JP2022501334A - キナーゼ阻害剤としてのインダゾールカルボキサミド - Google Patents
キナーゼ阻害剤としてのインダゾールカルボキサミド Download PDFInfo
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- JP2022501334A JP2022501334A JP2021513960A JP2021513960A JP2022501334A JP 2022501334 A JP2022501334 A JP 2022501334A JP 2021513960 A JP2021513960 A JP 2021513960A JP 2021513960 A JP2021513960 A JP 2021513960A JP 2022501334 A JP2022501334 A JP 2022501334A
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- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- JSSXHAMIXJGYCS-UHFFFAOYSA-N piperazin-4-ium-2-carboxylate Chemical compound OC(=O)C1CNCCN1 JSSXHAMIXJGYCS-UHFFFAOYSA-N 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
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- 230000008569 process Effects 0.000 description 1
- 229940072288 prograf Drugs 0.000 description 1
- 230000008741 proinflammatory signaling process Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 201000003651 pulmonary sarcoidosis Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 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
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
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- 230000004258 retinal degeneration Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
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- 201000003068 rheumatic fever Diseases 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
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- 108010038379 sargramostim Proteins 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
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- 229940075439 smac mimetic Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 238000009121 systemic therapy Methods 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
- 229960003676 tenidap Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 230000008359 toxicosis Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 229960003824 ustekinumab Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07—ORGANIC CHEMISTRY
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
Description
本願は、35U.S.C§119(e)に従い、米国仮特許出願第62/730,611号(2018年9月13日出願)の優先権を有し、その全体が本明細書に援用される。
本発明の化合物は治療において用いられうる。
本発明のこれらのおよび他の特徴は、開示が続くにつれて、拡大された形式で記載される。
ある局面において、本発明は、とりわけ、式(I)
