CN101636397B - Urea compounds, preparation methods and pharmaceutical uses thereof - Google Patents

Abstract

The urea compounds of formula I, pharmaceutically acceptable salts and solvates, their preparation methods, the pharmaceutical compositions comprising the said compounds and the uses as p38 kinase inhibitors thereof. The substituents are defined as the description.

Description

Urea compound, its preparation method and its medical application

technical field

The present invention relates to urea compounds for inhibiting p38 protein kinase, pharmaceutical compositions containing them, methods for preparing these compounds and their medical application.

Background technique

TNF and IL-1 are central players in many pathological processes associated with chronic inflammatory and autoimmune diseases. IL-1 is involved in mediating or exacerbating diseases such as rheumatoid arthritis (see, Arend, W.P.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. It has been found that excessive or dysregulated TNF production is involved in mediating or exacerbating diseases such as rheumatoid arthritis ((see, Maini, R.N. et al. APMIS.105 (4): 257-263, (1997); Feldmann, M., J .of the Royal College of Physicians ofLondon 30(6):560-570, (1996); Lorenz, H.M. et al. J.ofImmunology 156(4):1646-1653, (1996)), osteoarthritis, spondylitis, pus Toxicity, septic shock ((see, Abraham, E, etc. JAMA.277 (19): 1531-1538, (1997), adult respiratory distress syndrome, asthma ((see, Shah, A. etc. Clin. & Exp.Allergy 1038-1044, (1995) and Lassalle, P. et al. Clin. & Exp.Allergy 94 (1): 105-110, (1993)), bone resorptive disease, fever ((see, Cooper, A.L. et al. Am.J.of Physiology 267(6Pt.2):1431-1436)), encephalomyelitis, demyelination (see, Klindert, W.E. et al. J.of Neuroimmunol.72(2):163-168, (1997 )) and periodontal disease.

Clinical trials of IL-1 and TNF receptor antagonists have shown that blocking the ability of these cytokines to signal through their receptors can significantly improve inflammatory disease in humans. Therefore, modulation of these inflammatory cytokines is considered to be one of the most effective strategies to block chronic inflammation with positive therapeutic effects.

The mitogen-activated protein kinase (MAPK) cascade is the main signal transduction system in the cell, and the extracellular stimulus signal is transmitted to the nucleus through this system, which leads to cell growth, development, division, cytokine secretion and A series of physiological and pathological processes such as malignant transformation.

Most protein kinases in the cell are inactive, and activation of a specific upstream kinase signal causes the kinase to undergo a serine (S), threonine (T) or tyrosine (Y) residue Activated by phosphorylation. Different from other protein kinases, the activation of all MAPK family members requires dual-site phosphorylation of threonine and tyrosine residues, and the dual-site phosphorylation group of MAPK has the structure of Thr-Xaa-Tyr (T-X-Y) Sequence features (see Seger R, Krebs EG. The MAPK singing cascade. FASEB J. 19959: 726-735). The activation and phosphorylation of MAPK passes through a cascade reaction including upstream multilevel kinases, including three key kinases: MAPK, MAPK kinase (MAPK kinase, MAPKK or MEK/MKK), MAPK kinase kinase (MAPK kinase kinase, MAPKKK). MAPKKK phosphorylates the serine and threonine dual sites of MAPKK to activate it; the activated MAPKK further phosphorylates the serine and threonine dual sites of MAPK to activate it. (See Boulton T.G., Nye S.H., Bobbins D.J. et al. Cell 1991, 65:663:675).

The mammalian cell MAPK family includes at least four subfamilies, namely ERK (extracellular regulated protein kinase), JNK (c-JunN-terminal kinase), p38, and ERK5. The different subfamilies are mainly distinguished by differences in Xaa and/or upstream kinases between the dual phosphorylation sites.

Han et al first discovered and cloned a 38kDa MAPK in pre-B cells stimulated by endotoxin lipopolysaccharide (LPS) in 1993. The p38MAPK dual phosphorylation sites are located at tyrosine and threonine at positions 180 and 182. The specific double phosphorylation group of p38MAPK is Thr-Gly-Tyr. Four subtypes of p38MAPK have been found so far: p38α, p38β, p38γ, p3δ. There are about 60% homology between the four isomers, and about 40-45% homology with other MAPKs. The four p38 structures all have a ring-shaped active center containing a TGY tripeptide module , is the specific dual phosphorylation site of the upstream molecule. p38α and p38β widely exist in the human body, p38γ mainly exists in skeletal muscle, and p3δ mainly distributes in lung, kidney, testis, pancreas and small intestine. Different subtypes of p38 are distributed differently in different cells. Unactivated p38 is located in the cytoplasm, and activated p38 can be expressed in both the cytoplasm and the nucleus.

Lee's independent discovery of p38 kinase as a target molecule for a new class of anti-inflammatory agents provided conclusive evidence that p38 kinase is involved in the LPS-stimulated signaling pathway leading to the biosynthesis of pro-inflammatory cytokines [Lee et al. Nature, 372, 739 (1994)]. The discovery of p38 (which Lee named CSBP1 and 2) provided a mechanism of action for a class of anti-inflammatory compounds, of which SK&F 86002 is a prototypical example. These compounds inhibit IL-1 and TNF synthesis [Lee et al., Int.J.Immunopharmac.10 (7), 835 (1988)] in human monocytes in the low μ M concentration range and show activity in animal models, these Animal models are resistant to cyclooxygenase inhibitors [Lee et al., Annals N.Y. Acad. Sci., 696, 10149 (1993)]. It is now believed that CSBP/p38 is one of several kinases involved in the stress response signaling pathway parallel to and largely independent of the similar mitogen-activated protein kinase cascade. Stress response signals, including LPS, proinflammatory cytokines, oxidants, UV rays, and osmotic pressure, activate upstream kinases starting from CSBP/p38, which in turn phosphorylate CSBP/p38 at threonine 180 and tyrosine 182, Leads to activation of CSBP/p38. MAPKAP kinase-2, MAPKAP kinase-3 have been identified as downstream substrates of CSBP/p38, which in turn phosphorylate 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). Although many of the signaling pathways required for cytokine biosynthesis are unknown, it seems clear that many of the aforementioned p38 substrates are involved [Cohen, P. Trends Cell Biol., 353-361 (1997) and Lee, J.C. et al., Pharmacol. Ther .82:389-397, (1999)].

In addition to inhibiting IL-1 and TNF, p38 kinase inhibitors (SK&F86002 and SB203580) also decreased the synthesis of multiple pro-inflammatory proteins including IL-6, IL-8, GM-CSF and COX-2. Inhibitors of CSBP/p38 kinase have also been shown to inhibit TNF-α-induced expression of VCAM-1 on endothelial cells, TNF-α-induced phosphorylation and activation of cytoplasmic PLA2, and IL-1-stimulated collagenase and Synthesis of stromelysin. These and other data suggest that p38 is involved not only in cytokine synthesis but also in cytokine signaling [For a review of CSBP/P38 kinases, see [Cohen, P. Trends Cell Biol., 353-361 (1997)]

Contents of the invention

The purpose of the present invention is to find and develop small molecular compounds with p38MAPK inhibitory activity, which are used to treat cytokine (TNF-α, IL-1, etc.) mediated diseases, risk factors or diseases, such as psoriatic arthritis, Wright Earl's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint diseases, sepsis, Septic shock, endotoxic shock, Gram negative, sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, Adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, silicosis, pulmonary sarcoidosis, bone resorptive disease, osteoporosis, restenosis, cardiac and brain and renal reperfusion injury, congestive heart failure, coronary artery bypass grafting (CABG) surgery, blood test formation, glomerulonephritis, chronic renal failure, diabetes mellitus, diabetic retinopathy, macular degeneration, graft-versus-host reaction, allograft rejection, inflammatory bowel disease, segmental gynecomastia Enteritis, ulcerative colitis neurodegenerative disease, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, pneumonia caused by influenza, eczema, contact dermatitis, psoriasis, sunburn or conjunctivitis, etc.

The present inventors have found that compounds of general formula I can be used for the treatment or prevention of various diseases, risk factors or conditions mediated by cytokines (TNF-α, IL-1, etc.).

Therefore, in one aspect of the present invention, the present invention provides a compound of general formula (I), or a pharmaceutically acceptable salt or solvate thereof,

in:

Ar ₁ is C ₆ -C ₁₀ aromatic carbocycle, including but not limited to benzene ring, substituted benzene ring, cyclooctatetraene, cyclodepentacene, etc.; or C ₃ -C ₁₀ saturated or unsaturated non-aromatic carbocycle, Including but not limited to cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.; C ₅ -C ₁₀ aromatic heterocycles, including one or more selected from O, N , heteroatoms of S, including but not limited to imidazole, pyrazole, thiophene, thiazole, azole, pyrazine, morpholinopyridine, pyrimidine, indole, indazole, quinoline, etc.; or C ₅ -C ₈ monoheterocycle or C ₈ -C ₁₁ biheterocycle, including one or more selected from O , N, S heteroatoms, including but not limited to tetrahydrofuran, tetrahydrothiophene, piperidine, hexahydropyrimidine, octahydroindole, etc.; said Ar ₁ is independently and selectively replaced by one or more R ₁ , R ₂ replaced by

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：C₁-C₆直链或支链烷基，C₂-C₆直链或支链烯基，C₁-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，乙氧羰基，苯磺酰基，羟基，氨基，单或双C₁-C₄烷基取代的氨基，单或双C₁-C₄烷基取代的氨基磺酰基，腈基，硝基，氨基磺酰基；Ar ₂ is a benzo five-membered or six-membered heterocyclic ring. When it is a five-membered heterocyclic ring, the ring includes 1-3 heteroatoms selected from O, N, S, including but not limited to benzofuran, benzothiophene, benzopyrrole, benzopyrazole, benzobis Hydrofuran, benzodihydrothiophene, chromandihydropyrrole, benzodihydropyrazole, benzothiazole, benzodihydrothiazole, etc.; when it is a six-membered heterocyclic ring, there is a ring selected from O, S or 2-4 heteroatoms selected from O, N, S, including but not limited to benzopyran, benzothiopyran, benzopyrimidine, benzo

oxazine, chroman, chroman, benzopiperidine, benzodihydrothiazine, benzomorpholine, etc.; _{the Ar} can be selectively selected from the following 1-4 Substituent substitution: C ₁ -C ₆ straight or branched chain alkyl, C ₂ -C ₆ straight or branched alkenyl, C ₁ -C ₆ straight or branched alkoxy, C ₂ -C ₆ Straight chain or branched alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl, halogen, methoxycarbonyl, ethoxycarbonyl, benzenesulfonyl, hydroxyl, amino, mono or di-C ₁ - C ₄ alkyl substituted amino, mono or double C ₁ -C ₄ alkyl substituted aminosulfonyl, nitrile, nitro, aminosulfonyl;

L is independently

(1) key;

(2) C ₁ -C ₁₀ saturated or unsaturated, straight or branched carbon chain; one or more methylene groups are independently and selectively replaced by O, NH, S(O) _m or 0-2 Carbonyl; and the linking group can be optionally substituted by one or more halogen atoms;

m is 0, 1 or 2;

唑基，异唑基，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，1，2，4-三氨唑基，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：C₁-C₆直链或支链烷基，C₂-C₆直链或支链烯基，C₁-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C₁-C₄烷基取代的氨基，单或双C₁-C₄烷基取代的氨基酰基，C₁-C₄烷氧羰基，C₁-C₅酰氧基，单或双C₁-C₄烷基取代的氨基磺酰基，腈基，硝基，氨基磺酰基；P is phenyl, naphthyl, quinolinyl, isoquinolyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl,

Azolyl, iso Azolyl, thiazolyl, isothiazolyl, pyrrolyl, benzimidazolyl, furyl, thienyl, pyryl, naphthyridinyl, piperazinyl, pyrazolyl, thiazolyl, purinyl, pyrazolo[ 3,4-b]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, 1,3-oxazepine[4,5-b]pyridinyl , 1,2,3-Triazolyl, 1,2,4-Triazolyl, Tetrazolyl, Tetrahydropyranyl, Tetrahydrofuranyl, Dihydronaphthyl, Tetrahydronaphthyl, Dihydroquinoline Linyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 1,3-dioxanonyl, 1,3-dioxanonyl, 1,4-di Oxyhexanyl, morpholinyl, thiomorpholinyl, sulfomorpholinyl, sulfomorpholinyl, piperidinyl, piperidinonyl, piperidinol, tetrahydropyrimidinonyl, cyclohexyl Keto group, cyclohexanol group, thiahexyl group, pentamethylene sulfoxide group, pentamethylene sulfone group, tetrahydrothiophenyl group, tetramethylene sulfoxide group, tetramethylene sulfone group; The above groups may be optionally substituted by 1-3 substituents selected from the group consisting of C ₁ -C ₆ straight chain or branched chain alkyl, C ₂ -C ₆ straight chain or branched chain alkenyl, C ₁ -C ₆ Straight-chain or branched alkoxy, C ₂ -C ₆ straight-chain or branched alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl, halogen, benzenesulfonyl, hydroxyl, amino, Mono or double C ₁ -C ₄ alkyl substituted amino, mono or double C ₁ -C ₄ alkyl substituted aminoacyl, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₅ acyloxy, mono or double C ₁ -C ₄ alkyl substituted aminosulfonyl, nitrile, nitro, aminosulfonyl;

R ¹ is independently

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，C₁-C₆直链或支链烷基，C₃-C₈环烷基，C₅-C₈环烯基，羟基，腈基，C₁-C₆直链或支链烷氧基，三氟甲基，三氟甲氧基，氨基羰基，双C₁-C₄烷基取代的氨基羰基；(1) C ₁ -C ₁₀ straight chain or branched chain alkyl, said alkyl may be partially or fully halogenated, and may be optionally substituted by 1-3 phenyl, naphthyl or the following heterocycles: quinone Linyl, isoquinolyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, iso

Azolyl, isothiazolyl; the above phenyl, naphthyl or heterocycle can be substituted by 0-5 of the following groups: halogen, C ₁ -C ₆ straight chain or branched chain alkyl, C ₃ -C ₈ cycloalkane radical, C ₅ -C ₈ cycloalkenyl, hydroxyl, nitrile, C ₁ -C ₆ straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, bis C ₁ -C ₄ Alkyl-substituted aminocarbonyl;

(2) C ₃ -C ₁₀ cycloalkyl or cycloalkenyl, said group may be partially or fully halogenated, or optionally replaced by 1-3 C ₁ -C ₆ alkyl or C ₁ -C ₆ alkane Oxygen substitution; 1-3 methylene groups of the above-mentioned cycloalkyl or cycloalkenyl can be optionally replaced by O, NH, S, SO, SO ₂ , carbonyl, hydroxymethyl; the above-mentioned cycloalkyl or cycloalkene The group can be independently substituted by 0-5 of the following groups: halogen, C ₁ -C ₆ straight chain or branched chain alkyl, C ₁ -C ₆ straight chain or branched chain alkoxy;

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，C₁-C₆直链或支链烷基，C₃-C₁₀环烷基，C₅-C₈环烯基，羟基，腈基，C₁-C₆直链或支链烷氧基，三氟甲基，三氟甲氧基，氨基羰基，双C₁-C₄烷基取代的氨基羰基；(3) C ₃ -C ₁₀ straight chain or branched chain alkenyl, said alkyl group may be partially or fully halogenated, and may optionally be replaced by 1-3 C ₁ -C ₆ straight chain or branched chain alkyl groups, Phenyl, naphthyl, or a heterocyclic substitution of the following: quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl ,different

Azolyl, isothiazolyl; the above phenyl, naphthyl or heterocycle can be substituted by 0-5 of the following groups: halogen, C ₁ -C ₆ straight chain or branched chain alkyl, C ₃ -C ₁₀ cycloalkane radical, C ₅ -C ₈ cycloalkenyl, hydroxyl, nitrile, C ₁ -C ₆ straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, bis C ₁ -C ₄ Alkyl-substituted aminocarbonyl;

(4) Halogen, nitro, carboxyl, hydroxyl, nitrile, trifluoromethyl, trifluoromethoxy;

(5) NH ₂ -, R ³ NH-, R ³ ₂ N-, R ³ NCO-R ³ CONH-, R ³ COO-, R ³ OCO-, R ³ S(O) _m , R ³ S(O ) _m NH, R ³ NHS(O) _m -;

