WO2014125408A2 - Dérivés de 1h-pyrrolopyridinone substitués en tant qu'inhibiteurs de kinase - Google Patents

Dérivés de 1h-pyrrolopyridinone substitués en tant qu'inhibiteurs de kinase Download PDF

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WO2014125408A2
WO2014125408A2 PCT/IB2014/058881 IB2014058881W WO2014125408A2 WO 2014125408 A2 WO2014125408 A2 WO 2014125408A2 IB 2014058881 W IB2014058881 W IB 2014058881W WO 2014125408 A2 WO2014125408 A2 WO 2014125408A2
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methyl
phenyl
oxo
pyrrolo
benzamide
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WO2014125408A3 (fr
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Anima BORUAH
Srikanth CHITTY VENKATA
Subramanya Hosahalli
Sunil Kumar Panigrahi
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Aurigene Oncology Ltd
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Aurigene Discovery Technologies Ltd
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to compounds useful for the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder associated where there is an advantage in inhibiting kinase enzyme activity, and more particularly Bruton's tyrosine kinase (Btk).
  • Btk Bruton's tyrosine kinase
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of diseases or disorder associated with Btk.
  • Protein Kinase enzymes are known to be the key regulators of cell activities that constitute one of the largest and most functionally diverse gene families. Protein kinases participate in the signalling events that control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these protein kinases fall into several groups; those which preferentially phosphorylate serine and/or threonine residues and those which preferentially phosphorylate tyrosine residues.
  • diseases and/or disorders are associated with aberrant, abnormal or deregulated activity of one or more kinases.
  • diseases and/or disorders include, but are not limited to cancers, allergic diseases and/or disorders, autoimmune diseases and/or disorders, inflammatory diseases and/or disorder and/or conditions associated with inflammation and pain, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrosis diseases and/or disorders, metabolic disorders, muscle diseases and/or disorders respiratory diseases and/or disorders, pulmonary disorders, genetic developmental diseases, neurological and neurodegenerative diseases/or disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or heart diseases and/or disorders, ophthalmic/ocular diseases and/or disorders, wound repair, infection and viral diseases.
  • Bruton's Tyrosine Kinase (Btk) is a member of the Tec family of tyrosine kinases, and is a critical regulator of early B-Cell development as well as mature B-cell activation, signaling and survival (Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288).
  • Btk also plays role in a number of other hematopoietic cell signalling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediated TNF-a production in macrophages, IgE receptor signalling in Mast cells, inhibition of Fas/APO-1 apoptotic signalling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation (C. A. Jeffries, etal., (2003), Journal of Biological Chemistry 278:26258-26264; N. J. Horwood, et al., (2003), The Journal of Experimental Medicine 197 : 16031611 ) .
  • TLR Toll like receptor
  • cytokine receptor-mediated TNF-a production in macrophages IgE receptor signalling in Mast cells
  • Fas/APO-1 apoptotic signalling in B-lineage lymphoid cells
  • collagen-stimulated platelet aggregation C. A. Jeffries, etal
  • B-cell signaling through the B-cell receptor leads to a wide range of biological outputs, which in turn depend on the developmental stage of the B-cell.
  • Btk is recruited to the cell membrane and phosphorylated in the activation loop by src family kinases.
  • Btk auto-phosphorylation stabilizes the active confirmation and fully activates Btk kinase activity.
  • Activated Btk phosphorylates phospho lipase (PLCy), initiating calcium mobilization and generating diacylglycerol (DAG) as secondary signals, eventually leading to transcriptional activation and amplification of BCR stimulation (Satterthwaite AB, Witte ON (2000), Immunol. Rev.
  • Btk Aberrant BCR mediated signalling can cause deregulated B-cell proliferation and/or formation of pathogenic antibodies leading to multiple autoimmune and/or inflammatory diseases.
  • inhibitors of Btk may be useful as inhibitors of B-cell mediated pathogenic activity.
  • Btk-deficient mice e.g. in standard murine preclinical models of Systemic Lupus Erythematosus(SLE), Btk deficiency has been shown to result in a marked reduction of disease progression (Minoru Satoh et al (2003) Int. Immunol. 15 (9): 1117-1124.
  • Btk deficient mice are also resistant to developing collagen- induced arthritis and are less susceptible to Staphylococcus- induced arthritis (Svensson et al (1998) Clin Exp Immunol. March; 111(3): 521-526.
  • Btk activity appears to be useful for the treatment of autoimmune and/or inflammatory diseases such as SLE, rheumatoid arthritis, multiple vasculitides, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, and asthma.
  • ITP idiopathic thrombocytopenic purpura
  • Btk has been reported to play a role in apoptosis, thus inhibition of Btk activity is useful for the treatment of B-cell lymphoma and leukaemia. They may also be useful as part of other therapeutic regimens for the treatment of disorders, alone or in combination with protein kinase compounds well known by the one skilled in the art.
  • novel substituted lH-Pyrrolopyridinone derivatives according to the present invention may possess inhibitory activity of one or more protein kinases including Btk and are, therefore, expected to be useful in the treatment of kinase-associated diseases or disorders.
