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WO2024214019A1 - Composés tétracycliques utilisés en tant que agents de dégradation de smarca2 et/ou de smarca4 - Google Patents

Composés tétracycliques utilisés en tant que agents de dégradation de smarca2 et/ou de smarca4 Download PDF

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Publication number
WO2024214019A1
WO2024214019A1 PCT/IB2024/053500 IB2024053500W WO2024214019A1 WO 2024214019 A1 WO2024214019 A1 WO 2024214019A1 IB 2024053500 W IB2024053500 W IB 2024053500W WO 2024214019 A1 WO2024214019 A1 WO 2024214019A1
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Prior art keywords
cancer
compound
alkyl
formula
independently
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Inventor
Chandrasekhar ABBINENI
Susanta Samajdar
Bilash KUILA
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Aurigene Oncology Ltd
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Aurigene Oncology Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present application relates to tetracyclic compounds and a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof which are useful as SMARCA2 and/or SMARCA4 degraders and, for the treatment of diseases or disorders dependent on SMARCA2 and/or SMARCA4.
  • the present application also relates to a method of preparation of the said tetracyclic compounds and pharmaceutical compositions comprising the said compounds.
  • SWI/SNF SWItch/Sucrose Non- Fermentable chromatin remodelling complex
  • SWI/SNF complexes contain either of two closely related and evolutionarily conserved catalytic ATPase subunits: BRM/SMARCA2) or Brahma-related gene 1 (BRG1/SMARCA4). They share approximately 75% identity at the protein level. Although BRG1- and BRM-containing complexes show some redundancy, they may function distinctively. In human cancer, BRG1 seems to be one of the most frequently mutated subunit genes, whereas the BRM gene is rarely mutated. BRG1/SMARCA4 mutations occurring in ⁇ 10-15% of lung adenocarcinomas. BRM/SMARCA2 is essential for the growth of tumour cells that harbor loss of function mutations in BRG1/SMARCA4. Depletion of BRM in BRG1- deficient cancer cells leads to a cell cycle arrest, induction of senescence and increased levels of global H3K9me31(PNAS February 25, 2014. 111 (8) 3128-3133).
  • SMARCA2/4 synthetic lethal relationship translates in vivo which emphasizes SMARCA2 as a promising therapeutic target for the treatment SMARCA4- deficient cancers.
  • the SMARCA4-deficient patient population generally lacks targetable oncogenes (such as mutant EGFR or ALK translocations), which further emphasizes the potential of developing SMARCA2 inhibitors. Characterization of SMARCA4 function in tumours with high SMARCA4 levels, shows effects on signalling pathways that result in increased proliferation and survival. SMARCA4 knockdown in tumours that show elevated levels known to inhibit proliferation and other cancer cell properties.
  • the ubiquitin-proteasome system is a major pathway that regulates the levels of intracellular proteins and provides a fine balance between protein synthesis and degradation required for normal maintenance of cellular functions, such as proliferation, differentiation and cell death.
  • Ubiquitination is a post-translational modification, where a small protein, ubiquitin, is covalently attached to lysine residues on a substrate protein which is carried out sequentially by a cascade of enzymatic reactions involving an intimate collaboration between El activating, E2 conjugating and E3 ligating enzymes and subsequent degradation of the tagged proteins (J. Biosci. 31(1), March 2006, 137-155; Expert Opin. Ther. Targets. 2013 September; 17(9): 1091-1108 and Cell Research (2016) 26:484-498).
  • Proteolysis targeting chimeras are the heterobifunctional molecules that contain a ligand for a target protein of interest connected via a linker to a ligand for an E3 ubiquitin ligase.
  • the target protein is ubiquitinated and degraded by the proteasome in cells.
  • Many such bi-functional molecules have been developed to recruit E3 ubiquitin ligases to a variety of substrates using high-affinity ligands for the protein of interest.
  • Proteins effectively degraded using these approaches include RIPK2 and ERRa, BRD4, BRD9, BCR/Abl and Abl and Era.(Cell Chemical Biology 25, 1-10, January 18, 2018).
  • E3 ubiquitin ligases (of which over 600 are known in humans) confer substrate specificity for ubiquitination and are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates (Cancer Res. 2017 May 1; 77(9):2476-2487).
  • tetracyclic compounds and pharmaceutical compositions thereof that are useful as SMARCA2 and/or SMARCA4 degraders and for treating diseases or conditions or disorders that are dependent upon or mediated by SMARCA2 and/or SMARCA4.
  • A is phenyl or pyridyl; each R 1 and R 3 independently is halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, amino, halo(C 1 -
  • R 2 is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl or 3- to 8-membered cycloalkyl; wherein the alkyl and cycloalkyl is substituted with 0, 1, 2 or 3 substituents, independently, selected from hydroxy, halogen and alkoxy; ; wherein asterisk mark represents the point of attachment with Q;
  • L 1 and L 3 independently is a bond, (C 1 -C 6 )alkylenyl, 6- to 10-membered arylenyl or 4- to 6-membered heterocycloalkylenyl; wherein the alkylenyl, arylenyl and heterocycloalkylenyl, at each occurrence, independently is substituted with 0, 1, 2, 3 or 4 of R 7 ;
  • L 2 is (C 1 -C 6 )alkylenyl or 4- to 6-membered heterocycloalkylenyl substituted with 0, 1, 2, 3 or 4 ofR 7 ; each R 7 is halogen, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halo(C 1 -C 6 )alkyl;
  • Q is represented by formula Q1, Q2 or Q3:
  • X is a bond, O, -(CO)-NH- or -NH-;
  • X 1 is N or CH; each Z 1 and Z 6 is independently C, CH or N; each Z 2 , Z 3 Z 4 and Z 5 is independently C, CH or N; each R 4 is hydrogen or (C 1 -C 6 )alkyl; each R 5 is hydrogen, halogen, halo(C 1 -C 6 )alkyl or (C 1 -C 6 )alkyl;
  • R 6 and R6’ independently is hydrogen; or R 6 and R 6 ’ together represent an oxo group;
  • ‘n’ and ‘m’ are an integer, independently selected from 0, 1, 2 and 3.
  • the present application relates to the preparation of compound of formula (I).
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof and a pharmaceutically acceptable carrier or an excipient.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating diseases or conditions or disorders that are dependent upon or mediated by SMARCA2 and/or SMARCA4.
