JP6970859B2 - TAMおよびMETキナーゼの阻害薬としてのピラゾロ[3,4−b]ピリジン化合物 - Google Patents
TAMおよびMETキナーゼの阻害薬としてのピラゾロ[3,4−b]ピリジン化合物 Download PDFInfo
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- 210000003635 pituitary gland Anatomy 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 208000007525 plasmablastic lymphoma Diseases 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 229940034080 provenge Drugs 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
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229960002633 ramucirumab Drugs 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 201000001281 rectum adenocarcinoma Diseases 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 102220197908 rs121913244 Human genes 0.000 description 1
- 102220197954 rs121913245 Human genes 0.000 description 1
- 102220004853 rs121913246 Human genes 0.000 description 1
- 102220067223 rs121913247 Human genes 0.000 description 1
- 102220004852 rs121913671 Human genes 0.000 description 1
- 102220196649 rs121913671 Human genes 0.000 description 1
- 102220004854 rs121913673 Human genes 0.000 description 1
- 102220105198 rs121913673 Human genes 0.000 description 1
- 102220059662 rs786202724 Human genes 0.000 description 1
- HNMATTJJEPZZMM-BPKVFSPJSA-N s-[(2r,3s,4s,6s)-6-[[(2r,3s,4s,5r,6r)-5-[(2s,4s,5s)-5-[acetyl(ethyl)amino]-4-methoxyoxan-2-yl]oxy-6-[[(2s,5z,9r,13e)-13-[2-[[4-[(2e)-2-[1-[4-(4-amino-4-oxobutoxy)phenyl]ethylidene]hydrazinyl]-2-methyl-4-oxobutan-2-yl]disulfanyl]ethylidene]-9-hydroxy-12-(m Chemical compound C1[C@H](OC)[C@@H](N(CC)C(C)=O)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@@](C/3=C/CSSC(C)(C)CC(=O)N\N=C(/C)C=3C=CC(OCCCC(N)=O)=CC=3)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HNMATTJJEPZZMM-BPKVFSPJSA-N 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229960000714 sipuleucel-t Drugs 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 208000010485 smooth muscle tumor Diseases 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 208000012977 squamous cell carcinoma of rectum Diseases 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000007755 survival signaling Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 238000000123 temperature gradient gel electrophoresis Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 108010078373 tisagenlecleucel Proteins 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940022919 unituxin Drugs 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229950005972 urelumab Drugs 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 229940014556 xgeva Drugs 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/495—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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- 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
