阅读说明：本技术 泛酸激酶的小分子调节剂 (Small molecule modulators of pantothenate kinase ) 是由 R·E·李 R·P·唐加拉帕利 C·O·罗克 S·贾可斯基 A·V·爱德华 尹美京 C· 于 2018-12-26 设计创作，主要内容包括：本公开涉及调节泛酸激酶(PanK)活性以治疗代谢性疾病(例如II型糖尿病)、神经系统疾病(例如与泛酸激酶相关的神经变性)的化合物,包含此类化合物的药物组合物及其在治疗中的应用。本摘要旨在用作特定领域中进行搜索的扫描工具,并不旨在限制本发明。(The present disclosure relates to compounds that modulate pantothenate kinase (PanK) activity for the treatment of metabolic diseases (e.g., type II diabetes), nervous system diseases (e.g., neurodegeneration associated with pantothenate kinase), pharmaceutical compositions comprising such compounds, and uses thereof in therapy. This abstract is intended as a scanning tool for performing searches in a particular field and is not intended to be limiting of the present invention.)

1. A compound having the structure shown in the formula:

wherein Q²Is a structure selected from the group consisting of:

wherein R is^3a、R^3bAnd R^3cEach independently selected from: hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, with the proviso that R^3a、R^3bAnd R^3cAt least one is halogen; and

wherein R is⁴Selected from: hydrogen, halogen, -CN, SO₂NH₂、SO₂CH₃、SO₂CF₃And NO₂，

Or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein Q is²Is a structure selected from:

3. a compound according to claim 1, wherein Q is²Is a structure selected from:

4. a compound according to claim 1, wherein Q is²The structure is as follows:

5. the compound of claim 1, wherein R is^3aIs halogen.

6. The compound of claim 1, wherein R is^3ais-F.

7. The compound of claim 1, wherein R is^3aIs halogen and R^3bAnd R^3cEach is hydrogen.

8. The compound of claim 1, wherein R is^3ais-F and R^3bAnd R^3cEach is hydrogen.

9. The compound of claim 1, wherein R is^3cIs halogen.

10. As claimed in claim 1The compound of (1), wherein R is^3cis-F.

11. The compound of claim 1, wherein R is^3aAnd R^3cEach is-F and R^3bIs hydrogen.

12. The compound of claim 1, wherein R is⁴is-CN.

13. The compound of claim 1, wherein R is⁴is-Cl.

14. The compound of claim 1, wherein the compound has the structure:

15. the compound of claim 1, wherein the compound is selected from the group consisting of:

16. the compound of claim 1, wherein the compound is selected from the group consisting of:

17. a compound having the structure shown in the formula:

wherein A is selected from: o, CO, CH₂、CF₂、NH、N(CH₃) And CH (OH);

wherein R is^3a、R^3bAnd R^3cEach independently selected from: hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, with the proviso that R^3a、R^3bAnd R^3cAt least one is halogen; and

wherein R is⁴Selected from: hydrogen, halogen, -CN, SO₂NH₂、SO₂CH₃、SO₂CF₃And NO₂，

Or a pharmaceutically acceptable salt thereof.

18. The compound of claim 0, wherein R is^3aIs halogen.

19. The compound of claim 0, wherein R is^3ais-F.

20. The compound of claim 0, wherein R is^3aIs halogen and R^3bAnd R^3cEach is hydrogen.

21. The compound of claim 0, wherein R is^3ais-F and R^3bAnd R^3cEach is hydrogen.

22. The compound of claim 0, wherein R is^3cIs halogen.

23. The compound of claim 0, wherein R is^3cis-F.

24. The compound of claim 0, wherein R is^3aAnd R^cEach is-F and R^3bIs hydrogen.

25. The compound of claim 0, wherein R is⁴is-CN.

26. The compound of claim 0, wherein R is⁴is-Cl.

27. The compound of claim 0, wherein said compound is selected from the group consisting of:

28. a method of modulating the activity of at least one intracellular pantothenate kinase, said method comprising the step of contacting at least one cell with an effective amount of at least one compound of claim 1 or claim 0, or a pharmaceutically acceptable salt thereof.

29. The method of claim 28, wherein modulation is inhibition.

30. The method of claim 29, wherein said cell is involved in a pathological condition characterized by genetic heterogeneity associated with the enzyme pantothenate kinase.

31. The method of claim 29, wherein said cell is involved in a pathological condition characterized by a dysregulation of gene expression associated with the enzyme pantothenate kinase.

32. The method of claim 28, wherein the modulation is activation.

33. The method of claim 32, wherein said cell is involved in a pathological condition characterized by genetic heterogeneity associated with the enzyme pantothenate kinase.

34. The method of claim 32, wherein said cell is involved in a pathological condition characterized by misregulation of gene expression associated with the enzyme pantothenate kinase.

35. A method of treating a disease associated with pantothenate kinase activity in a subject, said method comprising administering to said subject an effective amount of at least one compound of claim 1 or claim 0, or a pharmaceutically acceptable salt thereof.

36. The method of claim 35, further comprising administering to the subject an effective amount of pantothenate and/or pantothenic acid.

37. The method of claim 35, wherein the disorder associated with pantothenate kinase activity is associated with dysregulation and/or elevated levels of coenzyme a leading to hyperglycemia.

38. The method of claim 35, wherein the disorder associated with pantothenate kinase activity is associated with pantothenate kinase or coenzyme a deficiency leading to neurodegeneration.

39. The method of claim 35, wherein the subject has neurodegeneration of brain iron accumulation or a neurological disorder characterized by decreased mitochondrial function.

40. The process of claim 35, wherein said disorder associated with pantothenate kinase activity is selected from the group consisting of: dystonia, extrapyramidal reactions, dysphagia, muscle stiffness and/or limb stiffness, choreoathetosis, tremor, dementia, spasticity, muscle weakness or seizures.

Background

Pantothenate kinase (PanK, EC 2.7.1.33) catalyzes the biochemical conversion of pantothenate (vitamin B5) to phosphopantothenate, thereby initiating the biosynthesis of coenzyme a (coa). In most organisms, the activity of the enzyme PanK modulates the intracellular concentration of CoA (Leonardi et al (2005) prog. lipid Res.44: 125-. CoA is an important cofactor and serves as a carboxylic acid substrate carrier in various synthetic and oxidative metabolic pathways such as the tricarboxylic acid cycle, sterol biosynthesis, heme biosynthesis, synthesis and metabolism of fatty acids and complex lipids, and epigenetic modification of chromatin. Four closely related active PanK subtypes have been identified in mammals: PanK1 α, PanK1 β, PanK2, and PanK3, encoded by three genes (Zhou et al, (2001) nat. Genet.28: 345-349; Zhang et al, (2005) J. biol. chem.280: 32594-32601; Rock et al, (2002) Gene 291: 35-43). PanK regulates CoA in cells by feedback inhibition of the activity of CoA or CoA thioesters on enzymes, each subtype responding differently to inhibition with different sensitivities (Leonardi et al (2005) prog. lipid Res.44: 125-153). The PanK subtype expression profiles differ among cell types, tissues and organs, and the relative abundance of one or more subtypes determines the respective CoA levels (Dansie et al (2014) biochem. Soc. Trans.42: 1033-1036).

Mutations in the human PANK2 gene result in a rare and life-threatening neurological disease known as PanK-associated neurodegeneration (PKAN) (Zhou et al (2001) Nat. Genet.28: 345-349; Johnson et al (2004) Ann. N.Y.Acad. Sci.1012: 282-298; Kotzbauer et al (2005) J. Neurosci.25: 689-698). PKAN is a hereditary autosomal recessive genetic disease that can lead to progressive dystonia, dysarthria, parkinson's disease and pigmented retinopathy. Classical PKAN begins to develop in the first 10 years of life, beginning around 3 years of age, and patients are likely to be in the morning. The PANK2 gene is highly expressed in human neuronal tissue, and many PKAN-related mutations result in either truncated or inactivated expression of the PanK2 protein, or greatly reduced activity (Zhang et al, (2006) J.biol.chem.281: 107-114). The RANK2 mutation is expected to result in a significant reduction in CoA levels, thereby reducing neuronal metabolism and function in PKAN patients. There is a lack of tools for investigating the relationship between CoA levels and neurodegeneration. Activation of either PanK1 or PanK3 proteins also expressed in neuronal tissue (Leonardi et al (2007) FEBS Lett.581: 4639-one 4644) may complement the reduction in PanK2 activity, as in Pank1^-/-And Pank2^-/-Functional redundancy between subtypes was demonstrated in a mouse model (Leonardi et al 2010).

The deletion of the mouse Pank1 gene limits the supply of CoA, thereby inhibiting the increase of liver CoA caused by fasting. This, in turn, reduces fatty acid oxidation and glucose production by the liver, resulting in fasting hypoglycemia (Leonardi et al (2010) PloS one 5: e 11107). Hypoglycemia and a significant reduction in fatty acid and ketone oxidation is Pank1 where both genes are deleted^-/-Pank2^-/-The leading cause of early death in mice (Garcia et al, (2012) PLoS one 7: e 40871). ob/ob leptin-deficient mice are a model of obesity-related type II diabetes and exhibit abnormally high liver CoA (Leonardi et al (2014) Diabetologia 57: 1466-1475). Consistent with the link between liver CoA levels and glucose homeostasis, deletion of Pankl in ob/ob mice reduced liver CoA and resulted in normalization of diabetic hyperglycemia and associated hyperinsulinemia in this strain (Leonardi et al (2014) Diabetolosis 57: 1466-1475). Genome-wide association studies (Sabatti et al (2009) Nature Genet.41:35-46) indicate that there is a significant correlation between RANK1 gene variation and insulin levels in humans, supporting the concept that PanK inhibitors may be useful therapeutics for diabetes. Taken together, these data demonstrate the effect of altering intracellular CoA levels on oxidative metabolism and glucose homeostasis.

The association of PanK with diseases such as PKAN and diabetes led us to identify and develop PanK activators and inhibitors that are capable of modulating CoA levels and to evaluate the feasibility of such compounds as therapeutics for these diseases. We have recently disclosed the initial high throughput screening work to achieve this goal (Sharma et al, (2015) J. Med. chem.58: 1563-. Our subsequent review, careful filtering of hits and pharmacochemical effects identified a new chemical form capable of modulating PanK activity.

Although PanK has been reported in the literature to be associated with diseases such as PKAN and diabetes, the feasibility of PanK antagonists capable of modulating CoA levels as disease therapeutics has not yet been established. Thus, there remains a need for effective PanK modulators to study the role of CoA in disease. The following disclosure describes a group of such compounds, as well as methods of making and using them.

Summary of the invention

In accordance with the purposes of the present invention, as embodied and broadly described herein, the present invention, in one aspect, relates to compositions and methods for the prevention and treatment of diseases associated with pantothenate kinase activity, e.g., PKAN and diabetes.

Disclosed are compounds having a structure represented by the formula:

wherein Q²Is a structure selected from:

wherein R is^3a、R^3bAnd R^3cEach independently selected from: hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, with the proviso that R^3a、R^3bAnd R^3cAt least one is halogen; and wherein R⁴Selected from: hydrogen, halogen, -CN, SO₂NH₂、SO₂CH₃、SO₂CF₃And NO₂，

Or a pharmaceutically acceptable salt thereof.

Also disclosed are compounds having the structure represented by the formula:

wherein A is selected from: o, CO, CH₂、CF₂、NH、N(CH₃) And CH (OH); wherein R is^3a、R^3bAnd R^3cEach independently selected from: hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, with the proviso that R^3a、R^3bAnd R^3cAt least one is halogen; and wherein R⁴Selected from: hydrogen, halogen, -CN, SO₂NH₂、SO₂CH₃、SO₂CF₃And NO₂，

Or a pharmaceutically acceptable salt thereof.

Also disclosed are methods of making the disclosed compounds.

Also disclosed are pharmaceutical compositions comprising at least one of the disclosed compounds.

Also disclosed are methods of modulating pantothenate kinase activity in at least one cell, the method comprising the step of contacting the at least one cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

Also disclosed are methods of treating a disease associated with pantothenate kinase activity in a subject, the method comprising administering to the subject an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

Also disclosed are methods of modulating levels of coenzyme a in a cell with an effective amount of at least one of the disclosed compounds or a pharmaceutically acceptable salt thereof or in combination with pantothenate and derivatives thereof.

Although various aspects of the invention may be described and claimed in particular legal categories (e.g., system legal categories), this is for convenience only and those skilled in the art will understand that each aspect of the invention may be described and claimed in any legal category. Unless expressly stated otherwise, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Thus, to the extent that the method claims do not specifically state in the claims or specification that the steps are to be limited to a particular order, this is in no way intended to imply that such order is to be inferred. This applies to any expressed or non-express basis for interpretation, including logical problems relating to the arrangement of steps or operational flows, explicit meanings derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

Detailed Description

The present invention may be understood more readily by reference to the following detailed description of the invention and the examples included therein.

Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to particular synthetic methods, unless otherwise specified, or to particular reagents, which may vary, unless otherwise specified. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are now described.

Although aspects of the invention may be described and claimed in particular legal categories (e.g., system legal categories), this is for convenience only and those skilled in the art will understand that each aspect of the invention may be described and claimed in any legal category. Unless expressly stated otherwise, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where the method claims do not specifically state in the claims or specification that the steps are to be limited to a particular order, this is by no means an order to be inferred, in any case. This applies to any non-express basis for interpretation, including logical issues related to the arrangement of steps or operational flows, explicit meanings derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which they pertain. The disclosed references are also individually and specifically incorporated by reference herein for the material contained therein, as discussed in the sentence in which the reference is incorporated. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates which may need to be independently confirmed.

A. Definition of

As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a functional group," "an alkyl group," or "a residue" includes mixtures of two or more such functional groups, alkyl groups, or residues, and the like.

As used in the specification and claims, the term "comprising" may include aspects "consisting of … …" and "consisting essentially of … …"

Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It will also be understood that a number of values are disclosed herein, and that each value is also disclosed herein as "about" that particular value, in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It is also understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13 and 14 are also disclosed.

As used herein, the terms "about" and "at or about" mean that the quantity or value in question may be a value designated as some other value that is approximately or about the same. As used herein, it is generally understood that it is a nominal value ± 10% variation, unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is to be understood that the quantities, dimensions, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. Generally, an amount, size, formulation, parameter or other quantity or characteristic is "about" or "approximately" whether or not explicitly stated. It is understood that where "about" is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

Reference in the specification and the claims to parts by weight of a particular element or component in a composition means the weight relationship between that element or component and any other element or component in the composition or article for which parts by weight are indicated. Thus, in a compound comprising 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a ratio of 2: 5, and is present in that ratio, regardless of whether additional components are included in the compound.

Unless specifically stated to the contrary, the weight percent (wt.%) of a component is based on the total weight of the formulation or composition in which the component is included.

As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

As used herein, the term "subject" may be a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the methods disclosed herein can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or gender. Thus, it is intended to cover adult and newborn subjects as well as fetuses, whether male or female. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder. The term "patient" includes both human and veterinary subjects.

As used herein, the term "treatment" refers to the medical management of a patient intended to cure, ameliorate, stabilize or prevent a disease, pathological condition or disorder. The term includes active treatment, i.e. treatment directed specifically to the improvement of a disease, pathological condition or disorder, and also includes causal treatment, i.e. treatment directed to the elimination of the cause of the associated disease, pathological condition or disorder. In addition, the term includes palliative treatment, i.e., treatment intended to alleviate symptoms rather than cure a disease, pathological condition, or disorder; prophylactic treatment, i.e. treatment aimed at minimizing or partially or completely inhibiting the development of the associated disease, pathological condition or disorder; supportive treatment, i.e. treatment for supplementing another specific treatment for improvement of the relevant disease, pathological condition or disorder. In various aspects, the term encompasses any treatment of a subject, including mammals (e.g., humans), and includes: (i) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e. arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal, e.g., a primate, and in another aspect, the subject is a human. The term "subject" also includes livestock (e.g., cats, dogs, etc.), livestock (e.g., cows, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mice, rabbits, rats, guinea pigs, drosophila, etc.).

As used herein, the term "prevent" or "preventing" refers to blocking, preventing, avoiding, pre-stopping, ending, or hindering the occurrence of something, particularly by acting in advance. It is to be understood that where reduction, inhibition, or prevention is used herein, the use of two other words is also expressly disclosed unless expressly stated otherwise.

As used herein, the term "diagnostic" refers to a condition that has been physically examined by a skilled artisan, e.g., a physician, and found to be suffering from a condition that can be diagnosed or treated by a compound, composition, or method disclosed herein.

As used herein, the terms "administration" and "administering" refer to any method of providing a pharmaceutical formulation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral, transdermal, inhalation, nasal, topical, intravaginal, ocular, otic, intracerebral, rectal, sublingual, buccal and parenteral administration, including injection, e.g., intravenous, intraarterial, intramuscular and subcutaneous administration. Administration may be continuous or intermittent. In various aspects, the formulation can be administered therapeutically; i.e., the formulation may be administered for treatment of an existing disease or condition. In further various aspects, the formulation may be administered prophylactically; i.e., for the prevention of a disease or disorder.

As used herein, the terms "effective amount" and "effective amount" refer to an amount sufficient to achieve a desired result or to affect an undesired condition. For example, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result or to have an effect on an undesired symptom, but generally insufficient to cause an adverse side effect. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disease being treated and the severity of the disease; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the particular compound used; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed and similar factors well known in the medical arts. For example, it is within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. If necessary, the effective daily dose may be divided into a plurality of doses for administration. Thus, a single dose composition may contain such amounts or submultiples thereof to make up the daily dose. In the case of any contraindication, the dosage may be adjusted by the individual physician. The dosage may vary and may be administered in one or more doses per day for one or more days. Guidelines for appropriate dosages can be found in the literature for a given class of drugs. In further various aspects, the formulation can be administered in a "prophylactically effective amount"; i.e., an amount effective to prevent a disease or condition.

As used herein, "dosage form" refers to a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. The dosage form may comprise the disclosed compound, the product of the disclosed manufacturing process, or a salt, solvate, or polymorph thereof, and a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms may be prepared using conventional pharmaceutical manufacturing and mixing techniques. The dosage form may contain inorganic or organic buffers (e.g., phosphate, carbonate, acetate, or sodium or potassium salts of citrate) and pH adjusters (e.g., hydrochloric acid, sodium or potassium hydroxide, citrate or acetate, amino acids, and mixtures thereof), antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonylphenol, sodium deoxycholate), solution and/or freeze/lyophilizate stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic modifiers (e.g., salts or sugars), antimicrobials (e.g., benzoic acid, phenol, gentamicin), antifoams (e.g., polydimethyl silicone), preservatives (e.g., thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers, and viscosity modifiers (e.g., polyvinylpyrrolidone, sodium or potassium salts of citrate), surfactants, and/or salts thereof, Poloxamer 488, carboxymethylcellulose) and co-solvents (e.g. glycerol, polyethylene glycol, ethanol). Formulations formulated for injectable use may have the disclosed compounds, products of the disclosed processes, or salts, solvates, or polymorphs thereof, suspended in sterile saline solution for injection, along with a preservative.

As used herein, "kit" refers to a collection of at least two components that make up the kit. These components together constitute a functional unit for a given purpose. The individual member components may be physically packaged together or individually. For example, a kit including instructions for using the kit may or may not physically include the instructions and other individual member components. Rather, the instructions may be provided as a single member component, in paper or electronic form, which may be provided on a computer-readable storage device or may be downloaded from an internet website, or provided as a recorded presentation.

As used herein, "instructions" refers to a document that describes relevant materials or methods in connection with the kit. These materials may include any combination of: background information, component lists and their availability information (purchase information, etc.), brief or detailed protocols using the suite, troubleshooting, referencing, technical support, and any other relevant information files. The instructions may be provided with the kit, as individual member components, in paper or electronic form, on a computer readable storage device, downloaded from an internet website, or as a recorded presentation. The specification may contain one or more documents and should contain future updates.

As used herein, the term "therapeutic agent" includes any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or non-human animal), induces a desired pharmacological, immunogenic and/or physiological effect through a local and/or systemic effect. Thus, the term encompasses those compounds or chemicals traditionally considered as drugs, vaccines and biopharmaceuticals, including molecules such as proteins, peptides, hormones, nucleic acids, genetic constructs, and the like. Examples of therapeutic agents are described in well-known literature references, such as the merck index (14 th edition), physician's case reference (64 th edition), and the pharmacological basis of therapeutics (12 th edition), including but not limited to drugs; a vitamin; a mineral supplement; substances for the treatment, prevention, diagnosis, cure or alleviation of a disease or condition; a substance or prodrug that affects body structure or function and that is biologically or more active when placed in a physiological environment. For example, the term "therapeutic agent" includes compounds or compositions used in all major therapeutic areas, including but not limited to adjuvants; anti-infective agents, such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorectics, anti-inflammatory agents, antiepileptics, local and systemic anesthetics, hypnotics, sedatives, antipsychotics, neuroleptics, antidepressants, anxiolytics, antagonists, neuronal blockers, anticholinergics and cholinergics, antimuscarinics and muscarinic agents, antiadrenergic agents, antiarrhythmics, antihypertensives, hormones and nutrients, antiarthritics, antiasthmatics, anticonvulsants, antihistamines, antiemetics, antineoplastic agents, antipruritics, antipyretics; antispasmodics, cardiovascular agents (including calcium channel blockers, beta agonists, and antiarrhythmics), hypotensives, diuretics, vasodilators, central nervous system stimulants, cough and cold preparations, decongestants, diagnostics, hormones, bone growth stimulants, and bone resorption inhibitors, immunosuppressants, muscle relaxants, psychostimulants, sedatives, tranquilizers, proteins, peptides and fragments thereof (whether naturally occurring, chemically synthesized, or recombinantly produced), nucleic acid molecules (polymeric forms of two or more nucleotides, including Ribonucleotides (RNA) or Deoxyribonucleotides (DNA) of double-and single-stranded molecules, gene constructs, expression vectors, antisense molecules, and the like), small molecules (e.g., doxorubicin), and other biologically active macromolecules such as proteins and enzymes. The agent may be a bioactive agent for use in medical (including veterinary) applications and agricultural (e.g. with plants) and other fields. The term "therapeutic agent" also includes, but is not limited to, drugs; a vitamin; a mineral supplement; substances for the treatment, prevention, diagnosis, cure or alleviation of a disease or condition; or substances that affect body structure or function; or a prodrug that is biologically or more active when placed in a predetermined physiological environment.

The term "pharmaceutically acceptable" describes materials that are not biologically or otherwise undesirable, i.e., do not cause unacceptable levels of undesirable biological effects or interact in a deleterious manner.

As used herein, the term "derivative" refers to a compound having a structure derived from the structure of the parent compound (e.g., a compound disclosed herein), and which structure is sufficiently similar to those disclosed herein and, based on that similarity, is expected by one skilled in the art to have the same or similar activity and utility as the claimed compound, or to induce, as a precursor, the same or similar activity and utility as the claimed compound. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of the parent compound.

The term "pharmaceutically acceptable carrier" as used herein refers to sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating material, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. Injectable depot forms are prepared by forming microcapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, polyorthoesters, and polyanhydrides. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of release of the drug can be controlled. Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Suitable inert carriers may include sugars such as lactose. Desirably, at least 95% by weight of the active ingredient particles have an effective particle size of from 0.01 to 10 microns.

As used in the specification and the appended claims, a residue of a chemical refers to the resulting product of the chemical, or a portion of a subsequent formulation or chemical product, in a particular reaction scheme, regardless of whether the portion is actually derived from the chemical. Thus, an ethylene glycol residue in a polyester refers to one or more-OCH's in the polyester₂CH₂O-units, whether or not ethylene glycol is used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more-CO (CH) residues in the polyester₂)₈The CO-moiety, whether or not the residue is obtained by reacting sebacic acid or an ester thereof to obtain a polyester.

As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and straight-chain, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, for example, those described below. For suitable organic compounds, the permissible substituents can be one or more and the same or different. For purposes of this disclosure, a heteroatom, such as nitrogen, may have a hydrogen substituent and/or any permissible substituents of organic compounds described herein that satisfy the valencies of the heteroatom. The present disclosure is not intended to be limited in any way by the permissible substituents of organic compounds. Moreover, the terms "substituted" or "substituted with … …" include the implicit proviso that such substitution is consistent with the permissible valences of the substituting atoms and substituents and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformations, e.g., rearrangements, cyclization, elimination, and the like. It is also contemplated that, in certain aspects, each substituent may be further optionally substituted (i.e., further substituted or unsubstituted), unless expressly stated to the contrary.

In defining the terms, "A" and "A" are used¹”、“A²”、“A³"and" A⁴"is used herein as a generic symbol to denote various specific substituents. These symbols may be any substituent, not limited to those disclosed herein, and in one example when they are defined as certain substituents, in another example they may be defined as certain other substituents.

As used herein, the term "aliphatic group" or "aliphatic group" means a hydrocarbon moiety that can be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and spiro-fused polycyclic) and can be fully saturated or can contain one or more units of unsaturation, but not aromatic units. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, straight or branched chain alkyl, alkenyl, and alkynyl groups, and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl, or (cycloalkyl) alkenyl.

The term "alkyl" as used herein is a branched or straight chain saturated hydrocarbon group having 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. The alkyl group may be cyclic or acyclic. The alkyl group may be branched or straight chain. Alkyl groups may also be substituted or unsubstituted. For example, an alkyl group may be substituted with one or more groups including, but not limited to, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. A "lower alkyl" group is an alkyl group containing 1 to 6 (e.g., 1 to 4) carbon atoms. The term alkyl may also be C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl and similar groups up to and including C1-C24 alkyl.

