WO2018109271A1 - Nouveaux inhibiteurs de bromodomaines - Google Patents

Nouveaux inhibiteurs de bromodomaines Download PDF

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WO2018109271A1
WO2018109271A1 PCT/FI2017/050879 FI2017050879W WO2018109271A1 WO 2018109271 A1 WO2018109271 A1 WO 2018109271A1 FI 2017050879 W FI2017050879 W FI 2017050879W WO 2018109271 A1 WO2018109271 A1 WO 2018109271A1
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alkyl
optionally substituted
indolin
hydroxy
cyclobutane
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PCT/FI2017/050879
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English (en)
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Chandrasekhar ABBINENI
Tero Linnanen
Subhendu MUKHERJEE
Susanta Samajdar
Olli Törmäkangas
Gerd Wohlfahrt
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Orion Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel spiro[cycloalkyl-1,3’-indolin]-2’-one derivatives of formula (I) which are useful as bromodomain inhibitors and to
  • the invention relates also to the use of compounds of formula (I) for the treatment or prevention of diseases or disorders, in particular those where bromodomain inhibition is desired.
  • Background of the invention The acetylation of histone lysine is central for providing the dynamic regulation of chromatin-based gene transcription.
  • the bromodomain (BRD) which is the conserved structural module in chromatin-associated proteins and histone acetyltranferases, is the sole protein domain known to recognize acetyl-lysine residues on proteins.
  • the BET family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRDT) which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction.
  • BRD2 and BRD3 are reported to associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation (Leroy et al., Mol.
  • BRD4 appears to be involved in the recruitment of the pTEF-[beta] complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al., Cell, 2009, 138(1): 129-145).
  • BRD4 or BRD3 may fuse with NUT (nuclear protein in testis) forming novel fusion oncogenes, BRD4-NUT or BRD3-NUT, in a highly malignant form of epithelial neoplasia (French et al., Cancer Research, 2003, 63, 304-307 and French et al., Journal of Clinical Oncology, 2004, 22 (20), 4135-4139).
  • BRD-NUT fusion proteins contribute to carcinogenesis (Oncogene, 2008, 27, 2237-2242).
  • BRD-t is uniquely expressed in the testes and ovary.
  • International patent application WO 2009/084693 discloses a series of thienotriazolodiazepiene derivatives that are said to inhibit the binding between an acetylated histone and a bromodomain containing protein and are said to be useful as anti-cancer agents.
  • International patent application WO 2011/054846 discloses a series of quinoline derivatives that inhibit the binding of BET family bromodomains with acetylated lysine residues.
  • International patent application WO 2015/092118 discloses spiro[cyclobutane- 1,3’-indolin]-2’-one derivatives which are useful as bromodomain inhibitors.
  • Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT consists of tandem bromodomains. These domains are frequently referred to as BD1 (first bromodomain) and BD2 (second bromodomain) respectively and they share a high sequence homology. Lack of availability of potent and selective inhibitors have hindered the progress of dissecting biology of such bromodomain selective BET inhibitors. Selective targeting of either of these BD domains might pose different therapeutic profile over the pan BET inhibitors. There remains a need for potent bromodomain inhibitors with desirable selectivity and pharmaceutical properties.
  • the present invention provides novel spiro[cycloalkyl-1,3’-indolin]-2’-one derivatives which are able to inhibit the binding of BET family bromodomains to acetylated lysine residues.
  • Such compounds will hereafter be referred to as
  • bromodomain inhibitors The compounds exhibit significant selectivity for BRD4 BD1 inhibition over BRD4 BD2 inhibition.
  • the compounds of the present invention are represented by formula (I):
  • ring Cy 1 and ring Cy 2 are selected, independently, from a 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected form N, O or S;
  • R 1 is hydrogen or C 1-7 alkyl
  • R 2 is -NHR 5 , -C(O)NHR 6 , -NHC(O)R 7 , -OR 8 , -C(O)R 9 , or -OC(O)R 10 , C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substitutedC 5-12 spiroheterocyclyl, optionally substituted aryl, optionally substituted aryl C 1-7 alkyl, wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C 1-7 alkyl, C 3-7 cycloalkyl or C 3-7 spirocycloalkyl;
  • L is absent or is selected from -O-, -NH- or C 1-7 alkylene;
  • R 3 at each occurrence is independently selected from halogen, C 1-7 alkyl, C 1-7 alkoxy, C1-7 alkoxy C1-7 alkyl, C3-7 cycloalkyl C1-7 alkyl, halo C1-7 alkyl, hydroxy, hydroxy C 1-7 alkyl, nitro, oxo, -NR 11 R 12, -SO 2 (C 1-7 alkyl) or heterocyclyl;
  • R 4 at each occurrence is independently selected from halogen, C 1-7 alkyl, C 1-7 alkoxy, halo C 1-7 alkyl, hydroxy, hydroxy C 1-7 alkyl, nitro, oxo, -NHSO 2 -C 1-7 alkyl, heterocyclyl optionally substituted by C 1-7 alkyl or -O-heterocyclyl optionally substituted by C 1-7 alkyl;
  • R 5 and R 6 are, independently, selected from hydrogen, halogen, halo C 1-7 alkyl, optionally substituted C 1-7 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C1-7 alkyl or C1-7 alkoxy;
  • R 7, R 8, R 9 and R 10 are, independently, selected from hydrogen, halo C 1-7 alkyl, C 1- 7 alkyl amino C 1-7 alkyl, optionally substituted C 1-7 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substituted C 5-12 spiroheterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C 1-7 alkyl, C 3-7 cycloalkyl, imino, C 3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C 1- 7 alkyl or C 1-7 alkoxy,
  • R 11 and R 12 are selected, independently, from hydrogen, C 1-7 alkyl,
  • n and n are selected, independently, from 0, 1, 2 or 3;
  • q 1 or 2;
  • the present invention provides a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutically acceptable salt thereof.
  • composition comprising spiro[cycloalkyl-1,3’-indolin]-2’-one derivative of formula (I) or a pharmaceutically acceptable salt thereof.
  • it provides spiro[cycloalkyl-1,3’- indolin]-2’-one derivatives of formula (I) or a pharmaceutically acceptable thereof for use in the treatment or prevention of diseases or disorders where bromodomain inhibition is desired, in particular for the treatment or prevention of an autoimmune disease, inflammatory disease or cancer.
  • An embodiment of the present application provides novel spiro[cycloalkyl-1,3’- indolin]-2’-one derivatives of formula (I) or pharmaceutically acceptable salts thereof which are useful as bromodomain inhibitors.
