MXPA06007537A - Pyrrole and pyrazole daao inhibitors - Google Patents

Abstract

Methods for increasing D-Serine concentration and reducing concentration of the toxic products of D-Serine oxidation, for enhancing learning, memory and/or cognition, or for treating schizophrenia, Alzheimer's disease, ataxia or neuropathic pain, or preventing loss in neuronal function characteristic of neurodegenerative diseases involve administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:(I)wherein R1 and R2 are independently selected from hydrogen, halo, nitro, alkyl, acyl, alkylaryl, and XYR5;or R1 and R2, taken together, form a 5, 6, 7 or 8-membered substituted or unsubstituted carbocyclic or heterocyclic group;X and Y are independently selected from O, S, NH, and (CR6R7)n;R3 is hydrogen, alkyl or M+;M is aluminum, calcium, lithium, magnesium, potassium , sodium , zinc ion or a mixture thereof;Z is N or CR4;R4 is from selected from hydrogen, halo, nitro, alkyl, alkylaryl, and XYR5;R5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;R6 and R7 are independently selected from hydrogen and alkyl;n is an integer from 1 to 6;at least one of R1, R2 and R4 is other than hydrogen;and at least one of X and Y is (CR6R7)n. D-serine or cycloserine may be coadministered along with the compound of formula (I).

Description

PIRROL AND PIRAZOL INHIBITORS OF D-AMINOACIDO-OXIDASE (DAAO) Field of the Invention The enzyme D-amino acid oxidase (DAAO) metabolizes D-amino acids, and in particular, metabolizes D-serine in vi tro at physiological pH. DAAO is expressed in the brain and periphery of mammals. The role of D-serine as a neurotransmitter is important in the activation of the selective subtype of N-methyl-D-aspartate (NMDA) of the glutamate receptor, an ion channel expressed in neurons, here denoted as an NMDA receptor. Small organic molecules, which inhibit the enzymatic cycle of DAAO, can control D-serine levels, and thus influence the activity of the NMDA receptor in the brain. NMDA receptor activity is important in a variety of disease states, such as schizophrenia, psychosis, ataxia, ischemia, various forms of pain including neuropathic pain, and deficits in memory and cognition. Background of the Invention Peganeous organic molecules that inhibit the enzymatic cycle of DAAO can also control the production of toxic metabolites from the oxidation of D-serine, such as hydrogen peroxide and ammonia. In this way, these molecules can have an influence on the Ref.: 174228 progress of cell loss in neurodegenerative disorders. Neurodegenerative diseases are diseases in which the CNS neurons and / or peripheral neurons undergo a progressive loss of function, usually accompanied by (and caused by) a physical deterioration of the structure of either the neuron itself or its interconnection with other neurons. These conditions include Parkinson's disease, Alzheimer's disease, Huntington's disease and neuropathic pain. The N-methyl-D-aspartate (NMDA) -glutamate receptors are expressed at excitatory synapses throughout the central nervous system (CNS). These receptors measured a wide variety of brain processes, including synaptic plasticity, which are associated with certain types of memory formation and learning. The NMDA-glutamate receptors regulate the binding of two agonists to effect neurotransmission. One of these agonists is the excitatory amino acid N-glutamate, while the second agonist, in the so-called "strychnine-insensitive site", is now thought to be D-serine. In animals, D-serine is synthesized from D-serine by serine-racemase and degraded to its corresponding ketoacid by DAAO. Together, serine-racemase and DAAO are thought to play a crucial role in the modulation of NMDA neurotransmission by regulating concentrations in the CNS of D-serine. Alzheimer's disease manifests as a form of dementia that typically comprises mental deterioration, reflected in memory loss, confusion and disorientation. In the context of the present invention, dementia is defined as a syndrome of progressive decline in multiple domains of cognitive function, which eventually lead to an inability to maintain normal social and / or occupational performance. Early symptoms include memory lapses and moderate, but progressive, impairment of specific cognitive functions, such as language aphasia, motor skills (apraxia) and perception (agnosia). The earliest manifestation of Alzheimer's disease is frequently the deterioration of memory, which is required for a diagnosis of dementia in both criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease-and the Alzheimer's Disease and Related Disorders Association (NTNCDS-ADRDA), (McKhann et al., 1984, Neurology 34: 939-944), which are specific for Alzheimer's disease, and criteria of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders , Fourth Edítion (DSM-IV), which are applicable for all forms of dementia. The cognitive function of a patient can also be assessed by the cognitive subscale of the Alzheimer's disease assessment scale (ADAS- cog).; "Rosen et al., 1984, Am. J. Psychiatry 141: 1356-1364.) Typically, Alzheimer's disease is treated by acetylcholine esterase inhibitors such as tacrine hydrochloride or donepezil.Unfortunately, the few forms of treatment of memory loss and impaired learning currently available are not considered effective enough to make any significant difference to a patient, and there is currently a lack of a normal nootropic drug for use in this treatment.Neurosychiatric disorders include schizophrenia, autism and attention deficit disorder.

Physicians recognize a distinction between these disorders, and there are many schemes to categorize them.

Diagnostic and Statistical Manual of Mental Disorders, Revised, Fourth Ed., (DSM-IV-R), published by American Psychiatric Association, provides a normal diagnostic system on which the experts depend and are incorporated herein as a reference. According to the framework of the DSM-IV, mental disorders of axis I include: disorders diagnosed in childhood (such as Attention Deficit Disorder (ADD) and disorder Attention Deficit Hyperactivity Disorder (ADHD)) and disorders diagnosed in adulthood. Disorders diagnosed in adulthood include (1) schizophrenia and psychotic disorders; (2) cognitive disorders; (3) mood disorders; (4) disorders related to anxiety; (5) eating disorders; (6) substance related disorders; (7) personality disorders and (8) "disorders not yet included" in the scheme. ADD and ADHD are disorders that are mainly prevalent in children and are associated with increased motor activity and decreased attention span. These disorders are commonly treated by administration of psychostimulants such as methylphenidate and dextroamphetamine sulfate. Schizophrenia represents a group of neuropsychiatric disorders characterized by dysfunctions of the thought process, such as false illusions, hallucinations, and extensive withdrawal of the patient's interest from other people. Approximately one percent of the world population is afflicted with schizophrenia, and this disorder is accompanied by high proportions of morbidity and mortality. The so-called negative symptoms of schizophrenia include disaffiliation of affect, anergy, alloy and social withdrawal, which can be measured using SANS (Andreasen, 1983, Scales for the Assessment of Negative Symptoms (SANS), Iowa City, Iowa). Positive symptoms of schizophrenia include false delusion and hallucination, which can be inhibited using PANSS (Positive and Negative Syndrome Scale) (Kay et al., 1987, Schizophrenia Bulletin 13: 261-276). Cognitive symptoms of schizophrenia include impairment in obtaining, organizing and using intellectual knowledge that after. measured by the cognitive sub-scale of the Positive and Negative Syndrome Scale (PANSS-cotuitive sub-scale) (Lindenmayer et al., 1994, J. Nerv. Ment. Dis. 182: 631-638) or with such cognitive tasks like the Wisconsin Card Classification Test. Conventional antipsychotic drugs, which act on the dopamine D2 receptor, can be used to treat the positive symptoms of schizophrenia, such as false delusion and hallucination. In general, conventional anti-psychotic drugs and atypical psychotic drugs, which act on the serotonin 5HT2 and dopamine D2 receptor, are limited in their ability to treat cognitive deficits and negative symptoms such as disaffiliation of affect (ie, lack of facial expressions), anergy and social withdrawal. Other conditions that manifest as memory and learning deficits include benign amnesia and closed brain injury. Benign amnesia refers to a moderate tendency to be unable to remember or retrieve information that was recorded once, learned and stored in memory (for example, the inability to remember where the keys were placed or where the key was left parked). car) . Benign amnesia typically affects individuals after 40 years of age and can be recognized by normal assessment instruments such as the Wechsler Memory Scale. Closed brain injury refers to a clinical condition after injury or brain trauma. This condition, which is characterized by cognitive and memory impairment, can be diagnosed as "amnestic disorder due to general medical condition" according to DSM-IV. The known inhibitors of DAAO include benzoic acid, pyrrole-2-carboxylic acids, and indole-2-carboxylic acids, as described by Frisell, et al., J. Biol. Chem., 223: 75-83 (1956) and Parikh et al., JACS, 80 : 953 (1958). Indole derivatives and particularly certain indole-2-carboxylates have been described in the literature for the treatment of neurodegenerative disease and neurotoxic injury. EP 396124 describes indole-2-carboxylates and derivatives for treatment or management of neurotoxic injury resulting from a CNS disorder or traumatic event or in treatment or management of a neurodegenerative disease. Several examples of traumatic events that can result in neurotoxic injury are given, including apoxia, anoxia and ischemia, associated with perinatal asphyxia, cardiac arrest or stroke. Neurodegeneration is associated with CNS disorders such as seizures and epilepsy. U.S. Patents Nos. 5,373,018; 5,374,649; 5,686,461; 5,962,496 and 6,100,289 Cugola, describe treatment of neurotoxic injury and neurodegenerative disease using indole derivatives. None of the above references mentioned improvement or improvement of learning, memory or cognition. WO 03/039540 describes improvement of learning, memory and cognition and treatment of neurodegenerative disorders using DAAO inhibitors, including indole-2-carboxylic acids. However, there remains a need for new drugs that are clinically effective in the treatment of memory defects, impaired learning and loss of cognition and other symptoms related to NMDA receptor activity or lack of it. Certain pyrazole-3-carboxylic acids are disclosed as partial agonists for the nicotinic acid receptor by van Herk, et al., (J. Med. Chem., 46 (18): 3945-51 (2003). A synthetic route for the preparation of the compounds is shown, and the inhibition of nicotinic acid binding by the compounds was determined.There is no mention of activity in the NMDA receptor or inhibition of DAAO.

Brief Description of the Invention Unexpectedly it has been found that certain pyrrole and pyrazole derivatives exhibit more potent inhibition of DAAO activity than known inhibitors. Dramatically low concentrations of these compounds have been found to inhibit DAAO in vi tro, particularly in relation to known DAAO inhibitors such as benzoic acid, pyrrole-2-carboxylic acid, and indole-2-carboxylic acid. Because of this ability to inhibit the activity of DAAO, certain pyrazole and pyrazole derivatives are useful in the treatment of a variety of diseases and / or conditions wherein the modulation of the levels of D-serine and / or its oxidative products is effective in the improvement of symptoms, along with a reduction of unwanted side effects. In particular, the compounds may be useful for increasing D-serine levels and reducing levels of toxic products of D-serine oxidation; in this way, the compounds are useful for improving learning, memory and / or cognition, or for treating schizophrenia, for treating or preventing memory loss and / or cognition associated with Alzheimer's disease, for treating ataxia, or for preventing loss of function neuronal characteristic of neurodegenerative diseases. Accordingly, in one aspect, the invention relates to methods for increasing D-serine and reducing the toxic products of D-serine oxidation, for improving learning, memory and / or cognition, or for treating schizophrenia, for treating or preventing memory loss and / or condition associated with Alzheimer's disease, to treat ataxia, to treat neuropathic pain, or to prevent loss of neuronal function characteristic of neurodegenerative diseases. The methods comprise administering to a subject a therapeutic amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof. wherein R1 and R2 are independently selected from hydrogen, halo, nitro, alkyl, acyl, alkylaryl and XYR5; or R1 and R2, taken together, form a substituted or unsubstituted carbocyclic or heterocyclic group of 5, 6, 7 or 8 members; X and Y are independently selected from 0, S, NH, and (CR6R7); R3 is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; Rs and R7 are independently selected from hydrogen and alkenyl; Z is N or CR4; R 4 is selected from hydrogen, halo, nitro, alkenyl, alkylaryl, and XYR 5; R5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; n is an integer from 1 to 6; at least one of R1, R2 and R4 is different from hydrogen; and at least one of X and Y is (CR6R7) n. In a second aspect, the invention relates to methods for treating autism, esguizophrenia, Alzheimer's disease, ataxia, neuropathic pain or neurodegenerative diseases, which comprises administering a therapeutically effective amount of the above D-amino acid oxidase (DAAO) inhibitor of the formula ia a subject in need of treatment for one or more of these conditions. In preferred embodiments, the compounds of the formula I are pyrrole-2-carboxylic acids or substituted pyrazole-3-carboxylic acids, for example: Detailed Description of the Invention The present invention relates to methods to increase D-serine and to reduce the toxic products of D-serine oxidation, to improve learning, memory and / or cognition, or to treat esguizophrenia, to treat or prevent memory loss and / or cognition associated with Alzheimer's disease, to treat ataxia, to prevent loss of neuronal function characteristic of neurodegenerative diseases. The methods include administering to a subject a therapeutic amount of a compound of formula I: I or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R2 are independently selected from hydrogen, halo, nitro, alkenyl, acyl, alkylaryl and XYR5; or R1 and R2, taken together, form a substituted or unsubstituted carbocyclic or heterocyclic group of 5, 6, 7 or 8 members; X and Y are independently selected from O, S, NH, and (CR6R7); R3 is hydrogen, alkenyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; Rs and R7 are independently selected from hydrogen and alkenyl; Z is N or CR4; R 4 is selected from hydrogen, halo, nitro, alkenyl, alkylaryl, and XYR 5; R5 se. selects from aryl, substituted aryl, heteroaryl and substituted heteroaryl; n is an integer from 1 to 6; at least one of R1, R2 and R4 is different from hydrogen; and at least one of X and Y is (CRdR7) n. Therapeutic treatment with a compound of formula I improves and / or enhances memory, learning and cognition, particularly in individuals suffering from neurodegenerative diseases such as Alzheimer's, Huntington's or Parkinson's disease. The compounds also improve cognitive dysfunctions associated with aging and improve catatonic esguizophrenia. The compounds of the formula I possess unique pharmacological characteristics with respect to the inhibition of DAAO, and have influence on the activity of the NMDA receptor in the brain, particularly by controlling the levels of D-serine. Therefore, these compounds are effective in the treatment of conditions and disorders, especially disorders related to the CNS, modulated by DAAO, D-serine and / or NMDA receptor activity, with diminished side effects compared to the administration of the drugs. current treatment standards. These conditions and disorders include, but are not limited to, neuropsiguiatric disorders, such as esguizophrenia, autism, attention deficit disorder (ADD and ADHD) and learning disorders in childhood, and neurodegenerative diseases and disorders, such as MLS ( cerebellar ataxia), Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Down's syndrome, neuropathic pain, dementia due to multi-infarction, status epilepticus, blunt injuries (for example, pressure in the spinal cord and brain injury), neurodegeneration induced by viral infection (for example AIDS, encephalopathy), epilepsy, benign amnesia and closed brain injury. The compounds of the formula I can also be useful for the treatment of neurotoxic injury following cerebral arrest, thromboembolic arrest, hemorrhagic arrest, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Accordingly, the present invention relates to methods for increasing the concentration of D-serine and / or for decreasing the concentration of toxic products of the oxidation of D-serine by DAAO in a mammal, to treat schizophrenia, to treat or prevent loss of memory and / or cognition associated with Alzheimer's disease, to treat ataxia, or to prevent loss of neuronal function characteristic of neurodegenerative diseases, to improve learning, memory and / or cognition, or to treat neuropathic pain. Each of the methods comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof: I wherein R1 and R2 are independently selected from hydrogen, halo, nitro, alkyl, acyl, alkylaryl, arylalkyl and XYR5; or R1 and R2, taken together, form a substituted or unsubstituted carbocyclic or heterocyclic group of 5, 6, 7 or 8 members; X and Y are independently selected from 0, S, NH, and (CR6R7); R3 is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; R6 and R7 are independently selected from hydrogen and alkyl; Z is N or CR4; R 4 is selected from hydrogen, halo, nitro, alkyl, alkylaryl, and XYR 5; R5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; n is an integer from 1 to 6; at least one of R1, R2 and R4 is different from hydrogen; and at least one of X and Y is (CRsR7) n. In some embodiments, D-serine or cycloserine can be co-administered together with the compounds of formula I. The compounds of formula I are typically more selective than the known inhibitors of DAAO, including indole-2-carboxylates, and of greater selectivity for inhibition of DAAO with respect to binding at the D-serine binding site of the NMDA receptor. The compounds also exhibit an advantageous profile of activity that includes good bioavailability. Accordingly, they offer advantages over many methods known in the art for treating disorders modulated by DAAO, D-serine or NMDA receptor activity. For example, different from many conventional anti-psychotic therapeutics, DAAO inhibitors can produce a desirable reduction in the cognitive symptoms of schizophrenia. Conventional antifungals frequently produce undesirable side effects, including tardive dyskinesia (irreversible involuntary movement disorder), extrapyramidal symptoms, and acatesia, and these can be reduced or eliminated by administering the compounds of formula I. In another aspect, the present invention also relates to compounds of formula IA or pharmaceutically acceptable salts or solvates thereof, and pharmaceutical compositions containing them: IA where Rla and R2a and R4 are independently selected from hydrogen, halo, nitro, alkyl, arylalkyl, alkylaryl and XYR5; X and Y are independently selected from O, S, NH, and (CR6R7); R3 is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; R5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; Rs and R7 are independently selected from hydrogen and alkyl; Z is N or CR4; n is an integer from 1 to 6; at least one of Rla and R2a is XYR5; and at least one of X and Y is (CR6R7) n; with the proviso that formula IA does not include 5-phenethyl-1H-pyrazole-3-carboxylic acid, that is, when Rla is hydrogen, R2a is XYR5; X and Y are (CRsR7) n; R3 is hydrogen, Rs and R7 are hydrogen; Z is N; n is 2, R5 can not be phenyl. The compounds of the formula IA form a secondary set of compounds of the formula I, and therefore can be used in the methods of the present invention without limitation. In preferred embodiments, the compounds of the formula I and IA are pyrrole-2-carboxylic acids, substituted at the 4-position or pyrazole-3-carboxylic acids, substituted at the 5-position, the preferred substituents for the compounds of the formula I and IA, 4-substituted pyrrole-2-carboxylic acids and 5-substituted pyrazole-3-carboxylic acids are arylalkyl, substituted arylalkyl, and higher alkyl (CSC20). Preferred arylalkyl substituents are arylethyl groups, particularly phenethyl, in these embodiments, the compounds of formula I and IA are pyrrole-2-carboxylic acids, substituted in the 4-position with a substituted or unsubstituted aryl group attached to the 4-position of the pyrrole through a tetrogen of two atoms, or a pyrazole-3-carboxylic acid, substituted in the 5-position with a substituted or unsubstituted aryl group attached to the 5-position of the pyrrole through a tetro of two atoms. In other preferred embodiments of the compounds of the formula I and LA, the pyrrole-2-carboxylic acids and pyrazole-3-carboxylic acids, R 1 and R 2, taken together, form a substituted or unsubstituted carbocyclic or heterocyclic group of 5,6. , 7 or 8 members. Particularly preferred D-amino acid-amidase pyrazole and pyrazole inhibitors include: The invention includes compounds of formula I and IA, as well as pharmaceutically acceptable salts and solvates of these compounds. The term "compounds or pharmaceutically acceptable salt or solvate of a compound" proposes the occlusive meaning of "or", ie a material that is both a salt and a solvate is encompassed. The pharmaceutically acceptable salts include, but are not limited to, inorganic salts of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, and organic salts of lysine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine. , meglumine (N-methylglucamine), procaine and tromethamine. The compounds of formula I and IA can be prepared by known methods, by the procedures illustrated in the examples, or by the methods shown in Reaction Schemes 1-5.

Reaction Scheme 1.- Method for the synthesis of 3-substituted-lH-pyrrole-2-carboxylic acid ester starting materials In Reaction Scheme 1, R 1 is hydrogen, halo, nitro, alkyl, acyl, alkylaryl, arylalkyl, or XYR; and R is aryl, substituted aryl, substituted heteroaryl heteroaryl.

Reaction Scheme 2.- Method for the synthesis of 5-substituted-lH-pyrrole-2-carboxylic acid ester starting materials Reaction Scheme 3. Method for the synthesis of 4-substituted, 3,4-disubstituted lH-pyrrole-2-carboxylic acids, 4, 5-disubstituted, or 3, 4, 5-trisubstituted Note: All acid chloride starting materials were either commercially available, or were synthesized from the commercially available carboxylic acid available using thionyl chloride or oxalyl chloride. The following are typical experimental conditions: A solution of the necessary acid in thionyl chloride (or in toluene with 10 equivalents of thionyl chloride) was heated at 60 ° C for 1 to 4 hours to obtain the corresponding acyl chloride, then the solvent evaporated under vacuum. Acid chlorides were used in the acylation reactions without further purification Reaction Scheme 4. - Method for the synthesis of amine-substituted lH-pyrrole-2-carboxylic acids using reductive amination: acetyl chloride / Pr2EtN CH C? 2 Note: In this scheme, Ar is an aromatic group such as phenyl or a substituted aromatic group, such as 4-chlorophenyl, or heteroaryl or substituted heteroaryl. Also, the other acid chlorides such as propionyl chloride, for example, can be used in place of acetyl chloride.

Reaction Scheme 5. - Barton-Zard method for the synthesis of 3,4-disubstituted lH-pyrrole-2-carboxylic acids In this Scheme, Ar is an aromatic group such as phenyl or a substituted aromatic, such as 4-chlorophenyl, n = 0, 1 or 2, or heteroaryl or substituted heteroaryl and R = hydrogen, halo, nitro, alkyl or acyl. Subjects for treatment according to the present invention include humans (patients) and other mammals in need of therapy for the condition indicated. Patients who need therapy to improve or benefit learning and memory are those who exhibit symptoms of dementia or loss of learning and memory. Individuals with an amnestic disorder are atrophied in their ability to learn new information or are unable to remember previously learned information or past events. The memory deficit is more evident in tasks that require spontaneous retentiveness and can also be evident when the examiner provides stimuli for the person to remember a previous moment. The memory disturbance must be sufficiently severe to cause marked damage in social or occupational functioning and must represent a significant decline from a previous level of functioning. The memory deficit may be related to age or be the result of illness or another cause. Dementia is characterized by multiple clinically significant deficits in cognition that represent a significant change from a previous level of functioning, including memory damage that includes inability to learn new material or forgetting previously learned material. Memory can be formally tested by measuring the ability to record, retain, remember and recognize information. A diagnosis of dementia also requires at least one of the following cognitive disturbances: aphasia, apraxia, agnosia or a disturbance in executive functioning. These deficits in language, motor performance, object recognition and abstract thinking, respectively, must be sufficiently severe in conjunction with the memory deficit to cause damage in occupational or social functioning and must represent a decline from a previously higher level of functioning. The compounds of formula I and IA can also be used in conjunction with therapy comprising administration of D-serine or an analog thereof, such as a D-serine salt, a D-serine ester, alkylated D-serine , or a precursor of D-serine, or can be used in conjunction with therapy comprising administration of antipsychotics, antidepressants, psychostimulants, and / or therapeutic products for Alzheimer's disease. In animals, several established models of memory learning are available to examine the beneficial effects of cognitive enhancement and the potential related side effects of treatment. Descriptions of the evidence that can be used to assess changes in cognition in non-human species are given in Sarter, Martin, rutera. J. Neuroscience, 32: 765-774 (1987). The tests include the Morris water maze (Stewart and Morris, Behavioral Neuroscience, R. Saghal, Ed., P.107 (1993)), no delayed correspondence to the sample and models of social discrimination. The Morris water maze is one of the best validated models of learning and memory, and is sensitive to the effects of cognitive improvement of a variety of pharmacological agents. The task performed in the maze is particularly sensitive to manipulations of the hippocampus in the brain, an area of the brain important for spatial learning in animals and memory consolidation in humans. In addition, the improvement in performance in the Morris water maze is predictive of clinical efficacy and a common cognitive enhancer compound. For example, treatment with cholinesterase inhibitors or selective muscarinic cholinergic agonists against learning deficit invested in the Morris maze animal model of learning and memory, as well as clinical populations with dementia. Furthermore, this animal paradigm actually models the increasing degree of damage with advanced age and the increased vulnerability of the memory trace for delay or pre-test interference that is characteristic of amnestic patients. The test is a simple spatial learning task in which the animal is placed in a tank of warm water, which is opaque due to the addition of milk powder. The animals learn the location of the platform in relation to visual indications located inside the maze and the test room; this learning is referred to as learning the place. Groups of animals receive control solution or a dose of the therapeutic agent, in the desired time interval before training or after training. Control animals typically reach the platform in the space of five to ten seconds after three days of training. The measurement of the memory modulating effects of a therapeutic agent is a change of this period of time. In the second phase or probe phase of the test, the animals that have previously learned the position of the platform are placed in the tank from which the platform has been removed. Animals that remember the position of the platform will spend more time in the quadrant that has contained the platform and will make more crosses on the position previously occupied by the platform. Increases in memory capacity or cognitive ability are manifested by more elapsed time of the animals in the correct quadrant or by making more crosses on the position previously occupied by the platform compared to the control animals. Decreases in memory or cognitive capacity are manifested by animals that spend less time in the correct quadrant or that make fewer crossings of the position of the platform that control animals do. In the test of non-correspondence delayed to the sample, an animal with a stimulus (for example, lever A) is presented. After a period of time, the animal is presented with two selections (for example, lever A and lever B). The selection of the choice that does not correspond to the original stimulus (lever B) results in a reward. Greater than the probability selection of the appropriate choice indicates that the original stimulus was recalled. As the time between the stimulus and the response of the choice increases, performance decreases and approaches pure probability. The number of correct choices in a given time is related to cognitive ability. Deficits in cognition or memory can be induced physically, biochemically or by the use of aged animals.

In the social interaction test, a foreign animal (animal B) is introduced into the cage of origin of the test animal (animal A). Animal A will recognize the animal introduced as a stranger and will investigate it. If animal B is removed and reintroduced at a later time, the test animal (animal A) will spend less time investigating the new cage mate since it remembers them from the previous introduction. As the time between introductions increases, more time will be spent investigating the new animal the second time since it is less well remembered. The time spent investigating the new cage partner during the second introduction is inversely related to cognitive ability. Deficits in cognition or memory can be introduced physically, biochemically or by the use of aged animals. In humans, methods to measure learning and memory can be measured by tests such as Wechsler's Memory Scale and Minimental test. A normal clinical test to determine if a patient has impaired learning and memory is the Minimental Test for Learning and Memory (Folstein et al., J. Psychiatric Res. 12: 185, 1975), especially for those suffering from brain trauma, disease of Korsakoffs or attack. The result of the test serves as an index of short-term working memory of the class that deteriorates rapidly in the early stages of amnestic or dementia disorders. Ten pairs of unrelated words (for example, armada-tabla) are read to the subject. The subject is then asked to remember the second word when the first word of each pair is given. The measurement of memory damage is a small number of associated words in par remembered in relation to a corresponding control group. The improvement in learning and memory constitutes either (a) a statistically significant difference between the performance of treated patients compared to members of a placebo group; or (b) a statistically significant change in performance in the direction of normality in the measures pertinent to the disease model. Animal models or clinical cases of disease exhibit symptoms that are by definition distinguishable from normal controls. In this way, the measure of effective pharmacotherapy will be a significant, but not necessarily complete, reversal of the symptoms. The improvement can be facilitated in both animal and human models of memory pathology by clinically effective "cognitive improvement" drugs that serve to improve the performance of a memory task. For example, cognitive enhancers or enhancers that function as cholinomimetic replacement therapies in patients suffering from dementia and memory loss of the Alzheimer type significantly improve short-term working memory in paradigms such as the task of pair association. Another potential application for therapeutic interventions against memory impairment is suggested by the age-related deficits in performance that are modeled effectively by the longitudinal study of recent memory in aging mice. The Wechsler Memory Scale is a widely used paper and pencil test of cognitive function and memory capacity. In the normal population, the standardized test produces an average of 100 and a standard deviation of 15, so that moderate amnesia can be detected with a reduction of 10-15 points in the score, a more severe amnesia with a reduction of 20 -30, and so on. During the clinical intervention, a battery of tests, including, but not limited to, the Minimental test, the Wechsler memory scale or the associated learning in pairs are applied to diagnose symptomatic memory loss. These tests provide general sensitivity to both general cognitive impairment and specific loss of learning / memory capacity (Squire, 1987). Apart from the specific diagnosis of dementia or amnestic disorders, these clinical instruments also identify cognitive decline related to age that reflects an objective decrease in mental function consequent to the aging process that is within normal limits given the age of the person (DSM IV, 1994). As previously noted "improvement" in learning and memory within the context of the present invention occurs when there is a statistically significant difference in the direction of normality in the associated test in pairs, for example, between the performance of patients treated with the therapeutic agent in comparison to members of the group with placebo or between subsequent tests given to the same patient. The pre-boost inhibition test can be used to identify compounds that are effective in the treatment of schizophrenia. The test is based on observations that animals or humans exposed to a loud sound will exhibit a surprise reflex and that human animals exposed to a series of lower intensity sounds before the higher intensity test sound will no longer exhibit a reflection of such intense surprise. This is called pre-impulse inhibition. Patients diagnosed with schizophrenia exhibit defects in pre-impulse inhibition, that is, lower intensity pre-impulses do not further inhibit the surprise reflex to the intense test sound. Similar effects in pre-booster inhibition can be induced in animals by drug treatments (scopolamine, ketamine, PCP or MK801) or by creating offspring in isolation. These defects in pre-boost inhibition in animals can be partially reversed by drugs that are known to be effective in patients with schizophrenia. It is perceived that the models of pre-booster inhibition animals have given value to predict efficacy of the compounds when treating patients with schizophrenia. If desired, the compounds of formula I and IA may also be used in conjunction with therapy comprising administration of D-serine or an analog thereof, such as a D-serine salt, a D-serine ester, D-serine alkylated, or a precursor of D-serine. The compounds can also be used in conjunction with therapy comprising administration of antipsychotics (to treat schizophrenia and other psychotic conditions), psychostimulants (to treat attention deficit disorder, depression or learning disorders), antidepressants, nootropics (e.g., piracetam). , oxiracetamo aniracetam), acetylcholinesterase inhibitors (for example, compounds related to physostigmine, tacrine or denepezil) and / or therapeutic products of Alzheimer's disease (to treat Alzheimer's disease). These methods for joint therapies are included within the invention. The phrase "therapeutically effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present invention that is effective to produce some desired therapeutic effect by inhibiting DAAO in at least one population. secondary of cells in an animal and thereby block the biological consequences of that route in the treated cells, at a reasonable benefit / risk ratio applicable to any medical treatment. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. The pharmaceutically acceptable base addition salts suitable for the compounds of the present invention include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or other organic salts made from lysine, N, N'-dibenzylethylene. diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, and tromethamine. In general, the compounds of the present invention are commercially available or can be prepared by methods well known to the person skilled in the art. In addition, the methods described below, or modifications thereof, which use readily available starting materials, reagents and conventional synthesis procedures, can be employed. In these reactions, it is also possible to make use of variants that are known per se, but are not mentioned in the present. In the context of the present invention, it is proposed to include linear, branched or cyclic hydrocarbon structures and combinations thereof, which include lower alger or higher alger. Preferred algal groups are C20 or lower. "Lower alkyl" refers to alkyl groups of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, and n-, s-, and t-butyl. "Higher aligyl" refers to aligyl groups having 7 or more carbon atoms, preferably 7-20 carbon atoms, and includes, for example, n-, s- and t-heptyl, octyl and dodecyl. Cycloalkyl is a secondary group of alkyl which includes cyclic hydrocarbon groups of 3 to 8 carbon atoms. Examples of cycloalguyl groups include cyclopropyl, cyclobutyl, cyclopentyl and norbornyl. Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from nitrogen, oxygen or sulfur; a 9 or 10-membered bicyclic aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from nitrogen, oxygen or sulfur; or a tricyclic 13 or 14 membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from nitrogen, oxygen or sulfur. Carbocyclic rings of 6 to 14 aromatic members include, for example, benzene, naphthalene, indane, tetralin and fluorene; and 5- to 10-membered aromatic heterocyclic rings include, for example, imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, pyrrole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole, and pyrazole. Arylalkyl means alkyl residue attached to an aryl ring. The examples are benzyl and phenethyl. "Heteroarylalkyl" means an alkyl residue attached to a heteroaryl ring. Examples include pyridinylmethyl and pyrimidinylethyl. "Alkylaryl" means an aryl residue having one or more alkyl groups attached thereto. Examples are tolyl and mesityl. Alkoxy or alkoxy refer to groups of 1 to 8 carbon atoms of a straight, branched or cyclic configuration and combinations thereof attached to the structure of origin through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy. "Lower alkoxy" refers to groups containing from 1 to 4 carbon atoms. Acyl refers to groups of 1 to 20 carbon atoms of a straight, branched or cyclic saturated, unsaturated and aromatic configuration and combinations thereof, attached to the structure of origin through a carbonyl functionality. One or more carbons in the acyl residue can be replaced by nitrogen, oxygen or sulfur while the point of attachment to the source remains in the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl and benzyloxycarbonyl. Lower acyl refers to groups containing one to four carbon atoms. "Heterocycle" or "heterocyclic" means a cycloalkyl or aryl residue in which one to two of the carbons are replaced by a heteroatom such as oxygen, nitrogen or sulfur. Examples of heterocycles that fall within the scope of the invention include pyrrolidine, pyrazole, pyrol, indole quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxane, benzodioxole (commonly referred to as methylenedioxyphenyl, when presented as a substituent), tetrazole, morpholine, thiazole , pyrine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane and tetrahydrofuran. Substituted refers to residues, including but not limited to alkyl, alkylaryl, aryl, arylalkyl and heteroaryl, wherein up to three H atoms of the residue are replaced with lower alkyl, substituted alkyl, substituted alkenyl, haloalkyl, alkoxy, carbonyl, carboxy , carboalkoxy, carboxamido, acyloxy, amidino, nitro, halogen, hydroxy, OCH (COOH) 2, cyano, primary amino, secondary amino, acylamino, alkylthio, sulfoxide, sulfone, phenyl, benzyl, phenoxy, benzyloxy, heteroaryl or heteroaryloxy. Haloalkyl refers to an alkyl residue, wherein one or more H atoms are replaced by halogen atoms; the term "haloalkyl" includes perhaloalkyl. Examples of haloalkyl groups that fall within the scope of the invention include CH2F, CHF2 and CF3. Oxaalkyl refers to an alkyl residue in which one or more carbon atoms have been replaced by oxygen. It is bound in the structure of origin through an alkyl residue. Examples include methoxypropoxy, 3, 6, 9-trioxadecyl and the like. The term "oxaalkyl" is intended to be understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, but without restriction of fl27 (a)], that is, it refers to compounds in the which oxygen is bound by an individual bond to its adjacent atoms (forming ether bonds); it does not refer to double-bound oxygen, as it would be found in carbonyl groups. Similarly, thia-alkyl and aza-alkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl. In the context of the present invention, compounds that are considered to possess activity as DAAO inhibitors are those that exhibit 50% inhibition of the enzymatic cycle of DAAO (IC50) at a concentration of about < 100 μM, preferably, approximately < 10 μM and more preferably about < 1 μM. Many of the compounds described herein may contain one or more asymmetric centers and in this way may cause enantiomers, diastereomers and other geometric shapes that can be defined in terms of absolute stereochemistry, such as (R) - or (S) -. The present invention is proposed to include all these possible isomers, as well as their racemic and optically pure forms. The (R) - and (S) - optically active isomers can be prepared using guiral synthesis or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is proposed that the compounds include both geometric isomers E and Z. Likewise, all tautomeric forms are also proposed to are included. While it may be possible for the compounds of formula I and IA to be administered as a natural chemical, it is preferred to present them as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I or IA or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutical carriers thereof and optionally one or more ingredients different therapeutic The carriers can be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and infraocular) administration. The most appropriate route may depend on the condition and disorder of the recipient. The formulations can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the pharmacy art. All methods include the step of bringing into association a compound or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier constituting one or more auxiliary ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, forming the product in the desired formulation. Oral formulations are well known to those skilled in the art, and general methods for preparing them are found in normal pharmacy textbooks, for example Remington: The Science and Practice of Pharmacy. , A.R. Gennaro, ed. (1995), the full description of which is incorporated herein by reference. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, amylaceous capsules or tablets each containing a predetermined amount of the active ingredient; as - a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, elucidate or paste.

