JPWO2019180631A5 - - Google Patents

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JPWO2019180631A5
JPWO2019180631A5 JP2020549740A JP2020549740A JPWO2019180631A5 JP WO2019180631 A5 JPWO2019180631 A5 JP WO2019180631A5 JP 2020549740 A JP2020549740 A JP 2020549740A JP 2020549740 A JP2020549740 A JP 2020549740A JP WO2019180631 A5 JPWO2019180631 A5 JP WO2019180631A5
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Claims (19)

式（Ｉ）
Figure 2019180631000001
 ［式中、
各Ｘ１、Ｘ２およびＸ３は、独立してＣＲ５またはＮであり、
環Ａは、シクロアルキル、アリール、ヘテロシクロアルキルまたはヘテロアリールであり、
Ｒは、水素、アルキルまたはハロであり、
Ｒ１は、
Figure 2019180631000002
 、
Figure 2019180631000003
 、
Figure 2019180631000004
 、または
Figure 2019180631000005
 であり、
Ｒ２は、水素またはアルキルであるか、
あるいはＲ１とＲ２は、それらが結合している窒素と一緒になって、Ｎ、ＯおよびＳから選択される１～３個の追加のヘテロ原子を任意に含む二環式ヘテロシクリル環を形成し、ここで、前記二環式ヘテロシクリル環は、１つまたは複数のＲ６で任意に置換されており、
Ｒ３は、水素またはアルキルであり、
Ｒ４は、各存在時に独立して、水素、ハロ、ハロアルキル、シアノ、アルキル、アルケニル、アルキニル、ヒドロキシ、アルコキシ、－Ｃ（Ｏ）Ｒ７、－アルキル－Ｃ（Ｏ）Ｒ７、－Ｓ（Ｏ）２Ｒ７であって、ここで、前記アルキル、アルケニルおよびアルキニルは、ヒドロキシル、ハロ、ヘテロシクロアルキルおよびヘテロアリールから選択される１～３つの基で任意に置換されているか、
あるいは同じ原子上の２つのＲ４は一緒になってオキソ（＝Ｏ）基を形成し
Ｒ５は、各存在時に独立して、水素、アルキル、ハロ、ハロアルキルまたはアルコキシであり、
Ｒ６は、アルキル、アルコキシ、ヒドロキシ、シアノ、ハロまたはハロアルキルであり、
Ｒ７は、アルキル、ヒドロキシ、アルコキシ、－ＮＲｅＲｆ、シクロアルキル、アリール、ヘテロシクロアルキルまたはヘテロアリールであって、ここで、各アルキル、シクロアルキル、アリール、ヘテロシクロアルキルおよびヘテロアリールは、１つまたは複数のＲ６でさらに任意に置換されており、
ＲａおよびＲｂは、それぞれ独立して水素またはアルキルであり、
ＲｃおよびＲｄは、それぞれ独立して水素またはアルキルであるか、あるいはＲｃとＲｄは一緒になってオキソ（＝Ｏ）基を表し、
ＲｅおよびＲｆは、それぞれ独立して水素またはアルキルであるか、あるいはＲｅとＲｆは、それらが結合している窒素と一緒になって、Ｎ、ＯおよびＳから選択される１～２個の追加のヘテロ原子を有する任意に置換された３～７員の複素環を形成し、ここで、任意の置換基は、１つまたは複数のＲ６であり、
「ｍ」は、１～３の整数であり、
「ｎ」は、０または１である］の化合物またはその薬学的に許容可能な塩もしくはその立体異性体。 Equation (I)
Figure 2019180631000001
 [During the ceremony,
Each X 1 , X 2 and X 3 is independently CR 5 or N and
Ring A is cycloalkyl, aryl, heterocycloalkyl or heteroaryl,
R is hydrogen, alkyl or halo,
R 1 is
Figure 2019180631000002
 ,
Figure 2019180631000003
 ,
Figure 2019180631000004
 ,or
Figure 2019180631000005
 And
Is R 2 hydrogen or alkyl?