  • the present invention relates to substituted lH-Pyrrolopyridinone derivatives of formula ( 1 ) which are useful as kinase inhibitors.
  • the resent invention relates to the compound of formula (1)
  • Ri is selected from hydrogen, alkyl, -C(0)OR a and -C(0)N(R b )R c ;
  • R 2 is selected from alkyl, cyanoalkyl, cycloalkylalkyl and aryl;
  • R 3 and R5 are selected from hydrogen and alkyl
  • R 4 is selected from hydrogen, halogen, alkyl, hydroxyalkyl, alkoxy and -CH 2 OC(0)alkyl;
  • R 6 is selected from hydrogen, halogen, alkyl, -N(R b )R c , haloalkyl, haloalkyloxy, cyanoalkyl and optionally substituted cycloalkyl; wherein the optional substituents are selected from alkyl and haloalkyl;
  • R a is selected from hydrogen and alkyl
  • R b and R c are independently selected from hydrogen and alkyl; alternatively, 3 ⁇ 4 and R c can be taken together with the nitrogen atom to which they are attached to form 3 to 6 membered cyclic ring having 0 to 3 heteroatoms independently selected from N, O and S ; and
  • 'p' is an integer selected from 1, 2, and 3.
  • the present invention relates to the pharmaceutical composition
  • the pharmaceutical composition comprising substituted lH-Pyrrolopyridinone derivatives of formula (1) and process for preparing them.
  • Embodiments of the present invention provide substituted lH-Pyrrolopyridinone derivatives of formula ( 1) which are useful as kinase inhibitors.
  • One of the embodiment of the present invention provide the compound of formula ( 1)
  • Ri is selected from hydrogen, alkyl, -C(0)OR a and -C(0)N(R b )R c ;
  • R 2 is selected from alkyl, cyanoalkyl, cycloalkylalkyl and aryl;
  • R 3 and R5 are selected from hydrogen and alkyl
  • R4 is selected from hydrogen, halogen, alkyl, hydroxyalkyl, alkoxy and -CH 2 0C(0)alkyl
  • R 6 is selected from hydrogen, halogen, alkyl, -N(Rb)R c , haloalkyl, haloalkyloxy, cyanoalkyl and optionally substituted cycloalkyl; wherein the optional substituents are selected from alkyl and haloalkyl;
  • R a is selected from hydrogen and alkyl
  • R b and R c are independently selected from hydrogen and alkyl
  • R and R c can be taken together with the nitrogen atom to which they are attached to form 3 to 6 membered cyclic ring having 0 to 3 heteroatoms independently selected from N, O and S ;
  • 'p' is an integer selected from 1, 2, and 3.
  • Ri is selected from hydrogen, alkyl, -C(0)OR a and -C(0)N(Rb)R c ; in particular alkyl is methyl.
  • R 2 is selected from alkyl, cyanoalkyl, cycloalkylalkyl and aryl; in particular alkyl is methyl, ethyl and isopropyl; cyanoalkyl is propionitrile; cycloalkylalkyl is cyclopropylmethyl; and aryl is phenyl.
  • R4 is halogen, alkyl, hydro xyalkyl, alkoxy and -CH 2 OC(0)alkyl; in particular halogen is fluoro; alkyl is methyl; alkoxy is methoxy; and hydroxy alkyl is hydroxymethyl.
  • R 6 is selected from halogen, alkyl, -N(Rb)R c , haloalkyl, cyanoalkyl and optionally substituted cycloalkyl.
  • halogen is fluoro
  • alkyl is methyl, isopropyl and tert-butyl
  • haloalkyl is l , l , l-trifluoropropan-2-yl and trifluoromethane
  • cyanoalkyl is 2-cyanopropane
  • - N(Rb)R c wherein R and R c are alkyl, in particular alkyl is methyl.
  • the compound of formula ( 1) is a com ound of formula ( la)
  • R 1 ; R 2 , R4 and R 6 are same as defined in formula ( 1).
  • the compound of formula ( l a) is a compound of formula ( lb)
  • R 1 ; R 2 and R4 are same as defined in formula ( 1). According to preceding embodiment, specifically provided are compounds formula
  • Rj is hydrogen, -C(0)OH, -C(0)OCH 2 CH 3 , -C(0)N(CH 3 ) 2 and .
  • R 2 is methyl and ethyl.
  • R4 is methyl, hydroxymethyl and methoxy.
  • the compound of formula (1) is selected from the group consisting of
  • the definition of "compounds of formula (1)" inherently includes all stereoisomers of the compound of formula (1) either as pure stereoisomer or as a mixture of two or more stereoisomers.
  • stereoisomers include enantiomers, diasteroisomers, racemates, cis-isomers, trans-isomers and mixture thereof.
  • the absolute configuration at an asymmetric atom is specified by either R or S.
  • Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1% of the other isomers.
