Pyridazinone phosphate compounds, pharmaceutical compositions, and medical uses thereof

Abstract

The invention provides pyridazinone phosphate compounds, pharmaceutical compositions, and methods of use thereof, such as in inhibiting a TRPC5 and / or treating or preventing a psychiatric condition or other condition.

Description

PYRIDAZINONE PHOSPHATE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND MEDICAL USES THEREOF CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to United States provisional patent application no.63 / 654,642, filed May 31, 2024, the entire contents of which are incorporated herein by reference. FIELD OF THE INVENTION

[0002] The invention provides pyridazinone phosphate compounds, pharmaceuticalcompositions, and methods of use thereof, such as in inhibiting a TRPC5 and / or treating or preventing a psychiatric condition or other condition. BACKGROUND

[0003] Psychiatric conditions impact a significant portion of the population. Types of psychiatricconditions impacting a significant number of patients include (i) depression, (ii) post-traumatic stress disorder, (iii) anxiety disorders, which often feature an emotion characterized by the anticipation of future danger or misfortune, along with excessive worrying, and (v) seasonal affective disorder. Existing therapies for these conditions are not effective for all patients and / or can have adverse side effects. New therapies are needed to treat psychiatric conditions.

[0004] Proteinuria is a condition in which an excessive amount of protein in the blood leaks intothe urine. Proteinuria occurs when there is a malfunction in the kidney's glomeruli, causing fluid to accumulate in the body. Prolonged protein leakage has been shown to result in kidney failure. For patients who respond positively to treatments currently available on the market, the rate of relapse is high. For example, about ninety percent of children with Nephrotic Syndrome have been reported to respond to currently available treatments, but nearly seventy-five percent will relapse. There is a need for more effective methods of treating kidney disease, e.g., proteinuria.

[0005] Mammalian transient receptor potential cation channel (TRPC) proteins form six-transmembrane cation-permeable channels. TRP channels are involved in numerous fundamental cell functions and play an important role in the pathophysiology of many diseases, including psychiatric conditions and kidney disease. One subfamily of TRPC proteins is subfamily C, member 5 (TRPC5). WO 2020 / 061162, WO 2019 / 055966, and WO 2020 / 210639 describes 1 60701001.1various pyridazinone compounds as inhibitors of TRPC5 and medical uses for the same. Additional compounds that inhibit TRPC5 are needed to treat conditions and diseases, including psychiatric conditions and kidney disease.

[0006] The present invention addresses the foregoing need and provides other related advantages.SUMMARY

[0007] The invention provides pyridazinone phosphate compounds, pharmaceuticalcompositions, and methods of use thereof, such as in inhibiting a TRPC5 and / or treating or preventing a psychiatric condition or other condition. In particular, one aspect of the invention provides a compound represented by Formula I: or a pharmaceuticallybe part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. Such compounds of Formula I undergo conversion in vivo to 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8- dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one (see Formula I-2 below), and as such are a useful way to deliver 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8- dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one to a subject.

[0008] Another aspect of the invention provides a method of treating or preventing a TRPC5-associated disorder or condition. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound represented by Formula I, to treat or prevent the TRPC5-associated disorder or condition.

[0009] Another aspect of the invention provides a method of treating or preventing a psychiatriccondition. The method comprises administering to a subject in need thereof a therapeutically 2 60701001.1effective amount of a compound described herein, such as a compound represented by Formula I, to treat or prevent the psychiatric condition.

[0010] Another aspect of the invention provides a method of treating or preventing a disease orcondition selected from kidney disease, pulmonary arterial hypertension, cancer, diabetic retinopathy, or pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound represented by Formula I, to treat or reduce the risk of developing the disease or condition.

[0011] Another aspect of the invention provides a method of inhibiting transient receptorpotential cation channel subfamily C, member 5 (TRPC5) in a subject, comprising administering to the subject an effective amount of a compound described herein, such as a compound represented by Formula I, to thereby inhibit the TRPC5.

[0012] Another aspect of the invention provides a method of delivering a compound of FormulaI-2 to a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I-2 is represented by: .DETAILED DESCRIPTION

[0013] The invention provides pyridazinone phosphate compounds, pharmaceuticalcompositions, and methods of use thereof, such as in inhibiting a TRPC5 and / or treating or preventing a psychiatric condition or other condition. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D.M. Weir & C.C. Blackwell, eds.); “Current protocols in molecular biology” 3 60701001.1(F.M. Ausubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (J.E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety.

[0014] Various aspects of the invention are set forth below in sections; however, aspects of theinvention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls. Definitions

[0015] Compounds of the present invention include those described generally herein, and arefurther illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0016] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e.,unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, 4 60701001.1linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0017] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclicring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally, or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:

[0018] The termalkyl group. Exemplarylower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. 5 60701001.1

[0019] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that issubstituted with one or more halogen atoms.

[0020] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0021] The term “unsaturated,” as used herein, means that a moiety has one or more units ofunsaturation.

[0022] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight orbranched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0023] The term “-(C0 alkylene)-“ refers to a bond. Accordingly, the term “-(C0-3 alkylene)-”encompasses a bond (i.e., C0) and a -(C1-3 alkylene)- group.

[0024] The term “halogen” means F, Cl, Br, or I.

[0025] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or“aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “phenylene” refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it.

[0026] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g.,“heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, 6 60701001.1pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0027] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and“heterocyclic ring” are used interchangeably and refer to a stable 3– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl).

[0028] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or 7 60701001.1more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “oxo-heterocyclyl” refers to a heterocyclyl substituted by one or more oxo group. The term “heterocyclylene” refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it. The term “oxo-heterocyclylene” refers to a multivalent oxo-heterocyclyl group having the appropriate number of open valences to account for groups attached to it.

[0029] As used herein, the term “partially unsaturated” refers to a ring moiety that includes atleast one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0030] As described herein, compounds of the invention may contain “optionally substituted”moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation ofstable or chemically feasible compounds. The term “stable,” as used herein, refers to compoundsthat are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0031] Each optional substituent on a substitutable carbon is a monovalent substituentindependently selected from halogen; –(CH2)0–4R^; –(CH2)0–4OR^; -O(CH2)0-4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR^)2; –(CH2)0–4SR^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; – 8 60701001.1N3; -(CH2)0–4N(R^)2; –(CH2)0–4N(R^)C(O)R^; –N(R^)C(S)R^; –(CH2)0–4N(R^)C(O)NR^2; -N(R^)C(S)NR^2; –(CH2)0–4N(R^)C(O)OR^; –N(R^)N(R^)C(O)R^; -N(R^)N(R^)C(O)NR^2; -N(R^)N(R^)C(O)OR^; –(CH2)0–4C(O)R^; –C(S)R^; –(CH2)0–4C(O)OR^; –(CH2)0–4C(O)SR^; -(CH2)0–4C(O)OSiR^3; –(CH2)0–4OC(O)R^; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R^; –(CH2)0–4C(O)NR^2; –C(S)NR^2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR^2;-C(O)N(OR^)R^; –C(O)C(O)R^; –C(O)CH2C(O)R^; –C(NOR^)R^; -(CH2)0–4SSR^; –(CH2)0–4S(O)2R^; –(CH2)0–4S(O)2OR^; –(CH2)0–4OS(O)2R^; –S(O)2NR^2; –S(O)(NR^)R^; – S(O)2N=C(NR^2)2; -(CH2)0–4S(O)R^; -N(R^)S(O)2NR^2; –N(R^)S(O)2R^; –N(OR^)R^; – C(NH)NR^2; –P(O)2R^; -P(O)R^2; -OP(O)R^2; –OP(O)(OR^)2; SiR^3; –(C1–4 straight or branched alkylene)O–N(R^)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R^)2.

[0032] Each R^ is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R^ selected from =O and =S; or each R^ is optionally substituted with a monovalent substituent independently selected from halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, – (CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^, –(C1–4 straight or branched alkylene)C(O)OR^, or –SSR^.

[0033] Each R^ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or – S(C(R*2))2–3S–, or a divalent substituent bound to vicinal substitutable carbons of an “optionallysubstituted” group is –O(CR*2)2–3O–, wherein each independent occurrence of R* is selected9 60701001.1from hydrogen, C1–6aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] When R* is C1–6 aliphatic, R* is optionally substituted with halogen, –R^, -(haloR^), -OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0035] An optional substituent on a substitutable nitrogen is independently –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, – C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R†is C1–6aliphatic, R†is optionally substituted with halogen, –R^, -(haloR^), -OH, –OR^, – O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to those salts whichare, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, 10 60701001.1nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0037] Further, acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference.

