JP2017504576A - RORガンマ(γ)モジュレータ - Google Patents
RORガンマ(γ)モジュレータ Download PDFInfo
- Publication number
- JP2017504576A JP2017504576A JP2016536162A JP2016536162A JP2017504576A JP 2017504576 A JP2017504576 A JP 2017504576A JP 2016536162 A JP2016536162 A JP 2016536162A JP 2016536162 A JP2016536162 A JP 2016536162A JP 2017504576 A JP2017504576 A JP 2017504576A
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- acetamide
- hydroxypropan
- hexafluoro
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 hydroxy, methoxy Chemical group 0.000 claims abstract description 250
- 150000001875 compounds Chemical class 0.000 claims abstract description 158
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 139
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 52
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 35
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 25
- 125000003118 aryl group Chemical group 0.000 claims abstract description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 20
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 18
- 150000002367 halogens Chemical class 0.000 claims abstract description 18
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 13
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 13
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 10
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims abstract description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 10
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 9
- 230000001404 mediated effect Effects 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 7
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 6
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 239000013543 active substance Substances 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- GMAFEFMNAQKDBN-UHFFFAOYSA-N 2-[3-(cyclopropylsulfamoyl)phenyl]-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-methylacetamide Chemical compound C1(CC1)NS(=O)(=O)C=1C=C(C=CC=1)CC(=O)N(C)C1=CC=C(C=C1)C(C(F)(F)F)(C(F)(F)F)O GMAFEFMNAQKDBN-UHFFFAOYSA-N 0.000 claims description 2
- KUHTZVVBMOGYHX-UHFFFAOYSA-N 2-[4-(cyclopropylmethylsulfonyl)phenyl]-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-2-oxoacetamide Chemical compound C1(CC1)CS(=O)(=O)C1=CC=C(C=C1)C(C(=O)NC1=CC=C(C=C1)C(C(F)(F)F)(C(F)(F)F)O)=O KUHTZVVBMOGYHX-UHFFFAOYSA-N 0.000 claims description 2
- CKDKXBGADMBGLR-UHFFFAOYSA-N 2-[4-(cyclopropylsulfamoyl)phenyl]-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-methylacetamide Chemical compound C1(CC1)NS(=O)(=O)C1=CC=C(C=C1)CC(=O)N(C)C1=CC=C(C=C1)C(C(F)(F)F)(C(F)(F)F)O CKDKXBGADMBGLR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- LSBDFXRDZJMBSC-UHFFFAOYSA-N Amide-Phenylacetic acid Natural products NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 claims 1