  • the compounds and pharmaceutically compositions of the present invention are used in the treatment and/or prevention of diseases and/or disorders in which aberrant, abnormal or deregulated activity of Bruton's tyrosine kinase (Btk) contribute to the pathology and/or symptomology of diseases and/or disorders associated with Btk.
  • Btk Bruton's tyrosine kinase
  • the compounds of formula (1) are useful as medicament in treatment of diseases and/or disorders associated with Btk, which includes but are not limited to cancer, autoimmune and inflammatory disorders such as multiple sclerosis and rheumatoid arthritis.
  • Diseases and/or disorders associated with aberrant, abnormal or deregulated activity of Btk include, but are not limited to allergic disorders and/or autoimmune and/or inflammatory diseases and/or conditions associated with inflammation and pain, cancers, proliferative diseases, hematopoietic disorders, hematological malignancies, bone disorders, fibrosis diseases and/or disorders, metabolic disorders, muscle diseases and/or disorders respiratory diseases and/or disorders, pulmonary disorders, genetic developmental diseases, neurological and neurodegenerative diseases/or disorders, chronic inflammatory demyelinating neuropathies, cardiovascular, vascular or heart diseases and/or disorders, ophthalmic/ocular diseases and/or disorders, wound repair, infection and viral diseases.
  • the compounds according to the present invention possess potential of providing cancer cell growth inhibiting effects and are effective in treating cancers, autoimmune and inflammatory diseases; in particular cancer includes all types of solid cancers and malignant lymphomas but not limited to leukaemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumour & etc; and particularly the compounds according to the present invention are used in the treatment of autoimmune and/or inflammatory diseases and/or conditions associated with inflammation and pain include, but are not limited to acid reflux, heart burn, acne, allergies and allergen sensitivities, bronchitis, carditis, celiac disease, chronic pain, cirrhosis, colitis, dementia, dermatitis, diabetes, dry eyes, edema, emphysema, eczema, fibromyalgia, gastroenteritis, gingivitis, heart disease, hepatitis, high blood pressure,
  • Alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms; in particular alkyl is Q-Qo alkyl group which may have 1 to 10 (inclusive) carbon atoms in it; in more particular alkyl is Ci-C 6 alkyl group which may have 1 to 6 (inclusive) carbon atoms in it and in more preferred particular alkyl is C ⁇ - C 4 alkyl group which may have 1 to 4 (inclusive) carbon atoms in it.
  • 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.
  • Alkoxy refers to the group alkyl-0- or -O-alkyl, where alkyl group is as defined above.
  • Exemplary Ci-Cioalkyl group containing alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, zso-propoxy, n-butoxy and i-butoxy.
  • An alkoxy group can be unsubstituted or substituted with one or more suitable groups.
  • Halogen or “halo” includes fluorine, chlorine, bromine or iodine.
  • Haloalkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with - F, -CI, -Br or -I.
  • Representative examples of an haloalkyl group include, but are not limited to -CH 2 F, -CC1 3 , -CF 3 , -CH 2 C1, -CH 2 CH 2 Br, - CH(CF 3 )CH 3 , -CH 2 CH 2 I, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 C1, -CH 2 CH 2 CH 2 CH 2 Br, - CH 2 CH 2 CH 2 CH 2 I, -CH 2 CH 2 CH 2 CH 2 CH 2 Br, -CH 2 CH 2 CH 2 CH 2 CH 2 I, -CH 2 CH(Br)CH 3 , - CH 2 CH(C1)CH 2 CH 3 , and -CH(F)CH 2 CH 3 .
  • Haloalkyloxy refers to the group haloalkyl-O- or -O-haloalkyl, where haloalkyl group is as defined above.
  • exemplary haloalkoxy groups include but are not limited to -OCH 2 F, - OCCl 3 , -OCF 3 , -OCH 2 Cl, -OCH 2 CH 2 Br, -OCH 2 CH 2 I, -OCH 2 CH 2 CH 2 F, -0CH 2 CH 2 CH 2 C1 and the like.
  • Haldroxy refers to -OH group.
  • Hydroxyalkyl refers to the an alkyl group substituted with one or more hydroxy groups; the alkyl group and hydroxy group are same as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with hydroxy group.
  • Representative examples of an hydroxyalkyl group includes but are not limited to -CH 2 OH, -CH 2 CH 2 OH, - CH 2 CH(OH)CH 3 , -CH 2 CH(OH)CH 2 CH 3 and the like.
  • Cyanoalkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with -CN.
  • Representative examples of an cyanoalkyl group include, but are not limited to -CH 2 CN, -CH 2 CH 2 CN, -C(CH 2 ) 2 CN, -CH 2 CH 2 CH 2 CN and the like.
  • Amino refers to an -N- group, the nitrogen atom of said group being attached to a hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or any suitable groups.
  • Representative examples of an amino group include, but are not limited to -NH 2 , -NHCH 3 and -NH-cyclopropyl.
  • An amino group can be unsubstituted or substituted with one or more of the suitable groups.
  • Aryl refers to an optionally substituted monocylic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms.
  • Examples of a C 6 -Ci4 aryl group include, but are not limited to phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl.
