Saturated cystic fibrosis transmembrane conductance regulator modulators

Abstract

Disclosed herein are compounds having cystic fibrosis transmembrane conductance regulator modulatory activity. The compounds are useful for treating respiratory disorders, including cystic fibrosis.

Description

Attorney Docket No. 10029-120W01SATURATED CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR MODULATORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to United States Provisional Patent Application No. 63 / 725,134 filed November 26, 2024, the disclosure of which is incorporated herein by reference in its entirety.STATEMENT OF SUPPORT

[0002] Research for this invention was supported by awards from the Cystic Fibrosis Foundation.BACKGROUND

[0003] Chronic upper and lower airway diseases (chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis (NCFB), chronic rhinosinusitis (CRS)) are among the most prevalent acquired airway diseases that demonstrate comparable clinical pathology (inflammation, hypersecretion of airway mucus, airway and / or lung parenchymal tissue damage). Similarly, cystic fibrosis (CF) is an autosomal recessive genetic disorder in which the cystic fibrosis transmembrane conductance regulator (CFTR) is functionally deficient in an inherited manner and shares similar clinical findings compared to certain chronic airway diseases. To date, 1085 pathologic variants have been identified in the CFTR gene, which leads to CF when both genetic loci are affected by disease-causing mutations. A subgroup of patients with COPD, NCFB, and CRS is expected to carry single allelic mutations in the CFTR gene that predispose them to lower or upper airway disease. Moreover, when such individuals are exposed to noxious environmental factors, an acquired CFTR deficiency state may result. CFTR activation is driven by protein kinase A (PKA)-mediated phosphorylation events regulated by compartmentalized intracellular cyclic adenosine monophosphate (cAMP) elevation. A meaningful approach to stimulate CFTR-dependent chloride transport and improve mucociliary clearance is to impede phosphodiesterase (PDE)-dependent cAMP degradation in an isoform-selective manner, a strategy that compa rtmentally elevates cAMP levels and activates PKA locally. Additionally, selective PDE inhibitors are shown to be effective in the treatment of chronic obstructive pulmonary disease (COPD) and psoriasis, with a mechanism ascribed to attenuation of chronic inflammatory states.

[0004] There remains a need for improved compositions and methods for treating respiratory disorders. There remains a need for improved compositions and methods for modulating the activity of cystic fibrosis transmembrane conductance regulator proteins. There remains a needAttorney Docket No. 10029-120W01for improved compositions and methods for treating conditions such as cystic fibrosis, chronic obstructive pulmonary disease, bronchiectasis, asthma, atelectasis, pneumonia, lung fluid, lung mucus, acute respiratory distress syndrome, ventilator-induced lung injury, bronchopulmonary dysplasia, airways hyperresponsiveness, allergic rhinitis, bronchitis, emphysema, viral infection, and bacterial infection.BRIEF DESCRIPTION OF THE FIGURES

[0005] FIGs. 1A, 1B, and 1C depict certain compounds according to the disclosure.

[0006] FIG. 2 depicts maximal CFTR activation by certain compounds according to the disclosure.Data expressed as mean ± SEM for maximal activation of CFTR by the compounds over 150 nM forskolin stimulation.

[0007] FIG. 3 depicts EC50analysis for certain compounds according to the disclosure. Data expressed as mean ± SEM.DETAILED DESCRIPTION

[0008] Before the present methods and systems are disclosed and described, it is to be understood that the methods and systems are not limited to specific synthetic methods, specific components, or to particular compositions. It is also to be understood that the terminology used herein is for the purpose of describing particular implementations only and is not intended to be limiting.

[0009] As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from "about" one particular value, and / or to "about" another particular value. When such a range is expressed, another implementation includes- from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another implementation. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0010] " Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0011] Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises," means "including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. " Exemplary" means "an example of" and is not intended to convey an indication of aAttorney Docket No. 10029-120W01preferred or ideal implementation. " Such as" is not used in a restrictive sense, but for explanatory purposes.

[0012] Disclosed are components that can be used to perform the disclosed methods and systems.These and other components are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these components are disclosed, that while specific reference of each various individual and collective combinations and permutations of these may not be explicitly disclosed, each is specifically contemplated and described herein, for all methods and systems. This applies to all aspects of this application, including, but not limited to, steps in disclosed methods. Thus, if there are a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific implementation or combination of implementations of the disclosed methods.

[0013] Compounds disclosed herein may be provided in the form of acceptable salts, for example, pharmaceutically acceptable salts. Examples of such salts are acid addition salts formed with inorganic acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids and the like; salts formed with organic acids such as acetic, oxalic, tartaric, succinic, maleic, fumaric, gluconic, citric, malic, methanesulfonic, p-toluenesulfonic, napthalenesulfonic, and polygalacturonic acids, and the like; salts formed from elemental anions such as chloride, bromide, and iodide; salts formed from metal hydroxides, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesium hydroxide; salts formed from metal carbonates, for example, sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate; salts formed from metal bicarbonates, for example, sodium bicarbonate and potassium bicarbonate; salts formed from metal sulfates, for example, sodium sulfate and potassium sulfate; and salts formed from metal nitrates, for example, sodium nitrate and potassium nitrate.

[0014] The term "alkyl" refers to a radical of a straight-chain or branched hydrocarbon group having a specified range of carbon atoms (e.g., a " C1-16alkyl" can have from 1 to 16 carbon atoms). An alkyl group can be a saturated alkyl group or an unsaturated alkyl group, i.e., an alkyl group having one or more carbon-carbon double / triple bonds, i.e., an alkenyl or alkynyl group. Unless specified to the contrary, an "alkyl" group includes both saturated alkyl groups and unsaturated alkyl groups. An alkyl group may be unsubstituted (i.e., no non-hydrogen substituents) or may be substituted one or more times by groups defined herein.

[0015] As used herein, a "haloalkyl" group is an alkyl group substituted by one or more, the same or different, halogen atoms: F, Cl, Br, or I. A haloalkyl group may be otherwise unsubstituted (i.e., substituted only by halogen atoms) or may include additional non-halogen substituents.Attorney Docket No. 10029-120W01

[0016] The term "heteroalkyl" refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. By way of example, a heteroC1-6alkyl (which may also be designated a C1-6heteroalkyl) group includes, but is not limited to, the following structures:

[0017] The term "heteroalkyl" preceded by a separate heteroatom refers to a heteroalkyl group bonded through the specified heteroatom. By way of example, a OC1-6heteroalkyl group includes, but it not limited to, the following structures:

[0018] As used herein "heterohaloalkyl" refers to a heteroalkyl group further substituted by one or more, the same or different, halogen atoms: F, Cl, Br, or I. Exemplary heterohaloalkyl groups include OCF3and CH2OCF3. The heterohaloalkyl group may be otherwise unsubstituted, or may include one or more additional non-halogen substituents.

[0019] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, " Ci-6alkyl" is intended to encompass Ci, C2, C3, C4, Cr„ C6, Ci-5, C1.5, Ci-4, C1-3, Ci-2, C2-6, C2-5, C2.4, C2-3, C3.5, C3-4, C4-6, C4.5, and C5.6 alkyl.

[0020] Affixing the suffix "-ene" to a group indicates the group is a polyvalent moiety, e.g., bonded to two or more groups. Alkylene is the polyvalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl (each of which parent groups as defined herein).

[0021] The term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.

[0022] The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having 6- 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (" C6-i4 aryl").Attorney Docket No. 10029-120W01" Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents.

[0023] " Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.

[0024] The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. " Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continues to designate the number of ring members in the heteroaryl ring system. " Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups, wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. For polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0025] Exemplary heteroaryl and heterocyclyl rings include: benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyL cirrnolinyl, decahydroquinolinyl, 2H,6H~ 1,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, IH- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyi, oxadiazolyi, 1,2,3-Attorney Docket No. 10029-120W01oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H- 1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl.

[0026] Unless specified to the contrary, the alkyl, alkenyl, alky nyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein (and the "ene" versions of said groups) may be substituted or unsubstituted. A substituted group includes a non-hydrogen substituent at a position where, in the unsubstituted version, a hydrogen atom would be found. Substituents include, but are not limited to, halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, - NRaSO2Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, - S(=O)2Ra, - OS(=O)2Raand -S(=O)2ORa. Raand Rbin this context can be the same or different and independently hydrogen, halogen, hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0027] As used herein, the designation of a polyvalent moiety without specifying the specific order of attachment is intended to cover all possible arrangements. By way of example, a compound represented by the formula:A-X-B,wherein X is NHC(=O) embraces both:O O

[0028] As used herein, a chemical bond depicted: ' i represents either a single, double, or triple bond, valency permitting. By way of example,Attorney Docket No. 10029-120W01

[0029] Some compounds disclosed herein may exist as one or more tautomers. Tautomers are interconvertible structural isomers that differ in the position of one or more protons or other labile atoms. By way of example:H

[0030] Unless stated to the contrary, a substituent drawn without explicitly specifying the point of attachment indicates that the substituent may be attached at any possible atom. For example, in a benzofuran depicted:the substituent may be present at any one of the six possible carbon atoms.

[0031] As used herein, the term "null," when referring to a possible identity of a chemical moiety, indicates that the group is absent, and the two adjacent groups are directly bonded to one another. By way of example, for a genus of compounds having the formula CH3-X-CH3, if X is null, then the resulting compound has the formula CH3-CH3. A group having the subscript '0' is understood to represent a null group as well. By way of example, in the compound CH3-(X)z-CH3, if X is CH2and z is 0, then the compound has the formula CH3-CH3.

[0032] In certain instances, two or more variable groups may together form a ring. It is understood that any depicted atoms falling between the identified groups will themselves form part of the ring. By way of example, R1and R2in the formula below together form a ring:When the variable groups are substituted on an aromatic system, the new ring will be a fused ring, and unless specified to the contrary, may be either aromatic or non-aromatic, carbocyclic or heterocyclic:The ring may further be defined by the number of carbon atoms in the specific ring formed by the variable groups, which includes the atoms separating the variable groups:Attorney Docket No. 10029-120W01R1and R2form a: C6cycloalkyl C6aryl C5heterocyclyl C5heteroaryl Each of the above results occurs when R1and R2together form a six-membered (or six-atom) ring. Other rings, including 3, 4, 5, 7, and 8-member rings, may also be formed, and the size of the ring may be defined by a specified number of carbon atoms. Although the singular "a ring" may be used to define the group, unless specified to the contrary, "a ring" includes both monocyclic and polycyclic rings:R1and R2form a: monocyclic ring polycyclic ring

[0033] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture. Unless stated to the contrary, a formula depicting one or more stereochemical features does not exclude the presence of other isomers.

[0034] As used herein, the chemical group " D" refers to deuterium at an isotopic abundance greater than 25%, 35%, 50%, 60%, 70%, 80%, or 90%. In certain implementations, the chemical group " D" refers to deuterium at an isotopic abundance greater than 50%.

[0035] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers, such as Sigma- Aldrich (formerly MilliporeSigma, Burlington, MA) or Thermo Fisher Scientific Inc. (Waltham, MA), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons, 2007); Organic Reactions (John Wiley and Sons, 2004); March's Advanced Organic Chemistry, (John Wiley and Sons, 8thEdition); and Larock's Comprehensive Organic Transformations (John Wiley and Sons, 3rdedition, 2017).

[0036] As used herein, the term "therapeutically effective amount” refers to an amount sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the specific composition employed; the age, bodyAttorney Docket No. 10029-120W01weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the particular compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to permanently halt the progression of the disease. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition can also be delaying the onset or even preventing the onset.

[0037] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to increase the dosage gradually until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for administration. Consequently, single-dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The individual physician can adjust the dosage in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the disclosure (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. However, a patient may insist on a lower or tolerable dose for medical reasons, psychological reasons, or virtually any other reason.

[0038] A response to a therapeutically effective dose of a disclosed compound or composition can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following the administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied, for example, by increasing or decreasing the amount of a disclosed compound or pharmaceutical composition, changing the disclosed compound or pharmaceutical composition administered, changing the route of administration, changing the dosage timing, and so on. Dosage can vary and can be administered in one or more dose administrations daily for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0039] As used interchangeably herein, "subject," "individual," or "patient" can refer to a vertebrate organism, such as a mammal (e.g., human). " Subject” can also refer to a cell, aAttorney Docket No. 10029-120W01population of cells, a tissue, an organ, or an organism, preferably to a human and constituents thereof. In certain implementations, the subject is a human.

[0040] As used herein, "treating" and "treatment" generally refer to obtaining a desired pharmacological or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in preventing or partially preventing a disease, symptom, or condition. The effect can be therapeutic regarding a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of a disorder in a subject, particularly a human. It can include any one or more of the following: (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease or its symptoms or conditions. The term "treatment," as used herein, can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (i.e., subjects in need thereof) can include those already with the disorder or those in which the disorder is to be prevented. As used herein, the term "treating" can include inhibiting the disease, disorder, or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder, or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such an agent does not treat the cause of the pain.

[0041] As used herein, "dose," "unit dose," or "dosage" can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

[0042] As used herein, "therapeutic" can refer to treating, healing, or ameliorating a disease, disorder, condition, or side effect or decreasing the rate of advancement of a disease, disorder, condition, or side effect.

[0043] As used herein, a " CFTR corrector" refers to a compound that at least partially rescues misfolded CFTR, resulting in an increase in the amount of functional CFTR protein to the cell surface and thus enhanced CFTR channel function.

[0044] As used herein, a " CFTR potentiator” refers to a compound that increases the ion channel activity of the CFTR protein located at the cell surface, resulting in enhanced ion transport.Attorney Docket No. 10029-120W01[00453 As used herein, a " CFTR pharmacological chaperone" refers to a compound that stabilizes the CFTR protein in its native state by binding directly to the protein.

