JPWO2021050915A5

JPWO2021050915A5 -

Info

Publication number: JPWO2021050915A5
Application number: JP2022516295A
Authority: JP
Publication date: 2023-09-13

Claims

a compound of formula (I),

or a pharmaceutically acceptable salt thereof,
During the ceremony,
R ¹ is hydrogen, halogen, hydroxyalkyl, -L-CN, -Y-C1-C5 alkyl, -Y-cycloalkyl, -Y-heterocyclyl, -Y-aryl, -Y-arC1-C3 alkyl, or - Y-heteroaryl, wherein said cycloalkyl, said heterocyclyl, said aryl, and said heteroaryl moiety are each optionally substituted with one or more R ² ,
each Y is independently a bond or -NR ⁴ -;
Each R ² is independently hydroxy, halogen, cyano, cyanomethyl, -(NR ⁴ ) ₂ , hydroxyalkyl, alkoxy, -SO ₂ C1-C3 alkyl, -X-arC1-C3 alkyl, heteroalkyl, C2- C4 alkynyl, -X-haloalkyl, -X-C1-C5 alkyl, -Z-C1-C5 alkyl, heterocyclyl, -XL-cycloalkyl, -Z-cycloalkyl, -X-aryl, -Z-aryl, or -X-heteroaryl, wherein said heterocyclyl, said cycloalkyl, said aryl, and said heteroaryl are optionally substituted with one or more R ⁵ , or each X is independently a bond, O, S, -NR ⁴ - or -NR ⁴ C(O)-,
each Z is independently a bond, -SO-, _-SO2- , -CH(OH)-, or -C(O)-;
each L is independently a bond or C1-C3 alkylene;
R ^3a and R ^3b are each independently hydrogen or deuterium, or R ^3a and R ^3b together are oxo;
each R ⁴ is independently hydrogen or C1-C3 alkyl;
Each R ⁵ is independently substituted with cyano, oxo, halogen, C1-C3 alkyl, hydroxyalkyl, alkoxy, -X-haloalkyl, -Z-cycloalkyl, -X-arC1-C3 alkyl, cyano and
The above compound or a pharmaceutically acceptable salt thereof, wherein R ⁶ is hydrogen, halogen, C1-C3 alkyl, haloalkyl, or alkoxy.

R ¹ is -Y-heteroaryl optionally substituted with one or more R ² ,
Y is a bond, and the heteroaryl is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, triazolyl, oxidazolyl, pyridyl, pyridiazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrazolopyridinyl, 1H-pyrrolopyridyl, pyrazolopyrimidinyl , imidazopyridyl, tetrahydropyrazolopyrazinyl,

,

, oxazolopyridyl, or 5,6-dihydro-8H-imidazooxazinyl, each optionally substituted with one or more ^R2 .

3. A compound according to claim 2 , wherein the heteroaryl is pyrazolyl optionally substituted with 1, 2 or 3 ^R2 groups.

4. A compound according to claim 3 , wherein said pyrazolyl is substituted with one ^R2 .

4. A compound according to claim 3 , wherein said pyrazolyl is substituted with two independently selected ^R2 .

The ^two R groups are (1) independently -t-X-C1-C5 alkyl, (2) -X-C1-C5 alkyl and halogen, (3) -X-C1-C5 alkyl and alkoxy, (4) -X-C1-C5 alkyl and -N(R ⁴ ) ₂ , (5) -X-C1-C5 alkyl and -X-haloalkyl, (6) -X-C1-C5 alkyl and arC1- C3 alkyl, (7) -X-C1-C5 alkyl and -XL-cycloalkyl, (8) -X-C1-C5 alkyl and -heterocyclyl, (9) -X-C1-C5 alkyl, and 1 -X-aryl optionally substituted with the above R ⁵ , (10) -X-C1-C5 alkyl, and -X-heteroaryl optionally substituted with one or more R ⁵ , (11) -X -C1-C5 alkyl and cyanomethyl, (12) -X-C1-C5 alkyl and cyano, (13) cyano and halogen (said halogen is chlorine or fluorine), (14) cyano and -XL-cycloalkyl , (15) independently halogen, (16) cyano and alkoxy (each X is a bond), (17) cyano and -X-aryl, (18) cyano and -X-heteroaryl, (19) cyano and 6. The compound according to claim 5 , which is heterocyclyl, (20) halogen and -X-arC1-C3 alkyl, or X-arC1-C3 alkyl substituted with cyano, and (21) halogen and -X-aryl.

A compound according to claim 1 having the formula (ID),

or a pharmaceutically acceptable salt thereof.

The compound is

, or a pharmaceutically acceptable salt thereof.

The compound is

or a pharmaceutically acceptable salt thereof.

The compound of formula (I) is

The compound according to claim 1, which is

The compound of formula (I) has the formula

2. The compound according to claim 1, which is a pharmaceutically acceptable salt of the compound.

a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 11 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. A pharmaceutical composition comprising:

12. A method for inhibiting PRMT5 activity in a cell, comprising treating said cell in which inhibition of PRMT5 activity is desired with an effective amount of a compound of formula (I) according to any one of claims 1 to 11 , or 13. A method as described above , comprising contacting with a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 12 .

Pharmaceutical composition according to claim 12 for treating cancer.

The cancers include heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas, and teratomas; lung: bronchogenic carcinoma (squamous Epithelial cells, undifferentiated small cells, undifferentiated large cells, adenocarcinoma), alveolar (bronchiolar) cancer, bronchial adenoma, sarcoma, lymphoma, chondrogenic hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous epithelium) cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, bipoma), small intestine (glandular cancer, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract : Kidney (adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), Testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: liver cancer ( hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampullary cancer, cholangiocarcinoma; bone: osteogenic sarcoma (osteosarcoma), Fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma , chondroblastoma, chondromyxofibroma, osteoid, and giant cell tumor; nervous system: cranial (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendrocytoma, Schwann Gynecology: Uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma); spinal neurofibroma, meningioma, glioma, sarcoma); cancer, unclassified carcinoma), granulosa theca, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma) , fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, grape sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); hematology: blood (myeloid leukemia) (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma , basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. 15. The pharmaceutical composition according to 14 .

The pharmaceutical composition according to claim 14 or 15 , wherein the cancer is a MTAP-related cancer.

The pharmaceutical composition according to claim 14 or 15 , wherein the cancer is hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, or head and neck cancer.