WO2025094065A1 - Composés de pyridazine à substitution amino utilisés en tant qu'agents de dégradation de smarca2 et/ou de smarca4 - Google Patents

Composés de pyridazine à substitution amino utilisés en tant qu'agents de dégradation de smarca2 et/ou de smarca4 Download PDF

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WO2025094065A1
WO2025094065A1 PCT/IB2024/060683 IB2024060683W WO2025094065A1 WO 2025094065 A1 WO2025094065 A1 WO 2025094065A1 IB 2024060683 W IB2024060683 W IB 2024060683W WO 2025094065 A1 WO2025094065 A1 WO 2025094065A1
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cancer
compound
membered
mmol
heterocycloalkylenyl
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Chandrasekhar ABBINENI
Susanta Samajdar
Bilash KUILA
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Aurigene Oncology Ltd
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Aurigene Oncology Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure 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.
  • 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.
  • 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, 78-87, 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.
  • amino-substituted pyridazine compounds and pharmaceutical compositions thereof that are useful as SMARCA2/4 degraders and for the treatment of disease or disorder dependent on or mediated by SMARCA2/4.
  • the present disclosure provides a compound of formula (I): or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein, R1 at each occurrence, independently, is hydroxy, halo(C1-C6)alkyl, (C1-C6)alkoxy, halogen, (C1-C6)alkyl, amino or cyano; q is 0, 1, 2 or 3; Q is hydroxy, (C 1 -C 6 )alkoxy, amino or (C 1 -C 6 )alkylamino; A is phenylenyl or 6-membered heteroarylenyl; wherein the phenylenyl and heteroarylenyl independently, are unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Ra; Ra represents halogen, (C1-C6)alkyl or halo(C1-C6)alkyl; L1 is -(3- to 12-membered heterocycloalkylen
  • the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, and a pharmaceutically acceptable carrier or an excipient.
  • the present disclosure provides a method of degrading a target protein in a subject comprising, administering to the subject in need thereof, a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.
  • the present disclosure provides a method of treating a condition of a disease or a disorder comprising, administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof to an individual, e.g., a human, in need thereof.
  • the disease or disorder is treatable by degradation of SMARCA2/4, for example, a cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis or a viral infection.
  • the present disclosure provides a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, for use as a medicament.
  • the present disclosure provides the use of a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder dependent upon SMARCA2 and/or SMARCA4; wherein the disease or disorder is cancer.
  • a compound of formula (I) which are useful as SMARCA2/4 degraders and for the treatment of conditions dependent on or mediated by SMARCA2/4.
  • the present disclosure further provides pharmaceutical compositions comprising the said compound or a stereoisomer or a tautomer thereof as therapeutic agents.
  • the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein, R 1 at each occurrence, independently, is hydroxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halogen, (C1-C6)alkyl, amino or cyano; q is 0, 1, 2 or 3; Q is hydroxy, (C 1 -C 6 )alkoxy, amino or (C 1 -C 6 )alkylamino; A is phenylenyl or 6-membered heteroarylenyl; wherein the phenylenyl and heteroarylenyl independently, are unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Ra; Ra represents halogen, (C1-C6)alkyl or halo(C1-C6)alkyl; L1 is -(3- to 12-membered heterocycl
  • R1 is hydroxy or halo(C1-C6)alkyl. In one embodiment, R 1 is -OH or -CF 3. In one embodiment, R 1 is halo(C 1 -C 6 )alkyl. In one embodiment, R1 is -CF3. In one embodiment, q is 1, 2, or 3. In one embodiment, q is 1. In one embodiment, Q is hydroxy, amino or (C1-C6)alkylamino. In one embodiment, Q is -NH2, -NHCH3 or -OH. In one embodiment, Q is amino or (C 1 -C 6 )alkylamino. In one embodiment, Q is amino or hydroxy. In one embodiment, Q is (C1-C6)alkylamino.
  • Q is -NH 2 , or -OH. In one embodiment, Q is -NHCH 3 or -OH. In one embodiment, Q is -NH2. In one embodiment, Q is -NHCH3. In one embodiment, Q is -OH. In one embodiment, ring A is phenylenyl; wherein phenylenyl is unsubstituted or substituted with 1 or 2 occurrence(s) of Ra. In one embodiment, ring A is phenylenyl; wherein phenylenyl is unsubstituted.
  • ring A is 6-membered heteroarylenyl; wherein the heteroarylenyl is pyridinylenyl, pyrimidinylenyl, triazinylenyl, or pyrazinylenyl. In one embodiment, ring A is 6-membered heteroarylenyl; wherein the heteroarylenyl is unsubstituted.
  • Ra is halogen or (C1-C6)alkyl. In one embodiment, Ra is -F or methyl. In one embodiment, Ra is halogen. In one embodiment, Ra is (C1-C6)alkyl. In one embodiment, Ra is F. In one embodiment, Ra is methyl.
  • L 1 is -(3- to 12-membered heterocycloalkylenyl)- *-(3- to 12- membered heterocycloalkylenyl)-(3- to 8-membered cycloalkylenyl)-, or *-N(Rx)-(3- to 12- membered heterocycloalkylenyl)-; wherein the heterocycloalkylenyl and cycloalkylenyl independently is unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Rd; wherein the asterisk mark represents the point of attachment with ring A.
  • L1 is -(6- to 10-membered heterocycloalkylenyl)-, *-(6- to 10- membered heterocycloalkylenyl)-(6- to 8-membered cycloalkylenyl)-, -(3- to 12-membered heterocycloalkylenyl)-(6- to 8-membered heterocycloalkylenyl)-, or *-N(Rx)-(6- to 10- membered heterocycloalkylenyl)-; wherein the heterocycloalkylenyl and cycloalkylenyl independently is unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Rd; wherein the asterisk mark represents the point of attachment with ring A.
  • Rd at each occurrence is (C1-C6)alkyl, halo(C1- C6)alkyl, halogen, hydroxy, or (C1-C6)alkoxy. In one embodiment, Rd at each occurrence, independently, is halogen. In one embodiment, Rd at each occurrence, independently, is fluorine. In one embodiment, Rx is hydrogen or (C1-C6)alkyl. In one embodiment, Rx is hydrogen.
  • L 2 is a bond, -(3- to 8-membered cycloalkylenyl)-, -(3- to 10- membered heterocycloalkylenyl), *-(CRxRy) n -(3- to 8-membered cycloalkylenyl)-, *- (CRxRy)n-(3- to 10-membered heterocycloalkylenyl)-, *-(3- to 10-membered heterocycloalkylenyl)-(CRxRy)n-; wherein the cycloalkylenyl and heterocycloalkylenyl, at each occurrence, independently is unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Rd; wherein the asterisk mark represents the point of attachment with L1.
  • L2 is a bond, -(3- to 8-membered cycloalkylenyl)-, -(3- to 10- membered heterocycloalkylenyl)-, *-(CRxRy) n -(3- to 8-membered cycloalkylenyl)- or *- (CRxRy)n-(3- to 10-membered heterocycloalkylenyl)-; wherein the cycloalkylenyl and heterocycloalkylenyl independently is substituted with 1, 2 or 3 occurrences of Rd; wherein the asterisk mark represents the point of attachment with L 1 .
  • L 2 is a bond, -(4- to 8-membered cycloalkylenyl)-, -(4- to 8- membered heterocycloalkylenyl), *-(CRxRy)n-(4- to 8-membered cycloalkylenyl)-, *- (CRxRy)n-(4- to 8-membered heterocycloalkylenyl)-, *-(4- to 8-membered heterocycloalkylenyl)-(CRxRy) n -; wherein the cycloalkylenyl and heterocycloalkylenyl, at each occurrence, independently is unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Rd; wherein the asterisk mark represents the point of attachment with L1.
  • Rd at each occurrence, independently, is (C 1 -C 6 )alkyl, halo(C 1 - C6)alkyl, or halogen. In one embodiment, Rd at each occurrence, independently, is halogen. In one embodiment, Rd at each occurrence, independently, is fluorine. In one embodiment, Rx and Ry, independently, is hydrogen or (C 1 -C 6 )alkyl. In one embodiment, Rx and Ry is hydrogen. In one embodiment, n represents 1, 2, or 3. In one embodiment, n represents 1. I n one embodiment, L2 is a bond, , , , mark indicates the point of attachment towards L 1 . In one embodiment, M is M 1 or M 2 : .
