WO2014108820A1 - Dérivés de 2-pyrazinone substitués en tant qu'inhibiteurs de kinase - Google Patents

Dérivés de 2-pyrazinone substitués en tant qu'inhibiteurs de kinase Download PDF

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WO2014108820A1
WO2014108820A1 PCT/IB2014/058074 IB2014058074W WO2014108820A1 WO 2014108820 A1 WO2014108820 A1 WO 2014108820A1 IB 2014058074 W IB2014058074 W IB 2014058074W WO 2014108820 A1 WO2014108820 A1 WO 2014108820A1
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methyl
phenyl
oxo
amino
pyrazin
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PCT/IB2014/058074
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Anima BORUAH
Subramanya Hosahalli
Sunil Kumar Panigrahi
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Aurigene Discovery Technologies Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • C07D403/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

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. Therefore, inhibition of one or more of kinases would have multiple therapeutic indications.
  • 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. Subsequent Btk auto-phosphorylation stabilizes the active confirmation and fully activates Btk kinase activity.
  • Btk phospholipase(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 175: 120-127; Khan WN (2001), Immunol Res 23: 147-156).
  • Abrant 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 2-pyrazinone 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 2-pyrazinone derivatives of formula ( 1 ) which are useful as kinase inhibitors.
  • the present invention relates to the compound of formula (1)
  • the dotted line [— ] represents a single or a double bond
  • Ri is selected from alkyl and optionally substituted aryl; wherein the optional substituent is selected from -NRsRg, -C(0)NR 8 R 9 and -C(O)Ri 0 ;
  • R 2 , R 3 , R4 and R5 are independently selected from hydrogen and alkyl
  • R 6 is selected from hydrogen, alkyl and optionally substituted aryl; wherein the optional substituent is alkyl;
  • R 7 is selected from hydrogen, alkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heterocyclyl; wherein the optional substituent at each occurrence is independently selected from one or more Ri 1 ;
  • Rs and R9 are independently selected from hydrogen, alkyl, hydroxyalkyl and alkoxyalkyl; alternatively, Rs and R9 can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocyclyl ring containing 0-2 additional heteroatoms independently selected from N and O; wherein the optional substituent is alkyl;
  • Rio is selected from alkyl, hydroxy and alkoxy
  • each Rn is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkyloxy, nitro and amino;
  • 'p' is an integer selected from 1 and 2.
  • the present invention relates to the compound of formula (A)
  • the dotted line [— ] comprises single or double bond
  • X is selected from N, C or CH in any stable combination
  • Ri is selected from hydrogen or optionally substituted C 1-6 alkyl;
  • R 2 is independently selected from hydrogen, hydroxy, cyano -COR 8 , -COOR 8 , -
  • Ri and R 2 combined together with the nitrogen to which they are attached to form optionally substituted 3-8 membered heterocyclic ring containing 1-3 hetero atoms selected form N, O and S in any stable combination;
  • R 3 and R 7 are independently selected from hydrogen, -COR8, -COOR8, -CONR8R 9 , - S0 2 R 8 , -S0 2 NRsR 9 , optionally substituted Ci_ 6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl in any stable combination;
  • R4 and R5 independently selected from hydrogen, halogen, cyano, hydroxy, nitro, - CORs, -COORs, -NR 8 R 9 , -CONR 8 R 9 , -NR 8 COOR 9 , -NR 8 COR 9 , -NR 8 S0 2 R 9 , -NR 8 CONR 8 R 9 , - OR 8 , -OCOR 8 , -OCONR 8 R 9 , -OS0 2 R 9 , -SR 8 , -S0 2 R 8 , optionally substituted Ci_ 6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl in any stable combination; or
  • R 3 and R4 combined together with the carbon and nitrogen to which they are attached to form optionally substituted carbocyclic or heterocyclic ring in any stable combination;
