Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • 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
  • 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
  • C07D487/08—Bridged systems

Definitions

• the present invention relates to 6-substituted pyridazine compounds, a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof which are useful as SMARCA2 and/or SMARCA4 degraders for the treatment of diseases or disorders dependent upon SMARCA2 and/or SMARCA4.
• the present invention also relates to a method of preparation of the said pyridazine compounds and pharmaceutical compositions comprising the said compounds.
• 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 harbour 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 of 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 function, including 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 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 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.
• 6-substituted pyridazine compounds and pharmaceutical compositions thereof that are useful as SMARCA2 and/or SMARCA4 degraders and for the treatment of diseases or disorders dependent upon or mediated by SMARCA2 and/or SMARCA4.
• the present invention provides compounds of formula (I): or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof; wherein
• A represents 5- to 6-membered heteroarylenyl or 6-membered arylenyl; wherein the arylenyl and heteroarylenyl are substituted with 1, 2 or 3 occurrences of Ra;
• Ra is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino or cyano;
• R 1 is halogen, alkyl, haloalkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, -COORb - CON(Rb) 2 , 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl are optionally substituted with 1, 2 or 3 groups independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, -ONa, -COORc and -OCORc;
• Rb and Rc at each occurrence, independently represents hydrogen, alkyl or aminoalkyl
• R 2 is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl or cyano;
• Rd at each occurrence, is independently selected from hydrogen, hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino and cyano;
• Rx and Ry are independently selected from hydrogen, alkyl and halogen
• M is selected from M-1 and M-2:
• Z is 5- to 6-membered heteroarylenyl optionally substituted with 1, 2 or 3 groups independently selected from hydroxy, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl and aminoalkynyl; wherein the aminoalkyl and aminoalkynyl are optionally substituted with 1 or 2 substituents selected from alkyl and -COCH 3 ;
• R 3 and R 8 independently represents alkyl, acyl, heteroalkyl, haloalkyl, hydroxyalkyl or aminoalkyl;
• R 4 and R 9 independently represents hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, -CO-aminoalkyl or acyl; wherein the alkyl is optionally substituted with -OCOR’ or -OP(O)(OR”) 2 ;
• R’ and R’’ are independently selected from hydrogen and alkyl
• R 5 , R 6 , R 10 and R 11 independently represents hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl-, -CONRuRv, acyl, -Na, -alkyl-heterocycloalkyl and - heteroalkyl-heterocycloalkyl; wherein the aminoalkyl and heterocyclo alkyl are optionally substituted with 1 or 2 substituents selected from alkyl and-COCH ,; or
• R 5 and R 6 together combine with the C atom to which they are attached form a 4- to 6- membered heterocycloalkyl optionally substituted with alkyl or -COCH 3 ; or R 10 and R 11 together combine with the C atom to which they are attached form a 4- to 6-membered heterocycloalkyl optionally substituted with alkyl or -COCH 3 ;
• Ru and Rv independently represents hydrogen, alkyl, 4- to 6-membered cycloalkyl or 6-membered aryl;
• R 7 and R 12 represents thiazolyl substituted with alkyl, hydroxy, amino or haloalkyl; p is an integer selected from 1, 2, 3 and 4; and n is an integer selected from 0, 1, 2 and 3.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
• the present invention relates to the preparation of compounds of formula (I).
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof for treating diseases or disorders that are dependent upon or mediated by SMARCA2 and/or SMARCA4.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof for treating or delaying progression of a disease or disorder wherein degradation of SMARCA2 and/or SMARCA4 proteins provides a benefit, e.g., cancer.
• the present invention provides a method of degrading a target protein comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof, wherein the compound is effective for degrading the target protein.
• the present invention provides a method for treating a subject afflicted with cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof.
• the present invention provides a method for inhibiting tumor growth in a subject afflicted with cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof.
• the present invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof, in the manufacture of a medicament for treating a disease or disorder that are dependent upon or mediated by SMARCA2 and/or SMARCA4.
• a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof in the manufacture of a medicament for treating a disease or disorder that are dependent upon or mediated by SMARCA2 and/or SMARCA4.
• the present invention provides 6-substituted pyridazine compounds, referred as a compound of formula (I), which are useful as SMARCA2 and/or SMARCA4 degraders and for the treatment of conditions dependent upon or mediated by SMARCA2 and/or SMARCA4.
• the present invention further provides pharmaceutical compositions comprising the said compound or a stereoisomer or a tautomer or a prodrug thereof as therapeutic agents.
• the present invention provides compounds of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof; wherein
• A represents 5- to 6-membered heteroarylenyl or 6-membered arylenyl; wherein the arylenyl and heteroarylenyl are substituted with 1, 2 or 3 occurrences of Ra;
• Ra is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino or cyano;
• R 1 is halogen, alkyl, haloalkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, -COORb - CON(Rb) 2 , 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl are optionally substituted with 1, 2 or 3 groups independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, -ONa, -COORc and -OCORc; Rb and Rc, at each occurrence, independently represents hydrogen, alkyl or aminoalkyl;
• R 2 is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl or cyano;
• Rd at each occurrence, is independently selected from hydrogen, hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino and cyano;
• Rx and Ry are independently selected from hydrogen, alkyl and halogen
• M is selected from M-1 and M-2: wherein,
• Z is 5- to 6-membered heteroarylenyl optionally substituted with 1, 2 or 3 groups independently selected from hydroxy, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl and aminoalkynyl; wherein the aminoalkyl and aminoalkynyl are optionally substituted with 1 or 2 substituents selected from alkyl and -COCH 3 ;
• R 3 and R 8 independently represents alkyl, acyl, heteroalkyl, haloalkyl, hydroxyalkyl or aminoalkyl;
• R 4 and R 9 independently represents hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, -CO-aminoalkyl or acyl; wherein the alkyl is optionally substituted with -OCOR’ or -OP(O)(OR”) 2 ;
• R’ and R’’ are independently selected from hydrogen and alkyl
• R 5 , R 6 , R 10 and R 11 independently represents hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl-, -CONRuRv, acyl, -Na, -alkyl-heterocycloalkyl and - heteroalkyl-heterocycloalkyl; wherein the aminoalkyl and heterocyclo alkyl are optionally substituted with 1 or 2 substituents selected from alkyl and-COCH 3 ; or
• R 5 and R 6 together combine with the C atom to which they are attached form a 4- to 6- membered heterocycloalkyl optionally substituted with alkyl or -COCH 3 ; or R 10 and R 11 together combine with the C atom to which they are attached form a 4- to 6-membered heterocycloalkyl optionally substituted with alkyl or -COCH 3 ;
• Ru and Rv independently represents hydrogen, alkyl, 4- to 6-membered cycloalkyl or 6-membered aryl;
• R 7 and R 12 represents thiazolyl substituted with alkyl, hydroxy, amino or haloalkyl; p is an integer selected from 1, 2, 3 and 4; and n is an integer selected from 0, 1, 2 and 3.
• R 1 is halogen, alkyl, haloalkyl, alkoxy, hydroxy, hydroxyalkyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl are optionally substituted with 1, 2 or 3 groups independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl and amino;
• R 1 is halogen, hydroxy, -CH 2 OH, -COOH, -COOCH 3 , -CONH 2 , - CONHCH 3 , 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein, the aryl and heteroaryl are optionally substituted with 1, 2 or 3 groups independently selected from hydroxy, alkoxy, halogen, alkyl and haloalkyl.
• R 1 is halogen, hydroxy, 6- to 10-membered aryl or 5- to 10- membered heteroaryl; wherein the aryl and heteroaryl are optionally substituted with 1, 2 or 3 groups independently selected from hydroxy, alkoxy, halogen, alkyl, haloalkyl, -OCOCH 3 and -CH(NH 2 )(CH(CH 3 ) 2 ).
• R 1 represents halogen, hydroxy, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl are optionally substituted with 1 or 2 groups independently selected from alkyl, hydroxy, alkoxy, halogen and haloalkyl.
• R 1 is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl are optionally substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, alkoxy, halogen and haloalkyl.
• R 1 is 6- to 10-membered aryl optionally substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, alkoxy, halogen and haloalkyl.
• R 1 represents phenyl optionally substituted with 1 or 2 groups independently selected from hydroxy, alkyl, haloalkyl and halogen.
• R 1 is 5- to 10-membered heteroaryl optionally substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, alkoxy, halogen and haloalkyl.
• R 1 represents and wherein each group is optionally substituted with 1, 2 or 3 groups independently selected from hydroxy, alkyl, haloalkyl and halogen.
• R 2 is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl or haloalkyl.
• R 2 is hydrogen, hydroxy, halogen, alkoxy, alkyl or haloalkyl.
• R 2 independently represent hydrogen or halogen.