Alternatively, R 1 and R 2 together with the nitrogen to which they are attached form a bicyclic heterocyclyl ring optionally containing 1 to 3 additional heteroatoms selected from N, O and S. Here, the bicyclic heterocyclyl ring is optionally substituted with one or more R6s .
R 3 is hydrogen or alkyl and is
R4 is independently present at each presence of hydrogen, halo, haloalkyl, cyano, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, -C (O) R 7 , -alkyl-C (O) R 7 , -S ( O) 2 R 7 , wherein the alkyl, alkenyl and alkynyl are optionally substituted with 1 to 3 groups selected from hydroxyl, halo, heterocycloalkyl and heteroaryl.
Alternatively, two R4s on the same atom together form an oxo (= O) group, where R5s are independently hydrogen, alkyl, halo, haloalkyl or alkoxy at each presence.
R 6 is alkyl, alkoxy, hydroxy, cyano, halo or haloalkyl.
R 7 is alkyl, hydroxy, alkoxy, -NR eR f , cycloalkyl, aryl, heterocycloalkyl or heteroaryl, where each alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl is. Further optionally replaced with one or more R6s ,
R a and R b are independently hydrogen or alkyl, respectively.
R c and R d are independently hydrogen or alkyl, respectively, or R c and R d together represent an oxo (= O) group.
Re and R f are independently hydrogen or alkyl, respectively, or Re and R f are selected from N, O and S together with the nitrogen to which they are attached. Form an arbitrarily substituted 3- to 7-membered heterocycle with two additional heteroatoms, where the optional substituent is one or more R6s .
"M" is an integer of 1 to 3 and
"N" is 0 or 1] or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 式（ＩＡ）
Figure 2019180631000006
 の化合物またはその薬学的に許容可能な塩もしくはその立体異性体を有する、請求項１に記載の化合物。 Formula (IA)
Figure 2019180631000006
 The compound according to claim 1, which has a compound of the above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 式（ＩＢ）
Figure 2019180631000007
の化合物またはその薬学的に許容可能な塩もしくはその立体異性体を有する、請求項１に記載の化合物。 Equation (IB)
Figure 2019180631000007
The compound according to claim 1, which has a compound of the above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 式（ＩＣ）、（ＩＥ）、（ＩＦ）、（ＩＨ）、（ＩＪ）または（ＩＫ）
Figure 2019180631000008
Figure 2019180631000009
Figure 2019180631000010
Figure 2019180631000011
Figure 2019180631000012
Figure 2019180631000013
 の化合物またはその薬学的に許容可能な塩もしくはその立体異性体を有する、請求項１に記載の化合物。 Equation (IC) , (IE), (IF), (IH), (IJ) or (IK)
Figure 2019180631000008
Figure 2019180631000009
Figure 2019180631000010
Figure 2019180631000011
Figure 2019180631000012
Figure 2019180631000013
 The compound according to claim 1, which has a compound of the above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 式（ＩＤ）
Figure 2019180631000014