^R2 is independently

唑基，异唑基，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，苯并唑基，苯并异

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；(1) Aromatic ring, aromatic heterocyclic group or fused aromatic ring, including phenyl, naphthyl, quinolinyl, isoquinolyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl,

Azolyl, iso Azolyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thienyl, pyryl, naphthyridinyl, piperazinyl, pyrazolyl, thiazolyl, purinyl, indolyl, benzimidazolyl, Benzofuryl, Benzopyrazolyl, Benzothienyl, Benzo Azolyl, benziso

Azolyl, benzothiazolyl, benzisothiazolyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl , 1,3-oxaza[4,5-b]pyridyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, tetrahydropyran base, tetrahydrofuranyl, dihydronaphthyl, tetrahydronaphthyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzocyclobutyl, indenyl, Indenyl. The above-mentioned aromatic ring, aromatic heterocyclic ring or fused aromatic ring group can be independently substituted by ^0-5 R groups;

(2) C ₃ -C ₁₀ cycloalkyl or cycloalkenyl, said group may be partially or fully halogenated, or optionally replaced by 1-3 C ₁ -C ₆ alkyl or C ₁ -C ₆ alkane Oxygen substitution;

(3) C ₁ -C ₁₀ straight-chain or branched-chain alkyl, which can be partially or fully halogenated;

(4) NH ₂ -, R ³ NH-, R ³ ₂ N-, R ³ NCO-R ³ CONH-, R ³ COO-, R ³ OCO-, R ³ S(O) _m , R ³ S(O ) _m NH, R ³ NHS(O) _m -;

^R3 independently for

Hydrogen atom, C ₁ -C ₆ straight or branched chain alkyl, C ₁ -C ₆ straight or branched alkenyl, phenyl, naphthyl, mono or double C ₁ -C ₄ alkylamino C ₁ -C ₆ alkyl; m is 0, 1 or 2;

^R4 independently for

a) Halogen, nitro, carboxyl, C ₁ -C ₆ straight chain or branched chain alkyl, C ₁ -C ₆ straight chain or branched chain alkenyl, C ₃ -C ₁₀ cycloalkyl, C ₅ -C ₈ ring Alkenyl, hydroxyl, nitrile, C ₁ -C ₆ straight or branched alkoxy, trifluoromethyl, trifluoromethoxy;

b) NH ₂ -, R ³ NH-, R ³ ₂ N-, R ³ NCO-R ³ CONH-, R ³ COO-, R ³ OCO-, R ³ S(O) _m , R ³ S(O) _m NH, R ³ NHS(O) _m -.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of general formula (I) of the present invention, which contains at least one compound of general formula (I) or a pharmaceutically acceptable salt, solvate thereof, and one or more drugs with carriers or excipients.

In another aspect, the present invention also relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof.

In yet another aspect, the present invention relates to the use of the compound of general formula (I) for the preparation of a medicament for treating and/or preventing diseases or conditions mediated by cytokines (TNF-α, IL-1, etc.).

In yet another aspect, the present invention provides methods for treating and/or preventing cytokine (TNF-α, IL-1, etc.) An effective amount of a compound of the invention. Cytokines (TNF-α, IL-1, etc.) mediated diseases, risk factors or diseases described in the present invention include psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis , acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint diseases, sepsis, septic shock, endotoxic shock, Gram negative, sepsis, Toxic shock syndrome, cerebral malaria, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, silicosis, Pulmonary sarcoidosis, bone resorption disease, osteoporosis, restenosis, heart and brain and kidney reperfusion injury, congestive heart failure, coronary artery bypass graft (CABG), blood test formation, glomerulonephritis, chronic Renal failure, diabetes, diabetic retinopathy, macular degeneration, graft versus host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis neurodegenerative disease, muscle degeneration, diabetic retinopathy disease, macular degeneration, tumor growth and metastasis, angiogenic disease, pneumonia due to influenza, eczema, contact dermatitis,

Psoriasis, sunburn or conjunctivitis etc.

In one embodiment of the present invention, the present invention provides the compound of general formula I, its pharmaceutically acceptable salt or solvate,

in:

唑、吡嗪、吗啉吡啶、嘧啶、吲哚、吲唑、喹啉等；或者C₅-C₈的单杂环或者C₈-C₁₁的双杂环，包括一到多个选自O，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Ar₁独立并选择性地被一到多个R₁，R₂所取代；Ar ₁ is C ₆ -C ₁₀ aromatic carbocycle, including but not limited to benzene ring, substituted benzene ring, cyclooctatetraene, cyclodepentacene, etc.; or C ₃ -C ₁₀ saturated or unsaturated non-aromatic carbocycle, Including but not limited to cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.; C ₅ -C ₁₀ aromatic heterocycles, including one or more selected from O, N , heteroatoms of S, including but not limited to imidazole, pyrazole, thiophene, thiazole,

azole, pyrazine, morpholinopyridine, pyrimidine, indole, indazole, quinoline, etc.; or C ₅ -C ₈ monoheterocycle or C ₈ -C ₁₁ biheterocycle, including one or more selected from O , N, S heteroatoms, including but not limited to tetrahydrofuran, tetrahydrothiophene, piperidine, hexahydropyrimidine, octahydroindole, etc.; said Ar ₁ is independently and selectively replaced by one or more R ₁ , R ₂ replaced by

Ar ₂ is a benzo five-membered or six-membered heterocyclic ring. When it is a five-membered heterocyclic ring, the ring includes 1-3 heteroatoms selected from O, N, S, including but not limited to benzofuran, benzothiophene, benzopyrrole, benzopyrazole, benzobis Hydrofuran, benzodihydrothiophene, chromandihydropyrrole, benzodihydropyrazole, benzothiazole, benzodihydrothiazole, etc.; when it is a six-membered heterocyclic ring, there is a ring selected from O, S or 2-4 heteroatoms selected from O, N, S, including but not limited to benzopyran, benzothiopyran, benzopyrimidine, benzo oxazine, chroman, chroman, benzopiperidine, benzodihydrothiazine, benzomorpholine, etc.; the _Ar can be selectively selected from the following 1-4 Substituent substitution: C ₁ -C ₆ straight or branched chain alkyl, C ₂ -C ₆ straight or branched alkenyl, C ₁ -C ₆ straight or branched alkoxy, C ₂ -C ₆ Straight chain or branched alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl, halogen, methoxycarbonyl, ethoxycarbonyl, benzenesulfonyl, hydroxyl, amino, mono or di-C ₁ - C ₄ alkyl substituted amino, mono or double C ₁ -C ₄ alkyl substituted aminosulfonyl, nitrile, nitro, aminosulfonyl;

L is independently

(1) key;

(2) C ₁ -C ₁₀ saturated or unsaturated, straight or branched carbon chain; one or more methylene groups are independently replaced by O, NH, S(O) _m or 0-2 carbonyl groups and the linking group may be substituted by one or more halogen atoms;

m is 0, 1 or 2;

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：C₁-C₆直链或支链烷基，C₂-C₆直链或支链烯基，C₁-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C₁-C₄烷基取代的氨基，单或双C₁-C₄烷基取代的氨基酰基，C₁-C₄烷氧羰基，C₁-C₅酰氧基，单或双C₁-C₄烷基取代的氨基磺酰基，腈基，硝基，氨基磺酰基；P is phenyl, naphthyl, quinolinyl, isoquinolyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, Azolyl, iso

Azolyl, thiazolyl, isothiazolyl, pyrrolyl, benzimidazolyl, furyl, thienyl, pyryl, naphthyridinyl, piperazinyl, pyrazolyl, thiazolyl, purinyl, pyrazolo[ 3,4-b]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, 1,3-oxazepine[4,5-b]pyridinyl , 1,2,3-Triazolyl, 1,2,4-Triazolyl, Tetrazolyl, Tetrahydropyranyl, Tetrahydrofuranyl, Dihydronaphthyl, Tetrahydronaphthyl, Dihydroquinoline Linyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 1,3-dioxanonyl, 1,3-dioxanonyl, 1,4-di Oxyhexacyclyl, morpholinyl, thiomorpholinyl, sulfomorpholinyl, sulfomorpholinyl, piperidinyl, piperidinonyl, piperidinol, tetrahydropyrimidinonyl, cyclohexyl Keto group, cyclohexanol group, thiahexyl group, pentamethylene sulfoxide group, pentamethylene sulfone group, tetrahydrothiophenyl group, tetramethylene sulfoxide group, tetramethylene sulfone group; The above groups may be optionally substituted by 1-3 substituents selected from the group consisting of C ₁ -C ₆ straight chain or branched chain alkyl, C ₂ -C ₆ straight chain or branched chain alkenyl, C ₁ -C ₆ Straight-chain or branched alkoxy, C ₂ -C ₆ straight-chain or branched alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl, halogen, benzenesulfonyl, hydroxyl, amino, Mono or double C ₁ -C ₄ alkyl substituted amino, mono or double C ₁ -C ₄ alkyl substituted aminoacyl, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₅ acyloxy, mono or double C ₁ -C ₄ alkyl substituted aminosulfonyl, nitrile, nitro, aminosulfonyl;

R ¹ is independently

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，C₁-C₆直链或支链烷基，C₃-C₈环烷基，C₅-C₈环烯基，羟基，腈基，C₁-C₆直链或支链烷氧基，三氟甲基，三氟甲氧基，氨基羰基，双C₁-C₄烷基取代的氨基羰基；(1) C ₁ -C ₁₀ straight-chain or branched-chain alkyl, which may be partially or fully halogenated, and may be substituted by 1-3 phenyl, naphthyl or the following heterocycles: quinolinyl , isoquinolyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, iso

Azolyl, isothiazolyl; the above phenyl, naphthyl or heterocycle can be substituted by 0-5 of the following groups: halogen, C ₁ -C ₆ straight chain or branched chain alkyl, C ₃ -C ₈ cycloalkane radical, C ₅ -C ₈ cycloalkenyl, hydroxyl, nitrile, C ₁ -C ₆ straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, bis C ₁ -C ₄ Alkyl-substituted aminocarbonyl;

(2) C ₃ -C ₁₀ cycloalkyl or cycloalkenyl, said group may be partially or fully halogenated, or 1-3 C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy Substitution; 1-3 methylene groups of the above-mentioned cycloalkyl or cycloalkenyl can be replaced by O, NH, S, SO, SO ₂ , carbonyl, hydroxymethyl; the above-mentioned cycloalkyl or cycloalkenyl can be independently Substituted by 0-5 of the following groups: halogen, C ₁ -C ₆ straight chain or branched chain alkyl, C ₁ -C ₆ straight chain or branched chain alkoxy;

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，C₁-C₆直链或支链烷基，C₃-C₁₀环烷基，C₅-C₈环烯基，羟基，腈基，C₁-C₆直链或支链烷氧基，三氟甲基，三氟甲氧基，氨基羰基，双C₁-C₄烷基取代的氨基羰基；(3) C ₃ -C ₁₀ straight chain or branched chain alkenyl, the alkyl can be partially or fully halogenated, and can be 1-3 C ₁ -C ₆ straight chain or branched chain alkyl, phenyl , naphthyl or the following heterocyclic substitutions: quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, iso

Azolyl, isothiazolyl; the above phenyl, naphthyl or heterocycle can be substituted by 0-5 of the following groups: halogen, C ₁ -C ₆ straight chain or branched chain alkyl, C ₃ -C ₁₀ cycloalkane radical, C ₅ -C ₈ cycloalkenyl, hydroxyl, nitrile, C ₁ -C ₆ straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, bis C ₁ -C ₄ Alkyl-substituted aminocarbonyl;

(4) Halogen, nitro, carboxyl, hydroxyl, nitrile, trifluoromethyl, trifluoromethoxy;

(5) NH ₂ -, R ³ NH-, R ³ ₂ N-, R ³ NCO-R ³ CONH-, R ³ COO-, R ³ OCO-, R ³ S(O) _m , R ³ S(O ) _m NH, R ³ NHS(O) _m -;

^R2 is independently

唑基，异

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

唑基，苯并异

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；(1) benzene ring, aromatic heterocyclic group or fused aromatic ring, including phenyl, naphthyl, quinolinyl, isoquinolyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl,

Azolyl, iso

Azolyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thienyl, pyryl, naphthyridinyl, piperazinyl, pyrazolyl, thiazolyl, purinyl, indolyl, benzimidazolyl, Benzofuryl, Benzopyrazolyl, Benzothienyl, Benzo

Azolyl, benziso

Azolyl, benzothiazolyl, benzisothiazolyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl , 1,3-oxaza[4,5-b]pyridyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, tetrahydropyran base, tetrahydrofuranyl, dihydronaphthyl, tetrahydronaphthyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzocyclobutyl, indenyl, Indenyl. The above-mentioned aromatic ring, aromatic heterocyclic ring or fused aromatic ring group can be independently substituted by ^0-5 R groups;

(2) C ₃ -C ₁₀ cycloalkyl or cycloalkenyl, said group may be partially or fully halogenated, or 1-3 C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy replace;

(3) C ₁ -C ₁₀ straight-chain or branched-chain alkyl, which can be partially or fully halogenated;

(4) NH ₂ -, R ³ NH-, R ³ ₂ N-, R ³ NCO-R ³ CONH-, R ³ COO-, R ³ OCO-, R ³ S(O) _m , R ³ S(O ) _m NH, R ³ NHS(O) _m -;

^R3 independently for

Hydrogen atom, C ₁ -C ₆ straight or branched chain alkyl, C ₁ -C ₆ straight or branched alkenyl, phenyl, naphthyl, mono or double C ₁ -C ₄ alkylamino C ₁ -C ₆ alkyl; m is 0, 1 or 2;

^R4 independently for

a) Halogen, nitro, carboxyl, C ₁ -C ₆ straight chain or branched chain alkyl, C ₁ -C ₆ straight chain or branched chain alkenyl, C ₃ -C ₁₀ cycloalkyl, C ₅ -C ₈ ring Alkenyl, hydroxyl, nitrile, C ₁ -C ₆ straight or branched alkoxy, trifluoromethyl, trifluoromethoxy;

b) NH ₂ -, R ³ NH-, R ³ ₂ N-, R ³ NCO-R ³ CONH-, R ³ COO-, R ³ OCO-, R ³ S(O) _m , R ³ S(O) _m NH, R ³ NHS(O) _m -;

In a preferred embodiment of the present invention, the present invention provides the compound represented by general formula I, its pharmaceutically acceptable salt or solvate,

in:

唑、吡嗪、吗啉吡啶、嘧啶、吲哚、吲唑、喹啉等；或者C₅-C₈的单杂环或者C₈-C₁₁的双杂环，包括一到多个选自O，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Ar₁独立并选择性地被一到多个R₁，R₂所取代；Ar ₁ is C ₆ -C ₁₀ aromatic carbocycle, including but not limited to benzene ring, substituted benzene ring, cyclooctatetraene, cyclodepentacene, etc.; or C ₃ -C ₁₀ saturated or unsaturated non-aromatic carbocycle, Including but not limited to cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.; C ₅ -C ₁₀ aromatic heterocycles, including one or more selected from O, N , heteroatoms of S, including but not limited to imidazole, pyrazole, thiophene, thiazole,

azole, pyrazine, morpholinopyridine, pyrimidine, indole, indazole, quinoline, etc.; or C ₅ -C ₈ monoheterocycle or C ₈ -C ₁₁ biheterocycle, including one or more selected from O , N, S heteroatoms, including but not limited to tetrahydrofuran, tetrahydrothiophene, piperidine, hexahydropyrimidine, octahydroindole, etc.; said Ar ₁ is independently and selectively replaced by one or more R ₁ , R ₂ replaced by

Ar ₂ is chromene or chromanyl; said Ar2 can be substituted by 1-4 substituents selected from the following: C ₁ -C ₆ straight chain or branched chain alkyl, C ₂ -C ₆ straight chain or branched chain alkenyl, C ₁ -C ₆ straight chain or branched chain alkoxy, C ₂ -C ₆ straight chain or branched chain alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl , aroyl, halogen, methoxycarbonyl, ethoxycarbonyl, benzenesulfonyl, hydroxyl, amino, mono- or double C ₁ -C ₄ alkyl substituted amino, mono or double C ₁ -C ₄ alkyl substituted aminosulfonyl Acyl, nitrile, nitro, aminosulfonyl;

L is independently

(1) key;