- A61K31/495—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Enzymes And Modification Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本出願は、2018年8月30日出願の米国特許仮出願第62/724,829号、および2019年6月7日出願の同第62/858,686号の優先権を請求し、それらの内容全体が参照により本明細書に援用される。
本発明の他の特徴および利点は、以下の詳細な説明および図面、ならびに特許請求の範囲から明らかになる。
[式中、
X1は、CHまたはNであり、
R1は、水素またはC1〜C6アルキルであり、
R2は、
(a)水素、
(b)C1〜C6アルキル、
(c)ヒドロキシC1〜C6アルキル、
(d)ジヒドロキシC2〜C6アルキル、
(e)OHで置換されていてもよいC1〜C6フルオロアルキル
(f)(ジ−C1〜C6アルコキシ)C2〜C6アルキル−、
(g)アルキル部分がOHで置換されていてもよい(C1〜C6アルコキシ)C1〜C6アルキル−、
(h)Cyc1、
(i)Cyc2、
(j)アルキル部分がOHで置換されていてもよい(hetCyc1)C1〜C6アルキル−、
(k)アルキル部分がOHで置換されていてもよい(Ar1)C1〜C6アルキル−、
(l)アルキル部分がOHで置換されていてもよい(hetAr1)C1〜C6アルキル−、または
(m)(HOSO3)C1〜C6アルキル−
であり、
Cyc1は、ハロゲン、ヒドロキシ、C1〜C3アルキル、ヒドロキシC1〜C3アルキル、C1〜C3アルコキシ、(C1〜C3アルコキシ)C1〜C3アルキル−およびR’R”NC(=O)−から独立に選択される1〜2個の置換基で置換されていてもよい3〜4員シクロアルキル環であり、
R’およびR”は独立に、水素またはC1〜C6アルキルであり、
Cyc2は、C1〜C3アルキル、(C1〜C3アルコキシ)C1〜C3アルキル−およびヒドロキシC1〜C3アルキル−から独立に選択される1〜2個の置換基で置換されている5員シクロアルキル環であり、
hetCyc1は、O、NおよびSO2から独立に選択される1〜2個の環ヘテロ原子を有する5〜6員飽和複素環式環であり、前記環は、オキソで置換されていてもよく、
Ar1は、フェニルであり、
hetAr1は、ピリジルであり、
Gは、
X2は、CまたはNであり、
環Aは、結合点の原子を含めて、X2がNである場合、追加の1〜2個の環窒素原子を有してもよく、かつX2がCである場合、1個の環窒素原子を有してもよい5〜6員複素環式環であり、
R3は、水素、メチルであるか、または存在せず、
環Bは、結合点の原子を含めて、オキソで置換されていてもよい6員飽和炭素環式またはOHで置換されていてもよい6員芳香族炭素環式環であり、
R6は、水素、ハロゲン、C1〜C6アルキル、C1〜C6アルコキシ、ヒドロキシC1〜C6アルキル、C3〜C6シクロアルキル、(C3〜C6シクロアルキル)C1〜C6アルキル−またはhetCyc2であり、ただし、R6が式Iの−NHC(=O)−部分に連結した炭素に隣接する環炭素原子上にある場合、R6はハロゲンではなく、
R7は、水素、C1〜C6アルキル、オキソまたはチオキソであるか、
または、R6およびR7が同じ炭素原子上にある場合、R6およびR7は、それらが結合している炭素原子と一緒に、シクロプロピル環を形成してもよく、
hetCyc2は、環窒素原子を有し、C1〜C6アルキルで置換されていてもよい4〜6員飽和複素環式環であり、
R8は、Ar2、hetAr2、C3〜C6シクロアルキル、hetCyc3またはC1〜C6アルキルであり、
Ar2は、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよいフェニルであり、
hetAr2は、1〜2個の環窒素原子を有し、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよい5〜6員ヘテロアリールであり、
hetCyc3は、環酸素原子を有する5〜6員複素環式環であり、
R9は、水素またはハロゲンである]を提供する。
R1は、水素またはC1〜C6アルキルである。前記実施形態の1つでは、R1は、水素である。前記実施形態の1つでは、R1は、C1〜C6アルキルである。前記実施形態の1つでは、R1は、メチルである。
R1は、水素またはC1〜C6アルキルである。前記実施形態の1つでは、R1は、水素である。前記実施形態の1つでは、R1は、C1〜C6アルキルである。前記実施形態の1つでは、R1は、メチルである。
ここで、R6は、C1〜C6アルキル、ヒドロキシC1〜C6アルキル、C3〜C6シクロアルキル、(C3〜C6シクロアルキル)C1〜C6アルキル−またはhetCyc2、およびhetCyc2であり、R8は、式Iについて定義したとおりである。式A−1の一実施形態では、R8は、Ar2であり、Ar2は、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよいフェニルである。一実施形態では、Ar2は、1個または複数のハロゲンで置換されていてもよいフェニルである。一実施形態では、Gは、式A−1であり、式A−1は、構造:
X1が、CHまたはNであり、
R1が、水素またはC1〜C6アルキルであり、
R2が、
(a)水素、
(b)C1〜C6アルキル、
(c)ヒドロキシC1〜C6アルキル、
(g)アルキル部分がOHで置換されていてもよい(C1〜C6アルコキシ)C1〜C6アルキル−、または
(h)Cyc1であり、
Cyc1が、ハロゲン、ヒドロキシ、C1〜C3アルキル、ヒドロキシC1〜C3アルキル、C1〜C3アルコキシ、(C1〜C3アルコキシ)C1〜C3アルキル−およびR’R”NC(=O)−から独立に選択される1〜2個の置換基で置換されていてもよい3〜4員シクロアルキル環であり、
X2が、Nであり、R3が存在せず、環Aが、1個の追加の環窒素原子を有する6員複素環式環であり、R7が、オキソであり、Gが、式A−1
R6が、C1〜C6アルキル、ヒドロキシC1〜C6アルキル、C3〜C6シクロアルキル、(C3〜C6シクロアルキル)C1〜C6アルキル−またはhetCyc2であり、
hetCyc2が、環窒素原子を有し、C1〜C6アルキルで置換されていてもよい4〜6員飽和複素環式環であり、
R8が、Ar2、hetAr2、C3〜C6シクロアルキル、hetCyc3またはC1〜C6アルキルであり、
Ar2が、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよいフェニルであり、
