Benzothiazole derivatives for treating diseases

Abstract

The present disclosure relates to PDE4 inhibitor compounds, pharmaceutical compositions containing the compounds, and methods of using such compounds to treat disease.

Description

[0001] BENZOTHIAZOLE DERIVATIVES FOR TREATING DISEASES

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 565,592, filed March 15, 2024, the entire disclosure of which is incorporated herein by reference.

[0004] BACKGROUND

[0005] Inhibition of PDE4 enzyme leads to regulation of various inflammatory mechanisms by elevation of cyclic adenosine monophosphate (cAMP) levels in the cells. The cAMP signaling systems regulate many physiological and pathophysiological responses, including cardiopulmonary, central nervous, cardiovascular, immune systems and others, of which low intracellular levels can lead to many human diseases. One way to increase the concentrations of cAMP in the cell is by preventing the hydrolysis of cAMP by inhibiting PDEs. More than 21 PDE genes have been identified in the human genome that are classified as 11 families (PDE1 to PDE11) on the basis of their sequence homogeneity, substrate specificity and inhibitor sensitivity. The PDE4 enzyme is a target for treatment of pulmonary, dermatological, and neurological inflammatory diseases. Several PDE4 inhibitor drugs Roflumilast, Apremilast, and Crisaborole were approved and marketed as Dalsirep™, Otezla™ and Eucrisa™ for the treatment of inflammatory pulmonary diseases, psoriatic arthritis, and atopic dermatitis. However, these drugs have adverse effects such as nausea, emesis, and gastrointestinal effects. Selective inhibitors of PDE4 isoforms have the potential for reduced gastrointestinal side effects including nausea, emesis. The existence of the upstream conserved regions UCR1, UCR2, and CR3 distinguishes PDE4 from other PDE gene members and selective interaction with these regions results in selective inhibition of PDE4 isoforms.

[0006] Epilepsy is a disorder of the central nervous system where abnormal electrical activity in the brain causes recurrent seizures, affecting consciousness, movement, and sensations. Many seizure medicines lower the excitability of nerve cells in the brain, and they can also affect normal activity. For instance, certain antiepileptic drugs (AEDs), such as levetiracetam and perampanel, are associated with undesirable behavioral side effects, including aggression and irritability. Other AEDs such as topiramate can cause undesirable cognitive impairments including “brain fog” as well as memory and language complications. In pathological states, including epilepsy, increased PDE4 activity contributes to a decrease in cAMP levels, which may exacerbate neuroinflammatory responses. Accordingly, there remains a need for PDE4 inhibitors for use in methods of treating diseases. For instance, compounds that provide therapeutic benefits in central nervous system disorders such as epilepsy while minimizing undesirable behavioral side effects and complications are highly desirable.

[0007] SUMMARY

[0008] In one aspect, the disclosure relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein:

[0009] R1is H, amino, or alkyl;

[0010] R2is heterocyclyl, cycloalkyl, heteroaryl, or aryl; and R3is heterocyclyl, cycloalkyl, heteroaryl, or aryl.

[0011] In certain aspects, the present disclosure relates to a compound of formula II, III, Illa, Illb, or IV, or a pharmaceutically acceptable salt thereof, (Illa),

[0012] wherein each of R1, R2, R3, R4, R5, X1, X2, and X3are as described herein.

[0013] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the disclosure and a pharmaceutically acceptable excipient.

[0014] In certain aspects, the present disclosure provides a method of treating disease in a patient, comprising administering to a patient in need thereof a compound or composition of the disclosure.

[0015] BRIEF DESCRIPTION OF FIGURES

[0016] FIGURE 1 shows a graph of cAMP increase as a percentage of vehicle alone in HEK293 cells transfected with PDE4B 1 (right graph) or endogenous protein levels of PDE4A and PDE4D (left graph). Data shown for the PDE4B-selective inhibitor A33 and Compound 1;

[0017] FIGURE 2A shows a graph of seizure frequency in all Compound 1 or vehicle exposed Scnla+ / - mice measured by vEEG;

[0018] FIGURE 2B shows a graph of seizure frequency in Compound 1 or vehicle exposed Scnla+ / - mice with severe phenotypes* removed measured by vEEG. *Mice experiencing seizures > Racine 4 during first 48 hours of treatment were excluded from seizure activity and longevity assays. " Mixed effects model (REML) Two-factor ANOVA, p= <0.0001, n= 6-8. BID=twice daily; Compound 1 dosing: 40mg / kg BID; Vehicle dosing: BID. BID= twice daily; vEEG = video electroencephalogram;

[0019] FIGURE 3 shows a graph of seizure activity in kvl.l (kcnal- / -) and GABA_A1 gabral- / - receptor knockouts, and PTZ-induced epileptic zebrafish exposed to Vehicle, Compound 1 or other anti-seizure medicines (ASMs). 'Two-way ANOVA (p<0.0001) with Sidak’s multiple comparisons test: ** p<0.01; **** p<0.0001; ns= not significant. Compound 1 dosing: 40mg / kg BID; Vehicle dosing: BID. BID=twice daily; gabral- / -=al subunit of GABA_A receptor knockout; kcnal- / -= Kvl.l potassium channel knockout; PTZ= pentylenetretazol, a generalized epilepsy induction model. Veh= Vehicle; WT= Wild Type;

[0020] FIGURE 4 shows a graph of percentage of protected wild type (WT) mice exposed to Compound 1 or vehicle in MES epilepsy model. Compound 1 dosing: 40mg / kg BID; Vehicle dosing: BID. BID= twice daily;

[0021] FIGURE 5 A shows a graph of Kaplan-Meier probability of survival in Compound 1 vs vehicle exposed Scnla+ / - epileptic mice;

[0022] FIGURE 5B shows a graph of median survival following cessation of treatment with Compound 1 vs vehicle exposed Scnla+ / - epileptic mice. ^Unpaired t-test, p=0.0081, n=9-19; Compound 1 dosing: 40mg / kg BID; Vehicle dosing: BID. BID= twice daily; PND= post-natal day;

[0023] FIGURE 6A shows a graph of time spent near Barnes Maze target in WT and Scnla+ / - epileptic mice exposed to Compound 1 vs WT mice exposed to vehicle;

[0024] FIGURE 6B shows a graph of number of novel Y-maze arm entries in WT and Scnla+ / - epileptic mice exposed to Compound 1 vs vehicle. Compound 1 dosing: 40mg / kg BID; Vehicle dosing: BID. BID= twice daily; Veh= vehicle; WT= wild type;

[0025] FIGURE 7A shows a graph of number of buried marbles in WT and Scnla+ / - epileptic mice exposed to Compound 1 vs WT mice exposed to vehicle;

[0026] FIGURE 7B shows a graph of distance travelled in open field with novel object in WT mice exposed to Compound 1 vs vehicle; and

[0027] FIGURE 7C shows a graph of time spent in center of open field with novel object in WT mice exposed to Compound 1 vs vehicle. ^One-way ANOVA, p=0.0115, n=3-l 1 ; ns= not significant; Compound 1 dosing: 40mg / kg BID; Vehicle dosing: BID. BID= twice daily; Veh= vehicle; WT= wild type.

[0028] DETAILED DESCRIPTION

[0029] An object of present disclosure is to provide selective PDE4 inhibitors. Selective PDE4 inhibitors of the disclosure find utility in treating central nervous system disorders, such as epilepsy, stroke, Alzheimer’s disease, schizophrenia, depression, multiple sclerosis, traumatic brain injury, Huntington’s disease, and other neurodevelopmental disorders. Selective PDE4 inhibitors of the disclosure, that inhibit tumor growth and metastases, find utility in the treatment and prevention of cancer. Such cancers may include esophageal cancer, brain cancer, pancreatic cancer, colon cancer, hematologic cancer, lung cancer, prostate cancer, skin cancer, head and neck cancer, CNS cancer, gastric cancer, breast cancer, bladder cancer, or ovarian cancer. Selective PDE4 inhibitors of the disclosure are useful in improving cognition, and therefore find utility in treating learning disorders, memory loss, Fragile X syndrome, or other cognitive and affective disorders. Selective PDE4 inhibitors are also useful for treating inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), psoriasis, atopic dermatitis, inflammatory bowel disease, and rheumatoid arthritis.

[0030] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended clauses.

[0031] For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[0032] As used herein and in the appended clauses, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the clauses may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of clause elements, or use of a “negative” limitation.

[0033] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0034] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and / or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.

[0035] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0036] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0037] Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[0038] As used herein and in connection with chemical structures depicting the various embodiments described herein, and “• AA ” each represent a point of covalent attachment of the chemical group or chemical structure in which the identifier is shown to an adjacent chemical group or chemical structure. For example, in a hypothetical chemical structure A-B, where A and B are joined by a covalent bond, in some embodiments, the portion

[0039] „ A > *" of A-B defined by the group or chemical structure A can be represented by ,

[0040] "A — **" , or "A -5-" where each — < P5- ” represents a bond to A and the point of covalent bond attachment to B. Alternatively, in some embodiments, the portion

[0041] _ i_>" of A-B defined by the group or chemical structure B can be represented by ,

[0042] " ** _ Tj n n n

[0043] , or , where each represents a bond to B and the point of covalent bond attachment to A.

[0044] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.

[0045] DEFINITIONS

[0046] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art.

[0047] The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, Mass. (2000).

[0048] Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, Calif. (1985).

[0049] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0050] The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known. The ability of such agents to inhibit AR or promote AR degradation may render them suitable as “therapeutic agents” in the methods and compositions of this disclosure.

[0051] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

[0052] “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0053] The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0054] “Administering” or “administration of a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0055] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

[0056] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.

[0057] A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject's size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0058] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.

[0059] It is understood that substituents and substitution patterns on the compounds of the present disclosure can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0060] As used herein, the term “optionally substituted’' refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, — OCO — CH2 — O-alkyl, — OP(O)(O-alkyl)2 or — CH2 — OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.

[0061] The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O) — , preferably alkylC(O) — .

[0062] The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH — .

[0063] The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O — , preferably alkylC(O)O — .

[0064] The term “alkoxy” refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[0065] The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0066] As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or Ci-Ciobranched-chain alkyl groups. Preferably, the “alkyl” group refers to Ci-Ce straight-chain alkyl groups or Ci-Co branched- chain alkyl groups. Most preferably, the “alkyl” group refers to C1-C4 straight-chain alkyl groups or Ci-C4branched-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1-propyl, 2 -propyl, n-butyl, sec -butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1 -hexyl, 2-hexyl, 3-hexyl, 1 -heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1 -octyl, 2-octyl, 3-octyl or 4-octyl and the like. Moreover, the term “alkyl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc. The term “Cx.y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A Ci-6 alkyl group, for example, contains from one to six carbon atoms in the chain.

[0067] The term “amide”, as used herein, refers to a group wherein R9and R10each independently represent a hydrogen or hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0068] The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by

[0069] U R1'1< A Rl ,rwherein R9, R10, and R10, each independently represent a hydrogen or a hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. Examples of amino groups include, but are not limited to, -NH2, -NH(alkyl), -N(alkyl)2. Examples where R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure (e.g., cyclic amino groups) include piperazine, pyrrolidine, piperidine, and morpholine.

[0070] The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0071] The term “carbamate” is art-recognized and refers to a group wherein R9and R10independently represent hydrogen or a hydrocarbyl group. The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0072] The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo |2.2.1 Jheptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo|4.2.0Joct- 3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH- indene and bicyclo[4. 1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0073] The term “carbonate” is art-recognized and refers to a group — OCO2 — .

[0074] The term “carboxy”, as used herein, refers to a group represented by the formula — CO2H.

[0075] As used herein, the term “cycloalkyl” refers to a 3 to 15 member all-carbon monocyclic ring, including an all-carbon 5-member / 6-member or 6-member / 6-member fused bicyclic ring, or a multicyclic fused ring (a “fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group, or a carbocyclic ring that is fused to another group such as a heterocyclic, such as ring 5- or 6-membered cycloalkyl fused to a 5- to 7- membered heterocyclic ring, where one or more of the rings may contain one or more double bonds but the cycloalkyl does not contain a completely conjugated pi- electron system. It will be understood that in certain embodiments, cycloalkyl may be advantageously of limited size such as C3-C13, C3-C9, C3-C6 and C4-C6. Cycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbomenyl, and the like. Illustrative examples of cycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties:

[0076]

[0077] As used herein, “cyano” refers to a -CN group.

[0078] The term “ester”, as used herein, refers to a group — C(O)OR8, wherein R8represents a hydrocarbyl group.

[0079] The term “ketone”, as used herein, refers to a group — C(O)R7, wherein R7represents a hydrocarbyl group (e.g., alkyl, aryl, heteroaryl). An illustrative example of a ketone group includes methyl ketone ( — C(O)CHr)

[0080] The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-0 — . Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl- O-alkyl.

[0081] The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0082] The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.

[0083] The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Illustrative heteroaryl groups include, for example, pyrazole, imidazole, oxazole, pyridine, pyridone, pyrimidine, and pyridazine.

[0084] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0085] The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

[0086] The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0087] The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbonhydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0088] The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

[0089] The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent). The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[0090] The term “sulfate” is art-recognized and refers to the group — OSO3H, or a pharmaceutically acceptable salt thereof.

[0091] The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae wherein R9and R10independently represents hydrogen or hydrocarbyl.

[0092] The term “sulfoxide” is art-recognized and refers to the group — S(O) — .

[0093] The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0094] The term “sulfone” is art-recognized and refers to the group — S(O)?-R9, wherein R9represents hydrocarbyl (e.g., alkyl, aryl, heteroaryl). An illustrative example of a sulfone group includes methyl sulfone ( — S OhCHs).

[0095] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0096] The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.

[0097] The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0098] “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.

[0099] The term “pharmaceutically acceptable acid addition salt” as used herein means any non-toxic organic or inorganic salt of any base compounds represented by Formula I. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non- pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0100] The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.

[0101] Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01 / 062726.

[0102] Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers.

[0103] Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present disclosure. For example, a compound having a tautomeric group, such as pyridone / hydroxypyridine group, may be represented by any tautomeric form.

[0104] “Prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of formula I). Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Pat. Nos. 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of this disclosure are metabolized to produce a compound of Formula I. The present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.

[0105] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.

[0106] The term “Log of solubility”, “LogS” or “logS” as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption. LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol / liter.

[0107] As used herein, the term “PDE4 inhibitor” as used herein refers to a compound that prevents, reverses, slows, or inhibits the activity of PDE4 or a PDE4 isoform.

[0108] In treatment methods according to the disclosure, an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).

[0109] REPRESENTATIVE EMBODIMENTS

[0110] In some embodiments, the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof, wherein R1, R2, and R3are as described herein.

[0111] In some embodiments, the present disclosure relates to a compound of the formula II, or a pharmaceutically acceptable salt thereof, wherein R2and R3are as described herein.

[0112] In some embodiments, the present disclosure relates to a compound of the formula III, or a pharmaceutically acceptable salt thereof, wherein R1, R3, X1, X2, and X3are as described herein.

[0113] In some embodiments, the present disclosure relates to a compound of the formula Illa, or a pharmaceutically acceptable salt thereof, (Illa), wherein R1, R3, R5, X1, and X3are as described herein.

[0114] In some embodiments, the present disclosure relates to a compound of the formula Illb, or a pharmaceutically acceptable salt thereof, wherein R1, R4, and R5are as described herein.

[0115] In some embodiments, the present disclosure relates to a compound of the formula IV, or a pharmaceutically acceptable salt thereof, wherein R4is as described herein.

[0116] In some embodiments, R1is H, amino, or alkyl. In some embodiments, R1is H, NH2, or Ci-Ce alkyl. In some embodiments, R1is H or amino. In some embodiments, R1is H or NH2. In some embodiments, R1is H. In certain preferred embodiments, R1is NH2. In some embodiments, R2is heterocyclyl, cycloalkyl, heteroaryl, or aryl. In some embodiments, R2is 3- to 8-membered heterocyclyl, C3-C8 cycloalkyl, 3- to 8-membered heteroaryl, or Ce-Cio aryl. In some embodiments, R2is heteroaryl or aryl. In some embodiments, R2is 3- to 8-membered heteroaryl or Ce-C aryl. In some embodiments, R2is 5- to 6-membered heteroaryl or Ce-C aryl.

[0117] In some embodiments, R2is heteroaryl. In some embodiments, R2is 3- to 8-membered heteroaryl. In some embodiments, R2is 5- or 6-membered heteroaryl. In certain preferred embodiments, R2is 6-membered heteroaryl.

[0118] In some embodiments, R2is pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl. In certain preferred embodiments, R2is pyridyl (e.g., 3- pyridyl).

[0119] In some embodiments, R2is optionally substituted with amino (e.g., -NH2, morpholinyl, or piperazinyl) or alkyl (e.g., Ci-Ce alkyl). In some embodiments, R2is optionally substituted with NH2 or G-G> alkyl. In some embodiments, R2is optionally substituted with NH2 or methyl. In some embodiments, R2is optionally substituted with NH2. In some embodiments, R2is optionally substituted with methyl. In some embodiments, R2is optionally substituted with NH2, morpholinyl, piperazinyl, or Ci-G, alkyl. In some embodiments, R2is optionally substituted with morpholinyl. In some embodiments, R2is optionally substituted with piperazinyl.

[0120] In some embodiments, R2is substituted with amino or alkyl. In some embodiments, R2is substituted with NH2 or G-G> alkyl. In some embodiments, R2is substituted with NH2 or methyl. In some embodiments, R2is substituted with NH2. In some embodiments, R2is substituted with G-G> alkyl (e.g., methyl).

[0121] In some embodiments, R2is 3- to 8-membered heteroaryl optionally substituted with amino or alkyl. In some embodiments, R2is 3- to 8-membered heteroaryl optionally substituted with NH2, morpholinyl, piperazinyl, or Ci-Ce alkyl. In some embodiments, R2is 3- to 8-membered heteroaryl optionally substituted with NH2 or G-G, alkyl. In some embodiments, R2is 3- to 8-membered heteroaryl optionally substituted with NH2, morpholinyl, piperazinyl, or methyl. In some embodiments, R2is 3- to 8-membered heteroaryl optionally substituted with NH2 or methyl. In some embodiments, R2is 3- to 8-membered heteroaryl optionally substituted with morpholinyl or piperazinyl. In some embodiments, R2is 3- to 8- membered heteroaryl optionally substituted with NH2. In some embodiments, R2is 3- to 8- membered heteroaryl optionally substituted with morpholinyl. In some embodiments, R2is 3- to 8-membered heteroaryl optionally substituted with piperazinyl. In some embodiments, R2is 3- to 8-membered heteroaryl optionally substituted with methyl.

[0122] In some embodiments, R2is 3- to 8-membered heteroaryl substituted with amino or alkyl. In some embodiments, R2is 3- to 8-membered heteroaryl substituted with NH2 or Ci- Ce alkyl. In some embodiments, R2is 3- to 8-membered heteroaryl substituted with NH2 or methyl. In some embodiments, R2is 3- to 8-membered heteroaryl substituted with NH2. In some embodiments, R2is 3- to 8-membered heteroaryl substituted with methyl.

[0123] In some embodiments, R2is 5- to 6-membered heteroaryl optionally substituted with amino or alkyl. In some embodiments, R2is 5- to 6-membered heteroaryl optionally substituted with NH2, morpholinyl, piperazinyl, or Ci-Ce alkyl. In some embodiments, R2is 5- to 6-membered heteroaryl optionally substituted with NH2 or Ci-Ce alkyl. In some embodiments, R2is 5- to 6-membered heteroaryl optionally substituted with NH2, morpholinyl, piperazinyl, or methyl. In some embodiments, R2is 5- to 6-membered heteroaryl optionally substituted with NH2 or methyl. In some embodiments, R2is 5- to 6-membered heteroaryl optionally substituted with morpholinyl or piperazinyl. In some embodiments, R2is 5- to 6- membered heteroaryl optionally substituted with NH2. In some embodiments, R2is 5- to 6- membered heteroaryl optionally substituted with morpholinyl. In some embodiments, R2is 5- to 6-membered heteroaryl optionally substituted with piperazinyl. In some embodiments, R2is 5- to 6-membered heteroaryl optionally substituted with methyl.

[0124] In some embodiments, R2is 5- to 6-membered heteroaryl substituted with amino or alkyl. In some embodiments, R2is 5- to 6-membered heteroaryl substituted with NH2, morpholinyl, piperazinyl, or Ci-Ce alkyl. In some embodiments, R2is 5- to 6-membered heteroaryl substituted with NH2, morpholinyl, piperazinyl, or methyl. In some embodiments, R2is 5- to 6-membered heteroaryl substituted with NH2 or methyl. In some embodiments, R2is 5- to 6-membered heteroaryl substituted with morpholinyl or piperazinyl. In some embodiments, R2is 5- to 6-membered heteroaryl substituted with NH2. In some embodiments, R2is 5- to 6-membered heteroaryl substituted with morpholinyl. In some embodiments, R2is 5- to 6-membered heteroaryl substituted with piperazinyl. In some embodiments, R2is 5- to 6- membered heteroaryl substituted with methyl.