  • the present application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating diseases or conditions or disorders that have altered SMARCA2 and/or SMARCA4 including mutations and overexpression.
  • the present application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating diseases or conditions or disorders wherein degradation of SMARCA2 and/or SMARCA4 proteins provide a benefit, e.g., cancer.
  • the present application provides a composition of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating diseases or conditions or disorders that are dependent upon altered activity of SWI/SNF complex with or without chromatic remodeling activities.
  • the present application provides methods of treating a condition or a disease or a disorder by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof to an individual, e.g., a human, in need thereof.
  • the conditions or diseases or disorders of interest is treatable by degradation of SMARCA2 and/or SMARCA4, for example, a cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis or a viral infection.
  • the present application provides a use of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for the manufacture of a medicament for treating a disease or a condition or a disorder of interest, e.g., cancer.
  • the present invention provides tetracyclic compounds, referred as a compound of formula (I), which are useful as SMARCA2 and/or SMARCA4 degraders and for the treatment of conditions dependent on or mediated by SMARCA2 and/or SMARCA4.
  • the present invention further provides pharmaceutical compositions comprising the said compound or a stereoisomer or a tautomer thereof as therapeutic agents.
  • the present invention provides compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein,
  • A is phenyl or pyridyl; each R 1 and R 3 independently is halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, amino, halo(Ci- Ce)alkyl, hydroxy, 3- to 8-membered cycloalkyl, hydroxy (C 1 -C 6 )alkyl or cyano;
  • R 2 is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl or 3- to 8-membered cycloalkyl; wherein the alkyl and cycloalkyl is substituted with 0, 1, 2 or 3 substituents, independently, selected from hydroxy, halogen and alkoxy; ; wherein asterisk mark represents the point of attachment with Q;
  • L 1 and L 3 independently is a bond, (C 1 -C 6 )alkylenyl, 6- to 10-membered arylenyl or 4- to 6-membered heterocycloalkyl enyl; wherein the alkylenyl, arylenyl and heterocycloalkylenyl, at each occurrence, independently is substituted with 0, 1, 2, 3 or 4 of R 7 ;
  • L 2 is (C 1 -C 6 )alkylenyl or 4- to 6-membered heterocycloalkylenyl substituted with 0, 1, 2, 3 or 4 R 7 ; each R 7 is halogen, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halo(C 1 -C 6 )alkyl;
  • Q is represented by formula Q1, Q2 or Q3: wherein,
  • X is a bond, O, -(CO)-NH- or -NH-;
  • X 1 is N or CH; each Z 1 and Z 6 is independently C, CH or N; each Z 2 , Z 3 Z 4 and Z 5 is independently C, CH or N; each R 4 is hydrogen or (C 1 -C 6 )alkyl; each R 5 is hydrogen, halogen, halo(C 1 -C 6 )alkyl or (C 1 -C 6 )alkyl;
  • R 6 and R 6 ’ independently is hydrogen; or R 6 and R 6 ’ together represent an oxo group;
  • ‘n’ and ‘m’ are an integer, independently selected from 0, 1, 2 and 3.
  • A is phenyl
  • A is pyridyl
  • R 1 and R 3 independently is halogen, (C 1 -C 6 )alkyl, (Ci-C 6 )alkoxy, amino, halo(C 1 -C 6 )alkyl, 3- to 8-membered cycloalkyl, or hydroxy.
  • R 1 and R 3 independently is halogen, (C 1 -C 6 )alkyl, (Ci-C 6 )alkoxy, halo(C 1 -C 6 )alkyl, amino or hydroxy.
  • R 1 and R 3 independently is halogen, amino or hydroxy.
  • R 1 and R 3 independently is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halo(C 1 - C 6 )alkyl.
  • R 1 and R 3 independently is selected from -Cl, -Br, -CH 3 , -CH 2 - CH 3 , -CH(CH 3 )-CH 3 , -CF 2 , -CF 3 , -O-CH 2 -CH 3 , -O-CH(CH 3 )-CH 3 and -NH 2 .
  • R 1 and R 3 independently is selected from cyclopropyl, cyclobutyl and cyclopentyl.
  • R 1 is -Br, -Cl, -OH or -NH 2 .
  • R 3 is -Br, -Cl, -OH or -NH 2 .
  • L is ; wherein asterisk mark represents the point of attachment with Q.
  • L 1 is a bond, 6- to 10-membered arylenyl or 4- to 6-membered heterocycloalkylenyl; wherein arylenyl and heterocycloalkylenyl, at each occurrence, independently is substituted with 0, 1, 2, 3 or 4 of R 7 .
  • L 1 is a bond
  • L 1 is a bond, phenylenyl or 4- to 6-membered heterocycloalkylenyl; wherein phenylenyl and heterocycloalkylenyl, at each occurrence, independently is substituted with 0, 1, 2, 3 or 4 of R 7 ;
  • L 2 is -CH 2 - or 4- to 6-membered heterocycloalkylenyl substituted with 0, 1, 2, 3 or 4 of R 7 ;
  • L 3 is a bond, (C 1 -C 6 )alkylenyl or 4- to 6-membered heterocycloalkylenyl; wherein the alkylenyl, and the heterocycloalkylenyl, at each occurrence, is substituted with 0, 1, 2, 3 or 4 R 7 .
  • L 3 is a bond or 4- to 6-membered heterocycloalkylenyl.
  • L 3 is a bond
  • L 3 is a bond or (C 1 -C 6 )alkylenyl; wherein the alkylenyl, at each occurrence, is substituted with 0, 1, 2, 3 or 4 R 7 .
  • L 3 is 4- to 6-membered heterocycloalkylenyl.
  • L 2 is (C 1 -C 6 )alkylenyl or 4- to 6-membered heterocycloalkylenyl, which is substituted with 0, 1, 2, 3 or 4 of R 7 .
  • L 2 is -CH 2 - or 4- to 6-membered heterocycloalkylenyl, which is substituted with 0, 1, 2, 3 or 4 of R 7 .
  • L 2 is 4- to 6-membered heterocycloalkylenyl, which is substituted with 0, 1, 2, 3 or 4 of R 7 .
  • L 2 is (C 1 -C 6 )alkylenyl.
  • L 2 is -CH 2 -. In one embodiment, L 2 is 6-membered heterocycloalkylenyl, which is substituted with 0, 1 or 2 ofR 7 .
  • L 2 is attached to Q, if L 3 is bond.
