1,3-Substituted cyclobutyl derivatives and their uses

Abstract

Compounds and pharmaceutical compositions useful for treating diseases or disorders mediated by the TRPV1 receptor are provided herein. The present invention provides for the treatment of ocular diseases or disorders to a subject in need thereof by administering to the subject a therapeutically effective amount of a compound represented by formula (I) [Formula 1] TIFF2024510778000541.tif64170 Also provided are methods of administering a compound of or a pharmaceutical composition described herein.

Description

[Technical Field]

[0001] The present disclosure relates to 1,3-substituted cyclobutyl compounds and pharmaceutical compositions and their use in antagonizing TRPV1 activity and treating ocular diseases or disorders (e.g., ocular surface disorders), such as dry eye disease. [Background technology]

[0002] Transient receptor potential cation channel, subfamily V, member 1 (TRPV1), also known as capsaicin receptor and vanilloid receptor 1 (VR1), is an ion channel belonging to the transient receptor potential (TRP) family. TRPV1 is a nonselective cation channel that can be activated by heat, protons, and vanilloid compounds (e.g., capsaicin). Activation of TRPV1 results in the release of neurotransmitters, causing pain and inflammation. TRPV1 antagonists that can reduce inflammation and pain caused by TRPV1 activation fall into two major categories: those that inhibit both capsaicin and proton activation, and those that inhibit capsaicin but not proton activation. Several such TRPV1 antagonists are known, as described by Roberts and Connor (2006, Recent Patents on CNS Drug Discovery 1:65-76). As discussed herein, TRPV1 antagonists can effectively reduce ocular pain and reduce dry eye symptoms without producing an anesthetic effect on the ocular surface.

[0003] The role of TRPV1 has been established in pain models. TRPV1 has also been implicated in other diseases where symptoms are potentially driven, in whole or in part, by neuronal hypersensitivity or hyperactivity due to its role in sensory signaling in peripheral nerves. Such diseases include asthma, rhinitis, cough, overactive bladder, reflux esophagitis, irritable bowel syndrome, and migraine. TRPV1 has been suggested to play a role in the afferent sensory loop of the cough reflex and increased cough sensitivity seen in these diseases (Grace, Dubuis, Birrell, and Belvisi (2012), TRP Channel Antagonists as Potential Antitussives, Lung 190:11-15; and Gu and Lee (2011), Airway irritation and cough evoked by acid: from human to ion channel, Current Opinion in Pharmacology 11:238-247). TRPV1 has been implicated in the inflammatory response occurring in dry eye syndrome (Pan, Wang, Yang, Zhang, & Reinach (2010), TRPV1 Activation is Required for Hypertonicity Stimulated Inflammatory Cytokine Release in Human Corneal Epithelial Cells, Manuscript IOVS, 10-5801). TRPV1 has also been suggested to play a role in metabolic diseases such as diabetes and obesity (Motter A L & Ahern GP (2008) FEBS Letters 582, 2257-2262; Suri & Szallasi A (2007), The emerging role of TRPV1 in diabetes and obesity, Trends in Pharm Sci, Rasavi et al (2006) Cell 127, 1123-1135).

[0004] The ocular surface, especially the cornea, is densely innervated by sensory nerves. The activity of corneal nerves can be altered by several factors, such as osmotic stress and tissue damage, and inflammation caused by nerve injury on the ocular surface. Ocular surface symptoms are an alarm system that indicates an imbalanced ocular surface homeostasis, which leads to chronic ocular surface pain due to continuous stimulation, which causes ocular surface stress and sensitization.

[0005] Patients suffering from ocular surface pain, especially chronic ocular surface pain, experience a significant decrease in quality of life. To date, efficacy studies have linked the burden of severe chronic ocular surface pain to moderate-to-severe angina, dialysis, or disabling hip fractures. Severe chronic ocular surface pain has also been associated with depression and suicidal ideation. In many patients, ocular surface pain remains unresolved despite treatment of the underlying pathology (e.g., recent trauma or surgery, infection, or inflammation). Furthermore, treatments used for short-term management of ocular pain (e.g., nonsteroidal anti-inflammatory drugs, steroids) cannot be used for long-term treatment. Thus, there remains a long-standing and unmet need for safe and effective treatments for ocular surface pain, especially chronic ocular surface pain, when no other options exist to improve patients' quality of life or complement current treatments.

[0006] Other approaches to treating ocular pain, such as topical application of anesthetics, nonsteroidal anti-inflammatory drugs (NSAIDs), or topical corticosteroids to the eye, are undesirable due to the side effects of chronic administration. Ocular pain manifests in several conditions, including dry eye disease, Sjögren's syndrome, lacrimal gland dysfunction due to autoimmune diseases such as Sjögren's syndrome or systemic lupus erythematosus, organ transplants such as graft-versus-host disease, or simply as a result of aging, including corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface diseases, blepharitis, meibomianitis, meibomian gland dysfunction, glaucoma, conjunctivochalasis, keratopathy, corneal infections, and the like. More effective treatments for addressing ocular pain in such patients are needed. Summary of the Invention

[0007] The present disclosure provides compounds for treating or alleviating pain generally, particularly ocular surface pain.

[0008] The present disclosure relates to compounds that are effective as TRPV1 antagonists, pharmaceutically acceptable salts thereof, compositions thereof, and their use in the treatment of the conditions and purposes detailed herein.

[0009] In a first aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula, W is C(=O) or absent; X is N or N-oxide; Y is N or CH; Z is NH, O or S; A is CH2 or absent; L is a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S; C6-C 10 aryl and 6-10 membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O and S; R A each occurrence independently represents halo, -CN, C1-C6 haloalkyl, C1-C6 alkyl, SF5, C3-C6 cycloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, 4-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O and S, -(CH2) p -NR 3 R 4 and —C(═O)—O—(C1-C6 alkyl), C3-C6 cycloalkyl and 4- to 6-membered heterocyclyl are each 0 to 4 R A1 are each independently substituted with; R A1is independently selected at each occurrence from halo and C1-C6 haloalkyl; R 1 is independently selected at each occurrence from hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, halo, C1-C6 haloalkyl, and NR 3 R 4 is selected from C1-C6 alkyl and C1-C6 haloalkyl are each 0 to 4 R 1a are each independently substituted with; R 1a represents independently at each occurrence hydroxyl, NR 3 R 4 and —C(═O)—OH; R 2 is selected from hydrogen and C1-C6 alkyl; R 3 is independently selected at each occurrence from hydrogen and C1-C6 alkyl; R 4 is independently expressed as -SO2R for each occurrence. 5 , hydrogen, —C(═O)—(C1-C6 alkyl) and C1-C6 alkyl; R 5 is independently selected at each occurrence from NH2 and C1-C6 alkyl; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3, 4 or 5; p is 0, 1 or 2 or a pharmaceutically acceptable salt thereof.

[0010] In a second aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0011] In a third aspect, there is provided a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] In a further aspect, there is provided a method of treating or preventing a disease or disorder mediated by TRPV1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0013] In a further aspect, there is provided a method of treating an ocular disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein the ocular disease or disorder is mediated by TRPV1.

[0014] In a further aspect, there is provided a method of treating an ocular surface disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] In a further aspect, there is provided a method of treating ocular surface pain (e.g., corneal-induced pain) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0016] In a further aspect, there is provided a method of treating ocular hyperemia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0017] In a further aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of ocular surface pain (e.g., corneal induced pain).

[0018] In a further aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of ocular hyperemia.

[0019] In a further aspect, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of an ocular surface disorder.

[0020] In a further aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating an ocular disease or disorder mediated by TRPV1.

[0021] In a further aspect, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of an ocular disease or disorder mediated by TRPV1.

[0022] In a further aspect, there is provided a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. DETAILED DESCRIPTION OF THE INVENTION

[0023] The compounds disclosed herein are effective as TRPV1 antagonists.Without being bound by theory, it is believed that the disclosed compounds can treat the disorders associated with TRPV1, including the treatment of the pain or discomfort associated with such disorders.In certain embodiments, pain is ocular surface pain, particularly corneal or ocular surface-induced pain and chronic ocular surface pain.

[0024] definition Unless otherwise specified, the terms "compounds of the disclosure," "compounds of this disclosure," or "compounds of this disclosure" refer to compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ii), (I-ii), exemplified compounds, salts thereof, particularly pharmaceutically acceptable salts thereof, hydrates, solvates, prodrugs, and all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitutions) and inherently formed moieties.

[0025] In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, e.g., C1-C 10Alkyl refers to an alkyl group or radical having 1 to 10 carbon atoms. Generally, for groups containing more than one subgroup, the last named group is the point of attachment of the group; for example, "alkylaryl" refers to a monovalent group of formula alkyl-aryl-, while "arylalkyl" refers to a monovalent group of formula aryl-alkyl-.

[0026] Furthermore, the use of a term indicating a monovalent radical where a divalent radical is appropriate should be construed to indicate the respective divalent radical, and vice versa. Unless otherwise specified, normal definitions of terms control, and normal stable valences are presumed and achieved in all formulas and groups. The articles "a" and "an" refer to one or more (e.g., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0027] The term "and / or" means "and" or "or," unless otherwise indicated.

[0028] The term "substituted" means that the specified group or moiety bears one or more suitable substituents, and the substituents may be attached to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl is bonded to or fused to the aryl and is connected to one atom of the aryl by sharing two or more common atoms.

[0029] As used herein, the term "C1-C6 alkyl" refers to a straight or branched hydrocarbon chain radical consisting exclusively of carbon and hydrogen atoms, containing no unsaturation, having 1 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond. The terms C1-C3 alkyl and C1-C5 alkyl shall be interpreted accordingly. Examples of C1-C6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (t-butyl), n-pentyl, and n-hexyl.

[0030] As used herein, the term "C1-C6 alkoxyl" refers to a group of the formula -OR a R refers to the group a is a C1-C6 alkyl group as generally defined above. Examples of C1-C6 alkoxyl include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, and hexoxy.

[0031] As used herein, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group as defined above substituted with one or more halo groups, as defined herein. Examples of C1-C6 haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoropropyl, 3,3-difluoropropyl, and 1-fluoromethyl-2-fluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobutan-2-yl.

[0032] As used herein, the term "C1-C6 haloalkoxyl" refers to a C1-C6 alkoxyl group, as defined herein, substituted with one or more halo groups. Examples of C1-C6 haloalkoxyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3,3-difluoropropoxy, and 3-dibromopropoxy. Preferably, one or more halo groups of the C1-C6 haloalkoxyl is fluoro. Preferably, the C1-C6 haloalkoxyl is selected from trifluoromethoxy, difluoromethoxy, fluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy and pentafluoroethoxy.

[0033] The term "halogen" or "halo" means fluorine, chlorine, bromine or iodine.

[0034] As used herein, the term "cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring containing 3 to 18 carbon atoms, where there are no delocalized pi-electrons (aromaticity) shared between ring carbons. The term "C3-C6 cycloalkyl" is to be interpreted accordingly. The term polycyclic encompasses bridged (e.g., norbornane), fused (e.g., decalin), and spirocyclic cycloalkyls. Preferably, cycloalkyl, e.g., C3-C6 cycloalkyl, is a monocyclic or bridged hydrocarbon group of 3 to 6 carbon atoms.

[0035] Examples of cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, bicyclo[1.1.1]pentanyl, and derivatives thereof.

[0036] Examples of C3-C6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0037] "Heterocyclyl" means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, and sulfur (O, N, and S), where there are no delocalized pi-electrons (aromaticity) shared between ring carbons or heteroatoms. The term "4- to 6-membered heterocyclyl" should be interpreted accordingly. The heterocyclyl ring structure may be substituted with one or more substituents. The substituents may themselves be optionally substituted. The heterocyclyl may be attached via a carbon atom or a heteroatom. The term polycyclic encompasses bridged, fused, and spirocyclic heterocyclyls.

[0038] Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl , oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl, imidazolidinyl, dihydroisoxazolinyl, pyrrolinyl, pyrazolinyl, oxazepinyl, dithiolanyl, homotropanyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl), oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl), and the like.

[0039] Examples of 4- to 6-membered heterocyclyl include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, dihydroisoxazolinyl, tetrahydropyranyl, morpholinyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl), and oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl).

[0040] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or polycyclic carbocyclic aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl (e.g., naphth-1-yl, naphth-2-yl), anthryl (e.g., anth-1-yl, anth-9-yl), phenanthryl (e.g., phenant-1-yl, phenant-9-yl), and the like. Aryl is also intended to include monocyclic, bicyclic, or polycyclic carbocyclic aromatic rings substituted with a carbocyclic aromatic ring. Representative examples are biphenyl (e.g., biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl), phenylnaphthyl (e.g., 1-phenylnaphth-2-yl, 2-phenylnaphth-1-yl), and the like. Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic rings having at least one unsaturated moiety (e.g., a benzo moiety). Representative examples are indanyl (e.g., indan-1-yl, indan-5-yl), indenyl (e.g., inden-1-yl, inden-5-yl), 1,2,3,4-tetrahydronaphthyl (e.g., 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-6-yl), 1,2-dihydronaphthyl (e.g., 1,2-dihydronaphth-1-yl, 1,2-dihydronaphth-4-yl, 1,2-dihydronaphth-6-yl), fluorenyl (e.g., fluoren-1-yl, fluoren-4-yl, fluoren-9-yl), and the like. Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or two bridges. Representative examples are benzonorbornyl (e.g., benzonorborn-3-yl, benzonorborn-6-yl), 1,4-ethano-1,2,3,4-tetrahydronaptyl (e.g., 1,4-ethano-1,2,3,4-tetrahydronapt-2-yl, 1,4-ethano-1,2,3,4-tetrahydronapt-10-yl), and the like. 10 "Aryl" shall be construed accordingly.

[0041] Examples of aryl include, but are not limited to, indenyl (e.g., inden-1-yl, inden-5-yl), phenyl (C6H5), naphthyl (C 10 H7) (e.g., naphth-1-yl, naphth-2-yl), indanyl (e.g., indan-1-yl, indan-5-yl), and tetrahydronaphthalenyl (e.g., 1,2,3,4-tetrahydronaphthalenyl). 10 Aryl is interpreted accordingly. C6-C 10 Examples of aryl include monocyclic or bicyclic carbocyclic aromatic rings.

[0042] C6~C 10 Examples of aryl include, but are not limited to, phenyl and naphthyl. In one embodiment, C6-C 10 Aryl is phenyl.

[0043] As used herein, the term "heteroaryl" is intended to include monocyclic heteroaromatic rings. Representative examples are pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl (e.g., 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, thiadiazinyl, azepinyl, azesinyl, and the like.

[0044] Heteroaryl is also intended to include bicyclic heteroaromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzopyranyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, cinnolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, thiazolopyridinyl, thiazolopyrimidinyl, imidazothiazolyl, triazolopyridinyl, triazolopyrimidinyl, and the like.

[0045] Heteroaryl is also intended to include polycyclic heteroaromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are carbazolyl, phenoxazinyl, phenazinyl, acridinyl, phenothiazinyl, carbolinyl, phenanthrolinyl, and the like.

[0046] The heteroaryl ring structure may be substituted with one or more substituents, which may themselves be optionally substituted. The heteroaryl ring may be attached via a carbon atom or a heteroatom.

[0047] The term "5- to 10-membered heteroaryl" shall be construed accordingly.

[0048] Examples of 5-10 membered heteroaryls include, but are not limited to, indolyl, imidazopyridyl, isoquinolinyl, benzoxazolonyl, pyridinyl, pyrimidinyl, pyridinonyl, benzotriazolyl, pyridazinyl, pyrazolotriazinyl, indazolyl, benzimidazolyl, quinolinyl, triazolyl (e.g., 1,2,4-triazolyl), pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrrolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4 ... Examples of thiadiazolyl include thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), imidazolyl, pyrrolopyridinyl, tetrahydroindazolyl, quinoxalinyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), pyrazinyl, oxazolopyridinyl, pyrazolopyrimidinyl, benzoxazolyl, indolinyl, isoxazolopyridinyl, dihydropyridoxazinyl, and tetrazolyl.

[0049] The term "partially saturated heterocyclyl" is intended to include partially saturated monocyclic, bicyclic, or polycyclic heterocyclyl containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are imidazolinyl, indolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzopyranyl, dihydropyridoxazinyl, dihydrobenzodioxinyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxinyl), benzodioxolyl (e.g., benzo[d][1,3]dioxole), dihydrobenzoxazinyl (e.g., 3,4-dihydro-2H-benzo[b][1,4]oxazine), tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydroimidazo[4,5-c]pyridyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and the like.

[0050] The term "6- to 10-membered partially saturated heterocyclyl" shall be construed accordingly.

[0051] Examples of 6- to 10-membered partially saturated heterocyclyl include, but are not limited to, indolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzopyranyl, dihydropyridoxazinyl, dihydrobenzodioxinyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxinyl), benzodioxolyl (e.g., benzo[d][1,3]dioxole), dihydrobenzoxazinyl (e.g., 3,4-dihydro-2H-benzo[b][1,4]oxazine), tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydroimidazo[4,5-c]pyridyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and tetrahydroquinoxalinyl.

[0052] "TRPV1 receptor" refers to transient receptor potential vanilloid 1, which has been characterized by molecular cloning and pharmacology. See, e.g., Caterina MJ, et al., Nature 1997;389:816-824. TRPV1 receptor activity is measured as described in WO 2005 / 120510, which is incorporated by reference in its entirety.

[0053] The terms "TRPV1 antagonist" and "TRPV1 inhibitor" include any agent that can inhibit the activity of TRPV1 (eg, block a TRPV1-mediated signaling cascade).

[0054] The term "effective amount" of a compound described herein refers to that amount of a therapeutic compound that is necessary or sufficient to perform its intended function in a mammal. The effective amount of a therapeutic compound may vary depending on factors such as the amount of causative agent already present in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compound of the present disclosure to treat a condition in which TRPV1 plays a role.

[0055] The phrase "ophthalmically compatible" refers to formulations, polymers and other materials and / or dosage forms that are suitable for use in contact with the ocular tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems. As used herein, "ocular surface" refers to the external surface of the eye, anatomically including the cornea (with its epithelium, Bowman's layer, corneal stroma, Descemet's membrane, endothelium), conjunctiva, conjunctival sac, and corneoscleral junction, i.e., limbus.

[0056] As used herein, the terms "treat," "treating," or "treatment," in reference to a disease or disorder, in some embodiments, refer to ameliorating the disease or disorder (i.e., delaying or arresting or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" refers to alleviating or ameliorating at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treat," "treating," or "treatment" refers to modulating the disease or disorder physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat," "treating," or "treatment" refers to preventing or delaying the onset, development, or progression of a disease or disorder or a symptom thereof.

[0057] As used herein, the term "subject" or "patient" refers to humans and non-human mammals, including, but not limited to, primates, rabbits, pigs, horses, dogs, cats, sheep, and cattle. In certain embodiments, a subject or patient is a human. In some embodiments, the term "patient" or "subject" refers to a human suffering from a condition (i.e., a disease or disorder) described herein and who would benefit from treatment. As used herein, a subject is "in need of" treatment if such a subject would benefit biologically, medically, or in quality of life from such treatment. In certain embodiments, a subject is an adult human at least about 18 years of age. In certain embodiments, a subject is an adult human between about 18 and about 75 years of age. In some embodiments, a subject is a human child up to about 18 years of age.

[0058] As used herein, "ocular surface" refers to the external surface of the eye that anatomically includes the cornea (with its epithelium, Bowman's layer, corneal stroma, Descemet's membrane, and endothelium), conjunctiva, conjunctival sac, and the corneoscleral junction, i.e., the limbus.

[0059] As used herein, administration to the eye includes administration to all parts of the eye, including all parts of the ocular surface, such as the cornea, conjunctiva, conjunctival sac, and the corneoscleral junction, i.e., the limbus.

[0060] As used herein, "pain" refers to a constant or intermittent sensation of actual pain, described as, but not limited to, stabbing, dull, sharp, or aching. Pain may also refer to similar related descriptors, such as, but not limited to, discomfort, burning, stinging, gritty, foreign body sensation, dryness, roughness, tiredness, itching, soreness, sensitivity to light, etc.

[0061] As used herein, "ocular surface pain" refers to pain on the surface of the eye, for example, on the cornea. Ocular pain can be nociceptive pain, which is generally caused by external physical or chemical harmful stimuli, such as corneal surgery, inflammation, or other damage to the corneal surface. Ocular pain can also be caused by neuropathic pain, which occurs due to direct damage to the body's neurons and can send pain messages to the central nervous system and brain regardless of the presence of noxious stimuli. As used herein, "ocular surface pain" includes both nociceptive pain and neuropathic pain.

[0062] Ocular surface pain can be measured using different scales. For example, the "visual analog scale" (VAS) is a measure of pain intensity, and subjects typically mark the point on the scale that corresponds to their level of pain. Pain is marked on a continuum from "no pain" (score of 0) to "the worst pain possible" or "the worst pain imaginable" (score of 100). See, for example, Hawker, et al., Arthritis Care & Research 63(11), pp. S240-S252 (November 2011). There are several other well-designed pain scales that can be used to assist in assessing pain intensity. Numeric rating scales (NRS) are often used, in which subjects use a number to rate pain. The number scale can be 1 to 10 or 1 to 100. The Wong-Baker FACES pain scale involves matching a picture and a number for pain rating. It can be used in children over 3 years of age and in adults. The six faces display different expressions ranging from happy to extremely unhappy. Each is matched with a numerical rating from 0 (smiling) to 10 (crying). The verbal pain intensity scale uses words on a scale to rate pain intensity: no pain / mild pain / moderate pain / severe pain / very severe pain / worst possible pain.

[0063] The Ocular Sensation Scale is a specific pain scale developed to measure the severity of ocular pain. See Caudle LE et al., Optom Vis Sci. 2007 Aug;84(8):752-62. In this scale, pain, discomfort, or light sensitivity is typically measured by five categories labeled "extreme," "severe," "moderate," "mild," or "none."

[0064] The Ocular Pain Assessment Survey (OPAS) is a quantitative, multidimensional questionnaire specifically designed to assess corneal and ocular surface pain and quality of life (QoL) changes. The OPAS assesses pain intensity, frequency of ocular and non-ocular pain, QoL changes, exacerbating factors, associated factors, and quantitative symptomatic relief, allowing for treatment response monitoring. See Qazi et al., Ophthalmology July 123(7):1458-1468 (2016).

[0065] As used herein, "ocular hyperemia" refers to the redness of the ocular surface. Ocular hyperemia can be a clinical marker for inflammation and / or irritation of the eye. Ocular hyperemia can be measured using a visual scale, such as the McMonnies scale with values ​​of 0 to 5, or any relevant method, based on standard photographs or photographs taken under standardized lighting conditions that can be digitally analyzed in a semi-automated or fully automated manner for reading.

[0066] The term "ocular surface disease" or "ocular surface disorder" encompasses diseases and related conditions resulting from a variety of abnormalities, including abnormal eyelid anatomy or function, abnormal or altered tear production or composition, and associated asymptomatic or clinical signs. Many diseases can result in ocular surface disorders. Patients with ocular surface disorders may exhibit clinical signs common to several diseases, including, but not limited to, chronic punctate keratopathy, filamentous keratopathy, recurrent corneal erosions, bacterial conjunctivitis, culture-negative conjunctivitis, cicatricial (scarring) conjunctivitis, persistent corneal epithelial defects, infectious keratitis, corneal melt, and ocular surface failure. The most common ocular surface disorders result from tear film abnormalities and / or meibomian gland dysfunction or blepharitis.

[0067] As used herein, the term "about" refers to a set value + / - 10% of the particular value.

[0068] As used herein, a pharmaceutical composition is a composition suitable for pharmaceutical use. A composition suitable for pharmaceutical use may be sterile, homogeneous, and / or isotonic. In certain embodiments, the pharmaceutical composition may be prepared in aqueous form, for example, in a pre-filled syringe or other single-dose or multi-dose container. In certain embodiments of the present invention, the pharmaceutical composition is compatible with the eye and is suitable for administration to the eye of a human subject, for example, by topical or other known methods of delivery. These methods include, but are not limited to, incorporating the compounds disclosed herein into an intraocular insert or ocular membrane that dissolves and releases the compound over an extended period of time.

[0069] As used herein, in the context of this disclosure (and particularly in the context of the claims), the terms "a," "an," "the," and similar terms are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0070] Various enumerated embodiments of the present disclosure are described herein, and it is recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure.

[0071] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, and includes, for example, suitable excipients, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, additives, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, e.g., Remington The Science and Practice of Pharmacy, 22nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0072] Enumerated Embodiments Embodiment 1. Formula (I) [ka] (In the formula, W is C(=O) or absent; X is N or N-oxide; Y is N or CH; Z is NH, O or S; A is CH2 or absent; L is a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S; C6-C 10 aryl and 6-10 membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O and S; R A each occurrence independently represents halo, -CN, C1-C6 haloalkyl, C1-C6 alkyl, SF5, C3-C6 cycloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, 4-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O and S, -(CH2) p -NR 3 R 4 and —C(═O)—O—(C1-C6 alkyl), C3-C6 cycloalkyl and 4- to 6-membered heterocyclyl are each 0 to 4 R A1 are each independently substituted with; R A1 is independently selected at each occurrence from halo and C1-C6 haloalkyl; R 1 is independently selected at each occurrence from hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, halo, C1-C6 haloalkyl, and NR 3 R 4 is selected from C1-C6 alkyl and C1-C6 haloalkyl are each 0 to 4 R 1a are each independently substituted with; R 1a represents independently at each occurrence hydroxyl, NR 3 R 4 and —C(═O)—OH; R 2 is selected from hydrogen and C1-C6 alkyl; R 3 is independently selected at each occurrence from hydrogen and C1-C6 alkyl; R 4 is independently expressed as -SO2R for each occurrence. 5 , hydrogen, —C(═O)—(C1-C6 alkyl) and C1-C6 alkyl; R 5 is independently selected at each occurrence from NH2 and C1-C6 alkyl; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3, 4 or 5; p is 0, 1 or 2 or a pharmaceutically acceptable salt thereof.

[0073] Embodiment 2. W is C(=O) or absent; X is N or N-oxide; Y is CH; Z is NH, O or S; A is CH2 or absent; L is a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S; C6-C 10 aryl and 6-10 membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O and S; R A each occurrence independently represents halo, -CN, C1-C6 haloalkyl, C1-C6 alkyl, SF5, C3-C6 cycloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O and S, and -(CH2) p -NR 3 R 4 is selected from C3-C6 cycloalkyl and 4- to 6-membered heterocyclyl are each 0 to 4 R A1 are each independently substituted with; R A1 is independently selected at each occurrence from halo and C1-C6 haloalkyl; R 1 is independently selected at each occurrence from C1-C6 alkyl, halo, C1-C6 haloalkyl, and NR 3 R 4 is selected from C1-C6 alkyl and C1-C6 haloalkyl are each 0 to 4 R 1a are each independently substituted with; R 1a represents independently at each occurrence hydroxyl, NR 3 R 4 and —C(═O)—OH; R 2 is selected from hydrogen and C1-C6 alkyl; R 3 is independently selected at each occurrence from hydrogen and C1-C6 alkyl; R 4 is independently expressed as -SO2R for each occurrence. 5 , hydrogen, —C(═O)—(C1-C6 alkyl) and C1-C6 alkyl; R 5is independently selected at each occurrence from NH2 and C1-C6 alkyl; n is 0, 1, 2, 3, 4; m is 0, 1, 2, 3, 4 or 5; The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0074] Embodiment 3. W is C(=O) or absent; X is N or N-oxide; Y is CH; Z is NH, O or S; A is CH2 or absent; L is a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S; C6-C 10 aryl and 6-10 membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O and S; R A each occurrence independently represents halo, -CN, C1-C6 haloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O and S, and -(CH2) p -NR 3 R 4 is selected from C3-C6 cycloalkyl and 4- to 6-membered heterocyclyl are each 0 to 4 R A1 are each independently substituted with; R A1 is independently selected at each occurrence from halo and C1-C6 haloalkyl; R 1 is independently selected at each occurrence from C1-C6 alkyl, halo, C1-C6 haloalkyl, and NH2; C1-C6 alkyl and C1-C6 haloalkyl are each 0 to 4 R 1a are each independently substituted with; R 1a represents independently at each occurrence hydroxyl, NR3 R 4 and —C(═O)—OH; R 2 is selected from hydrogen and C1-C3 alkyl; R 3 is independently selected at each occurrence from hydrogen and C1-C6 alkyl; R 4 is independently expressed as -SO2R for each occurrence. 5 , hydrogen, —C(═O)—(C1-C6 alkyl) and C1-C6 alkyl; R 5 is independently selected at each occurrence from NH2 and C1-C6 alkyl; n is 0, 1, 2 or 3; m is 0, 1, 2, 3 or 4; The compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0075] Embodiment 4. W is absent; X is N; Y is CH; Z is NH, O or S; A is non-existence; L is a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S; C6-C 10 aryl and 6-10 membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O and S; R A each occurrence independently represents halo, -CN, C1-C6 haloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxyl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O and S, and -(CH2) p -NR 3 R 4 is selected from C3-C6 cycloalkyl and 4- to 6-membered heterocyclyl are each 0 to 4 R A1 are each independently substituted with; RA1 is independently selected at each occurrence from halo and C1-C6 haloalkyl; R 1 is independently selected at each occurrence from C1-C6 alkyl, halo, and C1-C6 haloalkyl; C1-C6 alkyl and C1-C6 haloalkyl are each 0 to 4 R 1a are each independently substituted with; R 1a represents independently at each occurrence hydroxyl, NR 3 R 4 and —C(═O)—OH; R 2 is selected from hydrogen and C1-C3 alkyl; R 3 is independently selected at each occurrence from hydrogen and C1-C6 alkyl; R 4 is independently expressed as -SO2R for each occurrence. 5 , hydrogen, —C(═O)—(C1-C6 alkyl) and C1-C6 alkyl; R 5 is independently selected at each occurrence from NH2 and C1-C6 alkyl; n is 0, 1, 2 or 3; m is 0, 1, 2, 3 or 4; The compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

[0076] Embodiment 5. R A is selected from fluoro, —CN, —CF3, —CHF2, —CHFCH2F, —CH2F, C1-C4 alkyl, C3-C6 cycloalkyl, —OCF3, —OCHF2, —OCH2F, —OCHFCH2F and 4-membered heterocyclyl having one oxygen atom; C3-C6 cycloalkyl and 4-membered O-containing heterocyclyl are each 0 to 2 R A1 are each independently substituted with R A1is independently selected at each occurrence from fluoro and C1-C6 fluoroalkyl; or a pharmaceutically acceptable salt thereof.

[0077] Embodiment 6. R A is selected from fluoro, —CN, —CF3, —CHF2, —CHFCH2F, —CH2F, C1-C4 alkyl, C3-C6 cycloalkyl, —OCF3, —OCHF2, —OCH2F, —OCHFCH2F and 4-membered heterocyclyl having one oxygen atom; C3-C6 cycloalkyl and 4-membered O-containing heterocyclyl are each 0 to 2 R A1 are each independently substituted with R A1 is independently selected at each occurrence from fluoro and C1-C6 fluoroalkyl; or a pharmaceutically acceptable salt thereof.

[0078] Embodiment 7. R A is selected from fluoro, —CN, —CF 3 , —CHF 2 , —CHFCH 2 F, and —CH 2 F; or a pharmaceutically acceptable salt thereof.

[0079] Embodiment 8. L is C6 to C 10 aryl, 6-10 membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O and S, and [ka] 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O and S; C6~C 10 Aryl, 6- to 10-membered partially saturated heterocyclyl, and 5- to 10-membered heteroaryl are each 0 to 4 R A are each independently substituted with R AThe compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, as defined by any one of embodiments 1 to 7.

[0080] Embodiment 9. L is C6 to C 10 aryl, 6-10 membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O and S, and [ka] 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O and S; C6~C 10 Aryl and 6- to 10-membered partially saturated heterocyclyl are substituted with 0 to 2 R A are each independently substituted with R A is a compound according to any one of embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, as defined by any one of embodiments 1 to 8.

[0081] Embodiment 10. L is C6 to C 10 aryl, 6-10 membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O and S, and [ka] 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O and S; C6~C 10 Aryl and 6- to 10-membered partially saturated heterocyclyl are substituted with 0 to 2 R A1 are each independently substituted with R A is a compound according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, as defined by any one of embodiments 1 to 9.

[0082] Embodiment 11. L is a C6-C6 alkyl group selected from 6-10 membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O, and S, 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, and phenyl and naphthyl. 10 aryl; 6- to 10-membered partially saturated heterocyclyl, 5- to 10-membered heteroaryl, phenyl, and naphthyl are each independently selected from 0 to 4 R A are each independently substituted with R A is a compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, as defined by any one of embodiments 1 to 10.

[0083] Embodiment 12. L is a 6- to 10-membered partially saturated heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S, and [ka] Selected from C6 to C 10 aryl; 6- to 10-membered partially saturated heterocyclyl and 5- to 10-membered heteroaryl are 0 to 3 R A are each independently substituted with R A 12. A compound according to any one of embodiments 1 to 7, 11, or a pharmaceutically acceptable salt thereof, as defined by any one of embodiments 1 to 11.

[0084] Embodiment 13. L is a 6- to 10-membered partially saturated heterocyclyl having 1 to 3 heteroatoms independently selected from N, O, and S, a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S, and [ka] Selected from C6 to C 10 aryl; 6- to 10-membered partially saturated heterocyclyl and 5- to 10-membered heteroaryl are 0 to 3 R A are each independently substituted with R A A compound according to any one of embodiments 1 to 7, 11, 12, or a pharmaceutically acceptable salt thereof, wherein:

[0085] Embodiment 14. L is a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S, C-C 10 aryl, and [ka] is selected from a 6- to 10-membered partially saturated heterocyclyl selected from 5-10 membered heteroaryl, C6-C 10 Aryl and 6- to 10-membered partially saturated heterocyclyl are 0 to 4 R A are each independently substituted with R A is a compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, as defined by any one of embodiments 1 to 13.