Throughout the specification, "alkyl" is generally used to refer to both unsubstituted alkyl and substituted alkyl. However, substituted alkyl groups are also specifically mentioned herein by identifying specific substituents on the alkyl group. For example, the term "halogenated alkyl" or "haloalkyl" specifically refers to an alkyl group substituted with one or more halides, such as fluorine, chlorine, bromine, or iodine. Alternatively, the term "monohaloalkyl" specifically refers to an alkyl group substituted with a single halide, e.g., fluorine, chlorine, bromine, or iodine. The term "polyhaloalkyl" specifically refers to an alkyl group that is independently substituted with two or more halides, i.e., each halide substituent need not be the same halide as the other halide substituent, nor do multiple instances of a halide substituent need to be on the same carbon. The term "alkoxyalkyl" specifically refers to an alkyl group substituted with one or more alkoxy groups as described below. The term "aminoalkyl" refers specifically to an alkyl group substituted with one or more amino groups. The term "hydroxyalkyl" particularly refers to an alkyl group substituted with one or more hydroxyl groups. When "alkyl" is used in one instance and a specific term such as "hydroxyalkyl" is used in another instance, this is not meant to imply that the term "alkyl" nor that a specific term such as "hydroxyalkyl" or the like is intended.

This practice is also applicable to the other groups described herein. That is, although terms such as "cycloalkyl" refer to unsubstituted and substituted cycloalkyl moieties, substituted moieties may be otherwise specifically identified herein; for example, a particular substituted cycloalkyl group may be referred to as, for example, "alkylcycloalkyl". Similarly, substituted alkoxy groups may be specifically referred to as, for example, "haloalkoxy", and particular substituted alkenyl groups may be, for example, "alkenyl alcohols" and the like. Again, practice of using generic terms such as "cycloalkyl" and specific terms such as "alkylcycloalkyl" is not meant to imply that the generic term also does not include the specific term.

The term "cycloalkyl" as used herein is a non-aromatic carbon-based ring consisting of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term "heterocycloalkyl" is a type of cycloalkyl group as defined above and is included within the meaning of the term "cycloalkyl" wherein at least one carbon atom of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups may be substituted or unsubstituted. For example, cycloalkyl and heterocycloalkyl can be substituted with 0, 1,2,3, or 4 substituents independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, -NH, as described herein₂C1-C4 alkylamino, (C1-C4) (C1-C4) dialkylamino, ether, halogen, -OH, C1-C4 hydroxyalkyl, -NO₂Silyl, sulfo-oxo, -SH and C1-C4 thioalkyl.

As used herein, the term "polyalkylene" is a compound having two or more CH groups attached to each other₂The radical of (a). The polyalkylene may be of the formula- (CH)₂) a-represents, wherein "a" is an integer of 2 to 500.

The terms "alkoxy" and "alkoxy" as used herein refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, "alkoxy" may be defined as-OA¹Wherein A is¹Is alkyl or cycloalkyl as defined above. "alkoxy" also includes polymers of the alkoxy groups just described; that is, the alkoxy group may be a polyether, such as-OA¹-OA²or-OA¹-(OA²)_a-OA³Wherein "a" is an integer selected from 1 to 200, and A¹、A²And A³Is alkyl and/or cycloalkyl.

The term "alkenyl" as used herein is a hydrocarbon group having 2 to 24 carbon atoms, the structural formula of which contains at least one carbon-carbon double bond. Asymmetric structures, e.g. (A)¹A²)C＝C(A³A⁴) Intended to include both the E and Z isomers. This can be presumed in the structural formulae herein where an asymmetric olefin is present, or can be explicitly represented by the bond symbol C ═ C. The alkenyl group may be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

As used herein, the term "cycloalkenyl" is a non-aromatic carbon-based ring consisting of at least three carbon atoms and comprising at least one carbon-carbon double bond, i.e., C ═ C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term "heterocycloalkenyl" is a type of cycloalkenyl group as defined above, and is included within the meaning of the term "cycloalkenyl" where at least one carbon atom of the ring is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocycloalkenyl groups may be substituted or unsubstituted. For example, cycloalkenyl and heterocycloalkenyl can be substituted with 0, 1,2,3, or 4 substituents independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C3-C6 cycloalkenyl, C2-C4 alkynyl, aryl, heteroaryl, aldehyde, -NH, -C₂(C1-C4) alkylamino, (C1-C4) (C1-C4) dialkylamino, carboxylic acids, esters, ethers, halogens, -OH, C1-C4 hydroxyalkyl, ketones, azides, -NO₂Silyl, sulfo-oxo, -SH and C1-C4 thioalkyl.

The term "alkynyl" as used herein is a hydrocarbon group having from 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide as described herein, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol.

The term "cycloalkynyl" as used herein is a non-aromatic carbon-based ring consisting of at least seven carbon atoms and comprising at least one carbon-carbon triple bond. Examples of cycloalkynyl include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term "heterocycloalkynyl" is a type of cycloalkenyl group as defined above and is included within the meaning of the term "cycloalkynyl" wherein at least one carbon atom of the ring is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur or phosphorus. Cycloalkynyl and heterocycloalkynyl may be substituted or unsubstituted. The cycloalkynyl group and the heterocycloalkynyl group may be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

As used herein, the term "aromatic group" refers to a ring structure having a cyclic cloud of delocalized pi electrons above and below the plane of the molecule, where the pi cloud comprises (4n +2) pi electrons. Further discussion of aromaticity is found in Morrison and Boyd's organic chemistry (5 th edition, 1987), Chapter 13, entitled "aromaticity", pages 477-497, which is incorporated herein by reference. The term "aromatic group" includes aryl and heteroaryl groups.

The term "aryl" as used herein is a group containing any carbon-based aromatic group, including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group may be substituted or unsubstituted. The aryl group may be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, NH, as described herein₂Carboxylic acids, esters, ethers, halides,Hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol. The term "biaryl" is a specific type of aryl group and is included in the definition of "aryl". In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are fused ring structures or linked by one or more bridging groups (e.g., carbon-carbon bonds). For example, a biaryl group can be two aryl groups, joined together by a fused ring structure as in naphthalene, or connected by one or more carbon-carbon bonds as in biphenyl.

The term "aldehyde" as used herein is represented by the formula-c (o) H. Throughout the specification, "C (O)" or "CO" is an abbreviation for carbonyl, i.e., C ═ O.

The term "amine" or "amino" as used herein is represented by the formula-NA¹A²Is shown in the specification, wherein A¹And A²May independently be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein. A specific example of an amino group is-NH₂。

The term "alkylamino" as used herein is represented by the formula-NH (-alkyl), wherein alkyl is as described herein. Representative examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, (sec-butyl) amino, (tert-butyl) amino, pentylamino, isopentylamino, (tert-pentyl) amino, hexylamino, and the like.

The term "dialkylamino" as used herein is represented by the formula-N (-alkyl)₂Wherein alkyl is as described herein. Representative examples include, but are not limited to, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di (sec-butyl) amino, di (tert-butyl) amino, dipentylamino, diisoamylamino, di (tert-amyl) amino, dihexylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, and the like.

The term "carboxylic acid" as used herein is represented by the formula-C (O) OH.

The term "ester" as used herein is represented by the formula-OC (O) A¹or-C (O) OA¹Is shown in the specification, wherein A¹May be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein. As used herein, the term "polyester" is represented by the formula- (A)¹O(O)C-A²-C(O)O)_a-or- (A)¹O(O)C-A²-OC(O))_a-is represented by, wherein A¹And A²May independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein, and "a" is an integer between 1 and 500. "polyester" is a term used to describe a group produced by the reaction between a compound having at least two carboxylic acid groups and a compound having at least two hydroxyl groups.

The term "ether" as used herein is represented by formula A¹OA²Is shown in the specification, wherein A¹And A²May independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term "polyether" as used herein is defined by the formula- (A)¹O-A²O)_a-is represented by, wherein A¹And A²May independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein, and "a" is an integer from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

As used herein, the terms "halo", "halogen" or "halide" are used interchangeably and refer to F, Cl, Br or I.

The terms "pseudohalide," "pseudohalogen," or "pseudohalo" as used herein are used interchangeably and refer to a functional group that behaves substantially similar to a halide. Such functional groups include, for example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy.

As used herein, the term "heteroalkyl" refers to an alkyl group that includes at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein the nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. The heteroalkyl group may be substituted as defined above for alkyl.

As used herein, the term "heteroaryl" refers to an aromatic group having at least one heteroatom bound within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, with N-oxides, sulfur oxides, and dioxides being permissible heteroatom substitutions. Heteroaryl groups may be substituted or unsubstituted. The heteroaryl group may be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups may be monocyclic or fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolyl, isoquinolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridyl, and pyrazolopyrimidyl. Additional non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, pyrazolyl, imidazolyl, benzo [ d ] oxazolyl, benzo [ d ] thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo [1,2-b ] pyridazinyl, imidazo [1,2-a ] pyrazinyl, benzo [ c ] [1,2,5] thiadiazolyl, benzo [ c ] [1,2,5] oxadiazolyl, and pyridyl [2,3-b ] pyrazinyl.

As used herein, the terms "heterocycle" or "heterocyclyl" are used interchangeably and refer to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one ring member is not carbon. Thus, the term includes, but is not limited to, "heterocycloalkyl," heteroaryl, "" bicyclic heterocycle, "and" polycyclic heterocycle. Heterocycles include pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole (including 1,2, 3-oxadiazole, 1,2, 5-oxadiazole and 1,3, 4-oxadiazole), thiadiazole (including 1,2, 3-thiadiazole, 1,2, 5-thiadiazole and 1,3, 4-thiadiazole), triazole (including 1,2, 3-triazole, 1,3, 4-triazole), tetrazole (including 1,2,3, 4-tetrazole and 1,2,4, 5-tetrazole), pyridazine, pyrazine, triazine (including 1,2, 4-triazine and 1,3, 5-triazine), tetrazine (including 1,2,4, 5-tetrazine), pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, Tetrahydrofuran, dioxane, and the like. The term heterocyclyl may also be C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and heterocyclyl up to and including C2-C18 heterocyclyl, and the like. For example, C2 heterocyclyl includes groups having two carbon atoms and at least one heteroatom including, but not limited to, aziridinyl, diazacyclobutanyl, dihydrodiazacyclobutadienyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, C5 heterocyclyl includes groups having five carbon atoms and at least one heteroatom, including but not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, homopiperazinyl, pyridinyl, and the like. It is understood that, where chemically possible, a heterocyclyl group may be bonded through a heteroatom in the ring or one of the carbons comprising the heterocyclyl ring.

As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclyl" refers to a ring system wherein at least one ring member is not carbon. Bicyclic heterocyclic groups include ring systems in which an aromatic ring is fused to another aromatic ring, or in which an aromatic ring is fused to a non-aromatic ring. Bicyclic heterocyclic groups include ring systems in which a benzene ring is fused to a 5 or 6 membered ring containing 1,2 or 3 ring heteroatoms, or a pyridine ring is fused to a 5 or 6 membered ring containing 1,2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo [1,5-a ] pyridyl, benzofuranyl, quinolinyl, quinoxalinyl, 1, 3-benzodioxolyl, 2, 3-dihydro-1, 4-benzodioxinyl, 3, 4-dihydro-2H-chromenyl, 1H-pyrazolo [4,3-c ] pyridin-3-yl, 1H-pyrrolo [3,2-b ] pyridin-3-yl, and 1H-pyrazolo [3,2-b ] pyridin-3-yl.

As used herein, the term "heterocycloalkyl" refers to an aliphatic, partially unsaturated or fully saturated 3 to 14 membered ring system, including monocyclic as well as bicyclic and tricyclic ring systems of 3 to 8 atoms. The heterocycloalkyl ring system includes 1-4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuranyl.

The term "hydroxy" or "hydroxyl" as used herein is represented by the formula-OH.

The term "ketone" as used herein is represented by formula A¹C(O)A²Is shown in the specification, wherein A¹And A²May independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term "azide" or "azido" as used herein is defined by the formula-N₃And (4) showing.

The term "nitro" as used herein is defined by the formula-NO₂And (4) showing.

The term "nitrile" or "cyano" as used herein is represented by the formula-CN or-C.ident.N.

The term "silyl" as used herein is represented by the formula-SiA¹A²A³Is shown in the specification, wherein A¹、A²And A³May independently be hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein.

The term "sulfo-oxo" as used herein is represented by the formula-S (O) A¹、—S(O)₂A¹、—OS(O)₂A¹or-OS (O)₂OA¹Is shown in the specification, wherein A¹May be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein. Throughout the specification, "S (O)" is a shorthand form of S ═ O. The term "sulfonyl", as used herein, refers to a compound of the formula-S (O)₂A¹A sulfo-oxo group represented by¹May be hydrogen or an alkyl, cycloalkyl, as described herein,Alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl. The term "sulfone" as used herein is represented by formula A¹S(O)₂A²Is shown in the specification, wherein A¹And A²May independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term "sulfoxide" as used herein is represented by formula A¹S(O)A²Is shown in the specification, wherein A¹And A²May independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term "thiol" as used herein is represented by the formula-SH.