  • 4- to 6-membered heterocycloalkylenyl is selected from azetidinylenyl, pyrrolidinylenyl, piperidinylenyl, piperazinylenyl, tetrahydropyranylenyl, morpholinylenyl, thiomorpholinylenyl, 1,4-dioxanylenyl and tetrahydropyranylenyl .
  • L 1 , L 2 and L 3 are independently 4- to 6-membered heterocycloalkylenyl, wherein heterocycloalkylenyl is selected from piperidinylenyl and piperazinylenyl.
  • L 1 is a bond or a group selected from and
  • L 2 is selected from
  • L 3 is a bond or a group selected from -CH 2 -, -CH 2 -CH 2 -, -
  • L 1 and L 3 independently is a bond.
  • R 5 is hydrogen
  • R 4 is hydrogen or (C 1 -C 6 )alkyl.
  • Q is represented by formula QI : wherein
  • R 5 is hydrogen
  • R 6 and R 6 ’ independently is hydrogen; or R 6 and R 6 ’ together represent an oxo group; and R 4 is hydrogen or (C 1 -C 6 )alkyl.
  • Q is represented by formula Q2: wherein
  • X is a bond, -O-, -(CO)-NH- or -NH-;
  • X 1 is N or CH
  • R 5 is hydrogen or halogen
  • R 4 is hydrogen or (C 1 -C 6 )alkyl.
  • Q is represented by formula Q3:
  • R 4 is hydrogen or (C 1 -C 6 )alkyl; R 5 is hydrogen or halogen; each Z 1 and Z 6 is independently C or N; and each Z 2 , Z 3 Z 4 and Z 5 is independently C or N; wherein at least one of Z 3 and Z 4 is C.
  • R 6 and R 6 ’ independently is hydrogen.
  • R 6 and R 6 ’ together represent an oxo group.
  • R 4 is hydrogen. In one embodiment, X is a bond.
  • X is -O-, -(CO)-NH- or -NH-.
  • X 1 is CH.
  • ‘n’ is an integer selected from 0, 1, 2 and 3.
  • ‘m’ is an integer selected from 0, 1, 2 and 3. In one embodiment, ‘n’ is an integer selected from 0, 1 and 2.
  • ‘m’ is an integer selected from 0, 1 and 2.
  • n is an integer selected from 0 and 1.
  • ‘m’ is an integer selected from 0 and 1.
  • A is phenyl or pyridyl; each R 1 and R 3 independently is selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, amino and hydroxy;
  • R 2 is hydrogen, -CH 3 , -CH(CH 3 )2, cyclopropyl, cyclobutyl or cyclopentyl; ; wherein asterisk mark represents the point of attachment with Q; wherein L 1 , if present, is attached to fused phenyl ring and L 3 , if present, is attached to Q;
  • L 1 is a bond, phenylenyl or 4- to 6-membered heterocycloalkylenyl; wherein phenylenyl and heterocycloalkylenyl, at each occurrence, independently is substituted with 0, 1, 2, 3 or 4 ofR 7 ;
  • L 3 is a bond, alkylenyl or 4- to 6-membered heterocycloalkylenyl; wherein the alkylenyl, and the heterocycloalkylenyl, at each occurrence, is substituted with 0, 1, 2, 3 or 4 ofR 7 ; each R 5 is hydrogen, halogen, halo(C 1 -C 6 )alkyl or (C 1 -C 6 )alkyl; and each R 4 is hydrogen or (C 1 -C 6 )alkyl.
  • A is phenyl or pyridyl;
  • R 1 and R 3 independently is selected from -Cl, -Br, -CH 3 , -CH 2 -CH 3 , -CH(CH 3 )-CH 3 , - CF 2 , -CF 3 , -O-CH 2 -CH 3 , -O-CH(CH 3 )-CH 3 , -OH and -NH 2
  • L is selected from -piperazinylenyl-, -piperazinylenyl-azitidinylenyl-, -piperidinylenyl- piperidinylenyl-, -piperidinylenyl-piperazinylenyl-, -piperidinylenyl-piperidinylenyl-piperidinylenyl- piperidinylenyl-, -piperazinylenyl-alkylenyl-, -phenylenyl-piperidinylenyl-, -phenylenyl- piperazinylenyl-alkylenyl-, -phenylenyl-piperidinylenyl-alkylenyl- and -piperidinylenyl- piperazinylenyl-alkylenyl-; wherein each group is substituted with 0, 1 or 2 substituents selected
  • A is phenyl or pyridyl; wherein each ring is substituted with 0, 1 or 2 R 1 group(s);
  • R 1 and R 3 independently is selected from -Cl, -Br, -CH 3 , -CH 2 -CH 3 , -CH(CH 3 )-CH 3 , - CF 2 , -CF 3 , -O-CH 2 -CH 3 , -O-CH(CH 3 )-CH 3 , -OH and -NH 2 ;
  • R 2 is hydrogen, -CH 3 , -CH(CH 3 )2, cyclopropyl, cyclobutyl or cyclopentyl;
  • the present invention provides compound of formula (IA) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof: wherein R 1 , R 2 , R 3 , L 1 , L 2 , L 3 , Q and n are as defined in compound of formula (I).
  • R 1 and R 3 independently is selected from -CH 3 , -CH 2 -CH 3 , -CF 2 and -CF 3 .
  • L 1 is a bond, phenylenyl or 4- to 6-membered heterocycloalkylenyl;
  • L 2 is -CH 2 - or 4- to 6-membered heterocycloalkylenyl
  • L 3 is a bond, (C 1 -C 6 )alkylenyl or 4- to 6-membered heterocycloalkylenyl.
  • L 1 is a bond
  • L 1 is a bond or a group selected from
  • L 1 is a bond or a group selected from
  • L 2 is selected from
  • L 3 is selected from -CH 2 -, -CH 2 -
  • L 3 is selected from -CH 2 -, -CH 2 - CH 2 - and -CH(CH 3 )-CH 2 -.
