ES2365177T3 - REPLACED BICYCLOCARBOXIAMIDE COMPOUNDS. - Google Patents

Abstract

A compound of formula (I): ** Formula ** wherein Y1 and Y2 are each independently N or CH; provided that only one of Y1 and Y2 can be N; R1 and R2 are each independently hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) hydroxyalkyl or (C1-C2) alkoxy (C1-C2) alkyl; or R1 and R2, together with the carbon atom to which they are attached, can form a cyclopropyl group; R3 is (C1-C4) alkyl, (C1-C4) alkyl, cyclopropyl, (C1-C2) alkoxy (C1-C4) alkyl, or (C1-C4) hydroxyalkyl, each optionally substituted with halo or (C1-C2) haloalkyl ; R4 and R6 are each independently hydrogen, halo, cyano, (C3-C6) cycloalkyl, (C1-C6) alkoxy, or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, hydroxy, R7R8NC (O) - and R7OC (O) -; R5 is hydrogen, (C3-C6) cycloalkyl, or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, hydroxy, R7R8NC (O) - or R7OC (O) -; provided that at least one of R4, R5 and R6 is not hydrogen; and, R7 and R8 are each independently hydrogen or (C1-C4) alkyl; or a pharmaceutically acceptable salt or solvate thereof.

Description

Technical field

This invention relates to novel substituted bicyclocarboxamide compounds and their use in therapy. These

5 compounds are particularly useful as modulators of the VR1 receptor (Vainilloid type I) and thus are useful for the treatment of diseases such as pain, neuralgia, neuropathies, nerve damage, burns, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, bladder disease, inflammation, or the like in mammals, especially humans. The present invention also relates to a pharmaceutical composition comprising the above compounds.

10 Prior Art

The vanilloid receptor 1 (VR1) is a ligand-activated non-selective cation channel. It is believed to be a member of the transient potential receptor superfamily. VR1 is recognized as a polymodal nociceptor that integrates multiple painful stimuli, eg, noxious heat, protons, and vanilloids (European Journal of Physiology451: 151-159, 2005). One of the main distributions of VR1 is found in the sensory fibers (A6- and C-), which are bipolar neurons that have the bodies in the sensory ganglia. The peripheral fibers of these neurons innervate the skin, mucous membranes, and almost all internal organs. VR1 is also recognized to exist in the bladder, kidney, brain, pancreas, and various classes of organs. A corpus of studies using VR1 agonists, for example capsaicin or resiniferatoxin, has suggested that VR1-positive nerves are believed to be involved in a variety of physiological responses including nociception (Clinical Therapeutics. 13 (3): 338-395, 1991, Journal of

20 Pharmacology and Experimental Therapeutics 314: 410-421, 2005, and Neuroscience Letter 388: 75-80, 2005). Based on both the tissue distribution and the roles of VR1, VR1 antagonists would have good therapeutic potential.

WO2005070929 describes heterocyclic amine derivatives as ligands of the vanilloid receptor. WO2005070885 describes useful amide derivatives as vanilloid receptor ligands. WO2005003084 describes 4- (methylsulfonylamino) phenyl analogs which are said to have activity as VR1 antagonists. Document WO 2004069792 describes amide derivatives derived from quinoline useful for the prevention or treatment for example of inflammatory pain, burning pain, chronic obstructive pulmonary disease and osteoarthritis, which are modulators of the vanilloid 1 receptor. Document WO 2003080578 describes heteroaromatic urea derivatives that are modulators of the vanilloid-1 receptor that are used to treat diseases and conditions in which pain and / or inflammation predominate. WO 2003068749 describes quinoline or isoquinoline carboxamide derivatives useful as antagonists of the vanilloid receptor (VR1). WO 2003014064 describes useful amide derivatives as antagonists of the vanilloid 1 receptor. WO2002100819 describes N-arylphenylacetamide derivatives as antagonists of the vanilloid VR1 receptor for example to treat pain, mania and allergic rhinitis. WO2006051378 describes a variety of derivatives of

35 N-sulfonylaminobenzyl-2-phenoxyamide as modulators of the vanilloid receptor. JP11080107 describes amide compounds as bone formation promoters for use as anti-osteoporotic agents. Document WO2005033079 describes heterocyclic derivatives, useful for treating fungal infections. WO03035621 describes naphthylamide compounds as protein kinase and phosphatase inhibitors to treat eg diabetes, obesity and hearing loss (page 2a).

It would be desirable if an improved selective VR1 antagonist were provided with better VR1 receptor binding activity by systemic administration and with good metabolic stability. Other potential advantages include lower toxicity, good absorption, good solubility, low protein-binding affinity, less drug-drug interaction, less inhibitory activity in the HERG channel, less QT prolongation, and good metabolic stability.

45 Brief description of the invention

It has now been discovered that certain substituted carboxamide derivatives are potent VR1 antagonists with analgesic activity by systemic administration.

In one embodiment (A), the present invention provides a compound of the following formula (I):

image 1

50 (I)

in which

Y1 and Y2 are each independently N or CH; provided that only one of Y1 and Y2 can be N;

and R2 are each independently hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) hydroxyalkyl or (C1-C2) alkoxy (C1-C2) alkyl; or R1 and R2, together with the carbon atom to which they are attached, can form a cyclopropyl group;

R3 is (C1-C4) alkyl, (C1-C4) alkylcyclopropyl, (C1-C2) alkoxy (C1-C4) alkyl or

WO200306879 describes certain amide derivatives which are stated to act as antagonists of VR-1. US2005165049 describes amide derivatives that are stated to be useful in the treatment of receptor-mediated diseases. WO2004108133 describes amide derivatives which are found to be useful as modulators of the vanilloid receptor.

hydroxyalkyl (C1-C4), each optionally substituted with halo or haloalkyl (C1-C2);

R4 and R6 are each independently hydrogen, halo, cyano, (C3-C6) cycloalkyl, (C1-C6) alkoxy, or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, hydroxy, R7R8NC (O) - and R7OC (O) -;

R5 is hydrogen, (C3-C6) cycloalkyl, or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one

or more substituents selected from halo, amino, cyano, hydroxy, R7R8NC (O) - or R7OC (O) -;

provided that at least one of R4, R5 and R6 is not hydrogen; and,

R7 and R8 are each independently hydrogen or (C1-C4) alkyl;

or a pharmaceutically acceptable salt or solvate thereof.

Compounds of formula (I) containing one or more asymmetric carbon atoms may exist in the form of two or more stereoisomers. All stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I) are included in the scope of the present invention, including compounds that show more than one type of isomerism and mixtures of one or more thereof. In particular, when the carbon atom to which R1 and R2 are attached is asymmetric, the invention includes the racemate, the (R) enantiomer and the (S) enantiomer.

Detailed description of the invention

As used herein, the term "halogen" or "halo" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

As used herein, the terms "(C1-C6) alkyl" or "(C1-C4) alkyl" mean straight or branched chain saturated radicals having the required number of carbon atoms, including, but not limited to without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl groups. Preferred groups are methyl, ethyl, n-propyl, n-butyl, and tert-butyl groups.

As used herein, the terms "hydroxyalkyl (C1-C6)" or "hydroxyalkyl (C1-C4)" mean alkyl radical (C1-C4) as defined above that is substituted with at least one group hydroxy including, but not limited to, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-iso-propyl (eg, 1-hydroxy-1,1-dimethylmethyl), hydroxy-n-butyl, hydroxy-iso-butyl, hydroxy-sec-butyl and hydroxy-tert-butyl. Preferred groups are hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxy-iso-propyl (for example 1-hydroxy-1,1-dimethylmethyl), hydroxy-n-butyl and hydroxy-tert-butyl.

As used herein, the term "(C3-C6) cycloalkyl" means saturated or unsaturated noaromatic hydrocarbon ring, having the required number of carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein the terms "(C1-C6) haloalkyl" and "(C1-C4) haloalkyl" mean (C1-C6) alkyl or (C1-C4) alkyl radical that is substituted with one or more halogen atoms as defined above including, but not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro-1 groups, 1-dimethylethyl, 2,2,2-trichloroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl, trichloromethyl, iodomethyl, bromomethyl and 4,4,4-trifluoro-3-methylbutyl. Preferred groups are fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and 2,2,2-trifluoro-1,1-dimethylethyl groups.

In a preferred embodiment (A1), Y1 is CH and Y2 is CH; or Y1 is N and Y2 is CH; or Y1 is CH and Y2 is N: and R1-R8 are each as defined herein, or in embodiment (A), or in the following preferred embodiments.

Preferably, when Y1 is CH, Y2 is CH and R1 and R2 are both hydrogen; then R4 is hydrogen; R5 is (C3-C6) cycloalkyl or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, hydroxy, R7R8NC (O) - or R7OC (OR)-; and R6 is halo, cyano, (C3-C6) cycloalkyl, (C1-C6) alkoxy, or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one or more substituents selected from halo, amino , cyano, hydroxy, R7R8NC (O) - and R7OC (O) -; or R5 is hydrogen; and R4 and R6 are each independently halo, cyano, (C3-C6) cycloalkyl, (C1-C6) alkoxy, or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one or more substituents. selected from halo, amino, cyano, hydroxy, R7R8NC (O) - and R7OC (O) -; or

R4 is halo, cyano, (C3-C6) cycloalkyl, (C1-C6) alkoxy, or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, hydroxy, R7R8NC (O) - and R7OC (O) -; R5 is (C3-C6) cycloalkyl or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, hydroxy, R7R8NC (O) - or R7OC (OR)-; and R6 is hydrogen;

and R1, R2, R3, R7 and R8 are as defined above in embodiment (A).

In a preferred embodiment (A2), R1 and R2 are each independently hydrogen, or (C1-C2) alkyl, wherein (C1-C2) alkyl is optionally substituted with one or more halogen atoms; more preferably, R1 is hydrogen, ethyl or methyl, where methyl and ethyl are optionally substituted with one or more fluoro atoms and R2 is hydrogen; and Y1 and Y2 are as defined in embodiments (A) and (A1) and R3-R8 are each as defined herein, or in embodiment (A), or in the following preferred embodiments.

In a preferred embodiment (A3), R3 is 1-methylcyclopropyl or R3 is (C1-C4) alkyl, (C1-C2) alkoxy (C1-C4) alkyl or (C1-C4) hydroxyalkyl, each optionally substituted with halo or haloalkyl (C1-C2); more preferably, R3 is 1-methylcyclopropyl, isopropyl, tert-butyl, trifluoromethyl, 1-hydroxy-1-methylethyl, 2,2,2-trifluoro-1-hydroxy-1-methylethyl, 2,2,2-trifluoro-1 -methoxy-1-methylethyl or 2,2,2-trifluoro-1,1-dimethylethyl; more preferably, R3 is 1-methylcyclopropyl, tert-butyl, trifluoromethyl, 2,2,2-trifluoro-1-hydroxy-1-methylethyl or 2,2,2-trifluoro-1,1-dimethylethyl: and Y1, Y2, R1 and R2 are as defined above in embodiments (A), (A1) and (A2) and R4-R8 are each as defined herein, or in embodiment (A), or in following preferred embodiments.

In a preferred embodiment (A4), R4 is hydrogen, halo, cyano, (C1-C6) alkoxy or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one or more substituents selected from halo and hydroxy; more preferably, R4 is hydrogen, cyano, chloro, fluoro, hydroxymethyl, isopropyl, ethyl, methyl, or trifluoromethyl: and Y1, Y2 and R1-R3 are as defined above in embodiments (A) and (A1) - (A3 ) and R5-R8 are each as defined herein, or in embodiment (A), or in the following preferred embodiments.

In a preferred embodiment (A5), R5 is hydrogen, cyclopropyl, cyclobutyl or (C1-C4) alkyl, wherein (C1-C4) alkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, hydroxy, R7R8NC (O) - and R7OC (O); more preferably R5 is hydrogen, cyclopropyl, cyclobutyl or (C1-C4) alkyl, wherein (C1-C4) alkyl is optionally substituted with one or more substituents selected from fluoro, amino, (CH3) 2NC (O) -, ( CH3) NHC (O) -, H2NC (O) -, CH3OC (O) -, cyano or hydroxy; more preferably, R5 is hydrogen, cyclopropyl, cyclobutyl, methyl, ethyl, isopropyl, trifluoromethyl, methoxyoxomethyl, 2- (dimethylamino) -2-oxoethyl, 2- (methylamino) -2-oxoethyl, 1- (2-amino) -2 -oxoethyl, cyanomethyl, 2-amino-2-methylpropyl, 2-aminoethyl, 2-aminopropyl, 2-hydroxy-2-methylpropyl, hydroxyethyl, hydroxymethyl or 2,2,2, -trifluoroethyl; and Y1, Y2 and R1-R4 are as defined above in embodiments (A) and (A1) - (A4) and R6-R8 are each as defined herein, or in embodiment (A) , or in the following preferred embodiments

In a preferred embodiment (A6), R6 is hydrogen or (C1-C6) alkyl; more preferably R6 is hydrogen or (C1-C4) alkyl; more preferably R6 is hydrogen or methyl; and Y1, Y2 and R1-R5 are as defined above in embodiments (A) and (A1) - (A5) and R7-R8 are each as defined herein, or in embodiment (A ), or in the following preferred embodiments.

In a preferred embodiment (A7), R7 and R8 are each independently hydrogen or methyl; and Y1, Y2 and R1-R6 as defined above in embodiments (A) and (A1) - (A6).

As an alternative embodiment (A8), the invention provides a compound of formula (I) wherein Y1 and Y2 are each independently N or CH; provided that only one of Y1 and Y2 is N; R1 and R2 are each independently hydrogen, (C1-C4) alkyl or (C1-C4) haloalkyl; or R1 and R2, together with the carbon atom to which they are attached, can form a cyclopropyl group; R4, R5 and R6 are each independently hydrogen, (C1-C4) alkyl or hydroxyalkyl (C1-C4); provided that at least one of R4, R5 and R6 is not hydrogen; and, R3 is (C1-C4) alkyl, (C1-C4) alkylcyclopropyl or 2,2,2-trifluoro-1,1-dimethylethyl; or a pharmaceutically acceptable salt or solvate thereof.

As an alternative embodiment (A9), the invention provides a compound of formula (I) wherein Y1 and Y2 are each independently N or CH; provided that only one of Y1 and Y2 is N; R1 and R2 are each independently hydrogen, (C1-C4) alkyl or (C1-C4) haloalkyl; or R1 and R2, together with the carbon atom to which they are attached, can form a cyclopropyl group; R4, R5 and R6 are each independently hydrogen, alkyl

(C1-C6), (C1-C6) haloalkyl, cyano, (C3-C6) cycloalkyl or (C1-C６) hydroxyalkyl with the proviso that at least one of R4, R5 and R6 is not hydrogen; and, R3 is (C1-C4) alkyl, (C1-C4) alkylcyclopropyl, (C1-C4) hydroxyalkyl optionally substituted with halo or (C1-C4) haloalkyl; or a pharmaceutically acceptable salt or solvate thereof.

Specific preferred compounds of the invention are those listed in the Examples section below, and the pharmaceutically acceptable salts and solvates thereof.

Compounds of formula (I), which are VR1 antagonists, are potentially useful in the treatment of a variety of disorders, in particular in the treatment of pain, including chronic pain, acute pain, pain, neuropathic pain, inflammatory pain , postherpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthritis pain, osteoarthritis pain, burns, back pain, visceral pain, cancer pain, dental pain, headache, migraine, carpal tunnel syndrome , fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain and menstrual pain; bladder disease, such as urinary incontinence, lower urinary tract symptoms, urination disorders, renal colic, and cystitis, inflammation, such as burns, rheumatoid arthritis, and osteoarthritis; neurodegenerative disease, such as stroke, post-stroke pain, and multiple sclerosis; diseases of the respiratory tree that contribute to symptoms or pathology arising from the sensory afferent nervous system, such as cough, bronchoconstriction, irritation, inflammation, and other pathways in lower respiratory diseases such as asthma and COPD as well as those of the upper respiratory tract , such as allergic rhinitis and chronic sinusitis; gastrointestinal disorders, such as gastroesophageal reflux disease (GERD), dysphagia, ulcer, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis, and Crohn's disease; ischemia, such as cerebrovascular ischemia and acute cerebral ischemia; emesis, such as emesis induced by cancer chemotherapy; diabetes and obesity; or the like in mammals, especially humans. Treatment of pain, particularly inflammatory pain, is a preferred use.

Physiological pain is an important protective mechanism designed to warn of danger from potentially harmful stimuli from the external environment. The system functions through a specific set of primary sensory neurons and is activated by noxious stimuli via peripheral transduction mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a recapitulation). These sensory fibers are known as nociceptors and are characteristically small diameter axons with slow conduction speeds. Nociceptors encode the intensity, duration, and quality of noxious stimuli and, thanks to their topographically organized projection to the spinal cord, the location of the stimulus. Nociceptors are found in nociceptive nerve fibers of which there are two main types, A-delta fibers (with myelin) and C fibers (without myelin). The activity generated by the nociceptor information is transferred, after complex processing in the posterior horn, either directly, or through the transmission nuclei of the brainstem to the thalamus ventrobasal and then to the cortex, where the sensation of pain is generated.

Pain can be broadly classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the type of pain that can occur after specific injuries caused by surgery, dental work, a strain or a sprain. Acute pain generally does not produce any persistent psychological response. In contrast, chronic pain is long-term pain, which usually persists for more than three months and causes significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (eg, painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritis pain, and chronic postsurgical pain.

When there is a substantial injury to body tissues, due to disease or trauma, the characteristics of nociceptive activation are altered and sensitization occurs in the periphery, locally around the wound and centrally at the termination of nociceptors. These effects cause a greater sensation of pain. In acute pain, these mechanisms can be useful, to promote protective behaviors that can allow better repair processes to take place. What would normally be expected is that the sensitivity would return to normal once the injury has healed. However, in many chronic pain states, hypersensitivity lasts much longer than the healing process and is often due to injury to the nervous system. This injury often causes abnormalities in sensory nerve fibers associated with poor adaptation and aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when the patient's symptoms include discomfort and abnormal sensitivity. Patients tend to be very heterogeneous and may report a variety of pain symptoms. Such symptoms include: 1) spontaneous pain that may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by usually innocuous stimuli (allodynia - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and therefore different treatment strategies may be required. Pain can also therefore be classified into a number of different subtypes according to different pathophysiology, including nociceptive, inflammatory, and neuropathic pain.

Nociceptive pain is induced by tissue injury or by strong stimuli that have the potential to cause injury. Painful afferents are activated by the transduction of stimuli by nociceptors present at the site of injury and activate neurons in the spinal cord at the level where they terminate. This is then transmitted through the spinal cord to the brain where pain is felt (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibers. Myelinated A-delta fibers transmit rapidly and are responsible for sharp, stabbing pain sensations, while sinmyelin C fibers transmit at a slower speed and transmit a dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of pain caused by central nervous system trauma, strains / sprains, burns, myocardial infarction and acute pancreatitis, postoperative pain (pain after any type of surgical procedure), post-traumatic pain, colic kidney, cancer pain and back pain. Cancer pain can be chronic pain such as tumor-related pain (eg bone pain, headache, facial pain or visceral pain) or pain associated with cancer treatment (eg post-chemotherapy syndrome, chronic postsurgical pain syndrome, or post-radiation syndrome). Cancer pain can also occur in response to chemotherapy, immunotherapy, hormone therapy, or radiation therapy. Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumbar joint surfaces, the sacroiliac joints, the paraspinal muscles, or the posterior longitudinal ligament. Back pain can resolve naturally, but in some patients, lasting more than 12 weeks, it becomes a chronic condition that can be particularly debilitating.

Neuropathic pain is currently defined as pain that is initiated or caused by a primary injury or dysfunction of the nervous system. Nerve damage can be caused by trauma and disease, and thus the term 'neuropathic pain' encompasses many disorders with various etiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, post-stroke central pain, and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and vitamin deficiency. Neuropathic pain is pathological since it does not have any protective role. It is often present long after the original cause has disappeared, usually lasting for years and significantly diminishing the patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959-1964). Neuropathic pain symptoms are difficult to treat since they are often heterogeneous even among patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959- 1964). They include spontaneous pain, which may be continuous, and paroxysmal pain or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).

The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue damage or the presence of foreign substances, which causes inflammation and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56). Arthritis pain is the most common inflammatory pain. Rheumatoid disease is one of the most common chronic inflammatory conditions in developed countries, and rheumatoid arthritis is a common cause of disability. The exact etiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407). It has been estimated that nearly 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, the majority of whom are over 60 years of age, and the number is expected to increase to 40 million with increasing age. population, making this a public health problem of enormous magnitude (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most osteoarthritis patients seek medical attention due to associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in the last phase of life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis in the spine and sacroiliac joints. It ranges from intermittent episodes of back pain that occur throughout life to severe chronic disease that affects the spine, peripheral joints, and other organs of the body.

Another type of inflammatory pain is visceral pain, which includes pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, which includes the organs of the abdominal cavity. These organs include the sex organs, the spleen, and part of the digestive system. Viscera associated pain can be divided into digestive visceral pain and non-digestive visceral pain. Common gastrointestinal (GI) disorders that cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These GI disorders include a wide variety of disease states that are currently only moderately controlled, including, with respect to FBD, gastroesophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and with respect to IBD, Crohn's disease, ileitis, and ulcerative colitis, all of which produce visceral pain on a regular basis. Other types of visceral pain include pain associated with dysmenorrhea, cystitis and pancreatitis, and pelvic pain.

It should be noted that some types of pain have multiple etiologies and thus can be classified in more than one area, for example back pain and cancer pain both have nociceptive and neuropathic components.

Other types of pain include:

 pain caused by musculoskeletal disorders, including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis and pyomyositis;

 cardiac and vascular pain, including pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma, and skeletal muscle ischemia;

 headache, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache, mixed headache and headache associated with vascular disorders; and

 orofacial pain, including dental pain, ear pain, burning mouth syndrome, and temporomandibular myofascial pain.

Urinary incontinence (any condition in which an involuntary leakage of urine occurs), includes stress urinary incontinence, urinary urgency incontinence and mixed urinary incontinence, overactive bladder with associated urinary incontinence, enuresis, nocturnal enuresis, ongoing urinary incontinence, and urinary incontinence situational such as incontinence during sexual intercourse.

Lower urinary tract symptoms comprise three groups of urinary symptoms, which can be defined as storage (irritant), emptying (obstructive), and postvoid symptoms. Storage symptoms include urgency, polyuria, nocturia, urgency incontinence, and stress incontinence, which may be associated with overactive bladder (OAB) and benign prostatic hyperplasia (BPH). Symptoms of voiding include initial dysuria, poor flow, intermittency, straining to urinate, and dysuria. Postvoid symptoms include postvoid drip, postvoid drip, and a feeling of incomplete emptying.

Overactive bladder (OAB) is defined as urgency, with or without urge incontinence, usually with polyuria and nocturia [Abrams et al., Neurourology and Urodynamics 21: 167-178 (2002)]. The prevalence of OAB in men and women is similar, with approximately 16% of the US population suffering from the condition [Stewart et al, Prevalence of Overactive Bladder in the United States: Results from the NOBLE Program; Abstract presented at the 2nd International Incontinence Consultation, July 2001, Paris, France]. OAB includes wet OAB and dry OAB. The terms wet OAB and dry OAB describe OAB patients with or without urinary incontinence, respectively. Until recently, the main symptom of OAB was believed to be urinary incontinence. However, with the advent of new conditions, this name is obviously meaningless in the face of the large number of non-incontinence patients (ie dry OAB patients). Thus, a recent study by Liberman et al [‘Health Related Quality of Life Among Adults with Symptoms of Overactive Bladder: Results from AUS Community-Based Survey’; Urology 57 (6), 1044-1050, 2001] examined the impact of all OAB symptoms on the quality of life of an out-of-hospital sample of the US population. This study demonstrated that individuals with OAB without any demonstrable urine leakage have a lower quality of life when compared to controls.

BPH is a chronically progressive disease that can lead to complications such as acute urinary retention, recurrent urinary tract infections, bladder stones, and kidney dysfunction. The prevalence and mean severity of LUTS associated with BPH in men increases with age. BPH causes increased prostate volume, creating urethral and bladder outflow obstruction as well as secondary changes in bladder function. Its effects are manifested by both storage (irritant) and emptying (obstruction) symptoms.

The present invention provides a pharmaceutical composition that includes a compound of formula (I), or a salt

or a pharmaceutically acceptable solvate thereof, together with a pharmaceutically acceptable excipient. The composition is preferably useful for the treatment of the disease conditions defined above.

The present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.

The present invention further provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in treating the disease conditions defined above.

Furthermore, the present invention provides a method for the treatment of the disease conditions defined above in a mammal, preferably a human, which includes administering to said mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate of the same.

Still further, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the disease conditions defined above.

Still further, the present invention provides a combination of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and another pharmacologically active agent.

In this specification, especially in the "General Synthesis" and "Examples", the following may be used

abbreviations:

BEP

2-Bromo-1-ethylpyridinium tetrafluoroborate

BOP

Benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate

CDI

2-chloro-1,3-dimethylimidazolinium chloride

DCC

dicyclohexylcarbodiimide

DCM

dichloromethane

DME

1,2-dimethoxyethane, dimethoxyethane

DMF

N, N-dimethylformamide

DMSO

dimethyl sulfoxide

EDC

1-Ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrogen chloride

Et

ethyl

Et2O

diethyl ether

EtOAc

ethyl acetate

EtOH

ethanol

HBTU

2- (1H-benzenetriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate

HOBt

1-hydroxybenzotriazole

I

methyl

MeOH

methanol

NMP

N-methyl-2-pyrrolidone

T3P

cyclic 1-propylphosphonic acid anhydride

THF

tetrahydrofuran

TFA

trifluoroacetic acid

General synthesis

The compounds of the present invention can be prepared by a variety of procedures either

known for the preparation of compounds of this type, for example as shown in the following reaction schemes.

All of the starting materials for the following general syntheses may be commercially available or obtained by standard procedures known to those of skill in the art.

Scheme 1:

OR

image2 Y2 HO R2

R6 image2 R1 Y1 R3 R image2 6R1 R2 image2 ONH2 Y2 (III) NN

image2 N HN R4

Stage 1A N Y1 R3

R4R5 R5

image3 (I)

image2

image2

image2

This illustrates the preparation of compounds of formula (I).

Step 1A: In this Step, the amide compounds of the formula (I) can be prepared by the coupling reaction of an amine compound of the formula (II) with the acid compound of the formula (III) in the presence or absence of a coupling reagent in an inert solvent. Suitable coupling reagents are those commonly used in peptide synthesis including, for example, diimides (eg, DCC, EDC, 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, BEP, CDI, BOP , diethyl azodicarboxylate-triphenylphosphine, diethyl cyanophosphate, diethyl phosphorylazide, 2-chloro-1-methylpyridinium iodide, N, N'-carbonyldiimidazole, benzotriazole-1-yldiethyl phosphate, ethyl chlorobutylate reaction can be performed in chlorobutoformate. presence of a base such as HOBt, N, N-diisopropylethylamine, N-methylmorpholine or triethylamine. The amide compound of formula (I) can be formed by an acyl halide, which can be obtained by reaction with halogenating agents such as chloride of oxalyl, phosphorus oxychloride or thionyl chloride. The reaction is usually and preferably carried out in the presence of a solvent. There are no particular restrictions on the nature of the solvent to be used, provided ion that it has no adverse effects on the reaction or the reagents involved and that it can dissolve the reagents, at least to some degree. Examples of suitable solvents include: acetone; nitromethane; DMF; NMP; sulfolane; DMSO; 2-butanone; acetonitrile; halogenated hydrocarbons such as DCM, dichloroethane or chloroform; and ethers such as THF or 1,4-dioxane. The reaction can occur over a wide temperature range, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from -20 ° C to 100 ° C, more preferably from about 0 ° C to 60 ° C. The time required for the reaction can also vary greatly, depending on many factors, notably the reaction temperature and the nature of the reagents and solvents used. However, provided the reaction is carried out under the preferred conditions described above, a period of 5 minutes to 1 week will usually suffice, plus

30 preferably 30 minutes to 24 hours.

A compound of the formula (II) can be prepared from a compound of the formula (IV), as illustrated by Schemes 2 and 2 '.

Scheme 2:

R2R2 R2

image2 R7 R6 image2 R1 image2 R7

R6 image2 R6 OR R7NH2

N

N

H (VII)

R1M N

image2 NN image2 R4 Stage 2A image2 N image2 R4 Stage 2B N image2 R4

N

image2

R5 R5 R5

(IV) (V) (VI)

R2

image2 R1

R6 NH2

image2 N Stage 2C N image2 R4 R5

(II)

wherein R7 is tert-butylsulfinyl, hydrogen, benzyl, or diphenylmethyl; and M is a suitable metal, such as lithium; or MgZ, where Z is halogen.

5 Step 2A: In the above formula, a compound of the formula (V) can be prepared by coupling reaction of the compound of the formula (IV) with the amine of the formula (VII) with dehydration reagent and / or HCl-MeOH and / or Lewis acid. A preferred dehydrating reagent includes sodium sulfate, magnesium sulfate, calcium sulfate, or methyl ormate. Examples of Lewis acid include: titanium (IV) ethoxide; titanium (IV) isopropoxide; or titanium (IV) chloride. Examples of suitable solvents include: THF; 1,4-dioxane; DMF; acetonitrile; alcohols such as

10 MeOH or EtOH; halogenated hydrocarbons such as DCM, 1,2-dichloroethane, chloroform, or carbon tetrachloride; or acetic acid. The reaction temperature is generally in the range of 0 to 200 ° C, preferably in the range of 100 ° C to 140 ° C. The reaction time is, in general, from 1 minute to a day, preferably from 5 minutes to 1 hour. If necessary, microwave conditions are applied to the reaction.

Step 2B: When R1 is an alkyl group, the compound of the formula (VI) can be prepared by reacting the

15 compound of formula (V) with an appropriate organometallic reagent R1M. R1M can be prepared by reacting a halide compound of R1. For example, R1M, where M represents MgZ, can be generated by stirring Mg and R1Z, dibromoethane, and I2 heating from the 30-80 ° C range. This reaction can be carried out in the presence of an organometallic reagent or a metal. Examples of suitable organometallic reagents include alkyl lithiums such as n-butyllithium, sec-butyllithium or tert-butyllithium; aryl lithiums such as phenyllithium or lithium naphthalenide. Examples of

Suitable metal includes magnesium. If necessary, various metal salts such as cerium, copper, iron, nickel or zinc and / or Lewis acid additive such as trimethylaluminum, boron trifluoride complex and diethyl ether can be employed to facilitate this reaction. Preferred inert solvents include, for example, hydrocarbons, such as hexane or benzene; halogenated hydrocarbons such as DCM; ethers, such as diethyl ether, diisopropylether, DME, THF, or 1,4-dioxane; or mixtures thereof. The reaction temperature is generally in the range of -100 to

50 ° C, preferably in the range of -100 ° C to room temperature. The reaction time is, in general, from 1 minute to a day, preferably from 1 hour to 10 hours.

When R1 is hydrogen, the compound of formula (VI) can be prepared by reacting the compound of formula (V) with a reducing agent such as diborane, borane-methyl sulfide complex, sodium borohydride, lithium borohydride, L- Lithium Aluminum Selectride, Super Hydride, or Hydride in an inert solvent selected from THF, diethyl ether, or 1,4-dioxane. This reduction can also be carried out under known hydrogenation conditions such as in the presence of a metallic catalyst such as Raney nickel catalysts in the presence or absence of hydrazine, palladium catalysts or platinum catalysts under hydrogen atmosphere. This reaction can be carried out in an inert solvent such as MeOH, EtOH, and THF in the presence or absence of hydrogen chloride. If necessary, this reduction can be carried out at a suitable pressure in the range from

35 about 0.5 to 10 kg / cm2, preferably in the range from 1 to 6 kg / cm2.

Step 2C: In this Step, the compound of formula (II) can be prepared by deprotection and / or salt formation of the compound of formula (VI) under acidic conditions in an inert solvent using a procedure of Journal of American Chemical Society, 1999 , 121, 268-269 to D. Cogan et al. An acid includes, for example, but not limited to, hydrogen chloride, hydrogen bromide, trifluoromethanesulfonic acid, acetic acid, or p-toluenesulfonic acid. The reaction can also be carried out under known hydrogenation conditions such as in the presence of a metallic catalyst such as palladium-carbon catalyst or platinum catalysts under hydrogen atmosphere. This reaction can be carried out in an inert solvent such as MeOH, EtOH, and THF in the presence or absence of hydrogen chloride. If necessary, this reduction can be carried out at a suitable pressure in the range from about 0.5 to 10 kg / cm2, preferably in the range from 1 to 6 kg / cm2. The

The reaction temperature is generally in the range of -100 ° C to 250 ° C, preferably in the range of 0 ° C at the reflux temperature, but if necessary, a lower or higher temperature may be employed. The reaction time is, in general, from 1 minute to 2 days, preferably from 20 minutes to 24 hours.

