WO2015092118A1 - Spiro[cyclobutane-1,3'-indolin]-2'-one derivatives as bromodomain inhibitors - Google Patents

Spiro[cyclobutane-1,3'-indolin]-2'-one derivatives as bromodomain inhibitors Download PDF

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Publication number
WO2015092118A1
WO2015092118A1 PCT/FI2014/000040 FI2014000040W WO2015092118A1 WO 2015092118 A1 WO2015092118 A1 WO 2015092118A1 FI 2014000040 W FI2014000040 W FI 2014000040W WO 2015092118 A1 WO2015092118 A1 WO 2015092118A1
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Prior art keywords
cyclobutane
indolin
oxospiro
sulfonamide
benzenesulfonamide
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PCT/FI2014/000040
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French (fr)
Inventor
Ravi Kotrabasaiah Ujjinamatada
Subramanya Hosahalli
Susanta Samajdar
Chandrasekhar ABBINENI
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Orion Corporation
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Publication of WO2015092118A1 publication Critical patent/WO2015092118A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel spiro[cyclobutane-l,3'-indolin]-2'-one derivatives of formula (I) which are useful as bromodomain inhibitors and to pharmaceutical compositions thereof.
  • 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.
  • 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 BRD-t) 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.
  • Japanese patent application JP 2008-156311 discloses a benzimidazole derivative which is said to be a BRD2 bromodomain binding agent which has utility with respect to virus infection / proliferation.
  • bromodomain inhibitors Certain spiro[cyclobutane-l,3'-indolin]-2'-one derivatives have been found according to the present invention which inhibit the binding of BET family bromodomains to acetylated lysine residues. Such compounds will hereafter be referred to as "bromodomain inhibitors". Summary of the invention
  • the present invention provides new spiro[cyclobutane-l,3'-indolin]-2'-one derivatives which are able to inhibit the binding of BET family bromodomains to acetylated lysine residues.
  • the present invention provides a compound of formula (I)
  • Cy is selected from 4-12 membered monocyclic or bicyclic ring containing 0-4 hetero atoms independently selected form N, O or S;
  • L is a linker selected from -N(R 3a )S(0) 2 -, -S(0) 2 N(R 3b )-,
  • Ri and each R 2 are, independently, selected from hydrogen, halogen, alkoxy, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted
  • heterocyclyl wherein the optional substituent at each occurrence is independently selected from one or more, preferably one to three, R4 groups;
  • R3a, R3b, R3c, R3d, R3e and R 3 f are selected, independently, from hydrogen or alkyl;
  • R4 is selected from alkyl, alkoxy, halogen, cycloalkyl, aryl or heterocyclyl;
  • 'm' is selected from 1, 2 or 3;
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising spiro[cyclobutane-l,3'-indolin]-2'-one derivative of formula (I) or a pharmaceutically acceptable salt thereof.
  • spiro[cyclobutane-l,3'-indolin]-2'-one derivatives of formula (I) for 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[cyclobutane- l,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):
  • Cy is selected from 4-12 membered monocyclic or bicyclic ring containing 0-4 hetero atoms independently selected form N, O or S;
  • L is a linker selected from -N(R 3a )S(0) 2 -, -S(0) 2 N(R 3b )-,
  • Ri and each R 2 are, independently, selected from hydrogen, halogen, alkoxy, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heterocyclyl; wherein the optional substituent at each occurrence is independently selected from one or more, preferably one to three, R groups;
  • R3a, 3b, R 3c , R3d, 3 ⁇ 43e and R 3 f are selected, independently, from hydrogen or alkyl;
  • R4 is selected from alkyl, alkoxy, halogen, cycloalkyl, aryl or heterocyclyl;
  • 'm' is selected from 1, 2 or 3;
  • the compound of formula (I) is a com ound of formula (IA)
  • the compound of formula (I) is a compound of formula (IB)
  • Rj, R 2 , Cy and 'm' are same as defined in formula (I), or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is a c
  • the compound of formula (I) is a compound of formula (ID)
  • R 1; R 2i R3 ⁇ 4 Cy and 'm' are same as defined in formula (I), or a
  • ⁇ is hydrogen, halogen, Ci -6 alkoxy, hydroxy, Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl Q.6 alkyl, optionally substituted aryl alkyl, or an optionally substituted heteroaryl; wherein the optional substituent is independently selected from an Ci -6 alkyl.
  • R is hydrogen, halogen, Ci -6 alkoxy, hydroxy, Ci -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl Q.6 alkyl, optionally substituted aryl alkyl, or an optionally substituted heteroaryl; wherein the optional substituent is independently selected from an Ci -6 alkyl.
  • halogen such as CI or Br
  • C 1-6 alkyl such as methyl, ethyl or n-propyl
  • C 3-7 cycloalkyl such as cyclopropyl
  • aryl C is hydrogen, halogen (such as CI or Br), C 1-6 alkyl (such as methyl, ethyl or n-propyl), C 3-7 cycloalkyl (such as cyclopropyl), aryl C].
  • 6 alkyl such as benzyl
  • heteroaryl such as pyrazolyl, imidazolyl or pyrimidinyl
  • R 2 is hydrogen, halogen (such as F or CI), C 1-6 alkyl (such as methyl), Ci -6 alkoxy (such as methoxy or isopropoxy) or heteroaryl (such as pyrozole or imidazole); and m is 1 or 2.
  • compounds of formula (I) are compounds of formula (I), wherein R ⁇ is hydrogen, halogen, alkyl, cycloalkyl or benzyl, L is -NHS(0) 2 -, ring Cy is group (1), (2), (5), (6), (7), (8), (9), (12), (13) or (16), R 2 is hydrogen, halogen, alkyl or alkoxy, m is 1 or 2.
  • the compound of formula (I) is selected from the group consisting of: Compound Name
  • formulas (I), (IA), (IB) (IC) and (ID) encompass all stereoisomers, enantiomers and diastereomers that may be contemplated from the chemical structure of the compounds according to above formulas.
  • a pharmaceutical composition comprising a compound of formula (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.
  • Alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a Ci-6 alkyl group have from 1 to 6 (inclusive) carbon atoms in it.
  • Preferred alkyl group is Cr 6 alkyl.
  • Examples of Ci- 6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • An alkyl group can be unsubstituted or substituted with one or more suitable groups.
  • Halo or “halogen” refers to F, CI, Br and I.
  • Alkoxy refers to the group alkyl-O- or -O-alkyl, where alkyl group is as defined above.
  • Preferred alkoxy group is Ci- 6 alkoxy.
  • Ci- 6 alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, isopropoxy, n-butoxy and t-butoxy.
  • An alkoxy group can be unsubstituted or substituted with one or more suitable groups.
  • Haloalkoxy refers to alkoxy group, as defined above, wherein one or more of the alkoxy group's hydrogen atom has been replaced with a halogen atom as defined above.
  • Preferred haloalkoxy group is halo Cj-6 alkoxy. Examples of haloalkoxy group include chloromethoxy and trifluoromethoxy.
  • 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.
  • Aryl group can be unsubstituted or substituted with one or more suitable groups.
  • Arylalkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with an aryl group as defined above.
  • Preferred arylalkyl group is aryl Q-6 alkyl, particularly phenyl Ci.6 alkyl.
  • Examples of arylalkyl groups include, but are not limited to benzyl, benzhydryl, 1- phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1 -naphthylmethyl, 2- naphthylmethyl.
  • An arylalkyl group can be unsubstituted or substituted with one or more suitable groups.
  • Cycloalkyl refers to a C 3 . 10 non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system having 3 to 10 carbon atoms.
  • Preferred cycloalkyl group is C 3 . 7 cycloalkyl.
  • Representative examples of a C 3- io cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl and dodecahydros-indacen-4-yl.
  • a cycloalkyl can be unsubstituted or substituted with one or more suitable groups.
  • Cycloalkylalkyl refers to alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with a cycloalkyl group as defined above.
  • Preferred cycloalkylalkyl group is C 3-7 cycloalkyl Ci. 6 alkyl.
  • 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 or heterogroup selected from the group consisting of O, N, S, S(O), S(0) 2 , NH and C(O).
  • 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, 1,4- dioxanyl and the like.
  • a heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups.
  • Heteroaryl refers to a saturated, monocyclic, bicyclic, or polycyclic aromatic ring system 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 saturated, 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, 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-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline.
  • 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.
  • a heteroaryl group can be unsubstituted or substituted with one or more suitable groups.
  • 4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms 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 CO, N, NH, O, S, SO or S0 2 groups.
  • rings include, but are not limited to phenyl, pyridine, pyrimidine, morpholine, piperidine, piperazine, imidazole, pyrazole, pyrrole, thiophene, cyclopropyl, 2,3- dihydrobenzo[b][l,4]dioxine, 1,2,3,4-tetrahydroisoquinoline, quinoline, indazole, [l,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.
  • One particular embodiment of "optionally substituted or substituted” is 1-3 substituents selected from the group consisting of Ci- 6 alkyl, C3-6 cycloalkyl, halogen, nitro, cyano, amino, hydroxy, halo Ci- 6 alkyl, hydroxy Ci- 6 alkyl, Ci- 6 alkoxy and halo Q-6 alkoxy substituents.
  • the terms “treat”, “treating” or “treatment” encompass either or both responsive and prophylaxis measures, e.g. measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms.
  • 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-toluenesulf
  • 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.
  • 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.
  • N-benzoylproline for example N-benzoylproline or N-benzenesulfony
  • 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,
  • 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
  • Atherosclerosis Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes and acute rejection of transplanted organs.
  • 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
  • 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, endotoxaemia, 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.
  • diseases or conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic inflammatory response syndrome (SIRS),
  • 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, cardiopulmonary 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,
  • 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 carcinomas, mesenchymal, hepatic, renal and neurological tumours.
  • 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 carcinomas, mesenchymal, hepatic, renal and neurological tumours.
  • 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.
  • diseases associated with systemic inflammatory response syndrome such as sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia.
  • the bromodomain inhibitor would be
  • 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.
  • the disease or condition for which a 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.
  • 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 the raw chemical, 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 compound of the present invention is used simultaneously with one or more other drugs, a
  • 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
  • novel spiro[cyclobutane-l,3'-indolin]-2'-one derivatives of formula (I) may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. The details of the processes according to the present invention are given in the example section mentioned below.
  • 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 2 H ("D"), 3 H, l l C, , C, ,4 C, , 3 N, , 5 N, , 5 0, 17 0, , 8 0, 32 P, 33 P, 35 S, ,8 F, 36 C1, ,23 I and l25 I.
  • isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine such as 2 H (“D"), 3 H, l l C, , C, ,4 C, , 3 N, , 5 N, , 5 0, 17 0, , 8 0, 32 P, 33 P, 35 S, ,8 F, 36 C1, ,23 I and l25 I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • EDC HCl-l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride; CaO- Calciumoxide; CS 2 -carbondisulfide; HOBt-l-Hydroxybenzotriazole; TLC-Thin layer chromatography; K 0 3 -Potassium nitrate; H 2 S0 4 -Sulfuric acid; KOAC- Potassium acetate; NBS-N-Bromosuccinimide; NCS-N-Chlorosuccinimide;
  • the microwave chemistry was performed on a CEM Explorer.
  • Cyclobutanecarbonyl chloride (21.92 g, 184 mmol) was added dropwise at RT to phenyl hydrazine (20 g, 184 mmol) and pyridine (20 mL, 257 mmol) in 30 mL DMF. The mixture was stirred for 1 h at RT and poured into 200 mL of aq.1M HC1 solution. The precipitated solid was filtered, washed with 50 mL water and dried. The solid was washed with 20 mL of diethyl ether and dried under reduced pressure (32 g, 91%).
  • Step-b Spiro Icvclobutane- 1.3' -indolinl -2'-one: To a stirred suspension of calcium oxide (38 g, 680 mmol) in quinoline (200 mL) was added N-phenylcyclobutanecarbohydrazide (13 g, 68 mmol). The mixture was heated to 270-310°C for 60 min. The reaction mixture was cooled to RT and aq. 2M HC1 was added. The aq. layer was extracted twice with EtOAc. The combined extracts were washed with 2M hydrochloric acid, brine, dried over Na 2 S0 4 , filtered and concentrated.
  • Step-b tert-butyl 5-nitro-2-oxoindoline-l-carboxylate:
  • Step-c 1 ⁇ 2rf-butyl 5'-nitro-2'-oxospiro [cyclobutane-l. 3'-indolinel-l'- carboxylate:
  • N-Bromosuccinimide (0.122 g, 0.68 mmol) was added drop wise at RT to Intermediate- lc (0.1 g, 0.45 mmol) in concentrated H 2 S0 4 (1 mL). The mixture was stirred for 2 h at RT and poured into 200 mL of water. The precipitated solid was suction filtered, washed with 50 mL water and dried. The solid was washed with 20 mL ether and dried under reduced pressure to afford the titled compound as an off- white solid (0.108 g, 80%).
  • Step-b 5'-amino-7'-bromospirorcvclobutane-l .3'-indolinl-2'-one:
  • Step-a 7'-cyclopropyl-5'-nitrospirof cyclobutane- 1 ,3'-indolin1-2'-one:
  • Step-b 5'-amino-7'-cyclopropylspirofcvclobutane-1.3'-indolin1-2'-one:
  • Step-a 5'-nitro-7'-vinylspirorcvclobutane- 1.3'-indolin1-2'-one: To a stirred solution of intermediated (0.3 g, 1.01 mmol) in 1,4-dioxane (12 mL) and H 2 0 (3 mL), were added 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (0.31 g, 2.02 mmol), potassium carbonate (0.42 g, 3.04 mmol) and degassed with nitrogen purging for 20 min.
  • Step-b 5'-amino-7'-ethylspirorcvclobutane- 1.3'-indolinl-2'-one:
  • Step-a 5'-nitro-7'-( lH-pyrazol- 1 -vDspiroicvclobutane- 1.3'-indolin1-2'-one: To a stirred solution of intermediated (0.200 g, 0.673 mmol) in DMSO was added IH-imidazole (0.059 g, 0.875 mmol), copper oxide (0.026 g, 0.336 mmol) and cesium carbonate (0.662 g, 2.019 mmol). Then the reaction mixture degassed with nitrogen gas for 10-15 min and heated to 100-110°C for 12 h under nitrogen atmosphere or in a sealed tube.
  • IH-imidazole 0.059 g, 0.875 mmol
  • copper oxide 0.026 g, 0.336 mmol
  • cesium carbonate 0.662 g, 2.019 mmol
  • Step-b 5'-amino-7'-( lH-pyrazol- l-yl)spirofcvclobutane- 1.3'-indolin1-2'-one: The process of this step was adopted from step-b of Intermediate-4 (0.060 g, 96%); LC-MS: 255.2 [M+H] + .
  • Example-I 2,5-dimethyl-N-(2'-oxospirofcvclobutane- 1 ,3 '-indolinl-S'-vDthiophene- 3-sulfonamide (Compound- 1)
  • Step-i N-r7'-bromo-2'-oxospiro[cvclobutane-l,3'-indolinl-5'-yl)-2,4-difluoro- benzenesulfonamide :
  • Step-ii 2.4-difluoro-N-(2'-oxo-7'-( lH-pyrazol-4-yl)spirofcyclobutane- 1 ,3'- indolinl-S'-vDbenzenesulfonamide:
  • Example-I The process of this step was adopted from Example-I.
