or familial normal-tension glaucoma.

11. The compound according to claim 9, wherein the subject treated for adult on-set glaucoma, suffers from primary open-angle glaucoma (POAG), adult-onset normal tension glaucoma (NTG), pseudoexfoliation glaucoma, and / or primary angleclosure glaucoma.

12. The compound for use according to any one of claims 4 to 11, wherein the disorder results from deletion, mutation, loss of function, or a combination thereof, of one or more of the following genes: POMC, PCSK1, MC4R, LEP, LEPR, MYT1L, MRAP2, BDNF, SIM1, ADCY3, NTRK2, SH2B1, MAGEL2, HDAC4, TUB, KSR2, SRC1, TRAPPC9, MYOC, PITX2, FOXCI, PAX6, CY1B1, LTBP2, OPTN, TBK1, FNDC3B, COL8A2, CHSY1, HS3ST3B1 / PMP22, ZNF469, RXRA / COL5A1, FGF9 / SGCG, LCN12 / PTGDS, CWC27 / ADAMTS6, TGP1, GPR15, F0X01, LRRK1, USP37, AKAP13, SKYL1 / LTBP3, CDC7 / TGFBR3, SIX1, SIX6, CAV1, CAV2, IMC01, GAS7, CDKN2BAS, 8q22, DCLK1, and ATOH7.

13. A compound according to claim 1, or a pharmaceutically acceptable salt and / or solvate thereof, for use in increasing Hedgehog signaling, in a subject in need thereof.

14. The compound for use according to claim 13, wherein Hedgehog signaling is increased by increasing levels of GLI1 and / or PTCH.

15. A process of manufacturing a compound according to claim 1, comprising the formation of the tetrazole moiety by addition of an azide salt to (E)-N-(3-(2- cyanovinyl)phenyl)-3',4-difluoro-[l,r-biphenyl]-3-carboxamide.

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