[0125] In some embodiments, R2is unsubstituted 3- to 8-membered heteroaryl. In some embodiments, R2is unsubstituted 5- to 6-membered heteroaryl. In certain preferred embodiments, R2is unsubstituted 6-membered heteroaryl.

[0126] In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with amino or alkyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with NH2, morpholinyl, piperazinyl, or Ci-Ce alkyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with NH2 or C1-C6 alkyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with NH2, morpholinyl, piperazinyl, or methyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with NH2 or methyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with morpholinyl or piperazinyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with NH2. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with morpholinyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with piperazinyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with methyl.

[0127] In some embodiments, R2is pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with amino or alkyl. In some embodiments, R2is pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with NH2 or Ci-Ce alkyl. In some embodiments, R2is pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with NH2 or methyl. In some embodiments, R2is pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with NH2. In some embodiments, R2is pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl optionally substituted with methyl.

[0128] In some embodiments, R2is pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl substituted with amino or alkyl. In some embodiments, R2is pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl substituted with NH2 or Ci-Ce alkyl. In some embodiments, R2is pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl substituted with NH2 or methyl. In some embodiments, R2is pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl substituted with NH2. In some embodiments, R2is pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl substituted with methyl.

[0129] In some embodiments, R2is unsubstituted pyridyl, unsubstituted pyridone, unsubstituted pyrimidinyl, unsubstituted pyridazinyl, unsubstituted pyrazolyl, unsubstituted imidazolyl, or unsubstituted oxazolyl. In some embodiments, R2is unsubstituted pyridyl, unsubstituted pyrimidinyl, unsubstituted pyridazinyl, unsubstituted pyrazolyl, unsubstituted imidazolyl, or unsubstituted oxazolyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, or pyridazinyl optionally substituted with amino or alkyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, or pyridazinyl optionally substituted with NH2, morpholinyl, piperazinyl, or Ci-Ce alkyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, or pyridazinyl optionally substituted with NH2 or Ci-Ce alkyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, or pyridazinyl optionally substituted with morpholinyl or piperazinyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, or pyridazinyl optionally substituted with NH2 or methyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, or pyridazinyl optionally substituted with NH2. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, or pyridazinyl optionally substituted with morpholinyl. In some embodiments, R2is pyridyl, pyridone, pyrimidinyl, or pyridazinyl optionally substituted with piperazinyl.

[0130] In some embodiments, R2is pyridyl, pyrimidinyl, or pyridazinyl optionally substituted with amino or alkyl. In some embodiments, R2is pyridyl, pyrimidinyl, or pyridazinyl optionally substituted with NH2 or Ci-Ce alkyl. In some embodiments, R2is pyridyl, pyrimidinyl, or pyridazinyl optionally substituted with NH2 or methyl. In some embodiments, R2is pyridyl, pyrimidinyl, or pyridazinyl optionally substituted with NH2.

[0131] In some embodiments, R2is pyridyl, pyrimidinyl, or pyridazinyl substituted with amino or alkyl. In some embodiments, R2is pyridyl, pyrimidinyl, or pyridazinyl substituted with NH2 or Ci-C<> alkyl. In some embodiments, R2is pyridyl, pyrimidinyl, or pyridazinyl substituted with NH2 or methyl. In some embodiments, R2is pyridyl, pyrimidinyl, or pyridazinyl substituted with NH2.

[0132] In some embodiments, R2is unsubstituted pyridyl, unsubstituted pyridone, unsubstituted pyrimidinyl, or unsubstituted pyridazinyl. In some embodiments, R2is unsubstituted pyridyl, or unsubstituted pyridone. In some embodiments, R2is unsubstituted pyridyl, unsubstituted pyrimidinyl, or unsubstituted pyridazinyl. In some embodiments, R2is unsubstituted pyridyl (e.g., unsubstituted 3-pyridyl). In some embodiments, R2is unsubstituted pyrimidinyl. In some embodiments, R2is unsubstituted pyridazinyl. In some embodiments, R2is unsubstituted pyridone.

[0133] In some embodiments, R2is pyrazolyl, imidazolyl, or oxazolyl optionally substituted with amino or alkyl. In some embodiments, R2is pyrazolyl, imidazolyl, or oxazolyl optionally substituted with NH2 or Ci-C alkyl. In some embodiments, R2is pyrazolyl, imidazolyl, or oxazolyl optionally substituted with NH2 or methyl. In some embodiments, R2is pyrazolyl, imidazolyl, or oxazolyl optionally substituted with NH2. hi some embodiments, R2is pyrazolyl, imidazolyl, or oxazolyl substituted with amino or alkyl. In some embodiments, R2is pyrazolyl, imidazolyl, or oxazolyl substituted with NH2 or Ci-Ce alkyl. In some embodiments, R2is pyrazolyl, imidazolyl, or oxazolyl substituted with NH2 or methyl. In some embodiments, R2is pyrazolyl, imidazolyl, or oxazolyl substituted with NH2.

[0134] In some embodiments, R2is unsubstituted pyrazolyl, imidazolyl, or oxazolyl. In some embodiments, R2is unsubstituted pyrazolyl. In some embodiments, R2is unsubstituted imidazolyl. In some embodiments, R2is unsubstituted oxazolyl.

[0135] In some embodiments, R2is pyridyl optionally substituted with amino or alkyl. In some embodiments, R2is pyridyl optionally substituted with NH2, morpholinyl, piperazinyl, or Ci- Ce alkyl. In some embodiments, R2is pyridyl optionally substituted with NH2 or methyl. In some embodiments, R2is pyridyl optionally substituted with NH2, morpholinyl, piperazinyl. In some embodiments, R2is pyridyl substituted with NH2. In some embodiments, R2is pyridyl optionally substituted with morpholinyl. In some embodiments, R2is pyridyl optionally substituted with piperazinyl.

[0136] In some embodiments, R2is pyridyl substituted with amino or alkyl. In some embodiments, R2is pyridyl substituted with NH2, morpholinyl, piperazinyl, or Ci-Ce alkyl. In some embodiments, R2is pyridyl substituted with NH2 or methyl. In some embodiments, R2is pyridyl substituted with NH2, morpholinyl, piperazinyl. In some embodiments, R2is pyridyl substituted with NH2. In some embodiments, R2is pyridyl substituted with morpholinyl. In some embodiments, R2is pyridyl substituted with piperazinyl.

[0137] In some embodiments, R2is pyrimidinyl optionally substituted with amino or alkyl. In some embodiments, R2is pyrimidinyl optionally substituted with NH2 or Ci-Ce alkyl. In some embodiments, R2is pyrimidinyl optionally substituted with NH2 or methyl. In some embodiments, R2is pyrimidinyl optionally substituted with NH2.

[0138] In some embodiments, R2is pyrimidinyl substituted with amino or alkyl. In some embodiments, R2is pyrimidinyl substituted with NH2 or Ci-G, alkyl. In some embodiments, R2is pyrimidinyl substituted with NH2 or methyl. In some embodiments, R2is pyrimidinyl substituted with NH2.

[0139] In some embodiments, R2is imidazolyl optionally substituted with amino or alkyl. In some embodiments, R2is imidazolyl optionally substituted with NH2 or Ci-G, alkyl. In some embodiments, R2is imidazolyl optionally substituted with NH2 or methyl. In some embodiments, R2is imidazolyl optionally substituted with methyl.

[0140] In some embodiments, R2is imidazolyl substituted with amino or alkyl. In some embodiments, R2is imidazolyl substituted with NH2 or Ci-G, alkyl. In some embodiments, R2is imidazolyl substituted with NH2 or methyl. In some embodiments, R2is imidazolyl substituted with methyl. In some embodiments, R2is pyrazolyl optionally substituted with amino or alkyl. In some embodiments, R2is pyrazolyl optionally substituted with NH2 or Ci-Ce alkyl. In some embodiments, R2is pyrazolyl optionally substituted with NH2 or methyl. In some embodiments, R2is pyrazolyl optionally substituted with methyl. In some embodiments, R2is pyrazolyl substituted with amino or alkyl. In some embodiments, R2is pyrazolyl substituted with NH2 or Ci-Ce alkyl. In some embodiments, R2is pyrazolyl substituted with NH2 or methyl. In some embodiments, R2is pyrazolyl substituted with methyl.

[0141] In some embodiments, R2is selected from

[0142] In some embodiments, R2is selected from ,

[0143] ■r, ,s’ , ,5, arid5

[0144] In some embodiments, R2is selected from In some embodiments, R2is selected from

[0145] In some embodiments, R2is selected from

[0146] In some embodiments, R2is selected from

[0147] Tn some embodiments, R3is heterocyclyl, cycloalkyl, heteroaryl, or aryl. Tn some embodiments, R3is 3- to 8-membered heterocyclyl, C i-C« cycloalkyl, 3- to 8-membered heteroaryl, or Ce-Cio aryl. In some embodiments, R3is heterocyclyl, heteroaryl, or aryl. In some embodiments, R3is 3- to 8-membered heterocyclyl, 3- to 8-membered heteroaryl, or Ce- Cw aryl. In some embodiments, R3is heteroaryl or aryl. In some embodiments, R3is 3- to 8- membered heteroaryl or Ce-Cio aryl. In certain preferred embodiments, R3is aryl (e.g., phenyl).

[0148] In some embodiments, R3is heterocyclyl, cycloalkyl, heteroaryl, or aryl wherein each hydrogen atom in heterocyclyl, cycloalkyl, heteroaryl, or aryl is optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R3is heterocyclyl, heteroaryl, or aryl wherein each hydrogen atom in heterocyclyl, heteroaryl, or aryl is optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl.

[0149] In some embodiments, R3is heterocyclyl. In some embodiments, R3is 3- to 8- membered heterocyclyl. In some embodiments, R3is 3- to 8-membered heterocyclyl. In some embodiments, R3is 3- to 8-membered heterocyclyl, wherein each hydrogen atom in 3- to 8- membered heterocyclyl is optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R3is 6-membered heterocyclyl. In some embodiments, R3is 6- membered heterocyclyl, wherein each hydrogen atom in 6-membered heterocyclyl is optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R3is tetrahydropyranyl, dihydropyranyl, piperidinyl, or tetrahydropyridinyl. In some embodiments, R3is tetrahydropyranyl, dihydropyranyl, piperidinyl, or tetrahydropyridinyl, wherein each hydrogen atom in tetrahydropyranyl, dihydropyranyl, piperidinyl, or tetrahydropyridinyl is optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R3is tetrahydropyranyl, dihydropyranyl, piperidinyl, or tetrahydropyridinyl, wherein each hydrogen atom in tetrahydropyranyl, dihydropyranyl, piperidinyl, or tetrahydropyridinyl is optionally substituted by alkyl. In some embodiments, R3is tetrahydropyranyl, dihydropyranyl, piperidinyl, or tetrahydropyridinyl, wherein each hydrogen atom in tetrahydropyranyl, dihydropyranyl, piperidinyl, or tetrahydropyridinyl is optionally substituted by Ci-Ce alkyl. In some embodiments, R3is tetrahydropyranyl, dihydropyranyl, piperidinyl, or tetrahydropyridinyl, wherein each hydrogen atom in cyclohexyl is optionally substituted by methyl. In some embodiments, R3is N- methylpiperidinyl, or N-methyltetrahydropyridinyl. In some embodiments, R is unsubstituted tetrahydropyranyl, dihydropyranyl, piperidinyl, or tetrahydropyridinyl.

[0150] In some embodiments, R3is cycloalkyl. In some embodiments, R3is Ce-Cio cycloalkyl. In some embodiments, R3is cyclohexyl. In some embodiments, R3is cyclohexyl, wherein each hydrogen atom in cyclohexyl is optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R3is cyclohexyl, wherein one or two hydrogen atoms in cyclohexyl is optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R3is cyclohexyl, wherein each hydrogen atom in cyclohexyl is optionally substituted by halo. In some embodiments, R3is cyclohexyl, wherein one or two hydrogen atoms in cyclohexyl is optionally substituted by halo. In some embodiments, R is cyclohexyl, wherein each hydrogen atom in cyclohexyl is optionally substituted by chloro, bromo, iodo, or fluoro. In some embodiments, R3is cyclohexyl, wherein each hydrogen atom in cyclohexyl is optionally substituted by fluoro. In some embodiments, R3is 4, 4-difluoro- cyclohexyl. In some embodiments, R3is unsubstituted cyclohexyl.

[0151] In some embodiments, R3is heteroaryl. In some embodiments, R3is 3- to 8-membered heteroaryl. In some embodiments, R3is 5- or 6-membered heteroaryl. In some embodiments, R3is 5- or 6-membered heteroaryl, wherein each hydrogen atom in 5- or 6-membered heteroaryl is optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R3is thienyl. In some embodiments, R3is thienyl, wherein each hydrogen atom in thienyl is optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R3is thienyl, wherein each hydrogen atom in thienyl is optionally substituted by halo. In some embodiments, R3is thienyl, wherein each hydrogen atom in thienyl is optionally substituted by chloro, bromo, iodo, or fluoro. In some embodiments, R3is thienyl, wherein each hydrogen atom in thienyl is optionally substituted by chloro. In some embodiments, R3is 2-chloro-thienyl. In some embodiments, R3is unsubstituted thienyl.

[0152] In some embodiments, R3is aryl. In some embodiments, R3is Ce-Cio aryl. In some embodiments, R3is Ce-Cio aryl, wherein each hydrogen atom in Ce-Cio aryl is optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R3is phenyl. In some embodiments, R3is phenyl, wherein each hydrogen atom in phenyl is optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R3is phenyl, wherein one hydrogen atom in phenyl is optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R3is phenyl, wherein the hydrogen atom at the 3- position of phenyl is substituted by halo (e.g., chloro), cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R3is unsubstituted phenyl. In certain preferred embodiments, R3is phenyl, wherein the hydrogen atom at the 3-position of phenyl is substituted by halo (e.g., chloro) or nitro. In certain preferred embodiments, R is 3 -chlorophenyl or 3 -nitrophenyl. In certain preferred embodiments, R3is 3 -chlorophenyl.

[0153] In some embodiments, R3is selected from

[0154] In some embodiments, R3is selected from

[0155] In some embodiments, R3is selected from

[0156] In some embodiments, R4is halo, cyano, sulfone, nitro, ketone, or alkyl. In some embodiments, R4is halo, cyano, sulfone, nitro, or ketone. In some embodiments, R4is chloro, CN, SChMe, NO2, or C(0)Me. In certain preferred embodiments, R4is halo (e.g., chloro).

[0157] In some embodiments, each of X1and X3is independently CH or N. In some embodiments, X1is CH or N. In some embodiments, X3is CH or N. In some embodiments, X1is CH. In some embodiments, X1is N. In some embodiments, X3is CH. In some embodiments, X3is N. In some embodiments, X2is CH when X1is N. In some embodiments, X3is N. In some embodiments, X2is C-R5. In some embodiments, X2is CH or C-NH2. In some embodiments, X2is CH. In some embodiments, X2is C-NH2. In some embodiments, X2is CH when X1is N. In some embodiments, X1is CH when X3is N. In some embodiments, X2and X3are CH when X1is N. In some embodiments, each of X1and X3are CH, and X2is C-R5. In some embodiments, each of X1and X3are CH, and X2is CH or C-NH2. In some embodiments, each of X1and X3are CH, and X2is C-NH2. In some embodiments, each of X1, X2, and X3are

[0158] CH.

[0159] In some embodiments, Rsis H or amino (e.g., -NH2, morpholinyl, or piperazinyl). In certain preferred embodiments, R5is H. In some embodiments, R5is amino.

[0160] In some embodiments, R2is pyridyl when R1is H. In some embodiments, R2is pyridyl when R3is heterocyclyl or cycloalkyl. In some embodiments, R3is phenyl or thienyl when R1is H.

[0161] In some embodiments, R1is amino (e.g., NH2) and R2is heteroaryl (e.g., pyridyl, such as 3-pyridyl). In some embodiments, R1is amino (e.g., NH2) and R3is aryl (e.g., phenyl, such as 3-chlorophenyl). In some embodiments, R2is heteroaryl (e.g., pyridyl, such as 3-pyridyl) and R is aryl (e.g., phenyl, such as 3-chlorophenyl).

[0162] In some embodiments, the disclosure relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof, wherein R1is amino (e.g., NH2), R2is heteroaryl (e.g., pyridyl, such as 3-pyridyl), and R3is aryl (e.g., phenyl, such as 3-chlorophenyl).

[0163] In some embodiments, the compound is selected from: or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the compound is selected from:

[0165] or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the compound is selected from:

[0167]

[0168] 5 or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the compound is selected from: or a pharmaceutically acceptable salt thereof.

[0170] The following represent illustrative embodiments of compounds of Formula (I):

[0171] and pharmaceutically acceptable salts thereof.

[0172] In some embodiments, the compound of the present disclosure is a pharmaceutically acceptable salt (e.g., an HC1 salt of a compound of formula I). Those skilled in the art will recognize that the species listed or illustrated herein are not exhaustive, and that additional species within the scope of these defined terms may also be selected.

[0173] PHARMACEUTICAL COMPOSITIONS

[0174] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the disclosure and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0175] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the disclosure. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the disclosure. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0176] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0177] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxy methyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; ( 14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0178] A pharmaceutical composition (or preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[0179] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0180] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the disclosure, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Formulations of the disclosure suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0181] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0182] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactive or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0183] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may he sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0184] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0185] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0186] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0187] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0188] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0189] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0190] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present disclosure to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0191] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0192] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0193] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0194] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0195] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0196] For use in the methods of this disclosure, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0197] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0198] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0199] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0200] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with a compound of the disclosure. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0201] In general, a suitable daily dose of an active compound used in the compositions and methods of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0202] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present disclosure, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0203] The patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.

[0204] In certain embodiments, compounds of the disclosure may be used alone or conjointly administered with another type of therapeutic agent.

[0205] The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the disclosure in the compositions and methods of the present disclosure. In certain embodiments, contemplated salts of the disclosure include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the disclosure include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. Tn certain embodiments, contemplated salts of the disclosure include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the disclosure include, but are not limited to, 1 -hydroxy -2-naphthoic acid, 2,2-dichloroacetic acid, 2- hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4- acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1 -ascorbic acid, 1 -aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptonic acid, d-gluconic acid, d- glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, 1 -malic acid, malonic acid, mandelic acid, methanesulfonic acid , naphthalene- 1,5 -disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, 1 -pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, 1 -tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid salts.

[0206] The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0207] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: (1) water- soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. In certain embodiments, the present invention provides pharmaceutical compositions comprising a compound described herein, such as a compound of Formula I-IV. In certain embodiments, the pharmaceutical compositions further comprise a pharmaceutically acceptable excipient.

[0208] In certain embodiments, the pharmaceutical compositions may be for use in treating or preventing a condition or disease as described herein.

[0209] The compounds described herein are useful, for example, as therapeutics for the treatment of diseases. In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the disclosure and a pharmaceutically acceptable excipient.

[0210] In certain aspects, the present disclosure provides a method of treating a disease in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound or composition of the disclosure.

[0211] In certain aspects, the present disclosure provides a method of treating an inflammatory disease in a patient, comprising administering to a patient in need thereof a compound or composition of the disclosure. In certain aspects, the present disclosure provides methods of treating atopic dermatitis or inflammatory bowel disorders in a patient, comprising administering to a patient in need thereof a compound or composition of the disclosure.

[0212] In certain aspects, the present disclosure provides a method of treating a central nervous system disorder in a patient, comprising administering to a patient in need thereof a compound or composition of the disclosure. In certain aspects, the present disclosure provides methods of treating epilepsy, stroke, Alzheimer’s disease, schizophrenia, depression, multiple sclerosis, traumatic brain injury, Huntington’s disease, or neurodevelopmental disorders in a patient, comprising administering to a patient in need thereof a compound or composition of the disclosure. In certain aspects, the present disclosure provides a method of treating a neurodevelopmental disorder (e.g., epilepsy, autism, attention deficit disorder (ADD), or attention deficit hyperactivity disorder (ADHD)), an acute neurological disorder (e.g., stroke or traumatic brain injury), a neurodegenerative disorder (e.g., Alzheimer’s disease, dementia, multiple sclerosis, or Huntington’s disease), or a psychological / mental disorder (e.g., schizophrenia, depression, anxiety (e.g., generalized anxiety disorder or social anxiety), bipolar disorder, addiction, or obsessive compulsive disorder (OCD)) in a patient, comprising administering to a patient in need thereof a compound or composition of the disclosure.