- QJVUSPXVNQEGKC-UHFFFAOYSA-N C(C)(=O)NC1=C(C=C(C=C1)C(C(F)(F)F)(C(F)(F)F)O)C Chemical compound C(C)(=O)NC1=C(C=C(C=C1)C(C(F)(F)F)(C(F)(F)F)O)C QJVUSPXVNQEGKC-UHFFFAOYSA-N 0.000 claims 1
- KVSAXZUHZNSKNA-UHFFFAOYSA-N C(C)(=O)NC1=CC(=C(C=C1)C(C(F)(F)F)(C(F)(F)F)O)C Chemical compound C(C)(=O)NC1=CC(=C(C=C1)C(C(F)(F)F)(C(F)(F)F)O)C KVSAXZUHZNSKNA-UHFFFAOYSA-N 0.000 claims 1
- JKKJSVNDZAHPOK-UHFFFAOYSA-N N-[3-fluoro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]acetamide Chemical compound C(C)(=O)NC1=CC(=C(C=C1)C(C(F)(F)F)(C(F)(F)F)O)F JKKJSVNDZAHPOK-UHFFFAOYSA-N 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 3
- 101000585507 Solanum tuberosum Cytochrome b-c1 complex subunit 7 Proteins 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- 239000000243 solution Substances 0.000 description 46
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 44
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 38
- 239000011541 reaction mixture Substances 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 238000000034 method Methods 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 26
- 239000000460 chlorine Substances 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 22
- 235000019341 magnesium sulphate Nutrition 0.000 description 22
- 108091008773 RAR-related orphan receptors γ Proteins 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- 239000012267 brine Substances 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000003480 eluent Substances 0.000 description 18
- 102000013691 Interleukin-17 Human genes 0.000 description 16
- 108050003558 Interleukin-17 Proteins 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
- 229910004298 SiO 2 Inorganic materials 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 0 COC(*)(CC1CCCCC1)C1C=CC(*)=CC1 Chemical compound COC(*)(CC1CCCCC1)C1C=CC(*)=CC1 0.000 description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 102100039556 Galectin-4 Human genes 0.000 description 9
- 101000608765 Homo sapiens Galectin-4 Proteins 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000012911 assay medium Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- 108060001084 Luciferase Proteins 0.000 description 8
- 239000005089 Luciferase Substances 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 210000000068 Th17 cell Anatomy 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 6
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- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 108090000064 retinoic acid receptors Proteins 0.000 description 1
- 102000003702 retinoic acid receptors Human genes 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Chemical class 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- AAMCVENDCXWDPJ-UHFFFAOYSA-N sulfanyl acetate Chemical class CC(=O)OS AAMCVENDCXWDPJ-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 1