 の化合物またはその薬学的に許容可能な塩もしくはその立体異性体を有する、請求項１に記載の化合物。 Expression (ID)
Figure 2019180631000014
 The compound according to claim 1, which has a compound of the above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 式（ＩＧ）
Figure 2019180631000015
 の化合物またはその薬学的に許容可能な塩もしくはその立体異性体を有する、請求項１に記載の化合物。 Expression (IG)
Figure 2019180631000015
 The compound according to claim 1, which has a compound of the above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 式（ＩＬ）
Figure 2019180631000016
の化合物またはその薬学的に許容可能な塩もしくはその立体異性体を有する、請求項１に記載の化合物。 Formula (IL)
Figure 2019180631000016
The compound according to claim 1, which has a compound of the above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 環
Figure 2019180631000017
 が、
Figure 2019180631000018
 、
Figure 2019180631000019
 、
Figure 2019180631000020
 、
Figure 2019180631000021
 、
Figure 2019180631000022
 、
Figure 2019180631000023
 、
Figure 2019180631000024
 、
Figure 2019180631000025
 、
Figure 2019180631000026
 または
Figure 2019180631000027
 、

である、請求項１～３、６、７のいずれか一項に記載の化合物。 ring
Figure 2019180631000017
 but,
Figure 2019180631000018
 ,
Figure 2019180631000019
 ,
Figure 2019180631000020
 ,
Figure 2019180631000021
 ,
Figure 2019180631000022
 ,
Figure 2019180631000023
 ,
Figure 2019180631000024
 ,
Figure 2019180631000025
 ,
Figure 2019180631000026
 or
Figure 2019180631000027
 ,

The compound according to any one of claims 1 to 3 , 6 and 7. 環Ａが３～１０員の単環式環系である、または、縮合、架橋およびスピロ環式環系から選択される６～１２員の二環式環である、請求項１～３、５、７、８のいずれか一項に記載の化合物。 Claims 1 to 3 , 5 where ring A is a 3 to 10 member monocyclic ring system or a 6 to 12 member bicyclic ring selected from condensation, cross-linking and spiro ring systems. , 7, 8 The compound according to any one of. 環Ａが、
Figure 2019180631000028
 、
Figure 2019180631000029
 、
Figure 2019180631000030
 、
Figure 2019180631000031
 、
Figure 2019180631000032
 、
Figure 2019180631000033
 、
Figure 2019180631000034
 、
Figure 2019180631000035
 、
Figure 2019180631000036
 、
Figure 2019180631000037
 、
Figure 2019180631000038
 、
Figure 2019180631000039
 、
Figure 2019180631000040
 、
Figure 2019180631000041
 、
Figure 2019180631000042
 、
Figure 2019180631000043
 、
Figure 2019180631000044
 、
Figure 2019180631000045
 、
Figure 2019180631000046
 、
Figure 2019180631000047
 、
Figure 2019180631000048
 、
Figure 2019180631000049
 、
Figure 2019180631000050
 、
Figure 2019180631000051
 、
Figure 2019180631000052
 、
Figure 2019180631000053
 または
Figure 2019180631000054
 であり、ここで、
Figure 2019180631000055
 は、Ｘ１、Ｘ２およびＸ３を有する環との結合点である、請求項１～３、５、７、８のいずれか一項に記載の化合物。 Ring A is
Figure 2019180631000028
 ,
Figure 2019180631000029
 ,
Figure 2019180631000030
 ,
Figure 2019180631000031
 ,
Figure 2019180631000032
 ,
Figure 2019180631000033
 ,
Figure 2019180631000034
 ,
Figure 2019180631000035