  • R 6 is selected from halogen, cyano, hydroxy, nitro, -COR 8> -COOR 8 , -NR 8 R 9 , - CONR 8 R 9 , -NR 8 COOR 9 , -NR 8 COR 9 , -NR 8 S0 2 R 9 , -NR 8 CONR 8 R 9 , -OR 8 , -OCOR 8 , - OCONR 8 R 9 , -OS0 2 R 9 , -SR 8 , -S0 2 R 8 , optionally substituted C 1-6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or may form gem type of substituents on same carbon atom with two R 6 substituents or two R 6 substituents taken together with the carbons to which they are attached to form an optionally substituted fused carbocyclic or heterocyclic ring in any stable combination;
  • R 8 and R 9 independently selected from hydrogen, halogen, hydroxy, optionally substituted Ci_ 6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl in any stable combination; or R 8 and R 9 combined together to form an optionally substituted 3-8 membered heterocyclic ring containing 1-3 hetero atoms selected form N, O and S in any stable combination; 'm, n and p' independently selected from an integer selected from 0 to 2; both inclusive.
  • the present invention also relates to substituted 2-pyrazinone derivatives of formula (1) which is an embodiment of formula (A).
  • Embodiments of the present invention provide substituted 2-pyrazinone derivatives of formula (1) which are useful as kinase inhibitors.
  • One of the embodiment of the present invention provide the compound of formula (1)
  • the dotted line [— ] represents a single or a double bond
  • Ri is selected from alkyl and optionally substituted aryl; wherein the optional substituent is selected firom -NR 8 R9, -C(0)NR 8 R 9 and -C(O)Ri 0 ;
  • R 2 , R 3 , R4 and R5 are independently selected from hydrogen and alkyl
  • R 6 is selected from hydrogen, alkyl and optionally substituted aryl; wherein the optional substituent is alkyl;
  • R7 is selected from hydrogen, alkyl, optionally substituted aryl, optionally substituted arylalkyl and optionally substituted heterocyclyl; wherein the optional substituent at each occurrence is independently selected from one or more Ri 1 ;
  • R 8 and R9 are independently selected from hydrogen, alkyl, hydroxyalkyl and alkoxyalkyl;
  • R 8 and R9 can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocyclyl ring containing 0-2 additional heteroatoms independently selected from N and O; wherein the optional substituent is alkyl;
  • Rio is selected from alkyl, hydroxy and alkoxy
  • each Ri i is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkyloxy, nitro and amino;
  • 'p' is an integer selected from 1 and 2.
  • dotted line [— ] line represents single bond or double bond; more particularly single bond.
  • Ri is alkyl; in particular alkyl is isopropyl and tert-butyl.
  • Ri is optionally substituted aryl; in particular aryl is phenyl.
  • R 3 and R5 are alkyl; in particular alkyl is methyl.
  • R 7 is alkyl; in particular alkyl is methyl and ethyl.
  • R 7 is optionally substituted aryl; in particular aryl is phenyl.
  • halogen is fluoro and bromo
  • alkyl is methyl and t-butyl
  • haloalkyl is trifluoromethyl
  • alkoxy is methoxy
  • R 6 is alkyl; in particular alkyl is methyl and ethyl.
  • R 6 is optionally substituted aryl; in particular aryl is phenyl optionally substituted with methyl.
  • the compound of formula (1) is a compound of formula (la)
  • R 6 is hydrogen and R 7 is optionally substituted phenyl; wherein optional substituent is alkyl; in particular alkyl is methyl.
  • the compound of formula ( 1) is a compound of formula ( lb)
  • 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 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.
  • Niro refers to -N0 2 group.
  • Alkoxyalkyl refers to the an alkyl group substituted with one or more alkoxy groups; the alkyl group and alkoxy group are same as defined above, wherein one or more of the alkyl group's hydrogen atom has been replaced with alkoxy group.
  • Representative examples of an alkoxyalkyl group include but are not limited to -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , - CH 2 CH 2 OCH 2 CH 3 and the like.
  • 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.
  • 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.
  • 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.
  • arylalkyl group 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.
  • 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 a saturated, 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, lH-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.