  • the desired compound obtained as a white solid (0.12 g, 37.5 %).
  • Step-(ii) Synthesis of 2-methoxy-N-(7'-(l-methylpiperidin-4-yl)-2'- oxospiroicyclobutane- 1.3'-indolin1-5'-yl)benzenesulfonamide:
  • Example-rV Synthesis of N-(7'-bromo-2'-oxospiroicvclobutane-l,3'-indolin1-5'-yl)- 2-(2-methoxyphenyl)propanamide (Compound-83)
  • Example- VIII 4-fluoro-N-(2'-oxo-7'-(piperidin-4-yl)spirorcvclobutane-1.3'- indolinl-5'-yl)benzenesulfonamide (Compound-90)
  • Example- VII The desired compound was obtained as a white solid (0.036 g, 44 %).
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • Bet bromodomain TR-FRET assay has been used to identify compounds that bind to bet bromodomain and prevent its interaction with acetylated histone peptides.
  • the reaction mixture was further incubated for 30 min at RT on a plate shaker.
  • 2 nM of Europium labeled streptavidin and ⁇ of XL-665 labeled antibody diluted in detection buffer 50 mM HEPES, pH: 7.5, 50 mM NaCl, 500 ⁇ CHAPS and 800 mM KF
  • detection buffer 50 mM HEPES, pH: 7.5, 50 mM NaCl, 500 ⁇ CHAPS and 800 mM KF
  • 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 IC50 of the compounds was determined by fitting the dose response data to sigmoid curve fitting equation using Graph Pad Prism software V
  • the compounds were screened in the above mentioned assay and the results (IC 50 ) are summarized in the table below.
  • the IC50 values of the compounds are set forth in below Table wherein "A” refers to an IC 50 value of less than 150 nM, “B” refers to IC5 0 value in range of 150.01 to 250 nM and “C” refers to IC50 value of greater than 250 nM.

Abstract

The present invention provides novel spiro[cyclobutane-1,3'-indolin]-2'- derivatives of formula (I) in which Cy, R1, R2, L and 'm' are have the meaning given in the specification, and pharmaceutically acceptable salts thereof. The compounds of formula (I) are useful as bromodomain inhibitors in the treatment or prevention of diseases or disorders where bromodomain inhibition is desired.

Description

SPIROICYCLOBUTANE- '-INDOLIN^'-ONE DERIVATIVES AS BROMODOMAIN INHIBITORS
Technical field
The present invention relates to novel spiro[cyclobutane-l,3'-indolin]-2'-one derivatives of formula (I) which are useful as bromodomain inhibitors and to pharmaceutical compositions thereof.
Figure imgf000002_0001
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 BRD-t) 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. Cell., 2008, 30(1):51 -60), while 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). It has also been reported that 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). Data suggests that BRD- NUT fusion proteins contribute to carcinogenesis (Oncogene, 2008, 27, 2237-2242). BRD-t is uniquely expressed in the testes and ovary. All family members have been reported to have some function in controlling or executing aspects of the cell cycle, and have been shown to remain in complex with chromosomes during cell division suggesting a role in the maintenance of epigenetic memory. In addition some viruses make use of these proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication (You et al., Cell, 2004 1 17(3):349-60).
Japanese patent application JP 2008-156311 discloses a benzimidazole derivative which is said to be a BRD2 bromodomain binding agent which has utility with respect to virus infection / proliferation.
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.
However, there remains a need for potent bromodomain inhibitors with desirable pharmaceutical properties. Certain spiro[cyclobutane-l,3'-indolin]-2'-one derivatives have been found according to the present invention which inhibit the binding of BET family bromodomains to acetylated lysine residues. Such compounds will hereafter be referred to as "bromodomain inhibitors". Summary of the invention
The present invention provides new spiro[cyclobutane-l,3'-indolin]-2'-one derivatives which are able to inhibit the binding of BET family bromodomains to acetylated lysine residues. The present invention provides a compound of formula (I)
Figure imgf000004_0001
wherein
Cy is selected from 4-12 membered monocyclic or bicyclic ring containing 0-4 hetero atoms independently selected form N, O or S;
L is a linker selected from -N(R3a)S(0)2-, -S(0)2N(R3b)-,
-N(R3c)C(0)CH(R3d)- or -C(R3e)(OR3f)-;
Ri and each R2 are, independently, selected from hydrogen, halogen, alkoxy, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted
heterocyclyl; wherein the optional substituent at each occurrence is independently selected from one or more, preferably one to three, R4 groups;
R3a, R3b, R3c, R3d, R3e and R3f are selected, independently, from hydrogen or alkyl;
R4 is selected from alkyl, alkoxy, halogen, cycloalkyl, aryl or heterocyclyl;
'm' is selected from 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
In a further aspect, the present invention provides a pharmaceutical composition comprising spiro[cyclobutane-l,3'-indolin]-2'-one derivative of formula (I) or a pharmaceutically acceptable salt thereof.
In yet further aspect of the present invention, it provides the use of spiro[cyclobutane-l,3'-indolin]-2'-one derivatives of formula (I) for 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.
Detailed description of the invention
An embodiment of the present application provides novel spiro[cyclobutane- l,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):
Figure imgf000005_0001
wherein
Cy is selected from 4-12 membered monocyclic or bicyclic ring containing 0-4 hetero atoms independently selected form N, O or S;
L is a linker selected from -N(R3a)S(0)2-, -S(0)2N(R3b)-,
-N(R3c)C(0)CH(R3d)- or -C(R3e)(OR3f)-;
Ri and each R2 are, independently, selected from hydrogen, halogen, alkoxy, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heterocyclyl; wherein the optional substituent at each occurrence is independently selected from one or more, preferably one to three, R groups;
R3a, 3b, R3c, R3d, ¾3e and R3f are selected, independently, from hydrogen or alkyl;
R4 is selected from alkyl, alkoxy, halogen, cycloalkyl, aryl or heterocyclyl;
'm' is selected from 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. According to yet another embodiment of the present invention, the compound of formula (I) is a com ound of formula (IA)
wherein Ri, R2i Cy and 'm' are same as defined in formula (I), or a pharmaceutically acceptable salt thereof.
According to yet another embodiment of the present invention, the compound of formula (I) is a compound of formula (IB)
Figure imgf000006_0002
wherein, Rj, R2, Cy and 'm' are same as defined in formula (I), or a pharmaceutically acceptable salt thereof.
According to yet another embodiment of the present invention, the compound of formula (I) is a c
Figure imgf000006_0003
wherein Ri, R2, R3(j, Cy and 'm' are same as defined in formula (I), or a
pharmaceutically acceptable salt thereof.
According to yet another embodiment of the present invention, the compound of formula (I) is a compound of formula (ID)
Figure imgf000007_0001
wherein R1; R2i R¾ Cy and 'm' are same as defined in formula (I), or a
pharmaceutically acceptable salt thereof.
According to one embodiment, specifically provided are compounds of formula (I), (IA), (IB), (IC) or (ID) wherein Ri is hydrogen, halogen, Ci-6 alkoxy, hydroxy, Ci-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl Q.6 alkyl, optionally substituted aryl alkyl, or an optionally substituted heteroaryl; wherein the optional substituent is independently selected from an Ci-6 alkyl. In one subclass of the above embodiment are compounds wherein R! is hydrogen, halogen (such as CI or Br), C1-6 alkyl (such as methyl, ethyl or n-propyl), C3-7 cycloalkyl (such as cyclopropyl), aryl C].6 alkyl (such as benzyl) or heteroaryl (such as pyrazolyl, imidazolyl or pyrimidinyl) optionally substituted by methyl.
According to yet another embodiment, specifically provided are compounds of formula (I), (IA), (IB), (IC), (ID) or of any other embodiment or subclass referred above, wherein L is a linker selected from -NHS(0)2-, -S(0)2NH-,
-NHC(0)CH(CH3)- or -CH(OH)-.
According to yet another embodiment, specifically provided are compounds of formula (I), (IA), (IB), (IC), (ID) or of any other embodiment or subclass referred to above, wherein Cy is a 5-6 membered monocyclic ring containing 0-3 hetero atoms independently selected from the group consisting of N, O and S.
According to yet another embodiment, specifically provided are compounds of formula (I), (IA), (IB), (IC), (ID) or of any other embodiment or subclass referred to above, wherein Cy is 9-10 membered bicyclic ring containing 1-3 hetero atoms independently selected from the group consisting of N and O. According to yet another embodiment, specifically provided are compounds of formula (I), (IA), (ΓΒ), (IC), (ID) or of any other embodiment or subclass referred to above, wherein R2 is selected from hydrogen, halogen, Ci-6 alkyl, Ci-6alkoxy, halo Cj.6 alkoxy or heteroaryl; and m is 1, 2 or 3. In one subclass of the above embodiment are compounds wherein R2 is hydrogen, halogen (such as F or CI), C1-6 alkyl (such as methyl), Ci-6 alkoxy (such as methoxy or isopropoxy) or heteroaryl (such as pyrozole or imidazole); and m is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (Γ), (IA), (IB), (IC), (ID) or of any other embodiment or subclass referred to above, wherein ring Cy is one of the following groups or tautomers thereof
Figure imgf000008_0001
wherein each of the above rings are substituted by (R2)m as defined above. According to yet another embodiment, specifically provided are compounds of formula (I), (IA), (IB), (IC), (ID) or of any other embodiment or subclass referred to above, in which Cy-(R2)m is one of the following groups or tautomers thereof
Figure imgf000009_0001
(31·)
According to one embodiment are compounds of formula (I) are compounds of formula (I), wherein R\ is hydrogen, halogen, alkyl, cycloalkyl or benzyl, L is -NHS(0)2-, ring Cy is group (1), (2), (5), (6), (7), (8), (9), (12), (13) or (16), R2 is hydrogen, halogen, alkyl or alkoxy, m is 1 or 2.
In yet another particular embodiment of the present invention, the compound of formula (I) is selected from the group consisting of: Compound Name
2,5-dimethyl-N-(2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)thiophene-3- sulfonamide
N-(2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2,3-dihydrobenzo[b][l,4]- dioxine-6-sulfonamide
2-methoxy-N-(2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'- yl)benzenesulfonamide
N-(2'-oxospiro [cyclobutane- 1 ,3'-indolin]-5'-yl)quinoline-8-sulfonamide
N-(2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)- 1 ,2,3,4- tetrahydroisoqu'inoline-7 -sulfonamide
N-(2'-oxospiro [cyclobutane- 1 ,3 '-indolin] -5 -yl)- [ 1 ,2,4] triazolo [4,3- a]pyridine-6-sulfonamide
N-(2-methoxyphenyl)-2'-oxospiro[cyclobutane-l,3'-indoline]-5'- sulfonamide
N-(7'-bromo-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-2- methoxybenzenesulfonamide
N-(7'-bromo-2,-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-6-chloropyridine- 3-sulfonamide
N-(7'-bromo-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2,3-dihydro- benzo[b] [ 1 ,4]dioxine-6-sulfonamide
N-(7'-bromo-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yI)-3-( 1 H-pyrazol- 1- yl)benzenesulfonamide
N-(2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-3-( lH-pyrazoI- 1 - yl)benzenesulfonamide
N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2- methoxybenzenesulfonamide
N-(7'-chloro-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-3-( 1 H-pyrazol- 1 - yl)benzenesulfonamide
N-(7'-chloro-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)piperidine- 1- sulfonamide
N-(7'-chloro-2'-oxospiro [cyclobutane- 1 ,3 '-indolin]-5'-yl)- 1 -methyl- 1 H- pyrazole-4-sulfonamide
N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2,5- difluorobenzenesulfonamide
N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-4-fluorobenzene- sulfonamide
N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-6-methylpyridine- 3-sulfonamide
N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-6-fluoropyridine- 3 -sulfonamide
N-(7'-chloro-2,-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)cyclohexane- sulfonamide
N-(7 '-chloro-2'-oxospiro [cyclobutane- 1 ,3 -indolin] -5 -yl)-3 ,5 -difluoro-2- methoxybenzenesulfonamide
N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-3-fluoro-2- methoxybenzenesulfonamide
N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-isopropoxy- benzenesulfonamide
N-(7'-chloro-2'-oxospiro[cyclobutane- 1 ,3'-indolin] -5'-yl)- 1 -methyl- 1H- indazole-4-sulfonamide
N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2,4- difluorobenzenesulfonamide
6-methyl-N-(2'-oxo-7'-propylspiro[cyclobutane-l,3'-indolin]-5'-yl)pyridine- 3-sulfonamide
N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-4-fluoro- benzenesulfonamide
6-fluoro-N-(2'-oxo-7'-propylspiro[cyclobutane-l,3'-indolin]-5'-yl)pyridine- 3-sulfonamide
6-chloro-N-(2'-oxo-7'-propylspiro[cyclobutane-l,3'-indolin]-5'-yl)pyridine- 3-sulfonamide
l-methyl-N-(2'-oxo-7'-propylspiro[cyclobutane-l,3'-indolin]-5'-yl)-lH- pyrazole-4-sulfonamide
N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-iso- propoxybenzenesulfonamide
N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-3-(lH- pyrazol- 1 -yl)benzenesulfonamide
N-(7'-cyclopropyl-2'-oxospiro [cyclobutane- 1 , 3 -indolin] -5 '-yl)-2- methoxybenzenesulfonamide
N-(2'-oxo-7'-propylspiro[cyclobutane-l,3'-indolin]-5'-yl)pyridine-3- sulfonamide
2,4-difluoro-N-(7'-(l -methyl- lH-pyrazol-4-yl)-2'-oxospiro[cyclobutane- 1 ,3 '-indolin] -5 '-yl)benzenesulfonamide
2,4-difluoro-N-(2'-oxo-7'-(pyrimidin-5-yl)spiro[cyclobutane-l,3'-indolin]- 5'-yl)benzenesulfonamide
2,4-difluoro-N-(2'-oxo-7'-(pyridin-3-yl)spiro[cyclobutane-l,3'-indolin]-5'- yl)benzenesulfonamide
N-(7'-(l-methyl-lH-pyrazol-4-yl)-2'-oxospiro[cyclobutane-l,3'-indolin]-5'- yl)cyclohexanesulfonamide
4-fluoro-N-(7'-(l-methyl-lH-pyrazol-4-yl)-2'-oxospiro[cyclobutane-l,3'- indolin]-5'-yl)benzenesulfonamide
N-(7'-(l-methyl-lH-pyrazol-4-yl)-2,-oxospiro[cyclobutane-l(3'-indolin]-5'- yl)-3-( 1 H-pyrazol- 1 -yl)benzenesulfonamide
2-isopropoxy-N-(7'-( 1 -methyl- 1 H-pyrazol-4-yl)-2'-oxospiro[cyclobutane- l,3'-indolin]-5'-yl)benzenesulfonamide
N-(7'-( 1-methyl- lH-pyrazol-4-yl)-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'- yl)mo holine-4-sulfonamide
N-(2'-oxo-7'-(pyrimidin-5-yl)spiro[cyclobutane-l,3'-indolin]-5'- yl)piperidine- 1 -sulfonamide
N-(7'-( 1-methyl- 1 H-pyrazol-4-yl)-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'- yl)piperidine- 1 -sulfonamide
N-(7'-benzyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-isopropoxy- benzenesulfonamide
N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-3-(lH- imidazol- 1 -yl)benzenesulf onamide
N-(7'-cyclopropyl-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)piperidine- 1 - sulfonamide
N-(7'-(lH-imidazol-l-yl)-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-4- fluorobenzenesulfonamide
4-fluoro-N-(2'-oxo-7'-( IH-pyrazol- l-yl)spiro [cyclobutane- 1 ,3'-indolin]-5'- yl)benzenesulfonamide
N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-l-methyl- 1 H-indazole-4-sulf onamide
N-(2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)cyclohexanesulfonamide
N-(2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)piperidine- 1 -sulfonamide
2-methoxy-N-(7'-methyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)- benzenesulfonamide
N-(7 '-cyclopropyl-2'-oxospiro [cyclobutane- 1 ,3 -indolin] -5 '-yl)morpholine- 4-sulfonamide
6-chloro-N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)- pyridine-3-sulfonamide