  • One of the embodiments of the present invention provides a compound of formula (I) :
  • ring Cy 1 and ring Cy 2 are selected, independently, from a 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected form N, O or S;
  • R 1 is hydrogen or C 1-7 alkyl
  • R 2 is -NHR 5 , -C(O)NHR 6 , -NHC(O)R 7 , -OR 8 , -C(O)R 9 , or -OC(O)R 10 , C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C 1-7 alkyl, optionally substituted aryl, optionally substituted aryl C 1-7 alkyl, wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C1-7 alkyl, C3-7 cycloalkyl, C3-7 spiro- cycloalkyl, or C 3-7 spiroheterocyclyl optionally substituted by C 1-7 alkyl;
  • L is absent or is selected from -O-, -NH- or C 1-7 alkylene
  • R 3 at each occurrence is independently selected from halogen, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkoxy C 1-7 alkyl, C 3-7 cycloalkyl C 1-7 alkyl, halo C 1-7 alkyl, hydroxy, hydroxy C 1-7 alkyl, amino, nitro, oxo, -NR 11 R 12, -SO 2 (C 1-7 alkyl) or heterocyclyl;
  • R 4 at each occurrence is independently selected from halogen, C 1-7 alkyl, C 1-7 alkoxy, halo C1-7 alkyl, hydroxy, hydroxy C1-7 alkyl, nitro, oxo, -NHSO2-C1-7 alkyl, heterocyclyl optionally substituted by C 1-7 alkyl or -O-heterocyclyl optionally substituted by C 1-7 alkyl;
  • R 5 and R 6 are, independently, selected from hydrogen, halogen, halo C 1-7 alkyl, optionally substituted C 1-7 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C 1-7 alkyl or C 1-7 alkoxy;
  • R 7, R 8, R 9 and R 10 are, independently, selected from hydrogen, halo C 1-7 alkyl, C 1- 7 alkyl amino C 1-7 alkyl, optionally substituted C 1-7 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C 1-7 alkyl, C 3-7 cycloalkyl, halo C 1-7 alkyl, imino, C3-7 spirocycloalkyl, heterocyclyl optionally substituted by halogen, hydroxy, C1-7 alkyl or C 1-7 alkoxy, or C 3-7 spiroheterocyclyl optionally substituted by C 1-7 alkyl;
  • R 11 and R 12 are selected, independently, from hydrogen, C 1-7 alkyl,
  • n and n are selected, independently, from 0, 1, 2 or 3;
  • q 1 or 2;
  • the compound of formula (I) is a compound of formula (I’)
  • ring Cy 1 and ring Cy 2 are selected, independently, from a 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected form N, O or S;
  • R 1 is hydrogen or C 1-7 alkyl
  • R 2 is -NHR 5 , -C(O)NHR 6 , -NHC(O)R 7 , -OR 8 , -C(O)R 9 , or -OC(O)R 10 , C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C1-7 alkyl, optionally substituted aryl, optionally substituted aryl C 1-7 alkyl, wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C 1-7 alkyl, C 3-7 cycloalkyl or C 3-7 spiro- cycloalkyl;
  • L is absent or is selected from -O-, -NH- or C 1-7 alkylene
  • R 3 at each occurrence is independently selected from halogen, C 1-7 alkyl, C 1-7 alkoxy, halo C 1-7 alkyl, hydroxy, hydroxy C 1-7 alkyl, amino, nitro, oxo, or -NHSO 2 -C 1-7 alkyl;
  • R 4 at each occurrence is independently selected from halogen, C 1-7 alkyl, C 1-7 alkoxy, halo C 1-7 alkyl, hydroxy, hydroxy C 1-7 alkyl, amino, nitro, oxo, or -NHSO 2 -C 1-7 alkyl;
  • R 5 and R 6 are, independently, selected from hydrogen, halogen, halo C 1-7 alkyl, optionally substituted C 1-7 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C 1-7 alkyl or C 1-7 alkoxy;
  • R 7, R 8, R 9 and R 10 are, independently, selected from hydrogen, halo C 1-7 alkyl, C 1- 7 alkyl amino C 1-7 alkyl, optionally substituted C 1-7 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C1-7 alkyl, C3-7 cycloalkyl, C3-7 spirocyclo- alkyl or heterocyclyl optionally substituted by halogen, hydroxy, C 1-7 alkyl or C 1-7 alkoxy; m and n are selected, independently, from 0, 1, 2 or 3;
  • the compound of formula (I) is a compound of formula (IA)
  • the compound of formula (I) is a compound of formula (IB)
  • the compound of formula (I) is a compound of formula (IC)
  • the compound of formula (I) is a compound of formula (ID)
  • ring Cy 1 and ring Cy 2 are selected, independently, from a 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected form N, O or S;
  • R 1 is hydrogen
  • R 2 is -NHR 5 , -C(O)NHR 6 , -NHC(O)R 7 , -OR 8 , -C(O)R 9 , -OC(O)R 10 or optionally substituted C 5-12 spiroheterocyclyl;
  • L is absent or is selected from -O-, -NH- or C 1-7 alkylene
  • R 3 at each occurrence is independently selected from halogen, C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkoxy C 1-7 alkyl, C 3-7 cycloalkyl C 1-7 alkyl, halo C 1-7 alkyl, hydroxy, hydroxy C 1-7 alkyl, nitro, oxo, or -NR 11 R 12 or heterocyclyl;
  • R 4 at each occurrence is independently selected from halogen, C 1-7 alkyl, C 1-7 alkoxy, halo C1-7 alkyl, hydroxy, hydroxy C1-7 alkyl, amino, nitro, oxo, or -NHSO2-C1-7 alkyl;
  • R 5 and R 6 are, independently, selected from hydrogen, halogen, halo C 1-7 alkyl, optionally substituted C 1-7 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents independently selected from halogen, hydroxy, oxo, amino, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C 1-7 alkyl or C 1-7 alkoxy;
  • R 7, R 8, R 9 and R 10 are, independently, selected from hydrogen, halo C 1-7 alkyl, C 1- 7 alkyl amino C 1-7 alkyl, optionally substituted C 1-7 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C 1-7 alkyl, optionally substituted C5-12 spiroheterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C1-7 alkyl or C 1-7 alkoxy;
  • n and n are selected, independently, from 0, 1, 2 or 3;
  • q 1 or 2;
  • ring Cy 1 and ring Cy 2 are selected, independently, from a 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms independently selected form N, O or S;
  • R1 is hydrogen
  • R 2 is -NHR 5 , -C(O)NHR 6 , -NHC(O)R 7 , -OR 8 , -C(O)R 9 , or -OC(O)R 10 ;
  • L is absent or is selected from -O-, -NH- or C 1-7 alkylene
  • R 3 at each occurrence is independently selected from halogen, C 1-7 alkyl, C 1-7 alkoxy, halo C 1-7 alkyl, hydroxy, hydroxy C 1-7 alkyl, amino, nitro, oxo, or -NHSO 2 -C 1-7 alkyl;
  • R 4 at each occurrence is independently selected from halogen, C 1-7 alkyl, C 1-7 alkoxy, halo C1-7 alkyl, hydroxy, hydroxy C1-7 alkyl, amino, nitro, oxo, or -NHSO2-C1-7 alkyl;
  • R 5 and R 6 are, independently, selected from hydrogen, halogen, halo C 1-7 alkyl, optionally substituted C 1-7 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents independently selected from halogen, hydroxy, oxo, amino, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C 1-7 alkyl or C 1-7 alkoxy;
  • R 7, R 8, R 9 and R 10 are, independently, selected from hydrogen, halo C 1-7 alkyl, C 1- 7 alkyl amino C 1-7 alkyl, optionally substituted C 1-7 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; wherein the optional substitution at each occurrence is independently selected from 1-3 substituents selected from halogen, hydroxy, oxo, amino, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 spirocyclo- alkyl or heterocyclyl optionally substituted by halogen, hydroxy, C 1-7 alkyl or C 1-7 alkoxy; m and n are selected, independently, from 0, 1, 2 or 3;
  • ring Cy 1 is selected from a 4-12 membered monocyclic or bicyclic ring containing 1-4 heteroatoms independently selected form N, O or S.
  • ring Cy1 is selected from a 4-6 membered ring containing 1-4 heteroatoms N.
  • ring Cy1 is selected from the following groups
  • ring Cy 1 is selected from the following groups
  • R 3 is selected from C 1-7 alkyl, C 1-7 alkoxy, C 1-7 alkoxy C 1-7 alkyl, C 3-7 cycloalkyl C 1-7 alkyl, halo C 1-7 alkyl, NR 11 R 12 or heterocyclyl , and m is 0, 1 or 2.
  • heterocyclyl at each occurrence, is a monocyclic or polycyclic ring with 5 to 10 ring atoms of which 1-4 are heteroatoms independently selected from the group consisting of N, O and S.
  • R 5 is hydrogen or an optionally substituted heterocyclyl
  • the heterocyclyl is a monocyclic or polycyclic ring with 5 to 10 ring atoms of which 1-4 are heteroatoms independently selected from the group consisting of N, O and S, and the optional substitution is selected from 1-3 substituents independently selected from C 1-7 alkyl, C 3-7 cycloalkyl, halogen, amino or oxo.
  • R 5 is an optionally substituted piperidinyl, pyridinyl, piperazinyl, pyrrolidinyl, tetrahydro-2H-pyranyl or 1,1-dioxidotetrahydro-2H-thiopyranyl ring the optional substitution at each occurrence being independently selected from 1-3 substituents independently selected from C 1-7 alkyl, C 3-7 cycloalkyl, halogen, amino or oxo.
  • R5 is optionally substituted piperidine ring optionally substituted by 1-3 substituents independently selected from C 1-7 alkyl or C 3-7 cycloalkyl.
  • R 8 is hydrogen, C 1-7 alkyl amino C 1-7 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C 1-7 alkyl, optionally substituted C 5-12 spiroheterocyclyl, the optional substitution, at each occurrence, being independently selected from 1-3 substituents selected independently from halogen, hydroxy, oxo, amino, C 1-7 alkyl, C 3-7 cycloalkyl, C 3-7 spirocycloalkyl or heterocyclyl optionally substituted by halogen, hydroxy, C1-7 alkyl or C1-7 alkoxy.
