WO2008125014A1 - Composés d'urée, leurs procédés de préparation et leurs utilisations pharmaceutiques - Google Patents
Composés d'urée, leurs procédés de préparation et leurs utilisations pharmaceutiques Download PDFInfo
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- WO2008125014A1 WO2008125014A1 PCT/CN2008/000760 CN2008000760W WO2008125014A1 WO 2008125014 A1 WO2008125014 A1 WO 2008125014A1 CN 2008000760 W CN2008000760 W CN 2008000760W WO 2008125014 A1 WO2008125014 A1 WO 2008125014A1
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- tert
- butyl
- pyrazolyl
- urea
- alkenyl
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/88—Nitrogen atoms, e.g. allantoin
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/14—Nitrogen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/48—Nitrogen atoms not forming part of a nitro radical
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present invention relates to urea compounds which inhibit P38 protein kinase, pharmaceutical compositions containing them, methods for preparing these compounds and their medical use.
- TNF and IL-1 are central players in the pathogenesis associated with many chronic inflammation and autoimmune diseases.
- IL-1 is involved in mediating or worsening diseases such as rheumatoid arthritis (see, Arend, WP Arthritis & Rheumatism 38(2): 151-160, (1995)), osteoarthritis, bone resorption, toxic shock syndrome, Tuberculosis, atherosclerosis, diabetes, Hodgkin's disease, (see, Benharroch, D. et al. Euro. Cytokine Network 7(1): 51-57) and Alzheimer's disease.
- the kinase, MAPK) cascade is the main signal transduction system in the cell.
- the extracellular stimulation signal is transmitted to the nucleus through this system, which leads to a series of physiological and pathological processes such as cell growth, development, division, cytokine secretion and malignant transformation.
- threonine, T or tyrosine (y) residues are activated by phosphorylation.
- activation of all MAPK family members requires two-site phosphorylation of threonine and tyrosine residues, and the MAPK double-site phosphorylation group has
- T-X-Y Thr-Xaa-Tyr
- MAPKKK MAPK kinase kinase
- MAPKKK activates the phosphorylation of the serine and threonine sites of MAPKK; the activated MAPKK further activates the MAPK by phosphorylation of the serine and threonine sites.
- the MAPK family includes at least four subfamilies, namely ERK (extracel luar regulated protein kinase), c-Jun N-terminal kinase, p38, ERK5. Different subfamilies are distinguished primarily by differences in Xaa and/or upstream kinase between the phosphorylation sites.
- ERK extracel luar regulated protein kinase
- c-Jun N-terminal kinase p38
- ERK5 extracel luar regulated protein kinase
- Different subfamilies are distinguished primarily by differences in Xaa and/or upstream kinase between the phosphorylation sites.
- MAPKs have about 40-45% homology, and all four ⁇ 38 structures have a circular active center containing a TGY tripeptide module, which is a specific double phosphorylation site of the upstream molecule.
- ⁇ 38 ⁇ , ⁇ 38 ⁇ is widely present in the human body.
- ⁇ 38 ⁇ is mainly found in skeletal muscle, and ⁇ 3 ⁇ is mainly distributed in the lung, kidney, testis, pancreas and small intestine. Different subtypes of ⁇ 38 are distributed differently in different cells.
- the unactivated ⁇ 38 is located in the cytosol, and the activated ⁇ 38 is expressed in both the cytoplasm and the nucleus.
- o P 38 (Lee named it CSBP1 and 2) provides a mechanism for the action of a class of anti-inflammatory compounds, of which SK&F 86002 is a prototype. These compounds inhibit IL-1 and TNF synthesis in human monocytes at low ⁇ ⁇ concentrations [Lee et al., Int. J. I, nopharmac. 10 (7), 835 (1988)] and show up in animal models. Activity, these animal models are resistant to cyclooxygenase inhibitors [Lee et al, Annal s NY Acad. Sci., 696, 10 149 (1993)].
- CSBP/p38 is one of several kinases involved in the stress response signaling pathway that is parallel and largely independent of the similar mitogen-activated protein kinase cascade.
- Stress response signals including LPS, pro-inflammatory cytokines, oxidants, UV rays and osmotic pressure, activate the upstream kinase from CSBP/p38, which in turn phosphorylates CSBP/p38 at the sulphonic acid 180 and tyrosine 182 sites.
- MAPKAP kinase-2 has been identified and MAPKAP kinase-3 is
- a downstream substrate of CSBP/p38 which in turn phosphorylates the heat shock protein Hsp27.
- Other downstream substrates known to be phosphorylated by p38 include kinases (Mnk 1/2, MSK1/2 and PRAK) and transcription factors (CHOP, MEF2, ATF2 and CREB).
- kinases Mnk 1/2, MSK1/2 and PRAK
- transcription factors CHOP, MEF2, ATF2 and CREB
- p38 kinase inhibitors (SK&F86002 and SB 203580) also reduce a variety of pro-inflammatory proteins including IL-6, IL- 8. Synthesis of GM-CSF and C0X-2 It has also been shown that inhibitors of CSBP/p38 kinase inhibit TNF- ot-induced VCAM-1 expression on endothelial cells, TNF- ⁇ -induced phosphorylation of cellular cytoplasmic PLA2 And activation and synthesis of IL-1 stimulated collagenase and stromelysin.
- the object of the present invention is to find and develop a small molecule compound having p38 MAPK inhibitory activity for treating a cytokine (TNF-o, IL-1, etc.) mediated disease, a risk factor or a condition, such as psoriatic arthritis.
- cytokine TNF-o, IL-1, etc.
- Lyttle's syndrome gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, gouty arthritis and other joint diseases, sepsis , septic shock, endotoxic shock, Gram-negative, sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic stroke and hemorrhagic stroke, neurological trauma/closed head injury, asthma , adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, silicosis, pulmonary sarcoma, bone resorption, osteoporosis, restenosis, heart and brain and kidney reperfusion injury, congestive heart failure, coronary artery bypass Bypass (CABG) surgery, blood test formation, glomerulonephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, Graft versus host response, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative co
- the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,
- ⁇ is ⁇ - ⁇ .
- Aromatic carbocyclic rings including but not limited to benzene rings, substituted benzene rings, cyclooctatetraene, cyclopentapentene, etc.; or C ⁇ .
- a saturated or unsaturated non-aromatic carbocyclic ring including, but not limited to, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.; C 5 -d.
- An aromatic heterocyclic ring including one or more heteroatoms selected from 0, N, S, including but not limited to imidazole, pyrazole, phenazole, oxazole, oxazole, pyrocoat, morpholine pyridine, pyrimidine, hydrazine, carbazole and quinoline; or a C 5 - C 8 heteromonocyclic or C 8 -Cu double heterocycle, comprising one or more heteroatoms selected from 0, N, S heteroatoms, including but not limited to tetrahydrofuran, tetrahydrothiophene , piperidine, hexahydropyrimidine, octahydropurine, etc.; said A is independently and optionally substituted by one to more R 15 R 2 ;
- Ar 2 is a benzo five- or six-membered heterocyclic ring.
- the ring includes 1-3 heteroatoms selected from 0, N, S, including but not limited to benzofuran, benzothiophene, benzopyrrole, benzopyrazole, benzodiazepine Hydrofuran, benzodihydrothiophene, benzodihydropyrrole, benzodihydropyrazole, benzothiazole, benzodihydrothiazole, etc.;
- one ring is selected from 0, S Heteroatoms or 2-4 heteroatoms selected from 0, N, S, including but not limited to benzopyran, benzothiopyran, benzopyrimidine, benzoxazine, benzo Dihydropyran, benzoin, benzopiperidin, benzodihydrothiazide, benzomorpholine, etc.; said Ar 2
- n 0, 1 or 2;
- P is phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, benzene Imidazolyl, furyl, thienyl, pyranyl, naphthyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2, 3 - b pyridine, pyrrolo[3,4- b]pyridinyl, 1, 3-oxathia[4,5-pyridinyl, 1, 2, 3-triazolyl, 1, 2,4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydrofuranyl,
- R 1 is independent
- a cycloalkyl or cycloalkenyl group the group may be partially or fully halogenated, or optionally substituted by 1 to 3 C-C 6 fluorenyl or (a wide alkoxy group; the above-mentioned cycloalkyl or ring)
- the 1-3 methylene groups of the alkenyl group may be optionally substituted by 0, NH, S, SO, S0 2 , carbonyl, hydroxymethyl; the above cycloalkyl or cycloalkenyl group may be independently 0-5 or less Substituted: halogen, C 6 straight or branched fluorenyl, OC 6 straight or branched alkoxy;
- aromatic ring, aromatic heterocyclic or fused aromatic ring including phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, carbazolyl, iso Carbazolyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thienyl, pyranyl, naphthyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, fluorenyl, benzimidazolyl , benzofuranyl, benzopyrazolyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, pyrazolo[3, 4-b Pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-
- (-.cycloalkyl or cycloalkenyl, the group may be partially or fully halogenated, or optionally substituted by 1-3 dC 6 alkyl or d-C 6 alkoxy;
- a hydrogen atom a linear or branched fluorenyl group, a dC 6 straight or branched alkenyl group, a phenyl group, a naphthyl group, a mono or a double d-C 4 alkylamino C C 6 alkyl group; m is 0, 1 or 2;
- halogen nitro, carboxy, d-linear or branched alkyl, dC 6 straight or branched alkenyl, C 3 - .
- the invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) according to the invention, which comprises at least one compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, and one or more Use a carrier or excipient.
- the invention relates to a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
- the invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment and/or prevention of a cytokine (TNF-ct, IL-1, etc.) mediated disease or condition.
- a cytokine TNF-ct, IL-1, etc.
- the invention provides methods of treating and/or preventing a cytokine (TNF-a, IL-1, etc.) mediated disease, risk factor or disorder, comprising administering to a subject in need thereof treatment and/or prevention An effective amount of a compound of the invention.
- a cytokine TNF-a, IL-1, etc.
- cytokine (TNF- ot, IL-1, etc.) mediated diseases, risk factors or conditions described in the present invention include psoriatic arthritis, Lyttle's syndrome, gout, traumatic arthritis, rubella arthritis , acute synovitis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, gouty arthritis and other joint diseases, sepsis, septic shock, endotoxic shock, Gram-negative, sepsis, Toxic shock syndrome, cerebral malaria, meningitis, ischemic stroke and hemorrhagic stroke, neurological trauma/closed craniocerebral injury, asthma, adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, silicosis, Pulmonary sarcoma, bone resorption, osteoporosis, restenosis, heart and brain and kidney re-inflation injury, congestive heart failure, coronary artery bypass grafting (CABG), blood test, glomerulonep
- the invention provides a compound of formula I, a pharmaceutically acceptable salt or solvate thereof,
- Aromatic carbocyclic ring including but not limited to benzene ring, substituted benzene ring, cyclotetraene, cyclopentaene, etc.; or ⁇ - saturated or unsaturated non-aromatic carbocyclic ring, including but not limited to cyclopentane, cyclohexane , cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.;
- Aromatic heterocycles including one or more heteroatoms selected from 0, N, S, including but not limited to imidazole, pyrazole, rongha, ? : azole, carbazole, pyrotherapy, morpholine pyridine, pyrimidine, hydrazine, oxazole, quinoline, etc.; or C 5 -C 8 monoheterocycle or Cs-Cu diheterocycle, including one or more Heteroatoms from 0, N, S, including but not limited to tetrahydrofuran, tetrahydrothiophene, piperidine, hexahydropyrimidine, octahydropurine, etc.; said Ar! independently and selectively one to more, 11 2 Replaced
- Ar 2 is a benzo five- or six-membered heterocyclic ring.
- the ring includes 1-3 heteroatoms selected from 0, N, S, including but not limited to benzofuran, benzothiophene, benzopyrrole, benzopyrazole, benzodiazepine Hydrofuran, benzodihydrothiophene, benzodihydropyrrole, benzodihydropyrazole, benzothiazole, benzodihydrothiazole, etc.;
- when it is a six-membered heterocyclic ring one ring selected from 0, S Heteroatoms or 2 to 4 heteroatoms selected from 0, N, S, including but not limited to benzopyran, benzothiopyran, benzopyrimidine, benzoxazine, chroman, Benzohydropyran, benzopiperidine, benzodihydrothiazide, benzo Morpholine or the like; the Ar 2
- n 0, 1 or 2j
- P is phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, benzene Imidazolyl, furyl, thienyl, pyranyl, naphthyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2, 3 - b] pyridyl, pyrrolo[3,4-b]pyridyl, 1, 3-oxathia[4,5-pyridinyl, 1, 2, 3-triazolyl, 1 , 2,4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydr
- R 1 is independent
- a straight or branched alkyl group, the alkyl group may be partially or fully halogenated, and may be substituted by 1-3 phenyl, naphthyl or a heterocyclic ring: quinolyl, isoquinolinyl, pyridyl , pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thiahaki, isoxazolyl, isothiazolyl; the above phenyl, tea or heterocyclic ring can be 0 - 5 of the following groups replaced: !
- a cycloalkyl or cycloalkenyl group the group may be partially or fully halogenated, or substituted by 1-3 C-C 6 alkyl or Cr-C 6 alkoxy; the above cycloalkyl or cycloalkenyl
- the 1-3 methylene groups of the group may be replaced by 0, NH, S, SO, S0 2 , carbonyl, hydroxymethyl; the above cycloalkyl or cycloalkenyl group may be independently substituted by 0-5 groups: Halogen, straight or branched chain base, d-Cs straight or branched alkoxy;
- C 3 - a linear or branched alkenyl group which may be partially or fully halogenated, and may be substituted by 1 to 3 ( ⁇ -C 6 linear or branched alkyl, phenyl, naphthyl or the following heterocyclic ring)
- Substituents quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, isothiazolyl;
- the above phenyl, naphthyl or heterocyclic ring may be substituted by 0-5 groups: halogen, dC 6 straight or branched alkyl, C 3 - cycloalkyl, -cycloalkenyl, hydroxy, nitrile , dC 6 straight or branched alkoxy, trifluoromethyl
- phenyl ring, aromatic heterocyclic or fused aromatic ring including phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, carbazolyl, iso Olezolyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thienyl, pyranyl, phylyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, fluorenyl, benzimidazolyl , benzofuranyl, benzopyrazolyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazino, benzisothiazolyl, pyrazolo[3, 4- b]pyrimidinyl, pyrrolo[2,3-b]pyridyl, pyrrolo[
- the above aromatic ring, aromatic heterocyclic ring or fused aromatic ring group may be independently substituted by 0-5 R 4 groups;
- a cycloalkyl or cycloalkenyl group the group may be partially or fully halogenated, or substituted with 1-3 C-C 6 alkyl or dC 6 alkoxy;
- Hydrogen atom d-C 6 straight or branched alkyl group, CrC fi straight or branched alkenyl group, phenyl, naphthyl group, mono or di C 4 alkylamino group ( ⁇ -( ⁇ alkyl; m is 0 , 1 or 2;
- halogen nitro, carboxy, C-C 6 straight or branched alkyl, ( ⁇ - straight or branched alkenyl, CfC!.
- cycloalkyl -(: 8 cycloalkenyl, hydroxy, nitrile , d-C 6 straight or branched alkoxy, trifluoromethyl, trifluoromethoxy;
- Wide range R 3 NH-, R 3 2 N-, R 3 NCO-R 3 CONH-, R 3 C00 -, R 3 0C0 -, R 3 S (0) m , R 3 S (0) m NH, R 3 NHS (0) m - ;
- the invention provides a compound represented by formula I, a pharmaceutically acceptable salt or solvate thereof,
- Aromatic carbocyclic rings including but not limited to benzene rings, substituted benzene rings, cyclooctatetraene, cyclopentaene, etc., or . a saturated or unsaturated non-aromatic carbocyclic ring, including but not limited to cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.;
- a C 5 -C 1Q aromatic heterocycle comprising one or more heteroatoms selected from 0, N, S, including but not limited to imidazole, pyrazole, thiophene, thiazole, oxazole, pyridinium, morpholinium pyridine, pyrimidine, An oxime, a carbazole, a quinoline or the like; or a monoheterocyclic ring of C-C s or a bi-heterocyclic ring of c 8 - c u , including one or more heteroatoms selected from 0, N, S, including but not limited to Tetrahydrofuran, tetrahydrothiophene, piperidine, hexahydropyrimidine, octahydropurine, etc.; said A is independently and selectively substituted by one to more R 2 ;
- Ar 2 is a benzopyran or a chromanyl group; the Ar 2 may be substituted with from 1 to 4 substituents selected from C: C 6 straight or branched alkyl, C 2 - C 6 straight or branched alkenyl, dC 6 straight or branched alkoxy, C 2 -C 6 straight or branched alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl , halogen, methoxyhistyl, ethoxycarbonyl, phenylsulfonyl, hydroxy, amino, mono- or di-d-C-alkyl substituted amino, mono- or bi- Substituted aminosulfonyl, nitrile, nitro, aminosulfonyl;
- ( 2 ) ( ⁇ . Saturated or unsaturated, linear or branched carbon chain; one or more methylene groups independently replaced by 0, ⁇ , S ( 0 ) m or 0-2 And the linking group can be substituted by one or more halogen atoms;
- n 0, 1 or 2;
- P is phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, benzene Imidazolyl, furyl, thienyl, pyranyl, naphthyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2, 3-b] pyridyl, pyrrolo[3,4-b]pyridinyl, 1, 3-oxaza-[4,5-pyridinyl, 1, 2, 3-triazolyl, 1, 2,4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydrofuranyl, di
- R 1 is independent
- (1) d-. a linear or branched alkyl group the alkyl group may be partially or wholly halogenated And substituted by 1-3 phenyl, naphthyl or a heterocyclic ring: quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, fluorenyl, piperazinyl, pyrrolyl, imidazolyl, Pyrazolyl, furyl, thienyl, isotazolyl, isothiazolyl; the above phenyl, naphthyl or heterocyclic ring may be substituted by 0-5 groups: halogen, CrC 6 straight or branched alkane , ( ⁇ -cycloalkyl, C 5 -cycloalkenyl, hydroxy, nitrile, d-Cs straight or branched alkoxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, bis (wide) Alkyl substituted aminocarbonyl
- C factory d. a cycloalkyl or cycloalkenyl group, said group being partially or fully halogenated, or substituted by 1 to 3 d-C 6 alkyl or d-Ce alkoxy; above cycloalkyl or cycloalkenyl
- the 3 methylene groups may be replaced by 0, NH, S, SO, S0 2 , carbonyl, hydroxymethyl; the above cycloalkyl or cycloalkenyl may be independently substituted by 0-5 groups: halogen, d-Cs straight or branched alkyl, d-C 6 straight or branched alkoxy;
- C 3 - a linear or branched alkenyl group which may be partially or fully halogenated, and may be substituted by 1 to 3 ( ⁇ -C 6 linear or branched alkyl, phenyl, naphthyl or the following heterocyclic ring)
- Substituents quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, isothiazolyl;
- the above phenyl, naphthyl or heterocyclic ring may be substituted by 0-5 groups: halogen, dC 6 straight or branched alkyl, C 3 - cycloalkyl, 0 5 -( 8 cycloalkenyl, a hydroxy group, a nitrile group, a CrCe linear or
- a ring, an aromatic heterocyclic group or a fused aromatic ring including phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, carbazolyl, isoindole Azyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thiol, pyranyl, ca Pyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, fluorenyl, benzimidazolyl, benzofuranyl, benzopyrazolyl, benzothienyl, benzindenyl, benzo Isoxazolyl, benzothiazolyl, benzisothiazolyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2,3-b]pyridyl, pyrrol
- C 3 -C le cycloalkyl or cycloalkenyl said group may be partially or fully halogenated, or substituted by 1-3 ( ⁇ -( ⁇ alkyl or d-C 6 alkoxy) ;
- a hydrogen atom a straight or branched alkyl group of Ci-Cs, a linear or branched alkenyl group of d-Ce, a phenyl group, a naphthyl group, a mono or double dC 4 alkylamino dC 6 alkyl group; m is 0, 1 or 2;
- halogen nitro, carboxy, dC 6 straight or branched chain, Cr straight or branched alkenyl, C 3 - C 1D cycloalkyl, C 5 - (: 8 cycloalkenyl, hydroxy, nitrile Base, d-c 6 straight or branched alkoxy, trifluoromethyl, trifluoromethoxy;
- Preferred compounds of the invention include:
- the compound of formula I can be prepared by several methods, preferably method 3. method 1
- R 6 CCI 3 , C 6 H 4 N0 2 , OC 2 H 5 , imidiazole, Triazole
- reaction sequence of the above three methods can be reversed, that is, phosgene, chloroformate or carbonate can be first reacted with PL-Ar 2 -NH 2 , and the resulting intermediate is further reacted with A ri NH 2 .
- Ar 1 ? Ar 2 , L, P are as defined for Formula I.
- a heterocyclic amine is dissolved in dichloromethane, chloroform or dichloroacetic acid, added with an aqueous solution of sodium hydrogencarbonate or carbonic acid, cooled in a water bath, added with phosgene, stirred for 5-30 minutes,
- the intermediate is reacted with another heterocyclic amine in an anhydrous aprotic solvent (eg THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.) at 0-45 ° C. 2-24
- anhydrous aprotic solvent eg THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.
- a heterocyclic amine is dissolved in dichloromethane, chloroform or dichloroethane, added with a suitable base (such as triethylamine, etc.), then added with a chloroformate, and reacted at 0-85 Torr. 2 - 24 hours, the obtained intermediate and another heterocyclic amine in an anhydrous non-porous solvent (such as THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.) at 0-110
- anhydrous non-porous solvent such as THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.
- a heterocyclic amine is dissolved in dichloromethane, chloroform or dichloroethane, added with a suitable base (such as triethylamine, etc.), then carbonate is added, and the reaction is carried out at - 20-45 Torr.
- a suitable base such as triethylamine, etc.
- carbonate is added, and the reaction is carried out at - 20-45 Torr.
- the obtained intermediate is reacted with another heterocyclic amine in an anhydrous aprotic solvent (such as THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.) at 0-110 Torr.
- the compound of formula I is obtained in 240 hours.
- Ar ⁇ I ⁇ is synthesized by the following routes according to the structure.
- Rl, R2 are defined as the same formula I.
- the amine is at -10-10.
- C is subjected to heavy argonization to obtain a diazonium salt, and the diazonium salt is reduced by sodium sulfite or stannous chloride to obtain hydrazine.
- Ethyl acetate is reacted with ⁇ -bromo ketone under the action of a strong base (sodium, sodium hydride, sodium ethoxide, etc.), and the obtained diketoester V is reacted with sulfuric acid or hydrochloric acid in a solvent such as ethanol to obtain 3-furancarboxylic acid B.
- Ester VI, ethyl 3-furancarboxylate VI and hydrazine hydrate and formic acid are reacted to give 3-aminofuran compound VII.
- the diketone and Lawesson's reagent are refluxed in an anhydrous aprotic solvent for 1-10 hours to obtain a substituted thiophene, which is then nitrated by concentrated nitric acid, iron/hydrochloric acid or catalytic hydrogenation to give 3-aminothiophene compound VIII.
- nitrile aldehyde and the substituted amine are in the range of 50-90 in acetic acid/water.
- acyl nitrile, aldehyde, and anhydrous ammonium acetate are refluxed in acetic acid for 3-6 hours to give 4-amino ⁇ azole compound XI.
- the acid chloride is reacted with a nitrileamine at 0 ° C in a solvent such as tetrahydrofuran to obtain an amide oxime: hydrazine is dissolved in dry dichloromethane, ethanethiol is added, and dry hydrogen chloride gas is introduced. The reaction is carried out for 5-30 minutes, and the obtained product xm is at o. Hydrogen sulfide is introduced into the dried pyridine to saturation, and after 5 hours, the 5-aminocarbazole compound XIV is obtained.
- ⁇ XXI is added to 11 chloroketone and phthalic acid imide potassium salt in DMF for 2 hours to obtain the compound ⁇ , XIX and ⁇ , ⁇ -dimethylformamide dimethyl acetal in DMF
- the reaction was carried out at 100 ° C for 12 hours to give the compound XX.
- XX and substituted hydrazine are refluxed in 90% ethanol for 12 hours to give compound XX I, XX I is decomposed in ethanol to give 4-aminopyrazole XX oxime.
- the cyanoketone is reacted with 50% hydrazine under basic conditions with hydroxylamine hydrochloride to give 5-aminoisoxazole XX m.
- Physiologically acceptable salts of the compounds of formula I include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid.
- citric acid citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, water Salts of salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, s teroic, citric acid and the like.
- Other acids such as oxalic, while not in themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts.
- Suitable base salts include sodium, hydrate, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, N-methylglucamine and procaine salts.
- the present invention also encompasses prodrugs of the compounds of the invention which, upon administration, are chemically converted by metabolic processes and thereafter become active drugs.
- prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula (I).
- conventional methods for selecting and preparing suitable prodrug derivatives are described in "Design Of Prodrugs", H Bund Saard, Elsevier, ed., 1985.
- the invention also includes active metabolites of the compounds of the invention.
- compositions comprising a compound of the invention and at least one pharmaceutically acceptable carrier which is useful for in vivo treatment and is biocompatible.
- the pharmaceutical compositions can be prepared in a variety of forms depending on the route of administration.
- the compounds referred to in the present invention can also be prepared into various pharmaceutically acceptable salts.
- the agonistic effect of the compound of the present invention on PPAR can be measured by the following method.
- the THP- 1 cells were suspended in fetal calf serum containing 15%, 0. 02 nM 2- RMPI medium-mercaptoethanol at a cell concentration of 1-2 106 cells / mL, and plated in 96 well plates (each The pores contain 0.2 mL).
- the test compound was dissolved in DMS0 and then diluted with a medium to give a final concentration of DMSO of 5%. 25 test compound solutions or DMSO only medium (control) were added to each well.
- composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Intra, intraventricular, intrasternal, and intracranial injection or input, or by means of an explant reservoir.
- oral, intraperitoneal or intravenous administration is preferred.
- the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, gels, aqueous solutions or aqueous suspensions.
- the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
- the diluent used in the gelatin preparation generally comprises lactose and dried corn starch.
- Aqueous suspension preparations are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents Use. If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.
- the compounds of the invention When applied topically, especially in the treatment of facial or organs easily accessible by topical application, such as eye, skin or lower intestinal neuropathy, the compounds of the invention may be made into different parts according to different affected faces or organs.