  • Rz is hydrogen or (C1-C6)alkyl. In one embodiment, Rz is hydrogen or -CH 3. In one embodiment, Rz is hydrogen. In one embodiment, Rz is (C1-C6)alkyl. In one embodiment, Rz is -CH3. In one embodiment, X and X’, independently, is a bond, -NH-, -N(C 1 -C 6 )alkyl, or -O-. In one embodiment, X and X’, independently, is a bond, -NH-, -N(methyl)-, -O-. In one embodiment, X and X’, independently, is a bond, -NH-, or -N(methyl)-.
  • X and X’ independently, is a bond, or -NH-. In one embodiment, X and X’, independently is -NH- or -N(C1-C6)alkyl. In one embodiment, X and X’ is a bond In one embodiment, X and X’ is -NH-. In one embodiment, X and X’ is -N(methyl)-. In one embodiment, X and X’ is -O-. In one embodiment, X 1 and X 2, independently, is -N- or -CH-. In one embodiment, X1 and X2, is -CH-.In one embodiment, R2 is hydrogen, halogen, or halo(C1-C6)alkyl.
  • R 2 is halogen or halo(C 1 -C 6 )alkyl.
  • R2 is hydrogen, fluorine, or -CF3.
  • R2 is fluorine or -CF3.
  • R 2 is fluorine or chlorine.
  • R 2 is hydrogen.
  • R2 is fluorine.
  • R2 is halo(C1-C6)alkyl.
  • R 2 is -CF 3 .
  • R2 is (C1-C6)alkyl.
  • R3 and R3’ independently are hydrogen. In one embodiment, R 3 and R 3’ together represent an oxo group.
  • R 4 is hydrogen or (C 1 -C 6 )alkyl. In one embodiment, R4 is hydrogen or methyl. In one embodiment, R 4 is hydrogen. In one embodiment, R 4 is (C 1 -C 6 )alkyl. In one embodiment, R4 is methyl. In one embodiment, M1 is a group of formula
  • M 2 is a group of formula
  • R1 is hydroxy or halo(C1-C6)alkyl
  • Q is amino or hydroxy, (C1-C6)alkylamino
  • ring A is phenylenyl
  • M is
  • R 2 is hydrogen, halogen or halo(C 1 -C 6 )alkyl
  • R3 and R3’ independently are hydrogen; or R3 and R3’ together represent an oxo group.
  • the present disclosure provides a compound of formula (IA): or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein R 1 , Q, L 1 , L 2, and M are as described in classes and subclasses herein, both singly and in combination.
  • R1 at each occurrence independently is hydroxy or halo(C1- C 6 )alkyl.
  • R 1 at each occurrence independently is hydroxy.
  • R1 at each occurrence independently is halo(C1-C6)alkyl.
  • R1 at each occurrence, independently, is -OH or -CF3.
  • Q is hydroxy, amino or (C 1 -C 6 )alkylamino.
  • L1 is -(6- to 10-membered heterocycloalkylenyl)-, *-(6- to 10- membered heterocycloalkylenyl)-(6- to 8-membered cycloalkylenyl)-, -(3- to 12-membered heterocycloalkylenyl)-(6- to 8-membered heterocycloalkylenyl)-, or *-N(Rx)-(6- to 10- membered heterocycloalkylenyl)-; wherein the heterocycloalkylenyl and cycloalkylenyl independently is unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Rd; wherein the asterisk mark represents the point of attachment with ring A.
  • L2 is a bond, -(4- to 8-membered cycloalkylenyl)-, -(4- to 8-membered heterocycloalkylenyl), *-(CRxRy)n-(4- to 8-membered cycloalkylenyl)-, *- (CRxRy) n -(4- to 8-membered heterocycloalkylenyl)-, *-(4- to 8-membered heterocycloalkylenyl)-(CRxRy)n-; wherein the cycloalkylenyl and heterocycloalkylenyl, at each occurrence, independently is unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Rd; wherein the asterisk mark represents the point of attachment with L 1 .
  • L 2 is a bond, -(4- to 8-membered cycloalkylenyl)-, -(4- to
  • the present disclosure provides a compound of formula (IB): or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein R1, Q, L1, L2, X, R2, R3, R3’and R4 are as described in classes and subclasses herein, both singly and in combination.
  • R 1 at each occurrence independently is hydroxy or halo(C 1 - C6)alkyl.
  • Q is hydroxy, amino or (C1-C6)alkylamino.
  • L 1 is -(6- to 10-membered heterocycloalkylenyl)-, *-(6- to 10- membered heterocycloalkylenyl)-(6- to 8-membered cycloalkylenyl)-, -(3- to 12-membered heterocycloalkylenyl)-(6- to 8-membered heterocycloalkylenyl)-, or *-N(Rx)-(6- to 10- membered heterocycloalkylenyl)-; wherein the heterocycloalkylenyl and cycloalkylenyl independently is unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Rd; wherein the asterisk mark represents the point of attachment with ring A.
  • L 2 is a bond, -(4- to 8-membered cycloalkylenyl)-, -(4- to 8-membered heterocycloalkylenyl), *-(CRxRy) n -(4- to 8-membered cycloalkylenyl)-, *- (CRxRy)n-(4- to 8-membered heterocycloalkylenyl)-, *-(4- to 8-membered heterocycloalkylenyl)-(CRxRy)n-; wherein the cycloalkylenyl and heterocycloalkylenyl, at each occurrence, independently is unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Rd; wherein the asterisk mark represents the point of attachment with L1.
  • L2 is a bond, , wherein the asterisk mark indicates the point of attachment towards L1.
  • X is a bond, -NH-, -N(CH 3 )- or -O-.
  • X is a bond.
  • X is -NH-.
  • X is -N(CH 3 )-.
  • X is -O-.
  • R2 at each occurrence, independently, is hydrogen, halogen or halo(C 1 -C 6 )alkyl.
  • R 2 is hydrogen or fluorine.
  • R3 and R3’ are hydrogen.
  • R 3 and R 3 ’ together represent an oxo group.
  • R4 is hydrogen or (C1-C6)alkyl. In one embodiment, R4 is hydrogen or methyl.
  • the present disclosure provides a compound of formula (IC): or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein R 1 , Q, L 1 , L 2, X, R 2 , R 4, X 1 , X 2, and X' are as described in classes and subclasses herein, both singly and in combination.
  • R1 at each occurrence independently is hydroxy or halo(C1- C 6 )alkyl.
  • Q is hydroxy, amino or (C1-C6)alkylamino.
  • L1 is -(6- to 10-membered heterocycloalkylenyl)-, *-(6- to 10- membered heterocycloalkylenyl)-(6- to 8-membered cycloalkylenyl)-, -(3- to 12-membered heterocycloalkylenyl)-(6- to 8-membered heterocycloalkylenyl)-, or *-N(Rx)-(6- to 10- membered heterocycloalkylenyl)-; wherein the heterocycloalkylenyl and cycloalkylenyl independently is unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Rd; wherein the asterisk mark represents the point of attachment with ring A.
  • L2 is a bond, -(4- to 8-membered cycloalkylenyl)-, -(4- to 8-membered heterocycloalkylenyl), *-(CRxRy)n-(4- to 8-membered cycloalkylenyl)-, *- (CRxRy) n -(4- to 8-membered heterocycloalkylenyl)-, *-(4- to 8-membered heterocycloalkylenyl)-(CRxRy)n-; wherein the cycloalkylenyl and heterocycloalkylenyl, at each occurrence, independently is unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Rd; wherein the asterisk mark represents the point of attachment with L 1 .
  • L2 is a bond, towards L1. I n one embodiment, L2 is a bond, , wherein the asterisk mark indicates the point of attachment towards L 1 .
  • X’ is a bond, -NH- or -O-. In one embodiment, X’ is a bond. In one embodiment, X’ is -NH-. In one embodiment, X’, is -N(CH 3 )- In one embodiment, X’ is -O-. In one embodiment, X1 and X2 are CH. In one embodiment, X 1 and X 2 are N.
  • R2 is hydrogen, halogen, or halo(C1-C6)alkyl.
  • R2 is hydrogen, fluorine, or -CF3. In one embodiment, R 2 is hydrogen or fluorine. In one embodiment, R2 is hydrogen. In one embodiment, R2 is fluorine. In one embodiment, R 2 is -CF 3. In one embodiment, R 4 is hydrogen or (C 1 -C 4 )alkyl. In one embodiment, R4 is hydrogen or methyl. In one embodiment, R4 is hydrogen. In one embodiment, the present disclosure provides a compound of formula (ID): or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein L 1 , L 2, X, R 2 , R 3 , R 3’ and R 4 are as described in classes and subclasses herein, both singly and in combination.