[0046] As used herein, a " CFTR proteostasis regulator" refers to a compound that enhances the protein folding efficiency within the cell. Proteostasis regulators can alter the activity of transcriptional, folding and / or membrane trafficking machinery, as well as impede the degradation of partially folded, but functional, conformers at the endoplasmic reticulum (ER) or plasma membrane.[0047) Disclosed herein are compounds with cystic fibrosis transmembrane regulator protein modulating activity. In some implementations, the disclosed compounds can have the formula:R1or a pharmaceutically acceptable salt thereof, wherein:R1is selected from D, halo, CN, Rla, ORla, NHRia, NRlaRlb, C(=O)Ria, C(=O)OORla, C(=O)NHRia, C(=O) RlaRlc, OC(=O)Rla, wherein Rlais selected from H, Ci-6alkyl, Ci-6heteroalkyl, Cnhaloalkyl, Ci-sheterohaloalkyl, C38cycloalkyl, Ci-aheterocyclyl, Cs naryl, or Ci icheteroaryl; and Rlbis selected from Ci-6alkyl, Ci heteroalkyl, C3-8cycloalkyl, Ci.8heterocyclyl, C6.i2aryl, or Ci i0heteroaryl; wherein Rlaand Rlbcan together form a ring;R2is selected from D, halo, CN, R2a, OR2a, NHR2a, NR2aR2b, C(=O)R2a, C(=O)OOR2a, C(=O)NHR2a, C(=O) R2aR2c, OC(=O)R2a, wherein R2ais selected from H, Ci-salkyl, Ci-sheteroalkyl, Ci-shaloalkyl, Ci-sheterohaloalkyl, C3-scycloalkyl, Ci-sheterocyclyl, Cs-i2aryl, or Cnoheteroaryl; and R2bis selected from Ci.6alkyl, Cisheteroalkyl, Ci.6haloalkyl, Ci-sheterohaloalkyl, C3 scycloalkyl, Cisheterocyclyl, C6-i2aryl, or Cnoheteroaryl; wherein R2aand R2bcan together form a ring;R3is selected from D, halo, CN, R3a, OR3a, NHR3a, NR3aR3b, C(=O)R3a, C(=O)OOR3a, C(=O)NHR3a, C(=O)NR3aR1!:, OC(=O)R3a, wherein R3ais selected from H, Ci-galkyl, Ci-6heteroalkyl, Ci-ghaloalkyl, Ci-sheterohaloalkyl, C3.8cycloalkyl, Ci-sheterocyclyl, Cs-i2aryl, or Cnoheteroaryl; and R3bis selected from Ci-6alkyl, Ci-sheteroalkyl, C3-8cycloalkyl, Ci-sheterocyclyl, Ce-izaryl, or Cnoheteroaryl; wherein R3aand R3bcan together form a ring;wherein any two of R1, R2, and R3can together form a ring; andR;is Cn.-ary! or Cnoheteroaryl, substituted one or more times by a group independently selected from halo, CN, Ci.6alkyl, Ci-6heteroalkyl, Cnhaloalkyl, Ci-sheterohaloalkyl, C3-8cycloalkyl, Ci- sheterocyclyl, Cs-waryl, or Cnoheteroary, OR4a, NHR4a, N4aR2b, C(=O)R4a, C(=O)OOR4a, C(=O)NHR4a, C(=O)NR4aR4b, OC(=O)R4a, wherein R4ais selected from H, Ci-salkyl, Cnheteroalkyl,Attorney Docket No. 10029-120W01C3-gcycloalkyl, Ci-gheterocyclyl, Ce izaryl, or Cnoheteroaryl; and R4bis selected from Cnalkyl, Ci-6heteroalkyl, C3-gcycloalkyl, Ci-gheterocyclyl, C6-izaryl, or Cnoheteroaryl; wherein R4aand R4bcan together form a ring.

[0048] In certain implementations, R4has the formula:whereinRais selected from D, halo, CN, Raa, ORaa, NHRaa, NRaaRab, C(=O)Raa, C(=O)OORaa, C(=O)NHRaa, C(=O)aaRlb, OC(=O)Raa, wherein Raais selected from H, Cnalkyl, Cnheteroalkyl, Ci-6haloalkyl, Ci-eheterohaloalkyl, C3 gcycloalkyl, Ci-gheterocyclyl, Cg-izaryl, or Cnoheteroaryl; and Rabis selected from Cnalkyl, Cnheteroalkyl, C3.gcycloalkyl, Ci-gheterocyclyl, C6-izaryl, or Cnoheteroaryl; wherein Raaand Rabcan together form a ring;Rbis selected from D, halo, CN, Rba, ORba, NHRba, NRbaRbb, C(=O)Rba, C(=O)OORba, C(=O)NHRba, C(=O)NRbaRbb, OC(=O)Rba, wherein Rbais selected from H, C-.-ealkyl, Cnheteroalkyl, Cnhaloalkyl, Ci-sheterohaloalkyl, C3-gcycloalkyl, Ci-gheterocyclyl, Ce-izaryl, or Cnoheteroaryl; and Rbbis selected from Ona Ikyl, Cnheteroalkyl, C3.gcycloalkyl, Ci-gheterocyclyl, C&izaryl, or Cnoheteroaryl; wherein Rbaand Rbbcan together form a ring;Rcis selected from D, halo, CN, Rca, ORca, NHRca, NRcaRcb, C(=O)Rca, C(=O)OOR“, C(=O)NHRca, C(=O) RcaRcb, OC(=O)Rca, wherein Rcais selected from H, Cnalkyl, Cnheteroalkyl, Cnhaloalkyl, Cnheterohaioalkyl, C3-8cycloalkyl, Ci-gheterocyclyl, C6-izaryl, or Cnoheteroaryl; and Rcbis selected from Ci-ea Ikyl, Cnheteroalkyl, C3.gcycloalkyl, Ci-gheterocyclyl, Ce-izaryl, or Cnoheteroaryl; wherein Rcaand Rccan together form a ring;Rdis selected from D, halo, CN, Rda, ORda, NHRda, NRdaRdb, C(=O)Rda, C(=O)OORda, C(=O)NHRda, C(=O)NRdaRd", OC(=O)Rda, wherein Raais selected from H, Cnalkyl, Cnheteroalkyl, Cnhaloalkyl, Cnheterohaioalkyl, C3-gcycloalkyl, Ci-gheterocyclyl, C6- izaryl, or Cnoheteroaryl; and Rdbis selected from Ci-ea Ikyl, Cnheteroalkyl, C3.gcycloalkyl, Ci-gheterocyclyl, Ce-izaryl, or Cnoheteroaryl; wherein Rdaand Rdbcan together form a ring;R9is selected from D, halo, CN, R9a, 0R9a, NHRea, NReaR9b, C(=0)R9a, C(=O)OORea, C(=0)NHR9a, C(=0) R9aR9b, 0C(=0)R9a, wherein R9ais selected from H, Ci-6alkyl, Cnheteroalkyl, Cnhaloalkyl, Cnheterohaloalkyl, C3.gcycloalkyl, Ci-gheterocyclyl, C6. izaryl, or Cnoheteroaryl; and R9bis selected from Ci-salkyl, Cnheteroalkyl, C3.gcycloalkyl, Ci-gheterocyclyl, Cs-izaryl, or Cnoheteroaryl; wherein R9aand R9bcan together form a ring;Attorney Docket No. 10029-120W01wherein any two or more of Ra, Rb, Rc, Rd, and Recan together form a ring.

[0049] In some implementations, at least one of Ra, Rb, R9, Rd, and R9is not H.

[0050] In some implementations, at least one of R1, R2, or R3is not H, while in other implementations, each of R1, R2, or R3is H.

[0051] In some implementations, each of R1and R2is H, and R3is not H.

[0052] In some implementations, each of R2and R3is H, and R1is not H.

[0053] In some implementations, each of R1and R3is H, and R2is not H.

[0054] In some implementations, one of R1, R2, or R3is F, Cl, Br, I, Ci-3alkyl, Ci3haloalkyl, cyclopropyl, OH, OCi.3alkyl, OCi.3haloalkyl, NH2, NHCi-3alkyl, or N(Ci.3alkyl)2.

[0055] In some implementations, one of R1, R2, or R3are F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, O-cyclopropyl, CF3, CF2CF3, CH2CF3, CH2CH2CF3, CF2CH2CH3, CF(CH3)2, OCF3, OCF2CF3, OCH2CF3, NH2, NHCHJ, N(CH3)2, N(CH2CH3)2.

[0056] In some implementations, R3is F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, O-cyclopropyl, CF3, CF2CF3, CH2CF3, CH2CH2CF3, CF2CH2CH3, CF(CH3)2, OCF3, OCFZCF3, OCH2CF3, NHZ, NHCH3, N(CH3)2, N(CH2CH3)2.

[0057] In some implementations, R3is F, Ci, Br, I, NH2, CH3, CF3, CH(CH3)2, or OCH3.

[0058] In some implementations, R3is F. In some implementations, R3is Cl. In some implementations, R3is Br. In some implementations, R3is NH2. In some implementations, R3is CH3. In some implementations, R3is CF3. In some implementations, R3is CH(CH3)2. In some implementations, R3is OCH3.

[0059] In some implementations, each of R1and R2is H, and R3is F. In some implementations, each of R1and R2is H, and R3is Cl. In some implementations, each of R1and R2is H, and R3is Br. In some implementations, each of R1and R2is H, and R3is NH2. In some implementations, each of R1and R2is H, and R3is CH3. In some implementations, each of R1and R2is H, and R3is CF3. In some implementations, each of R1and R2is H, and R3is CH(CH3)2. In some implementations, each of R1and R2is H, and R3is OCH3.

[0060] In some implementations, R4is:

[0061] In some implementations, at least one of Ra, Rb, Rc, Rd, and R9is F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, or OCH(CH3)2.Attorney Docket No. 10029-120W01

[0062] In some implementations, one of Ra, Rb, Rc, Rd, and R9is F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, or OCH(CH3)2, and the remaining of R3, Rb, Rc, Rd, and R9are H.

[0063] In certain implementations, at least one of Ra, Rb, Rc, Rd, and R9is Cl or Br.

[0064] In some implementations, one of Ra, Rb, Rc, Rd, and R9is Cl or Br, and the remaining of Ra, Rb, Rc, Rd, and Rc'are H.

[0065] In some implementations, at least two of R3, Rb, Rc, Rd, and Reare independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2.

[0066] In some implementations, two of Ra, Rb, Rc, Rd, and R9are independently selected from F, Cl, Br, I, CH 3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2, and the remaining of Ra, Rb, Rc, Rd, and Reare H.

[0067] In some implementations, two of R3, Rb, Rc, Rd, and R9are independently selected from F, Cl, Br, and OCH3, and the remaining of Ra, Rb, Rc, Rd, and R9are H.

[0068] In some implementations, two of Ra, Rb, Rc, Rd, and R9are independently selected from Cl and Br, and the remaining of R3, Rb, Rc, Rd, and R9are H.

[0069] In some implementations, Raand Rbare independently selected from F, Cl, Br, I, CH 3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2, and Rc, Rd, and R9are H.

[0070] In some implementations, R3and Rcare independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2, and Rb, Rd, and Reare H.

[0071] In some implementations, R3and Rdare independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCHs, OCH2CH3, and OCH(CH3)2, and Rb, R9, and R9are H.

[0072] In some implementations, R3and R9are independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2, and Rb, Rc, and Rdare H.

[0073] In some implementations, R and Rcare independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2, and R3, Rd, and R9are H.

[0074] In some implementations, R and Rdare independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCHs, OCH2CH3, and OCH(CH3)2, and R3, Rdc, and R9are H.

[0075] In some implementations, the compound has the formula:wherein R3, Ra, Rb, Rc, Rd, and R9are as defined above.

[0076] In some implementations, the compound has the formula:Attorney Docket No. 10029-120W01wherein none of Ra, Rb, or R3are H.[00773 In some implementations, the compound has the formula:

[0078] In some implementations, the compound has the formula:

[0079] In some implementations, the compound has the formula:

[0080] In some implementations, the compound has the formula:Attorney Docket No. 10029-120W01wherein none of R", Rc, or R3is H.

[0081] In some implementations, the compound has the formula:wherein none of Rb, Rd, or R3is H.

[0082] In certain implementations, the compound is a (2,5-disubstituted phenyl) triazolopyridazineAttorney Docket No. 10029-120W01wherein R1, R2, and R3are as defined above.[00833 In certain implementations of the 2,5-disubstituted phenyl triazolopyridazines, at least one of R1, R2, or R3is not H. In other implementations, each of R1, R2, or R3is H. In further implementations, each of R1and R2is H, and R3is not H; each of R2and R3is H, and R1is not H; or each of R1and R3is H, and R2is not H.

[0084] In certain implementations of the 2,5-disubstituted phenyl triazolopyridazines, one of R1, R2, or R3is F, Cl, Br, I, Ci3alkyl, Ci.3haloalkyl, cyclopropyl, OH, OCi3alkyl, OCi.3haloalkyl, NH2, NHCi-3a Iky I, or N (Ci-3a I ky l)2and the other two of R:, R2, and R3are H. In some implementations of the 2,5-disubstituted phenyl triazolopyridazines, one of R1, R2, or R3is F, Cl, Br, I, Ci-3alkyl, Ci-3haloalkyl, cyclopropyl, OH, OCi.3alkyl, OCi.3haloalkyl, NH2, NHCi.3alkyl, or N(Ci.3alkyl)2and the other two of R1, R2, and R3are H. In certain preferred implementations of the 2,5-disubstituted phenyl triazolopyridazines, R3has the earlier given meanings and R1and R2are H. In some implementations of the 2,5-disubstituted phenyl triazolopyridazines, R1and R2are H and R3is F, Cl, Br, I, NH2, CH3, CF3, CH(CH3)2, or OCH3.

[0085] In certain implementations of the 2,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is F. In certain implementations of the 2,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is Cl. In certain implementations of the 2,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is Br. In certain implementations of the 2,5- disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is NH2. In certain implementations of the 2,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CH3. In certain implementations of the 2,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CF3. In certain implementations of the 2,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CH(CH3)2. In certain implementations of the 2,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is OCH3.

[0086] In certain implementations, the compound is a (2,3-disubstituted phenyl) triazolopyridazine having the formula:Attorney Docket No. 10029-120W01

[0087] In certain implementations of the 2,3-disubstituted phenyl triazolopyridazines, at least one of R1, R2, or R3is not H. In other implementations, each of R1, R2, or R3is H. In further implementations, each of R1and R2is H, and R3is not H; each of R2and R3is H, and R1is not H; or each of R1and R3is H, and R2is not H.]0088] In certain implementations of the 2,3-disubstituted phenyl triazolopyridazines, one of R:, R2, or R3is F, Cl, Br, I, Ci3alkyl, Ci3haloalkyl, cyclopropyl, OH, OCi.3alkyl, OCi3haloalkyl, NH2, NHCi..3alkyl, or N(Ci.3aikyi)2and the other two of R1, R2, and R3are H. In some implementations of the 2,3-disubstituted phenyl triazolopyridazines, one of R1, R2, or R3is F, Cl, Br, I, Ci-3alkyl, Ci.3haloalkyl, cyclopropyl, OH, OCi.3alkyl, OCi,3haloalkyl, NH2, NHCi.3alkyl, or N(C3,3alkyl)2and the other two of R1, R2, and R3are H. In certain preferred implementations of the 2,3-disubstituted phenyl triazolopyridazines, R3has the earlier given meanings and R1and R2are H. In some implementations of the 2,3-disubstituted phenyl triazolopyridazines, R1and R2are H and R3is F, Ci, Br, I, NH2, CH3, CF3, CH(CH3)2, or OCH3.Attorney Docket No. 10029-120W01

[0089] In certain implementations of the 2,3-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is F. In certain implementations of the 2,3-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is Cl. In certain implementations of the 2,3-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is Br. In certain implementations of the 2,3- disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is NH2. In certain implementations of the 2,3-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CH3. In certain implementations of the 2,3-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CF3. In certain implementations of the 2,3-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CH(CH3)2. In certain implementations of the 2,3-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is OCH3.

[0090] In certain implementations, the compound is a (3,4-disubstituted phenyl) triazolopyridazine having the formula:Attorney Docket No. 10029-120W01wherein R1, R2, and R3are as defined above.[00913 In certain implementations of the 3,4-disubstituted phenyl triazolopyridazines, at least one of R1, R2, or R3is not H. In other implementations, each of R1, R2, or R3is H. In further implementations, each of R1and R2is H, and R3is not H; each of R2and R3is H, and R1is not H; or each of R1and R3is H, and R2is not H.