[0086] Embodiment 15. L is a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S, C-C 10 aryl, and [ka] is selected from a 6- to 10-membered partially saturated heterocyclyl selected from 5-10 membered heteroaryl and C6-C 10 Aryl is 0 to 4 R A are each independently substituted with R A is a compound according to any one of embodiments 1 to 7, 14, or a pharmaceutically acceptable salt thereof, as defined by any one of embodiments 1 to 14.

[0087] Embodiment 16. L is a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S, C6-C 10 aryl, and [ka] is selected from a 6- to 10-membered partially saturated heterocyclyl selected from 5-10 membered heteroaryl and C6-C 10 Aryl is 0 to 4 R A are each independently substituted with R A A compound according to any one of embodiments 1 to 7, 14, 15, or a pharmaceutically acceptable salt thereof, as defined by any one of embodiments 1 to 15.

[0088] Embodiment 17. R 1 is independently selected at each occurrence from C1-C6 alkyl, halo, C1-C6 haloalkyl, and NH2; C1-C6 alkyl and C1-C6 haloalkyl are each 0 to 4 R 1a are each independently substituted with R 1a represents independently at each occurrence hydroxyl and NR 3 R 4 17. The compound of any one of embodiments 1 to 16, selected from:

[0089] Embodiment 18. R 1 is independently selected at each occurrence from C1-C6 alkyl, fluoro, NH2, —N(C1-C6 alkyl)2, and chloro; The compound of any of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein each occurrence of C1-C6 alkyl is independently substituted with 0-4 hydroxyl.

[0090] Embodiment 19. R 1is independently selected at each occurrence from C1-C6 alkyl and fluoro, and C1-C6 alkyl is independently substituted at each occurrence with 0-4 hydroxyl; or a pharmaceutically acceptable salt thereof.

[0091] Embodiment 20. The compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.

[0092] Embodiment 21. A compound of any one of embodiments 1-20, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3.

[0093] Embodiment 22. R 2 22. The compound of any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein:

[0094] Embodiment 23. A compound of any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

[0095] Embodiment 24. A compound of any one of embodiments 1-23, or a pharmaceutically acceptable salt thereof, wherein W is absent.

[0096] Embodiment 25. The compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein Z is O.

[0097] Embodiment 26. W is absent; X is N; Y is CH; Z is O; A is non-existence; L is C6~C 10 is aryl; R A is independently selected at each occurrence from halo, —CN, C1-C6 haloalkyl, and C1-C6 alkyl; R 1is independently selected at each occurrence from C1-C6 alkyl, halo, and C1-C6 haloalkyl; C1-C6 alkyl and C1-C6 haloalkyl are each 0 to 4 R 1a are each independently substituted with; R 1a represents independently at each occurrence hydroxyl and NR 3 R 4 Selected from; R 2 is selected from hydrogen and C1-C3 alkyl; R 3 is independently selected at each occurrence from hydrogen and C1-C6 alkyl; R 4 is independently expressed as -SO2R for each occurrence. 5 , selected from hydrogen and C1-C6 alkyl; R 5 is independently selected at each occurrence from NH2 and C1-C6 alkyl; n is 1, 2 or 3; 26. The compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, or 3.

[0098] Embodiment 27. W is absent; X is N; Y is CH; Z is O; A is non-existence; L is C6~C 10 is aryl; R A is independently selected at each occurrence from halo (e.g., fluoro), C1-C6 haloalkyl (e.g., C1-C6 fluoroalkyl), and C1-C6 alkyl; R 1 is independently selected at each occurrence from C1-C6 alkyl and halo (e.g., fluoro); C1-C6 alkyl is substituted with 0-4 hydroxyl; R 2 is hydrogen; n is 1, 2 or 3; 27. The compound of any one of embodiments 1-26, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, or 3.

[0099] Embodiment 28. R 1 is expressed independently for each occurrence of [ka] 28. The compound of any of embodiments 1-27, or a pharmaceutically acceptable salt thereof, wherein R is selected from fluoro and NH2.

[0100] Embodiment 29. R 1 is expressed independently for each occurrence of [ka] 29. The compound of any of embodiments 1-28, or a pharmaceutically acceptable salt thereof, wherein R is selected from fluoro and NH2.

[0101] Embodiment 30. R 1 is expressed independently for each occurrence of [ka] , fluoro and NH2; R 1b is hydrogen or C1-C5 alkyl, The compound of any of embodiments 1-29, or a pharmaceutically acceptable salt thereof, wherein C1-C5 alkyl is substituted with 0-3 hydroxyl.

[0102] Embodiment 31. Formula (Ia) [ka] (In the formula, W, L, R 1 , R 2 , R A , n and m are defined according to any of embodiments 1 to 30. 31. The compound of any one of embodiments 1 to 30, or a pharmaceutically acceptable salt thereof.

[0103] Embodiment 32. Formula (Ib) [ka] (In the formula, W, L, R 1 , R 2 , R A , n and m are defined according to any of embodiments 1 to 31. 32. The compound of any one of embodiments 1 to 31, or a pharmaceutically acceptable salt thereof.

[0104] Embodiment 33. Formula (Ig) [ka] (In the formula, W, L, R 1 , R 2 , R A , n and m are defined according to any of embodiments 1 to 32. 33. The compound of any one of embodiments 1 to 32, or a pharmaceutically acceptable salt thereof.

[0105] Embodiment 34. Formula (Ic) [ka] (In the formula, L, R 1 , R 2 , R A , n and m are defined according to any of embodiments 1 to 33. 34. The compound of any one of embodiments 1 to 33, or a pharmaceutically acceptable salt thereof.

[0106] Embodiment 35. Formula (Id) [ka] (In the formula, L, R 1 , R 2 , RA , n and m are defined according to any of embodiments 1 to 34. 35. The compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof.

[0107] Embodiment 36. Formula (Ih) [ka] (In the formula, L, R 1 , R 2 , R A , n and m are defined according to any of embodiments 1 to 35. 36. The compound of any one of embodiments 1 to 35, or a pharmaceutically acceptable salt thereof.

[0108] Embodiment 37. Formula (Ie) [ka] (In the formula, L, R 1 , R 2 , R A and m is defined according to any of embodiments 1 to 36. 37. The compound of any one of embodiments 1 to 36, or a pharmaceutically acceptable salt thereof.

[0109] Embodiment 38. Formula (If) [ka] (In the formula, L, R 1 , R 2 , R A and m is defined according to any of embodiments 1 to 37. 38. The compound of any one of embodiments 1 to 37, or a pharmaceutically acceptable salt thereof.

[0110] Embodiment 39. Formula (Ii) [ka] (In the formula, L, R 1 , R 2 , R A and m is defined according to any of embodiments 1 to 38. 39. The compound of any one of embodiments 1 to 38, or a pharmaceutically acceptable salt thereof.

[0111] Embodiment 40. A compound according to any one of embodiments 1 to 31, 34, or 37, or a pharmaceutically acceptable salt thereof, wherein the substituents at positions 1 and 3 of the cyclobutyl ring have a trans configuration.

[0112] Embodiment 41. A compound according to any one of embodiments 1 to 31, 34, or 37, or a pharmaceutically acceptable salt thereof, wherein the substituents at positions 1 and 3 of the cyclobutyl ring have a cis configuration.

[0113] Embodiment 42.

[0114] [Table 1]

[0115] [Table 2]

[0116] [Table 3]

[0117] [Table 4]

[0118] [Table 5]

[0119] [Table 6]

[0120] [Table 7]

[0121] [Table 8]

[0122] [Table 9]

[0123] [Table 10]

[0124] [Table 11]

[0125] [Table 12]

[0126] [Table 13] or a pharmaceutically acceptable salt thereof.

[0127] Embodiment 43. A compound according to any one of embodiments 1 to 42, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an acid addition salt.

[0128] Embodiment 44. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0129] Embodiment 45. A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof.

[0130] Embodiment 46. A method of treating or preventing a disease or disorder mediated by TRPV1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof.

[0131] Embodiment 47. A method for treating or preventing pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 43 or a pharmaceutically acceptable salt thereof. The pain can be acute, such as pain resulting from injury or surgery, or chronic. Examples of pain include, among others, pain such as bone and joint pain (osteoarthritis), cancer pain, myofascial pain (muscle injury, fibromyalgia), and perioperative pain (general surgery, perioperative pain). Other examples include chronic pain, particularly inflammatory pain, such as chronic inflammatory pain. Further examples of pain include pain in which TRPV1 activation plays or is implicated as playing a role, and therefore is amenable to treatment with the compounds disclosed herein. Such conditions include chronic pain with an inflammatory component, such as rheumatoid arthritis; bone and joint pain (osteoarthritis); post-operative pain; musculoskeletal pain, such as fibromyalgia; myofascial pain syndrome; headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain; ear pain; episiotomy pain; burns, especially the primary hyperalgesia associated therewith; deep and visceral pain, such as cardiac pain, muscular pain, ocular pain, orofacial pain, migraine, abdominal pain, gynecological pain, such as dysmenorrhea and labour pain; pain associated with the genitourinary tract, such as cystitis and vulvodynia; inflammatory skin disorders, such as psoriasis and chronic pain associated with nerve injury and / or diseases affecting the nervous system, such as neuropathic pain associated with post-herpetic neuralgia, diabetic neuropathy, chemotherapy-induced neuropathy, amputation ("phantom limb pain"), nerve entrapment and brachial plexus avulsion, low back pain, sciatica and ankylosing spondylitis, reflex sympathetic dystrophy and other chronic nerve injuries; complex regional pain syndrome; central nervous system pain, such as pain due to spinal cord or brainstem injury or stroke; gout; scar pain; pain associated with carcinoma, often referred to as cancer pain.

[0132] Embodiment 48. A method of treating or preventing an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt thereof. Exemplary inflammatory diseases include inflammatory airway diseases, such as chronic obstructive pulmonary disease (COPD) or asthma; cough; urinary incontinence; migraine headaches; visceral disorders, such as inflammatory bowel disease; rhinitis; cystitis, such as interstitial cystitis; pancreatitis; uveitis; inflammatory skin disorders, such as eczema and psoriasis; rheumatoid arthritis; inflammatory disorders of the intestine, such as irritable bowel syndrome; Crohn's disease; ulcerative colitis; and cystitis, such as interstitial cystitis, nephritis, and uveitis.

[0133] Embodiment 49. A method of achieving smooth muscle relaxation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof. Examples of diseases or conditions requiring a smooth muscle relaxant include treatment of spasms of the gastrointestinal tract or uterus, for example, in the treatment of Crohn's disease, ulcerative colitis, or pancreatitis.

[0134] Embodiment 50. A method for treating or preventing airway hyperresponsiveness or treating or preventing inflammatory events associated with airway disease, comprising administering to a subject a therapeutically effective amount of a compound of any one of embodiments 1 to 43 or a pharmaceutically acceptable salt thereof. Exemplary conditions include asthma, suppression or reversal of airway hyperresponsiveness in asthma. Other conditions include both intrinsic and, particularly, extrinsic asthma, e.g., allergic asthma, as well as, e.g., exercise-induced asthma, occupational asthma, asthma induced following bacterial infection, other non-allergic asthma, and "wheezing infant syndrome." Effectiveness in treating asthma is evidenced by a reduction in the frequency or severity of symptomatic attacks, e.g., acute asthma or bronchoconstriction attacks, and a reduced need for other symptomatic treatments, e.g., anti-inflammatory drugs, e.g., corticosteroids; or bronchodilators, e.g., β2-adrenergic therapy. Other inflammatory or obstructive airways diseases include, for example, aluminosis, anthracosis, asbestosis, stone disease, trichiasis, siderosis, silicosis, tobacco poisoning, and pneumoconiosis of any type or origin, including byssinosis (an inflammatory (generally occupational) disease of the lungs, often associated with repeated inhalation of dust). Further inflammatory or obstructive airways diseases and conditions include adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease or airways disease (COPD or COAD), and bronchitis, allergic and vasomotor rhinitis.

[0135] Embodiment 51. A method of treating or preventing septic shock in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof. Exemplary conditions include septic shock, e.g., as an antivolemic and / or antihypotensive agent; inflammatory bowel disease; cerebral edema; and in the treatment of headache.

[0136] Embodiment 52. A method of treating an ocular disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof.

[0137] Embodiment 53. A method of treating an ocular surface disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof.

[0138] Embodiment 54. The ocular surface disorder is selected from the group consisting of chronic ocular surface pain (COSP), dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophies (including recurrent corneal dystrophy), and epithelial basal layer disease. 54. The method of embodiment 53, wherein the patient is selected from patients recovering from membrane dystrophy, corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, graft versus host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, and neurotrophic keratitis.

[0139] Embodiment 55. The method of embodiment 54, wherein the ocular surface disorder is dry eye disease.

[0140] Embodiment 56. A method of treating or reducing ocular surface pain (e.g., corneal-induced pain) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof.

[0141] Embodiment 57. The method of embodiment 56, wherein administration of a compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof, results in a reduction in the subject's ocular pain compared to placebo. In some embodiments, the reduction in the subject's ocular pain is at least about 10%, at least about 15%, at least about 20%, or at least about 25%, compared to placebo, as measured on a pain scale, e.g., VAS or OPAS.

[0142] Embodiment 58. A method of treating or reducing corneal-induced pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof.

[0143] Embodiment 59. The method of embodiment 58, wherein administration of a compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof, results in a reduction in the subject's ocular pain compared to placebo. In some embodiments, the reduction in the subject's ocular pain is at least about 10%, at least about 15%, at least about 20%, or at least about 25%, compared to placebo, as measured on a pain scale, e.g., a VAS or OPAS.

[0144] Embodiment 60. The method of embodiments 56-59, wherein the ocular surface pain or corneal-induced pain is episodic, i.e., acute.

[0145] Embodiment 61. The method of embodiments 56-59, wherein the ocular surface pain or corneal-induced pain is chronic.

[0146] Embodiment 62. The ocular surface pain or corneal-induced pain is selected from the group consisting of dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, and corneal eczema. 62. The method of any of embodiments 56-61 associated with a patient recovering from one or more of: corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis.

[0147] Embodiment 63. The method of any of embodiments 56-62, wherein the ocular surface pain or corneal-evoked pain is associated with dry eye disease or Sjogren's syndrome.

[0148] Embodiment 64. The method of any of embodiments 56-63, wherein the subject is suffering from eye pain that has persisted for at least 3 months following laser photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK).

[0149] Embodiment 65. The method of any of embodiments 56-63, wherein the subject is suffering from conjunctivitis, subconjunctival hemorrhage, subconjunctival scar, conjunctival membrane, conjunctival ulcer, punctate superficial epithelial erosion, epithelial defect, eyelid margin ulcer, eyelid margin keratinization, synechiae, blepharophimosis, trichiasis, anterior blepharitis, lacrimal punctum occlusion, meibomian gland disease, corneal opacity, dry eye, distichiasis, limbal stem cell failure, or corneal angiogenesis.

[0150] Embodiment 66. A method of treating ocular hyperemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof.

[0151] Embodiment 67. The ocular hyperemia is caused by dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, and corneal erosions. 67. The method of embodiment 66, wherein the patient is recovering from one or more of: corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface disease, blepharitis, graft versus host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis.

[0152] Embodiment 68. The method of embodiment 66 or 67, wherein the ocular redness is associated with dry eye disease.

[0153] Embodiment 69. The method of any of embodiments 66-68, wherein the ocular redness persists for at least 3 months following photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK) surgery.

[0154] Embodiment 70. A compound of any of embodiments 1-43, or a pharmaceutically acceptable salt thereof, for use in treating or reducing ocular surface pain (e.g., corneal-induced pain).

[0155] Embodiment 71. The compound for use according to embodiment 70, wherein the compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof, results in a reduction in ocular pain in the subject compared to placebo. In some embodiments, the reduction in ocular pain in the subject is at least about 10%, at least about 15%, at least about 20%, or at least about 25%, compared to placebo, as measured on a pain scale, e.g., VAS or OPAS.

[0156] Embodiment 72. The compound or a pharmaceutically acceptable salt thereof for use according to embodiment 70 or 71, wherein the ocular surface pain is episodic, i.e., acute.

[0157] Embodiment 73. The compound or a pharmaceutically acceptable salt thereof for use according to embodiment 70 or 71, wherein the ocular surface pain is chronic. For example, the pain persists for at least 12 weeks, or at least 3 months, or at least 2 months, or at least 1 month.

[0158] Embodiment 74. The ocular surface pain is caused by dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, corneal erosion or abrasion (recurrent corneal 74. The compound or a pharmaceutically acceptable salt thereof for use according to any of embodiments 70-73 in association with a patient recovering from one or more of the following conditions: ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis.

[0159] Embodiment 75. The compound or a pharmaceutically acceptable salt thereof for use according to any of embodiments 70-74, wherein the ocular surface pain is associated with dry eye disease or Sjögren's syndrome.

[0160] Embodiment 76. A compound of any of embodiments 1-43, or a pharmaceutically acceptable salt thereof, for use in treating or reducing ocular redness.

[0161] Embodiment 77. The compound or pharmaceutically acceptable salt for use of any one of embodiments 1 to 43, wherein administration of the compound results in reduced Grade 1, Grade 2, Grade 3, or Grade 4 redness compared to placebo. In some embodiments, administration results in a reduction in ocular redness score of at least about 1, at least about 2, at least about 3, at least about 4, or at least about 5 on the McMonnies scale.

[0162] Embodiment 78. The ocular hyperemia is caused by dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, corneal erosion or abrasion (recurrent corneal 78. The compound or a pharmaceutically acceptable salt thereof for use according to embodiment 76 or 77 in association with one or more of the following: a patient recovering from: ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis.

[0163] Embodiment 79. The compound or a pharmaceutically acceptable salt thereof for use according to embodiment 76 or 77, wherein the ocular hyperemia is associated with dry eye disease.

[0164] Embodiment 80. The compound for use according to any of embodiments 76-78, wherein the ocular hyperemia persists for at least 3 months following photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK).

[0165] Embodiment 81. A compound of any of embodiments 1-43, or a pharmaceutically acceptable salt thereof, for use in treating an ocular surface disorder.

[0166] Embodiment 82. The ocular surface disorder is chronic ocular surface pain (COSP), dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, and corneal erosions. 82. The compound or a pharmaceutically acceptable salt thereof for use according to embodiment 81, wherein the patient is selected from patients recovering from: corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface disease, blepharitis, graft versus host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis.

[0167] Embodiment 83. The compound or a pharmaceutically acceptable salt thereof for use according to any of embodiments 68-72, 77, or 78, wherein the subject is suffering from eye pain that has persisted for at least 3 months following laser photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK).

[0168] Embodiment 84. The compound or a pharmaceutically acceptable salt thereof for use according to any of embodiments 70 to 75, 81, or 82, wherein the subject is suffering from conjunctivitis, subconjunctival hemorrhage, subconjunctival scarring, conjunctival membranes, conjunctival ulcers, punctate superficial epithelial erosions, epithelial defects, eyelid margin ulcers, eyelid margin keratinization, synechiae, blepharophimosis, trichiasis, anterior blepharitis, lacrimal punctum occlusion, meibomian gland disease, corneal opacity, dry eye, distichiasis, limbal stem cell failure, or corneal angiogenesis.

[0169] Embodiment 85. Use of a compound of any one of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an ocular disease or disorder mediated by TRPV1.

[0170] Embodiment 86. The use of embodiment 85, wherein the ocular disease or disorder is selected from ocular surface disorders, ocular surface pain (e.g., corneal-induced pain), and ocular hyperemia.

[0171] Embodiment 87. The ocular surface disorder is selected from the group consisting of chronic ocular surface pain (COSP), dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophies (including recurrent corneal dystrophy), and epithelial basement membrane dystrophy. 87. The use of embodiment 85 or 86, wherein the patient is selected from patients recovering from strophy, corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, graft versus host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, and neurotrophic keratitis.

[0172] Embodiment 88. The use of embodiment 86 or 87, wherein the ocular surface disorder is dry eye disease.

[0173] Embodiment 89. The use of embodiment 86, wherein the ocular surface pain is episodic, i.e., acute.

[0174] Embodiment 90. The use of embodiment 86, wherein the ocular surface pain is chronic.

[0175] Embodiment 91. The ocular surface pain is selected from the group consisting of dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, corneal erosion, and the like. The use of any of embodiments 86, 89, or 90 in association with a patient recovering from one or more of the following: abrasions (including recurrent corneal erosions or abrasions), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis.

[0176] Embodiment 92. The use of any of embodiments 86, 89-91, wherein the ocular surface pain is associated with dry eye disease or Sjögren's syndrome.

[0177] Embodiment 93. Ocular hyperemia is characterized by dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, and corneal erosions. The use of embodiment 86 is associated with a patient recovering from one or more of the following conditions: corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctival chalazion, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, and lagophthalmos keratopathy), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis. In certain embodiments, the ocular redness is associated with dry eye disease. In some embodiments of the methods described herein, the ocular redness persists for at least three months after laser photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK).

[0178] Embodiment 94. The use of a compound according to any of embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, in the treatment of an ocular disease or disorder, e.g., mediated by TRPV1.

[0179] Embodiment 95. The use of embodiment 94, wherein the ocular disease or disorder is selected from ocular surface disorders, ocular surface pain (e.g., corneal-induced pain), and ocular hyperemia.

[0180] Embodiment 96. The ocular surface disorder is selected from the group consisting of chronic ocular surface pain (COSP), dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophies (including recurrent corneal dystrophy), and epithelial basement membrane dystrophy. The use of embodiment 94 or 95, wherein the patient is selected from patients recovering from strophy, corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, and neurotrophic keratitis.

[0181] Embodiment 97. The use of any of embodiments 94-96, wherein the ocular surface disorder is dry eye disease.

[0182] Embodiment 98. The use of embodiment 95, wherein the ocular surface pain is episodic, i.e., acute.

[0183] Embodiment 99. The use of embodiment 95, wherein the ocular surface pain is chronic.

[0184] Embodiment 100. The ocular surface pain is caused by dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, corneal erosion, or The use of any of embodiments 95, 98 or 99 in association with a patient recovering from one or more of: abrasions (including recurrent corneal erosions or abrasions), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia or neurotrophic keratitis.

[0185] Embodiment 101. The use of any of embodiments 95, 98-100, wherein the ocular surface pain is associated with dry eye disease or Sjögren's syndrome.

[0186] Embodiment 102. The ocular hyperemia is characterized by dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, and corneal erosions. 96. The use of embodiment 95 in association with a patient recovering from one or more of the following: corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface disease, blepharitis, graft versus host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis.

[0187] Embodiment 103. The use of embodiment 95 or 102, wherein the ocular redness is associated with dry eye disease.

[0188] Embodiment 104. The use of any of embodiments 95, 102, or 103, wherein the ocular redness persists for at least 3 months after photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK) surgery.

[0189] Embodiment 105. A pharmaceutical combination comprising a compound according to any one of embodiments 1 to 43 or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents.

[0190] Depending on the selection of starting materials and procedures, compounds may exist in one of the possible isomeric forms or as mixtures thereof, e.g., as pure optical isomers or as isomeric mixtures, e.g., racemates and diastereomeric mixtures, depending on the number of asymmetric centers. The present disclosure is meant to include all such possible isomers, including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When a compound contains a di- or trisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. The present disclosure includes cis- and trans-configurations of substituted cycloalkyl groups, e.g., cyclobutyl groups, as well as mixtures thereof. All tautomeric forms are also intended to be included. In particular, when a heteroaryl ring containing N as a ring atom is a 2-pyridone, tautomers in which, for example, the carbonyl is shown as hydroxy (e.g., 2-hydroxypyridine) are included.

[0191] Thus, it should be recognized that in compounds of formula (I), the cyclobutyl ring portion of the molecule may be in the cis or trans configuration. For illustrative purposes, using formula (Ib) (where the substituents at positions 1 and 3 of the cyclobutyl ring have a trans configuration), (Ib * ) and (Ib ** Those skilled in the art will recognize that ) is an equivalent way of depicting a molecule of formula (Ib). [ka]

[0192] Separation of cis and trans isomers can be achieved by methods known to those skilled in the art, such as chromatographic methods involving tools such as HPLC (High Performance Liquid Chromatography), thin layer chromatography, SFC (Supercritical Fluid Chromatography), GC (Gas Chromatography) or recrystallization techniques.

[0193] pharmaceutically acceptable salts As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds of the present disclosure. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and are typically not physically or otherwise undesirable. The compounds of the present disclosure may be capable of forming acid salts and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0194] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, formic acid, trifluoroacetic acid, etc. In one embodiment, the compound of formula (I) is in the form of an HCl or formate salt.

[0195] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0196] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0197] In another aspect, the present disclosure provides an ester of hydroxybenzoates, including acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurate ... In one embodiment, the compound is provided in the form of a methylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate salt.

[0198] In another aspect, the disclosure provides compounds in the form of sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, or tromethamine salts.

[0199] Isotopically labeled compounds Any formula shown herein is also intended to represent unlabeled and isotopically labeled forms of the compound.Isotopically labeled compounds have the structure shown by the formula shown herein, except that one or more atoms are replaced by atoms with a selected atomic mass or mass number.Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C. 13 C. 14 C. 18 O. 15N, 18 F, 17 O. 18 O. 35 S, 36 Cl, 123 I, 124 I, 125 I. The present disclosure includes various isotopically labeled compounds as defined herein, including those containing radioactive isotopes, e.g. 3 H and 14 C is present or in which non-radioactive isotopes, e.g. 2 H and 13 These isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction kinetic studies (e.g., 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radioactive treatment of patients. 18 F compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) or sub-formulas thereof may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and General Schemes, substituting appropriate isotopically labeled reagents for previously used non-labeled reagents.

[0200] Furthermore, heavier isotopes, especially deuterium (i.e. 2Substitution with H or D) may confer particular therapeutic benefits resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is understood that deuterium is in this context considered to be a substituent of a compound of formula (I) or any of its subformulas. The concentration of such heavier isotopes, particularly deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor," as used herein, refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the present disclosure is designated as deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0201] Pharmaceutically acceptable solvates in accordance with the present disclosure include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0202] Compounds of the present disclosure that contain groups capable of acting as donors and / or acceptors for hydrogen bonds, i.e., compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ii), and (I-ii), may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) or any sub-formula thereof by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimating, co-melting compounds of (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ii), and (I-ii), or contacting compounds of (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ii), and (I-ii) in solution with a crystal former under crystallization conditions and isolating the co-crystals thereby formed. Suitable co-crystal formers include those described in WO 2004 / 078163.

[0203] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended merely to better clarify the disclosure and does not pose a limitation on the scope of the otherwise claimed disclosure.

[0204] The asymmetric centers (e.g., carbons) of the compounds of the present disclosure can be present in racemic or enantiomerically enriched configurations, such as the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, e.g., as a mixture of enantiomers, each asymmetric center is present in at least 10% enantiomeric excess, at least 20% enantiomeric excess, at least 30% enantiomeric excess, at least 40% enantiomeric excess, at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. In certain embodiments, for example, in an enantiomerically enriched form, each chiral center is present in at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. Thus, the compounds of the present disclosure can be present in racemic mixtures or in enantiomerically enriched or enantiopure forms or as mixtures of diastereoisomers.

[0205] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is present in an enantiomeric excess of at least 90%, an enantiomeric excess of at least 95%, or an enantiomeric excess of at least 99%.

[0206] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is present in at least 90% diastereomeric excess, at least 95% diastereomeric excess, or at least 99% diastereomeric excess.

[0207] In one embodiment, the compound of formula (I) has the formula (Ii): [ka] or a pharmaceutically acceptable salt thereof, wherein A, L, W, X, Y, Z, R 1, R 2 , R A , n and m are defined according to embodiment 1. In particular, A, L, W, X, Y, Z, R 1 , R 2 , R A , n and m may be defined according to any of embodiments 2-39.

[0208] In another embodiment, the compound of formula (I) has the formula (I-ii): [ka] or a pharmaceutically acceptable salt thereof, wherein A, L, W, X, Y, Z, R 1 , R 2 , R A , n and m are defined according to embodiment 1. In particular, A, L, W, X, Y, Z, R 1 , R 2 , R A , n and m may be defined according to any of embodiments 2-39.

[0209] In the formula of the present application, C-sp 3 The above term " [ka] " indicates the absolute stereochemical configuration (R) or (S). In the formula of this application, C-sp 3 The above term " [ka] " indicates the absolute stereochemical configuration (R) or (S). In the formula of this application, C-sp 3 The above term " [ka] " represents a covalent bond and the stereochemical configuration of the bond is not defined. This is the case for C-sp 3 The above term " [ka] " is meant to include either the (S) or (R) configuration of each chiral center. Additionally, mixtures may exist. Thus, mixtures of stereoisomers, e.g., mixtures of enantiomers, e.g., racemates and / or mixtures of diastereoisomers, are encompassed by the present disclosure.

[0210] For the avoidance of doubt, the combination [ka] When a compound structure is drawn with an undefined stereochemical configuration for any R group, as represented by:

[0211] For the avoidance of doubt, R 1 When a group is shown with attachment to both rings, in any of the formulas in this application, this is 1 The R group may be attached to either ring or multiple R 1 This means that the group can be attached to either ring.

[0212] Thus, as used herein, the compounds of the present disclosure may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, such as a substantially pure geometric (cis or trans) stereoisomer, diastereomer, optical isomer, racemate or mixtures thereof.

[0213] Any resulting mixtures of stereoisomers can be separated on the basis of the physical chemical differences of the constituents into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0214] Any resulting racemates of the compounds or intermediates of the present disclosure can be resolved into optical isomers (enantiomers) by known methods, for example, by separation of their diastereomeric salts obtained with optically active acids or bases and liberating the optically active acidic or basic compounds. In particular, basic moieties can be used in this manner to resolve the compounds of the present disclosure into their optical antipodes, for example, by fractional crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemates or racemic intermediates of the present disclosure can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0215] Furthermore, the compounds of the present disclosure, including their salts, may be obtained in the form of their hydrates or may contain other solvents used for their crystallization. The compounds of the present disclosure may inherently or intentionally form solvates with pharmaceutically acceptable solvents (including water); therefore, the present disclosure is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of the compounds of the present disclosure (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are commonly used in pharmaceutical technology, known to be harmless to recipients, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water. The presence of a solvate can be identified by those skilled in the art using tools such as NMR.

[0216] Compounds of the present disclosure, including their salts, hydrates and solvates, may inherently or intentionally form polymorphs.

[0217] How to make it The compounds of the present disclosure can be prepared in many ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as recognized by those skilled in the art.

[0218] In general, compounds of formula (I) can be prepared according to the schemes provided below.

[0219] The compounds provided herein can be prepared according to the following examples. In the following scheme, Y, R 1 , L, R A , n, and m are defined according to enumerated embodiment 1. In one embodiment, Y, R 1 , L, R A , n and m are defined according to any of the enumerated embodiments 2-21, 23, 26-30.

[0220] General Scheme 1 [ka] The starting material I-1 is commercially available or can be prepared by standard chemical transformations as described in the individual procedures or known in the art. I-1 can be reacted with commercially available cyclobutyl alcohol I-2 under Mitsunobu-type conditions, e.g., PPh3, DIAD in a solvent such as THF, to give I-3, which can then be treated under acidic conditions, e.g., HCl / dioxane, to give the amine derivative I-4. The resulting amine product I-4 can undergo reductive amination with the corresponding aldehyde I-5 to give I-6, e.g., R 1 under acidic conditions, e.g., with hydrochloric acid in dioxane or a fluoride source, e.g., tetra-n-butylammonium fluoride in THF. 1 and / or R A After deprotection of the protected functional groups present as substituents in the formula I-6, the final compound I-6 can be obtained.

[0221] Alternatively, the compounds can be prepared as shown in general scheme 2 below.

[0222] General Scheme 2 [ka] In Scheme 2, a compound such as I-1 can be reacted with II-7 under basic conditions, such as CsCO, to give I-3, which can be treated under acidic conditions to give amine I-4. The resulting amine can undergo reductive amination with the corresponding aldehyde I-5 (e.g., using conditions described in General Scheme 1) to give I-6 after deprotection as described in Step 4 of General Scheme 1.

[0223] Alternatively, the compounds can be prepared as shown in general scheme 3 below.

[0224] General Scheme 3 [ka] In Scheme 3, a compound such as III-8 (where X is halo, e.g., Cl) can be reacted with commercially available III-9 under basic conditions, e.g., NaH or CsCO and CuI, to give I-3, which can be treated under acidic conditions to give amine I-4. The resulting amine product can undergo reductive amination with the corresponding aldehyde I-5 (e.g., using conditions described in General Scheme 1) to give I-6 after deprotection as described in Step 4 of General Scheme 1.

[0225] Alternatively, the compounds can be prepared as shown in general scheme 4 below.

[0226] General Scheme 4 [ka] In Scheme 4, a compound such as I-4 is reacted with the corresponding bromide IV-10 under basic conditions, such as triethylamine, to give IV-11.

[0227] Alternatively, the compounds can be prepared as shown in general scheme 5 below.

[0228] General Scheme 5 [ka] In Scheme 5, an aldehyde, such as V-12, can be treated with a reducing agent, such as sodium borohydride, to give V-13. Bromination of V-13 using a suitable brominating reagent, such as phosphorus tribromide, gives V-14. Nucleophilic substitution with III-9 in the presence of a base, such as sodium hydride, gives V-15. Removal of the Boc protecting group under acidic conditions, such as HCl / dioxane, gives amine V-16. Subsequent reductive amination with the corresponding aldehyde V-17 (e.g., using conditions described in General Scheme 1, suitably condition 3) gives V-18.

[0229] Alternatively, the compounds can be prepared as shown in general scheme 6 below.