  • ID compound of formula (ID): or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein L 1 , L 2, X, R 2 , R 3 , R 3’ and R 4 are as described in classes and subclasses
  • the present disclosure provides a compound of formula (IE): or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein L1, L2, X, R2, and R4 are as described in classes and subclasses herein, both singly and in combination.
  • IE formula
  • the present disclosure provides compound of formula (I), wherein R1 is hydroxy or halo(C1-C6)alkyl; Q is hydroxy, amino or (C1-C6)alkylamino; A is phenylenyl; wherein phenylenyl is unsubstituted or substituted with 1 or 2 occurrence(s) of Ra; L1 is -(3- to 12-membered heterocycloalkylenyl)- *-(3- to 12-membered heterocycloalkylenyl)-(3- to 8-membered cycloalkylenyl)-, or *-N(Rx)-(3- to 12-membered heterocycloalkylenyl)-; wherein the heterocycloalkylenyl and cycloalkylenyl independently is unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Rd; wherein the asterisk mark represents the point of attachment with ring A; L
  • the present disclosure provides compound of formula (I), wherein R 1 is -OH or -CF 3 ; Q is amino; A is phenylenyl; L 1 is -(6- to 10-membered heterocycloalkylenyl)-, *-(6- to 10-membered heterocycloalkylenyl)-(6- to 8-membered cycloalkylenyl)-, -(3- to 12-membered heterocycloalkylenyl)-(6- to 8-membered heterocycloalkylenyl)-, or *-N(Rx)-(6- to 10- membered heterocycloalkylenyl)-; wherein the heterocycloalkylenyl and cycloalkylenyl independently is unsubstituted or substituted with 1, 2 or 3 occurrence(s) of Rd; wherein the asterisk mark represents the point of attachment with ring A; L 2 is a bond, -(
  • the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.
  • the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, and at least one pharmaceutically acceptable carrier or pharmaceutically acceptable excipients.
  • the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, and a pharmaceutically acceptable carrier or an excipient.
  • the pharmaceutically acceptable excipients such as a carrier or a diluent
  • a carrier such as a carrier or a diluent
  • 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.
  • 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
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • 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.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P.
  • 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.
  • Solid 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.
  • 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, to thereby form an injectable isotonic solution or suspension.
  • 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 present disclosure 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 a disease or disorder dependent upon SMARCA2 and/or SMARCA4, wherein the disease or disorder is cancer.
  • the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in treating or preventing cancers selected from the group consisting of hematologic cancers, lung cancer, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic myelogenous leukemia,
  • the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating diseases or conditions or disorders that are dependent upon or mediated by SMARCA2 and/or SMARCA4.
  • the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating a disease that has altered SMARCA2/4 including mutations and overexpression.
  • the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating a disease wherein degradation of SMARCA2/4 proteins provides a benefit, e.g., cancer.
  • the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating a disease dependent upon altered activity of SWI/SNF complex with or without chromatic remodeling activities.
  • the present disclosure provides, a method of degrading a target protein in a subject comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.
  • the target protein is SMARCA2 and/or SMARCA4.
  • the present disclosure provides, a method of treating or delaying progression of a disease or disorder dependent upon SMARCA2 and/or SMARCA4 in a subject comprising administering to the subject, in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.
  • the present disclosure provides a method for treating diseases or disorders dependent upon at least one of SMARCA2 and SMARCA4 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.
  • diseases or disorders that are dependent upon SMARCA2 and/or SMARCA4 is cancer.
  • the present disclosure provides a method of inhibiting tumor growth in a subject afflicted with cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof to the subject, in need thereof.
  • cancer is selected from hematologic cancers, lung cancer, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysprolife
  • the cancer dependent upon SMARCA2 and/or SMARCA4 is lung cancer such as NSCLC, i.e., non-small cell lung cancer. In one embodiment, the cancer dependent upon SMARCA2 and/or SMARCA4 is melanoma. In one embodiment, the present disclosure provides, a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, for use as a medicament. In one embodiment, the present disclosure provides, a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, for use in the treatment of a disease or disorder dependent upon SMARCA2 and/or SMARCA4.
  • a disease or disorder dependent upon SMARCA2 and/or SMARCA4 is cancer.
  • the present disclosure provides the use of a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder dependent upon SMARCA2 and/or SMARCA4.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, for use in the treatment of a disease or disorder dependent upon SMARCA2 and/or SMARCA4, wherein the disease or disorder is cancer.
  • the disease or disorder is cancer selected from hematologic cancers, lung cancer, non-small cell lung cancer, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic leukemia, promyelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, granulocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative
  • the present disclosure provides, a preparation of compound of formula (I).
  • Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present invention. The singular forms “a”, “an” and “the” encompass plural references unless the context clearly indicates otherwise.
  • 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.
  • substitution refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl or an acyl), a thiocarbonyl (such as a thioester, a thioacetate or a thioformate), an alkoxyl, an oxo, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heteroaryl, a heterocyclyl, an aralkyl
  • alkyl refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C3-C10 branched-chain alkyl groups.
  • alkyl refers to C 1 -C 6 straight-chain alkyl groups or C 3 -C 6 branched-chain alkyl groups.
  • the “alkyl” group refers to C1-C4 straight-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.
  • alkylamino refers to an amino group substituted with one or more “alkyl” group, wherein the alkyl group and amino group is as defined above.
  • alkylamino groups include but are not limited to -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , - N(CH3)(CH2CH3) and the like.
  • haloalkyl refers to alkyl substituted with one or more halogen atoms, wherein the halo and alkyl groups are as defined above.
  • haloalkyl contains (C 1 -C 6 )alkyl and preferably (C 1 -C 4 )alkyl.
  • haloalkyl include but are not limited to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, and 2,2,2- trifluoroethyl.
  • hydroxyalkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with hydroxyl group.
  • hydroxyalkyl contains (C1-C6)alkyl and preferably (C1-C4)alkyl.
  • hydroxyalkyl moieties include but are not limited to -CH 2 OH, -CH 2 CH 2 OH, - CH2CH2CH2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)CH3, -CH(CH3)CH2OH.
  • cycloalkylenyl refers to a divalent cycloalkyl group as defined herein.
  • cycloalkyl means C 3 -C 10 saturated cyclic hydrocarbon ring.
  • a cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms.
  • Examples of single ring cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a cycloalkyl may alternatively be polycyclic or contain more than one ring.
  • Examples of polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls.
  • 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 or C(O) with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur.
  • heterocycloalkyl or “heterocyclyl” 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 examples include, but not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, isoindolinyl, oxoisoindolinyl, dioxoisoindolinyl,
  • heterocycloalkylenyl examples include, but not limited to, azetidinylenyl, oxetanylenyl, pyrrolidinylenyl, piperidinylenyl and piperazinylenyl. Attachment of a heterocyclyl substituent can occur via either a carbon atom or a heteroatom.
  • a heterocyclyl group 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 heterocyclyl are optionally substituted by one or more aforesaid groups.
  • heterocycloalkenylenyl refers to a divalent heterocycloalkenyl group as defined herein.
  • heterocycloalkenyl is a 4- to 7-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 quarternized. Any suitable ring position of the heterocycloalkenyl moiety may be covalently linked to the defined chemical structure.
  • heterocycloalkenyl include but not limited to pyrroline, pyrazoline, tetrahydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine tetrahydro azepine and the like.
  • Heterocycloalkenyl group may be optionally further substituted.
  • heteroarylenyl refers to a divalent heteroaryl group as defined herein.
  • the term “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 or 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 quarternized. 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, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl (pyridinyl), 3-fluoropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinol
  • heteroarylenyl examples include, but not limited to, furanylenyl, thienylenyl, pyrrolylenyl, pyrazolylenyl, imidazolylenyl, oxazolylenyl, isoxazolylenyl, thiazolylenyl, isothiazolylenyl, 1H- tetrazolylenyl, oxadiazolylenyl, triazolylenyl, pyridylenyl (pyridinylenyl), pyrimidinylenyl, pyrazinylenyl, pyridazinylenyl, 1,2,3-triazinylenyl, 1,2,4-triazinylenyl and 1,3,5-triazinylenyl.
  • Heteroaryl group may be optionally further substituted.
  • amino refers to an —NH2 group.
  • 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 groups include but are not limited to methoxy, ethoxy, n-propoxy, n-butoxy or t-butoxy. An alkoxy group can be optionally substituted with one or more suitable groups.