- the form of the pharmaceutical preparation is specifically described as follows:
- the compound of the present invention can be formulated into a preparation form of a micronized suspension or solution, and the carrier used is an isotonic pH-stabilized saline solution, which can be added thereto. There may be no preservatives such as benzyl chloride alkoxide.
- the compound can also be formulated into a bone form such as vaseline.
- the compounds of the invention When applied topically to the skin, the compounds of the invention may be formulated in a suitable cartilage, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers.
- Carriers for cartilage preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams may be used including but not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions.
- a sterile injectable preparation including sterile aqueous or oily suspension or sterile injection solutions.
- carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
- sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
- the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor.
- a preferred dosage is from 0.01 to 100 mg/kg body weight per day, wherein the optimal dose is 5 mg/kg 10 mg/kg body weight per day.
- the melting point of the compound was determined by a YRT-3 type melting point apparatus, and the temperature was not corrected.
- NMR spectra were determined by a Bruker ARX 400 nuclear magnetic instrument.
- FAB mass spectra were determined by a Zabspect high resolution magnetic mass spectrometer.
- Aromatic amine (0.04 fflol) was added to 40 mL of concentrated hydrochloric acid, stirred, and cooled to -5 °C to precipitate white fine granular crystals.
- sodium nitrite solution (2. 90g sodium nitrite dissolved in 20mL water), control the temperature does not exceed 0 °C, and react for 1 hour after the addition.
- acyl acetonitrile (1.25 g, 0. Olmol) obtained in the step 3 and the aromatic hydrazine hydrochloride obtained in the step 2 are added to 50 mL of ethanol, and 2. OmL of concentrated hydrochloric acid is added dropwise, and the mixture is heated to reflux for 12-24 hours. The mixture was cooled, poured into 100 mL of water, adjusted to pH 12 with dilute sodium hydroxide, extracted with ethyl acetate and dried. The obtained crude product was subjected to silica gel column chromatography to afford white solid product.
- the title compound is prepared by using p-butyl chloromethyl ester as a general material,
- the title compound was obtained as a white solid using 3,4-dimethylaniline as a material.
- the title compound was obtained as a white solid using 4-ethylaniline as a crude material.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound is based on intermediate 1 and p-bromophenyl hydrazine.
- step 2 The product obtained in step 1 (0. Olmol) was dissolved in 20 mL of DMF, N,N-dimethylformamide dimethyl acetal (1.44 g, 0.012 mol) was added dropwise, 100 was reacted for 12 hours, and N was added. N-Dimethylformamide dimethyl acetal (1.44 g, 0.012 mol) was further reacted for 24 hours, cooled, poured into 100 mL of ice water, extracted with ethyl acetate, dried and then purified to afford white solid.
- step 3 The product obtained in step 2 (0. Olmol) is dissolved in 100 mL of 90% ethanol, substituted hydrazine (0. Ollmol) is added, heated under reflux for 12 hours, cooled, solid is precipitated, filtered, and the filter cake is washed with anhydrous diethyl ether and dried. A white solid product was obtained.
- step 3 The product obtained in step 3 (0. Olmol) was dissolved in 100 mL of ethanol, 85% hydrazine hydrate solution (0.04 mol) was added dropwise, and heated under reflux for 2 hours to precipitate a white solid, which was cooled, concentrated, and then added with 20 mL of diethyl ether, filtered and filtered. The cake was washed with anhydrous diethyl ether, and the filtrate was combined, concentrated, and purified to afford white powder.
- Intermediate 29 The product obtained in step 3 (0. Olmol) was dissolved in 100 mL of ethanol, 85% hydrazine hydrate solution (0.04 mol) was added dropwise, and heated under reflux for 2 hours to precipitate a white solid, which was cooled, concentrated, and then added with 20 mL of diethyl ether, filtered and filtered. The cake was washed with anhydrous diethyl ether, and the filtrate was combined, concentrated, and purified to afford white powder.
- the title compound is based on intermediate 29 and potassium phthalimide as a raw material.
- step 2 The product obtained in step 1 (0, Olmol), cyanamide (4.23 g, 0.1 mol) was refluxed in 100 mL of ethanol for 12 hours. Concentrate, add the residue to water, extract three times with ethyl acetate, combine the organic layer, then dilute sodium hydroxide solution, water, saturated salt Water washing, drying, and column separation gave a white solid product.
- the title compound is obtained as a white solid in a yield of 99.2%.
- P - L-Ar 2 NH 2 can be synthesized by the following route depending on the structure.
- Resorcinol 44. Og, 0.40 mol
- anhydrous potassium carbonate 66.24 g, 0.48 mol
- benzyl bromide 47.88 g, 0.28 mol
- the reaction was carried out for 5 hours, poured into cold dilute hydrochloric acid to make acidity, and extracted with ethyl acetate three times. The ethyl acetate layer was combined, washed with saturated brine, and dried. It turned into a white solid with a yield of 46.9%.
- the title compound is prepared from the intermediate 49 and morpholine as a general operation C.
- Example 2 Using the preparation method of Example 1, the intermediate 11 was changed to the intermediate 15 and the intermediate 41 was changed to the intermediate 40 to give the title compound as white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- Example 2 200 mg of the product obtained in Example 2 was dissolved in 50 mL of absolute ethanol, 0.2 g of palladium on charcoal was added, and the mixture was heated to 60 ° C, and 1.0 mL of hydrazine hydrate was added dropwise, followed by heating under reflux for 6 hours, cooled, filtered, and the filtrate was concentrated.
- the title compound 149 mg was obtained as a white solid.
- Example 2 Using the preparation method of Example 1, the intermediate 41 was changed to an intermediate 40, the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a yellow solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- Example 14 Using the preparation method of Example 15, the intermediate 59 was changed to an intermediate. 54 The title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- Example 36 Using the preparation method of Example 36, the intermediate 11 was changed to an intermediate. 16. The title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a yellow solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- Example 36 Using the preparation method of Example 36, the intermediate 11 was changed to an intermediate.
- Example 36 Using the preparation method of Example 36, the intermediate 11 was changed to an intermediate.
- the title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
- Example 36 Using the preparation method of Example 36, the intermediate 11 was changed to an intermediate.
- Example 36 Using the preparation method of Example 36, the intermediate 11 was changed to an intermediate.
- Example 61 l-[4-tert-butyl-1-(4-methylphenyl)- 1 ⁇ 2-imidazole Benzyl]-3- ⁇ 8- ⁇ 5-[2-(4-morphinolinyl)ethoxy]-2 ⁇ enyl ⁇ urea
- the preparation method of Example 36 was used to change the intermediate 11 The title compound was obtained as a white solid.
- the title compound was obtained as a white solid.
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Description
脲类化合物, 其制备方法及其医药用途 技术领域
本发明涉及抑制 P38蛋白激酶的脲类化合物,含有它们的药物 組合物, 制备这些化合物的方法及它们的医药用途。
背景技术
TNF和 IL-1在许多慢性炎症和自身免疫性疾病相关的病理过 程中成为核心参与者。 IL-1涉及介导或恶化疾病, 如类风湿性关 节炎(参见, Arend, W. P. Arthritis&Rheumatism 38(2) : 151-160, (1995)) , 骨关节炎, 骨吸收, 中毒性休克综合症, 结 核病,动脉粥样硬化,糖尿病,何杰金氏病, (参见, Benharroch, D.等. Euro. Cytokine Network 7(1): 51-57)和阿尔茨海默病。 已经发现过度或失调的 TNF生产参与介导或恶化疾病,如类风湿性 关节炎((参见, Ma.ini, R. N.等 APMIS. 105(4): 257-263, (1997); Feldmann, M. , J. of the Royal College of Physicians of London 30(6) : 560-570, (1996); Lorenz, H. M.等 J. of Immunology 156(4): 1646-1653, (1996)), 骨关节炎, 脊推炎, 脓毒症, 脓毒性休克((参见, Abraham, E, 等 JAMA. 277 (19): 1531-1538, (1997),成人呼吸窘迫综合征,哮喘((参见, Shah, A. 等 .Clin. & Exp. Allergy 1038-1044, (1995) 和 Lassalle, P. 等 Clin. & Exp. Allergy 94 ( 1 ) : 105-110, (1993)) , 骨吸 收病, 热病 ((参见, Cooper, A. L.等 Am. J. of Physiology 267 (6 Pt. 2): 1431-1436)), 脑脊髓炎,脱髓鞘作用(参见, Klindert, W. E.等: Γ. of Neuroimmunol. 72 (2): 163-168,(1997) )和牙周 疾病。
IL-1和 TNF受体拮抗剂的临床试验显示, 阻断这些细胞因子 通过其受体发出信号的能力可以在人体中明显改善炎性疾病。 所
以, 这些炎症细胞因子的调控被认为是一种最有效的阻断慢性炎 症并具有阳性治疗效果的策略。
丝裂素激活蛋白激醉(mi togen- act ivated protein
kinase, MAPK)级联是细胞内主要信号转导系统, 细胞外刺激信号 通过这一系统传递到细胞核, 进而导致细胞生长, 发育, 分裂, 细胞因子分泌及恶性转化等一系列生理和病理过程。
细胞中大多数蛋白激酶处于非活性状态, 当特定的上游激酶 信号激活时, 导致该激酶发生丝氨酸(seriene,S), 苏氨酸
(threonine, T)或酪氨酸(tyros ine, Y)残基磷酸化而激活。 与其 它蛋白激酶不同, 所有 MAPK家族成员的活化均需对苏氨酸和酪氨 酸残基双位点磷酸化来完成, MAPK双位点磷酸化基团具有
Thr-Xaa-Tyr (T-X-Y)的序列特征 (参见 Seger R, Krebs EG. The MAPK s ingal ing cascade. FASEB J. 1995 9: 726-735 ) 。 MAPK的 活化和磷酸化通过了包括上游多级激酶在内的级联反应, 其中包 括三级关键激酶: MAPK, MAPK激酶(MAPK kinase, MAPKK或
MEK/MKK) , MAPK激酶激酶(MAPK kinase kinase, MAPKKK)。 MAPKKK 对 MAPKK的丝氨酸,苏氨酸双位点磷酸化而将其激活;活化的 MAPKK 进一步对 MAPK进行丝氨酸,苏氨酸双位点磷酸化而将其激活。(参 见 Boul ton T. G. , Nye S. H., Bobbins D. J.等. Cel l 1991 , 65: 663: 675 ) 。
哺乳动物细胞 MAPK 家族至少包括四个亚家族, 即 ERK (extracel luar regulated protein kinase) , 皿 (c-Jun N-terminal kinase) , p38 , ERK5。 不同亚家族主要通过双磷酸 化位点之间的 Xaa和 /或上游激酶的差别来区分。
Han等于 1993年首先在内毒素脂多糖( LPS )刺激后的前 B细胞 中发现和克隆了一种 38kDa的 MAPK。 p38 MAPK双磷酸化位点位于笫 180位点和第 182位的酪氨酸和苏氨酸。 p38 MAPK的特异性双碑酸
化集团为 Thr-Gly-Tyr。迄今己发现四个 p38 MAPK亚型: ρ38 α , ρ38 β , Ρ38 γ , ρ3 δ。 四种异构体之间约有 60%的同源性, 与其它类
MAPKs则约有 40-45%的同源性,四种 ρ38的结构中均有一含 TGY三肽 模块的环状活性中心, 为上游分子的特异性双磷酸化位点。 Ρ38 α, ρ38 β在人体内广泛存在, ρ38 γ主要存在于骨骼肌中, ρ3 δ主 要分布于肺, 肾, 睾丸, 胰腺和小肠中。 不同亚型的 ρ38在不同的 细胞中分布不同。未活化的 ρ38位于胞浆中, 活化的 ρ38在胞浆和 胞核均可表达。
Lee通过对 ρ38激酶作为一类新的抗炎剂的靶分子的独立发 现, 提供了 Ρ38激酶参与 LPS—激发的导致促炎性细胞因子生物合 成产生的信号传导路径的确切证据 5 [Lee等, Nature, 372, 739
(1994) ] o P38 (Lee将其命名为 CSBP1和 2)的发现提供了一类抗炎化 合物的作用机制, 其中 SK&F 86002是原型实例。 这些化合物在低 μ Μ浓度范围内抑制人单核细胞中 IL- 1和 TNF合成 [Lee等, Int. J. I廳 nopharmac. 10 (7) , 835 (1988) ]并在动物模型中表现出 活性,这些动物模型对环加氧酶抑制剂有抗药性 [Lee等, Annal s N. Y. Acad. Sci. , 696, 10 149 (1993) ]。 现在确信 CSBP/p38是参与 应激反应信号传导路径的几种激酶之一其平行于并在很大程度上 独立于类似的丝裂素激活蛋白激酶级联。应激反应信号,包括 LPS, 促炎细胞因子, 氧化剂, UV线和渗透压, 由 CSBP/p38开始激活上 游激酶, 其依次在苏氛酸 180和酪氨酸 182位点磷酸化 CSBP/p38, 导致 CSBP/p38活化。 已确定 MAPKAP激酶- 2 , MAPKAP激酶- 3为
CSBP/p38的下游底物, 其依次磷酸化热激蛋白 Hsp27。 已知被 p38 磷酸化的其它下游底物包括激酶 (Mnk 1/2 , MSK1/2和 PRAK)以及转 录因子(CHOP , MEF2 , ATF2和 CREB)。 虽然需要细胞因子生物合成 的很多信号路径尚属未知,但似乎清楚其中涉及很多上述 P38的底 物 [Cohen, P. Trends Cel l Biol. , 353 361 (1997)和 Lee, J. C.
等, Pharmacol. Ther. 82: 389-397, ( 1999 ) ]„ 除了抑制 IL-1和 TNF外, p38激酶抑制剂(SK&F86002和 SB 203580)还降低多种促炎蛋白包括 IL-6, IL-8, GM - CSF和 C0X-2的合 成。 也已表明 CSBP/p38激酶的抑制剂抑制 TNF- ot诱发的 VCAM-1在 内皮细胞上的表达, TNF- α诱发的细胞胞质 PLA2的磷酸化和活化 以及 IL-1刺激的胶原酶和溶基质素的合成。 这些以及其它数据表 明 ρ38不仅参与细胞因子的合成, 还涉及细胞因子信号 【有关 CSBP/P38激酶综述, 见 [Cohen, P. Trends Cel l Biol. ,
353-361 (1997) ] 发明内容
本发明的目的是寻找并开发具有 p38 MAPK抑制活性的小分子 化合物, 用来治疗细胞因子 (TNF- o, IL- 1等)介导的疾病, 危 险因子或病症, 如为牛皮癬性关节炎, 莱特尔氏综合征, 痛风, 外伤性关节炎, 风疹性关节炎, 急性滑膜炎, 类风湿性关节炎, 类风湿性脊推炎, 骨关节炎, 痛风性关节炎及其它关节病, 败血 症, 脓毒性休克, 内毒素性休克, 革兰氏阴性, 败血症, 中毒性 休克综合征, 脑型疟, 脑膜炎, 局部缺血性中风和出血性中风, 神经外伤 /闭合性颅脑损伤, 哮喘, 成人呼吸窘迫综合症, 慢性肺 炎, 慢性阻塞性肺病, 矽肺, 肺肉瘤病, 骨吸收病, 骨质疏松, 再狹窄, 心脏及脑和肾再灌注损伤, 充血性心力衰竭, 冠状动脉 旁路搭桥 (CABG)术, 血检形成, 肾小球性腎炎, 慢性肾衰竭, 糖 尿病, 糖尿病性视网膜病, 黄斑变性, 移植物抗宿主反应, 同种 移植物排斥, 炎性肠疾病, 节段性回肠炎, 溃疡性结肠炎神经变 性疾病, 肌肉退化, 糖尿病性视网膜病, 黄斑变性, 肿瘤生长和 转移, 血管生成疾病, 流感引起的肺炎, 湿疹, 接触性皮炎, 牛 皮癣, 晒伤或结膜炎等。