[0230] General Scheme 6 [ka] In Scheme 6, an acid such as VI-19 can be reacted with I-4 under peptide coupling conditions such as HATU, DIPEA, using a solvent such as DMF. The protected functional group can then be deprotected as described in Step 4 of General Scheme 1 to give the amide VI-20.

[0231] Alternatively, the compounds can be prepared as shown in general scheme 7 below.

[0232] General Scheme 7 [ka] Mesylate VII-21 can be prepared by condensing alcohol I-1 (e.g., L is C6-C6) under basic conditions, e.g., CsCO3. 10 Nucleophilic substitution with cyclobutyl cis- and trans-isomers (which are aryl) affords VII-22. Deprotection under acidic conditions, e.g., HCl / dioxane, affords amine VII-23. VII-23 can undergo reductive amination with the corresponding aldehyde I-5 (e.g., using conditions described in General Scheme 1, suitably condition 3) to afford VII-24. The cyclobutyl cis- and trans-isomers are then separated.

[0233] Alternatively, the compounds can be prepared as shown in general scheme 8 below.

[0234] General Scheme 8 [ka] In Scheme 8, commercially available alcohol I-2 can be reacted with mesyl chloride under basic conditions, such as triethylamine, to give II-7. The thioester product VIII-25 can be formed by treatment of II-7 under nucleophilic conditions, such as with KSCMe. Deprotection under basic conditions, such as NaOH, gives VIII-26, which can then be reacted with the corresponding aryl bromide VIII-27 under Buchwald-type conditions using a Pd catalyst, such as Pd(dba) and a phosphine ligand, such as xantphos, and a base, such as DIPEA, in a solvent, such as dioxane, to produce VIII-28. Deprotection of VIII-28 with an acid, such as HCl, gives amine VIII-29, which can undergo reductive amination with the corresponding aldehyde VIII-30 (e.g., using conditions described in General Scheme 1, suitably Condition 1) to give VIII-31.

[0235] Alternatively, the compounds can be prepared as shown in general scheme 9 below.

[0236] General Scheme 9 [ka] Commercially available IX-32 can be reacted with aniline IX-33 under reductive amination conditions to give IX-34, which is subsequently deprotected under acidic conditions, such as HCl / dioxane, to give amine IX-35. Reaction with aldehyde I-5 under reductive amination conditions (e.g., those described in General Scheme 1, suitably using Condition 1) gives IX-36.

[0237] Alternatively, the compounds can be prepared as shown in general scheme 10 below.

[0238] General Scheme 10 [ka] In Scheme 10, oxidation of compound X-37 with, for example, MnO2, affords X-38. Nucleophilic addition of a cyanide source, such as TMSCN, to the aldehyde X-38 affords X-39. Deprotection of X-39 under acidic conditions, such as HCl, affords the acid X-40.

[0239] Alternatively, the compounds can be prepared as shown in general scheme 11 below.

[0240] General Scheme 11 [ka] In Scheme 11, reductive amination of aldehyde I-5 with (1s,3s)-3-aminocyclobutan-1-ol (e.g., using conditions described in General Scheme 1) affords XI-41. Reaction with I-1 under Mitsunobu-type conditions as described in Step 1 of General Scheme 1 affords I-6.

[0241] Alternatively, the nitrated compounds can be prepared as shown in general scheme 12 below.

[0242] General Scheme 12 [ka] In Scheme 12, nitration of XII-42 using, for example, H2SO4 and HNO3, gives XII-43, which is then reduced (e.g., with Zn and AcOH) to give XII-44 after separation of the regioisomers.

[0243] Alternatively, the compounds can be prepared as shown in general scheme 13 below.

[0244] General Scheme 13 [ka] In Scheme 13, cross-coupling of XIII-45 with potassium trifluoro(vinyl)borate under Suzuki-type conditions using a base such as TEA and a Pd catalyst such as Pd(dppf)Cl·CHCl affords XIII-46, which can then be oxidized, for example, with OsO, to provide diol XIII-47. Treatment of diol XIII-47 with a fluorinating reagent such as DAST affords XIII-48. Deprotection of XIII-48 under acidic conditions, for example, TFA, affords XIII-49, which can be reacted with aldehyde I-5 under reductive amination conditions (as described in Step 4 of General Scheme 1) to afford XIII-50.

[0245] Alternatively, the compounds can be prepared as shown in general scheme 14 below.

[0246] General Scheme 14 [ka] Cross-coupling of XIII-45 with the corresponding boronic ester, such as 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane, under Suzuki-type conditions, such as a base, KPO, and a Pd catalyst, such as Pd(dppf)Cl·CHCl, in a suitable solvent, such as 1,4-dioxane, affords XIV-51. Reduction of the alkene XIV-51 under hydrogenation conditions, such as Pd / C and H, affords XIV-52. Subsequent deprotection of XIV-52 under acidic conditions affords XIV-53, which undergoes reductive amination with the corresponding aldehyde I-5 (as described in Step 4 of General Scheme 1) to afford XIV-54.

[0247] Alternatively, the compounds can be prepared as shown in general scheme 15 below.

[0248] General Scheme 15 [ka] In Scheme 15, commercially available XV-55 can be brominated using, for example, bromine / acetic acid to provide XV-56. Subsequent reaction with I-2 under Mitsunobu-type conditions (e.g., as described in Step 1 of General Scheme 1) affords XV-57. Pd-catalyzed cyanation of XV-57 using Zn(CN) and a Pd catalyst, such as Pd(dba) and a ligand, such as dppf, affords XV-58, which is then deprotected under acidic conditions to afford XV-59. Reaction with aldehyde I-5 under reductive amination conditions (e.g., as described in Step 4 of General Scheme 1) affords XV-60.

[0249] Alternatively, the compounds can be prepared as shown in general scheme 16 below.

[0250] General Scheme 16 [ka] In Scheme 16, commercially available XVI-61 is reacted with III-9 under basic conditions, such as NaH or CsCO and CuI, to give XVI-62. XVI-62 is then reacted with NaOMe to give XVI-63. Subsequent reaction with aldehyde I-5 under reductive amination conditions (as described in Step 4 of General Scheme 1) gives XVI-64.

[0251] Alternatively, the compounds can be prepared as shown in general scheme 17 below.

[0252] General Scheme 17 [ka] In Scheme 17, Mitsunobu reaction of I-1 with commercially available III-9 (e.g., as described in Step 1 of General Scheme 1) affords XVII-65, which can be subsequently treated under acidic conditions to afford amine XVII-66. Further reaction with aldehyde I-5 under reductive amination conditions (e.g., as described in Step 4 of General Scheme 1) affords amine XVII-67, e.g., R 1 under acidic conditions with, for example, hydrochloric acid in dioxane or a fluoride source, e.g., tetra-n-butylammonium fluoride in THF. 1 and / or R A After deprotection of the protected functional groups present as substituents in XVII-67 is obtained.

[0253] In a further embodiment, the compound of formula (X) [ka] (In the formula, Z is NH, O or S; A is CH2 or absent; L is a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O, and S; C6-C 10 aryl and 6-10 membered partially saturated heterocyclyl having 1-3 heteroatoms independently selected from N, O and S; R A each occurrence independently represents halo, -CN, C1-C6 haloalkyl, C1-C6 alkyl, SF5, C3-C6 cycloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, 4-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O and S, -(CH2) p -NR 3 R 4 and —C(═O)—O—(C1-C6 alkyl), C3-C6 cycloalkyl and 4- to 6-membered heterocyclyl are each 0 to 4 R A1 are each independently substituted with; R A1is independently selected at each occurrence from halo and C1-C6 haloalkyl; R 2 is selected from hydrogen and C1-C6 alkyl; R 2A is selected from hydrogen and a nitrogen protecting group (PG), suitably tert-butylcarbamate (Boc); R 3 is independently selected at each occurrence from hydrogen and C1-C6 alkyl; R 4 is independently expressed as -SO2R for each occurrence. 5 , hydrogen, —C(═O)—(C1-C6 alkyl) and C1-C6 alkyl; R 5 is independently selected at each occurrence from NH2 and C1-C6 alkyl; m is 0, 1, 2, 3, 4 or 5 or a salt thereof.

[0254] In a further embodiment, the compound of formula (X) has the formula (Xa): [ka] wherein A, L, Z, R A , R 2 , R 2A and m are as defined for formula (X).

[0255] In a further aspect, the present disclosure provides a method for producing a pharmaceutical composition comprising: 1) reacting a compound of formula (X) (e.g., R 2A is hydrogen) or a salt thereof, for example, HCl, with a compound of formula (I-5) [ka] (In the formula, Y is selected from N and CH; R 1is independently selected at each occurrence from hydroxyl, C1-C6 alkyl, C1-C6 alkoxyl, halo, C1-C6 haloalkyl, and NR 3 R 4 is selected from C1-C6 alkyl and C1-C6 haloalkyl are each 0 to 4 R 1a are each independently substituted with; R 1a represents independently at each occurrence hydroxyl, NR 3 R 4 and —C(═O)—OH; R 3 is independently selected at each occurrence from hydrogen and C1-C6 alkyl; R 4 is independently expressed as -SO2R for each occurrence. 5 , hydrogen, —C(═O)—(C1-C6 alkyl) and C1-C6 alkyl; R 5 is independently selected at each occurrence from NH2 and C1-C6 alkyl; n is 0, 1, 2, 3 or 4 with a compound of: Optionally followed by 2) For example, R 1 and / or R A deprotecting the protected functional groups present as substituents of to obtain a compound of formula (I); The present invention provides a process for the preparation of a compound of formula (I) in free form or in the form of a pharmaceutically acceptable salt, comprising:

[0256] The reductive amination reaction can be carried out as described in the Examples section or by procedures known in the art.

[0257] In one embodiment, the reductive amination conditions are 1) NaBH4, NEt3, AcOH, solvent such as methanol, the reaction is carried out at room temperature or heated to a suitable temperature (e.g., reflux temperature); 2) NaBH(OAc)3, i-Pr2NEt, a solvent such as DCM, the reaction being carried out at room temperature or by heating to a suitable temperature (e.g., reflux temperature); and 3) NEt3 and a solvent such as benzene, heated to a suitable temperature (e.g., reflux), followed by the addition of NaBH4 or Na(CN)BH3 and a solvent such as methanol, the reaction being carried out at room temperature or with heating to a suitable temperature (e.g., reflux). is selected from.

[0258] For example, deprotection of protected amine or hydroxyl functions can be carried out as described in the Examples section or by procedures known in the art.

[0259] In one embodiment, the deprotection conditions are: 1) acidic conditions, such as with neat hydrochloric acid or hydrochloric acid in dioxane or trifluoroacetic acid; 2) a fluoride source, such as tetra-n-butylammonium fluoride, in a solvent, such as THF; and 3) Mixture of conditions 1 and 2 is selected from.

[0260] Pharmaceutical Composition In another aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds described herein or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers.

[0261] In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. For purposes of this disclosure, unless otherwise specified, solvates and hydrates are generally considered to be compositions.

[0262] The compounds of formula (I) and subformulas thereof described herein may be administered alone or as the active ingredient of a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions comprising a compound of formula (I) or any subformula thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0263] Methods for preparing various pharmaceutical compositions are known to those skilled in the art and may be described, for example, in Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms Tablets (Lieberman, Lachman and Schwartz, editors), current edition, published by Marcel Dekker, Inc.; and Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).

[0264] Pharmaceutical compositions can be formulated for a particular route of administration, such as oral, topical, parenteral, and rectal administration. Moreover, pharmaceutical compositions of the present disclosure can be made in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including but not limited to solutions, gels, suspensions, or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations, such as sterilization, and / or can contain conventional inert excipients, lubricants, or buffers, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, and the like.

[0265] Typically, the pharmaceutical composition comprises: a) excipients, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) disintegrants, such as starch, agar, alginic acid or its sodium salt or effervescent mixtures; and e) Absorbents, colorants, flavorings and sweeteners and a tablet or gelatin capsule containing the active ingredient together with one or more of the following.

[0266] In one embodiment, the pharmaceutical composition is a capsule containing only the active ingredient.

[0267] Tablets may be film coated or enteric coated by methods known in the art.

[0268] The mode of administration and pharmaceutical composition are closely related to the therapeutic amount of the compound or composition that is desired and effective for a given treatment application.The pharmaceutical compositions provided herein can be formulated for ocular, ocular, topical and transdermal administration.In certain embodiments, the pharmaceutical compositions provided herein are suitable for ocular administration.To prepare pharmaceutical compositions, the active ingredient can be mixed with one or more pharmaceutically acceptable carriers according to conventional pharmaceutical compounding techniques.Carriers can take a variety of forms depending on the form of preparation desired for administration.

[0269] Suitable compositions for oral administration include an effective amount of a compound of the present disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs, solutions, or solid dispersions. Oral compositions may be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be presented as hard gelatin capsules (in which the active ingredient is mixed with an inert solid excipient such as calcium carbonate, calcium phosphate, or kaolin) or as soft gelatin capsules (in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil).

[0270] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solution enhancers, salts for regulating osmotic pressure, and / or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared by conventional mixing, granulating, or coating methods, respectively, and contain about 0.1 to 75% of the active ingredient, or about 1 to 50% of the active ingredient.

[0271] Suitable compositions for transdermal application include an effective amount of the compound of the present disclosure with a suitable carrier.Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents that support the passage through the host's skin.For example, transdermal devices are in the form of bandages, including a backing component, a reservoir containing the compound optionally with a carrier, a rate-limiting barrier that optionally delivers the compound to the host's skin at a controlled, predetermined rate over a long period of time, and a means for fixing the device to the skin.

[0272] For example, suitable compositions for topical application to the skin and eyes include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations, e.g., for delivery by aerosol. Such topical delivery systems are particularly suitable for dermal application, e.g., for the treatment of skin cancer, and for prophylactic use, e.g., in sun creams, lotions, sprays, etc. As such, they are particularly suitable for topical use, including cosmetic formulations well known in the art. Such may contain solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0273] As used herein, topical application may also refer to inhalation or intranasal application, which may conveniently be delivered in the form of a dry powder from a dry powder inhaler (alone, in a mixture, e.g., as a dry blend with lactose or mixed component particles, e.g., with phospholipids) or an aerosol spray presentation from a pressurized container, pump, spray, atomizer, or nebulizer, with or without the use of a suitable propellant.

[0274] In certain embodiments, the pharmaceutical compositions provided herein are formulated as solutions, suspensions, gels, creams, ointments, liposomes, intraocular inserts, or other pharmaceutical compositions suitable for topical administration to the ocular surface, cornea, eyelid, eye margin, eyelashes, and / or eyelid margin, in certain embodiments, for delivery of the composition to the eye. In some embodiments, a liquid (aqueous or non-aqueous) solution may be used. In certain embodiments, the pharmaceutical compositions are formulated as eye drops for topical administration to the ocular surface, cornea, eyelid, eyelid margin, eyelashes, and / or eye margin, for delivery of the composition to the eye. The pharmaceutical composition may be applied using an applicator for delivering the formulation to the eye, such as the subject's finger, Weck-Cel®, Q-tip®, or other device capable of delivering the formulation to the eyelid, eyelashes, and / or eyelid margin. The pharmaceutical compositions provided herein may be viscous or semi-viscous; liquid, solid, or semi-solid; aqueous or non-aqueous, depending on the site of application, dosage, drug solubility, and various other factors considered by one of skill in the art.

[0275] Any of a variety of carriers may be used in the pharmaceutical compositions provided herein. In one embodiment, the pharmaceutically acceptable carrier is a non-aqueous carrier (e.g., an oil or oil mixture) having a viscosity ranging from about 50 cps to about 1000 cps, about 50 cps to about 500 cps, about 50 cps to about 200 cps, or about 60 cps to about 120 cps. In certain embodiments, the non-aqueous carrier comprises an oil, such as a vegetable oil, silicone oil, mineral oil, or any combination thereof. In some embodiments, the carrier may be liquid paraffin, white petrolatum, purified lanolin, gelling hydrocarbons, polyethylene glycol, hydrophilic ointment bases, white ointment bases, absorbent ointment bases, macrogol ointment bases, simple ointment bases, etc. In certain embodiments, the pharmaceutical composition may include monomeric polyols such as glycerol, propylene glycol, and ethylene glycol, polymeric polyols such as polyethylene glycol, cellulose esters such as hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose; dextrans such as dextran 70; water-soluble proteins such as gelatin, polymers such as polyvinyl alcohol, polyvinylpyrrolidone, and povidone; carbomers such as carbomer 934P, carbomer 941, carbomer 940, and carbomer 974P; and gums such as HP guar.

[0276] Additional additives may optionally be included in the pharmaceutical compositions provided herein. Examples of additional additives include, for example, tonicity enhancing agents, preservatives, solubilizers, non-toxic additives, demulcents, sequestering agents, pH adjusting agents, cosolvents, viscosity building agents, and combinations thereof.

[0277] For example, a buffer may be used to adjust the pH to physiological pH. In certain embodiments, the pH of the pharmaceutical composition is maintained within a range of about 4.0 to about 8.0, e.g., about 4.0 to about 6.0, e.g., about 6.5 to about 7.8. Suitable buffers may be added, such as boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, tris(hydroxymethyl)aminomethane (TRIS), and various mixed phosphate buffers (including combinations of NaHPO, NaHPO, and KHPO), as well as mixtures thereof. Generally, buffers may be used in amounts ranging from about 0.05 to about 2.5 weight percent, e.g., from about 0.1 to about 1.5 weight percent.

[0278] Tonicity may be adjusted, if necessary, by the use of tonicity enhancers. Such agents may be, for example, of the ionic and / or non-ionic type. Examples of ionic tonicity enhancers include, for example, alkali metal halides or alkaline earth metal halides, such as CaCl, KBr, KCl, LiCl, NaI, NaBr, or NaCl, NaSO, or boric acid. Non-ionic tonicity enhancers include, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose. In one embodiment, the pharmaceutical compositions provided herein may have an osmolality of about 225 to about 400 milliosmoles per kilogram (mOsm / kg). In one embodiment, an osmolality of about 280 to about 320 mOsm is achieved.

[0279] In further embodiments, the pharmaceutical compositions, e.g., topical compositions, provided herein may further comprise a preservative. The preservative is typically a quaternary ammonium compound, such as benzalkonium chloride, benzoxonium chloride (e.g., N-benzyl-N-(C-C 18dimethylammonium chloride). Examples of preservatives other than quaternary ammonium salts include, for example, alkylmercuric salts of thiosalicylic acid, such as thiomersal, phenylmercuric nitrate, phenylmercuric acetate, or phenylmercuric borate, sodium perborate, sodium chlorite, parabens, such as methylparaben or propylparaben, alcohols, such as chlorobutanol, benzyl alcohol, or phenylethanol, guanidine derivatives, such as chlorhexidine or polyhexamethylene biguanide, sodium perborate, or sorbic acid. Where appropriate, a sufficient amount of preservative may be added to the pharmaceutical compositions provided herein to ensure protection against cross-contamination during use caused by bacteria and fungi. In certain embodiments, the pharmaceutical compositions provided herein, such as topical compositions, may further comprise Polyquad®. In another embodiment, the pharmaceutical compositions provided herein do not contain a preservative.

[0280] The pharmaceutical compositions provided herein may further comprise a solubilizing agent. Suitable solubilizing agents include, but are not limited to, tyloxapol, fatty acid glycerol polyethylene glycol esters, fatty acid polyethylene glycol esters, polyethylene glycol, glycerol ethers, or cyclodextrins.

[0281] The pharmaceutical compositions provided herein may further include non-toxic additives, such as emulsifiers, wetting agents, or fillers, e.g., polyethylene glycols designated 200, 300, 400, and 600, or carbowaxes designated 1000, 1500, 4000, 6000, and 10000. The amount and type of additive added will depend on the specific requirements and generally range from approximately 0.0001 to approximately 90% by weight. Other compounds may also adjust (e.g., increase) the viscosity of the carrier in addition to the pharmaceutical compositions provided herein. Examples of viscosity-enhancing agents include, but are not limited to, polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, various polymers of the cellulose family, vinyl polymers, and acrylic acid polymers.

[0282] The pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension or solution. In one embodiment, the aqueous pharmaceutical composition of the present disclosure is in the form of an aqueous suspension.

[0283] Aqueous pharmaceutical compositions according to the present disclosure can be prepared using standard procedures familiar to those skilled in the art, for example, by mixing the various components, suitably at ambient temperature and atmospheric pressure. In one embodiment, the aqueous pharmaceutical composition of the present disclosure is suitable for administration to the eye.

[0284] In further embodiments, the pharmaceutical composition of the present disclosure is in the form of an eye ointment, eye gel, eye cream, or eye drops.

[0285] In a further embodiment, the pharmaceutical composition of the present disclosure is administered topically to the eye of a subject.

[0286] The compounds of formula (I), in free form or in the form of a pharmaceutically acceptable salt, exhibit valuable pharmacological properties, such as TRPV1 antagonistic properties, as shown in in vitro tests such as those provided in the Examples, and are therefore of use for therapy or as research chemicals, for example, for use as tool compounds.

[0287] Further properties of the disclosed compounds include good potency in the biological assays described herein, a favorable safety profile, and favorable pharmacokinetic properties.

[0288] Diseases and Disorders and Methods of Use In a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

[0289] In a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder for which a TRPV1 antagonist is indicated. In one embodiment, the disease or disorder is affected by inhibition of TRPV1 activity.

[0290] The compounds of formula (I) and pharmaceutically acceptable salts thereof have TRPV1 antagonist activity and are useful in the treatment or prevention of certain diseases or disorders or in the treatment of pain associated with these, such as respiratory diseases, asthma, cough, chronic obstructive pulmonary disease (COPD), bronchoconstriction, rhinitis, inflammatory disorders, pain, such as acute pain, chronic pain, neuropathic pain, post-operative pain, post-rheumatoid arthritis pain, osteoarthritic pain, back pain, visceral pain, cancer pain, hyperalgesia, neuralgia, toothache, headache, migraine, neuropathy, carpal tunnel syndrome, diabetic neuropathy, It is believed to be potentially useful for the treatment of HIV-associated neuropathy, post-herpetic neuralgia, fibromyalgia, neuritis, sciatica, nerve injury, ischemia, neurodegeneration, stroke, post-stroke pain, multiple sclerosis, esophagitis, heartburn, Barrett's dysplasia, dysphagia, gastroesophageal reflux disorder (GERD), gastric and duodenal ulcers, functional dyspepsia, irritable bowel syndrome, inflammatory bowel disease, colitis, Crohn's disease, pelvic hypersensitivity, pelvic pain, menstrual pain, renal colic, urinary incontinence, cystitis, burns, itch, psoriasis, pruritus and vomiting, eye diseases or disorders.

[0291] In one embodiment, the ocular disease or disorder is an ocular surface disorder. In a further embodiment, the ocular surface disorder is chronic ocular surface pain (COSP), dry eye disease (dry eye symptoms associated with refractive surgery, e.g., LASIK surgery), Sjogren's syndrome, conjunctivitis (including dry eye symptoms including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), ... Selected from patients recovering from membrane dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctival chalazion, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis.

[0292] In one embodiment, the ocular disease or disorder is ocular surface pain. In some embodiments, the ocular surface pain is acute or episodic ocular surface pain. In some embodiments, the ocular surface pain is chronic ocular surface pain, for example, lasting for at least 3 months.

[0293] In one embodiment, the ocular disease or disorder is ocular redness.

[0294] In view of their activity as TRPV1 inhibitors, the compounds of formula (I) and its subformulas, in free or pharmaceutically acceptable salt form, are useful in the treatment of conditions treatable by inhibition of TRPV1 activity. In one aspect, the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or its subformulas, or a pharmaceutically acceptable salt thereof.

[0295] In another aspect, the present disclosure provides a method for treating or preventing a disease or disorder affected by inhibition of TRPV1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof.

[0296] In another aspect, the present disclosure provides a method of inhibiting TRPV1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof.

[0297] In another aspect, the present disclosure provides a method of antagonizing TRPV1 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof.

[0298] In another aspect, the present disclosure provides a method for treating or preventing a disease or disorder mediated by TRPV1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof.

[0299] In another aspect, the present disclosure provides a method for treating, reducing, or preventing pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or its subformulas or a pharmaceutically acceptable salt thereof. The pain can be acute, for example, pain resulting from injury or surgery, or chronic. Examples of pain include, in particular, pain such as bone pain and joint pain (osteoarthritis), cancer pain, myofascial pain (muscle injury, fibromyalgia), and perioperative pain (general surgery, perioperative pain). Other examples include chronic pain, in particular inflammatory pain, for example, chronic inflammatory pain. Further examples of pain include pain in which TRPV1 activation plays or is suggested to play a role, and therefore is amenable to treatment with the compounds disclosed herein. Such conditions include chronic pain with an inflammatory component, such as rheumatoid arthritis; bone and joint pain (osteoarthritis); post-operative pain; musculoskeletal pain, such as fibromyalgia; myofascial pain syndrome; headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain; ear pain; episiotomy pain; burns, especially the primary hyperalgesia associated therewith; deep and visceral pain, such as cardiac pain, muscular pain, ocular pain, orofacial pain, migraine, abdominal pain, gynecological pain, such as dysmenorrhea and labour pain; pain associated with the genitourinary tract, such as cystitis and vulvodynia; inflammatory skin disorders, such as psoriasis and chronic pain associated with nerve injury and / or diseases affecting the nervous system, such as neuropathic pain associated with post-herpetic neuralgia, diabetic neuropathy, chemotherapy-induced neuropathy, amputation ("phantom limb pain"), nerve entrapment and brachial plexus avulsion, low back pain, sciatica and ankylosing spondylitis, reflex sympathetic dystrophy and other chronic nerve injuries; complex regional pain syndrome; central nervous system pain, such as pain due to spinal cord or brainstem injury or stroke; gout; scar pain; pain associated with carcinoma, often referred to as cancer pain.

[0300] In another aspect, the present disclosure provides a method for treating or preventing an inflammatory disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or its subformulas, or a pharmaceutically acceptable salt thereof. Exemplary inflammatory diseases include inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD) or asthma; cough; urinary incontinence; migraine headache; visceral disorders such as inflammatory bowel disease; rhinitis; cystitis, such as interstitial cystitis; pancreatitis; uveitis; inflammatory skin disorders such as eczema and psoriasis; rheumatoid arthritis; intestinal inflammatory disorders such as irritable bowel syndrome; Crohn's disease; ulcerative colitis; and cystitis, such as interstitial cystitis, nephritis, and uveitis.

[0301] In another aspect, the present disclosure provides a method for achieving smooth muscle relaxation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof. Examples of diseases or conditions requiring a smooth muscle relaxant include treatment of spasms of the gastrointestinal tract or uterus, for example, in the treatment of Crohn's disease, ulcerative colitis, or pancreatitis.

[0302] In another aspect, the present disclosure provides a method for treating or preventing airway hyperresponsiveness or treating or preventing inflammatory events associated with airway disease, comprising administering to a subject a therapeutically effective amount of a compound of Formula (I) or a subformula thereof or a pharmaceutically acceptable salt thereof. Exemplary conditions include asthma, suppression or reversal of airway hyperresponsiveness in asthma. Other conditions include both intrinsic and, particularly, extrinsic asthma, such as allergic asthma, as well as exercise-induced asthma, occupational asthma, asthma induced following bacterial infection, other non-allergic asthma, and "wheezing infant syndrome." Effectiveness in treating asthma is evidenced by a reduction in the frequency or severity of symptomatic attacks, such as acute asthma or bronchoconstriction attacks, and a reduced need for other symptomatic treatments, such as anti-inflammatory drugs, e.g., corticosteroids; or bronchodilators, e.g., β2-adrenergic therapy. Other inflammatory or obstructive airways diseases include, for example, aluminosis, anthracosis, asbestosis, stone disease, trichiasis, siderosis, silicosis, tobacco poisoning, and pneumoconiosis of any type or origin, including byssinosis (an inflammatory (generally occupational) disease of the lungs, often associated with repeated inhalation of dust). Further inflammatory or obstructive airways diseases and conditions include adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease or airways disease (COPD or COAD), and bronchitis, allergic and vasomotor rhinitis.

[0303] In another aspect, the present disclosure provides a method for treating or preventing septic shock in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof. Exemplary conditions include septic shock, e.g., as an antivolemic and / or antihypotensive agent; inflammatory bowel disease; cerebral edema; and in the treatment of headache.

[0304] In another aspect, the present disclosure provides a method of treating an ocular surface disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure relates to a method of treating dry eye disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof.

[0305] In another aspect, the disclosure provides a method for treating or reducing ocular surface pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the ocular surface pain is acute or episodic ocular surface pain. In some embodiments, the ocular surface pain is chronic ocular surface pain, e.g., lasting for at least three months. In one embodiment, the ocular surface pain or chronic ocular surface pain is associated with dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophies (including recurrent corneal dystrophy), upper eyelid ulcers, and the like. In patients recovering from one or more of: cortical basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctival chalazion, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis.

[0306] In certain embodiments, the ocular surface pain or chronic ocular surface pain is associated with dry eye disease or Sjögren's syndrome. In some embodiments of the methods described herein, the subject suffers from eye pain that persists for at least three months after laser photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK). In some embodiments, the subject suffers from conjunctivitis, subconjunctival hemorrhage, subconjunctival scarring, conjunctival membrane, conjunctival ulcer, punctate superficial epithelial erosion, epithelial defect, eyelid margin ulcer, eyelid margin keratinization, synechiae, blepharophimosis, trichiasis, anterior blepharitis, lacrimal punctum occlusion, meibomian gland disease, corneal opacity, dry eye, distichiasis, limbal stem cell failure, or corneal angiogenesis.

[0307] In another aspect, the disclosure provides a method for treating or reducing ocular redness in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the ocular redness is associated with dry eye disease, Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), geographic-punctate-fingerprint dystrophy, acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophies (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, and the like. The ocular hyperemia may be associated with one or more of the following conditions: trophy, corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctival laxity, keratopathy (including herpes keratopathy, filamentous keratopathy, band or bullous keratopathy, and lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis. In certain embodiments, the ocular hyperemia is associated with dry eye disease. In one embodiment of the methods described herein, the ocular hyperemia persists for at least three months after laser photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK).

[0308] All of the above embodiments relating to the methods of treating the above diseases may further comprise A compound of formula (I) or a sub-formula thereof or a pharmaceutically acceptable salt thereof for use in the treatment of the above diseases according to the present disclosure; Use of a compound of formula (I) or a sub-formula thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of the above diseases according to the present disclosure; Use of a compound of formula (I) or a sub-formula thereof or a pharmaceutically acceptable salt thereof for the treatment of the above diseases according to the present disclosure; and A pharmaceutical composition comprising a compound of formula (I) or any sub-formula thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers for use in the treatment of the above diseases according to the present disclosure. are equally applicable to

[0309] Dosage The pharmaceutical composition or combination of the present disclosure may be in a unit dosage of about 1 to 1000 mg of the active ingredient, or about 1 to 500 mg, or about 1 to 250 mg, or about 1 to 150 mg, or about 0.5 to 100 mg, or about 1 to 50 mg of the active ingredient for a subject weighing about 50 to 70 kg. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease being treated, and its severity.

[0310] The above dosage characteristics can be demonstrated in vitro and in vivo tests, preferably using mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and preparations thereof. The compounds of the present disclosure can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo, e.g., as a suspension or in aqueous solution, enterally, parenterally, preferably intravenously. The in vitro dosage is about 10 -3 Molar concentration ~10 -9 The therapeutically effective amount in vivo may range from about 0.1 to 500 mg / kg, or from about 1 to 100 mg / kg, depending on the route of administration.

[0311] In certain embodiments, the present disclosure provides for administration of a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof, to a subject in need thereof in an ophthalmically compatible pharmaceutical composition, wherein the compound is present at a concentration of about 0.01% w / v to about 10.0% w / v. In some embodiments, the compound of Formula I is administered to the subject 1 to 6 times daily, e.g., to the ocular surface, e.g., once, twice, three times, or four times daily. In some embodiments, the compound of Formula (I) is administered to the subject for a period of at least about 1 month, at least about 2 months, or at least about 3 months. The therapeutically effective dosage of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the subject, and the disorder or disease being treated and its severity.

[0312] Preferred compositions of the present invention are intended for administration to a human patient suffering from an ocular disease or disorder. Preferably, such compositions are administered topically.

[0313] The activity of compounds according to the present disclosure can be assessed by the in vitro methods described in the Examples.

[0314] Combination therapy In another aspect, the present disclosure provides a pharmaceutical combination comprising a compound of formula (I) or a sub-formula thereof or a pharmaceutically acceptable salt thereof and one or more further therapeutic agents for simultaneous, separate or sequential use in therapy.

[0315] The compounds of the present disclosure may be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present disclosure may be administered separately by the same or different administration routes, or together in the same pharmaceutical composition as other agents. A therapeutic agent is, for example, a compound, peptide, antibody, antibody fragment, or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with a compound of the present disclosure. Thus, in one embodiment, the present disclosure provides a combination comprising a therapeutically effective amount of a compound of formula or a subformula thereof or a pharmaceutically acceptable salt thereof and one or more therapeutically active agents.

[0316] In certain embodiments, a compound of formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof, may be administered together with an additional therapeutic agent. A non-limiting list of such agents includes cyclooxygenase-2 (COX-2) inhibitors, such as certain COX-2 inhibitors, e.g., celecoxib and rofecoxib; and nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid and propionic acid derivatives; tricyclic antidepressants, such as Anafranil®, Asendin®, Aventyl®, Elavil®, Endep®, Norfranil®, Norpramin®, Pamelor®, Sinequan®, Surmontil®, Tipramine®, Tofranil®, Vivactil®, Tofranil-PM®; anticonvulsants, such as carbamazepine, oxcarbazepine, and gabapentin; bradykinin B1 or B2 antagonists; and GABA B Agonists, such as L-baclofen, include pharmaceutical agents effective in treating diseases and conditions in which vanilloid receptor activation plays or is implicated as playing a role.