hetAr2が、1〜2個の環窒素原子を有し、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよい5〜6員ヘテロアリールであり、
hetCyc3が、環酸素原子を有する5〜6員複素環式環であり、
R9が、水素またはハロゲンである、式I−Aが含まれる。
X1が、CHまたはNであり、
R1が、水素またはC1〜C6アルキルであり、
R2が、
(c)ヒドロキシC1〜C6アルキル、
(d)ジヒドロキシC2〜C6アルキル、
(e)OHで置換されていてもよいC1〜C6フルオロアルキル、
(f)(ジ−C1〜C6アルコキシ)C2〜C6アルキル−、
(g)アルキル部分がOHで置換されていてもよい(C1〜C6アルコキシ)C1〜C6アルキル−、
(h)Cyc1、
(i)Cyc2、
(j)アルキル部分がOHで置換されていてもよい(hetCyc1)C1〜C6アルキル−、
(k)アルキル部分がOHで置換されていてもよい(Ar1)C1〜C6アルキル−、
(l)アルキル部分がOHで置換されていてもよい(hetAr1)C1〜C6アルキル−、または
(m)(HOSO3)C1〜C6アルキル−
であり、
Cyc1が、ハロゲン、ヒドロキシ、C1〜C3アルキル、ヒドロキシC1〜C3アルキル、C1〜C3アルコキシ、(C1〜C3アルコキシ)C1〜C3アルキル−およびR’R”NC(=O)−から独立に選択される1〜2個の置換基で置換されていてもよい3〜4員シクロアルキル環であり、
R’およびR”が独立に、水素またはC1〜C6アルキルであり、
Cyc2が、C1〜C3アルキル、(C1〜C3アルコキシ)C1〜C3アルキル−およびヒドロキシC1〜C3アルキル−から独立に選択される1〜2個の置換基で置換されている5員シクロアルキル環であり、
hetCyc1が、オキソで置換されていてもよい、O、N、およびSO2から独立に選択される1〜2個の環ヘテロ原子を有する5〜6員飽和複素環式環であり、
Ar1が、フェニルであり、
hetAr1が、ピリジルであり、
X2が、Nであり、R3が存在せず、環Aが、追加の環窒素原子を有する6員複素環式環であり、R7が、水素であり、Gが、式A−2
R6が、水素、C1〜C6アルキル、またはC3〜C6シクロアルキルであり、
R8が、Ar2、hetAr2、C3〜C6シクロアルキル、hetCyc3またはC1〜C6アルキルであり、
Ar2が、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよいフェニルであり、
hetAr2が、1〜2個の環窒素原子を有し、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよい5〜6員ヘテロアリールであり、
hetCyc3が、環酸素原子を有する5〜6員複素環式環であり、
R9が、水素またはハロゲンである、式I−Bが含まれる。
X1が、CHまたはNであり、
R1が、水素であり、
R2が、
(c)ヒドロキシC1〜C6アルキル、
(e)OHで置換されていてもよいC1〜C6フルオロアルキル、または
(g)アルキル部分がOHで置換されていてもよい(C1〜C6アルコキシ)C1〜C6アルキル−
であり、
X2が、Nであり、R3が存在せず、環Aが、6員複素環式環であり、Gが、式A−3
R6が、ハロゲン、C1〜C6アルキル、C1〜C6アルコキシ、またはC3〜C6シクロアルキルであり、
R7が、水素であり、
R8が、Ar2、hetAr2、C3〜C6シクロアルキル、hetCyc3またはC1〜C6アルキルであり、
Ar2が、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよいフェニルであり、
hetAr2が、1〜2個の環窒素原子を有し、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよい5〜6員ヘテロアリールであり、
hetCyc3が、1個の環酸素原子を有する5〜6員複素環式環であり、
R9が、水素またはハロゲンである、式I−Cが含まれる。
X1が、CHであり、
R1が、水素であり、
R2が、
(c)ヒドロキシC1〜C6アルキル、
(e)OHで置換されていてもよいC1〜C6フルオロアルキル、または
(g)アルキル部分がOHで置換されていてもよい(C1〜C6アルコキシ)C1〜C6アルキル−
であり、
R3が、存在せず、
X2が、Nであり、
X2が、Nであり、R3が存在せず、環Aが、2個の追加の環窒素原子を有する6員複素環式環であり、R7が、オキソまたはチオキソであり、Gが、式
R6が、C1〜C6アルキルであり、
Yが、OまたはSであり、
R8が、Ar2、hetAr2、C3〜C6シクロアルキル、hetCyc3またはC1〜C6アルキルであり、
Ar2が、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよいフェニルであり、
hetAr2が、1〜2個の環窒素原子を有し、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよい5〜6員ヘテロアリールであり、
hetCyc3が、環酸素原子を有する5〜6員複素環式環であり、
R9が、水素またはハロゲンである、式I−Dが含まれる。
X1が、CHまたはNであり、
R2が、
(c)ヒドロキシC1〜C6アルキル、
(e)OHで置換されていてもよいC1〜C6フルオロアルキル、または
(g)アルキル部分がOHで置換されていてもよい(C1〜C6アルコキシ)C1〜C6アルキル−
であり、
X2が、Cであり、R3が存在せず、環Aが、環窒素原子を有する6員複素環式環であり、Gが、式A−5
R6が、C1〜C6アルキルであり、
R7が、水素であり、
R8が、Ar2、hetAr2、C3〜C6シクロアルキル、hetCyc3またはC1〜C6アルキルであり、
Ar2が、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよいフェニルであり、
hetAr2が、1〜2個の環窒素原子を有し、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよい5〜6員ヘテロアリールであり、
hetCyc3が、1個の環酸素原子を有する5〜6員複素環式環であり、
R9が、水素またはハロゲンである、式I−Eが含まれる。
X1が、CHであり、
R1が、水素であり、