  • the present invention provides the compound of formula (IA) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein R 1 and R 3 independently is halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, amino, cyclopropyl, cyclobutyl, cyclopentyl or hydroxy; R 2 is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl or 3- to 8-membered cycloalkyl;
  • L 1 is a bond, phenylenyl or 4- to 6-membered heterocycloalkylenyl;
  • L 2 is -CH 2 - or 4- to 6-membered heterocycloalkylenyl
  • L 3 is a bond, (C 1 -C 6 )alkylenyl or 4- to 6-membered heterocycloalkylenyl
  • each R 4 is (C 1 -C 6 ) alkyl or hydrogen; and each R 5 is (C 1 -C 6 )alkyl or hydrogen;
  • R 1 and R 3 independently is selected from -Br, -Cl, -CH 3 , -CH 2 -CH 3 , -CH(CH 3 )-CH 3 , -O-CH 3 , -O-CH 2 -CH 3 , -O-CH(CH 3 )-CH 3 , - OH, -CF 3 , -CF 2 and -NH 2 ;
  • R 2 is hydrogen, -CH 3 , -CH(CH 3 )2, cyclopropyl, cyclobutyl or cyclopentyl;
  • n is an integer selected from 0, 1, 2 and 3.
  • the present invention provides compound of formula (IB) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof: wherein Y 1 and Y 2 independently is CH or N;
  • L 1 is a bond, phenylenyl or heterocycloalkylenyl
  • L 3 is a bond, (C 1 -C 6 )alkylenyl or heterocycloalkylenyl; and R 1 , R 2 , Q and n are as defined in compound of formula (I)
  • A is phenyl or pyridyl.
  • A is phenyl, which is substituted with halogen, (C 1 -C 4 )alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkyl, amino or hydroxy.
  • R 1 is halogen, (C 1 -C 6 )alkyl, (C 1 - C 6 )alkoxy, amino, halo (C 1 -C 6 )alkyl or hydroxy.
  • R 1 is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halo(C 1 -C 6 )alkyl.
  • R 1 is halogen, amino or hydroxy.
  • R 1 is selected from -Br, -Cl, -CH 3 , - CH 2 -CH 3 , -CH(CH 3 )-CH 3 , -CF 2 , -CF 3 , -O-CH 3 , -O-CH 2 -CH 3 , -O-CH(CH 3 )-CH 3 , -OH and -
  • R 2 is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl or 3- to 8-membered cycloalkyl.
  • R 2 is (C 1 -C 6 )alkyl or 3- to 8- membered cycloalkyl.
  • R 2 is hydrogen, -CH 3 , -CH(CH 3 )2, cyclopropyl, cyclobutyl or cyclopentyl.
  • L 1 is a bond or a group selected from
  • L 1 is a bond
  • L 1 is
  • L 3 is a bond or a group selected from
  • L 3 is a bond or a group selected from -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -.
  • n is an integer selected from 0, 1 and 2. ; wherein each R 1 is selected from -Cl, -Br, -CH 3 , -CF 2 , -CF 3 , -O-CH 3 , -
  • each R 2 is hydrogen, -CH 3 , -CH(CH 3 ) 2 , cyclopropyl, cyclobutyl or cyclopentyl.
  • Y 1 is CH or N. In one embodiment of compound of formula (IB), Y 1 is N.
  • Y 2 is CH.
  • Q represents In one embodiment, the present invention provides compound of formula (IB) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein
  • A is phenyl or pyridyl; each R 1 is halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, amino or hydroxy;
  • Y 1 and Y 2 independently is CH or N;
  • R 2 is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl or 3- to 8-membered cycloalkyl;
  • Y 1 and Y 2 independently is CH or N;
  • L 3 is (C 1 -C 6 )alkylenyl or 6-membered heterocycloalkylenyl; and R 1 , R 2 , R 4 , R 5 , R 6 and R 6 ’ are as defined in compound of formula (I).
  • Y 1 and Y 2 independently is CH or N.
  • Y 2 is CH or N.
  • Y 1 is N.
  • R 2 is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl or 3- to 8-membered cycloalkyl.
  • R 1 is selected from -Cl, -Br, -CH 3 , - CF 2 , -CF 3 , -0-CH 3 , -O-CH 2 -CH 3 , -O-CH(CH 3 )-CH 3 , -OH and -NH 2 .
  • R 1 is selected from -Br, -Cl, -NH2, - CH 3 , -OCH 3 , -OH and -CF 3 .
  • R 2 is hydrogen, -CH 3 , -CH(CH 3 )2, cyclopropyl, cyclobutyl or cyclopentyl.
  • R 1 is selected from -Br, -Cl, -NH 2 , -CH 3 , -OCH 3 , -OH and -CF 3 ;
  • R 2 is hydrogen, -CH 3 , -CH(CH 3 )2, cyclopropyl, cyclobutyl or cyclopentyl;
  • the present invention provides compound of formula (ID) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof: wherein Y 1 and Y 2 independently is CH or N;
  • L 3 is (C 1 -C 6 )alkylenyl or 6-membered heterocycloalkylenyl; and R 1 , R 2 , R 4 , R 5 , X and X 1 are as defined in compound of formula (I).
  • Y 1 and Y 2 independently is CH or
  • Y 2 is CH or N.
  • Y 1 is N.
  • R 2 is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl or 3- to 8-membered cycloalkyl.
  • R 1 is selected from -Cl, -Br, -CH 3 , - CF 2 , -CF 3 , -O-CH 3 , -O-CH 2 -CH 3 , -O-CH(CH 3 )-CH 3 , -OH and -NH 2 .
  • R 1 is selected from -Br, -Cl, -NH 2 , - CH 3 , -OCH 3 , -OH and -CF 3 .
  • R 2 is hydrogen, -CH 3 , -CH(CH 3 ) 2 , cyclopropyl, cyclobutyl or cyclopentyl.
  • L 3 is a bond or a group selected from In one embodiment of compound of formula (ID), L 3 is a bond.