[0317] In certain embodiments, the additional therapeutic agent may include, for example, other compounds and antibodies useful for treating eye disorders. A non-limiting list of such agents includes retinoid X receptor agonists, such as vitamin A, retinoic acid, phytanic acid, lithocholic acid, bexarotene, docosahexaenoic acid, or fluorobexarotene. Other additional therapeutic agents include ophthalmic steroids, such as dexamethasone, fluocinolone, loteprednol, difluprednate, fluorometholone, prednisolone, prednisone, medrysone, triamcinolone, betamethasone, rimexolone, or pharmaceutically acceptable salts thereof. Furthermore, other additional therapeutic agents include those used to target ocular surface disorders, such as dry eye disease. Non-limiting examples of such additional therapeutic agents include Xiidra® (lifitegrast), Restasis® (cyclosporine), minocycline, doxycycline, or other tetracycline antibiotics. Other examples include keratolytic agents such as selenium disulfide, salicylic acid, glycolic acid, and the like, or pharmaceutically acceptable salts thereof.

[0318] In certain embodiments, the additional therapeutic agent may include, for example, other compounds useful in the treatment of pain. In one embodiment, a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof, may be administered with an additional analgesic agent. Such an analgesic agent may be an NSAID (e.g., acetylsalicylic acid and propionic acid derivatives, e.g., Aleve®), an opioid, or a steroid.

[0319] In one embodiment, the present disclosure provides a product comprising a compound of Formula (I) or a sub-formula thereof, or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy. In one embodiment, the therapy is treatment of a disease or condition modulated by TRPV1. Products provided as combined preparations include compositions comprising a compound of Formula (I) or a sub-formula thereof, or a pharmaceutically acceptable salt thereof, and another therapeutic agent together in the same pharmaceutical composition, or in separate forms, e.g., in the form of a kit.

[0320] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof, and another therapeutic agent. Optionally, the pharmaceutical composition may include a pharmaceutically acceptable carrier, as described above.

[0321] In one embodiment, the present disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula (I) or a subformula thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises a means for retaining the compositions separately, such as a container, a divided bottle, or a divided foil packet. One example of such a kit is a blister pack, such as those typically used for packaging tablets, capsules, and the like.

[0322] In the combination therapy of the present disclosure, the compound of the present disclosure and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the present disclosure and the other therapeutic agent may be combined into a combination therapy (i) prior to release of the combination product to the physician (e.g., in the case of a kit containing the compound of the present disclosure and the other therapeutic agent); (ii) by (or under the direction of) the physician immediately prior to administration; or (iii) in the patient himself / herself, for example, during sequential administration of the compound of the present disclosure and the other therapeutic agent.

[0323] Preparation of compounds It is understood that in the following description, combinations of substituents and / or variables of the depicted formula are permissible only if such combinations result in stable compounds.

[0324] It will also be recognized by those skilled in the art that in the processes described below, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, phenol, amino, and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, and the like. Suitable protecting groups for amino, amidino, and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl, or arylalkyl esters.

[0325] Protecting groups can be added or removed according to standard techniques well known to those skilled in the art and as described herein. The use of protecting groups is described in detail in JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T.W. Greene and P.G.M. Buts, "Greene's Protective Groups in Organic Synthesis", Fourth Edition, Wiley, New York 2007; P.J. Kocienski, "Protecting Groups", Third Edition, Georg Thieme Verlag, Stuttgart and New York 2005; and "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th Edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974.

[0326] The protecting group can also be a polymer resin, such as a Wang resin or a 2-chlorotrityl chloride resin.

[0327] The following reaction examples illustrate methods for making the compounds of the present disclosure. Those skilled in the art will understand that these compounds can be made by similar methods or methods known to those skilled in the art. In general, the starting components and reagents can be obtained from sources such as, for example, Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI and Fluorochem USA, Strem, other commercial suppliers, or can be synthesized by sources known to those skilled in the art, or can be prepared as described in this disclosure.

[0328] Analytical methods, materials and instruments Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance spectrometer or a Varian Oxford 400 MHz spectrometer unless otherwise noted. Spectra are given in ppm (δ), and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26), or other solvents as indicated in the NMR spectral data. A small amount of dry sample (2–5 mg) was dissolved in an appropriate deuterated solvent (1 mL). Chemical names were generated using ChemBioDraw Ultra v12 from CambridgeSoft.

[0329] Mass spectra (ESI-MS) were collected using a Waters System (Acquity UPLC and Micromass ZQ mass spectrometer) or an Agilent-1260Infinity (6120 Quadrupole); all masses reported are the m / z of the protonated parent ion unless otherwise reported. Samples were dissolved in an appropriate solvent, e.g., MeCN, DMSO, or MeOH, and injected directly onto the column using an automated sample processor. The analysis is performed on a Waters Acquity UPLC system (Column: Waters Acquity UPLC BEH C18, 1.7 μm, 2.1 × 30 mm; Flow rate: 1 mL / min; 55 °C (column temperature); Solvent A: 0.05% formic acid in water, Solvent B: 0.04% formic acid in MeOH; Gradient: 95% solvent A from 0 to 0.10 min; 95% solvent A to 20% solvent A from 0.10 to 0.50 min; 20% solvent A to 5% solvent A from 0.50 to 0.60 min; Hold at 5% solvent A from 0.6 to 0.8 min; 5% solvent A to 95% solvent A from 0.80 to 0.90 min; and hold at 95% solvent A from 0.90 to 1.15 min).

[0330] List of abbreviations P(OEt)3 Triethyl phosphite rt room temperature h time aq water-based LCMS Liquid Chromatography Mass Spectrometry MS mass spectrometry m / z mass-to-charge ratio NMR nuclear magnetic resonance br Widening d;dd double line;double line of double lines m multiplet MHz Megahertz q quartet t triple line NBS N-Bromosuccinimide EtOAc ethyl acetate THF tetrahydrofuran DMF Dimethylformamide TEA Triethylamine MeOH Methanol MeCN acetonitrile AcOH acetic acid Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride DMAP 4-dimethylaminopyridine p-TsCl p-Toluenesulfonyl chloride IPA Isopropyl Alcohol t-BuOH t-butanol g grams mL milliliter mmol millimole mg milligram min TBDMS-Cl tert-butyldimethylsilyl chloride M mole HPLC High-Performance Liquid Chromatography Et2O ethyl ether DMSO dimethyl sulfoxide LDA Lithium diisopropylamide TBAF Tetra-n-butylammonium fluoride MeMgBr Methylmagnesium bromide DIBAL-H Diisobutylaluminum hydride TBDMS-OTf tert-butyldimethylsilyl trifluoromethylsulfonate Rt retention time CF3TMS Trifluoromethyltrimethylsilane NaOMe Sodium methoxide Boc2O di-tert-butyl dicarbonate PPh3 Triphenylphosphine n-BuLi n-butyllithium DAST Diethylaminosulfur trifluoride TFA trifluoroacetic acid HATU Hexafluorophosphate Azabenzotriazole Tetramethyluronium DIPEA N,N-Diisopropylethylamine MeNO2 Nitromethane Ms2O methanesulfonic anhydride PTSA p-toluenesulfonic acid MsCl methanesulfonyl chloride Ac2O acetic anhydride Cu(OTf)2 Copper II Trifluoromethanesulfonate TMSCN Trimethylsilyl cyanide m-CPBA meta-chloroperbenzoic acid Pd(dppf)(Cl2·CH2Cl2) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane

[0331] LCMS conditions: LCMS Method 1A: Instrument: API 2000, Triple Quad, ESI. Column: Mercury MS Synergi, 2µ (20 x 4.0 mm), C12; Gradient: A - 0.1% formic acid in water, B - acetonitrile; Time / %B: 0.0 / 30, 0.5 / 30, 1.5 / 95, 2.0 / 95, 2.5 / 30, 3.0 / 30; Flow Rate: 2.0 mL / min; UV Detection Array 190-400; Mass Detection 100-1000 (electrospray ionization); Column Temperature 30 °C.

[0332] LCMS Method 2A: Instrument: API3000, Column: Synergi, 2.5µ (50 × 4.6 mm), MAX-RP100A; Gradient: A - 0.1% formic acid in water, B - acetonitrile; Time / %B: 0.0 / 20, 0.2 / 50, 1.0 / 95, 2.5 / 95, 2.9 / 50, 3.2 / 20, 4 / 20; Flow rate: 1.2 mL / min; UV detection array 190–400 (full wavelength chromatogram), mass detection 100–1000 (electrospray ionization); Column temperature 30 °C.

[0333] LCMS Method 3A: Instrument: API 3200Q Trap, Triple Quad, ESI. Column: Synergi, 2.5µ (50 x 4.6 mm), MAX-RP100A. Gradient: A - 0.1% formic acid in water, B - acetonitrile. Time / %B: 0.0 / 20, 0.2 / 50, 1.0 / 95, 2.7 / 95, 2.8 / 50, 4.0 / 20. Flow rate: 1.2 mL / min. UV detector array: 190-400 (full wavelength chromatogram); Mass detector: 100-1000 (electrospray ionization). Column temperature: 30 °C.

[0334] LCMS Method 4A: Instrument: Agilent 1100 Series with a single quadrupole dual-mode mass spectrometer. Column: Zorbax XBD C18 (50 x 4.6 mm) 1.8 μm; Gradient: A - 0.1% formic acid in water, B - acetonitrile; Time / % B: 0.0 / 10, 0.5 / 10, 1.0 / 95.0, 2.0 / 95, 2.1 / 10, 3.5 / 10; Flow Rate: 1.2 mL / min; UV Detection Array 200-400; Mass Detection 100-1000 (electrospray ionization); Column Temperature 40 °C.

[0335] LCMS Method 4B: Instrument: Agilent 1100 Series with a single quadrupole dual-mode mass spectrometer. Column: Synergi, 2.5μ, MAX-RP100A Mercury; Gradient: A - 0.1% formic acid in water, B - acetonitrile; Time / %B: 0.0 / 10, 0.5 / 10, 1 / 95.0, 2.0 / 10, 3.0 / 10; Flow Rate: 2.0 mL / min; UV Detection Array 200-400; Mass Detection 100-1000 (electrospray ionization); Column Temperature 40 °C.

[0336] LCMS Method 5A: Instrument: Agilent 1290-Infinity II. Column: Kinetex EVO, 2.6µ (50 x 4.6 mm); Gradient: A - 0.1% formic acid in water, B - acetonitrile; Time / %B: 0.0 / 20, 0.25 / 20, 0.1 / 95.0, 2.5 / 95, 3.0 / 20, 4 / 20; Flow rate: 1.5 mL / min; UV detector: 200-400, Mass detector: 100-1000 (electrospray ionization); Column temperature: 40 °C.

[0337] LCMS Method 6A: Instrument: Shimadzu Nexera LCMS-2020 with single quadrupole. Column: Synergi, 2.5µ (20 x 4.0 mm), MAX-RP100A Mercury. Gradient: A - 0.1% formic acid in water, B - acetonitrile. Time / %B: 0.1 / 5, 0.5 / 5, 1.0 / 95, 1.5 / 95, 2.0 / 5, 3.0 / 5. Flow rate: 2.0 mL / min. UV detector array: 200-400; Mass detector: 100-1000 (electrospray ionization). Column temperature: 40 °C.

[0338] LCMS Method 7A: Instrument: Agilent 1290 Infinity RRLC equipped with Agilent 6120 Mass Detector and Diode Array Detector. Mobile phase (A) 2 mM ammonium acetate followed by 0.1% formic acid in water (B) 0.1% formic acid in acetonitrile. BEH C18 (50 * The column oven temperature was 22°C, the flow rate was 0.55 ml / min, and the run time was 3.0 min.

[0339] LCMS Method 7B: Instrument: Waters H-Class Acquity UPLC equipped with an SQ detector and a photodiode array detector with mobile phase (A) 2 mM ammonium acetate followed by 0.1% formic acid in water (B) 0.1% formic acid in acetonitrile. BEH C18 (50 * The column oven temperature was 22°C, the flow rate was 0.55 ml / min, and the run time was 3.0 min.

[0340] LCMS Method 7C: Instrument: Waters AcQuity UPLC equipped with Waters AcQuity UPLC PDA and Waters AcQuity UPLC ELSD. Mass Spectrometer: Waters Qda. Mobile phase: 0.1% formic acid in water followed by 0.1% formic acid in acetonitrile, AcQuity UPLC BEH C18, 1.7 μm, 2.1×30 mm, column temperature 50° C., flow rate 1 mL / min. Run time was 5.20 min.

[0341] NMR Instrument Details: Nuclear magnetic resonance spectroscopy was performed using one of the following instrument conditions: NMR-300: VARIAN300 (Mercury), equipped with ASW probe (proton, carbon, fluorine, phosphorus), Z-gradient, operating VnmrJ2.2 NMR-400: VARIAN400, equipped with ATB probe (proton, carbon, fluorine) and Z-gradients, running VnmrJ3.2 NMR-600: INOVA600, equipped with HCN probe (proton, carbon, nitrogen), Z-gradient, running VnmrJ2.2 NMR-400-b: Bruker 400, equipped with BBFO cryoprobe (proton, carbon, fluorine and broadband), Z-gradient, operated by TOPSPIN 3.5 NMR-400-c: Bruker NMR 400MHz Avance III HD with 5mm PABBO BB / 19F-1H / D Z-GRD

[0342] Testing Procedure: Example 1: Synthesis of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-methylisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl Step 1.1: Synthesis of 6-methylisoquinoline-5-carbaldehyde [ka] To a solution of 5-bromo-6-methylisoquinoline [CAS No. 1146298-61-4] (0.4 g, 1.80 mmol) in dry THF (10 mL), n-BuLi (2.5 M in THF) (1.1 mL, 2.70 mmol) was added dropwise at −78° C. and stirred for 30 minutes under an argon atmosphere. DMF (0.27 mL, 3.60 mmol) was added dropwise at −78° C., and the temperature was gradually raised to room temperature and stirred for 1 hour. The reaction mixture was quenched with 10% NH4Cl solution and extracted three times with EtOAc. The combined organic portions were washed with brine solution, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (12 g SiliCycle column, 0-50% EtOAc in hexanes eluent) to give 6-methylisoquinoline-5-carbaldehyde (0.16 g, 52%). MS (ESI+) [Method 1A]: m / z 172.0 (M+H); Rt 0.14 min. 1 H NMR(400MHz,CD3OD)δ 10.89(s,1H),9.22(s,1H),8.88(d,J=6.4Hz,1H),8.51(d,J=6.0Hz,1H),8.23(d,J=8.0Hz,1H),7.63(d,J=8.0Hz,1H),2.89(s,3H).

[0343] Step 1.2: Synthesis of tert-butyl ((1r,3r)-3-(4-fluoro-3(trifluoromethyl)phenoxy)cyclobutyl)carbamate [ka] To a solution of tert-butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate (6.0 g, 32.04 mmol) in THF (60 mL) was added 4-fluoro-3-(trifluoromethyl)phenol [CAS number 61721-07-1] (6.3 g, 35.25 mmol), PPh3 (12.6 g, 48.07 mmol), and diisopropyl azodicarboxylate (9.4 mL, 48.07 mmol) at room temperature. The reaction mixture was stirred at 50 °C under a N2 atmosphere for 16 h. The reaction mixture was concentrated, and the residue was purified by flash chromatography (40 g SiliCycle column, 0–30% EtOAc in hexane eluent) to give tert-butyl ((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)carbamate (8.4 g, 75%). 1 H NMR(300MHz,CDCl3)δ 7.12-7.08(m,1H),6.95-6.87(m,2H),4.79-4.72(m,1H),4.31-4.27(m,1H),2.59-2.50(m,2H),2.43-2.37(m,2H),1.45(s,9H).

[0344] Step 1.3: Synthesis of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl [ka] A round-bottom flask was charged with tert-butyl ((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)carbamate (8.4 g, 28.05 mmol) and HCl solution (20% in 1,4-dioxane) (80 mL) and stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was triturated with pentane and the solid that appeared was filtered and dried to give (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (5.1 g crude). LCMS [Method 6A]: m / z 250.1 [M+H] + ;Rt1.29 mins.

[0345] Step 1.4: Synthesis of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-methylisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl [ka] A solution of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (80 mg, 0.28 mmol), and TEA (40 mg, 0.28 mmol) in MeOH (2 mL) was stirred at room temperature for 15 minutes; then, 6-methylisoquinoline-5-carbaldehyde (43 mg, 0.25 mmol) and AcOH (0.01 mL) were added and stirred at room temperature for 16 hours under argon. NaBH (22 mg, 0.56 mmol) was then added at 0° C. and stirred at room temperature for another hour. The reaction mixture was concentrated in vacuo, and the residue was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine solution, dried over anhydrous NaSO, filtered, and concentrated in vacuo. Preparative HPLC of the crude material (column: XBRIDGE C18, (150 mm × 19 mm), 5.0 μm; mobile phase: 0.1% NH 4 OH in water and acetonitrile) gave (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-methylisoquinolin-5-yl)methyl)cyclobutan-1-amine. To a solution of the isolated product in 1,4-dioxane (1 mL) was added HCl solution (4 M in 1,4-dioxane) (2 mL) at 10 °C, stirred at room temperature for 4 hours, and then concentrated in vacuo to give (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-methylisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl (80 mg, 93%). MS(ESI+) [Method 5A]: m / z405.1(M+H); Rt1.32 min. 1H NMR(400MHz,CD3OD)δ 9.78(s,1H),8.72(s,2H),8.52(d,J=8.8Hz,1H),8.04(d,J=8.0Hz,1H),7.30(t,J=9.6Hz,1H),7.16-7.10(m ,2H),5.06-5.04(m,1H),4.84(s,2H),4.41-4.38(m,1H),2.94-2.90(m,2H),2.88(s,3H),2.78-2.72(m,2H).

[0346] Example 2: Synthesis of (1r,3r)-N-((6-methylisoquinolin-5-yl)methyl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutan-1-amine, HCl Step 2.1: Synthesis of tert-butyl ((1r,3r)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)carbamate [ka] To a solution of tert-butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate (200 mg, 1.07 mmol) in THF (5 mL) was added 6-(trifluoromethyl)pyridin-3-ol [CAS number 216766-12-0] (191 mg, 1.17 mmol), PPh (420 mg, 1.60 mmol), and diisopropyl azodicarboxylate (0.25 mL, 1.60 mmol) at room temperature. The reaction mixture was stirred at 50 °C under a N atmosphere for 16 hours. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine solution, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0-20% EtOAc in hexanes eluent) to give tert-butyl ((1r,3r)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)carbamate (300 mg, 71%). 1H NMR(300MHz,CDCl3)δ 8.26(d,J=2.8Hz,1H),7.60(s,1H),7.14(dd,J=8.8,3.2Hz,1H),4.90-4.85(m,1H), 4.78(br,1H),4.33-4.29(m,1H),2.62-2.56(m,2H),2.50-2.46(m,2H),1.45(s,9H).

[0347] Step 2.2: Synthesis of (1r,3r)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutan-1-amine, HCl [C-07838-037] [ka] To a solution of tert-butyl ((1r,3r)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)carbamate (300 mg, 0.90 mmol) in CHCl was added HCl solution (4 M in 1,4-dioxane) (3 mL) and stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo to give crude (1r,3r)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutan-1-amine, HCl (300 mg, 109%). LCMS [Method 6A]: m / z 233.1 [M+H] + ;Rt1.22 mins.

[0348] Step 2.3: Synthesis of (1r,3r)-N-((6-methylisoquinolin-5-yl)methyl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutan-1-amine, HCl [ka] The title compound was synthesized in a manner similar to that described in step 1.4 using (1r,3r)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutan-1-amine, HCl (100 mg, 0.37 mmol) and 6-methylisoquinoline-5-carbaldehyde (Example 1, step 1.1, 55 mg, 0.34 mmol). Purification of the crude material by flash chromatography (12 g SiliCycle column, 0–8% MeOH in CHCl eluent) followed by treatment with HCl solution (4 M in 1,4-dioxane) afforded (1r,3r)-N-((6-methylisoquinolin-5-yl)methyl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutan-1-amine, HCl (40 mg, 34%). MS (ESI+) [Method 6A]: m / z 388.3 (M+H); Rt 1.24 min. 1 H NMR(400MHz,CD3OD)δ 9.76(s,1H),8.71(s,2H),8.51(d,J=8.4Hz,1H),8.34(d,J=2.8Hz,1H),8.02(d,J=8.8Hz,1H),7.78(d,J=8.4Hz,1H),7. 48-7.46(m,1H),5.21-5.17(m,1H),4.85(s,2H),4.43-4.39(m,1H),3.02-2.97(m,2H),2.88(s,3H),2.81-2.77(m,2H).

[0349] Example 3: Synthesis of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl Step 3.1: Synthesis of 6-fluoroisoquinoline-5-carbaldehyde [ka] To a solution of 6-fluoroisoquinoline [CAS No. 1075-11-2] (0.4 g, 2.72 mmol) in anhydrous THF (10 mL), LDA (2 M in THF) (2.04 mL, 4.08 mmol) was added dropwise at −78° C. and stirred for 2.5 hours under a N atmosphere. Piperidine-1-carbaldehyde [CAS No. 2591-86-8] (0.92 g, 8.15 mmol) dissolved in THF (5 mL) was added dropwise over a period of 0.5 hours at −78° C. and stirred for 1 hour, during which time the temperature was allowed to slowly rise to 0° C. The reaction was then quenched with saturated NH4Cl solution and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (12 g SiliCycle column, 0-20% EtOAc in hexanes eluent) to give 6-fluoroisoquinoline-5-carbaldehyde (0.17 g, 35%). MS (ESI+) [Method 6A]: m / z 175.9 (M+H); Rt 0.86 min.

[0350] Step 3.2: Synthesis of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl [ka] (1r,3r)-3-(4-Fluoro-3-(trifluoromethyl)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl was prepared in a similar manner as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (step 1.3, 200 mg, 0.70 mmol) and 6-fluoroisoquinoline-5-carbaldehyde (111 mg, 0.63 mmol). The residue was purified by preparative HPLC (column: LUNA Phenomenex (150 mm × 21.2 mm), 5.0 μm; mobile phase: 0.1% HCOH in water and acetonitrile) to give the product. To the isolated product was added HCl solution (4 M in 1,4-dioxane) (4 mL) at 10° C., stirred at room temperature for 2 hours, concentrated in vacuo, and then lyophilized to give (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl (139 mg, 44%). MS (ESI+) [Method 6A]: m / z 409.1 (M+H); Rt 1.31 min. 1 H NMR(400MHz,CD3OD)δ 9.90(s,1H),8.87-8.85(m,1H),8.81-8.77(m,2H),8.02(t,J=9.2Hz,1H),7.28(t,J=9.6Hz,1H),7.15- 7.09(m,2H),5.09-5.05(m,1H),4.84(s,2H),4.31-4.27(m,1H),2.97-2.90(m,2H),2.73-2.68(m,2H).

[0351] Example 4 Synthesis of 3-fluoro-6-((1r,3r)-3-(((6-fluoroisoquinolin-5-yl)methyl)amino)cyclobutoxy)-2-(trifluoromethyl)aniline, HCl and 5-fluoro-2-((1r,3r)-3-(((6-fluoroisoquinolin-5-yl)methyl)amino)cyclobutoxy)-4-(trifluoromethyl)aniline, HCl Step 4.1: Synthesis of (1r,3r)-3-(4-fluoro-2-nitro-3-(trifluoromethyl)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine [ka] To a round-bottom flask charged with concentrated H2SO4 (2 mL) was added KNO3 (68 mg, 0.68 mmol) at 0 °C. Then, (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine (Step 3.2, 230 mg, 0.56 mmol) dissolved in H2SO4 (2 mL) was added dropwise at 0 °C and stirred at room temperature for 16 h. The reaction mixture was poured dropwise onto ice, basified with aqueous NH4OH (30%), and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a mixture of (1r,3r)-3-(4-fluoro-2-nitro-3-(trifluoromethyl)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine and (1r,3r)-3-(4-fluoro-2-nitro-5-(trifluoromethyl)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine (200 mg crude). MS (ESI+) [Method 6A]: m / z 454.1 (M+H); Rt 1.32 min.

[0352] Step 4.2: Synthesis of 5-fluoro-2-((1r,3r)-3-(((6-fluoroisoquinolin-5-yl)methyl)amino)cyclobutoxy)-4-(trifluoromethyl)aniline, HCl [ka] To a solution of (1r,3r)-3-(4-fluoro-2-nitro-5-(trifluoromethyl)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine and (1r,3r)-3-(4-fluoro-2-nitro-3-(trifluoromethyl)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine (200 mg, 0.44 mmol) in AcOH (2 mL), Zn powder (50 mg, 0.75 mmol) was added at 0° C. and stirred at room temperature for 4 hours. The reaction mixture was basified with 2N NaOH solution and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: XBRIDGE (150 mm × 21.20 mm), 5.0 μm; mobile phase: 0.02% NH OH in water and acetonitrile) to give the products 5-fluoro-2-((1r,3r)-3-(((6-fluoroisoquinolin-5-yl)methyl)amino)cyclobutoxy)-4-(trifluoromethyl)aniline and 3-fluoro-6-((1r,3r)-3-(((6-fluoroisoquinolin-5-yl)methyl)amino)cyclobutoxy)-2-(trifluoromethyl)aniline. To the isolated products was added HCl solution (4 M in 1,4-dioxane) (2 mL) at 10° C., stirred at room temperature for 2 hours, concentrated, and the residue was washed with EtO-pentane in vacuo to give the HCl salts. 3-Fluoro-6-((1r,3r)-3-(((6-fluoroisoquinolin-5-yl)methyl)amino)cyclobutoxy)-2-(trifluoromethyl)aniline, HCl (15 mg, 7%): Rf 11.684 min (Column: WATERS XBRIDGE C18 (150 mm × 4.6 mm) 5.0 μ; Mobile phase: 0.05% NH4OH in water and acetonitrile). MS (ESI+) [Method 6A]: m / z 424.2 (M+H); Rt 1.31 min. 1H NMR(400MHz,CD3OD)δ 9.92(s,1H),8.92-8.90(m,1H),8.83-8.78(m,2H),8.04(t,J=9.2Hz,1H),6.95-6.92(m,2H ),5.15-5.12(m,1H),4.85(s,2H),4.37-4.41(m,1H),2.95-2.92(m,2H),2.79-2.76(m,2H).

[0353] Example 5: Synthesis of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl Step 5.1: Synthesis of 8-nitro-5-vinylisoquinoline [ka] A stirred solution of 5-bromo-8-nitroisoquinoline [CAS No. 63927-23-1] (0.50 g, 1.98 mmol) and tributyl(vinyl)stannane (0.72 g, 2.37 mmol) in toluene (10 mL) was degassed with argon for 10 min. Pd(PPh3)2Cl2 (0.13 g, 0.19 mmol) was then added, degassed, and heated at 100 °C under an argon atmosphere for 13 h. The reaction mixture was cooled to room temperature, filtered through a celite bed, and the bed was washed with EtOAc. The combined filtrate was washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0–20% EtOAc in hexanes eluent) to give 8-nitro-5-vinylisoquinoline (0.10 g, 25%). MS(ESI+) [Method 6A]: m / z201.0(M+H); Rt1.47 min.

[0354] Step 5.2: Synthesis of 8-nitroisoquinoline-5-carbaldehyde [ka] To a solution of 8-nitro-5-vinylisoquinoline (0.15 g, 0.75 mmol) in t-BuOH-1,4-dioxane (15 mL, 1:2 v / v) was added OsO (6 mg, 0.02 mmol) at room temperature and stirred for 15 min. Then, NaIO (0.8 g, 3.76 mmol) dissolved in water (3 mL) was added dropwise and stirred for 16 h at room temperature. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0–25% EtOAc in hexane eluent) to give 8-nitroisoquinoline-5-carbaldehyde (60 mg, 40%). MS (ESI+) [Method 6A]: m / z 202.9 (M+H); Rt 0.40 min.

[0355] Step 5.3: Synthesis of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((8-nitroisoquinolin-5-yl)methyl)cyclobutan-1-amine [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (Step 1.3, 85 mg, 0.30 mmol) and 8-nitroisoquinoline-5-carbaldehyde (54 mg, 0.27 mmol). MS (ESI+) [Method 1A]: m / z 435.6 (M+H); Rt 0.45 min.

[0356] Step 5.4: Synthesis of 5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-amine, HCl [C-07482-074] [ka] To a solution of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((8-nitroisoquinolin-5-yl)methyl)cyclobutan-1-amine (70 mg, 0.16 mmol) in AcOH (5 mL) was added Zn powder (53 mg, 0.80 mmol) at room temperature and stirred for 2 h. The reaction mixture was filtered through a celite bed, and the bed was washed with AcOH. The combined filtrate was concentrated in vacuo. The residue was basified with saturated NaHCO solution and extracted twice with CHCl. ​​The combined organic portions were washed with brine solution, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: GEMINI-NX-C18 (150 mm × 21.20 mm), 5.0 μm; mobile phase: water and 0.01% NHOH in acetonitrile-MeOH (1:1)). To the isolated product was added HCl solution (4 M in 1,4-dioxane) (1 mL) at 10° C., stirred at room temperature for 1 h, concentrated in vacuo, triturated with EtO-pentane, and the collected solid was dried to give 5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-amine, HCl (8 mg, 11%). MS (ESI+) [Method 6A]: m / z 406.3 (M+H); Rt 1.29 min. 1 H NMR(400MHz,CD3OD)δ 9.73(s,1H),8.43(d,J=7.2Hz,1H),8.33(d,J=7.2Hz,1H),8.00(d,J=8.4Hz,1H),7.28(d,J=7.2Hz,1H),7. 12-7.08(m,3H),5.02-4.98(m,1H),4.55(s,2H),4.20-4.18(m,1H),2.86-2.80(m,2H),2.67-2.61(m,2H).

[0357] Example 6 Synthesis of (6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol, HCl (or trans-(6-fluoro-5-(((3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol) Step 6.1: Synthesis of 1-(2-bromo-4-fluorophenyl)-N-(2,2-dimethoxyethyl)methanimine [ka] A two-necked round-bottom flask equipped with a Dean-Stark apparatus was charged with 2-bromo-4-fluorobenzaldehyde [CAS No. 59142-68-6] (250.0 g, 1231.47 mmol), 2,2-dimethoxyethan-1-amine (268 mL, 2459.77 mmol), and toluene (1000 mL). The reaction mixture was stirred at 130 °C for 16 h during azeotropic removal of HO. The reaction mixture was then concentrated in vacuo to give crude 1-(2-bromo-4-fluorophenyl)-N-(2,2-dimethoxyethyl)methanimine. 1 H NMR(300MHz,CDCl3)δ 8.58(s,1H),8.04(dd,J=8.7,6.3Hz,1H),7.30(dd,J=8.1,2.4Hz,1H),7.05(td ,J=8.7,2.4Hz,1H),4.68(t,J=5.4Hz,1H),3.81(d,J=5.4Hz,1H),3.42(s,6H).

[0358] Step 6.2: Synthesis of N-(2-bromo-4-fluorobenzyl)-2,2-dimethoxyethan-1-amine [ka] To a stirred solution of 1-(2-bromo-4-fluorophenyl)-N-(2,2-dimethoxyethyl)methanimine (404.0 g, 1392.4 mmol) in MeOH (2000 mL) was added NaBH (105.3 g, 2784.9 mmol) in portions at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated in vacuo, and the residue was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give crude N-(2-bromo-4-fluorobenzyl)-2,2-dimethoxyethan-1-amine (378.0 g, 92%). MS (ESI+) [Method 6A]: m / z 292.1 (M+H); Rt 1.25 min. 1 H NMR(400MHz,CDCl3)δ 7.36(dd,J=8.4,2.0Hz,1H),7.27(dd,J=8.4,2.8Hz,1H),7.01-6.98(m,1H ),4.48(t,J=5.6Hz,1H),3.84(s,2H),3.36(s,6H),2.72(d,J=5.2Hz,2H).

[0359] Step 6.3: Synthesis of N-(2-bromo-4-fluorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide [ka] To a solution of N-(2-bromo-4-fluorobenzyl)-2,2-dimethoxyethan-1-amine (378.0 g, 1293.8 mmol), TEA (541 mL, 1940.7 mmol), and DMAP (15.8 g, 129.4 mmol) in CHCl (2000 mL) was added p-TsCl portionwise at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with water and extracted twice with CHCl. ​​The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel 60-120 mesh size, 0-30% EtOAc in hexane eluent) to give N-(2-bromo-4-fluorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (568 g, 98%). MS(ESI+) [Method 6A]: m / z414.0(M+H); Rt1.67 min. 1 H NMR(600MHz,CDCl3)δ 7.72(d,J=8.4Hz,2H),7.50(dd,J=9.0,6.0Hz,1H),7.33(d,J=8.4Hz,2H),7.26-7.24(m,1H),7.03(td ,J=9.0,3.0Hz,1H),4.48(s,2H),4.36(t,J=5.4,1H),3.29(d,J=5.4Hz,2H),3.23(s,6H),2.45(s,3H),

[0360] Step 6.4: Synthesis of 8-bromo-6-fluoroisoquinoline [ka] To a stirred solution of AlCl (836.0 g, 6269.68 mmol) in anhydrous CHCl (2200 mL) was added dropwise N-(2-bromo-4-fluorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (560.0 g, 1254.68 mmol) dissolved in CHCl (800 mL) at −10° C. The reaction mixture was then stirred at room temperature under N for 16 h. The reaction mixture was poured onto ice and basified with 30% NaOH solution. The formed solid was filtered through a celite bed, and the bed was washed with CHCl. ​​The organic portion was separated, and the aqueous layer was extracted twice with CHCl. ​​The combined organic layers were washed with brine, anhydrous NaSO, filtered, and concentrated in vacuo to give crude 8-bromo-6-fluoroisoquinoline (300 g, 106%). MS (ESI+) [Method 6A]: m / z 226.0, 228.0 (M+H); Rt 1.41 min. 1 H NMR(600MHz,CDCl3)δ 9.56(s,1H),8.60(d,J=6.0Hz,1H),7.66(dd,J=7.8,1.6Hz,1H),7.59(d,J=6.0Hz,1H),7.42(dd,J=8.4,1.8Hz,1H).

