Use of therapeutic agents with phosphodiesterase-7 inhibitory activity for the treatment and prevention of diseases associated with chronic fatigue, exhaustion and / or exertion intolerance

Abstract

The present invention relates to the use of substances having phosphodiesterase-7 inhibitory activity (PDE7 inhibitors) as active ingredients in therapeutic agents having phosphodiesterase-7 activity for the treatment and prevention of various diseases, syndromes, pathologies, or conditions associated with chronic fatigue, exhaustion, and / or exertion intolerance, using the PDE7 inhibitors alone or in combination with other therapeutic agents.

Description

[Technical Field]

[0001] The present invention relates to the use of substances having phosphodiesterase-7 inhibitory activity (PDE7 inhibitors) as active ingredients in therapeutic agents having phosphodiesterase-7 inhibitory activity for the treatment and prevention of various diseases, syndromes, pathologies, or conditions associated with chronic fatigue, exhaustion, and / or exertion intolerance, using the PDE7 inhibitors alone or in combination with other therapeutic agents. These diseases, syndromes, conditions, or conditions are encompassed by the term "chronic fatigue-related disorders" and abbreviated as (DACF), and include Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS), Systemic Exertional Intolerance, Exertional Intolerance, Long COVID complaints, Post-Covid-19 syndrome (PCS), Post-acute Covid syndrome (PACS), Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), Post-COVID-19 vaccination and post-vaccination syndrome against other pathogenic bacteria, viruses, and pathogens (Long Vax), and post-infectious fatigue after viral, bacterial, or fungal infections, particularly ME / CFS of non-infectious, non-inflammatory, and non-immune causes, cancer-related fatigue (where the chronic fatigue and exhaustion are symptoms of, or are related to, cancer), and disorders diagnosed as fatigue associated with fibromyalgia, Ehlers-Danlos syndrome, Marfan syndrome, Gulf War illness, and the autoimmune diseases rheumatoid arthritis, ANCA-associated vasculitis (antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis) and Sjogren's syndrome, and other autoimmune diseases with fatigue and exhaustion as debilitating symptoms. [Background technology]

[0002] PDE7 inhibitors are known, and their treatment is described in the context of inflammation, immunomodulation, immune system-related tumor diseases, respiratory diseases, circulatory diseases (acute myocardial infarction, stroke), neurodegenerative disorders (multiple sclerosis, Alzheimer's disease, Parkinson's disease), other neurological disorders (spinal cord injury, schizophrenia) and withdrawal from various addictions, for example, in US11,207,275, US8,846,654.The claim of treating neurodegenerative diseases and neurological diseases is based on the assumption that PDE7 inhibition exerts anti-inflammatory effects and treats autoimmune mechanisms in the nervous system.

[0003] The pathophysiology of chronic fatigue-related disorders (DACF) has been largely enigmatic, making it impossible to derive or develop rationally based pharmacological or therapeutic strategies. Therefore, specific effective treatments do not exist due to the lack of understanding of these disorders and their pathophysiology.

[0004] The present invention is directed to the analysis of sodium-potassium ATPase (Na ATPase) in skeletal muscle. + / K + This was established by a unified and comprehensive disease hypothesis stated by the present inventors, who found that it is possible to treat DACF by stimulating sodium-potassium ATPase (Na ATPase). The present inventors have found that an increase in cAMP (cyclic adenosine monophosphate) via PDE7 inhibition in skeletal muscle (muscle cells) stimulates the activity of sodium-potassium ATPase (Na ATPase). + / K + ATPase, which plays a strong pathophysiological role in the development and perpetuation of chronic fatigue, exhaustion, and / or exertion intolerance. + ) and subsequent intracellular and mitochondrial calcium (Ca 2+We have found that this prevents undesirable ion changes in the mitochondrial calcium transporter (NCLX). A second transporter equally important for preventing mitochondrial calcium overload is the mitochondrial sodium-calcium exchanger (NCLX), which exports calcium from mitochondria in exchange for sodium, limiting and preventing mitochondrial calcium overload. The activity of NCLX is also stimulated by cAMP. Therefore, the increase in cAMP due to PDE7 inhibition has a synergistic effect on these two ion transporters, preventing calcium overload and damage to cells and mitochondria. The increase in cAMP can be achieved by administering a PDE7 inhibitor, which inhibits the hydrolysis of cAMP and increases its level. Furthermore, the increase in cAMP due to PDE7 inhibition also occurs in the blood vessels of skeletal muscle and the brain, further enhancing organ blood flow for improved function. Because PDE7A variants are significantly more highly expressed in skeletal muscle than variant PDE7B, it is preferable that PDE7 inhibitors have a particularly strong inhibitory effect on PDE7A.

[0005] Currently, 11 families of phosphodiesterases (PDEs) have been identified. They are distinguished by their primary structure, substrate specificity, and sensitivity to various PDE-specific effectors and inhibitors. Each family consists of one or more genes expressed in various tissues in the form of splicing variants. For example, PDE4, PDE7, and PDE8 specifically hydrolyze cAMP, and PDE5, PDE6, and PDE9 specifically hydrolyze cGMP.

[0006] The PDE7 family is represented by the isoform PDE7A with its variants PDE7A1, PDE7A2, and PDE7A3, and the isoform PDE7B with its variants PDE7B1, PDE7B2, and PDE7B3, which are derived from two different genes. PDE7 is highly selective for cAMP. The Michaelis constant K of PDE7B for cAMP is mThe values ​​range from 0.13 μM to 0.2 μM. K of PDE7A1 and PDE7A2 for cAMP m The values ​​are 0.2 μM and 0.1 μM, respectively. The catalytic portion of PDE7B shows approximately 70% homology with the catalytic portion of PDE7A.

[0007] In conclusion, inhibition of PDE7 only increases cAMP, and the action of PDE7 inhibitors is largely restricted to tissues where PDE7 is expressed.

[0008] The existence of PDE7 isozymes in skeletal muscle (in muscle cells) is known, and there is a higher expression of PDE7A variants compared to PDE7B variants. Inhibition of PDE7 with an appropriate inhibitor increases the concentration of the second messenger cAMP, which is an important second messenger for the proper function of skeletal muscle. Another important factor for the treatment of DACF is the presence of PDE7 in blood vessels. Inhibition of PDE7 in blood vessels increases cAMP, which has a vasodilatory effect and improves organ blood flow, improving metabolic status and performance. Overall, increasing cAMP in skeletal muscle (muscle cells) and in the blood vessels supplying skeletal muscle and, in particular, the brain can improve or cure DACF, or prevent or prevent the recurrence of chronic fatigue, exhaustion, and / or exertion intolerance after infection. Due to the tissue distribution of PDE7, particularly its expression in skeletal muscle (muscle cells), and its role in degrading cAMP in skeletal muscle (muscle cells) and in the blood vessels of skeletal muscle and the brain, PDE7 inhibitors are capable of treating and preventing DACF with minimal side effects.

[0009] Among diseases associated with fatigue, exhaustion, and / or exertional intolerance, myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS) is the most debilitating condition. ME / CFS is common, affecting approximately 0.3% of the population even before COVID-19, yet remains largely unknown to most physicians. ME / CFS is characterized by severe fatigue, post-exertional malaise (PEM), exertional intolerance, cognitive dysfunction, and orthostatic intolerance, including postural orthostatic tachycardia syndrome (POTS), and is accompanied by numerous other symptoms, including muscle weakness and pain. While unrestful sleep is a typical symptom and can worsen a patient's condition, sleep disturbances are not the primary cause of severe fatigue and exhaustion, but are a consequence of ME / CFS that can further exacerbate the condition.

[0010] Prior to this invention, no specific treatment was available, and current symptomatic treatments only provide some symptomatic relief, not a cure. Many ME / CFS patients are bedridden or wheelchair-bound; most are unable to work. ME / CFS is often, but not always, triggered by infection with various viruses, such as Epstein-Barr virus (EBV), enteroviruses, influenza viruses, dengue fever, and, most recently, coronavirus (SARS-CoV-2). Persistent or newly occurring complaints after a previous acute coronavirus infection are referred to as Long COVID or Post-COVID-19 Symptoms (Post-COVID-19 Syndrome) (PCS), Post-COVID-19 Acute Syndrome (PACS), or Post-COVID-19 Acute Syndrome (PASC). Studies of PCS have shown the widest overlap in symptomology and mechanisms between the two conditions. Only a small proportion of PCS patients develop the full spectrum of ME / CFS. With regard to symptoms and reduced cerebral blood flow during orthostatic tolerance testing, ME / CFS patients and ME / CFS patients with PCS exhibit indistinguishable symptomatology. The prevalence of ME / CFS is expected to increase significantly due to Covid-19. Summary of the Invention [Problem to be solved by the invention]

[0011] Therefore, there is a strong need for drugs or therapeutic agents that can be used to treat and prevent chronic fatigue, exhaustion and / or exertion intolerance (DACF) associated with various diseases, syndromes and disease states.

[0012] Clearly, there is a great need in the art for new methods for treating and preventing chronic fatigue, exhaustion and / or exertion intolerance (DACF) associated with various diseases, syndromes and disease states. [Means for solving the problem]

[0013] The present invention provides a novel route to treating and preventing DACF by using substances with phosphodiesterase-7 inhibitory activity (PDE7 inhibitors) as the active ingredient in therapeutic agents with phosphodiesterase-7 inhibitory activity. DETAILED DESCRIPTION OF THE INVENTION

[0014] As used herein, the term "PDE7 inhibitor" includes chemical compounds, proteins or polypeptides, nucleic acids, ribozymes, DNAzymes, proteolytic inducers, gene therapy, or other such agents that directly or indirectly inhibit or block the phosphodiesterase 7 activity of PDE7 proteins (PDE7A, PDE7B) in a selective or non-selective manner. In some cases, the agent may bind to or directly interact with PDE7 proteins. Agents that bind to PDE7 may act to inhibit or block PDE7 activation by any suitable means, for example, by inhibiting the binding of cAMP or substrate ligands to PDE7. In other cases, PDE7 inhibitors may indirectly inhibit PDE7 activity, for example, by reducing the expression of PDE7 proteins. In some cases, PDE7 inhibitors may inhibit PDE7 activity by altering the cellular distribution of PDE7, for example, by interfering with the binding between PDE7 and intracellular anchor proteins.

[0015] As used herein, the term chronic fatigue-related disorders includes various diseases, syndromes, conditions, or conditions associated with chronic fatigue, exhaustion, and / or exertion intolerance, including myalgic encephalomyelitis / chronic fatigue syndrome (ME / CFS), systemic exertion intolerance, exertion intolerance, Long COVID complaints, post-COVID-19 syndrome (PCS), post-COVID-19 acute symptoms (PACS), post-COVID-19 acute symptoms (PASC), post-vaccine syndrome (Long Vax) following COVID-19 vaccination and vaccinations against other pathogenic bacteria, viruses, and pathogens, post-infectious fatigue and exhaustion following viral, bacterial, or fungal infection, particularly ME / CFS of non-infectious, non-inflammatory, and non-immune causes. The term further includes disorders in which chronic fatigue and exhaustion are symptoms of or associated with cancer (cancer-related fatigue), fibromyalgia, Ehlers-Danlos syndrome, Marfan syndrome, Gulf War illness, the autoimmune diseases rheumatoid arthritis, ANCA-associated vasculitis, and Sjogren's syndrome, as well as other autoimmune disorders with fatigue and exhaustion as debilitating symptoms. Hereinafter, these disorders, syndromes, conditions, syndromes, or states are encompassed as disorders associated with chronic fatigue (DACF).

[0016] In a preferred embodiment of the present invention, the PDE7 inhibitor inhibits the enzymatic activity of PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B) at a dose of IC 50 Even more preferably, the PDE7 inhibitor is a compound that is sufficiently potent to inhibit the enzymatic activity of PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B) at an IC50 of about 0.1 to about 600 nM. 50 In particular, the PDE7 inhibitor is potent enough to inhibit the enzymatic activity of PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B) with an IC of about 0.2 to about 100 nM. 50 and preferably an IC of about 1 to about 100 nM 50 It is potent at inhibiting

[0017] In the present invention, PDE7 inhibitors are used to inhibit the production of Na in skeletal muscle. + / K + -ATPase and NCLX to prevent unwanted ionic changes that cause mitochondrial and energetic dysfunction in skeletal muscle. + ) and subsequent detrimental increase in calcium (Ca 2+ ) changes in Na through PDE7 inhibition + / K + PDE7 inhibition is inhibited by stimulating ATPase and NCLX. + PDE7 inhibition improves the energetic status of skeletal muscle by preventing the disruption of important ions, metabolism, and energy in skeletal muscle caused by increased PDE7 levels, and by preventing subsequent undesirable changes in cellular and mitochondrial calcium, as well as by improving blood flow to the muscle. Furthermore, PDE7 inhibition restores the brain's energetic status by increasing cerebral blood flow, improving metabolic status and performance.

[0018] The improved energy status in skeletal muscle resulting from PDE7 inhibition prevents the release of vasoactive pain-inducing mediators in skeletal muscle. Normally, these mediators are released to compensate for poor metabolic status and physiologically act only locally in skeletal muscle. In disease states resulting from a severely impaired metabolic status in many muscle masses of the body, excessive production leads to overflow into the systemic circulation, resulting in these pain-inducing mediators potentially reaching and acting on all organs throughout the body. These mediators cause a wide variety of symptoms. In addition to the associated symptoms of fatigue and exhaustion, these include brain fog, cognitive impairment, sleep disturbances, orthostatic intolerance, muscle weakness, pain, post-exertional malaise (PEM), which is an exacerbation of typical symptoms after mild or moderate exercise, and many other complaints.

[0019] Due to these combined beneficial effects, PDE7 inhibition improves the symptoms of DACF and may cure the disease, as well as prevent recurrence and disease in a prophylactic manner.

[0020] Specific examples of PDE7 inhibitors for use in the present invention include compounds of formula 1A, formula 1B, Compound 1, Compound 2, formula 2A, formula 2B, formula 2C, compound 3, formula 3, compound 4, formula 4A, formula 4B, formula 5, formula 6, formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, formula 6H, formula 7A, formula 7B, formula 8, formula 8A, formula 9, formula 10, and formula 11, as described hereinafter. , Equation 11, Equation 12, Equation 13, Equation 14, Equation 15A, Equation 15B, Equation 16, Equation 16A, Equation 17A, Equation 17B, Equation 18, Equation 19, Equation 20, Equation 21, Equation 22, Equation 23, Equation 24 , Formula 25, Formula 26, Formula 27A, Formula 27B, Formula 27C, Formula 27D, Formula 28, Formula 29, Formula 30, Formula 31, Formula 32, Formula 33, Formula 34, Formula 35, , Formula 35A, Formula 36, ​​Formula 37 , Formula 38, Formula 39, Formula 40, Formula 41, Formula 42, Formula 42A, Formula 43A, Formula 43B, Formula 44, Formula 44A, Formula 44B, Formula 45, Formula 46, Formula 47, Formula 48, Formula 49, Formula 50 , Formula 51, Formula 52, Formula 53, Formula 54, Formula 55, Formula 55A, Formula 55B, Formula 55C, Formula 55D, Formula 55E, Formula 55F, Formula 55G, Formula 55H, Formula 55I, Formula 55J, Formula 56 , Formula 56B, Formula 56C, Formula 56D, Formula 56E, Formula 56F, Formula 56G, Formula 56H, Formula 57, Formula 57A, Formula 57B, Formula 57C, Formula 57D, Formula 57E, Formula 58, Formula 59, Formula 60, Formula 61, Formula 62, Formula 63, Formula 63A, Formula 64, dipyridamole, pentoxifylline, SUN11817, S14, S.14, and IBMX.

[0021] Methods of treating and preventing chronic fatigue-related disorders (DACF) using PDE7 inhibitors: Accordingly, the present invention includes methods for treating or preventing DACF comprising administering one or more PDE7 inhibitors to a subject having or at risk of developing DACF.

[0022] As used herein, "treat" and similar terms such as "treatment" or "treating" refer to an approach for obtaining beneficial or desired results, preferably clinical results, including clinical results, unless the context clearly dictates otherwise. Treatment may optionally include reduction or amelioration of a disease or condition, e.g., DACF, or may include slowing the progression of a disease or condition, e.g., DACF.

[0023] As used herein, unless the context clearly dictates otherwise, "prevent" and similar terms such as "prevention," "preventing," and the like, refer to an approach to preventing the onset or recurrence of a disease or condition (e.g., DACF), or preventing the occurrence after a viral infection such as Epstein-Barr virus, or the recurrence of symptoms of a disease or condition, or, as the case may be, to delay the onset or recurrence of a disease or condition, or to delay the onset or recurrence of symptoms of a disease or condition.

[0024] As used herein, the term "PDE7" is used generically to refer to all translation products encoded by the transcripts of either or both of these two genes: PDE7A and / or PDE7B.

[0025] As used herein, the "effective amount" or "therapeutically effective amount" of a substance, such as a PDE7 inhibitor, is the amount that is sufficient to produce desired biological or psychological effects, such as beneficial results, including clinical results.For example, in the context of treating DACF using the method of the present invention, the effective amount of a PDE7 inhibitor is the amount that is sufficient to treat and prevent DACF.Generally, the subject is provided with an effective amount of a PDE7 inhibitor.

[0026] Pharmaceutical compositions, routes of administration, unit dosage forms, kits: The compositions of the present invention can be administered to a subject as pharmaceutical compositions or formulations. In certain embodiments, the pharmaceutical compositions of the present invention can be in any form that allows the composition to be administered to a subject. For example, the composition can be in the form of a solid, liquid, or gas (aerosol). Typical administration routes include, but are not limited to, oral, topical, parenteral, sublingual, rectal, intravaginal, and intranasal. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, epidural, intrasternal injection, or infusion techniques.

[0027] Pharmaceutical compositions for use in accordance with the present invention comprise a PDE7 inhibitor, another therapeutic agent, and a pharmaceutically acceptable diluent, excipient, or carrier.

[0028] "Pharmaceutically acceptable carriers" for therapeutic use are well known in the pharmaceutical arts. For example, sterile saline and phosphate-buffered saline at physiological pH may be used. Preservatives, stabilizers, dyes, and flavoring agents may also be provided in the pharmaceutical composition. For example, sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid may be added as preservatives. Additionally, antioxidants and suspending agents may be used.

[0029] The pharmaceutical compositions of the present invention are generally formulated to allow the active ingredients contained therein to be bioavailable when the composition is administered to a subject.The composition administered to a subject can take the form of one or more dosage units, for example, tablets, capsules or cachets can be single dosage units, and the container containing the pharmaceutical combination of the present invention in aerosol form can hold multiple dosage units.In certain embodiments, the composition comprising a PDE7 inhibitor and finally another therapeutic agent is typically administered in one or more dosage tablets for oral administration.The tablet can be, for example, an immediate release formulation, a sustained release formulation, or a sustained release formulation.In one embodiment, the tablet contains an effective amount of the composition comprising a PDE7 inhibitor and finally another therapeutic agent. In certain embodiments, the tablet contains about 1, 5, 10, 20, 30, 50, 100, 150, 200, 250, or 300 mg of a PDE7 inhibitor and, ultimately, about 1, 5, 10, 20, 30, 50, 100, 150, 200, 250, or 300 mg of another therapeutic agent if used in combination.

[0030] By way of example, a unit dosage form of a compound according to the invention in the form of a tablet may contain the following ingredients: 50 mg of the compound of formula 55E, 223.75 mg of mannitol, 6 mg of croscarmellose sodium, 15 mg of corn starch, 2.25 mg of hydroxypropyl methylcellulose, and 3 mg of magnesium stearate.

[0031] Alternatively, in accordance with the present invention, a capsule formulation may, for example, comprise 50 mg of the compound of formula 55E and pharmaceutically acceptable excipients, wherein the excipients may comprise one or more selected from the group consisting of disintegrants, fillers, and lubricants, and may comprise an effective amount of a binder.

[0032] Preferably, the PDE7 inhibitor is provided to the subject in an amount ranging from 0.1 to 1000 mg per day, 1 to 1000 mg per day, 10 to 100 mg per day, or 25 to 50 mg per day.

[0033] Certain combinations of PDE7 inhibitors and other therapeutic agents may not be easily compatible with coformulation. For example, one agent may be more suitable for intravenous administration, while another may be more suitable for oral administration. Also, the serum half-lives of the two agents may be such that one agent must be administered more frequently than the other. Therefore, the present invention contemplates kits containing one or more unit dosage forms of a PDE7 inhibitor and one or more unit dosage forms of another therapeutic agent, such that both unit dosage forms can be provided to a subject in a therapeutically effective manner.

[0034] PDE7 proteins and inhibitors Cyclic nucleotide phosphodiesterase type 7 (PDE7) has been identified as a unique family based on its primary amino acid sequence and distinct enzymatic activities. The PDE genes identified as PDE7 (PDE7A and PDE7B) encode cAMP-specific PDEs. Biochemical and pharmacological characterization of PDE7 has shown that it is a high-affinity cAMP-specific PDE isozyme that does not alter cGMP levels. PDE7 is not inhibited by selective inhibitors of other PDE isozymes. The PDE7 enzyme selectively hydrolyzes cAMP and is characterized as an enzyme that is not inhibited by rolipram, a selective inhibitor of PDE4, another cAMP-specific PDE family. Two subtypes, PDE7A and PDE7B, have been identified within the PDE7 family. PDE7A and PDE7B are encoded by two separate genes located on chromosome 8, g13-q22 and 6q23-q24, respectively. The two gene products show 70% amino acid sequence identity in their C-terminal catalytic domains.

[0035] PDE7A (Uniprot ID: Q13946) has three splice variants in humans (PDE7A1, PDE7A2, and PDE7A3); these variants are generated by alternative splicing at the N- or C-terminus. PDE7A1 and PDE7A2 share 97% sequence identity and differ in their N-terminal regions, while PDE7A3 is a C-terminal variant of PDE7A1 but is a shorter protein that still shares 99% sequence identity with PDE7A1. The nucleotide sequence of PDE7A transcript variant 1 is available in public databases. The human PDE7A1 protein has 482 amino acids. The nucleotide sequence of PDE7A transcript variant 2 is available in public databases. The human PDE7A2 protein has 456 amino acids. The human PDE7A3 protein has 424 amino acids. The nucleotide sequence of PDE7A transcript variant 3 is available in public databases. The PDE7A protein has a region of approximately 270 amino acids at its carboxy terminus that shows significant similarity (approximately 23% homology) to similar regions of other cAMP-hydrolyzing PDEs. This region acts as a catalytic domain. The amino-terminal region of this protein differs from the amino-terminal regions of other PDEs and likely mediates the unique and regulatory properties that are unique to this enzyme family. In skeletal muscle, PDE7 is the predominant PDE isozyme. Expression of variant PDE7A is significantly higher than that of variant PDE7B.

[0036] Three splice variants of PDE7B have been reported: PDE7B1, PDE7B2, and PDE7B3, each with a unique N-terminal sequence. The protein sequence of human PDE7B (Uniprot ID: Q9NP56) is accessible in public databases. Like the PDE7A protein, the amino-terminal region of the PDE7B protein differs and is likely the primary cause of the distinctive regulatory properties unique to each PDE family. The PDE7B protein shows homology (approximately 23%) to other cAMP-dependent PDEs within the catalytic domain. The PDE7B polypeptide is 59% homologous to PDE7A.

[0037] PDE7 is also uniquely localized in mammalian subjects compared with other PDE families.PDE7A expression has been detected in the majority of tissues analyzed, including skeletal muscle, heart, kidney, and spleen.PDE7B expression has been detected in: brain, peripheral blood mononuclear cells, liver, heart, kidney, small intestine, and skeletal muscle.In skeletal muscle, PDE7A expression is significantly higher than the expression of variant PDE7B, and the latter shows higher expression in the brain. In carrying out the method of the present invention, representative PDE7 inhibitors that inhibit the phosphodiesterase activity of PDE7 include: molecules that bind to PDE7 and inhibit the enzymatic activity of PDE7 (e.g., small molecule inhibitors or blocking peptides or proteins / protein fragments / fusion proteins that bind to PDE7 and reduce its enzymatic activity), molecules that reduce the expression of PDE7 at the transcriptional and / or translational levels (e.g., PDE7 antisense nucleic acid molecules, PDE7-specific RNAi molecules, and PDE7 ribozymes, DNAzymes), and PDE7-specific gene therapy, thereby preventing PDE7 from cleaving cAMP.As discussed herein, PDE7 inhibitors can be used alone as primary therapy or in combination with other therapies as adjunctive therapy to enhance therapeutic effects.

[0038] Inhibition of PDE7 is characterized by at least one of the following changes that occur as a result of administration of a PDE7 inhibitor according to the methods of the present invention: inhibition of PDE7-dependent enzymatic cleavage of the 3'-phosphodiester bond in cAMP to form 5'-adenosine monophosphate (5'-AMP), e.g., a decrease in PDE7 gene or protein expression levels as measured by gene expression analysis (e.g., RT-PCR analysis) or protein analysis (e.g., Western blot).

[0039] In some embodiments, the PDE7 inhibitor is a molecule or composition that inhibits the expression of PDE7A, PDE7B, or both PDE7A and PDE7B, such as an antisense or small inhibitory nucleotide (e.g., siRNA) that specifically hybridizes to cellular mRNA and / or genomic DNA corresponding to the target PDE7 gene to inhibit their transcription and / or translation, or a ribozyme that specifically cleaves the target PDE7 mRNA.

[0040] PDE7 inhibitor efficacy: In one embodiment, the PDE7 inhibitors useful in the methods of the invention inhibit the enzymatic activity of PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B) at a rate of IC 50 IC<50 μM, preferably less than or about 1 μM 50 In one embodiment, the PDE7 inhibitor is a compound that is sufficiently potent to inhibit the enzymatic activity of PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B) with an IC of about 0.1 to about 600 nM. 50 In one embodiment, the PDE7 inhibitor is potent enough to inhibit the enzymatic activity of PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B) with an IC of about 0.2 to about 100 nM. 50 and preferably an IC of about 1 to about 100 nM 50 It has the effect of inhibiting

[0041] IC of PDE7 (PDE7A or PDE7B) inhibitors 50 Exemplary methods for determining β are well known in the art, such as scintillation proximity assay (SPA).

[0042] PDE7A or PDE7B selective inhibitors: In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a PDE7A inhibitor. In one embodiment, the PDE7A inhibitor inhibits the enzymatic activity of PDE7A with an IC of about 0.1 to about 600 nM. 50 It has the effect of inhibiting

[0043] In some embodiments, the PDE7 inhibitor exhibits isozyme-selective activity for PDE7A. A PDE7A-selective inhibitor reduces PDE7A activity by at least 2-fold more than PDE7B activity, more preferably by at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold more. In some embodiments, the PDE7A inhibitor is an inhibitor that is at least 10-fold (e.g., at least 20-fold, or at least 50-fold, or at least 100-fold) more selective for inhibiting PDE7A activity than the enzymatic activity of any other PDE (PDEs 1-6, 7B, and 8-11).

[0044] In one embodiment, the PDE7B inhibitor inhibits the enzymatic activity of PDE7B with an IC of about 0.1 to about 600 nM. 50 It has the effect of inhibiting

[0045] In some embodiments, the PDE7 inhibitor exhibits isozyme-selective activity against PDE7B. A PDE7B-selective inhibitor reduces PDE7B activity by at least 2-fold more than PDE7A activity, more preferably by at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold more. In some embodiments, the PDE7B inhibitor is an inhibitor that is at least 10-fold (e.g., at least 20-fold, or at least 50-fold, or at least 100-fold) more selective for inhibiting PDE7B activity than the enzymatic activity of any other PDE (PDEs 1-6, 7A, and 8-11).

[0046] Types of PDE7 inhibitors: The PDE7 inhibitor can be any type of drug, including, but not limited to, chemical compounds, proteins or polypeptides, peptidomimetics, nucleic acid molecules, ribozymes, DNAzymes, proteolytic inducers, or gene therapy. In some embodiments, the PDE7 inhibitor is a small molecule inhibitor, including natural and synthetic substances with low molecular weight, such as peptides, peptidomimetics, and non-peptide inhibitors, such as chemical compounds.

[0047] Chemical compound: PDE7 inhibitors useful in the methods of the present invention include agents that are administered into the bloodstream by conventional routes (e.g., oral, intramuscular, subcutaneous, transdermal, transbuccal, intravenous, etc.) and ultimately transported through the vascular system to inhibit PDE7 in skeletal muscle and the vasculature.

[0048] The following is a description of exemplary PDE7 inhibitors useful in the methods of the present invention, which may be orthosteric, allosteric, or other inhibitors. Unless explicitly defined hereinafter, the following terms have the following meanings: i) Aryl: A functional group derived from an aromatic ring or aromatic ring system, with or without heteroatoms, when one hydrogen is removed from such ring structure; ii) Alkyl: broadly defined, a hydrocarbon radical formed when a hydrogen atom is removed from an alkane, alkene, or alkyne group; iii) Alkoxy: A functional group containing an alkyl group attached to an oxygen; iv) Acyl: A functional group having the formula RC=O, where R is aryl, alkyl, or other structure.

[0049] In one embodiment, the PDE7 inhibitor useful in the method of the present invention is selected from the compounds generally or specifically disclosed in EP-A 1454897, WO2003 / 053975, and US 2005 / 0148604, U.S. Patent No. 7,268,128 (each of which is expressly incorporated herein by reference in its entirety).In one embodiment, the PDE7 inhibitor useful in the method of the present invention is represented by Formula 1A or 1B: [ka] ((1A), (1B): Also called pyrazolopyrimidinone derivatives) It has.

[0050] The substituents of compounds 1A and 1B above are defined as follows: A represents N or CR4; B' represents a hydrogen atom or a halogen atom; R1 is an optionally substituted C 3-7 represents cycloalkyl or tert-butyl, R2 represents hydrogen, methyl, or ethyl; R3 is hydrogen, nitro, cyano or a halogen atom, NR5R6, C(=X)R7, SO2NR5R6, OR8, NR8CONR5R6, NR8SO2R9, NR8CO2R9, a heteroaryl group, optionally substituted C 1-3 Alkyl, optionally substituted C 1-6 represents alkenyl, or optionally substituted saturated or unsaturated heterocycloalkyl; R4 is hydrogen or C optionally substituted with one or more fluorine atoms. 1-3 represents alkoxy, R5 and R6 are the same or different and are each a hydrogen atom, an optionally substituted C 1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted acyl, or together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino, piperazinyl, or homopiperazinyl, each of which groups is optionally substituted C 1-4 Alkyl, OH, C 1-3 optionally substituted with alkoxy, CO2H, NR5R6, oxo, NR9COR7, or C(=O)R7; R7 is an optionally substituted C 1-6 represents alkyl, OH, ORs, or NR5R6; R8 is hydrogen, optionally substituted C 1-6 represents an alkyl group or an optionally substituted heterocycloalkyl; R9 is an optionally substituted C 1-6 represents an alkyl group, and X represents O, S, or NH.

[0051] With respect to the above compounds, "optionally substituted" means an optionally substituted straight-chain, branched, or cyclic alkyl group, such as methyl, ethyl, propyl, or cyclohexyl; a hydroxyl group; a cyano group; an alkoxy group, such as methoxy or ethoxy; an optionally substituted amino group, such as amino, methylamino, or dimethylamino; an optionally substituted acyl group, such as acetyl or propionyl; a carboxyl group; an optionally substituted aryl group, such as phenyl or naphthyl; or an optionally substituted heteroaryl group. optionally substituted saturated or unsaturated heterocycloalkyl groups, such as piperazinyl or morpholinyl; optionally substituted carbamoyl groups; optionally substituted amido groups; halogen atoms, such as chlorine, fluorine or bromine; nitro groups; optionally substituted sulfone groups; optionally substituted sulfonylamido groups; oxo groups; urea groups; and optionally substituted straight-chain, branched or cyclic alkenyl groups, such as ethenyl, propenyl or cyclohexenyl. R 3 Examples of such heteroaryl groups include 5- to 7-membered monocyclic heteroaryl groups having 2 to 8 carbon atoms and containing 1 to 4 heteroatoms consisting of oxygen, nitrogen, or sulfur atoms, and polycyclic heteroaryl groups comprising two or more of the same or different monocyclic compounds described above fused together; examples of monocyclic and polycyclic heteroaryl groups are pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyridyl, pyrazyl, indolyl, quinolyl, isoquinolyl, and tetrazolyl.

[0052] In one embodiment, the PDE7 inhibitors useful in the present invention have the formula: [ka] [CAS Registry Number assigned by Chemical Abstracts Service (CAS): 553669-13-9] It has.

[0053] In other embodiments, the PDE7 inhibitors useful in the methods of the present invention have the formula: [ka] [ka] It has.

[0054] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention has the formula: [ka] CAS:553668-77-2 It has.

[0055] In other embodiments, the PDE7 inhibitors useful in the methods of the present invention have the formula:

[0056] [ka] It has.

[0057] The preparation of the above compounds is described in EPA-1454897, WO2003 / 053975, and US 2005 / 0148604.

[0058] The above formulas 1A, 1B, compound 1, and compound 2 are also referred to in U.S. Patent No. 11,207,275 and WO2012 / 064667, U.S. Patent No. 9,220,715, U.S. Patent No. 2012 / 0115849, WO2013 / 176877, and U.S. Patent No. 2022 / 0062194. The above formulas 1A, 1B, compound 1, and compound 2 are also referred to in U.S. Patent No. 9,119,822, U.S. Patent No. 8,637,528 and WO2010 / 129036, U.S. Patent No. 9,119,822, and U.S. Patent No. 2019 / 0183824 and WO2008 / 119057.

[0059] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in US2002 / 0198198, WO2002 / 076953, WO2002 / 074754, WO2006 / 092691, Bioorganic & Medicinal Chemistry Letters 14(2004)4623-4626, US2009 / 0111837 and Bioorganic & Medicinal Chemistry Letters 14(2004)4627-4631, each of which is expressly incorporated herein by reference in its entirety.In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound of the formula: [ka] ((2A), (2B), (2C): Spirocyclic derivatives / also called spiro rings) It has.