  • Aryl group can be unsubstituted or substituted with one or more suitable groups.
  • Cycloalkyl refers to a C 3 -C10 non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system.
  • C 3 -C12 cycloalkyl 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 an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with an cycloalkyl group as defined above.
  • Examples of cycloalkylalkyl group include, but are not limited to cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and the like.
  • a cycloalkylalkyl group can be unsubstituted or substituted with one or more suitable groups.
  • 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 of 3 to 10 member having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(0) 2 , NH and C(O).
  • Exemplary 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 an unsaturated, monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one heteroatom selected from oxygen, sulphur and nitrogen.
  • C5-C10 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, l-methyl-l,2,4-triazole, IH-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, aza
  • Bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heterocyclyl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom.
  • a heteroaryl group can be unsubstituted or substituted with one or more suitable groups.
  • Hetero atom refers to a sulfur, nitrogen or oxygen atom.
  • Comprise or “Comprising” is generally used in the sense of include, that is to say permitting the presence of one or more features or components.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable derivatives” is taken to mean an active ingredient, which comprises a compound of the formula (1) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier.
  • the pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body.
  • 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.
  • 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 newborn subjects, whether male or female, are intended to be covered.
  • terapéuticaally 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.
  • “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.
  • compositions can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual or transdermal
  • vaginal or parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • parenteral including subcutaneous, intramuscular, intravenous or intradermal
  • a therapeutically effective amount of a compound of the formula (1) and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet.
  • an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to lOmg/kg of body weight per day.
  • the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same.
  • An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.
  • the present invention relates to a process for preparing of 1H- pyrrolopyridinone derivatives of formula (1).
  • An embodiment of the present invention provides the compounds according to formula (1) 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 intermediates or compounds synthesized herein may be used in the further step with isolating or without isolating. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (°C) unless otherwise noted.
  • 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, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Ar Ar
  • ACN acetonitrile
  • brine NaCl solution
  • AIBN 2-2'- Azoisobutyronitrile
  • Pd(dppf)Ci 2 [1 , 1 '-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane
  • Pd(PPh 3 ) 2 Ci 2 Bis(triphenylphosphine)palladium(II) dichloride
  • TFA Trifluoroaceticacid
  • Pd(OAc) 2 palladiumacetate
  • NMU Neitrosomethylurea)
  • CH 3 MgBr methylmagnesiumbromide
  • Cy 3 P tricyclohexylphosphine
  • TBAF tetrabutyl ammonium fluoride
  • Another embodiment of the present invention provides methods useful for making the compounds of formula (1) are set forth in the Examples below and generalized in below schemes.
  • One of skill in the art will recognize that below schemes can be adapted to produce the compounds of formula ( 1) and pharmaceutically accepted salts of compounds of formula ( 1) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated. The process is represented herein with below schemes. .
  • Compound lb undergoes partial hydrolysis in acidic conditions such as HCl, AcOH at appropriate reaction conditions to give compound lc, which was N-alkylated with suitable alkyl halides such as methyl iodide, ethyl iodide, isopropyl bromide, bromo propionitrile, cyclopropane methyl bromide and the like, in presence of a suitable base such as Na 2 C0 3> K 2 C0 3> Cs 2 C0 3 and suitable solvents such as THF, DMF, DMA and DMSO to provide compound of formula Id; alternatively N-arylation (copper iodide/copper acetate/Pd-catalyzed C-N coupling reaction) can undergo with aryl boronate esters/acids, heteroaryl boronate esters/acids in presence of suitable coupling conditions in presence of suitable palladium catalysts in presence of suitable base such as DIPEA, TEA, Na
  • Compound of formula 3d undergoes reductive cyclization in presence of iron powder and acetic acid to give compound 3e, which on ester hydrolysis in presence of suitable deprotecting agents such as 10% aq.NaOH, KOH, LiOH.H 2 0 in suitable solvents such as MeOH, EtOH, THF, DMF, DMSO and the like to provide compound of formula 3f.
  • suitable deprotecting agents such as 10% aq.NaOH, KOH, LiOH.H 2 0 in suitable solvents such as MeOH, EtOH, THF, DMF, DMSO and the like to provide compound of formula 3f.
  • the acid-amine coupling of compounds of formula 3f was carried out by a conventional amide bond formation method by using a suitable coupling reagents such as benzotriazole-containing coupling reagents such as 1 -hydro xybenzotriazole (HOBt), benzotriazole-l-yloxytris (dimethylamino)phosphonium hexafluorophosphate and 2-(lH-benzotriazol-l-yl)-l, l,3,3-tetra methyluroniumhexafluoro phosphate and an azabenzotriazole-containing reagent such as 0-(7-azabenzotriazole-l-yl)-N and also the dicarboimides containing reagent such as l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, HATU and the like, in a suitable solvent
  • the microwave chemistry was performed on a CEM Explorer.
  • Step-g Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-L3,2- dioxaborolan-2-yl)phenyl)-4-(dimethylamino)benzamide (Intermediate- 1 )
  • reaction mixture was heated to 120°C for 3 h.
