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HK1116764A - N- (n-sulfonylaminomethyl) cyclopropanecarboxamide derivatives useful for the treatment of pain - Google Patents

N- (n-sulfonylaminomethyl) cyclopropanecarboxamide derivatives useful for the treatment of pain Download PDF

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HK1116764A
HK1116764A HK08105453.1A HK08105453A HK1116764A HK 1116764 A HK1116764 A HK 1116764A HK 08105453 A HK08105453 A HK 08105453A HK 1116764 A HK1116764 A HK 1116764A
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Hong Kong
Prior art keywords
phenyl
methyl
ethyl
amino
methylsulfonyl
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HK08105453.1A
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Chinese (zh)
Inventor
T．花泽
M．平野
T．井上
S．永山
中尾一成
Y．宍户
田中宏桥
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辉瑞大药厂
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Description

N- (N-sulfonamidomethyl) cyclopropanecarboxamide derivatives useful in the treatment of pain
Technical Field
The present invention relates to novel substituted N- (N-sulfonamidoarylmethyl) cyclopropanecarboxamides and their use in therapy. These compounds are particularly useful as antagonists of the VR1 (vanilloid type I) receptor and are therefore useful for the treatment of pain, neuralgia, neuropathy, nerve injury, burn injury, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, bladder disease, inflammation, and the like, in mammals, particularly humans. The invention also relates to pharmaceutical compositions comprising the above compounds and to intermediate compounds useful in the preparation of the above compounds.
Background
Vanilloid receptor 1(VR1) is a ligand-gated, non-selective cation channel. It is now considered to be a member of the latent superfamily of transient sensors. VR1 is considered to be a multi-modal nociceptor that integrates multiple pain stimuli such as noxious heat, protons, and vanilloids (European Journal of Physiology 451: 151-. VR1 is distributed primarily in sensory (a δ -and C-) fibers, which are bipolar neurons with somata in the sensory ganglia. The peripheral fibers of these neurons innervate the skin, mucosa and almost all internal organs. VR1 is also believed to be present in the bladder, kidney, brain, pancreas, and various organs. Extensive studies with VR1 agonists, such as capsaicin or cactus toxin, have suggested that VR1 positive nerves are thought to be involved in a variety of physiological responses, including nociception (clinical therapeutics.13 (3): 338-. Based on the tissue distribution and role of VR1, VR1 antagonists would have good therapeutic potential.
International patent application No. WO-A-2005003084 discusses 4- (methylsulfonylamino) phenyl analogs, which are said to have activity as VR1 antagonists. International patent application No. wo200216318 discloses a variety of sulfonylaminobenzylthiourea derivatives and N-sulfonylaminobenzyl-2-phenoxyacetamide derivatives as vanilloid receptor modulators. International patent application No.2004047738 discloses a variety of aryl cyclopropyl carboxylic acid amides as potassium channel openers.
It would be desirable to provide improved VR1 selective antagonists that have enhanced binding activity to the VR1 receptor and good half-life when administered systemically. Other potential advantages include less toxicity, good absorption, good solubility, low protein binding affinity, less drug-drug interaction, reduced HERG channel inhibitory activity, reduced QT prolongation and good metabolic stability.
Brief description of the invention
It has now been found that substituted N- (N-sulfonamidoarylmethyl) cyclopropanecarboxamide compounds are potent VR1 antagonists with analgesic activity when administered systemically. The compounds of the invention may exhibit lower toxicity, good absorption, good half-life, good solubility, low protein binding affinity, fewer drug-drug interactions, reduced HERG channel inhibitory activity, reduced QT prolongation and good metabolic stability.
The present invention provides compounds of formula (I); or a pharmaceutically acceptable salt or solvate thereof:
wherein
A and B are independently CR12Or N;
d and E are each independently CR9Or N;
R1is represented by (C)1-C6) An alkyl group;
R2represents hydrogen, halogen, hydroxy, (C) 1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy radical- (C1-C6) An alkyl group;
R3、R4、R5、R6、R10and R11Each independently represents hydrogen, halogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl or (C)1-C6) Alkoxy radical- (C1-C6) An alkyl group; or
R3And R4Together with the carbon atom to which they are attached form a 3-to 7-membered carbocyclic or heterocyclic ring in which one or two non-adjacent carbon atoms are optionally replaced by an oxygen atom, a sulfur atom or NH;
R7and R9Each independently represents hydrogen, halogen,(C1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy radical- (C1-C6) Alkyl, (C)1-C6) Alkoxy radical- (C1-C6) Alkoxy group, (C)1-C6) Alkylthio group, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl, NH2、[(C1-C6) Alkyl radical]NH-、[(C1-C6) Alkyl radical]2N-、H2N-(C1-C6) Alkoxy group, (C)1-C6) alkyl-NH- (C)1-C6) Alkoxy group, [ (C)1-C6) Alkyl radical]2N(C1-C6) An alkoxy group; h2N-(C1-C6) Alkoxy radical- (C1-C6) Alkyl, (C)1-C6) alkyl-NH- (C)1-C6) Alkoxy radical- (C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N(C1-C6) Alkoxy radical- (C1-C6) Alkyl or a 5-or 6-membered heterocyclic ring containing at least one nitrogen atom;
R8represents halogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy radical- (C1-C6) Alkyl, (C) 1-C6) Alkoxy radical- (C1-C6) Alkoxy, halo (C)1-C6) Alkylsulfonyl, halo (C)1-C6) Alkylsulfinyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkylthio [ (C)1-C6) Alkyl radical]NH-or [ (C)1-C6) Alkyl radical]2N-; or
When E is CR9When R is7And R8Together with the carbon atom to which they are attached form a 5-to 8-membered carbocyclic or heterocyclic ring in which one or two non-adjacent carbon atoms are optionally replaced by an oxygen, sulfur, N or NH group, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted by one or more groups each independently selected from hydroxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy and hydroxy (C)1-C6) Alkyl substituent substitution; and is
R12Represents hydrogen, halogen, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group.
Detailed description of the invention
The term "halogen" as used herein means a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom.
The term "(C) as used herein1-C6) Alkyl "and" (C)1-C3) Alkyl "means a straight or branched chain saturated group having the desired number of carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and 2-methylbutyl. Preferred alkyl groups are methyl, ethyl, n-propyl, n-butyl, tert-butyl and 2-methylbutyl.
The term "hydroxy (C) as used herein 1-C6) Alkyl "means (C) as defined above substituted by at least one hydroxy group1-C6) Alkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl (e.g., 2-hydroxy-1, 1-dimethylethyl), hydroxy-n-butyl, hydroxyisobutyl, hydroxy-sec-butyl, and hydroxy-tert-butyl. Preferred hydroxyalkyl groups are hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl (e.g. 2-hydroxy-1, 1-dimethylethyl) and hydroxy-n-butyl.
The term "(C) as used herein1-C6) Alkoxy "means (C)1-C6) alkyl-O- (wherein: (C1-C6) Alkyl groups are as defined above) including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, n-butoxy and tert-butoxy.
The term "hydroxy (C) as used herein1-C6) Alkoxy "means (C) as defined above substituted by hydroxy1-C6) Alkoxy groups, including but not limited to, hydroxymethoxy, hydroxyethoxy, hydroxy-n-propoxy, hydroxyisopropoxy, hydroxy-n-butoxy, hydroxyisobutoxy, hydroxy-sec-butoxy, and hydroxy-tert-butoxy. Preferred hydroxyalkoxy groups are hydroxymethoxy, hydroxyethoxy, hydroxy-n-propoxy and hydroxy-n-butoxy.
The term "(C) as used herein1-C6) Alkoxy radical- (C1-C6) Alkyl "means a radical defined as above (C)1-C6) Alkoxy-substituted (C) as defined above1-C6) An alkyl group.
The term "(C) as used herein1-C6) Alkoxy radical- (C1-C6) Alkoxy "means being (C) as defined above1-C6) Alkoxy-substituted (C) as defined above1-C6) An alkoxy group. Preferred alkoxy-alkoxy groups are methoxymethoxy, methoxyethoxy or ethoxyethoxy.
The term "halo (C) as used herein1-C6) Alkyl "means (C) substituted by one or more halogen atoms as defined above1-C6) Alkyl groups, including but not limited to fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2, 2, 2-trifluoro-1, 1-dimethylethyl, 2, 2, 2-trichloroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl, trichloromethyl, iodomethyl, bromomethyl, and 4, 4, 4-trifluoro-3-methylbutyl. Preferred is halo (C)1-C6) Alkyl is fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl and 2, 2, 2-trifluoro-1, 1-dimethylethyl.
The term "halo (C) as used herein1-C6) Alkoxy "and" halo (C) 1-C3) Alkoxy "means (C) substituted by one or more halogen atoms as defined above1-C6) alkyl-O-or (C)1-C3) alkyl-O-includes, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy, 2, 2, 2-trifluoro-1, 1-dimethylethoxy, 2, 2, 2-trichloroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, chloromethoxy, trichloromethoxy, iodomethoxy, bromomethoxy, and 4, 4, 4-trifluoro-3-methylbutoxy. Preferred is halo (C)1-C6) alkyl-O-or halo (C)1-C3) alkyl-O-is fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy and 2, 2, 2-trifluoro-1, 1-dimethylethoxy.
The term "halo (C) as used herein1-C6) Alkylthio "and" halo (C)1-C3) Alkylthio "means (C) substituted by one or more halogen atoms as defined above1-C6) alkyl-S-or (C)1-C3) alkyl-S-includes, but is not limited to, fluoromethylthio, difluoromethylthio, trifluoromethylthio, 2-fluoroethylthio, 2, 2-difluoroethylthio, 2, 2, 2-trifluoroethylthio, 2, 2, 2-trifluoro-1, 1-dimethylethylthio, 2, 2, 2-trichloroethylthio, 3-fluoropropylthio, 4-fluorobutylthio, chloromethylthio, trichloromethylthio, iodomethylthio, bromomethylthio, and 4, 4, 4-trifluoro-3-methylbutylthio. Preferred is halo (C) 1-C6) Alkylthio or halo (C)1-C3) Alkylthio is fluoromethylthio, difluoromethylthio, trifluoromethylthio, 2-fluoroethylthio, 2, 2-difluoroethylthio, 2, 2, 2-trifluoroethylthio and 2, 2, 2-trifluoro-1, 1-dimethylethylthio.
The term "halo (C) as used herein1-C6) Alkylsulfinyl "and" halo (C)1-C3) Alkylsulfinyl "means (C) substituted by one or more halogen atoms as defined above1-C6) alkyl-SO-or (C)1-C3) alkyl-SO-, including but not limited to fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 2, 2-difluoroethylsulfinyl, 2, 2, 2-trifluoroethylsulfinyl, 2, 2, 2-trifluoro-1, 1-dimethylethylsulfinyl, 2, 2, 2-trichloroethylsulfinyl, 3-fluoropropylsulfinyl, 4-fluorobutylsulfinyl, chloromethyl sulfinyl, trichloromethylsulfinyl, iodomethylsulfinyl, bromomethylsulfinyl and 4, 4, 4-trifluoro-3-methylbutylsulfinyl. Preferred is halo (C)1-C6) Alkylsulfinyl or halo (C)1-C3) Alkylsulfinyl is fluoromethylsulfinyl, difluoromethylsulfinyl, trifluoromethylsulfinyl, 2-fluoroethylsulfinyl, 2, 2-difluoroethylsulfinyl, 2, 2, 2-trifluoroethylsulfinyl and 2, 2, 2-trifluoro-1, 1-dimethylethylsulfinyl.
The term "halo (C) as used herein1-C6) Alkylsulfonyl "and" halo (C)1-C3) Alkylsulfonyl "means (C) substituted by one or more halogen atoms as defined above1-C6) alkyl-SO2-or (C)1-C3) alkyl-SO2-, including, but not limited to, fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 2, 2-difluoroethylsulfonyl, 2, 2, 2-trifluoroethylsulfonyl, 2, 2, 2-trifluoro-1, 1-dimethylethylsulfonyl, 2, 2, 2-trichloroethylsulfonyl, 3-fluoropropylsulfonyl, 4-fluorobutylsulfonyl, chloromethylsulfonyl, trichloromethylsulfonyl, iodomethylsulfonyl, bromomethylsulfonyl and 4, 4, 4-trifluoro-3-methylbutylsulfonyl. Preferred is halo (C)1-C6) Alkylsulfonyl or halo (C)1-C3) Alkylsulfonyl is fluoromethylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, 2-fluoroethylsulfonyl, 2, 2-difluoroethylsulfonyl, 2, 2, 2-trifluoroethylsulfonyl and 2, 2, 2-trifluoro-1, 1-dimethylethylsulfonyl.
The terms "3 to 7 membered carbocyclic ring" and "5 to 8 membered carbocyclic ring" as used herein mean saturated carbocyclic rings having the desired number of carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Preferred carbocycles are cyclopropyl, cyclopentyl and cyclohexyl.
The terms "3-to 7-membered heterocyclic ring" and "5-to 8-membered heterocyclic ring" as used herein mean a carbocyclic ring having the desired number of carbon atoms in which one or two non-adjacent carbon atoms are replaced by oxygen, sulfur or NH. Examples of such heterocycles include, but are not limited to, tetrahydrofuran, tetrahydrothiophene, thiazolidine, tetrahydropyrrole, tetrahydropyridine, tetrahydropyrazine, tetrahydropyrimidine, and 3, 4-dihydro-2H-pyran. Preferred heterocycles are tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, tetrahydropyridine and 3, 4-dihydro-2H-pyran.
The term "5-or 6-membered heterocyclic ring containing at least one nitrogen atom" as used herein means a 5-or 6-membered heterocyclic ring containing 1 to 3 nitrogen heteroatoms or 1 or 2 nitrogen heteroatoms and 1 oxygen or 1 sulfur heteroatom, including but not limited to 1H-pyrrole, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolidino, 2-pyrrolidinyl, 3-pyrrolidinyl, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, morpholino and thiomorpholino. Preferred 5-or 6-membered heterocycles are 2-pyridyl, 4-pyridyl, pyrrolidino, piperidino, morpholino and thiomorpholino.
The term "[ (C) as used herein1-C6) Alkyl radical]NH- "means alkyl-NH- (wherein alkyl is as defined above) including but not limited to methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino. Preferred alkylamino groups are methylamino, ethylamino, n-propylamino, n-butylamino 。
The term "[ (C) as used herein1-C6) Alkyl radical]2N- "means dialkyl-N- (wherein alkyl is as defined above) including, but not limited to, dimethylamino, diethylamino, methylethylamino, di-N-propylamino, methyl-N-propylamino, ethyl-N-propylamino-diisopropylamino, di-N-butylamino, methyl-N-butylamino-diisobutylamino, di-sec-butylamino, di-tert-butylamino. Preferred dialkylamino groups are dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino.
Preferably, A is CR12B is CR12Or N, D is CR9And E is CR9Or N; more preferably, A is CR12B is CR12Or N, D is CR9And E is CR9Or N, wherein B and E are not both N; even more preferably, A is CR12B is CR12Or N, D is CR9E is CR9Or N, except when B is N, and R8When is trifluoromethyl; or when E is N, and R2When is fluorine; most preferably, A is CR12B is CR12D is CR9And E is CR9。
Preferably, R1Is (C)1-C3) An alkyl group; more preferably methyl.
Preferably, R2Is hydrogen, halogen, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group; more preferably hydrogen, fluorine, methyl, ethyl, hydroxymethyl or hydroxyethyl.
Preferably, R3Is hydrogen or (C) 1-C3) An alkyl group; even more preferably hydrogen, methyl or ethyl; most preferred is methyl or ethyl.
Preferably, R4Is hydrogen or (C)1-C3) An alkyl group; even more preferably hydrogen, methyl or ethyl; most preferred is hydrogen.
Preferably, R5、R6、R10And R11Each independently of the others is hydrogen, halogen, (C)1-C3) Alkyl or hydroxy (C)1-C3) Alkyl, more preferably, R5Is hydrogen; more preferably, R6Is hydrogen, (C)1-C3) Alkyl, (C)1-C3) Alkoxy or hydroxy (C)1-C3) An alkyl group; even more preferably hydrogen, methyl, ethyl, methoxy or hydroxymethyl; most preferably methyl, ethyl or methoxy; more preferably, R10And R11Each independently is hydrogen.
Preferably, R7And R9Each independently hydrogen, halogen, hydroxy (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-, pyridyl, piperidino, pyrrolidino, or morpholino; more preferably hydrogen, fluorine, chlorine, hydroxymethyl, dimethylamino, 4-pyridyl (4-yl-pyridine), piperidino, pyrrolidino or morpholino; most preferred is hydrogen or fluorine.
Preferably, R8Is (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C3) Alkoxy group, (C)1-C6) Alkoxy radical- (C1-C6) Alkyl, halo (C)1-C3) Alkoxy, halo (C)1-C3) Alkylthio or halo (C)1-C3) An alkylsulfonyl group; more preferably (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, halo (C) 1-C3) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy radical- (C1-C6) Alkyl, halo (C)1-C3) Alkylthio or halo (C)1-C3) An alkylsulfonyl group; still more preferably tert-butyl, trifluoromethyl, 2, 2, 2-trifluoro-1, 1-dimethylethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, 2-hydroxy-1, 1-dimethylethyl or 2-methoxy-1, 1-dimethylethyl; most preferred are tert-butyl and trifluoromethyl2, 2, 2-trifluoro-1, 1-dimethylethyl, trifluoromethoxy or trifluoromethylthio.
Preferably, R12Is hydrogen, halogen, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group; more preferably hydrogen, fluorine, methyl, ethyl, hydroxymethyl or hydroxyethyl.
Preferably, R5And R6Is in the trans form.
Preferred compounds of the invention include those wherein each variable in formula (I) is selected from the preferred group for each variable.
Particularly preferred compounds of the invention are those listed in the examples in the following section and pharmaceutically acceptable salts and solvates thereof.
The compounds of formula (I) are VR1 antagonists, potentially useful in the treatment of a range of disorders, in particular in mammals, especially humans, for the treatment of acute cerebral ischaemia, pain, chronic pain, acute pain, nociceptive pain, neuropathic pain, inflammatory pain, post-herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-associated 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, menstrual pain, bladder disorders (e.g. incontinence, micturition disorders, renal colic and cystitis), inflammation (e.g. burns, rheumatoid arthritis and osteoarthritis), neurodegenerative disorders (e.g. stroke, osteoarthritis, post-herpetic neuralgia, nerve pain, nerve head pain, Post-stroke pain and multiple sclerosis), lung diseases (e.g., asthma, cough, Chronic Obstructive Pulmonary Disease (COPD), and bronchoconstriction), gastrointestinal disorders (e.g., gastroesophageal reflux disease (GERD), dysphagia, ulcers, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), colitis, and crohn's disease), ischemia (e.g., cerebrovascular ischemia), emesis (e.g., cancer chemotherapy-induced emesis), and obesity, among others. The treatment of pain, in particular neuropathic pain, is a preferred use.
Physiological pain is an important protective mechanism intended to guard against the risk of potentially noxious stimuli from the external environment. The system functions through a set of specific primary sensory neurons, activated by noxious stimuli only via peripheral transduction mechanisms (reviewed in Millan, 1999, prog. neurobiol., 57, 1-164). These sensory fibers are known as nociceptors, characteristic small diameter axons that conduct at slow rates. Nociceptors encode the intensity, duration and nature of noxious stimuli, and by virtue of their topographical histological projection to the spinal cord, also encode the location of the stimuli. Nociceptive nerve fibers found on nociceptors are of two major types, a-delta fibers (myelinated) and C fibers (unmyelinated). The activity generated by nociceptor input is transferred after complex processing in the posterior horn, either directly or via the brainstem interface (relay) nucleus, to the anterior basal (ventral) thalamus and then to the cortex where a painful sensation is generated.
Pain can be generally classified as acute or chronic. Acute pain starts suddenly and is transient (usually twelve weeks or less). It is often associated with a particular cause, such as a particular injury, and is often sharp and severe. It is a type of pain that occurs after a particular injury caused by surgery, dental manipulation, bruising or sprain. Acute pain generally does not result in any sustained physiological response. In contrast, chronic pain is chronic pain, which usually lasts more than three months, causing significant physiological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, post-herpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritis pain and chronic post-operative pain.
When substantial damage to body tissue occurs via disease or trauma, the characteristics of nociceptor activation are altered, with sensitization occurring locally and centrally around the periphery of nociceptor termination, around the injury. These effects cause a sensation of pain intensification. In acute pain, these mechanisms may be used to promote protective behavior, which may better enable the repair process to occur. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, hypersensitivity is far longer than the healing process and is often caused by damage to the nervous system. This damage often causes abnormalities in sensory nerve fibers associated with maladaptive adaptation and abnormal activity (Woolf & Salter, 2000, Science, 288, 1765-.
Clinical pain is manifested when there is discomfort and an abnormal sensitivity characteristic in the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1) spontaneous pain, which may be dull, burning or stinging; 2) exaggerated pain in response to noxious stimuli (hyperalgesia); 3) pain (allodynia) results from normal innocuous stimuli (Meyer et al, 1994, Textbook of Pain, 13-44). Although patients with various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and thus different treatment strategies may be required. Pain can therefore be divided into many different subtypes according to different pathophysiology, including nociceptive, inflammatory and neuropathic pain.
Nociceptive pain is induced by tissue injury or by intense stimuli that have the potential to cause injury. Nociceptors transduce stimuli at the site of injury to activate pain afferent fibers, at the level where they terminate, activating neurons in the spinal cord. The ascending spinal tract then interfaces to the brain where Pain is perceived (Meyer et al, 1994, Textbook of Pain, 13-44). Activation of nociceptors activates two types of afferent nerve fibers. The myelinated a-delta fibers are rapidly transported, responsible for sharp and intense and sudden pain sensations, while unmyelinated C fibers are transported at a slower rate, conveying dull or aching pain. Moderate to severe acute nociceptive pain is a prominent characteristic of pain as follows: central nervous system trauma pain, contusion/sprain pain, burn pain, myocardial infarction pain, acute pancreatitis pain, post-operative pain (pain after any type of surgery), post-traumatic pain, renal colic, cancer pain, and back pain. Cancer pain may be chronic pain, such as tumor-related pain (e.g., bone pain, headache, facial pain, or visceral pain) or pain associated with cancer therapy (e.g., post-chemotherapy syndrome, chronic post-operative pain syndrome, or post-radiation syndrome). Cancer pain can also occur in response to chemotherapy, immunotherapy, hormonal therapy, or radiation therapy. Back pain can be caused by a herniated or ruptured disc or abnormalities in the lumbar facet (lumbar facet) joint, sacroiliac joint, paraspinal muscles or posterior longitudinal ligaments. Back pain can dissipate naturally, but in some patients lasting 12 weeks it becomes a chronic disease that can be particularly debilitating.
Neuropathic pain is currently defined as pain that is caused or caused by a primary injury or dysfunction of the nervous system. Trauma and disease can lead to nerve damage, and thus the term "neuropathic pain" encompasses many disorders of different etiology. They include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke 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 because it has no protective effect. It is often present well after the initial cause has disappeared, generally lasting for years, significantly reducing the quality of life of the patient (Woolf and Mannion 1999Lancet 353: 1959-1964). The symptoms of neuropathic Pain are difficult to treat because they are often heterogeneous, even among patients with the same disease (Woolf & Decosterd, 1999, Pain Supp.6, S141-S147; Woolf and Mannion 1999Lancet 353, 1959-1964). They include spontaneous pain, which can be continuous and persistent or episodic, such as hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (sensitivity to normally innocuous stimuli).
Inflammatory processes are a complex series of biochemical and cellular events that are activated in response to tissue damage or the presence of foreign substances, resulting in swelling and Pain (Levine and Taiwo 1994, Textbook of Pain 45-56). Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the most common chronic inflammations in developed countries, and rheumatoid arthritis is a common cause of disability. The exact etiology of rheumatoid arthritis is unknown, but current assumptions suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-. Approximately sixteen million Americans are estimated to suffer from symptomatic Osteoarthritis (OA) or degenerative joint disease, most of which are over the age of 60, and are expected to increase to forty million with increasing population age, making it a significant public health problem (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-. Most osteoarthritis patients seek medical attention due to the accompanying pain. Arthritis has a significant influence on the psychosocial and physical functions, and is known to be a leading cause of disability in later life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from intermittent episodes of lifelong back pain to severe chronic disease that attacks the spine, peripheral joints and other body organs.
Another type of inflammatory pain is visceral pain, including pain associated with Inflammatory Bowel Disease (IBD). Visceral pain is pain associated with the viscera, encompassing the organs of the abdominal cavity. These organs include the sexual organs, spleen and a part of the digestive system. Visceral associated pain can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered Gastrointestinal (GI) disorders that cause pain include Functional Bowel Disorder (FBD) and Inflammatory Bowel Disease (IBD). These GI disorders include a wide range of disease states that are currently only moderately controlled, including gastro-esophageal reflux, dyspepsia, Irritable Bowel Syndrome (IBS) and Functional Abdominal Pain Syndrome (FAPS) in the case of FBD, and crohn's disease, ileitis and ulcerative colitis in the case of IBD, all of which often cause visceral pain. 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 can therefore be divided into areas, such as back pain and cancer pain, which have both nociceptive and neuropathic components.
Other types of pain include:
● musculoskeletal disorders including pain due to myalgia, fibromyalgia, spondylitis, serum-negative (non-rheumatoid) arthropathy, non-articular rheumatism, malnutrition, glycogenolysis, polymyositis and pyomyositis;
● cardiac and vascular pain including pain caused by angina pectoris, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleroderma, and skeletal muscle ischemia;
● headache, such as migraine (including migraine with and without aura), cluster headache, tension-type pain mixed pain and headache associated with vascular disorders;
● orofacial pain including toothache, ear pain, burning mouth syndrome and temporomandibular myofascial pain.
The present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. The composition is preferably useful for the treatment of a condition as 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.
Further, the present invention provides a method of treating a condition as defined above in a mammal, preferably a human, which comprises administering to said mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
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 a condition as defined above.
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 substance.
Further, the present invention provides an intermediate compound of formula (Ia); or a pharmaceutically acceptable salt or solvate thereof:
a, B, D, E, R therein1、R3、R4、R5、R6、R7、R8、R10、R11And R12Have the meaning as defined above; and R is2aIs represented by (C)1-C6) An alkoxycarbonyl group.
Preferably, R2aIs (C)1-C3) An alkoxycarbonyl group; more preferred is methoxycarbonyl or ethoxycarbonyl.
Further, the present invention provides an intermediate compound of formula (II); or a pharmaceutically acceptable salt or solvate thereof:
a, B, R therein1、R2、R3And R4Have the meaning as defined above.
Further, the present invention provides intermediate compounds of formula (III); or a pharmaceutically acceptable salt or solvate thereof:
D、E、R5、R6、R8、R7、R10and R11Have the meaning as defined above.
Preferred intermediate compounds of the invention include those wherein each variable in formula (Ia), (II) or (III) is selected from the preferred groups for each of the variables described above.
In the present description, in particular in the "general synthesis" and "examples", the following abbreviations may be used:
BEP 2-bromo-1-ethylpyridinium tetrafluoroborate
BOP benzotriazol-1-yloxy-tris (dimethylamino) * hexa
Fluorophosphate salts
CDI 2-chloro-1, 3-dimethylimidazolium chloride
Co (TPP) 5, 10, 15, 20-tetraphenyl-21H, 23H-porphine Co (II)
DCC dicyclohexylcarbodiimide
DCM dichloromethane
DME 1, 2-dimethoxyethane, dimethoxyethane
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
EDC 1-ethyl-3- (3' -dimethylaminopropyl) carbodiimide salt
Acid salts
EtOAc ethyl acetate
EtOH ethanol
HOBt 1-hydroxybenzotriazole
MeOH methanol
NMP N-methyl-2-pyrrolidone
PdCl2(pddf)·CH2Cl2Palladium dichloride-1, 1' -bis (diphenylphosphino) ferrocene-
Dichloromethane complex
THF tetrahydrofuran
TFA trifluoroacetic acid
General Synthesis
The compounds of the invention can be prepared by a variety of methods well known for the preparation of compounds of this type, for example as shown in the following reaction schemes. The term "protecting group" as used hereinafter denotes a hydroxy or amino protecting group selected, for example, from the group consisting of Protective Groups in organic Synthesis (edited by T.W.Greene et al) (John Wiley&Sons, 1999) typical hydroxy or amino protecting groups. In the following general procedure, A, B, D, E, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11And R12Is as defined hereinbefore for compounds of formula (I), unless otherwise specified.
The following reaction scheme illustrates the preparation of compounds of formula (I).
Scheme 1
Step 1A
In this step, an amide compound of formula (I) can be prepared as follows: the amine compound of formula (II) is subjected to a coupling reaction with an acid compound of formula (III) in an inert solvent in the presence or absence of a coupling reagent. The reaction can also be carried out via activated carboxylic acid derivatives. Suitable coupling reagents are those commonly used in peptide synthesis, including, for example, the diimides (e.g., DCC, EDC), 2-ethoxy-N-ethoxycarbonyl-1, 2-dihydroquinoline, BEP, CDI, BOP, diethyl azodicarboxylate-triphenylphosphine, diethyl cyanophosphate, diethylphosphoryl azide, 2-chloro-1-methylpyridinium iodide, N' -carbonyldiimidazole, benzotriazol-1-yl diethyl phosphate, ethyl chloroformate, and isobutyl chloroformate.
The reaction may be carried out in the presence of a base, such as HOBt, N-diisopropylethylamine, N-methylmorpholine or triethylamine.
The reaction is generally and preferably carried out in the presence of a solvent. There is no particular restriction on the nature of the solvent employed, provided that it does not adversely affect the reaction or the reagents involved, at least to some extent, and is capable of dissolving the reagents. Examples of suitable solvents include acetone; nitromethane; DMF; NMP; sulfolane; DMSO; 2-butanone; acetonitrile; halogenated hydrocarbons such as DCM, dichloroethane, chloroform; and ethers such as THF and 1, 4-dioxane.
The reaction can take place at a wide range of temperatures, the precise reaction temperature not being critical to the invention. The preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials or reagents used. In general, however, it has been found convenient to carry out the reaction at a temperature of from-20 ℃ to 100 ℃, more preferably from about 0 ℃ to 60 ℃. The time required for the reaction may also vary widely, depending on many factors, mainly the reaction temperature and the nature of the reagents and solvents employed. However, as long as the reaction is carried out under the above-mentioned preferred conditions, a time of 5 minutes to 1 week, more preferably 30 minutes to 24 hours, will usually suffice.
Alternatively, the compound of formula (III) may first be converted to the acid halide derivative by reaction with a halogenating agent such as oxalyl chloride, phosphoryl chloride and thionyl chloride. The resulting acid halide derivative may then be reacted with a compound of formula (II) as described above to provide a compound of formula (I).
Scheme 2
This scheme illustrates the preparation of the compound of formula (II)
Wherein X is a suitable leaving group, such as sulfoxy or a halogen, such as chloro;
M1is a metal, such as lithium, or MgY, wherein Y represents hydrogen or a halogen, such as fluorine, chlorine, bromine or iodine;
M2is a metal, such as lithium, or MgY, wherein Y represents hydrogen or a halogen, such as fluorine, chlorine, bromine or iodine.
Step 2A
In this step, the compound of formula (V) may be prepared as follows: cyanation of a compound of formula (IV) with a metal cyanide reagent in the presence of a transition metal catalyst in an inert solvent.
Examples of suitable solvents include: THF; 1, 4-dioxane; DMF; acetonitrile; alcohols, such as MeOH or ethanol; halogenated hydrocarbons, such as DCM, 1, 2-dichloroethane, chloroform or carbon tetrachloride; and a DME. Suitable metal cyanide reagents include, for example: alkali metal cyanides such as lithium cyanide, sodium cyanide or potassium cyanide; transition metal cyanides such as iron (II) cyanide, cobalt (II) cyanide, copper (I) cyanide, copper (II) cyanide or zinc (II) cyanide; sodium cyanoborohydride; and cyanated trimethylsilane.
The reaction may be carried out in the presence of a suitable transition metal catalyst. Also, there is no particular limitation on the nature of the catalyst used, and any catalyst commonly used in this type of reaction may be used herein as well. 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) trifluoromethanesulfonate, palladium (II) acetate, palladium (II) chloride, bis-acetonitrile dichloropalladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride. Preferred catalysts are tetrakis (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, palladium (II) chloride, bis acetonitrile palladium dichloride (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride.
The reaction may be carried out in the presence of suitable additives. Examples of such additives include: triphenylphosphine, tri-tert-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, tri-2-furanylphosphine, tri-o-tolylphosphine, 2- (dichlorohexylphosphino) biphenyl and triphenylarsine.
The reaction may be carried out at a temperature of 0 ℃ to 200 ℃, more preferably 20 ℃ to 120 ℃. The reaction time is generally 5 minutes to 48 hours, more preferably 30 minutes to 24 hours.
Step 2B
In this step, an imine compound of the formula (VI) can be prepared as follows: cyano compounds of formula (V) and formula R3M1Nucleophilic addition of an organometallic compound. The reaction may be carried out in the presence of a solvent. Examples of suitable solvents include, for example: hydrocarbons, such as hexane; ethers such as diethyl ether, diisopropyl ether, DME, THF and 1, 4-dioxane; or mixtures thereof. The reaction temperature is generally in the range of-100 to 50 ℃, preferably in the range of-100 ℃ to room temperature. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 10 hours.
Formula R3M1The organometallic compound may be represented by R3Reaction preparation of halide compounds. The reaction may be carried out in the presence of an organometallic reagent or a metal. Examples of suitable organometallic agents include: alkyl lithium such as n-butyl lithium, sec-butyl lithium and tert-butyl lithium; and aryl lithium such as phenyl lithium and naphthyl lithium. Examples of suitable metals include magnesium. Preferred inert solvents include, for example: hydrocarbons, such as hexane; ethers such as diethyl ether, diisopropyl ether, DME, THF, 1, 4-dioxane; or mixtures thereof. The reaction temperature is generally in the range of-100 ℃ to 50 ℃, preferably in the range of-100 ℃ to room temperature. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 10 hours.
Step 2C
In this step, the amine compound of formula (II) can be prepared as follows: imine compounds of the formula (VI) and R4M2Nucleophilic addition of an organometallic compound. The reaction may be carried out in the presence of a solvent. Examples of suitable solvents include, for example: hydrocarbons, such as hexane; ethers such as diethyl ether, diisopropyl ether, DME, THF and 1, 4-dioxane; or mixtures thereof. The reaction temperature is generally in the range of-100 to 50 ℃, preferably in the range of-100 ℃ to room temperature. The reaction time is generally 1 minute to 1 day, preferably 1 hourTo 10 hours.
Formula R4M2The organometallic compound may be represented by R4Reaction preparation of halide compounds. The reaction may be carried out in the presence of an organometallic reagent or a metal. Examples of suitable organometallic agents include: alkyl lithium such as n-butyl lithium, sec-butyl lithium and tert-butyl lithium; and aryl lithium such as phenyl lithium and naphthyl lithium. Examples of suitable metals include magnesium. Preferred inert solvents include, for example: hydrocarbons, such as hexane; ethers such as diethyl ether, diisopropyl ether, DME, THF, 1, 4-dioxane; or mixtures thereof. The reaction temperature is generally in the range of-100 ℃ to 50 ℃, preferably in the range of-100 ℃ to room temperature. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 10 hours.
When R is3And R4When both are hydrogen, the compounds of formula (II) can be prepared from the compounds of formula (V) as depicted in scheme 3.
Scheme 3
Step 3A
In this step, the compound of formula (II) may be prepared as follows: the hydrogenation of the compounds of the formula (V) is carried out, for example, under known hydrogenolysis conditions in the presence of a metal catalyst, under a hydrogen atmosphere, or in the presence of a hydrogen source, for example formic acid or ammonium formate, in an inert solvent. If desired, the reaction may be carried out under acidic conditions, for example in the presence of hydrochloric acid or acetic acid. Preferred metal catalysts are for example selected from: nickel catalysts, such as raney nickel; Pd-C; palladium hydroxide-carbon; platinum oxide; platinum-carbon; ruthenium-carbon; rhodium-alumina; and tris (triphenylphosphine) rhodium chloride. Examples of suitable inert aqueous or non-aqueous organic solvents include: alcohols such as methanol and 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 may be carried out at a temperature in the range of from 20 ℃ to 100 ℃, preferably in the range of from 20 ℃ to 60 ℃. The reaction time is generally 10 minutes to 4 days, preferably 30 minutes to 24 hours. The reaction may be carried out under a hydrogen atmosphere at a pressure of 1 to 100atm, preferably 1 to 10 atm.
Scheme 4
This scheme illustrates the preparation of the compound of formula (III).
RaAre suitable protecting groups, e.g. (C)1-C4) Alkyl or benzyl;
M3tributylstannane, trimethylstannane, triphenylstannane, tributylsilane, trimethylsilane, triphenylsilane, diphenylborane, dimethyl borate, magnesium bromide, and the like.
Step 4A
In this step, the compound of formula (VIII) may be prepared as follows: triflating the compound of formula (VII) under basic conditions in an inert solvent using triflic acid anhydride. Preferred bases are for example selected from, but not limited to: alkali metal or alkaline earth metal hydroxides, alcoholates, carbonates, halides or hydrides, such as sodium hydroxide, potassium hydroxide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium carbonate, potassium fluoride, sodium hydride or potassium hydride; or amines, such as triethylamine, tributylamine, diisopropylethylamine, 2, 6-lutidine, pyridine or dimethylaminopyridine. Examples of suitable solvents include: toluene; xylene; a DME; DMSO; THF; 1, 4-dioxane; DMF; acetonitrile; halogenated hydrocarbons, such as DCM, 1, 2-dichloroethane, chloroform or carbon tetrachloride; and diethyl ether. The reaction temperature is generally in the range of-78 ℃ to 200 ℃, preferably in the range of 0 ℃ to room temperature. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 20 hours.
Step 4B
In this step, the compound of formula (X) may be prepared as follows: the olefination of the compound of formula (VIII) with the compound of formula (IX) is carried out under olefination conditions with a vinyl metal, vinyl acetate or vinyl methyl ether reagent in the presence of a transition metal catalyst in an inert solvent. 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 diethyl ether; in the presence or absence of an aqueous base, e.g. aqueous KOH, NaOH, LiOH or K2CO3. Suitable vinyl reagents include, for example, metallic vinyl reagents such as tributylvinylstannane, isopropenylpotassium trifluoroborate, trimethylvinylstannane, triphenylvinylstannane, tributylvinylsilane, trimethylvinylsilane, triphenylvinylsilane, diphenylvinylborane, vinyldimethyl borate, and vinylmagnesium bromide.
The reaction may be carried out in the presence of a suitable transition metal catalyst. Also, there is no particular limitation on the nature of the catalyst used, and any catalyst commonly used in this type of reaction may be used herein as well. 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) trifluoromethanesulfonate, palladium (II) acetate, palladium (II) chloride, bis-acetonitrile dichloropalladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride. Preferred catalysts are tetrakis (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, palladium (II) chloride, bis acetonitrile palladium dichloride (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride.
The reaction may be carried out in the presence of suitable additives. Examples of such additives include: triphenylphosphine, tri-tert-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, tri-2-furanylphosphine, tri-o-tolylphosphine, 2- (dichlorohexylphosphino) biphenyl, triphenylarsine, tetrabutylammonium chloride, tetrabutylammonium fluoride, lithium acetate, lithium chloride, triethylamine, potassium sodium methoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate and/or sodium iodide. The reaction may be carried out at a temperature of 0 ℃ to 200 ℃, more preferably 20 ℃ to 120 ℃. The reaction time is generally 5 minutes to 96 hours, more preferably 30 minutes to 24 hours.
Step 4C
In this step, the compound of formula (XII) can also be prepared as follows: olefinating the compound of formula (X) with a compound of formula (XI) and a diazonium reagent in an inert solvent.
Examples of suitable solvents include: diethylene glycol dimethyl ether; DMSO; a DME; THF; 1, 4-dioxane; DMF; acetonitrile; halogenated hydrocarbons, such as DCM, 1, 2-dichloroethane, chloroform or carbon tetrachloride; and acetic acid. Suitable diazonium reagents include, for example, diazonium esters such as methyl diazoacetate, ethyl diazoacetate, benzyl diazoacetate and tert-butyl diazoacetate.
The reaction may be carried out in the presence of a suitable catalyst. Examples of such catalysts include: acetic acid Rh (II), Ru 2(OAc)4Cl、RuCl2(PPh3) (p-cymene), Cu (0), Cu (acetylacetonate)2Co (TPP) and Pd (OAc)2. The reaction may be carried out in the presence of suitable additives. Examples of such additives include: triphenylphosphine, tri-tert-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, tri-2-furanylphosphine, tri-o-tolylphosphine, 2- (dichlorohexylphosphino) biphenyl, triphenylarsine, tetrabutylammonium chloride, tetrabutylammonium fluoride, lithium acetate, lithium chloride, N-methylphosphineMethylimidazole, triethylamine, potassium sodium methoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate and/or sodium iodide. The reaction may be carried out at a temperature of 0 ℃ to 200 ℃, more preferably 20 ℃ to 120 ℃. The reaction time is generally 5 minutes to 96 hours, more preferably 30 minutes to 24 hours.
Step 4D
In this step, the acid compound of formula (III) may be prepared as follows: the hydrolysis of the ester compound of the formula (XII) is carried out in an inert solvent.
The hydrolysis can be carried out by means of conventional procedures. In a typical procedure, the hydrolysis is carried out under basic conditions, for example in the presence of sodium hydroxide, potassium hydroxide or lithium hydroxide. Suitable solvents include, for example: alcohols such as methanol, ethanol, 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. Preferred solvents are methanol, ethanol, propanol, THF, DME, 1, 4-dioxane, DMF and DMSO. The reaction may be carried out at a temperature in the range of-20 ℃ to 100 ℃, typically 20 ℃ to 65 ℃, for a period of 30 minutes to 24 hours, typically 60 minutes to 10 hours.
The hydrolysis may also be carried out under acidic conditions, for example in the presence of hydrohalides, such as hydrogen chloride and hydrogen bromide; sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid; pyridinium p-toluenesulfonate; or carboxylic acids such as acetic acid and TFA. Suitable solvents include, for example: alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol; ethers such as THF, DME and 1, 4-dioxane; amides such as DMF and hexamethylphosphoric acid (phospholic) triamide; and sulfoxides, such as DMSO. Preferred solvents are methanol, ethanol, propanol, THF, DME, 1, 4-dioxane, DMF and DMSO. The reaction may be carried out at a temperature in the range of-20 ℃ to 100 ℃, typically 20 ℃ to 65 ℃, for a period of 30 minutes to 24 hours, typically 60 minutes to 10 hours.
Scheme 5
This scheme illustrates the preparation of the compound of formula (X).
Step 5A
In this step, the compound of formula (X) may be prepared as follows: the phosphidinyl or phosphoranylidene compounds of formula (XIV) are used, prepared in situ from a suitable phosphine reagent and a methylene dihalide reagent, under olefination conditions or basic conditions in an inert solvent.
Examples of suitable solvents include: toluene; benzene; xylene; diethylene glycol dimethyl ether; DMSO; a DME; THF; diethyl ether; 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. Suitable phosphine reagents include, for example, triphenylphosphine and tributylphosphine. Suitable methylene dihalide reagents include, for example, methyl bromide, ethyl bromide, methyl iodide, ethyl iodide, methyl chloride, ethyl chloride, methyl bromoacetate, bromoacetonitrile, 1-bromoacetone, ethylene (triphenyl) phosphorane, (triphenylphosphoranylidene) acetonitrile and methyl (triphenylphosphinylidene) acetate.
Preferred bases are for example selected from, but not limited to: alkali metal or alkaline earth metal hydroxides, alcoholates, carbonates, halides or hydrides, such as sodium hydroxide, potassium hydroxide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium carbonate, potassium fluoride, sodium hydride or potassium hydride; or amines, such as triethylamine, tributylamine, diisopropylethylamine, 2, 6-lutidine, pyridine or dimethylaminopyridine.
The reaction may be carried out at a temperature of 0 ℃ to 300 ℃, more preferably 20 ℃ to 200 ℃. The reaction time is generally 5 minutes to 96 hours, more preferably 30 minutes to 24 hours.
When R is10And R11When both are fluorine, the compounds of formula (III) may be prepared from compounds of formula (XV), as depicted in scheme 6.
Scheme 6
Step 6A
In this step, the compound of formula (XVI) can be prepared as follows: cyclopropanating a compound of formula (XV) with sodium chlorodifluoroacetate in an inert solvent under cyclopropanation conditions using a carbene reagent prepared in situ. Examples of suitable solvents include: diethylene glycol dimethyl ether; DMSO; a DME; ethers such as THF, diethyl ether or 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. Suitable carbene reagents include, for example, CH 2I2、CHCl3Sodium chlorodifluoroacetate, trimethylsilylfluorosulfonyldifluoroacetate, trimethylsulfoxonium iodide, and diazomethane.
The reaction may be carried out in the presence or absence of a suitable catalyst. Also, there is no particular limitation on the nature of the catalyst used, and any catalyst commonly used in this type of reaction may be used herein as well. Examples of such catalysts include: zn (0), Cu (acetylacetonate)2Co (TPP) and Pd (OAc)2。
The reaction may be carried out in the presence of suitable additives. Examples of such additives include: acetyl chloride, methyl benzoate, sodium fluoride, triphenylphosphine, tri-tert-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, tri-2-furanylphosphine, tri-o-tolylphosphine, 2- (dichlorohexylphosphino) biphenyl, triphenylarsine, sodium hydride, potassium hydride, sodium methoxide and lithium diisopropylamide. The reaction may be carried out at a temperature of 0 ℃ to 300 ℃, more preferably 20 ℃ to 200 ℃. The reaction time is generally 5 minutes to 96 hours, more preferably 30 minutes to 24 hours.
Step 6B
In this step, the compound of formula (XVII) can be prepared as follows: the deprotection of the compound of formula (XVI) is carried out under acidic conditions or by hydrogenation.
When acidic conditions are employed, the reaction temperature is generally in the range of from 0 to 200 ℃, preferably room temperature. The reaction time is generally 1 minute to 24 hours, preferably 5 minutes to 1 hour. Suitable reagents include, for example, hydrochloric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid and acetic acid. 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 hydrogenation is carried out, for example, using known hydrogenolysis conditions in the presence of a suitable metal catalyst under a hydrogen atmosphere or in the presence of a hydrogen source, such as formic acid or ammonium formate, 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. Preferred metal catalysts are for example selected from: nickel catalysts, such as raney nickel; Pd-C; palladium hydroxide-carbon; platinum oxide; platinum-carbon; ruthenium-carbon; rhodium-alumina; and tris (triphenylphosphine) rhodium chloride. Examples of suitable inert aqueous or non-aqueous 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 may be carried out at a temperature in the range of from 20 ℃ to 100 ℃, preferably in the range of from 20 ℃ to 60 ℃. The reaction time is generally 10 minutes to 4 days, preferably 30 minutes to 24 hours. The reaction may be carried out under a hydrogen atmosphere at a pressure of 1 to 100atm, preferably 1 to 10 atm.
Step 6C
In this step, the compound of formula (III) may be prepared as follows: the oxidation of the compound of formula (XVII) is carried out using an oxidizing agent in an inert solvent. Examples of oxidizing agents include oxalyl chloride-DMSO (Swern oxidation conditions), pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), manganese dioxide, and tetrapropylammonium perruthenate (TPAP). The reaction may be carried out in a suitable inert solvent, for example halogenated hydrocarbons such as chloroform, dichloroethane and 1, 2-dichloroethane. The reaction may be carried out at a temperature in the range of-100 to 80 ℃, typically-80 to 50 ℃, for a period of 5 minutes to 30 hours, typically 15 minutes to 20 hours.
When R is1OAnd R11When both are hydrogen, the compounds of formula (III) can be prepared from the compounds of formula (XVII) as depicted in scheme 7.
Scheme 7
RaAre suitable protecting groups, e.g. (C)1-C4) Alkyl or benzyl.
Step 7A
In this step, the compound of formula (XIX) may be prepared as follows: cyclopropanating a compound of formula (XVIII) using carbene, prepared in situ, in an inert solvent under cyclopropanation conditions. Examples of suitable solvents include: diethylene glycol dimethyl ether; DMSO; a DME; THF; diethyl ether; 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. Suitable reagents include, for example, CH 2I2、CHCl3Sodium chlorodifluoroacetate, trimethylsilylfluorosulfonyldifluoroacetate, trimethylsulfoxonium iodide, and diazomethane.
The reaction may be carried out with or without a suitable catalystIn the presence of (a). Also, there is no particular limitation on the nature of the catalyst used, and any catalyst commonly used in this type of reaction may be used herein as well. Examples of such catalysts include: zirconium (0), copper (acetylacetonate)2Co (TPP) and Pd (OAc)2。
The reaction may be carried out in the presence of suitable additives. Examples of such additives include: acetyl chloride, methyl benzoate, sodium fluoride, triphenylphosphine, tri-tert-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, tri-2-furanylphosphine, tri-o-tolylphosphine, 2- (dichlorohexylphosphino) biphenyl, triphenylarsine, sodium hydride, potassium hydride, sodium methoxide and lithium diisopropylamide. The reaction may be carried out at a temperature of 0 ℃ to 300 ℃, more preferably 20 ℃ to 200 ℃. The reaction time is generally 5 minutes to 96 hours, more preferably 30 minutes to 24 hours.
Step 7B
In this step, the hydrolysis of the ester compound of formula (XIX) may be carried out as described in step 4D to produce the compound of formula (III).
When R is4When hydrogen, compounds of formula (II) can be prepared from compounds of formula (XX), as depicted in scheme 8.
Scheme 8
Step 8A
In this step, the compound of formula (XXI) can be prepared as follows: the triflic acid reaction of the compound of formula (XX) is carried out using triflic anhydride (triflic anhydride) under basic conditions in an inert solvent.
Preferred bases are for example selected from, but not limited to: alkali metal or alkaline earth metal hydroxides, alcoholates, carbonates, halides or hydrides, such as sodium hydroxide, potassium hydroxide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium carbonate, potassium fluoride, sodium hydride or potassium hydride; or amines, 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. The reaction temperature is generally in the range of-78 ℃ to 200 ℃, preferably in the range of 0 ℃ to room temperature. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 20 hours.