本发明人已经发现通式 I 的化合物可以用于治疗或预防细胞 因子 (TNF- a, IL-1等)介导的各种疾病、 危险因子或病症。
因此, 在本发明的一个方面, 本发明提供通式(I)化合物, 或 其可药用盐或溶剂化物,
^为^-^。芳香碳环,包括但不限于苯环、 取代苯环、 环辛四 烯、 环癸五烯等; 或 C ^。饱和或不饱和的非芳香碳环, 包括但不 限于环戊烷、 环己烷、 环戊烯、 环己烯、 环戊二烯、 环己二烯等; C5-d。芳香杂环, 包括一到多个选自 0, N, S的杂原子, 包括但不 限于咪唑、 吡唑、 吩、 唑、 喁唑、 吡漆、 吗啉吡啶、 嘧啶、 吲哚、 吲唑、 喹啉等; 或者 C5- C8的单杂环或者 C8-Cu的双杂环, 包 括一到多个选自 0, N, S的杂原子, 包括但不限于四氢呋喃、 四氢 噻吩、 哌啶、 六氢嘧啶、 八氢吲哚等; 所述 A 独立并选择性地被 一到多个 R15 R2所取代;
Ar2为苯并五元或六元杂环。 当为五元杂环时, 环上包括 1-3 个选自 0, N, S的杂原子, 包括但不限于苯并呋喃、 苯并噻吩、 苯 并吡咯、 苯并吡唑、 苯并二氢呋喃、 苯并二氢噻吩、 苯并二氢吡 咯、 苯并二氢吡唑、 苯并噻唑、 苯并二氢噻唑等; 当为六元杂环 时, 环上有一个选自 0, S的杂原子或 2-4个选自 0, N, S的杂原子, 包括但不限于苯并吡喃、 苯并噻喃、 苯并嘧啶、 苯并喁嗪、 苯并
二氢吡喃、 苯并二氢噻喃、 苯并哌啶、 苯并二氢噻臻、 苯并吗啉 等; 所述 Ar2可选择性地被 1-4个选自下面的取代基取代: (^-0!6直 链或支链烷基, C2- C6直链或支链烯基, d-C6直链或支链烷氧基, C广 C6直链或支链烯氧基, 三氟甲基, 三氟甲氧基, 乙酰基, 芳酰 基, 卤素, 甲氧羰基, 乙氧羰基, 苯磺酰基, 羟基, 氨基, 单或 双(^- C4烷基取代的氨基, 单或双 d-O^基取代的氨基磺酰基, 腈 基, 硝基, 氨基磺酰基;
L独立的为
( 2 ) C广 (^饱和或不饱和的, 直链或支链碳链; 其中的一到 多个亚甲基独立且选择性被 0, NH, S ( 0 ) ra或者 0-2个漿基所替代; 并且所述联接基团可选择性被一到多个卤原子取代;
m为 0, 1或 2;
P为苯基, 萘基, 喹啉基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪 基, 咪唑基, 喁唑基, 异喁唑基, 噻唑基, 异噻唑基, 吡咯基, 苯并咪唑基, 呋喃基, 噻吩基, 吡喃基, 萘啶基, 哌嗪基, 吡唑 基, 噻唑基, 嘌呤基, 吡唑并 [ 3, 4-b]嘧啶基, 吡咯并 [2 , 3 - b〗 吡啶基, 吡咯并 [3, 4- b]吡啶基, 1, 3-氧氮杂并 [4, 5- b]吡啶基, 1 , 2 , 3-三氮唑基, 1, 2, 4-三氮唑基, 四氮唑基, 四氢吡喃基, 四氢呋喃基, 二氢萘基, 四氢萘基, 二氢喹啉基, 四氢喹啉基, 二氢异喹啉基, 四氢异喹啉基, 1 , 3-二氧环戊酮基, 1, 3-二氧 环己酮基, 1, 4-二氧六环基, 吗啉基, 硫代吗啉基, 亚砜代吗啉 基, 砜代吗啉基, 哌啶基, 哌啶酮基, 哌啶醇基, 四氢嘧啶酮基, 环己酮基, 环己醇基, 硫杂己环基, 五亚甲基亚砜基, 五亚甲基 砜基, 四氢噻吩基, 四亚甲基亚砜基, 四亚甲基砜基; 所述基团 可任选被 1-3个选自下面的取代基取代: d-Cs直链或支链烷基, C2-C6直链或支链烯基, C6直链或支链烷氧基, C2-C6直链或支链
烯氧基, 三氟甲基, 三氟甲氧基, 乙酰基, 芳酰基, 卤素, 苯磺 酰基, 羟基, 氨基, 单或双 Cr" C4烷基取代的氨基, 单或双 (^- 烷 基取代的氨基酰基, C C^烷氧藏基, d- 酰氧基, 单或双 C广 C4烷 基取代的氨基磺酰基, 腈基, 硝基, 氨基磺酰基;
R1独立的为
( 1 ) d- 。直链或支链烷基, 所述烷基可部分或全部被卤 代,并且可选择性被 1-3个苯基,萘基或以下的杂环取代:喹啉基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪基, 哌嗪基, 吡咯基, 咪唑基, 吡唑基, 呋喃基, 噻吩基, 异喁唑基, 异噻唑基; 上述苯基, 萘 基或杂环可被 0-5个下述基团取代: 鹵素, d-C^直链或支链坑基, C3-C3环烷基, C5 Cs环烯基, 羟基, 腈基, d-Ce直链或支链烷氧基, 三氟甲基, 三氟甲氧基, 氨基羰基, 双 (^-(^烷基取代的氨基羰基;
( 2 ) CrC!。环烷基或环烯基, 所迷基团可部分或全部被卤 代, 或选择性被 1- 3个 C广 C6焼基或 (广^烷氧基取代; 上述的环烷 基或环烯基的 1-3个亚甲基可选择性被 0, NH, S, SO, S02, 羰基, 羟甲基替代; 上述环烷基或环烯基可独立的被 0-5个以下基团取 代: 卤素, C6直链或支链焼基, OC6直链或支链烷氧基;
( 3 ) ( · 。直链或支链烯基, 所迷烷基可部分或全部被卤 代, 并且可选择性被 1-3个 d-Oi直链或支链烷基, 苯基, 萘基或以 下的杂环取代: 喹啉基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪基, 哌嗪基, 吡咯基, 咪唑基, 吡唑基, 呋喃基, 噻吩基, 异喁唑基, 异噻唑基;上述苯基,萘基或杂环可被 0-5个下迷基团取代: 卤素, C广 C6直链或支链烷基, 。环烷基, 05-( 8环烯基, 羟基, 腈基, 直链或支链垸氧基, 三氟甲基, 三氟甲氧基, 氨基叛基, 双 (^-( 4烷基取代的氨基羰基;
( 4 ) 卤素, 硝基, 羧基, 羟基, 腈基, 三氟甲基, 三氟甲 氧基;
(5) NH-, R3NH -, R3 2N-, R3NCO-R3CONH -, R3C00-, R30C0-, R3S (0) ra, R3S (0) mNH, R3NHS(0)B- ;
R2独立的为
(1) 芳环, 芳杂环基或稠合芳环, 包括苯基, 萘基, 喹啉 基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪基, 咪唑基, 喁唑基, 异 喁唑基, 噻唑基, 异噻唑基, 吡咯基, 呋喃基, 噻吩基, 吡喃基, 萘啶基, 哌嗪基, 吡唑基, 噻唑基, 嘌呤基, 吲哚基, 苯并咪唑 基, 苯并呋喃基, 苯并吡唑基, 苯并噻吩基, 苯并喁唑基, 苯并 异噁唑基, 苯并噻唑基, 苯并异噻唑基, 吡唑并 [3, 4-b]嘧啶基, 吡咯并 [2, 3-b]吡啶基, 吡咯并 [3, 4-b]吡啶基, 1, 3-氧氮杂并 [4, 5- b]吡啶基, 1, 2, 3-三氮唑基, 1, 2, 4-三氮唑基, 四氮 唑基, 四氢吡喃基, 四氢呋喃基, 二氢萘基, 四氢蔡基, 二氢喹 啉基, 四氢喹啉基, 二氢异喹啉基, 四氢异喹啉基, 苯并环丁基, 茚基, 茚烯基。 上述芳环, 芳杂环或稠合芳环基可独立的被 0-5 个 R4基团取代;
(2) ( - 。环烷基或环烯基, 所迷基团可部分或全部被卤 代, 或选择性被 1-3个 d-C6烷基或 d- C6烷氧基取代;
(3) d-C^。直链或支链烷基, 所述烷基可部分或全部被卤 代;
(4) NH2-, R3NH -, R3 2N -, R3NCO-R3CONH -, R3C00 -, R30C0-, R3S(0)n, R3S (0) mNH, R3NHS (0) - ;
R3独立的为
氢原子, 直链或支链焼基, d-C6直链或支链烯基, 苯基, 萘基, 单或双 d- C4烷基氨基 C广 C6烷基; m为 0, 1或 2;
R4独立的为
a) 卤素, 硝基, 羧基, d- 直链或支链烷基, d-C6直链或 支链烯基, C3- 。环烷基, C5- (8环烯基, 羟基, 腈基, d-C6直链或
支链烷氧基, 三氟甲基, 三氟甲氧基;
b) ΝΗ2-, R3NH -, R3 2N -, R3NC0-R3CONH-, R3COO-5 R30C0-, R3S (0) ra, R3S (0) fflNH, R3NHS (0) - 。
另一方面,本发明提供包含本发明通式(I)化合物的药用组合 物,其含有至少一种通式(I)化合物或其可药用盐、 溶剂化物, 以 及一种或多种药用载体或赋形剂。
另一方面,本发明还涉及制备通式(I)化合物或者其可药用盐 或溶剂化物的方法。
再一方面, 本发明涉及通式(I)化合物用于制备治疗和 /或预 防细胞因子(TNF- ct, IL-1等)介导的疾病或病症的药物的用途。
在又一方面, 本发明提供了治疗和 /或预防细胞因子 (TNF- a , IL-1等)介导的疾病、危险因子或病症的方法,包括给予有此 需要的对象治疗和 /或预防有效量的本发明化合物。本发明中所述 的细胞因子 (TNF- ot, IL-1等)介导的疾病、 危险因子或病症包 括牛皮癣性关节炎, 莱特尔氏综合征, 痛风, 外伤性关节炎, 风 疹性关节炎, 急性滑膜炎, 类风湿性关节炎, 类风湿性脊推炎, 骨关节炎, 痛风性关节炎及其它关节病, 败血症, 脓毒性休克, 内毒素性休克, 革兰氏阴性, 败血症, 中毒性休克综合征, 脑型 疟, 脑膜炎, 局部缺血性中风和出血性中风, 神经外伤 /闭合性颅 脑损伤, 哮喘, 成人呼吸窘迫综合症, 慢性肺炎, 慢性阻塞性肺 病, 矽肺, 肺肉瘤病, 骨吸收病, 骨质疏松, 再狭窄, 心脏及脑 和肾再濯注损伤,充血性心力衰竭,冠状动脉旁路搭桥(CABG)术, 血检形成, 肾小球性肾炎, 慢性肾衰竭, 糖尿病, 糖尿病性视网 膜病, 黄斑变性, 移植物抗宿主反应, 同种移植物排斥, 炎性肠 疾病, 节段性回肠炎, 溃疡性结肠炎神经变性疾病, 肌肉退化, 糖尿病性视网膜病, 黄斑变性, 肿瘤生长和转移, 血管生成疾病, 流感引起的肺炎, 湿疹, 接触性皮炎,
牛皮癣, 晒伤或结膜炎等。
在本发明的一个实施方式中,本发明提供了通式 I化合物、其 可药用盐或溶剂化物,
I
其中:
为^-^。芳香碳环,包括但不限于苯环、 取代苯环、 环争四 烯、 环癸五烯等; 或^- 饱和或不饱和的非芳香碳环, 包括但不 限于环戊烷、 环己烷、 环戊烯、 环己烯、 环戊二烯、 环己二烯等;
G-d。芳香杂环, 包括一到多个选自 0, N, S的杂原子, 包括但不 限于咪唑、 吡唑、 蓉哈、 ? :唑、 喁唑、 吡療、 吗啉吡啶、 嘧啶、 吲哚、 吲唑、 喹啉等; 或者 C5-C8的单杂环或者 Cs-Cu的双杂环, 包 括一到多个选自 0, N, S的杂原子, 包括但不限于四氢呋喃、 四氢 噻吩、 哌啶、 六氢嘧啶、 八氢吲哚等; 所述 Ar!独立并选择性地被 一到多个 , 112所取代;
Ar2为苯并五元或六元杂环。 当为五元杂环时, 环上包括 1-3 个选自 0, N, S的杂原子, 包括但不限于苯并呋喃、 苯并噻吩、 苯 并吡咯、 苯并吡唑、 苯并二氢呋喃、 苯并二氢噻吩、 苯并二氢吡 咯、 苯并二氢吡唑、 苯并噻唑、 苯并二氢噻唑等; 当为六元杂环 时, 环上有一个选自 0 , S的杂原子或 2- 4个选自 0, N, S的杂原子, 凶、 包括但不限于苯并吡喃、 苯并噻喃、 苯并嘧啶、 苯并 嗪、 苯并二氢吡喃、 苯并二氢噻喃、 苯并哌啶、 苯并二氢噻嗪、 苯并
吗啉等;所述 Ar2可选择性地被 1-4个选自下面的取代基取代: d-Cs 直链或支链垸基, C2-C6直链或支链烯基, d-C6直链或支链烷氧基, C2 - C6直链或支链烯氧基, 三氟甲基, 三氟甲氧基, 乙酰基, 芳酰 基, 卤素, 甲氧羰基, 乙氧叛基, 苯磺酰基, 羟基, 氨基, 单或 双(^- C4烷基取代的氨基, 单或双 d- 烷基取代的氨基磺酰基, 腈 基, 硝基, 氨基磺酰基;
L独立的为
( 2 ) ^-^。饱和或不饱和的, 直链或支链碳链; 其中的一到多 个亚曱基独立的被 0, NH, S ( 0 ) a或者 0-2个叛基所替代; 并且所 述联接基团可被一到多个卤原子取代;
m为 0, 1或 2j
P为苯基, 萘基, 喹啉基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪 基, 咪唑基, 喁唑基, 异喁唑基, 噻唑基, 异噻唑基, 吡咯基, 苯并咪唑基, 呋喃基, 噻吩基, 吡喃基, 萘啶基, 哌嗪基, 吡唑 基, 噻唑基, 嘌呤基, 吡唑并 [3, 4-b]嘧啶基, 吡咯并 [2, 3 - b] 吡啶基, 吡咯并 [3, 4-b]吡啶基, 1, 3-氧氮杂并 [4 , 5-b]吡啶基, 1 , 2, 3-三氮唑基, 1 , 2, 4-三氮唑基, 四氮唑基, 四氢吡喃基, 四氢呋喃基, 二氢萘基, 四氢萘基, 二氢喹啉基, 四氢喹啉基, 二氢异喹啉基, 四氢异喹啉基, 1, 3-二氧环戊酮基, 1, 3-二氧 环己酮基, 1, 4-二氧六环基, 吗啉基, 硫代吗啉基, 亚砜代吗啉 基, 砜代吗啉基, 哌啶基, 哌啶酮基, 哌啶醇基, 四氢嘧啶酮基, 环己酮基, 环己醇基, 硫杂己环基, 五亚甲基亚砜基, 五亚甲基 砜基, 四氢噻吩基, 四亚甲基亚砜基, 四亚甲基砜基; 所述基团 可任选被 1-3个选自下面的取代基取代: d- C6直链或支链烷基, C2-Cfi直链或支链烯基, C广 Cfi直链或支链烷氧基, C2-C6直链或支链 烯氧基, 三氟甲基, 三氟甲氧基, 乙酰基, 芳酰基, 卤素, 苯磺
酰基, 羟基, 氨基, 单或双 烷基取代的氨基, 单或双 d-C4烷 基取代的氨基酰基, Cr^烷氧羰基, d-C5酰氧基, 单或双 (^-^烷 基取代的氨基磺酰基, 腈基, 硝基, 氨基磺酰基;
R1独立的为
( 1 ) d- 。直链或支链烷基, 所迷烷基可部分或全部被卤 代, 并且可被 1-3个苯基, 萘基或以下的杂环取代: 喹啉基, 异喹 啉基, 吡啶基, 嘧啶基, 哒嗪基, 哌嗪基, 吡咯基, 咪唑基, 吡 唑基, 呋喃基, 噻哈基, 异噍唑基, 异噻唑基; 上述苯基, 茶基 或杂环可被 0-5个下述基团取代: !¾素, d-C^直链或支链烷基, C3-C3环烷基, (^- 环烯基, 羟基, 腈基, 直链或支链烷氧基, 三氟甲基, 三氟甲氧基, 氨基羰基, 双 ( ^烷基取代的氨基漿基;
( 2 ) C3- 。环烷基或环烯基, 所迷基团可部分或全部被卤 代, 或被 1-3个 C广 C6烷基或 Cr-C6烷氧基取代; 上述的环烷基或环 烯基的 1-3个亚甲基可被 0, NH, S, SO, S02, 羰基, 羟甲基替代; 上述环烷基或环烯基可独立的被 0-5个以下基团取代: 卤素, 直链或支链貌基, d-Cs直链或支链烷氧基;
( 3 ) C3- 。直链或支链烯基, 所述烷基可部分或全部被卤 代, 并且可被 1-3个(^- C6直链或支链烷基, 苯基, 萘基或以下的杂 环取代: 喹啉基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪基, 哌嗪基, 吡咯基, 咪唑基, 吡唑基, 呋喃基, 噻吩基, 异嚙唑基, 异噻唑 基; 上述苯基, 萘基或杂环可被 0-5个下述基团取代: 鹵素, d-C6 直链或支链烷基, C3- 。环烷基, - 环烯基, 羟基, 腈基, d-C6 直链或支链烷氧基, 三氟甲基, 三氟甲氧基, 氨基羰基, ^C -C4 烷基取代的氨基羰基;
( 4 ) 卤素, 硝基, 羧基, 羟基, 腈基, 三氟甲基, 三氟甲 氧基;
( 5 ) NH2-, R3NH -, R3 2N -, R3NCO-R3CONH-, R3C00-, R30C0—,
R3S (0) ra, R3S (0) nNH, R3NHS (0) a- ;
R2独立的为
( 1 ) 苯环, 芳杂环基或稠合芳环, 包括苯基, 萘基, 喹淋 基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪基, 咪唑基, 喁唑基, 异 嚙唑基, 噻唑基, 异噻唑基, 吡咯基, 呋喃基, 噻吩基, 吡喃基, 茶啶基, 哌嗪基, 吡唑基, 噻唑基, 嘌呤基, 吲哚基, 苯并咪唑 基, 苯并呋喃基, 苯并吡唑基, 苯并噻吩基, 苯并喁唑基, 苯并 异喁唑基, 苯并噻唾基, 苯并异噻唑基, 吡唑并 [3, 4- b]嘧啶基, 吡咯并 [2 , 3-b]吡啶基, 吡咯并 [3, 4- b]吡啶基, 1, 3-氧氮杂并
[4, 5- b]吡啶基, 1, 2, 3-三氮唑基, 1, 2, 4-三氮唑基, 四氮 唑基, 四氢吡喃基, 四氢呋喃基, 二氢萘基, 四氢萘基, 二氢喹 啉基, 四氢喹啉基, 二氢异喹啉基, 四氢异喹啉基, 苯并环丁基, 茚基, 茚烯基。 上述芳环, 芳杂环或稠合芳环基可独立的被 0-5 个 R4基团取代;
( 2 ) C3- 。环烷基或环烯基, 所述基团可部分或全部被卤 代, 或被 1-3个 C广 C6烷基或 d-C6烷氧基取代;
( 3 ) d- 。直链或支链烷基, 所述烷基可部分或全部被卤 代;
( 4 ) NH2-, R3NH -, R3 2N -, R3NCO-R CONH-, R3C00-, R30C0-, R3S (0) m, R3S (0) fflNH, R3NHS (0) - ;
R3独立的为
氢原子, d- C6直链或支链烷基, CrCfi直链或支链烯基, 苯基, 萘基, 单或双 C4烷基氨基(^-(^烷基; m为 0, 1或 2;
R4独立的为
a) 卤素, 硝基, 羧基, C广 C6直链或支链烷基, (^- 直链或 支链烯基, CfC!。环烷基, -(:8环烯基, 羟基, 腈基, d- C6直链或 支链烷氧基, 三氟甲基, 三氟甲氧基;
b) 冊广, R3NH-, R3 2N-, R3NCO-R3CONH-, R3C00 -, R30C0 -, R3S (0) m, R3S (0) mNH, R3NHS (0) m- ;
在本发明的一个优选实施方式中, 本发明提供了通式 I 所代 表的化合物, 其可药用盐或溶剂化物,
I
其中:
^为 -^。芳香碳环,包括但不限于苯环、 取代苯环、 环辛四 烯、 环癸五烯等,' 或 。饱和或不饱和的非芳香碳环, 包括但不 限于环戊烷、 环己烷、 环戊烯、 环己烯、 环戊二烯、 环己二烯等;
C5-C1Q芳香杂环, 包括一到多个选自 0, N, S的杂原子, 包括但不 限于咪唑、 吡唑、 噻吩、 噻唑、 喁唑、 吡嚓、 吗啉吡啶、 嘧啶、 吲哚、 吲唑、 喹啉等; 或者 C广 cs的单杂环或者 c8- cu的双杂环, 包 括一到多个选自 0, N, S的杂原子, 包括但不限于四氢呋喃、 四氢 噻吩、 哌啶、 六氢嘧啶、 八氢吲哚等; 所述 A 独立并选择性地被 一到多个 R2所取代;
Ar2为苯并吡喃或苯并二氢吡喃基; 所述 Ar2可被 1-4个选自下 面的取代基取代: C「C6直链或支链烷基, C2- C6直链或支链烯基, d-C6直链或支链烷氧基, C2-C6直链或支链烯氧基, 三氟甲基, 三 氟甲氧基, 乙酰基, 芳酰基, 卤素, 甲氧叛基, 乙氧羰基, 苯磺 酰基, 羟基, 氨基, 单或双 d C^烷基取代的氨基, 单或双 (广^烷
基取代的氨基磺酰基, 腈基, 硝基, 氨基磺酰基;
L独立的为
( 1 )键;
( 2 ) ( ^。饱和或不饱和的, 直链或支链碳链; 其中的一到多 个亚甲基独立的被 0, ΝΗ, S ( 0 ) m或者 0-2个裁基所替代; 并且所 迷联接基团可被一到多个卤原子取代;
m为 0, 1或 2;
P为苯基, 萘基, 喹啉基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪 基, 咪唑基, 喁唑基, 异喁唑基, 噻唑基, 异噻唑基, 吡咯基, 苯并咪唑基, 呋喃基, 噻吩基, 吡喃基, 萘啶基, 哌嗪基, 吡唑 基, 噻唑基, 嘌呤基, 吡唑并 [3, 4- b]嘧啶基, 吡咯并 [2 , 3-b] 吡啶基, 吡咯并 [3 , 4- b]吡啶基, 1 , 3-氧氮杂并 [4, 5-b]吡啶基, 1, 2 , 3-三氮唑基, 1, 2, 4-三氮唑基, 四氮唑基, 四氢吡喃基, 四氢呋喃基, 二氢萘基, 四氢萘基, 二氢喹啉基, 四氢喹啉基, 二氢异喹啉基, 四氢异喹啉基, 1 , 3-二氧环戊酮基, 1, 3-二氧 环己酮基, 1 , 4-二氧六环基, 吗啉基, 硫代吗啉基, 亚砜代吗啉 基, 砜代吗啉基, 哌啶基, 哌啶酮基, 哌啶醇基, 四氢嘧啶酮基, 环己酮基, 环己醇基, 硫杂己环基, 五亚甲基亚砜基, 五亚甲基 砜基, 四氢噻吩基, 四亚甲基亚砜基, 四亚甲基砜基; 所述基团 可任选被 1-3个选自下面的取代基取代: 直链或支链垸基, C2- C6直链或支链烯基, d- 直链或支链烷氧基, C2-C6直链或支链 烯氧基, 三氟甲基, 三氟甲氧基, 乙酰基, 芳酰基, 卤素, 苯磺 酰基, 羟基, 氨基, 单或双 C广 C4烷基取代的氨基, 单或双 d-C4烷 基取代的氨基酰基, (广 4烷氧羰基, d-Cs酰氧基, 单或双 d- C4烷 基取代的氨基磺酰基, 腈基, 硝基, 氨基磺酰基;
R1独立的为
( 1 ) d- 。直链或支链烷基, 所述烷基可部分或全部被卤
代, 并且可被 1-3个苯基, 萘基或以下的杂环取代: 喹啉基, 异喹 啉基, 吡啶基, 嘧啶基, 哒嚓基, 哌嗪基, 吡咯基, 咪唑基, 吡 唑基, 呋喃基, 噻吩基, 异嚙唑基, 异噻唑基; 上述苯基, 萘基 或杂环可被 0-5个下述基团取代: 卤素, CrC6直链或支链烷基, (^- 环烷基, C5- 环烯基, 羟基, 腈基, d-Cs直链或支链烷氧基, 三氟甲基, 三氟甲氧基, 氨基羰基, 双 (广 烷基取代的氨基羰基;
( 2 ) C厂 d。环烷基或环烯基, 所述基团可部分或全部被鹵 代, 或被 1- 3个 d- C6烷基或 d-Ce烷氧基取代; 上述的环烷基或环 烯基的卜 3个亚甲基可被 0, NH, S, SO, S02, 羰基, 羟甲基替代; 上述环烷基或环烯基可独立的被 0-5个以下基团取代: 卤素, d-Cs 直链或支链烷基, d- C6直链或支链烷氧基;
( 3 ) C3- 。直链或支链烯基, 所述烷基可部分或全部被卤 代, 并且可被 1-3个(^- C6直链或支链烷基, 苯基, 萘基或以下的杂 环取代: 喹啉基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪基, 哌嗪基, 吡咯基, 咪唑基, 吡唑基, 呋喃基, 噻吩基, 异喵唑基, 异噻唑 基; 上述苯基, 萘基或杂环可被 0-5个下迷基团取代: 卤素, d-C6 直链或支链烷基, C3- 。环烷基, 05-( 8环烯基, 羟基, 腈基, CrCe 直链或支链烷氧基, 三氟甲基, 三氟甲氧基, 氨基羰基, 双 C广 C4 垸基取代的氨基羰基;
( 4 ) 卤素, 硝基, 羧基, 羟基, 腈基, 三氟甲基, 三氟甲 氧基;
( 5 ) NH2—, R3NH -, R3 2N -, R3NCO-R3CONH-, R3C00 -, R30C0 -, R3S (0) m, R3S (0) M, R3NHS (0) - ;
R2独立的为
( 1 ) 环, 芳杂环基或稠合芳环, 包括苯基,萘基, 喹啉基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪基, 咪唑基, 喁唑基, 异喁唑 基, 噻唑基, 异噻唑基, 吡洛基, 呋喃基, 噻喻基, 吡喃基, 蔡
啶基, 哌嗪基, 吡唑基, 噻唑基, 嘌呤基, 吲哚基, 苯并咪唑基, 苯并呋喃基, 苯并吡唑基, 苯并噻吩基, 苯并喁嗤基, 苯并异喁 唑基, 苯并噻唑基, 苯并异噻唑基, 吡唑并 [3, 4-b]嘧啶基, 吡 咯并 [2 , 3- b]吡啶基, 吡咯并 [3 , 4- b]吡啶基, 1, 3-氧氮杂并 [4 , 5-b]吡啶基, 1 , 2, 3-三氮唑基, 1 , 2 , 4-三氮唑基, 四氮唑基, 四氢吡喃基, 四氢呋喃基, 二氢萘基, 四氢萘基, 二氢喹啉基, 四氢喹啉基, 二氢异喹啉基, 四氢异喹啉基, 苯并环丁基, 茚基, 茚烯基。 上述芳环, 芳杂环或稠合芳环基可独立的被 0-5个 R4基团 取代;
( 2 ) C3- Cle环烷基或环烯基, 所述基团可部分或全部被卤 代, 或被 1-3个(^-(^烷基或 d- C6烷氧基取代;
( 3 ) d- 。直链或支链烷基, 所述烷基可部分或全部被卤 代;
( 4 ) NH2-, R3NH-, R3 2N -, R3NC0— R3C0NH -, R3C00 -, R30C0-, R3S (0) m, R3S (0) mNH, R3NHS (0) - ;
R3独立的为
氢原子, Ci-Cs直链或支链烷基, d-Ce直链或支链烯基, 苯基, 萘基, 单或双 d-C4烷基氨基 d-C6烷基; m为 0, 1或 2;
R4独立的为
a) 卤素, 硝基, 羧基, d-C6直链或支链坑基, Cr 直链或 支链烯基, C3- C1D环烷基, C5- (:8环烯基, 羟基, 腈基, d- c6直链或 支链烷氧基, 三氟甲基, 三氟甲氧基;
b) NH广, R3NH -, R3 2N -, R3NCO-R3CONH-, R3C00- , R30C0 -, R3S (0) ffi, R3S (0) mNH, R3NHS (0) - ;
本发明优选的化合物包括:
1- [ 3 -叔丁基- 1 -(4-甲基苯基) -1H-5 -吡唑基〗 -3- [8- (3, 4 二 氢 -5-甲氧基 -2^ "色烯基) ]脲
1- [3-叔丁基 -1- (4-氯苯基) -1^"5-吡唑基] -3- [8- (5-甲氧基
- 2^色烯基)]脲
1 - [3 -叔丁基 -1 -(4-甲基苯基) - 1H - 5-吡唑基] -3- [8- (5-甲氧 基- 2 色烯基) ]脲
1- [3-叔丁基 -1- (4-甲基苯基) - 1H-5-吡唑基] -3- {5- {8- [2- (4-吗啡啉基)乙酰氨基] -2^色烯基 } }脲
卜 [3-叔丁基 -1-苯基 -1^5-吡唑基 ] -3- [8- (3 , 4-二氢 -5 -甲 氧基 -2^"色烯基) ]脲
1- [ 3-叔丁基 -1- (4-甲基苯基) - 1H - 5 -吡唑基] -3 - {8- {3, 4 -二 氢 -5- [2- (4-吗啡啉基)乙氧基] -2^·色烯基 } }脲
1 - [3-叔丁基- 1- (4-甲基苯基) -1H-5-吡唑基] -3- [8- (5-硝基
- 2 色烯基)]脲
1 - [ 3-叔丁基 -1-苯基 -1^5-吡唑基] -3- {8- {3 , 4-二氢 -5- [2- (4-吗啡啉基)乙氧基] -2^色烯基 Π脲
1 -〖3-叔丁基 -1- (4-氟苯基) -1^-5-吡唑基] -3- {8- {3 , 4-二氢 - 5-〖2- (4-吗啡啉基)乙氧基] -2^"色烯基 } }脲
1- [ 3-叔丁基 -1 (4-氯苯基) -1^-5-吡唑基] -3- {8- {3, 4-二氢 -5 - [2- (4-吗啡啉基)乙氧基] 色烯基 } }脲