 ,
Figure 2019180631000036
 ,
Figure 2019180631000037
 ,
Figure 2019180631000038
 ,
Figure 2019180631000039
 ,
Figure 2019180631000040
 ,
Figure 2019180631000041
 ,
Figure 2019180631000042
 ,
Figure 2019180631000043
 ,
Figure 2019180631000044
 ,
Figure 2019180631000045
 ,
Figure 2019180631000046
 ,
Figure 2019180631000047
 ,
Figure 2019180631000048
 ,
Figure 2019180631000049
 ,
Figure 2019180631000050
 ,
Figure 2019180631000051
 ,
Figure 2019180631000052
 ,
Figure 2019180631000053
 or
Figure 2019180631000054
 And here,
Figure 2019180631000055
 The compound according to any one of claims 1 to 3, 5 , 7, and 8, wherein is a bonding point with a ring having X 1 , X 2 , and X 3 . Ｒ１が、
Figure 2019180631000056
 、
Figure 2019180631000057
 、
Figure 2019180631000058
 または
Figure 2019180631000059
 であり、Ｒ２が水素である、請求項１、２、５、６、７～１０のいずれか一項に記載の化合物。 R 1 is
Figure 2019180631000056
 ,
Figure 2019180631000057
 ,
Figure 2019180631000058
 or
Figure 2019180631000059
 The compound according to any one of claims 1, 2, 5, 6, 7 to 10, wherein R 2 is hydrogen. 前記基
Figure 2019180631000060
 が、
Figure 2019180631000061
Figure 2019180631000062
 、
Figure 2019180631000063
 、
Figure 2019180631000064
 または
Figure 2019180631000065
 である、請求項１、２、５、６、７～１１のいずれか一項に記載の化合物。 The group
Figure 2019180631000060
 but,
Figure 2019180631000061
Figure 2019180631000062
 ,
Figure 2019180631000063
 ,
Figure 2019180631000064
 or
Figure 2019180631000065
 The compound according to any one of claims 1, 2, 5, 6, 7 to 11 . Ｒ３、Ｒａ、Ｒｂ、ＲｃおよびＲｄがそれぞれ水素である、請求項１に記載の化合物。 The compound according to claim 1, wherein R 3 , R a , R b , R c and R d are hydrogen, respectively. 以下から選択される請求項１～１３のいずれか一項に記載の化合物：
（表１１）
Figure 2019180631000066
Figure 2019180631000067
Figure 2019180631000068
Figure 2019180631000069
Figure 2019180631000070
Figure 2019180631000071
Figure 2019180631000072
Figure 2019180631000073
またはその薬学的に許容可能な塩もしくは立体異性体。 The compound according to any one of claims 1 to 13 selected from the following:
(Table 11)
Figure 2019180631000066
Figure 2019180631000067
Figure 2019180631000068
Figure 2019180631000069
Figure 2019180631000070
Figure 2019180631000071
Figure 2019180631000072
Figure 2019180631000073
Or its pharmaceutically acceptable salt or stereoisomer. 請求項１～１４のいずれか一項に記載の化合物、またはその薬学的に許容可能な塩もしくは立体異性体と、少なくとも１種の薬学的に許容可能な担体または医薬品添加剤とを含む医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 , or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable carrier or pharmaceutical additive. thing. タンパク質アルギニンメチルトランスフェラーゼ５（ＰＲＭＴ５）を阻害における使用のための医薬組成物であって、請求項１～１４のいずれか一項に記載の式（Ｉ）の化合物を含む医薬組成物。 A pharmaceutical composition for use in inhibiting the protein arginine methyltransferase 5 (PRMT5), comprising the compound of formula (I) according to any one of claims 1-14. ＰＲＭＴ５によって媒介される疾患もしくは障害の治療または予防における使用のための医薬組成物であって、請求項１～１４のいずれか一項に記載の式（Ｉ）の化合物を含む医薬組成物。 A pharmaceutical composition for use in the treatment or prevention of a disease or disorder mediated by PRMT5, comprising the compound of formula (I) according to any one of claims 1-14. 前記ＰＲＭＴ５によって媒介される疾患または障害が、癌、血液障害、炎症性疾患、自己免疫疾患、代謝障害、遺伝性障害、ホルモン関連疾患、免疫不全障害、細胞死に関連する状態、骨破壊性疾患、トロンビン誘発血小板凝集、肝疾患、心血管障害またはヘモグロビン症であり、