Step 8B
In this step, the compound of formula (XXII) can be prepared as follows: the compounds of formula (XXI) are coupled with alkylsulfonamides in the presence of a catalyst and 4, 5-bis (diphenylphosphino) -9, 9-desmethylxanthene (Xantphos) under basic conditions in an inert solvent, as described in Buchwald, S.L. journal of American chemical society, 2002, 124, 6043-. Examples of suitable catalysts include tris (dibenzylideneacetone) dipalladium (0) and palladium reagents such as palladium acetate and palladium dibenzylacetonate. Preferred bases are for example selected from, but not limited to: alkali metal or alkaline earth metal hydroxides, alcoholates, carbonates, halides or hydrides, such as sodium hydroxide, potassium hydroxide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium carbonate, potassium carbonate, caesium carbonate, potassium fluoride, sodium hydride or potassium hydride; or amines, 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. The reaction temperature is generally in the range of 0 to 200 ℃, preferably in the range of 100 ℃ to 140 ℃. The reaction time is generally 1 minute to 1 day, preferably 5 minutes to 1 hour.
Step 8C
In this step, the compound of formula (XXIV) can be prepared as follows: the dehydration and reduction of the compound of formula (XXII) and the sulfenamide of formula (XXIII) are carried out in an inert solvent in the presence of a catalyst and a reducing agent. The dehydration is carried out in the presence of a dehydrating agent. Examples of suitable dehydrating agents include: hydrohalides such as hydrogen chloride and hydrogen bromide; sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid; sulfonyl chlorides such as methanesulfonyl chloride and p-toluenesulfonyl chloride; methoxycarbonylsulfamoyltriethylammonium hydroxide; p-toluenesulfonyl isocyanate; and titanium (IV) ethoxide. The reaction temperature is generally in the range of 0 to 200 ℃, preferably in the range of 50 ℃ to 100 ℃. The reaction time is generally 1 minute to 48 hours, preferably 12 hours to 24 hours. The reduction may be carried out in the presence of a suitable reducing agent, in an inert solvent or without a solvent. Preferred reducing agents are selected, for example, but not limited to, NaBH4、LiAlH4、LiBH4Fe, Sn or Zn. The reaction temperature is generally in the range of-78 ℃ to room temperature, preferably in the range of-70 ℃ to 0 ℃. The reaction time is generally 1 minute to 1 day, preferably 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.
Step 8D
In this step, the compound of formula (II) may be prepared as follows: deprotection and salt formation of the compound of formula (XXIV) is carried out under acidic conditions in an inert solvent using the method of D.Cogan et al, Journal of American Chemical Society, 1999, 121, 268-269. The reaction temperature is generally in the range of 0 to 200 ℃, preferably room temperature. The reaction time is generally 1 minute to 24 hours, preferably 5 minutes to 1 hour. 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.
Scheme 9
This scheme illustrates an alternative preparation of the compound of formula (XXII).
Step 9A
In this step, a compound of formula (XXVII) can be prepared as follows: the sulfonylation of the compound of the formula (XXV) is carried out with the compound of the formula (XXVI) in an inert solvent in the presence of a base under, for example, known sulfonylation conditions. Preferred bases are for example selected from, but not limited to: alkali metal or alkaline earth metal hydroxides, alcoholates, carbonates, halides or hydrides, such as sodium hydroxide, potassium hydroxide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium carbonate, potassium fluoride, sodium hydride or potassium hydride; or amines, such as triethylamine, tributylamine, diisopropylethylamine, 2, 6-lutidine, pyridine or dimethylaminopyridine. Examples of suitable inert aqueous or non-aqueous 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 may be carried out at a temperature in the range of from 20 ℃ to 100 ℃, preferably in the range of from 20 ℃ to 60 ℃. The reaction time is generally 10 minutes to 4 days, preferably 30 minutes to 24 hours.
Step 9B
In this step, the compound of formula (XXII) can be prepared as follows: with R in the presence of a metal and an acid halide under, for example, known Friedal-Crafts acylation conditions3Friedal-Crafts acylation of the compound of formula (XXVII) is carried out with Cl. The reaction may be carried out in an inert solvent. Examples of suitable solvents include: halogenated hydrocarbons such as DCM, dichloroethane or chloroform; and aromatic hydrocarbons such as nitrobenzene and chlorobenzene. Examples of suitable catalystsIncluding aluminum halides such as aluminum chloride and aluminum bromide. The reaction may be carried out at a temperature of-50 ℃ to 200 ℃, preferably about-10 ℃ to 150 ℃, for a period of 5 minutes to 48 hours, preferably 30 minutes to 24 hours.
When R is4When hydrogen, compounds of formula (II) can be prepared from compounds of formula (XXVII), as depicted in scheme 10.
Scheme 10
Step 10A
In this step, a compound of formula (XXIX) can be prepared as follows: the dehydration of the compound of formula (XXII) is carried out under basic conditions in an inert solvent using a lewis acid. Preferred lewis acids are for example selected from, but not limited to, titanium tetrachloride, aluminum tetrachloride or zirconium tetrachloride. Preferred bases are for example selected from, but not limited to, alkali or alkaline earth metal hydroxides, alcoholates, carbonates, halides or hydrides, such as sodium hydroxide, potassium hydroxide, sodium methanolate, sodium ethanolate, potassium tert-butanolate, sodium carbonate, potassium fluoride, sodium hydride or potassium hydride; or amines, 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. The reaction temperature is generally in the range of-78 to 200 ℃, preferably in the range of 0 ℃ to room temperature. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 20 hours.
Step 10B
In this step, compounds of formula (XXX) may be prepared as follows: in the presence of a suitable reducing agent, in an inert solvent or without a solventThe compound of formula (XXIX) is reduced. Preferred reducing agents are selected, for example, but not limited to, NaBH4、LiAlH4、LiBH4Fe, Sn or Zn. The reaction temperature is generally in the range of-78 ℃ to room temperature, preferably in the range of-70 ℃ to 0 ℃. The reaction time is generally 1 minute to 1 day, preferably 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 may also be carried out in the presence of a suitable metal catalyst under a hydrogen atmosphere in an inert solvent. Preferred metal catalysts are for example selected from: nickel catalysts, such as raney nickel; Pd-C; palladium hydroxide-carbon; platinum oxide; platinum-carbon; ruthenium-carbon; rhodium-alumina; and tris (triphenylphosphine) rhodium chloride. Examples of suitable inert aqueous or non-aqueous 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 may be carried out at a temperature in the range of from 20 ℃ to 100 ℃, preferably in the range of from 20 ℃ to 60 ℃. The reaction time is generally 10 minutes to 4 days, preferably 30 minutes to 24 hours. The reaction may be carried out under a hydrogen atmosphere at a pressure of 1 to 100atm, preferably 1 to 10 atm.
Step 10C
In this step, the compound of formula (II) may be prepared as follows: the hydrogenation of compounds of formula (XXX) is carried out under, for example, known hydrogenolysis conditions, in the presence of a metal catalyst, under an atmosphere of hydrogen, or in the presence of a hydrogen source, for example formic acid or ammonium formate, in an inert solvent. If desired, the reaction may be carried out under acidic conditions, for example in the presence of hydrochloric acid or acetic acid. Preferred metal catalysts are for example selected from: nickel catalysts, such as raney nickel; Pd-C; palladium hydroxide-carbon; platinum oxide; platinum-carbon; ruthenium-carbon; rhodium-alumina; and tris (triphenylphosphine) rhodium chloride. Examples of suitable inert aqueous or non-aqueous 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 may be carried out at a temperature in the range of from 20 ℃ to 100 ℃, preferably in the range of from 20 ℃ to 60 ℃. The reaction time is generally 10 minutes to 4 days, preferably 30 minutes to 24 hours. The reaction may be carried out under a hydrogen atmosphere at a pressure of 1 to 100atm, preferably 1 to 10 atm.
Step 10D
In this step, the compound of formula (II) may be prepared as follows: the compounds of formula (XXX) form salts with, for example, hydrogen chloride in methanol, 1, 4-dioxane and aqueous solutions. The reaction may be carried out at a temperature in the range of from 20 ℃ to 100 ℃, preferably in the range of from 20 ℃ to 60 ℃. The reaction time is generally 10 minutes to 4 days, preferably 30 minutes to 24 hours.
Scheme 11
This scheme illustrates the preparation of the compound of formula (X).
Step 11A
In this step, the compound of formula (X) may be prepared as follows: the compound of formula (VII) is alkylenated with a compound of formula (IX) under alkylenation conditions using a metal vinyl, vinyl acetate or vinyl methyl ether reagent in the presence of a transition metal catalyst in an inert solvent. 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 diethyl ether; in the presence or absence of an aqueous base, e.g. aqueous KOH, NaOH, LiOH or K2CO3. Examples of suitable vinyl reagentsSuch as including metallic vinyl reagents such as tributylvinylstannane, trimethylvinylstannane, triphenylvinylstannane, tributylvinylsilane, trimethylvinylsilane, triphenylvinylsilane, diphenylvinylborane, dimethylvinyl borate, potassium vinyltrifluoroborate, or vinylmagnesium bromide.
Examples of suitable transition metal 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) trifluoromethanesulfonate, palladium (II) acetate, palladium (II) chloride, bis-acetonitrile palladium (0) dichloride, bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride. Preferred catalysts are tetrakis (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, palladium (II) chloride, bis acetonitrile dichloropalladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride. The reaction may be carried out in the presence of suitable additives. Examples of such additives include: triphenylphosphine, tri-tert-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, tri-2-furanylphosphine, tri-o-tolylphosphine, 2- (dichlorohexylphosphino) biphenyl, triphenylarsine, tetrabutylammonium chloride, tetrabutylammonium fluoride, lithium acetate, lithium chloride, triethylamine, potassium sodium methoxide, sodium hydroxide, carbonate, sodium bicarbonate and/or sodium iodide. The reaction may be carried out at a temperature of 0 ℃ to 200 ℃, more preferably 20 ℃ to 120 ℃. The reaction time is generally 5 minutes to 96 hours, more preferably 30 minutes to 24 hours.
When R is4、R5、R6、R10And R11Are all hydrogen; d is CR9Wherein R is9Is H; e is N; and R is7Is NH2、(C1-C6) Alkyl NH or [ (C)1-C6) Alkyl radical]2When N, the compounds of formula (I) may be prepared from compounds of formula (XXXI) as in the schemes12, the method is as described in the specification.
Scheme 12
Step 12A
In this step, the compound of formula (X) may be prepared as follows: the olefination is carried out using the compound of formula (XI) or the phosphorane prepared in situ under olefination conditions in an inert solvent or under basic conditions in an inert solvent, followed by reduction of the compound of formula (XXXI) with a reducing agent under reducing conditions in an inert solvent. The reduction may be carried out in the presence of a suitable reducing agent, in an inert solvent or without a solvent. Preferred reducing agents are selected, for example, from, but not limited to, sodium borohydride, lithium aluminum hydride, or lithium borohydride. Examples of suitable solvents include: THF, 1, 4-dioxane, DMF, acetonitrile; alcohols, such as MeOH or ethanol; halogenated hydrocarbons, such as DCM, 1, 2-dichloroethane, chloroform or carbon tetrachloride; and acetic acid. The reaction temperature is generally in the range of-78 ℃ to room temperature, preferably in the range of-70 ℃ to 0 ℃. The reaction time is generally 1 minute to 1 day, preferably 3 hours to 6 hours.
Step 12B
The compound of formula (XII) can be prepared from the compound of formula (X) by means of the reaction as described above in step 4C.
Step 12C
The compound of formula (III) may be prepared from the compound of formula (XII) via a reaction as described above in step 4D.
Step 12D
The compound of formula (XXXII) may be prepared from the compound of formula (III) via a reaction as described above in step 1A.
Step 12E
In this step, the compounds of formula (I) may be prepared as follows: coupling a compound of formula (XXXII) with an amine HNR' R "in an inert solvent or in the absence of a solvent. Examples of suitable solvents include: THF; 1, 4-dioxane; DMF; acetonitrile; alcohols, such as methanol or ethanol; and halogenated hydrocarbons such as DCM, 1, 2-dichloroethane, chloroform or carbon tetrachloride. The reaction may be carried out at a temperature of 0 ℃ to 200 ℃, more preferably 20 ℃ to 120 ℃. The reaction time is generally 5 minutes to 96 hours, more preferably 30 minutes to 24 hours.
When D and E are both CR9，R8When it is tert-butyl or 2, 2, 2-trifluoro-1, 1-methylethyl, the compound of formula (VII) may be prepared from the compound of formula (XXXIII), as depicted in scheme 13.
Scheme 13
Step 13A
In this step, the organometallic compound of formula (XXXIV) can be prepared as follows: carrying out a direct metallation reaction of the compound of formula (XXXIII) with an alkyllithium. The reaction may be carried out in the presence of an organometallic reagent or a metal. Examples of suitable organometallic agents include: alkyl lithium such as n-butyl lithium, sec-butyl lithium and tert-butyl lithium; and aryl lithium such as phenyl lithium and naphthyl lithium. Preferred reaction-inert solvents include, for example: hydrocarbons, such as hexane; ethers such as diethyl ether, diisopropyl ether, DME, THF and 1, 4-dioxane; or mixtures thereof. The reaction temperature is generally in the range of-100 ℃ to 50 ℃, preferably in the range of-100 ℃ to room temperature. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 10 hours.
Step (ii) of13B
In this step, compounds of formula (XXXV) can be prepared as follows: nucleophilic addition of the compound of formula (XXXIV) to a ketone reagent is carried out. Examples of suitable ketone reagents include: dialkyl ketones such as acetone; and haloalkyl ketones such as 1, 1, 1-trifluoroacetone. Preferred reaction-inert solvents include, for example: hydrocarbons, such as hexane; ethers such as diethyl ether, diisopropyl ether, DME, THF and 1, 4-dioxane; or mixtures thereof. The reaction temperature is generally in the range of-100 ℃ to 50 ℃, preferably in the range of-100 ℃ to room temperature. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 10 hours.
Step 13C
In this step, compounds of formula (XXXVI) can be prepared as follows: halogenation of the compound of formula (XXXV) is carried out with a halogenating agent. Halogenation may be carried out in the presence of a suitable halogenating agent, in an inert solvent or in the absence of a solvent. Preferred reaction-inert solvents include, for example: hydrocarbons, such as benzene, toluene or xylene; halogenated hydrocarbons, such as DCM, 1, 2-dichloroethane, chloroform or carbon tetrachloride; or mixtures thereof. Preferred halogenating agents are selected from the following examples, but are not limited to: thionyl chloride, oxalyl chloride, phosphorus oxychloride, titanium chloride and phosphorus pentachloride, optionally in combination with a catalytic pyridine, most preferably thionyl chloride in combination with a catalytic pyridine. The reaction temperature is generally in the range of-100 ℃ to 200 ℃, preferably in the range of-40 ℃ to 100 ℃. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 10 hours.
Step 13D
In this step, a compound of formula (XXXVII) can be prepared as follows: the substitution reaction of the compound of formula (XXXVI) with the alkylating agent is carried out in an inert solvent. Preferred alkylating agents are selected from the following examples, but are not limited to: trialkyl metals such as trimethylaluminum, triethylaluminum; alkyl magnesium halides, such as methyl magnesium bromide, in the presence of an additive compound, such as lithium bromide; dialkylzinc halides, such as dimethylzinc dichloride prepared from dimethylzinc and titanium chloride; most preferred is trimethylaluminum. Preferred reaction-inert solvents include, for example: halogenated hydrocarbons, such as DCM, 1, 2-dichloroethane, chloroform or carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, DME, THF and 1, 4-dioxane; hydrocarbons such as n-hexane, cyclohexane, benzene and toluene; or mixtures thereof. The reaction temperature is generally in the range of-100 ℃ to 200 ℃, preferably in the range of-40 ℃ to 100 ℃. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 10 hours.
Step 13E
In this step, the compound of formula (VII) can be prepared as follows: dealkylation of the compound of formula (XXXVII) is carried out with a dealkylating agent in an inert solvent. Examples of suitable dealkylating agents include: boron halides, such as boron tribromide or boron trichloride; and hydrogen halides, such as hydrogen bromide. Preferred reaction-inert solvents include, for example: halogenated hydrocarbons, such as DCM, 1, 2-dichloroethane, chloroform or carbon tetrachloride; and acetic acid. The reaction temperature is generally in the range of-100 ℃ to 200 ℃, preferably in the range of-80 ℃ to 80 ℃. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 10 hours.
When B is N and A is CH or CR12Compounds of formula (XXII) may be prepared from compounds of formula (XXXVIII), as described in scheme 14.
Scheme 14
Step 14A
In this step, compounds of formula (XXXIX) may be prepared as follows: alkylation of the compound of formula (XXXVIII) is carried out with an alkylating agent in the presence of a suitable metal catalyst in an inert solvent. Preferred alkylating agents are selected from, but not limited to: trialkyl metals such as trimethylaluminum or triethylaluminum; and alkyl magnesium halides, such as methyl magnesium bromide. The reaction may be carried out in the presence of an additive compound, such as lithium bromide or a dialkyl zinc halide, such as dimethyl zinc dichloride prepared from dimethyl zinc and titanium chloride, preferably trimethylaluminum. Examples of suitable metal 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) trifluoromethanesulfonate, palladium (II) acetate, palladium (II) chloride, bis-acetonitrile dichloropalladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride. Preferred catalysts are tetrakis (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, palladium (II) chloride, bis acetonitrile dichloropalladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride. Preferred reaction-inert solvents include, for example: halogenated hydrocarbons, such as DCM, 1, 2-dichloroethane, chloroform or carbon tetrachloride; acetic acid; 1, 4-dioxane; THF; DMF; dimethyl sulfoxide; and diglyme.
The reaction may be carried out in the presence of suitable additives. Examples of such additives include: triphenylphosphine, tri-tert-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, tri-2-furanylphosphine, tri-o-tolylphosphine, 2- (dichlorohexylphosphino) biphenyl, triphenylarsine, tetrabutylammonium chloride, tetrabutylammonium fluoride, lithium acetate, lithium chloride, triethylamine, potassium sodium methoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate and/or sodium iodide.
The reaction temperature is generally in the range of-100 ℃ to 200 ℃, preferably in the range of-40 ℃ to 100 ℃. The reaction time is generally 1 minute to 1 day, preferably 1 hour to 10 hours.
Step 14B
In this step, a compound of formula (XXXX) may be prepared from a compound of formula (XXXIX) by a method as described above in step 9A.
Step 14C
In this step, a compound of formula (XXXXI) may be prepared from a compound of formula (XXXX) by means of a method as described above in step 2A.
Step 14D
In this step, the compound of formula (XXII) can be prepared as follows: alkylation of the compound of formula (XXXI) is carried out with an alkylating agent in an inert solvent. Preferred alkylating agents and inert solvents are the same as those of step 14A. The reaction may be carried out at a temperature of 0 ℃ to 200 ℃, more preferably 20 ℃ to 120 ℃. The reaction time is generally 5 minutes to 96 hours, more preferably 30 minutes to 24 hours.
Scheme 15
Step 15A
In this step, compounds of formula (xxxiii) may be prepared as follows: acetals are formed from compounds of formula (XXXXII) in an inert solvent or in the absence of a solvent in the presence of a suitable catalyst. The formation of the dialkyl acetal may be carried out in an inert solvent in the presence of a suitable acetal formation agent and a catalyst.
Examples of preferred acetal forming agents include trimethyl orthoformate and triethyl orthoformate. Examples of preferred catalysts include: tetrabutylammonium tribromide; tetrabutylammonium trichloride; hydrogen chloride; and metal chlorides such as aluminum (III) chloride, zinc chloride, or boron (III) trichloride. 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 reaction temperature is generally in the range of-78 ℃ to room temperature, preferably in the range of-70 ℃ to 0 ℃. The reaction time is generally 1 minute to 1 day, preferably 3 hours to 6 hours.
Step 15B
In this step, the compound of formula (X) may be prepared as follows: the olefination of the compound of formula (XXXIII) is carried out in the presence of a catalyst, in an inert solvent or without a solvent. The olefination reaction may be carried out in an inert solvent in the presence of suitable reagents and additives. Preferred agents are for example selected from, but not limited to: succinic anhydride and triethylamine; and succinic anhydride and pyridine. Preferred additives are selected, for example, from, but not limited to, benzoic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid. 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 reaction temperature is generally in the range of-78 ℃ to room temperature, preferably in the range of-70 ℃ to 0 ℃. The reaction time is generally 1 minute to 1 day, preferably 3 hours to 6 hours.
When R is3When methyl, compounds of formula (XXII) may be prepared from compounds of formula (XXXXIV), as illustrated in scheme 16.
Scheme 16
X represents halogen, such as iodine, bromine, chlorine or fluorine.
Step 16A
In this step, the compound of formula (XXII) can be prepared as follows: acylation of the compound of formula (xxxxxiv) is carried out using n-butyl vinyl ether as reagent under acylation conditions in the presence of a suitable transition metal catalyst, in the presence or absence of a base, in a water-organic co-solvent mixture, followed by hydrolysis under acidic conditions.
Examples of suitable organic 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 diethyl ether, in the presence or absence of an aqueous base, e.g. aqueous KOH, NaOH, LiOH or K2CO3. Examples of suitable 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) trifluoromethanesulfonate, palladium (II) acetate, palladium (II) chloride, bis (acetonitrile) dichloropalladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and [1, 1' -bis (diphenylphosphino) ferrocene dichloride ]Palladium (II). Preferred catalysts are tetrakis (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, palladium (II) chloride, bis (acetonitrile) dichloropalladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and [1, 1' -bis (diphenylphosphino) ferrocene dichloride]Palladium (II).
The reaction may be carried out in the presence of suitable additives. Examples of such additives include: triphenylphosphine, tri-tert-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, tri-2-furanylphosphine, tri-o-tolylphosphine, 2- (dichlorohexylphosphino) biphenyl, triphenylarsine, tetrabutylammonium chloride, tetrabutylammonium fluoride, lithium acetate, lithium chloride, triethylamine, potassium sodium methoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate and/or sodium iodide.
The reaction may be acidified with a suitable acid. Examples of such acid agents include: concentrated aqueous hydrogen chloride solution, sulfonic acid in the presence of water.
The reaction may be carried out at a temperature of from 0 ℃ to 200 ℃, preferably from 20 ℃ to 120 ℃. The reaction time is generally 5 minutes to 96 hours, more preferably 30 minutes to 24 hours.
Scheme 17:
this scheme illustrates the preparation of compounds of formula (XIII).
X is halogen.
Step 17A
In this step, the compound of formula (XIII) can be prepared as follows: coupling a compound of formula (XXXXV) with an alkyl or aryl metal reagent in an aqueous-organic cosolvent mixture under coupling conditions in the presence of a suitable transition metal catalyst, with or without a base.
Examples of suitable transition metal 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) trifluoromethanesulfonate, palladium (II) acetate, palladium (II) chloride, bis-acetonitrile dichloropalladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride. Preferred catalysts are tetrakis (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate, palladium (II) chloride, bis acetonitrile dichloropalladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and [1, 1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride.
Suitable alkyl or aryl metal reagents include, but are not limited to, hydrocarbylboronic acids, such as phenylboronic acid, 4-pyridylboronic acid, cyclopropylboronic acid, and methylboronic acid.
Examples of organic solvents suitable for the water-organic co-solvent mixture include: THF; 1, 4-dioxane(ii) a DMF; acetonitrile; alcohols, such as methanol or ethanol; halogenated hydrocarbons, such as DCM, 1, 2-dichloroethane, chloroform or carbon tetrachloride; and diethyl ether; in the presence or absence of an aqueous base, e.g. aqueous KOH, NaOH, LiOH or K 2CO3。
The reaction may be carried out in the presence of suitable additives. Examples of such additives include: triphenylphosphine, tri-tert-butylphosphine, 1' -bis (diphenylphosphino) ferrocene, tri-2-furanylphosphine, tri-o-tolylphosphine, 2- (dichlorohexylphosphino) biphenyl, triphenylarsine, tetrabutylammonium chloride, tetrabutylammonium fluoride, lithium acetate, lithium chloride, triethylamine, potassium sodium methoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate and/or sodium iodide. The reaction may be carried out at a temperature of 0 ℃ to 200 ℃, more preferably 20 ℃ to 120 ℃. The reaction time is generally 5 minutes to 96 hours, more preferably 30 minutes to 24 hours.
When R is3And R4When taken together with the carbon atom to which they are attached to form a cyclopropane ring, compounds of formula (II) can be prepared from compounds of formula (XXXXV), as depicted in scheme 18.
Scheme 18
Wherein P represents a suitable amine protecting group such as benzoyl or tert-methoxycarbonyl.
Step 18A
In this step, a compound of formula (xxxxxi) may be prepared as follows: the nitration of the compound of formula (xxxxxvi) is carried out under acidic conditions in an inert solvent. The nitration may be carried out in the presence of a suitable nitrating agent and an acid in an inert solvent.
Examples of preferred nitrating agents include, but are not limited to, nitric acid, potassium nitrate, and copper (II) nitrate. Examples of preferred acids include, but are not limited to, acetic acid, acetic anhydride, and sulfuric acid. Examples of suitable solvents include THF; 1, 4-dioxane; DMF; acetonitrile; water; ethyl acetate; alcohols, such as methanol or ethanol; and halogenated hydrocarbons such as DCM, 1, 2-dichloroethane, chloroform or carbon tetrachloride. The reaction temperature is generally in the range of-78 ℃ to 100 ℃, preferably in the range of-15 ℃ to 50 ℃. The reaction time is generally 1 minute to 1 day, preferably 3 hours to 6 hours.
Step 18B
In this step, a compound of formula (XXXXVIII) may be prepared as follows: cyclopropane formation of the compound of formula (xxxxvi) is carried out under alkylation conditions in an inert solvent. The alkylation may be carried out in an inert solvent in the presence of a suitable alkylating agent and a metal hydride.
Examples of preferred alkylating agents include, but are not limited to, dibromoethane, diiodoethane, and dichloroethane. Examples of preferred metal hydrides include, but are not limited to, sodium hydride, potassium hydride, and lithium hydride. Examples of suitable solvents include THF, 1, 4-dioxane, and DMF. The reaction temperature is generally in the range of-78 ℃ to 100 ℃, preferably in the range of-78 ℃ to room temperature. The reaction time is generally 1 minute to 1 day, preferably 3 hours to 6 hours.
Step 18C
In this step, compounds of formula (XXXXIX) may be prepared as follows: the hydrogenation of the compounds of formula (xxxxxviii) is carried out, for example, under known hydrogenolysis conditions, in the presence of a suitable metal catalyst, under a hydrogen atmosphere, or in the presence of a hydrogen source, such as formic acid or ammonium formate, in an inert solvent. If desired, the reaction may be carried out under acidic conditions, for example in the presence of hydrochloric acid or acetic acid. Preferred metal catalysts are for example selected from: nickel catalysts, such as raney nickel; Pd-C; palladium hydroxide-carbon; platinum oxide; platinum-carbon; ruthenium-carbon; rhodium-alumina; tris (triphenylphosphine) rhodium chloride; fe; zn; sn; and SnCl 2. Examples of suitable inert aqueous or non-aqueous organic solvents include: the alcohol(s) are (are) selected from the group consisting of,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 may be carried out at a temperature in the range of from 20 ℃ to 100 ℃, preferably in the range of from 20 ℃ to 60 ℃. The reaction time is generally 10 minutes to 4 days, preferably 30 minutes to 24 hours. The reaction may be carried out under a hydrogen atmosphere at a pressure of 1 to 100atm, preferably 1 to 10 atm.
Step 18D
In this step, a compound of formula (XXXXIX) may be prepared from a compound of formula (xxxxxii) by the method described above for step 9A.
Step 18E
In this step, a compound of formula (xxxxxx) can be prepared from a compound of formula (XXXXIX) by the method described above in step 4D.
Step 18F
In this step, a compound of formula (XXXXXI) may be prepared as follows: the conversion of the carboxylic acid of formula (xxxxxx) into the corresponding amine derivative is carried out in an inert solvent under known Curtius conditions. The Curtius reaction can be carried out after addition of the alcohol, in an inert solvent in the presence of a suitable phosphinic azide reagent and a base. Examples of preferred phosphinic azide reagents include, but are not limited to, diphenylphosphoryl azide. Examples of preferred bases include, but are not limited to, triethylamine, diisopropylamine, sodium methoxide, and tert-butyl ethoxide. Examples of preferred alcohols include, but are not limited to, benzyl alcohol and t-butanol. Examples of suitable solvents include THF, 1, 4-dioxane, DMF, DMSO, and diglyme. The reaction temperature is generally in the range of-78 ℃ to 200 ℃, preferably in the range of 0 ℃ to the reflux temperature of the solvent. The reaction time is generally 1 minute to 1 day, preferably 3 hours to 12 hours.
Step 18G
In this step, a compound of formula (XXXXXI) may be prepared as follows: deprotection of the compound of formula (xxxxxx) is carried out under known deprotection conditions. Hydrogenation conditions may be employed, as described above for step 10C. Alternatively, other deprotection conditions that may be used to convert carbamates, such as tert-butyl carbamate as a primary amine, include basic conditions in an inert solvent. Preferred bases include, for example, but are not limited to, potassium hydroxide, sodium hydroxide, and lithium hydroxide. Examples of suitable inert aqueous or non-aqueous 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 may be carried out at a temperature in the range of from 20 ℃ to 100 ℃, preferably in the range of from 20 ℃ to 60 ℃. The reaction time is generally 10 minutes to 4 days, preferably 30 minutes to 24 hours.
When R is10And R11When both are hydrogen, compounds of formula (X) can be prepared from compounds of formula (XXXXXII), as depicted in scheme 19.
Scheme 19
Step 19A
In this step, the compound of formula (X) may be prepared as follows: the dehydration of the compound of formula (XXXXXII) is carried out under acidic conditions in an inert solvent. Examples of preferred acids include, but are not limited to, p-toluenesulfonic acid, hydrogen chloride, and trifluoroacetic acid. Examples of preferred solvents include, but are not limited to: 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 may be carried out at a temperature in the range of 20 ℃ to 100 ℃, preferably in the range of 20 ℃ to 60 ℃. The reaction time is generally 10 minutes to 4 days, preferably 30 minutes to 24 hours.
When B is CR12；R2Is hydrogen, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy radical- (C1-C6) An alkyl group; and R is12Is hydrogen or (C)1-C6) Alkyl, compounds of formula (XXII) can be prepared from compounds of formula (XXV), as depicted in scheme 20.
Scheme 20
This scheme illustrates an improved process of scheme 9 for preparing a compound of formula (XXII) from a compound of formula (XXV). The compounds of the formula (XXII) and the formula (XXV) are included in the compounds of the formula (XXII) and the formula (XXV), respectively.
X: halogen atoms such as bromine and chlorine;
A，B：CH、CR12、N；
R2: hydrogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy radical- (C1-C6) An alkyl group;
R12: hydrogen or (C)1-C6) An alkyl group.
Step 20
In this step, the compound of formula (XXII) can be prepared as follows: conducting the sulfonylation reaction of the compound of formula (XXV) with the compound of formula (XXVI) in one pot, followed by conducting the reaction with R3Friedel-Crafts acylation of Cl. The formation of the undesired N-acylate is substantially suppressed by the one-pot procedure. The sulfonylation reaction is as in exampleAs carried out under known sulfonylation conditions in the presence of a base in an inert solvent. The reaction can be carried out without using a solvent. Examples of preferred bases and suitable inert organic solvents are the same as in step 9A. The reaction may be carried out at a temperature in the range of from 20 ℃ to 100 ℃, preferably in the range of from-20 ℃ to 40 ℃. The reaction time is generally 5 minutes to 4 days, preferably 10 minutes to 3 hours. After sulfonylation is complete, the reaction with R should be carried out 3Friedel-Crafts acylation of Cl without any work-up procedure to the previous reaction. And R3The Friedel-Crafts acylation of Cl is carried out, for example, under the known Friedel-Crafts acylation in the presence of a metal and an acid halide. The reaction may be carried out in an inert solvent. Examples of suitable solvents and suitable catalysts are the same as in step 9B. The reaction may be carried out at a temperature of-50 ℃ to 200 ℃, preferably about-10 ℃ to 150 ℃, for a period of 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
According to this scheme, the compound of formula (XXIId) can be prepared more selectively, with a small amount of by-products. In other words, the yield of the compound of formula (XXIId) can be effectively increased compared to known methods, for example as described in scheme 9 above or Kostsova, a.g.; tkachnko, n.n.; eveseeva, i.i.; zhurnal Obshcheni Khimii, 1961, 31, 2241-6.
When R is3Is methyl; and R is12Is hydroxy (C)1-C6) Alkyl, compounds of formula (II) can be prepared from compounds of formula (XXXXXII), as depicted in scheme 21.
Scheme 21
Step 21A
In this step, a compound of formula (xxxxiii) may be prepared by reduction of a compound of formula (XXXXXII) under the conditions of step 8C.
Step 21B
In this step, compounds of formula (II) may be prepared by deprotection of compounds of formula (XXXXXIII) under the conditions of step 8D.
When R is12Is hydroxy (C)1-C6) Alkyl, compounds of formula (I) can be prepared from compounds of formula (Ia), as depicted in scheme 22.
Scheme 22
Step 22
In this step, the compound of formula (I) may be prepared by reduction of the compound of formula (Ia) under the conditions described in step 8C.
The starting materials in the above general syntheses are commercially available or may be obtained by conventional methods known to those skilled in the art.
The compounds of formula (I) and intermediates mentioned in the above preparation processes can be isolated and purified by means of conventional procedures, for example recrystallization or chromatography.
The various general methods described above may be used to introduce the desired group at any stage of the stepwise formation of the desired compound, and it will be appreciated that these general methods may be combined in different ways in such multi-stage methods. The order of reaction in the multistage process should of course be chosen so that the reaction conditions used do not affect the desired groups in the molecule in the final product.
Methods for assessing biological activity:
human VR1 antagonistAnti-agent assay
Ca-expression using human VR1 highly expressing cells 2+VR1 antagonist activity can be determined by imaging assays. Cells that highly express the human VR1 receptor can be obtained from several different conventional methods. One standard method is cloning from human Dorsal Root Ganglia (DRG) or kidneys, for example according to journal articles; nature, 389, pp816-824, 1997. Alternatively, human horn-forming cells that highly express the VR1 receptor are also known and published in journal articles (Biochemical and Biophysical Research Communications, 291, pp124-129, 2002). In this article, human keratinocytes demonstrated VR 1-mediated intracellular Ca after capsaicin addition2+And (4) increasing. In addition, methods of up-regulating the human VR1 gene, which is typically a silent gene or does not produce detectable levels of the VR1 receptor, can also be used to obtain proprietary cells. Such gene modification methods are described in detail in nat. biotechnol., 19, pp440-445, 2001.
Cells expressing the human VR1 receptor were maintained in culture flasks at 37 ℃ in the presence of 5% CO2Until used for the assay. Intracellular Ca was performed by the following procedure2+Imaging assays to determine VR1 antagonistic activity.
The medium was removed from the flask and fura-2/AM fluorescent calcium indicator was added to the flask at a concentration of 5. mu.M in the medium. Placing the bottle in CO 2In the incubator, the culture was carried out for 1 hour. Cells expressing the human VR1 receptor were then detached from the vial, followed by washing with phosphate buffered saline PBS (-) and resuspended in assay buffer. To the assay plate was added an 80. mu.l aliquot of the cell suspension (3.75X 10)5Cells/ml), the cells were spun down by centrifugation (950rpm, 20 ℃, 3 min).
Capsaicin challenge assay:
changes in capsaicin-induced intracellular calcium concentration were monitored using FDSS 6000(Hamamatsu Photonics, Japan), a fluorescence imaging system. Will be in Krebs-RingRHEPES (KRH) buffer (115mM NaCl, 5.4mM KCl, 1mM MgSO 2)4，1.8mM CaCl211mM D-glucose, 25mM HEPES, 0.96mM Na2HPO4Ph7.3) was previously incubated with different concentrations of test compound or KRH buffer (buffer control) for 15 minutes at room temperature in the dark. Capsaicin solution was then added to the assay plate automatically with the aid of FDSS 6000, at a concentration of 300nM in the assay mixture.
Acid stimulation assay:
changes in acid-induced intracellular calcium concentration were monitored using FDSS 6000(Hamamatsu Photonics, Japan), a fluorescence imaging system. Cell suspensions in resting buffer (HBSS, supplemented with 10mM HEPES, pH 7.4) were pre-incubated with different concentrations of test compound or resting buffer (buffer control) for 15 minutes at room temperature in the dark. Cells were added automatically to the stimulation solution (HBSS, supplemented with MES, final assay buffer ph5.8) by FDSS 6000. IC of VR1 antagonist was determined from half the increase demonstrated by buffer control samples after acidic stimulation 50The value is obtained.
Determination of antagonist Activity
The change in fluorescence signal (λ ex 340nm/380nm, λ em 510-520nm) was monitored starting 1 min before the addition of capsaicin solution or acidic buffer for 5 min. IC of VR1 antagonist was determined from half the increase demonstrated by buffer control samples following agonist stimulation50The value is obtained.
Chronic contraction injury model (CCI model):
male Sprague-Dawley rats (270-300 g; B.W., Charles River, Tsukuba, Japan) were used. Chronic systolic injury (CCI) surgery was performed as described by Bennett and Xie (Bennett, G.J. and Xie, Y.K.pain, 33: 87-107, 1988). Briefly, animals were anesthetized with sodium pentobarbital (64.8mg/kg, i.p.), blunt dissected through the biceps femoris, and the left common sciatic nerve was exposed at the level of the mid-thigh. The adherent tissue was removed proximal to the ischial trifurcations and 4 ligatures (4-0 wires) were tied loosely around them, leaving about 1mm separation. Sham surgery was performed as with CCI surgery, except for sciatic nerve ligation. Two weeks after surgery, Von Frey Hairs (VFHs) were applied to the plantar surface of the hindpaw and mechanical allodynia was assessed. The minimum amount of VFH force required to elicit a response is recorded as the Paw Withdrawal Threshold (PWT). VFH tests were performed at 0.5, 1 and 2 hours post-dose. The experimental data were analyzed using the Kruskal-Wallis test followed by either the Dunn's test for multiple comparisons or the Mann-WhitneyU-test for pairwise comparisons.
Permeability of Caco-2
Caco-2 permeability was measured as described in Shiyin Yee, Pharmaceutical Research, 763 (1997).
Caco-2 cells were grown on filter media (Falcon HTS porous insert system) for 14 days. The media was removed from the apical and basolateral chambers and the single layer was preincubated with 0.3ml of the apical buffer and 1.0ml of the basolateral buffer in a shaking water bath at 37 ℃ for 0.75 hours with 50 cycles/min. The top buffer solution is composed of Hanks balanced salt solution, 25mM D-glucose monohydrate, 20mM MES biological buffer solution, 1.25mM CaCl2And 0.5mM MgCl2(pH 6.5). The buffer solution on the outer side of the substrate comprises Hanks balanced salt solution, 25mM D-glucose monohydrate, 20mM HEPES biological buffer solution and 1.25mM CaCl2And 0.5mM MgCl2(pH 7.4). At the end of the preincubation, the medium was removed and a solution of the test compound in buffer (10 μ M) was added to the top chamber. Inserts were moved to wells containing fresh buffer outside the substrate and incubated for 1 hour. The drug concentration in the buffer was measured by means of LC/MS analysis.
The outflow rate (F, mass/time) was calculated from the cumulative appearance slope of the substrate on the side of the receiver, and the apparent permeability coefficient (P) was calculated from the following equation app)。
Papp(cm/sec)＝(F*VD)/(SA*MD)
Wherein SA is the surface area (0.3 cm) of the transport means (transport)2) VD is the donor volume (0.3ml) and MD is the total amount of drug on the donor side at t-0. All data represent the mean of 2 inserts. Monolayer integrity was determined by means of the Lucifer Yellow transport tool.
Human dofetilide binding
A cell paste of HEK-293 cells expressing HERG product can be suspended in 10 volumes of 50mM Tris buffer at 25 ℃ with 2M HCl to pH7.5 containing 1mM MgCl2, 10mM KCl. Cells were homogenized with a Polytron homogenizer (at maximum power for 20 seconds) and centrifuged at 48,000g for 20 minutes at 4 ℃. The pellet was resuspended, homogenized and centrifuged once more in the same manner. The resulting supernatant was discarded and the final pellet resuspended (10 volumes of 50mM Tris buffer) and homogenized for 20 seconds at maximum power. The membrane homogenate was aliquoted and stored at-80 ℃ until use. Protein concentrations of aliquots were determined using the protein assay Rapid Kit and ARVO SX plate reader (Wallac). All operations, stock solutions and equipment were kept on ice at all times. For saturation experiments, experiments were performed in a total volume of 200. mu.l. For total binding or non-specific binding, 20. mu.l of dofetilide (20. mu.l) are incubated at room temperature in the presence or absence, respectively, of a final concentration of 10. mu.M 3H]Doffilide and 160. mu.l of membrane homogenate (20-30. mu.g protein per well) for 60 min, saturation was determined. All incubations were terminated by rapid vacuum filtration through Polyetherimide (PEI) impregnated glass fiber filter paper using a Skatron cell harvester followed by two washes with 50mM Tris buffer (pH7.5, 25 ℃). Liquid scintillation counting was performed using a Packard LS counter to quantify the radioactivity bound to the receptor.
For competition assays, compounds were diluted in a 96-well polypropylene plate in a semilog format into 4-point dilutions. All dilutions were first performed in DMSO and then transferred to 50mM Tris buffer (pH7.5, 25 ℃) containing 1mM MgCl210mM KCl for finalThe DMSO concentration is equal to 1%. Compounds were dispensed in triplicate (4 μ Ι) in assay plates. Total binding and non-specific binding wells were set to support and final concentration of dofetilide 10. mu.M in 6 wells, respectively. Radioligand was prepared at 5.6x final concentration and this solution (36 μ l) was added to each well. The Assay was started by adding YSi poly-L-lysine Scintillation Proximity (SPA) beads (50. mu.l, 1 mg/well) and membranes (110. mu.l, 20. mu.g/well). Incubation was continued at room temperature for 60 minutes. The plate was incubated at room temperature for another 3 hours, allowing the beads to settle. Radioactivity bound to the receptor was quantified by counting using a Wallac MicroBeta plate counter.
IHERGAssay method
Electrophysiological studies were performed using HEK293 cells stably expressing the HERG potassium channel. Methods for stably transfecting such channels in HEK cells can be found elsewhere (Z. Zhou et al, 1998, Biophysical Journal, 74, pp 230-241). Prior to the day of the experiment, cells were harvested from culture flasks and plated on glass coverslips in standard Minimal Essential Medium (MEM) containing 10% Fetal Calf Serum (FCS). The inoculated cells were stored in a 37 ℃ incubator maintained at 95% O2/5％CO2In the atmosphere of (c). Cells were studied between 15-28 hours post harvest.
HERG current was studied in whole cell mode using standard patch clamp techniques. During the experiment, cells were covered with standard external solutions of the following composition (mM): NaCl, 130; KCl, 4; CaCl2，2；MgCl21, 1; glucose, 10; HEPES, 5; adjusted to pH7.4 with NaOH. Whole cell recordings were performed using a patch clamp amplifier and a patch pipette, which had a resistance of 1-3 mega ohms when filled with a standard internal solution of composition (mM) as follows: KCl, 130; MgATP, 5; MgCl21.0; HEPES, 10; EGTA 5; adjusted to pH 7.2 with KOH. Only those cells with an entry resistance below 15 M.OMEGA.and a blocking resistance > 1 G.OMEGA.were subjected to further experiments. A series of resistance compensations was applied up to a maximum of 80%. The leakage is not subtracted. However, the acceptable entry resistance depends on what is recorded The magnitude of the current and the level of series resistance compensation that can be safely used. After reaching the whole cell configuration and sufficient time (> 5 minutes) for cell dialysis with pipette solution, a standard voltage protocol was applied to the cells to evoke membrane current. The voltage scheme is as follows. The membrane was depolarized from a holding potential of-80 mV to +40mV for 1000 ms. Followed by a down-column voltage ramp (ramp) (rate 0.5mV msec)-1) Back to the holding potential. The voltage protocol (0.25Hz) was applied to the cells continuously every 4 seconds during the experiment. The amplitude of the peak current induced during the ramp around-40 mV was measured. Once a stable evoked current response was obtained in the external solution, vehicle (0.5% DMSO in standard external solution) was administered by means of peristaltic pump for 10-20 minutes. As long as there is minimal change in the amplitude of the evoked current response under vehicle control conditions, 0.3, 1, 3, 10 μ M of test compound was administered for 10 minutes. The 10 minute time includes the time for the supply solution to pass through the test tube from the solution reservoir via the pump to the recording chamber. The time that the cells are exposed to the compound solution is more than 5 minutes after the drug concentration in the chamber has completely reached the attempted concentration. There was a subsequent wash period of 10-20 minutes to assess reversibility. Finally, cells were exposed to high doses of dofetilide (5 μ M), a specific IKr blocker, to assess insensitive endogenous currents.
All experiments were performed at room temperature (23. + -. 1 ℃). The evoked membrane currents were recorded on-line on a computer, filtered at 500-1KHz (Bessel-3dB) using a membrane clamp amplifier and dedicated data analysis software, and sampled at 1-2 KHz. The peak current amplitude, which occurs around-40 mV, was measured off-line on the computer.
The arithmetic mean of the ten amplitude values was calculated under vehicle control conditions and in the presence of the drug. The normalized current value of the following formula was used to obtain I in each experimentNPercent reduction of (c): i isN＝(1-ID/IC) X 100, wherein IDIs the average current value in the presence of the drug, ICIs the average current value under the control conditions. Separate experiments were performed for each drug concentration or time-matched control, arithmetic mean in each experimentIs defined as the result of the study.
Drug-drug interaction assay
This method essentially comprises determining the percent inhibition of product production from the fluorescent probe in the presence of 3 μ M of each compound.
More specifically, the measurement was performed as follows. The compound was preincubated with recombinant CYP, 100mM potassium phosphate buffer, and fluorescent probe as a substrate for 5 minutes. The reaction was started by adding a warmed NADPH-generating system consisting of 0.5mM NADP (expected; 0.03mM for 2D 6), 10mM MgCl 26.2mM DL-isocitrate and 0.5U/ml isocitrate dehydrogenase (ICD). The assay plates were incubated at 37 deg.C (expected; 30 deg.C for 1A2 and 3A 4) and fluorescence read every minute for 20 to 30 minutes.
The data calculation is implemented as follows:
1. calculating the slope of the Linear region (time-fluorescence units)
2. Percent inhibition of the compounds was calculated by the following equation
{(vo-vi)/voInhibition of } × 100 ═ percent
Wherein
voRate of control reaction (no inhibitor)
viRate of reaction in the presence of a compound
TABLE 1 conditions for drug-drug interaction assay
1A2 2C9 2C19 2D6 3A4
Substrate (. mu.M) enzyme (pmol) EX./Em (. lamda.) Vivid blue(Aurora)1050408/465 MFC(Gentest)3050408/535 Vivid blue(Aurora)105408/465 AMMC(Gentest)150400/465 Vivid red(Aurora)25530/595
Half-life in Human Liver Microsomes (HLM)
Test compounds (1. mu.M) were mixed with 3.3mM MgCl on 96-deep well plates2And 0.78mg/mL HLM (HL101) were incubated at 37 ℃ in 100mM potassium phosphate buffer (pH 7.4). The reaction mixture was divided into two groups, non-P450 group and P450 group. NADPH was added only to the reaction mixtures of group P450. Aliquots of the P450 set were collected at time points 0, 10, 30 and 60 minutes, where the 0 minute time point represents the time to add NADPH to the P450 set of reaction mixtures. Aliquots of the non-P450 groups were collected at-10 and 65 minute time points. The collected aliquots were extracted with acetonitrile solution containing an internal standard. The precipitated protein was spun down by centrifugation (2000rpm, 15 min). The concentration of the compound in the supernatant was measured by means of an LC/MS system.
The half-life values were obtained by plotting the natural logarithm of the peak area ratio of compound/internal standard versus time. The slope of the line best fitting each point is the metabolic rate (k). This is converted to a half-life value using the following equation:
half-life ═ ln 2/k
Monoiodoacetate (MIA) -induced OA model
Male 6-week-old Sprague-Dawley (SD, Japan SLC or Charles river Japan) rats were anesthetized with pentobarbital. Hair was cut from the MIA injection site (knee) and cleaned with 70% ethanol. Mu.l of MIA solution or saline was injected in the right knee using a 29G needle. The effect of joint injury on the weight distribution between the left (untreated) and right (injured) knees was evaluated using an incapacity (incapacitance) tester (Linton Instrumentation, Norfolk, UK). The force exerted by each hind limb was measured in grams. Weight-bearing (WB) defects were determined by the difference in weight loaded on each paw. Rats were trained to measure WB once a week until 20 days after MIA injection. The analgesic effect of the compounds was measured 21 days after MIA injection. Before compound administration, the "pre value" of WB deficiency was measured. Following administration of the compounds, attenuation of WB deficiency was measured as analgesic effect.
Complete Freund Adjuvant (CFA) -induced thermal and mechanical hyperalgesia in rats Thermal hyperalgesia
Male 6-week-old SD rats were used. The plantar surface of the rat hind paw was injected with complete Freund's adjuvant (CFA, 100. mu.L liquid paraffin (Wako, Osaka, Japan)) containing 300. mu.g M.tuberculosis (Mycobacterium tuberculosis) H37RA (Difco, MI)). Thermal hyperalgesia was measured 2 days after CFA injection using the plantar test apparatus (Ugo-base, Varese, Italy) by the method previously described (Hargreaves et al, 1988). Rats were acclimated to the test environment for at least 15 minutes prior to any stimulation. Thermal radiation was applied to the plantar surface of the hind paw and paw withdrawal latency (PWL, sec) was measured. The intensity of the thermal radiation is adjusted to produce a stable PWL for 10 to 15 seconds. Test compound was administered in a volume of 0.5mL per 100g of body weight. PWL was measured 1, 3 or 5 hours after dosing.
Mechanical hyperalgesia
Male 4-week-old SD rats were used. CFA (100. mu.L liquid paraffin (Wako, Osaka, Japan) containing 300. mu.g of Mycobacterium tuberculosis H37RA (Difco, MI)) was injected into the plantar surface of the rat hindpaw. Mechanical hyperalgesia was tested 2 days after CFA injection by measuring the paw withdrawal threshold (PWT, gram) for pressure using an algesimeter (Ugo-base, Varese, italy). The animals were gently restrained, applying steady state increased pressure via the plastic tip to the dorsal surface of the hind paw. The pressure required to initiate jaw retraction was measured. Test compound was administered in a volume of 0.5mL per 100g of body weight. PWT was measured 1, 3 or 5 hours after dosing.