  • aryl refers to a monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of 6 to 14 carbon atoms.
  • aryl groups include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, biphenylenyl and acenaphthyl.
  • Preferred aryl group is phenyl.
  • heteroatom as used herein designates a sulfur, nitrogen or oxygen atom.
  • the term 'compound(s)' comprise(s) the compound(s) disclosed in the present invention.
  • salt/salts refers to the salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N + (C 1-4 alkyl) 4 salts.
  • alkali metal e.g., sodium and potassium
  • alkaline earth metal e.g., magnesium
  • ammonium e.g., sodium and potassium
  • N + (C 1-4 alkyl) 4 salts e.g., sodium and potassium
  • ammonium e.g., sodium and potassium
  • N + (C 1-4 alkyl) 4 salts e.g., sodium and potassium
  • 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.
  • pharmaceutical composition refers to a composition(s) containing a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition(s) usually contain(s) about 1% to 99%, for example, about 5% to 75% or from about 10% to about 30% by weight of the compound of formula (I) or (II) or pharmaceutically acceptable salts thereof.
  • the amount of the compound of formula (I) or pharmaceutically acceptable salts thereof in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower than the aforementioned range.
  • tautomer refers to compounds in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged.
  • Compounds of the present invention, free form and salts thereof may exist in multiple tautomeric forms. It is understood that all tautomeric forms, insofar as they may exist, are included within the invention.
  • pyridine or pyridyl can be optionally substituted by oxo to form a respective pyridone or pyridon-yl and may include its tautomeric form such as a respective hydroxy-pyridine or hydroxy-pyridyl, provided said tautomeric form may be obtainable.
  • “pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surfactant or emulsifier that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • administer refers to either directly administering one or more disclosed compounds or a pharmaceutically acceptable salt of one or more disclosed compounds or a composition comprising one or more disclosed compounds to a subject or administering an 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.
  • the term “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • prevent prevent” and “prevention” refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • prevent also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
  • subject that may be interchangeable with ‘patient’, refers to an animal, preferably a mammal and most preferably a human.
  • terapéuticaally effective amount refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; or a composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, effective in producing the desired therapeutic response in a particular patient suffering from a diseases or disorder, in particular their use in diseases or disorder associated with cancer.
  • the term “therapeutically effective amount” includes the amount of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject.
  • the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment can also be considered.
  • the therapeutically effective amount of the compound or composition will be varied with the particular condition being treated, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the age and physical condition of the end user, the specific compound or composition employed the particular pharmaceutically acceptable carrier utilized.
  • 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
  • pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methyl
  • Certain compounds of the invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin.
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium or zinc salts.
  • “Pharmaceutically acceptable” means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • the present disclosure also provides methods for formulating the disclosed compounds as for pharmaceutical administration.
  • the aqueous solution is pyrogen-free or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • cancer is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease.
  • malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated.
  • neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors.
  • Exemplary cancers which may be treated by the present compounds either alone or in combination with at least one additional anti-cancer agent include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, hematologic cancers and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi
  • Additional cancers which may be treated using compounds according to the present invention include, for example, T-lineage Acute lymphoblastic Leukemia (T-ALL), T- lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.
  • T-ALL T-lineage Acute lymphoblastic Leukemia
  • T-LL T- lineage lymphoblastic Lymphoma
  • Peripheral T-cell lymphoma Peripheral T-cell lymphoma
  • Adult T-cell Leukemia Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma
  • Burkitts Lymphoma B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.
  • stereoisomers
  • the compounds of the formula (I) and related formulae are chiral, they can exist in racemic or in optically active form. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d-Isomers and l-Isomers and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centres or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns or any other appropriate method known in the art.
  • 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.
  • the compounds are the (,S)-enantiomer.
  • the term “diastereomers” refers to the set of stereoisomers which cannot be made superimposable by rotation around single bonds. For example, cis- and trans- double bonds, endo- and exo- substitution on bicyclic ring systems and compounds containing multiple stereogenic centres with different relative configurations are considered to be diastereomers.
  • diastereomer refers to any member of this set of compounds.
  • the synthetic route may produce a single diastereomer or a mixture of diastereomers.
  • the disclosure includes diastereomers of the compounds described herein.
  • the compounds of the present disclosure 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 disclosure 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 disclosure.
  • the pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, 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. Examples of the parenteral administration include administration by injection, percutaneous, transmucosal, transnasal and transpulmonary administrations.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters and polyoxyethylene.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
  • the pharmaceutical 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 disclosure, 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.
  • the pharmaceutical compositions of the present patent application may be prepared by conventional techniques known in literature. Suitable doses of the compounds for use in treating the disease or disorder 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.
  • the compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present disclosure also embraces isotopically-labeled variants of the present disclosure 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 disclosure and their uses.
  • Exemplary isotopes that can be incorporated into compounds of the disclosure 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 disclosure 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.
  • H2O Lithium hydroxide monohydrate; EDC.HCl – 1-(3-Dimethylaminopropyl)-3- ethylcarbodiimide. hydrochloride, DAST- diethylaminosulfur trifluoride, PPTs- Pyridinium p- toluenesulfonate, NaH – Sodium hydride, NH 4 OH- Ammonium hydroxide, NaOH – Sodium hydroxide, HCl – Hydrochloric acid, Pd(pph3)2Cl2.
  • General scheme – I Certain compounds of the present disclosure can be made by following the process as given in General scheme-I.
  • the general scheme-I for the synthesis of compound represented by formula (I’) is depicted in the above scheme.
  • the compound of formula (K 1 ) is reacted with the compound of formula (K 2 ) in a suitable solvent and suitable coupling reagent to yield compound of formula (K3) which upon further reaction with a compound of formula (B1) in the presence of suitable coupling reagent and solvent can provide a compound of formula (K 4 ).
  • the compound of formula (K4) undergoes a reduction reaction to result in compound of formula (K5) which further deprotected with a suitable deprotection reagent and solvent to yield compound of formula (K 6 ).
  • the compound of formula (K 4 ) undergoes deprotection in the presence of a suitable reagent and solvent to yield the compound of formula (K6).
  • the compound of formula (K6) reacts with the compound of formula (B2) with suitable solvent in high temperature to result in an amide compound of formula (K 7 ) which further can undergo deprotection reaction in the presence of a suitable reagent and solvent to provide a compound of formula (K8).
  • the compound of formula (K8) can undergo substitution reaction with the compound of formula (B 3 ) to result in the compound of formula (I’).
  • the compound of formula (K 6 ) undergoes substitution reaction with compound of formula (B 4 ) to result in compound of formula (I’).
  • Step-b Synthesis of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (Intermediate 1)
  • tert-butyl 4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)- carboxylate 5g, 14.78 mmol
  • dioxane 20 mL
  • bis pinacolato diboron (4.12g, 16.26 mmol)
  • KOAc 4.34g, 44.3 mmol
  • Pd(dppf)2Cl2.DCM 1.2g, 1.47 mmol
  • reaction mixture was degassed with nitrogen for 5 min then Pd(dppf)2Cl2.DCM (1.19g, 1.46 mmol) was added into the reaction mixture and heated at 100 oC for 16 h. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulphate, and concentrated under vacuum to give the residue which was purified by combi flash column chromatography using 15-20% ethyl acetate in hexane as eluent to afford the title compound as off-white solid (5.1g, 89.6 %).
  • 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 (Intermediate 3)
  • To a stirred solution of Tert-butyl 6-(4-bromophenyl)-2-azaspiro[3.3]heptane-2- carboxylate (1.3g, 3.69 mmol) in dioxane (35 mL) was added bis pinacolato diboron (1.4g, 5.53 mmol) and KOAc (0.90 g, 9.22 mmol) at RT and degassed with nitrogen for 5 min then Pd(dppf)2Cl2.DCM (0.30g, 0.36 mmol) was added into the reaction mixture and heated at 110 oC for 16 h.
  • Step-b Synthesis of 1-(4-bromophenyl)piperidin-4-one
  • THF 50 mL
  • 1(N) aq HCl 50 mL
  • the reaction mixture was heated for 6 h at 80 oC.
  • the reaction mixture was basified with NaHCO 3 and extracted with EtOAc.
  • Step-c Synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin- 4-one (Intermediate 4)
  • 1-(4-bromophenyl)piperidin-4-one (4g, 15.74 mmol) in dioxane (80 mL) was added bis pinacolato diboron (5.99 g, 23.60 mmol) and KOAc (4.63g, 47.22 mmol) at RT and degassed with nitrogen for 10 min then Pd(dppf)2Cl2.DCM (1.28 g, 1.57 mmol) was added into the reaction mixture and heated at 100 oC for 16 h.