[式中、
環Bはピペリジニル、ピペラジニル、またはモルホリニルであり;
R1はH、ハロ、C1−3アルキル、C1−3ハロアルキル、C1−3ジュウテロアルキル、C1−3アルコキシ、C1−3ハロアルコキシ、C1−3アルコキシ、C1−3ハロアルコキシ、またはC1−3ジュウテロアルコキシであり;
RbはH、C1−3アルキル、C1−3アルコキシ、C1−3ハロアルキル、C1−3ハロアルコキシ、C1−3ジュウテロアルキル、C1−3ジュウテロアルコキシ、ハロ、NH2、またはCNであり;
Rdは独立して、H、ハロ、またはC1−3アルキルであり;
LはC(O)NRaであり;
Raは独立して、H、C1−4アルキル、またはC1−4ジュウテロアルキルであり;
AはA’またはA’−L’であり;
A’は0〜1個のOHで置換されたC1−4アルキル、0〜1個のOHで置換されたC1−4ジュウテロアルキル、C3−6シクロアルキル−C0−3−アルキル−、C0−3−アルキル−C3−6シクロアルキル−、ピロリル−C1−3−アルキル−、C1−3−アルキル−ピロリル−、ピラゾリル−C1−3−アルキル−、またはC1−3−アルキル−ピラゾリル−であり;
L’は−O−であり;
R2はフェニル、またはNおよびOから選択される1〜4個のヘテロ原子を有する、5〜6員のヘテロ環であり、ここで、フェニルまたはヘテロ環基のいずれかは、0〜3個のR2aで置換され;
R2aはハロ、C1−6アルキル、C1−6アルコキシ、ヒドロキシ−C1−6アルコキシ、C1−6ジュウテロアルキル、C1−6ジュウテロアルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、C3−6シクロアルキル、C3−6ハロシクロアルキル、C3−6シクロアルコキシ、C3−6シクロアルキル−C1−3アルコキシ−、C3−6シクロアルキル−C1−3ジュウテロアルコキシ−、C3−6シクロアルキル−C1−3ハロアルコキシ−、C1−6アルコキシ−C1−3アルキル−、C3−6シクロアルコキシ−C1−3アルキル−、C1−4アルキル−SO2−、C3−6シクロアルキル−SO2−、C6−10アリール−S−、NR2cR2dCO−、ヘテロ環−、ヘテロ環−O−、ヘテロ環−CH2−であり、ここで、ヘテロ環はそれぞれ独立して、NおよびOから選択される1〜2個のヘテロ原子を有する、4〜6員環であり、ここで、アルキル、シクロアルキル、またはヘテロ環はそれぞれ、0〜2個のR2bで置換され;
R2bは、それぞれの事象において独立して、C1−3アルキル、ハロ、C=O、またはC1−3ハロアルキルであり;
R2cおよびR2dは独立して、H、C1−3アルキル、C1−3ジュウテロアルキル、C3−6シクロアルキルから選択されるか、あるいはそれらが結合するNと一緒になって、N、O、およびSから選択される0〜1個のさらなるヘテロ原子を有し、重水素およびハロから選択される0〜4個の置換基で置換されている、4〜6員のヘテロ環式環を形成し;
nは0、1、または2である。]
で示される化合物、またはその立体異性体、互変異性体、同位体、塩、薬学的に許容可能な塩、溶媒和物、もしくはプロドラッグを提供する。
環Bが、
であり、これらのいずれかは0〜1個のRbで置換され;
R4が、H、またはC1−3アルキルである、
式(I)の化合物、またはその立体異性体、互変異性体、同位体、塩、薬学的に許容可能な塩、溶媒和物、もしくはプロドラッグを提供する。
R2が、フェニル、またはピリジニル、またはピロリルであり、これらのいずれかは0〜3個のR2aで置換されている、
式(I)の化合物、またはその立体異性体、互変異性体、同位体、塩、薬学的に許容可能な塩、溶媒和物、もしくはプロドラッグを提供する。
A’が、0〜1個のOHで置換されたC1−4アルキル、または0〜1個のOHで置換されたC1−4ジュウテロアルキルである、
式(I)の化合物、またはその立体異性体、互変異性体、同位体、塩、薬学的に許容可能な塩、溶媒和物、もしくはプロドラッグを提供する。
R2aが、ハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、またはC3−6シクロアルキル−C1−3アルコキシ−である、
式(I)の化合物、またはその立体異性体、互変異性体、同位体、塩、薬学的に許容可能な塩、溶媒和物、もしくはプロドラッグを提供する。
Rbが、H、Cl、F、C1−3アルキル、またはC1−3アルコキシである、
式(I)の化合物、または立体異性体、互変異性体、同位体、塩、薬学的に許容可能な塩、溶媒和物、もしくはプロドラッグを提供する。
Aが、−CH2−、CD2−、−CH2CH2−、−CH(CH3)−、−CH(CD3)−、−CH2CH2CH(CH3)−、−CH2CH2CH(OH)−、または−CH2−シクロプロピル−である、
式(I)の化合物、またはその立体異性体、互変異性体、同位体、塩、薬学的に許容可能な塩、溶媒和物、もしくはプロドラッグを提供する。
Aが、−CH2−、−CH2CH2−、−CH2CH2CH(CH3)−、−CH2CH2CH(OH)−、−CH2CH(OH)CH2−O−、−CH2CH2CH2O−、−シクロヘキシル−、−ピロリジニル−CH2−、または−CH2−シクロプロピル−である、