The compounds of the examples were tested in the human VR1 antagonist assay and the HLM half-life assay methods described above. IC (integrated circuit)50And T1/2Values are listed in the table below.
Table 2.
Example # IC50(nM) T1/2(minutes)
1 330 13
2 11.2 32
3 885
4 190 9
5 40 5
6 18.3 18
7 15 33
8 38 37
9 171 42
10 3.59 22
11 3.59 22
12 27 83
13 146 12
14 203 ＞120
15 0.71 38
16 6.59 53
17 10.3 51
18 282 119
19a 23 ＞120
19b 71 ＞120
20 47 ＞120
21 20.1 ＞120
22 1.2 37
23 10.9 ＞120
24 19.3 23
25 26.6 30
26 78.3 38
27 7.83 25
28 12.3 61
29 17.9 19
30 138 32
31 192 ＞120
32 0.934 10.8
33 56.2 39
34 4.72 ＞120
35 156 25
36 19 23
37 197 41
38 70.9 40
39 9.12 15
40 32.5 35
41 0.234 21
42 0.713 19.7
43 20.7 41
44 2 29
45 5.84 29
46 12.6 23
47 7.64 11
48 203 21
49 125 3
50 239 4
51 15.6 5
52 1150
53 125 44
54 234 96
55 297 42
56 1251 ＞120
57 30.5 91
58 39.6 34
59 263 22
60 25.1 ＞120
61 3.17 ＞120
62 7.79 6
63 6.66 35.6
64 4.62 14
65 1043
66 0.421 34
67 5.64 95
68 62 18
69 212 30
70 0.83 38
71 0.48 15.8
72 8.5 52.6
73 0.76 ＞120
74 21 ＞120
75 11.8 10
76 26.3 33
77 50.5 50
78 ＜3
79 20.5 22
80 3.01 117
81 42.2 ＞120
82 62 26
83 63.8 65
84 24.5 3
85 52.7 Not counting
86 4.8
87 19.9
88 ＜3
89 ＜3
90 86.3
91 ＜3
Capsazepine (control) 237-455
Pharmaceutical substance
Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition and base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptanoate, gluconate, glucuronate, hexafluorophosphate, hydroxybenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/biphosphate, saccharate, stearate, succinate, tartrate, dihydrogenphosphate, glucarate, stearate, fumarate, salicylate, and salicylate, Tosylate and trifluoroacetate salts.
Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, dibenzylethylenediamine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts.
For a review of suitable Salts, see "Handbook of Pharmaceutical Salts: properties, Selection, and Use "by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Pharmaceutically acceptable salts of the compounds of formula (I) can be readily prepared as follows: a solution of compound (I) and a solution of the desired acid or base are mixed together, as desired. The salt may precipitate from solution, be collected by filtration, or may be recovered by evaporation of the solvent. The degree of ionization of the salt can range from completely ionized to almost non-ionized.
The compounds of the present invention may exist in unsolvated as well as solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. When the solvent is water, the term "hydrate" is used.
Included within the scope of the present invention are complexes, such as clathrates, i.e., drug-host inclusion complexes, wherein the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to solvates as described above. Also included are pharmaceutical complexes containing two or more organic and/or inorganic components, which may be present in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized or non-ionized. For an overview of such complexes see J Pharm Sci, 64(8), 1269-1288 by Haleblian (8 months 1975).
All references hereinafter to compounds of formula (I) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
The compounds of the present invention include compounds of formula (I) as defined above, polymorphs, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically-labeled compounds of formula (I) as defined below.
As mentioned, the present invention includes all polymorphic forms of the compound of formula (I) as defined above.
Also included within the scope of the present invention are so-called "prodrugs" of the compounds of formula (I). Thus, certain derivatives of the compounds of formula (I) which may themselves have little or no pharmacological activity, when administered to the body, can be converted to compounds of formula (I) having the desired activity, for example by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Further information on prodrug use can be found in 'Pro-drugs as Novel Delivery Systems', Vol.14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioversibleeariers in Drug Design', Pergamon Press, 1987(ed.E B Roche, American Pharmaceutical Association).
The prodrugs according to the invention can be produced, for example, as follows: appropriate functionalities present in the compounds of formula (I) are replaced by certain moieties known to those skilled in the art as "precursor moieties", for example as described in "Design of produgs" by H Bundgaard (Elsevier, 1985).
Some examples of prodrugs according to the invention include:
(i) if the compound of formula (I) contains a carboxylic acid functionality (-COOH), esters thereof are included, for example with (C)1-C8) Alkyl instead of hydrogen;
(ii) if the compound of formula (I) contains an alcohol functionality (-OH), then its ethers are included, for example with (C)1-C6) Alkanoyloxymethyl for hydrogen; and
(iii) if the compounds of formula (I) contain primary or secondary amino functionality (-NH)2or-NHR, where R.noteq.H), including the amides thereof, e.g. with (C)1-C10) Alkanoyl replaces one or both hydrogens.
Further examples of substituent groups according to the above examples and other examples of prodrug types can be found in the above references.
Finally, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).
The compounds of formula (I) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. If the compounds of formula (I) contain alkenyl or alkenylene groups, geometric cis/trans (or Z/E) isomers are possible. If the compounds contain, for example, keto or oxime groups or aromatic moieties, tautomerism (tautomerism) may occur. It follows that a single compound may have multiple types of isomerism.
All stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I) are included within the scope of the invention, including compounds which exhibit various types of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts in which the counterion is optically active, such as D-lactate or L-lysine, or racemic, such as DL-tartrate or DL-arginine.
The cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.
Conventional preparation/separation techniques for the individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative), for example using chiral High Performance Liquid Chromatography (HPLC).
Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, for example an alcohol, or, in the case of compounds of formula (I) containing an acidic or basic moiety, an acid or base, for example tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixtures can be separated by chromatography and/or fractional crystallization, and one or both of the diastereomers can be converted into the corresponding pure enantiomers by means well known to the skilled artisan.
The enantiomerically-enriched form of the chiral compound of the invention (and its chiral precursor) can be obtained by chromatography, typically HPLC, on an asymmetric resin, the mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% alkylamine, typically 0.1% diethylamine. The eluate is concentrated to obtain an enriched mixture.
Stereoisomeric assemblies may be isolated by conventional techniques known to those skilled 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-labelled compounds of the compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of the following elements: hydrogen, e.g.2H and3h, carbon, e.g.11C、13C and14c, chlorine, e.g.36Cl, fluorine, e.g.18F, iodine, e.g.123I and125i, nitrogen, e.g.13N and15n, oxygen, e.g.15O、17O and18o, phosphorus, e.g.32P, and sulfur, e.g. 35S。
Certain isotope-labeled compounds of formula (I), such as those that bind radioisotopes, are useful for drug and/or substrate tissue distribution studies. Radioisotope tritium, i.e.3H and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of binding and ease of detection.
By heavier isotopes, e.g. deuterium, i.e.2H substitution may be preferred in some circumstances because of greater metabolic stability which may provide certain therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements.
By positron-emitting isotopes, e.g.11C、18F、15O and13n substitution, can be used in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.
Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations, using an appropriate isotopically-labelled reagent in place of the non-labelled reagent employed above.
Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D2O、d6-acetone, d6-DMSO。
The compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. For example, they may be obtained as solid plugs, powders or films by precipitation, crystallization, freeze drying, spray drying or evaporation drying. Microwave or radio frequency drying may be used for this purpose.
They may be administered alone or in combination with one or more other compounds of the invention or with one or more other drugs (or any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compounds of the present invention. The choice of excipient will depend in large part on the particular mode of administration, the effect of the excipient on solubility and stability, and dosage form properties, among other factors.
Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods 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 ', 19 th edition (MackPublishing Company, 1995).
Oral administration
The compounds of the invention may be administered orally. Oral administration may include swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, whereby the compound enters the blood stream directly from the oral cavity.
Formulations suitable for oral administration include solid formulations such as tablets, capsules containing granules, liquids or powders, lozenges (including liquid filled), chews, multiparticulates and nanoparticles, gels, solid solutions, liposomes, films (including mucoadhesive), ovosomes, sprays and liquid formulations.
Liquid preparations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard gelatin 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 may also be prepared by reconstitution of a solid, for example from a sachet.
The compounds of the present invention may also be used in fast dissolving, fast disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-.
For tablet dosage forms, depending on the dosage, the drug may comprise from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
Binders are generally used to impart cohesive properties to the tablet. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.
The tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant may comprise from 0.2 wt% to 5 wt% of the tablet and the glidant may comprise from 0.2 wt% to 1 wt% of the tablet.
Tablets will also typically contain lubricating agents such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant generally comprises from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
Other possible ingredients include antioxidants, colorants, flavorants, preservatives, and taste masking agents.
Exemplary tablets contain up to about 80% drug, about 10 wt% to about 90 wt% binder, about 0 wt% to about 85 wt% diluent, about 2 wt% to about 10 wt% disintegrant, and about 0.25 wt% to about 10 wt% lubricant.
The tablet blend may be compressed into tablets either directly or with rollers. Tablet blends or blend portions may alternatively be wet-, dry-or melt-granulated, melt congealed or extruded and then tableted. The final formulation may comprise one or more layers, and may be coated or uncoated; it may even be encapsulated.
Formulation of tablets is discussed in "Pharmaceutical Dosage Forms" by h.lieberman and l.lachman: tablets, Vol.1 ", Marcel Dekker, N.Y., N.Y., 1980(ISBN 0-8247-6918-X).
Solid oral administration formulations may be formulated for immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.
Modified release formulations suitable for the purposes of the present invention are described in U.S. Pat. No.6,106,864. Other suitable delivery techniques, such as high energy dispersion and penetration and coating of particles are described in detail in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). Achieving controlled release with chewing gum is described in WO 00/35298.
Parenteral administration
The compounds of the invention may also be administered directly into the bloodstream, muscle or internal organs. Means suitable for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Devices suitable for parenteral administration include needle (including microneedle) syringes, needle-free syringes, and infusion techniques.
Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably to a pH of 3 to 9), but for some applications they may be more suitably formulated as sterile non-aqueous solutions or in the form of dry powders for use in association with suitable carriers such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, such as lyophilization, can be readily accomplished by those skilled in the art using standard pharmaceutical techniques.
The solubility of the compounds of formula (I) for use in preparing parenteral solutions can be increased using appropriate formulation techniques, for example by incorporating solubility enhancers. Formulations for administration by needleless injection will contain the compound of the invention in powder form in association with a suitable carrier, for example sterile, pyrogen-free water.
Formulations for parenteral administration may be formulated for immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release. Thus, the compounds of the present invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implant depot to provide modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
Topical administration of drugs
The compounds of the invention may also be administered topically to the skin or mucous membranes, i.e., transdermally 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 may also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, white mineral wax, glycerol, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88(10), 955-958(October 1999) of Finnin and Morgan.
Other topical administration means include the following delivery modes: electroporation, iontophoresis, phonophoresis (phonophoresis), sonophoresis (sonophoresis) and microneedles or needles-free (e.g. Powderject) TM、BiojectTMEtc.) for injection.
Topical formulations may be formulated for immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.
Inhalation/intranasal administration
The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (alone or, for example, as a mixture with lactose in dry admixture or as admixed component particles, for example, with a phospholipid such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, nebuliser (preferably one which utilises the electrohydrodynamic generation of a fine mist) or nebuliser, with or without the use of a suitable propellant, for example 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive, such as chitosan or cyclodextrin.
Pressurized containers, pumps, sprayers, atomizers or atomizers containing solutions or suspensions of the compounds of the invention, e.g., containing ethanol, aqueous ethanol or suitable substitutes, for dispersion, solubilization or extended release of the active ingredient; a propellant as a solvent; and optionally a surfactant, such as sorbitan trioleate, oleic acid or oligomeric lactic acid.
Prior to use in dry powder or suspension formulations, the drug product is micronized to a size suitable for inhalation delivery (typically less than 5 microns). This can be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing into nanoparticles, high pressure homogenization or spray drying.
Capsules (made, for example, from gelatin or HPMC), blister packs and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol or magnesium stearate. Lactose may be in the anhydrous or monohydrate form, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
Solution formulations suitable for use in an atomizer for generating a fine mist using electrohydrodynamic forces may contain from 1. mu.g to 20mg of a compound of the invention per actuation, and the actuation volume may vary from 1. mu.l to 100. mu.l. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.
Suitable flavouring agents, for example menthol or levomenthol, or sweetening agents, for example saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhalation/intranasal administration.
Formulations for inhalation/intranasal administration may be formulated for immediate and/or controlled release, for example using poly (DL-lactic-co-glycolic acid) (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.
In the case of dry powder inhalers and aerosols, the dosage unit is measured by a valve delivering a metered amount. The units according to the invention are generally arranged to administer a metered dose or "spray" containing from 1. mu.g to 10mg of a compound of formula (I). The total daily dose will generally be in the range 1 μ g to 10mg, which may be administered as a single dose or more usually as separate doses throughout the day.
Rectal/intravaginal administration
The compounds of the invention may be administered rectally or vaginally, for example in the form of suppositories, pessaries or enemas. Cocoa butter is a traditional suppository base, but various substitutes may be used if desired.
Rectal/vaginal administration formulations may be formulated for immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.
Other techniques
The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol containing polymers in order to enhance their solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the above modes of administration.
For example, drug-cyclodextrin complexes are found to be generally useful in most dosage forms and routes of administration. Inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, cyclodextrins may be used as an auxiliary additive, i.e. as a carrier, diluent or solubiliser. The most commonly used for these purposes are alpha-, beta-and gamma-cyclodextrins, examples of which can be found in international patent applications nos. WO 91/11172, WO 94/02518 and WO 98/55148.
Dosage form
For administration to human patients, the total daily dose of the compounds of the invention will generally be in the range of from 0.1mg to 3000mg, preferably from 1mg to 500mg, depending of course on the mode of administration. For example, oral administration may require a total daily dose of 0.1mg to 3000mg, preferably 1mg to 500mg, whereas intravenous doses may require only 0.1mg to 1000mg, preferably 0.1mg to 300 mg. The total daily dose may be administered in a single or divided dose.
These doses are based on an average human subject weighing about 65kg to 70 kg. A physician will be readily able to determine dosages for subjects with weights outside this range, such as infants and elderly.
For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment.
VR1 antagonists may be used in combination 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, particularly a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, may be administered simultaneously, sequentially or separately with one or more agents selected from:
● opioid analgesics, for example morphine, heroin, hydromorphone, oxymorphone, levomorphine, levorphanol, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalprofen, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
● non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, oxalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, or zomepirac;
● barbiturates, such as amobarbital, alprenol, butabarbital, mebendal, methabarbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbarbital, theamylal, or thiobarbital;
● benzodiazepines * with sedative effect, such as chlordiazepoxide, chlordiazepoxide *, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
● H with sedative effect1Antagonists, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine or clorizine;
● sedatives such as glutethimide, meprobamate, methaqualone or dichlofenoxate;
● skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, or oxyphennard;
● NMDA receptor antagonists, such as dextromethorphan ((+) -3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+) -3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid, budesonide, EN-3231 (morphine Dex ®, combined preparations of morphine and dextromethorphan), topiramate, neramexane or perzinfotel, including NR2B antagonists, for example ifenprodil, traxoprodil or (-) - (R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-1-piperidinyl ] -1-hydroxyethyl-3, 4-dihydro-2 (1H) -quinolinone;
● alpha-adrenergic agents, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine (dexmetatomidine), modafinil or 4-amino-6, 7-dimethoxy-2- (5-methane-sulfonylamino-1, 2, 3, 4-tetrahydroisoquinolin-2-yl) -5- (2-pyridyl) quinazoline;
● tricyclic antidepressants, such as desipramine, imipramine, amitriptyline or nortriptyline;
● anticonvulsant agents, such as carbamazepine, lamotrigine, topiramate or valproate;
● tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, such as (alpha 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, dapitan, or 3- [ [ 2-methoxy-5- (trifluoromethoxy) phenyl ] -methylamino ] -2-phenylpiperidine (2S, 3S);
● muscarinic antagonists such as oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, tilmicorin and ipratropium;
● COX-2 selective inhibitors, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
● coal tar analgesic, especially acetaminophen;
● neuroleptic agents, such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepprazole, blonanserin, ilone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, elicline, osanetant, rimonabant, mecliniertint, miraximon ®, or thalidomide;
● vanilloid receptor agonists (e.g., a cactus toxin (resiniferatoxin)) or antagonists (e.g., anti-capsaicin);
● beta-adrenergic agents, such as propranolol;
● local anesthetics, such as mexiletine;
● corticosteroids, such as dexamethasone;
● 5-HT receptor agonists or antagonists, especially 5-HT1B/1DAgonists, such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
●5-HT2AReceptor antagonists, e.g. R (+) - α - (2, 3-dimethoxy-phenyl) -1- [2- (4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
● cholinergic (nicotinic) analgesics such as isproniline (TC-1734), (E) -N-methyl-4- (3-pyridyl) -3-buten-1-amine (RJR-2403), (R) -5- (2-azetidinylmethoxy) -2-chloropyridine (ABT-594) or nicotine;
● Tramadol (Tramadol) ®;
● PDEV inhibitors, for example 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, 12 a-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-piperazin-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-pyridyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one, and pharmaceutically acceptable salts thereof, 5- (5-acetyl-2-propoxy-3-pyridyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-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) pyrrolidine- 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-methylpyrrolidin-2-yl) ethyl ] -4-propoxybenzenesulfonamide;
● alpha-2-delta ligands, for example gabapentin, pregabalin, 3-methylcarbapentin, (1 alpha, 3 alpha, 5 alpha) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-octanoic acid, (2S, 4S) -4- (3-chlorophenoxy) proline, (2S, 4S) -4- (3-fluorobenzyl) -proline, [ (1R, 5R, 6S) -6- (aminomethyl) bicyclo [3.2.0] hept-6-yl ] acetic acid, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1, 2, 4] oxadiazol-5-one, C- [1- (1H-tetrazol-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, 5-dimethyl-heptanoic acid, and mixtures thereof, (3R, 4R, 5R) -3-amino-4, 5-dimethyl-octanoic acid, (2S) -2-amino-4-ethyl-2-methylhexanoic acid and (2S) -2-aminomethyl-5-ethyl-heptanoic acid;
● cannabinoid;
● metabotropic glutamate subtype 1 receptor (mGluR1) antagonists;
● 5-hydroxytryptamine reuptake inhibitors such as sertraline, the sertraline metabolite desmethylsertraline, fluoxetine, norfluoxetine (the fluoxetine demethyl metabolite), fluvoxamine, paroxetine, citalopram, the citalopram metabolite desmethyl citalopram, escitalopram, d, l-fenfluramine, femoxetine, fluoxetine, cyanoduloxetine, ritoxetine, dapoxetine, nefazodone, cilazalone, and trazodone;
● norepinephrine reuptake inhibitors such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamide, tomoxetine, mianserin, bupropion, the bupropion metabolite hydroxybupropion, nomifensine, and viloxazine (Vivalan ®), especially selective norepinephrine reuptake inhibitors such as reboxetine, especially (S, S) -reboxetine;
● Dual 5-hydroxytryptamine-norepinephrine reuptake inhibitors such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran, and imipramine;
● Inducible Nitric Oxide Synthase (iNOS) inhibitors, for example 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- [ (1-iminoethyl) amino ] -5-heptenoic acid, 2- [ [ (1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) -butyl ] thio ] -5-chloro-3- Pyridine carbonitrile; 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-thiazolobutanol, 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, and mixtures thereof, N- [4- [2- (3-chlorobenzylamino) ethyl ] phenyl ] thiophene-2-carboxamidine or guanidinoethyl disulfide;
● acetylcholinesterase inhibitors, such as polylepezole;
● prostaglandin E2Subtype 4 (EP4) antagonists, e.g. 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;
● leukotriene B4 antagonists, such as 1- (3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl) -cyclopentanecarboxylic acid (CP-105696), 5- [2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl) -5E-hexenyl ] oxyphenoxy ] -pentanoic acid (ONO-4057) or DPC-11870;
● 5-lipoxygenase inhibitors, such as zileuton, 6- [ (3-fluoro-5- [ 4-methoxy-3, 4, 5, 6-tetrahydro-2H-pyran-4-yl ]) phenoxy-methyl ] -1-methyl-2-quinolinone (ZD-2138) or 2, 3, 5-trimethyl-6- (3-pyridylmethyl) -1, 4-benzoquinone (CV-6504);
● sodium channel blockers, such as lidocaine;
● 5-HT3 antagonists, such as ondansetron;
and pharmaceutically acceptable salts and solvates thereof.
Since it may be desirable to administer a combination of active compounds, for example for the purpose of treating a particular disease or condition, it is within the scope of the present invention to combine two or more pharmaceutical compositions, at least one of which contains a compound according to the invention, suitably in a kit (kit) form 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 separately containing said compositions, such as a container, a separate bottle or a separate foil pouch. Examples of such kits are the familiar blister packs used for packaging tablets, capsules and the like.
The kit of the invention is particularly suitable for administration of different dosage forms, e.g. oral and parenteral dosage forms, for administration of separate compositions at different dosage intervals, or for titration of separate compositions. To aid compliance, the kit typically contains instructions for administration and may be provided with a so-called memory aid.
Examples
The following non-limiting examples illustrate the invention, wherein, unless otherwise specified: all operations are carried out at room or ambient temperature, i.e. in the range of 18-25 ℃; evaporating the solvent under reduced pressure by using a rotary evaporator, wherein the bath temperature is 60 ℃ at most; the reaction was monitored by means of Thin Layer Chromatography (TLC), the reaction time being given for illustration only; the melting points (mp) given are uncorrected (polymorphism may lead to different melting points); ensuring the structure and purity of all isolated compounds by means of at least one of the following techniques: TLC (Merck silica gel 60F) 254Precoated TLC plates), mass spectrometry, nuclear magnetic resonance spectroscopy (NMR), infrared absorption spectroscopy (IR), or microanalysis. The yields are given for illustrative purposes only. Flash column chromatography was performed using Merck silica gel 60(230-400 mesh ASTM) or Fuji Silysia amino-bonded silica (Chromatorex, 30-50 μ M) or Biotage amino-bonded silica (35-75 μ M, KP-NH) or Biotage silica (32-63 μ M, KP-Sil). HPLC purification was performed with the following apparatus and conditions. The device comprises the following steps: UV-triggered preparative HPLC system, Waters (column: XTerraMS C18, 5 μm, 19X 50mm or 30X 50mm), Detector: UV 254nmConditions are as follows: CH (CH)3CN/0.05% HCOOH aqueous solution or CH3CN/0.01％ NH3An aqueous solution; 20ml/min (19X 50mm) or 40ml/min (30X 50mm), ambient temperature. The microwave apparatus used in the reaction was an emerys optimizer (Personal chemistry). Optical rotation was measured by means of P-1020 (Jasco). Low resolution mass spectral data (EI) were obtained on an Integrity (Waters) mass spectrometer. Low resolution mass spectral data (ESI) were obtained on a zmd (micromass) mass spectrometer. NMR data were measured at 270MHz (JEOL JNM LA 270 spectrometer) or 300MHz (JEOL JNM-LA300 spectrometer) using deuterated chloroform (99.8% D) or DMSO (99.9% D) as solvent, unless otherwise specified, expressed in parts per million (ppm) relative to Tetramethylsilane (TMS) internal standard; the conventional abbreviations used are: s is singlet, d is doublet, t is triplet, q is quartet, quint is quintet, m is multiplet, br. is broad, etc. The IR spectrum was measured by means of a Shimazu infrared spectrometer (IR-470). Chemical symbols have their usual meaning: bp (boiling point), mp (melting point), L (liter), mL (mL), g (g), mg (mg), mol (mol), mmol (mmol), eq. (equivalent), quant. (quantitative yield), sat. (saturation), aq (water).
In the following examples, the term "compound of example XX" refers to the title compound of example XX.
Example 1
2- (4-tert-butylphenyl) -N- { 3-fluoro-4- [ (methylsulfonyl) amino group]Benzyl cyclopropanecarboxamide
To a solution of trans-2- (4-tert-butylphenyl) cyclopropanecarboxylic acid (435mg, 1.89mmol)) [ Journal of medical chemistry, 2005, vol.48, 71-90] in DMF (10ml) were added EDC (572mg, 3.0mmol), DMAP (73mg, 0.6mmol), triethylamine (0.836ml) and N- [4- (aminomethyl) -2-fluorophenyl ] methanesulfonamide hydrochloride (507mg, 1.89mmol), and the mixture was stirred at room temperature for 5 hours. The reaction was then quenched with saturated aqueous sodium bicarbonate, extracted all with EtOAc/hexanes (3: 1), and dried over sodium sulfate. Then filtered, evaporated and purified by silica gel column chromatography eluting with hexane/EtOAc (1: 2) to give the title compound (75mg, 9% yield) as a white solid.
1H NMR(300HMz，CDCl3)δppm 1.30(9H，s)，1.59-1.69(3H，m)，2.48-2.55(1H，m)，3.02(3H，s)，4.45(2H，d，J＝5.9Hz)，5.98(1H，brs)，6.49(1H，brs)，7.03-7.12(4H，m)，7.31(2H，d，J＝8.1Hz)，7.53(1H，t，J＝8.4Hz)。MS(ESI)：m/z 419(M+H)+。
Example 2
2- (4-tert-butyl-3-fluorophenyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) cyclopropanecarboxamide
2A) 4-acetyl-2-methylphenyl trifluoromethanesulfonate
To a stirred solution of 1- (4-hydroxy-3-methylphenyl) ethanone (6.0g, 40mmol) in DCM (100ml) was added trifluoromethanesulfonic anhydride (8.7ml, 52mmol) and triethylamine (10ml) successively. The mixture was stirred at room temperature for 16 h, quenched with water and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with DCM/EtOAc (5: 1) to give 9.6g (85% yield) of the title compound as a yellow oil.
1H NMR(270MHz，CDCl3)δppm 2.45(3H，s)，2.62(3H，s)，7.35(1H，d，J＝8.6Hz)，7.86(1H，dd，J＝8.6，2.5Hz)，7.92(1H，s)。
2B) N- (4-acetyl-2-methylphenyl) methanesulfonamide
A tube suitable for microwave reaction was charged with tris (dibenzylideneacetone) dipalladium (0) chloroform adduct (205mg, 0.20mmol), the compound of example 2A (1.41g, 5.0mmol), methanesulfonamide (570mg, 6.0mmol) and cesium carbonate (1.63g, 7.0 mmol). The mixture was subjected to microwave irradiation at 120 ℃ while stirring for 10 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2: 1) to give 390mg (34% yield) of the title compound as a yellow solid.
1H NMR(270MHz，CDCl3)δppm 2.34(3H，s)，2.59(3H，s)，3.11(3H，s)，6.47(1H，br.s)，7.58(1H，d，J＝8.1Hz)，7.84(2H，m)。
MS(ESI)：m/z 228(M+H)+，226(M-H)-。
2C) N- [4- ((1R) -1- { [ (R) -tert-butylsulfinyl]Amino } ethyl) -2-methylphenyl] Methane sulfonamides
To a solution of titanium (IV) ethoxide (1.32g, 5.8mol) and the compound of example 2B (800mg, 3.5mmol) in THF (20ml) under a nitrogen atmosphere was added (R) - (+) -tert-butanesulfinamide and the mixture was heated at 70 ℃ for 16 h. The reaction was quenched with water and the resulting white precipitate was filtered off. The filtrate was partitioned between EtOAc and water. The organic layer was then separated, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with hexane/EtOAc (4: 1). The resulting yellow oil was dissolved in THF (10ml) and the solution was added to a solution of sodium borohydride (242mg, 6.4mmol) in THF (10ml) at-70 ℃. The mixture was stirred at-70 ℃ for 5 hours and then quenched with MeOH. After stirring at room temperature for 1 hour, the mixture was concentrated in vacuo to give 530mg (45% yield) of the title compound as a pale yellow solid.
MS(ESI)：m/z 333(M+H)+，331(M-H)-。
2D) N- {4- [ (1R) -1-aminoethyl]-2-methylphenyl } methanesulfonamide hydrochloride
To the compound of example 2C (530mg, 1.60mmol) was added hydrochloric acid-MeOH (2.0M, 5.0ml) and 1, 4-dioxane (5.0 ml). The solution was stirred at room temperature for 30 minutes, then concentrated in vacuo. Diethyl ether was added to precipitate the amine hydrochloride. The precipitate was then filtered and washed with diethyl ether to give 450mg (quant.) of the title compound as a white solid. Enantiomeric purity (> 99% ee) was determined by means of DaicelChiralcel OD-H (4.6X 250mm) eluting with 0.1% diethylamine in hexane/ethanol (80: 20 vol.) at a column temperature of 40 ℃. Retention time: 10.2 min (R-form), 12.8 min (S-form).
1H NMR(270MHz，DMSO-d6)δppm 1.45(3H，m)，2.31(3H，s)，2.98(3H，s)，4.27(1H，m)，7.31-7.38(3H，m)。
MS(ESI)：m/z 227(M-H)-。
2E) 4-tert-butyl-3-fluorophenol
A solution of zirconium tetrachloride (11.7g, 50mmol) in DCM (130ml), tert-butyl methyl ether (4.44g, 50mmol) and 3-fluorophenol (5.6g, 50mmol) were mixed at room temperature and the reaction mixture was stirred at 50 ℃ for 2 hours. The reaction was quenched with water, extracted all with ethyl acetate and dried over magnesium sulfate. After filtration, evaporation gave a crude residue which was purified by silica gel column chromatography eluting gradually from hexane only to hexane/ethyl acetate (9: 1) to give 4.25g (51% yield) of the title compound as a white solid.
1H NMR(CDCl3)δppm 1.34(9H，s)，4.97(1H，brs)，6.56-6.50(2H，m)，7.13(1H，t，J＝8.7Hz)。
2F) 4-tert-butyl-3-fluorophenyl trifluoromethanesulfonate
To a solution of the compound from example 2E (4.25g, 25mmol) in pyridine (30ml) and DCM (50ml) was added trifluoromethanesulfonic anhydride (10.6g, 37.5mmol) and DMAP (30mg, 0.25mmol), and the mixture was stirred at 0 ℃ for 2 h. After quenching with water, the mixture was extracted with hexane. The extracts were concentrated in vacuo and the crude product was purified by column chromatography on silica gel eluting gradually with hexane only to hexane/ethyl acetate (9: 1) to give 6.7g (88% yield) of the title compound as a colorless oil.
1H NMR(CDCl3)δppm 1.38(9H，s)，6.95-7.03(2H，m)，7.37(1H，t，J＝8.1Hz)。
MS(ESI)：m/z 301(M+H)+。
2G) 1-tert-butyl-2-fluoro-4-vinylbenzene
To a solution of the compound from example 2F (3.27g, 10.9mmol) in DMF (100ml) were added vinyltributylstannane (3.8g, 12.0mmol), lithium chloride (4.62g, 108mmol) and dichlorobis triphenylphosphine palladium (0.383g, 0.54mmol), and the mixture was stirred at room temperature for 30 min. After stirring at 30 ℃ for a further 20 hours, the reaction was quenched with water and extracted all with hexane. After evaporation of the solvent, the residue was purified by silica gel column chromatography, eluting with hexane, to give the title compound (1.87g, 96%) as a colorless oil.
1H NMR(CDCl3)δppm 1.33(s，9H)，5.25(1H，d，J＝10.8Hz)，5.72(1H，d，J＝18.9Hz)，6.65(1H，dd，J＝10.8，18.9Hz)，7.03-7.09(2H，m)，7.16-7.36(1H，m)。
2H) Ethyl 2- (4-tert-butyl-3-fluorophenyl) cyclopropanecarboxylate
To a solution of the compound from example 2G (1.86G, 10.4mmol), Co (TPP) (0.21G, 0.3mmol) and 1-methyl-1H-imidazole (2.56G, 31mmol) in toluene (12ml) was added ethyl diazoacetate (1.66G, 14.5mmol), and the mixture was stirred at room temperature for 5 minutes. The mixture was then stirred at 80 ℃ for another 1 hour. After evaporation of the solvent, the residue was purified by silica gel column chromatography eluting gradually from hexane to hexane/ethyl acetate (10: 1) to give the title compound (2.13g, 77%, trans) as a colorless oil.
1H NMR(CDCl3)δppm 0.88(3H，t，J＝8.1Hz)，1.24-1.30(1H，m)，1.35(9H，s)，1.55-1.62(1H，m)，1.84-1.90(1H，m)，2.43-2.50(1H，m)，4.17(2H，q，J＝8.1Hz)，6.73(1H，br，J＝8.1Hz)，6.82(1H，d，J＝8.1Hz)，7.19(1H，t，J＝8.1Hz)。
MS(ESI)：m/z 265(M+H)+。
2I)2- (4-tert-butyl-3-fluorophenyl) cyclopropanecarboxylic acid
To a solution of the compound from example 2H (2.13g, 6.8mmol) in THF (5ml) was added 2M aqueous sodium hydroxide (10ml) and MeOH (10ml) and the mixture was stirred at 80 ℃ for 30 min. After completion of the reaction, the basic mixture was acidified with 2M aqueous HCl and extracted all with EtOAc. The solvent was evaporated to give 1.63g (89% yield) of the title compound as a white solid.
MS(ESI)：m/z 235(M-H)-。
2J)2- (4-tert-butyl-3-fluorophenyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino) Base of]Phenyl } ethyl) cyclopropanecarboxamide
To a solution of the compound from example 2I (33mg, 0.14mmol) in THF (0.5ml) at room temperature was added CDI (22.7mg, 0.14mmol), the mixture was stirred at room temperature for 1 hour, and then to the reaction was added triethylamine (0.5ml) and the compound from example 2D (37mg, 0.14 mmol). After stirring the mixture for 3 h, it was filtered, evaporated and purified by silica gel column chromatography eluting with hexane/ethyl acetate/methyl chloride (1: 2) to give the title compound (7.5mg, 12%) as a white solid.
1H NMR(CDCl3)δppm 1.30(9H，br)，1.16-1.38(5H，m)，1.84-1.96(1H，m)，2.18-2.29(1H，m)，2.28(3H，br)，2.95(3H，br)，4.83-4.94(1H，m)，6.83-6.93(2H，m)，7.12-7.23(4H，m)，8.51-8.55(1H，m)，9.01(1H，br)。MS(ESI)：m/z 447(M+H)+。
Example 3
2- [4- (1-hydroxy-1-methylethyl) phenyl]-2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
3A) Ethyl 2- (4-acetylphenyl) -2-methylcyclopropanecarboxylate
Ethyl diazoacetate (0.65ml, 6.21mmol) was added in one portion to a stirred solution of 1- [4- (1-methylvinyl) phenyl ] ethanone (711mg, 4.44mmol, trans) (org. Lett., 2002, 4(1), 107-propanal 109), N-methylimidazole (1.06ml, 13.3mmol) and Co (TPP) (89mg, 0.13mmol) in toluene (10ml) at ambient temperature. A similar procedure as described in example 2H was performed to give the title compound (236mg, 22%) as a dark yellow oil.
1H NMR(270MHz，CDCl3)δ1.31(3H，t，J＝6.8Hz)，1.42-1.60(5H，m)，1.95-2.02(1H，m)，2.59(3H，s)，4.14-4.27(2H，m)，7.35-7.41(2H，m)，7.88-7.94(2H，m)。
3B)2- (4-Acetylphenyl) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) Amino group]Phenyl } ethyl) cyclopropanecarboxamide
A mixture of the compound from example 3A (236mg, 0.96mmol) in 2M aqueous sodium hydroxide (2ml, 4.0mmol) and MeOH (6ml) was heated at 85 deg.C for 1.5 h. After cooling to ambient temperature, the solvent was evaporated in vacuo and the residue was diluted with water. The aqueous solution was washed with diethyl ether, acidified to pH 1 with 2M aqueous hydrochloric acid and extracted with DCM. The combined solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude acid compound (205mg) as a dark yellow solid. To a stirred solution of the compound from example 2D (249mg, 0.94mmol), the crude acid compound (205mg, 0.94mmol), HOBt (144mg, 0.94mmol), EDC (324mg, 0.83mmol) in dry DMF (5ml) was added triethylamine (380mg, 3.76mmol) at ambient temperature. The reaction procedure described in example 1 was followed to give the title compound (310mg, 81%, 2 steps) as a pale yellow amorphous solid (mixture of diastereomeric products (1: 1)).
1H NMR(270MHz，CDCl3)δ1.37-1.65(8H，m)，1.70-1.82(1H，m)，2.32(3H，s)，2.58(3H，m)，3.02(3H，m)，5.06-5.20(1H，m)，5.94-6.05(1H，m)，6.24(1H，br.s)，7.15-7.25(2H，m)，7.29-7.45(3H，m)，7.86-7.92(2H，m)。
3C)2- [4- (1-hydroxy-1-methylethyl) phenyl]-2-methyl-N- ((1R) -1- { 3-methyl -4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
To a stirred solution of the compound from example 3B (245mg, 0.57mmol) in dry THF (30ml) at-78 deg.C was added 0.98mol/l methyl lithium in diethyl ether (2.92ml, 2.85 mmol). After 20 minutes at-78 ℃, the mixture was warmed to 0 ℃ and stirred for 40 minutes. The mixture was quenched with saturated aqueous ammonium chloride and extracted with DCM. The combined solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude product. Purification by amino-bonded silica gel column chromatography eluting with DCM-MeOH (30: 1-20: 1) afforded the title compound (128mg, 50%) as a white solid (mixture of diastereomeric products (1: 1)) which was recrystallized from hexane-EtOAc.
1H NMR(270MHz，CDCl3)δ1.32-1.80(16H，m)，2.31(3H，s)，3.00(3H，s)，5.05-5.20(1H，m)，5.85-5.96(1H，m)，6.30(1H，br.s)，7.14-7.26(4H，m)，7.37-7.46(3H，m)。
MS(ESI)：m/z 443(M-H)-，m/z 445(M+H)+。
Example 4
2- (4-tert-butyl-3-fluorophenyl) -N- { 3-methyl-4- [ (methylsulfonyl) amino]- Benzyl cyclopropanecarboxamide
4A)4- (4-cyano-2-methylphenyl) methanesulfonamide
A mixture of 4- (4-iodo-2-methylphenyl) methanesulfonamide (18.0g, 57.9mmol), zinc cyanide (8.49g, 74.3mmol) and tetrakis (triphenylphosphine) palladium (0) (6.68g, 5.78mmol) in DMF (130ml) was heated at 100 ℃ for 3 h. The mixture was diluted with EtOAc/toluene (8: 1) and the precipitate was filtered through a pad of celite. The organic layer was washed with water, then brine, dried over magnesium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel eluting with hexane/EtOAc (1: 1) to give a white solid which was separated from acetone-hexane to give 10.3g (85% yield) of the title compound as a white solid.
1H NMR(270MHz，DMSO-d6)δppm 2.31(3H，s)，3.11(3H，s)，7.50(1H，d，J＝8.1Hz)，7.64-7.76(2H，m)，9.50(1H，s)。
4B)4- [4- (aminomethyl) -2-methylphenyl]Methane sulfonamide monohydrochloride
A mixture of the compound from example 4A (10.0g, 47.6mmol) in THF (150ml) -MeOH (100ml) -concentrated aqueous hydrochloric acid (35ml) was hydrogenated over 10% Pd-C (1.50g) using a hydrogen balloon for 24 h. The reaction mixture was filtered through a pad of celite and the filter cake was washed with THF/water (1: 1) (300 ml). The filtrate and washings were evaporated in vacuo and the residue was diluted with EtOAc-water. The aqueous layer was separated and evaporated in vacuo to give the crude product, which was isolated from MeOH-diisopropyl ether to give 11.5g (95% yield) of the title compound as a white solid.
1H NMR(270MHz，DMSO-d6)δppm 2.31(3H，s)，2.99(3H，s)，3.95(2H，s)，7.27-7.41(m，3H)，8.66(3H，br.s)。MS(ESI)：m/z 213(M-H)-。
4C)2- (4-tert-butyl-3-fluorophenyl) -N- { 3-methyl-4- [ (methylsulfonyl) amino]Benzyl radical } Cyclopropanecarboxamides
To a solution of the compound from example 2I (94.5mg, 0.40mmol) in THF (2.0ml) was added CDI (71mg, 0.44mmol) at room temperature, the mixture was stirred at room temperature for 1 hour, and then to the reaction was added triethylamine (0.5ml) and the compound from example 4B (120mg, 0.48 mmol). The same procedure as described in example 2J was performed to give 89mg (51% yield) of the title compound as a white solid.
1H NMR(DMSO-d6)δppm 1.14-1.42(2H，m)，1.30(9H，s)，1.86-1.96(1H，m)，2.20-2.31(1H，m)，2.29(3H，s)，2.95(3H，s)，4.26(2H，d，J＝5.4Hz)，6.89(1H，d，J＝8.1Hz)，6.92(1H，s)，7.06-7.24(m，4H)，8.60(1H，t，J＝5.4Hz)，9.03(1H，br)。
MS(ESI)：m/z 433(M+H)+。
Example 5
2- (4-tert-butylphenyl) -2-methyl-N- { 3-methyl-4- [ (methylsulfonyl) amino ]- Benzyl cyclopropanecarboxamide
To a solution of trans-2- (4-tert-butylphenyl) -2-methylcyclopropanecarboxylic acid (92.9mg, 0.40mmol) [ EP 188887A 1(1986) ] in THF (2.0ml) was added CDI (71mg, 0.44mmol) at room temperature, the mixture was stirred at room temperature for 1 hour, and then to the reaction were added triethylamine (0.5ml) and the compound of example 4B (120mg, 0.48 mmol). The same procedure as described in example 2J was performed to give 7mg (4% yield) of the title compound as a white solid.
1H NMR(CDCl3)δppm 1.24-1.33(4H，m)，1.30(9H，s)，1.41(1H，dd，J＝5.4，8.1Hz)，1.73(1H，dd，J＝8.1Hz)，2.31(3H，s)，3.01(3H，s)，4.45(2H，d，J＝5.4Hz)，5.95(1H，br)，6.16-6.27(1H，m)，7.14-7.22(2H，m)，7.19(2H，d，J＝8.1Hz)，7.33(2H，d，J＝8.1Hz)，7.42(1H，d，J＝8.1Hz)。
MS(ESI)：m/z 429(M+H)+。
Example 6
N- { 3-methyl-4- [ (methylsulfonyl) amino group]Benzyl } -2- [4- (2, 2, 2-trifluoro-1, 1-) Dimethylethyl) phenyl]Cyclopropanecarboxamides
6A)4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyltrifluoromethanesulfonate
To a solution of 4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenol (1.2g, 6mmol) in pyridine (8ml) and DCM (12ml) were added trifluoromethanesulfonic anhydride (2.54g, 9mmol) and DMAP (12mg, 0.1mmol), and the mixture was stirred at 0 ℃ for 3 hours. The same procedure as described in example 2F was carried out to give the title compound (1.8g, 89%) as a colorless oil.
1H NMR(CDCl3)δ1.59(6H，s)，7.28(2H，d，J＝8.1Hz)，7.59(2H，d，J＝8.1Hz)。
6B)1- (2, 2, 2-trifluoro-1, 1-dimethylethyl) -4-vinylbenzene
To a solution of the compound from example 6B (1.80g, 5.3mmol) in DMF (50ml) were added vinyltributylstannane (1.86g, 5.8mmol), lithium chloride (2.25g, 53mmol) and dichlorobis triphenylphosphine palladium (186mg, 0.26mmol), and the mixture was stirred at room temperature for 30 min, followed by a further stirring at 28 ℃ for 10 h. The same procedure as described in example 2G was carried out to give the title compound (815mg, 72%) as a colorless oil.
1H NMR(CDCl3)δppm 1.57(6H，s)，5.27(1H，d，J＝10.8Hz)，5.76(1H，d，J＝16.2Hz)，6.71(1H，dd，J＝10.8，16.2Hz)，7.38-7.47(4H，m)。
6C)2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxylic acid ethyl ester
In the same procedure as described in example 2H, to a solution of the compound from example 6B (0.8g, 3.73mmol, trans), Co (TPP) (0.075g, 0.1mmol) and 1-methyl-1H-imidazole (0.92g, 11mmol) in toluene (4ml) was added ethyl diazoacetate (0.6g, 5.26mmol) to give the title compound (1.0g, 89%) as a colorless oil.
1H NMR(CDCl3)δppm 1.28(3H，t，J＝8.1Hz)，1.25-1.35(1H，m)，1.55(6H，s)，1.55-1.64(1H，m)，1.87-1.94(1H，m)，2.47-2.54(1H，m)，4.17(2H，q，J＝8.1Hz)，7.10(2H，d，j＝8.1Hz)，7.41(2H，d，J＝8.1Hz)。
MS(ESI)：m/z 301(M+H)+。
6D)2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxylic acid
In the same procedure as described in example 2I, to a solution of the compound from example 6C (1.0g, 3.3mmol) in THF (5ml) was added 2M sodium hydroxide solution (3ml) and MeOH (3ml) to give 0.82g (90% yield) of the title compound as a white solid.
MS(ESI)：m/z 271(M-H)-。
6E) N- { 3-methyl-4- [ (methylsulfonyl) amino group]Benzyl } -2- [4- (2, 2, 2-trifluoro-1, 1-di-tert-butyl) benzene Methyl) phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 6D (109mg, 0.4mmol) in THF (2.0ml) at room temperature was added CDI (71mg, 0.44mmol), the mixture was stirred at room temperature for 1 hour, and to this reaction were added triethylamine (0.5ml) and the compound from example 4B (120mg, 0.48 mmol). The same procedure as described in example 2J was performed to give the title compound (115mg, 64%) as a white solid.
1H NMR(DMSO-d6)δppm 1.20-1.31(1H，m)，1.36-1.45(1H，m)，1.52(6H，s)，1.89-1.98(1H，m)，2.29(3H，s)，2.95(3H，s)，4.26(2H，d，J＝5.4Hz)，7.07-7.17(2H，m)，7.16(2H，d，J＝8.1Hz)，7.24(1H，d，J＝8.1Hz)，7.43(2H，d，J＝8.1Hz)，8.61(1H，t，J＝5.4Hz)，9.03(1H，br)。
MS(ESI)：m/z 469(M+H)+。
Example 7
2- (4-tert-butylphenyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]- Phenyl } ethyl) cyclopropanecarboxamide
7A)2- (4-tert-butylphenyl) cyclopropanecarboxylic acid
Racemic trans-2- [4- (1, 1-dimethylethyl) phenyl ] cyclopropanecarboxylic acid [ Journal of medicinal chemistry, 2005, vol.48, 71-90] (column size: 2X 25cm, mobile phase: hexane/ethanol/trifluoroacetic acid: 95/5/0.1, column temperature: 40 ℃, flow rate: 20ml/min, detection: 220nm, retention time: 7.5min and 8.6min) was separated with DAICEL CHIRALPAK AD-H. The latter fractions were used for the next step.
[α]D281.1(c 0.94, methanol, bath temperature 21.0 ℃).
7B)2- (4-tert-butylphenyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Benzene and its derivatives Ethyl) cyclopropanecarboxamide
To a stirred solution of the compound from example 7A (276mg, 1.26mmol) in DCM (3ml) was added oxalyl chloride (240mg, 1.89mmol) and DMF (1 drop) at 0 deg.C. After stirring at room temperature for 1 hour, the mixture was evaporated in vacuo and the residue was dissolved in DCM (1 ml). The above solution was added to a solution of the compound from example 2D (288mg, 1.26mmol) and triethylamine (382mg, 3.78mmol) in DCM (5ml) at 0 deg.C. After stirring at room temperature for 5 hours, the mixture was diluted with DCM and washed with 2M aqueous hydrochloric acid, brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified on an amino-bound silica gel column (FUJI SILYSIA CHEMICAL ltd. size 30 to 50 μm) eluting with DCM-MeOH (200: 1) to give the desired compound. This product was isolated from hexanes-EtOAc to give 384mg (71% yield) of the title compound as a white solid.
1H NMR(DMSO-d6)δppm 1.10-1.37(14H，m)，1.82-1.93(1H，m)，2.14-2.25(1H，m)，2.29(3H，s)，2.96(3H，s)，4.82-4.95(1H，m)，7.00-7.33(7H，m)，8.48-8.55(1H，m)，9.01(lH，br)。
MS(ESI)：m/z 429(M+H)+。
Example 8
2- (4-tert-butylphenyl) -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) sulfonic acidAcyl) amino]- Phenyl } ethyl) cyclopropanecarboxamide
The carboxylic acid (50.0mg, 0.23mmol) used in example 1 and N- {4- [ (1R) -1-aminoethyl ] -2-fluorophenyl } methanesulfonamide hydrochloride (50mg, 0.23mmol) were treated in the same procedure as in example 7B to give 42.5mg (38% yield) of the title compound as a white solid.
1H NMR(CDCl3)δppm 1.30(9H，s)，1.45(3H，d，J＝6.6Hz)，1.56-1.64(2H，m)，2.44-2.50(1H，m)，3.02(3H，s)，5.04-5.13(1H，m)，5.92(1H，d，J＝7.4Hz)，6.60(1H，s)，7.00-7.33(7H，m)，7.51(1H，t，J＝8.9Hz)。MS(ESI)：m/z 419(M+H)+。
Example 9
2-methyl-N- ((1R) -1- { 6-methyl-5- [ (methylsulfonyl) amino]Pyridin-2-yl } ethyl 2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] -phenyl]Cyclopropanecarboxamides
9A) N- (6-chloro-2-methylpyridin-3-yl) methanesulfonamide
A mixture of 3-amino-6-chloro-2-methylpyridine (2.0g, 14.0mmol) and methanesulfonyl chloride (1.92g, 16.8mmol) in pyridine (40ml) was stirred at room temperature for 1 hour. After removal of the solvent, the crude product was purified by column chromatography on silica gel eluting with hexane/EtOAc (3: 2) to give 1.70g (55% yield) of the title compound as a pale yellow solid.
1H NMR(DMSO-d6)δppm 2.47(3H，s)，3.05(3H，s)，7.37(1H，d，J＝8.6Hz)，7.71(1H，d，J＝8.6Hz)，9.47(1H，s)。MS(ESI)：m/z 221(M+H)+。
9B) N- (6-cyano-2-methylpyridin-3-yl) methanesulfonamide
A test tube suitable for microwave use was charged with a solution of the compound from example 9A (1.66g, 7.52mmol), zinc cyanide (1.11g, 9.45mmol) and tetrakis (triphenylphosphine) palladium (0) (872mg, 0.754mmol) in DMF (14.1 ml). The mixture was subjected to microwave irradiation at 100 ℃ while stirring for 30 minutes. The mixture was then diluted with toluene/EtOAc (1: 10) and the precipitate was filtered off. The organic layer was washed with water, then brine, and dried over magnesium sulfate. After filtration, the organic layer was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with hexane/EtOAc (3: 2) to give the title compound (835mg, 53%) as a pale yellow solid.