• A represents phenylenyl substituted with 1 or 2 occurrences of Ra.
• A represents 5- to 6-membered heteroarylenyl substituted with 1 or 2 occurrences of Ra.
• A represents phenylenyl, furanylenyl, thienylenyl, pyrrolylenyl, imidazolylenyl, oxazolylenyl, isoxazolylenyl, thiazolylenyl, isothiazolylenyl, 1H- tetrazolylenyl, oxadiazolylenyl, triazolylenyl, pyrazolylenyl, pyridylenyl, pyrimidinylenyl, pyrazinylenyl, pyridazinylenyl, 1,2,3-triazinylenyl, 1,2,4-triazinylenyl, or 1,3,5-triazinylenyl; wherein each group is optionally substituted with 1 or 2 occurrences of Ra.
• A represents phenylenyl, pyridylenyl, pyrimidinylenyl, pyrazinylenyl, or pyridazinylenyl; wherein each group is optionally substituted with 1, 2 or 3 occurrences of Ra.
• A represents phenylenyl, furanylenyl, thienylenyl, pyrrolylenyl, imidazolylenyl, oxazolylenyl, isoxazolylenyl, thiazolylenyl, isothiazolylenyl, 1H- tetrazolylenyl, oxadiazolylenyl, triazolylenyl, pyrazolylenyl, pyridylenyl, pyrimidinylenyl, pyrazinylenyl, pyridazinylenyl, 1,2,3-triazinylenyl, 1,2,4-triazinylenyl, or 1,3,5-triazinylenyl; wherein each of said group is substituted with 1 or 2 substituents selected from hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, halo
• A represents phenylenyl, pyridylenyl, pyrimidinylenyl or pyrazinylenyl, wherein the phenylenyl, pyridylenyl, pyrimidinylenyl and pyrazinylenyl are optionally substituted with 1 or 2 substituents selected from hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino or cyano.
• A represents wherein each ring is optionally substituted with 1 or 2 occurrences of Ra; and wherein the left side of A is attached with pyridazine ring and right side of the ring is attached with L.
• A represents ; wherein each group is optionally substituted with 1 or
• L is a bond, -O-(CH 2 )p-, -O-(CH 2 )p-O-, -NRx-(CH 2 )p-, -NRx- (CH 2 )p-O-, -NRx-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-, (3- to 10-membered cycloalkylenyl)-(CRxRy)n-, (3- to 10-membered heterocycloalkylenyl)-(CRxRy)n or -O-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-; wherein the cycloalkylenyl and heterocycloalkylenyl are substituted with 1 or 2 occurrences of Rd.
• L is a bond and M is attached to A.
• L is -O- (CH 2 )p-.
• L is -O-CH 2 -.
• L is -O-CH 2 CH 2 -.
• L is -O-CH 2 CH 2 CH 2 -.
• L is -O-CH 2 CH 2 CH 2 CH 2 -.
• L is -O- CH 2 CH 2 CH 2 CH 2 -O-.
• L is -O-CH 2 CH 2 CH 2 -O-.
• L is -NRx-(CH 2 )p-. In one embodiment, L is -NRX-(CH 22 ) 1-4 - In one embodiment L is -NRX-CH 2 -. In one embodiment, L is -NRX-CH 2 CH 2 -. In one embodiment, L is -NRX-CH 2 CH 2 CH 2 -. In one embodiment, L is -NRX-CH 2 CH 2 CH 2 CH 2 -. In one embodiment, L is -NH-(CH 2 ) 1-4 -. In one embodiment, L is -NH-CH 2 -. In one embodiment L is -NH-CH 2 CH 2 -. In one embodiment, L is -NH-CH 2 CH 2 CH 2 -.
• L is -N(CH 3 )-CH 2 -. In one embodiment L is -N(CH 3 )- CH 2 CH 2 -. In one embodiment, L is -N(CH 3 )-CH 2 CH 2 CH 2 -. In one embodiment -N(CH 3 )- CH 2 CH 2 CH 2 -.
• L is -NRx-(CH 2 )p-O-. In one embodiment, L is -NRX-(CH 2 ) 1-4 -O- . In one embodiment, L is -NRX-CH 2 -O-. In one embodiment, L is -NRX-CH 2 CH 2 -O-. In one embodiment, L is -NRX-CH 2 CH 2 CH 2 -O-. In one embodiment, L is -NRX-CH 2 CH 2 CH 2 -O- . In one embodiment, L is -NRX-CH 2 CH 2 CH 2 CH 2 -O- . In one embodiment, L is -NH-CH 2 -O-. In one embodiment, L is -NH-CH 2 CH 2 -O-. In one embodiment, L is -NH-CH 2 CH 2 CH 2 -O-.
• L is -NH-CH 2 CH 2 CH 2 CH 2 -O-. In one embodiment, L is -N(CH3)-CH 2 -O-. In one embodiment, L is -N(CH3)-CH 2 CH 2 -O-. In one embodiment, L is -N(CH3)-CH 2 CH 2 CH 2 -O-. In one embodiment, L is -N(CH3)- CH 2 CH 2 CH 2 -O-. In one embodiment, L is -N(CH3)- CH 2 CH 2 CH 2 -O-.
• L is a bond, -O-CH 2 -, -O-CH 2 CH 2 -, -O-CH 2 CH 2 CH 2 -, -O-CH 2 - CH 2 CH 2 CH 2 -, -O-CH 2 O-, -O-CH 2 CH 2 -O-, -O-CH 2 CH 2 CH 2 -O-, -O-CH 2 CH 2 CH 2 CH 2 -O-, - NH-CH 2 -, -NH-CH 2 CH 2 -, -NH-CH 2 CH 2 CH 2 -, -NH-CH 2 CH 2 CH 2 -, -N(CH 3 )-CH 2 -, - N(CH 3 )-CH 2 CH 2 -, -N(CH 3 )-CH 2 CH 2 CH 2 -, -N(CH 3 )-CH 2 CH 2 CH 2 -, NH-CH 2 -O-, -NH- CH 2 CH 2 -O-, -NH- CH 2 CH 2
• L is -NRx-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-, (3- to 10-membered cycloalkylenyl)-(CRxRy)n-, (3- to 10-membered heterocycloalkylenyl) - (CRxRy)n or -O-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-; wherein the cycloalkylenyl and heterocycloalkylenyl are substituted with 1 or 2 occurrences of Rd.
• L is -NRx-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)o-3. In one embodiment, L is -NH-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)o-3. In one embodiment, L is -N(CH 3 )-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)o-3; wherein heterocycloalkylenyl is optionally substituted with 1 or 2 occurrences of Rd.
• L is (3- to 10-membered cycloalkylenyl)-(CRxRy)o-3; wherein cycloalkylenyl is optionally substituted with 1 or 2 occurrences of Rd.
• L is 3- to 10-membered heterocycloalkylenyl-(CRxRy)o-3-; wherein the heterocycloalkylenyl is optionally substituted with 1, 2 or 3 occurrences of Rd.
• L is -O-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)o-3-; wherein the heterocyclylenyl is optionally substituted with 1, 2 or 3 occurrences of Rd.
• L is -NRx-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)o-3.
• L is (3- to 10-membered cycloalkylenyl)-(CRxRy)o-3, wherein the cycloalkylenyl is selected from cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl and cycloheptylenyl.
• each ring is substituted with 1 or 2 occurrences of Rd; wherein each ring is substituted with 1 or 2 occurrences of Rd; and wherein the left side of L is attached with A and right side of the L is attached with M.