R2が、(c)ヒドロキシC1〜C6アルキルであり、
X2が、Nであり、R3が存在せず、環Aが、2個の追加の環窒素原子を有する6員複素環式環であり、Gが、式A−6
R6が、水素であり、
R7が、水素であり、
R8が、Ar2、hetAr2、C3〜C6シクロアルキル、hetCyc3またはC1〜C6アルキルであり、
Ar2が、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよいフェニルであり、
hetAr2が、1〜2個の環窒素原子を有し、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよい5〜6員ヘテロアリールであり、
hetCyc3が、1個の環酸素原子を有する5〜6員複素環式環であり、
R9が、水素またはハロゲンである、式I−Fが含まれる。
X1が、CHであり、
R1が、水素であり、
R2が、(c)ヒドロキシC1〜C6アルキルであり、
X2が、Nであり、R3が、水素またはメチルであり、環Aが、環窒素原子を有する6員複素環式環であり、
Gが、式A−7
R6が、水素であり、R7が、水素であるか、
またはR6およびR7が、同じ炭素原子上にあり、R6およびR7が、それらが結合している炭素原子と一緒に、シクロプロピル環を形成しており、
R8が、Ar2、hetAr2、C3〜C6シクロアルキル、hetCyc3またはC1〜C6アルキルであり、
Ar2が、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよいフェニルであり、
hetAr2が、1〜2個の環窒素原子を有し、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよい5〜6員ヘテロアリールであり、
hetCyc3が、環酸素原子を有する5〜6員複素環式環であり、
R9が、水素またはハロゲンである、式I−Gが含まれる。
X1が、CHであり、
R1が、水素であり、
R2が、(c)ヒドロキシC1〜C6アルキルであり、
X2が、Nであり、R3が存在せず、環Aが、追加の環窒素原子を有する5員複素環式環であり、Gが、式A−8
R6が、C1〜C6アルキルであり、
R7が、水素またはC1〜C6アルキルであり、
R8が、Ar2、hetAr2、C3〜C6シクロアルキル、hetCyc3またはC1〜C6アルキルであり、
Ar2が、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよいフェニルであり、
hetAr2が、1〜2個の環窒素原子を有し、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよい5〜6員ヘテロアリールであり、
hetCyc3が、1個の環酸素原子を有する5〜6員複素環式環であり、
R9が、水素またはハロゲンである、式I−Hが含まれる。
X1が、CHであり、
R1が、水素であり、
R2が、(c)ヒドロキシC1〜C6アルキルであり、
Gが、式B−1
R8が、Ar2、hetAr2、C3〜C6シクロアルキル、hetCyc3またはC1〜C6アルキルであり、
Ar2が、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよいフェニルであり、
hetAr2が、1〜2個の環窒素原子を有し、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよい5〜6員ヘテロアリールであり、
hetCyc3が、1個の環酸素原子を有する5〜6員複素環式環であり、
R9が、水素またはハロゲンである、式I−Iが含まれる。
X1が、CHであり、
R1が、水素であり、
R2が、(c)ヒドロキシC1〜C6アルキルであり、
Gが、式B−2
R8が、Ar2、hetAr2、C3〜C6シクロアルキル、hetCyc3またはC1〜C6アルキルであり、
Ar2が、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよいフェニルであり、
hetAr2が、1〜2個の環窒素原子を有し、ハロゲン、C1〜C2アルキルおよびC1〜C2アルコキシから独立に選択される1個または複数の置換基で置換されていてもよい5〜6員ヘテロアリールであり、
hetCyc3が、1個の環酸素原子を有する5〜6員複素環式環であり、
R9が、水素またはハロゲンである、式I−Jが含まれる。
X1が、CHまたはNであり、
R1が、水素またはC1〜C6アルキルであり、
R2が、
(a)水素、
(b)C1〜C6アルキル、
(c)ヒドロキシC1〜C6アルキル、
(d)ジヒドロキシC2〜C6アルキル、
(e)OHで置換されていてもよいC1〜C6フルオロアルキル、
(g)アルキル部分がOHで置換されていてもよい(C1〜C6アルコキシ)C1〜C6アルキル−、
(h)Cyc1、
(i)Cyc2、
(j)アルキル部分がOHで置換されていてもよい(hetCyc1)C1〜C6アルキル−、
(k)アルキル部分がOHで置換されていてもよい(Ar1)C1〜C6アルキル−、
(l)アルキル部分がOHで置換されていてもよい(hetAr1)C1〜C6アルキル−、または
(m)(HOSO3)C1〜C6アルキル−
であり、
Cyc1が、ハロゲン、ヒドロキシ、ヒドロキシC1〜C3アルキル、C1〜C3アルコキシ、(C1〜C3アルコキシ)C1〜C3アルキル−、およびR’R”NC(=O)−から独立に選択される1〜2個の置換基で置換されていてもよい3〜4員シクロアルキル環であり、
R’およびR”が、C1〜C6アルキルから独立に選択され、
Cyc2が、C1〜C3アルキル、(C1〜C3アルコキシ)C1〜C3アルキル−およびヒドロキシC1〜C3アルキル−から独立に選択される1〜2個の置換基で置換されている5員シクロアルキル環であり、
hetCyc1が、オキソで置換されていてもよい、O、NおよびSO2から独立に選択される1〜2個の環ヘテロ原子を有する5〜6員飽和複素環式環であり、
Ar1が、フェニルであり、
hetAr1が、ピリジルであり、
Gが、
X2が、CまたはNであり、
環Aが、結合点の原子を含めて、X2がNである場合、追加の1〜2個の環窒素原子を有してもよく、X2がCである場合、1個の環窒素原子を有してもよい5〜6員複素環式環であり、
R3が、水素であるか、または存在せず、