As used herein, "R¹”、“R²”、“R³”、“Rⁿ", wherein n is an integer, independently having one or more of the groups listed above. For example, if R¹Being a straight chain alkyl group, one of the hydrogen atoms of the alkyl group may be optionally substituted with hydroxyl, alkoxy, alkyl, halide, etc. Depending on the group selected, the first group may be combined with the second group, or alternatively, the first group may be pendent (i.e., attached) to the second group. For example, for the phrase "alkyl group comprising an amino group," the amino group can be incorporated into the backbone of the alkyl group. Alternatively, the amino group may be attached to the backbone of the alkyl group. If the first group is intercalated or attached to the second group, the nature of the selected group will be determined.

As described herein, the compounds of the present invention may comprise an "optionally substituted" moiety. Generally, the term "substituted", whether or not beginning with the term "optionally", means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents contemplated by the present invention are those that result in the formation of stable or chemically feasible compounds. It is also contemplated that, in certain aspects, each substituent may be further optionally substituted (i.e., further substituted or unsubstituted), unless expressly stated to the contrary.

As used herein, the term "stable" refers to a compound that is not substantially altered when subjected to conditions that allow its production, detection, and in some aspects, its recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on the substitutable carbon atom of the "optionally substituted" group are independently halogen, - (CH)₂)_0–4R^o、–(CH₂)_0–4OR^o、-O(CH₂)_0-4R^o、–O–(CH₂)_0–4C(O)OR^o、–(CH₂)_0–4CH(OR^o)₂、–(CH₂)_{0– 4}SR^o、–(CH₂)_0–4Ph (can be represented by R)^oSubstituted), - (CH)₂)_0–4O(CH₂)_0–1Ph (can be represented by R)^oSubstituted); -CH ═ CHPh (may be R)^oSubstituted); - (CH)₂)_0–4O(CH₂)_0–1-pyridyl (which may be substituted by R)^oSubstituted), -NO₂、–CN、–N₃、-(CH₂)_0–4N(R^o)₂、–(CH₂)_0–4N(R^o)C(O)R^o、–N(R^o)C(S)R^o、–(CH₂)_0–4N(R^o)C(O)NR^o ₂、-N(R^o)C(S)NR^o ₂、–(CH₂)_0–4N(R^o)C(O)OR^o、–N(R^o)N(R^o)C(O)R^o、-N(R^o)N(R^o)C(O)NR^o ₂、-N(R^o)N(R^o)C(O)OR^o、–(CH₂)_0–4C(O)R^o、–C(S)R^o、–(CH₂)_0–4C(O)OR^o、–(CH₂)_0–4C(O)SR^o、-(CH₂)_0–4C(O)OSiR^o ₃、–(CH₂)_0–4OC(O)R^o、–OC(O)(CH₂)_0–4SR–、SC(S)SR^o、–(CH₂)_0–4SC(O)R^o、–(CH₂)_0–4C(O)NR^o ₂、–C(S)NR^o ₂、–C(S)SR^o、-(CH₂)_{0– 4}OC(O)NR^o ₂、-C(O)N(OR^o)R^o、–C(O)C(O)R^o、–C(O)CH₂C(O)R^o、–C(NOR^o)R^o、-(CH₂)_0–4SSR^o、–(CH₂)_0–4S(O)₂R^o、–(CH₂)_0–4S(O)₂OR^o、–(CH₂)_0–4OS(O)₂R^o、–S(O)₂NR^o ₂、-(CH₂)_0–4S(O)R^o、-N(R^o)S(O)₂NR^o ₂、–N(R^o)S(O)₂R^o、–N(OR^o)R^o、–C(NH)NR^o ₂、–P(O)₂R^o、-P(O)R^o ₂、-OP(O)R^o ₂、–OP(O)(OR^o)₂、SiR^o ₃、–(C_1–4Straight or branched alkylene) O-N (R)^o)₂Or is- (C)_1–4Straight or branched alkylene) C (O) O-N (R)^o)₂Wherein each R^oEach of which is substituted as defined below and is independently hydrogen, C_1-6Aliphatic, -CH₂Ph、-O(CH₂)_0–1Ph、-CH₂- (5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated, aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two independently occurring R, although as defined above^oAnd their central atoms together form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

R^oAs above appropriateMonovalent substituents (or two independently occurring R^oAnd the ring formed by the intermediate atoms thereof) are independently halogen, - (CH)₂)_0–2R^·- (halogenated R)^·)、–(CH₂)_0–2OH、–(CH₂)_0–2OR^·、–(CH₂)_0–2CH(OR^·)₂(ii) a -O (halo R)^·)、–CN、–N₃、–(CH₂)_0–2C(O)R^·、–(CH₂)_0–2C(O)OH、–(CH₂)_0–2C(O)OR^·、–(CH₂)_0–2SR^·、–(CH₂)_0–2SH、–(CH₂)_0–2NH₂、–(CH₂)_0–2NHR^·、–(CH₂)_0–2NR^· ₂、–NO₂、–SiR^· ₃、–OSiR^· ₃、-C(O)SR^·、–(C_1–4Straight OR branched alkylene) C (O) OR^·or-SSR^·Wherein each R is^·Unsubstituted, "halo" in the former case has only one or more halogens and is independently selected from C_1-4Aliphatic, -CH₂Ph、-O(CH₂)_0–1Ph or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. At R^oSuitable divalent substituents on the saturated carbon atom of (a) include ═ O and ═ S.

Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: is one of O, S and NNR^* ₂、＝NNHC(O)R^*、＝NNHC(O)OR^*、＝NNHS(O)₂R^*、＝NR^*、＝NOR^*、–O(C(R^* ₂))_2–3O-or-S (C (R)^* ₂))_2–3S-, wherein each independently occurs R^*Selected from hydrogen, C1-6 aliphatic (which may be substituted as defined below), or unsubstituted 5-6 membered saturated, partially unsaturated, aryl rings having 0-4 rings independently selected from nitrogen, oxygen orA heteroatom of sulfur. Suitable divalent substituents bonded to the carbon substitutable at the ortho position of the "optionally substituted" group include: -O (CR)^* ₂)_2–3O-, wherein each occurrence of R is independently selected from hydrogen, C1-6 aliphatic (which may be substituted as defined below) or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic radical of R include halogen, -R^·- (halogenated R)^·)、-OH、–OR^·-O (halo R)^·)、–CN、–C(O)OH、–C(O)OR^·、–NH₂、–NHR^·、–NR^· ₂or-NO₂Wherein each R is^·Unsubstituted or preceded by "halo" and is independently C_1-4Aliphatic radical, -CH₂Ph、-O(CH₂)_0–1Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the substitutable nitrogen of the "optionally substituted" group include

OrEach of whichIndependently hydrogen, C which may be substituted as defined below_1-6An aliphatic radical, unsubstituted-OPh or an unsubstituted 5-to 6-membered saturated, partially unsaturated or aryl ring, having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, despite the above definitions, two independently occurIs/are as follows

And one or more of its intermediate atoms together form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl mono-or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic radical of (A) are each halogen, -R^·- (halogenated R)^·)、–OH、–OR^·-O (halo R)^·)、–CN、–C(O)OH、–C(O)OR^·、–NH₂、–NHR^·、–NR^· ₂or-NO₂Wherein each R is^·Unsubstituted or preceded by "halo" and is independently C_1-4Aliphatic radical, -CH₂Ph、-O(CH₂)_0–1Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

The term "leaving group" refers to an atom (or group of atoms) with electron withdrawing capability that can be displaced along with the bonding electrons as a stable species. Examples of suitable leaving groups include halides and sulfonates, including but not limited to triflate, mesylate, tosylate and bromosulfonate.

The terms "hydrolyzable group" and "hydrolyzable moiety" refer to a functional group capable of undergoing hydrolysis, for example, under basic or acidic conditions. Examples of hydrolyzable residues include, but are not limited to, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, e.g., "protecting groups in organic synthesis", t.w. greene, p.g. m.wuts, willi-international scientific press, 1999).

The term "organic residue" is defined as a carbon-containing residue, i.e., a residue comprising at least one carbon atom, and includes, but is not limited to, carbon-containing groups, residues or groups as defined above. The organic residue may contain various heteroatoms or be bonded to another molecule through heteroatoms (including oxygen, nitrogen, sulfur, phosphorus, and the like). Examples of organic residues include, but are not limited to, alkyl or substituted alkyl, alkoxy or substituted alkoxy, mono or di-substituted amino, amido, and the like. The organic residue may preferably contain 1 to 18 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In another aspect, the organic residue can comprise 2 to 18 carbon atoms, 2 to 15 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A close synonym for the term "residue" is the term "group", as used in the specification and the appended claims, referring to a fragment, group or substructure of a molecule described herein, regardless of the manner in which the molecule is prepared. For example, the 2, 4-thiazolidinedione group in a particular compound has the following structure:

whether or not thiazolidinediones are used to prepare the compounds. In some embodiments, the (i.e., substituted alkyl) group may be further modified by bonding one or more "substituents" to the group (e.g., alkyl). The number of atoms in a given group is not critical to the invention unless indicated to the contrary elsewhere herein.

The term "organic group" as defined and used herein comprises one or more carbon atoms. The organic group can have, for example, 1 to 26 carbon atoms, 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In another aspect, the organic group can have 2 to 26 carbon atoms, 2 to 18 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. The organic group, which typically has hydrogen, is bonded to at least some of the carbon atoms of the organic group. An example of an organic group that does not contain inorganic atoms is 5,6,7, 8-tetrahydro-2-naphthyl. In some embodiments, the organic group may contain 1-10 inorganic heteroatoms bonded thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic groups include, but are not limited to, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, alkoxycarbonyl, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocycle, or substituted heterocycle, wherein the terms are defined elsewhere herein. Some non-limiting examples of organic groups that include heteroatoms include alkoxy groups, trifluoromethoxy groups, acetoxy groups, dimethylamino radicals, and the like.

The term "inorganic group" as defined and used herein does not contain carbon atoms and therefore only contains atoms other than carbon. The inorganic groups comprise a bonded combination of atoms selected from the group consisting of hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens (e.g., fluorine, chlorine, bromine, and iodine), which may be present alone or bonded together in chemically stable combinations thereof. The inorganic group has 10 or less, or preferably 1 to 6 or 1 to 4 of the above-listed inorganic atoms bonded together. Examples of inorganic groups include, but are not limited to, amino, hydroxyl, halogen, nitro, thiol, sulfate, phosphate, and similar generally known inorganic groups. The inorganic group does not have a metal element (e.g., alkali metal, alkaline earth metal, transition metal, lanthanide metal, or actinide metal) in the periodic table bonded therein, although for anionic inorganic groups, such as sulfate, phosphate, or similar anionic inorganic groups, such metal ions can sometimes be used as pharmaceutically acceptable cations. The inorganic group does not contain a metalloid element, such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or a noble gas element, unless otherwise specified elsewhere herein.

The compounds described herein may contain one or more double bonds, thus potentially producing cis/trans (E/Z) isomers as well as other conformational isomers. Unless stated to the contrary, the present invention includes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, chemical formulae having chemical bonds, shown only in solid lines and not in wedges or dashed lines, encompass each possible isomer, e.g., each enantiomer and diastereomer, as well as mixtures of isomers, e.g., racemic or non-equivalent enantiomeric mixtures (scalemic mixtures). The compounds described herein may contain one or more asymmetric centers, thus potentially giving rise to diastereomers and optical isomers. Unless indicated to the contrary, the present invention includes all such possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers thereof, and pharmaceutically acceptable salts thereof. Also included are isolated specific stereoisomers and mixtures of stereoisomers. The products of such procedures may be mixtures of stereoisomers during the synthetic procedures used to prepare such compounds, or during the use of racemic or epimeric procedures known to those skilled in the art.

Many organic compounds exist in optically active forms that are capable of rotating the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule about its chiral center. The prefixes d and l or (+) and (-) are used to denote the sign of the compound rotating plane polarized light, where (-) or l denotes that the compound is left-handed. Compounds with (+) or d prefixes are dextrorotatory. For a given chemical structure, these compounds (called stereoisomers) are identical except that they are mirror images that are not superimposable on each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein may have one or more chiral centers and thus may exist in different enantiomeric forms. If desired, the chiral carbons may be indicated by an asterisk. When the bond to a chiral carbon is depicted as a straight line in the disclosed formula, it is understood that the (R) and (S) configurations of the chiral carbon are included in the formula, thus enantiomers and mixtures thereof. As used in the art, when it is desired to specify an absolute configuration with respect to a chiral carbon, one of the bonds to the chiral carbon may be described as a wedge (bonding to an atom above a plane), while the other may be described as a series or wedge of short parallel lines (bonding to an atom below a plane). The Cahn-Ingold-Prelog system can be used to assign either the (R) or (S) configuration to a chiral carbon.