(2) C ₁ -C ₁₀ saturated or unsaturated, straight or branched carbon chain; one or more methylene groups are independently replaced by O, NH, S(O) _m or 0-2 carbonyl groups and the linking group may be substituted by one or more halogen atoms;

m is 0, 1 or 2;

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：C₁-C₆直链或支链烷基，C₂-C₆直链或支链烯基，C₁-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C₁-C₄烷基取代的氨基，单或双C₁-C₄烷基取代的氨基酰基，C₁-C₄烷氧羰基，C₁-C₅酰氧基，单或双C₁-C₄烷基取代的氨基磺酰基，腈基，硝基，氨基磺酰基；P is phenyl, naphthyl, quinolinyl, isoquinolyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, Azolyl, iso

Azolyl, thiazolyl, isothiazolyl, pyrrolyl, benzimidazolyl, furyl, thienyl, pyryl, naphthyridinyl, piperazinyl, pyrazolyl, thiazolyl, purinyl, pyrazolo[ 3,4-b]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, 1,3-oxazepine[4,5-b]pyridinyl , 1,2,3-Triazolyl, 1,2,4-Triazolyl, Tetrazolyl, Tetrahydropyranyl, Tetrahydrofuranyl, Dihydronaphthyl, Tetrahydronaphthyl, Dihydroquinoline Linyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 1,3-dioxanonyl, 1,3-dioxanonyl, 1,4-di Oxyhexanyl, morpholinyl, thiomorpholinyl, sulfomorpholinyl, sulfomorpholinyl, piperidinyl, piperidinonyl, piperidinol, tetrahydropyrimidinonyl, cyclohexyl Keto group, cyclohexanol group, thiahexyl group, pentamethylene sulfoxide group, pentamethylene sulfone group, tetrahydrothiophenyl group, tetramethylene sulfoxide group, tetramethylene sulfone group; The above groups may be optionally substituted by 1-3 substituents selected from the group consisting of C ₁ -C ₆ straight chain or branched chain alkyl, C ₂ -C ₆ straight chain or branched chain alkenyl, C ₁ -C ₆ Straight-chain or branched alkoxy, C ₂ -C ₆ straight-chain or branched alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl, halogen, benzenesulfonyl, hydroxyl, amino, Mono or double C ₁ -C ₄ alkyl substituted amino, mono or double C ₁ -C ₄ alkyl substituted aminoacyl, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₅ acyloxy, mono or double C ₁ -C ₄ alkyl substituted aminosulfonyl, nitrile, nitro, aminosulfonyl;

R ¹ is independently

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，C₁-C₆直链或支链烷基，C₃-C₈环烷基，C₅-C₈环烯基，羟基，腈基，C₁-C₆直链或支链烷氧基，三氟甲基，三氟甲氧基，氨基羰基，双C₁-C₄烷基取代的氨基羰基；(1) C ₁ -C ₁₀ straight-chain or branched-chain alkyl, which may be partially or fully halogenated, and may be substituted by 1-3 phenyl, naphthyl or the following heterocycles: quinolinyl , isoquinolyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, iso

Azolyl, isothiazolyl; the above phenyl, naphthyl or heterocycle can be substituted by 0-5 of the following groups: halogen, C ₁ -C ₆ straight chain or branched chain alkyl, C ₃ -C ₈ cycloalkane radical, C ₅ -C ₈ cycloalkenyl, hydroxyl, nitrile, C ₁ -C ₆ straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, bis C ₁ -C ₄ Alkyl-substituted aminocarbonyl;

(2) C ₃ -C ₁₀ cycloalkyl or cycloalkenyl, said group may be partially or fully halogenated, or 1-3 C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy Substitution; 1-3 methylene groups of the above-mentioned cycloalkyl or cycloalkenyl can be replaced by O, NH, S, SO, SO ₂ , carbonyl, hydroxymethyl; the above-mentioned cycloalkyl or cycloalkenyl can be independently Substituted by 0-5 of the following groups: halogen, C ₁ -C ₆ straight chain or branched chain alkyl, C ₁ -C ₆ straight chain or branched chain alkoxy;

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，C₁-C₆直链或支链烷基，C₃-C₁₀环烷基，C₅-C₈环烯基，羟基，腈基，C₁-C₆直链或支链烷氧基，三氟甲基，三氟甲氧基，氨基羰基，双C₁-C₄烷基取代的氨基羰基；(3) C ₃ -C ₁₀ straight chain or branched chain alkenyl, the alkyl can be partially or fully halogenated, and can be 1-3 C ₁ -C ₆ straight chain or branched chain alkyl, phenyl , naphthyl or the following heterocyclic substitutions: quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, iso

Azolyl, isothiazolyl; the above phenyl, naphthyl or heterocycle can be substituted by 0-5 of the following groups: halogen, C ₁ -C ₆ straight chain or branched chain alkyl, C ₃ -C ₁₀ cycloalkane radical, C ₅ -C ₈ cycloalkenyl, hydroxyl, nitrile, C ₁ -C ₆ straight or branched chain alkoxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, bis C ₁ -C ₄ Alkyl-substituted aminocarbonyl;

(4) Halogen, nitro, carboxyl, hydroxyl, nitrile, trifluoromethyl, trifluoromethoxy;

(5) NH ₂ -, R ³ NH-, R ³ ₂ N-, R ³ NCO-R ³ CONH-, R ³ COO-, R ³ OCO-, R ³ S(O) _m , R ³ S(O ) _m NH, R ³ NHS(O) _m -;

^R2 is independently

唑基，异

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

唑基，苯并异唑基，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；(1) Ring, aromatic heterocyclic group or fused aromatic ring, including phenyl, naphthyl, quinolinyl, isoquinolyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl,

Azolyl, iso

Azolyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thienyl, pyryl, naphthyridinyl, piperazinyl, pyrazolyl, thiazolyl, purinyl, indolyl, benzimidazolyl, Benzofuryl, Benzopyrazolyl, Benzothienyl, Benzo

Azolyl, benziso Azolyl, benzothiazolyl, benzisothiazolyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl , 1,3-oxaza[4,5-b]pyridyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, tetrahydropyran base, tetrahydrofuranyl, dihydronaphthyl, tetrahydronaphthyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzocyclobutyl, indenyl, Indenyl. The above-mentioned aromatic ring, aromatic heterocyclic ring or fused aromatic ring group can be independently substituted by ^0-5 R groups;

(2) C ₃ -C ₁₀ cycloalkyl or cycloalkenyl, said group may be partially or fully halogenated, or 1-3 C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy replace;

(3) C ₁ -C ₁₀ straight-chain or branched-chain alkyl, which can be partially or fully halogenated;

(4) NH ₂ -, R ³ NH-, R ³ ₂ N-, R ³ NCO-R ³ CONH-, R ³ COO-, R ³ OCO-, R ³ S(O) _m , R ³ S(O ) _m NH, R ³ NHS(O) _m -;

^R3 independently for

Hydrogen atom, C ₁ -C ₆ straight or branched chain alkyl, C ₁ -C ₆ straight or branched alkenyl, phenyl, naphthyl, mono or double C ₁ -C ₄ alkylamino C ₁ -C ₆ alkyl; m is 0, 1 or 2;

^R4 independently for

a) Halogen, nitro, carboxyl, C ₁ -C ₆ straight chain or branched chain alkyl, C ₁ -C ₆ straight chain or branched chain alkenyl, C ₃ -C ₁₀ cycloalkyl, C ₅ -C ₈ ring Alkenyl, hydroxyl, nitrile, C ₁ -C ₆ straight or branched alkoxy, trifluoromethyl, trifluoromethoxy;

b) NH ₂ -, R ³ NH-, R ³ ₂ N-, R ³ NCO-R ³ CONH-, R ³ COO-, R ³ OCO-, R ³ S(O) _m , R ³ S(O) _m NH, R ³ NHS(O) _m -;

Preferred compounds of the invention include:

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxy-2H- Chromyl)]urea

1-[3-tert-butyl-1-(4-chlorophenyl)-1H-5-pyrazolyl]-3-[8-(5-methoxy-2H-chromenyl)]urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-[8-(5-methoxy-2H-chromenyl)]urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{5-{8-[2-(4-morpholinyl)acetamido] -2H-chromenyl}}urea

1-[3-tert-butyl-1-phenyl-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxy-2H-chromenyl)]urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4- Morpholinyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-[8-(5-nitro-2H-chromenyl)]urea

1-[3-tert-butyl-1-phenyl-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morpholinyl)ethoxy base]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine Phenyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-chlorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine Phenyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-bromophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine Phenyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methoxyphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4 -morpholino)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-aminosulfonylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4 -morpholino)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-nitrophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4- Morpholinyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-[3,4-dihydro-5-(4-morpholinyl) Acylmethoxy)-2H-chromenyl]}urea

唑基)-3-{8-{3，4-二氢-5-[2-(4-吗啡啉基)乙氧基]-2H-色烯基}}脲1-(3-tert-butyl-5-iso

Azolyl)-3-{8-{3,4-dihydro-5-[2-(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

唑基)-3-{8-{3，4-二氢-5-[2-(4-吗啡啉基)乙氧基]-2H-色烯基}}脲1-(5-tert-butyl-3-iso

Azolyl)-3-{8-{3,4-dihydro-5-[2-(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

1-[1-tert-butyl-3-(4-methylphenyl)-1H-4-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4- Morpholinyl)ethoxy]-2H-chromenyl}}urea

1-[4-tert-butyl-1-(4-methylphenyl)-1H-2-imidazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine Phenyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4- Pyridyl)oxyethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-{2-[4- (cis-2,6-dimethyl)morpholinyl]ethoxy}-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1- imidazolyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1- 1,2,4-Triazolyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-chlorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-{2-[4-( cis-2,6-dimethyl)morpholinyl]ethoxy}-2H-chromenyl}}urea

1-[3-tert-butyl-1-(3,4-dimethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2- (4-morpholino)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(3,4-dichlorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-( 4-morpholino)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(3-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4- Morpholinyl)ethoxy]-2H-chromenyl}}urea

1-[(3-tert-butyl-1-naphthyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morpholinyl) Ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1- Pyrazolyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1- piperidin-4-keto)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4- Morpholinyl)acetamido]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-trifluoromethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-( 4-morpholino)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-ethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4- Morpholinyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-tert-butylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4 -morpholino)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-trifluoromethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-( 1-imidazolyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy ]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4- Pyridyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-cyanophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4- Morpholinyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(3-chloro-4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2- (4-morpholino)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[(4-methoxyphenyl)methoxy ]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-[5-(4-morpholinoylmethoxy)-2H -chromenyl]}urea

1-[3-tert-butyl-1-(4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy] -2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-chlorophenyl)-1H5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy]-2H -chromenyl}}urea

1-[3-tert-butyl-1-(4-bromophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy] -2H-chromenyl}}urea

1-(3-tert-butyl-1-phenyl-1H-5-pyrazolyl)-3-{8-{5-[2-(4-morpholinyl)ethoxy]-2H-chromene urea

1-[3-tert-butyl-1-(4-methoxyphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy base]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-trifluoromethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethyl Oxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-nitrophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy ]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-cyanophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy ]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(1-1,2,4-tri Azolyl)ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-ethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy ]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-tert-butylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy base]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(3-chloro-4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl) Ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(3,4-dimethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl) Ethoxy]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(3,4-dichlorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethyl Oxy]-2H-chromenyl}}urea

唑基)-3-{8-{5-[2-(4-吗啡啉基)乙氧基]-2H-色烯基}}脲1-(3-tert-butyl-5-iso

Azolyl)-3-{8-{5-[2-(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

唑基)-3-{8-{5-[2-(4-吗啡啉基)乙氧基]-2H-色烯基}}脲1-(5-tert-butyl-3-iso

Azolyl)-3-{8-{5-[2-(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

1-[1-tert-butyl-3-(4-methylphenyl)-1H-4-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy ]-2H-chromenyl}}urea

1-[3-tert-butyl-1-(3-methylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy ]-2H-chromenyl}}urea

1-[(3-tert-butyl-1-naphthyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy]-2H- Chromyl}}urea

1-[4-tert-butyl-1-(4-methylphenyl)-1H-2-imidazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy] -2H-chromenyl}}urea

1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{5-{2-[4-(cis-2,6 -Dimethyl)morpholino]ethoxy}-2H-chromenyl}}urea

And its pharmaceutically acceptable salt or solvate.

Preparation of compounds of formula I:

Compounds of formula I can be prepared by the following methods, method 3 being preferred.

method 1

Method 2

Method 3

R ₆ ＝CCl ₃ , C ₆ H ₄ NO ₂ , OC ₂ H ₅ , Imidiazole, Triazole

The reaction sequence of the above three methods can be reversed, that is, phosgene, chloroformate or carbonate can react with PL-Ar ₂ -NH ₂ first, and then react with Ar ₁ NH ₂ as an intermediate. The definitions of Ar ₁ , Ar ₂ , L, and P are the same as those in general formula I.

In method 1, a heterocyclic amine is dissolved in methylene chloride, chloroform or ethylene dichloride, an aqueous solution of sodium bicarbonate or potassium carbonate is added, cooled in an ice-water bath, phosgene is added, and stirred for 5-30 minutes to obtain The intermediate is reacted with another heterocyclic amine in an anhydrous aprotic solvent (such as THF, ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.) at 0-45°C for 2-24 hours Compounds of formula I are obtained.

In method 2, a heterocyclic amine is dissolved in dichloromethane, chloroform or dichloroethane, an appropriate base (such as triethylamine, etc.) is added, and then chloroformate is added to react at 0-85°C 2 -24 hours, the obtained intermediate and another heterocyclic amine are mixed in anhydrous aprotic solvent (such as THF, diethyl ether, toluene, dioxane, methylene chloride, ethyl acetate, etc.) at 0-110°C The compound of formula I is obtained after reacting for 2-24 hours.

In method 3, a heterocyclic amine is dissolved in dichloromethane, chloroform or dichloroethane, and an appropriate base (such as triethylamine, etc.) is added, and then carbonate is added to react at -20-45°C 2- After 24 hours, react the obtained intermediate with another heterocyclic amine in an anhydrous aprotic solvent (such as THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.) at 0-110°C 2-240 hours to obtain the compound of formula I.

According to different structures, Ar ₁ NH ₂ can be synthesized by the following routes respectively. R1, R2 are defined with general formula I.

(1) 3-aminopyrazoles

The amine undergoes diazotization reaction at -10-10°C to obtain diazonium salt, and the diazonium salt is reduced by sodium sulfite or stannous chloride to obtain hydrazine II. The substituted chloromethyl ester reacts with anhydrous acetonitrile in anhydrous tetrahydrofuran under the action of alkali such as sodium hydride to obtain intermediate III; III and II are refluxed in ethanol for 16-48 hours under acidic conditions to obtain 3 - Aminopyrazole IV.

(2) 3-aminofurans

Ethyl acyl acetate reacts with α-bromoketone under the action of a strong base (sodium, sodium hydride, sodium ethoxide, etc.), and the obtained diketone ester V reacts with sulfuric acid or hydrochloric acid in ethanol and other solvents to obtain ethyl 3-furanoate Ester VI, ethyl 3-furancarboxylate VI, hydrazine hydrate and formic acid react to obtain 3-aminofuran compound VII.

(3) 3-Aminothiophenes

Diketone and Lawesson's reagent were refluxed in an anhydrous aprotic solvent for 1-10 hours to obtain substituted thiophene, and then nitrated with concentrated nitric acid, iron/hydrochloric acid or catalytic hydrogenation reduction to obtain 3-aminothiophene compound VIII.

(4) 2-aminopyrroles

Nitrile aldehyde and substituted amine were reacted in acetic acid/water at 50-90°C for 5-30 minutes to obtain aminonitrile IX, and IX was cyclized at room temperature in the presence of sodium ethoxide to generate 2-aminopyrrole compound X.

唑类(5) 4-Amino

Azole

唑类化合物XI。Acyl nitrile, aldehyde, anhydrous ammonium acetate are refluxed in acetic acid for 3-6 hours to give 4-amino

Azole compounds XI.

唑类(6) 5-amino

Azole

唑类化合物XIV。Acyl chloride and nitrile amine are reacted at 0°C in a solvent such as tetrahydrofuran to obtain amide XII, XII is dissolved in dry dihydromethane, ethanethiol is added, dry hydrogen chloride gas is passed through, and the reaction is 5-30 minutes to obtain the product XIII At 0°C, hydrogen sulfide was passed into dry pyridine to saturation, and 5-amino was obtained after 4 hours

Azole compounds XIV.