  • the reaction mixture was cooled to RT, diluted with EtOAc and filtered through a Celite pad and washed with EtOAc.
  • the organic layer was washed with water and brine, dried and concentrated.
  • the residue obtained was purified using column chromatography eluting with 15 % of EtOAc in hexane to afford title compound as a yellow solid (0.15 g, 55 %).
  • Step-b Synthesis of methyl 4-cyclopropyl-2-methylbenzoate
  • Step-d Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-cyclopropyl -2-methylbenzamide 4-cyclopropyl-2-methylbenzoic acid (0.550 g, 3.13 mmol) and thionyl chloride (10 ml) were refluxed for 2h, thionyl chloride was concentrated under reduced pressure. The residue obtained was dissolved in DCM (15 ml) and stirred at 0°C.
  • Step-e Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-4-cyclopropyl-2-methylbenzamide (Intermediate-7)
  • Step-b Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2- yPphenyPbenzamide (Intermediate- 11)
  • Step-b Synthesis of ethyl 4-(2-cyanopropan-2-yl)benzoate
  • step-d of intermediate-7 The process of this step was adopted from step-d of intermediate-7 to obtain the title compound (1.2 g, 33 %).
  • Step-e Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-L3,2- dioxaborolan-2-yl)phenyl)-4-(2-cyanopropan-2-yl)benzamide (Intermediate- 12)
  • step-g of intermediate- 1 The process of this step was adopted from step-g of intermediate- 1 to obtain the title compound (1.2 g, 92 %).
  • NMU 20% KOH, ether, 0°C to RT, 16h d) Xylene, 140°C, 16h e) CO (g) 80psi, DIPEA, Pd(dppf)Cl 2 .DCM, Ethanol, 80°C, 24h f) 20% NaOH, MeOH, THF, RT, 4h g) t) thionyl chloride, 80°C, 2h h) DIPEA, DMAP, DCM, 0°C to RT, 16h h) Bis(pinacolato)diboron, Pd(dppf)Cl 2 . DCM, OAc, 1,4-dioxane, 80°C, 2h
  • Step-a Synthesis of 2-(4-bromophenyl)- 1, 1, 1 -trifluoropropan-2-ol
  • Step-b Synthesis of l-bromo-4-(3,3,3-trifluoroprop-l-en-2-yl)benzene
  • 2-(4-bromophenyl)-l, l, l-trifluoropropan-2-ol 0.2 g, 0.743 mmol
  • THF 2 ml
  • pyridine 0.176 g, 2.23 mmol
  • S0C1 2 0.26 g, 2.23 mmol
  • Step-c Synthesis of 3-(4-bromophenyl)-3-(trifluoromethyl)-4,5-dihydro-3H-pyrazole
  • Step-e Synthesis of ethyl 4-(l-(trifluoromethyl)cyclopropyl)benzoate
  • step-b of intermediate- 12 The process of this step was adopted from step-b of intermediate- 12 to obtain the title compound (1.8 g, 90 %).
  • Step-f Synthesis of 4-(l-(trifluoromethyl)cyclopropyl)benzoic acid
  • MeOH MeOH
  • THF 10 ml
  • 20 % NaOH solution 20 ml
  • the reaction mixture was stirred at RT for a period of 4 h.
  • the reaction mixture was poured into ice cold water and acidified with 10 % HC1 solution.
  • the precipitated solid was collected by filtration, washed with water and dried under vaccum to afford the desired compound (1.31 g, 83 %).
  • Step-g Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-( 1 - (trifluoromethyDcyclopropyPbenzamide
  • step-d of intermediate-7 was adopted from step-d of intermediate-7 to obtain the title compound (0.5 g, 27 %).
  • Step-h Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-L3,2- dioxaborolan-2-yl)phenyl)-4-( 1 -(trifluoromethyl)cyclopropyl)benzamide (Intermediate- 13)
  • step-g of Intermediate- 1 The process of this step was adopted from step-g of Intermediate- 1 to obtain the title compound (0.8 g crude) and was proceeded for the next step without further purification.
  • Step-a Synthesis of ethyl 4-(3,3 -trifluoroprop-l-en-2-yl)benzoate The process of this step was adopted from step-b of intermediate- 12 to obtain the desired compound (2.8 g, 58 %).
  • Step-b Synthesis of ethyl 4-(l,l J -trifluoropropan-2-yl)benzoate
  • Step-c Synthesis of 4-( 1, 1,1 -trifluoropropan-2-yi) benzoic acid
  • Step-d Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-( 1,1,1- trifluoropropan-2-yl)benzamide
  • Step-e Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-4-( 1, 1, 1 -trifluoropropan-2-yl)benzamide (Intermediate- 14)
  • the process of this step was adopted from step-g of intermediate- 1 to obtain the title compound (1.41 g, crude) and was proceeded for the next step without purification.