[0361] Step 6.5: Synthesis of 6-fluoro-8-vinylisoquinoline [ka] A stirred solution of 8-bromo-6-fluoroisoquinoline [CAS No. 1258833-77-0] (25.0 g, 110.5 mmol), potassium trifluoro(vinyl)borate (29.6 g, 221.1 mmol), and TEA (61.6 mL, 442.3 mmol) in IPA (400 mL) was degassed with N for 10 min. Pd(dppf)Cl·CHCl (9.03 g, 11.05 mmol) was then added, degassed, and heated at 100 °C under a N atmosphere for 2 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (80 g SiliCycle column, 0-20% EtOAc in hexanes eluent) to give 6-fluoro-8-vinylisoquinoline (15.0 g, 78%). MS (ESI+) [Method 8]: m / z 174.1 (M+H); Rt 1.186 min.

[0362] Step 6.6: Synthesis of 6-fluoroisoquinoline-8-carbaldehyde [ka] The title compound was prepared according to the procedure in Step 5.2. The residue was purified by flash chromatography (80 g SiliCycle column, 0-25% EtOAc in hexanes eluent) to give 6-fluoroisoquinoline-8-carbaldehyde (11.0 g, 72%). MS (ESI+) [Method 1A]: m / z 176.1 (M+H); Rt 0.17 min.

[0363] Step 6.7: Synthesis of (6-fluoroisoquinolin-8-yl)methanol [ka] To a stirred solution of 6-fluoroisoquinoline-8-carbaldehyde (11.0 g, 62.79 mmol) in MeOH (220 mL) was added NaBH (3.56 g, 94.19 mmol) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was then concentrated in vacuo, and the residue was diluted with water and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give crude (6-fluoroisoquinolin-8-yl)methanol (11.0 g, 99%). MS (ESI+) [Method 1A]: m / z 178.2 (M+H); Rt 0.12 min.

[0364] Step 6.8: Synthesis of 8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoroisoquinoline [ka] To a stirred solution of (6-fluoroisoquinolin-8-yl)methanol (11.0 g, 62.08 mmol) and imidazole (21.1 g, 309.98 mmol) in DMF (110 mL) was added TBDMS-Cl (28.0 g, 185.77 mmol) portionwise at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with water and extracted twice with CHCl. ​​The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (80 g SiliCycle column, 0–15% EtOAc in hexanes eluent) to give 8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoroisoquinoline (11.0 g, 61%). MS (ESI+) [Method 1A]: m / z 292.2 (M+H); Rt 1.78 min.

[0365] Step 6.9: Synthesis of 8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoroisoquinoline-5-carbaldehyde [ka] To a stirred solution of 8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoroisoquinoline (5.0 g, 17.16 mmol) in anhydrous THF (50 mL) was added LDA (2 M in THF) (25.7 mL, 51.46 mmol) dropwise at −78° C. under a N atmosphere. After 2.5 h, ethyl formate (6.35 g, 85.78 mmol) dissolved in THF (25 mL) was added dropwise at −78° C. and stirred for an additional 1 h. The reaction was quenched with saturated NH4Cl solution and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40 g SiliCycle column, 0-10% EtOAc in hexanes eluent) to give 8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoroisoquinoline-5-carbaldehyde (3.4 g, 62%). MS (ESI+) [Method 4A]: m / z 320.2 (M+H); Rt 2.30 min.

[0366] Step 6.10: Synthesis of (1r,3r)-N-((8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (Step 1.3, 500 mg, 1.75 mmol) and 8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoroisoquinoline-5-carbaldehyde (830 mg, 2.63 mmol). The crude was purified by flash chromatography (12 g SiliCycle column, 0–25% EtOAc in hexanes eluent) to give (1r,3r)-N-((8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine (920 mg, 95%). MS(ESI+) [Method 6A]: m / z553.4(M+H); Rt1.42 min.

[0367] Step 6.11: Synthesis of (6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol, HCl [ka] To a solution of (1r,3r)-N-((8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine (920 mg, 1.66 mmol) in THF (15 mL) was added dropwise a TBAF solution (1 M in THF) (1.6 mL, 1.66 mmol) at 0 °C and stirred for 1 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic portions were washed with brine solution, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: EPIC (150 mm × 21.2 mm), 5.0 μ; mobile phase: 0.02% NHOH in water and acetonitrile). To the isolated product was added HCl solution (4 M in 1,4-dioxane) (4 mL) at 10° C., stirred at room temperature for 2 h, concentrated in vacuo, triturated with EtO-pentane, and the collected solid was dried to give (6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol, HCl (260 mg, 35%). MS (ESI+) [Method 6A]: m / z 439.2 (M+H); Rt 1.30 min. 1 H NMR(400MHz,CD3OD)δ 9.96(s,1H),8.84(d,J=7.2Hz,1H),8.79(d,J=7.2Hz,1H),8.04(d,J=10.4Hz,1H),7.29(t,J=9.6Hz,1H),7.15-7.09(m ,2H),5.31(s,2H),5.07-5.04(m,1H),4.81(d,J=1.2Hz,2H),4.31-4.26(m,1H),2.95-2.88(m,2H),2.74-2.67(m,2H).

[0368] Example 7: (S)-1-(6-fluoro-5-((((1r,3S)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol (or trans-(S)-1-(6-fluoro-5-(((3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol) and (R)-1-(6-fluoro-5-((((1r,3R)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol (or trans-(R)-1-(6-fluoro-5-(((3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol). Step 7.1: Synthesis of 6-fluoro-8-(oxiran-2-yl)isoquinoline [ka] To a solution of NaH (1.0 g, 41.45 mmol) and anhydrous DMSO (40 mL) was added trimethylsulfoxonium iodide (8.3 g, 37.68 mmol) at room temperature and stirred for 30 min. Then, 6-fluoroisoquinoline-8-carbaldehyde (Step 6.5, 3.3 g, 18.84 mmol) dissolved in DMSO (20 mL) was added dropwise at room temperature. After 5 min, the reaction was quenched with ice water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0–20% EtOAc in hexane eluent) to give 6-fluoro-8-(oxiran-2-yl)isoquinoline (2.3 g, 64%). MS (ESI+) [Method 6A]: m / z 190.1 (M+H); Rt 0.79 min. 1H NMR(600MHz,CDCl3)δ 9.55(s,1H),8.58(d,J=5.4Hz,1H),7.65(d,J=5.4Hz,1H),7.37(d,J=9.0Hz,2H),4.60-4.59(m,1H),3.37-3.35(m,1H),2.82-2.80(m,1H).

[0369] Step 7.2: Synthesis of 1-(6-fluoroisoquinolin-8-yl)ethane-1,2-diol [ka] To a solution of 6-fluoro-8-(oxiran-2-yl)isoquinoline (2.1 g, 11.11 mmol) in THF-HO (12 mL, 2:1 v / v) was added HSO (5 mL) dropwise at room temperature and stirred at 60 °C for 16 h. The reaction mixture was basified with saturated NaHCO solution and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0–5% MeOH in CHCl eluent) to give 1-(6-fluoroisoquinolin-8-yl)ethane-1,2-diol (1.6 g, 69%). MS (ESI+) [Method 4A]: m / z 208.3 (M+H); Rt 0.40 min. 1 H NMR(600MHz,CDCl3)δ 9.49(s,1H),8.49(d,J=6.0Hz,1H),7.67-7.63(m,2H),7.35(dd,J=8.4,1.8Hz,1H ),4.13-4.10(m,1H),4.06(dd,J=12.6,3.6Hz,1H),3.76(dd,J=11.4,3.6Hz,1H).

[0370] Step 7.3: Synthesis of 6-fluoro-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinoline [ka] To a solution of 1-(6-fluoroisoquinolin-8-yl)ethane-1,2-diol (1.5 g, 7.24 mmol) and imidazole (3.4 g, 50.68 mmol) in DMF (15 mL), TBDMS-Cl (5.4 g, 36.17 mmol) was added portionwise at 0 °C and stirred at room temperature for 16 h. The reaction mixture was then diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0–10% EtOAc in hexane eluent) to give 6-fluoro-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinoline (2.7 g, 85%). MS(ESI+) [Method 6A]: m / z436.3(M+H); Rt2.15 min. 1 H NMR(600MHz,CDCl3)δ 9.59(s,1H),8.52(d,J=4.8Hz,1H),7.61(d,J=5.4Hz,1H),7.55(dd,J=10.2,1.8Hz,1H),7.33(dd,J=9.0,2.4Hz,1H ),5.54(d,J=6.0Hz,1H),3.87-3.85(m,1H),3.77-3.74(m,1H),0.92(s,9H),0.90(s,9H),0.13(s,6H),0.09(s,6H).

[0371] Step 7.4: Synthesis of 6-fluoro-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinoline-5-carbaldehyde [ka] The title compound was prepared according to the procedure in step 6.8. The residue was purified by flash chromatography (40 g SiliCycle column, 0-15% EtOAc in hexanes eluent) to give 6-fluoro-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinoline-5-carbaldehyde (2.0 g, 62%). MS (ESI+) [Method 4A]: m / z 464.4 (M+H); Rt 1.77 min. 1 H NMR(600MHz,CDCl3)δ 9.57(s,1H),8.50(d,J=5.4Hz,1H),7.60(d,J=5.4Hz,1H),7.54(dd,J=7.8,2.4Hz,1H),7.32(dd,J=9.0,2.4Hz,1H) ,5.53(d,J=6.0Hz,1H),3.87-3.84(m,1H),3.76-3.73(m,1H),0.89(s,9H),0.75(s,9H),0.12(s,6H),-0.05(s,6H).

[0372] Step 7.5: Synthesis of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-fluoro-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinolin-5-yl)methyl)cyclobutan-1-amine [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (step 1.3, 1.0 g, 3.50 mmol) and 6-fluoro-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinoline-5-carbaldehyde (1.46 g, 3.15 mmol). The crude material was purified by flash chromatography (24 g SiliCycle column, 0–5% MeOH in CHCl3 eluent) to give (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-fluoro-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinolin-5-yl)methyl)cyclobutan-1-amine (1.5 g, 62%). MS (ESI+) [Method 6A]: m / z 697.3 (M+H); Rt 1.63 min.

[0373] Step 7.6: Synthesis of (S)-1-(6-fluoro-5-((((1r,3S)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol and (R)-1-(6-fluoro-5-((((1r,3R)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol [ka] To a solution of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-fluoro-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinolin-5-yl)methyl)cyclobutan-1-amine (1.5 g, 2.15 mmol) in THF (25 mL) was added dropwise a TBAF solution (1 M in THF) (5.4 mL, 5.38 mmol) at 0° C. and stirred for 2 hours. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic portions were washed with brine solution, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (24 g SiliCycle column, 0–10% MeOH in CHCl eluent) to give 1-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol (1.0 g, 98%). MS (ESI+) [Method 6A]: m / z 469.2 (M+H); Rt 1.29 min. 1 H NMR(400MHz,CD3OD)δ 9.57(s,1H),8.52(d,J=6.0Hz,1H),8.12(d,J=5.6Hz,1H),7.67(d,J=10.6Hz,1H),7.22(t,J=9.6Hz,1H),7.05-7.01(m,2H),5.58- 5.56(m,1H),4.85-4.82(m,1H),4.17(d,J=1.6Hz,2H),3.86-3.82(m,1H),3.78-3.74(m,1H),3.60-3.57(m,1H),2.36-2.33(m,4H).

[0374] Chiral preparative HPLC of the racemic compound (column: CHIRALPAK IG (250 mm × 20 mm); mobile phase: hexane and IPA:MeOH (1:1); isocratic: 60 / 40; flow rate: 15 mL / min) gave (S)-1-(6-fluoro-5-((((1r,3S)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol as a white solid peak 1 (395 mg, 40%): chiral HPLC: 99% (Rf 7.840 min; column: CHIRALPAK-IG (150 mm × 4.6 mm), 5.0 μm; mobile phase: n-hexane and EtOH; isocratic: 80 / 20; flow rate: 1 mL / min). MS(ESI+) [Method 1A]: m / z469.2(M+H); Rt1.29 min. 1 H NMR(400MHz,CD3OD)δ 9.57(s,1H),8.53(d,J=6.0Hz,1H),8.13(d,J=5.6Hz,1H),7.68(d,J=10.6Hz,1H),7.23(t,J=9.6Hz,1H),7.06-7.01(m,2H),5.5 and white Peak 2 (345 mg, 35%) was a colored solid: (R)-1-(6-fluoro-5-((((1r,3R)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol, chiral HPLC: 97% (Rf 17.481 min; column: CHIRALPAK-IG (150 mm × 4.6 mm), 5.0 μm; mobile phase: n-hexane and EtOH; isocratic: 80 / 20; flow rate: 1 mL / min). MS (ESI+) [Method 3A]: m / z 469.0 (M+H); Rt 1.25 min. 1H NMR(400MHz,CD3OD)δ 9.57(s,1H),8.53(d,J=6.0Hz,1H),8.13(d,J=5.6Hz,1H),7.68(d,J=10.6Hz,1H),7.23(t,J=9.6Hz,1H),7.06-7.01(m,2H),5.59- 5.56(m,1H),4.85-4.82(m,1H),4.18(d,J=1.2Hz,2H),3.87-3.83(m,1H),3.78-3.74(m,1H),3.60-3.57(m,1H),2.37-2.34(m,4H).

[0375] Example 8: Synthesis of 1-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethan-1-ol, HCl Step 8.1: Synthesis of 1-(6-fluoroisoquinolin-8-yl)ethan-1-ol [ka] To a stirred solution of 6-fluoroisoquinoline-8-carbaldehyde (Step 6.5, 0.7 g, 4.0 mmol) in anhydrous THF (10 mL) was added MeMgBr (3 M in EtO) (4.0 mL, 11.98 mmol) dropwise at 0 °C under a N atmosphere. The reaction mixture was stirred at 0 °C for 2 h and then quenched with saturated NH Cl solution. The reaction mixture was then extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous Na SO , filtered, and concentrated in vacuo to give 1-(6-fluoroisoquinolin-8-yl)ethan-1-ol (0.8 g crude). MS (ESI+) [Method 4B]: m / z 192.0 (M+H); Rt 0.20 min.

[0376] Step 8.2: Synthesis of 8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinoline [ka] The title compound was prepared by step 6.7. The residue was purified by flash chromatography (12 g SiliCycle column, 0-15% EtOAc in hexanes eluent) to give 8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinoline (0.9 g, 70%). MS (ESI+) [Method 6A]: m / z 306.2 (M+H); Rt 1.72 min. 1 H NMR(300MHz,CDCl3)δ 9.49(s,1H),8.51(d,J=5.4Hz,1H),7.62(d,J=4.5Hz,1H),7.55(dd,J=10.5,2.7Hz,1H),7.29(dd,J =9.3,2.7Hz,1H),5.66-5.62(m,1H),1.60(d,J=6.6Hz,3H),0.93(s,9H),0.11(s,3H),0.00(s,3H).

[0377] Step 8.3: Synthesis of 8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinoline-5-carbaldehyde [ka] The title compound was prepared by step 3.1, except that after adding piperidine-1-carbaldehyde, the reaction mixture was stirred at -78 °C for an additional 1 h. The residue was purified by flash chromatography (40 g SiliCycle column, 0-10% EtOAc in hexanes eluent) to give 8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinoline-5-carbaldehyde (0.7 g, 71%). MS (ESI+) [Method 6A]: m / z 334.1 (M+H); Rt 1.79 min.

[0378] Step 8.4: Synthesis of (1r,3r)-N-((8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (step 1.3, 0.3 g, 1.05 mmol) and 8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinoline-5-carbaldehyde (0.42 g, 1.26 mmol). The crude product was purified by flash chromatography (12 g SiliCycle column, 0–5% MeOH in CHCl eluent) to give (1r,3r)-N-((8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine (0.5 g, 84%). MS(ESI+) [Method 6A]: m / z567.2(M+H); Rt1.49 min.

[0379] Step 8.5: Synthesis of 1-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethan-1-ol, HCl [ka] To a solution of (1r,3r)-N-((8-(1-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine (0.5 g, 0.88 mmol) in THF (10 mL) was added dropwise a TBAF solution (1 M in THF) (1.06 mL, 1.06 mmol) at 0° C. and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic portions were washed with brine solution, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0–5% MeOH in CHCl eluent) to give 1-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethan-1-ol (0.4 g, quantitative). MS (ESI+) [Method 6A]: m / z 453.1 (M+H); Rt 1.33 min.

[0380] 100 mg of the product was repurified by preparative HPLC (column: GEMINI NX (150 mm × 21.2 mm), 5.0 μ; mobile phase: 0.02% NH OH in water and acetonitrile); to the isolated product was added HCl solution (4 M in 1,4-dioxane) (2 mL) at 10 °C, stirred at room temperature for 1 h, concentrated in vacuo, triturated with Et O, and the collected solid was dried in vacuo to give 1-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethan-1-ol, HCl as a white solid (33 mg, 33%). MS (ESI+) [Method 4A]: m / z 453.2 (M+H); Rt 1.47 min. 1H NMR(400MHz,CD3OD)δ 10.20(s,1H),8.90(d,J=6.8Hz,1H),8.78(d,J=6.8Hz,1H),8.06(d,J=10.8Hz,1H),7.30(t,J=9.6Hz,1H),7.15-7.09(m,2H),5. 73-5.70(m,1H),5.09-5.05(m,1H),4.82(s,2H),4.31-4.27(m,1H),2.97-2.90(m,2H),2.73-2.67(m,2H),1.68(d,J=6.8Hz,3H).

[0381] Example 9 Synthesis of 1-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)propane-1,3-diol, (S)-1-(6-fluoro-5-((((1r,3S)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)propane-1,3-diol, and (R)-1-(6-fluoro-5-((((1r,3R)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)propane-1,3-diol Step 9.1: Synthesis of ethyl 3-(6-fluoroisoquinolin-8-yl)-3-hydroxypropanoate [ka] A two-necked round-bottom flask was charged with EtOAc (1.51 mL, 15.41 mmol) and anhydrous THF (25 mL). LDA (2 M in hexanes) (8.6 mL, 17.12 mol) was then added dropwise at −78° C. and stirred under argon for 30 min. Finally, 6-fluoroisoquinoline-8-carbaldehyde (Step 6.5, 1.5 g, 8.56 mmol) dissolved in THF (5 mL) was added dropwise at −78° C. and stirred for 2.5 h. The reaction was quenched with saturated NH4Cl solution and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (24 g SiliCycle column, 0-20% EtOAc in hexanes eluent) to give ethyl 3-(6-fluoroisoquinolin-8-yl)-3-hydroxypropanoate (2.0 g, 88%). MS (ESI+) [Method 6A]: m / z 264.1 (M+H); Rt 1.24 min.

[0382] Step 9.2: Synthesis of 1-(6-fluoroisoquinolin-8-yl)propane-1,3-diol [ka] To a solution of ethyl 3-(6-fluoroisoquinolin-8-yl)-3-hydroxypropanoate (2.0 g, 7.59 mmol) in anhydrous THF (40 mL), DIBAL-H (1 M in toluene) (19.0 mL, 18.99 mmol) was added dropwise at −78° C. and stirred for 1 hour. The reaction mixture was then warmed to room temperature over 30 minutes. The reaction mixture was then quenched with saturated NH4Cl solution and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude 1-(6-fluoroisoquinolin-8-yl)propane-1,3-diol (1.8 g crude). MS (ESI+) [Method 6A]: m / z 222.1 (M+H); Rt 0.29 min.

[0383] Step 9.3: Synthesis of 6-fluoro-8-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-5-yl)isoquinoline [ka] To a stirred solution of 1-(6-fluoroisoquinolin-8-yl)propane-1,3-diol (1.8 g, 8.14 mmol), imidazole (2.7 g, 40.68 mmol), and DMAP (0.5 g, 4.07 mmol) in anhydrous DMF (35 mL) was added TBDMS-Cl (3.6 g, 24.4 mmol) at 0 °C and stirred at room temperature under a N atmosphere for 16 h. The reaction was diluted with water and extracted twice with CHCl. ​​The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (24 g SiliCycle column, 0-10% EtOAc in hexanes eluent) to give 6-fluoro-8-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-5-yl)isoquinoline (1.2 g, 30%). MS (ESI+) [Method 6A]: m / z 450.5 (M+H); Rt 2.44 min.

[0384] Step 9.4: Synthesis of 6-fluoro-8-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-5-yl)isoquinoline-5-carbaldehyde [ka] The title compound was prepared according to the procedure in step 6.8. The residue was purified by flash chromatography (24 g SiliCycle column, 0-15% EtOAc in hexanes eluent) to give 6-fluoro-8-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-5-yl)isoquinoline-5-carbaldehyde (0.8 g, 75%). MS (ESI+) [Method 1A]: m / z 478.3 (M+H); Rt 2.41 min.

[0385] Step 9.5: Synthesis of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-fluoro-8-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-5-yl)isoquinolin-5-yl)methyl)cyclobutan-1-amine [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (step 1.3, 0.4 g, 1.40 mmol) and 6-fluoro-8-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-5-yl)isoquinoline-5-carbaldehyde (0.8 g, 1.68 mmol). The crude material was purified by flash chromatography (24 g SiliCycle column, 0–5% MeOH in CHCl eluent) to give (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((6-fluoro-8-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-5-yl)isoquinolin-5-yl)methyl)cyclobutan-1-amine (0.97 g, 97%). MS (ESI+) [Method 6A]: m / z 711.3 (M+H); Rt 1.64 min.

[0386] Step 9.6: Synthesis of 1-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)propane-1,3-diol, (S)-1-(6-fluoro-5-((((1r,3S)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)propane-1,3-diol, and (R)-1-(6-fluoro-5-((((1r,3R)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)propane-1,3-diol [ka] The title compound was prepared according to the procedure in Step 7.6. Preparative HPLC of the residue (Column: WATERS X BRIDGE C18 (150 mm × 19.0 mm), 5.0 μ; Mobile phase: 0.02% NH4OH in water and acetonitrile) gave 1-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)propane-1,3-diol (335 mg, 51%). MS (ESI+) [Method 6A]: m / z 483.2 (M+H); Rt 1.30 min. 1 H NMR(400MHz,CD3OD)δ 9.64(s,1H),8.59(d,J=6.0Hz,1H),8.13(d,J=6.0Hz,1H),7.72(d,J=11.6Hz,1H),7.25(t,J=9.2Hz,1H),7.10-7.04(m,2H),5.76(dd,J=8.8 ,2.8Hz,1H),4.92-4.89(m,1H),4.17(s,2H),3.92-3.86(m,2H),3.75- 3.70(m,1H),2.56-2.47(m,4H),2.10-2.05(m,1H),2.02-1.95(m,1H).

[0387] Chiral preparative HPLC of the racemic compound (300 mg) (column: LUX AMYLOSE-1 (250 mm × 21.2 mm); mobile phase: hexane and EtOH:MeOH (1:1); isocratic: 75 / 25; flow rate: 15 mL / min) afforded (S)-1-(6-fluoro-5-((((1r,3S)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)propane-1,3-diol and (R)-1-(6-fluoro-5-((((1r,3R)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)propane-1,3-diol as white solids (peak 1: 130 mg, 43% and peak 2: 130 mg, 43%). Peak 1: Chiral HPLC: 98% (Rf 2.508 min; Column: LUX, AMYLOSE-1 (150 mm × 4.6 mm), 5.0 μ; Mobile phase: n-Hexane and 0.1% DEA in EtOH:MeOH (70:30); Isocratic: 50 / 50; Flow rate: 1 mL / min). MS (ESI+) [Method 5A]: m / z 483.2 (M+H); Rt 0.97 min. 1 H NMR (400 MHz, CD3OD) δ 9.59(s,1H),8.53(d,J=5.6Hz,1H),8.12(d,J=5.6Hz,1H),7.65(d,J=11.2Hz, 1H),7.22(t,J=9.2Hz,1H),7.06-7.01(m,2H),5.73(dd,J=8.8,3.2Hz,1H),4. 85-4.82(m,1H),4.17(d,J=1.6Hz,2H),3.91-3.85(m,1H),3.74-3.69(m,1H), 3.61-3.57(m,1H),2.45-2.35(m,,4H),2.10-2.04(m,1H),2.02-1.95(m,1H).

[0388] Peak 2: Chiral HPLC: 99% (Rf 3.035 min; Column: LUX, AMYLOSE-1 (150 mm × 4.6 mm), 5.0 μ; Mobile phase: n-Hexane and 0.1% DEA in EtOH:MeOH (70:30); Isocratic: 50 / 50; Flow rate: 1 mL / min). MS (ESI+) [Method 6A]: m / z 483.2 (M+H); Rt 1.32 min.1 H NMR (400 MHz, CD3OD) δ 9.59(s,1H),8.53(d,J=6.0Hz,1H),8.12(d,J=6.0Hz,1H),7.65(d,J=11.6Hz, 1H),7.22(t,J=10.0Hz,1H),7.06-7.01(m,2H),5.73(dd,J=8.8,3.6Hz,1H),4 .85-4.82(m,1H),4.17(d,J=2.0Hz,2H),3.91-3.85(m,1H),3.74-3.69(m,1H) ,3.61-3.58(m,1H),2.36-2.33(m,4H),2.08-2.06(m,1H),2.02-1.95(m,1H).

[0389] Example 10: Synthesis of 2-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethan-1-ol, HCl Step 10.1: Synthesis of (E)-8-(2-ethoxyvinyl)-6-fluoroisoquinoline [ka] To a stirred solution of 8-bromo-6-fluoroisoquinoline (Step 6.5, 1.0 g, 4.42 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.05 g, 5.31 mmol) in 1,4-dioxane-water (20 mL, 3:1 v / v) was added KPO (2.81 g, 13.27 mmol) and degassed with N for 10 min. Pd(dppf)Cl·CHCl (0.36 g, 0.44 mmol) was then added, degassed, and heated at 90 °C under a N atmosphere for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography (12 g SiliCycle column, 0-20% EtOAc in hexanes eluent) to give (E)-8-(2-ethoxyvinyl)-6-fluoroisoquinoline (1.0 g, 108%). MS (ESI+) [Method 6A]: m / z 218.0 (M+H); Rt 1.34 min. 1 H NMR(400MHz,CDCl3)δ 9.43(s,1H),8.49(d,J=5.6Hz,1H),7.55(d,J=5.6Hz,1H),7.26-7.22(m,2H),7.04(d ,J=12.4Hz,1H),6.52(d,J=12.8Hz,1H),4.04(q,J=7.2Hz,2H),1.41(t,J=7.2Hz,3H).

[0390] Step 10.2: Synthesis of 2-(6-fluoroisoquinolin-8-yl)acetaldehyde [ka] To a stirred solution of (£)-8-(2-ethoxyvinyl)-6-fluoroisoquinoline (0.5 g, 2.30 mmol) in THF (5 mL) was added 2N aqueous HCl (5 mL) and heated at 70 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO solution, and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give crude 2-(6-fluoroisoquinolin-8-yl)acetaldehyde (0.5 g, 87%). MS (ESI+) [Method 6A]: m / z 190.0 (M+H); Rt 1.37 min.

[0391] Step 10.3: Synthesis of 2-(6-fluoroisoquinolin-8-yl)ethan-1-ol [ka] To a solution of 2-(6-fluoroisoquinolin-8-yl)acetaldehyde (0.5 g, 2.64 mmol) in MeOH (5 mL) was added NaBH (0.15 g, 3.96 mmol) portionwise at 0 °C and stirred for 1 h. The reaction mixture was then concentrated in vacuo, and the residue was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give crude 2-(6-fluoroisoquinolin-8-yl)ethan-1-ol (0.5 g, 99%). MS (ESI+) [Method 6A]: m / z 192.2 (M+H); Rt 1.34 min.

[0392] Step 10.4: Synthesis of 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinoline [ka] The title compound was prepared by Step 6.7. The residue was purified by flash chromatography (12 g SiliCycle column, 0-15% EtOAc in hexanes eluent) to give 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinoline (0.11 g, 13%). MS (ESI+) [Method 6A]: m / z 306.0 (M+H); Rt 1.60 min.

[0393] Step 10.5: Synthesis of 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinoline-5-carbaldehyde [ka] To a stirred solution of 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinoline (0.11 g, 0.36 mmol) in anhydrous THF (1.5 mL) was added LDA (2 M in THF) (0.36 mL, 0.72 mmol) dropwise at −78° C. under a N atmosphere. After 2.5 h, piperidine-1-carbaldehyde (0.12 g, 1.08 mmol) dissolved in THF (0.5 mL) was added dropwise at −78° C. and stirred for an additional 1 h while the temperature was allowed to slowly rise to 0° C. The reaction was quenched with saturated NH4Cl solution and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0-10% EtOAc in hexanes eluent) to give 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinoline-5-carbaldehyde (70 mg, 58%). MS (ESI+) [Method 6A]: m / z 334.1 (M+H); Rt 1.70 min.

[0394] Step 10.6: Synthesis of (1r,3r)-N-((8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (step 1.3, 70 mg, 0.25 mmol) and 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinoline-5-carbaldehyde (65 mg, 0.20 mmol). The crude was purified by flash chromatography (12 g SiliCycle column, 0–5% MeOH in CHCl eluent) to give (1r,3r)-N-((8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine (100 mg, 72%). MS(ESI+) [Method 6A]: m / z567.2(M+H); Rt1.45 min.

[0395] Step 10.7: Synthesis of 2-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethan-1-ol, HCl [ka] Deprotection was carried out using the procedure in step 8.5. The residue was purified by preparative HPLC (Column: X-BRIDGE (150 mm × 19 mm), 5.0 μm; Mobile phase: 0.02% NH OH in water and acetonitrile). To the isolated product was added HCl solution (4 M in 1,4-dioxane) (2 mL) at 10 °C, stirred at room temperature for 1 h, concentrated in vacuo, triturated with Et O, and the collected solid was dried in vacuo to give 2-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethan-1-ol, HCl (22 mg, 25%). MS (ESI+) [Method 6A]: m / z 453.1 (M+H); Rt 1.33 min. 1 H NMR(400MHz,CD3OD)δ 10.01(s,1H),8.82(d,J=6.8Hz,1H),8.76(d,J=6.8Hz,1H),7.95(d,J=10.4Hz,1H),7.28(t,J=9.2Hz,1H),7.14-7.09(m,2H),5.06-5.0 3(m,1H),4.81(d,J=1.6Hz,2H),4.27-4.23(m,1H),3.99(t,J=6.0Hz,2H),3.55(t,J=6.0Hz,2H),2.93-2.87(m,2H),2.73-2.67(m,2H).

[0396] Example 11: Synthesis of 3,3,3-trifluoro-1-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)propan-1-ol Step 11.1: Synthesis of 3,3,3-trifluoro-1-(6-fluoroisoquinolin-8-yl)propan-1-ol [ka] A round-bottom flask containing AgF (1.09 g, 8.66 mmol) was degassed and flushed with oxygen (three times). 6-Fluoro-8-vinylisoquinoline (Step 6.5, 1.0 g, 5.77 mmol) and CF3TMS (0.85 mL, 5.77 mmol) dissolved in anhydrous DMF (10 mL) were then added in one portion at 0 °C. The reaction mixture was stirred under an oxygen atmosphere at 0 °C. After 1 h, another portion of CF3TMS (0.85 mL, 5.77 mmol) was added and stirred under the same conditions for 2 h. The reaction mixture was diluted with Et2O and filtered through a celite bed. The celite bed was washed thoroughly with Et2O. The filtrate was collected, washed with water (twice), brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (12 g SiliCycle column, 0-20% EtOAc in hexanes eluent) to give 3,3,3-trifluoro-1-(6-fluoroisoquinolin-8-yl)propan-1-ol (0.3 g, 20%). MS (ESI+) [Method 1A]: m / z 259.9 (M+H); Rt 0.17 min.

[0397] Step 11.2: Synthesis of 8-(1-((tert-butyldimethylsilyl)oxy)-3,3,3-trifluoropropyl)-6-fluoroisoquinoline [C-08422-047] [ka] To a solution of 3,3,3-trifluoro-1-(6-fluoroisoquinolin-8-yl)propan-1-ol (0.24 g, 0.93 mmol) and imidazole (0.31 g, 2.78 mmol) in DMF (5 mL), TBDMS-OTf (0.63 mL, 2.78 mmol) was added dropwise at 0 °C and stirred at room temperature. After 16 h, imidazole (0.31 g, 2.78 mmol) and TBDMS-OTf (0.63 mL, 2.78 mmol) were added again at 0 °C and stirred at room temperature for 20 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0-10% EtOAc in hexanes eluent) to give 8-(1-((tert-butyldimethylsilyl)oxy)-3,3,3-trifluoropropyl)-6-fluoroisoquinoline (0.25 g, 72%). MS (ESI+) [Method 1A]: m / z 374.3 (M+H); Rt 2.03 min.

[0398] Step 11.3: Synthesis of 8-(1-((tert-butyldimethylsilyl)oxy)-3,3,3-trifluoropropyl)-6-fluoroisoquinoline-5-carbaldehyde [ka] The title compound was prepared according to the procedure in Step 10.5. The residue was purified by flash chromatography (12 g SiliCycle column, 0-20% EtOAc in hexanes eluent) to give 8-(1-((tert-butyldimethylsilyl)oxy)-3,3,3-trifluoropropyl)-6-fluoroisoquinoline-5-carbaldehyde (0.15 g, 70%). MS (ESI+) [Method 1A]: m / z 402.5 (M+H); Rt 2.08 min.

