Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
  • C07D453/06—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention involves an optically active crosslinked piperidine derivative useful as a medicament, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing these, or a bond between menin containing these compositions and MLL.
• the present invention relates to a therapeutic or prophylactic agent for a disease state.
• MLL leukemia is a disease that accounts for about 6-7% of acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL), and about 1,100 people are newly diagnosed with MLL leukemia annually in the United States. It has been reported that the major fusion partner genes causing MLL leukemia are AF9, ELL, ENL, AF10 and AF6 in AML, and AF4, ENL and AF9 in ALL (Non-patent Document 1).
• Non-Patent Document 2 MThe MLL fusion protein fused with the fusion partner gene in this way is presumed to cause unrestricted proliferation of undifferentiated hematopoietic cells and cause leukemia. It has been reported that the MLL fusion protein first binds to menin to form a complex. Therefore, by inhibiting the binding of MLL fusion protein to menin, which is the first step, it is expected that canceration caused by MLL fusion protein will be prevented (Non-Patent Document 3).
• Non-Patent Document 4 menin acts as a coactivator of estrogen signal in breast cancer. Therefore, a low-molecular-weight inhibitor targeting the inhibition of binding between menin and MLL is expected to be useful as a therapeutic agent for the cancer.
• Non-Patent Document 5 menin or MLL is important for tumor growth also in Ewing sarcoma, liver cancer, and p53 gain-of-function mutant cancer. It is expected to be useful as a therapeutic agent against (Non-Patent Document 6).
• Patent Literatures 1 to 4 have been disclosed as low-molecular-weight inhibitors targeted at inhibiting the binding between menin and MLL.
• the compound of the present invention represented by the following formula (1), which is an optically active crosslinked piperidine derivative, is not disclosed or suggested at all.
• the problem to be solved by the present invention is to provide a compound which exerts an antitumor effect by inhibiting the binding of menin to an MLL fusion protein fused with AF4, AF9 or the like which is a typical fusion partner gene causing MLL leukemia. It is to be. More preferably, the purpose is to provide a compound that exhibits an antitumor effect by inhibiting the binding of menin to MLL and has excellent pharmacokinetics. That is, it is to provide an antitumor agent having a high therapeutic effect.
• the present inventors have conducted intensive studies and as a result, a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as “the compound of the present invention”) is menin. It has been found that the compound has a high inhibitory effect on the binding between MLL and MLL, thereby exhibiting an excellent antitumor effect, thereby completing the present invention.
• the present invention is as follows.
• M is, when there are a plurality of them, each independently a C 1-6 alkylene which may be substituted, a C 2-6 alkenylene which may be substituted, a C 2-6 alkynylene which may be substituted, An optionally substituted C 3-10 cycloalkylene, an optionally substituted 3-10 membered saturated heterocyclic group, an optionally substituted C 6-10 arylene or an optionally substituted 5-12 membered Represents heteroarylene, Q is, if there is more than one, each independently C 3-10 cycloalkyl which may be substituted, 3- to 10-membered saturated heterocyclic group which may be substituted, C 6- which may be substituted; Represents 10 aryl or optionally
• R 3 and R 4 each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, —OR 10 , A 10-membered saturated heterocyclic group, a C 6-10 aryl, or a 5- to 12-membered heteroaryl, wherein the alkyl may be substituted by 1 to 3 fluorine atoms;
• Z is the following formula (Z-1): [In the formula, * 3 represents a bond with Y] Represents R 14 represents a hydrogen atom, a halogen atom, —OR 15 , —NR 16 R 17 , cyano, C 1-3 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, R 15 represents C 1-6 alkyl, R 16 and R 17 each independently represent a hydrogen atom or C 1-6 alkyl, wherein when R 16 and R 17 bonded to the same nitrogen atom are both C 1-6 alkyl, Together with the nitrogen atom to which each is attached, they may form a 3- to 8-membered
• M is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-10 cycloalkylene, a 3-10 membered saturated heterocyclic group, C 6-10 arylene or 5-12 membered heteroarylene
• the alkylene, the alkenylene, the alkynylene, the cycloalkylene, the saturated heterocyclic group, the arylene and the heteroarylene are each independently (1) a halogen atom, (2) a hydroxyl group, (3) C 6-10 aryl, (4) 5- to 12-membered heteroaryl, (5) C 1-6 alkyl, (6) C 2-6 alkenyl, (7) C 2-6 alkynyl, (8) C 1-6 alkoxy, (9) C 3-10 cycloalkyl, (10) a 3- to 10-membered saturated heterocyclic group, (11) carboxyl, (12) -COR 21A , (13) —CO 2 R 21A , (14) -CONR 22A
• each independently represents C 1-6 alkyl
• R 22B and R 23B are each independently represent a hydrogen atom or a C 1-6 alkyl, when R 22B or R 23B there are a plurality, each R 22B or R 23B may be the same or different, wherein In the above, when R 22B and R 23B bonded to the same nitrogen atom are both C 1-6 alkyl, they together with the nitrogen atom bonded thereto form a 3- to 8-membered nitrogen-containing saturated heterocycle. May be) Item 7. The compound according to item 1, or a pharmaceutically acceptable salt thereof.
• M is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-10 cycloalkylene, a 3-10 membered saturated heterocyclic group, C 6-10 arylene or 5-12 membered heteroarylene
• the alkylene, the alkenylene, the alkynylene, the cycloalkylene, the saturated heterocyclic group, the arylene and the heteroarylene are each independently (1 ′) a halogen atom, (2 ′) a hydroxyl group, (3 ′) C 1-6 alkyl, (4 ′) C 2-6 alkynyl, (5 ′) C 1-6 alkoxy, (6 ′) C 3-7cycloalkyl , (7 ′) a 3- to 7-membered saturated heterocyclic group, (8 ')-COR 21A , (9 ′) — CO 2 R 21A , (10 ′) — CONR 22A R 23A , (11 ′) — NR
• Q is C 3-10 cycloalkyl, 3-10 membered saturated heterocyclic group, C 6-10 aryl or 5-12 membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, the aryl and the heteroaryl Are, independently of each other, (1) a halogen atom, (2) a hydroxyl group, (3) C 6-10 aryl, (4) 5- to 12-membered heteroaryl, (5) C 1-6 alkyl, (6) C 2-6 alkenyl, (7) C 2-6 alkynyl, (8) C 1-6 alkoxy, (9) C 3-10 cycloalkyl, (10) a 3- to 10-membered saturated heterocyclic group, (11) carboxyl, (12) -COR 21C , (13) —CO 2 R 21C , (14) -CONR 22C R 23C , (15) -NR 22C R 23C , (16) —NR 22C COR 21C , (17) —NR 22C SO 2 R
• R 21D independently represents C 1-6 alkyl when there is more than one
• R 22D and R 23D each independently represent a hydrogen atom or a C 1-6 alkyl
• each of R 22D or R 23D may be the same or different, wherein
• R 22D and R 23D bonded to the same nitrogen atom are both C 1-6 alkyl, they together with the nitrogen atom bonded to each form a 3- to 8-membered nitrogen-containing saturated heterocycle.
• Item 4 The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.
• Q is C 3-10 cycloalkyl, 3-10 membered saturated heterocyclic group, C 6-10 aryl or 5-12 membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, the aryl and the heteroaryl Are, independently of each other, (1 ′) a halogen atom, (2 ′) a hydroxyl group, (3 ′) C 1-6 alkyl, (4 ′) C 2-6 alkynyl, (5 ′) C 1-6 alkoxy, (6 ′) C 3-7cycloalkyl , (7 ′) a 3- to 7-membered saturated heterocyclic group, (8 ′)-COR 21C , (9 ′) — CO 2 R 21C , (10 ′) — CONR 22C R 23C , (11 ′) — NR 22C R 23C , (12 ′) — NR 22C COR 23C , (13 ′) — NR 22C SO 2 R 21C
• Lumpur are each independently a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, -CONR 22E R 23E, -NR 22E R 23E, Substituted by 1 to 5 identical or different substituent (s) selected from the group consisting of -NR 22E COR 21E , -NR 22E SO 2 R 21E , -SO 2 R 21E , -SO 2 NR 22E R 23E and cyano.
• R 21E if there is more than one, each independently represents C 1-6 alkyl; R 22E and R 23E are each independently represent a hydrogen atom or a C 1-6 alkyl, when R 22E or R 23E there are a plurality, each of R 22E or R 23E may be the same or different, wherein In the above, when R 22E and R 23E bonded to the same nitrogen atom are both C 1-6 alkyl, they together with the nitrogen atom bonded thereto form a 3- to 6-membered nitrogen-containing saturated heterocycle. May be) Item 6. The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.
• R 5B and R 6B each independently represent a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, a 3-10 membered saturated heterocyclic group, C 6-10 aryl or 5 to 12 membered heteroaryl (the alkyl, the alkenyl and the alkynyl are each independently a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a C 2-4 alkynyl, a C 1-3 Selected from the group consisting of alkoxy, -CONR 22E R 23E , -NR 22E R 23E , -NR 22E COR 21E , -NR 22E SO 2 R 21E , -SO 2 R 21E , -SO 2 NR 22E R 23E and cyano
• Lumpur are each independently a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 1-3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, -CONR 22E R 23E, -NR 22E R 23E, Substituted by 1 to 5 identical or different substituent (s) selected from the group consisting of -NR 22E COR 21E , -NR 22E SO 2 R 21E , -SO 2 R 21E , -SO 2 NR 22E R 23E and cyano.