式(I)の化合物、またはその立体異性体、互変異性体、同位体、塩、薬学的に許容可能な塩、溶媒和物、もしくはプロドラッグを提供する。
Lが、C(O)NHであり;
R2が、0〜3個のR2aで置換されたフェニルである、
式(I)の化合物、またはその立体異性体、互変異性体、同位体、塩、薬学的に許容可能な塩、溶媒和物、もしくはプロドラッグを提供する。
用語「ハロアルキル」は、1つ以上のハロ置換基を有する置換アルキルを意味する。例えば、「ハロアルキル」としては、モノ、ビ、およびトリフルオロメチルが挙げられる。
用語「ハロアルキル」は、1つ以上のハロ置換基を有する置換アルキルを意味する。例えば、「ハロアルキル」としては、モノ、ビ、およびトリフルオロメチルが挙げられる。
用語「重水素化アルキル」は、1つ以上の重水素原子を有する置換アルキルを意味する。例えば、用語「重水素化アルキル」としては、モノ、ビ、およびトリ重水素化メチルが挙げられる。
用語「ヘテロ原子」は、酸素、硫黄、および窒素を含むものとする。
表記「CO2」が本明細書において用いられる場合、基:
をいうことを意図することが当業者に理解される。
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 112, pp. 309−396, edited by K. Widder, et al. (Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krosgaard−Larsen and H. Bundgaard, Chapter 5, ‘‘Design and Application of Prodrugs,’’ by H. Bundgaard, pp. 113−191 (1991); and
c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, pp. 1−38 (1992),
これらのそれぞれは引用によって本明細書に援用される。
本発明の化合物は、RIPK1の調節などのキナーゼ活性を調節する。それによって、式(I)の化合物は、キナーゼ活性の調節、および特にRIPK1活性の選択的阻害に関連する病状の治療において有用性を有する。別の実施態様において、式(I)で示される化合物は、RIPK1活性の有利な選択性、好ましくは、他のキナーゼよりも少なくとも20倍から1000倍以上の選択性を有する。
HT29−L23ヒト大腸腺腫細胞を、10%熱不活性化FBS、1%ペニシリン−ストレプトマイシンおよび10mM HEPESを含む、RPMI 1640培地中に維持した。細胞を2,000細胞/ウェルで、384ウェル組織培養処理マイクロプレート(Greiner # 781090−3B)に播種し、37℃(5%CO2/95%O2)で2日間インキュベートした。アッセイの日、細胞を6.25から0.106μMの最終濃度で、37℃(5%CO2/95%O2)で30分間、試験化合物で処理した。ヒトTNFα(35ng/mL)(Peprotech #300−01A)、SMAC模倣物(US 2015/0322111 A1)(700nM)およびZ−VAD(140nM)(BD pharmingen #51−6936)の混合物を用いて、ネクロプトーシスを誘導した。37℃(5%CO2/95%O2)で6時間インキュベートした後、細胞を4%ホルムアルデヒド(ACROS 11969−0010)で、室温で15分間固定し、次いで0.2%Triton−X−100を含むリン酸緩衝生理食塩水(PBS)で10分間、透過処理した。抗MLKL(ホスホS358)抗体(Abcam #ab187091)(ブロッキング緩衝液[0.1%BSAを補充したPBS]中で1:1000希釈)を用いて、4℃で一晩インキュベーションすることによって、MLKLリン酸化を検出した。PBS中で3回洗浄した後、ブロッキング緩衝液中の抗ウサギ・ヤギAlexa−488(1:1000希釈)(Life Technologies,A11008)およびHoechst 33342(Life Technologies,H3570)(1:2000希釈)を、室温で1時間加えた。PBSでさらに3サイクル洗浄した後、マイクロプレートを密閉し、X1カメラを備えたCellomics ArrayScan VTI high−content imagerで、細胞画像を得た。10x対物レンズ、核およびMLKLリン酸化についてそれぞれ、386−23 BGRFRN_BGRFRNおよび485−20 BGRFRN_BGRFRNフィルターセットを用いて、蛍光画像を取得した。画像セットをCompartmental Analysis Bioapplicationソフトウェア(Cellomics)を用いて解析した。MLKLリン酸化量を、MEAN_CircRingAvgIntenRatioとして定量化した。最大の阻害性応答を、Nec1s(CAS#:852391−15−2、6.25μM)によって誘導される活性によって定義した。IC50値を、最大の阻害の50%を生じる化合物の濃度として定義した。データを、4パラメーター・ロジスティック方程式を用いて適合させ、IC50およびYmax値を計算した。