[0399] Step 11.4: Synthesis of (1r,3r)-N-((8-(1-((tert-butyldimethylsilyl)oxy)-3,3,3-trifluoropropyl)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (step 1.3, 120 mg, 0.42 mmol) and 8-(1-((tert-butyldimethylsilyl)oxy)-3,3,3-trifluoropropyl)-6-fluoroisoquinoline-5-carbaldehyde (150 mg, 0.38 mmol). The crude material was purified by flash chromatography (12 g SiliCycle column, 0–5% MeOH in CHCl3 eluent) to give (1r,3r)-N-((8-(1-((tert-butyldimethylsilyl)oxy)-3,3,3-trifluoropropyl)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine (130 mg, 48%). MS (ESI+) [Method 1A]: m / z 635.1 (M+H); Rt 1.65 min.

[0400] Step 11.5: Synthesis of 3,3,3-trifluoro-1-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)propan-1-ol [C-08422-059] [ka] Deprotection was performed using the procedure in step 8.5. The residue was purified by flash chromatography (12 g SiliCycle column, 0–5% MeOH in CHCl eluent). The isolated product was repurified by reverse-phase MPLC (C Gold column, 0–100% MeCN in HO eluent) to give 3,3,3-trifluoro-1-(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)propan-1-ol (44 mg, 41%). MS (ESI+) [Method 5A]: m / z 521.2 (M+H); Rt 1.10 min. 1H NMR(400MHz,CD3OD)δ 9.53(s,1H),8.56(d,J=6.0Hz,1H),8.13(d,J=6.0Hz,1H),7.67(d,J=11.6Hz,1H),7.22(t,J=10.0Hz,1H),7.06-6.99(m,2H) ),5.86-5.82(m,1H),4.87-4.82(m,1H),4.19(d,J=1.6Hz,2H),3.51-3.55(m,1H),2.82-2.73(m,2H),2.34(t,J=6.0Hz,4H).

[0401] Example 12: Synthesis of 6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-amine Step 12.1: Synthesis of N-(6-fluoroisoquinolin-8-yl)-1,1-diphenylmethanimine [ka] To a stirred solution of 8-bromo-6-fluoroisoquinoline (Step 6.4, 0.5 g, 2.23 mmol) and diphenylmethanimine (0.6 g, 3.31 mmol) in 1,4-dioxane (30 mL) was added CsCO (1.7 g, 5.22 mmol) and purged with N for 10 min. Pd(dba) (0.18 g, 0.20 mmol) and Xantphos (0.23 g, 0.40 mmol) were then added, and the reaction mixture was heated at 90 °C under N for 16 h. The reaction mixture was cooled to room temperature and filtered through a celite bed, washing with ethyl acetate. The filtrate was concentrated in vacuo, and the crude material was purified by flash chromatography (24 g SiliCycle column, 0-20% EtOAc in hexanes eluent) to give N-(6-fluoroisoquinolin-8-yl)-1,1-diphenylmethanimine (0.8 g, quantitative). MS (ESI+) [Method 6A]: m / z 327.2 (M+H); Rt 1.48 min. 1 H NMR(300MHz,CDCl3)δ 9.37(s,1H),8.49(d,J=6.0Hz,1H),7.89-7.86(m,2H),7.57-7.47(m,4H),7.26-7.18 (m,3H),7.10-7.06(m,2H),6.99(dd,J=9.0,1.8Hz,1H),6.36(dd,J=10.2,1.2Hz,1H).

[0402] Step 12.2: Synthesis of N-(5-bromo-6-fluoroisoquinolin-8-yl)-1,1-diphenylmethanimine [ka] To a stirred solution of N-(6-fluoroisoquinolin-8-yl)-1,1-diphenylmethanimine (0.5 g, 1.53 mmol) in MeCN (10 mL) was added NBS (0.4 g, 2.25 mmol) at 0 °C and stirred under N for 1 h while the temperature was allowed to slowly rise to room temperature. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0–10% EtOAc in hexane eluent) to give N-(5-bromo-6-fluoroisoquinolin-8-yl)-1,1-diphenylmethanimine (0.5 g, 82%). MS (ESI+) [Method 6A]: m / z 405.1 (M+H); Rt 1.74 min.

[0403] Step 12.3: Synthesis of N-(6-fluoro-5-vinylisoquinolin-8-yl)-1,1-diphenylmethanimine [ka] A stirred solution of N-(5-bromo-6-fluoroisoquinolin-8-yl)-1,1-diphenylmethanimine (0.3 g, 0.74 mmol) and vinylSnBu3 (0.25 g, 0.79 mmol) in 1,4-dioxane (20 mL) was degassed with argon for 10 minutes. Pd(PPh3)4 (80 mg, 0.07 mmol) was then added, degassed, and heated at 100 °C under an argon atmosphere for 16 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (24 g SiliCycle column, 0-15% EtOAc in hexanes eluent) to give N-(6-fluoro-5-vinylisoquinolin-8-yl)-1,1-diphenylmethanimine (0.3 g, 100%). MS (ESI+) [Method 6A]: m / z 353.2 (M+H); Rt 1.59 min.

[0404] Step 12.4: Synthesis of 8-((diphenylmethylene)amino)-6-fluoroisoquinoline-5-carbaldehyde [ka] To a solution of N-(6-fluoro-5-vinylisoquinolin-8-yl)-1,1-diphenylmethanimine (0.2 g, 0.57 mmol) in t-BuOH-1,4-dioxane (15 mL, 1:2 v / v), OsO (10% in t-BuOH) (0.1 mL, 0.04 mmol) was added at room temperature and stirred for 15 minutes. NaIO (0.5 g, 2.35 mmol) dissolved in water (5 mL) was then added dropwise and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0-15% EtOAc in hexanes eluent) to give 8-((diphenylmethylene)amino)-6-fluoroisoquinoline-5-carbaldehyde (90 mg, 47%). MS (ESI+) [Method 4A]: m / z 355.1 (M+H); Rt 1.28 min.

[0405] Step 12.5: Synthesis of (1r,3r)-N-((8-((diphenylmethylene)amino)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (65 mg, 0.22 mmol), and 8-((diphenylmethylene)amino)-6-fluoroisoquinoline-5-carbaldehyde (90 mg, 0.25 mmol). Crude (1r,3r)-N-((8-((diphenylmethylene)amino)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine (100 mg, 77%) was used in the next step without purification. MS (ESI+) [Method 6A]: m / z 588.3 (M+H); Rt 1.40 min.

[0406] Step 12.6: Synthesis of 6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-amine [ka] A solution of (1r,3r)-N-((8-((diphenylmethylene)amino)-6-fluoroisoquinolin-5-yl)methyl)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine (100 mg, 0.17 mmol) and HCl solution (4 M in 1,4-dioxane) (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo and purified by preparative HPLC (LUNA Phenomenex (250 mm × 21.2 mm), 5.0 μm column; mobile phase: 0.01% NH 4 OH in water and acetonitrile) to give 6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-amine (6 mg, 8%). MS(ESI+) [Method 6A]: m / z424.1(M+H); Rt1.30 min. 1H NMR(400MHz,CD3OD)δ 9.41(s,1H),8.49-8.47(m,2H),7.92(d,J=10.0Hz,1H),7.89(t,J=11.6Hz,1H),7.13-7.08(m,2H),6.68(d ,J=13.2Hz,1H),4.96-4.92(m,1H),4.40(s,2H),4.04-3.99(m,1H),2.70-2.64(m,2H),2.62-2.57(m,2H).

[0407] Example 13: Synthesis of 5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-amine Step 13.1: Synthesis of tert-butyl (5-bromoisoquinolin-3-yl)(tert-butoxycarbonyl)carbamate [ka] A stirred solution of 5-bromoisoquinolin-3-amine [CAS No. 1192815-01-2] (2.0 g, 8.97 mmol) in THF (20 mL) was cooled to 0 °C. DMAP (2.19 g, 17.93 mmol) and BocO (3.9 g, 17.93 mmol) were then added and stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (12 g SiliCycle column, 0–8% EtOAc in hexanes eluent) to give tert-butyl (5-bromoisoquinolin-3-yl)(tert-butoxycarbonyl)carbamate (1.2 g, 30%). MS (ESI+) [Method 6A]: m / z 423.2, 425.2 (M+H); Rt 1.70 min. 1 H NMR(600MHz,CDCl3)δ 9.09(s,1H),8.16(s,1H),7.78-7.76(m,1H),7.72(d,J=9.0Hz,1H),7.59(s,1H),1.44(s,18H).

[0408] Step 13.2: Synthesis of tert-butyl (tert-butoxycarbonyl) (5-vinylisoquinolin-3-yl)carbamate [ka] A stirred solution of tert-butyl (5-bromoisoquinolin-3-yl)(tert-butoxycarbonyl)carbamate (1.2 g, 2.83 mmol), potassium trifluoro(vinyl)borate (0.76 g, 5.67 mmol), and TEA (0.79 mL, 5.67 mmol) in IPA (20 mL) was degassed with argon for 10 minutes. Pd(dppf)Cl.CHCl (185 mg, 0.23 mmol) was then added, degassed, and heated at 80 °C under an argon atmosphere for 16 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (12 g SiliCycle column, 0-10% EtOAc in hexanes eluent) to give tert-butyl (tert-butoxycarbonyl) (5-vinylisoquinolin-3-yl)carbamate (0.8 g, 80%). MS (ESI+) [Method 6A]: m / z 370.9 (M+H); Rt 1.67 min. 1 H NMR(300MHz,CDCl3)δ 9.12(s,1H),7.88-7.77(m,3H),7.55(s,1H),6.89(dd,J=17.4,10.5Hz,1H),,5.92(d,J=17.7Hz,1H),5.43(d,J=11.1Hz,1H),1.44(s,18H).

[0409] Step 13.3: Synthesis of tert-butyl (tert-butoxycarbonyl) (5-formylisoquinolin-3-yl)carbamate [ka] To a solution of tert-butyl (tert-butoxycarbonyl) (5-vinylisoquinolin-3-yl)carbamate (0.8 g, 2.16 mmol) in t-BuOH-1,4-dioxane (18 mL, 1:2 v / v) was added OsO (16 mg, 0.06 mmol) at 0 °C and stirred at room temperature for 20 minutes. Then, NaIO (1.38 g, 6.48 mmol) dissolved in water (4 mL) was added dropwise and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0-15% EtOAc in hexanes eluent) to give tert-butyl (tert-butoxycarbonyl) (5-formylisoquinolin-3-yl)carbamate (0.6 g, 62%). MS (ESI+) [Method 6A]: m / z 373.2 (M+H); Rt 1.60 min 1 H NMR(400MHz,CDCl3)δ 10.19(s,1H),9.30(s,1H),8.48(d,J=0.8Hz,1H),8.16(dd,J=8.8,1.6Hz,1H),7.94(d,J=8.8Hz,1H),7.74(s,1H),1.48(s,18H).

[0410] Step 13.4: Synthesis of tert-butyl (tert-butoxycarbonyl) (5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (Step 1.3, 200 mg, 0.70 mmol) and tert-butyl(tert-butoxycarbonyl)(5-formylisoquinolin-3-yl)carbamate (260 mg, 0.70 mmol). Crude tert-butyl(tert-butoxycarbonyl)(5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate (250 mg, 59%) was used in the next step without purification. MS (ESI+) [Method 1A]: m / z 606.0 (M+H); Rt 1.36 min.

[0411] Step 13.5: Synthesis of 5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-amine [ka] A solution of tert-butyl (tert-butoxycarbonyl)(5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate (250 mg, 0.41 mmol) and HCl solution (4 M in 1,4-dioxane) (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and purified by preparative HPLC (column: KINETEX EVO C18 (150 mm × 21.0 mm), 5.0 μm; mobile phase: 0.02% NH4OH in water and acetonitrile) to give 5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-amine (100 mg, 59%). MS(ESI+) [Method 6A]: m / z406.2(M+H); Rt1.30 min. 1H NMR(400MHz,CD3OD)δ 9.23(s,1H),8.13(d,J=8.8Hz,1H),8.00(d,J=6.8Hz,1H),7.53-7.50(m,2H),7.30(t,J=10.2Hz,1H),7.1 7-7.11(m,2H),5.08-5.04(m,1H),4.58(s,2H),4.27-4.23(m,1H),2.94-2.89(m,2H),2.72-2.67(m,2H).

[0412] Example 14: Synthesis of 6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-amine, HCl Step 14.1: Synthesis of tert-butyl (tert-butoxycarbonyl) (6-fluoroisoquinolin-3-yl)carbamate [ka] A stirred solution of 6-fluoroisoquinolin-3-amine [CAS No. 1260760-86-8] (17.0 g, 104.43 mmol) in THF (100 mL) was cooled to 0 °C. DMAP (51.2 g, 419.09 mmol) and BocO (120.0 mL, 522.34 mmol) were then added and stirred at room temperature for 24 h. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (80 g SiliCycle column, 0–15% EtOAc in hexanes eluent) to give tert-butyl (tert-butoxycarbonyl)(6-fluoroisoquinolin-3-yl)carbamate (15.0 g, 39%). MS(ESI+) [Method 6A]: m / z363.2(M+H); Rt1.64 min.

[0413] Step 14.2: Synthesis of tert-butyl (tert-butoxycarbonyl) (6-fluoro-5-formylisoquinolin-3-yl)carbamate [ka] To a stirred solution of tert-butyl (tert-butoxycarbonyl)(6-fluoroisoquinolin-3-yl)carbamate (4.0 g, 11.03 mmol) in anhydrous THF (40 mL) was added dropwise LDA (2 M in THF) (13.8 mL, 27.59 mmol) under a N atmosphere at −78° C. After 2.5 h, piperidine-1-carbaldehyde (2.7 mL, 33.11 mmol) dissolved in THF (10 mL) was added dropwise at −78° C. and stirred for an additional 1 h. The reaction was quenched with saturated NH4Cl solution and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (24 g SiliCycle column, 0-20% EtOAc in hexanes eluent) to give tert-butyl (tert-butoxycarbonyl) (6-fluoro-5-formylisoquinolin-3-yl)carbamate (2.5 g, 58%). MS (ESI+) [Method 6A]: m / z 391.2 (M+H); Rt 1.63 min.

[0414] Step 14.3: Synthesis of tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (Step 1.3, 1.1 g, 3.85 mmol) and tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-formylisoquinolin-3-yl)carbamate (2.1 g, 5.39 mmol). The crude was purified by flash chromatography (24 g SiliCycle column, 0–2% MeOH in CHCl eluent) to give tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate (2.0 g, 82%). MS(ESI+) [Method 6A]: m / z624.3(M+H); Rt1.43 min.

[0415] Step 14.4: Synthesis of 6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-amine, HCl [ka] Deprotection was carried out according to step 13.5. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (column: WATERS XBRIDGE C18 (150 mm × 20.0 mm), 5.0 μm; mobile phase: water and 0.02% NH4OH in acetonitrile). The isolated product was added with HCl solution (4 M in 1,4-dioxane) (5 mL), stirred at room temperature for 1 h, concentrated in vacuo, triturated with Et2O, and the collected solid was dried in vacuo to give 6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-amine, HCl (360 mg, 24%). MS (ESI+) [Method 5A]: m / z 424.3 (M+H); Rt 0.30 min. 1H NMR(400MHz,CD3OD)δ 9.10(s,1H),8.26-8.22(m,1H),7.45(s,1H),7.37(t,J=10.0Hz,1H),7.31(t,J=9.6Hz,1H),7.15-7.08(m ,2H),5.05-5.01(m,1H),4.56(d,J=1.6Hz,2H),4.26-4.21(m,1H),2.91-2.84(m,2H),2.73-2.66(m,2H).

[0416] Example 15: Synthesis of 5-((((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)amino)methyl)-6-fluoroisoquinolin-3-amine, HCl Step 15.1: Synthesis of tert-butyl ((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)carbamate [ka] The title compound was synthesized following the steps as described in step 1.2 using tert-butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate (1.0 g, 5.34 mmol) and 2,4-difluorophenol [CAS number 367-27-1] (0.7 g, 5.34 mmol). The residue was purified by flash chromatography (24 g SiliCycle column, 0–20% EtOAc in hexanes eluent) to give tert-butyl ((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)carbamate (2.0 g, 124%). 1 H NMR(300MHz,CDCl3)δ 6.88-6.81(m,1H),6.75-6.65(m,2H),4.99-4.94(m,1H),4.30-4.26(m,1H),2.63-2.54(m,2H),2.40-2.33(m,2H),1.44(s,9H).

[0417] Step 15.2: Synthesis of (1r,3r)-3-(2,4-difluorophenoxy)cyclobutan-1-amine, HCl [ka] A round-bottom flask was charged with tert-butyl ((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)carbamate (2.0 g, 6.69 mmol) and HCl solution (20% in 1,4-dioxane) (10 mL) and stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was triturated with pentane, and the solid that appeared was filtered and dried to give (1r,3r)-3-(2,4-difluorophenoxy)cyclobutan-1-amine, HCl (1.3 g, 103%). 1 H NMR(300MHz,CDCl3)δ 7.04-6.97(m,1H),6.92-6.86(m,2H),4.97-4.92(m,1H),4.01-3.96(m,1H),2.64-2.60(m,4H).

[0418] Step 15.3: Synthesis of tert-butyl (tert-butoxycarbonyl)(5-((((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)amino)methyl)-6-fluoroisoquinolin-3-yl)carbamate [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(2,4-difluorophenoxy)cyclobutan-1-amine, HCl (120 mg, 0.51 mmol), and tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-formylisoquinolin-3-yl)carbamate (Step 14.2, 240 mg, 0.61 mmol). The crude was purified by flash chromatography (12 g SiliCycle column, 0–4% MeOH in CHCl eluent) to give tert-butyl (tert-butoxycarbonyl)(5-((((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)amino)methyl)-6-fluoroisoquinolin-3-yl)carbamate (200 mg, 68%). MS(ESI+) [Method 6A]: m / z574.4(M+H); Rt1.38 min.

[0419] Step 15.4: Synthesis of 5-((((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)amino)methyl)-6-fluoroisoquinolin-3-amine, HCl [ka] Deprotection was carried out according to step 13.5. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (column: GEMINI NX (150 mm × 21.2 mm), 5.0 μm; mobile phase: 0.02% NH OH in water and acetonitrile). HCl solution (4 M in 1,4-dioxane) (1 mL) was added to the isolated product and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was triturated with Et O. The formed solid was collected by filtration and dried in vacuo to give 5-((((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)amino)methyl)-6-fluoroisoquinolin-3-amine, HCl (33 mg, 23%). MS (ESI+) [Method 6A]: m / z 374.2 (M+H); Rt 1.29 min. 1H NMR(400MHz,CD3OD)δ 9.11(s,1H),8.28-8.23(m,1H),7.43(s,1H),7.38(t,J=10.0Hz,1H),7.08-6.90(m,3H), 5.05-5.01(m,1H),4.56(s,2H),4.28-4.23(m,1H),2.88-2.83(m,2H),2.77-2.72(m,2H).

[0420] Example 16: Synthesis of 6-fluoro-5-((((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-amine, HCl Step 16.1: Synthesis of tert-butyl ((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)carbamate [ka] To a solution of NaH (60% in mineral oil) (66 mg, 1.65 mmol) in DMF (2 mL) was added 4-chloro-2-(trifluoromethyl)pyridine [CAS No. 131748-14-6] (200 mg, 1.10 mmol) followed by tert-butyl ((1r,3r)-3-hydroxycyclobutyl)carbamate [CAS No. 389890-42-0] (207 mg, 1.10 mmol) at 0 °C and stirred at room temperature for 16 h. The reaction was quenched with ice water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0-6% EtOAc in hexanes eluent) to give tert-butyl ((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)carbamate (250 mg, 68%). MS (ESI+) [Method 6A]: m / z 333.1 (M+H); Rt 1.57 min.

[0421] Step 16.2: Synthesis of (1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutan-1-amine [ka] A round-bottom flask was charged with tert-butyl ((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)carbamate (250 mg, 1.14 mmol) and HCl solution (4 M in 1,4-dioxane) (5 mL) and stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo. The residue was triturated with pentane and the solid that appeared was filtered and dried to give (1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutan-1-amine, HCl (300 mg crude). LCMS [Method 6A]: m / z 233.1 [M+H] + ;Rt0.70 min.

[0422] Step 16.3: Synthesis of tert-butyl (tert-butoxycarbonyl) (6-fluoro-5-((((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate [C-07860-048] [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutan-1-amine, HCl (130 mg, 0.48 mmol), and tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-formylisoquinolin-3-yl)carbamate (Step 14.2, 220 mg, 0.58 mmol). The crude was purified by flash chromatography (12 g SiliCycle column, 0–4% MeOH in CHCl eluent) to give tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-((((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate (200 mg, 68%). MS(ESI+) [Method 6A]: m / z607.4(M+H); Rt1.36 min.

[0423] Step 16.4: Synthesis of 6-fluoro-5-((((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-amine, HCl [C-07860-054] [ka] Deprotection was carried out according to step 13.5. The reaction mixture was then concentrated in vacuo and purified by preparative HPLC (column: KINETEX EVO C18, (150 mm × 21.2 mm), 5.0 μm; mobile phase: 0.05% NH4OH in water and acetonitrile). To the isolated product was added HCl solution (4 M in 1,4-dioxane) (1 mL) and stirred at room temperature for 1 h. The solvent was evaporated and the residue was triturated with Et2O. The formed solid was collected by filtration and dried in vacuo to give 6-fluoro-5-((((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-amine, HCl (30 mg, 20%). MS (ESI+) [Method 6A]: m / z 407.2 (M+H); Rt 1.26 min. 1 H NMR(400MHz,CD3OD)δ 9.15(s,1H),8.58(d,J=6.0Hz,1H),8.31-8.27(m,1H),7.54(s,1H),7.42(t,J=9.6Hz,1H),7.34(d,J=2.4Hz,1H),7. 17-7.15(m,1H),5.26-5.22(m,1H),4.60(d,J=2.0Hz,2H),4.32-4.28(m,1H),3.02-2.96(m,2H),2.82-2.75(m,2H).

[0424] Example 17: Synthesis of 6-fluoro-5-((((1r,3r)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-amine, HCl Step 17.1: Synthesis of tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-((((1r,3r)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutan-1-amine, HCl (Step 2.2, 130 mg, 0.48 mmol) and tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-formylisoquinolin-3-yl)carbamate (Step 14.2, 220 mg, 0.58 mmol). The crude was purified by flash chromatography (12 g SiliCycle column, 0–4% MeOH in CHCl eluent) to give tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-((((1r,3r)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate (200 mg, 68%). MS(ESI+) [Method 6A]: m / z607.4(M+H); Rt1.38 min.

[0425] Step 17.2: Synthesis of 6-fluoro-5-((((1r,3r)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-amine, HCl [ka] Deprotection was carried out according to step 13.5. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (column: KINETEX EVO C18 (150 mm × 21.2 mm), 5.0 μm; mobile phase: 0.02% NH4OH in water and acetonitrile). HCl solution (4 M in 1,4-dioxane) (1 mL) was added to the isolated product and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was triturated with Et2O. The formed solid was collected by filtration and dried in vacuo to give 6-fluoro-5-((((1r,3r)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-amine, HCl (35 mg, 24%). MS (ESI+) [Method 4B]: m / z 407.2 (M+H); Rt 0.97 min.1 H NMR(400MHz,CD3OD)δ 9.10(s,1H),8.32(d,J=2.8Hz,1H),8.26-8.22(m,1H),7.77(d,J=8.8,1H),7.46-7.43(m,2H),7.37(t,J=9. 6Hz,1H),5.19-5.15(m,1H),4.57(d,J=2.0Hz,2H),4.28-4.23(m,1H),2.98-2.91(m,2H),2.78-2.72(m,2H).

[0426] Example 18: Synthesis of (3-amino-6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol, HCl Step 18.1: Synthesis of 2-bromo-4-fluorobenzaldehyde oxime [ka] To a solution of 2-bromo-4-fluorobenzaldehyde [59142-68-6] (50.0 g, 246.29 mmol) in EtOH (600 mL) was added a solution of NaHCO (41.4 g, 492.58 mmol) and hydroxylamine hydrochloride (25.7 g, 369.44 mmol) in water (600 mL) at room temperature and stirred for 16 h. The reaction mixture was concentrated in vacuo to remove EtOH, diluted with water, and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give crude 2-bromo-4-fluorobenzaldehyde oxime (53.0 g, 98%). MS (ESI+) [Method 6A]: m / z 217.9 (M+H); Rt 1.50 min. 1 H NMR(300MHz,CDCl3)δ 8.47(s,1H),7.89(brs,1H),7.84-7.80(m,1H),7.34-7.32(m,1H),7.08-7.03(m,1H).

[0427] Step 18.2: Synthesis of (2-bromo-4-fluorophenyl)methanamine [ka] To a stirred solution of 2-bromo-4-fluorobenzaldehyde oxime (48.0 g, 220.15 mmol) in EtOH (480 mL) was added concentrated HCl (240 mL) at 0 °C. Zn powder was then added portionwise at 0 °C and stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo to remove EtOH, diluted with water, basified with aqueous NH OH, and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated in vacuo to give crude (2-bromo-4-fluorophenyl)methanamine (33.0 g, 73%). MS (ESI+) [Method 6A]: m / z 203.9 (M+H); Rt 0.29 min.

[0428] Step 18.3: Synthesis of N-(2-bromo-4-fluorobenzyl)-2,2-diethoxyacetimidamide [ka] To a solution of (2-bromo-4-fluorophenyl)methanamine (33.0 g, 161.73 mmol) in MeOH (350 mL), methyl 2,2-diethoxyacetimidate (31.3 g, 194.07 mmol) was added dropwise at room temperature and stirred at 70 °C for 16 hours. The reaction mixture was concentrated in vacuo to give crude N-(2-bromo-4-fluorobenzyl)-2,2-diethoxyacetimidamide (54.8 g, 101%). MS (ESI+) [Method 6A]: m / z 333.1 (M+H); Rt 1.29 min. 1 H NMR(300MHz,CDCl3)δ 7.46-7.42(m,1H),7.30-7.27(m,1H),7.02-6.99(m,1H),4.93(s,1H),4.48(s,2H),3.64-3.54(m,4H),1.25-1.20(m,6H).

[0429] Step 18.4: Synthesis of 8-bromo-6-fluoroisoquinolin-3-amine [ka] To a round-bottom flask charged with N-(2-bromo-4-fluorobenzyl)-2,2-diethoxyacetimidamide (54.8 g, 164.61 mmol), concentrated H2SO4 (351 mL, 6458.40 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was then cooled to 0 °C and poured into ice water. The resulting solution was basified with 50% NaOH solution and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 60-120 mesh size, 35% EtOAc in hexane eluent) to give 8-bromo-6-fluoroisoquinolin-3-amine (14.0 g, 32%). MS (ESI+) [Method 6A]: m / z 240.9, 242.9 (M+H); Rt 1.42 min. 1 H NMR(300MHz,CDCl3)δ 9.12(s,1H),7.29-7.26(m,1H),7.09(d,J=9.3Hz,1H),6.61(s,1H),2.62(brs,2H).

[0430] Step 18.5: Synthesis of tert-butyl (8-bromo-6-fluoroisoquinolin-3-yl)(tert-butoxycarbonyl)carbamate [ka] To a stirred solution of 8-bromo-6-fluoroisoquinolin-3-amine (13.0 g, 53.93 mmol) and DMAP (9.9 g, 80.89 mmol) in THF (150 mL) was added BocO (35.3 g, 161.78 mmol) at 0 °C, followed by stirring at room temperature for 16 h. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 60-120 mesh size, 20% EtOAc in hexane eluent) to give tert-butyl (8-bromo-6-fluoroisoquinolin-3-yl)(tert-butoxycarbonyl)carbamate (12.0 g, 50%). MS(ESI+) [Method 6A]: m / z443.0(M+H); Rt1.74 min. 1 H NMR(300MHz,CDCl3)δ 9.43(s,1H),7.64(dd,J=8.1,2.1Hz,1H),7.59(s,1H),7.42(dd,J=9.0,2.1Hz,1H),1.47(s,18H).

[0431] Step 18.6: Synthesis of tert-butyl (tert-butoxycarbonyl) (6-fluoro-8-vinylisoquinolin-3-yl)carbamate [ka] A stirred solution of tert-butyl (8-bromo-6-fluoroisoquinolin-3-yl)(tert-butoxycarbonyl)carbamate (8.0 g, 18.13 mmol), potassium trifluoro(vinyl)borate (4.05 g, 36.26 mmol), and TEA (5.05 mL, 36.26 mmol) in IPA (80 mL) was degassed with N for 10 min. Pd(dppf)Cl·CHCl (1.48 g, 1.81 mmol) was then added, degassed, and heated at 100 °C under N for 2 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography (40 g SiliCycle column, 0-10% EtOAc in hexanes eluent) to give tert-butyl (tert-butoxycarbonyl) (6-fluoro-8-vinylisoquinolin-3-yl)carbamate (3.7 g, 51%). MS (ESI+) [Method 5A]: m / z 389.2 (M+H); Rt 1.83 min. 1 H NMR(300MHz,CDCl3)δ 9.39(s,1H),7.56(s,1H),7.49-7.41(m,2H),7.37-7.34(m,1H),5.91(d,J=17.1Hz,1H),5.67(d,J=10.8Hz,1H),1.45(s,18H).

[0432] Step 18.7: Synthesis of tert-butyl (tert-butoxycarbonyl) (6-fluoro-8-formylisoquinolin-3-yl)carbamate [ka] To a solution of tert-butyl (tert-butoxycarbonyl) (6-fluoro-8-vinylisoquinolin-3-yl)carbamate (2.8 g, 7.21 mmol) in t-BuOH-1,4-dioxane (45 mL, 1:2 v / v) was added OsO (55 mg, 0.22 mmol) and stirred at room temperature for 15 minutes. Then, NaIO (7.7 g, 36.04 mmol) dissolved in water (30 mL) was added dropwise and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0-15% EtOAc in hexanes eluent) to give tert-butyl (tert-butoxycarbonyl) (6-fluoro-8-formylisoquinolin-3-yl)carbamate (1.9 g, 67%). MS (ESI+) [Method 6A]: m / z 391.1 (M+H); Rt 1.64 min.

[0433] Step 18.8: Synthesis of tert-butyl (tert-butoxycarbonyl) (6-fluoro-8-(hydroxymethyl)isoquinolin-3-yl)carbamate [ka] A solution of tert-butyl (tert-butoxycarbonyl) (6-fluoro-8-formylisoquinolin-3-yl)carbamate (1.9 g, 4.87 mmol) in MeOH (30 mL) was cooled to 0 °C. NaBH (0.27 g, 7.30 mmol) was then added portionwise and stirred for 1 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give crude tert-butyl (tert-butoxycarbonyl) (6-fluoro-8-(hydroxymethyl)isoquinolin-3-yl)carbamate (1.9 g, 99%). MS (ESI+) [Method 1A]: m / z 393.1 (M+H); Rt 1.68 min.

[0434] Step 18.9: Synthesis of tert-butyl (tert-butoxycarbonyl) (8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoroisoquinolin-3-yl)carbamate [ka] The title compound was prepared by step 6.7. The residue was purified by flash chromatography (12 g SiliCycle column, 0–15% EtOAc in hexanes eluent) to give tert-butyl (tert-butoxycarbonyl) (8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoroisoquinolin-3-yl)carbamate (2.0 g, 81%). MS (ESI+) [Method 1A]: m / z 507.4 (M+H); Rt 2.03 min. 1 H NMR(300MHz,CDCl3)δ 9.25(s,1H),7.57(s,1H),7.46(dd,J=9.3,2.4Hz,1H),7.31(dd,J=9.3,2.4Hz,1H),5.26(s,2H),1.44(s,18H),0.96(s,9H),0.16(s,6H).

[0435] Step 18.10: Synthesis of tert-butyl (tert-butoxycarbonyl) (8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-5-formylisoquinolin-3-yl)carbamate [ka] The title compound was prepared by Step 14.2. The residue was purified by flash chromatography (12 g SiliCycle column, 0–10% EtOAc in hexanes eluent) to give tert-butyl (tert-butoxycarbonyl)(8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-5-formylisoquinolin-3-yl)carbamate (0.5 g, 47%). MS (ESI+) [Method 6A]: m / z 535.4 (M+H); Rt 2.02 min.

[0436] Step 18.11: Synthesis of tert-butyl (tert-butoxycarbonyl)(8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (step 1.3, 300 mg, 1.05 mmol) and tert-butyl(tert-butoxycarbonyl)(8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-5-formylisoquinolin-3-yl)carbamate (560 mg, 1.05 mmol). The crude material was purified by flash chromatography (12 g SiliCycle column, 0–4% MeOH in CHCl eluent) to give tert-butyl (tert-butoxycarbonyl)(8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate (550 mg, 68%). MS (ESI+) [Method 6A]: m / z 768.5 (M+H); Rt 1.55 min.

[0437] Step 18.12: Synthesis of tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)-8-(hydroxymethyl)isoquinolin-3-yl)carbamate [ka] Deprotection was performed according to step 8.5. The residue was purified by flash chromatography (12 g SiliCycle column, 0–5% MeOH in CHCl eluent) to give tert-butyl (tert-butoxycarbonyl) (6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)-8-(hydroxymethyl)isoquinolin-3-yl)carbamate (450 mg, 96%). MS (ESI+) [Method 4B]: m / z 654.2 (M+H); Rt 1.10 min.

[0438] Step 18.13: Synthesis of (3-amino-6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol, HCl [ka] Deprotection was carried out according to step 13.5. The product was purified by preparative HPLC (column: WATERS X BRIDGE C18 (150 mm × 19.0 mm), 5.0 μm; mobile phase: 0.02% NH4OH in water and acetonitrile). HCl solution (4 M in 1,4-dioxane) (2 mL) was added to the isolated product and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was triturated with Et2O. The formed solid was collected by filtration and dried in vacuo to give (3-amino-6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol, HCl (130 mg, 38%). MS (ESI+) [Method 4B]: m / z 454.2 (M+H); Rt 0.99 min. 1H NMR(400MHz,CD3OD)δ 9.14(s,1H),7.49(s,1H),7.40(d,J=10.8Hz,1H),7.29(t,J=9.6Hz,1H),7.15-7.09(m,2H),5.0 6-5.02(m,3H),4.54(d,J=1.6Hz,2H),4.25-4.22(m,1H),2.90-2.85(m,2H),2.73-2.66(m,2H).