A tablet may be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a fluid form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating agent, active, on the surface or dispersant. The molded tablets can be made by molding in a suitable machine a mixture of the wetted powder compound with an inert liquid diluent. The tablets may optionally be coated or labeled and formulated to provide sustained, delayed or controlled release of the active ingredient therein. Oral and parenteral sustained release drug delivery systems are well known to those skilled in the art, and general methods for achieving sustained release of orally or parenterally administered drugs are found, for example, in Remington: The Science and Practice of Pharmacy, pages 1660-1675 (1995). Formulations for parenteral administration include sterile aqueous and non-aqueous injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the proposed recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations can be presented in unit doses of I multi-dose containers, for example, sealed vials and flasks, which can be stored in a freeze dried (lyophilized) condition that requires only the addition of a sterile liquid carrier, eg, saline, phosphate buffered saline ( PBS) or similar, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind described above. Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol. Formulations for topical administration in the mouth, eg, buccal or sublingual, include lozenges comprising the active ingredient in a flavored base such as sucrose and acacia gum or tragacanth, and lozenges comprising the active ingredient in such a base. like gelatin and glycerin or sucrose or acacia gum. Pharmaceutical compositions containing the compounds of formula I or IA may conveniently be presented in the unit dosage form and prepared by any of the methods well known in the pharmacy art. Preferred unit dose formulations are those which contain an effective dose, or an appropriate fraction thereof, of the active ingredient, or a pharmaceutically acceptable salt thereof: The magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the dose. the condition to be treated and the administration route. The route, and perhaps the dose frequency, will also vary according to the age, body weight and response of the inhibiting patient. In general, the total daily dose ranges from about 1 mg per day to about 7000 mg per day, preferably about 1 mg per day to about 100 mg per day, more preferably, about 25 ng per day to about 50 mg per day, in individual or divided doses. In some embodiments, the total daily dose may vary from about 50 mg to about 500 mg per day, and preferably, from about 100 mg to about 500 mg per day. In addition, it is recommended that children, patients over 65 years of age, and those with impaired liver or kidney function, receive initially fewer doses and that the dose be titrated based on individual responses and blood levels. It may be necessary to use doses outside these ranges and in some cases, as will be apparent to those skilled in the art. In addition, it is noted that the treating physician or clinician knows how and when to interrupt, adjust or terminate the therapy in conjunction with the individual patient's response. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having considered the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

EXAMPLES Procedures for the preparation of pyrazoles Example 1. Synthesis of 6,6-dimethyl-1,4,5,6-tetrahydrocyclopentapyrazol-3-carboxylic acid (3) Synthesis of (3, 3-dimethyl-2-oxocyclopentyl) -oxoacetic acid ethyl ester (1): Sodium hydride (0.428 g, 17. 8 mmol) to an ice bath with NaCl containing EtOH (5.4 mL, 3.3 M) stirring under N2. They mixed together 2, 2-dimethylcyclopentanone (2.00 g, 17.83 mmol) and diethyloxalate (2.42 mL, 17.8 mmol), and then the cooled NaOEt solution was added. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred for 6 hours, at which point the reaction was judged complete by TLC. The reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H20, dried with Na2SO4, filtered and concentrated to yield 3.4084 g (90.0%) of crude 2 which was pure enough by NMR to go to the next step without further puration. Note: NaOEt purchased from Aldrich can be substituted for NaOEt synthesized in situ. ^? (CDC13, 400 MHz): d 4.29 (2H, q, J = 7.3 Hz), 2.82 (2H, t, J = 7.3 Hz), 1.76 (2H, t, J = 7.3 Hz), 1.32 (3H, t, J = 7.3 Hz), 1.07 (6H, s) ppm. 13 C (CDC13, 100 MHz): d 218, 162.89, 153.15, 115.98, 62.12, 46.16, 36.39, 23.98, 23.87, 14.22 ppm.

Synthesis of 6,6-dimethyl-1,4,6,6-tetrahydrocyclopentapyrazol-3-carboxylic acid ethyl ester (2): Hydrazine hydrate (0.229 mL, 4.71 mmol) was added to a stirring solution at room temperature. 1 (0.9961 g, 4.71 mmol) in EtOH (4.7 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC (2 h). The reaction was concentrated and purd by chromatography on silica gel (Combiflash column, Hexanes: CH2C12: NH3 2N in .. EtOH 70: 30: 2). Only the pure fractions were combined and concentrated to obtain 0.6955 g (71.2%) of 2. XH (CDC13, 400 MHz): d 11.04 (1H, broad s), 4.33 (2H, q, J = 7.3 Hz), - 2.76 (2H, t, J = 6.8 Hz), 2.26 (2H, t, J = 6.8 Hz), 1.33 (3H, t, J = 7.3 Hz), 1.31 (6H, s) t ppm. 13C (CDC13, 100 MHz): d 168.08, 160.61, 128.73, 127.27, 61.15, 47.22, 38.64, 27.57, 22.00, 14.48 ppm.

Synthesis of 6,6-dimethyl-l, 4,5,6-tetrahydrocyclopentapyrazol-3-carboxylic acid (3): Freshly prepared aqueous NaOH (10 M in H20, 15.1 mmol) was added to a stirring solution at room temperature. 2 (0.6289 g, 3.02 mmol) in MeOH (7.6 mL, 0.4 M) under N2,. The reaction was then heated to reflux until the reaction was judged complete by TLC (2.5 h). The reaction was concentrated, redissolved in EtOAc and H20, and extracted with EtOAc. 10% HCl was added dropwise until pH = 4, then the organic layer was removed, and the aqueous layer was extracted with EtOAc again. The combined organic layers were dried with NaS04, filtered and concentrated. A small amount of CH2C12 and hexanes was added to the colored solid product, and the colored impurity was pipetted. The remaining solid was dried to obtain 0.2371 g (43.6%) of 3 as an off-white solid.

Note: The precipitation method used below appears to be the preferred protocol ^ (CD3OD, 400 MHz): d 2.75 (2H, t, J = 6.8 Hz), 2.29 (2H, t, J = 6.8 Hz), 1.29 (6H , s) ppm. 13C (CD30D, 100 MHz): d 166.15, 162.23, 130.46, 126.93, 47.10, 38.22, 26.62, 21.52 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 26.62; CH2 carbons: 47.10, 21.52 ppm: LCMS: 181.4 (M + 1); 163.6 ((M + L-18) HPLC: 7.538 min.

Example: Synthesis of 3-methyl-l, 4,5,6-tetrahydrocyclopentapyrazol-3-carboxylic acid (6) Synthesis of (3-methyl-2-oxocyclopentyl) -oxoacetic acid ethyl ester (4): 2-methylcyclopentanone was mixed together (1.0058 g, 10.2 mmol) and diethyloxalate (1.38 mL, 10.2 mmol), and then added to a NaOEt solution (approximately 3 M, 3.4 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H20, dried with ~ Na2SO4, filtered and concentrated to yield crude. The crude material was purified with Hexanes: EtOAc from 98: 2 to 96: 4 to obtain 0.5635 g (27.7%) of 4. 2H (CDC13, 400 MHz): d 4.29 (2H, q, J = 7.1 Hz), 2.96 (1H, ddd, J = 17.6, 8.1, 1.5 Hz), 2.69 (1H, ddd, J = 17.6, 9.5, 8.1 Hz), 2.57 - 2.47 (1H, m), 2.24 (1H, dtd, J = 12.5, 8.3, 2.4 Hz), 1.49 (1H, dtd, J = 12.5, 10.3, 8.4 Hz), 1.34 (3H, t, J = 7.1 Hz), 1.13 (3H, d, J = 7.0 Hz) ppm. 13C (CDC13, 100 MHz): d 164.09, 153.19, 117.67, 62.92, 44.76, 30.60, 30.36, 26.55, 14.63, 14.37 ppm.

Synthesis of 6-methyl-1,4,6,6-tetrahydrocyclopentapyrazol-3-carboxylic acid ethyl ester (5): Hydrazine hydrate (0.101 mL, 2.05 mmol) was added to a stirring solution at room temperature of 4 ( 0.4055 g, 2.05 mmol) in EtOH (2.0 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC. The reaction was concentrated and purified by chromatography on silica gel (Combiflash column, Hexanes: 2N NH 3 in EtOH, 96: 4). Only the pure fractions were combined and concentrated to obtain 0.2003 g (50.4%) of 5. XH (CDC13, 400 MHz): d 9.55 (1H, broad s), 4.35 (2H, q, J = 7.1 Hz), 3.26 - 3.16 (1H, m), 2.89 - 2.63 (3H, m), 2.09 -1.98 (1H, m), 1.37 (3H, t, J = 7.2 Hz), 1.30 (3H, d, J = 6.9 Hz) ppm . 13C Partial (CDC13, 100 MHz): d 128.67, 61.32, 39.73, 32.64, 22.94, 19.62, 14.52 ppm. HPLC: 8901 min.

Synthesis of 6-methyl-1,4,6,6-tetrahydrocyclopentapyrazol-3-carboxylic acid (6): Freshly prepared aqueous NaOH (10 M in H20, 5.02 mmol) was added to a stirring solution at room temperature of 5 (0.1949 g, 1.00 mmol) in MeOH (12.5 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by TLC (0.5 h). The reaction was concentrated and then dissolved in 2 mL of H20. 10% aqueous HCl was added dropwise until pH = 2. The white solid which precipitated from the reaction was filtered off completely and washed with cold H20. The solid was dried under vacuum overnight to obtain 0.1223 g (73.3%) of 6. ^? (CD3OD, 400 MHz): d 3.18 - 3.07 (1H, m), 2.84 - 2.62 (3H, m), 2.08 - 1.96 (1H, m), 1.25 (3H, d, J = 6.8 Hz) ppm. 13C (CD30D, 100 MHz): d 164.49, 163.43, 131.67, 129.41, 40.87, 33.40, 23.61, 19.73 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 19.73; CH2 carbons of: 40.87, 23.61; CH carbons of: 33.40 ppm. HPLC: 7.006 min.

Example 3. Synthesis of 4-methyl-1,4,5,6-tetrahydrocyclopentapyrazol-3-carboxylic acid (11) and 5-methyl-1,4,5,6-tetrahydrocyclopentapyrazol-3-carboxylic acid (12) Synthesis of ethyl ester of (2-methyl-5-oxocyclopentyl) -oxoacetic acid (7) and 4-methyl-2-oxocyclopentyl) -oxoacetic acid ethyl ester (8): Sodium hydride (0.122 g, 5.09) was slowly added mmol) to an ice bath with NaCl containing EtOH (1.54 mL, 3.3 M) stirring under N2. 3-Methylcyclopentanone (0.500 g, 5.09 mmol) and diethyloxalate (0.69 mL, 5.09 mmol) were mixed together, and then added to the cooled NaOEt solution. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred for 6 hours, at which point the reaction was judged complete by TLC. The reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H20, dried with Na2SO4, filtered, and. they concentrated to produce 0.5591 g (55.4%) of 7 and 8 crudes as a mixture of approximately 1: 1.1. Although the conditions for separating the isomers were not found, the mixture was sufficiently pure by NMR to go to the next step without further purification. Note: NaOEt purchased from Aldrich can be substituted for NaOEt synthesized in situ. XH (CDC13, 400 MHz): d 4.33 & 4.31 (2H, q, J = 7.3 Hz, 3.54 - 3.45, 3.20 - 3.08, 2.64 - 2.30, 2.15 - 2.04, 1.74 - 1.66, 1.35 &1.34 (3H, t, J = 7.3 Hz, 1.16 &1.10 ( 3H, d, J = 7.3 &6.4 Hz) ppm 13C (CDC13, 100 MHz): d 214.05, 162.98, 152.36, 117.34, 62.23, 46.44, 35.92 &35.76, 29.45 &28.65, 21.00 &20.91, 14.25 &14.17 ppm.

Synthesis of 4-methyl-1,4,6,6-tetrahydrocyclopentapyrazol-3-carboxylic acid (9) and 5-methyl-l, 4,5,6-tetrahydrocyclopentapyrazol-3-carboxylic acid ethyl ester (10): added hydrazine hydrate (0.127 mL, 2.62 mmol) to a stirred solution at room temperature 7 and 8 (0.5064 g, 2.62 mmol) in EtOH (2.6 mL, 1 M) under N2.

The reaction was then heated to reflux until judged complete by TLC (2.3 h). The reaction was concentrated and purified by chromatography on silica gel (column Combiflash Hexanes: CH2C12: NH3 2N in EtOH 70: 30: 2). Only pure fractions were combined and concentrated to obtain 0. 3132 g (63.1%) of 9 and 10. The conditions for separating the isomers were not found. XH (CDC13, 400 MHz): d 11.26 & 11.18 (1H, broad s), 4.35 & 4.34 (2H, q, J = 7.3 Hz), 3.28 - 3.18 (0.48H, m), 3.02 - 2.90 (1.5H, m), 2.86 - 2.76 (0.52H, m), 2.74 - 2.61 (1H, m) , 2.09 - 1.88 (1H, m), 2.15-1.80 (0.52H, m), 1.36 & 1.35 (3H, t, J = 7.3 Hz), 1.28 & 1.19 (3H, d, J = 6.3 Hz for 1.28 &4.4 Hz for 1.19) ppm. 13C Partial (CDC13, 100 MHz): d 133.67, 128.61, 61.12, 40.25 S 39.35, 33.24 & 32.46, 32.30 & 23.91, 21.69 & 20.55, 14.48 & 14.46 ppm. DEPT (CDC13, 100 MHz): CH3 carbons: 21.69 & 20.55, 14.48 & 14.46; CH2 carbons: 61.12, 39.35, 33.24 & 32.46, 23.91; CH carbons: 40.25, 32.30 ppm. HPLC: 8.974 min.

Synthesis of 4-methyl-1,4,6,6-tetrahydrocyclopentapyrazol-3-carboxylic acid (11) and 5-methyl-1,4,6,6-tetrahydrocyclopentapyrazol-3-carboxylic acid (12): NaOH was added aqueous solution (10 M in H20, 8.07 mmol) was added to a solution at room temperature under stirring of 9 and 10 (0.3132 g, 1.61 mmol) in MeOH (4.0 mL, 0.4 M) under N. The reaction was then heated to reflux until the reaction was judged complete by TLC. The reaction was concentrated and then dissolved in 3 mL of H20. 10% aqueous HCl was added dropwise until pH = 2. The white solid which precipitated from the reaction was filtered off completely and washed with cold H20. The solid was dried under vacuum overnight to obtain 0.1781 g (66.4%) of a mixture of 11 and 12. XH (CD3OD, 400 MHz): d 3.34-3.16, 3.02-2.84, 2.80-2.58, 2.40-2.26, 2.10 -1.98, 1.28 & 1.20 (3H, d, J = 7.0 &6.3 Hz) ppm. 13C (CD3OD, 100 MHz): 162.36 & 162.19, 158.43 & 158.43, 133.52, 128.16, 40.37 & 39.18, 32.39 &32.06, 32.03 & 22.91, 20.61 & 19.68 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 20.61 & 19.68; CH2 carbons: 39.18, 32.39 & 32.06, 22.91; CH carbons: 40.37, 32.03 ppm. LCMS: 167.4 (M + 1); 149.4 ((M + 1) -18): HPLC: 6,984 min.

Example 4. Synthesis of 1,4,5,6,7,8-hexahydrocycloheptapyrazol-3-carboxylic acid (15): 13 14 15 Synthesis of oxo- (2-oxocycloheptyl) -acetic acid ethyl ester (13): Cycloheptanone (1.9998 g, 17.8 mmol) and diethyloxalate (2.42 mL, 17.8 mmol) were mixed. together, and then it was added to a NaOEt solution (about 3 M, 5.94 mL) stirring in a year of ice under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H20, dried with Na2SO4, filtered and concentrated to yield crude. The crude material was purified with Hexanes: CH2C12 1: 1 to obtain 1.9775 g (52.3%) of 13. Note: The product was not yet completely pure at this point, but it was taken to the next step. aH (CDC13, 400 MHz): d 4.31 (2H, q, J = 7.3 Hz), 2.66 -2.58 (2H, m), 2.48-2.43 (2H, m), 1.77-1.59 (6H, m), 1.34 ( 3H, t, J = 7.3H) ppm.

Synthesis of 1,4,5,6,7,8-Hexahydrocycloheptapyrazol-3-carboxylic acid ethyl ester (14): Hydrazine hydrate (0.142 mL, 2.94 mmol) was added to a stirring solution at room temperature of 13 ( 0.6229 g, 2.94 mmol) in EtOH (2.9 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC (4.5 h). The reaction was concentrated and purified by silica gel chromatography (Combiflash Hexanes column: CH2C12: 2N NH3 in EtOH 70: 30: 2). Only the pure fractions were combined and concentrated to obtain 0.4428 g (72.3%) of 14. XH CDC13, 400 MHz): 8.56 (1H, broad s), 4.30 (2H, q, J = 7.1 Hz), 2.92 - 2.86 (2H, m), 2.73 - 2.78 (2H, m), 1.84 - 1.76 (2H, m), 1.65 -1.57 (4H, m), 1.30 (3H, t, J = 7.1 Hz) ppm. 13C (CDC13, 100 MHz): 8 162.11, 150.70, 134.97, 124.58, 60.85, 32.33, 28.63, 28.32, 27.39, 24.42, 14.47 ppm. DEPT (CD30D, 100 MHz): carbons of CH3 e: 14.47; CH2 carbons of: 60.85, 32.33, 28.63, 28.32, 27.39, 24.42; ppm. HPLC: 9.19 min.

Synthesis of 1, 4, 5, 6, 7, 8-hexahydrocycloheptapyrazole-3-carboxylic acid (15): Freshly prepared aqueous NaOH-aqueous (10 M in H20, 9.66 mmol) was added to a solution at room temperature under stirring. (0.4029 g, 1.93 mmol) in MeOH (4.8 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by TLC (0.5 h): The reaction was concentrated and then dissolved in 3.8 mL of H20. 10% aqueous HCl was added dropwise until pH = 2. The white solid was precipitated from the reaction and completely filtered and washed with cold H20. The solid was dried under vacuum overnight to obtain 15: Note: an unwanted impurity that does not collapse the solution in addition to HCl has a retention time of 8,708 min by HPLC. XH (CD3OD, 400 MHz): d 2.98-2.90 (2H, m), 2.80-2.72 (2H, m), 1.92 -1.82 (2H, m), 1.70 - 1.58 (4H, m) ppm. 13 C (CD3OD, 100 MHz): d 164.81, 151.31, 136.87, 125.13, 33.36, 29.73, 28.78, 28.49, 25.17 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons of: 33.36, 29.73, 28.78, 28.49, 25.17 ppm. HPLC: 7.545 min.

Example 5. Synthesis of 5- (4-methylpentyl) -lH-pyrazole-3-carboxylic acid (18): 16 17-18 Synthesis of 8-methyl-2,4-dioxononanoic acid ethyl ester (16): Mixed together 6-methyl-2-heptanone (0.9981 g, 7.80 mmol) and diethyloxalate (1.06 mL, 7.80 mmol), and then added to a NaOEt solution (about 3 M, 2.6 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction is cooled rapidly to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H20, dried with NaS0, filtered and concentrated to yield crude. The crude material was purified with hexanes: CH2C12 1: 1 to obtain 0.8342 g (46.9%) of 16. XH (CD3OD, 400 MHz): d 6.36 (1H, s), 4.30 (2H, q, J = 7.1 Hz), 2.50 (2H, t, J = 7.3 Hz), 1.68 - 1.59 (2H, m), 1.61 - 1.50 (1H, m), 1.33 (3H, t, J = 7.1 Hz), 1.25 - 1.17 (2H, m), 0.89 (6H, d, J = 7.0 Hz) ppm. 13c (CD30D, 100 MHz): d 204.41, 166.93, 163.28, 102.66, 63.29, 41.89, 39.41, 28. 92, 23.65, 22.89, 14.33 ppm.

Synthesis of 5- (4-methylpentyl) -1H-pyrazole-3-carboxylic acid ethyl ester (17): Hydrazine hydrate (0.943 mL, 1.91 mmol) was added to a stirring solution at room temperature of 16 (0.4354 g, 1.91 mmol) in EtOH (1.9 L, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC- The reaction was concentrated and purified by chromatography on silica gel (Combiflash Hexanes: 2N in EtOH NH 3 96: 4 column). Only the pure fractions were combined and concentrated to obtain 0.3132 g (63.1%) of 17. XH (CDC13, 400 MHz): d 9.60 (1H, broad s), 6.58 (1H, s), 4.34 (2H, q, J = 7.2 Hz), 2.66 (2H, t, J = 7.7 Hz), 1.67 -1.57 (2H, m), 1.58 (1H, m), 1.36 (3H, t, J = 7.2 Hz), 1.24 -1.15 ( 2H, m), 0.85 (6H, d, J = 6.5 Hz) ppm. 13C Partial (CDCI3, 100 MHz): d 162.22, 106.59, 61.17, 38.58, 27.99, 27.20, 26.57, 22.72, 14.48 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons of: 22.72, 14.48; CH2 carbons: 61.17, 38.58, 27.20, 26.57; CH carbons: 106.59, 27.99 ppm. HPLC: 10,072 min.

Synthesis of 5- (4-methylpentyl) -lH-pyrazole-3-carboxylic acid (18): Freshly prepared NaOH (10 M in H20, 4.97 mmol) was added to a stirring solution at room temperature of 17 (0.2229 g, 0.994 mmol) in MeOH (12.4 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (20 min): The reaction was concentrated and then dissolved in 2.0 mL of H20. 10% aqueous HCl was added dropwise until pH = 2. The white solid that precipitated from the reaction was filtered off completely and washed with cold H20. The solid was dried under vacuum overnight to obtain 0.1565 g (80.2%) of 18. XH (CD30D, 400 MHz): d 6.56 (1H, s), 2.68 (2H, t, J = 7.6 Hz), 1.67 ( 2H, quintet, J = 7.8 Hz), 1.63 - 1.51 (1H, m), 1.23 (2H, dt, J = 8.8, 7.1 Hz), 0.89 (6H, d, J = 6.4 Hz) ppm. 13 C (CD3OD, 100 MHz): d 163.79, 149.69, 142.80, 107.65, 39.46, 28.92, 28.11, 26.90, 22.91 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.91; CH2 carbons: 39.46, 28.11, 26.90; CH carbons: 107.65, 28.92 ppm. HPLC: 8.579 min.

Example 6. Synthesis of 5-phenethyl-1H-pyrazole-3-carboxylic acid (21): 19 20 21 Synthesis of 2,4-dioxo-6-phenylhexanoic acid ethyl ester (19): Benzylacetone (1.0 g, 6.75 mmol) and diethyloxalate (0.92 mL, 6.75 mmol) were mixed together, and then added to a NaOEt solution ( about 3 M, 2.3 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H20, dried with Na2SO4, filtered and concentrated to yield crude. The crude material was purified with Hexanes: CH2C12 1: 1 to obtain 0.7348 g (43.9%) of 19. ^? (CD3OD, 400 MHz): d 7.27 - 7.12 (5H, m), 4.26 (2H, q, J = 7.2 Hz), 2.89 (2H, t, J = 7.3 Hz), 2.81 (2H, t, J = 7.3 Hz), 1.30 (3H, t, J = 7.1 Hz) ppm. 13C Partial (CD3OD, 100 MHz): d 163.32, 141.74, 129.43, 129.29, 127.16, 126.95, 103.06, 63.34, 43.46, 31.34, 14.24 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 14.24; CH2 carbons: 63.34, 43.46, 31.34; carbons of: CH 129.43, 129.29, 127.16, 103.06 ppm. HPLC: 10,279 min.

Synthesis of 5-phenethyl-1H-pyrazole-3-carboxylic acid ethyl ester (20): Hydrazine hydrate (0.109 mL, 2.24 mmol) was added to a stirring solution at room temperature of 19 (0.5570 g, 2.24 mmol) in EtOH (2.2 mL, 1 M) under N2. The reaction was then heated to reflux until it was judged complete by HPLC. The reaction was concentrated and purified by chromatography on silica gel (Combiflash Hexanes: CH2C12: NH32N in EtOH 70: 30: 2 column). Only the pure fractions were combined and concentrated to obtain 0.2983 g (54.4%) of 20 XH (CDC13, 400 MHz): d 11.7 (1H, broad s), 7.30 - 7.11 (5H, m), "6.60 (1H, s ), 4.32 (2H, q, J = 7.1 Hz), 3.07 - 2.92 (4H, m), 1.31 (3H, t, J = 7.1 Hz) ppm 13C Partial (CDC13, 100 MHz): d 162.13, 147.42, 140.97, 128.72, 128.59, "126.48, 106.79, 61.16, 35.63, 28.18, 14.47 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.47; CH2 carbons: 61.16, 35.63, 28.18; CH carbons: 128.72, 128.59, 126.48, 106.79 ppm. HPLC: 9.299 min.

Synthesis of 5-phenethyl-1H-pyrazole-3-carboxylic acid (21): Freshly prepared aqueous NaOH (10 M in H20, 5.06 mmol) was added to a stirring solution at room temperature of 17 (0.2477 g, 1.01 mmol) in MeOH (2.5 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (30 min). The reaction was concentrated and then dissolved in 2.0 mL of H20. 10% aqueous HCl was added dropwise until pH = 2. The white solid that precipitated from the reaction was filtered off completely and washed with cold H20. The solid was dried under vacuum overnight to obtain 21. Note: an undesired product that does not collapse from the solution in the addition of HCl has a retention time of 8,919 min by HPLC. ? (CD30D, 400 MHz): d 7.28 - 7.20 (2H, m), 7.20 - 6.92 (3H, m), 6.66 (1H, s), 3.02 - 2.92 (4H, m) ppm. 13C (CD3OD, 100 MHz): d 164.79, 148.33, 142.96, 142.11, 129.45, 129.43, 127.21, 107.51, 36.56, 28.97 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 36.50, 28.91; CH carbons of: 129.45, 129.43, 127.24, 107.60 ppm. HPLC: 8.050 min.

Example 7. Synthesis of 5- [2- (4-methoxyphenyl) -ethyl] -1H-pyrazole-3-carboxylic acid (24): Synthesis of 6- (4-methoxyphenyl) -2,4-dioxohexanoic acid ethyl ester (22): 4- (4-methoxyphenyl) -2-butanone (149908 g, 84.2 mmol) and diethyloxalate (12.3434 g, 84. 2 mmol), and then a NaOEt solution is added. (approximately 3 M, 28.1 mL) by stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred. After 10 minutes, the reaction solidified completely. An additional 100 mL of EtOH was added, the reaction was placed on a mechanical shaker overnight. The reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The organic layers were washed with H20, dried over Na 2 SO 4, filtered and concentrated to yield crude. The crude material was purified with 1: 1 CH 2 Cl 12 hexanes to obtain 22. XE (CDC13, 400 MHz): d 14.39 (1H, broad s), 7.10 (2H, d, J = 7.1 Hz), 6.82 (2H, d, J = 6.3 Hz), 6.34 (1H, s), 4.33 (2H, q, J = 7.1 Hz), 3.77 (3H, s), 2.91 (2H, t, J = 7.3 Hz), 2.78 (2H, t, J = 7.3 Hz), 1.36 (3H, t, J = 7.1 Hz) ppm. 13C (CDC13, 100 MHz): d 202.53, 166.46, 162.29, 158.36, 132.36, 129.44, 114.20, 102.11, 62.75, 55.47, 43.02, 29.94, 14.27 ppm. DEPT (CDC13, 100 MHz): CH3 carbons: 55.47, 14.27; CH2 carbons: 62.75, 43.02, 29.94; CH carbons: 129.44, 114.20, 102.11 ppm. HPLC: 10.12 min. (starting material: HPLC: 9.10 min.) Synthesis of 5- [2- (4-Methoxyphenyl) -ethyl] -lH-pyrazole-3-carboxylic acid ethyl ester (23): Hydrazine hydrate (0.513 mL, 10.6 mmol) was added to a stirred solution at room temperature environment of 22 (2.9241 g, 10.5 mmol) in EtOH (10.6 mL, 1 M) under N2. The reaction was then heated to reflux until it was judged complete by HPLC (45 min). The reaction was concentrated and recrystallized from EtOH to obtain 23. XH (CDC13, 400 MHz): d 11.67 (1H, broad s), 7.06 (2H, d, J = 8.3 Hz), 6.78 (2H, d, J = 8.3 Hz), 6.57 (1H, s), 4.30 (2H, q, J = 7.0 Hz), 3. 76 (3H, s), 2.98 (2H, t, J = 7.7 Hz), 2.88 (2H, t, J = 7.7 Hz), 1.30 (3H, t, J = 7.1 Hz) ppm. 13C (CDC13, 100 MHz): d 162.20, 158.13,. 147.05, 141.79, 132.94, 129.42, 113.98, 106.61, 61.02, 55.36, 34.65, 28.23, 14.37 ppm. DEPT (CDC13, 100 MHz): CH3 carbons: 55.36, 14.37; CH2 carbons: 61.02, 34.65, 28.23; CH carbons: 129.42, 113.98, 106.61 ppm. HPLC: 9,200 min.

Synthesis of 5- [2- (4-methoxyphenyl) -ethyl] -lH-pyrazole-3-carboxylic acid (24): Freshly prepared aqueous NaOH (10 M in H20, 25.4 mmol) was added to a stirred solution at room temperature atmosphere of 23 (1391 g, 5.07 mmol) in MeOH (12.7 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (30 min). The reaction was concentrated and then dissolved in 10 mL H20. The reaction was extracted with a small amount of EtOAc, then the aqueous layer was made acidic (pH = 2) with the dropwise addition of 10% aqueous HCl. The white solid that precipitated from the reaction was completely filtered and washed with cold H20. The solid was dried under vacuum overnight to obtain 0.3771 g of relatively pure 24. In addition 24 was purified by recrystallization from hot MeOH to obtain 0.1317 g of pure 24. No attempts were made to recover the remaining 24 of the mother liquor. XH (CD3OD, 400 MHz): d 7.07 (2H, d, J = 8.2 Hz), 6.84 (2H, d, J = 8.6 Hz), 6.53 (1H, s), 3.73 (3H, s), 2.97 - 2.84 (4H, m) ppm. 13C (CD30D, 100 MHz): d 164.86, 159.60, 148.26, 143.15, 134.01, 130.36, 114.81, 107.50, 55.60, 35.67, 29.10 ppm.

Example 8. Synthesis of 4-benzyl-1H-pyrrole-2-carboxylic acid methyl ester (26): Synthesis of 4-Benzyl-1H-pyrrole-2-carboxylic acid methyl ester (25): Triethylsilane (0.215 mL, 1.35 mmol) was added to a stirring solution at room temperature of methyl-4-benzoyl-1H-pyrrol- 2-carboxylate (0.1118 g, 0.488 mmol) in trifluoroacetic acid (TFA) (1.04 mL, 0.47 M) under N2. After stirring overnight, the reaction was completed by HPLC. The TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na 2 SO / filtered, concentrated, and purified by silica gel chromatography (Combiflash column, Hexanes: EtOAc 95: 5 ) to obtain pure 25 (0.0604 g, 57.5%): ^? (CDC13, 400 MHz): d 9.44 (1H, broad s), 7.34 - 7.21 (5H, m), 6.78 (1H, s), 6.75 (1H, s), 3.853 (2H, s), 3.846 (3H, s) ppm. 13C (CDC13, 100 MHz): d 162.09, 141.68, 128.85, 128.70, 126.25, 125.55, 122.67, 121.86, 115.74, 51.70, 33.41 ppm. HPLC: 9.693 min. (Starting material: 8.611 min.) Synthesis of 4-Benzyl-1H-pyrrole-2-carboxylic acid methyl ester (26): Freshly prepared aqueous NaOH (10 M in H20, 1.40 mmol) was added to a stirred solution, at room temperature of 25 (0.0602 g) , 0.280 mmol) in MeOH (0.70 mL, 0.4 M) under N2. Another 0.7 mL of MeOH was added due to the precipitation of the starting material, and the reaction was heated to reflux until the reaction was judged complete by HPLC. The reaction was concentrated and then dissolved in 0.55 mL of H20. 10% aqueous HCl was added dropwise until pH = 2. The white solid which precipitated from the reaction was filtered off completely and washed with cold H20. The solid was dried under vacuum overnight to obtain 0.0495 g (94.5%) of 26. XH (CD30D, 400 MHz): d 10.83 (1H, broad s), 7. 27 -7.11 (5H, m), 6.71 (1H, s), 6. 66 (1H, s), 3.78 (2H, s) ppm. 13 C (CD3OD, 100 MHz): d 164.45, 143.25, 129.58, 129.31, 126.81, 126.18, 123.70, 122.96, 116.68, 34.03 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 34.03; CH carbons: 129.58, 129.31, 126.81, 122.96, 116.68 ppm. HPLC: 8.647 min.

Example 9. Synthesis of 4-phenethyl-lH-pyrrole-2-carboxylic acid (28): Synthesis of 4-phenethyl-1H-pyrrole-2-carboxylic acid methyl ester (27): triethylsilane (0.323 mL, 2.03 mmol) was added to a stirring solution, at room temperature, of methyl-4-phenylacetyl-1H -pyrrole-2-carboxylate (0.1593 g, 0.655 mmol) in trifluoroacetic acid (TFA) (1.47 mL, 0.45 M) under N2. After stirring overnight, the reaction was complete by HPLC. The TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na 2 SO 4, filtered, concentrated, and purified by chromatography on silica gel (Combiflash column, Hexanes: EtOAc 95: 5 ) to obtain pure 27 (0.0755 g, 50.3%): XH (CDC13, 400 MHz): d 9.17 (1H, broad s), 7.32 - 7.25 (2H, m), 7.23 - 7.17 (3H, m), 6.80 ( 1H, s), 6. 69 (1H, s), 3.85 (3H, s), 2.93 - 2.85 (2H, m), 2.84 - 2.75 (2H, m) ppm. 13C (CDC13, 100 MHz): d 161.97, 142.15, 128.70, 128.55, 126.13, 125.96, 122.40, 121.26, 115.28, 51.67, 37.57, 28.92 ppm. DEPT (CDCl 3, 100 MHz): CH3 carbons: 51.67; CH2 carbons: 37.57, 28.92; CH carbons: 128.70, 128.55, 126.13, 121.26, 115.28 ppm. HPLC: 10,033 min. (Starting material: 8,751 min.) Synthesis of 4-phenethyl-1H-pyrrole-2-carboxylic acid (28): NaOH was added. aqueous solution (10 M in H20, 1.65 mmol) was added to a stirring solution, at room temperature of 27 (0.0755 g, 0.329 mmol) in MeOH (0.82 mL, 0.4 M) under N2. Another 0.7 mL of MeOH was added due to the precipitation of the starting material, and the reaction was heated to reflux until the reaction was judged complete by HPLC (2 h): The reaction was concentrated and then dissolved in 0.55 mL H0 Se added dropwise 10% aqueous HCl until pH = 2. The white solid which precipitated from the reaction was filtered off completely and washed with cold H20. The solid was dried under vacuum overnight to obtain pure 28. "" "H (CDC13, 400 MHz): d 10.87 (1H, broad s), 7.25 - 7.18 (2H, m), 7.17 - 7.69 (3H, m), 6.70 (1H, s), 6.67 (1H, s ), 2.83 (2H, t, J = 7.6 Hz), 2.74 (2H, t, J = 7.6 Hz) ppm 13C (CDC13, 100 MHz): d 164.53, 143.39, 129.50, 129.21, 126.76, 126.38, 123.49, 122.85, 116.48, 38.68, 29.94 ppm, DEPT (CDC13, 100 MHz): CH2 carbons: 38.68, 29.94, CH carbons: 129.50, 129.21, 126.76, 122.85, 116.48 ppm, HPLC: 8.579 min.

