Search

CN-122010910-A - Biazacycloalkane Menin-MLL protein inhibitor, pharmaceutical composition and application thereof

CN122010910ACN 122010910 ACN122010910 ACN 122010910ACN-122010910-A

Abstract

The invention provides biazacycloalkanes shown in formula I and formula II, pharmaceutically acceptable salts, hydrates, isomers, prodrugs or mixtures thereof, pharmaceutical compositions containing the biazacycloalkanes, and application of the biazacycloalkanes in preparing medicines for preventing, relieving or treating related diseases caused by the interaction of a Menin-MLL protein.

Inventors

  • MENG JIANG
  • ZHAO SHUCHUN
  • TANG YUANQING
  • TANG JUN
  • SU ZHONGHAI
  • DING PENG
  • LEI JIANLEI
  • ZHANG YAO
  • Chi Zhexin
  • ZHU YANQING
  • JI SEN
  • ZHOU XIAOXIA
  • ZHANG YI

Assignees

  • 赛诺哈勃药业（成都）有限公司

Dates

Publication Date
20260512
Application Date
20251110
Priority Date
20241111

Claims (19)

  1. 1. A compound of formula I or formula II, a pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof: In formula I or formula II, represents a bond which may be present, i.e Represents a single bond or a double bond; U, Y1, Y2, Y3, Y4 are each independently selected from CR3 or N, and no more than 3 of Y1, Y2, Y3, Y4 are N, and the different positions R3 are the same or different, and R3 may be independently selected from H, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-14 membered aryl, 5-14 membered heteroaryl, -NRsRt, -CONRsRt, -SO2NRsRt, or-NRsSO Rt, wherein Rs, rt are each independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy; ra is Wherein R1, R2 are each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or-ORx wherein Rx is substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or R1, R2 together with the attached nitrogen form a ring; or Ra is Wherein X1, X2, X3, X4 are independently selected from CRd or N, and no more than 3 of X1, X2, X3, X4 are N, the remainder are CRd; rc is- (CR 4R 5) pNR6R7 wherein p is 1 or 2, R4, R5, R6, R7 are independently selected from H or C1-C3 alkyl; Or Rc is Wherein Cy1 is a 3-14 membered, or 3-12 membered, or 3-10 membered alicyclic heterocycle containing the illustrated N atom, the illustrated N atom being spaced 0-2 ring atoms from the ring atom (labeled ". Times.") at the linker end, cy1 being a monocyclic ring, bridged ring, spiro ring or fused ring; In addition to the illustrated N atoms, cy1 may contain 0-3 or 0-2 atoms selected from N, O, S in the backbone atoms; Rb is selected from H, C-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl; In addition to Rb, cy1 may be independently substituted at any possible position with one or more R8, R8 may be selected from oxygen, hydroxy, amino, halogen, cyano, carboxylic acid groups, ester groups, amide groups, sulfonamide groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, C1-C3 alkylamino groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3-8 membered heterocycloalkyl groups, 5-8 membered aryl groups, 5-8 membered heteroaryl groups, or-ORy, wherein Ry is selected from C3-C8 cycloalkyl groups, 3-8 membered heterocycloalkyl groups, 5-8 membered aryl groups, or 5-8 membered heteroaryl groups, R8 may be substituted at any possible position with one or more Rv, which may be selected from hydroxy, amino, halogen, cyano, amide groups, sulfonamide groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, R8 may be the same or different when multiple R8 groups are present; rm, rn are each independently selected from H, halogen, cyano, hydroxy, amino, C1-C6 alkyl, C1-C6 alkoxy, 3-6 cycloalkyl or 3-6 heterocycloalkyl.
  2. 2. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof according to claim 1, Is double bond, U is N or CH, or U is N.
  3. 3. The compound of claim 1 or 2, a pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof, wherein any 2 of Y1, Y2, Y3, Y4 is N and the remainder are CR3, or Y1 and Y2 are N, Y3 and Y4 are CR3, or Y1 and Y3 are N, Y2 and Y4 are CR3, or Y1 and Y4 are N, Y2 and Y3 are CR3, or Y2 and Y3 are N, and Y1 and Y4 are CR3, or Any 1 of Y1, Y2, Y3 and Y4 is N, the rest is CR3, or Y1 is N, Y2, Y3 and Y4 are CR3, or Y2 is N, Y1, Y3 and Y4 are CR3, or Y3 is N, Y1, Y2 and Y4 are CR3, or Y4 is N, Y1, Y2 and Y3 are CR3, or Y1, Y2, Y3 and Y4 are CR3.