  • Step-b Synthesis of methyl 4-(l-methylcyclopropyl)benzoate
  • Step-d Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl) oxy) methyl) phenyl)-4-(l- methylcyclopropyPbenzamide
  • Step-e Synthesis of N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-4-( 1 -methylcyclopropyPbenzamide (Intermediate- 15)
  • step-g of intermediate- 1 The process of this step was adopted from step-g of intermediate- 1 to obtain the desired product (0.2 g, 91 %).
  • Step-a Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-(tert- butyPbenzamide
  • Step-b Synthesis of N-(3-bromo-2-(hvdroxymethyl)phenyl)-4-(tert-butyl)benzamide
  • Step-c Synthesis of 2-bromo-6-(4-(tert-butyl)benzamido)benzyl acetate
  • Step-a Synthesis of N-(3-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-4-isopropyl benzamide
  • the process of this step was adopted from step-f of intermediate- 1 to obtain 17.2 (0.8 g, 9.0 %) and 17.2A (0.7 g); LC/MS for 17.2A: 350.1 (M+l) + .
  • Step-b Synthesis of N-(3-bromo-2-(hydroxymethyl)phenyl)-4-isopropylbenzamide
  • Step-c Synthesis of 2-(4-isopropylbenzamido)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yDbenzyl acetate (Intermediate- 17)
  • step-g of intermediate- 1 The process of this step was adopted from step-g of intermediate- 1 to obtain the desired compound (0.5 g, 68 %).
  • Step-a Synthesis of 4-bromo-7-chloro-lH-pyrrolo r 2,3-clpyridine
  • Step-c Synthesis of 4-bromo-l-tosyl-lH-pyrrolor2.3-clpyridin-7(6H)-one
  • Step-c Synthesis of 5-bromo-L4-dimethyl-3-nitropyridin-2(lH)-one
  • DMF 200 ml
  • K 2 CO 3 21.39 g, 155 mmol
  • CH 3 I 21.86 g, 155 mmol
  • the reaction mixture was stirred at room temperature for 2h.
  • the reaction mixture was poured into ice cold water, the solid formed was filtered and dried under vacuum to afford title compound as off white solid (23.5 g, 92 %).
  • H NMR 400 MHz, DMSO-d 6 ) ⁇ 8.40 (s, 1H), 3.51 (s, 3H), 2.21 (s, 3H).
  • Step-e Synthesis of 4-bromo-6-methyl- lH-pyrrolo[2,3-clpyridin-7(6H)-one
  • Step-f Synthesis of 4-bromo-6-methyl- l-tosyl- lH-pyrrolor2,3-clpyridin-7(6H)-one
  • Example- 1 Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-lH- rrolo[2,3-c]pyridin-4-yl)phenyl)benzamide (Compound-1)
  • Step-a Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(6-methyl-7-oxo-l-tosyl-6,7-dihydro-lH- pyrrolo[2,3-clpyridin-4-yl)phenyl)benzamide
  • Step-b Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo
  • Example-2 Synthesis of 4-(tert-butyl)-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-3a,6,7,7a- tetrah dro- lH-pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide (Compound-2)
  • Step-a Synthesis of 4-(tert-butyl)-N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(6-methyl-7- oxo-l-tosyl-6,7-dihydro-lH-pyrrolor2,3-clpyridin-4-yl)phenyl)benzamide
  • Step-b Synthesis of 4-(tert-butyl)-N-(2-(hvdroxymethyl)-3-(6-methyl-7-oxo-l-tosyl-6,7- dihydro-lH-pyrrolor2,3-clpyridin-4-yl)phenyl)benzamide
  • 4-(tert-butyl)-N-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(6- methyl-7-oxo-l-tosyl-6,7-dihydro-lH-pyrrolo[2,3-c]pyridin-4-yl)phenyl)benzamide (0.250 g, 0.358 mmol) in dry THF (5 ml) was added TBAF (2 ml, 1.0 M in THF) drop wise.
  • reaction mixture Upon completion of addition the reaction mixture was slowly warmed to room temperature and stirred for about 2 h. The reaction mixture quenched with saturated ammonium chloride solution (15 ml) and the product was extracted with ethyl acetate (2x100 ml). The combined organic layers washed with brine (20ml). The organic layer was dried and evaporated to dryness under reduce to get the desired compound as a brown solid (0.1 g, 47 %); LC/MS: 584 (M+l) + .
  • Step-c Synthesis of 4-(tert-butyl)-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-3a,6,7,7a- tetrahydro-lH ⁇ yrrolo[2 -clpyridin-4-yl)phenyl)benzamide (Compound-2)
  • Step-a Synthesis of 4-bromo-6-phenyl-l-tosyl-lH-pyrrolor2,3-clpyridin-7(6H)-one
  • Step-b Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(7-oxo-6-phenyl-l-tosyl-6,7-dihydro-lH- pyrrolor2,3-clpyridin-4-yl)phenyl)benzamide
  • step-a of Example- 1 The process of this step was adopted from step-a of Example- 1 to isolate the desired compound (0.080 g, 20 %).