- 238000006692 trifluoromethylation reaction Methods 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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Abstract
Description
A11−A14はそれぞれNまたはCR11、CR12、CR13、CR14であり、ただし4つの位置Aのうちの2超が同時にNであることができない、
R1は、C(1−6)アルキル、C(3−6)シクロアルキル、C(3−6)シクロアルキルC(1−3)アルキル、(ジ)C(1−6)アルキルアミノ、(ジ)C(3−6)シクロアルキルアミノ、または(ジ)(C(3−6)シクロアルキルC(1−3)アルキル)アミノであり、それらはアルキル基のすべての炭素原子が一つ以上のFによって置換されていても良く、かつシクロアルキル基のすべての炭素原子が一つ以上のFまたはメチルによって置換されていても良く、
R2およびR3は独立してH、F、メチル、エチル、ヒドロキシ、メトキシ、またはR2およびR3は一緒になってカルボニルであり、ここで存在する場合はすべてのアルキル基が一つ以上Fによって置換されていても良く;
R4は、HまたはC(1−6)アルキルであり、
R5は、H、ヒドロキシエチル、メトキシエチル、C(1−6)アルキル、C(6−10)アリール、C(6−10)アリールC(1−3)アルキル、C(1−9)ヘテロアリール、C(1−9)ヘテロアリールC(1−3)アルキル、C(3−6)シクロアルキル、C(3−6)シクロアルキルC(1−3)アルキル、C(2−5)ヘテロシクロアルキル、またはC(2−5)ヘテロシクロアルキル−C(1−3)アルキルであり、ここで全ての基は、一つ以上のF、Cl、C(1−2)アルキル、C(1−2)アルコキシル、またはシアノによって置換されてもよく、
R1を有するスルホニル基は、R7、R8、またはR9の1つにより表され、
残ったR6−R14は、独立してH、ハロゲン、C(1−3)アルコキシル、(ジ)C(1−3)アルキルアミノ、またはC(1−6)アルキルであり、アルキル基の全てが一つ以上のFによって置換されていても良く、
そしてR15およびR16は、独立してH、C(1−6)アルキル、C(3−6)シクロアルキル、C(3−6)シクロアルキルC(1−3)アルキル、C(6−10)アリール、C(6−10)アリールC(1−3)アルキル、C(1−9)ヘテロアリール、C(1−9)ヘテロアリールC(1−3)アルキル、C(2−5)ヘテロシクロアルキルまたはC(2−5)ヘテロシクロアルキル−C(1−3)アルキルであり、すべての基が一つ以上のF、Cl、C(1−2)アルキル、C(1−2)アルコキシル、またはシアノによって置換されていても良い。
すべての炭素原子は、一つ以上のハロゲンまたはメチルによって置換されていても良い。
しかしながら、この場合、基R7、R8、またはR9の1つは、R1が結合されたスルホニル基である。
本願明細書において、式Iの化合物の言及は、特に明記されない限りそれらの塩の言及を含むことが理解される。
一般式I、ビルディングブロックII、およびビルディングブロックIIIの化合物を含む本願明細書において記載されている化合物は、下で表される反応スキームにより調製される。さらにまた、以下のスキームで、特定の酸、塩基、試薬、カップリング剤、溶媒その他が挙げられているが、他の適切な酸、塩基、試薬、カップリング剤、溶媒その他が使われることができ、本発明の範囲内に含まれるものと理解される。
反応条件、例えば、反応の温度、時間またはそれらの組み合わせに対する変更は、本発明の一部として意図される。一般的な反応シーケンスを用いて得られた化合物は、純度が不十分であり得る。化合物は、有機化合物の精製、例えば、適切な割合の種々の溶媒を用いた結晶化、またはシリカゲルまたはアルミナ カラムクロマトグラフィのための方法のいずれかを用いて精製されることができる。すべてのあり得る立体異性体は、本発明の範囲内であると意図される。
HATU:2−(7−アザ−1H−ベンゾトリアゾ−ル−1−イル)−1,1,3,3−4−メチルウロニウムヘキサフルオロホスフェイト;DMF:ジメチルホルムアミド;
DiPEA:ジイソプロピルエチルアミン;DMAP:4−(ジメチルアミノ)ピリジン;
DCC:N,N’−ジシクロヘキシルカルボジイミド;mCPBA:3−クロロ過安息香酸;TFA:トリフルオロ酢酸;TFAA:トリフルオロ酢酸無水物;THF:テトラヒドロフラン;DMSO:ジメチルスルホキシド;PTSA:p−トルエンスルホン酸;PyBOP:(ベンゾトリアゾ−ル−1−イルオキシ)トリピロリジノホスホニウムヘキサフルオロホスフェート;EtOH:エタノール;DIAD:ジイソプロピルアゾジカルボキシレート;TLC:薄層クロマトグライー;Pd(dba)2:ビス(ジベンジリデンアセトン)パラジウム(0);PPh3:トリフェニルホスフィン;NMP:N−メチル−2−ピロリドン;EDCI:1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド;BuLi:n−ブチルリチウム;TBAF:テトラ−N−ブチルアンモニウムフルオライド;
TMS:トリメチルシリル。
K2CO3のような塩基の存在下、アルキルハライドを使用した硫黄基のアルキル化は、対応するスルファニルフェニルアセテート誘導体3(R1=例えばアルキル、シクロアルキル、シクロアルキルアルキル)を与える。塩基性の条件(例えばEtOH中のNaOH)の下でのエステル部分の鹸化の後、R1、R2、R3、R6、R7、R9、およびR10が前述した通りの意味を有する、ビルディングブロックIIの、対応するフェニル酢酸誘導体を与えるスルホニルフェニルアセテート誘導体4を、例えばmCPBAを用いた酸化は与える。
ビルディングブロックII−1〜II−6
MS(ES+)m/z 243.2[M+H]+。
II−7: 2−(4−(エチルスルホニル)フェニル)プロパン酸。