N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)pyridine-2- sulfonamide
N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-5-fluoro- pyridine-2-sulfonamide
N-(7 '-chloro-2'-oxospiro [cyclobutane- 1 ,3 -indolin] -5 '-yl)morpholine-4- sulfonamide
N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-4-methyl- piperazine- 1 -sulfonamide
N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-l-isopropyl- 1 H-pyrazole-4-sulfonamide
N-(7'-ethyl-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-2- (trifluoromethoxy)benzenesulfonamide
N-(7'-ethyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-methoxybenzene- sulfonamide
N-(7'-ethyl-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-2,4- difluorobenzenesulfonamide
N-(7'-isopropyl-2'-oxospiro [cyclobutane- 1 ,3 -indolin] -5 '-yl)-2-methoxy- benzenesulfonamide
4-fluoro-N-(7'-isopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5,-yl)- benzenesulfonamide
2,4-difluoro-N-(7'-isopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)- benzenesulfonamide
N-(7'-isopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)cyclohexane- sulfonamide
2,4-difluoro-N-(7'-methyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5,-yl)- benzenesulfonamide
N-(7'-methyl-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)piperidine- 1 - sulfonamide
N-(7'-cyclohexyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-methoxy- benzenesulfonamide
2,4-difluoro-N-(2'-oxo-7'-( 1 H-pyrazol-4-yl)spiro[cyclobutane- 1 ,3'-indolin]- 5 '-yl)benzenesulf onamide
N-(7'-benzyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2,4-difluoro- benzenesulfonamide
2,4-difluoro-N-(7'-(4-methylbenzyl)-2'-oxospiro[cyclobutane-l,3'-indolin]- 5'-yl)benzenesulfonamide
2,4-difluoro-N-(7'-(4-methoxybenzyl)-2'-oxospiro[cyclobutane-l,3'- indolin]-5'-yl)benzenesulfonamide
N-(7 '-benzyl-2'-oxospiro [cyclobutane- 1 , 3 '-indolin] -5 '-yl)-4-fluorobenzene- sulfonamide
N-(7'-benzyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-fluorobenzene- sulfonamide
2,4-difluoro-N-(7'-(4-fluorobenzyl)-2,-oxospiro[cyclobutane-l,3'-indolin]- 5 '-yl)benzenesulfonamide
N-(7'-(4-chlorobenzyl)-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2,4- difluorobenzenesulfonamide
2,4-difluoro-N-(2,-o o-7'-pheneth lspiΓo[cyclobutane-l)3,-indolin]-5,- yl)benzenesulfonamide
N-(7'-benzyl-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-2- methoxybenzenesulfonamide
2-methoxy-N-(7'-( 1 -methylpiperidin-4-yl)-2'-oxospiro[cyclobutane- 1,3'- indolin] -5 '-yl)benzenesulfonamide
N-(7'-bromo-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-(2-methoxy- phenyl)propanamide
N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-(2-methoxy- phenyl)propanamide
2-(4-chlorophenyl)-N-(2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)- propanamide
N-(7'-hydroxy-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-methoxy- benzenesulfonamide
2,4-difluoro-N-(7'-hydroxy-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)- benzenesulfonamide
2,4-difluoro-N-(7'-methoxy-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-N- methylbenzenesulfonamide
6-chloro-N-(2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)pyridine-3- sulfonamide
4-fluoro-N-(2'-oxo-7'-(piperidin-4-yl)spiro[cyclobutane-l,3'-indolin]-5'- yl)benzenesulfonamide
2-methoxy-N-(2'-oxo-7'-(piperidin-4-yl)spiro[cyclobutane-l,3'-indolin]-5'- yl)benzenesulfonamide
N-(2'-oxo-7'-(piperidin-4-yl)spiro[cyclobutane-l,3'-indolin]-5'-yl)-2- (trifluoromethoxy)benzenesulfonamide
N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-methoxy- N-methylbenzenesulfonamide
N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-4-fluoro-N- methylbenzenesulfonamide
5'-((4-chlorophenyl)(hydroxy)methyl)spiro[cyclobutane-l,3'-indolin]-2'-one or pharmaceutically acceptable salts thereof. It should be understood that formulas (I), (IA), (IB) (IC) and (ID) encompass all stereoisomers, enantiomers and diastereomers that may be contemplated from the chemical structure of the compounds according to above formulas. In yet another embodiment according to the present patent application, it provides a pharmaceutical composition comprising a compound of formula (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). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
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 herein, the following definitions are supplied in order to facilitate the understanding of the present invention.
"Alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a Ci-6 alkyl group have from 1 to 6 (inclusive) carbon atoms in it. Preferred alkyl group is Cr6 alkyl. Examples of Ci-6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. An alkyl group can be unsubstituted or substituted with one or more suitable groups. "Halo" or "halogen" refers to F, CI, Br and I.
"Alkoxy" refers to the group alkyl-O- or -O-alkyl, where alkyl group is as defined above. Preferred alkoxy group is Ci-6 alkoxy. Examples of Ci-6 alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, isopropoxy, n-butoxy and t-butoxy. An alkoxy group can be unsubstituted or substituted with one or more suitable groups. "Haloalkoxy" refers to alkoxy group, as defined above, wherein one or more of the alkoxy group's hydrogen atom has been replaced with a halogen atom as defined above. Preferred haloalkoxy group is halo Cj-6 alkoxy. Examples of haloalkoxy group include chloromethoxy and trifluoromethoxy.
"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 group can be unsubstituted or substituted with one or more suitable groups.
"Arylalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with an aryl group as defined above. Preferred arylalkyl group is aryl Q-6 alkyl, particularly phenyl Ci.6 alkyl. Examples of arylalkyl groups include, but are not limited to benzyl, benzhydryl, 1- phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1 -naphthylmethyl, 2- naphthylmethyl. An arylalkyl group can be unsubstituted or substituted with one or more suitable groups. "Cycloalkyl" refers to a C3.10 non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system having 3 to 10 carbon atoms. Preferred cycloalkyl group is C3.7 cycloalkyl. Representative examples of a C3-io cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl and dodecahydros-indacen-4-yl. A cycloalkyl can be unsubstituted or substituted with one or more suitable groups.
"Cycloalkylalkyl" refers to alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with a cycloalkyl group as defined above. Preferred cycloalkylalkyl group is C3-7 cycloalkyl Ci.6 alkyl.
The term "heterocyclyl" includes the definitions of "heterocycloalkyl" and "heteroaryl". The term "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 or heterogroup selected from the group consisting of O, N, S, S(O), S(0)2, NH and C(O). 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. Examples of heterocycloalkyl groups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolanyl, 1,4- dioxanyl and the like. A heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups.
"Heteroaryl" refers to a saturated, monocyclic, bicyclic, or polycyclic aromatic ring system 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 saturated, 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, 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-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Examples of 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. A heteroaryl group can be unsubstituted or substituted with one or more suitable groups. Term "4-12 membered monocyclic or bicyclic ring containing 0-4 heteroatoms" 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 CO, N, NH, O, S, SO or S02 groups. Representative examples of such rings include, but are not limited to phenyl, pyridine, pyrimidine, morpholine, piperidine, piperazine, imidazole, pyrazole, pyrrole, thiophene, cyclopropyl, 2,3- dihydrobenzo[b][l,4]dioxine, 1,2,3,4-tetrahydroisoquinoline, quinoline, indazole, [l,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.
"Optionally substituted or substituted" as used herein means that at least one hydrogen atom of the optionally substituted group has been substituted with suitable groups as exemplified but not limited to halogen, nitro, cyano, hydroxy, oxo (=0), thio (=S), -N(Ci-3 alkyl)C(0)(Ci-6 alkyl), -NHC(0)(Cj-6 alkyl),
-NHC(0)(cycloalkyl), -NHC(0)(aryl), -NHC(0)(heterocyclyl), -NHC(0)(heteroaryl), -NHC(0)H, -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)NH(cycloalkyl),
-C(0)NH(heterocyclyl), -C(0)NH(heteroaryl), -C(0)N(d-6 alkyl)(Ci-6 alkyl), -S(0)NH(C,-6 alkyl), -S(0)2NH(Cr6 alkyl), -S(0)NH(cycloalkyl),
-S(0)2NH(cycloalkyl), carboxy, -C(0)0(d-6 alkyl), -C(0)(Ci-6 alkyl), =N-OH, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenylalkyl, cycloalkenyl, amino, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclic ring. One particular embodiment of "optionally substituted or substituted" is 1-3 substituents selected from the group consisting of Ci-6 alkyl, C3-6 cycloalkyl, halogen, nitro, cyano, amino, hydroxy, halo Ci-6 alkyl, hydroxy Ci-6 alkyl, Ci-6 alkoxy and halo Q-6 alkoxy substituents. As used herein, the terms "treat", "treating" or "treatment" encompass either or both responsive and prophylaxis measures, e.g. measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms. The terms "treat," "treating" or "treatment", include, but are not limited to, prophylactic and/or therapeutic treatments.
As used herein 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. In some embodiments, the subject is a subject in need of treatment or a subject with a disease or disorder. However, in other embodiments, 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.
As used herein 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-toluenesulfonic acid, camphor sulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxyl naphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. The term "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. When 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. In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are 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. Also advantageous is
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). 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 acute rejection of transplanted organs.
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.
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, endotoxaemia, 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.
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, cardiopulmonary 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 carcinomas, mesenchymal, hepatic, renal and neurological tumours.
In one embodiment 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. In this embodiment 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.
In another embodiment 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).
In a particular embodiment the disease or condition for which a bromodomain inhibitor is indicated is sepsis, sepsis syndrome, septic shock and endotoxaemia. In another embodiment, the bromodomain inhibitor is indicated for the treatment of acute or chronic pancreatitis. In another embodiment the bromodomain is indicated for the treatment of burns. In one embodiment the disease or condition for which a 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. In one particular embodiment 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.
While it is possible that for use in therapy, a compound of formula (I) as well as pharmaceutically acceptable salts thereof may be administered as the raw chemical, 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. When a compound of the present invention is used simultaneously with one or more other drugs, a
pharmaceutical composition containing such other drugs in addition to the compound of the present invention may also be preferred. Accordingly, the pharmaceutical 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. For example 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. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).
The novel spiro[cyclobutane-l,3'-indolin]-2'-one derivatives of formula (I) according to the present invention may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. The details of the processes according to the present invention are given in the example section mentioned below. In a further aspect, 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. For example, 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, l lC, , C, ,4C, , 3N, , 5N, , 50, 170, , 80, 32P, 33P, 35S, ,8F, 36C1, ,23I and l25I. 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.
The abbreviations used in the entire specification may be summarized herein below with their particular meaning.
MeOH-Methanol; EtOH-Ethanol; Me-methyl; Et-Ethyl; DEA- Diethanolamine; DME-l,2-dimethoxyethane; DCM-Dichloromethane; DMF-N,N- Dimethyl formamide; DMSO-Dimethylsulfoxide; CDC13-Deuterated chloroform; EtOAc-Ethylacetate; THF-Tetrahydrofuran; TEA-Triethylamine; DIEA- Diisopropylethylamine; HMPA- Hexamethylphosphoramide; mL-milliliter;
EDC.HCl-l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride; CaO- Calciumoxide; CS2-carbondisulfide; HOBt-l-Hydroxybenzotriazole; TLC-Thin layer chromatography; K 03-Potassium nitrate; H2S04-Sulfuric acid; KOAC- Potassium acetate; NBS-N-Bromosuccinimide; NCS-N-Chlorosuccinimide;
Na2C03-Sodium carbonate; SnCl2.2H20-Stannous chloride dihydrate; POCI3- Phosphorousoxychloride; NaOH-Sodium hydroxide; HCl-Hydrochloric acid; Pd (pph3)4-Tetrakis(triphenylphosphine)palladium(0); Pd/C-Palladium on activated carbon; Pd(amphos)Cl2-Bis(di-tert-butyl(4-dimethylaminophenyl)
phosphine)dichloropalladium(H); H20-Water; Fe-Iron powder; h- Hours; N-
Normality; M-Molarity; s-Singlet; d-Doublet; dd-Doublet of a doublet; t-Triplet; m- Multiplet; 'HNMR-Proton nuclear magnetic resonance; MS-Mass spectroscopy; LC-Liquid chromatography; HPLC-High performance liquid chromatography; 1H- Proton; MHz-Mega hertz; Hz-Hertz; ppm-Parts per million; bs-Broad singlet; ES- Electro spray; Conc-Concentrated; g-Gram; mmol-Millimol; min-minutes; μ-micro; nm-nano molar; δ-Chemical shift expressed in ppm; ee-enantiometric excess.
Examples Although the invention has been illustrated by following examples, it is not to be construed as being limited thereby. Various modifications and embodiments can be made without departing from the spirit and scope thereof.
The MS data provided in the examples described below were obtained as follows: Mass spectrum: LC/MS Agilent 6120 Quadrapole LC/MS.
The NMR data provided in the examples described below were obtained as follows: Ή-NMR: Varian 400 MHz.
The microwave chemistry was performed on a CEM Explorer.
The procedure for the compounds of Formula (I) are detailed herein below stepwise including the general synthesis of various intermediates involved in process of synthesis of the compounds according to the present invention. Intermediate- 1: S'-aminospirofcyclobutane-l.S'-indolinl^'-one
Figure imgf000025_0001
Step-a: N'-phenylcvclobutanecarbohydrazide:
Cyclobutanecarbonyl chloride (21.92 g, 184 mmol) was added dropwise at RT to phenyl hydrazine (20 g, 184 mmol) and pyridine (20 mL, 257 mmol) in 30 mL DMF. The mixture was stirred for 1 h at RT and poured into 200 mL of aq.1M HC1 solution. The precipitated solid was filtered, washed with 50 mL water and dried. The solid was washed with 20 mL of diethyl ether and dried under reduced pressure (32 g, 91%). 'H-NMR (400 MHz, DMSO- 6) δ 9.45 (s, 1H), 7.64 (d, 1H), 7.14 (m, 2H), 6.68 (m, 3H), 3.1 (m, 1H), 2.10 (m, 4H), 1.86 (m, 1H), 1.81 (m, 1H); LC-MS: 191.1 [M+H]+.