  • suitable groups
  • 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 substituted 2- pyrazinone 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
  • brine NaCl solution
  • Pd(dppf)Cl 2 [1, 1 '-Bis (diphenylphosphino)ferrocene] dichloropalladium (II), complex with dichloro methane; bs (broad singlet); J (coupling constant); CS 2 CO 3 (cesium carbonate); C (degree Celsius); DMF (dimethylformamide) ; DMSO (Dimethyl sulfoxide); DME (dimethoxyethane) ; PMB (4-methoxy benzaldehyde); DIPEA/DIEA (N,N- Diisopropylethylamine); Et 2 0 (diethyl ether); CH 2 C1 2 /DCM (dichloromethane); CDCI 3 (deuteriated chloroform); d (dublet); dd (doublet of dublet); E
  • 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 scheme.
  • One of skill in the art will recognize that the below scheme 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 by below scheme.
  • Substituted pyrizinone derivatives ( 1.0) and appropriate amines are reacted in presence of organic solvents (such as DMF, THF, Dioxane, DMA) at about 100°C to 110°C for about 6 to 16 h to get the compound of general formula 1.1.
  • organic solvents such as DMF, THF, Dioxane, DMA
  • Method-b Protected urea derivative compound of formula 2.1 was reacted in presence of base to give cyclic urea compound, which on deprotection results in the formation of deprotected cyclic urea compound.
  • This on reaction with appropriate alkyl halides in presence of a base at suitable conditions results in the formation of alkyl substituted cyclic urea compound.
  • On further reaction with Bis(pinacolato)diboran in presence of a base at suitable conditions results in the formation of boronic ester or acid of compound of formula (2.3).
  • Method-c An appropriate urea derivative of formula (2.2) was reacted with the base such as NaH in presence of organic solvents such as DMF, THF and the like for about 0.5 to 3 hrs at temperature range of -10°C to 40°C to get the cyclic urea compound, which was further reacts with Bis(pinacolato)diboran in presence of a base at suitable conditions results in the formation of Boronic ester compound of formula (2.3).
  • the base such as NaH
  • organic solvents such as DMF, THF and the like
  • Method- 1 An appropriate cyclic urea compound of formula (3.0) in presence of base such as CS2CO3, Cul in suitable organic solvents such as DMF, THF, ACN and the like, was reacted with R7-halides in presence of suitable ligands such as N,N'-dimethylethane-l,2-diamine at suitable temperature range of about 80°C-120°C for about 3-18 h results in the formation of compound of formula (1).
  • base such as CS2CO3
  • suitable organic solvents such as DMF, THF, ACN and the like
  • Method-2 An appropriate cyclic urea compound of formula (3.0) in presence of base such as NaH in suitable organic solvents such as DMF, THF, ACN and the like, was reacted with R 7 - halides at the suitable temperature range of about 20°C-60°C for about 3-6 h results in the formation of compound of formula (1).
  • base such as NaH
  • suitable organic solvents such as DMF, THF, ACN and the like
  • the microwave chemistry was performed on a CEM Explorer.
  • the procedure for the compounds of Formula (1) are detailed herein below stepwise including the general synthesis of various intermediates involved in process of manufacture of the compounds according to the present invention.
  • Step-iii Synthesis of l-(2-methyl-3-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) phenyl) imidazolidin-2-one (2)
  • the crude material was diluted with water (100 ml) and the product extracted with DCM (2x250 ml). The combined organic layers were washed with brine solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the crude material. The resulting crude material was purified by column chromatography using 100-200 silica gel, eluting with 3% MeOH in DCM afforded the titled compound (8 g, 67.56 %) as a yellow solid. !
  • Step ii Synthesis of l-(3-bromo-2-methylphenyl)- lH-imidazol-2(3H)-one (2.1b)
  • Step-iii Synthesis of l-(2-methyl-3-(4, 4, 5, 5-tetramethyl-L 3, 2-dioxaborolan-2-yl) phenyl)- lH-imidazol-2(3H)-one (2.1)
  • step-iii of intermediate-2 obtained the desired compound as a brown solid (1.5 g, 57.69 %).
