CN110869360A - 作为rock抑制剂的苯乙酰胺类 - Google Patents
作为rock抑制剂的苯乙酰胺类 Download PDFInfo
- Publication number
- CN110869360A CN110869360A CN201880045811.XA CN201880045811A CN110869360A CN 110869360 A CN110869360 A CN 110869360A CN 201880045811 A CN201880045811 A CN 201880045811A CN 110869360 A CN110869360 A CN 110869360A
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- Prior art keywords
- alkyl
- nhco
- radical
- independently
- heterocycle
- Prior art date
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- Granted
Links
- 239000011435 rock Substances 0.000 title abstract description 44
- 239000003112 inhibitor Substances 0.000 title abstract description 13
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical class NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 133
- 238000000034 method Methods 0.000 claims abstract description 84
- 150000003839 salts Chemical class 0.000 claims abstract description 51
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 210000002460 smooth muscle Anatomy 0.000 claims abstract description 5
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 4
- 150000003254 radicals Chemical class 0.000 claims description 136
- 125000000623 heterocyclic group Chemical group 0.000 claims description 100
- -1 Phenyl Chemical group 0.000 claims description 98
- 125000000217 alkyl group Chemical group 0.000 claims description 67
- 229910052736 halogen Inorganic materials 0.000 claims description 59
- 150000002367 halogens Chemical class 0.000 claims description 53
- 125000004432 carbon atom Chemical group C* 0.000 claims description 51
- 229910052757 nitrogen Inorganic materials 0.000 claims description 50
- 238000006467 substitution reaction Methods 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 229910052760 oxygen Inorganic materials 0.000 claims description 33
- 125000005842 heteroatom Chemical group 0.000 claims description 31
- 229910052731 fluorine Inorganic materials 0.000 claims description 30
- 229910052801 chlorine Inorganic materials 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 20
- 230000000694 effects Effects 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 19
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 230000002401 inhibitory effect Effects 0.000 claims description 14
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 13
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 12
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 12
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 11
- 108010041788 rho-Associated Kinases Proteins 0.000 claims description 11
- 102000000568 rho-Associated Kinases Human genes 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 206010020772 Hypertension Diseases 0.000 claims description 10
- 125000002837 carbocyclic group Chemical group 0.000 claims description 10
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 208000006011 Stroke Diseases 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 230000001594 aberrant effect Effects 0.000 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 3
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 230000003176 fibrotic effect Effects 0.000 claims description 3
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 208000012902 Nervous system disease Diseases 0.000 claims 1
- 208000031481 Pathologic Constriction Diseases 0.000 claims 1
- 208000018262 Peripheral vascular disease Diseases 0.000 claims 1
- 206010047163 Vasospasm Diseases 0.000 claims 1
- 208000026106 cerebrovascular disease Diseases 0.000 claims 1
- 208000010125 myocardial infarction Diseases 0.000 claims 1
- 230000001613 neoplastic effect Effects 0.000 claims 1
- 208000037804 stenosis Diseases 0.000 claims 1
- 230000036262 stenosis Effects 0.000 claims 1
- 230000002526 effect on cardiovascular system Effects 0.000 abstract description 4
- 206010016654 Fibrosis Diseases 0.000 abstract description 2
- 230000004761 fibrosis Effects 0.000 abstract description 2
- 230000001363 autoimmune Effects 0.000 abstract 1
- 230000007171 neuropathology Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 116
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 93
- 239000011541 reaction mixture Substances 0.000 description 81
- 238000005160 1H NMR spectroscopy Methods 0.000 description 79
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- 239000000543 intermediate Substances 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 53
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 52
- 238000004128 high performance liquid chromatography Methods 0.000 description 48
- 230000014759 maintenance of location Effects 0.000 description 45
- 239000007787 solid Substances 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- 229910001868 water Inorganic materials 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
- 230000002829 reductive effect Effects 0.000 description 41
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- 235000019439 ethyl acetate Nutrition 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- 239000002904 solvent Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 235000005152 nicotinamide Nutrition 0.000 description 26
- 239000011570 nicotinamide Substances 0.000 description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 25
- 239000000460 chlorine Substances 0.000 description 24
- 239000012453 solvate Substances 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 239000012267 brine Substances 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- 239000000651 prodrug Substances 0.000 description 20
- 229940002612 prodrug Drugs 0.000 description 20
- 239000012044 organic layer Substances 0.000 description 19
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 239000003814 drug Substances 0.000 description 16
- 230000000670 limiting effect Effects 0.000 description 16
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 238000004007 reversed phase HPLC Methods 0.000 description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- 125000005605 benzo group Chemical group 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 230000008878 coupling Effects 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 8
- 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 7
- 101150111584 RHOA gene Proteins 0.000 description 7
- 125000002619 bicyclic group Chemical group 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 229940124597 therapeutic agent Drugs 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 6
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 6
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- URJOUYRTHKWERB-UHFFFAOYSA-N 3-(difluoromethoxy)pyridin-2-amine Chemical compound NC1=NC=CC=C1OC(F)F URJOUYRTHKWERB-UHFFFAOYSA-N 0.000 description 5
- KJZJEUCIXBKYCH-UHFFFAOYSA-N ClC=1C=C(C=CC=1OC1=NC=CC=C1C#N)CC(=O)O Chemical compound ClC=1C=C(C=CC=1OC1=NC=CC=C1C#N)CC(=O)O KJZJEUCIXBKYCH-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229910052796 boron Inorganic materials 0.000 description 5
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 125000002883 imidazolyl group Chemical group 0.000 description 5
- 125000001041 indolyl group Chemical group 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 125000003373 pyrazinyl group Chemical group 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- DEPDDPLQZYCHOH-UHFFFAOYSA-N 1h-imidazol-2-amine Chemical compound NC1=NC=CN1 DEPDDPLQZYCHOH-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- RLIPCWGTDDONRJ-UHFFFAOYSA-N 2-[4-(3-carbamoylpyridin-2-yl)oxyphenyl]acetic acid Chemical compound NC(=O)C1=CC=CN=C1OC1=CC=C(CC(O)=O)C=C1 RLIPCWGTDDONRJ-UHFFFAOYSA-N 0.000 description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 4
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- WWNWNNKPTBFUAN-UHFFFAOYSA-N C(#N)C=1C(=NC=CC=1)OC1=C(C=C(C=C1)CC(=O)Cl)F Chemical compound C(#N)C=1C(=NC=CC=1)OC1=C(C=C(C=C1)CC(=O)Cl)F WWNWNNKPTBFUAN-UHFFFAOYSA-N 0.000 description 4
- ANRFNVFWNXDAPU-UHFFFAOYSA-N CC1=C(N=C(S1)N)C1=NC(=CC=C1)C Chemical compound CC1=C(N=C(S1)N)C1=NC(=CC=C1)C ANRFNVFWNXDAPU-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- 208000010228 Erectile Dysfunction Diseases 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 229910052805 deuterium Inorganic materials 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- NGOGFTYYXHNFQH-UHFFFAOYSA-N fasudil Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 description 4
- 229960002435 fasudil Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 125000004438 haloalkoxy group Chemical group 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
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Abstract
本申请提供式(I)化合物或其立体异构体、互变异构体或药学上可接受的盐,其中所有变量如本申请所定义。这些化合物为选择性ROCK抑制剂。本申请还涉及包含这些化合物的药物组合物及使用其治疗心血管、平滑肌、肿瘤学、神经病理学、自身免疫性、纤维化和/或炎性病症的方法。
Description
相关申请的交叉引用
本申请根据35U.S.C.§119(e)享有2017年7月12日提交的美国临时申请号62/531,624的优先权,将该临时申请的全部内容引入到本申请中。
技术领域
本申请总体上涉及作为Rho激酶抑制剂的新颖苯乙酰胺类及其类似物、含有其的组合物及使用其例如治疗或预防与异常Rho激酶活性相关的病症的方法。
背景技术
Rho激酶(ROCK)为丝氨酸-苏氨酸蛋白激酶家族的成员。ROCK以两种同工型即ROCK1和ROCK2存在(Ishizaki,T.等人,EMBO J.,15:1885-1893(1996))。已鉴定ROCK为RhoA的效应子分子,而RhoA为在多种细胞信号传导路径中发挥关健作用的小GTP结合蛋白(G蛋白)。ROCK和RhoA在各种组织中普遍表达。RhoA/ROCK信号传导路径参与多种细胞功能例如组织、细胞粘附、细胞迁移和细胞分裂(Riento,K.等人,Nat.Rev.Mol CellBiol.,4:446-456(2003))。其还直接参与调节平滑肌收缩(Somlyo,A.P.,Nature,389:908-911(1997))。RhoA在其受体活化后活化且其又活化ROCK。经活化的ROCK使肌球蛋白轻链磷酸酶的肌球蛋白结合亚基磷酸化,从而抑制所述磷酸酶的活性且引起收缩。血管平滑肌的收缩使血压升高,这导致高血压。
在文献中有相当多的证据表明RhoA/ROCK信号传导路径在由数种血管活性因子启动的信号转导中发挥重要作用,所述血管活性因子为例如血管紧张素II(Yamakawa,T.等人,Hypertension,35:313-318(2000))、尿压素II(Sauzeau,V.等人,Circ.Res.,88:1102-1104(2001))、内皮素-1(Tangkijvanich,P.等人,Hepatology,33:74-80(2001))、血清素(Shimokawa,H.,Jpn.Circ.J.,64:1-12(2000))、去甲肾上腺素(Martinez,M.C.等人,Am.J.Physiol.,279:H1228-H1238(2000))和血小板衍生生长因子(PDGF)(Kishi,H.等人,J.Biochem.,128:719-722(2000))。这些因子中的多种参与心血管疾病的发病机理。
文献中的其它研究[一些研究使用已知的ROCK抑制剂法舒地尔(Asano,T.等人,J.Pharmacol Exp.Ther.,241:1033-1040(1987))或Y-27632(Uehata,M.等人,Nature,389:990-994(1997))]进一步表明了ROCK与心血管疾病之间的关联。例如,已证实ROCK表达和活性在自发性高血压大鼠中是提高的,这表明与这些动物中高血压发展的关联(Mukai,Y.等人,FASEB J.,15:1062-1064(2001))。证实ROCK抑制剂Y-27632(Uehata,M.等人,Nature,同上)在高血压的三种大鼠模型(包括自发性高血压大鼠、肾高血压大鼠和乙酸去氧可的松高血压大鼠模型)中显著降低血压,而在对照大鼠中对血压仅具有轻微作用。这补充说明了ROCK与高血压之间的关联。
其它研究表明了ROCK与动脉粥样硬化之间的关联。例如,ROCK的显性阴性形式的基因转移抑制猪股动脉在泡沫化损伤后的新内膜形成(Eto,Y.等人,Am.J.Physiol.HeartCirc.Physiol.,278:H1744-H1750(2000))。在类似的模型中,ROCK抑制剂Y-27632还抑制大鼠的新内膜形成(Sawada,N.等人,Circulation,101:2030-2033(2000))。在由IL-1β诱发的冠状动脉狭窄的猪模型中,用ROCK抑制剂法舒地尔进行的长期治疗被证实逐渐减小冠状动脉狭窄和促进冠状动脉收缩重塑的消退(Shimokawa,H.等人,Cardiovascular.Res.,51:169-177(2001))。
其它研究表明ROCK抑制剂可用于治疗其它心血管疾病。例如,在大鼠中风模型中,法舒地尔被证实降低梗塞尺寸和神经缺陷(Toshima,Y.,Stroke,31:2245-2250(2000))。ROCK抑制剂Y-27632被证实在Dahl盐敏感性大鼠的充血性心力衰竭模型中改善心室肥大、纤维化和功能(Kobayashi,N.等人,Cardiovascular Res.,55:757-767(2002))。
其它动物或临床研究表明ROCK参与其它疾病,包括冠状血管痉挛(Shimokawa,H.等人,Cardiovasc.Res.,43:1029-1039(1999))、脑血管痉挛(Sato,M.等人,Circ.Res.,87:195-200(2000))、缺血/再灌注损伤(Yada,T.等人,J.Am.Coll.Cardiol.,45:599-607(2005))、肺动脉高压(Fukumoto,Y.等人,Heart,91:391-392(2005))、心绞痛(Shimokawa,H.等人,J.Cardiovasc.Pharmacol.,39:319-327(2002))、肾病(Satoh,S.等人,Eur.J.Pharmacol.,455:169-174(2002))和勃起功能障碍(Gonzalez-Cadavid,N.F.等人,Endocrine,23:167-176(2004))。