1 - [ 3-叔丁基 -1- (4-溴苯基) ~1^5-吡唑基] -3- {8- {3, 4-二氢 -5- [2- (4-吗啡啉基)乙氧基] - 2 色烯基 脲
1 - [ 3-叔丁基 -1 -(4-甲氧基苯基) -l 5-吡唑基] -3- {8- {3, 4- 二氢 -5- [2- (4-吗啡啉基)乙氧基] -2 色烯基 } }脲
1- [3-叔丁基 - 1- (4-氨基磺酰基苯基)- 吡唑 基] -3- {8- {3, 4 -二氢 -5- [2- (4-吗啡啉基)乙氧基〗 色烯基 } } 脲
1- [3-叔丁基-1- (4-硝基苯基) -1^"5-吡唑基] -3- {8- {3, 4 -二 氢- 5- [2- (4-吗啡啉基)乙氧基] -2^色烯基 } }脲
[3-叔丁基 : L- (4-甲基苯基) - 1H-5 -吡唑基] -3- {8- [3, 4 二 氢一 5- (4-吗啡啉基酰基甲氧基) -2 色烯基] }脲
1- (3-叔丁基 -5-异喁唑基) -3- {8- {3, 4-二氢 - 5- [2- (4-吗啡 啉基)乙氧基] - 2^色烯基 } }脲
1- (5-叔丁基 -3-异喁唑基) -3- {8- {3, 4-二氢 -5- [2- (4-吗啡 啉基)乙氧基] - 2 色烯基 } }脲
1- [1-叔丁基 -3- (4-甲基苯基) -1^4 -吡唑基] -3- {8- {3, 4 -二 氢 -5- [2- (4-吗啡啉基)乙氧基] 色烯基 } }脲
1- [4-叔丁基 -卜(4-甲基苯基) -1^2-咪唑基] -3- {8- {3, 4-二 氢- 5- [2- (4-吗啡啉基)乙氧基] - 色烯基 } }脲
1- [3-叔丁基- 1- (4 -甲基苯基) - 1H-5-吡唑基] -3- {8- {3, 4-二 氢 -5- [2- (4-吡啶基)氧基乙氧基] -2^~色烯基 } }脲
1- [3-叔丁基 -1- (4-甲基苯基) - 1H-5-吡唑基] - 3- {8- {3 , 4-二 氲 -5 - {2- [4- (顺式 - 2, 6-二甲基) 吗啡啉基]乙氧基 } - 2 ^色烯 基 "脲
1-〖3-叔丁基 -1- (4-甲基苯基) -1H-5 -吡唑基] -3- {8- {3, 4 -二 氢 -5- [2- (1-咪唑基)乙氧基] - 2 色烯基 } }脲
1- [3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑基] -3- {8- {3, 4 -二 氢- 5- [2- (1-1, 2, 4-三氮唑基)乙氧基] 色烯基 } }脲
1 - [3-叔丁基- 1-(4-氯苯基) -1^"5-吡唑基] -3- {8- {3, 4-二氢 - 5- {2- [4- (顺式 -2, 6-二甲基)吗啡啉基]乙氧基 } - 2^·色烯基 } } 脲
1- [3-叔丁基 -1- (3, 4 -二甲基苯基) -I 5 -吡唑基] -3- {8 - {3, 4 -二氢 -5- [2- (4-吗啡啉基)乙氧基] - 2^·色烯基 } }脲
1- [3-叔丁基 -1- (3, 4-二氯苯基) - l 5-吡唑基] -3- {8- {3 , 4 -二氢 -5- [2- (4-吗啡啉基)乙氧基〗 -2^"色烯基 } }脲
1- [3-叔丁基 - 1- (3-甲基苯基) -1^5 -吡唑基] -3- {8- {3, 4 -二
氢 -5- [2- (4-吗啡啉基)乙氧基] 2 色烯基 } }脲
1- [ (3-叔丁基- 1-萘基) -1^5-吡唑基] -3- {8- {3, 4-二氢 -5- [2- (4-吗啡啉基)乙氧基] -2^·色烯基 } }脲
1- [3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑基] -3- {8- {3, 4-二 氢- 5- [2- (1-吡唑基)乙氧基] - 色烯基 } }脲
1- [3-叔丁基 - 1- (4-甲基苯基) - 1H-5 吡唑基] -3- {8- {3, 4-二 氢 -5- U- (1-哌啶- 4-酮基)乙氧基] -2^~色烯基 } }脲
1- [3-叔丁基 -1- (4-甲基笨基) - 1H- 5-吡唑基] -3- {8- {3, 4-二 氢 -5- [2- (4-吗啡啉基)乙酰氨基] - 2^·色烯基 } }脲
1- [3-叔丁基 -1- (4-三氟甲基苯基) - 1^"5 -吡唑基] -3- {8- {3, 4-二氢- 5- [2- (4-吗啡啉基)乙氧基] - 2^·色烯基 } }脲
1- [3-叔丁基 -1- (4-乙基苯基) -1^"5-吡唑基] - 3- {8- {3 , 4-二 氢- 5- U- (4-吗啡啉基)乙氧基] - 色烯基 脲
1 - [3-叔丁基 -1- (4-叔丁基苯基) -1^-5-吡唑基] -3- {8- {3, 4- 二氢 -5- [2- (4-吗啡啉基)乙氧基] -2^·色烯基 } }脲
1- [ 3 -叔丁基- 1- (4-三氟甲基苯基) - 1^5-吡唑基] -3- {8- {3 , 4 -二氢 -5- [2- (1-咪唑基)乙氧基] 色烯基 } }脲
1- [3- 叔 丁 基 -1 -(4- 甲 基 苯 基 )-1Η-5- 吡 唑 基] -3- {8- {5- [2- (4-吗啡啉基)乙氧基] - 色烯基 } }脲
1- [3-叔丁基 -1- (4-甲基苯基) - 1H- 5 -吡唑基] -3- {8- {3, 4 二 氢- 5- [2- (4-吡啶基)乙氧基] - 色烯基 } }脲
1- [3-叔丁基 -1- (4-腈基苯基) - 1^5-吡唑基] -3- {8- {3, 4 -二 氢 -5- [2- (4-吗啡啉基)乙氧基] -2^·色烯基 H脲
1- [3-叔丁基 -1- (3-氯 -4-氟苯基) - 1^~5-吡唑基] -3- {8- {3 , 4 -二氢 -5- [2- (4-吗啡啉基)乙氧基〗 色烯基 } }脲
[3-叔丁基- 1- (4-甲基苯基) - 1H-5-吡唑基〗 -3- {8- {5- [ (4- 甲氧基苯基)甲氧基] -2 色烯基 } }脲
1- [3-叔丁基 -1- (4-曱基苯基) - 1H-5-吡唑基] -3- {8- [5- (4- 吗啡啉基酰基甲氧基) -2^色烯基] }脲
1 - [3-叔丁基 -1- (4-氟苯基) - 1^5-吡唑基] -3- {8- {5- [2- (4- 吗啡啉基)乙氧基] - 2 色烯基 }}脲
1 - [3-叔丁基 1- (4-氯苯基) - 1^5-吡唑基] -3- {8- {5- [2- (4- 吗啡啉基)乙氧基] - 2 色烯基 }}脲
1- [3-叔丁基 - 1- (4-溴苯基) - l 5-吡唑基] -3- {8- {5- [2- (4- 吗啡啉基)乙氧基] -2^"色烯基 脲
1-( 3-叔丁基 -1-苯基 -1^5-吡唑基) -3-{8-{5-[2-(4-吗啡 啉基)乙氧基〗 -2^"色烯基 }}脲
1-[3- 叔 丁 基 - 1-(4- 甲 氧 基 苯 基 吡 唑 基]- 3- {8- {5- U - (4-吗啡啉基)乙氧基] - 2 色烯基 }}脲
1 - [3-叔 丁 基 - 1- (4-三 氟 曱 基 苯基)-1 5- 吡 唑 基]- 3- {8- {5- [2- (4-吗啡啉基)乙氧基] -2^·色烯基 }}脲
1-[3- 叔 丁 基 - 1-(4- 硝 基 苯 基 )-1^"5- 吡 唑 基] -3- {8- {5- [2 -(4-吗啡啉基)乙氧基] -2^~色烯基 }}脲
1-[3- 叔 丁 基 -1- (4- 腈 基 苯 基 )-1 5- 吡 唑 基] -3-{8-{5- U-(4-吗啡啉基)乙氧基] 色烯基 }}脲
1 - [3- 叔 丁 基 - 1 -(4- 甲 基 苯 基 )-1Η-5- 吡 唑 基]-3-{8-{5-[2-(1一1, 2, 4-三氮唑基)乙氧基 ]-2 色烯基 }}脲
1-[3- 叔 丁 基 - 1-(4- 乙 基 苯 基 吡 唑 基 ]-3-{8- {5-[2- (4-吗啡啉基)乙氧基] - 2 色烯基 }}脲
1 [3- 叔 丁 基 -1-(4- 叔 丁 基 苯 基 )-1 ~5 - 吡 唑 基] -3- {8- {5- [2- (4 -吗啡啉基)乙氧基] -29"色烯基 }}脲
1-〖3- 叔 丁 基 -1-(3- 氯 - 4- 氟 苯 基 )-1 5- 吡 唑 基]- 3- {S-{5- U- (4-吗啡啉基)乙氧基] -2^~色烯基 }}脲
1 - [3-叔丁基 -1-(3 , 4 -二 甲 基苯基)- 1^~5-吡唑
基]-3-{8-{5-[2-(4-吗啡啉基)乙氧基] - 2 色烯基 }}脲
1 - [3- 叔 丁 基 - 1-(3 , 4- 二 氯 苯 基 )-1 ~5- 吡 唑 基]-3-{8-{5-[2-(4-吗啡啉基)乙氧基] -2 色烯基 }}脲
1- (3-叔丁基 -5-异喁唑基) -3- {8- {5- [2- (4-吗啡啉基)乙氧 基〗 -2 色烯基 }}脲
1-(5-叔丁基 -3-异喁唑基) -3- {8- {5- [2- (4-吗啡啉基)乙氧 基] - 2 色烯基 }}脲
1-[1- 叔 丁 基 -3-(4- 甲 基 苯 基 )-1^-4- 吡 唑 基] -3- {8- {5- [2- (4-吗啡啉基)乙氧基] - 2 色烯基 }}脲
1-[3- 叔 丁 基 - 1- (3- 甲 基 苯 基 )-lff~5- 吡 唑 基] -3 - {8- {5- [2- (4-吗啡啉基)乙氧基〗 -2^-色烯基 }}脲
1- [ (3-叔丁基 -1-萘基) - 1^~5-吡唑基] -3- {8- {5- [2- (4-吗啡 啉基)乙氧基] - 2 色烯基 }}脲
1-[4- 叔 丁 基 - 1-(4- 甲 基 苯 基 )- 1^2- 咪 唑 基] -3- {8- {5- [2- (4-吗啡啉基)乙氧基] - 2 色烯基 }}脲
1 - [3- 叔 丁 基 -1-(4- 甲 基 苯 基 )-1Η- 5- 吡 唑 基]- 3- {8- {5- {2- [4- (顺式 -2, 6-二甲基)吗啡啉基]乙氧基 } -2H- 色烯基 脲
以及其可药用盐或溶剂化物。 式 I的化合物的制备:
R. = OPh, CCL
方法 3
R6 = CCI3, C6H4N02, OC2H5, imidiazole, Triazole
上述三种方法的反应次序可以颠倒, 即光气, 氯甲酸酯或碳 酸酯可以先与 P-L-Ar2-NH2反应, 生成的中间体再与 AriNH2反应。
Ar1 ? Ar2, L, P的定义同通式 I。
在方法 1中, 一种杂环胺溶于二氯甲烷, 氯仿或二氯乙垸中, 加入碳酸氢钠或者碳酸钟的水溶液, 水水浴中冷却, 加入光气, 搅拌 5-30分钟,得到的中间体与另一杂环胺在无水的非质子性溶 剂中 (如 THF, 乙醚, 甲苯, 二氧六环, 二氯甲烷, 乙酸乙酯等) 于 0-45°C反应 2-24小时得到式 I的化合物。
在方法 2中, 一种杂环胺溶于二氯曱烷, 氯仿或二氯乙烷中, 加入适当的碱(如三乙胺等) , 然后加入氯甲酸酯, 于 0-85 Ό反 应 2 - 24小时,得到的中间体与另一杂环胺在无水的非廣子性溶剂 中 (如 THF, 乙醚, 甲苯, 二氧六环, 二氯甲烷, 乙酸乙酯等) 于 0- 110°C反应 2-24小时得到式 I的化合物。
在方法 3中, 一种杂环胺溶于二氯甲烷, 氯仿或二氯乙烷中, 加入适当的碱(如三乙胺等) , 然后加入碳酸酯, 于- 20-45Ό反 应 2-24小时,得到的中间体与另一杂环胺在无水的非质子性溶剂 中 (如 THF, 乙醚, 甲苯, 二氧六环, 二氯甲烷, 乙酸乙酯等) 于 0- 110Ό反应 2-240小时得到式 I的化合物。
Ar^I^根据结构的不同, 分别由以下路线合成。 Rl, R2 定义 同通式 I。
( 1 ) 3-氨基吡唑类
1. NaN02
R2-NH2 R2-NHNH2
2.还原
II
ΙΠ和 Π在酸性条件下, 在乙醇中回流 16 48小时, 得到 3-氨基吡 唑 IV。
( 2 ) 3-氨基呋喃类
酰基乙酸乙酯在强碱(钠, 氢化钠, 乙醇钠等) 的作用下与 α -溴代酮反应,得到的二酮酯 V在乙醇等溶剂中和硫酸或盐酸反 应得到 3-呋喃甲酸乙酯 VI, 3-呋喃甲酸乙酯 VI和水合肼以及甲酸 反应得到 3-氨基呋喃类化合物 VII。
( 3 ) 3-氨基噻吩类
( 4 ) 2-氨基吡咯类
、 N
K X
腈基醛和取代的胺在乙酸 /水中于 50-90。C反应 5_30分钟得 到氨基腈 IX, IX在乙醇钠的存在下于室温环合生成 2-氨基吡咯类 化合物 X。
XI
酰基腈, 醛, 无水乙酸铵在乙酸中回流 3-6小时, 得到 4-氨基§ 唑类化合物 XI。
ΧΠ
XIII XIV
酰氯与腈基胺在 0°C,在四氢呋喃等溶剂中反应得到酰胺 Π: ΧΠ溶解在干燥的二氯甲烷中,加入乙硫醇,通入干燥氯化氢气体,
反应 5-30分钟, 得到的产品 xm于 o ,在干燥的吡啶中通入硫 化氢至饱和, 4小时后得到 5-氨基喁唑类化合物 XIV。
(7) 5-氨基噻唑类
氨基腈, 硫磺溶于干燥的甲醇或乙醇, 滴加三乙胺, 加 热到 50°C, 反应 1-3小时, 得到产物 XV, XV经盐酸或对甲苯 磺酸水解得到 5-氨基噻唑 XVI。
νπ
在碱(碳酸氢钟, 碳酸钟等)存在下, α-氯代酮与取代的胺 在 DMF等溶剂中反应得到 α -氨基酮 X Vn, X VII在乙醇等溶剂中和 腈胺回流 12小时得到 2-氨基咪唑 X覆。
( 9 ) 4-氨基吡唑类
χκ
χχ XXI 入入 11 氯代酮与邻苯二曱酰亚胺钾盐在 DMF中于 反应 2小时, 得到化合物 ΧΚ, XIX与 Ν,Ν-二甲基甲酰胺二甲基缩醛在 DMF中 于 100°C反应 12小时, 得到化合物 XX。 XX和取代的肼在 90% 乙醇中回流 I2小时得到化合物 XX I , XX I在乙醇中肼解得到 4 -氨基吡唑 XX Π。
XXIII
腈基酮再碱性条件下于 50-ΙΟΟ 与盐酸羟胺反应, 得到 5- 氨基异喁唑 XX m。
本领域技术人员应该意识到, 本发明化合物也可以以其可药 用盐或溶剂化物的形式使用。 通式 I化合物的生理学上可接受的 盐包括由药学上可接受的无机酸或有机酸或者无机碱或有机碱形 成的常规的盐以及季铵的酸加成盐。 合适的酸盐的更具体的例子 包括盐酸、 氢溴酸、 硫酸、 磷酸、 硝酸、 高氯酸、 富马酸、 乙酸、 丙酸、 琥珀酸、 羟基乙酸、 甲酸、 乳酸、 马来酸、 酒石酸、 柠檬 酸、 朴酸、 丙二酸、 羟基马来酸、 苯乙酸、 谷氨酸、 苯甲酸、 水
杨酸、 富马酸、 甲苯磺酸、 甲磺酸、 萘 -2-磺酸、 苯磺酸、 羟基萘 甲酸、 氢碘酸、 苹果酸、 s teroic、 鞣酸等的盐。 其它的酸, 如草 酸, 虽然其本身并非药学上可接受的, 但可以用于制备用作中间 体的盐, 以获得本发明化合物及其可药用盐。 合适的碱盐的更具 体的例子包括钠、 裡、 钾、 镁、 铝、 钙、 锌、 N,N, -二苄基乙二 胺、 氯代普鲁卡因、 胆碱、 二乙醇胺、 乙二胺、 N-甲基葡糖胺和 普鲁卡因盐。 此后涉及到本发明的化合物时, 包括通式 I化合物 及其可药用盐和溶剂化物。
本发明还包括本发明化合物的前药,该前药一经给药, 即通 过代谢过程进行化学转化, 之后变成具有活性的药物。 通常, 这 类前药是本发明化合物的功能性衍生物, 其在体内容易转化成所 需的式(I)的化合物。 例如, 在 "Design Of Prodrugs" , H Bund Saard, Elsevier编辑, 1985中描述了选择和制备适宜前药衍生 物的常规方法。
本发明也包括本发明化合物的活性代谢物。
本发明的另一个方面涉及药物组合物, 其含有本发明化合物 和至少一种药学上可接受的载体, 其可用于体内治疗并具有生物 相容性。 所述药物组合物可以根据不同给药途径而制备成各种形 式。本发明所提及的化合物也可以被制备成各种药学可接受的盐。
本发明的化合物对 PPAR 的激动作用可以用下述方法进行测 定。 将 THP- 1细胞悬浮于含有 15%胎牛血清, 0. 02 nM 2-巯基乙 醇的 RMPI培养基中, 细胞浓度为 1-2 106个细胞 /mL, 然后在 96 孔平板上铺板(每孔含 0. 2 mL ) 。 实验化合物在 DMS0中溶解, 然后用培养基稀释, 使 DMS0的终浓度为 5%。 向每孔加入 25 实验化合物溶液或仅有 DMS0的培养基(对照) 。 ' 将细胞与实验化合物的系列稀释液一起于 37 Ό保温 30分钟, 然后加入 IFN- γ (
) ,并继续保温 18-24
N2008/000760 小时, 于 1600RPM离心 10分钟终止保温。用市售的 ELISA试剂盒 分析上清液中的 TNF- α含量。将本发明的化合物以 0. 1-3 μ Μ的 浓度进行实验。代表性的本发明的化合物可以在实验中抑制 TNF - α释放。
表 1部分本发明化合物对 TNF- α的抑制作用 ( 3 μ Μ )
本发明化合物的药物組合物可以以下面的任意方式施用: 口 服, 喷雾吸入, 直肠用药, 鼻腔用药, 颊部用药, 局部用药, 非 肠道用药, 如皮下、 静脉、 肌内、 腹膜内、 鞘内、 心室内、 胸骨 内和颅内注射或输入,或借助一种外植储器用药。其中优选口服、 腹膜内或静脉内给药方式。
当口服用药时,本发明化合物可制成任意口服可接受的制剂 形式,包括但不限于片剂、 胶袭、 水溶液或水悬浮液。 其中, 片剂 使用的载体一般包括乳糖和玉米淀粉, 另外也可加入润滑剂如硬 脂酸镁。 胶袁制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。 水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合
使用。 如果需要, 以上口服制剂形式中还可加入一些甜味剂、 芳 香剂或着色剂。
当局部用药时, 特别是治疗局部外敷容易达到的患面或器官, 如眼睛、 皮肤或下肠道神经性疾病时, 可才艮据不同的患面或器官 将本发明化合物制成不同的局部用药制剂形式, 具体说明如下: 当眼部局部施用时, 本发明化合物可配制成一种微粉化悬浮 液或溶液的制剂形式, 所使用载体为等渗的一定 pH的无菌盐水, 其中可加入也可不加防腐剂如氯化苄基烷醇盐。 对于眼用, 也可 将化合物制成骨剂形式如凡士林骨。
当皮肤局部施用时, 本发明化合物可制成适当的软骨、 洗剂 或霜剂制剂形式, 其中将活性成分悬浮或溶解于一种或多种载体 中。 软骨制剂可使用的载体包括但不限于: 矿物油, 液体凡士林, 白凡士林, 丙二醇, 聚氧化乙烯, 聚氧化丙烯, 乳化蜡和水; 洗 剂或霜剂可使用的载体包括但不限于: 矿物油, 脱水山梨糖醇单 硬脂酸酯, 吐温 60, 十六烷酯蜡, 十六碳烯芳醇, 2-辛基十二垸 醇, 苄醇和水。
本发明化合物还可以无菌注射制剂形式用药, 包括无菌注射 水或油悬浮液或无菌注射溶液。 其中, 可使用的载体和溶剂包括 水、 林格氏溶液和等渗氯化钠溶液。 另外, 灭菌的非挥发油也可 用作溶剂或悬浮介质, 如单甘油酯或二甘油酯。
另外需要指出, 本发明化合物的使用剂量和使用方法取决于 诸多因素, 包括患者的年龄、 体重、 性别、 自然健康状况、 营养 状况、 化合物的活性强度、 服用时间、 代谢速率、 病症的严重程 度以及诊治医师的主观判断。 优选的使用剂量介于 0. 01 ~ 100mg/kg体重 /天, 其中最优剂量在 5mg/kg 10mg/kg体重 /天。 具体实施方式
本发明用下述的中间体和实施例进一步说明, 这些中间体和 实施例不构成对本发明的限制。
化合物熔点由 YRT-3型熔点仪测定, 温度未经校正。 NMR 光谱由 Bruker ARX 400型核磁仪测定。 FAB质谱由 Zabspect 高分辨磁质谱仪测定。 中间体的制备
由芳香胺制备 2 , 5-二取代的 3-氨基吡唑的一般操作 A
1. NaN02 / HCI
R2— NH 2 R2— NHNH,
2. SnCI2 I HCI
1. 芳香胺( 0. 04 fflol )加入 40mL浓盐酸中, 搅拌, 冷却到 - 5 °C, 析出白色细小颗粒状晶体。慢慢滴加亚硝酸钠溶液(2. 90g 亚硝酸钠溶于 20mL水) , 控制温度不超过 0°C , 加完后反应 1小 时。
2. 18. Og氯化亚锡溶于 50mL浓盐酸, 冷却到 -5 °C , 滴加步 骤 1制备的重氮盐溶液, 析出白色晶体, 反应 1小时, 过滤, 滤 饼干燥即得产品芳香肼盐酸盐。
3. 30mL无水 THF在 加入氢化钠( 0. 6g, 60%, 0. 015mol ), 搅拌下加入取代的羧酸氯甲酯 ( 0. Olmol )和无水乙腈( 0. 82g, 0. 02mol ) , 加完后先室温反应 1小时, 然后加热回流 24小时。 冷却, 倒入 l OOmL冰水中, 用稀盐酸调到 pH 4 , 乙酸乙酯提取,
干燥, 浓缩, 得到粗品。 不纯化, 直接用于下一步的反应。
4. 步骤 3得到的酰基乙腈(1. 25g, 0. Olmol )和步骤 2得 到的芳香肼盐酸盐加入到 50mL乙醇中, 滴加 2. OmL浓盐酸,加热 回流 12- 24小时。 冷却, 倒入 lOOmL水水中, 用稀氢氧化钠调到 PH 12 , 乙酸乙酯提取, 干燥, 将得到的粗产物经硅胶柱层析, 得 到白色固体产品。
标题化合物以对特丁基氯甲酯为原料如一般操作 A,
所述制备, 得浅黄色油状物。
标题化合物以 3 , 4-二甲基苯胺为原料如一般操作 A,步驟 1, 2所述制备, 得白色固体。
中间体 3
标题化合物以 3, 4-二氯苯胺为原料如一般操作 A, 步骤 1 , 2所述制备, 得白色固体。
标题化合物以 1-萘胺为原料如一般操作 A, 步骤 1, 2所述制 备, 得白色固体。
中间体 6
标题化合物以 3-氯 4-氟苯胺为原料如一般操作 A, 步骤 1 , 2 所述制备, 得白色固体。
中间体 7
标题化合物以 4 -乙基苯胺为原料如一般操作 A, 步驟 1, 2 所迷制备, 得白色固体。
中间体 8
标题化合物以 4-异丙基苯胺为原料如一般操作 A, 步驟 1, 2 所述制备, 得白色固体。
中间体 9
标题化合物以 4-三氟甲基苯胺为原料如一般操作 A, 步骤 1, 2所述制备, 得白色固体。
中间体 10
标题化合物以 4-腈基苯胺为原料如一般操作 A, 步驟 1, 2 所迷制备, 得白色固体。
中间体 11
标题化合物以中间体 1和对甲基苯肼为原料如一般操作 A, 步骤 4所述制备, 得白色固体。
-醒 ( CDC13, 400 MHz ) 5 : 7. 40 (d, 2H, /=8. 4 Hz) , 7. 25 (d, 2H, /=3, 08 Hz) , 5. 50 (s, 1H), 3. 72 (s, 2H), 2. 37 (s, 3H) , 1. 32 (s, 9H)。
标题化合物以中间体 1和苯肼为原料如一般操作 A, 步骤 4 所述制备, 得白色固体。
中间体 13
标题化合物以中间体 1和对甲氧基苯肼为原料如一般操作 A, 步骤 4所述制备, 得白色固体。
中间体 14
标题化合物以中间体 1和
骤 4所述制备, 得白色固体。
标题化合物以中间体 1和对氯苯肼为原料如一般操作 A, 步 骤 4所迷制备, 得白色固体。
中间体 16
标题化合物以中间体 1和对溴苯肼为原料如
骤 4所述制备, 得白色固体。
中间体 17
标题化合物以中间体 1和对硝基苯肼为原料如一般操作 A, 步骤 4所述制备, 得黄色固体。
中间体 18
标题化合物以中间体 1和对氨基磺酰基苯肼为原料如一般操 作 A, 步骤 4所述制备, 得白色固体。
中间体 19
标题化合物以中间体 1和中间体 2为原料如一般操作 A, 步 骤 4所述制备, 得白色固体。
^-NMR (CDC13, 400MHz ) δ: 7.18-7.30 (m, 3H) , 5.49(s, 1H), 3.70(s, 2H), 2.28 (s, 3H) , 2.27(s, 3H) , 1.32 (s, 9H) 0 中间体 20
标题化合物以中间体 1和中间体 3为原料如一般操作 A, 步 骤 4所述制备, 得白色固体。
'H-NMR (CDCI3, 400MHz ) δ: 7.76 (t, 1H), 7.49 (m, 2H),
5.53 (s, 1H), 3.72 (s, 2H) , 1.30 (s
中间体 21
标题化合物以中间体 1和中间体 4为原料如一般操作 A, 步 骤 4所述制备, 得白色固体。
^-NMR (CDC13, 400MHz ) δ: 7.38 (s, 1H), 7.31-7.33 (m, 2H), 7.13(m, 1H) , 5.51 (s, 1H), 3.73(s, 2H) , 2.39 (s, 3H), 1.31 (s, 9H)。
中间体 22
标题化合物以中间体 1和中间体 5为原料如一般操作 A, 步 骤 4所述制备, 得白色固体。
'H-NMRCCDCls, 400MHz ) δ: 7.89-7.91 (m, 2H), 7.51-7.55 (m, 5H), 5.59 (s, 1H), 3.50(s, 2H) , 1.34 (s, 9H)。
中间体 23
中间体 24
标题化合物以中间体 1和中间体 7为原料如一般操作 A, 步 驟 4所述制备, 得白色固体。
中间体 25
标题化合物以中间体 1和中间体 8为原料如一般操作 A, 步 驟 4所迷制备, 得白色固体。
^-NM C CDC13, 400MHz ) δ: 7.44 (d, 2H, /=8.4 Hz), 7.29 (d, 2H, 7=8.4 Hz), 5.51(s, 1H), 3.72 (s, 2H), 2.93 (m, 1H), 1.31 (s 9H), 1.25 (d, 3H), 1.24 (d, 3H)。
标题化合物以中间体 1和中间体 9为原料如一般操作 A, 步 骤 4所述制备, 得白色固体。
-爾 R( CDC13, 400MHz ) δ: 7.77 (d, 2H, /=8.4 Hz), 7.69 (d, 2H, /=8.4 Hz) , 5.56 (s, 1H), 3.76 (s, 2H), 1.31 (s, 9H)。
中间体 27
标题化合物以中间体 1和中间体 10为原料如
骤 4所述制备, 得白色固体。
中间体 28
在 50mL 圆底瓶中加入特戊酰基乙腈 (中间体 1 ) l.25g ( 0. Olmol ), 氢氧化钠 ( 0.84g, 0.021mol )以及水 10mL, 搅拌, 加热到 50Ό, 分批加入盐酸羟胺( 0.76g, 0. Ollmol) 。 加完后 升温到 100"Ό, 反应 4小时, 冷却, 乙酸乙酯提取, 干燥, 柱分 离, 得白色片状固体 1.23g, 收率 88.0%。
XH-NMR (CDCls, 400MHz ) δ: 5.03 (s, 1H) , 4.32 (s, 2H) 1.27(s, 9H)。 由 α -氯代酮制备 1, 3-二取代 -4-氨基吡唑类的一般操作 B
1. a-氯代酮( 0. Olmol )溶于 lOmLDMF, 加入邻苯二甲酰 亚胺鉀盐( 0. Olmol ), 70Ό反应 2小时, 冷却, 倒到 lOOmL水水 中, 析出白色固体, 过滤, 干燥得到产品。