• R 21E if there is more than one, each independently represents C 1-6 alkyl; R 22E and R 23E are each independently represent a hydrogen atom or a C 1-6 alkyl, when R 22E or R 23E there are a plurality, each of R 22E or R 23E may be the same or different, wherein In the above, when R 22E and R 23E bonded to the same nitrogen atom are both C 1-6 alkyl, they together with the nitrogen atom bonded thereto form a 3- to 6-membered nitrogen-containing saturated heterocycle. May be) Item 6. The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.
• X is -C (O)-, Item 8.
• Y is (Y-2), Item 10.
• R 14 is a hydrogen atom, —OR 15 , —NR 16 R 17 or C 1-3 alkyl; R 15 is C 1-3 alkyl; When R 16 and R 17 are each independently a hydrogen atom or C 1-3 alkyl, and when R 16 and R 17 bonded to the same nitrogen atom are both C 1-3 alkyl, these are Together with the nitrogen atom to which they are attached, a 3- to 6-membered nitrogen-containing saturated heterocycle may be formed; Item 10.
• R 14 is a hydrogen atom, Item 11.
• U is CR 18 ; R 18 is —CF 3 or cyano; Item 12.
• Aryl (the alkyl is each independently a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C 2-4 alkynyl, C 1-3 alkoxy, -CONR 22E R 23E , -NR 22E R 23E , -NR 22E COR 21E , -NR 22E SO 2 R 21E , -SO 2 R 21E , -SO 2 NR 22E R 23E and may be substituted with the same or different 1 to 3 substituents selected from the group consisting of cyano; the cycloalkyl, saturated heterocyclic group, said aryl and said heteroaryl are each independently a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, C -3 alkyl, C 2-4 alkynyl, C 1-3 alkoxy, -CONR 22E R 23E, -NR 22E R 23E, -NR 22E COR 21E, -NR
• R 21A May form a ring, R 21A , if there is more than one, each independently represents C 1-6 alkyl; R 22A and R 23A each independently represent a hydrogen atom or a C 1-6 alkyl, when R 22A or R 23A is more, each of R 22A or R 23A may be the same or different, wherein In the above, when R 22A and R 23A bonded to the same nitrogen atom are both C 1-6 alkyl, they together with the nitrogen atom bonded thereto form a 3- to 6-membered nitrogen-containing saturated heterocycle.
• R 21C independently represents a C 1-6 alkyl when there is more than one
• R 22C and R 23C are each independently represent a hydrogen atom or a C 1-6 alkyl
• each R 22C or R 23C may be the same or different, wherein
• R 22C and R 23C bonded to the same nitrogen atom are both C 1-6 alkyl, they together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle.
• R 21E May be R 21E , if there is more than one, each independently represents C 1-6 alkyl; R 22E and R 23E are each independently represent a hydrogen atom or a C 1-6 alkyl, when R 22E or R 23E there are a plurality, each of R 22E or R 23E may be the same or different, wherein In the above, when R 22E and R 23E bonded to the same nitrogen atom are both C 1-6 alkyl, they together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle.
• each is independently a C 1-3 alkylene (the alkylene is selected from the group consisting of a fluorine atom, C 2-4 alkynyl, C 1-3 alkoxy, —NR 22A R 23A and cyano which may be substituted with the same or different 1 to 3 substituents)
• the alkylene is selected from the group consisting of a fluorine atom, C 2-4 alkynyl, C 1-3 alkoxy, —NR 22A R 23A and cyano which may be substituted with the same or different 1 to 3 substituents
• each is independently a C 3-6 cycloalkyl, a 3-6 membered saturated heterocyclic group, phenyl or a 5-6 membered heteroaryl (the cycloalkyl, the saturated heterocyclic group, Phenyl and the heteroaryl are each independently a fluorine atom, a chlorine atom, a bromine atom, a C 1-3 alkyl, a C 2-4 alkynyl, a C 1-3 alkoxy, a —CONR 22C R 23C , a —NR 22C R 23C , -NR 22C COR 21C , -NR 22C SO 2 R 21C , -SO 2 R 21C , -SO 2 NR 22C R 23C and the same or different 1 to 5 substituents selected from the group consisting of cyano May be) Item 18.
• Item 18 The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
• each is independently a C 3-6 cycloalkyl, a 3-6 membered saturated heterocyclic group, phenyl or a 5-6 membered heteroaryl (the cycloalkyl, the saturated heterocyclic group,
• the phenyl and the heteroaryl are each independently the same or different 1 to 4 selected from the group consisting of a fluorine atom, C 1-3 alkyl, —NR 22 C SO 2 R 21 C , —SO 2 NR 22 C R 23 C, and cyano. Which may be substituted with 5 substituents).
• Item 20 The compound according to any one of Items 1 to 19 or a pharmaceutically acceptable salt thereof.
• each is independently C 3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C 1-3 alkyl, —NR 22C SO 2 R 21C , —SO 2 NR 22C R 23C and cyano which may be substituted with one or two same or different substituents selected from the group consisting of Item 21.
• R 5A and R 6A are each independently a hydrogen atom, C 1-3 alkyl or C 3-6 cycloalkyl (said alkyl, fluorine atom, -NR 22E SO 2 R 21E, -SO 2 NR 22E R 23E And the same or different 1 or 2 substituents selected from the group consisting of and cyano;
• the cycloalkyl is each independently a fluorine atom, a C 1-3 alkyl, —NR 22ESO 2 R 21E , —SO 2 NR 22 R 23 and cyano, which may be substituted with the same or different one or two substituents) and a plurality of R 5A and R 6A May be such that each of R 5A and R 6A may be the same or different, wherein when R 5A and R 6A are both C 1-3 alkyl, Together with a carbon atom to form a 3- to 6-membered saturated carbocyclic ring; Item 22.
• R 5A and R 6A are each independently hydrogen atom or C 3-6 cycloalkyl (said cycloalkyl, fluorine atom, C 1-3 alkyl, -NR 22E SO 2 R 21E, -SO 2 NR 22E R a 23E and may be substituted by the same or different 1-2 substituents selected from the group consisting of cyano), if R 5A and R 6A have multiple, R 5A and R 6A is also the same May be different, Item 23.
• R 21E May be R 21E , if there is more than one, each independently represents C 1-6 alkyl; R 22E and R 23E are each independently represent a hydrogen atom or a C 1-6 alkyl, when R 22E or R 23E there are a plurality, each of R 22E or R 23E may be the same or different, wherein In the above, when R 22E and R 23E bonded to the same nitrogen atom are both C 1-6 alkyl, they together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle.
• R 3 and R 4 each independently represent a hydrogen atom or a fluorine atom, or R 3 and R 4 may together form OO or CRCR 5A R 6A , R 18 represents —CF 3 or cyano, However, when R 1 and R 2 are both hydrogen atoms, R 3 and R 4 are CRCR 5A R 6A . Or the pharmaceutically acceptable salt thereof.
• R 21E May be R 21E , if there is more than one, each independently represents C 1-6 alkyl; R 22E and R 23E are each independently represent a hydrogen atom or a C 1-6 alkyl, when R 22E or R 23E there are a plurality, each of R 22E or R 23E may be the same or different, wherein In the above, when R 22E and R 23E bonded to the same nitrogen atom are both C 1-6 alkyl, they together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle.
• R 3 and R 4 each independently represent a hydrogen atom or a fluorine atom, or R 3 and R 4 may together form ⁇ O or OCR 5A R 6A , R 18 represents —CF 3 or cyano, However, when R 1 and R 2 are both hydrogen atoms, R 3 and R 4 are CRCR 5A R 6A . Or the pharmaceutically acceptable salt thereof.
• R 1 and R 2 are each independently a hydrogen atom or —MQ; Item 26.
• R 5A and R 6A are each, independently, a hydrogen atom or a C 3-6 cycloalkyl, if R 5A and R 6A have more than one may be the same or different each R 5A and R 6A, Item 30.
• R 5A and R 6A are hydrogen atoms; Item 30.
• R 1 is a hydrogen atom
• R 2 is -MQ
• M is methylene
• Q is C 3-6 cycloalkyl
• R 3 is a hydrogen atom
• R 4 is a hydrogen atom or a fluorine atom
• R 18 is —CF 3 or cyano
• Item 34 The compound according to any one of Items 1 to 28 and 31, or a pharmaceutically acceptable salt thereof.
• R 1 is -MQ
• R 2 is a hydrogen atom
• M is methylene
• Q is C 3-6 cycloalkyl
• R 3 is a hydrogen atom or a fluorine atom
• R 4 is a hydrogen atom
• R 18 is —CF 3 or cyano
• Item 34 The compound according to any one of Items 1 to 28 and 31, or a pharmaceutically acceptable salt thereof.