(7) 5-aminothiazoles

Dissolve aldehydes, aminonitriles, and sulfur in dry methanol or ethanol, add triethylamine dropwise, heat to 50°C, and react for 1-3 hours to obtain product XV, which is hydrolyzed with hydrochloric acid or p-toluenesulfonic acid to obtain 5-aminothiazole XVI .

(8) 2-aminoimidazoles

In the presence of a base (potassium bicarbonate, potassium carbonate, etc.), α-chloroketone reacts with a substituted amine in a solvent such as DMF to obtain α-aminoketone XVII, and XVII is refluxed with nitrile amine in a solvent such as ethanol for 12 hours to obtain 2 - Aminoimidazole XVIII.

(9) 4-aminopyrazoles

Chloroketone and phthalimide potassium salt were reacted in DMF at 70°C for 2 hours to obtain compound XIX, and XIX was reacted with N,N-dimethylformamide dimethyl acetal in DMF at 100°C After 12 hours, compound XX was obtained. XX and substituted hydrazines were refluxed in 90% ethanol for 12 hours to give compound XXI, which was hydrazinolyzed in ethanol to give 4-aminopyrazole XXII.

(10) 5-aminoiso Azole

唑XXIII。Nitrile ketone reacts with hydroxylamine hydrochloride at 50-100°C under alkaline conditions to obtain 5-aminoiso

Azole XXIII.

Those skilled in the art will appreciate that the compounds of the present invention may also be used in the form of their pharmaceutically acceptable salts or solvates. The physiologically acceptable salts of the compounds of general formula I include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases and acid addition salts of quaternary ammoniums. 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, pamoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzene Salts of sulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, steroic acid, tannic acid, etc. Other acids, such as oxalic acid, although not pharmaceutically acceptable in themselves, can be used in the preparation of salts used as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable base salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethyl Diamine, N-methylglucamine and procaine salts. Hereinafter, references to compounds of the present invention include compounds of general formula I and pharmaceutically acceptable salts and solvates thereof.

The present invention also includes prodrugs of the compounds of the present invention, which, upon administration, are chemically transformed by metabolic processes and then become active drugs. Typically, such prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula (I). General methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design Of Prodrugs", H Bund Saard, Elsevier ed., 1985.

The present invention also includes active metabolites of the compounds of the present invention.

Another aspect of the present invention relates to pharmaceutical compositions comprising a compound of the present invention and at least one pharmaceutically acceptable carrier, which are useful for in vivo therapy and are biocompatible. The pharmaceutical composition can be prepared in various forms according to different administration routes. The compounds mentioned in the present invention can also be prepared into various pharmaceutically acceptable salts.

The agonistic effect of the compounds of the present invention on PPAR can be determined by the following method. Suspend THP-1 cells in RMPI medium containing 15% fetal calf serum and 0.02nM 2-mercaptoethanol at a cell concentration of 1-2× ¹⁰⁶ cells/mL, and then plate them on a 96-well plate (each well containing 0.2mL). Test compounds were dissolved in DMSO and then diluted with medium to give a final concentration of 5% in DMSO. 25 [mu]L of test compound solution or DMSO-only medium (control) was added to each well.

Incubate the cells with the serial dilutions of the test compound at 37°C for 30 minutes, then add IFN-γ (100U/mL) and LPS (5mg/mL), and continue to incubate for 18-24 hours, centrifuge at 1600RPM for 10 minutes to terminate the incubation . The TNF-α content in the supernatant was analyzed with a commercially available ELISA kit. Compounds of the invention were tested at a concentration of 0.1-3 [mu]M. Representative compounds of the present invention can inhibit TNF-α release in experiments.

The inhibitory effect (3 μ M) of the compound of the present invention to TNF-α of table 1 part

compound Inhibition rate(%) compound Inhibition rate(%) compound Inhibition rate(%) Example 2 34.47 Example 24 60.56 Example 44 19.01 Example 3 59.22 Example 26 62.50 Example 45 22.54 Example 6 24.27 Example 32 101.49 Example 47 12.68 Example 7 58.74 Example 33 84.82 Example 48 4.93 Example 9 57.28 Example 34 67.56 Example 55 68.94 Example 10 33.50 Example 35 83.93 Example 56 78.03 Example 11 30.99 Example 37 34.51 Example 57 83.71 Example 14 14.08 Example 38 11.97 Example 58 6.06 Example 17 56.25 Example 39 45.77 Example 59 36.74 Example 20 43.75 Example 40 61.27 Example 60 14.02 Example 21 95.24 Example 42 51.41 Example 61 19.32 Example 22 87.20 Example 43 16.90 Example 62 79.55

The pharmaceutical compositions of the compounds of this invention may be administered in any of the following ways: oral, inhalation spray, rectal, nasal, buccal, topical, parenteral, e.g. subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Intravenous, intraventricular, intrasternal and intracranial injection or infusion, or with the aid of an explanted reservoir. Among them, oral, intraperitoneal or intravenous administration is preferred.

When administered orally, the compounds of the present invention may be prepared in any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions or suspensions. Wherein, the carrier that tablet uses generally comprises lactose and cornstarch, also can add lubricating agent such as magnesium stearate in addition. Diluents used in capsule formulations generally include lactose and dried cornstarch. Aqueous suspensions are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added to the above oral preparation forms.

When using locally, especially when treating the affected areas or organs that are easily accessible by local external application, such as eyes, skin or lower intestinal nerve diseases, the compound of the present invention can be made into different topical preparations according to different affected areas or organs form, as follows:

When administered topically to the eye, the compounds of the present invention may be formulated as a micronized suspension or solution in the form of isotonic sterile saline at a pH with or without the addition of a preservative such as benzyl chloride. alkyl alkoxides. For ophthalmic use, the compounds may also be formulated in ointments such as petrolatum.

When applied topically to the skin, the compounds of the invention may be formulated in suitable ointments, lotions or creams, wherein the active ingredients are suspended or dissolved in one or more carriers. Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil Oil, sorbitan monostearate, Tween 60, cetyl esters wax, cetyl aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of this invention can also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oily suspensions or sterile injectable solutions. Among them, usable vehicles and solvents include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils, such as mono- or diglycerides, can be employed as a solvent or suspending medium.

In addition, it should be pointed out that the dose and method of use of the compounds of the present invention depend on many factors, including the patient's age, body weight, sex, natural health status, nutritional status, activity intensity of the compound, time of administration, metabolic rate, severity of the disease, and The subjective judgment of the treating physician. The preferred dosage ranges from 0.01 to 100 mg/kg body weight/day, and the optimal dosage is 5 mg/kg-10 mg/kg body weight/day.

Detailed ways

The present invention is further illustrated by the following intermediates and examples, which are not intended to limit the invention.

The melting points of the compounds were determined by a YRT-3 melting point apparatus, and the temperature was not corrected. ¹ H-NMR

Spectra were measured by a Bruker ARX 400 nuclear magnetic analyzer. The FAB mass spectrum was determined by a Zabspect high-resolution magnetic mass spectrometer.

Preparation of intermediates

General Procedure A for the Preparation of 2,5-Disubstituted 3-Aminopyrazoles from Aromatic Amines

1. Add aromatic amine (0.04mol) into 40mL concentrated hydrochloric acid, stir, cool to -5°C, white fine granular crystals are precipitated. Slowly add sodium nitrite solution (2.90g sodium nitrite dissolved in 20mL water) dropwise, control the temperature not to exceed 0°C, and react for 1 hour after the addition.

2. Dissolve 18.0g of stannous chloride in 50mL of concentrated hydrochloric acid, cool to -5°C, add dropwise the diazonium salt solution prepared in step 1, and white crystals are precipitated, react for 1 hour, filter, and dry the filter cake to obtain the product aromatic hydrazine hydrochloride Salt.

Add sodium hydride (0.6g, 60%, 0.015mol) to 3.30mL of anhydrous THF at 0°C, add substituted chloromethyl carboxylate (0.01mol) and anhydrous acetonitrile (0.82g, 0.02mol) under stirring, and complete the addition After that, it was reacted at room temperature for 1 hour, and then heated to reflux for 24 hours. Cooled, poured into 100mL ice water, adjusted to pH 4 with dilute hydrochloric acid, extracted with ethyl acetate, dried, concentrated to obtain crude product. It was directly used in the next reaction without purification.

4. Add the acyl acetonitrile (1.25 g, 0.01 mol) obtained in step 3 and the aromatic hydrazine hydrochloride obtained in step 2 to 50 mL of ethanol, add 2.0 mL of concentrated hydrochloric acid dropwise, and heat to reflux for 12-24 hours. Cooled, poured into 100mL ice water, adjusted to pH 12 with dilute sodium hydroxide, extracted with ethyl acetate, dried, and the obtained crude product was subjected to silica gel column chromatography to obtain a white solid product.

Intermediate 1

The title compound was prepared from p-tert-butylchloromethyl ester as described in General Procedure A, Step 3 to give a pale yellow oil.

Intermediate 2

The title compound was prepared from 3,4-dimethylaniline as described in General Procedure A, Steps 1 and 2 to give a white solid.

Intermediate 3

The title compound was prepared from 3,4-dichloroaniline as described in General Procedure A, Steps 1 and 2 to give a white solid.

Intermediate 4

The title compound was prepared from 3-methylaniline as described in General Procedure A, Steps 1 and 2 to give a white solid.

Intermediate 5

The title compound was prepared from 1-naphthylamine as described in General Procedure A, Steps 1 and 2 to give a white solid.

Intermediate 6

The title compound was prepared from 3-chloro4-fluoroaniline as described in General Procedure A, Steps 1 and 2 to give a white solid.

Intermediate 7

The title compound was prepared from 4-ethylaniline as described in General Procedure A, Steps 1 and 2 to give a white solid.

Intermediate 8

The title compound was prepared from 4-isopropylaniline as described in General Procedure A, Steps 1 and 2 to give a white solid.

Intermediate 9

The title compound was prepared from 4-trifluoromethylaniline as described in General Procedure A, Steps 1 and 2 to give a white solid.

Intermediate 10

The title compound was prepared from 4-cyanoaniline as described in General Procedure A, Steps 1 and 2 to give a white solid.

Intermediate 11

The title compound was prepared from Intermediate 1 and p-methylphenylhydrazine as described in General Procedure A, Step 4 to give a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.40(d, 2H, J=8.4Hz), 7.25(d, 2H, J=3.08Hz), 5.50(s, 1H), 3.72(s, 2H), 2.37(s, 3H), 1.32(s, 9H).

Intermediate 12

The title compound was prepared from Intermediate 1 and phenylhydrazine as described in General Procedure A, Step 4 to give a white solid.

Intermediate 13

The title compound was prepared from Intermediate 1 and p-methoxyphenylhydrazine as described in General Procedure A, Step 4 to give a white solid.

Intermediate 14

The title compound was prepared from Intermediate 1 and p-fluorophenylhydrazine as described in General Procedure A, Step 4 to give a white solid.

Intermediate 15

The title compound was prepared from Intermediate 1 and p-chlorophenylhydrazine as described in General Procedure A, Step 4 to give a white solid.

Intermediate 16

The title compound was prepared from Intermediate 1 and p-bromophenylhydrazine as described in General Procedure A, Step 4 to give a white solid.

Intermediate 17

The title compound was prepared from Intermediate 1 and p-nitrophenylhydrazine as described in General Procedure A, Step 4 to give a yellow solid.

Intermediate 18

The title compound was prepared from Intermediate 1 and p-aminosulfonylphenylhydrazine as described in General Procedure A, Step 4 to give a white solid.

Intermediate 19

The title compound was prepared from Intermediate 1 and Intermediate 2 as described in General Procedure A, Step 4 to give a white solid.

¹ H-NMR (CDCl ₃ , 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).

Intermediate 20

The title compound was prepared from Intermediate 1 and Intermediate 3 as described in General Procedure A, Step 4 to give a white solid.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.76 (t, 1H), 7.49 (m, 2H), 5.53 (s, 1H), 3.72 (s, 2H), 1.30 (s, 9H).

Intermediate 21

The title compound was prepared from Intermediate 1 and Intermediate 4 as described in General Procedure A, Step 4 to give a white solid.

¹ H-NMR (CDCl ₃ , 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).

Intermediate 22

The title compound was prepared from Intermediate 1 and Intermediate 5 as described in General Procedure A, Step 4 to give a white solid.

¹ H-NMR (CDCl ₃ , 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) .

Intermediate 23

The title compound was prepared from Intermediate 1 and Intermediate 6 as described in General Procedure A, Step 4 to give a white solid.

Intermediate 24

The title compound was prepared from Intermediate 1 and Intermediate 7 as described in General Procedure A, Step 4 to give a white solid.

Intermediate 25

The title compound was prepared from Intermediate 1 and Intermediate 8 as described in General Procedure A, Step 4 to give a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.44(d, 2H, J=8.4Hz), 7.29(d, 2H, J=8.4Hz), 5.51(s, 1H), 3.72(s, 2H), 2.93 (m, 1H), 1.31 (s, 9H), 1.25 (d, 3H), 1.24 (d, 3H).

Intermediate 26

The title compound was prepared from Intermediate 1 and Intermediate 9 as described in General Procedure A, Step 4 to give a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.77(d, 2H, J=8.4Hz), 7.69(d, 2H, J=8.4Hz), 5.56(s, 1H), 3.76(s, 2H), 1.31(s, 9H).

Intermediate 27

The title compound was prepared from Intermediate 1 and Intermediate 10 as described in General Procedure A, Step 4 to give a white solid.

Intermediate 28

Add 1.25 g (0.01 mol) of pivaloyl acetonitrile (intermediate 1), sodium hydroxide (0.84 g, 0.021 mol) and 10 mL of water into a 50 mL round bottom bottle, stir, heat to 50 ° C, and add hydroxylamine hydrochloride ( 0.76 g, 0.011 mol). After the addition, the temperature was raised to 100° C., reacted for 4 hours, cooled, extracted with ethyl acetate, dried, and separated by column to obtain 1.23 g of white flaky solid with a yield of 88.0%.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 5.03 (s, 1H), 4.32 (s, 2H), 1.27 (s, 9H).

General Procedure B for the Preparation of 1,3-Disubstituted-4-Aminopyrazoles from α-Chloroketones

1. Dissolve α-chloroketone (0.01mol) in 10mL DMF, add phthalimide potassium salt (0.01mol), react at 70°C for 2 hours, cool, pour into 100mL ice water, precipitate a white solid, filter , and dry to obtain the product.

2. Dissolve the product (0.01mol) obtained in step 1 in 20mL DMF, add N,N-dimethylformamide dimethyl acetal (1.44g, 0.012mol) dropwise, react at 100°C for 12 hours, add N, N-dimethylformamide dimethyl acetal (1.44 g, 0.012 mol) continued to react for 24 hours, cooled, poured into 100 mL of ice water, extracted with ethyl acetate, dried, and separated by column to obtain a white solid product.

3. The product (0.01mol) obtained in step 2 was dissolved in 100mL of 90% ethanol, added substituted hydrazine (0.011mol), heated to reflux for 12 hours, cooled, precipitated solid, filtered, the filter cake was washed with anhydrous ether, dried to obtain white solid product.

4. Dissolve the product (0.01mol) obtained in step 3 in 100mL ethanol, add dropwise 85% hydrazine hydrate solution (0.04mol), heat and reflux for 2 hours, a white solid precipitates, cool, concentrate, add 20mL ether, filter, filter cake Wash with anhydrous ether, combine the filtrates, concentrate and column separation to obtain a white powder product.

Intermediate 29

Suspend anhydrous aluminum trichloride (5.60g, 0.04mol) in 40mL of anhydrous toluene, stir, slowly add chloroacetyl chloride (4.52g, 0.04mol) dropwise at room temperature, aluminum trichloride gradually dissolves, and slowly heat up React at 80°C for 2 hours, cool, pour into a solution formed by 100g of crushed ice and 10mL of concentrated hydrochloric acid, separate the layers, extract the water layer with toluene three times, combine the toluene layers, and successively wash with 10% sodium hydroxide, water, and saturated saline After washing, drying and column separation, the product was obtained with a yield of 86.3%.