  • L 3 is selected from -CH 2 -, -CH 2 -
  • the present invention provides compound of formula (ID) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof: wherein
  • Y 1 and Y 2 independently is CH or N;
  • R 1 is selected from -Br, -Cl, -NH 2 , -CH 3 , -OCH 3 , -OH and -CF 3 ;
  • R 2 is hydrogen, -CH 3 , -CH(CH 3 )2, cyclopropyl, cyclobutyl or cyclopentyl;
  • the present invention provides a compound of formula (I) selected from the ones described herein, or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof. In one embodiment the present invention provides the compound of formula (IE), (IF) and (IG);
  • the present invention provides compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein,
  • A is phenyl or pyridyl; each R 1 and R 3 independently is halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, amino, halo(C 1 - C 6 )alkyl, hydroxy, 3- to 8-membered cycloalkyl, hydroxy (C 1 -C 6 )alkyl or cyano; R 2 is hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl or 3- to 8-membered cycloalkyl; wherein the alkyl and cycloalkyl is substituted with 0, 1, 2 or 3 substituents, independently, selected from hydroxy, halogen and alkoxy; wherein asterisk mark represents the point of attachment with Q;
  • L 1 and L 3 independently is a bond, (C 1 -C 6 )alkylenyl, 6- to 10-membered arylenyl or 5- to 6-membered heterocycloalkyl enyl; wherein the alkylenyl, arylenyl and heterocycloalkylenyl, at each occurrence, independently is substituted with 0, 1, 2, 3 or 4 R 7 ;
  • L 2 is 5- to 6-membered heterocycloalkylenyl which is substituted with 0, 1, 2, 3 or 4 R 7 ; each R 7 is halogen, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halo(C 1 -C 6 )alkyl;
  • Q is represented by formula QI or Q2: wherein,
  • X is a bond, -O- or -NH-;
  • X 1 is N or CH; each R 5 is hydrogen, halogen, halo(C 1 -C 6 )alkyl or (C 1 -C 6 )alkyl;
  • R 6 and R 6 ’ independently is hydrogen; or R 6 and R 6 ’ together represent an oxo group; and each R 4 is hydrogen or (C 1 -C 6 )alkyl; and
  • ‘n’ and ‘m’ are an integer, independently selected from 0, 1, 2 and 3.
  • the compound is selected from;
  • compositions or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or pharmaceutically acceptable excipients.
  • Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier, such as, but not limited to, a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol
  • the present invention provides a pharmaceutical composition for use in degrading a target protein in a subject, wherein the target protein is SMARCA2 and/or SMARCA4.
  • the present invention provides a pharmaceutical composition wherein the subject is afflicted with a disease or disorder dependent upon SMARCA2 and/or SMARCA4.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in treating or preventing cancers selected from the group consisting of hematologic cancers, lung cancer, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic, granulocytic, leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer
  • the present invention provides, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, for use as a medicament.
  • the present invention provides, a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, for use in the treatment of a disease or disorder dependent upon SMARCA2 and/or SMARCA4.
  • a disease or disorder dependent upon SMARCA2 and/or SMARCA4 is cancer.
  • the present invention provides, a method of degrading a target protein in a subject comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.
  • the present invention provides a method of degrading a target protein is SMARCA2 and/or SMARCA4.
  • the present invention provides, a method of treating or delaying progression of a disease or disorder dependent upon SMARCA2 and/or SMARCA4 in a subject comprising administering to the subject, in need thereof, a therapeutically effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.
  • the present invention provides a method for treating diseases or disorders dependent upon SMARCA2 and/or SMARCA4 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.
  • diseases or disorders that are dependent upon SMARCA2 and/or SMARCA4 include cancer.
  • the present invention provides a method of inhibiting tumor growth in a subject afflicted with cancer comprising administering a therapeutically effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof to the subject, in need thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, for use in degrading a target protein in a subject wherein the target protein is SMARCA2 and/or SMARCA4.
  • the subject is afflicted with a disease or disorder dependent upon at least one of SMARCA2 and SMARCA4, wherein the disease or disorder is cancer.
  • the present invention provides a use of a compound represented by formula (I), (IA), (IB), (IC), (ID), (IE), (IF) or (IG) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, in the manufacture of a medicament for the treatment of disease or disorder dependent upon SMARCA2 and/or SMARCA4.
  • disease or disorder dependent upon SMARCA2 and/or SMARCA4 is a cancer.
  • cancer is selected from hematologic cancers, lung cancer, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, promyelocytic, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, dysplasi
  • the cancer dependent upon SMARCA2 and/or SMARCA4 is lung cancer such as NSCLC, i.e., non-small cell lung cancer.
  • the cancer dependent upon SMARCA2 and/or SMARCA4 is melanoma.
  • the cancer is a SMARCA2 and/or SMARCA4 dependent cancer.
  • the present invention provides a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, for use in the treatment of a disease or disorder dependent upon SMARCA2 and/or SMARCA4, wherein the disease or disorder dependent upon SMARCA2 and/or SMARCA4 is cancer.
  • the present invention provides a use of compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder dependent upon SMARCA2 and/or SMARCA4; wherein the disease or disorder is cancer.
  • optionally substituted alkyl refers to an event or circumstance where the alkyl is substituted as well as the event or circumstance where the alkyl is not substituted.
  • optionally substituted alkyl can also be referred to as ‘unsubstituted or substituted alkyl’ group, wherein the substituent(s) are as stated therein.
  • substituted refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl or an acyl), a thiocarbonyl (such as a thioester, a thioacetate or a thioformate), an alkoxyl, an oxo, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heteroaryl, a heterocyclyl, an aralkyl
  • alkylenyl refers to a divalent alkyl group as defined herein.
  • alkyl refers to saturated aliphatic groups, including but not limited to C 1 -C 10 straight-chain alkyl groups or C 3 -C 10 branched-chain alkyl groups.
  • alkyl refers to C 1 -C 6 straight-chain alkyl groups or C 3 -C 6 branched-chain alkyl groups.
  • the “alkyl” group refers to C 1 -C 4 alkyl groups.
  • alkyl examples include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1- pentyl, 2-pentyl, 3 -pentyl, neo-pentyl, 1 -hexyl, 2-hexyl, 3 -hexyl, 1 -heptyl, 2-heptyl, 3 -heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl and 4-octyl.
  • alkylenyl examples include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, - CH(CH 3 )CH 2 CH 2 CH 2 - and -CH 2 CH(CH 3 )CH 2 CH 2 -,
  • the “alkyl” group may be optionally substituted.
  • the term “optionally substituted alkyl” can also be referred to as ‘unsubstituted or substituted alkyl’ group, wherein the substituent(s) are as stated therein.
  • halo is used herein interchangeably with the term “halogen” to mean F, Cl, Br or I atoms.
  • amino is art-recognized and refers to an -NH2 group.
  • haloalkyl refers to alkyl substituted with one or more halogen atoms, wherein the halo and alkyl groups are as defined above.
  • haloalkyl contains (C 1 -C 6 )alkyl and preferably (C 1 -C 4 )alkyl.