• R 1 and R 2 are both hydrogen atoms, R 3 and R 4 together form CHCH 2 , R 18 is —CF 3 or cyano; Item 34.
• p is 1, Item 34.
• Item 41 A medicament comprising the compound according to any one of Items 1 to 40 or a pharmaceutically acceptable salt thereof as an active ingredient.
• Item 41 An antitumor agent comprising the compound according to any one of Items 1 to 40 or a pharmaceutically acceptable salt thereof as an active ingredient.
• Tumors include acute leukemia (including MLL acute leukemia, MLL partial tandem acute leukemia, NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia), chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplasia Syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small Cell lung cancer, breast cancer, gastric cancer, gall bladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, villous epithelial cancer, endometrial cancer, cervix Cancer, ovarian cancer, bladder cancer, urothelial cancer, renal cancer, renal cell cancer, prostate cancer, testicular
• Tumors include acute leukemia (including MLL acute leukemia, MLL partial tandem acute leukemia, NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia), chronic myeloid leukemia, malignant lymphoma (B-cell lymphoma).
• the antitumor agent according to Item 42 or 43 which is a myeloma (including multiple myeloma), brain tumor, prostate cancer, breast cancer, neuroblastoma, Ewing sarcoma, or liver cancer.
• the tumor is MLL acute leukemia, MLL partial tandem overlapping leukemia, NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, chronic myelogenous leukemia, B-cell lymphoma, multiple myeloma, neuroblastoma Item 45.
• the antitumor agent according to any one of Items 42 to 44, which is a prostate cancer.
• the tumor is MLL acute leukemia, MLL partial tandem overlapping acute leukemia, NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia, chronic myelogenous leukemia, B-cell lymphoma, or multiple myeloma.
• the antitumor agent according to any one of 42 to 45.
• Item 46 The antitumor agent according to any one of Items 42 to 46, wherein the tumor is MLL acute leukemia or NPM mutant acute leukemia.
• [Item 50] 41 A method for treating a tumor, comprising administering a compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 40 to a patient in need of treatment.
• Item 51 The method according to Item 50, wherein the tumor is a tumor in which Menin-MLL is involved.
• Item 41 The compound according to any one of Items 1 to 40 or a pharmaceutically acceptable salt thereof for use in treating a tumor.
• a pharmaceutical composition comprising the compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof, which is combined with another drug or a pharmaceutically acceptable salt thereof.
• the other drug is an antitumor alkylating agent, an antitumor antimetabolite, an antitumor antibiotic, a plant-derived antitumor agent, an antitumor platinum coordination compound, an antitumor camptothecin derivative, an antitumor Tyrosine kinase inhibitor, antitumor serine threonine kinase inhibitor, antitumor phospholipid kinase inhibitor, antitumor monoclonal antibody, interferon, biological response regulator, hormone preparation, angiogenesis inhibitor, immune checkpoint inhibition Drugs, epigenetics-related molecular inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor agents It is one or more pharmaceutical compositions.
• the other drug is an antitumor alkylating agent, an antitumor antimetabolite, an antitumor antibiotic, a plant-derived antitumor agent, an antitumor platinum coordination compound, an antitumor camptothecin derivative, an antitumor camptothecin derivative, Tumor tyrosine kinase inhibitor, antitumor serine threonine kinase inhibitor, antitumor phospholipid kinase inhibitor, antitumor monoclonal antibody, interferon, biological response regulator, hormone preparation, angiogenesis inhibitor, immune check At least one selected from the group consisting of point inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor agents Is seed or The compound or a pharmaceutically acceptable salt thereof
• a binding inhibitor between menin and a MLL fusion protein comprising an optically active crosslinked piperidine derivative or a pharmaceutically acceptable salt thereof.
• the compound of the present invention is useful as a therapeutic agent for a disease involving the binding of menin to MLL, and specifically, MLL acute leukemia, NPM mutant acute leukemia, prostate cancer, breast cancer, Ewing sarcoma, liver cancer , P53 function-acquired mutation cancer and the like.
• Halogen atom includes, for example, fluorine atom, chlorine atom, bromine atom, iodine atom and the like. Preferably it is a fluorine atom.
• C 1-6 alkyl means alkyl having 1 to 6 carbon atoms
• C 6 alkyl means alkyl having 6 carbon atoms. The same applies to other numbers.
• C 1-6 alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
• preferably “C 1-4 alkyl” is used, and more preferably “C 1-3 alkyl” is used.
• Specific examples of “C 1-3 alkyl” include, for example, methyl, ethyl, propyl, 1-methylethyl and the like.
• Specific examples of “C 1-4 alkyl” include, for example, those exemplified as the specific examples of the above “C 1-3 alkyl”, and butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methyl Propyl and the like.
• C 1-6 alkyl include, in addition to those mentioned as specific examples of the above “C 1-4 alkyl”, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, -Methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like.
• C 2-6 alkenyl means a straight-chain or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds.
• C 2-6 alkenyl includes “C 2-4 alkenyl”.
• Specific examples of “C 2-4 alkenyl” include, for example, vinyl, propenyl, methylpropenyl, butenyl and the like.
• Specific examples of “C 2-6 alkenyl” include, for example, pentenyl, hexenyl and the like, in addition to those mentioned as specific examples of the above “C 2-4 alkenyl”.
• C 2-6 alkynyl means a straight-chain or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one triple bond.
• C 2-6 alkynyl preferably includes “C 2-4 alkynyl”.
• Specific examples of “C 2-4 alkynyl” include, for example, propynyl, methylpropynyl, butynyl and the like.
• Specific examples of “C 2-6 alkynyl” include, for example, methylbutynyl, pentynyl, hexynyl and the like, in addition to those mentioned as specific examples of the above “C 2-4 alkynyl”.
• C 1-6 alkoxy means “C 1-6 alkyloxy”, and the “C 1-6 alkyl” moiety has the same meaning as the above “C 1-6 alkyl”.
• C 1-6 alkoxy preferably includes “C 1-4 alkoxy”, and more preferably “C 1-3 alkoxy”.
• Specific examples of “C 1-3 alkoxy” include, for example, methoxy, ethoxy, propoxy, 1-methylethoxy and the like.
• Specific examples of “C 1-4 alkoxy” include, for example, butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methyl, in addition to those exemplified as the aforementioned “C 1-3 alkyl”. And propoxy.
• C 1-6 alkoxy include, in addition to those mentioned as specific examples of the above “C 1-4 alkyl”, pentoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, -Methylbutoxy, 2-methylbutoxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, hexyloxy and the like.
• C 1-6 alkylene means a straight or branched divalent saturated hydrocarbon group having 1 to 6 carbon atoms.
• C 1-6 alkylene preferably “C 1-4 alkylene” is used, and more preferably “C 1-3 alkylene” is used.
• Specific examples of “C 1-3 alkylene” include, for example, methylene, ethylene, propylene, 1-methylethylene and the like.
• Specific examples of “C 1-4 alkylene” include, for example, butylene, 1,1-dimethylethylene, 1-methylpropylene and 2-methyl, in addition to those exemplified as the aforementioned “C 1-3 alkylene”. Propylene and the like.
• C 1-6 alkylene include, for example, those described above as the specific examples of “C 1-4 alkylene”, pentylene, 1,1-dimethylpropylene, 1,2-dimethylpropylene, -Methylbutylene, 2-methylbutylene, 4-methylpentylene, 3-methylpentylene, 2-methylpentylene, 1-methylpentylene, hexylene and the like.
• C 2-6 alkenylene means a linear or branched divalent unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. I do.
• Preferred examples of “C 2-6 alkenylene” include “C 2-4 alkenylene”.
• Specific examples of “C 2-4 alkenylene” include, for example, vinylene, propenylene, methylpropenylene, butenylene and the like.
• Specific examples of “C 2-6 alkenylene” include, for example, pentenylene, hexenylene and the like, in addition to those mentioned as specific examples of the above “C 2-4 alkenyl”.
• C 2-6 alkynylene means a linear or branched divalent unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 triple bonds.
• Preferred examples of “C 2-6 alkynylene” include “C 2-4 alkynylene”.
• Specific examples of “C 2-4 alkynylene” include, for example, ethynylene, 1-butynylene, 2-pentynylene and the like.
• Specific examples of “C 2-6 alkynylene” include, for example, 2-pentynylene and the like in addition to the specific examples of the above “C 2-4 alkynylene”.
• C 3-10 cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure.
• C 3-10 cycloalkyl is preferably “C 3-7 cycloalkyl”, and more preferably “C 3-6 cycloalkyl”.
• Specific examples of “C 3-6 cycloalkyl” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
• C 3-7 cycloalkyl include, for example, cycloheptyl, in addition to those exemplified as the aforementioned “C 3-6 cycloalkyl”.
• C 3-10 cycloalkyl include, for example, cyclooctyl, cyclononyl, cyclodecyl, adamantyl and the like, in addition to those exemplified as the aforementioned "C 3-7 cycloalkyl”.
• the “C 3-10 cycloalkyl” also includes compounds condensed with an aromatic hydrocarbon ring. Specific examples of the condensed compound include, for example, structures shown below.