• L is -O-CH 2 -, -O-CH 2 CH 2 -, -O-CH 2 CH 2 CH 2 -, -O-CH 2 CH 2 -
• A represents 5- to 6-membered heteroarylenyl or 6-membered arylenyl; wherein, arylenyl and heteroarylenyl are substituted with 1, 2 or 3 occurrences of Ra;
• Ra is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino or cyano;
• R 1 is halogen, alkyl, haloalkyl, alkenyl, alkoxy, hydroxy, hydroxyalkyl, -COORb - CON(Rb) 2 , 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein, the aryl and heteroaryl are optionally substituted with 1, 2 or 3 groups independently selected from oxo, hydroxy, alkoxy, halogen, alkyl, haloalkyl, amino, -ONa, -COORc and -OCORc;
• Rb and Rc at each occurrence independently are selected from hydrogen, alkyl or aminoalkyl
• R 2 is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl or cyano;
• Rd at each occurrence is independently selected from hydrogen, hydroxy, halogen, alkoxy, alkyl, haloalkyl, amino, alkylamino and cyano;
• Rx and Ry at each occurrence independently are selected from hydrogen and alkyl
• M is selected from: wherein,
• Z is 5- to 6-membered heteroarylenyl optionally substituted with 1, 2 or 3 groups independently selected from hydroxy, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl and aminoalkynyl, wherein the aminoalkyl and aminoalkynyl are optionally substituted with 1 or 2 substituents selected from alkyl and -COCH 3 ;
• R 3 and R 8 independently represents alkyl, acyl, heteroalkyl, haloalkyl, hydroxyalkyl or aminoalkyl;
• R 4 and R 9 independently represents hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, -CO-aminoalkyl or acyl; wherein the alkyl is optionally substituted with -OCOR’ or -OP(O)(OR”) 2 ;
• R’ and R" are independently selected from hydrogen and alkyl
• R 5 , R 6 , R 10 and R 11 are independently selected from hydrogen, alkyl, halogen, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, -CONRuRv, acyl, -Na, -alkyl- heterocycloalkyl and -heteroalkyl-heterocycloalkyl; wherein the aminoalkyl and heterocycloalkyl are optionally substituted with 1 or 2 substituents selected from alkyl and- COCH 3 ; or
• R 5 and R 6 together combine with the C atom to which they are attached to form 4- to 6-membered heterocycloalkyl optionally substituted with alkyl, or -COCH 3 ; or R 10 and R 11 together combine with the C atom to which they are attached to form 4- to 6-membered heterocycloalkyl optionally substituted with alkyl, or -COCH 3 ;
• Ru and Rv independently represents hydrogen, alkyl, 4- to 6-membered cycloalkyl, or 6-membered aryl;
• R 7 and R 12 are independently thiazolyl substituted with alkyl, hydroxy, amino or haloalkyl; p is an integer selected from 1 and 2; n is an integer selected from 1, 2 and 3.
• M is M-1; wherein Z is oxazolylenyl or isoxazolylenyl; R 3 represents alkyl, haloalkyl or hydroxyalkyl; R 4 represents hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl or acyl; R 5 and R 6 independently represents hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl or (alkyl)aminoalkyl-; and R 7 represents thiazolyl substituted with alkyl.
• M is selected from M-1A, M-1B and M-1C: wherein,
• R 4 is hydrogen, alkyl, acyl or -Na; wherein the alkyl is optionally substituted with - OCOR’ or -OP(O)(OR”) 2 ;
• R’ and R" are independently selected from hydrogen and alkyl
• R 6 is hydrogen, alkyl, hydroxyalkyl, aminoalkyl, or haloalkyl; wherein aminoalkyl optionally substituted with 1 or 2 substituents selected from alkyl and -COCH 3 .
• M-1A is,
• R 4 is selected from hydrogen, alkyl, acyl and -Na; wherein the alkyl is optionally substituted with -OCOR’ and -OP(O)(OR”) 2 ;
• R’ and R" are independently selected from hydrogen and alkyl
• R 6 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl or aminoalkyl; wherein the aminoalkyl optionally substituted with 1 or 2 substituents selected from alkyl and -COCH 3 .
• M-1B and M-1C is, wherein, R 4 is selected from hydrogen, alkyl, acyl and -Na; wherein the alkyl is optionally substituted with -OCOR’ and -OP(O)(OR”) 2 ;
• R’ and R" are independently selected from hydrogen and alkyl; and R 6 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl and aminoalkyl; wherein the aminoalkyl optionally substituted with 1 or 2 substituents selected from alkyl and -COCH 3 .
• M-1A is represented by the formula: wherein,
• R 4 is selected from hydrogen and alkyl
• R 6 is selected from hydrogen, hydroxyalkyl, (alkyl)aminoalkyl- or alkyl.
• M-1A is represented by the structure:
• R 12 are as defined in compound of formula (I).
• M is M-2; wherein Z represents 5- to 6-membered hetero arylenyl optionally substituted with 1, 2 or 3 groups independently selected from hydroxy, halogen, alkyl, heteroalkyl, haloalkyl, hydroxy alkyl, aminoalkyl and aminoalkynyl; wherein the aminoalkyl and aminoalkynyl are optionally substituted with 1 or 2 substituents selected from alkyl and -COCH 3 ;
• R 8 represents alkyl, acyl, heteroalkyl, haloalkyl, hydroxyalkyl or aminoalkyl
• R 9 represents hydrogen, alkyl, acyl or -Na
• R 10 and R 11 are independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl and aminoalkyl; wherein the aminoalkyl optionally substituted with 1 or 2 substituents selected from alkyl or -COCH 3 ;
• R 12 is 5- to 6-membered heteroaryl substituted with alkyl, hydroxy, amino or haloalkyl.
• M is M-2; wherein Z is oxazolylenyl or isoxazolylenyl; R 8 represents alkyl, haloalkyl or hydroxyalkyl; R 9 represents hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl or acyl; R 10 and R 11 independently represents hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl or (alkyl)aminoalkyl-; and R 12 represents thiazolyl substituted with alkyl.
• M-2 is selected from M-2A, M-2B and M-2C: wherein,
• Z represents oxazolylenyl optionally substituted with 1, 2 or 3 groups independently selected from hydroxy, halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, aminoalkyl and aminoalkynyl, wherein the aminoalkyl and aminoalkynyl are optionally substituted with 1 or 2 substituents selected from alkyl and -COCH 3 ;
• R 9 is hydrogen, alkyl, acyl or -Na; and
• R 11 is hydrogen, alkyl, haloalkyl, hydroxyalkyl or aminoalkyl; wherein the aminoalkyl optionally substituted with 1 or 2 substituents selected from alkyl and -COCH 3 .
• M is selected from M-1A, M-1B, M-1C, M-2A, M-2B and M- 2C; wherein,
• Z represents 5- to 6-membered hetero arylenyl optionally substituted with 1, 2 or 3 groups independently selected from hydroxy, halogen, alkyl, heteroalkyl, haloalkyl, hydroxy alkyl, aminoalkyl and aminoalkynyl; wherein the aminoalkyl and aminoalkynyl are optionally substituted with 1 or 2 substituents selected from alkyl and -COCH 3 ;
• R 4 and R 9 independently is hydrogen, alkyl, acyl or -Na; wherein the alkyl is optionally substituted with -OCOR’ or -OP(O)(OR”) 2 ; R’ and R" are independently selected from hydrogen and alkyl; and
• R 6 and R 11 independently is hydrogen, alkyl, haloalkyl, hydroxyalkyl or aminoalkyl; wherein the aminoalkyl optionally substituted with 1 or 2 substituents selected from alkyl and -COCH 3 .
• Z represents isoxazolylenyl, oxazolylenyl, or pyrrazolylenyl.
• M-2 represented by the structure: wherein R 9 represents hydrogen; and R 11 represents hydrogen or alkyl.
• M is represented by the structure:
• M is attached to A in compound of formula (I).
• the present invention provides compound of formula (IA) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof: wherein R 1 , R 2 , Ra, L and M are as defined in compound of formula (I).
• R 1 is halogen, hydroxy, 6- to 10- membered aryl or 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl are optionally substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, alkoxy, halogen and haloalkyl.
• R 1 is 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl are optionally substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, alkoxy, halogen and haloalkyl.
• R 1 is -Cl, -OH,
• each ring is optionally substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, alkoxy, halogen and haloalkyl.
• R 2 is hydrogen, hydroxy, halogen, alkoxy, alkyl or haloalkyl.
• R 2 represents hydrogen or halogen.
• Ra is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino or cyano.
• Ra is hydrogen, hydroxy, hydroxyalkyl, halogen, alkoxy and haloalkyl.
• Ra is hydrogen, halogen, or haloalkyl.
• Ra is hydrogen or halogen
• L is a bond. In one embodiment of compound of formula (IA), L is a bond, -O-(CH 2 )p-, -O-(CH 2 )p- O-, -NRx-(CH 2 )p-, -NRx-(CH 2 )p-O-, -NRx-(3- to 10-membered heterocyclo alkylenyl) - (CRxRy)n-, (3- to 10-membered cycloalkylenyl)-(CRxRy)n-, (3- to 10-membered heterocycloalkylenyl)-(CRxRy)n or -O-(3- to 10-membered heterocycloalkylenyl)- (CRxRy)n-.
• L is -O-CH 2 CH 2 CH 2 CH 2 -, -O-CH 2 - CH 2 CH 2 -, O-CH 2 CH 2 -O-, -O-CH 2 CH 2 CH 2 -O-, -NH-CH 2 CH 2 -O-, -N(CH 3 )-CH 2 CH 2 -O-, -NH-
• M is selected from M-1 and M-2; wherein
• Z is oxazolylenyl or isoxazolylenyl;
• R 3 and R 8 independently represents alkyl, haloalkyl or hydroxyalkyl;
• R 4 and R 9 independently represents hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl or acyl;
• R 5 and R 6 independently represents hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl or (alkyl)aminoalkyl-;
• R 10 and R 11 independently represents hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl or (alkyl)aminoalkyl-;
• R 7 and R 12 represents thiazolyl substituted with alkyl.