The compounds described herein contain atoms in both natural isotopic and unnatural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example each²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³⁵S、¹⁸F and³⁶and (4) Cl. It is within the scope of the present invention for the compound to further comprise a prodrug thereof, a pharmaceutically acceptable salt of said compound or of said prodrug, which comprises the aforementioned isotopes and/or other isotopes of other atoms. Certain isotopically-labelled compounds of the invention, for example those into which a radioactive isotope such as³H and¹⁴c, useful in drug and/or substrate tissue distribution assays. Tritiated i.e.³H and carbon 14 i¹⁴Isotopes of C are particularly preferred for their ease of preparation and detectability. Furthermore, with heavier isotopes such as deuterium, i.e.²H substitution may provide certain therapeutic advantages because of higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in certain circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the following procedure by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The compounds described in the present invention may exist as solvates. In some cases, the solvent used to prepare the solvate is an aqueous solution, and thus the solvate is often referred to as a hydrate. The compounds may exist in the form of hydrates, which may be obtained, for example, by crystallization from solvents or aqueous solutions. In this regard, one, two, three or any number of solvent or water molecules may be combined with the compounds according to the present invention to form solvates and hydrates. Unless stated to the contrary, the present invention includes all such possible solvates.

The term "co-crystal" refers to a physical association of two or more molecules that is stable due to non-covalent interactions. One or more components of the molecular complex provide a stable framework in the crystal lattice. In some cases, guest molecules are incorporated in the crystal lattice in the form of anhydrates or solvates, see, for example, "crystal engineering of the pharmaceutical phase composition. Is the drug co-crystal represent a new way to improve the drug? "(Crystal Engineering of the Composition of Pharmaceutical drugs. Do Pharmaceutical Co-crystals reproduction a New Path to improved Medicines. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

It is also understood that certain compounds described herein may exist in equilibrium form as tautomers. For example, ketones having an alpha-hydrogen can exist in equilibrium in the keto form and the enol form.

Also, amides with N hydrogens can exist in the equilibrium amide form and imide acid form. As another example, pyrazoles may exist in two tautomeric forms, as shown below, N¹Unsubstituted, 3-A³And N¹Unsubstituted, 5-A³。

Unless stated to the contrary, the present invention includes all such possible tautomers.

Chemical substances are known to form solids that exist in different ordered states, which are referred to as polymorphic forms or variants. Different variations of polymorphs can vary greatly in physical properties. The compounds according to the invention may exist in different polymorphic forms, wherein a particular variant may be metastable. Unless stated to the contrary, the present invention includes all such possible polymorphic forms.

In certain aspects, the structure of a compound can be represented by the following formula:

it is understood to be equivalent to the following formula:

where n is typically an integer. Namely, RⁿIs understood to represent five independent substituents, R^n(a)、R^n(b)、R^n(c)、R^n(d)、R^n(e). By "independent substituents" is meant that each R substituent can be independently defined. For example, if R is in one instance^n(a)Is halogen, then R in this example^n(b)Not necessarily halogen.

Certain materials, compounds, compositions, and components disclosed herein are commercially available or can be readily synthesized using techniques generally known to those skilled in the art. For example, starting materials and reagents for preparing the disclosed compounds and compositions are commercially available from commercial suppliers, such as aldrich chemical (milwaukee, wi), ancews organics (morris factory, n.j.), fisher science (pittsburgh, Pa.) or sigma (st louis, m.j.), or prepared by methods known to those skilled in the art according to procedures described in the references, such as organic synthesis reagents of fischer and fischer, volumes 1-17 (john william father, 1991); luode's carbon chemical, Vol.1-5 and supplementary Vol.1 (Evereier science publishers, 1989); organic reactions, volume 1-40 (john willi and son, 1991); advanced organic chemistry by marchi (john willi father-son, 4 th edition); and the integrated organic transformation of raloke (VCH Press, 1989).

Unless expressly stated otherwise, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Thus, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This applies to any possible non-expressive basis for interpretation, including: logic issues regarding step arrangements or operational flows; simple meaning from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

Disclosed are the components used to prepare the compositions of the present invention, as well as the compositions themselves used in the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed, and a number of modifications that can be made to a number of molecules that include the compound are discussed, each and every combination and permutation of the compound and the modifications that are possible are specifically contemplated unless specifically indicated otherwise. Thus, if a class of molecules A, B and C is disclosed as well as a class of molecules D, E and F and an example of a combination molecule a-D is disclosed, then even if each is not individually recited, each can be individually and collectively considered, meaning that the combinations a-E, A-F, B-D, B-E, B-F, C-D, C-E and C-F are considered disclosed. Also, any subset or combination of these is also disclosed. Thus, for example, the subgroups of A-E, B-F and C-E will be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the present invention. Thus, if there are a number of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the method of the present invention.

It is understood that the compositions disclosed herein have certain functions. Certain structural requirements for performing the disclosed functions are disclosed herein, and it should be understood that there are a variety of structures that can perform the same functions related to the disclosed structures, and that these structures will typically achieve the same results.

B. Compound (I)

In one aspect, compounds useful for treating or preventing diseases associated with PanK activity, such as PKAN and diabetes, are disclosed. In another aspect, the disclosed compounds exhibit modulation of PanK activity. In another aspect, the disclosed compounds exhibit inhibition of PanK activity. In another aspect, the disclosed compounds exhibit activation of PanK activity.

In one aspect, as further described herein, the compounds of the invention are useful for treating or preventing diseases associated with PanK dysfunction and other diseases in which altered levels of PanK or CoA and CoA esters are involved.

It is contemplated that each of the disclosed derivatives may be optionally further substituted. It is also contemplated that any one or more derivatives may optionally be omitted from the present invention. It is understood that the disclosed compounds can be provided by the disclosed methods. It is also understood that the disclosed compounds can be used in the disclosed methods of use.

1. Structure of the product

In one aspect, compounds having a structure represented by the formula:

wherein Q²Is a structure selected from:

wherein R is^3a、R^3bAnd R^3cEach independently selected from: hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, with the proviso that R^3a、R^3bAnd R^3cAt least one is halogen; and wherein R⁴Selected from: hydrogen, halogen, -CN, SO₂NH₂、SO₂CH₃、SO₂CF₃And NO₂，

Or a pharmaceutically acceptable salt thereof.

In one aspect, compounds having a structure represented by the formula:

wherein A is selected from: o, CO, CH₂、CF₂、NH、N(CH₃) And CH (OH); wherein R is^3a、R^3bAnd R^3cEach independently selected from: hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, with the proviso that R^3a、R^3bAnd R^3cAt least one is halogen; and wherein R⁴Selected from: hydrogen, halogen, -CN, SO₂NH₂、SO₂CH₃、SO₂CF₃And NO₂，

Or a pharmaceutically acceptable salt thereof.

In another aspect, the compound has a structure represented by the formula:

in another aspect, the compound is selected from:

in another aspect, the compound is selected from:

in another aspect, the compound is selected from:

a.A radical

In one aspect, a is selected from: o, CO, CH₂、CF₂、NH、N(CH₃) And CH (OH). In one aspect, a is selected from: o, CO, CH₂、CF₂NH and CH (OH). In one aspect, is O, CO, CH₂、CF₂、N(CH₃) And CH (OH). In one aspect, a is selected from: o, CO, CH₂、CF₂And CH (OH).

In another aspect, a is selected from: o, CO, CH₂And CF₂. In yet another aspect, a is selected from: o, CO and CH₂. In yet another aspect, a is selected from: o and CO. In a further aspect, a is O. In yet another aspect, a is CO. In yet another aspect, A is CH₂. In a further aspect, A is CF₂。

In another aspect, a is selected from: NH and N (CH)₃). In yet another aspect, a is NH. In yet another aspect, A is N (CH)₃)。

In another aspect, a is selected from: NH and CH₂。

In another aspect, a is ch (oh).

b.Q²Radical (I)

In one aspect, Q²Is a structure selected from:

in one aspect, Q²Is a structure selected from:

in another aspect, Q²Is a structure selected from:

in yet another aspect, Q²Comprises the following steps:

in yet another aspect, Q²Is a structure selected from:

in a further aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in another aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in a further aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in a further aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in a further aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in another aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in a further aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in a further aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in a further aspect, Q²Is selected from the followingThe structure is as follows:

in yet another aspect, Q²Is a structure selected from:

in yet another aspect, Q²Is a structure selected from:

in another aspect, Q²The structure is as follows:

c.R^3a、R^3band R^3cRadical (I)

In one aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, with the proviso that R^3a、R^3bAnd R^3cAt least one is halogen. In another aspect, R^3bAnd R^3cEach is hydrogen. In yet another aspect, R^3aAnd R^3cEach is hydrogen. In yet another aspect, R^3aAnd R^3bEach is hydrogen.

In another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and s-butyl. In yet another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl and i-propyl. In yet another aspect, R^3a、R^3bAnd R^3cEach is independently selected from: hydrogen, -F, -Cl,-Br, methyl and ethyl. In a further aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen, -F, -Cl, -Br and methyl.

In another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, i-propyl, -OCH₃、–OCH₂CH₃、–O(CH₂)₂CH₃and-OCH (CH)₃)₂. In yet another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen, -F, -Cl, -Br, methyl, ethyl, -OCH₃and-OCH₂CH₃. In yet another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen, -F, -Cl, -Br, methyl and-OCH₃。

In another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen and C1-C4 alkyl. In yet another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen, methyl, ethyl, n-propyl and i-propyl. In yet another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen, methyl and ethyl. In a further aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen and ethyl. In yet another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen and methyl.

In another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen, -F, -Cl and-Br. In yet another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen, -F and-Cl. In yet another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen and-I. In a further aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen and-Br. In yet another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen and-Cl. In yet another aspect, R^3a、R^3bAnd R^3cEach independently selected from: hydrogen and-F.

In another aspect, R^3aIs halogen. In yet another aspect, R^3aSelected from: -F, -Cl and-Br. In yet another aspect, R^3ais-F.

In another aspect, R^3aIs halogen and R^3bAnd R^3cEach is hydrogen. In yet another aspect, R^3aSelected from: -F, -Cl and-Br and R^3bAnd R^3cEach is hydrogen. In yet another aspect, R^3ais-F and R^3bAnd R^3cEach is hydrogen.

In another aspect, R^3bIs halogen. In yet another aspect, R^3bSelected from: -F, -Cl and-Br. In yet another aspect, R^3bis-F.

In another aspect, R^3bIs halogen and R^3aAnd R^3cEach is hydrogen. In yet another aspect, R^3bSelected from: -F, -Cl and-Br and R^3aAnd R^3cEach is hydrogen. In yet another aspect, R^3bis-F and R^3aAnd R^3cEach is hydrogen.

In another aspect, R^3cIs halogen. In yet another aspect, R^3cSelected from: -F, -Cl and-Br. In yet another aspect, R^3cis-F.

In another aspect, R^3cIs halogen and R^3aAnd R^3bEach is hydrogen. In yet another aspect, R^3cSelected from: -F, -Cl and-Br and R^3aAnd R^3bEach is hydrogen. In yet another aspect, R^3cis-F and R^3aAnd R^3bEach is hydrogen.

d.R⁴Radical (I)

In one aspect, R⁴Selected from: hydrogen, halogen, -CN, SO₂NH₂、SO₂CH₃、SO₂CF₃And NO₂. In another aspect, R⁴Is hydrogen.

In another aspect, R⁴Selected from: -CN, SO₂NH₂、SO₂CH₃、SO₂CF₃And NO₂. In yet another aspect, R⁴Selected from: -CN, SO₂NH₂、SO₂CH₃And SO₂CF₃. In yet another aspect, R⁴Selected from: -CN, SO₂NH₂And SO₂CH₃. In a further aspect, R⁴Selected from: -CN and SO₂NH₂. In yet another aspect, R⁴Is NO₂. In yet another aspect, R⁴Is SO₂CF₃. In a further aspect, R⁴Is SO₂CH₃. In yet another aspect, R⁴Is SO₂NH₂. In yet another aspect, R⁴is-CN.

In another aspect, R⁴Selected from: hydrogen and halogen. In yet another aspect, R⁴Selected from: hydrogen, -F, -Cl and-Br. In yet another aspect, R⁴Selected from: hydrogen, -F and-Cl. In a further aspect, R⁴Selected from: hydrogen and-I. In yet another aspect, R⁴Selected from: hydrogen and-Br. In yet another aspect, R⁴Selected from: hydrogen and-Cl. In a further aspect, R⁴Selected from: hydrogen and-F.

In another aspect, R⁴Is halogen. In yet another aspect, R⁴Selected from: -F, -Cl and-Br. In yet another aspect, R⁴Selected from: -F and-Cl. In a further aspect, R⁴is-I. In yet another aspect, R⁴is-Br. In yet another aspect, R⁴is-Cl. In a further aspect, R⁴is-F.