Example 10. Synthesis of 5-benzyl-1H-pyrrole-2-carboxylic acid (32): Synthesis of 5-benzoyl-1H-pyrrole-2-carboxylic acid ethyl ester (29) and 4-benzoyl-1H-ethyl ester pyrrole-2-carboxylic acid (30): Ethylpyrrole-2-carboxylate (1.0013 g, 7.20 mmol) in a minimum amount (2.5 mL) of dichloroethane was added to an ice cooled stirring mixture of zinc chloride (1.96 g, 14.4 g). mmol) and benzoyl chloride (1.67 mL, 14.4 mmol) in dichloroethane (10.9 mL, 0.66 M) under N2. After stirring for 10 minutes, the ice bath was removed, and the reaction was heated to 50 ° C until it was judged complete by TLC (35 min, Hexanes: EtOAc 9: 1): The reaction was cooled, and poured Carefully in ice water. The reaction was extracted with CH2C12 with 3 portions of solvent. The combined organic layers were washed with H20, dilute HCl, and brine, then dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, Hexanes: EtOAc in 95: 5 to 50:50 ) to obtain 29 (upper Rf) and 30 pure (lower Rf, 0.5646 g, 32.3%): 29 was further purified by chromatography on silica gel (Combiflash column, 100% CH2C12) to achieve 0.6168 g (35.2%) of 29 Spectral data for 29: H (CDC13, 400 MHz): d 10.19 (1H, broad s), 7.90 (2H, d, J = 7.6 Hz), 7.59 (1H, t, J = 7.3 Hz), 7.49 (2H, t, J = 7.3 Hz), 6.94 (1H, dd, J = 3.9, 2.4 Hz), 6.83 (1H, dd, J = 3.9, 2.4 Hz), 4.38 (2H, g, J = 7.0 Hz), 1.38 ( 3H, t, J = 7.1 Hz) ppm. 13 C (CDCl 3, 100 MHz): d 185.37, 160.56, 137.69, 133.30, 132.72, 129.27, 128.69, 127.97, 118.75, 115.72, 61.39, 14.55 ppm. DEPT (CDC13, 100 MHz): carbons of CH3: 14.55; CH2 carbons: 61.39; CH carbons: 132.72, 129.27, 128.69, 118.75, 115.72 ppm. HPLC: 9.792 min. (Starting material: 8.36 min.). Spectral data for 30: ^? (CDC13, 400 MHz): d 10.29 (1H, broad s), 7.84 (2H, dd, J = 8.0, 1.2 Hz), 7.59 -7.53 (2H, m), 7.48 (2H, t, J = 7.6 Hz) , 7.36 (1H, dd, J = 2.4, 1.5 Hz), 4.38 (2H, t, J = 7.3 Hz), 1.35 (3H, t, J = 7.3 Hz) ppm. 13 C (CDCl 3, 100 MHz): d 190.93, 161.47, 139.21, 132.23, 129.22, 128.77, 128.61, 124.35, 116.91, 112.82, 61.30, 14.55 ppm. DEPT (CDC13, 100 MHz): Cll3 carbons: 14.55; CH2 carbons: 61.30; CH carbons: 132.23, 129.22, 128.77, 128.61, 116.91 ppm. HPLC: 9,048 min.

Synthesis of 5-benzyl-1H-pyrrole-2-carboxylic acid ethyl ester (31): Triethylsilane (0.323 mL, 2.03 mmol) was added to a stirred solution at room temperature of 5-benzoyl-1H ethyl ester -pyrrole-2-carboxylic acid (29) (0.4180 g, 1.72 mmol) in trifluoroacetic acid (TFA) (4.1 mL, 0.42 M) under N2. After stirring overnight, the reaction does not appear to be complete by HPLC. The addition of amounts of triethylsilane does not result in any additional change by HPLC, so the reaction was treated. The TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na 2 SO 4, filtered, concentrated, and purified by chromatography on silica gel (Combiflash column, Hexanes: EtOAc 98: 2 to 95: 5) to obtain pure 31 (0.2190 g, 55.6%). 2H (CDC13, 400 MHz): d 9.05 (1H, broad s), 7.35 - 7.28 (2H, m), 7.28 - 7.23 (1H, m), 7.23 - 7.18 (2H, m), 6.85 (1H, t, J = 3.2 Hz), 6.0 (1H, t, J = 3.2 Hz), 4.27 (2H, g, J = 7.1 Hz), 4.00 (2H, s), 1.32 (3H, t, J = 7.3 Hz) ppm. 13C Partial (CDC13, 100 MHz): d 138.51, 136.86, 128.99, 128.88, 126.98, 122.26, 116.08, 109.41, 60.39, 34.37, 14.70 ppm. DEPT (CDC13, 100 MHz): CH3 carbons: 14.70; CH2 carbons: 60.39, 34.37; CH carbons: 128.99, 128.88, 126.98, 116.08, 109.41 ppm. HPLC: 10,014 min.

Synthesis of 5-benzyl-1H-pyrrole-2-carboxylic acid (32): Freshly prepared aqueous NaOH (10 M in H20, 4.78 mmol) was added to a stirring solution, at room temperature of 31 (0.2190 g, 0.955 mmol) in MeOH (2.4 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC (40 min). The product was concentrated and then dissolved in 1.9 mL H20. 10% aqueous HCl was added dropwise until pH = 2. The white solid that precipitated from the reaction was completely filtered and washed with cold H0. The solid was dried under vacuum overnight to obtain 32 as an impure, pale pink solid (0.0845 g). 32 It was further purified by adding CHC13, stirring, and filtering the pure white solid (0.0445 g). Note: The unwanted impurity has a retention time of 9,643 min by HPLC. Also, the 13 C NMR of 32 at room temperature showed doublets for the peaks corresponding to the pyrrole carbons, benzyl carbon and acid carbon. When the NMR probe was heated to 28 ° C, all double peaks collapsed in individual peaks as reported below. XH (CD30D, 400 MHz): d 11.04 (1H, broad s), 7.27 - 7.13 (5H, m), 6.80 (1H, d, J = 3.4 Hz), 5.87 (1H, d, J = 3.4 Hz) 3.93 (2H, s) ppm. 13C (CD30D, 100 MHz): d 164.52, 140.71, 139.04, 129.56, 129.42, 127.27, 122.77, 117.59, 109.66, 34.65 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 34.65; CH carbons: 129.56, 129.42, 127.27, 117.59, 109.66 ppm. HPLC: 8.698 min.

Example 11. Synthesis of 5-phenethyl-1H-pyrrole-2-carboxylic acid (36): Synthesis of 5-phenylacetyl-lH-pyrrole-2-carboxylic acid ethyl ester (33) and 4-phenylacetyl-lH-pyrrole-2-carboxylic acid ethyl ester (34): Ethylpyrrole-2-carboxylate (2.5182 g, 18.1 mmol) in a minimum amount of dichloroethane was added to an ice cooled stirring mixture of zinc chloride (4.9891 g, 36.6 mmol) and phenylacetyl chloride (4.76 mL, 35.9 mmol) in dichloroethane (25 mL, 0.72 M) under N2 After stirring for 10 min, the ice bath was stirred, the reaction was heated to 50 ° C until it was judged complete by TLC (30 min., Hexanes: EtOAc 9: 1): The reaction was cooled and poured Carefully in ice water. The reaction was extracted into CH2C1 with 3 portions of solvent. The combined organic layers were washed with H20, dilute HCl, and brine, then dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, Hexanes: EtOAc 90:10 to 60:40). to obtain 33 (lower Rf) and 34 (upper Rf): 33 was found to contain a colored impurity that was easily removed by adding hexanes and removing the colored solution. After treatment with hexanes 33 (0.7239 g, 15.5%) was sufficiently "pure to continue to the next step." Spectral data for 33: XH (CDC13, 400 MHz): d 9.87 (1H, broad s), 7.35 - 7.23 (5H, m), 6.92 -6.87 (2H , m), 4.34 (2H, q, J = 7.1 Hz), 4.09 (2H, s), 1.36 (3H, t, J = 7.1 Hz) ppm 13C (CDC13, 100 MHz): d 188.72, 160.49, 134.40 , 133.63, 129.57, 128.96, 127.82, 127.32, 116.60, 115.73, 61.39, 45.59, 14.54 ppm DEPT (CDCl3, 100 MHz): CH3 carbons: 14.54; CH2 carbons: 61.39, 45.59; CH carbons: 129.57, 128.96, 127.32, 116.60, 115.73 ppm. HPLC: 9.714 min. (Start material: 8.36 min.) Spectral data for 34: XH (CDC13, 400 MHz): d 10.16 (1H, broad s), 7.74 (1H, s), 7.72 (1H, s), 7.44 -7.23 (5H , m), 4.33 (2H, q, J = 7.1 Hz), 4.18 (2H, s), 1.34 (3H, t, J = 7.1 Hz) ppm. 13C Partial (CDC13, 100 MHz): d 193.45, 160.64, 61.43, 47.97, 14.49 ppm. HPLC: 10.7 min.

Synthesis of 5-phenethyl-1H-pyrrole-2-carboxylic acid ethyl ester (35): triethylsilane (0.46 mL, 2.88 mmol) was added to a stirred solution, at room temperature, of 5-phenylacetyl-lH ethyl ester -pyrrole-2-carboxylic acid ethyl ester (3-3) (0.240 g, 0.929 mmol) in trifluoroacetic acid (TFA) (2.2 mL, 0.42 M) under N2. The reaction was judged complete by HPLC after 3.5 h. The TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na 2 SO 4, filtered, concentrated, and purified by chromatography on silica gel (Combiflash column, Hexanes: CH 2 C 12 60: 40 to obtain 35, which appeared pure by TLC, but impure by HPLC, pure 35 was obtained by preparative inverted phase HPLC with the following conditions: from 0 to 10 min, H20: CH3CN 35:65, 10 -11 min, H20: CH3CN from 35:65 to 0: 100, 20 mL / min,? = 254 nM, 50.8 mg / mL, 0.8 mL / injection, 2H (CDC13, 400 MHz): d 9.46 (1H, broad s), 7.33 - 7.16 (5H, m), 6.85 (1H, t, J = 2.9 Hz), 5.99 (1H, t, J = 2.9 Hz), 4.29 (2H, q, J = 7.1 Hz), 2.97 (4H, s ), 1.33 (3H, t, J = 7.1 Hz) ppm 13C (CDC13, 100 MHz): d 161.76, 141.16, 138.18, 128.69, 128.52, 126.46, 121.52, 116.06, 108.46, 60.36, 35.89, 29.83, 14.67 ppm DEPT (CDC13, 100 MHz): CH3 carbons: 14.67, CH2 carbons: 60.36, 35.89, 29.83, CH carbons: 128.69, 128.52, 126.46, 116.06, 108.46 ppm HPLC: 10,392 min.

Synthesis of 5-phenethyl-1H-pyrrole-2-carboxylic acid (36): Freshly prepared aqueous NaOH (10 M in H20, 1.67 mmol) was added to a stirring solution, at room temperature of 35 (0.0814 g, 0.333 mmol) in MeOH (0.83 L, 0.4 M) under N2. 0.4 mL of iPrOH was added to solubilize 35. The reaction was heated to reflux until the reaction was judged complete by HPLC. The product was concentrated and then dissolved in 1.9 mL of H20. 10% aqueous HCl was added dropwise until pH = 2. The white solid that precipitated from the reaction was completely filtered and washed with cold H20. The solid was dried under vacuum overnight to obtain 36 as a pale pink solid (Note: An unwanted impurity has a retention time of 12,055 min by HPLC.) Also, 13 C NMR of 36 at room temperature showed doublets for the peaks that correspond to the carbons of pyrrole, benzyl carbon and acid carbon.When the NMR probe was heated to 28 ° C, all the double peaks collapsed to individual peaks as reported below.? L (CD3OD, 400 MHz): d 10.97 (1H, broad s), 7.25 -7.20 (2H, m), 7.18 - 7.11 (3H, m), 6.76 (1H, d, J = 3.4 Hz), 5.90 (1H, d, J = 3.4Hz) 2.94 - 2.84 (4H,) ppm 13C (CD3OD, 100 MHz): 164.51, 142.68, 139.79, 129.40, 129.30, 126.98, 122.36, 117.47, 108.90, 37.00, 30.67 ppm DEPT (CDC13, 100 MHz): CH2 carbons: 37.00, 30.67; CH carbons: 129.40, 129.30, 126.98, 117.47, 108.90 ppm HPLC: 11.239 min.

Example 12. Synthesis of 4- [2- (4-chlorophenyl) -ethyl] -1H-pyrrole-2-carboxylic acid (39): Synthesis of 4- [2- (4-chlorophenyl) -acetyl] -lH-pyrrole-2-carboxylic acid ethyl ester (37): Ethylpyrrole-2-carboxylate (1.0195 g, 7.33 mmol) in a minimum amount of dichloroethane added to an aluminum-chilled stirring mixture of aluminum chloride (1934 g, 14.5 mmol) and 4-chlorobenzeneacetyl chloride (2.7841 g, 14.73 mmol) in dichloroethane (10.9 mL, 0.67 M) under N2. After stirring for 10 minutes, the ice bath was stirred, and the reaction was stirred at room temperature for 60 minutes, with small change by TLC (Hexanes: EtOAc 9: 1). After heating at 60 ° C for an additional hour, only a small amount of the starting material was left by TLC. The reaction was cooled to room temperature, PS-Trisamine ™ resin (6.3954 g, 24.30 mmol) and dichloroethane (10 mL) were added and the reaction was stirred for 3 hours. The reaction was then filtered through a funnel with glass frit directly into ice water. The resin was rinsed with CH2C12, then the organic layers were removed, dried over Na 2 SO 4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, Hexanes: EtOAc 95: 5 to 50:50) to obtain 1.0345 g (48.4%) of 37 as a pale orange solid. . Note: A small amount of CH2C12 was required to solubilize the crude product before placement on the silica column. XH (CDC13, 400 MHz): d 10.07 (1H, broad s), 7.55-7.52 (1H, m), 7.33-7.30 (1H, m), 7.27 (2H, d, J = 8.3 Hz), 7.14 (2H , d, J = 8.3 Hz), 4.35 (2H, q, J = 7.0 Hz), 4.04 (2H, s), 1.37 (3H, t, J = 7.1 Hz) ppm. 13C (CDC13, 100 MHz): d 192.55, 160.97, 133.10, 132.75, 130.76, 128.69, 126.80, 126.25, 124.30, 114.95, 61.06, 45.79, 14.31 ppm. DEPT (CDC13, 100 MHz): carbons of CH3: 14.31; CH2 carbons: 61.06, 45.79; CH carbons: 130.76, 128.69, 126.80, 114.96 ppm. HPLC: 10,049 min.

Synthesis of 4- [2- (4-chlorophenyl-ethyl] -lH-pyrrole-2-carboxylic acid ethyl ester (38) Triethylsilane (1.13 mL, 7.08 mmol) was added to a stirring solution, at room temperature of ester Ethyl 4- [2- (4-chlorophenyl) -acetyl] -lH-pyrrole-2-carboxylic acid (37) (0.6662 g, 2.28 mmol) in trifluoroacetic acid (TFA) (5.54 mL, 0.42 M) under N2. After stirring at room temperature for 4 hours, the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with NaS04 / filtered, concentrated, and purified by reverse phase HPLC. , preparative with the following conditions: from 0 to 12 min, H20: CH3CN 35:65, 12 -13 min, H20: CH3CN from 35:65 to 0: 100, 20 mL / min,? = 254 nM, 137 mg / mL, 1.0 mL / injection, 0.2704 g (42.6%) of 38 were obtained as a white foamy solid (Note: A desired impurity has a retention time of 12,055 minutes by HPLC.) ^? (CDC13, 400 MHz) : d 8.99 (1H, broad s), 7.23 (2H, d, J = 8.3 Hz), 7.09 (2H, d, J = 8.3 Hz), 6.76 (1H, s), 6.64 (1H, s), 4.30 (2H, q, J = 7.0 Hz), 2.84 (2H, t, J = 7.6 Hz), 2.75 (2H, t, J = 7.6 Hz), 1.35 (3H, t, J = 7.1 Hz) ppm. 13C (CDC13, 100 MHz): d 161.14, 140.25, 131.52, 129.80, 128.32, 125.17, 122.62, 120.66, 114.73, 60.25, 36.62, 28.53, 14.43 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.43; CH2 carbons: 60.25, 36.62, 28.53; CH carbons: 129.80, 128.32, 120.66, 114.73 ppm. HPLC: 11,049 min.

Synthesis of 4- [2- (4-chlorophenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (39): Freshly prepared aqueous NaOH (10 M in H20, 4.84 mmol) was added to a stirred solution, ambient temperature of 38 (0.2689 g, 0.968 mmol) in MeOH (2.42 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC (30 min): The product was concentrated and then dissolved in 5 mL H20. The product was extracted with EtOAc, then the aqueous layer was made acidic (pH = 2) with the dropwise addition of 10% aqueous HCl. The white solid that precipitated from the reaction was filtered and washed with cold H20. The solid was dried under vacuum overnight to obtain 39 as a pale pink solid (Note: An unwanted impurity has a retention time of 10 956 minutes by HPLC XH (CD30D, 400 MHz): d 10.89 (1H, broad s) , 7.22 (2H, d, J = 8.3 Hz), 7.13 (2H, d, J = 8.3 Hz), 6.69 (1H, s), 6.66 (1H, s), 2.82 (2H, t, J = 7.1 Hz) 2.73 (2H, t, J = 7.1 Hz) ppm 13C (CD3OD, 100 MHz): d 164.48, 142.15, 132.49, 131.15, 129.21, 125.97, 123.60, 122.88, 116.44, 37.92, 29.70 ppm DEPT (CDC13, 100 MHz): CH2 carbons: 37.92, 29.70, CH carbons: 131.15, 129.21, 122.88, 116.44 ppm HPLC: 9.996 min.

Example 13. Synthesis of 5-phenoxymethyl-1H-pyrazole-3-carboxylic acid (42): a 40 41 42 Synthesis of 2,4-dioxo-5-phenoxypentanoic acid ethyl ester (40): Phenoxyacetone (5.0240 g, 33.46 mmol) and diethyloxalate (4.52 mL, 33.29 mmol) were mixed together and then added to a NaOEt solution (about 3 M, 11.1 mL) by stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with Na 2 SO 4, filtered, and concentrated to yield 40. The crude material was purified with Hexanes: CH 2 Cl 2 1: 1 to obtain 1.3490 g (15.4%) of 40. aH (CDC13, 400 MHz): d 7.31 (2H, t, J = 7.5 Hz), 7.01 (1H, t, J = 7.3 Hz), 6.91 (2H, d, J = 8.8"Hz), 6.76 (1H, s), 4.67 (2H, s), 4.35 (2H, q, J = 7.1 Hz), 1.38 (3H, t , J = 7.1 Hz) ppm 13C (CDCl 3, 100 MHz): d 199.61, 166.38, 161.55, 157.37, 129. 63, 121.89, 114.48, 98.97, 70.13, 62.60, 13.90 ppm. DEPT (CDCl 3, 100 MHz): CH 3 carbons: 13.90; CH2 carbons: 70. 13, 62.60; CH carbons: 129.63, 121.89, 114.48, 98.97 ppm. HPLC: 10,180 min. (Starting material: 9,053 min) Synthesis of 5-phenoxymethyl-1H-pyrazole-3-carboxylic acid ethyl ester (41): Hydrazine hydrate (0.197 mL) was added, 4.06 mmol) was added to a stirring solution at room temperature of 40 (1.0163 g, 4.06 mmol) in EtOH (4.1 mL, 1 M) under N2. The reaction was then heated to reflux until it was judged complete by HPLC. The reaction was concentrated and purified by chromatography on silica gel (Combiflash column, Hexanes: CH2C12: NH3 2N in EtOH, '92: 4: 4): Only the pure fractions were combined and concentrated to obtain 0.5474 g (54.7%) of 41. ^? (CDC13, 400 MHz): d 12.12 (1H, broad s), 7. 28 (2H, t, J = 7.8 Hz), 7.01 - 6.94 (3H, m), 6.91 (1H, s), . 17 (2H, s), 4.36 (2H, q, J = 7.0 Hz), 1.36 (3H, t, J = 7.1 Hz) ppm. 13C Partial (CDC13, 100 MHz): d 158.11, 129.48, 121.26, 114.71, 107.83, 62.61, 61.31, 14.17 ppm. HPLC: 9.505 min.

Synthesis of 5-phenoxymethyl-1H-pyrazole-3-carboxylic acid (42): Freshly prepared aqueous NaOH (10 M in H20, 10.49 mmol) was added to a stirring solution, at room temperature of 41 (0.5164 g, 2.10 mmol ) in MeOH (5.2 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (20 min): The reaction was concentrated and then dissolved in 4.2 mL H20. 10% aqueous HCl was added dropwise until pH = 2. The white solid which precipitated from the reaction was filtered off completely and washed with cold H20. The solid was dried under vacuum overnight to obtain 0.4044 g (88.4%) of 42 as a white solid. Note: An unwanted impurity that does not collapse from the solution in the addition of HCl has a retention time of 9127 minutes per XH (CDC13, 400 MHz): d 7.26 (2H, t, J = 8.0 Hz), 6.99 (2H, d, J = 8.3 Hz), 6.94 (1H, t, J = 7.3 Hz), 6.85 (1H, s), 5.10 (2H, s) ppm. 13C (CDC13, 100 MHz): d 163.68, 159.73, 146.60, 141.13, 130.51, 122.27, 115.83, 108.88, 63.06 ppm. DEPT (CDC13, 100 MHz): CH2 carbons: 63.06; CH carbons: 130.51, 122.27, 115.83, 108.88 ppm. HPLC: 8.272 min.

Example 14. Synthesis of 4- (3-phenylpropyl) -lH-pyrrole-2-carboxylic acid (45): Synthesis of 4- (3-phenylpropionyl) -1H-pyrrole-2-carboxylic acid ethyl ester (43): Ethylpyrrole-2-carboxylate (1.6236 g, 11.67 mmol) in a minimum amount of dichloroethane was added to a stirring mixture ice-cooled aluminum chloride (3.1085 g, 23.30 mmol) and hydrocinnanomyl chloride (3.9058 g, 23.16 mmol) in dichloroethane (17.7 mL, 0.67 M) under N2. After stirring for 10 minutes, the ice bath was stirred and the reaction was stirred at room temperature for 60 minutes, with little change by TLC (Hexanes: EtOAc 9: 1): After heating at 60 ° C for one hour In addition, only a small amount of starting material was left by TLC. The reaction was cooled to room temperature, Polyamine HL resin (2.60 mmol / g, 16.41 g, 42.67 mmol) and dichloroethane (10 mL) were added, and the reaction was stirred for 3 hours. The reaction was then filtered through a funnel with glass frit directly into ice water. The resin was rinsed with CH2C12, then the organic layers were removed, dried with Na2SO4, filtered, concentrated, and purified by chromatography on silica gel (Combiflash column, Hexanes: CH2C12: NH3 2N in EtOH, 92: 8: 4) to obtain 0.5501 g (14.1%) of 43 as a pale orange solid. XH (CDC13, 400 MHz): d 10.70 (1H, broad s), 7.56 (1H, s), 7.36 - 7.17 (6H, m), 4.35 (2H, q, J = 7.0 Hz), 3.18 - 3.10 (2H , m), 3.10 - 3.01 (2H, m), 1.37 (3H, t, J = 7.1 Hz) ppm. 13 C (CDCl 3, 100 MHz): d 194.98, 161.18, 141.13, 128.31, 128.20, 126.64, 126.42, 125.92, 123.96, 114.72, 60.84, 41.19, 30.04, 14.16 ppm. DEPT (CDC13, 100 MHz): CH3 carbons: 14.16; CH2 carbons: 60.84, 41.19, 30.04; CH carbons: 128.31, 128.20, 126.64, 125.92, 114.72 ppm. HPLC: 9.975 min.

Synthesis of 4- (3-phenylpropyl) -1H-pyrrole-2-carboxylic acid ethyl ester (44): Triethylsilane (0.776 mL, 4.87 mmol) was added to a stirring solution, at room temperature 43 (0.5266 g, 1.57 mmol) in trifluoroacetic acid (TFA) (3.74 mL, 0.42 M) under N2. After stirring at room temperature for 4 hours, the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na 2 SO 4, filtered, concentrated, and purified by phase HPLC. Preparative inverted with the following conditions: from 0 to 11 minutes, H20: CH3CN 35:65. 11.5 -20 minutes, H20: CH3CN from 35:65 to 0: 100; 20 mL / min .; ? = 254 nM; 200 mg / mL, 0.7 mL / injection. 0.2455 g (48.7%) of 44 was obtained as a fluffy white solid. (Note: An unwanted impurity has a retention time of 12,062 min by HPLC.) AH (CDC13, 400 MHz): d 9.27 (1H, broad s), 7.34 -7.26 (2H, m), 7.24 - 7.17 (3H, m), 6.81 (1H, s), 6.75 (1H, s), 4.33 (2H, q, J = 7.1 Hz), 2.67 (2H, t, J = 7.8 Hz), 2.53 (2H, t, J = 7.8 Hz), 1.93 (2H, quintet, J = 7.8 Hz), 1.37 (3H, t, J = 7.1 Hz) ppm. 13C (CDC13, 100 MHz): d 161.34, 142.31, 128.40, 128.22, 125.99, 125.64, 122.47, 120.73, 114.82, 60.17, 35.33, 32.47, 26.17, 14.41 ppm. DEPT (CDC13, 100 MHz): CH3 carbons: 14.41; CH2 carbons: 60.17, 35.33, 32.47, 26.17; CH carbons: 128.40, 128.22, 125.64, 120.73, 114.82 ppm. HPLC: 11,140 min.

Synthesis of 4- (3-phenylpropyl) -lH-pyrrole-2-carboxylic acid (45): Freshly prepared aqueous NaOH (10 M in H20, 3.82 mmol) was added to a stirring solution, at room temperature of 44 (0.2455) g, 0.7644 mmol) in MeOH (1.9 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC (25 min): The product was concentrated and then dissolved in 1.5 mL H20. The product was extracted with EtOAc, then the aqueous layer was made acidic (pH = 2) with the dropwise addition of 10% aqueous HCl. EtOAc was added, and the product was extracted into the organic layer. The organic layer was dried with NaS04, filtered, and concentrated to obtain 56.1 mg of the product which contained a few minor impurities by HPLC. The product was taken in a minimum amount of CHC13 with heating and then a small amount of hexanes was added to precipitate the product. The product was filtered, and dried to obtain 16.0 mg of 45. (Note: Undesired impurity has a retention time of 10.843 min by HPLC.1H (CD3OD, 400 MHz): d 7.24 (2H, t, J = 7.3 Hz ), 7.16 (2H, d, J = 7.3 Hz), 7.13 (1H, t, J = 7.3 Hz), 6.75 (1H, s), 6.71 (1H, s), 2.61 (2H, t, J = 7.8 Hz ), 2.46 (2H, t, J = 7.8 Hz), 1.86 (2H, quintet, J = 7.8 Hz) ppm 13C (CD3OD, 100 MHz): d 164.54, 143.73, 129.47, 129.27, 126.73, 126.66, 123.49, 122.56, 116.34, 36.41, 34.23, 27.21 ppm, DEPT (CDCl3, 100 MHz): CH2 carbons: 36.41, 34.23, 27.21, CH carbons: 129.47, 129.27, 126.66, 122.56, 116.34 ppm, HPLC: 9.845 min.

Example 15. Synthesis of 5- (3-methylbutyl) -lH-pyrazole-3-carboxylic acid (48): ii 46 47 48 Synthesis of 7-methyl-2,4-dioxooctanoic acid ethyl ester (46): 5-Methyl-2-hexanone (5.0084 g, 43.9 mmol) and diethyloxalate (5.95 mL, 43.8 mmol) were mixed together, and then it was added to a NaOEt solution (approximately 3 M, 14.6 mL) by stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H20, dried with Na2SO4, filtered, and concentrated to yield 46. The crude material was purified with Hexanes: CH2C12 1: 1 to obtain 6.6035 g (70.3%) of 46. XH (CDC13 , 400 MHz): d 6.28 (1H, s), 4.25 (2H, q, J = 7.0 Hz), 2.40 (2H, t, 7.6 Hz), 1.54 -1.41 (3H, m), 1.27 (3H, t, J = 7.3 Hz), 0.82 (6H, d, J = 6.3 Hz) ppm. 13C (CDC13, 100 MHz): d 203. 40, 166.27, 161.85, 101.37, 62.15, 38.74, 33.39, 27.46, 21.99, 13.77 ppm. DEPT (CDC13, 100 MHz): CH3 carbons: 21.99, 13.77; CH2 carbons: 62.15, 38.74, 33.39; CH carbons: 101.37, 27.46 ppm. HPLC: 11,038 min.

Synthesis of 5- (3-methylbutyl) -1H-pyrazole-3-carboxylic acid ethyl ester (47): Hydrazine hydrate (1.43 mL, 2.95 mmol) was added to a stirring solution at room temperature of 46 (6.3112 g) , 2.95 mmol) in EtOH (29.5 mL, 1 M) under N2. The reaction was then stirred at room temperature until it was judged complete by HPLC (35 min): The reaction was concentrated and purified by chromatography on silica gel (Combiflash column, Hexanes: 2N NH 3 in EtOH 96: 4). combined the pure fractions and concentrated to obtain 4.3911 g (70.9%) of 47. XH (CDC13, 400 MHz): d 13.01 (1H, broad s), 6.52 (1H, s), 4.29 (2H, q, J = 7.1 Hz), 2.64 (2H, t, J = 7.8 Hz), 1.57 - 1.41 (3H, m), 1.26 (3H, t, J = 7.1 Hz), 5.85 (6H, d, J = 5.9 Hz) ppm. 13C (CDC13, 100 MHz): d 162.37, 146.26, 143.1, 105.73, 60.53, 37.88, 27.35, 23.42, 22.11, 14.06 ppm HPLC: 10.006 min.

Synthesis of 5- (3-methylbutyl) -lH-pyrazole-3-carboxylic acid (48): Freshly prepared aqueous NaOH (10 M in H20, 80.85 mmol) was added to a stirring solution, at room temperature of 47 (3.40. g, 16.17 mmol) in MeOH (40.4 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (6 min): The reaction was concentrated and then dissolved in 14 mL H20. 10% aqueous HCl was added dropwise until pH = 2. The white solid which precipitated from the reaction was filtered off completely and washed with cold H20. The solid was dried under vacuum overnight to obtain 2.8753 g (97.6%) of 48. (Note: A desired impurity has a retention time of 9,522 minutes by HPLC.) ^? (CDC13, 400 MHz): d 6.61 (1H, s), 2.70 (2H, t, J = 7.8 Hz), 1.63 - 1.51 (3H, m), 0.94 (6H, d, J = 6.3 Hz) ppm. 13C (CDC13, 100 MHz): d 164.35, 149.48, 143.00, 107.34, 39.35, 28.71, 24.69, 22.65 ppm. DEPT (CDCl3, 100 MHz): carbons of CH3: 22.65; CH2 carbons: 39.35, 24.69; CH carbons: 107.34, 28.71 ppm. HPLC: 9,522 min.

Example 16. Synthesis of 5- (4-Methylpent-3-enyl) -1H-pyrazole-3-carboxylic acid (51): 49 SQ 51 Synthesis of ethyl ester of 8-methyl-2,4-dioxonon-7-enoic acid (49): Sodium hydride (0.465 g, 19.4 mmol) was added slowly to an ice bath with NaCl containing EtOH (5.88 mL, 3.3 M) stirring under N2. 6-Methylhept-5-en-2-one (2.4412 g, 19.3 mmol) and diethyloxalate (2.63 mL, 0.19 mmol) were mixed together, and then added to a cooled solution of NaOEt. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred for 6 hours, at which point the reaction was judged complete by TLC. The reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H20, dried over Na2SO, filtered and concentrated, purified by silica gel chromatography (Combiflash column, Hexanes: CH2C12: NH3 2N 70: 30: 3 in EtOH): concentrated only the pure fractions to obtain 1.9190 g (43.8%) of 49. XH (CDC13, 400 MHz): d 14.44 (1H, broad s), 6.34 (1H, s), 5.06 (1H, t, J = 7.3 Hz, 4.33 (2H, q, J = 7.1 Hz), 2.49 (2H, t, J = 7.3 Hz), 2.31 (2H, q, J = 7.3 Hz), 1.66 (3H, s), 1.60 (3H, s), 1.35 (3H, t, J = 7. 1 Hz) ppm. 13 C (CDCl 3, 100 MHz): d 202.83, 166.39, 162.08, 133. 42, 121.90, 101.64, 62.40, 40.92, 25.59, 23.34, 17.61, 13. 96 ppm. DEPT (CDC13, 100 MHz): CH3 carbons: 25.59, 17.62, 13.97; CH2 carbons:, 62.40, 40.92, 23.34; CH carbons: 121.90, 101.64 ppm. HPLC: 11.007 min.

Synthesis of 5- (4-methylpent-3-enyl) -lH-pyrazole-3-carboxylic acid ethyl ester (50): Hydrazine hydrate (0.41 mL, 8.48 mmol) was added to a stirring solution at room temperature of 49 (0.1.9190 g, 8.48 mmol) in EtOH (8.5 mL, 1 M) under N2 The reaction was then heated to reflux until it was complete by HPLC (1/2 h): The reaction was concentrated and purified chromatography on silica gel (Combiflash column, Hexanes: NH2 2N 96: 4 in EtOH): XH (CDC13, 400 MHz): d 12.73 (1H, broad s), 6.57 (1H, s), 5.09 (1H, t , J = 6.8 Hz), 4.32 (2H, q, J = 7.1 Hz), 2.70 (2H, t, J = 7.5 Hz), 2.29 (2H, q, J = 7.5 Hz), 1.63 (3H, s), 1.52 (3H, s), 1.30 (3H, t, J = 7.1 Hz) ppm 13C Partial (CDC13, 100 MHz): d 162.27, 106.11, 60.65, 31.49, 27.53, 25.52, 17.51, 13.10 ppm HPLC: 9.986 min.

Synthesis of 5- (4-methylpent-3-enyl) -lH-pyrazole-3-carboxylic acid (51): Freshly prepared, aqueous NaOH (10 M in H20, 11.85 mmol) was added to a stirred solution at room temperature of 50 (0.0.5269 g, 2.37 mmol) in MeOH (5.9 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (5 min): The reaction was concentrated, redissolved in H20, and extracted with EtOAc. Aqueous HCl 10% was added dropwise. the aqueous layer until pH = 2. The white solid which precipitated from the reaction was completely filtered and washed with cold H20. The solid was dried under vacuum overnight to obtain 0.4034 g (87.6%) of 51. XH (CD30D, 400 MHz): d 6. 56 (1H, s), 5.14 (1H, t), 2.68 (2H, t, J = 7.3 Hz), 2.33 (2H, q, J = 7.3 Hz), 1.67 (3H, s), 1.56 (3H, s) ppm. 13C (CD30D, 100 MHz): d 164.94, 148.55, 143.23, 123.94, 107.32, 28.89, 27.04, 25.85, 17.69 ppm. DEPT (CD30D, 100 MHz): CH3 carbons: 25.85, 17.69; CH2 carbons: 28.89, 27.04; CH carbons: 123.94, 107.32 ppm: HPLC: 8.475 min.