  • R 8 is hydrogen, optionally substituted heterocyclyl or optionally substituted heterocyclyl C 1-7 alkyl or optionally substituted C 5-12 spiroheterocyclyl, the optional substitution at each occurrence being independently selected from 1-3 substituents independently selected from C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkoxy, amino or oxo.
  • heterocyclyl, at each occurrence is a monocyclic or polycyclic ring with 5 to 10 ring atoms of which 1-4 are heteroatoms independently selected from the group consisting of N, O and S.
  • the optionally substituted heterocyclyl is piperidinyl, pyridinyl, piperazinyl, pyrrolidinyl, tetrahydro-2H-pyranyl or 1,1-dioxidotetrahydro-2H-thiopyranyl ring the optional substitution at each occurrence being independently selected from 1-3 substituents independently selected from C 1-7 alkyl, C 3-7 cycloalkyl, C 1-7 alkoxy, halogen, amino or oxo.
  • the optionally substituted heterocyclyl ring is piperidinyl or pyrrolidinyl, optionally substituted by 1-3 substituents independently selected from C 1-7 alkyl or halogen.
  • specifically provided are compounds of formula (I), (I’), (IA), (IB), (IC) or (ID), or according to any other embodiment or subclass referred to above, wherein ring Cy2 is selected from phenyl, cyclohexyl, pyridinyl, piperidinyl, or tetrahydropyranyl ring.
  • R 4 is selected from halogen, halo C 1-7 alkyl, C 1-7 alkyl, or C 1-7 alkoxy, and n is 0, 1 or 2.
  • R 4 is selected from halogen, halo C 1-7 alkyl, C 1-7 alkyl, or C 1-7 alkoxy, and n is 0, 1 or 2.
  • a compound of formula I or I’ wherein
  • ring Cy 2 is phenyl; R 1 is hydrogen; R 2 is -OR 8 or -NHR 5 ; L is absent or -O-; R 8 and R 5 are, independently, optionally substituted piperidinyl or optionally substituted pyrrolidinyl wherein the optional substitution at each occurrence is independently selected from 1-3 substituents independently selected from C 1-7 alkyl or C 3- 7 cycloalkyl; R 3 at each occurrence is independently selected from halo C 1-7 alkyl, amino, or C 1-7 alkyl; R 4 at each occurrence is independently selected from halogen, C 1-7 alkyl or C 1-7 alkoxy; m is 0 or 1; n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of formula (I), (I’), (IA), (IB), (IC) or (ID) of the present invention and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • formulas (I), (I’), (IA), (IB), (IC) and (ID) encompass all stereoisomers, enantiomers, diastereomers and isotopes that may be contemplated from the chemical structure of the compounds according to above formulas.
  • the present compounds may also exist as tautomers or equilibrium mixtures thereof wherein a proton of a compound shifts from one atom to another.
  • tautomers include, but are not limited to, amido-imido, keto-enol, phenol-keto, oxime- nitroso, nitro-aci, imine-enamine and the like. All tautomeric forms of the compounds are intended to be encompassed by their structural formula even though only one tautomeric form may be depicted.
  • 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 herein, the following definitions are supplied in order to facilitate the understanding of the present invention.
  • C 1-7 alkyl refers to a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6 or 7 carbon atom(s).
  • Representative examples of C 1-7 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl and n-hexyl.
  • the term“C 1-3 alkyl” refers to a preferred embodiment of“C 1-7 alkyl” having 1, 2 or 3 carbon atoms.
  • C2-7 alkenyl refers to an aliphatic hydrocarbon group having 2 to 7 carbon atoms and containing one or several double bonds. Representative examples include, but are not limited to, ethy- lene, prop-1-ene, but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, hex-1-ene and hex-2-ene.
  • C 1-7 alkylene refers to a divalent moiety by removing two hydrogen atoms from one or two carbon atoms from a C 1-7 alkyl group.
  • “C 1-7 alkylene” groups include, but are not limited, to -CH 2 -, -CH 2 -CH 2 - and -CH 2 -CH 2 - CH 2 - groups.
  • C3-7 cycloalkyl refers to a saturated or partially saturated monocyclic hydrocarbon ring containing 3, 4, 5, 6 or 7 carbon atoms.
  • Representative examples of C 3-10 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 3-7 spirocycloalkyl refers to a saturated or partially saturated, monocyclic hydrocarbon ring having 3 to 7 carbon atoms which ring is attached to another group via spiro configuration.
  • C 5-10 spirocycloalkyl refers to a bicyclic saturated hydrocarbon ring system having 5-10 carbon ring atoms wherein one carbon atom is common to both rings.
  • halo or“halogen”, as employed herein as such or as part of another group, refers to chlorine, bromine, fluorine or iodine.
  • C 1-7 alkoxy as employed herein as such or as part of another group, refers to C1-7 alkyl, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of C 1-7 alkoxy include, but are not limited to methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • hydroxy as employed herein as such or as part of another group, refers to an–OH group.
  • amino refers to an–NH 2 group.
  • cyano refers to a–CN group.
  • carboxy refers to–COOH group.
  • hydroxy C 1-7 alkyl refers to at least one hydroxy group, as defined herein, appended to the parent molecular moiety through a C 1-7 alkyl group, as defined herein.
  • Representative examples of hydroxyl C 1-7 alkyl include, but are not limited to, hydroxymethyl, 2,2-dihydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 1- hydroxypropyl, 1-methyl-1-hydroxyethyl and 1-methyl-1-hydroxypropyl.
  • halo C 1-7 alkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a C 1-7 alkyl group, as defined herein.
  • Representative examples of halo C 1-7 alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl and 3-bromopropyl.
  • amino C 1-7 alkyl refers to at least one amino group, as defined herein, appended to the parent molecular moiety through a C 1-7 alkyl group, as defined herein.
  • C 1-7 alkyl amino C 1-7 alkyl refers to at least one C1-7 alkyl group, as defined herein, appended to the parent molecular moiety through amino C 1-7 alkyl group, as defined herein.
  • C 3-10 cycloalkyl C 1-7 alkyl refers to a C 3-10 cyclo- alkyl group, as defined herein, appended to the parent molecular moiety through a C 1-7 alkyl group, as defined herein.
  • phenyl C 1-7 alkyl refers to at least one phenyl group appended to the parent molecular moiety through a C 1-7 alkyl group, as defined herein.
  • halo phenyl C 1-7 alkyl refers to at least one halo group appended to the parent molecular moiety through a phenyl C 1-7 alkyl group, as defined herein.
  • aryl refers to a monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of 6 to 14 carbon atoms. Examples of aryl groups include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, biphenylenyl, and acenaphthyl. Preferred aryl group is phenyl.
  • aryl C 1-7 alkyl refers to at least one aryl group appended to the parent molecular moiety through a C 1-7 alkyl group, as defined herein.
  • aryl C 1-7 alkyl groups include, but are not limited to benzyl, benzhydryl, 1- phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl and 2- naphthylmethyl.
  • Preferred aryl C 1-7 alkyl group is phenyl C 1-7 alkyl.
  • aryl C 2-7 alkenyl refers to an aryl group appended to the parent molecular moiety through a C 2-7 alkenyl group, as defined herein.
  • aryl C 1-7 alkenyl groups include, but are not limited to 1-phenylethenyl, 2-phenylethenyl and 2- phenylprop-1-enyl.
  • aryl halo C 1-7 alkyl refers to at least one aryl group, as defined herein, appended to the parent molecular moiety through a halo C 1-7 alkyl group, as defined herein.
  • aryl halo C 1-7 alkyl groups include, but are not limited to phenyl fluoro methyl and 1-phenyl 2-chloro ethyl.
  • the term“heterocyclyl” includes the definitions of“heterocycloalkyl” and “heteroaryl”.
  • heterocycloalkyl refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system with 3 to 10 ring atoms of which at least one, preferably 1-4, is a heteroatom selected from the group consisting of O, N, and S.
  • One particular embodiment of“heterocycloalkyl” is a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system with 5 to 10 ring atoms of which 1-4 are heteroatoms selected from the group consisting of N, O and S.
  • heterocycloalkyl groups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl and 1,4-dioxanyl.
  • heteroaryl refers to a monocyclic, bicyclic, or polycyclic aromatic ring system of 6-14 ring atoms containing at least one, preferably 1 to 4, heteroatom selected from the group consisting of N, O and S.
  • One particular embodiment of“heteroaryl” is a monocyclic, bicyclic, or polycyclic aromatic ring with 5-10 ring atoms of which 1-4 are heteroatoms selected from the group consisting of N, O and S.