  • LC-MS 255 (M+l) + .
  • Intermediate-2.2 Synthesis of 4-ethyl-3-methyl-l-(2-methyl-3-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2- l)phenyl)imidazolidin-2-one
  • Step-ii Synthesis of 3-(3-bromo-2-methylphenyl)-l-(l-hvdroxybutan-2-yl)-l -(4-methoxy benzyDurea (2.2b)
  • Step-iii Synthesis of l-(3-bromo-2-methylphenyl)-4-ethyl-3-(4-methoxybenzyl) imidazolidin-2- one (2c)
  • Step-v Synthesis of l-(3-bromo-2-methylphenyl)-4-ethyl-3-methylimidazolidin-2-one (2e)
  • step-iii of intermediate-2 obtained the desired compound as an off white solid (0.3 g, 86 %).
  • Step-ii Synthesis of l-(3-bromo-2-methylphenyl)-4-phenyl-lH-imidazol-2(3H)-one (2.9b)
  • Step-iii Synthesis of l-(2-methyl-3-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)phenyl)-4- phenyl-lH-imidazol-2(3H)-one (2.9c)
  • the process of this step was adopted from step-iii of intermediate-2.
  • the desired compound obtained as an off white solid (1.0 g, 87.5 %).
  • Interemdiate-2.9d was prepared according to the procedure depicted in intermediate-2.9 step-i to step-iii by using appropriate starting compound.
  • Step-i Synthesis of l-(3-bromo-2-methylphenyl)-3-methyl-4-phenyl-lH-imidazol-2(3H)-one
  • Step-ii Synthesis of 3-methyl-l-(2-methyl-3-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl) phenyl)-4-phenyl-lH-imidazol-2(3H)-one
  • step-iii of intermediate-2 The process of this step was adopted from step-iii of intermediate-2.
  • the desired compound obtained as off white solid (0.3 g, 97 %).
  • Example-I Synthesis of 5-(3-(3-(4-fluorophenyl)-2-oxoimidazolidin-l-yl)-2-methylphenyl)-l- methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino)pyrazin-2(lH)-one (Compound-1)
  • Example-II Synthesis of ethyl 4-((6-(3-(3-(4-(tert-butyl)phenyl)-2-oxoimidazolidin-l-yl)-2- methylphenyl)-4-methyl-3-oxo-3,4-dihydro yrazin-2-yl)amino)benzoate (Compound-44)
  • Example-Ill Synthesis of 5-(3-(3-(4-fluorobenzyl)-2-oxoimidazolidin-l-yl)-2-methylphenyl)-l- methyl-3-((4-(morpholine-4-carbonyl)phenyl)amino)pyrazin-2(lH)-one (Compound-57)
  • Example-IV Synthesis of 4-((4-methyl-6-(2-methyl-3-(2-oxo-3-(p-tolyl)imidazolidin-l- yl)phenyl)-3-oxo-3,4-dihvdropyrazin-2-yl)amino)benzoic acid (compound-61)
  • Example-V Synthesis of 4-((4-methyl-6-(2-methyl-3-(2-oxo-3-(p-tolyl)imidazolidin-l- yl)phenyl)-3-oxo-3,4-dihvdropyrazin-2-yl)amino)benzamide (Compound-64)
  • Step-i Synthesis of N-(4-methoxybenzyl)-4-((4-methyl-6-(2-methyl-3-(2-oxo-3-(p-tolyl) imidazolidin- 1 -yl)phenyl)-3-oxo-3 ⁇ -dihydropyrazin-2-yl)amino)benzamide (64a)
  • N-(4- methoxybenzyl)-4-((4-methyl-6-(2-methyl-3-(2-oxoimidazolidin-l-yl)phenyl)-3-oxo-3,4-dihydro pyrazin-2-yl)amino)benzamide 120 mg, 0.222 mmol
  • l-bromo-4-methylbenzene 46 mg, 0.266 mmol
  • Step-ii Synthesis of 4-((4-methyl-6-(2-methyl-3-(2-oxo-3-(p-tolyl)imidazolidin-l-yl)phenyl)-3- oxo-3,4-dihydropyrazin-2-yl)aminobenzamide (64)
  • N-(4-methoxybenzyl)-4-((4-methyl-6-(2-methyl-3-(2-oxo-3-(p- tolyl) imidazolidin- l-yl)phenyl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)benzamide 70 mg, 0.111 mmol
  • trifluoroaceticacid was added (5 ml) and refluxed for 5 h. After the reaction was completed, the reaction mixture was basified with saturated Na 2 C0 3 solution. The product extracted with CHCI 3 (2 x 10 ml). The organic layers were washed with brine solution.
  • the below starting compounds 64b and 64c were prepared by procedure similar to the one described step-i of compound-64 by using the intermediate-4.6 and reacting with l-bromo-4- fluorobenzene and l-bromo-3,5-dimethylbenzene respectively.
  • the characteristics of the compounds are summarized herein below table.
  • Example- VII Synthesis o£ -(2-hvdroxyethyl)-4-((4-methyl-6-(2-methyl-3-(2-oxo-3-(p- tolyl)imidazolidin-l-yl)phenyl)-3-oxo-3 ⁇ -dihydropyrazin-2-yl)amino)benzamide (Compound- 76
  • 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 ⁇ 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 ⁇ 0.7 ⁇ were grouped as 'a', compounds exhibiting IC 50 value in the range 0.71 ⁇ to 1.0 ⁇ were grouped as 'b' and the compounds exhibiting IC 50 value >1.0 ⁇ were grouped as 'c'.
  • % inhibition of the selected compounds of the present invention at 1 ⁇ and 10 ⁇ are detailed in the below table.