  • Step-c Synthesis of 4-(tert-butyl)-N-(2-methyl-3-(7-oxo-6-phenyl-6J-dihydro-lH-pyrrolor2,3- cl pyr idin-4- vDphen vDbenzamide (Co mpound- 3 )
  • Step-b Synthesis of 4-(tert-butyl)-N-(2-(hydroxymethyl)-3-(6-methyl-7-oxo-6,7-dihydro-lH- pyrrolo[2,3-clpyridin-4-yl)phenyl)benzamide
  • Step-c Synthesis of 2-(4-(tert-butyl)benzamido)-6-(6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- clpyridin-4-yl)benzyl acetate (Compound-4)
  • step-c of intermediate- 16 The process of this step was adopted from step-c of intermediate- 16.
  • the desired compound was obtained as light brown solid (5 mg, 15.2 %).
  • 1H NMR (400 MHz, DMSO-d 6 ) ⁇ 12.12 (s, IH), 10.02 (s, IH), 7.90 (d, J 8.4 Hz, 2H), 7.56-7.48 (m, 4H),7.30-7.26 (m, 2H), 7.17 (s, IH), 5.95 (s, IH), 5.0 (bs, 2H), 3.68 (s, 3H), 1.76 (s, 3H), 1.32 (s, 9H); LC/MS: 472.3 (M+l) + .
  • Step-a Synthesis of ethyl 4-bromo-6-methyl-7-oxo-l-tosyl-6J-dihydro-lH-pyrrolor2,3- clpyridine-2-carboxylate LDA was prepared by adding n-BuLi (8.6 ml, 13.0 mmol, 1.5 M in hexane) to a solution of diisopropyl amine (1.01 g, 10.0 mmol) in THF (50 ml) at -78°C. The reaction mixture was stirred at same temperature for 30 min. The solution was warmed to room temperature and cooled to -78°C.
  • Step-b Synthesis of ethyl 4-(2-(acetoxymethyl)-3-(4-(tert-butyl)benzamido)phenyl)-6-methyl-7- oxo-l-tosyl-6.7-dihydro-lH-pyrrolor2.3-clpyridine-2-carboxylate
  • Step-c Synthesis of 4-(3-(4-(tert-butyl)benzamido)-2-(hydroxymethyl)phenyl)-6-methyl-7-oxo- 6.7-dihydro- lH-pyrrolor2.3-clpyridine-2-carboxylic acid (Compound-5)
  • Example-6 Synthesis of ethyl 4-(3-(4-(tert-butyl)benzamido)-2-(hydroxymethyl)phenyl)-6- methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxylate (Compound-6)
  • Step-a Synthesis of ethyl 3-(5-bromo-l-methyl-3-nitro-2-oxo-L2-dihydropyridin-4-yl)-2- oxopropanoate
  • Step-b Synthesis of ethyl 4-bromo-6-methyl-7-oxo-6J-dihydro-lH-pyrrolor2,3-clpyridine-2- carboxylate
  • Step-c Synthesis of ethyl 4-(3-(4-(tert-butyl)benzamido)-2-(((tert-butyldimethylsilyl)oxy) methyl)phenyl)-6-methyl-7-oxo-6,7-dihvdro-lH-pyrrolo[2,3-clpyridine-2-carboxylate
  • the process of this step was adopted from step-a of Example-2.
  • the desired compound was obtained as brown solid (0.35 g, 56 %).
  • Step-d Synthesis of ethyl 4-(3-(4-(tert-butyl)benzamido)-2-(hydroxymethyl)phenyl)-6-methyl- 7-oxo-6,7-dihydro-lH-pyrrolor2,3-clpyridine-2-carboxylate (Compound-6)
  • Example-7 N-(3-(2-(azetidine-l-carbonyl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- c]pyridin-4-yl)-2-(hydrox methyl)phenyl)-4-(tert-butyl)benzamide (Compound-7)
  • Step-a synthesis of N-(3-(2-(azetidine-l-carbonyl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3- clpyridin-4-yl)-2-(hydroxymethyl)phenyl)-4-(tert-butyl)benzamide (Compound-7)
  • step-b of intermediate- 11. The process of this step was adopted from step-b of intermediate- 11.
  • the desired compound was obtained as off white solid (0.018 g, 3 %).
  • Step-a Synthesis of 4-bromo-6-methyl-7-oxo-6 -dihydro-lH-pyrrolor2 -clpyridine-2- carboxylic acid
  • Step-b Synthesis of 4-bromo-N,N,6-trimethyl-7-oxo-6,7-dihydro-lH-pyrrolor2,3-clpyridine-2- carboxamide
  • step-b of intermediate- 11. The process of this step was adopted from step-b of intermediate- 11.
  • the desired compound was obtained as off white solid (0.15 g, 68 %).
  • Step-c Synthesis of 4-(3-(4-(tert-butyl)benzamido)-2-(((tert-butyldimethylsilyl)oxy)methyl) phenyl)-N,N,6-trimethyl-7-oxo-6,7-dihvdro-lH-pyrrolo[2,3-clpyridine-2-carboxamide
  • Step-d Synthesis of 4-(3-(4-(tert-butyl)benzamido)-2-(hvdroxymethyl)phenyl)-N,N,6-trimethyl- 7-oxo-6,7-dihydro-lH-pyrrolor2,3-clpyridine-2-carboxamide (Compound-8)
  • the process of this step was adopted from step-b of Example-2.