（ｉ）前記癌が、固形腫瘍、良性または悪性腫瘍、脳、腎臓、肺、肝臓、胃、膣、卵巣、食道、胃腫瘍、乳房、膀胱、結腸、前立腺、膵臓、肺、子宮頸、精巣、皮膚、骨または甲状腺の癌；肉腫、髄芽腫、神経膠芽腫、神経芽細胞腫、多発性骨髄腫、胃腸癌、首と頭の腫瘍、表皮の過剰増殖、乾癬、前立腺過形成、新生物、腺腫、腺癌、直腸腺癌、結腸腺癌、肺腺癌、角化棘細胞腫、類表皮癌、肝細胞癌、大細胞癌、腎細胞癌、乏突起膠腫、卵巣明細胞癌、卵巣漿液性嚢胞腺癌、非小細胞肺癌、リンパ腫、ホジキンリンパ腫および非ホジキンリンパ腫、乳癌、濾胞癌、乳頭癌、精上皮腫、黒色腫；白血病、びまん性大細胞型Ｂ細胞リンパ腫（ＤＬＢＣＬ）、活性化Ｂ細胞様ＤＬＢＣＬ、慢性リンパ球性白血病（ＣＬＬ）、慢性リンパ球性リンパ腫、原発性滲出性リンパ腫、バーキットリンパ腫／白血病、急性リンパ性白血病、Ｂ－細胞前リンパ球性白血病、リンパ形質細胞性リンパ腫、ワルデンストレームマクログロブリン血症（ＷＭ）、脾臓辺縁帯リンパ腫、血管内大細胞型Ｂ細胞リンパ腫、形質細胞腫および多発性骨髄腫から選択される造血器癌、血液悪性腫瘍であり、
（ｉｉ）前記血液障害が、鎌状赤血球貧血またはβサラセミアであり、
（ｉｉｉ）代謝障害が糖尿病または肥満である、
請求項１７に記載の使用のための医薬組成物。 Diseases or disorders mediated by PRMT5 include cancer, blood disorders, inflammatory diseases, autoimmune diseases, metabolic disorders, hereditary disorders, hormone-related diseases, immunodeficiency disorders, cell death-related conditions, bone-destroying diseases, Trombin-induced platelet aggregation, liver disease , cardiovascular disorders or hemoglobinosis ,
(I) The cancer is a solid tumor, benign or malignant tumor, brain, kidney, lung, liver, stomach, vagina, ovary, esophagus, gastric tumor, breast, bladder, colon, prostate, pancreas, lung, cervix, testis. , Skin, bone or thyroid cancer; sarcoma, myeloma, glioma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumors, epidermal overgrowth, psoriasis, prostate hyperplasia, Neoplasms, adenomas, adenocarcinomas, rectal adenocarcinomas, colon adenocarcinomas, lung adenocarcinomas, keratinized spinal carcinomas, epidermoid carcinomas, hepatocellular carcinomas, large cell carcinomas, renal cell carcinomas, oligodendroglioma, clear ovarian cells Cancer, ovarian serous cystic adenocarcinoma, non-small cell lung cancer, lymphoma, Hodgkin lymphoma and non-Hodgkin lymphoma, breast cancer, follicular cancer, papillary cancer, sperm epithelioma, melanoma; leukemia, diffuse large B-cell lymphoma (DLBCL) ), Activated B-cell-like DLBCL, Chronic lymphocytic leukemia (CLL), Chronic lymphocytic lymphoma, Primary exudative lymphoma, Berkit lymphoma / leukemia, Acute lymphocytic leukemia, B-precellular lymphocytic leukemia, Hematopoietic cancer selected from lymphoplasmatocyte lymphoma, Waldenstrem macroglobulinemia (WM), splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma and multiple myeloma, blood It is a malignant tumor
(Ii) The blood disorder is sickle cell anemia or β thalassemia.