  • Step-b Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-ylamino)isoindoline-1,3- dione hydrochloride (Intermediate 6)
  • reaction mixture was stirred at rt for 2h. Then the reaction mixture was cooled to 0 o C and sodium cyano borohydride (0.36 g, 5.78 mmol) was added and the reaction mixture was stirred for 12h at RT. Reaction was monitored by TLC. After completion of the reaction the reaction mixture was extracted in 10% MeOH in DCM and saturated ammonium chloride wash was given to the organic layer followed by saturated sodium chloride wash. The organic layer dried over anhydrous sodium sulphate and then concentrated under reduced pressure and the resultant residue. The crude compound was purified by combi flash column chromatography and eluted in 5% MeOH/DCM to afford the title compound as yellow solid (0.2g, 26 %).
  • Step-b Synthesis of 3-(1-oxo-4-((4-oxocyclohexyl)amino)isoindolin-2-yl)piperidine-2,6- dione (Intermediate 7) To a stirred solution of tert-butyl 3-(4-((1,4-dioxaspiro[4.5]decan-8-yl)amino)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (0.25g, 0.62 mmol) in THF (10 mL) was added 2 N aq.
  • Step-b Synthesis of tert-butyl 4-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)piperidine-1-carboxylate
  • 4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione 0.5 g, 1.72 mmol
  • tert-butyl 4-aminopiperidine-1-carboxylate (0.34 g, 1.72 mmol) DMSO (4 mL) was added DIPEA (1.11 g, 8.61 mmol) to the reaction mixture at rt and stirred at 130 o C in microwave for 1h.
  • Step-c Synthesis of 2-(1-methyl-2,6-dioxopiperidin-3-yl)-4-(piperidin-4-ylamino) isoindoline-1,3-dione hydrochloride (Intermediate 9)
  • To a stirred solution of tert-butyl 4-((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)piperidine-1-carboxylate (0.3 g, 0.63 mmol) in DCM (2 mL) was added 4M HCl in dioxane (5 mL) to the reaction mixture at 0 o C and stirred at rt for 2h.
  • Step-b Synthesis of 4-(dimethoxymethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl)piperidine (Intermediate 10)
  • 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine 1.1g, 3.5 mmol
  • dioxane 35 mL
  • bis pinacolato diboron (1.15 g, 4.55 mmol)
  • KOAc (1.03 g, 10.5 mmol) at RT and degassed with nitrogen for 10 min then Pd(dppf)2Cl2.DCM (0.28 g, 0.35 mmol) was added into the reaction mixture and heated at 100 oC for 12 h.
  • Step-b Synthesis of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1- carboxylate
  • tert-butyl 4-(4-(2-ethoxy-2-oxoethyl)phenyl)piperazine-1- carboxylate (2 g, 5.74 mmol) and acrylamide (0.36 g, 5.16 mmol) were taken in THF (20 mL) was added KO t Bu (0.70 g, 6.31 mmol) and the reaction mixture was heated for 12 h at 50 oC.
  • Step-c Synthesis of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione hydrochloride (Intermediate 11)
  • To a stirred solution of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1- carboxylate (0.82 g, 2.19 mmol) in DCM (10 mL) was added 4(N) dioxane HCl (10 mL) at 0 oC and then slowly brought to RT and stirred at RT for 16 h.
  • Step-b Synthesis of 1-(4-hydroxyphenyl)piperidin-4-one
  • 4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenol 1.5g, 13.41 mmol
  • 2(N) aq HCl 50 mL
  • the reaction mixture was heated for 9 h at 70 oC.
  • the reaction mixture was basified with NaHCO3 and extracted with EtOAc.
  • Step-c Synthesis of 3-(4-(4-oxopiperidin-1-yl) piperidine-2,6-dione (Intermediate 12) To a stirred solution of 1-(4-hydroxyphenyl)piperidin-4-one (1.2g, 6.27 mmol) in DMF (30 mL) was added NaH (0.37g, 15.68 mmol) at 0 o C temperature and stirred for 30 mins.
  • Example-I Synthesis of 4-((4-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperidin-1-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (Compound 1) zin-4-yl)phenyl)-3,6- To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (4.4g, 11.41 mmol), tert- butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)- carboxylate (2.38g, 11.41 mmol) in 1,4-dioxane (80 mL) and water (10 mL) was added K2CO3 (4.
  • Step-ii Synthesis of tert-butyl 4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (Intermediate-14) To a stirred solution of tert-butyl 4-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (3g, 7.75 mmol), (2-hydroxyphenyl)boronic acid (1.60g, 11.6 mmol) in 1,4-dioxane (50 mL) and water (13 mL) was added K2CO3 (3.21g, 23.26 mmol) and degassed with nitrogen for 10 min.
  • Step-iii Synthesis of tert-butyl 4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)piperidine-1-carboxylate (Intermediate-15) To a stirred solution of tert-butyl 4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.6g, 5.84 mmol) in ethanol (30 mL) and THF (30 mL) was added 10% Pd-C (1g) at 0 oC and then reaction mixture was stirred under hydrogen atmosphere for 12 h.
  • Step-iv Synthesis of 2-(6-amino-5-(4-(piperidin-4-yl)phenyl)pyridazin-3-yl)phenol hydrochloride (Intermediate-16)
  • To a stirred solution of tert-butyl 4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperidine-1-carboxylate (1g, 2.17 mmol) in DCM (5 mL) was added 4 N dioxane hydrochloride (10 mL) at 0 oC and then slowly brought to RT and stirred for 1h.
  • Step-v Synthesis of tert-butyl (4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)piperidin-1-yl)cyclohexyl)carbamate (Intermediate-17)
  • 2-(6-amino-5-(4-(piperidin-4-yl)phenyl)pyridazin-3-yl)phenol hydrochloride 0.5g, 1.44 mmol
  • tert-butyl (4-oxocyclohexyl)carbamate (0.30g, 1.44 mmol)
  • KOAc (0.29g, 4.32 mmol
  • acetic acid 0.2 mL
  • molecular sieves (4A o ) molecular sieves
  • reaction mixture was cooled to 0 o C and sodium tri acetoxy borohydride (0.91g, 4.32 mmol) was added and the reaction mixture was stirred for 4 h at RT.
  • the reaction was monitored by TLC.
  • the reaction mixture was extracted in DCM, and saturated ammonium chloride wash was given to the organic layer followed by saturated sodium chloride wash.
  • the organic layer dried over anhydrous sodium sulphate and then concentrated under reduced pressure and the resultant residue was washed with diethyl ether and dried under vacuum to afford the title compound as off white solid (0.5g, 64 %).
  • Step-vi Synthesis of 2-(6-amino-5-(4-(1-(4-aminocyclohexyl)piperidin-4-yl)phenyl) pyridazin-3-yl)phenol hydrochloride (Intermediate-18) To a stirred solution of tert-butyl (4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperidin-1-yl)cyclohexyl)carbamate (0.7g, 1.28 mmol) in DCM (7 mL), followed by adding 4 N dioxane hydrochloride (7 mL) at 0 oC and then slowly brought to RT and stirred for 4 h.
  • Step-vii Synthesis of 4-((4-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl) piperidin-1-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 1)
  • 2-(6-amino-5-(4-(1-(4-aminocyclohexyl)piperidin-4- yl)phenyl)pyridazin-3-yl)phenol hydrochloride (0.55g, 1.24 mmol) in DMSO (5 mL)
  • DIPEA 0.64g, 4.96 mmol
  • Example-II Synthesis of 4-((4-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)-3,6-dihydropyridin-1(2H)-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Compound 4)
  • Intermediates 20 to 22 and Compound-4 were prepared by a procedure similar to the one described in Example-I with appropriate variations in reactants, quantities of reagents, protections and deprotections solvents and reaction conditions
  • Example-III Synthesis of 5-((4-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)piperidin-1-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (Compound 5)
  • 2-(6-amino-5-(4-(1-(4-aminocyclohexyl)piperidin-4- yl)phenyl)pyridazin-3-yl)phenol hydrochloride (0.12g, 0.27 mmol) in DMSO (1 mL) was added DIPEA (0.35g, 2.70 mmol)) and stirred for 5 mins.