Step-b: Spiro Icvclobutane- 1.3' -indolinl -2'-one: To a stirred suspension of calcium oxide (38 g, 680 mmol) in quinoline (200 mL) was added N-phenylcyclobutanecarbohydrazide (13 g, 68 mmol). The mixture was heated to 270-310°C for 60 min. The reaction mixture was cooled to RT and aq. 2M HC1 was added. The aq. layer was extracted twice with EtOAc. The combined extracts were washed with 2M hydrochloric acid, brine, dried over Na2S04, filtered and concentrated. The obtained crude was purified by column chromatography using a mixture of 40-60% ethyl acetate/hexane as an eluent to get the desired compound as an orange solid (4 g, 35%). 'H-NMR (300 MHz, DMSO-<½) δ: 10.2 (s, 1H), 7.45 (d, 1H), 7.2 (t, 1H), 7.0 (t, 1H), 6.8 (s, 1H), 2.25 (m, 4H), 2.4 (m, 2H); LC-MS: 174.15 [M+H]+.
Step-c: 5'-nitrospirofcyclobutane-l,3'-indolin1-2'-one:
To a stirred solution of spiro[cyclobutane-l,3'-indolin]-2'-one (2.6 g, 15.01 mmol ) in 10 mL of concentrated sulfuric acid at -15°C was added fuming nitric acid (0.84 mL) dropwise and maintained the reaction temperature at -15°C. After completion of addition, the reaction mixture was stirred for 30 min and then poured into ice water. A yellow precipitate was formed which was isolated by filtration to provide the title compound (3.4 g, 98%). Ή-NMR (300 MHz, DMSO-</6): δ 11 (s, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 7.0 (s, 1H), 2.25 (m, 4H), 2.4 (m, 2H); LC-MS: 217.3 [M+H]+.
Step-d: 5'-aminospirorcyclobutane-1.3'-indolin1-2'-one:
5'-nitrospiro[cyclobutane-l,3'-indolin]-2'-one (0.356 g, 1.649 mmol) is hydrogenated in 30 mL of ethanol with 400 mg palladium on carbon (10%) at RT and normal pressure for 1 h. After catalyst is filtered off on celite bed and washed with excess ethanol. The filtrate concentrated by evaporation (0.32 g, 100%). Ή-NMR (300 MHz, DMSO-</6~): δ 9.80 (s, 1H), 6.85 (s, 1H), 6.45 (t, 2H), 2.40 (m, 2H), 2.20 (m, 4H); LC-MS: 189.1 [M+Hf.
Intermediate-2: tert-butyl 5'-amino-2'-oxospirorcvclobutane-1.3'-indolinel-r- carboxylate.
Figure imgf000027_0001
Step-a: 5-nitroindolin-2-one:
To a stirred solution of oxindole (20 g, 150.21 mmol) in 100 mL of concentrated H2S04 at -15°C was added fuming HN03 (9.47 g, 150.206 mmol) dropwise and maintained the reaction temperature at -15°C. After completion of addition, the mixture was stirred for 30 min and then poured into ice water. A yellow precipitate was formed which was isolated by filtration (13 g, 48%). Ή-NMR (300 MHz, DMSO-ito): δ 11 (s, 1H), 8.2 (d, 1H), 8.1 (s, 1H), 7.0 (d, 1H), 3.6 (s, 2H).
Step-b: tert-butyl 5-nitro-2-oxoindoline-l-carboxylate:
Di-tert-butyl dicarbonate (4.63 g, 21.2 mmol) and sodium hydrogen carbonate
(10.7 g, 127 mmol) were added to a stirred solution of 5-nitroindoIin-2-one (3.0 g, 14.2 mmol) in THF (150 mL) and the mixture was heated to 60°C. After 3h, the reaction mixture was cooled, filtered and the filtrate was concentrated under reduced pressure. The obtained crude was purified by chromatography by using silica gel using a mixture of 10% ethyl acetate/hexane as an eluent to get the desired compound as a white solid as (2.3 g, 51%). 1H-NMR (300 MHz, DMSO-i/6): δ 8.3 (d, 1H), 8.2 (s, 1H), 7.9 (d, 2H), 3.8 (s, 2H), 1.5 (s, 9H).
Step-c: ½rf-butyl 5'-nitro-2'-oxospiro [cyclobutane-l. 3'-indolinel-l'- carboxylate:
Cesium carbonate (20.7 g, 63.5 mmol) was added portionwise over a 20 min period to a stirred solution of tert-butyl 5-nitro-2-oxoindoline-l-carboxylate (6.0 g, 16.0 mmol) and 1,3-dichloropropane in DMF (10 mL) at -20°C under an argon atmosphere. After completion of addition, the mixture was warmed to RT and stirred for 16 h. The aqueous layer was extracted with ethyl acetate and the extracts were washed with water, brine dried over MgS04 and evaporated. The obtained crude was purified by flash chromatography (10: 1 hexane/ethyl acetate) gave the title compound as a pale yellow solid (1.09 g, 16%). 1H-NMR (300 MHz, OMSO-d6): δ 8.4 (d, 1H), 8.2 (d, IH), 7.9 (d, IH), 2.7 (m, 2H), 2.5 (m, 4H), 1.6 (s, 9H).
Step-d: tert-butyl 5'-amino-2'-oxospiro fcvclobutane-1, 3'-indolinel-l'- carboxylate:
356 mg of Intermediated is hydrogenated in 30 mL of ethanol with 400 mg palladium on carbon (10%) at RT for 3h. The catalyst was filtered through celite, the filtrate concentrated by evaporation to get the title compound (0.32 g, 100%). Ή- NMR (300 MHz, DMSO-i/6): δ 7.4 (d, IH), 6.8 (s, IH), 6.5 (d, IH), 5.0 (s, IH), 2.2 (m, 4H), 1.5 (s, 9H), 1.2 (d, 2H); LC-MS: 289.5 [M+H]+.
Intermediate-3: 2'-oxospiro rcyclobutane-1. 3 '-indolinel-5'-sulfonyl chloride
Figure imgf000028_0001
Intermediate- lb (0.2 g, 1.154 mmol) was added drop wise at RT to (1 mL) chlorosulfonic acid. The mixture was stirred for 2 h at RT and poured into 20mL of an ice water. The precipitated solid was suction filtered, washed with 50 mL water and dried (0.15 g, 50%). Ή-NMR (300 MHz, DMSO- 6): 6 10.2 (s, IH), 7.7 (s, IH), 7.4 (d, IH), 6.7 (d, IH), 2.4 (m, 2H), 2.2-2.4 (m, 4H); LC-MS: 272.1 [M+H]+.
Intermediate-4: 5'-arnino-7'-bromospiroicyclobutane- 1.3'-indolin1-2'-one
Figure imgf000028_0002
Intermediate-4
Step-a: 7'-bromo-5'-nitrospirorcyclobutane-l. 3'-indolinl-2'-one:
N-Bromosuccinimide (0.122 g, 0.68 mmol) was added drop wise at RT to Intermediate- lc (0.1 g, 0.45 mmol) in concentrated H2S04 (1 mL). The mixture was stirred for 2 h at RT and poured into 200 mL of water. The precipitated solid was suction filtered, washed with 50 mL water and dried. The solid was washed with 20 mL ether and dried under reduced pressure to afford the titled compound as an off- white solid (0.108 g, 80%). Ή-NMR (300 MHz, OMSO-d6): δ 11.3 (s, IH), 8.5 (s, IH), 8.3 (s, IH), 2.4 (m, 2H), 2.35 (m, 4H); LC-MS: 296.9 [M+H]+.
Step-b: 5'-amino-7'-bromospirorcvclobutane-l .3'-indolinl-2'-one:
To a stirred solution of 7'-bromo-5'-nitrospiro[cyclobutane-l,3'-indolin]-2'- one (0.11 g, 0.35 mmol), ammonium chloride (0.296 g, 5.6 mmol ) in THF H20 (5 n L/1 mL) was added zinc dust (0.184 g, 2.8 mmol) portionwise over a period of 5 min at 0°C. Then the reaction mixture was allowed to warm at RT, filtered through celite pad, dried over Na2S04 and concentrated to get title compound (45 mg, 47%). Ή-NMR (300 MHz, DMSO-_i6): δ 10.0 (s, IH), 6.8 (s, IH), 6.6 (s, IH), 5.0 (s, 2H), 2.4 (m, 2H), 2.35 (m, 4H); LC-MS: 268.75 [M+H]+.
Intermediate-5: 5'-amino-7'-chloros iro c clobutane-1.3'-indolin1-2'-one
Figure imgf000029_0001
Intermediate-5
The process of these steps were adopted from step-a and b of Intermediate-4 (0.220 g, 97%). 1H-NMR (300 MHz, DMSO-J6): δ 10.17 (s, IH), 6.79 (s, IH), 6.41 (s, IH), 5.0 (s, 2H), 2.4 (m, 2H), 2.35 (m, 4H); LC-MS: 223.0 [M+H]\
Intermediate-6: 5'-amino-7'-cyclopropylspirof cyclobutane- 1.3'-indolin"l-2'-one
Figure imgf000029_0002
Step-a: 7'-cyclopropyl-5'-nitrospirof cyclobutane- 1 ,3'-indolin1-2'-one:
To a stirred solution of 7'-bromo-5'-nitrospiro[cyclobutane-l,3'-indolin]-2'- one (0.200 g, 0.673 mmol) in mixture of solvents 1,4-dioxane (10 mL): water (3 mL) was added potassium phosphate (0.285 g, 1.34 mmol), Pd(amphos)Cl2 (0.047 g, 0.067 mmol) and cyclopropylboronic acid (0.069 g, 0.807 mmol). The reaction mixture was purged with nitrogen gas for 10-15 min and heated to 100-110°C for 12 h under nitrogen atmosphere or in a sealed tube. The reaction mixture was poured into ice cold water (10 mL) and extracted with ethyl acetate. The combined extracts were washed with water, dried over MgS04 and evaporated. The obtained crude was purified by silica gel chromatography using a mixture of 70% ethyl acetate/hexane as an eluent to get the desired compound as a pale yellow solid (0.120 g, 69.36%); LC- MS: 257.0 [M-H]\
Step-b: 5'-amino-7'-cyclopropylspirofcvclobutane-1.3'-indolin1-2'-one:
The process of this step was adopted from step-b of Intermediate-4 (0.050 g, 51.55%); LC-MS: 229.1 [M+H]+. The below Intermediates 7 to 11 were prepared according to the above protocol (Intermediate-6).
Figure imgf000030_0002
Intermediate- 12: 5'-amino-7'-ethylspiroicyclobutane- 1 ,3'-indolin1-2'-one
Figure imgf000030_0001
Step-a: 5'-nitro-7'-vinylspirorcvclobutane- 1.3'-indolin1-2'-one: To a stirred solution of intermediated (0.3 g, 1.01 mmol) in 1,4-dioxane (12 mL) and H20 (3 mL), were added 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (0.31 g, 2.02 mmol), potassium carbonate (0.42 g, 3.04 mmol) and degassed with nitrogen purging for 20 min. Then bis(triphenylphosphine)palladium(II)dichloride (0.07 g, 0.1 mmol) was added and heated at 100°C for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (100 ml), washed with water (100 mL), brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure. The obtained crude was purified by column chromatography to afford the title compound (0.17 g, 68%). 1H-NMR (400 MHz, DMSO-de): δ 11.22 (s, IH), 8.36 (d, J=2.4 Hz, IH), 8.33 (d, J=2.0 Hz, IH), 6.97- 6.90 (m, IH), 6.04 (d, J=17.2 Hz, IH), 5.47 (d, J=11.3 Hz, IH), 2.48-2.43 (m, 4H), 2.26-2.20 (m, 2H); LC-MS: m/z 243.1 [M-H]\
Step-b: 5'-amino-7'-ethylspirorcvclobutane- 1.3'-indolinl-2'-one:
The process of this step adopted from step-d of intermediate- 1. The desired compound obtained as pale brown oil (0.15 g, 88%). 1H-NMR (400 MHz, DMSO- de): δ 9.85 (s, IH), 6.65 (s, IH), 6.24 (s, IH), 4.62 (s, 2H), 2.43-2.37 (m, 4H), 2.16- 2.14 (m, 2H), 1.05 (t, J=7.3 Hz, 3H); ES-MS: m/z 217.2 (M+H)+.
The below intermediates 13-16 were prepared according to the above protocol (Intermediate- 12).
Figure imgf000031_0001
Intermediate- 17 : 5'-amino-7'-( 1 H-imidazol- 1 -vDspirofcvclobutane- 1.3'-indolin1-2'- one
Figure imgf000032_0001
nterme ate- 17
Step-a: 5'-nitro-7'-( lH-pyrazol- 1 -vDspiroicvclobutane- 1.3'-indolin1-2'-one: To a stirred solution of intermediated (0.200 g, 0.673 mmol) in DMSO was added IH-imidazole (0.059 g, 0.875 mmol), copper oxide (0.026 g, 0.336 mmol) and cesium carbonate (0.662 g, 2.019 mmol). Then the reaction mixture degassed with nitrogen gas for 10-15 min and heated to 100-110°C for 12 h under nitrogen atmosphere or in a sealed tube. After completion of the reaction, the reaction mixture diluted with water (20 mL) and ethyl acetate (20 mL). Both layers were separated and aqueous layer extracted with ethyl acetate twice (2 x 30 mL). The combined organic layer was washed with water, dried with MgS04 and evaporated. The obtained crude was purified by chromatography by using silicagel using a mixture of 70% ethyl acetate/hexane as an off white solid (0.070 g, 36.84%). LC-MS: 285.2 [M+H]+.
Step-b: 5'-amino-7'-( lH-pyrazol- l-yl)spirofcvclobutane- 1.3'-indolin1-2'-one: The process of this step was adopted from step-b of Intermediate-4 (0.060 g, 96%); LC-MS: 255.2 [M+H] +.
The below intermediate- 18 was prepared according to the above protocol
(Intermediate- 17).