在另一项研究中已证实对RhoA/ROCK信号传导路径的抑制可形成破坏单核细胞产生性迁移的多重竞争性片状伪足(Worthylake,R.A.等人,J.Biol.Chem.,278:13578-13584(2003))。还已报道Rho激酶的小分子抑制剂能够在体外抑制由MCP-1介导的趋化性(Iijima,H.,Bioorg.Med.Chem.,15:1022-1033(2007))。由于免疫细胞迁移对RhoA/ROCK信号传导路径的依赖性而预期对Rho激酶的抑制也应该有益于类风湿性关节炎、牛皮癣和炎性肠病等疾病。
上述研究证实了ROCK与心血管疾病、肾病和勃起功能障碍之间的关联,所述心血管疾病包括高血压、动脉粥样硬化、再狭窄、中风、心力衰竭、冠状血管痉挛、脑血管痉挛、缺血/再灌注损伤、肺动脉高压和心绞痛。鉴于ROCK对平滑肌的经证实的作用,ROCK抑制剂还可用于涉及平滑肌高反应性的其它疾病,包括哮喘,和青光眼(Shimokawa,H.等人,Arterioscler.Thromb.Vase.Biol.,25:1767-1775(2005))。另外,Rho激酶已被证实作为用于治疗各种其它疾病的药物靶标,包括呼吸道炎症和高应答性(Henry,PJ.等人,Pulm.Pharmacol Ther.,18:67-74(2005))、癌症(Rattan,R.等人,J.Neurosci.Res.,83:243-255(2006);Lepley,D.等人,Cancer Res.,65:3788-3795(2005))、纤维化疾病(Jiang,C.等人,Int.J.Mol Sci.,13:8293-8307(2012);Zhou,L.等人,Am.J.Nephrol.,34:468-475(2011))和神经病症例如脊髓损伤、阿尔茨海默病、多发性硬化、中风和神经性疼痛(Mueller,B.K.等人,Nat.Rev.Drug Disc.,4:387-398(2005);Sun,X.等人,J.Neuroimmunol.,180:126-134(2006))。
对于治疗心血管疾病的新颖药物仍存在尚未满足的医疗需求。在美国心脏协会的心脏病和中风统计的2012年更新(Circulation,125:e2-e220(2012))中报道心血管疾病占美国所有死亡人数的32.8%,其中冠心病占美国所有死亡人数的约1/6。经由这些数字发现美国成年人口的约33.5%为高血压且估计在2010年约660万美国成人患有心力衰竭。因此,尽管多种药物可用于治疗心血管疾病(CVD),包括利尿剂、β阻断剂、血管紧张素转化酶抑制剂、血管紧张素阻断剂和钙通道阻断剂,但是就许多患者而言,CVD尚未得以很好的控制或对当前的药物耐受。
有很多关于处于研究中的ROCK抑制剂的报道(参见例如US 2012/0122842 A1、US2010/0041645 A1、US 2008/0161297 A1和Hu,E.等人,Exp.Opin.Ther.Targets,9:715-736(2005))。报道还包括WO2014/113620、WO 2014/134388、WO 2014/134391、WO2015/002915、WO2015/002926、WO2016/010950、WO2016/028971、WO2016/112236和WO2016/144936,所有这些参考文献被转让给本申请的申请人。然而,法舒地尔为目前唯一的市售ROCK抑制剂。一种静脉内制剂在日本被批准用于治疗脑血管痉挛。因此,仍需要包括ROCK抑制剂在内的新颖疗法来治疗心血管疾病、癌症、神经病、肾病、纤维化疾病、支气管哮喘、勃起功能障碍和青光眼。
发明内容
本申请提供可用作Rho激酶选择性抑制剂的新颖苯乙酰胺类、其类似物,包括其立体异构体、互变异构体、药学上可接受的盐或溶剂化物。
本申请还提供制备本申请化合物的方法和中间体。
本申请还提供药物组合物,其包含药学上可接受的载体和至少一种本申请化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂化物。
本申请化合物可用于治疗和/或预防与异常ROCK活性有关的病状。
本申请化合物可用在疗法中。
本申请化合物可用于制备用于治疗和/或预防与异常ROCK活性有关的病状的药物。
在另一个方面,本申请涉及治疗心血管或相关疾病的方法,该方法包括向需要此类治疗的患者给药上述本申请化合物。可被治疗的此类疾病的实例包括例如高血压、动脉粥样硬化、再狭窄、中风、心力衰竭、肾衰竭、冠状动脉疾病、外周动脉疾病、冠状血管痉挛、脑血管痉挛、缺血/再灌注损伤、肺高血压、绞痛、勃起功能障碍和肾病。
在另一个方面,本申请涉及治疗涉及平滑肌高反应性的疾病(包括哮喘)、勃起功能障碍和青光眼的方法,该方法包括向需要此类治疗的患者给药上述本申请化合物。
在另一个方面,本申请涉及治疗至少部分由Rho激酶介导的疾病的方法,所述疾病包括纤维化疾病、肿瘤学、脊髓损伤、阿尔茨海默病、多发性硬化、中风、神经性疼痛、类风湿性关节炎、牛皮癣和炎性肠病,该方法包括向需要此类治疗的患者给药上述本申请化合物。
在其它方面,本申请涉及包含上述化合物的药物组合物、制备上述化合物的方法和在这些方法中使用的中间体。
本申请化合物可单独使用、与其它本申请化合物联用或与一种或多种优选一种至两种其它药物联用。
本申请这些及其它特征将随以下公开而以展开形式阐述。
具体实施方式
I.本申请化合物
在一个方面,本申请尤其提供式(I)化合物:
或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
A1在每次出现时独立地选自CR3和N;前提是A1不全是CR3,并且不超过两个A1变量是N;
R1选自-OH和NR5R5;
R2在每次出现时独立选自卤素、C1-6烷基、C1-4烷氧基、C1-4烷基硫基、C1-4卤代烷基、-OH、-CH2OH、-OCH2F、-OCHF2、-OCF3、CN、-NH2、-NH(C1-4烷基)、-N(C1-4烷基)2、-CO2H、-CH2CO2H、-CO2(C1-4烷基)、-CO(C1-4烷基)、-CH2NH2、-CONH2、-CONH(C1-4烷基)、-CON(C1-4烷基)2、-OCH2CO2H、-NHCO(C1-4烷基)、-NHCO2(C1-4烷基)、-NHSO2(C1-4烷基)、-SO2NH2、-C(=NH)NH2、碳环和杂环,其中所述烷基、烷氧基、烷基硫基、卤代烷基、碳环和杂环经0-4个R9取代;
R3在每次出现时独立选自H、卤素、C1-6烷基、C1-4烷氧基、C1-4烷基硫基、C1-4卤代烷基、-CH2OH、-OCH2F、-OCHF2、-OCF3、CN、-NH2、-NH(C1-4烷基)、-N(C1-4烷基)2、-CO2H、-CH2CO2H、-CO2(C1-4烷基)、-CO(C1-4烷基)、-CH2NH2、-CONH2、-CONH(C1-4烷基)、-CON(C1-4烷基)2、-OCH2CO2H、-NHCO(C1-4烷基)、-NHCO2(C1-4烷基)、-NHSO2(C1-4烷基)、-SO2NH2、-C(=NH)NH2、碳环和杂环,其中所述烷基、烷氧基、烷基硫基、卤代烷基、碳环和杂环经0-4个R9取代;
R4在每次出现时独立选自H、F和C1-4烷基;
R5在每次出现时独立选自H、-(CR6R6)n-C3-10碳环以及包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的-(CR6R6)n-4-15元杂环,其中所述烷基、碳环和杂环经1-4个R7取代;
或者,R5和R5与它们所连接的氮原子一起形成经1-4个R7取代的4至15元杂环;
R6在每次出现时独立选自H和C1-4烷基;
R7在每次出现时独立选自H、=O、NO2、卤素、C1-4烷基、C1-4烷氧基、CN、OH、CF3、-(CH2)n-CO2H、-(CH2)n-CO2(C1-4烷基)、-(CH2)n-NR8R8、-NHCO(C1-4烷基)、-NHCOCF3、-NHCO2(C1-4烷基)、-NHCO2(CH2)2O(C1-4烷基)、-NHCO2(CH2)3O(C1-4烷基)、-NHCO2(CH2)2OH、-NHCO2(CH2)2NH2、-NHCO2(CH2)2N(C1-4烷基)2、-NHCO2CH2CO2H、-CH2NHCO2(C1-4烷基)、-NHC(O)NR8R8、-NHSO2(C1-4烷基)、-SO2NH2、-SO2NH(C1-4烷基)、-SO2N(C1-4烷基)2、-SO2NH(CH2)2OH、-SO2NH(CH2)2O(C1-4烷基)、-(CH2)n-CONR8R8、-O(CH2)n-碳环、-O(CH2)n-杂环、-NHCO-碳环、-NHCO-杂环、-(CH2)n-碳环以及包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的-(CH2)n-杂环,其中所述烷基、烯基、炔基、烷氧基、碳环和杂环经0-4个R9取代;
R8在每次出现时独立选自H、C1-4烷基、C2-4烯基、C2-4炔基、-(CH2)n-C(O)C1-4烷基、-(CH2)n-C(O)碳环、-(CH2)n-C(O)杂环、-(CH2)n-C(O)NRaRa、-(CH2)n-C(O)O-烷基、-(CH2)n-C(O)O-碳环、-(CH2)n-C(O)O-杂环、-(CH2)n-SO2烷基、-(CH2)nSO2碳环、-(CH2)n-SO2杂环、-(CH2)n-SO2NRaRa、-(CH2)n-碳环和-(CH2)n-杂环,其中所述烷基、碳环和杂环经0-4个R9取代;
或者,R8和R8与它们所连接的氮原子一起形成经0-4个R9取代的4至10元杂环;
R9在每次出现时独立选自卤素、OH、NO2、CHF2、CF3、C1-4烷基、C1-4烷氧基、CH2OH、CO(C1-4烷基)、CO2H、CO2(C1-4烷基)、-(CH2)nNRaRa、-(CH2)nCONRaRa、-O(CH2)碳环、-O(CH2)杂环、-O(CH2)nNRaRa、-(CR10R10)n-4-10元杂环,其中所述烷基、烷氧基、碳环和杂环经0-4个Rb取代;
R10选自H和C1-4烷基;
Ra在每次出现时独立选自H、C1-4烷基、-(CH2)nOH、CO(C1-4烷基)、COCF3、CO2(C1-4烷基)、-CONH2、-CONH-C1-4亚烷基-CO2(C1-4烷基)、C1-4亚烷基-CO2(C1-4烷基)、Rc、CO2Rc和CONHRc;或者,Ra和Ra与它们所连接的氮原子一起形成4至10元杂环,其中所述烷基、亚烷基和杂环经0-4个Rb取代;
Rb在每次出现时独立选自=O、OH、卤素、C1-4烷基、C1-4烷氧基、OCF3、NH2、NO2、N(C1-4烷基)2、CO(C1-4烷基)、CO(C1-4卤代烷基)、CO2(C1-4烷基)、CONH2、-CONH(C1-4烷基)、-CON(C1-4烷基)2、-CONH-C1-4亚烷基-O(C1-4烷基)、-CONH-C1-4亚烷基-N(C1-4烷基)2、-CONH-C1-4亚烷基-N(C1-4烷基)2、-C1-4亚烷基-O-P(O)(OH)2、-NHCO2(C1-4烷基)、-Rc、CORc、CO2Rc和CONHRc;
Rc在每次出现时独立选自-(CH2)n-C3-6环烷基、-(CH2)n-苯基以及含有碳原子和1-4个选自N、NH、N(C1-4烷基)、O和S(O)p的杂原子的-(CH2)n-5至6元杂环;其中每个环部分经0-2个Rd取代;
Rd在每次出现时独立选自=O、卤素、-OH、C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、C1-4烷氧基和-NHCO(C1-4烷基)以及含有碳原子和1-4个选自N、NH、N(C1-4烷基)、O和S(O)p的杂原子的杂环;
n在每次出现时独立选自0、1、2、3和4;且
p在每次出现时独立选自0、1和2。
在另一个方面,本申请提供式(II)化合物:
或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R2独立地选自卤素和C1-6烷基;
R5为包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的4-15元杂环,其中所述杂环经1-4个R7取代;
R7在每次出现时独立选自H、=O、NO2、卤素、C1-4烷基、C1-4烷氧基、CN、OH、CF3、-(CH2)n-CO2H、-(CH2)n-CO2(C1-4烷基)、-(CH2)n-NR8R8、-NHCO(C1-4烷基)、-NHCOCF3、-NHCO2(C1-4烷基)、-NHCO2(CH2)2O(C1-4烷基)、-NHCO2(CH2)3O(C1-4烷基)、-NHCO2(CH2)2OH、-NHCO2(CH2)2NH2、-NHCO2(CH2)2N(C1-4烷基)2、-NHCO2CH2CO2H、-CH2NHCO2(C1-4烷基)、-NHC(O)NR8R8、-NHSO2(C1-4烷基)、-SO2NH2、-SO2NH(C1-4烷基)、-SO2N(C1-4烷,基)2、-SO2NH(CH2)2OH、-SO2NH(CH2)2O(C1-4烷基)、-(CH2)n-CONR8R8、-O(CH2)n-碳环、-O(CH2)n-杂环、-NHCO-碳环、-NHCO-杂环、-(CH2)n-碳环以及包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的-(CH2)n-杂环,其中所述烷基、烯基、炔基、烷氧基、碳环和杂环经0-4个R9取代;
R8在每次出现时独立地选自H、C1-4烷基、C(O)C1-4烷基、-(CH2)nC(O)NRaRa、C(O)O-烷基、SO2烷基、SO2NRaRa、-(CH2)n-碳环和-(CH2)n-杂环,其中所述烷基、碳环和杂环经0-4个R9取代;
R9在每次出现时独立地选自卤素、OH、NO2、CHF2、CF3、C1-4烷基、C1-4烷氧基、CH2OH、CO2H、CO2(C1-4烷基)、CONH2、-(CH2)nNRaRa、-(CH2)nCONRaRa、-O(CH2)n杂环、-O(CH2)(2-4)NRaRa、-(CH2)n-4-10元杂环,其中所述烷基、烷氧基、碳环和杂环经0-4个R9取代;
Ra在每次出现时独立选自H、C1-4烷基、-(CH2)nOH、CO(C1-4烷基)、COCF3、CO2(C1-4烷基)、-CONH2、-CONH-C1-4亚烷基-CO2(C1-4烷基)、C1-4亚烷基-CO2(C1-4烷基)、Rc、CO2Rc和CONHRc;或者,Ra和Ra与它们所连接的氮原子一起形成4至10元杂环,其中所述烷基、亚烷基和杂环经0-4个Rb取代;
Rb在每次出现时独立选自=O、卤素、C1-4烷基、C1-4烷氧基、OCF3、NH2、NO2、N(C1-4烷基)2、CO(C1-4烷基)、CO(C1-4卤代烷基)、CO2(C1-4烷基)、CONH2、-CONH(C1-4烷基)、-CON(C1-4烷基)2、-CONH-C1-4亚烷基-O(C1-4烷基)、-CONH-C1-4亚烷基-N(C1-4烷基)2、-CONH-C1-4亚烷基-N(C1-4烷基)2、-C1-4亚烷基-O-P(O)(OH)2、-NHCO2(C1-4烷基)、-Rc、CORc、CO2Rc和CONHRc;
Rc在每次出现时独立选自-(CH2)n-C3-6环烷基、-(CH2)n-苯基以及含有碳原子和1-4个选自N、NH、N(C1-4烷基)、O和S(O)p的杂原子的-(CH2)n-5至6元杂环;其中每个环部分经0-2个Rd取代;
Rd在每次出现时独立选自=O、卤素、-OH、C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、C1-4烷氧基和-NHCO(C1-4烷基)以及含有碳原子和1-4个选自N、NH、N(C1-4烷基)、O和S(O)p的杂原子的杂环;
n在每次出现时独立选自0、1、2、3和4;
p在每次出现时独立选自0、1和2。
在另一个方面,本申请提供式(II)化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R2独立地选自F、Cl和Br;
R7在每次出现时独立选自H、=O、卤素、C1-4烷基、C1-4烷氧基、CN、OH、CF3、-(CH2)n-CO2H、-(CH2)n-CO2(C1-4烷,基)、-(CH2)n-NR8R8、-NHCO(C1-4烷基)、-NHCOCF3、-NHCO2(C1-4烷基)、-NHCO2(CH2)2O(C1-4烷基)、-NHCO2(CH2)3O(C1-4烷基)、-NHCO2(CH2)2OH、-NHCO2(CH2)2NH2、-NHCO2(CH2)2N(C1-4烷基)2、-NHCO2CH2CO2H、-CH2NHCO2(C1-4烷基)、-NHC(O)NR8R8、-NHSO2(C1-4烷基)、-SO2NH2、-SO2NH(C1-4烷基)、-SO2N(C1-4烷基)2、-SO2NH(CH2)2OH、-SO2NH(CH2)2O(C1-4烷基)、-(CH2)n-CONR8R8、-O(CH2)n-碳环、-O(CH2)n-杂环、-NHCO-碳环、-NHCO-杂环、-(CH2)n-碳环以及包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的-(CH2)n-杂环,其中所述烷基、烯基、炔基、烷氧基、碳环和杂环经0-4个R9取代;
R8在每次出现时独立地选自H、C1-4烷基、-(CH2)n-碳环和-(CH2)n-杂环,其中所述烷基、碳环和杂环经0-4个R9取代;
R9在每次出现时独立地选自卤素、OH、NO2、CHF2、CF3、C1-4烷基、C1-4烷氧基、CH2OH、CO2H、CO2(C1-4烷基)、CONH2、-(CH2)nNH2、-(CH2)nCONH2、-O(CH2)n杂环、-O(CH2)(2-4)NH2、-(CH2)n-4-10元杂环;且
其它变量如在上式(II)中所定义。
在另一个方面,本申请提供式(II)化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R2独立地选自F和Cl;
R7在每次出现时独立地选自H、卤素、C1-4烷基、C1-4烷氧基、碳环以及包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的杂环,其中所述烷基、烯基、炔基、烷氧基、碳环和杂环经0-4个R9取代;
R8在每次出现时独立选自H、C1-4烷基和-(CH2)n-C3-6环烷基;
R9在每次出现时独立选自卤素、OH、CHF2、CF3、C1-4烷基、C1-4烷氧基、CH2OH、CO2H、CO2(C1-4烷基)和CONH2;且
其它变量如在上式(II)中所定义。
在另一个方面,本申请提供式(II)化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R7在每次出现时独立地选自H、F、Cl、Br、Me、Et、OMe、OEt、OCH2C(CH2)2OH、
R9在每次出现时独立选自F、Cl、Br、OH、CHF2、CF3、C1-4烷基和C1-4烷氧基;且
其它变量如在上式(II)中所定义。
在另一个方面,本申请提供式(I)化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R7选自H、CN、经0-4个R9取代的C1-4烷基、经0-4个R9取代的C1-4烷氧基;且
R9选自卤素、OH、C3-6环烷基、苯基和杂环。
在另一方面,本申请提供式(III)化合物:
或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R2选自F、Cl、Br和OC1-4烷基;
R4选自H和C1-4烷基;
R7在每次出现时独立选自H、=O、NO2、卤素、C1-4烷基、C1-4烷氧基、CN、OH、CF3、-(CH2)n-CO(C1-4烷基)、-(CH2)n-CO2H、-(CH2)n-CO2(C1-4烷基)、-(CH2)n-NR8R8、-NHCO(C1-4烷基)、-NHCOCF3、-NHCO2(C1-4烷基)、-NHCO2(CH2)2O(C1-4烷基)、-NHCO2(CH2)3O(C1-4烷基)、-NHCO2(CH2)2OH、-NHCO2(CH2)2NH2、-NHCO2(CH2)2N(C1-4烷基)2、-NHCO2CH2CO2H、-CH2NHCO2(C1-4烷基)、-NHC(O)NR8R8、-NHSO2(C1-4烷基)、-P(=O)(C1-3烷基)2、-SO2C1-4烷基、-SO2NH2、-SO2NH(C1-4烷基)、-SO2N(C1-4烷基)2、-SO2NH(CH2)2OH、-SO2NH(CH2)2O(C1-4烷基)、-(CH2)n-CONR8R8、-O(CH2)n-碳环、-O(CH2)n-杂环、-NHCO-碳环、-NHCO-杂环、-CO-碳环、-CO-杂环、-(CH2)n-碳环以及包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的-(CH2)n-杂环,其中所述烷基、烯基、炔基、烷氧基、碳环和杂环经0-4个R9取代;
R8在每次出现时独立选自H、C1-4烷基、C2-4烯基、C2-4炔基、-(CH2)n-C(O)C1-4烷基、-(CH2)n-C(O)碳环、-(CH2)n-C(O)杂环、-(CH2)n-C(O)NRaRa、-(CH2)n-C(O)O-烷基、-(CH2)n-C(O)O-碳环、-(CH2)n-C(O)O-杂环、-(CH2)n-SO2烷基、-(CH2)nSO2碳环、-(CH2)n-SO2杂环、-(CH2)n-SO2NRaRa、-(CH2)n-碳环和-(CH2)n-杂环,其中所述烷基、碳环和杂环经0-4个R9取代;
或者,R8和R8与它们所连接的氮原子一起形成经0-4个R9取代的4至10元杂环;
R9在每次出现时独立地选自卤素、OH、NO2、CHF2、CN、CF3、C1-4烷基、C1-4烷氧基、CH2OH、CO(C1-4烷基)、CO2H、CO2(C1-4烷基)、-(CH2)nNRaRa、-(CH2)nCONRaRa、-O(CH2)n碳环、-O(CH2)n杂环、-O(CH2)nNRaRa、NRaCO2(C1-4烷基)、S(O)pC1-4烷基、-(CR10R10)n-碳环、-(CR10R10)n-4-10元杂环,其中所述烷基、烷氧基、碳环和杂环经0-4个Rb取代;
R10选自H和C1-4烷基;
Ra在每次出现时独立选自H、C1-4烷基、-(CH2)nOH、CO(C1-4烷基)、COCF3、CO2(C1-4烷基)、-CONH2、-CONH-C1-4亚烷基-CO2(C1-4烷基)、C1-4亚烷基-CO2(C1-4烷基)、Rc、CO2Rc和CONHRc;或者,Ra和Ra与它们所连接的氮原子一起形成4至10元杂环,其中所述烷基、亚烷基和杂环经0-4个Rb取代;
Rb在每次出现时独立选自=O、OH、卤素、C1-4烷基、C1-4烷氧基、OCF3、NH2、NO2、N(C1-4烷基)2、CO(C1-4烷基)、CO(C1-4卤代烷基)、CO2(C1-4烷基)、CONH2、-CONH(C1-4烷基)、-CON(C1-4烷基)2、-CONH-C1-4亚烷基-O(C1-4烷基)、-CONH-C1-4亚烷基-N(C1-4烷基)2、-CONH-C1-4亚烷基-N(C1-4烷基)2、-C1-4亚烷基-O-P(O)(OH)2、-NHCO2(C1-4烷基)、-Rc、CORc、CO2Rc和CONHRc;
Rc在每次出现时独立选自-(CH2)n-C3-6环烷基、-(CH2)n-苯基以及含有碳原子和1-4个选自N、NH、N(C1-4烷基)、O和S(O)p的杂原子的-(CH2)n-5至6元杂环;其中每个环部分经0-2个Rd取代;
Rd在每次出现时独立选自=O、卤素、-OH、C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、C1-4烷氧基和-NHCO(C1-4烷基)以及含有碳原子和1-4个选自N、NH、N(C1-4烷基)、O和S(O)p的杂原子的杂环;
n在每次出现时独立选自0、1、2、3和4;且
p在每次出现时独立选自0、1和2。
在另一个方面,本申请提供式(III)化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R2选自F、Cl和OCH3;
R8选自H和任选经卤素取代的C1-3烷基;
Rb在每次出现时独立地选自OH和卤素。
在另一个方面,本申请提供式(III)化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R2独立地选自F、Cl和OCH3;
R7选自H、F、Cl、Br、经0-4个R9取代的C1-3烷基、经0-4个R9取代的C1-3烷氧基、CN、CO2C1-4烷基、P(=O)(C1-3烷基)2、SO2C1-4烷基、
R8选自H和经0-4个R9取代的C1-3烷基;
R9选自卤素、OH、CN、经0-4个Rb取代的C1-3烷基、经0-4个Rb取代的C1-3烷氧基、CO2(C1-4烷基)、CONH2、NHCO2(C1-3烷基)、C3-6环烷基、苯基和杂环;且
Rb在每次出现时独立地选自OH和卤素。
在另一个方面,本申请提供式(III)化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R2独立地选自F、Cl和OCH3;
R8选自H和经0-4个R9取代的C1-3烷基;
R9选自卤素、OH、CN、经0-4个Rb取代的C1-3烷基、经0-4个Rb取代的C1-3烷氧基、CO2(C1-4烷基)、CONH2、NHCO2(C1-3烷基)、C3-6环烷基、苯基和杂环;且
Rb在每次出现时独立地选自OH和卤素。
在另一个方面,本申请提供式(III)化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R2选自F、Cl和OCH3;