2. 步驟 1得到的产品( 0. Olmol )溶于 20mL DMF, 滴加 N, N -二甲基甲酰胺二甲基缩醛(1.44g, 0.012mol), 100 反应 12 小时, 补加 N, N -二甲基甲酰胺二甲基缩醛(1.44g, 0.012mol) , 继续反应 24小时, 冷却, 倒到 lOOmL冰水中, 乙酸乙酯提取, 干 燥, 柱分离, 得到白色固体产品。
3. 步骤 2得到的产品(0. Olmol)溶于 lOOmL 90%乙醇, 加 入取代的肼 (0. Ollmol) , 加热回流 12小时, 冷却, 析出固体, 过滤, 滤饼用无水乙醚洗涤, 干燥得到白色固体产品。
4. 步驟 3得到的产品 ( 0. Olmol )溶于 lOOmL 乙醇, 滴加 85%的水合肼溶液(0.04mol) , 加热回流 2小时, 析出白色固体, 冷却, 浓缩, 加入 20mL乙醚, 过滤, 滤饼用无水乙醚洗涤, 合并 滤液, 浓缩, 柱分离, 得到白色粉末状产品。
中间体 29
无水三氯化铝 ( 5. 60g, 0. 04mol ) 悬浮于 40mL无水甲苯中, 搅拌, 室温下慢慢滴加氯乙酰氯(4. 52g, 0. 04mol ) , 三氯化铝 逐渐溶解, 慢慢升温到 80°C反应 2小时, 冷却, 倒入 100g碎冰 和 lOfflL浓盐酸形成的溶液中, 分液, 水层用甲苯提取三次, 合并 甲苯层, 依次用 10%氢氧化钠, 水, 饱和食盐水洗涤, 干燥, 柱 分离, 得到产品, 收率 86. 3%。
标题化合物以中间体 29 和邻苯二甲酰亚胺钾盐为原料如一
.作 B, 步骤 1所述制备, 得白色固体, 收率 87. 8%。
'H-NMR ( CDC13, 400MHz ) δ : 7. 88-7. 91 (m, 4H) , 7. 76 (m,
7. 30-7. 32 (m, 2H) , 5. 51 (s, 2H), 2. 44 (s, 3H)。
标题化合物以中间体 30为原料如一般操作 B, 步驟 2所述制 备, 得白色固体, 收率 61. 5%。
标题化合物以中间体 31为原料如一般操作 B, 步驟 3所述制 备, 得白色固体, 收率 72.3%。
中间体 33
标题化合物以中间体 32为原料如一般操作 B, 步骤 4所述制 备, 得白色固体, 收率 82.6%。
H-NMR ( CDC13, 400MHz ) δ: 7.21-7.26 (m, 5H), 2.68 (s, 2H), 2.41(s, 3H), 1.41 (s, 9H)。
由 α -氯代酮制备 1, 4-二取代 -2-氨基咪唑类的一般操作 C
1. a-氯代酮( 0.012mol )与芳胺 ( 0. Olmol )溶于 20mLDMF, 加入碳酸氢钠 (1.26g, 0.015mol) , 75Ό反应 48小时, 冷却, 倒入 lOOmL水水中,析出固体,过滤,干燥得到产品。收率 99.2%。
2. 步驟 1得到的产品(0, Olmol),氰胺(4.23g, 0. lOmol ) 在 100mL乙醇中回流 12小时。 浓缩, 残余物加入水, 用乙酸乙酯 提取三次, 合并有机层, 依次用稀氢氧化钠溶液, 水, 饱和食盐
水洗涤, 干燥, 柱分雋得到白色固体产品。
中间体 34
标题化合物以对甲基苯胺和特戊酰基曱基氯为原料如一般操 作 C, 步骤 1所述制备, 得白色固体, 收率 99. 2%。
中间体 35
标题化合物以中间体 35为原料如一般操作 C, 步驟 1所述制 备, 得白色固体, 收率 56. 7%。
^- MR ( CDC13, 400MHz ) δ : 7. 26 (m, 4H) , 6. 35 (s, 1H), 4. 18 (s, 2H), 2. 39 (s, 3H), 1. 27 (s, 9H)。
P - L-Ar2NH2根据结构的不同, 可以由以下路线合成。
1. 8-氨基- 5-甲氧基 色烯的合成。
( 1 ) 3 -甲氧基苯酚( 4· 96g, 0.04mol )溶于 50mL丙酸, 冷 却至- 10°C, 滴加 0.5 mL 丙酸酐, 分 4比加入亚硝酸钠 (2.90g, 0.042mol ) , 析出棕色固体, 反应 1小时, 倒入 250mL水水中, 过滤, 水洗, 干燥得到 4.03g中间体 36, 为棕黄色固体。
( 2 ) 中间体 36 ( 1.53g, 0. Olmol )溶于 16mL丙酸, 冷却至 -12°C, 滴加发烟硝酸(1.26g, 0.02mol ) , 搅拌 2 小时, 倒入 50mL冰水中,析出固体,过滤,水洗,干燥得到 1.38g中间体 37, 为棕黄色固体, 收率 77.4%。
( 3) 中间体 37 (1.69g, 0. Olmol)溶于 15mLDMF,加入 3 -溴丙 炔(1.43g, 0.012mol ) , 70Ό反应 6小时, 冷却, 倒入冰水中, 析出土黄色固体, 过滤, 洗涤, 干躁, 得到 1.87 g 中间体 38, 为棕黄色固体, 收率 90.3°/。。
(4) 中间体 38 ( 8.46g, 0.041mol )溶于 88mL N,N-二乙基 苯胺, 加热到 180-210Ό反应 1-6小时, 冷却, 倒入 500mL冷稀 盐酸中, 过滤, 滤液用乙酸乙酯提取三次, 合并乙酸乙酯层, 饱 和食盐水洗, 干燥, 柱分离得到 1.84g中间体 39, 为黄色固体, 收率 21.8°/。。
(5)中间体 39 ( 1.24g, 6mmol )溶于 5 OmL乙酸乙酯和 5 OmL 乙醇, 分批加入二水合氯化亚锡(5.41g, 24mmol ) , 反应液变混 浊, 加热回流 8小时, 冷却, 加入饱和碳酸氢钠溶液, 直至出现 明显分层, 分液, 水层用乙酸乙酯提取 2次, 合并有机层, 用饱 和食盐水洗涤, 无水硫酸钠干燥, 过滤, 浓缩, 柱分离得到 0.64g 中间体 40, 收率 59.9%o
( 6 ) 中间体 39 ( 1.04g, 0.005mol )溶于 50mL无水乙醇, 假如 0.2g钯 /炭, 升温到 70V, 滴加 1. OmL水合肼 ( 85%) , 升 温回流 4小时, 冷却, 过滤, 滤液干燥, 浓缩得到 0.62g中间体 41, 收率 72.5%。
2. 8-氨基 -3, 4-二氢 -5-取代烷氧基- 2 色烯。 P 的定义同 通式 I。
48 49 XXIV XXV
( 1 ) 间苯二酚( 44. Og, 0.40mol )溶于 150mLDMF,加入无水 碳酸钾( 66.24g, 0.48mol ) , 水水浴冷却下滴加溴苄 ( 47.88g, 0.28mol ) , 加毕反应 5小时, 倒入冷稀盐酸中, 使显酸性, 乙酸 乙酯提取三次, 合并乙酸乙酯层, 饱和食盐水洗, 干燥, 柱分离 得到 26.25g 中间体 42, 为无色油状物, 放置后变为白色固体, 收率 46.9%。
(2) 中间体 43以中间体 42为原料, 按照合成中间体 37的
方法制备, 为棕色固体, 收率 74.1%。
( 3 ) 中间体 44以中间体 43为原料, 按照合成中间体 38的 方法制备, 为棕色固体, 收率 89.0%。
(4) 中间体 45以中间体 44为原料, 按照合成中间体 39的 方法制备, 为棕色固体, 收率 95.0%。
(5) 中间体 46以中间体 45为原料, 按照合成中间体 40的 方法制备, 为黄色固体, 收率 20- 25%。
(6) 5. Og中间体 46溶于 lOOmL无水乙醇, 滴加 2滴盐酸, 加入 2.0g钯 /炭, 加热至 60°C, 滴加 10. OmL水合肼(85%) , 升 温回流 6小时', 冷却, 过滤, 滤液干燥, 浓缩, 残余物溶于 lOOmL 二氯甲烷, 加入 3. OmL三乙胺, 水水浴冷却, 滴加 4.0 g(Boc)20, 然后室温反应过夜, 倒入水中, 二氯甲烷提取, 干燥, 柱分离得 到 1.69g中间体 48, 为白色粉末状固体。
(7)中间体 48( 2.20g, 8.3mmol )溶于 50mL乙腈,加入 1.37 g无水碳酸钾, 滴加 1, 2-二溴丙烷( 6.23g, 33mmol ) , 加热回 流 72小时, 浓缩, 残余物加入 30mL水, 乙酸乙酯提取三次, 合 并乙酸乙酯层, 饱和食盐水洗, 干燥, 柱分离得到 0.83g中间体 49, 并且回收原料 1.61g。
(8)合成中间体 XX V的一般操作 C。
a.中间体 49 ( 1.86g, 5mmol ) 溶于 2 OmL DMF,加入 0.83g无 水碳酸钾, 加入1^(611111101),80°(反应 1-6小时, 冷却, 倒入冷水 中, 乙酸乙酯提取, 干燥, 柱分离得到化合物 XX IV。
b. 化合物 XXIV (2mmol) 溶于 20mL二氯甲烷,冷却至 - 5Ό, 滴加 2. OmL三氟乙酸, 反应 2小时, 浓缩, 残余物加入 3 OmL水, 用 1N氢氧化钠调到 PH 10, 乙酸乙酯提取, 干燥, 浓缩, 得到 X XV的粗品, 不纯化, 直接用于下一步的反应。
标题化合物以中间体 49和吗啡啉为原料如一般操作 C所迷制
标题化合物以中间体 49和 4-哌啶酮为原料如一般操作 C所 述制备 o
中间体 52
标题化合物以中间体 49和咪唑为原料如一般操作 C所述制 中间体 53
中间体 54
标题化合物以中间体 49和顺式 -2, 6-二甲基吗啡啉为原料如 一般操作 C所述制备。
中间体 56
标题化合物以中间体 49和 4-羟基吡啶为原料如一般操作 C 所述制备。
48 57 58 中间体 48 ( 1, 59g, 6mmol )溶于 50 mL无水四氢呋喃, 加入 4- ( 2-羟基乙基) 吡啶(616 mg, 5 mmol ) , 三苯基磷( 1. 57g, 5 mmol )和 DEAD ( 1. 05g, 5 mmol ),加热回流 3小时, 反应完成。 柱分离得到 1. 76g中间体 57 , 收率 95. 0%。
中间体 58
标题化合物以中间体 57为原料如一般操作 C 步驟 b所述制 备。
标题化合物以中间体 48和 4- ( 2-氯乙酰基) 吡啶为原料如 一般操作 C所述制备。
3. 8 -氨基 -5-取代烷氧基- 2^色烯。 P的定义同通式 I。
63 64 XXVI XXW
(1) 中间体 45 ( 70.83g, 0.25mol )溶于 300mL乙酸乙酯, 加入 300mL氢溴酸, 加热回流 8小时, 减压蒸馏, 残余物柱分离 得到 31. l 中间体 60, 为红棕色固体, 收率 64.4%。
( 2 ) 中间体 60 ( 38.26g, 0.198mol )溶于 200mL DMF,加入 无水碳酸钾 ( 32.84g, 0.24mol ) , 加入对甲氧基氯苄(6腿 ol), 室温反 8小时, 倒入冷水中, 析出棕黄色固体, 过滤, 干蜾, 得 到 58.96 中间体 61, 收率 95.0%。
(3) 以中间体 61为原料, 采用中间体 46的制备方法, 得 到黄色的中间体 62, 收率 20-45%。
( 4 ) 中间体 61 ( 18.2g, 0.058mol )溶于 150mL二氯甲烷, 冷却到 - 10Ό, 滴加 10. OmL三氟乙酸, 反应 8小时, 浓缩, 残余 物加入 50mL水, 用 IN氢氧化钠调到 pH 10, 乙酸乙酯提取, 干 燥, 浓缩, 柱分离得到 7.5g中间体 63, 为黄色固体。
(5) 中间体 63 ( 5.97g, 31mmol) 溶于 150mL 乙腈, 加入 5.13 g无水碳酸钟, 滴加 1, 2-二溴丙烷( 23.23g, 124mmol ) ,
加热回流 2.5小时, 浓缩, 残余物加入 50mL水, 乙酸乙酯提取三 次, 合并乙酸乙酯层, 饱和食盐水洗, 干燥, 柱分离得到 4.69g 中间体 64, 为黄色固体, 收率 34.4%。
(6)合成中间体 XX VII的一般操作 D。
a.中间体 64 ( 1.50g, 5讓 ol )溶于 20mL DMF,加入 0, 83g无 7j碳酸钟, 加入 ΗΡ(6πιοιο1),80Χ反应 2-6小时, 冷却, 倒入冷水 中, 乙酸乙酯提取, 干燥, 柱分离得到化合物 XXVI。
b. 化合物 ¥1(5!1111101)溶于 501^乙酸乙酯和 50mL乙醇, 分批加入二水合氯化亚锡(4.50g, 20mmol ), 反应液变混浊, 加 热回流 8小时, 冷却, 加入饱和碳酸氢钠溶液, 直至出现明显分 层, 分液, 水层用乙酸乙酯提取 2次, 合并有机层, 用饱和食盐 水洗涤, 无水硫酸钠干燥, 过滤, 浓缩得到化合物 XXVII, 收率 85-95%。 不纯化, 直接用于下一步的反应。
中间体 65
标题化合物以中间体 64和吗啡啉为原料如一般操作 D所述制 备。
中间体 66
标题化合物以中间体 64和顺式 -2, 6-二甲基吗啡啉为原料如
一般操作 D所述制备。
标题化合物以中间体 64和 4-羟基吡啶为原料如一般操作 D 所述制备。
中间体 68
标题化合物以中间体 63和 4 ( 2-氯乙酰基)吡啶为原料如 一般操作 D所述制备。
中间体 69
标题化合物以中间体 64和 1, 2, 4-三氮唑为原料如一般操作 D 所述制备。
中间体 70
标题化合物以中间体 64和 4-哌啶酮为原料如一般操作 D所 述制备。
4. 8-氨基 -5-取代氨基 色烯。
74 75 76
( 1 ) 2 -氨基 -5 -硝基苯酚( 46.2g, 0.30mol )溶于 300mL二氯甲 烷, 冷却至 - 5°C, 加入三乙胺(36.3g, 0.33mol) , 搅拌下滴加 (Boc)20 (72.0g,0.33mol),然后加热回流 6小时。冷却,倒入 500mL 水中, 分液, 水层用二氯甲烷提取 2次, 合并有机层, 饱和食盐 水洗涤, 无水疏酸钠干燥, 浓缩得到中间体 71, 为黄色粘稠的固 体。
(2) 上步得到的中间体 71 溶于 200fflL DMF,加入无水碳酸钾 ( 41.4g, 0.30mol )和 3-溴丙炔 ( 35.7g, 0.30mol ), 加热至 70
°C反应 8小时, 冷却, 倒入水中, 析出黄色固体, 乙酸乙酯 /石油 醚重结晶得到 30.5g中间体 72。
(3) 中间体 72 (15.32g)溶于 lOOmL N,N-二乙基苯胺, 加热到 180°C反应 4 小时, 减压蒸馏, 除去溶剂, 残余物经柱分离得到 7.94 中间体 73, 为黄色固体, 收率 78.8%。
(4) 中间体 73 ( 1.92g, lOmmol )溶于 30mL二氯甲烷, 冷却至 - ,加入三乙胺( 1.21g, llramol ),搅拌下滴加氯乙酰氯( 1.24g, llmmol) , 回流 24小时, 冷却, 倒入水中, 二氯甲烷提取, 干燥, 柱分离得到 1.53g中间体 74, 为黄色固体, 收率 57.3%。
( 5 )中间体 74 ( 1.34g, 5mmol )溶于 lOmL DMF,加入无水碳酸钟 ( 0.83g, 6mmol )和吗啡啉( 0.52g, 6mmol ) , 80°C反应 4小时, 倒入水中, 乙酸乙酯提取, 干燥, 柱分离得到 1.48g中间体 75, 为黄色固体, 收率 92.7°/。。
(6) 中间体 75 ( 640mg, 2mmol )溶于 30mL乙酸乙酯和 30mL乙 醇, 分批加入二水合氯化亚锡(1.80g, 8mmol ), 反应液变混浊, 加热回流 8小时, 冷却, 加入饱和碳酸氢钠溶液, 直至出现明显 分层, 分液, 水层用乙酸乙酯提取 2次, 合并有机层, 用饱和食 盐水洗涤, 无水硫酸钠干燥, 过滤, 浓缩得到 545mg中间体 76, 收率 94.3%。 不纯化, 直接用于下一步的反应。
5. 5-氨基 -8-取代氨基 色烯。
80 81
(1) 中间体 73 ( 1.92g, lOmmol)溶于 30mL二氯甲烷, 冷却至 0 Ό, 加入三乙胺(1.21g, llmfflol) , 搅拌下滴加(Boc) 20 ( 2.38g, llmmol) , 回流 48小时, 冷却, 倒入水中, 二氯甲烷提取, 干燥, 柱分离得到 1.34g中间体 77, 为黄色固体, 收率 45.9%。
( 2 ) 中间体 77 ( 1. 5g, 5. 14mmol )溶于 50mL 乙醇, 加入 0. 3g 钯 /炭, 加热至 60Ό, 滴加 2. OmL水合肼( 85% ) , 升温回流 1小 时, 冷却, 过滤, 滤液干燥, 浓缩, 得到 1. 39g中间体 78。
( 3 )将中间体 78溶于 30mL二氯甲烷, 加入 1. 2mL三乙胺, 水水 浴冷却, 滴加氯乙酰氯( 0. 68g , 6mmol ),反应 2小时,倒入水中, 二氯甲烷提取, 干燥, 柱分离得到 378mg中间体 79, 为白色粉末 状固体。
( 4 ) 中间体 79 ( 534mg , 1. 57mmol )溶于 10mL DMF,加入无水碳 酸钾( 324mg, 2. 35醒 ol ) 和吗啡啉( 204mg, 2. 35mmol ) , 80 反应 4小时, 倒入水中, 乙酸乙酯提取, 干燥, 柱分离得到 313mg 中间体 80, 为白色颗粒状固体, 收率 50. 9%。
( 5 ) 中间体 80 (313mg, 0. 8mmol) 溶于 30mL二氯甲烷, 冷却至 0 °C, 滴加 1. 5mL三氟乙酸, 反应 4小时, 浓缩, 残余物加入 3 OmL 水, 用 1N氢氧化钠调到 pH 10, 乙酸乙酯提取, 干燥, 浓缩, 得 到 176mg中间体 81的粗品, 不纯化, 直接用于下一步的反应。 实施例
实施例 1 : 1- [3-叔丁基 -1- (4-甲基苯基)- 1H-5-吡唑 基] - 3- [8- (3, 4-二氢 -5-甲氧基 -2 色烯基)]脲
在 50mL三口瓶中加入 20mL干燥的二氯甲烷, 冷却到 -10Ό, 加入三光气(109mg, 0. 36mmol ) , 滴加 0. 4mL干燥的三乙胺, 慢 慢滴加中间体 41 ( 180mg, l. Ommol )溶于 10mL干燥二氯曱烷的 溶液, 反应 1小时。 加入中间体 11 ( 138mg , 0. 6mmol ) , 升温至 室温, 然后加热回流 48小时。 冷却, 倒入 50mL水中, 用二氯甲 烷提取 3次, 有机层用饱和食盐水洗涤, 无水硫酸钠干燥, 柱分 离 (洗脱体系: 石油醚 /乙酸乙酯)得到 1- [3-叔丁基 -1- (4-甲基 苯基) - 1H-5-吡唑基] - 3- [8- (3, 4-二氢 -5-甲氧基 -2 色烯基) ]
脲 94mg, 为白色晶体, 收率 21.8%。
'H-NMR ( DMS0, 00ΜΗζ) δ: 8.84 (s, 1H), 8.30(s, 1H),
7.77(d, IH, 7=8.96 Hz), 7.33~7.37 (m, 4H), 6.41 (d, 1H,
/=9.00 Hz), 6.33(s, IH), 4.14 (t, 2H, /=4.76 Hz), 3.71(s,
3H), 2.50 (t, 2H), 2.37 (s, 3H) , 1.88 (p, 2H) , 1.25 (s, 9H)。
MS (FAB) in/z: 435.1 [M+l〗+。 实施例 2: 1-[3 叔丁基-卜(4-氯苯基)-1^~5-吡唑基]-3-[8-(5- 甲氧基 2 色烯基)]脲
采用实施例 1 的制备方法, 将其中的中间体 11 改为中间体 15, 中间体 41改为中间体 40, 得到标题化合物, 为白色固体。
'H-NMR (DMS0, 400ΜΗζ) δ: 8.91 (s, 1H), 8.31 (s, IH) , 7.82 (d, IH), 7.52 - 7.60 (m, 4H), 6.65 (d, IH, 7=10.08 Hz), 6.50(d, IH, /=9.28 Hz), 6.36 (s, IH), 5.87 (m, IH), 4.76(t, 2H, /=1.68 Hz), 3.74 (s, 3H) , 1.26(s, 9H)。
MS (FAB) m/z: 453.0 [M+l]+ 0
'实施例 3 : l-[3-叔丁基 -1- (4-甲基苯基) -IH- 5-吡唑 基] - 3- [8- (5 -甲氧基- 2 色烯基) ]脲
采用实施例 1 的制备方法, 将其中的中间体 41 改为中间体 40, 得到标题化合物, 为白色固体。
'H-N RCDMSO, 400ΜΗζ) δ 8.83 (s, 1H), 8.35(s, IH), 7.81 (d, IH, 7=9.24 Hz) , 7.33— 7.37 (m, 4H), 6.65(d, IH, /=8.12 Hz), 6.50 (d, 1H, J=9.24 Hz), 6.33 (s, 1H), 5.85 (m, IH), 4.75 (t, 2H, 7=1.68 Hz), 3.74 (s, 3H), 2.37 (s, 3H) , 1.26(s, 9H)。 MS (FAB) m/z: 433.1 [M+l]+ 0
实施例 4 : 1-[3-叔丁基 - 1- (4-甲基苯基) -1H-5-吡唑 基] -3-{5-{8-[2- (4-吗啡啉基)乙酰胺基] 色烯基 脲
采用实施例 1 的制备方法, 将其中的中间体 41 改为中间体 76, 得到标题化合物, 为白色固体。
-丽 R (CDC13, 400MHz ) δ 9.46(s, 1H), 7.96 (s, 1H), 7.17-7.26 (m, 4H) , 6.85 (d, 1H), 6.71 (d, 1H, 7=1.36 Hz), 6.40 (s, 1H), 6.36 (d, 1H, 7=10.64 Hz), 5.76 (m, 1H), 4.76 (t, 2H), 3.78 (t, 4H), 3.04 (s, 2H) , 2.62 (t, 4H), 2.35 (s, 3H), 1.33(s, 9H)。
MS (FAB) m/z: 545.1 [M+l]+。 实施例 5: 1- [3-叔丁基 -1-苯基- 1^-5-吡唑基 ]-3- [8- (3, 4-二氢 -5-曱氧基 - 2 色烯基)]脲
实施例 2得到的产物 200mg溶于 50mL无水乙醇, 加入 0.2g 钯 /炭, 加热到 60°C, 滴加 1. OmL水合肼, 然后加热回流 6小时, 冷却, 过滤, 滤液浓缩, 柱分离得到标题化合物 149 mg, 为白色 固体。
'H-NMR (CDC13, 400MHz ) δ: 7.67 (d, 1H), 7.32-7.46 (m, 5H), 7.18 (s, 1H), 6.54 (s, 1H), 6.42 (s, 1H), 6.35 (d, 1H, 7=8.8 Hz) , 4.08 (t, 2H, 7=8.8 Hz) , 3.79 (s, 3H) , 2.62 (t, 2H, 7=6.8 Hz), 1.92 (p, 2H), 1.37 (s, 9H)。
MS (FAB) m/z: 421.1 [M+l]+。 实施例 6 : l-[3-叔丁基 -l-(4-曱基苯基)- 1H-5-吡唑 基]- 3-{8-{3, 4-二氢 -5- [2- (4-吗啡啉基)乙氧基] -2 色烯基 }} 脲
采用实施例 1 的制备方法, 将其中的中间体 41 改为中间体
40, 得到标题化合物, 为白色固体。
^- MR ( CDCI3, 400MHz ) δ: 7.69 (d, 1H, /=8.4 Hz), 7.29-7.31 (m, 3H), 7.16 (m, 2H) , 6.84 (s, 1H), 6.31-6.34 (m, 2H), 4.04 - 4.07 (m, 4H) , 3.72 (t, 4H), 2.80(t, 2H, 7=5.2 Hz), 2.60 (t, 2H), 2.59(t, 4H) , 2.31 (s, 3H) , 1.91 (p, 2H) , 1.34 (s, 9H)。
MS (FAB) ffl/z: 534.2 [M+l]+ 0 实施例 7 : 1 - [3-叔丁基 - 1 (4-甲基苯基) -1H- 5-吡唑 基] -3- [8- (5-硝基- 2 色烯基) ]脲
采用实施例 1 的制备方法, 将其中的中间体 41 改为中间体 73, 得到标题化合物, 为白色固体。
^-NMRCCDC^, 400MHz ) δ: 8.19 (d, 1H, 7=9.2 Hz) , 7.87(s, 1H), 7.71 (d, 1H, /=9.2 Hz) , 7.19-7.35 (m, 5H), 6.68 (s, 1H), 6.35 (s, 1H), 6.06 (m, 1H), 4.78 (t, 2H), 2.35 (s, 3H) , 1.37 (s, 9H)。
MS (FAB) m/z: 448.2 [M+l〗+。 实施例 8: 1- [3-叔丁基 1-苯基 -15~5-吡唑基 ] 3-{8-{3, 4-二氢 - 5- [2- (4-吗啡啉基)乙氧基] - 2^-色烯基 }}脲
在 50mL三口瓶中加入 20mL干燥的二氯甲烷, 冷却到 -10"C, 加入三光气(109mg, 0.36mmol ) , 慢慢滴加中间体 50 ( 280mg, 1.0麵 ol) 溶于 10mL干燥二氯甲烷的溶液, 有白色沉淀产生, 反 应 1小时,滴加 0.4mL千燥的三乙胺, 沉淀溶解。 加入中间体 12 ( 129mg, 0.6mmol ) , 升温至室温, 反应 5天, 倒入 50mL水中, 用二氯甲烷提取 3次, 有机层用饱和食盐水洗涤, 无水疏酸钠千 燥,柱分离(洗脱体系:石油醚 /乙酸乙酯)得到标题化合物 136mg,
为白色晶体, 收率 26.2%。
XH- R ( CDCI3, 400MHz ) δ: 7.67(d, 1H, /=8.4 Hz),
7.32-7.45 (m, 2H) , 7.34 (m, 3H), 7.28(m, 1H), 7.03 (s, 1H),
6.35 (s, 1H), 6.31 (d, 1H, 7=10.8 Hz), 4.04 - 4.06 (m, 4H), 3.70(t, 4H, 7=4.8 Hz) , 2.77 (t, 2H, 7=5.6 Hz) , 2.56-2.61 (m, 6H), 1.90 (p, 2H), 1.34 (s, 9H)。
MS (FAB) m/z: 520.2 [M+l]+ 0 实施例 9: 1- O叔丁基- 1-(4-氟苯基 )-1^"5-吡唑基 ]-3-{8-{3, 4 -二氢 -5- U- (4-吗啡淋基)乙氧基] 2^色烯基 }}脲
采用实施例 8的制备方法, 将其中的中间体 12改为中间体 14, 得到标题化合物, 为白色固体。
'H-NMR ( CDCI3, 400MHz ) δ: 7.64 (d, 1H, /=8.8 Hz) ,
7.38-7.41 (m, 3H) , 7.32 (s, 1H), 6.99 (m, 2H) , 6.30-6.32 (m, 2H), 4.04 - 4.08 (m, 4H) , 3.71 (t, 4H, 7=4.8 Hz) , 2.79 (t, 2H, 7=5.6 Hz), 2.56-2.59 (m, 6H), 1.90 (p, 2H), 1.32 (s, 9H)。