[0060] The substituents for compounds 2A, 2B, and 2C above are defined as follows: (a) X1, X2, X3, and X4 are the same or different, and: N, [with the proviso that not more than two of the groups X1, X2, X3, and X4 simultaneously represent a nitrogen atom], or C-R1, where R1 is: Q1, or lower alkyl, lower alkenyl, or lower alkynyl, [which groups are unsubstituted or substituted by one or several groups Q2]; selected from the group X5-R5, where X5 is: a single bond, lower alkylene, lower alkynyl, optionally interrupted by one or two heteroatoms selected from O, S, S(=O), SO2, or N. the carbon atoms of these groups are unsubstituted or substituted with one or several groups, which are the same or different, selected from SR, OR, NR, R, =O, =S, or =NR, where R and R are the same or different and are selected from hydrogen or lower alkyl, and R is selected from aryl, heteroaryl, cycloalkyl [optionally C(=O) or 1, 2 or 3 selected from O, S, S(=O), SO, or N, or 3 heteroatoms], cycloalkenyl [optionally interrupted by C(=O) or 1, 2, or 3 heteroatoms selected from O, S, S(=O), SO2, or N], or bicyclic groups, which are unsubstituted or substituted with one or several groups selected from Q3, heteroaryl, or lower alkyl optionally substituted with Q3; where Q1, Q2, and Q3 are the same or different and are: hydrogen, halogen, CN , NO2, SO3H, P(=O)(OH)2, OR2, OC(=O)R2, C(=O)OR2, SR2, S(=O)R2, NR3R4, Q-R2, Q-NR3R4, NR2-Q-NR3R4, or NR3-Q-R2, where Q is selected from C(=NR), C(=O), C(=S), or SO2, R is selected from hydrogen or lower alkyl, and R2, R3, and R4 are the same or different and are selected from: hydrogen, lower alkyl optionally interrupted by C(=O), (CH2) n -aryl, (CH2) n -heteroaryl, (CH2) n- cycloalkyl [optionally interrupted by C(=O) or 1 or 2 heteroatoms selected from O, S, S(=O), SO2, or N], where n is an integer selected from 0, 1, 2, 3, or 4; these groups are unsubstituted or substituted with one or several groups selected from lower alkyl, halogen, CN, CH3, SO3H, SO2CH3, CF3, C(=O)NHSO2CH3, OR6, COOR6, C(=O)R6, NR6R7, C(=O)NR6R7, or SO2NR6R7, where R6 and R7 are the same or different and are selected from hydrogen or lower alkyl optionally substituted with one or two groups selected from OR, COOR, or NR8, where R and R8 are hydrogen or lower alkyl, and R6 and R7 and / or R3 and R4 are can form, together with the nitrogen atom to which they are attached, a 4- to 8-membered heterocyclic ring, which can contain one or two heteroatoms selected from O, S, S(=O), SO2, or N, and can be substituted with a 4- to 8-membered heterocyclic ring [which can contain one or two heteroatoms selected from O, S, or N and can be substituted with lower alkyl], or lower alkyl optionally substituted with OR', NR'R'', C(=O)NR'R'' or COOR', where R' and R'' are the same or different and are selected from H, lower alkyl [optionally substituted with OR or COOR], where R is hydrogen or lower alkyl, and R' and R'' can form, together with the nitrogen atom to which they are attached, a 4- to 8-membered heterocyclic ring, which can contain one or two heteroatoms selected from O, S, or N; or (b) X is O, S, or NR9, where R9 is selected from hydrogen, CN, OH, NH2, lower alkyl, lower alkenyl, or lower alkynyl, which groups are unsubstituted or are selected from cycloalkyl [optionally interrupted by one or two heteroatoms selected from O, S, S(=O), SO2, or N], cycloalkenyl [optionally interrupted by one or two heteroatoms selected from O, S, S(=O), SO2, or N], aryl, heteroaryl, OR10 , or NR 10 R 11 where R 10 and R 11 are the same or different and are selected from hydrogen or lower alkyl; (c) Y is O, S, or NR 12 is selected from, where R 12 is selected from hydrogen, CN, OH, NH2, lower alkyl, lower alkenyl, or lower alkynyl, which groups are unsubstituted or are selected from cycloalkyl [optionally interrupted by 1 or 2 heteroatoms selected from O, S, S(=O), SO2, or N], cycloalkenyl [optionally interrupted by 1 or 2 heteroatoms selected from O, S, S(=O), SO2, or N], aryl, heteroaryl, OR 10 , or NR 10 R 11 where R 10 and R 11 are the same or different and are selected from hydrogen or lower alkyl; (d) Z is CH-NO2, O, S, or NR 13 is selected from, where R 13 is hydrogen, CN, OH, NH, aryl, heteroaryl, cycloalkyl [optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO, or N], cycloalkenyl [optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO, or N], C(=O)R 14 , C(=O)NR 14 R 15 , OR 14 or lower alkyl [unsubstituted or the same or differently selected OR 14 Or NR 14 R 15 substituted with one or several groups; R 14 and R 15 are independently selected from hydrogen or lower alkyl, or R 14 and R 15can form a 4- to 8-membered heterocyclic ring together with the nitrogen atom to which they are attached, which can contain 1 or 2 heteroatoms selected from O, S, or N and can be substituted with lower alkyl; (e) Z 1 is H, CH3, or NR 16 R 17 is selected from, where R 16 and R 17 are the same or different and are selected from hydrogen, CN, aryl, heteroaryl, cycloalkyl [optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO, or N], cycloalkenyl [optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO, or N], C(=O)R 14 , C(=O)NR 14 R 15 , OR 14 or lower alkyl [unsubstituted or OR 14 Or NR 14 R 15 and R is selected from the group consisting of 14 and R 15 is selected from hydrogen or lower alkyl, and R 14 and R 15 , and / or R 16 and R 17 can form, together with the nitrogen atom to which they are attached, a 4- to 8-membered heterocyclic ring, which can contain 1 or 2 heteroatoms selected from O, S, or N, and which can be substituted with lower alkyl;

[0061] (f) A is: [ka] is a ring selected from where A 1 , A 2 , A 3 , A 4 , A 5 , and A6 are the same or different and are O, S, C, C(=O), SO, SO2, or NR 18 is selected from, where R 18 is hydrogen, aryl, heteroaryl, cycloalkyl [optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO2, or N], cycloalkenyl [optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO2, or N], lower alkyl [unsubstituted or unsubstituted], aryl, heteroaryl, cycloalkyl [optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO2, or N], cycloalkenyl [optionally interrupted by one or several heteroatoms selected from O, S, S(=O), SO2, or N], CN, NR 19 R 20 , C(=O)NR 19 R 20 , OR 19 , C(=O)R 19 Or C(=O)OR 19 where R is the number of 19 and R 20 are the same or different and are selected from hydrogen or lower alkyl; represents a carbon atom shared between ring A and the skeletal ring containing X and / or Y; Each carbon atom of ring A is unsubstituted or the same or different and is selected from the group consisting of lower alkyl [OR 21 , N.R. 21 R 22 , COOR 21 or CONR 21 R 22 optionally substituted with], lower haloalkyl, CN, F, =O, SO2NR 19 R 20 , OR 19 , S.R. 19 , C(=O)OR 19 , C(=O)NR 19 R 20 , or NR 19 R 20 and wherein R is substituted with one or two groups selected from19 and R 20 are the same or different and are hydrogen or OR 21 , N.R. 21 R 22 , COOR 21 , or CONR 21 R 22 lower alkyl optionally substituted with 21 and R 22 are the same or different and are selected from hydrogen or lower alkyl, and R 19 and R 20 , and / or R 21 and R 22 can form, together with the nitrogen atom to which they are attached, a 4- to 8-membered heterocyclic ring; Two non-adjacent atoms of ring A may be linked by a chain of 2, 3 or 4 carbon atoms, which may be interrupted by one heteroatom selected from O, S or N; provided that group A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 may not simultaneously represent a heteroatom; and their tautomeric forms, their racemates, their isomers, and their pharmaceutically acceptable derivatives.

[0062] In the above compounds, halogen includes fluoro, chloro, bromo, and iodo. Preferred halogens are F and Cl. Lower alkyl includes straight and branched carbon chains having 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, isopropyl, and tert-butyl. Lower alkenyl includes straight and branched hydrocarbon radicals having 2 to 6 carbon atoms and at least one double bond. Examples of such alkenyl groups are ethenyl, 3-buten-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl. Lower alkynyl includes straight and branched hydrocarbon radicals having 2 to 6 carbon atoms and at least one triple bond. Examples of such alkynyl groups are ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl. Lower haloalkyl includes lower alkyl as defined above substituted with one or several halogens. An example of a haloalkyl is trifluoromethyl. Aryl is understood to refer to an aromatic carbocyclic ring containing between 6 and 10 carbon atoms. An example of an aryl group is phenyl. Heteroaryl includes an aromatic ring having 5 to 10 ring atoms, 1 to 4 of which are independently selected from the group consisting of O, S, and N. Representative heteroaryl groups have 1, 2, 3, or 4 heteroatoms in a 5- or 6-membered aromatic ring. Examples of such groups are tetrazole, pyridyl, and thienyl. Representative cycloalkyls contain 3 to 8 carbon atoms. Examples of such groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "interrupted" means that a carbon atom in the skeletal chain is replaced with a heteroatom or a group as defined herein. For example, in "cycloalkyl or cycloalkenyl optionally interrupted by C(=O) or one heteroatom selected from O, S, S(=O), SO, or N," the term "interposed" means that the C(=O) or heteroatom can replace a carbon atom of the ring. Examples of such groups are morpholine or piperazine.Cycloalkenyl includes 3- to 10-membered cycloalkyl containing at least one double bond. Heterocyclic ring includes heteroaryl as defined above and cycloalkyl or cycloalkenyl as defined above interrupted by 1, 2, or 3 heteroatoms selected from O, S, S(=O), SO2, or N. Bicyclic substituent refers to two rings that are the same or different and selected from aryl, heterocyclic ring, cycloalkyl, or cycloalkenyl, fused together to form the bicyclic substituent. An example of a bicyclic substituent is indolyl.

[0063] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has the formula: [ka] CAS:460346-28-5 It has.

[0064] The above formulas 2A, 2B, 2C, and compound 3 are also referenced in U.S. Pat. No. 11207275 and WO2012 / 064667, U.S. Pat. No. 9,220,715, US 2012 / 0115849, WO2013 / 176877, and US2022 / 0062194.

[0065] Formulas 2A, 2B, 2C, and compound 3 are also referenced in U.S. Pat. No. 9,119,822, U.S. Pat. No. 8,637,528, and WO2010 / 129036, and US2019 / 0183824 and WO2008 / 119057.

[0066] In other embodiments, the PDE7 inhibitors useful in the methods of the present invention have the formula: [ka] It has.

[0067] Any and all of the above chloro derivatives of Formula 2A are referred to as 8'-chloro-2',3'-dihydro-2'-oxospiro[cyclohexane-1,4'(1'H)-quinazolin]-5'-yl derivatives.

[0068] The preparation of the above compounds is described in US2002 / 0198198, WO2002 / 076953, WO2002 / 074754, WO2006 / 092691, Bioorganic & Medicinal Chemistry Letters 14(2004)4623-4626, and Bioorganic & Medicinal Chemistry Letters 14(2004)4627-4631.

[0069] In other embodiments, PDE7 inhibitors that may be useful in the methods of the present invention may be derived from compounds having formula 2A (also called spirocyclic quinazoline derivatives) in which another heterocycle having substituents at positions X1 and X2 forms a ring with the carbon atoms X1 and X2.

[0070] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in EP-A-1193261, WO2002 / 28847, US 2003 / 0045557, U.S. Patent No. 7,122,565, Bioorganic & Medicinal Chemistry Letters 14 (2004) 4607-4613, and Bioorganic & Medicinal Chemistry Letters 14 (2004) 4615-4621, each of which is expressly incorporated herein in its entirety. In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound represented by formula (3):

[0071] [ka] ((3): Also called thiadiazole derivatives and oxadiazole derivatives) It has.

[0072] The substituents for formula (3) above are defined as follows: Y is S or O; R1 is C1-C10 Alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, or polycyclic group; each optionally substituted with one or several groups X1-R4, which are the same or different, where X1 is a single bond, lower alkylene, C2-C6 alkenylene, cycloalkylene, arylene, or a divalent heterocycle, and R4 is: (1) H, =O, NO2, CN, halogen, lower haloalkyl, lower alkyl, carboxylic acid bioisosteres; (2) COOR5, C(=O)R5, C(=S)R5, SO2R5, SOR5, SO3R5, SR5, OR5; (3) C(=O)NR7R8, C(=S)NR7R8, C(=CH-NO2)NR7R8, C(=N-CN)NR7R8, C(=N-SO2NH2)NR7R8, C(=NR7)NHR8, C(=NR7)R8, C(=NR9)NHR8, C(=NR9)R8, SO2NR7R8, or NR7R8, where R7 and R8 are the same or different and are OH, R5, R6, C(=O)NR5R6, C(=O)R5, SO2R5, C(=NR9)NHR 10 , C(=NR9)R 10 , C(=CH-NO2)NR9R 10 , C(=N-SO2NH2)NR9R 10 , C(=N-CN)NR9R 10 , or C(=S)NR9R 10 Selected from; R2 is lower alkyl, C2-C 10 Alkenyl, C2-C 10 alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl; each optionally the same or different: (1) H, carboxylic acid bioisostere, lower haloalkyl, halogen, (2) COOR5, OR5, SO2R5, (3) SO2NR 11 R 12 , C(=O)NR 11 R 12 , N.R. 11 R12 wherein R is substituted with one or several groups selected from 11 and R 12 are the same or different, and OH, R5, R6, C(=O)NR5R6, C(=O)R5, SO2R5, C(=S)NR9R 10 , C(=CH-NO2)NR9R 10 , C(=N-CN)NR9R 10 , C(=N-SO2NH2)NR9R 10 , C(=NR9)NHR 10 , or C(=NR9)R 10 Selected from; R3 is X2-R'3, where X2 is a single bond or a group selected from C1-C4 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, respectively: (1) H, C1-C3 alkyl, C3-C4 cycloalkyl, aryl, heterocycle, ═O, CN, (2) OR5, =NR5; or (3) NR 13 R 14 and optionally substituted with one or several identical or different groups selected from 13 and R 14 are the same or different, and R, R, C(=O)NR, C(=O)R, SO, C(=S)NR 10 , C(=CH-NO2)NR9R 10 , C(=NR9)NHR 10 , or C(=NR9)R 10 Selected from; R'3 is a cycloalkyl, cycloalkenyl, aryl, heterocyclic, or polycyclic group; each of which may contain one or several groups X3-R 17 where X3 is a single bond, lower alkylene, C2-C6 alkenylene, C2-C6 alkynylene, cycloalkylene, arylene, a divalent heterocycle, or a divalent polycyclic group, and R 17 teeth: (1) H, ═O, NO2, CN, lower haloalkyl, halogen, carboxylic acid bioisostere, cycloalkyl, (2) COOR5, C(=O)R5, C(=S)R5, SO2R5, SOR5, SO3R5, SR5, OR5; (3) C(=O)NR 15 R 16 , C(=S)NR 15 R 16 , C(=N-CN)NR 15 R 16 , C(=N-SO2NH2)NR 15 R 16 , C(=CH-NO2)NR 15 R 16 , SO2NR 15 R 16 , C(=NR 15 )NHR 16 , C(=NR 15 )R 16 , C(=NR9)NHR 16 , C(=NR9)R 16 , or NR 15 R 16 [where R 15 and R 16 are the same or different, and OH, R5, R6, C(=O)NR5R6, C(=O)R5, SO2R5, C(=S)NR9R 10 , C(=CH-NO2)NR9R 10 , C(=N-CN)NR9R 10 , C(=N-SO2NH2)NR9R 10 , C(=NR9)NHR 10 or C(=NR9)R 10 selected from], (4) Heterocycles optionally substituted with one or several groups R5 wherein R5 and R6 are the same or different and are selected from H, lower alkyl, C2-C6 alkenyl, C2-C6 alkynyl, X4-cycloalkyl, X4-cycloalkenyl, X4-aryl, X4-heterocyclic or X4-polycyclic group, where X4 is a single bond, lower alkylene, or C2-C6 alkenylene; each is the same or different and is selected from halogen, ═O, COOR 20 , CN, OR 20 , in some cases OR 20O-lower alkyl substituted with C(=O)-lower alkyl, lower haloalkyl, [ka] wherein X5 is a single bond or lower alkylene, and R 18 , R 19 , and R 20 are the same or different and are selected from H or lower alkyl; X6 is optionally substituted with one or several groups selected from X6-heterocycle, X6-aryl, X6-cycloalkyl, X6-cycloalkenyl, or X6-polycyclic group, where X6 is a single bond or lower alkylene, and these groups may be the same or different and may be halogen, COOR 21 , OR 21 , or (CH2) n NR 21 R 22 where n is 0, 1, or 2, and R 21 and R 22 are the same or different and are selected from H or lower alkyl; R9 is H, CN, OH, lower alkyl, O-lower alkyl, aryl, heterocycle, SO2NH2, or [ka] wherein X5 is a single bond or lower alkylene, and R 18 and R 19 are the same or different and are selected from H or lower alkyl; R 10 is selected from hydrogen, lower alkyl, cyclopropyl, or heterocycle; or a pharmaceutically acceptable derivative thereof.

[0073] In the above compounds, aryl refers to an unsaturated carbocyclic ring containing only carbon atoms in the ring structure and having between 5 and 10 carbon atoms, such as phenyl, naphthyl, or tetrahydronaphthyl. Heterocycle refers to an unsaturated or saturated monocyclic ring containing between 1 and 7 carbon atoms in the ring structure and at least one heteroatom such as nitrogen, oxygen, or sulfur in the ring structure, preferably 1 to 4 heteroatoms, the same or different, selected from nitrogen, sulfur, and oxygen atoms. Suitable heterocycles include morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, pyrimidinyl, 2- and 3-furanyl, 2- and 3-thienyl, 2-pyridyl, 2- and 3-pyranyl, hydroxypyridyl, pyrazolyl, isoxazolyl, tetrazole, imidazole, triazole, and the like. Polycyclic groups include at least two rings, the same or different, selected from aryl, heterocyclic, cycloalkyl, and cycloalkenyl groups, fused together to form the polycyclic group, such as 2- and 3-benzothienyl, 2- and 3-benzofuranyl, 2-indolyl, 2- and 3-quinolinyl, acridinyl, quinazolinyl, indolyl benzo[1,3]dioxolyl, and 9-thioxanthanyl. Bicyclic groups refer to two rings, the same or different, selected from aryl, heterocyclic, cycloalkyl, or cycloalkenyl, fused together to form the bicyclic group. Halogen refers to fluorine, chlorine, bromine, or iodine. Lower alkyl refers to alkyls that are straight-chain or branched and contain 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, isobutyl, n-butyl, pentyl, hexyl, and the like. Alkenyl refers to a straight or branched unsaturated carbon atom chain containing one or several double bonds, preferably one or two double bonds. Alkynyl refers to a straight or branched unsaturated carbon atom chain containing one or several triple bonds, preferably one or two triple bonds. Lower haloalkyl refers to lower alkyl substituted with one or several halogens; preferred lower haloalkyl groups include perhaloalkyl groups such as CF3.Cycloalkyl refers to a saturated monocarbon ring containing 3 to 10 carbon atoms; examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkenyl refers to an unsaturated monocarbon ring containing 3 to 10 carbon atoms. Examples of suitable cycloalkenyls are 3-cyclohexene and 3-cycloheptene. Carboxylic acid bioisosteres have their classical meanings; common carboxylic acid bioisosteres are tetrazol-5-yl, C(=O)N(H)OH, isoxazol-3-yl, hydroxythiadiazolyl, sulfonamide, sulfonylcarboxamide, phosphonic acid, phosphonamide, phosphinic acid, sulfonic acid, acylsulfonamide, mercaptoazole, and acylcyanamide.

[0074] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has the formula: Compound 4: [ka] CAS:756535-34-9 It has.

[0075] The above formula 3 and compound 4 are also referenced in U.S. Pat. No. 11,207,275 and WO2012 / 064667, U.S. Pat. No. 9,220,715, US2012 / 0115849, WO2013 / 176877, and US2022 / 0062194.

[0076] The formula of 3 and compound 4 are also referenced in U.S. Pat. No. 9,119,822, U.S. Pat. No. 8,637,528, and WO2010 / 129036, US2019 / 0183824, and WO2008 / 119057.

[0077] In other embodiments, the PDE7 inhibitors useful in the methods of the present invention have the formula: [ka] It has.

[0078] The preparation of the above compounds is described in EP-A-1193261, WO02 / 28847, US2003 / 0045557, U.S. Pat. No. 7,122,565, Bioorganic & Medicinal Chemistry Letters 14(2004) 4607-4613, and Bioorganic & Medicinal Chemistry Letters 14(2004) 4615-4621.

[0079] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from compounds generally or specifically disclosed in WO2004 / 111054, US20060128728, and US20070270419 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitors useful in the methods of the present invention are represented by Formula 4A and / or 4B: [ka] ((4A), (4B): Also called pyridinylpyrazolopyrimidinone derivatives) It has.

[0080] The substituents of compounds 4A and 4B above are defined as follows: R1 is a substituted or unsubstituted C 3-8 a cycloalkyl group or a tert-butyl group; R2 is a hydrogen atom or C 1-3 is an alkyl group; R3 is a group: NR5R6, C(=O)R7, or S(O) 0-2 It is R8; R4 is a hydrogen atom or a C which is unsubstituted or substituted with one or more fluorine atoms. 1-3 is an alkoxyl group; R5 and R6 are the same or different from each other and are a hydrogen atom, a substituted or unsubstituted C 1-6alkyl groups, substituted or unsubstituted acyl groups, substituted or unsubstituted heterocycloalkyl groups, and substituted or unsubstituted heterocycloalkyl rings formed with the nitrogen atom bonded to R5 and R6; R7 is a group: OR9 or NR5R6; R8 is a hydrogen atom, a halogen atom, a group: NR5R6, a substituted or unsubstituted C 1-6 an alkyl group, or a substituted or unsubstituted aryl group; R9 is a hydrogen atom or a substituted or unsubstituted C 1-6 is an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.

[0081] With respect to the above compounds, the term "C1-C3 alkyl group" includes straight-chain or branched-chain alkyl groups having 1 to 3 carbon atoms. The term "C3-C8 cycloalkyl group" includes cycloalkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. The term "heterocycloalkyl group" refers to a 3- to 7-membered heterocyclic group containing 1 to 4 identical or different heteroatoms such as oxygen, nitrogen, or sulfur atoms, and examples include pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, tetrahydrofuryl, tetrahydrophyranyl, morpholinyl, and azetidinyl. The term "C1-C3 alkoxy group" refers to an alkoxy group having 1 to 3 carbon atoms. The term "acyl group" refers to an acyl group having 1 to 8 carbon atoms. The term "aryl group" refers to a phenyl, naphthyl, or biphenyl group having 6 to 12 carbon atoms, and the term "heteroaryl group" refers to a 5- to 7-membered monocyclic or polycyclic group containing 2 to 8 carbon atoms and 1 to 4 identical or different heteroatoms such as oxygen, nitrogen, or sulfur atoms. Examples include pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl, pyridazinyl, and pyrimidinyl. Suitable examples of substituents for the "substituted or unsubstituted C1-C6 alkyl group" include a hydroxyl group and a halogen atom, and suitable examples of substituents for the "substituted or unsubstituted acyl group" include a halogen atom and a nitro group. Furthermore, suitable examples of substituents for the "substituted or unsubstituted aryl group" include a C1-C3 alkyl, a halogen atom, an amino group, an acyl group, an amido group, a hydroxyl group, an acylamino group, a carboxyl group, and a sulfonyl group.Examples of suitable substituents for the "substituted or unsubstituted C3-C8 cycloalkyl group" include C1-C3 alkyl, a hydroxyl group, and an oxo group, and examples of suitable substituents for the "substituted or unsubstituted heterocycloalkyl group" include a carboxy group, an acyl group, an alkoxy group, an amino group, an alkylamino group, an acylamino group, a hydroxyl group, an oxo group, an ethylenedioxy group, a methyl group, an ethyl group, and a hydroxyethyl group.

[0082] In other embodiments, the PDE7 inhibitors useful in the methods of the present invention have the formula: [ka] It has.

[0083] The preparation of the above compounds is described in WO2004 / 111054, US2006 / 0128728, and US2007 / 0270419.

[0084] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from compounds generally or specifically disclosed in U.S. Patent No. 6,903,109, U.S. Patent No. 2004 / 0082578, WO2003 / 088963, and U.S. Patent No. 2006 / 0154949 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitors useful in the methods of the present invention are compounds represented by formula (5): [ka] ((5): Also called arylidenopyridine derivatives) It has.

[0085] The substituents for the above compound (5) are defined as follows: (a) R1 is: (i) COR5, [wherein R5 is H, optionally substituted C 1-8selected from straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl groups are selected from C 1-8 Alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21 [where R 20 and R 21 is hydrogen, C 1-8 straight or branched chain alkyl, C 3-7 selected from cycloalkyl, benzyl, or aryl; (ii) COOR6, [wherein R6 is H, optionally substituted C 1-8 selected from straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl groups are selected from C 1-8 Alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21 is selected from, where R 20 and R 21 is hydrogen, C 1-8 Straight or branched chain alkyl, C 3-7 independently selected from the group consisting of cycloalkyl, benzyl, or aryl; (iii) cyano; (iv) lactone or lactam formed with R4; (v) CONR7R [where R7 and R8 are H, C 1-8 Straight or branched chain alkyl, C 3-7independently selected from cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl, and heterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl, and heterocyclyl groups can be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy, or arylalkyl; or R7 and R8 together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group; (vi) carboxylic acid esters or carboxylic acid bioisosteres containing optionally substituted heteroaryl groups; selected from the group consisting of:

[0086] (b) R2 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, where heterocyclyl is 1,3-dioxolane or furan, or R2 is; [ka] and; (c) R3: (i) Hydrogen, Halo, C 1-8 Straight or branched chain alkyl, aryl alkyl, C 3-7 Cycloalkyl, C 1-8 Alkoxy, Cyano, C 1-4 Carboalkoxy, trifluoromethyl, C 1-8 Alkyl sulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8 carboxylate, aryl, heteroaryl, and heterocyclyl; (ii) NR 10 R11 [where R 10 and R 11 is H, C 1-8 Straight or branched chain alkyl, aryl alkyl, C 3-7 independently selected from cycloalkyl, carboxyalkyl, aryl, heteroaryl, or heterocyclyl, or R 10 and R 11 together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group; (iii) NR 12 COR 13 [where R 12 is selected from hydrogen or alkyl, and R 13 is hydrogen, alkyl, substituted alkyl, C 1-3 Alkoxyl, carboxyalkyl, R 30 R 31 N(CH2) p , R 30 R 31 NCO(CH2) p , aryl, arylalkyl, heteroaryl, or heterocyclyl, or R 12 and R 13 together with the carbonyl group form a carbonyl-containing heterocyclyl group, where R 30 and R 31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1 to 6, wherein the alkyl group can be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy, or arylalkyl; are 1 to 4 groups independently selected from the group consisting of: (d) R4: (i) hydrogen, (ii) C 1-3 straight or branched chain alkyl, (iii) benzyl, and (iv) NR 13 R 14 , where R 13and R 14 is hydrogen and C 1-6 alkyl; 1-3 Alkyl and benzyl groups are C 3-7 Cycloalkyl, C 1-8 Alkoxy, Cyano, C 1-4 Carboalkoxy, trifluoromethyl, C 1-8 Alkyl sulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8 Carboxylate, Amino, NR 13 R 14 , optionally substituted with one or more groups selected from aryl, and heteroaryl; selected from the group consisting of: (e) X is selected from S and O; and pharmaceutically acceptable salt forms, ester forms and prodrug forms thereof.

[0087] In an alternative embodiment, R1, R3, and R4 are as above, and R2 is NR 15 R 16 where R 15 and R 16 is hydrogen, C 1-8 Straight or branched chain alkyl, aryl alkyl, C 3-7 independently selected from cycloalkyl, aryl, heteroaryl, and heterocyclyl, or R 15 and R 16 together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group.

[0088] In the context of the above compounds, "alkyl" refers to straight-chain, cyclic, and branched alkyl. The alkyl group can be optionally substituted with one or more groups such as halogen, OH, CN, mercapto, nitro, amino, C-C-alkyl, C-C-alkoxyl, C-C-alkylthio, C-C-alkyl-amino, di(C-C-alkyl)amino, (mono-, di-, tri-, and per-)halo-alkyl, formyl, carboxy, alkoxycarbonyl, C-C-alkyl-CO—O—, C-C-alkyl-CO—NH—, carboxamido, hydroxamic acid, sulfonamido, sulfonyl, thiol, aryl, aryl(c-c)alkyl, heterocyclyl, and heteroaryl. The term "bioisostere" is defined as a group or molecule having chemical and physical properties that result in broadly similar biological properties. (Burger's Medicinal Chemistry and Drug Discovery, M.E. Wolff, 5th ed., Vol. 1, 1995, p. 785). As used herein, the term "acyl," whether used alone or as part of a substituent, means an organic radical (branched or straight chain) having 2 to 6 carbon atoms derived from an organic acid by removal of a hydroxyl group. "Aryl" or "Ar," whether used alone or as part of a substituent, is a carbocyclic aromatic radical, including, but not limited to, phenyl, 1- or 2-naphthyl, and the like. A carbocyclic aromatic radical may be substituted by independently replacing one to five hydrogen atoms on the carbocyclic aromatic radical with halogen, OH, CN, mercapto, nitro, amino, C-C-alkyl, C-C-alkoxyl, C-C-alkylthio, C-C-alkyl-amino, di(C-C-alkyl)amino, (mono-, di-, tri-, and per-)halo-alkyl, formyl, carboxy, alkoxycarbonyl, C-C-alkyl-CO—O—, C-C-alkyl-CO—NH—, or carboxamido.Exemplary aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carbethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl, and the like. The term "heteroaryl" refers to a fully unsaturated cyclic radical having 5 to 10 ring atoms, of which one ring atom is selected from S, O, and N; 0 to 2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical can be attached to the remainder of the molecule through any of the ring atoms. The terms "heterocycle," "heterocyclic," and "heterocyclic ring" refer to an optionally substituted, fully or partially saturated cyclic group having at least one heteroatom in a ring containing at least one carbon atom, e.g., a 4- to 7-membered monocyclic, a 7- to 11-membered bicyclic, or a 10- to 15-membered tricyclic ring system. Each ring of a heteroatom-containing heterocyclic group can have one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur atoms, where the nitrogen and sulfur heteroatoms can be optionally oxidized. The nitrogen atom can be optionally quaternized. The heterocyclic group can be bonded to any heteroatom or carbon atom.

[0089] In other embodiments, the PDE7 inhibitors useful in the methods of the present invention have the formula: [ka] It has.

[0090] The preparation of the above compounds is described in U.S. Patent No. 6,903,109, US2004 / 0082578, WO2003 / 088963, and US2006 / 0154949.

[0091] In another embodiment, the PDE7 inhibitor useful in the method of the present invention is selected from the compounds generally or specifically disclosed in US Patent No. 6,958,328, WO2002 / 085894 and US2003 / 0212089 (each of which is expressly incorporated herein by reference in its entirety).These PDE7 inhibitors have the same formula as the formula described above (for example, US Patent No. 6,903,109), except that R1 is not carboxylic acid ester or carboxylic acid bioisostere.The preparation of these compounds is described in US Patent No. 6,958,328, US2003 / 0212089 and WO2002 / 085894.

[0092] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in WO2006 / 004040, U.S. Pat. No. 7,932,250, and EP-A-1775298 (each of which is expressly incorporated herein by reference in its entirety).

[0093] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (6): [ka] ((6): Also known as thienopyrazole derivatives) It has.

[0094] The substituents for the above compound (6) are defined as follows: R1 is a substituted or unsubstituted C 3-8 an alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted heterocycloalkyl group (e.g., cyclohexyl, cycloheptyl, or tetrahydropyranyl); R2 is a hydrogen atom or a substituted or unsubstituted C 1-3 is an alkyl group (e.g., methyl); R3 is a hydrogen atom, a substituted or unsubstituted C 1-3 is an alkyl group, or a halogen atom; and R4 is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, or a group CONR5R6, or CO2R7; wherein R5 and R6 are the same or different and are each a hydrogen atom; 1-6 alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted cycloalkyl groups, groups NR7COR8, COR8, NR9R 10 a substituted or unsubstituted cycloalkyl group; a substituted or unsubstituted heterocycloalkyl group; a substituted or unsubstituted aryl group; a substituted or unsubstituted heteroaryl group; or a substituted or unsubstituted heterocycloalkyl group which, together with the nitrogen atom connecting R5 and R6, forms a ring; where R7 is a hydrogen atom or a substituted or unsubstituted C 1-3 is an alkyl group; where R8 is a substituted or unsubstituted heterocycloalkyl group, or a group OH, OR7, or NR9R 10 and; where R9 and R 10 are the same or different from each other and are a hydrogen atom; a substituted or unsubstituted C 1-3 an alkyl group, a substituted or unsubstituted heterocycloalkyl group; a substituted or unsubstituted acyl group; a group SO2R7, or a substituted or unsubstituted heterocycloalkyl group which forms a ring together with the nitrogen atom to which R5 and R6 are attached; or a pharmaceutically acceptable salt or solvate thereof.