• C 3-10 cycloalkylene means a cyclic divalent saturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure.
• C 3-10 cycloalkylene preferably, “C 3-7 cycloalkylene” is used.
• Specific examples of “C 3-7 cycloalkylene” include, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene and the like.
• C 3-10 cycloalkyl include, for example, cyclooctylene, cyclononylene, cyclodecylene, adamantylene and the like, in addition to those mentioned as specific examples of the above “C 3-7 cycloalkyl”.
• “3- to 8-membered saturated carbocycle” means a cyclic saturated hydrocarbon having 3 to 8 carbon atoms.
• the “3- to 8-membered saturated carbocycle” preferably includes a “4- to 6-membered saturated carbocycle”.
• Specific examples of “4- to 6-membered saturated carbocycle” include, for example, cyclobutane ring, cyclopentane ring, cyclohexane ring and the like.
• the “3- to 8-membered saturated carbocycle” include, in addition to those exemplified as the aforementioned “4- to 6-membered saturated carbocycle”, a cyclopropane ring, a cycloheptane ring, and a cyclooctane ring And the like.
• “3- to 10-membered saturated heterocyclic group” is composed of 1 to 2 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and 2 to 9 carbon atoms. Means a monovalent or divalent saturated heterocyclic group to be obtained, and includes those having a partially unsaturated bond and those having a crosslinked structure.
• the atoms constituting the ring may include those oxidized such as —C (O) —, —S (O) —, and —SO 2 —.
• the “3- to 10-membered saturated heterocyclic group” is preferably a “4- to 7-membered monocyclic saturated heterocyclic group”, and more preferably a “5- or 6-membered monocyclic saturated heterocyclic group”. Heterocyclic group ".
• “5- or 6-membered monocyclic saturated heterocyclic group” include, for example, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl , Thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofurylene, pyrrolidinylene, imidazolidinylene , Piperidinylene, morpholinylene, thiomorpholinylene, dioxothiomorpholinylene, hexamethyleneiminylene
• the “4- to 7-membered monocyclic saturated heterocyclic group” for example, in addition to those exemplified as the aforementioned “5- or 6-membered monocyclic saturated heterocyclic group”, oxetanyl, azetidinyl Oxetanylene, azetidinylene and the like.
• the “3- to 10-membered saturated heterocyclic group for example, in addition to those exemplified as the aforementioned “4- to 7-membered monocyclic saturated heterocyclic group”, oxiranyl, aziridinyl, oxiranylene, aziridinylene and the like can be mentioned. Is mentioned.
• the “3- to 10-membered saturated heterocyclic group” includes a 6-membered aromatic hydrocarbon ring or a bicyclic ring in which a condensed ring is formed with a 6-membered aromatic heterocycle.
• Examples of the 6-membered aromatic hydrocarbon ring forming a condensed ring include a benzene ring.
• Examples of the 6-membered aromatic heterocyclic ring forming a condensed ring include pyridine, pyrimidine, pyridazine and the like.
• bicyclic “3- to 10-membered saturated heterocyclic group” forming a condensed ring include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxa Nil, isoindolyl, indazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, dihydroindolinylene, dihydroisoindolinylene, dihydropurinylene, dihydrothiazolopyrimidinylene, dihydrobenzodioxanylene, isoindolin Rylene, indazolylen, tetrahydroquinolinylene, tetrahydroisoquinolinylene, tetrahydronaphthyridinylene and the like can be
• “3- to 8-membered nitrogen-containing saturated heterocycle” means a saturated heterocycle composed of one nitrogen atom and 2 to 7 carbon atoms.
• the “3- to 8-membered nitrogen-containing saturated heterocycle” is preferably “3- to 6-membered nitrogen-containing saturated heterocycle”, and more preferably “4- to 6-membered nitrogen-containing saturated heterocycle”.
• Can be Specific examples of the “4- to 6-membered nitrogen-containing saturated heterocycle” include, for example, an azetidine ring, a pyrrolidine ring, and a piperidine ring.
• Specific examples of the “3- to 6-membered nitrogen-containing saturated heterocycle” include, in addition to the specific examples of the “4- to 6-membered nitrogen-containing saturated heterocycle”, aziridine ring and the like.
• Specific examples of the “3- to 8-membered nitrogen-containing saturated heterocycle” include, for example, those exemplified as the aforementioned “3- to 6-membered nitrogen-containing saturated heterocycle”, and an azepan ring, an azocan ring and the like. No.
• C 6-10 aryl means an aromatic hydrocarbon ring group having 6 to 10 carbon atoms. Specific examples of “C 6-10 aryl” include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like. Preferably, phenyl is used.
• the “C 6-10 aryl” also includes a C 4-6 cycloalkyl or a bicyclic one which forms a condensed ring with a 5- to 6-membered saturated heterocycle. Specific examples of the bicyclic “C 6-10 aryl” forming a condensed ring include the following groups and the like.
• C 6-10 arylene means a divalent aromatic hydrocarbon ring group having 6 to 10 carbon atoms. Specific examples of “C 6-10 arylene” include, for example, phenylene, 1-naphthylene, 2-naphthylene and the like. Preferably, phenylene is used.
• aromatic hydrocarbon ring means a ring part of the above “C 6-10 aryl” and the above “C 6-10 arylene”.
• 5- to 12-membered heteroaryl refers to a monocyclic 5- to 7-membered aromatic containing from 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
• a heterocyclic ring or a bicyclic 8- to 12-membered aromatic heterocyclic ring is meant.
• it is "5- to 7-membered monocyclic heteroaryl”. More preferably, it is pyridyl, pyrimidinyl, quinolyl, or isoquinolyl. More preferably, it is pyridyl.
• 5- to 7-membered monocyclic heteroaryl include, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl , Triazolyl, oxadiazolyl, triazolyl, tetrazolyl and the like.
• “5 to 12-membered heteroaryl” include those exemplified as the aforementioned “5 to 7-membered monocyclic heteroaryl”, indolyl, indazolyl, chromenyl, quinolyl, isoquinolyl, benzofuranyl Benzothienyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzimidazolyl and the like.
• 5- to 12-membered heteroarylene refers to a divalent monocyclic 5- to 7-membered heterocyclic ring containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. It means an aromatic heterocycle or a divalent bicyclic 8- to 12-membered aromatic heterocycle.
• "5- to 7-membered monocyclic heteroarylene” is used. More preferably, it is pyridylene, pyrimidylene, quinolylene, or isoquinolylene. More preferably, it is pyridylene.
• “5- to 7-membered monocyclic heteroarylene” include, for example, pyridylene, pyridazinylene, isothiazolylene, pyrrolylene, furylene, thienylene, thiazolylen, imidazolylene, pyrimidinylene, thiadiazolylene, pyrazolylene, oxazolylene, isoxazolylene, pyrazinylene , Triazinylene, triazolylene, oxadiazolylene, triazolylene, tetrazolylene and the like.
• “5 to 12-membered heteroarylene” include those exemplified as the aforementioned “5 to 7-membered monocyclic heteroarylene”, and indolylene, indazolylene, chromenylene, quinolylene, isoquinolylene, benzofurenylene, benzothienylene Benzooxazolylene, benzothiazolylene, benzoisoxazolylene, benzoisothiazolylene, benzotriazolylene, benzimidazolylene, and the like.
• Aromatic heterocyclic ring means a ring portion of the above “5 to 12 membered heteroaryl” and the above "5 to 12 membered heteroarylene”.
• a bond crossing a ring represented by the following formula (W) means that a “group” is bonded at a substitutable position in the group.
• W When represented by the following formula (W-1), (W-2) or (W-3): It means that
• the stereochemistry of the substituent is illustrated as follows, for example.
• the bond written in a wedge shape represents a substituent on the near side of the paper
• the bond shown by a broken line represents a substituent on the far side of the paper.
• the bond indicated by a wavy line indicates that the substituents on the near side of the paper and the back side of the paper are present at an arbitrary ratio. Represents either one of the substituents.
• “Cancer” or “tumor” means a malignant tumor, and includes cancer, sarcoma, and hematological malignancy.
• Specific examples of “cancer” or “tumor” include, for example, acute leukemia (including MLL acute leukemia, MLL partial tandem overlapping acute leukemia, NPM mutant acute leukemia, MOZ acute leukemia, NUP98 acute leukemia, CALM acute leukemia), Chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma (including B-cell lymphoma), myeloma (including multiple myeloma), brain tumor, head and neck cancer, esophagus Cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, gall bladder / bile duct cancer, liver cancer, hepatocellular cancer, pancreatic cancer, colon cancer, rectal cancer, anal cancer , Vi
• the above-mentioned tumor may be accompanied by an increase in the expression of a specific gene or a mutation.
• tumors with increased gene expression include tumors with high expression of the HOXa gene group, tumors with high expression of the MEIS gene group, and the like.
• examples of a tumor with a gene mutation include a tumor with a p53 gain-of-function mutation.
• One embodiment of p is 1. In addition, one embodiment of p includes 2.
• X is preferably -C (O)-.
• ⁇ Y is preferably (Y-2).
• ⁇ Z is preferably (Z-1).