Scheme 2 '

R2R2 R2

R1 image2 image2 R1

R6

R6 image2 R6 image2

Or R1M

N3 N

image4 OH Stage 2D-1

N N

image5 N R4

N R4

N R4 R5

R5 R5

(IV) (VIII) (IX) R2

image2

image2

image2

image6

(II)

Step 2D-1: In this Step, a compound of formula (VIII) can be converted to a compound with a leaving group under conditions known to those skilled in the art. For example, the hydroxy group of the compound of formula (VIII) can be converted to the chloride using a chlorinating agent, for example thionyl chloride, oxalyl chloride in the presence or absence of an inert solvent, for example halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or 1,2-dichloroethane; or ethers such as diethyl ether, diisopropylether, THF

or 1,4-dioxane; DMF or DMSO. The hydroxy group of the compound of formula (VIII) can also be converted to the sulfonate group using a sulfonating agent, for example para-toluenesulfonyl chloride, para-toluenesulfonic anhydride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride in the presence or absence of a base, for example an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, hydride sodium or potassium hydride or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine, or dimethylaminopyridine in the presence or absence of a solvent

Inert, for example aliphatic hydrocarbons, such as hexane, heptane or petroleum ether; aromatic hydrocarbons, such as benzene, toluene, o-dichlorobenzene, nitrobenzene, pyridine, or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, or 1,2-dichloroethane; ethers such as diethyl ether, diisopropylether, THF, or 1,4-dioxane; DMF or DMSO.

Step 2D-2: A compound of formula (IX) can be prepared by introduction of azide. Compound

20 obtained in Step 2D-1 can be treated with diphenylphosphoryl azide (DPPA), sodium azide, or HN3 in the presence of dialkyl azodicarboxylate such as diethyl azodicarboxylate (DEAD) and phosphine reagent such as triphenylphosphine. Preferably, this reaction can performed in an inert solvent. Preferred inert solvents include, but are not limited to, THF, diethyl ether, DMF, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, DCM, 1,2-dichloroethane, or DME; or mixtures thereof. The reaction temperature is generally in the range of

25 -100 to 250 ° C, preferably in the range of 0 ° C to reflux temperature, but if necessary, a lower or higher temperature can be used. The reaction time is generally from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times can be employed if necessary.

Step 2E: In this Step, a compound of formula (II) can be prepared by reduction of the compound of

30 azide of formula (IX) with a reducing agent. This reaction can be carried out in the presence of a suitable reducing agent such as diborane, borane-methyl sulfide complex, or lithium aluminum hydride in an inert solvent such as THF or diethyl ether. The reaction can also be carried out under conditions similar to those described in Step 2C above.

A compound of formula (IV) can be synthesized from a compound of formula (X) as illustrated by Schemes 3, 3 'and 3' 'below.

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Four. Five

Scheme 3:

image2 OMeMeRO

image2 N R6 image2 R6 image2 R6 L

OR

OR CO

Me (OMe) NH.HCl

N

image2 N

image2 image2 N NR4 ROH NR4 image2 NR4

Stage 3B-1 Stage 3B-2 Stage 3A

R5 R5 R5

(X) (XI) (XII)

R2 R6 O

R2M

image7 N image2 N R4

R5

(IV)

wherein L is a suitable leaving group such as O-triflate, O-tosylate, or halogen;

R is (C1-C6) alkyl; and

M is a suitable metal, such as lithium; or MgZ, where Z is halogen.

Step 3A: When L is a leaving group such as trifluoromethanesulfonate, tosylate, iodide, bromide, or chloride, the compound of formula (XI) can be prepared by reacting the compound of formula (X) with carbon monoxide and alcohol (for example MeOH or EtOH) in the presence of a catalyst and / or base in an inert solvent. Examples of suitable catalysts include: palladium reagents, such as palladium acetate or palladium dibenzylacetone. Examples of suitable bases include: N, N-diisopropylethylamine, N-methylmorpholine, or triethylamine. If desired, this reaction can be carried out in the presence or absence of an additive such as 1,1'-bis (diphenylphosphino) ferrocene, triphenylphosphine or 1,3-bis- (diphenylphosphino) propane (DPPP). The reaction is usually and preferably carried out in the presence of a solvent. There are no particular restrictions on the nature of the solvent to be used, provided that it has no adverse effects on the reaction or the reagents involved and that it can dissolve the reagents, at least to some degree. Examples of suitable solvents include: acetone; nitromethane; DMF; sulfolane; DMSO; NMP; 2-butanone; acetonitrile; halogenated hydrocarbons such as DCM, dichloroethane, or chloroform; or ethers such as THF or 1,4-dioxane. The reaction can occur over a wide temperature range, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from -20 ° C to 150 ° C, more preferably from about 50 ° C to 80 ° C. The time required for the reaction can also vary greatly, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent used. However, provided the reaction is carried out under the preferred conditions described above, a period of 30 minutes to 24 hours, more preferably 1 hour to 10 hours, will usually suffice.

Step 3B-1: In this Step, an acid compound can be prepared by hydrolysis of the compound of formula (XI) in a solvent. The hydrolysis can be carried out by conventional procedures. In a typical procedure, the hydrolysis is carried out under basic conditions, in the presence of water, suitable bases include, for example, sodium hydroxide, potassium hydroxide or lithium hydroxide. Suitable solvents include, for example, alcohols such as MeOH, EtOH, propanol, butanol, 2-methoxyethanol, or ethylene glycol; ethers such as THF, DME, or 1,4-dioxane; amides such as DMF or hexamethylphosphoric triamide; or sulfoxides such as DMSO. This reaction can be carried out at a temperature in the range from -20 to 100 ° C, usually from 20 ° C to 65 ° C for 30 minutes to 24 hours, usually 60 minutes to 10 hours. The hydrolysis can also be carried out under acidic conditions, for example in the presence of hydrogen halides, such as hydrogen chloride and hydrogen bromide; sulfonic acids, such as p-toluenesulfonic acid and benzenesulfonic acid; pyridium p-toluenesulfonate; and carboxylic acid, such as acetic acid and trifluoroacetic acid. Suitable solvents include, for example, alcohols such as MeOH, EtOH, propanol, butanol, 2-methoxyethanol, and ethylene glycol; ethers such as THF, DME, and 1,4-dioxane; amides such as DMF and hexamethylphosphoric triamide; and sulfoxides such as DMSO. This reaction can be carried out at a temperature in the range of -20 to 100 ° C, usually 20 ° C to 65 ° C for 30 minutes to 24 hours, usually 60 minutes to 10 hours.

Step 3B-2: In this Step, an amide compound of formula (XII) can be prepared from the product of 3B-1 by the same procedure as Step 1. Alternatively, a compound of formula (XII) can be prepared directly from the compound of formula (XI) following the literature procedure (Tetrahedron Letters, 1995, 36, 5461-5464 by JM Williams et al.).

Step 3C: When R2 is an alkyl group, the compound of formula (IV) can be prepared by reacting the compound of formula (XII) with an organometallic reagent R2M as described in Step 2B.

image2

image2

image2

image2

When R2 is hydrogen, the compound of formula (IV) can be prepared by reacting the compound of formula (XII) with an appropriate reducing reagent such as DIBAL-H, lithium aluminum hydride, sodium borohydride in a suitable solvent such as toluene. , THF, or diethyl ether. The reaction temperature is generally in the range of -100 to 50 ° C, preferably in the range of -100 ° C to room temperature. The reaction time is, in general, from 1 minute to a day, preferably from 1 hour to 10 hours.

Scheme 3 ':

R2

R6 image2 image2 Or R6 image2

or R2CN

L

OR

image8 R2

X

N

N

N R4

N R4

image2

image2

R5 R5

(X) (IV)

where L is iodide, bromide, or hydrogen; and

10 X is halogen or N (OMe) Me.

Step 3D: When L is a halogen group such as bromine or iodine, a compound of formula (IV) can be prepared by reacting the corresponding organometallic reagent of the compound of formula (X), generated by halogen-metal exchange reaction using a reagent appropriate organometallic, with a suitable electrophile. Suitable organometallic reagents for halogen-metal exchange include: n-butyllithium, 15 sec-butyllithium, tert-butyllithium, isopropylmagnesium chloride with metal salt such as LiBr, LiCl, or mixtures thereof . Examples of solvents for this reaction include, but are not limited to: ethers, such as diethyl ether, diisopropylether, DME, THF, or 1,4-dioxane; hydrocarbons, such as hexane or benzene; or the mixture thereof. The reaction temperature is generally in the range of -100 ° C to 0 ° C, preferably in the range of -100 ° C to -10 ° C. The reaction time is, in general, from 1 minute to a day, preferably from 1 hour to 10

20 hours. When R2 is an alkyl group, suitable electrophiles for this reaction include the corresponding Weinreb amide, acid halide, or nitrile compound. When R2 is hydrogen, N, N-dimethylformamide (DMF) can be used as the electrophile. The reaction temperature for this step is generally in the range of -100 ° C to 90 ° C, preferably in the range of -100 ° C to room temperature.

When L is hydrogen and R2 is an alkyl group, a compound of formula (IV) can be prepared by reaction

25 of the Friedel-Crafts type of the compound of formula (X) and a suitable electrophile in the presence or absence of acid catalysts. Examples of electrophiles for this type of reaction include, but are not limited to: acid halide or acid anhydride. Examples of suitable solvents include: halogenated hydrocarbons such as DCM, 1,2-dichloroethane, chloroform, or carbon tetrachloride; or DME. This reaction can be carried out in the presence of a suitable catalyst such as aluminum (III) chloride, titanium (IV) chloride, or zirconium (IV) chloride. Temperature

Reaction is generally in the range of -100 to 90 ° C, preferably in the range of room temperature to 70 ° C. The reaction time is, in general, from 1 minute to a day, preferably from 1 hour to 10 hours.

When L is hydrogen and R2 is hydrogen, a compound of formula (IV) can be prepared by deVilsmeier reaction of the compound of formula (X) under standard conditions (eg DMF-POCl3).

When L is hydrogen and is arranged in the active position for deprotonation (for example, the adjacent substituent acts as a directed metallating group or L is positioned near the heteroatom of the heteroaromatic ring) a compound of formula (IV) can be prepared by the reaction of the corresponding organometallic reagent of the compound of formula (X), generated by deprotonation reaction using an appropriate organometallic base with a suitable electrophile. Examples of organometallic bases that can be applied

40 for this reaction include, but are not limited to: n-butyllithium, sec-butyllithium, tert-butyllithium, LDA, LHMDS, LTMP, iso-propylmagnesium chloride with a metal salt such as LiBr, LiCl, or the mixture of them. Examples of a targeted metallation group include, but are not limited to: trifluoromethyl, carboxamide, sulfonamide, alkoxy, halogen, carboxylic acid, ester, or amide. Other detailed conditions (electrophile, solvent, reaction temperature, reaction time) are similar to those for the halogen-metal exchange reaction described in Step 3D above.

Four. Five

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Four. Five

Scheme 3 ’’:

R2 R6 R6R6 L image2 image2 CN

O M '(CN) n

R2M N

N

image2 N Stage 3E

Stage 3C

image2 NR4 NR4 image2 NR4

image2

R5 R5R5

(X) (XIII) (IV)

wherein L is a suitable leaving group such as trifluoromethanesulfonate, tosylate, iodide, bromide, or chloride;

M is a suitable metal, such as lithium; or MgZ, where Z is halogen; and

M 'is a suitable metal.

Step 3E: A compound of formula (XIII) can be prepared by cyanating the compound of formula (X) under cyanation conditions with a transition metal catalyst and metal cyanide reagent in an inert solvent. Examples of suitable solvents include: THF; 1,4-dioxane; DMF; acetonitrile; alcohols such as MeOH or EtOH; halogenated hydrocarbons such as DCM, 1,2-dichloroethane, chloroform, or carbon tetrachloride; or DME. Suitable reagents include, for example, alkali metal cyanide such as lithium cyanide, sodium cyanide, potassium cyanide, transition metal cyanide such as iron (II) cyanide, cobalt (II) cyanide, copper (I) cyanide. , copper (II) cyanide, zinc (II) cyanide or trimethylsilyl cyanide. This reaction can be carried out in the presence of a suitable catalyst. Likewise, there are no particular restrictions on the nature of the catalysts to be used and any catalysts that are commonly used in reactions of this type can also be used here. Examples of such catalysts include: tetrakis (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride, copper (0), copper (I) acetate, copper (I) bromide, copper (I) chloride, copper (I) iodide, copper (I) oxide, copper (II) trifluoromethanesulfonate, copper (II) acetate, copper (II) bromide, copper (II) chloride, copper (II) iodide, oxide copper (II), copper (II) trifluoromethanesulfonate, palladium (II) acetate, palladium (II) chloride, bisacetonitrilodichloropaladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) or dichloride [1,1'-bis (diphenylphosphino) ferrocene] palladium (II). Preferable catalysts are tetrakis (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, palladium (II) chloride, bisacetonitryl dichloropalladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) or [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride. The reaction can be carried out in the presence of a suitable additive agent. Examples of such additive agents include: triphenylphosphine, tri-tert-butylphosphine, 1,1'-bis (diphenylphosphino) ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, 2- (dichlorohexylphosphino) biphenyl or triphenylarsine. The reaction can be carried out at a temperature of from 0 ° C to 200 ° C, more preferably from 20 ° C to 120 ° C. The reaction time is generally from 5 minutes to 48 hours, more preferably 30 minutes to 24 hours will normally suffice. If necessary, microwaves are applied to the reaction.

Scheme 4:

When R2 is methyl, a compound of formula (IV) can be prepared from a compound of formula (X) as illustrated below.

OR

image9 N R5 R5

(X) (IV)

wherein L is a suitable leaving group such as trifluoromethanesulfonate, tosylate, iodide, bromide, or chloride.

Step 4A: when L is a leaving group such as and R2 is methyl, a compound of formula (IV) can be prepared from the compound of formula (X) by a Heck-type reaction with an appropriate transition metal catalyst, a base, and additives in a solvent. Examples of suitable solvents include: protic solvents such as water, alcohols such as MeOH or EtOH and co-solvents of water or alcohols such as protic solvents mixed with THF, 1,4-dioxane, DMF or acetonitrile. This reaction can be carried out in the presence of a suitable catalyst. Likewise, there are no particular restrictions on the nature of the catalysts to be used and any catalysts commonly used in reactions of this type can also be used here. Examples of such catalysts include: tetrakis (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride, copper (0), copper (I) acetate, copper (I) bromide, copper (I) chloride, Copper (I) iodide, copper (I) oxide, copper (II) trifluoromethanesulfonate, copper (II) acetate, copper (II) bromide, copper (II) chloride, copper (II) iodide, copper (II) oxide copper (II), copper (II) trifluoromethanesulfonate, palladium (II) acetate, palladium (II) chloride, bisacetonitrilodichloropaladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipaladium (0) or dichloride from

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[1,1'-bis (diphenylphosphino) ferrocene] palladium (II). Preferable catalysts are tetrakis (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, palladium (II) chloride, bisacetonitryl dichloropalladium (0), bis (dibenzylideneacetone) palladium (0), triazylideneacetone) palladium (0). (dibenzylideneacetone) dipalladium (0) or [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride. This reaction can be carried out in the presence of a suitable additive agent. Examples of such additive agents include: triphenylphosphine, tri-tert-butylphosphine, 1,2-bis (diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane, 1,1'-bis (diphenylphosphino) ferrocene, tri-2- furylphosphine, tri-o-tolylphosphine, 2- (dichlorohexylphosphino) biphenyl or triphenylarsine. This reaction can be carried out in the presence of bases such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction can be carried out at a temperature of from 0 ° C to 200 ° C, more preferably from 20 ° C to 120 ° C. The reaction time is generally from 5 minutes to 48 hours, more preferably 30 minutes to 24 hours will usually suffice. If necessary, microwave irradiation can be applied to this reaction.

Scheme 5:

A compound of formulas (IV), (XI), and (XIII) can be synthesized through the formation of a pyrazole ring as illustrated below. This synthetic route can be considered an alternative procedure to the preparation of functionalized pyrazole derivatives.

R4 O

L CH (OEt) 3 or Me2NCH (OMe) 2 Stage 5A R4 OR R6 Z L R5NHNH2 Stage 5B N N R5 R6 R4 L + N N R5 R4 L R6

(XIV)

(XV) (IV) (L = COR2) (XVI) (L = COR2)

(XI) (L = CO2R)

(XVII) (L = CO2R)

(XIII) (L = CN)

(XVIII) (L = CN)

(X) (L = H)

(XIX) (L = H)

where L is COR2, CO2R, CN, or hydrogen; and

Z is OEt, NMe2, or OH.

Step 5A: when Z is OEt or NMe2, the compound of formula (XV) can be prepared from the compound of formula (XIV) by reaction with N, N-dimethylformamide dimethylacetal or triethyl orthoformate under known standard conditions. In the case of the reaction with triethyl orthoformate, the reaction can be carried out in acetic anhydride as solvent, although no particular additive or solvent is required for the reaction with N, N-dimethylformamide dimethylacetal. The reaction can be carried out at a temperature from 0 ° C to 200 ° C, more preferably from 20 ° C to 120 ° C. The reaction time is generally from 5 minutes to 48 hours, more preferably 30 minutes to 24 hours will usually suffice. If necessary, microwave irradiation can be applied to this reaction.

Step 5B: Compounds of formulas (IV), (XI), (X) and (XIII) can be synthesized through pyrazole ring formation with the compound of formula (XV) and the appropriate hydrazine derivative under conditions acidic or neutral in a suitable solvent. This reaction can provide regioisomeric products such as the compound of formula (XVI), (XVII), (XVIII) or (XIX) in each case, and the proportion of the regioisomers varies depending on the reaction conditions. Under acidic conditions, protic acids such as hydrochloric acid, sulfonic acids, triflic acid, nitric acid, and p-toluenesulfonic acid can be added for this reaction. A suitable solvent includes: ethers such as diethyl ether, THF, or 1,4-dioxane; alcohols such as MeOH, EtOH, or iPrOH; halogenated hydrocarbons such as DCM; or hydrocarbons such as pentane, hexane, or toluene. The reaction can be carried out at a temperature from -100 oC to 150 oC, more preferably from -20 oC to 100 oC. The reaction time is generally from 5 minutes to 48 hours, more preferably 30 minutes to 24 hours will normally suffice.

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Scheme 6:

R6 R6R4

image2 L image2 L image2 L R5X

N

image2 N + N

Stage 6A

NR4 NR4 NR6

H R5 R5

image2

(IV) (L = COR2) (XVI) (L = COR2) (IV) (L = COR2, R5 = H) (XI) (L = CO2R) (XVII) (L = CO2R)

(XI)

(L = CO2R, R5 = H)

(X)

(L = H, R5 = H) (XIII) (L = CN) (XVIII) (L = CN)

(XIII) (L = CN, R5 = H) (X) (L = H) (XIX) (L = H)

wherein X is a suitable leaving group such as halogen, O-triflate, O-tosylate or O-mesylate.

Step 6A: Compounds of formula (IV), (XI), (X) and (XIII) can be synthesized by N-alkylation of compounds of formulas (IV), (XI), (X) and (XIII) (where R5 is hydrogen) with the appropriate alkylating reagent and the appropriate base in an appropriate solvent or with the corresponding alcohol under standard Mitsunobu conditions in the presence of dialkyl azodicarboxylate such as diethyl azodicarboxylate (DEAD) and phosphine reagent such as triphenylphosphine . This reaction can provide regioisomeric products such as the compound of formula (XVI), (XVII), (XVIII) or (XIX) in each case, and the proportion of the regioisomers varies depending on the reaction conditions. Examples of base include, but are not limited to: alkali metal hydride and hydroxide, potassium carbonate. A suitable solvent includes: ethers such as diethyl ether, THF, DME, or 1,4-dioxane; alcohols such as MeOH, EtOH, or iPrOH; halogenated hydrocarbons such as DCM; hydrocarbons such as pentane, hexane, or toluene; acetone; ethyl acetate; acetonitrile; DMSO; or DMF. The reaction can be carried out at a temperature from -100 oC to 150 oC, more preferably from -20 oC to 100 oC. The reaction time is generally from 5 minutes to 48 hours, more preferably 30 minutes to 24 hours will normally suffice.

Scheme 7:

When R2, R4 and R5 are all hydrogen, a compound of formula (IV) can be prepared as illustrated below.

R6

H image2 CHO

image2 N

image2 NH2N

image2 DMF-POCl3

image10 NO

NR6 H

(XX) (IV)

Step 7A: When R2, R4, and R5 are all hydrogen, the compound of formula (IV) can be synthesized from the compound of formula (XX) and DMF-POCl3. The reaction can generally be carried out without any solvent. The reaction can be carried out at a temperature from -100 oC to 150 oC, more preferably from -20 oC to 100 oC. The reaction time is generally from 5 minutes to 48 hours, more preferably 30 minutes to 24 hours will usually suffice.

Scheme 8:

image2 CH3 image2 OO

image2 Y1 image2 Y1 O

NHO CH3

Stage 8A Y2 L

Y2 L (XXII) (XXI)

image2 image2 OR image2 CH3H3C

Y1 Y1 R '

image2 R 'Stage 8B

Stage 8C Y2L Y2L

(XXIII) (XXIV)

image2 H3C image2 CH3

image2 CH3H3C

image11 Y1 R '

Y1 R '

Stage 8D Y2 CO2R 'Stage 8E Y2 CO2H

(III) (XXV)

wherein R 'is an optionally substituted alkyl group; and

L is a suitable leaving group.

Step 8A: In this Step, an amide compound of the formula (XXII) can be prepared from the compound of the formula (XXI) by the same procedure of Step 1.

Step 8B: In this Step, the ketone compound of the formula (XXIII) can also be prepared from the compound of the formula (XXII) by the same procedure of Step 2B.

Step 8C: In this Step, a compound of formula (XXIV) can also be prepared by a reaction of

10 Alkylation of the compound of formula (XXIII) with a geminal alkylating reagent in an inert solvent. Examples of preferred alkylating agents include trialkyl metals such as trimethylaluminum, triethylaluminum, alkylmagnesium halides such as methylmagnesium bromide in the presence of an additive compound such as lithium bromide; dialkyl titanium halides such as dimethyl titanium dichloride prepared by dimethylzinc and titanium chloride; and most preferably it is dimethyl titanium dichloride. Examples of Preferred Inert Solvents

15 for the reaction include halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform or carbon tetrachloride; ethers, such as diethyl ether, diisopropylether, DME, THF, and 1,4-dioxane; hydrocarbons, such as hexane, cyclohexane, benzene, and toluene; or mixtures thereof. Reaction temperatures are generally in the range of –100 to 200 ° C, preferably in the range of -40 ° C to 100 ° C. Reaction times, in general, are from 1 minute to a day, preferably from 1 hour to 10 hours.

Step 8D: In this Step, the compound of the formula (XXV) can also be prepared from the compound of the formula (XXIV) by the same procedure of Step 3A.

Step 6E: In this Step, an acid compound of the formula (III) can be prepared from the compound of the formula

(XXV) by the same procedure of Step 3B-1 in a solvent.

Scheme 9:

R3 image2 R3 R3

image2

N CN

N

image2 N Stage 9A

Stage 9B

OR

(XXVIII)

(XXVII)

(XXVI)

25 (III)

image2

image2

image12

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fifteen

twenty

25

30

35

40

Four. Five

Step 9A: In this Step, an N-oxide compound of the formula (XXVII) can be prepared by oxidation of the compound of the formula (XXVI) in a reaction-inert solvent. The oxidation reaction can be carried out in the absence or presence of an additive agent in an inert solvent for the reaction. Examples of preferred oxidation reagents are meta-chloroperbenzoic acid (mCPBA), hydrogen peroxide, peracetic acid. Examples of preferred inert solvents for the reaction include halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether, diisopropylether, DME, THF, and 1,4-dioxane; acetonitrile, acetic acid and water or mixtures thereof. Reaction temperatures are generally in the range of 0 ° C to 250 ° C, more preferably in the range of 0 ° C to 100 ° C. Reaction times, in general, are from 1 minute to 10 days, more preferably from 20 minutes to 6 hours. This reaction can be carried out in the presence of a suitable catalyst. Likewise, there are no particular restrictions on the nature of the catalyst that is used and any catalyst that is commonly used in reactions of this type can also be used here. Examples of such catalysts include methyl trioxorenium (VII), tungstic acid, and dehydrated sodium tungstate.

Step 9B: In this Step, a cyano compound of the formula (XXVIII) can be prepared by cyanating the compound of the formula (XXVII) in a reaction-inert solvent. Examples of preferred cyanating reagents include trimethylsilane carbonitrile (TMSCN), the combination of trimethylchlorosilane and sodium cyanide, the combination of acylating agents such as N, N-dimethylcarbamoyl chloride with trimethylsilane carbonitrile (TMSCN). A preferred cyanating reagent is trimethylsilane carbonitrile (TMSCN) in the presence of a base such as triethylamine in a reaction inert solvent. Examples of preferred inert solvents for the reaction include halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether, DME, THF, and 1,4-dioxane; acetonitrile, DMF, DMSO, or mixtures thereof. Reaction temperatures are generally in the range of 0 ° C to 250 ° C, more preferably in the range of 0 ° C to 100 ° C. Reaction times are generally from 1 minute to 10 days, more preferably from 20 minutes to 24 hours.

Step 9C: In this Step, an acid compound of the formula (III) can be prepared by hydrolysis of the cyano compound of the formula (XXVIII) in a solvent. The hydrolysis can be carried out by conventional procedures. In a typical procedure, the hydrolysis can be carried out under basic conditions, for example, in the presence of sodium hydroxide, potassium hydroxide, or lithium hydroxide. Examples of suitable solvents include alcohols such as MeOH, EtOH, propanol, butanol, 2-methoxyethanol, and ethylene glycol; ethers such as THF, DME, and 1,4-dioxane; amides such as DMF and hexamethylphosphoric triamide; and sulfoxides such as DMSO. Preferable solvents are MeOH, EtOH, propanol, THF, DME, 1,4-dioxane, DMF, and DMSO. This reaction can be carried out at a temperature in the range from -20 to 150 ° C, usually from 20 ° C to 100 ° C for 30 minutes to 24 hours, usually 60 minutes to 10 hours.

Scheme 10:

alkylation with (R3-M) R3 image2 HN

image13 OR

OR

image2

Stage 10A OO (XXIX) (XXX)

oxidation image2 R3 hydrolysis with alkali R3 image2 N

N

image2 Oh

OR Stage 10C

Stage 10B

OO

(XXXI) (III)

wherein R is (C1-C6) alkyl or benzyl; and

M is a suitable metal, metal hydride, or metal halide.

Step 10A: In this Step, a 1,2-dihydroquinoline compound of the formula (XXX) can be prepared by alkylating the compound of the formula (XXIX) in a reaction-inert solvent. The organometallic compound of the formula R3-M can be prepared from the corresponding alkyl halide. M represents metal such as lithium, or MgX, where X represents a hydrogen atom, a halogen atom such as fluorine, chlorine, bromine or iodine. Examples of suitable organometallic reagents include alkyl lithiums such as methyl lithium, n-butyllithium, sec-butyllithium and tert-butyllithium; aryl lithiums such as phenyllithium and lithium naphthalide; alkylmagnesium halide such as demethylmagnesium halide, isopropylmagnesium halide and t-butylmagnesium halide; arylmagnesium halide such as phenylmagnesium halide. Examples of preferred inert solvents for the reaction include hydrocarbons, such as hexane; ethers, such as diethyl ether, diisopropylether, DME, THF, and 1,4-dioxane; or mixtures thereof. Reaction temperatures are generally in the range of -100 to 100 ° C, preferably in the range of -100 ° C to room temperature. Reaction times are generally 1 minute to a day, preferably 1 hour to 24

5

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fifteen

twenty

25

30

35

hours.

Step 10B: In this Step, a compound of formula (XXXI) can be prepared by oxidation of the compound of formula (XXX) in a solvent. Examples of suitable oxidizing agents include Cr reagents, such as chromium trioxide (CrO3), potassium chromate (K2CrO4), potassium dichromate (K2Cr2O7); Mn reagents, such as manganese dioxide (MnO2), potassium permanganate (KMnO4), quinine reagents, such as 2,3,5,6, -tetrachloro-1,4-benzoquinone (p-chloranyl), 2,3 -dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and oxidation in air. Examples of suitable solvents include THF, 1,4-dioxane, acetone, DMF, acetonitrile, halogenated hydrocarbons (eg, DCM, dichloroethane, chloroform), water; or mixtures thereof. The reaction can occur over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The preferred reaction temperature will depend on factors such as the nature of the solvent, and the starting material or reagent used. However, in general, we find it convenient to carry out the reaction at a temperature of from -78 ° C to 100 ° C, more preferably from about -60 ° C to 60 ° C. The time required for the reaction can also vary greatly, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out under the preferred conditions described above, a period of 1 minute to 24 hours, more preferably 30 minutes to 12 hours, will usually suffice.

Step 10C: In this Step, an acid compound of formula (III) can be prepared by hydrolysis of the compound of formula (XXXI) in a solvent by the procedure described in Step 3B-1.

Scheme 11

image2 OR Stage 11A TMSO image2 CF3 Stage 11B LK

image2 LKR J

image14 image2 R

image2 J

image2

G

image2 halogen

G

(XXXII) (XXXIII)

image2 CF3 Stage 11C image2 CF3 Stage 11D

HO X LK

image2 LK

R J

image2 R

image2 J

image2

G

image14 G

image14

(XXXV) (XXXXIV)

Stage 11E Stage 11F

CF3 CF3 CF3H3C H3C H3C

image2 Step 11F image2 LK

image2 image2 LK

image2 image2 LKR JRJ

image2

R

image2

J OR

image14 image2 Oh

G

G

G OO

image2

(XXXVI) (XXXVII) (XXXVIII)

where X is halogen, O-mesylate, O-tosylate, or O-triflate; and

R is (C1-C2) alkyl or benzyl.

Step 11A: In this Step, a compound of formula (XXXIII) can be prepared by nucleophilic trifluoromethylation of formula (XXXII) in a reaction-inert solvent. Examples of preferred trifluoromethylation reagents include the combination of trifluoromethyltrimethylsilane (TMSCF3) and initiator reagents. Examples of preferred catalytic initiator reagents include tetrabutylammonium fluoride (TBAF), cesium fluoride (CsF), lithium acetate (AcOLi), sodium acetate (AcONa), potassium acetate (AcOK), tetrabutylammonium acetate (AcO-nNBu4), pivalate lithium (t-BuCO2Li), lithium benzoate (PhCO2Li), potassium t-butoxide (KO-tBu), and sodium t-butoxide (NaO-tBu). Examples of preferred inert solvents for the reaction include hydrocarbons, such as hexane, benzene, toluene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane; ethers; such as diethyl ether, diisopropylether, 1,2-dimethoxyethane (DME), tetrahydrofuran, and dioxane; acetonitrile, ethyl acetate, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or mixtures thereof. Reaction temperatures are generally in the range of -78 ° C to 200 ° C, more preferably in the range of -78 ° C to 100 ° C. Reaction times are generally from 1 minute to 10 days, more preferably from 10 minutes to 24 hours.

5

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fifteen

twenty

25

30

35

40

Step 11B: In this Step, a hydroxylic compound of the formula (XXXIV) can be prepared from the O-trimethylsilyl compound of the formula (XXXIII) by hydrolysis under acidic conditions, in a solvent, by the procedure described in Step 3B-1.