[0439] Example 19: Synthesis of (3-amino-5-((((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)amino)methyl)-6-fluoroisoquinolin-8-yl)methanol, HCl Step 19.1: Synthesis of tert-butyl (tert-butoxycarbonyl)(8-(((tert-butyldimethylsilyl)oxy)methyl)-5-((((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)amino)methyl)-6-fluoroisoquinolin-3-yl)carbamate [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(2,4-difluorophenoxy)cyclobutan-1-amine, HCl (Step 15.2, 120 mg, 0.51 mmol) and tert-butyl(tert-butoxycarbonyl)(8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-5-formylisoquinolin-3-yl)carbamate (Step 18.10, 240 mg, 0.46 mmol). The crude material was purified by flash chromatography (12 g SiliCycle column, 0–4% MeOH in CHCl eluent) to give tert-butyl (tert-butoxycarbonyl)(8-(((tert-butyldimethylsilyl)oxy)methyl)-5-((((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)amino)methyl)-6-fluoroisoquinolin-3-yl)carbamate (200 mg, 54%). MS (ESI+) [Method 6A]: m / z 718.3 (M+H); Rt 1.53 min.

[0440] Step 19.2: Synthesis of tert-butyl (tert-butoxycarbonyl) (5-((((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)amino)methyl)-6-fluoro-8-(hydroxymethyl)isoquinolin-3-yl)carbamate [ka] Deprotection was performed according to step 8.5. The residue was purified by flash chromatography (12 g SiliCycle column, 0–5% MeOH in CHCl eluent) to give tert-butyl (tert-butoxycarbonyl) (5-((((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)amino)methyl)-6-fluoro-8-(hydroxymethyl)isoquinolin-3-yl)carbamate (120 mg, 71%). MS (ESI+) [Method 6A]: m / z 604.4 (M+H); Rt 1.38 min.

[0441] Step 19.3: Synthesis of (3-amino-5-((((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)amino)methyl)-6-fluoroisoquinolin-8-yl)methanol, HCl [C-07860-067] [ka] Deprotection was carried out according to step 13.5. The product was purified by preparative HPLC (column: GEMINI NX C18 (150 mm × 21.0 mm), 5.0 μm; mobile phase: 0.02% NH4OH in water and acetonitrile). To the isolated product, HCl solution (4 M in 1,4-dioxane) (1 mL) was added and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was triturated with Et2O. The formed solid was collected by filtration and dried in vacuo to give (3-amino-5-((((1r,3r)-3-(2,4-difluorophenoxy)cyclobutyl)amino)methyl)-6-fluoroisoquinolin-8-yl)methanol, HCl (18 mg, 20%). MS (ESI+) [Method 6A]: m / z 404.2 (M+H); Rt 1.27 min. 1 H NMR(400MHz,CD3OD)δ 9.14(s,1H),7.43(s,1H),7.39(d,J=10.8Hz,1H),7.03-6.87(m,3H),5.05(s,2H),5.0 1-4.97(m,1H),4.53(s,2H),4.23-4.20(m,1H),2.83-2.78(m,2H),2.73-2.68(m,2H).

[0442] Example 20: Synthesis of (3-amino-6-fluoro-5-((((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol, HCl Step 20.1: Synthesis of tert-butyl (tert-butoxycarbonyl)(8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-5-((((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutan-1-amine, HCl (Step 16.2, 70 mg, 0.26 mmol) and tert-butyl(tert-butoxycarbonyl)(8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-5-formylisoquinolin-3-yl)carbamate (Step 18.10, 98 mg, 0.18 mmol). The crude material was purified by flash chromatography (12 g SiliCycle column, 0–4% MeOH in CHCl eluent) to give tert-butyl (tert-butoxycarbonyl)(8-(((tert-butyldimethylsilyl)oxy)methyl)-6-fluoro-5-((((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate (100 mg, 51%). MS (ESI+) [Method 6A]: m / z 751.5 (M+H), Rt 1.49 min; 651.4 (M-Boc+H), Rt 1.44 min.

[0443] Step 20.2: Synthesis of tert-butyl (tert-butoxycarbonyl)(6-fluoro-8-(hydroxymethyl)-5-((((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate [ka] Deprotection was performed according to step 8.5. The residue was purified by flash chromatography (12 g SiliCycle column, 0–5% MeOH in CHCl eluent) to give tert-butyl (tert-butoxycarbonyl) (6-fluoro-8-(hydroxymethyl)-5-((((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate (60 mg, 71%). MS (ESI+) [Method 6A]: m / z 637.4 (M+H), Rt 1.36 min; 535.2 (M-Boc+H), Rt 1.33 min.

[0444] Step 20.3: Synthesis of (3-amino-6-fluoro-5-((((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol, HCl [ka] Deprotection was carried out according to step 13.5. The reaction mixture was then concentrated in vacuo and purified by preparative HPLC (Column: WATERS X BRIDGE C18 (150 mm × 19.0 mm), 5.0 μm; Mobile phase: 0.02% NH4OH in water and acetonitrile). To the isolated product was added HCl solution (4 M in 1,4-dioxane) (1 mL) and stirred at room temperature for 1 h. The solvent was evaporated, and the residue was triturated with Et2O. The formed solid was collected by filtration and dried in vacuo to give (3-amino-6-fluoro-5-((((1r,3r)-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol, HCl (14 mg, 31%). MS (ESI+) [Method 6A]: m / z 437.0 (M+H); Rt 1.27 min. 1H NMR(400MHz,CD3OD)δ 9.18(s,1H),8.57(d,J=9.0Hz,1H),7.56(s,1H),7.44(d,J=9.0Hz,1H),7.34(d,J=2.4Hz,1H),7.17-7.14(m ,1H),5.26-5.21(m,1H),5.08(s,2H),4.58(s,2H),4.32-4.28(m,1H),3.02-2.97(m,2H),2.80-2.75(m,2H).

[0445] Example 21: Synthesis of 1-(3-amino-6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol Step 21.1: Synthesis of tert-butyl (tert-butoxycarbonyl) (8-(1,2-dihydroxyethyl)-6-fluoroisoquinolin-3-yl)carbamate [ka] To a solution of tert-butyl (tert-butoxycarbonyl) (6-fluoro-8-vinylisoquinolin-3-yl)carbamate (Step 18.6, 3.7 g, 9.53 mmol) in acetone (40 mL) was added 4-methylmorpholine N-oxide (2.8 g, 23.82 mmol) dissolved in water (4 mL) at room temperature, followed by OsO (0.12 g, 0.48 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was diluted with water and extracted three times with 20% MeOH in CHCl. ​​The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0–8% MeOH in CHCl eluent) to give tert-butyl (tert-butoxycarbonyl) (8-(1,2-dihydroxyethyl)-6-fluoroisoquinolin-3-yl)carbamate (2.9 g, 72%). MS (ESI+) [Method 6A]: m / z 423.2 (M+H); Rt 1.48 min.

[0446] Step 21.2: Synthesis of tert-butyl (tert-butoxycarbonyl) (6-fluoro-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinolin-3-yl)carbamate [ka] To a stirred solution of tert-butyl (tert-butoxycarbonyl)(8-(1,2-dihydroxyethyl)-6-fluoroisoquinolin-3-yl)carbamate (2.9 g, 6.87 mmol) and imidazole (2.8 g, 41.21 mmol) in DMF-DCM (35 mL, 1:6 v / v) was added TBDMS-Cl (5.43 g, 34.34 mmol) portionwise at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with water and extracted twice with CHCl. ​​The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (24 g SiliCycle column, 0–15% EtOAc in hexanes eluent) to give tert-butyl (tert-butoxycarbonyl)(6-fluoro-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinolin-3-yl)carbamate (3.6 g, 80%). MS (ESI+) [Method 1A]: m / z 651.4 (M+H); Rt 2.54 min. 1 H NMR(600MHz,CDCl3)δ 9.50(s,1H),7.56(s,1H),7.48(d,J=9.0Hz,1H),7.31(d,J=9.0Hz,1H),4.12-4.09(m,1H),3.87-3 .84(m,1H),3.79-3.77(m,1H),1.43(s,18H),0.86(s,9H),0.78(s,9H),0.10(s,6H),-0.08(s,6H).

[0447] Step 21.3: Synthesis of tert-butyl (tert-butoxycarbonyl) (6-fluoro-5-formyl-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinolin-3-yl)carbamate [ka] The title compound was prepared by step 14.2. The residue was purified by flash chromatography (40 g SiliCycle column, 0–15% EtOAc in hexanes eluent) to give tert-butyl (tert-butoxycarbonyl) (6-fluoro-5-formyl-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinolin-3-yl)carbamate (0.74 g, 39%). MS (ESI+) [Method 1A]: m / z 679.6 (M+H); Rt 2.89 min. 1H NMR(300MHz,CDCl3)δ 10.72(s,1H),9.50(s,1H),9.10(s,1H),7.58(d,J=9.0Hz,1H),5.53-5.50(m,1H),3.87-3.79(m,2H) ),1.46(s,18H),0.90(s,9H),0.78(s,9H),0.14(s,3H),-0.03(s,3H),-0.09(s,3H),-0.14(s,3H).

[0448] Step 21.4: Synthesis of tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinolin-3-yl)carbamate [ka] The title compound was synthesized following the steps as described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (step 1.3, 0.59 g, 2.07 mmol) and tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-formyl-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinolin-3-yl)carbamate (1.4 g, 2.07 mmol). The crude material was purified by flash chromatography (12 g SiliCycle column, 0–10% MeOH in CHCl eluent) to give tert-butyl (tert-butoxycarbonyl)(6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)-8-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)isoquinolin-3-yl)carbamate (1.16 g, 61%). MS (ESI+) [Method 1A]: m / z 912.3 (M+H), Rt 2.10 min.

[0449] Step 21.5: Synthesis of tert-butyl (tert-butoxycarbonyl)(8-(1,2-dihydroxyethyl)-6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-3-yl)carbamate [ka] The title compound was prepared according to the procedure in step 7.6 to give the title compound. MS (ESI+) [Method 1A]: m / z 684.4 (M+H), Rt 1.39 min.

[0450] Step 21.6: Synthesis of 1-(3-amino-6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol [ka] Deprotection was carried out according to step 13.5 to give racemic 1-(3-amino-6-fluoro-5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol, HCl (0.65 g, 85%). MS (ESI+) [Method 1A]: m / z 484.3 (M+H); Rt 0.10 min.

[0451] The racemic compound (650 mg) was subjected to chiral preparative HPLC (column: CHIRALPAK IG (250 mm × 20 mm); mobile phase: hexane and 0.1% DEA in EtOH:MeOH (1:1); isocratic: 60 / 40; flow rate: 16 mL / min) gave (R)-1-(3-amino-6-fluoro-5-((((1r,3R)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol and (S)-1-(3-amino-6-fluoro-5-((((1r,3S)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)ethane-1,2-diol as white solids (peak 1: 155 mg, 24% and peak 2: 180 mg, 27%). Peak 1: Chiral HPLC: 99% (Rf 5.315 min; Column: CHIRAL PAK IG (150 mm × 4.6 mm), 5.0 μ; Mobile phase: n-hexane and 0.1% DEA in EtOH:MeOH (70:30); Isocratic: 70 / 30; Flow rate: 1 mL / min). MS (ESI+) [Method 6A]: m / z 484.1 (M+H); Rt 1.32 min. 1H NMR(400MHz,CD3OD)δ 9.11(s,1H),7.25-7.22(m,2H),7.09-7.04(m,2H),6.95(s,1H),5.45-5.42(m,1H),4.92-4 .89(m,1H),4.24(d,J=1.6Hz,2H),3.87-3.79(m,2H),3.72-3.68(m,1H),2.57-2.48(m,4H).

[0452] Peak 2: Chiral HPLC: 98% (Rf 7.812 min; Column: CHIRAL PAK IG (150 mm × 4.6 mm), 5.0 μ; Mobile phase: n-hexane and 0.1% DEA in EtOH:MeOH (70:30); Isocratic: 70 / 30; Flow rate: 1 mL / min). MS (ESI+) [Method 6A]: m / z 484.2 (M+H); Rt 1.32 min. 1 H NMR(400MHz,CD3OD)δ 9.12(s,1H),7.26-7.23(m,2H),7.09-7.05(m,2H),6.95(s,1H),5.47-5.43(m,1H),4.92-4.89( m,1H),4.29(s,2H),3.93-3.88(m,1H),3.82-3.79(m,1H),3.73-3.69(m,1H),2.61-2.52(m,4H).

[0453] Example 22: Synthesis of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-(isoquinolin-5-ylmethyl)cyclobutan-1-amine, HCl [ka] The title compound was synthesized using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (Step 1.3, 300 mg, 1.05 mmol) and isoquinoline-5-carbaldehyde (150 mg, 0.96 mmol) following the steps described in Step 1.4. Preparative HPLC of the crude material (column: XBRIDGE C18 (150 mm × 21.2 mm), 5.0 μm; mobile phase: 0.01% NH4OH in water and acetonitrile) followed by treatment with HCl solution (4 M in 1,4-dioxane) gave (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-(isoquinolin-5-ylmethyl)cyclobutan-1-amine, HCl (250 mg, 55%). MS (ESI+) [Method 6A]: m / z 391.1 (M+H); Rt 1.32 min. 1 H NMR(400MHz,CD3OD)δ 9.92(s,1H),8.85-8.83(m,1H),8.79-8.77(m,1H),8.67(d,J=8.0Hz,1H),8.51(d,J=7.6Hz,1H),8.16(t,J=8.0Hz,1H),7.31( t,J=9.6Hz,1H),7.17-7.11(m,2H),5.11-5.06(m,1H),4.87(s,2H),4.33-4.29(m,1H),3.00-2.92(m,2H),2.74-2.68(m,2H).

[0454] Example 23: Synthesis of 5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-ol, HCl Step 23.1: Synthesis of 1-(5-bromo-2-methoxyphenyl)-N-(2,2-dimethoxyethyl)methanimine [ka] A two-necked round-bottom flask equipped with a Dean-Stark apparatus was charged with 5-bromo-2-methoxybenzaldehyde [CAS No. 25016-01-7] (3.0 g, 13.95 mmol), 2,2-dimethoxyethan-1-amine (1.5 mL, 13.95 mmol), and toluene (50 mL). The reaction mixture was stirred at 140 °C for 16 h during azeotropic removal of HO. The reaction mixture was then concentrated in vacuo to give crude 1-(5-bromo-2-methoxyphenyl)-N-(2,2-dimethoxyethyl)methanimine (5.4 g, 128%). 1 H NMR(300MHz,CDCl3)δ 8.63(d,J=1.2Hz,1H),8.07(d,J=3.0Hz,1H),7.46(dd,J=8.7,3.0Hz,1H),6.79(d,J=8. 7Hz,1H),4.68(t,J=5.4Hz,1H),3.85(s,3H),3.78(dd,J=5.4,1.2Hz,2H),3.42(s,6H).

[0455] Step 23.2: Synthesis of 5-bromo-8-methoxyisoquinoline [ka] To a solution of 1-(5-bromo-2-methoxyphenyl)-N-(2,2-dimethoxyethyl)methanimine (5.4 g, 17.87 mmol) in CHCl3 (50 mL) was added ethyl carbonochloridate (1.7 mL, 17.87 mmol) and P(OEt)3 (2.5 mL, 21.45 mmol) at 0 °C and stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature, poured into ice-cold water, and the organic portion was separated. The aqueous portion was washed twice with CHCl2, basified with aqueous NH4OH, and then extracted twice with CHCl2. The combined organic portions were washed with brine, dried over anhydrous NaSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, 0–30% EtOAc in hexanes eluent) to give 5-bromo-8-methoxyisoquinoline (1.0 g, 28%). 1H NMR(600MHz,CDCl3)δ 9.61(s,1H),8.65(d,J=6.0Hz,1H),7.89(d,J=6.0Hz,1H),7.84(d,J=8.4Hz,1H),6.78(d,J=8.4Hz,1H),4.03(s,3H).

[0456] Step 23.3: Synthesis of 8-methoxy-5-vinylisoquinoline [ka] A stirred solution of 5-bromo-8-methoxyisoquinoline (1.0 g, 4.20 mmol), potassium trifluoro(vinyl)borate (1.12 g, 8.40 mmol), and TEA (1.2 mL, 8.40 mmol) in IPA (10 mL) was degassed with N for 10 min. Pd(dppf)Cl·CHCl (343 mg, 0.04 mmol) was then added, degassed, and heated at 90 °C under N for 3 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (12 g SiliCycle column, 0–30% EtOAc in hexanes eluent) to give 8-methoxy-5-vinylisoquinoline (0.56 g, 71%). MS(ESI+) [Method 6A]: m / z185.9(M+H); Rt1.28 min.

[0457] Step 23.4: Synthesis of 8-methoxyisoquinoline-5-carbaldehyde [ka] The compound was prepared from 8-methoxy-5-vinylisoquinoline (560 mg, 3.02 mmol) by analogy with step 5.2. The residue was purified by flash chromatography (12 g SiliCycle column, 0–50% EtOAc in hexanes eluent) to give 8-methoxyisoquinoline-5-carbaldehyde (188 mg, 33%). MS (ESI+) [Method 6A]: m / z 187.9 (M+H); Rt 0.62 min.

[0458] Step 23.5: Synthesis of 8-hydroxyisoquinoline-5-carbaldehyde [ka] To a solution of 8-methoxyisoquinoline-5-carbaldehyde (188 mg, 1.00 mmol) in CHCl (5 mL) was added BBr (1 M in heptane) (5.0 mL, 5.02 mmol) at 0 °C and stirred at room temperature for 16 h. MeOH was added to the reaction mixture, which was stirred for 15 min and then concentrated in vacuo to give crude 8-hydroxyisoquinoline-5-carbaldehyde (230 mg, 132%). MS (ESI+) [Method 6A]: m / z 174.2 (M+H); Rt 0.38 min.

[0459] Step 23.6: Synthesis of 5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-ol, HCl [ka] The title compound was synthesized according to the procedure described in Step 1.4. A solution of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (Step 1.3, 350 mg, 1.23 mmol), and TEA (0.2 mL, 1.47 mmol) in MeOH (5 mL) was stirred for 15 min, followed by the addition of 8-hydroxyisoquinoline-5-carbaldehyde (191 mg, 1.10 mmol) and AcOH (0.01 mL) and stirring at room temperature for 16 h under argon. NaBH (232 mg, 6.13 mmol) was then added at 0 °C and stirred at room temperature for an additional 2 h. The reaction mixture was quenched with water and extracted twice with EtOAc. The combined organic portions were acidified with HCl solution (4 M in 1,4-dioxane) (5.0 mL), washed with brine, dried over NaSO, filtered, and concentrated in vacuo. Preparative HPLC of the crude material (Column: KINETEX EVO (150 mm × 21.2 mm), 5.0 μm; Mobile phase: 0.1% HCOH in water and acetonitrile) followed by treatment of the isolated product with HCl solution (4 M in 1,4-dioxane) gave 5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-ol, HCl. MS (ESI+) [Method 6A]: m / z 407.2 (M+H); Rt 1.28 min. 1 H NMR(400MHz,CD3OD)δ 9.84(brs,1H),8.63(brs,2H),8.29(d,J=8.4Hz,1H),7.34(d,J=8.0Hz,1H),7.28(t,J=9.2Hz,1H),7.14 -7.08(m,2H),5.06-5.02(m,1H),4.68(s,2H),4.25-4.21(m,1H),2.91-2.85(m,2H),2.70-2.63(m,2H).

[0460] Example 24: Synthesis of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((8-methylisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl Step 24.1: Synthesis of 8-methylisoquinoline [ka] A sealed tube was charged with 8-bromoisoquinoline [CAS No. 63927-22-0] (1.5 g, 7.20 mmol), methylboronic acid (0.86 g, 14.40 mmol), KPO (6.1 g, 28.74 mmol), and toluene (20 mL) and degassed (argon) for 10 minutes. Pd(dba) (0.65 g, 0.72 mmol) and S-PHOS (0.59 g, 1.44 mmol) were then added, degassed, and the sealed tube was closed and heated at 125 °C for 20 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (24 g SiliCycle column, 0-20% EtOAc in hexanes eluent) to give 8-methylisoquinoline (1.0 g, 95%). MS (ESI+) [Method 2A]: m / z 143.6 (M+H); Rt 0.46 min. 1 H NMR(300MHz,CDCl3)δ 9.47(s,1H),8.55(d,J=5.7Hz,1H),7.89-7.55(m,3H),7.40(d,J=6.9Hz,1H),2.80(s,3H).

[0461] Step 24.2: Synthesis of 5-bromo-8-methylisoquinoline [ka] To a solution of 8-methylisoquinoline (0.5 g, 3.49 mmol) in concentrated HSO (5 mL) was added NBS (0.62 g, 3.49 mmol) at -10 °C and stirred at room temperature for 16 h. The reaction mixture was poured dropwise onto ice and extracted three times with CHCl. ​​The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude was purified by flash chromatography (12 g SiliCycle column, 0–20% EtOAc in hexanes eluent) to give 5-bromo-8-methylisoquinoline (0.55 g, 71%). MS (ESI+) [Method 1A]: m / z 221.8 (M+H); Rt 0.40 min. 1 H NMR(400MHz,CD3OD)δ 9.38(s,1H),8.56(d,J=6.0Hz,1H),8.03(d,J=6.0Hz,1H),7.92(d,J=8.0Hz,1H),7.36(d,J=7.2Hz,1H),2.75(s,3H).

[0462] Step 24.3: Synthesis of 8-methylisoquinoline-5-carbaldehyde [ka] To a solution of 5-bromo-8-methylisoquinoline (0.25 g, 1.12 mmol) in dry THF (5 mL), n-BuLi (2.5 M in THF) (0.65 mL, 1.68 mmol) was added dropwise at -78 °C and stirred for 30 min under an argon atmosphere. Anhydrous DMF (0.17 mL, 2.25 mmol) was then added dropwise at -78 °C, and the temperature was gradually raised to room temperature and stirred for 1 h. The reaction mixture was quenched with 10% NH4Cl solution and extracted three times with EtOAc. The combined organic portions were washed with brine solution, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography (12 g SiliCycle column, 0–30% EtOAc in hexane eluent) to give 8-methylisoquinoline-5-carbaldehyde (80 mg, 41%). MS(ESI+) [Method 1A]: m / z172.1(M+H); Rt0.15 min.1 H NMR(300MHz,CD3OD)δ 10.30(s,1H),9.53(s,1H),9.11(dd,J=6.9,1.2Hz,1H),8.63(d,J=6.0Hz,1H),8.26(d,J=7.2Hz,1H),7.70(dd,J=7.8,1.2Hz,1H),2.90(s,3H).

[0463] Step 24.4: Synthesis of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((8-methylisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl [ka] The title compound was synthesized following the steps described in step 1.4 using (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (Step 1.3, 70 mg, 0.24 mmol) and 8-methylisoquinoline-5-carbaldehyde (42 mg, 0.24 mmol). Preparative HPLC of the crude material (column: KINETEX EVO C18 (150 mm × 21.2 mm), 5.0 μm; mobile phase: 0.02% NH4OH in water and acetonitrile) followed by treatment with HCl solution (4 M in 1,4-dioxane) gave (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-N-((8-methylisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl as a brown solid (40 mg, 41%). MS (ESI+) [Method 1A]: m / z 404.8 (M+H); Rt 0.19 min. 1 H NMR(400MHz,CD3OD)δ 9.92(brs,1H),8.75(brs,2H),8.30(d,J=7.6Hz,1H),7.94(dd,J=7.6,0.8Hz,1H),7.28(t,J=9.6Hz,1H),7.15-7. 08(m,2H),5.06-5.01(m,1H),4.79(s,2H),4.28-4.24(m,1H),2.96(s,3H),2.94-2.87(m,2H),2.71-2.63(m,2H).

[0464] Example 25: Synthesis of (5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol, HCl Step 25.1: Synthesis of 5,8-dibromoisoquinoline [ka] To a solution of isoquinoline [CAS no. 119-65-3] (2.0 g, 15.48 mmol) in concentrated HSO (20 mL) was added NBS (8.26 g, 46.45 mmol) at -15 °C and stirred for 2 h. The reaction mixture was poured dropwise onto ice, basified with aqueous NHOH, and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude was purified by flash chromatography (24 g SiliCycle column, 0–10% EtOAc in hexane eluent) to give 5,8-dibromoisoquinoline (4.0 g, 90%). MS (ESI+) [Method 1A]: m / z 285.8, 287.8, 289.8 (M+H); Rt 1.55 min. 1 H NMR(600MHz,CDCl3)δ 9.61(s,1H),8.73(d,J=4.8Hz,1H),7.99(d,J=4.8Hz,1H),7.82(d,J=7.8Hz,1H),7.22(d,J=7.8Hz,1H).

[0465] Step 25.2: Synthesis of 5-bromoisoquinoline-8-carbaldehyde [ka] The title compound was synthesized according to the protocol reported in WO 2017 / 79162. To a solution of 5,8-dibromoisoquinoline (2.0 g, 6.97 mmol) in dry THF (20 mL), n-BuLi (2.5 M in THF) (3.6 mL, 9.06 mmol) was added dropwise at -78 °C and stirred under a N atmosphere for 30 minutes. Anhydrous DMF (1.88 mL, 2.36 mmol) was then added dropwise at -78 °C and stirred for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution and extracted twice with EtOAc. The combined organic portions were washed with brine solution, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (24 g SiliCycle column, 0–20% EtOAc in hexanes eluent) to give 5-bromoisoquinoline-8-carbaldehyde (300 mg, 18%) (30 mg of 8-bromoisoquinoline-5-carbaldehyde was isolated as a by-product). MS (ESI+) [Method 1A]: m / z 235.8, 237.8 (M+H); Rt 1.69 min. 1 H NMR(400MHz,CDCl3)δ 10.57(d,J=1.6Hz,1H),10.40(s,1H),8.81(d,J=8.0Hz,1H),8.17(d,J=10.4Hz,1H),8.11(dd,J=7.6,1.6Hz,1H),7.94(d,J=10.4Hz,1H).

[0466] Step 25.3: Synthesis of (5-bromoisoquinolin-8-yl)methanol [ka] To a stirred solution of 5-bromoisoquinoline-8-carbaldehyde (300 mg, 1.27 mmol) in anhydrous THF (5 mL) was added NaBH (72 mg, 1.91 mmol) portionwise at 0 °C. MeOH (5 mL) was then added dropwise and stirred at 0 °C for 2 h. The reaction was quenched with water and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product from the two batches was combined and purified by flash chromatography (12 g SiliCycle column, 0–30% EtOAc in hexanes eluent) to give (5-bromoisoquinolin-8-yl)methanol (360 mg, 59%). MS (ESI+) [Method 1A]: m / z 238.0, 240.0 (M+H); Rt 0.16 min. 1 H NMR(300MHz,CDCl3)δ 9.54(s,1H),8.67(d,J=5.7Hz,1H),8.03(dd,J=6.0,0.9Hz,1H),7.95(d,J=7.8Hz,1H),7.51(d,J=7.8Hz,1H),5.24(s,2H).

[0467] Step 25.4: Synthesis of (5-vinylisoquinolin-8-yl)methanol [ka] A stirred solution of (5-bromoisoquinolin-8-yl)methanol (300 mg, 1.26 mmol), potassium trifluoro(vinyl)borate (330 mg, 2.52 mmol), and TEA (0.35 mL, 2.52 mmol) in IPA (10 mL) was degassed with N for 10 min. Pd(dppf)Cl·CHCl (100 mg, 0.13 mmol) was then added, degassed, and heated at 100 °C under N for 3 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (12 g SiliCycle column, 0–30% EtOAc in hexanes eluent) to give (5-vinylisoquinolin-8-yl)methanol (200 mg, 85%). MS (ESI+) [Method 6A]: m / z 185.9 (M+H); Rt 0.69 min.

[0468] Step 25.5: Synthesis of 8-(hydroxymethyl)isoquinoline-5-carbaldehyde [ka] The title compound was prepared by step 5.2. The residue was purified by flash chromatography (12 g SiliCycle column, 0-30% EtOAc in hexanes eluent) to give 8-(hydroxymethyl)isoquinoline-5-carbaldehyde (120 mg, 59%). MS (ESI+) [Method 2A]: m / z 188.0 (M+H); Rt 0.56 min. 1 H NMR(400MHz,DMSO-d6)δ 10.38(s,1H),9.59(s,1H),8.95(d,J=6.0Hz,1H),8.72(d,J=6.0Hz,1H),8.42(d, J=7.6Hz,1H),7.94(d,J=7.6Hz,1H),5.73(t,J=5.6Hz,1H),5.20(d,J=5.2Hz,2H).

[0469] Step 25.6: Synthesis of (5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol, HCl [ka] A solution of (1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutan-1-amine, HCl (Step 1.3, 60 mg, 0.21 mmol), and TEA (0.03 mL, 0.21 mmol) in MeOH (3 mL) was stirred at room temperature for 10 min. Then, 8-(hydroxymethyl)isoquinoline-5-carbaldehyde (36 mg, 0.19 mmol) was added and stirred for 2 h. Finally, NaBH (16 mg, 0.42 mmol) was added at 0 °C and stirred for another 3 h at room temperature. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic portions were washed with brine solution, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: KINETEX C18 (150 mm × 21.2 mm), 5.0 μ; mobile phase: 0.02% NH4OH in water and acetonitrile). The isolated product was stirred with HCl solution (4 M in 1,4-dioxane) (1 mL) at room temperature for 1 h; then concentrated to dryness to give (5-((((1r,3r)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)cyclobutyl)amino)methyl)isoquinolin-8-yl)methanol, HCl (23 mg, 26%). MS (ESI+) [Method 6A]: m / z 421.30 (M+H); Rt 1.303 min. 1 H NMR(400MHz,CD3OD)δ 10.01(s,1H),8.78(s,2H),8.38(d,J=7.6Hz,1H),8.10(d,J=7.6Hz,1H),7.28(t,J=9.6Hz,1H),7.14-7.08(m ,2H),5.27(s,2H),5.07-5.03(m,1H),4.82(s,2H),4.29-4.26(m,1H),2.93-2.89(m,2H),2.72-2.66(m,2H).

[0470] Example 26: Synthesis of (1r,3r)-3-(2,4-difluorophenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine [ka] The title compound was synthesized following the steps described in step 25.6 using (1r,3r)-3-(2,4-difluorophenoxy)cyclobutan-1-amine, HCl (Step 15.2, 80 mg, 0.40 mmol) and 6-fluoroisoquinoline-5-carbaldehyde (Step 3.1, 70 mg, 0.40 mmol). The residue was purified by preparative HPLC (column: LUNA (250 mm × 21.20 mm), 5.0 μm; mobile phase: 0.1% HCOH in water and acetonitrile) to give (1r,3r)-3-(2,4-difluorophenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine (40 mg, 28%). MS (ESI+) [Method 6A]: m / z 359.2 (M+H); Rt 1.28 min. 1 H NMR(400MHz,CD3OD)δ 9.30(s,1H),8.58(d,J=6.4Hz,1H),8.26(dd,J=9.2,5.6Hz,1H),8.13(d,J=6.0Hz,1H),7.60(t,J=9.2Hz,1H),7.0 2-6.98(m,1H),6.90-6.85(m,2H),4.91-4.87(m,1H),4.40(d,J=2.0Hz,2H),3.87-3.83(m,1H),2.51-2.48(m,4H).

[0471] Example 27: Synthesis of (1r,3r)-3-(3,4-difluorophenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl Step 27.1: Synthesis of tert-butyl((1r,3r)-3-(3,4-difluorophenoxy)cyclobutyl) [ka] To a solution of tert-butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate (0.4 g, 2.08 mmol) in THF (10 mL) was added 3,4-difluorophenol [CAS number 2713-33-9] (0.27 g, 2.08 mmol), PPh (0.8 g, 3.12 mmol), and diisopropyl azodicarboxylate (0.61 g, 3.12 mmol) at room temperature. The reaction mixture was stirred at 50 °C under a N atmosphere for 16 hours. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine solution, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (8 g SiliCycle column, 0-20% EtOAc in hexanes eluent) to give tert-butyl ((1r,3r)-3-(3,4-difluorophenoxy)cyclobutyl)carbamate (0.5 g, 96%). 1 H NMR(300MHz,CDCl3)δ 7.08-6.96(m,1H),6.71-6.43(m,2H),4.72-4.67(m,1H),4.31-4.26(m,1H),2.58-2.49(m,2H),2.40-2.34(m,2H),1.45(s,9H).

[0472] Step 27.2: Synthesis of (1r,3r)-3-(3,4-difluorophenoxy)cyclobutan-1-amine, HCl [ka] A solution of tert-butyl ((1r,3r)-3-(3,4-difluorophenoxy)cyclobutyl)carbamate (0.5 g, 1.67 mmol) and HCl (20% in 1,4-dioxane) (2.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, the residue was triturated with pentane, and the solid that appeared was filtered and dried to give (1r,3r)-3-(3,4-difluorophenoxy)cyclobutan-1-amine, HCl (0.3 g, 75%). 1H NMR(400MHz,CD3OD)δ 7.19-7.15(m,1H),6.77-6.73(m,1H),6.61-6.58(M,1H),4.91-4.88(m,1H),3.98-3.93(m,1H),2.62-2.56(m,4H).