• M is represented by the structure:
• R 1 is halogen, hydroxy, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein the aryl and heteroaryl are optionally substituted with 1, 2 or 3 groups independently selected from hydroxy, alkoxy, halogen, alkyl and haloalkyl;
• R 2 is hydrogen or halogen
• Ra at each occurrence, independently represents hydrogen, halogen or haloalkyl
• L is a bond, -O-CH 2 CH 2 CH 2 -, -O-CH 2 CH 2 CH 2 CH 2 -, -O-CH 2 CH 2 -O-, -O-CH 2 CH 2 CH 2 -
• Z is oxazolylenyl or isoxazolylenyl;
• R 3 and R 8 independently represents alkyl, haloalkyl or hydroxyalkyl;
• R 4 and R 9 independently represents hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl or acyl;
• R 5 and R 6 independently represents hydrogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl or (alkyl)aminoalkyl-;
• R 10 and R 11 independently represents hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl or (alkyl)aminoalkyl-;
• R 7 and R 12 represents thiazolyl substituted with alkyl.
• each ring is optionally substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy, alkoxy, halogen and haloalkyl;
• R 2 is hydrogen or halogen
• Ra is hydrogen or halogen
• L is -O-CH 2 CH 2 CH 2 -, -O-CH 2 CH 2 CH 2 CH 2 -, -O-CH 2 CH 2 -O-, -O-CH 2 CH 2 CH 2 -O-, - NH-CH 2 CH 2 CH 2 CH 2 -, -N(CH 3 )-CH 2 CH 2 -O-, -N(CH 3 )-CH 2 CH 2 CH 2 CH 2 -, -NH-CH 2 CH 2 -O-,
• the present invention provides compound of formula (IB) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof:
• R 1 , R 2 , Ra, R 3 , R 4 , R 5 , R 6 and R 7 are as defined in compound of formula (I).
• R 1 represents -Cl, -OH, ; wherein each ring is optionally substituted with 1 or 2 groups independently selected from alkyl, hydroxy and halogen.
• L is a bond, -O-(CH 2 )p-, -O-(CH 2 )p-O- , -NRx-(CH 2 )p-, -NRx-(CH 2 )p-O-, -NRx-(3- to 10-membered heterocyclo alkylenyl) - (CRxRy)n-, (3- to 10-membered cycloalkylenyl)-(CRxRy)n-, (3- to 10-membered heterocycloalkylenyl)-(CRxRy)n or -O-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-
• L is -O-CH 2 CH 2 CH 2 -, -O-CH 2 CH 2 CH 2 CH 2 -, -O-CH 2 CH 2 -O-, -O-CH 2 CH 2 CH 2 -O-, - NH-CH 2 CH 2 CH 2 CH 2 -, -N(CH 3 )-CH 2 CH 2 -O-, -N(CH 3 )-CH 2 CH 2 CH 2 CH 2 -, -NH-CH 2 CH 2 -O-,
• each ring is optionally substituted with 1, 2 or 3 groups independently selected from alkyl, hydroxy and halogen;
• R 2 is hydrogen or halogen
• Ra is hydrogen or halogen
• L is a bond, -O-CH 2 CH 2 CH 2 -, -O-CH 2 CH 2 CH 2 CH 2 -, -O-CH 2 CH 2 -O-, -O-
• R 3 represents alkyl
• R 4 represents hydrogen or alkyl
• R5 represents hydrogen
• R 6 represents alkyl, halogen, haloalkyl, hydroxyalkyl or (alkyl)aminoalkyl-;
• R 7 represents thiazolyl substituted with alkyl.
• the present invention provides compound of formula (IC) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof: wherein X 1 and X 2 independently represents N or C; and R 1 , R 2 .Ra, Rd, Rx, Ry, X 1 , X 2 , n and M are as defined in compound of formula (I).
• each ring is optionally substituted with 1 or 2 groups independently selected from alkyl, hydroxy and halogen.
• Rx is hydrogen; and Ry is hydrogen or alkyl.
• M represents
• X 1 and X 2 independently represents N or C; wherein each ring is optionally substituted with 1 or 2 groups independently selected from alkyl, hydroxy and halogen;
• R 2 is hydrogen or halogen
• Ra represents hydrogen or halogen
• Rd is hydrogen or hydroxy
• Rx is hydrogen
• Ry is hydrogen or alkyl
• n 0, 1, 2 or 3.
• the present invention provides compound of formula (ID) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof: wherein R 1 , R 2 , Ra, Rd, R 3 , R 4 , R 5 , R 6 , R 7 and n are as defined in compound of formula (I).
• R 1 is halogen, hydroxy, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein, the aryl and heteroaryl are optionally substituted hydroxy, halogen, alkyl and haloalkyl;
• R 2 is hydrogen or halogen
• Ra represents hydrogen or halogen
• Rd is hydrogen or hydroxy
• R 3 represents alkyl, acyl or haloalkyl
• R 4 represents hydrogen or alkyl
• R 5 represents hydrogen
• R 6 represents hydrogen, alkyl, halogen, haloalkyl, hydroxy alkyl or (alkyl)aminoalkyl-;
• R 7 thiazolyl substituted with alkyl; and n is 0, 1, 2 or 3.
• R 1 is halogen, hydroxy, 6- to 10-membered aryl or 5- to 10-membered heteroaryl; wherein, the aryl and heteroaryl are optionally substituted hydroxy, halogen, alkyl and haloalkyl;
• R 2 is hydrogen or halogen
• Ra represents hydrogen or halogen
• Rd is hydrogen or hydroxy
• R 3 represents alkyl, acyl or haloalkyl
• R 4 represents hydrogen or alkyl
• R 5 represents hydrogen
• R 6 represents hydrogen, alkyl, halogen, hydroxyalkyl or (alkyl)aminoalkyl-;
• R 7 thiazolyl substituted with alkyl; and n is 0, 1, 2 or 3.
• the present invention provides compound of formula (IE) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof:
• R 1 , R 2 , R 8 , R 9 , R 10 , R 11 , R 12 , A and Z are as defined in compound of formula (I).
• R 1 represents -Cl, -OH, wherein each ring is optionally substituted with 1 or 2 groups independently selected from alkyl, hydroxy and halogen.
• R 2 is hydrogen or halogen; ; wherein each ring is substituted with 1 or 2 occurrences hydrogen or halogen;
• Z represents oxazolylenyl or isoxazolylenyl
• R 8 represents alkyl
• R 9 represents hydrogen
• R 10 represents hydrogen
• R 11 represents alkyl
• R 12 represents thiazolyl substituted with alkyl.
• the present invention provides a compound or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof; wherein the compound is selected from: or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof.
• the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof for use as a medicament.
• the present invention provides a use of a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer or a prodrug thereof, in the manufacture of a medicament for the treatment of diseases or disorders dependent upon SMARCA2 and/or SMARCA4.
• the present invention provides a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer or a prodrug thereof, for use in treating 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 comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof, wherein the compound is effective for degrading the target protein.
• the present invention provides a method for 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) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof.
• diseases or disorders that are dependent upon SMARCA2 and/or SMARCA4 include cancer.
• the present invention provides a method for inhibiting tumor growth in a subject afflicted with cancer comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof to the subject, in need thereof.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer or a tautomer or a prodrug thereof as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
• the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof.
• the compounds described in the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
• a pharmaceutically acceptable excipient such as a carrier or a diluent
• the present invention provides a pharmaceutical composition comprising a compound of formula (I), 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 SMARCA2 and/or SMARCA4.
• the subject is afflicted with cancer mediated by the target protein, wherein the target protein is SMARCA2 and/or SMARCA4.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof as described herein for use as a medicament.
• the present invention provides a pharmaceutical composition comprising a compound of formula (I), for use in treating or delaying progression of a disease or disorder mediated by SMARCA2 and/or SMARCA4.
• diseases or disorders that are dependent upon SMARCA2 and/or SMARCA4 are cancers selected from hematologic cancers, lung cancer (NSCLC i.e. nonsmall cell lung cancer), acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, 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, craniopharyngioma
• 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.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
• the oral compositions can also include adjuvants such as wetting agents, e
• Injectable preparations for example, sterile injectable aqueous, or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid are used in the preparation of injectables.
• compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this application with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
• compositions of a similar type may also be employed as fillers in soft and hard filled gelatine capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
• the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
• the solid dosage forms of tablets, draggers, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
• the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
• Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, including but not limited to tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
• the dosage forms may also comprise buffering agents.
• Dosage forms for topical or transdermal administration of a compound of this application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
• the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
• Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this application.