1H NMR(DMSO-d6)δppm 2.50(3H，s)，3.15(3H，s)，7.85(2H，s)，9.81(1H，s)。
MS(ESI)：m/z 212(M+H)+。
9C) N- (6-acetyl-2-methylpyridin-3-yl) methanesulfonamide
To a solution of the compound from example 9B (423mg, 2.0mmol) in THF (9.9ml) was added dropwise a solution of methylmagnesium bromide (6.7ml, 6.0mmol) in diethyl ether at 0 deg.C with stirring. After stirring at the same temperature for 2 hours, the reaction mixture was poured into ice-cold water (10ml) and extracted with EtOAc. The organic layer was dried over magnesium sulfate and concentrated to give a dark red solid, which was separated from EtOAc-hexanes to give 246mg (54% yield) of the title compound as a reddish solid.
1H NMR(300MHz，DMSO-d6)δppm 2.56(3H，s)，2.59(3H，s)，3.13(3H，s)，7.80-7.89(2H，m)，9.68(1H，s)。MS(ESI)：m/z 229(M+H)+。
9D) N- [ 2-methyl-6- ((1R) -1- { [ (1R) -1-phenylethyl]Amino } ethyl) pyridin-3-yl] Methane sulfonamides
At room temperature N2Next, to a solution of the compound from example 9C (959mg, 4.20mmol), (1R) -1-phenylethylamine (611mg, 5.04mmol) and triethylamine (2.34ml, 16.8mmol) in DCM (30ml) was added a solution of titanium (IV) chloride (495mg, 2.61mmol) in DCM (5 ml). After stirring at the same temperature for 17 hours, the reaction volume was reduced to a half by evaporation (ca.20m). The mixture was diluted with EtOH (40ml) and then in H2Pressure (4.3 kg/cm)2) Then, Raney nickel hydrogenation is carried out at room temperature. After stirring for 5 hours, the reaction mixture was filtered through a pad of celite and washed with DCM. The filtrate was concentrated and the residue was purified by silica gel column chromatography, eluting with acetone/hexane (1: 1) to give 0.67g (48% yield) of the title compound as a yellow viscous oil.
1H NMR(300MHz，DMSO-d6)δppm 1.09-1.25(6H，m)，2.45(3H，s)，3.02(3H，s)，3.26-3.48(2H，m)，7.13-7.37(6H，m)，7.61(1H，d，J＝8.1Hz)。
MS(ESI)：m/z 334(M+H)+。
9E) N- {6- [ (1R) -1-aminoethyl]-2-methylpyridin-3-yl } methanesulfonamide hydrochloride
At room temperature N2Next, to a solution of the compound from example 9D (0.82g, 2.46mmol) in EtOH (25ml) were added 10% Pd-C (0.32g) and ammonium formate (6.20g, 98 mmol). The resulting mixture was stirred at 65 ℃ for 2 hours. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was treated with 10% HCl-MeOH, then concentrated and the product was isolated from MeOH-ether to give 0.54g (83% yield) of the title compound as a white solid.
1H NMR(300MHz，DMSO-d6)δppm 1.48(3H，d，J＝6.6Hz)，2.56(3H，s)，3.06(3H，s)，4.38-4.54(1H，m)，7.40(2H，d，J＝9.0Hz)，7.76(1H，d，J＝9.0Hz)，8.40(2H，br.s.)，9.50(1H，s)。
MS(ESI)：m/z 230(M+H)+。
9F) 2-methyl-N- ((1R) -1- { 6-methyl-5- [ (methylsulfonyl) amino]Pyridin-2-yl } ethyl 2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] -phenyl]Cyclopropanecarboxamides
The procedure described in example 13C was followed using the compound from example 13D (99.2mg, 0.346mmol) and the compound from example 9E (92.1mg, 0.35mmol) to give a solid which was isolated from DCM-hexane to give 50.9mg (30% yield) of the title compound as a white solid.
1H NMR(DMSO-d6)δppm 1.18-1.47(8H，m)，1.54(6H，s)，1.94-2.10(1H，m)，2.49(3H，s)，3.01(3H，s)，4.84-5.01(1H，m)，7.13-7.23(1H，m)，7.29-7.37(2H，m)，7.42-7.52(2H，m)，7.57-7.66(1H，m)，8.53-8.71(1H，m)，9.27(1H，s)。
MS(ESI)：m/z 498(M+H)+。
Example 10
2- (6-tert-butylpyridin-3-yl) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) cyclopropanecarboxamide
10A) 6-tert-butylpyridin-3-yl-trifluoromethanesulfonate
In the same procedure as described in example 2F, to a solution of 6-tert-butylpyridin-3-ol (6.51g, 43.1mmol, Journal of Chemical Research, Synopses, 1978, 7, 246) in pyridine (50ml) and DCM (80ml) was added trifluoromethanesulfonic anhydride (14.6g, 51.7mmol) and 4- (dimethylamino) pyridine (53mg, 0.43mmol) to give 10.8g (89% yield) of the title compound as a pale yellow oil.
1H NMR(CDCl3)δppm 1.38(9H，s)，7.44(1H，d，J＝9.2Hz)，7.54(1H，dd，J＝2.6，9.2Hz)，8.51(1H，d，J＝2.6Hz)。
10B) 2-tert-butyl-5-isopropenylpyridine
The compound from example 10A (10.8g, 38.2mmol), potassium isopropenyltrifluoroborate (5.66g, 38.2mmol, org. Lett.2002, 4, 107), PdCl2(dppf)·CH2Cl2A mixture of (1.56g, 1.91mmol) and triethylamine (5.32ml, 38.2mmol) in n-propanol (400ml) was stirred at 80 ℃ for 1 hour and then at 90 ℃ for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted all with hexane. The extract was concentrated, and the residue was purified by silica gel column chromatography, eluting with hexane/ethyl acetate 30/1 to give the title compound (5.96g 89%) as a colorless oil.
1H NMR(CDCl3)δppm 1.37(9H，s)，2.15(3H，s)，5.12(1H，s)，5.39(1H，s)，7.31(1H，d，J＝7.9Hz)，7.68(1H，dd，J＝2.0，7.9Hz)8.68(1H，d，J＝2.0Hz)。
10C)2- (6-tert-butylpyridin-3-yl) cyclopropanecarboxylic acid ethyl ester
To a solution of 2-tert-butyl-5-isopropenylpyridine (5.96g, 34mmol), Co (TPP) (0.69g, 1.0mmol) and 1-methyl-1H-imidazole (8.37g, 102mmol) in toluene (60ml) was added ethyl diazoacetate (5.4g, 48mmol), and the mixture was stirred at room temperature for 5 minutes, followed by further stirring at 80 ℃ for 1 hour. The solvent was then evaporated and purified by silica gel column chromatography eluting gradually from hexane to hexane/ethyl acetate (30: 1) to give the title compound (3.51g, 39%, trans) as a white solid.
1H NMR(CDCl3)δppm 1.30(3H，t，J＝7.3Hz)，1.35(9H，s)，1.37-1.50(2H，m)，1.53(3H，s)，1.93(1H，dd，J＝5.9，8.6Hz)，4.19(2H，q，J＝7.3Hz)，7.28(1H，d，J＝8.6Hz)，7.51(1H，dd，J＝2.6，8.6Hz)，8.51(1H，dt，J＝2.5Hz)。MS(ESI)：m/z 248(M+H)+。
10D)2- (6-tert-butylpyridin-3-yl) -2-methylcyclopropanecarboxylic acid
To a solution of the compound from example 10C (3.51g, 13.4mmol) in THF (25ml) was added 2M aqueous sodium hydroxide (14ml) and MeOH (25ml) and the mixture was stirred at room temperature for 16 h. After completion of the reaction, the basic mixture was washed with diethyl ether, the aqueous layer was separated, neutralized to pH 5-6 with 2m hcl aqueous solution, and all extracted with ethyl acetate, followed by evaporation to give 3.22g (quant.) of the title compound as a white solid.
1H NMR(CDCl3)δppm 1.37(9H，s)，1.45-1.60(2H，m)，1.60(3H，s)，1.96-2.01(1H，m)，7.30(1H，d，J＝8.1Hz)，7.56(1H，dd，J＝2.2，8.1Hz)，8.58(1H，d，J＝2.2Hz)。
MS(ESI)m/z 232(M-H)-。
10E)2- (6-tert-butylpyridin-3-yl) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) Acyl) amino]Phenyl } ethyl) cyclopropanecarboxamide
In the same procedure as described in example 1, to a solution of the compound from example 10D (17mg, 0.073mmol) in DMF (0.5ml) was added EDC (21mg, 0.12mmol), HOBt (12mg, 0.080mmol), triethylamine (0.031ml) and the amine compound from example 2D (19mg, 0.073mmol) to give a mixture of diastereomeric products (1: 1) the title compound (19mg, 59% yield) as a white solid.
1H NMR(300MHz，CDCl3)δ1.32-1.73(18H，m)，2.32(3H，s)，3.03(3H，s)，5.07-5.16(1H，m)，5.82-5.86(1H，m)，6.10(1H，brs)，7.18-7.30(3H，m)，7.40-7.49(2H，m)，8.50(1H，d，J＝2.3Hz)。
MS(ESI)：m/z 444(M+H)+。
Example 11
2- (6-tert-butylpyridin-3-yl) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) cyclopropanecarboxamide monohydrochloride
11A) 2- (6-tert-butylpyridin-3-yl) -2-methylcyclopropanecarboxylic acid
Racemic 2- (6-tert-butylpyridin-3-yl) -2-methylcyclopropanecarboxylic acid was isolated via Daicel Chiralpak AD-H (20X 250mm) eluting with n-hexane/EtOH/TFA/diethylamine (95/5/0.05/0.05) at a column temperature of 40 ℃. The title compound was obtained as a later fraction (retention time 2.9 min).
11B)2- (6-tert-butylpyridin-3-yl) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) Acyl) amino]Phenyl } ethyl) cyclopropanecarboxamide
To a solution of the compound from example 11A (600mg, 2.57mmol) in DMF (10ml) was added EDC (739mg, 3.86mmol), HOBt (433mg, 2.83mmol), triethylamine (1.07ml) and the amine from example 2D (681mg, 2.57mmol), and the mixture was stirred at room temperature for 16 h. The reaction was then quenched with saturated aqueous sodium bicarbonate, extracted all with EtOAc/hexanes-3/1 and dried over sodium sulfate. Then filtered, evaporated and purified by silica gel column chromatography eluting with hexane/ethyl acetate 1/1 to give 878mg (77% yield) of the title compound as a white solid.
1H NMR(300HMz，CDCl3)δppm 1.35(9H，s)，1.35-1.39(1H，m)，1.49(3H，d，J＝6.6Hz)，1.50-1.55(1H，m)，1.55(3H s)，1.65-1.69(1H，m)，2.32(3H，s)，3.02(3H，s)，5.07-5.16(1H，m)，5.97(1H，d，J＝7.3Hz)，6.22(1H，m)，7.18-7.20(2H，m)，7.26(1H，d，J＝8.1Hz)，7.40-7.46(2H，m)，8.50(1H，d，J＝2.3Hz)。
MS(ESI)：m/z 444(M+H)+。
11C)2- (6-tert-butylpyridin-3-yl) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) Acyl) amino]Phenyl } ethyl) cyclopropanecarboxamide monohydrochloride
A solution of the compound from example 11B (878mg) in 10% HCl-MeOH (15ml) was stirred at room temperature for 30 min. The mixture was concentrated in vacuo and diluted with diisopropyl ether. The resulting precipitate was filtered and washed with diisopropyl ether to give 1.0g (100%) of the title compound as a white solid.
1H NMR(DMSOd-6，300MHz)：δppm 1.30-1.50(2H，m)，1.34(3H，d，J＝6.6Hz)，1.41(9H，s)，1.46(3H，s)，2.05-2.15(1H，m)，2.29(3H，s)，2.96(3H，s)，4.90-4.94(1H，m)，7.13-7.23(3H，m)，7.80-7.85(1H，m)，8.18-8.24(1H，m)，8.55-8.68(2H，m)，9.02(1H，s)，
MS(ESI)：m/z 444(M+H)+。
[α]D(c is 0.48, methanol, pool temperature is 21.0 ℃.)
Example 12
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxamides
12A) 5-isopropenyl-2- (trifluoromethyl) pyridine
5-bromo-2- (trifluoromethyl) pyridine (452mg, 2.0mmol), potassium isopropenyltrifluoroborate (355mg, 2.4mmol), PdCl were treated in the same procedure as described in example 10B2(dppf)·CH2Cl2(82mg, 0.1mmol) and triethylamine (0.28ml, 2.0mmol) in n-propanol (20 ml). The crude residue was chromatographed on silica gel eluting with a volumetric mixture of hexane and EtOAc (20/1) to give 219mg (59% yield) of the title compound as a colorless oil.
1H NMR(270MHz CDCl3)δppm 2.20(3H，s)，5.32(1H，s)，5.52(1H，s)，7.65(1H，d，J＝8.1Hz)，7.89(1H，d，J＝8.1Hz)，8.83(1H，s)。
12B) 2-methyl-2- [6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxylic acid ethyl ester
In the same procedure as described in example 2H, to a solution of 5-isopropenyl-2- (trifluoromethyl) pyridine (219mg, 1.17mmol), Co (TPP) (26mg, 0.039mmol) and 1-methyl-1H-imidazole (320mg, 3.9mmol) in toluene (2ml) was added ethyl diazoacetate (208mg, 1.8 mmol). The crude residue (201mg, 63% yield title compound as black oil) was used for further reaction without purification.
1H NMR(300MHz CDCl3)δppm 1.31(3H，t，J＝6.9Hz)，1.25-1.60(5H，m)，1.96-2.05(1H，m)，4.15-4.27(2H，m)，7.58-7.80(2H，m)，8.65-8.70(1H，m)。
MS(ESI)：m/z 274(M+H)+。
12C) 2-methyl-2- [6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxylic acid
The procedure described in example 2I was carried out using the compound from example 12B (201mg, 0.736mmol) in THF (4ml), 2M aqueous sodium hydroxide (1ml) and MeOH (5ml) to give 63mg (35% yield, trans) of the title compound as a brown oil.
1H NMR(300MHz CDCl3)δppm 1.53(3H，s)，1.50-1.62(2H，m)，1.98-2.07(1H，m)，7.64(1H，d，J＝7.9Hz)，7.76-7.82(1H，m)，8.68-8.71(1H，m)，
MS(ESI)：m/z 246(M+H)+。
12D) 2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl group } B 2- [6- (trifluoromethyl) pyridin-3-yl ] -phenyl- ]]Cyclopropanecarboxamides
The procedure described in example 1 was followed using a solution of the compound from example 12C (62mg, 0.253mmol) in DMF (2ml), EDC (73mg, 0.38mmol), HOBt (43mg, 0.278mmol), triethylamine (0.106ml) and the compound from example 2D (67mg, 0.253 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1/1) to give 31mg (27% yield) of the title compound as a white solid.
1H NMR(CDCl3，300MHz)δppm 1.41-1.80(8H，m)，2.30-2.40(4H，m)，3.01-3.08(3H，m)，5.08-5.20(1H，m)，5.90-5.95(1H，m)，6.17-6.19(1H，m)，7.14-7.22(2H，m)，，7.38-7.54(2H，m)，7.84-7.87(1H，m)，8.72(1H，s)。MS(ESI)＝m/z 456(M+H)+。
Example 13
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxamides
13A) 1-isopropenyl-4- (2, 2, 2-trifluoro-1,1-dimethylethyl) benzene
4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyltrifluoromethanesulfonate (13.3g, 40mmol), potassium isopropenyltrifluoroborate (7.0g, 47.6mmol), PdCl were used 2(dppf)·CH2Cl2A mixture of (1.6g, 1.98mmol) and triethylamine (5.5ml, 40mmol) in n-propanol (400ml) was subjected to the procedure described in example 10B. The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (100/1) to give 6.32g (70% yield) of the title compound as a colorless oil.
1H NMR(300MHz CDCl3)δppm 1.58(6H，s)，2.16(3H，s)，5.10(1H，s)，5.40(1H，s)，7.47(4H，s)。
13B) 2-methyl-2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxylic acid ethyl ester Esters
The procedure described in example 2H was followed using the compound from example 13A (6.32g, 27.7mmol), Co (TPP) (558mg, 0.83mmol) and a solution of 1-methyl-1H-imidazole (6.82g, 83mmol), ethyl diazoacetate (4.42g, 38.8mmol) in toluene (50 ml). The crude residue was chromatographed on silica gel eluting with a volumetric mixture of hexane and EtOAc (50/1) to give 6.75g (78% yield, trans) of the title compound as a colorless oil.
1H NMR(300MHz CDCl3)δppm 1.29(3H，t，J＝7.3Hz)，1.40-1.48(2H，m)1.53(3H，s)，1.57(6H，s)，1.96(1H，dd，J＝5.9，8.7Hz)，4.19(2H，q，J＝7.3Hz)，7.24(2H，d，J＝8.1Hz)，7.42(2H，d，J＝8.1Hz)。
13C) 2-methyl-2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxylic acid
The procedure described in example 2I was carried out using the compound from example 13B (6.75g, 21.5mmol) in THF (50ml), 2M aqueous sodium hydroxide (22ml) and MeOH (50ml) to give 5.16g (84% yield) of the title compound as a white solid.
1H NMR(300MHz CDCl3)δppm 1.48-1.57(2H，m)，1.57(6H，s)，1.59(3H，s)，1.99(1H，dd，J＝5.3，7.7Hz)，7.29(2H，d，J＝8.1Hz)，7.43(2H，d，J＝8.1Hz)。
MS(ESI)：m/z 285(M+H)-。
13D) 2-methyl-2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ]Cyclopropanecarboxylic acid
Racemic 2-methyl-2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] cyclopropanecarboxylic acid was isolated via Daicel Chiralpak OJ-H (20X 250mm) eluting with n-hexane/EtOH (98/2) containing 0.1% TFA at a column temperature of 40 ℃. The title compound was obtained as a later fraction (retention time 12 min).
13E) 2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl group } B 2- [6- (trifluoromethyl) pyridin-3-yl ] -phenyl- ]]Cyclopropanecarboxamides
At room temperature N2Next, oxalyl chloride (0.087ml, 1.0mmol) and DMF (one drop) were added to a solution of the compound from example 13D (100mg, 0.33mmol) in DCM (3 ml). After stirring for 1 hour, the resulting solution was evaporated and the residue was dissolved with toluene followed by evaporation. The resulting product was dissolved in anhydrous dichloromethane (3ml) and added to a solution of the compound from example 9E (94mg, 0.33mmol) in pyridine (3ml) at room temperature. After stirring for 1 hour, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1/2) to give 47mg (29%) of the title compound as a white solid.
1H NMR(CDCl3，300MHz)δppm 1.22-1.70(13H，m)，1.79-1.84(1H，m)，1.97-2.04(1H，m)，2.57(3H，s)，3.04(3H，s)，5.13-5.22(1H，m)，7.08(1H，d，J＝7.3Hz)，7.14(1H，d，J＝8.1Hz)，7.25-7.35(2H，m)，7.39-7.52(3H，m)，7.72(1H，d，J＝8.8Hz)。MS(ESI)：m/z 498(M+H)+。
Example 14
(1S, 2S) -2-methyl-N- ((1R) -1- { 6-methyl-5- [ (methylsulfonyl) amino]Pyridine-2- Ethyl) -2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
14A) 2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxylic acid ethyl ester
Ethyl diazoacetate (4.23g, 37.0mmol) was added to a solution of 1-isopropenyl-4- (trifluoromethyl) benzene (4.93g, 26.5mmol) [ Tetrahedron (2003), 59(17), 2999-propan 3002], Co (TPP) (534g, 0.795mmol) and 1-methyl-1H-imidazole (6.53g, 79.5mmol) in toluene (50 ml). The reaction and subsequent work-up were then carried out according to the procedure described in example 2H. The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (20/1) to give 5.92g (82% yield, trans) of the title compound as a colorless oil.
1H NMR(300MHz CDCl3)δppm 1.31(3H，t，J＝7.0Hz)1.40-1.54(2H，m)，1.54(3H，s)，1.95-2.00(1H，m)，4.15-4.28(2H，m)，7.41(2H，d，J＝8.1Hz)，7.56(2H，d，J＝8.1Hz)，
14B) 2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxylic acid (racemic)
The procedure described in example 2I was followed using 14A (5.92g, 21.7mmol) in THF (30ml), 2M aqueous sodium hydroxide (22ml) and MeOH (30ml) to give 5.0g (94% yield) of the title compound as a white solid.
1H NMR(270MHz CDCl3)δppm 1.50-1.57(2H，m)1.60(3H，s)，2.00(1H，dd，J＝5.9，8.1Hz)，7.42(2H，d，J＝8.1Hz)，7.58(2H，d，J＝8.1Hz)MS(ESI)：m/z 243(M+H)-。
14C) (1S, 2S) -2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxylic acid
The racemic compound from example 14B was isolated by means of Daicel Chiralpal OJ-H (20X 250mm), eluting with n-hexane/2-propanol/TFA-97/3/0.001 at a column temperature of 40 ℃. The title compound was obtained as a later fraction (retention time 8 min).
[α]D167.5 (c: 0.59, methanol, bath temperature: 21.0 ℃)
14D) (1S, 2S) -2-methyl-N- ((1R) -1- { 6-methyl-5- [ (methylsulfonyl) amino]Pyridine compound -2-yl } ethyl) -2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 14C (159mg, 0.651mmol) in DMF (6.5ml) were added HBTU (296mg, 0.782mmol), triethylamine (0.27ml, 1.95mmol) and the compound from example 9E (150mg, 0.651mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was then quenched with saturated aqueous sodium bicarbonate and extracted all with DCM. The extract was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by preparative thin layer chromatography (Merek, silica gel 60F 254, 1mm) eluting twice with hexane/EtOAc (1: 1) afforded the title compound (138mg, 46% yield) as a white solid, which was isolated from hexane-DCM.
1H NMR(CDCl3，300M Hz)δppm 1.39(1H，dd，J＝8.6，4.9Hz)，1.47(3H，d，J＝6.6Hz)，1.55-1.61(4H，m)，1.81(1H，dd，J＝8.6，5.9Hz)，2.57(3H，s)，3.05(3H，s)，5.09-5.24(1H，m)，6.24(1H，br.s.)，6.96(1H，d，J＝7.9Hz)，7.1 5(1H，d，J＝7.9Hz)，7.41(2H，d，J＝8.6Hz)，7.59(2H，d，J＝8.6Hz)，7.74(1H，d，J＝8.6Hz) MS(ESI)：m/z 456(M+H)+，454(M-H)-。
Example 15
(1S, 2S) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } - Ethyl) -2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 14C (262mg, 1.07mmol), triethylamine (0.472ml) and HBTU (514mg, 1.36mmol) in DMF (10ml) was added the amine from example 2D (328mg, 1.24 mmol). The reaction and subsequent work-up were then carried out according to the procedure described in example 14D. The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1/1) to give 481mg (99% yield) of the title compound as a white solid.
1H NMR(CDCl3，300MHz)δppm 1.49(3H，d，J＝7.3Hz)，1.37-1.57(2H，m)，1.59(3H，s)1.68-1.72(1H，m)，2.31(3H，s)，3.01(3H，s)，5.05-5.21(1H，m)，5.90(1H，d，J＝7.3Hz)，6.21(1H，s)，7.18-7.23(2H，m)，7.35-7.45(3H，m)，7.56(2H，d，J＝8.1Hz)。MS(ESI)：m/z455(M+H)+。
[α]D(c is 0.42, methanol, pool temperature is 21.0 ℃.)
Example 16
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) - 2- [4- (trifluoromethoxy) phenyl]Cyclopropanecarboxamides
16A) 1-isopropenyl-4- (trifluoromethoxy) benzene
To a stirred suspension of 60% sodium hydride (1.96g, 49mmol) was added DMSO (20ml) dropwise at 0 deg.C, and the mixture was stirred at 80 deg.C for 30 minutes. After cooling the mixture to 0 ℃ a solution of methyltriphenylbromide * (17.5g, 49mmol) in DMSO (60ml) was added dropwise at 0 ℃ and stirred at ambient temperature for 45 min. To this mixture was then added 1- [4- (trifluoromethoxy) phenyl ] ethanone (5g, 24.5mmol) dropwise at ambient temperature and stirred at ambient temperature for 1 hour. The reaction was quenched with a small amount of acetone and diluted with hexane and water. The resulting precipitate was filtered, and the organic layer was separated. After evaporation of the solvent, the residue was washed with hexane and concentrated in vacuo to give 5.1g (quant.) of the title compound as a colorless oil.
1H NMR(270MHz CDCl3)δppm 2.15(3H，s)，5.10-5.15(1H，m)，5.36(1H，s)，7.17(2H，d，J＝8.7Hz)，7.44-7.52(2H，m)，
16B) 2-methyl-2- [4- (trifluoromethoxy) phenyl]Cyclopropanecarboxylic acid ethyl ester
In the same procedure as described in example 2H, to a solution of the compound from example 16A (5.0g, 24.5mmol), Co (TPP) (494mg, 0.735mmol) and 1-methyl-1H-imidazole (6.0g, 73.5mmol) in toluene (50ml) was added ethyl diazoacetate (3.91g, 34.3 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (20/1), followed by hexane, at-10 ℃ for 2 hours. It is then filtered and the filtrate evaporated to give 4.25g (60% yield, trans) of the title compound as a violet oil.
1H NMR(270MHz CDCl3)δppm 1.30(3H，t，J＝6.1Hz)1.37-1.48(2H，m)，1.52(3H，s)，1.95(1H，dd，J＝5.9，7.9Hz)，4.15-4.26(2H，m)，7.14(2H，d，J＝7.9Hz)，7.28-7.35(2H，m)，
16C) 2-methyl-2- [4- (trifluoromethoxy) phenyl]Cyclopropanecarboxylic acid (racemic)
The procedure described in example 2I was carried out using the compound from example 16B (4.25g, 14.7mmol) in THF (20ml), 2M aqueous sodium hydroxide (15ml) and MeOH (20ml) to give 3.82g (quant.) of the title compound as a pale brown solid.
1H NMR(300MHz CDCl3)δppm 1.45-1.57(2H，m)1.58(3H，s)，1.98(1H，dd，J＝6.6，8.1Hz)，7.16(2H，d，J＝8.1Hz)，7.30-7.37(2H，m)，
MS(ESI)：m/z 259(M+H)-。
16D) 2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl group } B 2- [4- (trifluoromethoxy) phenyl ] phenyl]Cyclopropanecarboxamides
The procedure described in example 14D was followed using a solution of the compound from example 16C (100mg, 0.384mmol) in DMF (4ml), HBTU (175mg, 0.461mmol), triethylamine (0.16ml) and the compound from example 2D (102mg, 0.384 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1/1) to give 151mg (83% yield) of the title compound as a white solid.
1H NMR(CDCl3，270MHz)δppm 1.33-1.74(9H，m)，2.32(3H，s)，3.02(3H，s)，5.08-5.17(1H，m)，5.84-5.89(1H，m)，6.17(1H，s)，7.13-7.29(6H，m)，7.42(1H，d，J＝7.3Hz)，MS(ESI)：m/z 471(M+H)+。
Example 17
2-methyl-N- ((1R) -1- { 3-methoxy-4- [ (methylsulfonyl) amino]Phenyl } ethyl) - 2- [4- (trifluoromethoxy) phenyl]Cyclopropanecarboxamides
17A)5- ((1R) -1- { [ (R) -tert-butylsulfinyl]Amino } ethyl) -2- [ (methylsulfonyl) Amino group]Benzoic acid ethyl ester
To a mixture of methyl 5-acetyl-2- [ (methylsulfonyl) amino ] benzoate (13-2g, 49mmol, PCT International application WO2005003084), titanium (IV) ethoxide (100ml) and THF (100ml) was added (R) - (+) -2-methylpropane-2-sulfinamide (5.9g, 49mmol, Advanced asymmetry) and the mixture was stirred at 80 ℃ for 16 h. The mixture was cooled to room temperature, then to 0 ℃ and then added dropwise to a 0 ℃ solution of sodium borohydride (7.4g, 195 mmol). The mixture was stirred at 0 ℃ for 3 hours and then warmed to room temperature. The reaction was quenched with MeOH and stirred for 30 min. Water is then added to the mixture. After stirring for 10 min, the resulting suspension was filtered through a pad of celite and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to give a residue which was chromatographed on silica gel eluting with a volumetric mixture of DCM and EtOAc (1/1) to give 4.3g (23% yield) of the title compound as a pale yellow solid.
1H NMR(270MHz，CDCl3)δppm 1.24(9H，s)，1.43(3H，t，J＝6.8Hz)，1.53(3H，d，J＝6.6Hz)，3.07(3H，s)，3.39(1H，br.s )，4.41(2H，q，J＝6.8Hz)，4.55(1H，m)，7.56(1H，dd，J＝8.6，2.0Hz)，7.74(1H，d，J＝9.2Hz)，8.06(1H，d，J＝2.0Hz)，10.49(1H，br.s)。MS(ESI)：m/z 391[M+H]+，389[M-H]-。
17B)5- [ (1R) -1-aminoethyl ] -2- [ (methylsulfonyl) amino ] benzoic acid ethyl ester
To a solution of the compound from example 17A (4.3g, 11mmol) in MeOH (30ml) was added 10% hydrochloric acid-MeOH solution (30 ml). The mixture was then worked up following the procedure described in example 2D to give 3.1g (87% yield) of the title compound as a white solid.
1H NMR(270MHz，DMSO-d6)δppm 1.34(3H，t，J＝7.3Hz)，1.49(3H，d，J＝7.3Hz)，3.19(3H，s)，4.36(2H，q，J＝7.3Hz)，4.45(1H，m)，7.61(1H，d，J＝8.6Hz)，7.75(1H，dd，J＝8.6，2.0Hz)，8.09(1H，d，J＝2.0Hz)，8.35(2H，br.s)，10.14(1H，br.s)。
17C)2- [ (methylsulfonyl) amino group]-5- { (1R) -1- [ ({ 2-methyl-2- [4- (trifluoromethoxy) Phenyl radical]Cyclopropyl } carbonyl) amino]Ethyl } benzoic acid ethyl ester
The procedure described in example 14D was followed using a solution of the compound from example 16C (100mg, 0.384mmol) in DMF (4ml), HBTU (175mg, 0.461mmol), triethylamine (0.16ml) and the compound from example 17B (124mg, 0.384 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1/1) to give 175mg (86% yield) of the title compound as a colorless oil.
1H NMR(300MHz CDCl3)δppm 1.35-1.76(12H，m)，3.06(3H，s)，4.39(2H，t，J＝7.3Hz)，5.11-5.40(1H，m)，5.90-5.94(1H，m)，7.15(2H，d，J＝8.1Hz)，7.25-7.35(2H，m)，7.48-7.56(1H，m)，7.69-7.76(1H，m)，7.97-8.07(1H，m)，10.45-10.54(1H，m)。MS(ESI)：m/z 529(M+H)+。
17D) 2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl group } B 2- [4- (trifluoromethoxy) phenyl ] phenyl]Cyclopropanecarboxamides
To a mixture of lithium aluminium hydride (25mg, 0.66mmol) in THF (50ml) at 0 deg.C was added the solution of example 17C (175mg, 0.33 mmol). After stirring at 0 ℃ for 3 hours, potassium fluoride and sodium sulfate decahydrate were added. After stirring for 5 hours, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give a crude residue. The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1/4) to give 92mg (57% yield) of the title compound as a white solid.
1H NMR(CDCl3，270MHz)δppm 1.26-1.74(8H，m)，2.36-2.43(1H，m)，3.04(3H，s)，4.71-4.78(2H，m)，5.05-5.15(1H，m)，5.85-5.97(1H，m)，7.13-7.34(7H，m)，7.51(1H，d，J＝7.9Hz)，7.42-7.75(1H，m)。MS(ESI)：m/z 487(M+H)+。
Example 18
N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [4- (2, 2, 2- Trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxamides
Following a procedure analogous to that described for example 8, but using the carboxylic acid of example 6D (50.0mg, 0.23mmol) instead of the carboxylic acid of example 1, the title compound was obtained as a white solid (yield 71%).
1H NMR(DMSOd-6，270MHz)δppm 1.16-1.41(5H，m)，1.52(6H，s)，1.88-1.97(1H，m)，2.14-2.27(1H，m)，2.97-3.03(3H，m)，4.87-4.99(1H，m)，7.08-7.24(4H，m)，7.27-7.38 1H，m)，7.39-7.43(2H，m)，8.53-8.69(1H，m)，9.54(1H，s)。MS(ESI)：m/z 487(M+H)+。
Example 19
19a) N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [4- (tris) Fluoromethyl) phenyl]Cyclopropanecarboxamides (racemic)
The procedure described in example 1 was followed using 2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxylic acid (rac) (100mg, 0.434mmol) [ Journal of Organic Chemistry (1997), 62(26), 9114-. The crude residue was chromatographed on silica gel, eluting with a volumetric mixture of hexane and EtOAc (1/1), and separated from MeOH to give 20mg (10% yield) of the title compound as a white solid.
1H NMR(DMSOd-6，300MHz)δppm 1.32(3H，d，J＝7.3Hz)，1.23-1.43(2H，m)，1.99-2.05(1H，m)，2.29(3H，s)，2.28-2.39(1H，m)，2.96(3H，s)，4.85-4.96(1H，m)，7.11-7.23(3H，m)，7.36(2H，d，J＝8.1Hz)，7.63(2H，d，J＝8.1Hz)，8.56(1H，d，J＝8.1Hz)，9.02(1H，brs)。MS(ESI)：m/z 441(M+H)+。
19b) N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [4- (tris) Fluoromethyl) phenyl]Cyclopropanecarboxamides (diastereomer mixtures)
After example 19a, the filtrate was evaporated under reduced pressure to give the title compound (80mg, 42% yield) as a mixture of diastereomeric products (1: 2) as a white solid.
1H NMR(300MHz，DMSOd-6)δ1.24-1.43(5H，m)，1.99-2.05(1H，m)，2.26-2.35(4H，m)，2.94-2.96(3H，m)，4.85-4.94(1H，m)，7.09-7.23(3H，m)，7.30-7.40(2H，m)，7.57-7.64(2H，m)，8.53-8.62(1H，m)，8.99(1H，brs)。MS(ESI)：m/z 441(M+H)+。
Example 20
N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl group]Cyclopropanecarboxamides
20A) N- [4- ((1R) -1- { [ (R) -tert-butylsulfinyl]Amino } ethyl) -2- (hydroxymethyl) Phenyl radical]Methane sulfonamides
To a mixture of lithium aluminium hydride (1.6g, 43mmol) in THF (50ml) at 0 deg.C was added a solution of the compound from example 17B (4.2g, 11mmol) in THF (100 ml). After stirring at 0 ℃ for 3 hours, potassium fluoride and sodium sulfate decahydrate were added. After stirring for 5 hours, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give 3.6g (97% yield) of the title compound as a pale yellow oil.
MS(ESI)：m/z 391[M+H]+，389[M-H]-。
20B) N- [4- [ (1R) -1-aminoethyl group]-2- (hydroxymethyl) phenyl]Methane sulfonamides
To a solution of the compound from example 20A (3.6g, 10mmol) in methanol (30ml) was added 10% hydrochloric acid-MeOH solution (30ml) and the procedure described in example 2D was followed to give 2.5g (87% yield) of the title compound as a yellow oil.
1H NMR(270MHz，DMSO-d6)δppm 1.51(3H，t，J＝6.6Hz)，3.01(3H，s)，4.36(1H，m)，4.63(2H，s)，7.34(1H，d，J＝7.9Hz)，7.45(1H，dd，J＝7.9，2.0Hz)，7.58(1H，d，J＝2.0Hz)，8.56(2H，br.s)，9.13(1H，br.s)。
MS(ESI)：m/z 243[M-H]-。
20C) N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino ]Phenyl group } B 2- [4- (trifluoromethyl) phenyl ] -phenyl]Cyclopropanecarboxamides
The procedure described in example 1 was followed using a solution of 2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxylic acid (160mg, 0.695mmol) in DMF (2ml), EDC (200mg, 1.04mmol), HOBt (118mg, 0.765mmol), triethylamine (0.29ml) and the compound from example 20B (197mg, 0.695 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1/2) to give 44mg (14% yield) of the title compound as a white solid.
1H NMR(CDCl3，300MHz)δppm 1.30-1.72(5H，m)，2.43-2.72(2H，m)，2.97(3H，s)，4.66(2H，s)，5.02-5.06(1H，m)，6.22(1H，s)，7.12-7.27(5H，m)，7.41-7.60(4H，m)。MS(ESI)：m/z 457(M+H)+。
Example 21
(lS, 2S) -2-methyl-N- ((1R) -1- {4- [ (methylsulfonyl) amino]Phenyl } ethyl) - 2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
The procedure described in example 14D was followed using a solution of the carboxylic acid from example 14C (112mg, 0.459mmol) in DMF (4ml), HBTU (209mg, 0.55mmol), triethylamine (0.19ml) and N- {4- [ (1R) -1-aminoethyl ] phenyl } methanesulfonamide hydrochloride (115mg, 0.459 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1/1) to give 124mg (61% yield) of the title compound as a white solid.
1H NMR(CDCl3，300MHz)δppm 1.38-1.42(1H，m)，1.51(3H，d，J＝6.6Hz)，1.59(3H，s)，1.68-1.73(2H，m)，3.00(3H，s)，5.11-5.20(1H，m)，5.90(1H，d，J＝7.3Hz)，6.52(1H，s)，7.18(2H，d，J＝8.8Hz)，7.32(2H，d，J＝8.8Hz)，7.36(2H，d，J＝8.1Hz)，7.56(2H，d，J＝8.1Hz)。
MS(ESI)：m/z 441(M+H)+。
Example 22
(1S, 2S) -N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino]Phenyl } ethyl) - 2-methyl-2- [4- (trifluoromethyl) phenyl ]Cyclopropanecarboxamide;
22A)2- [ (methylsulfonyl) amino group]-5- { (1R) -1- [ ({ (1S, 2S) -2-methyl-2- [4- (trifluoro-1H-trifluoromethyl) Methyl) phenyl]Cyclopropyl } carbonyl) amino]Ethyl } benzoic acid ethyl ester
The procedure described in example 14D was followed using a solution of the carboxylic acid from example 14C (80mg, 0.328mmol) in DMF (3ml), HBTU (149mg, 0.394mmol), triethylamine (0.137ml) and the amine from example 17B (106mg, 0.328 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1/1) to give 154mg (92% yield) of the title compound as a white solid.
1H NMR(270MHz CDCl3)δppm 1.25-1.74(12H，m)，3.05(3H，s)，4.39(2H，t，J＝7.3Hz)，5.06-5.19(1H，m)，5.93(1H，d，J＝7.3Hz)，7.37(2H，d，J＝7.9Hz)，7.48-7.58(1H，m)，7.57(2H，d，J＝7.9Hz)，7.72(1H，d，J＝8.6Hz)，7.95-8.07(1H，m)，10.43-10.55(1H，m)，
MS(ESI)：m/z 513(M+H)+。
22B) (1S, 2S) -N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino]Phenyl group } B 2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
The procedure described in example 17D was carried out using a mixture of the compound from example 22A (154mg, 0.30mmol) and lithium aluminium hydride (23mg, 0.60mmol) in THF (3 ml). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (2/3) to give 88mg (63% yield) of the title compound as a white solid.
1H NMR(CDCl3，270MHz)δppm 1.35-1.40(1H，m)，1.49(3H，d，J＝7.3Hz)，1.58(3H，s)，1.66-1.71(1H，m)，2.44(1H，t，J＝5.6Hz)，3.04(3H，s)，4.74(2H，d，J＝5.3Hz)，5.05-5.15(1H，m)，5.96(1H，d，J＝7.3Hz)，7.19-7.21(1H，m)，7.25-7.33(2H，m)，7.35(2H，d，J＝8.6Hz)，7.51(1H，d，J＝7.9Hz)，7.56(2H，d，J＝8.6Hz)，7.44(1H，s)。MS(ESI)：m/z 471(M+H)+。
Example 23
(1S, 2S) -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- Methyl-2- [4- (trifluoromethyl) phenyl ]Cyclopropanecarboxamides
The procedure described in example 14D was followed using a solution of the carboxylic acid from example 14C (98mg, 0.402mmol) in DMF (4ml), HBTU (183mg, 0.482mmol), triethylamine (0.168ml) and the amine compound from example 8 (108mg, 0.402 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1/1) to give 157mg (85% yield) of the title compound as a white solid.
1H NMR(CDCl3，300MHz)δppm 1.40-1.44(1H，m)，1.50(3H，d，J＝6.6Hz)，1.58(3H，s)，1.68-1.73(2H，m)，3.03(3H，s)，5.10-5.19(1H，m)，5.90(1H，d，J＝6.6Hz)，6.48(1H，s)，7.10-7.19(2H，m)，7.37(2H，d，J＝8.1Hz)，7.52(1H，d，J＝8.8Hz)，7.57(2H，d，J＝8.1Hz)，MS(ESI)：m/z 459(M+H)+。
Example 24
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) - 2- {4- [ (trifluoromethyl) thio group]Phenyl cyclopropanecarboxamides
24A) 1-isopropenyl-4- [ (trifluoromethyl) thio group]Benzene and its derivatives
To a stirred suspension of 60% sodium hydride (363mg, 9.08mmol, washed with n-hexane) was added DMSO (4ml) dropwise at 0 ℃ and the mixture was stirred at 80 ℃ for 30 minutes. After cooling to 0 ℃ a solution of 0 ℃ methyltriphenylbromide * (3.24g, 9.08mmol) in DMSO (12ml) was added dropwise to the mixture and stirred at ambient temperature for 45 min. To this mixture was then added 1- [4- (trifluoromethyl) thio ] phenyl ] ethanone (1g, 4.54mmol) dropwise at ambient temperature and the mixture was stirred at ambient temperature for 1 hour. The reaction was quenched with a small amount of acetone and diluted with hexane and water. The resulting precipitate was filtered, and the organic layer was separated. After evaporation of the solvent, the residue was washed with hexane and concentrated in vacuo to give 520mg (52% yield) of the title compound as a colorless oil.
1H NMR(300MHz CDCl3)δppm 7.61(2H，d，J＝8.8Hz)，7.50(2H，d，J＝8.8Hz)，5.44(1H，s)，5.19(1H，s)，2.16(3H，s)。
24B) 2-methyl-2- {4- [ (trifluoromethyl) thio group]Phenyl } cyclopropanecarboxylic acid ethyl ester
In the same procedure as described in example 2H, to a solution of the compound from example 24A (1.23g, 5.67mmol), Co (TPP) (114mg, 0.170mmol) and 1-methyl-1H-imidazole (1.4g, 17.0mmol) in toluene (12ml) was added ethyl diazoacetate (905mg, 7.93 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (25/1) to give 1.3g (75% yield, trans) of the title compound as a violet oil.
1H NMR(270MHz CDCl3)δppm 1.30(3H，t，J＝6.9Hz)，1.41-1.52(2H，m)，1.54(3H，s)，1.97(1H，dd，J＝5.9，8.6Hz)，4.15-4.25(2H，m)，7.34(2H，d，J＝8.6Hz)，7.88(2H，d，J＝8.6Hz)。
24C) 2-methyl-2- {4- [ (trifluoromethyl) thio group]Phenyl cyclopropanecarboxylic acid
The procedure described in example 2I was carried out using the compound from example 24B (343mg, 1.12mmol) in THF (5ml), 2M aqueous sodium hydroxide (1.5ml) and MeOH (5ml) to give 320mg (quant.) of the title compound as a light yellow solid.
1H NMR(270MHz CDCl3)δppm 1.50-1.57(2H，m)，1.60(3H，s)，2.00(1H，dd，J＝6.6，7.9Hz)，7.39(2H，d，J＝8.1Hz)，7.60(2H，d，J＝7.9Hz)，
MS(ESI)：m/z 275(M+H)-。
24D) 2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl group } B 2- {4- [ (trifluoromethyl) thio ] -phenyl- ] -2]Phenyl cyclopropanecarboxamides
The procedure described in example 14D was followed using a solution of the carboxylic acid from example 24C (66mg, 0.238mmol), triethylamine (0.1ml) and HBTU (108mg, 0.286mmol) in DMF (4ml) and the compound from example 2D (63mg, 0.238 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1/1) to give 80mg (69% yield) of the title compound as a white solid.
1H NMR(300MHz CDCl3)δppm 1.35-1.80(9H，m)，2.31-2.38(3H，m)，3.01-3.15(3H，m)，5.07-5.22(1H，m)，5.82-5.99(1H，m)，6.17-6.25(1H，m)，7.18-7.47(5H，m)，7.56-7.65(2H，m)。
MS(ESI)：m/z 487(M+H)+。
Example 25
N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- Methyl-2- {4- [ (trifluoromethyl) thio group]Phenyl } cyclopropanemethyl ether amine
25A)2- [ (methylsulfonyl) amino group]-5- ((1R) -1- { [ (2-methyl-2- {4- [ (trifluoromethyl) Sulfur based radicals]Phenyl } cyclopropyl) carbonyl]Amino } ethyl) benzoic acid ethyl ester
The procedure described in example 14D was followed using a solution of the carboxylic acid from example 24C (253mg, 0.92mmol), triethylamine (0.38ml) and HBTU (417mg, 1.10mmol) in DMF (10ml) and the amine from example 17B (310mg, 0.96 mmol). The crude residue was chromatographed on a silica gel column, eluting with a volumetric mixture of hexane and EtOAc (1/1) to give 500mg (quant.) of the title compound as a pale purple solid.
1H NMR(300MHz CDCl3)δppm 1.36-1.68(10H，m)，1.70-1.80(2H，m)，3.05(3H，s)，4.39(2H，t，J＝7.3Hz)，5.07-5.32(1H，m)，5.96-6.05(1H，m)，7.25-7.35(2H，m)，7.48-7.70(3H，m)，7.71(1H，d，J＝9.5Hz)，7.98-8.05(1H，m)，10.44-10.55(1H，m)，
MS(ESI)：m/z 545(M+H)+。
25B) N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2-methyl 2- {4- [ (trifluoromethyl) thio ] -phenyl]Phenyl cyclopropanecarboxamides
The compound from example 25A (250mg, 0.459mmol) and LiAlH were used4(35mg, 0.918mmol) in THF (2.5ml) and diethyl ether (10ml) was addedThe procedure described in example 17C was followed. The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1/2) to give 145mg (63% yield) of the title compound as a white solid.
1H NMR(300MHz CDCl3)δppm 1.32-1.82(8H，m)，2.50-2.64(1H，m)，3.03(3H，s)，4.73(2H，s)，5.05-5.18(1H，m)，5.96-6.05(1H，m)，7.10-7.36(4H，m)，7.48-7.52(1H，m)，7.55-7.64(2H，m)，7.78(1H，d，J＝5.1Hz)。MS(ESI)：m/z 503(M+H)+。
Example 26
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) - 2- {4- [ (trifluoromethyl) sulfonyl group]Phenyl cyclopropanecarboxamides
26A) 2-methyl-2- {4- [ (trifluoromethyl) sulfonyl group]Phenyl } cyclopropanecarboxylic acid ethyl ester
To a solution of the compound (304mg, 1mmol) prepared in example 24B, sodium metaperiodate (642mg, 3mmol), tetrachloromethane (2ml) and acetonitrile (2ml) in water (4ml) was added ruthenium trichloride hydrate (0.1mg), and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with 1N-HCl aqueous solution and extracted all with EtOAc. Then evaporated and purified to give the title compound (347mg, quant., trans) as a colorless oil.
1H NMR(270MHz CDCl3)δ1.31(3H，t，J＝6.9Hz)，1.47-1.62(2H，m)，1.59(3H，s)，2.00-2.04(1H，m)，4.18-4.25(2H，m)，7.57(2H，d，J＝8.6Hz)，7.97(2H，d，J＝8.6Hz)。
26B) 2-methyl-2- {4- [ (trifluoromethyl) sulfonyl group]Phenyl cyclopropanecarboxylic acid
The procedure described in example 10D was carried out using the compound from example 26A (336mg, 1mmol) in THF (5ml), 2M aqueous sodium hydroxide (1ml) and MeOH (5ml) to give the title compound (62mg, 85% yield) as a white solid.
1H NMR(270MHz CDCl3)δ1.57-1.65(2H，m)，1.65(3H，s)，2.03-2.09(1H，m)，7.60(2H，d，J＝8.6Hz)，7.99(2H，d，J＝8.6Hz)MS(ESI)m/z 307(M-H)-。
26C) 2-methyl-N- ((lR) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl group } B 2- {4- [ (trifluoromethyl) sulfonyl ] -2- {4 [ ]]Phenyl cyclopropanecarboxamides
In the same procedure as described in example 14D, to a solution of the compound from example 26B (38mg, 0.125mmol) in DMF (2ml) were added the compound from example 2D (33mg, 0.125mmol), triethylamine (38mg, 0.375mmol) and HBTU (57mg, 0.15 mmol). The reaction was then quenched with water, extracted all with EtOAc/hexanes (3: 1), and dried over sodium sulfate. Then filtered, evaporated and purified by silica gel column chromatography eluting with hexane/EtOAc (1: 1) to give the title compound (64mg, 99% yield, white solid) as a mixture of diastereomeric products (1: 1).
1H NMR(270MHz CDCl3)δ1.30-1.85(9H，m)，2.32(3H，s)，3.02-3.03(3H，m)，5.10-5.16(1H，m)，5.88-5.93(1H，m)，6.15(1H，brs)，7.17-7.22(2H，m)，7.42(1H，d，J＝8.6Hz)，7.49-7.54(2H，m)，7.93-7.99(2H，m)。
MS(ESI)：m/z 519(M+H)+。
Example 27
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) - 2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxamides
In the same procedure as described in example 1, to a solution of the compound from example 13C (29mg, 0.10mmol) in DMF (0.5ml) were added EDC (29mg, 0.15mmol), HOBt (17mg, 0.11mmol), triethylamine (0.042ml) and the compound from example 2D (30mg, 0.11 mmol). The reaction was then quenched with 1N-HCI aqueous solution, extracted all with EtOAc/hexanes (3: 1), and dried over sodium sulfate. Then filtered, evaporated and purified by silica gel column chromatography eluting with hexane/EtOAc (1: 2) to give the title compound (14mg, 29% yield, white solid) as a mixture of diastereomeric products (1: 1).