R8选自H和经0-4个R9取代的C1-3烷基;
R9选自卤素、OH、CN、经0-4个Rb取代的C1-3烷基、经0-4个Rb取代的C1-3烷氧基、CO2(C1-4烷基)、CONH2、NHCO2(C1-3烷基)、C3-6环烷基、苯基和杂环;且
Rb在每次出现时独立地选自OH和卤素。
本申请可在不背离本申请的精神或基本属性的情况下以其它具体形式体现。本申请包括本申请所记载的本申请的替代方面的所有组合。应理解的是,本申请的任何和所有实施方案都可与任何其它实施方案结合以描述本申请的额外实施方案。另外,实施方案的任何要素(包括单独的可变定义)意欲与任何实施方案的任何和所有其它要素组合以描述额外的实施方案。
在另一个方面,本申请提供选自本申请所示例的化合物的任何子集列表的化合物。
在另一个实施方案中,本申请化合物的ROCK IC50值≤10μM。
在另一个实施方案中,本申请化合物的ROCK IC50值≤1μM。
在另一个实施方案中,本申请化合物的ROCK IC50值≤0.1μM。
在另一个实施方案中,本申请化合物的ROCK IC50值≤0.05μM。
在另一个实施方案中,本申请化合物的ROCK IC50值≤0.01μM。
II.本申请其它实施方案
在另一个实施方案中,本申请提供组合物,其包含至少一种本申请化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂化物。
在另一个实施方案中,本申请提供药物组合物,其包含药学上可接受的载体和至少一种本申请化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂化物。
在另一个实施方案中,本申请提供药物组合物,其包含药学上可接受的载体和治疗有效量的至少一种本申请化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂化物。
在另一个实施方案中,本申请提供制备本申请化合物的方法。
在另一个实施方案中,本申请提供用于制备本申请化合物的中间体。
在另一个实施方案中,本申请提供药物组合物,其进一步包含其它治疗剂。
在另一个实施方案中,本申请提供治疗和/或预防与异常ROCK活性有关的病状的方法,其包括向需要此类治疗和/或预防的患者给药治疗有效量的至少一种本申请化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂化物。本申请使用的术语“患者”包括所有哺乳动物物种。
本申请使用的“治疗”包括对哺乳动物特别是人类中的疾病状态进行治疗且包括:(a)抑制所述疾病状态即阻止其发展;和/或(b)缓解所述疾病状态即引起所述疾病状态消退。
本申请使用的“防止”或“预防”包括对哺乳动物特别是人类中的亚临床疾病状态进行预防性治疗,其目的是降低临床疾病状态发生的可能性。基于已知与一般人群相比使患上临床疾病状态的风险得以增加的因素对患者进行选择以接受预防性疗法。可将“预防”治疗分成(a)一级预防及(b)二级预防。一级预防被定义为在尚未表现出临床疾病状态的患者中进行的治疗,而二级预防被定义为预防相同或类似的临床疾病状态的再次发生。在另一个实施方案中,本申请提供本申请化合物和其它治疗剂用于在疗法中同时、分开或依序使用的组合制剂。
本申请可在不偏离本申请精神或基本属性的情况下以其它具体形式实施。本申请包括本申请所记载的本申请优选方面的所有组合。应理解的是,本申请的任何和所有实施方案都可与任何其它实施方案或多个其它实施方案组合以描述额外的实施方案。还应该理解的是,实施方案的每个单独要素本身即为独立的实施方案。另外,实施方案的任何要素意欲与任何实施方案的任何和所有其它要素组合以描述额外的实施方案。
III.化学
在说明书和所附权利要求书通篇中,所给出的化学式或化学名称在存在立体异构体和光学异构体的情况下应该包括所有立体异构体和光学异构体及其外消旋体。除非另有说明,所有手性形式(对映异构型式和非对映异构型式)和外消旋形式都在本申请范围内。在化合物中也可存在C=C双键、C=N双键、环系等的多种几何异构体且本申请包括所有此类稳定的异构体。描述了本申请化合物的顺式和反式(或E和Z)几何异构体且可被分离成异构体的混合物或被分离成分开的异构型式。本申请化合物可被分离成光学活性形式或外消旋形式。光学活性形式可如下制备:对外消旋形式进行拆分或由光学活性原料合成。用于制备本申请化合物的所有方法和在其中制备的中间体被视为本申请一部分。当制备对映异构产物或非对映异构产物时,其可通过常规方法例如通过色谱或分级结晶来分离。本申请最终产物基于工艺条件而以游离(中性)形式或盐形式得到。这些最终产物的游离形式和盐形式都在本申请范围内。可按需将化合物的一种形式转化成另一种形式。可将游离碱或游离酸转化成盐;可将盐转化成游离化合物或另一种盐;可将本申请异构化合物的混合物分离成单独的异构体。本申请化合物(游离形式及其盐)可按多种互变异构型式存在,其中氢原子换位到分子中的其它部分且分子中原子之间的化学键因此重排。应理解的是,所有互变异构型式只要它们可存在就都包括在本申请范围内。
术语“立体异构体”是指组成相同但其原子空间排列不同的异构体。对映异构体和非对映异构体为立体异构体的实例。术语“对映异构体”是指互为镜像但不可重叠的一对分子物质中的一个。术语“非对映异构体”是指不为镜像的立体异构体。术语“外消旋体”或“外消旋混合物”是指由等摩尔量的两种对映异构体质组成的组合物,其中所述组合物无光学活性。
符号“R”和“S”表示在手性碳原子周围的取代基的构型。异构体描述语“R”和“S”如本申请所描述的那样用于指示原子相对于核心分子的构型且意在如文献所定义的那样使用(IUPAC Recommendations 1996,Pure and Applied Chemistry,68:2193-2222(1996))。
术语“手性”是指分子的使其不可能与其镜像重叠的结构特征。术语“纯手性”是指对映异构体的纯度状态。术语“光学活性”是指纯手性分子或手性分子的非外消旋混合物使偏振光的平面发生旋转的程度。
本申请使用的术语“烷基”或“亚烷基”意在包括具有指定碳原子数的支链和直链饱和脂族烃基。例如,“C1至C10烷基”或“C1-10烷基”(或亚烷基)意在包括C1、C2、C3、C4、C5、C6、C7、C8、C9和C10烷基。另外,例如“C1至C6烷基”或“C1-6烷基”表示具有1至6个碳原子的烷基。烷基可未经取代或通过至少一个氢被另一种化学基团代替而经取代。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基、叔丁基)和戊基(例如正戊基、异戊基、新戊基)。当使用“C0烷基”或“C0亚烷基”时,其意在表示直接键。
“烯基”或“亚烯基”意在包括直链或支链构型的具有指定碳原子数和一个或多个、优选一个至两个可在链中任何稳定点存在的碳-碳双键的烃链。例如,“C2至C6烯基”或“C2-6烯基”(或亚烯基)意在包括C2、C3、C4、C5和C6烯基。烯基的实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。
“炔基”或“亚炔基”意在包括直链或支链构型的具有一个或多个、优选一个至三个可在链中任何稳定点存在的碳-碳三键的烃链。例如,“C2至C6炔基”或“C2-6炔基”(或亚炔基)意在包括C2、C3、C4、C5和C6炔基;例如乙炔基、丙炔基、丁炔基、戊炔基和己炔基。
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C1至C6烷氧基”或“C1-6烷氧基”(或烷基氧基)意在包括C1、C2、C3、C4、C5和C6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地,“烷基硫基”或“硫代烷氧基”表示通过硫桥连接的如上定义的具有指定碳原子数的烷基;例如甲基-S-和乙基-S-。
“卤代”或“卤素”包括氟(F)、氯(Cl)、溴(Br)和碘(I)。“卤代烷基”意在包括取代有一个或多个卤素的具有指定碳原子数的支链和直链饱和脂族烃基。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例还包括“氟代烷基”,其意在包括取代有一个或多个氟原子的具有指定碳原子数的支链和直链饱和脂族烃基。
“卤代烷氧基”或“卤代烷基氧基”表示通过氧桥连接的如上定义的具有指定碳原子数的卤代烷基。例如,“C1至C6卤代烷氧基”或“C1-6卤代烷氧基”意在包括C1、C2、C3、C4、C5和C6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地,“卤代烷基硫基”或“硫代卤代烷氧基”表示通过硫桥连接的如上定义的具有指定碳原子数的卤代烷基;例如三氟甲基-S-和五氟乙基-S-。
术语“环烷基”是指环化的烷基,其包括单环、二环或多环环系。“C3至C7环烷基”或“C3-7环烷基”意在包括C3、C4、C5、C6和C7环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基和降莰烷基。支链的环烷基例如1-甲基环丙基和2-甲基环丙基包括在“环烷基”的定义中。
本申请使用的“碳环”或“碳环残基”是指任何稳定的3、4、5、6、7或8元单环或二环或7、8、9、10、11、12或13元二环或三环烃环,其中任何环可以是饱和、部分不饱和、不饱和或芳族的。此类碳环的实例包括但不限于环丙基、环丁基、环丁烯基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环庚烯基、金刚烷基、环辛基、环辛烯基、环辛二烯基、[3.3.0]二环辛烷、[4.3.0]二环壬烷、[4.4.0]二环癸烷(萘烷)、[2.2.2]二环辛烷、芴基、苯基、萘基、茚满基、金刚烷基、蒽基和四氢萘基(萘满)。如上所示,桥环也包括在碳环的定义中(例如[2.2.2]二环辛烷)。除非另有说明,优选的碳环为环丙基、环丁基、环戊基、环己基、苯基和茚满基。当使用术语“碳环”时,其意在包括“芳基”。当一个或多个碳原子将两个不相邻的碳原子连接起来时,形成桥环。优选的桥为一个或两个碳原子。应注意的是,桥总是将单环转化成三环。当环被桥接时,就环所列举的取代基也可存在于桥上。
本申请使用的术语“二环碳环”或“二环碳环基”是指稳定的9或10元碳环环系,其含有两个稠环并由碳原子构成。在所述两个稠环中,一个环为与第二个环稠合的苯并环;且所述第二个环为饱和、部分不饱和或不饱和的5或6元碳环。二环碳环基可在形成稳定结构的任何碳原子处与其侧基连接。本申请所述二环碳环基可在任何碳上被取代,只要所得化合物是稳定的。二环碳环基的实例为但不限于萘基、1,2-二氢萘基、1,2,3,4-四氢萘基和茚满基。
“芳基”是指单环或多环芳烃,包括例如苯基、萘基和菲基。芳基是公知的且参见例如Lewis,R.J.编辑,Hawley’s Condensed Chemical Dictionary,第13版,John Wiley&Sons,Inc.,New York(1997)。“C6或C10芳基”或“C6-10芳基”是指苯基和萘基。除非另有说明,“芳基”、“C6或C10芳基”、“C6-10芳基”或“芳族残基”可以是未经取代的或经1至5个、优选1至3个基团取代,所述基团为例如OH、OCH3、Cl、F、Br、I、CN、NO2、NH2、N(CH3)H、N(CH3)2、CF3、OCF3、C(=O)CH3、SCH3、S(=O)CH3、S(=O)2CH3、CH3、CH2CH3、CO2H和CO2CH3。
本申请使用的术语“苄基”是指其中一个氢原子被苯基代替的甲基,其中所述苯基可任选经1至5个、优选1至3个基团取代,所述基团为例如OH、OCH3、Cl、F、Br、I、CN、NO2、NH2、N(CH3)H、N(CH3)2、CF3、OCF3、C(=O)CH3、SCH3、S(=O)CH3、S(=O)2CH3、CH3、CH2CH3、CO2H和CO2CH3。
本申请使用的术语“杂环”或“杂环基”是指稳定的3、4、5、6或7元单环或二环或7、8、9、10、11、12、13或14元多环杂环,其是饱和、部分不饱和或完全不饱和的且含有碳原子和1、2、3或4个独立选自N、O和S的杂原子;且包括其中任何上述杂环与苯环稠合的任何多环基团。氮杂原子和硫杂原子可任选被氧化(即N→O和S(O)p,其中p为0、1或2)。氮原子可经取代或未经取代(即N或NR,其中R为H或另一种取代基(若被定义))。杂环可在形成稳定结构的任何杂原子或碳原子处与其侧基连接。本申请所述杂环可在碳原子或氮原子上被取代,只要所得化合物是稳定的。杂环中的氮可任选被季铵化。优选地,当杂环中S原子和O原子的总数超过1时,则这些杂原子不彼此相邻。优选地,杂环中S原子和O原子的总数不大于1。当使用术语“杂环”时,其意在包括“杂芳基”。
杂环的实例包括但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、吲哚烯基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、二氢吲哚二酮基、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、苯并二氧杂环戊烯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、呸啶基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡崆烷基、吡崆啉基、吡崆并吡啶基、吡崆基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括含有例如上述杂环的稠环和螺环化合物。
5至10元杂环的实例包括但不限于吡啶基、呋喃基、噻吩基、吡咯基、吡崆基、吡嗪基、哌嗪基、哌啶基、咪崆基、咪崆烷基、吲哚基、四崆基、异噁唑基、吗啉基、噁唑基、噁二唑基、噁唑烷基、四氢呋喃基、噻二嗪基、噻二唑基、噻唑基、三嗪基、三唑基、苯并咪唑基、1H-吲唑基、苯并呋喃基、苯并硫代呋喃基、苯并四唑基、苯并三唑基、苯并异噁唑基、苯并噁唑基、羟吲哚基、苯并噁唑啉基、苯并噻唑基、苯并异噻唑基、二氢吲哚二酮基、异喹啉基、八氢异喹啉基、四氢异喹啉基、四氢喹啉基、异噁唑并吡啶基、喹唑啉基、喹啉基、异噻唑并吡啶基、噻唑并吡啶基、噁唑并吡啶基、咪唑并吡啶基和吡唑并吡啶基。
5至6元杂环的实例包括但不限于吡啶基、呋喃基、噻吩基、吡咯基、吡崆基、吡嗪基、哌嗪基、哌啶基、咪崆基、咪崆烷基、吲哚基、四崆基、异噁唑基、吗啉基、噁唑基、噁二唑基、噁唑烷基、四氢呋喃基、噻二嗪基、噻二唑基、噻唑基、三嗪基和三唑基。还包括含有例如上述杂环的稠环和螺环化合物。
本申请使用的术语“二环杂环”或“二环杂环基”是指稳定的9或10元杂环环系,其含有两个稠环并由碳原子和1、2、3或4个独立选自N、O和S的杂原子构成。在两个稠环中,一个环为5或6元单环芳环,其包括5元杂芳基环、6元杂芳基环或苯并环,其各自与第二个环稠合。第二个环为5或6元单环,其是饱和、部分不饱和或不饱和的且包括5元杂环、6元杂环或碳环(条件是当第二个环为碳环时,第一个环不是苯并环)。
二环杂环基可在形成稳定结构的任何杂原子或碳原子处与其侧基连接。本申请所述二环杂环基可在碳原子或氮原子上被取代,只要所得化合物是稳定的。优选地,当杂环中S原子和O原子的总数超过1时,这些杂原子不彼此相邻。优选地,杂环中S原子和O原子的总数不大于1。
二环杂环基的实例包括但不限于喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢喹啉基、2,3-二氢苯并呋喃基、色满基、1,2,3,4-四氢喹喔啉基和1,2,3,4-四氢喹唑啉基。
本申请使用的术语“芳族杂环基”或“杂芳基”是指稳定的包含至少一个杂原子环成员例如硫、氧或氮的单环和多环芳烃。杂芳基包括但不限于吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、呋喃基、喹啉基、异喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、异噁唑基、吡唑基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、异噻唑基、嘌呤基、咔唑基、苯并咪唑基、二氢吲哚基、苯并二氧杂环戊烷基和苯并二氧杂环己烷基。杂芳基是取代或未取代的。氮原子是取代或未取代的(即N或NR,其中R为H或另一种取代基(若被定义))。氮杂原子和硫杂原子可任选被氧化(即N→O和S(O)p,其中p为0、1或2)。
桥环还包括在杂环的定义中。当一个或多个原子(即C、O、N或S)将两个不相邻的碳原子或氮原子连接起来时,形成桥环。桥环的实例包括但不限于一个碳原子、两个碳原子、一个氮原子、两个氮原子和碳-氮基团。应注意的是,桥总是将单环转化成三环。当环被桥接时,就环所列举的取代基也可存在于桥上。
术语“抗衡离子”用于表示带负电的物质,例如氯离子、溴离子、氢氧根离子、乙酸根离子和硫酸根离子。
当在环结构中使用虚线环时,其表示所述环结构可以是饱和、部分饱和或不饱和的。
本申请使用的术语“取代”是指至少一个氢原子被非氢基团代替,条件是保持正常的化合价且取代导致稳定的化合物。当取代基为酮基(即=O)时,原子上的2个氢被代替。酮取代基不存在于芳族部分上。当描述环系(例如碳环或杂环)被羰基或双键取代时,其是指羰基或双键为环的一部分(即在环中)。本申请使用的“环双键”是形成在两个相邻环原子之间的双键(例如C=C、C=N或N=N)。
当在本申请化合物中存在氮原子(例如胺)时,这些氮原子可通过用氧化剂(例如mCPBA和/或过氧化氢)处理来转化成N-氧化物,以得到本申请其它化合物。因此,所显示和要求保护的氮原子被视为包括所显示的氮及其N-氧化物(N→O)衍生物。
当任何变量在化合物的任何组成或结构式中出现多于一次时,其在每次出现时的定义独立于其在每次其它出现时的定义。因此,例如若显示基团取代有0-3个R基团,则所述基团可任选取代有至多3个R基团且R在每次出现时独立选自R的定义。另外,只要取代基和/或变量的组合导致稳定的化合物,所述组合就是允许的。
当显示连接取代基的化学键跨过连接环中两个原子的化学键时,所述取代基可与环上的任何原子连接。当列出取代基而没有指明所述取代基通过哪个原子与给定结构式的化合物的其余部分连接时,所述取代基可通过所述取代基中的任何原子连接。只要取代基和/或变量的组合导致稳定的化合物,所述组合就是允许的。
本申请使用的短语“药学上可接受的”是指以下那些化合物、材料、组合物和/或剂型,其在合理的医药判断范围内适于与人类和动物的组织接触而没有过度的毒性、刺激性、变态反应和/或其它问题或并发症,这与合理的益处/风险比是相称的。
本申请使用的“药学上可接受的盐”是指所公开的化合物的衍生物,其中母体化合物通过制备其酸加成盐或碱加成盐来改性。药学上可接受的盐的实例包括但不限于碱性基团例如胺的无机酸盐或有机酸盐;和酸性基团例如羧酸的碱式盐或有机盐。药学上可接受的盐包括母体化合物的常规无毒盐或季铵盐,其例如由无毒无机酸或无毒有机酸制备。例如,此类常规无毒盐包括源于无机酸的那些盐,所述无机酸为例如盐酸、氢溴酸、硫酸、氨磺酸、磷酸和硝酸;和由有机酸制备的盐,所述有机酸为例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、枸橼酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯基乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸和羟乙磺酸。
本申请药学上可接受的盐可通过常规化学方法由含有碱性部分或酸性部分的母体化合物合成。通常,此类盐可如下制备:在水或有机溶剂或这二者的混合物中使这些化合物的游离酸形式或游离碱形式与化学计量的合适的碱或酸反应;通常,非水介质例如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。合适的盐的列举参见Remington’sPharmaceutical Sciences,第18版,Mack Publishing Company,Easton,PA(1990),在此将其所公开的内容引入作为参考。
另外,式I化合物可具有前药形式。任何可在体内转化以提供生物活性剂(即式I化合物)的化合物都是在本申请范围和主旨内的前药。各种形式的前药在本领域中是已知的。此类前药衍生物的实例参见:
a)Bundgaard,H.编辑,Design of Prodrugs,Elsevier(1985)和Widder,K.等人编辑,Methods in Enzymology,112:309-396,Academic Press(1985);
b)Bundgaard,H.,第5章:“Design and Application of Prodrugs”,Krosgaard-Larsen,P.等人编辑,A Textbook of Drug Design and Development,第113-191页,-Harwood Academic Publishers(1991);
c)Bundgaard,H.,Adv.Drug Deliv.Rev.,8:1-38(1992);
d)Bundgaard,H.等人,J.Pharm.Sci.,77:285(1988);和
e)Kakeya,N.等人,Chem.Pharm.Bull.,32:692(1984)。
含有羧基的化合物可形成生理上可水解的酯,所述酯通过在体内水解以产生式I化合物本身而作为前药。此类前药优选口服给药,这是因为水解在多数情况下主要在消化酶的影响下发生。若酯本身是具有活性的或在水解发生在血液中的情况下,则可使用胃肠外给药。式I化合物的生理上可水解的酯的实例包括C1-6烷基酯、C1-6烷基苄基酯、4-甲氧基苄基酯、茚满基酯、邻苯二甲酰基酯、甲氧基甲基酯、C1-6烷酰基氧基-C1-6烷基酯(例如乙酰氧基甲基酯、新戊酰基氧基甲基酯或丙酰基氧基甲基酯)、C1-6烷氧基羰基氧基-C1-6烷基酯(例如甲氧基羰基氧基甲基酯或乙氧基羰基氧基甲基酯、甘氨酰基氧基甲基酯、苯基甘氨酰基氧基甲基酯、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)-甲基酯)及其它例如在青霉素和头孢菌素领域中使用的已知的生理上可水解的酯。此类酯可通过本领域已知的常规技术来制备。
前药的制备在本领域中是已知的且参见例如King,F.D.编辑,MedicinalChemistry:Principles and Practice,The Royal Society of Chemistry,Cambridge,UK(1994);Testa,B.等人,Hydrolysis in Drug and Prodrug Metabolism.Chemistry,Biochemistry and Enzymology,VCHA and Wiley-VCH,Zurich,Switzerland(2003);Wermuth,C.G.编辑,The Practice of Medicinal Chemistry,Academic Press,SanDiego,CA(1999)。
本申请意在包括存在于本申请化合物中的原子的所有同位素。同位素包括原子序数相同但质量数不同的那些原子。概括举例但不限于此,氢的同位素包括氘和氚。氘在其原子核中具有一个质子和一个中子且其质量为普通氢的两倍。氘可通过符号例如“2H”或“D”来表示。本申请单独使用或用于修饰化合物或基团的术语“氘代”是指用氘原子代替一个或多个与碳连接的氢原子。碳的同位素包括13C和14C。
经同位素标记的本申请化合物通常可通过本领域技术人员已知的常规技术或通过与本申请所述方法类似的方法使用适当的经同位素标记的试剂代替原来使用的未经标记的试剂来制备。此类化合物具有多种潜在用途,例如在确定潜在药物化合物与靶蛋白或受体结合的能力中用作标准品和试剂或用于在体内或在体外使与生物受体结合的本申请化合物成像。
“稳定的化合物”和“稳定的结构”意在表明化合物是足够稳固的从而经受得住由反应混合物分离至有用的纯度并配制成有效的治疗剂。优选地,本申请化合物不含有N-卤素、S(O)2H或S(O)H基团。
术语“溶剂化物”是指本申请化合物与一个或多个有机或无机溶剂分子的物理缔合。该物理缔合包括氢键。在某些情况下将能够分离到溶剂化物,例如当一个或多个溶剂分子进到结晶固体的晶格中时。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂化物可包含化学计量或非化学计量的溶剂分子。“溶剂化物”包括溶液相和可分离的溶剂化物。溶剂化物的实例包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化的方法是本领域已知的。
本申请使用的缩写如下定义:“1×”表示一次,“2×”表示两次,“3×”表示三次,“℃”表示摄氏度,“eq”表示当量,“g”表示克,“mg”表示毫克,“L”表示升,“mL”表示毫升,“μL”表示微升,“N”表示当量浓度,“M”表示摩尔浓度,“mmol”表示毫摩尔,“min”表示分钟,“h”表示小时,“rt”表示室温,“RT”表示保留时间,“atm”表示大气压,“psi”表示磅/平方英寸,“conc.”表示浓(缩)的,“sat”或“sat’d”表示饱和的,“MW”表示分子量,“mp”表示熔点,“ee”表示对映异构体过量,“MS”或“Mass Spec”表示质谱,“ESI”表示电喷雾电离质谱,“HR”表示高分辨率,“HRMS”表示高分辨率质谱,“LCMS”表示液相色谱质谱,“HPLC”表示高压液相色谱,“RP HPLC”表示反相HPLC,“TLC”或“tlc”表示薄层色谱,“NMR”表示核磁共振光谱,“nOe”表示核奥弗豪泽效应谱,“1H”表示质子,“δ”表示德尔塔,“s”表示单峰,“d”表示二重峰,“t”表示三重峰,“q”表示四重峰,“m”表示多重峰,“br”表示宽峰,“Hz”表示赫兹且“α”、“β”、“R”、“S”、“E”和“Z”表示本领域技术人员所熟知的立体化学符号。