[0038] Salts derived from appropriate bases include alkali metal, alkaline earth metal,ammonium and N+(C1–4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0039] Unless otherwise stated, structures depicted herein are also meant to include allisomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as 11 60701001.1well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0040] Diastereomeric mixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.

[0041] Individual stereoisomers of the compounds of the invention may, for example, besubstantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as an atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this invention.

[0042] Chemical names, common names, and chemical structures may be usedinterchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom 12 60701001.1with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0043] The terms “a” and “an” as used herein mean “one or more” and include the pluralunless the context is inappropriate.

[0044] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as astraight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10alkyl, and C1-C6alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0045] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridgedcyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group.

[0046] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturatedaliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0047] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, asdefined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like.

[0048] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, acyclopentane susbstituted with an oxo group is cyclopentanone.

[0049] The symbol “ ” indicates a point of attachment.13 60701001.1

[0050] When any substituent or variable occurs more than one time in any constituent or thecompound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0051] One or more compounds of the invention may exist in unsolvated as well as solvatedforms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.

[0052] As used herein, “T1 / 2” refers to the time required for the plasma concentration of adrug to decrease by 50%.

[0053] As used herein, “Cmax” refers to the maximum plasma concentration reached.

[0054] As used herein, “Tmax” refers to the time from administration of a drug until Cmax isreached.

[0055] As used herein, “AUClast” refers to the area under the concentration time curveactually observed.

[0056] As used herein, “AUCInf” refers to the theoretical measure of the total exposure ofdrug to the body from time of administration until all of the drug is eliminated.

[0057] As used herein, “AUC_%Extrap_obs” refers to the area under the concentration-time curveextrapolated from the last observed time point to ∞ in % of the total area under the concentration-time curve (AUC).

[0058] As used herein, “MRTInf_obs” refers to the mean residence time from the first sampledtime extrapolated to infinity based on the last observed concentration.

[0059] As used herein, “AUClast / D” refers to the dose normalized area under the concentrationtime curve actually observed. 14 60701001.1

[0060] As used herein, the terms “subject” and “patient” are used interchangeably and refer toorganisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

[0061] As used herein, the term “effective amount” refers to the amount of a compoundsufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0062] As used herein, the term “pharmaceutical composition” refers to the combination of anactive agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0063] As used herein, the term “pharmaceutically acceptable carrier” refers to any of thestandard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0064] For therapeutic use, salts of the compounds of the present invention are contemplatedas being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0065] In addition, when a compound of the invention contains both a basic moiety (such as,but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an 15 60701001.1equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0066] Throughout the description, where compositions are described as having, including, orcomprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0067] As a general matter, compositions specifying a percentage are by weight unlessotherwise specified. I. Pyridazinone Phosphate Compounds

[0068] One aspect of the invention provides a compound represented by Formula I:or a pharmaceutically

[0069] In certain embodiments, the .16 60701001.1

[0070] In certain embodiments, the compound is a pharmaceutically acceptable salt of.

[0071] Methods are provided for treating and preventing medical disorders and conditionsusing a compound described herein that modulates transient receptor potential (TRP) cation channel subfamily C, member 5 (TRPC5). In one aspect, the medical disorder is a psychiatric condition. In another aspect, the medical condition is pain. In another aspect, the medical condition is kidney disease. Also provided are methods of inhibiting TRPC5 in a subject. Each are described in more detail below.

[0072] In certain embodiments, the compound is represented by Formula I:or a pharmaceutically

[0073] In certain embodiments, the compound is a pharmaceutically acceptable salt of:60701001.1

[0074] In certain embodiments, the compound is represented by Formula I:.

[0075] Suchto 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one, and as such are a useful way to deliver 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8- dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)pyridazin-3(2H)-one to a subject. Inhibiting TRPC 5

[0076] Another aspect of the invention provides a method of inhibiting transient receptorpotential cation channel subfamily C, member 5 (TRPC5) in a subject, comprising administering to the subject an effective amount of a compound described herein, such as a compound represented by Formula I or a pharmaceutically acceptable salt thereof, to thereby inhibit the TRPC5. In certain embodiments, the subject has a psychiatric condition. In certain embodiments, the psychiatric condition is one of the psychiatric conditions described herein below. In certain embodiments, the subject has a disease or condition selected from kidney disease, pulmonary arterial hypertension, cancer, diabetic retinopathy, or pain. In certain embodiments, the kidney disease, pulmonary arterial hypertension, cancer, diabetic retinopathy, or pain or one of the kidney disease, pulmonary arterial hypertension, cancer, diabetic retinopathy, or pain described herein below. Treat or Prevent a TRPC5-associated Disorder or Condition

[0077] One aspect of the invention provides a method of treating or preventing a TRPC5-associated disorder or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound represented by Formula I or a pharmaceutically acceptable salt thereof, treat or prevent the TRPC5-associated disorder or condition. In certain embodiments, the method is to treating a TRPC5-associated 18 60701001.1disorder or condition. In certain embodiments, the method is to preventing a TRPC5-associated disorder or condition. Treat or Prevent a Psychiatric Condition

[0078] One aspect of the invention provides methods of treating or preventing a psychiatriccondition using compounds that modulate transient receptor potential (TRP) cation channel subfamily C, member 5 (TRPC5). Cation channels such as TRPC5 modulate the flux of calcium and sodium ions across cellular membranes. Homomeric TRPC5 ion channels are signal transduction gated, Ca2+permeable channels predominantly expressed in neurons. Modulating the function of TRPC5 proteins provides a means of modulating calcium homeostasis, sodium homeostasis, membrane polarization, and / or intracellular calcium levels, and compounds that can modulate TRPC5 function are useful in many aspects. Compounds inhibiting TRPC5 containing ion channels are for example useful for treating and preventing conditions such as a psychiatric disorder.

[0079] Accordingly, one aspect of the invention provides a method of treating or preventing apsychiatric condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a represented by Formula I or a pharmaceutically acceptable salt thereof, to treat or prevent the psychiatric condition. In certain embodiments, the method is to treating a psychiatric condition. In certain embodiments, the method is to preventing a psychiatric condition.

[0080] In certain embodiments, the psychiatric condition is depression.

[0081] In certain embodiments, the psychiatric condition is borderline personality disorder,major depression, major depressive disorder, psychiatric depression, bipolar depression, dysthymia, postpartum depression, or seasonal affective disorder. In certain embodiments, the psychiatric condition is borderline personality disorder. In certain embodiments, the psychiatric condition is major depression. In certain embodiments, the psychiatric condition is major depressive disorder. In certain embodiments, the psychiatric condition is psychiatric depression. In certain embodiments, the psychiatric condition is dysthymia. In certain embodiments, the psychiatric condition is postpartum depression. In certain embodiments, the psychiatric condition is seasonal affective disorder. 19 60701001.1

[0082] In certain embodiments, the psychiatric condition is anxiety. In certain embodiments,the psychiatric condition is an anxiety and fear-related disorder. In certain embodiments, the psychiatric condition is selected from (i) a fear-related disorder, (ii) an anxiety and fear-related disorder, (iii) an anxiety and stress-related disorder, (iv) an anxiety and fear-related disorder, and (v) an anxiety and stress-related disorder also attributed to fear.

[0083] In certain embodiments, the psychiatric condition is post-traumatic stress disorder,panic disorder, agoraphobia, a social phobia, generalized anxiety disorder, social anxiety disorder, separation anxiety, substance or medication-induced anxiety disorder, or an anxiety disorder because of another medical condition. In certain embodiments, the psychiatric condition is generalized anxiety disorder. In certain embodiments, the psychiatric condition is post-traumatic stress disorder. In certain embodiments, the psychiatric condition is panic disorder. In certain embodiments, the psychiatric condition is agoraphobia. In certain embodiments, the psychiatric condition is a social phobia. In certain embodiments, the psychiatric condition is anxiety disorder. In certain embodiments, the psychiatric condition is separation anxiety. In certain embodiments, the psychiatric condition is a substance or medication-induced anxiety disorder. In certain embodiments, the psychiatric condition is an anxiety disorder because of another medical condition.Treat or Prevent a Kidney Disease, Pulmonary Arterial Hypertension, Cancer, DiabeticRetinopathy, & Pain

[0084] Another aspect of the invention provides a method of treating or preventing a disease orcondition selected from kidney disease, pulmonary arterial hypertension, cancer, diabetic retinopathy, or pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I or a pharmaceutically acceptable salt thereof, to treat or reduce the risk of developing the disease or condition. In certain embodiments, the method treats said disease or condition. In certain embodiments, the method prevents said disease or condition.