Example 17. Synthesis of 5 [2- (2,2,6-trimethylcyclohexyl) -ethyl] -lH-pyrazole-3-carboxylic acid (54): 52 53 54 Synthesis of 2,4-dioxo- 6- (2, 2, 6-trimethylcyclohexyl) -hexanoic acid (52): Sodium iodide (0.6447 g, 25.52 mmol) was added slowly to an ice bath with NaCl containing EtOH (10 mL, 2.6 M) stirring under N2. 4- (2, 2-, 6-trimethylcyclohexyl) -butan-2-one (5.0072 g, 25.50 mmol) and diethyloxalate (3.7241 g, 25.48 mmol) were mixed together and then added to the cooled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. The reaction solidified rapidly. An additional 10 mL of EtOH was added, and the reaction was allowed to stand for another 3 hours. The reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H20, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash Hexanes: CH2C12 1: 1 column): Only pure fractions were pooled and concentrated to obtain the same. aH (CDC13, 400 MHz): d. 14.51 (1H, broad s), 6.34 (1H, s), 4.34 (2H, g, J = 7.1 Hz), 2.44 (2H, t, J = 8.3 Hz), 1.96 - 1.84 (1H, m), 1.68 - 1.22 (m), 1.36 (3H, t, J = 7.1 Hz), 1.18 - 0.98 (m), 0.94 (3H, s), 0.87 (3H, s), 0.85 (3H, d, J = 7.3 Hz) ppm . Partial 13C (CDC13, 100 MHz): d 203.45, 167.17, 162.40, 101.80, 62.71, 49.28, 42.60, 30.46, 20.86, 14.27 ppm. Partial DEPT (CDC13, 100 MHz): CH3 carbons: 14.27; CH2 carbons: 62.71; CH carbons: 101.80 ppm. HPLC: 12.576 min.

Synthesis of 5- [2- (2,2,6-trimethylcyclohexyl) -ethyl] -lH-pyrazole-3-carboxylic acid ethyl ester (53): Hydrazine hydrate (0.867 mL, 17.9 mmol) was added to a solution under stirring at room temperature of 52 (5.2981 g, 17.9 mmol) in EtOH (17.9 mL, 1 M) under N2. The reaction was then heated to reflux until it was judged complete by HPLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, Hexanes: 2N NH3 97: 3 in EtOH) to obtain 1.6604 g (31.8%) of 53. XH Partial (CDC13, 400 MHz): d 12.45 (1H, broad s), 6.58 (1H, s), 4.32 (2H, g, J = 7.1 Hz), 2.63 (2H, t, J = 8.3 Hz), 1.31 (3H, t, J = 7.1 Hz), 0.90 (3H, s), 0.83 (3H, s), 0.78 (3H, d, J = 6.8 Hz) ppm. 13C Partial (CDC13, 100 MHz): d 106.04, 60.66, 48.99, 34.03, 30.10, 24.89, 14.17 ppm. HPLC: 12,000 min.

Synthesis of 5- [2- (2, 2,6-trimethylcyclohexyl) -ethyl] -1H-pyrazole-3-carboxylic acid (54): Freshly prepared aqueous NaOH (10 M in H20, 2.73 mmol) was added to a solution under stirring at room temperature of 53 (0.1594 g, 0.5451 mmol) in MeOH (1.36 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (5 min). The reaction was concentrated, redissolved in H20, and extracted with EtOAc. 10% aqueous HCl was added dropwise to the aqueous layer until pH = 2. The white solution which precipitated out from the reaction was completely filtered and washed with cold H20. The solid was dried under vacuum overnight to obtain 0.0119 g (8.2%) of 54. An additional 0.0590 g (40.9%) of 54, slightly impure aungue, was obtained from the EtOAc layer. ^? (CD3OD, 400 MHz): d 6.56 (1H, s), 2.64 (2H, t, J = 7.8 Hz), 2.03 - 1.89 (1H, m), 1.69 - 1.53 (2H, m), 1.55-1.41 (2H , m), 1.39 -1.27 (2H, m), 1.20 -1.06 (3H, m), 0.97 (3H, s), 0.91 (3H, s), 0.86 (3H, d, J = 6.8 Hz) ppm. 13C (CD3OD, 100 MHz): d 165.07, 149.02, 143.33, 107.26, 50.24, 37. 04, 35.11, 31.58, 31.33, 29.00, 28.87, 28.37, 26.30, 22. 13, 18.90 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 29. 00, 28.87, 18.90; CH2 carbons: 37.04. 31.33, 28.37, 26.30, 22.13; CH carbons: 107.26, 50.24, 31.58 ppm. HPLC: 10,497 min.

Example 18. Synthesis of 5- (2-phenylpropyl) -lH-pyrazole-3-carboxylic acid (58): Synthesis of 4-phenylpentan-2-one (55): 1.6 M methyl lithium (22.8 mL, 36.5 mmol) was added during 1 hour to a stirring solution at 0 ° C of 3-phenylbutyric acid (1.8298 g, 11.14 mmol ) in dry Et20 (56 mL, 0.2 M): The ice bath was stirred and the reaction was allowed to stir at room temperature for an additional 2 2/3 hours. Another 0.8 mL of MeLi (1.12 mmol, 0.10 eguivalents) was added and the reaction was stirred for another 30 minutes'. The reaction was then poured into ice water under rapid stirring containing aqueous HCl. The organic layer was stirred, washed with NaHCO3 and brine, then dried with Na2SO4, filtered and concentrated to give pure (1.2324 g, 68.2%): XH (CDC13, 400 MHz): d 7.30 (2H, t, J = 7.3 Hz), 7.22 (2H, d, J = 7.3 Hz), 7.20 (2H, t, J = 7.3 Hz), 3.37 -3.27 (1H, m), 2.76 (1H, dd, J = 16.1, 6.3 Hz), 2.66 (1H, dd, J = 16.1, 7.8 Hz), 2.05 (3H, s), 1.28 (3H, d, J = 7.3 Hz) ppm. 13 C (CDCl 3, 100 MHz): d 208.01, 146.42, 128.80, 127.03, 126.57, 52.16, 35.67, 30.77, 22.28 ppm. DEPT (CDCl 3, 100 MHz): CH 3 carbons: 30.77, 22.28; CH2 carbons: 52.16; CH carbons: 128.80, 127.03, 126.57, 35.67 ppm. HPLC: 10,017 min. (Note: SM has HPLC retention time of 9,041 min.) Synthesis of 2,4-dioxo-6-phenylheptanoic acid ethyl ester (56): Sodium hydride (0.1772 g, 7.09 mmol) was added slowly to an ice bath with NaCl containing EtOH (2.6 mL, 2.7 M ) shaking on N2. 4-Phenylpentan-2-one (55) (1.0493 g, 6.47 mmol) and diethyloxalate (0.88 mL, 6.47 mmol) were mixed together, and then added to the cooled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. After 90 minutes, the reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H0, dried with Na2SO4, filtered, concentrated to give 56 (0.7230 g, 42.6%) which was used without further purification in the next step. 1H (CDC13, 400 MHz): d 7.34 - 7.16 (5H, m), 6.30 (1H, s), 4.33 (2H, g, J = 7.0 Hz), 3.39 - 3.26 (1H, m), 2.82 (1H, dd, J = 15.1, 6.8 Hz), 2.72 (1H, dd, J = 15.1, 7.8 Hz), 1.36 (3H, t, J = 7.0 Hz), 1.32 (3H, d, J = 6.8 Hz) ppm. HPLC: 10.934 min.

Synthesis of 5- (2-phenylpropyl) -1H-pyrazole-3-carboxylic acid ethyl ester (57): Hydrazine hydrate (0.134 mL, 2.76 mmol) was added to a stirring solution at room temperature. 56 (0.7230 g, 2.76 mmol) in EtOH (2.8 mL, 1 M) under N2. The reaction was then heated to reflux until it was judged complete by HPLC (50 min) -: The reaction was concentrated and purified by preparative inverted phase HPLC under the following conditions: from 0 to 24 min, H20: CH3CN 55:45; of 24 - 25 min, H20: CH3N 55:45 to 0: 100: 20 mL / min .; ? = 214 nM; 100 mg / mL, 0.2 mL / injection. 0.0489 g of 57. ^? (CDC13, 300 MHz): d 10.77 (1H, broad s), 7.36 - 7.14 (5H, m), 6.49 (1H, s), 4.33 (2H, - g, J = 7.0 Hz), 3.16 - 2.86 (3H , m), 1.33 (3H, t, J = 7.0 Hz), 1.27 (3H, d, J = 5.9 Hz) ppm. 13 C (CDCl 3, 75 MHz): d 162.01, 145.94, 145.75, 141.50, 128.43, 126. 76, 126.32, 106.98, 60.87, 39.94, 34.64, 21.34, 14.12 ppm. DEPT (CDCl3, 75 MHz): CH3 carbons: 21.34, 14.12; CH2 carbons: 60.87, 34.64; carbons of CH: 128.43, 126. 77, 126.32, 106.98, 39.94 ppm. HPLC: 10,052 min.

Synthesis of 5- (2-phenylpropyl) -lH-pyrazole-3-carboxylic acid (58): Freshly prepared aqueous NaOH (10M in H20, 0.947 mmol) was added to a stirred solution at room temperature of 57 (0.0489 g, 0.1893 mmol) in MeOH (0.47 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (8 min): The reaction was concentrated, redissolved in H20, and extracted with EtOAc (1 mL): Aqueous HCl was added dropwise. 10% to the aqueous layer until pH = 2. The white solid was precipitated from the reaction and completely filtered and washed with cold H20. The solution was dried under vacuum overnight to obtain 0.0298 g (68.3%) of 58. XR (CD30D, 400 MHz): d 7.24 (2H, t, J = 7.3 Hz), 7.18 (2H, d, J = 7.3 Hz), 7.14 (1H, t, J = 7.3 Hz), 6.42 (1H, s), 3.11 - 3.01 (1H, m), 2.95 (1H, dd, J = 14.1, 7.3 Hz), 2.89 (1H, dd , J = 14.1, 7.8 Hz), 1.26 (3H, d, J = 6.8 Hz) ppm. 13C (CD3OD, 100 MHz): d 164.83, 147.35, 147.13, .143.02, 129.45, 127.92, 127.35, 108.07, 41.46, 35.58, 22.05 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.05; CH2 carbons: 35.58; CH carbons: 129.45, 127.92, 127.35, 108.07, 41.46 ppm. HPLC: 8.764 min.

Example 19. Synthesis of 5- (1-methyl-2-phenylethyl) -1H-pyrazole-3-carboxylic acid (62): OH? H Jf_ =.

Synthesis of 3-methyl-4-phenylbutan-2-one (59): 1.4 M methyl lithium (34.8 mL, 48.72 mmol) was added over 70 minutes to a stirring solution at 0 ° C of a-methylhydrocinnamic acid (4.0019) g, 24.36 mmol) in dry Et20 (122 mL, 0.2 M). The ice bath was removed, and the reaction was allowed to stir at room temperature for an additional 2 hours. The reaction was poured into ice water under rapid stirring containing aqueous HCl. The organic layer was stirred, washed with NaHCO 3 and brine, then dried with Na 2 SO, filtered, concentrated and purified by chromatography on silica gel (Combiflash column, hexanes: EtOAc 95: 5) to achieve pure 59 (2.3038). g, 58.3%): 2H (CDC13, 400 MHz): d 7.28 (2H, t, J = 7.3 Hz), 7.20 (1H, t, J = 7.3 Hz), 7.16 (2H, d, J = 7.3 Hz) , 3.00 (1H, dd, J = 13.7, 6.8 Hz), 2.83 (lH, app sex, 7.0 Hz), 2.56 (1H, dd, J = 13.7, 7.8 Hz), 2.08 (3H, s), 1.09 (3H , d, J = 6.8 Hz) ppm. 13C (CDC13, 100 MHz): d 211.99, 139.53, 128.79, 128.28, 126.10, 48.65, 38.75, 28.74, 16.10 ppm. DEPT (CDCl 3, 100 MHz): CH 3 carbons: 28.74, 16.10; CH2 carbons: 38.75; CH carbons: 128.79, 128.28, 126.10, 48.65 ppm. HPLC: 10,229 min. (Note: SM has HPLC retention time of 9.225 min.) Synthesis of 5-methyl-2,4-dioxo-6-phenylhexanoic acid ethyl ester (60): Sodium hydride (0.3965 g, 16. 52 mmol) to an ice bath of NaCl containing EtOH (5.6 mL, 2.6 M) stirring under N2. They mixed together 59 (2.2727 g, 14.01 mmol) and diethyloxalate (2.0649 g, 14.13 mmol), and then the cooled NaOEt solution was added. After stirring for 5 minutes, the reaction was warmed to room temperature. After stirring for 5 hours, the reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H20, dried over Na2SO4, filtered, concentrated and purified by chromatography on silica gel (Combiflash column, Hexanes: CH2C12: NH3 2N 67: 30: 3 in EtOH). Only the pure fractions were combined and concentrated to obtain 60. - "(CDC13, 400 MHz): d 14.55 (1H, s broad), 7.32-7.12 (5H, m), 6.36 (1H, s), 4.33 ( 2H, q, J = 7.0 Hz), 3.05 (1H, dd, J = 13.5, 6.8 Hz), 2.84 (1H, app sex, J = 7.0 Hz), 2.67 (1H, dd, J = 13.5, 7.8 Hz) , 1.36 (3H, t, J = 7.1 Hz), 2.33 (3H, d, J = 7.0 Hz) ppm 13C (CDC13, 100 MHz): d 205.78, 166.96, 161.88, 138.75, 128.80, 128.30, 126.29, 100.75 , 62.32, 46.35, 39.10, 16.51, 13.88 ppm DEPT (CDCl3, 100 MHz): CH3 carbons: 16.51, 13.88; CH2 carbons: 62.32, 39.10; CH carbons: 128.80, 128.30, 126.29, 100.75, 46.35 ppm. HPLC: 11,084 min.

Synthesis of 5- (2-phenylpropyl) -1H-pyrazole-3-carboxylic acid ethyl ester (61): Hydrazine hydrate (0.1564 mL, 3.23 mmol) was added to a stirring solution at room temperature of 60 (0.8460 g) , 3.223 mmol) in EtOH (3.2 mL, 1 M) under N2. The reaction was then heated to reflux until it was judged complete by HPLC. The reaction was concentrated and purified by chromatography on silica gel (Combiflash column, Hexanes: CH2C12: NH3 2N 87: 7: 4 in EtOH) to obtain 0.6423 g (77.1%) of 61. XH (CDC13, '300 MHz): d 7.26 - 7.14 (3H, m), 7.08 (2H, d, J = 7.0 Hz), 6.61 (1H, s), 4.34 (2H, q, J = 7.2 Hz), 3.23 (1H, app sex, J = 7.1 Hz), 3.00 (1H, dd, J = 13.5, 6.7 Hz), 2. 77 (1H, dd, J = 13.5, 8.0 Hz), 1.34 (3H, t, J = 7.1 Hz), 1. 26 (3H, d, J = 7.3 Hz) ppm. 13C Partial (CDC13, 75 MHz): d 161. 86, 139.47, 128.99, 128.20, 126.14, 104.99, 60.80, 43.37, 33.39, 19.60, 14.18 ppm. DEPT (CDCl3, 75 MHz): CH3 carbons: 19.60, 14.18; CH2 carbons: 60.80, 43.37; CH carbons: 128.99, 128.20, 126.14, 104.99, 33.39 ppm.

HPLC: 10129 min.

Synthesis of 5- (2-phenylpropyl) -lH-pyrazole-3-carboxylic acid (62): Freshly prepared aqueous NaOH (10 M in H20, 1.01 mmol) was added to a stirred solution at a room temperature of 61 (0.0523) -g, 0.2024 mmol) in MeOH (0.51 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (9 min). The reaction was concentrated, redissolved in H0, and extracted with EtOAc. 10% aqueous HCl was added dropwise to the aqueous layer until pH = 2. When a white solid did not precipitate as expected, EtOAc was added, and the organic layer was stirred, dried with Na 2 SO 4, filtered and concentrated to provide 62 pure. 1H (CD3OD, 400 MHz): d 7.24 - 7.18 (2H, m), 7.17 - 7.05 (31-1, m), 6.56 (1H, s), 3.17 (1H, app sex, J = 7.3 Hz), 2.96 (1H, dd, J = 13.6, 7.3 Hz), 2.80 (1H, dd, J = 13.7, 7.8 Hz), 1.25 (3H, d, J = 6.8 Hz) ppm. 13C (CD3OD, 100 MHz): d 164.88, 153.40, 142.91, 140.97, 130.09, 129.25, 127.21, 106.11, 44.41, 34.96, 20.35 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 20.35; CH2 carbons: 44.41; CH carbons: 130.09, 129.25, 127.21, 106.11, 34.96 ppm. HPLC: 8,849 min.

Example 20. Synthesis of 4- [2- (2-bromo-phenyl) -ethyl] -1H-pyrrole-2-carboxylic acid (65): Synthesis of 4- [2- (2-bromophenyl) acetyl] -lH-pyrrole-2-carboxylic acid ethyl ester (63): Ethylpyrrole-2-carboxylate (1.9428 g, 13. 96 mmol) in a minimum amount (about 5 mL) of dichloroethane to an ice-cooled stirring mixture of aluminum chloride (4.0458 g, 30.34 mmol) and 2-bromophenylacetyl chloride (6.7116 g, 28.74 mmol) in dichloroethane (44 mL, 0.66 M) under N2. The ice bath was removed, and the reaction was stirred at room temperature for 2 hours. 19.2977 g (2.6 mMol / g) of polyamine HL resin (200-400 mesh) and dichloroethane (20 mL) were added, and the reaction was stirred for about 100 minutes. The reaction was then filtered through a fritted glass funnel directly into ice water. The resin was rinsed with CH2C12, then the organic layers were removed, dried with Na2SO4, filtered, concentrated and purified by chromatography on silica gel (Combiflash column, hexanes: EtOAc 80:20 to 60:40) to obtain 2.5751 g (54.9%) of 63 as a white solid. Note: A small amount of CH2C1 was required to solubilize the crude product before placement on a silica column. "" "H (CDC13, 400 MHz): d 10.32 (1 H, broad s), 7.57 - 7.53 (2 H, m), 7.38 - 7.37 (1 H, m), 7.29 - 7.21 (2 H, m), 7.13 - 7.07 (1H, m), 4.35 (2H, q, J = 7.2 Hz), 4.25 (2H, s), 1.36 (3H, t, J = 7.2 Hz) ppm 13C (CDC13, 100 MHz): d 191.78, 161.04 , 134.91, 132.62, 131.66, 128.59, 127.40, 126.95, 126.25, 124.98, 124.17, 114.88, 60.92, 46.56, 14.26 ppm, DEPT (CDC13, 100 MHz): CH3 carbons: 14.26, CH2 carbons: 60.92, 46.56; CH carbons: 132.62, 131.66, 128.59, 127.40, 126.95, 114.88 ppm HPLC: 10,078 min.

Synthesis of 4- [2- (2-bromophenyl) -ethyl] -lH-pyrrole-2-carboxylic acid ethyl ester (64): triethylsilane (2.25 mL, 14.1 mmol) was added to a stirring solution at room temperature. 63 (1.5291 g, 4.55 mmol) in trifluoroacetic acid (TFA) (10.8 mL, 0.42 M) under N. After stirring at room temperature for 3 hours, the reaction was heated at 35 ° C for 35 minutes, then the TFA was removed under vacuum, and the crude product was taken up in EtOAc, taken with brine, dried with Na 2 SO, it was filtered, concentrated and purified by preparative inverted phase HPLC under the following conditions: from 0 to 12 minutes, CH3CN 35:65; 14 - 15 minutes, H20 CH3CN from 35:65 to 0: 100; 20 mL / min .; ? = 254 nM; 3.67 g / mL, 0.2 mL / injection, 0.8402 g (57.3%) of 64 was obtained as a spongy white solid (Note: A desired impurity has a retention time of 12,281 min, HPLC.) XH (CDC13, 400 MHz): d 9.07 (1H, broad s), 7.55 (1H, dd, J = 8.0, 1.3 Hz), 7.21 (1H, td, J = 7.3, 1.3 Hz), 7.17 (1H, dd, J = 7.6, 2.4 Hz), 7.06 (1H, ddd, J = 7.9, 7.0, 2.3 Hz), 6.82 (1H, s), 6.72 (1H, s), 4.32 (2H, t, J = 7.2 Hz), 2.99 (2H, t, J = 8.0 Hz), 2.78 (2H, t, J = 7.9 Hz), 1.36 (3H, t, J = 7.2 Hz) ppm. 13C (CDC13, 100 MHz): d 161.21, 141.03, 132.75, 130.41, 127.63, 127.32, 125.31, 124.43, 122.66, 120.68, 114.83, 60.22, 37.78, 27.03, 14.48 ppm. DEPT (CDC13, 100 MHz): CH3 carbons: 14.48; CH2 carbons: 60.22, 37.78, 27.03; CH carbons: 132.75, 130.41, 127.63, 127.32, 120.68, 114.83 ppm. HPLC: 11.355 min.

Synthesis of 4- [2- (2-bromo-phenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (65): Freshly prepared aqueous NaOH (10 M in H20, 13.04 mmol) was added to a stirring solution at room temperature of 64 (0.8402 g, 2.608 mmol) in MeOH (6.5 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC (10 min). The product was concentrated and then dissolved in 10 mL of H20. The product was extracted with EtOAc until the organic layer did not turn yellow for a longer time, then the aqueous layer became acidic (pH = 2) with dropwise addition of 10% aqueous HCl. The oiled product was out of solution, so that EtOAc was added and the organic layer was removed, dried with Na 2 SO 4, filtered, concentrated to obtain 65 (0.3934 g, 51. 3%) as a white solid (Note: A desired impurity has the retention time of 11,066 min by HPLC): XH (CD30D, 400 MHz): d 7.51 (1H, d, J = 7.8 Hz), 7.24 - 7.16 (2H, m), 7.05 (1H, ddd, J = 8.2, 6.3, 2.9 Hz), 6.72 (1H, s ), 6.71 (1H, s), 2.96 (2H, t, J = 8.0 Hz), 2.73 (2H, t, J = 7.8 Hz)) ppm. 13C (CD30D, 100 MHz): d 164.48, 142.42, 133.71, 131.80, 128.79, 128.53, 125.89, 125.20, 123.54, 122.61, 116.38, 38.99, 28.20 ppm. DEPT (CDC13, 100 MHz): CH2 carbons: 38.99, 28.20; CH carbons: 133.71, 131.80, 128.79, 128.53, 122.61, 116.38 ppm. HPLC: 10,035 min.

Example 21. Synthesis of 5- [2- (4-chlorophenyl) -ethyl] -1H-pyrazole-3-carboxylic acid (69) Synthesis of 4- (4-chlorophenyl) -butan-2-one (66). Methyl lithium was added at 1.6 M (33.9 mL, 54.17 mmol) for 70 min, to a solution at 0 ° C under stirring of 3- (4-chlorophenyl) -propionic acid (5.0072 g, 27.08 mmol) in dry Et20 ( 135 mL, 0.2 M): The ice bath was stirred, and the reaction was allowed to stir at room temperature overnight. The reaction was poured into ice water under rapid stirring containing aqueous HCl. The organic layer was stirred, washed with NaHCO 3 and brine, then dried with Na 2 SO, filtered, concentrated and purified by chromatography on silica gel (Combiflash column, Hexanes: EtOAc 98: 2 to 95: 5) to achieve 66 pure (2.4253 g, 49.0%): XH (CDC13, 400 MHz): d 7.14 (2H, d, J = 8.3 Hz), 7.03 (2H, d, J = 8.3 Hz), 2.77 (2H, t, J = 7.5 Hz), 2.64 (2H, t, J = 7.5 Hz), 2.04 (3H, s) ppm. 13C (CDC13, 100 MHz): d 207.12, 139.38, 131.59, 129.55, 128.35, 44.62, 29.82, 28.78 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 29.82; -C CH2 carbons: 44.62, 28.78; CH carbons: 129.55, 128.35 ppm. HPLC: 10.361 min. (Note: SM HPLC retention time of 9,409 min.) Synthesis of 6- (4-chlorophenyl) -2,4-dioxohexanoic acid ethyl ester (67): Sodium hydride (0.4163 g, 17.35 mmol) was slowly added to an ice bath with NaCl containing EtOH (5.3 mL, 2.5 M) stirring under N2. 66 (2.4253 g, 13.28 mmol) and diethyloxalate (1.803 g, 13.28 mmol) were mixed together, and then added to the cooled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. After 10 minutes, the reaction solidified and an additional 10 mL of EtOH was added. After stirring for about 5 hours, the reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H20, dried with Na2SO4, filtered, concentrated, and purified by chromatography on silica gel (Combiflash column, Hexanes: CH2Cl2 1: 1). Only pure fractions were combined and concentrated to obtain 67 (1.7561 g, 46.8%): XH (CDC13, 400 MHz): d 14.27 (1H, broad s), 7.22 (2H, d, J = 8.3 Hz), 7.10 ( 2H, d, J = 8.3 Hz), 6.32 (1H, s), 4.31 (2H, q, J "= 7.2 Hz), 2.92 (2H, t, J = 7.8 Hz), 2.78 (2H, t, J = 7.8 Hz), 1.34 (3H, t, J = 7.2 Hz) ppm 13C (CDC13, 100 MHz): d 201.59, 166.07, 161.79, 138.51, 132.00, 128.53, 128.54, 101.72, 62.38, 42.08, 29.60, 13.88 ppm DEPT (CDC13, 100 MHz): CH3 carbons: 13.88, CH2 carbons: 62.38, 42.08, 29.60, CH carbons: 129.53, 128.54, 101.72 ppm HPLC: 11.103 min.

Synthesis of 5- [2- (4-Chlorophenyl) -ethyl] -lH-pyrazole-3-carboxylic acid ethyl ester (68): Hydrazine hydrate (0.300 mL, 6.18 mmol) was added to a stirred solution at room temperature ambient of 67 (0.1.7484 g, 6.18 mmol) in EtOH (6.2 mL, 1 M) under N2. The reaction was then heated to reflux until it was judged complete by HPLC (40 min). Upon cooling, a white crystalline solid precipitated from the reaction. The solid was separated by filtration, washed with EtOH, dried to obtain pure 68 (0.9092 g, 52.7%): XH (CDC13, 300 MHz): d 12.44 (1H, broad s), 7.21 (2H, d, J = 8.3 Hz), 7.08 (2H, d, J = 8.1 Hz), 6.58 (1H, s), 4.33 (2H, q, J = 7.0 Hz), 3.00 (2H, t, J = 7.0 Hz), 2.93 (2H, t, J = 7.0 Hz), 1.33 (3H, t, J = 7.0 Hz) ppm. 13C Partial (CDC13, 75 MHz): d 139.12, 131. 93, 129.67, 128.50, 106.49, 60.94, 34.72, 14.20 ppm.

HPLC: 10,269 min.

Synthesis of 5- [2- (4-chlorophenyl) -ethyl] -lH-pyrazole-3-carboxylic acid (69): Freshly prepared aqueous NaOH (10 M in H20, 16.31 mmol) was added to a stirred solution at room temperature ambient of 68 (0.9092 g, 3.26 mmol) in MeOH (8.2 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (7 min). The reaction was concentrated, redissolved in H20 (5 mL), and extracted with EtOAc (2 mL). 10% aqueous HCl was added dropwise to the aqueous layer until pH = 2. The white solid that precipitated was filtered off completely and washed with cold H20. The solid was dried under vacuum overnight to obtain 0.7543 g (92.2%) of 69. Since 69 still contained a very small amount of an impurity, it was dissolved in 38 mL of toluene with 10 mL of EtOAc and 14 mL of EtOH while it is heated to reflux. The pure white solid precipitated from the reaction after settling overnight (0.4052 g). Solid (Note: An unwanted impurity has a retention time of 9,904 min, by HPLC). 2H (CD30D, 400 MHz): d 7.24 (2H, d, J = 8.3 Hz), 7.15 (2H, d, J = 8.3 Hz), 6.54 (1H, s), 2.95 (4H, s) ppm. 13C (CD30D, 100 MHz): d 164.68, 148.23, 142.84, 140.91, 133.00, 131.08, 129.46, 107.59, 35.83, 28.78 ppm. DEPT (CD30D, 100 MHz): CH2 carbons: 35.83, 28.78; CH carbons: 131.08, 129.46, 107.59 ppm. HPLC: 9,026 min.

Example 22. Synthesis of 5-bromo-4- [2- (4-chlorophenyl) ethyl) -pyrrole-2-carboxylic acid (70): Synthesis of 5-bromo-4- [2- (4-chlorophenyl) -ethyl] -1H-pyrrole-2-carboxylic acid (70): Bromine (0.049 mL, 0.962 mmol) was added dropwise over 5 minutes at a time. Agitated solution of 39 (0.200 g, 0.802 mmol) in acetic acid (2.5 mL). When the reaction was judged complete by HPLC (30 min), it was added H20, and the solid that precipitated was filtered completely and washed with H20. The light purple solid that was obtained was dissolved in EtOAc, washed with Na 2 SO 3 and H 2 O, then dried with Na 2 SO, filtered and concentrated. The product was purified by preparative inverted phase HPLC with H20: CH3CN 40:60 (with 0.05% TFA); 20 mL / min .; ? = 214 nM. They were obtained 0. 1520 g (57.7%) of 70 as a white foamy solid. ^? (CD30D, 400 MHz): d 7.22 (2H, d, J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz), 6.65 (1H, s), 2.81 (2H, t, J = 7.3 Hz), 2.67 (2H, t, J = 7.3 Hz) ppm. 13C Partial (CD3OD, 100 MHz): d 163.33, 141.42, 132.54, 131.03, 129.18, 124.73, 117.15, 105.84, 36.72, 29.04 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 36.72, 29.04; CH carbons: 131.03, 129.18, 117.15 ppm. HPLC: 10.484 min.

Example 23. Synthesis of 4- [2- (2-bromophenyl) -ethyl) -1H-pyrrole-2-carboxylic acid (73): Synthesis of 4- [2- (4-fluorophenyl) -acetyl] -lH-pyrrole-2-carboxylic acid ethyl ester (71): Ethylpyrrole-2-carboxylate (2.0589 g, 14.80 mmol) in a minimum amount of dichloroethane is added to an aluminum-chilled stirring mixture of aluminum chloride (3.9913 g, 29.93 mmol) and 4-fluorophenylacetyl chloride (5.1338 g, 29.75 mmol) in dichloroethane (22 mL, 0.66 M) under N2. The ice bath was removed, and the reaction was stirred at room temperature for 3.5 h. 20.6195 g were added (2.6 mMol / g) of Polyamine HL resin (200-400 mesh) and dichloroethane (20 L), and the reaction was stirred for about 60 minutes. The reaction was then filtered through a fritted glass funnel directly into ice water. The resin was rinsed with CH2C12, then the organic layers were removed, dried with Na2SO4, filtered and concentrated. When 6.5 mL of Hexanes: EtOAc 80:20 were added, the organic liquid turned yellow, leaving behind a light brown solid. The solid was removed by filtration, rinsed with Hexanes: EtOAc 80:20, and dried to obtain pure 71 (2.1838 g, 53.6%). 1H (CDC13, 400 MHz): d 10.03 (1H, broad s), 7.54 (1H, s), 7.32 (1H, s), 7.23 (2H, dd, J = 8.6, 5.3 Hz), 6.99 (2H, t , J = 8.6 Hz), 4.35 (2H, q, J = 7.1 Hz), 4.04 (2H, s), 1.37 (3H, t, J = 7.1 Hz) ppm. 13C (CDC13, 100 MHz): d 192.81, 161.84 (d, J = 244 Hz), 160.95, 130.89 (d, J = 7.8 Hz), 130.37 (d, J = 3.2 Hz), 126.72, 126.36, 124.30, 115.40 (d, J = 21.4 Hz), 114.96, 61.02, 45.63, 14.29 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.29; CH2 carbons: 61.02, 45.63; CH carbons: 130.89 (d, J = 7.8 Hz), 126.72, 115.40 (d, J = 21.4 Hz), 114.96 ppm. HPLC: 9.689 min.

Synthesis of 4- [2- (4-fluorophenyl) -ethyl] -lH-pyrrole-2-carboxylic acid ethyl ester (72): triethylsilane (3.84 mL, 24.1 mmol) was added to a stirring solution at room temperature. 71 (2.1400 g, 7.77 mmol) in trifluoroacetic acid (TFA) (18.5 mL, 0.42 M) under N2. When the reaction was judged complete by HPLC, the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na 2 SO 4, filtered, concentrated, and purified by reverse phase HPLC, preparation with the following conditions: from 0 to 12 minutes, H20: CH3CN, 35:65; 14 - 15 minutes, H20: CH3CN from 35:65 to 0: 100; 20 mL / min; ? = 254 nM; 3.67 g / mL, 0.2 mL / injection. 1.1571 g (57.0%) of.72 was obtained as a white foamy solid. (Note: An unwanted impurity has a retention time of 11,414 min by HPLC) XH (CDC13, 400 MHz): d 9.33 (1H, broad s), 7.13 (2H, dd, J = 8.5, 5.6 Hz), 6.96 ( 2H, t, J = 8.8 Hz), 6.79 (1H, s), 6.66 (1H, s), 4.33 (2H, t, J = 7.1 Hz), 2.86 (2H, t, J = 7.1 Hz), 2.77 ( 2H, t, J = 7.1 Hz), 1.36 (3H, t, J = 7.1 Hz) ppm. 13C (CDC13, 100 MHz): d 161.31, 161.22 (d, J = 242 Hz), 137.46 (d, J = 3.2 Hz), 129.71 (d, J = 7.7 Hz), 125.22, 122.52, 120.84, 114.89 (d , J = 21.9 Hz), 114.79, 60.19, 36.44, 28.73, 14.37 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.37; CH2 carbons: 60.19, 36.44, 28.73; CH carbons: 129.71 (d, J = 7.7 Hz), 120.84, 114.89 (d, J = 21.9 Hz), 114.79 ppm. HPLC: 10,797 min.

Synthesis of 4- [2- (4-fluorophenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (73): Freshly prepared aqueous NaOH (10 M in H20, 22.14 mmol) was added to a stirred solution at room temperature of 72 (1.1571 g, 4428 mmol) in MeOH (11.1 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC (10 min). In cooling, the reaction solidified. The product was concentrated and then dissolved in H20. The product was extracted with EtOAc, then the aqueous layer was made acidic (pH = 2) with the dropwise addition of 10% aqueous HCl. The product was oiled out of solution, so that EtOAc was added, and the organic layer was stirred, dried with Na 2 SO 4, filtered, concentrated to obtain 73 (0.8724 g, 84.4%) as an off-white solid. The product was further purified by repeating the above procedure. The product was dissolved in 10% NaOH, washed with EtOAc, and then acidified with 10% HCl. As before, the product was oiled out and therefore extracted into EtOAc, dried with Na 2 SO 4, filtered and concentrated. 1H (CD3OD, 400 MHz): d 7.14 (2H, dd, J = 8.8, 5.4 Hz), 6.94 (2H, t, J = 8.8 Hz), 6.68 (1H, d, J = 1.7 Hz), 6.66 (1H , d, J = 7.1 Hz), 2.82 (2H, t, J = 7.3 Hz), 2.72 (2H, t, J = 7.3 Hz) ppm. 13C (CD3OD, 100 MHz): d 164.48, 162.69 (d, J = 241 Hz), 139.28 (d, J = 3.2 Hz), 131.08 (d, J = 8.2 Hz), 126.08, 123.47, 122.68, 116.41, 115.68 (d, J = 21.0 Hz), 37.77, 29.94 ppm. DEPT (CDC13, 100 MHz): CH2 carbons: 37.77, 29.94; CH carbons: 131.08 (d, J = 8.2 Hz), 122.68, 116.41, 115.68 (d, = 21.0 Hz) ppm. HPLC: 9.575 min.