Intermediate 30

The title compound was prepared from Intermediate 29 and phthalimide potassium salt as described in General Procedure B, Step 1 to obtain a white solid in a yield of 87.8%.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.88-7.91 (m, 4H), 7.76 (m, 2H), 7.30-7.32 (m, 2H), 5.51 (s, 2H), 2.44 (s, 3H) .

Intermediate 31

The title compound was prepared from intermediate 30 as described in General Procedure B, Step 2 to obtain a white solid in a yield of 61.5%.

Intermediate 32

The title compound was prepared from intermediate 31 as described in General Procedure B, Step 3 to obtain a white solid in a yield of 72.3%.

Intermediate 33

The title compound was prepared from intermediate 32 as described in General Procedure B, step 4 to obtain a white solid in a yield of 82.6%.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.21-7.26 (m, 5H), 2.68 (s, 2H), 2.41 (s, 3H), 1.41 (s, 9H).

General Procedure C for the Preparation of 1,4-Disubstituted-2-Aminoimidazoles from α-Chloroketones

1. Dissolve α-chloroketone (0.012mol) and arylamine (0.01mol) in 20mL of DMF, add sodium bicarbonate (1.26g, 0.015mol), react at 75°C for 48 hours, cool, pour into 100mL of ice water, and precipitate a solid , filtered, and dried to obtain the product. Yield 99.2%.

2. The product obtained in step 1 (0.01mol), cyanamide (4.23g, 0.10mol) was refluxed in 100mL ethanol for 12 hours. Concentrate, add water to the residue, extract three times with ethyl acetate, combine organic layers, wash with dilute sodium hydroxide solution, water, saturated brine successively, dry, and column separation to obtain a white solid product.

Intermediate 34

The title compound was prepared from p-methylaniline and pivaloylmethyl chloride as described in General Procedure C, Step 1 to give a white solid in a yield of 99.2%.

Intermediate 35

The title compound was prepared from intermediate 35 as described in General Procedure C, Step 2 to give a white solid in a yield of 56.7%.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.26 (m, 4H), 6.35 (s, 1H), 4.18 (s, 2H), 2.39 (s, 3H), 1.27 (s, 9H).

PL-Ar ₂ NH ₂ can be synthesized by the following route according to the structure.

1. Synthesis of 8-amino-5-methoxy-2H-chromene.

(1) Dissolve 3-methoxyphenol (4.96g, 0.04mol) in 50mL propionic acid, cool to -10°C, add 0.5mL propionic anhydride dropwise, add sodium nitrite (2.90g, 0.042mol) in batches, and precipitate The brown solid was reacted for 1 hour, poured into 250 mL of ice water, filtered, washed with water, and dried to obtain 4.03 g of intermediate 36 as a brown-yellow solid.

(2) Intermediate 36 (1.53g, 0.01mol) was dissolved in 16mL propionic acid, cooled to -12°C, fuming nitric acid (1.26g, 0.02mol) was added dropwise, stirred for 2 hours, poured into 50mL ice water, and a solid precipitated , filtered, washed with water, and dried to obtain 1.38 g of intermediate 37 as a brown-yellow solid with a yield of 77.4%.

(3) Intermediate 37 (1.69g, 0.01mol) was dissolved in 15mL DMF, 3-bromopropyne (1.43g, 0.012mol) was added, reacted at 70°C for 6 hours, cooled, poured into ice water, precipitated a khaki solid, filtered , washed and dried to obtain 1.87g of intermediate 38 as a brownish-yellow solid with a yield of 90.3%.

(4) Intermediate 38 (8.46g, 0.041mol) was dissolved in 88mL N,N-diethylaniline, heated to 180-210°C for 1-6 hours, cooled, poured into 500mL cold dilute hydrochloric acid, filtered, the filtrate Extracted three times with ethyl acetate, combined the ethyl acetate layers, washed with saturated brine, dried, and separated by column to obtain 1.84 g of intermediate 39 as a yellow solid with a yield of 21.8%.

(5) Intermediate 39 (1.24g, 6mmol) was dissolved in 50mL ethyl acetate and 50mL ethanol, and stannous chloride dihydrate (5.41g, 24mmol) was added in batches, the reaction solution became turbid, heated to reflux for 8 hours, cooled, Saturated sodium bicarbonate solution was added until there were obvious layers, separated, the aqueous layer was extracted twice with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column to obtain 0.64 g Intermediate 40, yield 59.9%.

(6) Intermediate 39 (1.04g, 0.005mol) was dissolved in 50mL of absolute ethanol, assuming 0.2g of palladium/charcoal, heated to 70°C, 1.0mL of hydrazine hydrate (85%) was added dropwise, heated to reflux for 4 hours, cooled, After filtration, the filtrate was dried and concentrated to obtain 0.62 g of intermediate 41 with a yield of 72.5%.

2. 8-Amino-3,4-dihydro-5-substituted alkoxy-2H-chromene. The definition of P is the same as that of formula I.

(1) Resorcinol (44.0g, 0.40mol) was dissolved in 150mLDMF, anhydrous potassium carbonate (66.24g, 0.48mol) was added, and benzyl bromide (47.88g, 0.28mol) was added dropwise under ice-water cooling to complete the reaction After 5 hours, it was poured into cold dilute hydrochloric acid to make it acidic, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed with saturated brine, dried, and separated by a column to obtain 26.25g of intermediate 42 , which was a colorless oil and changed after standing. It is a white solid with a yield of 46.9%.

(2) Intermediate 43 was prepared from intermediate 42 according to the method for synthesizing intermediate 37. It was a brown solid with a yield of 74.1%.

(3) Intermediate 44 was prepared according to the method for synthesizing Intermediate 38 from Intermediate 43 as a brown solid with a yield of 89.0%.

(4) Intermediate 45 was prepared from intermediate 44 according to the method for synthesizing intermediate 39. It was a brown solid with a yield of 95.0%.

(5) Intermediate 46 was prepared by using intermediate 45 as a raw material according to the method for synthesizing intermediate 40. It was a yellow solid with a yield of 20-25%.

(6) Dissolve 5.0g of intermediate 46 in 100mL of absolute ethanol, add 2 drops of hydrochloric acid dropwise, add 2.0g of palladium/carbon, heat to 60°C, add 10.0mL of hydrazine hydrate (85%) dropwise, heat up and reflux for 6 hours, and cool , filtered, the filtrate was dried, concentrated, the residue was dissolved in 100mL of dichloromethane, 3.0mL of triethylamine was added, cooled in an ice-water bath, 4.0g of (Boc) ₂ O was added dropwise, then reacted overnight at room temperature, poured into water, dichloromethane Extraction, drying, and column separation yielded 1.69 g of intermediate 48 as a white powdery solid.

(7) Intermediate 48 (2.20g, 8.3mmol) was dissolved in 50mL of acetonitrile, 1.37g of anhydrous potassium carbonate was added, 1,2-dibromopropane (6.23g, 33mmol) was added dropwise, heated to reflux for 72 hours, concentrated, the residue 30 mL of water was added to the compound, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed with saturated brine, dried, and separated by column to obtain 0.83 g of intermediate 49 , and 1.61 g of the raw material was recovered.

(8) General Procedure C for Synthesis of Intermediate XXV.

a. Intermediate 49 (1.86g, 5mmol) was dissolved in 20mL DMF, 0.83g anhydrous potassium carbonate was added, HP (6mmol) was added, reacted at 80°C for 1-6 hours, cooled, poured into cold water, extracted with ethyl acetate, Drying and column separation yielded compound XXIV.

b. Compound XXIV (2mmol) was dissolved in 20mL of dichloromethane, cooled to -5°C, 2.0mL of trifluoroacetic acid was added dropwise, reacted for 2 hours, concentrated, the residue was added to 30mL of water, and adjusted to pH 10 with 1N sodium hydroxide, Extracted with ethyl acetate, dried and concentrated to obtain the crude product of XXV, which was directly used in the next reaction without purification.

Intermediate 50

The title compound was prepared as described in general procedure C starting from intermediate 49 and morpholine.

Intermediate 51

The title compound was prepared as described in general procedure C starting from intermediate 49 and 4-piperidone.

Intermediate 52

The title compound was prepared as described in general procedure C starting from intermediate 49 and imidazole.

Intermediate 53

The title compound was prepared as described in general procedure C starting from intermediate 49 and 1,2,4-triazole.

Intermediate 54

The title compound was prepared as described in general procedure C starting from intermediate 49 and pyrazole.

Intermediate 55

The title compound was prepared as described in general procedure C starting from intermediate 49 and cis-2,6-dimethylmorpholine.

Intermediate 56

The title compound was prepared as described in general procedure C starting from intermediate 49 and 4-hydroxypyridine.

Intermediate 57

Intermediate 48 (1.59 g, 6 mmol) was dissolved in 50 mL of anhydrous THF, 4-(2-hydroxyethyl) pyridine (616 mg, 5 mmol), triphenylphosphine (1.57 g, 5 mmol) and DEAD (1.05 g, 5 mmol) were added ), heated to reflux for 3 hours, and the reaction was completed. Column separation yielded 1.76 g of intermediate 57 with a yield of 95.0%.

Intermediate 58

Starting from intermediate 57, the title compound was prepared as described in general procedure C, step b.

Intermediate 59

The title compound was prepared as described in general procedure C starting from intermediate 48 and 4-(2-chloroacetyl)pyridine.

3. 8-Amino-5-substituted alkoxy-2H-chromene. The definition of P is the same as that of formula I.

(1) Intermediate 45 (70.83g, 0.25mol) was dissolved in 300mL of ethyl acetate, 300mL of hydrobromic acid was added, heated to reflux for 8 hours, vacuum distillation, and the residue was separated by column to obtain 31.1g of Intermediate 60 as a reddish-brown solid , yield 64.4%.

(2) Intermediate 60 (38.26g, 0.198mol) was dissolved in 200mL DMF, anhydrous potassium carbonate (32.84g, 0.24mol) was added, p-methoxybenzyl chloride (6mmol) was added, room temperature was reacted for 8 hours, and cold water was poured , a brownish-yellow solid was precipitated, filtered, and dried to obtain 58.96 g of intermediate 61 with a yield of 95.0%.

(3) Using the intermediate 61 as the raw material, the preparation method of the intermediate 46 was adopted to obtain the yellow intermediate 62 with a yield of 20-45%.

(4) Intermediate 61 (18.2g, 0.058mol) was dissolved in 150mL of dichloromethane, cooled to -10°C, 10.0mL of trifluoroacetic acid was added dropwise, reacted for 8 hours, concentrated, the residue was added to 50mL of water, and oxidized with 1N hydroxide Adjusted to pH 10 with sodium, extracted with ethyl acetate, dried, concentrated, and column separated to give 7.5 g of intermediate 63 as a yellow solid.

(5) Intermediate 63 (5.97g, 31mmol) was dissolved in 150mL of acetonitrile, 5.13g of anhydrous potassium carbonate was added, 1,2-dibromopropane (23.23g, 124mmol) was added dropwise, heated to reflux for 2.5 hours, concentrated, the residue Add 50 mL of water, extract three times with ethyl acetate, combine the ethyl acetate layers, wash with saturated brine, dry, and column separation to obtain 4.69 g of intermediate 64 as a yellow solid with a yield of 34.4%.

(6) General procedure D for the synthesis of intermediate XXVII.

a. Intermediate 64 (1.50g, 5mmol) was dissolved in 20mL DMF, 0.83g anhydrous potassium carbonate was added, HP (6mmol) was added, reacted at 80°C for 2-6 hours, cooled, poured into cold water, extracted with ethyl acetate, dried , column separation to obtain compound XXVI.

b. Dissolve compound XXVI (5mmol) in 50mL ethyl acetate and 50mL ethanol, add stannous chloride dihydrate (4.50g, 20mmol) in batches, the reaction solution becomes turbid, heat to reflux for 8 hours, cool, add saturated sodium bicarbonate Solution, until obvious stratification occurs, separate the layers, extract the aqueous layer twice with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain compound XXVII with a yield of 85-95% . It was directly used in the next reaction without purification.

Intermediate 65

The title compound was prepared as described in general procedure D starting from intermediate 64 and morpholine.

Intermediate 66

The title compound was prepared as described in general procedure D starting from intermediate 64 and cis-2,6-dimethylmorpholine.

Intermediate 67

The title compound was prepared as described in general procedure D starting from intermediate 64 and 4-hydroxypyridine.

Intermediate 68

The title compound was prepared as described in general procedure D starting from intermediate 63 and 4-(2-chloroacetyl)pyridine.

Intermediate 69

The title compound was prepared as described in general procedure D starting from intermediate 64 and 1,2,4-triazole.

Intermediate 70

The title compound was prepared as described in general procedure D starting from intermediate 64 and 4-piperidone.

4. 8-Amino-5-substituted amino-2H-chromenes.

(1) 2-Amino-5-nitrophenol (46.2g, 0.30mol) was dissolved in 300mL of dichloromethane, cooled to -5°C, added triethylamine (36.3g, 0.33mol), and added dropwise with stirring (Boc ) ₂ O (72.0 g, 0.33 mol), and then heated to reflux for 6 hours. Cool, pour into 500 mL of water, separate the layers, extract the aqueous layer twice with dichloromethane, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain intermediate 71 as a yellow viscous solid.

(2) Dissolve the intermediate 71 obtained in the previous step in 200mL DMF, add anhydrous potassium carbonate (41.4g, 0.30mol) and 3-bromopropyne (35.7g, 0.30mol), heat to 70°C for 8 hours, cool , poured into water, a yellow solid was precipitated, and recrystallized from ethyl acetate/petroleum ether to obtain 30.5 g of intermediate 72 .

(3) Intermediate 72 (15.32g) was dissolved in 100mL of N,N-diethylaniline, heated to 180°C for 4 hours, distilled under reduced pressure, and the solvent was removed. The residue was separated by column to obtain 7.94g of Intermediate 73 , which was Yellow solid, yield 78.8%.

(4) Intermediate 73 (1.92g, 10mmol) was dissolved in 30mL of dichloromethane, cooled to -5°C, triethylamine (1.21g, 11mmol) was added, and chloroacetyl chloride (1.24g, 11mmol) was added dropwise with stirring, Refluxed for 24 hours, cooled, poured into water, extracted with dichloromethane, dried, and separated by column to obtain 1.53g of intermediate 74 as a yellow solid with a yield of 57.3%.

(5) Intermediate 74 (1.34g, 5mmol) was dissolved in 10mL DMF, anhydrous potassium carbonate (0.83g, 6mmol) and morpholine (0.52g, 6mmol) were added, reacted at 80°C for 4 hours, poured into water, ethyl acetate Ester extraction, drying, and column separation gave 1.48 g of intermediate 75 as a yellow solid with a yield of 92.7%.

(6) Intermediate 75 (640mg, 2mmol) was dissolved in 30mL ethyl acetate and 30mL ethanol, and stannous chloride dihydrate (1.80g, 8mmol) was added in batches, the reaction solution became turbid, heated to reflux for 8 hours, cooled, and added Saturated sodium bicarbonate solution, until there are obvious layers, separate the layers, extract the aqueous layer twice with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 545mg of intermediate 76 , Yield 94.3%. It was directly used in the next reaction without purification.

5. 5-Amino-8-substituted amino-2H-chromene.

(1) Intermediate 73 (1.92g, 10mmol) was dissolved in 30mL of dichloromethane, cooled to 0°C, triethylamine (1.21g, 11mmol) was added, and (Boc) ₂ O (2.38g, 11mmol) was added dropwise under stirring , refluxed for 48 hours, cooled, poured into water, extracted with dichloromethane, dried, and separated by column to obtain 1.34 g of intermediate 77 as a yellow solid with a yield of 45.9%.

(2) Intermediate 77 (1.5g, 5.14mmol) was dissolved in 50mL of ethanol, 0.3g of palladium/carbon was added, heated to 60°C, 2.0mL of hydrazine hydrate (85%) was added dropwise, heated and refluxed for 1 hour, cooled, filtered, The filtrate was dried and concentrated to afford 1.39 g of intermediate 78 .

(3) Dissolve intermediate 78 in 30 mL of dichloromethane, add 1.2 mL of triethylamine, cool in an ice-water bath, dropwise add chloroacetyl chloride (0.68 g, 6 mmol), react for 2 hours, pour into water, extract with dichloromethane, Drying and column separation yielded 378 mg of intermediate 79 as a white powdery solid.