2. EXAMPLES Compounds

In one aspect, the compound may exist in one or more of the following structures:

or a pharmaceutically acceptable salt thereof.

In another aspect, the compound may exist in one or more of the following structures:

or a pharmaceutically acceptable salt thereof.

3. Prophetic compounds

The following compound examples are prophetic and may be prepared using the synthetic methods described herein above and other general methods as needed known to those skilled in the art. It is expected that the compounds will be predicted to have activity as PanK antagonists, and this activity can be determined using the assay methods described herein.

In one aspect, the compound may be selected from:

or a pharmaceutically acceptable derivative thereof.

C. Process for preparing compounds

The compounds of the invention can be prepared by reactions shown in the following schemes, in addition to other standard procedures known in the literature, exemplified in the experimental section or clear to those skilled in the art. For clarity, embodiments having a single substituent are shown, where multiple substituents are allowed according to the definitions disclosed herein.

The reactions used to produce the compounds of the present invention are prepared by employing the reactions shown in the following reaction schemes, as described and exemplified below. In certain embodiments, the disclosed compounds may be prepared by schemes I-VI, as described and exemplified below. The following examples are provided so that the invention may be more fully understood, are illustrative only, and should not be construed as limiting 1. route I

In one aspect, substituted PanK small molecule modulators can be prepared as shown below.

Scheme 1A.

The compounds are represented in general form, with substituents, as described in the description of the compounds elsewhere herein; wherein X is halogen. More specific examples are given below.

Scheme 1B.

In one aspect, compounds of type 1.7 and similar compounds can be prepared according to reaction scheme 1B above. Thus, compounds of type 1.7 are commercially available or may be prepared by arylation of a suitable amine, for example 1.1 as shown above, with a suitable aryl halide, for example 1.6 as shown above. Suitable amines and suitable aryl halides are commercially available or prepared by methods known to those skilled in the art. The arylation reaction is carried out in the presence of a suitable base such as Triethylamine (TEA) in a suitable solvent such as acetonitrile at a suitable temperature such as 160 ℃ for a suitable time, for example using microwave irradiation for 30 minutes. The arylation reaction is followed by deprotection. The deprotection is carried out in the presence of a suitable deprotection agent, such as trifluoroacetic acid (TFA), in a suitable solvent, such as dichloromethane, for a suitable time, such as 1 hour. As will be appreciated by those skilled in the art, the above reactions provide an example of a general approach in which compounds similar in structure to the specific reactants described above (compounds analogous to compounds of types 1.1 and 1.2) may be substituted in the reactions to provide substituted PanK small molecule modulators analogous to formula 1.3.

2. Route II

In one aspect, substituted PanK small molecule modulators can be prepared as shown below.

Scheme 2A.

The compounds are represented in general form, having substituents as described in the description of the compounds elsewhere herein, and wherein a is selected from: CH (CH)₂、CF₂And CH (OH). More specific examples are given below.

Scheme 2B.

In one aspect, compounds of type 2.6 and similar compounds can be prepared according to reaction scheme 2B above. Thus, compounds of type 2.6 may be prepared by coupling reaction of a suitable carboxylic acid, for example 2.4 as shown above, with a suitable amine, for example 2.5 as shown above. Suitable carboxylic acids and suitable amines are commercially available or prepared by methods known to those skilled in the art. The coupling reaction is carried out in the presence of a suitable coupling agent, such as 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxidohexafluorophosphate (HATU), and a suitable base, such as Diisobutylethylamine (DIPEA), in a suitable solvent, such as dichloromethane. As will be appreciated by those skilled in the art, the above reactions provide an example of a general approach in which compounds similar in structure to the specific reactants described above (compounds analogous to compounds of types 2.1 and 2.2) may be substituted in the reactions to provide substituted PanK small molecule modulators analogous to formula 2.3.

3. Route III

In one aspect, substituted PanK small molecule modulators can be prepared as shown below.

Scheme 3A.

The compounds are represented in general form, with substituents as described in the description of the compounds elsewhere herein, and wherein X is halogen. More specific examples are given below.

Scheme 3B.

In one aspect, compounds of type 3.12 and similar compounds can be prepared according to reaction scheme 3B above. Thus, compounds of type 3.2 can be prepared by coupling reactions of the appropriate amine, for example 3.1 as shown above. Suitable amines are commercially available or prepared by methods known to those skilled in the art. The coupling reaction is carried out in the presence of a suitable coupling agent, such as N, N-Carbonyldiimidazole (CDI), in a suitable solvent, such as dichloromethane. Compounds of type 3.9 may be prepared by reacting a suitable activated urea, for example 3.2, with a suitable phenol, for example 3.8 as indicated above. Suitable phenols are commercially available or prepared by methods known to those skilled in the art. The reaction is carried out in the presence of a suitable base such as triethylamine and cesium carbonate in a suitable solvent such as acetonitrile at a suitable temperature such as 70 ℃ for a suitable time such as 3-4 hours or overnight. The compound of type 3.10 can be prepared by deprotection of the appropriate piperazine, e.g. 3.9 as shown above. The deprotection reaction is carried out in the presence of a suitable deprotection agent, such as trifluoroacetic acid, and a suitable solvent, such as dichloromethane, for a suitable time, such as 2 hours. Compounds of type 3.12 may be prepared by arylation of a suitable amine, for example 3.10 as shown above, with a suitable aryl halide, for example 3.11 as shown above. Suitable aryl halides are commercially available or can be prepared by methods known to those skilled in the art. The arylation reaction is carried out in the presence of a suitable base such as triethylamine and a suitable solvent such as acetonitrile at a suitable temperature such as 160 ℃ for a suitable time such as 30 minutes using microwave irradiation. As will be appreciated by those skilled in the art, the above reactions provide an example of a general approach in which compounds similar in structure to the specific reactants described above (compounds similar to compounds of types 3.1, 3.2, 3.3, 3.4, 3.5 and 3.6) can be substituted in the reactions to provide substituted small molecule modulators of PanK similar to formula 3.7.

4. Route IV

In one aspect, substituted PanK small molecule modulators can be prepared as shown below.

Scheme 4A.

The compounds are represented in general form, with substituents as described in the description of the compounds elsewhere herein, and wherein X is halogen. More specific examples are given below.

Scheme 4B.

In one aspect, compounds of type 4.8 and similar compounds can be prepared according to reaction scheme 4B above. Thus, compounds of type 4.6 can be prepared by a urea bond forming reaction between a suitable amine, such as 4.2 as shown above, and a suitable isocyanate, such as 4.5 as shown above. Suitable amines and suitable isocyanates are commercially available or can be prepared by methods known to those skilled in the art. The nucleophilic substitution is carried out in the presence of a suitable solvent, such as diethyl ether, for a suitable time, such as 3 hours. Nucleophilic substitution is followed by deprotection reaction. The deprotection reaction is carried out in the presence of a suitable deprotection agent, such as trifluoroacetic acid, in a suitable solvent, such as dichloromethane, for a suitable time, such as 1 hour. Compounds of type 4.8 may be prepared by arylation of a suitable amine, for example 4.6 as shown above, with a suitable aryl halide, for example 4.7 above. Suitable aryl halides are commercially available or can be prepared by methods known to those skilled in the art. The arylation reaction is carried out using microwave radiation in the presence of a suitable base such as triethylamine in a suitable solvent such as acetonitrile at a suitable temperature such as 160 ℃ for a suitable time such as 30 minutes. As will be appreciated by those skilled in the art, the above reactions provide an example of a general method in which compounds similar in structure to the specific reactants described above (analogous to 3.6, 4.1, 4.2, and

4.3 type compounds) can be substituted in a reaction to provide 4-aryl-N-phenylpiperazine-1-carboxamide derivatives similar to formula 4.4.

5. Route V

In one aspect, substituted PanK small molecule modulators can be prepared as shown below.

Scheme 5A.

The compounds are represented in general form, with substituents as described in the description of the compounds elsewhere herein, and wherein X is halogen. More specific examples are given below.

Scheme 5B.

In one aspect, compounds of type 5.6 and similar compounds can be prepared according to reaction scheme 5B above. Thus, compounds of type 5.5 may be prepared by a coupling reaction of a suitable amine, for example 4.2 as shown above, and a suitable carboxylic acid, for example 5.4 as shown above. Suitable amines and suitable carboxylic acids are commercially available or can be prepared by methods known to those skilled in the art. The coupling reaction is carried out in the presence of a suitable coupling agent, such as HATU, and a suitable base, such as DIPEA, in a suitable solvent, such as dichloromethane. The coupling reaction is followed by a deprotection reaction. The deprotection reaction is carried out in the presence of a suitable deprotection agent, such as trifluoroacetic acid, in a suitable solvent, such as dichloromethane, for a suitable time, such as 1 hour. Compounds of type 5.6 may be prepared by arylation of a suitable amine, for example 5.5, with a suitable aryl halide, for example 3.11 as shown above. Suitable aryl halides are commercially available or can be prepared by methods known to those skilled in the art. The arylation reaction is carried out using microwave radiation in the presence of a suitable base such as triethylamine in a suitable solvent such as acetonitrile at a suitable temperature such as 160 ℃ for a suitable time such as 30 minutes. As will be appreciated by those skilled in the art, the above reactions provide an example of a general approach in which compounds similar in structure to the specific reactants described above (compounds similar to compounds of types 3.6, 4.2, 5.1, and 5.2) may be substituted in the reactions to provide substituted small molecule modulators of PanK similar to formula 5.3.

It is contemplated that each disclosed method may further comprise additional steps, operations, and/or components. It is also contemplated that any one or more steps, operations, and/or components may optionally be omitted from the present invention. It is to be understood that the disclosed methods can be used to provide the disclosed compounds. It is also understood that the products of the disclosed methods can be used in the disclosed methods of use.

D. Pharmaceutical composition

In one aspect, a pharmaceutical composition comprising the disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier is disclosed.

In various aspects, the compounds and compositions of the present invention may be administered in the form of pharmaceutical compositions formulated according to the intended method of administration. The compounds and compositions described herein may be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, the pharmaceutical composition may be formulated for local or systemic administration, e.g., by instillation or injection into the ear, insufflation (e.g., into the ear), intravenous, topical, or oral administration.

The nature of the pharmaceutical composition for administration depends on the mode of administration and can be readily determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. Therapeutic compositions featuring the present invention may comprise carriers or excipients, many of which are known to those skilled in the art. Excipients that may be used include buffers (e.g., citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (e.g., serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. Nucleic acids, polypeptides, small molecules and other regulatory compounds that are features of the invention can be administered by any standard route of administration. For example, parenteral, intravenous, subcutaneous or oral administration may be employed. The modulating compounds may be formulated in various ways depending on the respective route of administration. For example, the liquid solution may be administered by instillation into the ear, injection or ingestion. Can be made into gel or powder for ingestion or topical application. Methods of preparing such formulations are well known and may be found, for example, in Remington pharmaceutical sciences, 18 th edition, edited by Gennaro, Mark publishing Co., Iston, Pa., 1990.

In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The compositions of the invention include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the conditions of the active ingredient being administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

In various aspects, the pharmaceutical compositions of the invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of a compound of the invention. The compounds of the present invention or pharmaceutically acceptable salts thereof may also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier used may be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenient pharmaceutical medium may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions. And carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units wherein solid pharmaceutical carriers are employed. Alternatively, the tablets may be coated by standard aqueous or non-aqueous techniques.

Tablets containing the composition of the invention may be prepared by compression or molding, optionally together with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the invention comprise a compound of the invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally one or more other therapeutic agents or adjuvants. The compositions of the invention include compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend on the particular host, the nature and severity of the conditions of the active ingredient being administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

Pharmaceutical compositions of the invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compound in water. Suitable surfactants, such as hydroxypropyl cellulose, may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. In addition, preservatives may be included to prevent the unwanted growth of microorganisms.

Pharmaceutical compositions of the invention suitable for injectable use include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must flow effectively for ease of injection. The pharmaceutical compositions must be stable under the conditions of manufacture and storage. Therefore, it is preferable to preserve it against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions of the present invention may be in a form suitable for topical use, for example, aerosols, creams, ointments, lotions, dusting powders, mouthwashes, gargles, and the like. In addition, the composition may be in a form suitable for use in a transdermal device. These formulations may be prepared by conventional processing methods using the compounds of the present invention or pharmaceutically acceptable salts thereof. For example, a cream or ointment is prepared by mixing a hydrophilic material and water, and about 5 wt% to about 10 wt% of the compound, to prepare a cream or ointment having a desired consistency.

The pharmaceutical compositions of the present invention may be in a form suitable for rectal administration wherein the carrier is a solid. Preferably the mixture is formed into unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories may conveniently be formed by first mixing the composition with the softened or molten carrier, followed by cooling and shaping in a mould.