  • Examples of 5-10 membered heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, thiadiazole, isoxazole, isothiazole, imidazole, 1H-indazole N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1,2,3,4- tetrahydroisoquinoline 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, 3-quinuclidine, 3,4-dihydroisoquinolin-1(2H)-one, N- methylbenzimidazole, aza
  • bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heterocyclyl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom.
  • the term“C 5-12 spiroheterocyclyl” as employed herein as such or as part of another group refers to bicyclic ring system having 5-12 ring atoms of which at least one, preferably 1-4, is a heteroatom selected from the group consisting of O, N, and S and wherein one ring atom is common to both rings.
  • heterocyclyl C 1-7 alkyl refers to at least one heterocyclyl group, as defined herein, appended to the parent molecular moiety through a C 1-7 alkyl group.
  • heterocyclyl C 2-7 alkenyl refers to at least one heterocyclyl group, as defined herein, appended to the parent molecular moiety through a C 2-7 alkenyl group.
  • heterocyclyl C 3-7 cycloalkyl refers to at least one heterocyclyl group, as defined herein, appended to the parent molecular moiety through a C3-7 cycloalkyl group, wherein the heterocyclyl group is attached to C 3-7 cycloalkyl group via spiro
  • 4-12 membered monocyclic or bicyclic ring containing 0-4 hetero- atoms refers to a 4-12 membered monocyclic or bicyclic aromatic or non-aromatic cyclic ring in which 0-4 of the ring carbon atoms have been independently replaced with N, O or S.
  • rings include, but are not limited to phenyl, pyridine, pyrimidine, morpholine, piperidine, piperazine, imidazole, pyrazole, pyrrole, thiophene, cyclopropyl, 2,3dihydrobenzo[b][1,4]dioxine, 1,2,3,4-tetrahydroisoquinoline, quinoline, indazole, [1,2,4]triazolo[4,3-a]pyridine and tetrahydroisoquinoline.
  • a particular embodiment of "4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms” are a monocyclic or bicyclic aromatic or non-aromatic cyclic ring with 5- 10 ring atoms of which 0-4 are heteroatoms selected from a group consisting of N, O and S.
  • the term“4-10 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, or S” refers to aromatic, saturated or partially saturated monocyclic, bicyclic or polycyclic ring which have 4 to 10 ring member atoms of which 1 to 4 are
  • heteroatoms selected from a group consisting of O, N, and S heteroatoms selected from a group consisting of O, N, and S.
  • the term“9-12 membered heterocyclic ring having 1-3 heteroatoms selected from N or O” refers to aromatic, saturated or partially saturated monocyclic, bicyclic or polycyclic ring which have 9 to 12 ring member atoms of which 1 to 3 are heteroatoms selected from a group consisting of N and O.
  • -S(O) 2 NH(cycloalkyl), carboxy, -C(O)O(C 1 - 7 alkyl), -C(O)(C 1 - 7 alkyl), N-OH, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl- alkyl, cycloalkenyl, amino, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclic ring.
  • “optionally substituted or substituted” is 1-3 substituents selected from the group consisting of C 1 - 7 alkyl, C 3 - 7 cycloalkyl, halogen, nitro, cyano, amino, hydroxy, halo C 1 - 7 alkyl, hydroxy C 1 - 7 alkyl, C 1 - 7 alkoxy and halo C 1 - 7 alkoxy substituents.
  • the terms“treat”, “treating” or “treatment” encompass either or both responsive and prophylaxis measures, e.g.
  • the terms“treat,”“treating” or“treatment”, include, but are not limited to, prophylactic and/or therapeutic treatments.
  • the terms "subject” or “patient” are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human.
  • the subject is a subject in need of treatment or a subject with a disease or disorder.
  • the subject can be a normal subject.
  • the term does not denote a particular age or sex. Thus, adult and new-born subjects, whether male or female, are intended to be covered.
  • the term“therapeutically effective amount,” refers to a sufficient amount of a compound or a composition being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • the term“therapeutically effective amount” includes, for example, a prophylactically effective amount.
  • “Pharmaceutically acceptable” means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salt” refers to the salts of the compounds, that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Such salts include: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzene sulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluene- sul
  • stereoisomers refers to any enantiomers, diastereomers, or geometrical isomers of the compounds of formula (I) wherever they are chiral or when they bear one or more double bond.
  • the compounds of the formula (I) and related formulae are chiral, they can exist in racemic or in optically active form. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis.
  • diastereomers are formed from the mixture by reaction with an optically active resolving agent.
  • optically active acids such as the R and S forms of tartaric acid, diacetyl tartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline or N- benzenesulfonylproline), or the various optically active camphorsulfonic acids.
  • chromatographic enantiomer resolution with the aid of an optically active resolving agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatised methacrylate polymers immobilised on silica gel).
  • optically active resolving agent for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatised methacrylate polymers immobilised on silica gel.
  • Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/ acetonitrile, for example in the ratio 82:15:3.
  • Bromodomain inhibitors are believed to be useful in the treatment of a variety of diseases or conditions related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis and in the prevention and treatment of viral infections.
  • Bromodomain inhibitors may be useful in the treatment of a wide variety of chronic autoimmune and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes and
  • Bromodomain inhibitors may be useful in the treatment of a wide variety of acute inflammatory conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritisnodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organ involvement and acute rejection of transplanted organs.
  • acute inflammatory conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritisnodosa, Behcet's disease, Kawasaki disease
  • Bromodomain inhibitors may be useful in the prevention or treatment of diseases or conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endo- toxaemia, systemic inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, malaria and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex and coronavirus.
  • SIRS systemic inflammatory response syndrome
  • multi-organ dysfunction syndrome toxic shock syndrome
  • acute lung injury ARDS (adult respiratory distress syndrome)
  • ARDS adult respiratory distress syndrome
  • fulminant hepatitis burns
  • Bromodomain inhibitors may be useful in the prevention or treatment of conditions associated with ischaemia-reperfusion injury such as myocardial infarction, cerebro- vascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.
  • Bromodomain inhibitors may be useful in the treatment of disorders of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.
  • Bromodomain inhibitors may be useful in the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis. Bromodomain inhibitors may be useful in the prevention and treatment of viral infections such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses. Bromodomain inhibitors may be useful in the treatment of cancer, including hematological, epithelial including lung, breast and colon carcinomas, midline
  • the disease or condition for which a bromodomain inhibitor is indicated is selected from diseases associated with systemic inflammatory response syndrome, such as sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia.
  • the bromodomain inhibitor would be administered at the point of diagnosis to reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal injury and mortality.
  • the bromodomain inhibitor would be administered prior to surgical or other procedures associated with a high risk of sepsis, haemorrhage, extensive tissue damage, SIRS or MODS (multiple organ dysfunction syndrome).
  • the disease or condition for which a bromodomain inhibitor is indicated is sepsis, sepsis syndrome, septic shock and endotoxaemia.
  • the bromodomain inhibitor is indicated for the treatment of acute or chronic pancreatitis.
  • the bromodomain is indicated for the treatment of burns.
  • bromodomain inhibitor is indicated is selected from herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus.
  • a bromodomain inhibitor is indicated for the treatment of Human papilloma virus infections of skin or cervical epithelia.
  • the term "diseases or disorders where bromodomain inhibition is desired" is intended to include each of or all of the above disease states.
  • a compound of formula (I) as well as pharmaceutically acceptable salts thereof may be administered as such, it is common to present the active ingredient as a pharmaceutical composition.
  • the compounds and pharmaceutically compositions of the present invention may be used in combination with other drugs that are used in the treatment/prevention/- suppression or amelioration of the diseases or conditions for which compounds of the present invention may be useful.
  • Such other drugs may be administered, by a route and in an amount commonly used there for, simultaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention may also be preferred.
  • compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • a pharmaceutical composition of the invention may be formulated as being compatible with its intended route of administration, which may preferably be an oral administration.
  • the pharmaceutical compositions of the invention may be formulated for administration by inhalation, such as aerosols or dry powders; for oral administration, such in the form of tablets, capsules, gels, syrups, suspensions, emulsions, elixirs, solutions, powders or granules; for rectal or vaginal administration, such as suppositories; or for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion) such as a sterile solution, suspension or emulsion.