[0085] In certain embodiments, the disease or condition is cancer or diabetic retinopathy. Incertain embodiments, the disease or condition is cancer. In certain embodiments, the disease or condition is diabetic retinopathy. 20 60701001.1

[0086] In certain embodiments, the disease or condition is pain. In certain embodiments, thedisease or condition is neuropathic pain or visceral pain. In certain embodiments, the disease or condition is neuropathic pain. In certain embodiments, the disease or condition is visceral pain.

[0087] In certain embodiments, the disease or condition is kidney disease. In certainembodiments, the disease or condition is a kidney disease selected from Focal Segmental Glomerulosclerosis (FSGS), Diabetic nephropathy, Alport syndrome, hypertensive kidney disease, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change disease, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex-mediated MPGN, complement-mediated MPGN, Lupus nephritis, postinfectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis (primary), c1q nephropathy, rapidly progressive GN, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, or IgA nephropathy.

[0088] In certain embodiments, the disease or condition is Focal Segmental Glomerulosclerosis(FSGS). In certain embodiments, the disease or condition is Diabetic nephropathy. In certain embodiments, the disease or condition is Alport syndrome. In certain embodiments, the disease or condition is hypertensive kidney disease. In certain embodiments, the disease or condition is nephrotic syndrome. In certain embodiments, the disease or condition is steroid-resistant nephrotic syndrome. In certain embodiments, the disease or condition is minimal change disease. In certain embodiments, the disease or condition is membranous nephropathy. In certain embodiments, the disease or condition is idiopathic membranous nephropathy. In certain embodiments, the disease or condition is membranoproliferative glomerulonephritis (MPGN). In certain embodiments, the disease or condition is immune complex-mediated MPGN. In certain embodiments, the disease or condition is complement-mediated MPGN. In certain embodiments, the disease or condition is lupus nephritis. In certain embodiments, the disease or condition is postinfectious glomerulonephritis. In certain embodiments, the disease or condition is thin basement membrane disease. In certain embodiments, the disease or condition is mesangial proliferative glomerulonephritis. In certain embodiments, the disease or condition is amyloidosis (primary). In certain embodiments, the disease or condition is c1q nephropathy. In certain embodiments, the disease or condition is rapidly progressive GN. In certain embodiments, the disease or condition is anti-GBM disease. In certain embodiments, the disease or condition is C3 glomerulonephritis. 21 60701001.1In certain embodiments, the disease or condition is hypertensive nephrosclerosis. In certain embodiments, the disease or condition is IgA nephropathy.

[0089] In certain embodiments, the kidney disease is proteinuric kidney disease.

[0090] In certain embodiments, the kidney disease is microalbuminuria or macroalbuminuriakidney disease. In certain embodiments, the kidney disease is microalbuminuria. In certain embodiments, the kidney disease is macroalbuminuria kidney disease.

[0091] In certain embodiments, the disease or condition is pulmonary arterial hypertension.Exemplary References – Impact of TRPC5 on Medical Conditions

[0092] Exemplary publications describing the impact of TRPC5 on various medical conditionsare provided below.^ WO 2020 / 061162 (PCT / US2019 / 051680) – describing the activity of various compounds in aTRPC5 inhibition assay and rat glomerular injury model, and that TRPC5 has been reported to contribute to the mechanisms underlying regulation of innate fear responses.^ Riccio et al., J Neurosci. 2014 Mar 5; 34(10): 3653-3667. Decreased anxiety-like behaviorand Gαq / 11-dependent responses in the amygdala of mice lacking TRPC4 channels.^ WO 2014 / 143799 – describing various compounds that inhibit TRPC5, including a compoundthat has been demonstrated to provide anxiolytic and antidepressant activity in a number of preclinical models, including the elevated plus maze, forced swim test, chronic stress-induced fear hyperactivity, marble burying, tail suspension test, and startle reflex.^ Just et al., PLoS One. 2018 Jan 31;13(1):e0191225. doi: 10.1371 / journal.pone.0191225.Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice. Method of Delivering a Compound of Formula I-2

[0093] Another aspect of the invention provides a method of delivering a compound of FormulaI-2 to a subject in need thereof, comprising administering to the subject a pharmaceutical composition described herein, such as a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I-2 is represented by: 22 60701001.1. Subjects

[0094] In certain embodiments, the subject is a human. In certain embodiments, the subject isan adult human. In certain embodiments, the subject is a pediatric human. Medical Uses

[0095] Another aspect of the invention provides for the use of a compound of Formula I, or apharmaceutically acceptable salt thereof, in the manufacture of a medicament. In certain embodiments, the medicament is for treating or preventing a disorder described herein, such as a psychiatric condition. In certain embodiments, the medicament is for treating a disorder described herein, such as a psychiatric condition. In certain embodiments, the medicament is for preventing a disorder described herein, such as a psychiatric condition.

[0096] Another aspect of the invention provides for the use of a compound of Formula I, or apharmaceutically acceptable salt thereof, for treating or preventing a disorder described herein. In certain embodiments, the compound is for treating a disorder described herein. In certain embodiments, the compound is for preventing a disorder described herein. In certain embodiments, the compound is for treating or preventing a psychiatric condition. In certain embodiments, the compound is for treating a psychiatric condition. In certain embodiments, the compound is for preventing a psychiatric condition.III. Pharmaceutical Compositions and Dosing Considerations

[0097] Another aspect of the invention provides a pharmaceutical composition comprising acompound described herein and a pharmaceutically acceptable carrier. In certain embodiments, the compound is represented by Formula I: 23 60701001.1or a pharmaceutically acc

[0098] In certain embodiments, the compound is a pharmaceutically acceptable salt of:

[0099] In certainFormula I:[000100] As indicatedcompositions, whichcomprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration (PO), for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, 24 60701001.1intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained- release formulation; (3) topical application, for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. In certain embodiments, the invention provides a pharmaceutical composition comprising a compound described herein (such as a compound of Formula I, or other compounds in Section II) and a pharmaceutically acceptable carrier.[000101] The phrase “therapeutically effective amount” as used herein means that amount of acompound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit / risk ratio applicable to any medical treatment.[000102] The phrase “pharmaceutically acceptable” is employed herein to refer to thosecompounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.[000103] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.[000104] Examples of pharmaceutically-acceptable antioxidants include: (1) water solubleantioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.[000105] Formulations of the present invention include those suitable for oral, nasal, topical(including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be 25 60701001.1combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.[000106] In certain embodiments, a formulation of the present invention comprises an excipientselected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.[000107] Methods of preparing these formulations or compositions include the step of bringinginto association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.[000108] Formulations of the invention suitable for oral administration may be in the form ofcapsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.[000109] In solid dosage forms of the invention for oral administration (capsules, tablets, pills,dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, 26 60701001.1polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non- ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.[000110] A tablet may be made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.[000111] The tablets, and other solid dosage forms of the pharmaceutical compositions of thepresent invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in 27 60701001.1a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.[000112] Liquid dosage forms for oral administration of the compounds of the invention includepharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.[000113] Besides inert diluents, the oral compositions can also include adjuvants such as wettingagents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.[000114] Suspensions, in addition to the active compounds, may contain suspending agents as,for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.[000115] Formulations of the pharmaceutical compositions of the invention for rectal or vaginaladministration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.[000116] Formulations of the present invention which are suitable for vaginal administration alsoinclude pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.[000117] Dosage forms for the topical or transdermal administration of a compound of thisinvention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and 28 60701001.1inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically- acceptable carrier, and with any preservatives, buffers, or propellants which may be required.[000118] The ointments, pastes, creams and gels may contain, in addition to an active compoundof this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.[000119] Powders and sprays can contain, in addition to a compound of this invention, excipientssuch as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.[000120] Transdermal patches have the added advantage of providing controlled delivery of acompound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.[000121] Ophthalmic formulations, eye ointments, powders, solutions and the like, are alsocontemplated as being within the scope of this invention.[000122] Pharmaceutical compositions of this invention suitable for parenteral administrationcomprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.[000123] Examples of suitable aqueous and nonaqueous carriers which may be employed in thepharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be 29 60701001.1maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.[000124] These compositions may also contain adjuvants such as preservatives, wetting agents,emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.[000125] In some cases, in order to prolong the effect of a drug, it is desirable to slow theabsorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally- administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.[000126] Injectable depot forms are made by forming microencapsule matrices of the subjectcompounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.[000127] When the compounds of the present invention are administered as pharmaceuticals, tohumans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.[000128] The preparations of the present invention may be given orally, parenterally, topically,or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred. 30 60701001.1[000129] The phrases “parenteral administration” and “administered parenterally” as used hereinmeans modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.[000130] The phrases “systemic administration,” “administered systemically,” “peripheraladministration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.[000131] These compounds may be administered to humans and other animals for therapy by anysuitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.[000132] Regardless of the route of administration selected, the compounds of the presentinvention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.[000133] Actual dosage levels of the active ingredients in the pharmaceutical compositions ofthis invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.[000134] The selected dosage level will depend upon a variety of factors including the activity ofthe particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. 31 60701001.1[000135] In general, a suitable daily dose of a compound of the invention will be that amount ofthe compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the compounds are administered at about 0.01 mg / kg to about 200 mg / kg, more preferably at about 0.1 mg / kg to about 100 mg / kg, even more preferably at about 0.5 mg / kg to about 50 mg / kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone.[000136] If desired, the effective daily dose of the active compound may be administered as two,three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.[000137] The invention further provides a unit dosage form (such as a tablet or capsule)comprising a compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein. EXAMPLE 1 – Preparation of (5-chloro-4-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8- dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-6-oxopyridazin-1(6H)-yl)methyl dihydrogen phosphate, Compound I-1[000138] Step 1: Potassium phosphate (265.0 g, 1243.0 mmol) was added to a stirred solution of 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)- yl)pyridazin-3(2H)-one (250.0 g, 565.0 mmol) in N,N-dimethylacetamide (2000 mL). The mixture 32 60701001.1was heated to 50oC and stirred for 30 min. Di-tert-butyl (chloromethyl) phosphate (250.0 g, 962.5 mmol) was dissolved into N,N-dimethylacetamide (500 mL), and added dropwise into the reaction mixture over 2 h at 50°C. The resulting mixture was stirred for at least 18 h at 50°C. The reaction was confirmed complete by HPLC. The reaction mixture was cooled to 25°C and diluted with ethyl acetate (2500 mL). The resulting mixture was washed with water (6250 mL) and brine (2x2500 mL). The organic layer was concentrated, and the residue was applied to a silica gel column and eluted with DCM (contain 1.0% TEA) to afford 195 g of di-tert-butyl ((5-chloro-4-(4-(4-fluoro-2- (trifluoromethyl) phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-6-oxopyridazin-1(6H)- yl)methyl) phosphate as a yellow solid with 61.4% purity. The crude product was used for the next step directly.1H NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 8.20 (s, 1H), 7.78 (dd, J = 3.2, 8.4 Hz, 1H), 7.69 (td, J = 3.2, 8.4 Hz, 1H), 7.62 (dd, J = 4.8, 9.2 Hz, 1H), 5.68 (d, J = 7.6 Hz, 2H), 4.76 (s, 2H), 3.87 (t, J = 5.6 Hz, 2H), 2.99 (t, J = 5.6 Hz, 2H), 1.42 (s, 18H). m / z: [ESI+] 664 (M+H)+. The compound 4-chloro-5-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin- 7(6H)-yl)pyridazin-3(2H)-one can be prepared according to procedures described in international patent application WO 2020 / 061162.[000139] Step 2: To a stirred solution of di-tert-butyl ((5-chloro-4-(4-(4-fluoro-2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-6-oxopyridazin-1(6H)- yl)methyl) phosphate (100.0 g, 150.0 mmol) in dichloromethane (1000 mL) was added trifluoroacetic acid (138.0 g, 1200 mmol) dropwise at 25oC under a nitrogen atmosphere. The resulting mixture was stirred for 1 h at 25oC under a nitrogen atmosphere. The resulting mixture was concentrated to 500 mL under reduced pressure. The resulting mixture was swapped with ethyl acetate (2x1000 mL). To the resulting mixture was charged heptane (500 mL). The slurry was filtered and the filter cake was washed with ethyl acetate (500 mL). The crude mixture was then purified by filtering a slurry in THF / Heptane (2 / 1, 1500 mL). The filter cake was washed with THF / Heptane (2 / 1, 500 mL) and dried under nitrogen to afford 28.9 g of (5-chloro-4-(4-(4-fluoro-2- (trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-6-oxopyridazin-1(6H)- yl)methyl dihydrogen phosphate as an off-white solid with 98.6% purity, yield of 2 steps was 19.6%.1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.18 (s, 1H), 7.78 (dd, J = 8.8, 3.0 Hz, 1H), 7.66 (m, J = 2H), 5.69 (d, J = 7.6 Hz, 2H), 4.76 (s, 2H), 3.86 (t, J = 5.7 Hz, 2H), 3.01 (t, J = 5.7 Hz, 2H). m / z: [ESI+] 552 (M+H)+. 33 60701001.1EXAMPLE 2 – Solubility Evaluation of Compound I-1[000140] Compound I-1 was evaluated in a solubility assay, along with comparative compoundsI-2 and diclofenac. Compound I-2 has the following chemical structure:[000141] Experimental procedures and results are provided below.Part I – Experimental Procedure[000142] Preparation of stock solutions: The stock solutions of test compounds and controlcompound diclofenac were prepared in DMSO at a concentration of 10 mM. [000143] Chromatographic conditions:^ LC system: Shimadzu^ MS analysis: Triple Quad 6500+ instrument from AB Inc with an ESI interface forCompound I-1 and Compound I-2 ^MS analysis: Triple Quad 4500 instrument from AB Inc with an ESI interface fordiclofenac ^Column temperature: 40 °C^ Column: HALO 90 Å Biphenyl 2.7 μM (2.1×50 mm) for Compound I-1 andCompound I-2 ^Column: XSelect HSS T32.5um 2.1×50mm Column for diclofenac^ Mobile phase: A, water (0.1% formic acid); B, acetonitrile (0.1% formic acid)^ Injection volume: 1 μL for Compound I-1 and Compound I-2^ Injection volume: 3 μL for diclofenac^ Elution rate: 0.8 mL / min^ Elution Gradient:34 60701001.1Time (min) 0 0.2 0.5 0.9 0.951.2% B 5 5 98 98 55