[0092] In certain implementations of the 3,4-disubstituted phenyl triazolopyridazines, one of R1, R2, or R3is F, Cl, Br, I, Ci-3alkyl, Ci.3haloalkyl, cyclopropyl, OH, OCi.3alkyl, OCi-3haloalkyl, NH2, NHCi-3alkyl, or N(Ci-3alkyl)2and the other two of R:, R2, and3are H. In some implementations of the 3,4-disubstituted phenyl triazolopyridazines, one of R1, R2, or R3is F, Cl, Br, I, Ci,3alkyl, Ci- shaloalkyl, cyclopropyl, OH, OCi.3alkyl, OCi.3haloalkyl, NH2, NHCi.3alkyl, or N(Ci.3alkyl)2and the other two of R1, R2, and R3are H. In certain preferred implementations of the 3,4-disubstituted phenyl triazolopyridazines, R3has the earlier given meanings, and R1and R2are H. In some implementations of the 3,4-disubstituted phenyl triazolopyridazines, R1and R2are H and R3is F, Cl, Br, I, NH2, CH3, CF3, CH(CH3)2, or OCH3.

[0093] In certain implementations of the 3,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is F. In certain implementations of the 3,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is Cl. In certain implementations of the 3,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is Br. In certain implementations of the 3,4- disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is NH2. In certain implementations of the 3,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3isAttorney Docket No. 10029-120W01CHs. In certain implementations of the 3,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CF3. In certain implementations of the 3,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CH(CH3)Z, In certain implementations of the 3,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is OCH3.

[0094] In certain implementations, the compound is a (3,5-disubstituted phenyl) triazolopyridazine having the formula:wherein R1, R2, and R3are as defined above.

[0095] In certain implementations of the 3,5-disubstituted phenyl triazolopyridazines, at least one of R1, R2, or R3is not H. In other implementations, each of R1, R2, or R3is H. In further implementations, each of R1and R2is H, and R3is not H; each of R2and R3is H, and R1is not H; or each of R1and R3is H, and R2is not H.

[0096] In certain implementations of the 3,5-disubstituted phenyl triazolopyridazines, one of R\ R2, or R3is F, Cl, Br, I, Ci.3alkyl, Ci-shaloalkyl, cyclopropyl, OH, OCi-3alkyl, OCi.3haloalkyl, NHz, NHCi-3alkyl, or N (Ci-3a I y 1)2 and the other two of R1, R2, and R3are H. In some implementations of the 3,5-disubstituted phenyl triazolopyridazines, one of R1, R2, or R3is F, Cl, Br, I, Ci-3alkyl, C-.-Attorney Docket No. 10029-120W01shaloalkyl, cyclopropyl, OH, OCi3alkyl, OCi3haloalkyl, NHz, NHCi3alkyl, or N(Ci3alkyl)3and the other two of R1, R2, and R3are H. In certain preferred implementations of the 3,5-disubstituted phenyl triazolopyridazines, R3has the earlier given meanings, and R1and R2are H. In some implementations of the 3,5-disubstituted phenyl triazolopyridazines, R1and R2are H and R3is F, Cl, Br, I, NHz, CH3, CF3, CH(CH3)2, or OCH3.

[0097] In certain implementations of the 3,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is F. In certain implementations of the 3,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is Cl. In certain implementations of the 3,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is Br. In certain implementations of the 3,5- disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is NH2. In certain implementations of the 3,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CH3. In certain implementations of the 3,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CF3. In certain implementations of the 3,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CH(CH3)2. In certain implementations of the 3,5-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is OCH3.

[0098] In certain implementations, the compound is a (2,4-disubstituted phenyl) triazolopyridazine having the formula:Attorney Docket No. 10029-120W01wherein R1, R2, and R3are as defined above.

[0099] In certain implementations of the 2,4-disubstituted phenyl triazolopyridazines, at least one of R1, R2, or R3is not H. In other implementations, each of R1, R2, or R3is H. In further implementations, each of R1and R2is H, and R3is not H; each of R2and R3is H, and R1is not H; or each of R1and R3is H, and R2is not H.

[0100] In certain implementations of the 2,4-disubstituted phenyl triazolopyridazines, one of R:, R2, or R3is F, Cl, Br, I, Ci-salkyl, Ci ahaloalkyl, cyclopropyl, OH, OCi-salkyl, OCi ahaloalkyl, NHz, NHCi salkyl, or N(Ci-3alkyl)2 and the other two of R1, R2, and R3are H. In some implementations of the 2,4-disubstituted phenyl triazolopyridazines, one of R1, R2, or R3is F, Cl, Br, I, Ci-salkyl, C-;. shaloalkyl, cyclopropyl, OH, OCi-jalkyl, OCi-shaloalkyl, NH2, NHCi^alkyl, or N(Ci-3alkyl)2 and the other two of R1, R2, and R3are H. In certain preferred implementations of the 2,4-disubstituted phenyl triazolopyridazines, R3has the earlier given meanings and R1and R2are H. In some implementations of the 2,4-disubstituted phenyl triazolopyridazines, R1and R2are H and R3is F, Cl, Br, I, NHZ, CH3, CF3, CH(CH3)Z, or OCH3.

[0101] In certain implementations of the 2,4-disubstituted phenyl triazolopyridazines, R1and2are H, and R3is F. In certain implementations of the 2,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is Cl. In certain implementations of the 2,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is Br. In certain implementations of the 2,4- disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is NHz. In certain implementations of the 2,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CH3. In certain implementations of the 2,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CF3. In certain implementations of the 2,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is CH(CH3)2. In certain implementations of the 2,4-disubstituted phenyl triazolopyridazines, R1and R2are H, and R3is OCH3.

[0102] In certain implementations, the compound is a compound depicted in FIG. 1A, FIG. IB, or FIG. 1C.

[0103] In certain implementations, the compound isAttorney Docket No. 10029-120W01or a pharmaceutically acceptable salt thereof.

[0104] In certain implementations, the compound isor a pharmaceutically acceptable salt thereof.

[0105] In certain implementations, the compound isor a pharmaceutically acceptable salt thereof.

[0106] In certain implementations, the compound isor a pharmaceutically acceptable salt thereof.Attorney Docket No. 10029-120W01

[0107] In certain implementations, the compound isHDYL 04or a pharmaceutically acceptable salt thereof.

[0108] In certain implementations, the compound isHDYL 05or a pharmaceutically acceptable salt thereof.

[0109] In certain implementations, the compound isHDYL 06or a pharmaceutically acceptable salt thereof.

[0110] In certain implementations, the compound isAttorney Docket No. 10029-120W01HDYL 08or a pharmaceutically acceptable salt thereof.

[0111] In certain implementations, the compound isClClNNHDYL 09or a pharmaceutically acceptable salt thereof.

[0112] In certain implementations, the compound isBrNNHDYL 10or a pharmaceutically acceptable salt thereof.

[0113] In certain implementations, the compound isCF3Br / NNHDYL 11or a pharmaceutically acceptable salt thereof.

[0114] In certain implementations, the compound isAttorney Docket No. 10029-120W01or a pharmaceutically acceptable salt thereof.

[0115] In certain implementations, the compound isor a pharmaceutically acceptable salt thereof.

[0116] In certain implementations, the compound isHDYL 14or a pharmaceutically acceptable salt thereof.

[0117] In certain implementations, the compound isHDYL 15or a pharmaceutically acceptable salt thereof.

[0118] In certain implementations, the compound isAttorney Docket No. 10029-120W01HDYL 17or a pharmaceutically acceptable salt thereof.

[0119] In certain implementations, the compound isClNHDYL 18or a pharmaceutically acceptable salt thereof.

[0120] In certain implementations, the compound isClNHDYL 14.3or a pharmaceutically acceptable salt thereof.

[0121] In certain implementations, the compound isNHDYL 19or a pharmaceutically acceptable salt thereof.

[0122] In certain implementations, the compound isAttorney Docket No. 10029-120W01HDYL 19.3 NH2or a pharmaceutically acceptable salt thereof.

[0123] In certain implementations, the compound isHDYL 20or a pharmaceutically acceptable salt thereof.In certain implementations, the compound isor a pharmaceutically acceptable salt thereof.

[0124] In certain implementations, the compound isHDYL 22or a pharmaceutically acceptable salt thereof.

[0125] In certain implementations, the compound isAttorney Docket No. 10029-120W01or a pharmaceutically acceptable salt thereof.

[0126] In certain implementations, the compound isHDYL 24or a pharmaceutically acceptable salt thereof.

[0127] In certain implementations, the compound isHDYL 24.3or a pharmaceutically acceptable salt thereof.

[0128] In certain implementations, the compound isHDYL 24.4or a pharmaceutically acceptable salt thereof.

[0129] In certain implementations, the compound isAttorney Docket No. 10029-120W01HDYL 25or a pharmaceutically acceptable salt thereof.

[0130] In certain implementations, the compound isHDYL-26or a pharmaceutically acceptable salt thereof.

[0131] In certain implementations, the compound isor a pharmaceutically acceptable salt thereof.

[0132] In certain implementations, the compound isHDYL 28or a pharmaceutically acceptable salt thereof.

[0133] Also disclosed herein are methods of treating a respiratory disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of theAttorney Docket No. 10029-120W01compound disclosed herein. The compounds may be administered in an amount effective to treat the targeted respiratory disorder. In some implementations, the compounds may be administered in an amount of 1-1,000 mg / day, for example, 1-100 mg / day, 50-250 mg / day, 100- 500 mg / day, 250-1,000 mg / day, or 500-1,000 mg / day. The compound may be administered in a once daily dosing event or may be administered in approximately equal doses multiple times a day, for example, twice a day or three times a day.

[0134] In certain implementations, the compounds can also be used to treat a respiratory disorder such as cystic fibrosis, chronic obstructive pulmonary disease, bronchiectasis, bronchitis, asthma, atelectasis, pneumonia, abnormal lung fluid, abnormal lung mucus, acute respiratory distress syndrome, ventilator induced lung injury, bronchopulmonary dysplasia, airways hyperresponsiveness, allergic rhinitis; bronchiectasis, sinusitis (including chronic sinusitis), allergic bronchopulmonary aspergillosis, idiopathic pulmonary fibrosis, or emphysema.

[0135] In some preferred implementations, the respiratory disorder is cystic fibrosis (" CF").

[0136] In some implementations, the CF is characterized by CFTR having a premature truncation codon. In some implementations, the CF is characterized by a CFTR mutation in which an amino acid codon has been replaced with a stop codon such as UAG, UAA, or UGA.

[0137] In some implementations, the CF is characterized by a CFTR mutation such as W1282X, G551D, F508del, G542X, N1303K, R117H, R553X, or a combination thereof. In some implementations, the CF is characterized by a CFTR mutation such as W1282X.

[0138] In some implementations, the method further includes administering one or more agents in addition to the compound disclosed herein. In some implementations, the additional agent can be a PDE4 inhibitor, a CFTR modulator, or a combination thereof.

[0139] In some implementations, the CFTR modulator can be a CFTR potentiator, a CFTR corrector, a CFTR pharmacological chaperone, a CFTR proteostasis regulator, or a combination thereof.

[0140] In some implementations, the further additional agent can be ivacaftor, lumacaftor, tezacaftor, elexacaftor, vanzacaftor, galicaftor, cavosonstat, (FDL169) 2-(7-ethoxy-4-(3- fluorophenyl)-l-oxophthalazin-2(lH)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide, SION-719, SION-451, SION-102, or a combination thereof.

[0141] In some implementations, the further CFTR modulator is lumacaftor and ivacaftor. In some implementations, the CFTR modulator is tezacaftor and ivacaftor. In some implementations, the CFTR modulator is elexacaftor, tezacaftor, and ivacaftor.

[0142] The compounds of the disclosure may be administered to needful subjects via a variety of routes. In some implementations, the compounds can be administered enterally, parenterally, inhalationally, intranasally, or topically.Attorney Docket No. 10029-120W01

[0143] When the compound is to be administered enterally, it can be preferred that it is administered orally or sublingually.

[0144] When the compound is to be administered parenterally, it can be preferred that it is administered intravenously, subcutaneously, or intramuscularly.

[0145] When the compound is to be administered inhalationally or intranasally, it can be administered via manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer.

[0146] In some implementations, the disclosed compounds can be administered in combination with at least one other therapeutic for a respiratory disorder.

[0147] Also disclosed herein are pharmaceutical compositions including at least one of the compounds of the disclosure. Pharmaceutical compositions for use in the present disclosure typically comprise an effective amount of a compound, a pharmaceutically acceptable excipient, or an effective amount of a disclosed compound and a suitable pharmaceutical acceptable carrier. The preparations may be prepared in a manner known per se, which usually involves mixing the at least one compound according to the disclosure with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions.

[0148] For an oral administration form, the compound can be mixed with suitable additives, such as excipients, stabilizers, or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, cornstarch. In this case, the preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate-release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, and lactose, and / or other excipients, binders, extenders, disintegrants, diluents, and lubricants known in the art.

[0149] When administered by nasal aerosol or inhalation, the compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing orAttorney Docket No. 10029-120W01dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions, or emulsions of the compounds of the disclosure or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the formulation may additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers, and stabilizers, as well as a propellant.

[0150] The compounds or compositions disclosed herein may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result. The exact amount of the compounds or compositions will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the medical disorder, the particular compound or composition, its mode of administration, its mode of activity, and the like. The compounds described herein are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compounds will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

[0151] The exact amount of the compounds or compositions described herein required to achieve a therapeutically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or a person skilled in the art and can be lower or the same as that administered to an adult.

[0152] Useful dosages of the compounds or compositions disclosed herein can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice and other animals to humans are known to the art.

[0153] The dosage ranges for the administration of the compounds or compositions are those large enough to produce the desired effect in which the symptoms or disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted crossreactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age,Attorney Docket No. 10029-120W01condition, sex, and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any contraindications.

[0154] A number of aspects of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other aspects are within the scope of the following claims.

[0155] By way of non-limiting illustration, examples of certain aspects of the present disclosure are given below.EXAMPLES

[0156] The following examples are for the purpose of illustration only and are not intended to limit the scope of the present disclosure in any manner whatsoever.

[0157] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.Example 1: Synthesis of hydrazineyl-pyridazines

[0158] General Procedure 1: To a 30 mL pressure tube charged with a magnetic stir bar was added 3-chloro-6-all<ylpyridazine (1.0 equiv). Ethanol (17 equiv) was added. Hydrazine hydrate (16 equiv) was then added. The pressure tube was sealed and the reaction mixture was set to stir at reflux for 30 hours. The reaction mixture was allowed to cool down to room temperature as it continued to stir. Solvent was removed in vacuo, and the crude material was taken up in dichloromethane, and dried over anhydrous magnesium sulfate and collected by gravity or vacuum filtration.

[0159] 3-hydrazineyl-6-isopropylpyridazine

[0160] Following general procedure 1 with 3-chloro-6-isopropylpyridazine (0.500 g, 1.0 equiv, 3.19 mmol) and hydrazine hydrate (2.56 g, 2.48 mL, 50% wt, 16 Eq, 51.1 mmol), 392.0 mg (96% yield).1H NMR (500 MHz, MeOD) 67.37 - 7.34 (d, J = 9.3 Hz, 1H), 7.13 - 7.11 (d, J = 9.3 Hz, 1H), 3.15 - 3.06 (hept, J = 7.0 Hz, 1H), 1.29 - 1.28 (d, J = 7.0 Hz, 9H). HRMS (+APC I) (m / z): [M + H+] calcd for C7H12N4, 153.11347; found 153.11359.