Figure imgf000032_0002
Intermediate- 19: 5'-amino-7'-methylspiroicvclobutane-l .3'-indolinl-2'-one
Figure imgf000033_0001
Intermediate- 19
Step-a: (E)-2-(hvdroxyimino')-N-(2-methyl-4-nitrophenyl> acetamide:
To a stirred suspension of 2-methyl-4-nitro aniline (5 g, 0.032 mol) in water 100 mL was added chloral hydrate (5.98 g, 32.8 mmol), anhydrous sodium sulphate (37.3 g, 36.0 mmol), hydroxylamine hydrochloride (7.54 g, 108 mmol), and 5 mL of con HC1. The resulting mixture was stirred at 120°C for 40 min. The reaction mixture was cooled to RT and the precipitated solid was collected and dried under vacuum to afford the title compound as a pale yellow color solid (7 g, 95%). Ή NMR (400 MHz, DMSO-d6): δ 12.41 (s, 1H), 9.67 (s, 1H), 8.09-8.01 (m, 2H), 7.78 (s, 1H), 7.75 (s, 1H), 2.24 (s, 3H); ES-MS: 222.1 (M-H)\
Step-b: 7-methyl-5-nitroindoline-2.3-dione:
To a stirred concentrated sulphuric acid solution (70 mL) was added (E)-2- (hydroxyimino)-N-(2-methyl-4-nitrophenyl)acetamide (7 g, 31.39 mmol) in portions at 60-70°C. After completion of addition, the reaction mixture was heated to 80°C for 20 min. The reaction mixture was then allowed to cool to RT and poured into ice cold water (150 mL). The precipitated solid was filtered and dried under vacuum to afford the title compound as brick red solid (3 g, 46%). Ή NMR (400 MHz, DMSO- d6): δ 1 1.71 (s, 1 H) 8.32 (s, 1H), 8.06 (s, 1H), 2.38 (s, 3H). ES-MS: m/z 205.1 (M- H)\
Step-c: 7-methyl-5-nitroindolin-2-one:
To a stirred suspension of 7-methyl-5-nitroindoline-2,3-dione (1 g, 4.8 mmol) in 20 mL of ethylene glycol was added hydrazine hydrate (0.233 g, 7.2 mmol). The reaction mixture was heated at 120°C for 16 h and was cooled to RT. The formation of solid was filtered and purified by column chromatography (3-10% MeOH in CH2C12) over silica gel to afford the title compound as a pale yellow color solid (0.55 g, 59%). 1H NMR (400 MHz, DMSO-d6): δ 11.09 (bs, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 3.64 (s, 2H), 2.32 (s, 3H); ES-MS: m/z 191.2 (M-H)\
Step-d: 7'-methyl-5'-nitro spirolcyclobutane- 1.3'-indolin1-2'-one:
To a stirred solution of 7-methyl-5-nitroindolin-2-one (0.45g, 2.3 mmol) in dry THF was added LiHMDS (7.02 mL, 3 eq) dropwise at 0°C and stirred there for 15 min. Subsequently, 1, 3-diiodo propane (1.3 mL, 11.7 mmol) was added and the reaction mixture was stirred at 0°C to RT for 2 h. The reaction mixture was quenched with IN HC1. The aqueous layer was extracted with ethyl acetate and washed with water and brine, dried over MgS04 and evaporated. The crude material was purified by column chromatography using 5 % ethyl acetate in hexanes as eluent to afford the title compound as a pale yellow solid (0.060 g, 10%). Ή-NMR (400 MHz, DMSO- d6): 8 10.99 (bs, 1H), 8.29 (d, 8.01 (s, 1H), 2.45-2.41 (m, 4H), 2.28 (s, 3H), 2.25- 2.19 (m, 2H); ES-MS: m z 231.2 (M-H)\
Step-e: 5'-amino-7'-methyl spirorcvclobutane- 1 ,3'-indolinl-2'-one:
To a stirred solution of 7'-methyl-5'-nitrospiro[cyclobutane- 1 ,3'-indolin]-2'- one (0.060 g, 0.37 mmol) in methanol (15 mL), was added 10% Pd/C (20 mg) under nitrogen. The reaction mixture was stirred at room temperature under hydrogen atmosphere (45 psi) for 2h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford titled compound as a brown color liquid (0.030 g, 60%). ES-MS: 203.1 [M+H]+.
The present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds according to the invention. Example-I: 2,5-dimethyl-N-(2'-oxospirofcvclobutane- 1 ,3 '-indolinl-S'-vDthiophene- 3-sulfonamide (Compound- 1)
Figure imgf000034_0001
To a stirred solution of 5'-aminospiro[cyclobutane-l,3'-indolin]-2'-one (0.07 g, 0.23 mmol) in 30 mL of DCM was added pyridine (0.5 mL). The solution was cooled to -30°C and 2,5-dimethylthiophene-3-sulfonyl chloride (0.059 g, 0.27 mmol) was added dropwise. On completion of the addition, the reaction mixture was stirred at RT for 1 h until precipitate was formed. The solid was filtered, washed with water (50 mL x 3) and dried under vacuum to afford the title compound as a white solid (0.06 g, 83 %). 1H-NMR (300 MHz, DMSO-<½): δ 1 1 (s, 1H), 9.65 (s, 1H), 7.2 (s, 1H), 6.8 (m, 2H), 6.65 (d, 1H), 2.4 (m, 2H), 2.35 (s, 3H), 2.3 (s, 3H), 2.1 (m, 4H); LC-MS: 363.4 [M+H]+.
The below compounds were prepared by procedure similar to the one described in Example-I with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.
Comp.
Structure Characterization data
No
Ή-NMR (300 MHz, DMSO-<ft5): δ 11 (s, 1H), 9.8 (s, 1H), 7.2 (s, 3H), 7.0 (d, 1H), 6.8 (d, 1H),
2
6.6 (d, 1H), 4.3 (s, 4H), 2.4 (m, 2H), 2.35 (s, 4H); LC-MS: 387.2 [M+Hf.
Ή-NMR (600 MHz, CD3OD): δ 7.7 (d, 1H), 7.5 (t, 1H), 7.3 (s, 1H), 7.2 (d, 1H), 6.9 (t, 1H), 6.8
3
(dd, 1H), 6.6 (d, 1H), 4.0 (s, 3H), 2.5 (m, 2H), 2.35 (s, 4H); LC-MS: 357 [M+H]+.
Ή-NMR (300 MHz, DMSO-<f6): 8 10.0 (s, 1H), 9.8 (s, 1H), 9.2 (s, 1H), 8.6 (s, 1H), 8.3 (s, 2H),
4 7.8 (m, 1H), 7.7 (t, 1H), 7.1 (s, 1H), 6.7 (d, 1H),
6.5 (d, 1H), 2.4 (m, 2H), 2.3 (s, 2H), 2.2 (m, 2H); LC-MS: 380 [M+H]+.
Ή-NMR (400 MHz, CD3OD): δ 7.6 (m, 2H), 7.4 (d, 1H), 7.25 (s, 1H), 6.85 (d, 1H), 6.65 (d, 1H),
5
4.3 (s, 2H), 3.5 (m, 2H), 3.1 (m, 2H), 2.5 (m, 2H), 2.2 (m, 4H); LC-MS: 380 [M+Hf.
Ή-NMR (400 MHz, DMSO-i/6): 5 10.2 (s, 1H),
6 10.1 (s, 1H), 9.2 (s, 1H), 9.0 (s, 1H), 8.0 (d, 1H),
7.5 (d,lH), 6.9 (d, 1H), 6.8 (d, 1H), 6.7 (d, 1H), 1.8 (m, 4H), 1.6 (m, 2H), 1.4 (m, 2H); LC-MS: 370.1 [M+H]+.
Ή-NMR (300 MHz, DMSO-i/6): δ 10.8 (s, IH), 9.2 (s, IH), 7.8 (s, IH), 7.6 (d, IH), 7.4 (d, IH), 7.2 (t, IH), 6.85 (m, 3H), 3.5 (s, 3H), 2-1.8 (ra, 2H), 1.6 (m, 4H);LC-MS: 357.3 [M+H]+.
H ΒΓ Ή-NMR (400 MHz, CD30D): δ 7.7 (d, IH), 7.5
(t, IH), 7.3 (s, IH), 7.2 (d, IH), 7.05 (s, IH), 6.9 (t, IH), 4.0 (s, 3H), 2.5 (m, 2H), 2.35 (s, 4H). LC-MS: 438.9 [M+H] +.
Ή-NMR (400 MHz, DMSO-c/6): 5 10.6 (s, IH), 10.4 (s, IH), 8.66 (d, IH), 8.07 (dd, IH), 7.75 (d, IH), 7.72 (s, IH), 6.99 (s, IH), 2.39 (m, 2H), 2.16 (m, 4H). LC-MS: 443.80 [M+H]+.
Ή-NMR (400 MHz, DMS0-dr5): δ 10.75 (s, IH), 10 (s, IH), 7.18 (m, 3H), 7.01 (m, 2H), 4.27 (m, 4H), 2.37(m, 2H), 2.15 (m, 4H); LC-MS: 464.90 [M+H]+.
'H-NMR (400 MHz, DMSO-<¾): 5 10.5 (s, IH),
H Br ? 10.2 (s, IH), 8.59 (d, IH), 8.03 (d, 2H), 7.81 (d,
3H), 7.24 (d, IH), 6.98(d, IH), 6.60 (t, IH), 2.40 (m, 2H), 2.15 (m, 4H); LC-MS: 475.2 [M+H]+.
'H-NMR (400 MHz, DMSO-d6): 6 10.2 (s, IH), 9.9 (s, IH), 8.58 (d, IH), 8.01 (d, 2H), 7.80 (dd, 3H), 7.21 (d, IH), 6.81(dd, IH), 6.64 (d, IH), 6.60 (t,lH), 2.35 (m, 2H), 2.12 (m, 4H); LC-MS: 394.11 [M+H]+.
Ή-NMR (400 MHz, DMSC ft): δ 10.6 (s, IH), 10 (s, IH), 7.75 (dd, IH), 7.6 (t, IH), 7.2 (dd, 2H), 7 (t, IH), 6.9 (s, IH), 3.9 (s, 3H), 2.4 (m, 2H), 2.2 (m, IH), 2 (m, 3H); LC-MS: 393.3 [M+H]+. Ή-NMR (400 MHz, DMSO-rf<5): δ 10.7 (s, IH),
H ? 10.2 (s, IH), 8.59 (s, IH), 8.03 (d, 2H), 7.81 (d,
3H), 7.21 (s, IH), 6.87 (s, IH), 6.60 (s, IH), 2.35 (m, 2H), 2.15 (m, 4H); LC-MS: 429 [M+H]+.
Ή-NMR (400 MHz, DMSO- 6): δ 10.85 (s, IH), 9.8 (s, IH), 7.35 (s, IH), 7.02 (s, IH), 3.1 (s, 4H), 2.3 (s, IH), 2.24 (m, 4H), 2.12 (m, IH), 1.42 (s, 6H); LC-MS: 370 [M+H]+.
H ? ' Ή-NMR (400 MHz, DMSO-<¾): δ 10.75 (s,
IH), 10.00 (s, IH), 8.18 (d, IH), 7.67 (d, IH), 7.23 (s, IH), 6.90 (s, IH), 3.82 (s, 3H), 2.40 (m, 2H), 2.18 (m, 4H); LC-MS: 367 [M+H]+
Ή-NMR (400 MHz, DMSO-d6): δ 10.90 (s, IH), 10.50 (s, IH), 7.86 (m, IH), 7.55 (m, IH), 7.24 (m, 2H), 6.90 (s, IH), 2.37 (m, 2H), 2.13 (m, 4H); LC-MS: 399 [M+H]+.
„ CI „ Ή-NMR (300 MHz, DMSO-i/6): 6 10.75 (s,
IH), 10.2 (s, IH), 7.74 (dd, 2H), 7.39 (t, 2H), 7.14 (s, IH), 6.83 (s, IH), 2.37 (m, 2H), 2.10 (m, 4H); LC-MS: 382.9 [M+Hf.
Cl Ή-NMR (400 MHz, DMSC .6): δ 10.70 (s,
IH), 10.20 (s, IH), 8.70 (d, IH), 7.94 (dd, IH), 7.43 (d, IH), 7.20 (s, IH), 6.90 (s, IH), 2.40 (m, 2H), 2.30 (m, 4H). LC-MS: 378.35 [M+H]+.
Ή-NMR (400 MHz, DMSO-<¾): δ10.75 (s, IH), 10.40 (s, IH), 8.54 (d, IH), 8.24 (m, IH), 7.41 (dd, IH), 7.19 (d, IH), 6.88 (d, IH), 2.41 (m, 2H), 2.17 (m, 4H). LC-MS: 381.95 [M+H]+.
Ή-NMR (400 MHz, DMSO-i/6): δ 10.75 (s, IH), 9.70 (s, IH), 7.36 (d, IH), 7.05 (d, IH), 2.97 (t, IH), 2.40 (m, 2H), 2.28 (m, 3H), 2.09 (m, 3H), 1.75 (d, 2H), 1.55 (d, IH), 1.38 (m, 2Η). LC-MS: 369 [Μ+Η]+.
Ή-NMR (400 MHz, DMSO-d<5): δ 10.70 (s, IH), 10.50 (s, IH), 7.62 (t, IH), 7.44 (t, IH),
22
7.25 (s, IH), 6.92 (s, IH), 3.84 (s, 3H), 2.39 (m, 2H), 2.14 (m, 4H); LC-MS: 429.4 [M+H]+.
Ή-NMR (400 MHz, DMSO- ό): δ 10.80 (s, IH), 10.20 (s, IH), 7.58 (t, 2H), 7.22 (d, 2H),
23 6.90 (s, IH), 3.97 (s, 3H), 2.35 (m, 3H), 2.12 (m,
3H); LC-MS: 411.05 [M+H]+.
'H-NMR (400 MHz, DUSO-d6 : δ 10.60 (s, IH), 9.80 (s, IH), 7.77 (d, IH), 7.52 (t, IH), 7.18
24 (d, 2H), 6.98 (t, IH), 6.91 (s, IH), 4.79 (m, IH),
2.32 (m, 2H), 2.09 (m, 4H), 1.28 (d, 6H). LC- MS: 421.0 [M+H]+.
1 H-NMR (400 MHz, DMSO-i.6): δ 10.70 (s, IH), 10.40 (s, IH), 8.18 (s, IH), 7.96 (d, IH),
25 7.54 (m, 2H), 7.10 (s, IH), 6.78 (s, IH), 4.07(s,
Figure imgf000038_0001
3H), 2.32 (m, 2H), 2.04 (m, 4H). LC-MS: 417.2
[M+H]+.
'H-NMR (400 MHz, DMSO-i/6): δ 10.40 (s, IH), 10.20 (s, IH), 7.76 (dd, IH), 7.53 (t, IH),
26 7.22 (t, IH), 7.01 (s, IH), 6.31 (s, IH), 2.37 (m,
2H), 2.08 (m, 4H), 1.86 (m, IH), 0.80 (t, 2H), 0.38 (dd, 2H); LC-MS: 405.1 [M+H]+.
'H-NMR (400 MHz, DMSO-<¾): δ 10.50 (s, IH), 9.90 (s, IH), 8.61 (s, IH), 7.88 (d, IH),
27 7.42 (d, IH), 7.02 (s, IH), 6.58 (s, IH), 2.34 (m,
4H), 2.11 (m, 5H), 1.34 (m, 2H), 0.74 (t, 3H); LC-MS: 386.3 [M+H]+.
1 H-NMR (400 MHz, DMSO--i6): δ 10.40 (s, IH), 9.80 (s, IH), 7.69 (dd, 2H), 7.38 (t, 2H),
28 6.95 (s, IH), 6.23 (s, IH), 2.37 (m, 2H), 2.09 (m,
Figure imgf000038_0002
4H), 1.83 (m, IH), 0.85 (d, 2H), 0.35 (dd, 2H);
LC-MS: 387.0 [M+H]+.