[0213] In certain aspects, the present disclosure provides methods of treating pulmonary, dermatological, and neurological inflammatory disease in a patient, comprising administering to a patient in need thereof a compound or composition of the disclosure. In certain aspects, the present disclosure provides methods of treating asthma, chronic obstructive pulmonary disease (COPD), psoriasis and rheumatoid arthritis in a patient, comprising administering to a patient in need thereof a compound or composition of the disclosure.

[0214] In certain aspects, the present disclosure provides methods of improving cognition in a patient, comprising administering to a patient in need thereof a compound or composition of the disclosure. In certain aspects, the present disclosure provides methods of treating a cognitive and affective disorders in a patient, comprising administering to a patient in need thereof a compound or composition of the disclosure. In certain aspects, the present disclosure provides methods of treating a learning disorder, memory loss, or fragile x syndrome in a patient, comprising administering to a patient in need thereof a compound or composition of the disclosure.

[0215] In certain aspects, the present disclosure provides a method increasing longevity in a patient. In certain aspects, the present disclosure provides a method of treating a disease in a patient, thereby increasing longevity in the patient. In certain aspects, the present disclosure provides a method of increasing longevity in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound or composition of the disclosure.

[0216] In certain aspects, the compounds and pharmaceutical compositions of the disclosure specifically target a phosphodiesterase (PDE) enzyme, in particular a PDE4 isoform. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of PDE4. In preferred embodiments, methods of treating a target inflammatory disease are described.

[0217] In certain aspects, the present disclosure provides a method of treating an inflammatory disease. In certain aspects, the present disclosure provides methods of treating pulmonary, dermatological, and neurological inflammatory disease. In certain aspects, the present disclosure provides methods of treating asthma, chronic obstructive pulmonary disease (COPD), psoriasis and rheumatoid arthritis. In certain aspects, the present disclosure provides methods of treating atopic dermatitis or inflammatory bowel disorders.

[0218] In certain aspects, the present disclosure provides a method of treating a central nervous system disorder. In certain aspects, the present disclosure provides methods of treating epilepsy, stroke, Alzheimer’s disease, schizophrenia, depression, multiple sclerosis, traumatic brain injury, Huntington’s disease, or neurodevelopmental disorders. In certain aspects, the present disclosure provides a method of treating a neurodevelopmental disorder (e.g., epilepsy, autism, attention deficit disorder (ADD), or attention deficit hyperactivity disorder (ADHD)), an acute neurological disorder (e.g., stroke or traumatic brain injury), a neurodegenerative disorder (e.g., Alzheimer’s disease, dementia, multiple sclerosis, or Huntington’s disease), or a psychological / mental disorder (e.g., schizophrenia, depression, anxiety (e.g., generalized anxiety disorder or social anxiety), bipolar disorder, addiction, or obsessive compulsive disorder (OCD)).

[0219] Tn certain aspects, the present disclosure provides methods of inhibiting a phosphodiesterase (PDE) enzyme, in particular a PDE4 isoform. In certain aspects, the present disclosure provides methods of inhibiting PDE4 and elevating cyclic adenosine monophosposphate (cAMP). In certain aspects, the present disclosure provides methods of inhibiting the hydrolysis of cAMP by inhibiting PDE, such as PDE4.

[0220] In certain aspects, the present disclosure provides methods of treating cancer. In certain embodiments, the cancer is a solid tumor. In certain aspects, the present disclosure provides methods of treating esophageal cancer, brain cancer, pancreatic cancer, colon cancer, hematologic cancer, lung cancer, prostate cancer, skin cancer, head and neck cancer, CNS cancer, gastric cancer, breast cancer, bladder cancer, or ovarian cancer. In certain aspects, the present disclosure provides methods of inhibiting tumor growth and metastases.

[0221] In certain aspects, the present disclosure provides methods of improving cognition. In certain aspects, the present disclosure provides methods of treating cognitive and affective disorders. In certain aspects, the present disclosure provides methods of treating a learning disorder, memory loss, and fragile x syndrome.

[0222] In certain aspects, the compounds of the present disclosure are for use in treating inflammatory diseases, such as pulmonary, dermatological, and neurological inflammatory diseases. In certain aspects, the compounds of the present disclosure are for use in treating asthma, chronic obstructive pulmonary disease (COPD), psoriasis and rheumatoid arthritis. In certain aspects, the compounds of the present disclosure are for use in treating atopic dermatitis or inflammatory bowel disorders.

[0223] In certain aspects, the compounds of the present disclosure are for use in treating a central nervous system disorder. In certain aspects, the compounds of the present disclosure are for use in treating epilepsy, stroke, Alzheimer’s disease, schizophrenia, depression, multiple sclerosis, traumatic brain injury, Huntington’s disease, or neurodevelopmental disorders. In certain aspects, the compounds of the present disclosure are for use in treating a neurodevelopmental disorder (e.g., epilepsy, autism, attention deficit disorder (ADD), or attention deficit hyperactivity disorder (ADHD)), an acute neurological disorder (e.g., stroke or traumatic brain injury), a neurodegenerative disorder (e.g., Alzheimer’s disease, dementia, multiple sclerosis, or Huntington’s disease), or a psychological / mental disorder (e.g., schizophrenia, depression, anxiety (e.g., generalized anxiety disorder or social anxiety), bipolar disorder, addiction, or obsessive compulsive disorder (OCD)).

[0224] In certain aspects, the present disclosure provides methods of reducing seizure frequency, such as in epilepsy. In certain aspects, the present disclosure provides methods of treating epilepsy, thereby reducing seizure frequency. In certain aspects, the present disclosure provides methods of reducing seizure frequency, such as in epilepsy, wherein the methods further provide a reduction in behavioral side effects and / or cognitive impairments, including but not limited to aggression, irritability, brain fog, memory complications, and language complications.

[0225] In certain aspects, the compounds of the present disclosure are for use in treating an inflammatory disease in a patient. In certain aspects, the compounds of the present disclosure are for use in treating pulmonary, dermatological, and neurological inflammatory disease. In certain aspects, the compounds of the present disclosure are for use in treating asthma, chronic obstructive pulmonary disease (COPD), psoriasis and rheumatoid arthritis in a patient. In certain aspects, the compounds of the present disclosure are for use in treating atopic dermatitis or inflammatory bowel disorders in a patient.

[0226] In certain aspects, the compounds of the present disclosure are for use in inhibiting PDE4. In certain aspects, the compounds of the present disclosure are for use in inhibiting PDE4 and elevating cyclic adenosine monophosposphate (cAMP). In certain aspects, the compounds of the present disclosure are for use in inhibiting the hydrolysis of cAMP by inhibiting PDE, such as PDE4.

[0227] In certain aspects, the compounds of the present disclosure are for use in increasing longevity. In certain aspects, the compounds of the present disclosure are for use in treating a disease (e.g., epilepsy), thereby increasing longevity. In certain aspects, the compounds of the present disclosure are for use in treating a disease (e.g., epilepsy), thereby improving cognition.

[0228] In certain aspects, the compounds of the present disclosure are for use in treating cancer. In certain aspects, the compounds of the present disclosure are for use in treating esophageal cancer, brain cancer, pancreatic cancer and colon cancer. In certain aspects, the compounds of the present disclosure are for use in inhibiting tumor growth and metastases.

[0229] In certain aspects, the compounds of the present disclosure are for use in improving cognition. In certain aspects, the compounds of the present disclosure are for use in treating cognitive and affective disorders. In certain aspects, the compounds of the present disclosure are for use in treating learning disorders, memory loss, and fragile x syndrome. In certain aspects, the compounds of the present disclosure are for use in improving cognition in a nondisease model. In certain aspects, the present disclosure provides a method of treating a mammal suffering from an inflammatory disease. In certain aspects, the present disclosure provides methods of treating a mammal suffering from pulmonary, dermatological, and neurological inflammatory disease. In certain aspects, the present disclosure provides methods of treating a mammal suffering from asthma, chronic obstructive pulmonary disease (COPD), psoriasis and rheumatoid arthritis. In certain aspects, the present disclosure provides a method of treating a mammal suffering from atopic dermatitis or inflammatory bowel disorders.

[0230] In certain aspects, the present disclosure provides a method of treating a mammal suffering from a central nervous system disorder. In certain aspects, the present disclosure provides a method of treating a mammal suffering from epilepsy, stroke, Alzheimer’ s disease, schizophrenia, depression, multiple sclerosis, traumatic brain injury, Huntington’s disease, or neurodevelopmental disorders. In certain aspects, the present disclosure provides a method of treating a mammal suffering from epilepsy, thereby reducing frequency of seizures. In certain aspects, the present disclosure provides a method of treating a mammal suffering from a neurodevelopmental disorder (e.g., epilepsy, autism, attention deficit disorder (ADD), or attention deficit hyperactivity disorder (ADHD)), an acute neurological disorder (e.g., stroke or traumatic brain injury), a neurodegenerative disorder (e.g., Alzheimer’s disease, dementia, multiple sclerosis, or Huntington’s disease), or a psychological / mental disorder (e.g., schizophrenia, depression, anxiety (e.g., generalized anxiety disorder or social anxiety), bipolar disorder, addiction, or obsessive compulsive disorder (OCD)).

[0231] In certain aspects, the present disclosure provides a method of treating a mammal suffering from a cognitive or affective disorder. In certain aspects, the present disclosure provides a method of treating a mammal suffering from learning disorder, memory loss, and fragile x syndrome. In certain aspects, the present disclosure provides a method of improving cognition in a non-disease model.

[0232] In certain aspects, the present disclosure provides methods of treating a mammal suffering from cancer. In certain aspects, the present disclosure provides methods of treating a mammal suffering from esophageal cancer, brain cancer, pancreatic cancer and colon cancer.

[0233] In certain embodiments, compounds of the disclosure are prodrugs of the compounds described herein. For example, wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or a carboxylic acid present in the parent compound is presented as an ester. In certain such embodiments, the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl or carboxylic acid).

[0234] In certain embodiments, compounds of the disclosure may be racemic. In certain embodiments, compounds of the disclosure may be enriched in one enantiomer. For example, a compound of the disclosure may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee. In certain embodiments, compounds of the disclosure may have more than one stereocenter. In certain such embodiments, compounds of the disclosure may be enriched in one or more diastereomers. For example, a compound of the disclosure may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.

[0235] CHEMICAL SYNTHESIS METHODS

[0236] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula I, II, III, and IV.

[0237] Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:

[0238] The proposed targets can be prepared via the conventional chemistry or following the general schemes as shown below.

[0239] Synthesis of benzothiazole PDE4 inhibitors

[0240] Reagents were purchased as at least reagent grade from Aldrich, Acros, Alfa Aesar or other vendors and used without further purification. Compounds were synthesized according to general methods described below, and purity determined using HPLC.

[0241] Compound synthesis was carried out using Hugerschoff ’ s reaction to synthesize the benzothiazole heterocycle, amide coupling introduced the R2 substituent and Suzuki cross coupling introduced the Ri substituent.

[0242] Scheme 1. A representative synthesis of benzothiazole compounds of the disclosure. a. KSCN (4eq) / Br2(leq), AcOH, RT 20 h (96%); b. NBS (1.5eq), THF, RT, 20 h (90%); c. DMAP (1.2eq), di-tert-butyl decarbonate (1.5eq), DCM, RT, 20 h. d. LiOH (4eq), MeOH / water, 60°C, 20 h ( 95%); e. 3-amino pyridine (1.2eq), EDC.HC1 (1.2eq), DMAP (0.8eq), THF, 20 h (67%); f. 3- substituted boronic acid (1.2eq), Cesium carbonate (1.5eq), Bis(triphenylphosphine)palladium (II) dichloride (0.15eq), Dioxane,

[0243] EtOH-H2O (1 :1) (50-70%); g. 4M HCl / Dioxane; h. t-butyl nitrite, tetrahydrofuran

[0244] (THF), 60 °C 16 h, (15-32%); i. 4M HCl / Dioxane, ethyl acetate, (90%).

[0245] Table 1. Benzothiazole analogues of the disclosure.

[0246] Table 2. Synthesized benzothiazole analogues of the disclosure.

[0247]

[0248] Intermediate Synthesis

[0249] Preparation of tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl) benzothiazol-2-yl) carbamate (1-5)

[0250] Step 1: Ethyl 2-aminobenzothiazole-6-carboxylate

[0251] Ethyl 4- aminobenzoate (50 mmol, 8.25 g) was dissolved in acetic acid (200 ml).

[0252] Potassium thiocyanate (KSCN) (200 mmol, 19.43 g) was added to the mixture. Bromine (B ) (50 mmol, 2.56 ml) was added to the mixture slowly for 30 min. Then reaction mixture was stirred at RT for 20 h. Then the reaction mixture was poured into ice cold water and basified to pH 8 using ammonium hydroxide (NH4OH). Then precipitate was extracted with ethyl acetate and water. The organic layer was separated, dried, and evaporated to get product Ethyl 2-aminobenzothiazole-6-carboxylate as light-yellow solid (10.78g, 97% yield). TLC (SiOz, EtOAc / Hexane 1 :1) Rf = 0.38;' H NMR (500 MHz, DMSO) 5 8.29 (d, J= 1.8 Hz, 1H), 7.92 (s, 2H), 7.82 (dd, 7 = 8.5, 1.8 Hz, 1H), 7.38 (d, 7 = 8.5 Hz, 1H), 4.29 (q, 7 = 7.1 Hz, 2H), 1.31 (t, 7 = 7.1 Hz, 3H).13C NMR (125 MHz, DMSO) 5 170.21, 166.11, 157.32, 131.60, 127.52, 122.96, 122.45, 117.53, 60.82, 14.72.

[0253] Step 2: Ethyl 2-amino-4-bromobenzothiazole-6-carboxylate (1-2)

[0254] Ethyl 2-aminobenzothiazole-6-carboxylate (20 mmol, 4.45 g) dissolved in acetic acid (100 ml). Bromine (Brz) (40 mmol, 2.05 ml) in 20 ml acetic acid was added to the mixture slowly for 30 min. Then reaction mixture was stirred at 80 °C for 20 h. Then reaction mixture was poured into ice cold water and basified to pH 8 using ammonium hydroxide (NH4OH). Then precipitate was extracted with ethyl acetate and water. Organic layer was separated, dried, and evaporated to get product Ethyl 2-amino-4-bromobenzothiazole-6-carboxylate as light orange solid (5.06 g, 84% yield). TLC (SiOz, EtOAc / Hexane 1: 1) Rf = 0.58;!H NMR (500 MHz, DMSO) 5 8.30 (d, 7 = 1.6 Hz, 1H), 7.95 (d, 7 = 1.6 Hz, 1H), 7.51 (s, 2H), 4.29 (q, 7 = 7.1 Hz, 2H), 1.31 (t, 7 = 7.1 Hz, 3H).13C NMR (125 MHz, DMSO) 5 170.73, 164.97, 154.01 , 131.54, 130.09, 123.76, 122.51, 109.64, 61.29, 14.65.

[0255] Step 3: Ethyl 4-bromo-2-((tert-butoxy carbonyl) amino) benzothiazole-6-carboxylate

[0256] Ethyl 2-amino-4-bromobenzothiazole-6-carboxylate (5 mmol, 1.5 g) was dissolved in dichloromethane (100) ml. 4-(Diethylamino) pyridine (6 mmol, 733 mg) was added to reaction mixture. Di-terr-butyl dicarbonate (10 mmol, 2.18 g) was added to the mixture. Reaction mixture was stirred at RT for 20 h. After 20 h. solvent was evaporated, and crude was purified using 20 % Ethyl acetate / Dichloromethane to get Ethyl 4-bromo-2-((tert-butoxy carbonyl) amino) benzothiazole-6-carboxylate as white solid (1.8 g, 90% yield). TLC (SiOz, EtOAc / Hexane 1 :1) Rf= 0.68;!H NMR (500 MHz, DMSO) 5 12.40 (s, 1H), 8.62 (d, 7 = 1.6 Hz, 1H), 8.12 (d, 7 = 1.6 Hz, 1H), 4.35 (q, 7 = 7.1 Hz, 2H), 1.52 (s, 9H), 1.35 (t, 7 = 7.1 Hz, 3H).13C NMR (126 MHz, DMSO) 5 164.93, 164.54, 153.40, 151.41, 133.03, 130.05, 125.95, 123.45, 113.13, 82.88, 28.25, 14.65. Step 4: 4-bromo-2-((tert-butoxy carbonyl) amino) benzothiazole-6-carboxylic acid

[0257] Ethyl 4-bromo-2-((tert-butoxy carbonyl) amino) benzothiazole-6-carboxylate (4 mmol, 1.60g, 1 eq) was dissolved in methanol 50 ml. Lithium hydroxide (LiOH) (16 mmol, 383 mg, 4 eq) dissolved in DI water 10 ml. Lithium hydroxide (LiOH) solution was added to reaction mixture. Then reaction mixture was stirred at 60°C for 16 h. Then the reaction mixture was cooled, solvent was evaporated. Then residue was dissolved in DI water 100 ml and acidified to pH 4 using 1 M HC1. The precipitate formed was filtered out by vacuum filtration to get product 4-bromo-2-((tert-butoxy carbonyl) amino) benzothiazole-6-carboxylic acid as white solid (1.35 g, 91% yield). TLC (SiO2, EtOAc / Hexane 1:1) Rf= 0.28; ’H NMR (500 MHz, DMSO) 5 12.36 (s, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1H), 1.50 (s, 9H).13C NMR (126 MHz, DMSO) 5 166.42, 164.19, 151.12, 132.88, 130.32, 126.99, 123.50, 113.01, 82.79, 28.24.

[0258] Step 5: tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl) benzothiazol-2-yl) carbamate (1-5)

[0259] 4-bromo-2-((tert-butoxy carbonyl) amino) benzothiazole-6-carboxylic acid (8.45 mmol, 3 g) was dissolved in tetrahydrofuran THF (100) ml. 4-(Dimethyl amino) pyridine (6.76 mmol, 825 mg), EDC.HC1 (12.87 mmol, 2.43 g) was added to the mixture. 3-amino pyridine (10 mmol, 941 mg) was added to the mixture. Reaction mixture was stirred at RT under inert atmosphere for 20 h. Then solvent was evaporated, and crude was extracted with ethyl acetate / water. Ethyl acetate layer was dried evaporated, and crude was purified over silica using 10% methanol in Methylene chloride to get tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl) benzothiazol-2-yl) carbamate as light- yellow solid (3.07 g, 81% yield). TLC (SiCh, MeOH / DCM 1:9) Rf= 0.58;]H NMR (500 MHz, DMSO) 5 12.39 (s, 1H), 10.55 (s, 1H), 8.95 (d, 7 = 2.6 Hz, 1H), 8.57 (d, 7 = 1.7 Hz, 1H), 8.33 (dd, 7 = 4.7, 1.5 Hz, 1H), 8.25 - 8.19 (m, 2H), 7.42 (dd, 7= 8.3, 4.7 Hz, 1H), 1.51 (s, 9H).13C NMR (126 MHz, DMSO) 5 169.88, 164.71, 150.75, 145.08, 142.47, 142.39, 136.27, 132.89, 128.89, 127.80, 124.03, 123.99, 121.58, 112.78, 82.10, 28.34. Preparation of 4-bromo-6-(bromomethyl)benzothiazole (1-8)

[0260] Step 1: Ethyl 4-bromobenzothiazole-6-carboxylate (1-6)

[0261] Ethyl 2-amino-4-bromobenzothiazole-6-carboxylate (15 mmol, 4.51 g) was dissolved in Dioxane (50 ml), t-butyl nitrite (22.5 mmol, 2.65 ml) was added to reaction mixture. Reaction mixture was stirred at 60°C for 4 h. Then solvent was evaporated, and crude was extracted with ethyl acetate and water. Organic layer was separated, dried, evaporated and purified over silica using 40% ethyl acetate / hexane to get product Ethyl 4- bromobenzothiazole-6-carboxylate as orange solid (3.02 g, 47% yield). TLC (SiO2, EtOAc / Hexane 1 :4) Rf= 0.48;]H NMR (500 MHz, CDC13) 59.25 (s, 1H), 8.66 (d, 7= 1.5 Hz, 1H), 8.42 (d, 7 = 1.5 Hz, 1H), 4.46 (q, 7 = 7.1 Hz, 2H), 1.46 (t, 7= 7.2 Hz, 3H).13C NMR (126 MHz, CDCh) 5 164.90, 157.76, 154.08, 134.49, 130.60, 129.01, 123.27, 117.19, 61.81, 14.34.