[000] ass pec roscopy parame ers:^ Ion source: Turbo spray^ Ionization model: ESI^ Scan type: MRM^ Collision gas: 9 L / min^ Curtain gas: 40 L / min^ Nebulize gas: 55 L / min^ Auxiliary gas: 55 L / min^ Temperature: 500 °C^ Ionspray voltage: +5500 V(positive) / -4500 V(negative)Compound Q1 (m / z) Q3 (m / z) DP (v) CE (v) I2442073 406148 80 35 [000145] Compounds: The test compound I-1 was prepared as described above in Example 1.Compound purity data for the aliquots used in this experiment is presented below. Compound Purity[000146] Control compound diclofenac was purchased from Sigma.[000147] Test Solutions:[000148] Phosphate buffer solution (PBS) pH 7.4: First, 100 mM Na2HPO4 solution wasprepared by adding 1.42 g Na2HPO4into 100 mL deionized water. Then, 100 mM NaH2PO4solution was prepared by adding 1.20 g NaH2PO4 into 100 mL deionized water. Finally, 40 mL of 100 mM Na2HPO4 and 10 mL of 100 mM NaH2PO4 were combined, and the mixed solution was adjusted to pH 7.4 with 100 mM Na2HPO4 / NaH2PO4solution. 35 60701001.1[000149] FaSSIF: Buffer A was prepared by dissolving 0.420 g of NaOH, 3.438 g of NaH2PO4and 6.186 g of NaCl into about 900 mL ultrapure water and adjusting the pH of the solution to 6.5 with 1 N NaOH or 1 N HCl then diluting the solution with ultrapure water to 1000 mL at room temperature. 2.240 g of FaSSIF, FeSSIF and FaSSGF powder were added to about 500 mL of buffer A. The solution was stirred until the powder was completely dissolved. Then the solution was diluted with buffer A to 1000 mL at room temperature.[000150] FeSSIF: Buffer B was prepared by dissolving 4.040 g of NaOH, 8.650 g of glacialacetic acid, and 11.874 g of NaCl into about 900 mL ultrapure water and adjusting the pH of the solution to 5.0 with 1 N NaOH or 1 N HCl. Then the solution was diluted with ultrapure water to 1000 mL at room temperature.11.200 g of FaSSIF, FeSSIF and FaSSGF powder was added to about 500 mL of buffer B and stirred until the powder was completely dissolved. Then the solution was diluted with buffer B to 1000 mL at room temperature.[000151] Simulated Gastric Fluid: 234 mL of concentrated hydrochloric acid was added intoone 1000 mL volumetric flask, and diluted with ultrapure water to 1000 mL.16.4 mL of diluted hydrochloric acid, 800 mL of ultrapure water and 10 g of pepsin were added into one new 1000 mL volumetric flask, then mixed and diluted with ultrapure water to 1000 mL.[000152] Preparation of 300 µM standards (STD): From the 10 mM DMSO STD plate, 6 µLwas transferred into the remaining empty plate, and then 194 µL of DMSO was added to that plate to have a STD concentration of 300 µM. From the 300 µM DMSO STD plate, 5 µL DMSO STD and 5 µL PBS pH 7.4, FaSSIF, FeSSIF and SGF were transferred into the remaining empty plate, and then 490 µL of a mixture of H2O and acetonitrile containing internal standard (1:1) was added to that plate to have a final STD concentration of 3 µM. A certain proportion of ultrapure water was used to dilute the diluent according to the peak shape. The concentrations of the standard samples were changed according to the LC-MS signal response.[000153] Procedure for solubility determination: 15 µL of stock solution (10 mM) of eachsample was placed in order into their proper 96-well rack.485 µL of PBS pH 7.4, FaSSIF, FeSSIF and SGF was added into each vial of the cap-less Solubility Sample plate. The assay was performed in duplicate. One stir stick was added to each vial and sealed using a molded PTFE / Silicone plug. Then the solubility sample plate was transferred to the Eppendorf Thermomixer Comfort plate shaker and shaken at 25°C at 1100 rpm for 2 hours. After 36 60701001.1completion of the 2 hours, plugs were removed and the stir sticks were removed using a magnet. Then the samples from the Solubility Sample plate were transferred into the filter plate. Using the Vacuum Manifold, all the samples were filtered. Aliquots of 5 µL were taken from the filtrate followed by addition of 5 µL of DMSO and 490 µL of a mixture of H2O and acetonitrile containing internal standard (1:1). A certain proportion of ultrapure water was used to dilute the diluent according to the peak shape. The dilution factor was changed according to the solubility values and the LC-MS signal response.[000154] Procedure for sample analysis: The plate was placed into the well plate autosampler.The samples were evaluated by LC-MS / MS analysis.[000155] Data analysis: All calculations were carried out using Microsoft Excel. The filtratewas analyzed and quantified against a standard of known concentration using LC coupled with mass spectral peak identification and quantitation. Solubility values of the test compound and control compound were calculated as follows: [Sample]=^^^^^^^^ ^^^^^^^^^^ ^^^^^^^^^^^^×^^^^ ^^^^^^^^^^^^×[^^^^^^]^^^^^^^^ ^^^^^^^^^^ ^^^^^^[000156] Any value of thelimits was rejected andthe experiment was repeated. Part II – Results[000157] The results of the above solubility assay are presented below.Table 1. Solubility in PBS pH 7.4 Compound Solubility (μM)Table 2. Solubility in FaSSIF CompoundSolubility (μM)37 60701001.1Table 3. Solubility in FeSSIF Compound Solubility (μM) Diclofenac308.65[000158] The upper limit was set at 300 µM. Any value close to or above 300 µM indicates thatthe compound may have a solubility at or above 300 µM. EXAMPLE 3 – Evaluation of Compound I-2 Rat Maze Assay[000159] Compound I-2 and a positive control (Diazepam) were tested in the Rat Elevated PlusMaze Assay in order to determine the anxiolytic effectiveness of the compounds in-vivo. Experimental procedures and results are provided below. Part I – Experimental Procedure[000160] Animals: Wistar male rates were used; 10 rats were assigned per group, for a total for60 animals. The age at the time of the study was 8-10 weeks. The body weight range was 200- 280 g. Rats were acclimatized for 7 days before starting the experiment. Experimental procedures and results are provided below.[000161] Dosing: Animals were brought to the laboratory at least 1 h prior to evaluation toacclimatize to the laboratory conditions. The experiment was done across 2 days with equal number of animals (n=5) from each group being subjected to experimentation. On the day of the experiment, 60 minutes prior to trial, the rats were treated either with vehicle, Compound I-2, or diazepam. The testing groups were allocated as below: Group 1. Vehicle (1% methyl cellulose, 5 mL / kg, p.o.) Group 2. Diazepam (10 mg / kg, p.o.) Group 3. Compound I-2 (1 mg / kg, p.o.) Group 4. Compound I-2 (3.2 mg / kg, p.o.) Group 5. Compound I-2 (10 mg / kg, p.o.) 38 60701001.1Table 4. Compound Formulations Group Day of Test I Strength Weight / Vehicle Formulation No. Prep tem (mg / mL) Volume Volume[000162] Maze Procedure: The elevated plus maze was a black colored arena in the form of aplus sign. It had two open arms (50 x 11 cm) and two closed arms (50 x 11 cm) partially enclosed on 3 sides by walls (39 cm height) and connected by a central square (10 x 10 cm). The experiment was done under constant lighting conditions (~50 lux in the open arms). Rats were placed in the central square facing the enclosed arm. Tracking was done for a period of 5 minutes with the help of TSE Videomot 2 version 8.04. The maze was cleaned with 70% v / v alcohol after each trial. The time spent in the open arms, time in enclosed arms, and total distance travelled in the elevated plus maze were calculated with the help of TSE Videomot 2 software. Within 10 minutes of completion of behavioral study, rats from group 3 to 6 were euthanized on both days 39 60701001.1of the experiment. Subsequently, brain and plasma were collected from these groups. As outlined below.[000163] Maze Data Analysis: For Compound I-2: The anxiolytic effect of the test compoundswere analyzed by comparing the duration of time spent in the open arms, time in the enclosed arms and total distance travelled, using one-way ANOVA followed by Dunnett’s multiple comparison test against vehicle treated group. In this analysis, data from the diazepam group was not considered. *P<0.05 was considered as a statistically significant effect.[000164] For Diazepam: The anxiolytic effect of diazepam was analyzed by comparing thespent time in the open arms, time in the enclosed and total distance travelled using unpaired Student’s t test against the vehicle treated group. *P<0.05 was considered as a statistically significant effect.[000165] Plasma and Brain Homogenates Procedure: From each animal, Plasma and Brainhomogenates samples were subjected for quantification of Compound I-2 using LC-MS / MS method. A total of 60 samples (30 plasma and 30 brain samples) were subjected for analysis of Compound I-2.[000166] Sample preparation Compound I-2: 50 ^L of test sample (5 ^L of respectiveworking stock for calibration standards or quality control samples and 45^L of blank plasma) was taken into 0.6 mL microcentrifuge tube. To the above tube, 150 ^L of acetonitrile was added and subjected to vortex for 1 minute and centrifuged at 10,000 rpm for about 10 min at 10°C ± 1°C.50 ^L of supernatant clear solutions were diluted with 50 ^L of mobile phase, vortexed and transferred into vials and 1.0 ^L was injected to LC-MS / MS system.[000167] Plasma and Brain Homogenates Analysis: The brain and plasma homogenates wereanalyzed using the below standards and procedures. 40 60701001.1Table 5. MS / MS Calibration – Spiked Standard Curve MS / MS Q1→Q3 Mode of Detection Concentrations for LC-MS / MS Transitions 2Internal Standard Working 60 ng / mL CWoonrckeinntrastoioluntion diluent Water : Methanol (50:50)s. g p p Instrument / make NexeraX2 UHPLC (Shimadzu)41 60701001.1Flow rate 0.4 mL / min Injection Volume 1.0 µL. Instrument 6500+ (Triple Quad) LC-MS / MS (BRL / 2017 / 005)Ionization mode Positive[000168] Concentration of Compound I-2 in plasma and brain were included for individualanimals and summarized as a group mean. The data was subjected to Grubbs outlier test. Values which were considered as outliers by the test were not included in the final analysis. 