R6が、水素、ハロゲン、C1〜C6アルキル、C1〜C6アルコキシ、ヒドロキシC1〜C6アルキル、C3〜C6シクロアルキル、(C3〜C6シクロアルキル)C1〜C6アルキル−またはhetCyc2であり、ただし、R6がハロゲンであり、式Iの−NHC(=O)−部分に連結した炭素に隣接する環炭素原子上にある場合、R6が、ハロゲンではなく、
R7が、水素、C1〜C6アルキル、オキソまたはチオキソであり、
hetCyc2が、C1〜C6アルキルで置換された環窒素原子を有する4員飽和複素環式環であり、
環Bが、結合点の原子を含めて、オキソで置換されていてもよい6員飽和炭素環式またはOHで置換されていてもよい6員芳香族炭素環式環であり、
R8が、Ar2、hetAr2、C3〜C6シクロアルキル、hetCyc3またはC1〜C6アルキルであり、
Ar2が、ハロゲンから独立に選択される1個または複数の置換基で置換されていてもよいフェニルであり、
hetAr2が、1〜2個の環窒素原子を有し、C1〜C2アルキルから独立に選択される1個または複数の置換基で置換されていてもよい5〜6員ヘテロアリールであり、
R9が、水素またはハロゲンである、式IIの化合物ならびにその立体異性体、互変異性体および薬学的に許容できる塩が含まれる。
(a)下式を有する化合物
場合により、その薬学的に許容できる塩を形成するステップと
を含むプロセスを提供する。
一実施形態では、(a)実施例番号201の化合物、またはその薬学的に許容できる塩もしくは溶媒和物と、(b)それぞれ場合によりその薬学的に許容できる塩または溶媒和物の形態の(i)ニボルマブ(またはそのバイオ後続品)、(ii)ペムブロリズマブ(またはそのバイオ後続品)、(iii)セミプリマブ(またはそのバイオ後続品)、(iv)ピジリズマブ(またはそのバイオ後続品)、(v)1141PDCA−170(またはそのバイオ後続品)、(vi)アテゾリズマブ(またはそのバイオ後続品)、(vii)アベルマブ(またはそのバイオ後続品)、および(viii)デュルバルマブ(またはそのバイオ後続品)からなる群から選択される追加の抗がん薬、ならびにその任意の組合せとを含む医薬組合せを提供する。
(実施例A)
AXL酵素アッセイ
InvitrogenのLanthaScreen(商標)Eu Kinase Binding技術を使用して、式Iの化合物を、AXLキナーゼを阻害するそれらの能力についてスクリーニングした。Hisタグ付き組み換えヒトAXL細胞質ドメインを、試験化合物に加えて20nMのAlexa−Fluor(登録商標)Tracer 236(PR9078A)、2nMのビオチン化抗His(カタログ番号M4408)、および2nMのユーロピウム標識Streptavidin(カタログ番号PV5899)と共に、25mMのHEPES、pH7.4、10mMのMgCl2、0.01%のTriton X−100、および2%のDMSOからなるバッファー中でインキュベートした。化合物を典型的にはDMSO中での3倍系列希釈で調製し、アッセイに添加して、適当な最終濃度を得た。22℃での60分間のインキュベーション後に、TR−FRET二重波長検出を介するPerkinElmer EnVisionマルチモードプレートリーダーを使用して反応を測定し、対照に対するパーセント(POC)を、比率算出発光因子(ratiometric emissionfactor)を使用して計算した。100POCは、試験化合物を使用せずに決定し、0POCは、酵素を完全に阻害する濃度の対照化合物を使用して決定した。POC値を、4パラメーターロジスティック曲線にフィットさせ、IC50値を、曲線が50POCと交差する点とする。
MER酵素アッセイ
InvitrogenのLanthaScreen(商標)Eu Kinase Binding技術を使用して、式Iの化合物を、AXLキナーゼを阻害するそれらの能力についてスクリーニングした。Hisタグ付き組み換えヒトMER細胞質ドメイン(5nM)を、試験化合物に加えて20nMのAlexa−Fluor(登録商標)Tracer 236(PR9078A)、2nMのビオチン化抗His(カタログ番号M4408)、および2nMのユーロピウム標識Streptavidin(カタログ番号PV5899)と共に、25mMのHEPES、pH7.4、10mMのMgCl2、0.01%のTriton X−100、および2%のDMSOからなるバッファー中でインキュベートした。化合物を典型的にはDMSO中での3倍系列希釈で調製し、アッセイに添加して、適当な最終濃度を得た。22℃での60分間のインキュベーション後に、TR−FRET二重波長検出を介するPerkinElmer EnVisionマルチモードプレートリーダーを使用して反応を測定し、対照に対するパーセント(POC)を、比率算出発光因子を使用して計算した。100POCは、試験化合物を使用せずに決定し、0POCは、酵素を完全に阻害する濃度の対照化合物を使用して決定した。POC値を、4パラメーターロジスティック曲線にフィットさせ、IC50値を、曲線が50POCと交差する点とする。
TYRO3酵素アッセイ
InvitrogenのLanthaScreen(商標)Eu Kinase Binding技術を使用して、式Iの化合物を、TYRO3キナーゼを阻害するそれらの能力についてスクリーニングした。Carna製のGSTタグ付き組み換えヒトTYRO3キナーゼドメイン(5nM;カタログ番号PR7480A)を、試験化合物に加えて20nMのAlexa−Fluor(登録商標)Tracer 236(PR9078A)および2nMのユーロピウム−抗GST(カタログ番号A15116)と共に、25mMのHEPES、pH7.4、10mMのMgCl2、0.01%のTriton X−100、および2%のDMSOからなるバッファー中でインキュベートした。化合物を典型的にはDMSO中での3倍系列希釈で調製し、アッセイに添加して、適当な最終濃度を得た。22℃での60分間のインキュベーション後に、TR−FRET二重波長検出を介するPerkinElmer EnVisionマルチモードプレートリーダーを使用して反応を測定し、対照に対するパーセント(POC)を、比率算出発光因子を使用して計算した。100POCは、試験化合物を使用せずに決定し、0POCは、酵素を完全に阻害する濃度の対照化合物を使用して決定した。POC値を、4パラメーターロジスティック曲線にフィットさせ、IC50値を、曲線が50POCと交差する点とする。
c−Met酵素アッセイ
実験