Step 11C: In this Step, a compound of formula (XXXV) can be prepared by treating a compound of formula (XXXXIV) with a suitable halogenating or O-activating agent, in a reaction-inert solvent or without solvent. . The halogenation reaction can be carried out with a halogenation reagent in an inert solvent or without a solvent. Examples of suitable solvents include tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, acetonitrile; halogenated hydrocarbons, such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride, and acetic acid. Examples of suitable halogenating reagents include thionyl chloride, oxalyl chloride, phosphorous pentachloride, phosphorus tribromide; phosphorous oxyhalide such as phosphorous oxychloride and phosphorous oxybromide; Lewis acids such as titanium chloride, tin chloride, and aluminum chloride. The reaction can be carried out at a temperature of from -78 ° C to 200 ° C, more preferably from -20 ° C to 150 ° C. Reaction times are generally from 5 minutes to 10 days, more preferably from 30 minutes to 24 hours. The O-mesylation, O-tosylation and O-triflation reactions can be carried out by reacting O-activating reagents with the compound of formula (XLVII) in the presence of a base in an inert solvent or without a solvent. Examples of suitable O-activating reagents include methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, and trifluoromethanesulfonic acid anhydride. Examples of suitable bases include alkyl lithium such as n-butyllithium, sec-butyllithium and tert-butyllithium; potassium t-butoxide and sodium t-butoxide (NaO-tBu); triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, and pyridine. Examples of preferred inert solvents for the reaction include hydrocarbons, such as hexane, benzene, toluene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether, diisopropylether, 1,2-dimethoxyethane (DME), tetrahydrofuran, and dioxane; acetonitrile, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or mixtures thereof. The reaction can be carried out at a temperature of -78 ° C to 150 ° C, more preferably -78 ° C to 100 ° C. Reaction times are generally 5 minutes to 48 days, more preferably 30 minutes to 24 hours.

Step 11D: In this Step, a compound of the formula (XXXVI) can be prepared by a dealkylation reaction of the compound of the formula (XXXV) with an alkylating reagent in an inert solvent. Examples of preferred alkylating agents include trialkyl metals such as trimethylaluminum, triethylaluminum; alkyl magnesium halides such as methyl magnesium bromide in the presence of additive compound such as lithium bromide; dialkyl titanium halides such as dimethyl titanium dichloride prepared by dimethylzinc and titanium chloride; and most preferably trimethylaluminum. Examples of preferred inert solvents for the reaction include halogenated hydrocarbons, such as dichloromethane (DCM), 1,2-dichloroethane, chloroform, or carbon tetrachloride; ethers, such as diethyl ether, diisopropylether, 1,2-dimethoxyethane (DME), tetrahydrofuran ( THF) and 1,4-dioxane; hydrocarbons, such as n-hexane, cyclohexane, benzene, and toluene; or mixtures thereof. Reaction temperatures are generally in the range of –100 ° C to 200 ° C, preferably in the range of –40 ° C to 100 ° C. Reaction times are generally 1 minute to 10 days, preferably 1 hour to 24 hours.

Step 11E: In this Step, a compound of the formula (XXXVII) can be prepared by inserting alkoxycarbonyl reaction of the compound of the formula (XXXVI) in a solvent by the procedure described in Step 6E.

Step 11F: In this Step, an acid compound of the formula (XXXVIII) can be prepared by hydrolysis of the compound of the formula (XXXVII) in a solvent by the procedure described in Step 3B-1.

Scheme 12

When R1 is hydrogen, an amine of formula (II) can be prepared as illustrated below.

image15 CH3 R2

R6

R2 R6

N

OR

image2

N STAGE 12A

STAGE 12B

N

N

Ph

image2 R4 image2 N R4

R5 R5

(XXXIX) (XXXX)

R image2 6R2 R image2 6R2 R image2 6 R2 CH3

image16 NH2

image17 NH2

N N

N

N

H

N N

R4

R4N

image2 R4 R5 R5 R

5

(XXXXI) (II)

(XXXXII)

image2

image2

Step 12A: In this Step, the compound of the formula (XXXX) can be prepared by dehydrating the compound of the formula (XXXIX) using a Lewis acid under basic conditions in an inert solvent. Examples of preferred Lewis acids include titanium tetrachloride, aluminum tetrachloride, or zirconium tetrachloride. Examples of preferred bases include an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, ethoxide. sodium, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride; or an amine such as triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine, or dimethylaminopyridine. Examples of suitable solvents include THF; 1,4-dioxane; DMF; acetonitrile; alcohols, such as methanol or ethanol; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform, or carbon tetrachloride; and acetic acid. Reaction temperatures are generally in the range of -78 to 200 ° C, preferably in the range of 0 ° C to room temperature. Reaction times are, in general, from 1 minute to a day, preferably from 1 hour to 20 hours.

Step 12B: In this Step, the compound of formula (XXXXI) can be prepared by reducing the compound of formula (XXXX) in the presence of a suitable reducing agent in an inert solvent or without solvent. Examples of preferred reducing agents include NaBH4, LiAlH4, LiBH4, Fe, Sn or Zn. Reaction temperatures are generally in the range of -78 ° C to room temperature, preferably in the range of -70 ° C to 0 ° C. Reaction times are, in general, from 1 minute to a day, preferably from 3 hours to 6 hours. Examples of suitable solvents include THF; 1,4-dioxane; DMF; acetonitrile; alcohols, such as methanol or ethanol; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform, or carbon tetrachloride, and acetic acid.

The reduction can also be carried out in the presence of a suitable metal catalyst under a hydrogen atmosphere in an inert solvent. Examples of suitable metal catalysts include nickel catalysts such as Raney nickel; Pd-C; palladium-carbon hydroxide; platinum oxide; platinum-carbon; ruthenium-carbon; aluminum oxide - rhodium; and tris [triphenylphosphine] rhodium chloride. Examples of suitable aqueous or nonaqueous inert organic solvents include: alcohols, such as methanol or ethanol; ethers, such as THF or 1,4-dioxane; acetone, dimethylformamide; halogenated hydrocarbons, such as DCM, dichloroethane, or chloroform; and acetic acid; or mixtures thereof. The reaction can be carried out at a temperature in the range of 20 ° C to 100 ° C, preferably in the range of 20 ° C to 60 ° C. Reaction times are, in general, from 10 minutes to 4 days, preferably from 30 minutes to 24 hours. This reaction can be carried out under a hydrogen atmosphere at a pressure ranging from 1 to 100 atmospheres (101.3-10132.5 KPa), preferably from 1 to 10 atmospheres (101.3-1013.3 KPa).

Step 12C: In this Step, the compounds of the formula (XXXXII) can be prepared by hydrogenation of the compound of the formula (XXXXI), for example, under known hydrogenolysis conditions in the presence of a metal catalyst under a hydrogen atmosphere, or in the presence of hydrogen sources such as formic acid or ammonium ormate in an inert solvent. If desired, the reaction is carried out under acidic conditions, for example, in the presence of hydrochloric acid or acetic acid. Examples of preferred metal catalysts include nickel catalysts such as Raney nickel; Pd-C; palladium-carbon hydroxide; platinum oxide; platinum-carbon; ruthenium-carbon; aluminum oxide - rhodium; and tris [triphenylphosphine] rhodium chloride. Examples of suitable aqueous or non-aqueous organic inert solvents include: alcohols, such as methanol or ethanol; ethers, such as THF or 1,4-dioxane; acetone; dimethylformamide; halogenated hydrocarbons, such as DCM, dichloroethane, or chloroform; and acetic acid; or mixtures thereof. The reaction can be carried out at a temperature in the range of 20 ° C to 100 ° C, preferably in the range of 20 ° C to 60 ° C. Reaction times are, in general, from 10 minutes to 4 days, preferably from 30 minutes to 24 hours. This reaction can be carried out under a hydrogen atmosphere at a pressure ranging from 1 to 100 atmospheres (101.3-10132.5 KPa), preferably from 1 to 10 atmospheres (101.3-10132.5 KPa).

Step 12D: In this Step, the compounds of the formula (XXXXIII) can be prepared from the compound of the formula (XXXXII) by salt formation with, for example, hydrogen chloride and methanol solution, 1,4-dioxane solution and aqueous solution. The reaction can be carried out at a temperature in the range of 20 ° C to 100 ° C, preferably in the range of 20 ° C to 60 ° C. Reaction times are generally 10 minutes to 4 days, preferably 30 minutes to 24 hours.

Scheme 13:

When R3 is a fluoroalkyl group, such as trifluoromethyl or pentafluoroethyl, a carboxylic acid of formula (III) can be prepared as illustrated below.

image18

OO

image2 Or Stage 13A

Stage 13B-1 -HO

RO

RO image2 N - image2 NCF3

Stage 13B-2

NO

(XXIX)

(XXXXIV) image2 (III)

(XXXXV)

wherein R is (C1-C6) alkyl or benzyl;

Step 13A: In this Step, an N-oxide compound of the formula (XXXXIV) can be prepared by oxidation of the compound of the formula (XXIX) in a reaction-inert solvent, as described in Step 9A.

Step 13B-1: In this Step, an ester derivative of the trifluoromethyl compound of the formula (III) can be prepared by trifluoromethylation of the compound of the formula (XXXXIV) in a reaction-inert solvent. An example of a preferred trifluoromethylation reagent is (trifluoromethyl) trimethylsilane. The reaction is carried out in the presence of a fluoride or catalytic or stoichiometric source. Examples of preferred fluoride sources are CsF, KF, tetrabutylammonium fluoride, and tetraethylammonium fluoride. Examples of inert solvents for the reaction

Preferred include halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether, DME, THF, and 1,4-dioxane; acetonitrile, DMF, DMSO, or mixtures thereof. Reaction temperatures are generally in the range of -10 ° C to 50 ° C, more preferably in the range of 0 ° C to 25 ° C. Reaction times are generally 1 minute to 10 days, more preferably 20 minutes to 24 hours.

Step 13B-2: In this Step, a compound of formula (III) can be prepared from the product of Step 13B-1 by hydrolysis, as described in Step 3B-1.

Step 13C: In this Step, a trifluoromethyl compound of the formula (XXXXV) can be prepared by trifluoromethylation of the compound of the formula (XXXXIV) in a reaction-inert solvent. An example of a preferred trifluoromethylating reagent is (trifluoromethyl) trimethylsilane. The reaction is carried out in the presence of a base. Examples of preferred bases are potassium t-butoxide, sodium ethoxide and sodium methoxide. Examples of preferred inert solvents for the reaction include halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether, DME, THF, and 1,4-dioxane; acetonitrile, DMF, DMSO, or mixtures thereof. Reaction temperatures are generally in the range of -10 ° C to 50 ° C, more preferably in the range of 0 ° C to 25 ° C. Reaction times are generally 1

25 minutes to 10 days, more preferably 20 minutes to 24 hours.

Step 13D-1: In this Step, an ester derivative of the trifluoromethyl compound of the formula (III) can be prepared by reducing the compound of the formula (XXXXV) in a reaction-inert solvent. This would typically be a hydrogenation at a pressure of 15 mm Hg (2KPa) to 100 mm Hg (13.3 KPa) of hydrogen gas. Reaction temperatures are generally in the range of 20 ° C to 100 ° C, more preferably in the range of

30 20 ° C to 50 ° C. Reaction times are generally 30 minutes to 3 days, more preferably 60 minutes to 6 hours. This reaction is carried out in the presence of a suitable catalyst. Likewise there are no particular restrictions on the nature of the catalyst that is used and any catalyst that is commonly used in reactions of this type can also be used here. Examples of such catalysts include palladium on carbon, palladium hydroxide on carbon, and Raney nickel.

Step 13D-2: In this Step, a compound of formula (III) can be prepared from the product of Step 13D-1 by hydrolysis, as described in Step 3B-1.

Scheme 14:

When R2 is hydrogen, R6 is hydrogen, R4 is hydroxy and R5 is alkyl, a compound of formula (IV) can be prepared as illustrated below.

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twenty

25

30

35

40

R6 image2 H R6

CHO

N R4

image2 N

image2 R4N N

Stage 14A

R5 R5

(XXXXVI) (IV)

Step 14A: A compound of the formula (IV) can be synthesized from the compound of the formula (XXXXVI) and DMF-POCl3. The reaction can generally be carried out without any solvent. The reaction can be carried out at a temperature from -100 ° C to 150 ° C, more preferably from -20 ° C to 100 ° C. The reaction time is generally from 5 minutes to 48 hours, more preferably 30 minutes to 24 hours will normally suffice.

Scheme 15

When R2 is hydrogen, a compound of formula (IV) can be prepared as illustrated below.

RO

R6 image2 R6R6 CHOOHO MH Ox

image2 NN

image2 N

R4 Stage 15A image2 R4 Stage 15B

NN image2 NR4 R5 R5R5

(XXXXVII) (XXXXVIII) (IV)

wherein MH is a suitable metal hydride reducing agent.

Step 15A: A compound of the formula (XXXXVIII) can be prepared by reacting a compound of the formula (XXXXVII) with an appropriate reducing reagent such as lithium aluminum hydride, sodium borohydride or lithium borohydride in a suitable solvent such as toluene. , THF, or diethyl ether. The reaction temperature is generally in the range of -100 to 100 ° C, preferably in the range of 0 ° C to 70 ° C. The reaction time is generally 1 minute to a day, preferably 2 hours to 20 hours.

Step 15B: A compound of formula (IV) can be prepared by reacting a compound of formula (XXXXVIII) with an appropriate oxidizing agent such as "activated" DMSO reagents eg Swern's reagent, Dess-Martin, chlorochromate pyridinium, manganese dioxide, sodium hypochlorite, and ruthenium dioxide.

The various general procedures described above may be useful for the introduction of the desired groups at any stage of the stepwise formation of the required compound, and it will be appreciated that these general procedures may be combined in different ways in such multi-stage processes. The sequence of reactions in multi-stage processes should of course be chosen so that the reaction conditions used do not affect the groups on the molecule that are desired in the final product.

Examples

The invention is illustrated in the following non-limiting examples in which, unless otherwise stated: all operations were carried out at room temperature, that is, in the range of 18-25 ° C; evaporation of the solvent was carried out using a rotary evaporator under reduced pressure with a bath temperature of up to 60 oC; reactions were monitored by thin layer chromatography (TLC) and reaction times are provided as illustration only; the melting points (mp) reported are uncorrected (the polymorphism can yield different melting points); the structure and purity of all isolated compounds were ensured by at least one of the following techniques: TLC (Merck F254 Silica Gel 60 Precoated TLC Plates), Mass Spectrometry, Nuclear Magnetic Resonance (NMR) Spectra, infrared (IR) absorption spectra or microanalysis. Yields are reported for illustrative purposes only. Flash column chromatography was performed using Merck silica gel 60 (ASTM 230-400 mesh) or amino-linked silica from Fuji Silysia (Chromatorex, 30-50 µM) or amino-linked silica from Biotage (35-75 µm, KP-NH) or Biotage silica (32-63 µm, KP-Sil). Purification using HPLC was performed with the following apparatus and conditions. Apparatus: UV firing preparative HPLC system, Waters (Column: XTerra EM C18, 5 µm, 19 x 50 mm or 30 x 50 mm), Detector: UV 254 nm Conditions: CH3CN / 0.05% aqueous HCOOH solution or CH3CN / 0.01% aqueous NH3 solution; 20 ml / min (19 x 50 mm)

or 40 ml / min (30 x 50 mm) at room temperature. The microwave apparatus used in the reaction was Emrys optimizer (Personal chemistry). Optical rotation was measured by P-1020 (Jasco). Low resolution mass spectral (IE) data was obtained on an Integrity mass spectrometer (Waters). Low resolution mass spectral data (IEP) were obtained on a ZMD mass spectrometer (Micromass). NMR data was determined at 270 MHz (JEOL JNMLA 270 spectrometer) or 300 MHz (JEOL JNMLA300 spectrometer) using deuterated chloroform (99.8% D) or DMSO (99.9% D) as the solvent unless otherwise specified. indicate otherwise,

image2

image2

image2

relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); the conventional abbreviations used are: s = singlet, d = doublet, t = triplet, q = quadruplet, quint = quintuplet, m = multiplet, a. = width, etc. IR spectra were measured by a Shimazu infrared spectrometer (IR-470). Chemical symbols have their usual meanings; bp (boiling point), mp (melting point), l (liter (s)), ml (milliliter (s)), g (gram (s)), mg5 (milligram (s)), mol (moles) , mmol (millimoles), eq. (equivalent (s)), quant. (quantitative yield), rt (room temperature), sat. (saturated), aq (aqueous). In the following Examples, "Me" means methyl and "Et" means ethyl.

Preparations

The following Preparations illustrate the preparation of certain amine and carboxylic acid intermediates that are used to prepare the Examples below.

10 Amine 1: (1,5-dimethyl-1H-pyrazol-4-yl) ethanamine dihydrochloride

NH2

2HCl

H3C

A solution of 1- (1,5-dimethyl-1H-pyrazol-4-yl) ethanone (J. Heterocyclic Chem. 1986, 23, 275-279., 2.17 g, 15.7 mmol, containing 14% 1- (1,3-dimethyl-1H-pyrazol-4-yl) ethanone), (R) - (+) - 2-methyl-2-propanesulfinylamide (2.00 g, 16.5mmol) and titanium ethoxide (IV) (9.86 ml, 47.3 mmol) in THF (5 ml) heated at 90 oC for 3 h, then stirred with microwave irradiation (80 oC, 2 h, 90 oC 2 h), it was heated at 90 oC for 14 h. Then an additional quantity of titanium (IV) ethoxide (16.44 ml, 78.7 mmol) was added and the whole mixture was heated at 90 ° C for 24 h. After cooling to room temperature, the resulting mixture was added to a suspension of NaBH4 (4.75 g, 126 mmol) in THF (42 ml) at 0 ° C, then the whole mixture was stirred for 3 h at this temperature. The reaction mixture was quenched by adding MeOH (8 ml) at 0 ° C. Celite was added to the mixture and it was stirred vigorously for 10 min. After that, H2O (4 ml) was added and the resulting mixture was stirred for 60 min. plus. The resulting suspension was filtered through a pad of celite, and the residue was washed well with THF. The combined filtrate was concentrated to provide a dark brown oily material. The crude material was purified by silica gel column chromatography (CH2Cl2: MeOH = 50: 1), followed by an amine gel column (CH2Cl2: MeOH = 200: 1) affording N-1- (1,5-dimethyl -1H-pyrazol-4-yl) ethyl) -2-methylpropane-2-sulfinamide in the form of a mixture enriched in a 25 diastereoisomer (1.26 g, 42% yield, diastereoisomeric ratio approx. 2: 1 by NMR of 1 HOUR). 1H NMR (300 MHz, CDCl3) δ 1.21 (9H, s), 1.49 (3H, d, J = 6.0 Hz), 2.35 (3H, s), 3.18 (1H, bs), 3.88 (3H, s), 4.44-4.52 (1H, m), 7.65 (1H, s). This compound was treated with 10% by weight of HCl-MeOH (4.5 ml), and the reaction mixture was stirred for 2 h at room temperature. After removing all volatiles, the crude material was recrystallized from MeOH / ether to provide 1- (1,5-dimethyl-1H-pyrazol-4-yl) ethanamine dihydrochloride as a

30 white solid (0.44 g, 46% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.47 (3H, d, J = 6.0 Hz), 2.25 (3H, s), 3.72 (3H, s), 4.21- 4.28 (1H, m), 7.63 (1H, s), 8.42 (3H, bs). MS (ESI) m / z 140 (M + H) +.

Amine 2: (1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethanamine dihydrochloride

NH2

2HCl

H3C

Step A2A: (1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) -N - [(1R) -1-phenylethyl] ethanamine

35 1- (1,5-Dimethyl-1H-pyrazol-4-yl) ethanone (J. Heterocyclic Chem. 1986, 23, 275-279., 4.82 g, 34.9 mmol) and (R) -1 -phenylethylamine (5.07 g, 41.9 mmol) in titanium tetraisopropoxide (22.1 g, 77.7 mmol) were stirred at room temperature for 16 hours. Ethanol (30 ml) and THF (30 ml) were added at -20 ° C, then sodium borohydride (3.96 g, 105 mmol) was added at -20 ° C then the whole mixture was stirred for 3 h while heating at room temperature. The reaction was quenched with water (20 ml) and diluted with ethyl acetate-THF. The mixture was then filtered at

40 through celite and washed with ethyl acetate. The filtrate was dried over Na2SO4, concentrated, and purified by silica gel column chromatography eluting with ethyl acetate / n-hexane = 2/1 to 100/0 to provide the title compound (3.44 g, 41% of yield) as a colorless oil. 1H NMR (270 MHz, CDCl3) δ 1.26 (3H, d, J = 6.6 Hz), 1.27 (3H, d, J = 6.6 Hz), 1.96 (3H, s) , 3.44 (1H, q, J = 6.6Hz), 3.60 (1H, q, J = 6.6Hz), 3.76 (3H, s), 7.20-7.38 ( 6H, m).

45 Step A2B: (1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethanamine dihydrochloride

A suspension of the compound from Step A2A (3.44 g, 13.3 mmol) and 10% palladium on carbon (300 mg) in ethanol (80 ml) was stirred at 70 ° C under hydrogen atmosphere (1 atm) for 6 hours. After cooling the mixture to room temperature, the catalyst was removed by filtration through celite, washed with methanol. The filtrate was concentrated to give a colorless oil. The oil was dissolved in methanol and 10% HCl-MeOH (10 ml) was added.

image19

image19

After 30 min, the solvent was removed in vacuo and co-evaporated with toluene and ethyl acetate to provide the title compound (2.48 g, 88% yield,> 99% ee detected by HPLC; DACEL CHIRALPAK AD-H4, 6x250mm, n-hexane / ethanol / Diethylamine = 98/2 / 0.1 ~ 50/50 / 0.1 as eluent, less polar peak, retention time: 11.4 min) as a white solid. 1H NMR (270 MHz, DMSO-d6) δ 1.47 (3H, d, J = 6.6 Hz), 2.24 (3H, s), 3.71 (3H, s), 4.21- 4.28 (1H, m), 7.51 (1H, s), 8.27 (3H, bs).

Amine 3: (R) -4- (1-aminoethyl) -1-methyl-1H-pyrazole-5-carbonitrile dihydrochloride

image20

Step A3A: 5-chloro-N-methoxy-N, 1-dimethyl-1H-pyrazole-4-carboxamide

To a stirring suspension of N, O-dimethylhydroxyamine hydrochloride (0.668 g, 6.85 mmol) and triethylamine (2.60 ml, 18.7

10 mmol) in DMF (6 ml) was added 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid (1.00 g, 6.23 mmol, purchased from Nissan Chemical) and HBTU (2.60 g , 6.85 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate-toluene (1: 1, 200 ml), washed with water (200 ml), saturated aqueous sodium bicarbonate (200 ml), water (200 ml) and brine (200 ml). The organic phase was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on a silica gel column, using ethyl acetate-hexane (1: 1) as

15 eluent to provide the title compound (1.39 g, quant.) As a white solid. 1H NMR (270MHz, CDCl3) δ.ppm 3.34 (3H, s), 3.67 (3H, s), 3.88 (3H, s), 7.93 (1H, s). MS (ESI): m / z 204 (M + H) +

Step A3B: 1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethanone

To a stirring solution of the product from Step A3A (1.39 g, 6.83 mmol) in THF (34 ml) was added demethylmagnesium bromide (0.97 M in THF, 14.1 ml, 13.7 mmol) at 0 ° C, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with brine (30 ml) and 10% citric acid aqueous solution (10 ml), and extracted with ethyl acetate (150 ml 3 times). The combined organic phase was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on a silica gel column eluting with ethyl acetate-hexane

(1: 1) providing a title compound (0.98 g, 91% yield) as a white solid. 1H NMR (270MHz, CDCl3) δ 2.48 (3H, s), 3.88 (3H, s), 7.93 (1H, s). MS (ESI): m / z 159 (M + H) +.

25 Step A3C: 4-acetyl-1-methyl-1H-pyrazole-5-carbonitrile

A mixture of the product from Step A3B (0.96 g, 4.71 mmol) and sodium cyanide (462 mg, 9.43 mmol) in DMF (8 ml) was heated at 100 ° C for 24 hours. After cooling, the reaction mixture was diluted with ethyl acetate-toluene (1: 1, 100 ml), and washed with a 20% aqueous solution of sodium thiosulfate (50 ml), water (50 ml) and brine. (50 ml). The organic phase was dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on a column of

Silica gel eluting with ethyl acetate-hexane (1: 1) to provide the title compound (774 mg, quant.) As a white solid. 1H NMR (270MHz, CDCl3) δ 2.54 (3H, s), 4.11 (3H, s), 7.95 (1H, s). MS (ESI) m / z: no M + peak observed.

Step A3D: (R) -N - ((R) -1- (5-cyano-1-methyl-1H-pyrazol-4-yl) ethyl) -2-methylpropane-2-sulfinamide

To a solution of titanium (IV) ethoxide (4.34 ml, 20.7 mmol) and the product of Step A3C (400 mg, 2.07 mmol) in

35 THF (4.34 ml), (R) - (+) - tert-butanosulfinamide (276 mg, 2.26 mmol) was added under nitrogen atmosphere and the mixture was heated at 80 ° C for 16 hours. After cooling, the reaction mixture was added dropwise to a suspension of sodium borohydride (235 mg, 6.21 mmol) in THF (10 ml) at 0 ° C over 30 minutes. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was carefully quenched with MeOH and water, and the formed precipitate was removed by filtering through celite, washing with ethyl acetate. The organic phase was dried over

Sodium sulfate, concentrated, purified by silica gel eluting with ethyl acetate-hexane (4: 1 to 1: 0) to provide the title compound as a colorless oil (473 mg, 90% yield). 1H NMR (270MHz, CDCl3) δ 1.24 (9H, s), 1.59 (3H, d, J = 6.6Hz), 3.45 (1H, sa), 4.04 (3 H, s), 4.57-4.75 (1H, m), 7.54 (1H, s). MS (ESI) m / z: 255 (M + H) +.

Step A3E: (R) -4- (1-aminoethyl) -1-methyl-1H-pyrazole-5-carbonitrile dihydrochloride

A mixture of the product from Step A3D (200 mg, 0.786 mmol) in 10% solution of hydrochloric acid in ethanol (3 ml) was stirred at room temperature for 3 hours. The reaction mixture was evaporated and dried in vacuo to provide the crude title compound as a white solid (284 mg). This crude product was used for the next step without further purification. 1H NMR (270 MHz, DMSO-d6) δ 1.09 (9 H, s), 1.57 (3 H, d, J = 7.3 Hz), 4.01 (3 H, s), 4 , 28-5.00 (3H, m), 7.96 (1H, s), 8.77 (2H, bs). MS (ESI): m / z 134 (M + H -NH2) +.

50 Amine 4: (R) - (4- (1-aminoethyl) -1-methyl-1H-pyrazol-5-yl) methanol dihydrochloride

CH3

image21

Step A4A: 1- (5- (bromomethyl) -1-methyl-1H-pyrazol-4-yl) ethanone

To a stirring solution of 1- (1,5-dimethyl-1H-pyrazol-4-yl) ethanone (471 mg, 3.42 mmol) in THF (13 ml) was added N-bromosuccinimide (637 mg, 3, 58 mmol) and benzoyl peroxide (41 mg, 0.17 mmol) at room temperature in

5 nitrogen atmosphere, then the resulting mixture was refluxed for 20 h. After cooling, the reaction mixture was evaporated to remove solvents. The residue was chromatographed on a silica gel column eluting with ethyl acetate-hexane (1: 1) to provide the title compound as a white solid (574 mg, 78% yield). 1H NMR (270 MHz, CDCl3) δ

2.47 (3H, s), 3.91 (3H, s), 4.87 (2H, s), 7.83 (1H, s). MS (ESI) m / z: 217 (M + H) +.

10 Step A4B: (4-acetyl-1-methyl-1H-pyrazol-5-yl) methyl acetate

A mixture of the product from Step A4A (574 mg, 2.64 mmol), potassium acetate (519 mg, 5.29 mmol), 18-crown-6 (140 mg, 0.529 mmol) and acetonitrile (11 ml) was stirred at room temperature for 20 hours. After the solvent was removed in vacuo, the residue was diluted with brine (50 ml) and extracted with ethyl acetate (50 ml, 3 times). The combined organic extracts were dried over sodium sulfate and concentrated. The residue is

Chromatographed on a silica gel column eluting with ethyl acetate-hexane (1: 1) to provide the title compound as a white solid (536 mg, 100% yield). 1H NMR (270MHz, CDCl3) δ 2.09 (3H, s), 2.47 (3H, s), 3.92 (3H, s), 5.48 (2H, s), 7.86 (1H, s). MS (ESI) m / z 197 (M + H) +.

Step A4C: (R) -N - ((R) -1- (5- (hydroxymethyl) -1-methyl-1H-pyrazol-4-yl) ethyl) -2-methylpropane-2-sulfinamide

The title compound was prepared by the same procedure as Amine 1 to provide the compound of the

Title as a white solid (259 mg, 45% yield). 1H NMR (270 MHz, CDCl3) δ 1.19 (9 H, s), 1.54 (3 H, d, J = 7.3 Hz), 3.66 (1 H, m), 3.99 (3H, s), 4.42-4.62 (2H, m), 4.83 (1H, da, J = 13.8Hz), 5.41 (1H, dd, J = 4 , 6Hz, 9.2Hz), 7.65 (1H, s). MS (ESI) m / z: no M + peak observed.

Step A4D: (R) - (4- (1-aminoethyl) -1-methyl-1H-pyrazol-5-yl) methanol dihydrochloride

The title amine was prepared by the same procedure as Amine 1 to provide the title compound

25 as a white solid (133 mg, 88% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.48 (3 H, d, J = 6.6 Hz), 3.79 (3 H, s), 4.07-4.95 (6 H, m), 7.53 (1H, s), 8.29 (2H, da). MS (ESI) m / z: no M + peak observed.

Amine 5: 1- (1,5-dimethyl-1H-pyrazol-4-yl) propan-1-amine dihydrochloride

CH3

NH2

2HCl

H3C

Step A5A: (E) -N - ((1,5-dimethyl-1H-pyrazol-4-yl) methylene) -2-methylpropane-2-sulfinamide

30 A mixture of 1,5-dimethyl-1H-pyrazole-4-carbaldehyde (Zhurnal Obshchei Khimii 1980, 50, 2370-5, 2.0 g, 16.1 mmol), tert-butylsulfinamide (2.05 g, 16 , 9 mmol), and Ti (OEt) 4 (6.76 ml, 32.2 mmol) in THF (32 ml) was heated under reflux for 18 h under nitrogen atmosphere. After cooling to room temperature, the mixture was poured into brine (32ml) with stirring. The resulting suspension was filtered through a pad of Celite, and the filter cake was washed with EtOAc. The filtrate was transferred to a separatory funnel, and the organic phase was washed with brine. The aqueous phase is then

Washed with EtOAc and the combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography (CH2Cl2: MeOH = 50: 1-30: 1) to provide the desired product as a white solid (3.55 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ 1.23 (9H, s), 2.52 (3H, s), 3.83 (3H, s), 7.81 (1H, s), 8.49 ( 1H, s). MS (ESI) m / z 228 (M + H) +

Step A5B: N- (1- (1,5-dimethyl-1H-pyrazol-4-yl) propyl) -2-methylpropane-2-sulfinamide

40 To a solution of (E) -N - ((1,5-dimethyl-1H-pyrazol-4-yl) methylene) -2-methylpropane-2-sulfinamide (Step A5A) (600 mg, 2.64 mmol) in CH2Cl2 (15 ml) a 3.0 M solution of Et MgBr in ether (1.76 ml, 5.28 mmol) was added at -48 ° C under nitrogen atmosphere. After stirring for 120 min, the reaction mixture was allowed to warm to room temperature slowly over 2 hr and further stirred for 15 hr at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl, diluted with water, and the aqueous phase was extracted with CH2Cl2 3 times.

image22

The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (CH2Cl2: MeOH = 50: 1 to 20: 1) to provide the desired product as a light yellow oil (650 mg,> 96% yield). 1H NMR (270 MHz, CDCl3) δ 0.87 (3H, t, J = 5.4 Hz), 1.17 (9H, s), 1.77-1.85 (2H, m), 2, (3H, s), 3.78 (3H, s), 3.31 (1H, bs), 4.16-4.22 (1H, m), 7.31 (1H, 5 s).

Step A5C: 1- (1,5-dimethyl-1H-pyrazol-4-yl) propan-1-amine dihydrochloride

N- (1- (1,5-dimethyl-1H-pyrazol-4-yl) propyl) -2-methylpropane-2-sulfinamide (Step A5B) (650 mg, 1.8 mmol) was dissolved in 10% HCl in MeOH (5 ml) and the resulting mixture was stirred for 15 h. The mixture was concentrated to provide a light yellow solid, which was recrystallized (MeOH-ether) to provide the title product as a solid.