[0095] With respect to the above compounds, the term "cycloalkyl group" refers to a cycloalkyl group having 3 to 8 carbon atoms. The term "heterocycloalkyl group" can be a 3- to 7-membered monocyclic or polycyclic heterocyclic group containing 1 to 4 identical or different heteroatoms such as oxygen, nitrogen, or sulfur atoms, and examples can include piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, azetidinyl, imidazolidinyl, oxazolidinyl, hexahydropyrrolidinyl, octahydroindolizinyl, octahydroquinolidinyl, octahydroindolyl, and oxo derivatives thereof. The term "aryl" group can be an aromatic hydrocarbon group consisting of a mono-benzene ring or bonded or fused benzene rings, such as phenyl, naphthyl, biphenyl, etc.; as well as bicyclic or tricyclic groups consisting of a benzene ring fused with a cycloalkyl or heterocyclic ring, such as 1,2,3,4-tetrahydronaphthalene, 2,3-dihydroindene, indoline, coumarone, etc. The term "heteroaryl group" can be a 5- to 7-membered monocyclic heteroaryl group or a polycyclic heteroaryl group having 2 to 8 carbon atoms with 1 to 4 heteroatoms such as oxygen, nitrogen, or sulfur atoms, where the polycyclic heteroaryl group has ring systems fused together with the same or different monocyclic heteroaryl or benzene rings; or the polycyclic group consists of a heteroaryl group fused with a cycloalkyl or heterocycloalkyl ring.Examples of suitable substituents of the present invention include linear, branched or cyclic C1-C8 alkyl groups optionally substituted with one or more methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, cyclohexyl, cycloheptyl, methoxymethyl, hydroxymethyl, trifluoromethyl, C1-C3 alkoxy groups, halogen atoms, and hydroxyl groups; hydroxyl groups; cyano groups; substituted or unsubstituted alkoxy groups, for example, methoxy and ethoxy groups; amino groups optionally substituted with C1-C6 alkyl groups or acyl groups, for example, amino, methylamino, ethylamino. , dimethylamino, acylamino, etc.; carboxyl groups; substituted or unsubstituted ester groups; phosphate groups; sulfone groups; substituted or unsubstituted aryl groups; substituted or unsubstituted heteroaryl groups; optionally substituted saturated or unsaturated heterocycloalkyl groups; substituted or unsubstituted carbamoyl groups; substituted or unsubstituted amido groups; substituted or unsubstituted thioamide groups; halogen atoms; nitro groups; substituted or unsubstituted sulfone groups; substituted or unsubstituted sulfonylamido groups; oxo groups; substituted or unsubstituted urea groups; straight-chain, branched-chain, or cyclic alkenyl groups, for example, ethenyl, propenyl, cyclohexenyl, etc.

[0096] In other embodiments, the PDE7 inhibitors useful in the methods of the present invention have formulas 6A, 6B, 6C, 6D, 6E, 6F, 6G, and 6H: [ka] [ka] ((6A, 6B, 6C, 6D, 6E, 6F, 6G, 6H): Also known as 3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide derivatives). ((6E, 6F): also known as 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-thieno[2,3-c]pyrazole-5-carboxamide derivatives).

[0097] The preparation of compounds 6A-6H above is described in EP-A-1775298, U.S. Pat. No. 7,932,250, and WO2006 / 004040 and EP-A-2433943, and U.S. Pat. No. 8,901,315.

[0098] Formulae 6, 6A, 6B, 6C, 6D, 6E, 6F, 6G, and 6H are also referred to in U.S. Pat. No. 11,207,275 and WO2012 / 064667, U.S. Pat. No. 9,220,715, US2012 / 0115849, WO2013 / 176877, and US2022 / 0062194. In these descriptions, particularly in U.S. Pat. No. 11,207,275, Formulae 6 and OMS182399 (respectively OMS527) are also referred to. JP6082058, KR101741853, AU2010245250, CA 2760786, CN115192711, and RU2600869 ((6E) and (6F)).

[0099] Formulas 6, 6A, 6B, 6C, 6D, 6E, 6F, 6G, and 6H are also referenced in U.S. Pat. No. 9,119,822, U.S. Pat. No. 8,637,528, and WO2010 / 129036, U.S. Pat. No. 9,119,822, and US2019 / 0183824 and WO2008 / 119057.

[0100] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in WO2004 / 111053 and US2006 / 0128707 (each of which is expressly incorporated herein by reference in its entirety).

[0101] In one embodiment, the PDE7 inhibitors useful in the methods of the present invention have formulas (7A) and (7B): [ka] ((7A), (7B): also known as imidazotriazinone derivatives) It has.

[0102] The substituents for compounds 7A and 7B above are defined as follows: A is N or CR4; B is N or CH; R1 is a substituted or unsubstituted C 3-8 a cycloalkyl group or a tert-butyl group; R2 is a hydrogen atom or C 1-6 is an alkyl group; R3 is a hydrogen atom; a nitro group; a cyano group; a halogen atom; a heteroaryl group; a substituted or unsubstituted C 1-6 Alkyl group; substituted or unsubstituted C 2-6 Alkenyl groups; substituted or unsubstituted saturated or unsaturated heterocycloalkyl groups; groups: NR5R6, C(O)R7, SO2R7, OR8, NR8COR7, NR8SO2R7; R4 is a hydrogen atom or a C 1-3 is an alkoxy group; R5 and R6 are the same or different and are each a hydrogen atom; a substituted or unsubstituted C 1-6 an alkyl group; a substituted or unsubstituted acyl group; or a substituted or unsubstituted heterocycloalkyl group; R7 is a hydrogen atom; a substituted or unsubstituted C 1-6 an alkyl group; a substituted or unsubstituted heterocycloalkyl group; OH; OR or NR; R8 is a hydrogen atom, a substituted or unsubstituted C 1-6 an alkyl group; or a substituted or unsubstituted heterocycloalkyl group; or a pharmaceutically acceptable salt or solvate thereof.

[0103] With respect to the above compounds, the term "C1-C6 alkyl group" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and the term "C2-C6 alkenyl group" refers to a straight-chain or branched-chain alkenyl group having 2 to 6 carbon atoms. The term "cycloalkyl group" refers to a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "heterocycloalkyl group" refers to a 3- to 7-membered heterocyclic group containing 1 to 4 identical or different heteroatoms such as oxygen, nitrogen, or sulfur atoms, and examples include piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, azetidinyl, and homopiperazinyl. The term "heteroaryl group" refers to a 5- to 7-membered monocyclic or polycyclic group containing 2 to 8 carbon atoms and 1 to 4 identical or different heteroatoms such as oxygen, nitrogen, or sulfur atoms. Examples include pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl, pyridazinyl, and pyrimidinyl. A "halogen atom" includes fluorine, chlorine, bromine, and iodine.Examples of suitable substituents for the "substituted or unsubstituted C1-C6 alkyl group," "substituted or unsubstituted C3-C8 cycloalkyl group," "substituted or unsubstituted alkenyl group," "substituted or unsubstituted heterocycloalkyl group," and "substituted or unsubstituted acyl group" include straight-chain or branched, or substituted or unsubstituted alkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, substituted or unsubstituted cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; hydroxyl groups; cyano groups; alkoxy groups, such as substituted or unsubstituted saturated or unsaturated heterocycloalkyl groups; substituted or unsubstituted carbamoyl groups; substituted or unsubstituted amido groups; halogen atoms; nitro groups; substituted or unsubstituted sulfone groups; oxo groups; urea groups; and substituted or unsubstituted straight-chain, branched-chain, or cyclic alkenyl groups, such as ethenyl, propenyl, and cyclohexenyl.

[0104] In other embodiments, the PDE7 inhibitors useful in the methods of the present invention have the formula: [ka] It has.

[0105] The preparation of the above compounds is described in US2006 / 0128707 and WO2004 / 111053.

[0106] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,617,357, US2002 / 0156064, and Molecular Pharmacology 66:1679-1689, 2004 (each of which is expressly incorporated herein by reference in its entirety).

[0107] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (8): [ka] ((8): Also known as benzenesulfonamide derivatives) It has.

[0108] The substituents for formula (8) above are defined as follows: R1 is NR a R b where R a and R b are independently H or C 1-6 is alkyl or represents a 5- to 7-membered ring composed of carbon or of carbon and one or more additional heteroatoms selected from O, N, or S; R2 is H, C 1-8 Alkyl, C 1-3 Alkyl-Ar, C 1-3 Alkyl-C 3-6 Cycloalkyl, C 2-8 Alkenyl, C 2-4 Alkenyl-Ar or C 2-4 Alkenyl-C 3-6 cycloalkyl, where Ar is substituted or unsubstituted phenyl; R3 is NO2, halo, CN, C(O)OR7, COR1, or NR a R b where R a and R b are independently H or C 1-6 is alkyl; R4 is H, OC 1-6 Alkyl, halo, C(O)NR a R b , C(O)OR7, C 1-8 Alkyl, OCHF2, CH2OR8, OC 1-3 alkyl-Ar, or CH2NHC(O)CH3; R5 is H, halo, or alkyl; R6 is C 1-8 Alkyl, OC 1-4 alkyl, or halo; R7 is hydrogen or an ester- or amide-forming group; R8 is hydrogen or C 1-6 is alkyl; or a pharmaceutically acceptable salt or solvate thereof.

[0109] In one embodiment, the PDE7 inhibitors useful in the methods of the present invention have the formula 8A: [ka] CAS:433695-36-4 It has.

[0110] The preparation of compound 8A is described in US Pat. No. 6,617,357, US2002 / 0156064, and Molecular Pharmacology 66:1679-1689, 2004.

[0111] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in U.S. Pat. No. 6,852,720, EP-A-1348433, and WO 2003 / 082277 (each of which is expressly incorporated herein by reference in its entirety).

[0112] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (9): [ka] ((9): Also known as thiazol-2-yl-imine derivatives) It has.

[0113] The substituents for formula (9) above are defined as follows: R1 is a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, which groups may be the same or different and include halogen, trifluoromethyl, nitro, cyano, oxo, NR4R5, CO2R4, CONR4R5, OR4, S(O)n R4, S(O) n and optionally substituted with one or more groups independently selected from NR4R5, tetrazolyl, and (C1-C6)alkyl, which are the same or different and optionally substituted with 1 to 3 groups independently selected from OR4, NR4R5, and CO2R4; where n is an integer from 0 to 2, inclusive, and R4 and R5 are the same or different and independently represent a hydrogen atom or a group of formula X1-R a where X1 is a single bond or a (C1-C6) alkylene group, and R a is a group selected from (C1-C6) alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R2 is a group selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, aryl, and cycloalkyl; R3 is a group selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which groups include halogen, nitro, cyano, trifluoromethyl, oxo, (C1-C6) alkyl, OR6, NR6R7, COR6, CO2R6, CONHOH, CONR6R7, S(O) m R6, S(O) m and optionally substituted with one or more groups, the same or different, independently selected from NR6R7, NR6COR7, NR6SO2R7, N(SO2R7)2, NR6CONR7R8, C(=NCN)NR6R7, NR8C(=NCN)NR6R7, and tetrazolyl [optionally substituted with (C1-C4)alkyl], where m is an integer from 0 to 2 inclusive, and R6 and R7 are the same or different and independently represent a hydrogen atom or a group of formula X2R b where X2 is a single bond or a (C1-C6) alkylene group, and R bis a group selected from (C1-C6) alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, which are optionally substituted with 1 to 3 identical or different groups independently selected from hydroxy, (C1-C6) alkoxy, (C1-C6) alkyl, amino, mono(C1-C6) alkylamino, di(C1-C6) alkylamino (each alkylamino is the same or different and independent of each other), carboxy, (C1-C6) alkoxycarbonyl and benzyl, and R8 represents a hydrogen atom or a (C1-C6) alkyl group; its racemate, its isomer, its N-oxide, or its pharmaceutically acceptable acid salt or base group.

[0114] The preparation of the above compounds is described in US Pat. No. 6,852,720, EP-A-1348433, and WO2003 / 082277.

[0115] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in U.S. Pat. No. 6,753,340, US 2003 / 0191167, EP-A-1348701, and WO 2003 / 082839 (each of which is expressly incorporated herein in its entirety).

[0116] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (10): [ka] ((10): Also known as (4,2-disubstituted-thiazol-5-yl)amine derivatives) It has.

[0117] The substituents for formula (10) above are defined as follows: R 1a is a group selected from hydrogen, (C1-C6) alkyl and aryl(C1-C6) alkyl, R 1bis a group selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, which groups include halogen, trifluoromethyl, nitro, cyano, oxo, NR4R5, CO2R4, CONR4R5, OR4, S(O) n R4, S(O) n and optionally substituted with one or more groups, which may be the same or different, independently selected from NR4R5, tetrazolyl, and (C1-C6)alkyl [optionally substituted with 1 to 3 groups, which may be the same or different, independently selected from OR4, NR4R5, and CO2R4], where n is an integer of 0 to 2, inclusive; R4 and R5 are the same or different and independently represent a hydrogen atom or a group of formula X1-R a where X1 is a single bond or a (C1-C6) alkylene group, and R a is a group selected from (C1-C6) alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R2 is a group selected from (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, aryl and cycloalkyl; R3 is a group selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which groups include halogen, nitro, cyano, trifluoromethyl, oxo, (C1-C6) alkyl, OR6, NR6R7, COR6, CO2R6, CONHOH, CONR6R7, S(O) m R6, S(O) m and optionally substituted with one or more groups, the same or different, independently selected from NR6R7, NR6COR7, NR6S02R7, N(S02R7)2, NR6CONR7R8, C(=N-CN)NR6R7, NR8C(=N-CN)NR6R7, and tetrazolyl [optionally substituted with (C1-C4)alkyl], where m is an integer from 0 to 2 inclusive, and R6 and R7 are the same or different and independently represent a hydrogen atom or a group of formula X2-R b where X2 is a single bond or a (C1-C6) alkylene group, and R bis a group selected from (C1-C6) alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which are optionally substituted with 1 to 3 identical or different groups independently selected from hydroxy, (C1-C6) alkoxy, (C1-C6) alkyl, amino, mono(C1-C6) alkylamino, di(C1-C6) alkylamino (each alkylamino is the same or different and independent of each other), carboxy, (C1-C6) alkoxycarbonyl, and benzyl, and R8 is a hydrogen atom or a (C1-C6) alkyl group, or a racemic form, an isomer, an N-oxide, or a pharmaceutically acceptable acid or base salt thereof.

[0118] The preparation of these compounds is described in US Pat. No. 6,753,340, US 2003 / 0191167, EP-A-1348701, and WO 2003 / 082839.

[0119] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from compounds generally or specifically disclosed in U.S. Patent No. 6,849,638, US20030119829, and WO2002 / 088138 (each of which is expressly incorporated herein by reference in its entirety).

[0120] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (11): [ka] ((11): Also known as amine-substituted thiopheno[2,3-d]pyrimidine derivatives) It has.

[0121] The substituents for the above formula (11) are defined as follows: R1 and R2 are hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, fully saturated heterocycle of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S and O, aryl of 6 to 12 carbon atoms [optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level, haloalkoxy of 1 to 6 carbon atoms and up to a perhalogen level, aryl of 6 to 12 carbon atoms or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O], heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O [1 to 6 carbon atoms and R4-R5, optionally substituted with alkyl of 10 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O; or R1 and R2 combine together with the nitrogen atom to which they are attached to form a 5-7 membered saturated ring which may contain 1 to 2 additional heteroatoms selected from the group consisting of NH, NR8, S, and O, or combine together with the nitrogen atom to which they are attached to form a 5-7 membered unsaturated ring which may contain 1 to 2 additional heteroatoms selected from the group consisting of N, S, and O; wherein the saturated or unsaturated ring is selected from the group consisting of OH, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, fully saturated heterocycle of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S, and O, halogen, haloalkyl of 1 to 2 carbon atoms and up to the perhalo level of halogen atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms and up to the perhalo level of halogen atoms, and R-R 10 or R1 and R2, together with the nitrogen atom to which they are attached, combine to form an 8- to 10-membered bicyclic saturated ring; R3 is selected from the group consisting of NH, S, S(=O)2, and O; R4 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, C(=C), S(=O)2, and C(=O)O; R5 is hydrogen, OH, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, aryl of 6 to 12 carbon atoms [alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and the number of halogen atoms up to the perhalo level, haloalkyl of 1 to 6 carbon atoms and the number of halogen atoms up to the perhalo level, aryl of 6 to 12 carbon atoms and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, optionally substituted], 4 to 11 carbon atoms and N, S, and O, heteroaryl of 1 to 2 heteroatoms [optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O], cycloalkyl of 3 to 7 carbon atoms, fully saturated heterocycle of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S, and O, and NR6R7; R6 and R7 are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and alkynyl of 2 to 8 carbon atoms, or R6 and R7, together with the nitrogen atom to which they are attached, combine to form a 5- to 7-membered unsaturated ring which may contain 1 to 2 additional heteroatoms selected from N, S, and O, or form a 5- to 7-membered saturated ring which may contain 1 to 2 additional heteroatoms selected from N, S, and O; R8 is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, R 11 -R 12, cycloalkyl of 3 to 7 carbon atoms, fully saturated heterocycle of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S, and O, aryl of 6 to 12 carbon atoms [alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalogen level of halogen atoms, aryl of 6 to 12 carbon atoms or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O] heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O [optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O]; R9 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and alkynyl of 2 to 8 carbon atoms; R 10is optionally substituted with OH, aryl of 6 to 12 carbon atoms [alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S and O], and aryl of 4 to 11 carbon atoms and N , S, and O; heteroaryl of 1 to 2 heteroatoms, optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O; R 11 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and alkynyl of 2 to 8 carbon atoms; and R 12is a cycloalkyl of 3 to 7 carbon atoms, a fully saturated heterocycle of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S, and O, an aryl of 6 to 12 carbon atoms [alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O]. and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O [optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O]; and pharmaceutically acceptable salts thereof.

[0122] The preparation of these compounds is described in US Pat. No. 6,849,638, US 2003 / 0119829, and WO 2002 / 088138.

[0123] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in US 2005222138 and WO2003 / 064389 (each of which is expressly incorporated herein by reference in its entirety).

[0124] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (12): [ka] ((12): Also known as nitrogen-containing bicyclic compound derivatives) It has.

[0125] The substituents for formula (12) above are defined as follows: R1 and R2 are each independently (1) a hydrogen atom or (2) C 1-8 alkyl, or R1 and R2 together with the carbon atoms to which they are attached can form Cyc1, wherein R1 and R2 do not simultaneously represent hydrogen atoms; Z is (1) CR3R4, (2) O, (3) S, or (4) a bond; R3 and R4 are each independently (1) a hydrogen atom, (2) C 1-8 Alkyl, (3)C 1-8 alkoxy, or (4) hydroxy; or R3 and R4 together with the carbon atom to which they are attached may form Cyc1 or C(O); R5 and R6 are each independently (1) a hydrogen atom, or (2) C 1-8 alkyl, or R5 and R6 together with the carbon atoms to which they are attached can form Cyc1; Cyc1 represented by R1 and R2, R3 and R4, and R5 and R6 each independently represents (1) C 3-10 cycloalkyl, or (2) a 3- to 10-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from oxygen, nitrogen, and sulfur, and Cyc1 is R 10 may be substituted with; R 10 (1)C 1-8 Alkyl, (2) C 1-8 Alkoxy, (3) Hydroxy, (4) COOR 11 , (5) Oxo, (6) SO2R 12 , or (7) COR 13 and; R 11 is a hydrogen atom or C 1-8 is alkyl; R 12 and R 13 (1)C 1-8 alkyl, or (2) C 1-8 phenyl optionally substituted with alkyl; R7 and R8 are each independently (1) a hydrogen atom, (2) C 1-8 Alkyl, (3)C 1-8 Alkoxy, (4) hydroxy, (5) cyano, (6) halogen atom, (7) COOR 14 , (8)CONR 15 R 16 , (9)Cyc2, (10)C 2-8 Alkenyl, (11)C 2-8 Alkynyl, (12)NR 51 R 52 , (13) nitro, (14) formyl, (15) C 2-8 Acyl, (16) Hydroxy, C 1-8 Alkoxy, Cyc2, NR 51 R 52 , or NR 53 -C substituted with Cyc2 1-8 Alkyl, (17)NR 54 COR 55 , (18)NR 56 SO2R 57 , (19)SO2NR 58 R 59 , (20)COOR 14 C replaced with 2-8 Alkenyl, (21) CH═N—OH, (22) C 1-8 Alkylene-NR 60 -(C 1-8 alkylene)-R 61 , (23)C 1-8 Alkylthio, (24) C substituted with 1 to 3 halogen atoms 1-8 Alkyl, (25) C substituted with 1 to 3 halogen atoms 1-8 Alkoxy, (26)Cyc2-substituted C 1-8 Alkoxy, (27)0-Cyc2, (28)OSO2R 65 , or (29) CH=N-OR 137 and; R 14 is a hydrogen atom or C1-8 is alkyl; R 15 and R 16 are each independently a hydrogen atom or C 1-8 is alkyl; R 51 and R 52 , R 58 and R 59 are each independently a hydrogen atom or C 1-8 is alkyl; R 53 , R 54 , R 56 , and R 60 are each independently a hydrogen atom or C 1-8 is alkyl; R 55 is a hydrogen atom, C 1-8 Alkyl or C 1-8 Alkoxy; R 57 is C 1-8 is alkyl; R 61 is NR 62 R 63 or hydroxy; R 62 and R 63 are each independently a hydrogen atom or C 1-8 is alkyl; R 65 is C 1-8 is alkyl; R 137 is C 1-8 is alkyl;

[0126] [ka] (hereinafter abbreviated as ring) is Cyc2, where the group attached to the carbonyl is carbon; R7, R8, and Cyc2 represented by the ring are each independently selected from the group consisting of: (1) C 3-15 (2) a monocyclic, bicyclic, or tricyclic (fused or spiro) carbocycle, or (3) a 3- to 15-membered monocyclic, bicyclic, or tricyclic (fused or spiro) heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur; Cyc2 has 1 to 5 R 17 or R 17’ may be substituted with; R 17 (1)C 1-8 Alkyl, (2) C 2-8 Alkenyl, (3)C 2-8 Alkynyl, (4)C 1-8 Alkoxy, (5)C 1-8 Alkylthio, (6) hydroxy, (7) halogen atom, (8) nitro, (9) oxo, (10) carboxy, (11) formyl, (12) cyano, (13) NR 18 R 19 , (14) 1 to 5 R 20 (15) phenyl, phenoxy, or phenylthio, optionally substituted with 1 to 5 R 21 optionally substituted with C 1-8 Alkyl, C 2-8 Alkenyl, C 1-8 Alkoxy or C 1-8 Alkylthio, (16)OCOR 22 , (17)CONR 23 R 24 , (18)SO2NR 25 R 26 , (19) COOR 27 , (20) COCOOR 28 , (21)COR 29 , (22) COCOR 30 , (23)NR 31 COR 32 , (24)SO2R 33 , (25)NR 34 SO2R3-5, or (26)SOR 64 and; R 18 and R 19 , R 31 and R 34 are each independently a hydrogen atom or C 1-8 is alkyl; R 20 and R 21 is C 1-8 Alkyl, C 1-8 Alkoxy, hydroxy, halogen atom, nitro, or COOR36 and; R 22 and R 64 are each independently, C 1-8 alkyl; R 23 , R 24 , R 25 and R 26 are each independently a hydrogen atom, C 1-8 alkyl, or phenyl; R 27 , R 28 , R 29 , R 30 , R 32 , R 33 and R 35 (1)C 1-8 Alkyl, (2) C 2-8 alkenyl, (3) 1 to 5 R 37 C replaced with 1-8 (4) diphenylmethyl, (5) triphenylmethyl, (6) Cyc3, (7) substituted with Cyc3, C 1-8 Alkyl or C 2-8 Alkenyl, (8) C substituted with O-Cyc3, S-Cyc3 or SO2-Cyc3 1-8 is alkyl; R 36 is a hydrogen atom or C 1-8 is alkyl; R 37 is C 1-8 Alkoxy, C 1-8 Alkylthio, benzyloxy, halogen atom, nitro or COOR 38 and; R 38 is a hydrogen atom, C 1-8 Alkyl or C 2-8 is alkenyl; Cyc3 is (1)C 3-15 (2) a monocyclic, bicyclic, or tricyclic (fused or spiro) carbocycle, or (3) a 3- to 15-membered monocyclic, bicyclic, or tricyclic (fused or spiro) heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur; Cyc3 has 1 to 5 R 39 may be substituted with; R 39(1)C 1-8 Alkyl, (2) C 2-8 Alkenyl, (3)C 2-8 Alkynyl, (4)C 1-8 Alkoxy, (5)C 1-8 Alkylthio, (6) hydroxy, (7) halogen atom, (8) nitro, (9) oxo, (10) cyano, (11) benzyl, (12) benzyloxy, (13) 1 to 5 R 40 Replaced by C 1-8 Alkyl, C 1-8 Alkoxy or C 1-8 Alkylthio, (14) 1 to 5 R 41 phenyl, phenoxy, phenylthio, phenylsulfonyl or benzoyl, optionally substituted with (15)OCOR 42 , (16)SO2R 43 , (17)NR 44 COR 45 , (18)SO2NR 46 R 47 , (19) COOR 48 , or (20)NR 49 R 50 and; R 40 is a halogen atom; R 41 is C 1-8 Alkyl, C 1-8 alkoxy, halogen atom, or nitro; R 42 , R 43 and R 45 is C 1-8 is alkyl; R 44 and R 48 is a hydrogen atom or C 1-8 is alkyl; R 46 and R 47 , R 49 and R 50 are each independently a hydrogen atom or C 1-8 is alkyl; R 17 are (1) SH, (2) NR 66 CHO, (3) Cyc5, (4) Cyc5 substituted, C 1-8Alkyl, C 2-8 Alkenyl or C 2-8 Alkynyl, (5) CO—(NH-amino acid residue-CO) n -OH, (6)NR 67 CONR 68 R 69 , (7)CONR 70 NR 71 R 72 , (8)CONR 73 OR 74 , (9)CONR 75 COR 76 , (10)C(S)NR 77 R 78 , (11)CONR 79 C(S)COOR 80 , (12)NR 81 COCOOR 82 , (13)NR 83 COOR 84 , (14)CONR 85 C(S)R 86 , (15)OCOR 87 , (16)SOR 88 , (17)CONR 89 R 90 , (18)SO2NR 91 R 92 , (19) COOR 93 , (20) COCOOR 94 , (21)COR 95 , (22) COCOR 96 , (23)NR 97 COR 98 , (24)SO2R 99 , (25)NR 100 SO2R 101 , or (26)NR 102 R 103 and; n is an integer of 1 or 2; R 66 , R 73 , R 75 , R 77 , R 79 , R 81 , R 83 , R 85 , R 97 , R 100 and R 102is a hydrogen atom or C 1-8 is alkyl; R 67 and R 68 , R 70 and R 71 are each independently a hydrogen atom or C 1-8 is alkyl; R 89 and R 91 are (1) hydrogen atoms, (2) C 1-8 alkyl, (3) phenyl, or (4) cyano or C 1-8 Alkoxy-substituted C 1-8 alkyl; R 103 is Cyc6; R 69 , R 72 , R 74 , R 76 , R 78 , R 80 , R 82 , R 84 , R 86 , R 87 , R 88 , R 90 and R 92 are (1) hydrogen atoms, (2) C 1-8 Alkyl, (3)C 2-8 Alkenyl, (4)C 2-8 Alkynyl, (5) 1 to 5 R 104 C replaced with 1-8 Alkyl, (6) diphenylmethyl, (7) triphenylmethyl, (8) Cyc6, (9) Cyc6-substituted, C 1-8 Alkyl or C 2-8 alkenyl, or (10) C substituted with O-Cyc6, S-Cyc6, or SO2-Cyc6 1-8 is alkyl; R 104 (1)C 1-8 Alkoxy, (2)C 1-8 Alkylthio, (3) benzyloxy, (4) halogen atom, (5) nitro, (6) COOR 105 , (7) Cyano, (8) NR 106 R 107 , (9)N 108 COR 109, (10) Hydroxy, (11) SH, (12) SO3H, (13) S(O)OH, (14) OSO3H, (15) C 2-8 Alkenyloxy, (16)C 2-8 Alkynyloxy, (17)COR 110 , (18)SO2R 111 or (19) hydroxy-substituted C 1-8 Alkoxy or C 1-8 is alkylthio; R 105 is a hydrogen atom, C 1-8 Alkyl, or C 2-8 is alkenyl; R 106 and R 107 are each independently a hydrogen atom or C 1-8 is alkyl; R 108 is a hydrogen atom or C 1-8 is alkyl; R 109 and R 111 is C 1-8 is alkyl; R 110 is C 1-8 alkyl, or halogen atom; R 93 , R 94 , R 95 , R 96 , R 98 , R 99 and R 101 (1)C 2-8 Alkynyl, (2) 1 to 4 R 29 R may be substituted with 128 C replaced with 1-8 Alkyl, (3) Cyc8, (4) Cyc8-substituted, C 1-8 Alkyl or C 2-8 alkenyl, or (5) C substituted with O-Cyc8, S-Cyc8, or SO2-Cyc8 1-8 alkyl; R 128 are (1) cyano, (2) NR 106 R 107 , (3)NR 108 COR 109, (4) Hydroxy, (5) SH, (6) SO3H, (7) S(O)OH, (8) OSO3H, (9) C 2-8 Alkenyloxy, (10)C 2-8 Alkynyloxy, (11)COR 110 , (12)SO2R 111 or (13) hydroxy-substituted C 1-8 Alkoxy or C 1-8 is alkylthio; R 129 is R 104 has the same meaning as; Cyc5 and Cyc6 have 1 to 5 R 112 may be substituted with; R 112 (1)C 1-8 Alkyl, (2) C 2-8 Alkenyl, (3)C 2-8 Alkynyl, (4)C 1-8 Alkoxy, (5)C 1-8 Alkylthio, (6) hydroxy, (7) halogen atom, (8) nitro, (9) oxo, (10) cyano, (11) benzyl, (12) benzyloxy, (13) 1 to 5 R 113 Replaced by C 1-8 Alkyl, C 1-8 Alkoxy or C 1-8 Alkylthio, (14) 1 to 5 R 114 phenyl, phenoxy, phenylthio or benzoyl, optionally substituted with (15) COR 115 , (16)SO2R 116 , (17)NR 117 COR 118 , (18)SO2NR 119 R 120 , (19) COOR 121 , (20)NR 122 R 123 , (21)COR 124 , (22)CONR 125 R 126 , (23) SH, (24) hydroxy or NR 127 -benzoyl-substituted C 1-8 alkyl, or (25)Cyc7; R113 is a halogen atom; R 114 is C 1-8 Alkyl, C 1-8 alkoxy, halogen atom, or nitro; R 115 , R 116 and R 118 is C 1-8 is alkyl; R 117 , R 121 , R 124 and R 127 is a hydrogen atom or C 1-8 is alkyl; R 119 and R 120 , R 122 and R 123 , R 125 and R 126 are each independently a hydrogen atom or C 1-8 is alkyl; Cyc7 is (1)C 1-8 Alkyl, (2) C 1-8 (3) optionally substituted with 1 to 5 groups selected from alkoxy, (4) halogen atoms, or (5) nitro; Cyc8 is R 130 and may be substituted with 1 to 4 R 131 may be further substituted with; R 130 (1) COR 124 ,(2)CONR 125 R 126 (3) SH, (4) hydroxy or NR 127 -benzoyl-substituted C 1-8 alkyl, or (5) Cyc7; R 131 is R 112 has the same meaning as; Cyc5, Cyc6, Cyc7, and Cyc8 are (1)C 3-15 (2) a monocyclic, bicyclic, or tricyclic (fused or spiro) carbocycle, or (3) a 3-15 membered monocyclic, bicyclic, or tricyclic (fused or spiro) heterocycle containing 1-4 heteroatoms selected from 1-4 oxygen, nitrogen, or sulfur; where R 17 If is Cyc5, then Cyc5 is C 1-8 Alkyl, C 1-8 Alkoxy, hydroxy, halogen atom, nitro, COOH, or COO(C 1-8 alkyl); Here, Cyc7 is not phenyl; Cyc4 is (1)C 57 a monocyclic carbocycle, or (2) a 5- to 7-membered monocyclic heterocycle containing 1 to 2 heteroatoms selected from oxygen, nitrogen, and sulfur; (hereinafter abbreviated as dashed line a) and (hereinafter abbreviated as dashed line b) are (1) a bond, or (2) a double bond; R9 is (1) absent or (2) a hydrogen atom; where: (1) When the dashed line a is a bond, the dashed line b is a double bond, and R9 does not exist; (2) When the dashed line a is a double bond, the dashed line b is a bond, and R9 is a hydrogen atom and R6 is absent, and (3) 2-(3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylindene)-1-phenylethan-1-one is excluded, or a pharmacologically acceptable salt thereof.

[0127] The preparation of these compounds is described in US 2005 / 222138 and WO 2003 / 064389.

[0128] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in WO2003 / 057149, which is expressly incorporated herein by reference in its entirety.

[0129] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (13): [ka] ((13): Also called 4-substituted fused heteropyrimidine and fused hetero-4-pyrimidone derivatives) It has.

[0130] The substituents for formula (13) above are defined as follows: (1) X is selected from halogen and NRR; (2) Y is selected from NR3, S, and O, provided that when X is C1, Y is not S; (3) R1 and R2 are selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, polycyclic alkyl of 5 to 9 carbon atoms, heterocycloalkyl of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S, and O, aryl of 6 to 12 carbon atoms [alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, and perhalogen up to 1 to 6 carbon atoms and 1 to 6 carbon atoms]. haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level, haloalkoxy of 1 to 6 carbon atoms and up to a perhalogen level, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O], heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O [alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, 1 to 6 carbon atoms and R4R5, or R1 and R2, taken together with the nitrogen atom to which they are attached, optionally substituted with haloalkyl of 1 to 6 carbon atoms and a number of halogen atoms up to the perhalo level, haloalkoxy of 1 to 6 carbon atoms and a number of halogen atoms up to the perhalo level, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O; and R4R5, or R1 and R2, taken together with the nitrogen atom to which they are attached, optionally contain 1 to 2 additional heteroatoms selected from the group consisting of NH, NR6, S, and O. or, when combined together with the nitrogen atom to which they are attached, form a fused 6-10 membered polycyclic saturated ring optionally containing 1-2 additional heteroatoms selected from the group consisting of NH, NR6, S, and O, or, when combined together with the nitrogen atom to which they are attached, form a 5-7 membered unsaturated ring optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, wherein the monocyclic saturated ring, polycyclic saturated ring, or unsaturated ring is selected from the group consisting of OH, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms,optionally substituted with 1 to 2 substituents selected from the group consisting of alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, heterocycloalkyl of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S, and O, halogen, haloalkyl of 1 to 2 carbon atoms and up to the perhalo level of halogen atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms and up to the perhalo level of halogen atoms, and R7R8; (4) R3 is selected from hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level, haloalkoxy of 1 to 6 carbon atoms and up to a perhalogen level, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O; (5) R4 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, C(=O), S(=O)2, and C(=O)O; (6) R5 is hydrogen, OH, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, thioxy of 1 to 8 carbon atoms, aryl of 6 to 12 carbon atoms [alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalogen level, haloalkoxy of 1 to 6 carbon atoms and up to a perhalogen level, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O], Heteroaryl of carbon atoms and 1 to 2 heteroatoms selected from N, S, and O [optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O], cycloalkyl of 3 to 7 carbon atoms, heterocycloalkyl of 2 to 6 carbon atoms and 1 to 2 heteroatoms selected from NH, S, and O, and NR9R 10 is selected from (7) R6 and R7 are independently selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and alkynyl of 2 to 8 carbon atoms; (8) R8 is substituted with OH, aryl of 6 to 12 carbon atoms [alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, haloalkoxy of 1 to 6 carbon atoms and up to a perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O. and heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O, optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, haloalkyl of 1 to 6 carbon atoms and up to the perhalo level of halogen atoms, aryl of 6 to 12 carbon atoms, or heteroaryl of 4 to 11 carbon atoms and 1 to 2 heteroatoms selected from N, S, and O; (9) R9 and R 10 are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and alkynyl of 2 to 8 carbon atoms, or R and R 10 combine together with the nitrogen atom to which they are attached to form a 5- to 7-membered unsaturated ring which may contain 1 to 2 additional heteroatoms selected from N, S, and O, or NH, NR 11 , S, and O; forming a 5-7 membered saturated ring which may contain 1-2 additional heteroatoms selected from; (10) R1 is selected from alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, and alkynyl of 2 to 8 carbon atoms, and pharmaceutically acceptable salts thereof.