粗生成物が、精製することなく次の工程で使われた。
MS(ES+)m/z 243.2[M+H]+。
II−9: 2−(4−(N−メチルスルファモイル)フェニル)酢酸。
i)
残渣は、ヘプタン中の10%〜20%の酢酸エチルを溶出液として用いてSiO2上で精製され、固体としてエチル2−(4−(N−メチルスルファモイル)フェニル)アセテート(0.41g)が与えられた。
II−18:2−(3−(エチルスルホニル)フェニル)酢酸。
II−23:2−(3−(N−メチルスルファモイル)フェニル)酢酸。
残渣は、ヘプタン中の0%〜100%酢酸エチルを溶出液として用いてSiO2上で精製され、黄色のオイルとしてエチル2−(4−((シクロプロピルメチル)チオ)フェニル)−2−オキソアセテート(5.57g)が与えられた。
MS(ES+)m/z 268.2[M+H]+。
ビルディングブロックIII〜1−III−8
III−1:2−(4−アミノフェニル)−1,1,1,3,3,3−ヘキサフルオロプロパン−2−オ−ル。
以下の化合物は、Parkway Scientificから購入された:
残渣は、ヘプタン中の0%〜20%の酢酸エチルを溶出液として用いてSiO2上で精製され、1−(4−ブロモフェニル)ブタン−1−オン(5.6g)が固体として与えられた。
III−33:2−(4−アミノフェニル)プロパン−2−オ−ル。
一緒にされた固体は減圧下40°Cで乾燥され、白色固体として3級ブチル(4−ブロモフェニル)カルバメート(16.73g)が与えられた。
δ7.12−7.05(m、2H)、6.52−6.44(m、2H)、4.82(s、2H)、4.66(s、1H)、1.35(s、6H)。
ヘキサフルオロアセトンガスが約30秒間吹き込まれ、反応混合物は−78°Cでさらに40分間撹拌された。室温へ温められた後、反応混合物が5%NH4Cl水性溶液、水、塩水により洗浄され、硫酸マグネシウムで乾燥され、溶媒が減圧下で取り除かれた。黄色のオイル(532mg)として2−(5−ブロモピリジン−2−イル)−1,1,1,3,3,3−ヘキサフルオロプロパン−2−オ−ルが与えられた。
1HのNMR(500MHz、DMSO−d6):δ10.46(s、1H)、8.61(s、1H)、7.88−7.86(m、2H)、7.71−7.68(m、2H)、7.59−7.56(m、4H)、3.80(s、2H)、3.17(s、3H)。
DCCの代わりにEDCIを用いて実施例28のために記載された方法に類似した方法に習って、以下の化合物は調製された。
80°Cで17時間撹拌した後に、反応混合物は室温に冷やされ、溶媒は減圧下で除去された。残渣は、ヘプタン中の20%の酢酸エチルを溶出液として使用して、SiO2上で精製され、白色固体として標記化合物2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−(2,2,2−トリフルオロエトキシ)プロパン−2−イル)フェニル)アセトアミド(11mg)が与えられた。MS(ES+)m/z 552.2[M+H]+。
RORγGAL4レポーター遺伝子アッセイにおいて、RORγ活性を阻害する能力について、実施例のインヒビター1〜114は試験された。アッセイ手順および結果が以下に説明される。
ルシフェラーゼ読み取りを用いたGAL4 1−ハイブリッド レポーター システムは、293FT細胞におけるRORγの抑制を決定するために確立された。RORγリガンド−結合領域(LBD)は、酵母GAL4 DNA結合領域(DBD)に融合され、発現ベクターpFN26A(プロメガ)および標準組換えDNAクローニング方法を用いて、ヒトサイトメガロウイルス(CMV)最初期プロモータの制御の基に置かれた。アッセイにおいて対照として役立つために、その中でGAL4−DBDがヘルペス単純ウイルスタンパク質16(VP16)、構成転写アクティベータに融合されている類似のベクトルが作成された。
293FT細胞(Invitrogen)は、GAL4融合タンパク発現ベクター(上記の通り)および転写レポーター構造物(pGL4.35、プロメガ)によって、トランスフェクションされた。60μLのトランスIT−293トランスフェクション試薬(Mirus Bio)は、1500μlの Opti−MEM I 還元血清培地(Invitrogen)に滴下により添加され、5〜20分間室温(RT)でインキュベートされた。1500μLのこの試薬混合物は、5μgのGAL4融合タンパク発現ベクターおよび5μgの転写レポーター構造物に添加され、室温で20分間インキュベートされた。
抗CD3/抗CD28で刺激されたヒト血液から分離された末梢血単核細胞(PBMC)中のIL−17A生産を阻害する能力を、実施例のインヒビター2、9、32、33、35、37、43、44、45、46、51、53、54、59、60、67、71、83、107、113、114は試験された。下記に、アッセイ手順および結果が説明される。
IL−17A産生のRORγにより介在される阻害を測定する目的で、抗CD3/抗CD28でを刺激されたPBMCから分泌されたIL−17Aのレベルを測定するように、このアッセイは設計されている。
抗CD3抗体(BD Pharmingen)は、PBS(Lonza)中で10μg/mlに希釈された。10μg/mlの抗CD3溶液30μLは、いくつかの負の対照ウェルを除いて、96ウェル細胞培養処理U−底プレート(Greiner)の内側60ウェルに添加された。プレートは、37°Cおよび5%のCO2で終夜(16〜24時間)インキュベートされた。
Claims (28)
- 式Iに従う化合物
A11〜A14はそれぞれNまたはCR11、CR12、CR13、CR14であり、ただし4つの位置Aのうちの2つ超が同時にNであることができない;
R1は、C(1−6)アルキル、C(3−6)シクロアルキル、C(3−6)シクロアルキルC(1−3)アルキル、(ジ)C(1−6)アルキルアミノ、(ジ)C(3−6)シクロアルキルアミノ、または(ジ)(C(3−6)シクロアルキルC(1−3)アルキル)アミノであり、アルキル基のすべての炭素原子が一つ以上のFによって置換されていてもよく、かつシクロアルキル基のすべての炭素原子が一つ以上のFまたはメチルによって置換されていても良く;