42 60701001.1Part II – Results[000169] The results from the above maze assay are provided below. Oral treatment withCompound I-2 at a dose of 10 mg / kg increased the time spent in the open arms (**p<0.01) and reduced the time spent in the enclosed arms (**p<0.01). However, at lower doses of 1 and 3.2 mg / kg, no significant effects of treatment were observed in the time spent in the open arms or enclosed arms. There was an increase in the distance travelled in the elevated plus maze at doses of 3.2 (*p<0.05) and 10 mg / kg, administered orally (**p<0.01). Anxiolytic Effect Results: Table 9. Time Spent in Open Arm (ms) Group-2: Group-3: Group-4: Group-5: ,*- P<0.05, diazepam vs. vehicle treatment, Student’s unpaired-t-test (n=10); ** P<0.01 Vs. vehicle, one- way ANOVA followed by Dunnett’s multiple comparison test (n=9-10);#- excluded on the basis of Grubb’s outlier test for parameter total distance travelled;##- excluded as the rat fell from the maze. 43 60701001.1Table 10. Time Spent in Enclosed Arm (ms) l G Group-3: Group-4: Group-5: Anima Group-1: roup-2: Diaze am Com ound I-2 Compound I-2 Compound I-2, 9-10);# - excluded on the basis of Grubb’s outlier test for parameter- total distance travelled; ##- excluded as the rat fell from the maze. Table 11. Total Distance Travelled (cm) Group-2: Group-3: Group-4: Group-5: ,44 60701001.1Animal Group-1: Group-2: Group-3: Group-4: Group-5: Diazepam, Compound I-2, Compound I-2, Compound I-2,* - P<0.05, ** - P<0.01, *** - P<0.001 Vs. vehicle, one-way ANOVA followed by Dunnett’s multiple comparison test (n=9-10); # - excluded on the basis of Grubb’s outlier test for parameter; ##- excluded as the rat fell from the maze.[000170] The group treated with diazepam spent a greater time in the open arms (*p<0.05) buthad no significant effect on the time spent in the enclosed arms (p>0.05). Treatment with diazepam increased the total distance travelled in the elevated plus maze (**p<0.01).[000171] Oral treatment with Compound I-2 at a dose of 10 mg / kg increased the time spent inthe open arms (**p<0.01) and reduced the time spent in the enclosed arms (**p<0.01). However, at lower doses of 1 and 3.2 mg / kg, no significant effects of treatment were observed in the time spent in the open arms or enclosed arms. There was an increase in the distance travelled in the elevated plus maze at doses of 3.2 (*p<0.05) and 10 mg / kg, administered orally (**p<0.01). One animal from the Compound I-2 , 10 mg / kg fell from the plus maze and was excluded from the study. 45 60701001.1[000172] Plasma and Brain Concentration Results:Table 12. Individual Plasma and Brain Concentration of Compound I-2 Group-3: Compound I-2, Group-4: Compound I-2, Group-5: Compound I-2, 1 mg / kg 3.2 mg / kg 10 mg / kg A i l L)[1to 10 mg / kg, administered orally. EXAMPLE 4 – Evaluation of Compound I-1 and Compound I-2 in Rat Maze Assay[000174] Compound I-1 and Compound I-2 were tested in a Rat Elevated Plus Maze Assay inorder to determine the anxiolytic effectiveness of the compounds in vivo. Experimental procedures and results are provided below. Part I – Experimental Procedure[000175] Animals: Wistar male rates were used; 10 rats were assigned per group, for a total for60 animals. The age at the time of the study was 8-10 weeks. The body weight range was 200- 280 g. Rats were acclimatized for 7 days before starting the experiment.[000176] Dosing: Animals were brought to the laboratory at least 1 h prior to evaluation toacclimatize to the laboratory conditions. The experiment was done across 2 days with equal 46 60701001.1number of animals (n=5) from each group being subjected to experimentation. On the day of the experiment, 60 minutes prior to trial, the rats were treated either with vehicle, Compound I-1, Compound I-2, or diazepam. The testing groups were allocated as below: Group 1. Vehicle (1% methyl cellulose, 5 mL / kg, p.o.) Group 2. Diazepam (10 mg / kg, p.o.) Group 3. Compound I-1 (1 mg / kg, p.o.) Group 4. Compound I-1 (3.2 mg / kg, p.o.) Group 5. Compound I-1 (10 mg / kg, p.o.) Group 6. Compound I-2 (10 mg / kg, p.o.). Table 13. Compound Formulations Group Day of Test Item Strength Weight / Vehicle Formulation47 60701001.16 Compound I-2 dose 1 2 15.97 mg in 7.906 mL of 1%w / v MC 7.906 mL[000178] Maze Data Analysis: The maze data analysis is described above in Example 3.[000179] Plasma and Brain Homogenates Procedure: From each animal, plasma and brainhomogenates samples were subjected for quantification of Compound I-1 and Compound I-2 using LC-MS / MS method. A total of 80 samples for Compound I-2 and 60 samples for Compound I-1 were subjected for analysis.[000180] To prepare the samples, 50 μL of test sample (5 μL of respective working stock forcalibration standards or quality control samples and 45 μL of blank plasma) was taken into 0.6 mL micro centrifuge tube. To the above tube, 150 μL of acetonitrile containing internal standard was added and subjected to vortex for 1 minute and centrifuged at 10,000 rpm for about 10 min at 10°C ± 1°C.100 µL of supernatant clear solutions were diluted with 50 µL of mobile phase (A), vortexed and transferred into vials and 5.0 μL was injected to LC-MS / MS system.[000181] Plasma and Brain Homogenates Analysis: The brain and plasma homogenates wereanalyzed using the below standards and procedures. Table 14. MS / MS Calibration – Spiked Standard Curve C n ntr ti n f r LC-MS / MS MS / MS Q1→Q348 60701001.11.0, 2.0, 10, 50, 100, 500, 800,1000, Compound I-2 2000 and 2500 ng / mL, R ≥0.99 inInternal Standard Working Concentration 30 ng / mLd )a e . romaograp c on ons or ompoun - an ompoun - Instrument make NexeraX2 UHPLC (Shimadzu)49 60701001.1Flow rate 0.5 mL / minInjection Volume 5 µLInstrument 6500Q TRAP LC-MS / MS (BRL / 2015 / 006)Ionization mode Positive[000182] Concentrations of Compound I-1 and Compound I-2 in plasma and brain were includedfor individual animals and summarized as a group mean. The data was subjected to Grubbs outlier test. Values which were considered as outliers by the test were not included in the final analysis. 50 60701001.1Part II – Results[000183] The results from the above maze assay are provided below. Overall, Compound I-1exhibited anxiolytic like effect in the current experimental conditions at the tested doses of 3.2 and 10 mg / kg, administered orally. This was observed as an increase in the time spent in the open arms and a decrease in the time spent in the enclosed arms. At these doses, Compound I-1 increased the total distance travelled as well. Anxiolytic Effect Results: Table 18. Time Spent in Open Arm (ms) Animal Group-1: Group-2: Group-3: Group-4: Group-5: Group-6: Diazepam Compound I-1 Compound I- Compound I- Compound I-2,** - P<0.01, diazepam Vs. vehicle treatment, Student s unpaired-t-test (n=10); *** - P<0.001, ** - P<0.01 Vs. vehicle, one-way ANOVA followed by Dunnett’s multiple comparison test (n=9-10); # - excluded on the basis of Grubb’s outlier test for parameter time spent in open arm 51 60701001.1Table 19. Time Spent in Enclosed Arm (ms) Animal Group-1: Group-2: Group-3: Group-4: Group-5: Group-6: ID Vehicle Diazepam, Compound I- Compound I-1, Compound I- Compound I- g *- . , aepa s. e ce ea e , ue s upa e--es = ; **** - P<0.0001 , *** - P<0.001 vs. vehicle, one-way ANOVA followed by Dunnett’s multiple comparison test (n=9-10);#- excluded on the basis of Grubb’s outlier test for parameter time spent in open arm. Table 20. Total Distance Traveled (cm) Animal Group-1: Group-2: Group-3: Group-4: Group-5: Group-6: -2,52 60701001.1Animal Group-1: Group-2: Group-3: Group-4: Group-5: Group-6: ID Vehicle Diazepam, Compound I-1, Compound I-1, Compound I-1, Compound I-2,. , . . , (n=9-10);#- excluded on the basis of Grubb’s outlier test for parameter- time spent in open arm.[000184] The group treated with diazepam spent a significantly greater time in open arms(**p<0.01) and lesser time in enclosed arms (**p<0.01) in comparison to the vehicle treated group. Diazepam did not have any significant effect on the total distance travelled in the elevated plus maze as well (p> 0.05).[000185] Compound I-1 at doses of 1 mg / kg did not have a significant effect on the time spentin the open arms or enclosed arms (p>0.05). A trend to decrease the time spent in the enclosed arms was observed at this dose. At this dose, no significant effect on the total distance travelled was observed.[000186] Compound I-1 at a dose of 3.2 mg / kg increased the time spent in the open arms(***p<0.001) and decreased the time spent in the enclosed arms (****p<0.0001). Treatment with 3.2 mg / kg of Compound I-1 increased the total distance travelled in the elevated plus maze (*p<0.05).[000187] Compound I-1 at a dose of 10 mg / kg increased the time spent in the open arms(***p<0.001) and decreased the time spent in the enclosed arms (***p<0.001). At this dose of 53 60701001.1Compound I-1, an increase in the total distance travelled was observed (***p<0.001). One animal from this group was excluded on the basis of Grubb’s outlier test.[000188] Treatment with 10 mg / kg of Compound I-2 increased the time spent in the open arms(**p<0.01) and decreased the time spent in the enclosed arms (***p<0.001). Compound I-2, at a dose of 10 mg / kg increased the total distance travelled in the elevated plus maze (*p<0.05).[000189] Overall, Compound I-1 exhibited anxiolytic like effect in the current experimentalconditions at the tested doses of 3.2 and 10 mg / kg, administered orally. This was observed as an increase in the time spent in the open arms and a decrease in the time spent in the enclosed arms. At these doses, Compound I-1 increased the total distance travelled as well. The lower dose of 1 mg / kg, administered orally, did not exhibit anxiolytic like effects.