[0131] The preparation of these compounds is described in WO2003 / 057149.

[0132] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from compounds generally or specifically disclosed in US 2003 / 0092721, U.S. Patent No. 7,022,849, WO2002 / 102315, and US 2006 / 116516, U.S. Patent No. 7,601,836 (each of which is expressly incorporated herein by reference in its entirety).

[0133] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (14): [ka] ((14): Also known as 2-amine-substituted quinazoline and pyrido[2,3-d]pyrimidine derivatives) It has.

[0134] The substituents for formula (14) above are defined as follows: R 1 is H or alkyl; R 2 is (a) heteroaryl or heterocyclo, either of which is optionally substituted with one to three groups T1, T2, T3; or (b) aryl fused to a heteroaryl or heterocyclo ring, wherein the combined ring system is optionally substituted with one to three groups T1, T2, T3; L is (a) OR4, C(O)R4, C(O)OR4, SR4, NR3R4, C(O)NR3R4, NR3SO2R 4b , halogen, nitro, or haloalkyl; or (b) alkyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, each of which is optionally substituted with 1 to 3 groups T1a, T2a, and / or T3a; Y 1 , Y 2 and Y 3 are independently (a) hydrogen, halo, or -OR 4aor (b) alkyl, alkenyl, or alkynyl, each of which is optionally substituted with 1 to 3 groups T1b, T2b and / or T3b; R3 and R4 are independently H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which are optionally substituted with 1 to 3 groups T1a, T2a, and / or T3a; or R3 and R4, together with the nitrogen atom to which they are attached, may combine to form a 4-8 membered heterocyclo ring optionally substituted with 1-3 groups T1a, T2a and / or T3a; R 4a is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, cycloalkyl, or (cycloalkyl)alkyl, any of which is optionally substituted with 1 to 3 groups T1b, T2b and / or T3b; R 4b is alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which may be optionally substituted with 1 to 3 groups T1a, T2a, and / or T3a; Z is N or CH; T1-1b, T2-2b, and T3-3b, each independently; (1) hydrogen or T6, wherein T6 is (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii) group (i) itself substituted with one or more of the same or different groups (i); or (iii) group (i) or (ii) independently substituted with one or more of the following groups (2) to (13) in the definitions of T1-1b, T2-2b, and T3-3b; (2) -OH or -OT6; (3) -SH or -ST6; (4) -C(O) t H, -C(O) t T6, or -OC(O)T6, [where t is 1 or 2]; (5) -SO3H, -S(O) t T6 or S(O) t N(T9)T6; (6) Halo; (7) Cyano; (8) Nitro; (9) -T4-NT7T8; (10) -T4-N(T9)-T5-NT7T8; (11) -T4-N(T10)-T5-T6; (12) -T4-N(T10)-T5-H; and (13) oxo; and; T4 and T5 each independently represent a single bond, T11S(O) t T12-, T11C(O)T12-, T11C(S)T12, T110T12, T11ST12, T11OC(O)T12, T11C(O)OT12, T11C(=NT9a)T12, or T11C(O)C(O)T12; T7, T8, T9, T9a and T10 are: (1) each independently represents hydrogen or a group as defined in the definition of T6, or (2) T7 and T8 together with the atoms to which they are attached may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring, which ring is unsubstituted or substituted with one or more groups listed in the descriptions of T1-1b, T2-2b, and T3-3b; or (3) T7 or T8, together with T9, can be an alkylene or alkenylene that completes a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached, and the ring is unsubstituted or substituted with one or more groups listed in the descriptions of T1-1b, T2-2b, and T3-3b; or (4) T7 and T8 or T9 and T10, together with the nitrogen atom to which they are attached, can combine to form the group N=CT13T14, where T13 and T14 are each independently H or a group as defined in the definition of T6; and T11 and T12 are each independently a single bond, alkylene, alkenylene, or alkynylene. The preparation of these compounds is described in US2003 / 0092721, US Pat. No. 7,022,849, WO2002 / 102315, and US2006 / 116516, US Pat. No. 7,601,836.

[0135] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in U.S. Patent No. 6,838,559, US 2003 / 0100571, and WO 2002 / 102314 (each of which is expressly incorporated herein by reference in its entirety).

[0136] In one embodiment, the PDE7 inhibitors useful in the methods of the present invention have formula 15A and / or 15B: [ka] ((15A), (15B): also called purine derivatives) It has.

[0137] The substituents for formulas 15A and 15B above are defined as follows: R1 is H or alkyl; R2 is (a) heteroaryl or heterocyclo, each of which is optionally substituted with one to three groups T1, T2, T3; (b) aryl substituted with one to three groups T1, T2, T3, provided that at least one of T1, T2, T3 is other than H; or (c) aryl fused to a heteroaryl or heterocyclo ring, where the combined ring system is optionally substituted with one to three groups T1, T2, T3; Y is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl or (heteroaryl)alkyl, any of which may be optionally substituted with 1 to 3 groups T1a, T2a, T3a; J is (a) hydrogen, halo, or OR4, or (b) alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, each of which is optionally substituted with 1 to 3 groups T1b, T2b, T3b; Z is (a) OR4, SR4, NR3R4, NR3SO2R 4a halogen, nitro, haloalkyl; or (b) alkyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, each of which is optionally substituted with one to three groups T1c, T2c, T3c; R3 is H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which is optionally substituted independently, if valences allow, with 1 to 3 groups T1c, T2c, T3c; R4 is alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which is optionally substituted, if valences allow, with one to three groups T1d, T2d, or T3d independently; or R3 and R4, together with the nitrogen atom to which they are attached, can combine to form a 4-8 membered heterocyclo ring optionally substituted with 1-3 groups T1c, T2c, or T3c; R 4a is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, cycloalkyl or (cycloalkyl)alkyl, any of which is optionally substituted with one to three groups T1d, T2d or T3d; T1, T1a, T1b, T1c, T1d, T2, T2a, T2b, T2c, T2d, T3, T3a, T3b, T3c and T3d (hereinafter abbreviated as T1-1d, T2-2d and T3-3d) independently represent (1) Hydrogen or T6, [wherein T6 is (a) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (b) a group (a) itself substituted with one or more of the same or different groups (a); or (c) Group (a) or (b) independently substituted with one or more (preferably 1 to 3) of the following groups (2) to (13) in the definitions of T1-1d, T2-2d, and T3-3d: is], (2) OH or OT6, (3) SH or ST6, (4) C(O) t H, C(O) tT6, or OC(O)T6, [where t is 1 or 2]; (5) SO3H, S(O) t T6 or S(O) t N(T9)T6, (6) Halo, (7) Cyano, (8) Nitro, (9) T4NT7 T8, (10) T4N(T9)-T5NT7 T8, (11) T4N(T10)-T5-T6, (12) T4N(T10)-T5H, (13) Oxo and T4 and T5 each independently represent a single bond, T11-S(O) t -T12, T11-C(O)-T12, T11-C(S)-T12, T11-O-T12, -T11S-T12, -T11OC(O)-T12, -T11-C(O)O-T12, -T11C(=NT9a)-T12, or T11-C(O)-C(O)-T12; T7, T8, T9, T9a and T10 are (1) each independently represents hydrogen or a group as defined in the definition of T6, or (2) T7 and T8 together with the atoms to which they are attached may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring, which ring is unsubstituted or substituted with one or more groups listed in the descriptions of T1-1d, T2-2d, and T3-3d, or (3) T7 or T8, together with T9, can be an alkylene or alkenylene that completes a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached, and the ring is unsubstituted or substituted with one or more groups listed in the descriptions of T1-1d, T2-2d, and T3-3d, or (4) T7 and T8 or T9 and T10, together with the nitrogen atom to which they are attached, can combine to form the group N=CT13T14, wherein T13 and T14 are each independently H or a group defined in the definition of T6; and T11 and T12 are each independently a single bond, alkylene, alkenylene, or alkynylene.

[0138] The preparation of these compounds is described in US Pat. No. 6,838,559, US 2003 / 0100571, and WO 2002 / 102314.

[0139] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in U.S. Patent No. 7,087,614, US2003 / 0162802, and WO2002 / 102313 (each of which is expressly incorporated herein by reference in its entirety).

[0140] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (16): [ka] It has.

[0141] The substituents for formula (16) above are as described below for formula (16A).

[0142] In a related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula (16A): [ka] ((16), (16A), (54): also known as amine-substituted pyrimidine derivatives) It has.

[0143] The substituents for the above formulae (16) and (16A) are defined as follows: R 1a is hydrogen or alkyl; R 2a teeth, [ka] and W is O or S; X 1 is alkoxy; and X 2 is alkyl; Z* is halogen, haloalkyl, oxazolyl, NR 3a R 4a , C(O)—N(H)-alkylene-COOH, or unsubstituted or heteroaryl, CO t H or CO t phenyl optionally substituted with T6; R 3a is hydrogen or alkyl; R 4a is alkyl, alkoxy, unsubstituted or substituted (heteroaryl)alkyl, unsubstituted or substituted heterocyclo, unsubstituted or substituted (heterocyclo)alkyl, or (aryl)alkyl, where the aryl group is substituted with one or two groups T1 and / or T2 and / or further substituted with a group T3; or R 3a and R 4a combine together with the nitrogen atom to which they are attached to form an unsubstituted or substituted heterocyclo ring; R 5a is unsubstituted or substituted (heteroaryl)alkyl or (aryl)alkyl, where the aryl group is substituted with one or two groups T1 and / or T2 and / or further substituted with a group T3; or R 5a and R 6a combine together with the nitrogen atom to which they are attached to form an unsubstituted or substituted heterocyclo ring; R 6a is hydrogen or alkyl; J* is hydrogen or alkyl; T1 and T2 are independently alkoxy, alkoxycarbonyl, heteroaryl, SO3H, or SO2R 8a where R 8ais alkyl, amino, alkylamino, or dialkylamino; or T1 and T2, together with the aryl ring to which they are attached, combine to form a bicyclic ring; T3 is H, alkyl, halo, haloalkyl, or cyano; t is 1 or 2; and T6 is alkyl, haloalkyl, cycloalkyl, alkoxy, or heteroaryl.

[0144] The preparation of these compounds is described in US Pat. No. 7,087,614, US 2003 / 0162802, and WO 2002 / 102313.

[0145] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in US2003 / 0104974, WO2002 / 088080, and WO2002 / 088079 (each of which is expressly incorporated herein by reference in its entirety).

[0146] In one embodiment, the PDE7 inhibitors useful in the methods of the present invention have formula (17A) and / or (17B): [ka] ((17A), (17B): also called amine-substituted purine derivatives) It has.

[0147] The substituents for formulae (17A) and (17B) above are defined as follows: R1 is H or alkyl; R2 is optionally substituted heteroaryl or 4-substituted aryl; R3 is hydrogen or alkyl; R4 is alkyl, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted heterocyclo, or optionally substituted (heterocyclo)alkyl; or R3 and R4 can combine with the nitrogen atom to which they are attached to form an optionally substituted heterocyclo ring; R5 is alkyl, optionally substituted (aryl)alkyl, or optionally substituted (heteroaryl)alkyl; and R6 is hydrogen or alkyl.

[0148] In related embodiments, the PDE7 inhibitors useful in the methods of the invention have the formula: [ka] and In the formula, R 1a is H or alkyl; R 2a is an optionally substituted heteroaryl; Z is halogen, alkyl, substituted alkyl, haloalkyl, or NR 3a R 4a and;R 3a is hydrogen or alkyl; R 4a is alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted heterocyclo, optionally substituted (heterocyclo)alkyl, or (aryl)alkyl, where the aryl group is substituted with one or two groups T1 and T2 and optionally further substituted with a group T3; or R 3a and R 4a may combine together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring; R 5a is (aryl)alkyl, wherein the aryl group is substituted with one or two groups T1 and T2 and optionally further substituted with a group T3; R 6a is hydrogen or alkyl; R 7ais hydrogen or alkyl; T1 and T2 are independently alkoxy, alkoxycarbonyl, heteroaryl, or SO2R 8a where R 8a is alkyl, amino, alkylamino, or dialkylamino; or T1 and T2, together with the atoms to which they are attached, can combine to form a ring (e.g., benzodioxole); T3 is H, alkyl, halo, haloalkyl, or cyano.

[0149] In another related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula: [ka] and In the formula, R 1b is H or alkyl; R 2b is an optionally substituted heteroaryl; R 3a is H or alkyl; R 3b is optionally substituted (aryl)alkyl; R 5b is H, alkyl, or C(O)(CH2) v OYR 6b where Y is a bond or C(O), and R 6b is hydrogen or alkyl, and v is an integer from 0 to 2; J1 and J2 are independently optionally substituted C 1-3alkylene, with the proviso that J and J are not both greater than C alkylene; X and X are optional substituents attached to any available carbon atom in one or both of J and J and are independently selected from hydrogen, OR, NR, R, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl; R is hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl, C(O)substituted cycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)O-alkyl, C(O)O-substituted alkyl, C(O)heterocycloalkyl, C(O)heteroaryl, aryl, substituted aryl, heterocycloalkyl and heteroaryl; and R and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, C(O)alkyl, C(O)substituted alkyl, C(O)cycloalkyl, C(O)substituted cycloalkyl, C(O)aryl, C(O)substituted aryl, C(O)Oalkyl, C(O)Osubstituted alkyl, C(O)heterocycloalkyl, C(O)heteroaryl, S(O)alkyl, S(O)substituted alkyl, S(O)cycloalkyl, S(O)substituted cycloalkyl, S(O)aryl, S(O)substituted aryl, S(O)heterocycloalkyl, S(O)heteroaryl, aryl, substituted aryl, heterocycloalkyl, and heteroaryl, or R and R together with the nitrogen atom to which they are attached complete an optionally substituted heterocycloalkyl or heteroaryl ring.

[0150] In further related embodiments, the PDE7 inhibitors useful in the methods of the invention have the formula: [ka] and In the formula, R 1c is H or alkyl; R2c is an optionally substituted heteroaryl; R 3c is H or alkyl; R 4c is an optionally substituted (aryl)alkyl; and X and X are optional substituents attached to any available carbon atom in one or both of J and J, and are independently selected from hydrogen, OR, NR, R, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, or heteroaryl.

[0151] The preparation of these compounds is described in US2003 / 0104974, WO2002 / 088080, and WO2002 / 088079.

[0152] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is a compound selected from the compounds disclosed generically or specifically in US2003 / 0092908 and WO2002 / 087513 (each of which is expressly incorporated herein by reference in its entirety).

[0153] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (18): [ka] ((18): also known as fused heterocyclic derivatives containing 2-amine-substituted pyrimidines) It has.

[0154] The substituents for the above formula (18) are defined as follows: R 1 is hydrogen or alkyl; R 2is (a) heteroaryl, or heterocyclo, each of which is optionally substituted with 1 to 3 groups T1, T2, T3; (b) aryl substituted with 1 to 3 groups T1, T2, T3, provided that at least one of T1, T2, T3 is other than H; or (c) aryl fused to a heteroaryl or heterocyclo ring, where the combined ring system is optionally substituted with 1 to 3 groups T1, T2, T3; Z is NR3R4, NR3SO2R 4a , OR4, SR4, haloalkyl, or halogen; R3 and R4 are independently H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which are optionally and independently substituted, if valences allow, with one to three groups T1a, T2a, or T3a; or R3 and R4, together with the nitrogen atom to which they are attached, can form, where valences allow, a heterocyclo or heteroaryl ring optionally and independently substituted with 1 to 3 groups T1a, T2a, or T3a; R 4a is alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which is optionally substituted independently, if valences allow, with one to three groups T1a, T2a, or T3a; R 3b and R 4b is independently H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl; R 5 teeth, (1) Hydrogen or cyano; (2) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, each of which is optionally substituted, where valences allow, with one to three groups T1b, T2b, or T3b; or (3) C(O)R6, C(O)OR6, C(O)-C(O)OR, or SO2R 6a and; R6 is H, alkyl, alkenyl, NR 3b R 4b , heterocyclo, (heterocyclo)alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (NR 3b R 4b ) alkyl, heteroaryl, aryl, or (aryl)alkyl, any of which may be optionally substituted independently, if valences allow, with 1 to 3 groups T1b, T2b, or T3b; R 6a is alkyl, alkenyl, NR 3b R 4b , heterocyclo, (heterocyclo)alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (NR 3b R 4b ) alkyl, heteroaryl, aryl, or (aryl)alkyl, any of which may be optionally substituted independently, if valences allow, with 1 to 3 groups T1b, T2b, or T3b; J1 and J2 are independently optionally substituted C 1-3 alkylene, with the proviso that J1 and J2 cannot both be greater than C2 alkylene; and T1-1b, T2-2b, and T3-3b are each independently (1) hydrogen or T6, wherein T6 is (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii) group (i) itself substituted with one or more groups (i) that are the same or different; or (iii) group (i) or (ii) independently substituted with one or more (preferably 1 to 3) of the following groups (2) to (13) defined in T1-1b, T2-2b, and T3-3b, (2) OH or OT6, (3) SH or ST6, (4) C(O)tH, C(O)tT6, or OC(O)T6, where t is 1 or 2; (5) SO3H, S(O) t T6 or S(O) t N(T9)T6, (6) Halo, (7) Cyano, (8) Nitro, (9) T4-NT7T8, (10) T4-N(T9)-T5-NT7T8, (11) T4-N(T10)-T5-T6, (12) T4-N(T10)-T5H, (13) Oxo and T4 and T5 each independently represent: (1) a single bond, (2) T11-S(O), t -T12, (3) T11-C(O)-T12, (4) T11-C(S)-T12, (5) -T11-O-T12, (6) T11-S-T12, (7) T11-OC(O)-T12, (8) T11-C(O)-O-T12, (9) T11-C(=NT9a)-T12, or (10) T11-C(O)-C(O)-T12, T7, T8, T9, T9a and T10 (1) each independently represents hydrogen or a group as defined in the definition of T6, or (2) T7 and T8 together with the atoms to which they are attached may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring, which ring is unsubstituted or substituted with one or more groups listed in the descriptions of T1-1b, T2-2b, and T3-3b; or (3) T7 or T8, together with T9, can be an alkylene or alkenylene that completes a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached, and the ring is unsubstituted or substituted with one or more groups listed in the descriptions of T1-1b, T2-2b, and T3-3b; or (4) T7 and T8 or T9 and T10 can combine together with the nitrogen atom to which they are attached to form the group N=CT13T14, where T13 and T14 are each independently H or a group defined in the definition of T6; and T11 and T12 are each independently a single bond, alkylene, alkenylene, or alkynylene.

[0155] The preparation of these compounds is described in US20030092908 and WO2002 / 087513.

[0156] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in US 20040127707 and WO2002 / 085906 (each of which is expressly incorporated herein by reference in its entirety).

[0157] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (19): [ka] ((19): Also known as phthalazinone derivatives) It has.

[0158] The substituents for the above formula (19) are defined as follows: R1 is 1-2C-alkoxy or fully or predominantly fluorine-substituted 1-2C-alkoxy, R2 is fluorine, bromine, or chlorine; R3 and R4 are both hydrogen or together form an additional bond; R5, R6, C m H 2m -R7, C n H 2n -C(O)R8, CH(R9)2, C p H 2p -Y-aryl 1, R 12 or R 26 where R61-8C-alkyl, 3-10C-cycloalkyl, 3-7C-cycloalkylmethyl, 3-7C-alkenyl, 3-7C-alkynyl, phenyl-3-4C-alkenyl, 7-10C-polycycloalkyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, quinazolinyl, quinoxalinyl, cinnolinyl, isoquinolinyl, quinolinyl, indanyl, indazolyl, benzoxazolyl, benzothiazolyl, oxazolyl, thiazolyl, N- methylpiperidyl, tetrahydropyranyl, 6-methyl-3-trifluoromethyl-pyridin-2-yl, 1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl, 3-thiophen-2-yl[1,2,4]thiadiazol-5-yl, 1,1-dioxide-tetrahydrothiophen-3-yl-1, 1-oxo-1,3-dihydro-isobenzofuran-5-yl, 4-(4-yl-but-1-oxy)benzoic acid, or unsubstituted or R 61 and / or R 62 a phenyl radical substituted with R 61is hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, nitro, cyano, halogen, carboxyl, hydroxycarbonyl-1-4C-alkyl, 1-4C-alkoxycarbonyl, hydroxy-1-4C-alkyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, aminosulfonyl, mono- or di-1-4C-alkylaminosulfonyl, 4-methylphenylsulfonamido, imidazolyl; tetrazol-5-yl, 2-(1-4C-alkyl)tetrazol-5-yl or 2-benzyltetrazol-5-yl, and R 62 is 1-4C-alkyl, 1-4C-alkoxy, nitro or halogen, R7 is hydroxyl, halogen, cyano, nitro, nitroxy (O—NO2), carboxyl, carboxyphenyloxy, phenoxy, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, amino, mono- or di-1-4C-alkylamino, or unsubstituted or R 71 and / or R 72 a piperidyl, piperazinyl, pyrrolidinyl or morpholinyl radical substituted with R 71 is hydroxyl, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxycarbonyl, and R 72 is 1-4C-alkyl, carboxyl, aminocarbonyl or 1-4C-alkoxycarbonyl, R8 is unsubstituted or R 81 and / or R 82 a phenyl, naphthyl, phenanthrenyl or anthracenyl radical substituted with R81 is hydroxyl, halogen, cyano, 1-4C-alkyl, 1-4C-alkoxy, carboxyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino or 1-4C-alkoxy which is completely or predominantly substituted by fluorine, and R 82 is hydroxyl, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxy completely or predominantly substituted by fluorine, R9 is C q H2q-phenyl, Y is a bond or O (oxygen); Aryl 1 is an unsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, isoquinolyl, quinolyl, coumarinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, N-benzosuccinimidyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, furyl, thienyl, pyrrolyl, 2-(1-4C-alkyl)-thiazol-4-yl radical, or R 10 and / or R 11 is a phenyl radical substituted with R 10 is hydroxyl, halogen, nitro, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, carboxyl, hydroxycarbonyl-1-4C-alkyl, 1-4C-alkylcarbonyloxy, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, aminocarbonyl, mono- or di-1-4C-alkylamino-carbonyl, imidazolyl or tetrazolyl, and R 11 is hydroxyl, halogen, nitro, 1-4C-alkyl or 1-4C-alkoxy, m is an integer from 1 to 8, n is an integer from 1 to 4, and p is an integer from 1 to 6; q is an integer from 0 to 2,

[0159] R 12 is the formula (a)N [ka] is a radical of where R 13 is S(O)2-R 14 , S(O)2-(CH2) r -R 15 , (CH2) s -S(O)2R 16 , C(O)R 17 , C(O)-(CH2) r -R 18 , (CH2) s -C(O)-R 19 , Het aryl1, aryl2 or aryl3 is 1-4C-alkyl, R 14 is 1-4C-alkyl, 5-dimethylaminonaphthalen-1-yl, N(R 20 )R 21 , phenyl or R 22 and / or R 23 is phenyl substituted with R 15 is N(R 20 )R 21 and R 16 is N(R 20 )R 21 and R 17 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl, 4-ethyl-piperazine-2,3-dione-1-yl, 2-oxo-imidazolidin-1-yl or N(R 20 )R 21 and R 18 is N(R 20 )R 21 and R 19 is N(R 20 )R 21 , phenyl, R 22 and / or R 23 and / or R 24is phenyl substituted with R 20 and R 21 are independently of one another hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or phenyl, or R 20 and R 21 are, together with the nitrogen atom to which they are attached, a 4-morpholinyl ring, a 1-pyrrolidinyl ring, a 1-piperidinyl ring, a 1-hexahydroazepino ring or a ring represented by the formula (b) [ka] forming a 1-piperazinyl ring of where R 25 is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C-alkyl-dimethylamino, dimethylaminocarbonylmethyl, N-methyl-piperidin-4-yl, 4-morpholino-ethyl or tetrahydrofuran-2-ylmethyl-, and R 22 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino, aminocarbonyl 1-4C-alkylcarbonylamino or mono- or di-1-4C-alkylaminocarbonyl, and R 23 is halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy, R 24 is a halogen, HetAryl1 is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl, 1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl, thiazolyl, imidazolyl or furanyl, and Aryl2 is pyridyl, phenyl or R 22 and / or R 23 aryl 3 is pyridyl, phenyl, R 22 and / or R 23 phenyl, 2-oxo-2H-chromen-7-yl or 4-(1,2,3-thiadiazol-4-yl)phenyl substituted with r is an integer from 1 to 4, and s is an integer from 1 to 4;

[0160] R 26 is expressed as equation (c) [ka] is a radical of where R 27 is C(O)R 28 , (CH2) t -C(O)R 29 , (CH2) u R 30 , aryl4, Het aryl2, phenylprop-1-en-3-yl or 1-methylpiperidin-4-yl, and R 28 Hydrogen, 1-4C-alkyl, OR 31 , furanyl, indolyl, phenyl, pyridyl, R 34 and / or R 35 Phenyl substituted with or R 36 and / or R 37 pyridyl substituted with R 29 is N(R 32 )R 33 and R 30 is N(R 32 )R 33 , tetrahydrofuranyl, or pyridinyl, and R 31 is 1-4C-alkyl, and R 32 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, and R 33 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or R 32 and R 33 form together with the nitrogen atom to which they are attached a 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl or 1-hexahydroazepinyl ring, Aryl 4 is phenyl, pyridyl, pyrimidinyl, R 34 and / or R 35 phenyl substituted with R 36 and / or R 37pyridyl substituted with R 34 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, and R 35 is halogen or 1-4C-alkyl, R 36 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, and R 37 is halogen or 1-4C-alkyl, HetAryl2 is indol-4-yl, 2-methyl-quinolin-4-yl, 5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-y-1, 3-phenyl-1,2,4-thiadiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl, t is an integer of 1 to 4, u is an integer of 1 to 4, v is an integer of 1 to 2, and X is -C(O)- or -S(O)2-, and salts of these compounds.

[0161] The preparation of these compounds is described in US2004 / 0127707 and WO2002 / 085906.

[0162] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in U.S. Pat. No. 6,818,651, US 2004 / 0044212, and WO2002 / 040450 (each of which is expressly incorporated herein by reference in its entirety).

[0163] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (20): [ka] ((20): Also known as 3,4-dihydroisoquinoline and isoquinoline derivatives) It has.

[0164] The substituents for the above formula (20) are defined as follows: R1 represents hydrogen and R2 represents fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or R1 represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano and R2 represents hydrogen, R' and R'' both represent hydrogen or together represent a bond, and Ar is a group of formula IIa, IIb, or IIc [ka] represents a phenyl radical of the formula In the formula, R3 represents hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl, R4 represents 1-4C-alkyl, naphthalenyl, 5-dimethylaminonaphthalen-1-yl, phenylethen-2-yl, 3,5-dimethylisoxazol-4-yl, 5-chloro-3-methylbenzo[b]thiophen-2-yl, 6-chloro-imidazo[2,1b]-thiazol-5-yl, or a phenyl or thiophene radical that is unsubstituted or substituted by one or more identical or different radicals selected from the group halogen, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy fully or largely substituted by fluorine, 1-4C-alkoxy, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonyl, phenylsulfonyl or isoxazolyl, or its hydrates, solvates, salts, hydrates of salts, or solvates of salts;

[0165] The preparation of these compounds is described in US Pat. No. 6,818,651, US 2004 / 0044212, and WO2002 / 040450.

[0166] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in WO2002 / 040449, which is expressly incorporated herein by reference in its entirety.

[0167] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (21): [ka] ((21): 1-Phenyl derivatives, also known as substituted 3,4-dihydroisoquinoline derivatives) It has.

[0168] The substituents for the above formula (21) are defined as follows: R1 represents hydrogen and R2 represents fluorine, chlorine, bromine, cyano, trifluoromethyl or phenoxy, or R1 represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl or cyano, and R2 represents hydrogen; R' and R'' both represent hydrogen or together represent a bond; R3 represents hydrogen, hydroxyl, nitro, amino, carboxyl, aminocarbonyl, 1-4C-alkoxy, trifluoromethoxy, 1-4C-alkoxycarbonyl or mono- or di-1-4C-alkylaminocarbonyl, and R4 represents C(O)—X—R5, N(H)—C(O)—R6 or N(H)—C(O)—N(H)—R2, wherein X represents O or N(H); R5 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkylmethyl, 6,6-dimethylbicyclo[3,3,I]hept-2-yl, 3-7C-alkynyl, 1-4C-alkylcarbonyl-1-4C-alkyl, aminocarbonyl-1-4C-alkyl, furan-2-ylmethyl, 2-pyridin-2-yleth-1-yl, 2-pyridin-3-ylmethyl, N-methylpiperidin-3-yl, 1-benzylpiperidin-4-yl, morpholin-4-yl-eth-2-yl, morpholin-4-yl-eth-1-yl, 2-benzo[1,3]dioxol-4-yl-eth-1-yl, chroman-4-yl, 1-methylpiperidin ... -methoxycarbonyl-2-indol-3-yl-eth-1-yl, 1,3-bis-methoxycarbonylprop-1-yl, 1-methoxycarbonyl-3-methylsulfanyl-eth-1-yl, 1-methoxycarbonyl-2-thiazol-2-yl-eth-1-yl, or 4-methylthiazol-5-yl-eth-2-yl, or represents a benzyl-, phenyl-eth-1-yl, or 1-methoxycarbonyl-2-phenyl-eth-2-yl radical, which is unsubstituted or substituted by one or more radicals selected from the group of halogen, trifluoromethyl, and phenyl, R6 represents 2,4-dichlorophenoxymethyl, 2-tert-butoxycarbonylamino-eth-1-yl, 1-acetylpiperidin-4-yl, Ar1 or Ar2-CH=CH-; wherein Ar1 represents 3-chlorophenyl, 4-trifluoromethoxyphenyl, 3-phenoxyphenyl, indol-5-yl, 2-methylpyridin-5-yl, quinolin-6-yl or 2-benzothiazol-6-yl, and Ar2 represents furan-2-yl, furan-3-yl, thiophen-2-yl, indol-3-yl, 3-trifluoromethylphenyl, 3-methoxyphenyl or pyridin-3-yl; R7 represents a 1-4C-alkyl, 3-7C-alkenyl, 3-7C-cycloalkyl, 1-ethoxycarbonyl-2-phenyl-eth-1-yl, thiophen-2-yleth-1-yl or phenyl radical unsubstituted or substituted by one or more radicals selected from the group halogen, cyano, 1-4C-alkyl, trifluoromethyl, 1-4C-alkylthio, 1-4C-alkoxy, 1-4C-alkoxy completely or largely substituted by fluorine, 1-4C-alkylcarbonyl and phenoxy, or That salt.

[0169] The preparation of these compounds is described in WO2002 / 040449.

[0170] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in WO2001 / 098274, which is expressly incorporated herein by reference in its entirety.

[0171] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (22): [ka] ((22): Also known as sulfonamide derivatives) It has.

[0172] The substituents for formula (22) above are defined as follows: W, X, Y, and Z, which may be the same or different, each represent a nitrogen atom or a C(R) group, where R is a hydrogen or halogen atom, or an alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, -NO, or -CN group, provided that two or more of W, X, Y, and Z are C(R); R1, R2 and R3 may be the same or different and each represent an atom or a group -L1(Alk1) r L2(R6) swherein L and L, which may be the same or different, are each a covalent bond or a linker atom or group; r is zero or the integer 1; Alk is an aliphatic or heteroaliphatic chain; s is the integer 1, 2, or 3; and R is a hydrogen or halogen atom, or an alkyl, —OR [where R is a hydrogen atom or an optionally substituted alkyl group], —SR, NR, R [where R is as defined above for R and may be the same or different], —NO, CN, CO, R, SO, H, S(O)R, SO, OCO, R, CONR, R, OCONR, R, CSNR, R, OCR, OCOR, N(R)COR, N(R)CSR, S(O)NR, R, SO, N(R)SOR, N(R)CON(R)(R). [wherein R9 is a hydrogen atom or an optionally substituted alkyl group], a group selected from N(R7)CSN(R8)(R9), N(R7)SON(R8)(R9), C(R7)=NO(R8), a cycloaliphatic group, a heterocycloaliphatic group, an aryl group, or a heteroaryl group]; provided that one or more of R1, R2, or R3 is a substituent other than a hydrogen atom; R4 represents an optionally substituted phenyl, 1- or 2-naphthyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group; and its salts, solvates, hydrates, and N-oxides;

[0173] The preparation of these compounds is described in WO2001 / 098274.

[0174] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in WO2001 / 074786, which is expressly incorporated herein by reference in its entirety.

[0175] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (23): [ka] ((23): Also called heterobiaryl sulfonamide derivatives) It has.

