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JP-2026076261-A - Cyclin-dependent kinase inhibitor compounds for treating medical disorders

JP2026076261AJP 2026076261 AJP2026076261 AJP 2026076261AJP-2026076261-A

Abstract

[Problem] To provide novel compounds, methods, compositions, and manufacturing processes for inhibiting undesirable cell cycles in a host, such as a human. [Solution] For example, compounds represented by formula (I), or pharmaceutically acceptable salts, N-oxides, isotopic analogs, and/or pharmaceutically acceptable compositions thereof are provided. This includes selective CDK2 inhibitors for medical treatment, as well as pharmaceutically acceptable salts and compositions thereof. [Selection Diagram] None

Inventors

  • ストラム ジェイ コープランド

Assignees

  • ファーマコスモス ホールディング エー／エス

Dates

Publication Date
20260511
Application Date
20260123
Priority Date
20200519

Claims (20)

  1. formula: (In the formula, X1 , X2 , X3 , X4 , and X5 are independently selected from N, CH, CR2 , and CR4 , such that at least one of X1 , X2 , X3 , X4 , and X5 is CR2 , and two or fewer of X1 , X2 , X3 , X4 , and X5 are N. X11 , X12 , X13 , X14 , and X15 are independently selected from N, CH, CR2 , and CR4 , and two or fewer of X11 , X12 , X13 , X14 , and X15 are selected such that they are N. Each R1 is independently selected from the group consisting of hydrogen, halogen, -OR 14 , NR 14 R 15 , alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, alkyl-hydroxyl, and heterocycle. Two R1s , together with the ring atom to which they are bonded, can optionally constitute a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, or a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocycle having one, two, or three heteroatoms selected from N, O, and S. The cycloalkyl or heterocycle formed by the bonding of two R1s with the atom to which they are bonded may optionally be substituted with one or two substituents independently selected from R 50 . Each R 2 is independently selected from the group consisting of -NR 14 C(O)R 6 , -NR 14 S(O)R 6 , -NR 14 S(O) 2 R 6 , -NR 14 C(S)R 6 , -OC(O)R 6 , -OS(O)R 6 , -OS(O) 2 R 6 , -OC(S)R 6 , -C(O)R 6 , -C(S)R 6 , -S(O)R 6 , -S(=NR 14 ) 2 R 6 , -S(=NR 14 )(O)R 6 and -S(O) 2 R 6 . R3 is selected from the group consisting of hydrogen, -OR 14 , -NR 14 R 15 , alkyl, alkenyl, alkynyl, -C(O)R 6 , -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl , heteroaryl, heterocyclic, -alkyl-aryl, and -alkyl-heteroaryl. Each R4 is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocyclic, halogen, cyano, -OR 14 , -NR 14 R 15 , -NR 14 C(O)R 6 , -NR 14 S(O)R 6 , -NR 14 S(O) 2 R 6 , -NR 14 C(S)R 6 , -OC(O)R 6 , -OS(O)R 6 , -OS(O) 2 R 6 , -OC(S)R 6 , -C(O)R 6 , -C(S)R 6 , -S(O)R 6, and -S( O ) 2 R 6 . R 5 is hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 , or -NR 14 R 15 , Each R6 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl , NR7R7 , and OR7 , and each of the R6s other than hydrogen, NR7R7 , and OR7 is optionally substituted with one, two, three , or four R8 groups. Each R7 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, and each R7 other than hydrogen is optionally substituted with one, two, three, or four R8 groups. Each R 8 is independently selected from the group consisting of hydrogen, halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O) 2alkyl , NR 12 R 13 , alkyl-heteroaryl, alkyl-aryl, and OR 12 . Each R12 and R13 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl , -S(O)alkyl, heteroaryl, alkyl-aryl, cycloalkyl, heterocyclic, and alkyl-heteroaryl. Each R14 and R15 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, -C(O) R6 , -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl , heterocyclic, -alkyl-aryl, and -alkyl-heteroaryl. R17 and R18 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, and each except hydrogen is optionally substituted with 1, 2, 3, or 4 R8 groups. R 19 is hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 , or -NR 14 R 15 , and each R 50 is independently selected from the group consisting of hydrogen, -NR 14 R 15 , OR 14 , and R 4 . Compounds thereof, or pharmaceutically acceptable salts, N-oxides, isotopic analogs thereof, and/or pharmaceutically acceptable compositions thereof.
  2. formula: (In the formula, each R 2 is independently selected from the group consisting of -NR 14 C(O)R 6 , -NR 14 S(O)R 6 , -NR 14 S(O) 2 R 6 , -NR 14 C(S)R 6 , -OC(O)R 6 , -OS(O)R 6 , -OS(O) 2 R 6 , -OC(S)R 6 , -C(O)R 6 , -C(S)R 6 , -S(O)R 6 , and -S(O) 2 R 6 )) A compound according to claim 1, or a pharmaceutically acceptable salt, N-oxide, isotope analog thereof, and/or a pharmaceutically acceptable composition thereof.
  3. formula: The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
  4. The compound according to claim 1, wherein R5 is a hydroxyl group.
  5. formula: The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
  6. The compound according to claim 1, wherein one R1 is hydrogen.
  7. The compound according to claim 1, wherein R1 is always hydrogen.
  8. The compound according to claim 1, wherein R1 is not hydrogen in any of the cases.
  9. formula: The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
  10. formula: The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
  11. formula: The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
  12. formula: The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
  13. The compound according to any one of claims 10 to 12, wherein X 11 is CH.
  14. The compound according to any one of claims 10 to 12, wherein X 11 is N.
  15. The compound according to any one of claims 10 to 12, wherein X 11 is CR 4 .
  16. The compound according to any one of claims 10 to 15, wherein X 12 is CH.
  17. The compound according to any one of claims 10 to 15, wherein X 12 is N.
  18. The compound according to any one of claims 10 to 15, wherein X 12 is CR 4 .
  19. The compound according to any one of claims 10 to 18, wherein X 13 is CH.
  20. The compound according to any one of claims 10 to 18, wherein X 13 is N.