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
JH-NMR (400 MHz, DMSO- d6): 5 10.40 (s, IH), 9.80 (s, IH), 8.58 (d, IH), 7.99 (d, 2H), 7.81 (d, IH), 7.74 (d, 2H), 7.01(d, IH), 6.60 (t, H 0 IH), 6.27 (d, lH), 2.33 (m, 2H), 2.10 (m, 4H),
1.83 (m, IH), 0.84 (m, 2H), 0.36 (m, 2H); LC- MS: 435.1 [M+H]+.
Ή-NMR (400 MHz, DMSO-<½): δ 10.42 (s, IH), 9.50 (s, IH), 7.18 (s, IH), 6.52 (s, IH), 3.05 (s, 4H), 2.42 (m, 2H), 2.20 (m, 4H), 1.93 (m, IH), 1.39 (s, 6H), 0.91 (m, 2H), 0.51 (m, 2H); LC-MS: 376.05 [M+H]+.
Ή-NMR (400 MHz, DMSO-.i6): δ 10.75 (s, IH), 10.40 (s, IH), 9.27 (s, IH), 7.82 (q, 4H), 7.41 (m, 3H), 7.04 (s, IH), 2.42 (m, 2H), 2.18 (m, 4H); LC-MS: 413.85 [M+H]\
Ή-NMR (400 MHz, CD3OD): 8 8.05 (s, IH), 7.77 (d, 3H), 7.20 (m, 4H), 6.53 (s, IH), 2.57 (m, 2H), 2.22 (m, 4H); LC-MS: 413.20 [M+H]+.
Ή-NMR (400 MHz, DMSO-<i6): δ 10.39 (s, IH), 10.00 (s, IH), 8.09 (s, IH), 7.94 (dd, IH), 7.52 (m, 2H), 6.90 (s, IH), 6.16 (d, IH), 4.01 (s, 3H), 2.31 (m, 2H), 2.02 (m, 4H), 1.77 (m, IH),
Figure imgf000042_0001
0.80 (m, 2H), 0.22 (m, 2H); LC-MS: 423.45 [M+H] +.
Ή-NMR (400 MHz, DMSO-d6): δ 10.2 (s, IH), 9.46 (s, IH), 7.38 (d, IH), 7.02 (dd, IH), 6.70 (d, IH), 2.87 (t, IH), 2.44-2.40 (m, 2H), 2.38-2.20 (m, 3H), 2.11-1.98 (m, 3H), 1.77-1.74 (m, 2H), 1.59-1.56 (m, IH), 1.40-1.37 (m, 2H), 1.35-1.17 (m, 3H); ES-MS: 335.1 [M+H]+. Ή-NMR (400 MHz, DMSO-<¾): δ 10.18 (s, 1Η), 9.53 (s, IH), 7.38 (d,lH), 6.99 (dd, IH), 6.72 (d, IH), 3.31-3.06 (m, 4H), 2.52-2.44 (m, 2H), 2.21-2.19 (m, 4H), 1.50-1.40 (m, 6H); ES- MS m/e 334 [M-H]\
Ή-NMR (400 MHz, DMSCW6): δ 10.17 (bs, IH), 9.56 (bs, IH), 7.67 (dd, IH), 7.56-7.51 (m, IH), 7.16 (d, IH), 7.02-6.96 (m, 2H), 6.68 (d,
Figure imgf000043_0001
IH), 3.92 (s, 3H), 2.37-2.32 (m, 2H), 2.19-2.06
(m, 4H), 2.03 (s, 3H); ES-MS: 373.2 [M+H]+.
Ή-NMR (300 MHz, DMSC to): δ 10.42 (s, IH), 9.58 (s, IH), 7.19-7.18 (d, IH), 6.53-6.52 (d, IH), 3.49 (m, 4H), 3.03 (m, 4H), 2.42(m, 2H), 2.22 (m, 4H), 2.15 (m, IH), 0.91 (m, 2H), 0.54 (m, 2H); LC-MS: 377.95 [M+H]+.
Ή-NMR (400 MHz, DMSO-ito): δ 10.47 (s, IH), 10.05 (s, IH), 8.565-8.560 (d, IH), 8.01- 7.92 (dd, IH) IH), 7.74-7.72 (d, IH), 6.977- 6.974 (d, IH), 6.245-6.24 (d, IH), 2.36 (m, 2H), 2.10 (m, 4H), 1.83 (m, IH), 0.86 (m, 2H), 0.37 (m, 2H); LC-MS: 404.2 [M+H]+.
Ή-NMR (400 MHz, DMSO-i.6): δ 8.76-8.75 (d, IH), 8.03-7.99 (m, IH), 7.85-7.83 (d, IH), 7.66 (m, IH), 7.026-7.021 (d, IH), 6.38-6.314 (d, IH), 2.37 (m, 2H), 2.08 (m, 4H), 1.83 (m, IH), Η
0.85 (m, 2H), 0.35 (m, 2H); LC-MS: 396.95 [M+H] +.
Ή-NMR (400 MHz, CD30D-</6): δ 8.639-8.632 (d, IH), 7.94-7.9 (m, IH), 7.77-7.72 (m, IH), 7.14 (s, IH), 6.54 (s, IH), 2.51 (m, 2H), 2.29 (m,
Figure imgf000043_0002
4H), 1.78 (m, IH), 0.93 (m, 2H), 0.51 (m, 2H);
LC-MS: 388.1 [M+H] +.
Figure imgf000044_0001
Ή-NMR (400 MHz, DMSO-i/6): δ 10.18 (s, IH), 9.53 (s, IH), 7.66 (d, J=7.4 Hz, IH), 7.53 (t, J=7.8 Hz, IH), 7.15 (d, J=8.3 Hz, IH), 7.06 (s, IH), 6.98 (t, J=7.3 Hz, IH), 6.73 (s, IH), 3.91
Figure imgf000045_0001
(s, 3H), 2.89-2.86 (m, IH), 2.40-2.33 (m, 2H),
2.22-2.06 (m, 4H), 0.98 (d, J=6.8 Hz, 6H); ES- MS: m/z 401.2 [M+H]+.
'H-NMR (400 MHz, DMSCW6): δ 10.25 (s, IH), 9.81 (s, IH), 7.73-7.69 (m, 2H), 7.41-7.37 (m, 2H), 7.03 (s, IH), 6.61 (s, IH), 2.94-2.89 (m,
Figure imgf000045_0002
IH), 2.41-2.33 (m, 2H), 2.20-2.03 (m, 4H), 1.00- 0.98 (d, 6H); LC-MS: 389.3 [M+H]+.
Ή- MR (400MHz DMSC to): δ 10.30 (s, IH), 10.19 (s, IH), 7.80-7.74 (m, IH), 7.58-7.53 (m, IH), 7.24-7.21 (m, IH), 7.06 (s, IH), 6.68 (s, IH), 2.95-2.88 (m, IH), 2.39-2.33 (m, 2H), 2.18-
Figure imgf000045_0003
2.04 (m, 4H), 1.30-1.24 (m, 2H), 1.01 (d, 6H), 0.88-0.84 (m, 2H); LC-MS: 406.7 [M+H]+.
1 H-NMR (400 MHz, DMSO-d6): δ 10.30 (s, IH), 9.37 (s, IH), 7.23 (s, IH), 6.94 (s, IH), ½ 3.02-2.98 (m, IH), 2.88-2.82 (m, IH), 2.44-2.40
(m, 3H), 2.39-2.20 (m, 4 2.19-2.02 (m, 2 H 0O H), H),
1.77-1.74 (m, 2H), 1.59-1.40 (m, IH), 1.43-1.34 (m, 2H), 1.24-1.17 (m, 2H), 1.11 (d, J=6.8 Hz, 6H); LC-MS: m/z 377.2 [M+H]+.
'H-NMR (400 MHz, DMSO-i/6): δ 10.25 (s,
H 1 * F IH), 10.22 (s, IH), 7.83-7.77 (m, IH), 7.56-7.51
(m, IH), 7.24-7.20 (m, IH), 7.03 (s, IH), 6.68 (s, IH), 2.40-2.33 (m, 2H), 2.22-2.09 (m, 4H), 2.06 (s, 3H); ES-MS: m z 379.1 [M+H]+.
'H-NMR (400 MHz, DMSO-i/6): δ 10.24 (s, IH), 9.47 (s, IH), 7.22 (s, IH), 6.80 (d, J=1.0 Hz, IH), 3.07-3.06 (m, 4H), 2.44-2.40 (m, 2H), 2.21-2.16 (m, 4H), 2.14 (s, 3H), 1.41-1.30 (m, 6H); ES-MS: m/z 348.5 [M-H]\ Ή-NMR (400MHz DMSO-i/6): 5 10.25 (s, 1H),
9.55 (s, 1H), 7.67-7.65 (m, 1H), 7.55-7.51 (m, 1H), 7.17 (d, 1H), 7.05 (s, 1H), 7.00-6.96 (m, 1H), 6.71 (s, 1H), 3.91 (s, 3H), 2.33-2.17 (m, 2H), 2.17-2.15 (m, 1H), 2.09-2.05 (m, 3H), 1.68- 1.65 (m, 3H), 1.56-1.53 (d, 2H), 1.35-1.23 (m, 3H), 1.21-1.06 (m, 3H); LC-MS: 441.2 [M+H]+.
Example-II; 2.4-difluoro-N-(2'-oxo-7'-( lH-pyrazol-4-yl)spirofcvclobutane- 1 ,3'- indolinl-5'-yl)benzenesulfonamide (Compound-72)
Figure imgf000046_0001
Step-i: N-r7'-bromo-2'-oxospiro[cvclobutane-l,3'-indolinl-5'-yl)-2,4-difluoro- benzenesulfonamide :
The process of this step was adopted from Example-I. The title compound was obtained as a white solid (50.0 g, 63%). 1H-NMR (400 MHz, DMSO-i/6): δ 9.47 (s, 1H), 7.13-7.09 (m, 2H), 6.70-6.63 (m, 3H), 3.12-3.08 (m,lH), 2.20-2.06 (m, 4H), 1.96-1.77 (m, 2H ); LC-MS: 191.2 [M+H]+.
Step-ii: 2.4-difluoro-N-(2'-oxo-7'-( lH-pyrazol-4-yl)spirofcyclobutane- 1 ,3'- indolinl-S'-vDbenzenesulfonamide:
To a stirred solution of compound-73a (0.2 g, 0.45 mmol) in 1,4-dioxane (10 mL) and H20 (2 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxa- borolan-2-yl)-lH-pyrazole-l-carboxylate (0.27 g, 0.9 mmol), potassium phosphate (0.29 g, 1.35 mmol) and the mixture was degassed with nitrogen purging for 20 min. Then pd(amphos)Cl2 (0.032 g, 0.045 mmol) was added and the mixture was heated at 100°C to 120°C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (100 mL), washed with water (100 mL), brine (100 mL) and dried over sodium sulphate. The product was concentrated under reduced pressure and purified by column chromatography to afford the title compound as off-white solid (0.01 g, 5%). 1H-NMR (400 MHz, DMSO-<¾): δ 13.05 (bs, IH), 10.33 (s, IH), 9.95 (s, IH), 8.03-8.00 (m, IH), 7.88-7.82 (m, IH), 7.61 (bs, IH), 7.58-7.53 (m, IH), 7.22-7.19(m, IH), 7.10 (d, J=2.0 Hz, IH), 6.97(d, J=2.0 Hz, IH), 2.44-2.33 (m, 2H), 2.23-2.05 (m, 4H); LC-MS: m/z 431.2 [M+H]+.
The below compounds were prepared by procedure similar to the one described in Example-Π with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.
No Structure Characterization data
'H-NMR (400 MHz, DMSO-<¾): δ 10.43 (s, IH), 10.19 (s, IH), 7.70-7.67 (m, IH), 7.48- 7.46 (m, IH), 7.27-7.23 (m, 2H), 7.20-7.16(m,
73 2H), 7.11 (d, J=1.9 Hz, IH), 7.04 (d, J=7.4 Hz,
2H), 6.57 (d, J=1.5 Hz, IH), 3.77 (s, 2H), 2.40- 2.36 (m, 2H), 2.19-2.11 (m, 4H); LC-MS: m z 455.1 (M+H)+.
'H-NMR (400 MHz, DMSO-i 6): δ 10.39 (s, IH), 10.16 (s, IH), 7.72-7.65 (m, IH), 7.50- 7.44 (m, IH), 7.19-7.15 (m, IH), 7.10 (s, IH),
74 7.05 (d, J=7.8 Hz, 2H), 6.92 (d, J=7.8 Hz, 2H),
H ° 6.54 (d, J=0.9 Hz, IH), 3.72 (s, 2H), 2.42-2.33
(m, 2H), 2.26 (s, 3H), 2.30-1.99 (m, 4H); LC- MS: m/z 469.1 (M+H)+.
lH-NMR (400 MHz, DMSO-i/6): δ 10.39 (s, T IH), 10.18 (s, IH), 7.73-7.67 (m, IH), 7.52- 7.46 (m, IH), 7.21-7.16 (m, IH), 7.10 (d, J=2.0
75
Hz, IH), 6.96 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.3 H ° Hz, 2H), 6.55 (d, J=2.0 Hz, IH), 3.72 (s, 3H),
3.64 (s, 2H), 2.42-2.32 (m, 2H), 2.20-2.03 (m,
Figure imgf000048_0001
'H-NMR (400 MHz, DMSO-de): δ 10.33 (s,
IH), 9.53 (s, IH), 7.60 (dd, J=7.9 Hz & 1.5
Ηζ,ΙΗ), 7.56-7.52 (m, IH), 7.27-7.23 (m, 2Η),
7.20-7.16 (m, IH), 7.11-7.09 (m, 2Η), 7.03-7.01
81
(m, 2Η), 6.97 (t, J=7.8 Hz, IH), 6.62 (d, J=1.5 Hz, IH), 3.80 (s, 3H), 3.74 (s, 2Η), 2.40-2.33 (m, 2H), 2.18-2.15 (m, IH), 2.10-1.99 (m, 3H); LC-MS: m/z 449.1 [M+H]+.
Example-HI: 2-methoxy-N-(7'-f 1 -methyl- 1.2.3.6-tetrahvdropyridin-4-yl)-2'-oxo- spirorcvclobutane- 1.3'-indolin1-5'-yl)benzenesulfonamide (Compound-82)
Figure imgf000049_0001
Step-(i): 4-fluoro-N-(7'-(l-methyl-1.2.3.6-tetrahvdropyridin-4-yl')-2'- oxospirorcyclobutane-l,3'-indolin1-5'-yl)benzenesulfonamide:
The process of this step was adopted from Example-I. The desired compound obtained as a white solid (0.12 g, 37.5 %). LC-MS: 454.4 [M+H]+.