[0161] 3-hydrazineyl-6-(trifluoromethyl)pyridazine.Attorney Docket No. 10029-120W01

[0162] Following general procedure 1 with 3-chloro-6-(trifluoromethyl)pyridazine (0.500 g, 1.0 equiv, 2.74 mmol) and hydrazine hydrate (4.39 g, 4.26 mL, 50% wt, 16 Eq, 43.8 mmol), 423.4 mg (87% yield).1H NMR (600 MHz, cdcl3) 67.47 (d, J = 9.4 Hz, 1H), 7.17 (d, J = 9.3 Hz, 1H). HRMS (+APCI) (m / z): [M + H+] calcd for C5H6N4F3, 179.05391; found 179.05388.

[0163] 3-hydrazineyl-6-methylpy ridazine

[0164] Following general procedure 1 with 3-chloro-6-methylpyridazine (0.500 g, 1.0 equiv, 3.89 mmol) and hydrazine hydrate (6.23 g, 6.05 mL, 50% Wt, 16 equiv, 62.2 mmol), 470.5 mg (97% yield). NMR (400 MHz, CDCI3) 67.11 (d, J = 9.0 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H). HRMS (+APCI) (m / z): [M + H+] calcd for C5H9N4, 125.08217; found 125.08217.

[0165] 3-hydrazineyl-6-iodopyridazine

[0166] 3,6-diiodopyridazine (2g, 1.0 equiv, 6.02 mmol) was placed in a 100-mL round-bottomed flask equipped with a stir bar and added aqueous ammonia (28% wt, 3.12 mL, 3.6 equiv, 22.0 mmol) and hydrazine hydrate (5.8 mL, 2.6 equiv, 15.6 mmol). The reaction flask was connected to a findenser, and the mixture was heated to 90°C for 3 h while stirring. The mixture was then cooled to 0°C, and the solid was collected by filtration with water, yielding 1.49 g (53% yield).1H NMR (400 MHz, DMSO) 67.11 (s, 1H), 6.59 (d, J = 9.2 Hz, 1H), 5.80 (d, J = 9.3 Hz, 1H), 3.30 (s, 2H).Example 2: Synthesis of triazolopyridazinesX= I, Br, Cl, etc

[0167] General Procedure 2: To a flame-dry 50 mL round bottom flask equipped with a magnetic stir bar and under an inert atmosphere was added benzoic acid (1.0 equiv) and 1,1'- carbonyldiimidazole (CDI) (1.0 equiv). Anhydrous tetrahydrofuran was then added to obtain a 0.3 M mixture. The mixture was stirred at room temperature for 30 minutes, and then at 40°C for 30 minutes. The mixture was then cooled back to room temperature. Using a syringe, an anhydrous tetrahydrofuran solution (0.3 M) of 3-hydrazineyl pyridazine (1 equiv) was added dropwise. The reaction mixture was stirred overnight. The crude mixture was transferred into a flame-dried 30 mL pressure tube equipped with a magnetic stir bar and a rubber septum under inert atmosphere. The residue was taken up in anhydrous acetonitrile (0.1 M). Using a syringe, POCI3(50 equiv) was then added. The reaction tube was sealed with a screw-on cap and heated to 105°C overnight. The reaction mixture was allowed to cool to room temperature. The reaction mixture was quenched with cold NaHCO3and extracted 3x with ethyl acetate. The combinedAttorney Docket No. 10029-120W01organic layers were washed with brine and dried over magnesium sulfate. The solution was then filtered and concentrated in vacuo. The crude residue was dry-mounted onto SiO2and purified by flash column chromatography (SiO2) to obtain the desirable triazolopyridazine product.

[0168] 3-(2-bromo-5-methoxyphenyl)-6-isopropyl-[l,2,4]triazolo[4,3-b]pyridazine (HDCF198).

[0169] Following general procedure 2 with 2-bromo-5-methoxybenzoic acid (130 mg,. 1.1 equiv, 0.55 mmol), 3-hydrazineyl-6-iodopyridazine (76 mg, 1.0 equiv, 0.50 mmol), 1,1'- carbonyldiimidazole (81 mg, 1.0 equiv, 0.50 mmol), and POCl3(1.51 mL, 50 equiv, 16.2 mmol), 30 mg as a white semisolid (18% yield, 0.08 mmol).1H NMR (500 MHz, Chloroform-d) δ8.09 (d, J = 9.6 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 3.1 Hz, 1H), 7.10 (d, J = 9.6 Hz, 1H), 6.97 (dd, J = 8.9, 3.1 Hz, 1H), 3.83 (s, 3H), 3.13 (hept, J = 6.9 Hz, 1H), 1.31 (d, J = 6.9 Hz, 6H). ”C NMR (126 MHz, cdcl3) 6 162.4, 158.7, 148.6, 144.2, 134.1, 128.6, 124.8, 120.5, 118.5, 117.9, 114.6, 55.8, 34.6, 21.5. HRMS (APCI) (m / z): [M + H’] calc'd for C15H16ON479Br, 347.0502; found 347.0510.

[0170] 3-(2-bromo-5-chlorophenyl)-6-isopropyl-[l,2,4]triazolo[4,3-b]pyridazine (HDCF190).

[0171] Following general procedure 2 with 2-bromo-5-chlorobenzoic acid (100 mg, 1.0 equiv, 0.43 mmol), 3-hydrazineyl-6-iodopyridazine (65 mg, 1.0 equiv, 0.43 mmol), l,l'-carbonyldiimidazole (69 mg, 1.0 equiv, 0.43 mmol), and POCl3(1.51 mL, 50 equiv, 16.2 mmol), 61 mg as a translucent yellow oil (53% yield, 0.17 mmol).1H NMR (500 MHz, cdcl3) 68.10 (d, J = 9.6 Hz, 1H), 7.70 - 7.67 (m, 2H), 7.39 (dd, J = 8.7, 2.5 Hz, 1H), 7.12 (d, J = 9.6 Hz, 1H), 3.14 (hept, J = 7.0 Hz, 1H), 1.32 (d, J = 6.9 Hz, 6H).13C NMR (126 MHz, cdcl3) 8 162.7, 134.5, 133.5, 132.9, 131.8, 124.9, 122.2, 120.8, 34.6, 21.4. HRMS (APCI) (m / z): [M + H+] calc'd for C14H13N479Br’5CI, 351.0007; found 351.0001.HDYL 02

[0172] Following general procedure-2 with 3,5-dichlorobenzoic acid (63 mg, 1.0 equiv, 0.33 mmol), 3-hydrazineyl-6-isopropylpyridazine (50 mg, 1.0 equiv, 0.33 mmol), di(lH-imidazol-l- yl)methanone (53 mg, 1.0 equiv, 0.33 mmol), and phosphoryl trichloride (1.40 mL, 50 equiv, 15.0 mmol), 34.5 mg (37%) HDYL 02 was afforded as a white amorphous solid.1H NMR (600 MHz, cdcl3) δ8.56 (d, J = 1.9 Hz, 1H), 8.13 (d, J = 9.5 Hz, 1H), 7.48 (t, J = 1.9 Hz, 1H), 7.15 (d, J = 9.6 Hz, 1H), 3.25 (p, J = 6.9 Hz, 1H), 1.44 (d, J = 6.9 Hz, 6H).13C NMR (151 MHz, CDCl3) 6 163.2, 145.7, 145.1, 135.5, 129.9, 129.4, 125.7, 125.2, 120.7, 34.9, 21.5. HRMS (+APCI) (m / z): [M + H+] calcd for C14H13N435CI2, 307.05118; found 307.05051.Attorney Docket No. 10029-120W01HDYL 03

[0173] Following general procedure-2 with 2,5-dichlorobenzoic acid (63 mg, 1 Equiv, 0.33 mmol), 3- hydrazineyl-6-isopropylpyridazine (50 mg, 1.0 equiv, 0.33 mmol), di(lH-imidazol-l-yl)methanone (53 mg, 1.0 equiv, 0.33 mmol), and phosphoryl trichloride (1.40 ml, 50 equiv, 15.0 mmol), 49.24 mg (53%) HDYL03 was afforded as a white amorphous solid.1H NMR (600 MHz, CDCl3) δ8.11 (d, J = 9.6 Hz, 1H), 7.75 (dd, J = 2.5, 0.4 Hz, 1H), 7.52 (dd, J = 8.6, 0.4 Hz, 1H), 7.48 (dd, J = 8.6, 2.5 Hz, 1H), 7.13 (d, J = 9.6 Hz, 1H), 3.14 (p, J = 6.9 Hz, 1H), 1.33 (d, J = 6.9 Hz, 6H).13C NMR (151 MHz, CDCIs) 6162.8, 146.6, 144.4, 133.3, 132.8, 132.6, 131.6, 131.4, 127.3, 124.9, 120.8, 34.7, 21.5. HRMS (+APCI) (m / z): [M + H+] calcd for C14H13N435Cl2, 307.05118; found 307.05063.Cl / HDYL 04

[0174] Following general procedure-2 with 2,4-dichlorobenzoic acid (63 mg, 1 Equiv, 0.33 mmol), 3-hydrazineyl-6-isopropylpyridazine (50 mg, 1.0 equiv, 0.33 mmol), di(lH-imidazol-l-yl)methanone (53 mg, 1.0 equiv, 0.33 mmol), and phosphoryl trichloride (1.40 mL, 50 equiv, 15.0 mmol), 25.10 mg (27%) HDYL 04 was afforded as a white amorphous solid.1H NMR (600 MHz, cdcl3) δ8.10 (d, J = 9.6 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.3, 2.1 Hz, 1H), 7.12 (d, J = 9.6 Hz, 1H), 3.13 (p, J = 6.9 Hz, 1H), 1.32 (d, J = 6.9 Hz, 6H).13C NMR (151 MHz, CDCI3) 5 162.7, 146.8, 144.4, 137.3, 135.8, 133.5, 130.3, 127.4, 124.9, 124.6, 120.7, 34.7, 21.5. HRMS (+APCI) (m / z): [M + H’] calcd for CuH^N^Ck, 307.05118; found 307.05067.HDYL 05Attorney Docket No. 10029-120W01

[0175] Following general procedure-2 with 2,3-dichlorobenzoic acid (63 mg, 1 Equiv, 0.33 mmol), 3- hydrazineyl-6-isopropylpyridazine (50 mg, 1.0 equiv, 0.33 mmol), di(lH-imidazol-l-yl)methanone (53 mg, 1.0 equiv, 0.33 mmol), and phosphoryl trichloride (1.40 mL, 50 equiv, 15.0 mmol), 49.24 mg (71%) HDYL05 was afforded as a white amorphous solid.1H NMR (600 MHz, CDCI3) δ8.10 (d, J = 9.6 Hz, 1H), 7.67 (dd, J = 8.1, 1.3 Hz, 1H), 7.64 - 7.55 (m, 1H), 7.44 - 7.33 (m, 1H), 7.12 (d, J = 9.6 Hz, 1H), 3.12 (hept, J = 6.9 Hz, 1H), 1.30 (dd, J = 6.9, 0.9 Hz, 6H).13C NMR (151 MHz, CDCI3) 6 162.7, 147.3, 144.4, 134.1, 133.5, 132.4, 131.1, 128.1, 127.4, 124.8, 120.6, 34.6, 21.5. HRMS (+APCI) (m / z): [M + H+] calcd for C14H13N435CI2, 307.05118; found 307.05102.CH3HDYL 06

[0176] Following general procedure-2 with 3,4-dichlorobenzoic acid (63 mg, 1 Equiv, 0.33 mmol), 3-hydrazineyl-6-isopropylpyridazine (50 mg, 1.0 equiv, 0.33 mmol), di(lH-imidazol-l-yl)methanone (53 mg, 1.0 equiv, 0.33 mmol), and phosphoryl trichloride (1.40 mL, 50 equiv, 15.0 mmol), 62.78 mg (68%) HDYL 06 was afforded as a white amorphous solid.1H NMR (600 MHz, CDCI3) 68.78 (d, J = 2.0 Hz, 1H), 8.44 (dd, J = 8.5, 2.0 Hz, 1H), 8.12 (d, J = 9.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 9.6 Hz, 1H), 3.24 (p, J = 6.9 Hz, 1H), 1.44 (d, J = 6.9 Hz, 6H).13C NMR (151 MHz, CDCI3) 6 163.0, 146.0, 145.0, 134.3, 133.1, 130.9, 129.3, 126.7, 126.6, 125.2, 120.5, 34.8, 21.5. HRMS (+APCI) (m / z): [M + H+] calcd for C14H13N435CI2, 307.05118; found 307.05069.HDYL 08

[0177] Following general procedure-2 with 3,5-dichlorobenzoic acid (54 mg, 1 Equiv, 0.28 mmol) 3- hydrazineyl-6-(trifluoromethyl)pyridazine (50 mg, 1.0 equiv, 0.28 mmol), di(lH-imidazol-l- yl)methanone (46 mg, 1.0 equiv, 0.28 mmol), and phosphoryl trichloride (1.30 mL, 50 equiv, 14.0 mmol), 31.63 mg (34%) HDYL 08 was afforded as a white amorphous solid.1H NMR (600 MHz, CDCl3) δ8.47 (d, J = 1.9 Hz, 1H), 8.44 (dd, J = 9.6, 0.6 Hz, 1H), 7.54 (t, J = 1.9 Hz, 1H), 7.48 (d, J = 9.7 Hz, 1H).13C NMR (151 MHz, CDCI3) 6 146.5, 146.0 (q, J = 37.1 Hz), 144.6, 135.9, 130.9, 128.0,Attorney Docket No. 10029-120W01128.0, 125.8, 120.2 (q, J = 275.2 Hz), 116.3.19F NMR (376 MHz, CDCl3) δ -67.13. HRMS (+APCI) (m / z): [M + H+] calcd for C12H5N435CI2F3, 332.99161; found 332.99193.HDYL 09

[0178] Following general procedure-2 with 2,3-dichlorobenzoic acid (54 mg, 1.0 equiv, 0.28 mmol), 3-hydrazineyl-6-(trifluoromethyl)pyridazine (50 mg, 1.0 equiv, 0.28 mmol), di(lH-imidazol-l- yl)methanone (46 mg, 1.0 equiv, 0.28 mmol), and phosphoryl trichloride (1.30 mL, 50 equiv, 14.0 mmol), 55.20 mg (55%) HDYL 09 was afforded as a white amorphous solid.1H NMR (600 MHz, CDCl3) δ8.42 (dd, J = 9.6, 0.7 Hz, IH), 7.73 (dd, J = 8.1, 1.6 Hz, 1H), 7.61 (dd, J = 7.7, 1.6 Hz, 1H), 7.47 (d, J = 9.7 Hz, 1H), 7.43 (dd, J = 8.1, 7.7 Hz, 1H).13C NMR (151 MHz, CDCI3) 8148.2, 145.8 (q, J = 37.2 Hz), 143.9, 134.4, 133.5, 133.2, 131.1, 127.8, 127.5, 126.7, 120.2 (q, J = 275.3 Hz), 116.6.19F NMR (565 MHz, CDCl3) 6 -66.96. HRMS (+APCI) (m / z): [M + H+] calcd for C12H5N435Cl2F3, 332.99161; found 332.99159.HDYL 10