Description

[Cross-reference of related applications] This application claims the interests of U.S. Provisional Patent Application No. 63/027,113, filed on 19 May 2020, and U.S. Provisional Patent Application No. 63/085,672, filed on 30 September 2020. These applications in their entirety constitute part of this specification by reference for all purposes. This invention relates to pyrimidine compounds for the treatment of disorders involving abnormal cell proliferation, including but not limited to the treatment of cancer and tumors. In normal tissues, cell proliferation is generally limited to cells necessary for tissue replenishment. Once cells have differentiated, they acquire specialized functions and no longer divide. Most tissues are composed of non-dividing cells. Thus, normal cell proliferation is strictly controlled to ensure that only necessary cells divide. Furthermore, a delicate balance exists between cell division and programmed cell death (apoptosis). Cell division, sometimes called the cell cycle, consists of four phases: G1 phase (synthesis of various enzymes necessary for DNA replication), S phase (DNA replication resulting in two identical sets of chromosomes), G2 phase (important protein synthesis including microtubule formation), and M phase (nuclear division, cytokinesis, and formation of a new cell membrane). Cell division also involves a complex system of cellular signaling networks that enable cells to interpret information from numerous extracellular signals, including receptor proteins, inflammatory factors, and pro-apoptotic and anti-apoptotic signals. Dysfunction signals include those resulting from gene mutations, infections, exposure to environmental factors including toxins, systemic stress, autoimmune disorders, and inflammation. When the cell proliferation process malfunctions, a variety of disorders can occur, including benign tumors, neoplasms, tumorigenesis, carcinogenesis, autoimmune disorders, inflammatory disorders, graft-versus-host rejection, and fibrous disorders. Numerous broad-spectrum anti-neoplastic agents have been developed. Cytoskeletal agents such as paclitaxel target tubulin to halt mitotic cell division and are used to treat a variety of cancers, including ovarian, breast, lung, pancreatic, and testicular tumors (see, for example, Non-Patent Document 1). Organometallic-based drugs such as cisplatin are used to treat lymphoma, sarcoma, germ cell tumors, and several cancers, including bladder cancer, small cell lung cancer, and ovarian cancer. Cisplatin has the ability to bind nitrogenous bases and induce large-scale DNA crosslinking, ultimately leading to apoptosis (see, for example, Non-Patent Document 2). Intercalation and alkylating agents are also widely used clinically to treat various neoplasms, but the overall toxicity associated with these drugs raises significant concerns for patients requiring long-term therapy. Palbociclib (PD-033299; Ibrance) is marketed by Pfizer in combination with letrozole for the treatment of estrogen-positive HER2-negative breast cancer. This compound inhibits CDK4 and CDK6. The structure of palbociclib is as follows: Abemaciclib (LY2835219) is a CDK4/6 inhibitor currently undergoing human clinical trials as a treatment for various types of cancer. Phase III trials are being conducted for stage IV non-small cell lung cancer, in combination with fulvestrant in women with breast cancer, and as a first-line treatment for breast cancer in combination with either anastrozole or letrozole. The structure of abemaciclib is as follows: Ribociclib (Lee011; Kisqali) is a CDK4/6 inhibitor approved for use in combination with aromatase inhibitors in the treatment of certain metastatic breast cancers, and is currently undergoing clinical trials for the treatment of other specific tumors. The structure of ribociclib is as follows: Lerocyclib is an orally selective CDK4/6 inhibitor currently in clinical development by G1 Therapeutics for use in combination with other targeted therapies in multiple oncological indications. Lerocyclib is currently being evaluated in two Phase 1/2 clinical trials: one in combination with fulvestrant (Faslodex®) in patients with estrogen receptor-positive HER2-negative (ER+, HER2-) breast cancer (NCT02983071), and another in combination with osmirtinib (Tagrisso®) in EGFRm non-small cell lung cancer. Lerocyclib has the following structure: Trilasiclib is a selective CDK4/6 inhibitor being clinically developed by G1 Therapeutics as a first-in-class bone marrow preservation therapy designed to improve the prognosis of patients undergoing chemotherapy by preserving the function of hematopoietic stem cells and progenitor cells (HSPCs) and the immune system. Trilasiclib is a short-acting intravenous CDK4/6 inhibitor administered prior to chemotherapy and is currently being evaluated in four randomized phase 2 clinical trials, including the first-line SCLC trial (NCT02499770) in combination with the etoposide and carboplatin