• M is preferably substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, C 2-4 alkynyl, C 1-3 alkoxy, —NR 22A R 23A and cyano. And C 1-3 alkylene. More preferably, C 1-3 alkylene is used. More preferably, it is methylene.
• Q is preferably 1 to 5 identical or different substituents selected from the group consisting of a fluorine atom, C 1-3 alkyl, —NR 22 C SO 2 R 21 C , —SO 2 NR 22 C R 23 C, and cyano.
• C 3-6 cycloalkyl the same or different 1 selected from the group consisting of a fluorine atom, C 1-3 alkyl, —NR 22C SO 2 R 21C , —SO 2 NR 22CR 23C and cyano to five of may 3-6 membered optionally substituted with a substituent a saturated heterocyclic group; fluorine atom, C 1-3 alkyl, -NR 22C SO 2 R 21C, from -SO 2 NR 22C R 23C and cyano Phenyl optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of: a fluorine atom, C 1-3 alkyl, and —NR 22C S 5- to 6-membered heteroaryl optionally substituted with 1 to 5 identical or different substituent (s) selected from the group consisting of O 2 R 21C , -SO 2 NR 22C R 23C and cyano.
• a and c are preferably 1.
• B and d are preferably 1 or 2. More preferably, b and d are both 1 or 2.
• E, f, g and h are preferably 0 or 1.
• I, j, k and l are preferably 1, 2 or 3.
• R 1 is preferably a hydrogen atom or —MQ. More preferably, it is -MQ.
• R 2 is preferably a hydrogen atom or -MQ. More preferably, it is a hydrogen atom.
• R 3 is preferably a hydrogen atom or a fluorine atom. More preferably, it is a fluorine atom.
• R 4 is preferably a hydrogen atom or a fluorine atom. More preferably, it is a hydrogen atom.
• R 1 , R 2 , R 3 and R 4 is a case where R 1 is a hydrogen atom, R 2 is —MQ, R 3 is a hydrogen atom, and R 4 is a hydrogen atom or a fluorine atom.
• R 1 is a hydrogen atom
• R 2 is —MQ
• R 3 is a hydrogen atom
• R 4 is a hydrogen atom or a fluorine atom.
• R 1 , R 2 , R 3 and R 4 is a case where R 1 is —MQ, R 2 is a hydrogen atom, R 3 is a hydrogen atom or a fluorine atom, and R 4 is a hydrogen atom.
• R 1 is —MQ
• R 2 is a hydrogen atom
• R 3 is a hydrogen atom or a fluorine atom
• R 4 is a hydrogen atom.
• R 5A and R 6A preferably a hydrogen atom or a fluorine atom, C 3-6 cycloalkyl (said cycloalkyl, C 1-3 alkyl, -NR 22E SO 2 R 21E, -SO 2 NR 22E R 23E and cyano which may be substituted with 1 to 2 identical or different substituents selected from the group consisting of More preferably, it is a hydrogen atom.
• R 5B and R 6B are preferably the same or different 1 to 4 selected from the group consisting of a hydrogen atom or a fluorine atom, C 1-3 alkyl, —NR 22E SO 2 R 21E , —SO 2 NR 22E R 23E and cyano.
• C 3-6 cycloalkyl which may be substituted with two substituents is exemplified. More preferably, it is a hydrogen atom.
• R 7 , R 15 , R 21A , R 21B , R 21C , R 21D , and R 21E are preferably C 1-3 alkyl.
• R 8, R 9, R 11 , R 12, R 13, R 16, R 17, R 19, R 20, R 22A, R 22B, R 22C, R 22D, R 22E, R 23A, R 23B, R 23C , R 23D and R 23E are preferably a hydrogen atom or C 1-3 alkyl.
• R 10 is preferably a hydrogen atom.
• R 14 is a hydrogen atom, —OR 15 , —NR 16 R 17 or C 1-3 alkyl. More preferably, it is a hydrogen atom.
• R 18 is preferably a hydrogen atom, a halogen atom, C 1-3 alkyl (the alkyl is substituted with 1 to 5 identical or different substituent (s) selected from a fluorine atom, —OR 19 and —NR 19 R 20 ) ), -CO 2 R 19 , -CONR 19 R 20 or cyano. More preferably, it is —CF 3 or cyano.
• Equation (1) is equation (1b) or equation (1c), p is 1 or 2, R 1 and R 2 each independently represent a hydrogen atom or —MQ, or R 1 and R 2 may together form CRCR 5A R 6A ,
• M is plural, each is independently C 1-3 alkylene;
• Q is plural, each is independently C 3-6 cycloalkyl (the cycloalkyl is a fluorine atom, C 1-3 alkyl, —NR 22C SO 2 R 21C , —SO 2 NR 22C R 23C and cyano
• R 5A and R 6A each independently represent a hydrogen atom, a C 3-6 cycloalkyl (the cycloalkyl is a fluorine atom, a C 1-3 alkyl, —NR 22E SO 2 R 21E , —SO 2
• R 21E is plural, each is independently C 1-6 alkyl;
• R 22E and R 23E are each independently represent a hydrogen atom or a C 1-6 alkyl, when R 22E or R 23E there are a plurality, each of R 22E or R 23E may be the same or different, wherein In the above, when R 22E and R 23E bonded to the same nitrogen atom are both C 1-6 alkyl, they together with the nitrogen atom bonded to each form a 3- to 6-membered nitrogen-containing saturated heterocycle.
• R 3 and R 4 each independently represent a hydrogen atom or a fluorine atom, or R 3 and R 4 may together form OO or CRCR 5A R 6A , R 18 is —CF 3 or cyano, Provided that when R 1 and R 2 are both hydrogen atoms, R 3 and R 4 are CRCR 5A R 6A or a pharmaceutically acceptable salt thereof.
• One embodiment of the compound of the present invention represented by the formula (1) includes the following (C).
• (C) Equation (1) is equation (1b) or equation (1c), p is 1 or 2, R 1 is a hydrogen atom, R 2 is -MQ, M is methylene, Q is C 3-6 cycloalkyl, R 3 is a hydrogen atom, R 4 is a hydrogen atom or a fluorine atom, R 18 is —CF 3 or cyano; A compound or a pharmaceutically acceptable salt thereof.
• One embodiment of the compound of the present invention represented by the formula (1) includes the following (D).
• (D) Equation (1) is equation (1b) or equation (1c), p is 1 or 2, R 1 and R 2 are both hydrogen atoms, R 3 and R 4 together form CHCH 2 , R 18 is —CF 3 or cyano; A compound or a pharmaceutically acceptable salt thereof.
• Equation (1) is equation (1b) or equation (1c), p is 1 or 2, R 1 is -MQ, R 2 is a hydrogen atom, M is methylene, Q is C 3-6 cycloalkyl, R 3 is a hydrogen atom or a fluorine atom, R 4 is a hydrogen atom, R 18 is —CF 3 or cyano; A compound or a pharmaceutically acceptable salt thereof.
• the compound of the present invention can be prepared, for example, by using a known compound as a starting material, for example, the following production methods A, B, C, D, E, F, G, H, I, J, K, L, and M, or a method similar thereto. It can be produced by appropriately combining methods or synthetic methods known to those skilled in the art. In each step, R 1 , R 2 , R 3, and R 4 may be appropriately converted to another substituent by substituent conversion.
• the compound of the present invention represented by the formula (A1) can be produced, for example, by the following method.
• LG 1 represents a leaving group
• P 1 represents amino protection. Means a group.
• the LG for example, a halogen atom, methanesulfonyloxy, p- toluenesulfonic acid oxy, trifluoromethanesulfonic acid oxy, phenoxy, trifluoromethyl phenoxy, tetra-fluorophenoxy, pentafluorophenoxy, and nitrophenoxy like.
• the P for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and the protecting group for amino or the like according to. Further, the stereochemistry of the carbon indicated by * means that it has not been inverted by the reaction. ]
• Compound (a3) is obtained by reacting compound (a1) obtained by the following production method with compound (a2) obtained by the following production method in an appropriate solvent in the presence or absence of an appropriate base. Can be manufactured.
• a compound (B1) obtained by the following production method B or a compound (C1) obtained by the following production method C can be used.
• a compound (D1) obtained by the following production method D or a compound (E1) obtained by the following production method E can be used.
• Examples of the base include triethylamine, diisopropylethylamine, tributylamine, 1.5-diazabicyclo [4.3.0] non-5-ene (DBN), and 1,8-diazabicyclo [5.4.0] undec-7.
• Organic bases such as -ene (DBU), pyridine, 4- (dimethylamino) pyridine, picoline, N-methylmorpholine (NMM), or sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide;
• inorganic bases such as potassium hydroxide.
• Preferred bases include triethylamine, diisopropylethylamine, potassium carbonate, sodium hydroxide and the like.
• the solvent is not particularly limited as long as it does not react under the reaction conditions of this step.
• the solvent include alcohol solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol) and tert-butanol; diethyl ether, diisopropyl Ether solvents such as ether, tetrahydrofuran, methylcyclopentyl ether and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole and xylene; ester solvents such as ethyl acetate and methyl acetate; acetonitrile; Aprotic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide; and mixtures thereof.