0.2nM 抗GST−Tb(Cisbio,61GSTTLB)、90.6nM プローブおよび1nM His−GST−TVMV−hRIPK1(1−324)を、FRET緩衝液(20mM HEPES、10mM MgCl2、0.015% Brij−35、4mM DTT、0.05mg/mL BSA)中に包含することによって、溶液を調製した。Formulatrix Tempestを用いて、検出抗体/酵素/プローブ溶液(2mL)を、DMSO中に適切な濃度において10nLの対象の化合物を含む、1536プレート(Black Low Binding ポリスチレン 1536プレート(Corning、3724))のウェルに分散させた。プレートを室温で1時間インキュベートした。FRETをEnVisionプレートリーダー(励起:340nM、発光:520nM/495nM)を用いて測定した。総シグナル(0%阻害)を、10nL DMSOのみを含むウェルから計算した。ブランクシグナル(100%阻害)を、10nLの15nM スタウロスポリンおよび内部対照を含むウェルから計算した。
5’末端におけるNdeI部位、および3’末端における停止コドンTGAおよびXhoI部位に隣接するヒトRIPK1(1−324)のコード領域は、最適化されたコドンであり、遺伝子はGenScript USA Inc.(Piscataway,NJ)によって合成され、N末端His−GST−TVMVタグによって修飾されたpFastBac1ベクター(Invitrogen,Carlsbad,CA)にサブクローン化され、His−GST−TVMV−hRIPK1(1−324)−pFBを生成した。合成フラグメントの忠実度はシーケンシングによって確認した。
RIPK1含有細胞ペーストを、50mM Tris pH7.5、150mM NaCl、10mM イミダゾール、5%グリセロール、5mM MgSO4、1mM TCEP、25U/ml ベンゾナーゼ、およびコンプリートプロテアーゼ阻害剤錠剤(1/50ml, Roche Diagnostics, Indianapolis, IN)中に再懸濁させた。525 PSIの非攪拌圧力容器(Parr Instrument Company, Moline, IL)を用いて、窒素キャビテーションによって細胞を可溶化した。懸濁液を4℃で40分間、136,000xgで遠心分離することによって、清澄化した。溶解物をペレットからデカントし、AKTA Pure(GE Healthcare)を用いて、5ml NiNTA Superflow カートリッジ(Qiagen,Valencia,CA)を通した。カラムは、50mM Tris7.5、150mM NaCl、500mM イミダゾール、5%グリセロール、1mM TCEP中で、10CVの直線状勾配によって溶出した。ピーク画分をプールし、5ml GSTrap 4B カラム(GE Healthcare)に直接ロードした。カラムを50mM Tris 7.0、150mM NaCl、5%グリセロール、1mM DTTで洗浄し、50mM Tris 8.0、150mM NaCl、20mM 還元型グルタチオン、5%グリセロール、1mM DTT中で、10CVの直線状勾配で溶出した。RIPK1を含むSDS−PAGEによって特定した画分をプールし、30kDa MWCO スピンコンセントレーター(Amicon Ultra−15, Millipore, Billerica, MA)を用いて濃縮し、25mM Tris 7.5、150mM NaCl、2mM TCEP、5%グリセロールで平衡化したHiLoad 26/600 Superdex 200カラム(GE Healthcare)にロードした。RIPK1タンパク質は、SECカラムから二量体として溶出した。
式(I)の化合物、および式(I)の化合物の製造において用いられる中間体は、以下の実施例および関連する方法において示される方法を用いて合成することができる。これらの実施例において用いられる方法および条件、およびこれらの実施例において合成される実際の化合物は、限定することを意図するものではなく、式(I)の化合物をどのように合成することができるかを実証することを意図する。これらの実施例において用いられる出発物質および試薬は、本明細書において記載される方法によって合成されない場合、一般に市販されているか、または化学文献において報告されているか、または化学文献において記載される方法を用いて合成されうる。
方法A:カラム:Waters Acquity UPLC BEH C18、2.1x50mm、1.7μM粒子;移動相A:10mM 酢酸アンモニウムを含む、5:95 アセトニトリル:水;移動相B:10mM 酢酸アンモニウムを含む、95:5 アセトニトリル:水;温度:50℃;勾配:3分間にわたり、0−100%B、次いで0.75分間、100%Bで保持;流速:1.11mL/分;検出:220nmにおけるUV。
方法B:カラム:Waters Acquity UPLC BEH C18、2.1x50mm、1.7μm粒子;移動相A:0.1%TFAを含む、5:95 アセトニトリル:水;移動相B:0.1%TFAを含む、95:5 アセトニトリル:水;温度:50℃;勾配:3分にわたり、0−100%B、次いで0.75分間、100%Bで保持;流速:1.11mL/分;検出:220nmにおけるUV。