In addition to the above-mentioned carrier ingredients, the above-mentioned pharmaceutical preparations may also include one or more other carrier ingredients, as appropriate, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants and the like), and the like. In addition, other adjuvants may be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing the compounds of the present invention and/or pharmaceutically acceptable salts thereof may also be prepared in the form of a powder or liquid concentrate.

In another aspect, the effective amount is a therapeutically effective amount. In another aspect, the effective amount is a prophylactically effective amount.

In another aspect, the pharmaceutical composition is administered to a mammal. In another aspect, the mammal is a human. In a further aspect, the human is a patient.

In another aspect, the pharmaceutical composition is for treating a disease associated with pantothenate kinase activity, such as PKAN and diabetes.

It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be used in the disclosed methods of use.

E. Methods of treating diseases associated with PanK activity

In various aspects, the compounds and compositions disclosed herein are useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of diseases associated with pantothenate kinase activity, including, for example, PKAN, aging, and diabetes. Thus, in one aspect, methods of treating a disease associated with pantothenate kinase activity in a subject are disclosed, the methods comprising administering to the subject an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

In various aspects, the disclosed compounds can be used in combination with one or more other drugs to treat, prevent, control, ameliorate, or reduce the risk of a disease associated with PanK activity, where the disclosed compounds or other drugs can be used wherein the drugs in combination are safer or more effective than either drug alone. These other drugs may be administered simultaneously with the compounds of the present invention or sequentially by the routes and amounts generally used therefor. When the compounds of the present invention are used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the disclosed compounds is preferred. However, combination therapy may also include therapies in which the disclosed compound and one or more other drugs are administered on different overlapping schedules. It is also contemplated that the disclosed compounds and other active ingredients, when used in combination with one or more other active ingredients, may be used in lower doses than when each is used alone.

Accordingly, in addition to the compounds of the present invention, pharmaceutical compositions also include those comprising one or more other active ingredients.

In another aspect, the compound exhibits inhibition of PanK activity. In another aspect, the compound exhibits reduced PanK activity.

In another aspect, the compounds exhibit inhibition of panK activity, IC₅₀From about 0.001 μ M to about 25 μ M. In another aspect, the compounds exhibit inhibition of panK activity, IC₅₀From about 0.001 μ M to about 15 μ M. In another aspect, the compounds exhibit inhibition of panK activity, IC₅₀From about 0.001 μ M to about 10 μ M. In another aspect, the compounds exhibit inhibition of PanK activity, IC₅₀From about 0.001 μ M to about 5 μ M. In another aspect, the compounds exhibit inhibition of panK activity, IC₅₀From about 0.001. mu.M to about 1. mu.M. In another aspect, the compounds exhibit inhibition of panK activity, IC₅₀From about 0.001 μ M to about 0.5 μ M. In another aspect, the compounds exhibit inhibition of PanK activity, IC₅₀From about 0.001 μ M to about 0.1 μ M. In another aspect, the compounds exhibit inhibition of panK activity, IC₅₀From about 0.001 μ M to about 0.05 μ M. In another aspect, the compounds exhibit inhibition of panK activity, IC₅₀From about 0.001. mu.M to about 0.01. mu.M. In another aspect, the compounds exhibit inhibition of PanK activity, IC₅₀From about 0.001. mu.M to about 0.005. mu.M. In another aspect, the compounds exhibit inhibition of panK activity, IC₅₀From about 0.005 μ M to about 25 μ M. In another aspect, the compounds exhibit inhibition of panK activity, IC₅₀From about 0.01. mu.M to about 25. mu.M. In another aspect, the compounds exhibit inhibition of PanK activity, IC₅₀From about 0.05 μ M to about 25 μ M. In another aspect, the compounds exhibit inhibition of panK activity, IC₅₀From about 0.1 μ M to about 25 μ M. In another aspect, the compounds exhibit inhibition of PanK activity，IC₅₀From about 0.5 μ M to about 25 μ M. In another aspect, the compounds exhibit inhibition of PanK activity, IC₅₀From about 1 μ M to about 25 μ M. In another aspect, the compounds exhibit inhibition of panK activity, IC₅₀From about 5 μ M to about 25 μ M. In another aspect, the compounds exhibit inhibition of panK activity, IC₅₀From about 10 μ M to about 25 μ M. In another aspect, the compounds exhibit inhibition of PanK activity, IC₅₀From about 15 μ M to about 25 μ M.

In another aspect, the subject is a mammal. In another aspect, the mammal is a human.

In another aspect, prior to the administering step, the subject has been diagnosed as in need of treatment for the disease. In another aspect, the subject is at risk of developing a disease prior to the administering step.

In another aspect, the method further comprises identifying a subject at risk of developing a disease prior to the administering step.

F. Method for modulating at least one intracellular PanK activity

In one aspect, a method of modulating pantothenate kinase activity in at least one cell is disclosed, the method comprising the step of contacting the at least one cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In another aspect, the modulation is inhibition.

In another aspect, the cell is mammalian. In another aspect, the cell is human. In another aspect, the cells have been isolated from the mammal prior to the contacting step.

In another aspect, the contacting is by administering to the mammal.

G. Methods of using the compositions

Methods of using the disclosed compositions or medicaments are provided. In one aspect, the method of use relates to the treatment of a disease. In another aspect, the disclosed compounds may be used as single agents or in combination with one or more other drugs for which utility is found in the treatment, prevention, control, amelioration, or reduction of risk of the aforementioned diseases, disorders, and conditions, wherein the drugs are combined together to be safer or more effective than either drug alone. The other drug or drugs can be administered, either simultaneously or sequentially with the disclosed compounds, by the routes and amounts commonly used. When the disclosed compounds are used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing the drug and the disclosed compounds is preferred. However, the combination therapy may also be performed on an overlapping schedule. It is also envisioned that combinations of one or more active ingredients and the disclosed compounds are more effective than any one as a single agent.

The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds as described herein, which are typically used to treat the pathological conditions described above.

1. Preparation of a medicament

In one aspect, the invention relates to a method for preparing a medicament for treating a condition associated with PanK dysfunction in a mammal, the method comprising combining a therapeutically effective amount of a disclosed compound or a product of a disclosed method with a pharmaceutically acceptable combination carrier or diluent.

For these uses, the method comprises administering to an animal, particularly a mammal, more particularly a human, a therapeutically effective amount of a compound having inhibitory effect on proteins, particularly PanK. In the context of the present invention, the dose administered to an animal, particularly a human, should be sufficient to affect the therapeutic response of the animal within a reasonable time. One skilled in the art will recognize that the dosage will depend on a variety of factors, including the condition of the animal, the weight of the animal, and the severity and stage of the disease.

Thus, in one aspect, the invention relates to the manufacture of a medicament comprising admixing a disclosed compound or product of a disclosed manufacturing process, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.

2. Use of Compounds and compositions

Uses of the disclosed compounds and compositions are also provided. Thus, in one aspect, the invention relates to the use of a modulator of PanK.

In another aspect, the invention relates to the use of a disclosed compound or a product of a disclosed method for the manufacture of a medicament for treating diseases associated with PanK activity and levels of coenzyme a, such as PKAN and diabetes.

In another aspect, the use relates to a method for preparing a pharmaceutical composition for use as a medicament, comprising a therapeutically effective amount of the disclosed compound or a product of the disclosed method and a pharmaceutically acceptable carrier.

In another aspect, the use relates to a method of making a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a disclosed compound or a product of a disclosed method.

In various aspects, the use relates to treating PKAN in a vertebrate. In another aspect, the use relates to treating PKAN in a human subject.

In another aspect, the use is in the treatment of diabetes. In another aspect, the diabetes is type II diabetes.

It is to be understood that the disclosed uses can be used in conjunction with the disclosed compounds, methods, compositions, and kits. In another aspect, the invention relates to the use of the disclosed compounds or pharmaceutical compositions in the treatment of diseases associated with PanK activity in a mammal.

In another aspect, the invention relates to the use of a disclosed compound or composition in the manufacture of a medicament for treating a disorder associated with PanK activity selected from PKAN and diabetes.

3. Reagent kit

In one aspect, a kit is disclosed comprising a disclosed compound and one or more of: (a) at least one agent known to treat PKAN; (b) at least one agent known to treat diabetes; (c) instructions for treating PKAN; (d) indications for the treatment of diabetes, metabolic syndrome and/or aging side effects.

In various aspects, the agents and pharmaceutical compositions described herein may be provided in kits. The kit may also include a combination of the agents and pharmaceutical compositions described herein.

In various aspects, the informational material may be descriptive, instructive, marketing, or other material related to the methods described herein and/or related to the use of an agent in the methods described herein. For example, the information material can relate to the use of an agent herein in treating a subject having or at risk of developing a disease associated with PanK activity. The kit may further comprise means for administering the agent of the invention to cells (in culture or in vivo) and/or for administering cells to a patient.

In various aspects, the informational material may include instructions for administering the pharmaceutical composition and/or the cell for treating a human in a suitable manner, e.g., in a suitable dose, dosage form, or administration (e.g., a dose, dosage form, or administration described herein). In another aspect, the informational material can include instructions for administering the pharmaceutical composition to a suitable subject, e.g., a human having or at risk of developing a disease associated with PanK activity.

In various aspects, the composition of the kit can include other ingredients, such as solvents or buffers, stabilizers, preservatives, fragrances, or other cosmetic ingredients. In these aspects, the kit can include instructions for mixing the reagents and other ingredients or for using one or more compounds with other ingredients.

In another aspect, the compound is co-formulated with at least one agent known to treat PKAN. In another aspect, the compound is co-packaged with at least one agent known to treat PKAN.

In another aspect, the compound is co-formulated with at least one agent known for the treatment of diabetes. In another aspect, the compound is co-packaged with at least one agent known for the treatment of diabetes.

In another aspect, the at least one agent known to treat PKAN is selected from: baclofen, trihexyphenidyl, botulinum toxin and iron chelators. In yet another aspect, the iron chelator is deferiprone.

In another aspect, the kit further comprises a plurality of dosage forms comprising one or more doses; wherein each dose comprises an effective amount of the compound and at least one agent known to treat PKAN. In another aspect, the effective amount is a therapeutically effective amount. In another aspect, the effective amount is a prophylactically effective amount. In another aspect, each dose of the compound is co-packaged with at least one agent known to treat PKAN. In another aspect, each dose of the compound is co-formulated with at least one agent known to treat PKAN.

In another aspect, the at least one agent known for the treatment of diabetes is selected from: insulin, abiglutide, exenatide, liraglutide, pramlintide, dulaglutide, acarbose, alogliptin, bromocriptine mesylate, canagliflozin, chloropropionamide, colesevelam, dapagliflozin, ipagliflozin, glimepiride, glipizide, linagliptin, metformin, miglitol, nateglinide, pioglitazone, repaglinide, rosiglitazone, saxagliptin, and sitagliptin.

In another aspect, the kit further comprises a plurality of dosage forms comprising one or more doses; wherein each dose comprises an effective amount of the compound and at least one agent known to treat diabetes. In another aspect, the effective amount is a therapeutically effective amount. In another aspect, the effective amount is a prophylactically effective amount. In another aspect, each dose of the compound is co-packaged with at least one agent known to treat diabetes. In yet another aspect, each dose of the compound is co-formulated with at least one agent known to treat diabetes.

4. Test subject

In various aspects, the subject of the methods disclosed herein is a vertebrate, e.g., a mammal. Thus, the subject of the methods disclosed herein can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or gender. Thus, it is intended to cover adult and newborn subjects as well as fetuses, whether male or female. A patient refers to a subject suffering from a disease or disorder. The term "patient" includes both human and veterinary subjects.

In some aspects of the disclosed methods, the subject has been diagnosed as in need of treatment prior to the administering step. In some aspects of the disclosed methods, prior to the administering step, the subject has been diagnosed with a disorder associated with PanK activity. In some aspects of the disclosed methods, the subject has been identified in need of treatment prior to the administering step. In one aspect, a subject can be treated prophylactically with a compound or composition disclosed herein, as discussed elsewhere herein.

a. Dosage form

Toxicity and therapeutic efficacy of the agents and pharmaceutical compositions described herein can be determined by standard pharmaceutical procedures, and LD can be determined using cells in culture or cells of experimental animals₅₀(lethal dose in 50% of the population) and ED₅₀(effective therapeutic dose in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD₅₀/ED₅₀. Polypeptides or other compounds with a large therapeutic index are preferred.

Data obtained from cell culture assays and further animal studies can be used to formulate a range of dosage for use in humans. The dosage of such compounds is preferably such that ED is included₅₀Has little or no toxicity and has little or no adverse effect on human hearing ability. The dosage may vary within this range depending upon the dosage form employed and the route of administration employed. For any agent used in the methods described herein, a therapeutically effective dose can first be estimated from cell culture assays. The dosage can be formulated in animal models to achieve IC including determination in cell culture₅₀(i.e., the concentration of test compound that achieves half-maximal inhibition of symptoms). Such information can be used to more accurately determine useful dosages for humans. Exemplary doses of a differentiating agent are at least about 0.01 to 3000mg per day, for example at least about 0.00001, 0.0001, 0.001, 0.01, 0.1, 1,2,5, 10, 25, 50, 100, 200, 500, 1000, 2000, or 3000mg or more per kg per day.