  • the compounds of the present invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethyl cellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • macroemulsions for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2H (“D”), 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I and 125I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Step-b Spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-b 5'-Aminospiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-b 5'-Amino-7'-bromospiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-a 2-(2'-Oxospiro[cyclobutane-1,3'-indolin]-5'-yl)isoindoline-1,3-dione
  • phthalic anhydride 4.2 g, 20.48 mmol
  • Step-b 2-(7'-Nitro-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)isoindoline-1,3- dione
  • Step-b 5'-Acetyl-7'-bromospiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-c 5'-Acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'-indolin]- 2'-one
  • 5'-acetyl-7'-bromospiro[cyclobutane-1,3'-indolin]-2'- one 6.5 g, 22.1 mmol
  • DMF 100 mL
  • cesium carbonate 21.6 g, 66.3 mmol
  • 1-(chloromethyl)-4-methoxybenzene 3.6 mL, 26.52 mmol
  • Step-a 7'-Nitro-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclo- butane-1,3'-indolin]-2'-one
  • Step-b 5-Bromo-1-(2,4-difluorophenyl)-1H-1,2,4-triazole
  • Step-b 5'-Acetyl-1'-(4-methoxybenzyl)-7'-nitrospiro[cyclobutane-1,3'-indolin]-2'- one
  • Step-c (E)-5'-(3-(dimethylamino)acryloyl)-1'-(4-methoxybenzyl)-7'-nitrospiro- [cyclobutane-1,3'-indolin]-2'-one
  • Step-c tert-Butyl 2,6-dimethyl-4-oxopiperidine-1-carboxylate
  • Step-a tert-Butyl 4-((trimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate
  • TMSCl 4.8 mL, 37.68 mmol
  • triethyl amine 10.5 mL, 75.36 mmol
  • TLC TLC was monitored, and the reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was washed with aqueous NaHCO3, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by
  • Step-b tert-Butyl 3-fluoro-4-oxopiperidine-1-carboxylate
  • Step-b 5'-Bromo-7'-iodo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'- one
  • Step-c 5'-Bromo-7'-hydroxy-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'- indolin]-2'-one
  • Step-b 5'-Acetyl-7'-methoxy-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'- indolin]-2'-one
  • Step-c 5'-(3-(Dimethylamino) acryloyl)-7'-methoxy-1'-(4-methoxybenzyl)spiro- [cyclobutane-1,3'-indolin]-2'-one
  • Step-a tert-butyl 2-(Tetrahydro-4H-pyran-4-ylidene)hydrazine-1-carboxylate
  • a solution of tert-butyl hydrazine carboxylate (6.6 g, 5.0 mmol) in n-hexane (100 mL) was added tetrahydro-4H-pyran-4-one (5.0 g, 5.0 mmol) dropwise followed by stirring at RT for 30 min and then heating to 90oC for 2 h. TLC was monitored and the mixture was cooled to RT.
  • Step-b tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazine-1-carboxylate
  • Step-c (tetrahydro-2H-pyran-4-yl)hydrazine trifluoroacetate To a solution of tert-butyl 2-(tetrahydro-2H-pyran-4-yl) hydrazine-1-carboxylate (2.0 g, 9.25 mmol) in DCM (30 mL) was added trifluoro acetic acid (3.5 mL, 46.25 mmol) followed by stirring at RT for 2 h.
  • Step-b 5'-Acetyl-7'-bromospiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-c 5'-Acetyl-7'-bromo-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'-indolin]- 2'-one
  • Step-ii (A) (E)-5'-(3-(Dimethylamino)acryloyl)-7'-nitrospiro[cyclobutane-1,3'- indolin]-2'-one
  • Example-II 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-((1-methylpiperidin-4-yl)- amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-3)
  • Step-ii 7'-Benzyl-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)spiro[cyclobutane- 1,3'-indolin]-2'-one
  • Example-IV 7'-Amino-5'-(2-(2,4-difluorophenyl)-1H-pyrrol-1-yl)spiro[cyclobutane- 1,3'-indolin]-2'-one (Compound-6)
  • Example-V N-(5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-2'-oxospiro[cyclobutane- 1,3'-indolin]-7'-yl)-1-methylpiperidine-4-carboxamide (Compound-7)
  • Step-ii 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-1'-methylspiro- [cyclobutane-1,3'-indolin]-2'-one
  • Example-IX 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-hydroxyspiro[cyclobutane- 1,3'-indolin]-2'-one (Compound-11) & 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'- ((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-12) p p p p
  • Step-ii 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-7'-hydroxyspiro[cyclo- butane-1,3'-indolin]-2'-one
  • Step-ii 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(4-methylpiperazin-1-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XI 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)spiro[cyclo- butane-1,3'-indolin]-2'-one (Compound-14) & 5’-(1-(2,4-Difluorophenyl)-1H-1,2,4- triazol-5-yl)-7'-((1-methylpiperidin-4-yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one Com ound-15
  • Step-ii 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)spiro[cyclo- butane-1,3'-indolin]-2'-one
  • Step-ii 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-imidazol-2-yl)spiro[cyclobutane- 1,3'-indolin]-2'-one
  • the compound was prepared using the process described in Example-VIII.1H NMR (400 MHz, DMSO-d6): ⁇ 9.99 (bs, 1H), 7.70-7.64 (m, 1H), 7.58-7.53 (m, 1H), 7.42 (s, 1H), 7.32-7.28 (m, 1H), 7.16 (s, 1H), 6.83 (s, 1H), 6.40 (s, 1H), 4.96-4.91 (m, 1H), 3.17-3.01 (m, 3H), 2.59-2.54 (m, 2H), 2.41-2.33 (m, 3H), 2.20-1.91 (m, 4H), 1.78- 1.71 (m, 2H), 1.5
  • Step-ii 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-N-(1-methylpiperidin-4-yl)- 2'-oxospiro[cyclobutane-1,3'-indoline]-7'-carboxamide
  • the compound was prepared using the process described in step-ii of Example-X.
  • Example-XIV 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(4-methyl- i erazine-1-carbon l s iro c clobutane-13'-indolin -2'-one Com ound-18
  • Step-ii 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(4-methylpiperazine-1- carbonyl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XV 5'-(1-(4-Methoxyphenyl)-1H-pyrazol-5-yl)-7'-((1-methylpiperidin-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-19)
  • Step-i 1'-(4-Methoxybenzyl)-5'-(1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-7'-nitro- spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-ii 7'-Amino-1'-(4-methoxybenzyl)-5'-(1-(4-methoxyphenyl)-1H-pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XVI 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-3-yl)spiro[cyclo- butane-1,3'-indolin]-2'-one (Compound-21) & 5’-(1-(2,4-Difluorophenyl)-1H-pyrazol-3- yl)-7'-((1-methylpiperidin-4-yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-
  • Step-ii 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-3-yl)-1'-(4-methoxybenzyl)-7'- nitrospiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-3-yl)-7'-nitrospiro[cyclobutane- 1,3'-indolin]-2'-one
  • Step-ii 5'-(1-Benzyl-1H-pyrazol-5-yl)-1'-(4-methoxybenzyl)-7'-((1-methyl- piperidin-4-yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 5'-(1-Benzyl-1H-pyrazol-5-yl)-7'-((1-methylpiperidin-4-yl)amino)spiro- [cyclobutane-1,3'-indolin]-2'-one
  • Example-XVIII 5'-(1-(2,4-Difluorobenzyl)-1H-pyrazol-3-yl)-7'-((1-methylpiperidin-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-25)
  • Step-ii 5'-(1-(2,4-Difluorobenzyl)-1H-pyrazol-3-yl)-7'-nitrospiro[cyclobutane- 1,3'-indolin]-2'-one
  • Step-iii 7'-Amino-5'-(1-(2,4-difluorobenzyl)-1H-pyrazol-3-yl)spiro[cyclobutane- 1,3'-indolin]-2'-one
  • Step-ii 7'-Amino-5'-(1-(2,4-difluorophenyl)-3-methyl-1H-pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 5'-(1-(2,4-Difluorophenyl)-3-methyl-1H-pyrazol-5-yl)-7'-((1-methyl- piperidin-4-yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-ii 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XXI 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl)-7'-((1-methylpiperidin-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-49)
  • Step-ii 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)spiro[cyclobutane- 1,3'-indolin]-2'-one
  • Step-iii 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl)-7'-((1-methylpiperidin-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one
  • the compound was prepared using the process described in Example-VIII.