[0176] The substituents for formula (23) above are defined as follows: R1 represents an aryl or heteroaryl group; A, B, P, and E, which may be the same or different, each represent a nitrogen atom or a C(R) group, where R is a hydrogen or halogen atom, or an alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, -NO, or -CN group, provided that two or more of A, B, D, and E are C(R); X represents an oxygen or sulfur atom, or an N(R) group, where R is a hydrogen atom or an alkyl group; Q, R, S, and T may be the same or different and each represent a nitrogen atom or a group C(R4), where R4 is an atom or group -L1(Alk1)rL2(R5) swherein L and L may be the same or different and are each a covalent bond or a linker atom or group, r is zero or the integer 1, alkyl is an aliphatic or heteroaliphatic chain, s is the integer 1, 2, or 3, and R is a hydrogen or halogen atom, or alkyl, OR [where R is a hydrogen atom or an optionally substituted alkyl group], SR, NR R [where R is as defined above for R and may be the same or different], NO, CN, CO R, SO H, S(O)R, SO R, OCO R, CONR R, OCONR R, CSNR R, OCR, OCOR, N(R)COR, N(R)CSR, S(O)NR R, SO NRR, N(R)SOR; N(R)CON(R)(R). [wherein R8 is a hydrogen atom or an optionally substituted alkyl group], N(R6)CSN(R7)(R8), N(R6)SON(R7)(R8), C(R6)=NO(R7) is a group selected from a cycloaliphatic group, a heterocycloaliphatic group, an aryl group, or a heteroaryl group], with the proviso that two or more of Q, R, S, and T are C(R4) groups; and salts, solvates, hydrates, and N-oxides thereof.

[0177] The preparation of these compounds is described in WO2001 / 074786.

[0178] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in WO2000 / 068230, which is expressly incorporated herein by reference in its entirety.

[0179] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (24): [ka] ((24): Also known as the naphthalenyl derivative of dihydropurin-6-one) It has.

[0180] The substituents for formula (24) above are defined as follows: XYZ represents NR4-C=N or N=C-NR4; R1 represents H, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or heterocycloalkyl; R2 is OR8, NR8R9, SR 13 , alkyl or CF3; R3 represents halogen, alkyl, CF3 or OR8; R4 [which may be attached to either X or Z] is [ka] is a residue selected from wherein the bond is through any position on the saturated ring, provided that the bond is not adjacent to V, and the saturated ring may be substituted with one or more R6 at any position; A, B, D, and may be the same or different, and each may be Cl. n R5 represents N or NO; V is O, S, NR7 or C(L 1 m R 14 )(L 2 n R 14 ) represents; Q and W are the same or different and each represent a C n represents R5 or N; T represents O, S or NR7; L 1 and L 2 are the same or different, and C(R 15 )2 represents; m and n are the same or different and each represent 0, 1, 2, 3, 4, or 5; R5 may be the same or different and each may be H, halogen, alkyl, cycloalkyl, OR8, NR8R9, CO2R 10 ,CONR 11 R12 , CONHOH, SO2NR 11 R 12 ,SON 11 R 12 , C.O.R. 13 , SO2R 13 , SOR 13 , S.R. 13 , CF3, NO2 or CN; R6 is H, alkyl, cycloalkyl, OR8, NR8R9, CO2R 10 ,CONR 11 R 12 , SO2NR 11 R 12 ,SON 11 R 12 , C.O.R. 13 , SO2R 13 , SOR 13 , S.R. 13 , CF3, CN or =O; R7 represents H or alkyl; R8 represents H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl; R9 represents R8 or alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, cycloalkylcarbonyl, cycloalkoxycarbonyl, cycloalkylsulfonyl, cycloalkylalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkylsulfonyl, arylcarbonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, heterocyclocarbonyl, heterocyclosulfonyl, arylalkylcarbonyl, arylalkoxycarbonyl, arylalkylsulfonyl, heteroarylalkylcarbonyl, heteroarylalkoxycarbonyl, heteroarylsulfonyl, heterocycloalkylcarbonyl, heterocycloalkoxycarbonyl, or heterocycloalkylsulfonyl; or NR8R9 represents a heterocyclic ring such as morpholine; R 10represents H, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or heterocycloalkyl; R 11 and R 12 are the same or different and are each R8 or NR 11 R 12 represents a heterocyclic ring such as morpholine; R 13 represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl; R 14 are the same or different and are each H, alkyl, cycloalkyl, OR, NR, R, CO, R 10 ,CONR 11 R 12 , CONHOH, SO2NR 11 R 12 ,SON 11 R 12 , C.O.R. 13 , SO2R 13 , SOR 13 , S.R. 13 , CF3, NO2 and CN, provided that when m and n both represent 0, one R 14 is OR8, NR8R9 or SR 13 If so, the other is OR8, NR8R9 or SR 13 not; and R 15 represents H, alkyl or F; or and pharmaceutically acceptable salts thereof.

[0181] The preparation of these compounds is described in WO2000 / 068230, which is incorporated herein by reference in its entirety.

[0182] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from compounds generally or specifically disclosed in US 2004 / 0106631, U.S. Patent No. 7,429,598, EP-A-1400244, and WO2004 / 026818 (each of which is expressly incorporated herein by reference in its entirety).

[0183] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (25): [ka] ((25): Also known as spiro c (spiroc) derivatives) It has.

[0184] The substituents for formula (25) above are defined as follows: m is 1, 2 or 3; R1 is methyl, chloro, bromo or fluoro; R2 is -Q 1 -Q 2 -Q 3 -Q 4 or (C1-C6) alkyl, wherein the (C1-C6) alkyl is substituted with 1 to 3 OR4, COOR4, NR4R5, NRC(=O)R4, C(=O)NR4R5, or SO2NR4R5; R4 is (C1-C6)alkyl substituted with one to three F, CN, S(=O)R6, SO3H, SO2R6, SR7, C(=O)-NH-SO2-CH3, C(=O)R7, NR'C(=O)R7, NR'S02R6, C(=O)NR7R8, OC(=O)NR7R8 or SO2NR7R8; R5 is H or (C1-C6)alkyl optionally substituted with one to three of F, CN, S(=O)R6, SO3H, SO2R6, SR7, C(=O)-NH-SO2-CH3, C(=O)R7, NR'C(=O)R7, NR'S02R6, C(=O)NR7R8, OC(=O)NR7R8 or SO2NR7R8; or the (C1-C6)alkyl is (1) 1 to 3 OC(=O)R 4a , S.R.4a , S(=O)R3, C(=NR9)R 4a , C(=NR9)-NR 4a R 5a , NR-C(=NR9)-NR 4a R 5a , NRCOOR 4a , NR-C(=O)NR 4a R 5a , NR-SO2-NR 4a R 5a , NR-C(=NR9)-R 4a or substituted by NR-SO2-R3; and (2) One or two ORs 4a , COOR 4a , C(=O)-R 4a , N.R. 4a R 5a , NRC(=O)R 4a , C(=O)NR4R 5a or SO2NR 4a R 5a optionally replaced by; R9 is H, CN, OH, OCH3, SO2CH3, SO2NH2, or (C1-C6)alkyl; and R3 is (C1-C6)alkyl optionally substituted with one to three of F, CN, S(=O)R6, SO3H, SO2R6, C(=O)-NH-SO2-CH3, OR7, SR7, COOR7, C(=O)R7, OC(=O)NR7R8, NR7R8, NR'C(=O)R7, NR'S02R6, C(=O)NR7R8, or SO2NR7R8; R 4a and R 5a are the same or different and are H or (C1-C6)alkyl optionally substituted with 1-3 of F, CN, S(=O)R6, SO3H, SO2R6, C(=O)-NH-SO2-CH3, OR7, SR7, COOR7, C(=O)R7, OC(=O)NR7R8, NR7R8, NR'C(=O)R7, NR'S02R6, C(=O)NR7R8 or SO2NR7R8; Q 1 is a single bond or (C1-C6) alkylene; Q 2 is a saturated 4-6 membered heterocyclyl containing one or two O or N; Q3 is (C1-C6) alkylene; Q 4 is a 4-8 membered aromatic or non-aromatic heterocyclyl containing 1-4 of O, S, S(=O), SO2, or N, said heterocyclyl optionally substituted with 1-3 of OR, NRR', -CN, or (C1-C6)alkyl; R is H or (C1-C6) alkyl; R6 is (C1-C6) alkyl optionally substituted with one or two OR'; R7 and R8 are the same or different and are H or (C1-C6) alkyl optionally substituted with one or two OR'; R9 is H, CN, OH, OCH3, SO2CH3, SO2NH2 or (C1-C6)alkyl; R' is H or (C1-C6) alkyl; and R'' is H or (C1-C6) alkyl; However, (1) Q 1 Q bonded to 2 is a carbon atom; and (2) Q 3 Q bonded to 4 The atoms of are carbon atoms; or a racemate, isomer, or pharmaceutically acceptable derivative thereof.

[0185] The preparation of these compounds is described in US2004 / 0106631, US Pat. No. 7,429,598, EP-A-1400244, and WO2004 / 026818.

[0186] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in U.S. Pat. Nos. 6,936,609 and US 2004 / 0249148, and WO 2003 / 000693, each of which is incorporated herein by reference in its entirety.

[0187] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (26): [ka] ((26): Also known as imidazotriazine derivatives) It has.

[0188] The substituents in the above formula (26) are defined as follows: R1 is optionally substituted with the same or different radicals selected from the group consisting of halogen, formyl, carbamoyl, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, nitro, (C1-C6)-alkyl or (C1-C6)-alkoxy and optionally substituted with a radical of formula SO2NR5R6, (C6-C 10 )-aryl, where R5 and R6, independently of one another, denote hydrogen or (C1-C6)-alkyl, or NR5R6 denotes a 4- to 8-membered heterocyclyl, optionally substituted with identical or different radicals selected from the group consisting of oxo, halogen, (C1-C6)-alkyl and (C1-C6)-acyl, and bonded via a nitrogen atom; R2 represents a saturated or partially unsaturated hydrocarbon radical having 1 to 10 carbon atoms; R3 represents methyl or ethyl; A represents O, S or NR7, where R7 denotes hydrogen or (C1-C6)-alkyl optionally substituted with (C1-C3)-alkoxy, E represents a bond or a (C1-C3)-alkanediyl; R4 is (C6-C 10)-aryl or 5-10 membered heteroaryl, in which aryl and heteroaryl are optionally substituted by the same or different radicals selected from the group consisting of halogen, formyl, carboxyl, carbamoyl, -SO3H, aminosulfonyl, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy, nitro, (C1-C6)-alkyl, (C1-C6)-alkoxy, 1,3-dioxa-propane-1,3-diyl, (C1-C6)-alkylthio, (C1-C6)-alkylsulfinyl and (C1-C6)-alkyl-sulfonyl, -NR8R9, and (end) optionally methyl-substituted 5- to 6-membered heteroaryl or phenyl, wherein R8 and R9 independently represent hydrogen, (C1-C6)-alkyl or (C1-C6)-acyl, or a salt thereof.

[0189] The preparation of these compounds is described in US Pat. No. 6,936,609 and US 2004 / 0249148, and WO 2003 / 000693.

[0190] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in WO2006 / 092692, which is expressly incorporated herein by reference in its entirety.

[0191] In one embodiment, the PDE7 inhibitors useful in the methods of the present invention are represented by formulas (27A), (27B), (27C), and (27D): [ka] wherein n is an integer from 1 to 4, and if stereocenters are present, each center may independently be R or S. ((27A), (27B), (27C), (27D): also known as spiro-fused 4-amino-butanecarboxylic acid derivatives) It has.

[0192] The preparation of these compounds is described in WO2006 / 092692.

[0193] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in US2006 / 229306 and WO2004 / 065391 (each of which is expressly incorporated herein by reference in its entirety).

[0194] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (28): [ka] ((28): Also known as 4-amine-substituted thieno[2,3-d]pyrimidine-6-carbonitrile derivatives) It has.

[0195] The substituents for the above formula (28) are defined as follows: R1 and R2 are (1) independently: (a) a hydrogen atom; (b) a group selected from alkyl, alkenyl, and alkynyl groups, wherein each alkyl, alkenyl, and alkynyl group is optionally substituted with one or more substituents independently selected from halogen atoms, hydroxy, alkoxy, aryloxy, alkylthio, hydroxycarbonyl, alkoxycarbonyl, mono- and di-alkylaminoacyl, oxo, amino, and mono- and di-alkylamino groups; or (c) a group of formula (CH n -R6, wherein n is an integer from 0 to 4, and R6 represents a cycloalkyl or cycloalkenyl group; (2) R1 and R2, together with the nitrogen atom to which they are attached, form a 3- to 8-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, which ring is saturated or unsaturated and optionally substituted with one or more substituents selected from halogen atoms, alkyl, hydroxy, alkoxy, acyl, hydroxycarbonyl, alkoxycarbonyl, alkylenedioxy, amino, mono- and di-alkylamino, mono- and di-alkylaminoacyl, nitro, cyano, and trifluoromethyl groups; Either; R3 is a group of the formula (CH2) n-G wherein n is an integer from 0 to 4, and G represents a monocyclic or bicyclic aryl or heteroaryl group containing 0 to 4 heteroatoms, the group being: (1) Halogen atoms; (2) alkyl and alkylene groups, wherein each alkyl and alkylene group is independently optionally substituted with one or more substituents selected from halogen atoms; and (3) phenyl, hydroxy, hydroxyalkyl, alkoxy, alkylenedioxy, aryloxy, alkylthio, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, cyano, difluoromethoxy, and trifluoromethoxy groups; optionally substituted with one or more substituents selected from R4 represents a hydrogen atom, an alkyl group, or an aryl group.

[0196] The preparation of these compounds is described in US2006229306 and WO2004 / 065391.

[0197] Other compounds useful in the methods of the present invention include imidazopyridine derivatives (WO 2001 / 034601), dihydropurine derivatives (WO 2000 / 068230), pyrrole derivatives (WO 2001 / 032618), benzothiopyranoimidazolone derivatives (DE 19950647), guanine derivatives (Bioorg. Med. Chem. Lett. 11:1081-1083, 2001), heterocyclic derivatives (WO 2012 / 150369), arylidenopyridine and arylindenopyrimidine derivatives (U.S. Pat. No. 7,754,730), sulfonylbenzene derivatives (JP 2006290791), trans-aconitic acid (U.S. Pat. No. 9,610,268), thienopyrimidine / thienopyrimidinone derivatives (Org Biomol Chem 12(24):4233-4242, 2014), 2-(isopropylamino)thieno[3,2-d]pyrimidin-4(3H)-one derivatives (Bioorg Med Chem Lett 25(9):1910-1914, 2015), isothiazole and isoxazole fused pyrimidone derivatives (Bioorg Med Chem Lett 22(9):3223-3228, 2012), imidazopyridazinone derivatives (Bioorg Med Chem Lett 22(19):6286-6291, 2012), sulfide derivatives (J Med Chem 57(20):8590-8607, 2014), dihydronaphthyridinedione derivatives (Bioorg Med Chem Lett 21(22):6652-6656, 2011), furan derivatives (J Med Chem 55(7):3274-3284, 2012), S-substituted quinazolines (U.S. Patent No. 9,796,687), 1,2-dihydro-3-phenyl-2-thioxo-4(3H)-quinazolinone (S14, S.14, CAS:18741-24-7, Curr Med Chem 24(7):673-700, 2017), SUN11817 (CAS:873539-34-5, Curr Med Chem 24(7):673-700, 2017), 3-phenyl-2,4(1H,3H)-quinazolinedithione (TC3.6, CAS:16081-93-9, Curr Med Chem 24(7):673-700, 2017), benzothienothiadiazine derivatives (Eur.J.Med.Chem.36:333-338, 2001), PDE7 inhibitors listed in Liras and Bell, Phosphodiesterases and Their Inhibitors, Wiley-VCH (pp. 165-190), steroids, podocarpan, and fused thiophenes (Journal of Biomolecular Screening, 15(4), 359-367), as well as IBMX (3-isobutyl-1-methylxanthine, CAS:28822-58-4) and dipyridamole. These include (2,2',2'',2'''-[[4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine-2,6-diyl]dinitrilo]tetraethanol, CAS: 58-32-2) (Curr Med Chem 24(7):673-700, 2017) and ibudilast (CAS: 50847-11-5), and other derivatives, including non-selective PDE inhibitors with significant inhibitory properties against PDE7, such as IBMX, caffeine, theophylline, theobromine, paraxanthine, 7-methylxanthine, aminophylline, and other methylxanthine derivatives such as pentoxifylline (CAS: 6493-05-6).

[0198] The disclosures of each published patent application and journal article cited above are expressly incorporated herein by reference in their entirety.

[0199] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in WO2008 / 130619, which is expressly incorporated herein by reference in its entirety.

[0200] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (29): [ka] ((29): Also known as pyrimidin-2-yl sulfide derivatives) It has.

[0201] The substituents for formula (29) above are defined as follows: X is SO or SO2, R1 is H or alkyl; R2 is alkyl or halogen.

[0202] In certain embodiments, R1 is Me. In other particular embodiments, R1 is F. In certain embodiments, R2 is t-Bu. In certain embodiments, R1 is methyl. In more particular embodiments, the compound is: [ka] is selected from.

[0203] In a related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula (30): [ka] wherein R1 is alkyl, R2 is aryl or heteroaryl; R3 is alkyl, aryl, cycloakyl, or alkylaryl. ((30): also called 5-oxo-pyrrole-3-carboxylate derivative).

[0204] In certain embodiments, R1 is methyl. In certain embodiments, R2 is furanyl or thiophenyl. In other certain embodiments, R2 is substituted phenyl or benzyl. In a preferred embodiment, R3 is iso-butyl. In more particular embodiments, the compound is: [ka] [ka] is selected from.

[0205] In another related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula (31): [ka] wherein R1 is a nitrile or an alkyl carboxylate; R2 is alkyl, aryl, or heteroaryl. ((31): also known as thieno[2,3-b]thiophene-3-amine derivatives).

[0206] In certain embodiments, R1 is nitrile or methyl carboxylate. In certain embodiments, R2 is a 5-membered heteroaryl. In more particular embodiments, R2 is furanyl or thienyl. In other embodiments, R2 is a 6-membered aryl. In more particular embodiments, R2 is substituted phenyl. [ka]

[0207] In another related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula (32): [ka] wherein R1 is an alkyl, alkenyl, or alkylcarboxylic acid; R2 is a halogen. ((32): Also known as indolo[2,3-b]quinoxaline derivatives).

[0208] In certain embodiments, R1 is butyl. In other embodiments, R1 is terminal alkenyl.

[0209] In more particular embodiments, R1 is allyl or vinyl. 1-4 In certain embodiments, R1 is alkyl. In certain embodiments, R2 is methylcarboxylic acid. In certain embodiments, R2 is Cl or Br. In more particular embodiments, the compound is: [ka] [ka] is selected from.

[0210] In other related embodiments, the PDE7 inhibitor useful in the methods of the present invention has the formula (33): [ka] wherein R1 is CO or an alkyl alcohol, R2 is alkyl, R3 is alkoxy, and the C4 and C9 stereocenters are independently (R) or (S).

[0211] In certain embodiments, R1 is carbonyl or 2-methylpropan-1-ol. In certain embodiments, R2 is methyl. In certain embodiments, R3 is methoxy. In more particular embodiments, the compound is: [ka] is selected from.

[0212] In another related embodiment, the PDE7 inhibitor useful in the methods of the invention has the formula (34): [ka] wherein R1 is hydrogen, hydroxyl, carbonyl, or alkyl alcohol; R2 and R3 are independently selected from hydrogen, alkyl, alkylcarboxylate, or carboxylic acid; R4 is hydrogen or alkyl; R5 is hydrogen, alkyl, hydroxyl, or acetate; R6 is hydrogen or alkoxy, and the C4 and C9 stereocenters are independently (R) or (S). ((33) and (34): also called methylphenanthrene derivatives).

[0213] In certain embodiments, R1 is 2-methylpropan-1-ol. In certain embodiments, R2 is methyl. In certain embodiments, R2 is methyl carboxylate. In certain embodiments, R2 and R3 are both methyl. In other embodiments, R2 is methyl and R3 is methyl carboxylate. In certain embodiments, R4 is isopropyl. In certain embodiments, R5 is methyl. In certain embodiments, R6 is methoxy.

[0214] In a more particular embodiment, the compound is: [ka] is selected from.

[0215] With respect to the above compounds, the terms "alkyl," "alkenyl," and the prefix "alk-" include both straight-chain and branched-chain groups and cyclic groups, i.e., cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain 1 to 20 carbon atoms, and alkenyl groups contain 2 to 20 carbon atoms. Preferred groups have up to 10 total carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, adamantly, norbornane, and norbornee. This also applies to groups containing the prefix "alkyl-," such as alkylcarboxylic acids, alkylalcohols, alkylcarboxylates, alkylaryls, and the like. Examples of suitable alkylcarboxylic acid groups are methylcarboxylic acid, ethylcarboxylic acid, and the like. Examples of suitable alkylalcohols are methyl alcohol, ethyl alcohol, isopropyl alcohol, 2-methylpropan-1-ol, and the like. Examples of suitable alkyl carboxylates are methyl carboxylate, ethyl carboxylate, etc. Examples of suitable alkylaryl groups are benzyl, phenylpropyl, etc.

[0216] The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl, and indenyl. The term "heteroaryl" includes aromatic rings or ring systems containing at least one ring heteroatom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, thiazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and the like.

[0217] Aryl and heteroaryl groups may be unsubstituted or include alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, arylcarbonyloxy, arylcarbonylthio, alkylaminosulfonyl, alkylsulfonyl, aryl ... and, in the case of heterocyclyl, may be substituted by one or more substituents independently selected from the group consisting of aryl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, arylcarbonylaminoalkyl, heteroarylcarbonylatonin, heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonylamino, heteroarylaminocarbonylamino, heteroarylalkylaminocarbonylamino, and, in the case of heterocyclyl, oxo.When other groups are described as "substituted" or "optionally substituted," those groups may be substituted with one or more of the substituents listed above.

[0218] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in WO2008 / 142550 and US2010 / 0216823 (expressly incorporated herein by reference in their entireties). In one embodiment, the PDE7 inhibitors useful in the methods of the present invention are represented by formula (35): [ka] ((35): Also known as spirocyclic and substituted quinazoline derivatives) It has.

[0219] The substituents for formula (35) above are defined as follows: m is 0, 1 or 2, and n is 0, 1, 2 or 3; X is O, S or N-CN; R 1 is halogen or CN, A is a single bond, CH, O or S; B is a single bond, CH2 or OCH2, and each R 2 are independently halogen, (C 1-6 ) alkyl (optionally substituted with 1 to 3 fluorine atoms), OH, (C 1-6 ) alkylthio or CN, R 3 is the following group (i) to (x): [ka] is selected from R is H or (C 1-6 ) alkyl (optionally substituted with 1 to 3 fluorine atoms), and R' is (C 1-6) alkyl (optionally substituted with 1 to 3 fluorine atoms), or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.

[0220] In the above compounds, the term "alkyl" refers to a linear or branched, monovalent saturated hydrocarbon chain containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylbutyl, and 2,2-dimethylbutyl. Preferred alkyl groups are especially methyl and ethyl, especially methyl.

[0221] Where stated, alkyl groups may be substituted with 1 to 3 fluorine atoms. Substitution may be at any position on the alkyl chain. Preferably, such fluorinated alkyl groups have 1 to 4 carbon atoms, more preferably 1 or 2 carbon atoms. Mono-, di-, and trifluoromethyl groups (especially trifluoromethyl), and mono-, di-, and trifluoroethyl groups (especially 2,2,2-trifluoroethyl) are particularly preferred.

[0222] The term "alkoxy" refers to "alkyl-O-", where "alkyl", in both its broadest and preferred embodiments, is as defined above. Preferred alkoxy groups are, in particular, methoxy and ethoxy groups. The term "alkylthio" refers to "alkyl-S-", where "alkyl", in both its broadest and preferred embodiments, is as defined above. Preferred alkylthio groups are (C 1-4 ) alkylthio groups, especially methylthio and ethylthio. The term "halogen" denotes fluoro, chloro, bromo or iodo. Preferred halogen groups are fluoro and chloro.

[0223] Preferably, m is 0 or 1, more preferably 1.

[0224] Preferably, n is 0 or 1, and more preferably 0.

[0225] Preferably, X is O or N-CN, more preferably O.

[0226] Preferably, R 1 is F or Cl, more preferably C1.

[0227] Preferably, A is a single bond or O, more preferably O.

[0228] When group B is OCH2, the oxygen atom is attached to the benzene ring and the methylene group is attached to group R 3 is combined with

[0229] Preferably, B is a single bond.

[0230] Preferably, R 2 is F or Cl, more preferably F.

[0231] Preferably, R 3 is group (i), (ii), (iii), (iv), (v) or (vi), more preferably group (i) or (ii), and especially group (ii).

[0232] In one embodiment, the group -BR 3 is at the 2-position of the phenyl ring (whereas the position of group A is at the 1-position). 3 is at position 3. In a further embodiment, the group -BR 3 is in fourth place.

[0233] PDE7 inhibitors useful in the methods of the present invention include those in which each variable in the formula is selected from the appropriate and / or preferred group for each variable.Even more preferred PDE7 inhibitors in the methods of the present invention include those in which each variable in the formula is selected from the more preferred or most preferred group for each variable.

[0234] In related embodiments, the following PDE7 inhibitors are useful in the methods of the invention: 5-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)]-2-fluorobenzoic acid, 3-(8'-chloro-2-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-ylbenzoic acid, 5-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline] -4'-yl)]-2-fluorobenzoic acid, 8-chloro-5'-[4-fluoro-3-(2H-tetrazol-5-yl)phenyl]-1'H-spiro[cyclohexane-1,4'-quinazoline]-2'(3'H)-one, [3-(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)phenoxy]acetic acid, 2-{(8'-chloro-2'-oxo-2,3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)ox 2-{(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclopentane-1,4'-quinazoline]-5'-oxy}-3-fluorobenzoic acid, 3-chloro-2-{(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy}benzoic acid, 3-chloro-2-{(8'-fluoro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy}benzoic acid phenyl)oxy}benzoic acid, 8'-chloro-5'-[2-fluoro-6-(2H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazoline]-2'(3'H)-one, 8'-chloro-5'-[4-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazoline]-2'(3'H)-one, 8'-chloro-5'-[6-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[4-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[6-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[6-chloro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one pentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-fluoro-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-fluoro-6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 2-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazolin]-5'-yl)oxy]-3-fluoro-N-(methylsulfonyl)benzamide , N-{2-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy]-3-fluorophenyl}-1,1,1-trifluoromethanesulfonamide, {2-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy]-3-fluorophenyl}acetic acid, {2-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazoline]-5'-yl)oxy]-3-fluorophenyl}acetic acid,4'-quinazolin]-5'-yl)oxy]phenoxy}acetic acid, {4-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazolin-5'-yl)oxy]phenoxy}acetic acid, 2-[(8'-chloro-2'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazolin]-5'-yl)oxy]-3-fluorobenzoate methyl ester, and pharmaceutically acceptable salts, solvates and prodrugs thereof.

[0235] In another related embodiment, the following PDE7 inhibitors are useful in the methods of the invention: 8'-chloro-5'-[2-fluoro-6-(2H-tetrazol-5-yl)phenoxy]-1'H-spirocyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[4-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[6-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[4-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one 8'-chloro-5'-[6-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[6-chloro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[6-chloro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1, 4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazolin]-2'(3'H)-one, 8'-chloro-5'-[2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazolin]-2'(3'H)-one, and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

[0236] The following compounds are most preferred: 8'-chloro-5'-[2-fluoro-6-(2H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazoline]-2'(3'H)-one, 8'-chloro-5'-[4-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazoline]- 2'(3'H)-one, 8'-chloro-5'-[6-fluoro-2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclopentane-1,4'-quinazoline]-2'(3'H)-one, 8'-chloro-5'-[2-(1H-tetrazol-5-yl)phenoxy]-1'H-spiro[cyclohexane-1,4'-quinazoline]-2'(3'H)-one, and pharmaceutically acceptable salts, solvates and prodrugs thereof.

[0237] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has the formula: [ka] CAS:1086424-30-7 It has.

[0238] Formula 35A is also mentioned in ISBN: 978-3-527-33219-9 (Liras and Bell, Phosphodiesterases and Their Inhibitors, Wiley-VCH).

[0239] The preparation of these compounds is described in WO2008 / 142550 and US2010 / 0216823.

[0240] In another embodiment, the PDE7 inhibitor useful in the methods of the present invention is selected from the compounds generally or specifically disclosed in U.S. Patent No. 7,498,334, US2005 / 0059686 and WO2003 / 055882 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitor useful in the methods of the present invention is represented by formula (36): [ka] ((36): Also known as pyrrolopyrimidine derivatives) It has.

[0241] The substituents for formula (36) above are defined as follows: X is phenyl or Het, each of which is unsubstituted or mono- or polysubstituted by R1 and / or R2, R1 and R2 are each, independently of one another, A, OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA', CN, NO2, NH2, NHA, NAA', NHCOA, NHCOOA, COOH, COOA, CONH2, CONHA, CONAA' or Hal, or R' and R2 together are -OCHO- or -OCH2CH2O-, and R 3 is A, OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA', CN, NO2, NH2, NHA, NHB, NAA', NHCOA, NHCOOA, NHCOB, NHCOOB, COOH, COOA, COOB, CONH2, CONHA, CONHB, CONAA' or Hal; 4is a branched or unbranched alkyl or alkenyl having up to 10 carbon atoms, optionally substituted with 1 to 5 F and / or Cl atoms and / or in which one or more CH groups may be replaced by O, S, SO, SO, NH, NA, NHCO, NACO, NHCOO or NACOO, or a cycloalkyl or cycloalkenyl having 3 to 7 carbon atoms, in which one or two CH groups may be replaced by O, S, SO, SO, SONH, SONA, NH, NHA, NHCONH, NACONH, NACONA, NHCO, NACO, NHCOO or NACOO, and R 5 is OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA', CN, NO2, NH2, NHA, NAA', NHCOA, NHCOOA, COOH, COOA, CONH2, CONHA, CONAA' or Hal; R 6is H, OH, OA, SA, SOA, SO2A, SO2NH2, SO2NHA, SO2AA', CN, NO2, NH2, NHA, NAA', NHCOA, NHCOOA, COOH, COOA, CONH2, CONHA, CONAA', or Hal, and A and A' are each, independently of one another, branched or unbranched alkyl or alkenyl having up to 10 carbon atoms, which may be substituted with 1 to 5 F and / or Cl atoms, and / or in which one or more CH2 groups may be replaced by O, S, SO, SO2, NH, NR7, NHCO, NR7CO, NHCOO, or NR7COO. Alternatively, A and A' together are alkylene having 3 to 7 carbon atoms, in which one or two CH2 groups may be replaced by CHR7, CHR7R8, O, S, SO, SO2, NH, NR7, NHCO, NR7CO, NHCOO, or NR7COO. B is phenyl or Het, each of which is unsubstituted or mono- or polysubstituted by R1 and / or R2; Het is an aromatic 5- or 6-membered heterocyclic ring having 1 to 3 N, O and / or S atoms, which is unsubstituted or mono-, di- or trisubstituted by A″, Hal or CF3; R7 and R8 are each, independently of one another, branched or unbranched alkyl or alkenyl having up to 5 carbon atoms, which may be substituted by 1 to 5 F and / or Cl atoms and / or in which one or more CH2 groups may be replaced by O, S, SO, SO2 or NH; A″ is alkyl having 1 to 6 carbon atoms; and Hal is F, C1, Br or I, as well as pharmaceutically usable derivatives, solvates, and stereoisomers thereof, including mixtures thereof in all ratios.

[0242] In a related embodiment, the PDE7 inhibitor useful in the methods of the invention is 5 is OH, which includes compounds of the formula: [ka] These may also be in the form of their tautomers:

[0243] With regard to the above-mentioned compounds, the PDE7 inhibitors useful in the method of the present invention include the optically active forms (stereoisomers), enantiomers, racemates, diastereomers, and hydrates and solvates of these compounds.The term solvate of a compound is understood to mean the addition of inert solvent molecules to the compound, which is formed due to their mutual attractive force.Solvate is, for example, monohydrate, dihydrate or alcoholate.

[0244] With respect to the above compounds, the term "pharmaceutically usable derivatives" is understood to mean, for example, salts of the above compounds and so-called prodrug compounds. The term "prodrug derivatives" is understood to mean, for example, the above compounds which are modified with alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism, thereby releasing the active compound. These also include biodegradable polymer derivatives of the above compounds, as described, for example, in Int. J. Pharm. 115, 61-67 (1995).

[0245] With regard to the above compounds, the meanings of all radicals which occur more than once are independent of one another in each occurrence.

[0246] A and A' are preferably alkyl, more preferably alkyl substituted with 1 to 5 fluorine and / or chlorine atoms, and even more preferably alkenyl.

[0247] In the above formula, alkyl is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms, and is preferably methyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, even more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl. Methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl, n-hexyl or n-decyl are particularly preferred.

[0248] A" is preferably alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl or propyl, even more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl. Methyl, ethyl, propyl, isopropyl or butyl are particularly preferred.

[0249] Cycloalkyl preferably has 3 to 7 carbon atoms and is preferably cyclopropyl or cyclobutyl, even more preferably cyclopentyl or cyclohexyl, and even more preferably cycloheptyl; cyclopentyl is especially preferred.

[0250] Alkenyl is preferably vinyl, allyl, 2- or 3-butenyl, isobutenyl or sec-butenyl; more preferably 4-pentenyl, isopentenyl or 5-hexenyl.

[0251] Alkylene is preferably unbranched and is preferably methylene or ethylene, even more preferably propylene or butylene.

[0252] Hal is preferably F, Cl or Br, but also I.

[0253] The radicals R1 and R2 may be the same or different and are preferably in the 2- or 4-position of the phenyl ring. They are, for example, A or Hal independently of one another or together methylenedioxy.

[0254] However, they are preferably methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, respectively, but also fluoro-, difluoro- or trifluoro-methoxy, or 1-fluoro-, 2-fluoro-, 1,2-difluoro-, 2,2-difluoro-, 1,2,2-trifluoro- or 2,2,2-trifluoroethoxy, and also fluorine or chlorine.

[0255] R1 is particularly preferably fluorine, chlorine, methyl, ethyl or propyl.

[0256] R2 is particularly preferably fluorine, chlorine, methyl, ethyl or propyl.

[0257] X is preferably a phenyl radical monosubstituted by R1 or an unsubstituted Het.

[0258] X is particularly preferably 2-chlorophenyl, 2-fluorophenyl, 4-methylphenyl, 3-chlorophenyl or 4-chlorophenyl.