InvitrogenのLanthaScreen(商標)Eu Kinase Binding技術を使用して、野生型および突然変異型ヒトMETキナーゼに結合する化合物の親和性を測定する。簡単に述べると、Signal Chem製のGSTタグ付き組み換えヒトMETキナーゼドメイン(アッセイでの濃度については下の表8を参照されたい)を、試験化合物に加えて50nMのAlexa−Fluor(登録商標)Tracer236(Invitrogenカタログ番号PR9078A)および2nMのユーロピウム−抗GST(Invitrogenカタログ番号A15116)と共に、25mMのHEPES、pH7.4、10mMのMgCl2、0.01%のTriton X−100、1mMのDTT、および2%のDMSOからなるバッファー中でインキュベートする。化合物を典型的にはDMSO中での3倍系列希釈で調製し、アッセイに添加して、適当な最終濃度が得られる。22℃での60分間のインキュベーション後に、TR−FRET二重波長検出を介するPerkinElmer EnVisionマルチモードプレートリーダーを使用して反応を測定し、対照に対するパーセント(POC)を、比率算出発光因子を使用して計算する。100POCは、試験化合物を使用せずに決定し、0POCは、酵素を完全に阻害する濃度の対照化合物を使用して決定する。POC値を、4パラメーターロジスティック曲線にフィットさせ、IC50値を、曲線が50POCと交差する点とする。
合成中間体の合成
調製1
3−フルオロ−4−((3−ヨード−1−(4−メトキシベンジル)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)アニリン
2−(4−フルオロフェニル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボン酸
2,5−ジオキソ−1−フェニル−1,2,5,6,7,8−ヘキサヒドロキノリン−3−カルボン酸
3−(4−フルオロフェニル)−1−イソプロピル−2,4−ジオキソ−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸
3−(4−フルオロフェニル)−1−(1−メチルアゼチジン−3−イル)−2,4−ジオキソ−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸ヒドロクロリド
1−シクロプロピル−3−(4−フルオロフェニル)−2,4−ジオキソ−1,2,3,4−テトラヒドロピリミジン−5−カルボン酸
4−エトキシ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボン酸
2−(4−フルオロフェニル)−1−メチル−3−オキソ−2,3−ジヒドロ−1H−ピラゾール−4−カルボン酸
1−(4−フルオロフェニル)−6−メチル−2−オキソ−1,2−ジヒドロピリジン−3−カルボン酸
1−(4−フルオロフェニル)−4−メチル−2−オキソ−1,2−ジヒドロピリジン−3−カルボン酸
1−(4−フルオロフェニル)−5−メチル−2−オキソ−1,2−ジヒドロピリジン−3−カルボン酸
5−シクロプロピル−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボン酸
5−ブロモ−1−(4−フルオロフェニル)−2−オキソ−1,2−ジヒドロピリジン−3−カルボン酸
4−(4−フルオロフェニル)−3−オキソ−3,4−ジヒドロピラジン−2−カルボン酸
6−シクロプロピル−2−(4−フルオロフェニル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボン酸
4−(4−フルオロフェニル)−2−イソプロピル−5−オキソ−3−チオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボン酸
4−(4−フルオロフェニル)−2−イソプロピル−3,5−ジオキソ−2,3,4,5−テトラヒドロ−1,2,4−トリアジン−6−カルボン酸
5−(4−フルオロフェニル)−1−メチル−4−オキソ−1,4−ジヒドロピリジン−3−カルボン酸
1−(4−フルオロフェニル)−2−オキソ−5−ビニル−1,2−ジヒドロピリジン−3−カルボン酸
5−(4−フルオロフェニル)−6−オキソ−5−アザスピロ[2.5]オクタン−7−カルボン酸
1−(4−フルオロフェニル)−3−メチル−2−オキソピペリジン−3−カルボン酸
4−((6−アミノピリジン−3−イル)オキシ)−N−(1−メトキシ−2−メチルプロパン−2−イル)−1−(4−メトキシベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−アミン
(R)−2−((4−(4−アミノ−2−フルオロフェノキシ)−1−(4−メトキシベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル)アミノ)プロパン−1−オール
(R)−2−((4−((6−アミノピリジン−3−イル)オキシ)−1−(4−メトキシベンジル)−1H−ピラゾロ[3,4−b]ピリジン−3−イル)アミノ)プロパン−1−オール
N−(3−フルオロ−4−((3−ヨード−1−(4−メトキシベンジル)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−2−(4−フルオロフェニル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボキサミド
N−(3−フルオロ−4−((3−ヨード−1−(4−メトキシベンジル)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−3−(4−フルオロフェニル)−1−イソプロピル−2,4−ジオキソ−1,2,3,4−テトラヒドロピリミジン−5−カルボキサミド
N−(3−フルオロ−4−((3−((2−ヒドロキシエチル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−2−(4−フルオロフェニル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボキサミド
1H), 8.27 (d, 1H), 8.16 (s, 1H), 8.04 (d, 1H), 7.69 (m, 1H), 7.61 (m, 1H), 7.51
(t, 1H), 7.42 (m, 2H), 6.04 (d, 1H), 3.64 (t, 2H), 3.36 (t, 2H).