  4. 4. A compound according to claim 3, wherein R3 in different positions is the same or different and R3 is independently selected from H, halogen, cyano, hydroxy, amino, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C2-C3 alkenyl, C2-C3 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, -NRsRt, -CONRsRt, -SO2NRsRt, or-NRsSO 2Rt, wherein Rs, rt are each independently selected from H, C-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy, or R3 in different positions is independently selected from H, F, cl, br, I, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2-trifluoroethyl, chloromethoxy, fluoromethoxy, vinyl, prop-1-enyl, prop-2-enyl, ethynyl, prop-1-ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, phenyl, -CONHCH3, -CONHCH2CH3, -SO2NHCH2CH3, -NHSO2CH3, -NCH3SO2CH3 or-NHSO 2CH2CH3.
  5. 5. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof according to claim 1, wherein Ra is Wherein R1, R2 are independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted 3-4 membered heterocycloalkyl, or-ORx, rx is substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted 3-6 membered heterocycloalkyl, or R1, R2 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2-trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl or substituted cyclopropyl, cyclopropoxy, cyclobutyl or substituted cyclobutyl, or R1 is isopropyl, R2 is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, cyclopropyl, cyclobutyl, 3-difluorocyclobutyl.
  6. 6. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof according to claim 1, wherein Ra is Wherein R1, R2 together with the nitrogen to which they are attached form a 3-10 membered alicyclic ring which may be selected from the group consisting of monocyclic or polycyclic rings, which may be fused, spiro or bridged, and which contains from 0 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, in addition to the nitrogen present, or R1, R2 together with the nitrogen to which they are attached form a 3-8 membered alicyclic ring, or R1, R2 together with the nitrogen to which they are attached form a 3-6 membered alicyclic ring, or R1, R2 together with the attached nitrogen form the structure: the alicyclic ring formed by R1, R2 and the attached nitrogen is substituted at any possible position with one or more groups selected from oxygen, hydroxy, amino, carboxy, halogen, cyano, C1-C6 alkyl, C1-C3 alkylamino, C3-C8 cycloalkyl or 3-8 membered heterocycloalkyl.
  7. 7. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof according to any one of claims 1-6, wherein one or more hydrogen atoms in the ring formed by R1, R2 or R1 and R2 are replaced by deuterium atoms.
  8. 8. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof according to claim 1, wherein Ra is Wherein X1, X2, X3, X4 are independently selected from CRd or N, and no more than 3 of X1, X2, X3, X4 are N, the remainder are CRd, rd in different positions are the same or different and may be independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, or Rd in different positions may be independently selected from H, halogen, cyano, C1-C3 alkyl, or Rd may be independently selected from H, fluoro, chloro, bromo, iodo, methyl, ethyl, n-propyl or isopropyl.
  9. 9. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof according to claim 8, wherein one of X1, X2, X3, X4 is N and the others are CRd, or X1 is N, X2, X3, X4 is CRd, or X2 is N, X1, X3, X4 is CRd, or X3 is N, X1, X2, X4 is CRd, or X4 is N, X1, X2, X3 is CRd, or X1 is CRd Two of X1, X2, X3 and X4 are N, the rest are CRa, or X1 and X3 are N, X2 and X4 are CRd, or X1 and X4 are N, X2 and X3 are CRd, or X2 and X4 are N, X1 and X3 are CRd, or X1 and X2 are N, X3 and X4 are CRd, or X1, X2, X3, X4 are CRd, or Ra is substituted or unsubstituted as follows, substituted or unsubstituted with the above condition Rd:
  10. 10. the compound of claim 1, a pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof, characterized in that Rc is Wherein m is 0 or 1, n is 0,1 or 2; T is absent, or T is CR11R12 wherein R11, R12 may be independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl, or R11 and R12 taken together with the attached carbon form a ring; When L is selected from CH2 or CH2CH2, Z is-Q- (CH 2) Q-, Q is 0,1,2 or 3, Q is selected from-NRb, O or S atom, or Q is absent, i.e. Z is- (CH 2) Q-; When L is absent, i.e. Rc is Z is Wherein Q is optionally attached to the alpha carbon atom end or remote from the alpha carbon atom end, Represents an optionally cyclic ring, Q is selected