Step-(ii): Synthesis of 2-methoxy-N-(7'-(l-methylpiperidin-4-yl)-2'- oxospiroicyclobutane- 1.3'-indolin1-5'-yl)benzenesulfonamide:
A solution of compound-82a (0.12 g, 0.26 mmol) in ethanol (5 mL) was added 10% Pd-C (0.012 g) and stirred under hydrogen atmosphere using a bladder for 3 h. Pd-C was filtered through celite pad and filtrates were concentrated to afford the title compound as an off-white solid (0.02 g, 16.6 %). 1H-NMR (400 MHz, CD3OD): δ 7.72 (d, IH), 7.56 (t, IH), 7.17 (d, IH), 7.12 (s, IH), 6.99-6.93 (m, 2H), 4.02 (s, 3H), 3.64 (d, 2H), 3.10-3.04 (m, 2H), 2.93 (s, 3H), 2.81-2.78 (m, IH), 2.52- 2.50 (m, 2H), 2.27-2.15 (m, 4H), 1.98-1.94 (m, 2H), 1.85-1.82 (m, 2H); LC-MS: 455.8 [M+H]+. Example-rV: Synthesis of N-(7'-bromo-2'-oxospiroicvclobutane-l,3'-indolin1-5'-yl)- 2-(2-methoxyphenyl)propanamide (Compound-83)
Figure imgf000050_0001
To a stirred solution of intermediate-4 (0.050 g, 0.19 mmol) in DCM (5 mL) was added DIPEA (0.083 mL, 0.469 mmol), EDC.HC1 (0.043 g, 0.22 mmol), HOBt (0.027 g, 0.206 mmol) and 2-(2-methoxyphenyl)propanoic acid (0.033 g, 0.19 mmol) at 0-5°C. The reaction mass was stirred at RT for 16 h. The mixture was diluted with DCM (50 mL), washed with saturated sodium bicarbonate solution, brine solution and dried over Na2S04. The obtained crude product was purified by chromatography with silica gel using a mixture of 50 % ethylacetate/hexane as an eluent to get the desired compound as a white solid (0.020 g, 25 %). 1H-NMR (400 MHz, OMSO-d6) δ 10.40 (s, 1H), 9.95 (s, 1H), 7.76 (s, 1H), 7.66 (s, 1H), 7.22 (m, 2H), 6.95 (d, 1H), 6.89 (t, 1H), 4.05 (m, 1H), 3.77 (s, 3H), 2.39 (m, 2H), 2.14 (m, 4H), 1.31 (d, 3H); LC-MS: 429.0 [M+H]+.
The below compounds were prepared by procedure similar to the one described in Example-IV with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.
No Structure Characterization data
Ή-NMR (400 MHz, DMSCW6) δ 10.60 (s, 1H), 9.95 (s, 1H), 7.76 (s, 1H), 7.57 (s, 1H), 7.22 (m,
84 2H), 7.00 (d, 1H), 6.89 (t, 1H), 4.1 (m, 1H), 3.82 (s,
3H), 2.42 (m, 2H), 2.21 (m, 4H), 1.36 (d, 3H); LC- MS: 385.1 [M+H]+.
Ή-NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 10.00 (s, 1H), 7.83 (s, 1H), 7.40 (s, 4H), 7.29 (d,
85
1H), 6.70 (d, 1H), 3.81 (m, 1H), 2.41 (m, 2H), 2.21(m, 4H), 1.40 (d, 3H); LC-MS: 355.1 [M+H]\ Example- V: N-(7'-hvdroxy-2'-oxospirorcvclobutane- 1.3'-indolin1-5'-yl)-2-
Figure imgf000051_0001
Compound-8 Compound-86
To a stirred solution of quinolin-7-ol (0.017 g, 0.11 mmol) and
copper(I)iodide (0.011 g, 0.057 mmol) in DMSO (1.5 mL) were added compound-8 (0.25 g, 0.57 mmol), n-Bu4NOH.5H20 (Tetrabutylammonium hydroxide.5H20) and water (1 mL) over a period of 5 min and the mixture was stirred at 110°C for 12 h. After completion of the reaction, the reaction mixture was cooled to RT. n-Bu4NOH in methanol (1 mL) and copper (1) iodide (0.01 g) were added and the mixture was stirred at 130°C for 5 h. The reaction mixture was acidified with 0.5N HC1 and extracted with EtOAc (100 mL), washed with water (100 mL), brine (50 mL), dried over sodium sulphate and concentrated under reduced pressure. The resulted crude compound was purified by column chromatography to afford the title compound as a white solid (0.004 g, 2 %). 1H-NMR (400 MHz, OMSO-d6): 6 9.85 (s, IH), 9.50 (bs, IH), 7.67 (dd, J=1.5 Hz, 7.8 Hz, IH), 7.54 (t, J=6.8 Hz, IH), 7.17 (d, J=8.3 Hz, IH), 6.99 (t, J=7.3 Hz, IH), 6.71 (d, J=1.5 Hz, IH), 6.51 (d, J=1.5 Hz, IH), 3.93 (s, 3H), 2.44-2.33 (m, 2H), 2.20-1.02 (m, 4H); ES-MS: m/z 373.2 [M-H]\ The below compound was prepared by procedure similar to the one described in Example-V with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.
No Structure Characterization data
Ή-NMR (400MHz CD3OD): δ 7.85-7.80 (m, IH), 7.22 (t, IH), 7.09 (t, IH), 6.80 (s, IH), 6.60 (s,
87 IH), 2.55-2.47 (m, 2H), 2.29-2.18 (m, 4H). LC- MS: 379.0 [M+H]+. Example- VI: Synthesis of 2,4-difluoro-N-(7'-methoxy-2'-oxospiro[cyclobutane-l,3'- indolin]- '-yl)-N-methylbenzenesulfonamide (Compound-88)
Figure imgf000052_0001
Compund-87 Compound-88
To a stirred solution of compound-87 (0.05 g, 0.13 mmol) in acetonitrile (2 mL) was added potassium carbonate (0.06 g, 0.39 mmol) followed by methyl iodide (0.01 mL, 0.16 mmol) and the mixture was stirred at RT for 5 h. Reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL), brine (50 mL), dried over sodium sulphate, concentrated under reduced pressure and column purified to afford the title compound as an off-white solid (0.03 g, 56 %). Ή-NMR (400 MHz, DMSO-</<5): δ 10.38 (s, 1H), 7.67-7.59 (m, 2H), 7.28-7.23 (m, 1H), 6.88 (s, 1H), 6.68 (d, J=1.5 Hz, 1H), 3.70 (s, 3H), 3.26 (s, 3H), 2.36-2.32 (m, 2H), 2.15- 2.00 (m, 4H); LC-MS: m z 409.1 [M+H]+. Example-VII: 6-chloro-N-(2'-oxospirorcyclobutane- 1 ,3 ' -indolin1-5'-yl) pyridine-3- sulfonamide (Compound-89)
Figure imgf000052_0002
Step-(i): tert-butyl 5'-(6-chloropyridine-3-sulfonamido)-2'-oxospiroicvclo- butane-1. 3'-indoline1- -carboxylate (compound 89a):
The process of this step was adopted from step-(i) of compound- 1 (Example-
I). The obtained crude product (0.04 g, 49%) was used in next step without analytical data.
Step-(ii): 6-chloro-N-(2'-oxospirorcvclobutane-1.3'-indolinl-5'-yl)pyridine-3- sulfonamide (compound-89):
In a 50 mL round bottle flask filled with 2 mL of TFA and 20 mL of DCM, compound-89a (0.2 g, 0.431 mmol) was added at 0°C. The progress of the reaction was monitor by TLC. The reaction mixture after 1.5 h was extracted with ethyl acetate (40 mLx3). The extract was washed with saturated NaHC03 solution (20 mL), brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The obtained crude product was purified by chromatography with silica gel using a mixture of 50 % ethyl acetate/hexane as an eluent to get the desired compound as a white solid (0.035 g, 45 %). 1H-NMR (400 MHz, DMSO-c/6) δ 10.3 (s, IH), 10.20 (s, IH), 8.61 (d, IH), 8.01 (dd, IH), 7.74 (d, IH), 7.18 (d, IH), 6.82 (dd, IH), 6.68 (d, IH), 2.38 (m, 2H), 2.18-2.11 (m, 4H); LC-MS: 364 [M+H]+.
Example- VIII: 4-fluoro-N-(2'-oxo-7'-(piperidin-4-yl)spirorcvclobutane-1.3'- indolinl-5'-yl)benzenesulfonamide (Compound-90)
Figure imgf000053_0001
Step-(i): tert-butyl 4-(5'-((4-fluorophenyl)sulfonanudo)-2'-oxospirorcyclo- butane- 1 ,3'-indolin1-7'-yl)piperidine- 1 -carboxylate (90a)
Intermediate- 15 was coupled with 4-fluorobenzenesulfonyl chloride using the protocol explained in step-(i) of compound- 1 (Example-I). Yield: 0.07 g, 57 %. LC- MS: 528.1 [M-H]".
Step-iii): 4-fluoro-N-(2'-oxo-7'-(piperidin-4-yl)spirorcvclobutane- 1.3'- indolin1-5'-yl)benzenesulfonamide (compound-90)
The process of this step was adopted from step-(ii) of compound-89
(Example- VII). The desired compound was obtained as a white solid (0.036 g, 44 %). Ή-NMR (400 MHz, DMSO-ito): δ 10.25 (s, IH), 7.72-7.69 (m, 2H), 7.37-7.33 (m, 2H), 7.00 (s, IH), 6.59 (s, IH), 3.09 (s, IH), 2.96-2.93 (d, 2H), 2.67-2.55 (m, 2H), 2.40-2.34 (m, 2H), 2.30 (s, IH), 2.18-2.03 (m, 4H), 1.49-1.46 (d, 2H), 1.28-1.20 (m, 3H); LC-MS: 430.0 [M+H]+.
The below compounds were prepared by procedure similar to the one described in Example- Vin with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table. Com
Structure Characterization data
No
H
N 'H-NMR (400 MHz, DMSO-Λί): δ 10.41 (s, IH),
10.17 (s, IH), 7.79-7.73 (m, IH), 7.57-7.53 (t, IH), 7.24-7.20 (t, IH), 7.01 (s, IH), 6.30 (s, IH),
91
2.40-2.37 (m, 2H), 2.21-2.03 (m, 4H), 1.86-1.82 (m, IH), 0.88-0.86 (d, 2H), 0.38-0.37 (d, 2H); LC-MS: 440.05 [M+H] \
H 'H-NMR (400 MHz, DMSO-c¾): δ 10.18 (s, IH),
[ r*S1 F^ F F 7.87-7.85 (d, IH), 7.64-7.61 (t, IH), 7.44-7.40 (t,
2H), 6.99 (s, IH), 6.59 (s, IH), 3.03-3.00 (m,
92
o¾ «00 2H), 2.65-2.56 (m, 2H), 2.33-2.31 (m, 2H), 2.15- H ° 2.02 (m, 4H), 1.51-1.28 (m, 4H).
LC-MS: 496.1 [M+H]+.
Example-IX; N-(7'-cvclopropyl-2'-oxospirofcvclobutane- 1.3'-indolinl-5'-yl)-2- methoxy-N-methylbenzenesulfonamide (Compound-93)
Figure imgf000054_0001
To a stirred solution of intermediate-6 (0.5 g, 2.24 mmol) in methanol (10 mL) was added paraformaldehyde (0.1 g, 3.36 mmol) at 0°C and the mixture was stirred for 12 h by gradual warming to RT. The mixture was then cooled to 0°C, sodium cyanoborohydride (347 mg, 5.53 mmol) was added and the mixture was stirred for 4 h. The mixture was then concentrated. The obtained residue was treated with 2-methoxybenzene-l-sulfonyl chloride (0.462 g, 2.24 mmol) as described for compound- 1 (Example-I). Purification by preparative HPLC afforded the title compound (0.1 g, 11.1 ). 'H-NMR (400 MHz, DMSO-i/6) δ 10.43 (s, IH), 7.61 (m, IH), 7.51 (dd, IH), 7.26 (d, IH), 7.04 (d, IH), 6.98 (t, IH), 6.31 (d, IH), 3.89 (s, 3H), 3.34 (s, 3H), 2.32 (m, 2H), 2.18-199 (m, 4H), 1.84 (m, 1H), 0.84 (m, 2H), 0.36 (m, 2H); LC-MS: 413.1 [M+H]+.
The below compound was prepared by procedure similar to the one described in Example- C with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.
Figure imgf000055_0002
Example-X: 5'-((4-chlorophenyl)(hvdroxy')methyl)spirorcvclobutane- 1.3'-indolinl-2'- one (Compound-95)
Figure imgf000055_0001
Step-(i): 5'-(4-chlorobenzoyl)spirorcvclobutane- 1 ,3 ' -indolin1-2'-one
(compound 95a-):
A mixture of 2.2 g of Spiro[cyclobutane-l,3'-indolin]-2'-one, 3.21 g of 4- chloro benzoyl chloride and 13 g of aluminum chloride in 50 mL of carbon disulfide was refluxed to 50°C for 48 hours. The reaction mixture was poured into ice water and the resulting solid filtered off, washed with water and dried under reduced pressure (0.110 g, 30.5 ). LC-MS: 314.05 [M+H] +.
Step-(ii): 5'-((4-chlorophenyl)(hvdroxy methyl')spirorcvclobutane-1.3'- indolinl-2'-one:
A suspension of compound-95a (0.110 g, 0.353 mmol) in 120 mL of methanol was treated at 0°C with sodium borohydride (0.013 g, 0.353 mmol). The mixture was stirred at 25-35°C for 18 h until the suspended solid was dissolved. The solvent was removed under reduced pressure and the residue partitioned between 10% methanol in DCM and water. The extract was dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. (0.035 g, 31 %). 1H- NMR (300 MHz, DMSO-</6~) δ 10.2 (d, 1H), 7.6 (s, 1H), 7.4 (m, 4H), 7.1 (d, 2H), 6.6 (d, 1H), 5.9 (s, 1H), 5.8 (d, 1H), 2.4 (m, 2H), 2.3 (s, 4H); LC-MS: 314 [M+H] +.
Biological Data
In-Vitro Biochemical Data of spiro[cyclobutane-l,3'-indolin]-2'-one derivatives in time-resolved fluorescence resonance energy transfer (TR-FRET) assay.
The Bet bromodomain TR-FRET assay has been used to identify compounds that bind to bet bromodomain and prevent its interaction with acetylated histone peptides.
In the assay, optimized concentration of in-house Bet bromodomain protein and 300nM of acetyl histone peptide substrate were diluted in assay buffer (50 mM HEPES, pH: 7.5, 50 mM NaCl, 500 μΜ 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 20mM DMSO were prepared. Compounds were serially diluted and added to the test wells in 384-well
polypropylene plates. The reaction mixture was further incubated for 30 min at RT on a plate shaker. 2 nM of Europium labeled streptavidin and ΙΟηΜ of XL-665 labeled antibody diluted in detection buffer (50 mM HEPES, pH: 7.5, 50 mM NaCl, 500 μΜ 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 IC50 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 (IC50) are summarized in the table below. The IC50 values of the compounds are set forth in below Table wherein "A" refers to an IC50 value of less than 150 nM, "B" refers to IC50 value in range of 150.01 to 250 nM and "C" refers to IC50 value of greater than 250 nM.