1H NMR(300MHz，CDCl3)δ1.20-1.89(15H，m)，2.31(3H，s)，3.00(3H，s)，5.09-5.20(1H，m)，5.88-5.97(1H，m)，6.31(1H，brs)，7.10-7.30(4H，m)，7.39-7.47(3H，m)。MS(ESI)：m/z 497(M+H)+。
Example 28
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- {4- [ (trifluoromethyl) oxy group]Phenyl } cyclopropanecarboxamide (Single isomer)
The diastereomer mixture of the compound from example 16D was separated by means of Daicel Chiralpal AS-H (20 × 250mm), eluting with n-hexane/isopropanol/diethylamine ═ 80/20/0.1, the column temperature was 40 ℃. The title compound was obtained as an earlier fraction (single isomer; retention time 10 min; white solid).
1H NMR(270MHz，CDCl3)δ1.33-1.74(9H，m)，2.32(3H，s)，3.01(3H，s)，5.08-5.17(1H，m)，5.91(1H，d，J＝7.3Hz)，6.33(1H，s)，7.13-7.29(6H，m)，7.42(1H，d，J＝8.1Hz)。MS(ESI)：m/z 471(M+H)+。
Example 29
N- ((1R) -1- { 3-Ethyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) -2-methyl-2- {4- [ (trifluoromethyl) oxy group]Phenyl } cyclopropanecarboxamide (diastereomer mixture)
The procedure described in example 14D was followed using a solution of the compound from example 16C (321mg, 1.15mmol) in DMF (5ml), HBTU (523mg, 1.38mmol), triethylamine (0.48ml) and the compound from example 32C (300mg, 1.15 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1: 1) to give the title compound (490mg, 89% yield, white solid) as a mixture of diastereomeric products (1: 1).
1H NMR(300MHz，CDCl3)δ1.25(3H，t，J＝7.7Hz)，1.34-1.73(9H，m)，2.66(2H，q，J＝7.7Hz)，3.02-3.03(3H，m)，5.10-5.20(1H，m)，5.83-5.90(1H，m)，6.18(1H，s)，7.14-7.47(7H，m)。
MS(ESI)：m/z 485(M+H)+。
Example 30
2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]-N- ((1R) -1- { 3-methyl- 4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide (single isomer)
30A)2- (2, 6-difluoro-4-methoxyphenyl) -1, 1, 1-trifluoropropan-2-ol
To a solution of 1, 3-difluoro-5-methoxybenzene (7g, 48.6mmol) in THF (100ml) at-78 deg.C was added dropwise a 1.6M solution of n-butyllithium (30ml, 48.6mmol) in hexane over 30 minutes, and the mixture was stirred at-78 deg.C for 2 hours. 1, 1, 1-trifluoroacetone (6.5g, 58.3mmol) is then added at-78 ℃ and the mixture is stirred for 2 hours at-78 ℃. After stirring at room temperature for another 1 hour, the reaction was quenched with water. All extracted with EtOAc, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel column chromatography eluting with hexane/EtOAc (10: 1) afforded the title compound (9.7g, 78% yield) as a colorless oil.
1H NMR(270MHz，CDCl3)δ1.83-1.85(3H，m)，3.94(3H，s)，6.17(1H，s)，6.49-6.60(2H，m)。
30B)2- (1-chloro-2, 2, 2-trifluoro-1-methylethyl) -1, 3-difluoro-5-methoxybenzene
A solution of the compound from example 30A (8.7g, 34.1mmol) and pyridine (26mg, 0.34mmol) in thionyl chloride (25ml) was stirred at 70 ℃ for 3 h. The reaction was then concentrated in vacuo and quenched with water. All extracted with hexane and the extracts dried over sodium sulfate. After filtration and evaporation, the title compound (8.84g, 94% yield) was obtained as a colorless oil.
1H NMR(270MHz，CDCl3)δ2.24-2.29(3H，m)，3.81(3H，s)，6.44-6.54(2H，m)。
30C)1, 3-difluoro-5-methoxy-2- (2, 2, 2-trifluoro-1, 1-dimethylethyl) benzene
To a solution of the compound from example 30B (8.84g, 32.2mmol) in cyclohexane (100ml) was added a 1.0M solution of trimethylaluminum (129ml, 129mmol) in hexane at room temperature and the mixture was stirred at reflux for 4 h. The reaction was then quenched with 2N-HCl aqueous solution and extracted all with hexane. The extracts were dried over sodium sulfate, filtered, and concentrated to give the title compound (7.93g, 97% yield) as a colorless oil.
1H NMR(300MHz，CDCl3)δ1.71(6H，s)，3.78(3H，s)，6.39-6.49(2H，m)。
30D)3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenol
A mixture of the compound from example 30C (7.93g, 31.2mmol) and 1M boron tribromide (150ml, 150mmol) in DCM was stirred at room temperature for 16 h. The reaction was then carefully quenched with water and extracted all with EtOAc. The extract was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography eluting with hexane/EtOAc (10: 1) afforded the title compound (7.79g, quant.) as a brown solid.
1H NMR(270MHz，CDCl3)δ1.71(6H，s)，5.27(1H，brs)，6.36-6.50(2H，m)。
30E)3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyltrifluoromethanesulfonate ester
The procedure described in example 2G was followed using a solution of the compound from example 30D (456mg, 1.9mmol) in pyridine (5ml) and DCM (10ml), trifluoromethanesulfonic anhydride (643mg, 2.28mmol) and 4- (dimethylamino) pyridine (2mg, 0.02 mmol). The crude residue was chromatographed on silica gel eluting with a volumetric mixture of hexane and ethyl acetate (9: 1) to give the title compound (440mg, 62% yield) as a colorless oil.
1H NMR(300MHz，CDCl3)δ1.75-1.77(6H，m)，6.86-6.95(2H，m)
30F) 5-vinyl-1.3-Difluoro-2- (2, 2, 2-trifluoro-1, 1-dimethylethyl) benzene
The procedure described in example 2G was followed using a solution of the compound from example 30E (440mg, 1.18mmol) in DMF (5ml), vinyltributylstannane (450mg, 1.42mmol), lithium chloride (500mg, 11.8mmol) and bis (triphenylphosphine) palladium chloride (41mg, 0.059 mmol). The crude residue was chromatographed on silica gel eluting with hexane to give the title compound as a crude product, including vinyltributylstannane (crude 829mg) as a colorless oil.
1H NMR(270MHz，CDCl3)δ5.66(1H，d，J＝10.6Hz)，6.05(1H，d，J＝17.8Hz)，6.86(1H，dd，J＝10.6，17.8Hz)，7.14-7.22(2H，m)。
30G)2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxylic acid Ethyl ester
The procedure described in example 2H was followed using a solution of the crude compound from example 30F (829mg) in toluene (3ml), Co (TPP) (24mg, 0.035mmol), 1-methyl-1H-imidazole (484mg, 5.9mmol) and ethyl diazoacetate (262mg, 2.6 mmol). The crude residue was chromatographed on silica gel eluting gradually from hexane to hexane/ethyl acetate (10: 1) to give the crude title compound (trans), including vinyltributylstannane, as a black oil.
1H NMR(270MHz，CDCl3)δ0.88-1.93(12H，m)，2.40-2.47(1H，m)，4.14-4.20(2H，m)，6.57-6.66(2H，m)。
30H)2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxylic acid
The procedure described in example 10D was carried out using a solution of the crude compound from example 30G in THF (5ml), 2M aqueous sodium hydroxide (2ml) and MeOH (5ml) to give the title compound (198mg, 54% yield, 3 steps) as a white solid.
MS(ESI)m/z 307(M-H)-。
30I)2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) benzene Base of]-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) cyclopropanecarboxamide (Single isomer)
The procedure described in example 14D was followed using a solution of the compound from example 30H (60mg, 0.195mmol) in DMF (2ml), HBTU (89mg, 0.234mmol), triethylamine (0.082ml) and the compound from example 2D (52mg, 0.195 mmol). The crude residue was chromatographed on a silica gel column eluting with a volume mixture of hexane and EtOAc (1: 1), the diastereomers were separated by HPLC (XTerra MS C18, 5um, 30X 50mm), eluting with acetonitrile/0.05% aqueous formic acid (32: 68 to 68: 32, the latter fractions being the title compound) to give the title compound (16mg, 16% yield) as a white solid.
1H NMR(300MHz，CDCl3)δ1.15-1.24(1H，m)，1.47(3H，d，J＝6.6Hz)，1.57-1.70(2H，m)，1.70-1.75(6H，m)，2.32(3H，s)，2.39-2.46(1H，m)，3.02(3H，s)，5.03-5.12(1H，m)，5.90(1H，d，J＝7.3Hz)，6.21(1H，s)，6.54-6.62(2H，m)，7.15-7.20(2H，m)，7.41(1H，d，J＝8.8Hz)。
MS(ESI)：m/z 519(M+H)+。
Example 31
(1S, 2S) -2-methyl-N- ((1R) -1- {4- [ (methylsulfonyl) amino]Phenyl } propyl) -2- [4- (trifluoromethyl) phenyl group]Cyclopropanecarboxamides
31A) N- [4- ((1R) -1- { [ (R) -tert-butylsulfinyl]Amino } propyl) phenyl]Methane sulfonic acid Amides of carboxylic acids
To a solution of titanium (IV) ethoxide (2.0ml) and N- (4-propionylphenyl) methanesulfonamide (280mg, 1.2mmol, Bioorganic & Medicinal Chemistry Letters, 2004, 14(7), 1751-propan-1755) in THF (5.0ml) was added (R) - (+) -2-methyl-2-propanesulfinamide (149mg, 1.2mmol), and the mixture was stirred at 70 ℃ for 16 hours. According to TLC determination, after completion, the mixture was cooled to room temperature and then to 0 ℃ and the reaction mixture was added dropwise to a suspension of sodium borohydride (185mg, 4.9mmol) in THF (12ml) at 0 ℃. The procedure described in example 2C was followed to give the title compound (240mg, 72%) as a yellow oil.
MS(ESI)m/z 333(M+H)+。
31B) N- {4- [ (1R) -1-aminopropyl]Phenyl } methanesulfonamide hydrochloride
To a solution of the compound from example 31A (280mg, 1.60mmol) in MeOH (5.0ml) were added HCl-MeOH (2.0M, 5.0ml) and 1, 4-dioxane (5.0 ml). The same procedure as described in example 2D was performed to give the title compound (180mg, 89%) as a white solid.
MS(ESI)m/z 227(M-H)-。
31C) (1S, 2S) -2-methyl-N- ((1R) -1- {4- [ (methylsulfonyl) amino]Phenyl } propane 2- [4- (trifluoromethyl) phenyl ] -phenyl ]Cyclopropanecarboxamides
To a solution of the compound from example 14C (40mg, 0.15mmol) in DMF (2.0ml) were added HBTU (68mg, 0.18mmol), triethylamine (0.1ml) and the compound from example 31B (40mg, 0.15mmol), and the mixture was stirred at room temperature for 16 h. The same procedure as described in example 14D was performed to give the title compound (40mg, 22% yield) as a white solid.
1H NMR(300MHz，DMSO-d6)δ0.84(3H，t，J＝7.3Hz)，1.32(2H，d，J＝7.3Hz)，1.43(3H，s)，1.60-1.70(2H，m)，2.01(1H，t，J＝7.3Hz)，2.95(3H，s)，4.73(1H，q，J＝7.3Hz)，7.14(2H，d，J＝8.1Hz)，7.26(2H，d，J＝8.1Hz)，7.54(2H，d，J＝8.1Hz)，7.69(2H，d，J＝8.1Hz)，8.55(1H，d，J＝8.8Hz)，9.68(1H，brs)。
MS(ES))m/z 513(M+H)+，511(M-H)-。
Example 32
(1S, 2S) -N- ((1R) -1- { 3-Ethyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) - 2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
32A) N- (4-acetyl-2-ethylphenyl) methanesulfonamide
Methanesulfonyl chloride (7.74ml, 11.4g, 105mmol) was added dropwise over 10 minutes to a solution of 2-amino-1-ethylbenzene (from TCI, 12.1g, 100mmol) in pyridine (8.5ml) and DCM (20ml) at 0 deg.C. The reaction mixture was stirred at room temperature for 1 hour. After cooling to 0 deg.C, aluminum trichloride (33.3g, 250mmol) was carefully added to the reaction mixture. Acetyl chloride (11ml, 12g, 150mmol) was then added dropwise over 15 minutes. The reaction mixture was diluted with toluene (50ml) and poured into 2M aqueous HCl (100ml) and stirred at 0 ℃. The precipitate was filtered, washed with water and dried in vacuo to give the title compound (18g, 75%) as a yellow solid.
1H NMR(300MHz，DMSO-d6)δ1.17(3H，t，J＝7.3Hz)，2.55(3H，s)，2.75(2H，q，J＝7.3Hz)，3.09(3H，s)，7.46(1H，d，J＝8.1Hz)，7.82(2H，m)，9.36(1H，s)。MS(ESI)m/z 243(M+H)+，241(M-H)-。
32B) N- [4- ((1R) -1- { [ (R) -tert-butylsulfinyl]Amino } ethyl) -2-ethylphenyl] Methane sulfonamides
To a solution of titanium (IV) ethoxide (20ml) and the compound of example 32A (2.4g, 10mmol) in THF (20ml) was added (R) - (+) -2-methyl-2-propanesulfinamide (1.2g, 10mmol) and the mixture was stirred at 80 ℃ for 16 h. Upon completion, the mixture was cooled to room temperature and then to 0 ℃ according to LC-MS assay, and the reaction mixture was added dropwise to a suspension of sodium borohydride (1.5g, 24mmol) in THF (20ml) at 0 ℃. The same procedure as described in example 2C was carried out to give the title compound (1.35g, 48%) as a yellow oil.
MS(ESI)m/z 347(M+H)+，345(M-H)-。
32C) N- {4- [ (1R) -1-aminoethyl]-2-ethylphenyl } methanesulfonamide hydrochloride
To a solution of the compound from example 32B (1.65g, 4.76mmol) in MeOH (30ml) was added HCl-MeOH (2.0M, 30 ml). The same procedure as described in example 2D was carried out to give the title compound (1.2g, 90%) as a white solid. MS (ESI) M/z 241(M-H)-。
32D) (1S, 2S) -N- ((1R) -1- { 3-Ethyl-4- [ (methylsulfonyl) amino group]Phenyl group } B 2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 14C (50mg, 0.21mmol) in DMF (1.0ml) were added HBTU (93mg, 0.25mmol), triethylamine (0.1ml) and the compound from example 32C (57mg, 0.21mmol), and the mixture was stirred at room temperature for 16 h. The same procedure as described in example 14D was performed to give the title compound (67mg, 70% yield) as a white solid.
1H NMR(300MHz，DMSO-d6)δ1.15(3H，t，J＝7.3Hz)，1.30-1.35(5H，m)，1.45(3H，s)，2.01(1H，t，J＝7.3Hz)，2.69(2H，q，J＝7.3Hz)，2.96(3H，s)，4.95(1H，m)，7.14(1H，d，J＝8.1Hz)，7.20-7.21(2H，m)，7.54(2H，d，J＝8.1Hz)，7.68(2H，d，J＝8.1Hz)，8.63(1H，d，J＝8.1Hz)，9.04(1H，brs)。
MS(ESI)m/z 467(M+H)+，469(M-H)-。
Example 33
N- ((1R) -1- { 3-Ethyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
33A) Trans-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxylic acid
The racemic title compound (4.0g) [ Journal of Organic Chemistry, vol.62(No.26)9114-9122(1997) ] (column size: 2X 25cm, mobile phase: hexane/2-propanol/TFA 97/3/0.1, column temperature: 40 ℃, flow rate: 20ml/min, detection: 230nm, run time: 13.5 min, retention time: 8 min and 10 min) was isolated using DAICEL CHIRALCEL OJ-H. The latter fraction was collected as a white solid (1.81 g).
[α]D246.4(c is 0.46, methanol, pool temperature is 21.0 ℃)
33B) N- ((1R) -1- { 3-Ethyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) -2- [4- (tris) Fluoromethyl) phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 33A (50mg, 0.22mmol) in DMF (1.0ml) were added HBTU (99mg, 0.26mmol), triethylamine (0.1ml) and the amine compound from example 32C (60mg, 0.22mmol), and the mixture was stirred at room temperature for 16 hours. The same procedure as in example 14D was carried out to give the title compound (69mg, 70% yield) as a white solid.
1H NMR(300MHz，DMSO-d6)δ1.15(3H，t，J＝7.3Hz)，1.24-1.41(2H，m)，1.33(2H，d，J＝7.3Hz)，1.99-2.05(1H，m)，2.32-2.39(1H，m)，2.68(2H，q，J＝7.3Hz)，2.95(3H，s)，4.91(1H，m)，7.11(1H，m)，7.18-7.23(2H，m)，7.37(2H，d，J＝8.1Hz)，7.63(2H，d，J＝8.1Hz)，8.60(1H，d，J＝7.3Hz)。
MS(ESI)m/z 455(M+H)+，453(M-H)-。
Example 34
(1S, 2S) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ]Phenyl } - Propyl) -2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
34A) N- (2-methyl-4-propionylphenyl) methanesulfonamide
To a solution of 2-methylaniline (2.2g, 20mmol, ex TCI) in pyridine (1.7ml.1.7g, 21.4mmol) and DCM (85ml) was added dropwise methanesulfonyl chloride (1.6ml, 2.3g, 20mmol) at 0 ℃ over a period of 10 minutes. The reaction mixture was stirred at room temperature for 1 hour. After cooling to 0 deg.C, aluminum trichloride (6.8g, 51mmol) was carefully added to the reaction mixture. Acetyl chloride (1.9g, 20mmol) was then added dropwise over 15 minutes. The reaction mixture was diluted with toluene (25ml), poured into 2M aqueous HCl (500ml) and stirred at 0 ℃. The precipitate was filtered, washed with water and dried in vacuo to give the title compound (2.1g, 43%) as a yellow solid.
MS(ESI)m/z 240(M+H)+，242(M-H)-。
34B) N- [4- ((1R) -1- { [ (R) -tert-butylsulfinyl]Amino } propyl) -2-methylphenyl] Methane sulfonamides
To a solution of titanium (IV) ethoxide (20ml) and the compound of example 34A (1.5g, 6.2mmol) in THF (20ml) was added (R) - (+) -2-methyl-2-propane sulfinamide (753mg, 6.2mmol), and the mixture was stirred at 80 ℃ for 16 h. Upon completion, the mixture was cooled to room temperature and then to 0 ℃ according to LC-MS assay, and then added dropwise to a suspension of sodium borohydride (941mg, 25mmol) in THF (20ml) at 0 ℃. The same procedure as described in example 2C was carried out to give the title compound (1.13g, 53%) as a yellow oil.
1H NMR(300MHz，DMSO-d6)δ0.81(3H，t，J＝7.3Hz)，1.23(9H，s)，1.73-1-78(1H，m)，1.97-2.05(1H，m)，2.32(3H，s)，3.03(3H，d，J＝3.0Hz)，3.35(1H，m)，4.20(1H，m)，6.36(1H，brs)，7.17(2H，m)，7.43(1H，dd，J＝3.0，8.8Hz)。MS(ESI)m/z 347(M+H)+，345(M-H)-。
34C) N- {4- [ (1R) -1-aminopropyl]-2-methylphenyl } methanesulfonamide
To a solution of the compound from example 34B (1.13g, 3.3mmol) in MeOH (20ml) was added HCl-MeOH (2.0M, 20 ml). The same procedure as described in example 2D was performed to give the title compound (610mg, 67%) as a white solid.
1H NMR(300MHz，DMSO-d6)δ0.76(3H，t，J＝7.3Hz)，1-72-1.96(2H，m)，2.31(3H，s)，2.99(3H，s)，4.06(1H，m)，7.28-7.35(3H，m)，8.53(3H，brs)。
MS(ESI)m/z 242(M-H)-。
34D) (1S, 2S) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl radical } Propyl) -2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 14C (55mg, 0.23mmol) in DMF (2.0ml) were added HBTU (102mg, 0.27mmol), triethylamine (0.1ml) and the compound from example 34C (63mg, 0.23mmol), and the mixture was stirred at room temperature for 16 h. The same procedure as described in example 14D was carried out to give the title compound (70mg, 60%) as a white solid.
1H NMR(300MHz，DMSO-d6)δ0.85(3H，t，J＝6.6Hz)，1.32(2H，d，J＝6.6Hz)，1.59-1.70(2H，m)，2.02(1H，t，J＝6.6Hz)，2.28(3H，s)，2.94(3H，s)，4.72(1H，m)，7.10-7.22(3H，m)，7.54(2H，d，J＝8.1Hz)，7.69(2H，d，J＝8.1Hz)，8.55(1H，d，J＝8.8Hz)，9.05(1H，brs)。MS(ESI)m/z 469(M+H)+，467(M-H)-。
Example 35
N- ((1R) -1- { 6-ethyl-5- [ (methylsulfonyl) amino]Pyridin-2-yl } ethyl) -2-methyl- 2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxamides
35A) 6-chloro-2-ethylpyridin-3-ylamine
To a solution of 3-amino-2, 6-dichloropyridine (8.1g, 50mmol, ex TCI) in 1, 4-dioxane (248ml) was added tetrakis (triphenylphosphine) palladium (0) (920mg, 0.80mmol) and triethylaluminium (52mmol, 0.94M in hexane) at room temperature and the mixture was stirred at 100 ℃ for 3 h. After cooling, the mixture was quenched with 2M aqueous HCl and the aqueous and organic phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography on silica eluting with hexane/EtOAc (2: 1) to give the title compound (2.73g, 35%).
1H NMR(300MHz，DMSO-d6)δ1.13(3H，t，J＝7.3Hz)，2.55(2H，q，J＝7.3Hz)，5.24(2H，brs.)，6.97(2H，s)。MS(ESI)m/z 157(M+H)+。
35B) N- (6-chloro-2-ethylpyridin-3-yl) methanesulfonamide
To a solution of the compound from example 35A (4.76g, 30.4mmol) in DCM (122ml) was added pyridine (2.88g, 36.5mmol) and methanesulfonyl chloride (3.83g, 33.4mmol) at room temperature. After 16 h additional methanesulfonyl chloride (0.37g, 3.2mmol) was added and the reaction mixture was stirred for 5 h. Additional methanesulfonyl chloride (0.37g, 3.2mmol) was added. After 95 hours, the mixture was washed with brine, and then the organic phase was separated, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluting with hexane/EtOAc (1: 1) to give the title compound (5.55g, 78%) as a pale yellow solid.
1H NMR(300MHz，DMSO-d6)δ1.18(3H，t，J＝7.3Hz)，2.83(2H，q，J＝7.3Hz)，3.05(3H，s)，7.36(1H，d，J＝8.8Hz)，7.72(1H，d，J＝8.8Hz)，9.45(1H，s)。MS(ESI)m/z 235(M+H)+，233(M-H)-。
35C) N- (6-cyano-2-ethylpyridin-3-yl) methanesulfonamide
A test tube suitable for microwave use was charged with a solution of the compound from example 35B (3.54g, 15mmol), zinc cyanide (2.19g, 19mmol) and tetrakis (triphenylphosphine) palladium (0) (1.73g, 1.5mmol) in N, N' -dimethylformamide (15 ml). The same procedure as described in example 9B was carried out to give the title compound (3.18g, quant) as a pale yellow solid.
MS(ESI)m/z 226(M+H)+，224(M-H)-.
35D) N- (6-acetyl-2-ethylpyridin-3-yl) methanesulfonamide
To a solution of the compound from example 35C (1.1g, 4.9mmol) in THF (20ml) was added dropwise a solution of methylmagnesium bromide (18ml, 14.7mmol) in THF at 0 deg.C with stirring. The same procedure as described in example 9C was performed to give the title compound (720mg, 61% yield) as a brown solid.
1H NMR(300MHz，DMSO-d6)δ1.41(2H，t，J＝7.3Hz)，2.70(3H，s)，2.83(2H，q，J＝7.3Hz)，3.11(3H，s)，6.57(1H，brs)，7.93(2H，d，J＝2.0Hz)。MS(ESI)m/z 243(M+H)+，241(M-H)-。
35E) N- [6- ((1R) -1- { [ (R) -tert-butylsulfinyl]Amino } ethyl) -2-ethylpyridine -3-yl]Methane sulfonamides
To a solution of titanium (IV) ethoxide (6.0ml) and the compound from example 35D (330mg, 1.3mmol) in THF (6.0ml) was added (R) - (+) -2-methyl-2-propanesulfinamide (157mg, 1.3mmol) under a nitrogen atmosphere and the mixture was stirred at 80 ℃ for 16 h. According to TLC determination, after completion, the mixture was cooled to room temperature and then to 0 ℃ and then added dropwise to a suspension of sodium borohydride (197mg, 5.2mmol) in THF (12ml) at 0 ℃. The same procedure as described in example 2C was carried out to give the title compound (280mg, 62%) as a yellow oil.
1H-NMR(CDCl3)δ1.28(9H，s)，1.30(3H，s，J＝7.3Hz)，1.48(3H，d，J＝6.6Hz)，2.79(2H，q，J＝7.3Hz)，3.00(3H，s)，4.58(1H，m)，5.21(1H，m)，6.73(1H，m)，7.13(1H，d，J＝8.6Hz)，7.72(1H，d，J＝7.9Hz)。
MS(ESI)m/z 348(M+H)+，346(M-H)-。
35F) N- {6- [ (1R) -1-aminoethyl]-2-ethylpyridin-3-yl } methanesulfonamide hydrochloride
To a solution of the compound from example 35E (280mg, 0.81mmol) in MeOH (5.0ml) was added HCl-MeOH (2.0M, 5.0 ml). The same procedure as described in example 2D was performed to give the title compound (170mg, 54%) as a yellow solid.
MS(ESI)m/z 244(M+H)+。
35G) N- ((1R) -1- { 6-Ethyl-5- [ (methylsulfonyl) amino)Base of]Pyridin-2-yl } ethyl) -2- Methyl-2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 13D (82mg, 0.29mmol) in DMF (2.0ml) were added HBTU (133mg, 0.35mmol), triethylamine (0.12ml, 0.87mmol) and the compound from example 35F (70mg, 0.29mmol), and the mixture was stirred at room temperature for 16 h. The same procedure as described in example 14D was performed to give the title compound (33mg, 22% yield) as a white solid.
1H-NMR(CDCl3)δ1.33(3H，s，J＝7.9Hz)，1.47(3H，d，J＝6.6Hz)，1.51(2H，m)1.55(3H，s)，1.57(6H，s)，1.79(1H，m)，2.85(2H，q，J＝7.9Hz)，3.04(3H，s)，5.18(1H，m)，6.97(1H，m)，7.14(1H，d，J＝8.6Hz)，7.30(1H，d，J＝8.6Hz)，7.46(1H，d，J＝8.6Hz)，7.76(1H，d，J＝8.6Hz)。
MS(ESI)m/z 429(M+H)+512，(M-H)-510
Example 36
2- [ 4-tert-butyl-3-fluorophenyl)]-N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) cyclopropanecarboxamide
To a solution of the compound from example 20B (40mg, 0.14mmol) in DMF (2ml) was added the compound from example 2I (33mg, 0.14mmol), EDC (40mg) and DMAP (0.5mg, 0.004 mmol). The solution was stirred at room temperature for 16 h, then partitioned between EtOAc and water. The same procedure as described in example 1 was carried out to give the title compound (32mg, 49%) as a white solid.
1H NMR(270MHz，DMSO-d6)δppm 1.08-1.14(1H，m)，1.34(9H，s)，1.41(3H，d，J＝6.6Hz)，1.48-1.52(1H，m)，1.59-1.65(1H，m)，1.88(1H，brs)，2.36-2.45(1H，m)，2.99(3H，s)，4.66(2H，s)，4.95-5.04(1H，m)，6.43(1H，d，J＝8.1Hz)，6.68(1H，dd，J＝2.2，13.2Hz)，6.81(1H，dd，J＝2.2，8.1Hz)，7.15-7.27(3H，m)，7.46(1H，d，J＝8.1Hz)，7.98(1H，s)。MS(ESI)m/z 463[M+H]+.461[M-H]-。
Example 37
2-methyl-N- ((1R) -1- { 4-methyl-5- [ (methylsulfonyl) amino]Pyridin-2-yl } ethyl) - 2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 9E and the compound from example 13D (124mg, 0.434mmol) in DMC (4.3ml) was added triethylamine (0.18ml, 132mg, 1.30mmol) and HBTU (198mg, 0.521mmol) at room temperature. After 2 hours, the mixture was quenched with saturated aqueous sodium bicarbonate and washed with brine. The aqueous layer was separated, dried over magnesium sulfate and concentrated. The same procedure as described in example 14D was performed to give the title compound (97.7mg, 45%) as a white solid.
1H NMR(270MHz，CDCl3)δ1.36(1H，dd，J＝4.6，7.9Hz)，1.47(3H，d，J＝6.6Hz)，1.50-1.64(10H，m)，1.80(1H，dd，J＝5.9，7.9Hz)，2.38(3H，s)，3.08(3H，s)，5.08-5.24(1H，m)，6.33(1H，s)，6.87(1H，d，J＝7.3Hz)，7.17(1H，s)，7.27(2H，d，J＝8.6Hz)，7.45(2H，d，J＝8.6Hz)，8.51(1H，s)。
MS(ESI)m/z 498(M+H)+，496(M-H)-。
Example 38
2- [ 4-tert-butyl-3, 5-difluorophenyl ]-N- ((1R) -1- {4- [ (methylsulfonyl) amino]- Phenyl } ethyl) cyclopropanecarboxamide
38A) 4-tert-butyl-3, 5-difluorophenol
A mixture of 3, 5-difluorophenol (TCI, 14g, 107mmol), tert-butyl methyl ether (12.8ml, 108mmol) and zirconium (IV) chloride (25g, 107mmol) was stirred at 55 ℃ for 12 h, followed by the addition of tert-butyl methyl ether (6.4ml, 54 mmol). An additional injection of t-butyl methyl ether (6.4ml, 54mmol) was repeated 8 times at 24 hour intervals, and the reaction was then quenched with saturated aqueous ammonium chloride and 2M aqueous HCl. All were extracted with DCM, washed with brine and dried over magnesium sulfate. Evaporation of the organic layer gave a crude residue which was purified by silica gel column chromatography eluting gradually from hexane only to hexane/EtOAc (10: 1) to give the title compound (10.8g, 54%) as a white solid.
1H NMR(270MHz，CDCl3)δ1.42(9H，t，J＝2.3Hz)，5.16(1H，brs)，6.26-6.37(2H，m)。
MS(ESI)m/z 185(M-H)-。
38B) 4-tert-butyl-3, 5-difluorophenyl trifluoromethanesulfonate
To a solution of the compound from example 38A (5.0g, 26.9mmol) in pyridine (30ml) and DCM (44ml) were added trifluoromethanesulfonic anhydride (11.4g, 54mmol) and 4-dimethylaminopyridine (55mg, 0.4mmol) and the mixture was stirred at 0 ℃ for 2 h. After quenching with water, all were extracted with hexane, evaporated and purified by silica gel column chromatography eluting with hexane/EtOAc (10: 1) to give the title compound (6.6g, 77%) as a colorless oil.
1H NMR(CDCl3)δ2.57(300MHz，9H，t，J＝2.6Hz)，6.76-6.86(2H，m)
38C) 2-tert-butyl-5-vinyl-1, 3-difluorobenzene
To a solution of the compound from example 38B (6.5g, 20.4mmol) in DMF (230ml) were added vinyltributylstannane (13.0g, 40.8mmol), lithium chloride (18.7g, 204mmol) and bis (triphenylphosphine) palladium chloride (716mg, 1.02mmol), and the mixture was stirred at 80 ℃ for 2 h. The reaction was quenched with water and extracted all with hexane. Then evaporated and purified by silica gel column chromatography eluting with hexane to give the title compound (4.0g, 99%) as a colorless oil.
1H NMR(270MHz，CDCl3)δ1.45-1.46(9H，m)，5.30(1H，d，J＝10.6Hz)，5.71(1H，d，J＝17.8Hz)，6.56(1H，dd，J＝17.5，10.9Hz)，6.79-6.89(2H，m)。
38D)2- [ 4-tert-butyl-3, 5-difluorophenyl]Cyclopropanecarboxylic acid
To a solution of the compound from example 38C (4.0g, 20.4mmol), Co (TPP) (411mg, 0.61mmol) and 1-methyl-1H-imidazole (5.0g, 61.2mmol) in toluene (50ml) was added ethyl diazoacetate (3.5g, 30.6mmol), and the mixture was stirred at room temperature for 5 minutes followed by another 2 hours at 80 ℃. Then evaporated and purified by silica gel column chromatography eluting gradually from hexane to hexane/EtOAc (20: 1) to give ethyl 2- (4-tert-butyl-3, 5-difluorophenyl) cyclopropanecarboxylate (4.4g, 76%, trans). To a solution of ethyl 2- (4-tert-butyl-3, 5-difluorophenyl) cyclopropanecarboxylate (4.4g, 15.5mmol) in THF (5ml) were added 2M aqueous sodium hydroxide (30ml) and MeOH (30ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the aqueous layer was extracted, then acidified with 2M aqueous HCl, all extracted with EtOAc, followed by evaporation to give the title compound (3.48g, 88%) as a white solid.
MS(ESI)m/z 253(M-H)-。
38E)2- [ 4-tert-butyl-3, 5-difluorophenyl]-N- ((1R) -1- {4- [ (methylsulfonyl) amino] Phenyl- } ethyl) cyclopropanecarboxamide
To a solution of the amine compound (200mg, 0.8mmol) from example 21 in DMF (10ml) were added the compound from example 38D (203mg, 0.8mmol), HBTU (394mg, 1.0mmol) and triethylamine (0.33ml, 2.4mmol) and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted all with EtOAc. Then evaporated and purified by HPLC (column used MS C30 × 50mm, conditions acetonitrile/0.01% ammonia, elution 32 to 68) to give the title compound (81mg, 22%) as a white solid. The desired product had a cut time of 4.61 minutes.
1H NMR(300MHz，DMSO-d6)δ1.15-1.48(14H，m)，1.90-1.96(1H，m)，2.20-2.26(1H，m)，2.96(3H，s)，4.86-4.95(1H，m)，6.82(2H，d，J＝12.5Hz)，7.15-7.28(4H，m)，8.53(1H，d，J＝7.3Hz)，9.69(1H，brs)。
MS(ESI)m/z 449(M-H)-，451(M+H)+。
Example 39
2- (4-tert-butyl-3, 5-difluorophenyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) cyclopropanecarboxamide
To a solution of the compound from example 2D (200mg, 0.8mmol) in DMF (10ml) were added the compound from example 38D (192mg, 0.8mmol), HBTU (375mg, 1.0mmol) and triethylamine (0.32ml, 2.3mmol) and the mixture was stirred at room temperature for 2 h. The same procedures as described in example 38E were carried out to give the title compound (105mg, 30%). The desired product had a cut time of 4.8 minutes.
1H NMR(270MHz，DMSO-d6)δ1.18-1.51(14H，m)，1.87-2.02(1H，m)，2.15-2.37(4H，m)，2.96(3H，s)，4.81-4.97(1H，m)，6.82(2H，d，J＝11.9Hz)，7.11-7.24(3H，m)，8.53(1H，d，J＝7.3Hz)，9.04(1H，brs)。
MS(ESI)m/z 463(M-H)-，465(M+H)+。
Example 40
2- (4-tert-butyl-3, 5-difluorophenyl) -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) cyclopropanecarboxamide
To a solution of the amine compound (210mg, 0.8mmol) from example 8 in DMF (10ml) were added the compound from example 38D (200mg, 0.8mmol), HBTU (394mg, 1.0mmol) and triethylamine (0.33ml, 2.4mmol) and the mixture was stirred at room temperature for 2 hours. The same procedure as described in example 38E was followed, but using HPLC conditions of acetonitrile/0.05% aqueous formic acid 32 to 68, to give the title compound (33mg, 9%) for 4.7 minutes.
1H NMR(300MHz，DMSO-d6)δ1.22-1.50(14H，m)，1.86-1.97(1H，m)，2.18-2.30(1H，m)，3.00(3H，s)，4.86-4.99(1H，m)，6.82(2H，d，J＝11.7Hz)，7.07-7.24(2H，m)，7.33(1H，t，J＝8.4Hz)，8.60(1H，d，J＝8.0Hz)，9.58(1H，brs)。
MS(ESI)m/z 467(M-H)-，469(M+H)+。
EXAMPLE 41
(1S，2S)-N-((1R)-1- { 2-fluoro-5-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) - 2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
41A) N- (5-fluoro-2-methylphenyl) methanesulfonamide
To a solution of 2-fluoro-5-methylaniline (from ACROS, 3.5g, 28mmol) in pyridine (20ml) and DCM (40ml) was added methanesulfonyl chloride (from WAKO, 4.3ml, 56mmol) at room temperature and the mixture was stirred for 20 h. The reaction was quenched with 2M aqueous sodium hydroxide, and the aqueous layer was separated and washed with DCM. The layer was cooled to 0 ℃ and acidified to pH 2.0 with 2M aqueous HCl. The precipitate was collected and the solvent was evaporated in vacuo to give the title compound (5.1g, 90%). MS (ESI) M/z 202(M-H) -
41B) N- (4-acetyl-5-fluoro-2-methylphenyl) methanesulfonamide
To a suspension of aluminium trichloride (WAKO, 4.9g, 36.9mmol) in DCM (45ml) was slowly added acetyl chloride (from WAKO, 1.9g, 24.6mmol) at room temperature, the mixture was stirred for 20 min, then to the mixture was added a solution of the compound of example 41A (2.5g, 12.3mmol) in dichloromethane (15ml) and the reaction was stirred at room temperature for 2.5 h. The reaction mixture was poured into ice water and all extracted with DCM. The organic layer was dried over magnesium sulfate and the solvent was evaporated to give the title compound (1.4g, 46%).
1H NMR(270MHz，DMSO-d6)δ2.24-2.31(3H，m)，2.54(3H，d，J＝4.6Hz)，3.15(3H，s)，7.27(1H，d，J＝13.2Hz)，7.28(1H，d，J＝7.9Hz)，9.54(1H，brs)。
41C) N- [4- ((1R) -1- { [ (R) -tert-butylsulfinyl]Amino } ethyl) -5-fluoro-2-methyl Phenyl radical]Methane sulfonic acidAmides of carboxylic acids
To a solution of the compound from example 41B (1.4g, 5.5mmol) and (R) - (+) -2-methyl-2-propanesulfinylamide (1.0g, 8.26mmol) in THF (5ml) under a nitrogen atmosphere was added titanium (IV) ethoxide (5.0ml, 21.9mmol) and the mixture was subjected to microwave irradiation at 70 ℃ and stirred for 2.5 hours. By LC-MS (ESI) M/z 347(M-H)-，349(M+H)+) After imine formation was confirmed, the mixture was cooled to 0 deg.C, sodium borohydride (707mg, 18.7mmol) was added, and the reaction mixture was stirred at 0 deg.C for 2 hours. The reaction mixture was partitioned between water and ethanol, and then the mixture was stirred at room temperature for 1 hour. The mixture was filtered through a pad of celite, the filtrate evaporated and concentrated in vacuo to give the title compound (1.9g, 99%).
MS(ESI)m/z 349(M-H)-，351(M+H)+
41D) N- {4- [ (1R) -1-aminoethyl]-5-fluoro-2-methylphenyl } methanesulfonamide hydrochloride
To the compound from example 41C (1.9g, 5.5mmol) were added HCl-MeOH (2.0M, 15.0ml) and 1, 4-dioxane (15.0 ml). The same procedure as described in example 2D was carried out to give the title compound (1.2g, 74%) as a white solid.
MS(ESI)m/z 245(M-H)-。
41E) (1S, 2S) -N- ((1R) -1- { 2-fluoro-5-methyl-4- [ (methylsulfonyl) amino]Phenyl radical } Ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 41D (115mg, 0.4mmol) in DMF (8ml) were added the compound from example 14C (100mg, 0.4mmol), HBTU (202mg, 0.5mmol) and triethylamine (0.2ml, 1.2mmol) and the mixture was stirred at room temperature for 2 h. The same procedures as described in example 38E were performed to give the title compound (54mg, 28%). The desired product had a cut time of 4.0 minutes.
1H NMR(300MHz，DMSO-d6)δ1.27-1.37(5H，m)，1.44(3H，s)，1.98-2.07(1H，m)，2.25(3H，s)，3.01(3H，s)，5.09-5.20(1H，m)，7.07(1H，d，J＝11.0Hz)，7.24(1H，d，J＝8.8Hz)，7.54(2H，d，J＝8.1Hz)，7.68(2H，d，J＝8.1Hz)，9.20(1H，brs)。
MS(ESI)m/z 471(M-H)-，473(M+H)+。
Example 42
N- ((1R) -1- { 2-fluoro-5-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [3- Fluoro-4- (trifluoromethyl) phenyl]-2-methylcyclopropanecarboxamide
To a solution of the compound (129mg, 0.5mmol) prepared in example 41D in DMF (8ml) were added the compound prepared in example 66C (120mg, 0.5mmol), HBTU (227mg, 0.6mmol) and triethylamine (0.2ml, 1.4 mmol)), and the mixture was stirred at room temperature for 2 hours. The same procedures as described in example 38E were carried out to give the title compound (23mg, 10%). The desired product had a cut time of 3.9 minutes.
1H NMR(300MHz，DMSO-d6)δ1.26-1.49(8H，m)，2.01-2.12(1H，m)，2.24(3H，s)，3.01(3H，s)，5.06-5.20(1H，m)，7.07(1H，d，J＝11.7Hz)，7.23(1H，d，J＝8.1Hz)，7.36(1H，d，J＝8.1Hz)，7.45(1H，d，J＝12.5Hz)，7.72(1H，t，J＝7.7Hz)，8.68(1H，d，J＝8.1Hz)，9.22(1H，brs)。
MS(ESI)m/z 489(M-H)-，491(M+H)+。
Example 43
2- (4-tert-butyl-3, 5-difluorophenyl) -2-methyl-N- ((1R) -1- {4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) cyclopropanecarboxamide
43A) 2-tert-butyl-13-difluoro-5-isopropenylbenzene
A mixture of the compound from example 38B (2.7g, 8.5mmol), potassium isopropenyltrifluoroborate (1.5g, 10.2mmol, org. Lett.2002, 4, 107), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (350mg, 0.4mmol) and triethylamine (1.2ml, 8.5mmol) in 2-propanol (86ml) was stirred at 80 ℃ for 2 h. The reaction mixture was cooled to room temperature and evaporated. All extracted with hexane, dried over magnesium sulfate and the solvent evaporated. The crude residue was purified by silica gel column chromatography eluting with hexane to give the title compound (1.1g, 63%) as a colorless oil.
1H NMR(300MHz，CDCl3)δ1.46(9H，t，J＝1.8Hz)，2.08(3H，s)，5.11(1H，s)，5.38(1H，s)，6.84-6.95(2H，m)。
43B)2- (4-tert-butyl-3, 5-difluorophenyl) -2-methylcyclopropanecarboxylic acid ethyl ester
To a solution of the compound from example 43A (1.1g, 5.3mmol), Co (TPP) (107mg, 0.16mmol) and 1-methyl-1H-imidazole (1.31ml, 16.0mmol) in toluene (50ml) was added ethyl diazoacetate (0.9ml, 8.0mmol), and the mixture was stirred at room temperature for 5 minutes followed by another 2 hours at 80 ℃. Then evaporated and purified by silica gel column chromatography eluting gradually with hexane to hexane/EtOAc (20: 1) to give the title compound (912mg, 58%, trans).
1H NMR(300MHz，CDCl3)δ1.24-1.52(17H，m)，1.85-1.94(1H，m)，4.09-4.28(2H，m)，6.64-6.78(2H，m)。
43C)2- (4-tert-butyl-3, 5-difluorophenyl) -2-methylcyclopropanecarboxylic acid
To a solution of the compound from example 43B (900mg, 3.0mmol) in THF (5ml) was added 2M aqueous sodium hydroxide (10ml) and MeOH (10ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the aqueous layer was extracted and acidified with 2M aqueous HCl. Extraction with all EtOAc followed by evaporation of the solvent gave the title compound (516mg, 63%).
MS(ESI)m/z 267(M-H)-。
43D)2- (4-tert-butyl-3, 5-difluorophenyl) -2-methyl-N- ((1R) -1- {4- [ (methylsulfonyl) amide Radical) amino]Phenyl } ethyl) cyclopropanecarboxamide
To a solution of the amine compound (140mg, 0.6mmol) from example 21 in DMF (10ml) were added the compound from example 43C (150mg, 0.6mmol), HBTU (276mg, 0.7mmol) and triethylamine (0.2ml, 1.7mmol) and the mixture was stirred at room temperature for 2 hours. The same procedures as described in example 38E were carried out to give the title compound (70mg, 27%). The desired product had a cut time of 5.1 minutes.
1H NMR(300MHz，DMSO-d6)δ1.16-1.62(17H，m)，1.88-2.05(1H，m)，2.95(3H，s)，4.83-5.00(1H，m)，6.93(2H，d，J＝12.5Hz)，7.15(2H，d，J＝8.1Hz)，7.27(2H，d，J＝8.1Hz)，8.56(1H，d，J＝7.3Hz)，9.66(1H，brs)。
MS(ESI)m/z 463(M-H)-，465(M+H)+。
[α]D95.8(c is 0.5, methanol, pool temperature is 21.6 ℃)
Example 44
2- (4-tert-butyl-3, 5-difluorophenyl) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
To a solution of the compound from example 2D (140mg, 0.5mmol) in DMF (10ml) were added the compound from example 43C (142mg, 0.5mmol), HBTU (261mg, 0.7mmol) and trimethylamine (0.2ml, 1.6mmol) and the mixture was stirred at room temperature for 2 h. The same procedures as described in example 38E were carried out to give the title compound (76mg, 30%).
1H NMR(300MHz，DMSO-d6)δ1.17-1.57(17H，m)，1.89-2.04(1H，m)，2.30(3H，s)，2.96(3H，s)，4.84-4.99(1H，m)，6.93(2H，d，J＝12.5Hz)，7.08-7.32(3H，m)，8.57(1H，d，J＝7.3Hz)，9.04(1H，brs)。
MS(ESI)m/z 477(M-H)-，479(M+H)+。
Example 45
2- (4-tert-butyl-3, 5-difluorophenyl) -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) -2-methylcyclopropanecarboxamide
To a solution of the amine compound (140mg, 0.5mmol) from example 8 in DMF (10ml) were added the compound from example 43C (142mg, 0.5mmol), HBTU (261mg, 0.7mmol) and triethylamine (0.2ml, 1.6mmol), and the mixture was stirred at room temperature for 2 hours. The same procedures as described in example 40 were carried out to give the title compound (76mg, 30%). The desired product had a cut time of 5.3 minutes.
1H NMR(300MHz，DMSO-d6)δ1.16-1.54(17H，m)，1.90-2.05(1H，m)，3.00(3H，s)，4.87-5.04(1H，m)，6.93(2H，d，J＝12.5Hz)，7.07-7.41(3H，m)，8.62(1H，d，J＝6.6Hz)，9.60(1H，brs)。
MS(ESI)m/z 481(M-H)-，483(M+H)+。
[α]D+85.1(c is 0.5, methanol, pool temperature is 21.3 ℃)
Example 46
N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [ 2-pyrrolidine- 1-yl-6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxamides
46A) 2-pyrrolidin-1-yl-6- (trifluoromethyl) nicotinic acid
A mixture of 2-chloro-6- (trifluoromethyl) nicotinic acid (from APOLLO, 5.0g, 22.2mmol) and pyrrolidine (40ml, 562mmol) was stirred at room temperature for 24 hours according to j.med.chem., 2005, 48, 71-90. The reaction mixture was then evaporated in vacuo to give the title compound (5.5g, 95%).
MS(ESI)m/z 259(M-H)-，260(M+H)+
46B) 2-pyrrolidin-1-yl-6- (trifluoromethyl) pyridin-3-yl]Methanol
To a solution of lithium aluminium tetrahydride (1.6g, 42.3mmol) in THF (50ml) at 0 deg.C was added a solution of the compound of example 46A (5.5g, 21.1mmol) in THF (40ml) and the mixture was stirred at 0 deg.C for 5 minutes followed by a further stirring at 65 deg.C for 24 hours. The reaction mixture was cooled to 0 ℃, partitioned with 10% aqueous sodium potassium tartrate tetrahydrate and EtOAc, and the mixture was stirred at room temperature for 2 hours. Water was added to the mixture, the organic layer was extracted, and 2M sodium hydroxide solution was used The solution was washed with brine and evaporated. The residue was purified by column chromatography on silica eluting with hexane/EtOAc (7: 1) to give the title compound (2.6g, 51%). MS (ESI) M/z247(M + H)+
46C) 2-pyrrolidin-1-yl-6- (trifluoromethyl) nicotinaldehyde
To a solution of ethanedioldichloride (2.7ml, 21.1mmol) in DCM (35ml) was added dimethyl sulfoxide (2.5ml, 31.8mmol) at-78 deg.C and the mixture was stirred at this temperature for 15 minutes. A solution of the compound from example 46B (2.6g, 10.6mmol) in DCM was then added slowly to the mixture at-78 deg.C, and the mixture was stirred for 30 minutes, followed by the addition of triethylamine (10ml, 106mmol) and stirred for 30 minutes at-78 deg.C. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was then quenched with water, extracted with EtOAc, dried over magnesium sulfate and evaporated. The crude residue was purified by column chromatography on silica eluting with hexane/EtOAc (10: 1) to give the title compound (1.3g, 51%).