方法A:カラム:Sunfire C18、3.0x150mm、3.5μM粒子;移動相A:0.1%TFAを含む、5:95 アセトニトリル:水;移動相B:0.1%TFAを含む、95:5 アセトニトリル:水;勾配:10分にわたり、0−100%B;流速:1mL/分;検出:220および254nmにおけるUV
方法B:カラム:Xbridgeフェニル、3.0x150mm、3.5μM粒子;移動相A:0.1%TFAを含む、5:95 アセトニトリル:水;移動相B:0.1%TFAを含む、95:5 アセトニトリル:水;勾配:10分にわたり、0−100%B;流速:1mL/分;検出:220および254nmにおけるUV
方法C:カラム:XBridge C18、3.0x150mm、3.5μM粒子;移動相A:10mM 重炭酸アンモニウムを含む、5:95 メタノール:水;移動相B:10mM 重炭酸アンモニウムを含む、95:5 メタノール:水;勾配:15分にわたり、0−100%B;流速:1mL/分;検出:220および254nmにおけるUV。
方法D:カラム:XBridgeフェニル、3.0x150mm、3.5μM粒子;移動相A:10mM 重炭酸アンモニウムを含む、5:95 メタノール:水;移動相B:10mM 重炭酸アンモニウムを含む、95:5 メタノール:水;勾配:15分にわたり、0−100%B;流速:1mL/分;検出:220および254nmにおけるUV。
1A:6−ブロモ−1H−インダゾール−3−カルボン酸:メチル 6−ブロモ−1H−インダゾール−3−カルボキシレート(5g、19.60mmol)および1N NaOH(49.0mL、49.0mmol)のMeOH(70mL)中の溶液を、80℃で2時間加熱した。反応混合物を濃縮し、粗生成物を得て、水(100mL)に溶解させた。この水溶液を、pHが約4−5になるまで、0℃において1N HCl溶液で酸性化した。固形物を6−ブロモ−1H−インダゾール−3−カルボン酸(4.60g、19.08mmol、97%)として回収した。
MS ESI m/z 241.1 (M+H)
1H NMR (400 MHz, CD3OD) δ 8.08 (dd, J=8.7, 0.6 Hz, 1H), 7.87 − 7.77 (m, 1H), 7.41 (dd, J=8.7, 1.6 Hz, 1H)。
MS ESI m/z 254.0 (M+H)。
MS ESI m/z 374.0 (M+H)。
MS ESI m/z 437.2 (M+H)
1H NMR (400 MHz, CD3OD) δ 8.00 (d, J=9.0 Hz, 1H), 7.19 (d, J=8.8 Hz, 2H), 7.05 (dd, J=9.0, 2.1 Hz, 1H), 6.89 − 6.83 (m, 2H), 6.80 (d, J=1.8 Hz, 1H), 5.52 (s, 2H), 3.74 (s, 3H), 3.72 − 3.62 (m, 4H), 3.53 − 3.43 (m, 1H), 3.12 (dd, J=12.5, 9.3 Hz, 1H), 2.94 (s, 3H), 2.93 − 2.84 (m, 1H), 2.75 − 2.64 (m, 1H), 2.01 − 1.94 (m, 1H), 1.86 − 1.63 (m, 3H)。
MS ESI m/z 317.2 (M+H)。
MS ESI m/z 303.2 (M+H)。
MS ESI m/z 476.3 (M+H)
1H NMR (500 MHz, DMSO−d6) δ 8.46 (br t, J=5.6 Hz, 1H), 8.18 (br d, J=4.6 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 7.44 − 7.30 (m, 4H), 7.04 (br d, J=8.9 Hz, 1H), 6.80 (s, 1H), 4.44 − 4.27 (m, 2H), 3.82 − 3.64 (m, 2H), 2.86 (br t, J=11.6 Hz, 1H), 2.79 (d, J=4.6 Hz, 3H), 2.76 − 2.68 (m, 1H), 2.59 (br s, 1H), 1.91 (br d, J=3.4 Hz, 1H), 1.77 (br s, 1H), 1.66 − 1.54 (m, 2H), NHは水抑制において消失した。
2A:1−tert−ブチル 2−メチル 4−(1−(4−メトキシベンジル)−3−(メチルカルバモイル)−1H−インダゾール−6−イル)ピペラジン−1,2−ジカルボキシレート:6−ブロモ−1−(4−メトキシベンジル)−N−メチル−1H−インダゾール−3−カルボキサミド(148mg、0.395mmol)、1−N−Boc−ピペラジン−2−カルボン酸 メチルエステル(145mg、0.593mmol)、Pd(OAc)2(5.33mg、0.024mmol)、Cs2CO3(193mg、0.593mmol)および2−(ジシクロヘキシルホスフィノ)−2’,4’,6’−トリイソプロピルビフェニル、XPhos(18.85mg、0.040mmol)の、トルエン(1mL)中の脱気した溶液を、100℃で2日間加熱した。反応混合物を濃縮した。水を苦和え、スラリーを10分間超音波処理した。固形物を1−tert−ブチル 2−メチル 4−(1−(4−メトキシベンジル)−3−(メチルカルバモイル)−1H−インダゾール−6−イル)ピペラジン−1,2−ジカルボキシレートとして回収した。