R2およびR3は独立してH、F、メチル、エチル、ヒドロキシ、メトキシ、またはR2およびR3は一緒になってカルボニルであり、ここで存在する場合はすべてのアルキル基が一つ以上Fによって置換されていてもよく;
R4は、HまたはC(1−6)アルキルであり;
R5は、H、ヒドロキシエチル、メトキシエチル、C(1−6)アルキル、C(6−10)アリール、C(6−10)アリールC(1−3)アルキル、C(1−9)ヘテロアリール、C(1−9)ヘテロアリールC(1−3)アルキル、C(3−6)シクロアルキル、C(3−6)シクロアルキルC(1−3)アルキル、C(2−5)ヘテロシクロアルキル、またはC(2−5)ヘテロシクロアルキルC(1−3)アルキルであり、ここで全ての基は、一つ以上のF、Cl、C(1−2)アルキル、C(1−2)アルコキシル、またはシアノによって置換されていてもよく;
R1を有するスルホニル基は、R7、R8、またはR9の1つにより表され;
残ったR6−R14は、独立してH、ハロゲン、C(1−3)アルコキシル、(ジ)C(1−3)アルキルアミノ、またはC(1−6)アルキルであり、アルキル基の全てが一つ以上のFによって置換されていてもよく;および
R15およびR16は、独立して、H、C(1−6)アルキル、C(3−6)シクロアルキル、C(3−6)シクロアルキルC(1−3)アルキル、C(6−10)アリール、C(6−10)アリールC(1−3)アルキル、C(1−9)ヘテロアリール、C(1−9)ヘテロアリールC(1−3)アルキル、C(2−5)ヘテロシクロアルキル、またはC(2−5)ヘテロシクロアルキルC(1−3)アルキルであり、すべての基が一つ以上のF、Cl、C(1−2)アルキル、C(1−2)、またはシアノによって置換されていてもよい。 - R1がC(1−2)アルキル、シクロプロピル、C(3−4)シクロアルキルC(1−3)アルキル、メチルアミノ、またはC(3−4)シクロアルキルアミノである請求項1に記載の化合物。
- R1がエチル、シクロプロピルアミノ、またはシクロプロピルメチルである請求項2に記載の化合物。
- R1はシクロプロピルアミノまたはシクロプロピルメチルである請求項3に記載の化合物。
- R1はシクロプロピルメチルである請求項4に記載の化合物。
- R2およびR3が独立してH、メチル、またはヒドロキシである請求項1〜5のいずれか一つに記載の化合物。
- R2およびR3が独立してHまたはメチルである請求項6に記載の化合物。
- R4がHまたはC(1−2)アルキルである請求項1〜7のいずれか一つに記載の化合物。
- R5がH、ヒドロキシエチル、メトキシエチル、またはC(1−6)アルキルであり、すべてのアルキル基が一つ以上のFによって置換されていても良く請求項1〜8のいずれか一つに記載の化合物。
- R5はHまたはC(1−3)アルキルである請求項9に記載の化合物。
- R5がC(6)アリールC(1−3)アルキルまたはC(3−6)シクロアルキルC(1−3)アルキルである請求項1〜8のいずれか一つに記載の化合物。
- R5はベンジルである請求項11に記載の化合物。
- R6〜R10がHであり、ただし基R7、R8、またはR9の1つがR1を有するスルホニル基である請求項1〜12のいずれか一つに記載の化合物。
- R8がR1を有するスルホニル基である請求項13に記載の化合物。
- R8がR1を有するスルホニル基であり、ここでR10はメチルであり、残りのR6、R7、およびR9はHである請求項1〜12のいずれか一つに記載の化合物。
- A11〜A14の全てが炭素である請求項1〜15のいずれか一つに記載の化合物。
- A11またはA12が窒素であり、かつ残りのA11〜A14が炭素である請求項1〜15のいずれか一つに記載の化合物。
- R11〜R14が独立してH、ハロゲン、メチル、またはメトキシである請求項1〜17のいずれか一つに記載の化合物。
- R11〜R14はHである請求項18に記載の化合物。
- R15がCF3であり、かつR16がH、C(1−6)アルキル、C(3−6)シクロアルキル、またはC(3−6)シクロアルキルC(1−3)アルキルである請求項1〜19のいずれか一つに記載の化合物。
- R15がCF3であり、かつR16がCF3、プロピル、イソプロピル、2−メチルプロピル、2,2−ジメチルプロピル、シクロプロピル、シクロペンチル、またはシクロヘキシルメチルである請求項20に記載の化合物。
- R15及びR16は、両方ともCF3である請求項21に記載の化合物。
- 請求項1から選択される化合物であって以下の群から選択される化合物:
N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−(メチルスルホニル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−(イソプロピルスルホニル)フェニル)アセトアミド;
N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−(プロピルスルホニル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)プロパンアミド;
N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−(Nメチルスルファモイル)フェニル)アセトアミド;
N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−(N−イソプロピルスルファモイル)フェニル)アセトアミド;
2−(4−(N−シクロプロピルメチル)スルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−(N−エチルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−(N、N−ジメチルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(3−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(3−(N−エチルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(3−(N、N−ジメチルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(3−フルオロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−2−メチルフェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−N−メチルアセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−エチル−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(3−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−N−メチルアセトアミド;