Example 24. Synthesis of 4- (3-Cyclopentylpropyl) -1H-pyrrole-2-carboxylic acid (76): Synthesis of 4- (3-Cyclopentylpropionyl) -IH-pyrrole-2-carboxylic acid ethyl ester (74): Ethylpyrrole-2-carboxylate (1.8593 g, 13.36 mmol) in a minimum amount of dichloroethane was added to a stirring mixture Chilled with aluminum chloride ice (3.5756 g, 26.82 mmol) and 3-cyclopentylpropionyl chloride (4.1 mL, 26.59 mmol) in dichloroethane (20 mL, 0.66 M) under N2 The ice bath was removed, and the reaction was stirred at room temperature for 4 h. 18.18 g were added (2.6 mMol / g) of Polyamine HL resin (200-400 mesh) and dichloroethane (20 mL), and the reaction was stirred for about 60 minutes. The reaction was then filtered through a fritted glass funnel directly into ice water. The resin was rinsed with CH2C12, then the organic layers were removed, dried with Na2SO4, filtered and concentrated. The crude product was recrystallized from Hexanes / ethyl acetate. The crude product was dissolved in a minimum amount of warm ΔtOAc, then allowed to cool slowly to room temperature. When the product did not crystallize, a small amount of hexanes was pipetted to the sides of the flask. Pure crystals of the desired product were obtained (2.3068 g, 65.6%) after settling overnight. ^? (CDC13, 400 MHz): d 10.04 (1H, broad s), 7.55 (1H, s), 7.29 (1H, s), 4.34 (2H, q, J = 7.1 Hz), 2.77 (2H, t, J = 7.6 Hz), 1.85 -1.67 (5H, m), 1.64 -1.46 (4H, m), 1.36 (3H, t, J = 7.1 Hz), 1.78 - 1.06 (2H, m) ppm. 13C (CDC13, 100 MHz): d 196.38, 161.09, 127.03, 126.14, 124.05, 114.76, 60.91, 39.82, 39.06, 32.53, 30.82, 25.11, 14.31 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.31; CH2 carbons: 60.91, 39.06, 32.53, 30.82, 25.11; CH carbons: 126.14, 114.76, 39.82 ppm. HPLC: 10,800 min.

Synthesis of 4- (3-cyclopentylpropyl) -IH-pyrrole-2-carboxylic acid ethyl ester (75): triethylsilane (4.28 mL, 26.86 mmol) was added to a stirring solution at room temperature of 74 (2.2816 g, 8.66 mmol) in trifluoroacetic acid (TFA) (20.6 mL, 0.42 M) under N2. When the reaction was judged complete by HPLC, the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na 2 SO 4, filtered, concentrated, and purified by reverse phase HPLC, preparation with the following conditions: H20: CH3CN 30:70; 20 mL / min .; ? = 254 nm. 75 was obtained as a white foamy solid. XH (CDC13, 400 MHz): d 9.43 (1H, broad s), 6.77 (1H, s), 6.74 (1H, s), 4.32 (2H, q, J = 7.1 Hz), 2.46 (2H, t, J = 7.6 Hz), 1.83 - 1.71 (3H, m), 1.64 - 1.46 (6H, m), 1.35 (3H, t, J = 7.1 Hz), 1.36-1.31 (2H, m), 1.14 -1.02 (2H, m) ppm. 13C (CDC13, 100 MHz): d 161.46, 126.62, 122.33, 120.74, 114.86, 60.10, 40.00, 35.82, 32.65, 30.14, 26.94, 25.13, 14.39 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.39; CH2 carbons: 60.10, 35.82, 32.65, 30.14, 26.94, 25.13; CH carbons: 120.74, 114.86, 40.00 ppm. HPLC: 12.379 min.

Synthesis of 4- (3-cyclopentylpropyl) -lH-pyrrole-2-carboxylic acid (76): Freshly prepared aqueous NaOH (10 M in H20, 11.23 mmol) was added to a stirred solution at room temperature of 75 (0.56 g). , 2.25 mmol) in MeOH (5.6 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC (10 min). In cooling, the reaction solidified. The product was concentrated and H20 was added. When the product was dissolved in H20, EtOAc was added followed by 10% HCl to acidify the aqueous layer. The organic layer was then stirred, dried with Na 2 SO 4, filtered, concentrated and purified by preparative inverted phase HPLC under the following conditions: H0: CH 3 CN 30:70; 20 mL / min .; ? = 254 nm. 76 was obtained as a white foamy solid. (Note: An unwanted impurity has a retention time of 12,073 -min per HPLC). XH (CD30D, 400 MHz): d 10.80 (1H, s), 6.72 (1H, s), 6.68 (1H, s), 2.43 (2H, t, J = 7.6 Hz), 1.82 -1.70 (3H, m) , 1.64 -1.46 (6H, m), 1.38-1.29 (2H), 1.14 -1.02 (2H, m) ppm. 13C (CD30D, 100 MHz): d 164.45, 127.29, 122.45, 116. 39, 41.31, 37.00, 33.73, 31.43, 27.96, 26.11 ppm. DEPT (CDC13, 100 MHz): carbons of CH2: 37.00, 33.73, 31.43, 27. 96, 26.11; CH carbons: 122.45, 116.39, 41.31 ppm.

HPLC: 10.977 min.

Example 25. Synthesis of. (S) -5- (2-Phenylpropyl) -1H-pyrazole-3-carboxylic acid (80): Synthesis of (S) -4-Phenylpentan-2-one (77): 1.6 M methyl lithium (17.8 mL, 24.9 mmol) was added over 1 hour to a stirring solution at 0 ° C of (S) -3 acid Phenylbutyric (2.0147 g, 12.18 mmol) in dry Et20 (61 mL, 0.2 M): The wire bath was removed, and the reaction was allowed to stir at room temperature for an additional 1 1/2 hours. The reaction was then poured into ice water under rapid stirring containing aqueous HCl. The organic layer was stirred, washed with NaHCO 3 and brine, then dried with Na 2 SO 4, filtered and concentrated to obtain pure 77 (2.0487 g, (2.0487 g, ~ 100%): HPLC: 10,081 min.

(Note: SM has HPLC retention time of 9,127 min.) Synthesis of (S) -2,4-dioxo-6-phenylheptanoic acid (78) ethyl ester: - Sodium hydride (0.3790 g, . 8 mmol) was added to an ice bath with NaCl containing EtOH (4.9 mL, 2.5 M) while stirring under N2. S-4-Phenylpentan-2-one (78) (2.0487 g, 12.63 mmol) and diethyloxalate (1.67 mL, 12.30 mmol) were mixed together, and then added to the cooled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. After 60 minutes, the reaction was rapidly cooled to 0 ° C with 1N HCl and extracted 2x with CH2C12. The combined organic layers were washed with H20, dried with Na2SO4, filtered, concentrated and purified with Hexanes: CH2C12 1: 1 to 1: 3 to obtain 78 (0.6895 g, 20.8%): HPLC: 10.940 min.

Synthesis of (S) -5- (2-phenylpropyl) -lH-pyrazole-3-carboxylic acid ethyl ester (79): Hydrazine hydrate (0.126 mL, 2.59 mmol) was added to a stirring solution at room temperature. 78 (0.6895 g, 2.63 mmol) in EtOH (2.6 mL, 1 M) under N2. The reaction was then heated to reflux until it was judged complete by HPLC (45 min): The reaction was concentrated and purified with Hexanes: (CH2C12: NH3 2N 3: 1 in EtOH) 9: 1 to 8: 1 to achieve 0.6153 g (90.6%) of 79. HPLC: 10,001 min.

Synthesis of (S) -5- (2-phenylpropyl) -lH-pyrazole-3-carboxylic acid (80): Freshly prepared aqueous NaOH (10 M in H20, 11.9 mmol) was added to a stirring solution at room temperature. 79 (0.6153 g, 0.2.38 mmol) in MeOH (6 mL, 0.4 M) under N2. The reaction was then heated to reflux until it was judged complete by HPLC (7 min): The reaction was concentrated, redissolved in H20, and extracted with EtOAc (1 mL): aqueous 10% HCl was added dropwise to drop to the aqueous layer until pH = 2. The white solid which precipitated from the reaction was filtered off completely and washed with cold H20. The solution was dried under vacuum overnight to obtain 0.250 g (45.6%) of 80. 1H (CD30D, 400 MHz): d 7.30 -7.23 (2H, m), 7.22 - 7.13 (3H, m), 6.62 (1H , s), 3.14 (1H, app sex, J = 7.3 Hz), 3.03 (2H, d, J = 7.8 Hz), 1.31 (3H, d, J = 6.8 Hz) ppm. 13 C (CD3OD, 100 MHz): d 162.00, 149.20, 146.35, 141.76, 129.62, 127.93, 127.64, 109.16, 41.21, 35.22, 22.11 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.11; CH2 carbons: 35.22; CH carbons: 129.62, 127.93, 127.64, 109.16, 41.21 ppm. HPLC: 8,771 min.

Analytical HPLC conditions: Inverted phase analytical column. At time = 0, H20: CH3CN 95: 5; rising to H20: CH3CN 60:40 for 4 min; Example 26: In Vitro Measurements of DAAO Activity: Purified pork DAAO, added to a buffered mixture of 50 mM D-Serine, produces H202 in stoichiometric amounts for each oxidized D-Serine molecule. The production of H202 can be monitored with a commercially available dye, Amplex Red, which in the presence of H202, is converted to resorufin, a fluorescent product. For each inhibitor described, fluorescence was also measured during additions of 80 μM H202 in the absence of DAAO, to control the artifactual inhibition of dye conversion, and to quantitate the amount of H202 produced. In an alternative DAAO activity assay, the purified DAAO from pig was added to buffered mixture of 1 mM phenylglycine in the presence of the compounds. The activity of DAAO is monitored spectrophotometrically by its enzymatic conversion of phenylglycine to benzoylmorphic acid with optical absorption at 252 nm. The inhibitors of the enzymatic cycle of DAAO were serially diluted to reduce the level of inhibition. The parameters of a non-linear equation were adjusted to adjust the resulting series of inhibition levels to extrapolate the concentration of the compound where 50% inhibition (IC50) is achieved. These numbers are averaged for the number (n) of independent measurements (on separate days) of the inhibition. Inhibition is reported in Table 1.

Table 1 Compound No. Inhibition Compound No. Inhibition or Structure of DAAO, IC50 or Structure of DAAO, IC50 3 • < 10μM 45 < 100μM 6 < 10μM 48 < 10μM 11 + 12 < 10μM 51 < lμM 15 < 10μM. 54 < 100μM- 18 < lμM 58 < lmM 21 < lμM 62 < lμM 24 < lμM 65 < lμM 26 < 100μM 69 < lμM 32 < 100μM 70 < 100μM 36 < 100μM 73 < lmM 39 < lμM 76 < 10μM Compound No. Inhibition Compound No. Inhibition Compound No. Inhibition Compound No. Inhibition or Structure of DAAO, IC50 or Structure of DAAO, IC50 It can be seen from Table 1 that the IC 50 values of the DAAO inhibitors previously reported are all greater than the 1 μM compound for more than 50% inhibition of DAAO activity. The pyrrole and pyrazole derivatives of the present invention exhibit at least this considerable inhibitory activity, and several individual examples are 5 times or more, more active, with less than 200 nM of the compounds regulating to inhibit 50% of DAAO activity.

Example 27: Measurement of NMDA Receptor Affinity To measure the affinity of the compounds reported herein for the D-Serine binding site at the NMDA receptor (also known as the "Glycine site" or the "site of strychnine insensitive glycine "), a radioligand binding assay was performed with membranes prepared from rat cerebral cortex. The radioactive ligand was [3H] MDL105, 519. The amount of radioactivity displaced by the compounds was assessed by scintillation counting. The non-specific binding is counted in the presence of 1 mM glycine. The affinities of the values of percent inhibition of specific binding of [3H] MDL105, 519 by the test compounds are calculated. The indole-2-carboxylic acid inhibited 77% of the specific binding of the radiolabeled compound when tested at 100 μM, while the following compounds, example of pyroles and substituted pyrazoles, do not show affinity (less than 20% inhibition of specific binding to [3 H] MDL-509,519 when tested at 100 μM) for the D-Serine binding site of the NMDA receptor: Example 28: Measurement of Rat Brain Uptake Experiments that evaluate rat brain penetration of test compounds use an infusion system where a cannula is inserted into the left carotid artery and the branching arteries are cut. The test compound plus internal controls are perfused for 30 seconds in the left hemisphere in phosphate buffered saline at pH 7.4. The internal controls are atenolol (with low brain uptake) and antipyrine (with high brain uptake). After a 30-second wash with perfusate, the brain is removed in a guirurgical fashion. The left hemisphere is homogenized; the test compounds (plus internal controls) of the brain homogenate are extracted, and analyzed using LC / MS / MS to determine the concentration of the test compound and internal controls in the brain. The brain uptake ratios for the selected compounds, expressed as pmol / g of brain / second + SD for N of 4 rats, are shown in Table 2.

Table 2 Compound No. (of Examples) or Rate of Uptake in Brain Structure of Rats, pmol / g of brain / second Example 29: The Measurement of D-Serine Levels in the Brain Measurements of d-serine in mammalian brains indicate that the level of endogenous production is balanced by the degradation of d-serine. D-serine is produced from 1-serine by the action of serine-racemase, while d-serine is metabolized by the action of DAAO. Exogenously administered D-serine produces short-term increases in cerebral d-serine due to the action of DAAO. Likewise, the DAAO inhibitors are shown in this invention that they increase the cerebral levels of d-serine several times. The clinical utility of exogenously administered d-serine has been demonstrated in esguizofrénicos; see Coyle, Joseph J., Ann. N. Y. Acad. Sci. , 1003: 318-327 (2003) and U.S. Patent Nos. 6,227,875; 6,420,351; and 6,667,297. Therefore, measurements of cerebral levels of d-serine in rats are useful to assess the potential therapeutic action of DAAO inhibitors in the increases in d-serine for the treatment of schizophrenia. In vivo increase in D-serine brain. Compounds were suspended in phosphate-buffered saline (pH 7.4 with 2% TweendO) and administered intraperitoneally in male Sprague Daly rats, adults (40-60 days old, Charles River Laboratories, Inc.) weighing 185 -225 g at the time of the experiment. After several hours, the rats were killed by decapitation and the cerebellum was rapidly removed and frozen at -80 ° C for further analysis. The rest of the brain likewise stirred and froze. On the day of the analysis, the brain tissue was homogenized in 5 times its volume in 5% trichloroacetic acid cooled with ice. The homogenate was centrifuged at 18,000 times the gravity for 30 minutes. The sediments were discarded. The supernatant was washed 3 times with diethyl ether saturated with water, discarding the organic layer. After filtration of the aqueous layer through a filter membrane with a pore size of 0.45 μm, the samples were ready for derivatization with o-phthaldialdehyde (OPA) and BOC L-Cys-OH according to the Hashimoto methods and collaborators (Hashimoto A, et al., J Chromatogr., 582 (1-2): 41-8 (1992)).

Briefly, 50 mg of each derivatization reagent was dissolved in 5 ml of methanol. An aliquot of 200 μl of this was added to 100 μl of sample dissolved in 700 μl of borate buffer (0.4 M, pH adjusted to 9.0 with sodium hydroxide). The D-serine levels were then detected fluorometrically (excitation wavelength of 344 nm, emission wavelength of 443 nm) by injecting 10 μl aliquots into the high performance liquid chromatography system. Compounds of examples of these in this patent produced strong and significant increases in D-Serine levels in the rat brain. In particular, a pyrrole derivative administered in two separate doses (125 ng / kg followed by 75 mg / kg 3 hours later) produced a 4-fold increase in cerebellar D-Serine levels, 6 hours after the first dose .

Example 30: Reduction of Neuropathic Pain by DAAO Inhibitors in Animal Model (Spinal Nerve Ligation Model (SNL) Animals: Sprague-Dawley Rats (Had: Sprague-Dawley® MRSD®MR, Harían, Indianapolis Indiana, USA) They weigh 232 ± 2 g, the day of behavior test were housed three per cage.The animals had free access to food and water and were kept in a light / dark program of 12:12 hours during the entire duration of the study. Animal colony was maintained at 21 ° C and 60% humidity.All experiments were carried out in accordance with the guidelines of the International Association for the Study of Pain and has the approval of the Committee on the Care of Animal Use. chronic neuropathic pain: The Spinal Nerve Ligation (SNL) model was used (Kim and Chung, 1992) to induce chronic neuropathic pain. The animals were anesthetized with isoflurane, the left transverse process L5 was removed, and the spinal nerves L5 and L6 were tightly ligated with 6-0 silk satura. The wound was then closed with external sutures and external staples. The tweezers were removed from the wound 10-11 days after surgery. Mechanical allodynia test: Baseline, post-injury and post-treatment values for non-noxious mechanical sensitivity were evaluated using 8 Semmes-Weinstein filaments (Stoelting, Wood Dale, IL, USA) with variable stiffness (0.4, 0.7, 1.2, 2.0, 3.6, 5.5, 8.5, and 15 g) according to the up-down method (Chaplan et al., 1994). The animals were placed on a perforated metal platform and allowed to acclimate to their environment for a minimum of 30 minutes before the test. The mean and normal error of the mean (SEM) were determined for each animal in each treatment group. Since this stimulus is not normally considered painful, the significant increases induced by sensitivity injury to this test are interpreted as a measure of mechanical allodynia.

Experimental Groups: Timeline: 4- [2- (4-Chlorophenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (39) and (vehicle) (1) von Frey test (baseline) (2) 0 minutes: administration of drug (3) 120 minutes: von Frey test (4) 240 minutes: von Frey test (5) 360 minutes: von Frey test (6) 480 minutes: von Frey test (7) 495 minutes: collection Plasma procedure with control: Drugs were administered by a separate experimenter that was not included in the performance test The control was not fractionated until the end of the study Data analysis: Statial studies were carried out using the Prisma ™ 4.01 (GraphPad, San Diego, CA, USA) 'Mechanical hypersensitivity of the injured leg was determined by comparing the contralateral to ipsilateral values of the paw within the vehicle group.The data was analyzed using the Mann test -Whitney The stability of the values of the injured leg of the vehicle group during time it was tested using Friedman's two-dimensional analysis of variance by classification. The effect of the drug at each time point was analyzed by performing a one-way Kruskal-Wallis analysis of variance by classification followed by a Dunn post hoc test or a classification test signed by Mann-Whitney. Results: 4- [2- (4-Chlorophenyl) -ethyl] -1H-pyrrole-2-carboxylic acid induced a substantial decrease in mechanical allodynia that was statially significant at 240 and 360 min. The maximum effect was observed 360 minutes after the dose.

References Chaplan SR, Bach FW, Pogrel JW, Chung JM and Yaksh TL (1994) Quantitative assessment of tactile allodynia'in the rat paw. J Neurosci Methods 53: 55-63. Kim SH and Chung JM (1992) An experimental model for neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50: 355-63.

Example 31: Dosage Forms Dosage Forms in Lactose-Free Tablet Table 3 provides the ingredients for a dosage form in lactose-free tablet and a compound of formula I: * Water evaporates during processing.

The active ingredient is mixed with the cellulose until a uniform mixture is formed. The smallest amount of corn starch is mixed with an adequate amount of water to form a corn starch paste. This is then mixed with the uniform mixture until a uniform moist mass is formed. The remaining corn starch is added to the resulting wet mass and mixed until uniform granules are obtained. The granules are then screened through a suitable grinding machine, using a 1/4 inch stainless steel screen. The milled granules are then dried in a suitable drying oven until the desired moisture content is obtained. The dried granules are then milled through a suitable grinding machine using a 1/4 mesh stainless steel screen. The magnesium stearate is then mixed and the resulting mixture is compressed into tablets of the desired shape, desired thickness, hardness and desired disintegration. The tablets are coated by normal aqueous or non-aqueous technique.

Tablet Dose Form Another tablet dose formulation suitable for use with the active ingredients of the invention is provided in Table 4.

The active ingredient is sifted and mixed with cellulose, starch and pregelatinized corn starch. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are sieved and mixed with the magnesium stearate. The granules are then compressed into tablets using punches. Tablets of other strength can be prepared by altering the ratio of the active ingredient or pharmaceutically acceptable carrier, the compression weight, or by using different punches.

Example 32: Synthesis of 4- [2- (4-chloro-phenyl) -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid (87): 85 as 87 Synthesis of (Toluene-4-sulfonylamino) -acetic acid ethyl ester (81): Tosyl chloride (14.75 g, 77.37 mmol) was added to a stirring mixture of glycine ethyl ester hydrochloride (9. 0 g, 64.48 g). mmol) and pyridine (11.45 mL, 141.85 mmol) in 100 mL of dichloromethane. After stirring, overnight, the mixture was washed with water and dilute NaOH. The combined organic layers were dried with Na 2 SO 4, filtered, evaporated under reduced pressure to give 16.0 g (96%) of 81, which was used without purification in the next reaction. NMR-XH (400 MHz, CDC13): d 1.18 (t, 3H), 2.42 (s, 3H), 3.76 (d, 2H), 4.08 (q, 2H), 5.22 (m, 1H), 7.30 (d, 2H), 7.75 (d, 2H) ppm. 13 C NMR (100 MHz, CDC13): d 13.99, 21.55, 44.19, 61.89, 127.28, 129.76, 136.20, 143.81, 168.87 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 13.99, 21.55; CH2 carbons: 44.19, 61.89; CH carbons: 127.28, 129.76 ppm. LC / MS: 95%, m / z = 257.

Synthesis of ~ 3-hydroxy-3-methyl-1- (toluene-4-sulfonyl) -pyrrolidine-2-carboxylic acid ethyl ester (82): 1,8-diazabicyclo [5.4.0] -undec-7 was added -eno (DBU) (7 mL, 47.08 mmol) was added to a stirred solution of ethyl vinyl ketone (1.75 mL, 21.4 mmol) and ethyl N-p-toluenesulfonylglycinate 81 (5.5 g, 21.4 mL) in THF (50 mL). The resulting mixture was stirred overnight at room temperature. The mixture was diluted with ether, washed with 5% aqueous HCl, 5% sodium bicarbonate solution and water. The combined organic layers were dried with Na 2 SO, filtered, evaporated under reduced pressure to give 82 crude (5.3 g, 76%) as a yellow oil (mixture of diastereoisomers). NMR-H (400 MHz, CDC13): d 1.29 (m, 6H), 1.75 (m, 1H), 2.09 (m, 1H), 2.43 (s, 3H), 3.40 (m, 1H), 3.56 (m, 1H), 4.04 (s, 1H), 4.20 (m, 2H), 7.30 (d, 2H), 7.75 (d, 2H) ppm. 13 C-NMR (100 MHz, CDC13): d 14.12, 15.28, 23.04, 25.60, 26.27, 38.20, 38.86, 46.26, 46.46, 61.49, 61.65, 69.10, 71.69, 127.51, 129.70, 134.83, '134.91, 143.58, 143.84, 170.03, 170.45 ppm. DEPT (100 MHz, CDCl 3): CH 3 carbons: 14.12, 15.28, 23.04, 25.60, 26.27; CH2 carbons: 38.20, 38.86, 46.26, 46.46, 61.49, 61.65; CH carbons: 69.10, 71.69, 127.51, 129.70 ppm.

LC / MS: 97.60%, m / z = 327.

Synthesis of 3-methyl-1- (toluene-4-sulfonyl) -2,5-dihydro-1H-pyrrole-2-carboxylic acid ethyl ester (83): The pyrrolidine oil 82 (10.5 g, 32.11 mmol) is dissolved in pyridine (86 mL). P0C13 (7.48 mL, 80.27 mmol) was added dropwise and the resulting mixture was stirred overnight at room temperature. The mixture was poured onto ice, extracted with ether and washed with 5% aqueous HCl, 5% sodium bicarbonate solution and water. The ether layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give crude solid. (8.80 g, 88%). RMN-1 !! (400 MHz, CDC13): d 1.28 (t, 3H), 1.69 (m, 3H), 2.43 (s, 3H), 4.10 (m, 1H), 4.20 (q, 2H), 4.21 (m, 1H), 7.31 (d, 2H), 7.75 (d, 2H) ppm. 13 C-NMR (100 MHz, CDC13): d 13.58, 14.10, 21.56, 54.64, 61.62, 70.55, 110.02, 122.51, 127.51, 129.73, 169.87 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 13.58, 14.10, 21.56; carbons of ~ CH2: 54.64, 61.62; CH carbons: 70.55, 122.51, 127.51, 129.73 ppm. LC / MS: 100%, m / z = 309.

Synthesis of 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84): Pyrroline 83 (8.80 g, 28.48 mmol) was dissolved in THF (70 mL). DBU (9.78 mL, 65.50 mmol) was added dropwise and the resulting solution was stirred under reflux overnight. The mixture was cooled to room temperature, diluted with ether and washed with 5% aqueous HCl, 5% sodium bicarbonate solution and water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give crude solid (4.30 g, 98%). NMR- ^? (400 MHz, CDC13): d 1.37 (t, 3H), 2.35 (s, 3H), 4.31 (q, 2H), 6.08 (d, 1H), 6.81 (d, 1H), 8.90 (s broad, 1H) ppm. NMR-13C (100 MHz, CDC13): d 12.76, 14.53, 59.96, 112.58, 119.35, 121.53, 127.96, 162.01 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 12.76, 14.53; CH2 carbons: 59.96; CH carbons: 112.58, 121.53 ppm. LC / MS: 90.74%, m / z = 153.

Synthesis of 4- [2- (4-chloro-phenyl) -acetyl] -3-methyl-lH-pyrrole-2-carboxylic acid ethyl ester (85): A solution of (4-chlorophenyl) chloride was added. acetyl (3 mmol) in dichloromethane or 1,2-dichloroethane (4 ml) to a solution cooled to -40 ° C of 84 (0.229 g, 1.5 mmol) and A1C13 (0.400 g, 3 mmol) was added. The reaction mixture was stirred for 30 minutes at the same temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with NaOH (2 M) and brine, dried over Na 2 SO, and evaporated to dryness under vacuum to give crude product 85. Crude yield: 96% RMN-XH (400 MHz, CDC13): d 1.37 (t, 3H), 2.60 (s, 3H), 4.00 (s, 2H), 4.35 (q, 2H), 7.27 (m, 4H) , 7.49 (d, 1H), 8.83 (broad s, 1H) ppm. 13 C-NMR (100 MHz, CDC13): d 11.81, 14.38, 46.52, 60.94, 121.65, 124.57, 127.46, 128.81, 130.81, 133.54, 162.13, 193.36 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 11.81, 14.38; CH2 carbons: 46.52, 60.94; CH carbons: 121.65, 128.81, 130.81 ppm. LC / MS: 90.32%, m / z = 305.

Synthesis of 4- [2- (4-chloro-phenyl) -ethyl] -3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (86): triethylsilane (3 equivalents) was added to a solution of 85 in trifluoroacetic acid (2 mL per mmol). The mixture was stirred for 48 hours at room temperature. The TFA was removed under vacuum and the crude product was taken up in AcOET, washed with NaOH (2 M), brine, dried with Na 2 SO 4, filtered and concentrated to give the crude product. The residue was purified by HPLC. Performance: 46% during two steps. NMR-XH (400 MHz, CDCl 3): d 1.35 (t, 3H), 2.26 (s, 3H), 2.69 (m, 2H), 2.78 (m, 2H), 4.31 (q, 2H), 6.55 (d, 1H), 7.08 (d, 2H), 7.22 (d, 2H), 8.86 (s broad, 1H) ppm.

Synthesis of 4- [2- (4-chloro-phenyl) -ethyl] -3-methyl-1H-pyrrole-2-carboxylic acid (87): Aqueous NaOH (1M in H2O, 10 equivalents) was added at room temperature to the stirred solution of 86 (1 equivalent) in one of 1,4-dioxane and H20 (v / v 3: 1). The solution was heated to 80 ° C until the reaction was judged complete by TLC. The product was extracted with Et20, then the aqueous layer was made acidic (pH = 1) with the dropwise addition of 10% aqueous HCl. The solid was completely filtered and washed with water. The solid was dried under vacuum overnight to obtain 87. Yield: 66%. RMN-1 !! (400 MHz, CD3OD): d 2.19 (s, 3H), 2.69 (m, 2H), 2.78 (m, 2H), 6.58 (d, 1H), 7.11 (d, 2H), 7.22 (d, 2H) ppm . LC / MS: 100%, m / z = 263. HPLC (200-400 nm): 95.93% Example 33. Synthesis of 4- [2- (4-methoxy-phenyl) -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid (90) Synthesis of 4- [2- (4-methoxy-phenyl) -acetyl] -3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (88): The ethyl ester of 4- [2- ( 4-methoxy-phenyl) -acetyl] -3-methyl-lH-pyrrole-2-carboxylic acid (88) from the ethyl ester 3-methyl-lH-pyrrole-2-carboxylic acid (84) following the procedure described in Example 32. Crude Yield: 97% RMN-1 !! (400 MHz, CDC13): d 1.36 (t, 3H), 2.61 (s, 3H), 3.79 (s, 3H), 3.97 (s, 2H), 4.33 (q, 2H), 6.50 (d, 2H) , 7.16 (d, 2H), 7.46 (d, 1H), 9.27 (s broad, 1H) ppm. NMR-13C (100 MHz, CDC13): d 11.75, 14.41, 46.60, 55.27, 60.68, 114.07, 127.09, 130.43, 158.45, 194.19 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 11.75, 14.41, 55.27; CH2 carbons: 46.60, 60.68; CH carbons: 114.07, 127.09, 130.43 ppm. LC / MS: 76.86%, m / z = 301.

Synthesis of 4- [2- (4-methoxy-phenyl) -ethyl] -3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (89): The ethyl ester of 4- [2- ( 4-methoxy-phenyl) -ethyl] -3-methyl-1H-pyrrole-2-carboxylic acid (89) from 4- [2- (4-methoxy-phenyl) -acetyl] -3-methyl ethyl ester -lH-pyrrole-2-carboxylic acid (88) following the procedure described in Example 32. Yield: 23% RMN-1! (400 MHz, CDC13): d 1.36 (t, 314), 2.27 (s, 3H), 2.69 (m, 2H), 2.76 (m, 2H), 3.79 (s, 3H), 4.31 (q, 2H), 6.59 (d, 1H), 6.82 (m, 2H), 7.08 (m, 2H), 8.70 (broad s, 1H) ppm. 13 C-NMR (100 MHz, CDCl 3): d 10.23, 14.56, 27.34, 35.78, 55.27, 59.85, 113.70, 119.69, 129.35, 134.14, 157.81 ppm. DEPT (100 MHz, CDC13): CH3 carbons of: 10.23, 14.56, 55.27; CH2 carbons of: 27.34, 35.78, 59.85; CH carbons of: 113.70, 119.69, 129.35, 134.14 ppm. LC / MS: 100%, m / z = 287.

Synthesis of 4- [2- (4-methoxy-phenyl) -ethyl] -3-methyl-1H-pyrrole-2-carboxylic acid (93): 4- [2- (4-Methoxy-phenyl) was synthesized -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid (93) from the ethyl ester of 4- [2- (4-methoxy-phenyl) -ethyl] -3-methyl-lH- ethyl ester. pyrrole-2-carboxylic acid (92) following the procedure described in Example 32. Yield: 66%. RMN-1 !! (400 MHz, CD30D): d 2.19 (s, 3H), 2.65 (m, 2H), 2.72 (m, 2H), 3.75 (s, 3H), 6.59 (d, 1H), 6.79 (m, 2H), 7.04 (m, 2H) ppm. NMR-13C (100 MHz, CDC13): d 10.46, 28.51, 37.32, 55.62, 114.64, 121.89, 125.45, 127.46, 130.44, 135.54, 165.07 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 10.46, 55.62; CH2 carbons: 28.51, 37.32; CH carbons: 114.64, 121.89, 130.44 ppm. LC / MS: 100%, m / z = 259. HPLC (200-400 nm): 94.17%.

Example 34. Synthesis of 4- [2- (3-methoxyphenyl) -ethyl) -3-methyl-lH-pyrrole-2-carboxylic acid (90): 84 m «2 93 Synthesis of 4- [2- (3-methoxy-phenyl) -acetyl] -3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (91): The ethyl ester of acid 4 was synthesized - [2- (3-methoxy-phenyl) -acetyl] -3-methyl-1H-pyrrole-2-carboxylic acid (91) from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-methoxyphenyl) -acetyl chloride following the procedure described in Example 32. Crude yield: 95%. NMR- ^? (400 MHz, CDC13): d 1.36 (t, 3H), 2.61 (s, 3H), 3.77 (s, 3H), 3.99 (s, 2H), 4.32 (q, 2H), 6.81 (m, 3H), 7.24 (m, 1H), 7.45 (d, 1H), 9.41 (broad s, 1H) ppm. 13 C-NMR (100 MHz, CDC13): d 11.75, 14.40, 47.59, 55.19, 60.66, 112.19, 115.04, 121.71, 127.22, 129.58, 136.75, 159.75, 193.65 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 11.75, 14.40, 55.19; CH2 carbons: 47.59, 60.66; CH carbons: 112.19, 115.04, 121.71, 127.22, 129.58 ppm. LC / MS: 60.20%, m / z = 301 Synthesis of 4- [2- (3-methoxyphenyl) -ethyl] -3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (92): 4- [2- (3- (3-ethyl) ethyl ester was synthesized methoxyphenyl) -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid (92) from 4- [2- (3-methoxyphenyl) -acetyl] -3-methyl-lH-pyrrole-2-ethyl ester -carboxylic (91) following the procedure described in Example 32. Yield: 18%. RMN-1 !! (400 MHz, CDCl 3): d 1.36 (t, 3H), 2.28 (s, 3H), 2.72 (m, 2H), 2.79 (m, 2H), 3.79 (s, 3H), 4.31 (q, 2H), 6.61 (d, 1H), 6.67 (m, 3H), 7.20 (m, 1H), 8.72 (broad s, 1H) ppm. 13 C-NMR (100 MHz, CDC13): d 10.24, 14.56, 26.99, 36.73, 55.16, 59.87, 111.11, 114.27, 119.65, 120.89, 129.28, 159.04 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 10.24, 14.56, 55.16; CH2 carbons: 26.99, 36.73-, 59.87; CH carbons: 111.11, 114.27, 119.65, 120.89, 129.28 ppm. LC / MS: 100%, m / z = 287.

Synthesis of 4- [2- (3-Methoxyphenyl) -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid (93) 4- [2- (3-methoxy-phenyl) - ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid (93) from 4- [2- (3-methoxyphenyl) -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid ethyl ester ( 92) following the procedure described in Example 32. Yield: 57%. RMN-XH (400 MHz, CD3OD): d 2.20 (s, 3H), 2.70 (m, 2H), 2.76 (m, 2H), 3.73 (s, 3H), 6.61 (d, 1H), 6.72 (m, 3H), 7.13 (m, 1H) ppm. 13 C-NMR (100 MHz, CDCl 3): d 10.48, 28.18, 38.25, 55.51, 112.30, 115.17, 121.95, 125.37, 130.18, 145.05, 161.10 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 10.48, 55.51; CH2 carbons: 28.18, 38.25; CH carbons: 112.30, 115.17, 121.95, 130.18 ppm. LC / MS: 93.45%, m / z = 259. HPLC (200400 nm): 69.03%.

Example 35. Synthesis of 4- [2- (4-fluoro-phenyl) -ethyl] -3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (96): M 95 S Synthesis of 4-ethyl ester - [2- (4-fluorophenyl) -acetyl] -3-methyl-lH-pyrrole-2-carboxylic acid (94): 4- [2- (4-fluorophenyl) -acetyl] -3 ethyl ester was synthesized -methyl-lH-pyrrole-2-carboxylic acid (94) from the ethyl ester of 3-methyl-lH-pyrrole-2-carboxylic acid (84) and chloride- (4-fluorophenyl) -acetyl following the procedure described in Example 32. [MLG - INCOMP. SENTENCE?] Crude yield: 94%. NMR-XH (400 MHz, CDC13): d 1.36 (t, 3H), 2.61 (s, 3H), 4.01 (s, 2H), 4.35 (q, 2H), 7.01 (m, 2H), 7.22 (m, 2H), 7.50 (d, 1H), 9.70 (broad s, 1H) ppm. 13 C-NMR (100 MHz, CDC13): d 11.79, 14.38, 46.36, 60.89, 115.51, 127.27, 129.93, 130.77, 162.04, 193.62 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.79, 14.38; CH carbons: 46.36, 60.89; CH carbons: 115.51, 127.27, 129.93, 130.77 ppm. LC / MS: 77.48%, m / z = 289.

