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JP-7856636-B2 - Substituted N-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)arylsulfonamide analog as a modulator of cereblon protein

JP7856636B2JP 7856636 B2JP7856636 B2JP 7856636B2JP-7856636-B2

Inventors

  • フィッシャー， マーカス
  • チャン， ユンチャオ
  • ケラマトニア， ファテメ
  • マクゴーワン， ケビン
  • ミン， ジェキ
  • ニシグチ， ジゼル エー．
  • プライス， ジャニーヌ
  • ランコビッチ， ゾラン
  • ダス， スーラヴ
  • マリガン， チャールズ ジー．

Assignees

  • セント ジュード チルドレンズ リサーチ ホスピタル インコーポレイテッド

Dates

Publication Date
20260511
Application Date
20210923
Priority Date
20200923

Claims (20)

  1. A compound having the structure represented by the following formula, or a pharmaceutically acceptable salt thereof. (In the formula, n is an integer selected from 0, 1, and 2. R1 may be a 5- to 10- membered aryl or heteroaryl group which is substituted with a group selected from (a ) halogen, -SF5 , -CN , -N3 , -NH2 , -OH, -CN, -SCF3, C1 - C3 alkoxy, C1 - C3 haloalkyl, C1- C3 aminoalkyl, C1 - C3 alkylamino, C1 - C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3- C8 cycloalkyl, C1 - C6 alkyl, and phenyl, and (b) halogen, -SF5 , -CN, -N3 , -NH2 , -OH, -CN, -SCF3 , C1 - C3 alkoxy, C1 - C3 haloalkyl, C1 -C3 aminoalkyl, C1 - C3 alkylamino, C1 - C (Selected from 5-10 membered cycloalkyl groups, which may be substituted with groups selected from 3- hydroxyalkyl, -O-( C1 - C3 haloalkyl), C3 - C8 cycloalkyl, C1 - C6 alkyl, and phenyl.)
  2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n is an integer selected from 0 and 1.
  3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having a structure represented by the following formula. (In the formula, n is an integer selected from 0, 1, and 2. Each of R11 , R12 , R13 , R14 , and R15 is independently selected from hydrogen, halogens, -SF5 , -CN, -N3 , -NH2 , -OH, -CN, -SCF3 , C1 - C3 alkoxys, C1 - C3 haloalkyls, C1 -C3 aminoalkyls, C1 - C3 alkylaminos, C1 - C3 hydroxyalkyls, -O-( C1 - C3 haloalkyls), C3 - C8 cycloalkyls, C1 - C6 alkyls, and phenyls.
  4. R11 , R12 , R13 , R14 , and R15 are not hydrogen, the compound according to claim 3 or a pharmaceutically acceptable salt thereof.
  5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having a structure represented by the following formula. (In the formula, R1a is selected from bromo, methyl, -CF3 , and -OCF3 . Each of R1b , R1d , and R1e is independently selected from hydrogen, halogen, and methyl. R1c is independently selected from hydrogen, halogen, methyl, and phenyl.
  6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1a is selected from -CF 3 and -OCF 3 .
  7. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R1b , R1c , R1d , and R1e are hydrogen.
  8. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having a structure represented by the following formula.
  9. A compound according to claim 7 or a pharmaceutically acceptable salt thereof having a structure represented by the following formula.
  10. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in claim 1 and a pharmaceutically acceptable carrier.
  11. The pharmaceutical composition according to claim 10, further comprising at least one agent known to treat cancer.
  12. A pharmaceutical composition for treating disorders of uncontrolled cell proliferation in mammals by administration to mammals, A pharmaceutical composition containing at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof in a therapeutically effective amount.
  13. The pharmaceutical composition according to claim 12, wherein the mammal is a mammal that has been diagnosed prior to the administration as requiring treatment for the disorder of uncontrolled cell proliferation.
  14. The pharmaceutical composition according to claim 12, wherein the impairment of uncontrolled cell proliferation is related to cereblon (CRBN) dysfunction.
  15. The pharmaceutical composition according to claim 12, wherein the impairment of uncontrolled cell proliferation is cancer.
  16. The pharmaceutical composition according to claim 15, wherein the cancer is selected from brain cancer, lung cancer, hematological cancer, bladder cancer, colon cancer, cervical cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, peritoneal cancer, breast cancer, gastric cancer, colorectal cancer, prostate cancer, pancreatic cancer, genitourinary tract cancer, lymphatic cancer, stomach cancer, laryngeal cancer, malignant melanoma, colorectal cancer, endometrial cancer, thyroid cancer, rhabdomyosarcoma, liver cancer, and combinations thereof.
  17. The lung cancer is selected from small cell lung cancer, non-small cell lung cancer, and combinations thereof. The aforementioned renal cancer is a clear cell carcinoma of the kidney. The brain cancer is selected from glioblastoma, medulloblastoma, glioma, and combinations thereof. The aforementioned bladder cancer is urothelial carcinoma of the bladder, The aforementioned liver cancer is hepatocellular carcinoma. The aforementioned blood cancers include: pediatric acute leukemia (AL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), large granular lymphocytic leukemia (LGL), acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burket's lymphoma, and Hodgkin's lymphoma. The pharmaceutical composition according to claim 16, selected from lymphoma, non-Hodgkin lymphoma, and combinations thereof.
  18. The pharmaceutical composition according to claim 12, for administration in combination with at least one therapeutically effective dose of an agent known to treat cancer.
  19. The aforementioned at least one drug is uracil mustard, chlormetine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobromane, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozolomide, thiotepa, altretamine, methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabinol Pentostatin, bortezomib, vinblastine, vincristine, vinorelbine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, dexamethasone, clofarabine, cladribine, pemextreced, idarubicin, paclitaxel, docetaxel, ixabepirone, mitramycin, topotecan, irinotecan, deoxycoformycin, mitomycin-C, L-asparaginase, interferon, etoposide Teniposide 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testactone, megestrol acetate, tamoxifen, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremi A pharmaceutical composition according to claim 18, selected from fen, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrin, procarbazine, mitotane, mitoxantrone, levamisol, navelben, anastrazole, letrazole, capecitabine, reloxafine, doroxafine, hexamethylmelamine, oxaliplatin, gefitib, capecitabine, erlotinib, azacitidine, temozolomide, gemcitabine, vasostatin, and combinations thereof.
  20. The pharmaceutical composition according to claim 18, wherein the at least one agent is a DNA methyltransferase inhibitor, an HDAC inhibitor, a glucocorticoid, an mTOR inhibitor, a cytotoxic agent, or a combination thereof.