[0179] Following general procedure-2 with 2-bromo-5-chlorobenzoic acid (66 mg, 1 Equiv, 0.28 mmol), 3-hydrazineyl-6-(trifluoromethyl)pyridazine (50 mg, 1.0 equiv, 0.28 mmol), di( 1H- imidazol-l-yl)methanone (46 mg, 1.0 equiv, 0.28 mmol), and phosphoryl trichloride (1.30 mL, 50 equiv, 14.0 mmol), 56.66 mg (54%) HDYL 10 was afforded as a white amorphous solid.1H NMR (600 MHz, CDCI3) δ8.42 (d, J = 9.7 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 2.6 Hz, 1H), 7.68 - 7.65 (m, IH), 7.47 (d, J = 9.6 Hz, IH), 7.46 (dd, J = 8.6, 2.6 Hz, IH).13C NMR (151 MHz, CDCI3) 6 148.5, 145.8 (q, J = 37.1 Hz), 143.9, 134.8, 133.9, 133.0, 132.6, 128.2, 127.5, 122.2, 120.2 (q, J = 275.1 Hz), 116.7.19F NMR (565 MHz, CDCI3) 6 -67.00. HRMS (+APCI) (m / z): [M + H+] calcd for C12H6N479Br35ClF3, 376.94110; found 376.94099.Attorney Docket No. 10029-120W01HDYL 11

[0180] Following general procedure-2 with 2-bromo-5-(trifluoromethyl)benzoic acid (88 mg, 1 Equiv, 0.33 mmol), 3-hydrazineyl-6-isopropylpyridazine (50 mg, 1.0 equiv, 0.33 mmol), di(lH- imidazol-l-yl)methanone (53 mg, 1.0 equiv, 0.33 mmol), and phosphoryl trichloride (1.50 ml, 50 equiv, 17.0 mmol), 63.28 mg (50%) HDYL 11 was afforded as a white amorphous solid.1H NMR (600 MHz, CDCI3) 88.13 (d, J = 9.6 Hz, 1H), 8.00 (dt, J = 2.3, 0.6 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.67 (ddd, J = 8.3, 2.2, 0.5 Hz, 1H), 7.14 (d, J = 9.6 Hz, 1H), 3.14 (p, J = 6.9 Hz, 1H), 1.33 (d, J = 6.9 Hz, 6H).13C NMR (151 MHz, CDCI3) 6 162.9, 147.4, 144.4, 134.3, 130.1 (q, J = 33.0 Hz), 130.1 (q, J = 3.8 Hz), 129.0, 128.6 - 126.3 (m), 124.9, 122.7 (p), 121.0, 34.7, 21.4.19F NMR (565 MHz, CDCI3) 6 -62.81. HRMS (+APCI) (m / z): [M + H+] calcd for C15H13N479BrF3, 385.02702; found 385.02703.CH3H3CX rAHDYL 12

[0181] Following general procedure-2 with 5-bromo-2-chlorobenzoic acid (77 mg, 1.0 equiv, 0.33 mmol), 3-hydrazineyl-6-isopropylpyridazine (50 mg, 1 Equiv, 0.33 mmol), di(lH-imidazol-l- yl)methanone (53 mg, 1.0 equiv, 0.33 mmol), and phosphoryl trichloride (1.50 mL, 50 equiv, 17.0 mmol), 51.40 mg (53%) HDYL 12 was afforded as a white amorphous solid.:H NMR (600 MHz, CDCI3) 68.10 (d, J = 9.6 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 8.6, 2.4 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 9.6 Hz, 1H), 3.13 (p, J = 6.9 Hz, 1H), 1.32 (d, J = 6.9 Hz, 1H).13C NMR (151 MHz, CDCI3) 8 162.7, 146.4, 144.4, 135.5, 134.5, 134.0, 131.6, 127.6, 124.8, 120.8, 120.3, 34.6, 21.4. HRMS (+APCI ) (m / z): [M + H+] calcd for C14H13N479Br35CI, 351.00066; found 351.00087.H3C / ^V-BrCH3 / k / N. JH3C N \\| ■ NHDYL 13Attorney Docket No. 10029-120W01

[0182] Following general procedure-2 with 5-bromo-2-methoxybenzoic acid (76 mg, 1 Equiv, 0.33 mmol), 3-hydrazineyl-6-isopropylpyridazine (50 mg, 1.0 equiv, 0.33 mmol), di(lH-imidazol-l- yl)methanone (53 mg, 1.0 equiv, 0.33 mmol), and phosphoryl trichloride (1.50 mL, 50 equiv, 17.0 mmol), the crude compound was purified in florisil chromatography, was recrystallized in dichloromethane and pentane, and isolated on preparative HPLC. 3.11 mg (3%) HDYL 13 was afforded as a white amorphous solid. » NMR (600 MHz, CDCI3) 68.06 (d, J = 9.6 Hz, 1H), 7.84 (d, J = 2.5 Hz, 1H), 7.61 (dd, J = 8.9, 2.5 Hz, 1H), 7.07 (d, J = 9.6 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H), 3.80 (s, 3H), 3.11 (p, J = 6.9 Hz, 1H), 1.31 (d, J = 6.9 Hz, 6H).13C NMR (151 MHz, CDCI3) 5 162.1, 157.5, 146.4, 144.3, 134.5, 134.5, 124.7, 120.4, 117.5, 113.2, 112.6, 56.0, 34.6, 21.5.1SF NMR (565 MHz, CDCI3) 6 -75.48. HRMS (’APCI) (m / z): [M + H+] calcd for C15H15ON479Br, 347.0502; found 347.0502.R Br" / VCIOK 7rx\ N,HDYL 14(0183) Following general procedure-2 with 2-bromo-5-chlorobenzoic acid (62 mg, 1 Equiv, 0.26 mmol), 3-bromo-6-hydrazineylpyridazine (50 mg, 1.0 equiv, 0.26 mmol), di(lH-imidazol-l- yl)methanone (43 mg, 1.0 equiv, 0.26 mmol), and phosphoryl trichloride (1.30 mL, 50 equiv, 14.0 mmol), 32.56 mg (35%) HDYL 14 was afforded as a white amorphous solid.1H NMR (600 MHz, CDCh) 68.18 (d, J = 9.6 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.44 (dd, J = 8.6, 2.5 Hz, 1H), 7.21 (d, J = 9.6 Hz, 1H).13C NMR (151 MHz, CDCI3) 6 149.9, 147.7, 143.3, 134.7, 133.8, 132.9, 132.5, 128.5, 126.6, 123.0, 122.3. HRMS (+APCI) (m / z): [M + H+] calcd for C11H5N479Br35Cl2, 342.91474; found 342.91495.Aci-^OCI\ xN, JV5-N xsL x N 'NHDYL 14.3

[0184] Following general procedure-2 with 2,4-dichlorobenzoic acid (51 mg, 1.0 Equiv, 0.26 mmol), 3-bromo-6-hydrazineylpyridazine (50 mg, 1 equiv, 0.26 mmol), di(lH-imidazol-l-yl)methanone (43 mg, 1.0 equiv, 0.26 mmol), and phosphoryl trichloride (1.30 mL, 50 equiv, 14.0 mmol), 31.52 mg (40%) HDYL 14.3 was afforded as a white amorphous solid.1H NMR (400 MHz, CDCI3) 68.18 (d, J = 9.6 Hz, 1H), 7.63 (dd, J = 5.2, 3.1 Hz, 2H), 7.46 (dd, J = 8.3, 2.0 Hz, 1H), 7.20 (d, J = 9.6 Hz,Attorney Docket No. 10029-120W011H).13C NMR (151 MHz, CDCIs) 8 149.9, 146.9, 143.4, 138.0, 135.8, 133.4, 130.5, 127.6, 126.6, 123.5, 122.9. HRMS (+APCI) (m / z): [M + H+] calcd for C11H5N435Cl3, 298.96526; found 298.96539.-ClF3C.XN., / I ■ NHDYL 15

[0185] Following general procedure-2 with 3-chlorobenzoic acid (44 mg, 1.0 equiv, 0.28 mmol) and 3-hydrazineyl-6-(trifluoromethyl)pyridazine (50 mg, 1.0 equiv, 0.28 mmol), di(lH-imidazol-l- yl)methanone (46 mg, 1.0 equiv, 0.28 mmol), and phosphoryl trichloride (1.30 mL, 50 equiv, 14.0 mmol), 36.95 mg (44%) HDYL 15 was afforded as a white amorphous solid.:H NMR (600 MHz, CDCI3) 68.54 (dt, J = 1.7, 1.1 Hz, 1H), 8.46 - 8.36 (m, 2H), 7.56 - 7.52 (m, 2H), 7.45 (d, J = 9.6 Hz,13C NMR (151 MHz, CDCI3) 6 147.6, 145.7 (q, J = 37.1 Hz), 144.4, 135.2, 131.1, 130.4, 127.8, 127.8, 127.0, 125.7, 120.3 (q, J = 275.2 Hz), 116.0.19F NMR (565 MHz, CDCI3) 5 -67.11. HRMS (+APCI) (m / z): [M + H’] calcd for C12H7N435CIF3, 299.03059; found 299.03070.HDYL 17

[0186] Following general procedure-2 with 3-chlorobenzoic acid (63 mg, 1.0 equiv, 0.40 mmol), 3- hydrazineyl-6-methylpyridazine (50 mg, 1.0 equiv, 0.40 mmol), di(lH-imidazol-l-yl)methanone (65 mg, 1.0 equiv, 0.40 mmol), and phosphoryl trichloride (1.30 mL, 50 equiv, 14.0 mmol), 51.45 mg (52%) HDYL 17 was afforded as a white amorphous solid.]H NMR (600 MHz, CDCI3) 88.58 (td, J = 1.7, 0.8 Hz, 1H), 8.44 (ddd, J = 6.7, 2.5, 1.6 Hz, 1H), 8.08 (d, J = 9.5 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.05 (d, J = 9.5 Hz, 1H), 2.69 (s, 3H).13C NMR (151 MHz, CDCh) 6 155.0, 146.7, 144.7, 134.8, 130.3, 130.1, 128.3, 127.6, 125.9, 124.9, 122.1, 22.2. HRMS (+APCI) (m / z): [M + H’] calcd for C12H9N435Cl, 245.05885; found 245.05883.ClHDYL 8Attorney Docket No. 10029-120W01

[0187] Following general procedure-2 with 2,4-dichlorobenzoic acid (77 mg, 1 Equiv, 0.40 mmol), 3- hydrazineyl-6-methylpyridazine (50 mg, 1.0 equiv, 0.40 mmol), di(lH-imidazol-l-yl)methanone (65 mg, 1.0 equiv, 0.40 mmol), and phosphoryl trichloride (1.30 ml, 50 equiv, 14.0 mmol), 62.98 mg (56%) HDYL 18 was afforded as a white amorphous solid.1H NMR (600 MHz, CDCI3) 68.07 (d, J = 9.5 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.3, 2.0 Hz, 1H), 7.05 (d, J = 9.5 Hz, 1H), 2.57 (s, 1H).13C NMR (151 MHz, CDCI3) 6 154.9, 146.6, 144.0, 137.4, 135.8, 133.5, 130.3, 127.4, 124.6, 124.4, 122.7, 21.9. HRMS fAPCI) (m / z): [M + H+] calcd for C12H9N435CI2, 279.01988; found 279.01947.HDYL 19

[0188] Following general procedure-2 with 2,3-dichlorobenzoic acid (152 mg, 1.0 equiv, 0.79 mmol), 3-bromo-6-hydrazineylpyridazine (150 mg, 1.0 equiv, 0.79 mmol), di(lH-imidazol-l- yl)methanone (129 mg, 1.0 equiv, 0.79 mmol), and phosphoryl trichloride (1.50 mL, 20 equiv, 16.0 mmol), 162.3 mg (68%) HDYL 19 was afforded as a white amorphous solid.1H NMR (400 MHz, CDCIs) 88.18 (d, J = 9.6 Hz, 1H), 7.71 (dd, J = 8.0, 1.7 Hz, 1H), 7.58 (dd, J = 7.7, 1.6 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.21 (d, J = 9.6 Hz, 1H). ' 'C NMR (151 MHz, CDCI3) 6 149.9, 147.4, 143.4, 134.3, 133.6, 133.1, 131.1, 127.7, 127.1, 126.6, 122.9. HRMS (+APCI) (m / z): [M + H’] calcd for CnHeN^Ch, 298.96526; found 298.9658.NH?OH CK, N, 7Ci-: - »-,,. / ciN 1,4-dioxane, 110’C, 3h, microwaveM2N'y>N'N''4,(> 99% conversion) I NHDYL 19 HDYL 19.3 NH2

[0189] To a microwave reactor vial equipped with a stir bar, HDYL 19 (15 mg, 1 equiv, 50.1 pmol), 1.5 mL aqueous ammonia (28%) and 1 mL dioxane were added. The reaction mixture was stirred and heated to 110°C for 3 h in a microwave reactor. The reaction mixture was allowed to cool to rt, the solids were filtered, washed with water and pentane and dried to yield 13.11 mg HDYL 19.3 NHZ (93%) as an off-white solid.1H NMR (400 MHz, CD3OD_SPE) 67.89 (d, J = 9.9 Hz, 1H), 7.75 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (dd, J = 7.7, 1.6 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 9.9 Hz, 1H).13C NMR (151 MHz, CDCh) 8 157.6, 147.3, 144.7, 134.7, 134.4, 133.7, 132.3, 129.5,Attorney Docket No. 10029-120W01129.1, 124.8, 119.4. HRMS (+APCI) (m / z): [M + FT] calcd for C11H8N535Cl2, 280.01513; found 280.0152.HDYL 20[01903 Following general procedure-2 with 2,3-dichlorobenzoic acid (51 mg, 1.0 equiv, 0.26 mmol), 3-bromo-6-hydrazineylpyridazine (50 mg, 1.0 equiv, 0.26 mmol), di(lH-imidazol-l-yl)methanone (43 mg, 1.0 equiv, 0.26 mmol), and tosylic acid monohydrate (0.46 g, 10 equiv, 2.6 mmol), 1.95 mg (2%) HDYL 20 was afforded as a white amorphous solid.1H NMR (600 MHz, CDCIs) 68.08 (d, J = 9.6 Hz, 1H), 7.71 (dd, J = 8.1, 1.6 Hz, 1H), 7.58 (dd, J = 7.7, 1.5 Hz, 1H), 7.41 (dd, J = 8.1, 7.7 Hz, 1H), 7.30 (d, J = 9.6 Hz, 1H).13C NMR (151 MHz, CDCI3) 6 147.4, 143.3, 140.1, 134.3, 133.6, 133.0, 131.1, 127.7, 127.1, 125.7. HRMS (+APCI) (m / z): [M + H*] calcd for C11H6N479Br35Cl2, 342.91474; found 342.91477.