N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(3−(N−メチルスルファモイル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(5−フルオロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−2−メトキシフェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(5−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)ピリジン−2−イル)アセトアミド;
N−(5−クロロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−2−メトキシフェニル)−2−(4−(エチルスルホニル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−2,6−ジメチルフェニル)アセトアミド;
2−(3−(N−シクロブチルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−(N−シクロブチルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(3−フルオロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−2−メチルフェニル)アセトアミド;
N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−(イソブチルスルホニル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(2−フルオロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−3−メチルフェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(3−フルオロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−2−メチルフェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−3−メチルフェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(3−フルオロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−フェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−2−メチルフェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(2−フルオロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−フェニル)アセトアミド;
2−(3−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−3−メチルフェニル)アセトアミド;
2−(4−(シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(3−(N−シクロプロピルスルファモイル)フェニル)−N−(3−フルオロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−フェニル)アセトアミド;
2−(3−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−2−メチルフェニル)アセトアミド;
2−(3−(N−シクロプロピルスルファモイル)フェニル)−N−(2−フルオロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−フェニル)アセトアミド;
2−(3−(N−(シクロプロピルメチル)スルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)−3−フルオロフェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−(シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−2−メチルフェニル)アセトアミド;
2−(4−(シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−3−メチルフェニル)アセトアミド;
2−(4−(シクロプロピルメチル)スルホニル)フェニル)−N−(3−フルオロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−フェニル)アセトアミド;
2−(4−(シクロプロピルメチル)スルホニル)フェニル)−N−(2−フルオロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−メトキシプロパン−2−イル)フェニル)アセトアミド;
N−(4−(2−エトキシ−1,1,1,3,3,3−ヘキサフルオロプロパン−2−イル)フェニル)−2−(4−(エチルスルホニル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−プロポキシプロパン−2−イル)フェニル)アセトアミド;