Me 甲基
Et 乙,基
Pr 丙基
i-Pr 异丙基
Bu 丁基
i-Bu 异丁基
t-Bu 叔丁基
Ph 苯基
Bn 苄基
Boc 叔丁基氧基羰基
AcOH或HOAc 乙酸
AlCl3 氯化铝
AIBN 偶氮二异丁腈
BBr3 三溴化硼
BCl3 三氯化硼
BEMP 2-叔丁基亚氨基-2-二乙基氨基-1,3-二甲基全氢-1,3,2-二氮杂磷杂苯
BOP试剂 苯并三唑-1-基氧基三(二甲基氨基)鏻六氟磷酸盐
Boc2O 一缩二碳酸二叔丁酯
Burgess试剂 1-甲氧基-N-三乙基铵基磺酰基-甲酰胺负离子(1-methoxy-N-triethylammonioSulfonyl-methanimidate)
CBz 苄基氧基羰基
CH2Cl2 二氯甲烷
CH3CN或CAN 乙腈
CDCl3 氘代氯仿
CHCl3 氯仿
mCPBA 或m-CPBA 间氯过苯甲酸
Cs2CO3 碳酸铯
Cu(OAc)2 乙酸铜(II)
Cy2NMe N-环己基-N-甲基环己胺
DBU 1,8-二氮杂二环[5.4.0]十一-7-烯
DCE 1,2-二氯乙烷
DCM 二氯甲烷
DEA 二乙胺
Dess-Martin 试剂1,1,1-三(乙酰基氧基)-1,1-二氢-1,2-苯并碘杂氧杂环戊烯-3(1H)-酮
DIC或DIPCDI 二异丙基碳二亚胺
DIEA、DIPEA 或Hunig’s碱 二异丙基乙基胺
DMAP 4-二甲基氨基吡啶
DME 1,2-二甲氧基乙烷
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
cDNA 互补DNA
Dppp (R)-(+)-1,2-二(二苯基膦基)丙烷
DuPhos (+)-1,2-二((2S,5S)-2,5-二乙基磷杂环戊基)苯
EDC N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺
EDCI N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺盐酸盐
EDTA 乙二胺四乙酸
(S,S)-EtDuPhos三氟甲磺酸(+)-1,2-二((2S,5S)-2,5-二乙基磷杂环戊
Rh(I) 基)苯(1,5-环辛二烯)铑(I)
Et3N或TEA 三乙胺
EtOAc 乙酸乙酯
Et2O 乙醚
EtOH 乙醇
G3预催化剂 Buchwald G3(第三代)催化剂
GMF 玻璃微纤维过滤器
Grubbs(II) (1,3-二(2,4,6-三甲基苯基)-2-咪唑烷亚基)二氯(苯基亚甲基)(三环己基膦)钌
HCl 盐酸
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸盐
HEPES 4-(2-羟基乙基)哌嗪-1-乙磺酸
Hex 己烷
HOBt或HOBT 1-羟基苯并三唑
H2SO4 硫酸
H2SO4 碳酸钾
KOAc 乙酸钾
K3PO4 磷酸钾
LAH 氢化锂铝
LG 离去基团
LiOH 氢氧化锂
MeOH 甲醇
MgSO4 硫酸镁
MsOH或MSA 甲磺酸
NaCl 氯化钠
NaH 氢化钠
NaHCO3 碳酸氢钠
Na2CO3 碳酸钠
NaOH 氢氧化钠
Na2SO3 亚硫酸钠
Na2SO4 硫酸钠
NBS N-溴琥珀酰亚胺
NCS N-氯琥珀酰亚胺
NH3 氨
NH4Cl 氯化铵
NH4OH 氢氧化铵
OTf 三氟甲磺酸盐/酯
Pd2(dba)3 三(二亚苄基丙酮)二钯(0)
Pd(OAc)2 乙酸钯(II)
Pd/C 钯/炭
Pd(dppf)Cl2 [1,1’-二(二苯基膦基)-二茂铁]二氯化钯(II)
Ph3PCI2 三苯基二氯化膦
PG 保护基团
POCl3 磷酰氯
i-PrOH或IPA 异丙醇
PS 聚苯乙烯
SEM-Cl 2-(三甲基甲硅烷基)乙氧基甲基氯
SiO2 二氧化硅
SnCl2 氯化锡(II)
TBAI 四正丁基碘化铵
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TMSCHN2 三甲基甲硅烷基重氮甲烷
T3P 丙烷膦酸酐
TRIS 三(羟基甲基)氨基甲烷
本申请化合物可按有机合成领域技术人员已知的多种方式来制备。
IV.生物学
体外测定
本申请化合物作为ROCK抑制剂的有效性可在30μl以下测定液中确定,所述测定液含有20mM HEPES(pH 7.5)、20mM MgCl2、0.015%Brij-35、4mM DTT、5μM ATP和1.5μM肽底物(FITC-AHA-AKRRRLSSLRA-OH)(SEQ ID No.1)。将化合物溶于DMSO中以使DMSO的最终浓度<2%且用Rho激酶变体启动反应。温育后,经由添加EDTA终止反应且使用3000读取器(Caliper Life Sciences)分离磷酸化肽与非磷酸化肽。对照由不含有化合物的测定液构成,且背景由含有酶和底物但自反应开始就具有EDTA以抑制激酶活性的测定液构成。以剂量-响应模式测试化合物且计算化合物的每种浓度对激酶活性的抑制。使用曲线拟合程序拟合抑制数据以确定IC50即抑制50%激酶活性所需要的化合物浓度。
在上述ROCK测定中测试代表性实施例且发现其具有ROCK抑制活性。观察到ROCK抑制活性(IC50值)范围≤50μM(50000nM)。下表A列出了对于以下实施例测量的ROCK IC50值。
表A
V.药物组合物、制剂和组合
本申请化合物可按口服剂型来给药,例如片剂、胶囊剂(其各自包括持续释放或定时释放制剂)、丸剂、粉剂、颗粒剂、酏剂、酊剂、混悬剂、糖浆剂和乳剂。它们还可按静脉内(推注或输注)、腹膜内、皮下或肌内形式给药,其都使用药学领域技术人员所熟知的剂型。它们可单独给药,但是通常将与药物载体一起给药,所述药物载体基于所选择的给药途径和标准的药学实践来选择。
术语“药物组合物”是指包含本申请化合物和至少一种其它药学上可接受的载体的组合物。“药学上可接受的载体”是指本领域通常接受的用于将生物活性剂递送至动物特别是哺乳动物的介质,包括辅料、赋形剂或媒介物,例如稀释剂、防腐剂、填充剂、流动调节剂、崩解剂、润湿剂、乳化剂、助悬剂、甜味剂、矫味剂、香味剂、抗细菌剂、抗真菌剂、润滑剂和分散剂,其取决于给药模式和剂型的性质。根据本领域技术人员所考虑的多种因素来配制药学上可接受的载体。这些因素包括但不限于所配制的活性剂的类型和性质、含有药物的组合物所要给药的患者、组合物的预期给药途径和所靶向的治疗适应症。药学上可接受的载体包括水性和非水性液体介质及各种固体和半固体剂型。除活性剂外,上述载体可包括多种不同的成分和添加剂,由于本领域技术人员所熟知的各种原因例如使活性剂、粘合剂等得以稳定而将上述其它成分包含在制剂中。合适的药学上可接受的载体和在选择它们时涉及的因素参见各种容易得到的资料例如Remington’s Pharmaceutical Sciences,第18版(1990)。
当然,本申请化合物的给药方案可随已知的因素而变化,例如特定药物的药物动力学性质及其给药模式和途径;接受者的物种、年龄、性别、健康、医学状况和体重;症状的性质和程度;并行治疗的种类;治疗的频率;给药途径;患者的肾功能和肝功能;和所期望的作用。医生或兽医可确定预防、逆转或阻止病症的进展所需要的药物有效量并开具处方。
作为一般指导,每种活性成分当用于所指定的作用时的每天口服剂量将为约0.001至约1000mg/kg体重,优选约0.01至约100mg/kg体重/天且最优选约0.1至约20mg/kg/天。对于静脉内给药,在恒定速率输注期间最优选的剂量将为约0.001至约10mg/kg/分钟。本申请化合物可按单次每天剂量来给药或总每天剂量可按每天两次、三次或四次的分份剂量来给药。
本申请化合物还可通过胃肠外给药(例如静脉内、动脉内、肌内或皮下)来给药。当静脉内或动脉内给药时,剂量可连续给药或间歇给药。另外,可开发用于肌内和皮下递送的确保活性药物成份逐渐释放的制剂。
本申请化合物可通过局部使用合适的鼻内媒介物以鼻内形式给药或通过经皮途径使用经皮皮肤贴剂来给药。当以经皮递送系统形式给药时,给药在整个给药方案中当然将是连续而非间歇的。
所述化合物通常与合适的药物稀释剂、赋形剂或载体(在本申请中统称为药物载体)混合给药,所述药物载体根据预期的给药形式例如口服片剂、胶囊剂、酏剂和糖浆剂来合适地选择并与常规的药学实践一致。
例如,对于以片剂或胶囊剂形式口服给药,活性药物组分可与口服、无毒、药学上可接受的惰性载体组合,例如乳糖、淀粉、蔗糖、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、硫酸钙、甘露醇、山梨醇等;对于以液体形式口服给药,口服药物组分可与任何口服无毒药学上可接受的惰性载体组合,例如乙醇、甘油、水等。另外,当期望或需要时,还可将合适的粘合剂、润滑剂、崩解剂和着色剂引入到混合物中。合适的粘合剂包括淀粉、明胶、天然糖例如葡萄糖或β-乳糖、玉米甜味剂、天然胶和合成胶例如阿拉伯胶、西黄蓍胶或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。在这些剂型中使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
本申请化合物还可按脂质体递送系统形式给药,例如单层小泡、单层大泡和多层囊泡。脂质体可由各种磷脂例如胆固醇、硬脂酰胺或磷脂酰胆碱形成。
本申请化合物还可与作为靶向药物载体的可溶性聚合物偶联。上述聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺苯酚、聚羟乙基天冬氨酸酰胺苯酚或取代有棕榈酰基的聚氧化乙烯聚赖氨酸。另外,本申请化合物可与一类可用于实现药物受控释放的生物可降解的聚合物偶联,例如聚乳酸、聚乙醇酸、聚乳酸和聚乙醇酸的共聚物、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲性嵌段共聚物。
适于给药的剂型(药物组合物)可在每个剂量单位中含有约1毫克至约1000毫克活性成分。在这些药物组合物中,活性成分按组合物的总重量计将通常以约0.1-95%重量的量存在。
明胶胶囊剂可含有活性成分和粉末状载体例如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸等。类似的稀释剂可用于制备压制片。片剂和胶囊剂都可被制备成缓释产品以历时数小时提供连续释放的药物。压制片可以是糖衣或覆膜的以掩盖任何令人不悦的味道并使片剂与空气隔离或可以是肠溶衣的以在胃肠道中选择性地崩解。
用于口服给药的液体剂型可含有着色剂和矫味剂以提高患者接受性。
通常,水、合适的油、盐水、右旋糖(葡萄糖)水溶液和相关糖溶液和二醇例如丙二醇或聚乙二醇是胃肠外溶液剂的合适载体。用于胃肠外给药的溶液剂优选含有活性成分的水溶性盐、合适的稳定剂和按需的缓冲物质。抗氧化剂例如单独或组合的亚硫酸氢钠、亚硫酸钠或抗坏血酸是合适的稳定剂。还使用枸橼酸及其盐和EDTA钠。另外,胃肠外溶液剂可含有防腐剂例如苯扎氯铵、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯和氯丁醇。
本申请化合物可单独给药或与一种或多种其它治疗剂组合给药。“组合给药”或“组合疗法”的意思是将本申请化合物与一种或多种其它治疗剂共同给药于所治疗的哺乳动物。当组合给药时,每种组分可同时给药或在不同时间点以任何顺序先后给药。因此,每种组分可分开给药,但是在时间上足够接近以提供所期望的疗效。
本申请化合物还可用作标准化合物或参照化合物,例如在涉及抑制ROCK的试验或测定中用作质量标准品或对照品。上述化合物可按商业试剂盒形式提供,例如在涉及ROCK的药物研究中使用。例如,本申请化合物可用作测定中的参照品以将其已知的活性与活性未知的化合物进行比较。这可使实验人员确保测定被正确地进行并为比较提供依据,特别是当试验化合物为参照化合物的衍生物时。当开发新的测定或方案时,可使用本申请化合物来测试其有效性。
本申请还包括制品。本申请使用的“制品”意在包括但不限于试剂盒和包装。本申请制品包含:(a)第一容器;(b)放置在第一容器中的药物组合物,其中所述组合物包含第一治疗剂,所述第一治疗剂包含本申请化合物或其药学上可接受的盐形式;和(c)包装说明书,其说明所述药物组合物可用于治疗心血管和/或炎性病症(如上定义)。在另一个实施方案中,所述包装说明书说明所述药物组合物可与第二治疗剂联用(如上定义)以治疗心血管和/或炎性病症。所述制品还可包含:(d)第二容器,其中组分(a)和(b)放置在第二容器中,而组分(c)放置在第二容器中或放置在第二容器外。放置在第一容器中和放置在第二容器中是指各个容器容纳物品在其边界内。
第一容器是用于容纳药物组合物的容器。该容器可用于制备、贮存、运输和/或零售/批发。第一容器意在包括瓶、罐、小瓶、细颈瓶、注射器、管(例如用于乳膏剂)或用于制备、容纳、贮存或分配药品的任何其它容器。
第二容器是用于容纳第一容器和任选容纳包装说明书的容器。第二容器的实例包括但不限于盒子(例如厚纸板盒或塑料盒)、板条箱、硬纸盒、袋子(例如纸袋或塑料袋)、小药袋和大药袋。包装说明书可通过带子、胶水、钉书钉或其它附着方法来物理地附着在第一容器的外侧或可将其置于第二容器中而不使用任何物理手段来附着在第一容器上。可选择地,将包装说明书置于第二容器的外侧。当置于第二容器的外侧时,包装说明书优选通过带子、胶水、钉书钉或其它附着方法来物理地附着。可选择地,其可与第二容器的外侧相邻或接触而不物理地附着。
包装说明书是记载与置于第一容器中的药物组合物有关的信息的标签、签条、标识等。所记载的信息通常将由管理所述制品销售区域的管理机构(例如美国食品与药品监督管理局)确定。优选地,包装说明书具体地记载所述药物组合物已被批准的适应症。包装说明书可由人们能够读取其中或其上所含信息的任何材料制成。优选地,包装说明书是其上已形成所需信息(例如印刷或涂布的信息)的印刷材料(例如纸张、塑料、纸板、箔片、背面涂胶的纸张或塑料等)。
本申请其它特征将通过以下关于示例性实施方案的描述而变得显而易见,给出这些示例性实施方案用于说明本申请而非意在限制本申请。已使用本申请公开的方法制备、分离和表征了以下实施例。
VI.包括方案在内的一般合成
-通过一般方案所描述的方法制备的本申请化合物的实例在下述中间体和实施例章节中给出。纯手性实施例的制备可通过本领域技术人员已知的技术来进行。例如,纯手性化合物可通过使用手性相制备型HPLC分离外消旋产物来制备。可选择地,实施例化合物可通过产生富含对映异构体的产物的已知方法来制备。这些方法包括但不限于在外消旋中间体中引入手性辅助官能团,其用于控制转化的非对映异构体选择性,从而在裂解手性辅助官能团后提供富含对映异构体的产物。
还应理解的是,在本领域中当筹划任何合成途径时另一项主要考虑是对用于保护存在于本申请所述化合物中的反应性官能团的保护基进行明智的选择。为本领域技术人员描述多种替换措施的权威说明为Greene等人(Protective Groups in OrganicSynthesis,第4版,Wiley-Interscience(2006))。
本申请的化合物可如下制备:通过用2-(4-羟苯基)乙酸(B)取代芳基或杂芳基卤化物(A),然后使用偶联剂如BOP将2-(4-((3-氨基甲酰基吡啶-2-基)氧基)苯基)乙酸(C)与二环或单环杂环胺(D或F)进行标准偶联。在R7处具有卤素取代基的酰胺(E或G)可通过本领域已知的铃木(Suzuki)交叉偶联方法进一步加工。
经由正相或反相色谱对中间体和最终产物进行纯化。除非另有说明,否则正相色谱使用以己烷和EtOAc、DCM和MeOH的梯度洗脱的预填充的SiO2柱来进行。反相制备型HPLC如下进行:C18柱,用溶剂A(90%水、10%MeOH、0.1%TFA)和溶剂B(10%水、90%MeOH、0.1%TFA,UV 220nm)的梯度或用溶剂A(90%水、10%CH3CN、0.1%TFA)和溶剂B(10%水、90%CH3CN、0.1%TFA,UV 220nm)的梯度或用溶剂A(98%水、2%CH3CN、0.05%TFA)和溶剂B(98%CH3CN、2%水、0.05%TFA,UV 220nm)的梯度洗脱;(或)Sunfire Prep C18 OBD 5u30x100mm,0-100%B的25分钟梯度,A=H2O/CH3CN/TFA 90∶10∶0.1,B=CH3CN/H2O/TFA 90∶10∶0.1
除非另有说明,经由反相分析型HPLC对最终产物进行分析。
方法A:Waters Acquity UPLC BEH C18,2.1x 50mm,1.7-μm颗粒;流动相A:5∶95乙腈∶水,含有10mM乙酸铵;流动相B:95∶5乙腈∶水,含有10mM乙酸铵;温度:50℃;梯度:经3分钟0-100%B,随后在100%B保持0.75分钟;流量:1.11mL/min。
方法B:Waters Acquity UPLC BEH C18,2.1x 50mm,1.7-μm颗粒;流动相A:5∶95乙腈∶水,含有0.05%TFA;流动相B:95∶5乙腈∶水,含有0.05%TFA;温度:50℃;梯度:经3分钟0-100%B,随后在100%B保持0.75分钟;流量:1.11mL/min。
方法C SunFire(4.6x 150mm)(15min梯度-95∶5H2O/乙腈-至95∶5乙腈/H2O-0.05%TFA)。
中间体1. 2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酸
向在DMSO(5mL)中的2-氯吡啶-3-甲腈(0.489g,3.53mmol)中添加2-(3-氟-4-羟苯基)乙酸(0.6g,4mmol)和K2CO3(1.072g,7.760mmol),并将反应混合物加热至60℃持续14小时。使反应混合物冷却至室温,通过添加1N HCl淬灭并将所得固体过滤并在真空下干燥,得到(0.9g,90%产率)呈棕褐色固体的中间体1。1H NMR(400MHz,CD3OD)δ8.32(dd,J=5.0,1.9Hz,1H),8.25(dd,J=7.7,2.0Hz,1H),7.35-7.23(m,3H),7.23-7.10(m,1H),3.70(s,2H)。LCMS m/z=273.0(M+H).+
中间体2. 2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酰氯
向中间体1(1.6g,5.9mmol)在DCE(11.7mL)中的悬浮液中添加SOCl2(4.29ml,58.8mmol),并将反应混合物加热至50℃。反应混合物变澄清并将其搅拌1小时。真空蒸发溶剂,得到呈白色固体的2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酰氯(1.71g,100%)。对于甲酯,LCMS m/z=286.9(M+H)+。
中间体3. 2-(4-((3-氰基吡啶-2-基)氧基)苯基)乙酸,HCl.
如对于中间体1所述,用2-(4-羟苯基)乙酸代替2-(3-氟-4-羟苯基)乙酸来制备2-(4-((3-氰基吡啶-2-基)氧基)苯基)乙酸,HCl(14.7g,99%产率),棕色固体。1H NMR(400MHz,DMSO-d6)δ12.39(br s,1H),8.88-8.18(m,2H),7.42-7.29(m,3H),7.23-7.15(m,2H),2.63(s,2H)。LCMS m/z=255.1(M+H).+
中间体4. 2-(3-氯-4-((3-氰基吡啶-2-基)氧基)苯基)乙酸
如对于中间体1所述,用2-(3-氯-4-羟苯基)乙酸代替2-(3-氟-4-羟苯基)乙酸来制备2-(3-氯-4-((3-氰基吡啶-2-基)氧基)苯基)乙酸(1.5g,97%产率)。1H NMR(400MHz,CD3OD)δ8.35-8.20(m,2H),7.52(d,J=2.0Hz,1H),7.40-7.33(m,1H),7.32-7.21(m,2H),3.70(s,2H)。LCMS(ESI)m/z:289-290.9(M+H).+
中间体5. 2-(4-((3-氨基甲酰基吡啶-2-基)氧基)-3-氟苯基)乙酸,HCl
将中间体1(3g,10mmol)溶于DMSO(55.1mL)中,然后添加K2CO3(6.09g,44.1mmol)。将反应混合物在水浴(不冷冻的DMSO)中稍微冷却。在5分钟内向反应混合物中滴加过氧化氢(30%重量水溶液)(11.26ml,110.0mmol)(轻微放热),并在室温搅拌反应混合物。在72小时后,小心地添加浓HCl,过滤所得白色固体,用过量的水洗涤,并在真空下干燥,得到(2.86g,79.0%产率)中间体5。1H NMR(400MHz,DMSO-d6)δ12.46(br s,1H),8.47-8.09(m,2H),7.81(br d,J=8.1Hz,2H),7.40-7.23(m,3H),7.16(dd,J=8.1,1.3Hz,1H),3.66(s,2H)。LCMS m/z=291.1(M+H).+
中间体6. 2-(4-((3-氨基甲酰基吡啶-2-基)氧基)苯基)乙酸,HCl
以与中间体5类似的方式制备2-(4-((3-氨基甲酰基吡啶-2-基)氧基)苯基)乙酸,HCl(1.3g,87%产率),浅黄色固体。1H NMR(500MHz,DMSO-d6)δ8.26-8.11(m,2H),7.78(br.s.,1H),7.75(br.s.,1H),7.36-7.27(m,2H),7.22(dd,J=7.4,4.7Hz,1H),7.16-7.05(m,2H),3.48-3.32(m,1H),2.59-2.52(m,2H)。LCMS m/z=273.1(M+H).+
中间体7. 2-(3-氯-4-((3-氰基吡啶-2-基)氧基)苯基)乙酸,HCl
如对于中间体5所述,用2-(3-氯-4-((3-氰基吡啶-2-基)氧基)苯基)乙酸代替2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酸来制备2-(3-氯-4-((3-氰基吡啶-2-基)氧基)苯基)乙酸,HCl(0.45g,100%产率),白色固体。1H NMR(400MHz,DMSO-d6)δ12.48(br s,1H),8.40-8.03(m,2H),7.97-7.69(m,2H),7.49(d,J=2.0Hz,1H),7.44-6.89(m,3H),3.32(s,2H)。LCMS m/z:306.9(M+H).+
中间体8. 2-(4-(2-((5-溴苯并[d]噻唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺,HCl
步骤1.向中间体1(0.35g,1.3mmol)在DCE(4mL)中的悬浮液中添加SOCl2(0.925mL,12.7mmol),并将反应混合物加热至50℃。反应物变澄清并将其搅拌1小时。减压除去溶剂,并向所得固体中添加5-溴苯并[d]噻唑-2-胺(0.32g,1.4mmol)、THF(3mL)和DIEA(0.66mL,3.8mmol)。在24小时后,将溶剂减压蒸发,并将残余物通过硅胶色谱用DCM/0-100%乙酸乙酯洗脱进行纯化,得到(0.385g,62.9%产率)的呈黄色固体的N-(5-溴苯并[d]噻唑-2-基)-2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酰胺。1H NMR(400MHz,CDCl3)δ9.06(br s,1H),8.34(dd,J=4.8,2.0Hz,1H),8.07(dd,J=7.7,2.0Hz,1H),7.93(d,J=1.8Hz,1H),7.72(d,J=8.6Hz,1H),7.55-7.46(m,1H),7.51-7.45(m,1H),7.36(t,J=8.0Hz,1H),7.28-7.14(m,2H),3.92(s,2H)。LCMS m/z=484.9(M+H).+
步骤2.将N-(5-溴苯并[d]噻唑-2-基)-2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酰胺(0.38g,0.78mmol)溶于DMSO(3.93mL)中,然后添加K2CO3(0.435g,3.14mmol)。将反应混合物在水浴中稍微冷却,并在5分钟内滴加30%的过氧化氢(0.80mL,7.9mmol)(轻微放热),并将反应混合物在室温搅拌14小时。将反应混合物通过小心添加HCl淬灭并将所得固体过滤并在真空下干燥,得到(0.45g,106%产率)呈棕褐色固体的中间体8。1H NMR(400MHz,DMSO-d6)δ12.82(br s,1H),8.29-8.14(m,2H),7.98(dd,J=5.2,3.2Hz,2H),7.82(br s,1H),7.80(br s,1H),7.53-7.46(m,1H),7.42-7.33(m,2H),7.25(dd,J=7.4,5.0Hz,2H),3.93(s,2H)。LCMS m/z=500.9-501.9(M+H).+
实施例1. 2-(2-氟-4-(2-((7-甲氧基-4,5-二氢萘并[1,2-d]噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