MS (FAB) m/z: 538.1 [M+l]+。 实施例 10: 1-[3-叔丁基-1-(4-氯苯基)-1^5-吡唑基] 3-{8 {3, 4 -二氢 -5- U- (4 吗啡啉基)乙氧基〗 -2^·色烯基 }}脲
釆用实施例 8 的制备方法, 将其中的中间体 12改为中间体 15, 得到标题化合物, 为白色固体。
'H-NMRC CDCI3, 400MHz ) δ: 7.63 (d, 1H, /=8.0 Hz), 7.42 (m, H), 7.35 (m, 2H) , 7.11 (s, 1H), 6.55(s, 1H), 6.37 (s, 1H), .34 (d, 1H), 4.08 (m, 4H), 3.74 (t, 4H, /=4.4 Hz) , 2.82 (t, H, /=5.6 Hz) , 2.62-2.65 (m, 6H), 1.94 (p, 2H), 1.36 (s, 9H)。
MS (FAB) m/z: 554.0 [M+l]+。
实施例 11: l-[3-叔丁基- 1 -(4-溴苯基)-l 5-吡唑基 ]-3 - {8-{3, 4 -二氢 -5 -〖2- (4-吗啡啉基)乙氧基] - 2^色烯基 }}脲
采用实施例 8的制备方法, 将其中的中间体 12改为中间体 16, 得到标题化合物, 为白色固体。
^-NMRC CDC13, 400MHz ) δ: 7.64 (d, 1Η, /=8. OHz), 7.47(m, 2H), 7.37 (m, 2H), 7.20(s, 1H), 6.88 (s, 1H), 6.37 (s, 1H), 6.34 (d, 1H, 7=8.8 Hz) , 4.08 (m, 4H), 3.73 (t, 4H, 7=4.4 Hz) , 2.83(t, 2H, 7=5.6 Hz), 2.60-2.61 (m, 6H) , 1.92 (p, 2H) , 1.36 (s, 9H)。
MS (FAB) m/z: 598.0 [M+l]+。 实施例 12: 1- [3-叔丁基 - 1- (4-甲氧基苯基)
吡唑 基]- 3- {8- {3, 4-二氢- 5- [2- (4 -吗啡淋基)乙氧基] - 2^·色烯基 }} 脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体 13, 得到标题化合物, 为白色固体。
H-N R( CDC13, 400MHz ) δ: 7.70 (d, IH, 7=8.4 Hz), 7.35 (m, 2H), 7.24 (s, 1H), 6.90(m, 2H) , 6.52 (s, IH) , 6.34 (s, IH), 6.32 (d, 1H), 4.08 (m, 4H) , 3.79 (s, 3H) , 3.74 (t} 4H, 7=4.4 Hz), 2.81 (t, 2H, 7=6.0 Hz) , 2.59-2.63 (m, 6H), 1.93 (p, 2H) , 1.35 (s, 9H)。
MS (FAB) m/z: 550.1 [M+l]+。 实施例 13: 1- [3-叔丁基 -1- (4-氨基磺酰基苯基) -I 5-吡唑 基]- 3- {8- {3, 4 -二氢 -5- [2 -(4-吗啡淋基)乙氧基] - 2^·色烯基 }} 脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体 18, 得到标题化合物, 为白色固体。
XH-NMR( CDC135400MHz ) δ 8.80 (d, 2Η, 7=8.8 Hz) , 7.78 (d, 2H, /=8.8 Hz) , 7.66 (d, IH), 6.29 (d, IH, 7=9.2 Hz) , 5.56(s, IH), 5.23 (t, 2H), 4.12 (t, 2H), 3.79 (m, 6H), 2.90 (t, 2H) , 2.63-2.70 (m, 6H) , 2.00 (p, 2H), 1.29 (s, 9H)。
MS (FAB) m/z: 599,1 [M+l]+。 实施例 14 : l-[3-叔丁基 - 1-(4-硝基苯基) -1^5-吡唑 基]- 3- {8-{3, 4-二氢- 5- [2- (4-吗啡啉基)乙氧基] -2^色烯基 }} 脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体 17, 得到标题化合物, 为黄色固体。
'H-NMRC CDC13, 400MHz ) δ: 8.13 (d, 2Η, 7=9.6 Hz) , 7.84 (s, 1Η), 7.73 (d, 2Η, 7=9.2 Hz) , 7.55 (d, IH, 7=8.4 Hz) , 7.43 (s, IH), 6.38 (s, IH), 6.29(d, 1H, 7=8.8 Hz) , 4.07 (m, 4H) , 3.72 (t 4H, 7=4.8 Hz) , 2.81 (t, 2H), 2.58-2.62 (m, 6H), 1.91 (p, 2H),
I.33 (s, 9H)。
MS (FAB) m/z: 565.0 [M+l]+。 实施例 15 : 1- [3-叔丁基 - 1-(4-甲基苯基)- 1H-5-吡唑 基〗 -3- {8- [3, 4 -二氢 -5- (4-吗啡啉基酰基甲氧基) -2^"色烯基] } 脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体
II, 中间体 50改为中间体 59, 得到标题化合物, 为白色固体。
'Ε-ΜΠ CDC13, 400MHz ) δ: 7.75 (d, IH, 7=9.2 Hz) , 7.34 (d,
2H, 7=8.4 Hz) , 7.25 (d, 2H), 6.38 (s, IH), 6.34 (d, IH, 7=9.2
Hz), 4.64 (s, 2H), 4.11 (t, 2H, 7=3.6 Hz) , 3.63 - 3,67 (m, 8H),
2.67 (t, 2H, 7=6.4 Hz), 2.37 (s, 3H) , 1.95 (p, 2H) , 1.36(s, 9H)。
MS (FAB) m/z: 548.1 [M+l]+。 实施例 16: l-(3-叔丁基 - 5-异喁唑基) -3-{8-{3, 4-二氢 -5- [2- (4-吗啡啉基)乙氧基] 色烯基 }}脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体 28, 得到标题化合物, 为白色固体。
XH-NMR( CDC13, 400MHz ) 5: 8.59 (s, IH), 7.67 (d, IH, 7=8.0 Hz), 6.36 (d, IH, /=9.2 Hz) , 6.12 (s, IH), 4.08-4.10(m, 4H) ,
3.75 (t, 4H, /=4.4 Hz) , 2.83(t, 2H, 7=5.6 Hz) , 2.60 - 2.64 (m, 6H), 1.92 (p, 2H), 1.30(s, 9H)。
MS (FAB) m/z: 445.1 [M+l]+。 实施例 17: l-(5-叔丁基 - 3-异喁唑基)- 3-{8-{3, 4-二氢 -5-[2-(4-吗啡啉基)乙氧基] - 色烯基 脲
采用实施例 8的制备方法, 将其中的中间体 12改为 3-氨基 -5 -叔丁基异喁唑, 得到标题化合物, 为白色固体。
'H-NMRC CDC13J 400MHz ) δ: 8.75 (s, 2Η) , 7.86 (d, 1Η, /=8.8 Hz), 6.37 (d, 1H, /=8.8 Hz) , 6.07(s, IH), 4.23(t, 2H, 7=4.8 Hz), 4.10 (t. 2H), 3.74 (t, 4H, 7=4.4 Hz) , 2.82 (t, 2H, /=5.2 Hz), 2.61-2.67 (m, 6H) , 1.99 (p, 2H), 1.34 (s, 9H)。
MS (FAB) m/z: 445.1 [M+l]+。 实施例 18 : 叔丁基 - 3-(4-甲基苯基)- 吡唑 ] -3- {8- {3, 4-二氢 -5- [2- (4-吗啡啉基)乙氧基] -2^色烯基 }}
脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体 33, 得到标题化合物, 为白色固体。
'H-NMRCCDCls, 400MHz ) δ: 7.70(s, IH), 7.63 (d, IH, 7=9.2 Hz), 7.14-7.17 (m, 4H) , 6.86 (s, IH), 6.29 (d, IH, 7=8.4 Hz) ,
5.80 (s, IH), 4.04-4.06 (m, 4H) , 3.71 (t, 4H, 7=4.0 Hz),
2.78 (t, 2H), 2.56-2.58 (m, 6H) , 2.36 (s, 3H) , 1.92 (p, 2H), 1.43 (s, 9H)。
MS (FAB) m/z: 534.2 [M+l]+。 实施例 19 : l-[4-叔丁基 -1- (4-甲基苯基) - 咪唑 基] - 3-{8- {3, 4 -二氢 -5- [2- (4-吗啡啉基)乙氧基] -2^·色烯基 }} 脲
采用实施例 8 的制备方法, 将其中的中间体 12改为中间体 35, 得到标题化合物, 为白色固体。
'H-NMR (CDC13, 400MHz) δ: 11.56 (s, IH), 7.98 (d, 1H, 7=9.2 Hz), 7.21 - 7.26 (m, 4H) , 6.75 (s, 1H), 6.45(s, IH),
6.37 (d, 1H, 7=8.8 Hz) , 4.29(t, 2H) , 4.08 (t, 2H, 7=5.6 Hz) ,
3.71(t, 4H, 7=4.8 Hz), 2.79 (t, 2H), 2.70(t, 2H), 2.58 (t, 4H, /=4.4 Hz), 2.39 (s, 3H), 2.32 (p, 2H) , 1.34 (s, 9H)。
MS (FAB) m/z: 534.2 [M+l]+。 实施例 20 : l-[3-叔丁基 -l-(4-甲基苯基) -1H-5-吡唑 基]- 3-{8-{3, 4-二氢 -5- [2- (4-吡啶基)氧基乙氧基] - 色烯 基 "脲
采用实施例 15的制备方法, 将其中的中间体 59改为中间体 56, 得到标题化合物, 为白色固体。
'H-NMRC CDCI3, 400MHz ) 5: 8.44 (dd, 2H, 7=4.8 Hz, 1.2Hz),
7.79(d, 1H, /=8.8 Hz) , 7.33 (d, 2H, /=8.0 Hz), 7.28(s, IH),
7.21(d, 2H), 6.91 (dd, 2H, /=4.8 Hz, 1.6Hz), 6.43 (s, IH),
6.40 (d, 1H, 7=9.2 Hz) , 6.37 (s, IH), 4.40(t, 2H, 7=5.2 Hz) ,
4.33 (t, 2H, 7=5.2 Hz), 4.12 (t, 2H) , 2.58 (t, 2H, 7=6.8 Hz) , 2.36 (s, 3H), 1.90 (p, 2H), 1.36 (s, 9H)。
MS (FAB) m/z: 542.0 [M+l]+ 0 、 实施例 21 : l-[3-叔丁基 - 1-(4-甲基苯基)- 1H-5-吡唑 基〗- 3-{8-{3, 4-二氢- 5 - {2- [4- (顺式 -2, 6 -二甲基)吗啡啉基] 乙氧基 } -2^色烯基 }}脲
采用实施例 15的制备方法, 将其中的中间体 59改为中间体 55, 得到标题化合物, 为白色固体。
'H-NMRC CDCI3, 400MHz ) δ: 7.71 (d, IH, /=9.2 Hz) , 7.31 (d, 2H, /=8.4 Hz) , 7.21 (d, 2H) , 7.17(s, IH), 6.31-6.36 (m, 3H) , 4.08-4.10 (m, 4H), 3.71 (m, 2H), 2.80-2.86 (m, 4H) , 2.63 (t, 2H, 7=6.4 Hz) , 2.36 (s, 3H) , 1.92-1.95 (m, 4H) , 1.35 (s, 9H) , 1.17 (d, 3H), 1.15 (d, 3H)。
MS (FAB) m/z: 562.2 [M+l]+。 实施例 22 : l-[3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑 基] -3-{8 - {3, 4 -二氢 -5- [2- (1-咪唑基)乙氧基] 色烯基 }} 脲
采用实施例 15的制备方法, 将其中的中间体 59改为中间体 52, 得到标题化合物, 为白色固体。
Hz) , 7.73(s, IH), 7.53 (s, 1H), 7.32 (d, 2H, 7=8.0 Hz), 7.15 (d, 2H, 7=8.0
Hz), 6.93 (s, 1H), 6.89(s, 1H), 6.41 (s, 1H), 6.22 (d, 1H, 7=8.8 Hz), 4.32 (t, 2H, /=4.8 Hz), 4.12(t, 2H, /=5.6 Hz),
3.62 (t, 2H), 2.35 (t, 2H) , 2.32 (s, 3H) , 1.61 (p, 2H) , 1.35 (s, 9H)。
MS (FAB) m/z: 515.2 [M+l]+„ 实施例 23 : l-[3-叔丁基 -l-(4-甲基苯基) -1H- 5-吡唑 基]- 3-{8-{3, 4-二氢- 5 - [2 -(1-1, 2, 4 -三氮唑基)乙氧基] -2 - 色烯基 }}脲
采用实施例 15的制备方法, 将其中的中间体 59改为中间体 53, 得到标题化合物, 为白色固体。
XH-NMR(CDC13, 400MHz ) δ: 8.08 (s 1H) , 7.82 - 7.84 (m, 2H), 7.45(s, 1H), 7.32 (d, 2H, 7=8.4 Hz) , 7.17 (d, 2H, 7=8.4 Hz) , 6.40 (s, IH), 6.27 (d, 1H, /=9.2 Hz) , 4.56 (t, 2H, /=4.8 Hz) ,
4.23 (t, 2H, 7=4.8 Hz), 3.77 (t, 2H) , 2.33-2.36 (m, 5H), 1.69 (p, 2H), 1.35 (s, 9H)。
MS (FAB) m/z: 516.3 [M+l]+。 实施例 24: 1-[3-叔丁基-1-(4-氯苯基)-1^-5-吡唑基]-3-{8-{3, 4-二氢- 5- {2- [4- (顺式 -2, 6-二甲基) 吗啡啉基]乙氧基 } -1B- 色烯基 }}脲
釆用实施例 8 的制备方法, 将其中的中间体 12 改为中间体 5, 中间体 50改为中间体 55, 得到标题化合物, 为白色固体。 - NMR(CDC13, 400MHz) δ: 7.63 (d, 1H, 7=8.4 Hz) , 7.42 (d, H, /=8.4 Hz) , 7.34 (d, 2H, 7=8.8 Hz), 7.16 (s, 1H), 6.96 (s, H), 6.37 (s, 1H), 6.34 (d, IH, /=8.8 Hz) , 4.06-4.09 (m, 4H), .70 (m, 2H), 2.80—2.85 (m, 4H) , 2.63(t, 2H, 7=6.4 Hz),
1.91-1.95 (m, 4H), 1.34(s, 9H) , 1.17(d, 3H), 1.15 (d, 3H)。
MS (FAB) m/z: 582.1 [M+l]+。 实施例 25: 1- [3 叔丁基 -1- (3, 4-二甲基苯基)- 1^"5-吡唑 基] -3-{8-{3, 4 -二氢 -5- [2- (4-吗啡啉基)乙氧基] -2 色烯基 }} 脲
采用实施例 8 的制备方法, 将其中的中间体 12改为中间体
19, 得到标题化合物, 为白色固体。
'H-NMRC CDC13, 400MHz ) δ: 7.68 (d, 1H, 7=8.8 Hz) , 7.30 (s, 1H), 7.19 (s, IH), 7.08-7.10 (m, 2H), 6.80 (s, IH), 6.34 (s, IH), 6.32 (d, IH, =8.8 Hz) , 4.04-4.06 (m, 4H), 3.71 (t, 4H, /=4.4 Hz) , 2.79 (t, 2H), 2..57-2.61 (m, 6H), 2.20-2.21 (m, 6H) 1.90 (p, 2H), 1.34 (s, 9H)。
MS (FAB) m/z: 548.1 [M+l]+ 0 实施例 26: 1- [3-叔丁基 -1 (3, 4-二氯苯基)- 1^-5-吡唑 基] -3 {8- {3, 4-二氢 -5- [2- (4 -吗啡啉基)乙氧基] -2^·色烯基 }} 脲
釆用实施例 8 的制备方法, 将其中的中间体 12改为中间体
20, 得到标题化合物, 为白色固体。
^-NMRCCDCL, 400MHz ) δ: 7.76 (d, 1H, /=2.0 Hz) , 7.58 (d, IH), 7.43(d, 1H, 7=8.4 Hz) , 7.37 (d, 1H), 7.17 (s, 1H), 6.81 (s IH), 6.37 (s, 1H), 6.34 (d, IH, 7=8.8 Hz) , 4.09-4.11 (m, 4H) , 3.74 (t, 4H, /-4.4 Hz), 2.83 (t, 2H, 7=5.2 Hz), 2.61 - 2.64 (m, 6H), 1.94 (p, 2H), 1.34 (s, 9H)。
MS (FAB) m/z: 588.0 [M+l]+。
实施例 27 : 1 - [3 -叔丁基 -1 -(3 -甲基苯基) -1^~5-吡唑 基] -3- {8- {3, 4-二氢- 5- [2- (4-吗啡淋基)乙氧基] - 2^色烯基 }} 脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体
21, 得到标题化合物, 为白色固体。
-醒 ( CDCl" 400MHz ) δ: 7.68 (d, 1H, /=8.4 Hz), 7.21-7.26 (m, 4H), 7.11 (d, IH), 6.83(s, IH), 6.36 (s, 1H), 6.32 (d, IH, /=8.8 Hz) , 4.05-4.08 (m, 4H) , 3.73 (t, 4H, 7=4.4 Hz), 2.80 (t, 2H, /=5.6 Hz), 2..57-2.62 (m, 6H), 2.32 (s, 3H), 1.91 (p, 2H) , 1.35 (s, 9H)。
MS (FAB) m/z: 534.2 [M+l]+ 0 实施例 28: 1-[(3-叔丁基-1-萘基)-1^5-吡唑基]-3-{8-{3, 4- 二氢 -5- [2- (4-吗啡啉基)乙氧基] -2^色烯基 }}脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体
22, 得到标题化合物, 为白色固体。
'H-NMRCCDCla, 400MHz ) δ: 7.85-7.89 (m, 2H) , 7.43-7.45 (m 4H), 7.37 (d, IH), 7.04 (s, IH), 6.46 (m, 2H) , 6.19 (d, 1H, 7=8.8 Hz), 4.03 (t, 2H, 7=5.6 Hz), 3.97 (t, 2H, 7=4.8 Hz) , 3.70(t, 4H, 7=4.4 Hz) , 2.80 (t, 2H, 7=5.2 Hz) , 2.55— 2.57 (m, 6H), 1.85 (p, 2H), 1.38 (s, 9H)。
MS (FAB) m/z: 570.1 [M+l〗+。 实施例 29 : l-[3-叔丁基 - 1-(4-甲基苯基)- 1H-5-吡唑 基]- 3- {8-{3, 4-二氢 -5- [2 -(1-吡唑基)乙氧基] -2 色烯基 }} 脲
采用实施例 15的制备方法, 将其中的中间体 59改为中间体
54, 得到标题化合物, 为白色固体。
^- MR (CDCI3, 400MHz ) δ: 7.71 (d, 1H) , 7.50-7.53 (m, 2H), 7.31 (d, 2H), 7.21(d, 2H, /二 8.0 Hz), 6.37 (s, 1H), 6.30 (d, 1H, 7=8.4 Hz), 6.26 (t, 1H), 4.52 (t, 2H, 7=5.2 Hz) , 4.28 (t, 2H, 7=5.2 Hz), 4.07 (t, 2H, 7=5.6 Hz), 2.54 (t, 2H, /=6.4 Hz) , 2.35 (s, 3H), 1.91 (p, 2H), 1.36 (s, 9H)。
MS (FAB) m/z: 515.1 [M+l]+。 实施例 30 : l-[3-叔丁基 -l-(4-甲基苯基)- lfi-5-吡唑 基]- 3- {8-{3, 4 -二氢 -5- [2- (1-哌啶 -4-酮基)乙氧基] -2^色烯 基 "脲
采用实施例 15的制备方法, 将其中的中间体 59改为中间体 51, 得到标题化合物, 为白色固体。
^- MR ( CDCla, 00MHz ) δ: 7.73 (d, 1H, 7=8.8 Hz), 7.30-7.32 (m, 3H), 7.16 (d, 2H), 6.85 (s, 1H), 6.34 - 6· 35 (m, 2H), 4.10(t, 2H), 4.06 (t, 2H) , 2.91 - 2.94 (m, 6H) , 2.62 (t, 2H), 2.47 (t, 4H, 7=6.0 Hz), 2.32 (s, 3H) , 1.91 (p, 2H) , 1.35 (s 9H)。
MS (FAB) m/z: 546.0 [M+l]+。 实施例 31 : 1 - [3-叔丁基 -l-(4-甲基苯基) -1H-5-吡唑 基〗 - 3-{8 - {3, 4 -二氢 -5-[2- (4-吗啡啉基)乙酰胺基] -2 ^色烯 基 "脲
釆用实施例 15的制备方法, 将其中的中间体 59改为中间体 81, 得到标题化合物, 为白色固体。
-腿 ( CDC1" 400MHz ) δ: 7.94 (d, 1H, 7=8.8 Hz), 7.47 (s, 1H), 7.35 (d, 2H, 7=8.4 Hz), 7.23 (d, 2H, /=8.0 Hz),
6.36 - 6.38 (m, 2H), 4.12(t, 2H, /=4.4 Hz), 3.79(t, 3.18 (t, 2H), 2.61-2.68 (m, 6H) , 2.37 (s, 3H), 2.03 (p
1.36 (s, 9H)。
MS (FAB) m/z: 547.2 [M+l]+ e 实施例 32: l-[3-叔丁基 - 1- (4-三氟甲基苯基)- 1 5-吡唑 基〗- 3-{8-{3, 4 -二氢 -5 - [2 - (4-吗啡啉基)乙氧基] 色烯基 }} 脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体 26, 得到标题化合物, 为白色固体。
'H-NMR (CDCls, 400MHz ) d: 7.61-7.65 (m, 5H) , 7.07 (s, 1H), 6.60(s, 1H), 6.41(s, 1H) , 6.34 (d, 1H, 7=8.8 Hz), 4.07-4.09 (m, 4H) , 3.74 (t, 4H, 7=4.4 Hz), 2.82 (t, 2H), 2.61-2.64 (m, 6H) , 1.92 (p, 2H), 1.35 (s, 9H)。
MS (FAB) m/z: 588.0 [M+l]+。 实施例 33 : l-[3-叔丁基 - 1-(4-乙基苯基) -1^5-吡唑 基] -3-{8-{3, 4-二氢 5- [2-(4-吗啡啉基)乙氧基] - 2^色烯基 }} 脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体 24, 得到标题化合物, 为白色固体。
^-NMRC CDCls, 400MHz ) δ: 7.70 (d, 1Η, 7=8.8 Hz) , 7.32 (d, 2H, 7=8.4 Hz) , 7.16 (d, 2H, =8.0 Hz), 6.93 (s, 1H), 6.34 (s, 1H), 6.32 (d, 1H, 7=8.8 Hz) , 4.04-4.06 (m, 4H) , 3.70 (t, 4H, 7=4.8 Hz), 2.78 (t, 2H) , 2.57-2.61 (m, 8H), 1.90 (p, 2H) , 1.34 (s, 9H), 1.18 (t, 3H, /=7.6 Hz)。
MS (FAB) m/z: 548.1 [M+l]+。
实施例 34: 1- [3-叔丁基 - 1- (4-叔丁基苯基) -1^5-吡唑 基〗 -3- {8-{3, 4-二氢 -5- [2- (4-吗啡啉基)乙氧基] -2^色烯基 }} 脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体
25, 得到标题化合物, 为白色固体。
'Ε-ΜΠ CDC13, 400MHz ) δ: 7.72 (d, IH, 7=8.8 Hz) , 7.34 (d, 2H), 7.26 (m, 2H), 7.18 (s, IH) , 6.34-6.37 (m, 3H) , 4.08 - 4.11 (m, 4H), 3.74 (t, 4H, 7=4.4 Hz), 2.82 (t, 2H),
2.62-2.65 (m, 6H) , 1.94 (p, 2H), 1.35 (s, 9H) , 1.24 (d, 3H) , 1.23 (d, 3H)。
MS (FAB) m/z: 562.1 [M+l]+ 0 实施例 35: 1- [3-叔丁基 -l-(4-三氟甲基苯基)-l 5-吡唑 基 ]-3-{8-{3, 4 -二氢 -5- [2- (1 -咪唑基)乙氧基] - 色烯基 脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体
26, 中间体 50改为中间体 52, 得到标题化合物, 为白色固体。
^-NMR (CDC13, 400MHz ) δ: 8.08 (s, IH) , 7.91 (d, IH,
7=9.2 Hz), 7.63 (d, 2H, 7=8.4 Hz), 7.54 (d, 2H, 7=8.4 Hz), 7.46 (s, IH), 6.86 (s, IH), 6.74 (s, IH), 6.51 (s, IH), 6.18 (d, IH, 7=8.8 Hz) , 4.29 (t, 2H, 7=4.4 Hz) , 4.06 (t, 2H, /=4.8 Hz) ,