• the ointments, pastes, creams, and gels may contain, in addition to an active compound of this application, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• Powders and sprays can contain, in addition to the compounds of this application, excipients such as lactose, talc, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
• Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
• Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
• dosage forms can be made by dissolving or dispensing the compound in the proper medium.
• Absorption enhancers can also be used to increase the flux of the compound across the skin.
• the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
• Administration of the disclosed compounds and pharmaceutical compositions can be accomplished via any mode of administration for therapeutic agents.
• These modes include systemic or local administration such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
• the disclosed compounds or pharmaceutical compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time -release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
• injectables tablets, suppositories, pills, time -release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
• they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.
• Illustrative pharmaceutical compositions are tablets and gelatine 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, corn 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
• Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
• one or more disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
• a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
• Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.
• One or more disclosed compounds or compositions can be delivered by parental administration.
• the parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
• Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
• the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
• “optionally substituted alkyl” refers to the alkyl may be substituted as well as the event or circumstance where the alkyl is not substituted.
• 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 an 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. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.
• alkylenyl refers to divalent alkyl groups as defined herein.
• alkyl refers to saturated aliphatic groups, including but not limited to Ci-Cio straight-chain alkyl groups or C3-C10 branched-chain alkyl groups.
• alkyl refers to Ci-Ce straight-chain alkyl groups or C3-C6 branched-chain alkyl groups.
• the “alkyl” group refers to C1-C4 straight-chain alkyl groups or C3-C8 branched- chain 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 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.
• haloalkyl refers to alkyl substituted with one or more halogen atoms, wherein the halo and alkyl groups are as defined above.
• haloalkyl include but are not limited to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.
• aminoalkyl refers to an alkyl group substituted with an amino group, wherein the amino and alkyl groups are as defined above.
• aminoalkyl include but are not limited to -CH 3 -NH 2 , -CH 2 -CH 2 -NH 2 , -CH 2 -CH 2 -CH 2 -NH 2 , -CH(CH 3 )-CH 2 -NH 2 , -CH 2 -CH 2 -NH (CH 3 ) and -CH 2 -CH 2 -N(CH 3 ) 2 .
• alkylamino refers to an amino group substituted with one or two alkyl group(s), wherein the amino and alkyl groups are as defined above.
• alkylamino include but are not limited to -NH (CH 3 ), -N(CH 3 ) 2 , -NH (C2H5) and -NH (C2Hs) 2 .
• hydroxylalkyl or “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.
• hydroxylalkyl 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.
• cycloalkylenyl refers to a divalent cycloalkylenyl group as defined herein.
• the term “cycloalkyl” means C 3 -Cio 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.
• polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls.
• examples of ‘cycloalkylenyl 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, S, S(O), S(O) 2 , NH and C(O) 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, S, S(O), S(O) 2 , NH and C(O).
• heterocycloalkyl 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, tetrahydr
• heterocycloalkylenyl examples include, but not limited to, azetidinylenyl, oxetanylenyl, pyrrolidinylenyl, piperidinylenyl, piperazinylenyl, tetrahydropyridinylenyl, diazobicyclooctanylenyl, azabicyclooctanylenyl, azaspiroheptanylenyl, tetrahydropyranyl, tetrahydropyridazinylenyl, morpholinylenyl, thiomorpholinylenyl, 1,4-dioxanylenyl, dioxidothiomorpholinylenyl, oxapiperazinylenyl, oxapiperidinylenyl, tetrahydropyranylenyl, dihydropyranylenyl and
• heterocycloalkyl can be optionally substituted with one or more suitable groups by one or more aforesaid groups.
• heterocycloalkyl refers to 5- to 6-membered ring (unless the ring size is specifically mentioned) selected from the group consisting of imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl and thiomorpholinyl. All heterocycloalkyl are optionally substituted by one or more aforesaid groups.
• heteroarylenyl refers to a divalent heteroaryl group as defined herein.
• heteroaryl alone or in combination with other term(s) means a completely unsaturated ring system containing a total of 5 to 14 ring atoms, unless the ring size is specifically mentioned. At least one of the ring atoms is a heteroatom (i.e., O, N, or S), with the remaining ring atoms/groups being independently selected from C, N, O and S.
• a heteroaryl may be a single-ring (monocyclic) or multiple rings (bicyclic, tricyclic or polycyclic) fused together or linked covalently.
• heteroaryl is a 5- to 6-membered ring, unless the ring size is specifically mentioned.
• the rings may contain from 1 to 4 additional heteroatoms selected from N, O and S, wherein the N atom is optionally quartemized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure.
• heteroaryl examples include, but not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, IH-tetrazolyl, oxadiazolyl, triazolyl, pyridyl (pyridinyl), 3-fluoropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzo triazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, iso
• heteroarylenyl examples include, but not limited to, furanylenyl, thienylenyl, pyrrolylenyl, pyrazolylenyl, imidazolylenyl, oxazolylenyl, isoxazolylenyl, thiazolylenyl, isothiazolylenyl, 1H- tetrazolylenyl, oxadiazolylenyl, triazolylenyl, pyridylenyl (pyridinylenyl), pyrimidinylenyl, pyrazinylenyl and pyridazinylenyl. Heteroaryl group may be optionally further substituted.
• alkenyl refers to a carbon chain which contains at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof.
• alkenyl include, but not limited to, vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1 -propenyl, 2-butenyl and 2-methyl-2-butenyl.
• amino refers to an -NH 2 group.
• halo or halogen alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.
• hydroxy or “hydroxyl” alone or in combination with other term(s) means -OH.
• alkoxy refers to the group -O-alkyl, where alkyl groups are as defined above.
• Exemplary C1-C10 alkoxy group include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, t-butoxy or n-pentoxy.
• An alkoxy group can be optionally substituted with one or more suitable groups.
• the term “alkoxy” refers to C1-C4 alkoxy groups. Few examples of C1-C4 alkoxy include methoxy, ethoxy, n-propoxy, n-butoxy or t-butoxy.
• aryl refers to a monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of 6 to 14 carbon atoms.
• aryl refers to (C6-Cio)aryl.
• 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. Accordingly, examples of arylenyl groups include, but are not limited to phenylenyl, naphthylenyl, biphenylenyl and anthrylenyl.
• acyl refers to a group R-CO- or -CO-R wherein R is an optionally substituted alkyl group defined above.
• R is an optionally substituted alkyl group defined above.
• ‘acyl’ groups are, but not limited to, CH 3 CO-, CH 3 CH 2 CO-, CH 3 CH 2 CH 2 CO- or (CH 3 ) 2 CHCO-.
• heteroatom designates a sulfur, nitrogen or oxygen atom.
• the term 'compound(s)' comprises the compounds 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 or a stereoisomer 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 50% or from about 10% to about 30% by weight of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.
• the amount of the compound of formula (I) or pharmaceutically acceptable salt or a stereoisomer 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.
• the expression “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 or a stereoisomer 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.
• the term “subject” refers to an animal, preferably a mammal and most preferably a human.
• “delaying progression” of a disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late-stage cancer, such as development of metastasis, may be delayed.
• terapéuticaally effective amount refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof; or a composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a prodrug thereof, effective in producing the desired therapeutic response in a particular subject suffering from a disease or disorder, in particular their use in disease or disorder associated with cancer mediated by SMARCA2 and/or SMARCA4.
• 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 or a prodrug thereof, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to delay the progression of, or is 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 subject, the specific compound or composition employed the particular pharmaceutically acceptable carrier utilized.
• “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.
• 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
• 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
• 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.
• 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.
• cancer is SMARCA2 and/or SMARCA4 mediated cancer.
• exemplary cancer include but not limited to hematologic cancers, lung cancer (NSCLC i.e. non-small cell lung cancer), acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, 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, craniopharyngio
• stereoisomers refers to any enantiomers, diastereomers or geometrical isomers of the compounds 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 present invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d-Isomers and l-Isomers and mixtures thereof.
• Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers 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,
• 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 centers 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, trans nasal 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.
• 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.
• prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., compound of structure (I)).
• prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
• a prodrug is inactive when administered to a subject, but is converted in-vivo to an active compound, for example, by hydrolysis.
• the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
• prodrugs are also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
• Prodrugs of an active compound, as described herein are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
• Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
• Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
• prodrugs include compounds of structure (I) having a phosphate, phosphoalkoxy, ester or boronic ester substituent. Without being bound by theory, it is believed that such substituents are converted to a hydroxyl group under physiological conditions. Accordingly, embodiments include any of the compounds of the present invention, wherein a hydroxyl group has been replaced with a phosphate, phosphoalkoxy, ester or boronic ester group, for example a phosphate or phosphoalkoxy group. For example, in some embodiments a hydroxyl group on R 4 or R 9 moiety is replaced with a phosphate, phosphoalkoxy, ester or boronic ester group, for example a phosphate or alkoxy phosphate group.