[0262] Step 2: (4-bromobenzothiazol-6-yl) methanol

[0263] Ethyl 4-bromobenzothiazole-6-carboxylate (3 mmol, 858 mg) was dissolved in tetrahydrofuran THF 30 ml. Diisobutylaluminium hydride (IM in hexane) (12 ml) was added at -70°C under inert atmosphere. Then reaction mixture was stirred at RT for 16 h. Saturated sodium potassium tartrate (4 ml) and water (4 ml) was added to reaction mixture. Reaction mixture was stirred for 1 h and extracted with ethyl acetate and water. Organic phase was separated, dried, evaporated and purified over silica using 10% ethyl acetate / dichloromethane to get (4-bromobenzothiazol-6-yl) methanol as light-orange solid (0.25 g, 34% yield). TLC (SiO2, EtOAc / DCM 1:9) Rf= 0.26; ’H NMR (300 MHz, DMSO) 5 7.58 (d, 7 = 1.7 Hz, 1H), 7.41 (s, 1H), 7.28 (d, 7 = 8.1 Hz, 1H), 7.15 (dd, 7 = 8.2, 1.7 Hz, 1H), 4.49 (s, 2H).13C NMR (75 MHz, DMSO) 5 166.65, 152.21, 135.77, 131.21, 124.87, 119.54, 117.71, 63.48.

[0264] Step 3: 4-bromo-6-(bromomethyl)benzothiazole (1-8)

[0265] (4-bromobenzothiazol-6-yl) methanol (1 mmol, 244 mg) was dissolved in diethyl ether 25 ml. phosphorus tribromide (PBr2) (1.5 mmol, 0.15 ml) in diethyl ether 10 ml was added to reaction mixture slowly. Reaction mixture was stirred at RT overnight. Then solvent was evaporated, and residue extracted with ethyl acetate and water. Ethyl acetate layer was separated, dried, and evaporated to get 4-bromo-6-(bromomethyl) benzothiazole as lightyellow solid (200 mg, 65% yield). TLC (SiO2, EtOAc / DCM 2:3) Rf = 0.53;!H NMR (500 MHz, CDCh) 5 9.12 (s, 1H), 7.96, 7.96, (s, 1H), 7.80, 7.80 (s, 1H), 4.61 (s, 2H).13C NMR (126 MHz, CDCh) 5 155.49, 151.42, 136.77, 134.91, 130.79, 121.51, 117.45, 31.8

[0266] Preparation of Ethyl 4-(3-chlorophenyl) benzothiazole-6-carboxylate (1-9)

[0267] Ethyl 4-bromobenzothiazole-6-carboxylate (13 mmol, 3.71g) dissolved in toluene (30 ml) Ethanol / water (10 ml 1 :1), 3-chloro phenyl boronic acid (15.6 mmol, 2.43 g) was added to the mixture. Bis(triphenylphosphine) palladium (II) dichloride (Pd (PPh3)2Cl2) (0.78 mmol, 901mg), potassium carbonate K2CO3 (26 mmol, 3.59 g) was added to the reaction mixture. Reaction mixture was stirred under Argon at 80°C for 20 h. Then solvent was evaporated and extracted with ethyl acetate. Crude product purified over silica using 30% ethyl acetate / hexane to get Ethyl 4-(3-chlorophenyl) benzothiazole-6-carboxylate as white solid (2.89g, 70% yield). TLC (SiO2, EtOAc / Hexane 2:3) Rf= 0.48;!H NMR (500 MHz, CDCh) 5 9.21 (s, 1H), 8.73 (d, 7 = 1.6 Hz, 1H), 8.28 (d, 7 = 1.6 Hz, 1H), 7.88 (t, 7= 1.9 Hz, 1H), 7.77 (dt, 7= 7.5, 1.5 Hz, 1H), 7.51 - 7.41 (m, 2H), 4.49 (q, 7 = 7.1 Hz, 2H), 1.48 (t, 7 = 7.1 Hz, 3H).13C NMR (126 MHz, CDCh) 5 165.93, 156.99, 153.43, 139.79, 135.18, 135.01, 134.33, 129.71, 129.64, 128.19, 128.04, 127.85, 127.33, 123.53, 61.56, 14.41. Compound Synthesis

[0268] Preparation of 2-amino-4-(3-chlorophenyl)-N-(pyridin-3-yl) benzothiazole-6- carboxamide, HC1 Salt (Compound 1)

[0269] Step 1: 2-amino-4-(3-chlorophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl) benzothiazol-2-yl) carbamate (0.9 mmol, 404 mg) dissolved in dioxane (8 ml) Ethanol / water (4 ml 1 :1), 3-chloro phenyl boronic acid (1 mmol, 156 mg) was added to the mixture. Bis(triphenylphosphine) palladium (II) dichloride (Pd (PPhs Ch) (0.1 mmol, 71 mg), cesium carbonate CS2CO3 (1 mmol, 325 mg) was added to the reaction mixture. Reaction mixture was stirred under Argon at 160°C for 30 min in Biotage microwave initiator. Then solvent was evaporated and extracted with ethyl acetate. Crude product purified over silica using 50 % ethyl acetate / hexane to get 2-amino-4- (3-chlorophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide as light-yellow solid (140 mg, 41% yield). TLC (SiO2, MeOH / DCM 1:9) Rf= 0.38; HPLC- 96.42%. 'H NMR (500 MHz, DMSO) 5 10.38 (s, 1H), 8.94 (dd, 7 = 2.6, 0.8 Hz, 1H), 8.34 (d, 7 = 1.8 Hz, 1H), 8.31 (dd, 7 = 4.7, 1.5 Hz, 1H), 8.20 (ddd, 7= 8.3, 2.6, 1.5 Hz, 1H), 8.01 (s, 1H), 8.01 (s, 2H), 7.93 (t, 7= 1.9 Hz, 1H), 7.81 (dt, 7= 7.9, 1.2 Hz, 1H), 7.52 (t, 7 = 7.9 Hz, 1H), 7.48 - 7.37 (m, 2H).nC NMR (126 MHz, DMSO) 5 169.61, 165.78, 153.50, 144.87, 142.48, 141.51, 136.47, 133.19, 132.74, 130.40, 129.37, 128.37, 128.15, 127.78, 127.52, 127.17, 126.07, 123.99, 121.22. HRMS [M+H]+= 381.0571 ; [M+Na]+= 403.0391.

[0270] Step 2: 2-amino-4-(3-chlorophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide, HC1 Salt (Compound 1)

[0271] To a solution of tert-butyl (4-(3-chlorophenyl)-6-(pyridin-3- ylcarbamoyl)benzo[d]thiazol-2-yl)carbamate (115 mg, 0.24mmol) in 1,4-dioxane (20 mL), was added 4 M HC1 in 1 ,4-dioxane and the reaction was stirred at 60 °C overnight. The mixture was concentrated under reduced pressure to yield the product as a white solid (96 mg, 96% yield). ’H NMR (300 MHz, DMSO-d6) 5 9.58 (s, 1H), 8.81 (m, 1H), 8.59 (m,lH), 8.44 (m, 1H), 8.06-8.04 (m, 1H), 7.89-7.76 (m, 2H), 7.43-7.32 (m, 2H).

[0272] Preparation of 2-amino-4-(3-cyanophenyl)-N-(pyridin-3-yl) benzothiazole-6- carboxamide (Compound 2) tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl) benzothiazol-2-yl) carbamate (0.67 mmol, 300 mg) dissolved in dioxane (8 ml) Ethanol / water (4 ml 1: 1), 3-cyano phenyl boronic acid (0.8 mmol, 146 mg) was added to the mixture. Bis(triphenylphosphine) palladium (II) dichloride (Pd (PPh Cb) (0.1 mmol, 71 mg), cesium carbonate CS2CO (1 mmol, 325 mg) was added to the reaction mixture. Reaction mixture was stirred under Argon at 160 °C for 30 min in Biotage microwave initiator. Then solvent was evaporated and extracted with ethyl acetate. Crude product washed with methanol to get 2-amino-4-(3-cyano phenyl) -N-(pyridin- 3-yl) benzothiazole-6-carboxamide as light-yellow solid (180 mg, 72% yield). TLC (SiCh, MeOH / DCM 1 :9) Rf= 0.32; HPLC- 97%; ’H NMR (500 MHz, DMSO) 8 10.40 (s, 1H), 8.94 (d, 7 = 2.6 Hz, 1H), 8.38 - 8.33 (m, 2H), 8.32 (dd, 7 = 4.7, 1.5 Hz, 1H), 8.24 - 8.18 (m, 2H), 8.06 (d, 7 = 2.0 Hz, 3H), 7.87 - 7.84 (m, 1H), 7.71 (t, 7 = 7.8 Hz, 1H), 7.43 - 7.39 (m, 1H).13C NMR (126 MHz, DMSO) 5 169.85, 165.74, 153.50, 144.90, 142.48, 140.50, 136.45, 134.49, 133.13, 132.79, 131.30, 129.87, 127.79, 127.34, 127.26, 126.1 1, 124.01, 121.55, 119.51 , 111.66. HRMS [M+H]+= 372.0914; [M+Na]+= 394.0733.

[0273] Preparation of 2-amino-4-(3-(methyl sulfonyl) phenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide (Compound 3) and 2-amino-4-(3-(methyl sulfonyl) phenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide, HC1 Salt (Compound 7)

[0274] Step 1: 2-amino-4-(3-(methyl sulfonyl) phenyl)-N-(pyridin-3-yl) benzothiazole-6- carboxamide (Compound 3) tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl) benzothiazol-2-yl) carbamate (0.67 mmol, 300 mg) dissolved in dioxane (8 ml) Ethanol / water (4 ml 1 : 1), 3-methyl sulfonyl phenyl boronic acid (0.8 mmol, 160 mg) was added to the mixture. Bis(triphenylphosphine) palladium (II) dichloride (Pd (PPto Ch) (0.1 mmol, 71 mg), cesium carbonate CS2CO3 (1 mmol, 325 mg) was added to the reaction mixture. Reaction mixture was stirred under Argon at 160 °C for 30 min in Biotage microwave initiator. Then solvent was evaporated and extracted with ethyl acetate. Crude product was washed with methanol to get 2-amino-4-(3- methyl sulfonyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide as light-yellow solid (200 mg, 71% yield). TLC (SiO2, MeOH / DCM 1:9) Rf= 0.42; HPLC- 96.86%; ’H NMR (500 MHz, DMSO) 5 10.42 (s, 1H), 8.95 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 1.8 Hz, 1H), 8.34 (t, J =

[0275] 1.8 Hz, 1H), 8.32 (dd, 7 = 4.7, 1.5 Hz, 1H), 8.21 (ddd, J = 8.3, 2.8, 1.5 Hz, 2H), 8.04 (d, 7 =

[0276] 1.9 Hz, 1H), 8.00 (s, 2H), 7.96 - 7.92 (m, 1H), 7.77 (t, 7 = 7.8 Hz, 1H), 7.41 (dd, 7 = 8.4, 4.7 Hz, 1H), 3.29 (s, 3H).nC NMR (126 MHz, DMSO) 5 169.72, 165.84, 153.58, 144.88, 142.43, 141.26, 140.56, 136.48, 134.85, 132.70, 129.65, 128.01, 127.74, 127.31, 126.28, 126.02, 124.01 , 121.40, 55.38, 44.11. HRMS [M+H]+= 425.0737; [M+Na]+= 447.0556. Step 2: 2-amino-4-(3-(methyl sulfonyl) phenyl)-N-(pyridin-3-yl) benzothiazole-6- carboxamide, HC1 Salt (Compound 7)

[0277] Compound 7 was prepared according to similar methods described in step 2 of the preparation of Compound 1.

[0278] Preparation of 2-amino-4-(5-chlorothiophen-2-yl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide (Compound 4) and 2-amino-4-(5-chlorothiophen-2-yl)-N- (pyridin-3-yI) benzothiazole-6-carboxamide, HO salt (Compound 8)

[0279] Step 1: 2-amino-4-(5-chlorothiophen-2-yl)-N-(pyridin-3-yl) benzothiazole-6- carboxamide (Compound 4) tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl) benzothiazol-2-yl) carbamate (0.45 mmol, 200 mg) dissolved in dioxane (8 ml) Ethanol / water (4 ml 1:1), 5-chloro thiophene-2- boronic acid (0.53 mmol, 87 mg) was added to the mixture. Bis(triphenylphosphine) palladium (11) dichloride (Pd(PPh3)2Ch) (0.08 mmol, 47 mg), cesium carbonate CS2CO3 (0.68 mmol, 217 mg) was added to the reaction mixture. Reaction mixture was stirred under Argon at 160 °C for 30 min in Biotage microwave initiator. Then solvent was evaporated and extracted with ethyl acetate. Crude product purified over silica using 50 % ethyl acetate / hexane to get 2-amino-4-(5-chlorothiophen-2-yl)-N-(pyridin-3-yl) benzothiazole- 6- carboxamide as light-yellow solid (103 mg, 60% yield). TLC (SiCP, MeOH / DCM 1 :9) Rf = 0.46; HPLC- 95.69%. ' H NMR (500 MHz, DMSO) 5 10.42 (s, 1H), 8.95 (d, J = 2.6 Hz, 1H), 8.32 (dd, 7 = 4.7, 1.5 Hz, 1H), 8.29 (d, 7 = 1.8 Hz, 1H), 8.25 (d, 7 = 1.7 Hz, 1H), 8.21 (ddd, 7 = 8.4, 2.6, 1.5 Hz, 1H), 8.16 (s, 2H), 7.80 (d, 7 = 4.1 Hz, 1H), 7.42 (dd, 7 = 8.3, 4.7 Hz, 1H), 7.21 (d, 7 = 4.1 Hz, 1H)13C NMR (126 MHz, DMSO) 5 169.58, 165.76, 151.20, 144.92, 142.49, 139.14, 136.44, 132.42, 129.66, 127.78, 127.31, 126.87, 124.85, 124.01, 122.23, 121.64, 120.35. HRMS [M+H]+= 387.0136; [M+Na]+= 408.9955.

[0280] Step 2: 2-amino-4-(5-chlorothiophen-2-yl)-N-(pyridin-3-yl) benzothiazole-6- carboxamide, HC1 salt (Compound 8)

[0281] Compound 8 was prepared according to similar methods described in step 2 of the preparation of Compound 1.

[0282] Preparation of 2-amino-4-(3-nitrophenyl)-N-(pyridin-3-yl) benzothiazole-6- carboxamide (Compound 5) and 2-amino-4-(3-nitrophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide, HC1 Salt (Compound 10)

[0283] Step 1 : 2-amino-4-(3-nitrophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide (Compound 5) tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl) benzothiazol-2-yl) carbamate (0.9 mmol, 404 mg) dissolved in dioxane (8 ml) Ethanol / water (4 ml 1: 1), 3-nitro phenyl boronic acid (1 mmol, 156 mg) was added to the mixture. Bis(triphenylphosphine) palladium (II) dichloride (Pd (PPln^Ch) (0.1 mmol, 71 mg), cesium carbonate CS2CO3 (1 mmol, 325 mg) was added to the reaction mixture. Reaction mixture was stirred under Argon at 160°C for 30 min in Biotage microwave initiator. Then solvent was evaporated and extracted with ethyl acetate. Crude product purified over silica using hexane / ethyl acetate to get 2-amino-4-(3-nitro phenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide as light-yellow solid (100 mg, 57% yield). TLC (SiO2, MeOH / DCM 1:9) Rf= 0.42; HPLC- 95.25%;:H NMR (500 MHz, DMSO) 5 10.43 (s, 1H), 8.94 (d, J = 2.6 Hz, 1H), 8.73 (t, J = 2.0 Hz, 1H), 8.39 (d, 7 = 1.8 Hz, 1H), 8.32 (td, 7 = 5.7, 1.5 Hz, 2H), 8.23 (dddd, 7 = 22.3, 8.4, 2.5, 1.3 Hz, 2H), 8.08 (d, 7 = 1.8 Hz, 1H), 8.06 (s, 2H), 7.80 (t, 7= 8.0 Hz, 1H), 7.41 (dd, 7= 8.3, 4.7 Hz, 1H).13C NMR (126 MHz, DMSO) 5 169.95, 165.75, 153.51, 148.19, 144.91, 142.46, 140.92, 136.44, 136.27, 132.82, 130.15, 127.78, 127.30, 127.12, 126.19, 124.17, 124.02, 122.48, 121.68. HRMS [M+H]+= 392.0812; [M+Na]+= 414.0631.

[0284] Step 2: 2-amino-4-(3-nitrophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide, HC1 Salt (Compound 10)

[0285] Compound 10 was prepared according to similar methods described in step 2 of the preparation of Compound 1.

[0286] Preparation of 4-(3-acetylphenyl)-2-amino-N-(pyridin-3-yl) benzothiazole-6- carboxamide (Compound 6) and 4-(3-acetyIphenyl)-2-amino-N-(pyridin-3-yl) benzothiazole-6-carboxamide, HC1 salt (Compound 9)

[0287] Step 1: 4-(3-acetylphenyl)-2-amino-N-(pyridin-3-yl) benzothiazole-6-carboxamide (Compound 6) tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl) benzothiazol-2-yl) carbamate (0.45 mmol, 200 mg) dissolved in dioxane (8 ml) Ethanol / water (4 ml 1 : 1), 3-acetyl phenyl boronic acid (0.53 mmol, 88 mg) was added to the mixture. Bis(triphenylphosphine) palladium (II) dichloride (Pd (PPhs Ch) (0.08 mmol, 47 mg), cesium carbonate CS2CO3 (0.68 mmol, 217 mg) was added to the reaction mixture. Reaction mixture was stirred under Argon at 160°C for 30 min in Biotage microwave initiator. Then solvent was evaporated and extracted with ethyl acetate. Crude product was washed with methanol to get 2-amino-4-(3 -acetyl phenyl)-N- (pyridin-3-yl) benzothiazole-6-carboxamide as light-yellow solid (56 mg, 33% yield). TLC (SiO2, MeOH / DCM 1 :9) Rf = 0.42; HPLC- 95%;]H NMR (500 MHz, DMSO) 5 10.41 (s, 1H), 8.95 (d, J = 2.6 Hz, 1H), 8.37 (t, J = 1.8 Hz, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.31 (dd, 7 = 4.7, 1.5 Hz, 1H), 8.21 (ddd, J= 8.4, 2.6, 1.5 Hz, 1H), 8.12 - 8.09 (m, 1H), 8.02 (d, J= 1.9 Hz, 1H), 7.98 (s, 3H), 7.64 (t, 7 = 7.7 Hz, 1H), 7.43 - 7.39 (m, 1H), 2.67 (s, 3H).13C NMR (126 MHz, DMSO) 8 198.56, 169.49, 165.88, 153.65, 144.85, 142.44, 139.88, 137.23, 136.50, 134.49, 132.63, 129.33, 129.02, 128.94, 127.72, 127.48, 127.24, 126.17, 124.00, 121.02, 27.43. HRMS [M+H]+= 389. 1067; [M+Na]+= 411.0886.

[0288] Step 2: 4-(3-acetylphenyl)-2-amino-N-(pyridin-3-yl) benzothiazole-6-carboxamide, HC1 salt (Compound 9)

[0289] Compound 9 was prepared according to similar methods described in step 2 of the preparation of Compound 1.

[0290] Preparation of 4-(3-chlorophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide,

[0291] HC1 Salt (Compound 11)

[0292] Step 1: 4-(3-chlorophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide

[0293] 2-amino-4-(3-chlorophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide (0.263 mmol, 100 mg) was dissolved in THF (50 ml), tert-butyl nitrite (0.53mmol, 0.063ml) was added to the reaction mixture and reaction mixture was stirred at 60 °C for 16 h. Then solvent was evaporated, crude product was extracted with ethyl acetate and ethyl acetate layer was dried and evaporated. The residue was dissolved in dichloromethane (5 ml) and hexane (5 ml) was added to precipitate out 4-(3-chlorophenyl)-N-(pyridin-3-yl) benzothiazole-6- carboxamide as light brown solid (31mg, 32% yield). *H NMR (500 MHz, Acetone) 5 10.07 (s, 1H), 9.53 (s, 1H), 9.02 (s, 1H), 8.86 (d, J = 1.4 Hz, 1H), 8.39 (d, 7 = 1.9 Hz, 1H), 8.38 (s, 1H), 8.34 (d, 7 = 2.6 Hz, 1H), 8.34 (d, 7 = 0.8 Hz, 1H), 8.07 (t, 7 = 1.8 Hz, 1H), 7.96 (d, 7 = 2.7 Hz, 1H), 7.94 (d, 7 = 2.7 Hz, 1H), 7.61 (t, 7 = 15.5 Hz, 1H), 7.53 (d, 7 = 3.2 Hz, 1H), 7.43 (d, 7= 13.0 Hz, 1H).13C NMR (126 MHz, Acetone) 5 165.13, 158.05, 152.73, 144.73, 141.84, 141.76, 140.19, 135.63, 134.39, 133.58, 132.23, 129.91, 129.67, 128.26, 127.87, 127.21, 127.12, 125.30, 123.48, 122.16. HRMS [M+H]+= 366.0462; [M+Na]+= 388.0282.