N−(3−フルオロ−4−((3−((1−(メトキシメチル)シクロプロピル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−2−(4−フルオロフェニル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボキサミド
(d, 1H), 8.26 (d, 1H), 8.14 (d, 1H), 8.02 (dd, 1H), 7.68 (m, 2H), 7.59 (m, 1H),
7.48 (t, 1H), 7.41 (m, 2H), 6.03 (m, 1H), 5.72 (s, 1H), 3.55 (s, 2H), 3.25 (s,
3H), 0.82 (m, 2H), 0.72 (m, 2H).
N−(4−((3−((1,3−ジヒドロキシ−2−メチルプロパン−2−イル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)−3−フルオロフェニル)−2−(4−フルオロフェニル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボキサミド
(d, 1H), 8.26 (d, 1H), 8.15 (d, 1H), 8.03 (dd, 1H), 7.68 (m, 2H), 7.59 (m, 1H),
7.50 (t, 1H), 7.41 (m, 2H), 6.04 (dd, 1H), 5.24 (s, 1H), 4.87 (t, 2H), 3.65
(dd, 2H), 3.50 (dd, 2H), 1.32 (s, 3H).
N−(3−フルオロ−4−((3−((1−(ヒドロキシメチル)シクロプロピル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−2−(4−フルオロフェニル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボキサミド
(d, 1H), 8.26 (d, 1H), 8.14 (d, 1H), 8.03 (dd, 1H), 7.68 (m, 2H), 7.59 (m, 1H),
7.48 (t, 1H), 7.41 (m, 2H), 6.03 (m, 1H), 5.76 (s, 1H), 3.59 (s, 2H), 0.75 (m,
4H).
2−(4−フルオロフェニル)−N−(5−((3−((1−メトキシ−2−メチルプロパン−2−イル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)ピリジン−2−イル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボキサミド
(d, 1H), 8.33 (d, 1H), 8.22 (d, 1H), 8.17 (m, 1H), 7.67-7.60 (m, 3H), 7.22 (m,
2H), 6.10 (d, 1H), 5.02 (br s, 1H), 3.52 (s, 2H), 3.36 (s, 3H), 1.47 (s, 6H).
(R)−N−(3−フルオロ−4−((3−((1−ヒドロキシプロパン−2−イル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−3−(4−フルオロフェニル)−1−イソプロピル−2,4−ジオキソ−1,2,3,4−テトラヒドロピリミジン−5−カルボキサミド
(d, 1H), 7.90 (dd, 1H), 7.30 (m, 1H), 7.27 (s, 2H), 7.25 (s, 2H), 7.22 (d, 1H),
6.12 (d, 1H), 4.98 (m, 1H), 4.02 (m, 1H), 3.83 (dd, 1H), 3.71 (dd, 1H), 1.51
(d, 6H), 1.34 (d, 3H).
(R)−N−(3−フルオロ−4−((3−((1−ヒドロキシプロパン−2−イル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−3−(4−フルオロフェニル)−1−メチル−2,4−ジオキソ−1,2,3,4−テトラヒドロピリミジン−5−カルボキサミドヒドロクロリド
(d, 1H), 7.95 (dd, 1H), 7.36-7.22 (m, 6H), 6.22 (d, 1H), 4.02 (m, 1H), 3.76 (m,
1H), 3.71 (s, 3H), 3.65 (m, 1H), 1.35 (d, 3H).
(R)−N−(3−フルオロ−4−((3−((1−ヒドロキシプロパン−2−イル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−5−ヒドロキシ−2−オキソ−1−フェニル−1,2−ジヒドロキノリンe−3−カルボキサミド
1H), 8.00 (dd, 1H), 7.71-7.57 (m, 3H), 7.40 (ddd, 1H), 7.35-7.29 (m, 6H), 7.23
(t, 1H), 6.73 (d, 1H), 6.14 (d, 1H), 6.09 (dd, 1H), 3.93 (m, 1H), 3.70 (d, 2H),
1.34 (d, 3H).
(R)−2−(4−フルオロフェニル)−N−(5−((3−((1−ヒドロキシプロパン−2−イル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)ピリジン−2−イル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボキサミドヒドロクロリド
(d, 1H), 8.40 (d, 1H), 8.34 (d, 1H), 8.22 (s, 1H), 7.96 (m, 1H), 7.69 (m, 2H),
7.41 (m, 2H), 6.13 (d, 1H), 3.80 (m, 1H), 3.73-3.65 (m, 2H), 3.55-3.45 (m, 3H),
1.22 (d, 3H).
(R)−N−(3−フルオロ−4−((3−((1−メトキシプロパン−2−イル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−3−(4−フルオロフェニル)−1−イソプロピル−2,4−ジオキソ−1,2,3,4−テトラヒドロピリミジン−5−カルボキサミドヒドロクロリド
(d, 1H), 8.03 (dd, 1H), 7.57 (dd, 1H), 7.50 (t, 1H), 7.43 (m, 2H), 7.36 (m,
2H), 6.11 (dd, 1H), 4.78 (m, 1H), 3.98 (m, 1H), 3.51 (dd, 1H), 3.39 (dd, 1H),
1.43 (d, 6H), 1.23 (d, 3H).