[0259] Het is preferably, for example, unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, even more preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, or 1,2,3-thia-diazol-4- or -5-yl.

[0260] R 3 is preferably, for example, COOA″ or COOH.

[0261] R 4 is preferably unbranched or branched alkyl, for example having 2, 3, 4, 5 or 6 carbon atoms, optionally substituted with 1 to 5 F or Cl atoms, preferably methyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, even more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or n-hexyl. Methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl, n-hexyl or n-decyl are particularly preferred.

[0262] R 5 is preferably Cl or OH.

[0263] R 6 is preferably H.

[0264] For the above compounds, at least one of the above radicals has one of the preferred meanings indicated above.

[0265] In related embodiments, the PDE7 inhibitors useful in the methods of the invention are those in which X is a phenyl radical monosubstituted with R1 or is unsubstituted Het; R1 is A or Hal; and R 3 is COOA'' or COOH; R 4 is unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms optionally substituted with 1 to 5 F or Cl atoms; R 5 is Cl or OH; and R 6 is H; In other related embodiments, the PDE7 inhibitors useful in the methods of the invention are those in which X is a phenyl radical monosubstituted with R1 or is unsubstituted Het, R1 is A or Hal, and R 3 is COOA'' or COOH, and R 4 is unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, which may be substituted with 1 to 5 F or Cl atoms; R5 is Cl or OH, and R 6 is H; Het is furyl, thienyl, pyrrolyl, imidazolyl, pyridyl or pyrimidinyl; A and A″ are each, independently of one another, unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, optionally substituted with 1 to 5 F or Cl atoms; and Hal is F, Cl or Br, as well as pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

[0266] The preparation of the above compounds and the starting materials for their preparation are also described in the literature (for example, in standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart) as being exactly as known and under suitable reaction conditions for the above reactions. Here, variants which are known per se can also be used, but will not be described in more detail here.

[0267] In another related embodiment, PDE7 inhibitors useful in the methods of the present invention include: Ethyl 5-isopropyl-4-oxo-7-p-tolyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate, Ethyl 5-methyl-4-oxo-7-(3-chlorophenyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate, Ethyl 5-methyl-4-oxo-7-(2-chlorophenyl)-4,7-dihydro-3H-pyrrolo[2, 3-d]pyrimidine-6-carboxylate, ethyl 5-methyl-4-oxo-7-(2-fluorophenyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate, ethyl 5-propyl-4-oxo-7-(2-chlorophenyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate, ethyl 5-methyl-4-oxo-7-(4-chlorophenyl)-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate 5-methyl-4-oxo-7-(2-chlorophenyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate, 5-methyl-4-oxo-7-(p-tolyl)-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine-6-carboxylate, 5-methyl-4-oxo-7-(2-chlorophenyl ... Pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including methyl-4-oxo-7-phenyl-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidine-6-carboxylate, methyl-5-methyl-4-oxo-7-(2-thienyl)-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidine-6-carboxylate, and mixtures thereof in all ratios.

[0268] The preparation of the above compounds is described in US Pat. No. 7,498,334 and WO2003 / 055882.

[0269] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generally or specifically in U.S. Patent No. 6,884,800 and WO2001 / 036425 (each of which is expressly incorporated herein by reference in its entirety). In one embodiment, the PDE7 inhibitors useful in the methods of the present invention are compounds represented by formula (37): [ka] It has.

[0270] The substituents for the above formula (37) are defined as follows: R 1 and R 2 are each independently A1, OA1, SA1 or Hal, where A1 represents H, A, alkenyl, cycloalkyl or alkylenecycloalkyl, A represents alkyl having 1 to 10 carbon atoms, Hal represents F, Cl, Br or I, and x represents O, S, SO or SO2, as well as physiologically acceptable salts and / or solvates thereof.

[0271] In the above compounds, A represents alkyl having 1 to 10 carbon atoms, and preferably represents methyl, ethyl, or propyl, even more preferably isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, but also n-pentyl, neopentyl, isopentyl, or hexyl. In these radicals, 1 to 7 H atoms may be replaced by F and / or Cl. Thus, A may also represent, for example, trifluoromethyl or pentafluoroethyl. Cycloalkyl has 3 to 9 carbon atoms and preferably represents, for example, cyclopentyl or cyclohexyl. Alkenyl has 2 to 10 carbon atoms, is linear or branched, and preferably represents vinyl, propenyl, or butenyl. Alkylenecycloalkyl has 4 to 10 carbon atoms and represents, for example, methylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl, or ethylenecyclohexyl. R 1 and R 2 preferably denote, in each case independently of one another, H, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, cyclopentyl or cyclohexyl.

[0272] In a related embodiment, the PDE7 inhibitor useful in the methods of the invention is one having the formula: X is S; X is S and R 1 is H; X is S and R 1 is F or Cl; X is S and R 2 is H; X is S and R 2 is F or Cl; X is S and R 1 is H and R 2 is F or Cl X is S and R 1 is F or Cl, and R 2 is H; X is S; A1 is H or A, where A is alkyl having 1, 2, 3 or 4 carbon atoms; X is S and R 1 and R 2 represent, independently of one another, A1 or Hal, where A1 is H or A, A is alkyl having 1, 2, 3 or 4 carbon atoms, and Hal is F or Cl; This includes the following compounds and their physiologically acceptable salts and solvates:

[0273] In another related embodiment, PDE7 inhibitors useful in the methods of the present invention include the following compounds: 10-chloro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 4-chloro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 10-methoxy-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 10-propoxy-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 10-methylthio-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine 10-Fluoro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 4,10-Dichloro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 10-Trifluoromethyl-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 4-Cyclopentoxy-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine, 10-Chloro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine b-Azabenz[de]-anthracene, and 10-chloro-3-imidazol-1-yl-2,3-dihydro-1H-pyrido[3,2,1-kl]phenothiazine 7,7-dioxide.

[0274] The preparation of these compounds is described in US Pat. No. 6,884,800 and WO 01 / 036425.

[0275] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in U.S. Pat. No. 6,531,498 and WO 2001 / 032175 (each of which is expressly incorporated herein by reference in its entirety).

[0276] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (38): [ka] ((38): Also known as isoxazole derivatives) It has.

[0277] The substituents in the above formula (38) are defined as follows: R 1 , R 2 , R 3 , R 4 are each, independently of one another, Ha1, OA1, SA1, A, H, COOA1, CN, or CONA1A2, R 5 is COOA1, CN or CONA1A2, A1 and A2 are each independently H, A, alkenyl, cycloalkyl or alkylenecycloalkyl; A is alkyl having 1 to 10 C atoms, Hal is F, Cl, Br or I; and physiologically acceptable salts and / or solvates thereof.

[0278] In the above compounds, A is alkyl having 1 to 10 carbon atoms, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and is preferably methyl, ethyl or propyl, also preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl. It is also possible for 1 to 7 hydrogen atoms in the radical to be replaced by F and / or Cl. Thus, A can also be, for example, trifluoromethyl or pentafluoroethyl.

[0279] Cycloalkyl has 3 to 9 C atoms and is preferably, for example, cyclopentyl or cyclohexyl. Alkenyl has 2 to 10 C atoms, is linear or branched, and is preferably vinyl, propenyl or butenyl.

[0280] Alkylenecycloalkyl has 4 to 10 C atoms and is, for example, methylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl or ethylenecyclohexyl.

[0281] In a related embodiment, the PDE7 inhibitor useful in the methods of the invention is one having the formula: R 1 is H; R 1 and R 2 is H; R 1 is H, and R 2 is F or Cl; R 1 , R 2 are each, independently of one another, H or Hal; R 1 , R 2 are each, independently of one another, H or Hal, and A1, A2 are each, independently of one another, H or A; A1 and A2 are each independently H or A; R 1 , R 2 are each, independently of one another, H or Hal, A1, A2 are each, independently of one another, H or A, A is alkyl having 1, 2, 3 or 4 C atoms, and Hal is F or Cl, Contains compounds.

[0282] In another related embodiment, the PDE7 inhibitor useful in the methods of the present invention is the compound: 5-[2-(2-fluoro-4-hydroxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole, 5-[2-(2,4-difluorophenylamino)vinyl]-4-cyano-3-phenylisoxazole, 5-[2-(3-methylthiophenylamino)vinyl]-4-cyano-3-phenylisoxazole, 5-[2-(2,4-dimethoxyphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole, 5-(2-amino-2-phenylvinyl)-4-methylaminocarbonyl- 3-Phenylisoxazole, 5-(2-phenylaminovinyl)-4-methoxycarbonyl-3-phenylisoxazole, 5-[2-(4-carboxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole, 5-[2-(4-carboxyphenylamino)vinyl]-4-methoxycarbonyl-3-phenylisoxazole, 5-[2-(5-chloro-2-hydroxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole, 5-[2-(3,4-dimethylphenylamino)vinyl]-4 -cyano-3-(2-chlorophenyl)isoxazole, 5-[2-(4-chlorophenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole, 5-(2-phenylaminovinyl)-4-cyano-3-(2-chlorophenyl)isoxazole, 5-[2-(4-methoxyphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole, 5-[2-(4-carboxyphenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole, 5-[2-(2-fu S-[2-(4-fluorophenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole, S-[2-(4-fluorophenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole, 5-[2-(3,5-dichlorophenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole, S-[2-(3-chlorophenylamino)vinyl]-4-cyano-3-(2-chlorophenyl)isoxazole, S-(2-phenylaminovinyl)-4-cyano-3-(2,6-dichlorophenyl)isoxazole, S-[2-(4-chlorophenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole, S-(2-phenylaminovinyl)-4-methoxycarbonyl-3-(2,6-dichlorophenyl)isoxazole, 5-[2-(4-chlorophenylamino)vinyl]-4-methoxycarbonyl-3-(2,6-dichlorophenyl)isoxazole, S-[2-(4-carboxyphenylamino)vinyl]-4-methoxycarbonyl-3-(2,6-dichlorophenyl)isoxazole, S-[2-(2,4-difluorophenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole, 5-[2-(2,4-dichlorophenylamino)vinyl]-4-cyano- 3-(2,6-dichlorophenyl)isoxazole, S-[2-(4-carboxyphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole, S-[2-(3,5-dichlorophenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole, 5-[2-(4-methoxyphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole, 5-[2-(2,4-dimethoxyphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole, 5-[2-(2-phenylphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole, 5-[2-(4-methylphenylamino)vinyl]-4-cyano-3-(2,6-dichlorophenyl)isoxazole, 5-(2-phenylaminovinyl)-4-cyano-3-(2-chloro-6-fluorophenyl)isoxazole, 5-[2-(4-carboxyphenylamino)vinyl]-4-cyano-3-(2-chloro-6-fluorophenyl)isoxazole, 5-[2-(4-chlorophenylamino)vinyl]-4-cyano-3-(2-chloro-6-fluorophenyl)isoxazole, 5-[2-(3-methoxyphenylamino)vinyl]-4-cyano-3-(2-chloro-6-fluorophenyl)isoxazole, 5-[2-(4-chlorophenylamino)vinyl]-4-methoxycarbonyl-3-(2-chloro-6-fluorophenyl)isoxazole, 5-(2-phenylaminovinyl)-4-methoxycarbonyl-3-(2-chloro-6-fluorophenyl)isoxazole, 5-[2-(2,4-dichlorophenylamino) vinyl]-4-methoxycarbonyl-3-(2-chloro-6-fluorophenyl)isoxazole, 5-(2-phenylaminovinyl)-4-cyano-3-phenylisoxazole, 5-[2-(3-trifluoromethoxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole, 5-[2-(4-methoxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole, 5-[2-(4-methoxyphenylamino)vinyl]-4-methoxycarbonyl-3-(2-chloro-6-fluorophenyl)isoxazole, 5-[2-(3-methylthiophenylamino)vinyl]-4-cyano-3-phenylisoxazole, 5-[2-(2,4-difluorophenylamino)vinyl]-4-cyano-3-phenylisoxazole, 5-[2-(2-fluoro-4-hydroxyphenylamino)vinyl]-4-cyano-3-phenylisoxazole, Includes.

[0283] The preparation of these compounds is described in US Pat. No. 6,531,498 and WO 01 / 032175.

[0284] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in U.S. Pat. No. 7,491,742 and WO 2001 / 029049, each of which is incorporated by reference in its entirety.

[0285] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (39): [ka] ((37), (39): Also known as imidazole derivatives) It has.

[0286] The substituents in the above formula (39) are defined as follows: R 1 is H, A, benzyl, indan-5-yl, 1,2,3,4-tetrahydronaphthalen-5-yl, dibenzothien-2-yl, or phenyl that is unsubstituted or mono-, di- or trisubstituted by Hal, A, A-CO-NH, benzyloxy, alkoxy, COOH or COOA, and R 2 is H or A, X is O or S, Hal is F, Cl, Br or I and A is alkyl having 1 to 6 C atoms, as well as physiologically acceptable salts and / or solvates thereof.

[0287] In the above compounds, A is alkyl having 1 to 6 carbon atoms, and has 1, 2, 3, 4, 5 or 6 carbon atoms, and is preferably methyl, ethyl or propyl, also preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but also n-pentyl, neopentyl, isopentyl or hexyl. A can also be cycloalkyl, such as cyclohexyl. Alkoxy is preferably methoxy, ethoxy, propoxy or butoxy. Hal is preferably F or C1. A-CO-NH is preferably acetamido.

[0288] In related embodiments, the PDE7 inhibitors useful in the methods of the invention are selected from the following compounds: 1-Phenyl-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-benzyl-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-cyclohexyl-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-cyclopentyl-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-butyl-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-isopropyl-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one )-one, 1-propyl-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-ethyl-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-methyl-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, [1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 2-methyl-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-phenyl-[1]benzothiopyrano[3,4-d]imidazol-4-(1H)-one, 1-benzo 1-Cyclohexyl-[1]benzothiopyrano[3,4-d]imidazol-4-(1H)-one, 1-Cyclopentyl-[1]benzothiopyrano[3,4-d]imidazol-4-(1H)-one, 1-Butyl-[1]benzothiopyrano[3,4-d]imidazol-4-(1H)-one, 1-Isopropyl-[1]benzothiopyrano[3,4-d]imidazol-4-(1H)-one, 1-Propyl-[1]benzothiopyrano[3,4-d]imidazol-4-(1H)-one Imidazol-4-(1H)-one, 1-ethyl-[1]benzothiopyrano[3,4-d]imidazol-4-(1H)-one, 1-methyl-[1]benzothiopyrano[3,4-d]imidazol-4-(1H)-one, [1]benzothiopyrano[3,4-d]imidazol-4-(1H)-one, 2-methyl-[1]benzothiopyrano[3,4-d]imidazol-4-(1H)-one, 1-(2-chlorophenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(4-methylphenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(4-fluorophenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(2,4-dimethyl-phenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(3-chlorophenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(2,4-dichlorophenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(2,5-dichlorophenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(4-acetamido-phenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(2-fluorophenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(3-fluorophenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(2-benzyloxy-phenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(2,6-dimethyl- 1-(2-Methoxyphenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(2,3-dimethylphenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(2,3-dichlorophenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(indan-5-yl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(2,5-dimethyl-phenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(4-chlorophenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(1,2,3,4-tetrahydronaphthalen-5-yl)-[1]benzopyrano-[3,4-d]imidazol-4-(1H)-one, 1-(dibenzothien-2-yl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(3-methoxy-phenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, 1-(4-carboxy-2-methyl-phenyl)-[1]benzopyrano[3,4-d]imidazol-4-(1H)-one, and physiologically acceptable salts and / or solvates thereof.

[0289] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in U.S. Pat. No. 6,737,436 and WO 2001 / 032618, which are expressly incorporated by reference herein in their entireties.

[0290] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (40): [ka] ((40): Also known as 4-cyano-1H-pyrrole-2-carboxylate derivative) It has.

[0291] The substituents for formula (40) above are defined as follows: R 1 and R 2 are each independently H, A, OA, SA or Hal, R 3 represents H or A, R 4 represents A or NH2, R 5 represents H, NH2, NHA or A2, A represents an alkyl, alkenyl, cycloalkyl, or alkylenecycloalkyl having 1 to 10 carbon atoms; Hal represents F, Cl, Br or I; and physiologically acceptable salts and / or solvates thereof.

[0292] In the above compound A, A represents alkyl having 1 to 10 carbon atoms, and has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and preferably represents methyl, ethyl, or propyl, even more preferably isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, but also represents n-pentyl, neopentyl, isopentyl, or hexyl. In these radicals, 1 to 7 H atoms may also be replaced by F and / or Cl. Thus, A also represents, for example, trifluoromethyl or pentafluoroethyl.

[0293] A also denotes cycloalkyl having 3 to 8 carbon atoms and preferably denotes, for example, cyclopentyl or cyclohexyl. A also represents alkenyl. Alkenyl has 2 to 10 carbon atoms, is linear or branched, and represents, for example, vinyl, propenyl, or butenyl. A further represents alkylenecycloalkyl. Alkylenecycloalkyl has 4 to 10 carbon atoms and preferably represents, for example, methylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl, or ethylenecyclohexyl.

[0294] R 1 and R 2 preferably each independently of one another denotes H, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, S-methyl, S-ethyl, F or Cl. R 3 preferably denotes H, methyl or ethyl. R 4 preferably denotes methyl, ethyl, propyl, butyl or NH2. R 5 preferably denotes H, amino, methylamino, ethylamino, dimethylamino or diethylamino.

[0295] In a related embodiment, the PDE7 inhibitor useful in the methods of the invention is a compound of the formula: 1 and R2 and R cannot both be H. 1 or R 2 This includes compounds of the above formula where if one of is H, the other cannot be CH3, OCH3, or C1.

[0296] In another related embodiment, the PDE7 inhibitor useful in the methods of the invention is a compound of the formula: R 1 , R 2 , R 3 and R 5 is H, and R 4 is methyl; R 1 is 4-C1, and R 2 is H and R 3 is ethyl, and R 4 is amino, and R 5 is H; R 1 and R 2 is H and R 3 is ethyl, and R 4 is methyl, and R 5 is an amino; R 1 and R 2 is H and R 3 is ethyl, and R 4 is amino, and R 5 is H; R 1 and R 2 is H and R 3 is ethyl, and R 4 is H, and R 5 is an amino; R 1 is 3-C1, and R 2 is 4-O-methyl and R 3 is ethyl, and R 4 is amino, and R 5 is H; R 1 is 3-C1, and R 2 is 4-O-methyl and R 3 is ethyl, and R 4 is methyl, and R5 is an amino; R 1 is 4-OCF3, and R 2 is H and R 3 is ethyl, and R 4 is amino, and R 5 is H; R 1 is 3-Cl, and R 2 is 4-O-methyl and R 3 is ethyl, and R 4 is amino, and R 5 is H; R 1 is 3-Cl, and R 2 is 4-O-methyl and R 3 is ethyl, and R 4 is methyl, and R 5 is an amino; R 1 is 4-OCF3, and R 2 is H and R 3 is ethyl, and R 4 is amino, and R 5 is H, Contains compounds.

[0297] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds generally or specifically disclosed in U.S. Pat. No. 6,613,778 and WO 2001 / 034601, which are expressly incorporated by reference herein in their entireties.

[0298] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (41): [ka] ((41): Also known as imidazo[4,5-c]pyridine derivatives) It has.

[0299] The substituents for formula 41 above are defined as follows: R 1indicates CONR4R5, R 2 represents H or A, R4 and R5, independently of one another, each represent H or A1; R 3 indicates Hal, Hal represents F, Cl, Br or I; A is alkyl having 1 to 4 carbon atoms; A1 represents alkyl having 1 to 10 carbon atoms; X represents an alkylene having 1 to 4 carbon atoms, wherein the ethylene group may be replaced by a double or triple bond; and physiologically acceptable salts and / or solvates thereof.

[0300] In the above compounds, A is alkyl having 1 to 4 carbon atoms, and has 1, 2, 3, or 4 carbon atoms, and preferably represents methyl, ethyl, or propyl, and even more preferably represents isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. 1 to 7 H atoms in the radical may be replaced by F and / or Cl. Thus, A may also represent, for example, trifluoromethyl or pentafluoroethyl.

[0301] A1 represents alkyl having 1 to 10 carbon atoms, and has 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, and preferably represents methyl, ethyl, or propyl, even more preferably isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, but also n-pentyl, neopentyl, isopentyl, or hexyl. 1 to 7 H atoms in the radical may also be replaced by F and / or Cl. Thus, A1 also represents, for example, trifluoromethyl or pentafluoroethyl.

[0302] X represents alkylene having 1 to 4 carbon atoms, preferably methylene, ethylene, propylene, or butylene, where one ethylene group may be replaced by a double or triple bond. Thus, X may also represent, for example, -CH2-CH=CH-H2- or -C≡C-.

[0303] In a related embodiment, PDE7 inhibitors useful in the methods of the invention include the following compound: 2-(3-butyl-7-chloro-3H-imidazo[4,5-c]pyridin-4-ylsulfanyl)-N,N-dimethylacetamide [ka] 2-(3-butyl-7-chloro-3H-imidazo[4,5-c]pyridin-4-ylsulfanyl)acetamide, 2-(3-butyl-7-chloro-3H-imidazo[4,5-c]pyridin-4-ylsulfanyl)propionamide, 2-(3-butyl-7-chloro-3H-imidazo[4,5-c]pyridin-4-ylsulfanyl)butyramide, 2-(3-butyl-7- Chloro-3H-imidazo[4,5-c]pyridin-4-ylsulfanyl)-N-hexylacetamide, 2-(3-butyl-7-chloro-3H-imidazo[4,5-c]pyridin-4-ylsulfanyl)-N-octylacetamide, 4-(3-butyl-7-chloro-3H-imidazo[4,5-c]pyridin-4-ylsulfanyl)-but-2-enoic acid dimethylamide.

[0304] In another related embodiment, the PDE7 inhibitor useful in the methods of the invention is a compound of the formula: R 3 is Cl; R 3 is Cl and X is alkylene having 1 to 4 carbon atoms; R 3 is Cl, X is alkylene having 1, 2, 3 or 4 carbon atoms, and A1 is alkyl having 1, 2, 3 or 4 carbon atoms; Includes compounds according to formula (41).

[0305] The preparation of these compounds is described in US Pat. No. 6,613,778 and WO 01 / 034601.

[0306] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from compounds generally or specifically disclosed in WO2008 / 113881, US2010 / 0152213, and ES 2308916, U.S. Patent No. 9,192,610, WO2010 / 133742, and EP-A-2433637 (each of which is expressly incorporated herein by reference in its entirety).

[0307] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (42): [ka] ((42): Also known as quinazoline derivatives) It has.

[0308] The substituents for formula (42) above are defined as follows: A is a 5-, 6-, or 7-membered fused carbocyclic or heterocyclic ring and may be saturated or unsaturated; the dashed lines independently represent single or double bonds; X and Y are independently selected from the group consisting of alkyl, hydrogen, =O, =S, -N(alkyl), -N(aryl), aryl, O-alkyl, O-aryl, alkyl-S, and -S-aryl; and R 1 and R 2 is hydrogen, halogen, alkyl, haloalkyl, aryl, cycloalkyl, (Z) n -aryl, heteroaryl, -OR3; -C(O)OR3, -(Z) n Independently selected from the group consisting of -C(O)OR3 and -S(O), or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof. Exclusions: if A is unsubstituted benzene, then X=O, Y=S; if A is unsubstituted benzene, then X=O, Y=O; if A is unsubstituted benzene, then X=O, Y=S-Me; if A is unsubstituted thiophene, then X=O, Y=S; and if A is unsubstituted benzothiophene, then X=O, Y=S.

[0309] In related embodiments, the compounds constitute useful pharmaceutical compositions comprising a therapeutically effective amount of the compounds, or mixtures thereof, salts, derivatives, prodrugs, solvates or pharmaceutically acceptable stereoisomers thereof, together with a carrier, adjuvant or pharmaceutically acceptable vehicle for intravenous (IV) administration to a patient.

[0310] In other related embodiments, PDE7 inhibitors useful in the methods of the present invention include the following compounds: 4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline and derivatives thereof selected from the group consisting of: [ka] 6-Bromo-2,3,4-tetrahydroquinazoline, 6-Bromo-(2,6-difluorophenyl)-4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline, 6-Bromo-(2,3,4-trifluorophenyl)-4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline, 6-Bromo-(2-bromophenyl)-4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline quinazoline, 3-(2,6-difluorophenyl)-8-methyl-4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline, 3-(2,3,4-trifluorophenyl)-8-methyl-4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline, and 3-(2-bromophenyl)-8-methyl-4-oxo-2-dioxo-1,2,3,4-tetrahydroquinazoline. 6-Bromo-(2,6-difluorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline, 6-Bromo-(2,3,4-trifluorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline, 6-Bromo-(2-bromophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline, 3-(2,6-difluorophenyl)-8-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline, 3-(2,3,4-trifluorophenyl)- 8-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline, and 3-(2-bromophenyl)-8-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline, and 3-phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline, 3-(2,6-difluorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline, and 3-(2-bromophenyl)-8-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazoline.

[0311] In further related embodiments, PDE7 inhibitors useful in the methods of the present invention include the following compounds: 2-methylthio-4-oxo-3,4-dihydroquinazoline and derivatives thereof selected from the group consisting of: [ka] 6-Bromo-(2,6-difluorophenyl)-2-methylthio-4-oxo-3,4-dihydroquinazoline, 6-Bromo-(2,3,4-trifluorophenyl)-2-methylthio-4-oxo-3,4-dihydroquinazoline, 6-Bromo-(2-bromophenyl)-2-methylthio-4-oxo-3,4-dihydroquinazoline, 3-phenyl-8-methyl-2-methylthio-4-oxo oxo-3,4-dihydroquinazoline, 3-(2,6-difluorophenyl)-8-methyl-2-methylthio-4-oxo-3,4-dihydroquinazoline, 3-(2,3,4-trifluorophenyl)-8-methyl-2-methylthio-4-oxo-3,4-dihydroquinazoline, and 3-(2-bromophenyl)-8-methyl-2-methylthio-4-oxo-3,4-dihydroquinazoline.

[0312] In another related embodiment, PDE7 inhibitors useful in the methods of the present invention include the following compounds: 2,4-dithioxo-1,2,3,4-tetrahydroquinazoline and derivatives thereof selected from the group consisting of: [ka] 3-phenyl-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline, 3-(2,6-difluorophenyl)-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline, and 3-(2,3,4-trifluorophenyl)-2,4-dithioxo-1,2,3,4-tetrahydroquinazoline.

[0313] In a more particular embodiment, the compound has formula (42A) shown below: [ka] CAS:16081-93-9 is.

[0314] In another related embodiment, PDE7 inhibitors useful in the methods of the present invention include the following compounds: (2-methylthio-4-thioxo-3,4-dihydroquinazoline) and derivatives thereof selected from the group consisting of: [ka] 3-phenyl-2-methylthio-4-thioxo-3,4-dihydroquinazoline, 3-(2,6-difluorophenyl)-2-methylthio-4-thioxo-3,4-dihydroquinazoline, 3-(2,3,4-trifluorophenyl)-2-methylthio-4-thioxo-3,4-dihydroquinazoline, and 3-(2-bromophenyl)-2-methylthio-4-thioxo-3,4-dihydroquinazoline.

[0315] The preparation of the above compounds is described in WO2008 / 113881, US2010 / 0152213, and ES2308916.

[0316] In related embodiments, PDE7 inhibitors useful in the methods of the present invention are described in WO2008 / 113881, US2010 / 0152213, and ES 2308916, which are expressly incorporated herein by reference in their entireties.

[0317] In one embodiment, the PDE7 inhibitors useful in the methods of the present invention have formula (43A) and / or (43B): [ka] CAS:1062094-00-1, CAS:1062094-26-1 It has.

[0318] In another embodiment, the PDE7 inhibitors useful in the methods of the present invention are selected from the compounds disclosed generically or specifically in U.S. Pat. No. 7,214,676 and US 2007 / 0049558, each of which is expressly incorporated herein by reference in its entirety.

[0319] In one embodiment, PDE7 inhibitors useful in the methods of the present invention include the following compounds: Spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 6'-methoxyspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, spiro[cycloheptane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 7'-methoxyspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 6'-phenylspiro[cycloheptane-1-4'-(3',4'-dihydro)quinazoline]-2 '(1'H)-one, 8'-methoxyspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chlorospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 7'-chlorospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 5'-chlorospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-methylspiro[cyclohexane-1-4'-( 3',4'-dihydro)quinazoline]-2'(1'H)-one, 6'-chlorospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-bromospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-fluorospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 6'-methylspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 5',8' -Dichlorospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 6',7'-dichlorospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 5',6'-dichlorospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 6'-phenylspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-iodospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazolin]-2'(1'H)-one, 8'-bromospiro[cyclobutane-1-4'-(3',4'-dihydro)quinazolin]-2'(1'H)-one, 8'-bromospiro[cycloheptane-1-4'-(3',4'-dihydro)quinazolin]-2'(1'H)-one, 8'-bromo-4-methylspiro[cyclohexan- 8'-Bromospiro[bicyclo[3,2,1]octan-2-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 6',8'-Dichlorospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one quinazoline, 8'-chloro-6'-iodospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-methoxyspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-phenylspiro[cycloheptane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-phenylspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-methylspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-Chloro-6'-(3-pyridyl)spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-(4-pyridyl)spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 6'-(4-carboxyphenyl)-8'-chlorospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 6'-(3-carboxyphenyl)-8'-chlorospiro(cyclohexane-1-4'-(3',4' -dihydro)-quinazoline]-2'(1'H)-one, 8'-chloro-6'-(1H-indol-5yl)spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-(2-pyridyl)spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-(3-dimethylamino-prop-1-ynyl)spiro[cyclohexane-1-4'-(3',4'-dihydro)-quinazoline]-2'(1'H)-one, 8'-chloro-6'-(3-dimethylamino-prop-1-ynyl)spiro[cyclohexane-1-4'-(3',4'-dihydro)-quinazoline]-2'(1'H)-one, 8'-chloro- 6'-(3-Methylamino-prop-1-ynyl)spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-[4-(4-methyl-piperazine-1-carbonyl)phenyl]spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-[4-(3-N-dimethylamino-propylcarboxamido)phenyl]-spiro-[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one quinazolin-2'(1'H)-one, 8'-chloro-6'-[4-(2-N-dimethylamino-ethylcarboxamido)phenyl]-spiro-[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-[3-(3-N-dimethylamino-propylcarboxamido)phenyl]-spiro-[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-[3-(4-methyl-piperazine-1-carbonyl)-phenyl]spiro-[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-[3-(2-N-dimethylamino-ethylcarboxamido)phenyl]spiro-[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chlorospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-thione, 8'-chloro-2'-cyanoiminospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline, 8'-chloro-6'-[4-( 4-pyrimidin-2-yl-piperazine-1-carbonyl)phenyl]spiro[-cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-[4-(4-(2-morpholin-4-yl-ethyl)-piperazine-1-carbonyl)-phenyl]spiro[-cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-[4-(4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl (phenyl)phenyl]spiro[-cyclohexane-1-4'-(3',4'-dihydro)quinazolin]-2'(1'H)-one, 8'-chloro-6'-[4-(4-(2-hydroxy-ethoxy)-ethyl)-piperazine-1-carbonyl)-phenyl]spiro[-cyclohexane-1-4'-(3',4'-dihydro)quinazolin]-2'(1'H)-one, spiro[cyclohexane-1-9'-(8',9'-dihydro)-pyrazolo[4',3'-f]quinazolin]-7'(6'H)-one, 8'-chloro-5'-methoxyspiro[-cyclohexane-1-4'-(3',4'-dihydro)quinazolin]-2'(1'H)-one, 5',8'-difluorospiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-methylspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-(morpholin-4-yl)methylspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-Chloro-5'-hydroxyspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-hydroxy-6'-iodo-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-iodo-5'-methoxy-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-cyano-5'-methoxy-spiro[cyclohexane-1-4' -(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-[2-(4-morpholino)ethoxy]spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-[2-dimethylaminoethoxy]spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-(2-aminoethoxy)-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one 'H)-one, 8'-chloro-5'-[2-(methylamino)ethoxy]-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-[2-(2-aminoethoxy)ethoxy]spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-[3-dimethylaminopropoxy]spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5' -Ethoxycarbonylmethoxyspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 5'-carboxymethoxy-8'-chloro-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 5'-carboxypropoxy-8'-chloro-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-(3-sulfopropoxy)-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazolin]-2'(1'H)-one, 8'-chloro-5'-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-(2-hydroxy-ethoxy)-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-(5-ethoxycarbonyl-furan-2-ylmethoxy)-spiro[cyclohexane-1-4'-(3' ,4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-(5-carboxy-furan-2-ylmethoxy)-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-cyanomethoxyspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-(1H-tetrazol-5-ylmethoxy)-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one H)-one, 8'-chloro-5'-(5-hydroxy-[1,2,4]oxadiazol-3-ylmethoxy)-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-iodo-5'-[2-dimethylamino-ethoxy]spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 6'-(4-carboxyphenyl)-8'-chloro-5'-methoxyspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline ]-2'(1'H)-one, 6'-(3-carboxyphenyl)-8'-chloro-5'-methoxyspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-[2-(4-methyl-piperazine-1-carbonyl)phenyl]spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-[2-methyl-4-(4-methyl-piperazine-1-carbonyl)phenyl]spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazolin]-2'(1'H)-one, 8'-chloro-6'-[4-(piperazine-1-carbonyl)phenyl]spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-[4-carbamoyl-phenyl]spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-[4-((1-methyl-piperidin-4-yl)-piperazine-1-carbonyl)phenyl]spiro[cyclohexane-1-4 '-(3',4'-dihydro)quinazolin]-2'(1'H)-one, 8'-chloro-5'-methoxy-6-[4-(4-methyl-piperazine-1-carbonyl)phenyl]spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-trifluoromethylspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-6'-cyanomethylspiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one 8'-chloro-5'-(3-dimethylamino-2-hydroxy-propoxy)-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-(3-methylamino-2-hydroxy-propoxy)-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-[2-(ethoxycarbonylmethyl-amino)-ethoxy]-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1 'H)-one, 8'-chloro-5'-[2-(carboxymethyl-amino)-ethoxy]-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one hydrochloride, 8'-chloro-5'-(2-methanesulfonylamino-2-oxo-ethoxy)-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazoline]-2'(1'H)-one, 8'-chloro-5'-(2-[(5-methyl-isoxazol-3-ylmethyl)-amino]ethoxy)-spiro[cyclohexane-1-4'-(3',4'-dihydro)quinazolin]-2'(1'H)-one.