(4) Intermediate 79 (534mg, 1.57mmol) was dissolved in 10mL DMF, anhydrous potassium carbonate (324mg, 2.35mmol) and morpholine (204mg, 2.35mmol) were added, reacted at 80°C for 4 hours, poured into water, ethyl acetate Ester extraction, drying, and column separation yielded 313 mg of intermediate 80 as a white granular solid with a yield of 50.9%.

(5) Intermediate 80 (313mg, 0.8mmol) was dissolved in 30mL of dichloromethane, cooled to 0°C, 1.5mL of trifluoroacetic acid was added dropwise, reacted for 4 hours, concentrated, the residue was added to 30mL of water, adjusted with 1N sodium hydroxide To pH 10, extracted with ethyl acetate, dried, and concentrated to obtain 176 mg of crude intermediate 81 , which was directly used in the next reaction without purification.

Example

Example 1: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxy 2H-chromenyl)]urea

Add 20 mL of dry dichloromethane into a 50 mL three-necked flask, cool to -10°C, add triphosgene (109 mg, 0.36 mmol), dropwise add 0.4 mL of dry triethylamine, and slowly add intermediate 41 (180 mg, 1.0 mmol) was dissolved in 10 mL of dry dichloromethane, and reacted for 1 hour. Intermediate 11 (138 mg, 0.6 mmol) was added, warmed to room temperature, and then heated to reflux for 48 hours. Cooled, poured into 50mL water, extracted 3 times with dichloromethane, washed the organic layer with saturated brine, dried over anhydrous sodium sulfate, and separated by column (elution system: petroleum ether/ethyl acetate) to obtain 1-[3-tert Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxy-2H-chromenyl)]urea 94 mg, white crystals, yield 21.8%.

¹ H-NMR (DMSO, 400MHz) δ: 8.84(s, 1H), 8.30(s, 1H), 7.77(d, 1H, J=8.96Hz), 7.33-7.37(m, 4H), 6.41(d, 1H, J=9.00Hz), 6.33(s, 1H), 4.14(t, 2H, J=4.76Hz), 3.71(s, 3H), 2.50(t, 2H), 2.37(s, 3H), 1.88( p, 2H), 1.25 (s, 9H).

MS (FAB) m/z: 435.1 [M+1] ⁺ .

Example 2: 1-[3-tert-butyl-1-(4-chlorophenyl)-1H-5-pyrazolyl]-3-[8-(5-methoxy-2H-chromenyl) ] urea

Using the preparation method of Example 1, intermediate 11 was changed to intermediate 15, and intermediate 41 was changed to intermediate 40 to obtain the title compound as a white solid.

¹ H-NMR (DMSO, 400MHz) δ: 8.91(s, 1H), 8.31(s, 1H), 7.82(d, 1H), 7.52-7.60(m, 4H), 6.65(d, 1H, J=10.08 Hz), 6.50(d, 1H, J=9.28Hz), 6.36(s, 1H), 5.87(m, 1H), 4.76(t, 2H, J=1.68Hz), 3.74(s, 3H), 1.26( s, 9H).

MS (FAB) m/z: 453.0 [M+1] ⁺ .

Example 3: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-[8-(5-methoxy-2H-chromenyl) )] urea

Using the preparation method of Example 1, intermediate 41 was changed to intermediate 40 to obtain the title compound as a white solid.

¹ H-NMR (DMSO, 400MHz) δ: 8.83(s, 1H), 8.35(s, 1H), 7.81(d, 1H, J=9.24Hz), 7.33-7.37(m, 4H), 6.65(d, 1H, J=8.12Hz), 6.50(d, 1H, J=9.24Hz), 6.33(s, 1H), 5.85(m, 1H), 4.75(t, 2H, J=1.68Hz), 3.74(s, 3H), 2.37(s, 3H), 1.26(s, 9H).

MS (FAB) m/z: 433.1 [M+1] ⁺ .

Example 4: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{5-{8-[2-(4-morpholinyl) )acetamido]-2H-chromenyl}}urea

Using the preparation method of Example 1, intermediate 41 was changed to intermediate 76 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 9.46(s, 1H), 7.96(s, 1H), 7.17-7.26(m, 4H), 6.85(d, 1H), 6.71(d, 1H, J= 1.36Hz), 6.40(s, 1H), 6.36(d, 1H, J=10.64Hz), 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+1] ⁺ .

Example 5: 1-[3-tert-butyl-1-phenyl-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxy-2H-chromene Base)] urea

Dissolve 200 mg of the product obtained in Example 2 in 50 mL of absolute ethanol, add 0.2 g of palladium/carbon, heat to 60 ° C, dropwise add 1.0 mL of hydrazine hydrate, then heat to reflux for 6 hours, cool, filter, concentrate the filtrate, and separate by column to obtain the title Compound 149 mg, as a white solid.

¹ H-NMR (CDCl ₃ , 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, J=8.8Hz), 4.08(t, 2H, J=8.8Hz), 3.79(s, 3H), 2.62(t, 2H, J=6.8Hz), 1.92(p, 2H), 1.37 (s, 9H).

MS (FAB) m/z: 421.1 [M+1] ⁺ .

Example 6: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 1, intermediate 41 was changed to intermediate 40 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.69 (d, 1H, J=8.4Hz), 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, J=5.2Hz), 2.60(t, 2H), 2.59(t, 4H), 2.31( s, 3H), 1.91 (p, 2H), 1.34 (s, 9H).

MS (FAB) m/z: 534.2 [M+1] ⁺ .

Example 7: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-[8-(5-nitro-2H-chromenyl) ] urea

Using the preparation method of Example 1, intermediate 41 was changed to intermediate 73 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.19(d, 1H, J=9.2Hz), 7.87(s, 1H), 7.71(d, 1H, J=9.2Hz), 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+1] ⁺ .

Example 8: 1-[3-tert-butyl-1-phenyl-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morpholine base) ethoxy] -2H-chromenyl}} urea

Add 20 mL of dry dichloromethane into a 50 mL three-necked flask, cool to -10°C, add triphosgene (109 mg, 0.36 mmol), and slowly add intermediate 50 (280 mg, 1.0 mmol) dissolved in 10 mL of dry dichloromethane solution, a white precipitate was produced, reacted for 1 hour, and 0.4 mL of dry triethylamine was added dropwise, and the precipitate was dissolved. Add intermediate 12 (129mg, 0.6mmol), warm up to room temperature, react for 5 days, pour into 50mL water, extract 3 times with dichloromethane, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, column separation (washing Desystemization: petroleum ether/ethyl acetate) to obtain 136 mg of the title compound as white crystals, with a yield of 26.2%.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.67(d, 1H, J=8.4Hz), 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, J=10.8Hz), 4.04-4.06(m, 4H), 3.70(t, 4H, J=4.8Hz), 2.77(t, 2H, J=5.6 Hz), 2.56-2.61 (m, 6H), 1.90 (p, 2H), 1.34 (s, 9H).

MS (FAB) m/z: 520.2 [M+1] ⁺ .

Example 9: 1-[3-tert-butyl-1-(4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2- (4-morpholino)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 14 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.64 (d, 1H, J=8.8Hz), 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, J=4.8Hz), 2.79(t, 2H, J=5.6Hz), 2.56-2.59(m, 6H), 1.90( p, 2H), 1.32 (s, 9H).

MS (FAB) m/z: 538.1 [M+1] ⁺ .

Example 10: 1-[3-tert-butyl-1-(4-chlorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2- (4-morpholino)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 15 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.63(d, 1H, J=8.0Hz), 7.42(m, 2H), 7.35(m, 2H), 7.11(s, 1H), 6.55(s, 1H ), 6.37(s, 1H), 6.34(d, 1H), 4.08(m, 4H), 3.74(t, 4H, J=4.4Hz), 2.82(t, 2H, J=5.6Hz), 2.62-2.65 (m, 6H), 1.94 (p, 2H), 1.36 (s, 9H).

MS (FAB) m/z: 554.0 [M+1] ⁺ .

Example 11: 1-[3-tert-butyl-1-(4-bromophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2- (4-morpholino)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 16 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.64(d, 1H, J=8.0Hz), 7.47(m, 2H), 7.37(m, 2H), 7.20(s, 1H), 6.88(s, 1H ), 6.37(s, 1H), 6.34(d, 1H, J=8.8Hz), 4.08(m, 4H), 3.73(t, 4H, J=4.4Hz), 2.83(t, 2H, J=5.6Hz ), 2.60-2.61 (m, 6H), 1.92 (p, 2H), 1.36 (s, 9H).

MS (FAB) m/z: 598.0 [M+1] ⁺ .

Example 12: 1-[3-tert-butyl-1-(4-methoxyphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[ 2-(4-Morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 13 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.70(d, 1H, J=8.4Hz), 7.35(m, 2H), 7.24(s, 1H), 6.90(m, 2H), 6.52(s, 1H ), 6.34(s, 1H), 6.32(d, 1H), 4.08(m, 4H), 3.79(s, 3H), 3.74(t, 4H, J=4.4Hz), 2.81(t, 2H, J= 6.0Hz), 2.59-2.63 (m, 6H), 1.93 (p, 2H), 1.35 (s, 9H).

MS (FAB) m/z: 550.1 [M+1] ⁺ .

Example 13: 1-[3-tert-butyl-1-(4-aminosulfonylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[ 2-(4-Morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 18 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.80(d, 2H, J=8.8Hz), 7.78(d, 2H, J=8.8Hz), 7.66(d, 1H), 6.29(d, 1H, J =9.2Hz), 5.56(s, 1H), 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+1] ⁺ .

Example 14: 1-[3-tert-butyl-1-(4-nitrophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 17 to obtain the title compound as a yellow solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.13(d, 2H, J=9.6Hz), 7.84(s, 1H), 7.73(d, 2H, J=9.2Hz), 7.55(d, 1H, J =8.4Hz), 7.43(s, 1H), 6.38(s, 1H), 6.29(d, 1H, J=8.8Hz), 4.07(m, 4H), 3.72(t, 4H, J=4.8Hz), 2.81 (t, 2H), 2.58-2.62 (m, 6H), 1.91 (p, 2H), 1.33 (s, 9H).

MS (FAB) m/z: 565.0 [M+1] ⁺ .

Example 15: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-[3,4-dihydro-5-(4 -morpholinoylmethoxy)-2H-chromenyl]}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 11, and intermediate 50 was changed to intermediate 59 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.75(d, 1H, J=9.2Hz), 7.34(d, 2H, J=8.4Hz), 7.25(d, 2H), 6.38(s, 1H), 6.34(d, 1H, J=9.2Hz), 4.64(s, 2H), 4.11(t, 2H, J=3.6Hz), 3.63-3.67(m, 8H), 2.67(t, 2H, J=6.4Hz ), 2.37 (s, 3H), 1.95 (p, 2H), 1.36 (s, 9H).

MS (FAB) m/z: 548.1 [M+1] ⁺ .

唑基)-3-{8-{3，4-二氢-5-[2-(4-吗啡啉基)乙氧基]-2H-色烯基}}脲Example 16: 1-(3-tert-butyl-5-iso

Azolyl)-3-{8-{3,4-dihydro-5-[2-(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 28 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.59(s, 1H), 7.67(d, 1H, J=8.0Hz), 6.36(d, 1H, J=9.2Hz), 6.12(s, 1H), 4.08-4.10(m, 4H), 3.75(t, 4H, J=4.4Hz), 2.83(t, 2H, J=5.6Hz), 2.60-2.64(m, 6H), 1.92(p, 2H), 1.30 (s, 9H).

MS (FAB) m/z: 445.1 [M+1] ⁺ .

唑基)-3-{8-{3，4-二氢-5-[2-(4-吗啡啉基)乙氧基]-2H-色烯基}}脲Example 17: 1-(5-tert-butyl-3-iso

Azolyl)-3-{8-{3,4-dihydro-5-[2-(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

唑，得到标题化合物，为白色固体。Using the preparation method of Example 8, the intermediate 12 is changed to 3-amino-5-tert-butyliso

azole to afford the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.75(s, 2H), 7.86(d, 1H, J=8.8Hz), 6.37(d, 1H, J=8.8Hz), 6.07(s, 1H), 4.23(t, 2H, J=4.8Hz), 4.10(t.2H), 3.74(t, 4H, J=4.4Hz), 2.82(t, 2H, J=5.2Hz), 2.61-2.67(m, 6H ), 1.99 (p, 2H), 1.34 (s, 9H).

MS (FAB) m/z: 445.1 [M+1] ⁺ .

Example 18: 1-[1-tert-butyl-3-(4-methylphenyl)-1H-4-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 33 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.70(s, 1H), 7.63(d, 1H, J=9.2Hz), 7.14-7.17(m, 4H), 6.86(s, 1H), 6.29(d , 1H, J=8.4Hz), 5.80(s, 1H), 4.04-4.06(m, 4H), 3.71(t, 4H, J=4.0Hz), 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+1] ⁺ .

Example 19: 1-[4-tert-butyl-1-(4-methylphenyl)-1H-2-imidazolyl]-3-{8-{3,4-dihydro-5-[2- (4-morpholino)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 35 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 11.56(s, 1H), 7.98(d, 1H, J=9.2Hz), 7.21-7.26(m, 4H), 6.75(s, 1H), 6.45(s , 1H), 6.37(d, 1H, J=8.8Hz), 4.29(t, 2H), 4.08(t, 2H, J=5.6Hz), 3.71(t, 4H, J=4.8Hz), 2.79(t , 2H), 2.70(t, 2H), 2.58(t, 4H, J=4.4Hz), 2.39(s, 3H), 2.32(p, 2H), 1.34(s, 9H).

MS (FAB) m/z: 534.2 [M+1] ⁺ .

Example 20: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(4-pyridyl)oxyethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 15, intermediate 59 was changed to intermediate 56 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.44 (dd, 2H, J=4.8Hz, 1.2Hz), 7.79 (d, 1H, J=8.8Hz), 7.33 (d, 2H, J=8.0Hz) , 7.28(s, 1H), 7.21(d, 2H), 6.91(dd, 2H, J=4.8Hz, 1.6Hz), 6.43(s, 1H), 6.40(d, 1H, J=9.2Hz), 6.37 (s, 1H), 4.40(t, 2H, J=5.2Hz), 4.33(t, 2H, J=5.2Hz), 4.12(t, 2H), 2.58(t, 2H, J=6.8Hz), 2.36 (s, 3H), 1.90 (p, 2H), 1.36 (s, 9H).

MS (FAB) m/z: 542.0 [M+1] ⁺ .

Example 21: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-{2 -[4-(cis-2,6-dimethyl)morpholinyl]ethoxy}-2H-chromenyl}}urea

Using the preparation method of Example 15, intermediate 59 was changed to intermediate 55 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.71(d, 1H, J=9.2Hz), 7.31(d, 2H, J=8.4Hz), 7.21(d, 2H), 7.17(s, 1H), 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, J=6.4Hz), 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+1] ⁺ .

Example 22: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(1-imidazolyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 15, intermediate 59 was changed to intermediate 52 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.88(d, 1H, J=8.8Hz), 7.73(s, 1H), 7.53(s, 1H), 7.32(d, 2H, J=8.0Hz), 7.15(d, 2H, J=8.0Hz), 6.93(s, 1H), 6.89(s, 1H), 6.41(s, 1H), 6.22(d, 1H, J=8.8Hz), 4.32(t, 2H , J=4.8Hz), 4.12(t, 2H, J=5.6Hz), 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+1] ⁺ .

Example 23: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(1-1,2,4-triazolyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 15, intermediate 59 was changed to intermediate 53 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.08(s 1H), 7.82-7.84(m, 2H), 7.45(s, 1H), 7.32(d, 2H, J=8.4Hz), 7.17(d, 2H, J=8.4Hz), 6.40(s, 1H), 6.27(d, 1H, J=9.2Hz), 4.56(t, 2H, J=4.8Hz), 4.23(t, 2H, J=4.8Hz) , 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+1] ⁺ .

Example 24: 1-[3-tert-butyl-1-(4-chlorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-{2- [4-(cis-2,6-dimethyl)morpholinyl]ethoxy}-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 15, and intermediate 50 was changed to intermediate 55 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.63 (d, 1H, J = 8.4Hz), 7.42 (d, 2H, J = 8.4Hz), 7.34 (d, 2H, J = 8.8Hz), 7.16 ( s, 1H), 6.96 (s, 1H), 6.37 (s, 1H), 6.34 (d, 1H, J=8.8Hz), 4.06-4.09 (m, 4H), 3.70 (m, 2H), 2.80-2.85 (m, 4H), 2.63 (t, 2H, J=6.4Hz), 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+1] ⁺ .