(Iii) The metabolic disorder is diabetes or obesity,
The pharmaceutical composition for use according to claim 17 . ＰＲＭＴ５によって媒介される疾患または障害の治療のための医薬品の製造における、請求項１～１４のいずれか一項に記載の化合物の使用であって、
前記ＰＲＭＴ５によって媒介される疾患または障害が、癌、血液障害、炎症性疾患、自己免疫疾患、代謝障害、遺伝性障害、ホルモン関連疾患、免疫不全障害、細胞死に関連する状態、骨破壊性疾患、トロンビン誘発血小板凝集、肝疾患、心血管障害またはヘモグロビン症であり、
（ｉ）前記癌が、固形腫瘍、良性または悪性腫瘍、脳、腎臓、肺、肝臓、胃、膣、卵巣、食道、胃腫瘍、乳房、膀胱、結腸、前立腺、膵臓、肺、子宮頸、精巣、皮膚、骨または甲状腺の癌；肉腫、髄芽腫、神経膠芽腫、神経芽細胞腫、多発性骨髄腫、胃腸癌、首と頭の腫瘍、表皮の過剰増殖、乾癬、前立腺過形成、新生物、腺腫、腺癌、直腸腺癌、結腸腺癌、肺腺癌、角化棘細胞腫、類表皮癌、肝細胞癌、大細胞癌、腎細胞癌、乏突起膠腫、卵巣明細胞癌、卵巣漿液性嚢胞腺癌、非小細胞肺癌、リンパ腫、ホジキンリンパ腫および非ホジキンリンパ腫、乳癌、濾胞癌、乳頭癌、精上皮腫、黒色腫；白血病、びまん性大細胞型Ｂ細胞リンパ腫（ＤＬＢＣＬ）、活性化Ｂ細胞様ＤＬＢＣＬ、慢性リンパ球性白血病（ＣＬＬ）、慢性リンパ球性リンパ腫、原発性滲出性リンパ腫、バーキットリンパ腫／白血病、急性リンパ性白血病、Ｂ－細胞前リンパ球性白血病、リンパ形質細胞性リンパ腫、ワルデンストレームマクログロブリン血症（ＷＭ）、脾臓辺縁帯リンパ腫、血管内大細胞型Ｂ細胞リンパ腫、形質細胞腫および多発性骨髄腫から選択される造血器癌、血液悪性腫瘍であり、
（ｉｉ）前記血液障害が、鎌状赤血球貧血またはβサラセミアであり、
（ｉｉｉ）代謝障害が糖尿病または肥満である、使用。 The use of the compound according to any one of claims 1 to 14 in the manufacture of a pharmaceutical product for the treatment of a disease or disorder mediated by PRMT5.
Diseases or disorders mediated by PRMT5 include cancer, blood disorders, inflammatory diseases, autoimmune diseases, metabolic disorders, hereditary disorders, hormone-related diseases, immunodeficiency disorders, cell death-related conditions, bone-destroying diseases, Trombin-induced platelet aggregation, liver disease, cardiovascular disorders or hemoglobinosis,
(I) The cancer is a solid tumor, benign or malignant tumor, brain, kidney, lung, liver, stomach, vagina, ovary, esophagus, gastric tumor, breast, bladder, colon, prostate, pancreas, lung, cervix, testis. , Skin, bone or thyroid cancer; sarcoma, myeloma, glioma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumors, epidermal overgrowth, psoriasis, prostate hyperplasia, Neoplasms, adenomas, adenocarcinomas, rectal adenocarcinomas, colon adenocarcinomas, lung adenocarcinomas, keratinized spinal carcinomas, epidermoid carcinomas, hepatocellular carcinomas, large cell carcinomas, renal cell carcinomas, oligodendroglioma, clear ovarian cells Cancer, ovarian serous cystic adenocarcinoma, non-small cell lung cancer, lymphoma, Hodgkin lymphoma and non-Hodgkin lymphoma, breast cancer, follicular cancer, papillary cancer, sperm epithelioma, melanoma; leukemia, diffuse large B-cell lymphoma (DLBCL) ), Activated B-cell-like DLBCL, Chronic lymphocytic leukemia (CLL), Chronic lymphocytic lymphoma, Primary exudative lymphoma, Berkit lymphoma / leukemia, Acute lymphocytic leukemia, B-precellular lymphocytic leukemia, Hematopoietic cancer selected from lymphoplasmatocyte lymphoma, Waldenstrem macroglobulinemia (WM), splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma and multiple myeloma, blood It is a malignant tumor
(Ii) The blood disorder is sickle cell anemia or β thalassemia.
(Iii) Use, if the metabolic disorder is diabetes or obesity .
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