Synthesis of 4- [2- (4-fluorophenyl) ethyl] -3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (95): 4- [2- (4-fluorophenyl) ethyl ester was synthesized ) -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid (95) from 4- [2- (4-fluorophenyl) -acetyl] -3-methyl-lH-pyrrole-2-ethyl ester carboxylic acid (94) followed by the procedure described in Example 32. Yield: 23% RMN-1! (400 MHz, CDC13): d 1.36 (t, 3H), 2.26 (s, 3H), 2.69 (, 2H), 2.78 (m, 2H), 4.31 (q, 2H), 6.57 (d, 1H), 6.95 (m, 2H), 7.10 (m, 2H), 8.70 (s broad, 1H ) ppm. RMN-13C (100 MHz, CDC13): d 10.21, 14.55, 27.20, 35.90, 59.89, 114. 89, 115.10, 119.70, 124.60, 129.77, 137.58, 160.00 ppm DEPT (100 MHz, CDC13): CH3 carbons: 10.21, 14.55; CH2 carbons: 27.20, 35.90, 59.89; carbons of: CH 121.65, 128.81, 130.81 ppm. LC / MS: 100%, m / z = 275.

Synthesis of 4- [2- (4-fluorophenyl) -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid (96): 4- [2- (4-fluorophenyl) -ethyl] - was synthesized 3-methyl-lH-pyrrole-2-carboxylic acid (96) from 4- [2- (4-fluorophenyl) -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid ethyl ester (95) following the procedure described in Example 32. Yield: 22%. NMR-XH (400 MHz, CDC13): d 2.19 (s, 3H), 2.68 (m, 2H), 2.77 (m, 2H), 6.58 (d, 1H), 6.95 (m, 2H), 7.12 (m, 2H) ppm. DEPT (100 MHz, CDC13): CH3 carbons: 10.43; CH2 carbons: 28.32, 37.31; CH carbons: 115.61, 121.90, 131.11 ppm. LC / MS: 100%, m / z = 247. HPLC (200-400 nm): 98.44%.

Example 36. Synthesis of 4- [2- (3-fluorophenyl) -ethyl] -3-methyl-IH-pyrrole-2-carboxylic acid (99) 84 97 89 Synthesis of 4- [2- (4-Fluorophenyl) -acetyl] -3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (97): The ethyl ester of 4- [2-] acid was synthesized (3-fluorophenyl) -acetyl] -3-methyl-1H-pyrrole-2-carboxylic acid from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-fluorophenyl) chloride - acetyl following the procedure described in Example 32. Crude yield: 93%. NMR-XH (400 MHz, CDC13): d 1.37 (t, 3H), 2.61 (s, 3H), 4.03 (s, 2H), 4.35 (q, 2H), 7.00 (m, 3H), 7.27 (m, 1H), 7.49 (d, 1H), 9.57 (broad s, 1H) ppm. RMN-1 !! (100 MHz, CDC13): d 11.76, 14.38, 46.93, 60.84, 113.64, 116. 30, 125.13, 127.17, 129.94, 137.42, 161.64, 193.02 ppm.

DEPT (100 MHz, CDC13): CH3 carbons: 11.76, 14.38; CH2 carbons: 46.93, 60.84; CH carbons: 116.30, 125.13, 127.17, 129.94 ppm. LC / MS: 91.29%, m / z = 289.

Synthesis of 4- [2- (3-fluoro-phenyl) -ethyl] -3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (98): The ethyl ester of 4- [2- ( 3-fluoro-phenyl) -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid (98) from 4- [2- (3-fluorophenyl) -acetyl] -3-methyl-lH ethyl ester -pyrrole-2-carboxylic acid (98) following the procedure described in Example 32. Yield: 27% RMN-1! (400 MHz, CDC13): d 1.36 (t, 3H), 2.27 (s, 3H), 2.72 (m, 2H), 2.81 (m, 2H), 4.31 (q, 2H), 6.59 (d, 1H), 6. 88 (m, 3H), 7.22 (m, 1H), 8.79 (broad s, 1H) ppm. RMN-13C (100 MHz, CDC13): d 10.22, 14.55, 26.80, 36.43, 59.93, 112. 64, 115.18, 119.72, 124.16, 129.72, 144.51, 161.65 ppm.

DEPT (100 MHz, CDC13): CH3 carbons: 10.22, 14.55; CH2 carbons: 26.80, 36.43, 59.93; CH carbons: 112. 64, 115.18, 119.72, 124.16, 129.72 ppm. LC / MS: 100%, m / z = 275.

Synthesis of 4- [2- (3-fluoro-phenyl) -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid (99): 4- [2- (3-fluoro-phenyl) was synthesized -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid (99) from 4- [2- (3-fluorophenyl) -ethyl] -3-methyl-lH-pyrrole-2-carboxylic acid ethyl ester (98) following the procedure described in Example 32. Yield: 55%. RMN-XH (400 MHz, CDC13): d 2.20 (s, 3H), 2.69 (m, 2H), 2.81 (m, 2H), 6.61 (d, 114), 6.87 (m, 2H), 6.95 (m, 1H), 7.24 (m, 1H) ppm. DEPT (100 MHz, CDCl 3): CH 3 carbons: 10.43; CH2 carbons: 27. 95, 37.84; CH carbons: 113.53, 116.27, 121.87, 125.48, 130.79 ppm. LC / MS: 100%, m / z = 247. HPLC (200-400 nm): 80.81%. Example 37. Synthesis of 3-methyl-4- [2- (4-trifluoromethyl-phenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (93): 84 100 101 102 Synthesis of 3-methyl-4- [2- (4-trifluoromethyl-phenyl) -acetyl-lH-pyrrole-2-carboxylic acid ethyl ester (100): Ethyl 4- [2- (4- (4-)] -ethyl ester was synthesized trifluoromethylphenyl) -acetyl] -lH-pyrrole-2-carboxylic acid (100) from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (4-trifluoromethylphenyl) -acetyl chloride following the procedure described in Example 32. Crude yield: 96%. NMR-XH (400 MHz, CDC13): d 1.38 (t, 3H), 2.61 (s, 3H), 4.11 (s, 2H), 4.35 (q, 2H), 7.37 (m, 2H), 7.51 (d, 1H), 7.58 (m, 2H), 9.29 (broad s, 1H) ppm. 13 C-NMR (100 MHz, CDCl 3): d 11.71, 14.41, 46.90, 60.78, 123. 70, 124.70, 125.49, 126.75, 129.41, 129.85, 130.00, 161.98, 193.49 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 11.71, 14.41; CH2 carbons: 46.90, 60.78; CH carbons: 123.70, 124.70, 125.49, 126.75, 129.41, 129.85, 130.00 ppm. LC / MS: 73.23%, m / z = 339.

Synthesis of 3-methyl-4- [2- (4-trifluoromethyl-phenyl) -ethyl] -IH-pyrrole-2-carboxylic acid ethyl ester (101): 3-methyl-4- [2-ethyl] ethyl ester was synthesized - (4-trifluoromethylphenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (101) from 3-methyl-4- [2- (4-trifluoromethyl-phenyl) -acetyl] -lH-pyrrole ethyl ester -2-carboxylic acid (100) following the procedure described in Example 32. Yield: 22%. NMR ^ H (400 MHz, CDC13): d 1.36 (t, 3H), 2.27 (s, 3H), 2.73 (m, 21-1), 2.87 (m, 2H), 4.31 (q, 2H), 6.56 ( d, 1H), 7.26 (m, 2H), 7.52 (m, 2H), 8.72 (broad s, 1H) ppm. 13 C-NMR (100 MHz, CDC13): d. 10.21, 14.54, 26.78, 36.51, 59.95, 119.70, 124.23, 125.18, 128.81, 161.68 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 10.21, 14.54; CH2 carbons: 26.78, 36.51, 59.95; CH carbons: 119.70, 124.23, 125.18, 128.81 ppm. LCIMS: 100%, m / z = 325.

Synthesis of 3-methyl-4 [2- (4-trifluoromethyl-phenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (102): 3-Methyl-4- [2- (4-trifluoromethyl-phenyl) - was synthesized ethyl] -lH-pyrrole-2-carboxylic acid (102) from 3-methyl-4- [2- (4-trifluoromethylphenyl) -ethyl] -lH-pyrrole-2-carboxylic acid ethyl ester (101) following the procedure described in Example 32. Yield: 60%. RMN-1 !! (400 MHz, CDC13): d 2.20 (s, 3H), 2.73- (m, 2H), 2.89 (m, 2H), 6.59 (d, 1H), 7.32 (m, 2H), 7.54 (m, 2H) ppm. 13 C-NMR (100 MHz, CDC13): d 10.42, 27.84, 37.90, 120.14, 121.92, 124.74, 126.04, 127.37, 130.26, 148.11, 164.99 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 10.42; CH2 carbons: 27.84, 37.90; CH carbons: 121.92, 126.04, 130.27 ppm. LC / MS: - 100%, m / z = 297. HPLC (200-400 nm): 94.63%.

Example 38. Synthesis of 3-Methyl-4- [2- (3-trifluoromethyl-phenyl) -ethyl) -lH-pyrrole-2-carboxylic acid (96): Synthesis of 3-methyl-4- [2- (3-trifluoromethyl-phenyl) -acetyl] -lH-pyrrole-2-carboxylic acid ethyl ester (105): The 3-methyl-4- ethyl ester was synthesized [2- (3-trifluoromethylphenyl) -acetyl] -lH-pyrrole-2-carboxylic acid (103) from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-trifluoromethylphenyl) chloride ) -acetylated following the procedure described in Example 32. Crude Yield: 97%. NMR ^ H (400 MHz, CDC13): d 1.38 (t, 3H), 2.62 (s, 3H), 4.11 (s, 214), 4.35 (q, 2H), 7.45 (m, 2H), 7.51 (m, 3H), 9.40 (broad s, 1H) ppm. 13 C-NMR (100 MHz, CDC13): d 11.73, 14.40, 46.73, 60.78, 123.70, 124.70, 126.82, 128.93, 129.71, 133.01, 135.85, 161.61, 192.58 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 11.73, 14.40; CH2 carbons: 46.73, 60.78; CH carbons: 123.70, 126.82, 128.93, 129.71, 133.01 ppm. LC / MS: 79.18%, m / z = 339.

Synthesis of 3-methyl-4- [2- (3- (trifluoromethyl-phenyl) -ethyl] -lH-pyrrole-2-carboxylic acid ethyl ester (104): 3-Methyl-4- [ethyl] ethyl ester was synthesized 2- (3-trifluoromethylphenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (104) from 3-methyl-4- [2- (3-trifluoromethylphenyl) -acetyl] -lH-pyrrolethyl ethyl ester 2-carboxylic acid (103) following the procedure described in Example 32. Yield: 16% 2 H NMR (400 MHz, CDC13): d 1.36 (t, 3H), 2.26 (s, 3H), 2.74 (m, 2H) 2.87 (m, 2H), 4.31 (q, 2H), 6.58 (d, 1H), 7.38 (m, 4H), 8.72 (broad s, 1H) ppm, 13C NMR (100 MHz, CDC13): d 10.20, 14.54, 26.87, 35.56, 59.93, 119.67, 122.77, 124.25, 125.16, 128.67, 131.95, 142.77 ppm, DEPT (100 MHz, CDC13): CH3 carbons: 10.20, 14.54; CH2 carbons: 26.87, 35.56, 59.93; CH carbons: 119.67, 122.77, 125.16, 128.67, 131.95 ppm. LC / MS: 100%, m / z = 325.

Synthesis of 3-Methyl-4-l-2- (3-trifluoromethyl-phenyl) -ethyl-1H-pyrrole-2-carboxylic acid (105): 3-Methyl-4- [2- (3- trifluoromethyl-phenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (105) from 3-methyl-4- [2- (3-trifluoromethyl-phenyl) -ethyl] -lH-pyrrole-2-carboxylic acid ethyl ester (104) following the procedure described in Example 32. XH NMR (400 MHz, CDC13): d 2.18 (s, 3H), 2.73 (, 2H), 2.89 (m, 2H), 6.60 (d, 1H), 7.42. '(m, 4H) ppm. 13 C NMR (100 MHz, CDC13): d 10.39, 27.93, 37.87, 121.93, 123.57, 124.69, 126.22, 127.40, 129.94, 133.52, 144.72, 165.01 ppm. DEPT (100 MHz, CDC13): CH3 carbons: 10.39; CH2 carbons: 27.93, 37.87; CH carbons: 121.93, 123.57, 126.22, 129.94, 133.52 ppm. LC / MS: 100%, m / z = 297. HPLC (200-400 nm): 96.89%.

Example 39. Acid - [2- (4-Chlorophenyl) -ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (110): 108 • 10β? Synthesis of 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107): Sodium nitrite (11.5 g; 0. 160 mol) in water (20 ml) was added to an ice-cooled acetoacetate solution (20.7 g, 0.159 mol) in acetic acid (20 ml). The reaction temperature was maintained below 10 ° C. The mixture was stirred for an additional 1 hour at 5 ° C and stored overnight at 0 ° C to give the oxime 97 as an orange-red solution. This solution was added to a mixture of acetoaldehyde-dimethyl acetal (21 g, 0.159 mol) and glacial acetic acid (35 ml), previously heated to 60 ° C, and a mixture of zinc powder was added simultaneously and slowly. (30 g, 0.459 mol) and sodium acetate (30 g, 0.364 mol). After the addition, the mixture was stirred for an additional 2 hours. The mixture was poured into ice water (300 ml) to give a yellow precipitate. Filtration and recrystallization from methanol / water yielded 3.5 g (27%) of 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) as cream colored needles. 1H (CDC13, 400 MHz): d 9.10 (NH, broad s), 6.82 (1H, d), 5.95 (1H, s), 4.29 (2H, q), 2.31 (3H, s), 1.35 (3H, t ) ppm. 13C (CDC13, 100 MHz): d 161.5, 134.1, 121.2, 116.1, 101.8, 60.1, 15.5, 13.1 ppm. LC / MS: 97%.

Synthesis of 4- [2- (4-Chlorophenyl) -acetyl] -5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (108): 4- [2- (4- Chlorophenyl) ethyl ester was synthesized ) -acetyl] -5-methyl-lH-pyrrole-2-carboxylic acid (108) from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-chlorophenyl) -acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane / RT. Purification: recrystallization from ether / pentane. Performance: 83%. 2H (CDC13, 400 MHz): d 9.65 (NH, broad s), 7.28 (3H, m), 7.2 (2H, d), 4.35 (2H, q), 4.04 (2H, s), 2.57 (3H, s) ), 1.38 (3H, t) ppm. 13C (CDC13, 100 MHz): d 193.7, 161.5, 141.0, 133.5, 132.6, 130.9, 130.7, 128.9, 128.6, 121.4, 120.5, 116.9, 61.0, 46.1, 14.4, 14.0 ppm. LC / MS: 100% Synthesis of 4- [2- (4-Chloro-phenyl) -ethyl] -5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (109): The 4- [2- (4- (4-ethyl) ethyl ester was synthesized Chlorophenyl) -ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (109) from ethyl 4- [2- (4-chlorophenyl) -acetyl] -5-methyl-lH-pyrrole-2-ethyl ester carboxylic following the procedure described in Example 32. Purification: Recrystallization from ether / pentane. Performance: 82%. ^? (CDC13, 400 MHz): d 9.65 (NH, broad s), 7.20 (2H, d), 7.04 (2H, d), 6.72 (1H, s), 4.29 (2H, q), 2.78 (2H, dd) , 2.64 (2H, dd), 2.04 (3H, s), 1.35 (3H, t) ppm. 13 C (CDCl 3, 100 MHz): d 161.6, 140.4, 131.5, 131.2, 129.9, 128.3, 121.3, 119.8, 115.7, 60.1, 36.7, 27.8, 14.5, 11.0 ppm. LC / MS: 96%.

Synthesis of 4- [2- (4-Chlorophenyl) -ethyl] -5-methyl-1H-pyrrol-2-carboxylic acid (110): To a solution of 4- [2- (4-chlorophenyl) ethyl ester) ethyl) -5-methyl-lH-pyrrole-2-carboxylic acid in dioxane, 10 equivalents of aqueous NaOH (1.5 M) were added, then the mixture was heated at 80 ° C for 3 hours. While the reaction was judged complete, the solvent was removed under vacuum, H20 was added and an equal volume of Et20 was added. The organic layer was removed, then the aqueous layer was made acidic with HCl (1 M). If the product precipitates at this point, it is filtered, washed with H20, and dried to obtain the desired pure product. If the product did not collapse when the acid layer became acidic, Et20 was added, and the organic layer was removed (2 x). The organic layer was dried with Na 2 SO 4, filtered and concentrated to obtain the desired product. Purification: precipitation. Quantity: 20.6 mg. 2H (MeOD, 400 MHz): d 7.2 (2H, dd), 7.08 (2H, dd), 6.59 (1H, s), 2.76 (2H, dd), 2.63 (2H, dd), 1.97 (3H, s) ppm. DEPT (CD30D, 100 MHz): CH3: d 10.8, CH2: d 28.9, 38.0, CH: 116.4, 129.1, 131.3 ppm. HPLC (20 min): 97.8%. LC / MS: 100%.

Example 40. Synthesis of 4- [2- (4-Fluoro-phenyl) -ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (113): 107 111 112 113 Synthesis of 4- [2- (4-Fluorophenyl) -acetyl] -methyl-lH-pyrrole-2-carboxylic acid ethyl ester (111): 4- [2- (4-Fluorophenyl) ethyl ester was synthesized) -acetyl] -5-methyl-lH-pyrrole-2-carboxylic acid (111) from the 5-methyl-lH-pyrrole-2-carboxylic acid ethyl ester (107) and (4-fluorophenyl) -acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane / RT. Purification: recrystallization from ether / pentane. Yield: 76%. XH (CDC13 400 MHz): d 10.5 (NH, broad s), 7.31 (1H, s), 7.22 (2H, dd), 6.99 (2H, dd), 4.36 (2H, q), 4.06 (2H, s) , 2.58 (3H, s), 1.39 (3H, t) ppm. 13C (CDC13, 100 MHz): d 194.1, 163.0, 161.5, 160.6, 141.0, 131.1, 130.7, 121.5, 120.5, 116.9, 115.4, 115.2, 61.0, 45.9, 14.4, 14.0 ppm. LC / MS: 100%.

Synthesis of 4- [2- (4-Fluoro-phenyl) -ethyl] -5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (112): The ethyl ester of 4- [2- ( 4- Fluorophenyl) -ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (112) from 4- [2- (4-Fluoro-phenyl) -acetyl] -5-methyl-lH ethyl ester -pyrrole-2-carboxylic acid (111) following the procedure described in Example 32. Purification: Recrystallization from ether / pentane. Performance: 86%. XH (CDC13, 400 MHz): d 9.45 (NH, broad s), 7.06 (2H, m), 6.94 (2H,), 6.72 (1H, s), 4.29 (2H, q), 2.78 (2Ht dd), 2.64 (2H, dd), 2.03 (3H, s), 1.34 (3H, t) ppm. 13C (CDC13, 100 MHz): d 162.5, 160.1, 137.6, 131.1, 129.9, 121.4, 119.8, 115. 7, 115.0, 60.0, 36.5, 28.0 14.5, 11.0 ppm. LC / MS: 100%.

Synthesis of 4- [2- (4-Fluorophenyl) -ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (113): 4- [2- (4-fluorophenyl) -ethyl ethyl ester was synthesized - ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (113) from 4- [2- (4-Fluoro-phenyl) -ethyl] -5-methyl-lH-pyrrole-2-ethyl ester carboxylic acid (112) following the procedure described in Example 39. Purification: precipitation. Amount: 21.5 mg. XH (CD30D, 400 MHz): d 7.10 (2H, dd), 6.94 (2H, dd), 6.60 (1H, s), 2.77 (2H, dd), 2.64 (2H, dd), 1.97 (3H, s) ppm. 13C (CD30D, 100 MHz): d 166.0, 161.5, 139.4, 131.5, 131.3, 131.2, 122.5, 121.9, 116.6, 115. 8, 115.5, 37.8, 29.1, 10.8 ppm. HPLC (20 min): 96.6%.

Example 41. Synthesis of 4- [2- (3-Fluoro-phenyl) -ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (116): Synthesis of 4- [2- (3-Fluoro-phenyl) -acetyl] -5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (114): The ethyl ester of 4- [2- ( 3-Fluorophenyl) -acetyl] -5-methyl-lH-pyrrole-2-carboxylic acid (114) from the 5-methyl-lH-pyrrole-2-carboxylic acid ethyl ester (107) and (3-fluorophenyl) chloride ) -acetyl following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane / RT. Purification: recrystallization from ether / pentane. Performance: 78%. XH (CDC13 / 400 MHz): d 10.6 (NH, broad s), 7.30 (1H, s), 7.26 (1H, dd), 7.04 (1H, d), 6.99 (1H, d), 6.92 (1H, dd) ), 4.37 (2H, q), 4.07 (2H, s), 2.58 (3H, s), 1.39 (3H, t) ppm. 13C (CDC13, 100 MHz): d 193.5, 164.0, 161.6, 141.0, 137.4, 130.0, 125.3, 121.5, 120.5, 116.9, 116.4, 113.7, 61.0, 46.4, 14.4, 14.0 ppm. LC / MS: 98%.

Synthesis of 4- [2- (3-Fluoro-phenyl) -ethyl] -5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (115): The 4- [2- (3-ethyl) ethyl ester was synthesized Fluorophenyl) -ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (115) from 4- [2- (3-Fluoro-phenyl) -acetyl] -5-methyl-lH-pyrrole ethyl ester -2-carboxylic acid (114) following the procedure described in Example 32. Purification: Recrystallization from ether / pentane. Performance: 79%. XH (CDCl3f 400 MHz): d 9.55 (NH, broad s), 7.19 (1H, m), 6.86 (3H, m), 6.72 (1H, s), 4.29 .. (2H, q), 2.80 (2H, dd), 2.66 (2H, dd), 2.07 (3H, s), 1.34 (3H, t) ppm. 13 C (CDCl 3, 100 MHz): d 164.1, 161.6, 144.6, 131.1, 129.7, 124.2, 121.3, 119.8, 115.6, 115.2, 112.6, 60.1, 37.1, 27.6, 14.5, 11.0 ppm. LC / MS: 93%.

Synthesis of 4- [2- (3-Fluorophenyl) -ethyl) -5-methyl-1H-pyrrole-2-carboxylic acid (116): 4- [2- (3-Fluorophenyl) -ethyl] - was synthesized 5-Methyl-lH-pyrrole-2-carboxylic acid (117) from 4- [2- (3-Fluorophenyl) -ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid ethyl ester (116) following the procedure described in Example 39. Purification: Extraction. Amount: 10 mg. XH (MeOD, 400 MHz): d 7.23 (1H, m), 6.94 (1H, d), 6.84 (2H, m), 6.65 (1H, s), 2.79 (2H, dd), 2.66 (2H, dd) , 2.0 (3H, s) ppm. DEPT (MeOD, 100 MHz): CH3: d 10.8, CH2: d 28.7, 38.3, CH: 113.3, 116.3, 117.4, 125.5, 130.7 ppm. HPLC (20 min): 96.4%. LC / MS: 94%.

Example 42. Synthesis of 5-Methyl-4- [2- (4-trifluoromethyl-phenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (119) 107 117 118 119 Synthesis of 5-Methyl-4- [2- (4-trifluoromethylphenyl) -acetyl-1H-pyrrole-2-carboxylic acid ethyl ester (117): 5-Methyl-4-ethyl ester was synthesized - [2- (4-trifluoromethyl-phenyl) -acetyl] -lH-pyrrole-2-carboxylic acid (117) from the 5-methyl-lH-pyrrole-2-carboxylic acid ethyl ester (107) and ( 4-trifluoromethylphenyl) -acetyl following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane / -40 ° C. Purification: prep / HPLC. Performance: 33%. XH (CDC13, 400 MHz): d 10.5 (NH, broad s), 7.56 (2H, d), 7.34 (2H, d), 7.32 (1H, s), 4.37 (2H, q), 4.15 (2H, s) ), 2.59 (3H, s), 1.38 (3H, t) ppm. 13C (CDC13, 100 MHz): d 193.3, 161.5, 141.0, 139.0, 130.9, 125.5, 128.6, 121.4, 120.6, 114.0 61.0, 46.5, 14.5, 14.0 ppm. LC / MS: 98%.

Synthesis of 5-Methyl-4- [2- (4-trifluoromethyl-phenyl) -ethyl-1H-pyrrole-2-carboxylic acid ethyl ester (118) 5-Methyl-4- [2- ( 4-trifluoromethylphenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (118) from 5-methyl-4- [2- (4-trifluoromethylphenyl) -acetyl] -lH-pyrrole-2-carboxylic acid ethyl ester (117) following the procedure described in Example 32. Purification: prep / HPLC. Yield: 50%. ^? (CDC13, 400 MHz): d 9.35 (NH, broad s), 7.50 (2H, d7.23 (2H, d), 6.72 (1H, s), 4.29 (2H, q), 2.85 (2H, dd), 2.66 (2H, dd), 2.03 (3H, s), 1.34 (3H, t) ppm, HPLC: 100%.

Synthesis of 5-Methyl-4- [2- (4-trifluoromethyl-phenyl) -ethyl-1H-pyrrole-2-carboxylic acid (119): 5-Methyl-4- [2- (4-trifluoromethyl-phenyl) was synthesized ) -ethyl] -lH-pyrrole-2-carboxylic acid (119) from 5-methyl-4- [2- (4-trifluoromethyl-phenyl) -ethyl] -lH-pyrrole-2-carboxylic acid ethyl ester ( 118) following the procedure described in Example 39. Purification: Extraction. Quantity: 11.6 mg. E (CDC13 / 400 MHz): d 9.15 (NH, broad s), 7.50 (2H, d), 7.24 (2H, d), 6.86 (1H, s), 2.89 (2H, dd), 2.68 (2H, dd) ), 2.04 (3H, s) ppm. 13C (CDC13, 100 MHz): d 165.7, 145.9, 132.5, 128.4, 128.13, 125.2, 122.0, 118.8, 117.9, 37.0, 27.5, 11.2 ppm. HPLC (20 min): 94.5%. LC / MS: 97%.

Example 43. Synthesis of 5-Methyl-4- [2- (3-trifluoromethyl-phenyl-ethyl] -lH-pyrrole-2-carboxylic acid (122): Synthesis of 5-Methyl-4- [2- (3-trifluoromethyl-phenyl) -acetyl-1H-pyrrole-2-carboxylic acid ethyl ester (120): 5-Methyl-4- [ethyl] ethyl ester was synthesized 2- (3-trifluoromethyl-phenyl) -acetyl] -lH-pyrrole-2-carboxylic acid (120) from the ethyl ester of 5-methyl-lH-pyrrole-2-carboxylic acid (107) and chloride (3-trifluoromethylphenyl) -acetyl following the procedure described in Example 32. Reaction Conditions: 1,2- dichloroethane / -40 ° C. Purification: prep / HPLC. Performance: 16% XH (CDC13, 400 MHz): d 10.7 (NH, broad s), 7.48 (4H, m), 7.34 (1H, s), 4.37 (2H, q), 4.15 (2H, s), 2.59 (3H, s) ), 1. 39 (3H, t) ppm. 13 C (CDCl 3, 100 MHz): d 193.3, 161.6, 141. 2, 136.0, 133.2, 131.2, 128.8, 128.2, 126.4, 123.6, 121. 4, 120.6, 116.9, 61.0, 46.3, 14.3, 13.9 ppm. LC / MS: 100% Synthesis of 5-Methyl-4- [2- (3-trifluoromethyl-phenyl) -ethyl] -lH-pyrrole-2-carboxylic acid ethyl ester (121): 5-Methyl-4-ethyl ester was synthesized [2- (3-trifluoromethyl-phenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (121) from 5-Methyl-4- [2- (3-trifluoromethyl-phenyl) -acetyl] ethyl ester] -lH-pyrrole-2-carboxylic acid (120) following the procedure described in Example 32. Purification: prep / HPLC. XH (CDC13, 400 MHz): d 9.25 (NH, broad s), 7.4 (4H, m), 6.72 (1 H, s), 4.30 (2H, q), 2.87 (2H, dd), 2.68 (2H, dd), 2.03 (3H, s), 1.35 (3H, t) ppm. 13C (CDC13, 100 MHz): d 161.5, 142.8, 132.0, 130.9, 130.7, 130.4, 128.7, 125.2, 122.7, 121.0, 120.0, 115.6, 60.1, 37.2, 27.7, 14.5, 11.0 ppm. LC / MS: 94%.

Synthesis of 5-Methyl-4- [2- (3-trifluoromethyl-phenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (122): 5-Methyl-4- [2- (3- trifluoromethyl-phenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (122) from the ethyl ester of 5-Methyl-4- [2- (3-trifluoromethyl-phenyl) -ethyl] -lH-pyrrole-2-ethyl ester carboxylic acid (121) following the procedure described in Example 39. Purification: Extraction. Quantity: 9.5 mg. XH (CD3OD, 400 MHz): d 7.4 (4H,), 6.65 (1 H, s), 2.87 (2H, dd), 2.69 (2H, dd), 1.95 (3H, s) ppm. 13C (CD30D, 100 MHz): d 164.5, 144.7, 133.6, 132.6, 131.3, 129.9, 126.3, 123.6, 121.8, 121.0, 117.4, 38.3, 28.7, 10.7 ppm. HPLC (20 min): 95.6%. LC / MS: 100%.

Example 44. Synthesis of 4- [2- (4-methoxy-phenyl) -ethyl) -5-methyl-1H-pyrrole-2-carboxylic acid (125): Synthesis of 4- [2- (4-Methoxy-phenyl) -acetyl] -5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (123): The ethyl ester of 4- [2- ( 4-Methoxy-phenyl) -acetyl] -5-methyl-1H-pyrrole-2-carboxylic acid (123) from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4) Methoxyphenyl) -acetyl following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane / -40 ° C. Purification: prep / HPLC. Yield: 72%. XH (CDC13, 400 MHz): d 10.45 (NH, broad s), 7.31 (1H, s), 7.18 (2H, d), 6.84 (2H, d), 4.37 (2H, q), 4.01 (2H, s) ), 3.74 (3H, s), 2.57 (3H, s), 1.38 (3H, t) ppm. 13C (CDC13, 100 MHz): d 194.7, 161.5, 158.4, 140.8, 130.5, 127.1, 121.6, 120.4, 117.1, 114.0, 60.8, 55.2, 46.0, 14.4, 14.0 ppm. LC / MS: 100%.

Synthesis of 4- [2- (4-Methoxy-phenyl) -ethyl] -5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (124): The ethyl ester of 4- [2- ( 4-Methoxy-phenyl) -ethyl] -5-methyl-1H-pyrrole-2-carboxylic acid (124) from the ethyl ester of 4- [2- (4-methoxy-phenyl) -acetyl] -5- methyl-lH-pyrrole-2-carboxylic acid (123) following the procedure described in Example 32. Purification: Recrystallization from ether / pentane. Performance: 75%. aH (CDC13, 400 MHz): d 9.0 (NH, broad s), 7.05 (2H, d), 6.82 (2H, d), 6.74 (1H, s), 4.29 (2H, q), 3.78 (3H, s ), 2.75 (2H, dd), 2.64 (2H, dd), 2.05 (3H, s), 1.34 (3H, t) ppm. 13 C (CDCl 3, 100 MHz): d 158.8, 135.2, 131.7, 130.4, 122.9, 120.8, 116.6, 114.7, 63.0, 61.0 56.3, 37.4, 29.2, 15.5, 12.2 ppm.

Synthesis of 4- [2- (4-Methoxy-phenyl) -ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (125): 4- [2- (4-Methoxy-phenyl) - ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (125) from 4- [2- (4-Methoxy-phenyl) -ethyl] -5-methyl-lH-pyrrole-2-ethyl ester carboxylic acid (124) following the procedure described in Example 39. Purification: precipitation. Amount: 27.4 mg. XH (CD30D, - 400 MHz): d 7.01 (2H, dd), 6.78 (2H, dd), 6.64 (1H, s), 3.30 (3H, s), 2.71 (2H, dd), 2.62 (2H, dd) ), 1.98 (3H, s) ppm. 13C (CD30D, 100 MHz): d 159.3, 135.5, 132.7, 130.5, 122.7, 120.7, 117.5, 114.6, 55.6, 37.8, 29.3, 10.8 ppm. HPLC (20 min): 95.6%. LC / MS: 100%.

Example 45. Synthesis of 4- [2- (3-Methoxy-phenyl) -ethyl] -5-methyl-1H-pyrrole-2-carboxylic acid (128): Synthesis of 4- [2- (3-ethyl ester -Metoxy-phenyl) -acetyl] -5-methyl-lH-pyrrole-2-carboxylic acid (126): 4- [2- (3-Methoxy-phenyl) -acetyl] -5-methyl ethyl ester was synthesized -lH-pyrrole-2-carboxylic acid (126) from the 5-methyl-lH-pyrrole-2-carboxylic acid ethyl ester (107) and (3-methoxyphenyl) -acetyl chloride following the procedure described in Example 32 Reaction Conditions: 1,2-dichloroethane / -40 ° C. Purification: Recrystallization from ether / pentane. Yield: 50%. ^ (CDCl ^ 400 MHz): d 10.80 (NH, broad s), 7.32 (1H, s), 7.18 (1H, dd), 6.85 (1H, d), 6.83 (1H, s), 6.75 (1H, d) ), 4.33 (2H, q), 4.04 (2H, s), 3.74 (3H, s), 2.55 (3H, s), 1.36 (3H, t) ppm. 13C (CDC13, 100 MHz): -d 194.3, 161.5, 159.7, 141.1, 136.7, 129.4, 121.9, 121.6, 120.4, 117.2, 115.2, 112.1, 60.8, 55.1, 47.0, 14.4, 13.9 ppm. LC / MS: 100%.

Synthesis of 4- [2- (3-Methoxy-phenyl) -ethyl] -5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (127): The ethyl ester of 4- [2- ( 3-Methoxy-phenyl) -ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (127) from 4- [2- (3-methoxy-phenyl) -acetyl] -5-methyl ethyl ester -lH-pyrrole-2-carboxylic acid (126) following the procedure described in Example 32. Purification: Recrystallization from ether / pentane. Performance: 82%. XH (CDC13, 400 MHz): d 9.40 (NH, broad s), 6.74 (4H, m), 4.30 (2H, q), 3.77 (3H, s), 2.78 (2H, dd), 2.67 (2H, dd ), 2.08 (3H, s), 1.34 (3H, t) ppm. 13C (CDC13, 100 MHz): d 161.5, 159.6, 143.7, 131.0, 129.3, 121.8, 121.0, 119.8, 115.7, 114.3, 111.2, 60.0, 55.2, 37.4, 27.9, 14.5, 11.1 ppm. LC / MS: 93%. Synthesis of 4- [2- (3-Methoxyphenyl) -ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (128): To a solution of 4- [2- (3-methoxy) ethyl ester phenyl) -ethyl] -5-methyl-lH-pyrrole-2-carboxylic acid (127) in EtOH, 3 equivalents of aqueous NaOH (3 M) were added then the mixture was heated at 80 ° C for 1 hour. When the reaction was judged complete, the solvent was removed under vacuum, H20 was added and an equal volume of Et20 was added. The organic layer was removed, then the aqueous layer was made acidic with HCl (1 M). If the product precipitated at this point, it was completely filtered, washed with H20, and dried to obtain the desired pure product. If the product does not collapse when the aqueous layer becomes acidic, Et20 is added, and the organic layer is removed (2 x). The organic layer was dried with Na 2 SO 4, filtered and concentrated to obtain the desired product. Purification: Extraction. Quantity: 37 mg. XH (CDCl 3, 400 MHz): d 8.90 (NH, broad s), 7.19 (1H, dd), 6.88 (1H, s), 6.75 (2H, m), 6.94 (1H, s), 3.78 (3H, s) ), 2.80 (2H, dd), 2.68 (2H, dd), 2.08 (3H, s) ppm. 13C (CDC13, 100 MHz): d 165.5, 159.6, 143.5, 132.3, 129.3, 122.6, 121.0, 118.7, 117.8, 114.2, 111.2, 55.2, 37.3, 27.8, 11.3 ppm. HPLC (20 min): 91.6%. LC / MS: 97%.