MS(ESI)m/z 245(M+H)+
46D)2- [ 2-pyrrolidin-1-yl-6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxylic acid
To a suspension of methyltriphenylbromide * (3.8g, 10.6mmol) in THF (25ml) at 0 deg.C was added a 1.60M solution of n-butyllithium in hexane (6.7ml, 10.6mmol) and the reaction was stirred for 30 min. Then a solution of the compound from example 46C (1.3g, 5.3mmol) in THF (5ml) was added at room temperature and stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride, extracted all with EtOAc, dried over magnesium sulfate and evaporated. The crude residue was purified by column chromatography on silica eluting with hexane/EtOAc (10: 1) to give 2-pyrrolidin-1-yl-6- (trifluoromethyl) -3-vinylpyridine (1.03g, 80%, trans). To a solution of 2-pyrrolidin-1-yl-6- (trifluoromethyl) -3-vinylpyridine (1-03g, 4.3mmol), Co (TPP) (142mg, 0.2mmol) and 1-methyl-1H-imidazole (1.22ml, 14.9mmol) in toluene (15ml) was added ethyl diazoacetate (1.0ml, 8.5mmol), and the mixture was stirred at room temperature for 5 minutes followed by a further stirring at 80 ℃ for 2 hours. Then evaporated and purified by column chromatography on silica eluting with hexane/EtOAc (20: 1) to give ethyl 2- [ 2-pyrrolidin-1-yl-6- (trifluoromethyl) pyridin-3-yl ] cyclopropanecarboxylate (1.3g, 93%). To a solution of this compound (1.3g, 4.0mmol) in THF (10ml) were added 2M aqueous sodium hydroxide (15ml) and MeOH (15ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the aqueous layer was extracted and then acidified with 2M aqueous HCl. Extraction with EtOAc all followed by evaporation gave the title compound (1.1g, 92%).
MS(ESI)m/z 299(M-H)-，301(M+H)+
46E) N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [ 2-pyridine Pyrrolidin-1-yl-6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxamides
To a stirred solution of the compound from example 46D (200mg, 0.7mmol) in DCM (10ml) was added oxalyl chloride (0.2ml, 1.3mmol) and DMAP (1 drop) at 0 ℃. After stirring at room temperature for 45 min, the mixture was evaporated in vacuo and the residue was dissolved in DCM (5 ml). The above solution was added to a solution of the compound from example 2D (195mg, 0.7mmol) in pyridine (5ml) at room temperature. After stirring at room temperature for 2 h, the mixture was evaporated in vacuo to give the crude product, which was purified by HPLC (MS C30 × 50mm, acetonitrile/0.05% aqueous formic acid 04 to 96) to give the title compound (81mg, 24%). The desired product had a cut time of 4.4 minutes.
1H-NMR(300MHz，DMSO-d6) δ 1.23-1.42(5H, m), 1.77-1.96(5H, m), 2.29(3H, s), 2.35-2.47(1H, m), 2.96(3H, s), 3.51-3.66(4H, m), 4.88-5.03(1H, m), 7.00(1H, d, J ═ 8.1Hz), 7.10-7.30(3H, m), 7.48(1H, J ═ 7.3Hz), 8.62(1H, J ═ 8.1Hz), 9.04(1H, brs), as a white solid.
MS(ESI)m/z 509(M-H)-，511(M+H)+。
Example 47
N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino ]Phenyl } ethyl) -2- [2- Pyrrolidin-1-yl-6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxamides
To a solution of the compound from example 17B (215mg, 0.7mmol) in DMF (15ml) were added the compound from example 46D (200mg, 0.7mmol), HBTU (330mg, 0.9mmol) and triethylamine (0.3ml, 2.0mmol) and the mixture was stirred at room temperature for 1.5 h. The reaction was quenched with water, extracted all with EtOAc and evaporated in vacuo to give 2- [ (methylsulfonyl) amino]-5- { (1R) -1- [ ({2- [ 2-pyrrolidin-1-yl-6- (trifluoromethyl) pyridin-3-yl]Cyclopropyl } carbonyl) amino]Ethyl } benzoate (MS (ESI) M/z 567(M-H) -, 569(M + H)+). This product was used for the next reaction without purification. To a solution of lithium aluminum hydride (300mg, 7.9mmol) in THF (10ml) was added a solution of the above compound in THF (5ml), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ℃ and quenched with 10% aqueous sodium potassium tartrate tetrahydrate and EtOAc. The mixture was stirred at room temperature for 2 hours and quenched with water. The organic layer was extracted and washed with 2M aqueous sodium hydroxide and brine. The organic layer was evaporated to give a residue which was purified by HPLC (MS C30 × 50mm, acetonitrile/0.05% aqueous formic acid, eluting with 32 to 68) to give the title compound (37mg, 10%). The desired product had a cut time of 3.7 minutes.
1H-NMR(270MHz，DMSO-d6) δ 1.22-1.44(5H, m), 1.75-1.97(5H, m), 2.34-2.47(1H, m), 2.97(3H, s), 3.52-3.63(4H, m), 4.61(2H, s), 4.93-5.06(1H, m), 7.00(1H, d, J ═ 7.9Hz), 7.16-7.32(2H, m), 7.37-7.54(2H, m), 8.66(1H, d, J ═ 7.9 Hz). H of OH and NH could not be observed.
MS(ESI)m/z 525(M-H)-，527(M-H)+。
Example 48
N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 17B (237mg, 0.7mmol) in DMF (15ml) were added the compound from example 6D (200mg, 0.7mmol), HBTU (365mg, 1.0mmol) and trimethylamine (0.3ml, 2.2mmol) and the mixture was stirred at room temperature for 1.5 h. The reaction was quenched with water, extracted all with EtOAc and evaporated in vacuo to give 2- [ (methylsulfonyl) amino]-5- { (1R) -1- [ ({2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropyl } carbonyl) amino]Ethyl } benzoate (MS (ESI) M/z 539(M-H)-，541(M+H)+). The same procedure as described in example 47 was followed, using HPLC conditions of acetonitrile/0.05% aqueous formic acid 4 to 96, to give the title compound (230mg, 62%). The desired product had a cut time of 4.0 minutes.
1H-NMR(270MHz，DMSO-d6) δ 1.16-1.40(5H, m), 1.53(6H, s), 1.88-2.01(2H, m), 2.18-2.30(1H, m), 2.99(3H, s), 4.62(2H, s), 4.86-5.02(1H, m), 7.09-7.29(4H, m), 7.38-7.48(3H, m), 8.59(1H, d, J ═ 7.9 Hz). No NH-generated signal was observed.
MS(ESI)m/z 497(M-H)-，499(M+H)+。
Example 49
2- (6-tert-butyl-2-piperidin-1-ylpyridin-3-yl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
49A) 6-tert-butyl-2-piperidin-1-ylnicotinonitrile
A mixture of 6-tert-butyl-2-chloronicotinonitrile (Tetrahedron 1965, 21, 2453-2467, 1.5g, 7.7mmol) and piperidine (15ml, 176mmol) was stirred at room temperature for 20 hours. The reaction mixture was then evaporated in vacuo to remove the piperidine to give the title compound (1.8g, 98%).
MS(ESI)m/z 244(M+H)+
49B) 6-tert-butyl-2-piperidin-1-ylnicotinaldehyde
To a solution of the compound from example 49A (1.8g, 7.6mmol) in diethyl ether (17ml) was added a 0.94M solution of diisobutylaluminum hydride in toluene (12.1ml, 11.4mmol) at-78 deg.C and the mixture was warmed to room temperature for 2 hours while stirring. The reaction was then quenched with 10% aqueous sodium potassium tartrate tetrahydrate, extracted all with EtOAc, washed with 2M aqueous sodium hydroxide and brine. Evaporation of the organic layer gave a residue which was purified by silica gel column chromatography eluting with hexane/EtOAc (5: 1) to give the title compound (1.8g, 97%).
MS(ESI)m/z 247(M+H)+
49C) 6-tert-butyl-2-piperidin-1-yl-3-vinylpyridine
To a suspension of methyltriphenylbromide * (5.3g, 14.8mmol) in THF (24ml) at 0 deg.C was added a 1.60M solution of n-butyllithium (9.3ml, 14.8mmol) in hexane and the reaction was stirred for 30 min. To this mixture was then added a solution of the compound from example 49B (1.8g, 7.5mmol) in THF (5ml) at 0 deg.C and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted all with EtOAc, dried over magnesium sulfate and the solvent evaporated. The crude residue was purified by column chromatography on silica eluting with hexane/EtOAc (10: 1) to give the title compound (1.70g, 93%).
1H-NMR(270MHz，CDCl3)δ1.31(9H，s)，1.59-1.75(6H，m)，3.13-3.24(4H，m)，5.16-5.24(1H，m)，5.56-5.67(1H，m)，6.76(1H，dd，J＝17.8，10.6Hz)，6.85(1H，d，J＝7.9Hz)，7.57(1H，d，J＝7.3Hz)。
49D)2- (6-tert-butyl-2-piperidin-1-ylpyridin-3-yl) cyclopropanecarboxylic acid
To a solution of the compound from example 49C (1.7g, 6.9mmol), Co (TPP) (140mg, 0.2mmol) and 1-methyl-1H-imidazole (1.7ml, 21mmol) in toluene (15ml) was added ethyl diazoacetate (1.1ml, 9.7mmol), and the mixture was stirred at room temperature for 5 minutes followed by another stirring at 80 ℃ for 2 hours. Then evaporated and purified by silica gel column chromatography eluting with hexane/EtOAc (20: 1) to give ethyl 2- (6-tert-butyl-2-piperidin-1-ylpyridin-3-yl) cyclopropanecarboxylate (2.0g, 89%, trans). To a solution of this compound (1.98g, 6.0mmol) in THF (6ml) was added 2M aqueous sodium hydroxide (6ml) and MeOH (6ml) and the mixture was stirred at 80 ℃ for 2 h. After completion of the reaction, ethyl acetate was added, the aqueous layer was separated, and then acidified with 2M aqueous HCl. Extraction with EtOAc all followed by evaporation gave the title compound (1.4g, 76%).
MS(ESI)m/z 301(M-H)-，303(M+H)+
49E)2- (6-tert-butyl-2-piperidin-1-ylpyridin-3-yl) -N- ((1R) -1- { 3-methyl-4- [ (methyl) Arylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
To a stirred solution of the compound from example 49D (127mg, 0.4mmol) in DCM (7ml) at 0 deg.C was added oxalyl chloride (107mg, 0.84mmol) and DMAP (1 drop). After stirring at room temperature for 30 min, the mixture was evaporated in vacuo and the residue was dissolved in DCM (2 ml). The above solution was added to a solution of the compound from example 2D (122mg, 0.5mmol) in pyridine (7ml) at room temperature. After stirring at room temperature for 2.5 h, the mixture was evaporated in vacuo and the crude product was purified by silica gel column chromatography eluting with hexane/EtOAc (2: 1) and the resulting product was recrystallized from hexane and ethyl acetate co-solvent to give the title compound (95mg, 19%) as a white solid.
1H-NMR(300MHz，DMSO-d6)δ1.18-1.50(18H，m)，1.52-1.82(4H，m)，2.28(3H，m)，2.89-3.25(7H，m)，4.85-4.99(1H，m)，6.82-6.93(1H，m)，7.05-7.25(4H，m)，8.53(1H，d，J＝8.1Hz)，9.02(1H，brs)。
MS(ESI)m/z 511(M-H)-，513(M+H)+
Example 50
2- (6-tert-butyl-2-piperidin-1-ylpyridin-3-yl) -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
To a stirred solution of the compound from example 49D (127mg, 0.4mmol) in DCM (7ml) at 0 deg.C was added oxalyl chloride (100mg, 0.8mmol) and DMAP (1 drop). After stirring at room temperature for 30 min, the mixture was evaporated in vacuo and the residue was dissolved in DCM (2 ml). The above solution was added to a solution of the amine compound of example 8 (124mg, 0.5mmol) in pyridine (8ml) at room temperature. After stirring at room temperature for 2.5 h, the mixture was evaporated in vacuo and purified by silica gel column chromatography eluting with dichloromethane/EtOAc (10: 1) and the product recrystallized to give the title compound (60mg, 28%) as a white solid.
1H-NMR(300MHz，DMSO-d6)δ1.1 7-1.83(21H，m)，2.16-2.32(1H，m)，2.90-3.21(7H，m)，4.87-5.02(1H，m)，6.82-6.93(1H，m)，7.07-7.39(4H，m)，8.57(1H，d，J＝8.1Hz)，9.53(1H，brs)。
MS(ESI)m/z 515(M-H)-，517(M+H)+
Example 51
2- (6-tert-butyl-2-pyrrolidin-1-ylpyridin-3-yl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
51A) 6-tert-butyl-2-chloro-3-vinylpyridine
To a solution of 6-tert-butyl-2-chloronicotinonitrile (Tetrahedron 1965, 21, 2453-2453, 1.0g, 5.4mmol) in diethyl ether (17ml) was added a 0.94M solution of diisobutylaluminum hydride in toluene (8.6ml, 8.0mmol) at-78 deg.C, and the reaction was allowed to warm to room temperature over 2 hours while stirring. The reaction was then quenched with 10% aqueous sodium potassium tartrate tetrahydrate, extracted all with EtOAc, washed with 2M aqueous sodium hydroxide and brine. The organic layer was evaporated and purified by silica gel column chromatography eluting with hexane/EtOAc (5: 1) to give 6-tert-butyl-2-chloronicotinaldehyde (1.0g, 95%). To a suspension of methyltriphenylbromide * (5.3g, 14.8mmol) in THF (24ml) at 0 deg.C was added a 1.60M solution of n-butyllithium (9.3ml, 14.8mmol) in hexane, and the reaction was stirred for 30 min. To this mixture was then added a solution of 6-tert-butyl-2-chloronicotinaldehyde (1.0g, 5.2mmol) in THF (5ml) at 0 deg.C and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted all with EtOAc, and dried over magnesium sulfate. The organic layer was evaporated and purified by silica gel column chromatography eluting with hexane/EtOAc (10: 1) to give the title compound (735mg, 71%).
1H-NMR(270MHz，DMSO-d6)δ1.35(9H，s)，5.43(1H，d，J＝11.2Hz)，5.72(1H，d，J＝17.1Hz)，7.01(1H，dd，J＝17.5，10.9Hz)，7.22-7.28(1H，m)，7.78(1H，d，J＝7.9Hz)。
51B)2- (6-tert-butyl-2-chloropyridin-3-yl) cyclopropanecarboxylic acid ethyl ester
To a solution of the compound from example 51A (365mg, 1.9mmol), Co (TPP) (38mg, 0.06mmol) and 1-methyl-1H-imidazole (461mg, 5.6mmol) in toluene (4ml) was added ethyl diazoacetate (300mg, 2.6mmol), and the mixture was stirred at room temperature for 5 minutes, followed by another stirring at 80 ℃ for 2 hours. Then evaporated and purified by silica gel column chromatography eluting with hexane/EtOAc (20: 1) to give the title compound (440mg, 84%, trans).
MS(ESI)m/z 282(M+H)+
51C) 2- (6-tert-butyl-2-chloropyridin-3-yl) cyclopropanecarboxylic acid
To a solution of the compound from example 51B (220mg, 0.8mmol) in THF (3ml) was added 2M aqueous sodium hydroxide (3ml) and MeOH (3ml) and the mixture was stirred at 80 ℃ for 1.5 h. After completion of the reaction, the aqueous layer was partitioned with EtOAc, separated and then acidified with 2M aqueous HCl. Extraction with EtOAc all followed by evaporation gave the title compound (135mg, 68%).
MS(ESI)m/z 252(M-H)-，253(M+H)+
51D)2- (6-tert-butyl-2-chloropyridin-3-yl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) Radical) amino]Phenyl } ethyl) cyclopropanecarboxamide
To a stirred solution of the compound from example 51C (30mg, 0.12mmol) in DCM (1.5ml) at 0 deg.C was added oxalyl chloride (0.03ml, 0.24mmol) and DMAP (1 drop). After stirring at room temperature for 30 min, the mixture was evaporated in vacuo and the residue was dissolved in DCM (1 ml). The above solution was added to a solution of the compound from example 2D (35mg, 0.13mmol) in pyridine (2ml) at room temperature. After stirring at room temperature for 2.5 h, the mixture was evaporated in vacuo and purified by silica gel column chromatography eluting with DCM/EtOAc (4: 1) and the product was recrystallized from hexane and EtOAc to give the title compound (45mg, 80%).
MS(ESI)m/z 462(M-H)-，464(M+H)+
51E)2- (6-tert-butyl-2-pyrrolidin-1-ylpyridin-3-yl) -N- ((1R) -1- { 3-methyl -4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
To a solution of the compound from example 51D (45mg, 0.01mmol) in DMSO (1.5ml) were added pyrrolidine (0.5ml, 7.0mmol) and tetrabutylammonium fluoride (0.5ml, 1.9mmol) and the mixture was subjected to microwave irradiation at 150 ℃ for 5 hours. All extracted with EtOAc, evaporated and purified by silica gel column chromatography eluting with DCM/EtOAc (10: 1) and the product was recrystallized from hexane and EtOAc to give the title compound (13mg, 27%).
1H-NMR(300MHz，CDCl3)δ1.12-1.78(17H，m)，1.84-1.97(2H，m)，2.28-2.38(3H，m)，2.52-2.65(1H，m)，2.99-3.03(3H，m)，3.40-3.72(4H，m)，5.05-5.22(1H，m)，5.92(1H，dd J＝7.3，2.9Hz)，6.24(1H，brs)，6.56(1H，dd，J＝7.3，5.9Hz)，7.09-7.24(3H，m)，7.37-7.47(1H，m)。
MS(ESI)m/z 497(M-H)-，499(M+H)+
Example 52
2- [ 6-tert-butylpyridin-3-yl]-N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) cyclopropanecarboxamide
52A) 5-bromo-2-tert-butylpyridine
To a suspension of copper cyanide (1.79g, 20mmol) in THF (40ml) dried under reduced pressure for 4 hours at-78 deg.C was added dropwise a 1.0M solution of t-butylmagnesium chloride (40ml, 40mmol) in THF over 30 minutes, and the mixture was stirred at-78 deg.C for 1 hour. 5-bromo-2-iodopyridine (2.83g, 10mmol) was added at-78 deg.C and the mixture was stirred at-78 deg.C for 1 hour, followed by another 16 hours at room temperature. The reaction was then quenched with 25% aqueous ammonia (40ml), the precipitate was removed by filtration and washed with EtOAc. The filtrate and washings were combined and concentrated in vacuo. Then filtered, evaporated and purified by silica gel column chromatography eluting with hexane/EtOAc (20: 1) to give the title compound (1.07g, 50% yield) as a colorless oil.
1H NMR(300MHz，CDCl3)δ1.35(9H，s)，7.24(1H，d，J＝8.1Hz)，7.72(1H，dd，J＝2.2，8.1Hz)，8.61-8.62(1H，m)。
52B) 2-tert-butyl-5-vinylpyridine
In the same procedure as described in example 2G, to a solution of the compound from example 52A (915mg, 4.27mmol) in DMF (20ml) was added vinyltributylstannane (3.14G, 9.90mmol), lithium chloride (2.1G, 49.5mmol) and bis (triphenylphosphine) palladium chloride (173mg, 0.25 mmol). The crude residue was chromatographed on a silica gel column, eluting with hexane/EtOAc (20: 1) to give the title compound (766mg, quant.) as a pale yellow oil.
1H NMR(270MHz，CDCl3)δ1.36(9H，s)，5.32(1H，d，J＝11.2Hz)，5.77(1H，d，J＝17.8Hz)，6.69(1H，dd，J＝10.6，17.8Hz)，7.30(1H，d，J＝8.6Hz)，7.67(1H，dd，J＝2.6，8.6Hz)，8.56(1H，d，J＝2.6Hz)。
MS(ESI)：m/z 162(M+H)+。
52C)2- [ 6-tert-butylpyridin-3-yl]Cyclopropanecarboxylic acid ethyl ester
In the same procedure as described in example 2H, to a solution of the title compound of example 52B (766mg, 4.27mmol), Co (TPP) (85mg, 0.126mmol) and 1-methyl-1H-imidazole (1.03g, 12.6mmol) in toluene (7ml) was added ethyl diazoacetate (671mg, 5.88 mmol). The crude product was diluted with 2M aqueous HCl and washed with diethyl ether. The aqueous layer was separated, basified with saturated aqueous sodium bicarbonate, extracted all with EtOAc, and dried over sodium sulfate. Then filtered and the solvent evaporated to give the crude title compound (crude 1.11g) as a black oil.
1H NMR(270MHz，CDCl3)δ1.28(3H，t，J＝7.3Hz)，1.34(9H，s)，1.58-1.65(1H，m)，1.86-1.92(1H，m)，2.45-2.53(1H，m)，4.18(3H，q，J＝7.3Hz)，7.06(1H，s)，7.44(1H，s)，8.39(1H，s)。
MS(ESI)：m/z 248(M+H)+。
52D)2- [ 6-tert-butylpyridin-3-yl]Cyclopropanecarboxylic acid
A solution of the crude compound from example 52C (crude 1.11g) in MeOH (10ml) and 2M aqueous sodium hydroxide (4ml) were stirred at 40 ℃ for 15 min. After completion of the reaction, the basic mixture was washed with diethyl ether, the aqueous layer was separated, neutralized to pH 5-6 with 2M aqueous HCl, and all extracted with EtOAc followed by evaporation to give the title compound (785mg, 84% yield, 2 steps, trans) as a white solid.
1H NMR(300MHz，CDCl3)δ0.86-1.45(1H，m)，1.35(9H，s)，1.65-1.71(1H，m)，1.88-1.94(1H，m)，2.54-2.61(1H，m)，7.24-7.35(2H，m)，8.44(1H，s)。
MS(ESI)m/z 220(M+H)+。
52E)2- [ 6-tert-butylpyridin-3-yl]-N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino] Phenyl } ethyl) cyclopropanecarboxamide
The procedure described in example 10E was followed using a solution of the compound from example 52D (117mg, 0.533mmol) in DMF (1ml), triethylamine (0.22ml), EDC (153mg, 0.80mmol), HOBt (90mg, 0.59mmol) and N- {4- [ (1R) -1-aminoethyl ] -2-fluorophenyl } methanesulfonamide HCl (143mg, 0.533 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1: 1) to give the title compound (133mg, 57% yield, white solid) as a mixture of diastereomeric products (1: 1).
1H NMR(300MHz，CDCl3)δ1.12-1.70(15H，m)，2.43-2.52(1H，m)，3.02-3.03(3H，m)，5.09-5.13(1H，m)，5.92-5.94(1H，m)，6.51(1H，brs)，7.09-7.14(2H，m)，7.22-7.33(2H，m)，7.49-7.56(1H，m)，8.35(1H，d，J＝11.0Hz)MS(ESI)：m/z 434(M+H)+。
Example 53
2- [ 6-tert-butylpyridin-3-yl]-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) cyclopropanecarboxamide
In the same procedure as in example 1, to a solution of the compound from example 52D (252mg, 1.15mmol) in DMF (1ml) was added triethylamine (0.48ml), EDC (331mg, 1.73mmol), HOBt (194mg, 1.27mmol) and the amine compound from example 2D (304mg, 1.15 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1: 1) to give the title compound (302mg, 61% yield, white solid) as a mixture of diastereomeric products (1: 1).
1H NMR(270MHz，CDCl3)δ0.86-1.65(15H，m)，2.31-2.32(3H，m)，2.45-2.51(1H，m)，3.01-3.02(3H，m)，5.05-5.15(1H，m)，5.90(1H，d，J＝7.3Hz)，6.20(1H，s)，7.18-7.25(4H，m)，7.39-7.43(1H，m)，8.35-8.37(1H，m) MS(ESI)：m/z 430(M+H)+。
Example 54
(1S, 2S) -2-methyl-N- ((1R) -1- { 6-methyl-5- [ (methylsulfonyl) amino]Pyridine-2- Ethyl-2- (4-trifluoromethyl) phenyl]Cyclopropanecarboxamides
Triethylamine (0.14ml), EDC (95mg, 0.50mmol), HOBt (56mg, 0.36mmol) and the compound from example 9E (100mg, 0.33mmol) were added to a solution of the compound from example 14B (81mg, 0.33mmol) in DMF (2ml) in the same procedure as described in example 1. The crude residue was chromatographed on silica gel eluting with a volumetric mixture of hexane and EtOAc (1: 1) to give the title compound (44mg, 29% yield, white solid) as a mixture of diastereomeric products (1: 1).
1H NMR(270MHz，CDCl3)δ0.86-1.47(1H，m)，1.46-1.48(3H，m)，1.50-1.60(4H，m)，1.78-1.85(1H，m)，2.56-2.58(3H，m)，3.04-3.05(3H，m)，5.12-5.21(1H，m)，6.93-7.02(1H，m)，7.14(1H，d，J＝8.1Hz)，7.25-7.49(3H，m)，7.55-7.63(2H，m)，7.72-7.75(1H，m) MS(ESI)：m/z 456(M+H)+，454(M-H)-。
Example 55
2- [ 4-tert-butylphenyl l-N- ((1R) -1- { 6-methyl-5- [ (methylsulfonyl) amino group]Pyridine- 2-yl } ethyl) cyclopropanecarboxamide
In the same procedure as in example 1, to a solution of the compound from example 7A (72mg, 0.33mmol) in DMF (2ml) was added triethylamine (0.14ml), EDC (95mg, 0.50mmol), HOBt (56mg, 0.36mmol) and the amine compound from example 9E (100mg, 0.33 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1: 1) to give the title compound (single isomer; 44mg, 31% yield) as a white solid.
1H NMR(300MHz，CDCl3)δ1.19-1.30(1H，m)，1.31(9H，s)，1.43(3H，d，J＝6.6Hz)，1.52-1.71(2H，m)，2.46-2.52(1H，m)，2.56(3H，s)，3.04(3H，s)，5.08-5.17(1H，m)，6.35(1H，s)，6.96(1H，d，J＝6.6Hz)，7.06(2H，d.J＝8.1Hz)，7.12(1H，d，J＝8.3Hz)，7.32(2H，d，J＝8.1Hz)，7.72(1H，d，J＝8.3Hz)。
MS(ESI)：m/z 430(M+H)+
Example 56
N- ((1R) -1- { 6-methyl-5- [ (methylsulfonyl) amino]Pyridin-2-yl } ethyl) -2- [4- (trifluoromethyl) phenyl group]Cyclopropanecarboxamides
In the same procedure as described in example 1, to a solution of 2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxylic acid (rac) (76mg, 0.33mmol) [ Journal of Organic Chemistry (1997), 62(26), 9114-. The crude residue was chromatographed on silica gel eluting with a volumetric mixture of hexane and EtOAc (1: 1) to give the title compound (13mg, 9% yield, single diastereomeric product) as a white solid.
1H NMR(300MHz，CDCl3)δ1.23-1.79(6H，m)，2.57(3H，s)，2.55-2.63(1H，m)，3.05(3H，s)，5.10-5.18(1H，m)，6.25(1H，brs)，7.03(1H，d，J＝5.9Hz)，7.13(1H，d，J＝8.1Hz)，7.22(2H，d，J＝8.1Hz)，7.54(2H，d，J＝8.1Hz)，7.74(1H，d，J＝8.1Hz)MS(ESI)：m/z 442(M+H)+。
Example 57
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxamides
57A) 2-methyl-2- [6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxylic acid
The racemic compound of example 12C was isolated by means of Daicel Chiralpal AD-H (20X 250mM), eluting with 0.1mM ammonium trifluoroacetate in n-hexane/ethanol (96/4, v/v), at a column temperature of 40 ℃. The title compound was obtained as a later fraction (retention time 20 min).
57B) 2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl group } B 2- [6- (trifluoromethyl) pyridin-3-yl ] -phenyl- ]]Cyclopropanecarboxamides (Single isomers)
In the same procedure as in example 14D, to a solution of the compound from example 57A (112mg, 0.46mmol) in DMF (4ml) were added HBTU (208mg, 0.55mmol), triethylamine (0.2ml) and the amine compound from example 2D (121mg, 0.46 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1: 1) to give the title compound (single isomer; 166mg, 78% yield) as a white solid.
1H NMR(300MHz，CDCl3)δ1.40-1.45(1H，m)，1.50(3H，d，J＝7.3Hz)，1.57-1.76(5H，m)，2.32(3H，s)，3.02(3H，s)，5.09-5.17(1H，m)，5.98(1H，d，J＝7.3Hz)，6.19(1H，s)，715-7.25(1H，m)，7.42(1H，d，J＝8.8Hz)，7.62(2H，d，J＝8.1Hz)，7.69-7.74(1H，m)，8.62-8.65(1H，m)MS(ESI)：m/z 456(M+H)+。
Example 58
2- [ 4-tert-butyl-3-fluorophenyl)]-N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) cyclopropanecarboxamide
58A)2- [ 4-tert-butyl-3-fluorophenyl)]Cyclopropanecarboxylic acid
Racemic 2- [ (4-tert-butyl-3-fluorophenyl) cyclopropanecarboxylic acid was isolated using Daicel CHIRALPAK AD-H [ trade mark ] (column size; 2X 25cm, temperature; 40 ℃, solvent; hexane/EtOH ═ 1/1). The next step was carried out using the latter fraction (retention time 7.8 min).
58B)2- [ 4-tert-butyl-3-fluorophenyl)]-N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino] Phenyl } ethyl) cyclopropanecarboxamide
To a solution of the compound from example 58A (100mg, 0.42mmol) in THF (1.0ml) at room temperature was added 2-chloro-1, 3-dimethylimidazolium Chloride (CDI) (68mg, 0.42mmol), the mixture was stirred at room temperature for 1 hour, then to this reaction was added triethylamine (1.0ml) and the compound from example 8 (113mg, 0.42 mmol). The same procedure as described in example 2J was followed to give the title compound as a white solid.
1H NMR(CDCl3，270MHz)δppm 1.31(9H，s)，1.06-1.39(5H，m)，1.84(1H，br)，2.23(1H，br)，2.94(3H，s)，3.38(1H，br)，4.86(1H，t，J＝5.4Hz)，6.78-6.93(2H，m)，7.02-7.37(4H，m)，8.54(1H，d，J＝5.4Hz)。
MS(ESI)：m/z 451(M+H)+。
Example 59
2- [ 4-tert-butylphenyl group]-2- (hydroxymethyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) cyclopropanecarboxamide
Mixtures of trans diastereomers
59A)2- [ 4-tert-butylphenyl group]Prop-2-en-1-yl acetate
To a stirred suspension of methyltriphenylbromide * (8.48g, 23.7mmol) in THF (75ml) was added potassium tert-butoxide (2.66g, 23.7mmol) at room temperature. The mixture was stirred at 40 ℃ for 1 hour. After cooling to room temperature, a solution of 2- [ 4-tert-butylphenyl ] -2-oxoethyl acetate (U.S. Pat. No. 3,3526634, 2.78g, 11.9mmol) in THF (25ml) was added to the mixture. The mixture was heated at reflux for 3 hours. The mixture was concentrated, diluted with EtOAc, washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with hexane/EtOAc (9: 1) to give the title compound (2.13g, 77%) as a yellow oil.
1H NMR(300MHz，CDCl3)δ1.33(9H，s)，2.09(3H，s)，4.98(2H，s)，5.33(1H，s)，5.56(1H，s)，7.38(4H，s)。
59B)2- [ (acetoxy) methyl group]-2- [ 4-tert-butylphenyl]Cyclopropanecarboxylic acid tert-butyl ester
To a solution of the compound from example 59A (1.0g, 4.3mmol), Co (TPP) (86.6mg, 0.13mmol) and 1-methyl-1H-imidazole (1.0ml, 12.9mmol) in toluene (20ml) was added tert-butyl diazoacetate (0.83ml, 6.0mmol) and the mixture was stirred at room temperature for 5 minutes followed by another 3 hours at 80 ℃. Then evaporated and purified by silica gel column chromatography eluting with hexane/EtOAc (20: 1) to give the title compound (644mg, 43%) as a brown oil.
1H NMR(300MHz，CDCl3)δ1.31(9H，s)，1.48(9H，s)，1.35-1.60(2H，m)，1.98(3H，s)，2.02-2.07(1H，m)，4.33(1H，d，J＝11.0Hz)，4.61(1H，d，J＝11.7Hz)，7.25(2H，d，J＝8.8Hz)，7.33(2H，d，J＝8.1Hz)。
59C) Acetic acid (1- [ 4-tert-butylphenyl)]-2- { [ ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) Amino group]Phenyl } ethyl) amino]Carbonyl } cyclopropyl) methyl ester (trans diastereomer mixture)
To a solution of the compound from example 59B (280mg, 0.81mmol) in DCM (12ml) was added TFA (3 ml). After stirring at room temperature for 4 hours, the mixture was evaporated in vacuo and the residue was dissolved in DMF (5 ml). To the above solution were added the compound of example 2D (195mg, 0.74mmol), EDC (211mg, 1.1mmol), HOBt (149mg, 1.1mmol) and triethylamine (1.0ml, 7.35mmol) at room temperature. After stirring at room temperature for 4 days, the mixture was concentrated, diluted with EtOAc, washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by NH2 silica gel column (YAMAZEN. size 40 μm) chromatography eluting with hexane/EtOAc (1: 2) to give the title compound (128mg, 35%) as a yellow oil.
1H-NMR(CDCl3)δ1.30-1.72(14H，m)，1.81-1.88(1H，m)，1.99-2.05(3H，m)，2.32-2.33(3H，m)，3.01-3.02(3H，m)，4.31-4.42(1H，m)，4.53-4.68(1H，m)，5.07-5.17(1H，m)，5.92-5.98(1H，m)，6.22-6.32(1H，m)，7.18-7.44(7H，m)。
59D)2- [ 4-tert-butylbenzeneBase of]-2- (hydroxymethyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) sulfonic acid Acyl) amino]Phenyl } ethyl) cyclopropanecarboxamide (trans diastereomer mixture)
To a solution of the compound from example 59C (100mg, 0.20mmol) in ethanol (2ml) was added 2M aqueous sodium hydroxide (0.5ml) at room temperature. After stirring at room temperature for 3 hours, the mixture was evaporated in vacuo and the residue was acidified with 2M aqueous HCl and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product is passed over NH 2Purification by column chromatography on silica gel (Biotage) eluting with EtOAc afforded a white solid. The solid was recrystallized from hexane-EtOAc to give the title compound (58mg, 64%) as a white solid.
1H NMR(300MHz，DMSO-d6)δ1.14-1.41(14H，m)，1.89-1.98(1H，m)，3.03(3H，s)，2.96(3H，s)，3.67-3.69(1H，m)，3.73-3.81(1H，m)，4.38-4.47(1H，m)，4.87-4.97(1H，m)，7.12-7.22(3H，m)，7.30-7.32(4H，m)，8.57(1H，d，J＝8.1Hz)，8.96(1H，br s)。
Example 60
(1S, 2S) -N- ((1R) -1- {2, 5-difluoro-4- [ (methylsulfonyl) amino]Phenyl } ethyl) - 2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
60A) N- (2, 5-difluoro-4-iodophenyl) methanesulfonamide
To a solution of 2, 5-difluoro-4-iodoaniline (5.3g, 19.4mmol, Can. J. chem., 2000 (78)), 1081-iodoaniline (50ml) in DCM (50ml) was added methanesulfonyl chloride (1.65ml, 21.3mmol) and pyridine (4.7ml, 58.2mmol) at 0 deg.C. The mixture was stirred at room temperature for 24 hours. The mixture was partitioned between EtOAc and 2M aqueous HCl. The organic layer was separated, washed with 2m hcl aqueous solution and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting gradually from hexane/EtOAc (4: 1) to hexane/EtOAc (3: 1) to give the title compound (5.6g, 87%) as a violet solid.
1H NMR(270MHz，CDCl3)δ3.09(3H，s)，6.81(1H，br s)，7.39(1H，dd，J＝6.9，8.2Hz)，7.53(1H，dd，J＝5.3，9.2Hz)。
MS(ESI)m/z 332(M-H)-。
60B) N- (4-acetyl-2, 5-difluorophenyl) methanesulfonamide
A tube suitable for microwaveable reactions was charged with a mixture of palladium (II) acetate (20mg, 0.09mmol), 1, 3-bis (diphenylphosphino) propane (74mg, 0.18mmol), the compound from example 60A (1000mg, 3.0mmol), n-butyl vinyl ether (1.94ml, 15.0mmol) and potassium carbonate (622mg, 4.5mmol) in DMF (7.5ml) -water (1.9 ml). The mixture was subjected to microwave irradiation at 100 ℃ and stirred for 30 minutes. The mixture was diluted with THF, acidified with 2M aqueous HCl and stirred at room temperature for 2 hours. The mixture was extracted with EtOAc and the organic layer was dried over sodium sulfate and then concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with hexane/EtOAc (3: 1) to give the title compound (353mg, 47% yield) as a white solid.
1H NMR(270MHz，CDCl3)δ2.63(3H，s)，3.15(3H，s)，6.95(1H，br s)，7.45(1H，dd，J＝6.3，11.5Hz)，7.71(1H，dd，J＝6.3，10.9Hz)。MS(ESI)m/z 248(M-H)-。
60C) N- [4- ((1R) -1- { [ (R) -tert-butylsulfinyl]Amino } ethyl) -2, 5-difluorobenzene Base of]Methane sulfonamides
To a solution of the compound from example 60B (350mg, 1.4mmol) and titanium (IV) ethoxide (2.6ml) in THF (2.6ml) was added (R) - (+) -2-methyl-2-propanesulfinamide (170mg, 1.4mmol) under a nitrogen atmosphere and the mixture was stirred at 70 ℃ for 30 h. After cooling to 0 deg.C, sodium borohydride (159mg, 4.2mmol) was added to the mixture. The mixture was allowed to warm to room temperature, stirred for 18 hours, and then quenched with MeOH and water. The resulting precipitate was filtered off and the filtrate was concentrated in vacuo to give the title compound (882mg, 100% yield) as a yellow solid.
1H NMR(270MHz，DMSO-d6) δ 1.09(9H, s), 1.32(3H, d, J ═ 6.6Hz), 2.54(3H, s), 4.43-4.50(1H, m), 6.88-6.97(2H, m). No signal due to NH was observed.
MS(ESI) m/z 355(M+H)+，353(M-H)-。
60D) N- {4- [ (1R) -1-aminoethyl]-2, 5-difluorophenyl } methanesulfonamide hydrochloride
A mixture of the compound from example 60C (882mg, 1.4mmol) and HCl-MeOH (10%, 10ml) was stirred at room temperature for 24 h, then concentrated in vacuo. Diethyl ether and MeOH were added to precipitate the amine hydrochloride. The precipitate was then filtered and washed with diethyl ether to give the title compound (540mg, 100% yield) as a white solid.
1H NMR(270MHz，DMSO-d6)δ1.53(3H，d，J＝6.6Hz)，3.12(3H，s)，4.45(1H，br s)，7.33(1H，dd，J＝6.9，10.9Hz)，7.74-7.80(1H，m)，8.84(2H，br s)，10.06(1H，br s)。
MS(ESI)m/z 249(M-H)-。
6E) (1S, 2S) -N- ((1R) -1- {2, 5-difluoro-4- [ (methylsulfonyl) amino]Phenyl group } B 2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 60D (176mg, 0.614mmol) in DMF (10ml) was added the compound from example 14C (100mg, 0.41mmol), HBTU (233mg, 0.61mmol) and triethylamine (0.23ml, 1.64mmol) at room temperature. After stirring at room temperature for 14 hours, the mixture was concentrated. The crude product was purified by column chromatography on silica gel eluting gradually with hexane/EtOAc (2: 1) to hexane/EtOAc (1: 1) to give a pale yellow solid which was recrystallized from EtOAc-hexane to give the title compound (102mg, 53% yield) as a white solid.
1H-NMR(270MHz，DMSO-d6)δ1.29-1.36(5H，m)，1.44(3H，s)，2.00-2.05(1H，m)，3.08(3H，s)，5.09-5.19(1H，m)，7.14-7.30(2H，m)，7.54(2H，d，J＝8.6Hz)，7.69(2H，d，J＝8.6Hz)，8.71(1H，d，J＝7.9Hz)，9.81(1H，s)。
MS(ESI)m/z 477(M+H)+，475(M-H)-。
Example 61
(1S, 2S) -N- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino]Phenyl } ethyl) - 2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
61A) N- (4-bromo-2, 6-difluorophenyl) methanesulfonamide
To a solution of 4-bromo-2, 6-difluoroaniline (3.0g, 14.4mmol) in pyridine (20ml) was added methanesulfonyl chloride (2.23ml, 28.8mmol) at room temperature. The mixture was then stirred at 50 ℃ for 6 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The resulting residue was dissolved in THF (40 ml). To this solution was added 2M aqueous sodium hydroxide (40ml), and the reaction was stirred at room temperature for 4 hours. The mixture was acidified with 2M aqueous HCl and extracted all with EtOAc. The organic layer was washed with 2M aqueous HCl, brine and dried over sodium sulfate. After concentration in vacuo, the title compound (4.05g, 98% yield) was obtained as an orange solid.
1H NMR(270MHz，CDCl3)δ3.22(3H，s)，6.08(1H，br s)，7.17-7.24(2H，m)。
MS(ESI)m/z 286(M+H)+，284(M-H)-。
61B) N- (4-acetyl-2, 6-difluorophenyl) methanesulfonamide
A tube suitable for the microwave reaction was charged with a mixture of palladium (II) acetate (12mg, 0.05mmol), 1, 3-bis (diphenylphosphino) propane (43mg, 0.11mmol), the compound from example 61A (500mg, 1.75mmol), n-butyl vinyl ether (1.1ml, 8.75mmol) and potassium carbonate (290mg, 2.10mmol) in DMF (4.8ml) -water (1.2 ml). The mixture was subjected to microwave irradiation at 100 ℃ and stirred for 30 minutes. The mixture was diluted with THF, acidified with concentrated HCl and stirred at room temperature for 14 hours. The mixture was partitioned between EtOAc and water. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting gradually with hexane/EtOAc (2: 1) to hexane/EtOAc (1: 1) to give the title compound (214mg, 49%) as a white solid.
1H NMR(270MHz，CDCl3) δ 2.59(3H, s), 3.32(3H, s), 7.55-7.63(2H, m). No signal due to NH was observed. MS (ESI) M/z 248(M-H)-。
61C) N- [4- ((1R) -1- { [ (R) -tert-butylsulfinyl]Amino } ethyl) -2, 6-difluorobenzene Base of]Methane sulfonamides
To a solution of the compound from example 61B (270mg, 1.1mmol) and titanium (IV) ethoxide (2ml) in THF (2ml) was added (R) - (+) -2-methyl-2-propanesulfinamide (131mg, 1.1mmol) under a nitrogen atmosphere and the mixture was stirred at 70 ℃ for 18 h. After cooling to-20 deg.C, sodium borohydride (123mg, 3.2mmol) was added to the mixture. The mixture was allowed to warm to room temperature, stirred for 16 h, then quenched with MeOH and water and the resulting white precipitate filtered off. The filtrate was concentrated in vacuo to give the title compound (423mg, 100%) as a yellow solid.
1H NMR(270MHz，CDCl3) δ 1.18(9H, s), 1.40(3H, d, J ═ 6.6Hz), 2.92(3H, s), 3.84-3.85(1H, m), 4.30-4.38(1H, m), 6.87(2H, d, J ═ 8.6 Hz). No signal due to NH was observed.
61D) N- {4- [ (1R) -1-aminoethyl]-2, 6-difluorophenyl } methanesulfonamide hydrochloride
A mixture of the compound from example 61C (423mg, 1.1mmol) and HCl-MeOH (10%, 10ml) was stirred at room temperature for 24 h, then concentrated in vacuo. Diethyl ether and MeOH were added to precipitate the amine hydrochloride. The precipitate was filtered and washed with diethyl ether to give the title compound (290mg, 94%) as a yellow solid.
1H NMR(270MHz，DMSO-d6)δ1.51(3H，d，J＝6.6Hz)，3.08(3H，s)，4.44(1H，br s)，7.44-7.47(2H，m)，8.67(2H，br s)，9.67(1H，s)。MS(ESI)m/z 249(M-H)-。
61E) (1S, 2S) -N- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino]Phenyl group } B 2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 61D (117mg, 0.41mmol) in DMF (5ml) was added the compound from example 14C (100mg, 0.41mmol), HBTU (233mg, 0.61mmol) and triethylamine (0.17ml, 1.23mmol) at room temperature. After stirring at room temperature for 18 h, the mixture was concentrated, diluted with EtOAc, then washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with gradually from hexane/EtOAc (3: 1) to hexane/EtOAc (2: 1) to give a light yellow solid. With XTerra MSC18, 5 μm (column size; 30X 50mm, ambient temperature, solvent; CH) 3CN/0.05% HCOOH aq.) to give a white solid, which was triturated with hexane-EtOAc to give the title compound (59mg, 30%) as a white solid.
1H-NMR(270MHz，DMSO-d6)δ1.30-1.38(5H，m)，1.44(3H，s)，2.06-2.00(1H，m)，3.04(3H，s)，4.92-5.02(1H，m)，7.14(2H，d，J＝8.6Hz)，7.54(2H，d，J＝7.5Hz)，7.69(2H，d，J＝7.9Hz)，8.69(1H，d，J＝7.9Hz)，9.50(1H，br s)。
MS(ESI) m/z 477(M+H)+，475(M-H)-。
[α]D111.3(c is 0.50, methanol, pool temperature 21.4 ℃)
Example 62
2- [ 6-tert-butylpyridin-3-yl]-2-ethyl-N- ((1R) -1- { 3-methyl-4- [ (sulfonyl) - Amino group]Phenyl } ethyl) cyclopropanecarboxamide
62A)1- [ 6-tert-butylpyridin-3-yl]Propane-1-ones
To a 10% aqueous solution (22ml) of 3-propionyl pyridine (Lancaster, 2.70g, 20mmol) in sulfuric acid was added trimethylacetic acid (10.21g, 0.1mol), silver nitrate (0.68g, 4mmol) and an aqueous solution (36ml) of ammonium persulfate, and the mixture was stirred at 70 ℃ for 1.5 hours. The mixture was then basified with 25% ammonia solution (pH 9-10) and extracted with DCM. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed to give a residue, which was purified by column chromatography eluting with hexane/EtOAc (5: 1) to give the title compound (3.75g, 98%) as a yellow oil.
1H NMR(270MHz，CDCl3)δ1.24(3H，t，J＝7.3Hz)，1.39(9H，s)，3.01(2H，q，J＝7.3Hz)，7.44(1H，d，J＝7.3Hz)，8.17(1H，dd，J＝2.2Hz，8.1Hz)，9.12(1H，d，J＝1.5Hz)。MS(ESI)m/z 192.08(M+H)+。
62B) 2-tert-butyl-5- (1-methylenepropyl) pyridine
A mixture of sodium hydride (0.80g, 20mmol) and DMSO (10ml) was stirred at 80 ℃ for 45 min. To this reaction was then added a solution of methyl triphenyl bromide * (7.15g, 20mmol) in DMSO (10ml) and the reaction was stirred at room temperature for 1 hour. To this reaction was then added dropwise a solution of the compound from example 62A (1.91g, 10mmol) in DMSO (10ml) and the reaction was stirred at room temperature for 20 h. After quenching with saturated aqueous sodium bicarbonate, the resulting product was extracted with diethyl ether, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with hexane/EtOAc (10: 1) to give the title compound (1.89g, 100%) as a yellow oil.
1H NMR(270MHz，CDCl3)δ1.12(3H，t，J＝7.9Hz)，1.37(9H，s)，2.50(2H，q，J＝7.3Hz)，5.10(1H，br.s)，5.30(1H，br.s)，7.29(1H，dd，J＝1.3Hz，8.6Hz)，7.62(1H，dd，J＝2.6Hz，8.6Hz)，8.63(1H，d，J＝1.3Hz)。
MS(ESI)m/z 190.22(M+H)+。
62C)2- [ 6-tert-butylpyridin-3-yl]-2-ethylcyclopropanecarboxylic acid ethyl ester
To a solution of the compound from example 62B (1.89g, 10mmol) in toluene (100ml) were added Co (TPP) (0.17g, 0.25mmol), 1-methyl-1H-imidazole (2.39ml, 30mmol) and ethyl diazoacetate (1.58ml, 15mmol), and the mixture was stirred at room temperature for 5 minutes followed by another stirring at 80 ℃ for 1.5 hours. The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica eluting with hexane/EtOAc (1: 10) to give the title compound (1.34g, 49%, trans) as a brown oil.
1H NMR(270MHz，CDCl3)δ0.79(3H，t，J＝7.3Hz)，1.31(3H，dt，J＝2.0Hz，7.3Hz)，1.36(9H，s)，1.82(1H，dd，J＝2.0Hz，7.3Hz)，1.87(1H，dd，J＝2.6Hz，7.3Hz)，1.94(1H，dd，J＝5.9Hz，7.9Hz)，4.21(2H，q，J＝6.6Hz)，4.28(2H，q，J＝6.6Hz)，7.27(1H，d，J＝7.9Hz)，7.53(1H，dd，J＝2.0Hz，7.9Hz)，8.51(1H，d，J＝2.3Hz)。
MS(ESI)m/z 276.23(M+H)+。
62D)2- [ 6-tert-butylpyridin-3-yl]-2-ethylcyclopropanecarboxylic acid
To a solution of the compound from example 62C (1.34g, 4.87mmol) in ethanol (20ml) was added 2M aqueous sodium hydroxide (5ml) and the mixture was stirred at 80 ℃ for 6 hours. After completion of the reaction, the basic mixture was washed with diethyl ether. The aqueous layer was acidified with 2M aqueous HCl (5ml, pH 5-6) and the whole was extracted with DCM followed by evaporation to give the title compound (0.63g, 52%) as a brown solid.
1H NMR(270MHz，CDCl3) δ 0.84(3H, t, J ═ 7.3 z), 1.30-1.46(10H, m, including 9H, s, 1.36ppm), 1.49(1H, t, J ═ 5.3Hz), 1.91(2H, q, J ═ 7.3Hz), 1.98(1H, dd, J ═ 5.9Hz, 7.9Hz), 7.29(1H, d, J ═ 7.9Hz), 7.55(1H, dd, J ═ 2.6Hz, 7.9Hz), 8.53(1H, d, J ═ 2.0 Hz).
MS(ESI)m/z 248.22(M+H)+。
62E)2- [ 6-tert-butylpyridin-3-yl]-2-ethyl-N- ((1R) -1- { 3-methyl-4- [ (sulfonyl) Radical) amino]Phenyl } ethyl) cyclopropanecarboxamide
To a solution of the compound from example 62D (150mg, 0.61mmol) in DMF (6ml) were added HBTU (276mg, 0.73mmol), triethylamine (0.25ml, 1.82mmol) and the compound from example 2D (160mg, 0.61mmol), and the mixture was stirred at room temperature for 24 h. The same procedure as described in example 14D was carried out to give the title compound (212mg, 76%) as a white solid.