10 blank (460mg,> 99% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.76 (3H, t, J = 6.0 Hz), 1.70-1.84 (1H, m), 1.89-2.03 (1H , m), 2.23 (3H, s), 3.72 (3H, s), 3.96-4.03 (1H, m), 7.54 (1H, s), 8.35 (3H, sa).

Amine 6: 1- (5-Methyl-1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) ethanamine dihydrochloride

NH2

2HCl

Step A6A: 1- (5-Methyl-1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) ethanone

15 To a solution of 3- (ethoxymethylene) pentane-2,4-dione (Perkin 1. 2000, 1455-1460, 1.95 g, 12.5 mmol) in MeOH (33 ml) was added a solution of 2, 2,2-trifluoroethylhydrazine (1.54 g, 13.5 mmol) and concentrated HCl (2.6 ml) in MeOH (10 ml) (previously cooled to 0 oC) dropwise at -15 oC. The resulting mixture was then stirred for 24 h at room temperature. After removal of the solvent at room temperature, the residue was made basic with 2N aqueous NaOH, and the aqueous phase was extracted several times with EtOAc. The combined organic extracts are

Dried over Na2SO4, and concentrated in vacuo to provide the crude product as a single regioisomer (1.41 g, 51% yield). 1H NMR (300 MHz, CDCl3) δ 2.46 (3H, s), 2.62 (3H, s), 4.66 (1H, d, J = 6.0 Hz), 4.72 (1H, d, J = 9.0 Hz), 7.92 (1H, s). MS (ESI) m / z 207 (M + H) +.

Step A6B: 1- (5-Methyl-1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) ethanamine dihydrochloride

The title compound was prepared in> 99% yield by the same process as described for

25 (R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethanamine dihydrochloride (Amine 2) using 1- (5-methyl-1- (2,2,2-trifluoroethyl) -1H- pyrazol-4-yl) ethanone (Step A6A) as a starting material. 1H NMR (300 MHz, DMSO-d6) δ 1.49 (3H, d, J = 6.0 Hz), 2.32 (3H, s), 4.29-4.33 (1H, m), 5.07 (1H, d, J = 9.0Hz), 5.13 (1H, d, J = 9.0Hz), 7.72 (1H, s), 8.34 (3H, sa).

Amine 7: (1R) -1- (5-Methyl-1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) ethanamine dihydrochloride

NH2

image23

image24

2HCl

30

Step A7A: (1R) -1- [5-Methyl-1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl] -N - [(1R) -1-phenyl

ethyl] ethanamine

To a stirring solution of 1- [5-methyl-1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl] ethanone (10.5 g, 50.7 mmol) in CH2Cl2 (150 ml ) (R) -1-Phenylethylamine (7.4 ml, 58 mmol), titanium tetrachloride (3.9 ml, 36 mmol) and Et3N (27 ml, 190 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 18 hours to provide a solution of the desired imine in CH2Cl2. Then, to this solution, MeOH (80 ml) was added and the mixture was cooled to 0 ° C, then sodium borohydride (5.75 g, 152 mmol) was added. The reaction mixture was stirred at 0 ° C for 2 hours and then quenched with saturated aqueous NaHCO3 at 0 ° C. The mixture was extracted with AcOEt and the combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with 2/1 to 1/1 ethyl acetate / n-hexane) to provide the title compound (1,5-substituted product 1.26 g, 8, 0%) in the form of a yellowish oil. The chemical structure (1,5-substitution on the pyrazole ring) was determined by NMR analysis (1H, 13C-1D, DEPT, COZY, HMBC, HMQC, NOESY). 1H NMR (300 MHz, DMSO-d6) δ 1.16 (3H, d, J = 6.6 Hz), 1.17 (3H, d, J = 6.6 Hz), 1.88 (3H , s), 3.24-3.42 (2H, m), 4.95 (1H, d, J = 8.8 Hz), 5.01 (1H, d, J = 8.8 Hz), 7 , 16-7.24 (3H, m), 7.25-7.34 (2H, m), 7.46 (1H, s).

Step A7B: (1R) -1- (5-Methyl-1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) ethanamine dihydrochloride

To a stirred suspension of the product of Example A7A (1.46 g, 4.05 mmol) in EtOH (50 ml) was added Pd / C (100 mg) and the resulting mixture was stirred at 80 ° C under H2 atmosphere. After 5 hours, the catalyst was removed by filtration through a pad of celite, washed with MeOH and the combined filtrate and the rinses were concentrated at

5 empty. The residue was dissolved in MeOH and 10% MeOH-HCl. And then the mixture was stirred for 30 min. After further removing the Pd catalyst by filtration, the filtrate and rinses were concentrated in vacuo to provide the title compound (1.10 g, 97%) as a yellowish solid. 1H NMR (300 MHz, DMSO-d6) δ 1.48 (3H, d, J = 6.6 Hz), 2.31 (3H, s), 4.24-4.41 (1H, m), 5.07 (1H, d, J = 9.5Hz), 5.13 (1H, d, J = 9.5Hz), 7.70 (1H, s), 8.19-8.87 (2H , sa).

10 Amine 8: 2- (4- (1-aminoethyl) -5-methyl-1H-pyrazol-1-yl) methyl acetate dihydrochloride

image25

Step A8A: methyl 2- (4-acetyl-5-methyl-1H-pyrazol-1-yl) acetate

To a solution of 3- (ethoxymethylene) pentane-2,4-dione (Perkin 1. 2000, 1455-1460, 1.95 g, 12.5 mmol) in MeOH (33 ml) was added to ethyl hydrazinoacetate hydrochloride solution (2.09 g, 13.5 mmol) and concentrated HCl (2.6 ml) in 15 MeOH (10 ml) (previously cooled to 0 oC) dropwise to -15 oC. The resulting mixture was then stirred for 24 hours at room temperature. After removal of the solvent at room temperature, the residue was made basic with 2N aqueous NaOH and the aqueous phase was extracted several times with EtOAc. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The aqueous phase was acidified to pH 1 with 2N aqueous HCl and extracted with EtOAc 6 times. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo.

Yielding crude 2- (4-acetyl-5-methyl-1H-pyrazol-1-yl) acetic acid as a mixture of regioisomers (1.17 g, <51% yield), 1H NMR ( 300 MHz, DMSO-d6) δ 2.37 (3H, s), 2.43 (3H, s), 4.99 (2H, s), 7.81 (1H, s), 13.2 (1H, sa).

To a solution of 2- (4-acetyl-5-methyl-1H-pyrazol-1-yl) acetic acid (1.17 g, 6.42 mmol, as a mixture of regioisomers from the previous step) in MeOH (8.8 ml) -toluene (30.6 ml) a 2M solution of

25 (trimethylsilyl) diazomethane in ether (4.8 ml, 9.6 mmol) dropwise at 0 ° C. The resulting solution was allowed to warm to room temperature and stirred for 120 min. The reaction was quenched by addition of AcOH (3 mL) and the solvent was concentrated in vacuo. The crude product was purified by silica gel column chromatography (CH2Cl2: MeOH = 30: 1) to provide the desired product together with a mixture of regioisomers (> 99% yield). 1H NMR (270MHz, CDCl3) δ 2.45 (3H, s), 2.53 (3H, s), 3.79 (3H, s), 4.90 (2H, s), 7.88 ( 1H, s).

30 Step A8B: 2- (4- (1-aminoethyl) -5-methyl-1H-pyrazol-1-yl) methyl acetate dihydrochloride

The title compound was prepared in 6.6% yield by the process described for (R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethanamine dihydrochloride (Amine 2) using 2 - Methyl (4-acetyl-5-methyl-1H-pyrazol-1-yl) acetate (Step A8A) as a starting material. 1H NMR (300 MHz, DMSO-d6) δ 1.48 (3H, d, J = 6.0 Hz), 2.22 (3H, s), 3.69 (3H, s), 4.29- 4.33 (1H, m), 5.05 (2H, s), 7.59 (1H, s), 8.26 (3H, bs).

35 Amine 9: 1- (5-Methyl-1H-pyrazol-4-yl) ethanamine dihydrochloride

NH2

2HCl

Step A9A: 5-Methyl-1H-pyrazole-4-carbaldehyde

POCl3 (8.9 ml, 95.5 mmol) was added slowly to DMF (14.8 ml) under nitrogen atmosphere at 0 ° C, and the resulting mixture was stirred for 15 min at this temperature. Acetone semicarbazone (5 g, 43.440 mmol) was added portionwise to this mixture, and the reaction mixture was heated at 70 ° C for 4 h. The reaction mixture was poured onto ice and neutralized with 2N aqueous NaOH and heated at 50-60 ° C for 5 min, cooled, and acidified to pH 6 with 2N aqueous HCl. The solution was extracted with AcOEt 3 times and the combined organic extracts were dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (hexane: AcOEt = 1: 2) to provide the desired product as a white solid (2.49 g, 52.1% yield). 1H NMR (300MHz, CDCl3) δ 2.61 (3H, s), 8.03 (1H, s), 9.97 (1H, s). MS (ESI) m / z 109 (MH) -, 111 (M

+ H) +.

image26

Step A9B: (E) -2-methyl-N - ((5-methyl-1H-pyrazol-4-yl) methylene) propane-2-sulfinamide

The title compound was prepared in 85% yield by a procedure similar to the preparation of (E) -N - ((1,5-dimethyl-1H-pyrazol-4-yl) methylene) -2-methylpropane-2 -sulfinamide (Step A5A) as described above. 1H NMR (300MHz, CDCl3) δ 1.24 (9H, s), 2.56 (3H, s), 7.93 (1H, s), 8.57 (1H, s).

5 Step A9C: 2-Methyl-N- (1- (5-methyl-1H-pyrazol-4-yl) ethyl) propane-2-sulfinamide

To a solution of (E) -2-methyl-N - ((5-methyl-1H-pyrazol-4-yl) methylene) propane-2-sulfinamide (Step A9B) (2.1 g, 9.29 mmol) in THF (45 ml) a 1 M solution of Me MgBr in THF (27.9 ml, 27.9 mmol) was added at -48 ° C under nitrogen atmosphere. After stirring for 60 min, the reaction mixture was allowed to warm to room temperature and then heated at 90 ° C for 4 hours. The reaction was quenched by adding saturated aqueous solution of

10 NH4Cl, was diluted with water, and the aqueous phase was extracted with AcOEt three times. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to provide the crude material (1.43 g, 67% yield), which was used in the next reaction without further purification. 1H NMR (300 MHz, CDCl3) δ 1.19 (9H, s), 1.56 (3H, d, J = 9.0 Hz), 2.31 (3H, s), 3.35 ( 1H, da, J = 3.0Hz), 4.50-4.54 (1H, m), 7.45 (1H, s).

Step A9D: 1- (5-Methyl-1H-pyrazol-4-yl) ethanamine dihydrochloride

The title compound was prepared in 88% yield by a procedure similar to the preparation of 1- (1,5-dimethyl-1H-pyrazol-4-yl) propan-1-amine dihydrochloride (Amine 5) such as described above. 1H NMR (300 MHz, DMSO-d6) δ 1.48 (3H, d, J = 6.0 Hz), 2.24 (3H, s), 4.24-4.31 (1H, m), 7.68 (1H, s), 8.23 (3H, s).

Amine 10: (S) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethanamine dihydrochloride and Amine 10a: (R) -1- (5-chloro-1-methyl-1H-pyrazole -4-yl) ethanamine dihydrochloride

CH3 CH3

image2

image2

image2

N image2 NH2 .2HCl N image2 NH2 .2HCl and

NN Cl Cl 20 H3C H3C

Step A10A: 1-methyl-1H-pyrazol-5-ol

3-Methoxyacrylic acid methyl ester (4 g, 34.45 mmol) was dissolved in methanol (50 mL) and cooled to 00C. Methylhydrazine (1.75 g, 37.9 mmol) in methanol (20 ml) was added dropwise over 30 minutes. The reaction was stirred at room temperature for 10 minutes then refluxed for 4 hours. The reaction is then

25 was concentrated and purified by silica gel column chromatography eluting with ethyl acetate / methanol = 100/0 to 80/20 to recover the title product as a white solid (2.5 g, 73% yield ). 1H NMR (400 MHz, DMSO-d6) δ 3.46-3.47 (3H s) 5.28-5.29 (1H d) 7.06-7.08 (1H d) 10.75-10, 81 (1H sa)

Step A10B: 5-chloro-1-methyl-1H-pyrazole-4-carbaldehyde

N, N-Dimethyl formamide (2980 mg, 40.8 mmol) was added to 1-methyl-1H-pyrazol-5-ol (1000 mg, 10.19 mmol). Later

30 added phosphorous oxychloride (7.46 ml, 81.5 mmol) dropwise over 10 minutes. The reaction was then heated to 800C for 6 hours. The reaction was concentrated in vacuo and the crude material was neutralized with saturated aqueous NaHCO3 solution. The product was then extracted with ethyl acetate (2 x 25 ml), the combined organic phases were washed with brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo to provide the title product as a brown oil which formed a crystalline solid on standing (1130 mg, 77%

35 performance). 1H NMR (400MHz, CD3OD) δ 3.84-3.87 (3H s) 7.95-7.97 (1H d) 9.76-9.78 (1H d).

Step A10C: (R, E) -N - ((5-chloro-1-methyl-1H-pyrazol-4-yl) methylene) -2-methylpropane-2-sulfinamide

5-chloro-1-methyl-1H-pyrazole-4-carbaldehyde (1130 mg, 7.82 mmol) was suspended in THF (20 ml), Ti (OEt) 4 (4.29 ml, 16.4 mmol) was added followed by (R) - (+) - 2-methyl-2-propanesulfinamide and the reaction was refluxed for 18 hours. The reaction was then cooled to room temperature, poured into EtOAc: brine (20 mL: 20 mL) filtered through

40 celite and washed with EtOAc (2x20 ml). The organic phase was then separated, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated to provide the title compound as a viscous brown oil (1690 mg, 87.3% yield). 1H NMR (400 MHz, CDCl3) δ 1.22-1.23 (9Hs) 3.88 (3Hs) 7.92 (1Hs) 8.43 (1Hs) MS (ESI / APCI) m / z 248 (M + H) +

Step A10D: (R) -N - ((S) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2-methylpropane-2-sulfinamide

45 (R, E) -N - ((5-chloro-1-methyl-1H-pyrazol-4-yl) methylene) -2-methylpropane-2-sulfinamide (100 mg, 0.404 mmol) was dissolved in dichloromethane (10 ml) was introduced under a nitrogen atmosphere and cooled to -780C. A 1.4M methylmagnesium bromide solution (toluene: THF 3: 1, 1.04 mL, 1.45 mmol) was added dropwise and the reaction was stirred overnight while warming to room temperature. Saturated aqueous ammonium chloride solution (20 ml) was added to the reaction and stirred for 5 minutes. The product was extracted with EtOAc (2x15 ml), the combined organic phases were

50 washed with brine (15 ml), dried over Na2SO4, filtered and concentrated and purified by silica gel column chromatography eluting with heptane / ethyl acetate = 100/0 to 0/100 to provide the title product in form of a clear gum (57 mg, 53% yield). 1H NMR (400 MHz, CD3OD) δ 1.18-1.19 (9H s) 1.54-1.56 (3H d) 3.81-3.82 (3H s) 4.41-4, 47 (1Hq) 7.50-7.51 (1H s) MS (ESI) m / z 264 (M + H) +

Step A10E: (S) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethanamine dihydrochloride

(R) -N - ((S) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2-methylpropane-2-sulfinamidamide (48 mg, 0.18 mmol) is dissolved endichloromethane (5 mL), then 4M HCl in dioxane (0.91 mL, 3.64 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was then concentrated to provide the hydrochloride salt of the title compound.

5 as a white gum (38 mg, 90% yield). NMR (400 MHz, CD3OD) δ 1.60-1.63 (3H d) 3.85-3.86 (3H s) 4.39-4.45 (1Hq) 7.68 (1H s) MS ( IEP / APCI) m / z 160 (M + H) +

Step A10F: (S, E) -N - ((5-chloro-1-methyl-1H-pyrazol-4-yl) methylene) -2-methylpropane-2-sulfinamide

5-chloro-1-methyl-1H-pyrazole-4-carbaldehyde (500 mg, 3.46 mmol) was suspended in THF (20 ml), Ti (OEt) 4 (1.51 ml, 7.26 mmol) was added followed by (S) - (+) - 2-methyl-2-propanesulfinamide (440 mg, 3.63 mmol) and the reaction was heated under reflux

10 for 6 hours. The reaction was then cooled to room temperature, poured into EtOAc: brine (20 ml: 20 ml), filtered through celite and washed with EtOAc (2x20 ml). The organic phase was then separated, washed with brine (20 ml), dried over Na2SO4, filtered and concentrated to provide the title compound as a viscous brown oil (760 mg, 88.7% yield). 1H NMR (400 MHz, CDCl3) δ 1.22-1.23 (9H s) 3.88 (3H s) 7.92 (1H s) 8.43 (1H br. S) MS (ESI / APCI ) m / z 248 (M + H) +

15 Step A10G: (S) -N - ((R) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2-methylpropane-2-sulfinamide

(S, E) -N - ((5-chloro-1-methyl-1H-pyrazol-4-yl) methylene) -2-methylpropane-2-sulfinamide (750 mg, 3.03 mmol) was dissolved in THF (25 ml) was introduced under a nitrogen atmosphere and cooled to -780C. A 1.4M methyl magnesium bromide solution (toluene: THF 3: 1, 8.65 mL, 12.1 mmol) was added dropwise and the reaction was stirred overnight while warming to room temperature. Saturated aqueous ammonium chloride solution (20 ml) was added to the reaction and

20 stirred for 5 minutes. The product was extracted with EtOAc (2x15 ml), the combined organic phases were washed with brine (15 ml), dried over Na2SO4, filtered and concentrated to provide the title product as a brown gum (690 mg, 86 , 4% yield). 1H NMR (400 MHz, CDCl3) δ 1.18-1.19 (9H s) 1.55-1.57 (3H d) 1.62-1.64 (3H s) 3.20-3, 22 (1H d) 4.41-4.47 (1H q) 7.42 (1H s) MS (ESI) m / z 264 (M + H) +

Step A10H: (R) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethanamine dihydrochloride

25 (S) -N - ((R) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2-methylpropane-2-sulfinamidamide (690 mg, 2.62 mmol) It was dissolved in dichloromethane (5 ml), then 4M HCl in dioxane (6.54 ml, 26.2 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was then concentrated to provide the hydrochloride salt of the title compound as a light brown solid (600mg, 98.6% yield). NMR (400 MHz, CD3OD) δ 1.60-1.63 (3H d) 3.85-3.86 (3H s) 4.39-4.45 (1Hq) 7.68 (1H s) MS ( IEP / APCI) m / z 160 (M + H) +

30 Amine 11: (S) -1- (1-Methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethanamine dihydrochloride and Amine 11a: (R) -1- (1-Methyl-5- (trifluoromethyl ) -1H-pyrazol-4-yl) ethanamine, dihydrochloride

H3C image2 H3C image2

image2 NH2 .2HCl

NH2 .2HCl

and

N image2 N image2 N CF3 N CF3

image2

CH3 CH3

Step A11A: Ethyl 1-methyl-5- (trifluoromethyl) -1H-pyrazole-4-carboxylate

Ethyl 2- (Ethoxymethylene) -4,4,4-trifluoro-3-oxobutanoate (10 g, 0.042 mol) was dissolved in ethanol (120 ml) and cooled to 0 ° C. Methyl hydrazine (2.11g, 0.046 mol) (pre-stirred in concentrated HCl (4 ml) -EtOH (4 ml), 0 ° C, 30min) in EtOH (20 ml) was added at 0 ° C, and the resulting solution was stirred at room temperature for 18 h. The yellow solution was evaporated and the residue was suspended in water and made basic with sodium carbonate solution (saturated) and extracted with ethyl acetate (3x30 ml). The organic phase was separated and washed again with brine (2x30 ml). The organic phase

40 was separated, dried (Na2SO4), filtered and evaporated to provide an oil. Yield 7 g. 1H NMR (300 MHz, CDCl3) shows a 6: 1 ratio of the desired regioisomer. The oil was dissolved in dichloromethane and purified using an ISCO Companion (70 g silica column, heptane to ethyl acetate: heptane 1: 1). The appropriate fractions were combined and evaporated to provide a colorless oil, 5.71 g, 62% yield. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H) 4.36, 4.34, 4.32, 4.30 (q, 2H) 4.08 (s, 3H) 1.38, 1.36, 1.34 (t, 3H). MS (ESI): m / z 223

45 (M + H) +. LC-MS ELSD 100% m / z 223 (M + H) +. TLC ethyl acetate: heptane 1: 1 0.7 UV + ve

Step A11B: (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) methanol

LiBH4 in THF (2M, 15 mL, 0.03 mol) was added dropwise to a stirring solution of 1-methyl-5- (trifluoromethyl) -1H-pyrazole-4-carboxylate ethyl ester (3.32 g, 0.015 mol) in THF (40 ml) at room temperature under nitrogen atmosphere. The solution was then stirred under reflux for 18 h. After cooling, the cloudy solution was evaporated at room temperature to provide an oil. Water (white solid weighed) was added and the mixture was cooled and cautiously treated with hydrochloric acid (2M) at pH 2 (until no solid remained, providing an oil). The mixture was neutralized with sodium carbonate and the mixture was extracted with diethyl ether (3x20 ml). The organic phase was separated and washed again with brine (3x30 ml). The organic phase was separated, dried (Na2SO4), filtered and evaporated to provide an oil. Yield 3 g. An aliquot (150 mg) was dissolved in dichloromethane and

purified using an ISCO Companion (column of 4 g silica CH2Cl2 to CH2Cl2: ethyl acetate 9: 1). The appropriate fractions were combined and evaporated to provide an oil, 72 mg. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H) 4.69, 4.48 (d, 2H) 4.00 (s, 3H) 1.70, 1.68, 1.67 ( t, 1H). MS (ESI) m / z 181 (M + H) +. LC-MS m / z 181 (M + H) GC-MS FID 100% CI + 181 (M + H) +. TLC CH2Cl2: ethyl acetate 9: 1 0.25 UV-ve DNPH + ve.

Step A11C: 1-methyl-5- (trifluoromethyl) -1H-pyrazole-4-carbaldehyde

The crude alcohol (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) methanol (2.57 g, 0.014 mol) was dissolved in dichloromethane (30 ml) and added to a stirred suspension of 1,1,1-triacetoxy-1,1-dihydro-1,2-benzodoxol-3 (1H) -one (Dess-Martin periodinane, 7.26 g, 0.017 mol) in dichloromethane (80 ml). (An exothermic reaction was observed which was controlled by cooling with an ice bath). The mixture was stirred while warming to room temperature overnight and the dichloromethane was reduced to ~ 40 ml under vacuum at room temperature. Diethyl ether (200 ml) was added and the mixture was poured into stirring sodium hydroxide solution. (1.3M, 150 ml) and the mixture was stirred until the turbidity disappeared. The organic phase was separated and washed again with sodium hydroxide solution (1.3M, 100 ml) and brine (2x100 ml). The organic phase was separated, dried (Na2SO4), filtered and evaporated to give a solid. Yield 2.0 g. The solid was dissolved in dichloromethane and purified using an ISCO Companion (column of 40 g of silica and hexane to CH2Cl2). The appropriate fractions were combined and evaporated at room temperature to provide a solid. Yield 1.45g, 57%. 1H NMR (400MHz, CDCl3) δ 10.05 (s, 1H) 8.02 (s, 1H) 4.08 (s, 3H). TLC CH2Cl2 0.6 UV + ve. GC-MS FID purity 100% CI +. observed m / z 177, 179, 196.

Step A11D: (R, E) -2-methyl-N - ((1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) methylene) propane-2-sulfinamide

1-Methyl-5- (trifluoromethyl) -1H-pyrazole-4-carbaldehyde (1.0 g, 0.0056 mol) was dissolved in THF (20 ml) and Ti (OEt) 4 (2.56 g, 0.011 mol) in THF (5 ml) and the solution was stirred under a nitrogen atmosphere. (R) - (+) - 2-methyl-2-propanesulfinamide (680 mg, 0.0056 mol) was added in a single portion and the reaction was stirred under reflux and under nitrogen for 6 hours. The solution was cooled to 0-5 ° C and added to a cold mixture of brine and ethyl acetate (1: 1, 120 ml) with rapid stirring. The mixture was filtered through Celite and the solids were washed with more ethyl acetate. The organic phase was separated and washed again with brine (2x60 ml). The organic phase was separated, dried (Na2SO4), filtered and evaporated to give a cloudy oil. Yield 1.7 g. The oil was dissolved in dichloromethane and purified using an ISCO Companion (40 g silica column, hexane to hexane: 1: 1 ethyl acetate). The appropriate fractions were combined and evaporated to provide an oil, which solidified on standing. Yield 1.43g, 90%. 1H NMR (400MHz, CDCl3) δ 8.63 (s, 1H) 8.02 (s, 1H) 4.07 (s, 3H) 1.25 (s, 9H). MS (ESI) m / z 282 (M + H) +. LC-MS ESLD 100% m / z 282 (M + H) +. TLC ethyl acetate: heptane 1: 1 0.8 UV + ve. GC-MS CI + m / z 282 (M + H) +.

Step A11E: (R) -N - ((S) -1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2-methyl

propane-2-sulfinamide

Methylmagnesium chloride (3M in diethyl ether, 3.56 ml, 0.0107 mol) was added dropwise to a stirring solution of (R, E) -2-methyl-N - ((1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) methylene) propane-2-sulfinamide (1.0 g, 0.035mol) in dichloromethane (30 ml) at -70 ° C under nitrogen atmosphere. The mixture was allowed to warm to room temperature to provide a cloudy solution and the solution was stirred overnight at room temperature under a nitrogen atmosphere. Ammonium chloride solution (saturated) was added slowly dropwise to quench the reaction. The mixture was diluted with water and extracted with ethyl acetate (3x20 ml). The organic phase was separated and washed again with brine (2x30 ml). The organic phase was separated, dried (Na2SO4), filtered and evaporated to provide an oil. Yield 1.1 g. 1H NMR (300 MHz CDCl3) 4.5: 1 ratio of diastereoisomers. The diastereoisomers were separated by silica gel chromatography using 20:80 IPA / heptane. The upper diastereoisomer (100%) was isolated. Yield 660mg, 62%. 1H NMR (400 MHz CD3OD) δ 7.48 (s, 1H) 4.79, 4.78, 4.76, 4.75, 4.73 (quin, 1H) 3.23, 3.21 (d , 1H) 1.58, 1.57 (d, 3H) 1.21 (s, 9H). MS (ESI) m / z 298 (M + H) +. GC-MS CI + 298 (M + H) +. TLC CH2Cl2: MeOH: NH4OH 95: 5: 0.5 0.3 UV-ve I2 + ve. [α] D = -13.94 or (c 1.65, CH3OH).

Step A11F: (R) -N - {(1R) -1- [1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl] ethyl} -2-methyl propane-2-sulfinamide

The lower diastereoisomer (100%) was isolated. Yield 130mg, 12%. 1H NMR (400MHz CD3OD) δ 7.53 (s, 1H) 4.77, 4.76, 4.75, 4.74, 4.73 (quin, 1H) 3.38, 3.39 (d , 1H) 1.53, 1.52 (d, 3H) 1.22 (s, 9H). MS (ESI) m / z 298 (M + H) +. GC-MS CI + 298 (M + H) +. TLC CH2Cl2: MeOH: NH4OH 95: 5: 0.5 0.28 UV-ve I2 + ve.

Step A11G: (S) -1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethanamine dihydrochloride

(R) -N - ((S) -1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2-methylpropane-2-sulfinamide (0.66 g, 0, 0022 mol) was dissolved in HCl in dioxane (4M, 12 ml) and the solution was stirred at room temperature overnight under nitrogen atmosphere. The solution was evaporated and the residue was suspended in ether and the white solid was removed by filtration under nitrogen atmosphere. Yield 420mg, 71% (hygroscopic). 1H NMR (400 MHz CD3OD) δ 7.73 (s, 1H) 4.67, 4.65, 4.63, 4.62 (q, 1H) 4.02 (s, 3H) 1.62, 1 , 60 (d, 3H). MS (ESI) m / z 194 (M + H) + 177 (M + H-NH3) +. TLC CH2Cl2: MeOH: NH4OH 95: 5: 0.5 0.2 UV-ve KMnO4 + ve. The free base was isolated using a SCX column eluting with methanol and then methanolic ammonia (1M) to liberate the amine. [α] D = -11.43 or (c 5.25, CH3OH).

Step A11H: (R) -1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethanamine, dihydrochloride

(R) -N - ((R) -1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2-methylpropane-2-sulfinamide (0.135 g, 0.00045 mol ) was dissolved in HCl in dioxane (4M, 8 ml) and the solution was stirred at room temperature overnight under nitrogen atmosphere. The solution was evaporated and the residue was suspended in ether and the white solid was removed by filtration under nitrogen atmosphere. Yield 120mg, 99% (hygroscopic). 1H NMR (400MHz CD3OD) 7.74 (s, 1H) 4.67.4.66, 4.64, 4.62 (q, 1H) 4.02 (s, 3H) 1.63, 1, 61 (d, 3H) MS (ESI) m / z 194 (M + H) + 177 (M + H-NH3) + TLC CH2Cl2: MeOH: NH4OH 95: 5: 0.5 0.2 UV-ve KMnO4 + ve [α] D = + 2.87o (c = 2.003, CH3OH)

Carboxylic acid 1: 2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxylic acid

Step CA1A: 6-bromo-N-methoxy-N-methylquinoline-2-carboxamide

To a solution in DMF (1 ml) of 6-bromoquinoline-2-carboxylic acid (4000 mg, 15.9 mmol, doc

5 US2005165049A1), triethylamine (6.64 ml, 47.6 mmol), N, O-dimethylhydroxyamine hydrochloride (1860 mg, 19.0 mmol) and HBTU (6620 mg, 17.5 mmol) were added and the mixture was stirred for 24 hours at room temperature. The reaction was quenched with saturated aqueous NaHCO3 and water, and the product was extracted with EtOAc 3 times. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude residue was applied to silica gel column chromatography and eluting with hexane / ethyl acetate (4: 1) affording the

Title compound (4.29 g, 92% yield) as an orange solid. 1H NMR (300 MHz, CDCl3) δ 3.47 (3H, s), 3.80 (3H, s), 7.68-7.80 (1H, sa), 7.81-7.85 (1H , m), 8.00-8.06 (2H, m), 8.17 (1H, d, J = 8.1 Hz). MS (ESI): m / z295, 297 (M + H) +.

Step CA1B: 1- (6-Bromoquinolin-2-yl) ethanone

To a solution of the product from Step 1A (4.29 g, 14.5 mmol) in THF (100 ml) was added methyl magnesium bromide

15 (18.2 ml, 17.4 mmol, 0.96 M in THF solution) at 0 ° C dropwise and the mixture was stirred at 0 ° C for 1 hour. The mixture was then quenched with saturated aqueous ammonium chloride solution (50 ml) and water (200 ml). After stirring for 30 min, the product was extracted with ethyl acetate and dried over sodium sulfate. Filtration, evaporation, and purification by silica gel column chromatography, eluting with hexane / ethyl acetate

(4: 1) provided the title compound (3.47 g, 96% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.66 (3H, s), 7.83-7.88 (1H, m), 8.02-8.20 (4H, m). MS (ESI): m / z 250, 252 (M + H) +.

Step CA1C: 2- (6-Bromoquinolin-2-yl) -1,1,1-trifluoropropan-2-ol

A solution in DMF (5 ml) of the product of Step CA1B (129 mg, 0.52 mmol), (trifluoromethyl) trimethylsilane (220 mg, 1.55 mmol) and tetrabutylammonium fluoride (13.5 mg, 0.052 mmol) stirred at 100 ° C for 2 hours. The mixture was then cooled to room temperature and 1N hydrochloric acid (2 ml) was added. After 4 hours, the mixture was quenched

25 with saturated aqueous sodium bicarbonate solution and the product was extracted with ethyl acetate which was dried over sodium sulfate. Filtration, evaporation, and purification by silica gel column chromatography, eluting with hexane / ethyl acetate (4: 1) provided the title compound (175 mg, quant.) As a white solid. 1H NMR (300 MHz, CDCl3)  δ 1.81 (3H, s), 6.51 (1H, s), 7.64 (1H, d, J = 8.1 Hz), 7.66- 7.89 (1H, m), 8.00-8.12 (2H, m), 8.21 (1H, d, J = 8.8 Hz). MS (ESI): m / z 320, 322 (M + H) +.