Example 46. Synthesis of 5-Methyl-4- (2-naphthalen-1-yl-ethyl) -lH-pyrrole-2-carboxylic acid (131): 107 129 130 131 Synthesis of 5-Methyl-4- (2-naphthalen-1-yl-acetyl) -lH-pyrrole-2-carboxylic acid ethyl ester (129): 5-Methyl-4- (2-ethyl) ethyl ester was synthesized -naphthalen-1-yl-acetyl) -lH-pyrrole-2-carboxylic acid (129) from the 5-methyl-lH-pyrrole-2-carboxylic acid ethyl ester (107) and following the procedure described in Example 32 Reaction Conditions: 1,2-dichloroethane / -40 ° C. Purification: prep / HPLC. Yield: 52%. LC / MS: 62%.

Synthesis of 5-Methyl-4- (2-naphthalen-1-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (130): 5-Methyl-4- (2-ethyl) ethyl ester was synthesized -naphthalene-l-yl-ethyl) -lH-pyrrole-2-carboxylic acid (130) from the ethyl ester of 5-Methyl-4- (2-naphthalen-1-yl-acetyl) -IH-pyrrole-2-ethyl ester -carboxylic (129) following the procedure described in Example 32. Purification: Without purification.

Synthesis of 5-Methyl-4- (2-naphthalen-1-yl-ethyl) -1H-pyrrole-2-carboxylic acid (131): 5-Methyl-4- (2-naphthalene) ethyl ester was synthesized l-yl-ethyl) -lH-pyrrole-2-carboxylic acid (131) from 5-methyl-4- (2-naphthalen-1-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester ( 130) following the procedure described in Example 45. Purification: preparative HPLC. Amount: 5.2 mg. XH (CD3OD, 400 MHz): d 8.06 (1H, d), 7.82 (1H, d), 7.67 (1H, d), 7.45 (2H, m), 7.31 (1H, s), 7.18 (1H, d), 6.72 (1 H, s), 3.24 (2H, dd), 2.76 (2H, dd), 1.84 (3H, s) ppm. DEPT (CD3OD, 100 MHz): CH3: d 10.8, CH2: d 28.4, 35.9, CH: 116.8, 124.8, 126.4, 126.5, 126.7, 127.4, 127.6, 129.8 ppm. HPLC (20 min): 98.6%. LC / MS: 100 Example 47. Synthesis of 5-Methyl-4- (3-naphthalen-2-yl-propyl) -lH-pyrrole-2-carboxylic acid (134): 107 132 133 134 Synthesis of 5-Methyl-4- (3-naphthalen-2-yl-acryloyl) -lH-pyrrole-2-carboxylic acid ethyl ester (132): 5-Methyl-4- (3-ethyl) ethyl ester was synthesized -naphthalen-2-yl-acryloyl) -lH-pyrrole-2-carboxylic acid (132) from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and 3-naphthalene-2-chloride il-acryloyl following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane / -40 ° C - > RT Purification: Without purification. LC / MS: 40%.

Synthesis of 5-Methyl-4- (3-naphthalen-2-yl-propyl) -lH-pyrrole-2-carboxylic acid (133): 5-Methyl-4- (3-naphthalen-2) ethyl ester was synthesized -yl-propyl) -lH-pyrrole-2-carboxylic acid (133) from 5-methyl-4- (3-naphthalen-2-yl-acryloyl) -lH-pyrrole-2-carboxylic acid ethyl ester (132 ) following the procedure described in Example 32. The reduction of 132 gives both the reduction of the carbonyl and the double bond: Purification: Without purification. Performance: 100% by LC / MS.

Synthesis of 5-Methyl-4- (3-naphthalen-2-yl-propyl) -1H-pyrrole-2-carboxylic acid (134): 5-Methyl-4- (3-naphthalen-2-yl) was synthesized -propyl) -lH-pyrrole-2-carboxylic acid (134) from 5-methyl-4- (3-naphthalen-2-yl-propyl) -1H-pyrrole-2-carboxylic acid ethyl ester (133) following the procedure described in Example 45. Purification: Extraction and preparative HPLC. Amount: 20 mg. XH (CDC13 / 400 MHz): d 8.95 (NH, broad s), 7.77 (3H, m), 7.60 (1H, s), 7.42 (2H, m), 7. 32 (1H, d), 6.89 (1H, s), 2.80 (2H, m), 2.46 (2H, m), 2.18 (3H, s), 1.96 (2H, m) ppm. DEPT (CDC13, 100 MHz): CH3: d 11.6, CH2: d 25.2, 32.0, 35.5, CH: 117.9, 125.0, 125.9, 126.4, 127.4, 127.6, 127.7, 127.8 ppm. HPLC (20 min): 88.4%. LC / MS: 94%.

Example 48. Synthesis of 5-Methyl-4- (2-naphthalen-2-yl-ethyl) -lH-pyrrole-2-carboxylic acid (137): Synthesis of 5-Methyl-4- (2-naphthalen-2-yl-acetyl) -lH-pyrrole-2-carboxylic acid ethyl ester (135): 5-Methyl-4- (2-ethyl) ethyl ester was synthesized -naphthalen-2-yl-acetyl) -lH-pyrrole-2-carboxylic acid (135) from the 5-methyl-lH-pyrrole-2-carboxylic acid ethyl ester (107) and naphthalene-2-yl chloride acetyl following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane / -40 ° C- > RT Purification: Without purification. LC / MS: 80%.

Synthesis of 5-Methyl-4- (2-naphthalen-2-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (136): 5-Methyl-4- (2-ethyl) ethyl ester was synthesized -naphthalen-2-yl-ethyl) -lH-pyrrole-2-carboxylic acid (136) from the ethyl ester of 5-Methyl-4- (2-naphthalen-2-yl-acetyl) -lH-pyrrole-2-ethyl ester -carboxylic (135) following the procedure described in Example 32. Purification: Without purification.

Synthesis of 5-Methyl-4- (2-naphthalen-2-yl-ethyl) -1H-pyrrole-2-carboxylic acid (137): 5-Methyl-4- (2-naphthalen-2-yl) was synthesized -ethyl) -lH-pyrrole-2-carboxylic acid (137) from the ethyl ester of 5-Methyl-4- (2-naphthalen-2-yl-ethyl) -1H-pyrrole-2-carboxylic acid (136) following the procedure described in Example 45. Purification: preparative HPLC.

- Quantity: 12.6 mg. XH (CD3OD, 400 MHz): d 7.77 (1H, d), 7.73. (2H, m), 7.54 (1H, s), 7.38 (2H, m), 7.28 (1H, dd), 6.68 (1 H, s), 2.95 (2H, dd), 2.74 (2H, dd) ppm. X3C (CD3OD, 100 MHz): d 165.8, 141.04, 135.15, 133.6, 131.9, 128.7, 128.6, 128. 5, 128.4, 127.6, 126.7, 126.1, 122.3, 122.0, 116.9, 38. 8, 29.0, 10.9 ppm. HPLC (20 min): 99.0%. LC / MS: 100%.

Example 49. Synthesis of 5-Methyl-4- (2-phenyl-propyl) -1H-pyrrole-2-carboxylic acid (140): Synthesis of 5-Methyl-4- (2-phenyl-propionyl) -lH-pyrrole-2-carboxylic acid ethyl ester (138): 5-Methyl-4- (2-phenyl-propionyl) ethyl ester was synthesized ) -lH-pyrrole-2-carboxylic acid (138) from the 5-methyl-lH-pyrrole-2-carboxylic acid ethyl ester (107) and 2-phenyl-propionyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane / -40 ° C - > RT Purification: Without purification. LC / MS: 86%.

Synthesis of 5-Methyl-4- (2-phenyl-propyl) -lH-pyrrole-2-carboxylic acid ethyl ester (139) 5-Methyl-4- (2-phenyl-propyl) ethyl ester was synthesized -lH-pyrrole-2-carboxylic acid (139) from 5-Methyl-4- (2-phenyl-propionyl) -1H-pyrrole-2-carboxylic acid ethyl ester (138) following the procedure described in Example 32 Purification: Without purification.

Synthesis of 5-Methyl-4- (2-phenyl-propyl) -lH-pyrrole-2-carboxylic acid (140): 5-Methyl-4- (2-phenyl-propyl) -lH-pyrrole- 2-carboxylic acid (140) from 5-Methyl-4- (2-phenyl-propyl) -lH-pyrrole-2-carboxylic acid ethyl ester (139) following the procedure described in Example 45.

Purification: preparative HPLC. Amount: 13 mg. XH (CDC13 / 400 MHz): d 8.7 (NH, broad s), 7.27 (3H, m), 7.18 (2H, m), 6. 77 (1H, s), 2.90 (1H, m), 2.62 (2H, m), 1.97 (3H, s), 1.27 (3H, d) ppm. DEPT (CDC13, 100 MHz): CH3: d 11.3, 20.9 CH2: d . 0, CH: 41.4, 118.6, 126.0, 127.1, 128.3 ppm. HPLC (20 min): 93.1%. LC / MS: 96%.

Example 50. Synthesis of 4- (2-Naphthalen-2-yl-ethyl) -1H-pyrrole-2-carboxylic acid (128): 141 142 143 Synthesis of 4- (2-naphthalen-2-yl-acetyl) -lH-pyrrole-2-carboxylic acid ethyl ester (141): 4- (2-Naphthalen-2-yl-acetyl) ethyl ester was synthesized ) -lH-pyrrole-2-carboxylic acid (141) from the ethyl ester of lH-pyrrole-2-carboxylic acid and naphthalen-2-yl-acetyl chloride following the procedure described in Example 32 .. Reaction Conditions: 1,2-dichloromethane / -40 ° C - > RT Purification: Without purification. LC / MS: 78%.

Synthesis of 4- (2-Naphthalen-2-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (142): 4- (2-Naphthalen-2-yl-ethyl) ethyl ester was synthesized ) -IH-pyrrole-2-carboxylic acid (142) from the 4- (2-Naphthalen-2-yl-acetyl) -1H-pyrrole-2-carboxylic acid ethyl ester (141) following the procedure described in the Example 32. Purification: Without purification.

Synthesis of 4- (2-naphthalen-2-yl-ethyl) -lH-pyrrole-2-carboxylic acid (143): 4- (2-Naphthalen-2-yl-ethyl) -1H- pyrrole- 2-carboxylic acid (143) from 4- (2-Naphthalen-2-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (142) following the procedure described in Example 45. Purification: chromatography on silica gel; - .. (eluent: CH2C12 AcOEt). XH (MeOD, 400 MHz): d 7.77 (3H, m), 7.61 (1H, s), 7.54 (1H, s), 7.38 (3H, m), 7.34 (1H, s), 6.68 (1 H, s), 3.01 (2H, dd), 2.86 (2H, dd) ppm. DEPT (MeOD, 100 MHz): CH2: d 29.8, 38.9, CH: 116.4, 122.7, 126.1, 126.8, 127.5, 128.4, 128.5, 128.6, 128.7 ppm. HPLC (20 nm): 96.9% LC / MS: 100% Example 51. Synthesis of 4- (2-14-Bromophenyl-ethyl) -1H-pyrrole-2-carboxylic acid (146): Synthesis of 4- (2- [4-bromophenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid ethyl ester (144): 4- (2- [4-ethyl] ethyl ester was synthesized - Bromophenyl-2-yl-acetyl) -lH-pyrrole-2-carboxylic acid (144) from the ethyl ester of lH-pyrrole-2-carboxylic acid and 4-bromophenyl-2-yl-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane / -40 ° C - > RT Purification: Without purification.

Synthesis of ethyl 4-2-4-bromophenyl] -2-yl-ethyl) lH-pyrrole-2-carboxylic acid ester (145): 4- (2 [4-Bromophenyl-2-] ethyl ester was synthesized il-ethyl) -lH-pyrrole-2-carboxylic acid (145) from 4- (2 [4-bromophenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid ethyl ester (144) following the procedure described in Example 32. Purification: Without purification.

Synthesis of 4- (2- [4-bromophenyl] -2-yl-ethyl) -IH-pyrrole-2-carboxylic acid (146): 4- (2 [4-Bromophenyl] -2-yl- was synthesized ethyl) -lH-pyrrole-2-carboxylic acid (146) from 4- (2- [4-bromophenyl] -2-yl-ethyl) -IH-pyrrole-2-carboxylic acid ethyl ester (145) following the procedure described in Example 45. Purification: Crystallization from water. X H NMR (CD30D, 400 MHz): d 7.36 (2 H, d), 7.07 (2 H, d), 6.69 (1 H, s); 6.67 (1H, s); 2.81 (2H, m); 2.72 (2H, m) ppm. X3C NMR (CD30D, 100 MHz): 164.5, 142.7, 132.26, 131.6, 125.9, 123.5, 122.8, 120.4, 116.4, 38.0, 29.7 ppm. HPLC (20 nm): 92.75% Yield 91%.

Example 52. Synthesis of 4- (2- [2-fluorophenyl] -ethyl) -1H-pyrrole-2-carboxylic acid (149): Synthesis of 4- (2- [4-fluorophenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid ethyl ester (147): The 4- (2- [4] ethyl ester was synthesized - Fluorophenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid (147) from the ethyl ester of lH-pyrrole-2-carboxylic acid and (4-fluorophenyl) -2-yl-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane / -40 ° C - > RT Purification: Without purification. -j_ ^ Synthesis of 4- (2- [4-fluorophenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (148): 4- (2-) ethyl ester was synthesized [4- Fluorophenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid (148) from 4- (2 [4-fluorophenyl] -2-yl-0-acetyl) -lH- ethyl ester pyrrole-2-carboxylic acid (147) following the procedure described in Example 32. Purification: Without purification.

Synthesis of 4- (2- [4-fluorophenyl-ethyl) -lH-pyrrole-2-carboxylic acid (149): The 4- (2- [4-fluorophenyl] -ethyl) -lH-pyrrole-2-carboxylic acid (149) was synthesized from 4- (2- [4-fluorophenyl] -2-yl- ethyl ester. ethyl) -lH-pyrrole-2-carboxylic acid (148) following the procedure described in Example 45. Purification: Crystallization from water. X H NMR (CDC13, 400 MHz): d 7.16 (2H,), 7.03 (2H, m), 6.70 (2H, m); 2.87 (2H, m), 2.73 (2H, m) ppm. 13 C NMR (CD30D, 100 MHz): 164.4, 161.4, 132.0, 130.0, 128.8, 126.0, 125.0, 123.5, 122.8, 116.4, 115.8, 31.8, 28.5 ppm. Performance 71%. HPLC 20 min: 97.76%.

Example 53 Synthesis of 4- (2- [4-methyl-phenyl] -ethyl) -1H-pyrrole-2-carboxylic acid (152): 150 151 152 Synthesis of 4- (2- [4-methylphenyl] -2-yl-acetyl) -IH-pyrrole-2-carboxylic acid ethyl ester (150): The 4- (2- [4-] ethyl ester was synthesized Methylphenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid (150) from the ethyl ester of lH-pyrrole-2-carboxylic acid and p-tolyl-2-yl-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane / -40 ° C - > RT Purification: Without purification.

Synthesis of 4- (2 [4-methylphenyl] -yl-ethyl) -lH-pyrrole-2-carboxylic acid (151): 5 ethyl ester of 4- (2- [4- Methylphenyl] was synthesized -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid (151) from 4- (2- [4-methylphenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid ethyl ester (150) following the procedure described in Example 32. Purification: Without purification.

Synthesis of 4- (2- [4-methylphenyl] ethyl) -lH-pyrrole-2-carboxylic acid (152): 4- (2- [4-Methylphenyl] -ethyl) -15 lH-pyrrole- 2-carboxylic acid (152) from 4- (2- [(methylphenyl) -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid (151) ethyl ester following the procedure described in Example 45. Purification : Crystallization from water. X H NMR (CDCl 3, 400 MHz): d 7.04 (4H, m), 6.68 (1H, s); 6.67 (1H, s); 2.78 (2H, m), 2.72 (2H, m), 2.27 (3H, s) ppm. X3C NMR (CD30D, 100 MHz): 164.5, 140.3, 136.2, 129.9, 129.4, 126.5, 123.3, 122.7, 116.5, 38.3, 30.1, 21.1 ppm. Performance 55%. HPLC 20 mn: 96.23% -25 Example 54. Synthesis of 4- (2- [2-methylphenyl] -ethyl) -1H-pyrrole-2-carboxylic acid (155): 153 154 155 Synthesis of 4- (2- [2-methylphenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid ethyl ester (153): The ethyl ester of 4- (2- [2- Methylphenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid (153) from the ethyl ester of lH-pyrrole-2-carboxylic acid and I o-tolyl-2-yl-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane / -40 ° C - > RT Purification: Without purification.

Synthesis of 4- (2- [2-methylphenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (154): 4- (2- [2- (2-ethyl) ethyl ester was synthesized Methylphenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid (154) from 4- (2- [2-methylphenyl] -2-yl-acetyl) -lH-pyrrole-2-ethyl ester carboxylic (153) following the procedure described in Example 32. Purification: Without purification.

Synthesis of 4- (2- [2-methylphenyl] -ethyl) -lH-pyrrole-2-carboxylic acid (155): The 4- (2- [2-methyl-phenyl] -ethyl) -lH-pyrrole-2-carboxylic acid (155) was synthesized from 4- (2- [2-methylphenyl] -2-yl- ethyl ester. ethyl) -lH-pyrrole-2-carboxylic acid (153) following the procedure described in Example 45. Purification: Crystallization from water. X H NMR (CDC13, 400 MHz): d 7.08 (4H, m), 6.71 (1H, s); 6.69 (1H, s); 2.83 (2H, m), 2.69 (2H, m), 2.27 (3H, s) ppm. XR NMR (CD3OD, 100 MHz): 164.5, 141.5, 136.9, 131.0, 130.0, 127.0, 126.9, 126.58, 123.4, 122.6, 116.4, 63.1, 28.9, 19.4 ppm. Yield 73% HPLC 20 mn: 96.95%.

Example 55 Synthesis of 4- (2- [3-methylphyl] -ethyl) -1H-pyrrole-2-carboxylic acid (158): Synthesis of 4- (2- [3-methylphenyl-2-yl-acetyl) -lH-pyrrole-2-carboxylic acid ethyl ester (156): 4- (2- [3-Methylphenyl] ethyl ester was synthesized ] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid (156) from the ethyl ester of lH-pyrrole-2-carboxylic acid and m-tolyl-2-yl-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane / -40 ° C - > RT Purification: Without purification.

Synthesis of 4- (2- [3-methylphenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (157): The 4- (2- [3- ethyl] ethyl ester was synthesized Methylphenyl-2-yl-ethyl) -lH-pyrrole-2-carboxylic acid (157) from 4- (2 - [3-methylphenyl] -2-yl-acetyl) -lH-pyrrole-2-ethyl ester -carboxylic (156) following the procedure described in Example 32. Purification: Without purification. Synthesis of 4- (2- [3-methylphenyl] -ethyl) -lH-pyrrole-2-carboxylic acid (158): 4- (2- [3-Methylphenyl] -ethyl) -lH-pyrrol- was synthesized 2-carboxylic acid (158) from the 4- (2- [3-methylphenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (157) following the procedure described in Example 45. Purification: Crystallization from water. X H NMR (CDC13, 400 MHz): d 9.00 (1H, broad s), 7.18 (1H, m), 7.00 (3H, m), 6.91 (1H, s), 6.75 (1H, s), 2.82 (4H, m), 2.38 (3H, s) ppm. LC / MS: 100%, m / z = 229g / mol. Yield = 72%.

Example 56. Synthesis of 4- (2- [2-chloro-4-fluorophenyl] -ethyl) -lH-pyrrole-2-carboxylic acid (161): Synthesis of 4- (2- [2-chloro-4-fluorophenyl] -2-yl-acetyl) -IH-pyrrole-2-carboxylic acid ethyl ester (159): The ethyl ester of 4- ( 2- [2- chloro-4-fluorophenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid (159) from lH-pyrrole-2-carboxylic acid ethyl ester and (2-chloro) chloride -4-fluorophenyl) -2-yl-acetyl following the procedure described in the Example 32. Reaction Conditions: 1,2-dichloromethane / -40 ° C > RT Purification: Without purification.

Synthesis of 4- (2- [2-chloro-4-fluorophenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (160): 4- (2-ethyl) ethyl ester was synthesized - [2-chloro-4-fluorophenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid (160) from 4- (2- [2-chloro-4-fluorophenyl-2] ethyl ester -yl-acetyl) -lH-pyrrole-2-carboxylic acid (159) following the procedure described in Example 32. Purification: Without purification.

Synthesis of 4- (2- [2-chloro-4-fluorophenyl] -ethyl) -1H-pyrrole-2-carboxylic acid (161): 4- (2- [2-chloro-4-ethyl] ethyl ester was synthesized -fluorophenyl] -ethyl) -lH-pyrrole-2-carboxylic acid (161) from 4- (2- [2-chloro-4-fluorophenyl] -2-yl-ethyl) -lH-pyrrol- ethyl ester 2-carboxylic acid (160) following the procedure described in Example 45. Purification: precipitation from water. X H NMR (CDC13, 400 MHz): d 7.19 (2H, m), 6.96 (1H, m); 6.70 (2H, m); 2.95 (2H, m), 2.73 (2H, m) ppm. X NMR (CD3OD, 100 MHz): 164.4, 161.2, 136.9, 135.4, 132.9, 125.7, 123.6, 122.7, 117.4, 116.4, 114.7, 35.7, 28.0 ppm. Yield 51%. HPLC 20 mn: 98.85% Example 57. Synthesis of 4- (2- [2,4-dichlorophenyl] -ethyl) -lH-pyrrole-2-carboxylic acid (164): Synthesis of 4- (2- [2, 4-dichlorophenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid ethyl ester (162): The ethyl ester of 4- (2- [ 2,4-dichlorophenyl-2-yl-acetyl) -lH-pyrrole-2-carboxylic acid (162) from lH-pyrrole-2-carboxylic acid ethyl ester and o, p-dichlorophenyl-2-yl chloride acetyl following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane / -40 ° C - > RT Purification: Without purification.

Synthesis of 4- (2- [2,4-dichlorophenyl] -2-ethyl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (163): The ethyl ester of 4- (2- [ 2,4-dichlorophenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid (163) from 4- (2- [2, 4-dichlorophenyl] -2-yl-acetyl) ethyl ester) -lH-pyrrole-2-carboxylic acid (162) following the procedure described in Example 32. Purification: Without purification.

Synthesis of 4- (2- [2,4-dichlorophenyl] -ethyl) -lH-pyrrole-2-carboxylic acid (164): 4- (2- [2,4-dichlorophene] ethyl) -lH was synthesized -pyrrole-2-carboxylic acid (164) from 4- (2- [2,4-dichlorophenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (163) following the procedure described in Example 45 (Note: reaction solvent changed to ethanol). Purification: precipitation from water. X H NMR (CD30D, 400 MHz): d 7.43 (1H, s), 7.20 (2H, m), 6.69 (2H, s), 2.96 (2H, t), 2.78 (2H, t) ppm. Yield = 46%.

Example 58. Synthesis of 4- (2- [3,4-dichlorophenyl] -ethyl) -lH-pyrrole-2-carboxylic acid (167): Synthesis of 4- (2- [3,4-dichlorophenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid ethyl ester (165): The ethyl ester of 4- (2- [ 3,4-dichlorophenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid (165) from the ethyl ester of lH-pyrrole-2-carboxylic acid and of m, p-dichlorophenyl-2-chloride il-acetyl following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane / -40 ° C - > R. Purification: Without purification.

Synthesis of 4- (2- [3,4-dichlorophenyl] -2-ethyl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (166): The ethyl ester of 4- (2- [ 3,4-dichlorophenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid (166) from 4- (2- [3,4-dichlorophenyl] -2-yl-acetyl) ethyl ester) -lH-pyrrole-2-carboxylic acid (165) following the procedure described in Example 32. Purification: Without purification.

Synthesis of 4- (2- [3,4-dichlorophenyl] -ethyl) -lH-pyrrole-2-carboxylic acid (167): 4- (2- [3,4-dichlorophenyl] ethyl) ethyl ester was synthesized ) -lH-pyrrole-2-carboxylic acid (167) from 4- (2- [3,4-dichlorophenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (166) following the procedure described in Example 45 (Note: reaction solvent changed to ethanol). Purification: precipitation from water. XH NMR (CD3OD, 400 MHz): d 7.36 (2H, m), 7.08 (1H, m), 6.68 (2H, m), 2.83 (4H, m) ppm. Performance "= 87%.

Example 59. Synthesis of 4- (2- [2, 4-difluorophenyl] -ethyl) -IH-pyrrole-2-carboxylic acid (170): Synthesis of 4- (2- [2, 4-difluorophenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid ethyl ester (168): The ethyl ester of 4- (2- [ 2,4-Difluorophenyl] -2-yl-acetyl) -lH-pyrrole-2-carboxylic acid (168) from the ethyl ester of lH-pyrrole-2-carboxylic acid and o-p-difluorophenyl-2-yl chloride -acetyl following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane / -40 ° C - > RT Purification: Without purification.

Synthesis of 4- (2- [2,4-difluorophenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (169): Ethyl 4- (2- [ 2,4-difluorophenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid (169) from 4- (2- [2, 4-difluorophenyl] -2-yl-acetyl) ethyl ester) -lH-pyrrole-2-carboxylic acid (168) following the procedure described in Example 32. Purification: Without purification.

Synthesis of 4- (2- [2,4-difluorophenyl] ethyl) -lH-pyrrole-2-carboxylic acid (170): 4- (2- [2,4-difluorophenyl] -ethyl) ethyl ester was synthesized ) -lH-pyrrole-2-carboxylic acid (170) from 4- (2- [2, 4-difluorophenyl] -2-yl-ethyl) -lH-pyrrole-2-carboxylic acid ethyl ester (169) following the procedure described in Example 45. Purification: precipitation from water. X H NMR (CDC13, 400 MHz): d 6.76 (2H, m), 6.70 (3H, m); 2.87 (2H, m), 2.75 (2H, m) ppm. 3 C NMR (CD30D, 100 MHz): 165.6, 164.5, 163.2, 148.0, 125.6, 123.6, 122.7, 116.3, 112.4, 112.2, 101.9, 38.3, 29.2 ppm. Yield 70%. HPLC 20 mn: 99.05% Example 60. Synthesis of 4,5,6,7,7-tetrahydro-2H-isoindole-1-carboxylic acid (172).

Synthesis of 4,5,6,7-tetrahydro-2H-isoindol-1-carboxylic acid ethyl ester (171): 1,8-Diazabicyclo [5.4.0] -undec-7-ene (6.2 mL, 41.5 was added mmol) in 2-propanol (45 mL) per addition funnel for about 25 minutes to a stirred solution of 1-nitrocyclohexene (5.0441 g, 39.67 mmol) and ethyl isocyanoacetate (4.3340 g, 37.16 mmol) in THF (45 mL). The reaction was judged complete after stirring overnight at room temperature. 2N HCl (approximately 100 mL) and EtOAc (approximately 50 mL) were added. The organic layer was removed, then washed with H20, 5% NaHCO3 and H20. The crude product was dried with Na 2 SO, filtered, concentrated and purified by chromatography on silica gel (Combiflash column, 100% CH 2 C 12) to obtain 171 contaminated with a minor impurity. Attempts to recrystallize from hexanes were unsuccessful in removing the impurity, so that the product was taken to the next step without further purification. XH (CDC13, 400 MHz): d 9.01 (1H, broad s), 6.64 (1H, s), 4.31 (3H, q, J = 7.2 Hz), 2.82 (2H, t, J = 5.6 Hz), 2.55 ( 2H, t, J = 5.6 Hz), 1.80 - 1.68 (4H, m), 1.36 (3H, t, J = 7.2 Hz) ppm. X3C (CD30D, 100 MHz): d 161.71, 128.06 and 127.84, 121.98 and 121. 96, 118.74 and 118.55, 118.03 and 117.71, 59.62, 23.41 and 2. 3 . 39, 23 36 and 23. 33, 23 16 and 23. 13, 21 88 and 21. 86, 14 48 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 14.48; CH2 carbons: 59.62, 23.41 and 23.39, 23.36 and 23.33, 23.16 and 23.13, 21.88 and 21.86; CH carbons: 118.74 and 118.55 ppm. HPLC: 10689 min.

Synthesis of 4,5,6,7-tetrahydro-2H-isoindol-l-carboxylic acid (172): Freshly prepared aqueous NaOH (10 M in H20, 10.3 mmol) was added to a stirring solution at room temperature of 171 ( 0.3966 g, 2.05 mmol) in MeOH (5.1 mL, 0.4 M) under N2. The reaction was then heated to reflux for 20 minutes. A small amount of the starting material remained. A large amount of undesired product together with only a small amount of desired product was observed by HPLC. The reaction was concentrated, redissolved in H20, and extracted with EtOAc (1 mL). 10% aqueous HCl was added dropwise to the aqueous layer until pH = 2. The white solid which precipitated from the reaction was filtered and washed with cold H20. The solid was dried under vacuum overnight to obtain 0.0076 g (11.6%) 172. XH (CD30D, 400 MHz): d 5.62 (1H, s), 2.77 (2H, t, J = 5.6 Hz), 2.52 (2H, t, J = 5.4 Hz), 1.78 - 1.66 (4H, m) ppm. 13C (CD3OD, 100 MHz): d 164.87, 129.69, 122.48, 120.57, 118.42, 24. 74, 24.69, 24.35, 22.94 ppm. DEPT (CD30D, 100 MHz): CH2 carbons: 24.74, 24.69, 24.35, 22.94; CH carbons: 120. 57 ppm. HPLC: 8896 min.

Example 61. Synthesis of 5-bromo-4- [2- (2-bromophenyl) -ethyl] IH-pyrrole-2-carboxylic acid (173): Synthesis of 5-bromo-4- [2- (2-bromophenyl) -ethyl] -1H-pyrrole-2-carboxylic acid (173): Bromine (0.021 mL, 0.414 mmol) was added dropwise over 5 minutes at a time. 65 shaking solution (0.1014 g, 0.345 mmol) in acetic acid (1.1 mL). When the reaction was judged complete by HPLC (20 min), it was added H20, and the solid which precipitated was filtered completely and washed with H20. The light purple solid obtained was dissolved in EtOAc, washed with Na 2 SO 3 and H 2 O, then dried with Na 2 SO 4, filtered and concentrated. The product was purified by preparative inverted phase HPLC with H20: CH3CN 40:60 (with 0.05% TFA); 20 mL / min .; ? = 214 nM. 0.0574 g (44.6%) of 173 were obtained as a pale pink foamy solid. XH (CD3OD, 400 MHz): d 7.50 (1H, d, J = 7.8 Hz), 7.24 -7.00 (3H, m), 6.68 (1H, s), 2.92 (211, t, J = - 7.8 Hz), 2.67 (2H, t, J = - 7.8 Hz) ppm. Partial X3C (CD30D, 100 MHz): 163.25, 141.86, 133.73, 131.85, 128.89, 128.54, 125.26, 124.68, 117.16, 105.89, 37.91, 27.62 ppm. DEPT (CD3OD, 100 MHz): CH carbons: 37.91, 27.62; CH carbons: 133.73, 131.85, 128.89, 128.54, 117.16 ppm. HPLC: 10,473 min.

Example 62. Synthesis of 5-bromo-4- [2- (4-chlorophenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (174) -.

Synthesis of 5-bromo-4- [2- (4-chlorophenyl) -ethyl] -1H-pyrrole-2-carboxylic acid (174): 5-Bromo-4- [2- (4-chlorophenyl) acid was made ethyl) -lH-pyrrole-2-carboxylic acid using the procedure of Example 61: XH (CD3OD, 400 MHz): d 7.22 (2H, d, 'J = 8.8 Hz), 7.12 (2H, d, J = 8.8 Hz ), 6.65 (1H, s), 2.81 (2H, t, J = 7.3 Hz), 2.67 (211, t, J = 7.3 Hz) ppm. X3C (CD3OD, 100 MHz): d 163.33, 141.42, 132.54, 131.03, 129.18, 124.73, 117.46, 105.84, 36.72, 29.04 ppm.

Example 63. Synthesis of 5- (3-phenylpropyl) -lH-pyrrole-2-carboxylic acid (177).

Synthesis of 5- (3-phenylpropionyl) -1H-pyrrole-2-carboxylic acid ethyl ester (175) and 4- (3-phenylpropionyl) -lH-pyrrole-2-carboxylic acid ethyl ester (43): Ethylpyrrole-2 -carboxylate (2.0211 g, 14.5 mmol) in a minimum amount of dichloroethane (2 mL) was added to an ice-cooled mixture of zinc chloride (4.0151 g, 29.5 mmol) and hydrocinnamoyl chloride (5.0348 g, 29.9 mmol) in dichloroethane (20 mL, 0.66 M) under N2.

After stirring for 10 minutes, the ice bath was removed, and the reaction was allowed to warm to room temperature until it was judged complete by HPLC (2 hours 45 minutes). PS-Trisamine ™ resin (13.44 g) was added and the reaction was stirred at room temperature for about 1.5 hours. The reaction was filtered through a frit in a flask containing ice water. The frit was washed with CH2C12, then the combined organic layers were washed with H20, dried over Na2SO, filtered, concentrated and purified by chromatography on silica gel (Combiflash 25: 75-Hexanes: CH2C12 column) to obtain 0.5374 g. (14%) of 175 (lower Rf). No attempt was made to isolate 43 (upper Rf).

HPLC: 10.58 min. (Start material: 8.90 min).

Synthesis of 5- (3-phenylpropyl) -1H-pyrrole-2-carboxylic acid ethyl ester (176): triethylsilane (0.977 mL, 6.14 mmol) was added to a stirring solution at room temperature of 5-ethyl ester. (3-phenylpropionyl) lH-pyrrole-2-carboxylic acid (175) (0.5374 g, 1.98 mmol) in trifluoroacetic acid (TFA) (4.72 mL, 0.42 M) under N2. The reaction was judged complete by HPLC after stirring at room temperature overnight. The TFA was removed under vacuum, and the crude product was purified by preparative inverted phase HPLC with the following conditions: H20: CH3CN 35:65, 20 mL / min; ?, = 254 nM. HPLC: 11.12 min.

Synthesis of 5- (3-phenylpropyl) -lH-pyrrole-2-carboxylic acid (177): Freshly prepared aqueous NaOH (10 M in H20, 1.22 mmol) was added to a stirred solution at room temperature of 5- (3-phenylpropyl) -1H-pyrrole-2-carboxylic acid ethyl ester (85) (0.0629 g, 0.244 mmol) in MeOH (0.61 mL, 0.4 M) under N2. The reaction was heated to reflux until the reaction was judged complete by HPLC. The product was concentrated and then 2 mL of diethyl ether and 2 mL of H20 were added. The organic layer was removed and discarded, then 2 mL of diethyl ether was added, and 10% aq. Aqueous HCl was added dropwise. HCl to pH = 2. The diethyl ether layer was removed, and the aqueous layer was extracted with another portion of diethyl ether. The combined organic layers were dried, and concentrated to provide the desired product. (Note: An unwanted impurity has retention time of 10.85 min by HPLC HPLC: 9.91 min.

Example 64. Deconversion 4- [2- (4-chlorophenyl) -ethyl] -lH-pyrrole-2-carboxylic acid to sodium salt (178): Formation of sodium salt of 4- [2- (4-chlorophenyl) -ethyl] -lH-pyrrole-2-carboxylic acid (178): 4- [2- (4-Chlorophenyl) -ethyl] -1H- was dissolved pyrrole-2-carboxylic acid (39) (4.2668 g, 17.09 mmol) in 60 mL (0.17 M) of MeOH. The solution was cooled in an ice bath at 0 ° C, then an aqueous solution of sodium hydroxide (0.6872 g, 17.09 mmol NaOH, 2.7 M) slowly with stirring. A white solid squeezed out of the solution. The methanol was removed in the rotoevaporator, then 32 mL of H20 was added and the flask was mixed well to dissolve at room temperature. The light pink discoloration observed when the starting acid was dissolved in methanol was removed when the solution was filtered through filter paper. Lyophilization of the colorless solution gave 4.5345 g (97.7%) of a white foamy solid.

Example 65. Synthesis of 4-Methyl-2-phenethyl-1H-pyrrole-2-carboxylic acid ethyl ester (182).