from N, O or S atoms, or Q is absent, i.e. Z is R9, R10 are independently selected from H, C-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl, or R9 and R10 taken together with the attached carbon form a ring; Cy is absent, i.e. Rc is Or Cy is selected from a 3-10 membered alicyclic ring, or said Cy is selected from a 3-6 membered alicyclic ring, and said Cy is optionally substituted with one or more groups selected from oxygen, halogen, cyano, carboxylic acid groups, ester groups, amide groups, amino groups, hydroxyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, or C1-C6 haloalkyl groups; G is selected from O, -OCH 2 -, substituted or unsubstituted alkylene, wherein the substituted alkylene is optionally independently substituted with one or two groups selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl; rb is selected from H, C-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl.
  11. 11. The compound of claim 10, a pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof, characterized in that Rc is Or Rc is Or (b) Rc is selected from a substituted or unsubstituted 3-8 membered monocyclic ring, or Rc is selected from the group consisting of N-heterocyclobutylalkyl, pyrrolidinyl, piperidinyl, azepanyl, azacyclooctyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydroimidazolyl, tetrahydropyridinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl.
  12. 12. The compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt, hydrate, isomer, prodrug or a mixture thereof, characterized in that Rc is selected from the structures:
  13. 13. The compound of claim 12, wherein Rb is selected from H, C-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, 3-6 cycloalkyl, or 3-6 heterocycloalkyl, wherein Rb may be independently substituted at any possible position with a group selected from halo, cyano, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl, or Rb is selected from H, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethyl, chloromethyl, bromomethyl, trifluoromethyl, 2-trifluoroethyl, -CH 2OCH3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  14. 14. The compound, pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof according to any one of claims 1 to 13, wherein Rm, rn are each independently selected from H, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, rm, rn are substituted at possible positions with a group selected from halogen, hydroxy, amino, or Rm is hydrogen, rn is selected from hydrogen, fluoro, chloro, cyano, hydroxy, amino, methyl, methoxy, fluoromethyl, chloromethyl or trifluoromethyl.
  15. 15. A compound, a pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof, selected from the group consisting of:
  16. 16. a pharmaceutical composition comprising a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof, a pharmaceutically acceptable adjuvant and/or carrier.
  17. 17. Use of a compound according to any one of claims 1-15, a pharmaceutically acceptable salt, hydrate, isomer, prodrug or mixture thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for the prevention, alleviation or treatment of a related disorder caused by a messenger-MLL protein interaction.
  18. 18. The use according to claim 17, wherein the disease caused by the interaction of the Menin-MLL protein comprises a malignancy, diabetes or complications associated with said disease, wherein the malignancy comprises a hematological tumor, a lymphoma, a solid tumor.
  19. 19. The use according to claim 18, wherein hematological neoplasms include leukemias and myelomas, including but not limited to acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, acute monocytic leukemia disease, chronic monocytic leukemia, childhood leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, mixed leukemia, hairy cell leukemia, precursor T-cell lymphocytic leukemia, large granular lymphocytic leukemia, meningeal leukemia, myelodysplastic syndrome, myeloproliferative diseases, myeloproliferative neoplasia, plasmacytoma, multiple myeloma; Lymphomas include, but are not limited to, cutaneous T-cell lymphomas, AIDS-related lymphomas, hodgkin's lymphomas, non-hodgkin's lymphomas, or malignant lymphomas; solid tumors include, but are not limited to, pancreatic, colon, rectal, liver, gastric, glioblastoma, lung, breast, and prostate; Such related complications include, but are not limited to, leukemia meningitis.