30 Step CA1D: 1- (6-Bromoquinolin-2-yl) -2,2,2-trifluoro-1-methylethyl methanesulfonate

To a solution of the product from Step CA1C (1.93 g, 6.03 mmol) in THF (20 ml) was added sodium hydride (241 mg, 7.23 mmol) portionwise at 0 ° C and the mixture was stirred at room temperature for 1 hour. A solution of methanesulfonyl chloride (829 mg, 7.23 mmol) in THF (2 ml) was added at 0 °. The reaction mixture was then stirred at room temperature for 16 hours. The mixture was quenched with saturated aqueous sodium bicarbonate solution, and the product was extracted with ethyl acetate and dried over sodium sulfate. Filtration, evaporation, and purification by silica gel column chromatography, eluting with hexane / ethyl acetate (15: 1 to 5: 1) provided the title compound (1.11 g, 46% yield) as a white solid. 1H NMR (300 MHz, CDCl3)  δ 2.45 (3H, s), 3.24 (3H, s), 7.81-7.86 (2H, m), 7.96-8.05 (2H, m), 8.17 (1H, d, J = 8.8 Hz). MS (ESI): m / z 397, 399 (M + H) +.

Step CA1E: 6-Bromo-2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline

To a suspension of the product from Step CA1D (1.40 g, 3.52 mmol) in cyclohexane (14 ml) was added trimethylaluminum (14 ml, 14 mmol, 1.03 M solution in hexane) at room temperature, and The mixture was stirred at room temperature for 16 hours. The reaction was carefully quenched with saturated aqueous sodium bicarbonate solution (10 ml), brine (10 ml), and diluted with ethyl acetate (100 ml). After stirring the mixture for 30 minutes, the formed precipitate was removed by filtration through celite and washed with ethyl acetate. The filtering is

Concentrated and purified by silica gel column chromatography eluting with hexane only to provide the title compound (951 mg, 85% yield) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.72 (6H, s), 7.66 (1H, d, J = 8.8 Hz), 7.75-7.80 (1H, m), 7 , 96-8.00 (2H, m), 8.06 (1H, d, J = 8.8Hz). MS (ESI): m / z 318.320 (M + H) +.

Step CA1F: methyl 2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxylate

50 A mixture of the product from Step CA1E (950 mg, 3.0 mmol), triethylamine (1.25 ml, 9.0 mmol), 1,3-bis (diphenylphosphine) propane (123 mg, 0.3 mmol) , palladium acetate (67mg, 0.3mmol) and methanol (4.8ml) in DMF (10ml) was stirred under reflux under carbon monoxide (1atm) (101.3KPa) for 16 hours. The reaction was then quenched with saturated aqueous sodium bicarbonate solution and the product was extracted with ethyl acetate which was dried over sodium sulfate. Filtration, evaporation and purification by silica gel column chromatography

55 eluting with hexane / ethyl acetate (25: 1) provided the title compound (777 mg, 88% yield) in

image27

5

10

fifteen

twenty

25

30

35

40

Four. Five

form of a white solid. 1H NMR (300 MHz, CDCl3) δ 1.74 (6H, s), 4.00 (3H, s), 7.71 (1H, d, J = 8.8 Hz), 8.14 (1H, d, J = 8.8 Hz), 8.25 (1H, d, J = 8.8 Hz), 8.28-8.32 (1H, m), 8.58-8.59 (1H, m ). MS (ESI): m / z 298 (M + H) +.

Step CA1G: 2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxylic acid

A solution in methanol (6 ml) and THF (6 ml) of the product of Step CA1F (777 mg, 2.6 mmol) and 2M aqueous sodium hydroxide solution (2.6 ml, 5.2 mmol) was heated at 60 ° C for 3 hours. After cooling to room temperature, the solvent was evaporated in vacuo and the residue was acidified to pH 2 with 2M hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the combined solution was washed with brine, dried over sodium sulfate and Evaporated in vacuo to provide the crude product which was recrystallized from ethyl acetate and hexane to provide the title compound (735 mg, 99% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.75 (6H, s), 7.74 (1H, d, J = 8.8 Hz), 8.19 (1H, d, J = 8.8 Hz ), 8.29 (1H, d, J = 8.8Hz), 8.35-8.40 (1H, m), 8.69-8.70 (1H, m). MS (ESI): m / z 284 (M + H) +.

Carboxylic acid 2: 6-tert-butyl-2-naphthoic acid

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CH3

Stage CA2A: Methyl 6-tert-butyl-2-naphthoate

A mixture of 2-bromo-6-tert-butylnaphthalene (980 mg, 3.72 mmol), palladium acetate (84 mg, 0.37 mmol), 1,3-bis (diphenylphosphino) propane (153 mg, 0, 37 mmol) and triethylamine (1.56 ml, 11.2 mmol) in methanol (6 ml) and DMF (10 ml) was heated at 80 ° C with carbon monoxide gas pressure (balloon) for 15 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate-toluene (8: 1) (160 ml) and filtered through a pad of celite. The filtrate and rinses were washed with water, brine, dried over sodium sulfate, and evaporated in vacuo to provide the crude product which was purified by silica gel column chromatography, eluting with hexane / EtOAc (10: 1), affording the title compound as a colorless oil (843 mg, 94%). 1H NMR (300 MHz, CDCl3): δ 1.43 (9H, s), 3.97 (3H, s), 7.61-7.67 (1H, m), 7.79-7.93 ( 3H, m), 8.01-8.07 (1H, m), 8.57 (1H, s, a).

Stage CA2B: 6-tert-Butyl-2-naphthoic acid

A mixture of methyl 6-tert-butyl-2-naphthoate (Step CA2A) (843 mg, 3.48 mmol) and 2 M solution of sodium hydroxide (6.96 mmol, 3.48 mmol) in methanol (30 ml ) was treated according to the procedure described in step CA1G to provide the title compound as a white solid (614 mg, 77%). 1H NMR (270MHz, DMSO-d6): δ 1.39 (9H, s), 7.70-7.76 (1H, m), 7.90-8.08 (4H, m), 8 , 55 (1H, s, a), 13.00 (1H, s, a).

Carboxylic acid 3: 6-tert-butylquinoline-2-carboxylic acid

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CH3

Stage CA3A: 6-tert-butylquinoline 1-oxide

A mixture of 6-tert-butylquinoline (400 mg, 2.16 mmol, Journal of the Indian Chemical Society, 1998, 823) and mCPBA (639 mg, 2.59 mmol) in chloroform (10 ml) was stirred for 2 hours at room temperature. The mixture was concentrated and the crude residue was applied to silica gel column chromatography (NH silica) and conditioned chloromethane / methanol (20: 1) was eluted to provide the title compound (433 mg, quant.) As a light orange oil. 1H NMR (300 MHz, CDCl3) δ 1.43 (9H, s) 7.26-7.30 (1H, m), 7.73 (1H, d, J = 8.1 Hz), 7.78 (1H, s), 7.85 (1H, dd, J = 1.5, 8.8Hz), 8.49 (1H, d, J = 5.9Hz), 8.67 (1H, d, J = 8.8 Hz). MS (ESI): m / z 202 (M + H) +.

Step CA3B: 6-tert-butylquinoline-2-carbonitrile

A mixture of the product from Step CA3A (310 mg, 1.54 mmol), trimethylsilylcyanide (458 mg, 4.62 mmol), trimethylamine (312 mg, 3.08 mmol) in acetonitrile (3 ml) was stirred for 15 minutes at 120 ° C with microwave irradiation. The mixture was applied to silica gel column chromatography and eluted with hexane / ethyl acetate (20: 1) to provide the title compound (295 mg, 91% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.44 (9H, s), 7.68 (1H, d, J = 8.8 Hz), 7.79 (1H, d, J = 2.2 Hz) , 7.94 (1H, d, J = 2.2, 8.8Hz), 8.11 (1H, d, J = 8.8Hz), 8.26 (1H, d, J = 8.8 Hz). MS (ESI): m / z 211 (M + H) +.

Step CA3C: 6-tert-butylquinoline-2-carboxylic acid A solution of the product from Step CA3B (295 mg, 1.40 mmol) and 2M aqueous sodium hydroxide (3 ml) in ethanol (4.5 ml) was stirred for 4 hours at reflux. The mixture was diluted with water (10 ml), neutralized by 2M aqueous hydrochloride, and extracted with ethyl acetate (30 ml). The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (313 mg, quant.) As a white solid. 1H NMR (300 MHz, DMSO-d6) δ1.40 (9H, s), 7.93-7.97 (2H, m), 8.01-8.11 (2H, m), 8.41 ( 1H, d, J = 8.1 Hz). MS (ESI): m / z 230 (M + H) +.

Carboxylic acid 4: 2- (2,2,2-trifluoro-1-hydroxy-1-methylethyl) quinoline-6-carboxylic acid

Step CA4A: Methyl 2- (2,2,2-trifluoro-1-hydroxy-1-methylethyl) quinoline-6-carboxylate The title compound was prepared from intermediate CA1C using the procedure of CA1F 10 1H NMR ( 300 MHz, CDCl3) δ

1.82 (3H, s), 4.02 (3H, s), 6.55 (1H, s), 7.69 (1H, d, J = 8.1Hz), 8.18 (1H, d , J = 8.8 Hz), 8.37-8.41 (2H, m), 8.66-8.68 (1H, m). MS (ESI): m / z 300 (M + H) +.

Step CA4B: 2- (2,2,2-trifluoro-1-hydroxy-1-methylethyl) quinoline-6-carboxylic acid

The title compound was prepared from intermediate CA4A using the procedure of CA1G 1H NMR (300 MHz, CDCl3) δ

1.84 (3H, s), 7.72 (1H, d, J = 8.1 Hz), 8.23 (1H, d, J = 8.8 Hz), 8.42-8.47 (2H , m), 8.77-8.78 (1H, m). MS 15 (ESI): m / z 286 (M + H) +.

Carboxylic acid 5: 2- (1-methylcyclopropyl) quinoline-6-carboxylic acid

image30

image31

Step CA5A: 6-bromo-2-isopropenylquinoline

A stirring suspension of (methyl) triphenylphosphonium bromide (2000 mg, 5.60 mmol) in dry THF (15 ml) was

20 added a solution of potassium tert-butoxide (628 mg, 5.60 mmol) in dry THF (10 ml) under ice-cooling. The mixture was then allowed to warm to room temperature. After 2 hours at room temperature, to this was added a solution of 1- (6-bromoquinolin-2-yl) ethanone (Step CA1B) (700 mg, 2.80 mmol) in dry THF (15 ml) under ice-cooling , then the mixture was allowed to warm to room temperature. After 3 hours at room temperature, the mixture was quenched with water and extracted with ethyl acetate (x 2). The combined solution was washed with

25 brine, dried over sodium sulfate and concentrated in vacuo to provide the crude product, which was purified by column chromatography on silica gel (250 g) with hexane-ethyl acetate (10: 1) to provide the title compound ( 661 mg, 95%) as a tan solid. 1H NMR (270MHz, CDCl3) δ 2.34 (3H, s), 5.50 (1H, s), 5.93 (1H, s), 7.65-7.78 (2H, m), 7.88-8.03 (3H, m). MS (ESI): m / z 248.11, 250.14 [M + H] +.

Step CA5B: methyl 2-isopropenylquinoline-6-carboxylate

30 A mixture of 6-bromo-2-isopropenylquinoline (200 mg, 1.45 mmol), palladium acetate (18.1 mg, 0.081 mmol), 1,3-bis (diphenylphosphino) propane (33 mg, 0.081 mmol) , triethylamine (245 mg, 2.42 mmol. 0.337 ml) and methanol (1.03 g, 1.31 ml 32.2 mmol) in dry DMF (2.5 ml) was heated to 80 ° C under an atmosphere of monoxide gas carbon (balloon) all night (15 hours). The mixture was diluted with ethyl acetate-toluene (8: 1) (159 ml) and the precipitate was filtered through a pad of celite. The organic phase was washed with water (x 2), brine, dried over sodium sulfate, and concentrated to

35 vacuum providing the crude product. The crude product was purified by silica gel (150 g) column chromatography with hexane-ethyl acetate (15: 1) to provide the title compound (150 mg, 82%) as a dark yellow solid. 1H NMR (270 MHz, CDCl3) δ 2.36 (3H, s), 3.99 (3H, s), 5.53-5.57 (1H, m), 5.98 (1H, s), 7.73-7.78 (1H, m), 8.08-8.31 (3H, m), 8.54-8.56 (1H, m). MS (ESI): m / z 228.21 [M + H] +.

Step CA 5C: Methyl 2- (1-methylcyclopropyl) quinoline-6-carboxylate

40 To a stirring suspension of trimethylsulfoxonium iodide (435 mg, 2.06 mmol) in dimethyl sulfoxide (3 ml) and THF (2 ml) was added potassium tert-butoxide (231 mg, 2.06 mmol) in a portion at room temperature. After 30 min. at the same temperature, to this (colorless solution) was added a solution of methyl 2-isopropenylquinoline-6-carboxylate (312 mg, 1.37 mmol) in THF (3 ml) at room temperature. The mixture was stirred at room temperature for 40 min then 1 hour at 60 ° C. The mixture was quenched with water and diluted

45 with ethyl acetate-toluene (8: 1) (90 ml). The organic solution was separated and washed with water (x 2), brine, dried over sodium sulfate, and concentrated in vacuo to provide the crude product. The crude product was purified by silica gel column chromatography (250g) with hexane-ethyl acetate (10: 1) to provide the title compound (225mg, 68%) as a white solid. 1H NMR (270 MHz, CDCl3) δ 0.91-0.98 (2H, m), 1.38-1.45 (2H, m), 1.64 (3H, s), 3.98 (3H , s), 7.42-7.48 (1H, m), 7.97-8.27 (3H, m), 8.50-8.55 (1H, m). MS (ESI): m / z 242.15 [M + H] +.

5 Step CA5D: 2- (1-methylcyclopropyl) quinoline-6-carboxylic acid

A solution of methyl 2- (1-methylcyclopropyl) quinoline-6-carboxylate (225 mg, 0.93 mmol) and 2 M solution of sodium hydroxide (2 ml, 4 mmol) in methanol (10 ml) was heated to 60 ° C for 2 hours. After evaporating the solvent in vacuo, the residue was dissolved in water. The aqueous solution was neutralized with 2M hydrochloric acid solution (2 ml) and the precipitated white solid was extracted with ethyl acetate (x 3). The combined solution was washed with brine, dried

10 over sodium sulfate and concentrated in vacuo to provide crude white solid, which was recrystallized from ethyl acetate and hexane to provide the title compound (177 mg, 84%) as a white solid. MS (ESI): m / z 228.15 [M + H] +, 226.13 [MH] -.

Carboxylic acid 6: 6- (1-methylcyclopropyl) -2-naphthoic ACID

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15 Step CA6A: methyl 6- (prop-1-en-2-yl) -2-naphthoate

To a suspension of methyl triphenylphosphonium bromide (2.41 g, 6.74 mmol) in THF (20 ml) was added potassium tert-butoxide (756 mg, 6.74 mmol) in THF (20 ml) dropwise to 0 ° C, and the mixture was stirred at room temperature for 1.5 hours. Then, methyl 6-acetyl-2-naphthoate (J. Org. Chem, 1990, 55, 319-324, 769 mg, 3.37 mmol) in THF (5 ml) was added at room temperature, and the resulting mixture stirred at room temperature for 2 hours.

The reaction was quenched with water (100 ml) and extracted with ethyl acetate-hexane (1: 2). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with ethyl acetate-hexane (0: 100 to 1:20) affording 0.67 g (88% yield) of the title compound as a white solid. . 1H NMR (270MHz, CDCl3) δ 2.28 (3H, s), 3.99 (3H, s), 5.26 (1H, s), 5.58 (1H, s), 7.74 ( 1H, d, J = 8.6Hz), 7.82-7.97 (3H, m), 8.05 (1H, d, J = 8.6Hz), 8.58 (1H, s).

25 Step CA6B: Methyl 6- (1-methylcyclopropyl) -2-naphthoate

Diethylzinc (1.0 M solution in hexane, 6.30 mL, 6.30 mmol) was added to a solution of the product from Step CA6A (0.57 g, 2.5 mmol) in 1,2-dichloroethane (25 ml) at 0 ° C. Diiodomethane (1.01 ml, 12.6 mmol) was then added dropwise to the solution and the resulting mixture was stirred at 60 ° C for 20 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous ammonium chloride solution (30 ml), and the mixture was extracted with

30 dichloromethane (30 ml x 3 times). The combined organic phase was washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml), and the organic phase was dried over sodium sulfate. Removal of the solvent provided a residue, which was chromatographed on a silica gel column, eluting with ethyl acetate-hexane (1:20), affording 0.91 g of the title compound as a white solid. This crude product was used in the next step without further purification.

1H NMR (270 MHz, CDCl3) δ 0.75-0.95 (2H, m), 0.95-1.13 (2H, m), 1.52 (3H, s), 3, 97 (3H, s), 7.41 (1H, d, J = 9.9 Hz), 7.74 (1H, s), 7.82 (1H, d, J = 7.8 Hz), 7, 86 (1H, d, J = 8.6Hz), 8.04 (1H, d, J = 8.6Hz), 8.56 (1H, s).

Step CA6C: 6- (1-methylcyclopropyl) -2-naphthoic acid

A mixture of the product from Step CA6B (crude 0.91 g, 2.5 mmol) and 2M solution of sodium hydroxide (3.8 ml) in methanol (7.6 ml) was heated at 60 ° C for 2 hours . After cooling to room temperature, the mixture was washed with

40 diethyl ether (100 ml). The aqueous phase was acidified to pH <3 with 2M hydrochloric acid solution and the mixture was extracted with dichloromethane-methanol (10: 1, 150 ml x 3 times). The combined organic phase was dried over sodium sulfate and concentrated in vacuo to provide 0.444 g (78% yield in 2 steps) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 0.77-0.92 (2H, m), 0.95-1.11 (2H, m), 1.49 (3H, s), 7, 42 (1H, d, J = 8.8 Hz), 7.84 (1H, s), 7.90-7.97 (2H, m), 8.01 (1H, d, J = 8.8 Hz ), 8.54 (1H, s). MS (ESI): m / z 225 (MH) <->.

45 Carboxylic acid 7: 6- (2,2,2-trifluoro-1-hydroxy-1-methylethyl) -2-naphthoic acid

CF3

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Step CA7A: 2- (6-bromo-2-naphthyl) -1,1,1-trifluoropropan-2-ol

To a solution in DMF (25 ml) of 1- (6-bromo-2-naphthyl) ethanone (2.5 g, 10.0 mmol, Tetrahedron Letters (2001), 42 (2), 265-266), Trifluoromethyltrimethylsilane (2.14 g, 15.1 mmol) and lithium acetate (33.1 mg, 0.5 mmol) were added and the mixture was stirred for 12 hours at room temperature. The reaction was then partitioned with aqueous sodium acetate and ethyl acetate. The organic phase was dried over sodium sulfate and filtered. Then evaporation gave the crude residue which was treated with hydrogen chloride and methanol with stirring for 5 hours. Then evaporation provided the crude residue which was purified by silica gel column chromatography, eluting with hexane: ethyl acetate (5: 1), affording the title compound as a colorless oil in 83% yield. 1H NMR (300 MHz, CDCl3) δ 2.50 (1H, s), 7.58 (1H, d, J = 8.8 Hz), 771-7.81 (3H, m), 8.04 ( 2H, d, J =

10 8.9 Hz).

Step CA7B; Methyl 6- (2,2,2-trifluoro-1-hydroxy-1-methylethyl) -2-naphthoate

To a solution in DMA (25 ml) and methanol (1 ml) of the product from Step CA7A (1.0 g, 3.1 mmol), palladium acetate (70.0 mg, 0.31 mmol), diphenylphosphine propane (129 mg, 0.31 mmol) and triethylamine (951 mg, 9.4 mmol) and the mixture was stirred for 12 hours at 100 ° C under a CO gas atmosphere (balloon pressure). Then the reaction is

15 fractionated with water and ethyl acetate. The organic phase was dried over sodium sulfate and filtered. Then evaporation gave the crude residue which was purified by silica gel column chromatography, eluting with hexane: ethyl acetate (5: 1), affording the title compound as a colorless oil in 50% yield. 1H NMR (300 MHz, DMSO-d6) δ 1.81 (3H, s), 3.93 (3H, s), 6.85 (1H, s), 7.81-8.00 (1H, m), 8.11-8.26 (4H, m), 8.66 (1H, s).

20 Step CA7C: 6- (2,2,2- trifluoro-1-hydroxy-1-methylethyl) -2-naphthoic acid

To an ethanol solution (30 ml) of the product of Step CA7B (1.16 g, 3.1 mmol), an aqueous solution of sodium hydroxide (2M) (15 ml) was added and the mixture was stirred for 5 hours at room temperature. The reaction was then acidified with dilute hydrochloric acid (20 ml) and the product was extracted with ethyl acetate and dried over sodium sulfate. After filtration and evaporation gave the title compound as a white solid with 90% of

25 performance. 1H NMR (300 MHz, DMSO-d6) δ 1.81 (3H, s), 6.85 (1H, s), 7.82 (1H, d, J = 9.2 Hz), 7.99- 8.25 (4H, m), 8.62 (1H, s), 12.9 (1H, bs).

Carboxylic acid 8: 6- (2,2,2- trifluoro-1-methoxy-1-methylethyl) -2-naphthoic acid

Step CA8A: Methyl 6 (2,2,2-trifluoro-1-methoxy-1-methylethyl) -2-naphthoate

To a THF solution of the product from Step CA7B (0.45 g, 1.5 mmol), sodium hydride (80 mg, 2.2 mmol) was added and the mixture was stirred for 30 minutes at 0 ° C. Then, methyl iodide (642 mg, 4.5 mmol) was added to the mixture and it was allowed to stir for a further 3 hours. The product was then extracted with ethyl acetate and dried over sodium sulfate. After filtration, evaporation, and purification by silica gel column chromatography, eluting with hexane: ethyl acetate = 4: 1, provided the title compound as a white solid with

35 a 58% yield. 1H NMR (270MHz, DMSO-d6) δ 1.91 (3H, s), 3.22 (3H, s), 3.93 (3H, s) 7.72-7.75 (1H, m) , 8.02-8.05 (1H, m), 8.13-8.24 (3H, m), 8.68 (1H, s).

Step CA8B: 6 (2,2,2-trifluoro-1-methoxy-1-methylethyl) -2-naphthoic acid

The title compound was prepared by the same procedure of Step CA7C using the product of Step CA8A in place of the product of Step CA7B providing the title compound in 98% yield in

40 in the form of a white solid.

1H NMR (300 MHz, DMSO-d6) δ 1.91 (3H, s), 3.22 (3H, s) 7.71-7.74 (1H, m), 8.01-8.21 ( 4H, m), 8.64 (1H, s), 13.2 (1H, bs).

Carboxylic acid 9: 2-tert-butylquinoline-6-carboxylic acid

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image35

CH3

image36

6-Quinolinecarboxylic acid (500mg, 2.89mmol) was dissolved in tetrahydrofuran (10ml) under nitrogen atmosphere and cooled to 00C. 1.8M t-butyllithium in pentane (3.53 mL, 6.35 mmol) was added dropwise to the reaction over 30 minutes. The reaction was allowed to warm to room temperature for 1 hr then stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride solution (20 ml) was added and then extracted with ethyl acetate (2 x 20 ml). The combined organic fractions were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The 2-tert-butyl-1,2-dihydro-quinoline-6-carboxylic acid intermediate was purified by silica gel column chromatography, eluting with heptane / ethyl acetate = 100/0 to 0/100. The product containing fractions was combined; Manganese dioxide (2510 mg, 28.9 mmol) was added directly to this solution and the whole was stirred together for 1 hr. The reaction was then filtered through celite to provide the title product.

10 in the form of a cream solid. (300mg, 45% yield). NMR (400 MHz, DMSO-d6) δ 1.38-1.40 (9H s) 7.59-7.62 (1H d) 7.77-7.80 (1H d) 8.16-8, 20 (1H dd) 8.25-8.29 (1H d) 8.32-8.35 (1H d). MS (ESI / APCI) m / z 230 (M + H) + m / z 415 (MH) -.

Carboxylic acid 10: 2- (trifluoromethyl) quinoline-6-carboxylic acid

15 Step CA10A: tert-butyl quinoline-6-carboxyl

1,1'-carbonyldiimidazole (11.2 g, 69.3 mmol) was added to a suspension of 6-quinolinecarboxylic acid (12 g, 69 mmol) in DMF (100 ml) and the mixture was stirred at 40 ° C for 1 hour. Tert-butanol (13 ml, 139 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (10.4 ml, 69.3 mmol) were added and the mixture was stirred at 80 ° C for 4 h. After cooling to room temperature the reaction mixture was quenched with water (400 ml) and extracted with ethyl acetate / heptane20 (1: 3, 2 x 400 ml). The organic phase was dried over MgSO4 and concentrated to provide quinoline-6-carboxylic acid t-butyl ester (14.54 g, 92%). 1H NMR (400 MHz, CDCl3) δ 1.63 (9H, s), 7.42-7.46 (1H, m), 8.10 (1H, d), 8.23 (1H, d), 8.26 (1H, d), 8.50 (1H, d), 8.96-8.98 (1H, m). LCMS: retention time: 1.42 min. MS (ESI) m / z 230 (M

+ H) +

Step CA10B: tert-butyl 1-oxyquinoline-6-carboxyl

To a solution of tert-butyl quinoline-6-carboxyl (14.54 g, 63 mmol) in dichloromethane (100 ml) was added meta-chloroperbenzoic acid (16.4 g, 95.1 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with more dichloromethane (250 ml) and washed with saturated aqueous NaHCO3 (200 ml). The organic phase was dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to provide a crude residue that was purified by silica gel column chromatography (EtOAc: heptane = 7: 3; 17: 3; 19: 1

30 then CH2Cl2: MeOH = 190: 1) affording 1-oxyquinoline-6-carboxylic acid tert-butyl ester (10.69 g, 69%). 1H NMR (400 MHz, CDCl3) δ 1.65 (9H, s), 7.33-7.38 (1H, m), 7.83 (1H, d), 8.26-8.30 (1H , m), 8.54 (1H, d), 8.57-8.59 (1H, m), 8.78 (1H, d). LCMS: retention time: 1.31 min. MS (ESI) m / z 246 (M + H) +.

Step CA10C: tert-butyl 2- (trifluoromethyl) quinoline-6-carboxyl

To a solution of tert-butyl 1-oxyquinoline-6-carboxyl (6 g, 20 mmol) and (trifluoromethyl) trimethylsilane (6.15 ml, 41.6

35 mmol) in THF (100 ml) at 0 ° C, cesium fluoride (400 mg, 2.6 mmol) was added and the reaction mixture was warmed to room temperature and allowed to stir for 16 h. The reaction mixture was cooled to 0 ° C and more (trifluoromethyl) trimethylsilane (4.70 ml, 31.8 mmol) and cesium fluoride (400 mg, 2.6 mmol) were added. THF was removed under reduced pressure to provide a crude residue which was dissolved in EtOAc (150 mL) and washed with saturated aqueous NaHCO3 (2 x 50 mL) and then brine (2 x 30 mL). The organic phase was dried over magnesium sulfate, filtered

40 and solvent was removed under reduced pressure to provide a crude residue which was purified by silica gel column chromatography (EtOAc: heptane = 7: 3) to provide 2-trifluoromethylquinoline-6-carboxylic acid tert-butyl ester (3, 53 g, 50%). 1H NMR (400 MHz, CDCl3) δ 1.66 (9H, s), 7.80 (1H, d), 8.25 (1H, d), 8.36 (1H, dd), 8.47 ( 1H, d), 8.59 (1H, d). LCMS: retention time: 1.75 min. MS (ESI) m / z 298 (M + H) +.

Step CA10D: 2- (trifluoromethyl) quinoline-6-carboxylic acid

To a solution of tert-butyl 2-trifluoromethylquinoline-6-carboxyl (2 g, 7 mmol) in dichloromethane (50 ml), cooled to 0 ° C, was added trifluoroacetic acid (5.18 ml, 67.2 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 36 h. The reaction mixture was concentrated under reduced pressure and the crude product obtained was triturated with heptane (4 x 10 ml) to provide 2-trifluoromethylquinoline-6-carboxylic acid (1.58 g, 98%). 1H NMR (400 MHz, CD3OD) δ 7.93 (1H, d), 8.24 (1H, d), 8.42 (1H, dd), 8.73 (1H, d), 8.78 (1H, d). EMCL: time of

50 retention: 1.38 min. MS (ESI) m / z 242 (M + H) +.

Carboxylic acid 11: 2- (pentafluoroethyl) quinoline-6-carboxylic acid

OR

image37

Step CA11A: tert-butyl 2- (pentafluoroethyl) quinoline-6-carboxyl

To a solution of tert-butyl 1-oxyquinoline-6-carboxyl (0.20 g, 0.815 mmol) and (pentafluoroethyl) trimethylsilane (300 mg, 1.56 mmol) in THF (5 ml) at 0 ° C was added fluoride of cesium (15 mg, 0.1 mmol) and the reaction mixture was warmed to room temperature and allowed to stir for 3 h. More (pentafluoroethyl) trimethylsilane (0.175 mL, 0.90 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was dissolved in EtOAc (60 ml) and washed with saturated aqueous NaHCO3 (30 ml). The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to provide a crude residue which was purified by silica gel column chromatography (EtOAc: heptane = 85: 15) to provide t-butyl acid 2 -pentafluoroethylquinoline-6-carboxylic acid (165 mg,

10 58%). 1H NMR (400 MHz, CDCl3) δ 1.66 (9H, s), 7.80 (1H, d), 8.25 (1H, d), 8.36 (1H, dd), 8.47 ( 1H, d), 8.60 (1H, d). LCMS: retention time: 1.84 min. MS (ESI) m / z 348 (M + H) +.

Step CA11B: 2- (pentafluoroethyl) quinoline-6-carboxylic acid

To a solution of tert-butyl 2-pentafluoroethylquinoline-6-carboxyl (165 mg, 0.475 mmol) in dichloromethane (5 ml), cooled to 0 oC, trifluoroacetic acid (2 ml, 26 mmol) was added and the reaction mixture allowed to warm to temperature

15 ambient and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to provide the crude product, 2-pentafluoroethylquinoline-6-carboxylic acid (140 mg, 100%). 1H NMR (400 MHz, CDCl3 +2 drops of CD3OD) δ 7.79 (1H, d), 8.26 (1H, d), 8.39 (1H, dd), 8.47 (1H, d) , 8.67 (1H, d). LCMS: retention time: 1.49 min. MS (ESI) m / z 292 (M + H) +.

Examples

20 Example 1: N - [(1R) - (1,5-dimethyl-1H-pyrazol-4-yl) ethyl)] - 2- (2,2,2-trifluoro-1,1

dimethylethyl) quinoline-6-carboxamide

CH3

To a solution in DMF (3.8 ml) of (1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethanamine dihydrochloride (80 mg, 0.38 mmol), acid 6- tert-butyl-2-naphthoic acid (107 mg, 0.38 mmol), HBTU (150 mg, 0.396 mmol) and N, N-diisopropylethylamine 25 (0.197 ml, 1.13 mmol) and the mixture was stirred for 24 hours at room temperature. The reaction was quenched with saturated aqueous NaHCO3 and water, and the product was extracted with EtOAc 3 times. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by HPLC (column: CMS 30x 50mm, acetonitrile: 0.01% aqueous NH3 = 96: 4 to 4:96 as eluent, retention time = 3.90 min) to provide the title product (140mg, 92%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.65 (3H, d, J = 6.0

30 Hz), 1.73 (6H, s), 2.30 (3H, s), 3.79 (3H, s), 5.28-5.37 (1H, m), 6.30 (1H, da, J = 9.0 Hz), 7.49 (1H, s), 7.70 (1H, d, J = 9.0 Hz), 8.01 (1H, d, J = 9.0 Hz) , 8.14 (1H, d, J = 9.0Hz), 8.21 (1H, d, J = 9.0Hz), 8.25 (1H, s). MS (ESI) m / z 403 (MH) -, 405 (M + H) +.

The following compounds were prepared by a procedure analogous to that described in Example 1 and Scheme 1, using the starting materials detailed below.