[0320] The preparation of these compounds is described in US Pat. No. 7,087,614, US 2007 / 0049558 and WO 2002 / 074754.

[0321] In another embodiment, the PDE7 inhibitors and dual PDE4 / 7 inhibitors useful in the methods of the present invention are selected from compounds generally or specifically disclosed in U.S. Pat. No. 7,087,614, US 2003 / 0162802, and WO 2002 / 102313 (each of which is expressly incorporated herein by reference in its entirety).

[0322] In one embodiment, the PDE7 inhibitor useful in the methods of the present invention has formula (54): [ka] ((42): Also known as 2-amino-substituted pyrimidine derivatives) It has.

[0323] PDE7 inhibitors useful in the methods of the present invention include enantiomers, diastereomers, tautomers, and pharmaceutically acceptable salts, prodrugs, and solvates of the compounds of the above formula.

[0324] The substituents for formula (54) above are defined as follows: R 1 is H or alkyl; R 2 is (a) heteroaryl, or heterocyclo, each of which is optionally substituted with one to three groups T1, T2, T3; (b) aryl substituted with one to three groups T1, T2, T3, provided that at least one of T1, T2, T3 is other than H; or (c) aryl fused to a heteroaryl or heterocyclo ring, where the combined ring system is optionally substituted with one to three groups T1, T2, T3; Z is (a) —OR, —C(O)R, —C(O)OR, —SR, —NRR, —C(O)NR, —NRSO, R, halogen, nitro, haloalkyl; or (b) alkyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which is optionally substituted with one to three groups T, T, T; J is (a) hydrogen, halo, -OR4a, or (b) alkyl, alkenyl, or alkynyl, any of which is optionally substituted with 1 to 3 groups T1b, T2b, or T3b; L is (a) hydrogen, —OR, —C(O)R, —C(O)OR, —SR, —NR, —C(O)NR, —NRSO, —R, halogen, haloalkyl, nitro, or (b) alkyl, aryl, heteroaryl, heterocyclo, or cycloalkyl, any of which is optionally substituted with one to three groups T, T, or T; R3 and R4 are independently H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which is optionally substituted with 1 to 3 groups T1a, T2a, or T3a; or R3 and R4 together with the nitrogen atom to which they are attached can combine to form a 4-8 membered heterocyclic ring optionally substituted with 1-3 groups T1a, T2a or T3a; R4a is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, cycloalkyl or (cycloalkyl)alkyl, any of which is optionally substituted with 1 to 3 groups T1b, T2b or T3b; R4b is hydrogen, alkyl, alkenyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, heterocyclo, (heterocyclo)alkyl, cycloalkyl, or (cycloalkyl)alkyl, any of which is optionally substituted with 1 to 3 groups Tlc, T2c, or T3c; R4c and R4d are independently alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which is optionally substituted with 1 to 3 groups T1a, T2a, or T3a; R5 and R6 are independently H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo, or (heterocyclo)alkyl, any of which are optionally and independently substituted, if valences allow, with 1 to 3 groups T1c, T2c, or T3c; or R5 and R6, together with the nitrogen atom to which they are attached, can combine to form a 4-8 membered heterocyclo ring optionally substituted with 1-3 groups T1c, T2c, or T3c; T1-1c, T2-2c, and T3-3c are each independently (1) hydrogen or T6, where T6 is (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (ii) a group (i) itself substituted with one or more of the same or different groups (i); or (iii) a group (i) or (ii) independently substituted with one or more (preferably 1 to 3) of the following groups (2) to (13) in the definitions of T1-1c, T2-2c, and T3-3c, (2) -OH or -OT6, (3) -SH or -ST6, or (4) -C(O) t H, -C(O)t T6, or -OC(O)T6, where t is 1 or 2; (5) -SO3H, -S(O)T6, or S(O) t N(T9)T6, (6) halo, (7) cyano, (8) nitro, (9) -T4-NT7T8, (10) -T4-N(T9)-T5-NT7T8, (11) -T4-N(T10)-T5-T6, (12) -T4-N(T10)-T5-H, (13) oxo; T4 and T5 each independently represent: (1) a single bond, (2) -T11-S(O), t -T12-, (3) -T11-C(O)-T12-, (4) -T11-C(S)-T12-, (5) -T11-O-T12-, (6) -T11-S-T12-, (7) -T11-OC(O)-T12-, (8) -T11-C(O)-O-T12-, (9) -T11-C(=NT9a)-T12-, or (10) -T11-C(O)-C(O)-T12, T7, T8, T9, T9a, and T10 are (1) each independently hydrogen or a group as defined in the definition of T6, or (2) T7 and T8 together with the atoms to which they are attached can be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring, which is unsubstituted or substituted with one or more groups as listed in the descriptions of T1-1c, T2-2c, and T3-3c, or (3) T7 or T8 together with T9 can be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached, which is unsubstituted or substituted with one or more groups as listed in the descriptions of T1-1c, T2-2c, and T3-3c, or (4) T7 and T8 or T9 and T10 may combine together with the nitrogen atom to which they are attached to form a group -N=CT13T14, where T13 and T14 are each independently H or a group as defined in the definition of T6; and T11 and T12 are each independently (1) a single bond, (2) alkylene, (3) alkenylene, or (4) alkynylene.

[0325] In a related embodiment, the PDE7 inhibitor useful in the methods of the invention is one having the formula: Z is (a) halogen, alkoxy, haloalkyl, —NR3R4, —C(O)OR4, —C(O)NR3R4; (b) aryl or heteroaryl, any of which may be selected from one or more of T1a, T2a, T3a (in particular cyano, optionally substituted alkyl, (hydroxy)alkyl, —OH, —OT6, —ST6, —SO t T6, -CO t H, -CO t (c) optionally substituted alkyl (especially one or more of -OH, -CO t H, -CO t -T6, -T4-NT7T8, -T4-N(T10)-T5-H, or -T4-N(T10)-T5-T6); J is (a) H, or (b) alkyl or alkenyl, each of which may optionally contain one or more of -OH, -OT, -CO t H or -CO t T6); L is (a) H; (b) halogen, alkoxy, haloalkyl, -NR5R6, -C(O)OR 4b , —C(O)NR5R6; (c) aryl or heteroaryl [any of which may be selected from the group consisting of one or more of T1c, T2c, T3c (especially cyano, optionally substituted alkyl, (hydroxy)alkyl, —OH, —OT6, —ST6, —SO t T6, -CO t H, -CO t or (d) optionally substituted alkyl (particularly one or more of -OH, -CO t H, -CO t -T6, -T4-NT7T8, -T4-N(T10)-T5-H, or; -T4-N(T10)-T5-T6); R 1is H or alkyl; R 2 is (a) preferably H, alkyl, haloalkyl, halo, heteroaryl, cyano, C(O) t (b) heteroaryl optionally substituted with one to three groups T1, T2, T3 (preferably thiazolyl or oxazolyl), including -T6, -OT6, -T4NT7T8; (b) heteroaryl optionally substituted with one to three groups T1, T2, T3 (preferably heteroaryl (preferably imidazolyl, oxazolyl, or thiazolyl, any of which may be further optionally substituted), cyano, C(O) t T6, S(O) t N(T9)T6, haloalkyl, and haloalkyl); or (c) aryl fused to a heterocyclic ring (e.g., 2,3-dihydro-1H-indole bonded through an aryl ring, quinolyl (especially quinol-6-yl) bonded through an aryl ring, quinazolinyl (especially quinazolin-7-yl) bonded through an aryl ring, cinnolinyl (especially cinnolin-6-yl) bonded through an aryl ring, isoquinolinyl (especially isoquinol-6-yl) bonded through an aryl ring, and phthalazinyl (especially phthalazin-6-yl) bonded through an aryl ring), wherein the combined ring system is fused to one to three groups T1, T2, T3 (especially halo, OH, OT6, alkyl, -CO t H, -CO t -C(O)NT7T8); R3 is H or optionally substituted alkyl (particularly substituted with one or more -OH, or -OT6); R4 is (a) hydrogen; (b) (aryl)alkyl, wherein the aryl group is selected from the group consisting of one or more groups T1a, T2a, T3a (in particular optionally substituted alkyl, halo, cyano, nitro, (hydroxy)alkyl, -OH, -OT6, -ST6, -CO t H, -CO t T6, -SO3H, -SO t T6, -SO t(c) (heteroaryl)alkyl, optionally independently substituted with one or more groups T1a, T2a, T3a (in particular optionally substituted alkyl, halo, cyano, nitro, (hydroxy)alkyl, -OH, -OT6, -ST6, -CO t H, -CO t T6, -SO3H, -SO t T6, -SO t (d) (heterocyclo)alkyl, optionally independently substituted by one or more groups T1a, T2a, T3a (in particular optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy)alkyl, -OH, -OT6, -ST6, -CO t H, -CO t T6, -SO3H, -SO t T6, -SO t (e) one or more groups T1a, T2a, T3a (especially -OH, -OT6, -CO t H, -CO t (f) alkyl optionally independently substituted with one or more groups T1a, T2a, T3a (in particular optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heterocyclo, cyano, -OH, -OT6, -CO t H, -CO t heterocyclo optionally independently substituted with T6, oxo, hydroxy(alkyl), (alkoxy)alkyl, -T4-N(T10)-T5-T6, or -T4-NT2T8); or R3 and R4 together with the nitrogen atom to which they are attached combine to form one to three groups T1a, T2a, T3a (in particular optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heterocyclo, cyano, -OH, -OT6, -CO t H, -CO t forming a 4-8 membered heterocyclic ring (especially pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl, diazapanyl or 1,4-dioxa-8-azaspiro[4.5]decan-8-yl) optionally substituted with T6, oxo, hydroxy(alkyl), (alkoxy)alkyl, -T4-N(T10)-T5-T6, or -T4-NT7T8); R5 is hydrogen or alkyl; R6 is (a) hydrogen; (b) (aryl)alkyl, wherein the aryl group is selected from the group consisting of one or more groups T1c, T2c, T3c (in particular optionally substituted alkyl, halo, cyano, nitro, (hydroxy)alkyl, -OH, -OT6, -ST6, -CO t H, -CO t T6, -SO3H, -SO t T6, -SO t (c) (heteroaryl)alkyl, optionally independently substituted with one or more groups T1c, T2c, T3c (particularly optionally substituted alkyl, halo, cyano, nitro, (hydroxy)alkyl, -OH, -OT6, -ST6, -CO t H, -CO t T6, -SO3H, -SO t T6, -SO t (d) (heterocyclo)alkyl, optionally independently substituted with one or more groups T1c, T2c, T3c (particularly optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy)alkyl, -OH, -OT6, -ST6, -COt H, -CO t T6, -SO3H, -SO t T6, -SO t (e) one or more groups T1c, T2c, T3c (especially -OH, -OT6, -CO t H, -CO t (f) alkyl optionally independently substituted with one or more groups T1c, T2c, T3c (in particular optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heterocyclo, cyano, -OH, -OT6, -CO t H, -CO t heterocyclo optionally independently substituted with T6, oxo, hydroxy(alkyl), (alkoxy)alkyl, -T4-N(T10)-T5-T6, or -T4-NT7T8); or R5 and R6 together with the nitrogen atom to which they are attached combine to form a 4- to 8-membered heterocyclo ring (in particular pyrrolidinyl, piperadinyl, piperazinyl, morpholinyl, diazapanyl or 1,4-dioxa-8-azaspiro[4.5]decan-8-yl) optionally substituted by one to three groups T1c, T2c, T3c (in particular optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heterocyclo, cyano, -OH, -OT6, -COtH, -COtT6, oxo, hydroxy(alkyl), (alkoxy)alkyl, -T4-N(T10)-T5-T6 or -T4-NT7T8); The above compounds are included.

[0326] In another related embodiment, the PDE7 inhibitor useful in the methods of the invention is a compound of the formula: Z is (a) halogen, alkoxy, haloalkyl, -NR3R4, -C(O)OR4, -C(O)NR3R4; (b) aryl or heteroaryl, any of which may be cyano, optionally substituted alkyl, (hydroxy)alkyl, -OH, -OT6, -ST6, -SO t T6, -CO t H, -CO t T4 is a bond or -C(O)-; T5 is -C(O)- or -C(O)O-; T6 is alkyl or haloalkyl; T7 and T8 are independently H; alkyl cycloalkyl optionally substituted with cycloalkyl, heteroaryl, hydroxy, or -NT7T8; or aryl optionally substituted with halogen; or T7 and T8, taken together with the nitrogen atom to which they are attached, are (hydroxy)alkyl, CO t H or CO t T6 forms an optionally substituted heterocyclic ring, and T10 is hydrogen; (c) one or more -OH, -CO t H, -CO t alkyl optionally substituted with T6, -T4-NT7T8, -T4-N(T10)-T5-H, or -T4-N(T10)-T5-T6 [wherein T4 is -C(O)-; T5 is -alkylene-O-; T6 is alkyl; T7 and T8 are independently H, alkyl, cycloalkyl, aryl, (aryl)alkyl (optionally substituted as described in the definition of R4), or heterocyclo (optionally substituted as described in the definition of R3 and R4 and combined to form a heterocyclo ring); and T10 is H]; J is (a) H, or (b) alkyl or alkenyl, each of which may be substituted with one or more of -OH, -OT6, -CO t H or -CO t optionally substituted with T6, wherein T6 is alkyl; L is (a) H; (b) halogen, alkoxy, haloalkyl, -NR5R6, -C(O)OR4b, -C(O)NR5R6; (c) aryl or heteroaryl, any of which may be substituted with cyano, optionally substituted alkyl (especially CO t H or CO t T6), (hydroxy)alkyl, -OH, -OT6, -ST6, -SO t T6, -CO t H, -CO t T4 is a bond or -C(O)-; T5 is -C(O)- or -C(O)O-; T6 is alkyl or haloalkyl; T7 and T8 are independently H; alkyl optionally substituted with cycloalkyl, heteroaryl, hydroxy, or -NT7T8; cycloalkyl; or aryl optionally substituted with halogen; or T7 and T8, taken together with the nitrogen atom to which they are attached, are (hydroxy)alkyl, CO t H or CO t T6 forms an optionally substituted heterocyclic ring; T10 is hydrogen; (d) one or more -OH, -CO t H, -CO t alkyl optionally substituted with T6, -T4-NT7T8, -T4-N(T10)-T5-H, or -T4-N(T10)-T5-T6 [wherein T4 is -C(O)-; T5 is -alkylene-O-; T6 is alkyl; T7 and T8 are independently H, alkyl, cycloalkyl, aryl, (aryl)alkyl (optionally substituted as described in the definition of R4), or heterocyclo (optionally substituted as described in the definition of R3 and R4 and combined to form a heterocyclo ring); and T10 is H]; R 1 is H or alkyl; R 2is (a) one to three groups T1, T2, T3, [preferably H, alkyl, haloalkyl, halo, heteroaryl, cyano, C(O) t (b) one to three groups T1, T2, T3 (preferably heteroaryl (preferably imidazolyl, oxazolyl, or thiazolyl, any of which may be further optionally substituted), cyano, C(O) t T6, S(O) t or (c) an aryl fused to a heterocyclic ring (e.g., 2,3-dihydro-1H-indole bonded via an aryl ring), wherein the combined ring system is substituted with one to three groups T1, T2, T3 (especially halo, -OH, -OT6, alkyl, -CO t H, -CO t -C(O)NT7T8); R3 is H or optionally substituted alkyl (particularly substituted with one or more -OH, or -OT6); R4 is (a) hydrogen; (b) (aryl)alkyl, wherein the aryl group is optionally substituted alkyl, halo, cyano, nitro, (hydroxy)alkyl, -OH, -OT6, -ST6, -CO t H, -CO t T6, -SO3H, -SO t T6, -SO tT7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (c) (heteroaryl)alkyl, optionally substituted with one or more groups T1a, T2a, T3a selected from optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy)alkyl, -OH, -OT6, -ST6, -CO(O)-, -T4NT7T8, -T4N(T10)-T5-T6, heterocyclo, or heteroaryl, wherein T4 is a bond, -SO2-, or -C(O)-; T5 is -SO2- or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (c) (heteroaryl)alkyl, wherein the heteroaryl group is optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy)alkyl, -OH, -OT6, -ST6, -CO(O)-, -T4NT7T8, -T4N(T10)-T5-T6, heterocyclo, or heteroaryl; t H, -CO t T6, -SO3H, -SO t T6, -SO t and T9 and T10 are hydrogen; (d) (heterocyclo)alkyl, optionally substituted by one or more groups T1a, T2a, T3a selected from N(T9)(T6), -T4NT7T8, -T4-N(T10)-T5-T6, heterocyclo, or heteroaryl, wherein T4 is a bond, -SO2-, or -C(O)-; T5 is -SO2- or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (d) (heterocyclo)alkyl, wherein the heterocyclo group is optionally substituted alkyl, halo, cyano, nitro, (hydroxy)alkyl, -OH, -OT6, -ST6, -CO t H, -CO t T6, -SO3H, -SO t T6, -T4NT7T8, -T4-N(T10)-T5-T6, heterocyclo, or heteroaryl, where T4 is a bond, -SO2-, or -C(O)-; T5 is -SO2-, or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (e) -OH, -OT6, -CO t H, -CO talkyl optionally substituted independently by one or more groups T1a, T2a, T3a selected from T6, -T4NT7T8 or -T4-N(T10)-T5-T6 [wherein T4 is a bond; T5 is -C(O)-; T6 is alkyl; T7 and T8 are independently H or alkyl; and T10 is hydrogen]; optionally substituted alkyl (especially substituted by -T4NT7T8), optionally substituted aryl (especially substituted by halogen or haloalkyl), cyano, -OH, -OT6, -CO t H, -CO t T6, heterocyclo optionally substituted independently with one or more groups T1a, T2a, T3a selected from oxo, hydroxy(alkyl), (alkoxy)alkyl, -T4-N(T10)-T5-T6, or -T4-NT7T8 (wherein T4 is a bond or -C(O)-; T5 is -C(O)-, -SO2-, or -alkylene-C(O)O-; T6 is alkyl, alkoxy, or heteroaryl; T7 and T8 are independently H, alkyl, or cycloalkyl; or T7 and T8, together with the nitrogen atom to which they are attached, combine to form an optionally substituted heterocyclo ring); or R3 and R4 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring selected from pyrrolidinyl, piperazinyl, morpholinyl, diazapanyl or 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, any of which is optionally substituted alkyl (especially substituted by -T4NT7T8), optionally substituted aryl (especially substituted by halogen or haloalkyl), cyano, -OH, -OT6, -CO t H, -CO tT6 is optionally substituted independently with one to three groups T1a, T2a, T3a selected from oxo, hydroxy(alkyl), (alkoxy)alkyl, -T4-N(T10)-T5-T6, or -T4-NT7T8, where T4 is a bond or -C(O)-; T5 is -C(O)-, -SO2-, or -alkylene-C(O)O-; T6 is alkyl, alkoxy, or heteroaryl; T7 and T8 are independently H, alkyl, or cycloalkyl; or T7 and T8, together with the nitrogen atom to which they are attached, combine to form an optionally substituted heterocyclo ring; R5 is hydrogen or alkyl; R6 is (a) hydrogen; (b) (aryl)alkyl, wherein the aryl group is optionally substituted alkyl, halo, cyano, nitro, (hydroxy)alkyl, -OH, -OT6, -ST6, -CO t H, -CO t T6, -SO3H, -SO t T6, -SO t T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (c) (heteroaryl)alkyl, wherein the heteroaryl group is optionally substituted with one or more groups T1c, T2c, T3c selected from: N(T9)(T6), -TNT7T8, -T4-N(T10)-T5-T6, heterocyclo, or heteroaryl, wherein T4 is a bond, -SO2-, or -C(O)-; T5 is -SO2-, or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (c) (heteroaryl)alkyl, wherein the heteroaryl group is optionally substituted alkyl, halo, cyano, nitro, oxo, (hydroxy)alkyl, -OH, -OT6, -ST6, -CO t H, -CO t T6, -SO3H, -SO t T6, -SO tand T9 and T10 are hydrogen; (d) (heterocyclo)alkyl, optionally substituted by one or more groups T1c, T2c, T3c selected from N(T9)(T6), -T4NT7T8, -T4-N(T10)-T5-T6, heterocyclo, or heteroaryl, where T4 is a bond, -SO2-, or -C(O)-; T5 is -SO2-, or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (d) (heterocyclo)alkyl, wherein the heterocyclo group is optionally substituted alkyl, halo, cyano, nitro, (hydroxy)alkyl, -OH, -OT6, -ST6, -CO t H, -CO t T6, -SO3H, -SO t T6, -T4NT7T8, -T4-N(T10)-T5-T6, heterocyclo, or heteroaryl, where T4 is a bond, -SO2-, or -C(O)-; T5 is -SO2-, or -alkylene-O-; T6 is alkyl or cycloalkyl; T7 and T8 are independently H or alkyl; and T9 and T10 are hydrogen; (e) -OH, -OT6, -OC t H, -CO t alkyl optionally substituted independently by one or more groups T1c, T2c, T3c selected from T6, -T4NT7T8 or -T4-N(T10)-T5-T6 [wherein T4 is a bond; T5 is -C(O)-; T6 is alkyl; T7 and T8 are independently H or alkyl; and T10 is hydrogen]; optionally substituted alkyl (especially substituted by -T4NT7T8), optionally substituted aryl (especially substituted by halogen or haloalkyl), cyano, -OH, -OT6, -CO t H, -CO tT6, heterocyclo optionally substituted independently with one or more groups T1c, T2c, T3c selected from oxo, hydroxy(alkyl), (alkoxy)alkyl, -T4-N(T10)-T5-T6, or -T4-NT7T8, wherein T4 is a bond or -C(O)-; T5 is -C(O)-, -SO2-, or -alkylene-C(O)O-; T6 is alkyl, alkoxy, or heteroaryl; T7 and T8 are independently H, alkyl, or cycloalkyl; or T7 and T8, together with the nitrogen atom to which they are attached, combine to form an optionally substituted heterocyclo ring; or R5 and R6 together with the nitrogen atom to which they are attached combine to form a heterocyclo ring selected from pyrrolidinyl, piperazinyl, morpholinyl, diazapanyl or 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, any of which is optionally substituted alkyl (especially substituted by -T4NT7T8), optionally substituted aryl (especially substituted by halogen or haloalkyl), cyano, -OH, -OT6, -CO t H, -CO t T6 is optionally substituted independently with one to three groups T1a, T2a, T3a selected from oxo, hydroxy(alkyl), (alkoxy)alkyl, -T4-N(T10)-T5-T6, or -T4-NT7T8, where T4 is a bond or -C(O)-; 5 is -C(O)-, -SO2-, or -alkylene-C(O)O-; T6 is alkyl, alkoxy, or heteroaryl; T7 and T8 are independently H, alkyl, or cycloalkyl; or T7 and T8, together with the nitrogen atom to which they are attached, combine to form an optionally substituted heterocyclo ring, The above compounds are included.