  • Example-XXII 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-((1-methylpyrrolidin-3- yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-50)
  • Step-ii 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxybenzyl)-7'-((1- methylpyrrolidin-3-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-((1-methylpyrrolidin-3- yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XXIII 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-2'-oxospiro- c clobutane-13'-indolin -7'- l 4-meth l i erazine-1-carbox late Com ound-52
  • Step-i 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxybenzyl)-2'- oxospiro[cyclobutane-1,3'-indolin]-7'-yl 4-methylpiperazine-1-carboxylate
  • 5'-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)-7'- hydroxy-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.12 g, 0.25 mmol) in DMF (3.0 mL) were added potassium carbonate (0.1 g, 0.75 mmol) and DMAP (0.006 g, 0.05 mmol) followed by 4-methylpiperazine-1-carbonyl chloride hydrochloride (0.1 g, 0.5 mmol).
  • Example-XXIV 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(pyridin-2-yloxy)- s iro c clobutane-13'-indolin -2'-one Com ound-53
  • Step-ii 5'-(1-(2,4-Difluorophenyl)-1H-pyrazol-5-yl)-7'-(pyridin-2-yloxy)spiro- [cyclobutane-1,3'-indolin]-2'-one
  • Example-XXV 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-(pyridin-4-yl)-1H-pyrazol-3- yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-54)
  • Step-ii 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(1-(pyridin-4-yl)-1H-pyrazol-3- yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XXVI 5'-(1-(2,4-Difluorophenyl)-1H-pyrrol-2-yl)-7'-((1-methylpiperidin-4- yl)amino)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-55)
  • Step-ii 7'-Amino-5'-(1-(2,4-difluorophenyl)-1H-pyrrol-2-yl)spiro[cyclobutane- 1,3'-indolin]-2'-one
  • Step-iii 5'-(1-(2,4-Difluorophenyl)-1H-pyrrol-2-yl)-7'-((1-methylpiperidin-4-yl)- amino)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-i tert-Butyl 4-((5'-(1-(2-fluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxy- benzyl)-2'-oxospiro[cyclobutane-1,3'-indolin]-7'-yl)oxy)piperidine-1-carboxylate
  • Step-ii 5'-(1-(2-Fluorophenyl)-1H-pyrazol-5-yl)-1'-(4-methoxybenzyl)-7'-(piperi- din-4-yloxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 5'-(1-(2-Fluorophenyl)-1H-pyrazol-5-yl)-7'-(piperidin-4-yloxy)spiro- [cyclobutane-1,3'-indolin]-2'-one
  • the compound was prepared using the process described in step-ii of Example-X.
  • Example-XXVIII 7'-((3-Fluoro-1-methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-pyrazol- 5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-61)
  • Step-i 7'-((3-Fluoro-1-methylpiperidin-4-yl)oxy)-1'-(4-methoxybenzyl)-5'-(1- phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-ii 7'-((3-Fluoro-1-methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • the compound was prepared using the process described in step-ii of Example-X.
  • Step-ii 7'-cyclopropyl-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'- indolin]-2'-one
  • Step-i 7'-Cyclopropoxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-ii 7'-Cyclopropoxy-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'- indolin]-2'-one
  • Step-i 7'-(2-(Dimethylamino)ethoxy)-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-ii 7'-(2-(Dimethylamino)ethoxy)-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclo- butane-1,3'-indolin]-2'-one:
  • Step-i 7'-((2-Chloropyridin-4-yl)oxy)-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-ii 7'-((2-Chloropyridin-4-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclo- butane-1,3'-indolin]-2'-one
  • Step-iii 7'-((2-Oxo-1,2-dihydropyridin-4-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one
  • a solution of 7'-((2-chloropyridin-4-yl)oxy)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (0.36 g, 0.64 mmol) in TFA (6 mL) was heated to 120 oC for 16 h.
  • Example-XXXIII 5'-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-7'-((1-methylpiperidin-4-yl)- oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-67)
  • Step-ii 7'-Bromo-1'-(4-methoxybenzyl)-5'-(3-methyl-1-phenyl-1H-pyrazol-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(3-methyl-1-phenyl-1H-pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XXXIV 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-1,2,4-triazol-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-68)
  • Step-ii 7-Amino-5'-(1-phenyl-1H-1,2,4-triazol-5-yl)spiro[cyclobutane-1,3'- indolin]-2'-one
  • Step-iii 7'-Bromo-5'-(1-phenyl-1H-1,2,4-triazol-5-yl)spiro[cyclobutane-1,3'- indolin]-2'-one
  • Step-vii 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-1,2,4-triazol-5-yl)- spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XXXV 5'-(4-Methoxy-1-phenyl-1H-pyrazol-5-yl)-7'-((1-methylpiperidin-4- l ox s iro c clobutane-13'-indolin -2'-one Com ound-69
  • Step-ii 7'-Bromo-5'-(2-methoxyacetyl)-1'-(4-methoxybenzyl)spiro[cyclobutane- 1,3'-indolin]-2'-one
  • Step-iii (Z)-7'-bromo-5'-(3-(dimethylamino)-2-methoxyacryloyl)-1'-(4-methoxy- benzyl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-vii 5'-(4-Methoxy-1-phenyl-1H-pyrazol-5-yl)-7'-((1-methylpiperidin-4-yl)- oxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-i tert-Butyl 4-((1'-(4-methoxybenzyl)-5'-(3-methyl-1-phenyl-1H-pyrazol-5- yl)-2'-oxospiro[cyclobutane-1,3'-indolin]-7'-yl)oxy)-2,6-dimethylpiperidine-1-carboxylate
  • Step-ii 7'-((2,6-Dimethylpiperidin-4-yl)oxy)-1'-(4-methoxybenzyl)-5'-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XXXVII 5'-(1-Phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7'-((1,2,6-tri- meth l i eridin-4- l ox s iro c clobutane-13'-indolin -2'-one Com ound-71
  • Step-ii 7'-Bromo-1'-(4-methoxybenzyl)-5'-(1-phenyl-3-(trifluoromethyl)-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-3-(trifluoromethyl)-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iv tert-Butyl 4-((1'-(4-methoxybenzyl)-2'-oxo-5'-(1-phenyl-3-(trifluoro- methyl)-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-7'-yl)oxy)-2,6-dimethylpipe- ridine-1-carboxylate
  • Step-vii 5'-(1-Phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7'-((1,2,6-trimethyl- piperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XXXVIII 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-3-(trifluoromethyl)- 1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-72)
  • Step-i 1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-(1-phenyl-3- (trifluoromethyl)-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-ii 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-3-(trifluoromethyl)-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-i 1'-(4-Methoxybenzyl)-7'-((6-nitropyridin-3-yl)oxy)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-ii 7'-((6-Aminopyridin-3-yl)oxy)-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 7'-((6-Aminopyridin-3-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclo- butane-1,3'-indolin]-2'-one
  • Example-XL 5'-(4-Methyl-1-phenyl-1H-pyrazol-5-yl)-7'-((1-methylpiperidin-4-yl)oxy)- spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-74)
  • Step-i 5'-Propionylspiro[cyclobutane-1,3'-indolin]-2'-one
  • DCE DCE
  • propionyl chloride 1.9 mL, 22.2 mmol
  • Spiro[cyclo- butane-1,3'-indolin]-2'-one 3.2 g, 18.50 mmol
  • TLC TLC was monitored, and the reaction mixture was quenched with ice and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure.
  • Step-iii 7'-Bromo-1'-(4-methoxybenzyl)-5'-propionylspiro[cyclobutane-1,3'- indolin]-2'-one
  • Step-vii 1'-(4-Methoxybenzyl)-5'-(4-methyl-1-phenyl-1H-pyrazol-5-yl)-7'-((1- methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-viii 5'-(4-Methyl-1-phenyl-1H-pyrazol-5-yl)-7'-((1-methylpiperidin-4-yl)- oxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-i 1'-(4-Methoxybenzyl)-7'-((2-oxo-1,2-dihydropyridin-4-yl)oxy)-5'-(1- phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-ii 1'-(4-Methoxybenzyl)-7'-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy)- 5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 7'-((1-Methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XLII 5'-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-7'-((1-methylpiperidin-4- l ox s iro c clobutane-13'-indolin -2'-one Com ound-76
  • Step-ii 5'-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-1'-(4-methoxybenzyl)-7'- ((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 5'-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-7'-((1-methylpiperidin-4- yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-i Synthesis of N-(4-(2,4-difluorophenoxy)-3-(1'-(4-methoxybenzyl)-7'-((1- methylpiperidin-4-yl)oxy)-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)phenyl)ethane- sulfonamide
  • Step-ii N-(4-(2,4-difluorophenoxy)-3-(7'-((1-methylpiperidin-4-yl)oxy)-2'-oxo- spiro[cyclobutane-1,3'-indolin]-5'-yl)phenyl)ethanesulfonamide
  • the compound was prepared using the process described in step-ii of Example-X.