• the solvent include 2-propanol, tetrahydrofuran, toluene, acetonitrile, N, N-dimethylformamide and the like.
• the reaction temperature is usually from -80 ° C to heating under reflux, preferably from 25 ° C to 90 ° C.
• the reaction time is generally 30 minutes to 48 hours, preferably 6 to 12 hours.
• the coupling reaction between compound (a1) and compound (a2) may be carried out in the presence of a suitable metal catalyst in a suitable solvent.
• a suitable metal catalyst for example, Ulmann-type conditions (for example, a method of heating and refluxing in an aprotic solvent such as DMF using a metal catalyst such as copper (II) acetate), and Buchwald-type conditions (for example, Inactive to the reaction conditions, such as toluene, using a alkali metal carbonate such as cesium carbonate or the like; BINAP; a palladium catalyst such as Pd 2 (dba) 3 or Pd (OAc) 2 ; and a ligand such as dppf or Xantphos.
• Ulmann-type conditions for example, a method of heating and refluxing in an aprotic solvent such as DMF using a metal catalyst such as copper (II) acetate
• Buchwald-type conditions for example, Inactive to the reaction conditions, such as toluene, using a al
• the solvent is not particularly limited as long as it does not react under the reaction conditions of this step.
• the solvent include alcohol solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol) and tert-butanol; diethyl ether, diisopropyl Ether solvents such as ether, tetrahydrofuran, methylcyclopentyl ether, anisole and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene and xylene; ester solvents such as ethyl acetate and methyl acetate; acetonitrile; An aprotic solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide; water; or a mixture thereof
• the solvent include tetrahydrofuran, toluene, acetonitrile, N, N-dimethylformamide and the like.
• the reaction temperature is usually from -80 ° C to heating under reflux, preferably from 25 ° C to 90 ° C.
• the reaction time is generally 30 minutes to 48 hours, preferably 6 to 12 hours.
• Step 2 Compound (A1) can be produced by removing the protecting group P 1 of the compound (a3). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, written by Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
• the compound represented by the formula (B1) can be produced, for example, by the following method. [Wherein, M 1 represents a hydrogen atom or an ester, R 14 and R 18 have the same meaning as in item 1, and LG 1 has the same meaning as that in Production Method A. ]
• Compound (b1) can be produced by the method described in WO 2014/164543 or the like or a method analogous thereto.
• Compound (b2) can be obtained from Tetrahedron Letters, 49 (48): 6850-6852 (2008), J. Med. Chem., 48 (18): 5794-5804 (2005), Journal of Heterocyclic Chemistry, 28 (8): Compound (b1) can be produced by the method described in 1953-1955 (1991) or a method analogous thereto.
• the compound represented by the formula (C1) can be produced, for example, by the following method. [Wherein, M 2 represents an ester or an amide, R 14 has the same meaning as in item 1, and LG 1 has the same meaning as in Production Method A. ]
• Compound (c1) was prepared according to a method described in WO 2014/164543, WO 2017/112768, J. Med. Chem., ⁇ 59 (3): ⁇ 892-913 ⁇ (2016), or the like. It can be manufactured by a method.
• Step 1 Compound (c2) was prepared from compound (c1) by the method described in WO 2017/112768, J. Med. Chem., 59 (3): 892-913 (2016) or a method analogous thereto. Can be manufactured.
• the compound represented by the formula (D1) can be produced, for example, by the following method.
• LG 2 means a leaving group
• P 1 has the same meaning as in production method A
• P 2 Represents an amino protecting group.
• the LG 2 for example, a halogen atom, a hydroxyl group, and the like.
• the P 2 for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and the protecting group for amino or the like according to. Further, the stereochemistry of the carbon indicated by * means that it has not been inverted by the reaction. ]
• Compound (d1) is available as a commercial product.
• Compound (d3) is produced by reacting compound (d1) with compound (d2) such as carboxylic acid or acid chloride in a suitable solvent in the presence of a suitable condensing agent and / or a suitable base.
• a suitable condensing agent such as carboxylic acid or acid chloride
• a suitable condensing agent such as carboxylic acid or acid chloride
• a suitable condensing agent such as carboxylic acid or acid chloride
• a suitable base include amines such as triethylamine, diisopropylethylamine and pyridine; and alkali metal carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate.
• the base preferably includes triethylamine, diisopropylethylamine or pyridine.
• the condensing agent is appropriately selected from condensing agents commonly used in organic synthetic chemistry, and preferably includes 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole and the like.
• the solvent is not particularly limited as long as it does not react under the reaction conditions of this step, and examples thereof include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, and 1,4-dioxane; benzene, Aromatic hydrocarbon solvents such as toluene, chlorobenzene, anisole, and xylene; ester solvents such as ethyl acetate and methyl acetate; acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone Aprotic solvents such as 1,3-dimethyl-2-imidazolidinone and dimethyl sulfoxide; halogenated hydrocarbon solvents such as dichloromethane (methylene chloride), chloroform and 1,2-dichloroethane; or mixtures thereof.
• ether solvents such as diethyl ether,
• the solvent include tetrahydrofuran, toluene, acetonitrile, N, N-dimethylformamide, dichloromethane and the like.
• the reaction time is generally 5 minutes to 72 hours, preferably 30 minutes to 24 hours.
• the reaction temperature is generally -78 ° C-200 ° C, preferably -78 ° C-80 ° C.
• Compound (D1) can be prepared by removing the protecting group P 2 of the compound (d3). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, written by Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
• the compound represented by the formula (E1) can be produced, for example, by the following method. [Wherein, p, R 1 , R 2 , R 3 , R 4 and Y have the same meanings as in item 1, P 1 has the same meaning as in production method A, and P 2 has the same meaning as in description of production method D. . Further, the stereochemistry of the carbon indicated by * means that it has not been inverted by the reaction. ]
• Compound (e2) can be obtained from J. Am. Chem. Soc., 93 (12): 2897-2904 (1971), J. Org. Chem., 37 (10): 1673-1674 (1972), J. Org. Chem., 61 (11): 3849-3862 (1996), Tetrahedron, 60: 7899-7906 (2004) and the like, or a method analogous thereto, from compound (d1) and compound (e1). be able to.
• Step 2 Compound (E1) can be prepared by removing the protecting group P 2 of the compound (e2). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, written by Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
• Manufacturing method F The compound of the present invention represented by the formula (F1) can be produced, for example, by the following method.
• p, R 1 , R 2 , R 3 , R 4 , R 14 , U and Y have the same meanings as in item 1
• LG 1 has the same meaning as described in Production Method A
• LG 2 has the same meaning as in Production Method A.
• P 1 is the same as that of the production method A
• P 2 is the same as the description of the production method D.
• the stereochemistry of the carbon indicated by * means that it has not been inverted by the reaction.
• Compound (f1) can be produced from compound (a1) and compound (d1) by the method described in Step 1 of Production Method A or a method analogous thereto.
• Compound (f2) can be prepared by removing the protecting group P 2 of the compound (f1). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, written by Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
• Step 3 Compound (f3) can be produced from compound (f2) and compound (d2) by the method described in Step 1 of Production Method D or a method analogous thereto. .
• Step 4 Compound (F1) can be produced by removing the protecting group P 1 of the compound (f3). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, written by Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
• the compound of the present invention represented by the formula (G1) can be produced, for example, by the following method.
• p, R 1 , R 2 , R 3 , R 4 , R 14 , U and Y have the same meanings as in item 1, and P 1 has the same meaning as in the description of Production method A. Further, the stereochemistry of the carbon indicated by * means that it has not been inverted by the reaction. ]
• Compound (g1) can be produced from compound (f2) and compound (e1) by the method described in Step 1 of Production Method E or a method analogous thereto.
• Compound (G1) can be prepared by removal of the protecting group P 1 of the compound (g1). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, written by Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
• the compound represented by the formula (H1) can be produced, for example, by the following method.
• P 1 has the same meaning as described in Production Method A
• P 3 represents a carboxylic acid-protecting group.
• the P 3 for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and the protecting group of a carboxylic acid such as described.
• the stereochemistry of the carbon indicated by * means that it has not been inverted by the reaction.
• Compound (h3) can be obtained by the methods described in Synthetic Communications, 28: 1743-1753 (1998), Chemistry Letters, 6: 875-878 (1983), Journal of Organic Chemistry, 28: 6-16 (1963), or the like. Can be produced from compound (h2) by a method according to
• Compound (H1) may be prepared by removing the protecting group P 3 of the compound (h4). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, written by Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
• the compound represented by the formula (I1) can be produced, for example, by the following method. [Wherein, p and Q have the same meanings as in item 1, P 1 has the same meaning as in the description of the production method A, and P 3 has the same meaning as in the description of the production method H. Further, the stereochemistry of the carbon indicated by * means that it has not been inverted by the reaction. ]
• Compound (i1) is available as a commercial product.
• Step 2 Compound (I1) can be prepared by removing the protecting group P 3 of the compound (h3). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, written by Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
• the compound represented by the formula (J1) can be produced, for example, by the following method.