Description

Biazacycloalkane Menin-MLL protein inhibitor, pharmaceutical composition and application thereof Technical Field The invention relates to a diazacycloalkane type Menin-MLL protein inhibitor, a pharmaceutical composition containing the same, and application of the diazacycloalkane type Menin-MLL protein inhibitor and the pharmaceutical composition in preparing medicines for preventing, relieving or treating related diseases caused by the interaction of the Menin-MLL protein. Background MLL (Mixed Lineage Leukemia) protein is a histone methyltransferase, also known as KMT2A (Histone-lysine N-METHYLTRANSFERASE A). MLL rearrangement (MLL-r) leukemia results from translocation of the 11q23 chromosomal locus containing the gene encoding KMT2A, which is currently known to produce more than 60 oncogenic fusion proteins-fused from the amino terminus of MLL with a variety of different proteins-with the MLL-AF4/9 fusion mutation being the most malignant. MLL-r leukemia accounts for 5% -10% of adult acute leukemia and 70% of infant acute leukemia, and the current treatment schemes are limited, most of the treatment schemes are chemotherapy drugs, and the prognosis is poor and the recurrence is very easy. Menin is a protein mainly located in the nucleus, is encoded by multiple endocrine tumor type I (Multiple Endocrine Neoplasia Type, MEN 1) genes, is an important cofactor of oncogenic MLL-r fusion proteins, and has high affinity with MLL-r proteins. After binding of the Menin to the MLL-r protein, a chromatin modifying enzyme such as Dot1L or pTEFb complex is recruited, resulting in enhanced transcription of genes including HOXA, MEIS1, etc., whose abnormal expression impedes differentiation and promotes proliferation of hematopoietic cells. In vitro and in vivo experiments have shown that the Menin inhibitors disrupt the interaction of Menin with MLL-r and specifically lead to growth inhibition and apoptosis of mutant leukemia cells carrying MLL-r (CANCER CELL, 660-673). The study also found that the Menin inhibitors were also effective against leukemia with NPM1 gene mutations, which account for approximately 20-30% of the cases of acute myelogenous leukemia (Science 367, 586-590). A number of Menin inhibitors are currently being developed for clinical phase 1/2 studies in patients with relapsed/refractory acute leukemia carrying MLL-r or NPM1 mutations, such as KO-539 of SNDX-5613,Kura Oncology from Syndax, and DS-1594b from Japanese first Co (Daichi Sankyo Group). Of 60 patients who could be evaluated in one clinical trial, AUGMENT-101, 53 had responded to the drug, however, after the second treatment cycle, some had developed resistance to SNDX-5613. These drug resistant patients were found to have undergone a mutation in the MEN1 gene resulting in amino acid changes in the Menin proteins M3271, M327V, G331R, G331D, T349M and S160C. These amino acid point mutations located within the binding pocket of the Menin drug interfere with the binding of the drug molecule to the target protein, thereby reducing the affinity of the drug, and importantly, the affinity of these mutant Menin proteins for KMT2A peptides is not greatly affected by structural changes. Studies have shown that the sensitivity of the M327I and T349M point mutated proteins to the reported inhibitors is significantly reduced, thus obtaining significant selection advantages (Nature 615, 913-919). Therefore, it is important to develop inhibitors that bind to both the Menin wild type and the muteins, particularly the M327I and T349M point muteins, which would bring about a cure hope for this part of drug resistant patients. In addition, some researchers have found that some of the existing Menin inhibitors have problems of CYP inhibition, particularly CYP3A4 inhibition and hERG inhibition, which result in potential risks of affecting drug combination and cardiotoxicity, and how to solve the problems at the same time is one of the important points of the research on the Menin inhibitors. Furthermore, too high levels of expression of Menin can lead to a blockage of the beta cell proliferation process, resulting in relatively insufficient insulin secretion. A Menin-MLL inhibitor has been shown to enhance beta cell proliferation, thereby providing potential for use in the field of diabetes. There are currently 1 compound BMF-219 in the form of a phase 2 clinical study of type II diabetes. In conclusion, the Menin-MLL interaction inhibitor has good application prospect as a medicament, and has good clinical requirements for developing the Menin-MLL interaction inhibitor. Disclosure of Invention The present invention provides a compound of formula I, a pharmaceutically acceptable salt, hydrate, isomer (e.g., stereoisomer or tautomer), prodrug or mixture thereof: in formula I, represents a chemical bond that may be present (i.e., Representing a single bond or a double bond). In an embodiment of the present invention in some embodiments,Representing a double bon