  • Example-IV Synthesis of 3-(4-((4-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)piperidin-1-yl)cyclohexyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 6)
  • 2-(6-amino-5-(4-(piperidin-4-yl)phenyl)pyridazin-3-yl)phenol hydrochloride (0.06g, 0.16 mmol)
  • 3-(1-oxo-4-((4-oxocyclohexyl)amino)isoindolin-2- yl)piperidine-2,6-dione (0.30g, 1.44 mmol) in methanol (2 ml) was added a pre-mixture solution of ZnCl2 (0.08 g, 0.05 mmol) and
  • the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched to ice water and the solid formed was filtered and dried. Filtrate was taken and extracted with 20% MeOH in DCM. The organic layer was collected washed with brine solution dried over Na2SO4 and concentrated to get crude product.
  • the Crude product was purified first by combi flash column chromatography using 3-4% methanol in DCM system followed by prep HPLC, pure fractions were dried under lyophilization to afford the title compound as light yellow solid (0.02g, 17 %).
  • Example-V Synthesis of 4-((4-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)piperidin-1-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (Compound 7)
  • 4-bromo-6-chloropyridazin-3-amine 1.6g, 7.72 mmol
  • tert- butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (2g, 5.15 mmol) in 1,4-dioxane (30 mL) and water (5 mL) was added K 2 CO 3 (1.77g, 12.8 mmol) and degassed with nitrogen for 10 min, followed by adding Pd(dppf)2
  • reaction mixture was diluted with EtOAc.
  • the combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to get crude product which was purified by combi flash column chromatography using 80% EtOAc in Hexane as eluent to afford the title compound as off white solid (0.98g, 48.8%).
  • Step-iii Synthesis of 2-(6-amino-5-(4-(piperazin-1-yl)phenyl)pyridazin-3-yl)phenol hydrochloride (Intermediate-26)
  • To a stirred solution of tert-butyl 4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperazine-1-carboxylate (0.68 g, 1.53 mmol) in DCM (3 mL) was added 4 N dioxane hydrochloride (3 mL) at 0 oC and then slowly brought to RT and stirred for 1h.
  • Step-iv Synthesis of tert-butyl (4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)piperidin-1-yl)cyclohexyl)carbamate (Intermediate-27)
  • 2-(6-amino-5-(4-(piperazin-1-yl)phenyl)pyridazin-3-yl)phenol hydrochloride 0.3g, 0.78 mmol
  • tert-butyl (4-oxocyclohexyl)carbamate (0.16g, 0.78 mmol) in 4.5mL THF:DMSO (2:1) mixture was added KOAc (0.23g, 2.34 mmol) and acetic acid (0.16 mL) and molecular sieves (4A o ) and the reaction mixture was stirred at 45 o C for 4 hours.
  • reaction mixture was cooled to 0 o C and sodium triacetoxy borohydride (0.48g, 2.34 mmol) was added and the reaction mixture was stirred for 4h at RT.
  • the reaction was monitored by TLC.
  • the reaction mixture was extracted in DCM and saturated ammonium chloride wash was given to the organic layer followed by saturated sodium chloride wash.
  • the organic layer was dried over anhydrous sodium sulphate and then concentrated under reduced pressure and the resultant residue was washed with diethyl ether and dried under vacuum to afford the title compound as off white solid (0.14g, 32.9 %).
  • Step-v Synthesis of 2-(6-amino-5-(4-(4-(4-aminocyclohexyl)piperazin-1-yl)phenyl) pyridazin-3-yl)phenol hydrochloride (Intermediate-28)
  • tert-butyl (4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperidin-1-yl)cyclohexyl)carbamate (0.14g, 0.25 mmol) in DCM (2 mL) was added 4 N dioxane hydrochloride (2 mL) at 0 oC and then slowly brought to RT and stirred for 4 h.
  • reaction mixture was poured in ice cold water and stirred for 30 minutes and filtered through Buchner funnel to get crude product (as a solid).
  • crude product was purified first by combi flash column chromatography using 3- 4% methanol in DCM system followed by prep HPLC, pure fractions were dried under lyophilization to afford the title compound as yellow solid (0.08g, 36 %).
  • Example-VI Synthesis of 5-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) ridin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Step-i Synthesis of tert-butyl 3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)piperidin-1-yl)azetidine-1-carboxylate (Intermediate-29) To a stirred solution of 2-(6-amino-5-(4-(piperazin-1-yl)phenyl)pyridazin-3-yl)phenol hydrochloride (0.2g, 0.57 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (0.109g, 0.63 m
  • Step-ii Synthesis of 2-(6-amino-5-(4-(1-(azetidin-3-yl)piperidin-4-yl)phenyl)pyridazin-3- yl)phenol hydrochloride (Intermediate-30)
  • To a stirred solution of tert-butyl 3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperidin-1-yl)azetidine-1-carboxylate (0.17g, 0.34 mmol) in DCM (1 mL) was added 4 N dioxane hydrochloride (5 mL) at 0 oC and then slowly brought to RT and stirred for 2 h.
  • Step-iii Synthesis of 5-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl) piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 10)
  • 2-(6-amino-5-(4-(1-(azetidin-3-yl)piperidin-4- yl)phenyl)pyridazin-3-yl)phenol hydrochloride 0.1g, 0.24 mmol
  • DIPEA 0.22g, 1.75 mmol
  • Example-VII Synthesis of 5-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)piperazin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 11)
  • Compound-11 was prepared by procedure similar to the one described in Example-VI with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions.
  • Example-VIII Synthesis of 5-(4-(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)-2-azaspiro[3.3]heptan-2-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 12)
  • Compound-12 was prepared by a procedure similar to the one described in Example- VII with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents, and reaction conditions.
  • Example-IX Synthesis of 4-((4-(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)-2-azaspiro[3.3]heptan-2-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (Compound 13)
  • Step-i Synthesis of tert-butyl 6-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)-2-azaspiro [3.3]heptane-2-carboxylate (Intermediate-31) To a stirred solution of 4-bromo-6-chloropyridazin-3-amine (0.62g, 3.00 mmol), tert- butyl6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl
  • reaction mixture was diluted with EtOAc.
  • the combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate, and concentrated under vacuum to get crude product which was purified by combi flash column chromatography using 60-80% Ethyl acetate in hexane to afford the title compound as white solid (0.35g, 42%).
  • Step-ii Synthesis of tert-butyl 6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate-32)
  • tert-butyl 6-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)-2- azaspiro[3.3]heptane-2-carboxylate (0.35g, 0.87 mmol)
  • (2-hydroxyphenyl)boronic acid (0.24g, 1.74 mmol) in 1,4-dioxane (5 mL) and water (2 mL)
  • K2CO3 (0.30g, 2.18 mmol
  • degassed with nitrogen for 10 min followed by adding Pd(dppf)2Cl2.DCM (0.07g, 0.08 mmol) and the reaction mixture was heated for 16 h
  • Step-iii Synthesis of 2-(5-(4-(2-azaspiro[3.3]heptan-6-yl)phenyl)-6-aminopyridazin-3-yl) phenol (Intermediate-33)
  • tert-butyl 6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.20g, 0.43 mmol) in DCM (2 mL) was added Trifluoroacetic acid (1 mL) at 0 oC and then slowly brought to RT and stirred for 1 h.
  • Step-iv Synthesis of tert-butyl (4-(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)-2-azaspiro[3.3]heptan-2-yl)cyclohexyl)carbamate (Intermediate-34)
  • 2-(5-(4-(2-azaspiro[3.3]heptan-6-yl)phenyl)-6-aminopyridazin- 3-yl)phenol (0.15g, 0.41 mmol) and tert-butyl (4-oxocyclohexyl)carbamate (0.08g, 0.41 mmol) in 9 mL THF:DMSO (2:1) mixture was added KOAc (0.08g, 0.83 mmol) and acetic acid (0.1 mL) and molecular sieves (4A o ) and the reaction mixture was stirred at 45 o C for 4 hours.
  • reaction mixture was cooled to 0 o C and sodium triacetoxy borohydride (0.17g, 0.83 mmol) was added and the reaction mixture was stirred for 16 h at RT.
  • the reaction was monitored by TLC.
  • the reaction mixture was extracted in DCM and saturated ammonium chloride wash was given to the organic layer followed by saturated sodium chloride wash.
  • the organic layer dried over anhydrous sodium sulphate and then concentrated under reduced pressure, and the resultant residue was washed with diethyl ether and dried under vacuum to afford the title compound as off white solid (0.10g, 43%).