  • the desired compound was obtained as off white solid (0.010 g, 4 %).
  • Example-9 Synthesis of 4-(3-(4-cyclopropyl-2-fluorobenzamido)-2-(hydroxymethyl) phenyl)-6-methyl-7-oxo-6,7-dihydro-lH-pyrrolo[2,3-c]pyridine-2-carboxylicacid
  • Step-a Synthesis of ethyl 4-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(4-cyclopropyl-2- fluorobenzamido)phenyl)-6-methyl-7-oxo-6 -dihydro-lH-pyrrolor2,3-clpyridine-2-carboxylate
  • step-a of Example-2 The process of this step was adopted from step-a of Example-2.
  • the desired compound was obtained as brown solid (0.18 g, 43 %).
  • Step-b Synthesis of ethyl 4-(3-(4-cyclopropyl-2-fluorobenzamido)-2-(hydroxymethyl)phenyl)-6- methyl-7-oxo-6,7-dihvdro-lH-pyrrolo[2,3-clpyridine-2-carboxylate
  • step-b of Example-2 The process of this step was adopted from step-b of Example-2.
  • the desired compound was obtained as grey solid (0.12g, 81%).
  • Step-c Synthesis of 4-(3-(4-cyclopropyl-2-fluorobenzamido)-2-(hydroxymethyl)phenyl)-6- methyl-7-oxo-6,7-dihydro- lH-pyrrolor2,3-clpyridine-2-carboxylic acid (Compound-9)
  • BTK TR-FRET kinase assay measures the phosphorylation of Ulight fluorescence acceptor labelled substrate by full length human recombinant BTK enzyme and the detection using Eu-labeled antiphosphotyrosine antibody. The binding of antibody to the phosphorylated tyrosine brings Eu closer to Ulight label. Due to the proximity, Eu excited at 340 nm, can transfer energy to Ulight label which emits at 665 nm.
  • TR-FRET assays are usually done as ratiometric measurements. The output signal is measured as the ratio of 665 nm emission of Ulight to 615 nm emission of Eu and it is proportional to the level of Ulight peptide phosphorylation.
  • test compounds at 20 mM DMSO are prepared. Compounds are serially diluted in 384-well pplypropylene plates. Diluted compounds are incubated with 5 ng of recombinant BTK enzyme and incubated for 30 minutes at room temperature. After the incubation, 40 nM Ultra light poly GT substrate mix from Perkin Elmer and 6 ⁇ ATP were added to the reaction and incubated for 30 min at room temperature. Reactions are quenched after 30 min by addition of 40 mM EDTA. After stopping the reaction, 0.5 nM of Eu-labelled antiphosphotyrosine antibody was added to the reaction.
  • the degree of phosphorylation of Ultra Light poly GT substrate was measured using a time -resolved fluorimeter (Perkin Elmer WALLAC 1420 Multi label Counter Victor 3) as ratio of specific 665 nm energy transfer signal to reference europium 615 nm signals.
  • the compounds IC 50 was determined by fitting the dose response data to sigmoidal curve fitting equation using GraphPad Prism software V5. The compounds were screened at nM concentration and the results are summarized in table below.
  • IC 50 values of the selected compounds of present invention were provided in below table, Compounds exhibiting IC 50 values ⁇ 500 nM were grouped as 'a', compounds exhibiting IC 50 value in the range 500.01 nM to 1000 nM were grouped as 'b' and the compounds exhibiting IC 50 value >1000.01 nM were grouped as 'c'. % inhibition of the selected compounds of the present invention at 1 ⁇ and 10 ⁇ are detailed in the below table.

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Abstract

La présente invention concerne de nouveaux dérivés de 1H-pyrrolopyridinone substitués de formule (1) en tant qu'inhibiteurs de protéines kinases, dans laquelle R1, R2, R3, R4, R5, R6 et 'p' ont les significations proposées dans la spécification, et leurs sels pharmaceutiquement acceptables qui sont utiles dans le traitement et la prévention de maladies ou de troubles, en particulier leur utilisation dans des maladies ou des troubles pour lesquels l'inhibition d'une enzyme kinase est avantageuse, plus particulièrement l'inhibition de l'enzyme BTK. La présente invention concerne en outre des procédés de synthèse et d'administration des composés inhibiteurs de kinase. La présente invention concerne en outre des formulations pharmaceutiques comprenant au moins un composé inhibiteur de kinase conjointement à un vecteur, un diluant ou un excipient, pharmaceutiquement acceptables, pour celles-ci.
PCT/IB2014/058881 2013-02-12 2014-02-10 Dérivés de 1h-pyrrolopyridinone substitués en tant qu'inhibiteurs de kinase Ceased WO2014125408A2 (fr)

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WO2017177955A1 (fr) * 2016-04-15 2017-10-19 Abbvie Inc. Inhibiteurs de bromodomaine
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