N−(4−(2−(ベンジルオキシ)−1,1,1,3,3,3−ヘキサフルオロプロパン−2−イル)フェニル)−2−(4−(エチルスルホニル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−イソプロポキシプロパン−2−イル)フェニル)アセトアミド;
N−(4−(2−(ブトキシ)−1,1,1,3,3,3−ヘキサフルオロプロパン−2−イル)フェニル)−2−(4−((シクロプロピルメチル)スルホニル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(2−エトキシ−1,1,1,3,3,3−ヘキサフルオロプロパン−2−イル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−メトキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−2−メトキシフェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−3−メトキシフェニル)アセトアミド;
N−(2−アミノ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−((シクロプロピルメチル)スルホニル)フェニル)アセトアミド;
N−(4−(2−(2−シクロプロピルエトキシ)−1,1,1,3,3,3−ヘキサフルオロプロパン−2−イル)フェニル)−2−(4−((シクロプロピルメチル)スルホニル)フェニル)アセトアミド;
N−(4−(2−(ベンジルオキシ)−1,1,1,3,3,3−ヘキサフルオロプロパン−2−イル)フェニル)−2−(4−((シクロプロピルメチル)スルホニル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−プロポキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
N−(3−クロロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−((シクロプロピルメチル)スルホニル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシペンタン−2−イル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシヘキサン−2−イル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシ−3−メチルブタン−2−イル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシ−4−メチルペンタン−2−イル)フェニル)アセトアミド;
N−(4−(1−シクロプロピル−2,2,2−トリフルオロ−1−ヒドロキシエチル)フェニル)−2−(4−((シクロプロピルメチル)スルホニル)フェニル)アセトアミド;
N−(4−(3−シクロペンチル−1,1,1−トリフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−((シクロプロピルメチル)スルホニル)フェニル)アセトアミド;
N−(4−(3−シクロヘキシル−1,1,1−トリフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−((シクロプロピルメチル)スルホニル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(2,2,2−トリフルオロ−1−ヒドロキシエチル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシヘキサン−2−イル)フェニル)アセトアミド;
N−(4−(1−シクロプロピル−2,2,2−トリフルオロ−1−ヒドロキシエチル)フェニル)−2−(4−(エチルスルホニル)フェニル)アセトアミド;
N−(4−(3−シクロヘキシル−1,1,1−トリフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−(エチルスルホニル)フェニル)アセトアミド;
N−(4−(1−シクロペンチル−2,2,2−トリフルオロ−1−ヒドロキシエチル)フェニル)−2−(4−((シクロプロピルメチル)スルホニル)フェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシ−4−メチルペンタン−2−イル)フェニル)アセトアミド;
2−(3−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシ−4−メチルペンタン−2−イル)フェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシブタン−2−イル)フェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシペンタン−2−イル)フェニル)アセトアミド;
2−(3−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシペンタン−2−イル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシ−4,4−ジメチルペンタン−2−イル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシブタン−2−イル)フェニル)アセトアミド;
N−(3−クロロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−(エチルスルホニル)フェニル)アセトアミド;
N−(4−(1−シクロペンチル−2,2,2−トリフルオロ−1−ヒドロキシエチル)フェニル)−2−(4−(エチルスルホニル)フェニル)アセトアミド;
N−(4−(3−シクロペンチル−1,1,1−トリフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−(エチルスルホニル)フェニル)アセトアミド;