  • Step-vi Synthesis of 4-((4-(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)-2- azaspiro[3.3]heptan-2-yl)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (Compound 13)
  • 2-(6-amino-5-(4-(2-(4-aminocyclohexyl)-2- azaspiro[3.3]heptan-6-yl)phenyl)pyridazin-3-yl)phenol (0.10g, 0.21 mmol)
  • DIPEA 0.14g, 1.09 mmol
  • reaction mixture was poured into ice cold water and stirred for 30 minutes and filtered through Buchner funnel to get crude product as a solid.
  • the crude product was purified first by combi flash column chromatography using 2.5% methanol in DCM system followed by prep HPLC, pure fractions were dried under lyophilization to afford the title compound as yellow solid (0.005g, 5.8 %).
  • Example-XI Synthesis of 4-(6-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)- 2-azaspiro[3.3]heptan-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 15)
  • Compound 15 was prepared by procedure similar to the one described in Example-X with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions.
  • Example-XII Synthesis of 5-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)- [1,4'-bipiperidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (Compound 16)
  • Compound 16 was prepared by procedure similar to the one described in Example-IV with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions.
  • reaction mixture was diluted with EtOAc.
  • the combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under vacuum to get crude product which was purified by combi flash column chromatography using 70-90% EtOAc in hexane as eluent to afford the title compound as white solid (5.0g, 50%).
  • Step-ii Synthesis of 1-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)piperidin- 4-one (Intermediate 37)
  • 1-(4-(3-amino-6-chloropyridazin-4-yl)phenyl)piperidin-4-one 11g, 36.33 mmol
  • (2-hydroxyphenyl)boronic acid 7.01g, 50.86 mmol
  • 1,4-dioxane 50 mL
  • water 13 mL
  • K2CO3 15.0g, 138.2 mmol
  • degassed with nitrogen for 10 min followed by adding Pd(dppf) 2 Cl 2 .DCM (2.96 g, 3.63 mmol) and the reaction mixture was heated for 4 h at 120 oC in a sealed tube.
  • Step-iii Synthesis of 4-((1'-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)- [1,4'-bipiperidin]-4-yl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 17)
  • 1-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperidin-4-one (0.10g, 0.27 mmol)
  • 2-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4- ylamino)isoindoline-1,3-dione hydrochloride (0.13g, 0.33 mmol) in 9mL THF:DMSO (2:1) mixture was added KOAc (0.082g, 0.83 mmol) and acetic
  • reaction mixture was cooled to 0 o C and sodium triacetoxy borohydride (0.17g, 0.83 mmol) was added and the reaction mixture was stirred at RT for 16h.
  • the reaction was monitored by TLC.
  • the reaction mixture was extracted in DCM and saturated ammonium chloride wash was given to the organic layer followed by saturated sodium chloride wash.
  • the organic layer dried over anhydrous sodium sulphate and then concentrated under reduced pressure and the resultant residue was washed with diethyl ether and dried under vacuum to afford the title compound as off white solid (0.02g, 11 %).
  • Example-XIV Synthesis of 5-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl) piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 28)
  • 2-(6-amino-5-(4-(piperidin-4-yl)phenyl)pyridazin-3-yl)phenol hydrochloride (0.10g, 0.28 mmol) in DMSO (2 mL) was added DIPEA (0.11g, 0.86 mmol)) and stirred for 5 mins.2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.08 g, 0.28 mmol) was added to the reaction mixture and heated at 130 o C for 4h.
  • reaction mixture was poured into ice cold water and stirred for 30 minutes and filtered through Buchner funnel to get crude product as a solid.
  • the crude product was purified first by combi flash column chromatography using 3-4% methanol in DCM system to afford the title compound as off white solid (0.05g, 27.8 %).
  • Example-XV Synthesis of 5-(3-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3- dione (Compound 29)
  • Compound 29 was prepared by procedure similar to the one described in Example-XIV with appropriate variations in reactants, quantities of reagents, protections and deprotections, solvents and reaction conditions.
  • Step-ii Synthesis of tert-butyl (1-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)piperidin-4-yl)carbamate (Intermediate 38A) To a stirred solution of tert-butyl (1-(4-(3-amino-6-chloropyridazin-4- yl)phenyl)piperidin-4-yl)carbamate (0.28g, 0.69 mmol) and (2-hydroxyphenyl)boronic acid (0.124g, 0.90 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was added K2CO3 (0.28g, 2.07 mmol) and degassed with nitrogen for 10 min, followed by adding Pd(dppf)2Cl2.DCM (0.057g, 0.06 mmol) and the reaction mixture was heated at 120 oC in a sealed tube for 4h.
  • Step-iii Synthesis of 2-(6-amino-5-(4-(4-aminopiperidin-1-yl)phenyl)pyridazin-3-yl) phenol hydrochloride (Intermediate 39)
  • tert-butyl (1-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperidin-4-yl)carbamate (0.15g, 0.32 mmol) in DCM (2 mL) was added 4 M dioxane hydrochloride (2 mL) at 0 oC and then slowly brought to RT and stirred for 4 h.
  • reaction mixture was cooled to 0 o C, and sodium triacetoxy borohydride (0.183g, 0.86 mmol) was added and the reaction mixture was stirred at RT for 16 h.
  • the reaction was monitored by TLC.
  • the reaction mixture was extracted in 10% MeOH/DCM, and brine wash was given to the organic layer.
  • the organic layer was dried over anhydrous sodium sulphate and then concentrated under reduced pressure to get the crude product.
  • the crude product was purified by combi flash column chromatography by eluting 5- 6% MeOH/DCM to afford the title compound as a light yellow solid (0.08g, 57 %).
  • Step-ii Synthesis of 4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl) piperazin-1-yl)cyclohexan-1-one (Intermediate 41)
  • 2-(5-(4-(4-(1,4-dioxaspiro[4.5]decan-8-yl)piperazin-1- yl)phenyl)-6-aminopyridazin-3-yl)phenol (0.08g, 0.16 mmol)
  • THF 4 mL
  • 3 N aq. HCl solution 4 mL
  • reaction was monitored by TLC. After completion of the reaction, the reaction mixture was basified using K 2 CO 3 and extracted in 10% MeOH/DCM. The organic layer was washed with brine solution and dried over anhydrous sodium sulphate and then concentrated under reduced pressure to afford the title compound as a light yellow solid.
  • Step-iii Synthesis of 3-(5-(4-(4-(4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)piperazin-1-yl)cyclohexyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione (Compound 31)
  • 4-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperazin-1-yl)cyclohexan-1-one (0.176g, 0.39 mmol)
  • 3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.13g, 0.39 mmol) in 4.5 mL THF:DMSO (2:1) mixture was added KOAc (0.
  • reaction mixture was cooled to 0 o C and sodium cyanoborohydride (0.075g, 1.18 mmol) was added and the reaction mixture was stirred at RT for 12h.
  • the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice water to obtain the solid, filtered and washed with water to get the crude product.
  • the crude product was purified by preparative HPLC to afford the title compound as a light yellow solid (0.045g, 15 %).
  • Step-ii Synthesis of 2-(6-amino-5-(4-aminophenyl)pyridazin-3-yl)phenol (Intermediate 44)
  • 2-hydroxyphenyl boronic acid (0.68g, 4.98 mmol) in 1,4-dioxane (25 mL) and water (5 mL)
  • K2CO3 (1.87g, 13.6 mmol)
  • Pd(dppf)2Cl2.DCM 0.37g, 0.45 mmol
  • Step-iii Synthesis of 5-(4-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl) amino)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 33)
  • 2-(6-amino-5-(4-aminophenyl)pyridazin-3-yl)phenol 0.4g, 0.14 mmol
  • 2-(2,6-dioxopiperidin-3-yl)-5-(4-oxopiperidin-1-yl)isoindoline-1,3- dione(0.05g, 0.14 mmol) (synthesized using Ref WO2020/81450) in 1.5mL THF:DMSO (2:1) mixture was added KOAc (0.042g, 0.42 mmol) and acetic acid (0.1 mL) and molecular
  • reaction mixture was cooled to 0 o C and sodium cyanoborohydride (0.027g, 0.42 mmol) was added and the reaction mixture was stirred for 16h at RT.
  • the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice water to obtain the precipitate, filtered, and washed with water to get the crude, which was further purified prep HPLC to afford the title compound as yellow solid (0.020g, 23%).