Example 25: 1-[3-tert-butyl-1-(3,4-dimethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5 -[2-(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 19 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.68(d, 1H, J=8.8Hz), 7.30(s, 1H), 7.19(s, 1H), 7.08-7.10(m, 2H), 6.80(s , 1H), 6.34(s, 1H), 6.32(d, 1H, J=8.8Hz), 4.04-4.06(m, 4H), 3.71(t, 4H, J=4.4Hz), 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+1] ⁺ .

Example 26: 1-[3-tert-butyl-1-(3,4-dichlorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5- [2-(4-Morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 20 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.76(d, 1H, J=2.0Hz), 7.58(d, 1H), 7.43(d, 1H, J=8.4Hz), 7.37(d, 1H), 7.17(s, 1H), 6.81(s, 1H), 6.37(s, 1H), 6.34(d, 1H, J=8.8Hz), 4.09-4.11(m, 4H), 3.74(t, 4H, J= 4.4Hz), 2.83(t, 2H, J=5.2Hz), 2.61-2.64(m, 6H), 1.94(p, 2H), 1.34(s, 9H).

MS (FAB) m/z: 588.0 [M+1] ⁺ .

Example 27: 1-[3-tert-butyl-1-(3-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 21 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.68(d, 1H, J=8.4Hz), 7.21-7.26(m, 4H), 7.11(d, 1H), 6.83(s, 1H), 6.36(s , 1H), 6.32(d, 1H, J=8.8Hz), 4.05-4.08(m, 4H), 3.73(t, 4H, J=4.4Hz), 2.80(t, 2H, J=5.6Hz), 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+1] ⁺ .

Example 28: 1-[(3-tert-butyl-1-naphthyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4- Morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 22 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.85-7.89 (m, 2H), 7.43-7.45 (m, 4H), 7.37 (d, 1H), 7.04 (s, 1H), 6.46 (m, 2H) , 6.19(d, 1H, J=8.8Hz), 4.03(t, 2H, J=5.6Hz), 3.97(t, 2H, J=4.8Hz), 3.70(t, 4H, J=4.4Hz), 2.80 (t, 2H, J = 5.2 Hz), 2.55-2.57 (m, 6H), 1.85 (p, 2H), 1.38 (s, 9H).

MS (FAB) m/z: 570.1 [M+1] ⁺ .

Example 29: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(1-pyrazolyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 15, intermediate 59 was changed to intermediate 54 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.71(d, 1H), 7.50-7.53(m, 2H), 7.31(d, 2H), 7.21(d, 2H, J=8.0Hz), 6.37(s , 1H), 6.30(d, 1H, J=8.4Hz), 6.26(t, 1H), 4.52(t, 2H, J=5.2Hz), 4.28(t, 2H, J=5.2Hz), 4.07(t , 2H, J=5.6Hz), 2.54(t, 2H, J=6.4Hz), 2.35(s, 3H), 1.91(p, 2H), 1.36(s, 9H).

MS (FAB) m/z: 515.1 [M+1] ⁺ .

Example 30: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(1-piperidin-4-one)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 15, intermediate 59 was changed to intermediate 51 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.73 (d, 1H, J=8.8Hz), 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, J=6.0Hz), 2.32( s, 3H), 1.91 (p, 2H), 1.35 (s, 9H).

MS (FAB) m/z: 546.0 [M+1] ⁺ .

Example 31: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(4-morpholino)acetamido]-2H-chromenyl}}urea

Using the preparation method of Example 15, intermediate 59 was changed to intermediate 81 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.94(d, 1H, J=8.8Hz), 7.47(s, 1H), 7.35(d, 2H, J=8.4Hz), 7.23(d, 2H, J =8.0Hz), 6.36-6.38(m, 2H), 4.12(t, 2H, J=4.4Hz), 3.79(t, 4H), 3.18(t, 2H), 2.61-2.68(m, 6H), 2.37 (s, 3H), 2.03 (p, 2H), 1.36 (s, 9H).

MS (FAB) m/z: 547.2 [M+1] ⁺ .

Example 32: 1-[3-tert-Butyl-1-(4-trifluoromethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5- [2-(4-Morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 26 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.61-7.65 (m, 5H), 7.07 (s, 1H), 6.60 (s, 1H), 6.41 (s, 1H), 6.34 (d, 1H, J= 8.8Hz), 4.07-4.09(m, 4H), 3.74(t, 4H, J=4.4Hz), 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+1] ⁺ .

Example 33: 1-[3-tert-butyl-1-(4-ethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 24 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.70 (d, 1H, J = 8.8Hz), 7.32 (d, 2H, J = 8.4Hz), 7.16 (d, 2H, J = 8.0Hz), 6.93 ( s, 1H), 6.34(s, 1H), 6.32(d, 1H, J=8.8Hz), 4.04-4.06(m, 4H), 3.70(t, 4H, J=4.8Hz), 2.78(t, 2H ), 2.57-2.61 (m, 8H), 1.90 (p, 2H), 1.34 (s, 9H), 1.18 (t, 3H, J=7.6Hz).

MS (FAB) m/z: 548.1 [M+1] ⁺ .

Example 34: 1-[3-tert-butyl-1-(4-tert-butylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[ 2-(4-Morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 25 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.72(d, 1H, J=8.8Hz), 7.34(d, 2H), 7.26(m, 2H), 7.18(s, 1H), 6.34-6.37(m , 3H), 4.08-4.11(m, 4H), 3.74(t, 4H, J=4.4Hz), 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+1] ⁺ .

Example 35: 1-[3-tert-Butyl-1-(4-trifluoromethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5- [2-(1-Imidazolyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 26, and intermediate 50 was changed to intermediate 52 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.08(s, 1H), 7.91(d, 1H, J=9.2Hz), 7.63(d, 2H, J=8.4Hz), 7.54(d, 2H, J =8.4Hz), 7.46(s, 1H), 6.86(s, 1H), 6.74(s, 1H), 6.51(s, 1H), 6.18(d, 1H, J=8.8Hz), 4.29(t, 2H , J=4.4Hz), 4.06(t, 2H, J=4.8Hz), 3.23(t, 2H), 2.18(t, 2H, J=6.4Hz), 1.34(s, 9H).

MS (FAB) m/z: 569.3 [M+1] ⁺ .

Example 36: 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl) )ethoxy]-2H-chromenyl}}urea

Add 20 mL of dry dichloromethane into a 50 mL three-necked flask, cool to -10°C, add triphosgene (109 mg, 0.36 mmol), and slowly add intermediate 65 (277 mg, 1.0 mmol) in 10 mL of dry dichloromethane solution, a white precipitate was produced, reacted for 1 hour, and 0.4 mL of dry triethylamine was added dropwise, and the precipitate was dissolved. Add intermediate 11 (138mg, 0.6mmol), warm up to room temperature, react for 5 days, pour into 50mL water, extract 3 times with dichloromethane, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, column separation (washing Desystemization: petroleum ether/ethyl acetate = 1:1) to obtain 145 mg of the title compound as white crystals, with a yield of 27.3%.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.74 (d, 1H, J = 8.8Hz), 7.33 (d, 2H, J = 8.4Hz), 7.21 (d, 2H, J = 8.0Hz), 7.13 ( s, 1H), 6.72-6.74(dd, 1H, J=8.4Hz, 1.6Hz), 6.39(d, 1H, J=9.2Hz), 6.35(s, 1H), 6.34(s, 1H), 5.72( m, 1H), 4.71(t, 2H, J=2.0Hz), 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+1] ⁺ .

Example 37: 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(4-pyridyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 11, and intermediate 50 was changed to intermediate 58 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.57(d, 2H, J=4.8Hz), 7.75(d, 1H, J=9.2Hz), 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=9.2Hz), 4.14(t, 2H, J=6.0Hz), 3.94(t , 2H), 3.10(t, 2H, J=6.0Hz), 2.47(t, 2H, J=6.4Hz), 2.28(s, 3H), 1.82(p, 2H), 1.34(s, 9H).

MS (FAB) m/z: 526.2 [M+1] ⁺ .

Example 38: 1-[3-tert-Butyl-1-(4-cyanophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 27 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.63-7.70 (m, 5H), 7.18 (s, 1H), 6.96 (s, 1H), 6.40 (s, 1H), 6.35 (d, 1H, J= 9.2Hz), 4.08-4.11(m, 4H), 3.73(t, 4H, J=4.4Hz), 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+1] ⁺ .

Example 39: 1-[3-tert-Butyl-1-(3-chloro-4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5 -[2-(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 8, intermediate 12 was changed to intermediate 23 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 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, J=4.0Hz), 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+1] ⁺ .

Example 40: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[(4-methoxyphenyl) )methoxy]-2H-chromenyl}}urea

Intermediate 62 (617mg, 2mmol) was dissolved in 25mL ethyl acetate and 25mL ethanol, and stannous chloride dihydrate (1.80g, 8mmol) was added in batches, the reaction solution became turbid, heated to reflux for 8 hours, cooled, and saturated bicarbonate was added Sodium solution, until there are obvious layers, separate the layers, extract the aqueous layer twice with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 541 mg of the reduced product, with a yield of 95% .

Add 30 mL of dry dichloromethane into a 100 mL three-necked flask, cool to -10°C, add triphosgene (208 mg, 0.70 mmol), and slowly add the product (541 mg, 1.9 mmol) obtained in the previous step into 20 mL of dry dichloromethane. In the solution of methyl chloride, a white precipitate was produced. After reacting for 1 hour, 1.0 mL of dry triethylamine was added dropwise, and the precipitate was dissolved. Add intermediate 11 (261mg, 1.14mmol), warm up to room temperature, react for 5 days, pour into 50mL water, extract 3 times with dichloromethane, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, column separation (washing Desystemization: petroleum ether/ethyl acetate = 1:1) to obtain 350 mg of the title compound as white crystals, with a yield of 34.2%.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.68(d, 1H, J=8.8Hz), 7.32-7.35(m, 4H), 7.17(m, 2H), 6.91(d, 2H, J=8.8Hz ), 6.77(d, 1H), 6.46(d, 1H, J=9.2Hz), 6.36(s, 1H), 5.68(m, 1H), 4.95(t, 2H), 4.68(t, 2H, J= 1.6Hz), 3.83(s, 3H), 2.33(s, 3H), 1.35(s, 9H).

MS (FAB) m/z: 526.2 [M+1] ⁺ .

Example 41: 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-[5-(4-morpholinoylmethoxy) base)-2H-chromenyl]}urea

Using the preparation method of Example 36, intermediate 50 was changed to intermediate 59 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.76(d, 1H, J=9.2Hz), 7.34(d, 2H, J=8.4Hz), 7.22(d, 2H), 6.72(d, 1H, J =10.0Hz), 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+1] ⁺ .

Example 42: 1-[3-tert-Butyl-1-(4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl) Ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 14 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.67(d, 1H, J=8.4Hz), 7.43(m, 2H), 7.07-7.11(m, 3H), 6.73(d, 1H, J=10.4Hz ), 6.58(s, 1H), 6.38(d, 1H, J=9.2Hz), 6.35(s, 1H), 5.73(m, 1H), 4.71(t, 2H, J=2.0Hz), 4.11(t , 2H, J=5.2Hz), 3.75(t, 4H), 2.83(t, 2H), 2.61(t, 4H), 1.35(s, 9H).

MS (FAB) m/z: 536.2 [M+1] ⁺ .

Example 43: 1-[3-tert-Butyl-1-(4-chlorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl) Ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 15 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.65(d, 1H, J=8.8Hz), 7.43(d, 2H), 7.35(d, 2H, J=8.8Hz), 7.10(s, 1H), 6.74(d, 1H, J=10.0Hz), 6.68(s, 1H), 6.36-6.38(m, 2H), 5.72(m, 1H), 4.69(t, 2H, J=2.0Hz), 4.10(t , 2H, J=5.2Hz), 3.74(t, 4H, J=4.4Hz), 2.81(t, 2H, J=4.8Hz), 2.59(t, 4H), 1.35(s, 9H).

MS (FAB) m/z: 552.2 [M+1] ⁺ .

Example 44: 1-[3-tert-Butyl-1-(4-bromophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl) Ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 16 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.65(d, 1H), 7.50(d, 2H, J=8.8Hz), 7.36(d, 2H, J=8.8Hz), 7.12(s, 1H), 6.77(s, 1H), 6.73(d, 1H, J=10.4Hz), 6.38(d, 1H, J=7.2Hz), 6.36(s, 1H), 5.72(m, 1H), 4.69(t, 2H , J=1.6Hz), 4.10(t, 2H, J=1.6Hz), 3.74(t, 4H, J=4.4Hz), 2.82(t, 2H, J=4.8Hz), 2.60(t, 4H), 1.34(s, 9H).

MS (FAB) m/z: 598.0 [M+1] ⁺ .

Example 45: 1-(3-tert-Butyl-1-phenyl-1H-5-pyrazolyl)-3-{8-{5-[2-(4-morpholinyl)ethoxy]- 2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 12 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.71(d, 1H, J=8.8Hz), 7.45(d, 2H), 7.40(t, 2H), 7.29(t, 1H), 7.20(s, 1H ), 6.72(d, 1H, J=10.0Hz), 6.69(s, 1H), 6.36-6.38(m, 2H), 5.71(m, 1H), 4.69(t, 2H, J=2.0Hz), 4.09 (t, 2H), 3.73 (t, 4H, J = 4.4Hz), 2.81 (t, 2H, J = 5.2Hz), 2.59 (t, 4H), 1.36 (s, 9H).

MS (FAB) m/z: 518.1 [M+1] ⁺ .

Example 46: 1-[3-tert-Butyl-1-(4-methoxyphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholine) base) ethoxy] -2H-chromenyl}} urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 13 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.72(d, 1H, J=8.8Hz), 7.33(d, 2H, J=9.2Hz), 7.25(s, 1H), 6.88(d, 2H, J =9.2Hz), 6.75(d, 1H), 6.73(s, 1H), 6.36(d, 1H), 6.33(s, 1H), 5.70(m, 1H), 4.67(t, 2H, J=1.6Hz ), 4.10(t, 2H), 3.77(s, 3H), 3.74(t, 4H, J=4.4Hz), 2.80(t, 2H, J=5.6Hz), 2.59(t, 4H), 1.35(s , 9H).

MS (FAB) m/z: 548.1 [M+1] ⁺ .

Example 47: 1-[3-tert-Butyl-1-(4-trifluoromethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine Phenyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 26 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.65 (m, 5H), 7.07 (s, 1H), 6.76 (s, 1H), 6.73 (d, 1H, J=9.6Hz), 6.40 (s, 1H) ), 6.38(d, 1H, J=8.8Hz), 5.70(m, 1H), 4.70(t, 2H, J=1.6Hz), 4.10(t, 2H, J=5.2Hz), 3.74(t, 4H , J=4.0Hz), 2.82(t, 2H), 2.60(t, 4H), 1.36(s, 9H).

MS (FAB) m/z: 586.1 [M+1] ⁺ .

Example 48: 1-[3-tert-Butyl-1-(4-nitrophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl) )ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 17 to obtain the title compound as a yellow solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.18(d, 2H, J=9.2Hz), 7.74(d, 2H, J=8.8Hz), 7.55(d, 1H), 7.30(s, 1H), 6.71(d, 1H, J=10.0Hz), 6.39(s, 1H), 6.34(d, 1H, J=9.2Hz), 5.70(m, 1H), 4.68(t, 2H, J=1.6Hz), 4.09(t, 2H, J=6.0Hz), 3.74(t, 4H, J=4.4Hz), 2.81(t, 2H, J=6.0Hz), 2.60(t, 4H), 1.34(s, 9H).

MS (FAB) m/z: 563.0 [M+1] ⁺ .

Example 49: 1-[3-tert-Butyl-1-(4-cyanophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl) )ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 27 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.64-7.70 (m, 5H), 7.15 (s, 1H), 7.05 (s, 1H), 6.74 (d, 1H, J=10.0Hz), 6.40 (s , 1H), 6.38(d, 1H, J=8.8Hz), 5.73(m, 1H), 4.71(t, 2H, J=1.6Hz), 4.11(t, 2H, J=4.4Hz), 3.74(t , 4H, J=4.8Hz), 2.83(t, 2H), 2.61(t, 4H), 1.34(s, 9H).