[000190] Compound I-2 exhibited anxiolytic like effect in the current experimental conditions.There was an increase in the time spent in the open arms and a decrease in the time spent in the enclosed arms. Administration of Compound I-2 at a dose of 10 mg / kg, administered orally, increased the total distance travelled in the elevated plus maze. Plasma and Brain Concentration Results: Table 21. Individual Plasma and Brain Concentration of Compound I-1 in Rats Treated with Compound I-1 Group-3: Group-4: Group-5: kg54 60701001.110 < LLOQ < LLOQ < LLOQ < LLOQ < LLOQ 0.31 Mean - 0.31 - 0.31 - 0.38w t Compound - or - Group-3: Group-4: Group-5: Group-6: Compound I-1, 1 Compound I-1, 3.2 Compound I-1, 10 Compound I-2, 10 )[000191] In the group treated with Compound I-1 (1 to 10 mg / kg, p.o), the brain and plasmaexposures of Compound I-1 were generally below the limit of quantification (0.2 ng / mL), whereas the exposures of Compound I-2 in the same rats showed a dose-dependent increase. Accordingly, Compound I-1 converted to Compound I-2 completely and rapidly, and did not accumulate in the brain. Rats treated with 3.2 mg / kg Compound I-1 showed comparable or greater exposure to Compound I-2 than rats treated with 10 mg / kg Compound I-2. Rats treated with 10 mg / kg Compound I-1 showed an average exposure to Compound I-2 that was about 5- fold greater than rats treated with 10 mg / kg Compound I-2. 55 60701001.1[000192] Overall, there were quantifiable exposures of Compound I-2 in the brain and plasmaof rats treated with Compound I-1 and Compound I-2 (10 mg / kg, p.o). EXAMPLE 5 - Compound I-1 Pharmacokinetics Study[000193] Compound I-1 was dosed to rats as part of a rat pharmacokinetics (PK) study in orderto determine the pharmacokinetic parameters and metabolism of the compound in-vivo. The plasma concentrations of Compound I-1, and its metabolite Compound I-2, were analyzed at various time points after dosing with Compound I-1. Experimental procedures and results are provided below. Part I – Procedure[000194] Animals: Male Sprague Dawley (SD) rats were used in the study. The age at the timeof the study was 6-8 weeks. Three rats were assigned per dosing group, for a total of 18 rats.[000195] Dosing: Animals were dosed orally (P.O.) with their designated Compound I-1formulation via oral gavage.[000196] Compound I-1 was administered at a dose of 12.5 mg / kg, 37.5 mg / kg, 125 mg / kg,375 mg / kg, 749 mg / kg, or 1249 mg / kg. Compound I-1 was formulated for dosing as shown in the Table below. Table 23. Compound I-1 Formulations Dose Dose v l V l m Concentr 1% CMC and Total C m nd L ation 01% Tw n 80 v l me 1 4 0 7 6 5[000197] Sampling Procedure: The rats were subjected to jugular vein cannulation at 0.25, 0.5,1, 2, 4, 6, 8, 12, 24 and 48 hours post dosing.200 µL of blood were collected and stored at -80 °C.[000198] Analysis Procedures:[000199] The above samples were prepared and tested to calculate the plasma concentrations ofCompound I-1 and Compound I-2 using the below equipment and procedures.[000200] Preparation of Standard Solutions of Compound I-1: The desired serial concentrationsof working solutions were achieved by diluting stock solution of acetonitrile in ultrapure water.5 µL of working solutions (10, 20, 50, 100, 200, 400, 500, 1000, 2000, 5000 ng / mL) were added to 50 μL of the blank SD Rat plasma to achieve calibration standards of 1~500 ng / mL (1, 2, 5, 10, 20, 40, 50, 100, 200, 500 ng / mL) in a total volume of 55 μL. Five quality control samples at 2 ng / mL, 5 ng / mL, 10 ng / mL, 50 ng / mL and 400 ng / mL for plasma were prepared independently of those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards.[000201] Preparation of Standard Solutions of Compound I-2: The desired serial concentrationsof working solutions were achieved by diluting stock solution of acetonitrile in ultrapure water.5 µL of working solutions (10, 20, 50, 100, 200, 500, 1000, 5000, 10000, 50000 ng / mL) were added to 50 μL of the blank SD Rat plasma to achieve calibration standards of 1~5000 ng / mL (1, 2, 5, 10, 20, 50, 100, 500, 1000, 5000 ng / mL) in a total volume of 55 μL. Five quality control samples at 2 ng / mL, 5 ng / mL, 10 ng / mL, 50 ng / mL and 4000 ng / mL for plasma were prepared independently of those used for the calibration curves. These QC samples were prepared on the day of analysis in the same way as calibration standards.[000202] Plasma Sample Preparation: 55 μL standards, 55 μL QC samples and 55 μL unknownsamples (50 µL plasma with 5 µL blank solution) were added to 200 μL of acetonitrile containing IS mixture for precipitating protein respectively. Then the samples were vortexed for 30 s. After centrifugation at 4 degree Celsius, 4000 rpm for 15 min. The supernatant was diluted with ultrapure water at a ratio of 1:2 (V / V, 1:2), then 5 uL of diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.[000203] HPLC Instrument: SHIMADZU ( LC-40D X3 CN, Serial NO.L22436001522 AE andL22436001508 AE; DGU-405 Serial NO.L22175906266 IX; CBM-40 CN Serial NO.L22116002718 CD; SIL-40C X3CN, Serial NO: L22465901444 AE; CTO-40C CN, Serial NO: L22246004999 IK ); Plate Changer CN Serial No. L222260000620 CZ; Column: Raptor Biphenyl 2.7μm 50x2.1mm (SN:19053680). 57 60701001.1[000204] MS Instrument: AB API 5500+ LC / MS / MS instrument (Serial NO. EX233982204)[000205] HPLC Elution Conditions:Solution A: 5% Acetonitrile in Water (0.1%Formic acid) Solution B: 95% Acetonitrile in Water (0.1%Formic acid) Flow rate: 0.6 mL / min Injection volume: 5 μL Table 24. HPLC Gradient for Compound I-1 Time (min) A (%) B (%) 2 1Table 25. HPLC Gradient for Compound I-2 Time (min) A (%) B (%)Part II – Results[000206] Compound I-1 and Compound I-2 concentrations in plasma were analyzed. Results,including pharmacokinetic parameters for each of Compound I-1 and Compound I-2, are provided below. The abbreviation “BLOQ” refers to below the quantifiable limit of 1 ng / mL. 58 60701001.1Compound I-1 Plasma Concentration Data:[000207] For Compound I-1, plasma concentrations (ng / mL) were evaluated at 0.25, 0.5, 1, 2, 4,6, 8, 12, 24 and 48 hours post dosing. The mean was calculated, along with standard deviation (SD, ng / mL). The Coefficient of Variation (CV, %) was calculated using the following equation: CV = (Standard Deviation / Mean) * 100.[000208] The plasma concentration of Compound I-1 at dose levels of 12.5 mg / kg, 37.5 mg / kg,and 125 mg / kg were below the level of quantification for every rat tested at every time point after dosing. Compound I-1 was quantifiable in plasma from only one rat at two time points in the 375 mg / kg group, and only two rats at two timepoints in the 749 mg / kg group. Accordingly, no pharmacokinetic parameters were calculated for Compound I-1 at these doses. Table 26. Compound I-1 Plasma Concentration-Time Data in Rats Dosed 375 mg / kg of Compound I-1 TimeConcentration (ng / mL)MeanSD CV59 60701001.1Table 27. Compound I-1 Plasma Concentration-Time Data in Rats Dosed 749 mg / kg of Compound I-1 TimeConcentration (ng / mL)MeanSD CV (h)Rat 13 Rat 14 Rat 15(ng / mL) (ng / mL)(%)Table 28. Compound I-1 Plasma Concentration-Time Data in Rats Dosed 1249 mg / kg of Compound I-1 TimeConcentration (ng / mL)MeanSD CVData in bold were used for T1 / 2 calculation. 60 60701001.1Compound I-1 Pharmacokinetic Parameters:[000209] Based on the above plasma concentration data, pharmacokinetic parameters werecalculated for Compound I-1 by non-compartmental model using WinNonlin 8.3. Due to the limited number of data points above the limit of quantification for the 375 mg / kg and 749 mg / kg doses, the pharmacokinetic parameters were not able to be accurately calculated at dose amounts of 375 mg / kg and 749 mg / kg of Compound I-1. Pharmacokinetic parameters for the 1249 mg / kg dose of Compound I are provided below. Table 29. Compound I-1 Pharmacokinetic Parameters in Rats Dosed 1249 mg / kg of Compound I-1 PK Parameter Unit Rat 16 Rat 17 Rat 18 Mean SD CV (%)Compound I-2 Plasma Concentration Data:[000210] For Compound I-2, plasma concentrations (ng / mL) were determined at 0.25, 0.5, 1, 2,4, 6, 8, 12, 24 and 48 hours post dosing of Compound I-1. The mean plasma concentration was calculated, along with SD, and CV, as described above. Table 30. Compound I-2 Plasma Concentration-Time Data in Rats Dosed 12.5 mg / kg of Compound I-1 TimeConcentration (ng / mL)MeanSD CV61 60701001.11 1450 1240 1140 1277 158 12.4 2 1720 1590 1500 1603 111 690Table 31. Compound I-2 Plasma Concentration-Time Data in Rats Dosed 37.5 mg / kg of Compound I-1 TimeConcentration (ng / mL)MeanSD CV62 60701001.1Data in bold were used for T1 / 2 calculations. Table 32. Compound I-2 Plasma Concentration-Time Data in Rats Dosed 125 mg / kg of Compound I-1 TimeConcentration (ng / mL)MeanSD CV (h)R t 7 R t 8 R t 9(ng / mL) (ng / mL)(%)Table 33. Compound I-2 Plasma Concentration-Time Data in Rats Dosed 375 mg / kg of Compound I-1 TimeConcentration (ng / mL)MeanSD CV63 60701001.124 10400 18000 10700 13033 4304 33.0 48 973 574 290 440 476 108Table 34. Compound I-2 Plasma Concentration-Time Data in Rats Dosed 749 mg / kg of Compound I-1 TimeConcentration (ng / mL)MeanSD CV (h)R 1 R 14 R 1(n / mL) (n / mL)%. Table 35. Compound I-2 Plasma Concentration-Time Data in Rats Dosed 1249 mg / kg of Compound I-1 TimeConcentration (ng / mL)MeanSD CV64 60701001.18 14400 19600 19600 17867 3002 16.8 12 12400 16000 18300 15567 2974 191Compound I-2 Pharmacokinetic Parameters:[000211] Based on the above plasma concentration data, pharmacokinetic parameters werecalculated for Compound I-2. Table 36. Compound I-2 Pharmacokinetic Parameters in Rats Dosed 12.5 mg / kg of Compound I-1 PK Parameter Unit Rat 1 Rat 2 Rat 3 Mean SDCV (%)Table 37. Compound I-2 Pharmacokinetic Parameters in Rats Dosed 37.5 mg / kg of Compound I-1 PK Parameter Unit Rat 4 Rat 5 Rat 6 Mean SDCV ) 7 3 3 23965 60701001.1PK Parameter Unit Rat 4 Rat 5 Rat 6 Mean SDCV (%) 3 2 TableCompound I-1 PK Parameter Unit Rat 7 Rat 8 Rat 9 Mean SDCV (%)Table 39. Compound I-2 Pharmacokinetic Parameters in Rats Dosed 375 mg / kg of Compound I-1 PK Parameter Unit Rat 10 Rat 11 Rat 12 Mean SD CV (%)66 60701001.1Table 40. Compound I-2 Pharmacokinetic Parameters in Rats Dosed 725 mg / kg of Compound I-1 PK Parameter Unit Rat 13 Rat 14 Rat 15 Mean SD CV (%)Ta e . ompoun - armaco ne c arameers n as ose mg / g o Compound I-1 PK Parameter Unit Rat 16 Rat 17 Rat 18 Mean SD CV (%)Conclusions:[000212] The above data demonstrate rapid and exhaustive conversion of Compound I-1 to itsmetabolite, Compound I-2, in-vivo. 67 60701001.1INCORPORATION BY REFERENCE[000213] The entire disclosure of each of the patent documents and scientific articles referred toherein is incorporated by reference for all purposes. EQUIVALENTS[000214] The invention may be embodied in other specific forms without departing from thespirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein. 68 60701001.1