• 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 Cl, 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.
• Step-b Synthesis of Tert-butyl 2-(4-(4-bromophenyl piperazin-1-yl)acetate)
• 1-(4-bromophenyl)piperazine hydrochloride 5.0 g, 18.1 mmol
• DIPEA 4.66 g, 36.2 mmol
• Tert-butyl 2-bromoacetate 5.3 g, 27.15 mmol
• Step-c Synthesis of tert-butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazin-1-yl)acetate
• tert-butyl 2-(4-(4-bromophenyl piperazin-1-yl)acetate) (4.2 g, 11.8 mmol) in dioxane (80 mL) was added bis pinacolato diboron (4.52 g, 17.8 mmol) and KOAc (2.33 g, 23.7 mmol) at RT and degassed with nitrogen for 5 min then Pd(dppf)Cl 2 .DCM (0.89 g, 1.18 mmol) was added into the reaction mixture and heated at 100 oC for 4 h.
• Step b Synthesis of ethyl 2-(1-(2-amino-4-bromophenyl)piperidin-4-yl)acetate
• ethyl 2-(1-(4-bromo-2-nitrophenyl)piperidin-4-yl)acetate 1.3g, 3.5 mmol
• iron 3. g, 28 mmol
• NH4OH 1.5 g, 28 mmol
• Step c Synthesis of ethyl 2-(1-(4-bromophenyl)piperidin-4-yl)acetate
• ethyl 2-(1-(2-amino-4-bromophenyl)piperidin-4-yl)acetate 1.0 g, 2.9 mmol
• tert butyl nitrite 0.58 g, 5.1 mmol
• the reaction mixture was diluted with EtOAc.
• the combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to get crude product.
• Step d Synthesis of ethyl 2-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperidin-4-yl)acetate
• ethyl 2-(1-(4-bromophenyl)piperidin-4-yl)acetate (0.37 g, 1.13 mmol) in dioxane (10 mL) was added bis pinacolato diboron (0.45 g, 1.7 mmol) and KOAc (0.22 g, 2.27 mmol) at RT and degassed with nitrogen for 5min.
• Step a Synthesis of 4-bromobenzaldehyde oxime To a solution of 4-bromobenzaldehyde (30 g, 162.16 mmol) and hydroxylamine hydrochloride (14.64 g, 210.8 mmol) in ethanol (300 mL) was added pyridine (19.21 mL, 243.2 mmol) to the reaction mixture and stirred at RT for 6 h.
• Step b Synthesis of 2-(3-(4-bromophenyl)isoxazol-5-yl)ethan-1-ol
• NCS N-(2-bromobenzaldehyde oxime
• reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to get the residue which was purified by combiflash column chromatography using 10% ethyl acetate in hexane as eluent to afford the title compound as white solid (7.5 g, 37%).
• Step e Synthesis of ethyl 2-(3-(4-bromophenyl)isoxazol-5-yl)-3-methylbutanoate
• Step f Synthesis of ethyl 3-methyl-2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)isoxazol -5-yl)butanoate
• Step-b Synthesis of 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride
• tert-butyl 4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)- carboxylate 1 g, 2.95 mmol
• DCM 1,4-dioxane
• 4M HCl 1,4-dioxane
• the reaction mixture was stirred at room temperature for 2h. After completion of the reaction (monitored by TLC) the reaction mixture was concentrated under reduced pressure and washed with diethyl ether to afford the title compound (0.8 g, 98%). %).
• Step-c Synthesis of tert-butyl 2-(4-(4-bromophenyl)-3,6-dihydropyridin-1(2H)-yl)acetate
• 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride 0.8 g, 2.91 mmol
• DMF dimethyl methoxyethyl
• DIPEA 1,2,3,6-tetrahydropyridine hydrochloride
• Step-d Synthesis of tert-butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl')phenyl')- 3,6-dihvdroDyridin-l(2H)-yl)acetate
• Step-i Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate
• Step-ii Synthesis of tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)piperazine-1-carboxylate
• tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate (0.65 g, 1.81 mmol) in dioxane (10 mL) was added bis pinacolato diboron (0.55 g, 2.17 mmol) and KOAc (0.53 g, 5.43 mmol) at RT and degassed with nitrogen for 5 min then Pd(dppf)Cl2.DCM (0.15 g, 0.18 mmol) was added into the reaction mixture and heated at 90 oC for 16h.
• Step-b Synthesis of ethyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6- dihydropyridin-1(2H)-yl)propanoate
• ethyl 2-(4-(4-bromophenyl)-3,6-dihydropyridin-1(2H)- yl)propanoate 0.8 g, 2.36 mmol
• dioxane 15 mL
• bis pinacolato diboron 0.9 g, 3.54 mmol
• KOAc 0.69 g, 7.09 mmol
• Pd(dppf)Cl2.DCM 0.19g, 0.23 mmol
• Step-b Synthesis of ethyl 2-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5- tetrahydro-[1,1'-biphenyl]-4-yl)acetate
• ethyl 2-(4'-bromo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- yl)acetate 0.5 g, 1.54 mmol
• dioxane 5 mL
• bis pinacolato diboron (0.58 g, 2.32 mmol
• KOAc 0.38 g, 3.86 mmol
• Step-a Synthesis of tert-butyl (lR,5S)-8-(4-bromophenyl)-3,8-diazabicyclor3.2.1]octane-3- carboxylate
• Step-b Synthesis of tert-butyl (1R,5S)-8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-3 , 8-diazabicyclo[3.2.1]octane-3-carboxylate
• reaction mixture was diluted with EtOAc.
• the combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to afford the title compound as pale-yellow solid (0.5 g, 40 %).
• Step-a Synthesis of methyl 5-((4-bromophenyl)amino)pentanoate
• Step-b Synthesis of methyl 5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)amino)pentanoate
• methyl 5-((4-bromophenyl)amino)pentanoate (0.28 g, 0.97 mmol) in dioxane (5 mL) was added bis pinacolato diboron (0.32 g, 1.26 mmol) and KOAc (0.29 g, 2.93 mmol) at RT and degassed with nitrogen for 5 min then Pd(dppf)Cl2.DCM (0.08 g, 0.09 mmol) was added into the reaction mixture and heated at 80 oC for 16h.
• Step-b Synthesis of tert-butyl 3-(4-bromophenyl)azetidine-1-carboxylate 70
• tert-butyl 3-(2-((4- methoxyphenyl)sulfonyl)hydrazineylidene)azetidine-1-carboxylate 1.2 g, 3.37 mmol
• (4- bromophenyl)boronic acid 1.01 g, 5.06 mmol
• dioxane 35 mL
• Cs2CO3 1.65 g, 5.06 mmol
• Step-c Synthesis of 3-(4-bromophenyl)azetidine
• tert-butyl 3-(4-bromophenyl)azetidine-1-carboxylate 0.36 g, 1.15 mmol
• DCM 3 mL
• trifluoro acetic acid 0.3 mL
• the reaction mixture was evaporated under reduced pressure, the resultant residue was washed with diethyl ether and dried under vacuum to afford the title compound off-white solid (0.28 g, 97.7%).
• Step-d Synthesis of tert-butyl 2-(3-(4-bromophenyl)azetidin-1-yl)acetate
• 3-(4-bromophenyl)azetidine (0.28 g, 1.12 mmol) in DMF (5 mL)
• DIPEA 0.72 g, 5.63 mmol
• Tert-butyl 2-bromoacetate (0.24 g, 1.24 mmol
• Step-e Synthesis of tert-butyl 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)azetidin-1-yl)acetate
• tert-butyl 2-(3-(4-bromophenyl)azetidin-1-yl)acetate (0.28 g, 0.85 mmol) in dioxane (5 mL) was added bis pinacolato diboron (0.32 g, 1.28 mmol) and KOAc (0.21 g, 2.14 mmol) at RT and degassed with nitrogen for 5 min then Pd(dppf)Cl 2 .DCM (0.07 g, 0.08 mmol) was added into the reaction mixture and heated at 110 oC for 16h.
• Step-b Synthesis of tert-butyl 6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2-carboxylate
• tert-butyl 6-(2-((4-methoxyphenyl)sulfonyl)hydrazineylidene)-2- azaspiro[3.3]heptane-2-carboxylate 2.8 g, 7.08 mmol
• (4-bromophenyl)boronic acid 2.13 g, 10.6 mmol
• dioxane 60 mL
• reaction mixture was heated for 16h at 110 oC in sealed tube. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc and filtered. Filtrate was concentrated under vacuum to give the residue which was purified by combiflash column chromatography using 20% ethyl acetate in hexane as eluent to afford the title compound as colourless liquid (1.3g, 52%).