• p, M and Q have the same meanings as in claim 1
• LG 3 has the same meaning as LG 1 according to the preparation A
• P 1 has the same meaning as described production method A
• P 3 production Synonymous with the description in Law H.
• the stereochemistry of the carbon indicated by * means that it has not been inverted by the reaction.
• Compound (j1) is available as a commercial product.
• Step 2 Compound (J1) can be prepared by removing the protecting group P 3 of the compound (j2). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, written by Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
• the compound of the present invention represented by the formula (A1) can be produced, for example, by the following method. [Wherein, p, R 1 , R 2 , R 3 , R 4 , R 14 , U, X and Y have the same meanings as in item 1, and LG 1 has the same meaning as in Production Method A. Further, the stereochemistry of the carbon indicated by * means that it has not been inverted by the reaction. ]
• Compound (A1) can be produced from compound (a1) and compound (k1) obtained by the following production method by the method described in Step 1 of Production Method A or a method analogous thereto.
• As the compound (k1) a compound (L1) obtained by the following production method L or a compound M1 obtained by the following production method M can be used.
• the compound represented by the formula (L1) can be produced, for example, by the following method. [Wherein, p, R 1 , R 2 , R 3 , R 4 and Y have the same meanings as in item 1, P 1 has the same meaning as in production method A, and LG 2 has the same meaning as in production method D. Further, the stereochemistry of the carbon indicated by * means that it has not been inverted by the reaction. ]
• Compound (11) is commercially available.
• Compound (l2) can be produced from compound (l1) and compound (d2) by the method described in Step 1 of Production Method D or a method analogous thereto.
• Compound (L1) can be prepared by removal of the protecting group P 1 of the compound (l2). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, written by Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
• the compound represented by the formula (M1) can be produced, for example, by the following method. [Wherein, p, R 1 , R 2 , R 3 , R 4 and Y have the same meanings as in item 1, and P 1 has the same meaning as in production method A. Further, the stereochemistry of the carbon indicated by * means that it has not been inverted by the reaction. ]
• Compound (m1) can be produced from compound (l1) and compound (e1) by the method described in Step 1 of Production Method E or a method analogous thereto.
• Compound (M1) can be prepared by removal of the protecting group P 1 of the compound (m1). This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, written by Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999).
• a protecting group can be used as necessary even if the use of the protecting group is not explicitly specified. For example, if any functional group other than the reaction point changes under the described reaction conditions, or it is inappropriate to carry out the described method without a protecting group, the other than the reaction point may be protected as necessary.
• the target compound can be obtained by deprotection after the completion of the reaction or after performing a series of reactions.
• a protecting group described in Protective Groups in Organic Synthesis Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999
• amino-protecting group examples include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like.
• hydroxyl-protecting group examples include, for example, trialkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, benzyl and the like.
• Introduction and elimination of the protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, see Protective Groups in Organic Synthesis described above) or a method analogous thereto.
• protecting groups, condensing agents and the like may be represented by abbreviations of IUPAC-IUB (Biochemical Nomenclature Committee) commonly used in this technical field.
• IUPAC-IUB Biochemical Nomenclature Committee
• the compound names used in the present specification do not always follow the IUPAC nomenclature.
• the intermediate or the target compound in the above-described production method may be appropriately converted into its functional group (for example, the functional group may be protected or deprotected if necessary, and amino, hydroxyl, carbonyl, halogen atom, etc.
• the functional group can be converted by a general method commonly used (for example, see Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999)).
• the intermediates and target compounds in the above-described production methods are isolated by a purification method commonly used in organic synthetic chemistry (eg, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc.). It can be purified. Further, the intermediate can be used for the next reaction without purification.
• a purification method commonly used in organic synthetic chemistry eg, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc.
• “Pharmaceutically acceptable salts” include acid addition salts and base addition salts.
• acid addition salts hydrochlorides, hydrobromides, sulfates, hydroiodates, nitrates, inorganic salts such as phosphates, or citrates, oxalates, phthalates, Fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonic acid
• Organic salts such as salts and camphorsulfonate are exemplified.
• the base addition salt examples include inorganic salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt and aluminum salt, or trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine. , Triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, N, N-dibenzylethylamine and the like.
• the “pharmaceutically acceptable salt” also includes an amino acid salt with a basic amino acid such as arginine, lysine, ornithine, aspartic acid, or glutamic acid or an acidic amino acid.
• Suitable salts of starting materials and intermediates and salts acceptable as pharmaceutical materials are conventional non-toxic salts. These include, for example, organic acid salts (eg, acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonic acid) Salts) and acid addition salts such as inorganic acid salts (eg, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), amino acids (eg, arginine, aspartic acid, glutamic acid, etc.) ), Metal salts such as alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), ammonium salts, and organic base salts (eg, trimethylamine salt, triethylamine salt) Pyridine salts,
• hydrogen atom includes 1 H and 2 H (D), and any one or two or more 1 Hs of the compound represented by the formula (1) is replaced with 2 H (D). Is also included in the compound represented by the formula (1).
• the present invention includes the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
• the compound of the present invention may exist in the form of a hydrate and / or a solvate with various solvents (such as an ethanol solvate), and these hydrates and / or solvates are also present in the present invention. Included in compounds of the invention.
• the compounds of the present invention include optical isomers based on optically active centers, atropisomers based on axial or planar chirality generated by the constraint of intramolecular rotation, other stereoisomers, tautomers, Also included are all possible isomers, such as geometric isomers, and all forms of crystalline forms, as well as mixtures thereof.
• optical isomers and atropisomers can be obtained as racemates or optically active isomers when optically active starting materials or intermediates are used.
• the corresponding raw material, a racemate of the intermediate or final product, a method using an optically active column, by a known separation method such as fractional crystallization They can be physically or chemically separated into their optical antipodes.
• a method for these resolutions for example, a racemate is reacted with an optically active resolving agent to synthesize two diastereomers, and by utilizing the fact that physical properties are different, a diastereomer is separated by a method such as fractional crystallization. Stereomer method and the like can be mentioned.
• a pharmaceutically acceptable salt of the compound of the present invention when it is desired to obtain a pharmaceutically acceptable salt of the compound of the present invention, when the compound represented by the formula (1) is obtained in the form of a pharmaceutically acceptable salt, it can be purified as it is. If it is obtained in a free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or a base may be added to form a salt by a usual method.
• anti-tumor agent examples include, for example, anti-cancer alkylating agents, anti-cancer antimetabolites, anti-cancer antibiotics, plant-derived anti-cancer agents , Anticancer platinum coordination compound, anticancer camptothecin derivative, anticancer tyrosine kinase inhibitor, anticancer serine threonine kinase inhibitor, anticancer phospholipid kinase inhibitor, anticancer At least one selected from the group consisting of monoclonal antibodies, interferons, biological response modifiers, hormone preparations, immune checkpoint inhibitors, epigenetics-related molecular inhibitors, protein post-translational modification inhibitors, and other antitumor agents More than one antitumor agent or a pharmaceutically acceptable salt thereof is mentioned.
• ⁇ anti-tumor agent '' that can be used in combination or in combination include, for example, azacitidine, vorinostat, decitabine, romidepsin, idarubicin, daunorubicin, doxorubicin, enocitabine, cytarabine, mitoxantrone, thioguanine, etoposide, ifosfamide, cyclophosphamido Do, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, melphalan, ranimustine, all-trans retinoic acid, tamivalotene, cisplatin, carboplatin, oxaliplatin, irinotecan, bleomycin, mitomycin C, methotrexate, paclitaxel, docetaxitaxemotexemotexetatexemotexemotexetatexemotexemotexemotexemotexemotexemotexemotexe
• the administration route of the compound of the present invention may be any of oral administration, parenteral administration, rectal administration or ophthalmic administration, and the daily dose varies depending on the type of compound, administration method, symptom / age of the patient, etc. .
• oral administration usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per 1 kg body weight of a human or mammal can be administered in one or several divided doses.
• parenteral administration such as intravenous injection, for example, about 0.01 to 300 mg, more preferably about 1 to 100 mg, per kg body weight of a human or mammal can be administered.
• the compound of the present invention can be formulated and administered by oral administration or parenteral administration, directly or using an appropriate dosage form.
• dosage form include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and cataplasms.
• the preparation is produced by a known method using pharmaceutically acceptable additives.
• excipients can be used as additives, depending on the purpose.
• disintegrants binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners Agents, perfumes and the like.
• additives include, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl Examples include alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.
• THF tetrahydrofuran
• DMF N, N-dimethylformamide
• DMSO dimethylsulfoxide
• MeCN acetonitrile
• Me methyl Et: ethyl Ph: phenyl
• Bn benzyl Boc: tert-butoxycarbonyl n-: normal- tert-: tertiary- p-: para
• BINAP 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl
• Pdba) 3 tris (dibenzylideneacetone) dipalladium (0)
• Ac acetyl dppf: 1,1'-bis (diphenylphosphino) ferrocene
• Xantphos 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene Dess-Martin rea
• NMR (Nuclear Magnetic Resonance) data used for compound identification was obtained by a JNM-ECS400 type nuclear magnetic resonance apparatus (400 MHz) of JEOL Ltd.