MS ESI m/z 538.4 (M+H)。
MS ESI m/z 524.4 (M+H)
1H NMR (400 MHz, CD3OD) δ 8.03 (d, J=9.0 Hz, 1H), 7.21 (d, J=8.8 Hz, 2H), 6.90 − 6.84 (m, 4H), 5.54 (s, 2H), 4.78 − 4.65 (m, 1H), 4.32 − 4.20 (m, 1H), 4.00 − 3.91 (m, 1H), 3.77 − 3.74 (m, 4H), 3.59 (br dd, J=7.2, 4.5 Hz, 1H), 2.98 − 2.92 (m, 4H), 2.84 − 2.70 (m, 1H), 1.49 (br d, J=11.9 Hz, 9H)。
MS ESI m/z 424.2 (M+H)。
MS ESI m/z 438.1 (M+H)
1H NMR (400 MHz, CD3OD) δ 8.10 (d, J=8.9 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H), 7.14 − 7.08 (m, 1H), 7.00 − 6.96 (m, 1H), 6.89 − 6.82 (m, 2H), 5.57 (s, 2H), 4.14 − 4.00 (m, 1H), 3.87 − 3.77 (m, 1H), 3.75 (s, 3H), 3.70 − 3.61 (m, 1H), 3.44 − 3.33 (m, 2H), 3.27 − 3.16 (m, 2H), 3.05 (s, 2H), 2.95 (s, 3H)。
MS ESI m/z 318.1 (M+H)。
MS ESI m/z 437.2 (M+H)
1H NMR (500 MHz, DMSO−d6) δ 8.30 − 8.20 (m, 2H), 7.94 (d, J=8.9 Hz, 1H), 7.23 (br t, J=7.5 Hz, 1H), 7.16 (br d, J=7.3 Hz, 1H), 7.03 (br d, J=8.8 Hz, 1H), 6.97 (br d, J=8.2 Hz, 1H), 6.89 (br t, J=7.4 Hz, 1H), 6.81 (s, 1H), 4.28 (br d, J=5.7 Hz, 2H), 3.78 (s, 3H), 3.68 − 3.57 (m, 1H), 3.03 − 2.73 (m, 8H), 2.35 − 2.26 (m, 1H), 2.19 (s, 3H)。
3A:エチル 4−(1−(4−メトキシベンジル)−3−(メチルカルバモイル)−1H−インダゾール−6−イル)モルホリン−2−カルボキシレート:6−ブロモ−1−(4−メトキシベンジル)−N−メチル−1H−インダゾール−3−カルボキサミド(195.6mg、0.523mmol)、エチル モルホリン−2−カルボキシレート(125mg、0.784mmol)、Pd(OAc)2(7.04mg、0.031mmol)、Cs2CO3(255mg、0.784mmol)および2−(ジシクロヘキシルホスフィノ)−2’,4’,6’−トリイソプロピルビフェニル、XPhos(24.92mg、0.052mmol)の、トルエン(3mL)中の脱気した溶液を、100℃で16時間加熱した。反応混合物を濾過し、濃縮して、粗生成物を得て、これをシリカゲルカラム上でCH2Cl2/EtOAc(2/1)によって精製し、エチル 4−(1−(4−メトキシベンジル)−3−(メチルカルバモイル)−1H−インダゾール−6−イル)モルホリン−2−カルボキシレート(99mg、0.208mmol、40%)を得た。
MS ESI m.z 453.1 (M+H)
1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=8.9 Hz, 1H), 7.16 − 7.10 (m, 2H), 7.03 (dd, J=9.0, 2.0 Hz, 1H), 6.89 − 6.83 (m, 2H), 6.61 (d, J=1.7 Hz, 1H), 5.46 (s, 2H), 4.36 (dd, J=9.0, 3.1 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 4.18 (dt, J=11.5, 3.4 Hz, 1H), 3.90 − 3.81 (m, 1H), 3.78 (s, 3H), 3.70 (dd, J=12.5, 2.1 Hz, 1H), 3.38 − 3.31 (m, 1H), 3.12 (dd, J=12.1, 8.9 Hz, 1H), 3.07 − 2.99 (m, 4H), 1.35 (t, J=7.2 Hz, 3H)。
MS ESI m/z 333.1 (M+H)。
MS ESI m/z 305.1 (M+H)。
MS ESI m/z 473.9 (M+H)