• Step-c Synthesis of tert-butyl 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2- azaspiro[3.3]heptane-2-carboxylate
• tert-butyl 6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2- carboxylate 1.3 g, 3.69 mmol
• dioxane 35 mL
• KOAc 0.90 g, 9.22 mmol
• reaction mixture was heated at 90 °C for 3 h. After completion of the reaction (monitored by TLC) the reaction mixture was allowed to cool to RT and poured into ice cold water. The resulting mixture was extracted with ethyl acetate (2 X 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combiflash column chromatography using 50% ethyl acetate in hexane as eluent to afford the title compound (0.5 g, 30 %).
• Step-b Synthesis of 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-ol hydrochloride
• tert-butyl (2-hydroxy-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)carbamate 0.3 g, 0.89 mmol
• 4M HCl 1,4-dioxane
• Step-c Synthesis of tert-butyl ((2S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamate
• 2-amino-2-(4-(4-methylthiazol-5-yl)phenyl)ethan-1-ol hydrochloride 0.2 g, 0.85 mmol
• (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)- 4-hydroxypyrrolidine-2-carboxylic acid (0.35 g, 1.02 mmol) in DMF (3 mL) at 0°C was added HATU (0.48 g, 1.28 mmol) followed by
• Step-c Synthesis of NLNl-dimethyl-2-(4-(4-methyhhiazol-5-yl)phenyl)ethane-1,2-diamine hydrochloride
• N 1 ,N 1 -Dimethyl-2-(4-(4-methylthiazol-5-yl)phenyl)ethane- 1 ,2-diamine hydrochloride was prepared by procedure similar to the one described in step-b of Intermediate 19.
• Step-d Synthesis of tert-butyl ((2S)-1-((2S,4R)-2-((2-(dimethylamino)-1-(4-(4-methylthiazol- 5-yl)phenyl)ethyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2- yl)carbamate
• Step-e Synthesis of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-(2-(dimethylamino)-1- (4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide hydrochloride
• Example-1 (2S,4R)-4-Hydroxy-1-(2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 1, Racemic)
• Step-i Synthesis of Ethyl 2-(3-(4-(6-chloropyridazin-4-yl)phenyl)isoxazol-5-yl)-3- methylbutanoate
• reaction mixture was heated for Ih at 110 °C in microwave. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combiflash column chromatography using 50-60% ethyl acetate in hexane as eluent to afford the title compound as off-white solid (1 g, 71%).
• Step-ii Synthesis of Ethyl 2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)- 3 -methylbutanoate A mixture of 1,4-dioxane (15 mL) and water (3 mL) were taken in microwave vial and degassed with nitrogen for 5 min.
• Step-iii Synthesis of 2-(3-(4-(6-(2-Hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3- methylbutanoic acid
• ethyl 2-(3-(4-(6-(2-Hydroxyphenyl)pyridazin-4- yl)phenyl)isoxazol-5-yl)-3-methylbutanoate (0.75 g, 1.69 mmol) in THF (5 mL) and H2O (5 mL) mixture was added LiOH.H 2 O (0.21 g, 5.07 mmol) at 0 °C.
• reaction mixture was stirred for 3h at RT. Then the reaction mixture was evaporated under reduced pressure and the resultant residue was diluted with methanol and acidified to pH 6 using amberlite IT120 (acidic rasin) and filtered and filtrate was concentrated under vacuum to afford the title compound as a dark brown solid (0.65 g, 93%).
• Step-iv Synthesis of ((2S,4R)-4-Hydroxy-1-(2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide To a solution of 2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)isoxazol-5-yl)-3- methylbutanoic acid (0.1 g, 0.24 mmol), (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (0.11g, 0.28 mmol) and HATU
• Example-2 (2S,4R)-4-Hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 2) Step-i : Synthesis of Tert-butyl 2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetate
• Step-ii Synthesis of Tert-butyl 2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin- 1-yl) acetate
• Step-iii Synthesis of 2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1- yl)acetic acid
• Step-iv Synthesis of (2S,4R)-4-Hydroxy-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide
• reaction mixture was poured into ice cold water and extracted with ethyl acetate.
• the combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to get the crude product which was purified by combiflash column chromatography using 5% methanol in DCM as eluent to afford the title compound as yellow solid (0.11g, 11%).
• Example-3 (2S,4R)-1-((S)-2-(2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1- yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 3)
• Step-i Synthesis of 2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid
• tert-butyl 2-(4-(4-(6-chloropyridazin-4-yl)phenyl)piperazin-1- yl)acetate (0.07 g, 0.179 mmol) in DCM (5 mL) was added 4N-dioxane hydrochloride (2 mL) at 0 °C and then slowly brought to RT and stirred for 16h.
• Example-4 (2S,4R)-1-((S)-2-(2-(4-(4-(6-(5-Fluoro-2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 4)
• Step-i Synthesis of Tert-butyl 2-(4-(4-(6-(5-fluoro-2-hydroxyDhenyl)Dyridazin-4- yPphenyPpiperazin- 1 -yI )acetate
• Step-ii Synthesis of 2-(4-(4-(6-(5-Fluoro-2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin- 1-yl) acetic acid
• Step-iii Synthesis of (2S,4R)-1-((S)-2-(2-(4-(4-(6-(5-Fluoro-2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperazin- 1 -yl)acetamido) -3 ,3 -dimethylbutanoyl)-4-hydroxy-N-((S)-1 -(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
• reaction mixture was stirred for 3 h at RT. Then the reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to get the crude product which was purified by preparative HPLC to afford the title compound as yellow solid (0.014g, 10%).
• Step-ii Synthesis of Tert-butyl 2-(4-(5-(6-chloropyridazin-4-yl)pyridin-2-yl)piperazin-1- yla)cetate
• Step-iii Synthesis of Tert-butyl 2-(4-(5-(6-(2-hydroxyphenyl)pyridazin-4-yl)pyridin-2- yl)piperazin-1-yl)acetate
• tert-butyl 2-(4-(5-(6-chloropyridazin-4-yl)pyridin-2- yl)piperazin-1-yl)acetate 0.25 g, 0.64 mmol
• (2-hydroxyphenyl)boronic acid (0.13g, 0.96 mmol) in 1,4-dioxane (10 mL) was added 2M Na 2 CO 3 (0.27 g, 2.56 mmol) 1.2 mL solution and degassed with nitrogen for 15 min.
• Step-iv Synthesis of 2-(4-(5-(6-(2-Hydroxyphenyl)pyridazin-4-yl)pyridin-2- yl)piperazin-1-yl)acetic acid
• a stirred solution of tert-butyl 2-(4-(5-(6-(2-Hydroxyphenyl)pyridazin-4-yl)pyridin- 2-yl)piperazin-1-yl)acetate (0.15 g, 0.33 mmol) in DCM (10 mL) was added 4 N dioxane hydrochloride (5 mL) at 0 oC and then slowly brought to RT and stirred at RT for 2 h.
• Example-6 (2S,4R)-4-Hydroxy-1-((S)-2-(2-(1-(4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperidin-4-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 6)
• Step-i Synthesis of 2-(1-(4-(6-Chloropyridazin-4-yl)phenyl)piperidin-4-yl)acetic acid
• 5-Bromo-3-chloropyridazine (0.13 g, 0.67 mmol)
• ethyl 2-(1- (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl)acetate (0.25g, 0.67 mmol) and Na2CO3 (0.28 g, 2.68 mmol) in 1,4-dioxane (5 mL) and water (2 mL) and degassed with nitrogen for 15 min.