在小瓶中,向中间体5(0.02g,0.07mmol)、7-甲氧基-4,5-二氢萘并[1,2-d]噻唑-2-胺(0.02g,0.07mmol)的混合物中添加BOP(0.030g,0.069mmol)、DMF(0.3mL)和DIEA(0.060ml,0.35mmol)。在72小时后,将反应混合物过滤并进行反相HPLC纯化,得到实施例1(4.4mg,9.9%)。1H NMR(500MHz,DMSO-d6)δ8.34-8.04(m,2H),7.85-7.81(m,1H),7.80-7.73(m,1H),7.58(d,J=8.2Hz,1H),7.42-7.29(m,2H),7.27-7.12(m,2H),6.91-6.79(m,2H),3.83(s,2H),3.33(br s,1H),3.02-2.93(m,2H),2.92-2.84(m,2H),3.77(s,3H)。LCMS m/z=505.0(M+H)+;HPLC纯度>96%,保留时间1.81分钟。[方法A]
实施例2. 2-(4-(2-((5-甲氧基苯并[d]噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
向中间体6(20mg,0.065mmol)和5-甲氧基苯并[d]噻唑-2-胺(11.68mg,0.06500mmol)的混合物中添加DMF(0.3mL),含有BOP(28.7mg,0.0650mmol)和DIEA(0.057mL,0.32mmol)的DMF(0.5mL)溶液。在24小时后,将反应混合物过滤并进行反相HPLC纯化,得到实施例2(1.6mg,4.2%产率),1H NMR(500MHz,DMSO-d6)δ1H NMR(500MHz,DMSO-d6)δ12.58(br s,1H),8.29-8.00(m,2H),7.82(br d,J=8.5Hz,1H),7.79(br s,1H),7.75(br s,1H),7.40(br d,J=8.2Hz,2H),7.28(s,1H),7.21(br dd,J=7.3,4.9Hz,1H),7.16(br d,J=8.2Hz,2H),6.94(dd,J=8.5,1.8Hz,1H),3.86(s,2H)3.82(s,3H)。LCMS m/z=434.9(M+H)+;HPLC纯度>94%,保留时间1.52分钟。[方法B]
实施例3. 2-(2-氟-4-(2-((5-(2-羟基-2-甲基丙氧基)苯并[d]噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.将2-氨基苯并[d]噻唑-5-醇(0.066g,0.40mmol)悬浮在MeCN(4.5mL)中,然后添加2,2-二甲基环氧乙烷(0.35ml,4.0mmol)、K2CO3(0.220g,1.59mmol)和水(0.300mL)。将反应混合物在微波辐射下于120℃搅拌30分钟。将反应混合物用MeOH稀释,减压浓缩,并通过硅胶色谱使用DCM/0-15%MeOH作为洗脱剂进行纯化,得到(73mg,77%产率)的呈澄清状物的1-((2-氨基苯并[d]噻唑-5-基)氧基)-2-甲基丙-2-醇。1H NMR(400MHz,CDCl3)δ7.47(d,J=8.8Hz,1H),7.14(d,J=2.4Hz,1H),6.82(dd,J=8.6,2.4Hz,1H),5.34(d,J=7.7Hz,2H),3.85(s,2H),3.52(s,1H),1.41-1.37(m,6H)。LCMS m/z=238.9(M+H).+
步骤2.在小瓶中,向中间体5(12.18mg,0.04200mmol)和1-((2-氨基苯并[d]噻唑-5-基)氧基)-2-甲基丙-2-醇(10mg,0.042mmol)中添加DMF(0.3mL)、BOP(18.56mg,0.04200mmol)和DIEA(0.037ml,0.21mmol)。将反应混合物在室温搅拌72小时。将反应混合物过滤并进行反相HPLC纯化,得到实施例3(1.5mg,5.4%产率)。1H NMR(500MHz,DMSO-d6)δ8.30-8.11(m,2H),7.84(br s,1H),7.82(br s,1H),7.79(br d,J=8.7Hz,1H),7.47-7.30(m,2H),7.30-7.17(m,3H),6.93(br d,J=8.8Hz,1H),3.86(s,2H),3.78(s,2H),2.55(s,1H),1.83(br s,1H),1.23(s,6H)。LCMS m/z=511.0(M+H)+;HPLC纯度>94%,保留时间1.45分钟。[方法B]
实施例4. 2-(4-(2-((5-(1,3-二甲基-1H-吡唑-4-基)苯并[d]噻唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺
向小瓶中添加中间体8(25mg,0.050mmol)、1,3-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(16.61mg,0.07500mmol)、3M磷酸三钾(83μl,0.25mmol)和DMF(1.5mL)。将反应混合物用N2脱气,添加氯(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯)(2’-氨基-1,1′-联苯-2-基)钯(II)(3.92mg,4.99μmol),并将反应混合物加热至70℃。在1小时后,将反应混合物冷却至室温,过滤并进行反相HPLC纯化,得到实施例4(4.4mg,14%产率)。1H NMR(500MHz,DMSO-d6)δ8.21(br d,J=7.5Hz,1H),8.20-8.16(m,1H),7.95(d,J=8.2Hz,1H),7.92(s,1H),7.75(s,1H),7.72(br s,1H),7.66(br s,1H),7.37(br t,J=8.2Hz,3H),7.25(br dd,J=7.3,4.4Hz,2H),3.92(s,2H),3.81(s,3H),2.34(s,3H),1.02(m,1H)。LCMS m/z=517.1(M+H).+HPLC纯度>98%,保留时间1.41分钟。[方法B]
按照实施例4的一般操作所述制备实施例5和6
实施例7. 2-(2-氯-4-(2-((1-(环丙基甲基)-1H-苯并[d]咪唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.向在MeOH(4mL)/H2O(1mL)中的可商购获得的N1-(环丙基甲基)苯-1,2-二胺(0.18g,1.1mmol)中添加氰化溴(0.17g,1.7mmol)。在搅拌24小时后,将反应混合物减压浓缩并用浓NH4OH处理。收集固体沉淀物并真空干燥,得到呈红色/棕色固体的1-(环丙基甲基)-1H-苯并[d]咪唑-2-胺(0.138g,66.4%产率)。1H NMR(400MHz,DMSO-d6)δ7.17(dt,J=7.6,0.7Hz,1H),7.12(d,J=7.4Hz,1H),6.97-6.84(m,2H),6.34(s,2H),3.91(d,J=7.0Hz,2H),2.73-2.54(m,1H),1.27-1.15(m,1H),0.50-0.37(m,4H)。LCMS m/z=188.1(M+H).+
通过步骤1的产物和中间体7(9.6mg,32.8%产率)的BOP偶联制备实施例7。1H NMR(500MHz,DMSO-d6)δ8.48-8.04(m,2H),7.96-7.74(m,2H),7.66-7.48(m,3H),7.34(br d,J=16.9Hz,2H),7.30-6.85(m,3H),4.00(br s,2H),3.69(br s,2H),1.23(br s,2H),0.43(brd s,4H)。LCMS m/z=476.1(M+H).+HPLC纯度>92%,保留时间1.38分钟。[方法B]
实施例8. 2-(2-氟-4-(2-((7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.向中间体2(0.25g,0.86mmol)和7-甲氧基-[1,2,4]三唑[1,5-a]吡啶-2-胺(0.14g,0.86mmol)中添加THF(3mL)和吡啶(0.21mL,2.6mmol)。在24小时后,蒸发溶剂,并将残余物通过硅胶色谱纯化,用DCM/0-100%EtOAc洗脱,然后用DCM/10%MeOH洗脱,得到呈棕褐色固体的2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)-N-(7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)乙酰胺(35mg,9.7%产率)。1H NMR(400MHz,CD3OD)δ8.38-8.28(m,2H),8.27-8.17(m,2H),7.34-7.18(m,5H),4.00-3.89(m,2H),3.34(s,3H)。LCMS m/z=419.0(M+H).+
实施例8.如对于中间体5所述水解步骤1的产物,然后进行反相HPLC纯化,得到白色固体(14mg,28.9%产率)。1H NMR(400MHz,DMSO-d6)δ10.96(br s,1H),8.67(d,J=7.5Hz,1H),8.30-8.15(m,2H),7.86-7.81(m,1H),7.80-7.71(m,1H),7.45-7.30(m,2H),7.27-7.16(m,2H),7.09(d,J=2.4Hz,1H),6.78(dd,J=7.5,2.6Hz,1H),3.90(s,3H),3.88-3.67(m,2H)。LCMS m/z=436.9(M+H).+HPLC纯度>95%,保留时间6.07分钟。[方法C]
实施例9. 2-(4-(2-((6-溴咪唑并[1,2-a]吡啶-2-基)氨基)-2-氧代乙基)-2-氯苯氧基)吡啶-3-甲酰胺
如实施例1中所述通过中间体7和6-溴咪唑并[1,2-a]吡啶-2-胺的BOP偶联制备实施例9,并将残余物通过反相HPLC纯化,得到所需的产物(2.6mg,1.1%产率)。1H NMR(500MHz,DMSO-d6)δ8.89(br s,1H),8.21(dd,J=7.4,1.7Hz,1H),8.19-8.13(m,1H),8.10(s,1H),7.84(br s,1H),7.79(br s,1H),7.56(s,1H),7.43(d,J=9.4Hz,1H),7.41-7.28(m,3H),7.24(dd,J=7.4,4.9Hz,1H),3.76(s,2H)。LCMS m/z=500-501.9(M+H).+HPLC纯度>95%,保留时间1.20分钟。[方法B]
实施例10. 2-(2-氯-4-(2-((1-甲基-1H-吡唑并[3,4-b]吡啶-3-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.如对于实施例1所述,使用BOP将中间体4(28mg,0.097mmol)与1-甲基-1H-吡唑并[3,4-b]吡啶-3-胺(14mg,0.097mmol)偶联,得到2-(3-氯-4-((3-氰基吡啶-2-基)氧基)苯基)-N-(1-甲基-1H-吡唑并[3,4-b]吡啶-3-酰基)乙酰胺,其无需进一步纯化即可使用。LCMS m/z=419.0(M+H).+
步骤2.向来自步骤1的中间体中添加过量的K2CO3(0.054g,0.39mmol)、DMSO(0.3mL)和30%H2O2(0.040mL,0.39mmol)。在72小时后,将反应混合物通过添加NaSO3水溶液淬灭,过滤并通过反相HPLC纯化,得到实施例10(8mg,10%产率)。1H NMR(500MHz,DMSO-d6)δ11.04(s,1H),8.53(br d,J=4.0Hz,1H),8.39(br d,J=7.9Hz,1H),8.22(dd,J=7.5,1.7Hz,1H),8.17(dd,J=4.7,1.7Hz,1H),7.81(br s,1H),7.77(br s,1H),7.59(s,1H),7.48-7.31(m,2H),7.24(dd,J=7.3,4.9Hz,1H),7.15(dd,J=8.2,4.3Hz,1H),3.98(s,3H),3.83(s,2H)。LCMS m/z=437.1(M+H).+HPLC纯度>99%,保留时间1.23分钟。[方法B]
按照实施例1的一般操作所述制备实施例11、12、14和16
实施例13. 2-(2-氟-4-(2-((4-(6-氟吡啶-2-基)-5-甲基噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.向在DCM(50mL)中的6-氟吡啶甲酸(980mg,6.95mmol)中添加DMF(50μL,0.65mmol),然后逐滴添加草酰氯(650μL,7.43mmol)。在1.2小时后,添加N,O-二甲基羟胺HCl(1.05g,10.8mmol),并将反应混合物冷却至0℃。添加吡啶(2.6mL,32mmol),并使反应混合物升温至室温并搅拌72小时。通过添加水淬灭反应混合物,并分层。用二氯甲烷萃取水相,并用盐水洗涤合并的有机层,干燥(MgSO4),过滤并减压浓缩,得到呈澄清浅黄色油状物的6-氟-N-甲氧基-N-甲基吡啶-2-甲酰胺(1.09g,85.0%产率)。1H NMR(500MHz,CD3C1)δ7.88(q,J=7.8Hz,1H),7.56(br.s.,1H),7.02(dd,J=8.2,2.4Hz,1H),3.79(br.s.,3H),3.37(br.s.,3H)。LCMS m/z=185.0(M+H).+
步骤2.向6-氟-N-甲氧基-N-甲基吡啶-2-甲酰胺(1.23g,6.68mmol)在THF(40mL)中的0℃溶液中逐滴添加CH3CH2MgBr(9ml,30mmol)。在0℃下1.5小时后,通过添加NH4Cl水溶液小心地淬灭反应混合物。将各层分配,并用Et2O萃取水层。将合并的有机层用盐水洗涤,干燥(MgSO4),过滤并减压浓缩至干。将残余物通过硅胶色谱使用己烷至30%EtOAc作为洗脱剂进行纯化。获得呈澄清无色油状物的1-(6-氟吡啶并-2-基)丙-1-酮(684mg,66.9%产率)。1H NMR(500MHz,CD3Cl)δ7.86-8.05(m,2H),7.12(ddd,J=5.6,3.1,2.9Hz,1H),3.16(q,J=7.3Hz,2H),1.19(t,J=7.3Hz,3H)。LCMS m/z=154.0(M+H).+
步骤3.向温热至90℃的在AcOH(30mL,524mmol)中的1-(6-氟吡啶-2-基)丙-1-酮(680mg,4.44mmol)中添加Br2(230μL,4.46mmol)。在15分钟后,将反应混合物真空浓缩。向残余物中添加NaHCO3水溶液。用Et2O萃取水层。将合并的有机层用盐水洗涤,干燥(MgSO4),过滤并浓缩至干,得到呈澄清浅黄色油状物的2-溴-1-(6-氟吡啶-2-基)丙-1-酮(1.01g,98.0%产率)。1H NMR(500MHz,CD3Cl)δ7.88-8.05(m,2H),7.17(dd,J=7.8,2.6Hz,1H),5.85(q,J=6.7Hz,1H),1.88(d,J=6.7Hz,3H)。
步骤4.向在EtOH(30mL)中的2-溴-1-(6-氟吡啶-2-基)丙-1-酮(1.00g,4.31mmol)中添加硫脲(335mg,4.40mmol)。将反应混合物加热至80℃持续16小时。在冷却至室温后,在真空下减少溶剂体积,并将剩余的混合物置于冷冻机中2小时。滤出沉淀的固体,并用Et2O洗涤。将固体悬浮在水中,并添加NH4OH。用Et2O萃取水层。将合并的有机层用盐水洗涤,干燥(MgSO4),过滤并浓缩至干,得到呈灰白色固体的4-(6-氟吡啶-2-基)-5-甲基噻唑-2-胺(760mg,84%产率)。1H NMR(500MHz,DMSO-d6)δ7.98(q,J=8.3Hz,1H),7.78(dd,J=7.6,2.4Hz,1H),6.99(dd,J=8.1,2.6Hz,1H),6.89(s,2H),2.61(s,3H)。LCMS m/z=209.7(M+H).+
如实施例1所述通过BOP偶联,用4-(6-氟吡啶-2-基)-5-甲基噻唑-2-胺代替7-甲氧基-4,5-二氢萘并[1,2-d]噻唑-2-胺来获得实施例13(3.4mg,5.05%产率)。1H NMR(500MHz,DMSO-d6)δ12.45(br s,1H),8.24-8.17(m,2H),8.08(q,J=8.2Hz,1H),7.89(brd,J=7.6Hz,1H),7.83(br s,1H),7.81-7.77(m,1H),7.44-7.31(m,2H),7.27-7.21(m,2H),7.10(dd,J=8.1,2.0Hz,1H),3.86(s,2H),2.73(s,3H)。LCMS m/z=482.0(M+H).+HPLC纯度100%,保留时间1.72分钟。[方法B]
实施例15. 2-(4-(2-(苯并[d]噻唑-2-基氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺
在涉及1,3-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑的铃木(Suzuki)反应期间,通过脱卤由中间体8制备实例15(0.6mg,2.2%产率)。1H NMR(500MHz,DMSO-d6)δ8.25-8.15(m,2H),7.88(br d,J=7.6Hz,1H),7.83(br s,1H),7.79(brs,1H),7.66(br d,J=8.2Hz,1H),7.45-7.31(m,3H),7.27-7.14(m,3H),3.82(s,2H)。LCMSm/z=422.8(M+H).+HPLC纯度>97%,保留时间1.48分钟。[方法A]
实施例17. 2-(2-氟-4-(2-((4-(1-甲基-2-氧代-1,2-二氢吡啶-4-基)噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.向中间体1(1.0g,3.7mmol)在DCE(10mL)中的悬浮液中添加SOCl2(2.7mL,37mmol),并将反应混合物加热至50℃。在1小时后,减压除去溶剂,并添加THF(10ml)、4-溴噻唑-2-胺(0.70g,4.0mmol)和DIEA(2mL,11mmol)。在24小时后,减压除去溶剂,将残余物通过硅胶色谱纯化,得到(1.1g,71%产率)的呈棕色固体的N-(4-溴噻唑-2-基)-2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酰胺。LCMS(ESI)m/z:432.7-434.7(M+H).+ 1H NMR(400MHz,CD3OD)δ8.32(dd,J=5.0,1.9Hz,1H),8.27(dd,J=7.6,1.9Hz,1H),7.39-7.25(m,4H),7.08(s,1H),3.90(s,2H)。
步骤2.以与中间体5类似方式,将N-(4-溴噻唑-2-基)-2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酰胺(1.0g,2.3mmol)氧化,得到2-(4-(2-((4-溴噻唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺,HCl(0.98g,87%产率)。LCMS(ESI)(ESI)m/z:450.9-452.9(M+H).+ 1H NMR(400MHz,DMSO-d6)δ12.72(s,1H),8.24-8.17(m,2H),7.87-7.81(m,1H),7.80-7.73(m,1H),7.45-7.30(m,3H),7.25(dd,J=7.4,5.0Hz,1H),7.21(dd,J=8.8,1.1Hz,1H),3.86(s,2H)
步骤3.如先前对实施例4所述,由步骤2的产物通过铃木(Suzuki)交叉偶联方式制备实施例17(2.4mg,4.0%产率)。1H NMR(500MHz,DMSO-d6)δ8.26-8.11(m,2H),7.92(s,1H),7.83(br s,1H),7.79(br s,1H),7.74(d,J=7.3Hz,1H),7.43-7.31(m,2H),7.27-7.18(m,2H),6.91(s,1H),6.74(br d,J=7.0Hz,1H),3.84(s,2H),3.41(s,3H)。LCMS m/z=480.1(M+H).+HPLC纯度94%,保留时间1.10分钟。[方法B]
实施例18. 2-(2-氟-4-(2-氧代-2-((4-(2-氧代-1,2-二氢吡啶-4-基)噻唑-2-基)氨基)乙基)苯氧基)吡啶-3-甲酰胺
步骤1.向在二噁烷(10mL)中的4-溴吡啶-2(1H)-酮(0.90g,5.2mmol)中添加5,5,5′,5′-四甲基-2,2′-双(1,3,2-二氧硼杂环己烷)(1.3g,5.7mmol)、乙酸钾(1.5g,16mmol)。将反应混合物用N2脱气15分钟,并添加PdCl2(dppf)DCM(0.21g,0.26mmol),并将反应混合物加热至90℃持续24小时。将反应混合物用水(20mL)和乙酸乙酯(50mL)分配。用乙酸乙酯(2x20mL)萃取水层。将合并的有机层用盐水(15mL)洗涤并干燥(MgSO4),过滤并减压浓缩,得到呈深色油状物的4-(5,5-二甲基-1,3,2-二氧硼杂环己烷-2-基)吡啶-2(1H)-酮。LCMS m/z=208(M+H).+
步骤2.以与实施例17所述相同的方式,使用4-(5,5-二甲基-1,3,2-二氧硼杂环己烷-2-基)吡啶-2(1H)-酮,由步骤2的产物制备实施例18(3.7mg,6.0%产率)。1H NMR(500MHz,DMSO-d6)δ8.29-8.13(m,2H),7.85(s,1H),7.71(br s,1H),7.66(br s,1H),7.46-7.28(m,3H),7.27-7.04(m,2H),6.84(s,1H),6.68(br d,J=6.7Hz,1H),3.83(s,2H),2.99(s,1H)。LCMS m/z=465.9(M+H).+HPLC纯度96%,保留时间1.04分钟。[方法A]
实施例19.(4-(2-(2-(4-((3-氨基甲酰基吡啶-2-基)氧基)-3-氟苯基)乙酰氨基)-5-甲基噻唑-4-基)吡啶-2-基)氨基甲酸甲酯
步骤1.向在THF(2mL)中的中间体1(0.3g,1mmol)中添加4-溴-5-甲基噻唑-2-胺(0.2g,1mmol)和吡啶(0.3mL,3mmol),并将反应混合物搅拌18小时。将反应混合物减压浓缩,并将残余物通过硅胶色谱纯化,得到N-(4-溴-5-甲基噻唑-2-基)-2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酰胺(0.46g,99%产率)。LCMS(ESI)m/z:444-446.8(M+H).+ 1HNMR(400MHz,DMSO-d6)δ12.54(s,1H),8.47(dd,J=7.5,2.0Hz,1H),8.43-8.36(m,1H),7.45-7.32(m,3H),7.23(dd,J=8.3,1.0Hz,1H),3.85(s,2H),2.27(s,3H)。
步骤2.将2-(二环己基膦基)-2′,4′,6′-三异丙基联苯(0.13g,0.27mmol)、KOAc(4g,40mmol),第二代xphos预催化剂(0.1g,0.1mmol)、(4-氯吡啶-2-基)氨基甲酸甲酯(2.5g,13mmol)和连二硼酸(1.8g,20mmol)在EtOH(130mL)中的混合物通过真空/N2填充循环脱气3次。将反应混合物在80℃加热3小时。经真空除去溶剂,并将固体悬浮于甲醇和DCM的混合物中。过滤悬浮液,浓缩滤液,得到呈黄色固体的(2-((甲氧基羰基)氨基)吡啶-4-基)硼酸。LCMS(ESI)m/z:197.1(M+H).+
步骤3.以与实施例4类似的方式,使用N-(4-溴-5-甲基噻唑-2-基)-2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酰胺和(2-((甲氧基羰基)氨基)吡啶-4-基)硼酸由步骤2的产物制备实施例19(1mg,3%产率)。1H NMR(500MHz,DMSO-d6)δ8.30(d,J=5.2Hz,1H),8.21(br d,J=4.0Hz,2H),8.19(s,1H),7.83(br s,1H),7.79(br s,1H),7.39-7.31(m,3H),7.27-7.23(m,1H),7.21(br d,J=8.2Hz,1H),3.91(s,1H),3.77(br s,2H),3.70(s,3H),2.56(s,3H),1.65(s,1H)。LCMS m/z=537.1(M+H).+HPLC纯度98%,保留时间1.46分钟。[方法A]
实施例20. 2-(2-氟-4-(2-((5-甲基-4-(1-甲基-6-氧代-1,6-二氢吡啶-3-基)噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.向在二噁烷中的5-溴-1-甲基吡啶-2(1H)-酮(0.75g,3.9mmol)中添加5,5,5′,5′-四甲基-2,2′-双(1,3,2-二氧硼杂环己烷)(1.0g,4.4mmol)、KOAc(1.2g,12mmol)。将反应混合物用N2脱气,然后添加PdCl2(dppf)-DCM(0.16g,0.19mmol),并将反应混合物加热至90℃持续18小时。使反应混合物冷却,过滤,并用水(20mL)和EtOAc(50mL)分配。用EtOAc(2x 20mL)萃取水层。将合并的有机层用盐水(15mL)洗涤,干燥(MgSO4),过滤并减压浓缩,得到呈深色油状物的5-(5,5-二甲基-1,3,2-二氧硼杂环己烷-2-基)-1-甲基吡啶-2(1H)-酮(0.67g,76%产率)。LCMS m/z=222(M+H).+