Group Compound No
4, 8, 10, 13, 15, 17, 18, 21, 24, 26, 32, 34, 40, 45, 46, 52, 54, 56, 62,
A
69, 70, 81, 91.
2, 3, 23, 25, 27, 29, 30, 33, 36, 39, 42, 47, 48, 55, 57, 58, 71, 72, 78,
B
82, 88.
5, 9, 11, 12, 14, 16, 19, 20, 22, 31, 35, 37, 43, 44, 49, 50, 53, 64, 66,
C
67.

Claims

Claims
1. A compound of formula (I)
Figure imgf000058_0001
wherein
Cy is selected from 4-12 membered monocyclic or bicyclic ring containing 0-4 hetero atoms independently selected form N, O or S;
L is a linker selected from -N(R3a)S(0)2-, -S(0)2N(R3b)-,
-N(R3c)C(0)CH(R3d)- or -C(R3e)(OR3f)-;
Ri and each R2 are, independently, selected from hydrogen, halogen, alkoxy, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heterocyclyl; wherein the optional substituent at each occurrence is independently selected from one or more R4 groups;
R3a, R3b, R3c, R3d, 3e and R3f are selected, independently, from hydrogen or alkyl;
R4 is selected from alkyl, alkoxy, halogen, cycloalkyl, aryl or heterocyclyl;
'm' is selected from 1, 2 or 3;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein the compound of formula (I) is represented by formula (IA):
Figure imgf000058_0002
wherein Rj, R2, Cy and m are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1, wherein the compound of formula (I) represented by formula (IB):
Figure imgf000059_0001
wherein R^ R2, Cy and m are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1, wherein the compound of formula (I) represented by formula (IC):
Figure imgf000059_0002
wherein R1; R2, R3<1, Cy and m are as defined in claim 1, or a
pharmaceutically acceptable salt thereof.
5. The compound according to claim 1, wherein the compound of formula (I) is represented by formula (ID):
Figure imgf000059_0003
wherein Ri, R2, R3f, Cy and m are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
6. A compound according to any of claims 1-5, wherein Ri is hydrogen, halogen, d-e alkoxy, hydroxy, Ci-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl Ci-6 alkyl, optionally substituted arylalkyl, or an optionally substituted heteroaryl; wherein the optional substituent is independently selected from an Ci-6 alkyl.
7. A compound according to claim 6, wherein Ri is hydrogen, halogen, Ci-6 alkyl, C3-7 cycloalkyl, aryl Ci-6 alkyl or heteroaryl optionally substituted by methyl.
8. A compound according to any of claims 1-7, wherein L is a linker selected from -NHS(0)2-, -S(0)2NH-, -NHC(0)CH(CH3)- or -CH(OH)-.
9. A compound according to any of claims 1-8, wherein Cy is 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.
10. A compound according to claim 9, wherein Cy is a 5-6 membered monocyclic ring containing 0-3 heteroatoms independently selected from the group consisting of N, O and S.
11. A compound according to claim 9, wherein Cy is a 9- 10 membered bicyclic ring containing 1-3 heteroatoms independently selected from the group consisting of N and O.
12. A compound according to any of claims 1-1 1, wherein R2 is selected from hydrogen, halogen, alkyl, alkoxy, haloalkoxy or heteroaryl; and m is 1, 2 or 3.
13. A compound according to any of claims 1-12, wherein ring Cy is one of the following groups or tautomers thereof
Figure imgf000061_0001
wherein each of the above rings are substituted by (R2)m as defined above.
14. A compound according to any of claims 1-13, wherein Cy-(R2)m is one of the following groups or tautomers thereof
(15k') (16') (17') (18·) K (19)') 'c (20')-
Figure imgf000062_0001
(31·)
15. A compound according to any of claims 1-14, wherein Rj is hydrogen, halogen, alkyl, cycloalkyl or benzyl, L is -NHS(0)2-, ring Cy is group (1), (2), (5), (6), (7), (8), (9), (12), (13) or (16), R2 is hydrogen, halogen, alkyl or alkoxy, and m is 1 or 2.
16. A compound according to claim 1 selected from the group consisting of
No. Compound name
1. 2,5-dimethyl-N-(2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)thiophene-3- sulfonamide
2. N-(2'-oxospirotcyclobutane-l,3'-indolin]-5'-yl)-2,3-dihydrobenzo[b][l,4]- dioxine-6-sulfonamide
3. 2-methoxy-N-(2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'- yl)benzenesulfonamide
4. N-(2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)quinoline-8-sulfonamide
5. N-(2'-oxospiro[cyclobutane- 1 ,3'-indolin] -5'-yl)- 1 ,2,3 ,4- tetrahydroisoquinoline-7-sulfonamide
6. N-(2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-[ 1 ,2,4]triazolo[4,3- a]pyridine-6-sulfonamide
7. N-(2-methoxyphenyl)-2'-oxospiro[cyclobutane- 1 ,3'-indoline]-5'- sulfonamide
8. N-(7'-bromo-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-2- methoxybenzenesulfonamide
9. N-(7'-bromo-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-6-chloropyridine- 3 -sulfonamide
10. N-(7'-bromo-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2,3-dihydro- benzo [b] [ 1 ,4]dioxine-6-sulfonamide
11. N-(7'-bromo-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-3-( IH-pyrazol- 1 - yl)benzenesulfonamide
12. N-(2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-3-( IH-pyrazol- 1 - yl)benzenesulfonamide
13. N-(7'-chloro-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-2- methoxybenzenesulfonamide
14. N-(7'-chloro-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-3-( 1 H-pyrazol- 1 - yl)benzenesulfonamide
15. N-(7'-chloro-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)piperidine- 1 - sulfonamide
16. N-(7'-chloro-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)- 1 -methyl- 1H- pyrazole-4-sulfonamide
17. N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2,5- difluorobenzenesulfonamide
18. N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-4-fluorobenzene- sulfonamide
19. N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-6-methylpyridine- 3-sulfonamide
20. N-(7'-chloro-2,-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-6-fluoropyridine- 3-sulfonamide
21. N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)cyclohexane- sulfonamide
22. N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-3,5-difluoro-2- methoxybenzenesulfonamide
23. N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-3-fluoro-2- methoxybenzenesulfonamide
24. N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-isopropoxy- benzenesulfonamide
25. N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-l-methyl-lH- indazole-4-sulfonamide
26. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2,4- difluorobenzenesulfonamide
27. 6-methyl-N-(2'-oxo-7'-propylspiro[cyclobutane-l,3'-indolin]-5'-yl)pyridine- 3-sulfonamide
28. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-4-fluoro- benzenesulfonamide
29. 6-fluoro-N-(2'-oxo-7'-propylspiro[cyclobutane-l,3'-indolin]-5'-yl)pyridine- 3-sulfonamide
30. 6-chloro-N-(2'-oxo-7'-propylspiro[cyclobutane-l,3'-indolin]-5'-yl)pyridine- 3-sulfonamide
31. 1 -methyl-N-(2'-oxo-7'-propylspiro[cyclobutane- 1 ,3 '-indolin]-5'-yl)- 1 H- pyrazole-4-sulfonamide
32. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-iso- propoxybenzenesulfonamide
33. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-3-(lH- pyrazol- 1 -yl)benzenesulfonamide
34. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3,-indolin]-5'-yl)-2- methoxybenzenesulfonamide
35. N-(2'-oxo-7'-propylspiro[cyclobutane-l,3'-indolin]-5'-yl)pyridine-3- sulfonamide
36. 2,4-difluoro-N-(7'-(l-methyl-lH-pyrazol-4-yl)-2'-oxospiro[cyclobutane- l,3'-indolin]-5'-yl)benzenesulfonamide
37. 2,4-difluoro-N-(2'-oxo-7'-(pyrimidin-5-yl)spiro[cyclobutane-l,3'-indolin]- 5'-yl)benzenesulfonamide
38. 2,4-difluoro-N-(2'-oxo-7'-(pyridin-3-yi)spiro[cyclobutane-l,3'-indolin]-5'- yl)benzenesulfonamide
39. N-(7'-( 1 -methyl- 1 H-pyrazol-4-yl)-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'- yl)cyclohexanesulfonamide
40. 4-fluoro-N-(7'-( 1-methyl- lH-pyrazol-4-yl)-2'-oxospiro[cyclobutane- 1 ,3'- indolin] -5 '-yl)benzenesulfonamide
41. N-(7'-( 1 -methyl- 1 H-pyrazol-4-yl)-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'- yl)-3-( 1 H-pyrazol- 1 -yl)benzenesulfonamide
42. 2-isopropoxy-N-(7'-( 1 -methyl- 1 H-pyrazol-4-yl)-2'-oxospiro[cyclobutane- l,3'-indolin]-5'-yl)benzenesulfonamide
43. N-(7'-( 1 -methyl- lH-pyrazol-4-yl)-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'- yl)morpholine-4-sulfonamide
44. N-(2'-oxo-7'-(pyrimidin-5-yl)spiro[cyclobutane-l,3'-indolin]-5'- yl)piperidine- 1 -sulfonamide
45. N-(7'-( 1 -methyl- 1 H-pyrazol-4-yl)-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'- yl)piperidine- 1 -sulfonamide
46. N-(7'-benzyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-isopropoxy- benzenesulfonamide
47. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3,-indolin]-5,-yl)-3-(lH- imidazol- 1 -yl)benzenesulfonamide
48. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)piperidine-l- sulfonamide
49. N-(7'-( lH-imidazol- 1 -yl)-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)-4- fluorobenzenesulfonamide
50. 4-fluoro-N-(2'-oxo-7'-(lH-pyrazol-l-yl)spiro[cyclobutane-l,3'-indolin]-5'- yl)benzenesulfonamide
51. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)- 1 -methyl- 1 H-indazole-4-sulfonamide
52. N-(2' -oxospiro [cyclobutane- 1 ,3 '-indolin] -5'-yl)cyclohexanesulfonamide
53. N-(2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)piperidine-l-sulfonamide
54. 2-methoxy-N-(7'-methyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)- benzenesulfonamide
55. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)morpholine- 4-sulfonamide
56. 6-chloro-N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)- pyridine-3-sulfonamide
57. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)pyridine-2- sulfonamide
58. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-5-fluoro- pyridine-2-sulfonamide
59. -(7'-chloro-2,-oxospiΓo[cyclobutane-l,3'-indolin]-5'-yl)moφholine-4- sulfonamide
60. N-(7 '-cyclopropyl-2'-oxospiro [cyclobutane- 1 ,3 '-indolin] -5 '-yl)-4-methyl- piperazine- 1 -sulfonamide
61. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane- 1 ,3'-indolin]-5'-yl)- 1 -isopropyl- 1 H-pyrazole-4-sulfonamide
62. N-(7'-ethyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2- (trifluoromethoxy)benzenesulfonamide
63. N-(7'-ethyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-methoxybenzene- sulfonamide
64. N-(7'-ethyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2,4- difluorobenzenesulfonamide
65. N-(7'-isopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-methoxy- benzenesulfonamide
66. 4-fluoro-N-(7'-isopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)- benzenesulfonamide
67. 2,4-difluoro-N-(7'-isopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)- benzenesulfonamide
68. N-(7'-isopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)cyclohexane- sulfonamide
69. 2,4-difluoro-N-(7'-methyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)- benzenesulfonamide
70. N-(7'-methyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)piperidine-l- sulfonamide
71. N-(7'-cyclohexyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-methoxy- benzenesulfonamide
72. 2,4-difIuoro-N-(2'-oxo-7'-( lH-pyrazol-4-yl)spiro [cyclobutane- 1 ,3'-indolin]- 5'-yl)benzenesulfonamide
73. N-(7'-benzyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2,4-difluoro- benzenesulfonamide
74. 2,4-difluoro-N-(7'-(4-methylbenzyl)-2'-oxospiro[cyclobutane-l,3'-indolin]- 5 '-yl)benzenesulfonamide
75. 2,4-difluoro-N-(7'-(4-methoxybenzyl)-2'-oxospiro[cyclobutane-l,3'- indolin]-5'-yl)benzenesulfonamide
76. N-(7'-benzyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-4-fluorobenzene- sulfonamide
77. N-(7'-benzyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-fluorobenzene- sulfonamide
78. 2 ,4-difluoro-N-(7'-(4-fluorobenzyl)-2'-oxospiro [cyclobutane- 1 ,3 '-indolin] - 5'-yl)benzenesulfonamide
79. N-(7'-(4-chlorobenzyl)-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2,4- difluorobenzenesulfonamide
80. 2,4-difluoro-N-(2'-oxo-7'-phenethylspiro[cyclobutane-l,3'-indolin]-5'- yl)benzenesulfonamide
81. N-(7'-benzyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2- methoxybenzenesulfonamide
82. 2-methoxy-N-(7'-( 1 -methylpiperidin-4-yl)-2'-oxospiro [cyclobutane- 1,3'- indolin]-5'-yl)benzenesulfonamide
83. N-(7'-bromo-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-(2-methoxy- phenyl)propanamide
84. N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-(2-methoxy- phenyl)propanamide
85. 2-(4-chlorophenyl)-N-(2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)- propanamide
86. N-(7'-hydroxy-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-methoxy- benzenesulfonamide
87. 2,4-difluoro-N-(7'-hydroxy-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)- benzenesulfonamide
88. 2,4-difluoro-N-(7'-methoxy-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-N- methylbenzenesulfonamide
89. 6-chloro-N-(2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)pyridine-3- sulfonamide
90. 4-fluoro-N-(2'-oxo-7'-(piperidin-4-yl)spiro[cyclobutane-l,3'-indolin]-5'- yl)benzenesulfonamide
91. 2-methoxy-N-(2'-oxo-7'-(piperidin-4-yl)spiro[cyclobutane-l,3'-indolin]-5'- yl)benzenesulfonamide
92. N-(2'-oxo-7'-(piperidin-4-yl)spiro[cyclobutane-l,3'-indolin]-5'-yl)-2- (trifluoromethoxy)benzenesulfonamide
93. N-(7'-cyclopropyl-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-2-methoxy- N-methylbenzenesulfonamide
94. N-(7'-chloro-2'-oxospiro[cyclobutane-l,3'-indolin]-5'-yl)-4-fluoro-N- methylbenzenesulfonamide
95. 5'-((4-chlorophenyl)(hydroxy)methyl)spiro[cyclobutane-l,3'-indolin]-2'-one or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound of claim 1 together with a pharmaceutically acceptable carrier.
18. A method for the treatment or prevention of diseases or disorders where bromodomain inhibition is desired comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1.
19. A method according to claim 18, wherein the disease or disorder is an autoimmune disease, an inflammatory disease or cancer.
20. Use of a compound of formula (I) in the manufacture of a medicament for the treatment or prevention of diseases or disorders where bromodomain inhibition is desired.
21. Use according to claim 20, where the disease or disorder is an
autoimmune disease, inflammatory disease or cancer.
PCT/FI2014/000040 2013-12-17 2014-12-16 Spiro[cyclobutane-1,3'-indolin]-2'-one derivatives as bromodomain inhibitors WO2015092118A1 (en)

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