• s is a singlet
• d is a doublet
• dd is a doublet of a doublet
• t is a triplet
• td is a doublet of a triplet
• q is a quadruple
• br is a wide
• brs is a wide singlet
• brm is a wide multiplet
• J is a coupling constant.
• Reference Examples 3 to 5 The compounds of Reference Examples 3 to 5 shown in the following table were obtained in the same manner as in Reference Example 2 using the corresponding starting compounds.
• Trifluoroacetic acid 32 mL
• boron trifluoride diethyl ether complex 53 mL
• 1,3-cyclohexadiene 42 mL
• the reaction was warmed to room temperature and stirred overnight.
• a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
• the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution.
• the organic layer was dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure.
• reaction solution is filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (chloroform / methanol) to give the title compound ethyl (1S, 3S, 4S, 5R) -5-hydroxy-2-azabicyclo [ 2.2.2] octane-3-carboxylate (19.0 g) and ethyl (1S, 3S, 4R, 6S) -6-hydroxy-2-azabicyclo [2.2.2] octane-3-carboxylate ( 5.05 g) were each obtained.
• Total 2H, m 2.74-2.60 (total 1H, m), 2.60-2.43 (total 1H, m), 2.34-2.23 (total 1H, m), 1.94-1.54 (total 3H, m), 1.54-1.41 (total 1H, m), 1.41-1.19 (total 9H, m).
• the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate).
• the mixture of the low-polarity stereoisomer of the title compound (9.3 g) and the high-polarity stereoisomer mixture (9.3 g) was obtained. 10.2 g).
• Reference Examples 27 to 51 The compounds of Reference Examples 27 to 51 shown in the following table were obtained in the same manner as in Reference Example 26 using the corresponding starting compounds.
• reaction solution was added with tert-butyl 7-[(1S, 3S, 4S) -2- (tert-butoxycarbonyl) -5-oxo-2-azabicyclo [2.2.2] octane-3-carbonyl] -2, 7-Diazaspiro [3.5] nonane-2-carboxylate (22.5 g) was added, and the mixture was stirred at room temperature for 2 hours.
• Methyl (triphenyl) phosphanium bromide (8.4 g) and potassium tert-butoxide (2.6 g) were added, and the mixture was further stirred at room temperature for 1 hour.
• the reaction solution was concentrated under reduced pressure, diluted with water, and extracted with chloroform.
• the obtained aqueous layer was basified with a 5 mol / L aqueous sodium hydroxide solution and extracted with chloroform.
• the organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered.
• the solvent was distilled off under reduced pressure to obtain the title compound (0.8 g). The obtained compound was used for the next reaction without purification.
• Example 1 To a solution of the compound (80 mg) obtained in Reference Example 27 in dichloromethane (9.0 mL) was added TFA (1.0 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was purified by amine silica gel column chromatography (ethyl acetate / methanol) to obtain Example 1 (47.0 mg).
• Examples 2 to 26 The compounds of Examples 2 to 26 shown in the following table were obtained in the same manner as in Example 1 using the corresponding starting compounds.
• Example 27 [(1S, 3S, 4R) -5-methylidene-2-azabicyclo [2.2.2] octan-3-yl] ⁇ 2- [2- (2,2,2-trifluoroethyl) -5- ( Trifluoromethyl) thieno [2,3-b] pyridin-4-yl] -2,7-diazaspiro [3.5] nonan-7-yl ⁇ methanone
• 2-propanol 2 mL
• N, N-diisopropylethylamine (0.21 mL)
• Example 28 4- ⁇ 7-[(1S, 3S, 4R) -5-methylidene-2-azabicyclo [2.2.2] octane-3-carbonyl] -2,7-diazaspiro [3.5] nonan-2-yl ⁇ -2- (2,2,2-trifluoroethyl) thieno [2,3-b] pyridine-5-carbonitrile
• Example 28 (70 mg) was obtained in the same manner as in Example 27.
• Test example Test Example 1 Menin-MLL binding inhibition experiment Menin 1-615 (hereinafter, His-Menin 1-615 ) having a 6xHis tag and an HA tag inserted at the N-terminus and a myc tag inserted at the C-terminus was subjected to a final concentration of 30 nmol / L.
• Assay buffer 25 mmol / L HEPES, 150 mmol / L NaCl, 1 mmol / L dithiothreitol, 0.5% (w / v) Tween 80, 0.3% (w / v) BSA, 0.3 % (W / v) Skim milk).
• the evaluation compound was diluted with an assay buffer so that the concentration of the evaluation compound was 0.005 to 5 ⁇ mol / L.
• the prepared His-Menin 1-615 was added to a 384-well low-volume plate (Corning, # 4514) for shading at 2 ⁇ L / well and the evaluation compound at 6 ⁇ L / well, and a shading lid (Corning, # 3935) was added. And incubated for 3 hours at room temperature. After the incubation, MLL 1-172 (MLL 1-172- FLAG) having a FLAG tag inserted at the C-terminus was diluted with an assay buffer to a final concentration of 50 nmol / L.
• the prepared MLL 1-172 -FLAG was added at 2 ⁇ L / well to the above plate, covered with a light-shielding lid, and incubated at room temperature for 1 hour.
• an anti-6HIS-d2 antibody cisbio, 61HISDLA
• an anti-FLAGM2-K antibody cisbio, 61FG2KLA
• an antibody dilution buffer 50 mmol / L Tris, 150 mmol / L NaCl
• the prepared antibody mixture was added to the above plate at 10 ⁇ L / well, covered, and incubated at 4 ° C. for 17 to 24 hours. After the incubation, a signal was detected by RUBYstar (BMG LABTECH).
• the binding inhibition rate (%) at each concentration of the evaluation compound was determined using the following formula, and an IC 50 value corresponding to the concentration of the evaluation compound at which the binding inhibition rate was 50% was calculated.
• Binding inhibition rate (%) ⁇ 1- (AC) / (BC) ⁇ ⁇ 100
• Test Example 1 The evaluation results of Test Example 1 are shown in the table below.
• Test Example 2 Cell Growth Inhibition Experiment RS4; 11 cells were obtained from the American Type Culture Collection (ATCC). The cells were cultured in RPMI1640 medium containing 10% fetal bovine serum, 1% penicillin / streptomycin at 37 ° C. in the presence of 5% CO 2 . Separately, MOLM-13 cells were obtained from DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH). The cells were cultured in RPMI 1640 medium containing 20% fetal bovine serum, 1% penicillin / streptomycin at 37 ° C. in the presence of 5% CO 2 .
• 2,000 cells were seeded per well in a 96-well plate, and an evaluation compound was added so that the final concentration of DMSO was 0.1%, followed by culturing for 7 days. After completion of the culture, cell viability was calculated using PrestoBlue (registered trademark) Cell Viability Reagent (Invitrogen, A13261). From the survival rate curve, an IC 50 value corresponding to the concentration of the evaluation compound at which the cell proliferation inhibition rate was 50% was calculated.
• PrestoBlue registered trademark
• Cell Viability Reagent Invitrogen, A13261
• Test Example 2 The evaluation results of Test Example 2 are shown in the table below.
• Examples 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 14, 17, 18, 21, 22, 23, 24, 25, 26, 27 Compounds Nos. And 28 exhibited good cell growth inhibitory effects. Among them, the compounds of Examples 1, 2, 5, 6, 11, 12, 17, 21, 22, 23, 24, 25, 26, 27, and 28 showed particularly strong cell growth inhibition.
• Test Example 3 Test of mRNA transcription control by test substance MV4; 11 cells were obtained from the American Type Culture Collection (ATCC). The cells were cultured in RPMI1640 medium containing 10% fetal bovine serum, 1% penicillin / streptomycin at 37 ° C. in the presence of 5% CO 2 . MV4; 11 cells were added with an evaluation compound at a final concentration of 1 ⁇ mol / L, and cultured at 37 ° C. in the presence of 5% CO 2 for 20 to 24 hours.
• ATCC American Type Culture Collection
• RNeasy registered trademark
• VILO registered trademark
• cDNA Synthesis Kit Invitrogen, # 11754250.
• the amount of cDNA obtained from the RNA obtained from the quantified RNA obtained from the quantified RNA obtained from the cDNA obtained from the Applied Biosystems was obtained using the TaqMan® probe (Applied Biosystems).
• Test Example 3 The evaluation results of Test Example 3 are shown in the table below.
• Test example 4 Pharmacokinetic test A test compound suspended in 0.5% methylcellulose was administered to a 7-week-old male NOD. CB17-Prkdcscid / J mice were orally administered at 100 mg / kg, and blood was collected from the jugular vein under anaesthesia up to 24 hours after administration. The plasma obtained by centrifuging the blood was pretreated by a methanol extraction method, and the concentration of the test compound was quantified using LC-MS / MS. The AUC was calculated by the trapezoidal method from 0 hours after the administration to the time (t) at which the concentration of the test compound in the plasma could be determined. The evaluation results of Test Example 4 are shown in the table below.
• the compound of the present invention can exert an anticancer effect by inhibiting the binding of MLL to a MLL fusion protein.

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