1H-NMR(300HMz，DMSO-d6) δ 0.54(1.5H, t, J ═ 7.3Hz), 0.71(1.5H, t, J ═ 6.6Hz), 1.06-1.19(1H, m), 1.19-1.26(1H, m), 1.30(9H, s), 1.36(3H, d, J ═ 6.6Hz), 1.67(1H, q, J ═ 7.3Hz), 1.79(1H, q, J ═ 8.1Hz), 1.91-2.02(1H, m), 2.29, 2.30(3H, s), 2.94, 2.95(3H, s), 4.85-5.01(1H, m), 7.10-7.28(2H, m), 7.37(1H, d, J ═ 8.1, 7.60, 7.01 (1H, 60, 7.72H, 7.53H, 1H, 3 br), 1.7.7.7.28 (8H, m), 7.7.7.8H, 8H, 3H, 1H, m).
MS(ESI)m/z 458.21(M+H)+. Compound (TG/DTA) at m.p.209.9 ℃. C25H35N3O3Analytical calculation of S: c, 65.61; h, 7.71; and N, 9.18. Measured value: c, 65.55; h, 7.65; and N, 9.16.
Example 63
N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ]Phenyl } ethyl) -2- (methoxy) propanoic acid 2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
63A)1- [1, 1-bis- (methoxy) ethyl]-4- (trifluoromethyl) benzene
To a stirred solution of 4- (trifluoromethyl) acetophenone (purchased from Aldrich, 3.76g, 20mmol) in MeOH (3ml) were added sequentially trimethyl orthoformate (2.33g, 22mmol) and tetrabutylammonium tribromide (96.4mg, 0.2 mmol). The mixture was stirred at room temperature for 24 hours, quenched with saturated aqueous sodium bicarbonate and extracted with diethyl ether. The organic layer was washed with brine and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo to give the crude title compound (5.95g) as a colorless oil.
1H NMR(270MHz，CDCl3) δ 1.56(3H, m), 3.19(6H, s), 7.61(4H, s). MS (ESI) M/z No M was observed+Peak(s).
63B)1- [ 1-methoxy) ethenyl]-4- (trifluoromethyl) benzene
To a solution of the compound from example 63A (crude 5.95g, 20mmol) in diglyme (2ml) were added succinic anhydride (2.20g, 22mmol), benzoic acid (61mg, 0.5mmol) and pyridine (1.58g, 20mmol) and the mixture was stirred at 110 ℃ for 1.5 h. The reaction was quenched with 2M aqueous sodium hydroxide and extracted all with diethyl ether. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude title compound (7.80g) as a brown oil.
1H NMR(300MHz，CDCl3)δ3.76(3H，s)。4.33(1H，d，J＝2.9Hz)，4.75(1H，d，J＝3.7Hz)，
7.59(2H, d, J ═ 8.1Hz), 7.72(2H, d, J ═ 8.1 Hz). MS (ESI) M/z No M was observed+Peak(s).
63C)2- (methoxy) -2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxylic acid ethyl ester
To a solution of the compound from example 63B (crude 7.80g, 20mmol) in toluene (100ml) were added Co (TPP) (0.34g, 0.5mmol), 1-methyl-1H-imidazole (4.78ml, 60mmol) and ethyl diazoacetate (3.15ml, 30mmol), and the mixture was stirred at room temperature for 5 minutes followed by another 4 hours at 80 ℃. The reaction mixture was diluted with EtOAc, washed with 2M HCl solution, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product. The crude product was purified by column chromatography on silica eluting with hexane/EtOAc (1: 10) to give the title compound (4.00g, trans) as a brown oil.
1H NMR(270MHz，CDCl3)δ1.31(3H，t，J＝7.3Hz)，1.45-1.60(1H，m)，2.02-2.20(2H，m)，3.19(3H，s)，4.24(2H，q，J＝7.3Hz)，7.45(2H，d，J＝8.6Hz)，7.63(2H，d，J＝7.9Hz)。
MS (ESI) M/z No M was observed+Peak(s).
63D)2- (methoxy) -2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxylic acid
To a solution of the compound from example 63C (crude 4.00g, 20mmol) in ethanol (100ml) was added 2M aqueous sodium hydroxide (30ml) and the mixture was stirred at 50 ℃ for 14 h. After completion of the reaction, the basic mixture was washed with DCM. The aqueous layer was acidified with 2M aqueous HCl and all extracted with DCM followed by evaporation to give the crude product. The crude product was purified by column chromatography eluting with hexane/EtOAc (1: 1) to give the title compound (0.40g, 8%, 4 steps) as a brown solid.
1H NMR(270MHz，CDCl3)δ1.61(1H，m)，2.01(1H，t，J＝6.5Hz)，2.16(1H，t，J＝7.2Hz)，3.30(3H，s)，7.47(2H，d，J＝7.9Hz)，7.65(2H，d，J＝7.9Hz)。
MS(ESI)m/z 259.18(M-H)+。
63E) N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- (methoxy group 2- [4- (trifluoromethyl) phenyl ] -phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 63D (130mg, 0.50mmol) in DMF (3ml) were added HBTU (228mg, 0.60mmol), triethylamine (0.21ml, 1.5mmol) and the compound from example 2D (132mg, 0.50mmol), and the mixture was stirred at room temperature for 20 hours. The same procedure as described in example 14D was performed to give the title compound (173mg, 73%). The resulting racemic compound 60mg was separated using DAICEL CHIRALCEL OJ-H (column size: 2X 25cm, mobile phase: 0.1% diethylamine in hexane/ethanol 70/30, column temperature: 40 ℃, flow rate: 20ml/min, detection: 230nm, retention time: 5min and 7 min). The latter fraction was collected as a white solid (25 mg).
1H-NMR(270HMz，DMSO-)δ1.32(3H，t，J＝7.3Hz)，1.43(1H，dd，J＝5.9Hz，8.6Hz)，1.89(1H，dd，J＝5.9Hz，7.3Hz)，2.20(1H，dd，J＝7.9Hz，9.2Hz)，2.28(3H，s)，2.94(3H，s)，3.17(3H，s)，4.90(1H，m)，7.05-7.25(3H，m)，7.54(2H，d，J＝7.9Hz)，7.74(2H，d，J＝8.6Hz)，8.48(1H，d，J＝7.9Hz)，8.90(1H，br.s)。
MS(ESI)m/z 471.22(M+H)+。
Example 64
2- [ 4-tert-butylphenyl group]-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]- Phenyl } ethyl) -2- (methoxy) cyclopropanecarboxamide
64A)1- [1, 1-bis (methoxy) ethyl]-4-tert-butylbenzene
To a stirred solution of 4' -tert-butylbenzophenone (purchased from Aldrich, 1.76g, 10mmol) in MeOH (1ml) were added sequentially trimethyl orthoformate (1.97g, 11mmol) and tetrabutylammonium tribromide (48.2mg, 0.1 mmol). The same reaction procedure as described in example 63A was conducted to give the title compound (2.33g) as a yellow oil.
1H NMR(300MHz，CDCl3)δ1.32(9H，s)，1.54(3H，s)，3.19(6H，s)，7.36(2H，d，J＝8.8Hz)，7.41(2H，d，J＝8.8Hz)。
64B) 4-tert-butyl-1- [1- (methoxy) ethenyl]Benzene and its derivatives
To a solution of the compound from example 64A (crude 2.33g, 10mmol) in diglyme (1ml) was added succinic anhydride (1.10g, 11mmol), benzoic acid (30.5mg, 0.25mmol) and pyridine (0.79g, 10mmol) successively. The same reaction procedure as described in example 63B was carried out to give the title compound (4.28g) as a red oil.
1H NMR(300MHz，CDCl3) δ 1.32(9H, s), 3.74(3H, s), 4.18(1H, d, J ═ 2.9Hz), 4.62(1H, d, J ═ 3.0Hz), 7.36(2H, d, J ═ 8.0Hz), 7.55(2H, d, J ═ 8.0 Hz). MS (ESI) M/z No M was observed+Peak(s).
64C)2- [ 4-tert-butylphenyl group]-2- (methoxy) cyclopropanecarboxylic acid ethyl ester
To a solution of the compound from example 64B (crude 4.28g, 10mmol) in toluene (100ml) were added successively Co (TPP) (0.34g, 0.5mmol), 1-methyl-1H-imidazole (2.39ml, 30mmol) and ethyl diazoacetate (1.58ml, 15 mmol). The same procedures as described in example 63C were carried out to give the title compound (0.45g, 16%, 3 steps) as a red oil.
1H NMR(300MHz，CDCl3)δ1.29(3H，t，J＝6.6Hz)，1.32(9H，s)，1.46(1H，dd，J＝5.7Hz，8.7Hz)，1.90-2.05(1H，m)，2.05-2.20(1H，m)，3.23(3H，s)，4.10-4.30(2H，m)，7.28(2H，d，J＝8.1Hz)，7.38(2H，d，J＝8.1Hz)。
MS(ESI)m/z 277.25(M+H)+。
64D)2- [ 4-tert-butylphenyl group]-2- (methoxy) cyclopropanecarboxylic acid
To a solution of the compound from example 64C (0.45g, 1.62mmol) in THF (5ml) was added 2M aqueous sodium hydroxide (1ml) and MeOH (5ml) and the mixture was stirred at room temperature for 20 h, followed by an additional stirring at 70 ℃ for 8 h. The same procedure as described in example 63D was carried out to give the title compound (0.18g, 45%) as a brown oil.
1H NMR(300MHz，CDCl3)δ1.32(9H，s)，1.50-1.70(1H，m)，1.80-1.96(1H，m)，2.07-2.17(1H，m)，3.36(3H，s)，7.30(2H，d，J＝8.0Hz)，7.40(2H，d，J＝8.0Hz)。
MS(ESI)m/z 247.29(M-H)+。
64E)2- [ 4-tert-butylphenyl group]-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino] Phenyl } ethyl) -2- (methoxy) cyclopropanecarboxamide
To a solution of the compound from example 64D (105mg, 0.42mmol) in DMF (2ml) were added EDC (122mg, 0.63mmol), HOBt (83mg, 0.63mmol), triethylamine (0.24ml, 1.69mmol) and the compound from example 2D (112mg, 0.42mmol), and the mixture was stirred at room temperature for 24 hours. The same procedure as described in example 10E was carried out to give the title compound (123mg, 63%) as a white solid.
1H-NMR(270HMz，CDCl3)δ1.32(9H，s)，1.46(3H，d，J＝7.3Hz)，1.50-1.63(1H，m)，1.69(1H，t，J＝5.9Hz)，1.92(1H，dd，J＝7.3Hz，9.9Hz)，2.31(3H，s)，3.01(3H，s)，3.23(3H，s)，5.10(1H，m)，6.12(1H，br.s)，6.47(1H，br.d，J＝7.9Hz)，7.14-7.30(4H，m)，7.33-7.45(3H，m)。
MS(ESI)m/z 459.28(M+H)+。m.p.230.8℃(TG/DTA)。
C25H34N2O4S·0.2 H2Analytical calculation of O: c, 64.96; h, 7.50; and N, 6.06. Measured value: c, 64.74; h, 7.38; and N, 5.99.
Example 65
2- [ 4-tert-butyl-2-pyridin-4-ylphenyl]-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
65A) 2-bromo-4-tert-butyl-1-vinylbenzene
To a stirred suspension of methyltriphenylbromide * (12.3g, 33.7mmol) in dry THF (40ml) at 0 deg.C was added n-butyllithium (1.60mol/l, in hexane) (33.7mmol, 21.1 ml). After 30 minutes at 0 ℃, a solution of 2-bromo-4-tert-butylbenzaldehyde (4.06g, 16.8mmol) (prepared according to j.med. chem.2005, 48, 71-90) in anhydrous THF (10ml) was added thereto at 0 ℃. The reaction mixture was stirred at ambient temperature for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography eluting with hexane to give the title compound (3.27g, 81%) as a colorless oil.
1H NMR(270MHz，CDCl3)δ1.31(9H，s)，5.28-5.35(1H，m)，5.62-5.72(1H，m)，6.96-7.10(1H，m)，7.28-7.34(1H，m)，7.47-7.52(1H，m)，7.54-7.56(1H，m)。
65B)2- [ 2-bromo-4-tert-butylphenyl ] -2]Cyclopropanecarboxylic acid ethyl ester
To a stirred solution of the compound from example 65A (3.27g, 13.7mmol), N-methylimidazole (3.27ml, 41.0mmol) and Co (TPP) (276mg, 0.41mmol) in toluene (25ml) was added ethyl diazoacetate (2.01ml, 19.2mmol) at ambient temperature in one portion. The same procedure as described in example 2H was followed to give the title compound (3.46g, 78%, trans) as a dark yellow oil.
1H NMR(270MHz，CDCl3)δ1.25-1.36(13H，m)，1.55-1.65(1H，m)，1.73-1.82(1H，m)，2.62-2.72(1H，m)，4.12-4.30(2H，m)，6.91-6.97(1H，m)，7.21-7.28(1H，m)7.58-7.56(1H，m)。
65C)2- [ 2-bromo-4-tert-butylphenyl ] -2]Cyclopropanecarboxylic acid phenylmethyl ester
A mixture of the compound from example 65B (3.46g, 10.6mmol) in 2M aqueous sodium hydroxide (10.6ml, 21.3mmol) and MeOH (50ml) was heated at 45 ℃ for 5 h. After cooling to ambient temperature, the solvent was evaporated in vacuo and the residue was diluted with water. The aqueous solution was washed with diethyl ether, acidified to pH3 with 2M aqueous HCl, and extracted with DCM. The combined solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude acid compound (2.93g) as a pale purple solid. A mixture of the crude acid (2.91g, 9.78mmol), benzyl chloroformate (1.76g, 9.78mmol), triethylamine (1.09g, 10.8mmol) and 4- (dimethylamino) pyridine (120mg, 0.98mmol) in dry DCM (40ml) was stirred at 0 deg.C for 1 hour. The resulting mixture was diluted with DCM and saturated aqueous ammonium chloride. The organic layer was separated and the aqueous solution was extracted with DCM. The combined solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography eluting with hexane/EtOAc (50: 1-30: 1) to give the title compound (3.21g, 78%) as a colorless oil.
1H NMR(270MHz，CDCl3)δ1.28(9H，s)，1.25-1.40(1H，m)，1.60-1.69(1H，m)，1.79-1.87(1H，m)，2.65-2.76(1H，m)，5.13-5.26(2H，m)，6.91-6.96(1H，m)，7.21-7.26(1H，m)，7.30-7.42(5H，m)，7.55-7.58(1H，m)。
65D)2- [ 4-tert-butyl-2-pyridin-4-ylphenyl]Cyclopropanecarboxylic acid phenylmethyl ester
A mixture of the compound from example 65C (1.00g, 2.58mmol), 4-pyridylboronic acid (381mg, 3.10mmol), tetrakis (triphenylphosphine) palladium (0) (298mg, 0.26mmol) in 2M aqueous sodium carbonate (3.87ml, 7.74mmol), toluene (15ml) and ethanol (4ml) was heated at 100 ℃ for 12 h. After cooling to ambient temperature, the mixture was diluted with EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by column chromatography on silica gel eluting with hexane/EtOAc (5: 1) to give the title compound (873mg, 88%) as a yellow viscous oil.
1H NMR(270MHz，CDCl3)δ1.32(9H，s)，1.22-1.37(1H，m)，1.46-1.56(1H，m)，1.72-1.81(1H，m)，2.42-2.52(1H，m)，4.97-5.13(2H，m)，7.01-7.06(1H，m)，7.21-7.43(9H，m)，8.54-8.59(2H，m)。
65E)2- [ 4-tert-butyl-2-pyridin-4-ylphenyl]Cyclopropanecarboxylic acid
A mixture of the compound from example 65D (870mg, 2.26mmol) in MeOH (30ml) was hydrogenated over 10% Pd-C (100mg) under balloon pressure for 5 h. The catalyst was filtered through a pad of celite and the filter cake was washed with MeOH. After evaporation of the filtrate in vacuo, the residue was recrystallized from EtOAc-hexanes to give the title compound (591mg, 89%) as a white solid.
1H NMR(270MHz，CDCl3)δ1.34(9H，s)，1.40-1.59(3H，m)，2.28-2.38(1H，m)，7.13-7.18(1H，m)，7.24-7.27(1H，m)，7.37-7.48(3H，m)，8.55-8.60(2H，m)。
65F)2- [ 4-tert-butyl-2-pyridin-4-ylphenyl ]-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) sulfonic acid Acyl) amino]Phenyl } ethyl) cyclopropanecarboxamide
To a stirred solution of the amine compound from example 2D (122mg, 0.46mmol), the compound from example 65E (136mg, 0.46mmol), HOBt (70mg, 0.46mmol) and EDC (159mg, 0.83mmol) in anhydrous DMF (5ml) at ambient temperature was added triethylamine (106mg, 1.84 mmol). The same procedure as described in example 1 was carried out to give the title compound (182mg, 78%, mixture of diastereomeric products (1: 1)) as a pale yellow amorphous solid.
1H NMR(270MHz，CDCl3) δ 1.05-1.30(2H, m), 1.32 and 1.33 (total of 9H, each s), 1.38-1.55(4H, m), 2.30 and 2.35 (total of 3H, each s), 2.38-2.58(1H, m), 3.00 and 3.06 (total of 3H, each s), 4.86-5.10(1H, m), 5.37-5.45 and 5.64-5.71 (total of 1H, each m), 6.20-6.50(1H, br.s), 6.98-7.48(8H, m), 8.37-8.42(1H, m), 8.65-8.69(1H, m) ms (esi): m/z 504(M-H)-，m/z506(M+H)+。
Example 66
2- [ 3-fluoro-4- (trifluoromethyl) phenyl]-2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
66A) 2-fluoro-4- (1-methylethenyl) -1- (trifluoromethyl) benzene
DMSO (40ml) was added in one portion to a 60% sodium hydride suspension (1.96g, 49.0mmol) at 0 ℃ and the reaction mixture was heated at 80 ℃ for 40 min. After cooling to ambient temperature, a 0 ℃ solution of methyltriphenylbromide * (17.5g, 49.0mmol) in anhydrous DMSO (50ml) was added dropwise. After stirring for 1 hour at ambient temperature, a 0 ℃ solution of 1- [ 3-fluoro-4- (trifluoromethyl) phenyl ] ethanone (5.04g, 24.5mmol) in anhydrous DMSO (40ml) was added dropwise and the reaction stirred for 1.5 hours at ambient temperature. The mixture was quenched with water (150ml) and extracted with hexane. The combined solutions were washed with water, then brine, dried over sodium sulfate and concentrated in vacuo to give the crude title compound (3.20g, containing hexanes) as a yellow oil.
1H NMR(270MHz，CDCl3)δ2.15(3H，s)，5.24(1H，s)，5.47(1H，s)，7.22-7.35(2H，m)，7.51-7.59(1H，m)。
66B)2- [ 3-fluoro-4- (trifluoromethyl) phenyl]-2-methylcyclopropanecarboxylic acid ethyl ester
To a stirred solution of the compound from example 66A (3.20g, 15.7mmol), N-methylimidazole (3.86ml, 47.0mm0l) and Co (TPP) (316mg, 0.47mmol) in toluene (30ml) was added ethyl diazoacetate (2.50g, 21.9mmol) in one portion at ambient temperature. The same procedure as described in example 2H was carried out to give the title compound (1.40g, 31%, trans) as a dark violet oil.
1H NMR(270MHz，CDCl3)δ1.31(3H，t，J＝7.3Hz)，1.39-1.47(1H，m)，1.54(3H，s)，1.49-1.57(1H，m)，1.93-2.00(1H，m)，4.13-4.31(2H，m)，7.06-7.19(2H，m)，7.49-7.58(1H，m)。
66C)2- [ 3-fluoro-4- (trifluoromethyl) phenyl]-2-methylcyclopropanecarboxylic acid
A mixture of the compound from example 66B (1.40g, 4.82mmol) in 2M aqueous sodium hydroxide (10ml) and MeOH (30ml) was heated at 80 ℃ for 6 h. After cooling to ambient temperature, the solvent was evaporated in vacuo and the residue was diluted with water. The aqueous layer was washed with diethyl ether and acidified to pH < 2 with 2M aqueous HCl. The mixture was extracted with DCM and the organic layers were combined, washed with water, then brine, dried over sodium sulfate and concentrated in vacuo to give the title compound (1.19g, 94%) as a pale brown solid.
1H NMR(270MHz，CDCl3)δ1.49-1.62(2H，m)，1.60(3H，s)，1.96-2.04(1H，m)，7.10-7.22(2H，m)，7.51-7.60(1H，m)。
66D)2- [ 3-fluoro-4- (trifluoromethyl) phenyl]-2-methyl-N- ((1R) -1- { 3-methyl -4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
To a stirred solution of the compound from example 2D (200mg, 0.76mmol), the compound from example 66C (198mg, 0.76mmol) and HBTU (344mg, 0.91mmol) in anhydrous DMF (10ml) at ambient temperature was added triethylamine (229mg, 2.27 mmol). The same procedure as described in example 14D was carried out to give the title compound (333mg, 94%, mixture of diastereomeric products (1: 1)) as a white solid.
1H NMR(270MHz，CDCl3)δ1.33-1.80(9H，m)，2.32(3H，s)，3.00-3.03(3H，m)，5.04-5.18(1H，m)，5.87-5.97(1H，m)，6.24(1H，br.s)，7.01-7.22(4H，m)，7.38-7.44(1H，m)，7.48-7.57(1H，m)。
MS(ESI)：m/z 471(M-H)-，m/z 473(M+H)+。
Example 67
N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [ 3-fluoro-4- (trifluoromethyl) phenyl]-2-methylcyclopropanecarboxamide
To a stirred solution of the amine compound from example 8 (200mg, 0.74mmol), the compound from example 66C (195mg, 0.74mmol) and HBTU (339mg, 0.89mmol) in dry DMF (10ml) at ambient temperature was added triethylamine (226mg, 2.23 mmol). The same procedure as described in example 14D was followed to give the title compound (256mg, 72%, mixture of diastereomeric products (1: 1)) as a white solid.
1H NMR(270MHz，CDCl3) δ 1.36-1.80(9H, m), 3.01-3.04(3H, m), 5.05-5.20(1H, m), 5.89-5.99(1H, m), 7.03-7.17(4H, m), 7.48-7.58(1H, m) (no signal due to NH observed).
MS(ESI)：m/z 475(M-H)-，m/z 477(M+H)+。
Example 68
2- [ 4-tert-butyl-2- (hydroxymethyl) phenyl ]-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
68A) 5-tert-butyl-2- (2- { [ (phenylmethyl) oxy)]Carbonyl } cyclopropyl) benzoic acid methyl ester
A mixture of the compound from example 65C (1.63g, 4.20mmol), palladium acetate (94mg, 0.42mmol), 1, 3-bis (diphenylphosphino) propane (173mg, 0.42mmol), triethylamine (1.27g, 12.6mmol) and MeOH (5.38g, 168mmol) in anhydrous DMF (10ml) was heated at 80 ℃ for 15 h under a carbon monoxide balloon. After cooling to ambient temperature, the mixture was diluted with EtOAc-toluene (8: 1), washed with water and then brine, dried over sodium sulfate and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica eluting with hexane/EtOAc (10: 1) to give the title compound (1.21g, 79%) as a colorless oil.
1H NMR (270MHz，CDCl3)δ1.31(9H，s)，1.29-1.41(1H，m)，1.55-1.67(1H，m)，1.75-1.84(1H，m)，3.06-3.16(1H，m)，3.79(3H，s)，5.14-5.25(2H，m)，7.03-7.09(1H，m)，7.30-7.47(6H，m)，7.88-7.90(1H，m)。
68B)2- { 4-tert-butyl-2- [ (methoxy) carbonyl]Phenyl cyclopropanecarboxylic acid
A mixture of the compound from example 68A (1.20g, 3.27mmol) in MeOH (40ml) was hydrogenated over 10% Pd-C (150mg) under balloon pressure. The same procedure as described in example 65E was carried out to give the title compound (882mg, 98%) as a pale purple solid.
1H NMR(270MHz，CDCl3)δ1.32(9H，s)，1.35-1.46(1H，m)，1.60-1.78(2H，m)，3.07-3.20(1H，m)，3.91(3H，s)，7.05-7.11(1H，m)，7.43-7.49(1H，m)，7.91-7.94(1H，m)。
68C) 5-tert-butyl-2- (2- { [ ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino group ]Phenyl radical } Ethyl) amino group]Carbonyl } cyclopropyl) benzoic acid methyl ester
To a stirred solution of the amine compound from example 2D (370mg, 1.39mmol), the compound from example 68B (350mg, 1.27mmol), HOBt (194mg, 1.27mmol) and EDC (438mg, 2.29mmol) in anhydrous DMF (10ml) at ambient temperature was added triethylamine (514mg, 5.08 mmol). The same procedure as described in example 1 was carried out to give the title compound (503mg, 81%) as a white solid (mixture of diastereomeric products (1: 1)).
1H NMR(270MHz，CDCl3) δ 1.22-1.35(10H, m), 1.41-1.60(5H, m), 2.30-2.34(3H, m), 2.86-3.00(1H, m), 3.01(3H, s), 3.72 and 3.91 (total 3H, each s), 5.05-5.20(1H, m), 6.04-6.11(1H, m), 6.19(1H, br s), 7.02-7.08(1H, m), 7.15-7.30(2H, m), 7.37-7.48(2H, m), 7.82-7.87(1H, m).
MS(ESI)：m/z 485(M-H)-，m/z 487(M+H)+。
68D)2- [ 4-tert-butyl-2- (hydroxymethyl) phenyl]-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) sulfonic acid Acyl) amino]Phenyl } ethyl) cyclopropanecarboxamide
To a stirred suspension of lithium aluminium hydride (85mg, 1.80mmol) in dry THF (5ml) at 0 deg.C was added dropwise a solution of the compound from example 68C (437mg, 0.90mmol) in dry THF (10 ml). After stirring at ambient temperature for 3 hours, the mixture was quenched with 0 ℃ 2M aqueous HCl (10ml) and extracted with EtOAc. The combined solutions were washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by amino-linked silica gel column chromatography eluting with DCM/MeOH (40: 1) to give the title compound (360mg, 87%) as a yellow amorphous solid (mixture of diastereomeric products (1: 1)).
1H NMR(270MHz，CDCl3) δ 1.20-1.30(1H, m), 1.30 and 1.31 (total 9H, each s), 1.44-1.60(5H, m), 2.13(1H, br s), 2.29-2.32(3H, m), 2.38-2.57(1H, m), 2.98-3.00(3H, m), 4.61-4.91(2H, m), 5.02-5.16 (1H, m)H，m)，6.18-6.30(1H，m)，6.92-6.99(1H，m)，7.08-7.30(3H，m)，7.33-7.43(2H，m)。
MS(ESI)：m/z 457(M-H)-，m/z 459(M+H)+。
Example 69
N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- Methyl-2- {4- [ (trifluoromethyl) sulfonyl group]Phenyl cyclopropanecarboxamides
69A) [2- [ (methylsulfonyl) amino group]-5- ((1R) -1- { [ (2-methyl-2- {4- [ (trifluoromethyl) Sulfur based radicals]Phenyl } cyclopropyl) carbonyl]Amino } ethyl) phenyl]Methyl acetate
To a solution of the compound from example 25B (113mg, 0.224mmol), pyridine (0.2ml) and DMAP (1mg) in THF (1ml) was added acetic anhydride (23mg, 0.224mmol) at 0 deg.C and the mixture was stirred at 0 deg.C for 3 h. The reaction was then quenched with 1M aqueous HCl and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude title compound.
MS(ESI)：m/z 545(M+H)+。
69B) [2- [ (methylsulfonyl) amino group]-5- ((1R) -1- { [ (2-methyl-2- {4- [ (trifluoromethyl) Sulfonyl radical]Phenyl } cyclopropyl) carbonyl]Amino } ethyl) phenyl]Methyl acetate
To a solution of the crude compound of example 69A, sodium metaperiodate (144mg, 0.672mmol), tetrachloromethane (1ml) and acetonitrile (1ml) in water (2ml) was added ruthenium trichloride hydrate (0.1mg), and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate, extracted all with EtOAc, and dried over sodium sulfate. Filtration and evaporation then gave the crude title compound.
MS(ESI)：m/z 575(M-H)-。
69C) N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2-methyl 2- {4- [ (trifluoromethyl) sulfonyl ] -2]Phenyl cyclopropanecarboxamides
A solution of the crude compound from example 69B in MeOH (4ml) and 2M aqueous sodium hydroxide (1ml) were stirred at room temperature for 4 hours. After completion of the reaction, the mixture was quenched with 1M aqueous HCl and extracted with EtOAc. The organic layer was dried over sodium sulfate. Then filtered, evaporated and purified by silica gel column chromatography eluting with hexane/EtOAc (1: 2) to give the title compound (50mg, 42% yield, 3 steps) as a white solid (mixture of diastereomeric products (1: 1)).
1H NMR(300MHz，CDCl3)δ1.35-1.92(9H，m)，2.99-3.00(3H，m)，4.65-4.69(2H，m)，5.02-5.11(1H，m)，6.30-6.43(1H，m)，7.18-7.27(2H，m)，7.42-7.53(3H，m)，7.82-7.97(3H，m)。MS(ESI)：m/z 535(M+H)+。
Example 70
(1S, 2S) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) - 2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
In the same procedure as described in example 10E, to a solution of the compound from example 14B (63mg, 0.258mmol), triethylamine (0.11ml) and EDC (71mg, 0.387mmol) in DMF (1ml) were added HOBt (43mg, 0.284mmol) and the amine compound from example 2D (68mg, 0.258 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1: 1) to give the title compound (70mg, 60% yield) as a white solid (mixture of diastereomeric products (1: 1)).
1H NMR(300MHz，CDCl3)δ1.30-1.77(9H，m)，2.32(3H，s)，3.01-3.02(3H，m)，5.10-5.20(1H，m)，5.85-5.91(1H，m)，6.19(1H，s)，7.18-7.23(2H，m)，7.35-7.45(3H，m)，7.56(2H，d，J＝7.6Hz)。
MS(ESI)：m/z 455(M+H)+。
Example 71
2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]-2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
71A)1, 3-difluoro-5-isopropenyl-2- (2, 2, 2-trifluoro-1, 1-dimethylethyl) benzene
The compound from example 30E (3.37g, 9.05mmol), potassium isopropenyltrifluoroborate (2.0g, 13.6mmol, org. Lett.2002, 4, 107), PdCl were used2(dppf)·CH2Cl2A mixture of (370mg, 0.45mmol) and triethylamine (1.9ml, 13.6mmol) in n-propanol (90ml) was subjected to the procedure described in example 10B. The crude residue was chromatographed on silica gel eluting with a volumetric mixture of hexane and ethyl acetate (30: 1) to give the title compound (1.67g, 70% yield) as a colorless oil.
1H NMR(300MHz，CDCl3)δ1.72-1.78(6H，m)，2.10(3H，s)，5.19(1H，s)，5.43(1H，s)，6.93-6.72(2H，m)。
71B)2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]-2-methylcyclopropane Alkanecarboxylic acid ethyl ester
To a solution of the compound from example 71A (1.67g, 6.32mmol) in toluene (10ml) was added Co (TPP) (127mg, 0.19mmol), 1-methyl-1H-imidazole (2.6g, 31.6mmol) and ethyl diazoacetate (1.0g, 8.85mmol) following the procedure described for example 2H. The reaction was quenched with 1M aqueous HCl and extracted with hexane. The organic layer was dried over sodium sulfate. Then filtered and evaporated to give a crude residue, which was dissolved in a small amount of hexane and cooled to 0 ℃. The resulting precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (crude 1.95g) as a black oil.
1H NMR(300MHz，CDCl3)δ0.89-1.96(15H，m)，4.15-4.25(2H，m)，6.75-6.84(2H，m)。
71C)2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]-2-methylcyclopropane Alkanecarboxylic acid
The procedure described in example 21 was followed using a solution of the compound from example 71B (1.95g) in THF (6ml) -MeOH (6ml) and 2M aqueous sodium hydroxide (6ml) to give the title compound (886mg, 44% yield, 2 steps, trans) as a grey solid.
1H NMR(300MHz，CDCl3)δ0.85-2.00(12H，m)，6.77-6.84(2H，m)。MS(ESI)m/z 321(M-H)-。
71D)2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]-2-methyl -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) cyclopropanecarboxamide (mono One isomer)
The procedure described in example 14D was followed using a solution of the compound from example 71C (100mg, 0.31mmol) in DMF (2ml), HBTU (141mg, 0.37mmol), triethylamine (0.13ml) and the compound from example 2D (82mg, 0.31 mmol). The crude residue was chromatographed on a silica gel column eluting with a volume mixture of hexane and EtOAc (1: 1). The diastereomers were separated by HPLC (column used XTerra MS C18, 5um, 30X 50mm), eluting with acetonitrile/0.05% aqueous formic acid (32: 68 to 68: 32, later fractions were the title compound) to give the title compound (single isomer; 45mg, 27% yield) as a white solid.
1H NMR(300MHz，CDCl3)δ1.34(1H，dd，J＝5.0，8.3Hz)，1.48(3H，d，J＝7.3Hz)，1.51(3H，s)，1.50-1.68(2H，m)，1.70-1.75(6H，m)，2.31(3H，s)，3.01(3H，s)，5.05-5.15(1H，m)，5.87(1H，d，J＝7.3Hz)，6.15(1H，s)，6.69-6.77(2H，m)，7.17-7.21(2H，m)，7.41(1H，d，J＝8.6Hz)。
MS(ESI)：m/z 533(M+H)+。
Example 72
2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ]-N- ((1R) -1- { 3-ethyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) -2-methylcyclopropanecarboxamide (single isomer)
In the same procedure as described in example 14D, to a solution of the compound from example 71C (100mg, 0.31mmol) in DMF (2ml) was added HBTU (141mg, 0.37mmol), triethylamine (0.13ml) and the compound from example 32C (86mg, 0.31 mmol). The crude residue was chromatographed on silica gel eluting with a volume mixture of hexane and EtOAc (1: 1), the diastereomers were separated by HPLC (XTerra MS C18, 5um, 30X 50mm) eluting with acetonitrile/0.05% aqueous formic acid (32: 68 to 68: 32, later fractions are title compound) to give the title compound (single isomer; 48mg, 29% yield) as a white solid.
1H NMR(270MHz，CDCl3)δ1.25(3H，t，J＝7.6Hz)，1.34(1H，dd，J＝5.0，8.3Hz)，1.49(3H，d，J＝7.3Hz)，1.52(3H，s)，1.50-1.69(2H，m)，1.70-1.75(6H，m)，2.65(2H，q，J＝7.6Hz)，3.02(3H，s)，5.08-5.18(1H，m)，5.84(1H，d，J＝7.9Hz)，6.14(1H，s)，6.70-6.77(2H，m)，7.16-7.22(2H，m)，7.44(1H，d，J＝8.6Hz)。MS(ESI)：m/z 547(M+H)+。
Example 73
N- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [ 3-fluoro-4- (trifluoromethyl) phenyl]-2-methylcyclopropanecarboxamide
To a solution of the compound from example 61D (170mg, 0.59mmol) in DMF (10ml) was added the compound from example 66C (155mg, 0.591mmol), HBTU (338mg, 0.89mmol) and triethylamine (0.25ml, 1.78mmol) at room temperature. The same procedure as described in example 60E was carried out to give the title compound (50mg, 17%) as a white solid.
1H-NMR(270MHz，DMSO-d6)δ1.33-1.43(8H，m)，2.04-2.10(1H，m)，3.05(3H，s)，4.93-4.99(1H，m)，7.15(2H，d，J＝8.6Hz)，7.36(1H，d，J＝7.9Hz)，7.46(1H，d，J＝12.5Hz)，7.73(1H，t，J＝8.2Hz)，8.70(1H，d，J＝7.3Hz)，9.50(1H，s)。
MS(ESI)m/z 495(M+H)+，493(M-H)-。
[α]D89.5(c is 0.50, methanol, pool temperature 21.4 ℃)
Example 74
N- ((1R) -1- {3, 5-bisFluoro-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [ 3-fluoro- 4- (trifluoromethyl) phenyl]-2-methylcyclopropanecarboxamide
To a solution of the compound from example 61D (170mg, 0.59mmol) in DMF (10ml) was added the compound from example 66C (155mg, 0.591mmol), HBTU (338mg, 0.89mmol) and triethylamine (0.25ml, 1.78mmol) at room temperature. The same procedure as described in example 60E was carried out to give the title compound (45mg, 15%) as a white solid.
1H-NMR(270MHz，DMSO-d6)δ1.32-1.43(8H，m)，2.07-2.12(1H，m)，3.05(3H，s)，4.91-4.97(1H，m)，7.14(2H，d，J＝8.6Hz)，7.38(1H，d，J＝7.3Hz)，7.49(1H，d，J＝13.2Hz)，7.74(1H，t，J＝7.9Hz)，8.73(1H，d，J＝7.3Hz)，9.48(1H，s)。
MS(ESI)m/z 495(M+H)+，493(M-H)-。
[α]D138.7 (-0.50 c, methanol, 21.4 ℃ C.)
Example 75
N- ((1R) -1- { 3-Ethyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) -2-methyl-2- [4- (trifluoromethoxy) phenyl group]Cyclopropanecarboxamides (Single isomers)
The mixture of the diastereomeric compounds of example 29 was separated by HPLC (XTerra MS C18, 5um, 30X 50mm), eluting with acetonitrile/0.05% aqueous formic acid (32: 68 to 68: 32, the latter fractions being the title compound) to give the title compound (single isomer) as a white solid.
1H NMR(270MHz，CDCl3)δ1.25(3H，t，J＝7.6Hz)，1.35(1H，dd，J＝4.9，8.2Hz)，1.51(3H，d，J＝6.6Hz)，1.54(3H，s)，1.51-1.58(1H，m)，1.67(1H，dd，J＝5.9，8.6Hz)，2.65(2H，q，J＝7.6Hz)，3.02(3H，s)，5.10-5.20(1H，m)，5.87(1H，d，J＝7.9Hz)，6.18(1H，s)，7.14-7.30(6H，m)，7.44(1H，d，J＝7.9Hz)。
MS(ESI)：m/z 485(M+H)+。
Example 76
2- (4-tert-butyl-3, 5-difluorophenyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) - Amino group]Phenyl } propyl) cyclopropanecarboxamide
To a solution of the compound from example 34C (219mg, 0.8mmol) in DMF (10ml) were added the compound from example 38D (200mg, 0.8mmol), HBTU (390mg, 1.0mmol) and triethylamine (0.3ml, 2.4mmol) and the mixture was stirred at room temperature for 2 h. The same procedures as described in example 38E were carried out to give the title compound (101mg, 27%). The desired product had a cut time of 5.1 minutes.
1H NMR(300MHz，DMSO-d6)δ1.11-1.76(15H，m)，1.88-2.39(6H，m)，2.96(3H，s)，4.54-4.83(1H，m)，6.72-6.93(2H，m)，7.03-7.28(3H，m)，8.41-8.59(1H，m)，9.03(1H，brs)。
MS(ESI)m/z 477(M-H)-，479(M+H)+。
Example 77
N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2-methyl-2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]Cyclopropanecarboxamides (Single isomers)
In the same procedure as described in example 14D, to a solution of the compound from example 13D (200mg, 0.7mmol) in DMF (3ml) were added HBTU (319mg, 0.84mmol), triethylamine (0.29ml) and N- {4- [ (1R) -1-aminoethyl ] -2-fluorophenyl } methanesulfonamide hydrochloride (188mg, 0.7 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1: 1) to give the title compound (single isomer; 176mg, 50% yield) as a white solid.
1H NMR(270MHz，CDCl3)δ1.40(1H，dd，J＝4.6，7.9Hz)，1.48(3H，d，J＝7.3Hz)，1.49-1.60(10H，m)，1.70(1H，dd，J＝5.9，7.9Hz)，3.02(3H，s)，5.07-5.17(1H，m)，5.87(1H，d，J＝7.3Hz)，6.47(1H，s)，7.10-7.16(2H，m)，7.21-7.26(2H，m)，7.44(2H，d，J＝8.6Hz)，7.50-7.56(1H，m)。
MS(ESI)：m/z 501(M+H)+。
Example 78
2- (4-tert-butyl-3, 5-difluorophenyl) -N- ((1R) -1- { 2-fluoro-5-methyl-4- [ (methylsulfonyl) - Amino group]Phenyl } ethyl) -2-methylcyclopropanecarboxamide
To a solution of the compound from example 41D (100mg, 0.4mmol) in DMF (7ml) were added the compound from example 43C (95mg, 0.4mmol), HBTU (173mg, 0.5mmol) and trimethylamine (0.2ml, 1.1mmol) and the mixture was stirred at room temperature for 2 h. All extracted with ethyl acetate, evaporated and purified by column chromatography on silica eluting with dichloromethane/ethyl acetate (1: 1) to give the title compound (56mg, 32%).
1H NMR(300MHz，DMSO-d6)δ1.19-1.47(17H，m)，1.80-2.08(1H，m)，2.20-2.31(3H，m)，2.96-3.08(3H，m)，4.80-5.20(1H，m)，6.64-7.28(4H，m)，7.37(0.5H，brs)，8.64(1H，d，J＝7.3Hz)，9.22(0.5H，brs)。
MS(ESI)m/z 495(M-H)-，497(M+H)+。
Example 79
2- [2- (dimethylamino) -6- (trifluoromethyl) pyridin-3-yl]-N- ((1R) -1- { 2-fluoro-5-methyl- 4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
79A)2- (dimethylamino) -6- (trifluoromethyl) nicotinic acid
A mixture of 2-chloro-6- (trifluoromethyl) nicotinic acid (APOLLO, 2.5g, 11.1mmol) and 2M N-methyl methylamine in THF solvent (50ml, 25mmol) was stirred at room temperature for 24 hours according to j.med.chem., 2005, 48, 71. The reaction mixture was then evaporated in vacuo to give the title compound (2.5g, 96%).
1H NMR(270MHz，DMSO-d6)δ2.99(6H，s)，7.07(1H，d，J＝7.3Hz)，8.03(1H，d，J＝7.3Hz)。
MS(ESI)m/z 233(M-H)-，235(M+H)+。
79B) [2- (dimethylamino) -6- (trifluoromethyl) pyridin-3-yl]Methanol
To a solution of lithium aluminum tetrahydride tetrakis (1.0g, 26.8mmol) in THF (40ml) at 0 deg.C was added a solution of the compound from example 79A (2.5g, 10.7mmol) in THF (10ml), and the mixture was stirred at 0 deg.C for 5 minutes followed by another stirring at 65 deg.C for 4.5 hours. The reaction mixture was cooled to 0 ℃, partitioned with 10% aqueous sodium potassium tartrate tetrahydrate and EtOAc, and the mixture was stirred at room temperature for 2 hours. Water was added to the mixture and the organic layer was extracted, washed with 2M aqueous sodium hydroxide and brine and evaporated. The residue was purified by column chromatography on silica eluting with hexane/EtOAc (4: 1) to give the title compound (1.26g, 54%).
1H NMR(300MHz，CDCl3)δ2.92(6H，s)，4.26(2H，s)，7.23(1H，d，J＝8.1Hz)，7.76(1H，d，J＝8.1Hz)。
MS(ESI)m/z 221(M+H)+
79C)2- (dimethylamino) -6- (trifluoromethyl) nicotinaldehyde
To a solution of ethanedioldichloride (1.5ml, 11.4ml) in DCM (17ml) was added dimethyl sulfoxide (1.3ml, 17.2mmol) at-78 deg.C and the mixture was stirred for 15 min at-78 deg.C. A solution of the compound from example 79B (1.3g, 5.7mmol) in DCM was then added slowly to the mixture at-78 deg.C, and the mixture was stirred for 30 minutes, followed by the addition of triethylamine (5.8ml, 57.2mmol) and stirred for 30 minutes at-78 deg.C. The reaction temperature was allowed to warm to room temperature and stirred for 1 hour. The reaction was then quenched with water, extracted with EtOAc, dried over magnesium sulfate and the solvent evaporated. The crude residue was purified by column chromatography on silica eluting with hexane/EtOAc (7: 1) to give the title compound (1.0g, 83%).
1H NMR(300MHz，CDCl3)δ3.14-3.19(6H，m)，7.02-7.11(1H，m)，8.03-8.12(1H，m)，8.03-8.12(1H，m)，9.97-10.0(1H，m)。
79D)2- [2- (dimethylamino) -6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxylic acid
To a suspension of methyltriphenylbromide * (3.3g, 9.2mmol) in THF (20ml) at 0 deg.C was added a 1.60M solution of n-butyllithium in hexane (5.7ml, 9.2mmol) and the reaction was stirred for 30 min. A solution of the compound from example 79C (1.0g, 4.6mmol) in THF (5ml) was then added to the mixture at room temperature and the reaction stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride, extracted all with EtOAc, dried over magnesium sulfate and evaporated. The crude residue was purified by column chromatography on silica eluting with hexane/EtOAc (10: 1) to give N, N-dimethyl-6- (trifluoromethyl) -3-vinylpyridin-2-amine (847mg, 86%, trans). To a solution of this compound (840mg, 3.9mmol), Co (TPP) (78mg, 0.1mmol) and 1-methyl-1H-imidazole (1.00ml, 11.7mmol) in toluene (15ml) was added ethyl diazoacetate (0.7ml, 5.8mmol), and the mixture was stirred at room temperature for 5 minutes followed by another stirring at 80 ℃ for 2 hours. Then evaporated and purified by column chromatography on silica eluting with hexane/EtOAc (20: 1) to give ethyl 2- [2- (dimethylamino) -6- (trifluoromethyl) pyridin-3-yl ] cyclopropanecarboxylate (427mg, 36%). To a solution of this compound (427mg, 1.4mmol) in THF (5ml) were added 2M aqueous sodium hydroxide (7ml) and MeOH (7ml), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the aqueous layer was extracted and then acidified with 2M aqueous HCl. Extraction with all EtOAc followed by evaporation of the solvent gave the title compound (260mg, 67%).
MS(ESI)m/z 273(M-H)-，275(M+H)+
79E)2- [2- (dimethylamino) -6- (trifluoromethyl) pyridin-3-yl]-N- ((1R) -1- { 2-fluoro-5- Methyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
To a solution of the compound from example 41D (130mg, 0.5mmol) in DMF (10ml) were added the compound from example 79D (226mg, 0.5mmol), HBTU (227mg, 0.6mmol) and trimethylamine (0.3ml, 1.4mmol) and the mixture was stirred at room temperature for 2 hours. The same procedure as described in example 38E was followed, but using HPLC conditions of acetonitrile/0.05% aqueous formic acid 4 to 96, to give the title compound (10mg, 4%). The desired product had a cut time of 4.2 minutes.
1H NMR(300MHz，DMSO-d6) δ 1.26-1.43(5H, m), 1.93-2.04(1H, m), 2.18-2.35(4H, m), 2.92(6H, s), 2.96(3H, s), 5.06-5.21(1H, m), 7.05(1H, d, J ═ 12.5Hz), 7.23(2H, dd, J ═ 15.8, 7.7Hz), 7.50(1H, d, J ═ 7.3Hz), 8.67(1H, d, J ═ 7.3 Hz). The H of OH cannot be observed.
MS(ESI)m/z 501(M-H)-，503(M+H)+
Example 80
N- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [3, 5-difluoro- 4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl]-2-methylcyclopropanecarboxamide
To a solution of the compound from example 61D (170mg, 0.59mmol) in DMF (10ml) was added the compound from example 71C (155mg, 0.591mmol), HBTU (338mg, 0.89mmol) and triethylamine (0.25ml, 1.78mmol) at room temperature. The same procedure as described in example 60E was performed to give the title compound (50mg, 17% yield) as a white solid.
1H-NMR(270MHz，DMSO-d6)δ1.33-1.43(8H，m)，2.04-2.10(1H，m)，3.05(3H，s)，4.93-4.99(1H，m)，7.15(2H，d，J＝8.6Hz)，7.36(1H，d，J＝7.9Hz)，7.46(1H，d，J＝12.5Hz)，7.73(1H，t，J＝8.2Hz)，8.70(1H，d，J＝7.3Hz)，9.50(1H，s)。
MS(ESI)m/z 495(M+H)+，493(M-H)-。
[α]D(c is 0.56, methanol, pool temperature is 21.4 ℃)
Example 81
N- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2-methyl-2- {4- [ (trifluoromethyl) oxy group]Phenyl cyclopropanecarboxamides
To a solution of the compound from example 61D (170mg, 0.59mmol) in DMF (10ml) was added the compound from example 16C (154mg, 0.59mmol), HBTU (338mg, 0.89mmol) and triethylamine (0.25ml, 1.78mmol) at room temperature. The same procedure as described in example 60E was carried out to give the title compound (22mg, 8%) as a white solid.
1H-NMR(270MHz，DMSO-d6)δ1.25-1.41(8H，m)，1.95-2.010(1H，m)，3.05(3H，s)，4.92-5.01(1H，m)，7.15(2H，d，J＝8.6Hz)，7.32(2H，d，J＝7.9Hz)，7.45(2H，d，J＝8.6Hz)，7.45(2H，d，J＝8.6Hz)，8.69(1H，d，J＝7.9Hz)，9.49(1H，s)。
MS(ESI)m/z 493(M+H)+，491(M-H)-。
[α]D81.6(c is 0.50, methanol, pool temperature is 21.4 ℃)
Example 82
(1S, 2S) -2-methyl-N- ((1S) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } - Ethyl) -2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
82A) N- [4- ((1S) -1- { [ (S) -tert-butylsulfinyl]Amino } ethyl) -2-methylphenyl] Methane sulfonamides
To a mixture of the compound from example 2B (1.6g, 7.0mmol), titanium (IV) ethoxide (10ml) and THF (10ml) was added (S) - (-) -2-methylpropane-2-sulfinamide (846mg, 7.0mmol, available from Advanced asymmetry) and the mixture was stirred at 80 ℃ for 16 h. The mixture was cooled to room temperature, then to 0 ℃ and then added dropwise to a 0 ℃ solution of sodium borohydride (1.1g, 28 mmol). The mixture was stirred at 0 ℃ for 3 hours and then warmed to room temperature. The reaction was quenched with MeOH and stirred for 30 min. Water was added and the mixture was stirred for 10 minutes. The resulting suspension was filtered through a pad of celite and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to give a residue, which was chromatographed on silica gel, eluting with a volume of mixture of DCM and EtOAc (1/1), to give 1.76g (76% yield) of the title compound as a pale yellow solid.