1H NMR (500 MHz, DMSO−d6) δ 8.24 (br d, J=4.5 Hz, 1H), 7.99 − 7.89 (m, 2H), 7.38 − 7.28 (m, 2H), 7.15 (br s, 1H), 7.05 (br d, J=8.8 Hz, 1H), 6.84 (s, 1H), 4.58 (br s, 1H), 4.13 − 3.96 (m, 2H), 3.52 (br d, J=11.7 Hz, 1H), 3.24 − 3.10 (m, 2H), 2.86 − 2.74 (m, 4H), 2.67 (br t, J=11.3 Hz, 1H), 1.84 − 1.67 (m, 2H)。 2CHは水抑制によって埋もれている。
4A:tert−ブチル 4−(1−(4−メトキシベンジル)−3−(メチルカルバモイル)−1H−インダゾール−6−イル)−2−((3−フェニルブチル)カルバモイル)ピペラジン−1−カルボキシレート:1−(tert−ブトキシカルボニル)−4−(1−(4−メトキシベンジル)−3−(メチルカルバモイル)−1H−インダゾール−6−イル)ピペラジン−2−カルボン酸(25mg、0.048mmol)、3−フェニルブタン−1−アミン、HCl(8.87mg、0.048mmol)、およびDIPEA(0.021mL、0.119mmol)の、DMF(1mL)中の溶液に、BOP(25.3mg、0.057mmol)を加えた。反応混合物を23℃で1時間撹拌した。反応混合物を濃縮し、水(2mL)を加え、スラリーを5分間超音波処理した。固形物を、tert−ブチル 4−(1−(4−メトキシベンジル)−3−(メチルカルバモイル)−1H−インダゾール−6−イル)−2−((3−フェニルブチル)カルバモイル)ピペラジン−1−カルボキシレート(58.2mg)として回収し、これをそのまま次の化学に用いた。
MS ESI m/z 655.4 (M+H)
MS ESI m/z 435 (M+H)
1H NMR (500 MHz, DMSO−d6) δ 8.21 (br d, J=4.7 Hz, 1H), 7.93 (br d, J=9.1 Hz, 1H), 7.84 (br s, 1H), 7.28 (br d, J=4.2 Hz, 2H), 7.21 (br d, J=7.2 Hz, 2H), 7.19 − 7.13 (m, 1H), 7.03 (br d, J=8.6 Hz, 1H), 6.77 (s, 1H), 3.51 (br d, J=9.2 Hz, 1H), 3.11 − 2.67 (m, 11H), 1.78 − 1.64 (m, 2H), 1.19 (br d, J=6.8 Hz, 3H)。
注意:1つのCHがNMR溶媒によって不明確になった。
5A:tert−ブチル 3−(3−(メチルカルバモイル)−1H−インダゾール−6−イル)−5,6−ジヒドロピリジン−1(2H)−カルボキシレート:6−ブロモ−N−メチル−1H−インダゾール−3−カルボキサミド(100mg、0.394mmol)、tert−ブチル 3−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−5,6−ジヒドロピリジン−1(2h)−カルボキシレート(122mg、0.394mmol)、PdCl2(dppf)−CH2Cl2付加体(19.28mg、0.024mmol)、およびリン酸カリウム、三塩基酸の2M溶液(0.590mL、1.181mmol)の、DMF(2.0mL)中の脱気した溶液を、100℃で4時間撹拌した。反応混合物をEtOAc(50mL)で希釈し、これを10%LiCl(20mLx2)、ブライン(20mL)で洗浄し、Na2SO4で乾燥させた。濾過および濃縮によって粗生成物を得て、これをMeOH(2mL)でトリチュレートした。固形物をtert−ブチル 3−(3−(メチルカルバモイル)−1H−インダゾール−6−イル)−5,6−ジヒドロピリジン−1(2H)−カルボキシレート(96.5mg、0.267mmol、68%)として回収した。
MS ESI m/z 357.3 (M+H)。
MS ESI m/z 357.4 (M−H)。
MS ESI m/z 259.1 (M+H)。
MS ESI m/z 434.1 (M+H)
1H NMR (500 MHz, DMSO−d6) δ 8.31 (br d, J=4.6 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.41 (s, 1H), 7.31 − 7.25 (m, 2H), 7.24 − 7.13 (m, 4H), 6.44 (br s, 1H), 4.08 − 3.94 (m, 2H), 3.02 − 2.92 (m, 1H), 2.91 − 2.84 (m, 1H), 2.80 (d, J=4.7 Hz, 3H), 2.77 − 2.62 (m, 4H), 1.93 (br d, J=9.7 Hz, 1H), 1.75 − 1.64 (m, 4H), 1.50 − 1.40 (m, 1H), 1.18 (d, J=6.9 Hz, 3H)。
Claims (13)
- 式(I):
[式中、
環Bは、ピペリジニル、ピペラジニル、またはモルホリニルであり;