[0191] Following general procedure-2 with 2,3-dichlorobenzoic acid (152 mg, 1.0 equiv, 0.79 mmol), 3-bromo-6-hydrazineylpyridazine (150 mg, 1.0 equiv, 0.279 mmol), di(lH-imidazol-l- yl)methanone (129 mg, 1.0 equiv, 0.79 mmol), and tosylic acid monohydrate (1.51 g, 10 equiv, 7.94 mmol), 141.05 mg (52%) HDYL 21 was afforded as a white amorphous solid.1H NMR (600 MHz, CDCh) 68.08 (d, J = 9.6 Hz, 1H), 7.69 (dd, J = 2.4, 0.5 Hz, 1H), 7.56 - 7.48 (m, 2H), 7.31 (d, J = 9.6 Hz, 1H).13C NMR (151 MHz, CDCI3) 6 146.5, 143.2, 140.0, 133.2, 133.0, 132.4, 132.1, 131.4, 126.2, 126.0, 125.6. HRMS (+APCI) (m / z): [M + l-f] calcd for C11H6N479Br35Cl2, 342.91474,; found 342.91487.HDYL 22Attorney Docket No. 10029-120W01

[0192] Following general procedure-2 with 2,5-dichlorobenzoic acid (121 mg, 1.0 equiv, 0.64 mmol), 3-hydrazineyl-6-iodopyridazine (150 mg, 1.0 equiv, 0.64 mmol), di(lH-imidazol-l-yl)methanone (104 mg, 1.0 equiv, 0.64 mmol), and tosylic acid monohydrate (1.21 g, 10 equiv, 6.36 mmol), 113.29 mg (46%) HDYL 22 was afforded as an off-white amorphous solid.1H NMR (600 MHz, CDCI3) 67.89 (d, J = 9.5 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H ), 7.57 - 7.49 (m, 2 H), 7.45 (d, J = 9.5 Hz, 1H).13C NMR (151 MHz, CDCIj) 6i3C NMR (151 MHz, CDCI3) 6 146.4, 143.2, 133.4, 133.1, 132.6, 132.2, 131.5, 130.9, 126.5, 125.1, 114.8. HRMS (4APCI ) (m / z): [M + H+] calcd for C11H6N435Cl2127I, 390.90087; found 390.90114. / ^\-Brci-- _ -yY N vL -NHDYL 23

[0193] Following general procedure-2 with 5-bromo-2-chlorobenzoic acid (200 mg, 1.0 equiv, 0.85 mmol), 3-hydrazineyl-6-iodopyridazine (200 mg, 1.0 equiv, 0.85 mmol), di(lH-imidazol-l- yl)methanone (139 mg, 1.0 equiv, 0.85 mmol), and tosylic acid monohydrate (1.61 g, 10 equiv, 8.47 mmol), 115.5 mg (29%) HDYL 23 was afforded as an off-white amorphous solid.2H N R (600 MHz, CDCh) 67.89 (d, J = 9.5 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.6, 2.4 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 9.5 Hz, 1H).:3C NMR (151 MHz, CDCI3) 6 146.3, 143.2, 135.5, 135.1, 134.1, 131.8, 130.8, 126.8, 125.1, 120.6, 114.8. HRMS (+APCI) (m / z): [M + H / | calcd for C11H6N479Br35Cl127I, 434.85036; found 434.85098.HDYL 24

[0194] Following general procedure-2 with 5-bromo-2-chlorobenzoic acid (249 mg, 1.0 equiv, 1.06 mmol), 3-bromo-6-hydrazineylpyridazine (200 mg, 1 equiv, 1.06 mmol), di(lH-imidazol-l- yl)methanone (174 mg, 1.0 equiv, 1.06 mmol), and phosphoryl trichloride (1.5 mL, 15 equiv, 16 mmol), 227.57 mg (63%) HDYL 24 was afforded as an off-white amorphous solid.2H NMR (600 MHz, CDCI3) 61H NMR (600 MHz, CDCb) 68.18 (d, J = 9.6 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 8.6, 2.4 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 9.7 Hz, 1H).13C NMR (151 MHz, CDCI3) 8 149.9, 146.6, 143.4, 135.4, 135.2, 134.0, 131.8, 126.6, 123.0, 120.6. HRMS (+APCI ) (m / z): [M + H+] calcd for C11H5N479Br35Cl2, 342.91474; found 342.91482.Attorney Docket No. 10029-120W01NH2OH 1,4-dioxane, 110°C, 3h, microwave76% yieldHDYL 24.3 NH2HDYL 24

[0195] To a microwave reactor vial equipped with a stir bar, HDYL 24 (30 mg, 1 equiv, 87.2 pmol), 3.0 mL aqueous ammonia (28%) and 1.5 mL dioxane were added. The reaction mixture was stirred and heated to 110°C for 3 h in a microwave reactor. The reaction mixture was allowed to cool to rt, the solids were filtered, washed with water and pentane. The product was triturated with 20% acetonitrile in dichloromethane, and dried to yield 21.41 mg (76%) HDYL 24.3 as a light-pink amorphous solid.:H NMR (400 MHz, MeOD) 6 7.92 (d, J = 9.8 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.73 (dd, J = 8.6, 2.4 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 9.8 Hz, 1H).13C NMR (151 MHz, CDCI3) 6 157.6, 146.2, 144.6, 136.2, 136.0, 135.2, 132.7, 128.9, 124.8, 121.2, 119.4. HRMS (’APCI) (m / z): [M + H+] calcd for C11H8N579Br35Cl, 323.96461; found 323.96436.HDYL 24.4 OMe(0196) To a 4-mL flame-dried vial equipped with a septa and a stir bar and purged with nitrogen, HDYL 24 (30 mg, 1 equiv, 87.2 pmol), sodium methoxide (0.5 M in methanol, 0.2 mL, 1.2 equiv, 0.10 mmol) was added, and 0.4 mL dry tetrahydrofuran was added to the vial via a syringe. An argon ballon was inserted, and the reaction was stirred overnight. The crude mixture was diluted with ethyl acetate and extracted with deionized water 4 times. After washing the organic layer with brine, the obtained organic solution was dried over anhydrous magnesium sulfate and gravity-filtered with filter paper. The collected organic solution was concentrated onto silica gel. The crude material was then solid loaded and purified on an automated Florisil® chromatography column (Isolera Biotage®, 0~20% acetonitrile in dichloromethane) to obtain 22.39 mg HDYL 24.4 OMe as a white amorphous solid (76%).:H NMR (600 MHz, CDC!3) 68.03 (d, J = 9.8 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 8.6, 2.4 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 6.86 (d, J= 9.8 Hz, 1H), 3.95 (s, 3H).13C NMR (151 MHz, CDCI3) 6 161.0, 146.5, 144.0, 135.4, 134.6, 133.8, 131.6, 127.6, 126.4, 120.4, 116.6, 55.4. HRMS (+APCI) (m / z): [M + H+] calcd for C12H9ON479Br35CI, 338.96428; found 338.96383.Attorney Docket No. 10029-120W01ClHDYL-25

[0197] Following general procedure-2 with 2,4-dichlorobenzoic acid (81 mg, 1.0 equiv, 0.42 mmol), 3-bromo-6-hydrazineylpyridazine (100 mg, 1 equiv, 0.42 mmol), di(lH-imidazol-l-yl)methanone (70 mg, 1.0 equiv, 0.43 mmol), and tosyiic acid monohydrate (806 mg, 10 equiv, 4.24 mmol), 27.99 mg (17%) HDYL 25 was afforded as an off-white amorphous solid.iH NMR (600 MHz, MeOD) 57.81 (d, J = 9.2 Hz, IH), 7.68 (d, J = 8.2 Hz, IH), 7.61 (d, J = 1.9 Hz, 1H), 7.48 (dd, J = 8.2, 2.0 Hz, IH), 6.92 (d, J = 9.2 Hz, IH).13C NMR (151 MHz, MeOD) 5 167.2, 159.9, 138.5, 136.7, 132.7, 132.3, 130.4, 129.6, 127.2, 115.6, 113.0. HRMS (+APCI) (m / z): [M + H+] calcd for C11H6N435Cl3127I, 390.90087; found 390.89956.HDYL-26

[0198] Following general procedure-2 with 2-bromo-5-methoxybenzoic acid (100 mg, 1.02 equiv, 0.43 mmol), 3-hydrazineyl-6-iodopyridazine (100 mg, 1 equiv, 0.42 mmol), di(lH-imidazol-l- yl)methanone (70 mg, 1.0 equiv, 0.43 mmol), and tosyiic acid monohydrate (730 mg, 10 equiv, 4.24 mmol), 44.47 mg (24%) HDYL 26 was afforded as an off-white amorphous solid.]H NMR (600 MHz, CDCIs) 67.87 (d,7 = 9.5 Hz, IH), 7.64 (d, 7 = 8.9 Hz, IH), 7.42 (d, 7 = 9.5 Hz, IH), 7.17 (d, 7 = 3.0 Hz, IH), 7.01 (dd, 7 = 8.9, 3.0 Hz, IH), 3.84 (s, 3H).13C NMR (151 MHz, CDCb) 6 158.9, 148.5, 143.0, 134.3, 130.6, 127.7, 125.1, 118.9, 118.0, 114.6, 114.5, 55.9. HRMS (+APCI) (m / z): [M + H+] calcd for C12H11ON479Br127I, 430.89856; found 430.90017.HDYL 27Attorney Docket No. 10029-120W01

[0199] Following general procedure 2 with 5-bromo-2-chlorobenzoic acid (125 mg, 1.0 equiv., 0.53 mmol), 3-bromo-6-hydrazineylpyridazine (100 mg, 1.0 equiv., 0.53 mmol), di(lH-imidazol-l-yl) methanone (86.9 mg, 1.0 equiv., 0.53 mmol), and tosylic acid monohydrate (1.0 g, 9.9 equiv., 5.30 mmol), lOlmg HDYL 27 was afforded as a white amorphous solid (49% yield).1H NMR (400 MHz, CDCI3) 6 8.08 (d, J = 9.6 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.66 (dd, J = 8.6, 2.3 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 9.7 Hz, 1H).1 3C NMR (151 MHz, CDCI3) 6 146.5, 143.4, 140.1, 135.4, 135.2, 134.1, 131.8, 126.7, 126.1, 125.7, 120.6. HRMS (+APCI) (m / z): [M+ H+] calcd for CnHgN -’Brz^CI, 386.86423; found 386.86428.ClNNHDYL 28(0200) Following general procedure 2 with 2,3-dichlorobenzoic acid (80.9 mg, 1.0 equiv., 424mol), 3-hydrazineyl-6-iodopyridazine (100 mg, 1.0 equiv., 424 mol), di(lH-imidazol-l- yl)methanone (68.7 mg, 1.0 equiv., 424 pmol), and tosylic acid monohydrate (811 mg, lO.lequiv., 4.26 mmol), 22 mg of HDYL 28 was afforded as a white amorphous solid( 14% yield).2H NMR (400 MHz, CDCI3) 5 7.89 (d, J = 9.5 Hz, 1H), 7.71 (dd, J = 8.1, 1.6 Hz, 1H), 7.59 (dd, J = 7.7, 1.6 Hz, 1H), 7.48 - 7.37 (m, 2H).13C NMR (201 MHz, CDCI3) 3 147.1, 143.2, 134.3, 133.6, 133.0, 131.1, 130.8, 127.7, 127.2, 125.1, 114.8. HRMS (+APCI) (m / z): [M + H+] calcd for C11H6N435Cl127I, 390.9009; found 390.9006.Example 3: Biological assay

[0201] Compounds demonstrated selective inhibition toward the PDE4 isotype and served as a prototype for our SAR studies. ICso of the hit compound tested on PDE4B exhibits a low nanomolar level. In the course of SAR, compounds were tested for activating VX-770 corrected G551D CFTR in Fischer Rat Thyroid (FRT) cells, a cell model that is widely used in cystic fibrosis (CF) drug discovery. Table 1 below discloses data regarding CFTR activation for various compounds:Table 1CFTR activation CFTR ECso Compound ID Compound Name(pA / cm2) (pM)Attorney Docket No. 10029-120W013-(2-bromo-5-methoxyphenyl)-6- HDCF 189 isopropyl-[l,2,4]triazolo[4,3- 151.9 41.0 b]pyridazine3-(2-bromo-5-chlorophenyi)-6- HDCF 190 isopropyl-[l,2,4]triazolo[4,3- 190.0 7.2 b]pyridazine3-(3,5-dichlorophenyl)-6-isopropyl- HDYL 02 67.9 71.7[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL03 180.5 10.2[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 04 203.3 9.2[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL05 77.2 34.5[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 06 100.7 8.2[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 08 44.0 17.9[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 09 93.6 59.3[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 10 225.3 25.1[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 11 166.1 17.8[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 12 223.7 5.5[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 13 92.5 26.9[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 14 206.8 44.5[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichloropheny!)-6-isopropyi- HDYL 14.3 92.3 50.4[l,2,4]triazolo[4,3-b]py ridazine3-(3-chlorophenyl)-6- HDYL 15 (trifluoromethyl)- 80.9 12.4[l,2,4Jtriazolo[4,3-b]py ridazine3-(3-chlorophenyl)-6-methyi- HDYL 17 132.9 35.7[l,2,4Jtriazolo[4,3-b]py ridazine3-(2,4-dichlorophenyl)-6-methyl- HDYL 18 86.0 83.1[l,2,4Jtriazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 19 53.1 88.7[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 20 43.0 36.0[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 21 127.4 18.2[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 22 116.6 0.2[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 23 137.7 4.0[l,2,4]triazolo[4,3-b]py ridazine3-(2,5-dichlorophenyl)-6-isopropyl- HDYL 24 145.8 20.5[l,2,4]triazolo[4,3-b]py ridazineAttorney Docket No. 10029-120W013-(5-bromo-2-chlorophenyl)- HDYL 24.3 [l,2,4]triazolo[4,3-b]pyridazin-6- 165.8 7.1 amine3-(5-bromo-2-chlorophenyl)-6- HDYL 24.4 methoxy-[l,2,4]triazolo[4,3- 140.4 11.6 b]pyridazine3-(2,4-dichlorophenyl)-6-iodo- HDYL 25 inactive inactive [l,2,4]triazolo[4,3-b]py ridazine3-(2-bromo-5-methoxyphenyl)-6- HDYL 26 iodo-[l,2,4]triazolo[4,3- 123.0 10.8 b]pyridazine6-bromo-3-(5-bromo-2- HDYL 27 chlorophenyl)- 204 2.7[l,2,4]triazolo[4,3-b]py ridazine3-(2,3-dichiorophenyl)-6-iodo- DHYL 28 102 11.8[l,2,4]triazolo[4,3-b]py ridazine

[0202] Compounds in this class (but not the specific agents shown herein) have previously been shown to activate wild-type (WT) CFTR and synergistically enhance the function of modulator- corrected diverse variants of the CFTR ion channel. Each compound was tested for maximal activation levels and ECso regarding CFTR-dependent chloride transport. Figure 2 depicts examples of the maximal activation of CFTR by the compounds, and Figure 3 presents the EC5o of CFTR activation.Example 4. PDE Selectivity Screen

