JPWO2021168193A5 - - Google Patents

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JPWO2021168193A5
JPWO2021168193A5 JP2022549829A JP2022549829A JPWO2021168193A5 JP WO2021168193 A5 JPWO2021168193 A5 JP WO2021168193A5 JP 2022549829 A JP2022549829 A JP 2022549829A JP 2022549829 A JP2022549829 A JP 2022549829A JP WO2021168193 A5 JPWO2021168193 A5 JP WO2021168193A5
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pharmaceutical composition
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disease
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Priority claimed from PCT/US2021/018703 external-priority patent/WO2021168193A1/en
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Claims (16)

式(I)：
Figure 2021168193000001
 式(I)
［式中、
Aは、1つまたは複数の水素、ハロゲン、ヒドロキシル、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、-(C0-6アルキル)シクロアルキル、C-6ハロアルキル、C1-6アルコキシ、NO2、シアノ、CO2H、PO(R6)2、NH2、NH(C1-6アルキル)またはN(C1-6アルキル)2で任意に置換されたアリールまたはヘテロアリールから選択される；
Xは、O、NR7、SまたはCH2から選択される；
Yは、水素、ハロゲンまたはトリフルオロメチルから選択される；
Zは、水素、ハロゲン、トリフルオロメチルまたはC1-6アルキルから選択される；
R1は、水素、C1-6アルキル、-(C1-6アルキル)C1-6アルコキシ、-C0-6アルキル(シクロアルキル)、C1-6ハロアルキル、-(C1-6アルキル)CNまたは-(C1-6アルキル)P(O)(R6)2から選択される；
R2は、水素、C1-6アルキル、-(C1-6アルキル)C1-6アルコキシ、-C0-6アルキル(シクロアルキル)、C1-6ハロアルキル、-(C1-6アルキル)CN、-(C1-6アルキル)P(O)(R6)2から選択されるか、またはR3と一緒になって、3-6員架橋環を形成する；
R3は、水素、C1-6アルキル、-(C1-6アルキル)C1-6アルコキシ、-C0-6アルキル(シクロアルキル)、C1-6ハロアルキル、-(C1-6アルキル)CN、-(C1-6アルキル)P(O)(R6)2から選択されるか、またはR2と一緒になって、3-6員架橋アルキル環を形成する；
nは、1-3である；
R4は、水素、ハロゲン、C1-3アルキル、C1-3ハロアルキル、-(C1-3アルキル)CF3または-(C1-3アルキル)C1-6アルコキシから選択される；
R5は、H、C1-6アルキル、C3-6シクロアルキルまたは-(C1-6アルキル)P(O)(R6)2から選択される；
R6は、H、C1-6アルキル、C3-6シクロアルキル、C1-6アルコキシ、C3-6シクロアルコキシ、ヒドロキシル、アリールまたはアリールオキシから選択される；
R7は、H、C1-6アルキル、またはC3-6シクロアルキルから選択される］
で示される化合物またはその塩、溶媒和物、もしくはプロドラッグ。 Formula (I):
Figure 2021168193000001
 Formula (I)
[In the formula,
A is one or more hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -(C 0-6 alkyl)cycloalkyl, C -6 haloalkyl, C 1 Aryl or hetero optionally substituted with -6 alkoxy, NO 2 , cyano, CO 2 H, PO(R 6 ) 2 , NH 2 , NH(C 1-6 alkyl) or N(C 1-6 alkyl) 2 selected from aryls;
X is selected from O, NR7 , S or CH2 ;
Y is selected from hydrogen, halogen or trifluoromethyl;
Z is selected from hydrogen, halogen, trifluoromethyl or C 1-6 alkyl;
R 1 is hydrogen, C 1-6 alkyl, -(C 1-6 alkyl)C 1-6 alkoxy, -C 0-6 alkyl (cycloalkyl), C 1-6 haloalkyl, -(C 1-6 alkyl) )CN or -( C1-6alkyl )P(O)( R6 ) 2 ;
R 2 is hydrogen, C 1-6 alkyl, -(C 1-6 alkyl)C 1-6 alkoxy, -C 0-6 alkyl (cycloalkyl), C 1-6 haloalkyl, -(C 1-6 alkyl) )CN, -(C 1-6 alkyl)P(O)(R 6 ) 2 or together with R 3 form a 3-6 membered bridged ring;
R 3 is hydrogen, C 1-6 alkyl, -(C 1-6 alkyl)C 1-6 alkoxy, -C 0-6 alkyl (cycloalkyl), C 1-6 haloalkyl, -(C 1-6 alkyl) )CN, -(C 1-6 alkyl)P(O)(R 6 ) 2 or together with R 2 form a 3-6 membered bridged alkyl ring;
n is 1-3;
R 4 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, -(C 1-3 alkyl)CF 3 or -(C 1-3 alkyl)C 1-6 alkoxy;
R 5 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl or -(C 1-6 alkyl)P(O)(R 6 ) 2 ;
R 6 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, hydroxyl, aryl or aryloxy;
R 7 is selected from H, C 1-6 alkyl, or C 3-6 cycloalkyl]
A compound represented by or a salt, solvate, or prodrug thereof. 式(I)で示される化合物が、以下の化合物1a-1zもしくは2a-2nまたはその塩、溶媒和物、もしくはプロドラッグから選択される、請求項１に記載の化合物：
Figure 2021168193000002
Figure 2021168193000003
Figure 2021168193000004
Figure 2021168193000005
Figure 2021168193000006
 。 A compound according to claim 1, wherein the compound of formula (I) is selected from the following compounds 1a-1z or 2a-2n or a salt, solvate or prodrug thereof:
Figure 2021168193000002
Figure 2021168193000003
Figure 2021168193000004
Figure 2021168193000005
Figure 2021168193000006