[0294] Step 2: 4-(3-chlorophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide, HC1 Salt (Compound 11)

[0295] 4-(5-chlorothiophen-2-yl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide (30 mg, 0.08 mmol) was dissolved in EtOAc (10 mL) and 4M HC1 in 1,4-dioxane (1 mL) was added and the solution was stirred at RT for 2 h. The solvent was then removed under reduced pressure to yield the product 4-(5-chlorothiophen-2-yl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide hydrochloride as a solid (25 mg, 78% yield).

[0296] Preparation of 4-(3-nitrophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide, HC1 Salt (Compound 12)

[0297] Step 1: 4-(3-nitrophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide

[0298] 2-amino-4-(3-nitrophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide (0.256 mmol, 100 mg) was dissolved in THF (50 ml), tert-butyl nitrite (0.53 mmol, 0.063 ml) was added to the reaction mixture and reaction mixture was stirred at 60 °C for 16 h. Then solvent was evaporated, crude product was extracted with ethyl acetate and ethyl acetate layer was dried and evaporated. The residue was dissolved in dichloromethane (5 ml) and hexane (5 ml) was added to precipitate out 4-(3-nitrophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide as light brown solid (30 mg, 33% yield). *H NMR (500 MHz, Acetone) 5 10.12 (s, 1H), 9.59 (s, 1H), 9.05 (d, J = 2.2 Hz, 1H), 8.93 (d, J = 1.7 Hz, 2H), 8.47 (d, 7 = 2.7 Hz, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.42 (d, 7 = 3.6 Hz, 1H), 8.37 (dd, 7 = 1.3, 8.2 Hz, 1H), 7.89 (t, 7 = 8.0 Hz, 1H), 7.49 (dd, 7 = 8.2 Hz, 1H).13C NMR (126 MHz, Acetone) 8 165.04, 158.57, 152.71, 148.40, 144.55, 141.53, 139.72, 135.91, 135.76, 133.42, 132.35, 129.65, 125.50, 124.47, 123.61, 122.68. HRMS [M+H]+= 377.0703; [M+Na]+= 399.0522.

[0299] Step 2: 4-(3-nitrophenyl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide, HC1 Salt (Compound 12)

[0300] Compound 12 was prepared according to similar methods described in step 2 of the preparation of Compound 11.

[0301] Preparation of 4-(5-chlorothiophen-2-yI)-N-(pyridin-3-yl) benzothiazole-6- carboxamide, HC1 Salt (Compound 13)

[0302] Step 1: 4-(5-chlorothiophen-2-yl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide

[0303] 2-amino-4-(5-chlorothiophen-2-yl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide (0.26 mmol, 100 mg) was dissolved in THF (50 ml), tert-butyl nitrite (0.53 mmol, 0.063 ml) was added to the reaction mixture and reaction mixture was stirred at 60 °C for 16 h. Then solvent was evaporated, crude product was extracted with ethyl acetate and ethyl acetate layer was dried and evaporated. The residue was dissolved in dichloromethane (5 ml) and hexane (5 ml) was added to precipitate out 4-(5-chlorothiophen-2-yl)-N-(pyridin-3-yl) benzothiazole- 6- carboxamide as light brown solid (15 mg, 15% yield). H NMR (500 MHz, Acetone) 8 10.02 (s, 1H), 9.59 (s, 1H), 9.01 (d, 7 = 2.0 Hz, 1H), 8.74 (d, 7 = 1.5 Hz, 1H), 8.55 (d, 7 = 1.6 Hz, 1H), 8.38 (d, J = 1.3 Hz, 1H), 8.36 (d, J = 2.5 Hz, 1H), 7.96 (d, J = 4.1 Hz, 1H), 7.42 (dd, 7 = 4.7, 8.2 Hz, 1H), 7.19 (d, J = 4.0 Hz, 1H).13C NMR (126 MHz, Acetone) 5 165.13, 158.06, 144.98, 141.98, 137.95, 135.46, 132.46, 131.72, 127.90, 126.89, 126.64, 126.17, 123.38, 121.88, 121.09. HRMS [M+H]+= 372.0027; [M+Na]+= 393.9846. Step 2: 4-(5-chlorothiophen-2-yl)-N-(pyridin-3-yl) benzothiazole-6-carboxamide, HC1

[0304] Salt (Compound 13)

[0305] Compound 13 was prepared according to similar methods described in step 2 of the preparation of Compound 11. Preparation of 2-amino-4-(3-chlorophenyl)-N-(pyridin-3-yl)benzo[d]thiazole-6- carboxamide, HC1 Salt (Compound 1)

[0306] Step 1: methyl 2-aminobenzo[d]thiazole-6-carboxylate

[0307] Bromine (3.10 g, 19.85 mmol) was dissolved in acetic acid (18 mL) and slowly added Methyl 4-aminobenzoate (3.00 g, 19.85 mmol) dropwise and KSCN (6.89 g, 70.86 mmol) in acetic acid (67 mL). The reaction was allowed to proceed overnight at room temperature. Quenched with water, the pH was adjusted to 9 with a saturated NtoCCh solution. It was extracted with EA three times, washed with saturated brine, dried over anhydrous NaiSCU, and then filtered and purified by column chromatography (PE / EA=3 / 1) to give the title compound (3.30 g, yield: 80%) as a white solid. LCMS: Calculated Exact Mass =208.0, Found (ESI+) [M+H]+= 209.0

[0308] Step 2: methyl 2-amino-4-bromobenzo[d]thiazole-6-carboxylate

[0309] To a solution of methyl 2-aminobenzo[d]thiazole-6-carboxylate (1 g, 4.81 mmol) in DMF (11 mL) was added NBS (1.25 g, 7.21 mmol) and stirred at 20°Cfor 3 h. After the reaction was completed, the mixture was diluted with EA (20 mL) and washed with H2O (3 x 20 mL), aq.NazSCh and brine. Then the organic layer was dried over anhydrous NazSCL, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (PE / EA=3 / 1) to give the desired product as a yellow solid (1.0 g, 72.7% yield). LCMS: Calculated Exact Mass =285.9, Found (ESI+) [M+H]+= 286.9, 288.9

[0310] Step 3: methyl 4-bromo-2-((tert-butoxycarbonyl)amino)benzo[d]thiazole-6- carboxylate

[0311] To a mixture of methyl 2-amino-4-bromobenzo[d]thiazole-6-carboxylate (1.5 g, 5.25 mmol), TEA (1 g, 10.49 mmol) and BOC2O (1.37 mg, 6.29 mmol) in DMF (14 mL) was added DMAP (128 mg, 1.05 mmol). The mixture was stirred at 25°Cfor 3 h. After the reaction was completed, the resulting reaction was diluted with water (20 mL), extracted with EA (3 x 30 mL). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (PE: EA=3:1) to give the desired product as a white solid (1.2 g, 74.5% yield). LCMS: Calculated Exact Mass =386.0, Found (ESI+) [M+H]+= 387.0, 389.0

[0312] Step 4: 4-bromo-2-((tert-butoxycarbonyl)amino)benzo[d]thiazole-6-carboxylic acid

[0313] To a solution of methyl 4-bromo-2-((tert-butoxycarbonyl)amino)benzo[d]thiazole-6- carboxylate (1.0 g, 2.59 mmol) in MeOH (40 mL) was added LiOH (250 mg, 10.36 mmol) in H2O (8 mL). The reaction was stirred at 50°Cfor 2h and aq. HC1 (IN) was added to adjust pH <3. The mixture was extracted with EA (3 x 20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give the desired product as a white solid (820 mg, 85.2% yield). LCMS: Calculated Exact Mass =372.0, Found (ESI+) [M+H]+= 373.0, 375.0

[0314] Step 5: tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl)benzo[d]thiazol-2-yl)carbamate

[0315] To the mixture of 4-bromo-2-((tert-butoxycarbonyl)amino)benzo[d]thiazole-6- carboxylic acid (820 mg, 2.2 mmol), DMAP (220 mg, 2.46 mmol) and pyridin-3-amine (250 mg, 2.64 mmol) in DMF (6 mL) was added EDCI (0.5 g, 2.64 mmol), and the reaction was stirred at 20°Cfor 16 h. The mixture was diluted with EA (30 mL) and washed with brine (5x 30 mL). The organic layer was dried over anhydrous NaiSCU, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (DCM / MeOH=lO / 1) to give the desired product as a white solid (0.8 g , 83. 1 % yield). LCMS: Calculated Exact Mass =448.0, Found (ESI+) [M+H]+= 449.0, 451.0

[0316] Step 6: tert-butyl (4-(3-chlorophenyl)-6-(pyridin-3-ylcarbamoyl)benzo[d]thiazol-2- yl)carbamate

[0317] A mixture of tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl)benzo[d]thiazol-2- yl)carbamate (0.4 g, 0.89 mmol), (3-chlorophenyl)boronic acid (153 mg, 4.31 mmol), Pd(dppf)C12 (80 mg, 0.11 mmol) and CS2CO3 (0.48 g, 1. 51 mmol) in 1,4-dioxane (12mL) and H2O (2 mL) was stirred at 120°C for 2 h under nitrogen. The resulting mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (DCM / MeOH=10 / l) to give the desired product as a yellow solid (260 mg, 60.7% yield). LCMS: Calculated Exact Mass =480.1, Found (ESI+) [M+H]+= 481.1

[0318] Step 7 : 2-amino-4-(3-chlorophenyl)-N-(pyridin-3-yl)benzo[d]thiazole-6-carboxamide

[0319] To a solution of tert-butyl (4-(3-chlorophenyl)-6-(pyridin-3- ylcarbamoyl)benzo[d]thiazol-2-yl)carbamate (200 mg, 0.42 mmol) in DCM (5 mL) was added 4 N HC1 (in 1.4-dioxane, 10 mL) at 0°C, and the reaction was stirred at 25°C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was suspended in MTBE (20 mL) and stirred for 0.5 hr, filtered and washed with MTBE, collecting the solid and dried in vacuo to give the desired product as a white solid (103 mg, 59.2% yield). LCMS: Calculated Exact Mass =380.0, Found (ESI+) [M+H]+= 381.0

[0320] ’H NMR (400 MHz, DMSO-76) 5 10.39 (s, 1H), 8.94 (d, J = 2.3 Hz, 1H), 8.34 (d, 7 = 1.8 Hz, 1H), 8.31 (dd, 7 = 4.7, 1.3 Hz, 1H), 8.22 - 8.17 (m, 1H), 8.05 - 7.98 (m, 3H), 7.93 (t, 7 = 1.8 Hz, 1H), 7.83 - 7.79 (m, 1H), 7.52 (t, 7 = 7.9 Hz, 1H), 7.44 (ddd, 7 = 8.0, 2.1, 1.1 Hz, 1H), 7.40 (dd, 7 = 8.2, 4.6 Hz, 1H).

[0321] Preparation of 2-amino-4-(3,6-dihydro-2H-pyran-4-yl)-N-(pyridin-3- yI)benzo[d]thiazole-6-carboxamide (Compound 14)

[0322]

[0323] Step 1 : tert-butyl (4-(3,6-dihydro-2H-pyran-4-yl)-6-(pyridin-3- ylcarbamoyl)benzo[d]thiazol-2-yl) carbamate

[0324] A mixture of tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl)benzo[d]thiazol-2- yl)carbamate (200 mg, 0.445 mmol) in dioxane (4 mL) was added H2O (2 mL), 2-(3,6-dihydro- 2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (105 mg, 0.49 mmol), Pd(dppf)Clz (40 mg, 0.05 mmol) and Cs2CO,(290 mg, 0.82 mmol). The mixture was stirred at 120°Cfor 2 h under nitrogen. After completed, the resulting reaction was diluted with H2O, extracted with EA, washed with brine, dried over Na^SOr, filtered and concentrated, the residue was purified by flash chromatography using fluent MeOH in DCM (0-10%) to give the desired product (150 mg, 74.4% yield) as a yellow solid. LCMS: Calculated Exact Mass =452.2, Found (ESI+) [M+H]+ = 453.2

[0325] Step 2: 2-amino-4-(3,6-dihydro-2H-pyran-4-yl)-N-(pyridin-3-yl)benzo|d|thiazole-6- carboxamide

[0326] To a solution of tert-butyl (4-(3,6-dihydro-2H-pyran-4-yl)-6-(pyridin-3- ylcarbamoyl)benzo[d]thiazol-2-yl) carbamate (100 mg, 0.445 mmol) in DCM (5 mL) was added 4 N HC1 (in 1.4-dioxane, 10 mL) at 0°C, and the reaction was stirred at 25°C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in EA (20 mL) and washed with aq.NaHCOs (20 mL), brine, dried over anhydrous NazSC , filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the desired product as a white solid (65 mg, 83.3% yield). LCMS: Calculated Exact Mass =352.1, Found (ESI+) [M+H]+= 353.1

[0327] ' H NMR (400 MHz, DMSO-cL) 5 10.34 (s, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.30 (dd, J = 4.7, 1.5 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.21 - 8.15 (m, 1H), 7.91 (s, 2H), 7.78 (d, 7 = 1.8 Hz, 1H), 7.39 (dd, J = 8.3, 4.7 Hz, 1H), 6.58 - 6.55 (m, 1H), 4.27 (m, 2H), 3.86 (t, 7 = 5.5 Hz, 2H), 2.71 - 2.65 (m, 2H).

[0328] Preparation of 2-amino-N-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4- yl)benzo[d]thiazole-6-carboxamide (Compound 15)

[0329] Step 1: tert-butyl (6-(pyridin-3-ylcarbamoyl)-4-(tetrahydro-2H-pyran-4- yl)benzo[d]thiazol-2-yl) carbamate

[0330] To a solution of tert-butyl (4-(3,6-dihydro-2H-pyran-4-yl)-6-(pyridin-3- ylcarbamoyl)benzo[d]thiazol-2-yl) carbamate (200 mg, 0.412 mmol) in MeOH (10 mL) was added Pd(OH)2 / C (50 mg). The mixture was hydrogenated at 40 °C for 5 h under H2 at 45psi. After the completion of the reaction, the reaction was filtered through celite and the filtrated was concentrated under reduced pressure to give the desired product as a yellow solid ( 163 mg, 81.1 % yield). LCMS: Calculated Exact Mass =454.2, Found (ESI+) [M+H]+= 455.2

[0331] Step 2: 2-amino-N-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6- carboxamide

[0332] To a solution of tert-butyl (6-(pyridin-3-ylcarbamoyl)-4-(tetrahydro-2H-pyran-4- yl)benzo[d]thiazol-2-yl) carbamate (100 mg, 0.22 mmol) in DCM (5 mL) was added 4 N HC1 (in 1.4-dioxane, 10 mL) at 0°C, and the reaction was stirred at 25°C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in EA (20 mL) and washed with aq. NaHCCL (20 mL), brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the desired product as a white solid (60 mg, 75.1% yield). LCMS: Calculated Exact Mass =354.1, Found (ESI+) [M+H]+= 355.1 ’H NMR (400 MHz, DMSO-6) 5 10.28 (s, 1H), 8.92 (d, J = 2.4 Hz, 1H), 8.30 (dd, J = 4.7, 1.4 Hz, 1H), 8.22 - 8.16 (m, 2H), 7.90 (s, 2H), 7.78 (d, J= 1.6 Hz, 1H), 7.40 (dd, J = 8.3, 4.7 Hz, 1H), 4.00 (dd, 7 = 11.0, 3.6 Hz, 2H), 3.50 - 3.34 (m, 3H), 1.95 - 1.85(m, 2H), 1.78 - 1.75 (m, 2H).

[0333] Preparation of 2-amino-4-(4,4-difluorocyclohexyl)-N-(pyridin-3- yl)benzo[d]thiazole-6-carboxamide (Compound 16)

[0334] Step 1 : tert-butyl(4-(4,4-difluorocyclohex- 1 -en- 1 -yl)-6-(pyridin-3- ylcarbamoyl)benzo[d]thiazol-2 -yl)carbamate

[0335] A mixture of tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl)benzo[d]thiazol-2- yl)carbamate (300 mg, 0.67 mmol) in dioxane (6 mL) was added H2O (2 mL), 2-(4,4- difluorocyclohex-l-en-l-yl)-4,4,5,5-tetramethyl -1,3,2- dioxaborolane (244 mg, 1.0 mmol), Pd(dppf)Ch (73 mg, 0.1 mmol) and Cs2COs(650 mg, 2.0 mmol). The mixture was stirred at 120°C for 2 h under nitrogen. After completed, the resulting reaction was diluted with H2O, extracted with EA, washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by silica gel chromatography using fluent MeOH in DCM (0-10%) to give the desired product (240 mg, 73.8% yield) as a yellow solid. LCMS: Calculated Exact Mass =486.2, Found (ESI+) [M+H]+ = 487.2

[0336] Step 2: tert-butyl(4-(4,4-difluorocyclohexyl)-6-(pyridin-3- ylcarbamoyl)benzo[d]thiazol-2-yl) carbamate

[0337] To a solution of tert-butyl(4-(4,4-difluorocyclohex-l-en-l-yl)-6-(pyridin-3- ylcarbamoyl)benzo[d]thiazol-2 -yl) carbamate (100 mg, 0.20 mmol) in MeOH (4 mL) and THF (4 mL) was added Pd / C (100 mg) and Pd(OH)2 / C(50 mg). The mixture solution was stirred at r.t for 16h under H2 at 45psi. The reaction mixture was filtrated and washed with MeOH, the filtration was concentrated to get the desired product (100 mg, 100% yield) as a light yellow solid. LCMS: Calculated Exact Mass =488.2, Found (ESI+) [M+H]+ = 489.2

[0338] Step 3: 2-amino-4-(4,4-difluorocyclohexyl)-N-(pyridin-3-yl)benzo[d]thiazole-6- carboxamide

[0339] To a solution of tert-butyl (4-(4,4-difluorocyclohexyl)-6-(pyridin-3-ylcarbamoyl) benzo[d]thiazol-2-yl)carbamate (100 mg, 0.20 mmol) in dioxane (3 mL) was added 4N HC1 in dioxane (3 mL) and 0.2 mL of H2O. The mixture was stirred at r.t for 3 h. After completed, the resulting reaction was concentrated and purified by Prep-HPLC to give the desired product (40 mg, 50.5% yield) as a white solid. LCMS: Calculated Exact Mass =388.1, Found (ESI+) [M+H]+= 389.1

[0340] ’H NMR (400 MHz, CD3OD) 5 8.91 (d, J = 2.3 Hz, 1H), 8.33 - 8.26 (m, 2H), 8.16 - 8.14 (m, 1H), 7.83 (s, 1H), 7.49 - 7.44 (m, 1H), 3.46 - 3.36 (m, 1H), 2.27 - 2.15 (m, 2H), 2.12 - 1.87 (m, 6H).