MS (FAB) m/z: 543.1 [M+1] ⁺ .

Example 50: 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(1-1,2 , 4-triazolyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 65 was changed to intermediate 69 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.10(s, 1H), 7.86(s, 1H), 7.83(d, 1H, J=8.0Hz), 7.38(s, 1H), 7.32(d, 2H , J=8.4Hz), 7.18(d, 2H), 6.39(s, 1H), 6.36(d, 1H), 6.29(d, 1H, J=9.2Hz), 5.47(m, 1H), 4.55(t , 2H, J=4.8Hz), 4.44(t, 2H), 4.28(t, 2H, J=4.8Hz), 2.33(s, 3H), 1.35(s, 9H).

MS (FAB) m/z: 514.2 [M+1] ⁺ .

Example 51: 1-[3-tert-Butyl-1-(4-ethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl) )ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 24 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.74(d, 1H, J=8.8Hz), 7.36(d, 2H, J=8.4Hz), 7.25(d, 2H), 7.14(s, 1H), 6.73(d, 1H, J=10.0Hz), 6.35-6.40(m, 3H), 5.72(m, 1H), 4.71(t, 2H, J=2.0Hz), 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+1] ⁺ .

Example 52: 1-[3-tert-Butyl-1-(4-tert-butylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholine base) ethoxy] -2H-chromenyl}} urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 25 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.74(d, 1H, J=9.2Hz), 7.34(d, 2H), 7.26(d, 2H), 7.15(s, 1H), 6.73(d, 1H , J=10.0Hz), 6.43(s, 1H), 6.39(d, 1H, J=9.2Hz), 6.35(s, 1H), 5.72(m, 1H), 4.71(t, 2H, J=2.0Hz ), 4.09(t, 2H, J=5.2Hz), 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+1] ⁺ .

Example 53: 1-[3-tert-Butyl-1-(3-chloro-4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4- Morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 23 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.60(m, 2H), 7.38(m, 1H), 7.08-7.14(m, 3H), 6.72(d, 1H, J=9.6Hz), 6.38(d , 1H, J=8.8Hz), 6.35(s, 1H), 5.72(m, 1H), 4.70(t, 2H, J=1.6Hz), 4.10(t, 2H, J=5.2Hz), 3.74(t , 4H, J=4.4Hz), 2.83(t, 2H), 2.61(t, 4H), 1.34(s, 9H).

MS (FAB) m/z: 570.0 [M+1] ⁺ .

Example 54: 1-[3-tert-Butyl-1-(3,4-dimethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4- Morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 19 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.72(d, 1H, J=8.8Hz), 7.12-7.21(m, 4H), 6.72(d, 1H, J=10.4Hz), 6.60(s, 1H ), 6.38(d, 1H), 6.34(s, 1H), 5.70(m, 1H), 4.68(t, 2H, J=2.0Hz), 4.10(t, 2H, J=5.6Hz), 3.74(t , 4H, J=4.4Hz), 2.82(t, 2H, J=5.6Hz), 2.60(t, 4H), 2.23(s, 3H), 2.21(s, 3H), 1.35(s, 9H).

MS (FAB) m/z: 546.0 [M+1] ⁺ .

Example 55: 1-[3-tert-Butyl-1-(3,4-dichlorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine Phenyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 20 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.67(s, 1H), 7.58(d, 1H), 7.45(s, 1H), 7.38(m, 2H), 7.23(s, 1H), 6.71(d , 1H, J=10.0Hz), 6.36(d, 1H, J=9.2Hz), 6.35(s, 1H), 5.69(m, 1H), 4.68(t, 2H, J=1.6Hz), 4.10(t , 2H, J=5.6Hz), 3.73(t, 4H, J=4.8Hz), 2.82(t, 2H, J=5.2Hz), 2.60(t, 4H), 1.34(s, 9H).

MS (FAB) m/z: 586.0 [M+1] ⁺ .

唑基)-3-{8-{5-[2-(4-吗啡啉基)乙氧基]-2H-色烯基}}脲Example 56: 1-(3-tert-Butyl-5-iso

Azolyl)-3-{8-{5-[2-(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 28 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 9.27(s, 1H), 7.74(d, 1H, J=8.8Hz), 7.40(s, 1H), 6.67(d, 1H, J=10.0Hz), 6.37(d, 1H, J=9.2Hz), 6.13(s, 1H), 5.63(m, 1H), 4.62(t, 2H, J=1.6Hz), 4.10(t, 2H, J=5.6Hz), 3.77(t, 4H, J=4.4Hz), 2.83(t, 2H, J=5.2Hz), 2.69(t, 4H), 1.30(s, 9H).

MS (FAB) m/z: 443.0 [M+1] ⁺ .

唑基)-3-{8-{5-[2-(4-吗啡啉基)乙氧基]-2H-色烯基}}脲Example 57: 1-(5-tert-Butyl-3-iso

Azolyl)-3-{8-{5-[2-(4-morpholinyl)ethoxy]-2H-chromenyl}}urea

唑，得到标题化合物，为白色固体。Using the preparation method of Example 36, the intermediate 11 was changed to 3-amino-5-tert-butyliso

azole to afford the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.77(s, 1H), 8.27(s, 1H), 7.86(d, 1H, J=8.8Hz), 6.75(d, 1H, J=10.0Hz), 6.42(d, 1H, J=9.6Hz), 6.02(s, 1H), 5.76(m, 1H), 4.84(t, 2H, J=2.0Hz), 4.12(t, 2H, J=6.8Hz), 3.76(t, 4H), 2.84(t, 2H), 2.62(t, 4H), 1.36(s, 9H).

MS (FAB) m/z: 443.0 [M+1] ⁺ .

Example 58: 1-[1-tert-Butyl-3-(4-methylphenyl)-1H-4-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl) )ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 33 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.67-7.70 (m, 2H), 7.18-7.20 (m, 4H), 6.73 (d, 1H, J=10.0Hz), 6.68 (s, 1H), 6.36 (d, 1H, J=9.2Hz), 5.72(m, 1H), 5.49(s, 1H), 4.71(t, 2H, J=2.0Hz), 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+1] ⁺ .

Example 59: 1-[3-tert-Butyl-1-(3-methylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl) )ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 21 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.22(d, 1H, J=8.8Hz), 7.26-7.29(m, 3H), 7.15(d, 2H), 6.73(d, 1H, J=10.0Hz ), 6.58(s, 1H), 6.38(d, 1H, J=9.6Hz), 6.36(s, 1H), 5.72(m, 1H), 4.71(t, 2H, J=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 [M+1] ⁺ .

Example 60: 1-[(3-tert-Butyl-1-naphthyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morpholinyl)ethoxy ]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 22 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.88-7.90 (m, 2H), 7.48-7.50 (m, 5H), 7.38 (d, 1H), 6.95 (s, 1H), 6.68 (d, 1H, J=10.0Hz), 6.48(s, 1H), 6.24-6.27(m, 2H), 5.67(m, 1H), 4.63(t, 2H, J=1.6Hz), 4.07(t, 2H, J=5.2 Hz), 3.75(t, 4H, J=4.4Hz), 2.82(t, 2H), 2.61(t, 4H), 1.40(s, 9H).

MS (FAB) m/z: 568.1 [M+1] ⁺ .

Example 61: 1-[4-tert-Butyl-1-(4-methylphenyl)-1H-2-imidazolyl]-3-{8-{5-[2-(4-morpholinyl) Ethoxy]-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 11 was changed to intermediate 35 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 8.03(d, 1H, J=9.2Hz), 7.26-7.30(m, 5H), 6.78(d, 1H, J=10.0Hz), 6.44(s, 1H ), 6.41(d, 1H, J=9.2Hz), 5.77(m, 1H), 4.88(t, 2H), 4.13(t, 2H, J=6.8Hz), 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+1] ⁺ .

Example 62: 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{5-{2-[4-(cis -2,6-Dimethyl)morpholinyl]ethoxy}-2H-chromenyl}}urea

Using the preparation method of Example 36, intermediate 50 was changed to intermediate 66 to obtain the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400MHz) δ: 7.74 (d, 1H, = 9.2Hz), 7.33 (d, 2H, J = 8.0Hz), 7.22 (d, 2H), 7.14 (s, 1H), 6.74 (d, 1H, J=10.0Hz), 6.45(s, 1H), 6.39(d, 1H, J=9.2Hz), 6.35(s, 1H), 5.72(m, 1H), 4.71(t, 2H, J=1.6Hz), 4.12(t, 2H, J=4.0Hz), 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).

MS (FAB) m/z: 532.4 [M+1] ⁺ .

Claims (11)

1. compound of Formula I, or its pharmacologically acceptable salt,

Wherein:

Ar ₁Be pyrazolyl, imidazolyl Huo isoxazolyl; Said Ar ₁Independently by one or more R ₁, R ₂Replace;

Ar ₂Be benzopyranyl or chromanyl;

L independently does

(1) key;

(2) C ₁-C ₄Saturated or undersaturated, the straight or branched carbochain; One or more methylene radical wherein are independent of O, and a NH or 0-2 carbonyl substitutes; And said spacer group can be replaced by one or more halogen atoms;

P is an imidazolyl, pyrazolyl, 1,2,4-triazol radical, morpholinyl or piperidone base; Said group can be chosen wantonly by 1-3 and be selected from following substituting group replacement: C ₁-C ₆The straight or branched alkyl;

R ¹Independently be C ₁-C ₁₀The straight or branched alkyl;

R ²Independently be phenyl or naphthyl, said phenyl or naphthyl can be independently by 0-5 R ⁴Group replaces;

R ³It independently is Wasserstoffatoms;

R ⁴Independently be halogen, nitro, C ₁-C ₆The straight or branched alkyl, itrile group, C ₁-C ₆The straight or branched alkoxyl group, trifluoromethyl; R ³NHS (O) _m-, m is 0,1 or 2.

2. following compound, it is selected from:

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxyl group-2H-chromenyl)] urea

1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-[8-(5-methoxyl group-2H-chromenyl)] urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(5-methoxyl group-2H-chromenyl)] urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{5-{8-[2-(4-morphine quinoline base) acetamido]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-phenyl-1H-5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxyl group-2H-chromenyl)] urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-[8-(5-nitro-2H-chromenyl)] urea

1-[the 3-tertiary butyl-1-phenyl-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-bromophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-p-methoxy-phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-amino-sulfonyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-nitrophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-[3,4-dihydro-5-(4-morphine quinoline base acyl group methoxyl group)-2H-chromenyl] } urea

1-(the 3-tertiary butyl-5-isoxazolyl)-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-(the 5-tertiary butyl-3-isoxazolyl)-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 1-tertiary butyl-3-(4-aminomethyl phenyl)-1H-4-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 4-tertiary butyl-1-(4-aminomethyl phenyl)-1H-2-imidazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-pyridyl) oxygen base oxethyl]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-{2-[4-(cis-2,6-dimethyl-) morphine quinoline base] oxyethyl group }-the 2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-imidazolyl) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-1,2,4-triazol radical) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-{2-[4-(cis-2,6-dimethyl-) morphine quinoline base] oxyethyl group }-the 2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(3, the 4-3,5-dimethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(3, the 4-dichlorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(3-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[(the 3-tertiary butyl-1-naphthyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-pyrazolyl) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-piperidin-4-one-base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) acetamido]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-trifluoromethyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-ethylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-tert-butyl-phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-trifluoromethyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(1-imidazolyl) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-pyridyl) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-itrile group phenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(3-chloro-4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[(4-p-methoxy-phenyl) methoxyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-[5-(4-morphine quinoline base acyl group methoxyl group)-2H-chromenyl] } urea

1-[the 3-tertiary butyl-1-(4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(4-chloro-phenyl-)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(4-bromophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-(the 3-tertiary butyl-1-phenyl-1H-5-pyrazolyl)-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(4-p-methoxy-phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(4-trifluoromethyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(4-nitrophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(4-itrile group phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(1-1,2,4-triazol radical) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(4-ethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(4-tert-butyl-phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(3-chloro-4-fluorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(3, the 4-3,5-dimethylphenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(3, the 4-dichlorophenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-(the 3-tertiary butyl-5-isoxazolyl)-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-(the 5-tertiary butyl-3-isoxazolyl)-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 1-tertiary butyl-3-(4-aminomethyl phenyl)-1H-4-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(3-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[(the 3-tertiary butyl-1-naphthyl)-1H-5-pyrazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 4-tertiary butyl-1-(4-aminomethyl phenyl)-1H-2-imidazolyl]-3-{8-{5-[2-(4-morphine quinoline base) oxyethyl group]-2H-chromenyl } } urea

1-[the 3-tertiary butyl-1-(4-aminomethyl phenyl)-1H-5-pyrazolyl]-3-{8-{5-{2-[4-(cis-2,6-dimethyl-) morphine quinoline base] oxyethyl group }-the 2H-chromenyl } urea

With and pharmacologically acceptable salt.

3. the method for preparing the said compound of Formula I of claim 1, this method comprises the compound of following formula:

With P-L-Ar ₂-NH ₂At suitable solvent, obtained the compound of formula I in 1 hour to 120 hours in 0 ℃-100 ℃ reactions in the suitable alkali, wherein, Ar ₁, Ar ₂, L, the same general formula I of the definition of P, R ⁶Be trichloromethyl, p-nitrophenyl, oxyethyl group, imidazolyl or triazolyl.

4. the described method of claim 3, wherein said formula (A) compound is following:

Make the compound of following formula:

With Ar ₁NH ₂At suitable solvent, obtained the compound of formula (A) in 10 minutes to 24 hours in-15 ℃-25 ℃ reactions in the suitable alkali, wherein, Ar ₁The same general formula I of definition, R ⁶Be trichloromethyl, p-nitrophenyl, oxyethyl group, imidazolyl or triazolyl.

5. the method for preparing the said compound of Formula I of claim 1, this method comprises the compound of following formula:

With Ar ₁NH ₂At suitable solvent, obtained the compound of formula I in 1 hour to 120 hours in 0 ℃-100 ℃ reactions in the suitable alkali, wherein, Ar ₁, Ar ₂, L, the same general formula I of the definition of P, R ⁶Be trichloromethyl, p-nitrophenyl, oxyethyl group, imidazolyl or triazolyl.

6. the described method of claim 5, wherein said formula (B) compound is following:

Make the compound of following formula:

With P-L-Ar ₂-NH ₂At suitable solvent, obtained the compound of formula (B) in 10 minutes to 24 hours in-15 ℃-25 ℃ reactions in the suitable alkali, wherein, Ar ₂, L, the same general formula I of the definition of P, R ⁶Be trichloromethyl, p-nitrophenyl, oxyethyl group, imidazolyl or triazolyl.

7. medicinal compsns, it contains claim 1 or 2 each compound or pharmaceutically acceptable salt thereof and at least a pharmaceutically acceptable carrier or vehicle.

8. the medicinal compsns of claim 7, wherein said vehicle is a thinner.

9. claim 1 or 2 each compounds are used to prepare the alpha mediated disease of treatment TNF-, the purposes of the medicine of risk factor or illness.

10. the purposes of claim 9, wherein said disease, risk factor or illness are arthritic psoriasis, conjunctivo-urethro-synovial syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis; Rheumatoid arthritis, osteo-arthritis, urarthritis, septic shock, endotoxin shock, Gram-negative, septicemia; Toxic shock syndrome, cerebral malaria, meningitis, ischemic stroke and hemorrhagic stroke, neurotrauma/closed trauma of head, asthma; Adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, silicosis, lung sarcosis, bone absorpting disease; Osteoporosis, restenosis, heart and brain and renal reperfusion injury, congestive heart failure, coronary artery bypass bridging (CABG) art, blood examination forms; Glomerulonephritis, chronic renal failure, mellitus, diabetic retinopathy, degeneration of macula, graft-vs-host reaction; Homograft rejection, inflammatory bowel disease, Crohn disease, ulcerative colitis neurodegenerative disease, muscle deterioration, tumor growth and transfer; The pneumonia that vasculogenesis disease, influenza cause, eczema, contact dermatitis, psoriasis, sunburn or conjunctivitis.

11. claim 1 or 2 each compounds are used to prepare the purposes that suppresses p38 protein kinase medicine.