  • Examples of “haloalkyl” include but are not limited to fluoromethyl, difluor omethyl, chloromethyl, trifluoromethyl and 2,2,2- trifluoroethyl.
  • hydroxyalkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group’s hydrogen atoms have been replaced with hydroxyl group.
  • hydroxyalkyl contains (C 1 -C 6 )alkyl and preferably (C 1 -C 4 )alkyl.
  • Examples of hydroxyalkyl moieties include but are not limited to -CH 2 OH, -CH 2 CH 2 OH, - CH 2 CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 OH, -CH 2 CH(OH) CH 3 , -CH(CH 3 )CH 2 OH.
  • hydroxy or “hydroxyl” alone or in combination with other term(s), is art-recognized and refers to -OH.
  • alkoxy refers to the group -O-alkyl, where alkyl groups are as defined above.
  • Exemplary C 1 -C 10 alkoxy group include but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy or t-butoxy.
  • the “alkoxy” group refers to Ci- C>, alkoxy groups.
  • the “alkoxy” group refers to C 1 -C 4 alkoxy groups.
  • An alkoxy group can be optionally substituted with one or more suitable groups. In some emodiments, alkoxy group can be unsubstituted or substituted with one or more substitutents, wherein the substitutetns are described herein.
  • cycloalkyl means C 3 -C 10 saturated cyclic hydrocarbon ring.
  • a cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single ring cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls.
  • cycloalkylenyl examples include, but not limited to, cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl and cycloheptylenyl.
  • heterocycloalkylenyl refers to a divalent heterocycloalkyl group as defined herein.
  • heterocycloalkyl refers to a non-aromatic, saturated or partially saturated, bridged bicyclic, spirocyclic, monocyclic or polycyclic ring system of 3 to 15 member, unless the ring size is specifically mentioned, having at least one heteroatom or heterogroup selected from O, N and S with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur.
  • heterocycloalkyl also refers to the bridged bicyclic ring system having at least one heteroatom or hetero group selected from O, N and S.
  • heterocycloalkyl examples include, but not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, isoindolinyl, oxoisoindolinyl, dioxoisoindolinyl,
  • heterocycloalkylenyl examples include, but not limited to, azetidinyl enyl, oxetanylenyl, pyrrolidinylenyl, piperidinylenyl and piperazinylenyl. All “heterocycloalyl” and “heterocycloalkylenyl” are optionally substituted by one or more aforesaid groups.
  • arylenyl refers to a divalent aryl group as defined herein.
  • aryl as employed herein as such or as part of another group, refers to a monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of 6 to 14 carbon atoms. Examples of aryl groups include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, biphenylenyl and acenaphthyl. Preferred aryl group is phenyl.
  • arylenyl refers to a divalent aryl group.
  • arylenyl groups include, but are not limited to phenylenyl, naphthylenyl, biphenylenyl and anthrylenyl.
  • optionally substituted aryl can also be referred to as ‘unsubstituted or substituted aryl’ group, wherein the substituent(s) are as stated therein.
  • compound(s) comprise(s) the compound(s) disclosed in the present invention.
  • salt/salts refers to the salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N + (C 1-4 alkyl) 4 salts.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • composition refers to a composition(s) containing a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition(s) usually contain(s) about 1% to 99%, for example, about 5% to 75% or from about 10% to about 30% by weight of the compound of formula (I) or (II) or pharmaceutically acceptable salts thereof.
  • the amount of the compound of formula (I) or pharmaceutically acceptable salts thereof in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower than the aforementioned range.
  • tautomer refers to compounds in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged.
  • Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms. It is understood that all tautomeric forms, insofar as they may exist, are included within the invention.
  • pyridine or pyridyl can be optionally substituted by oxo to form a respective pyridone or pyridon-yl and may include its tautomeric form such as a respective hydroxy -pyridine or hydroxy-pyridyl, provided said tautomeric form may be obtainable.
  • “pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surfactant or emulsifier that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • administer refers to either directly administering one or more disclosed compounds or a pharmaceutically acceptable salt of one or more disclosed compounds or a composition comprising one or more disclosed compounds to a subject or administering a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body.
  • carrier encompasses carriers, excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ or portion of the body to another organ or portion of the body of a subject.
  • treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • prevent refers to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • prevent also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject’s risk of acquiring a disease.
  • the term “subject” that may be interchangeable with ‘patient’ refers to an animal, preferably a mammal and most preferably a human.
  • terapéuticaally effective amount refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; or a composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, effective in producing the desired therapeutic response in a particular patient suffering from a diseases or disorder, in particular their use in diseases or disorder associated with cancer.
  • the term “therapeutically effective amount” includes the amount of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject.
  • the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment can also be considered.
  • the therapeutically effective amount of the compound or composition will be varied with the particular condition being treated, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the age and physical condition of the end user, the specific compound or composition employed the particular pharmaceutically acceptable carrier utilized.
  • the term “pharmaceutically acceptable salt” refers to a product obtained by reaction of the compound of the present invention with a suitable acid or a base.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts;
  • suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate
  • Certain compounds of the invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin.
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium or zinc salts.
  • “Pharmaceutically acceptable” means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • the present invention also provides methods for formulating the disclosed compounds as for pharmaceutical administration.
  • the aqueous solution is pyrogen-free or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • cancer is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease.
  • Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated.
  • neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors.
  • Exemplary cancers which may be treated by the present compounds include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, hematologic cancers and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt’s lymphoma and Non- Hodgkin’s lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing’s sarcoma, hemangiosarcoma, Kaposi’s sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependym
  • Additional cancers which may be treated using compounds according to the present invention include, for example, T-lineage Acute lymphoblastic Leukemia (T-ALL), T- lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre- B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.
  • T-ALL T-lineage Acute lymphoblastic Leukemia
  • T-LL T- lineage lymphoblastic Lymphoma
  • Peripheral T-cell lymphoma Peripheral T-cell lymphoma
  • Adult T-cell Leukemia Pre- B ALL, Pre-B Lymphomas, Large B-cell Lymphoma
  • Burkitts Lymphoma B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.
  • stereoisomers refers to any enantiomers, diastereoisomers or geometrical isomers of the compound of formula (I), wherever they are chiral or when they bear one or more double bonds. When the compounds of the formula (I) and related formulae are chiral, they can exist in racemic or in optically active form. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d -Isomers and /-Isomers and mixtures thereof.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centres or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds of the present invention may exist as geometric Isomers.