R1は、H、ハロ、C1−3アルキル、C1−3ハロアルキル、C1−3ジュウテロアルキル、C1−3アルコキシ、C1−3ハロアルコキシ、C1−3アルコキシ、C1−3ハロアルコキシ、またはC1−3ジュウテロアルコキシであり;
Rbは、H、C1−3アルキル、C1−3アルコキシ、C1−3ハロアルキル、C1−3ハロアルコキシ、C1−3ジュウテロアルキル、C1−3ジュウテロアルコキシ、ハロ、NH2、またはCNであり;
Rdは、独立して、H、ハロ、またはC1−3アルキルであり;
Lは、C(O)NRaであり;
Raは、独立して、H、C1−4アルキル、またはC1−4ジュウテロアルキルであり;
Aは、A’またはA’−L’であり;
A’は、0〜1個のOHで置換されたC1−4アルキル、0〜1個のOHで置換されたC1−4ジュウテロアルキル、C3−6シクロアルキル−C0−3−アルキル−、C0−3−アルキル−C3−6シクロアルキル−、ピロリル−C1−3−アルキル−、C1−3−アルキル−ピロリル−、ピラゾリル−C1−3−アルキル−、またはC1−3−アルキル−ピラゾリル−であり;
L’は、−O−であり;
R2は、フェニル、またはNおよびOから選択される1〜4個のヘテロ原子を有する、5〜6員のヘテロ環であり、ここで、フェニルまたはヘテロ環基のいずれかは、0〜3個のR2aで置換され;
R2aは、ハロ、C1−6アルキル、C1−6アルコキシ、ヒドロキシ−C1−6アルコキシ、C1−6ジュウテロアルキル、C1−6ジュウテロアルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、C3−6シクロアルキル、C3−6ハロシクロアルキル、C3−6シクロアルコキシ、C3−6シクロアルキル−C1−3アルコキシ−、C3−6シクロアルキル−C1−3ジュウテロアルコキシ−、C3−6シクロアルキル−C1−3ハロアルコキシ−、C1−6アルコキシ−C1−3アルキル−、C3−6シクロアルコキシ−C1−3アルキル−、C1−4アルキル−SO2−、C3−6シクロアルキル−SO2−、C6−10アリール−S−、NR2cR2dCO−、ヘテロ環−、ヘテロ環−O−、ヘテロ環−CH2−であり、ここで、ヘテロ環はそれぞれ独立して、NおよびOから選択される1〜2個のヘテロ原子を有する、4〜6員環であり、ここで、アルキル、シクロアルキル、またはヘテロ環はそれぞれ、0〜2個のR2bで置換され;
R2bはそれぞれ独立して、C1−3アルキル、ハロ、C=O、またはC1−3ハロアルキルであり;
R2cおよびR2dは独立して、H、C1−3アルキル、C1−3ジュウテロアルキル、C3−6シクロアルキルから選択されるか、あるいはそれらが結合するNと一緒になって、N、O、およびSから選択される0〜1個のさらなるヘテロ原子を有し、重水素またはハロから選択される0〜4個の置換基で置換されている、4〜6員のヘテロ環式環を形成し;
nは0、1、または2である。]
を有する化合物、またはその塩。 - R2が、フェニル、ピリジニル、またはピロリルであり、これらのいずれかは0〜3個のR2aで置換されている、
請求項1〜2に記載の化合物、またはその塩。 - A’が、0〜1個のOHで置換されたC1−4アルキル、または0〜1個のOHで置換されたC1−4ジュウテロアルキルである、
請求項1〜3に記載の化合物、またはその塩。 - R2aが、ハロ、C1−6アルキル、C1−6アルコキシ、C1−6ハロアルキル、C1−6ハロアルコキシ、またはC3−6シクロアルキル−C1−3アルコキシ−である、
請求項1〜4に記載の化合物、またはその塩。 - Rbが、H、Cl、F、C1−3アルキル、またはC1−3アルコキシである、
請求項1〜5に記載の化合物、またはその塩。 - Aが、−CH2−、CD2−、−CH2CH2−、−CH(CH3)−、−CH(CD3)−、−CH2CH2CH(CH3)−、−CH2CH2CH(OH)−、または−CH2−シクロプロピル−である、
請求項1〜6に記載の化合物、またはその塩。 - Aが、−CH2−、−CH2CH2−、−CH2CH2CH(CH3)−、−CH2CH2CH(OH)−、−CH2CH(OH)CH2−O−、−CH2CH2CH2O−、−シクロヘキシル−、−ピロリジニル−CH2−、または−CH2−シクロプロピル−である、
請求項1〜6に記載の化合物、またはその塩。 - LがC(O)NHであり;
R2が0〜3個のR2aで置換されたフェニルである、
請求項7に記載の化合物、またはその塩。 - 化合物が実施例から選択される、請求項1〜9に記載の化合物、またはその塩。
- 請求項1〜10に記載の1つ以上の化合物、またはその薬学的に許容可能な塩、および薬学的に許容可能な担体を含む、医薬組成物。
- 治療上の有効量の請求項1〜10に記載の1つ以上の化合物を必要な患者に投与することを特徴とする、患者におけるカゼインキナーゼRIPK1活性の阻害方法。
- 治療上の有効量の請求項12に記載の少なくとも1つを必要な対象に投与することを特徴とする、疾患の治療方法であって、当該疾患が、炎症性腸疾患、潰瘍性大腸炎、クローン病、乾癬、リウマチ性関節炎(RA)、および心不全から選択される、方法。
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