  • Example-XLIV 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(3-morpholino-1-phenyl-1H- razol-5- l s iro c clobutane-13'-indolin -2'-one Com ound-78
  • Step-ii 7'-Bromo-1'-(4-methoxybenzyl)-5'-(3-(methylthio)-3-morpholino- acryloyl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • a suspension of 5'-(3,3-bis(methylthio)acryloyl)-7'-bromo-1'-(4-methoxy- benzyl)spiro[cyclobutane-1,3'-indolin]-2'-one (2.1 g, 4.05 mmol) in toluene (25 mL) was added morpholine (0.17 mL, 2.02 mmol) followed by heating at 100 oC for 6 h.
  • Step-iii 7'-Bromo-1'-(4-methoxybenzyl)-5'-(3-morpholino-1-phenyl-1H-pyrazol- 5-yl)spiro [cyclobutane-1,3'-indolin]-2'-one
  • Example-XLV 7'-Methoxy-5'-(1-(3-morpholinophenyl)-1H-pyrazol-5-yl)spiro- c clobutane-13'-indolin -2'-one Com ound-79
  • Step-ii 5'-(1-(3-Aminophenyl)-1H-pyrazol-5-yl)-7'-bromo-1'-(4-methoxybenzyl)- spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-v 7'-Methoxy-1'-(4-methoxybenzyl)-5'-(1-(3-morpholinophenyl)-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XLVI 7'-Methoxy-5'-(1-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-1H-pyrazol- 5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-81)
  • Step-ii 5'-(1-(4-Hydroxyphenyl)-1H-pyrazol-5-yl)-7'-methoxy-1'-(4-methoxy- benzyl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 7'-Methoxy-1'-(4-methoxybenzyl)-5'-(1-(4-((1-methylpiperidin-4-yl)- oxy)phenyl)-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-XLVII 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(2-phenyl-1H-imidazol-1-yl)spiro c clobutane-13'-indolin -2'-one Com ound-83
  • Step-i 7’-Bromo-1'-(4-methoxybenzyl)-5'-nitrospiro[cyclobutane-1,3'-indolin]-2'-one
  • DMF 130 mL
  • Cs 2 CO 3 28.5 g, 87.51 mmol
  • 4- methoxybenzyl chloride 7.2 mL, 52.5 mmol
  • Step-ii 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-nitrospiro[cyclobutane-1,3'-indolin]- 2'-one
  • Step-iii 1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-nitrospiro- [cyclobutane-1,3'-indolin]-2'-one
  • Step-v 1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-(2-phenyl-1H- imidazol-1-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • benzaldehyde 0.05 mL, 0.48 mmol
  • MeOH MeOH
  • Step-ii 7'-Methoxy-5'-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)spiro- [cyclobutane-1,3'-indolin]-2'-one
  • Example-XLIX 7'-((2-Methyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-86)
  • Step-i tert-Butyl-6-((1'-(4-methoxybenzyl)-2'-oxo-5'-(1-phenyl-1H-pyrazol-5- yl)spiro [cyclobutane-1,3'-indolin]-7'-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate
  • Step-ii 7'-((2-Azaspiro[3.3]heptan-6-yl)oxy)-1'-(4-methoxybenzyl)-5'-(1-phenyl- 1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one trifluoro acetate
  • the compound was prepared using the process described in step-a of Inter- mediate-23 and proceeded further without purification for the next step.
  • Step-iii 1'-(4-Methoxybenzyl)-7'-((2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5'- (1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iv 7'-((2-Methyl-2-azaspiro[3.3]heptan-6-yl)oxy)-5'-(1-phenyl-1H-pyrazol- 5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-L 7'-((2-Azaspiro[3.3]heptan-6-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5-yl)- s iro c clobutane-13'-indolin -2'-one Com ound-87
  • Example-LI 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-1,2,3-triazol-5- l s iro c clobutane-13'-indolin -2'-one Com ound-88
  • Step-i 1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H- 1,2,3-triazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • 1-phenyl-1H-1,2,3-triazole (0.25 g, 1.72 mmol)
  • 5'-bromo-1'- (4-methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'- one (0.83 g, 1.72 mmol) in DMF (10 mL) was added Cs 2 CO 3 (1.12 g, 3.44 mmol) followed by degassing with nitrogen purging for 15 min.
  • Tri(o-tolyl)phosphine 0.1 g, 0.34 mmol
  • Pd(OAc) 2 0.04 g, 0.17 mmol
  • Step-ii 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-1,2,3-triazol-5-yl)spiro- [cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 7'-Methoxy-5'-(1-(piperidin-4-yl)-1H-pyrazol-5-yl)spiro[cyclobutane- 1,3'-indolin]-2'-one
  • Step-i tert-Butyl4-((1'-(4-methoxybenzyl)-2'-oxo-5'-(1-phenyl-1H-pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-7'-yl)oxy)piperidine-1-carboxylate
  • Step-ii 1'-(4-Methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)-7'-(piperidin-4- yloxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 1'-(4-Methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)-7'-((1-(2,2,2- trifluoroethyl) piperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-LIV 7'-(6-Methyl-2,6-diazaspiro[3.3]heptan-2-yl)-5'-(1-phenyl-1H- razol-5- l s iro c clobutane-13'-indolin -2'-one Com ound-91
  • Step-i 1'-(4-Methoxybenzyl)-7'-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)-5'-(1- phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-ii 7'-(6-Methyl-2,6-diazaspiro[3.3]heptan-2-yl)-5'-(1-phenyl-1H-pyrazol-5- yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-LV 7'-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5- l s iro c clobutane-13'-indolin -2'-one Com ound-94
  • Step-ii 7'-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5-yl)spiro- [cyclobutane-1,3'-indolin]-2'-one
  • Example-LVI 5'-(1-Methyl-2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-4-yl)-7'- ((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-95)
  • Step-ii tert-Butyl(2-(7'-bromo-1'-(4-methoxybenzyl)-2'-oxospiro[cyclobutane- 1,3'-indolin]-5'-yl)-2-oxoethyl)(methyl)carbamate
  • 7'-bromo-5'-(2-bromoacetyl)-1'-(4-methoxybenzyl)- spiro[cyclobutane-1,3'-indolin]-2'-one 1.0 g, 2.02 mmol
  • THF(2M) methylamine in THF(2M) (1.2 mL, 2.42 mmol) followed by stirring for 2 h at 0 oC.
  • Triethyl amine (0.84 mmol, 6.06 mmol) and (Boc) 2 O (1.4 mL, 6.06 mmol) were added followed by stirring at RT for 16 h. TLC was monitored, and the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure.
  • Step-iii 7'-Bromo-1'-(4-methoxybenzyl)-5'-(1-methyl-2-oxo-3-phenyl-2,3- dihydro-1H-imidazol-4-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Triethyl amine (0.36 mL, 2.58 mmol) and phenyl isocyanate (0.17 mL, 1.55 mmol) were added followed by stirring at RT for 16 h. TLC was monitored, and the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by CombiFlash® to afford the title compound as off white solid (0.32 g, 45 %).