Example 2: N - [(1,5-dimethyl-1H-pyrazol-4-yl) methyl] -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide

image38

image39

CH3

5

10

fifteen

twenty

25

It was prepared using 1- (1,5-dimethyl-1H-pyrazol-4-yl) methanamine and Carboxylic Acid 1. 1H NMR (300 MHz, CDCl3) δ 1.74 (6H, s), 2.33 ( 3H, s), 3.82 (3H, s), 4.53 (2H, d, J = 5.2 Hz), 6.25 (1H, s), 7.48 (1H, s), 7, 73-8.28 (5H, m). MS (ESI) m / z 391 (M + H) +.

Example 3: (R) -N- (1- (5-cyano-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinolin-6 -carboxamide

image2 CH3 image40 OR

NN H CF3

N CH3

H3C N CH3

It was prepared using Amine 3 and Carboxylic Acid 1. 1H NMR (270 MHz, DMSO-d6) δ 1.57 (3 H, d, J = 7.3 Hz), 1.71 (6 H, s ), 3.98 (3H, s), 5.30 (1H, m), 7.11 (1H, d, J = 11.9Hz), 7.74 (1H, s), 7, 88 (1H, d, J = 8.6Hz), 8.09 (1H, d, J = 9.2Hz), 8.23 (1H, dd, J = 2.0Hz, 8, 6Hz), 8.49-8.60 (2H, m), 9.16 (1H, d, J = 7.9Hz). MS (ESI): m / z 416 (M + H) +, 414 (MH) -.

Example 4: (R) -N- (1- (5- (hydroxymethyl) -1-methyl-1H-pyrazol-4-yl) ethyl) -2- (2,2,2

trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide

image2 CH3 image40 OR

NN H CF3

N CH3H3C

HO CH3

It was prepared using Amine 4 and Carboxylic Acid 1. 1H NMR (270 MHz, DMSO-d6) δ 1.51 (3 H, d, J = 7.3 Hz), 1.71 (6 H, s ), 3.79 (3H, s), 4.52 (1H, dd, J = 5.3Hz, 13.2Hz), 4.61 (1H, dd, J = 5.3Hz, 13.2 Hz), 5.16 (1H, t, J = 5.3Hz), 5.25 (1H, m), 7.45 (1H, s), 7.87 (1H, d, J = 9.2 Hz), 8.06 (1H, d, J = 9.2 Hz), 8.19 (1H, d, J = 8.6 Hz), 8.46-8, 56 (2H, m), 8.89 (1H, d, J = 8.9Hz). MS (ESI): m / z 421 (M + H) +, 419 (MH) -.

Example 5: N- (1- (5-methyl-1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) ethyl) -2- (2,2,2

trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide

image2 image2 CH3 image40 OR

NN H CF3N

CH3 H3C CH3F

FF

It was prepared using Amine 6 and Carboxylic Acid 1. 1H NMR (300 MHz, DMSO-d6) δ 1.51 (3H, d, J = 6.0 Hz), 1.71 (6H, s), 2 , 31 (3H, s), 5.02 (1H, d, J = 9.0Hz), 5.08 (1H, d, J = 9.0Hz), 5.16-5.25 (1H, m), 7.60 (1H, s), 7.88 (1H, d, J = 9.0 Hz), 8.08 (1H, d, J = 9.0 Hz), 8.19-8, 23 (1H, m), 8.51-8.54 (2H, m), 8.93 (1H, da, J = 9.0 Hz). MS (ESI) m / z 471 (M

-H) -, 473 (M + H) +. The chemical structure (1,5-substitution on the pyrazole ring) of the title compound was evaluated by NMR analysis (1H-1D, COZY, pNOESY and pROESY).

Example 6: N - ((1R) -1- (5-methyl-1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) ethyl) -2 (2,2,2-trifluoro- 1,1-dimethylethyl) quinoline-6-carboxamide

image2 image2 CH3 image40 OR

NN H CF3N

CH3 H3C CH3F

FF

It was prepared using Amine 7 and Carboxylic Acid 1. The 1H NMR data of Example 6 is the same as that of Example 5. Optical purity (> 99% e.e.) of Example 6 was detected by chiral HPLC; DAICEL Chiralpak AD-H4.6x250mm, n-hexane / 2-Propanol / Diethylamine = 85/15 / 0.1 (v / v / v) as eluent, Retention time: 10.0 mim;

5 retention time of the corresponding racemic compound: 10.1, 13.0 min.

Example 7: N- [1- (1,5-dimethyl-1H-pyrazol-4-yl) propyl] -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide

CH3

It was prepared using Amine 5 and Carboxylic Acid 1. 1H NMR (300 MHz, DMSO-d6) δ 0.89 (3H, t, J = 6.6 Hz), 1.71 (6H, s), 1 , 75-1.98 (2H, m), 2.24 (3H, s), 3.68 (3H, s), 4.91-4.96 (1H, m), 7.38 (1H, s ), 7.86 (1H, d, J = 8.1 Hz), 8.06 (1H,

10 d, J = 8.8 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.50-8.53 (2H, m), 8.77 (1H, d, J = 8.1 Hz). MS (ESI): m / z 419 (M + H) +.

Example 8: N - [(1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) propyl] -2- (2,2,2-trifluoro

1,1-dimethylethyl) quinoline-6-carboxamide

CH3

The racemic compound of Example 7 was separated by DAICEL CHIRALPAK AD-H (250mm x 20mm, temperature

15 from column: 40 ° C). The mobile phase is n-hexane / Isopropanol / Diethylamine = 85/15 / 0.1 and the flow rate is 18.9 ml / min. The 1st peak, with retention time of 9.1 min, was the unwanted enantiomer of the title compound and the 2nd peak, with retention time of 13.1 min, was the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.89 (3H, t, J = 6.6 Hz), 1.71 (6H, s), 1.75-1.98 (2H, m) , 2.24 (3H, s), 3.68 (3H, s), 4.91-4.96 (1H, m), 7.38 (1H, s), 7.86 (1H, d, J = 8.1 Hz), 8.06 (1H, d, J = 8.8 Hz), 8.19 (1H, d, J = 8.8 Hz), 8.50-8.53 (2H, m ), 8.77 (1H, d, J = 8.1 Hz). MS (ESI): m / z 419 (M + H) +.

20 Example 9: N- [1- (5-methyl-1H-pyrazol-4-yl) ethyl] -2- (2,2,2-trifluoro-1,1-dimethyl

ethyl) quinoline-6-carboxamide

CH3

image41

image41

image42

It was prepared using Amine 9 and Carboxylic Acid 1. 1H NMR (270 MHz, DMSO-d6) δ 1.50 (3H, d, J = 6.5 Hz), 1.71 (6H, s), 2 , 19 (3H, bs), 5.14-5.28 (1H, m), 7.40-7.70 (1H, bs), 7.87 (1H, d, J = 8.4Hz), 8.07 (1H, d, J = 9.2Hz), 8.18-8.25 (1H, m), 8.48-8.56 (2H, m), 8.81 (1H, bs ), 12.20-12.50 (1H, bs).

image43

It was prepared using Amine 8 and Carboxylic Acid 1 (10% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.51 (3H, d, J = 6.0 Hz), 1.71 (6H, s), 2.21 (3H, s), 3.68 (3H, s), 5.00 (2H, s), 5.17-5.27 (1H, m), 7.50 (1H, s), 7.88 (1H, d, J = 9.0 Hz), 8.08 (1H, d, J = 9.0Hz), 8.20-8.23 (1H, m), 8.51-8.54 (2H, m), 8.91 (1H , da, J = 6.0 Hz). MS (ESI) m / z 461 (M

-H) -, 463 (M + H) +. The chemical structure (1,5-substitution on the pyrazole ring) of the title compound was evaluated by NMR analysis (1H-1D, COZY, pNOESY and pROESY).

Example 11: N- (1- (1- (2-hydroxyethyl) -5-methyl-1H-pyrazol-4-yl) ethyl) -210 (2,2,2-trifluoro-1,1-dimethylethyl) quinoline- 6-carboxamide

LiBH4 powder (3.25 mg, 0.15 mmol) was added to a solution of Example 10 (23 mg, 0.05 mmol) in THF (3 ml) at room temperature, and the resulting mixture was heated to 65 ° C. , then MeOH (3 drops) was added and the resulting mixture was heated at the same temperature for 60 min. After cooling to room temperature, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl and the aqueous phase was extracted with AcOEt 3 times. The combined organic extracts were washed with water and brine successively, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by HPLC (column: CMS 30 x 50 mm, acetonitrile: 0.01% aqueous NH3 = 96: 4 to 4:96 as eluent) to provide the title compound as a white solid (16 , 6 mg, 77% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.50 (3H, d, J = 6.0 Hz), 1.71 (6H, s), 2.26 (3H, s), 3.67

20 (2H, dd, J = 6.0, 12.0 Hz), 4.03 (2H, t, J = 6.0 Hz), 4.84 (1H, t, J = 6.0 Hz), 5.14-5.24 (1H, m), 7.46 (1H, s), 7.87 (1H, d, J = 9.0 Hz), 8.07 (1H, d, J = 9, 0 Hz), 8.19-8.23 (1H, m), 8.50-8.53 (2H, m), 8.85 (1H, da, J = 6.0 Hz). MS (ESI) m / z 433 (MH) -, 435 (M + H) +.

Example 12: N- (1- (1- (2-hydroxy-2-methylpropyl) -5-methyl-1H-pyrazol-4-yl) ethyl) -2

(2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide

HO

25

image44

image45

To a suspension of sodium hydride (30.7 mg, 0.768 mmol, 60% in oil, washed with hexane 3 times) in DMF (2 ml) was added Example 9 (100 mg, 0.256 mmol) at 0 ° C in atmosphere nitrogen, and the mixture was stirred at room temperature for 1 hour. Then 1,1-dimethyloxyran (22.2 mg, 0.307 mmol) was added to the mixture, and it was stirred for another 20 hours at 60 ° C. After cooling, the reaction mixture was quenched with water, poured into saturated aqueous sodium bicarbonate (30 ml), and extracted with dichloromethane (50 ml, 3 times). The combined organic phase was dried over sodium sulfate, filtered, and evaporated. The crude material was purified by a TLC plate (1mm thick plate, MeOH-DCM = 1:10) to provide the title compound as a white solid (20.1 mg, 17% yield). 1H NMR (270 MHz, DMSO-d6) δ 1.08, 1.09 (each 3 H, s), 1.50 (3 H, d, J = 6.6 Hz), 1.71 (6 H, s), 2.27 (3H, s), 3.91 (2H, s), 4.65 (1H, s), 5.21 (1H, m), 7.48 (1 H, s), 7.87 (1H, d, J = 9.2Hz), 8.07 (1H, d, J = 8.6Hz),

8.22 (1H, d, J = 7.3Hz), 8.46-8.59 (2H, m), 8.85 (1H, d, J = 7.9Hz). MS (ESI) m / z: 463 (M + H) +, 461 (MH) -.

Example 13: N - [(1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -2- (1-methylcyclopropyl) quinoline-6-carboxamide

CH3 O

It was prepared using Amine 2 and Carboxylic Acid 5. 1H NMR (300 MHz, DMSO-d6) δ, 0.91-0.97 (2H, m), 1.29-1.34 (2H, m) , 1.48 (3H, d, J = 7.3Hz), 1.59 (3H, s), 2.23 (3H, s), 3.68 (3H, s), 5.10-5, 22 (1H, m), 7.39 (1H, s), 7.53 (1H, d, J = 8.8 Hz), 7.89 (1H, d, J = 8.8 Hz), 8, 10 (1H, dd, J = 2.2, 8.8 Hz), 8.33 (1H, d, J = 8.8 Hz), 8.42 (1H, d, J = 2.2

5Hz), 8.76 (1H, d, J = 8.1Hz). MS (ESI) m / z 347 (MH) -, 349 (M + H) +.

Example 14:

N - [(1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -2- (2,2,2-trifluoro-1-hydroxy-1-methylethyl) quinolin-6- carboxamide

image2 CH3 image2 OR

N FN FH

NCH3 NF H3C HO CH3

image2

It was prepared using Amine 2 and Carboxylic Acid 4. 1H NMR (300 MHz, DMSO-d6) δ1.49 (3H, d, J = 7.3 Hz), 1.84

10 (3H, s), 2.24 (3H, s), 3.69 (3H, s), 5.13-5.23 (1H, m), 6.99 (1H, s), 7.37 -7.43 (1H, m), 7.98 (1H, d, J = 9.2 Hz), 8.08 (1H, d, J = 8.5 Hz), 8.20-8.23 ( 1H, m), 8.54-8.57 (2H, m), 8.84 (1H, d, J = 8.5 Hz). MS (ESI): m / z 407 (M + H) +. Mixture of diastereoisomers (1: 1)

Example 15: N - [(1-ethyl-5-methyl-1H-pyrazol-4-yl) methyl] -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide

image46

F

It was prepared using commercially available 1- (1-ethyl-5-methyl-1H-pyrazol-4-yl) methanamine and Carboxylic Acid 1. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (3H , t, J = 7.3 Hz), 1.71 (6H, s), 2.28 (3H, s), 4.02 (2H, q, J = 7.3 Hz), 4.31 (2H , d, J = 5.1 Hz), 7.35 (1H, s), 7.86 (1H, d, J = 8.8 Hz), 8.07 (1H, d, J = 8.8 Hz ), 8.19 (1H, d, J = 8.8 Hz), 8.51 (1H, d, J = 8.8 Hz), 8.52 (1H, s), 8.89 (1H, t , J = 5.1 Hz). MS (ESI): m / z 405 (M + H) +

Example 16: N- [1- (1-ethyl-5-methyl-1H-pyrazol-4-yl) ethyl] -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide

F

20 It was prepared using commercially available 1- (1-ethyl-5-methyl-1H-pyrazol-4-yl) ethanamine and Carboxylic Acid 1H NMR (300 MHz, DMSO-d6) δ 1.27 (3H, t, J = 7.3 Hz), 1.49 (3H, d, J = 6.6 Hz), 1.71 (6H, s), 2.25 (3H, s), 4.01 (2H, q, J = 7.3 Hz), 5.15-5.26 (1H, m), 7.44 (1H, s), 7.87 (1H, d, J = 8.8 Hz), 8, 06 (1H, d, J = 8.8 Hz), 8.20 (1H, d, J = 8.8 Hz), 8.51 (1H, d, J = 8.8 Hz), 8.53 ( 1H, s), 8.85 (1H, d, J = 8.1 Hz). MS (ESI): m / z 419 (M + H) +.

Example 17: N- (1-cyclobutyl-5-methyl-1H-pyrazol-4-yl) ethyl) -2- (2,2,2-trifluoro-1,1-dimethylpropan-2-yl) quinoline-6-carboxamide

image47

image48

5

10

fifteen

twenty

25

30

35

image2 CH3 image49 O NN H CH3N

image2 CH3 CH3 F

F

To a stirred suspension of Example 9 (50.2 mg, 0.129 mmol) in toluene (10 ml), cyclobutanol (20 µl, 0.3 mmol) and cyanomethylene tri-N-butylphosphorane (40.0 mg, 0.166 mmol) were added to room temperature for 18 hours. The mixture was then heated to 100 ° C and stirred for 3 hours. The reaction mixture was concentrated in vacuo and the residue was purified by means of a TLC plate (1 mm thick plate, AcOEt-DCM = 1: 2) followed by preparative HPLC (Apparatus: Waters EM-trigger AutoPurification ™ system, Column: Waters XTerra C18, 19 x 50 mm, 5 µm particles, eluent: 0.01% aqueous MeOH / NH4OH) giving the title compound as a colorless oil (15.2 mg, 27% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.49 (3H, d, J = 6.6 Hz), 1.71 (6H, s), 1.71-1.82 (2H, m), 2.22 (3H, s), 2.23-2.35 (2H, m), 2.41-2.58 (2H, m), 4.76 (1H, tt, J = 8.1 Hz) , 5.11-5.24 (1H, m), 7.50 (1H, s), 7.87 (1H, d, J = 8.8 Hz), 8.06 (1H, d, J = 8 , 8 Hz), 8.20 (1H, dd, J = 1.5, 8.8 Hz), 8.49-8.54 (1H, m), 8.52 (1H, d, J = 1, 5Hz), 8.86 (1H, d, J = 8.1Hz). MS (ESI) m / z: 445 (M + H) +.

Example 18: (S) -N- (1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinolin -6-carboxamide and

Example 18a: (R) -N- (1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (2,2,2-trifluoro -1,1-dimethylethyl) quinolin -6-carboxamide

CH3 image2 Or and image2 CH3 image2 OR

image2 NN NN HH CF3

CF3 N

N

image2 NN

ClH3C image2 H3C H3C H3CCl CH3 CH3

Example 18: (S) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethanamine dihydrochloride (amine 10, 45 mg, 0.19 mmol), acid 2- (2,2,2 -trifluoro-1,1-dimethyl-ethyl) -quinoline-6-carboxylic acid (55 mg, 0.194 mmol) and 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3 hexafluorophosphate -tetramethyluronium (HATU) (73.8 mg, 0.194 mmol) were suspended in dichloromethane (5 ml). N, N-Diisopropylethylamine (0.102 ml, 0.58 mmol) was added and the reaction was stirred for 18 hours. The reaction was diluted with dichloromethane (10 ml), and washed with water (15 ml) then brine (15 ml), dried over Na2SO4, filtered and concentrated. The product was then purified by silica gel column chromatography, eluting with heptane / ethyl acetate = 100/0 to 0/100, to recover the title product as a white solid (55 mg, 67% yield) . NMR (400 MHz, CDCl3) δ 1.62-1.65 (3H, d) 1.71-1.73 (6H, s) 3.83 (3H, s) 5.30-5.38 (1H, dq) 6.43-6.47 (1H, da) 7.53-7.54 (1H, s) 7.66-7.70 (1H, d) 8.00-8.03 (1H, dd) 8.10-8.13 (1H, d) 8.17-8.20 (1H, d) 8.25-8.26 (1H, d). MS (ESI / APCI) m / z 425 (M + H) +. [α] D = +80.48 or (c 1.05, CH3OH).

Example 18a: (R) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethanamine dihydrochloride (amine 10a, 50 mg, 0.215 mmol), acid 2- (2,2,2-trifluoro- 1,1-dimethyl-ethyl) -quinoline-6-carboxylic acid (88.7 mg, 0.313 mmol) and 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3- hexafluorophosphate tetramethyluronium (HATU) (137 mg, 0.360 mmol) were suspended in dichloromethane (5 ml). N, N-Diisopropylethylamine (0.218 ml, 1.25 mmol) was added and the reaction was stirred for 18 hours. The reaction was diluted with dichloromethane (10 ml), and washed with water (15 ml) then brine (15 ml), dried over Na2SO4, filtered and concentrated. The product was then purified by silica gel column chromatography, eluting with heptane / ethyl acetate = 100/0 to 0/100, to recover the title product as a clear gum (80 mg, 51% yield) . NMR (400 MHz, CDCl3) δ 1.62-1.65 (3H, d) 1.71-1.73 (6H, s) 3.83 (3H, s) 5.30-5.38 (1H, dq) 6.43-6.47 (1H, da) 7.53-7.54 (1H, s) 7.66-7.70 (1H, d) 8.00-8.03 (1H, dd) 8.10-8.13 (1H, d) 8.17-8.20 (1H, d) 8.25-8.26 (1H, d). MS (ESI / APCI) m / z 425 (M + H) +. [α] D = -42.38 or (c 1.05, CH3OH).

Example 19: (S) -N- (1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide and

Example 19a: (R) -N- (1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide

CH3 image40 Or image2 CH3 image2 OR

and

image2 N

N

N

N

H

H

F

F

N

N

image2 N

Cl

Cl

H3C image2 FH3C F

FF

Example 19: The free base of (S) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) -ethanamine was formed by fractionating 150 mg of the hydrochloride salt (amine 10) between saturated aqueous NaHCO3 solution (20 ml) and ethyl acetate (20 ml), the organic phase was separated, washed with brine (10 ml), dried over Na2SO4, filtered and concentrated in vacuo. The free base (60 mg, 0.38 mmol), 2-trifluoromethylquinoline-6-carboxylic acid (90.7 mg, 0.376 mmol) and 5 2- (7-aza-1H-benzotriazol-1-yl) hexafluorophosphate - 1,1,3,3-tetramethyluronium (HATU) (143 mg, 0.376 mmol) were suspended in dichloromethane (5 ml). N, N-Diisopropylethylamine (0.196 ml, 1.13 mmol) was added and the reaction was stirred for 18 hours. The reaction was diluted with dichloromethane (10 ml), and washed with water (15 ml) then brine (15 ml), dried over Na2SO4, filtered and concentrated. The product was then purified by silica gel column chromatography, eluting with heptane / ethyl acetate = 100/0 to 0/100, and recrystallized from tert-butyl methyl ether to

10 Recover the title product as a white solid (100 mg, 70% yield). 1H NMR (400 MHz, CDCl3) δ 1.60-1.63 (3H, d) 3.79-3.80 (3H, s) 5.28-5.36 (1H, dq) 6.75- 6.80 (1H, da) 7.51 (1H, s) 7.73-7.76 (1H, d) 8.09-8.12 (1H, dd) 8.18-8.21 (1H, d) 8.34-8.35 (1H, d) 8.35-8.38 (1H, d). MS (ESI) m / z 383 (M + H) +.

Example 19a: (R) -N- (1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide can be prepared by the procedure of Example 19, using (R) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) -ethanamine instead of

15 enantiomer (S).

Example 20: N- (1- (1-ethyl-5-methyl-1H-pyrazol-4-yl) ethyl) -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide

CH3

To a DMF (3 ml) solution of 1- (1-ethyl-5-methyl-1H-pyrazol-4-yl) ethanamine (95 mg, 0.62 mmol), acid (2,2,2- trifluoro-1,1-dimethylethyl) quinoline-6-carboxylic acid (176 mg, 0.62 mmol), HBTU (284 mg, 0.748 mmol) and triethylamine

20 (0.434 ml, 3.12 mmol) and the mixture was stirred for 3 hours at room temperature. The reaction was quenched with saturated aqueous NaHCO3 and water, and the product was extracted with EtOAc / hexane (4: 1) (3x20 mL). The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography, using EtOAc / hexane (2: 1) to provide the title product (31 mg, 12%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ

1.27 (3H, t) 1.49 (3H, d), 1.71 (6H, s), 2.25 (3H, s), 4.0125 (1H, q), 5.19 (1H, m), 7.44 (1H, s), 7.86 (1H, d), 8.06 (1H, d), 8.20 (1H, d), 8.51 (1H, d), 8, 53 (1H, bs) 8.86 (1H, d). LCMS (ESI) RT = 3.11mins, m / z 417 (MH) -, 419 (M + H) +.

Example 21: (S) -N- (1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide and

Example 21a: (R) -N- (1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide

image38

CH3 image40 OR image2 CH3 image2 Or and

N NN NH HN NF F

H3C image2 image2 F H3CF N FF

F

F FFF F

image2

image2

image2

Example 21: N, N-Diisopropylethylamine (109 mg, 0.00084 mol) was added to 2- (trifluoromethyl) quinoline-6-carboxylic acid (81 mg, 0.00034 mol) in dichloromethane (4 ml) at room temperature under nitrogen atmosphere. O- (7-azabenzotriazol-1-yl) N, N, N ', N'-tetramethyluronium hexafluorophosphate (106 mg, 0.00028 mol) was added and the solution was stirred at room temperature for 5 minutes. (1S) -1- [1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl] ethanamine dihydrochloride (75 mg, 0.00028 mol) was dissolved in dichloromethane (2 ml) and added to the mixture reaction and the solution was stirred at

35 room temperature overnight. The solution was evaporated and the residue was dissolved in ethyl acetate and extracted with sodium carbonate solution (1x20 ml) and brine (2x20 ml). The organic phase was separated, dried (Na2SO4), filtered and evaporated to give a semisolid. The gum was dissolved in diethyl ether (3x10 ml) and evaporated to provide a solid. Yield 150 mg. The solid was dissolved in dichloromethane and purified using an ISCO Companion (column of 4 g silica and heptane to ethyl acetate: heptane 2: 3). The appropriate fractions were combined and

40 evaporated to give a white paper-like solid. The solid was suspended in diethyl ether (3x10 ml) and evaporated to give a white solid. Yield 90mg, 77%. 1H NMR (400 MHz CD3OD) δ 8.70, 8.68 (d, 1H) 8.51 (s, 1H) 8.24 (s, 2H) 5.50.5.49, 5.47, 5 , 45 (q, 1H) 4.00 (s, 3H) 1.62, 1.61 (d, 3H). MS (ESI) m / z 417 (M + H) +. LC-MS ESLD 100% m / z 417 (M + 1). TLC ethyl acetate: heptane 1: 1 0.6 UV + ve. Tpf 182-184 ° C. [α] D = +67.20 or (c 1.25, CH3OH).

Example 21a: (R) -N- (1- (1-Methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide can

45 prepared by the procedure of Example 21, using (1R) -1- [1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl] ethanamine dihydrochloride in place of the corresponding (S) enantiomer.

Example 22: (S) -N- (1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2 -il) quinoline-6-carboxami gives and

5

10

fifteen

twenty

25

30

35

40

Example 22a: (R) -N- (1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2 -il) quinoline-6-carboxami gives

image2 CH3 image40 OR image2 CH3 image40 O and N

image2 N NN HH CH3CH3 NN

image2 CF3 CF3 CF3

CF3 H3C

H3C

H3C H3C Example 22: N, N-Diisopropylethylamine (146 mg, 0.0013 mol) was added to 2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxylic acid (106 mg, 0 , 00038 mol) in dichloromethane (4 ml) at room temperature under nitrogen atmosphere. O- (7-azabenzotriazol-1-yl) N, N, N ', N'-tetramethyluronium hexafluorophosphate (143 mg, 0.00038 mol) was added and the solution was stirred for 5 minutes. (1S) -1- [1-Methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl] ethanamine dihydrochloride (100 mg, 0.00038 mol) was added to the reaction mixture and the solution was stirred at room temperature all night. The solution was evaporated and the residue was dissolved in ethyl acetate and washed with 10% sodium carbonate solution (2x20 ml) and brine (3x20 ml). The organic phase was separated, dried (Na2SO4), filtered and evaporated to give a colorless gum. Yield 170 mg. The gum was dissolved in dichloromethane and purified using an ISCO Companion (column of 12 g of silica and heptane to ethyl acetate: heptane 2: 3). The appropriate fractions were combined and evaporated to provide a colorless foam. Yield 150mg, 87%. 1H NMR (400MHz CD3OD) δ 8.41-8.39 (m, 2H) 8.13 (s, 2H) 7.83, 7.81 (d, 1H) 7.67 (s, 1H) 5 , 51, 5.49, 5.47, 5.45 (q, 1H) 4.00 (s, 3H) 1.75 (s, 6H) 1.62, 1.60 (d, 3H). MS (ESI) m / z 459 (M + H) +. LC-MS 100% ESLD m / z 459 (M + H) +. TLC ethyl acetate: heptane 1: 1 0.6 UV + ve. [α] D = +73.91 or (c 2.07, CH3OH).

Example 22a: N, N-Diisopropylethylamine (110 mg, 0.00085 mol) was added to 2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxylic acid (80.2 mg, 0 , 00028 mol) in dichloromethane (4 ml) at room temperature under nitrogen atmosphere. O- (7-azabenzotriazol-1-yl) N, N, N ', N'-tetramethyluronium hexafluorophosphate (180 mg, 0.00028 mol) was added and the solution was stirred for 5 minutes. (1R) -1- [1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl] ethanamine dihydrochloride (75.2 mg, 0.00028 mol) was added to the reaction mixture and the solution was stirred at room temperature overnight. The solution was evaporated and the residue was dissolved in ethyl acetate and washed with 10% sodium carbonate solution (2x20 ml) and brine (3x20 ml). The organic phase was separated, dried (Na2SO4), filtered and evaporated to provide a colorless gum. The gum was dissolved in dichloromethane and purified using an ISCO Companion (4 g silica column, heptane to ethyl acetate: heptane 1: 1). The appropriate fractions were combined and evaporated to provide a colorless foam. Yield 60mg, 46% 1H NMR (400MHz CD3OD) 8.41-8.39 (m, 2H) 8.13 (s, 2H) 7.83, 7.81 (d, 1H) 7.66 (s, 1H) 5.50, 5.48, 5.47, 5.45 (q, 1H) 4.00 (s, 3H) 1.75 (s, 6H) 1.62, 1.60 (d , 3H). MS (ESI) m / z 459 (M + H) + LC-MS 100% ESLD m / z 459 (M + H) + TLC ethyl acetate: heptane 1: 1 0.6 UV + ve [α] D = -71.25 or (c 1.0, CH3OH)

Example 23: (R) -N- (1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide

image2 CH3 image40 O NN H FN image2 CH3 FH3C F

2-Trifluoromethylquinoline-6-carboxylic acid (100 mg, 0.415 mmol) was dissolved in DCM (10 ml) and N, N-di-iso-propylethylamine (Hunig's base, 268 µl, 1.54 mmol) was added. HATU (158 mg, 0.415 mmol) was added followed by (1R) -1- [1,5-dimethyl-1H-pyrazol-4-yl] ethanamine dihydrochloride (88 mg, 0.415 mmol) and the solution was stirred at room temperature all night. The reaction mixture was concentrated and the residue was dissolved in EtOAc (65 ml) then fractionated with saturated aqueous NaHCO3 (2 x 20 ml) and then with brine (30 ml). The organic phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure to provide a golden oil / gum. The product was purified using an ISCO (12 g column), eluting with EtOAc: heptane (5:95 increasing to 100: 0). The fractions containing pure product were concentrated under reduced pressure to provide a white foamy solid, 150 mg, yield = 41%. 1H NMR (400MHz, CD3OD) δ 8.68 (1H, d), 8.47-8.49 (1H, m), 8.20-8.23 (2H, m), 7.92 (1H , d), 7.48 (1H, s), 5.29 (1H, q) 3.76 (3H, s), 2.33 (3H, s) and 1.61 (3H, d). LCMS (2 minute cycle): UV (1.37 min, 82%); ELSD (1.37 min, 100%). Ion mass: 363 = MH +

Example 24: 6-tert-butyl-N- [1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -2-naphtamide

CH3 O

CH3

It was prepared by the procedure of Example 1 using Amine 1 and Carboxylic Acid 2. 1H NMR (300 MHz, DMSO-d6) δ 1.39 (9H, s), 1.49 (3H, d, J = 8 , 1Hz), 2.24 (3H, s), 3.69 (3H, s), 5.14-5.20 (1H, m), 7.40 (1H, s), 7.70 (3H , d, J = 10.8 Hz), 7.87-7.96 (4H, m), 8.39 (1H, s), 8.69 (1H, d, J = 8.1 Hz). MS (ESI) m / z 348 (MH) -, 350 (M + H) +.

5 Example 25: 6-tert-butyl-N - [(3,5-dimethyl-1H-pyrazol-4-yl) methyl] -2-naphtamide

CH3

It was prepared by the procedure of Example 1 using (3,5-dimethyl-1H-pyrazol-4-yl) methanamine and Carboxylic Acid 2. 1H-NMR (300 MHz, CDCl3) δ 1.42 (9H, s), 2.32 (3H, s), 4.49 (2H, d, J = 6.0Hz), 6.13 (1H, bs), 7.61-7.65 (1H, m), 7.76 -7.87 (4H, m), 8.22 (1H, s). MS (ESI) m / z 334 (MH) -, 336 (M + H) +.

10 Example 26: 6-tert-butyl-N - [(1,3-dimethyl-1H-pyrazol-4-yl) methyl] -2-naphtamide

CH3

It was prepared by the procedure of Example 1 using (1,3-dimethyl-1H-pyrazol-4-yl) methanamine and Carboxylic Acid 2. 1H-NMR (300 MHz, CDCl3) δ 1.42 (9H, s), 2.30 (3H, s), 3.83 (3H, s), 4.50 (2H, d, J = 6.0 Hz), 6.26 (1H, br. S), 7.36 (1H , s), 7.62-7.66 (1H, m), 7.76-7.87 (4H, m), 8.22 (1H, s). MS (ESI) m / z 334 (MH) -, 336 (M + H) +.