[0001] Methods employed in this example have been adapted from the scientific literature to maximize reliability and reproducibility. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained. Assays were performed under conditions as described in the following tables.Table 2. 156500 Phosphodiesterase PDE10A2Source Human recombinant Pre-Incub Time / Temp 15 min @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cAMP incubation Time / Temp 30 min @ 25°C Vehicle 1.0% DMSO Incubation Buffer 10 pM Tris-HCI, pH 7.2,10 mM MgCI2, 0.05% NaNs, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Gross-Langenhoff M, Hofbauer K, Weber J, Schultz A and Schultz JE (2006) cAMPis a ligand for the tandem GAF domain of human phosphodiesterase 10 andAttorney Docket No. 10029-120W01cGMP forthe tandem GAF domain of phosphodiesterase 11. J Biol Chem. 281(5):2841-2846.Table 3. 156600 Phosphodiesterase PDE11A4Source Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cAMP incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO Incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCh, 0.05% NaNa, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Yuasa K, Kotera J, Fujishige K, Michibata H, Sasaki T and Omori K (2000) Isolation and characterization of two novel phosphodiesterase PDE11A variants showing unique structure and tissue-specific expression. J Biol Chem. 275(40): 31469-31479.Table 4. 146100 Phosphodiesterase PDE1ASource Human recombinant Pre-incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cGMP incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCh, 0.05% NaNa, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Sonnenburg WK, Seger D, Kwak KS, Huang J, Charbonneau H and Beavo JA (1995) Identification of inhibitory and calmodulin-binding domains of the PDE1A1 and PDE1A2 calmodulin-stimuiated cyclic nucleotidephosphodiesterases. J Biol Chem. 270(52): 30989-31000.Table 5. 148100 Phosphodiesterase PDE2ASource Human recombinant Pre-incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cAMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO Incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCI2, 0.05% NaNs, 0.1% phosphate-free BSAAttorney Docket No. 10029-120W01Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Martinez SE, Wu AY, Glavas NA, Tang XB, Turley S, Hol WG and Beavo JA (2002)The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding. Proc Natl Acad Sci U S A. 99(20): 13260- 13265.Seyboid J, Thomas D, Witzenrath M, Boral S, Hocke AC, Burger A, Hatzelmann A, Tenor H, Schudt C, Krull M, Schutte H, Hippenstiel S and Suttorp N (2005) Tumor necrosis factor-alpha-dependent expression of phosphodiesterase 2: role inendothelial hyperpermeability. Blood. 105(9): 3569-3576.Table 6. 152300 Phosphodiesterase PDE3ASource Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cAMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO Incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgClz, 0.05% NaNs, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Hambleton R, Krall J, Tikishvili E, Honeggar M, Ahmad F, Manganiello VC and Movsesian MA (2005) Isoforms of cyclic nucleotide phosphodiesterase PDE3 and their contribution to cAMP hydrolytic activity in subcellular fractions of human myocardium. J Biol Chem. 280(47): 39168-39174.Hung SH, Zhang W, Pixley RA, Jameson BA, Huang YC, Colman RF and Colman RW (2006) New insights from the structure-function analysis of the catalytic region of human platelet phosphodiesterase 3A: a role for the unique 44-aminoacid insert. J Biol Chem. 281(39): 29236-29244.Table 7. 152320 Phosphodiesterase PDE3BSource Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cAMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO Incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCh, 0.05% NaNs, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Hambleton R, Krall J, Tikishvili E, Honeggar M, Ahmad F, Manganiello VC andMovsesian MA (2005) isoforms of cyclic nucleotide phosphodiesterase PDE3 andAttorney Docket No. 10029-120W01their contribution to cAMP hydrolytic activity in subcellular fractions of human myocardium. J Biol Chem. 280(47): 39168-39174.Hung SH, Zhang W, Pixley RA, Jameson BA, Huang YC, Colman RF and Colman RW (2006) New insights from the structure-function analysis of the catalytic region of human platelet phosphodiesterase 3A: a role for the unique 44-aminoacid insert. J Biol Chem. 281(39): 29236-29244.Table 8. 154100 Phosphodiesterase PDE4A1ASource Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cAMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO Incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCh, 0.05% NaNs, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Richter W, Unciuleac L, Hermsdorf T, Kronbach T and Dettmer D (2001)Identification of inhibitor binding sites of the cAMP-specific phosphodiesterase 4. Cell Signal. 13(4): 287-297.Wang H, Liu Y, Chen Y, Robinson H and Ke H (2005) Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7. JBiol Chem. 280(35): 30949-30955.Table 9. 154200 Phosphodiesterase PDE4B1Source Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cAMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCh, 0.05% NaNa, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Richter W, Unciuleac L, Hermsdorf T, Kronbach T and Dettmer D (2001)Identification of inhibitor binding sites of the cAMP-specific phosphodiesterase 4. Cell Signal. 13(4): 287-297.Wang H, Liu Y, Chen Y, Robinson H and Ke H (2005) Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7. JBiol Chem. 280(35): 30949-30955.Table 10. 154300 Phosphodiesterase PDE4C1Attorney Docket No. 10029-120W01Source Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cAMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO Incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCI?, 0.05% NaNs, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Wang H, Liu Y, Chen Y, Robinson H and Ke H (2005) Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7. J Biol Chem. 280(35): 30949-30955.Wang H, Peng MS, Chen Y, Geng J, Robinson H, Houslay MD and Cai J, Ke H (2007) Structures of the four subfamilies of phosphodiesterase-4 provide insightinto the selectivity of their inhibitors. Biochem J. 408(2): 193-201.Table 11. 154420 Phosphodiesterase PDE42D2Source Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cAMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO Incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCh, 0.05% NaNs, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Houslay MD (2005) The long and short of vascular smooth muscle phosphodiesterase-4 as a putative therapeutic target. Mol Pharmacol.68(3):563-567.Mackenzie SJ and Houslay MD (2000) Action of rolipram on specific PDE4 cAMP phosphodiesterase isoforms and on the phosphorylation of cAMP-response- element-binding protein (CREB) and p38 mitogen-activated protein (MAP)kinase in U937 monocytic cells. Biochem J. 347(Pt 2): 571-578.Table 12. 156020 Phosphodiesterase PDE5ASource Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cGMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO Incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCI2, 0.05% NaNa, 0.1% phosphate-free BSAAttorney Docket No. 10029-120W01Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Bruder S, Schultz A and Schultz JE (2006) Characterization of the tandem GAF domain of human phosphodiesterase 5 using a cyanobacteria! adenylyl cyclase as a reporter enzyme. J Biol Chem. 281(29): 19969-19976.Filippi S, Morelli A, Sandner P, Fibbi B, Mancina R, Marini M, Gacci M, Vignozzi L, Vannelli GB, Carini M, Forti G and Maggi M (2007) Characterization and functional role of androgen-dependent PDE5 activity in the bladder.Endocrinology. 148(3): 1019-1029.Table 13. 156130 Phosphodiesterase PDE6CSource Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cGMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO Incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCh, 0.05% NaNa, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Baehr W, Devlin MJ and Applebury ML. Isolation and characterization of cGMP phosphodiesterase from bovine rod outer segments. J. Biol. Chem. 254 (22): 11669-11677, 1979.Gillespie PG and Beavo JA. Inhibition and stimulation of photoreceptor phosphodiesterases by dipyridamole and M& B 22, 948. Mol Pharm. 36: 773-781,1989.Table 14. 156200 Phosphodiesterase PDE7Source Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cAMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCh, 0.05% NaNs, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Bender AT and Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 58(3): 488-520.Wang H, Liu Y, Chen Y, Robinson H and Ke H (2005) Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7. JBiol Chem. 280(35): 30949-30955.Attorney Docket No. 10029-120W01Table 15. 156250 Phosphodiesterase PDE7BSource Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cAMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCh, 0.05% NaNa, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Sasaki T, Kotera J, Yuasa K and Omori K (2000) Identification of human PDE7B, a cAMP-specific phosphodiesterase. Biochem Biophys Res Commun. 271(3): 575- 583.Wang H, Liu Y, Chen Y, Robinson H and Ke H (2005) Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7. JBiol Chem. 280(35): 30949-30955.Table 16. 156300 Phosphodiesterase PDE8A1Source Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cAMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO Incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCh, 0.05% NaNa, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation of Fluorescein-AMP-IMAP Literature Reference Gamanuma M, Yuasa K, Sasaki T, Sakurai N, Kotera J and Omori K (2003)Comparison of enzymatic characterization and gene organization of cyclicnucleotide phosphodiesterase 8 family in humans. Cell Signal. 15(6): 565-574.Table 17. 156420 Phosphodiesterase PDE9A2Source Human recombinant Pre-Incub Time / Temp 15 minutes @ 25°C insect Sf9 cellsSubstrate 0.1 pM FAM-cGMP Incubation Time / Temp 30 minutes @ 25°C Vehicle 1.0% DMSO Incubation Buffer 10 mM Tris-HCI, pH 7.2,10 mM MgCh, 0.05% NaNs, 0.1% phosphate- free BSA Significance Crit. >50% of max stimulation Quantitation Method Spectrofluorimetric or inhibition quantitation ofFluorescein-AMP-IMAPAttorney Docket No. 10029-120W01Literature Reference Soderling SH, Bayuga SJ and Beavo JA (1998) Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J Biol Chem. 273(25):15553-15558.

[0002] When presented, IC5o values were determined by a non-linear, least squares regression analysis. Where inhibition constants (K.) are presented, the Ki values were calculated using the equation of Cheng and Prusoff (Cheng., Y., Prusoff, W. H., Biochem. Pharmacol. 22:3099-3108, 1973) using the observed IC50of the tested compound, the concentration of radioligand employed in the assay, and the historical values for the Ko of the ligand. The Hill coefficient (nn) defining the slope of the competitive binding curves was calculated where presented. Hill coefficients significantly different than 1.0 may suggest that the binding displacement does not follow the laws of mass action with a single binding site. Where ICso, Ki, and / or OH data are presented without Standard Error of the Mean (SEM), data are insufficient to be quantitative.

[0003] For primary assays, only the lowest concentration with a significant response judged by the assays' criteria is shown below. Where applicable, either the secondary assay results with the lowest dose / concentration meeting the significance criteria or, if inactive, the highest dose / concentration that did not meet the significance criteria is shown. Primary screening in duplicate with quantitative data (e.g., IC5Q± SEM, Ki ± SEM,, and nH) are shown where applicable for individual assays. In screening packages, primary screening in duplicate with semi- quantitative data (e.g., estimated IC5o, Ki;and nH) are shown where applicable (concentration range of 4 log units); available secondary functional assays are carried out (30 mM) and MED or MIC determined only if active in primary assays >50% at 1 log unit below initial test concentration.Table 18. HDYL12Cat # Assay Name Spec. Rep. Cone. % Inh.156500 Phosphodiesterase PDE10A2 hum 2 10 pM 33 156600 Phosphodiesterase PDE11A4 hum 2 10 pM 5 146100 Phosphodiesterase PDE1A hum 2 10 pM 28 148100 Phosphodiesterase PDE2A hum 2 10 pM 44 152300 Phosphodiesterase PDE3A hum 2 10 pM 9 152320 Phosphodiesterase PDE3B hum 2 10 pM 8 154100 Phosphodiesterase PDE4A1A hum 2 10 pM 71 154200 Phosphodiesterase PDE4B1 hum 2 10 pM 79 154300 Phosphodiesterase PDE4C1 hum 2 10 pM 62 154420 Phosphodiesterase PDE4D2 hum 2 10 pM 72 156020 Phosphodiesterase PDE5A hum 2 10 pM 31 156130 Phosphodiesterase PDE6C hum 2 10 pM 63Attorney Docket No. 10029-120W01Cat# Assay Name Spec. Rep. Cone. % Inh.156200 Phosphodiesterase PDE7A hum 2 10 pM 33 156250 Phosphodiesterase PDE7B hum 2 10 pM 31 156300 Phosphodiesterase PDE8A1 hum 2 10 pM 1156420 Phosphodiesterase PDE9A2 hum 2 10 pM 12 hum = humanValues in bold meet inhibition criteriaTable 19. HDYL22Cat# Assay Name Spec. Rep. Cone. % Inh.156500 Phosphodiesterase PDE10A2 hum 2 10 pM 30 156600 Phosphodiesterase PDE11A4 hum 2 10 pM 6 146100 Phosphodiesterase PDE1A hum 2 10 pM 26 148100 Phosphodiesterase PDE2A hum 2 10 pM 55 152300 Phosphodiesterase PDE3A hum 2 10 p. M 13 152320 Phosphodiesterase PDE3B hum 2 10 |1M 22 154100 Phosphodiesterase PDE4A1A hum 2 10 p. M 76 154200 Phosphodiesterase PDE4B1 hum 2 10 pM 88 154300 Phosphodiesterase PDE4C1 hum 2 10 pM 65 154420 Phosphodiesterase PDE4D2 hum 2 10 pM 89 156020 Phosphodiesterase PDE5A hum 2 10 |1M 21 156130 Phosphodiesterase PDE6C hum 2 10 p. M 22 156200 Phosphodiesterase PDE7A hum 2 10 pM 20 156250 Phosphodiesterase PDE7B hum 2 10 pM 22 156300 Phosphodiesterase PDE8A1 hum 2 10 pM 1156420 Phosphodiesterase PDE9A2 hum 2 10 |1M 5 hum = humanValues in bold meet inhibition criteriaTable 20. HDYL24.3Cat # Assay Name Spec. Rep. Cone. % Inh.156500 Phosphodiesterase PDE10A2 hum 2 10 p. M 22 156600 Phosphodiesterase PDE11A4 hum 2 10 |1M 6 146100 Phosphodiesterase PDE1A hum 2 10 p. M 19 148100 Phosphodiesterase PDE2A hum 2 10 pM 36 152300 Phosphodiesterase PDE3A hum 2 10 pM 8 152320 Phosphodiesterase PDE3B hum 2 10 pM 10 154100 Phosphodiesterase PDE4A1A hum 2 10 |1M 25 154200 Phosphodiesterase PDE4B1 hum 2 10 p. M 35 154300 Phosphodiesterase PDE4C1 hum 2 10 pM 30 154420 Phosphodiesterase PDE4D2 hum 2 10 pM 42 156020 Phosphodiesterase PDE5A hum 2 10 pM 17 156130 Phosphodiesterase PDE6C hum 2 10 pM 8156200 Phosphodiesterase PDE7A hum 2 10 p. M 3Attorney Docket No. 10029-120W01Cat# Assay Name Spec. Rep. Cone. % Inh.156250 Phosphodiesterase PDE7B hum 2 10 |1M 24 156300 Phosphodiesterase PDE8A1 hum 2 10 pM 0156420 Phosphodiesterase PDE9A2 hum 2 10 pM 5 hum = humanValues in bold meet inhibition criteria^0203] The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims, and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods, in addition to those shown and described herein, are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less. However, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. The term "comprising" and variations thereof, as used herein, is used synonymously with the term "including" and variations thereof and are open, non-limiting terms. Although the terms "comprising" and "including" have been used herein to describe various implementations, the terms "consisting essentially of" and "consisting of" can be used in place of "comprising" and "including" to provide for more specific implementations of the disclosure, and are also disclosed. Other than in the examples, or where otherwise noted, ail numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches.