  • Step-v 1'-(4-Methoxybenzyl)-5'-(1-methyl-2-oxo-3-phenyl-2,3-dihydro-1H- imidazol-4-yl)-7'-((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-LVII 5'-(3-((2-Hydroxyethyl)(methyl)amino)-1-phenyl-1H-pyrazol-5-yl)-7'- ((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-99) Step-i: 5'-(3,3-Bis(methylthio)acryloyl)-7'-bromo-1'-(4-methoxybenzyl)spiro- [cyclobutane-1,3'-indolin]-2'-one
  • Step-ii 7'-Bromo-5'-(3-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amino)-3- (methylthio)acryloyl)-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-v 5'-(3-((2-Hydroxyethyl)(methyl)amino)-1-phenyl-1H-pyrazol-5-yl)-1'-(4- methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • a stirring solution of 7'-hydroxy-5'-(3-((2-hydroxyethyl)- (methyl)amino)-1-phenyl-1H-pyrazol-5-yl)-1'-(4-methoxybenzyl)spiro[cyclobutane-1,3'- indolin]-2'-one 1.0 g, 1.91 mmol
  • 4-chloro-1-methylpiperidine (1.04 g, 7.63 mmol) in DMSO (10 mL) was added potassium carbonate (0.79 g, 5.73 mmol) followed by heating at 130
  • Example-LVIII 5'-(5-Ethoxy-1-phenyl-1H-pyrazol-3-yl)-7'-((1-methylpiperidin-4-yl)- oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-100)
  • Step-ii 5'-(5-Ethoxy-1-phenyl-1H-pyrazol-3-yl)-7'-((1-methylpiperidin-4-yl)- oxy)spiro [cyclobutane-1,3'-indolin]-2'-one
  • Example-LIX 7'-((1-Imino-1-oxidohexahydro-1 ⁇ 6-thiopyran-4-yl)oxy)-5'-(1-phenyl- 1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-101)
  • Step-ii N-(4-((1'-(4-Methoxybenzyl)-2'-oxo-5'-(1-phenyl-1H-pyrazol-5-yl)spiro- [cyclobutane-1,3'-indolin]-7'-yl)oxy)tetrahydro-2H-1 ⁇ 4-thiopyran-1-ylidene)cyanamide
  • 1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)-7'-((tetra- hydro-2H-thiopyran-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one 0.4 g, 0.72 mmol
  • cyanamide 0.4 g, 0.94 mmol
  • tBuOK 0.1 g, 0.87 mmol
  • NBS (0.19 g, 1.09 mmol
  • Step-iii N-(4-((1'-(4-Methoxybenzyl)-2'-oxo-5'-(1-phenyl-1H-pyrazol-5-yl)spiro [cyclobutane-1,3'-indolin]-7'-yl)oxy)-1-oxidotetrahydro-2H-1 ⁇ 6-thiopyran-1-ylidene)- cyanamide
  • Step-v 7'-((1-Imino-1-oxidohexahydro-1 ⁇ 6-thiopyran-4-yl)oxy)-1'-(4-methoxy- benzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-vi 7'-((1-Imino-1-oxidohexahydro-1 ⁇ 6-thiopyran-4-yl)oxy)-5'-(1-phenyl- 1H-pyrazol-5-yl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Example-LX 5'-(4-(Ethylsulfonyl)-1-phenyl-1H-1,2,3-triazol-5-yl)-7'-((1-methyl- piperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one (Compound-102)
  • Step-ii 7'-Bromo-5'-(4-(ethylthio)-1-phenyl-1H-1,2,3-triazol-5-yl)-1'-(4- methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-iii 7'-Bromo-5'-(4-(ethylsulfonyl)-1-phenyl-1H-1,2,3-triazol-5-yl)-1'-(4- methoxybenzyl)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-v 5'-(4-(Ethylsulfonyl)-1-phenyl-1H-1,2,3-triazol-5-yl)-1'-(4-methoxy- benzyl)-7'-((1-methylpiperidin-4-yl)oxy)spiro[cyclobutane-1,3'-indolin]-2'-one
  • Step-vii 7'-Bromo-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)spiro- [cyclopentane-1,3'-indolin]-2'-one
  • Step-viii 7'-Hydroxy-1'-(4-methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)spiro- [cyclopentane-1,3'-indolin]-2'-one
  • Step-ix 1'-(4-Methoxybenzyl)-7'-((1-methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H- pyrazol-5-yl)spiro[cyclopentane-1,3'-indolin]-2'-one
  • 1-methylpiperidin-4-ol (0.37 g, 3.20 mmol) in THF (10 mL)
  • triphenyl phosphine 0.84 g, 3.20 mmol
  • DIAD 0.5 mL, 2.56 mmol
  • Step-x 7'-((1-Methylpiperidin-4-yl)oxy)-5'-(1-phenyl-1H-pyrazol-5-yl)spiro- [cyclopentane-1,3'-indolin]-2'-one
  • Step-ii 7'-Methoxy-5'-(1-phenyl-1H-pyrazol-5-yl)spiro[cyclopentane-1,3'- indolin]-2'-one
  • Step-i 1'-(4-Methoxybenzyl)-5'-(1-phenyl-1H-pyrazol-5-yl)-7'-(pyridin-2-yloxy)- spiro[cyclopentane-1,3'-indolin]-2'-one
  • Step-ii 5'-(1-Phenyl-1H-pyrazol-5-yl)-7'-(pyridin-2-yloxy)spiro [cyclopentane- 1,3'-indolin]-2'-one
  • Bet BRD4 BD1 inhibition The Bet bromodomain TR-FRET assay has been used to identify compounds that bind to Bet BRD4 BD1 bromodomain and prevent its interaction with acetylated histone peptides (Chung, C. et al., J. Med. Chem., 54, 3827-3838, 2011).
  • optimized concentration of in-house Bet BRD4 BD1bromodomain protein and 300 nM of acetyl histone peptide substrate were diluted in assay buffer (50 mM HEPES, pH: 7.5, 50 mM NaCl, 500 ⁇ M CHAPS) and were added to the positive control and test control wells in a 384 well plate.
  • Substrate control wells have 300 nM of acetyl histone peptide substrate diluted in assay buffer. Buffer blank wells were added with assay buffer. The reaction mixture was allowed for incubation at RT for 30 min. Stock solutions of test compounds at 20 mM DMSO were prepared. Compounds were serially diluted and added to the test wells in 384-well polypropylene plates.
  • reaction mixture was further incubated for 30 min at RT on a plate shaker.2 nM of Europium labeled streptavidin and 10 nM of XL-665 labeled antibody diluted in detection buffer (50 mM HEPES, pH: 7.5, 50 mM NaCl, 500 ⁇ M CHAPS and 800 mM KF) were added to all the wells excluding the buffer blank wells. The reaction plate was incubated for additional 30 min at RT on plate shaker. The plate was read in Perkin Elmer WALLAC 1420 Multilabel Counter Victor 3 (Ex: 340 nm Em: 615 and 665 nm).
  • the amount of displacement of the peptide was measured as ratio of specific 665 nm energy transfer signal to 615 nm signals.
  • the IC 50 of the compounds was determined by fitting the dose response data to sigmoid curve fitting equation using Graph Pad Prism software V5. The compounds were screened in the above mentioned assay and the results (IC 50 ) are summarized in the table below.
  • the IC 50 values of the compounds are set forth in below Table 1 wherein“A” refers to an IC 50 value of less than 600 nM,“B” refers to IC50 value in range of 600.01 to 1000 nM and“C” refers to IC50 value of greater than 1000 nM. Table 1.
  • Selectivity for BD1 inhibition over BD2 inhibition can be determined using the fluorescence resonance energy transfer (TR-FRET) assay protocol described above using both BRD4 BD1 and BRD4 BD2 proteins.
  • TR-FRET fluorescence resonance energy transfer
  • the compounds were screened in the above mentioned assay for determining the selectivity for BRD4 BD1 inhibition over BRD4 BD2 inhibition.
  • the results are summarized in the Table 2 below wherein“A” refers to selectivity higher than 10 fold, “B” refers to selectivity lower than 10 fold.
  • the selectivity ratios were calculated based on IC 50 values for BD1 and BD2 inhibition. The compounds appeared to exhibit substantial selectivity for inhibiting BD1 protein over BD2 protein.

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Abstract

La présente invention concerne de nouveaux dérivés spiro[cycloalkyl-1,3'-indolin]-2'-one de formule (I) dans laquelle Cy1,Cy2,R1,R2, R3,R4, L, m, n et q ont la signification donnée dans la spécification, et des sels pharmaceutiquement acceptables de ceux-ci. Les composés de formule (I) sont utiles en tant qu'inhibiteurs de bromodomaines dans le traitement ou la prévention de maladies ou de troubles dans lesquels l'inhibition de bromodomaines est souhaitée.
PCT/FI2017/050879 2016-12-13 2017-12-12 Nouveaux inhibiteurs de bromodomaines WO2018109271A1 (fr)

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CN110183372A (zh) * 2019-06-20 2019-08-30 山东大学 靛红类化合物及其制备方法和应用
CN115043770A (zh) * 2022-07-21 2022-09-13 南京大学 一种吲哚/氮杂吲哚类化合物的光诱导合成方法

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CN110183372A (zh) * 2019-06-20 2019-08-30 山东大学 靛红类化合物及其制备方法和应用
CN115043770A (zh) * 2022-07-21 2022-09-13 南京大学 一种吲哚/氮杂吲哚类化合物的光诱导合成方法
CN115043770B (zh) * 2022-07-21 2023-09-08 南京大学 一种吲哚/氮杂吲哚类化合物的光诱导合成方法

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