• Step-ii Synthesis of (2S,4R)-1-((S)-2-(2-(1-(4-(6-Chloropyridazin-4-yl)phenyl)piperidin-4- yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide
• 2-(1-(4-(6-Chloropyridazin-4-yl)phenyl)piperidin-4-yl)acetic acid (0.09 g, 0.27 mmol)
• Step-i Synthesis of Tert-butyl 2-(4-(4-(6-(2-fluorophenyl)pyridazin-4-yl)phenyl)piperazin-1- yl)acetate
• Step-ii Synthesis of 2-(4-(4-(6-(2-Fluorophenyl)pyridazin-4-yl)phenyl)piperazin-1-yl)acetic acid hydrochloride
• Step-iii Synthesis of (2S,4R)-1-((S)-2-(2-(4-(4-(6-(2-Fluorophenyl)pyridazin-4- yl)phenyl)piperazin- 1 -yl)acetamido) -3 ,3 -dimethylbutanoyl)-4-hydroxy-N-(( S )- 1 -(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
• Example-8 (2S,4R)-4-Hydroxy-1-((S)-2-(3-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperazin-1-yl)propanamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 8)
• Step-i Synthesis of Tert-butyl 4-(4-(6-chloropyridazin-4-yl)phenyl)piperazine-1-carboxylate
• 5-bromo-3-chloropyridazine (0.72 g , 3.8 mmol)
• tert-butyl 4- (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate 1 g, 2.57 mmol
• 1,4-dioxane 20 mL
• water 4 mL
• Na2CO3 0.82 g, 7.73 mmol
• Step-ii Synthesis of Tert-butyl 4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazine-1- carboxylate
• tert-butyl 4-(4-(6-chloropyridazin-4-yl)phenyl)piperazine-1- carboxylate 0.5 g , 1.33 mmol
• (2-hydroxyphenyl)boronic acid 0.22 g, 1.60 mmol
• Na 2 CO 3 (0.42 g, 4.01 mmol
• Step-iii Synthesis of 2-(5-(4-(Piperazin-1-yl)phenyl)pyridazin-3-yl)phenol
• Step-v Synthesis of 3-(4-(4-(6-(2-Hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1- yl)propanoic acid
• Step-ii Synthesis of methyl 5-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanoate
• methyl 5-(4-(6-chloropyridazin-4-yl)phenoxy)pentanoate 0.5 g , 1.56 mmol
• (2-Hydroxyphenyl)boronic acid 0.43 g, 3.12 mmol
• Na2CO3 0.50 g, 4.68 mmol
• Step-iii Synthesis of 5-(4-(6-(2-Hydroxyphenyl)pyridazin-4-yl)phenoxy)pentanoic acid
• methanol:THF:H2O 3mL:4mL:3mL
• LiOH.H2O 0.03 g, 1.51 mmol
• the Compound 35 was prepared by procedure similar to the one described in Example- 10 with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions.
• Example-12 (2S,4R)-4-Hydroxy-1-((S)-2-(5-((4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)amino)pentanamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 36)
• the Compound 36 was prepared by procedure similar to the one described in Example- 10 with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions.
• Example-13 (2S,4R)-4-Hydroxy-1-(2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 42, Racemic) Step-i: Synthesis of 5-(4-(2-Bromoethoxy)phenyl)-3-chloropyridazine
• Step-ii Synthesis of Methyl 2-(3-(2-(4-(6-chloropyridazin-4-yl)phenoxy)ethoxy)isoxazol-5- yl)-3-methylbutanoate
• compound methyl 2-(3-hydroxyisoxazol-5-yl)-3- methylbutanoate (0.2g, 1 mmol) and 5-(4-(2-Bromoethoxy)phenyl)-3-chloropyridazine (0.38g, 1.2 mmol) in DMF (5mL) was added Methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (0.2g, 1 mmol), K2CO3 (0.30 g, 2.2 mmol) (0.2g, mmol) at RT and the reaction mixture was heated at 70 o C temp in a sealed for 12 h.
• Step-iii Synthesis of Methyl 2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoate
• Methyl 2-(3-(2-(4-(6-chloropyridazin-4- yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoate (0.16 g, 0.37 mmol)
• (2- Hydroxyphenyl)boronic acid 0.1 g, 0.74 mmol
• 1,4-dioxane 3 mL
• water 1 mL
• Step-iv Synthesis of 2-(3-(2-(4-(6-(2-Hydroxyphenyl)pyridazin-4- yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoic acid
• methyl 2-(3-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenoxy)ethoxy)isoxazol-5-yl)-3-methylbutanoate (0.08g, 0.16 mmol) in methanol:THF:H2O (1mL:1mL:1mL) mixture was added LiOH.H2O (0.022 g, 0.49 mmol) at 0 °C.
• reaction mixture was stirred for 16h at RT.
• the reaction mixture was then evaporated under reduced pressure and the resultant residue was diluted with methanol and acidified to pH 6 using Amberlite ® IT120 and filtered and filtrate was concentrated under vacuum to afford the title compound as a sticky solid (0.06 g, 77%).
• the Compound 43 was prepared by procedure similar to the one described in Example-13 with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions.
• the Compound 44 was prepared by procedure similar to the one described in Example- 13 with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions.
• Step-ii Synthesis of Tert-butyl 4-((4-(6-chloropyridazin-4-yl)phenyl)amino)piperidine-1- carboxylate
• 4-(6-Chloropyridazin-4-yl)aniline 0.5 g, 2.43 mmol
• Tert- butyl 4-oxopiperidine-1-carboxylate (0.96 g, 4.86 mmol) in ethanol (10 mL) was added acetic acid (0.05 mL) and stirred at RT for 2 hrs.
• sodium cyanoborohydride (0.96 g, 4.86 mmol) was added into the reaction mixture and stirred at RT for 12 hrs.
• Step-iii Synthesis of N-(4-(6-chloropyridazin-4-yl)phenyl)piperidin-4-amine hydrochloride
• a stirred solution of Tert-butyl 4-((4-(6-chloropyridazin-4- yl)phenyl)amino)piperidine-1-carboxylate (0.1 g, 0.25 mmol) in DCM (1 mL) was added dioxane HCl (1 mL) at 0 oC and then slowly brought to RT and stirred at RT for 1 h.
• Step-iv Synthesis of Tert-butyl 2-(4-((4-(6-chloropyridazin-4-yl)phenyl)amino)piperidin-1- yl)acetate
• N-(4-(6-Chloropyridazin-4-yl)phenyl)piperidin-4-amine hydrochloride (0.08 g, 0.24mmol) in DMF (2 mL) was added DIPEA (0.16 g, 1.23 mmol) at RT and stirred for 15 min then added tert-butyl 2-bromoacetate (0.06 g, 0.295 mmol) and stirred for 2 h at RT under nitrogen atmosphere.
• Step-v Synthesis of Tert-butyl 2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)amino)piperidin-1-yl)acetate
• 2-hydroxyphenyl boronic acid 0.04 g, 0.298 mmol
• 1,4-dioxane 2 mL
• water 2 mL
• Step-vi Synthesis of 2-(4-((4-(6-(2-Hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidin-1- yl)acetic acid hydrochloride
• To a stirred solution of Tert-butyl 2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)amino)piperidin-1-yl)acetate (0.04 g, 0.48 mmol) in DCM (1 mL) was added 4 N dioxane hydrochloride (0.4 mL) at 0 oC and then slowly bring to RT and stirred at RT for 16h.
• Step-vii Synthesis of (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((4-(6-(2-hydroxyphenyl)pyridazin- 4-yl)phenyl)amino)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
• 2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)amino)piperidin- l-yl)acetic acid hydrochloride (0.03g, 0.074 mmol)
• ((2S,4R)-1-((S)-2-amino-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5)
• Example-17 (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-((4-(6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)(methyl)amino)piperidin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4- (4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (Compound 46)
• the Compound 46 was prepared by procedure similar to the one described in Example-16 with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions.
• Step-i Synthesis of (2S,4R)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazol-5- yl)phenyl)ethyl)-1-((S)-2-(2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperazin-1- yl)acetamido)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide
• the Compound 50 was prepared by procedure similar to the one described in Example-13 with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions.
• Example-Pl Determination of Anti proliferative activity of compounds in cell lines A549 by Cell Titer Glo®(promega) assay
• A549 (ATCC CCL-185) cells were seeded in 96 well plate flat black clear bottom plates (Corning, Cat. No 3904) using complete F-12K Medium.
• Compounds of the present invention were added to cells from 10 mM stocks made in DMSO (Sigma Cat no. D2650) on the following day. Each concentration of compound was tested in triplicate with DMSO concentration at a final percentage not exceeding 0.3 in the cells. After the compound incubation (8 days for A549) assay was terminated using 50 pl of CellTiter Gio® reagent (Promega, Cat. no G7572).
• Example-Pl From the experiment described in Example-Pl, the selected compounds of the present invention were found to have IC50 values of less than 1 pM.
• Example-P2 Determination of SMARCA2 and SMARCA4 degradation in VCaP cells by Western blot
• VCaP (ATCC CRL-2876) was plated in 6 well plates using complete Dulbecco's Modified Eagle'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 0.3 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.
• Example-P3 Determination of Anti proliferative activity of compounds by Cell Titer Glo®(promega) assay
• EC50 Selected compounds of the present invention were screened in the above-mentioned assay procedures for determination of EC50 (SK- MEL-5) values and the results are summarized into groups A, B and C in below table.
• group “A” refers to EC50 values lower than 250nM
• “B” refers to EC50 values between 250.01nM-500nM (both inclusive)
• “C” refers to EC50 values greater than 500nM.
• RERF-LC-A1 cell line data for selected compounds of the present invention are summarized in table below.
• group “++” refers to EC50 (RERF-LC-A1) values lower than lOOnM and “+” refers to EC50 (RERF-LC-A1) values greater than lOOnM.

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