(R)−1−(シクロプロピルメチル)−N−(3−フルオロ−4−((3−((1−メトキシプロパン−2−イル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−3−(4−フルオロフェニル)−2,4−ジオキソ−1,2,3,4−テトラヒドロピリミジン−5−カルボキサミド
(s, 1H), 8.13 (d, 1H), 8.00 (dd, 1H), 7.53 (ddd, 1H), 7.45 (m, 3H), 7.36 (m,
2H), 6.02 (dd, 1H), 5.09 (d, 1H), 3.96 (m, 1H), 3.86 (d, 2H), 3.50 (dd, 1H),
3.37 (dd, 1H), 3.27 (s, 3H), 1.22 (d, 3H), 0.57 (m, 2H), 0.44 (m, 2H).
N−(3−フルオロ−4−((3−((1−(2−ヒドロキシプロパン−2−イル)シクロペンチル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−2−(4−フルオロフェニル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボキサミド
(d, 1H), 8.18 (d, 1H), 7.97 (dd, 1H), 7.60 (m, 2H), 7.42 (ddd, 1H), 7.32-7.22
(m, 3H), 6.10 (dd, 1H), 5.02 (s, 1H), 2.36 (m, 2H), 2.16 (m, 2H), 1.85 (m, 4H),
1.55 (s, 6H).
2−((4−(2−フルオロ−4−(2−(4−フルオロフェニル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボキサミド)フェノキシ)−1H−ピラゾロ[3,4−b]ピリジン−3−イル)アミノ)−2−メチルプロピル水素スルファート
8.37 (d, 1H), 8.27 (d, 1H), 8.18 (m, 1H), 8.03 (dd, 1h), 7.69 (m, 2H),
7.61-7.49 (m, 2H), 7.41 (m, 2H), 6.08 (d, 1H), 3.86 (s, 2H), 1.40 (s, 6H).
(S)−N−(3−フルオロ−4−((3−((3−ヒドロキシ−3−メチルブタン−2−イル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−2−(4−フルオロフェニル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボキサミド(実施例184)および(R)−N−(3−フルオロ−4−((3−((3−ヒドロキシ−3−メチルブタン−2−イル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−2−(4−フルオロフェニル)−3−オキソ−2,3−ジヒドロピリダジン−4−カルボキサミド(実施例185)
N−(4−((3−アミノ−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)−3−フルオロフェニル)−3−(4−フルオロフェニル)−1−イソプロピル−2,4−ジオキソ−1,2,3,4−テトラヒドロピリミジン−5−カルボキサミド
(s, 1H), 8.21 (d, 1H), 7.89 (dd, 1H), 7.29 (ddd, 1H), 7.27-7.20 (m, 4H), 6.11
(dd, 1H), 4.98 (m, 1H), 4.50 (s, 2H), 1.51 (d, 6H).
(R)−N−(3−フルオロ−4−((3−((1−ヒドロキシプロパン−2−イル)アミノ)−1H−ピラゾロ[3,4−b]ピリジン−4−イル)オキシ)フェニル)−1−(4−フルオロフェニル)−5−イソプロピル−2−オキソ−1,2−ジヒドロピリジン−3−カルボキサミドヒドロクロリド
(d, 1H), 8.06 (dd, 1H), 7.46-7.39 (m, 4H), 7.31-7.24 (m, 3H), 6.12 (d, 1H),
5.32 (br s, 1H), 4.17 (m, 1H), 3.92 (dd, 1H), 3.72 (dd, 1H), 2.87 (m, 1H), 1.38
(d, 3H), 1.30 (d, 6H).
実施形態1。実施例番号25、37、46、48、55、58、72、76、77、78、83、84、85、91、97、100、103、105、107、108、114、115、119、121、124、125、126、127、129、151、152、163、169、188、190、199、200、もしくは201の化合物、またはその薬学的に許容できる塩もしくは溶媒和物である、式Iの化合物。
Claims (4)
- 請求項1の化合物またはその薬学的に許容できる塩と、薬学的に許容できる希釈剤または担体とを含む、医薬組成物。
- 請求項1の化合物と、薬学的に許容できる希釈剤または担体とを含む、医薬組成物。
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WO2022217100A1 (en) * | 2021-04-09 | 2022-10-13 | Tachyon Therapeutics, Inc. | Treatment of cancer with kdm4 inhibitors |
WO2023002360A1 (en) | 2021-07-22 | 2023-01-26 | Pfizer Inc. | Solid forms and formulations of an inhibitor of tam and c-met kinases |
IT202100022682A1 (it) * | 2021-09-01 | 2023-03-01 | Luigi Frati | Derivati pirimidinici e loro uso nel trattamento di tumori |
CN115850301A (zh) * | 2021-09-24 | 2023-03-28 | 中山医诺维申新药研发有限公司 | 吡唑酮类化合物及其组合物和用途 |
CN118159538A (zh) * | 2021-11-05 | 2024-06-07 | 上海海和药物研究开发股份有限公司 | 含met受体酪氨酸激酶抑制剂的药物组合及应用 |
AU2022383315A1 (en) * | 2021-11-05 | 2024-06-20 | Haihe Biopharma Co., Ltd. | Solid dispersion, preparation method therefor, and solid formulation containing same |
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TW202340177A (zh) | 2021-12-30 | 2023-10-16 | 美商拜歐米富士恩股份有限公司 | 作為 flt3抑制劑之吡嗪化合物 |
CN116768868B (zh) * | 2023-08-15 | 2023-12-08 | 云南省药物研究所 | 一种哒嗪酮硫代衍生物及其制备方法和应用 |
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