[0341] Preparation of 4-(3,6-dihydro-2H-pyran-4-yl)-N-(pyridin-3-yl)benzo[d]thiazole- 6-carboxamide (Compound 17) and N-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4- yl)benzo[d]thiazole-6-carboxamide (Compound 18)

[0342] Step 1: methyl 4-bromobenzo[d]thiazole-6-carboxylate To a solution of methyl 2-amino-4-bromobenzo[d]thiazole-6-carboxylate carbamate (2.5 g, 8.71 mmol) in THF (50 mL) was added t-BuONO (2.7 g, 26.13 mmol). The mixture solution was stirred at reflux for 2h under N2. After completed, the resulting reaction was concentrated in vacuo and purified by silica gel chromatography using fluent EA in PE (0- 10%) to give the desired product (1 .3 g, 55.1 % yield) as a white solid. LCMS : Calculated Exact Mass =270.9, Found (ESI+) [M+H]+= 271.9,273.9

[0343] Step 2: 4-bromobenzo[d]thiazole-6-carboxylic acid

[0344] To a solution of methyl 4-bromobenzo[d]thiazole-6-carboxylate (1.3 g, 4.78 mmol) in MeOH (20 mL) was added LiOH (400 mg, 16.73 mmol) in H2O (4 mL). The reaction was stirred at 25°Cfor 16h and aq. HC1 (IN) was added to adjust pH<3. The mixture was extracted with EA (3 x 20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give the desired product as a yellow solid (1.1 g, 90.2% yield). LCMS: Calculated Exact Mass =256.9 Found (ESI+) LM+HJ+= 257.9, 259.9 Step 3: 4-bromo-N-(pyridin-3-yl)benzo[d]thiazole-6-carboxamide

[0345] To the mixture of 4-bromobenzo[d]thiazole-6-carboxylic acid (600 mg, 2.33 mmol), DMAP (310 mg, 2.56 mmol) and pyridin-3 -amine (260 mg, 2.79 mmol) in DMF (6 mL) was added EDCI (0.53 g, 2.79 mmol), and the reaction was stirred at 20°Cfor 16 h. The mixture was diluted with EA (30 mL) and washed with brine (5x 30 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (DCM / MeOH=10 / l) to give the desired product as a white solid (0.55 g, 70.87 % yield). LCMS: Calculated Exact Mass =333.0, Found (ESI+) [M+H]+= 334.0, 336.0

[0346] Step 4: 4-(3,6-dihydro-2H-pyran-4-yl)-N-(pyridin-3-yl)benzo[d]thiazole-6- carboxamide

[0347] A mixture of 4-bromo-N-(pyridin-3-yl)benzo[d]thiazole-6-carboxamide (0.15 g, 0.45 mmol), Pd(dppf)Ch (73 mg, 0.10 mmol) 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (120 mg, 0.58 mmol), and CS2CO3 (0.29 g, 0.9 mmol) in 1 ,4-dioxane (2.5 mL) and H2O (0.5 mL) was stirred at 120°Cfor 2 h under nitrogen. The resulting mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (DCM / MeOH=10 / l) to give the desired product as a yellow solid (120 mg, 78.95% yield). LCMS: Calculated Exact Mass =337.1, Found (ESI+) [M+H]+= 338.1

[0348] ’H NMR (400 MHz, CD3OD) 5 9.38 (s, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.34 - 8.28 (m, 2H), 8.03 (d, J = 1.8 Hz, 1H), 7.47 (ddd, J = 8.4, 4.9, 0.6 Hz, 1H), 6.57- 6.54 (m, 1H), 4.40 (q, 7= 2.8 Hz, 2H), 4.01 (t, 7 = 5.4 Hz, 2H), 2.86 - 2.81 (m, 2H). Step 5 : N-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)benzo[d]thiazole-6- carboxamide

[0349] To a solution of 4-(3,6-dihydro-2H-pyran-4-yl)-N-(pyridin-3-yl)benzo[d]thiazole-6- carboxamide (120 mg, 0.36 mmol) in MeOH (4 mL) and THF (4 mL) was added Pd / C (50 mg) and Pd(OH)2 / C(50 mg). The mixture solution was stirred at 60°Cfor 16h under H2 at 45psi. The reaction mixture was filtrated and washed with MeOH, the filtration was concentrated and purified by Prep-HPLC to give the desired product (50 mg, 41.67% yield) as a light white solid. LCMS: Calculated Exact Mass =339.1, Found (ESI+) [M+H]+ = 340.1

[0350] H NMR (400 MHz, CD3OD) 5 9.42 (s, 1H), 8.95 (d, J = 2.3 Hz, 1H), 8.61 (d, J = 1.7 Hz, 1H), 8.36 - 8.30 (m, 2H), 8.04 (d, 7 = 1.5 Hz, 1H), 7.50 (dd, J = 8.2, 4.7 Hz, 1H), 3.81 - 3.71 (m, 1H), 2.29 - 2.20 (m, 2H), 2.17 - 2.02 (m, 6H).

[0351] Preparation of 4-(4,4-difluorocyclohexyI)-N-(pyridin-3-yl)benzo[d]thiazole-6- carboxamide (Compound 19)

[0352] Step 1 : 4-(4,4-difluorocyclohex- 1 -en- 1 -yl)-N-(pyridin-3 -yl)benzo | d ] thiazole-6- carboxamide

[0353] A mixture of 4-bromo-N-(pyridin-3-yl)benzo[d]thiazole-6-carboxamide (0.15 g, 0.45 mmol), Pd(dppf)Ch (73 mg, 0.10 mmol), 2-(4, 4-difhiorocyclohex-l-en-l-yl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (140 mg, 0.58 mmol), and CS2CO3 (0.29 g, 0.9 mmol) in 1,4- dioxane (2.5 mL) and H2O (0.5 mL) was stirred at 120°Cfor 2 h under nitrogen. The resulting mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (DCM / MeOH=10 / l) to give the desired product as a yellow solid (120 mg, 71.86% yield). LCMS: Calculated Exact Mass =371.1, Found (ESI+) [M+H]+= 372.1 Step 2: 4-(4,4-difluorocyclohexyl)-N-(pyridin-3-yl)benzo[d]thiazole-6-carboxamide

[0354] To a solution of 4-(4,4-difluorocyclohex-l-en-l-yl)-N-(pyridin-3-yl)benzo[d]thiazole- 6-carboxamide (100 mg, 0.27 mmol) in MeOH (3 mL) and THF (2 mL) was added Pd / C (150 mg) and Pd(OH)2 / C(150 mg). The mixture solution was stirred at 50°C for 16h under H2 at 45psi. The reaction mixture was filtrated and washed with MeOH, the filtration was concentrated and purified by Prep-HPLC to give the desired product (40 mg, 39.8% yield) as a white solid. LCMS: Calculated Exact Mass =373.1, Found (ESI+) [M+H]+ = 374.1

[0355] 'H NMR (400 MHz, CD3OD) 5 9.42 (s, 1H), 8.95 (d, 7 = 2.3 Hz, 1H), 8.61 (d, J = 1.7 Hz, 1H), 8.36 - 8.30 (m, 2H), 8.04 (d, 7 = 1.5 Hz, 1H), 7.50 (dd, 7 = 8.2, 4.7 Hz, 1H), 3.82 - 3.70 (m, 1H), 2.29 - 2.20 (m, 2H), 2.17 - 2.02 (m, 6H).

[0356] Preparation of 2-amino-4-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-N-(pyridin-

[0357] 3-yI)benzo[d]thiazoIe -6-carboxamide (Compound 20)

[0358] Step 1 : tert-butyl (4-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-6-(pyridin-3- ylcarbamoyl)benzo[d] thiazol-2-yl)carbamate

[0359] A mixture of tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl)benzo|dJthiazol-2- yl)carbamate (200 mg, 0.445 mmol) in dioxane (4 mL) was added H2O (2 mL), l-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetra hydropyridine (120 mg, 0.53 mmol), Pd(dppf)C12 (40 mg, 0.05 mmol) and Cs2CO3(290 mg, 0.82 mmol). The mixture was stirred at 120°C for 2 h under nitrogen. After completed, the resulting reaction was diluted with H2O, extracted with EA, washed with brine, dried over Na2SC>4, filtered and concentrated, the residue was purified by flash chromatography using fluent MeOH in DCM (0-10%) to give the desired product (103 mg, 49.8% yield) as a yellow solid. LCMS: Calculated Exact Mass =465.2, Found (ESI+) [M+H]+ = 466.2

[0360] Step 2: 2-amino-4-(l -methyl- 1,2, 3, 6-tetrahydropyridin-4-yl)-N-(pyridin-3- yl)benzo[d]thiazole -6-carboxamide

[0361] To a solution of tert-butyl (4-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-6-(pyridin-3- ylcarbamoyl)benzo[d]thiazol -2-yl)carbamate (100 mg, 0.215 mmol) in DCM (5 mL) was added 4 N HC1 (in 1.4-dioxane, 10 mL) at 0°C, and the reaction was stirred at 25°Cfor 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in EA (20 mL) and washed with aq.NaHCO, (20 mL), brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the desired product as a white solid (43 mg, 54.80% yield). LCMS: Calculated Exact Mass =365.1, Found (ESI+) [M+H]+= 366.1

[0362] ’H NMR (400 MHz, DMSO-76) 5 10.33 (s, 1H), 8.93 (d, J = 2.2 Hz, 1H), 8.30 (dd, J = 4.7, 1.4 Hz, 1H), 8.24 - 8.16 (m, 2H), 7.88 (s, 2H), 7.76 (d, J = 1.8 Hz, 1H), 7.39 (dd, 7 = 8.2, 4.7 Hz, 1H), 6.43 - 6.39 (m, 1H), 3.07- 3.01 (m, 2H), 2.74- 2.67 (m, 2H), 2.58 (t, 7 = 5.6 Hz, 2H), 2.30 - 2.2 (m, 2H).

[0363] Preparation of 2-amino-4-(l-methylpiperidin-4-yl)-N-(pyridin-3- yl)benzo[d]thiazole-6-carboxamide (Compound 21)

[0364] Step 1 : tert-butyl(4-(l -methyl-1 ,2,3,6-tetrahydropyridin-4-yl)-6-(pyridin-3- ylcarbamoyl)benzo [d] thiazol-2-yl)carbamate

[0365] To a solution of tert-butyl (4-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-6-(pyridin-3- ylcarbamoyl)benzo [d]thiazol -2-yl)carbamate (200 mg, 0.430 mmol) in MeOH (10 mL) was added Pd(OH)2 / C (50 mg) . The mixture was stirred at 40°C for 16h under H2 at 45psi. The reaction mixture was filtrated and washed with MeOH, the filtration was concentrated and purified by Prep-HPLC to give the desired product as a white solid (103 mg, 50.3% yield).

[0366] LCMS: Calculated Exact Mass =467.2, Found (ESI+) [M+H]+= 468.2

[0367] Step 2: 2-amino-4-(l-methylpiperidin-4-yl)-N-(pyridin-3-yl)benzo[d]thiazole-6- carboxamide

[0368] To a solution of tert-butyl(4-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-6-(pyridin-3- ylcarbamoyl) benzo[d] thiazol -2-yl)carbamate (100 mg, 0.213 mmol) in DCM (2 mL) was added 4 N HC1 (in 1.4-dioxane, 8 mL) at 0°C, and the reaction was stirred at 25°Cfor 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in EA (20 mL) and washed with aq.NaHCCh (20 mL), brine, dried over anhydrous NazSCL, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the desired product as a white solid (34 mg, 43.26% yield). LCMS: Calculated Exact Mass =367.1, Found (ESI+) |M+HJ+= 368.1

[0369] 'H NMR (400 MHz, DMSO-76) 5 10.29 (s, 1H), 8.92 (d, 7 = 2.1 Hz, 1H), 8.32 - 8.28 (m, 1H), 8.21- 8.15 (m, 2H), 7.90 - 7.74 (m, 3H), 7.39 (dd, 7 = 8.3, 4.7 Hz, 1H), 3.21 - 3.11 (m, 1H), 2.94 - 2.86 (m, 2H), 2.22 (s, 3H), 2.02 - 1.74 (m, 6H).

[0370] Preparation of 2-amino-N-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-3- yl)benzo[d]thiazole-6-carboxamide (Compound 22)

[0371] Step 1 : tert-butyl (4-(3,4-dihydro-2H-pyran-5-yl)-6-(pyridin-3- ylcarbamoyl)benzo[d]thiazol-2-yl) carbamate

[0372] A mixture of tert-butyl (4-bromo-6-(pyridin-3-ylcarbamoyl)benzo[d]thiazol-2- yl)carbamate (200 mg, 0.445 mmol) in dioxane (4 mL) was added H O (2 mL), 2-(3,4-dihydro- 2H-pyran-5-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (105 mg, 0.49 mmol), Pd(dppf)CL (40 mg, 0.05 mmol) and CS2CO3 (290 mg, 0.82 mmol). The mixture was stirred at 120°Cfor 2 h under nitrogen. After completed, the resulting reaction was diluted with H2O, extracted with EA, washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by flash chromatography using fluent MeOH in DCM (0-10%) to give the desired product (168 mg, 83.13% yield) as a yellow solid. LCMS: Calculated Exact Mass =452.2, Found (ESI+) [M+H]+ = 453.2

[0373] Step 2: tert-butyl (6-(pyridin-3-ylcarbamoyl)-4-(tetrahydro-2H-pyran-3- yl)benzo[d]thiazol-2-yl) carbamate

[0374] To a solution of tert-butyl (4-(3,4-dihydro-2H-pyran-5-yl)-6-(pyridin-3- ylcarbamoyl)benzo[d]thiazol-2-yl)carba mate (200 mg, 0.412 mmol) in MeOH (10 mL) was added Pd / C (50 mg) . The mixture was stirred at 40°C for 16h under H2 at 45psi. The reaction mixture was filtrated and washed with MeOH, the filtration was concentrated to give the desired product as a white solid (163 mg, 81.1% yield). LCMS: Calculated Exact Mass =454.2, Found (ESI+) [M+H]+= 455.2

[0375] Step 3: 2-amino-N-(pyridin-3-yl)-4-(tetrahydro-2H-pyran-3-yl)benzo[d]thiazole-6- carboxamide

[0376] To a solution of tert-butyl (6-(pyridin-3-ylcarbamoyl)-4-(tetrahydro-2H-pyran-3- yl)benzo[d]thiazol-2-yl) carbamate (100 mg, 0.22 mmol) in DCM (2 mL) was added 4 N HC1 (in 1.4-dioxane, 10 mL) at 0°C, and the reaction was stirred at 25°Cfor 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in EA (20 mL) and washed with aq.NaHCO? (20 mL), brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep- HPLC to give the desired product as a white solid (66 mg, 86.44% yield). LCMS: Calculated Exact Mass =354.1, Found (ESI+) [M+H]+= 355.1

[0377] ’H NMR (400 MHz, DMSO-d6) 5 10.30 (s, 1H), 8.92 (d, J= 2.4 Hz, 1H), 8.30 (dd, J = 4.7, 1.4 Hz, 1H), 8.21 - 8.15 (m, 2H), 7.92 (s, 2H), 7.74 (d, J = 1.5 Hz, 1H), 7.40 (dd, J = 8.3, 4.7 Hz, 1H), 3.97 - 3.86 (m, 2H), 3.54 - 3.47 (m, 2H), 2.04 - 1.91(m, 3H), 1.75 - 1.64 (m, 2H).

[0378] Preparation of 2-amino-4-(3-chlorophenyl)-N-(pyridazin-3-yl)benzo[d]thiazole-6- carboxamide (Compound 23)

[0379] Step 1: ethyl 2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)benzo[d]thiazole-6- carboxylate

[0380] A mixture of ethyl 4-bromo-2-((tert-butoxycarbonyl)amino)benzo[d]thiazole-6- carboxylate (4 g, 10 mmol) in 1.4-dioxane (40 mL) was added H2O (8 mL), (3- chlorophenyl)boronic acid (2 g, 13 mmol), Pd(dppf)C12 (732 mg, 1 mmol) and Cs2CO3(6.5 g, 20 mmol). The mixture was stirred at 120°Cfor 2 h under nitrogen. After completed, the resulting reaction was diluted with H2O, extracted with EA, washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by flash chromatography using fluent EA in PE (0-10%) to give the desired product (3.6 g, 83.72% yield) as a yellow solid. LCMS: Calculated Exact Mass =432.1, Found (ESI+) [M+H]+ = 433.1

[0381] Step 2: 2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)benzo[d]thiazole-6- carboxylic acid

[0382] To a solution of ethyl 2-((tert-butoxycarbonyl)amino)-4-(3- chlorophenyl)benzo[d]thiazole-6-carboxylate (4.5 g, 10.4 mmol) in MeOH (40 mL) was added LiOH (870 mg, 36.4 mmol) in H2O (13 mL). The reaction was stirred at 40°C for 16h and aq. HC1 (IN) was added to adjust pH<3. The mixture was extracted with EA (3 x 20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuum to give the desired product as a white solid (4.1 g, 97.6% yield). LCMS: Calculated Exact Mass = 404.1, Found (ESI+) [M+H]+= 405.1

[0383] Step 3: tert-butyl (4-(3-chlorophenyl)-6-(pyridazin-3-ylcarbamoyl)benzo[d]thiazol-2- yl) carbamate

[0384] To a solution of 2-((tert-butoxycarbonyl)amino)-4-(3-ch]orophenyl)henzo[d]thiazole- 6-carboxylic acid (100 mg, 0.25 mmol) in THF (10 mF) was added DIEA (111 mg, 0.86 mmol), HATU (122 mg, 0.32 mmol) and pyridazin-3 -amine (31 mg, 0.32 mmol) in sequence at 0°C. Then the mixture was stirred at 25 °C for 16 h. After the reaction was completed, the resulting reaction was diluted with H2O (50 mF), extracted with EA (3 x 20 mF). The organic layers were washed with brine (3 x 20 mF), dried over Na2SOr, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM:MeOH=20:l) to give the desired product as a solid (70 mg, 58.33% yield). ECMS: Calculated Exact Mass = 481.1, Found (ES1+) |M+HJ+= 482.1

[0385] Step 4: 2-amino-4-(3-chlorophenyl)-N-(pyridazin-3-yl)benzo[d]thiazole-6- carboxamide

[0386] To a solution of tert-butyl (4-(3-chlorophenyl)-6-(pyridazin-3- ylcarbamoyl)benzo[d]thiazol-2-yl) carbamate

[0387] (200 mg, 0.42 mmol) in DCM (4 mF) was added 4 N HC1 (in 1.4-dioxane, 10 mF) at 0°C, and the reaction was stirred at 25°Cfor 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in EA (20 mF) and washed with aq. N'aHCCh (20 mF), brine, dried over anhydrous NazSCh, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPEC to give the desired product as a white solid (100 mg, 62.5% yield). FCMS: Calculated Exact Mass =381.0, Found (ESI+) [M+H]+= 382.0

[0388] ’H NMR (400 MHz, DMSO-d6) 5 11.51 (s, 1H), 9.02 (d, 7 = 4.6 Hz, 1H), 8.44 - 8.38 (m, 2H), 8.15 (d, 7 = 1.2 Hz, 1H), 8.10 - 7.98 (m, 3H), 7.91 (d, 7 = 7.6 Hz, 1H), 7.74 (dd, 7 = 9.0, 4.7 Hz, 1H), 7.54 - 7.41 (m, 2H).

[0389] Preparation of 2-amino-4-(3-chlorophenyl)-N-(pyrimidin-5-yl)benzo[d]thiazole- 6-carboxamide (Compound 24)

[0390]

[0391] Step 1 : tert-butyl (4-(3-chlorophenyl)-6-(pyrimidin-5-ylcarbamoyl)benzo[d]thiazol-2- yl) carbamate

[0392] To a solution of 2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)benzo[d]thiazole- 6-carboxylic acid (100 mg, 0.25 mmol) in DMF (3 mL) was added DIEA (64 mg, 0.50 mmol), HATU (95 mg, 0.30 mmol) and pyrimidin-5-amine (24 mg, 0.25 mmol) in sequence at 0°C. Then the mixture was stirred at 25 °C for 16 h. After the reaction was completed, the resulting reaction was diluted with H2O (50 mL), extracted with EA (3 x 20 mL). The organic layers were washed with brine (3 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM:MeOH=20:l) to give the desired product as a solid (20 mg, 16.7% yield). LCMS: Calculated Exact Mass = 481.1, Found (ESI+) [M+H]+= 482.1

[0393] Step 2: 2-amino-4-(3-chlorophenyl)-N-(pyrimidin-5-yl)benzo[d]thiazole-6- carboxamide

[0394] To a solution of tert-butyl (4-(3-chlorophenyl)-6-(pyrimidin-5- ylcarbamoyl)benzo[d]thiazol-2-yl) carbamate

[0395] (50 mg, 0.10 mmol) in DCM (4 mL) was added 4 N HC1 (in 1.4-dioxane, 5 mL) at 0°C, and the reaction was stirred at 25 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in EA (20 mL) and washed with aq.NaHCCL (20 mL), brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the desired product as a white solid (30 mg, 78.9% yield). LCMS: Calculated Exact Mass =381.0, Found (ESI+) [M+H]+= 382.0 ’H NMR (400 MHz, CD3OD) 5 9.22 (s, 2H), 8.90 (s, 1H), 8.29 (d, J = 1.9 Hz, 1H), 8.02 (d, J= 1.9 Hz, 1H), 7.91 (t, J= 1.8 Hz, 1H), 7.77 - 7.73 (m, 1H), 7.45 (t, 7 = 7.9 Hz, 1H), 7.40 - 7.36 (m, 1H).