15 Example 27: 6-tert-butyl-N - [(1,5-dimethyl-1H-pyrazol-4-yl) methyl] -2-naphtamide

image50

image51

Image52

CH3

It was prepared by the procedure of Example 1 using 1- (1,5-dimethyl-1H-pyrazol-4-yl) methanamine and Carboxylic Acid 2. 1H NMR (300 MHz, DMSO-d6) δ 1.38 (9H , s), 2.27 (3H, s), 3.69 (3H, s), 4.29 (2H, d, J = 5.9 Hz), 7.32 (1H, s), 7.69 (1H, dd, J = 8.8, 2.2 Hz), 7.85-7.98 (4H, m), 8.39 (1H, s), 8.85 (1H, t, J = 5 , 5 Hz). HPLC Prep (Basic 32-68,

20 TR = 3.52 min).

Example 28: 6-tert-butyl-N- (1- (1,5-dimethyl-1H-pyrazol-4-yl) propyl) -2-naphtamide

image53

image54

It was prepared by the procedure of Example 1 using Amine 5 and Carboxylic Acid 2. 1H NMR (300 MHz, CDCl3) δ 1.01 (3H, t, J = 6.0 Hz), 1.42 (9H, s), 1.90-2.09 (2H, m), 2.31 (3H, s), 3.79 (3H, s), 5.06-5.14 (1H, m), 6.22 (1H, da, J = 6.0Hz), 7.44 (1H, s), 7.61-7.64 (1H, m), 7.75-7.86 (4H, m), 8, 20 (1H, s). MS (ESI) m / z 362 (MH) -, 364 (M + H) +.

5 Example 29: N- (1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl) -6- (trifluoromethyl) -2-naphtamide

It was prepared by the procedure of Example 1 using Amine 1 and 6- (trifluoromethyl) -2-naphthoic acid. 1H NMR (300 MHz, DMSO-d6) δ 1.49 (3H, d, J = 6.0 Hz), 2.24 (3H, s), 3.69 (3H, s), 5.13- 5.22 (1H, m), 7.41 (1H, s), 7.80-7.84 (1H, m), 8.04-8.08 (1H, m), 8.19-8, 27 (2H, m), 8.48 (1H, s), 8.55 (1H, s), 8.83 (1H, da, J = 9.0 Hz). MS (ESI) m / z 360 (M

10-H) -, 362 (M + H) +.

Example 30: N - [(1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -6- (1-methylcyclopropyl) -2-naphthamide

It was prepared by the procedure of Example 1 using Amine 2 and Carboxylic Acid 6. 1H NMR (270 MHz, DMSO-d6) δ 0.79-0.92 (2H, m), 0.92-1, 04 (2H, m), 1.42-1.55 (6H, m, including 3H, s, 1.49 ppm), 2.23 (3H, s), 3.68

(3H, s), 5.16 (1H, m), 7.33-7.44 (2H, m), 7.80 (1H, s), 7.84-7.95 (3H, m) , 8.37 (1H, s), 8.68 (1H, d, J = 8.6 Hz). MS (ESI): m / z 348 (M + H) +.

Example 31: N - [(1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -6- (2,2,2-trifluoro-1-hydroxy-1-methylethyl) - 2-naphtamide and

Example 32: N - [(1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -6 - [(1R) -2,2,2-trifluoro -1-hydroxy-1 -methylethyl] -2-naphtamide

H3C HO CH3

To a solution in DMF (1.0 ml) of (1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethanamine hydrochloride (amine 2) (75 mg, 0.352 mmol), were added (R, S) -6- (2,2,2-Trifluoro-1-hydroxy-1-methylethyl) -2-naphthoic acid (Carboxylic acid 7) (100mg, 0.352mmol), HBTU (160mg, 0.422mmol ) and triethylamine (0.245 ml, 1.76 mmol) and the mixture was stirred for 2 hours at room temperature. The reaction was quenched with saturated aqueous NaHCO3 and water, and the product was extracted with EtOAc. The organic extract was dried over Na2SO4, and concentrated in vacuo. The mixture was applied to a chromatography in

25 silica gel column and eluted with hexane / ethyl acetate (1: 2) to provide the diastereoisomer mixture (Example 31, 77 mg, 54% yield) as a white solid. The product was purified by HPLC (column: DAICEL CHIRALPAK AD-H 250mm x 20mm, n-hexane / ethanol / Diethylamine = 80/20 / 0.1 as eluent) to provide the title product (Example 32, 5.7 mg , 2nd peak, retention time: 17.9 min) as a white solid as a single diastereoisomer. 1H NMR (300 MHz, CDCl3) δ 1.64 (3H, d, J = 6.6 Hz), 1.89 (3H, s), 2.32

30 (3H, s), 3.80 (3H, s), 5.31-5.39 (1H, m), 6.34-6.38 (1H, m), 7.54 (1H, s) , 7.70-8.09 (5H, m), 8.24 (1H, s). MS (ESI): m / z 406 (M + H) +.

image55

image56

Image57

Example 32a: N - [(1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -6 - [(1S) -2,2,2-trifluoro -1-hydroxy-1 -methylethyl] -2-naphtamide

5

10

fifteen

twenty

25

image2 CH3 Image58 O NN

H N

image2 F

CH3H3C HO CH3

To a solution in DMF (4 ml) solution of Amine 2 ((1R) -1- (1,5-dimethyl-1H-pyrazol-4-yl) ethanamine dihydrochloride, 74.6mg, 0.352 mmol), the Carboxylic acid 7, (6- (2,2,2- trifluoro-1-hydroxy-1-methylethyl) -2-naphthoic acid, 100 mg, 0.352 mmol), HBTU (160 mg, 0.422 mmol) and triethylamine (0.245 ml , 1.76 mmol) and the mixture was stirred for 24 hours at room temperature. The reaction was quenched with saturated aqueous NaHCO3 and water, and the product was extracted with EtOAc 3 times. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to provide the product as a mixture of diastereoisomers, which were purified by chiral HPLC to provide the title product as a white amorphous solid. (18.3 mg, 12.8% yield). 1H NMR (300 MHz, CDCl3) δ 1.64-1.66 (3H, d), 1.88-1.89 (3H, s) 2.30-2.33 (3H, s) 3.79 -3.81 (3H s) 5.31-5.36 (1H, m) 6.33-6.38 (1H, da) 7.54 (1H, s) 7.72-7.76 (1H, dd) 7.87-7.90 (1H, d) 7.91-7.94 (2H, dt) 8.08-8.09 (1H, s) 8.23-8.24 (1H, s) MS (ESI) m / z 406 (M + H) +.

Example 33: N- [1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -6- (2,2,2-trifluoro-1-methoxy-1-methylethyl) -2-naphthamide

image2 CH3 image2 Or *

N FN F

H N

image2 CH3 * F

H3C H3CO CH3

It was prepared by the procedure of Example 1 from Amine 2 and Carboxylic Acid 8. 1H NMR (300 MHz, CDCl3) δ 1.65 (3H, d, J = 5.8 Hz), 1.90 (3H, s), 2.31 (3H, s), 3.28 (3H, s), 3.80 (3H, s), 5.31-5.36 (1H, m), 6.27- 6.29 (1H, m), 7.51 (1H, s), 7.71-7.98 (5H, m), 8.26 (1H, s). MS (ESI): m / z 420 (M + H) +.

Example 34: 6-tert-butyl-N - [(1,5-dimethyl-1H-pyrazol-4-yl) methyl] quinoline-2-carboxamide

OR

N N

N H

image2 CH3N image2 CH3 CH3H3C CH3

It was prepared by the procedure of Example 1 using 1- (1,5-dimethyl-1H-pyrazol-4-yl) methanamine and Carboxylic Acid 3. 1H NMR (300 MHz, DMSO-d6) δ 1.39 (9H , s), 2.28 (3H, s), 3.68 (3H, s), 4.33 (2H, d, J = 6.6 Hz), 7.34 (1H, s), 7.93 -8.15 (4H, m), 8.51 (1H, d, 8.8Hz), 9.04 (1H, t, J = 6.24Hz). HPLC-Prep (basic 32-68, RT = 3.72 min) MS (ESI) m / z 337 (M + H) +.

Example 35: 6-tert-butyl-N - ((1,3,5-trimethyl-1H-pyrazol-4-yl) methyl) -2-naphtamide

OH3 image2 C NN H

image2 CH3N CH3 CH3H3C CH3

It was prepared by the procedure of Example 1 using (1,3,5-trimethyl-1H-pyrazol-4-yl) methanamine and Acid 5

10

fifteen

twenty

25

30

35

carboxylic 2. 1H NMR (300 MHz, CDCl3) δ 1.42 (9H, s), 2.27 (6H, s), 3.74 (3H, s), 4.46 (2H, d, J = 6.0 Hz), 6.10 (1H, bs), 7.61-7.65 (1H, m), 7.75-7.86 (4H, m), 8.21 (1H, s). MS (ESI) m / z 348 (MH) -, 350 (M + H) +

Example 36: 6-tert-butyl-N - [(1-methyl-1H-pyrazol-4-yl) methyl] -2-naphtamide

OR

N image59 CH3

CH3H3C CH3

It was prepared by the procedure of Example 1 using (1-methyl-1H-pyrazol-4-yl) methanamine and Carboxylic Acid

2. 1H-NMR (300 MHz, CDCl3) δ 1.42 (9H, s), 3.89 (3H, s), 4.55 (2H, d, J = 6.0 Hz), 6.43 (1H, bs), 7.45 (1H, s), 7.52 (1H, s), 7.61-7.65 (1H, m), 7.79-7.86 (4H, m), 8.23 (1H, s). MS (ESI) m / z 320 (MH) -, 322 (M + H) +

Example 37: N- [1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -6- (1-hydroxy-1-methylethyl) -2-naphtamide

image60 CH3 image2 O NN H OHN CH3

H3C H3C CH3

To a solution in DMF (3 ml) of 6- (1-hydroxy-1-methyl-ethyl) -naphthalene-2-carboxylic acid (US 4638087, published January 20, 1987, 95 mg, 0.413 mmol), Amine 9 (1- (5-Methyl-1H-pyrazol-4-yl) ethanaminadhydrochloride, 95 mg, 0.352 mmol), HBTU (188 mg, 0.495 mmol) and triethylamine (0.173 ml, 1.24 mmol) were added and the mixture was stirred for 24 hours at room temperature. The reaction was quenched with saturated aqueous NaHCO3 and water, and the product was extracted with EtOAc 3 times. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) to provide the title product as a white solid (84.4 mg, 58.2% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.46-1.49 (3H, d), 1.50-1.53 (6H, s) 2.22-2.24 (3H, s) 3 , 67-3.68 (3H s) 5.13-5.20 (2H, m) 7.38-7.39 (1H, s) 7.69-7.72 (1H, d) 7.81- 8.00 (4H, m) 8.39-8.40 (1H, s) 8.68-8.72 (1H, d). MS (ESI) m / z 352 (M + H) +.

Example 38: N - ((1S) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (pentafluoroethyl) quinoline-6-carboxamide

image2 CH3 image61 OR

image2 NN

F N

H F ClH3C FF

(S) -1- (5-chloro-1-methyl-1H-pyrazol-4-yl) -ethanamine dihydrochloride (36 mg, 0.155 mmol), 2-pentafluoroethylquinoline-6-carboxylic acid (45 mg, 0.16 mmol ) and 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (65 mg, 0.171 mmol) were suspended in dichloromethane (5 ml). N, N-Diisopropylethylamine (0.108 mL, 0.62 mmol) was added and the reaction was stirred for 18 hours. The reaction was diluted with dichloromethane (15 ml), and washed with water (15 ml), the organics were concentrated to provide the crude product. The product was then purified by an ISCO Biotage column using 0-100% EtOAc in heptane to provide the title product as a clear gum (55mg, 70% yield). NMR (400 MHz, CD3OD) δ 1.60-1.63 (3H, d) 3.81 (3H, s) 5.28 (1H, dq) 7.61 (1H, s) 7.92 (1H, d) 8.23 (2H, dd) 8.50 (1H, s) 8.67 (1H, d) 8.97 (1H da). LCMS: retention time: 1.55 minutes, MS (ESI) m / z 433 (M + H +).

Procedure for evaluating biological activities

Human VR1 antagonist assay

VR1 antagonist activity can be determined by the Ca2 + imaging assay using cells highly expressing human VR1. Cells with high expression of human VR1 receptors can

obtained by a number of different conventional procedures. A standard procedure is human dorsal root ganglion (DRG) or kidney cloning according to the procedures described in Nature, 389, pages 816-824, 1997. Alternatively, human keratinocytes are also known. with high expression of VR1 receptors and have been published in the publication article5 Biochemical and Biophysical Research Communications, 291, pages 124-129, 2002). In this article, human keratinocytes demonstrated a VR1-mediated intracellular increase of Ca2 + by the addition of capsaicin. In addition, the method of upregulating the human VR1 gene, which is usually a silent gene or does not produce detectable levels of VR1 receptors, is also available to obtain suitable cells. Said genetic modification procedure was described in detail; Nat. Biotechnol., 19, pages

10 440-445, 2001.

Cells expressing human VR1 receptors were kept in a culture flask at 37 ° C in an environment containing 5% CO2 until use in the assay. Intracellular Ca2 + imaging assay to determine VR1 antagonism activities were performed by the following procedures.

The culture medium was removed from the flask and fura-2 / AM fluorescent calcium indicator was added to the flask at a

5 µM concentration in the medium. The flask was placed in a CO2 incubator and incubated for 1 hour. Cells expressing human VR1 receptors were then removed from the flask followed by washing with phosphate buffered saline, PBS (-) and resuspended in assay buffer. 80 µl aliquot of cell suspension (3.75 x 105 cells / ml) was added to the assay plate and the cells were pelleted by centrifugation (950 rpm, 20 ° C, 3 minutes).

The compounds of the examples were tested in the human VR1 antagonist assay described above. The 50% inhibition concentration (IC50) values are presented in the following table.

Table 1

No. of Ex.

IC50 (nM) No. of Ex. IC50 (nM) No. of Ex. IC50 (nM) No. of Ex. IC50 (nM)

1

25.2 eleven 16.4 24 2. 3 33 139

2

261 12 79.9 25 118 3. 4 254

3

322 13 313 26 443 35 1870

4

607 14 63.7 27 73 36 3480

5

44.1 fifteen 71.7 28 57.4 37 1000

6

26.6 16 28.9 29 189

7

145 17 124 30 20.1

8

66.0 18 18a 17.97 3 31 177

9

323 2. 3 121 32 32a 52.7 3190 capsazepine 237-455

Capsaicin Stimulation Assay

Capsaicin-induced changes in intracellular calcium concentration were monitored using FDSS 6000 (Hamamatsu Photonics, Japan), a fluorometric imaging system. The cell suspension in Krebs-Ringer HEPES (KRH) buffer (115 mM NaCl, 5.4 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 11 mM D-Glucose, 25 mM HEPES, 0.96 mM Na2HPO4, a pH 7.3) were pre-incubated with varying concentrations of the test compounds or with KRH buffer (buffer control) for 15 minutes at room temperature in the dark.

Capsaicin solution, giving 300 nM in assay mix, was then automatically added to the assay plate by the FDSS 6000.

Acid stimulation test

Acid-induced changes in intracellular calcium concentration were monitored using FDSS 6000 (Hamamatsu Photonics, Japan), a fluorometric imaging system. The cell suspension in resting buffer (HBSS supplemented with 10 mM HEPES, pH 7.4) was pre-incubated with varying concentrations of the test compounds or resting buffer (buffer control) for 15 minutes at room temperature in the dark. Cells were automatically added to the stimulation solution (HBSS supplemented with MES, final pH of assay buffer 5.8) using FDSS 6000. IC50 values of VR1 antagonists were determined based on half the increase they demonstrated buffer control samples after

40 acid stimulation.

Determination of antagonist activity

Monitoring of changes in fluorescence signals (λex = 340 nm / 380 nm, λem = 510-520 nm) started 1 minute before addition of capsaicin or acid buffer solution and continued for 5 minutes. The IC50 values of the VR1 antagonists were determined based on half the increase that the buffer control samples demonstrated after agonist stimulation.

Human VR1 Agonist Assay

Cells expressing human VR1 receptors were kept in a culture flask at 37 ° C in an environment containing 5% CO2 until use in the assay. Intracellular Ca2 + imaging assay to determine VR1 agonism activities were performed by the following procedures. The culture medium was removed from the flask and fura-2 / AM fluorescent calcium indicator was added to the flask at a concentration of 5 µM in the medium. The flask was placed in a CO2 incubator and incubated for 1 hour. Cells expressing human VR1 receptors were then removed from the flask followed by washing with phosphate buffered saline, PBS (-) and resuspended in Krebs-Ringer HEPES buffer (KRH): 115 mM NaCl, 5.4 mM KCl, MgSO4 1 mM, 1.8 mM CaCl2, 11 mM D-Glucose, 25 mM HEPES, 0.96 mM Na2HPO4, pH 7.3.

Assay in 96-well format

Test compound-induced changes in intracellular calcium concentration were monitored using FDSS 6000 (Hamamatsu Photonics, Japan), a fluorometric imaging system. The 80 µl aliquot of the cell suspension (3.75 x 105 cells / ml) in KRH buffer was distributed into the 96-well plates, and then this assay plate was introduced into the FDSS6000. Finally 20 µl of varying concentrations of test compounds or KRH buffer (buffer control) or 1 µM capsaicin (maximum response control) were automatically added to the assay plate by the FDSS 6000.

384-well format assay

The 30 µl aliquot of the cell suspension (8 x 105 cells / ml) in KRH buffer was distributed into the 384-well plates, and then this assay plate was introduced into the FDSS6000. Finally 15 µl of varying concentrations of test compounds or KRH buffer (buffer control) were automatically added

or 2 µM capsaicin (maximum response control) to the assay plate using the FDSS 6000.

Determination of agonist activity

The control of the changes of the fluorescence signals (λex = 340 nm / 380 nm, λem = 510 - 520 nm) was started 1 minute (96-well format) or 15 seconds (384-well format) before the addition of the test compounds and continued for 5 minutes. The EC50 values of the compounds were determined from the maximum response of the test compounds. Emax values were determined in terms of percentage of the response induced by 1 µM (96-well format) or 2 µM (384-well format) capsaicin.

Chronic Constriction Injury Model (ICC Model)

Male Sprague-Dawley rats (270-300 g; B.W., Charles River, Tsukuba, Japan) were used. Chronic constriction injury (CCI) operation was performed according to the procedure described in Bennett and Xie (Bennett, G.J. and Xie, Y.K. Pain, 33: 87-107, 1988). Briefly, the animals were anesthetized with sodium pentobarbital (64.8 mg / kg, i.p.) And the left common sciatic nerve was exposed at the mid-thigh level by blunt dissection through the biceps femoris. The part proximal to the sciatic trifurcation was freed from the adherent tissues and 4 ligatures (4-0 silk thread) were tied loosely around it with a gap of approximately 1 mm. The sham operation was performed the same as the ICC operation with the exception of the sciatic nerve ligation. Two weeks after the operation, mechanical allodynia was assessed by applying von Frey filaments (VFH) to the plantar surface of the posterior leg. The minimum amount of VFH force required to elicit a response was recorded as the Paw Withdrawal Threshold (PWT). The VFH test was performed 0.5, 1, and 2 hours after dosing. The experimental data were analyzed using a Kruskal-Wallis test followed by a Dunn test for multiple comparisons or a Mann-Whitney U test for the paired comparison.

Mono-iodoacetate (MIA) -induced osteoarthritis model

6 week old male Sprague-Dawley rats (SD, Japan SLC or Charles River Japan) were anesthetized with pentobarbital. The MIA injection site (knee) was shaved and cleaned with 70% EtOH. 25 µl of MIA or saline solution was injected into the right knee joint using a 29 gauge needle. The effect of joint damage on weight distribution between the right (damaged) and left (untreated) knee was evaluated using a disability meter (Linton Instrumentation, Norfolk, UK). The force exerted by each hind limb was measured in grams. Weight bearing deficit (WB) was determined by the difference in weight loaded on each leg. Rats were trained to measure WB once a week for up to 20 days after MIA injection. The analgesic effect of the compounds was measured 21 days after MIA injection. Before compound administration, WB deficit was measured prior to administration. After the administration of the compounds, the attenuation of the WB deficits was determined as the analgesic effect.

Complete Freund's Adjuvant (CFA) Induced Thermal and Mechanical Hyperalgesia in Rats

Thermal hyperalgesia

6 week old male SD rats were used. Freund's complete adjuvant (CFA, 300 µg Mycobacterium Tuberculosis H37RA (Difco, MI) in 100 µl liquid paraffin (Wako, Osaka, Japan)) was injected into the plantar surface of the hind legs of rats. Two days after the CFA injection, thermal hyperalgesia was determined by the procedure described above (Hargreaves et al., 1988) using the plantar test apparatus (Ugo-Basil, Varese, Italy). The rats were adapted to the test environment for at least 15 minutes before any stimulation. Radiant heat was applied to the plantar surface of the hind paw and latencies to paw withdrawal (PWL, seconds) were determined. The intensity of the radiant heat was adjusted to produce a stable PWL for 10 to 15 seconds. The test compound was administered in a volume of 0.5 ml per 100 g of body weight. PWLs were measured 1, 3, or 5 hours after drug administration.

Mechanical hyperalgesia

4 week old male SD rats were used. CFA (300 µg of Mycobacterium Tuberculosis H37RA (Difco, MI) in 100 µl of liquid paraffin (Wako, Osaka, Japan)) was injected into the plantar surface of the hind paw of rats. Two days after CFA injection, mechanical hyperalgesia was determined by measuring the paw withdrawal threshold (PWT, grams) at pressure using the analgesia meter (Ugo-Basil, Varese, Italy). The animals were gently restrained and the pressure applied to the dorsal surface of a hind leg was uniformly increased by means of a plastic spike. The pressure necessary to cause withdrawal of the paw was determined. The test compound was administered in a volume of 0.5 ml per 100 g of body weight. PWTs were measured 1, 3, or 5 hours after drug administration.

Permeation test of parallel artificial membranes （PAMPA）

Experiments were performed in 96-well donor and recipient plates. Such a 96-well system was described in Journal of Medicinal Chemistry, 1998, vol. 41, no. 7, 1007-1010. As material of the artificial membrane, 4% phosphatidylcholine and 1% stearic acid in dodecane were used. The receiving plate (96-well hydrophobic filter plate (MAIP N45, Millipore)) was prepared by adding 5 µl of artificial membrane material on top of the filter and the plate was filled with 250 µl of buffered Hank's Balanced Salt Solution (HBSS). with 2- (N-morpholino) ethanesulfonic acid (MES) (pH 6.5). The donor plate (Transport Receiver plate (MATRNPS50, Millipore)) was filled with 300 µl of MES-buffered HBSS (pH 6.5) containing 10 µM of the test compounds. The recipient plate was placed on the donor plate forming a "sandwich" and incubated at 30 ° C for 2.5 hours. After the incubation period, the recipient, donor and initial donor (control) solution were analyzed by LCMS / MS. The data were expressed in terms of the effective permeability value in cm X 106 / sec and the retention value of the membrane.

Human dofetilide binding

A paste of HEK-293 cells expressing the HERG product can be suspended in a 10-fold volume of 50 mM Tris buffer adjusted to pH 7.5 at 25 ° C with 2 M HCl containing 1 mM MgCl2 and 10 mM KCl. Cells were homogenized using a Polytron homogenizer (at maximum power for 20 seconds) and centrifuged at

48,000 g for 20 minutes at 4 ° C. The pellet was resuspended, homogenized and centrifuged once more in the same way. The resulting supernatant was discarded and the final pellet was resuspended (10-fold volume of 50 mM Tris buffer) and homogenized at full power for 20 seconds. The membrane homogenate was aliquoted and stored at -80 ° C until use. An aliquot was used to determine protein concentration using a Protein Assay Rapid Kit and an ARVO SX plate reader (Wallac). All handling, stock solution, and equipment were kept on ice at all times. For saturation tests, experiments were performed in a total volume of 200 µl. Saturation was determined by incubating 20 µl of [3H] -dofetilide and 160 µl membrane dehomogenates (20-30 µg protein per well) for 60 min at room temperature in the absence or presence of 10 µM dofetilide at final concentrations (20 µl) for total or non-specific binding, respectively. All incubations were terminated by rapid vacuum filtration on polyetherimide (PEI) soaked glass fiber filter papers using a Skatron cell harvester followed by two washes with 50 mM Tris buffer (pH 7.5 at 25 ° C). Receptor-bound radioactivity was quantified by liquid scintillation counting using a Packard LS counter.

For the competition assay, compounds were diluted in 96-well polypropylene plates with 4-point dilutions in half-log format. All dilutions were made in DMSO first and then transferred to 50 mM Tris buffer (pH 7.5 at 25 ° C) containing 1 mM MgCl2, 10 mM KCl so that the final DMSO concentration was 1%. Compounds were dispensed in triplicate into assay plates (4 µl). The total binding and non-specific binding wells were established in 6 wells as vehicle and 10 µM dofetilide with final concentration, respectively. The radioligand was prepared to a final concentration of 5.6x and this solution was added to each well (36 µl). The assay was initiated by the addition of YSi poly-L-lysine scintillation proximity assay (SPA) beads (50 µl, 1 mg / well) and membranes (110 µl, 20 µg / well). Incubation was continued for 60 min at room temperature. The plates were incubated for another 3 hours at room temperature for the beads to settle. The radioactivity bound to the receptors was quantified using a Wallac MicroBeta plate counter.

IHERG trial

HEK 293 cells stably expressing the HERG potassium channel were used for the electrophysiological study. The methodology for stable transfection of this channel in HEK cells can be found elsewhere (Z. Zhou et al., 1998, Biophysical Journal, 74, pages 230-241). Before the day of experimentation, cells were harvested from culture flasks and plated on glass covers in Minimum Essential (MEM) standard with 10% fetal calf serum (FCS). The plated cells were stored in an incubator at 37 ° C and kept in an atmosphere of 95% O2 / 5% CO2. Cells were studied 15-28 hours after harvesting.

HERG currents were studied using standard whole cell mode voltage control techniques. During the experiment, cells were superfused with a standard external solution of the following composition (mM); NaCl, 130; KCl, 4; CaCl2, 2; MgCl2, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. Whole cell recordings were made using a voltage control amplifier and patch pipettes having a resistance of 1-3MOhm when loaded with the standard internal solution of the following composition (mM); KCl, 130; MgATP, 5;

MgCl2, 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH. Only cells with access resistances below 15 MΩ and sealing resistances> 1 GΩ were accepted for further experimentation. Series resistance compensation was applied up to a maximum of 80%. No escape subtraction was performed. However, the acceptable access resistance depended on the magnitude of the recorded currents and the level of series resistor compensation that can be safely used. After achieving full cell configuration and sufficient time for cell solution pipetting dialysis (> 5 min), a standard voltage protocol was applied to the cell to elicit membrane currents. The voltage protocol is as follows. The membrane was depolarized from the resting potential of -80 mV to +40 mV for 1000 ms. This was followed by a decrease in voltage (rate 0.5 mV ms-1) to resting potential. The voltage protocol was applied to the cell continuously throughout the experiment every 4 seconds (0.25Hz). The amplitude of the peak current elicited at approximately -40 mV during the descent was measured. Once stable responses of the current elicited in the external solution were obtained, vehicle (0.5% DMSO in the standard external solution) was applied for 10-20 min by means of a peristaltic pump. When the changes in the amplitude of the current response elicited under the vehicle control conditions were minimal, the test compound was applied at 0.3, 1, 3, 10 µM for a period of 10 minutes. 10 minutes included the time that the supply solution passed through the tube from the solution reservoir to the recording chamber via the pump. The exposure time of the cells to the compound solution was greater than 5 min after the drug concentration in the chamber had well reached the intended concentration. There was a subsequent washout period of 10-20 minutes to assess reversibility. Finally, the cells were exposed to a high dose of dofetilide (5 µM), a blocker

20 specific to IKr, to evaluate the endogenous insensitive current.

All experiments were carried out at room temperature (23 ± 1ºC). The evoked membrane currents were recorded online on a computer, filtered at 500-1 KHz (Bessel -3dB) and sampled at 1-2 KHz using the voltage control amplifier and a specific data analysis program. The maximum amplitude of the current, which occurred at approximately -40mV, was measured offline on the computer.

The arithmetic mean of the ten amplitude values was calculated under the vehicle control conditions and in the presence of drug. The percentage decrease of IN in each experiment was obtained through the normalized current value using the following formula: IN = (1- ID / IC) x100, where ID is the mean value of the current in the presence of drug and IC is the value medium of the current under the control conditions. Separate experiments were performed for each drug or control concentration at the same times and the arithmetic mean of each experiment was

30 defined as the result of the study.

Substrate Cocktail Single Point Drug Interaction Assay (cDDI)

Test compounds (3 µM) were preincubated in 0.1 mg / ml human liver microsomes with 1 mM MgCl2, 1 mM NADP +, 5 mM isocitric acid, and 1 U / ml isocytric dehydrogenase in 100 mM potassium phosphate buffer. (pH7.4) at 37 ° C in a number of 96-well plates. After 5 minutes of preincubation, the reaction was started

35 by adding substrate cocktail that included all substrates shown in the following Table. After an 8 minute incubation, a plate was removed from the incubator and the reaction was terminated with an incubation volume of acetonitrile. The concentrations of the metabolites in supernatant were measured by a LC / MS / MS system. The percent inhibition for each CYP was calculated using the following equation:

% Inhibition = (1- (the amount of metabolite with the test compound) / (Average amount of the metabolite without the 40 test compound)) X 100

Table 2: Conditions for the drug interaction test

CYP

substratum Substrate conc. (ΜM) Metabolite

1A2

Tacrine 2 1'-hydroxytacrine

2C9

Diclofenac 5 4'-hydroxydiclofenac

2C19

S-Mephenytoin 40 4'-hydroxymephenytoin

2D6

Dextromethorphan 5 Dextrorphan

3A

Midazolam 2 1'-hydroxymidazolam

Intrinsic removal

Test compounds (1 µM) were incubated with 1 mM MgCl2, 1 mM NADP, 5 mM isocytric acid, 1 U / ml of

Isocyteric dehydrogenase and 0.8 mg / ml HLM (human liver microsomes) in 100 mM potassium phosphate buffer (pH 7.4) at 37 ° C in a number of 384-well plates. At various times a plate was removed from the incubator and the reaction was terminated with two incubation volumes of acetonitrile. The concentration of the compound in the supernatant was measured by a LC / MS / MS system. The intrinsic removal value (Clint) was calculated using the following equations:

50 Elint (µl / min / mg protein) = (k x incubation volume) / protein concentration

k (min1) = - slope of ln (concentration as a function of time)

Determination of pA2 values against capsaicin stimulation

Antagonist pA2 values versus capsaicin dose response were determined using a Ca2 + imaging assay with cells expressing elevated levels of human VR1 (for explanation of the theory behind pA2 determinations, see Terry P. Kenakin A Pharmacological Primer: Theory, Applications, and Methods 2nd edition, pages 102-108, Academic Press, New York, 2006). Cells expressing high levels of VR1 were obtained by generating a human keratinocyte cell line with heterologous expression of VR1 controlled by an inducible promoter. Specifically, cells expressing human VR1 controlled by a human cytomegalovirus (CMV) immediate-early promoter and two tetracycline 2 (TetO2) operator sites were prepared using the T-REx system (Invitrogen, Carlsbad, CA, USA). . Details and procedures relating to this system have been published (Hum. Gene Ther. 9, pages 1939-1950, 1998; Annu. Rev. Microbiol. 48, pages 345-369, 1994; Mol. Biol. 169, pages 707-721, 1983). VR1 was subcloned into the T-REx System pcDNA5 / TO vector (Invitrogen Catalog # V1033-20) which was transfected into the T-REx System Human Keratinocyte line (Invitrogen Catalog # R710-07) to from which a stable cell line expressing VR1 was established after induction by exposure to tetracycline or doxycycline (Hum. Gene Ther. 9, pages 1939-1950, 1998; instructions that come with the purchase of the products listed above) . Cells were maintained in a CO2 incubator (5% CO2) at 37 ° C in culture medium containing DMEM with phenol red (Mediatech catalog no: 15-017-CV) supplemented with 10% fetal bovine serum. Heat Inactivated, 5% Penicillin-Streptomycin (Mediatech Cat #: 30-002-CI), 5% Glutamax® (L-Alanyl-L-Glutamine, Mediateach Cat #: 25-015-CI) , 200 µg / ml hygromycin (Mediatech #: 30-240-CR), 0.5 µg / ml blasticidin (Invitrogen # 46-1120)).