  • Example-XX Synthesis of 5-(6-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl) amino)-2-azaspiro[3.3]heptan-2-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3- dione (Compound 34)
  • 2-(6-amino-5-(4-aminophenyl)pyridazin-3-yl)phenol 0.05g, 0.18 mmol
  • tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate 0.076g, 0.36 mmol
  • acetic acid 0.022g, 0.36 mmol
  • Example-XXI Synthesis of 3-(4-(1'-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl) phenyl)-[1,4'-bipiperidin]-4-yl)phenoxy)piperidine-2,6-dione (Compound 35)
  • Step-i Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-1- carboxylate (Intermediate-46) To a stirred solution of tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (synthesized using Ref.
  • Step-ii Synthesis of 3-(4-(piperidin-4-yl)phenoxy)piperidine-2,6-dione hydrochloride (Intermediate-47) To a stirred solution of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl) piperidine-1-carboxylate (1.1g, 2.83 mmol) in DCM (10 mL) was added 4 N dioxane hydrochloride (10 mL) at 0 oC and then slowly brought to RT and stirred for 4h.
  • reaction mixture was cooled to 0 o C and sodium triacetoxy borohydride (0.4 g, 2.08 mmol) was added and the reaction mixture was stirred at RT for 16h.
  • the reaction was monitored by TLC.
  • the reaction mixture was extracted in DCM and saturated ammonium chloride wash was given to the organic layer followed by saturated sodium chloride wash.
  • the organic layer was dried over anhydrous sodium sulphate and then concentrated under reduced pressure and the resultant residue was washed with diethyl ether and dried under vacuum to afford the title compound as a light yellow solid (0.03g, 7 %).
  • Example-XXII Synthesis of 3-(4-(4-(1-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione (Compound 42) To a stirred solution of 1-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperidin-4-one (0.13g, 0.36 mmol) and 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6- dione hydrochloride (synthesized using Ref.
  • WO2021/83949 (0.10g, 0.366mmol) in 9mL THF:DMSO (2:1) mixture was added KOAc (0.108g, 1.09 mmol) and acetic acid (0.2 mL) and molecular sieves (4A o ) and the reaction mixture was stirred at 45 o C for 4h. Then the reaction mixture was cooled to 0 o C and sodium tri acetoxy borohydride (0.23g, 1.09 mmol) was added and the reaction mixture was stirred at RT for 16h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted in DCM and saturated ammonium chloride wash was given to the organic layer followed by saturated sodium chloride wash.
  • reaction mixture was cooled to 0°C and sodium tri- acetoxyborohydride (0.63g, 2,97 mmol) was added and the reaction mixture was stirred for 12h at RT.
  • the reaction was monitored by TLC. After completion of the reaction the reaction mixture was poured into ice water to obtain the precipitate, filtered and washed with water to get the crude product.
  • the crude product was purified by column chromatography using 5-10 % MeOH in DCM to afford the title compound as light brown solid (0.063g, 10%).
  • Example XXIV Synthesis of 3-(4-(4-((1-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)piperidine-2,6-dione (Compound 51)
  • Step-i Synthesis of 6-chloro-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)pyridazin- 3-amine (Intermediate 48)
  • 4-bromo-6-chloropyridazin-3-amine (1.25 g, 3.45 mmol)
  • 4- (dimethoxymethyl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (0.72 g, 3.45 mmol) in 1,4-dioxane (16 mL) and water (4
  • reaction mixture was diluted with EtOAc.
  • the combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate, and concentrated under vacuum to get crude product which was purified by combi flash column chromatography using 5-8% methanol in DCM as eluent to afford the title compound as light brown solid (0.75g, 59.7%).
  • reaction mixture was dissolved in 10%MeOH/DCM and passed through celite, and filtrate was concentrated under reduced pressure to give the residue which was purified by combi flash column chromatography using 60-70 % ethyl acetate in hexene as eluent to afford the title compound as light brown solid (0.19 g, 71%).
  • Step-iii Synthesis of 1-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl) piperidine-4-carbaldehyde (Intermediate 50)
  • To a stirred solution of 1-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl)phenyl)piperidine-4-carbaldehyde (0.19g, 0.42 mmol) in THF (3 mL) was added 3 N aq. hydrochloride (0.5 mL) at 0 oC and then slowly brought to RT and stirred for 6 h.
  • reaction mixture was quenched with ice water and pH was adjusted to pH-8 by the addition of K2CO3 solid pinch-wise. Then the reaction mass was extracted with 10%MeOH in DCM organic layer, washed with brine solution dried over Na2SO4, and concentrated to afford the title compound as orange solid (0.168 g, 99%).
  • reaction mixture was cooled to 0 o C and sodium cyanoborohydride (0.025g, 0.40 mmol) was added and the reaction mixture was stirred for 16h at RT.
  • the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice water to obtain the precipitate, filtered, and washed with water to get the crude, which was further purified prep HPLC to afford the title compound as a light yellow solid (0.030g, 35%).
  • Example-P1 Determination of Anti proliferative activity of compounds in cell line SK- MEL-5 by Cell Titer Glo®(Promega) assay
  • Cells were seeded into 96-well plates and the plates were incubated at 37°C in incubator overnight. The next day, compounds were diluted 3-fold to cover the 9-point concentration range in DMSO. Intermediate plate dilution was prepared in media followed with compound treatment in cells.
  • Treatment of cells with compound dilutions was performed on Day 4 and assay was terminated on day 8 for SK-MEL-5 cells using 100 ⁇ l of CellTiter-Glo and the plate was kept on orbital shaker for 20 minutes at RT. Luminescence signal was recorded on VICTOR5 instrument.
  • EC 50 value was calculated using GraphPad® software. Selected compounds of the present disclosure were screened in the above-mentioned assay procedures for determination of EC 50 (SK-MEL-5) values and the results are summarized into groups A, B and C in below table-7.
  • group “A” refers to EC 50 values ⁇ 100 nM
  • “B” refers to EC50 values >100 nM to ⁇ 500 nM
  • “C” refers to EC50 values >500 nM.
  • Example-P2 Determination of Anti proliferative activity of compounds in cell lines MV- 4-11 by Cell Titer Glo®(promega) assay: MV-4-11 (CRL-9591TM) cells were seeded in 96 well plate flat black clear bottom plates using complete DMEM Medium. Next day, compounds listed in the present disclosure were added to cells from 10 mM stocks made in DMSO. Each concentration of compound was tested in triplicate with DMSO concentration at a final percentage not exceeding 0.3 in the cells. After the incubation of MV-4-11 cells with compound for 3 days; assay was terminated using 100 ⁇ l of CellTiter Glo® reagent. Luminescence readings were taken in Victor-5 instrument.
  • % inhibition 100-(luminescence value of test/luminescence value of DMSO control) * 100.
  • EC50 was calculated using graph pad prism software. Selected compounds of the present disclosure were screened in the above-mentioned assay procedures for determination of EC50 (MV-4-11) values and the results are summarized into groups A, B and C in below table-8.
  • group “A” refers to EC50 values ⁇ 100 nM and “B” refers to EC 50 values >100 nM.
  • Table-8 Example-P3: Determination of SMARCA2 and SMARCA4 degradation in MV-4-11 cells by Western blot.
  • MV-4-11 (CRL-9591TM) cells were plated in 6 well plates using complete Dulbecco's Modified Eagle's Medium.
  • selected compounds of the present disclosure were added to cells from 10 mM stocks made in DMSO. Each concentration of compound was tested with DMSO not exceeding the final percentage of 0.1 in the cells.
  • Cells were incubated with the compound for 16 hours followed by harvesting with 1X RIPA lysis buffer containing protease inhibitor cocktail. An equal amount of protein was loaded on SDS-PAGE gel for electrophoresis.
  • Western blot was carried out for detection of either SMARCA2 (Cell signalling technologies, catalogue number #11966) or SMARCA4 antibody (Cell signalling technologies, catalogue number #52251).

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Abstract

La présente divulgation concerne des composés de pyridazine à substitution amino de formule (I), qui sont thérapeutiquement utiles en tant qu'agents de dégradation de SMARCA2 et/ou de SMARCA4. Ces composés sont utiles dans le traitement et/ou le retardement de la progression d'une maladie ou d'un trouble dépendant de SMARCA2 et/ou de SMARCA4 chez un sujet. La présente divulgation concerne également des compositions pharmaceutiques comprenant au moins l'un des composés de formule (I) ou un sel pharmaceutiquement acceptable ou un stéréoisomère ou un tautomère de celui-ci.
PCT/IB2024/060683 2023-11-01 2024-10-30 Composés de pyridazine à substitution amino utilisés en tant qu'agents de dégradation de smarca2 et/ou de smarca4 Pending WO2025094065A1 (fr)

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