The formulation and route of administration can be tailored to the disease or condition being treated as well as to the particular person being treated. For example, a subject may receive a dose of the agent once or twice or more daily for a period of one week, one month, six months, one year, or more. The treatment may be continued indefinitely, for example throughout a lifetime of the human. Treatment may be carried out periodically or aperiodically (every other day or twice a week), and the dosage and timing of administration may be adjusted throughout the treatment. The dosage may remain constant during the course of the treatment regimen, or may decrease or increase during the course of treatment.

In various aspects, the dosage promotes the intended purpose of prophylaxis and therapy without adverse side effects, such as toxicity, irritation, or allergic response. While individual requirements may vary, it is within the skill of the art to determine the optimal range of an effective amount of a formulation. Human doses can be readily inferred from animal studies (Katocs et al, (1990) Remington's pharmaceutical sciences, 18 th edition, Gennaro's eds., Mark Press, Chapter 27 in Iston, Pa.). In general, the required dosage to provide an effective amount of the formulation will be adjusted by one of skill in the art and will depend on several factors, including age, health, physical condition, body weight, the subject's disease or type and extent of disease, the frequency of treatment, the nature of concurrent treatment if necessary, and the nature and extent of the effect desired (Nies et al, (1996), see: Goodman and Gilman's pharmacological basis, 9 th edition, edited by Hardman et al, McGraw-Hill, New York, N.Y., Chapter 3).

b. Route of administration

Also provided are routes of administration for the disclosed compounds and compositions. The compounds and compositions of the present invention may be administered by direct therapy using systemic and/or topical administration. In various aspects, the route of administration can be determined by the patient's health care provider or clinician, for example, after the patient is evaluated. In various aspects, the therapy of an individual patient may be customized, for example, the type of agent used, route of administration, and frequency of administration may be personalized. Alternatively, treatment may be carried out using standard therapeutic procedures, e.g., using a preselected agent and a preselected route and frequency of administration.

Systemic routes of administration may include, but are not limited to, parenteral routes of administration, such as intravenous, intramuscular, and intraperitoneal injection; enteral routes of administration, such as oral, lozenge, compressed tablet, pill, tablet, capsule, drop (e.g. ear drop), syrup, suspension and emulsion; rectal administration, e.g., rectal suppositories or enemas; vaginal suppositories; urethral suppositories; the transdermal route of administration; and inhalation (e.g., nasal spray).

In various aspects, the above modes of administration can be combined in any order.

H. Examples of the embodiments

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices, and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, temperature is in degrees Celsius or at ambient temperature, and pressure is at or near atmospheric.

The examples provided herein are intended to illustrate the invention and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way.

1. Chemical experiments

a. General synthetic procedure

i. The method A comprises the following steps: 6- (4- (2- (4-cyclopropyl-3-fluorophenyl) acetyl) piperazin-1-yl) pyridazine-3-carbonitrile

To a mixture of cold (ice), stirred 2- (4-cyclopropyl-3-fluorophenyl) acetic acid (150mg, 0.772mmol), 4- (6-cyanopyridazin-3-yl) piperazin-1-ium chloride (218mg, 0.850mmol, 88%) and HATU (382mg, 1.0mmol) in DMF (3.0mL) was added pure DIPA (404 μ L, 2.32 mmol). Mixing the raw materialsThe mixture was warmed to room temperature, stirred for 16 hours, and then heated at 50 ℃ for 1 hour. Next, the mixture was cooled to room temperature, diluted with water (10mL), and extracted with ethyl acetate (2X 15 mL). The combined extracts were washed with aqueous 1N HCl, bicarbonate solution and brine, and Na₂SO₄Dried and concentrated. The residue was taken up in 25g of SiO₂Purification on column using a gradient (50% to 100%, and 100%) solution of ethyl acetate in hexanes gave the title compound (160mg, 56.7%) as a beige solid. Rf ═ 0.25 (EtOAc).

Method B6- (4- (2- (4-cyclopropyl-3-fluorophenyl) acetyl) piperazin-1-yl) pyridazine-3-carbonitrile

To a mixture of cold (ice), stirred 2- (4-cyclopropyl-3-fluorophenyl) acetic acid (3.35g, 17.2mmol) and 1- (6-cyanopyridazin-3-yl) piperazine-1, 4-diiumchloride (4.97g,19.0mmol) in DMF (35mL) was added a solution of 50% propylphosphonic anhydride (13.3mL, 22.4mmol) in DMF followed by pure DIPA (13.8mL, 79.3 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 17 hours. Next, the reaction was slowly quenched with water (100mL) (slightly exothermic), stirred for 10 minutes, then filtered using a buchner funnel, washed with water (500mL), and dried under high vacuum to give 6- (4- (2- (4-cyclopropyl-3 fluorophenyl) acetyl) piperazin-1-yl) pyridazine-3-carbonitrile (5.95g, 94.4%) as an off-white solid. The purity of the product is more than 95%. The product (4.77g) was added to a mixture of MeOH-EtOAc (1: 1, 100 mL). The suspension was then heated at 80 ℃ for 10 minutes to give a clear pale yellow solution. The solution was filtered off and the filtrate was kept at room temperature for 24 hours. The solid was filtered, washed with EtOAc (10mL) and dried to give 6- (4- (2- (4-cyclopropyl-3-fluorophenyl) acetyl) piperazin-1-yl) pyridazine-3-carbonitrile (3.65g, 76.5%) as an off-white solid. HPLC purity, > 99.9%.

b. Spectral data of exemplary Compounds

i. Example 1: 6- (4- (2- (4-cyclopropyl-3-fluorophenyl) acetyl) piperazin-1-yl) pyridazine-3-carbonitrile

¹H NMR(600MHz,CDCl₃)7.50(d,J＝9.6Hz,1H),6.96–6.95(m,1H),6.94(s,1H),6.88(t,J＝7.9Hz,1H),6.85(d,J＝9.6Hz,1H),3.87–3.82(m,2H),3.82–3.78(m,2H),3.76(s,2H),3.74–3.70(m,2H),3.67–3.63(m,2H),2.11–2.02(m,1H),1.02–0.96(m,2H),0.75–0.69(m,2H).¹⁹F NMR(376MHz,CDCl₃)-119.81(dd,J＝11.0,7.9Hz).LRMS,m/z:388.07(M+Na)⁺,364.03(M-1).

Example 2: 1- (4- (6-chloropyridazin-3-yl) piperazin-1-yl) -2- (4-cyclopropyl-3-fluorophenyl) ethan-1-one

¹H NMR (500MHz, chloroform-d) 7.27(d, J ═ 14.5Hz,1H), 7.05-6.77 (M,4H), 3.89-3.51 (M,10H), 2.18-1.97 (M,1H), 1.06-0.87 (M,2H),0.72(dd, J ═ 5.1,1.8Hz,2H), ESI-MS (M +1):375.52.

Example 3: (S) -6- (4- (2- (4-cyclopropyl-3-fluorophenyl) acetyl) -3-methylpiperazin-1-yl) pyridazine-3-carbonitrile

¹H NMR (500MHz, chloroform-d) 7.40(d, J ═ 9.5Hz,1H), 6.96-6.66 (M,4H), 4.95-4.46 (M,1H), 4.44-3.91 (M,3H),3.64(s,2H), 3.47-2.90 (M,3H), 2.05-1.91 (M,2H), 1.16-1.05 (M,3H),0.90(dd, J ═ 8.3,2.0Hz,2H),0.63(d, J ═ 5.3Hz,2H). ESI-MS (M +1):380.52.

v. example 4: (R) -6- (4- (2- (4-cyclopropyl-3-fluorophenyl) acetyl) -3-methylpiperazin-1-yl) pyridazine-3-carbonitrile

¹H NMR (500MHz, chloroform-d) 7.40(d, J ═ 9.4Hz,1H), 6.95-6.65 (m,4H), 4.93-4.45 (m,1H), 4.44-3.89 (m,3H), 3.76-3.58 (m,2H), 3.46-2.91 (m,3H), 2.08-1.91 (m,1H),1.12(d, J ═ 6.6Hz,3H), 0.97-2.91 (m,3H), c, f–0.82(m,2H),0.68–0.55(m,2H).ESI-MS(M+1):380.52.

Example 5: (R) -1- (4- (6-chloropyridazin-3-yl) -2-methylpiperazin-1-yl) -2- (4-cyclopropyl-3-fluorophenyl) ethan-1-one

¹H NMR (500MHz, chloroform-d) 7.26 to 7.12(M,1H),6.93 to 6.71(M,4H),4.92 to 4.39(M,1H),4.30 to 3.74(M,3H),3.64(s,2H),3.45 to 2.91(M,3H),1.97(td, J ═ 8.4,4.3Hz,1H),1.18 to 1.08(M,3H),0.95 to 0.82(M,2H),0.69 to 0.53(M,2H) ESI-MS (M +1):389.42.

Example 6: (S) -1- (4- (6-chloropyridazin-3-yl) -2-methylpiperazin-1-yl) -2- (4-cyclopropyl-3-fluorophenyl) ethan-1-one

¹H NMR (500MHz, chloroform-d) 7.24-7.09 (M,1H), 6.92-6.63 (M,4H), 4.95-4.40 (M,1H), 4.31-3.74 (M,3H),3.64(s,2H), 3.44-3.15 (M,1H), 3.15-2.75 (M,2H), 2.03-1.91 (M,1H), 1.17-1.06 (M,3H), 0.95-0.83 (M,2H),0.63(dd, J5.2, 1.8Hz,2H) ESI-MS (M +1):389.42.

Example 7: 1- (4- (6-chloropyridazin-3-yl) piperazin-1-yl) -2- (4-cyclopropylphenyl) ethan-1-one

¹H NMR (500MHz, chloroform-d) 7.31 to 7.11(M,1H),7.07(d, J ═ 7.8Hz,2H),6.95(d, J ═ 7.8Hz,2H),6.81(d, J ═ 9.5Hz,1H),3.86 to 3.27(M,8H),1.88 to 1.74(M,1H),0.96 to 0.77(M,2H),0.59(d, J ═ 5.2Hz,2H), ESI-MS (M +1):357.31.

ix, example 8: (R) -6- (4- (2- (4-cyclopropylphenyl) acetyl) -3-methylpiperazin-1-yl) pyridazine-3-carbonitrile

¹H NMR (500MHz, chloroform-d) 7.38(d, J ═ 9.6Hz,1H),7.05(d, J ═ 6.9Hz,2H),6.95(d, J ═ 7.8Hz,2H), 6.78-6.63 (M,1H), 4.97-4.45 (M,1H), 4.38-3.91 (M,2H), 3.79-3.59 (M,3H), 3.45-2.98 (M,3H),1.79(ddd, J ═ 13.5,8.7,5.1Hz,1H),1.10(d, J ═ 6.7Hz,3H), 0.94-0.81 (M,2H), 0.66-0.53 (M,2H), ESI-MS (M +1):362.56.

x. example 9: (S) -6- (4- (2- (4-cyclopropylphenyl) acetyl) -3-methylpiperazin-1-yl) pyridazine-3-carbonitrile

¹H NMR (500MHz, chloroform-d) 7.47(d, J ═ 9.6Hz,1H),7.14(d, J ═ 6.9Hz,2H),7.04(d, J ═ 7.7Hz,2H), 6.91-6.70 (M,1H),4.79(dd, J ═ 170.2,10.0Hz,1H), 4.48-3.98 (M,2H), 3.86-3.69 (M,3H), 3.55-2.93 (M,3H),1.88(tt, J ═ 8.6,5.0Hz,1H),1.19(d, J ═ 6.7Hz,3H),0.97(dd, J ═ 8.4,2.1Hz,2H), 0.73-0.63 (M, 2H): 362.47M + M.

Example 10: (R) -1- (4- (6-chloropyridazin-3-yl) -2-methylpiperazin-1-yl) -2- (4-cyclopropylphenyl) ethan-1-one

¹H NMR(500MHz,DMSO-d₆)7.53(d,J＝9.6Hz,1H),7.38(dt,J＝14.5,6.0Hz,1H),7.11(dd,J＝12.5,7.4Hz,2H),7.01(d,J＝7.7Hz,2H),4.71–4.20(m,2H),4.18–4.05(m,2H),3.92–3.56(m,3H),3.26–2.80(m,2H),1.88(tt,J＝8.5,5.1Hz,1H),1.05(d,J＝6.6Hz,3H),0.92(dd,J＝8.5,2.2Hz,2H),0.70–0.56(m,2H).ESI-MS(M+1):371.42.

2. Characterization of the exemplified Compounds

The compounds in table 1 below were synthesized using the same or similar methods as those described herein. The necessary starting materials are either commercially available, described in the literature, or readily synthesized by those skilled in the art of organic synthesis.

TABLE 1

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.