Synthesis of 4-Nitro-l-phenyl-pentan-3-ol (179): Following the procedure of One et al, J. Heterocyclic Chem., 1994, 31, 707-710, which is incorporated by reference, nitroethane was dissolved (10 mL, 139.2 mmol, 96%) and 3-phenylpropionaldehyde (18.49 mL, 139.9 mmol) in THF (70 mL, 2 M). After cooling to -10 ° C in a brine bath, 1,8-diazabicyclo [5.4.0] -undec-7-ene (DBU) (1.46 mL, 9.74 mmol) was added and allowed to stir until complete by HPLC. (75 min). The reaction was diluted with diethyl ether and H20, and then the organic layer was stirred and washed with saturated aqueous NaHCO3 and brine. The aqueous layers were extracted again with diethyl ether, and the organic layers were dried with Na 2 SO 4, filtered, and concentrated to give 179, which was used without further purification in the next step. HPLC: 9.68 min. (Note: the retention time for the starting materials is as follows: nitroethane: 6.49 min, 3-phenylpropionaldehyde: 9.45 min.) Synthesis of 2-nitro-l-phenethylpropyl acetate ester (180): The crude 4-nitro-l-phenyl-3-ol (179) of the above was dissolved in CH2C12 (60 mL) and cooled in an ice bath under nitrogen. Concentrated sulfuric acid (0.76 mL, 14.2 mmol) was added slowly followed by acetic anhydride (13.83 mL, 146.2 mmol), and the reaction was allowed to warm to room temperature, and stirred until it was judged complete by HPLC (3 hours, 40 minutes ). (Note: The reaction turned black so soon after the addition of acetic anhydride). The reaction was quenched by slowly pouring into water, then the organic layer was stirred, washed with aqueous NaHCO3, dried, filtered and concentrated. The crude product was purified by chromatography on silica gel (Combiflash Column, 95: 5 Hexanes: EtOAc) to achieve pure 180 (21.4447 g, 65.5%, 2 steps). HPLC: 10.45 min.

Synthesis of 4-Methyl-2-phenethyl-1H-pyrrole-2-carboxylic acid ethyl ester (181): 2-Nitro-1-phenethylpropyl acetic acid ester (180) (10.4302 g, 44.2 mmol) and isocyanoacetate were weighed ethyl acetate (4.957 g, 44.2 mmol) in a 250 L round bottom flask. The flask was sealed with a septum, purged with nitrogen, and then dissolved in a THF and isopropyl alcohol solution (1.6: 1.44). mL, 1M). The reaction was cooled in an ice bath, then DBU (13.6 mL, 2.05 mmol) was added. The reaction was allowed to warm to room temperature, and was allowed to stir at room temperature until it was completely judged by HPLC (2 hours, 25 min.). The reaction was diluted with H20 and diethyl ether, and the organic layer was removed, extracted with 2 N HCl, H20 and NaHCO3. The combined organic layers were dried with Na 2 SO 4, filtered and concentrated. The crude product was purified by chromatography on silica gel (Combiflash Column, 95: 5 Hexanes: EtOAc). The product crystallized from the fractions with combined Combiflash to obtain a batch of 3.3224 g (29%) of 181 pure and 3.7709 g of 181 containing a small amount of impure material. HPLC: 11.27 min.

Synthesis of 4-Methyl-2-phenethyl-1H-pyrrole-2-carboxylic acid (182): 4-Methyl-2-phenethyl-1H-pyrrole-2-carboxylic acid ethyl ester (181) was hydrolyzed as described previously to obtain the desired pure product. XH (CD3OD, 400 MHz): d 10.60 (1H, br s), 7.24 -7.00 (5H, m), 6.62 (1H, s), 2.99 (211, dd, J = 9.6, 7.3 Hz), 2.67 (2H) , dd, J = 9.6, 7.8 Hz), 1.83 (3H, s) ppm. X3C (CD3OD, 100 MHz): d 164.75, 143.86, 132.12, 129.58, 129.10, 126.61, 122.27, 122.10, 120.68, 38.32, 28.61, 9.80 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 38.32, 28.61; CH carbons: 129.58, 129.10, 126.61, 122.27 ppm. HPLC: 9.947 min.

Example 66. Synthesis of 4- [2- (4-chlorophenyl) -ethyl] -lH-pyrrole-2-carboxylic acid ethyl ester (38).

Synthesis of 4- [2- (4-chlorophenyl) -ethyl-1H-pyrrole-2-carboxylic acid amide (38): To a solution of 39 (0.5026 g, 2.01 mmol) in CH2C12 (8.4 mL, 0.24 M) was added 1- [3- (dimethylamine) propyl] -3-ethylcarbodiimide hydrochloride (EDCI, 0.4700 g, 2. 42 mmol), 4- (dimethylamino) pyridine (DMAP, 0.0270 g, 0.20 mmol), and EtOH (0.352 L, 6.04 mmol), and the reaction was stirred at room temperature overnight. The solid by-product was completely filtered and rinsed with CH2C12, then the combined organic layers were washed with 5% aqueous NaHC03, 5% aqueous HCl and H20. The combined organic layers were dried with Na 2 SO 4, filtered and concentrated. The product was purified by chromatography on silica gel (Combiflash Column, 90:10 Hexanes: EtOAc) to obtain 0.2974 g (53.2%) of 38. Analytical data for 38 corresponded to that when synthesized before by a different method. • HPLC 11,261 min. (Note: HPLC of start material = 10,028 min.).

Example 67. Synthesis of 4-phenylaminomethyl-1H-pyrrole-2-carboxylic acid (184).

Synthesis of 4-phenylaminomethyl-1H-pyrrole-2-carboxylic acid ethyl ester (183): 0.2012 g (1.20 mmol) of 4-formyl-1H-pyrrole-2-carboxylic acid ethyl ester were dissolved in 4.8 mL (0.25 M) of 5% acetic acid in methanol. Aniline (0.13 mL g, 1.44 mmol) was added and the reaction was stirred at room temperature under nitrogen for 45 minutes, then sodium cyanoborohydride (0.1244 g, 1.98 mmol) was added slowly and the reaction was allowed to stir at room temperature during the reaction. night. Approximately 2 mL of saturated K2CO3 was added, and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with saturated NaHCO 3 (approximately 3 mL and brine (approximately 3 mL), then the combined organic layers were dried with Na 2 SO 4, filtered and concentrated in vacuo The crude product was purified by chromatography on silica gel ( Combiflash Column, 85:15 Hexanes: ethyl acetate) to obtain 0.2663 g (91%) of the 4-phenylaminomethyl] -lH-pyrrole-2-carboxylic acid ethyl ester (183) as a colorless viscous oil: Note: Starting ethyl ester of 4-formyl-lH-pyrrole-2-carboxylic acid has a retention time in HPLC of 7337 min XH (CDCl3, 400 MHz): d 9.49 (1H, broad s), 7.19 (2H, dd, J = 8.6, 7.3 Hz), 6.73 (1H, tt, J = 7.3, 1.1 Hz), 6.66 (2H, dd, J = 8.6, 1.1 Hz), 6.91 (1H, d, J = 2.0 Hz), 6.90 ( 1H, d, J = 2.0 Hz), 4.33 (2H, q, J = 7.2 Hz), 4.19 (2H, s), 3.90 (1H, broad s), 1.36 (3H, t, J = 7.2 Hz) ppm. HPLC: 6.936 min.

Synthesis of 4-phenylaminomethyl-lH-pyrrole-2-carboxylic acid (184): 4-phenylaminomethyl] -lH-pyrrole-2-carboxylic acid ethyl ester (183) (0.0773 g, 0.316 mmol) was weighed in a round background. A stir bar, condenser and septum are added, and the flask was purged with N2. The ester was dissolved in EtOH (0.70 mL, 0.45 M), and then fresh aqueous NaOH (0.0354 g, 0.283 mL of H20) was added with stirring to the ester solution. The reaction flask was immersed immediately in an oil bath preheated to 85 ° C, and the reaction was heated and stirred under N2 until it was judged complete by HPLC (15 min). The solvent was removed in the rotoevaporator, and 0.8 mL of H20 was added. The aqueous layer was acidified in a slow and careful manner with 10% aqueous HCl. The product was purified by reverse phase preparative HPLC (H20 with 0.05% TFA: CH3CN with 0.05% TFA, 45:55) to obtain pure 4-phenylaminomethyl-lH-pyrrole-2-carboxylic acid. XH (CD3OD, 400 MHz): d 7.51-7.40 (5H, m), 6.99 (1H, d, J = 1.5 Hz), 6.86 (1H, d, J = 1.5 Hz), 4.46 (2H, s) ppm. X3C (CD3OD, 100 MHz): d 163.92, 137.17, 131.10, 129.97, 125.95, 125.07, 123.71, 117.37, 115.77, 49.38 ppm. DEPT (CD30D, 100 MHz): CH2 carbons: 49.38; CH carbons: 131.10, 129.97, 125.94, 123.71, 117.37 ppm. HPLC: 5.724 min.

Example 68. Synthesis of 4- [(Acetylphenylamino) -methyl) -lH-pyrrsl-2-carboxylic acid (186).

Synthesis of 4- [(Acetyl-enylamino) -methyl] -lH-pyrrole-2-carboxylic acid ethyl ester (185): 4-Phenylaminomethyl-1H-pyrrole-2-carboxylic acid ethyl ester (183) was weighed ( 0.1523 g, 0.623 mmol) in a 10 mL flask. A stirring bar and septum were added, and the flask was purged with nitrogen. The amine was dissolved in methylene chloride (1.6 mL, 0.4 M) and then the flask was cooled to 0 ° C. N, N-diisopropyl-ethyl-amine (0.1194 mL, 0.686 mmol) was added, then acetyl chloride (0.0488 mL, 0.686 mmol) was added slowly by syringe to a stirring solution at 0 ° C. The reaction was then allowed to warm to room temperature. When the reaction was judged complete by HPLC (35 min.) The reaction was diluted with methylene chloride and cooled with water. The organic phase was stirred, washed with brine, dried with Na 2 SO, filtered and concentrated in vacuo. The crude product was sufficiently pure by HPLC and the NMR analysis that was used in the next step without further purification(0.1625 g, 91%, white crystalline solid). XH (CD30D, 400 MHz): d 11.22 (1H, broad s), 7.43 - 7.31 (3H, m), 7.08 (2H, dd, J = 7.0, 1.5 Hz), 6.75 (1H, d, J = 1.5 Hz), 6.68 (1H , d, J = 1.5 Hz), 4.70 (2H, s), 4.24 (2H, q, J = 7.0 Hz), 1.81 (3H, s), 1.31 (3H, t, J = .7.0 Hz) ppm. X3C (CD3OD, 100 MHz): d 172.47, 162.64, 143.86, 130.68, 129.34, 129.27, 124.50, 124.33, 122.19, 116.72, 61.16, 46.60, 22.64, 14.75 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.64, 14.75; CH2 carbons: 61.16, 46.60; CH carbons: 130.68, 129.34, 129.27, 124.33, 116.72 ppm. HPLC: 8.738 min.

Synthesis of 4- [(Acetylphenylamino) -methyl] -lH-pyrrole-2-carboxylic acid (186): 4- [(Acetylphenylamino) -methyl] -lH-pyrrole-2-carboxylic acid ethyl ester was weighed (185) ) (0.1353 g, 0.473 mmol) in a round bottom flask. Agitation bar, condenser and septum were added and the flask was purged with N2. The ester was dissolved in EtOH (1.05 mL, 0.45 M), and then fresh aqueous NaOH (0.0529 g, 0.42 mL of H20) was added with stirring to the ester solution. The reaction flask was immersed immediately in an oil bath preheated to 85 ° C, and the reaction was heated and stirred under N2 until it was judged complete by HPLC (45 min.). The solvent was removed in the rotoevaporator, and 1.0 mL of CH2C12 and 1.0 mL of H2O were added. The aqueous layer was slowly and carefully acidified with 10% aqueous HCl. Although it did not become cloudy, there was no precipitate. The product was extracted from the aqueous layer with three portions of CH2C12, dried with Na2SO4, filtered and concentrated in vacuo to obtain 4- [(Acetylphenylamino) -methyl] -lH-pyrrole-2-carboxylic acid (186, 0.0968 mg , 79%). XH (CD3OD, 400 MHz): d 11.11 (1H, broad s), 7.46-7.31 (3H, m), 7.09 (2H, dd, J = 7.0, 1.5 Hz), 6.74 (1H, s), 6.68 (1H , s), 4.71 (2H, s), 1.82 (3H, s) ppm. X3C (CD30D, 100 MHz): d 172.49, 164.19, 143.87, 130.69, 129.37, 129.28, 124.41, 124.24, 122.14, 116.88, 46.64, 22.64 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.64; CH2 carbons: 46.64; CH carbons: 130.69, 129.37, 129.28, 124.24, 116.88 ppm. HPLC: 7.518 min.

Example 69. Synthesis of 4- [(4-chlorophenylamino) -methyl] -lH-pyrrole-2-carboxylic acid (188).

Synthesis of 4- [(4-chlorophenylamino) -methyl] -lH-pyrrole-2-carboxylic acid ethyl ester (187): 0.5052 g (3.02 mmol) of 4-formyl-1H-pyrrole-4-methyl ester was dissolved. 2-carboxylic acid in 12.0 mL (0.25 M) of 5% acetic acid in methanol. 4-Chloroaniline (0.4633 g, 3.63 mmol) was added, and the reaction was stirred at room temperature under nitrogen for 30 minutes, then sodium cyanoborohydride (0.3013 g, 4.79 mmol) was added slowly and the reaction was allowed to stir at room temperature overnight. Approximately 5 mL of saturated K2CO3 was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with saturated NaHCO 3 (approximately 6 mL) and brine (approximately 6 mL), then the combined organic layers were dried with Na 2 SO, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (Combiflash column, hexanes: ethyl acetate 85:15) to obtain 0.5806 g (69%) of the ethyl ester of 4- [(4-chlorophenylamino) -methyl] -lH- pyrrole-2-carboxylic acid (187) as light brown solid. Note: 4-formyl-lH-pyrrole-2-carboxylic acid ethyl ester start material has a retention time by HPLC = 7.337 min. HPLC: 8.543 min.

Synthesis of 4- [(4-chlorophenylamino) -methyl] -lH-pyrrole-2-carboxylic acid (188): 4 - [(4-chlorophenylamino) -methyl] -lH-pyrrole-2-ethyl ester was weighed carboxylic (187) (0.1070 g, 0.384 mmol) in a round bottom flask. A stir bar, condenser and septum are added, the flask was purged with N2. The ester was dissolved in EtOH (0.85 mL, 0.45 M), and then fresh aqueous NaOH (0.0432 g, 0.123 mL of H20) was added with stirring to the ester solution. The reaction flask was immersed immediately in a preheated oil bath at 85 ° C, and the reaction was heated and stirred under N2 until it was judged complete by HPLC. (30 min) . The solvent was removed in the rotoevaporator, and 0.8 mL of H20 was added. The aqueous layer was slowly and carefully acidified with 10% aqueous HCl. The product was purified by reverse phase preparative HPLC (H20 with 0.05% TFA: CH3CN with 0.05% TFA, 45:55) to obtain 4- [(4-chlorophenylamino) -methyl] -lH-pyrrole-2-acid. carboxylic (188). XH (CD3OD, 400 MHz): d 7.12 (2H, d, J = 8.4 Hz), 6.92 (111, s), 6.85 (1H, s), 6.95 (2H, d, J = 8.4 Hz), 4.16 (2H, s) ppm. X3C (CD3OD, 100 MHz): d 164.24, 146.44, 129.96, 124.87, 124.15, 123.56, 122.98, 117.22, 116.24, 43.18 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 43.18; CH carbons: 129.96, 123.56, 117.22, 116.24 ppm. HPLC: 7.137 min.

Synthesis of 4- [(Acetyl- (4-chlorophenyl) -amino-methyl] -lH-pyrrole-2-carboxylic acid (190) 187 189 190 Synthesis of 4- [(Acetyl- (4-chlorophenyl) -amino) -methyl] -lH-pyrrole-2-carboxylic acid ethyl ester (189): The ethyl ester of 4 - [(4)] was weighed -chlorophenylamino) -methyl] lH-pyrrole-2-carboxylic acid (187) (0.2868 g, 1.03 mmol) in a 10 mL flask. A stirring bar is added, and septum, the flask was purged with nitrogen. The amine was dissolved in methylene chloride (2.6 mL, 0.4 M), and then the flask was cooled to 0 ° C. N, N-diisopropyl-ethyl-amine (0.0805 mL, 1.13 mmol) was added, then acetyl chloride (0.0805 mL, 1.13 mmol) was added slowly by eringa to the stirring solution at 0 ° C. The reaction was allowed to warm to room temperature. When the reaction was judged complete by HPLC (90 min) the reaction was diluted with methylene chloride and quenched with water. The organic layer was stirred, washed with brine, dried with Na 2 SO, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Combiflash column, hexanes: ethyl acetate 2: 1) to obtain pure 4- (4-acetyl- (4-chlorophenyl) -amino) -methyl] -lH-pyrrole-2-carboxylic acid ethyl ester (189, 0.2701 g, 82%) as a white sticky solid. XH (CD3OD, 400 MHz): d 11.25 (1H, broad s), 7.35 (2H, d, J = 8.4 Hz), 7.05 (2H, d, J = 8.4 Hz), 6.76 (1H, s), 6. 69 (1H, s), 4.68 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 1.81 (3H, s), 1.29 (3H, t, J = 7.1 Hz) ppm. 13 C (CD3OD, 100 MHz): d 172.17, 162.50, 142.39, 134.87, 130.94, 130.70, 124.46 & 124.30, 123.94, 121.91 & 121.88, 116.64, 61.13, 46.43, 22.70, 14.75 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.70, 14.75; CH2 carbons: 61.13, 46.43; CH carbons: 130.94, 130.70, 124.46 & 124.30, 116.64 ppm. HPLC: 9.247 min.

Synthesis of 4- [(Acetyl- (4-chlorophenyl) -amino) -methyl] -lH-pyrrole-2-carboxylic acid (190): 4- [(Acetyl- (4-chlorophenyl)] ethyl ester was weighed -amino) -methyl] lH-pyrrole-2-carboxylic acid (0.2701 g, 0.842 mmol) in a round bottom flask. A stir bar, condenser and septum are added, the flask was purged with N2. The ester was dissolved in EtOH (1.87 mL, 0.45 M), and then fresh aqueous NaOH (0.0943 g, 0.75 mL of H20) was added with stirring to the ester solution. The reaction flask was immersed immediately in an oil bath preheated to 85 ° C, and the reaction was heated and stirred under N2 until it was judged complete by HPLC (11 min). The solvent was removed in the rotoevaporator, and 1.6 mL of CH2C12 and 1.6 mL of H2O were added. The aqueous layer was slowly and carefully acidified with 10% aqueous HCl. The product drained. The product was extracted from the aqueous layer with three portions of CH2C12, dried with Na2SO4, filtered, and concentrated in vacuo to obtain [(acetyl- (4-chlorophenyl) -amino) -methyl] -lH-pyrrole- Pure 2-carboxylic acid (190, 0.2242 mg, 91%). XH (CD3OD, 400 MHz): d 11.14 (111, broad s), 7.38 (2H, d, J = 8.4 Hz), 7.07 (2H, d, J = 8.4 Hz), 6.75 (1H, s), 6.69 ( 1H, s), 4.69 (2H, s), 1.82 (311, s) ppm. X3C (CD3OD, 100 MHz): d 172.32, 164.16 & 164.13, 142.41, 134.98, 131.02, 130.74, 124.43, 124.27, 121.90 & 121.86, 116.85 & 116.81, 46.49, 22.67 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.67; CH2 carbons: 46.49; CH carbons: 131.02, 130.74, 124.27 & 124.09, 116.85 & 116.81 ppm. HPLC: 8.077 min.

Example 71. Synthesis of acid 4-. { [(4-chlorophenyl) -methylamino] methyl] -lH-pyrrole-2-carboxylic acid (192).

Synthesis of ethyl ester of acid 4-. { [(4-chlorophenyl) -methylamino] methyl] -lH-pyrrole-2-carboxylic acid (191): 4-chloro-N-methylaniline (0.225 mL, 1.86 mmol) was added to a stirring solution at room temperature of ethyl ester. of 4-formyl-lH-pyrrole-2-carboxylic acid (0.2585 g, 1.55 mmol) in 5% acetic acid in methanol under N2. after stirring at room temperature for 30 minutes, sodium cyanoborohydride (0.1585 g, 2.52 mmol) was added, and the reaction was stirred at room temperature overnight. Approximately 3 mL of saturated K2CO3 was added, and the reaction was extracted twice with ethyl acetate. The combined organics were washed with saturated NaHCO 3 (approximately 4 mL) and brine (approximately 4 mL), then the combined organic layers were dried with Na 2 SO, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Combiflash column, hexanes: ethyl acetate 85:15) to obtain 0.3419 g (76%) of 5- ethyl ester. { [(4-chlorophenyl) -methylamino] methyl] -lH-pyrrol2-carboxylic acid (191) as a light brown solid. Note: the starting material ethyl ester of 4-formyl-lH-pyrrole-2-carboxylic acid has a retention time of HPLC = 7.337 min. HPLC: 8.478 min.

Synthesis of acid 4-. { [(4-chlorophenyl) -methylamino] methyl] -lH-pyrrole-2-carboxylic acid (192): 4-ethyl ester was weighed. { [(4-chlorophenyl) -methylamino] methyl] -lH-pyrrole-2-carboxylic acid (191) (0.3419 g, 1.17 mmol) in a round bottom flask. Filtration bar, condenser and septum were added, and the flask was purged with N2. The ester was dissolved in EtOH (2.6 mL, 0.45 M), and fresh aqueous NaOH (0.1336 g, 1.0 mL of H20) was then added with stirring to the ester solution. The reaction flask was immersed immediately in an oil bath preheated to 85 ° C, and the reaction was heated and stirred under N2 until it was-completed by HPLC (15 min). The solvent was removed in the rotoevaporator and the crude product was immediately purified by reverse phase preparative HPLC (H20 with 0.05% TFA: CH3CN with 0.05% TFA, 45:55) to obtain 4- acid. { [(4-chlorophenyl) -methylamino] methyl] -lH-pyrrole-2-carboxylic acid (192). XH (CD3OD, 400 MHz): d 7.22 (2H, d, J = 9.2 Hz), 6.95 (2H, d, J = 9.2 Hz), 6.81 (1H, d, J = 1.5 Hz), 6.70 (1H, d , J = 1.5 Hz), 4.43 (2H, s), 3.00 (3H, s') ppm. Partial 13C (CD3OD, 100 MHz): d 130.12, 124.02, 117.99, 116.47, 52.37, 39.91 ppm. DEPT (CD30D, 100 MHz): CH3 carbons: 14.48; CH2 carbons: 59.62, 23.41 and 23.39, 23.36 and 23.33, 23.16 and 23.13, 21.88 and 21.86; CH carbons: 118.74 and 118.55 ppm.

Example 72. Synthesis of 4-benzyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (198): Synthesis of 4-oxo-4,5,6,7-tetrahydro-lH-indole-2-carboxylic acid methyl ester (193): A solution of 4-oxo-4,5,6,7-tetrahydro-lH- indole-2-carbonitrile (4.5 g, 28.1 mmol, prepared as described in Synth, Comm. 1995, 25, 507-514) in methanol saturated with HCl gas (200 ml) and refluxed for 6 days. The solvent was removed under vacuum. The resulting product (3.5 g) was a 65/35 mixture of the expected ester and starting material as shown by NMR analysis. This mixture was used in the next step without any further purification.

Synthesis of 4-oxo-l- (2-trimethylsilyl-ethoxymethyl) -4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid methyl ester (194): A solution in DMF (3 ml) was added ) of ester (500 mg, 2.6 mmol) to a cooled (0 ° C) suspension of sodium hydride (114 mg, 60% in oil, 2.8 mmol) in DMF (2 ml). After 10 minutes, SEM-C1 (550 μl, 3.1 mmol) was added. The mixture was then stirred at room temperature for 2 hours, then cooled in ice water and extracted with ethyl acetate. After concentration, the expected compound was obtained as a crude oil (930 mg). X H NMR (CDC13, 400 MHz): d 7.27 (1H, s), 5.78 (2H, s), 3.61 (2H, m), 2.94 (2H, m), 2.50 (2H, m), 2.18 (2H, m) ), 0.92 (2H, m) ppm. LC / MS: 60% Synthesis of 4-benzylidene-1- (2-trimethylsilyl-ethoxymethyl) -4,5,6,7-tetrahydro-1H-indol-2-carboxylic acid methyl ester (195): A THF solution (7 ml) was added ) of protected ester (900 mg, 2.78 mmol) to a solution of benzylmagnesium chloride (3.4 ml, 2M in THF, 6.8 mmol) in THF (10 ml). After 2 hours at room temperature, some more benzylmagnesium chloride (1.7 ml, 2M in THF, 3.4 mmol) was added. The mixture was then refluxed overnight. Then water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give the above title compound (900 mg). LC / MS: 50%, m / z = 397 g / mol.

Synthesis of 4-benzylidene-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid methyl ester (196): Tetrabutylammonium fluoride (23 ml, 1M in THF, 23 mmol) was added over 5 minutes to a solution of ester (900 mg, 2.26 mmol) in cooled THF (0 ° C). The reaction mixture was then heated for 4 hours at 80 ° C. After 48 hours at room temperature, the reaction mixture was partitioned between ether and water. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the crude title compound above. Chromatography on silica gel (eluent, cyclohexane / AcOEt: 80/20) gave the pure starting material (100 mg) and the corresponding deprotected nitrile (80 mg). The still protected pure ester (100 mg, 0.25 mmol) was mixed with THF (750 μL, 0.75 mmol). The THF was removed under vacuum. After concentration, the reaction mixture was heated with ethylenediamine (0.25 ml) in DMF (1 ml) for 16 hours. After concentration, the above title compound was obtained in an oil (80 mg). LC / MS: 76%, m / z = 267 g / mol.

Synthesis of 4-benzyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid methyl ester (197): The saturated ester derivative was hydrogen at normal pressure over Pd in EtOH for 3 hours. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to give the above title compound, which was purified by chromatography on silica gel (eluent, cyclohexane / CH2Cl2: 50/50). Yield: 20 mg. LC / MS: 60%, m / z = 269 g / mol.

Synthesis of 4-benzyl-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid (198): Freshly prepared aqueous NaOH (1M in H20, 0.8 ml, 0.8 mmol) at room temperature to a stirred solution of ester (20 mg, 0.08 mmol) in EtOH (5 ml). The reaction was heated to 80 ° C until the reaction was judged complete by TLC. The product was extracted with Et20, then the aqueous layer was made acidic (pH = 1) with the dropwise addition of 10% aqueous HCl. The solid was completely filtered and washed with water. The solid was dried under vacuum overnight to give the above title compound (19 mg). XH NMR (CDC13, 400 MHz): d 8.8 (1H, broad s), 7.3-7.33 (2H, m), 7.2-7.26 (3H, m), 6.81 (1H, s), 3.09 (1H, dd), 2.9 (1H, m), 2.55-2.65 (3H ~, m), 1.9-2.0 (1H, m), 1.6-1.8 (2H, m), 1.3-1.4 (1H, m). LC / MS: 89%, m / z = 255 g / mol. It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention.

Claims (42)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compound of formula IA, or a pharmaceutically acceptable salt or solvate thereof: IA characterized because RXa and R2 are independently selected from hydrogen, halo, nitro, alkyl, arylalkyl, alkylaryl, and XYR5; X and Y are independently selected from O, S, NH, and (CR6R7) n; R3 is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; Z is N or CR4; R 4 is selected from hydrogen, halo, nitro, alkyl, arylalkyl, alkylaryl, and XYR 5; R5 is selected from aryl, 'substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently selected from hydrogen and alkyl; n is an integer from 1 to 6; at least one of RXa and R2a is XYR5; and at least one of X and Y is (CR6R7) n; with the proviso that formula 1A does not include 5-phenethyl-1H-pyrazole-3-carboxylic acid.
2. 2. Compound according to claim 1, characterized in that R3 is hydrogen.
3. 3. Compound in accordance with the claim 1, characterized in that Z is N.
4. 4. Compound according to claim 1, characterized in that Z is CR.
5. 5. Compound according to claim 1, characterized in that RXa is hydrogen and R2a is XYR5.
6. 6. Compound according to claim 4 or 5, characterized in that X and Y are CR6R7.
7. 7. Compound according to claim 5, characterized in that R5 is substituted aryl.
8. 8. Compound according to claim 6, characterized in that R6 and R7 are hydrogen.
9. 9. Compound according to claim 1, characterized in that the compound is selected from
10. 10. Compound according to claim 1, characterized in that the compound is
11. 11. Compound according to claim 1, characterized in that the compound is
12. 12. Method for increasing the concentration of D-serine and / or decreasing the concentration of toxic products of the oxidation of D-serine by DAAO in a mammal, method characterized in that it comprises administering to a subject a therapeutically effective amount of a compound of the formula I , or a pharmaceutically acceptable salt or solvate thereof. I wherein R x and R 2 are independently selected from hydrogen, halo, nitro, alkyl, acyl, alkylaryl, arylalkyl, and XYR 5; or Rx and R2, taken together, form a carbocyclic or heterocyclic group, substituted or unsubstituted, of 5, 6, 7 or 8 members; X and Y are independently selected from O, S, NH, and (CRsR7) n; R3 is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; Z is N or CR4; R 4 is selected from hydrogen, halo, nitro, alkyl, alkylaryl, arylalkyl, and XYR 5; R5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; Rd and R7 are independently selected from hydrogen and alkyl; n is an integer from 1 to 6; at least one of Rx, R2 and R4 is different from hydrogen; and at least one of X and Y is (CR6R7) n.
13. 13. Method to treat schizophrenia, to treat or prevent memory loss and / or cognition associated with Alzheimer's disease, to treat ataxia, or to prevent loss of neuronal function characteristic of neurodegenerative diseases, the method is characterized by which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R2 are independently selected from hydrogen, halo, nitro, alkenyl, acyl, alkylaryl, arylalkyl, and XYR5; or R1 and R2, taken together, form a carbocyclic or heterocyclic group, substituted or unsubstituted, of 5, 6, 7 or 8 members; X and Y are independently selected from O, S, NH, and (CR6R7) n; R3 is hydrogen, alkenyl or M *; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; Z is N or CR4; R 4 is selected from hydrogen, halo, nitro, alkyl, alkylaryl, arylalkyl, and XYR 5; R5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently selected from hydrogen and alkenyl; n is an integer from 1 to 6; at least one of Rx, R2 and R4 is different from hydrogen; and at least one of X and Y is (CR6R7) n;
14. 14. Method for improving learning, memory and / or cognition, the method is characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt or solvate: wherein R x and R 2 are independently selected from hydrogen, halo, nitro, alkyl, acyl, alkylaryl, arylalkyl, and XYR 5; or R1 and R2, taken together, form a carbocyclic or heterocyclic group, substituted or unsubstituted, of 5, 6, 7 or 8 members; X and Y are independently selected from 0, S, NH, and (CR6R7) n; R3 is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; Z is N or CR4; R 4 is selected from hydrogen, halo, nitro, alkyl, alkylaryl, arylalkyl, and XYR 5; R5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently selected from hydrogen and alkyl; n is an integer from 1 to 6; at least one of Rx, R2 and R4 is another hydrogen; and at least one of X and Y is (CR6R7) n.
15. 15. Method for treating neuropathic pain, characterized in that it comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the formula I or a pharmaceutically acceptable salt or solvate thereof: wherein R1 and R2 are independently selected from hydrogen, halo, nitro, alkyl, acyl, alkylaryl, arylalguilo, and XYR5; or R1 and R2, taken together, form a carbocyclic or heterocyclic group, substituted or unsubstituted, of 5, 6, 7 or 8 members; X and Y are independently selected from O, S, NH, and (CR6R7) n; R3 is hydrogen, alkyl or M +; M is aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; Z is N or CR4; R 4 is selected from hydrogen, halo, nitro, alkyl, alkylaryl, arylalguyl, and XYR 5; R5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently selected from hydrogen and alkenyl; n is an integer from 1 to 6; at least one of R1, R2 and R4 is different from hydrogen; and at least one of X and Y is (CR6R7) n.
16. 16. Method according to any of claims 12-15, characterized in that R1 and R2 are independently selected from hydrogen, halo, nitro, alkyl, arylalkyl, alkylaryl, and XYR5; at least one of R1 and R2 is XYR5; and at least one of X and Y is (CR6R7) n.
17. 17. Method according to any of claims 12-15, characterized in that R3 is hydrogen.
18. Method according to any of claims 12-15, characterized in that Z is N.
19. 19. Method according to any of claims 12-15, characterized in that Z is CR.
20. 20. Method according to any of claims 12-15, characterized in that n is 1 or 2.
21. 21. Method according to any of claims 12-15, characterized in that X and Y are (CRsR7) n and n is 1.
22. 22 Method according to any of claims 12-15, characterized in that Rs and R7 are hydrogen.
23. 23. Method according to any of claims 12-15, characterized in that Rx is hydrogen and R2 is XYR5.
24. 24. Method according to any of claims 12-15, characterized in that R5 is substituted aryl.
25. 25. Method according to any of claims 12-15, characterized in that the compound of the formula I is selected from
26. 26. Method according to any of claims 12-15, characterized in that the compound of the formula I is
27. 27. Method according to any of claims 12-15, characterized in that the compound of the formula I is
28. 28. Method according to any of claims 12-15, characterized by additionally comprising co-administering D-serine or cycloserine.
29. 29. Pharmaceutical composition characterized by comprising a compound of the formula I and a pharmaceutically acceptable carrier wherein R1 and R2 are independently selected from hydrogen, halo, nitro, alkenyl, acyl, alkylaryl, arylalguilo, and XYR5; or Rx and R2, taken together, form a carbocyclic or heterocyclic group, substituted or unsubstituted, of 5, 6, 7 or 8 members; X and Y are independently selected from 0, S, NH, and (CR6R7) n; R3 is hydrogen, alkyl or M *; M is a bond of aluminum, calcium, lithium, magnesium, potassium, sodium, zinc or a mixture thereof; Z is N or CR4; R4 is selected from hydrogen, halo, nitro, alkyl, alkylaryl, arylalguilo, and XYR5; R5 is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; R6 and R7 are independently selected from hydrogen and alkyl; n is an integer from 1 to 6; at least one of Rx, R2 and R4 is different from hydrogen; and at least one of X and Y is (CR6R7) n.
30. 30. Pharmaceutical composition according to claim 29, characterized in that it additionally comprises D-serine or cycloserine.
31. 31. Pharmaceutical composition according to claim 29 or 30, characterized in that R1 and R2 are independently selected from hydrogen, halo, nitro, alkenyl, arylalkyl, alkylaryl, and XYR5; at least one of R1 and R2 is XYR5; and at least one of X and Y is (CRsR7) n.
32. 32. Pharmaceutical composition according to claim 29 or 30, characterized in that R3 is hydrogen.
33. 33. Pharmaceutical composition according to claim 29 or 30, characterized by Z is N.
34. 34. Pharmaceutical composition according to claim 29 or 30, characterized by Z is CR4.
35. 35. Pharmaceutical composition according to claim 29 or 30, characterized in that n is 1 or 2.
36. 36. Pharmaceutical composition according to claim 29 or 30, characterized by X and Y are (CR6R7) n and n is 1.
37. 37. Pharmaceutical composition according to claim 29 or 30, characterized in that R6 and R7 are hydrogen.
38. 38 Pharmaceutical composition according to claim 29 or 30, characterized by Rx is hydrogen.
39. 39 Pharmaceutical composition according to claim 29 or 30, characterized in that R5 is substituted aryl.
40. 40 Pharmaceutical composition according to claim 29 or 30, characterized in that the compound of I is selected from
41. 41. Pharmaceutical composition according to claim 29 or 30, characterized by the compound of the formula I is
42. 42. Pharmaceutical composition according to claim 29 or 30, characterized in that the compound of the formula I is