MS(ESI)m/z 391[M+H]+，389[M-H]-。
82B) N- {4- [ (1S) -1-aminoethyl]-2-methylphenyl } methanesulfonamide
To a solution of the compound from example 82A (1.7g, 5.3mmol) in methanol (30ml) was added 10% hydrochloric acid-MeOH solution (30 ml). The solution was stirred at room temperature for 30min, then concentrated under reduced pressure. The resulting residue was recrystallized from MeOH-diethyl ether. The precipitate was then filtered, washed with diethyl ether and collected to give 1.2g (64% yield) of the title compound as a white solid.
MS(ESI)m/z 227[M-H]-。
82C) (1S, 2S) -2-methyl-N- ((1S) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl radical } Ethyl) -2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
To a stirred solution of the compound from example 82B (76mg, 0.29mmol), the compound from example 14C (70mg, 0.29mmol) and HBTU (131mg, 0.34mmol) in anhydrous DMF (2ml) at ambient temperature was added triethylamine (87mg, 0.86 mmol). The same procedure as described in example 14D was carried out to give the title compound as a single isomeric product (112mg, 86%) as a white solid.
1H NMR(270MHz，CDCl3)δ1.37-1.61(8H，m)，1.71-1.79(1H，m)，2.32(3H，s)，3.02(3H，s)，5.06-5.19(1H，m)，5.88-5.96(1H，m)，6.30(1H，br.s)，7.15-7.21(2H，m)，7.32-7.44(3H，m)，7.53-7.59(2H，m)。
MS(ESI)：m/z 453(M-H)-，m/z 455(M+H)+。
[α]D151.1(c 0.48, methanol, pool temperature 21.0 ℃)
Example 83
N- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [3, 5-difluoro- 4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ]-2-methylcyclopropanecarboxamide
To a solution of the compound from example 61D (170mg, 0.59mmol) in DMF (10ml) was added the compound from example 71C (155mg, 0.591mmol), HBTU (338mg, 0.89mmol) and triethylamine (0.25ml, 1.78mmol) at room temperature. The same procedure as described in example 60E was carried out to give the title compound (45mg, 15%) as a white solid.
1H-NMR(270MHz，DMSO-d6)δ1.32-1.43(8H，m)，2.07-2.12(1H，m)，3.05(3H，s)，4.91-4.97(1H，m)，7.14(2H，d，J＝8.6Hz)，7.38(1H，d，J＝7.3Hz)，7.49(1H，d，J＝13.2Hz)，7.74(1H，t，J＝7.9Hz)，8.73(1H，d，J＝7.3Hz)，9.48(1H，s)。
MS(ESI)m/z 495(M+H)+，493(M-H)-。
[α]D155.0(c is 0.56, methanol, pool temperature is 21.4 ℃)
Example 84
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [ 2-Morpholin-4-yl-6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxamides
84A)1- [ 2-morpholin-4-yl-6- (trifluoromethyl) pyridin-3-yl]Ethanol
To a solution of 2-morpholin-4-yl-6- (trifluoromethyl) pyridine-3-carbaldehyde (journal of medicinal Chemistry, 2005, 48, p71-90, 0.88g, 3.4mmol) in diethyl ether (7.0ml) at 0 ℃ was added a solution of methylmagnesium chloride in THF (3.0M, 1.36ml) and the mixture was stirred for 0.5 h. The same procedure as described in example 9C was followed to give the title compound as a colorless oil (quant.0.9 g).
84B)1- [ 2-morpholin-4-yl-6- (trifluoromethyl) pyridin-3-yl]Ethanones
To a solution of oxalyl chloride (647mg, 5.1mmol) in dichloromethane (15ml) at-78 deg.C was added DMSO (797mg, 10.2mmol), the mixture was stirred at-78 deg.C for 15 minutes, and to this reaction was added the compound of example 84A (1.3g, 12.6 mmol). The mixture was stirred at room temperature for 1 hour, and the reaction was quenched with water. The crude residue was extracted with dichloromethane and the organic layer was dried over magnesium sulfate. Then filtered and purified by column chromatography on silica eluting with hexane/EtOAc (4: 1) to give the title compound as a colorless oil (700mg, 75%).
1H NMR(CDCl3，270MHz)δppm 2.59(3H，s)，3.41-3.45(4H，m)，3.78-3.84(4H，m)，7.17(1H，d，J＝8.1Hz)，7.84(1H，d，J＝8.1Hz)。MS(ESI)：m/z 275(M+H)+。
84C)4- [3- (1-methylethenyl) -6- (trifluoromethyl) pyridin-2-yl]Morpholine
To a solution of the compound from example 84B (650mg, 2.37mmol) in THF (5ml) at 0 deg.C was added a solution of μ -chlorobis (cyclopentadienyl) (dimethylaluminum) - μ -methylenetitanium in toluene (0.5N, 4.8ml), the mixture was stirred at 0 deg.C for 1 hour, and then to this reaction were added water (0.1ml) and a 2N aqueous solution of sodium hydroxide (0.2 ml). Magnesium sulfate was added to the reaction, and the mixture was filtered. Evaporation of the solvent gave a crude residue which was purified by column chromatography on silica eluting with hexane/EtOAc (6: 1) to give the title compound as a colorless oil (160mg, 24%).
1H NMR(CDCl3，270MHz)δppm 2.11(3H，s)，3.32-3.45(4H，m)，3.76-3.84(4H，m)，5.17-5.22(2H，m)，7.15(1H，d，J＝8.1Hz)，7.48(1H，d，J＝8.1Hz)。
84D) 2-methyl-2- [ 2-morpholin-4-yl-6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxylic acid ethyl ester Esters
The same procedure as described in example 2H was followed, using the compound from example 84C (280mg, 1.0mmol) instead of the compound from example 2G, to give the title compound as a colorless oil (76mg, 21%).
1H NMR(CDCl3，270MHz)δppm 1.33(3H，t，J＝8.1Hz)，1.46-1.53(1H，m)，1.58-1.64(5H，m)，3.32-3.52(4H，m)，3.84-3.89(4H，m)，4.23(2H，q，J＝8.1Hz)，7.20(1H，d，J＝8.1Hz)，7.75(1H，d，J＝8.1Hz)。
MS(ESI)：m/z 359(M+H)+。
84E) 2-methyl-2- [ 2-morpholin-4-yl-6- (trifluoromethyl) pyridin-3-yl]Cyclopropanecarboxylic acid
The same procedure as described in example 2H was followed, using the compound from example 84D (76mg, 0.2mmol) instead of the compound from example 2H, to give the title compound as a white solid (60mg, 86%).
MS(ESI)：m/z 331(M+H)+。
84F) 2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl group } B 2- [ 2-morpholin-4-yl-6- (trifluoromethyl) pyridin-3-yl ] -phenyl]Cyclopropanecarboxamides
The same procedure as described in example 7B was followed, using the compound from example 84E (60mg, 0.18mmol) instead of the compound from example 7A, to give the title compound as a white oil (17mg, 17%).
1H NMR(CDCl3，300MHz)δppm 1.26(1H，t，J＝7.4Hz)，1.44-1.70(6H，m)，2.33(3H，d，J＝7.3Hz)，3.03(3H，d，J＝5.9Hz)，3.33-3.45(4H，m)，3.72-3.88(4H，m)，5.13-5.18(1H，m)，5.93-6.00(1H，m)，6.32(1H，d，J＝7.4Hz)，7.17-7.27(3H，m)，7.40-7.47(1H，m)，7.68-7.74(1H，m)。
MS(ESI)：m/z 539(M-H)-。
Example 85
2- {4- [1, 1-dimethyl-2- (methoxy) ethyl]-3-fluorophenyl } -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino group]Phenyl } ethyl) cyclopropanecarboxamide
85A)2- (4-bromo-2-fluorophenyl) -2-methylpropyl methyl ether
To a solution of 2- (4-bromo-2-fluorophenyl) -2-methylpropan-1-ol (199mg, 0.8mmol, WO2004074270A2) in DMF (4ml) at 0 ℃ was added 60% sodium hydride (35mg, 0.88mmol) and the mixture was stirred at 0 ℃ for 15 minutes followed by an additional 1 hour at room temperature. After cooling the mixture to 0 ℃, methyl iodide (342mg, 2.4mmol) was added and the mixture was stirred at 0 ℃ for 30 minutes followed by another 16 hours at room temperature. The reaction was then quenched with water, extracted all with EtOAc, and dried over sodium sulfate. Then filtered, evaporated and purified by silica gel column chromatography eluting with hexane/EtOAc (20: 1) to give the title compound (174mg, 83% yield) as a colorless oil.
1H NMR(300MHz，CDCl3)δ1.35(6H，m)，3.31(3H，s)，3.51(2H，s)，7.12-7.25(3H，m)。
85B)1- [1, 1-dimethyl-2- (methoxy) ethyl]-2-fluoro-4- (1-methylvinyl) benzene
The compound from example 85A (174mg, 0.67mmol), potassium isopropenyltrifluoroborate (118mg, 0.8mmol, org. Lett.2002, 4, 107), PdCl were used2(dppf)·CH2Cl2A mixture of (27mg, 0.033mmol) and triethylamine (0.11ml, 0.8mmol) in n-propanol (7ml) was subjected to the procedure described in example 10B. The crude residue was chromatographed on silica gel eluting with a volumetric mixture of hexane and ethyl acetate (30: 1) to give the title compound (58mg, 39% yield) as a brown oil.
1H NMR(300MHz，CDCl3)δ1.37(6H，m)，2.11(3H，s)，3.32(3H，s)，3.54(2H，s)，5.08(1H，s)，5.37(1H，s)，7.08-7.27(3H，m)。
85C)2- {4- [1, 1-dimethyl-2- (methoxy) ethyl]-3-fluorophenyl } -2-methylcyclopropaneAlkane (I) and its preparation method Formic acid
In the same procedure as described in example 2H, to a solution of the compound from example 85B (58mg, 0.26mmol), Co (TPP) (14mg, 0.021mmol) and 1-methyl-1H-imidazole (172mg, 2.1mmol) in toluene (1ml) was added ethyl diazoacetate (112mg, 0.98 mmol). The reaction mixture was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (30: 1) to give the crude ethyl ester as a black oil, diluted with MeOH (3ml), THF (3ml) and 2M aqueous sodium hydroxide (1ml) and the mixture was worked up using the same procedure as described in example 2I to give the title compound (21mg, 11% yield, 2 steps) as a black oil.
1H NMR(300MHz，CDCl3)δ1.36(6H，s)，1.22-1.58(5H，m)，1.93-1.98(1H，m)，3.32(3H，s)，3.53(2H，s)，6.90-7.04(2H，m)，7.16-7.30(1H，m)。MS(ESI)m/z 279(M-H)-。
85D)2- {4- [1, 1-dimethyl-2- (methoxy) ethyl]-3-fluorophenyl } -2-methyl -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) cyclopropanecarboxamide
In the same procedure as described in example 10E, to a solution of the compound from example 85C (20mg, 0.07mmol) in DMF (0.5ml) was added triethylamine (0.03ml), EDC (20mg, 0.1mmol), HOBt (12mg, 0.078mmol) and the amine compound from example 2D (19mg, 0.07 mmol). The crude residue was chromatographed on a silica gel column eluting with a volumetric mixture of hexane and EtOAc (1: 1) to give the title compound (10mg, 29% yield) as a white solid (mixture of diastereomeric products (1: 1)).
1H NMR(300MHz，CDCl3)δ1.24-1.72(15H，m)，2.31(3H，s)，3.00(3H，s)，3.30(3H，s)，3.52(2H，s)，5.04-5.17(1H，m)，5.902-5.96(1H，m)，6.34(1H，rs)，6.82-6.98(2H，m)，7.12-7.27(3H，m)，7.40(1H，d，J＝7.3Hz)。MS(ESI)：m/z 491(M+H)+。
Example 86
(1S, 2S) -N- ((1R) -1- {3- (2-hydroxyethyl) -4- [ (methylsulfonyl) amino]Phenyl } - Ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
86A) 4-bromo-2- (2- { [ (1, 1-dimethylethyl) (dimethyl) silyl]Oxy } ethyl group) Aniline
To a solution of 1-amino-2- [2- (tert-butyldimethylsiloxy) ethyl ] benzene (3.96g, 0.015mol) [ European journal of organic chemistry, 2001, 48 th, 2447. sup. sec. 2462] in DMF (50ml) was added N-bromosuccinimide (2.67g, 0.015mol), and the mixture was stirred at ambient temperature for 24 hours. The reaction was then poured onto saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (10: 1 to 5: 1) to give 3.62g (73% yield) of the title compound as a brown oil.
1H NMR(300MHz，CDCl3)δ-0.02(6H，s)，0.86(9H，s)，2.71(2H，t，J＝5.9Hz)，3.85(2H，t，J＝5.9Hz)，4.01(2H，br s)，6.54(1H，d，J＝9.5Hz)，7.08-7.15(2H，m)。
MS(ESI)m/z 332(M+H)+
86B) N- [ 4-bromo-2- (2- { [ (1, 1-dimethylethyl) (dimethyl) silyl]Oxy } B Radical) phenyl]Methane sulfonamides
To a solution of the compound from example 86A (3.62g, 0.011mol) in dichloromethane (10ml) was added pyridine (2.66ml, 0.0329mol) and methanesulfonyl chloride (1.27ml, 0.0164mol) at 0 ℃ and the mixture was stirred at ambient temperature for 2 hours. The reaction was then quenched with 2N aqueous HCl and extracted all with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2: 1 to 1: 1) to give 3.07g (69% yield) of the title compound as a green oil.
1H NMR(300MHz，CDCl3)δ-0.02(6H，s)，0.82(9H，s)，2.85(2H，t，J＝5.3Hz)，2.93(3H，s)，3.86(2H，t，J＝5.9Hz)，7.08-7.53(3H，m)，8.48(1H，d，J＝4.0Hz)。MS(ESI)m/z 408(M+H)+
86C) N- [ 4-acetyl-2- (2- { [ (1, 1-dimethylethyl) (dimethyl) silyl]Oxy } Ethyl) phenyl]Methane sulfonamides
A mixture of the compound from example 86B (3.07g, 7.52mmol), palladium (II) acetate (51mg, 0.23mmol), 1, 3-bis (diphenylphosphino) propane (186mg, 0.45mmol), n-butyl vinyl ether (1.88g, 18.79mmol) and potassium carbonate (1.25g, 9.02mmol) in DMF (80ml) -water (10ml) was stirred at 80 ℃ for 20 h. The reaction mixture was cooled to room temperature, diluted with toluene-ethyl acetate (2: 1), washed with 2N aqueous HCl, water, saturated aqueous sodium bicarbonate, water, and brine. The organic layer was dried over sodium sulfate, filtered off and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (5: 1 to 1: 1) to give 0.21g (8% yield) of the title compound as a brown syrup.
1H NMR(270MHz，CDCl3)δ-0.05(6H，s)，0.82(9H，s)，2.54(3H，s)。2.89(2H，t，J＝5.3Hz)，2.98(3H，s)，3.89(2H，t，J＝5.3Hz)，7.59(1H，d，J＝7.9Hz)，7.69-7.91(2H，m)，8.88(1H，br s)。
MS(ESI)m/z 372(M+H)+，370(M-H)+
86D) N- [2- (2- { [ (1, 1-Dimethylethyl) (dimethyl) silyl]Oxy } B Yl) -4- ((1R) -1- { [ (R) - (1, 1-Dimethylethyl) sulfinyl]Amino } ethyl) phenyl]Methane sulfonic acid Amides of carboxylic acids
A test tube for microwave was charged with the compound from example 86C (0.21g, 0.57mmol), titanium (IV) ethoxide (2.5ml), THF (2.5ml) and (R) - (+) -2-methyl-2-propanesulfinamide (82mg, 0.68 mmol). The mixture was subjected to microwave irradiation at 80 ℃ and stirred for 1.5 hours. Upon completion, the mixture was cooled to room temperature and then to 0 ℃ according to LC-MS assay, then 0 ℃ sodium borohydride (86mg, 2.26mmol) was added. After stirring at ambient temperature for 3 hours, the reaction mixture was carefully quenched with MeOH, diluted with ethyl acetate, washed with 2N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered off and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1: 1) -dichloromethane/methanol (10: 1) to give 46mg (17% yield) of the title compound as a brown syrup.
1H NMR(270MHz，CDCl3)δ-0.02(6H，s)，0.84(9H，s)，1.48(3H，d，J＝6.6Hz)，2.84(2H，t，J＝5.3Hz)，2.96(3H，s)，3.87(2H，t，J＝5.3Hz)，4.40-4.55(1H，m)，7.08-7.28(2H，m)，7.47(1H，d，J＝8.6Hz)，8.58(1H，br s)。MS(ESI)m/z 477(M+H)+，475(M-H)-。
86E) N- [4- [ (1R) -1-aminoethyl group]-2- (2-hydroxyethyl) phenyl]Methane sulfonamides
To a solution of the compound from example 86D (46mg, 0.096mmol) was added HCl-MeOH (2.0M, 2 ml). The same procedure as in example 2D was performed to give the title compound (crude, 30mg) as a white solid. MS (ESI) M/z 257(M-H) -。
86F) (1S, 2S) -N- ((1R) -1- {3- (2-hydroxyethyl) -4- [ (methylsulfonyl) amino]Phenyl radical } Ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl]CyclopropanAlkanecarboxamides
To a solution of the carboxylic acid compound (24mg, 0.096mmol) of example 14C in DMF (2ml) were added HBTU (44mg, 0.116mmol), triethylamine (0.054ml, 0.385mmol) and the amine compound (crude 30mg, 0.096mmol) of example 86E, and the mixture was stirred at room temperature for 4 hours. The same procedure as in example 14D was carried out to give the title compound (30mg, 65% yield, 2 steps) as a white solid.
1H NMR(300MHz，CDCl3) δ 1.20-1.35(1H, m), 1.40-1.60(7H, m, including 3H, s, 1.52ppm and 3H, d, J ═ 6.6Hz, 1.47 ppm), 1.70(1H, dd, J ═ 5.9Hz, 8.8Hz), 2.82(2H, t, J ═ 5.1Hz), 2.92(3H, s), 3.17(1H, br s), 3.83(2H, m), 5.00-5.15(1H, m), 6.33(1H, d, J ═ 6.0Hz), 7.14(1H, s), 7.18(1H, d, J ═ 8.1Hz), 7.35(2H, d, J ═ 8.1Hz), 7.42(1H, d, J ═ 8.8, 7.54H, 8.1Hz), 7.35 (1H, d, J ═ 8.1 Hz).
MS(ESI)m/z 485(M+H)+，483(M-H)-
Example 87
(1S, 2S) -N- ((1R) -1- { 3-Ethyl-4- [ (methylsulfonyl) amino group]Phenyl } propyl) -2- Methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
87A) N- (2-ethyl-4-propionylphenyl) methanesulfonamide
To a solution of 2-amino-1-ethylbenzene (5ml, 5.0g, 41mmol) in pyridine (3.5ml) and dichloromethane (10ml) was added dropwise methanesulfonyl chloride (3.2ml.4.7g, 41mmol) over 10min at 0 ℃. The reaction mixture was stirred at room temperature for 1 hour. After cooling to 0 ℃ aluminum trichloride (13.8g, 103mmol) was added carefully to the reaction mixture. Propionyl chloride (3.6ml, 3.8g, 41mmol) was then added dropwise over 15 min. The reaction mixture was diluted with toluene (25ml) and poured into 2M aqueous hydrochloric acid (50ml) with stirring at 0 ℃. The precipitated solid was filtered, washed with water and dried in vacuo to give the desired product (4.5g, 43% yield) as a yellow solid.
1H NMR(DMSO-d6，300MHz)δ1.07(3H，t，J＝7.3Hz)，1.17(3H，t，J＝7.3Hz)，2.75(2H，d，J＝7.3Hz)，3.02(2H，t，J＝7.3Hz)，3.08(3H，s)，4.64-4.90(1H，m)，7.45(1H，d，J＝8.0Hz)，7.82(2H，m)，9.35(1H，br s)。
87B) N- {4- [ (1R) -1-aminopropyl]-2-ethylphenyl } methanesulfonamide
To a stirred solution of N- (2-ethyl-4-propionylphenyl) methanesulfonamide (7.8mmol) in tetrahydrofuran (15ml) and titanium (IV) ethoxide (15ml) was added (R) - (+) -2-methyl-2-propanesulfinamide (7.8 mmol). The mixture was stirred at 80 ℃ for 16 hours. Upon completion, the mixture was cooled to room temperature and then to 0 ℃ according to LC-MS assay, and then added dropwise to a 0 ℃ solution of sodium borohydride (1.18g, 31mmol) in tetrahydrofuran (15 ml). The mixture was stirred at 0 ℃ for 3 hours and then quenched with methanol. After stirring at room temperature for 2 hours, a pad of celite and water was added to the mixture, which was filtered through celite, washing with dichloromethane-ethyl acetate-methanol. The filtrate was evaporated under reduced pressure and the resulting residue was purified on silica gel eluting with dichloromethane-ethyl acetate (1: 1) to give the title compound as a yellow oil. This was dissolved in methanol (30ml), and hydrochloric acid-methanol (30ml) was added. The solution was stirred at room temperature for 1 hour. After removal of the solvent under reduced pressure, the product was recrystallized from diethyl ether-methanol to give the desired product as the hydrochloride salt.
1H NMR(DMSO-d6，300MHz)δ0.81(3H，t，J＝7.3Hz)，1.21(3H，m)，1.67-1.82(1H，m)，1.95-2.07(1H，m)，2.69(2H，d，J＝7.3Hz)，3.01(3H，s)，4.21-4.26(1H，m)，6.96(1H，s)，7.16-7.19(2H，m)，7.42(1H，d，J ═ 8.1 Hz). No NH was observed2。
87C) (1S, 2S) -N- ((1R) -1- { 3-Ethyl-4- [ (methylsulfonyl) amino group]Phenyl } propane 2-methyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxamides
To a solution of the carboxylic acid compound (80mg, 0.328mmol) of example 14C in DMF (3ml) were added HBTU (149mg, 0.393mmol), triethylamine (0.13ml, 0.983mmol) and the amine compound of example 87B (95mg, 0.328mmol), and the mixture was stirred at room temperature for 3 hours. The same procedure as in example 14D was carried out to give the title compound (97mg, 61% yield) as a white solid.
1H NMR(300MHz，DMSO-d6)δ0.86(3H，t，J＝6.0Hz)，1.15(3H，t，J＝6.0Hz)，1.32(2H，d，J＝6.0Hz)，1.44(3H，s)，1.55-1.81(2H，m)，2.02(2H，t，J＝6.0Hz)，2.69(2H，q，J＝6.0Hz)，2.96(3H，s)，4.64-4.90(1H，m)，7.02-7.15(1H，m)，7.15-7.28(2H，m)，7.55(2H，d，J＝9.0Hz)，7.70(2H，d，J＝9.0Hz)，8.57(1H，d，J＝9.0Hz)，9.03(1H，br s)。MS(ESI)m/z 483(M+H)+，481(M-H)-。
C24H29F3N2O3Analytical calculation of S: c, 59.73; h, 6.06; and N, 5.81. Measured value: c, 59.37; h, 6.03; n, 5.67.
Example 88
2-Ethyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl group]Cyclopropanecarboxamides
88A)1- (1-Methylenepropyl) -4- (trifluoromethyl) -benzene
To a stirred suspension of methyltriphenylbromide * (3.53g, 9.89mmol) in THF (30ml) at 0 deg.C was added dropwise a solution of potassium tert-butoxide (1.11g, 9.89mmol) in THF (10ml) and the mixture was stirred at ambient temperature for 2 h. To this mixture was then added a 0 deg.C solution of 4- (trifluoromethyl) propiophenone (Aldrich, 1.00g, 4.95mmol) in THF (10ml) and stirred at ambient temperature for 2 hours. The reaction was quenched with a small amount of water and the solvent was removed by evaporation. The crude mixture was diluted with hexane. The resulting precipitate was filtered, and the organic layer was separated. After evaporation of the solvent, the residue was chromatographed on silica gel eluting with hexane to give 1.12g (crude, 100%) of the title compound as a red oil.
1H NMR(270MHz，CDCl3)δppm 1.11(3H，t，J＝7.2Hz)，2.53(2H，q，J＝7.2Hz)，5.17(1H，s)，5.34(1H，s)，7.51(2H，d，J＝8.5Hz)，7.59(2H，d，J＝8.5Hz)。
88B) 2-ethyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxylic acid ethyl ester
In the same procedure as in example 2H, a solution of the compound from example 88A (crude, 1.12g, 4.95mmol), Co (TPP) (66mg, 0.099mmol) and 1-methyl-1H-imidazole (1.18ml, 14.84mmol) in toluene (10ml) was treated with ethyl diazoacetate (0.78ml, 7.42 mmol). The crude residue was chromatographed on silica gel eluting with a volumetric mixture of hexane and EtOAc (10/1) to give 219mg (15% yield, 2 steps) of the title compound as a brown oil.
1H NMR(270MHz，CDCl3)δppm 0.70-2.05(11H，m)，3.80-4.30(2H，m)，7.30-7.60(4H，m)。
Ms (esi): no M was observed+Peak(s).
88C) 2-ethyl-2- [4- (trifluoromethyl) phenyl]Cyclopropanecarboxylic acid (racemic)
To a solution of the compound from example 88B (219mg, 0.76mmol) in ethanol (3ml) was added 2M aqueous sodium hydroxide (0.28ml, 0.56mmol) and the mixture was stirred at ambient temperature for 20 h. After completion of the reaction, the basic mixture was washed with dichloromethane, acidified with 2M aqueous HCl and extracted all with dichloromethane. The organic layer was dried over sodium sulfate, filtered, followed by evaporation to give 100mg (69% yield, trans) of the title compound as a white solid.
1H NMR(270MHz，CDCl3)δppm 0.82(3H，t，J＝7.3Hz)，1.43(1H，dd，J＝5.3Hz，8.6Hz)，1.51(1H，t，J＝5.3Hz)，1.92(2H，q，J＝7.3Hz)，2.00(1H，dd，J＝5.9Hz，7.9Hz)，7.43(2H，d，J＝7.9Hz)，7.58(2H，d，J＝8.6Hz)。
MS(ESI)：m/z 257(M-H)-。
88D) 2-Ethyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino]Phenyl group } B 2- [4- (trifluoromethyl) phenyl ] -phenyl]Cyclopropanecarboxamides
To a solution of the compound from example 88C (49mg, 0.188mmol) in DMF (2ml) were added HBTU (85mg, 0.225mmol), triethylamine (0.078ml, 0.563mmol) and the compound from example 2D (60mg, 0.225mmol), and the mixture was stirred at room temperature for 2 hours. The same procedure as in example 14D was carried out to give the title compound (59mg, 67% yield) as a white solid.
1H NMR(300MHz，CDCl3) δ ppm 0.69, 0.80(3H, each t, J ═ 7.3Hz), 1.20-1.35(1H, m), 1.45-1.55(1H, m), 1.49, 1.52(3H, each d, J ═ 4.4Hz), 1.67-2.00(3H, m), 2.31, 2.32(3H, each s), 3.00, 3.01(3H, each s), 5.13(1H, m), 6.00-6.20(1H, m), 6.40-6.60(1H, m), 7.15-7.25(2H, m), 7.32-7.46(3H, m), 7.50-7.60(2H, m). Ms (esi): m/z 469(M + H)+，467(M-H)-。
C23H27F3N2O3S·0.2H2Analytical calculation of O: c, 58.51; h, 5.85; and N, 5.93. Measured value: c, 58.51;H，5.74；N，5.79。
example 89
2-Ethyl-N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino]Phenyl } ethyl) -2-
[4- (trifluoromethyl) phenyl group]Cyclopropanecarboxamides
To a solution of the compound (51mg, 0.196mmol) obtained in example 88C in DMF (2ml) were added HBTU (89mg, 0.236mmol), triethylamine (0.082ml, 0.589mmol) and the amine compound (63mg, 0.236mmol) obtained in example 8, and the mixture was stirred at room temperature for 2 hours. The same procedure as in example 14D was carried out to give the title compound (55mg, 59% yield) as a white solid.
1H NMR(300MHz，CDCl3) δ ppm 0.69, 0.80(3H, each t, J ═ 7.3Hz), 1.20-1.40(1H, m), 1.45-1.57(1H, m), 1.51, 1.52(3H, each d, J ═ 2.9Hz), 1.67-1.96(3H, m), 3.02(3H, s), 5.14(1H, m), 6.00(1H, br t, J ═ 6.6Hz), 6.55(1H, br s), 7.10-7.20(2H, m), 7.32-7.45(2H, m), 7.48-7.62(3H, m).
MS(ESI)：m/z 473(M+H)+，471(M-H)-。
C22H24F4N2O3S·0.5H2Analytical calculation of O: c, 54.88; h, 5.23; n, 5.82.
Measured value: c, 54.51; h, 5.02; and N, 5.70.
Example 90
2- (4-tert-butyl-3, 5-difluorophenyl) -2-methyl-N- ((1R) -1- {4- [ (methylsulfonyl) - Amino group]Phenyl } propyl) cyclopropanecarboxamide
To a solution of the compound from example 31B (108mg, 0.4mmol) in DMF (10ml) were added the compound from example 43C (109mg, 0.4mmol), HBTU (202mg, 0.5mmol) and trimethylamine (0.2ml, 1.2mmol) and the mixture was stirred at room temperature for 2 h. The same reaction procedure as described in example 38E was carried out to give the title compound (101mg, 24%). The desired product had a cut time of 5.4 minutes.
1H NMR(270MHz，DMSO-d6)δ0.83(3H，t，J＝7.3Mz)，1.20-1.31(2H，m)，1.33-1.49(12H，m)，1.56-1.72(2H，m)，1.92-2.01(1H，m)，2.95(3H，s)，4.64-4.77(1H，m)，6.86-7.00(2H，m)，7.10-7.19(2H，m)，7.21-7.30(2H，m)，8.49(1H，d，J＝8.6Mz)，9.70(1H，brs)。
MS(ESI)m/z 477(M-H)-，479(M+H)+
Example 91
2- (4-tert-butyl-3, 5-difluorophenyl) -2-methyl-N- ((1R) -1- { 3-methyl-4-
[ (methylsulfonyl) amino group]Phenyl } propyl) cyclopropanecarboxamide
To a solution of the compound from example 34C (153mg, 0.6mmol) in DMF (10ml) were added the compound from example 43C (147mg, 0.6mmol), HBTU (271mg, 0.7mmol) and trimethylamine (0.2ml, 1.7mmol) and the mixture was stirred at room temperature for 2 h. The same reaction procedure as described in example 38E was carried out to give the title compound (101mg, 27%). The desired product had a cut time of 5.8 minutes.
1H NMR(270MHz，DMSO-d6)δ0.75-0.90(3H，m)，1.20-1.31(2H，m)，1.34-1.46(12H，m)，1.56-1.75(2H，m)，1.92-2.02(1H，m)，2.29(3H，s)，2.95(3H，s)，4.63-4.76(1H，m)，6.86-7.00(2H，m)，7.07-7.25(3H，m)，8.50(1H，d，J＝8.6Mz)，9.03(1H，brs)。
MS(ESI)m/z 491(M-H)-，493(M+H)+
The following preparations illustrate two synthetic methods for preparing certain intermediates used in the preceding examples.
Preparation example 1
1A) N- (4-acetyl-2-methylphenyl) methanesulfonamide
To a solution of o-toluidine (10.7ml, 100mmol) and pyridine (8.49ml, 105mm0l) in dichloromethane (20ml) was added methanesulfonyl chloride (7.74ml, 100mmol) over 15 minutes at 0 ℃. The reaction mixture was stirred at room temperature for 1 hour. After cooling to 0 ℃ aluminum chloride (33.3g, 250mmol) was added carefully to the reaction mixture. Acetyl chloride (10.7ml, 150mmol) was then added dropwise over a period of 20 minutes at 5-20 ℃. The reaction mixture was stirred at room temperature for 0.5 h, using TLC and1the reaction was monitored by H-NMR and, after completion of the reaction, the reaction mixture was diluted with toluene, poured into 2N aqueous HCl and stirred at 0 ℃. The precipitated solid was filtered, washed with water and heptane, and dried in vacuo to give the title compound (20.3g, 89.3mmol, 89% yield, 2 steps) as a pale orange powder.
1H NMR(300MHz，CDCl3)δppm 2.35(3H，s)，2.58(3H，s)，3.11(3H，s)，6.60(1H，brs)，7.59(1H，d，J＝12.0Hz)，7.83-7.85(2H，m)。MS(ESI)：m/z 228(M+H)+，226(M-H)-
Preparation example 2
N- (4-acetyl-2-methylphenyl) methanesulfonamide
2A) N- (2-methylphenyl) methanesulfonamide
To a solution of o-toluidine (1.07ml, 10mmol) and pyridine (0.86ml, 10.6mmol) in dichloromethane (2ml) was added dropwise methanesulfonyl chloride (0.81ml, 10.5mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with 1N aqueous HCl and extracted with EtOAc. The organic layer was concentrated in vacuo to give the title compound (1.84g, 10mmol, quant.) as an orange solid.
1H NMR(300MHz，CDCl3)δppm 2.38(3H，s)，3.05(3H，s)，7.12-7.24(3H，m)，7.46(1H，d，J＝9.0Hz)。
2B) N- (4-acetyl-2-methylphenyl) methanesulfonamide
At 0 ℃ to N- (2-methylphenyl)A solution of methanesulfonamide (1.84g, 10mmol) in dichloromethane (2ml) was carefully added aluminium chloride (3.3g, 25 mmol). Acetyl chloride (1.07ml, 15mmol) was then added dropwise. The reaction mixture was stirred at room temperature for 0.5 h. By TLC and1the reaction was monitored by H-NMR and, after completion of the reaction, the reaction mixture was diluted with toluene, poured into 2N aqueous HCl and stirred at 0 ℃. The precipitated solid was filtered, washed with water and dried to give a mixture of the title compound and by-product (N-acetylated product) (2.31g, title compound: by-product: 81: 19 (ratio: from1H-NMR measurement) as a flesh-colored powder.
1H NMR(300MHz，CDCl3)δppm 1.92(0.70H，s)，2.35(3H，s)，2.45(0.70H，s)，2.58(3H，s)，2.64(0.70H，s)，3.11(3H，s)，3.53(0.70H，s)，6.60(1H，brs)，7.33(0.23H，d，J＝9.0Hz)，7.59(1H，d，J＝12.0Hz)，7.83-7.85(2H，m)，7.89(0.23H，d，J＝9.0Hz)，7.96(0.23H，s)。

Claims (19)

1. A compound of formula (I); or a pharmaceutically acceptable salt or solvate thereof:
wherein A and B are independently CR12Or N; d and E are each independently CR9Or N; r1Is represented by (C)1-C6) An alkyl group; r2Represents hydrogen, halogen, hydroxy, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy or (C)1-C6) Alkoxy radical- (C1-C6) An alkyl group; r3、R4、R5、R6、R10And R11Each independently represents hydrogen, halogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl or (C)1-C6) Alkoxy radical- (C1-C6) An alkyl group; or R3And R4Together with the carbon atom to which they are attached form a 3-to 7-membered carbocyclic or heterocyclic ring in which one or two non-adjacent carbon atoms are optionally replaced by an oxygen atom, a sulfur atom or NH; r7And R9Each independently represents hydrogen, halogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy radical- (C1-C6) Alkyl, (C)1-C6) Alkoxy radical- (C1-C6) Alkoxy group, (C)1-C6) Alkylthio group, (C)1-C6) Alkylsulfinyl (C)1-C6) Alkylsulfonyl, NH2、[(C1-C6) Alkyl radical]NH-、[(C1-C6) Alkyl radical]2N-、H2N-(C1-C6) Alkoxy group, (C)1-C6) alkyl-NH- (C)1-C6) Alkoxy group, [ (C)1-C6) Alkyl radical]2N(C1-C6) An alkoxy group; h2N-(C1-C6) Alkoxy radical- (C1-C6) Alkyl, (C)1-C6) alkyl-NH- (C)1-C6) Alkoxy radical- (C1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N(C1-C6) Alkoxy radical- (C 1-C6) Alkyl radicals or containingA 5-or 6-membered heterocyclic ring of at least one nitrogen atom; r8Represents halogen, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy radical- (C1-C6) Alkyl, (C)1-C6) Alkoxy radical- (C1-C6) Alkoxy, halo (C)1-C6) Alkylsulfonyl, halo (C)1-C6) Alkylsulfinyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkylthio [ (C)1-C6) Alkyl radical]NH-or [ (C)1-C6) Alkyl radical]2N-; or when E is CR9When R is7And R8Together with the carbon atom to which they are attached form a 5-to 8-membered carbocyclic or heterocyclic ring in which one or two non-adjacent carbon atoms are optionally replaced by an oxygen, sulfur, N or NH group, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted by one or more groups each independently selected from hydroxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy and hydroxy (C)1-C6) Alkyl substituent substitution; and R is12Represents hydrogen, halogen, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group.
2. A compound according to claim 1 wherein a represents CR12And D represents CR9；R1Is represented by (C)1-C3) An alkyl group; r3And R4Each independently represents hydrogen or (C)1-C3) An alkyl group; r5Represents hydrogen, R7Represents hydrogen, halogen, hydroxy (C)1-C6) Alkyl, [ (C)1-C6) Alkyl radical]2N-, pyridyl, piperidino, pyrrolidino, or morpholino; r 8Is represented by (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy radical- (C1-C6) Alkyl, halo (C)1-C3) Alkoxy, halo (C)1-C3) Alkylthio or halo (C)1-C3) An alkylsulfonyl group; and R is12Represents hydrogen, halogen, (C)1-C3) Alkyl or hydroxymethyl.
3. A compound according to claim 1 or 2, wherein R10And R11Each independently represents hydrogen.
4. A compound according to any one of claims 1 to 3, wherein B and E are not both N; r1Represents a methyl group; r3And R4Each independently represents hydrogen, methyl or ethyl; and R is8Represents tert-butyl, trifluoromethyl, 2, 2, 2-trifluoro-1, 1-dimethylethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl, 2-hydroxy-1, 1-dimethylethyl or 2-methoxy-1, 1-dimethylethyl; except that when B represents N, and R8When represents trifluoromethyl; or when E represents N, and R2When represents fluorine.
5. A compound according to any one of claims 1 to 4, wherein R2Represents hydrogen, fluorine, methyl, ethyl, hydroxymethyl or hydroxyethyl; r4And R5Each independently represents hydrogen; r6Represents hydrogen, methyl, ethyl, methoxy or hydroxymethyl; r7And R9Each independently represents hydrogen or fluorine; and R is12Represents hydrogen, fluorine, methyl, ethyl, hydroxymethyl or hydroxyethyl.
6. A compound according to any one of claims 1 to 5, wherein R3Represents methyl or ethyl; and R is8Represents tert-butyl, trifluoromethyl, 2, 2, 2-trifluoro-1, 1-dimethylethyl, trifluoromethoxy or trifluoromethylthio.
7. A compound according to any one of claims 1 to 6, wherein R6Represents methyl, ethyl or methoxy.
8. A compound according to any one of claims 1 to 7, wherein R5And R6Is in the trans form.
9. A compound according to claim 1, selected from:
2- (4-tert-butylphenyl) -N- { 3-fluoro-4- [ (methylsulfonyl) amino ] benzyl } cyclopropanecarboxamide;
2- (4-tert-butyl-3-fluorophenyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- [4- (1-hydroxy-1-methylethyl) phenyl ] -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- (4-tert-butyl-3-fluorophenyl) -N- { 3-methyl-4- [ (methylsulfonyl) amino ] benzyl } cyclopropanecarboxamide;
2- (4-tert-butylphenyl) -2-methyl-N- { 3-methyl-4- [ (methylsulfonyl) amino ] benzyl } cyclopropanecarboxamide;
n- { 3-methyl-4- [ (methylsulfonyl) amino ] benzyl } -2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] cyclopropanecarboxamide;
2- (4-tert-butylphenyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- (4-tert-butylphenyl) -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2-methyl-N- ((1R) -1- { 6-methyl-5- [ (methylsulfonyl) amino ] pyridin-2-yl } ethyl) -2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] cyclopropanecarboxamide;
2- (6-tert-butylpyridin-3-yl) -2-methyl-N- ((1R) -1- { 3-methyl 4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [6- (trifluoromethyl) pyridin-3-yl ] cyclopropanecarboxamide;
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [6- (trifluoromethyl) pyridin-3-yl ] cyclopropanecarboxamide;
(1S, 2S) -2-methyl-N- ((1R) -1- { 6-methyl-5- [ (methylsulfonyl) amino ] pyridin-2-yl } ethyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
(1S, 2S) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (trifluoromethoxy) phenyl ] cyclopropanecarboxamide;
2-methyl-N- ((1R) -1- { 3-methoxy-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (trifluoromethoxy) phenyl ] cyclopropanecarboxamide;
n- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] cyclopropanecarboxamide;
n- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
n- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
(1S, 2S) -2-methyl-N- ((1R) -1- {4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
(1S, 2S) -N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
(1S, 2S) -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- {4- [ (trifluoromethyl) thio ] phenyl } cyclopropanecarboxamide;
n- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- {4- [ (trifluoromethyl) thio ] phenyl } cyclopropanecarboxamide;
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- {4- [ (trifluoromethyl) sulfonyl ] phenyl } cyclopropanecarboxamide;
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl) ethyl) -2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] cyclopropanecarboxamide;
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- {4- [ (trifluoromethyl) oxy ] phenyl } cyclopropanecarboxamide;
n- ((1R) -1- { 3-ethyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- {4- [ (trifluoromethyl) oxy ] phenyl } cyclopropanecarboxamide;
2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
(1S, 2S) -2-methyl-N- ((1R) -1- {4- [ (methylsulfonyl) amino ] phenyl } propyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
(1S, 2S) -N- ((1R) -1- { 3-ethyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
n- ((1R) -1- { 3-ethyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
(1S, 2S) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } propyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
n- ((1R) -1- { 6-ethyl-5- [ (methylsulfonyl) amino ] pyridin-2-yl } ethyl) -2-methyl-2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] cyclopropanecarboxamide;
2- [ 4-tert-butyl-3-fluorophenyl ] -N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2-methyl-N- ((1R) -1- { 4-methyl-5- [ (methylsulfonyl) amino ] pyridin-2-yl } ethyl) -2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] cyclopropanecarboxamide;
2- [ 4-tert-butyl-3, 5-difluorophenyl ] -N- ((1R) -1- {4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- (4-tert-butyl-3, 5-difluorophenyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- (4-tert-butyl-3, 5-difluorophenyl) -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
(1S, 2S) -N- ((1R) -1- { 2-fluoro-5-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
n- ((1R) -1- { 2-fluoro-5-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -2-methylcyclopropanecarboxamide
2- (4-tert-butyl-3, 5-difluorophenyl) -2-methyl-N- ((1R) -1- {4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- (4-tert-butyl-3, 5-difluorophenyl) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- (4-tert-butyl-3, 5-difluorophenyl) -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methylcyclopropanecarboxamide;
n- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [ 2-pyrrolidin-1-yl-6- (trifluoromethyl) pyridin-3-yl ] cyclopropanecarboxamide;
n- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [ 2-pyrrolidin-1-yl-6- (trifluoromethyl) pyridin-3-yl ] cyclopropanecarboxamide;
n- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] cyclopropanecarboxamide;
2- (6-tert-butyl-2-piperidin-1-ylpyridin-3-yl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- (6-tert-butyl-2-piperidin-1-ylpyridin-3-yl) -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- (6-tert-butyl-2-pyrrolidin-1-ylpyridin-3-yl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- [ 6-tert-butylpyridin-3-yl ] -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- [ 6-tert-butylpyridin-3-yl ] -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
(1S, 2S) -2-methyl-N- ((1R) -1- { 6-methyl-5- [ (methylsulfonyl) amino ] pyridin-2-yl } ethyl) -2- (4-trifluoromethyl) phenyl ] cyclopropanecarboxamide;
2- [ 4-tert-butylphenyl ] -N- ((1R) -1- { 6-methyl-5- [ (methylsulfonyl) amino ] pyridin-2-yl } ethyl) cyclopropanecarboxamide;
n- ((1R) -1- { 6-methyl-5- [ (methylsulfonyl) amino ] pyridin-2-yl } ethyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [6- (trifluoromethyl) pyridin-3-yl ] cyclopropanecarboxamide;
2- [ 4-tert-butyl-3-fluorophenyl ] -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- [ 4-tert-butylphenyl ] -2- (hydroxymethyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
(1S, 2S) -N- ((1R) -1- {2, 5-difluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
(1S, 2S) -N- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
2- [ 6-tert-butylpyridin-3-yl ] -2-ethyl-N- ((1R) -1- { 3-methyl-4- [ (sulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
n- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- (methoxy) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
2- [ 4-tert-butylphenyl ] -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- (methoxy) cyclopropanecarboxamide;
2- [ 4-tert-butyl-2-pyridin-4-ylphenyl ] -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
n- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -2-methylcyclopropanecarboxamide;
2- [ 4-tert-butyl-2- (hydroxymethyl) phenyl ] -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- {4- [ (trifluoromethyl) sulfonyl ] phenyl } cyclopropanecarboxamide;
(1S, 2S) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] -N- ((1R) -1- { 3-ethyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methylcyclopropanecarboxamide;
n- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -2-methylcyclopropanecarboxamide;
n- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -2-methylcyclopropanecarboxamide;
n- ((1R) -1- { 3-ethyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (trifluoromethoxy) phenyl ] cyclopropanecarboxamide;
2- (4-tert-butyl-3, 5-difluorophenyl) -N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } propyl) cyclopropanecarboxamide;
N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] cyclopropanecarboxamide;
2- (4-tert-butyl-3, 5-difluorophenyl) -N- ((1R) -1- { 2-fluoro-5-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methylcyclopropanecarboxamide;
2- [2- (dimethylamino) -6- (trifluoromethyl) pyridin-3-yl ] -N- ((1R) -1- { 2-fluoro-5-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
n- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] -2-methylcyclopropanecarboxamide;
n- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- {4- [ (trifluoromethyl) oxy ] phenyl } cyclopropanecarboxamide;
(1S, 2S) -2-methyl-N- ((1S) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
n- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] -2-methylcyclopropanecarboxamide;
2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [ 2-morpholin-4-yl-6- (trifluoromethyl) pyridin-3-yl ] cyclopropanecarboxamide;
2- {4- [1, 1-dimethyl-2- (methoxy) ethyl ] -3-fluorophenyl } -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
(1S, 2S) -N- ((1R) -1- {3- (2-hydroxyethyl) -4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
(1S, 2S) -N- ((1R) -1- { 3-ethyl-4- [ (methylsulfonyl) amino ] phenyl } propyl) -2-methyl-2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
2-ethyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
2-ethyl-N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
2- (4-tert-butyl-3, 5-difluorophenyl) -2-methyl-N- ((1R) -1- {4- [ (methylsulfonyl) amino ] phenyl } propyl) cyclopropanecarboxamide; and
2- (4-tert-butyl-3, 5-difluorophenyl) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } propyl) cyclopropanecarboxamide;
or a pharmaceutically acceptable salt or solvate thereof.
10. A compound according to claim 9, selected from:
(1S, 2S) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
(1S, 2S) -N- ((1R) -1- {3- (hydroxymethyl) -4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
(1S, 2S) -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
2- (4-tert-butyl-3, 5-difluorophenyl) -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide;
2- (4-tert-butyl-3, 5-difluorophenyl) -N- ((1R) -1- { 3-fluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methylcyclopropanecarboxamide;
(1S, 2S) -N- ((1R) -1- {2, 5-difluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
(1S, 2S) -N- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2-methyl-2- [4- (trifluoromethyl) phenyl ] cyclopropanecarboxamide;
2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] -2-methyl-N- ((1R) -1- { 3-methyl-4- [ (methylsulfonyl) amino ] phenyl } ethyl) cyclopropanecarboxamide; and
n- ((1R) -1- {3, 5-difluoro-4- [ (methylsulfonyl) amino ] phenyl } ethyl) -2- [3, 5-difluoro-4- (2, 2, 2-trifluoro-1, 1-dimethylethyl) phenyl ] -2-methylcyclopropanecarboxamide;
Or a pharmaceutically acceptable salt or solvate thereof.
11. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
12. A compound of formula (I) as defined in any one of claims 1 to 10 or a pharmaceutically acceptable salt or solvate thereof for use as a medicament.
13. Use of a compound of formula (I) as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate or composition thereof, in the manufacture of a medicament for the treatment of a disease for which an VR1 antagonist is indicated.
14. Use according to claim 13, wherein the disease is selected from acute cerebral ischaemia, pain, chronic pain, acute pain, nociceptive pain, neuropathic pain, inflammatory pain, post-herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-associated 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, menstrual pain, bladder diseases such as incontinence, micturition disorders, renal colic and cystitis, inflammations such as burns, rheumatoid arthritis and osteoarthritis, neurodegenerative diseases such as stroke, post-stroke pain and multiple sclerosis, lung diseases such as asthma, cough, asthma, rheumatoid arthritis, pain, inflammatory pain, neuropathic pain, pain due to rheumatoid arthritis, burns, chronic Obstructive Pulmonary Disease (COPD) and bronchoconstriction, gastrointestinal disorders such as gastroesophageal reflux disease (GERD), dysphagia, ulcers, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), colitis and crohn's disease, ischemia such as cerebrovascular ischemia, emesis such as cancer chemotherapy-induced emesis and obesity.
15. A method of treatment of a mammal, including a human being, to treat a disease for which an antagonist of VR1 is indicated, which comprises treating said mammal with an effective amount of a compound of formula (I) as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate or composition thereof.
16. A combination of a compound of formula (I) as defined in any one of claims 1 to 10 and another pharmacologically active substance.
17. An intermediate compound of formula (Ia); or a pharmaceutically acceptable salt or solvate thereof:
a, B, D, E, R therein1、R3、R4、R5、R6、R7、R8、R10、R11And R12Has the meaning as defined in claim 1; and R is2aIs represented by (C)1-C6) An alkoxycarbonyl group.
18. An intermediate compound of formula (II); or a pharmaceutically acceptable salt or solvate thereof:
a, B, R therein1、R2、R3And R4Having the claims1, as defined in claim 1.
19. An intermediate compound of formula (III); or a pharmaceutically acceptable salt or solvate thereof:
d, E, R therein5、R6、R8、R7、R10And R11Have the meaning defined in claim 1.
HK08105453.1A 2005-03-17 2006-03-07 N- (n-sulfonylaminomethyl) cyclopropanecarboxamide derivatives useful for the treatment of pain HK1116764A (en)

Applications Claiming Priority (3)

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US60/699,800 2005-07-15
US60/733,651 2005-11-04

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