For assay preparation, cells expressing human VR1 were plated as described above in 96-well plates (Becton Dickinson [DA] poly-D-lysine coated 96-well plates, Catalog # 356692) at 55,000 cells. per well in culture medium (described above) that also contained 1 µg / ml doxycycline. The plated cells were then placed in an incubator (5% CO2) and incubated for 20-26 hours at 37 ° C. The medium was then aspirated from the cells and 50 µl of buffer containing dye (from Molecular Devices FLIPR Calcuim 4 Assay Kit, Catalog # R8141) was added to each well. The cells were then left in the dark at room temperature for 1.5-2 hours. The plates with cells were then loaded into the FLIPR TETRA (Molecular Devices, CA, USA). Antagonists and capsaicin were added to each well using the FLIPR TETRA fluid management tool. Antagonists in saline (130 mM NaCl, 17 g / L sucrose, 1.8 g / L glucose, 8.8 mM HEPES, 3 mM KCl, 0.60 mM MgCl, 1.0 mM CaCl; adjusted to pH 7.4 using 10 N or 1 N NaOH; with 0.03% BSA added on the day of the experiment), or vehicle control in saline solution, they were pre-incubated at the desired final concentrations in the dark at room temperature for 2 or 30 minutes (please see Table 2 for the preincubation times used) with cells that already contained the continte buffer mentioned above. Capsaicin plus the appropriate concentration of antagonist was then added to saline at varying concentrations to achieve final concentrations spanning the range of 17 pM - 3 µM final capsaicin and the same final concentration of antagonist, or vehicle control, that was already in the well from the antagonist preincubation step described above. The changes in the fluorescence signal (λex = 470-495 nm, λem = 515-575 nm) were monitored throughout the experiment before the addition of the agonist and for at least 2 min after the addition of the agonist (sufficient time for the fluorescence response will reach and then fall below the absolute maximum signal obtained induced by the agonist). For each well, the final relative fluorescence units (RFU) were calculated as the difference between the maximum fluorescence signal obtained in the experiment after the addition of agonist and the level of signal observed at the beginning, before the addition of the agonist, but after antagonist addition (the absolute minimum level of fluorescence signal observed in the 10 seconds before agonist addition). These final RFU values were represented as a function of the corresponding capsaicin concentrations, obtaining response curves as a function of the dose in the entire range of capsaicin doses analyzed; a dose-versus-response curve for each antagonist concentration tested and one for the dose-versus-dose response of capsaicin without antagonist (vehicle control). The data was fitted to an ideal curve using the 4-parameter sigmoid curve fitting function of the GraphPad Prism program (version 4, GraphPad Software, Inc., San Diego, CA, USA) from which it was obtained a value of EC50. The dose ratio (RD) for each antagonist concentration analyzed was then calculated as the ratio of the EC50 value of the response curve as a function of dose of capsaicin in the presence of a given concentration of antagonist between the EC50 value of the curve dose-dependent response of capsaicin without antagonist (vehicle control). For each antagonist, at least three concentrations were tested. The dose ratio values were then used to prepare a standard Schild plot - log [antagonist concentration] versus log [DR-1], see Kenakin reference above for theoretical background and procedure. A linear regression curve fit was then performed at these plotted points. If the linear regression provided an R2 value ≥0.8 and there were at least two antagonist concentrations analyzed that gave a DR value greater than 1, then the pA2 values were calculated and expressed in terms of pA2 = Log (DR- 1) - Log [antagonist] for the lowest concentration of antagonist analyzed with which (DR-1)> 0 (Table 2). If these conditions were not met, then the antagonist was reprocessed in a pA2 assay using different concentrations of antagonist until the above conditions were met.

The pA2 values for Examples 1, 6, and 18 versus response as a function of capsaicin agonist dose were determined in the assay described above and are presented in the table below.

Table 3

No. of Ex

pA2 Preincubation (minutes) No. of Ex pA2 Preincubation (minutes)

1

8.76 2 18 8.28 30

6

8.73 2

Drug substance

The pharmaceutically acceptable salts of the compounds of formula (I) include the acid and base addition salts thereof.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrochloride / hydrochloride, hydrobromide / chloride salts. , iodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate,

10 methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

Suitable base salts are formed from bases that form non-toxic salts. Examples include the salts of aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc.

15 For a recap of suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

A pharmaceutically acceptable salt of a compound of formula (I) can be easily prepared by mixing solutions of the compound of formula (I) and the desired acid or base, as appropriate. The salt can precipitate out of solution and be collected by filtration or it can be recovered by evaporation of the solvent.

20 The degree of ionization in salt can range from fully ionized to almost non-ionized.

The compounds of the invention can exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, eg, EtOH. The term "hydrate" is used when said solvent is water.

Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes in which, unlike the solvates mentioned above, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug that contain two or more organic and / or inorganic components that may be present in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized, or

30 non-ionized. For a review of such complexes, see Haleblian's J Pharm Sci, 64 (8), 1269-1288 (August 1975).

Hereinafter, all references to compounds of formula (I) include references to their salts, solvates and complexes and to solvates and complexes of their salts.

The compounds of the invention include compounds of formula (I) as defined above in the

This document, its polymorphs, prodrugs and isomers (including optical, geometric and tautomeric isomers) as defined below and isotopically labeled compounds of formula (I).

As indicated, the invention includes all polymorphs of the compounds of formula (I) as defined hereinbefore.

So-called "prodrugs" of the compounds of formula (I) are also within the scope of the invention.

40 Thus, certain derivatives of compounds of formula (I) that may have little or no pharmacological activity in themselves, when administered to the interior or on the body, can be converted into compounds of formula (I) that have the desired activity, for for example, by hydrolytic cleavage. Such derivatives are called "prodrugs". More information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol.14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987

45 (ed. E B Roche, American Pharmaceutical Association).

Prodrugs according to the invention can be produced, for example, by substituting appropriate functionalities present in the compounds of formula (I) for certain moieties known to those skilled in the art as "prorests" as described, for example, in "Design of Prodrugs "by H. Bundgaard (Elsevier, 1985).

Some examples of prodrugs according to the invention include:

(I) when the compound of formula (I) contains a carboxylic acid function (-COOH), an ester thereof, for example, substitution of hydrogen by (C1-C8) alkyl;

(ii) when the compound of formula (I) contains an alcohol (-OH) function, an ether thereof, for example, substitution of hydrogen by (C1-C6) alkanoyl oxymethyl; and

(iii) when the compound of formula (I) contains a primary or secondary amino function (-NH2 or -NHR where R is not H), an amide thereof, for example, substitution of one or both hydrogens by alkanoyl (C1 -C10).

Additional examples of substitution groups according to the above examples and examples of other types of drugs can be found in the references mentioned above.

Finally, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Compounds of formula (I) containing one or more asymmetric carbon atoms can exist in the form of two or more stereoisomers. When a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. When the compound contains, for example, a keto uoxime group, an aromatic moiety, or a heteroaromatic ring that includes more than two nitrogen, tautomeric isomerism ("tautomerism") may occur. It follows that a single compound can show more than one type of isomerism.

All stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I) are included in the scope of the present invention, including compounds showing more than one type of isomerism and mixtures of one or more thereof. Also included are acid or base addition salts in which the counterion is optically active, eg, D-lactate or L-lysine, or racemic, eg, DL-tartrate or DL-arginine.

The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, eg, chromatography and fractional crystallization.

Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis of a suitable optically pure precursor or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) can be reacted with a suitable optically active compound, for example an alcohol or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereoisomeric mixture can be separated by chromatography and / or fractional crystallization and one or both diastereoisomers converted to the corresponding pure enantiomer (s) by means known to a person skilled in the art.

The chiral compounds of the invention (and the chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography, usually HPLC, on an asymmetric resin with a mobile phase constituted by a hydrocarbon, usually heptane or hexane, containing 0 to 50% of isopropanol, usually 2% to 20%, and 0 to 5% of an alkylamine, usually 0.1% diethylamine. Concentration of the eluate provides the enriched mixture.

Stereoisomeric conglomerates can be separated by conventional techniques known to those of skill in the art, see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel (Wiley, New York, 1994).

The present invention includes all pharmaceutically acceptable isotopically labeled compounds of formula (I) in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the prevailing atomic mass or mass number. in nature.Examples of isotopes suitable for inclusion in the compounds of the invention include hydrogen isotopes, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O, and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically-labeled compounds of formula (I), for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. Radioactive isotopes of tritium ie 3H, and carbon-14, ie 14C, are particularly useful for this purpose in view of the ease of their incorporation and easy means of detection. Substitution with heavier isotopes such as deuterium, i.e. 2H, may achieve certain therapeutic advantages resulting from increased metabolic stability, eg, longer in vivo half-life or need for lower doses, and may therefore be preferred in some circumstances. Substitution with positron-emitting isotopes, such as 11C, 18F, 15O, and 13N, may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by procedures analogous to those described in the accompanying Examples and Preparations using appropriate isotopically-labeled reagents in place of the unlabeled reagent employed above.

Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent may be isotopically substituted, for example D2O, d6-acetone, d6-DMSO.

The compounds of the invention intended for pharmaceutical use can be administered in the form of crystalline or amorphous products. They can be obtained, for example, in the form of solid plugs, powders or films by processes such as precipitation, crystallization, lyophilization, or spray drying or evaporative drying. Microwave or radio frequency drying can be used for this purpose.

They can be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or in the form of any combination thereof). In general, they will be administered in the form of a formulation associated with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound (s) of the invention. The choice of excipient will largely depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the administration of compounds of the present invention and procedures for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).

Oral administration

The compounds of the invention can be administered orally. Oral administration may involve swallowing, causing the compound to penetrate the gastrointestinal tract, or buccal or sublingual administration may be employed whereby the compound enters the bloodstream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particles, liquids or powders, lozenges (including those filled with liquid), chewing gums, multiparticulates and nanoparticles, gels, solid solution, liposomes, films (including mucoadhesives), ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations can be used as a filler in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by reconstitution of a solid, for example, from a sachet.

The compounds of the invention can also be used in fast dissolving, fast disintegrating pharmaceutical forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).

For pharmaceutical tablet forms, depending on the dose, the drug may comprise from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form. of the drug, tablets generally contain a disintegrant. Examples of disintegrators include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropyl cellulose, and pregetinized starch, sodium alginate. Generally, the disintegrant will comprise from 1% by weight to 25% by weight, preferably from 5% by weight to 20% by weight of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous, and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surfactants can comprise from 0.2% by weight to 5% by weight of the tablet, and glidants can comprise from 0.2% by weight to 1% by weight of the tablet.

Tablets generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise 0.25 to 10% by weight , preferably 0.5 to 3% by weight of the tablet.

Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, and flavor masking agents.

Exemplary tablets contain up to about 80% drug, from about 10% by weight to about 90% by weight binder, from about 0% by weight to about 85% by weight of diluent, from about 2% by weight to about 10% by weight. weight of disintegrant, and from about 0.25% by weight to about 10% by weight of lubricant.

Tablet blends can be compressed directly or by roller to form tablets. Alternatively, the tablet blends or portions of blends may be wet, dry, or cast granulated, melt frozen, or extruded prior to tableting. The final formulation can comprise one or more layers and can be coated or uncoated; it can even be encapsulated.

The tablet formulation is described in Pharmaceutical Dosage Forms: Tablets, Vol. 1 ", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and timed release.

Modified release formulations suitable for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable delivery technologies such as high energy dispersions and osmotic and coated particles can be found in Pharmaceutical Technology On-line, 25 (2), 1-14 by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

Parenteral administration

The compounds of the invention can also be administered directly to the bloodstream, muscle, or internal organ. Suitable routes for parenteral administration include intravenous, intraarterial, intraperitoneal,

5 intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle injectors (including microneedle injectors), needle injectors, and infusion techniques.

Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffering agents (preferably at a pH of 3 to 9), but, for some applications,

10 may more suitably be formulated in the form of a sterile non-aqueous solution or in a dry powder form for use in conjunction with a suitable vehicle such as sterile pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can easily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of formula (I) that are used in the preparation of parenteral solutions can

15 be augmented by the use of appropriate formulation techniques, such as the incorporation of agents that enhance solubility. Formulations for use with administration by injection without needles comprise a compound of the invention in powder form together with a suitable vehicle such as sterile pyrogen-free water.

Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed,

20 controlled, directed and programmed. Thus, the compounds of the invention can be formulated as a solid, semi-solid or thixotropic liquid for administration in the form of an implanted reservoir that provides modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.

Topical administration

The compounds of the invention can also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petroleum jelly, glycerin, polyethylene glycol, and propylene glycol. May

30 incorporate penetration enhancers; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).

Other means of topical administration include administration by electroporation, iontophoresis, phonophoresis, sonphoresis, and injection with microneedles or without needles (eg Powderject ™, Bioject ™, etc.).

Inhaled / intranasal administration

The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, in the form of a mixture, for example in a dry mixture with lactose, or in the form of a particulate of components mixed, e.g. mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or in the form of an aerosol spray with a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamic processes to produce a

40 fine atomized), or nebulizer, using or not a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example chitosan or cyclodextrin.

The pressurized container, pump, sprayer, atomizer or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent.

45 to disperse, solubilize, or extend the release of the active compound, a propellant (s) as a solvent, and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Formulations for inhaled / intranasal administration can be formulated to be immediate and / or modified controlled release using, for example, poly (DL-lactic-coglycolic acid) (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and timed release.

In the case of inhalers and dry powder aerosols, the dose unit is determined by a valve that delivers a measured amount. Units according to the invention are typically arranged to administer a metered dose or "puff" containing 0.001 mg to 10 mg of the compound of formula (I). The total daily dose will typically be in the range of 1 µg to 10 mg which can be administered in a single dose or, more usually, in divided doses throughout the day.

55 Rectal / Intravaginal Administration

The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate.

Other technologies The compounds of the invention can be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polymers containing polyethylene glycol, to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability, to use in any of the administration modes mentioned above.

It is generally found that complexes of drug and cyclodextrin, for example, are useful for most pharmaceutical forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. Those most commonly used for these purposes are alpha, beta and gamma-cyclodextrins, examples of which can be found in international patent applications WO 91/11172, WO 94/02518 and WO 98/55148.

DOSE

For administration to human patients, the total daily dose of the compounds of the invention is usually in the range of 0.1 mg to 3000 mg, preferably 1 mg to 500 mg, depending, of course, on the mode of administration. For example, oral administration may need a total daily dose of 0.1 mg to 3000 mg, preferably 1 mg to 500 mg, while an intravenous dose may only need 0.1 mg to 1000 mg, preferably 0, 1 mg to 300 mg. The total daily dose can be administered in a single dose or in divided doses.

These doses are based on an average human subject weighing approximately 65 to 70 kg. The physician will easily be able to determine dosages for subjects whose weight is outside this range, such as children and the elderly.

For the avoidance of doubt, references herein to "treatment" include references to curative, palliative, and prophylactic treatment.

A VR1 antagonist can be usefully combined with another pharmacologically active compound or with two or more other pharmacologically active compounds, particularly in the treatment of pain. For example, a VR1 antagonist, in particular a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined above, can be administered simultaneously, sequentially or separately in combination with one or more agents selected from:

 an opioid pain reliever, for example morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmephene, nalorphrenolorphine, naloxone, nalorphine, naloxone, nalorphalorphine, naloxorphine or pentazocine;

 a non-steroidal anti-inflammatory drug (NSAID), for example aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, nitrophurbofenamic acid, methofenoxymic acid, naprofenic acid, naproxenic acid , olsalazine, oxaprozine, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetine or zomepirac;

 a sedative barbiturate, for example amobarbital, aprobital, butabarbital, butabital, mephobarbital, metabital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, teamilal or thiopental;

 a benzodiazepine that has a sedative action, for example chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

 an H1 antagonist having a sedative action, for example diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

 a sedative such as glutethimide, meprobamate, methaqualone, or dichloralphenazone;

 a skeletal muscle relaxant, for example baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;

 an NMDA receptor antagonist, for example dextromethorphan ((+) - 3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+) - 3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-acid 4- (phosphonomethyl) -2-piperidinecarboxylic, budipine, EN-3231 (MorphiDex®, a combined formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel that includes an NR2B antagonist, for example ifenprodil, traxoprodil or (-) - (R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-1-piperidinyl] -1-hydroxyethyl-3,4-dihydro-2 (1H) -quinolinone;

 an alpha-adrenergic, for example doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol- 2-yl) -5- (2-pyridyl) quinazoline;

 a tricyclic antidepressant, for example desipramine, imipramine, amitriptyline or nortriptyline;

 an anticonvulsant, for example carbamazepine, lamotrigine, topiratmate or valproate;

 a tachykinin (NK) antagonist, in particular an NK-3, NK-2 or NK-1 antagonist, for example (R, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8 , 9,10,11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocino [2,1-g] [1,7] -naphthyridine-6-13-dione ( TAK-637), 5 - [[(2R, 3S) -2 - [(1R) -1- [3,5-bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4-morpholinyl] - methyl] -1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3 - [[2-methoxy-5- (trifluoromethoxy) phenyl] - methylamino] -2-phenylpiperidine (2S, 3S);

 a muscarinic antagonist, for example oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

 a selective COX-2 inhibitor, for example celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

 a coal tar analgesic, in particular paracetamol;

 a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, perchlopyrone, blisoprone, blisopronaprone, blisoprone, blisapprone , lurasidone, amisulpride, balaperidone, palindor, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion®, or sarizotan;

 a vanilloid receptor agonist (eg resinferatoxin) or vanilloid receptor antagonist (eg capsazepine);

 a beta-adrenergic such as propranolol;

 a local anesthetic such as mexiletine;

 a corticosteroid such as dexamethasone;

 a 5-HT receptor agonist or antagonist, in particular a 5-HT1B / 1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

 a 5-HT2A receptor antagonist such as R (+) - alpha- (2,3-dimethoxy-phenyl) -1- [2- (4-fluorophenylethyl)] - 4-piperidinemethanol (MDL-100907);

 a cholinergic (nicotinic) pain reliever, such as ispronicline (TC-1734), (E) -N-methyl-4- (3-pyridinyl) -3-buten-1-amine (RJR-2403), (R) - 5- (2-azetidinylmethoxy) -2-chloropyridine (ABT-594) or nicotine;

 Tramadol®;

 a PDEV inhibitor, such as 5- [2-ethoxy-5- (4-methyl-1-piperazinyl-sulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (sildenafil), (6R, 12aR) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) - pyrazino [2 ', 1': 6.1] -pyrido [3,4-b] indole-1,4-dione (IC-351 or tadalafil), 2- [2-ethoxy-5- (4-ethyl-piperazine- 1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one (vardenafil), 5- (5 -acetyl-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5- (5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine- 7-one, 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 4 - [(3-chloro-4-methoxybenzyl) amino] -2 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -N- ( pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide, 3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) - N- [2- (1-methyl pyrrolidin-2-yl) ethyl] -4-propoxybenzenesulfonamide;

 an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (1, 3, 5) acid (3-amino-methyl-bicyclo [3,2,0] hept-3-yl) -acetic, (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5- acid methyl-octanoic, (2S, 4S) -4- (3-chlorophenoxy) proline, (2S, 4S) -4- (3-fluorobenzyl) -proline, [(1R, 5R, 6S) -6- (aminomethyl) acid bicyclo [3,2,0] hept-6-yl] acetic, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one, C- [1- (1H-tetrazole -5-ylmethyl) -cycloheptyl] -methylamine, (3S, 4S) - (1-aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid, (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid , (3S, 5R) -3-amino-5-methyl-nonanoic acid, (3S, 5R) -3-amino-5-methyl-octanoic acid, (3R, 4R, 5R) -3-amino-4 acid, 5-dimethyl-heptanoic, (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid, (2S) -2-amino-4-ethyl-2-methylhexanoic acid and (2S) -2 acid -aminomethyl-5-ethyl-heptanoic acid;

 a cannabinoid;

 Metabotropic glutamate receptor subtype 1 antagonist (mgluR1);

 a serotonin reuptake inhibitor such as sertraline, sertraline metabolite desmethylsertraline, fluoxetine, norfluoxetine (desmethyl metabolite of fluoxetine), fluvoxamine, paroxetine, citalopram, citalopram metabolitodesmethylcitalopram, escitalopramine, phenoxyetine d, lofluoxetine , lithoxetine, dapoxetine, nefazodone, cericlamine, and trazodone;

 a norepinephrine reuptake inhibitor (norepinephrine), such as maprotiline, lofepramine, mirtazepine, oxaprotiline, phezolamine, tomoxetine, mianserin, buproprion, hydroxyibuproprion metabolite of buproprion, nomifensine, and a selective Vilopramine inhibitor (especially a selective Vilopramine inhibitor) denoradrenaline such as reboxetine, in particular (S, S) -reboxetine;

 a dual serotonin and norepinephrine uptake inhibitor, such as venlafaxine, venlafaxine O-desmethylvenlafaxine metabolite, clomipramine, clomipramine desmethylclomipramine metabolite, duloxetine, milnacipran, and imipramine;

 an inducible nitric oxide synthase (iNOS) inhibitor such as S- [2 - [(1-iminoethyl) amino] ethyl] -L-homocysteine, S- [2 - [(1-iminoethyl) -amino] ethyl] - 4,4-dioxo-L-cysteine, S- [2 - [(1-iminoethyl) amino] ethyl] -2-methyl-L-cysteine, (2S, 5Z) -2-amino-2-methyl-7 acid - [(1-iminoethyl) amino] -5-heptenoic, 2 - [[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) -butyl] thio] -5-chloro-3 -pyridinecarbonitrile; 2 - [[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -4-chlorobenzonitrile, (2S, 4R) -2-amino-4 - [[2- chloro-5- (trifluoromethyl) phenyl] thio] -5-thiazolbutanol, 2 - [[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -6- (trifluoromethyl ) -3 pyridinecarbonitrile, 2 - [[(1R, 3S) -3-amino-4-hydroxy- 1 - (5-thiazolyl) butyl] thio] -5-chlorobenzonitrile, N- [4- [2- (3- chlorobenzylamino) ethyl] phenyl] thiophene-2-carboxamidine, or guanidinoethyl disulfide;

 an acetylcholinesterase inhibitor such as donepezil;

 a prostaglandin E2 subtype 4 (EP4) antagonist such as N - [({2- [4- (2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) phenyl] ethyl} amino) -carbonyl] -4-methylbenzenesulfonamide

or 4 - [(1S) -1 - ({[5-chloro-2- (3-fluorophenoxy) pyridin-3-yl] carbonyl} amino) ethyl] benzoic acid;

 a leukotriene B4 antagonist; such as acid 1- (3-Biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl) -cyclopentanecarboxylic acid (CP-105696), acid 5- [2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl) -5E- hexenyl] oxyphenoxy] valeric (ONO-4057) or DPC-11870,

 a 5-lipoxygenase inhibitor, such as zileuton, 6 - [(3-fluoro-5- [4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl]) phenoxy-methyl] -1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6- (3-pyridylmethyl), 1,4-benzoquinone (CV-6504);

 a sodium channel blocker, such as lidocaine;

 a 5-HT3 antagonist, such as ondansetron;

and the pharmaceutically acceptable salts and solvates thereof.

Since it may be desirable to administer a combination of active compounds, for example, in order to treat a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound according to With the invention, they can be conveniently combined in the form of a kit suitable for co-administration of the compositions.

Thus, the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) according to the invention, and means for keeping said compositions separate, such as a container, divided bottle or separate aluminum container. An example of such a kit is the familiar blister pack that is used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different pharmaceutical forms, for example oral and parenteral, for administering the different compositions with different dose ranges, or for titrating separate compositions from each other. To aid compliance, the kit typically comprises instructions for administration and may be provided with what is called a reminder.

Claims (15)

1. A compound of formula (I): R6 R1R2 O image 1 (I) Wherein Y1 and Y2 are each independently N or CH; provided that only one of Y1 and Y2 can be N; R1 and R2 are each independently hydrogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) hydroxyalkyl or (C1-C2) alkoxy (C1-C2) alkyl; or R1 and R2, together with the carbon atom to which they are attached, can form a cyclopropyl group; R3 is (C1-C4) alkyl, (C1-C4) alkyl, cyclopropyl, (C1-C2) alkoxy (C1-C4) alkyl, or (C1-C4) hydroxyalkyl, each optionally substituted with halo or halo (C1-C2) alkyl; R4 and R6 are each independently hydrogen, halo, cyano, (C3-C6) cycloalkyl, (C1-C6) alkoxy, or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, hydroxy, R7R8NC (O) - and R7OC (O) -; R5 is hydrogen, (C3-C6) cycloalkyl, or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one

or more substituents selected from halo, amino, cyano, hydroxy, R7R8NC (O) - or R7OC (O) -; provided that at least one of R4, R5 and R6 is not hydrogen; and, R7 and R8 are each independently hydrogen or (C1-C4) alkyl;

or a pharmaceutically acceptable salt or solvate thereof.

A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is N and Y2 is CH; or Y1 is CH and Y2 is N.

3.

A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y1 is CH and Y2 is CH.

Four.

A compound according to any one of claims 1 to 3, or a salt or solvate thereof

Pharmaceutically acceptable wherein R1 and R2 are each independently hydrogen, ethyl or methyl, wherein methyl and ethyl are optionally substituted with one or more fluorine atoms.

5.

A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, ethyl or methyl and R2 is hydrogen.

6.

A compound according to any one of claims 1 to 5, or a salt or solvate thereof

30 pharmaceutically acceptable, wherein R3 is 1-methylcyclopropyl or R3 is (C1-C4) alkyl, (C1-C2) alkoxy (C1-C4) alkyl or (C1-C4) hydroxyalkyl, each optionally substituted with halo or haloalkyl ( C1-C2).

7.

A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is hydrogen or (C1-C6) alkyl

8.

A compound according to any one of claims 1 to 7, or a salt or solvate thereof

Pharmaceutically acceptable, wherein R4 is hydrogen, halo, cyano, (C1-C6) alkoxy or (C1-C6) alkyl, wherein (C1-C6) alkyl is optionally substituted with one or more substituents selected from halo and hydroxy. 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen, cyclopropyl, cyclobutyl or (C1-C4) alkyl, wherein (C1- C4) is optionally substituted with one or more substituents selected from halo, amino, cyano, hydroxy, R7R8NC (O) - and R7OC (O) -. 10. A compound according to claim 1, said compound being selected from among N- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2-yl) quinoline-6-carboxamide; N - [(1,5-dimethyl-1H-pyrazol-4-yl) methyl] -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide; N- (1- (5-cyano-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2-yl) quinoline-6-carboxamide; N- (1- (5- (hydroxymethyl) -1-methyl-1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2-yl) quinolin-6- carboxamide; N- (1- (5-methyl-1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2- yl) quinoline-6-carboxamide; N- (1- (5-methyl-1- (2,2,2-trifluoroethyl) -1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2- yl) quinoline-6-carboxamide; N- [1- (1,5-dimethyl-1H-pyrazol-4-yl) propyl] -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide; N- [1- (5-methyl-1H-pyrazol-4-yl) ethyl] -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide; 2- (5-methyl-4- (1- (2- (1,1,1-trifluoro-2-methylpropan-2-yl) quinoline-6-carboxamido) ethyl) -1H-pyrazol-1-yl) acetate ; N- (1- (1- (2-hydroxyethyl) -5-methyl-1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2-yl) quinolin- 6-carboxamide; N- (1- (1- (2-hydroxy-2-methylpropyl) -5-methyl-1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2- yl) quinoline-6-carboxamide ; N- [1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -2- (1-methylcyclopropyl) quinoline-6-carboxamide; N- [1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -2- (2,2,2-trifluoro-1-hydroxy-1-methylethyl) quinoline-6-carboxamide; N - [(1-ethyl-5-methyl-1H-pyrazol-4-yl) methyl] -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide; N- [1- (1-ethyl-5-methyl-1H-pyrazol-4-yl) ethyl] -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide; N- (1-cyclobutyl-5-methyl-1H-pyrazol-4-yl) ethyl) -2- (2,2,2-trifluoro-1,1-dimethylpropan-2-yl) quinoline-6-carboxamide; N- (1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2-yl) quinoline-6-carboxamide; N- (1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide; N- (1- (1-ethyl-5-methyl-1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2-yl) quinoline-6-carboxamide; N- (1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide; N- (1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2-yl) quinolin-6- carboxamide; N- (1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide; 6-tert-butyl-N- [1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -2-naphthamide; 6-tert-butyl-N - [(3,5-dimethyl-1H-pyrazol-4-yl) methyl] -2-naphtamide; 6-tert-butyl-N - [(1,3-dimethyl-1H-pyrazol-4-yl) methyl] -2-naphtamide; 6-tert-butyl-N - [(1,5-dimethyl-1H-pyrazol-4-yl) methyl] -2-naphtamide; 6-tert-butyl-N- (1- (1,5-dimethyl-1H-pyrazol-4-yl) propyl) -2-naphtamide; N- (1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl) -6- (trifluoromethyl) -2-naphtamide; N- [1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -6- (1-methylcyclopropyl) -2-naphtamide; N- [1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -6- (2,2,2-trifluoro-1-hydroxy-1-methylethyl) -2-naphthamide; N- [1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -6- (2,2,2-trifluoro-1-methoxy -1-methylethyl) -2-naphthamide; 6-tert-butyl-N - [(1,5-dimethyl-1H-pyrazol-4-yl) methyl] quinoline-2-carboxamide; 6-tert-butyl-N - ((1,3,5-trimethyl-1H-pyrazol-4-yl) methyl) -2-naphtamide; 6-tert-butyl-N - [(1-methyl-1H-pyrazol-4-yl) methyl] -2-naphtamide; N- [1- (1,5-dimethyl-1H-pyrazol-4-yl) ethyl] -6- (1-hydroxy-1-methylethyl) -2-naphtamide; (S) -N- (1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinolin-6- carboxamide; (R) -N- (1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinolin-6- carboxamide; (S) -N- (1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide; (R) -N- (1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide; (S) -N- (1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide; (R) -N- (1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2- (trifluoromethyl) quinoline-6-carboxamide; (S) -N- (1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2-yl) quinoline-6-carboxamide; (R) -N- (1- (1-methyl-5- (trifluoromethyl) -1H-pyrazol-4-yl) ethyl) -2- (1,1,1-trifluoro-2-methylpropan-2-yl) quinoline-6-carboxamide; N - [(1R) - (1,5-dimethyl-1H-pyrazol-4-yl) ethyl)] -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide; N - [(1S) - (1,5-dimethyl-1H-pyrazol-4-yl) ethyl)] -2- (2,2,2-trifluoro-1,1-dimethylethyl) quinoline-6-carboxamide; and N- (1- (5-chloro-1-methyl-1H-pyrazol-4-yl) ethyl) -2- (pentafluoroethyl) quinoline-6-carboxamide; and the pharmaceutically acceptable salts and solvates thereof.

eleven.

A compound according to any one of claims 1 to 10 for use as a medicine.

12.

A pharmaceutical composition including a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 10, together with a pharmaceutically acceptable container.

13.

A use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 10, for the manufacture of a medicament for treating a disease for which it is indicated a VR1 antagonist.

14.

A use according to claim 13, wherein the disease is selected from pain, including chronic pain, acute pain, nociceptive pain, neuropathic pain, inflammatory pain, post-herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy. , nerve injuries, rheumatoid arthritis pain, osteoarthritis pain, burns, back pain, visceral pain, cancer pain, dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain and menstrual pain; bladder disease, such as urinary incontinence, lower urinary tract symptoms, urination disorders, renal colic, and cystitis; inflammation, such as burns, rheumatoid arthritis, and osteoarthritis; neurodegenerative disease, such as stroke, post-stroke pain, and multiple sclerosis; diseases of the respiratory tree that contribute to symptoms or pathology arising from the sensory afferent nervous system, such as cough, bronchoconstriction, irritation, inflammation, and other pathways in lower respiratory diseases such as asthma and COPD as well as those of the upper respiratory tract , such as allergic rhinitis and chronic sinusitis; gastrointestinal disorders, such as gastroesophageal reflux disease (GERD), dysphagia, ulcer, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis, and Crohn's disease; ischemia, such as cerebrovascular ischemia and acute cerebral ischemia; emesis, such as emesis induced by cancer chemotherapy; diabetes and obesity.

fifteen.

A combination of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 10, and another pharmacologically active agent.

16.

A pharmaceutical composition including a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in any one of claims 1 to 10, and another pharmacologically active agent.