[0396] Preparation of 2-amino-N-(2-aminopyrimidin-5-yl)-4-(3- chlorophenyl)benzo[d]thiazole-6-carboxamide (Compound 25)

[0397] Step 1: tert-butyl (6-((2-aminopyrimidin-5-yl)carbamoyl)-4-(3- chlorophenyl)benzo[d]thiazol -2-yl)carbamate

[0398] To a solution of 2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)benzo[d]thiazole- 6-carboxylic acid (300 mg, 0.75 mmol) in DMF (20 mL) was added DIEA (390 mg, 3.0 mmol), HATU (285 mg, 0.75 mmol) and pyrimidine-2,5-diamine (100 mg, 0.90 mmol) in sequence at 0°C. Then the mixture was stirred at 25 °C for 16 h. After the reaction was completed, the resulting reaction was diluted with H2O (50 mL), extracted with EA (3 x 20 mL). The organic layers were washed with brine (3 x 20 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM: MeOH= 20:1) to give the desired product as a solid (250 mg, 67.2% yield). LCMS: Calculated Exact Mass = 496.1, Found (ESI+) [M+H]+= 497.1

[0399] Step 2: 2-amino-N-(2-aminopyrimidin-5-yl)-4-(3-chlorophenyl)benzo[d]thiazole-6- carboxamide

[0400] To a solution of tert-butyl (6-((2-aminopyrimidin-5-yl)carbamoyl)-4-(3- chlorophenyl)benzo[d]thiazol -2-yl)carbamate (250 mg, 0.5 mmol) in DCM (4 mL) was added 4 N HC1 (in 1.4-dioxane, 10 mL) at 0 °C, and the reaction was stirred at 25 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in EA (20 mL) and washed with aq. NaHCCE (20 mL), brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the desired product as a white solid (120 mg, 60.6% yield). LCMS: Calculated Exact Mass =396.1, Found (ESI+) [M+H]+= 397.1

[0401] ’H NMR (400 MHz, DMSO-76) 5 10.06 (s, 1H), 8.51 (s, 2H), 8.29 (d, J= 1.7 Hz, 1H), 8.02 - 7.97 (m, 3H), 7.92 (d, J = 1.8 Hz, 1H), 7.82 - 7.78 (m, 1H), 7.51 (t, 7 = 7.8 Hz, 1H), 7.47 - 7.42 (m, 1H), 6.53 (s, 2H).

[0402] Preparation of 2-amino-4-(3-chlorophenyI)-N-(l-methyl-lH-imidazol-4- yl)benzo[d]thiazole-6-carboxamide(Compound 26)

[0403] Step 1: tert-butyl (4-(3-chlorophenyl)-6-((l-methyl-lH-imidazol-4- yl)carbamoyl)benzo[d] thiazol-2-yl)carbamate

[0404] To a solution of 2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)benzo[d]thiazole- 6-carboxylic acid (300 mg, 0.75 mmol) in DMF (10 mL) was added DIEA (390 mg, 3.0 mmol), HATU (285 mg, 0.75 mmol) and 1 -methyl- lH-imidazol-4-amine (87 mg, 0.90 mmol) in sequence at 0°C. Then the mixture was stirred at 25°C for 16 h. After the reaction was completed, the resulting reaction was diluted with H2O (50 mL), extracted with EA (3 x 20 mL). The organic layers were washed with brine (3 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM: MeOH= 20:1) to give the desired product as a solid (100 mg, 27.5% yield). LCMS: Calculated Exact Mass = 483.1, Found (ESI+) [M+H]+= 484.1

[0405] Step 2: 2-amino-4-(3-chlorophenyl)-N-(l-methyl-lH-imidazol-4-yl)benzo[d]thiazole- 6-carboxamide To a solution of tert-butyl (4-(3-chlorophenyl)-6-((l-methyl-lH-imidazol-4- yl)carbamoyl)benzo[d] thiazol-2-yl) carbamate (100 mg, 0.21 mmol) in DCM (4 mL) was added 4 N HC1 (in 1.4-dioxane, 10 mL) at 0°C, and the reaction was stirred at 25°Cfor 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in EA (20 mL) and washed with aq.NaHCCL (20 mL), brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the desired product as a white solid (40 mg, 49.4% yield). LCMS: Calculated Exact Mass =383.1, Found (ESI+) [M+H]+= 384.1

[0406] H NMR (400 MHz, DMSO-tfc) 5 10.78 (s, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.07 (d, J = 1.8 Hz, 1H), 8.00 (t, J = 1.8 Hz, 1H), 7.94 (s, 2H), 7.91 - 7.87 (m, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.38 (d, J= 1.3 Hz, 1H), 3.66 (s, 3H).

[0407] Preparation of 2-amino-4-(3-chIorophenyl)-N-(l-methyI-lH-pyrazol-4- yl)benzo[d]thiazole-6-carb oxamide (Compound 28)

[0408] Step 1: tert-butyl (4-(3-chlorophenyl)-6-((l-methyLlH-pyrazol-4- yl)carbamoyl)benzo[d] thiazol-2-yl)carbamate

[0409] To a solution of 2-((tert-butoxycarbonyl)amino)-4-(3-chlorophenyl)benzo[d]thiazole- 6-carboxylic acid (300 mg, 0.75 mmol) in DMF (10 mL) was added DIEA (390 mg, 3.0 mmol), HATU (285 mg, 0.75 mmol) and 1 -methyl- lH-pyrazol-4-amine (87 mg, 0.90 mmol) in sequence at 0°C. Then the mixture was stirred at 25°Cfor 16 h. After the reaction was completed, the resulting reaction was diluted with H2O (50 mL), extracted with EA (3 x 20 mL). The organic layers were washed with brine (3 x 20 mL), dried over NaaSCL. filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM: MeOH= 20:1) to give the desired product as a solid (250 mg, 68.9% yield). LCMS: Calculated Exact Mass = 483.1, Found (ESI+) [M+H]+= 484.1

[0410] Step 2: 2-amino-4-(3-chlorophenyl)-N-(l-methyl-lH-pyrazol-4-yl)benzo[d]thiazole- 6-carb oxamide

[0411] To a solution of tert-butyl (4-(3-chlorophenyl)-6-((l-methyl-lH-pyrazol-4- yl)carbamoyl)benzo[d] thiazol-2-yl) carbamate (250 mg, 0.52 mmol) in DCM (4 mL) was added 4 N HC1 (in 1.4-dioxane, 10 mL) at 0°C, and the reaction was stirred at 25°Cfor 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was dissolved in EA (20 mL) and washed with aq.NaHCCL (20 mL), brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC to give the desired product as a white solid (125 mg, 63.1% yield). LCMS: Calculated Exact Mass =383.1, Found (ESI+) [M+H]+= 384.1

[0412] ’H NMR (400 MHz, CD3OD)5 8.20 (d, J = 1.0 Hz, 1H), 8.03 (s, 1H), 7.93 (d, J = 1.3 Hz, 1H), 7.89 - 7.87 (m, 1H), 7.76 - 7.71 (m, 1H), 7.65 (s, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.38 - 7.35 (m, 1H), 3.89 (s, 3H).

[0413] Preparation of 2-amino-N-(6-aminopyridin-3-yl)-4-(3- chlorophenyl)benzo[d]thiazole-6-carboxamide (Compound 29)

[0414] Step 1 : rert-Butyl (6-((6-aminopyridin-3-yl)carbamoyl)-4-(3- chlorophenyl)benzo[d]thiazol-2-yl)carbamate

[0415] To a solution of 2-((tert-butoxycarbonyl)amino)-4-(2-chlorophenyl)benzo[d]thiazole- 6-carboxylic acid (500 mg, 1.2 mmol) in DMF (10 mL) was added pyridine-2,5-diamine (202 mg, 1.8 mmol), HATU (940 mg, 2.5 mmol) and DIEA (399 mg, 3.0 mmol). The reaction mixture was stirred at 0 °C to room temperature for 5 hours under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by water (20 mL) and extracted with EA (30 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford the product (500 mg, 82 % yield) as brown solid. LCMS: Calculated Exact Mass = 495.1, Found (ESI+) [M+H]+= 496.1.

[0416] Step 2: 2-Amino-N-(6-aminopyridin-3-yl)-4-(3-chlorophenyl)benzo[d]thiazole-6- carboxamide

[0417] To a solution of tert-butyl (6-((6-aminopyridin-3-yl)carbamoyl)-4-(3- chlorophenyl)benzo[d]thiazol-2-yl)carbamate (500 mg, 1.0 mmol) in DCM (10 mL) was added a solution of 4M HC1 in dioxane (10 mL). The reaction mixture was stirred at 0 °C to room temperature for 5 hours under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the solid was collected by filtration, washed with DCM (30mL x 3) and dried under reduced pressure. The crude was purified by MPLC (CH3OH / H2O) to afford the product (20 mg, 5 % yield) as gray solid. LCMS: Calculated Exact Mass = 395.9, Found (ESI+) [M+H]+= 396.9.

[0418] ’H NMR (400 MHz, DMSO) 5 9.97 (s, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.22 (d, J= 2.4 Hz, 1H), 7.97 (s, 3H), 7.92 (t, 7 = 1.7 Hz, 1H), 7.81 (d, 7= 7.8 Hz, 1H), 7.71 (dd, 7 = 8.8, 2.6 Hz, 1H), 7.51 (t, 7= 7.8 Hz, 1H), 7.46 - 7.41 (m, 1H), 6.47 (d, 7 = 8.8 Hz, 1H), 5.81 (s, 2H). Preparation of N-(6-aminopyridin-3-yl)-4-(3-dilorophenyl)benzo[d]thiazoIe-6- carboxamide (Compound 30) Step 1: Ethyl 4-bromobenzo[d]thiazole-6-carboxylate

[0419] To a solution of ethyl 2-amino-4-bromobenzo[d]thiazole-6-carboxylate (12 g, 39.9 mmol) in THF (120 mL) was added isopentyl nitrite (9.4 g, 79.8 mmol). The reaction mixture was stirred at 70 °C for 0.5 hours in oil bath under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by water (100 mL) and extracted with EA (100 mL x 3). The organic layers were combined and washed with brine (100 mL x 3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The reaction mixture was purified by silica gel flash chromatography (PE / EA = 3 / 1) to afford the product (4.5 g, 39% yield) as yellow solid. LCMS: Calculated Exact Mass = 285.0, Found (ESI+) [M+H]+= 286.0.

[0420] Step 2: Ethyl 4-(3-chlorophenyl)benzo[d]thiazole-6-carboxylate

[0421] To a solution of ethyl 4-bromobenzo[d]thiazole-6-carboxylate (2.2 g, 7.7 mmol) in 1,4- dioxane (12.5 mL) and H2O (2.5 mL) was added (3-chlorophenyl)boronic acid (2.4 g, 15.4 mmol), Pd (dppf)Ch (562 mg, 0.8 mmol) and K2CO3 (2.1 g, 15.4 mmol) at 25 °C. The reaction mixture was stirred at 120 °C for 2 hours under microwave irradiation. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by water (20 mL) and extracted with EA (40 mL x 3). The organic layers were combined and washed with brine (30 mL x 3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The reaction mixture was purified by silica gel flash chromatography (PE / EA = 3 / 1) to afford the product (1.1 g, 46% yield) as white solid. LCMS: Calculated Exact Mass = 317.0, Found (ESI+) [M+H]+= 318.0.

[0422] Step 3: 4-(3-Chlorophenyl)benzo[d]thiazole-6-carboxylic acid

[0423] To a solution of ethyl 4-(3-chlorophenyl)benzo[d]thiazole-6-carboxylate (1.1 g, 3.5 mmol) in MeOH (10 mL) and H2O (2.5 mL) was added LiOH (332 mg, 13.8 mmol). The reaction mixture was stirred at 60 °C for 5 hours in oil bath under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the reaction mixture was adjusted PH to 3 with HC1 (3 mol / L). The reaction mixture was quenched by water (20 mL) and extracted with EA (20 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford the product (900 mg, 90% yield) as white solid. LCMS: Calculated Exact Mass = 289.0, Found (ESI+) [M-H]+= 288.0.

[0424] Step 4: Synthesis of N-(6-aminopyridin-3-yl)-4-(3-chlorophenyl)benzo[d]thiazole-6- carboxamide (Compound 30)

[0425] To a solution of 4-(3-chlorophenyl)benzo|d|lhiazole-6-carboxylic acid (200 mg, 0.7 mmol) in DMF (10 mL) was added pyridine-2,5-diamine (152 mg, 1.4 mmol), HATU (532 mg, 1.4 mmol) and DIEA (270 mg, 2.1 mmol). The reaction mixture was stirred at 0 °C to room temperature for 5 hours under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by water (30 mL) and extracted with EA (50 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The reaction mixture was purified by MPLC (MeOH / H2O) to afford the product (37.7 mg, 14% yield) as purple solid. LCMS: Calculated Exact Mass = 380.0, Found (ESI+) [M+H]+= 381.0

[0426] 'H NMR (400 MHz, DMSO) 8 10.91 (s, 1H), 9.65 (s, 1H), 8.87 (d, J = 1.5 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 1.5 Hz, 1H), 8.23 (dd, J = 9.5, 2.1 Hz, 1H), 8.05 (s, 1H), 7.94 (d, J = 7.5 Hz, 2H), 7.64 - 7.51 (m, 2H), 7.06 (d, J = 9.5 Hz, 1H).

[0427] Preparation of 4-(3-chlorophenyl)-N-(6-morpholinopyridin-3- yl)benzo[d]thiazole-6-carboxamide (Compound 31)

[0428] To a solution of 4-(3-chlorophenyl)benzo[d]thiazole-6-carboxylic acid (400 mg, 1.4 mmol) in DMF (10 mL) was added 6-morpholinopyridin-3-amine (500 mg, 2.8 mmol), HATU (760 mg, 2.0 mmol) and DIEA (387 mg, 3.0 mmol). The reaction mixture was stirred at 0 °C to room temperature for 5 hours under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by water (30 mL) and extracted with EA (50 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The reaction mixture was purified by MPLC ( MeOH / tLO) to afford the product (235 mg 37% yield) as purple solid. LCMS: Calculated Exact Mass = 450.1, Found (ESI+) [M+H]+= 451.2.

[0429] ’H NMR (400 MHz, MeOD) 5 9.44 (s, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.29 (dd, J = 9.8, 2.5 Hz, 1H), 8.22 (d, J = 1.7 Hz, 1H), 7.97 (t, J = 1.7 Hz, 1H), 7.89 - 7.81 (m, 1H), 7.56 - 7.44 (m, 3H), 3.94 - 3.83 (m, 4H), 3.75 - 3.63 (m, 4H). Preparation of 4-(3-chlorophenyl)-N-(6-(piperazin-l-yl)pyridin-3- yI)benzo[d]thiazole-6-carboxamide (Compound 32)

[0430] Step 1 : Tert-butyl 4-(5-(4-(3-chlorophenyl)benzo[d]thiazole-6-carboxamido)pyridin- 2-yl)piperazine- 1 -carboxylate

[0431] To a solution of 4-(3-chlorophenyl)benzo[d]thiazole-6-carboxylic acid (300 mg, 1.0 mmol) in DMF (10 mL) was added tert-butyl 4-(5-aminopyridin-2-yl)piperazine-l- carboxylate (500 mg, 1.8 mmol), HATU (760 mg, 2.0 mmol) and DIEA (387 mg, 3.0 mmol). The reaction mixture was stirred at 0 °C to room temperature for 5 hours under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by water (20 mL) and extracted with EA (20 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The reaction mixture was purified by silica gel flash chromatography (PE / EA = 4 / 1) to afford the product (300 mg 52% yield) as yellow solid. LCMS: Calculated Exact Mass = 549.2, Found (ESI+) [M+H]+= 550.2.

[0432] Step 2: 4-(3-Chlorophenyl)-N-(6-(piperazin- l-yl)pyridin-3-yl)benzo[d]thiazole-6- carboxamide (Compound 32)

[0433] To a solution of Tert-butyl 4-(5-(4-(3-chlorophenyl)benzo[d]thiazole-6- carboxamido)pyridin-2-yl)piperazine-l -carboxylate (200 mg, 0.36 mmol) in DCM (10 mL) was added a solution of 4M HC1 in dioxane (10 mL). The mixture was stirred at 0 °C to RT for 5 hours under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the solid was collected by filtration and washed with DCM (30mL x 3) and dried under reduced pressure to afford the product HC1 salt (95 mg, 54% yield) as yellow solid. LCMS: Calculated Exact Mass = 449.1, Found (ESI+) [M+H]+= 450.0

[0434] ’H NMR (400 MHz, MeOD) 5 9.45 (s, 1H), 8.91 (d, J = 2.5 Hz, 1H), 8.75 (d, J = 1.7 Hz, 1H), 8.40 (dd, 7 = 9.8, 2.5 Hz, 1H), 8.23 (d, 7 = 1.8 Hz, 1H), 7.97 (t, 7 = 1.7 Hz, 1H), 7.84 (dt, 7 = 7.6, 1.4 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.53 - 7.45 (m, 2H), 4.06 - 3.96 (m, 4H), 3.54 3.44 (m, 4H).

[0435] Preparation of 2-amino-4-(3-chIorophenyl)-N-(6-morphoIinopyridin-3- yl)benzo[d]thiazole-6-carboxamide (Compound 33)

[0436]

[0437] Step 1 : tert-butyl (4-(3-chlorophenyl)-6-((6-morpholinopyridin-3- yl)carbamoyl)benzo[d]thiazol-2-yl)carbamate To a solution of 2-((tert-butoxycarbonyl)amino)-4-(2-chlorophenyl)benzo[d]thiazole-

[0438] 6-carboxylic acid (500 mg, 1.2 mmol) in DMF (10 mL) was added 6-morpholinopyridin-3- amine (332 mg, 1.8 mmol), HATU (940 mg, 2.5 mmol) and DIEA (399 mg, 3.0 mmol). The reaction mixture was stirred at 0 °C to room temperature for 5 hours under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by water (20 mL) and extracted with EA (30 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford the product (500 mg, 72 % yield) as brown solid. LCMS: Calculated Exact Mass = 565.2, Found (ESI+) [M+H]+= 566.2.

[0439] Step 2: 2-Amino-4-(3-chlorophenyl)-N-(6-morpholinopyridin-3-yl)benzo[d]thiazole- 6-carboxamide (Compound 33)

[0440] To a solution of tert-butyl (4-(3-chlorophenyl)-6-((6-morpholinopyridin-3- yl)carbamoyl)benzo[d]thiazol-2-yl)carbamate (500 mg, 0.9 mmol) in DCM (10 mL) was added a solution of 4M HC1 in dioxane (10 mL). The reaction mixture was stirred at 0 °C to room temperature for 5 hours under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the solid was collected by filtration, washed with DCM (30mL x 3) and dried under reduced pressure. The crude was purified by MPLC (CH3OH / H2O with 0.1% HC1) to afford the product (90 mg, crude) as yellow solid. The crude was purified by Prep-HPLC (CH3CN / H2O with 0.05% FA) to afford the product (34.1 mg, 29 % yield) as pale yellow solid. LCMS: Calculated Exact Mass = 466.0, Found (ESI+) [M+H]+= 467.0.

[0441] ’H NMR (400 MHz, DMSO) 5 10.12 (s, 1H), 8.48 (d, 7= 2.6 Hz, 1H), 8.30 (d, 7 = 1.8 Hz, 1H), 7.98 (d, 7 = 1.7 Hz, 3H), 7.96 - 7.91 (m, 2H), 7.83 - 7.77 (m, 1H), 7.51 (t, 7 = 7.9 Hz, 1H), 7.43 (ddd, 7 = 8.0, 2.1, LI Hz, 1H), 6.87 (d, 7 = 9.1 Hz, 1H), 3.74 - 3.69 (m, 4H), 3.42 - 3.38 (m, 4H).

[0442] Preparation of 2-amino-4-(3-chlorophenyl)-N-(6-(piperazin-l-yl)pyridin-3- yI)benzo[d]thiazole-6-carboxamide (Compound 34)

[0443]

[0444] Step 1: tert-Butyl 4-(5-(2-((tert-butoxycarbonyl)amino)-4-(3- chlorophenyl)benzo[d]thiazole-6-carboxamido)pyridin-2-yl)piperazine-l-carboxylate To a solution of 2-((tert-butoxycarbonyl)amino)-4-(2-chlorophenyl)benzo[d]thiazole-

[0445] 6-carboxylic acid (500 mg, 1.2 mmol) in DMF (10 mL) was added tert-butyl 4-(5- aminopyridin-2-yl)piperazine- 1 -carboxylate (516 mg, 1.8 mmol), HATU (940 mg, 2.5 mmol) and DIEA (399 mg, 3.0 mmol). The reaction mixture was stirred at 0 °C to room temperature for 5 hours under N atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by water (20 mL) and extracted with EA (30 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The reaction mixture was purified by silica gel flash chromatography (PE / EA = 4 / 1) to afford the product (380 mg, 61% yield) as yellow solid. LCMS: Calculated Exact Mass = 664.2, Found (ESI+) [M+H]+= 665.2. Step 2: 2-Amino-4-(3-chlorophenyl)-N-(6-(piperazin-l-yl)pyridin-3- yl)benzo[d]thiazole-6-carboxamide (Compound 34)

[0446] To a solution of tert-butyl 4-(5-(2-((tert-butoxycarbonyl)amino)-4-(3- chlorophenyl)benzo[d]thiazole-6-carboxamido)pyridin-2-yl)piperazine-l -carboxylate (380 mg, 0.6 mmol) in DCM (10 mL) was added a solution of 4M HC1 in dioxane (10 mL). The reaction mixture was stirred at 0 °C to room temperature for 5 hours under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the solid was collected by filtration, washed with DCM (30mL x 3) and dried under reduced pressure to afford the product HC1 salt (267 mg, 93 % yield) as pale yellow solid. LCMS: Calculated Exact Mass = 501.4, Found (ESI+) [M+H]+= 502.4.