Claims

1. Attorney Docket No. 10029-120W012.CLAIMS3.What is claimed is:

1. A compound having the formula:

6. 8.or a pharmaceutically acceptable salt thereof, wherein:9.R1is selected from D, halo, CN, Rla, ORla, NHRla, NRlaRlb, C(=O)Rla, C(=O)OORla, C(=O)NHRla, C(=O)NRlaRlb, OC(=O)Rla, wherein Riais selected from H, Cnalkyl, Ci-6heteroalkyl, C;shaloalkyl, Ci-oheterohaloalkyl, C3.gcycloalkyl, Ci-8heterocyclyl, Ce-izaryi, or Ci-ioheteroaryl; and R:bis selected from Ciealkyl, Ci gheteroalkyl, C3.8cycioalkyl, Ci gheterocyclyi, Cg-izaryl, or Cnoheteroaryl; wherein Rlaand Rlbcan together form a ring;10.R2is selected from D, halo, CN, R2a, OR2a, NHR2a, NR2aR2b, C(=O)R2a, C(=O)OOR2a, C(=O)NHR2a, C(=O)NR2aR2b, OC(=O)R2a, wherein R2ais selected from H, Ci-6alkyl, Ci-gheteroalkyl, Ci- shaloalkyl, Ci-oheterohaloalkyl, C3.gcycloalkyl, Ci-8heterocyclyl, Ce-izaryi, or Ci-ioheteroaryl; and R2bis selected from Ci6alkyl, Ci gheteroalkyl, Cnhaloalkyl, Ci6heterohaloalkyl, C3scycloalkyl, Ci-gheterocyclyl, C6-izaryl, or Cnoheteroaryl; wherein R2aand R2bcan together form a ring;11.R3is selected from D, halo, CN, R3a, OR3a, NHR3a, NR3aR3b, C(=O)R3a, C(=O)OOR3a, C(=O)NHR3a, C(=O)NR3aRlb, OC(=O)R3a, wherein R3ais selected from H, Ci.6alkyl, Ci-6heteroalkyl, Ci- shaloalkyl, Ci-6heterohaloalkyl, C-! Scycloalkyl, Ci-gheterocyclyl, C6-izaryl, or Cnoheteroaryl; and R3bis selected from Cnalkyl, Ci.6heteroalkyl, C3gcycloalkyl, Ci gheterocyclyl, C6 i2aryl, or Cnoheteroaryl; wherein R3aand R3bcan together form a ring;12.wherein any two of R1, R2, and R3can together form a ring;13.R4is Ce-izaryl or Cnoheteroaryl, substituted one or more times by a group independently selected from halo, CN, Ci-6alkyl, Cnheteroalkyl, Ci-6ha loalky I, Cnheterohaloalkyl, C3. scycloalkyl, Ci-gheterocyclyl, Cg-izaryl, or Cnoheteroary, OR4a, NHR4a, NR4aR2b, C(=O)R4a, C(=O)OOR4a, C(=O)NHR4a, C(=O)NR4aR4b, OC(=O)R4a, wherein R4ais selected from H, Ci-6aikyi, Ci-6heteroalkyl, C3-gcycloalkyl, Ci-gheterocyclyl, C6-izaryl, or Cnoheteroaryi; and R4bis selected from Ci.6alkyl, Ci-6heteroalkyl, C3.8cycloalkyl, Ci-gheterocyclyl, C6-izaryl, or C-;. loheteroaryl; wherein R4aand R4bcan together form a ring. Attorney Docket No. 10029-120W012. The compound of claim 1, wherein R4has the formula:15.RG17.

18. Rais selected from D, halo, CN, Raa, ORaa, NHRaa, NRaaRab, C(=O)Raa, C(=O)OORaa, C(=O)NHRaa, C(=O)NRaaRlb, OC(=O)Raa, wherein Raais selected from H, Ci.6alkyl, Ci.6heteroalkyl, Ci- chaloalkyl, Ci.cheterohaloalkyl, Cg.gcycloalkyl, Ci.gheterocyclyl, Cf,-iz.aryl, or Ci-ioheteroaryl; and Rabis selected from Ci-.-:alkyl, Ci-cheteroalkyl, C3.g.cycloalkyl, Ci.gheterocyclyl, Ce-izaryl, or Cnoheteroaryl; wherein Raaand Rabcan together form a ring;19.Rbis selected from D, halo, CN, Rba, ORba, NHRba, NRbaRbb, C(=O)Rba, C(=O)OORba, C(=O)NHRba, C(=O)NRbaRbb, OC(=O)Rba, wherein Rbais selected from H, Ci.6alkyl, Ci.heteroalkyl, Ci- chaloalkyl, Ci.cheterohaloalkyl, Cg.gcycloalkyl, Ci.gheterocyclyl, Cf,-iz.aryl, or Cnoheteroaryl; and Rbbis selected from Ci-calkyl, Ci-cheteroalkyl, Cg.gcycloalkyl, Ci.gheterocyclyl, Cc-izaryl, or Cnoheteroaryl; wherein Rbaand Rbbcan together form a ring;20.Rcis selected from D, halo, CN, Rca, ORca, NHRca, NR“Rcb, C(=O)Rca, C(=O)OORca, C(=O)NHRca, C(=O)NR“Rcb, OC(=O)Rca, wherein Rcais selected from H, Ci ealkyl, Ci-cheteroalkyl, Ci- chaloalkyl, Ci.cheterohaloalkyl, C3.gcycloalkyl, Ci.gheterocyclyl, C6-izaryl, or Ci-ioheteroaryl; and R':" is selected from Ci-6alkyl, C-.-cheteroalkyl, C.g.gcycloalkyl, Ci.gheterocyclyl, C6-iz.aryl, or Cnoheteroaryl; wherein Rcaand Rcbcan together form a ring;21.Rdis selected from D, halo, CN, Rda, ORda, NHRda, NRdaRdb, C(=O) Rda, C(=O)OORda, C(=O)NHRda, C(=O)NRdaRdb, OC(=O)Rda, wherein Rdais selected from H, Ci-calkyl, Ci-cheteroalkyl, Ci- chaloalkyl, Ci.cheterohaloalkyl, C3-8cycloalkyl, Ci.gheterocyclyl, C6.izaryl, or Ci io eteroaryl; and Rdbis selected from Ci.6alkyl, Ci.6heteroalkyl, C3.scycloalkyl, Ci.gheterocyclyl, C6-i aryl, or Cnoheteroaryl; wherein Rdaand Rdbcan together form a ring;22.Reis selected from D, halo, CN, Rea, ORea, NHRea, NReaReb, C(=O)Rea, C(=O)OORea, C(=O)NHRea, C(=O)NReaReb, OC(=O)Rea, wherein Reais selected from H, Ci-calkyl, Ci-cheteroalkyl, Ci- chaloalkyl, Ci.cheterohaloalkyl, C3.gcycloalkyl, Ci.gheterocyclyl, Ce-izaryl, or Ci io eteroaryl; and Rebis selected from Ci-galkyl, Ci-cheteroalkyl, C3.gcycloalkyl, Cigheterocyclyl, Cc-izaryl, or Cnoheteroaryl; wherein Reaand Rebcan together form a ring; and23.wherein any two or more of Ra, Rb, R':, Rd, and Recan together form a ring.

3. The compound of claim 2, wherein at least one of Ra, Rb, Rc, Rd, and Reis not H.

4. The compound of any one of claims 1-3, wherein at least one of R1, R2, or R3is not H.Attorney Docket No. 10029-120W015. The compound of any one of claims 1-3, wherein each of R1, R2, or R3is H.

6. The compound of any one of claims 1-3, wherein each of R1and R2is H, and R3is not H.

7. The compound of any one of claims 1-3, wherein each of R2and R3is H, and R1is not H.

8. The compound of any one of claims 1-3, wherein each of R1and R3is H, and R2is not H.

9. The compound of any one of claims 1-8, wherein one of R1, R2, or R3is F, Cl, Br, I, Ci-3alkyl, Ci-3haloalkyl, cyclopropyl, OH, OCi.3alkyl, OCi.3haloalkyl, NH2, NHCi.3alkyl, or N (Chalky l)2.

10. The compound of any one of claims 1-9, wherein one of R1, R2, or R3are F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, O-cyclopropyl, CF3, CF2CF3, CH2CF3, CH2CH2CF3, CF2CH2CH3, CF(CH3)2, OCF3, OCF2CF3, OCHJCF3, NH2, NHCH3, N(CH3)2, N(CH2CH3)2.

11. The compound of any one of claims 1-10, wherein R3is F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, O-cyclopropyl, CF3, CF2CF3, CH2CF3, CH2CH2CF3, CF2CH2CH3, CF(CH3)2, OCF3, OCF2CF3, OCH2CF3, NH2, NHCH3, N(CH3)2, N(CH2CH3)2.

12. The compound of any one of claims 1-11, wherein R3is F, Cl, Br, I, NH2, CH3, CF3, CH(CH3)2, or OCH3.

13. The compound of any one of claims 1-12, wherein R3is F.

14. The compound of any one of claims 1-12, wherein R3is Cl.

15. The compound of any one of claims 1-12, wherein R3is Br.

16. The compound of any one of claims 1-12, wherein R3is I.

17. The compound of any one of claims 1-12, wherein R3is NH2.

18. The compound of any one of claims 1-12, wherein R3is CH3.

19. The compound of any one of claims 1-12, wherein R3is CF3.

20. The compound of any one of claims 1-12, wherein R3is CH(CH3)2.

21. The compound of any one of claims 1-12, wherein R3is OCH3.

22. The compound of any one of claims 1-21, wherein R':is:40.Re42.

23. The compound of any one of claims 2-22, wherein at least one of Ra, Rb, Rc, Rd, and Reis F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, or OCH(CH3)2.

24. The compound of any one of claims 2-22, wherein one of Ra, Rb, Rc, Ra, and Reis F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, or OCH(CH3)2, and the remaining of Ra, Rb, Rc, Rd, and Reare H.Attorney Docket No. 10029-120W0125. The compound of any one of claims 2-22, wherein at least one of Ra, Rb, Rc, Rd, and Reis Cl or Br.

26. The compound of any one of claims 2-22, wherein one of R3, Rb, Rc, Rd, and Reis Cl or Br, and the remaining of Ra, Rb, Rc, Rd, and Reare H.

27. The compound of any one of claims 2-22, wherein at least two of Ra, Rb, Rc, Rd, and Reare independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2.

28. The compound of any one of claims 2-13, wherein two of Ra, Rb, Rc, Rd, and Reare independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2, and the remaining of Ra, Rb, Rc, Rd, and Reare H.

29. The compound of any one of claims 2-22, wherein two of Ra, Rb, Rc, Rd, and Reare independently selected from F, Cl, Br, and OCH3, and the remaining of Ra, Rb, Rc, Rd, and Reare H.

30. The compound of any one of claims 2-22, wherein two of Ra, Rb, Rc, Rd, and Reare independently selected from Cl and Br, and the remaining of Ra, R", Rc, Rd, and Reare H.

31. The compound of any one of claims 2-22, wherein Raand Rbare independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2, and Rc, Rd, and Reare H.

32. The compound of any one of claims 2-22, wherein Raand Rcare independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2, and Rb, Rd, and Reare H.

33. The compound of any one of claims 2-22, wherein Raand Rdare independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2, and Rb, Rc, and Reare H.

34. The compound of any one of claims 2-22, wherein Raand Reare independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2, and Rb, Rc, and Rdare H.

35. The compound of any one of claims 2-22, wherein Rband Rcare independently selected from F, Cl, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2, and Ra, Rd, and Reare H.

36. The compound of any one of claims 2-22, wherein Rband Rdare independently selected from F, Ci, Br, I, CH3, CH2CH3, CH(CH3)2, OCH3, OCH2CH3, and OCH(CH3)2, and Ra, Rdc, and Reare H.

37. The compound of any one of claims 2-36, having the formula:

59.

60. Attorney Docket No. 10029-120W0138. The compound of any one of claims 2-36, having the formula:

63. 65.wherein none of Ra, R“, or R3is H.

39. The compound of any one of claims 2-36, having the formula:67.Rc69. 71.wherein none of Ra, Rc, or R3is H.

40. The compound of any one of claims 2-36, having the formula:73.Ra75. 77.wherein none of Ra, Ra, or R3is H.

41. The compound of any one of claims 2-36, having the formula:

80. 82.wherein none of Ra, Re, or R3is H.

42. The compound of any one of claims 2-36, having the formula:Attorney Docket No. 10029-120W0185. 87.wherein none of R\ Rc, or R3is H.

43. The compound of any one of claims 2-36, having the formula:

90. 92.wherein none of Rc, Rbd, or R3is H.

44. The compound of claim 1 or claim 2, wherein the compound is selected from:

95.

96. Attorney Docket No. 10029-120W0198.

99. Attorney Docket No. 10029-120W01101.

102. Attorney Docket No. 10029-120W01103.or a pharmaceutically acceptable salt thereof.

45. A pharmaceutical composition comprising the compound according to any one of claims 1- 44.

46. A method of treating a respiratory disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-44 or the pharmaceutical composition of claim 45.

47. The method of claim 46, wherein the respiratory disorder comprises cystic fibrosis, chronic obstructive pulmonary disease, bronchiectasis, bronchitis, asthma, atelectasis, pneumonia, abnormal lung fluid, abnormal lung mucus, acute respiratory distress syndrome, ventilator induced lung injury, bronchopulmonary dysplasia, airways hyperresponsiveness, allergic rhinitis; bronchiectasis, sinusitis (including chronic sinusitis), allergic bronchopulmonary aspergillosis, idiopathic pulmonary fibrosis, or emphysema.

48. The method of any one of claims 46-47, wherein the respiratory disorder comprises cystic fibrosis.

49. The method of any one of claims 46-47, wherein the respiratory disorder comprises cystic fibrosis characterized by CFTR having a premature truncation codon.

50. The method of any one of claims 46-47, wherein the respiratory disorder comprises cystic fibrosis characterized by a CFTR mutation in which an amino acid codon has been replaced with a stop codon comprising UAG, UAA, or UGA.

51. The method of any one of claims 46-47, wherein the respiratory disorder comprises cystic fibrosis characterized by a CFTR mutation selected from W1282X, G551D, F508del, G542X, N1303X, R117H, R553X, or a combination thereof.

52. The method of any one of claims 46-47, wherein the respiratory disorder comprises W128X cystic fibrosis.

53. The method of claim 46-52, wherein the compound is administered enterally, parenterally, I nhalationally, intranasally, or topically.

54. The method of any of claims 46-52, wherein the compound is administered orally or sublingually.

55. The method of any of claims 46-52, wherein the compound is administered intravenously, subcutaneously, or intramuscularly.

56. The method of any of claims 46-52, wherein the compound is administered via manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer.Attorney Docket No. 10029-120W0157. The method of any of claims 46-56, wherein the compound is administered in combination with at least one other therapeutic for a respiratory disorder.

58. The method of claim 57, wherein the at least one other therapeutic comprises a PDE4 inhibitor, a CFTR modulator, or combinations thereof.

59. The method of claim 58, wherein the CFTR modulator comprises a CFTR potentiator, a CFTR corrector, a CFTR pharmacological chaperone, a CFTR proteostasis regulator, or combinations thereof.

60. The method of claim 57, wherein the at least one other therapeutic comprises ivacaftor, lumacaftor, tezacaftor, elexacaftor, vanzacaftor, cavosonstat, galicaftor, (FDL169) 2-(7- ethoxy-4-(3-fluorophenyl)-l-oxophthalazin-2(lH)-yl)-N-methyi-N-(2-methylbenzo[d]oxazol- 6-yi)acetamide, SION-719, SION-451, SION-102, or combinations thereof.

61. The method of claim 57, wherein the at least one other therapeutic comprises tezacaftor and ivacaftor.

62. The method of claim 57, wherein the at least one other therapeutic comprises elexacaftor, tezacaftor, and ivacaftor.

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