  • the present invention includes all cis, trans, syn, anti,
  • Mechanism I and sixteen (Z) Isomers as well as the appropriate mixtures thereof.
  • enantiomers refers to a pair of stereoisomers which are non-superimposable mirror images of one another.
  • enantiomer refers to a single member of this pair of stereoisomers.
  • racemic refers to a 1 : 1 mixture of a pair of enantiomers.
  • the disclosure includes enantiomers of the compounds described herein. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form or any other form in terms of stereochemistry. In some embodiments the compounds are the (S)-enantiomer.
  • diastereomers refers to the set of stereoisomers which cannot be made superimposable by rotation around single bonds. For example, cis- and trans- double bonds, endo- and exo- substitution on bicyclic ring systems and compounds containing multiple stereogenic centres with different relative configurations are considered to be diastereomers.
  • diastereomer refers to any member of this set of compounds.
  • the synthetic route may produce a single diastereomer or a mixture of diastereomers.
  • the disclosure includes diastereomers of the compounds described herein.
  • the compounds of the present invention may be used as single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials.
  • the compounds of the invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention.
  • the pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents and solvents.
  • the pharmaceutical composition can be administered by oral, parenteral or inhalation routes.
  • parenteral administration include administration by injection, percutaneous, transmucosal, transnasal and transpulmonary administrations.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters and polyoxyethylene.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
  • compositions may be in conventional forms, for example, tablets, capsules, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
  • Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted routes of administration of pharmaceutical compositions.
  • the route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular or topical.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
  • Liquid formulations include, but are not limited to, syrups, emulsions and sterile injectable liquids, such as suspensions or solutions.
  • Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
  • compositions of the present patent application may be prepared by conventional techniques known in literature.
  • Suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention and their uses.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H (“D”), 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples herein below, by substituting an isotopically labeled reagent for a non -isotopically labeled reagent.
  • Bis(diphenylphosphino)ferrocene]-dichloropalladium (II) dichloromethane complex NaoMe - Sodium methoxide, BINAP - (2,2'-bis(diphenylphosphino)-l,l'-binaphthyl), H2SO4 - Sulfuric acid, NaHCCE - Sodium bicarbonate, TEA - Triethyl amine; DEA- Diethyl amine, LiOH H2O - Lithium hydroxide monohydrate; EDC.HC1 - l-(3-Dimethylaminopropyl)-3- ethylcarbodiimide.
  • the compound of formula (A 6 ) undergoes Suzuki or Buchwald coupling with the compound of formula (B 2 ) to provide compound of formula (A 7 ) which further undergoes Sandmeyer reaction or halogenation reaction in presence of sodium nitrite and copper chloride to result the compound of formula (A 9 ).
  • the compound of formula (A 7 ) undergoes de-amination recti on in presence of sodium nitrite to result the compound of formula
  • the general scheme for the synthesis of compound represented by formula (I’) is depicted in above scheme.
  • the compound of formula (A 5 ) was obtained by the reaction of compound of formula (A 4 ) with the compound of formula (Bs) with suitable solvent in high temperature.
  • the compound formula (A5) undergoes cyclization reaction in the presence of suitable reagent and solvent to provide compound of formula (A 6 ) which further undergoes Suzuki or Buchwald coupling with the compound of formula (B 2 ) to provide compound of formula (A 7 ).
  • the compound of formula (A7) undergoes Sandmeyer reaction or halogenation reaction in presence of sodium nitrite and copper chloride to result the compound of formula (A 9 ).
  • Step-b Synthesis of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-l- carboxylate
  • Step-a Synthesis of tert-butyl 4-(4-amino-2-fluorophenyl)-3.,6-dihvdropyridine-1(2H)- carboxylate
  • reaction mixture was heated to 110 °C for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chromatography using 20-30% ethyl acetate in hexane as eluent to afford the title compound as yellow solid (38 g, 98.8%).
  • Step-b Synthesis of tert-butyl 4-(4-amino-2-fluorophenyl)piperidine-l-carboxylate
  • Step-c Synthesis of tert-butyl 4-(4-((2.,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidine-l-carboxylate
  • reaction mixture was diluted with EtOAc, washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combi flash column chromatography using 40-50% ethyl acetate in hexane as eluent to afford the title compound as yellow solid (0.350 g, 13%).
  • Step b Synthesis of 5-bromo-N1-cyclopentylbenzene-1.,2-diamine
  • Step c Synthesis of 6-bromo-l-cvclopentyl-lH-benzo[d]imidazol-2-amine
  • Step d Synthesis of 2-amino-6-bromo-N-(6-bromo-l-cvclopentyl-lH-benzo[d]imidazol- 2-yl)benzamide
  • Step e Synthesis of 4-amino-9-bromo-7-cyclopentylbenzo[4.,5]imidazo[1.,2-a]quinazolin- 5(7H)-one
  • reaction mixture was diluted with 10% methanol in DCM and filtered through celite and thoroughly washed with 10% methanol in DCM.
  • the combined organic layer was concentrated under vacuum to get crude material which was purified by combi flash column chromatography using 3-5% methanol in DCM as eluent to afford the title compounds as yellowish green solid (2.1 g, 50.5 %).
  • Step f Synthesis of 4-amino-7-cyclopentyl-9-(1.,4-dioxa-8-azaspiro[4.5]decan-8- vlbenzo[4.5] imid azo[ 1 ,2-a] q uinazolin-5(7H)-one
  • reaction mixture was diluted with DCM and quenched with NH4CI solution and extracted with DCM.
  • the combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combiflash column chromatography using 2-4% methanol in DCM as eluent to afford the title as light brown solid (1.8 g, 34%).
  • Step g Synthesis of 4-amino-7-cyclopentyl-9-(4-oxopiperidin-l-yl)benzo[4,5]imidazo[1.2- a] quinazolin-5(7H)-one
  • Step a Synthesis _ of _ 4-chloro-7-cyclopentyl-9-(4-oxopiperidin-l- vlbenzo [4,5] imidazo [1 ,2-a] q uinazolin-5(7H)-one
  • HC1 was added dropwise at the at 0 °C. The mixture was allowed to reach RT and then stirred at 50 °C for 30 minutes. Then the reaction mixture was diluted with water and basified with sodium bicarbonate solution to pH 8 and extracted with DCM:MeOH (9: 1) three times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to get crude compound which was purified by combiflash column chromatography using 3-4% methanol in DCM as eluent to afford mixture of ketal and keto compound. Mixture of ketal and keto compounds were taken in THF and added 6N HC1, stirred at 60 °C for 8h. Reaction mixture was quenched with bicarbonate solution and extracted with 10% MeOH in DCM.