[0447] ’H NMR (400 MHz, DMSO) 5 10.08 (s, 1H), 8.44 (d, J = 2.6 Hz, 1H), 8.30 (d, J = 1.8 Hz, 1H), 7.98 (s, 3H), 7.93 - 7.87 (m, 2H), 7.83 - 7.78 (m, 1H), 7.51 (t, J = 7.9 Hz, 1H), 7.44 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H), 6.83 (d, 7= 9.2 Hz, 1H), 3.82 (s, 1H), 3.38 - 3.35 (m, 4H), 2.88 - 2.76 (m, 4H).

[0448] Preparation of 2-amino-4-(3-chlorophenyl)-N-(6-hydroxypyridin-3- yl)benzo[d]thiazole-6-carboxamide (Compound 35)

[0449]

[0450] Step 1: tert-Butyl (4-(3-chlorophenyl)-6-((6-hydroxypyridin-3- yl)carbamoyl)benzo[d]thiazol-2-yl)carbamate To a solution of 2-((tert-butoxycarbonyl)amino)-4-(2-chlorophenyl)benzo[d]thiazole-

[0451] 6-carboxylic acid (500 mg, 1.2 mmol) in DMF (10 mL) was added 5-aminopyridin-2(lH)-one (204 mg, 1.8 mmol), BTFFH (782 mg, 2.5 mmol) and DIEA (399 mg, 3.0 mmol). The reaction mixture was stirred at 0 °C to room temperature for 5 hours under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by water (20 mL) and extracted with EA (30 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford the product (500 mg, 82% yield) as white solid. LCMS: Calculated Exact Mass = 496.1, Found (ESI+) [M+H]+= 497.1.

[0452] Step 2: 2-amino-4-(3-chlorophenyl)-N-(6-hydroxypyridin-3-yl)benzo[d]thiazole-6- carboxamide (Compound 35)

[0453] To a solution of tert-butyl (4-(3-chlorophenyl)-6-((6-hydroxypyridin-3- yl)carbamoyl)benzo[d]thiazol-2-yl)carbamate (500 mg, 1.0 mmol) in DCM (10 mL) was added a solution of 4M HC1 in dioxane (10 mL). The reaction mixture was stirred at 0 °C to room temperature for 5 hours under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the solid was collected by filtration, washed with DCM (30mL x 3) and dried under reduced pressure. The crude was purified by MPLC (CH3OH / H2O) to afford the product (20 mg, 5% yield) as white solid.

[0454] !H NMR (400 MHz, DMSO) 8 11.53 (s, 1H), 9.99 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 7.98 (s, 2H), 7.95 (dd, 7 = 7.7, 2.3 Hz, 2H), 7.91 (t, J = 1.8 Hz, 1H), 7.81 - 7.77 (m, 1H), 7.68 (dd, J = 9.7, 2.9 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.44 (ddd, J = 8.0, 2.1 , 1.1 Hz, 1H), 6.40 (d, J = 9.7 Hz, 1H).

[0455] Preparation of 4-(3-chlorophenyl)-N-(6-hydroxypyridin-3-yl)benzo[d]thiazole-6- carboxamide (Compound 36)

[0456] To a solution of 4-(3-chlorophenyl)benzo[d]thiazole-6-carboxylic acid (200 mg, 0.7 mmol) in DMF (10 mL) was added BTFFH (442 mg, 1.4 mmol), DIEA (225 mg, 1.7 mmol) and 5-aminopyridin-2(lH)-one (154 mg, 1.4 mmol). The reaction mixture was stirred at 0 °C to room temperature for 6 hours under N2 atmosphere via balloon. The reaction was monitored by LCMS. Upon completion, the reaction mixture was quenched by water (20 mL) and extracted with EA (20 mL x 3). The organic layers were combined and washed with brine (20 mL x 3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The reaction mixture was purified by MPLC (CH3OH / H2O) to afford the product (27 mg, 18 % yield) as white solid. LCMS: Calculated Exact Mass = 381.0, Found (ESI+) [M+H]+= 382.0 ’H NMR (400 MHz, DMSO) 5 11.52 (s, 1H), 10.28 (s, 1H), 9.62 (s, 1H), 8.77 (s, 1H), 8.21 (s, 1H), 8.07 - 7.98 (m, 2H), 7.91 (d, J= 7.5 Hz, 1H), 7.71 (dd, J= 9.8, 2.5 Hz, 1H), 7.61 - 7.53 (m, 2H), 6.43 (d, J = 9.7 Hz, 1H).

[0457] BIOLOGICAL ASSAY METHODS

[0458] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following assays and methods may be modified by choice of suitable materials and methods.

[0459] EXAMPLE 1

[0460] PDE4 enzyme assay-cAMP detection

[0461] The inhibition of cAMP production at the human PDE4B was evaluated using Revvity’s cAMP Gi kit as described by the manufacturer. Compounds were serially diluted as 10-points in 100% DMSO, and 90 nL of the serially diluted compounds were distributed into a 384-well assay plate (6007290, PerkinElmer) by using liquid handler equipment (mosquito® LV, sptlabtech). 5 pL of full length and kinase domain of PDE4 protein diluted in reaction buffer (IX HBSS, 5 mM HEPES, 3 mM MgCh, 0.1 % BSA, pH 7.4) were transferred into each well using a liquid handling instrument, Apricot S2, to make its final concentration in 0.5 nM and 2.5 nM respectively. After this, the above plates were placed on a plate shaker and incubated at room temperature for lOmin. 5 pL of cAMP were dispensed into each well to make its final concentration in 16 nM, after spin at 1000 rpm for 10s, place the plate at room temperature for 1-hour incubation. A mixer of 5 pL of IX cAMP Eu Cryptate reagent working solution and 5 pL of IX cAMP d2 antibody working solution diluted in Lysis & detection Buffer8 and supplemented with 1 mM IB MX was added into each well. Then, the assay plates were incubated at room temperature for another 1 hour. The fluorescence was read using an EnVision plate reader (PerkinElmer) with excitation at 330 nm and emissions of 615 and 665 nm.

[0462] A33 D'28 Apremites^ Table 3. Hill slope and IC50 values for compounds against PDE4B2 full-length protein and PDE4B2 catalytic domain only.

[0463] N / A = not available

[0464] * Data provided from a second independent trial PDE4 cell-based cAMP detection

[0465] The inhibition of cAMP production by human PDE4 isoforms was evaluated using Meso Scale Discovery cAMP kit as described by the manufacturer. HEK293 cells were seeded into 96 well-plates and incubated for 2 hrs at 37 °C with 5% CO2 to ensure adherence. PDE4B 1 was transfected into HEK293 cells using Lipofectamine. Compounds were assayed at 10 pM concentrations in DMSO diluted in PBS. HEK293 control cells were used to determine PDE4A / PDE4D selectivity due to endogenously high levels of these isoforms as determined by qPCR. HEK293-PDE4B1 overexpression was used to determine PDE4B selectivity. Cells were pre-treated with forskolin for 1 hour, followed by treatment with the PDE4 inhibitor for 15 minutes prior to measuring cAMP (pM) accumulation using the MSD plate reader (Meso Scale Discovery). Results are shown in Fig. 1.

[0466] EXAMPLE 2

[0467] Animal Models and Housing:

[0468] All experiments were conducted in accordance with institutional animal care guidelines. Scnla+ / - and wild-type (WT) mice (B6129F1) were housed in temperature- and humidity-controlled rooms under a 12-hour light / dark cycle with ad libitum access to food and water. Kvl.l (kcnal- / - and GABA_A1 receptor (gabral- / -} knockout zebrafish (Danio rerio) were similarly maintained. Zebrafish were housed in standard aquaria at 28 °C with a 14-hour light / 10-hour dark cycle and fed twice daily.

[0469] Pharmacological Treatments:

[0470] Compound 1, in a vehicle of 1:1 :4:4 (DMSO: Tween-80: fractionated coconut oil: sterile water), was administered at 40 mg / kg via oral gavage twice daily in mice, or diluted in DMSO to a concentration of 50 pM in E3 media (5.0mM NaCl, 0,17mM KC1, 0.33mM CaCh, 0.33MgSO4, and O.lmg / L Methylene Blue) for zebrafish studies. Positive controls included Valproic Acid (VPA, 250 mg / kg in mice, 50 pM in fish), Carbamazepine (CBZ, 50 pM), Levetiracetam (LEV, 50 pM), Lamotrigine (LTG, 50 pM), and VPA + Clobazam (VPA 50 pM + CLO, 50 pM). Vehicle groups received an equivalent volume of the drug solvent.

[0471] Seizure Monitoring via Video-EEG (vEEG) in Scnla+ / - Mice (Figures 2A and 2B):

[0472] Scnla+ / ~ mice were implanted with epidural EEG electrodes on postnatal day 18 and continuously monitored for 10 days using a tethered video-EEG monitoring system (Pinnacle Technology, Inc.) beginning on postnatal day 20. Pharmacological treatments or vehicle were administered on the first day of vEEG monitoring, and for 10 days thereafter. Video-EEG data was acquired at a sampling rate of 250 Hz and bandpass filtered at 0.5 - 100 Hz. Seizure frequency (seizures per day) was quantified over the 10-day treatment period in Compound 1 or vehicle-exposed Scnla+ / _mice (Fig. 2A). Seizures were scored using a modified Racine scale: 1, mouth and facial automatisms; 2, head-nodding; 3, unilateral forelimb clonus; 4, bilateral forelimb clonus with rearing; 5, generalized tonic-clonic seizure, rearing, falling over; 6, generalized tonic-clonic seizure with uncontrolled and erratic running and jumping. In a separate analysis, mice exhibiting severe phenotypes (Racine stage > 4 in the first 48 hours) were excluded from seizure activity and survival assays (Fig. 2B).

[0473] Locomotor Seizure Activity in Genetic and PTZ-Induced Zebrafish Models (Figure 3):

[0474] 5-day post fertilization (dpf) kvl.l- / - kcnal- / -) and GABA_A1- / - gabral- / -) knockout zebrafish larvae were acclimated in the Zebrabox (ViewPoint Behavior Technology) for 30 mins and assessed for seizure activity using accepted locomotor methodology. Larvae demonstrating confirmed seizure activity at baseline were used for experiments moving forward. Tail Long (TL, wild type) 5dpf zebrafish larvae were exposed to PTZ (5 mM) for 30 mins during acclimation phase in the Zebrabox and assessed for seizure activity. TL larvae with confirmed seizure activity at baseline were selected for experiments moving forward. An additional set of TL larvae exposed to Vehicle were acclimated and used for experiments as a negative control.

[0475] Following acclimation, baseline locomotor readings were taken on all zebrafish. Larvae were then exposed to Compound 1, VPA, CBZ, LEV, LTG or VPA + CLO for 1.5 hours and test locomotor readings were collected. Following test readings, larvae moved to fresh plates with E3 for continued monitoring following drug washout.

[0476] Maximal Electroshock Seizure (MES) Model (Fig. 4):

[0477] WT mice, approximately 60 days old, were subjected to MES stimulation (60 Hz, 0.6 ms pulse width, 0.2 sec duration, 50 mA) using ear clip electrodes. Compound 1 or Vehicle was administered for 3 days, with the last dose given 40 minutes before MES testing. VPA was administered 10 minutes prior to MES stimulation.

[0478] Survival Analysis (Figs. 5 A and 5B):

[0479] Scnla+ / - mice were monitored for survival following removal of vEEG probes in their home cages. Kaplan-Meier survival analysis was conducted to compare Compound 1 vs. vehicle groups. Median survival following treatment cessation was also assessed.

[0480] Barnes Maze Test for Learning, Memory and Search Strategy (Fig. 6A):

[0481] WT mice exposed to Vehicle or Compound 1 , and Scnla+ / - mice exposed to Vehicle or Compound 1, approximately 60 days old, were trained using an accelerated Barnes Maze protocol across 4 days with a probe trial on day 5. On day 1, the mice were habituated to the maze and the escape box, on days 2-4 mice received 4, 3-minute training trials with a 15- minute inter-trial-interval, for a total of 12 training trials. Learning curves were generated and represented as the “latency to escape” during each trial. On day 5 (24-hour probe trial), the escape box was removed, and mice were given 1 -minute to freely explore the maze. Time spent near the “target hole” during the probe trial was quantified post-treatment with Compound 1 or Vehicle.

[0482] Y-Maze Test for Spatial Recognition Memory (Fig. 6B):

[0483] Mice were tested for spatial recognition memory using a forced Y-maze. On the training trial, mice were placed in a Y-maze with one arm blocked and allowed to explore freely for 5 minutes and then returned to their home-cage. After a 30-minute inter-trial-interval, the closed arm of the Y-maze was opened, and mice were returned for a 5-minute probe trial. The number of novel arm entries was recorded as an indicator of working memory and spatial recognition in WT and Scnla+ / - mice treated with Compound 1 or Vehicle.

[0484] Marble Burying Test for Anxiety and Repetitive Behaviors (Fig. 7A):

[0485] The marble burying test was conducted to assess repetitive and anxiety-related behaviors in WT and Scnla+ / - epileptic mice treated with Compound 1 or vehicle. Mice were placed in a static-cage with 5 cm of clean bedding arrayed with 18 evenly spaced glass marbles and allowed to explore for 30 minutes. The number of buried marbles (>2 / 3 covered) were quantified. Greater numbers of buried marbles is an indicator of repetitive and anxiety-like behaviors.

[0486] Open Field Test with novel object (Figs. 7B and 7C):

[0487] The open field test with a novel object was used to evaluate locomotor activity, exploration, and anxiety-like behavior in WT mice exposed to Compound 1 or vehicle. Mice were placed in a 50 x 50 cm arena under moderate lighting, with a novel object positioned at the center. Behavior was recorded over 10 minutes, measuring total distance traveled and time spent in the center zone. Increased time in the center was interpreted as reduced anxiety, while reduced movement suggested potential sedation or altered exploratory behavior.

[0488] Statistical Analysis:

[0489] Data were analyzed using GraphPad Prism. Statistical significance was assessed using two-way ANOVA with Sidak’s post hoc test, Kaplan-Meier survival analysis, and unpaired t- tests, where appropriate. Data are presented as mean ± SEM with p-values indicated (p < 0.05 considered significant).

[0490] INCORPORATION BY REFERENCE

[0491] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0492] EQUIVALENTS While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula (I),or a pharmaceutically acceptable salt, wherein:R1is amino, H, or alkyl;R2is heteroaryl, heterocyclyl, cycloalkyl, or aryl; andR3is aryl, heterocyclyl, cycloalkyl, or heteroaryl.

2. The compound of claim 1 , wherein R2is heteroaryl.

3. The compound of claim 1 or 2, wherein R2is pyridyl, pyridone, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, or oxazolyl.

4. The compound of any one of claims 1-3, wherein R2is pyridyl (e.g., 3-pyridyl).

5. The compound of any one of claims 1-4, wherein R2is optionally substituted with amino (e.g., -NH2, morpholinyl, or piperazinyl) or alkyl (e.g., Ci-Ce alkyl).

6. The compound of any one of claims 1-5, wherein R2is selected from the group consisting of7. The compound of any one of claims 1-6, wherein R3is optionally substituted with halo, cyano, sulfone, nitro, ketone, or alkyl.

8. The compound of any one of claims 1-7, wherein R3is aryl.

9. The compound of any one of claims 1-8, wherein R3is phenyl, wherein each hydrogen atom in phenyl is independently optionally substituted by halo, cyano, sulfone, nitro, ketone, or alkyl.

10. The compound of any one of claims 1-9, wherein R3is phenyl, wherein each hydrogen atom in phenyl is independently optionally substituted by halo (e.g., chloro).

11. The compound of any one of claims 1-10, wherein R3is 3-chlorophenyl.

12. The compound of any one of claims 1-9, wherein R3is phenyl, wherein each hydrogen atom in phenyl is independently optionally substituted by nitro.

13. The compound of any one of claims 1-9 or 12, wherein R3is 3-nitrophenyl.

14. The compound of any one of claims 1-7, wherein R3is heteroaryl.

15. The compound of any one of claims 1-7 or 14, wherein R3is thienyl, wherein each hydrogen atom in thienyl is independently optionally substituted by halo (e.g., chloro).

16. The compound of any one of claims 1-7, wherein R3is heterocyclyl.

17. The compound of any one of claims 1-7 or 16, wherein R3is tetrahydropyranyl, dihydropyranyl, piperidinyl, or tetrahydropyridinyl.

18. The compound of any one of claims 1-7 or 16-17, wherein R3is piperidinyl or tetrahydropyridinyl, wherein each hydrogen atom in piperidinyl or tetrahydropyridinyl is independently optionally substituted with alkyl (e.g., Ci-Ce alkyl).

19. The compound of any one of claims 1-7, wherein R3is cycloalkyl.

20. The compound of any one of claims 1-7 or 19, wherein R3is cyclohexyl, wherein each hydrogen atom in cyclohexyl is independently optionally substituted by halo (e.g., fluoro).

21. The compound of any one of claims 1-7, wherein R3is selected from the group consisting of22. The compound of any one of the preceding claims, wherein R1is H or NH2.

23. The compound of claim 1, wherein the compound is of formula (II)or a pharmaceutically acceptable salt thereof, wherein:R2is heteroaryl or aryl; andR3is heterocyclyl, cycloalkyl, heteroaryl, or aryl.

24. The compound of claim 1, wherein the compound is of formula (III)or a pharmaceutically acceptable salt thereof, wherein: each of X1and X3is independently CH or N;X2is CH or C-NH2;R1is H, amino, or alkyl; andR3is heterocyclyl, cycloalkyl, heteroaryl, or aryl;provided that at least one of X1and X3is not N.

25. The compound of claim 1, wherein the compound is of formula (Illa)(Illa), or a pharmaceutically acceptable salt thereof, wherein: each of X1and X3is independently CH or N;R1is H, amino, or alkyl;R3is heterocyclyl, cycloalkyl, heteroaryl, or aryl; andR5is H or amino; provided that at least one of X1and X3is not N.

26. The compound of claim 1 , wherein the compound is of formula (Illb)(Illb), or a pharmaceutically acceptable salt thereof, wherein:R1is H, amino, or alkyl;R4is halo, cyano, sulfone, nitro, ketone, or alkyl; and R5is H or amino.

27. The compound of claim 1, wherein the compound is of formula (IV)or a pharmaceutically acceptable salt thereof, wherein:R4is halo, cyano, sulfone, nitro, ketone, or alkyl.

28. The compound of claim 1 , selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1 , selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

30. The compound of any one of the preceding claims, wherein the compound is a pharmaceutically acceptable salt.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 -30 and a pharmaceutically acceptable excipient.

32. A method of treating a disease in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound according to any one of claims 1-30.

33. The method of claim 32, wherein the disease is an inflammatory disease selected from the group consisting of a pulmonary inflammatory disease, a dermatological inflammatory disease, and a neurological inflammatory disease.

34. The method of claim 33, wherein the disease is an inflammatory disease selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), psoriasis, atopic dermatitis, inflammatory bowel disease, and rheumatoid arthritis.

35. The method of claim 32, wherein the disease is a cognitive or affective disorder selected from the group consisting of a learning disorder, memory loss, and Fragile X syndrome.

36. The method of claim 32, wherein the disease is a cancer.

37. The method of claim 36, wherein the cancer is a solid tumor.

38. The method of claim 36, wherein the cancer is isesophageal cancer, brain cancer, pancreatic cancer, colon cancer, hematologic cancer, lung cancer, prostate cancer, skin cancer, head and neck cancer, CNS cancer, gastric cancer, breast cancer, bladder cancer, or ovarian cancer.

39. The method of claim 32, wherein the disease is a central nervous system disorder (e.g., epilepsy).

40. The method of claim 39, wherein the central nervous system disorder is a neurodevelopmental disorder (e.g., epilepsy, autism, attention deficit disorder (ADD), or attention deficit hyperactivity disorder (ADHD)), an acute neurological disorder (e.g., stroke or traumatic brain injury), a neurodegenerative disorder (e.g., Alzheimer’s disease, dementia, multiple sclerosis, or Huntington’s disease), or a psychological / mental disorder (e.g., schizophrenia, depression, anxiety (e.g., generalized anxiety disorder or social anxiety), bipolar disorder, addiction, or obsessive compulsive disorder (OCD)).