步骤2.以与实施例4类似的方式,使用5-(5,5-二甲基-1,3,2-二氧硼杂环己烷-2-基)-1-甲基吡啶基-2(1H)-酮和N-(4-溴-5-甲基噻唑-2-基)-2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酰胺由步骤1的产物制备实施例20(1.8mg,5.0%产率)。1H NMR(500MHz,DMSO-d6)δ8.21(br d,J=7.5Hz,1H),8.18(br d,J=2.9Hz,1H),7.89(br s,1H),7.73(brdd,J=9.3,2.3Hz,2H),7.63(br s,1H),7.41-7.29(m,2H),7.24(dd,J=7.3,5.0Hz,1H),7.21(br d,J=8.2Hz,1H),6.48(d,J=9.3Hz,1H),3.81(s,2H),3.51(s,3H),2.42(s,3H),1.25(br s,1H)。LCMS m/z=494.2(M+H).+HPLC纯度92%,保留时间1.20分钟。[方法A]
实施例21. 2-(4-(2-((4-(1-(二氟甲基)-6-氧代-1,6-二氢吡啶-3-基)-5-甲基噻唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺
以与实施例20类似的方式,用5-溴-1-(二氟甲基)吡啶-2-2(1H)-酮代替5-溴-1-甲基吡啶-2(1H)-酮来制备实施例21(11mg,31%)。1H NMR(500MHz,DMSO-d6)δ12.27(br s,1H),8.28-8.13(m,2H),7.94-7.85(m,3H),7.71(br s,1H),7.65(br s,1H),7.41-7.30(m,2H),7.28-7.14(m,2H),6.63(d,J=9.3Hz,1H),3.83(s,2H),2.45(s,3H)。LCMS m/z=529.9(M+H).+HPLC纯度100%,保留时间1.42分钟。[方法B]
实施例22. 2-(2-氯-4-(2-((5-甲基-4-(6-甲基吡啶-2-基)噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.向加热至90℃的1-(6-甲基吡啶-2-基)丙-1-酮(0.3g,2mmol)和AcOH(3mL)中添加在AcOH(1mL)中的Br2(0.1mL,2mmol)。在1小时后,减压除去溶剂,并向残余物中添加EtOH(15mL)和硫脲(0.15g,2.0mmol),并将反应混合物加热至60℃持续72小时。减压除去溶剂,并将残余物用稀NH4OH(20mL)和EtOAc(50mL)分配。用乙酸乙酯(2x 20mL)萃取水层。将合并的有机层用盐水(15mL)洗涤,干燥(MgSO4),得到呈棕褐色固体的5-甲基-4-(6-甲基吡啶-2-基)噻唑-2-胺(0.3g,70%产率)。1H NMR(400MHz,CDCl3)δ7.68-7.51(m,2H),7.05(dd,J=7.3,1.1Hz,1H),4.91(br s,2H),2.68(s,3H),2.61(s,3H)。LCMS(ESI)m/z:206.0(M+H).+
步骤3.以与实施例2类似的方式,使用中间体7和5-甲基-4-(6-甲基吡啶-2-基)噻唑-2-胺获得实施例22(2mg,3%产率)。1H NMR(500MHz,DMSO-d6)δ12.39(s,1H),8.26-8.20(m,1H),8.20-8.15(m,1H),7.81(br s,1H),7.78-7.72(m,3H),7.57(s,1H),7.31-7.21(m,2H),7.19-7.09(m,2H),3.84(s,2H),2.75(s,3H),2.52(s,3H),LCMS m/z=494.0(M+H).+HPLC纯度96%,保留时间1.57分钟。[方法B]
实施例23. 2-(2-氯-4-(2-((4-环丁基-5-(吡啶-2-基)噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.将1-环丁基-2-(吡啶-2-基)乙酮(2.40g,13.7mmol)和NaOAc(1.24g,15.1mmol)合并并溶于AcOH(75mL)中。将Br2(0.5mL,9mmol)一次性添加到反应混合物中。将反应混合物在室温搅拌20分钟,然后在减压下浓缩。向残余物中添加水,并用EtOAc(2x100mL)萃取。将合并的有机萃取物用NaHCO3水溶液、盐水洗涤两次,干燥(MgSO4),过滤并然后浓缩至干。将残余物通过硅胶色谱使用己烷/EtOAc纯化。获得呈浅黄色固体的2-溴-1-环丁基-2-(吡啶-2-基)乙酮(2g,60%产率)。1H NMR(500MHz,CDCl3)δ8.52(d,J=4.88Hz,1H)7.72(td,J=7.71,1.68Hz,1H)7.56(d,J=7.93Hz,1H)7.23(dd,J=7.48,4.73Hz,1H)5.53(s,1H)3.64(quin,J=8.47Hz,1H)2.18-2.40(m,2H)2.00-2.18(m,2H)1.87-2.00(m,1H)1.74-1.87(m,1H)。LCMS m/z=254.0,256.0(M+H).+
步骤2.向在EtOH(50mL)中的2-溴-1-环丁基-2-(吡啶-2-基)乙酮(2g,8mmol)中添加K2CO3(1.1g,8.1mmol),然后添加硫脲(0.6g mg,8mmol)。将反应混合物加热至60℃保持18小时,冷却,并将反应混合物过滤。将滤液减压浓缩。向残余物中添加水,并用EtOAc(2x100mL)萃取。将合并的有机层用盐水洗涤,干燥(MgSO4),过滤并然后浓缩至干。将残余物在DCM和己烷中研磨。将固体滤出并用己烷洗涤,得到作为棕褐色固体的4-环丁基-5-(吡啶-2-基)噻唑-2-胺(1.3g,74%产率)。1H NMR(500MHz,DMSO-d6)δ8.65(s,0.5H)8.34-8.56(m,1H)7.59-7.83(m,1H)7.31-7.44(m,1H)7.20(s,1.5H)7.02-7.16(m,1H)4.01(quin,J=8.62Hz,0.4H)3.91(quin,J=8.55Hz,0.6H)2.30-2.46(m,2H)2.10-2.30(m,2H)1.94(spt,J=9.41Hz,1H)1.70-1.87(m,1H)。LCMS m/z=232.0(M+H).+
步骤3.以与实施例2类似的方式,使用中间体7和4-环丁基-5-(吡啶-2-基)噻唑-2-胺获得实施例23(5mg,7%产率)。1H NMR(500MHz,DMSO-d6)δ8.55(br d,J=4.3Hz,1H),8.23(br d,J=7.4Hz,1H),8.16(br d,J=3.4Hz,1H),7.83(t,J=7.7Hz,1H),7.69(br s,1H),7.64(br s,1H),7.55(s,1H),7.50(d,J=8.0Hz,1H),7.36(q,J=8.3Hz,2H),7.25(td,J=8.0,5.0Hz,2H),4.00(quin,J=8.3Hz,1H),3.85(s,2H),2.43-2.24(m,4H),2.00(sxt,J=9.3Hz,1H),1.93-1.81(m,1H)。LCMS m/z=520.2(M+H).+HPLC纯度95%,保留时间1.91分钟。[方法A]
按照用于实施例4的一般操作所述制备下列实施例24-48
实施例106. 2-(4-(1-((7-甲氧基-4,5-二氢萘并[1,2-d]噻唑-2-基)氨基)-1-氧代丙-2-基)苯氧基)吡啶-3-甲酰胺
步骤1.向在DMSO(10ml)中的2-(4-羟苯基)乙酸甲酯(2.23g,13.4mmol)中添加2-(4-羟苯基)乙酸甲酯(2.23g,13.4mmol)和K2CO3(4.08g,29.5mmol),并将反应混合物加热至60℃持续24小时。添加水(25mL),并将反应混合物用乙酸乙酯(3x 30mL)萃取。将合并的有机层用水(25mL)、然后盐水(25mL)洗涤,干燥(MgSO4),过滤并减压浓缩,得到呈棕褐色固体的2-(4-((3-氰基吡啶-2-基)氧基)苯基)乙酸甲酯(2.9g,81%产率);1H NMR(400MHz,CDCl3)δ8.34(dd,J=5.1,2.0Hz,1H),8.04(dd,J=7.5,2.0Hz,1H),7.48-7.37(m,2H),7.23-7.15(m,2H),7.12(dd,J=7.5,5.1Hz,1H),3.74(s,3H),3.69(s,2H)。LCMS(ESI)m/z:268.9(M+H).+
步骤2.向冷却至0℃的在DMF(3mL)中的2-(4-((3-氰基吡啶-2-基)氧基)苯基)乙酸甲酯(0.20g,0.74mmol)和碘甲烷(0.046ml,0.74mmol)中添加NaH(0.066g,1.6mmol)(在油中的60%悬浮液)。在24小时后,将反应混合物通过添加水(10mL)淬灭,并用乙酸乙酯(3x10mL)萃取。将合并的有机层用盐水(15mL)洗涤,并干燥(MgSO4)。获得呈黄色油状物的2-(4-((3-氰基吡啶-2-基)氧基)苯基)丙酸甲酯(0.149g),其无需进一步纯化即可用于下一步骤。LCMS(ESI)m/z:282.9(M+H).+
步骤3.如对于中间体5所述,由2-(4-((3-氰基吡啶-2-基)氧基)苯基)丙酸甲酯的H2O2氧化,然后添加LiOH(0.2g),获得2-(4-((3-氨基甲酰基吡啶-2-基)氧基)苯基)丙酸(0.2g)。在24小时后,将反应混合物通过添加1N HCl酸化至pH=5,并用乙酸乙酯(3x 20mL)萃取。将合并的有机层用盐水(15mL)洗涤,干燥(MgSO4),过滤并减压浓缩,得到白色固体。LCMS(ESI)m/z:286.9(M+H).+
以与实施例1所述类似的方式,通过将2-(4-((3-氨基甲酰基吡啶-2-基)氧基)苯基)丙酸和7-甲氧基-4,5-二氢萘并[1,2-d]噻唑-2-胺偶联制备实施例106(1.4mg,4.5%)。1H NMR(500MHz,DMSO-d6)δ8.15(br.s.,2H),7.94-7.81(m,1H),7.80-7.70(m,1H),7.67-7.51(m,1H),7.42(d,J=7.7Hz,2H),7.24-7.15(m,1H),7.14(d,J=7.7Hz,2H),6.85(br.s.,2H),4.41-4.30(m,1H),4.08-3.95(m,1H),2.92(d,J=7.3Hz,2H),2.90-2.80(m,2H),1.45(d,J=6.6Hz,3H)在溶剂下方一个Me。LCMS m/z=500.9(M+H).+HPLC纯度95.9%,保留时间1.91分钟。[方法A]
实施例107. 2-(4-(2-((5-(2-羟基-2-甲基丙氧基)苯并[d]噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
以与实施例3类似的方式,用中间体6代替中间体5来制备实施例107(3.3mg,6.8%产率)。1H NMR(500MHz,DMSO-d6)δ8.23-8.11(m,2H),7.82(d,J=8.5Hz,2H),7.78(br.s.,1H),7.40(d,J=8.2Hz,2H),7.27(s,1H),7.25-7.19(m,1H),7.16(d,J=8.2Hz,2H),6.96(d,J=8.6Hz,1H),4.69(br.s.,1H),3.85(s,2H),3.78(s,2H),1.23(s,6H)。LCMS m/z=493.0(M+H).+HPLC纯度100%,保留时间1.39分钟。[方法B]
实施例108. 2-(4-(2-((7-(2-羟基-2-甲基丙氧基)-4,5-二氢萘并[1,2-d]噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.向在DCM(5ml)中搅拌的7-甲氧基-4,5-二氢萘并[1,2-d]噻唑-2-胺,氢溴酸盐(0.22g,0.70mmol)中添加BBr3(0.702ml,0.702mmol)。在72小时后,将反应混合物冷却至0℃,通过添加K2CO3水溶液和MeOH淬灭,过滤并减压浓缩,并通过硅胶色谱使用DCM/0-10%MeOH作为洗脱剂进行纯化,得到呈浅棕色固体的2-氨基-4,5-二氢萘并[1,2-d]噻唑-7-醇(0.22g)。LCMS(ESI)m/z:218.8(M+H).+
步骤2.以与实施例3中所述类似的方式,由2-氨基-4,5-二氢萘并[1,2-d]噻唑-7-醇制备1-((2-氨基-4,5-二氢萘并[1,2-d]噻唑-7-基)氧基)-2-甲基丙-2-醇(0.12g,61%)。1H NMR(400MHz,CDCl3)δ7.66-7.62(m,1H),6.87-6.79(m,2H),4.91(br.s.,2H),3.84(s,2H),3.07-2.97(m,2H),2.90-2.82(m,2H),2.44-2.24(m,1H),1.38(s,6H),LCMS(ESI)m/z:290.9(M+H).+
如实施例2中所述,通过1-((2-氨基-4,5-二氢萘并[1,2-d]噻唑-7-基)氧基)-2-甲基丙-2-醇和2-(4-((3-氨基甲酰基吡啶-2-基)氧基)苯基)乙酸的偶联获得实施例108(4.3mg,8.4%)。1H NMR(500MHz,DMSO-d6)δ8.20-8.10(m,2H),7.84(br.s.,1H),7.76(br.s.,1H),7.56(d,J=8.3Hz,1H),7.38(d,J=8.2Hz,2H),7.25-7.18(m,1H),7.14(d,J=8.2Hz,2H),6.90-6.83(m,1H),6.86-6.78(m,1H),4.78(br.s.,1H),3.00-2.91(m,2H),2.90-2.81(m,2H),1.27-1.16(m,7H),隐藏在水峰下方的峰。LCMS m/z=545.1(M+H).+HPLC纯度99%,保留时间1.59分钟。[方法B]
实施例109. 2-(4-(2-((6-(2-羟基-2-甲基丙氧基)苯并[d]噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
如之前对于实例3所述,通过用中间体6代替中间体5来制备实例109(5.2mg,11%)。1H NMR(500MHz,DMSO-d6)δ8.23-8.12(m,2H),7.79(br.s.,1H),7.75(br.s.,1H),7.63(d,J=8.8Hz,1H),7.54(s,1H),7.39(d,J=8.2Hz,2H),7.21(br.s.,1H),7.20-7.11(m,2H),7.04(d,J=8.8Hz,1H),3.83(s,2H),3.75(s,2H),1.27-1.15(m,8H);LCMS m/z=493.0(M+H),+HPLC纯度97%,保留时间1.32分钟。[方法B]
实施例110. 2-(2-氟-4-(2-((7-(2-羟基-2-甲基丙氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.向在AcOH(3mL)中的7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-胺(0.23g,1.4mmol)中添加48%HBr(1.5mL),并将反应混合物加热至100℃持续48小时。减压除去溶剂,并将残余物与甲苯(2x 10mL)共沸,得到呈棕色固体的氨基-[1,2,4]三唑并[1,5-a]吡啶-7-醇,氢溴酸盐(0.30g,36%)。LCMS m/z=151.1(M+H).+
步骤2.以与实施例3所述类似的方式,由氨基-[1,2,4]三唑并[1,5-a]吡啶-7-醇氢溴酸盐制备1-((2-氨基-[1,2,4]三唑并[1,5-a]吡啶-7-基)氧基)-2-甲基丙-2-醇(23mg,23%产率)。1H NMR(400MHz,CD3OD)δ8.55(d,J=7.5Hz,1H),7.19(d,J=2.6Hz,1H),7.12(dd,J=7.4,2.8Hz,1H),4.04(s,2H),3.34(dt,J=3.3,1.7Hz,1H),1.37(s,6H)。LCMSm/z=223.1(M+H).+
步骤3.以与实施例8所述类似的方式,使用中间体2和1-((2-氨基-[1,2,4]三唑并[1,5-a]吡啶-7-基)氧基)-2-甲基丙-2-醇获得实施例110(7.0mg,12%产率)。1H NMR(500MHz,DMSO-d6)δ10.95(br s,1H),8.65(br s,1H),8.27-8.14(m,2H),7.82(br s,1H),7.78(br s,1H),7.44-7.29(m,2H),7.28-7.17(m,2H),7.06(br s,1H),6.78(br d,J=7.3Hz,1H),4.75(s,1H),3.86(s,2H),3.39(s,2H),1.23(s,6H)。LCMS m/z=495.3(M+H).+HPLC纯度99%,保留时间1.05分钟。[方法A]
实施例111. 2-(4-(2-((1-(2,2-二氟乙基)-1H-苯并[d]咪唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺
步骤1.向在MeOH(25ml)中的中间体5(0.8g,3mmol)中添加过量亚硫酰氯(1.5ml,21mmol)。在24小时后,将反应混合物减压浓缩,并通过硅胶色谱使用己烷/EtOAc作为洗脱剂进行纯化,得到(0.30g,35%)2-(4-((3-氨基甲酰基吡啶-2-基)氧基)-3-氟苯基)乙酸甲酯。LCMS(ESI)m/z:304.8(M+H).+
步骤2.向在甲苯(2ml)中的1-(2,2-二氟乙基)-1H-苯并[d]咪唑-2-胺(15mg,0.076mmol)和2-(4-((3-氨基甲酰基吡啶-2-基)氧基)-3-氟苯基)乙酸甲酯(28mg,0.091mmol)中添加三甲基铝(0.11ml,0.23mmol)。在5分钟后,将反应混合物在微波辐射下于120℃加热30分钟。将反应混合物浓缩并通过添加TFA淬灭并通过反相HPLC纯化,得到(1.9mg,4.1%)的实施例111。1H NMR(500MHz,DMSO-d6)δ8.18(d,J=7.2Hz,2H),7.83(d,J=11.2Hz,2H),7.66-7.44(m,2H),7.44-7.12(m,6H),4.69-4.55(m,2H),3.71(br.s.,2H)。LCMS m/z=470.1(M+H).+HPLC纯度100%,保留时间1.19分钟。[方法B]
实施例112. 2-(2-氯-4-(2-((5-(2-羟基-2-甲基丙氧基)苯并[d]噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
以与实施例108类似的方式,用中间体4代替中间体5来制备实施例112(4mg,7%产率)。1H NMR(500MHz,DMSO-d6)δ8.39-8.07(m,2H),7.79(br d,J=12.8Hz,2H),7.64(br d,J=8.9Hz,1H),7.56(br d,J=13.1Hz,1H),7.38(s,2H),7.24(br dd,J=7.2,5.0Hz,1H),7.05(br d,J=8.5Hz,1H),4.03-3.84(m,2H),3.76(s,2H),1.21(s,6H),LCMS m/z=526.9(M+H).+HPLC纯度100%,保留时间1.45分钟。[方法A]
实施例113. 2-(2-氯-4-(2-((7-(2-羟基-2-甲基丙氧基)-4,5-二氢萘并[1,2-d]噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
以与实施例108类似的方式,通过用1-((2-氨基-4,5-二氢萘并[1,2-d]噻唑-7-基)氧基)-2-甲基丙-2-醇代替1-((2-氨基苯并[d]噻唑-5-基)氧基)-2-甲基丙-2-醇来制备实施例113(2mg,3%产率)。1H NMR(500MHz,DMSO-d6)δ8.39-8.07(m,2H),7.79(br d,J=12.8Hz,2H),7.64(br d,J=8.9Hz,1H),7.56(br d,J=13.1Hz,1H),7.38(s,2H),7.24(brdd,J=7.2,5.0Hz,1H),7.05(br d,J=8.5Hz,1H),4.03-3.84(m,2H),3.76(s,2H),1.21(s,6H),LCMS m/z=579.2(M+H).+HPLC纯度100%,保留时间1.69分钟。[方法A]
实施例114. 2-(2-氟-4-(2-(6-(2-羟基-2-甲基丙氧基)二氢吲哚-1-基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.以与实施例3中所述类似的方式,用6-羟基二氢吲哚-1-甲酸叔丁酯代替2-氨基苯并[d]噻唑-5-醇来制备呈澄清油状物的6-(2-羟基-2-甲基丙氧基)二氢吲哚-1-甲酸叔丁酯(0.12g,0.40mmol,94%产率)。1H NMR(400MHz,CDCl3)δ7.65-7.45(m,1H),7.04(d,J=8.1Hz,1H),6.52(dd,J=8.1,2.4Hz,1H),4.07-3.94(m,2H),3.82(s,2H),3.04(t,J=8.6Hz,2H),2.16(br.s.,1H),1.59(br.s.,9H),1.35(s,6H),LCMS(ESI)m/z:308.1(M+H).+
步骤2.向在DCM中的6-(2-羟基-2-甲基丙氧基)二氢吲哚-1-甲酸叔丁酯(0.12g,0.40mmol)中添加过量的在二噁烷中的4N HCl(5mL),并搅拌24小时。将反应混合物减压浓缩,得到呈深色膜状物的1-(二氢吲哚-6-基氧基)-2-甲基丙-2-醇,HCl(98mg,100%产率)。LCMS(ESI)m/z:208.1(M+H).+
步骤3.如实施例3中所述,将1-(二氢吲哚-6-基氧基)-2-甲基丙-2-醇,HCl与2-(4-((3-氨基甲酰基吡啶-2-基)氧基)-3-氟苯基)乙酸,HCl偶联,得到实施例114(4mg,11%产率)。1H NMR(500MHz,DMSO-d6)δ8.23-8.13(m,2H),7.88(br.s.,1H),7.79(br.s.,1H),7.71(s,1H),7.33(t,J=8.2Hz,1H),7.29-7.20(m,2H),7.13(dd,J=19.1,8.2Hz,2H),6.57(dd,J=8.2,2.1Hz,1H),4.20(t,J=8.4Hz,2H),3.95-3.86(m,2H),3.21-3.03(m,2H),1.17(s,6H)。LCMS m/z=480.3(M+H).+HPLC纯度100%,保留时间1.48分钟。[方法A]
实施例115. 2-(2-氯-4-(2-((5-甲氧基苯并[d]噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
向中间体4(28mg g,0.090mmol)和5-甲氧基苯并[d]噻唑-2-胺(17mg,0.090mmol)中添加1ml DCM,然后添加吡啶(7.8μl,0.090mmol)和POCl3(9μl,0.09mmol)。在搅拌24小时后,减压除去溶剂,并将残余物用饱和NaHCO3(2mL)溶液和EtOAc(3mL)分配。用EtOAc(2mL)萃取水层。将合并的有机层减压浓缩,并向残余物中添加过量的K2CO3(54mg,0.38mmol)、几片MgO和DMSO(0.3ml)。向反应混合物中添加H2O2(0.040ml,0.38mmol)。在搅拌24小时后,将反应混合物通过添加亚硫酸氢钠水溶液(2mL)淬灭并用EtOAc(3x 2mL)萃取。减压除去溶剂,并将残余物通过反相HPLC纯化,得到(3.1mg,5.0%产率)的实施例115。1H NMR(500MHz,DMSO-d6)δ8.22(d,J=7.6Hz,1H),8.16(d,J=5.3Hz,1H),7.87-7.73(m,3H),7.57(s,1H),7.38(s,2H),7.33-7.20(m,2H),6.94(dd,J=8.7,2.3Hz,1H),3.89(d,J=3.1Hz,3H),3.82(s,2H)。LCMS m/z=496.1(M+H).+HPLC纯度100%,保留时间1.55分钟。[方法B]
实施例116. 2-(2-氯-4-(2-((7-甲氧基-4,5-二氢萘并[1,2-d]噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
以与实施例115所述类似的方式,通过用7-甲氧基-4,5-二氢萘并[1,2-d]噻唑-2-胺,HBr代替5-甲氧基苯并[d]噻唑-2-胺来制备实例116(4.3mg,7.2%产率)。1H NMR(500MHz,DMSO-d6)δ8.28-8.12(m,2H),7.87-7.73(m,2H),7.60-7.50(m,2H),7.41-7.28(m,2H),7.28-7.15(m,1H),6.96-6.60(m,2H),3.84(s,2H),3.70(s,3H),3.06-2.93(m,2H),2.93-2.82(m,2H)。LCMS m/z=521.1(M+H).+HPLC纯度100%,保留时间1.87分钟。[方法B]