[0327] In further related embodiments, PDE7 inhibitors useful in the methods of the present invention include the following compounds: 2-[[4-[[[4-(Aminosulfonyl)phenyl]methy(methy)]amino]-6-(4-methyl-1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[(3,4-Dimethoxyphenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester trifluoroacetate;2-[[4-[[[4-(Aminosulfonyl)phenyl]methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;4-Methyl-2-[[4-[[[4-(Methylsulfonyl)phenyl]methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester 2-[[4-[[(4-Methoxyphenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[(3-Methoxyphenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[(3-Methoxyphenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarbo 2-[[4-[[(2-methoxyphenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;4-Methyl-2-[[4-(1-piperazinyl)-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[(2-ethoxyphenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester 2-[[4-[[(2,5-dimethoxyphenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[(3,5-dimethoxyphenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[(3,5-dimethoxyphenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[(2,6-Dimethylphenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[[4-(Methoxycarbonyl)phenyl]methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[(3-Bromophenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl)amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester 2-[[4-[(1,3-Benzodioxol-5-ylmethyl)amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;4-Methyl-2-[[4-[methyl(3-pyridinylmethyl)amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid ethyl ester;4-Methyl-2-[[4-(1-piperazinyl)-6-[[[4-(1,2,3-thiadiazol-4-yl)phenyl]methyl]amino]-2-pyrimidinyl 2-[[4-[[[3-(cyclopentyloxy)-4-methoxyphenyl]methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;4-Methyl-2-[[4-[(phenylmethyl)amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid ethyl ester;4-Methyl-2-[[4-(4-methyl-1-piperazinyl)-6-[[(3,4,5-trimethoxyphenyl)amino]-5-thiazolecarboxylic acid ethyl ester 2-[[4-(4-hydroxy-1-piperidinyl)-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;4-Methyl-2-[[4-[[2-(1-methylethoxy)ethyl]amino]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid ethyl ester;2-[[4-[3-(Aminocarbonyl)-1-piperidinyl]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[(2-(1H-imidazol-4-yl)ethyl]amino]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;4-Methyl-2-[[4-[[4-(methylsulfonyl)phenyl]methyl]amino]-6-[[3-(4-morpholinyl)propyl]amino]-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid ethyl ester;2-[[4-[(2-Methoxy-1-methylethyl)amino]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino 4-Methyl-2-[[4-[[4-(methylsulfonyl)phenyl]methyl]amino]-6-[[(tetrahydro-2-furanyl)methyl]amino]-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid ethyl ester;2-[[4-[4-(2-hydroxyethyl)-1-piperazinyl]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[2-(aminocarbonyl)-1-pyrrolidinyl]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester; 4-Methyl-2-[[4-[methyl(3-pyridinylmethyl)amino]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid ethyl ester;2-[[4-[4-(hydroxymethyl)-1-piperidinyl]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[2-(diethylamino)ethyl]methylamino]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester 4-Methyl-2-[[4-[[4-(methylsulfonyl)phenyl]methyl]amino]-6-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid ethyl ester;2-[[4-[3-(hydroxymethyl)-1-piperidinyl]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester 2-[[4-[[2-[(acetylamino)ethyl]amino]-6-[[[(4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-(4-ethyl-1-piperazinyl)-6-[ ... 2-[[4-(4-Acetyl-1-piperazinyl)-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[2-(dimethylamino)ethyl]amino]-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[2-(dimethylamino)ethyl]amino]-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[3-(Aminocarbonyl)-1-piperazinyl]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-(3-Hydroxy-1-pyrrolidinyl)-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[(4-hydroxybutyl)amino]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester 2-[[4-[(2,3-Dihydroxypropyl)amino]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[(4-Amino-1-piperidinyl)-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[(4-Amino-1-piperidinyl)-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester 2-[[4-[4-Hydroxy-3-(hydroxymethyl)-1-piperidinyl]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-(4-Dimethylamino-1-piperidinyl)-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[4-( Aminosulfonyl)phenyl]methyl]amino]-6-(methylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4,6-bis-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(4-hydroxy-piperidin-1-yl)-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(3-hydroxymethyl-piperidin-1-yl)-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;4-Methyl-2-[4-(4-methyl-piperazin-1-yl)-6-morpholin-4-yl-pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl ester;2-[4-(4-amino-piperidin-1-yl)-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4,6-bis-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[4-(4-oxo-piperidin-1-yl)-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(4-methyl-4-hydroxy-piperidin-1-yl)-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[-(4-hydroxy-piperidin-1-yl)-6-(4-dimethylmethyl-piperazine- 2-[4-(4-hydroxymethyl-piperidin-1-yl)-6-(4-dimethylmethyl-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(3-hydroxymethyl-piperidin-1-yl)-6-(4-dimethylmethyl-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(3-hydroxymethyl-piperidin-1-yl)-6-(4-dimethylmethyl-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester 2-[4-(4-hydroxymethyl-piperidin-1-yl)-6-(4-hydroxy-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;4-Methyl-2-[4-(4-hydroxy-piperazin-1-yl)-6-morpholin-4-yl-pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl ester;2-[[(4-[[[4-(methylsulfonyl)phenyl]methyl]amino]-6-chlor 2-[[4-[[4-(aminosulfonyl)phenyl]methyl]amino]-6-chloro-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-(dimethylamino)-1-piperidinyl]-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[1-piperidinyl]-6-methyl-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-(4-amino-1-piperidinyl)-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-hydroxy-1-piperidinyl]-6-methyl-6-[[(3 ,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-(hydroxymethyl)-1-piperidinyl]-6-methyl-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(4-hydroxypiperidin-1-yl)-6-(3-oxo-piperazin-1-yl)-pyrimidine-2 -ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[[4-[3-(aminocarbonyl)-1-piperidinyl]-6-methyl-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[1-morpholinyl]-6-methyl-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarbo 2-[[4-[3-oxo-1-piperidinyl]-6-[[(1,1-dioxide-3-oxo-1,2-benzisothiazol-2-(3H)-yl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-oxo-1-piperidinyl]-6-[[(4-(ethylsulfonylamino)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester; 2-[[4-[3-oxo-1-piperidinyl]-6-[[(4-(hydroxysulfonyl)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(4-hydroxypiperidin-1-yl)-6-(4-methyl-3-oxo-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(4(dimethylamino)-piperidin-1-yl)-6-(4-((1-pyrrolidinyl)carbonylmethyl)pipera 2-[[4-[3-(aminocarbonyl)-1-piperazinyl]-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-(4-amino-1-piperidinyl)-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester; 2-[[4-[4-(hydroxymethyl)-1-piperidinyl]-6-[4-[tetrazol-5-yl]-4-hydroxypiperidin-1-yl]2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-methyl-1-piperazinyl]-6-[N-methyl-N-[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-hydroxy-1-piperidinyl]-6-[[(4-hydroxy 2-[[4-[[(4-cyanophenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;Trifluoroacetate (1:1);2-[[4-[[[4-(aminosulfonyl)phenyl]methyl]amino]-6-(4-morpholinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-Hydroxy-1-piperidinyl]-6-[(1-oxa-3,8-diazaspiro[4.5]decane-2,4,dione-8-yl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(2-(dimethylamino)ethyl)-piperazin-1-yl)-6-(4-methylpiperazin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid, ethyl ester;2-[[4-(4-Hydroxy-1-piperidinyl)-6-[(1-oxa-3,8-diazaspiro[4.5]decane-2,4,dione-8-yl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester 2-[[4-[4-Hydroxy-3-hydroxymethylpiperidin-1-yl]-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-(3,4-Dihydro-6,7-dihydroxy-2(1H)-isoquinolinyl)-6-(4-methyl-1 -piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester, trifluoroacetate 1:1;2-[[4-[4-[(methoxyacetyl)amino]-1-piperidinyl]-6-[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[[(3,4-dimethoxyphenyl)methyl]amino]-6-[4-(dimethylamino)-1-piperidinyl]-2 -pyrimidinyl]amino]-4-methyl-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-(hydroxyethyl)piperidin-1-yl]-6-[4-(dimethylamino)-1-piperidinyl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-(dimethylamino)-1-piperidinyl]-6-[methyl(3-pyridinylmethyl)amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-(hydroxy)piperidin-1-yl]-6-[4-(methoxycarbonyl)-1-piperidinyl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-(hydroxy)piperidin-1-yl]-6-[4-(methyl)-4-(hydroxy)-1-piperidinyl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(3-oxopiperazin-1-yl)-6-(4-methylpiperazin-1-yl) 2-[[4-[[(4-cyanophenyl)methyl]amino]-6-[4-dimethylamino)-1-piperidinyl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;4-Methyl-2-[[4-[[(3-nitrophenyl)methyl]amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid, ethyl ester, trifluoroacetate (1:1);2- [[4-(4-Hydroxy-1-piperidinyl)-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(dimethylamino)-piperazin-1-yl)-6-(4-methylpiperazin-1-yl)-pyrimidin-2-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(dimethylamino)-piperidin-1-yl)-6-(3-(aminocarbonyl)-1-piperazinyl 2-[4-(2-hydroxyethyl)-piperazin-1-yl)-6-(4-methyl-1-piperazinyl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[[4-[4-(aminocarbonyl)-1-piperidinyl]-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester; 2-[[4-[4-(hydroxymethyl)-1-piperidinyl]-6-[N-methyl-N-(3-pyridinylmethyl)amino]-2-pyrimidinyl]amino]-4-methy(methy)-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-methylpiperazin-1-yl]-6-[[(3,4-dimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[piperazin-1-yl]-6-[[(4-carboxyphenyl)methyl]amino] 2-[[4-[3-Hydroxymethylpiperidin-1-yl]-6-[[N-[(3,4,5-trimethoxyphenyl)methyl]-N-(methyl)amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(4-Hydroxypiperidin-1-yl)-6-(4-carboxypiperidin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid, ethyl ester 2-[[4-[piperazin-1-yl]-6-[[(3,4-dimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-(4-formyl-1-piperazinyl)-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(4-hydroxypiperidin-1-yl)-6-(4-(hydroxy)-4-(4-chlorophenyl) )piperidin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;4-methyl-2-[[4-[4-dimethylamino-1-piperidinyl]-6-[[(tetrahydro-2-furanyl)methyl]amino]-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid ethyl ester;2-[[4-[piperazin-1-yl]-6-[[N-methyl-N-(5-tetrazolylmethyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-morpholinyl]-6-[4-[tetrazol-5-yl]-4-hydroxypiperidin-1-yl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-hydroxy-1-piperidinyl]-6-[[(1,1-dioxide-3-oxo-1,2-benzisothiazol-2-(3H)-yl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(4-hydroxypiperidin-1-yl)-6-(4-( 1-Methyl-1-hydroxyethyl)piperidin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid, ethyl ester;2-[[4-[3-(aminocarbonyl)-1-piperidinyl]-6-[[N-methyl-N-(3-pyridinylmethyl)]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-hydroxymethyl-1-piperidinyl]-6-[[(4-(ethylsulfonylamino)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4 -Methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-hydroxy-1-piperidinyl]-6-[4-[tetrazol-5-yl]-4-hydroxypiperidin-1-yl]2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-tert-butyloxycarbonylamino-1-piperidinyl]-6-[[N-[(3,4,5-trimethoxyphenyl)methyl]]-N-(methyl)amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester ter;2-[[4-[[(4-cyanophenyl)methyl]amino]-6-(4-methyl-1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester, trifluoroacetate (1:1);2-[[4-[4-[[(2-ethoxy-2-oxoethyl)amino]carbonyl]-1-piperazinyl]-6-[methyl(3-pyridinylmethy)amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester, trifluoroacetate (1:1);2-[4-(4-hydroxypiperidin-1-yl)-6-(3-hydroxypiperidin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(4-hydroxypiperidin-1-yl)-6-(4-hydroxy-4-phenyl-1-piperidinyl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;4-Methyl-2-[[4-[4-morpholinyl]-6-[[(tetrahydro-2-furanyl)methyl]amino]amino 2-[[4-[(tetrahydro-2-furanyl)methyl]amino]-6-[[N-[(3,4,5-trimethoxyphenyl)methyl]]-N-(methyl)amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-morpholinyl]-6-[[(4-(hydroxysulfonyl)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester Acid, ethyl ester;2-[bis-4,6-(4-cyano-1-piperidinyl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid, ethyl ester;2-[[4-[4-(cyclopentylaminocarbonyl)-1-piperazinyl]-6-[N-methyl-N-(3-pyridinylmethyl)amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(2-methoxyethyl)-piperazin-1-yl)-6-(4-methyl-1-piperdinyl(p 2-[4-(4-hydroxypiperidin-1-yl)-6-(3-carboxypiperidin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[[4-[4-methylpiperazin-1-yl]-6-[3-(acetylamino)-1-pyrrolidinyl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-(Aminocarbonyl)-1-piperazinyl]-6-[[N-methyl-N-(3-pyridinylmethyl)]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[2-Methyl-3-oxol-piperidinyl]-6-[4-methyl-1-piperazinyl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-(Aminocarbonyl)-1-piperazinyl]-6-(4-methyl-1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4 -[3-(Aminocarbonyl)-1-piperidinyl]-6-(4-dimethylamino-1-piperidinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[1-piperazinyl]-6-[[N-methyl-N-(2-furylmethyl)]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[[(4-methoxycarbonylphenyl)methyl]amino]-6-(4-dimethyl-1-piperidinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester, trifluoroacetate (1:1); 2-[[4-[3-Oxo-1-piperazinyl]-6-[[(4-(methylsulfonylamino)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-Oxo-1-piperazinyl]-6-[[(4-(propylsulfonylamino)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-(Aminocarbonyl)-1-piperidinyl]-6-[[(3,4,5-trimethylamino)phenyl]methyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester 2-[bis-4,6-(4-hydroxy-4-methyl-1-piperidinyl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid, ethyl ester;4-Methyl-2-[[4-[4-dimethylamino-1-piperidinyl]-6-[[(2-oxo-1-pyrrolidinyl)propyl]amino]-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[ 3-Oxo-1-piperazinyl]-6-[[(4-(iso-propylsulfonylamino)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(4-hydroxypiperidin-1-yl)-6-(3-hydroxymethyl-1-piperidinyl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;4-Methyl-2-[[4-[4-hydroxy-1-piperidinyl]-6-[[(2-(4-morpholinyl)ethyl]amino]a [amino]-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[[4-(ethylaminosulfonyl)phenyl]methyl]amino]-6-methoxy-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, methyl ester, trifluoroacetate (1:1);2-[[4-[4-morpholinyl]-6-[(1-oxa-3,8-diazaspiro[4.5]decane-2,4,dione-8-yl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-Hydroxy-1-piperidinyl]-6-[[(4-(ethylsulfonylamino)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[tert-butyloxycarbonyl-1-piperazinyl]-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-(aminocarbonyl )-1-piperidinyl]-6-[[(3,4-dimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-ethoxycarbonyl-1-piperazinyl]-6-[[N-methyl-N-(5-tetrazolylmethyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-oxo-1-piperidinyl]-6-[[(4-(cyclopropylsulfonyl) 2-[[4-[4-hydroxymethyl-1-piperidinyl]-6-[[(4-(methylsulfonylamino)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-hydroxymethyl-1-piperidinyl]-6-[[(4-(methylsulfonylamino)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(4-dimethylamino-1-piperazinyl)-6-(4-tert-butyloxycarbonylamino-1-piperidinyl)- Pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(4-hydroxypiperidin-1-yl)-6-(4-methoxymethyl-1-piperidinyl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(4-hydroxypiperidin-1-yl)-6-(4-hydroxyethyl-1-piperidinyl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(4-Hydroxypiperidin-1-yl)-6-(4-(hydroxy)-4-(3-trifluoromethylphenyl)piperidin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid, ethyl ester;2-[[4-[4-morpholinyl]-6-[4-[1-methyl-1-hydroxyethyl]-1-piperidinyl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-(3-oxo-1-piperidinyl]-6-[[3-pyridyl]oxy] -2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-methyl-1-piperazinyl]-6-[(1,4-dioxaspiro[4.5]decan-8-yl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-morpholinyl]-6-[[(4-(methylsulfonylamino)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-oxo- 1-Piperazinyl]-6-[(1-oxa-3,8-diazospiro[4.5]decane-2,4,dione-8-yl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-hydroxy-1-piperidinyl]-6-[[(4-(carboxy)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(4-hydroxypiperidin-1-yl)-6-(4-(hydroxy)-4-(4-bromophenyl)piperazinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester Lysin(1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[[4-[4-morpholinyl]-6-[[(4-ethylsulfonylamino)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl]-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-(aminocarbonyl)-1-piperazinyl]-6-[[(3,4-dimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-Formyl-1-piperazinyl]-6-[[(3-(5-(1H)tetrazolyl)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-(hydroxymethyl)-1-piperidinyl]-6-[[N-methyl-N-(5-tetrazolylmethyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester; 2-[[4-[4-Methyl-1-piperazinyl]-6-[[(2,5-dimethyl)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-6-[N-methyl-N-(3-pyridinylmethyl)amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[(1-morpholinyl)]-6-[[N-methyl-N-(5-thiazolecarboxylic acid 2-[[4-[4-Methyl-1-piperazinyl]-6-[4-[methylsulfonylamino]-1-piperidinyl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-Hydroxy-1-piperidinyl]-6-[[(2,5-dimethyl)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester Acid, ethyl ester;4-Methyl-2-[[4-(4-morpholinyl)-6-[[(3,4,5-trimethoxyphenyl)methyl]amino-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid, ethyl ester;2-[4-(4-hydroxypiperidin-1-yl)-6-(3-hydroxy-1-piperidinyl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;4-Methyl-2-[[4-(4-methyl-1-piperazinyl)-6-[methyl(3-pyridinylmethyl) )amino]-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-oxo-1-piperazinyl]-6-[[(2-(5-(1H)tetrazolyl)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-4-thiazolecarboxylic acid, ethyl ester;2-[[4-[(2-furanylmethyl)amino]-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester, trifluoroacetate (1:1);2-[[4-[[(3,4-Dimethoxyphenyl)methyl]amino]-6-(4-morpholinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;4-Methyl-2-[[4-[methyl(3-pyridinylmethyl)amino]-6-[[(tetrahydro-2-furanyl)methyl]amino]-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[(4-hydroxy-1-piperidinyl)]-6-[[N-methyl-N-(5-tetrazolylmethyl]amino] -2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4-(4-hydroxypiperidin-1-yl)-6-[(4-(hydroxy)-4-(phenylmethyl)piperidin-1-yl)]-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(4-dimethylamino-1-piperazinyl)-6-[[2-(1-morpholinyl)ethyl]amino]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[[4-[4-hydroxy-1-piperidinyl]-6-[[(3-pyridinylmethyl)]oxy]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-(aminocarbonyl)-1-piperidinyl]-6-[[(2,6-dimethylphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-hydroxy-1-piperidinyl]-6-[[(4-(methylsulfonylamino)phenyl)methyl]amino] 2-[[4-[4-hydroxy-1-piperidinyl]-6-[[(4-(propylsulfonylamino)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-(aminocarbonyl)-1-piperidinyl]-6-(4-methyl-1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-(3,4-Dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-6-(4-methyl-1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-Formyl-1-piperazinyl]-6-[[N-methyl-N-(5-tetrazolylmethyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[[(4-carboxyphenyl)methyl]amino]-6-[4-(hydroxyphenyl) 2-[[4-[[(4-carboxyphenyl)methyl]amino]-6-(4-methyl-1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester, monohydrochloride;4-Methyl-2-[[4-(4-methyl-1-piperazinyl)-6-[[(tetrahydro-2-furanyl)methyl]amino]-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid, ethyl ester, monohydrochloride ethyl ester;2-[[4-[[(4-carboxyphenyl)methyl]amino]-6-[3-(hydroxymethyl)-1-piperidinyl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[[[4-[[(2-methoxyethyl)amino]carbonyl]phenyl]methyl]amino]-6-(4-methyl-1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester, trifluoroacetate (1:1);2-[4,6-bis- (1-Morpholinyl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[[4-[3-(aminocarbonyl)-1-piperazinyl]-6-[[N-methyl-N-(5-tetrazolylmethyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;4-Methyl-2-[[4-[-methyl(3-pyridinylmethyl)amino]-6-[4-morpholinyl]-2-pyridinylmethyl]amino]-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-(aminocarbonyl)-1-piperazinyl]-6-[[[4-(methoxycarbonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-chloro-6-[(1-oxa-3,8-diazaspiro[4.5]decane-2,4,dione-8-yl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester; 2-[[4-[4-(hydroxymethyl)-1-piperidinyl]-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-(hydroxymethyl)-1-piperidinyl]-6-[[N-methyl-N-(5-tetrazolylmethyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-(hydroxymethyl)-1-pyrrolidinyl]-6-[[N-methyl-N-(5-tetrazolylmethyl)amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester Trazolylmethyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;4-Methyl-2-[[4-[methyl(phenylmethyl)amino]-6-(4-methyl-1-piperazinyl)-2-pyrimidinyl]amino]-5-thiazolecarboxylic acid, ethyl ester;2-[[4-(dimethylamino)-6-[[[4-(methylsulfonyl)phenyl]methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-Hydroxy-1-piperidinyl ]-6-[[(3-(5-(1H)tetrazolyl)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-hydroxymethyl-1-piperidinyl]-6-[[(4-(propylsulfonylamino)phenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-hydroxymethyl-1-piperidinyl]-6-[[(4-(cyclopropylsulfonylamino)phenyl)methyl]amino]-2 -pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[3-(hydroxymethyl)-1-piperidinyl]-6-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-tetrahydropyranyl]oxy-6-[[N-[(3,4,5-trimethoxyphenyl)methyl]]-N-(methyl)amino]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-Methyl-1-piperazinyl]-6-[(4-methoxyphenyl)oxy]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;4-Methyl-2-[4-(4-methyl-piperazin-1-yl)-6-[[[4-(aminosulfonyl)phenyl]methyl]amino]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl ester;2-[4-Isopropyl-6-(4-sulfamoyl-benzylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;4-Methyl-2-[4-(4-sulfamoyl-benzylamino)-6-methyl-pyrimidin-2-ylamino]-thiazole-5-carboxylic acid, ethyl ester Azole-5-carboxylic acid ethyl ester;4-Methyl-2-[4-(4-sulfamoyl-benzylamino)-6-hydroxymethyl-pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl ester;4-Methyl-2-[4-(4-methyl-piperazin-1-yl)-6-[4-(1H-tetrazol-5-yl)-benzylamino]-pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl ester;2-[4-(4-Hydroxy-piperidin-1-yl)-6-[4-(1H-tetrazol-5-yl)-benzylamino]-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester; 4-Methyl-2-[4-[(tetrahydro-furan-2-ylmethyl)-amino]-6-[4-(1H-tetrazol-5-yl)-benzylamino]-pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl ester;4-Methyl-2-[4-morpholin-4-yl-6-[4-(1H-tetrazol-5-yl)-benzylamino]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl ester;2-[4-(3-carbamoyl-piperidin-1-yl)-6-[4-(1H-tetrazol-5-yl)-benzylamino]thiazole-5-carboxylic acid ethyl ester 2-[4-(4-hydroxymethylpiperidin-1-yl)-6-[4-(1H-tetrazol-5-yl)-benzylamino]-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(2-hydroxymethyl-1-pyrrolidinyl)-6-[4-(1H-tetrazol-5-yl)-benzylamino]-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[4-(3-N,N-Diethylcarbamoyl-1-piperidinyl)-6-[4-(1H-tetrazol-5-yl)benzylamino]-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(3-Hydroxy-1-pyrrolidinyl)-6-[4-(1H-tetrazol-5-yl)benzylamino]-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;4-Methyl-2-[[[2-[4-morpholin-4-yl]ethyl]amino-6-[4-(1H- 4-Methyl-2-[[[4-hydroxyl]butyl]amino-6-[4-(1H-tetrazol-5-yl)-benzylamino]-pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl ester;2-[4-(4-formyl-1-piperazinyl)-6-[4-(1H-tetrazol-5-yl)-benzylamino]-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[[4-[[(4-Chlorophenyl)methyl]amino]-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[(4-aminosylphenyl)methyl]amino]-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-Morpholino-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarbo 2-[[4-[[(3,4-Dimethoxyphenyl)methyl]amino]-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[4-Hydroxy-4-phenyl-piperidinyl]-6-(5-oxazolyl)-2-pyrimidinyl]amino]- 4-Methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[(4-Methylsulfonylphenyl)methyl]amino]-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[4-hydroxy-piperidinyl]-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[4-ethoxycarbonyl-piperidinyl]-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4 -Methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-piperidinyl-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[N-Methylpiperazinyl-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[N-(2-Furylcarbonyl)piperazinyl-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[N-Acetyl-[1,4-diazepyr]-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[N-Methyl-N-(N-methyl-4-piperidinyl)-amino]-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[N-Methyl-[1,4]-diazepyr]-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester 2-[[4-N,N-Dimethoxyethylamino-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[(1',4)-bipiperidinyl]-6-(5-oxazolyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[4-(4-Hydroxy-piperidin-1-yl)-6-(3,4,5-trimethoxy-phenyl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[(4 -(4-Hydroxy-piperidin-1-yl)-6-[4-(1H-tetrazol-5-yl)-phenyl]-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-Hydroxy-piperidin-1-yl)-6-pyridin-3-yl-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-Methanesulfonyl-benzylamino ... 2-[4-(4-hydroxy-piperidin-1-yl)-6-pyrimidin-4-yl-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-cyano-phenyl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-acetyl-phenyl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-Hydroxymethyl-phenyl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-Hydroxy-phenyl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-Methanesulfonyl-benzylamino)-6-(3,4,5-trimethoxy-phenyl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester; 2-[4-(4-Methanesulfinylphenyl)-6-(4-hydroxypiperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-(amino)phenyl)-6-(4-hydroxypiperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-carboxymethyl-phenyl)-6-(4-hydroxypiperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester ]-4-Methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-(trifluoromethylcarbonylamino)phenyl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-(ethoxycarbonylmethyl)phenyl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(1,2,3 ,6-tetrahydropyridin-4-yl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(3-(cyano)phenyl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-(methoxycarbonyl)phenyl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester ]-4-Methylthiazole-5-carboxylic acid ethyl ester;2-[4-(2-(methoxy)-5-pyridinyl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-Methyl-1-piperazin-yl)-6-(3,4,5-trimethoxy-phenyl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-morpholinyl)-6-(3,4,5-trimethoxy-phenyl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester 2-[4-(4-morpholinyl)-6-(3-pyridinyl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(piperidin-4-yl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[[4-[4-hydroxy-piperidinyl]-6-(3,5-dimethyl-4-isoxazolyl)-2-pyrimidin-4 ... 2-[4-(4-methylphenyl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[4-(4-cyano-phenyl)-6-(4-methanesulfonyl-benzylamino)-pyrimidin-2-ylamino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[4-(4-methanesulfonylphenyl) -6-(4-hydroxypiperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-methanesulfanylphenyl)-6-(4-hydroxypiperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-carboxy-phenyl)-6-(4-hydroxy-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4-(4-carboxyphenyl)-6-(3-oxo-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-carboxyphenyl)-6-(4-methyl-piperazin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-carboxyphenyl)-6-morpholin-4-yl-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-carboxyphenyl)-6-(4-methyl-[1,4]diazepan-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester ]-4-Methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-Carboxy-phenyl)-6-(3-R-hydroxy(hydrox)-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-Carboxy-phenyl)-6-(3-hydroxymethyl-piperidin-1-yl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-Acetyl-[1,4]diazepan-1-yl)-6-(4-carboxy-phenyl)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester; 2-[4-(4-Carboxyphenyl)-6-[N-methyl-N-(1-N-methyl-piperidin-4-yl)-amino]pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-Carboxyphenyl)-6-piperazin-1-yl-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester;2-[4-(4-Carboxyphenyl)-6-(4-sulfamoyl-benzylamino)-pyrimidin-2-ylamino]-4-methylthiazole-5-carboxylic acid ethyl ester 2-[[4-[[5-Allyl[4-(aminosulfonyl)phenyl]methyl]amino]-6-chloro-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[[[4-(aminosulfonyl)phenyl]methyl]amino]-5-methyl-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester, trifluoroacetate (1:3);2-[[4-[[[4-(aminosulfonyl)phenyl]methyl]amino]-5 -Methyl-6-(4-morpholinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[[5-allyl[4-(aminosulfonyl)phenyl]methyl]amino]-6-(4-methylpiperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[[5-[2-[2-methylprop-3-ene]]-4-[4-(aminosulfonyl)phenyl]methyl]amino]-6-(4-methylpiperazinyl)-2-pyrimidinyl]amino] -4-Methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[[[(3,4,5-(trimethoxy)phenyl]methyl]amino]-5-methyl-6-(1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester, trifluoroacetate;2-[[4-[[5-[2,3-propanediol][4-(aminosulfonyl)phenyl]methyl]amino]-6-(4-methylpiperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[[[3,4,5-(Trimethoxy)phenyl]methyl]amino]-5-methyl-6-(4-methyl-1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester, trifluoroacetate;2-[[4-[[5-[2-[2-methylprop-3-ene]]-4-[4-(aminosulfonyl)phenyl]methyl]amino]-6-chloro-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[[[4-(Aminosulfonyl) 2-[[4-[N-[[3,4,5-(trimethoxy)phenyl]methyl]-N-methylamino]-5-methyl-6-(4-methyl-1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[N-[[3,4,5-(trimethoxy)phenyl]methyl]-N-methylamino]-5-methyl-6-(4-methyl-1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[4,6-bis-(4-hydroxy-piperidin-1-yl)-5-methylpyrimidinyl]amino]- 2-[4,6-Bis-(3-oxo-piperazin-1-yl)-5-[ethoxycarbonylmethyl]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[4,6-Bis-(4-hydroxy-piperidin-1-yl)-5-methoxypyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;2-[[4-[N-[[3,4,5-(trimethoxy)phenyl]methyl] -N-Methylamino]-5-methoxy-6-(4-methyl-1-piperazinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[[3-pyridyl]methyloxy]-5-(2-propenyl-6-(4-morpholinyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid, ethyl ester;2-[(4-ethoxycarbonylmethyl-6-morpholin-4-yl-pyrimidin-2-yl)-amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[(4-Ethoxycarbonylmethyl-6-[3-oxo-1-piperazinyl]-pyrimidin-2-yl)-amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[(4-Carboxymethyl-6-morpholin-4-yl-pyrimidin-2-yl)-amino]-4-methyl-5-thiazolecarboxylic acid;2-[4-morpholin-4-yl-6-[(3,4,5-trimethoxy-phenylcarbamoyl)-methyl]-pyrimidin-2-ylamino]-4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[2-Oxo-2-(3-oxo-piperazin-1-yl)-ethyl]-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-(4-Sulfamoyl-benzylamino)-6-[(4-sulfamoyl-benzylcarbamoyl)-methyl]-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[4-[2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl) -2-oxo-ethyl]-6-(4-sulfamoylbenzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[(4-chlorophenyl)-methyl-carbamoyl]-methyl]-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-6-(4-sulfamoyl-benzylamino)-2- Pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[2-(4-ethoxycarbonyl-piperidin-1-yl)-2-oxo-ethyl]-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-(2-oxo-2-piperidin-1-yl-ethyl)-6-(4-sulfamoyl-benzylamino)2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[2-[4-(Furan-2-carbonyl)-piperazin-1-yl]-2-oxo-ethyl]-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[(cyclohexyl-methyl-carbamoyl)-methyl]-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[ 4-[2-(4-Acetyl-[1,4]diazepan-1-yl)-2-oxo-ethyl]-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[methyl-(1-methyl-piperidin-4-yl)-carbamoyl]-methyl]-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester; 2-[[4-[2-(4-methyl-[1,4]diazepan-1-yl)-2-oxo-ethyl]-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[[bis-(2-methoxy-ethyl)-carbamoyl]-methyl]-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-(2-[1,4']bipiperidinyl-1 2-[[4-[2-(4-Hydroxy-4-phenyl-piperidin-1-yl)-2-oxo-ethyl]-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[2-(4-Hydroxy-4-phenyl-piperidin-1-yl)-2-oxo-ethyl]-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-Ethoxycarbonyl-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester 2-[[4-Carboxymethyl-carbamoyl)-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-Carboxymethyl-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-(Carboxymethyl-carbamoyl)-6-(4-sulfamoyl-benzylamino)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[4-(4-Hydroxy-piperidin-1-yl)-6-(4-methyl 2-[4-(4-hydroxy-piperidin-1-yl)-6-(4-methanesulfonyl-benzyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[4-(4-hydroxy-piperidin-1-yl)-6-(4-methanesulfonyl-benzyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-(4-hydroxy-piperidin-1-yl)-6-(4-methanesulfonyl-benzyl)-2-pyrimidinyl]amino]-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-[[4-[4-Methyl-1-piperazinyl]-6-[N-methyl-N-[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-trifluoromethyl-5-thiazolecarboxylic acid, ethyl ester;2-[[4-[4-Methylpiperazin-1-yl]-6-(N-methyl-N-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-methyl-5-cyanothiazole;2-[[4-[4-Methyl-1-piperazinyl]-6-(N-methyl-N-[[(3,4,5-trimethoxyphenyl)methyl]amino]-2-pyrimidinyl]amino]-4-trifluoromethyl-5-thiazolecarboxylic acid, ethyl ester 2-[[4-[4-hydroxy-piperidin-1-yl]-6-[N-methyl[[N-[(3,4,5-trimethoxyphenyl)methyl][-N-methyl]amino]-2-pyr...

Claims

1. A substance having phosphodiesterase-7 inhibitory activity (PDE7 inhibitor) for use as an active ingredient in a therapeutic agent having phosphodiesterase-7 inhibitory activity for the treatment and prevention of chronic fatigue, exhaustion and / or exertion intolerance, and for the treatment and prevention of diseases associated with chronic fatigue, exhaustion and / or exertion intolerance.

2. 2. The substance according to claim 1, wherein the diseases associated with chronic fatigue, exhaustion and / or exertion intolerance are diseases diagnosed as Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME / CFS), Systemic Exercise Intolerance, Exercise Intolerance, Long COVID complaints, Post COVID-19 Symptoms (PCS), Post COVID-19 Acute Symptoms (PACS), Post COVID-19 Acute Symptoms (PASC), Post COVID-19 Vaccination (Long Vax) and post-vaccination syndrome after vaccination against other pathogenic bacteria, viruses and pathogens, and post-infectious fatigue after viral, bacterial or fungal infection, in particular ME / CFS of non-infectious, non-inflammatory and non-immune etiology.

3. 2. The substance of claim 1, wherein the chronic fatigue and exhaustion are symptoms associated with or are related to cancer (cancer-related fatigue), fibromyalgia, Ehlers-Danlos syndrome, Marfan syndrome, Gulf War illness, the autoimmune diseases rheumatoid arthritis, ANCA-associated vasculitis and Sjogren's syndrome, and other autoimmune diseases with fatigue and exhaustion as debilitating symptoms.

4. PDE7 inhibitors inhibit the enzymatic activity of PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B) at an IC ５０ <50 μM, preferably IC ５０ IC<1 μM, more preferably 0.1-600 nM ５０ and particularly preferably about 0.2 to about 100 nM IC ５０ and more particularly preferably an IC of about 1 to about 100 nM ５０ The substance according to any one of claims 1 to 3, which is a substance that inhibits

5. The PDE7 inhibitor is a substance that inhibits the enzymatic activity of PDE7A, and preferably the PDE7 inhibitor inhibits the enzymatic activity of PDE7A at an IC ５０ <50 μM, preferably IC ５０ IC<1 μM, more preferably 0.1-600 nM ５０ and particularly preferably about 0.2 to about 100 nM IC ５０ and more particularly preferably an IC of about 1 to about 100 nM ５０ The substance according to any one of claims 1 to 3, which is a substance that inhibits

6. PDE7 inhibitors inhibit Na in skeletal muscle ＋ / K ＋ - A substance according to any one of claims 1, 2, 3, 4 and 5, which improves blood flow to skeletal muscles and the brain by stimulating ATPase and NCLX and increasing cAMP.

7. The substance according to any one of claims 1 to 6, wherein the PDE7 inhibitor is present in a pharmaceutical formulation, preferably in the form of an oral drug, intravenous, subcutaneous, intramuscular, pharyngeal and nasal administration.

8. The substance according to any one of claims 1 to 7, wherein the PDE7 inhibitor is a chemical compound, a protein or polypeptide, a nucleic acid molecule, a ribozyme, a DNAzyme, a proteolytic inducer, or a gene therapy substance.

9. The chemical compounds are small molecule inhibitors, including natural and synthetic substances with low molecular weights, such as peptides, peptidomimetics, and non-peptide inhibitors, such as classical small molecule chemical compounds, preferably the small molecule inhibitors have a molecular weight of less than about 750 g / mol and an IC ５０ <50 μM, preferably IC ５０ IC<1 μM, more preferably 0.1-600 nM ５０ and particularly preferably an IC of about 0.2 to about 100 nM ５０ and more particularly preferably an IC of about 1 to about 100 nM ５０ IC for inhibiting PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B) ５０ 9. The substance of claim 8, having the formula:

10. The chemical compounds are small molecule inhibitors, including natural and synthetic substances with low molecular weight, such as peptides, peptidomimetics and non-peptide inhibitors, such as classical small molecule chemical compounds, preferably the small molecule inhibitors have a molecular weight of less than about 750 g / mol, and wherein the PDE7 inhibitor is a substance that inhibits the enzymatic activity of PDE7A, preferably the PDE7 inhibitor inhibits the enzymatic activity of PDE7A at a concentration of 1000 kJ / min, IC ５０ <50 μM, preferably IC ５０ IC<1 μM, more preferably 0.1-600 nM ５０ and particularly preferably about 0.2 to about 100 nM IC ５０ and more particularly preferably an IC of about 1 to about 100 nM ５０ The substance according to claim 8, which is a substance that inhibits

11. 9. The substance of claim 8, wherein the PDE7 inhibitor is a protein or polypeptide comprising an antibody, nanobody, or functionally related protein or protein fragment or fusion protein comprising a single chain variable fragment or a designed ankyrin repeat protein or lipocalin / anticalin that binds to PDE7.

12. The substance described in claim 8, wherein the PDE7 inhibitor inhibits PDE7 expression and is an antisense nucleic acid molecule such as an antisense oligonucleotide, antisense RNA, antisense mRNA, antisense DNA, or a PDE7 RNAi molecule, siRNA, microRNA or other such molecule, or a ribozyme that modulates PDE7, or a DNAzyme that modulates PDE7.

13. The substance of claim 8, wherein the PDE7 inhibitor is a protein degradation inducer such as PROTAC, SNIPER, HaloPROTAC, HyT, LYTAC, AUTAC, ATTEC, RIBOTEC, monomeric degradation inducers, dual mechanism degradation inducers, SARD, TF-PROTAC, dual PROTAC, SERD, bispecific aptamer chimera, AbTAC, GlueTAC, AUTOTAC, CMA-based degradation inducers, MADTAC, ATAC, molecular glue, biodegradation inducers, biodegradation inducer protein mRNA, and biodegradation inducer protein mRNA in a lipid nanoparticle formulation, all of which target PDE7.

14. 9. The substance of claim 8, wherein the PDE7 inhibitor is a gene therapy that alters, completes, replaces or deletes the PDE7 gene.

15. PDE7 inhibitors are compounds based on the structural units pyrazolopyrimidinone, spirocycle, spirocyclic quinazoline, 8'-chloro-2',3'-dihydro-2'-oxospiro[cyclohexane-1,4'(1'H)-quinazoline]-5'-yl, thiazole and oxadiazole, pyridinylpyrazolopyrimidinone, arylindenopyridine, thienopyrazole, 3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide, 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-thieno[2,3-c]pyrazole-5-carboxamide, imidazolate, Riazinone, benzenesulfonamide, thiazol-2-yl-imine, (4,2-disubstituted-thiazol-5-yl)amine, amine-substituted thiopheno[2,3-d]pyrimidine, nitrogen-containing bicycles, 4-substituted fused heteropyrimidines and fused hetero-4-pyrimidones, 2-amine-substituted quinazolines and pyrido[2,3-d]pyrimidines, purines, amine-substituted pyrimidines, fused heterocycles containing amine-substituted purines, 2-amine-substituted pyrimidines, phthalazinone, 3,4-dihydroisoquinoline and isoquinoline, 1-phenyl-substituted 3,4- Dihydroisoquinolines, sulfonamides, heterobiarylsulfonamides, naphthalenyl dihydropurin-6-ones, spiro-fused quinazolin-2-ones, spirocyclic and substituted quinazolines, imidazotriazines, spiro-fused 4-amino-butanecarboxylic acids, 4-amine substituted thieno[2,3-d]pyrimidine-6-carbonitriles, pyrimidin-2-yl sulfides, 5-oxo-pyrrole-3-carboxylates, thieno[2,3-b]thiophen-3-amines, indolo[2,3-b]quinoxalines, methylphenanthrene, sulfonyl benzoates, benzophenones ... Pyrrocyclic and 5,8-substituted (1H,3H)-quinazolines, pyrrolopyrimidines, imidazoles, isoxazoles, 4-cyano-1H-pyrrole-2-carboxylates, imidazo[4,5-c]pyridines, quinazolines, 3-substituted 2,3-dihydro-2-thioxo-4(1H)-quinazolinones and 3-substituted 2,3-dihydro-2-oxo-4(1H)-quinazolinones, 3-substituted 2,3-dihydro-2-thioxothieno[3,2-d]pyrimidin-4(1H)-ones, 3-substituted 2,3-dihydro-2-thioxothieno[3,2-d]pyrimidin-4(1H)-ones, 3-substituted 2,3-dihydro-2-thioxo[1]benzothieno[3,2-d]pyrimidin-4(1H)-one, ethyl-substituted purin-2-amine, quinazolinedione, bicyclic nitrogen-containing heterocycles substituted with amino groups, 3,5-substituted 1,2,3-triazolo[4,5-d]pyrimidin-7-amine, bicyclic 3-substituted 1,2,4-triazole, 2-pyrimidinone, isochromenone, 5-imino-1,2,4-thiadiazole, 4,5-dihydroisoxazole-substituted pyrazolopyrimidine, imidazopyridine, dihydropurine, pyrrole, benzothiopyranoimidazolone, guanine, arylindenopyrimidinone The substance according to any one of claims 1 to 14, wherein the compound is selected from the group consisting of thienothiadiazine-containing compounds, such as thienothiadiazines, sulfonylbenzenes, trans-aconitic acid, thienopyrimidines / thienopyrimidinones, 2-(isopropylamino)thieno[3,2-d]pyrimidin-4(3H)-ones, isothiazole- and isoxazole-fused pyrimidones, imidazopyridazinones, sulfides, steroids, podocarpans, fused thiophenes, dihydronaphthyridinediones, furans, S-substituted quinazolines, methylxanthines, and benzothienothiadiazine-containing compounds.

16. The inhibitors were assigned by Chemical Abstracts Service (CAS) under the CAS registration numbers 553669-13-9, 553668-77-2, 460346-28-5, 756535-34-9, 873540-36-4, 873537-95-2, 873538-20-6, 873538-81-9, 873541-44-7, 873541-70-9, 873541-14-1, 873541- 04-9, 433695-36-4, 1086424-30-7, 16081-93-9, 1062094-00-1, 1062094-26-1, 87 3541-45-8, 908570-13-8, 908570-12-7, 873541-45-8 (H2O), 906079-12-7, 104184 6-43-8, 1374784-19-6, 1041846-46-1, 1140589-61-2, 1140589-71-4, 1140589-76-9, 1140590-16-4, 1162649-94-6, 1162650-34-1, 1140590-71-1, 1162650-04-5, 11 16. The material of any one of claims 1 to 15, selected from the group consisting of compounds having the following structural formulas: 62650-22-7, 1162650-24-9, 1251701-48-0, 1251701-62-8, 1251702-51-8, 1251702-23-4, 1251702-27-8, 1251701-58-2, 1251702-08-5, 1281681-33-1, 1281681-33-1 2HBr-free, 58-32-2, 6493-05-6, 873539-34-5, 18741-24-7, and 28822-58-4.

17. A pharmaceutical composition comprising at least one PDE7 inhibitor according to any one of claims 1 to 16.

18. (i) at least one PDE7 inhibitor according to claim 9, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, polymorph, ester, ether, enantiomer, prodrug, or metabolite thereof, and at least one pharmaceutically acceptable diluent or excipient; or (ii) 18. A pharmaceutical composition according to claim 17, characterized in that it comprises at least one compound of the formula according to claim 14 or claim 16, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, polymorph, ester, ether, enantiomer, prodrug, or metabolite thereof, and at least one pharmaceutically acceptable diluent or excipient.

19. Use of a compound having phosphodiesterase-7 inhibitory activity (PDE7 inhibitor) for the manufacture of a medicament for the treatment and prevention of chronic fatigue, exhaustion and / or exertion intolerance, wherein the PDE7 inhibitory compound preferably inhibits the enzymatic activity of PDE7 (PDE7A, PDE7B, or PDE7A and PDE7B) at a dose of 100 mg / kg or more, more preferably ... ５０ <50 μM, preferably IC ５０ IC<1 μM, more preferably 0.1-600 nM ５０ and particularly preferably an IC of about 0.2 to about 100 nM ５０ and more particularly preferably an IC of about 1 to about 100 nM ５０ Inhibits, use as above.

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