3.23 (t, 2H), 2.18 (t, 2H, 7=6.4 Hz), 1.34 (s, 9H)。
MS (FAB) m/z: 569.3 [M+l]+ 0 实施例 36: 1- [3-叔丁基 -1- (4-甲基苯基) - 1H 5-吡唑 ]- 3 - {8-{5-[2- (4-吗啡啉基)乙氧基] -2^色烯基 }}脲
在 50mL三口瓶中加入 20mL干燥的二氯甲烷, 冷却到 -10Ό, 加入三光气(109mg, 0.36mmol ) , 慢慢滴加中间体 65 ( 277mg,
1.0讓 ol )溶于 10mL干燥二氯甲烷的溶液, 有白色沉淀产生, 反 应 1小时,滴加 0.4mL干燥的三乙胺, 沉淀溶解。 加入中间体 11
( 138mg, 0.6mmol ) , 升温至室温, 反应 5天, 倒入 50mL水中, 用二氯甲烷提取 3次, 有机层用饱和食盐水洗涤, 无水硫酸钠干 燥, 柱分离 (洗脱体系: 石油醚 /乙酸乙酯 =1: 1 )得到标题化合物 145fflg, 为白色晶体, 收率 27.3%。
XH-NMR( CDC13, 400MHz ) δ: 7.74 (d, 1H, 7=8.8 Hz) , 7.33 (d, 2H, 7=8.4 Hz), 7.21 (d, 2H, /=8.0 Hz), 7.13(s, 1H) , 6.72-6.74 (dd, 1H, 7=8.4 Hz, 1.6 Hz), 6.39 (d, 1H, 7=9.2 Hz) , 6.35 (s, 1H), 6.34 (s, 1H), 5.72 (m, 1H), 4.71 (t, 2H, 7=2.0 Hz), 4.11 (t, 2H), 3.74(t, 4H) , 2.82 (t, 2H) , 2.60(t, 4H) ,
2.36 (s, 3H), 1.35 (s, 9H)。
MS (FAB) m/z: 532.2 [M+l]+。 实施例 37 : l-[3-叔丁基 -l-(4-甲基苯基)- 1H-5-吡唑 基]- 3-{8-{3, 4-二氢 -5- [2- (4-吡啶基)乙氧基] -2^·色烯基 }} 脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体 11, 中间体 50改为中间体 58, 得到标题化合物, 为白色固体。
'H- MR CDC^, 400MHz ) δ: 8.57 (d, 2H, /=4.8 Hz) , 7.75 (d, 1H, 7=9.2 Hz) , 7.38 (s, 1H), 7.28-7.32 (m, 4H), 7.12 (d, 2H) , 6.82 (s, 1H), 6.34 (s, 1H), 6.27(d, 1H, J=9.2 Hz), 4.14 (t, 2H, 7=6.0 Hz) , 3.94 (t, 2H) , 3.10(t, 2H, 7=6.0 Hz) , 2.47 (t, 2H, 7=6.4 Hz) , 2.28(s, 3H), 1.82 (p, 2H) , 1.34 (s, 9H)。
MS (FAB) m/z: 526.2 [M+l]+。
实施例 38 : l-[3-叔丁基 - 1-(4-腈基苯基) -1^5-吡唑 基]-3-{8-{3, 4 二氢- 5- [2 - (4-吗啡啉基)乙氧基] -2^色烯基 }} 脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体 27, 得到标题化合物, 为白色固体。
'H-NMR (CDC13, 400MHz ) δ: 7.63-7.70 (m, 5H) , 7.18 (s, 1H), 6.96 (s, 1H), 6.40 (s, 1H), 6.35 (d, 1H, /=9.2 Hz), 4.08-4.11 (m, 4H) , 3.73 (t, 4H, 7=4.4 Hz), 2.84 (t, 2H), 2.61-2.65 (m, 6H), 1.95 (p, 2H), 1.35 (s, 9H)。
MS (FAB) m/z: 545.3 [M+l]+ 0 实施例 39: l-[3-叔丁基 -l-(3-氯 -4-氟苯基)- 1^5-吡唑 基] -3 {8-{3, 4-二氢- 5- [2- (4-吗啡啉基)乙氧基] - 2^·色烯基 }} 脲
采用实施例 8 的制备方法, 将其中的中间体 12 改为中间体 23, 得到标题化合物, 为白色固体。
^-NMR (CDCI3, 400MHz ) δ 7.59 (m, 2H), 7.36 (m, 1H), 7.10 - 7.14 (m, 2H) , 6.88 (s, 1H) , 6.33-6.36 (m, 2H) , 4.08-4.11 (m, 4H) , 3.72 (t, 4H, /=4.0 Hz), 2.81 (t, 2H), 2.61-2.64 (m, 6H), 1.93 (p, 2H), 1.34 (s, 9H)。
MS (FAB) m/z: 572.2 [M+l]+„ 实施例 40 : l-[3-叔丁基 -l-(4-甲基苯基)- 1H-5-吡唑 基]- 3-〖8- (5- [ (4-甲氧基苯基)甲氧基] -2^色烯基 }}脲
中间体 62 ( 617mg, 2mmol )溶于 25mL乙酸乙酯和 mL乙醇, 分 4比加入二水合氯化亚锡( 1.80g, 8mmol ) , 反应液变混浊, 加
热回流 8小时, 冷却, 加入饱和碳酸氢钠溶液, 直至出现明显分 层, 分液, 7j层用乙酸乙酯提取 2次, 合并有机层, 用饱和食盐 水洗涤, 无水硫酸钠干燥, 过滤, 浓缩得到 541mg还原产物, 收 率 95%。
在 lOOmL三口瓶中加入 30mL干燥的二氯甲烷,冷却到 - 1(TC, 加入三光气 ( 208mg, 0.70mmol ) , 慢慢滴加上步的得到的产物 (541mg, 1.9 mmol)溶于 20mL干燥二氯甲烷的溶液, 有白色沉 淀产生, 反应 1小时,滴加 1. OmL干燥的三乙胺, 沉淀溶解。 加入 中间体 11 (261mg, 1.14mmol) , 升温至室温, 反应 5天, 倒入 50mL水中, 用二氯甲綻提取 3次, 有机层用饱和食盐水洗涤, 无 水硫酸钠干燥, 柱分离(洗脱体系: 石油醚 /乙酸乙酯 =1:1)得到 标题化合物 350mg, 为白色晶体, 收率 34.2%。
'H-NMR ( CDC13 , 400MHz ) δ: 7.68 (d, 1H, 7=8.8 Hz), 7.32-7.35 (m, 4H) , 7.17 (m, 2H), 6.91 (d, 2H, =8.8 Hz), 6.77 (d, 1H), 6.46 (d, 1H, 7=9.2 Hz) , 6.36 (s, 1H) , 5.68 (m, 1H), 4.95 (t, 2H), 4.68 (t, 2H, J .6 Hz), 3.83 (s, 3H) , 2.33 (s 3H), 1.35 (s, 9H)。
MS (FAB) m/z: 526.2 [M+l]+。 实施例 41 : l-[3-叔丁基 -1- (4-甲基苯基) -1H- 5-吡唑 基〗 -3- {8- [5- (4-吗啡啉基酰基甲氧基) - 2^色烯基] }脲
采用实施例 36的制备方法, 将其中的中间体 50改为中间体 59,'得到标题化合物, 为白色固体。
XH-NMR( CDC13, 400MHz ) δ: 7.76 (d, 1H, 7=9.2 Hz) , 7.34 (d 2H, 7=8.4 Hz), 7.22(d, 2H), 6.72 (d, 1H, 7=10.0 Hz), 6.35-6.38 (m, 2H) , 5.73(m, 1H), 4.71 (s, 2H), 4.64(s, 2H) , 3.55-3.67 (m, 8H), 2.36 (s, 3H) , 1.36 (s, 9H)。
MS (FAB) m/z: 546.2 [M+l]+ 0 实施例 42: l-[3-叔丁基 -l-(4-氟苯基)- 1^"5-吡唑 基] -3- {8- {5- [2- (4-吗啡啉基)乙氧基] -2^"色烯基 H脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体 14, 得到标题化合物, 为白色固体。
'H-NMRCCDCls, 400MHz ) δ: 7.67 (d, 1H, 7=8.4 Hz) , 7.43(m, 2H), 7.07-7.11 (m, 3H) , 6.73 (d, 1H, 7=10.4 Hz), 6.58 (s, IH) , 6.38 (d, 1H, 7=9.2 Hz), 6.35 (s, IH) , 5.73 (m, IH), 4.71 (t, 2H, 7=2.0 Hz) , 4.11 (t, 2H, /=5.2 Hz) , 3.75 (t, 4H) , 2.83(t, 2H), 2.61 (t, 4H), 1.35 (s, 9H)。
MS (FAB) m/z: 536.2 [M+l]+„ 实施例 43: 1-[3-叔丁基 -1- (4-氯苯基 )-lJ?-5-吡唑 基] -3- {8- {5- [2- (4 -吗啡啉基)乙氧基] - 2^"色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体 15, 得到标题化合物, 为白色固体。
^-NMRCCDC^, 400MHz ) δ: 7.65 (d, 1H, 7=8.8 Hz) , 7.43(d, 2H), 7.35 (d, 2H, 7=8.8 Hz), 7.10(s, IH) , 6.74 (d, IH, 7=10.0 Hz), 6.68 (s, IH), 6.36- 6.38 (m, 2H) , 5.72 (m, 1H), 4.69 (t, 2H, 7=2.0 Hz) , 4.10(t, 2H, 7=5.2 Hz) , 3.74 (t, 4H, /=4.4 Hz) , 2.81 (t, 2H, 7=4.8 Hz), 2.59(t, 4H) , 1.35 (s, 9H)。
MS (FAB) m/z: 552.2 [M+l]+ 0 实施例 44: 1- [3-叔丁基 - 1-(4-溴苯基 )-1^5-吡唑 ] -3- {8- {5- [2- (4 -吗啡啉基)乙氧基] - 2 色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体
16, 得到标题化合物, 为白色固体。
'H-N RCCDC^, 400MHz ) δ: 7.65 (d, 1H), 7.50(d, 2H, 7=8.8 Hz), 7.36 (d, 2H, /-8.8 Hz), 7.12(s, IH), 6.77(s, IH) , 6.73(d 1H, 7=10.4 Hz), 6.38 (d, IH, 7.2 Hz), 6.36 (s, IH), 5.72(m, IH), 4.69(t, 2H, /=1.6 Hz), 4.10(t, 2H, 6 Hz), 3.74(t, 4H, 7=4.4 Hz), 2.82 (t, 2H, 7=4.8 Hz), 2.60(t, 4H), 1.34 (s, 9H)。
MS (FAB) m/z: 598.0 [M+l]÷ c 实施例 45: l-( 3-叔丁基 - 1-苯基 -1^·5-吡唑基)-3-{8-{5-U- (4 - 吗啡啉基)乙氧基] - 2^色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体 12, 得到标题化合物, 为白色固体。
'H-NMRC CDC13, 400MHz ) δ: 7.71 (d, IH, /=8.8 Hz), 7.45 (d, 2H), 7.40 (t, 2H), 7.29 (t, IH), 7.20(s, IH), 6.72 (d, IH, 7=10.0 Hz), 6.69(s, IH), 6.36-6.38 (m, 2H), 5.71 (m, 1H), 4.69 (t, 2H, 7=2.0 Hz) , 4.09 (t, 2H), 3.73(t, 4H, 7=4.4 Hz) , 2.81 (t, 2H, 7=5.2 Hz) , 2.59 (t, 4H), 1.36 (s, 9H)。
MS (FAB) m/z: 518.1 [M+l〗+。 实施例 46: 1 - [3-叔丁基 -1- (4~甲氧基苯基) -li?~5-吡唑 基] -3- {8 - {5- [2- (4 -吗啡啉基)乙氧基] -2^~色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体 13, 得到标题化合物, 为白色固体。
Hz), 7.33 (d, 2H, 7=9.2 Hz) , 7.25 (s, 1H), 6.88 (d, 2H, /=9.2 Hz) , 6.75(d, IH), 6.73 (s, 1H), 6.36 (d, 1H), 6.33 (s, IH), 5.70 (m, IH) ,
4.67 (t, 2H, /=1.6 Hz), 4.10 (t, 2H), 3.77 (s, 3H), 3.74 (t, 4H, 7=4.4 Hz) , 2.80(t, 2H, /=5.6 Hz) , 2.59(t, 4H) , 1.35 (s, 9H)。
MS (FAB) m/z: 548.1 [M+l]+。 实施例 47: l-[3-叔丁基 三氟甲基苯基)-1 5-吡唑 基] 3- {8- {5- [2 (4-吗啡啉基)乙氧基〗 色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体 26, 得到标题化合物, 为白色固体。
'H-N R (CDC13, 400MHz ) δ: 7· 65 (m, 5Η) , 7.07 (s, IH), 6.76 (s, IH), 6.73(d, IH, 7=9.6 Hz) , 6.40(s, IH), 6.38 (d, IH, /=8.8 Hz), 5.70 (m, IH), 4.70 (t, 2H, 1=1.6 Hz), 4.10(t, 2H, 7=5.2 Hz) , 3.74 (t, 4H, 7=4.0 Hz) , 2.82 (t, 2H) , 2.60(t, 4H), 1.36 (s, 9H)。
MS (FAB) m/z: 586.1 [M+l]+ 0 实施例 48 : 1- [3-叔丁基 -l-(4-硝基苯基)- 1^-5-吡唑 基] - 3- {8- {5- [2- (4-吗啡啉基)乙氧基] 色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体 17, 得到标题化合物, 为黄色固体。
'H-NMRC CDCI3, 400MHz ) δ: 8.18 (d, 2H, /=9.2 Hz) , 7.74 (d, 2H, /=8.8 Hz) , 7.55 (d, IH), 7.30 (s, IH), 6.71 (d, 1H, /=10.0 Hz), 6.39 (s, 1H), 6.34 (d, IH, 7=9.2 Hz), 5.70 (m, IH) , 4.68(t, 2H, 6 Hz), 4.09 (t, 2H, /=6.0 Hz) , 3.74 (t, 4H, 7=4.4 Hz) , 2.81 (t, 2H, 7=6.0 Hz) , 2.60(t, 4H) , 1.34 (s, 9H)。
MS (FAB) m/z: 563.0 [M+l]+„
实施例 49 : l-[3-叔丁基 - 1-(4-腈基苯基) -I 5-吡唑 基]- 3- {8- {5- [2- (4-吗啡啉基)乙氧基] - 2^色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体 27, 得到标题化合物, 为白色固体。
^-N R (CDC13, 400MHz ) δ: 7.64-7.70 (m, 5H), 7.15 (s, 1H), 7.05 (s, IH), 6.74 (d, IH, 7=10.0 Hz), 6.40(s, IH), 6.38 (d, 1H, 7-8.8 Hz), 5.73 (m, IH), 4.71 (t, 2H, /=1.6 Hz), 4. ll(t, 2H, 7=4.4 Hz) , 3.74(t, 4H, 7=4.8 Hz) , 2.83(t, 2H) , 2.61 (t, 4H), 1.34 (s, 9H)。
MS (FAB) m/z: 543.1 [M+l]+。 实施例 50 : l-[3-叔丁基 1- (4-甲基苯基)- 1H-5 吡唑 基〗-3-{8-{5-[2-(1-1, 2, 4-三氮唑基)乙氧基 ]-2^色烯基 }}脲 采用实施例 36的制备方法, 将其中的中间体 65改为中间体 69, 得到标题化合物, 为白色固体。
^•-N R (CDCI3, 400MHz ) δ: 8.10(s, IH) , 7.86 (s, IH), 7.83 (d, IH, /=8.0 Hz) , 7.38 (s, IH), 7.32 (d, 2H, /=8.4 Hz) , 7.18 (d, 2H), 6.39 (s, 1H), 6.36 (d, IH), 6.29(d, 1H, 7=9.2 Hz), 5.47 (m, IH), 4.55 (t, 2H, 7=4.8 Hz) , 4.44 (t, 2H), 4.28 (t 2H, 7=4.8 Hz), 2.33 (s, 3H), 1.35 (s, 9H)。
MS (FAB) m/z: 514.2 [M+l]+ 0 实施例 51 : l-[3-叔丁基 -1- (4-乙基苯基) -1^"5-吡唑 ] -3- {8- {5- [2- (4-吗啡啉基)乙氧基〗 - 2 色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体 24, 得到标题化合物, 为白色固体。
JH-N R( CDCI3, 400MHz ) δ 7.74 (d, 1H, /=8.8 Hz) , 7.36 (d,
2H, 7=8.4 Hz) , 7.25 (d, 2H) , 7.14 (s, IH), 6.73 (d, 1H, 7=10.0 Hz), 6.35-6.40 (m, 3H) , 5.72 (m, IH), 4.71 (t, 2H, /=2.0 Hz) , 4.12 (t, 2H), 3.75 (t, 4H), 2.84 (t, 2H), 2.62-2.68 (m, 6H) , 1.36 (s, 9H), 1.22 (t, 3H)。
MS (FAB) m/z: 546.0 [M+l]+。 实施例 52: l-[3-叔丁基 -l-(4-叔丁基苯基) -1^5-吡唑 基]- 3- {8- {5- [2- (4-吗啡啉基)乙氧基] - 2^·色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体 25, 得到标题化合物, 为白色固体。
'E-mU CDC13, 400MHz ) δ: 7.74 (d, 1H, /=9.2 Hz), 7.34 (d, 2H), 7.26 (d, 2H), 7.15 (s, IH) , 6.73 (d, 1H, /-10.0 Hz), 6.43 (s, IH), 6.39 (d, IH, 7=9.2 Hz) , 6.35 (s, IH), 5.72 (m, 1H), 4.71 (t, 2H, /-2.0 Hz), 4.09 (t, 2H, 7=5.2 Hz) , 3.73 (t, 4H), 2.81 (t, 2H), 2.59 (t, 4H), 1.36(s, 9H), 1.24 (d, 3H), 1.22 (d, 3H)。
MS (FAB) m/z: 560.1 [M+l]+ 0 实施例 53: l-[3-叔丁基 - 1-(3-氯 -4-氟苯基)- 吡唑 基] -3- {8- {5- [2- (4-吗啡啉基)乙氧基] 2^色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体 23, 得到标题化合物, 为白色固体。
^-NMR (CDCI3, 400MHz ) δ: 7.60 (m, 2H), 7.38 (m, IH), 7.08-7.14 (m, 3H), 6.72 (d, 1H, /=9.6 Hz) , 6.38 (d, IH, 7=8.8 Hz), 6.35 (s, 1H), 5.72 (m, 1H), 4.70(t, 2H, /=1.6 Hz), 4.10(t 2H, 1=5.2 Hz) , 3.74 (t, 4H, 7=4.4 Hz) , 2.83(t, 2H), 2.61 (t, 4H), 1.34 (s, 9H)。
MS (FAB) m/z: 570.0 [M+l]+ 0 实施例 54: l-[3_叔丁基 -l-(3, 4-二甲基苯基) -1^5-吡唑 基] -3- {8- {5- [2- (4-吗啡啉基)乙氧基] -2 色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体
19, 得到标题化合物, 为白色固体。
^- MR ( CDC13 , 400MHz ) δ: 7.72 (d, 1H, /=8.8 Hz), 7.12-7.21 (m, 4H), 6.72 (d, 1H, /=10.4 Hz), 6.60 (s, IH),
6.38 (d, 1H), 6.34 (s, IH) , 5.70(m, 1H), 4.68 (t, 2H, 7=2.0 Hz), 4.10 (t, 2H, 1=5.6 Hz) , 3.74 (t, 4H, 4.4 Hz) , 2.82 (t, 2H, 7=5.6 Hz), 2.60(t, 4H), 2.23 (s, 3H) , 2.21 (s, 3H) , 1.35 (s 9H)。
MS (FAB) m/z: 546.0 [M+l]+ 0 实施例 55: 1- [3-叔丁基 -l-(3, 4-二氯苯基) -1^"5-吡唑 基] -3- {8- {5- [2 -(4-吗啡啉基)乙氧基] -2^~色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体
20, 得到标题化合物, 为白色固体。
'H-NMR (CDCI3, 400MHz ) δ: 7.67 (s, IH), 7.58 (d, IH),
7.45(s, 1H), 7.38 (m, 2H), 7.23(s, IH), 6.71 (d, 1H, 7=10.0 Hz), 6.36 (d, 1H, 7=9.2 Hz) , 6.35 (s, IH), 5.69 (m, IH), 4.68 (t 2H, 7=1.6 Hz), 4.10 (t, 2H, 7=5.6 Hz) , 3.73 (t, 4H, 7=4.8 Hz) , 2.82 (t, 2H, /=5.2 Hz), 2.60(t, 4H) , 1.34 (s, 9H)。
MS (FAB) m/z: 586.0 [M+l]+。 实施例 56: 1- (3-叔丁基 - 5-异噁唑基) -3- {8 - {5- [2-(4-吗啡啉基) 乙氧基] -2 色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体 28, 得到标题化合物, 为白色固体。
JH-NMR (CDC 13, 400MHz ) δ: 9.27 (s, 1H), 7.74 (d, IH, 7=8.8 Hz), 7.40 (s, IH), 6.67(d, 1H, 7=10.0 Hz), 6.37 (d, 1H, 7=9.2 Hz), 6.13(s, IH), 5.63(m, IH), 4.62 (t, 2H, 7=1.6 Hz), 4.10(t, 2H, 7=5.6 Hz) , 3.77 (t, 4H, 7=4.4 Hz) , 2.83(t, 2H, 7=5.2 Hz) , 2.69 (t, 4H), 1.30(s, 9H)。
MS (FAB) m/z: 443.0 [M+l]+。 实施例 57: 1- (5-叔丁基 -3-异嚙唑基) -3- {8- {5- [2- (4-吗啡啉基) 乙氧基] -2^色烯基 }}脲
釆用实施例 36的制备方法,将其中的中间体 11改为 3-氨基 -5 -叔丁基异喁唑, 得到标题化合物, 为白色固体。
'H-NMR (CDCls, 400MHz ) δ: 8.77 (s, IH), 8.27 (s, IH), 7.86 (d, 1H, /=8.8 Hz) , 6.75 (d, 1H, 7=10.0 Hz), 6.42 (d, IH, /=9.6 Hz), 6.02(s, 1H), 5.76 (m, IH), 4.84 (t, 2H, /-2.0 Hz), 4.12 (t, 2H, 1=6.8 Hz) , 3.76 (t, 4H) , 2.84 (t, 2H), 2.62 (t, 4H), 1.36 (s, 9H)。
MS (FAB) m/z: 443.0 [M+l]+ 0 实施例 58 : 1- [ 叔丁基 -3-(4-曱基苯基) -1^4-吡唑 基] -3- {8- {5- U- (4-吗啡啉基)乙氧基] -2^~色烯基 H脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体 33, 得到标题化合物, 为白色固体。
ιΕ-ΜΠ CDC13, 400MHz ) δ: 7.67-7.70 (m, 2Η) , 7.18-7.20 (m, 4Η), 6.73 (d, IH, 7=10.0 Hz), 6.68 (s, 1H), 6.36 (d, 1H, 7=9.2 Hz), 5.72(m, IH), 5.49 (s, 1H), 4.71 (t, 2H, 1=2.0 Hz) , 4.11 (t,
2H), 3.76 (t, 4H), 2.83(t, 2H), 2.62 (t, 4H), 2.39 (s, 3H),
1.46 (s, 9H)。
MS (FAB) m/z: 532.1 [M+l]+。 实施例 59 : 1 - [3-叔丁基 - 1-(3-甲基苯基) -l 5-吡唑 基] - 3- {8- {5- [2- (4-吗啡啉基)乙氧基] -2^色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体
21, 得到标题化合物, 为白色固体。
'H-NMR ( CDCls, 400MHz ) δ: 7.22 (d, 1H, 7=8.8 Hz), 7.26-7.29 (m, 3H), 7.15(d, 2H), 6.73 (d, 1H, 7=10.0 Hz), 6.58 (s, 1H), 6.38 (d, 1H, 7=9.6 Hz), 6.36 (s, 1H), 5.72 (m, 1H), 4.71(t, 2H, /=1.6Hz), 4.12 (t, 2H) , 3.76 (t, 4H) , 2.84(t 2H), 2.63(t, 4H), 2.36 (s, 3H) , 1.36 (s, 9H)。