  • Step a Synthesis of 7-cyclopentyl-9-(4-oxopiperidin-l-yl)benzo[4.,5]imidazo[l.,2- a] quinazolin-5(7H)-one
  • reaction mixture was quenched with bicarbonate solution and extracted with 10% MeOH in DCM.
  • the combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo to get afford mixture of ketal and keto compound.
  • Mixture of ketal and keto compound was taken in THF, 6N HC1 was added and stirred at 60 °C for 6h.
  • Reaction mixture was quenched with bicarbonate solution and extracted with 10% MeOH in DCM.
  • the combined organic layer was taken for purification by combiflash column chromatography using 1-3% methanol in DCM as eluent to afford the title compound as yellow solid (0.040 g, 51%).
  • Example-1 3-(5-(l , -(4-Bromo-7-cyclopentyl-5-oxo-5,7-dihydrobenzo [4,5] imidazo [1,2- a]quinazolin-9-yl)-[l,4 , -bipiperidin]-4-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (Compound 1)
  • Example-2 _ Synthesis _ of _ 3-((4-(4-(4-(4-aiiiino-7-methyl-5-oxo-5.7- dihydrobenzo[4.,5]imidazo[l.,2-a]quinazolin-9-yl)phenyl)piperazin-l-yl)-3- fluorophenyl)amino)piperidine-2.,6-dione (Comound-49)
  • Step a Synthesis of tert-butyl 4-(4-(4-amino-7-methyl-5-oxo-5.,7- dihydrobenzo[4.,5]imidazon[ 1 ,2-a]quinazolin-9-yl)phenyl)piperazine-l-carboxylate
  • Step-b Synthesis 4-amino-7-methyl-9-(4-(piperazin-l-yl)phenyl)benzo[4.,5]imidazon.,2- a] quinazolin-5(7H)-one tert-butyl 4-(4-(4-amino-7-methyl-5-oxo-5,7-dihydrobenzo[4,5]imidazo[l,2- a]quinazolin-9-yl)phenyl)piperazine-l -carboxylate (0.550 g, 1.048 mmol) was dissolved in DCM (5 mL) to obtain a solution.
  • Step-c Synthesis of 4-amino-9-(4-(4-(2-fluoro-4-nitrophenyl)piperazin-l-yl)phenyl)-7- methylbenzo[4.,5]imidazo[l.,2-a]quinazolin-5(7H)-one
  • Step-d Synthesis of 4-amino-9-(4-(4-(4-amino-2-fluorophenyl)piperazin-l-yl)phenyl)-7- methylbenzo[4.,5]imidazo[1.,2-a]quinazolin-5(7H)-one
  • reaction mixture was passed through celite bed and thoroughly washed with EtOAc. Filtrate was washed with Sat. bicarbonate solution, water and brine solution and dried over Na 2 SO 4 . Collective organic layer was concentrated to afford the title compound as brick red sticky solid (0.170 g, crude); LC- MS: m/z 534.2 (M+H).
  • Step-e Synthesis of 3-((4-(4-(4-(4-(4-amino-7-methyl-5-oxo-5.,7- dihydrobenzo[4.,5]imidazo[l.,2-a]quinazolin-9-yl)phenyl)piperazin-l-yl)-3- fluorophenyl)amino)piperidine-2.,6-dione
  • Example-Pl Determination of Anti proliferative activity of compounds in cell lines SK- MEL-5 by Cell Titer Glo®(promega) assay
  • Example-P2 Determination of Anti proliferative activity of compounds in cell lines MV- 4-11 by Cell Titer Glo®(promega) assay:
  • MV-4-11 (CRL-9591TM) cells were seeded in 96 well plate flat black clear bottom plates (Corning, Cat. No 3904) using complete DMEM Medium. Next day, selected compounds of the present invention were added to cells from 10 mM stocks made in DMSO (Sigma Cat no. D2650). Each concentration of compound was tested in triplicate with DMSO concentration at a final percentage not exceeding 0.3 in the cells. After the incubation of MV- 4-11 cells with compound for 3 days; assay was terminated using 100 pl of CellTiter Gio® reagent (Promega, Cat. no G7572).
  • group “A” refers to EC 50 values lower than 10 nM
  • group “B” refers to EC 50 values between 10.01 nM to 100 nM (both inclusive)
  • group “C” refers to EC 50 values greater than 100.
  • Example-P3 Determination of SMARCA2 and SMARCA4 degradation in MV-4-11 cells by Western blot
  • MV-4-11 (CRL-9591TM) cells were plated in 6 well plates using complete Iscove's Modified Dulbecco's Medium.
  • compounds of present invention were added to cells from 10 mM stocks made in DMSO (Sigma Cat no. D2650). Each concentration of compound was tested with DMSO not exceeding final percentage of 0.1 in the cells.
  • Cells were incubated with the compound for 16 hours followed by harvesting with IX RIPA lysis buffer (Thermo Fischer, catalogue number# 89900) containing protease inhibitor cocktail (Sigma catalogue number #P-8340). Equal amount of protein was loaded on SDS PAGE gel for electrophoresis.

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Abstract

La présente invention concerne des composés tétracycliques de formule (I), qui sont thérapeutiquement utiles en tant qu'agents de dégradation de SMARCA2 et/ou de SMARCA4. Ces composés sont utiles dans le traitement et/ou la prévention de maladies ou de troubles dépendant de SMARCA2 et/ou SMARCA4 chez un sujet. La présente invention concerne également la préparation des composés et des compositions pharmaceutiques comprenant un composé de formule (I) ou un sel pharmaceutiquement acceptable ou un stéréoisomère ou un tautomère de celui-ci.
PCT/IB2024/053500 2023-04-12 2024-04-10 Composés tétracycliques utilisés en tant que agents de dégradation de smarca2 et/ou de smarca4 Pending WO2024214019A1 (fr)

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WO2025106480A1 (fr) * 2023-11-13 2025-05-22 Regents Of The University Of Michigan Composés et compositions utilisés comme agents de dégradation de smarca2 ou de smarca4 et leurs utilisations

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