Claims

Claims:

1. A compound represented by Formula I:or a2. The compound of claim 1, wherein the compound is.

3. The compound ofacceptable salt of.

4. A pharmaceuticalof claims 1-3 and apharmaceutically acceptable carrier.

5. A method of inhibiting transient receptor potential cation channel subfamily C, member 5(TRPC5) in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1-3 to thereby inhibit the TRPC5.

6. The method of claim 5, wherein the subject has a psychiatric condition.69 60701001.

17. The method of claim 5, wherein the subject has a disease or condition selected fromkidney disease, pulmonary arterial hypertension, cancer, diabetic retinopathy, or pain.

8. A method of treating or preventing a TRPC5-associated disorder or condition, comprisingadministering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-3 to treat or prevent the TRPC5-associated disorder or condition.

9. A method of treating or preventing a psychiatric condition, comprising administering to asubject in need thereof a therapeutically effective amount of a compound of any one of claims 1-3 to treat or prevent the psychiatric condition.

10. The method of claim 9, wherein the method treats the psychiatric condition.

11. The method of claim 9, wherein the method prevents the psychiatric condition.

12. The method of any one of claims 6 or 9-11, wherein the psychiatric condition isborderline personality disorder, major depression, major depressive disorder, psychiatric depression, dysthymia, postpartum depression, or seasonal affective disorder.

13. The method of any one of claims 6 or 9-11, wherein the psychiatric condition is majordepressive disorder.

14. The method of any one of claims 6 or 9-11, wherein the psychiatric condition is anxiety.

15. The method of any one of claims 6 or 9-11, wherein the psychiatric condition is ananxiety and fear-related disorder.

16. The method of any one of claims 6 or 9-11, wherein the psychiatric condition is selectedfrom (i) a fear-related disorder, (ii) an anxiety and fear-related disorder, (iii) an anxiety and stress-related disorder, (iv) an anxiety and fear-related disorder, and (v) an anxiety and stress-related disorder also attributed to fear.

17. The method of any one of claims 6 or 9-11, wherein the psychiatric condition is post-traumatic stress disorder, panic disorder, agoraphobia, a social phobia, generalized anxiety disorder, social anxiety disorder, separation anxiety, substance or medication- induced anxiety disorder, or an anxiety disorder because of another medical condition. 70 60701001.

118. The method of any one of claims 6 or 9-11, wherein the psychiatric condition isgeneralized anxiety disorder.

19. The method of any one of claims 6 or 9-11, wherein the psychiatric condition isdepression.

20. A method of treating or preventing a disease or condition selected from kidney disease,pulmonary arterial hypertension, cancer, diabetic retinopathy, or pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-3 to treat or reduce the risk of developing the disease or condition.

21. The method of claim 20, wherein the method treats the disease or condition.

22. The method of claim 20, wherein the method prevents the disease or condition.

23. The method of any one of claims 7 or 20-22, wherein the disease or condition is cancer ordiabetic retinopathy.

24. The method of any one of claims 7 or 20-22, wherein the disease or condition is pain.

25. The method of any one of claims 7 or 20-22, wherein the disease or condition isneuropathic pain or visceral pain.

26. The method of any one of claims 7 or 20-22, wherein the disease or condition is kidneydisease.

27. The method of claim 26, wherein the disease or condition is a kidney disease selectedfrom Focal Segmental Glomerulosclerosis (FSGS), Diabetic nephropathy, Alport syndrome, hypertensive kidney disease, nephrotic syndrome, steroid-resistant nephrotic syndrome, minimal change disease, membranous nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), immune complex- mediated MPGN, complement-mediated MPGN, Lupus nephritis, postinfectious glomerulonephritis, thin basement membrane disease, mesangial proliferative glomerulonephritis, amyloidosis (primary), c1q nephropathy, rapidly progressive GN, anti-GBM disease, C3 glomerulonephritis, hypertensive nephrosclerosis, or IgA nephropathy. 71 60701001.

128. The method of claim 26, wherein the kidney disease is proteinuric kidney disease.

29. The method of claim 26, wherein the kidney disease is microalbuminuria ormacroalbuminuria kidney disease.

30. The method of any one of claims 7 or 20-22, wherein the disease or condition ispulmonary arterial hypertension.

31. The method of any one of claims 5-30, wherein the subject is a human.

32. A method of delivering a compound of Formula I-2 to a subject in need thereof,comprising administering to the subject a pharmaceutical composition comprising a compound of any one of claims 1-3, wherein Formula I-2 is represented by: .72 60701001.1

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