2−(4−シクロプロピルメタンスルフォニルフェニル)−N−[4−(1,1,1−トリフルオロ−2−ヒドロキシ−3−フェニルプロパン−2−イル)フェニル]アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(2,2,2−トリフルオロ−1−ヒドロキシ−1−フェニルエチル)フェニル)アセトアミド;
N−(3−クロロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−(N−シクロプロピルスルファモイル)フェニル)アセトアミド;
N−(4−(1−シクロペンチル−2,2,2−トリフルオロ−1−ヒドロキシエチル)フェニル)−2−(4−(N−シクロプロピルスルファモイル)フェニル)アセトアミド;
N−(3−クロロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(3−(N−シクロプロピルスルファモイル)フェニル)アセトアミド;
N−(4−(1−シクロペンチル−2,2,2−トリフルオロ−1−ヒドロキシエチル)フェニル)−2−(3−(N−シクロプロピルスルファモイル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)−2−メチルフェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシ−4,4−ジメチルペンタン−2−イル)フェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシ−3−メチルブタン−2−イル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシ−4,4−ジメチルペンタン−2−イル)フェニル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(2,2,2−トリフルオロ−1−ヒドロキシ−1−フェニルエチル)フェニル)アセトアミド;
N−(2−クロロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−((シクロプロピルメチル)スルホニル)フェニル)アセトアミド;
N−(4−(3−シクロペンチル−1,1,1−トリフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−(N−シクロプロピルスルファモイル)フェニル)アセトアミド;
N−(4−(3−シクロヘキシル−1,1,1−トリフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−(4−(N−シクロプロピルスルファモイル)フェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(4−(2,2,2−トリフルオロ−1−ヒドロキシ−1−フェニルエチル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−オキソアセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(2−ヒドロキシプロパン−2−イル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシ−5−メチルヘキサン−2−イル)フェニル)アセトアミド;
2−(4−(N−シクロプロピルスルファモイル)フェニル)−N−(5−フルオロ−4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)−2−メトキシフェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(ジシクロプロピル(ヒドロキシ)メチル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(5−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)ピリジン−2−イル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1−トリフルオロ−2−ヒドロキシ−6−メチルヘプタン−2−イル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)プロパンアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(6−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)ピリジン−3−イル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(6−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)ピリジン−3−イル)アセトアミド;
2−(4−(エチルスルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−(2,2,2−トリフルオロエトキシ)プロパン−2−イル)フェニル)アセトアミド;
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−(2,2,2−トリフルオロエトキシ)プロパン−2−イル)フェニル)アセトアミドおよび
2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)−2−ヒドロキシアセトアミド。 - 2−(4−((シクロプロピルメチル)スルホニル)フェニル)−N−(4−(1,1,1,3,3,3−ヘキサフルオロ−2−ヒドロキシプロパン−2−イル)フェニル)アセトアミドである請求項23に記載の化合物。
- 治療に用いるための請求項1〜24のいずれか一つに記載の化合物またはにその薬理学的に許容される塩。
- RORγ媒介疾患または状態の治療のための請求項1〜24のいずれか一つに記載の化合物またはその薬理学的に許容される塩。
- 請求項1〜24のいずれか一つに従う式Iの化合物またはその薬理学的に許容される塩、および一つ以上の薬理学的に許容される賦形剤を含有する医薬組成物。
- 少なくとも一つの追加的な治療上の活性剤を更に含有する請求項27に記載の医薬品組成物。
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