[0473] Step 27.3: Synthesis of (1r,3r)-3-(3,4-difluorophenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl [ka] The title compound was synthesized according to the procedure described in step 1.4 using (1r,3r)-3-(3,4-difluorophenoxy)cyclobutan-1-amine, HCl (70 mg, 0.14 mmol) and 6-fluoroisoquinoline-5-carbaldehyde (step 3.1, 45 mg, 0.12 mmol). Preparative HPLC of the crude material (column: YMC-ACTUS TRIART C18 (150 mm × 21.2 mm), 5.0 μm; mobile phase: 0.02% NH4OH in water and acetonitrile) followed by treatment with HCl solution (4 M in 1,4-dioxane) gave (1r,3r)-3-(3,4-difluorophenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl (10 mg, 18%). MS(ESI+) [Method 6A]: m / z359.2(M+H); Rt1.30 min. 1 H NMR(400MHz,CD3OD)δ 9.88(s,1H),8.80-8.76(m,3H),8.03(t,J=9.6Hz,1H),7.25-7.18(m,1H),6.84-6.79(m,1H),6.68-6.63( m,1H),5.01-4.97(m,1H),4.84(d,J=2.0Hz,2H),4.32-4.27(m,1H),2.92-2.85(m,2H),2.74-2.67(m,2H).

[0474] Example 28: Synthesis of (1r,3r)-3-(3-chloro-4-fluorophenoxy)-N-(isoquinolin-5-ylmethyl)cyclobutan-1-amine, HCl Step 28.1: Synthesis of tert-butyl ((1r,3r)-3-(3-chloro-4-fluorophenoxy)cyclobutyl)carbamate [ka] The following compound was synthesized following the steps as described in step 1.2 using tert-butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate (0.6 g, 3.20 mmol) and 3-chloro-4-fluorophenol [CAS number 2613-23-2] (0.46 g, 3.20 mmol). The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography (12 g SiliCycle column, 0–10% EtOAc in hexanes eluent) to give tert-butyl ((1r,3r)-3-(3-chloro-4-fluorophenoxy)cyclobutyl)carbamate (0.8 g, 79%). 1 H NMR(600MHz,CDCl3)δ 7.02-7.00(m,1H),6.77-6.76(m,2H),6.63-6.61(m,1H),4.71-4.69(m,1 H),4.30-4.27(m,1H),2.55-2.51(m,2H),2.39-2.35(m,2H),1.45(s,9H).

[0475] Step 28.2: Synthesis of (1r,3r)-3-(3-chloro-4-fluorophenoxy)cyclobutan-1-amine, HCl [ka] A round-bottom flask was charged with tert-butyl ((1r,3r)-3-(3-chloro-4-fluorophenoxy)cyclobutyl)carbamate (0.8 g, 2.53 mmol) and HCl solution (20% in 1,4-dioxane) (10 mL) and stirred at room temperature for 16 h. The reaction mixture was then concentrated in vacuo. To the residue was added EtO and stirred for 10 min. The solid was collected by filtration and dried to give (1r,3r)-3-(3-chloro-4-fluorophenoxy)cyclobutan-1-amine, HCl (0.5 g, 78%). MS (ESI+) [Method 6A]: m / z 216.1 (M+H); Rt 1.29 min. 1 H NMR(300MHz,DMSO-d6)δ 8.38(brs,3H),7.33(t,J=9.6Hz,1H),7.01-6.98(m,1H),6.84-6.78(m,1H), 5.02-4.96(m,1H),3.81-3.77(m,1H),2.64-2.55(m,2H),2.42-2.35(m,2H).

[0476] Step 28.3: Synthesis of (1r,3r)-3-(3-chloro-4-fluorophenoxy)-N-(isoquinolin-5-ylmethyl)cyclobutan-1-amine, HCl [ka] The title compound was synthesized using (1r,3r)-3-(3-chloro-4-fluorophenoxy)cyclobutan-1-amine, HCl (80 mg, 0.32 mmol) and isoquinoline-5-carbaldehyde (45 mg, 0.29 mmol) following the steps described in step 1.4. Preparative HPLC of the crude material (column: KINETEX C18 (150 mm × 21.2 mm), 5.0 μm; mobile phase: 0.02% NH4OH in water and acetonitrile) followed by treatment with HCl solution (4 M in 1,4-dioxane) gave (1r,3r)-3-(3-chloro-4-fluorophenoxy)-N-(isoquinolin-5-ylmethyl)cyclobutan-1-amine, HCl (110 mg, 88%). MS(ESI+) [Method 6A]: m / z357.3(M+H); Rt0.14 min.1 H NMR(400MHz,CD3OD)δ 9.91(s,1H),8.83(d,J=6.8Hz,1H),8.75(d,J=6.8Hz,1H),8.64(d,J=8.0Hz,1H),8.48(d,J=7.2Hz,1H),8.14(dd,J=8.4,7.6Hz,1H),7.17(d, J=8.8Hz,1H),6.97-6.95(m,1H),6.83-6.79(m,1H),5.02-4.98(m,1H) ,4.85(s,2H),4.29-4.25(m,1H),2.95-2.88(m,2H),2.70-2.63(m,2H).

[0477] Example 29: Synthesis of (1r,3r)-3-(3-(difluoromethoxy)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl Step 29.1: Synthesis of tert-butyl ((1r,3r)-3-(3-(difluoromethoxy)phenoxy)cyclobutyl)carbamate [ka] The title compound was synthesized following the steps described in step 1.2 using tert-butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate (0.4 g, 2.14 mmol) and 3-(difluoromethoxy)phenol [CAS number 88798-13-4] (0.35 g, 2.14 mmol). tert-Butyl ((1r,3r)-3-(3-(difluoromethoxy)phenoxy)cyclobutyl)carbamate was isolated (0.6 g, 84%). 1 H NMR(600MHz,CDCl3)δ 7.23-7.18(m,2H),6.68-6.61(m,1H),6.61-6.59(m,1H),6.51(t,J=95.4Hz,1H),4.7 5-4.73(m,1H),4.30-4.27(m,1H),2.55-2.53(m,2H),2.39-2.35(m,2H),1.44(s,9H).

[0478] Step 29.2: Synthesis of (1r,3r)-3-(3-(difluoromethoxy)phenoxy)cyclobutan-1-amine, HCl [ka] A round-bottom flask was charged with tert-butyl ((1r,3r)-3-(3-(difluoromethoxy)phenoxy)cyclobutyl)carbamate (0.6 g, 1.81 mmol) and HCl solution (20% in 1,4-dioxane) (5 mL) and stirred at room temperature for 1 h. The reaction mixture was then concentrated in vacuo. The residue was triturated with EtO, and the solid was collected by filtration and dried to give (1r,3r)-3-(3-(difluoromethoxy)phenoxy)cyclobutan-1-amine, HCl (0.35 g, 72%). 1 H NMR(300MHz,DMSO-d6)δ 8.24(brs,3H),7.34(t,J=8.4Hz,1H),7.25(t,J=74.4Hz,1H),6.78-6.75(m,1H),6.71-6.68(m,1H) ),6.62-6.60(m,1H),5.02-4.97(m,1H),3.84-3.79(m,1H),2.63-2.57(m,2H),2.46-2.41(m,2H).

[0479] Step 29.3: Synthesis of (1r,3r)-3-(3-(difluoromethoxy)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl [ka] The title compound was synthesized following the steps described in step 25.6 using (1r,3r)-3-(3-(difluoromethoxy)phenoxy)cyclobutan-1-amine, HCl (300 mg, 1.13 mmol) and 6-fluoroisoquinoline-5-carbaldehyde (step 3.1, 176 mg, 1.01 mmol). Preparative HPLC of the crude material (column: LUNA Phenomenex (250 mm × 21.2 mm), 5.0 μm; mobile phase: water and acetonitrile-0.01% HCOH in MeOH) followed by treatment with HCl solution (4 M in 1,4-dioxane) gave (1r,3r)-3-(3-(difluoromethoxy)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl (140 mg, 30%). MS (ESI+) [Method 6A]: m / z 389.1 (M+H); Rt 1.29 min. 1 H NMR(400MHz,CD3OD)δ 9.83(s,1H),8.80-8.71(m,3H),8.00(t,J=9.2Hz,1H),7.33(d,J=8.0Hz,1H),6.84(t,J=74.0Hz,1H),6.78(dd,J=8.0,2.0Hz,1H),6.7 4-6.71(m,1H),6.64-6.62(m,1H),5.05-4.99(m,1H),4.83(d,J=2.0Hz,2H),4.31-4.26(m,1H),2.91-2.84(m,2H),2.75-2.68(m,2H).

[0480] Example 30: Synthesis of (1r,3r)-3-(4-(difluoromethoxy)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl Step 30.1: Synthesis of 1-(benzyloxy)-4-(difluoromethoxy)benzene [ka] To a solution of 4-(benzyloxy)phenol [CAS no. 103-16-2] (1.0 g, 4.99 mmol) in DMF-water (8.2 mL, 40:1 v / v) was added sodium 2-chloro-2,2-difluoroacetate (1.14 g, 7.49 mmol) and NaOH (0.24 g, 5.99 mmol), and the reaction mixture was heated at 130 °C under N for 2 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic portions were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (12 g SiliCycle column, hexane elution) to give 1-(benzyloxy)-4-(difluoromethoxy)benzene (0.15 g, 12%). MS (ESI+) [Method 6A]: m / z 249.1 (M−H); Rt 1.63 min.

[0481] Step 30.2: Synthesis of 4-(difluoromethoxy)phenol [ka] To a solution of 1-(benzyloxy)-4-(difluoromethoxy)benzene (300 mg, 1.20 mmol) in THF (10 mL) was added Pd / C (10% w / w) (50 mg) under argon. The reaction mixture was degassed, connected to a H balloon, and stirred at room temperature for 2 h. The reaction mixture was filtered through a celite bed, and the bed was washed with EtOAc. The combined filtrates were concentrated in vacuo to give 4-(difluoromethoxy)phenol (200 mg, 104%). MS (ESI+) [Method 6A]: m / z 159.1 (M−H); Rt 1.44 min. 1 H NMR(300MHz,CDCl3)δ 7.02(d,J=8.7Hz,2H),6.80(dd,J=6.6,2.1Hz,2H),6.41(t,J=74.1Hz,1H).

[0482] Step 30.3: Synthesis of tert-butyl ((1r,3r)-3-(4-(difluoromethoxy)phenoxy)cyclobutyl)carbamate [ka] The title compound was synthesized following the steps as described in step 1.2 using tert-butyl ((1s,3s)-3-hydroxycyclobutyl)carbamate (230 mg, 1.25 mmol) and 4-(difluoromethoxy)phenol (200 mg, 1.25 mmol). The crude product was purified by flash chromatography (12 g SiliCycle column, 0–10% EtOAc in hexanes eluent) to give tert-butyl ((1r,3r)-3-(4-(difluoromethoxy)phenoxy)cyclobutyl)carbamate (200 mg, 48%). MS (ESI+) [Method 6A]: m / z 659.2 (2M+H); Rt 1.44 min. 1 H NMR(300MHz,CDCl3)δ 7.04(d,J=8.7Hz,2H),6.73(d,J=9.3Hz,2H),6.41(t,J=74.1Hz,1H),4.77-4.7 1(m,1H),4.32-4.28(m,1H),2.59-2.50(m,2H),2.41-2.35(m,2H),1.45(s,9H).

[0483] Step 30.4: Synthesis of (1r,3r)-3-(4-(difluoromethoxy)phenoxy)cyclobutan-1-amine, HCl [ka] A solution of tert-butyl ((1r,3r)-3-(4-(difluoromethoxy)phenoxy)cyclobutyl)carbamate (0.2 g, 0.61 mmol) and HCl solution (20% in 1,4-dioxane) (4 mL) was stirred at room temperature for 4 h. The reaction mixture was then concentrated in vacuo to give crude (1r,3r)-3-(4-(difluoromethoxy)phenoxy)cyclobutan-1-amine, HCl (0.2 g, 124%). MS (ESI+) [Method 6A]: m / z 230.7 (M−H); Rt 1.28 min.

[0484] Step 30.5: Synthesis of (1r,3r)-3-(4-(difluoromethoxy)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl [ka] The title compound was synthesized following the steps described in step 25.6 using (1r,3r)-3-(4-(difluoromethoxy)phenoxy)cyclobutan-1-amine, HCl (200 mg, 0.87 mmol) and 6-fluoroisoquinoline-5-carbaldehyde (step 3.1, 152 mg, 0.87 mmol). Preparative HPLC of the crude material (column: LUNA C18 (250 mm × 21.2 mm), 5.0 μm; mobile phase: water and acetonitrile-MeOH (1:1) with 0.01% HCOH) followed by treatment with HCl solution (4 M in 1,4-dioxane) gave (1r,3r)-3-(4-(difluoromethoxy)phenoxy)-N-((6-fluoroisoquinolin-5-yl)methyl)cyclobutan-1-amine, HCl (120 mg, 36%). MS (ESI+) [Method 6A]: m / z 389.2 (M+H); Rt 1.28 min. 1 H NMR(400MHz,CD3OD)δ 9.91(s,1H),8.86-8.78(m,3H),8.04(t,J=9.6Hz,1H),7.09(dd,J=6.8,1.6Hz,2H),6.87-6.85(m,2H),6.69(t,J =74.4Hz,1H),5.01-4.98(m,1H),4.83(d,J=2.0Hz,2H),4.28-4.24(m,1H),2.89-2.84(m,2H),2.72-2.65(m,2H).

[0485] Example 31: Synthesis of (1r,3r)-N-((6-fluoroisoquinolin-5-yl)methyl)-3-(naphthalen-2-yloxy)cyclobutan-1-amine, HCl Step 31.1: Synthesis of tert-butyl ((1r,3r)-3-(naphthalen-2-yloxy)cyclobutyl)carbamate [ka] The title c...

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, W is either C (=O) or does not exist; X is N or N oxide; Y is either N or CH; Z is NH, O, or S; A is CH ２ or non-existent; L is a 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, C ６ ~C １０ Selected from aryl and 6-10 membered partially saturated heterocyclines having 1-3 heteroatoms independently selected from N, O, and S; The aforementioned 6-10 membered partially saturated heterocycline is 【Chemistry 2】 Selected from; R Ａ is, each time it appears independently, halo, -CN, C １ ~C ６ haloalkyl, C １ ~C ６ alkyl, SF ５ 、C ３ ~C ６ cycloalkyl, C １ ~C ６ alkoxyl, C １ ~C ６ haloalkoxyl, a 4- to 6-membered heterocyclyl having 1 to 2 heteroatoms independently selected from N, O and S, -(CH ２ ) ｐ -NR ３ R ４ and -C(=O)-O-(C １ ~C ６ alkyl) selected from,​ Said C ３ ~C ６ Cycloalkyls and 4-6 membered heterocyclines have 0-4 R Ａ１ Each is substituted independently; R Ａ１ Each time they appear, Halo and C appear independently. １ ~C ６ Selected from haloalkyls; R １ Each time it appears, hydroxyl, C appears independently. １ ~C ６ Alkyl, C １ ~C ６ Alkoxyl, Halo, C １ ~C ６ Haloalkyl and NR ３ R ４ Selected from, Said C １ ~C ６ Alkyl and C １ ~C ６ Haloalkyl groups have 0 to 4 R groups. １ａ Each is substituted independently; R １ａ Each time it appears, hydroxyl, NR ３ R ４ And selected from -C(=O)-OH; R1-1 is NH2 or a halo; R1-2 is NH2 or a halo; R ２ is hydrogen and C １ ~C ６ Selected from alkyl groups; R ３ Each time they appear, hydrogen and C appear independently. １ ~C ６ Selected from alkyl groups; R ４ Each instance of it is independently -SO ２ R ５ , hydrogen, -C(=O)-(C １ ~C ６ Alkyl) and C １ ~C ６ Selected from alkyl groups; R ５ Each time it appears, NH ２ and C １ ~C ６ Selected from alkyl groups; m is 0, 1, 2, 3, 4, or 5; p is 0, 1, or 2. Compounds of or pharmaceutically acceptable salts thereof.

2. W is either C (=O) or does not exist; X is N or N oxide; Y is CH; Z is NH, O, or S; A is CH ２ or non-existent; L is a 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, C ６ ~C １０ Selected from aryl and 6-10 membered partially saturated heterocyclines having 1-3 heteroatoms independently selected from N, O, and S; The aforementioned 6-10 membered partially saturated heterocycline is 【Transformation 3】 Selected from; R Ａ Each instance of these appears independently as Halo, -CN, and C. １ ~C ６ Haloalkyl, C １ ~C ６ Alkyl, SF ５ , C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkoxyls, 4-6 membered heterocyclines having 1-2 heteroatoms independently selected from N, O, and S, and -(CH ２ ) ｐ -NR ３ R ４ Selected from, Said C ３ ~C ６ Cycloalkyls and 4-6 membered heterocyclines have 0-4 R Ａ１ Each is substituted independently; R Ａ１ Each time they appear, Halo and C appear independently. １ ~C ６ Selected from haloalkyls; R １ is, each time it appears independently, C １ to C ６ alkyl, halo, C １ to C ６ haloalkyl and NR ３ R ４ selected from, Said C １ to C ６ alkyl and C １ to C ６ haloalkyl is each independently substituted with 0 to 4 R １ａ ; and R １ａ Each time it appears, hydroxyl, NR ３ R ４ And selected from -C(=O)-OH; R ２ is hydrogen and C １ ~C ６ Selected from alkyl groups; R ３ Each time they appear, hydrogen and C appear independently. １ ~C ６ Selected from alkyl groups; R ４ Each instance of it is independently -SO ２ R ５ , hydrogen, -C(=O)-(C １ ~C ６ Alkyl) and C １ ~C ６ Selected from alkyl groups; R ５ Each time it appears, NH ２ and C １ ~C ６ Selected from alkyl groups; m is 0, 1, 2, 3, 4, or 5; The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein p is 0, 1, or 2.

3. W is either C (=O) or does not exist; X is N or N oxide; Y is CH; Z is NH, O, or S; A is CH ２ or non-existent; L is a 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, C ６ ~C １０ Selected from aryl and 6-10 membered partially saturated heterocyclines having 1-3 heteroatoms independently selected from N, O, and S; The aforementioned 6-10 membered partially saturated heterocycline is 【Chemistry 4】 Selected from; R Ａ Each instance of these appears independently as Halo, -CN, and C. １ ~C ６ Haloalkyl, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxyl, C １ ~C ６ Haloalkoxyls, 4-6 membered heterocyclines having 1-2 heteroatoms independently selected from N, O, and S, and -(CH ２ ) ｐ -NR ３ R ４ Selected from, Said C ３ ~C ６ Cycloalkyls and 4-6 membered heterocyclines have 0-4 R Ａ１ Each is substituted independently; R Ａ１ Each time they appear, Halo and C appear independently. １ ~C ６ Selected from haloalkyls; R １ Each time it appears, C １ ~C ６ Alkyl, Halo, C １ ~C ６ Haloalkyl and NH ２ Selected from, Said C １ ~C ６ Alkyl and C １ ~C ６ Haloalkyl groups have 0 to 4 R groups. １ａ Each is substituted independently; R １ａ Each time it appears, hydroxyl, NR ３ R ４ And selected from -C(=O)-OH; R ２ is hydrogen and C １ ~C ３ Selected from alkyl groups; R ３ Each time they appear, hydrogen and C appear independently. １ ~C ６ Selected from alkyl groups; R ４ Each instance of it is independently -SO ２ R ５ , hydrogen, -C(=O)-(C １ ~C ６ Alkyl) and C １ ~C ６ Selected from alkyl groups; R ５ Each time it appears, NH ２ and C １ ~C ６ Selected from alkyl groups; m is 0, 1, 2, 3, or 4; The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein p is 0, 1, or 2.

4. W is nonexistent; X is N; Y is CH; Z is NH, O, or S; A is non-existent; L is a 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, C ６ ~C １０ Selected from aryl and 6-10 membered partially saturated heterocyclines having 1-3 heteroatoms independently selected from N, O, and S; The aforementioned 6-10 membered partially saturated heterocycline is 【Transformation 5】 Selected from; R Ａ Each instance of these appears independently as Halo, -CN, and C. １ ~C ６ Haloalkyl, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Haloalkoxyls, 4-6 membered heterocyclines having 1-2 heteroatoms independently selected from N, O, and S, and -(CH ２ ) ｐ -NR ３ R ４ Selected from, Said C ３ ~C ６ Cycloalkyls and 4-6 membered heterocyclines have 0-4 R Ａ１ Each is substituted independently; R Ａ１ Each time they appear, Halo and C appear independently. １ ~C ６ Selected from haloalkyls; R １ Each time it appears, C １ ~C ６ Alkyl, Halo, C １ ~C ６ Selected from haloalkyl groups, Said C １ ~C ６ Alkyl and C １ ~C ６ Haloalkyl groups have 0 to 4 R groups. １ａ Each is substituted independently; R １ａ Each time it appears, hydroxyl, NR ３ R ４ And selected from -C(=O)-OH; R ２ is hydrogen and C １ ~C ３ Selected from alkyl groups; R ３ Each time they appear, hydrogen and C appear independently. １ ~C ６ Selected from alkyl groups; R ４ Each instance of it is independently -SO ２ R ５ , hydrogen, -C(=O)-(C １ ~C ６ Alkyl) and C １ ~C ６ Selected from alkyl groups; R ５ Each time it appears, NH ２ and C １ ~C ６ Selected from alkyl groups; m is 0, 1, 2, 3, or 4; The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein p is 0, 1, or 2.

5. R Ａ is fluoro, chloro, -CN, C １ ~C ６ Fluoroalkyl (for example, C １ ~C ３ Fluoroalkyl), C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Selected from fluoroalkoxyls and four-membered heterocyclines having one oxygen atom, Said C ３ ~C ６ The cycloalkyl and the four-membered oxygen-containing heterocyclyl have 0 to 3 R Ａ１ Each is replaced independently. R Ａ１ Each time they appear, Halo and C appear independently. １ ~C ６ A compound according to any one of claims 1 to 4, selected from haloalkyls, or a pharmaceutically acceptable salt thereof.

6. R Ａ Fluoro, -CN, -CF ３ ,-CHF ２ yan-CHFCH ２ F, -CH ２ F, C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, -OCF ３ , -OCHF ２ , -OCH ２ F, -OCHFCH ２ Selected from a 4-membered heterocycline having F and one oxygen atom, Said C ３ ~C ６ The cycloalkyl and the four-membered oxygen-containing heterocyclyl have 0 to 2 R Ａ１ Each is replaced independently. R Ａ１ Each time they appear, fluoro and C appear independently. １ ~C ６ A compound according to any one of claims 1 to 5, selected from fluoroalkyls, or a pharmaceutically acceptable salt thereof.

7. R Ａ Fluoro, -CN, -CF ３ ,-CHF ２ yan-CHFCH ２ F and -CH ２ A compound or pharmaceutically acceptable salt thereof, selected from F, according to any one of claims 1 to 6.

8. L is C ６ ~C １０ Ariel, 【Transformation 6】 A 6-10 membered partially saturated heterocycline having 1-3 heteroatoms selected from, and 【Transformation 7】 Selected from a 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, Said C ６ ~C １０ Aryls, 6-10 membered partially saturated heterocyclyls, and 5-10 membered heteroaryls have 0-4 R Ａ Each is substituted independently, R Ａ is a compound or a pharmaceutically acceptable salt thereof as defined by any one of claims 1 to 7.

9. L is C ６ ~C １０ Ariel, 【Transformation 8】 A 6-10 membered partially saturated heterocycline having 1-3 heteroatoms selected from, and 【Chemistry 9】 Selected from a 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, Said C ６ ~C １０ Aryl and 6-10 membered partially saturated heterocyclines have 0-2 R Ａ Each is replaced independently. R Ａ is a compound or a pharmaceutically acceptable salt thereof as defined by any one of claims 1 to 8.

10. L is C ６ ~C １０ Ariel, 【Chemistry 10】 A 6-10 membered partially saturated heterocycline having 1-3 heteroatoms selected from, and 【Chemistry 11】 Selected from a 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, Said C ６ ~C １０ Aryl and 6-10 membered partially saturated heterocyclines have 0-2 R Ａ Each is substituted independently, R Ａ is a compound or a pharmaceutically acceptable salt thereof as defined by any one of claims 1 to 9.

11. L is 【Chemistry 12】 A 6-10 member partially saturated heterocycline having 1-3 heteroatoms selected from, a 5-10 member heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, and C selected from phenyl and naphthyl. ６ ~C １０ Selected from the alphabet, The aforementioned 6-10 membered partially saturated heterocyclines, 5-10 membered heteroaryls, phenyls, and naphthyls contain 0-4 R Ａ Each is substituted independently, R Ａ is a compound or pharmaceutically acceptable salt thereof as defined by any one of claims 1 to 7, as defined by any one of claims 1 to 10.

12. L is 【Chemistry 13】 A 6-10 membered partially saturated heterocycline having 1-3 heteroatoms selected from, a 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O and S, and 【Chemistry 14】 C selected from ６ ~C １０ Selected from the alphabet, The aforementioned 6-10 membered partially saturated heterocyclyls and 5-10 membered heteroaryls have 0-3 R Ａ Each is substituted independently, R Ａ This refers to the compound or pharmaceutically acceptable salt thereof as defined by any one of claims 1 to 11, or any one of claims 1 to 7 or 11.

13. L is 【Chemistry 15】 A 6-10 membered partially saturated heterocycline having 1-3 heteroatoms selected from, a 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O and S, and 【Chemistry 16】 C selected from ６ ~C １０ Selected from the alphabet, The aforementioned 6-10 membered partially saturated heterocyclyls and 5-10 membered heteroaryls have 0-3 R Ａ Each is substituted independently, R Ａ This refers to the compounds or pharmaceutically acceptable salts thereof as defined by any one of claims 1 to 7, 11, or 12.

14. L is a 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, C ６ ~C １０ Ariel, and 【Chemistry 17】 Selected from 6-10 member partially saturated heterocyclines, and the 5-10 member heteroaryl, C ６ ~C １０ Aryl and 6-10 membered partially saturated heterocyclines have 0-4 R Ａ Each is substituted independently, R Ａ is a compound or pharmaceutically acceptable salt thereof as defined by any one of claims 1 to 7, as defined by any one of claims 1 to 13.

15. L is a 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, C ６ ~C １０ Ariel, and [Chemistry 18] Selected from 6-10 member partially saturated heterocyclines, the 5-10 member heteroaryl and C ６ ~C １０ A aryl has 0 to 4 R Ａ Each is substituted independently, R Ａ This refers to the compound or pharmaceutically acceptable salt thereof as defined by any one of claims 1 to 14, or any one of claims 1 to 7 or 14.

16. L is a 5-10 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, C ６ ~C １０ Ariel, and 【Chemistry 19】 Selected from 6-10 member partially saturated heterocyclines, the 5-10 member heteroaryl and C ６ ~C １０ A aryl has 0 to 4 R Ａ Each is substituted independently, R Ａ This refers to the compounds or pharmaceutically acceptable salts thereof as defined by any one of claims 1 to 15, according to any one of claims 1 to 7, 14, or 15.

17. R １ Each time it appears, C １ ~C ６ Alkyl, Halo, C １ ~C ６ Haloalkyl and NH ２ Selected from, Said C １ ~C ６ Alkyl and C １ ~C ６ Haloalkyl groups have 0 to 4 R groups. １ａ Each is replaced independently. R １ａ Each time it appears, hydroxyl and NR ３ R ４ A compound or a pharmaceutically acceptable salt thereof, selected from any one of claims 1 to 16.

18. R １ Each time it appears, C １ ~C ６ Alkyl, fluoro, NH ２ , -N(C １ ~C ６ Alkyl) ２ and selected from chloro, Said C １ ~C ６ The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein each alkyl group is independently substituted with 0 to 4 hydroxyl groups.

19. R １ Each time it appears, C １ ~C ６ Selected from alkyl and fluoro, the C １ ~C ６ The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein each alkyl group is independently substituted with 0 to 4 hydroxyl groups.

20. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, wherein m is 1, 2, or 3.

21. R ２ The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 20, wherein is hydrogen.

22. Y is CH, the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

23. W is absent, the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof.

24. Z is O, the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 23.

25. W is nonexistent; X is N; Y is CH; Z is O; A is non-existent; L is C ６ ~C １０ It is an allele; R Ａ Each instance of these appears independently as Halo, -CN, and C. １ ~C ６ Haloalkyl, C １ ~C ６ Selected from alkyl groups; R １ Each time it appears, C １ ~C ６ Alkyl, halo, and C １ ~C ６ Selected from haloalkyl groups, Said C １ ~C ６ Alkyl and C １ ~C ６ Haloalkyl groups have 0 to 4 R groups. １ａ Each is substituted independently; R １ａ Each time it appears, hydroxyl and NR ３ R ４ Selected from; R ２ is hydrogen and C １ ~C ３ Selected from alkyl groups; R ３ Each time they appear, hydrogen and C appear independently. １ ~C ６ Selected from alkyl groups; R ４ Each instance of it is independently -SO ２ R ５ , hydrogen and C １ ~C ６ Selected from alkyl groups; R ５ Each time it appears, NH ２ and C １ ~C ６ Selected from alkyl groups; A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein m is 0, 1, 2, or 3.

26. W is nonexistent; X is N; Y is CH; Z is O; A is non-existent; L is C ６ ~C １０ It is an allele; R Ａ Each instance of appearance is independent of the halo (e.g., fluoro) and C. １ ~C ６ Haloalkyl (for example, C １ ~C ６ Fluoroalkyl) and C １ ~C ６ Selected from alkyl groups; R １ Each time it appears, C １ ~C ６ Selected from alkyl and halo (e.g., fluoro), Said C １ ~C ６ Alkyl groups are substituted with 0 to 4 hydroxyl groups; R ２ is hydrogen; The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, wherein m is 1, 2, or 3.

27. R １ Each time it appears, it is independent, 【Chemistry 20】 , fluoro and NH ２ A compound or a pharmaceutically acceptable salt thereof, selected from any one of claims 1 to 26.

28. R １ Each time it appears, it is independent, 【Chemistry 21】 , fluoro and NH ２ A compound or a pharmaceutically acceptable salt thereof, selected from any one of claims 1 to 27.

29. R １ Each time it appears, it is independent, 【Chemistry 22】 , fluoro and NH ２ Selected from, R １ｂ is hydrogen or C １ ~C ５ It is alkyl, Said C １ ~C ５ The alkyl group is substituted with 0 to 3 hydroxyl groups, the compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof.

30. Equation (Ia) 【Chemistry 23】 (In the formula, W, L, R １ , R ２ , R Ａ (R1-1, R1-2, and m are defined by any one of claims 1 to 29) The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 29.

31. Formula (Ib) 【Chemistry 24】 (In the formula, W, L, R １ , R ２ , R Ａ (R1-1, R1-2, and m are defined by any one of claims 1 to 30) The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 30.

32. Formula (Ic) 【Chemistry 25】 (In the formula, L, R １ , R ２ , R Ａ (R1-1, R1-2, and m are defined by any one of claims 1 to 31) The compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof.

33. Formula (Id) 【Chemistry 26】 (In the formula, L, R １ , R ２ , R Ａ (R1-1, R1-2, and m are defined by any one of claims 1 to 32.) The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 32.

34. Equation (Ie) 【Chemistry 27】 (In the formula, L, R １ , R ２ , R Ａ (R1-1 and m are defined by any one of claims 1 to 33) The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 33.

35. Equation (If) 【Chemistry 28】 (In the formula, L, R １ , R ２ , R Ａ (R1-1 and m are defined by any one of claims 1 to 34) The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 34.

36. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the following: Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13

37. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36 and a pharmaceutically acceptable carrier or additive.

38. A pharmaceutical composition for treating or preventing a disease or disorder mediated by TRPV1 in a target area, comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 36.

39. A pharmaceutical composition for treating an eye disease or disorder in a subject requiring treatment, comprising a therapeutically effective amount of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, wherein the eye disease or disorder is mediated by TRPV1.

40. A pharmaceutical composition for treating ocular surface disorders in a subject requiring treatment, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof.

41. The aforementioned ocular surface disorders include chronic ocular surface pain (COSP), dry eye disease, Sjögren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), and epithelial basement membrane. The pharmaceutical composition according to claim 40, selected from patients who have recovered from dystrophy, corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface diseases, blepharitis, graft-versus-host disease, meibomian gland inflammation, glaucoma, conjunctival laxity, keratopathy (including herpetic keratopathy, filamentous keratopathy, zoonotic or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerosis, and neurotrophic keratitis.

42. The pharmaceutical composition according to claim 41, wherein the ocular surface disorder is a dry eye disease.

43. A pharmaceutical composition for treating ocular surface pain (e.g., corneal-induced pain) in a subject requiring treatment, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof.

44. The pharmaceutical composition according to claim 43, wherein the ocular surface pain is accidental, i.e., acute.

45. The pharmaceutical composition according to claim 43, wherein the ocular surface pain is chronic.

46. The aforementioned ocular surface pain can be caused by dry eye disease, Sjögren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, corneal erosion, or abrasion. A pharmaceutical composition according to any one of claims 43 to 45, relating to one or more patients recovering from hyperinjury (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, graft-versus-host disease, meibomian gland inflammation, glaucoma, conjunctival laxity, keratopathy (including herpetic keratopathy, filamentous keratopathy, zoonotic or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerosis, or neurotrophic keratitis.

47. The pharmaceutical composition according to any one of claims 43 to 46, wherein the ocular surface pain is associated with dry eye disease or Sjögren's syndrome.

48. A pharmaceutical composition for treating ocular congestion in a subject requiring treatment, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof.

49. The aforementioned conjunctival hyperemia can be caused by dry eye disease, Sjögren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, eye pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, and corneal erosion. The pharmaceutical composition according to claim 48, relating to one or more patients who have recovered from abrasions (including recurrent corneal erosions or abrasions), ocular surface diseases, blepharitis, graft-versus-host disease, meibomian gland inflammation, glaucoma, conjunctival laxity, keratopathy (including herpetic keratopathy, filamentous keratopathy, zoonotic or bullous keratopathy, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerosis, or neurotrophic keratitis.

50. A combination of pharmaceuticals comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36 and one or more further therapeutic agents.

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