Abstract

La présente invention concerne de nouveaux dérivés de 2-pyrazinone substitués de formule (1) en tant qu'inhibiteurs de protéine kinase, dans lesquels R1, R2, R3, R4, R5, R6, R7 et 'p' ont les significations données dans la description, et des sels pharmaceutiquement acceptables de ceux-ci qui sont utiles dans le traitement et la prévention de maladies ou d'un trouble, en particulier leur utilisation dans des maladies ou un trouble où il y a un avantage à inhiber l'enzyme kinase, plus particulièrement l'enzyme BTK. La présente invention concerne également des procédés de synthèse et d'administration des composés inhibiteurs de kinase. La présente invention concerne également des formulations pharmaceutiques comprenant au moins un des composés inhibiteurs de kinase conjointement à un support, diluant ou excipient pharmaceutiquement acceptable de celui-ci.
PCT/IB2014/058074 2013-01-08 2014-01-06 Dérivés de 2-pyrazinone substitués en tant qu'inhibiteurs de kinase WO2014108820A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2019180631A1 (fr) * 2018-03-22 2019-09-26 Aurigene Discovery Technologies Limited Dérivés d'imidazolidine-2-one substitués en tant qu'inhibiteurs de prmt5
WO2021043245A1 (fr) * 2019-09-06 2021-03-11 Ono Pharmaceutical Co., Ltd. Dérivé d'hydantoïne

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WO2008033858A2 (fr) * 2006-09-11 2008-03-20 Cgi Pharmaceuticals, Inc. Inhibiteurs de kinase et procédés d'utilisation et d'identification des inhibiteurs de kinase
WO2009039397A2 (fr) * 2007-09-20 2009-03-26 Cgi Pharmaceuticals, Inc. Amides substitués, procédé pour les préparer et procédé pour les utiliser
WO2009137596A1 (fr) * 2008-05-06 2009-11-12 Cgi Pharmaceuticals, Inc. Amides substitués, leur méthode de préparation et d'utilisation en tant qu'inhibiteurs de btk
WO2010000633A1 (fr) * 2008-07-02 2010-01-07 F. Hoffmann-La Roche Ag Nouvelles phénylpyrazinones en tant qu’inhibiteurs de kinases
WO2011140488A1 (fr) * 2010-05-07 2011-11-10 Gilead Connecticut, Inc. Composés de pyridone et d'aza-pyridone et leurs procédés d'utilisation
WO2012031004A1 (fr) * 2010-09-01 2012-03-08 Gilead Connecticut, Inc. Pyridinones/pyrazinones, leur procédé de fabrication et leur méthode d'utilisation

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Publication number Priority date Publication date Assignee Title
WO2008033858A2 (fr) * 2006-09-11 2008-03-20 Cgi Pharmaceuticals, Inc. Inhibiteurs de kinase et procédés d'utilisation et d'identification des inhibiteurs de kinase
WO2009039397A2 (fr) * 2007-09-20 2009-03-26 Cgi Pharmaceuticals, Inc. Amides substitués, procédé pour les préparer et procédé pour les utiliser
WO2009137596A1 (fr) * 2008-05-06 2009-11-12 Cgi Pharmaceuticals, Inc. Amides substitués, leur méthode de préparation et d'utilisation en tant qu'inhibiteurs de btk
WO2010000633A1 (fr) * 2008-07-02 2010-01-07 F. Hoffmann-La Roche Ag Nouvelles phénylpyrazinones en tant qu’inhibiteurs de kinases
WO2011140488A1 (fr) * 2010-05-07 2011-11-10 Gilead Connecticut, Inc. Composés de pyridone et d'aza-pyridone et leurs procédés d'utilisation
WO2012031004A1 (fr) * 2010-09-01 2012-03-08 Gilead Connecticut, Inc. Pyridinones/pyrazinones, leur procédé de fabrication et leur méthode d'utilisation

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Publication number Priority date Publication date Assignee Title
WO2019180631A1 (fr) * 2018-03-22 2019-09-26 Aurigene Discovery Technologies Limited Dérivés d'imidazolidine-2-one substitués en tant qu'inhibiteurs de prmt5
CN112105609A (zh) * 2018-03-22 2020-12-18 奥瑞基尼探索技术有限公司 作为prmt5抑制剂的取代的咪唑烷-2-酮衍生物
JP2021518366A (ja) * 2018-03-22 2021-08-02 オーリジーン ディスカバリー テクノロジーズ リミテッド Ｐｒｍｔ５阻害剤としての置換イミダゾリジン−２−オン誘導体
US11542275B2 (en) 2018-03-22 2023-01-03 Aurigene Discovery Technologies Limited Substituted imidazolidin-2-one derivatives as PRMT5 inhibitors
JP7254094B2 (ja) 2018-03-22 2023-04-07 オーリジーン ディスカバリー テクノロジーズ リミテッド Ｐｒｍｔ５阻害剤としての置換イミダゾリジン－２－オン誘導体
IL277518B1 (en) * 2018-03-22 2023-09-01 Aurigene Oncology Ltd inhibitors of prmt5
WO2021043245A1 (fr) * 2019-09-06 2021-03-11 Ono Pharmaceutical Co., Ltd. Dérivé d'hydantoïne

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