Description

Detailed description of the invention [0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Application No. 63/082,365, filed on 23 September 2020, which is incorporated in its entirety herein by reference. [background] [0002] Cancer is primarily characterized by an increase in the number of abnormal cells originating from a given normal tissue, invasion of adjacent tissue by these abnormal cells, or lymphatic or blood-borne transmission (metastasis) of malignant cells to regional lymph nodes and distant sites. There is a great need for new methods, treatments, and compositions that can be used to treat patients with cancer. [0003] Proteolysis plays a role in various cellular functions; specifically, the concentration of regulatory proteins is regulated by their breakdown into smaller peptides to maintain cellular health and productivity. Cereblon is a protein that forms an E3 ubiquitin ligase complex, which ubiquitinates various other proteins. Specifically targeting proteolysis offers the intriguing prospect of targeting oncogeneic proteins that are currently untreatable by drug discovery, such as transcription factors and chimeric fusion oncogeneic proteins. [0004] Despite advances in research on the clinical improvement of cancer, there is still a lack of potent, effective, and selective modulators of proteolysis, such as compounds that are potent and selective modulos of cereblon. These and other needs are met by the present disclosure. [overview] [0005] In accordance with the purposes of this disclosure, as embodied and broadly described herein, this disclosure relates in one aspect to a substituted N-(2-(2,6-dioxopiperidinyl-3-yl)-1,3-dioxoisoindorin-5-yl)arylsulfonamide analog useful as a modulator of cereblon (CRBN) activity, a method for producing the same, a pharmaceutical composition comprising the same, and a method for using the same to treat various clinical conditions and disorders, e.g., disorders of uncontrolled cell proliferation, e.g., cancers that may be associated with cereblon protein dysfunction. In various further embodiments, the disclosed compound can act to selectively modulate the degradation of the GSPT1 protein, i.e., the disclosed compound can act as a GSPT1 degrader. In further embodiments, the disclosed compound is shown selectively for GSPT1 degradation by at least 5 times compared to IKZF1 degradation. [0006] Compounds having a structure represented by the following formula: (wherein n is an integer selected from 0, 1, and 2, each of A1 and A2 is independently selected from -(C=O)- and -CH2- , wherein at least one of A1 and A2 is -(C=O)-, and R1 is (a) a 5- to 10-membered aryl or heteroaryl optionally substituted with a group selected from halogens, -SF5, -CN, -N3 , -NH2 , -OH, -CN, -SCF3 , C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, and (b) halogens, -SF5 , -CN, -N3 , -NH2 ) Disclosed are 5- to 10-membered cycloalkyl groups (selected from ,-OH,-CN,-SCF 3 , C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, optionally substituted with a group selected from these) or pharmaceutically acceptable salts thereof. [0007] Compounds having a structure represented by the following formula: (wherein n is an integer selected from 0, 1, and 2, each of A1 and A2 is independently selected from -(C=O)- and -CH2- , wherein at least one of A1 and A2 is -(C=O)-, and R1 is (a) a 5- to 10-membered aryl or heteroaryl optionally substituted with a group selected from halogens, -SF5, -CN, -N3 , -NH2 , -OH, -CN, -SCF3 , C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, and (b) halogens, -SF5 , -CN, -N3 , -NH2 ) Also disclosed are 5-10 membered cycloalkyls (selected from ,-OH,-CN,-SCF 3 , C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 aminoalkyl, C1-C3 alkylamino, C1-C3 hydroxyalkyl, -O-(C1-C3 haloalkyl), C3-C8 cycloalkyl, C1-C6 alkyl, and phenyl, optionally substituted with a group selected from phenyl) or pharmaceutically acceptable salts thereof, provided that the compound has the following structure: (wherein R 20a is selected from bromo, methyl, -CF 3 , and -OCF 3 , and each of R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, halogen, and methyl) or a pharmaceutically acceptable salt thereof, and compounds having a structure represented by the following formula: or not a pharmaceutically acceptable salt thereof. [0008] Compounds having a structure represented by the following formula: (wherein R 1a is selected from bromo, methyl, -CF 3 , and -OCF 3 , and each of R 1b , R 1c , R 1d , and R 1e is independently selected from hydrogen, halogen, and methyl) or pharmaceutically acceptable salts thereof are also disclosed. [