实施例117. 2-(2-甲氧基-4-(2-((5-甲氧基苯并[d]噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.向2-氯吡啶-3-甲腈(0.31g,2.2mmol)在DMSO(2ml)中的溶液中添加2-(4-羟基-3-甲氧基苯基)乙酸乙酯(0.50g,2.2mmol)和K2CO3(0.70g,4.9mmol),并将反应混合物加热至60℃持续24小时。将冷却的反应混合物用水稀释,收集所得固体并真空干燥,得到呈棕色固体的2-(4-((3-氰基吡啶-2-基)氧基)-3-甲氧基苯基)乙酸乙酯(55mg,79%产率)。LCMS(ESI)m/z:313.1(M+H).+1H NMR(400MHz,CDCl3)δ8.30(dd,J=5.1,2.0Hz,1H),8.01(dd,J=7.5,2.0Hz,1H),7.16(d,J=8.1Hz,1H),7.08(dd,J=7.6,5.0Hz,1H),7.01(d,J=1.8Hz,1H),6.96(dd,J=7.9,2.0Hz,1H),4.21(q,J=7.1Hz,2H),3.77(s,3H),3.65(s,2H),1.38-1.27(m,3H)。
步骤2.向在甲苯(2ml)中的2-(4-((3-氰基吡啶-2-基)氧基)-3-甲氧基苯基)乙酸乙酯(50mg,0.16mmol)和5-甲氧基苯并[d]噻唑-2-胺(0.032g,0.18mmol)中添加Me3Al(0.24ml,0.48mmol)。在5分钟后,将反应混合物在微波辐射下于120℃加热30分钟。将反应混合物通过添加1N HCl(2mL)淬灭,用EtOAc(3x 2mL)萃取,将有机层用饱和NaHCO3溶液洗涤并减压浓缩,得到2-(4-((3-氰基吡啶-2-基)氧基)-3-甲氧基苯基)-N-(5-甲氧基苯并[d]噻唑-2-基)乙酰胺。LCMS(ESI)m/z:447.1(M+H).+
步骤3.如实施例115中所述将2-(4-((3-氰基吡啶-2-基)氧基)-3-甲氧基苯基)-N-(5-甲氧基苯并[d]噻唑-2-基)乙酰胺转化为甲酰胺117,并通过反相HPLC纯化,得到实施例117(2.3mg,2.3%产率)。1H NMR(500MHz,DMSO-d6)δ8.20(dd,J=7.6,1.8Hz,1H),8.14(d,J=5.4Hz,1H),7.82(d,J=8.5Hz,1H),7.80-7.77(m,1H),7.70(br s,1H),7.28(d,J=2.1Hz,1H),7.22-7.13(m,3H),7.04-6.88(m,2H),3.88-3.78(m,5H),3.68(s,3H)LCMS m/z=465.1(M+H).+HPLC纯度95%,保留时间1.49分钟。[方法A]
实施例118. 2-(4-(2-((5-(2-羟基-2-甲基丙氧基)苯并[d]噻唑-2-基)氨基)-2-氧代乙基)-2-甲氧基苯氧基)吡啶-3-甲酰胺
以与实施例115所述类似的方式,通过用1-((2-氨基苯并[d]噻唑-5-基)氧基)-2-甲基丙-2-醇(实施例3,步骤1)代替5-甲氧基苯并[d]噻唑-2-胺来制备实施例118(2.6mg,4.0%产率)。1H NMR(500MHz,DMSO-d6)δ8.20(br d,J=7.4Hz,1H),8.14(br d,J=3.0Hz,1H),7.82(br s,1H),7.71(br s,1H),7.64(d,J=8.8Hz,1H),7.55(d,J=2.2Hz,1H),7.25(br s,1H),7.23-7.13(m,3H),7.05(br dd,J=8.7,2.4Hz,1H),6.97(br d,J=8.0Hz,1H),3.83(s,2H),3.75(s,2H),3.68(s,3H),3.57(br s,1H),3.17(s,1H),1.21(s,6H)。LCMS m/z=522.9(M+H).+HPLC纯度95%,保留时间1.42分钟。[方法B]
实施例119. 2-(2-溴-4-(2-((7-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.向在DMSO(20ml)中的2-氯吡啶-3-甲腈(3.4g,24mmol)中添加2-(3-溴-4-羟苯基)乙酸(5.6g,24mmol)和K2CO3(7.4g,53mmol),并将反应混合物加热至80℃持续24小时。将冷却的反应混合物用水稀释,用HCl酸化,过滤,得到呈棕褐色固体的2-(3-溴-4-((3-氰基吡啶-2-基)氧基)苯基)乙酸(7.8g,96%产率)。1H NMR(400MHz,CDCl3)δ8.32(dd,J=5.0,1.9Hz,1H),8.07(dd,J=7.5,2.0Hz,1H),7.66(d,J=2.0Hz,1H),7.38(dd,J=8.3,2.1Hz,1H),7.26(d,J=8.1Hz,1H),7.15(dd,J=7.6,5.0Hz,1H),3.71(s,2H)。LCMS(ESI)m/z:333-334.9(M+H).+
步骤2.向2-(3-溴-4-((3-氰基吡啶-2-基)氧基)苯基)乙酸(0.8g,2.5mmol)在DCE(5ml)中的悬浮液中添加亚硫酰氯(1.8ml,24mmol),并将反应混合物加热至50℃持续3小时。将反应混合物减压浓缩,得到呈褐色固体的2-(3-溴-4-((3-氰基吡啶-2-基)氧基)苯基)乙酰氯(0.88g,100%产率)。对于甲酯,LCMS(ESI)m/z:346-348.9(M+H)+。
步骤3.以与实施例8所述类似的方式,通过使用2-(3-溴-4-((3-氰基吡啶-2-基)氧基)苯基)乙酰氯和7-甲氧基-[1,2,4]三唑[1,5-a]吡啶-2-胺制备实施例119(1.8mg,3.0%产率)。1H NMR(500MHz,DMSO-d6)δ11.06-10.88(m,1H),8.62(br d,J=6.7Hz,1H),8.23(dd,J=7.5,1.7Hz,1H),8.16(dd,J=4.6,1.5Hz,1H),7.81(br s,1H),7.75(br s,1H),7.69(s,1H),7.48-7.38(m,1H),7.33(d,J=8.2Hz,1H),7.24(dd,J=7.3,4.9Hz,1H),7.06(br s,1H),6.77(br d,J=7.0Hz,1H),3.88(s,2H),3.56(s,3H),LCMS m/z=496.7(M+H).+HPLC纯度98%,保留时间1.03分钟。[方法A]
实施例120. 2-(4-(2-((1-(2,2-二氟乙基)-5-甲氧基-1H-苯并[d]咪唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺
步骤1.向冷却至0℃的在DMF(5ml)中的5-甲氧基-1H-苯并[d]咪唑-2-胺(0.34g,2.1mmol)和1,1-二氟-2-碘乙烷(0.4g,2mmol)中添加在油中的NaH(0.17g,4.2mmol),并将反应混合物在室温搅拌。在72小时后,将反应混合物通过添加水(20mL)淬灭,并用乙酸乙酯(3x30mL)萃取。将合并的有机层用盐水(15mL)洗涤,并干燥(MgSO4)。将残余物通过硅胶色谱纯化,用DCM/0-10%MeOH洗脱,得到0.2g为异构体混合物的棕色泡沫状物。LCMS(ESI)m/z:228.0(M+H).+通过SFC纯化此异构体混合物的160mg样品,得到1-(2,2-二氟乙基)-5-甲氧基-1H-苯并[d]咪唑-2-胺(27mg,25%产率)和1-(2,2-二氟乙基)-6-甲氧基-1H-苯并[d]咪唑-2-胺(58mg,51%产率)。
步骤2.向中间体1(2.2g,8.1mmol)在DCE(16ml)中的悬浮液中添加SOCl2(5.9ml,81mmol),并将反应混合物加热至50℃。反应物变澄清并将其搅拌1小时。减压除去溶剂,得到呈白色固体的2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酰氯(2.3g,98%产率)。
步骤3.向在THF(2mL)和吡啶(28μL,0.34mmol)中的2-(4-((3-氰基吡啶-2-基)氧基)-3-氟苯基)乙酰氯(33mg,0.11mmol)中添加1-(2,2-二氟乙基)-5-甲氧基-1H-苯并[d]咪唑-2-胺(26mg,0.11mmol)并将反应混合物在室温搅拌24小时。如实施例115中所述,将反应混合物减压浓缩并将残余物氧化,得到实施例120(2.8mg,3.8%产率);1H NMR(500MHz,DMSO-d6)δ8.29-8.13(m,2H),7.79-7.69(m,1H),7.67-7.58(m,1H),7.48-7.38(m,1H),7.36-7.29(m,2H),7.27-7.19(m,2H),7.16(br s,1H),6.86(br d,J=8.8Hz,1H),6.55-6.19(m,2H),4.64-4.56(m,2H),3.81(s,3H),3.78(s,2H)。LCMS m/z=500.1(M+H).+HPLC纯度95%,保留时间1.18分钟。[方法B]
按照用于实施例8或实施例9和中间体8的一般操作所述制备实施例121-131
实施例134. 2-(4-(2-((7-溴-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺
如对于中间体8所述,通过将中间体2与7-溴-[1,2,4]三唑并[1,5-a]吡啶-2-胺偶联,然后进行H2O2氧化,制备2-(4-(2-((7-溴-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺134(0.17g,30%)。1H NMR(400MHz,DMSO-d6)δ11.18(br s,1H),8.96-8.69(m,1H),8.40-8.15(m,3H),8.07(d,J=2.0Hz,1H),7.82(br s,1H),7.80(br s,1H),7.35-7.31(m,2H),7.27-7.23(m,2H),3.83(br s,2H),LCMS m/z=487.1(M+H).+HPLC纯度96%,保留时间1.12分钟。[方法A]
按照用于实施例4的一般操作制备实施例135-137
实施例138. 2-(2-氟-4-(2-((6-(1-甲基-1H-吡唑-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.使用与实施例134类似的方法,用6-溴-[1,2,4]三唑并[1,5-a]吡啶-2-胺代替7-溴-[1,2,4]三唑并[1,5-a]吡啶-2-胺来制得2-(4-(2-((6-溴-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺(28mg,7.0%产率)。LCMSm/z=485-488.1(M+H).+
步骤2.如实施例4中所述,使用与2-(4-(2-((6-溴-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺和1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑的铃木(Suzuki)反应)制备实施例138(1.4mg,4.0%产率)。1H NMR(500MHz,DMSO-d6)δ9.15(s,1H),8.27-8.15(m,2H),7.87(s,1H),7.85-7.81(m,3H),7.54(d,J=1.5Hz,1H),7.42-7.31(m,2H),7.28-7.15(m,2H),6.57(d,J=1.5Hz,1H),3.93(s,3H),3.91(s,2H),2.56(s,1H)。LCMS m/z=486.9(M+H).+HPLC纯度96%,保留时间0.98分钟。[方法A]
实施例139. 2-(4-(2-((8-(二氟甲氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺
步骤1.向在二噁烷(2mL)中的3-(二氟甲氧基)吡啶-2-胺(0.20g,1.2mmol)中添加O-乙氧羰基异硫氰酸酯(0.16mL,1.4mmol),在2小时后,添加EtOH(3mL)、盐酸羟胺(0.4g,6mmol)和DIEA(0.7mL,4mmol),并将反应混合物加热至60℃。在48小时后,滤出白色固体,并将滤液浓缩,用EtOAc萃取,用盐水洗涤并干燥(MgSO4)。收集(0.25g)8-(二氟甲氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺,其无需进一步纯化即可使用。1H NMR(400MHz,DMSO-d6)δ9.43(br s,2H),8.48(dd,J=6.7,1.0Hz,1H),7.72-7.40(m,1H),7.38-7.22(m,1H),6.87(dd,J=7.9,6.6Hz,1H)。
步骤2.如中间体8中所述,通过将8-(二氟甲氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-胺和中间体2偶联,然后进行氧化,制备实施例139(5.6mg,9.5%产率)。1H NMR(500MHz,DMSO-d6)δ11.30(br s,1H),8.78(d,J=6.7Hz,1H),8.25-8.13(m,2H),7.84(br s,1H),7.79(br s,1H),7.54-7.46(m,2H),7.43-7.32(m,2H),7.28-7.20(m,2H),7.15(t,J=7.3Hz,1H),3.83(br s,2H)。LCMS m/z=473.0(M+H).+HPLC纯度99%,保留时间1.08分钟。[方法B]
实施例140. 2-(2-氟-4-(2-氧代-2-((6-(三氟甲氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)乙基)苯氧基)吡啶-3-甲酰胺
使用与实施例139相同的方法,通过在步骤1中用5-(三氟甲氧基)吡啶-2-胺代替3-(二氟甲氧基)吡啶-2-胺来制备实施例140(2.2mg,3.5%产率)。1H NMR(500MHz,DMSO-d6)δ9.29(br s,1H),8.21(br d,J=7.4Hz,1H),8.18(br d,J=3.6Hz,1H),7.87-7.72(m,3H),7.71(br s,1H),7.63(br s,1H),7.36-7.30(m,2H),7.26-7.20(m,2H),3.85(br s,2H)。LCMS m/z=491.0(M+H).+HPLC纯度97%,保留时间1.40分钟。[方法A]
实施例141. 2-(2-氟-4-(2-氧代-2-((8-(三氟甲基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)乙基)苯氧基)吡啶-3-甲酰胺
使用与实施例139相同的方法,通过在步骤1中用3-(三氟甲基)吡啶-2-胺代替3-(二氟甲氧基)吡啶-2-胺来制备实施例141(3.5mg,5.7%产率)。1H NMR(500MHz,DMSO-d6)δ11.50(br s,1H),9.17(br d,J=6.4Hz,1H),8.33-8.16(m,2H),8.14(br d,J=7.0Hz,1H),7.85(br s,1H),7.81(br s,1H),7.48-7.34(m,2H),7.31(br t,J=7.0Hz,1H),7.26(br d,J=7.0Hz,2H),3.93(br s,2H)。LCMS m/z=475.0(M+H).+HPLC纯度96%,保留时间1.17分钟。[方法B]
实施例142. 2-(2-氟-4-(2-((7-氟-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
使用与实施例139相同的方法,通过在步骤1中用4-氟吡啶-2-胺代替3-(二氟甲氧基)吡啶-2-胺来制备实施例142(0.6mg,1%产率)。1H NMR(500MHz,DMSO-d6)δ10.01(s,1H),9.04-8.79(m,1H),8.21(br d,J=7.5Hz,1H),8.19(br d,J=4.6Hz,1H),7.70(br s,1H),7.64(br s,1H),7.57(dd,J=9.1,2.3Hz,1H),7.38-7.29(m,2H),7.28-7.18(m,2H),7.14(td,J=7.7,2.5Hz,1H),3.85(br s,2H)。LCMS m/z=425.1(M+H).+HPLC纯度97%,保留时间0.93分钟。[方法A]
实施例143. 2-(4-(2-((7-(苄氧基)-[1,2,4]三唑并[1,5-a]吡啶-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺
使用与实施例139类似的方法,通过在步骤1中用4-(苄氧基)吡啶-2-胺代替3-(二氟甲氧基)吡啶-2-胺来制备实施例143(1.3mg,2%产率)。1H NMR(500MHz,DMSO-d6)δ8.70(br d,J=7.3Hz,1H),8.26-8.16(m,2H),7.84(br s,1H),7.81(br s,1H),7.53(br d,J=7.3Hz,2H),7.45(br t,J=7.3Hz,2H),7.44-7.31(m,4H),7.30-7.17(m,3H),6.86(br dd,J=7.0,2.1Hz,1H),5.27(s,2H),3.93(s,2H)。LCMS m/z=513.2(M+H).+HPLC纯度94%,保留时间1.45分钟。[方法B]
实施例144. 2-(4-(2-((1-(环丙基甲基)-6-(1-甲基-1H-吡唑-4-基)-1H-苯并[d]咪唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺
步骤1.向冷却至0℃的在THF(2mL)中的4-溴-2-氟-1-硝基苯(0.60g,2.5mmol)中添加环丙基甲胺(0.19g,2.7mmol)和DIEA(0.5mL,3.0mmol)。将反应混合物在室温搅拌18小时。将反应混合物减压浓缩,将残余物溶于丙酮(3mL)/水(1.5mL)中,冷却至0℃,并缓慢添加NH4Cl(0.70g,12mmol)和锌(1.6g,25mmol)。将锌滤出,将丙酮减压浓缩。将水层用EtOAc(50mL)分配。用EtOAc(2x 20mL)萃取水层。将合并的有机层用盐水(15mL)洗涤并干燥(Na2SO4)。将残余物通过硅胶色谱纯化并用DCM/0-10%MeOH洗脱,得到呈深色油状物的5-溴-N1-(环丙基甲基)苯-1,2-二胺(0.40g,67%产率)。1H NMR(400MHz,CDCl3)δ6.88-6.71(m,1H),6.60(d,J=8.1Hz,1H),6.33(br d,J=7.7Hz,1H),3.79-3.40(m,1H),3.08-2.84(m,2H),1.13-0.99(m,1H),0.71-0.54(m,2H),0.40-0.12(m,2H)。
步骤2.在MeOH(6.6ml)/H2O(1.6ml)中搅拌5-溴-N1-(环丙基甲基)苯-1,2-二胺(0.40g,1.7mmol)和氰化溴(0.26g,2.5mmol)持续18小时。在减压下减少溶剂并然后通过添加氢氧化铵淬灭。在用水稀释后,滤出深褐色固体,得到6-溴-1-(环丙基甲基)-1H-苯并[d]咪唑-2-胺(0.36g,83%产率)。LCMS(ESI)m/z:265-267.9(M+H).+ 1H NMR(400MHz,DMSO-d6)δ7.41(t,J=1.1Hz,1H),7.05(d,J=1.1Hz,2H),6.53(s,2H),3.92(d,J=7.0Hz,2H),1.32-1.12(m,1H),0.63-0.25(m,4H)。
步骤3.如实施例2中所述,将中间体5与6-溴-1-(环丙基甲基)-1H-苯并[d]咪唑-2-胺偶联,得到呈橙色固体的2-(4-(2-((6-溴-1-(环丙基甲基)-1H-苯并[d]咪唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺(72mg,36%产率)。LCMS(ESI)m/z:537-539.9(M+H).+
步骤4.以与实施例4类似的方式制备实施例144(4.0mg,21%产率)。1H NMR(500MHz,DMSO-d6)δ8.39-8.08(m,4H),7.91(s,1H),7.80(br s,2H),7.72(br s,1H),7.42(br s,2H),7.37-7.27(m,2H),7.23(br d,J=8.5Hz,2H),4.03(br d,J=7.6Hz,2H),3.88(s,3H),3.69(s,2H),1.33(m,1H),0.47(br s,4H)。LCMS m/z=540.1(M+H).+HPLC纯度99%,保留时间1.19分钟。[方法B]
实施例145. 2-(4-(2-((1-(环丙基甲基)-6-(二甲基磷酰基)-1H-苯并[d]咪唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺
将2-(4-(2-((6-溴-1-(环丙基甲基)-1H-苯并[d]咪唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺(32mg,0.060mmol)、二甲基氧化膦(46.mg,0.60mmol)和TEA(25L,0.18mmol)在乙腈(2.3mL)中合并,并用N2流脱气。在吹扫5分钟后,添加(Ph3P)4Pd(0)(7mg,6μmol),并将反应混合物在微波辐射下于120℃加热40分钟。使反应混合物冷却,过滤并通过反相HPLC纯化,得到实施例145(14mg,35%产率)。1H NMR(500MHz,DMSO-d6)δ8.21(br d,J=7.4Hz,1H),8.18(br s,1H),7.86(br d,J=10.7Hz,1H),7.70(br s,1H),7.66(br s,1H),7.59(br d,J=5.8Hz,2H),7.44-7.28(m,2H),7.23(br d,J=5.4Hz,2H),4.05(br s,2H),3.96-3.64(m,2H),2.55(s,1H),1.71(s,3H),1.69(s,3H),1.30(br s,1H),0.47(br d,J=7.6Hz,3H),0.32(br s,1H),LCMS m/z=536.1(M+H).+HPLC纯度100%,保留时间1.09分钟。[方法A]
按照用于实施例145的一般操作制备下列实施例146-150
实施例151. 2-(2-氟-4-(2-((5-甲基-4-(6-甲基吡啶-2-基)噻唑-2-基)氨基)-2-氧代乙基)苯氧基)吡啶-3-甲酰胺
步骤1.向加热至90℃的1-(6-甲基吡啶-2-基)丙-1-酮(0.30g,2.0mmol)和AcOH(3mL)中添加在AcOH(1mL)中的Br2(0.10mL,2.0mmol)。在1小时后,减压除去溶剂,然后添加EtOH(15mL)和硫脲(0.15g,2.01mmol),并将反应混合物加热至60℃持续72小时。减压除去溶剂,并将残余物用0.1M NH4OH(20mL)和EtOAc(50mL)分配。用EtOAc(2x 20mL)萃取水层。将合并的有机层用盐水(15mL)洗涤,干燥(MgSO4),过滤并浓缩,得到呈棕褐色固体的5-甲基-4-(6-甲基吡啶-2-基)噻唑-2-胺(0.30g,74%产率)。1H NMR(400MHz,CDCl3)δ7.68-7.51(m,2H),7.05(dd,J=7.3,1.1Hz,1H),4.91(br s,2H),2.68(s,3H),2.61(s,3H)。LCMS(ESI)m/z:206.0(M+H).+
步骤2.如实施例2中所述,使用BOP将中间体5和5-甲基-4-(6-甲基吡啶-2-基)噻唑-2-胺偶联来制备实施例151(6mg,8%产率)。1H NMR(500MHz,DMSO-d6)δ12.38(s,1H),8.28-8.13(m,2H),7.83(br s,1H),7.79(br s,1H),7.77-7.66(m,2H),7.48-7.31(m,2H),7.30-7.20(m,2H),7.16(br d,J=6.7Hz,1H),2.84(s,2H),2.75(s,3H),2.50(s,3H),LCMSm/z=478.1(M+H).+HPLC纯度95%,保留时间1.62分钟。[方法A]
实施例152. 2-(4-(2-((1-(环丁基甲基)-1H-苯并[d]咪唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺的制备
步骤1.将KOH(105mg,1.88mmol)和(溴甲基)环丁烷(0.21mL,1.9mmol)添加到2-氨基苯并咪唑(250mg,1.87mmol)在丙酮(10mL)中的溶液中,并在60℃加热保持8小时,然后冷却至室温。在搅拌48小时后,将溶剂减压蒸发。将残余物溶于EtOAc中,用水、盐水洗涤,经Na2SO4干燥,过滤,并减压浓缩。将残余物通过正相色谱(100%DCM至10%MeOH/90%DCM)纯化,得到1-(环丁基甲基)-1H-苯并[d]咪唑-2-胺。1H NMR(400MHz,DMSO-d6)δ7.17-7.05(m,2H),6.93-6.81(m,2H),6.33(s,2H),4.00(d,J=7.3Hz,2H),2.80-2.66(m,1H),1.92-1.75(m,6H)。LCMS m/z=202.0(M+H).+