MS (FAB) m/z: 532.1 [ +l]+ 0 实 施 例 60 : 1-[(3- 叔 丁 基 -1- 萘 基 )- 1^5- 吡 唑 基] -3- {8- {5- [2- (4-吗啡啉基)乙氧基] - 2^色烯基 }}脲
采用实施例 36的制备方法, 将其中的中间体 11改为中间体
22, 得到标题化合物, 为白色固体。
^一履 R( CDCI3, 400MHz ) 5: 7.88-7.90 (m, 2H) , 7.48-7.50 (m: 5Η), 7.38 (d, 1Η), 6.95 (s, 1Η), 6.68(d, 1H, /=10.0 Hz), 6.48(s, 1H), 6.24-6.27 (m, 2H) , 5.67 (m, 1H), 4.63(t, 2H, /-1.6 Hz), 4.07 (t, 2H, 7=5.2 Hz), 3.75 (t, 4H, 7=4.4 Hz),
2.82 (t, 2H), 2.61 (t, 4H), 1.40(s, 9H)。
MS (FAB) m/z: 568.1 [M+l]+„ 实施例 61 : l-[4-叔丁基 -1- (4-甲基苯基)- 1^~2-咪唑
基] -3- {8 - {5- [2- (4-吗啡啉基)乙氧基] - 2^·色烯基 } }脲 采用实施例 36的制备方法, 将其中的中间体 11改为中间体 35, 得到标题化合物, 为白色固体。
'H-NMR ( CDC13 , 400MHz ) δ: 8.03 (d, IH, /=9.2 Hz), 7.26-7.30 (m, 5H), 6.78(d, 1H, 7=10.0 Hz), 6.44 (s, IH), 6.41(d, IH, 1=9.2 Hz) , 5.77 (m, IH) , 4.88 (t, 2H), 4.13(t, 2H, /-6.8 Hz), 3.76 (t, 4H), 2.84 (t, 2H) , 2.62 (t, 4H) , 2.42 (s 3H), 1.34 (s, 9H)。
MS (FAB) m/z: 532.4 [M+l]+ 0 实施例 62 : l-[3-叔丁基 - 1-(4-甲基苯基)- 1H-5-吡唑 基]- 3-{8- {5- {2- [4 -(顺式 - 2, 6 -二甲基)吗啡啉基]乙氧基 } -li 色烯基 }}脲
釆用实施例 36的制备方法, 将其中的中间体 50改为中间体 66, 得到标题化合物, 为白色固体。
JH-NMR (CDC13, 400MHz ) δ: 7.74 (d, IH, 7=9.2 Hz) , 7.33 (d, 2H, /-8.0 Hz), 7.22 (d, 2H), 7.14 (s, IH), 6.74 (d, IH, 7=10.0 Hz), 6.45(s, IH), 6.39 (d, 1H, /=9.2 Hz) , 6.35 (s, IH), 5.72 (m: IH), 4.71(t, 2H, 7=1.6 Hz), 4.12 (t, 2H, 7=4.0 Hz), 3.74 (m, 2H), 2.83(m, 4H) , 2.36 (s, 3H) , 1.94 (m, 2H) , 1.36 (s, 9H), 1.17 (d, 3H), 1.16 (d, 3H)。
S (FAB) m/z: 532.4 [M+l]+。
Claims
1. 通式 I化合物, 其可药用盐或溶剂化物,
I
其中:
入^为^- 。芳香碳环或 C3- 。饱和或不饱和的非芳香碳环; C -C。芳香杂环, 包括一到多个选自 0, N, S的杂原子; 或者 C5-C8 的单杂环或者 C8- 的双杂环, 包括一到多个选自 0, N, S的杂原 子; 所述 A 独立并选择性地被一到多个 112所取代;
Ar2为苯并五元或六元杂环。 当为五元杂环时, 环上包括 1-3 个选自 0, N, S的杂原子; 当为六元杂环时, 环上有一个选自 0, S 的杂原子或 2-4个选自 0, N, S的杂原子; 所述 Ar2可选择性被 1-4 个选自下面的取代基取代: C!-C^直链或支链烷基, C2-Cfi直链或支 链烯基, d- 直链或支链烷氧基, C2-C6直链或支链烯氧基, 三氟 曱基, 三氟甲氧基, 乙酰基, 芳酰基, 鹵素, 甲氧叛基, 乙氧羰 基, 苯磺酰基, 羟基, 氨基, 单或双 d- C4烷基取代的氨基, 单或 双(^-(:4烷基取代的氨基磺酰基, 腈基, 硝基, 氨基磺酰基;
L独立的为
( 1 )键;
( 2 ) d-Ci。饱和或不饱和的, 直链或支链碳链; 其中的一到多 个亚甲基独立并选择性被 0, NH, S ( 0 ) a或者 0-2个羰基所替代; 并且所述联接基团可选择性被一到多个卤原子取代;
m为 0, 1或 2;
P为咪唑基, 噁唑基, 异喁唑基, 噻唑基, 异噻唑基, 吡咯基, 苯并咪唑基, 呋喃基, 噻吩基, 吡喃基, 萘啶基, 哌嗪基, 吡唑 基, 噻 基, 嘌呤基, 吡唑并 [3, 4-b]嘧啶基, 吡咯并 [2 , 3 - b〗 吡啶基,吡咯并 [3, 4-b]吡啶基, 1, 3-氧氮杂并 [4 , 5-b]吡啶基, 1 , 2, 3-三氮唑基, 1 , 2, 4-三氮唑基, 四氮唑基, 四氢吡喃基, 四氢呋喃基, 二氢萘基, 四氢萘基, 二氢奎啉基, 四氢喹啉基, 二氢异喹啉基, 四氢异喹啉基, 1 , 3-二氧环戊酮基, 1 , 3-二氧 环己酮基, 1, 4-二氧六环基, 吗啉基, 硫代吗啉基, 亚砜代吗啉 基, 砜代吗啉基, 哌啶基, 哌啶酮基, 哌啶醇基, 四氢嘧啶酮基, 环己酮基, 环己醇基, 硫杂己环基, 五亚甲基亚砜基, 五亚甲基 砜基, 四氢噻吩基, 四亚甲基亚砜基, 四亚甲基砜基; 所述基团 可任选被 1-3个选自下面的取代基取代: d- C6直链或支链烷基, C2-C6直链或支链烯基, d- 直链或支链烷氧基, C2-C6直链或支链 烯氧基, 三氟甲基, 三氟甲氧基, 乙酰基, 芳酰基, 卤素, 苯磺 酰基, 羟基, 氨基, 单或双 d- C4¾基取代的氨基, 单或双 (;广 烷 基取代的氨基酰基, d- 烷氧羰基, d-C5酰氧基, 单或双 C广 (:4烷 基取代的氨基磺酰基, 腈基, 硝基, 氨基磺酰基;
R1独立的为
( 6 ) d- 。直链或支链烷基, 所述烷基可部分或全部被卤 代,并且可选择性被 1-3个苯基,萘基或以下的杂环取代:喹啉基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪基, 哌嗪基, 吡咯基, 咪唑基, 吡唑基, 呋喃基, 噻吩基, 异喁唑基, 异噻唑基; 上述苯基, 萘 基或杂环可被 0-5个下述基团取代: 卤素, (;广 直链或支链烷基, 0;3-( 8环烷基, C5-C^、烯基, 羟基, 腈基, C6直链或支链垸氧基, 三氟甲基, 三氟甲氧基, 氨基羰基, 双 (广 烷基取代的氨基羰基;
( 7 ) Cr^。环烷基或环烯基, 所述基团可部分或全部被卤
代, 或选择性被 1-3个(^-(^烷基或 d-Cs烷氧基取代; 上述的环烷 基或环烯基的卜 3个亚甲基可选择性被 0, NH, S, SO, S02, 藏基, 羟甲基替代;上迷环烷基或环烯基可独立的选择性被 0-5个以下基 团取代: 卤素, d-Ce直链或支链烷基, (广 直链或支链垸氧基;
( 8 ) ( -C,。直链或支链烯基, 所述垸基可部分或全部被卤 代, 并且可选择性被 1- 3个(^-(^直链或支链烷基, 苯基, 萘基或以 下的杂环取代: 喹啉基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪基, 哌嗪基, 吡咯基, 咪唑基, 吡唑基, 呋喃基, 噻吩基, 异喁唑基, 异噻唑基;上述苯基,萘基或杂环可被 0-5个下述基团取代: 卤素, C Ce直链或支链烷基, C3- 。环烷基, C广 (^环烯基, 羟基, 腈基, d-C6直链或支链烷氧基, 三氟甲基, 三氟甲氧基, 氨基羰基, 双 d-O^基取代的氨基羰基;
( 9 ) 卤素, 硝基, 羧基, 羟基, 腈基, 三氟甲基, 三氟甲 氧基;
( 10 ) NH2-, R3NH~, R3 2N -, R3NCO-R3CONH-, R3C00-, R30C0 -, R3S (0) m, R3S (0) mNH, R3NHS (0) - ;
R2独立的为
( 5 ) 芳环, 芳杂环基或稠合芳环, 包括苯基, 萘基, 喹啉 基, 异喹啉基, 吡啶基, 嘧啶基, 哒嗪基, 咪唑基, 喁唑基, 异 喁唑基, 噻唑基, 异噻唑基, 吡咯基, 呋喃基, 噻哈基, 吡喃基, 萘啶基, 哌嗪基, 吡唑基, 噻唑基, 嘌呤基, 吲哚基, 苯并咪唑 基, 苯并呋喃基, 苯并吡唑基, 苯并噻吩基, 苯并喁唑基, 苯并 异喁峻基, 苯并噻唑基, 苯并异噻唑基, 吡唑并 [3, 4-b]嘧啶基, 吡咯并 [2, 3-b]吡啶基, 吡咯并 [3, 4-b]吡啶基, 1, 3-氧氮杂并 [4, 5 - b]吡啶基, 1 , 2, 3-三氮唑基, 1, 2 , 4-三氮唑基, 四氮 唑基, 四氢吡喃基, 四氢呋喃基, 二氢萘基, 四氢萘基, 二氢喹 啉基, 四氢喹啉基, 二氢异喹啉基, 四氢异喹啉基, 苯并环丁基,
茚基, 茚烯基。 上述芳环, 芳杂环或稠合芳环基可独立的被 0-5 个 R4基团取代;
( 6 ) C Ci。环烷基或环烯基, 所述基团可部分或全部被卤 代, 或选择性被 1- 3个(^- C6烷基或 (^- 6烷 基取代;
( 7 ) d- 。直链或支链烷基, 所述烷基可部分或全部被卤 代;
( 8 ) NH -, R3NH-, R3 2N-, R3NCO-R3CONH-, R3C00- , R30C0 -, R3S (0) m, R3S (0) BNH, R3NHS (0) - ;
R3独立的为
氢原子, d- C6直链或支链烷基, d- c6直链或支链烯基, 苯基, 萘基, 单或双 -0;4烷基氨基 d-Cs烷基; m为 0, 1或 2;
R4独立的为
c) 卤素, 硝基, 羧基, d-C6直链或支链烷基, d-C6直链或 支链烯基, CH^。环烷基, 05-(:8环烯基, 羟基, 腈基, Cf~C6直链或 支链垸氧基, 三氟甲基, 三氟甲氧基;
NH2-, R3NH-, R3 2N -, R3NC0 - R3C0NH -, R3C00 -, R30C0-, R3S (0) a, R3S (0) mNH, R3NHS (0) m -。
2. 权利要求 1的化合物, 其中:
!^为苯基, 吡唑基, 咪唑基, 喁唑基, 异喁唑基, 噻唑基, 异噻唑基, 吡咯基, 苯并咪唾基, 呋喃基, 噻吩基, 吡喃基, 萘 基, 噻唑基, 嘌呤基, 喹啉基, 嘧啶基。
3. 权利要求 2的化合物, 其中:
Ar2为苯并吡喃基, 苯并二氢吡喃基, 苯并吡喃酮基, 苯并哒 嗪基, 苯并嘧啶基, 苯并吡嗪基, 苯并哌啶基, 苯并噻唑基, 苯 并噁唑基, 苯并异喁唑基, 苯并吡唑基, 苯并异噻唑基, 苯并三
氮唑基, 1, 3 苯并间二氧杂环基。
4. 权利要求 3的化合物, 其中:
L独立的为
( 2 ) d- C4饱和或不饱和的, 直链或支链碳链; 其中的一到多 个亚甲基独立的被 0, NH, S ( 0 ) ra或者 0-2个羰基所替代; 并且所 述联接基团可被一到多个卤原子取代; m为 0, 1或 2。
5. 权利要求 1-4任一项的化合物, 其选自:
1 - [3-叔丁基 -1- (4 -甲基苯基) -1H-5-吡唑基] -3- [8- (3, 4 -二 氢- 5-甲氧基 -2 色烯基)〗脲
1- [3-叔丁基 -1- (4-氯苯基) -1 5-吡唑基] -3- [8 (5-甲氧基
- 2 色烯基)]脲
1- [3-叔丁基 - 1- (4 -甲基苯基) - 1H- 5 -吡唑基] -3- [8- (5-甲氧 基 -2^色烯基)〗脲
1- [3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑基] -3- {5- {8- [2- (4_吗啡啉基)乙酰氨基] - 2 色烯基 脲
1 - [3-叔丁基 -1 -苯基 -1^·5-吡唑基] -3- [8- (3 , 4-二氢 -5-甲 氧基 -2 色烯基)]脲
1 - [3-叔丁基 -1- (4 甲基苯基) -1H- 5-吡唑基] -3- {8- {3, 4 -二 氢- 5- [2- (4-吗啡啉基)乙氧基] -2^色烯基 } }脲
1- [3-叔丁基 -1- (4-甲基苯基) -1Η-5-吡唑基〗 -3- [8- (5-硝基
- 2^ "色烯基)]脲
1 - [3-叔丁基 -1-苯基 -1^5-吡唑基 ] -3- {8- {3 , 4-二氢 -5- [2- (4-吗啡啉基)乙氧基] -2^色烯基 } }脲
1- [3-叔丁基 -1- (4 -氟苯基) -li?~5-吡唑基] -3- {8- {3, 4-二氢
一 5_[2-(4—吗啡啉基)乙氧基] -2^色烯基 }}脲
1- [3-叔丁基 -1- (4-氯苯基) -1^·5-吡唑基] -3- {8- {3, 4-二氢 -5- [2- (4-吗啡啉基)乙氧基] -2^·色烯基 }}脲
1- [3-叔丁基 -1- (4-溴苯基) -1^5 -吡唑基] -3- {8- {3, 4 -二氢 -5-〖2 - (4-吗啡啉基)乙氧基] -2^色烯基 }}脲
1- [3-叔丁基 -1- (4-甲氧基苯基) - 1^·5-吡唑基] -3- {8- {3, 4 - 二氢 -5- [2- (4-吗啡啉基)乙氧基] -2^·色烯基 }}脲
1-[3-叔丁基 - 1-(4-氨基磺酰基苯基)-1 5-吡唑 基] -3-{8-{3, 4-二氢 -5- [2- (4-吗啡啉基)乙氧基] -2^·色烯基 }} 脲
1 - [3-叔丁基 - 1- (4-硝基苯基) -1^"5-吡唑基] -3- {8- {3, 4-二 氢 -5 -〖2- (4-吗啡啉基)乙氧基] 色烯基 }}脲
1- [3-叔丁基 - 1- (4-甲基苯基) -1H-5-吡唑基〗 -3- {8-[3, 4 -二 氢一 5- (4-吗啡啉基酰基甲氧基) -2^·色烯基] }脲
1 -(3-叔丁基 -5-异喁唑基) -3- {8- {3, 4-二氢 -5- [2- (4-吗啡 啉基)乙氧基] -2^~色烯基 }}脲
1- (5 -叔丁基- 3-异噁唑基) -3- {8- {3 , 4 -二氢 -5 - [2- (4-吗啡 啉基)乙氧基] -2^"色烯基 脲
1 - [1 -叔丁基- 3- (4-甲基苯基) -1^·4-吡唑基〗 -3- {8- {3, 4 -二 氢一 5— [2一(4一吗啡啉基)乙氧基〗 -2^色烯基 }}脲
1- [4-叔丁基 -1- (4-甲基苯基) -l?"2 -咪唑基] -3- {8- {3, 4-二 氢一 5一〖2一(4一吗啡啉基)乙氧基] -2 色烯基 }}脲
1- [3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑基] -3- {8- {3, 4-二 氢 -5- [2- (4-吡啶基)氧基乙氧基〗 -2^·色烯基 脲
' 1- [3 -叔丁基- 1-(4-甲基苯基) -1H-5-吡唑基] - 3-{8-{3, 4-二 氢一 5— {2一[4— (顺式一2, 6-二甲基) 吗啡啉基〗乙氧基 } -2^"色烯 基 "脲
1- [3-叔丁基- 1- (4-甲基苯基) - 1H-5-吡唑基] -3- {8- {3, 4-二 氢 -5-U-(l-咪唑基)乙氧基] -2^色烯基 }}脲
1- [3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑基〗 -3- {8- {3, 4 -二 氢 -5 - [2-(1-1, 2, 4 -三氮唑基)乙氧基] - 2 色烯基 }}脲
1- [3-叔丁基 -1- (4-氯苯基) -1^5-吡唑基] -3- {8- {3, 4-二氢 -5- {2- [4- (顺式 -2, 6-二甲基)吗啡啉基]乙氧基 } -2^色烯基 }} 脲
1- [3-叔丁基 -1- (3, 4-二甲基苯基) -1^5-吡唑基] -3- {8- {3, 4 -二氢 -5- [2- (4-吗啡啉基)乙氧基] -2^色烯基 }}脲
1- [3-叔丁基 -1- (3, 4-二氯苯基) - 1^5-吡唑基] -3 - {8- {3, 4 -二氢 -5-〖2- (4-吗啡啉基)乙氧基] -2^色烯基 }}脲
1- [3 -叔丁基- 1- (3-甲基苯基) -1^5-吡唑基] -3- {8- {3, 4-二 氢 -5- [2- (4-吗啡啉基)乙氧基] - 2 色烯基 }}脲
1 - [ (3-叔丁基 -1-萘基) -1 5-吡唑基] -3- {8- {3, 4-二氢 -5-[2-(4-吗啡啉基)乙氧基] -2^"色烯基 }}脲
1- [3-叔丁基 -1-(4-甲基苯基) -1H-5 -吡唑基] -3- {8- {3, 4-二 氢- 5- [2- (1-吡唑基)乙氧基] -2^·色烯基 }}脲
1- [3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑基] -3- {8- {3, 4-二 氳- 5- [2- (1-哌啶 -4-酮基)乙氧基] - 2 色烯基 }}脲
1- [3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑基] -3- {8- {3, 4 -二 氢 -5-[2- (4-吗啡啉基)乙酰氨基] -2¥"色烯基 }}脲
1- [3-叔丁基 -1- (4-三氟甲基苯基) -1^-5-吡唑基] -3- {8- {3, 4-二氢 -5- [2- (4-吗啡啉基)乙氧基〗 -2^色烯基 }}脲
1-[3-叔丁基 -1-(4-乙基苯基) -1^5-吡唑基 ]-3- {8-{3, 4 -二 氢- 5- [2- (4-吗啡啉基)乙氧基] -2^·色烯基 }}脲 -
1- [ 3-叔丁基 -1- (4-叔丁基苯基) -1 ^"5-吡唑基] -3- {8- {3 , 4- 二氢- 5- [2- (4-吗啡啉基)乙氧基] -2^色烯基 }}脲
1- [3 -叔丁基" 4- (4-三氟甲基苯基) -1^-5 -吡唑基] -3- {8- {3 , 4-二氢- 5- [2- (1-咪唑基)乙氧基] - 2^色烯基 } }脲
1- [3- 叔 丁 基 -1- (4- 甲 基 苯 基 )- 1H-5 - 吡 唑 基] 3 - {8- {5 - [2- (4-吗啡啉基)乙氧基] 色烯基 H脲
1 - [3-叔丁基 -1- (4 -甲基苯基) - 1H-5 -吡唑基] -3- {8- {3, 4 -二 氢- 5- [2- (4-吡啶基)乙氧基] 色烯基 } }脲
1- [3 -叔丁基- 1- (4 腈基苯基) -1^-'5-吡唑基] -3- {8- {3 , 4-二 氢- 5- [2- (4-吗啡啉基)乙氧基] - 2 色烯基 } }脲
1- [3-叔丁基 -1- (3 -氯- 4-氟苯基) -1 5 -吡唑基] -3- {8- {3, 4-二氢- 5- [2 -(4-吗啡啉基)乙氧基] -2^色烯基 } }脲
1- [3-叔丁基- 1- (4-甲基苯基) -1H-5-吡唑基] -3- {8- {5- [ (4 - 甲氧基苯基)甲氧基] - 色烯基 } }脲
1- [3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑基] - 3- {8- [5- (4- 吗啡啉基酰基甲氧基) -2 ^色烯基] }脲
1- [3-叔丁基 - 1- (4-氟苯基) - li¥~5-吡唑基 ] -3- {8- {5- [2- (4- 吗啡啉基)乙氧基] - 2^色烯基 } }脲
1- [3 -叔丁基- 1-(4-氯苯基) -1^5 -吡唑基] - 3- {8- {5- [2- (4- 吗啡啉基)乙氧基〗 -2^色烯基 脲
1- [3-叔丁基 -1- (4-溴苯基) -1^5-吡唑基] -3- {8- {5- [2- (4- 吗啡啉基)乙氧基] -2^·色烯基 } }脲
1 -( 3-叔丁基 1-苯基 -1^5-吡唑基) -3- {8- {5- [2- (4-吗啡 啉基)乙氧基] -2 色烯基 } }脲
1- [3- 叔 丁 基 - 1- (4- 甲 氧 基 苯 基 )-1 5- 吡 唑 基] -3- {8- {5- [2 -(4-吗啡啉基)乙氧基] 2^色烯基 } }脲
1- [3-叔'丁 基 -1- (4-三 氟 甲 基 苯基 -1 & ·5- 吡 唑 ] -3- {8- { [2- (4-吗啡啉基)乙氧基] -2 ?"色烯基 } }脲
1 - [3- 叔 丁 基 -1- (4- 硝 基 苯 基 )-1^5- 吡 唑
基] -3- {8- {5- [2- (4-吗啡啉基)乙氧基] - 2 色烯基} }脲
1-[3- 叔 丁 基 - 1- (4- 腈 基 苯 基 )- 1 5- 吡 唑 基] -3- {8- {5- [2- (4-吗啡啉基)乙氧基] - 2^色烯基 }}脲
1-C3- 叔 丁 基 - 1-(4- 甲 基 苯 基 )-1Η-5- 吡 唑 基] -3- {8- {5- [2- (1-1, 2, 4 -三氮唑基)乙氧基 ]- 色烯基 }}脲
1-[3- 叔 丁 基 -1-(4- 乙 基 苯 基 )-1^~5- 吡 唑 基 ]-3- {8- {5- [2- (4-吗啡啉基)乙氧基] -2^色烯基 }}脲
1-[3- 叔 丁 基 -1- (4- 叔 丁 基 苯 基 )-1^5- 吡 唑 基] 3- {8- {5- [2 -(4-吗啡啉基)乙氧基] -2 色烯基 }}脲
1-[3- 叔 丁 基 -1- (3- 氯 -4- 氟 苯 基 )- 1^~5- 吡 唑 基] -3- {8- {5- [2- (4-吗啡啉基)乙氧基] 2^·色烯基 } }脲
1-[3-叔丁基 -1-(3 , 4-二 甲 基苯基)-1^5-吡唑 基]- 3- {8- {5- [2- (4-吗啡啉基)乙氧基〗 -2 色烯基 }}脲
1- [3-叔 丁 基 -1-(3 , 4- 二 氯 苯 基 )-1^5- 吡 唑 基]- 3-{8- {5-[2-(4-吗啡啉基)乙氧基] - 2 色烯基 }}脲
1 -(3-叔丁基 -5-异喁唑基) -3- {8- {5- [2 (4-吗啡啉基)乙氧 基] - 2 色烯基 }}脲
1- (5-叔丁基 -3-异噁唑基) -3- {8- {5- [2- (4 -吗啡啉基)乙氧 基] - 2^色烯基 }}脲
叔 丁 基 -3- (4- 甲 基 苯 基 )-li¾M- 吡 唑 基] -3 - {8-{5 - [2-(4 -吗啡啉基)乙氧基] -2^色烯基 }}脲
1-[3- 叔 丁 基 -1- (3- 甲 基 苯 基 )- 1^~5- 吡 唑 基]-3-{8-{5-[2-(4-吗啡啉基)乙氧基] - 2^色烯基 }}脲
1- [ (3-叔丁基 -1-萘基) -1^-5-吡唑基] -3- {8- {5- [2- (4-吗啡 啉基)乙氧基] -25~色烯基 }}脲
1-E4- 叔 丁 基 -1- (4- 甲 基 苯 基 )-1^~2- 咪 唑 基]-3-{8-{5-[2_(4-吗啡啉基)乙氧基] - 2^色烯基 H脲
l-[3- 叔 丁 基 - 1-(4- 甲 基 苯 基 )-1Η 5- 吡 唑 基]-3-{8-{5-{2-[4-(顺式-2,6-二甲基)吗啡淋基〗乙氧基 } -2ff- 色烯基 }}脲
以及其可药用 Jk或溶剂化物。
6. 制备权利要求 1-5任一项所述化合物的方法, 该方法包括 下式的化合物: o
Ar1 H"^OR6
(A)
与 P- L-Ar 2-冊2在合适的溶剂, 合适的碱中于 100°C反应 1 小时到 120小时得到式 I的化合物, 其中, Α^Α^,Ι^Ρ的定义同通 式 I, Rfi为三氯甲基, 对硝基苯基, 乙氧基, 咪唑基, 三唑基等。
7. 权利要求 6所述的方法, 其中所迷式(A)化合物制备如下: 使下式的化合物:
X o
ReO^OR6
与 ΑΓιΝΗ2在合适的溶剂,合适的碱中于- 15 -25 Ό反应 10分钟 到 24小时得到式(A)的化合物, 其中, A 的定义同通式 I, R6为三 氯甲基, 对硝基苯基, 乙氧基, 咪唑基, 三唑基等。
(B)
与 ΑΓιΝΗ2在合适的溶剂,合适的碱中于 反应 1小时到 120小时得到式 I的化合物, 其中, ^ ^^,?的定义同通式^ R6 为三氯甲基, 对硝基苯基, 乙氧基, 咪唑基, 三唑基等。
与 P- L-Ar2-冊2在合适的溶剂, 合适的碱中于" -15 Ό -25 °C反应 10分钟到 24小时得到式(B)的化合物。 其中, Ar2, L,P的定义同通 式 I, R6为三氯甲基, 对硝基苯基, 乙氧基, 咪唑基, 三唑基等。
10. 药用组合物, 其含有权利要求 1 - 5中任一项的化合物, 其 可药用盐或溶剂化物以及至少一种药学上可接受的载体、 稀释剂 或赋形剂。
11. 权利要求 1-5 中任一项的化合物用于制备治疗细胞因子 ( TNF- α , IL- 1等)介导的疾病,危险因子或病症的药物的用途。
12. 权利要求 8的用途, 其中所述疾病、危险因子或病症为牛皮 癣性关节炎, 莱特尔氏综合征, 痛风, 外伤性关节炎, 风疹性关 节炎, 急性滑膜炎, 类风湿性关节炎, 类风湿性脊推炎, 骨关节 炎, 痛风性关节炎及其它关节病, 败血症, 脓毒性休克, 内毒素 性休克, 革兰氏阴性, 败血症, 中毒性休克综合征, 脑型疟, 脑
膜炎,局部缺血性中风和出血性中风,神经外伤 /闭合性颅脑损伤, 哮喘, 成人呼吸窘迫综合症, 慢性肺炎, 慢性阻塞性肺病, 矽肺, 肺肉瘤病, 骨吸收病, 骨质疏松, 再狭窄, 心脏及脑和肾再灌注 损伤, 充血性心力衰竭, 冠状动脉旁路搭桥 (CABG)术, 血检形成, 肾小球性肾炎, 慢性肾衰竭, 糖尿病, 糖尿病性视网膜病, 黄斑 变性, 移植物抗宿主反应, 同种移植物排斥, 炎性肠疾病, 节段 性回肠炎, 溃疡性结肠炎神经变性疾病, 肌肉退化, 糖尿病性视 网膜病, 黄斑变性, 肿瘤生长和转移, 血管生成疾病, 流感引起 的肺炎, 湿疹, 接触性皮炎, 牛皮癣, 晒伤或结膜炎等。
13. 权利要求 1 一 5中任一项的化合物用于制备抑制 ρ38蛋白 激酶药物的用途。
14. 治疗或预防细胞因子 (TNF- a , IL-1等)介导的疾病、 危 险因子或病症的方法,包括给予有此需要的对象治疗有效量的权 利要求 1-5中任一项的本发明化合物。
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CN107652193A (zh) * | 2017-10-20 | 2018-02-02 | 荆楚理工学院 | 一种2‑氨基对甲苯乙酮盐酸盐的生产方法 |
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