 . 請求項１～２のいずれか1つに記載の化合物、またはその塩、溶媒和物、もしくはプロドラッグを、薬学的に許容される担体とともに含む医薬組成物。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 2, or a salt, solvate, or prodrug thereof, together with a pharmaceutically acceptable carrier. 患者の疾患、障害、または病状の治療用医薬組成物であって、請求項１～３のいずれか1つに記載の化合物、またはその塩、溶媒和物、もしくはプロドラッグを含む、医薬組成物。 A pharmaceutical composition for the treatment of a disease, disorder or condition in a patient , comprising a compound according to any one of claims 1 to 3, or a salt, solvate or prodrug thereof. thing . 患者の疾患、障害、または病状がさまざまながんである、請求項４に記載の医薬組成物。 5. The pharmaceutical composition of claim 4, wherein the patient's disease, disorder, or condition is various cancers. 該疾患、障害、または病状が、KRASを介して媒介される、請求項５に記載の医薬組成物。 6. The pharmaceutical composition of claim 5, wherein the disease, disorder, or condition is mediated through KRAS. 該疾患、障害、または病状が、KRAS突然変異体G12Cを介して媒介される、請求項５に記載の医薬組成物。 6. The pharmaceutical composition of claim 5, wherein the disease, disorder, or condition is mediated through the KRAS mutant G12C. がんが、神経膠腫(神経膠芽腫)、急性骨髄性白血病(acute myelogenous leukemia)、急性骨髄性白血病(acute myeloid leukemia)、骨髄異形成/骨髄増殖性腫瘍、肉腫、慢性骨髄単球性白血病、非ホジキンリンパ腫、星細胞腫、黒色腫、非小細胞肺がん、胆管がん、軟骨肉腫、結腸がんまたは膵臓がんから選択される、請求項５に記載の医薬組成物。 The cancer is glioma (glioblastoma), acute myelogenous leukemia, acute myeloid leukemia, myelodysplastic/myeloproliferative tumor, sarcoma, chronic myelomonocytic Pharmaceutical composition according to claim 5, selected from leukemia, non-Hodgkin's lymphoma, astrocytoma, melanoma, non-small cell lung cancer, bile duct cancer, chondrosarcoma, colon cancer or pancreatic cancer. 少なくとも1つの追加の治療剤をさらに含む、請求項４～８のいずれか1つに記載の医薬組成物。 Pharmaceutical composition according to any one of claims 4 to 8, further comprising at least one additional therapeutic agent . 式(I)で示される化合物が、化合物2l：
Figure 2021168193000007
 2l
、またはその塩、溶媒和物、もしくはプロドラッグである、請求項２に記載の化合物。 The compound represented by formula (I) is compound 2l:
Figure 2021168193000007
 2l
, or a salt, solvate, or prodrug thereof. 化合物2l：
Figure 2021168193000008
 2l
、またはその塩、溶媒和物、もしくはプロドラッグを、薬学的に許容される担体とともに含む、請求項３に記載の医薬組成物。 Compound 2l :
Figure 2021168193000008
 2l
, or a salt, solvate, or prodrug thereof, together with a pharmaceutically acceptable carrier. 患者の疾患、障害、または病状を治療するための、請求項１１に記載の医薬組成物。 12. A pharmaceutical composition according to claim 11 for treating a disease, disorder, or condition in a patient. 疾患、障害、または病状が、さまざまながんを包含する、請求項１２に記載の医薬組成物。 13. The pharmaceutical composition of claim 12, wherein the disease, disorder, or condition includes various cancers. 該疾患、障害、または病状が、KRASを介して媒介される、請求項１２に記載の医薬組成物。 13. The pharmaceutical composition of claim 12, wherein the disease, disorder, or condition is mediated through KRAS. 該疾患、障害、または病状が、KRAS突然変異体G12Cを介して媒介される、請求項１４に記載の医薬組成物。 15. The pharmaceutical composition of claim 14, wherein the disease, disorder, or condition is mediated through the KRAS mutant G12C. がんが、神経膠腫(神経膠芽腫)、急性骨髄性白血病(acute myelogenous leukemia)、急性骨髄性白血病(acute myeloid leukemia)、骨髄異形成/骨髄増殖性腫瘍、肉腫、慢性骨髄単球性白血病、非ホジキンリンパ腫、星細胞腫、黒色腫、非小細胞肺がん、胆管がん、軟骨肉腫、結腸がんまたは膵臓がんから選択される、請求項１３に記載の医薬組成物。 The cancer is glioma (glioblastoma), acute myelogenous leukemia, acute myeloid leukemia, myelodysplastic/myeloproliferative tumor, sarcoma, chronic myelomonocytic 14. The pharmaceutical composition according to claim 13, selected from leukemia, non-Hodgkin's lymphoma, astrocytoma, melanoma, non-small cell lung cancer, bile duct cancer, chondrosarcoma, colon cancer or pancreatic cancer.
JP2022549829A 2020-02-20 2021-02-19 Pyridopyrimidine derivatives as KRAS inhibitors Pending JP2023515479A (en)

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US202062978954P 2020-02-20 2020-02-20
US62/978,954 2020-02-20
PCT/US2021/018703 WO2021168193A1 (en) 2020-02-20 2021-02-19 Pyridopyrimidine derivatives as kras inhibitors

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EP (1) EP4077328A4 (en)
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CN (1) CN115135650A (en)
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