步骤2.将中间体2(72mg,0.25mmol)添加到1-(环丁基甲基)-1H-苯并[d]咪唑-2-胺(50mg,0.20mmol)和吡啶(60μl,0.70mmol)在THF中的0℃溶液中。使反应混合物达到室温。在搅拌18小时后,将反应混合物用EtOAc稀释,并用水、盐水洗涤,经硫酸钠干燥,过滤,并减压浓缩。将残余物通过正相色谱纯化(100%DCM至10%MeOH/90%DCM),得到棕褐色固体。以与实施例8中所述类似的方式,将腈水解为伯酰胺,得到呈白色固体的实施例152(25mg,17%)。1H NMR(500MHz,DMSO-d6)δ8.21-8.15(m,2H),7.84-7.76(m,2H),7.72-7.62(m,1H),7.61-7.55(m,1H),7.42-7.29(m,4H),7.24(dd,J=7.4,5.0Hz,2H),4.29(br s,2H),3.89(br s,2H),2.80(dt,J=15.1,7.5Hz,1H),1.95-1.88(m,2H),1.87-1.77(m,4H)。LCMS m/z=474.0(M+H).+HPLC纯度:98%,保留时间8.37分钟。[方法C]
实施例153. 2-(2-氟-4-(2-((1-异丙基-1H-苯并[d]咪唑-2-基)氨基)-2-氧代乙基)-苯氧基)吡啶-3-甲酰胺
步骤1.以与实施例152的步骤1所述类似的方式,通过用2-溴丙烷代替(溴甲基)环丁烷,制备1-异丙基-1H-苯并[d]咪唑-2-胺(110mg,34%)。LCMS m/z=176.1(M+H).+
步骤2.以与实施例152类似的方式,通过用1-异丙基-1H-苯并[d]咪唑-2-胺代替1-(环丁基甲基)-1H-苯并[d]咪唑-2-胺来制备2-(2-氟-4-(2-((1-异丙基-1H-苯并[d]咪唑-2-基)氨基)-2-氧代乙基)-苯氧基)吡啶-3-甲酰胺153(49mg,13%)。1H NMR(500MHz,DMSO-d6)δ8.20-8.16(m,2H),7.84-7.77(m,3H),7.62(br s,1H),7.39-7.30(m,4H),7.26-7.22(m,2H),5.04-4.96(m,1H),3.96-3.88(m,2H),1.59(s,3H),1.58(s,3H)。LCMS m/z=448.0(M+H).+HPLC纯度:93%,保留时间7.49分钟。[方法C]
按照用于实施例152的一般操作制备实施例154-177。
实施例178. 2-(4-(2-((1-(环丙基甲基)-6-(2-羟基-2-甲基丙氧基)-1H-苯并[d]咪唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺
步骤1.将3-氟-4-硝基苯酚(1.0g,6.4mmol)、(溴甲基)苯(0.80mL,7.0mmol)、K2CO3(2.6g,19mmol)和TBAI(16mg,0.050mmol)的混合物添加至DMF(15mL)中并在室温搅拌。在搅拌18小时后,添加水(75mL),并通过真空过滤收集所得固体,用水洗涤,干燥,得到呈黄色固体的4-(苄氧基)-2-氟-1-硝基苯(1.5g,95%)。1H NMR(500MHz,DMSO-d6)δ8.16(t,J=9.1Hz,1H),7.51-7.45(m,2H),7.45-7.40(m,2H),7.39-7.35(m,1H),7.28(dd,J=13.6,2.6Hz,1H),7.08-7.03(m,1H),5.30-5.26(m,2H)。LCMS m/z=248.1(M+H).+
步骤2.将4-(苄氧基)-2-氟-1-硝基苯(869mg,3.52mmol)、环丙基甲胺(250mg,3.52mmol)和Cs2CO3(1.1g,3.5mmol)添加到ACN(15mL)中并在120℃照射15分钟。将反应混合物减压浓缩,并将残余物在EtOAc和水之间分配。将有机层用盐水洗涤,经硫酸钠干燥,过滤并浓缩。将中间体溶于EtOH(30mL)中,并用在水(15mL)中的NH4Cl(0.90g,18mmol)处理。将溶液温热至60℃,之后添加Zn(3.4g,53mmol)。在2小时后,使混合物冷却至室温,通过硅藻土塞过滤,并用EtOAc洗涤。将有机层用水、盐水洗涤,并经Na2SO4干燥。将残余物通过正相色谱纯化,得到所需产物(396mg,42%)。LCMS m/z=269.1(M+H).+
步骤3.向5-(苄氧基)-N1-(环丙基甲基)苯-1,2-二胺(0.40g,1.5mmol)在MeOH(6ml)和水(1.5ml)中的溶液中添加氰化溴(0.171g,1.62mmol)并在室温搅拌。在18小时后,将反应混合物通过添加浓NH4OH调节至pH=9并用水(75mL)稀释。收集所得固体并通过真空过滤干燥,得到呈红橙色固体的6-(苄氧基)-1-(环丙基甲基)-1H-苯并[d]咪唑-2-胺。LCMSm/z=294.0(M+H).+
步骤4.向6-(苄氧基)-1-(环丙基甲基)-1H-苯并[d]咪唑-2-胺(200mg,0.682mmol)在THF(15mL)中的溶液中添加TEA(0.095mL,0.68mmol)和BOC-酸酐(0.24mL,1.0mmol)。在搅拌18小时后,将反应物用水稀释并用EtOAc(3x)萃取。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并减压浓缩。将残余物溶于EtOH中,用Pd/C(145mg)处理,并经受氢气气氛(55psi)。在2小时后,将悬浮液通过硅藻土塞过滤,并浓缩滤液,得到(1-(环丙基甲基)-6-羟基-1H-苯并[d]咪唑-2-基)氨基甲酸叔丁酯(150mg,71%)。LCMS m/z=304.1(M+H).+
步骤5.以与实施例3的步骤1类似的方式,由(1-(环丙基甲基)-6-羟基-1H-苯并[d]咪唑-2-基)氨基甲酸叔丁酯制备(1-(环丙基甲基)-6-(2-羟基-2-甲基丙氧基)-1H-苯并[d]咪唑-2-基)氨基甲酸叔丁基酯。该物质无需进一步纯化即可用于下一反应。LCMS m/z=376.1(M+H).+
步骤6.将(1-(环丙基甲基)-6-(2-羟基-2-甲基丙氧基)-1H-苯并[d]咪唑-2-基)氨基甲酸酯叔丁基(24mg,0.060mmol)溶于HCl(4.0M在二噁烷中)(320μl,1.28mmol),并在室温搅拌。在1小时后,添加额外的HCl(4.0M在二噁烷中)(320μl,1.28mmol)和一滴HCl(浓),继续搅拌。在搅拌总共6小时后,将反应混合物在减压下浓缩并在高真空下放置14小时。1-((2-氨基-1-(环丙基甲基)-1H-苯并[d]咪唑-6-基)氧基)-2-甲基丙-2-醇,HCl盐无需进一步纯化即可用于下一反应。LCMS m/z=276.1(M+H).+
步骤7.以与实施例152类似的方式,通过用1-((2-氨基-1-(环丙基甲基)-1H-苯并[d]咪唑-6-基)氧基)-2-甲基丙-2-醇HCl盐代替1-(环丁基甲基)-1H-苯并[d]咪唑-2-胺来制备2-(4-(2-((1-(环丙基甲基)-6-(2-羟基-2-甲基丙氧基)-1H-苯并[d]咪唑-2-基)氨基)-2-氧代乙基)-2-氟苯氧基)吡啶-3-甲酰胺实施例178(4.9mg,11%)。1H NMR(500MHz,DMSO-d6)δ8.18-8.12(m,2H),7.87-7.82(m,1H),7.78-7.74(m,1H),7.49(d,J=8.9Hz,1H),7.36-7.31(m,2H),7.29-7.26(m,1H),7.25-7.21(m,2H),6.96(br d,J=8.9Hz,1H),4.19-4.12(m,2H),3.91-3.87(m,1H),3.80-3.76(m,1H),1.29-1.16(m,8H),0.52-0.39(m,4H)。LCMS m/z=548.3(M+H).+HPLC纯度:96%,保留时间1.54分钟。[方法A]
序列表
<110> 百时美施贵宝公司
<120> 作为ROCK抑制剂的苯乙酰胺类
<130> 12941-WO-PCT
<150> 62/531624
<151> 2017-07-12
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> MISC_FEATURE
<223> FITC-AHA在N末端附接在A1 - A11
<220>
<221> MISC_FEATURE
<223> OH在C末端附接在A1 - A11
<400> 1
Ala Lys Arg Arg Arg Leu Ser Ser Leu Arg Ala
1 5 10
Claims (18)
1.式(I)化合物或其药学上可接受的盐:
其中
A1在每次出现时独立地选自CR3和N;前提是A1不全是CR3,并且不超过两个A1变量是N;
R1选自-OH和NR5R5;
R2在每次出现时独立选自卤素、C1-6烷基、C1-4烷氧基、C1-4烷基硫基、C1-4卤代烷基、-OH、-CH2OH、-OCH2F、-OCHF2、-OCF3、CN、-NH2、-NH(C1-4烷基)、-N(C1-4烷基)2、-CO2H、-CH2CO2H、-CO2(C1-4烷基)、-CO(C1-4烷基)、-CH2NH2、-CONH2、-CONH(C1-4烷基)、-CON(C1-4烷基)2、-OCH2CO2H、-NHCO(C1-4烷基)、-NHCO2(C1-4烷基)、-NHSO2(C1-4烷基)、-SO2NH2、-C(=NH)NH2、碳环和杂环,其中所述烷基、烷氧基、烷基硫基、卤代烷基、碳环和杂环经0-4个R9取代;
R3在每次出现时独立选自H、卤素、C1-6烷基、C1-4烷氧基、C1-4烷基硫基、C1-4卤代烷基、-CH2OH、-OCH2F、-OCHF2、-OCF3、CN、-NH2、-NH(C1-4烷基)、-N(C1-4烷基)2、-CO2H、-CH2CO2H、-CO2(C1-4烷基)、-CO(C1-4烷基)、-CH2NH2、-CONH2、-CONH(C1-4烷基)、-CON(C1-4烷基)2、-OCH2CO2H、-NHCO(C1-4烷基)、-NHCO2(C1-4烷基)、-NHSO2(C1-4烷基)、-SO2NH2、-C(=NH)NH2、碳环和杂环,其中所述烷基、烷氧基、烷基硫基、卤代烷基、碳环和杂环经0-4个R9取代;
R4在每次出现时独立选自H和C1-4烷基;
R5在每次出现时独立选自H、-(CR6R6)n-C3-10碳环以及包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的-(CR6R6)n-4-15元杂环,其中所述烷基、碳环和杂环经1-4个R7取代;
或者,R5和R5与它们所连接的氮原子一起形成经1-4个R7取代的4至15元杂环;
R6在每次出现时独立选自H和C1-4烷基;
R7在每次出现时独立选自H、=O、NO2、卤素、C1-4烷基、C1-4烷氧基、CN、OH、CF3、-(CH2)n-CO2H、-(CH2)n-CO2(C1-4烷基)、-(CH2)n-NR8R8、-NHCO(C1-4烷基)、-NHCOCF3、-NHCO2(C1-4烷基)、-NHCO2(CH2)2O(C1-4烷基)、-NHCO2(CH2)3O(C1-4烷基)、-NHCO2(CH2)2OH、-NHCO2(CH2)2NH2、-NHCO2(CH2)2N(C1-4烷基)2、-NHCO2CH2CO2H、-CH2NHCO2(C1-4烷基)、-NHC(O)NR8R8、-NHSO2(C1-4烷基)、-SO2NH2、-SO2NH(C1-4烷基)、-SO2N(C1-4烷基)2、-SO2NH(CH2)2OH、-SO2NH(CH2)2O(C1-4烷基)、-(CH2)n-CONR8R8、-O(CH2)n-碳环、-O(CH2)n-杂环、-NHCO-碳环、-NHCO-杂环、-(CH2)n-碳环以及包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的-(CH2)n-杂环,其中所述烷基、烯基、炔基、烷氧基、碳环和杂环经0-4个R9取代;
R8在每次出现时独立选自H、C1-4烷基、C2-4烯基、C2-4炔基、-(CH2)n-C(O)C1-4烷基、-(CH2)n-C(O)碳环、-(CH2)n-C(O)杂环、-(CH2)n-C(O)NRaRa、-(CH2)n-C(O)O-烷基、-(CH2)n-C(O)O-碳环、-(CH2)n-C(O)O-杂环、-(CH2)n-SO2烷基、-(CH2)nSO2碳环、-(CH2)n-SO2杂环、-(CH2)n-SO2NRaRa、-(CH2)n-碳环和-(CH2)n-杂环,其中所述烷基、碳环和杂环经0-4个R9取代;
或者,R8和R8与它们所连接的氮原子一起形成经0-4个R9取代的4至10元杂环;
R9在每次出现时独立选自卤素、OH、NO2、CHF2、CF3、C1-4烷基、C1-4烷氧基、CH2OH、CO(C1-4烷基)、CO2H、CO2(C1-4烷基)、-(CH2)nNRaRa、-(CH2)nCONRaRa、-O(CH2)碳环、-O(CH2)杂环、-O(CH2)nNRaRa、-(CR10R10)n-4-10元杂环,其中所述烷基、烷氧基、碳环和杂环经0-4个Rb取代;
R10选自H和C1-4烷基;
Ra在每次出现时独立选自H、C1-4烷基、-(CH2)nOH、CO(C1-4烷基)、COCF3、CO2(C1-4烷基)、-CONH2、-CONH-C1-4亚烷基-CO2(C1-4烷基)、C1-4亚烷基-CO2(C1-4烷基)、Rc、CO2Rc和CONHRc;或者,Ra和Ra与它们所连接的氮原子一起形成4至10元杂环,其中所述烷基、亚烷基和杂环经0-4个Rb取代;
Rb在每次出现时独立选自=O、OH、卤素、C1-4烷基、C1-4烷氧基、OCF3、NH2、NO2、N(C1-4烷基)2、CO(C1-4烷基)、CO(C1-4卤代烷基)、CO2(C1-4烷基)、CONH2、-CONH(C1-4烷基)、-CON(C1-4烷基)2、-CONH-C1-4亚烷基-O(C1-4烷基)、-CONH-C1-4亚烷基-N(C1-4烷基)2、-CONH-C1-4亚烷基-N(C1-4烷基)2、-C1-4亚烷基-O-P(O)(OH)2、-NHCO2(C1-4烷基)、-Rc、CORc、CO2Rc和CONHRc;
Rc在每次出现时独立选自-(CH2)n-C3-6环烷基、-(CH2)n-苯基以及含有碳原子和1-4个选自N、NH、N(C1-4烷基)、O和S(O)p的杂原子的-(CH2)n-5至6元杂环;其中每个环部分经0-2个Rd取代;
Rd在每次出现时独立选自=O、卤素、-OH、C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、C1-4烷氧基和-NHCO(C1-4烷基)以及含有碳原子和1-4个选自N、NH、N(C1-4烷基)、O和S(O)p的杂原子的杂环;
n在每次出现时独立选自0、1、2、3和4;且
p在每次出现时独立选自0、1和2。
2.根据权利要求1所述的化合物或其药学上可接受的盐,所述化合物具有式(II):
其中
R2独立地选自卤素和C1-6烷基;
R5为包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的4-15元杂环,其中所述杂环经1-4个R7取代;
R7在每次出现时独立选自H、=O、NO2、卤素、C1-4烷基、C1-4烷氧基、CN、OH、CF3、-(CH2)n-CO2H、-(CH2)n-CO2(C1-4烷基)、-(CH2)n-NR8R8、-NHCO(C1-4烷基)、-NHCOCF3、-NHCO2(C1-4烷基)、-NHCO2(CH2)2O(C1-4烷基)、-NHCO2(CH2)3O(C1-4烷基)、-NHCO2(CH2)2OH、-NHCO2(CH2)2NH2、-NHCO2(CH2)2N(C1-4烷基)2、-NHCO2CH2CO2H、-CH2NHCO2(C1-4烷基)、-NHC(O)NR8R8、-NHSO2(C1-4烷基)、-SO2NH2、-SO2NH(C1-4烷基)、-SO2N(C1-4烷基)2、-SO2NH(CH2)2OH、-SO2NH(CH2)2O(C1-4烷基)、-(CH2)n-CONR8R8、-O(CH2)n-碳环、-O(CH2)n-杂环、-NHCO-碳环、-NHCO-杂环、-(CH2)n-碳环以及包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的-(CH2)n-杂环,其中所述烷基、烯基、炔基、烷氧基、碳环和杂环经0-4个R9取代;
R8在每次出现时独立地选自H、C1-4烷基、C(O)C1-4烷基、-(CH2)nC(O)NRaRa、C(O)O-烷基、SO2烷基、SO2NRaRa、-(CH2)n-碳环和-(CH2)n-杂环,其中所述烷基、碳环和杂环经0-4个R9取代;
R9在每次出现时独立地选自卤素、OH、NO2、CHF2、CF3、C1-4烷基、C1-4烷氧基、CH2OH、CO2H、CO2(C1-4烷基)、CONH2、-(CH2)nNRaRa、-(CH2)nCONRaRa、-O(CH2)杂环、-O(CH2)(2-4)NRaRa、-(CH2)n-4-10元杂环,其中所述烷基、烷氧基、碳环和杂环经0-4个Rb取代;
Ra在每次出现时独立选自H、C1-4烷基、-(CH2)nOH、CO(C1-4烷基)、COCF3、CO2(C1-4烷基)、-CONH2、-CONH-C1-4亚烷基-CO2(C1-4烷基)、C1-4亚烷基-CO2(C1-4烷基)、Rc、CO2Rc和CONHRc;或者,Ra和Ra与它们所连接的氮原子一起形成4至10元杂环,其中所述烷基、亚烷基和杂环经0-4个Rb取代;
Rb在每次出现时独立选自=O、卤素、C1-4烷基、C1-4烷氧基、OCF3、NH2、NO2、N(C1-4烷基)2、CO(C1-4烷基)、CO(C1-4卤代烷基)、CO2(C1-4烷基)、CONH2、-CONH(C1-4烷基)、-CON(C1-4烷基)2、-CONH-C1-4亚烷基-O(C1-4烷基)、-CONH-C1-4亚烷基-N(C1-4烷基)2、-CONH-C1-4亚烷基-N(C1-4烷基)2、-C1-4亚烷基-O-P(O)(OH)2、-NHCO2(C1-4烷基)、-Rc、CORc、CO2Rc和CONHRc;
Rc在每次出现时独立选自-(CH2)n-C3-6环烷基、-(CH2)n-苯基以及含有碳原子和1-4个选自N、NH、N(C1-4烷基)、O和S(O)p的杂原子的-(CH2)n-5至6元杂环;其中每个环部分经0-2个Rd取代;
Rd在每次出现时独立选自=O、卤素、-OH、C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、C1-4烷氧基和-NHCO(C1-4烷基)以及含有碳原子和1-4个选自N、NH、N(C1-4烷基)、O和S(O)p的杂原子的杂环;
n在每次出现时独立选自0、1、2、3和4;
p在每次出现时独立选自0、1和2。
3.根据权利要求2所述的化合物或其药学上可接受的盐,其中
R2独立地选自F、Cl和Br;
R7在每次出现时独立选自H、=O、卤素、C1-4烷基、C1-4烷氧基、CN、OH、CF3、-(CH2)n-CO2H、-(CH2)n-CO2(C1-4烷基)、-(CH2)n-NR8R8、-NHCO(C1-4烷基)、-NHCOCF3、-NHCO2(C1-4烷基)、-NHCO2(CH2)2O(C1-4烷基)、-NHCO2(CH2)3O(C1-4烷基)、-NHCO2(CH2)2OH、-NHCO2(CH2)2NH2、-NHCO2(CH2)2N(C1-4烷基)2、-NHCO2CH2CO2H、-CH2NHCO2(C1-4烷基)、-NHC(O)NR8R8、-NHSO2(C1-4烷基)、-SO2NH2、-SO2NH(C1-4烷基)、-SO2N(C1-4烷基)2、-SO2NH(CH2)2OH、-SO2NH(CH2)2O(C1-4烷基)、-(CH2)n-CONR8R8、-O(CH2)n-碳环、-O(CH2)n-杂环、-NHCO-碳环、-NHCO-杂环、-(CH2)n-碳环以及包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的-(CH2)n-杂环,其中所述烷基、烯基、炔基、烷氧基、碳环和杂环经0-4个R9取代;
R8在每次出现时独立地选自H、C1-4烷基、-(CH2)n-碳环和-(CH2)n-杂环,其中所述烷基、碳环和杂环经0-4个R9取代;且
R9在每次出现时独立地选自卤素、OH、NO2、CHF2、CF3、C1-4烷基、C1-4烷氧基、CH2OH、CO2H、CO2(C1-4烷基)、CONH2、-(CH2)nNH2、-(CH2)nCONH2、-O(CH2)n杂环、-O(CH2)(2-4)NH2、-(CH2)n-4-10元杂环。
7.具有式(III)的化合物或其药学上可接受的盐:
其中
R2选自F、Cl、Br和OC1-4烷基;
R4选自H和C1-4烷基;
R7在每次出现时独立地选自H、=O、NO2、卤素、C1-4烷基、C1-4烷氧基、CN、OH、CF3、-(CH2)n-CO(C1-4烷基)、-(CH2)n-CO2H、-(CH2)n-CO2(C1-4烷基)、-(CH2)n-NR8R8、-NHCO(C1-4烷基)、-NHCOCF3、-NHCO2(C1-4烷基)、-NHCO2(CH2)2O(C1-4烷基)、-NHCO2(CH2)3O(C1-4烷基)、-NHCO2(CH2)2OH、-NHCO2(CH2)2NH2、-NHCO2(CH2)2N(C1-4烷基)2、-NHCO2CH2CO2H、-CH2NHCO2(C1-4烷基)、-NHC(O)NR8R8、-NHSO2(C1-4烷基)、-P(=O)(C1-3烷基)2、-SO2C1-4烷基、-SO2NH2、-SO2NH(C1-4烷基)、-SO2N(C1-4烷基)2、-SO2NH(CH2)2OH、-SO2NH(CH2)2O(C1-4烷基)、-(CH2)n-CONR8R8、-O(CH2)n-碳环、-O(CH2)n-杂环、-NHCO-碳环、-NHCO-杂环、-CO-碳环、-CO-杂环、-(CH2)n-碳环以及包含碳原子和1-4个选自N、NR8、O和S(O)p的杂原子的-(CH2)n-杂环,其中所述烷基、烯基、炔基、烷氧基、碳环和杂环经0-4个R9取代;
R8在每次出现时独立选自H、C1-4烷基、C2-4烯基、C2-4炔基、-(CH2)n-C(O)C1-4烷基、-(CH2)n-C(O)碳环、-(CH2)n-C(O)杂环、-(CH2)n-C(O)NRaRa、-(CH2)n-C(O)O-烷基、-(CH2)n-C(O)O-碳环、-(CH2)n-C(O)O-杂环、-(CH2)n-SO2烷基、-(CH2)nSO2碳环、-(CH2)n-SO2杂环、-(CH2)n-SO2NRaRa、-(CH2)n-碳环和-(CH2)n-杂环,其中所述烷基、碳环和杂环经0-4个R9取代;
或者,R8和R8与它们所连接的氮原子一起形成经0-4个R9取代的4至10元杂环;
R9在每次出现时独立地选自卤素、OH、NO2、CHF2、CN、CF3、C1-4烷基、C1-4烷氧基、CH2OH、CO(C1-4烷基)、CO2H、CO2(C1-4烷基)、-(CH2)nNRaRa、-(CH2)nCONRaRa、-O(CH2)n碳环、-O(CH2)n杂环、-O(CH2)nNRaRa、NRaCO2(C1-4烷基)、S(O)pC1-4烷基、-(CR10R10)n-碳环、-(CR10R10)n-4-10元杂环,其中所述烷基、烷氧基、碳环和杂环经0-4个Rb取代;
R10选自H和C1-4烷基;
Ra在每次出现时独立选自H、C1-4烷基、-(CH2)nOH、CO(C1-4烷基)、COCF3、CO2(C1-4烷基)、-CONH2、-CONH-C1-4亚烷基-CO2(C1-4烷基)、C1-4亚烷基-CO2(C1-4烷基)、Rc、CO2Rc和CONHRc;或者,Ra和Ra与它们所连接的氮原子一起形成4至10元杂环,其中所述烷基、亚烷基和杂环经0-4个Rb取代;
Rb在每次出现时独立选自=O、OH、卤素、C1-4烷基、C1-4烷氧基、OCF3、NH2、NO2、N(C1-4烷基)2、CO(C1-4烷基)、CO(C1-4卤代烷基)、CO2(C1-4烷基)、CONH2、-CONH(C1-4烷基)、-CON(C1-4烷基)2、-CONH-C1-4亚烷基-O(C1-4烷基)、-CONH-C1-4亚烷基-N(C1-4烷基)2、-CONH-C1-4亚烷基-N(C1-4烷基)2、-C1-4亚烷基-O-P(O)(OH)2、-NHCO2(C1-4烷基)、-Rc、CORc、CO2Rc和CONHRc;
Rc在每次出现时独立选自-(CH2)n-C3-6环烷基、-(CH2)n-苯基以及含有碳原子和1-4个选自N、NH、N(C1-4烷基)、O和S(O)p的杂原子的-(CH2)n-5至6元杂环;其中每个环部分经0-2个Rd取代;
Rd在每次出现时独立选自=O、卤素、-OH、C1-4烷基、NH2、NH(C1-4烷基)、N(C1-4烷基)2、C1-4烷氧基和-NHCO(C1-4烷基)以及含有碳原子和1-4个选自N、NH、N(C1-4烷基)、O和S(O)p的杂原子的杂环;
n在每次出现时独立选自0、1、2、3和4;且
p在每次出现时独立选自0、1和2。
12.一种药物组合物,其包含一种或多种根据权利要求1-11中任一项所述的化合物和药学上可接受的载体或稀释剂。
13.根据权利要求1-11中任一项所述的化合物,其用于治疗。
14.根据权利要求1或7所述的化合物,其中所述化合物选自示例性实施例或其立体异构体、互变异构体或药学上可接受的盐。
15.根据权利要求1-11中任一项所述的化合物在预防和/或治疗与异常Rho激酶活性有关的病症中的用途。
16.根据权利要求15所述的用途,其中所述病症选自心血管病症、平滑肌相关病症、纤维化疾病、炎性疾病、神经病症、肿瘤病症和自身免疫病症。
17.根据权利要求16所述的用途,其中所述心血管病症选自心绞痛、动脉粥样硬化、中风、脑血管疾病、心力衰竭、冠状动脉疾病、心肌梗塞、外周血管疾病、狭窄、血管痉挛、高血压和肺动脉高压。
18.一种用于抑制Rho激酶活性的方法,其包括:(a)提供靶细胞和包含根据权利要求1或7所述的化合物的组合物;(b)在使所述组合物与所述靶细胞结合的条件下,将所述靶细胞暴露于所述组合物,从而抑制所述靶细胞内的Rho激酶活性。
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